33
– 1 – Advanced Organic Chemistry III Contents 1. Stereochemistry of Organic Compounds 2. Stereocontrol in Organic Reactions 3. Stereocontrol in Catalytic Reactions References General Eliel, E. L.; Wilen, S. H. Stereochemistry of Organic Compounds, Wiley, 1993. Robinson, M. J. T. Organic Stereochemistry, Oxford University Press, 2000. (+" # ( ;%/<, , 2002.) Kagan, H. B. La Stereochimie Organique, Press Universitaires de France, 1975. (" 2 ( ;%<, , 1981.) , ', ",0 ;NMR %<, *)$, 2012. Kirby, A. J. Stereoelectronic Effects, Oxford University Press, 1996. (. ( ;%1<, , 1999.) Procter, G. Stereoselectivity in Organic Symthesis, Oxford University Press, 1998. ( !, & , ( ;=%-<, , 2001.) Abbreviations of substituents http://pubs.acs.org/paragonplus/submission/joceah/joceah_abbreviations.pdf 1. Stereochemistry of Organic Compounds (1) Structure and size of organic compounds (a) Bond length bond length (Å) bond length (Å) bond length (Å) bond length (Å) CH 1.09 CF 1.38 CC 1.53 C=C 1.34 CC 1.53 CCl 1.77 CC= 1.50 C=C= 1.31 CN 1.47 CBr 1.94 CCº 1.46 =C=C= 1.28 CO 1.43 CI 2.14 =CC= 1.48 CF 1.38 =CCº 1.4? CºC 1.20 C=O 1.22 ºCCº 1.38 CC (in C6H6) 1.39 • Bond length is defined as the distance between two nuclei. • Distortion hardly affects bond length. (b) Bond angle • Bond angle is defined with the positions of three nuclei. • Typically, the bond angles involved with sp-, sp 2 -, and sp 3 -hybridized carbons are 180°, 120°, and 109.5°, respectively. > Distortion hardly restricts the bond angles. Therefore, the C–C–C bond angle in cyclopropane is allowed to be 60°. However, the strain does not highly distort the angle of two sp 3 orbitals. The C–C bond in cyclopropane is constituted with a banana shaped orbital. (c) Dihedral angle • Bond angle is defined with the positions of four nuclei. • Shape of molecule can be defined with bond lengths, bond angles, and dihedral angles. • In stable conformation, each dihedral angle should be 60°, 180°, or 120° (if the molecule have sp 2 -hybridized atom). (see Conformation of organic molecules) (d) Van der Waals radius Bondi, A. J. Phys. Chem. 1964, 68, 441. atom H C N O F P S Cl Br I radii (Å) 1.20 1.70 1.55 1.52 1.47 1.80 1.80 1.75 1.85 1.98 CH3 2.0 Å C6H6 (thickness) 1.7 Å • Generally, van der Waals radius is useful for considering the bulkiness of substituent. • However, van der Waals volume, which is calculated from the radii, does not contains the effect of bond rotation. • Solvent accessible surface area is sometimes used for evaluating the accessibility of a reagent to a substrate. e C f d C b a c e f d b a c θ dihedral angle

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Page 1: Advanced Organic Chemistry III 1. Stereochemistry of ...• The chirality is seen in some spiro bicyclic compounds and alkylidene cycloalkanes. (c) Planar chirality • Planar chirality

– 1 –

Advanced Organic Chemistry III Contents

1. Stereochemistry of Organic Compounds 2. Stereocontrol in Organic Reactions 3. Stereocontrol in Catalytic Reactions

References General Eliel, E. L.; Wilen, S. H. Stereochemistry of Organic Compounds, Wiley, 1993. Robinson, M. J. T. Organic Stereochemistry, Oxford University Press, 2000.

(+" #� ( ;%����/<, ����, 2002.) Kagan, H. B. La Stereochimie Organique, Press Universitaires de France, 1975.

(�" 2� ( ;��%���<, ����, 1981.) ���, �'��, �",0 ;NMR%���<, *)$, 2012. Kirby, A. J. Stereoelectronic Effects, Oxford University Press, 1996.

(.� � ( ;%�1���<, ����, 1999.) Procter, G. Stereoselectivity in Organic Symthesis, Oxford University Press, 1998.

(� !, �& �, ( ;���=%�-��<, ����, 2001.) Abbreviations of substituents http://pubs.acs.org/paragonplus/submission/joceah/joceah_abbreviations.pdf

1. Stereochemistry of Organic Compounds (1) Structure and size of organic compounds

(a) Bond length bond length (Å) bond length (Å) bond length (Å) bond length (Å) C–H 1.09 C–F 1.38 C–C 1.53 C=C 1.34 C–C 1.53 C–Cl 1.773 C–C= 1.50 C=C= 1.31 C–N 1.47 C–Br 1.94 C–Cº 1.46 =C=C= 1.28 C–O 1.43 C–I 2.14 =C–C= 1.48 C–F 1.38 =C–Cº 1.4? CºC 1.20 C=O 1.22 ºC–Cº 1.38 C–C (in C6H6) 1.39

• Bond length is defined as the distance between two nuclei. • Distortion hardly affects bond length.

(b) Bond angle • Bond angle is defined with the positions of three nuclei. • Typically, the bond angles involved with sp-, sp2-, and sp3-hybridized carbons are 180°, 120°, and

109.5°, respectively. > Distortion hardly restricts the bond angles. Therefore, the C–C–C bond angle in cyclopropane is

allowed to be 60°. However, the strain does not highly distort the angle of two sp3 orbitals. The C–C bond in cyclopropane is constituted with a banana shaped orbital.

(c) Dihedral angle

• Bond angle is defined with the positions of four nuclei. • Shape of molecule can be defined with bond lengths, bond angles, and dihedral angles. • In stable conformation, each dihedral angle should be 60°, 180°, or 120° (if the molecule have

sp2-hybridized atom). (see Conformation of organic molecules)

(d) Van der Waals radius Bondi, A. J. Phys. Chem. 1964, 68, 441. atom H C N O F P S Cl Br I radii (Å) 1.20 1.70 1.55 1.52 1.47 1.80 1.80 1.75 1.85 1.98

CH3 2.0 Å C6H6 (thickness) 1.7 Å • Generally, van der Waals radius is useful for considering the

bulkiness of substituent. • However, van der Waals volume, which is calculated from the radii,

does not contains the effect of bond rotation. • Solvent accessible surface area is sometimes used for evaluating

the accessibility of a reagent to a substrate.

e

Cf dC

b a

c

e

f d

b a

c

θdihedral angle

Page 2: Advanced Organic Chemistry III 1. Stereochemistry of ...• The chirality is seen in some spiro bicyclic compounds and alkylidene cycloalkanes. (c) Planar chirality • Planar chirality

– 2 –

(e) A-value

R A-value R A-value R A-value R A-value R A-value H 0.00 CºCH 0.41 F 0.25 OMe 0.55 CHO 0.56 Me 1.74 CH=CH2 1.49 Cl 0.53 O(t-Bu) 0.75 COMe 1.02 Et 1.79 Ph 2.8 Br 0.48 OSiMe3 0.74 CO2H 1.4 i-Pr 2.21 SiH3 1.45 I 0.47 NHMe 1.29 CO2Me 1.2 Cy 2.2 SiMe3 2.5 OH 0.60 NMe2 1.53 CN 0.2 t-Bu 4.7 SnMe3 1.0 NH2 1.23 PMe2 1.5 CF3 2.4 Sn(i-Pr)3 1.10 NH3+ 1.7 PPh2 1.8

• A-value is widely used for discussing the steric effect of substituent. • In general, A-value correlates with the size of substituent. Furthermore, the value includes the

effect of bond rotation. Therefore, the value reflects the steric environment around the atom bearing the substituent.

• A-value is affected by bond length (C–R) as well as by van der Waals radius.

(f) Tips to consider steric effect of a substituent i) Where is the most important for the related steric repulsion (near or far)?

• If you will consider the steric effect around the atom , t-Bu or 2,6-xylyl must be larger than

-CºC(t-Bu) group. • If you would like to create a steric hindrance far from , -CºC(t-Bu) should be larger than t-Bu

and 2,6-xylyl. ii) Snapshot or motion blur? (in the case of aryl group)

(top view) (side view) (snapshot) (motion blur) • Snapshot may be preferable when you consider the steric hindrance in dynamic phenomena. • Motion blur may be suitable for thermodynamic phenomena. • In snapshot steric effect, phenyl group can be regarded as a smaller substituent than methyl one. • In motion blur steric effect, phenyl group can be regarded as a larger substituent than secondary

alkyl ones.

(g) Steric parameters other than A-value 1) Taft steric constant (Es)

R. W. Taft, J. Am. Chem. Soc., 74, 2729 (1952); J.-E. Dubois, Tetrahedron, 34, 3553 (1978). • Taft steric constant was based on the average ratio of the rate constants between the acetate

and carboxylate solvolyses or related esterifications under acidic conditions. As a premise, the acid-catalyzed hydrolysis is considered to be scarcely affected by the polar effect of the substituent.

• Similarly, steric constant had been defined with the solvolyses and esterifications involving o-substituted benzoates.

2) Charton parameters (n) M. Charton, J. Am. Chem. Soc., 91, 615 (1969); ibid., 97, 1552 (1975); J. Org. Chem., 41, 2217 (1976).

• Charton parameter is the difference in van der Waals radus between a substituent and hydrogen atom. The radii of substituents are rv,min in the following figure.

3) Interference value (!"#$%–') S. Sternhell, J. Am. Chem. Soc., 102, 5618 (1980).

• Interference value is an index of the steric repulsion between the o-substituent and proton in biaryl compounds.

∆)‡ = !"#$%–' + !"#$-–'

• The rotational barrier (DG‡) of 2,2’-disubstituted biaryl compounds can be predicted with sum of two interference values.

4) Sterimol parameters (B1, B5, L etc.) A. Verloop, in “Drug Design Vol. III,” ed. by E. J. Ariens, Academic Press, (1976) p. 133.

• Sterimol parameters describe the dimension of substituents and are based on space-filling model, which indicates the van der Waals surface of molecule. The parameter is orginally used in a computer program, STERIMOL.

• Parameters B indicate widths of the substituent and are based on the axis of the bond between the parent skeleton and substituent. B1 and B5 are the smallest and largest width, respectively.

• Parameter L indicates length of the substituent from the parent skeleton.

RR

Geq GaxA value = –ΔG0 = Gax – Geq (in kcal/mol)

MeMe

Me

Me

Me

Me

MeMevs vs

Me

Me

Cl

R CO2R’ + H2O R CO2H + R’OHk k: rate constant for any R

k0: rate constant for R = Me

δ : sensitivity factor to steric effectEs: steric constant

log(k/k0)δ

Es =

cat. H+

CH HH

CH

Hrv,min

rv,max l

rv,||ν = rv,min – rH

top view side view

r: van-der-Waals-based radiusl: covalent radius

X H

YH

X H

YH

ΔG‡I X–H340

I Y–H340

Page 3: Advanced Organic Chemistry III 1. Stereochemistry of ...• The chirality is seen in some spiro bicyclic compounds and alkylidene cycloalkanes. (c) Planar chirality • Planar chirality

– 3 –

(2) Chiral Compounds and Enantiomers • Chiral molecule cannot overlap with its mirror image. Therefore, chiral compounds have no

symmetry plane (s) or rotation-reflection axis (Sn). • Achiral compounds are the compounds that are not chiral. • "Chiral molecule" means the molecule possessing any chirality. • "Chiral compound" means the mass of chiral molecules. • "Racemic compound (racemate)" means the 1:1 mixture of both enantiomers (R and S). Each

molecule constituting a racemic compound should be "chiral molecule". • "Optically active compound" means the chiral compound other than racemate. A mixture of

enantiomers is often categorized as optically active compounds, even if R:S is 51:49. However, the term often indicates pure enantiomer (enantiopure compound or optically pure compound).

• "Enantiomer" originally means the mirror image of a chiral molecule (e.g. (S)-2-octanol is the enantiomer of (R)-2-octanol.). The term often indicates the enantiopure compound, whose absolute configuration has been known.

• "Diastereomer" means any stereoisomers other than enantiomer. • "Epimer" means stereoisomers bearing only one chiral center with the opposite absolute

configuration. The configuration of other chiral centers in the epimer must be identical to the original compound.

(a) Central chirality

• The chirality caused by asymmetric atom is called "central chirality". • Asymmetric atom is not limited to carbon (e.g. N, S, P, etc.). Lone pair can function as a

substituent and is regarded as atomic number 0 in CIP rule (see 3–5).

• Spiro compound 6 is chiral, although they seem to have no asymmetric atom. However,

compound 7 is achiral because its tetrahydrofuran ring is symmetry plane.

• The molecules possessing symmetry plane (see 8, 9) or rotation-reflection axis (see 10) must be

achiral, even if they have asymmetric atoms (e.g. meso compound).

• Metal complexes are possible to be chiral when they are tetrahedral, trigonal bipyramidal, or

octahedral.

MeMe

Me: van der Waals surface of CH3 (rvdw = 2.0 Å)

H

: van der Waals surface of H (rvdw = 1.2 Å)

: the atom bonding to the substituent

top view side view

LB1

B5

d

Ca

bc

d

Ca

bc =

d

Ca

cb

180°

NH2

Me CO2HH

+N

Ph MePh

N

N

1 2 3

Me PPh

OMe:

Ph SMe

O

:

4 5

O O OO =180°

O

O

6O7

Me MeOH

OHMe Me

OHOH =Me Me

HO OH

8 9O

OO

Me O

Me

10

Page 4: Advanced Organic Chemistry III 1. Stereochemistry of ...• The chirality is seen in some spiro bicyclic compounds and alkylidene cycloalkanes. (c) Planar chirality • Planar chirality

– 4 –

(b) Axial chirality • Axial chirality takes two forms: atropisomerism and isomerism in allenes. Atropisomerism • Atropisomerism is caused by inhibition of free rotation of a single bond. The inhibition of free

rotation is often observed in the biaryl compounds bearing four ortho-substituents or some sterically hindered carboxamides.

• A racemate of axially chiral compound can be resolved into each enantiomer when the rotation

barrier is over 20 kcal/mol. • Axial chirality will be stable at room temperature when the rotation barrier is over 30 kcal/mol. • Herical chirality is originated from the accumulation of axial chirality.

Isomerism in allenes • Each terminal carbon in C=C=C is plane because it is sp2-hybridized. One of the planes is

perpendicular to another because the internal carbon in C=C=C is linear and hybridized in sp manner to form two C–C double bonds. Therefore, substituted allenes are possible to be chiral as with biaryls.

• The chirality is seen in some spiro bicyclic compounds and alkylidene cycloalkanes.

(c) Planar chirality

• Planar chirality appears when a planar molecule loses its symmetry plane by bridging with short tether or forming p-complex.

• The chirality is seen in some cyclophanes, metallocenes, and trans-cycloalkenes.

(d) Notations of absolute configuration 1) R/S notation

• According to CIP rule, determine the priority of each substituent involved with the chirality. Central chirality

(in the case of spiro compounds)

Axial chirality

i) Determine the priority of the two substituents on each atom involved with the chiral axis. ii) The sequence of substituents becomes a > b > c > d or c > d > a > b. Both sequences result

in the same configuration. iii) Put the substituent with the lowest priority (d or b) on the location far from you. Confirm the

direction of a 5 b 5 c (or c 5 d 5 a).

iv) To distinguish the axial chirality from others, prefix 'a' (or sufix 'a') is sometimes attached to the

chiral descriptor R or S (e.g. (aS)-2,3-pentadiene or (Sa)-2,3-pentadiene) Planar chirality (cyclophanes, trans-cycloalkenes etc.)

i) Determine 'pilot atom' from the bridging tether. The pilot atom is out of the plane and closest to the plane. There are two candidates in general. The pilot atom is the candidate binding to the in-plane atom with higher priority in CIP rule.

ii) Among the atoms in the chiral plane, the atom binding the pilot atom is assigned to 'a'. The next atom is 'b', and the third atom is 'c'. If there are two candidates, the atom with higher priority is assigned to 'c' (or 'b').

iii) View the molecule from the pilot atom.

iv) To distinguish the planar chirality from others, prefix 'p' (or sufix 'p') is sometimes attached to

the chiral descriptor R or S (e.g. (pS)-(E)-cyclooctene or (Sp)-(E)-cyclooctene)

b

aa

bb

aa

b

=180°

a

ba

b a ≠ b

OHOH

N

O

Pht-Bu

NO

Me

Me

•a

b

a

ba ≠ b

CO2H

H

HHO2C

HMe

HO2C

H

FeCO2Me

Br

CO2H

=

a

Cb

cd

a > b > c > d

a

b c

d

aC

a'

b b'

a > b

1 2

3 4

a

b a'

b'

d

ca

b a > b, c > d

=a

b dc

b

ac

d

Br cb a

Br: pilot atom

a → b → c clockwise ··· R anticlockwise ··· S

a → a' → b clockwise ··· R anticlockwise ··· S

a → b → c clockwise ··· R anticlockwise ··· S

a → b → c clockwise ··· R anticlockwise ··· S

Page 5: Advanced Organic Chemistry III 1. Stereochemistry of ...• The chirality is seen in some spiro bicyclic compounds and alkylidene cycloalkanes. (c) Planar chirality • Planar chirality

– 5 –

Planar chirality (metallocenes) • Three rules have been proposed to assign the stereochemical descriptor, R or S, for the planar

chiral metallocenes. One is based on central chirality and proposed by Prelog, Cahn, and Schloegl (Rule 3). Others are based on planar chirality and proposed by Ugi and Schloegl, independently (Rule 1 and 2).

• Unfortunately, the rules 1 and 2 resulted in configuration different from each other. However, rules 2 and 3 reach the same result in most cases. Rule 1 (i) View the substituted Cp ligand from the side opposite to the metal atom. (ii) Confirm the direction of a 5 b.

I. Ugi et al., J. Am. Chem. Soc. 92, 5389 (1970).

Rule 2 (i) Assign the metal atom to the pilot atom. (ii) Regard the centroid of the substituted Cp ligand as atom 'a'. (iii) The cyclopentadienyl atom bearing the substituent with the highest priority is 'b'. (iv) The ortho-atom with higher priority is assigned to 'c'. (v) View the Cp ring from the pilot atom, and then confirm the direction of a 5 b 5 c.

K. Schloegl, J. Organomet. Chem. 300, 219 (1986).

Rule 3 (i) Treat chirality of metallocene as central chirality of the cyclopentadienyl carbon with the

highest priority. (ii) Consider the metal atom to bond to the carbons in Cp ring. (iii) The absolute configuration can be similarly assigned to R or S with the rule for central

chirality.

K. Schloegl, Forschr. Chem. Forsch. 6, 479 (1966).

2) P/M notation • P/M notation is based on the chirality of helix (helicity). • The descriptor P is used for right-handed helicity, and M is used for left-handed helicity (from

before backward).

• The notation can be applied to axial and planar chiralities. • In the case of planar chirality, pR and pS configurations correspond to P and M, respectively.

3) D/L notation

• D/L notation is sometimes used for the stereochemistries of carbohydrates and a-amino acids. • Descriptors D and L strongly relate to the stereochemistries of (R)-(+)- and

(S)-(–)-glyceraldehyde, respectively. D and L, must be smaller in size than other characters.

4) Notations based on the direction of optical rotation

• Descriptor (+) or (–) corresponds to the direction of optical rotation. (+) and (–) are used for dextrorotatory and levorotatory compounds, respectively.

• Descriptors d and l are equivalent to (+) and (–), respectively. • dl notation is not related to D/L notation.

(e) Characteristic properties of chiral compounds • Most properties of an enantiopure compounds are identical to those of its enantiomer.

Exceptionally, the direction of optical rotation is different. • However, an enantiopure compound is different in most properties from its racemate. 1) Crystals of racemate

• Three types of crystalline racemate are known, as follows: racemic conglomerate, racemic compound, and psudoracemate. Most racemates preferentially to form racemic compounds.

Racemic conglomerate

Feb

a Fe b

a

90°

a > b

FeBr

Mec

b Br

Me

•a

FeBr

Me

C Br

Me

Fe2

1

3

4

Fe

CBrC

C4

3Me

1

2

(P)-[6]helicene (M)-[6]helicene

c d

d

ca

ba > b, c > d

a

b

90°a

b

d cor

For axial chirality

For planar chirality

a

bdc

Br

• The a–b–c–d unit can be regarded as a helix.• View the helix from a.• Confirm the direction of the helix.

HOOH

CHO

D-glyceraldehyde

HOOH

CHO

L-glyceraldehyde

CHOOHH

CH2OH

CHOHHO

CH2OH

CO2HHH2N

CH2OHL-serine

OOH

HOHOHO

OH

CHOOHH

HO HH OH

HO HOH

=

D-glucose

a → b clockwise ··· R anticlockwise ··· S

a → b → c clockwise ··· R anticlockwise ··· S

1 → 2 → 3 clockwise ··· R anticlockwise ··· S

from before backward clockwise ··· P anticlockwise ··· M

Page 6: Advanced Organic Chemistry III 1. Stereochemistry of ...• The chirality is seen in some spiro bicyclic compounds and alkylidene cycloalkanes. (c) Planar chirality • Planar chirality

– 6 –

• Racemic conglomerate is a mechanical 1:1 mixture of R crystals and S crystals. Each crystal in the mixture is homochiral (constits of a sole enantiomer).

• Preferential formation of racemic conglomerate requires that the interaction between R and R (or S and S) is stronger than that between R and S.

• Racemic conglomate is much rarer than racemic compound. • Chiral compounds, which preferentially form racemic conglomerate, can be resolved into each

enantiomer through preferential crystallization without any other chiral source. Racemic compound • In racemic compound (true racemate), each crystal contains R and S molecules in 1:1 ratio.

The both enantiomers form a racemic pair in a unit cell. • Most chiral compounds prefer the formation of racemic compound to that of racemic

conglomerate. In many cases, a chiral molecule has stronger affinity for its enantiomer than for itself.

• Nevertheless, homochiral crystals are preferentially obtained from the compound with relatively high enantiomeric excess

Psudoracemate • In crystals of psudoracemate, both enantiomers coexist in an unordered manner. • This type of chiral compound is very rare.

2) Melting point

• Melting point of chiral compound is affected by its enantiomeric excess. Each type of crystalline racemate exhibits characteristic behavior in solid-liquid phase transition.

• In racemic compound, racemate is generally higher in melting point than its enantiopure form.

Binary phase diagrams describing the melting behavior of a) 3-fluoromandelic acid (racemic compound); b) 2,3-diacetoxybutane (psudoracemate); c) 1.2-diphenylethane-1,2-diol (racemic conglomerate).

(f) Resolution of chiral compounds 1) Use of resolving agent

• Although an enantiomer is impossible to be separated from its racemate, an epimer is physically separable from the mixture of diastereomers.

• Therefore, formation of diastereomers with an optically active resolving agent is very useful for the optical resolution of racemates.

Crystallization of diastereomeric salts • This method is useful for resolution of chiral carboxylic (phosphonic or sulfonic) acids, amines,

and phosphine oxides.

• Acidic functional group (e.g. -CO2H, -SO3H) can readily form salts with basic functional groups (e.g. -NH2). The acid–base pair is easier to crystallize from organic solvent than each compound, because the salt is generally less soluble.

• Treating racemic carboxylic acid 1 with stoichiometric enantiopure amine 2 gives the mixture of ammonium salt 3RR and 3SR. If 3RR is less soluble than 3SR, 3RR can selectively be obtained through crystallization. Purity of the crystals can be enhanced by recrystallization. Enantiopure (R)-1 will be obtained by decomposing the pure 3RR in hand with acid.

• Equimolar resolving agent (to racemate) is requires for the resolution controlled by type 1

thermodynamics. Halfmolar resolving agent may be enough for an efficient resolution, if it is controlled by type 2 or 3 thermodynamics.

• Representative resolving agents

Crystallization or chromatographic separation after derivatization • This method is useful for the resolution of chiral alcohols and ketones. It is applicable for the

resolution of chiral (secondary or primary) amines and acids. • In the resolution of a racemic alcohol 4 (e.q. R and S), the racemate is esterified with an

enantiopure acid anhydride 5 (e.g. R), which is the resolving agent. The esterification will give a

RRRRRR

SSSSSS

RSRSRS

SRSRSR

racemic conglomerate racemic compound

RRSRSS

SRRSSR

psudoracemate(true racemate)

CO2HMeO

PhH

CO2HMeO

HPh

+ H2NH

Me

PhR

R

S

CO2–MeO

PhHR

· H2NH

Me

PhR+

CO2–MeO

HPhS

· H2NH

Me

PhR+

3RR

3SR

(R)-1

(S)-12

(crystallize)

(in solution)

H3O+CO2H

MeO

PhHR

(R)-1

R + S

S + S

R•S (less soluble)

(more soluble)

Type 1R + S

S + S

R•S (less soluble)

(soluble)

Type 2

S•S S•S

R + S

S + S

R•SType 3

S•S

N

O

O

N

H

H

HH

R

R

for acids

brucine (R = OMe)strychnine (R = H)

N

NOH

OMe

quinine

NOH

N

OMequinidine Me

NH2

Me

NH2

for bases

HO2C CO2HOH

OH

tartaric acid

HO2C CO2HOBz

OBz

HO2C CO2H

OH

malic acid

CO2H

OH

mandelic acid

O

Me Me

HO3S

camphorsulfonic acid

OP

O OOH

Page 7: Advanced Organic Chemistry III 1. Stereochemistry of ...• The chirality is seen in some spiro bicyclic compounds and alkylidene cycloalkanes. (c) Planar chirality • Planar chirality

– 7 –

mixture of diastereomeric esters 6RR and 6SR (RR and SR). Both diastereomers can be separated by column chromatography or crystallization. Each pure diastereomer in hand can be transformed to (R)- or (S)-alcohol through hydrolysis.

• A racemic chiral ketone or aldehyde can be resolved through the reaction with an enantiopure

primary amine, which gives a mixture of diasteromeric imines. • Representative resolving agents

2) Chiral HPLC

• A racemate is resolved to each enantiomer through the column chromatography with a chiral stationary phase, which is typically composed of a chiral compound and silica gel.

• Information of each chiral column can be obtained from the following web sites.

Daicel: http://www.daicelchiral.com Sumichiral: http://www.scas.co.jp/service/apparatus/

hplc/sumichiral_introduction.html Astec: http://www.sigmaaldrich.com/japan/

analytical-chromatography/hplc/chiral-astec.html 3) Preferential crystallization

• Racemic conglomerate can be resolved through recrystallization without resolving agent, if you have its homochiral single crystal.

• To a saturated hot solution of the racemate, its homochiral crystal (e.g. R) is installed. The same enantiomer (R) will be crystallized in preference to the antipode (S). The resulting mother liquor will be S-enriched. The recrystallization of the mother liquor will preferentially form the crystals of S-compound.

4) Kinetic resolution • In general, chiral reagents and catalysts exhibit different reaction rate for each enantiomer of

substrates. If the reaction of the R-enantiomer is faster than that of S-isomer, the recovered substrate should be S-enriched. Therefore, the reaction of a racemate with a chiral reagent (or through asymmetric catalysis) is usable for the resolution.

• The efficiency of kinetic resolution (s) is expressed by the ratio of the reaction rate of each

enantiomer (kR/kS). s = kR/kS = ln[(1–C)(1-ee)]/ln[(1–C)(1+ee)] = ln[1–C(1+ee')]/ ln[1–C(1–ee')]

C: conversion ee = enatiomeric excess of unreacted substrate ee' = enatiomeric excess of product

• Examples

Marshall, J. A. Org. Synth. 2005, 82, 43.

Sharpless, K. B. J. Am. Chem. Soc. 1981, 103, 6237.

(g) Method for determining absolute configuration 1) Chemical transformation

a) The target molecule is reacted with a known optically active compound. If the product, which must have two chiral centers, is crystalline solid, it is subjected to X-ray crystal structure analysis. The absolute configuration of the target is found through the resulting structure, because the absolute configuration of one of its chiral centers is known.

b) The target molecule is transformed to a known optically active compound. Possibility for

racemization must be considered during the transformation. The specific rotation of the resulting product is compared with the reported [a]D. Comparison of the retention times in the

MeOH

PhHO

H

H

O

OMe

OHHPh

R

S

RR+

(R)-4

(S)-4HO2C

O

O

Ph

MeH

5HO2C

O

O

Ph

HMe

R S

6RR 6SR

(separable with chromatography or crystallization)

hydrolysis

(R)-4 (S)-4

for alcohols

O

O

O

H

H

O

O

OH

H

H

Me

Me Me

NCO

(for urea derivatization)

(for lactor derivatization)

(for ester derivatization)

O

O

CO2HMe Me

Me OH

O

O

Me

MeMe Me Me Me

H

for ketones and aldehydes

Noe reagent

EtO2C CO2EtOH

OH

diethyl tartarate

NNH2

OMe

SAMPMeHN NHMe

Ph Ph

kR R&S

(50:50)

+ aR + a R a

kSS + a S a

(fast)

(slow)

if kR >> kS R a&S (almost enantiopure)

Me

OH

TMS

Amano Lipase AK

OAc , pentane Me

OH

TMS49%

Me

OAc

TMS47%

C6H13

OH Ti(O-i-Pr)4 & (+)-DIPT

t-BuOOH C6H13

OH

C6H13

OH

Os = 83

R1 R2

OH

(target)

Ph COCl

OMe

S

Ph O

O

R1R1MeO

SX-ray crystal structure

a

b Compare the stereochemistry of chiral center a with that of chiral center b.

Page 8: Advanced Organic Chemistry III 1. Stereochemistry of ...• The chirality is seen in some spiro bicyclic compounds and alkylidene cycloalkanes. (c) Planar chirality • Planar chirality

– 8 –

chiral HPLC analyses is also useful for the assignment of absolute configuration.

c) The authentic sample of the target molecule is synthesized from a known optically active

compound. The specific rotation or the chiral HPLC retention time of the authentic sample allow us to assign the absolute configuration.

2) Crystallography (Bijvoet method)

• Commonly, X-ray single crystal analysis gives no information about the absolute configuration of the chiral compound. However, the configuration can be determined with the crystallography, when the compound has one heavy-weight atom.

• The heavy-weight atom induces anomalous X-ray scattering, which caused that intensity F(h k l) is not equal to that of F(–h –k –l) in a chiral crystal.

• Flack parameter (x) is widely used for estimating the absolute configuration of crystal structure. I(h k l) = (1–x)|F(h k l)|2 + x|F(–h –k –l)|2

x: Flack parameter I: the square of the scaled observed structure factor F: the calculated structure factor

If x is near 0, the crystal structure has the correct absolute configuration. If the crystal structure has the inverted configuration, x is near 1.

• Bijvoet method is applicable for chiral compounds bearing no heavy-weight atom. In this case, a protective group containing a heavy-weight atom (e.g. p-bromobenzoyl) is installed to the target molecule.

3) Advanced Mosher method and its related methods see: Riguera, R. Chem. Rev. 2004, 104, 17. Advanced Mosher method • Advanced Mosher method is empirical, but very useful for determining the absolute configuration

of an unknown chiral secondary alcohol. This method is applicable for the chiral secondary alkyl primary amines.

(original) Mosher, H. S. J. Am. Chem. Soc. 1973, 95, 512.

(alcohol) Kusumi, T.; Kakisawa, H. J. Am. Chem. Soc. 1991, 113, 4092. (amine) Kusumi, T.; Kakisawa, H. Tetrahedron Lett. 1991, 32, 2939.

• Prepare two samples of the secondary alcohol. Each Sample is esterified with (R)- or (S)-MTPA to prepare (R)- and (S)-MTPA esters (MTPA is 3,3,3-trifluoro-2-methoxy-2-phenylpropionic acid).

For each proton in the secondary alcohol moiety, calculate the difference between the 1H NMR chemical shifts of (S)- and (R)-MTPA esters (Dd = dS – dR) as shown in above figure.

• In MTPA esters, their CF3 groups are located at the pseudo eclipse of the proton attaching to the chiral carbon of the secondary alcohol. The aromatic ring in MTPA induces upfield shift of the resonances of the protons in the secondary alcohol moiety. Therefore, if Dd is negative, the proton should be located over the aromatic ring of (S)-MTPA.

Trost method • Trost method uses O-methylmandelic acid instead of MTPA. The procedure is very similar to

advanced Mosher method. • O-Methylmandelic acid is easier to react with secondary alcohols than MTPA, but may be

racemized during the esterification. • In the O-methylmandelates, their OMe groups are located at the pseudo eclipse of the proton

attaching to the chiral carbon of the secondary alcohol.

Trost, B. M. J. Org. Chem. 1986, 51, 2370.

PGME method • PGME (phenylglycine methyl ester) method is useful for determining the absolute configuration

of the chiral a-carbon of carboxylic acid. • In the PGME amides, their CO2Me groups are located at the pseudo eclipse of the a-proton of

the chiral carboxylic acid.

Kusumi, T. Tetrahedron Lett. 1995, 36, 1853; J. Org. Chem. 2000, 65, 397.

4) Circular dichroism (CD) spectrum • Circular dichroism is active for only optically active compounds. • Positive Cotton effect means that an enantiomer gives a positive peak in its CD spectrum. Octant rule • This method is empirical and useful for determining

the absolute configuration of cyclic ketones. • First, consider the most stable conformation for the

target molecule. Geometry optimization with MO or MM may be useful for the consideration.

• Space around the carbonyl group is divided into eight sectors as shown in figure (a).

• In octant rule, the atoms in the + sectors induces a

target other compound(Its [α]D has been reported.)

Measure its optical rotation and caluculate [α]D.

Compare it with the [α]D reported in the literature.

other compound(Its [α]D has been reported.)

authenticsample optical rotation.

retention time in chiral HPLC.Measure its

Compare the value with that of the target.

R1

H

O

O

OMe

CF3

R2

S

(S)-MTPA ester

upfield shift

R1

H

O

O

MeO

CF3

R2

R

(R)-MTPA ester

upfield shift

Δδ = δS – δR

If Δδ > 0, the proton belongs to R2.If Δδ < 0, the proton belongs to R1.

R1

H

O

O

H

OMeR2

R

(R)-O-methylmandelate

upfield shift

R1

H

O

O

H

OMeR2

S

upfield shift

Δδ = δS – δR

If Δδ > 0, the proton belongs to R1.If Δδ < 0, the proton belongs to R2.

(S)-O-methylmandelate

R1

H

R2

(S)-PGME amide

upfield shift

R1

HNH

H

CO2MeR2

R

upfield shift

NH

H

CO2Me

O O

S

(R)-PGME amide

Δδ = δS – δR

If Δδ > 0, the proton belongs to R2.If Δδ < 0, the proton belongs to R1.

Octant rule for standard ketones. (a) Signs of the sectors in a left-handed Cartesian coordinate system; (b) projection of the rear sectors (z < 0).

Page 9: Advanced Organic Chemistry III 1. Stereochemistry of ...• The chirality is seen in some spiro bicyclic compounds and alkylidene cycloalkanes. (c) Planar chirality • Planar chirality

– 9 –

positive Cotton effect. The atoms in the – sectors induces a negative Cotton effect. • The Cotton effect can be predicted as above. Compare the prediction with the observed CD

spectrum (n5p* (C=O), ca. 300 nm). Exciton chirality method • This method is theoretical and useful for determining the absolute configuration of

cycloalkanediol or diamine. Two equivalent chromophores (e.g. p-Me2NC6H4CO2-) in a molecule are required for the assignment.

• The two chromophores cause the split of their CD peak. One is negative and the other is positive.

• When the longer wavelength band of the split peak describes a positive Cotton effect and the shorter one describes a negative Cotton effect, the two chromophores arranged in a right-handed helix.

(h) Method for analyzing enantiomeric excess

• Percentage of enantiomeric excess (% ee) is commonly used for representing the ratio of enantiomers. (% ee (R-enriched) = ([R] – [S])/([R] + [S]) 4 100)

1) Specific rotation • Specific rotation is usable for measuring enantiomeric excess, if specific rotation of enantiopure

compound has been reported. % ee = [a]D (sample)/[a]D (100% ee) 4 100

• However, the specific rotation is significantly affected by inpurity, solvent, and temperature. Sometimes, concentration of the sample affects the specific rotation.

2) Chiral HPLC and GC • Chiral HPLC or GC analysis is commonly used for measuring enantiomeric excess. • Chiral HPLC is effective for relatively polar compounds (alcohol, ketone, ester, amide etc.) with a

UV active moiety (p-bond). • Chiral GC is usable for less polar compounds (hydrocarbon, ether etc.) as well as above

compounds. UV active moiety is not required, but the sample must be volatile. 3) Chiral shift reagent

• Prepare NMR sample of the target compound in CDCl3 or C6D6 and measure 1H NMR. Add a small amount of a shift reagent to the NMR sample, and then measure 1H NMR again. Repeat the process several times until a proton signal completely splits. The enantiomeric excess of the sample is calculated from the ratio of the integrals of each split peak.

• Representative chiral shift reagents

OH

NMe2

OO

Ar

O

O

ArOHOH

Ar

O

Cl==

HO

HO

NMe2Δε

λ

O

OM

Rf

Me

Me

Me 3

Rf = CF3 (tfc) or C3F7 (hfc)M = Yb or Eu

NO2

HNO

OHN

N

N

O

O

HN

HN

O

OM(tfc)3 or M(hfc)3

Page 10: Advanced Organic Chemistry III 1. Stereochemistry of ...• The chirality is seen in some spiro bicyclic compounds and alkylidene cycloalkanes. (c) Planar chirality • Planar chirality

– 10 –

(3) Diastereomers (a) Notations of diastereomeric stereochemistry

1) E/Z notation for alkenes • As with R/S notation, E/Z notation unambiguously defines the geometrical configuration of

alkenes. The notation is based on CIP rule. i) Determine the priority of the two substituents on each atom involved with the C–C double

bond. ii) Confirm the positional relationship of each substituent with higher priority.

2) cis/trans notation

• Cis/Trans notation is ambiguous, but often used for indicating the geometrical configuration of alkenes or the relative configuration of cyclic skeletons including two chiral centers.

• Priority of each substituent is determined with common sense, which causes the ambiguity (CIP priority or main chain in IUPAC nomenclature?).

• In the case of alkene geometry, cis and trans configurations correspond to Z and E, respectively.

3) erythro/threo notation for relative configuration

• Erythro/threo notation is ambiguous, but often used for indicating the relative configuration of acyclic vicinal chiral centers. Erythro and threo forms are strongly related to the stereochemistry of erythrose and threose.

• If the substituents on each chiral carbon are arranged in a similar manner, the configuration is threo. Otherwise, the configuration is erythro.

4) syn/anti notation for relative configuration

• Syn/anti notation is less ambiguous than erythro/threo notation and applicable to various acyclic compounds.

• Draw the structure of the target compound with zig-zag projection. If two substituents are arranged on the same face, the configuration is syn. Otherwise, the configuration is anti.

5) R*/S* (or RS/SR) notation for relative configuration • R/S notation is applicable in relative configuration. This notation is unambiguous. • Assign the absolute configurations of all chiral center in an enantiomer. Attach an asterisk to

each R or S descriptor. • (2R*, 3S*) is equivalent to (2S*, 3R*).

6) l/u notation for relative configuration

• Determine the absolute configurations (R/S or P/M) of all chiral centers, and then arrange them according to the numbering rule in IUPAC nomenculture.

• If the absolute configurations of two neighboring chiral centers are identical or similar each other, the relative configuration is l (like). Otherwise, u (unlike) must be used as the stereochemical descriptor. For example, uu-1,2,3,5-hexanetetraol is equivalent to (2R*,3S*,5R*)-1,2,3,5-hexanetetraol.

(b) Treatment of stereochemistry in CIP rule

In CIP rule 6 Atomic number larger 5 higher priority 7 Isotope atomic mass: larger 5 higher priority 8 Alkene stereochemistry priority: Z > E (cis > trans)

In most cases, the priority of two geometrically isomeric groups can be determined by Z/E system. However, the system is useless to 4-substituted alkylidenecyclohexanes, although they can be regarded as axially chiral molecules. In this case, the alkene configuration is determined from the substituent bearing the chiral center.

9 Diastereomeric groups priority: l > u (: Enantiomeric groups R > S or M > P?)

(c) How to determine stereochemistry of diastereomer 1) Crystallography

• If the sample is crystalline solid, its X-ray crystal structure analysis is the most reliable. 2) NMR

i) 1,2-Disubstituted alkene nOe (nuclear Overhauser effect) difference spectrum • Positive nOe will be observed between two substituents, which are located in the cis position

each other.

a

b

c

d

a > b, c > d

a

b

c

d

a

b

c

da > b, c > d

a

b

c

d

a

d

b

c

a

d

b

c

CHOOH

OHD-erythrose HO

CHOOH

OHD-threose HO

==

==

CH2OH

H OH

OHC

H OH

CH2OH

H OH

OHC

HO H

b'

c' a'

b

c a

b'

c' a'

b

a c

2

1

33

1

2

2

1

33

1

2

Me

OH OH

OH2 4

5Me 2,4-syn, 2.5-anti

Me OHOH

OHOH(2R*,3S*,5R*)-1,2,3,5-hexanetetraol

= (2S*,3R*,5S*)-1,2,3,5-hexanetetraol

O OHOH

HOHOHO

CHO

OH

OH

OH

OHHO RR

R S

D-glucose uul-2,3,4,5,6-pentahydroxyhexanal

CO2H

H Me

H Me

HO2C

CO2Hcistrans

12

34S

positional relationship between a and c the same side ··· Z opposite side ··· E

positional relationship between a and c the same side ··· cis opposite side ··· trans

a → b → c vs a' → b' → c' the same direction ··· erythro opposite direction ··· threo

Page 11: Advanced Organic Chemistry III 1. Stereochemistry of ...• The chirality is seen in some spiro bicyclic compounds and alkylidene cycloalkanes. (c) Planar chirality • Planar chirality

– 11 –

• NOESY should be avoid to use for the purpose.

Vicinal H–H coupling (3JH–H) • In general, the coupling constant between the two alkenyl the alkenyl protons is 10–13 Hz

when the protons are arranged with cis configuration. In the trans isomer, the coupling constant is 15–17 Hz.

• The above rule is useful only when a carbon atom attaches to each alkenyl carbon. Heteroatom substituents causes decrease in the coupling constant.

ii) Saturated four- and five-membered ring

NOESY or nOe difference spectrum • Use only transannular nOe. Sometimes, nOe is observed between vicinal hydrogens with

trans configurations, because these protons couple with each other.

iii) Saturated six-membered ring

Chemical shift • In general, an axial proton appears in higher field (ca. 0.5 ppm) than its corresponding

equatorial proton. Vicinal H–H coupling • Karplus equation: 3JH–H = A cos2q + B cos q + C (q: dihedral angle)

(e.g. A = 9.4, B = –1.4, C = 0.4 (for hydrocarbons)) • 3JHax–Hax is 8–14 Hz, because dihedral angle q for Hax–C–C–Hax is 180°. 3JHax–Heq and 3JHeq–Heq

is 2–4 Hz, because the related dihedral angles are 60°. • Higher magnetic field NMR spectrometer should be used for assigning the relative

configuration of cyclohexane derivative. Assign as many paeks as possible by using not only 1D-NMR but also H–H cosy, HMBC. HSQC etc.

• Assign the stereochemistry by using each coupling constant in a similar way to solving a puzzle.

iv) Acyclic compound see: Bifulco, G.; Riccio, R. Chem. Rev. 2007, 107, 3744. General methods • JBCA (J-based configuration analysis) see, Murata, M. J. Org. Chem. 1999, 64, 866. • UDB (Universal NMR Database) see, Kishi, Y. Org. Lett. 1999, 1, 2177 and 2188. • Use of quantum mechanical calculation

1,2- or 1,3-diols (diamine) • Protect the diol with acetone (or 2,2-dimethoxy propane, phosgene etc.) to give the

corresponding acetonide. Analyze the resulting cyclic acetal with NOESY, nOe difference spectrum, H–H coupling constrants etc.

1,3-diols • Acetonides of syn-1,3-diols have chair conformation, while those of anti-1,3-diols prefer twist

boat conformation. Therefor, the relative configuration of 1,3-diols can be elucidated with the 13C NMR resonances of the methyl groups of their acetonides.

H H H CHR2 R2HC CHR2 H OCH3

HOCH3

O?

CH3

OCH3O

?

H H

C C3JH–H = 10–13 Hz

H C

C H3JH–H = 15–17 Hz

abd

c

• The nOe between a and d (red) is reliable for determing the relative configulation.• The nOe between a and b (blue) should be avoid to use for the purpose, because an nOe is sometimes observed between a and c.

R1 R2

OH OH

R1 R2

O O

Me Me

R1 R2

OH OH

R1 R2

O O

Me Me

==

==

OO

R1

R2 Me

Me

OO

R1

R2

Me

MeOOR2

R1

H

H

MeMe

δ 24.6 ± 0.76

δ 19.4 ± 0.21

δ 30.0 ± 0.15

δ 98.1 ± 0.83

δ 100.6 ± 0.25syn-1,3-diol

anti-1,3-diol

Page 12: Advanced Organic Chemistry III 1. Stereochemistry of ...• The chirality is seen in some spiro bicyclic compounds and alkylidene cycloalkanes. (c) Planar chirality • Planar chirality

– 12 –

(4) Conformation of organic compounds (a) Acyclic saturated compounds

1) Ethane • The staggered conformer (q = 60° or

180°) is more stable than the eclipsed one (q = 0° or 120°) (DE‡ = 2.9 kcal /mol).

• The ecripsed conformer is a transition state and not energy minimum.

• The sC–H–s*C–H interaction stabilizes the staggered conformer.

• The steric repulsion between the vicinal protons scarcely contributes to rotational barrier.

2) Butane • Butane has two energy minima: one is anti, and the

other is gauche. • Anti conformer is more stable than gauche one (DE =

0.9 kcal /mol). • Each conformer, including unstable conformers, can be

named with the dihedral angle q as shown below.

3) Pentane

• In the conformational analysis of pentane, the free rotations of C2–C3 and C3–C4 should be considered.

• Conformer aa is the most stable conformer of pentane. • Conformers g+g– and g–g+ are the least stable. The energies of these

conformers has been estimated to lie over 3.3 kcal/mol above that of conformer aa.

• The steric repulsion is called 'syn-pentane interaction'. 4) Effect of s–s* or n–s* interaction

• Conformation involved with C(sp3)–C(sp3) bond is affected by the hyperconjugation between

vicinal C–X bonds. In the hyperconjugation, one of the s orbital of C–X bond donates electrons to s*-orbital of another C–X.

• Electron donating ability: nN > nO > sC–C, sC–H > sC–X (X: N > O > S > Hal) • Electron accepting ability: pC=O > s*C–Hal > s*C–O > s*C–N > s*C–C, s*C–H • Gauche effect: In some compounds, gauche conformer is preferable to anti conformer.

• Anomeric effect: The ratio of a- and b-glucose is 38:62 in water. The unusual ratio (A value of

OH is 0.60) is caused by anomeric effect, the interaction between nO and s*C–O orbital.

(b) Acyclic unsaturated compounds

1) X–CH2–CH=Y (Y = CH2, O) • Energy minima appear when the C(sp3)–X (or H) bond overlaps to the C=Y bond in the Newman

projection. Another conformer, in which the C–X bond overlaps to the C(sp2)–H bond, is a torsional barrier.

• Steric repulsion between X and Y is often considerable in the eclipsed conformer (1,3-allylic strain). Therefore, the gauche conformer is generally preferable to the eclipsed one.

• The gauche or ecripsed conformation is stable in substituted benzenes. • Allylic strain:

2) X=CH–CH=Y

• In general, s-trans conformer is more stable than s-cis, when there is no steric repulsion in the conjugated molecule.

• However, gauche conformer is preferable to s-cis one, if X and/or Y have a substituent and both double bonds have Z-configuration.

Ra

bb

ccd

RC A

B

a: synperiplanar (ecripsed, –30° < θ < 30°)b: synclinal (gauche, 30° < θ < 90° (±))c: anticlinal (90° < θ < 150° (±))d: antiperiplanar (anti, 150° < θ < 180° (±))

θ

CH2FCH2F:

F

FHH

HH F

HHH

HF

ΔE = – 2.0–2.6 kcal/mol

OHOHO

HOOH

HO OHOHO

HOOH

HO

α-glucose β-glucoseOH

OnO

σ*C–O

X

HH

Y

H

H

XH

Y

HH

XH

Y

Hbisecting

(rotational barrier)gauche

(a stable confomer)eclipsed

(less stable than gauche)

X

H

H Y

HFelkin–Anh-type

(not stable)

RR

HHH

RH

HHR

1,3-allylic strain (A(1,3)-strain)

R

HH

H

RH

RR1,2-allylic strain (A(1,2)-strain)

Y

H

X

H

X YH

Y

X

H

XY

s-ciss-trans

Y

H

X

H

X Y

gauche

The s–s* interation between the vicinal C–H bonds.

H

H

σ*σ

syn-pentane interaction

H

HMe

Me

HH

Page 13: Advanced Organic Chemistry III 1. Stereochemistry of ...• The chirality is seen in some spiro bicyclic compounds and alkylidene cycloalkanes. (c) Planar chirality • Planar chirality

– 13 –

3) Carboxamides • C–N bond of carboxamide possesses double bond character, because structure 2 remarkably

contributes to the resonance hybrid. Therefore, the rotation of C–N bond is relatively slow. • In NMR analysis, a set of signals are often observed because the Z–E isomerization of amide is

slow in NMR time scale.

(c) 4-Membered rings

• In 4-membered rings, planar structure is unfavorable because torsional strain is maximum. • Puckered structure is preferable to planar one in order to escape the strain. The 4-membered

ring is released from the ecripsed conformation. • The angle of pucker is 28° and the barrier of ring inversion is 1.45 kcal/mol in cyclobutane.

(d) 5-Membered rings

• Conformation analysis of 5-mambered rings is significantly complicated as compared to those of 4- and 6-membered rings, because their conformation is very flexible.

• Stable conformations of cyclopentane are envelope and half-chair conformations. The former is more stable than latter, but the energy difference of both conformers is very small (0.5 kcal/mol).

• The envelope conformer is Cs-symmetry, and the half-chair conformer is C2-symmetry. • Equilibrium between envelope and half-chair conformers is remarkably affected by substituents.

(e) 6-Membered rings

1) Saturated rings • Stable conformations of saturated 6-membered rings are chair and twist boat. Boat

configuration is the transition state of the interconversion between two twist boat conformers. • In most cases, chair conformer is more stable than twist boat conformer. Rarely, twist boat is

preferable to chair in order to avoid large 1,3-diaxial interaction.

• Stability of conformer of substituted 6-membered rings is affected by A-value, 1,3-diaxial

interaction, and the presence of gauche conformation etc.

Fused ring systems • Bicyclic system of cis-fused cyclohexane, such as cis-decaline, is possible to invert. In contrast,

ring inversion of the trans-isomer is impossible.

2) Cyclohexene

• The most stable conformation of cyclohexene is half-chair.

• In 1,6-disubstituted cyclohexenes, substituent R' at the 6-position induces considerable

A(1,2)-strain if it occupies the pseudo-equatorial position. To avoid the strain, R' tends to occupy the psudo-axial position.

3) Cyclohexanone

• Cyclohexanones prefer chair conformation. Their conformations are affected by the dipole and planar structure of carbonyl group.

O

R1N

R2

R3 –O

R1N+

R2

R3

1 2

ON

H

Me

HΔE‡ = 20.6 kcal/mol

ON

Me

Me

HΔE‡ = 21.3 kcal/mol

5

6

7

84

3

1

2

2

1

4

37

8

6

5

ΔE‡ = 1.45 kcal/mol

envelope

σ

C2

half-chair

• •‡‡

chair half-chair twist boat boatR

R

axialequatorial

cis-decaline trans-decaline

==

half-chair

pseudo-axialpseudo-equatorial

R'R'

H HRR A(1,2)-strain

more stable

R R 1,3-diaxial interaction

Page 14: Advanced Organic Chemistry III 1. Stereochemistry of ...• The chirality is seen in some spiro bicyclic compounds and alkylidene cycloalkanes. (c) Planar chirality • Planar chirality

– 14 –

2. Stereocontrol in Organic Reactions (1) Principles in selective organic reactions

(a) Curtin–Hammett principle Selectivities are controlled by the relative energies of two transition states. The difference of

reactants or products does not affect the selectivity. • Curtin-Hammett principle is useful for considering selectivities of organic reactions, when the

reaction forms different products (C and D) from two substrates (or intermediates) (A and B) in rapid equilibrium with one another (eq. 1).

• The selectivity, [C]/[D], is equal to exp(–DDG‡/RT). Therefore, the selectivity depends on only DDG‡, although DDG‡ = DG2‡ – (DG1‡ + DG).

• Even if the reactant (or intermediate) A is less stable than B, product C would be the major product when TS1 is more stable than TS2.

• Avoid to discuss the selectivity with the structures of reactants (or intermediates).

J. I. Seeman, Chem. Rev., 1983, 83, 83.

(b) Hammond’s postulate If two states, as for example, a transition state and an unstable intermediate, occur consecutively

during a reaction process and have nearly the same energy content, their interconversion will involve only a small reorganization of the molecular structure.

The postulate is useful for predicting the property of the transition state in highly exothermic or endothermic process (Figs a and b). Do not apply the postulate to the reactions, in which the reactant is similar in potential energy to the product (Fig c). 1) Highly exothermic reaction

• The energy diagram of a highly exothermic step (Fig a) indicates that the reactant reaches the transition state at early stage. Therefore, the transition state is similar in structure and energy to the reactant. � Selectivities, including stereoselectivity, would be affected by the relative energy of each

reactant (or its conformer). 2) Highly endothermic reaction

• The energy diagram of a highly endothermic step (Fig b) indicates that the reactant reaches the transition state at late stage. Therefore, the transition state is similar in structure and energy to the product.

� Selectivities, including stereoselectivity, would be affected by the relative energy of each possible product.

G. S. Hammond, J. Am. Chem. Soc., 1955, 77, 334. See also, J. E. Leffler, Science, 1953, 117, 340.

A BC Dk1 K k2

(1)

AB

reactantsproduct

product

CD

ΔG

ΔG1‡ΔG2‡

ΔΔG‡TS1

TS2

G

Ereactant

product

(a) highly exothermic reaction

E

reactant

product

(b) highly endothermic reaction

TS‡ TS‡

similar similarE

reactant product

(c) other

TS‡

Page 15: Advanced Organic Chemistry III 1. Stereochemistry of ...• The chirality is seen in some spiro bicyclic compounds and alkylidene cycloalkanes. (c) Planar chirality • Planar chirality

– 15 –

(2) Stereoselective reaction and prochirality (a) Enantioselective reaction

1) Features • Enantioselective reaction is the reaction that produces an optically active compound from an

achiral or racemic starting material with an optically active reagent or catalyst. • It is ordinary that an achiral compound is converted into a 1:1 mixture of R- and S-products, if the

reaction creates a new chiral center. Both pathways leading to R- and S-products proceed through enantiomeric transition states, which have the same energy level each other.

• The optically active reagent or catalyst can discriminate the prochirality of the substrate.

• Commonly, the stereoselectivity in the enantioselective reaction, which is called enantioselectivity, is equivalent to the enantiomeric excess of the optically active product.

• There are two types of stereodiscrimination in enantioselective reaction. One involves the discrimination of enantiotopic faces; another involves that of enantiotopic groups.

2) Prochirality of achiral compounds Enantiotopic face (re/si) • In general, achiral unsaturated molecules have a symmetry plane involving the double bond.

The plane has two faces. If the attack of a reagent on each face leads to forming different enantiomer, the face is called 'enantiotopic face'. � Prochirality of enantiotopic face can be indicated with descriptor re or si. The prochirality is

assigned as follows: i) Determine the priority of the three substitutents on the atom, which will become a chiral center

after the enantioselective reaction. ii) View the face from above. The face is called re-face when the direction of a → b → c is

clockwise. Otherwise, the face is si-face.

Enantiotopic group (or atom) (pro-R/pro-S) • When two equivalent groups (or atoms) are attached on a sp3-hybridized carbon, the reaction

occurring on one of the groups results in forming a new chiral center. Different enantiomers will be obtained from the reactions on each group. The two equivalent groups are called 'enantiotopic group'.

• Prochirality of enantiotopic group can be indicated with descriptor pro-R or pro-S. The prochirality is assigned as follows: i) Determine the priority of the four substituents on the atom, which will become a chiral center

after the enantioselective reaction. Here, one of the enantiotopic groups is tentatively assume to be dominant over another.

ii) Determine the R/S configuration with the above tentative priority. When the configuration is R, the prochirality of the substituent with higher priority is assigned to pro-R. Otherwise, the prochirality is pro-S.

3) Discrimination of enantiotopic faces • In most enantioselective reactions, a chiral reagent or catalyst discriminates two enantiotopic

faces of the unsaturated bond in the substrate (or intermediate) to give the enantio-enriched product (See the figure in the left column).

• After the stereoselective reaction, no unreacted unsaturated bond remains in the resulting product. Therefore, the enantioselectivity of the reaction reflects the selection of the enantiotopic faces.

Examples

4) Differentiation of enantiotopic groups (or atoms) • In some enantioselective reactions, a chiral reagent or catalyst discriminates two enantiotopic

groups of a substrate to give an enantio-enriched product. • After forming the chiral product, one of the enantiotopic groups remains in the product. The

desired product will further react with the reagent, if the chiral reagent or catalyst exhibits low stereoselectivity. However, the overreaction may lead to increasing in the enantiomeric excess of the product. The enantiomeric excess of the product does not reflect the selection of the enantiotopic groups.

O

HPh+ MeMgBr

O

H PhMe– a Me–b

OMgBr

Me PhH

OMgBrHPh Meor

1 3a2

R S

3b

TSa

1 + 2 3a

E

1 + 2 3b

E

TSbO

PhH Me

δ–δ–O

PhHMe

δ–δ–

bc

a

a

b

c'c

MeO2C HHHO

=

MeMe

MeMeMe BH

2 H2O2, OH–

MeMe OH

98.4% ee

L-proline cat.NR2 O OH

H

O

Me

Me

Me

O

H+

Me Me

Me

MeH anti/syn = 24/1

>99% ee

AcO OAcMeMe PLE

AcO OHMeMe

(α = k1/k2 = 2.47 ± 0.36)at 36% yield ··· 80% eeat 15% yield ··· 95% ee

a → b → c clockwise ··· re-face anticlockwise ··· si-face

If c > c', the tentative configuration is S. The prochirality of c is pro-S. The prochirality of c' is pro-R.

PhO

H 1

2

3si-face

PhO

Hre-face

PhHCNHAc

Me

1

2 3

re-face

Me

H

CO2MeCO2Me

1

1

3

4

pro-Spro-R

Page 16: Advanced Organic Chemistry III 1. Stereochemistry of ...• The chirality is seen in some spiro bicyclic compounds and alkylidene cycloalkanes. (c) Planar chirality • Planar chirality

– 16 –

C. J. Sih, J. Am. Chem. Soc. 1984, 106, 3695. See also, S. L. Schreiber, J. Am. Chem. Soc., 1987, 109, 1525.

(b) Diastereoselective reaction 1) Properties

• Diastereoselective reaction produces a new chiral center on the substrate, which has a chiral center. The diastereoselectivity reflects the ratio of the diastereoisomeric products.

• The stereogenic center in the substrate can control the stereochemistry of the reaction (i. e. diastereoselectivity). Therefore, an achiral reagent can selectively produce a single diastereomer in diastereoselective reaction.

• The stereoselectivity in the diastereoselective reaction is often evaluated with diastereomeric excess (de, %), which is the difference between percentages of major and minor products, (de (%) = 100([major product] – [minor product])/([major product] + [minor product]).

• There are two manners of stereocontrol in diastereoselective reaction. One is the stereocontrol by the chirality of the substrate; another is that by the chirality of the reagent or catalyst.

How to predict the major product • By transition state: In principle, the stereoselectivity is controlled by the difference in energy

between favorable and unfavorable transition states. Comparing the two possible transition states is useful for predicting the major product. However, it is not easy to predict structure and energy of each transition state.

• By structure of the chiral substrate: The structure sometimes strongly relates to the stereoselectivity. When the reaction is known to proceed through early transition state (in Hammond postulate), the major product can be predicted with the steric hindrance imagined from the structure of the substrate.

• By structures of the diastereomeric products (or intermediates): The difference in

thermodynamic stability between the possible diastereomeric products sometimes strongly relates to the stereoselectivity. When the reaction is known to proceed through late transition state (in Hammond postulate), the major product can be predicted with the thermodynamic stability of each possible product.

2) Substrate-controlled reaction � In the substrate-controlled reaction, the stereochemistry of the substrate predominantly controls

the stereoselectivity. � All diastereoselective reactions are substrate-controlled reactions when they are conducted with

an achiral reagent (or catalyst).

D. A. Nelson, Tetrahedron Lett. 1986, 27, 3091.

D. A. Evans, Tetrahedron Lett. 1985, 26, 6005.

• Choice of the achiral reagent may bring about reversal of the stereoselectivity. However, such a reaction should be treated as a substrate-contorolled reaction, because the interaction between the reagent and the substrate must strongly affect the stereoselectivity.

K. Oshima, K. Utimoto, Tetrahedron, 1993, 49, 11169.

(review) O. Reiser, Chem. Rev., 1999, 99, 1191.

3) Double stereodifferentiation (review) S. Masamune, Angew. Chem. Int. Ed. Engl., 1985, 24, 1. • In the reaction between two chiral molecules, both of the substrates affect the stereoselectivity.

The effect of the combination of two chiral molecules is called double strereodifferentiation. • If the stereochemical effect of the chiral substrate is predominant over that of the reagent, the

reaction should be categorized as substrate-controlled reaction. • If the effect of the chiral reagent or catalyst is predominant over that of the substrate, the reaction

should be categorized as a reagent-controlled reaction. • When the chiral substrate and reagent (or catalyst) are comparable in the effect on

H

OPh H

Me+ MeMgBr Me– a Me–b

2

Ph MeMe

OH

or Ph MeMe

OH

1

O

H

PhMe

3a 3b

TSa

1 + 2 3a

E

1 + 2 3b

E

TSbO

H Meδ–

δ–

Me HPh

OHMe

δ–δ–

HMePh

OMe

OAr Et2O, 23°C

Zn(BH4)2OH

Me

OAr

OHMe

OAr1 2

Ar = 2-MeOC6H4Ar = 2-(t-Bu)C6H4

1/2 = >99/11/2 = <1/99

Et

OH

TBSO

OBzMe

Et

OH

TBSO

OBzMe

[Rh] cat.

H2, CH2Cl2, 25°CEt

OH

TBSO

OBzMe

1 2[Rh] = Rh(dppb)+

[Rh] = Rh[(R)-binap]+[Rh] = Rh[(S)-binap]+

1/2 = 89/111/2 = 97/31/2 = 92/8

t-Bu

OCO2Et

MeMeOH, 0°C

NaBH4, MClnt-Bu

OHCO2Et

Met-Bu

OHCO2Et

Me1 2MCln = noneMCln = MnCl2

1/2 = 10/901/2 = 95/5

If the pro-R-c is more reactive than pro-S-c in 1, (S)-2 is obtained as the major product (k1 > k2).

The minor product (R)-2 still has pro-R-c. The group c would be more reactive than pro-S-c remaining in (S)-2. Therefore, (R)-2 would be easier to be converted into achiral 3 than (S)-2 (k4 > k3).

c

c

ba

d

c

ba

c

d

ba

k1

k2

k3

k4

d

d

ba

pro-R

pro-S

S

(achiral)R1

2

3

Page 17: Advanced Organic Chemistry III 1. Stereochemistry of ...• The chirality is seen in some spiro bicyclic compounds and alkylidene cycloalkanes. (c) Planar chirality • Planar chirality

– 17 –

stereoselectivity, the direction of asymmetric induction arising from each compound should be carefully considered.

• Diastereoselectivity of the reaction would enhance, when the directions of both asymmetric induction are parallel. The combination of the substrate and reagent is called matched pair. If the directions are opposite each other, the stereochemical combination is called mismatched pair.

(Diasteleoselective aldol reaction controlled by chiral aldehyde)

(Diasteleoselective aldol reaction controlled by chiral enolate)

(Aldol reaction with matched pair)

(Aldol reaction with mismatched pair)

S. Masamune, Angew. Chem. Int. Ed. Engl., 1980, 19, 557.

4) Reagent-controlled reaction • In the reagent-controlled reactions, the stereochemistry of the reagent (or catalyst)

predominantly affects the stereoselectivity of the reaction. • A new chiral center possessing the desired configuration can be created on a chiral substrate

independent of its stereochemistry by choosing the enantiomeric reagent (or catalyst). (Substrate-controlled epoxidation)

(Enantioselective epoxidation (Katsuki-Sharpless oxidation))

(Reagent-controlled epoxidation)

S. Masamune, K. B. Sharpless J. Am. Chem. Soc., 1982, 47, 1373. See also, S. Masamune, Angew. Chem. Int. Ed. Engl., 1985, 24, 1.

(c) How to control stereochemistry 1) Chiral reagent

• In the reaction producing a chiral compound from an achiral substrate, the product may be obtained as an optically active form, if the reagent is modified with an enantiopure substituent.

• The optically active reagent is called chiral reagent. • The reaction with the chiral reagent proceeds enantioselectively. The product does not contain

the chiral substituent on the chiral reagent. • Stoichiometric or excess amount of the chiral reagent is required to obtain the desired chiral

product with high ee.

R. Noyori, J. Am. Chem. Soc., 1979, 101, 3129; 1984, 106, 6709; 1984, 106, 6717.

2) Chiral catalyst • If the reaction proceeds through a catalyst, the chiral product may be obtained as an optically

active form, if the catalyst is modified with an enantiopure substituent or compound. • The optically active catalyst and the enantiopure ligand are called chiral catalyst and chiral ligand,

respectively. The enantioselective reaction through a chiral catalyst is called catalytic asymmetric reaction.

• In the catalytic asymmetric reaction, a prochiral substrate (S) interacts with a chiral catalyst (C*) to form a chiral intermediate (S–C*), which is often called catalyst–substrate complex. The

HCy

Me

O+

OLiMe OTBS

Me Me

Cy

Me

OH

Me

OOTBS

MeMe

Cy

Me

OH

Me

OOTBS

MeMe2 3

2/3 = 1/2.71

SR S

Ph H

O+

OLiMe OTBS

Ph MePh

OH

Me

OOTBS

Ph Me

S Ph

OH

Me

OOTBS

Ph MeS R

4 5 65/6 = 1/3.5

OLiMe OTBS

Ph Me

S

4

Cy

Me

OH

Me

OOTBS

Ph Me

Cy

Me

OH

Me

OOTBS

Ph Me7 8

R S

7/8 = 1/8

1 +

OLiMe OTBS

Me Ph

R

ent-4

Cy

Me

OH

Me

OOTBS

MePh

Cy

Me

OH

Me

OOTBS

MePh9 10

R S

9/10 = 1.5/1

1 +

OHO

OTi(O-i-Pr)4

TBHP OHO

OO

OHO

OO

1 2 1/2 = 2.3/1

OHBnOTi(O-i-Pr)4, (+)-DET

TBHP, –20°COHBnO O 99/1

OHO

O

OHO

OO

Ti(O-i-Pr)4, (–)-DET

TBHP, –20°C

Ti(O-i-Pr)4, (+)-DET

TBHP, –20°C OHO

OO

1

2

1/2 = 90/1

1/2 = 1/22

mismatched

matched

THPO

THPO

CO2Me

O

Me(S)-BINAL-H

THF, –100 to –78°C

THPO

THPO

CO2Me

OH

Me15S

15S/15R = 100:0

OAl

O H

OEt

Li+

(S)-BINAL-H

Page 18: Advanced Organic Chemistry III 1. Stereochemistry of ...• The chirality is seen in some spiro bicyclic compounds and alkylidene cycloalkanes. (c) Planar chirality • Planar chirality

– 18 –

complex reacts with another substrate (or reagent) (R) to form the desired product (S–R). The chiral catalyst is regenerated and then activates S again.

• The reagents employed in catalytic asymmetric reactions are achiral.

W. S. Kowles, J. Am. Chem. Soc., 1975, 97, 2567; Acc. Chem. Res. 1983, 16, 106.

3) Chiral auxiliary • An achiral or racemic substrate can be modified with an enantiopure compound in order to obtain

the enantio-enriched product, when it has a reactive functional group, e.g. carboxylate, alcohol, or amine. The enantiopure compound for the chiral modification is called chiral auxiliary.

• The chiral auxiliary can be removed with hydrolysis etc. after the desired stereoselective reaction. The used chiral auxiliary can be recycled.

• In this case, the substrate has the chiral center stemming from the auxiliary. Therefore, the stereoselective reaction involving the chiral auxiliary is not enantioselective reaction, but diastereoselective one.

• It is relatively easy to design the key intermediate involving the substrate and chiral auxiliary and to predict the stereochemistry of the product. Therefore, the stereoselective reaction using a chiral auxiliary is frequently used in organic synthesis as compared to other methods.

D. A. Evans, J. Am. Chem. Soc., 1981, 103, 2127.

(3) Stereochemistry in the nucleophilic addition and reduction of carbonyl groups 1) Acyclic 1,2-asymmetric induction

• Nowadays, the nucleophilic addition is believed to mostly proceed through the transition state proposed by Felkin and Ahn. However, several transition state models have been proposed and used for illustrating the stereochemistry of the nucleophilic addition. This section describes not only the Felkin-Ahn model but also the other transition state models.

Felkin–Ahn model • In a nucleophilic addition, the nucleophile

donates its lone pair to the p* orbital of carbonyl group.

• In the transition state, the electrons shared between the nucleophile and p* orbital conjugate the s* orbital of Ca–X bond.

• The hyperconjugation stabilizes the transition state.

• In the transition state, the angle of Nu–C–O (q) is ca. 110°. • If the carbonyl substrate has a chiral center on its a-carbon,

the largest substituent (L) is located on the antiperiplanar position of Nu.

• To avoid the steric hindrance to the attack of the nucleophile to the carbonyl, the middle (M) and smallest substituent (S) are respectively located by the carbonyl oxygen and carbonyl substituent R in the favorable transition state.

polar-Felkin–Ahn model • In a C–X bond, the large electronegativity of X causes decrease in the energy level of its s*

orbital. The effect enhances the ability to accept electrons through the hyperconjugation. • Therefore, an additional rule is required for predicting or explaining the stereochemistry of the

nucleophilic addition, when the electrophilic substrate has a polar substituent on its a-carbon of carbonyl group.

• The polar substituent X, e.g. OMe, Cl, etc., prefers the antiperiplanar position of the nucleophile Nu in the Felkin-Ahn transition state.

• To avoid the steric hindrance to the attack of the nucleophile to the carbonyl, the large (L) and small substituent (S) are respectively located by the carbonyl oxygen and carbonyl substituent R in the favorable transition state.

Cram's rule • Cram's rule is an empirical method for predicting the

stereochemistry of the nucleophilic addition. • It is assumed that the largest substituent (L) prefers to stay in

the eclipsed position of carbonyl substituent R. • The nucleophile Nu attacks on the carbonyl carbon from the

side of the smallest substituent S. • In the case of ketone or aldehyde bearing a polar substituent X

SC*

S C*R

prochiralsubstrate

catalyst–substratecomplex

(diastereoisomeric)

S C*R

chiral catalyst

S Rchiral

product

enantioselective

CO2Na

NHAc

0.05% cat. {Rh(cod)[(R,R)-DiPAMP]}BF4

50% MeOH, 25°C, 4 h+ H2(4 atm)

CO2Na

NHAc

PP PhPh

MeO

OMe

(R,R)-DiPAMP

96% ee

ON

OOMe

i-PrR H

O+

Bu2BOTf

i-Pr2NEtON

OO

Mei-Pr

OH

RH2O2

LiOH

O

Me

OH

R OH

>99% ee (2S,3R)(R = Bu, i-Pr, Ph)

OHN

O

i-Pr

+

R O

X

Nuθ

OCα

R

X

Nu

:

π*

σ*

hyperconjugation

Newman projection

R

O

L

MSNu Nu

(favorable) (unfavorable)

Cram's rule

R OS M

L

Nu

Felkin–Ahn model(L > M > S)

O RS M

L

Nu

(favorable) (unfavorable)

R OS L

X

Nu

polar-Felkin–Ahn model(L > S, X = polar substituent)

O RS L

X

Nu

(favorable) (unfavorable)

R

O

X

LSNu Nu

(favorable) (unfavorable)

Conforth model

Page 19: Advanced Organic Chemistry III 1. Stereochemistry of ...• The chirality is seen in some spiro bicyclic compounds and alkylidene cycloalkanes. (c) Planar chirality • Planar chirality

– 19 –

on the a-carbon, the polar substituent prefers to stay in the eclipsed position of carbonyl substituent R because of the dipole interaction between C=O and Ca–X (Cornforth model).

2) Chelation-controlled 1,2-asymmetric induction • Stereoselectivity in the nucleophilic addition is often controlled by a metal

atom, when the substrate has a Lewis basic heteroatom (e.g. -OR) on its a-carbon and the metal atom has sufficient Lewis acidity.

• The heteroatom and the carbonyl oxygen interact with the metal atom to form a chelate complex as shown in the right figure. The coordination of carbonyl oxygen to metal enhances the reactivity of the substrate.

• The nucleophile Nu attacks on the carbonyl carbon from the side of the smaller substituent S.

• In general, the chelation-controlled reaction proceeds with the opposite stereoselectivity to the Felkin–Ahn-controlled reaction.

H. Yamamoto, J. Am. Chem. Soc. 1988, 110, 3588.

G. E. Keck, Tetrahedron Lett. 1984, 25, 265.

3) 1,3-Asymmetric induction i) Chelation-controlled 1,3-asymmetric induction • Stereoselectivity in the nucleophilic addition is sometimes controlled by the stereochemistry of

the b-carbon of the substrate, which has a Lewis basic heteroatom on its b-carbon. • The substrate readily forms a 6-membered chelate complex with a

Lewis acid possessing multiple coordination sites (e.g. TiCl4, SnCl4) as shown in the right figure. The nucleophilic addition will occur from the chelate intermediate.

• The nucleophile Nu accesses the carbonyl carbon from above to avoid the steric interaction with the pseudo-axial proton at the a-position.

M. T. Reetz, J. Am. Chem. Soc. 1983, 105, 4833.

K. Narasaka, Tetrahedron 1984, 40, 2233.

ii) Non-chelation-controlled 1,3-asymmetric induction • The nucleophilic addition (Sakurai-Hosomi reaction) provides the 1,3-anti-product with high

diastereoselectivity when BF3 is used as a promoter, although BF3 cannot form the chelate intermediate.

• In the favorable transition state, substituent R1 on the b-carbon would be located at the antiperiplanar position of the formyl group.

• The carbonyl double bond faces the opposite direction to the C–X bond to avoid the dipole repulsion.

• The nucleophile Nu attacks on the carbonyl carbon from the opposite side to the b-carbon.

M. T. Reetz, Tetrahedron Lett. 1984, 25, 729. D. A. Evans, Tetrahedron Lett. 1994, 35, 8537.

4) Stereochemistry in the reaction of cyclohexanone • The stereoselectivity of the nucleophilic addition of cyclohexanone is strongly affected by the

substituent and/or the size of the nucleophile. • Small nucleophiles prefer the axial attack in general. Large ones prefer the equatorial attack.

Nu = LiAlH4 (R = H) 90 : 10 Nu = Li(s-Bu)3BH (L-selectride) (R = H) 12 : 88 Nu = MeLi (R = Me) 21 : 79 Nu = MeLi (with MAD) (R = Me) 99 : 1

H. Yamamoto, J. Am. Chem. Soc. 1985, 107, 4573.

MeH

O+ BuMgBr

–78°C

Me

OH

BuMe

OH

Bu

syn anti81%syn : anti = 89 : 11

OR

O

H SnBu3+Lewis acid (LA)

OR

OH

OR

OHsyn anti

LA = BF3•OEt3, R = TBSLA = BF3•OEt3, R = BnLA = MgBr2, R = TBSLA = MgBr2, R = Bn

CH2Cl2

syn : anti = 9 : 91 (Felkin-controlled)syn : anti = 39 : 61syn : anti = 21 : 79syn : anti = >250 : 1 (chelation-controlled)

Me

OBnCHO + SiMe3

TiCl4CH2Cl2–78°C

Me

OBn OH

anti : syn = 95 : 5

Ph

OH O

Ph

Bu3B

THFPh

O O

Ph

Bu2B NaBH4

–78°C Ph

OH OH

Ph Ph

OH OH

Phsyn antisyn : anti = 98 : 2

Me

OBnCHO + SiMe3

BF3

CH2Cl2–78°C

Me

OBn OH

anti : syn = 91 : 9

t-BuO

+ Nu t-Bu OH

R

t-Bu R

OH

equatorial-attackaxial-attackt-Bu

ONu

Nu(nucleophile)

O RX

L

S+M

Nu

chelation model(L > S, X = OR etc.)

O TiCl4OBn

HH

HMe

H

Nu

Nu

(favorable)

(unfavorable)

ORH H

XR1

H

Nu

ORH H

XR1

H

Nu

(favorable)

ROH H

XR1

H

(unfavorable)

Nu

Page 20: Advanced Organic Chemistry III 1. Stereochemistry of ...• The chirality is seen in some spiro bicyclic compounds and alkylidene cycloalkanes. (c) Planar chirality • Planar chirality

– 20 –

(4) Stereochemistry in the reaction of enolates 1) Stereochemistry in the formation of enolates

• Enolates are generated from carbonyl compounds through the deprotonation of the a-proton with a base. The enolates are possible to possess geometric isomerism. The stereochemistry can be controlled by metal and/or reaction conditions.

Lithium enolate • The deprotonation often proceeds through the conformation in which a Ca–H bond is

perpendicular to the carbonyl group, because the s-orbital of the C–H bond is required to interact with p*-orbital of the C=O bond in order to form the C=C bond in the resulting enolate.

• Repulsion between R1 and R2 in the carbonyl substrate controls the E/Z selectivity of the enolate.

R. E. Ireland, J. Org. Chem. 1991, 56, 650.

• The deprotonation is believed to proceed through Ireland’s transition state model, when lithium dialkylamide was used as the base.

• Higher reaction temperature is advantageous to the formation of E-enolate. Z-Enolate may be kinetically preferable, and E-enolate may be thermodynamically preferable.

L. Xie, J. Org. Chem. 1997, 62, 7516.

R. E. Ireland, J. Am. Chem. Soc. 1976, 98, 2868.

Soft enolization T. Mukaiyama, Chem. Lett. 1976, 559: Bull. Chem. Soc. Jpn. 1980, 53, 174. • Ketones and thioesters can be transformed into their enolates in the presence of a tertiary amine

and a Lewis acid (soft enolization). The interaction between the carbonyl oxygen and the Lewis acid facilitates the deprotonation of the a-hydrogen.

• The soft enolization is useful for preparing boron, tin, silicon, titanium, magnesium enolates. • Stereochemistry of the boron enolate can be controlled by choosing the boron Lewis acid.

Z-Enolate will be selectively formed when two alkyl substituents on the boron atom are relatively small.

• Triflate or iodide is favorable for the formation of Z-enolate. Chloride is favorable for the formation of E-enolate.

H. C. Brown, J. Org. Chem. 1993, 58, 147.

2) Stereochemistry in the reaction of chiral enolates with electrophiles

Cyclohexanone enolate • The enolates of cyclohexanones take a half-chair conformation. The substituent on the

cyclohexene ring prefers an equatorial position. • An electrophile preferentially approaches the enolate from above in order to avoid the steric

hindrance of the pseudo-axial proton.

M. E. Kuehne, J. Org. Chem. 1970, 35, 171.

Evans’s oxazolidinone • Optically active oxazolidinones, which are readily prepared from b-amino alcohols and phosgene,

are widely used as the chiral auxiliaries for carboxylate enolates. • In general, the N-acyloxazolidinone gives its Z-enolate through deprotonation. • The carbonyl oxygen of the oxazolidinone can bond to the metal atom of the enolate. The

chelation fixes the conformation of the enolates.

Me OEt

O 1. LDA, solvent

2. TBSCl MeOTBS

OMeMe

OTBS

OMe

in THF–45% DMPUin THF

Z : E = 93 : 7Z : E = 6 : 94

Z E

N NMeO

Me

DMPU

O R1

H

R2 HO R1

H

H R2R1 R2O base (B) B: B:

(favorable) (unfavorable)

O–

R2R1

Z-enolate

Et

OMe

R2NLi

THF

with (t-Bu)(TMS)NLi at 23°Cwith Ph(TMS)NLi at –78°C

Et

OLiMe

E : Z = 94 : 6E : Z = 7 : 93

t-Bu

OMe

R2NLi

THF

with (t-Bu)(TMS)NLi at 23°Cwith Ph(TMS)NLi at –78°C

t-Bu

OLiMe

E : Z = 11 : 89E : Z = 0 : 100

R1 R2O

O

H

NLi

R1

L1

L2R2

H

O

H

NLi

R1

L1

L2H

R2

L1L2NLi

(if R1 is large, L1 is small)

(if R1 is small, L1 is large) R1

R2

OLi

R1 R2OLi

Z-enolate

E-enolate

O

Ph MeEt3N

BOTfO

Ph Me

9-BBN (c-Hex)2BCl

Et3N

O

PhMe

(c-Hex)2B

Z E

Z : E = >97 : <3 Z : E = <3 : >97

O

R1 Me

O

R1 Me

BR2

R2 X

R22BX

O

R1 Me

BX

R2R2

OR1

H

H MeBR2

2XR3N

OR1

H

Me HBR2

2XR3N

(if R2 is small)

(if R2 is large)

OBR22

R1 Me

Z-enolate

OBR22

R1

MeE-enolate

NR3

NR3

OCO2Me

t-Bu

LiNH2

C6H623 °C

MeO2C

Ht-BuH

H OLi

I Me

I Me

Me I t-BuMeO2C

Me

O

OCO2Me

t-Bu

Me=

Page 21: Advanced Organic Chemistry III 1. Stereochemistry of ...• The chirality is seen in some spiro bicyclic compounds and alkylidene cycloalkanes. (c) Planar chirality • Planar chirality

– 21 –

• Electrophiles preferentially approaches the enolate to avoid the steric hindrance of the substituent R.

• Various electrophiles are possible to react with the chiral enolate to give the optically active a-substituted carboxylates with high enantiomeric excesses.

(R–X) D. A. Evans, J. Am. Chem. Soc. 1982, 104, 1737; 1990, 112, 8215.

(ArSO2N3) D. A. Evans, J. Am. Chem. Soc. 1990, 112, 4011. (BocN=NBoc) D. A. Evans, Tetrahedron 1988, 44, 5525.

(Davis reagent) D. A. Evans, J. Am. Chem. Soc. 1985, 107, 4346.

Enders’s hydrazone (SAMP/RAMP) • SAMP and RAMP are prepared from (S)-proline and (R)-glutamic acid, respectively. These

hydrazones can form chiral hydrazones with an achiral ketone or aldehyde. • The hydrazones are readily deprotonated with lithium dialkylamides to give their azaenolates.

Coordination of the methoxy group to lithium fixes the conformations of the azaenolates. • Electrophiles react with the azaenolates from the same side of the MeO group to avoid the steric

hindrance of the pyrrolidine ring.

D. Enders, Angew. Chem., Int. Ed. Engl. 1976, 15, 549; (review) Tetrahedron 2002, 58, 2253.

(5) Stereoselective aldol reaction 1) Problems in aldol reaction

• Aldol reaction is the reaction of an enolate with an aldehyde or a ketone, giving b-hydroxy carbonyl compound (aldol).

• Chemoselectivity

• Regioselectivity in the formation of enolate

These problems are solved by preformed enolate. Formation of more substituted enolate is thermodynamically favored. Formation of less substituted enolate is kinetically favored.

H. O. Hause, J. Org. Chem. 1969, 34, 2324. (modified method) � 4� ���� 24, p 154.

• Diastereo- and enantioselectivities (stereoselectivity)

2) Stereocontrol of vicinal chiral centers of the aldol product

• In the aldol reactions of prochiral enolates with carbonyl compounds, the aldol products have vicinal chiral centers. The stereochemistry of the vicinal chiral centers is often controllable.

Aldol reactions through Zimmerman-Traxler transition state • The electrophilic substrate is activated by the interaction between its carbonyl oxygen and the

metal atom of enolate, when the enolate has a strong Lewis acidic metal. The complexation allows the intramolecular aldol reaction through 6-membered transition state (Zimmerman–Traxler transition state).

• In the aldol reactions through Zimmerman–Traxler transition state, Z-enolates selectively yield syn-product. Anti-aldols are preferentially obtained from E-enolates.

NO

OR

O

R'

R2NM

orTiCl4, i-Pr2NEt

(M = Li, Na, K)NO

OR

O

R'

MEl (electrophile)

NO

OR

O

R'El

>90% de(R' = Bn or i-Pr)

El:R X

(X = Br or I)ArSO2N3 BocN NBoc N

O

Ph SO2Ph

O

R1 R2 N

R1 R2

N

MeOSAMP N

R2R1

N

OLi

Me

R2OR2O

El

El

LiNR2 El N

R1 El

N

MeO

R2

O3

O

R1 R2

El

NNH2

OMe

SAMP

NNH2

OMe

RAMP

H3C CH3

O

H3C

O

H+

H3C

OH

CH3

O

H3C

OH

CH3

O

CH3

H3C

OH

H

O

H3C

OH

H

O

CH3

H3C

O

Ph

O

H+ CH3 Ph

OH OPh

OH

CH3

O

CH3CH3

MeO

MeOSiMe3

MeOSiMe3

(thermodynamically favored)(kinetically favored)

(1) LDA, THF, –78°C (2) Me3SiCl, –78°C to rtEt3N, Me3SiCl, DMF, 130°C, 90 h

99 : 112 : 88

Ph

O

Ph

O

H+ CH3

Ph

OH

Ph

O

CH3

Ph

OH

Ph

O

CH3

Ph

OH

Ph

O

CH3

Ph

OH

Ph

O

CH3

Page 22: Advanced Organic Chemistry III 1. Stereochemistry of ...• The chirality is seen in some spiro bicyclic compounds and alkylidene cycloalkanes. (c) Planar chirality • Planar chirality

– 22 –

H. C. Brown, J. Am. Chem. Soc. 1989, 111, 3441.

H. E. Zimmerman, J. Am. Chem. Soc. 1956, 79, 1920.

Aldol reactions through open transition state model • If the metal atom of enolate cannot interact with the carbonyl oxygen, their aldol reaction

proceeds through the antiperiplanar transition state, in which the dipole of C=O is arrayed to avoid the repulsion of the dipole of C–OSi.

• Both of E- and Z-enolates selectively give the syn-aldol product, because the stereochemistry is mainly controlled by the steric repulsion between R2 and R3.

R. Noyori, J. Am. Chem. Soc. 1981, 103, 2106; 1983, 105, 1598.

3) Stereocontrol with the chiral center of the electrophilic substrate (aldehyde) • In the aldol reactions of chiral a-substituted aldehydes, the stereochemistry is controlled by

Felkin–Ahn or chelate model.

Felkin–Ahn-controlled aldol reaction

C. H. Heathcock, J. Am. Chem. Soc. 1983, 105, 1667.

Polar-Felkin–Ahn-controlled aldol reaction

C. H. Heathcock, J. Am. Chem. Soc. 1987, 109, 3353.

Chelation-controlled aldol reaction

M. T. Reetz, Tetrahedron Lett. 1984, 25, 729.

Double stereodifferentiation: Felkin–Ahn model and Zimmerman–Traxler model • Reactions of Z- and E-enolates

R = Ph (syn, syn) : (syn, anti) = 81 : 19 R = c-C6H11 (syn, syn) : (syn, anti) = 27 : 73 R = CH2OAc (syn, syn) : (syn, anti) = 21 : 79

Ph

OMe

9-BBN-Cl

i-Pr2NEt

(c-Hex)2BCl

Et3N

Ph

OBMe

Ph

OB

Me

>99% (Z)

>99% (E)

1. PhCHO

2. H2O2

1. PhCHO

2. H2O2Ph

OH

Ph

O

Me

Ph

OH

Ph

O

Me 98% syn

95% anti

R1 R2O M

O

MO

R1

HR2

H

R3 O

MO

R1

HR2

R3

HZ-enolate

+ R3CHO

R3

OH

R1

O

R2

(favorable) (unfavorable)syn-aldol

R1

R2

O M

O

MO

R1

R2

H

H

R3 O

MO

R1

R2

H

R3

HE-enolate

+ R3CHO

R3

OH

R1

O

R2

(favorable) (unfavorable)anti-aldol

Ph

OSiMe3Me + PhCHO

F– Me

H

H

OPh

Me3SiO

Ph

Ph

OH

Ph

O

Me

Ph

OSiMe3

Me

+ PhCHOF– Me

H

H

OPh

Ph

Me3SiO

Ph

OH

Ph

O

Me

syn : anti = 95 : 5

syn : anti = 94 : 6

R2

H

R3

OH

SiO

R1

(unfavorable)

OTBS

t-BuPh

MeH

O+

BF3•Et2OO

t-Bu

OHPh

Me

O

t-Bu

OHPh

Mesyn : anti = 24 : 1

(Felkin–Ahn) (anti-Felkin–Ahn)

OLi

t-BuPh

OMeH

O+

O

t-Bu

OHPh

OMe

O

t-Bu

OHPh

OMesyn : anti = 17 : 83

(anti-Felkin–Ahn) (Felkin–Ahn)

OTBS

t-BuMe

OBnH

O+

TiCl4 or SnCl4O

t-Bu

OHMe

OBn

O

t-Bu

OHMe

OBn–78°C

syn : anti = >95 : 5(anti-Felkin–Ahn) (Felkin–Ahn)

OLi

Me Me

TMSO Me

HMe

RO O

Me Me

TMSO

Me

OHR

Me

O

Me Me

TMSO

Me

OHR

MeFelkin product (syn,syn) anti-Felkin product (syn,anti)

HMe

PhO

OLi

ArOMe Ph

OH

Me

ArO2C

MeFelkin product

(anti,syn)

PhOH

Me

ArO2C

Meanti-Felkin product

(anti,anti)80 : 20

Page 23: Advanced Organic Chemistry III 1. Stereochemistry of ...• The chirality is seen in some spiro bicyclic compounds and alkylidene cycloalkanes. (c) Planar chirality • Planar chirality

– 23 –

• In the aldol reaction of Z-enolate, the matched-pair transition state is unfavorable because of the syn-pentane interaction between the enolate a-substituent and the middle-sized a-substituent of aldehyde. Therefore, the stereoselectivity varies along with the substituent R of the aldehyde.

• In the aldol reaction of E-enolate, the matched-pair transition state is favorable. Therefore, the

aldol reaction generally proceeds through Felkin-Ahn transition state to give (2,3-anti, 3,4-syn)-product with good selectivity.

W. Roush, J. Org. Chem. 1991, 56, 4151.

Double stereodifferentiation: polar-Felkin–Ahn model vs Zimmerman–Traxler model • Reactions of Z- and E-enolates

• Chiral a-oxy-substituted aldehydes react with Z-enolates in high stereoselectivity. Meanwhile, the stereoselectivity is disturbed in the aldol reaction of E-enolate.

• Cornforth model is more plausible for the aldol reaction than Felkin-Ahn model.

D. A. Evans, Angew. Chem. Int. Ed. 2003, 42, 1761.

4) Stereocontrol with the chiral center of the enolate substrate Reaction of Z-enolate bearing a chiral center at its a-position • The Z-enolate of chiral ketone 1 reacts with an aldehyde to give the 1,2-syn-2,4-syn aldol product

with high stereoselectivity.

S. Masamune, J. Am. Chem. Soc. 1981, 103, 1566.

D. A. Evans, J. Am. Chem. Soc. 1991, 113, 1047.

O

MO

HMe

RO

R'

H

Me

H

H

Me

R

O

MOR

H

MeR'

H

Me

H

+OM

R' MeZ

OH

Me

RO

MeR'

syn, syn

OH

Me

RO

MeR'

2,3-syn, 3,4-anti

syn-pentaneinteraction

Felkin (matched pair)

anti-Felkin (mismatched pair)

O

MO

HMe

RO

R'

Me

H

H

H

Me

R

O

MOR

H

MeR'

Me

H

H

+OM

R'Me

E

OH

Me

RO

MeR'

anti, anti

OH

Me

RO

MeR'

2,3-anti, 3,4-syn

Felkin (matched pair)

anti-Felkin (mismatched pair)

i-Pr

OBMe +

O

H Me

OTBSi-Pr

O

Me

OHMe

OTBSi-Pr

O

Me

OHMe

OTBSFelkin anti-Felkin98 : 2

i-Pr

OB

Me

+

O

H Me

OTBSi-Pr

O

Me

OHMe

OTBSi-Pr

O

Me

OHMe

OTBSFelkin anti-Felkin21 : 79

Z

E

HOSi

RO

+OM

R' MeZ

(polar-Felkin-Ahn model) (Cornforth model)

M

OO

H

R

SiOMe

HH

R'M

OO

OSi

H

RMe

HH

R'

vs R'

O

Me

OHR

OSi

HOSi

RO

+OM

R'Me

E

(polar-Felkin-Ahn model) (Cornforth model)

M

OO

H

R

SiOH

MeH

R'M

OO

OSi

H

RH

MeH

R'

vs R'

O

Me

OHR

OSi

O

MeTBSO

O

RH+

(c-C5H9)BOTf(i-Pr)2NEt

O

MeTBSOR

OH O

MeTBSOR

OH

(+ others)R = PhR = EtR = i-Pr (Bu2BOTf)

75 : 1>100 : 1>100 : 1

124

syn

syn

1

RL

RS

OMMe

Z

RCHO OR

H

OC

RL

HH

MRSOC

= RL

RS

O

MeR

OH

1,2-syn, 2,4-syn

O

M

Me

H

H

RL

RS

O

MO

Me

H

RS

R

HH

RL

= OC

RL

RSH

MH

OC

RL

RS

O

MeR

OH

(favorable)

(unfavorable)

Page 24: Advanced Organic Chemistry III 1. Stereochemistry of ...• The chirality is seen in some spiro bicyclic compounds and alkylidene cycloalkanes. (c) Planar chirality • Planar chirality

– 24 –

• According to Evans, the large-sized substituent RL on the a-carbon locates the antiperiplanar position of the forming bond to avoid the steric repulsion between RL and the aldehyde. In the transition state, the middle-sized substituent RS is oriented to the enolate C=C bond to escape the steric repulsion toward the enolate metal M.

• The chiral center of b-position scarcely affects the stereochemistry of the aldol reaction.

D. A. Evans, J. Am. Chem. Soc. 1991, 113, 1047.

Reaction of E-enolate bearing a chiral center at its a-position • The E-enolate of a chiral ketone 2 reacts with an aldehyde to give the 1,2-anti, 2,4-syn aldol

product with high stereoselectivity.

D. A. Evans, Tetrahedron 1992, 48, 2127.

see also, C. Gennari, I. Paterson, Tetrahedron 1993, 49, 685.

• Sometimes, the aldol reactions of E-enolate selectively gives 1,2-anti, 2,4-anti aldol product.

D. A. Evans, Tetrahedron 1992, 48, 2127.

5) Asymmetric aldol reaction of the enolate modified with a chiral auxiliary Syn-selective Evans asymmetric aldol reaction • Chiral N-alkanoyloxazolidinones react aldehydes to give syn-aldol products with high

stereoselectivities. Boron or titanium Lewis acid is commonly used for the enolization. • In general, the alkanoyl group is converted to its Z-enolate, which react with an aldehyde through

Zimmerman-Traxler transition state. • It is noteworthy that the aldehyde preferentially reacts the re-face of the enolate bearing

(4S)-oxazolidinone to give the (2S,3R) product. Other electrophiles, e.g. haloalkane, attack the si-face in general.

• When the oxazolidinone derived from (1S,2R)-norephedirine is used as the chiral auxiliary, the aldol reaction selectively gives the syn-(2R,3S)-aldol.

D. A. Evans, J. Am. Chem. Soc. 1980, 113, 1047.

D. A. Evans, J. Am. Chem. Soc. 1991, 113, 1047.

• Possible reaction pathways and transition states:

• In the transition state of the asymmetric aldol reaction, the carbonyl oxygen of the oxazolidinone

is dissociated from the metal (B or Ti) of the enolate. The C=O of the chiral auxiliary is oriented to the antiperiplanar position of the C–O bond of enolate in order to cancel these dipoles.

• The aldehyde attacks the enolate to avoid the steric hindrance of the substituent of chiral oxazolidinone.

O

MeMe

Me

Me

TBSO O

H Me

Me

+TiCl4Et3N

or(i-Pr)2NEt

C5

C5 ··· RC5 ··· S

O

MeMe

Me

Me

TBSO OHMe

Me

O

MeMe

Me

Me

TBSO OHMe

Me(+ others)

C5

95 : 595 : 5

(c-C6H11)2BClEt3N

94 : 696 : 4

O

MeMe

Me

Me

TBSO O

H Me

Me

+C5

C5 ··· RC5 ··· S

O

MeMe

Me

Me

TBSO OHMe

Me

O

MeMe

Me

Me

TBSO OHMe

Me(+ others)

C5

124

2

O

MOR

H

Me

HH

RL

RS

O

MO

H

Me

RS

R

HH

RL

OC

RL

RSMe

MH

OC

RL

RS

OM

Me

E RCHO= RL

RS

O

MeR

OH

1,2-anti, 2,4-syn

= RL

RS

O

MeR

OH

(favorable)

(unfavorable)

OC

RL

HMe

MRSOC

NO

OO

Me

O

MeBn

Xq

+O

i-PrH(c-C6H11)2BCl

Et3NXq

O

Me

O

Mei-Pr

OH

Xq

O

Me

O

Mei-Pr

OH

2,4-anti 2,4-syn84 : 16

O N

OMe

O

i-Pr+ R CHO

O N

O

Me

O

i-PrBu2BOTf

i-Pr2NEt

R

OH

O N

OMe

O

Me

O N

O

Me

O

R

OH

Ph MePhR = Bu, i-Pr, Ph

syn : anti = > 99 : 1>99% ee (2S,3R)

syn : anti = > 99 : 1>99% ee (2R,3S)

O N

OMe

O

Bn

TiCl4TMEDA

i-PrCHOO N

O

Me

O

Bn

i-Pr

OH

others

98 : 2

S

O

BO

H

R

BuBu

N

OOi-Pr

MeH

ON

OMe

i-Pr

O

BBu2

O N

OMe

BBu2O

i-Pr

O

BOH

R

Bu

Bu

N

MeH

OO i-Pr

O N

O

Me

O

i-Pr

R

OH

O N

O

Me

O

i-Pr

R

OH

Z

Z : E = >100 : 1

RCHO

RCHO

O N

OMe

O

i-Pr

Bu2BOTf

i-Pr2NEt

Page 25: Advanced Organic Chemistry III 1. Stereochemistry of ...• The chirality is seen in some spiro bicyclic compounds and alkylidene cycloalkanes. (c) Planar chirality • Planar chirality

– 25 –

• In the titanium-mediated aldol reaction of N-alkanoyloxazolidinethione 1, each stereoisomer of the syn-aldol product can be selectively prepared by choosing amine base and Lewis acid stoichiometry.

• The aldol reaction of 1 gives (2S)-aldol 2, which corresponds to the Evans aldol product, when it is conducted with 2 eq. of TiCl4 and 2.5 eq. of diamine, such as TMEDA or spartein.

• The antipode, 3, is obtained from the reaction with 1 eq. of TiCl4 and 1.1 eq. of monoamine, such as i-Pr2NEt. The thiocarbonyl group forms a chelate with the titanium atom in the transition state.

M. T. Crimmins, J. Am. Chem. Soc. 1997, 119, 7883.

See also, E. R. Thornton, J. Org. Chem. 1991, 56, 2489.

Anti-selective Evans asymmetric aldol reaction • The aldol reaction of N-alkanoyloxazolidinone is promoted in the presence of TMSCl by a

magnesium(II) catalyst to give the anti-aldol product. • The N-acyloxazolidinone 1a is selectively converted into the aldol product 2 with

2R-configuration. Meanwhile, the anti-(2S)-aldol 3 is selectively obtained from the reaction of the thiazolidinethione 1b.

• The Z-enolate is exclusively formed in the soft enolization with the magnesium Lewis acid. However, the magnesium-catalyzed aldol reaction selectively affords the anti-aldol products, because it proceeds through boat transition states.

(X = O) D. A. Evans, J. Am. Chem. Soc. 2002, 124, 392.

(X = S and PM3 study on TS) D. A. Evans, Org. Lett. 2002, 4, 1127.

Abiko-Masamune chiral auxiliary • In contrast to imides, carboxylate esters is readily converted to E- and Z-enolates by choosing

boron triflate and amine. • N-(Arenesulfonyl)-N-benzylnorephedrines are sometimes employed as the chiral auxiliary for the

asymmetric aldol reaction. It is noteworthy that the chiral auxiliary allows the selective formation of E-enolate and the anti-selective asymmetric aldol reaction. Bulky boron triflate (c-Hex)2BOTf and small amine Et3N is of choice for the anti-selective aldol reaction.

• The chiral auxiliary is possible to use for the syn-selective asymmetric aldol reaction. Use of small boron triflate and bulky amine allows the syn-selective aldol reaction.

(anti-selective) A. Abiko, S. Masamune, J. Am. Chem. Soc. 1997, 119, 2586.

(syn-selective) A. Abiko, S. Masamune, Tetrahedron Lett. 1998, 39, 1873. A. Abiko, S. Masamune, J. Org. Chem. 2002, 67, 5250. (see also) ����, � �������, 2003, 61, 24.

O N

OMe

S

Bn

i-PrCHOO N

O

Me

S

Bn

i-Pr

OHRTiCl4, R3N

CH2Cl2O N

O

Me

S

Bn

i-Pr

OHS

& anti

1 2 3

TiCl4 (2 eq.), i-Pr2NEt (1.1 eq.)TiCl4 (1 eq.), (–)-spartein (2.5 eq.)

2 : 3 : anti = 95 : 0 : 52 : 3 : anti = 2 : 97 : 1

X N

OMe

X

Bn

+ PhCHO

1. MgY2 (10%) Et3N, TMSCl2. H+

X N

O

Me

X

Bn

OH

Ph

2a : 3a (& others) = 32 : 12b : 3b (& others) = 1 : 19

X N

O

Me

X

Bn

OH

Ph

X = O (1a)X = S (1b)

MgCl2MgBr2•Et2O

2 3

O

O Me

N

PhMe

ArBn

1. R2BOTf, R'3N

2. i-PrCHO

O

OMeN

PhMe

ArBn

i-Pr

OH O

OMeN

PhMe

ArBn

i-Pr

OH

Ar = Mes

Ar =

R = c-Hex, R'3N = Et3N

R = Bu, R'3N = i-Pr2NEt

anti : syn = >98 (96% de) : 2

anti : syn = 6 : >94 (94% de)

anti syn

O

TiO

H

R

SN

Oi-Pr

MeH Cl

ClCl

Page 26: Advanced Organic Chemistry III 1. Stereochemistry of ...• The chirality is seen in some spiro bicyclic compounds and alkylidene cycloalkanes. (c) Planar chirality • Planar chirality

– 26 –

(6) Stereochemistry in the addition to alkenes 1) Stereochemistry of common electrophilic addition

Overview • Electrophilic addition to alkenes starts from the interaction between the C–C double bond and an

electrophilic (cationic) species (El+). • El+ enhances the electrophilicity of the alkene to facilitate the attack of the nucleophilic (anionic)

species (Nu–) through an SN2-like pathway. • Therefore, the reaction proceeds with anti-selectivity.

Electrophilic addition to cyclohexenes (Fürst-Plattner rule) • In the epoxide opening, the nucleophilic species site-selectively attacks the carbon to form the

diaxial conformer (Fürst-Plattner rule), because the ring opening is similar to the reversed reaction of the intramolecular nucleophilic substitution of halohydrins.

• Fürst-Plattner rule is adaptable for the nucleophilic attack to the 3-memered ring intermediate in

the electrophilic addition to alkenes. • Oxy-mercuration

• Hydrobromination

D. J. Pasto, J. Am. Chem. Soc. 1970, 92, 7480.

Stereoselective iodocarboxylation to acyclic alkenes • Iodoacetoxylation of allylic alcohols

A. R. Chemberlin, Tetrahedron 1984, 40, 2297.

• Iodolactonization of allylic alcohols

A. R. Chemberlin, J. Am. Chem. Soc. 1983, 105, 5819.

A mechanistic analysis with MO

• The iodohydroxylation or iodoacetoxylation proceed through the iodonium ion intermediate. • In the iodolactonization, the nucleophile can attack to the iodine–alkene p-complex

intermediate because of neighboring effect. A. R. Chemberlin and W. J. Hehre, J. Am. Chem. Soc. 1987, 109, 672.

2) Epoxidation of alkenes Steric repulsion vs directing group

b

a

d

c El+a

bc

d

El+

ab

cd

El+

Nu–

b

Nu

a El

cd

1 2

El

Nuab

dc

or/and

path 1 path 2

OOt-Bu

H

H

Nut-Bu=

OHt-Bu

Nu

t-Bu NuOHab

(path a, favorable) (path b, unfavorable)

OO

t-Bu

H

H

Nu

t-Bu=

Nu

t-Bu

OH

t-Bu OHNu

(path a, favorable) (path b, unfavorable)

ab

Rt-Bu

Hg(OAc)2

THF, H2Ot-Bu

HgOAc

OHR

t-BuOH

HgOAcR

R = HR = Me

41%100%

48%0%

Met-Bu

HBr

t-Bu

BrMe t-Bu

MeBr

89% 11%HOAc

Bu

OH

Me

HO

BuHH Me

HI+ OH

BuHHI+

MeHBu

OH

Me

OAc

I(unfavorable)(favorable)

Bu

OH MeHO

BuHH H

MeI+ OH

BuHHI+

HMeBu

OH

Me

OAc

I(unfavorable)(favorable)

IOAc

IOAc

98 : 2

94 : 6

OHOH

HO2C Me

I2, NaHCO3

THF, H2OH

H

CO2–

I+ HMe O

I

Me

OH

O

H

95 : 5

HR

HOH

H Me

OHH

RH

H Me

HR

HOH

H Me

I2

HR

HOH

H Me

I+

OHH

RH

H Me

OHH

RH

H MeI2 I+

favored conformation

disfavored conformation

disfavored π-complex favored iodonium ion

Nufavored π-complex

disfavored iodonium ion

Bu

OH

Me

OH

I

H2O

O

I

Me

OH

O

H

R

C CR

H H H=

[O]unfavorable

[O]

[O]O

H

H

RSteric control Stereocontrol with directing group

X

C CX

H H H=

[O]favorable

[O]

[O]O

H

H

X

Page 27: Advanced Organic Chemistry III 1. Stereochemistry of ...• The chirality is seen in some spiro bicyclic compounds and alkylidene cycloalkanes. (c) Planar chirality • Planar chirality

– 27 –

Stereoselective epoxidation controlled by steric effect of substituent

B. Ganem, Tetrahedron Lett. 1985, 26, 4895.

Stereoselective epoxidation controlled by directing group

B. Ganem, Tetrahedron Lett. 1985, 26, 4895.

The stereochemistry of the epoxidation of homoallylic alcohols is mainly controlled by the chiral center at the allylic position.

E. D. Mihelich, J. Am. Chem. Soc. 1981, 103, 7690.

Y. Kishi, J. Am. Chem. Soc. 1979, 100, 2933.

3) Hydroboration Overview • Hydroboration proceeds through a 4-center transition state. Therefore, the reaction proceeds

with syn-selectivity.

Acyclic hydroboration controlled by A(1,3)-strain • Stereochemistry of the hydroboration of alkenes bearing A(1,3)-strain is controlled by the chiral

center at the allylic position.

Y. Kishi, J. Am. Chem. Soc. 1979, 101, 259.

• In the transition state of the hydroboration, the hydrogen of the chiral center is oriented to the synperiplanar position of the C=C bond to avoid the A(1,3)-strain.

• In the favorable transition state, the largest substituent is oriented to the antiperiplanar position of the forming B–C bond.

K. N. Houk, Tetrahedron 1984, 40, 2257.

Acyclic hydroboration controlled by A(1,2)-strain • Alkenes bearing A(1,2)-strain also can undergo the stereoselective hydroboration controlled by the

allylic chiral center. • The stereoselective hydroboration of 2-propenyl group was used for the synthesis of Lynomycin

A. The syn-product was selectively obtained from the reaction with BH3, while dialkylborane, such as 9-BBN, selectively yielded anti-product.

• In the case of BH3, A(1,2)-strain controls the conformation of the transition state. Therefore, the

hydrogen on the chiral center is oriented to the synperiplanar position of the methyl in the favorable transition state, because the allylic strain overcomes A(1,3)-strain. The borane reagent attacks the C–C double bond to avoid the steric hindrance of the substituent L.

OTBS mCPBA

CH2Cl2, 0°COTBSO

H

HOTBSO

H

H

6.7 : 1

OH OHOH

HOHO

H

H

24 : 150 : 1

CH2Cl2

[O]

[O] = mCPBA[O] = CF3CO3H

R3 R2OH

R1t-BuOOH

VO(acac)2

VOR1

H

R2

H

Ln ORO

H

HR3 R3 R2

OH

R1O

>100 : 1R3 R2

OH

R1O

OHAr

Me Et

EtMe

t-BuOOH

VO(acac)2 OAr

Me

Et OH

EtMe

(Ar = p-MeOC6H4) dr = 8 : 1

b

a

d

c BH3a

bcd

H2B H

ab

cd

H2B H

H2B

ab

H

cd =

H2B

ab H

cd

OMe Me

OBn1. B2H6

2. H2O2, OH– OMe Me

OBn

OH

Hdr = 8 : 1

OMe

OMe

Me

Me

OH

1. B2H6

2. H2O2, OH– OMe

OMe

Me

OH

MeOH

Hdr = 12 : 1

HS H

L

H

B

CH2OR

HH

MeH

L H

S

H

BCH2OR

HH

Me

A(1,3)-strain

(favorable) (unfavorable)

L > SHH S

L

H

BMe

HH

CH2OR

OOMe H

MeOMe

Me

MeN

O

Me

OH

MeO

O

Bn

R

OH

MeOH

= R

R

OH

MeOH

1. R2BH

2. H2O2, OH–H H

R2BH = BH3•SMe2R2BH = 9-BBN

85% (92 : 8)60% (<5: 95)

Page 28: Advanced Organic Chemistry III 1. Stereochemistry of ...• The chirality is seen in some spiro bicyclic compounds and alkylidene cycloalkanes. (c) Planar chirality • Planar chirality

– 28 –

• In the case of 9-BBN, the steric repulsion between the borane reagent and the substituent S

overcomes the A(1,2)-strain. Therefore, the hydrogen on the chiral center is oriented to the synperiplanar position of the C–C double bond in the favorable transition state.

D. A. Evans, J. Am. Chem. Soc. 1995, 117, 3448.

(7) Pericyclic reactions (a) Diels–Alder Reaction

• Diels–Alder reaction is the [4+2] cycloaddition of 1,3-dienes and alkenes (dienophile). Commonly, the cycloaddition proceed through the interaction between the HOMO of diene and the LUMO of dienophile.

• In common Diels-Alder reaction, its rate is enhanced by installing an electron-withdrawing group to the alkene. Also, electron-donating group in the diene substrate accelerates the formation of [4+2] cycloadduct.

• The cycloaddition is possible to proceed with substrate combination of electron-deficient 1,3-diene and electron-rich alkene. The cycloaddition is called inverse-electron-demand Diels-Alder reaction.

Stereochemistry in Diels-Alder reaction • Diels–Alder reaction is stereospecific. For example, the [4+2] cycloaddition of trans-alkene

specifically produces trans-4,5-disubstituted cyclohexene. Meanwhile, cis-alkene provide cis-4,5-disubstituted cyclohexene.

• Endo-rule: Increasing the interaction between the HOMO and LUMO is preferable for the Diels–

Alder reaction. Commonly, the cycloaddition of cyclic 1,3-diene with dienophile selectively give endo-product. However, the exo isomer is obtained as a major product when the reaction proceeds under thermodynamic control.

BS H

L

CH2Me

H

BH S

L

CH2Me

H

BH L

S

CH2Me

H

(favorable) (unfavorable)L > S

A(1,2)-strain

HH

HH

HH

(favorable) (unfavorable)L > S

BS H

L

CH2Me

H RR

BL H

S

CH2Me

H RR

BH S

L

CH2Me

H RR

repulsion

Ψ1

Ψ2*Ψ3*

Ψ2

Ψ2

Ψ3*

Ψ1

Ψ2*

EWGEDG

Ψ2

Ψ3*

Ψ1

Ψ2*

EDGEWG

Diels-Alder reactionInverse-electron-demand

Diels-Alder reaction

a

b

c

d+

a

b

c

d& regioisomers

a

b

c

d

O O

O

O

+ OO

O

O

O

O

ΔOO

O

endoexo

Page 29: Advanced Organic Chemistry III 1. Stereochemistry of ...• The chirality is seen in some spiro bicyclic compounds and alkylidene cycloalkanes. (c) Planar chirality • Planar chirality

– 29 –

(b) Frontier Molecular Orbital (FMO) Theory 1) p-Molecular orbital in conjugate system • Pictures and phases of p-orbitals in various p-conjugation system

• Electrons was put into the orbitals on Hund’s rule. • The highest energy orbital, which is occupied with two electrons, is called HOMO (highest

occupied molecular orbital). • The lowest energy orbital, which has no electron, is called LUMO (lowest unoccupied molecular

orbital). • The orbital having an unpaired electron is called SOMO (singly occupied molecular orbital).

2) Frontier molecular orbital (FMO) theory • In the reaction between two molecules, the HOMO of one (nucleophilic or electron-rich) substrate

interacts with LUMO of the other (electrophilic or electron-deficient) substrate. • A bond forms between the atoms having the largest coefficient in the HOMO and LUMO. • A pair of molecular orbitals having the same phase leads to the bond formation. The orbital pair

generates a new bonding molecular orbital. • A pair of molecular orbitals, whose phases are different from each other, leads to the generation

of an antibonding molecular orbital. K. Fukui, J. Chem. Phys. 1952, 20, 722.

3) Applications of FMO theory (i) Thermal [4+2] cycloaddition

Possible HOMO–LUMO interactions • The interaction between HOMO of 1 and LUMO of 2 in TS.

The orbitals on C1 and C4 overlap those on C6 and C5 with the same phase in TS,

respectively. Therefore, the thermal cycloaddition is ‘allowed’.

• The interaction between LUMO of 2 and HOMO of 1 in TS.

As with the interaction between HOMO of 1 and LUMO of 2, the orbitals on C1 and C4

overlap those on C6 and C5 with the same phase, respectively. However, this orbital interaction scarcely affects common Diels–Alder reaction. The inverse-electron-demand Diels–Alder reaction was governed by this interaction.

(ii) [4+2] Photocycloaddition • In photo-induced pericyclic reaction, one of the substrates (diene or dienophile in Diels–Alder

reaction) is excited by the photo-irradiation. In the excited molecule, an electron in HOMO transfers to LUMO, giving two SOMOs.

• The higher and lower SOMOs interact with the LUMO and HOMO of the other substrate, respectively.

• In frontier molecular orbital theory, the interaction between HOMOs or LUMOs must be

considered for photo reactions.

In both HOMO–HOMO and LUMO–LUMO interactions, the orbital on C4 overlaps that on

C5 with the same phase. Meanwhile, the orbital on C1 overlaps that on C6 with the opposite phase. Therefore, the photocycloaddition is ‘forbidden’.

antibonding

bonding

E

•••••••

ψ1

ψ2

ψ1

ψ2

ψ3

ψ1

ψ2

ψ3

ψ4

ψ1

ψ2

ψ3

ψ4

ψ5

ψ1

ψ2

ψ3

ψ4

ψ5

ψ6

OHC+

CHO1 2

OO

HOMO (1) LUMO (2) CHO12

3 4 567

OO

LUMO(1) HOMO (2) CHO12

3 4 567

HOMO

LUMOhν

1 1* 2exciplex product

OO

LUMO (1*) LUMO (2)

12

3 4 567 No Reaction

OO

HOMO (1*) HOMO (2)

12

3 4 567 No Reaction

Page 30: Advanced Organic Chemistry III 1. Stereochemistry of ...• The chirality is seen in some spiro bicyclic compounds and alkylidene cycloalkanes. (c) Planar chirality • Planar chirality

– 30 –

(c) Woodward–Hoffmann Rule A ground-state pericyclic change is symmetry-allowed when the total number of (4q+2)s and

(4r)a components is odd (q, r = integral number). R. B. Woodward, R. Hoffmann, Angew. Chem. Int. Ed. 1969, 8, 781.

• Here, ‘components’ means a bond or orbital taking part in a pericyclic reaction as a single unit. e.g. s2a p4s w0s etc. (molecular orbital)(Number of electrons)(reaction manner)

1) Procedure for using Woodward–Hoffmann rule � Draw the equation of the pricyclic reaction including its TS. � Choose all components (bonds or orbitals) involved with the pericyclic reaction. � Assign each component to p, s, or w. (non-essential)

p: p bond s: s bond w: single orbital (e.g. lone pair or carbocation)

� Count the number electrons in each component. � Assign each component to s or a.

• p component s (suprafacial): The component forms new two bonds on

the same face at both ends. a (antarafacial): The component forms new two bonds on

opposite faces at both ends. • s component

s (suprafacial): The component forms new two bonds with the large lobe of sp3 orbital on each atom.

a (antarafacial): The component forms a bond with the large lobe of sp3 orbital on an atom. On the other atom, the small lobe of sp3 orbital is used for the formation of another bond.

• w component This component can participate in either a suprafacial or antarafacial manner.

� Count the number N of (4q+2)s and (4r)a components. • Thermal reaction

If N = odd, the pericyclic reaction is allowed. If N = even, the pericyclic reaction is forbidden. • Photoreaction

If N = even, the pericyclic reaction is allowed. If N = odd, the pericyclic reaction is forbidden. 2) Applications of Woodward–Hoffmann rule

(i) Diels–Alder reaction

This reaction is classified into [p4s + p2s] cycloaddition. N = 1 (p2s) � allowed (thermal)

(ii) retro Diels–Alder reaction

This reaction is classified into retro [p2s + s2s + s2s] cycloaddition. N = 3 (p2s, 2�s2s) � allowed (thermal)

(iii) [2+2] cycloaddition

This reaction is classified into [p2s + p2s] cycloaddition. N = 2 (2�p2s) � forbidden (thermal)

(d) Electrocyclic Reaction 1) Electrocyclic reaction of neutral molecules

• All electrocyclic reactions are allowed thermally as well as photochemically. • Photocyclization proceeds in opposite stereochemistry to the corresponding thermal cyclization.

• An electrocyclic reaction is classified into disrotatory or conrotatory reaction from the viewpoint

of stereochemistry. • In disrotatory reactions, one group rotates clockwise and the other group rotates anti-clockwise.

a

bc

d

e f

g h+

b a

f

d

h

e

gc

c

d

a

b

gf

h

e

‡π4s

π2s

b a

f

d

h

e

gc

=σ2s

σ2s

π2s+

a b

c d

a b

c d+

a b

c d

a b

c d

‡a

c c

ab b

d dπ2s π2s

Ph

PhΔ

Ph

Ph

OO O

O

Ph

Ph

O

O

H

H

R'O

Me

RMeΔ hν

R'O

Me

RMe

R'O

Me

RMe

HH

–10 °C, 30 h 20 °C, 8 hH

H

9 °C, 155 h 40 °CH

H

suprafacial antarafacial

suprafacial antarafacial

Page 31: Advanced Organic Chemistry III 1. Stereochemistry of ...• The chirality is seen in some spiro bicyclic compounds and alkylidene cycloalkanes. (c) Planar chirality • Planar chirality

– 31 –

• In conrotatory reactions, the two groups taking part in the bond formation or cleavage rotate in the same direction: both clockwise or both anticlockwise.

2) Woodward–Hofmann rule in electrocyclic reaction

• Disrotatory reaction is suprafacial. Conrotatry reaction is antarafacial.

equation thermal reaction photoreaction

4e system

con close: [p4a] open: [p2s + s2a]

dis close: [p4s] open: [p2s + s2s]

6e system

dis close: [p6s] open: [p4s + s2s]

con close: [p6a] open: [p4s + s2a]

8e system

con close: [p8a] open: [p6s + s2a]

dis close: [p8s] open: [p6s + s2s]

con: conrotatory, dis: disrotatory

• Any electrocyclic reactions are symmetry-allowed. However, the reaction is restricted by steric or geometrical reason. (e.g. formation of trans-olefin etc.)

3) Electrocyclic reaction of ionic molecules

• Ring-opening [w0a + s2s] electrocyclic reaction

• Nazarov cyclization ([p4a] electrocyclization)

This reaction can be regarded as the electrocyclic reaction of pentadienyl cation.

• Ring-opening [p4s + s2s] electrocyclic reaction

In this reaction, the allyl anion moiety is 4p-electron component.

(e) Sigmatropic Rearrangement 1) [m,n]-Sigmatropic rearrangements

[3,3]-Sigmatropic (Cope, Claisen) rearrangement

Structure of TS

• Chair-form is commonly preferable to boat-form. • When the dissociating bond in TS is treated as s2s, this rearrangement is [s2s + p2s + p2s], in

which N = 3. The thermal sigmatropic reaction is symmetry-allowed. • When the dissociating bond in TS is treated as s2a, this rearrangement is [s2a + p2a + p2s], in

which N = 1. The thermal sigmatropic reaction is symmetry-allowed. Stereochemistry of Cope rearrangement

[2,3]-Sigmatropic (Wittig) rearrangement

R

R

R

R

conrotatory

disrotatory

R

RR

R

D

D

D

D

D

H

D

H180 °C

H H

D

D

H

H

Cl– Cl–

H

H

+

+ ClCl–Cl=

OMe3Si OMe3Si FeCl3–

+FeCl3

H H

OMe3SiFeCl3–

+

O

H H

H

Ph Ph

NaOR

Ph Ph

Ph Ph

Ph Ph Ph Ph

or

1

1'

m

n

1

1'

m

n

[m,n]

O O

π2s π2s

σ2s

π2s π2s

σ2s

chair-form boat-form

180 °C

18 h

‡E

E

‡ E

Z

240 °C

24 h

97%

97%

‡ E

Z

‡E

E

OPh

BuLi

OPh– Ph

σ2s

π2sω2s

Ph OH

Page 32: Advanced Organic Chemistry III 1. Stereochemistry of ...• The chirality is seen in some spiro bicyclic compounds and alkylidene cycloalkanes. (c) Planar chirality • Planar chirality

– 32 –

• This rearrangement is [s2s + p2s + w2s], in which N = 3. • If the [2,3]-rearrangement proceed through the corresponding benzyl cation intermediate, it will

be [s2s + p2s + w0s], in which N = 2. The reaction will be symmetry-forbidden. 2) [1,n]-Sigmatropic hydrogen shifts

• The [1,n]-hydrogen shift is possible to proceed through either suprafacial or antarafacial

pathway. The stereochemistry of the product depends on the reaction pathway.

Stereochemistry of [1,n]-hydrogen shift in Woodward–Hoffmann rule • The [1,n]-sigmatropic hydrogen shift is [s2s + p(n–1)s] or [s2s + p(n–1)a]. • The C–H bond participating in the reaction is always s2s. • If n = 4p + 1, the reaction proceeds through suprafacial

pathway. • If n = 4p – 1, the reaction proceeds through antarafacial

pathway. • Symmetry-allowed [1,n]-hydrogen shifts may be restricted by steric or geometrical reason.

equation thermal reaction photoreaction

[1,3]-H shift

a [s2s + p2a] s [s2s + p2s]

[1,5]-H shift

s [s2s + p4s] a [s2s + p4a]

[1,7]-H shift

a [s2s + p6a] s [s2s + p6s]

[1,9]-H shift

s [s2s + p8s] a [s2s + p8a]

a: antarafacial, s: suprafacial

Examples

• Suprafacial pathway in [1,5]-sigmatropic hydrogen shifts was proved by the observed

stereochemistry of the rearrangement product.

• Antarafacial pathway in [1,7]-sigmatropic hydrogen shifts was proved by the observed

stereochemistry and deuterium distribution of the recovered substrate. 3) [1,n]-Sigmatropic alkyl shifts

• Antarafacial pathway is allowed for the s component in [1,n]-alkyl shifts, while [1,n]-hydrogen shift limits the s component to suprafacial.

[1,3]-Sigmatropic alkyl shift

• [1,3]-Sigmatropic alkyl-shift is possible to proceed, but the stereogenic center on the alkyl group

inverts. Stereochemistry of [1,n]-alkyl shift in Woodward–Hoffmann rule • In thermal reaction with 4p+2 electron system, the configuration of the stereogenic center in R is

retained when R suprafacially migrates to the reaction terminus (si, ar). • In thermal reaction with 4p electron system, the configuration inverts when R suprafacially

migrates to the reaction terminus.

H

R

H

R R

H

[1,5]-hydrogen shift [1,7]-hydrogen shift

R

H

HH

H

a

b

path a path b

suprafacial antarafacial

H H13

H1

5 H

H1

7 H

H1

9 H

DEtHMe Me

Me MeH

DEtR E E S =

Me HD

MeEt

MeEtDMe H=

MeMeEtD H

Et HMe

MeZ R R Z

D

Me HMe

DEtE R

not observedEt Me

HDMe

Z S

RDHMe

OH

MeR

D

OH

MeMeH RH

MeD

OH

Me

de

acb

σ2s

π2s

e

d

a

c b

[σ2s + π2s] symmetry-forbidden

de

acb

σ2sπ2a

e

d [σ2s + π2a] symmetry-alloweda c

b(but sterically impossible)

de

acb

σ2a

π2s

e

d

a

cb [σ2a + π2s] symmetry-allowed

Hπ4s

σ2sHπ6a

σ2s

Page 33: Advanced Organic Chemistry III 1. Stereochemistry of ...• The chirality is seen in some spiro bicyclic compounds and alkylidene cycloalkanes. (c) Planar chirality • Planar chirality

– 33 –

• In thermal reaction with 4p electron system, the configuration is retained when R antarafacially migrates to the reaction terminus.

equation thermal reaction photoreaction

2e system

sr ai

[s2s + w0s] [s2a + w0a]

sr ai

[s2s + w0a] [s2a + w0s]

4e system

si ar

[s2a + p2s] or [s2a + w2s] [s2s + p2a] or [s2s + w2a]

sr ai

[s2s + p2s] or [s2s + w2s] [s2a + p2a] or [s2a + w2a]

6e system

sr ai

[s2s + p4s] [s2a + p4a]

si ar

[s2a + p4s] [s2s + p4a]

8e system

si ar

[s2a + p6s] [s2s + p6a]

sr ai

[s2s + p6s] [s2a + p6a]

p component: a ··· antarafacial, s ··· suprafacial s component: r ··· retention, I ··· inversion

Examples

R+[1,2]

R–

R[1,2] R+

[1,3] [1,4]

R–[1,4] R [1,5] R + [1,6]

RR – [1,6] [1,7] R+

[1,8]

D

OAcAcOD

H

H inversion

D

HRD

D

RD

H DR

D

H

[1,3]

[1,5] [1,5]

H

D

R

D

R

H D

DR

D

D

H