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Tandem Reaction Sequences
Chris Borths
MacMillan Group Meeting
November 21, 2000
I. Cationic Transformations
II. Anionic Transformations
III. Pericyclic Transformations
IV. Metal-catalyzed Transformations
Reviews: Ho, T.L. Tandem Organic Reactions; Wiley: New York, 1992. Tietze, L.F.; Beifuss, U. Angew. Chem. Int. Ed. Engl. 1993, 32, 131. Tietze, L.F. CHem. Rev. 1996, 96, 115.
Why Tandem Reactions?
Practical Considerations
! Reduction of waste
! Avoids isolation of intermediates
! Reduces labor, time to effect given transformation
Academic Considerations
! Builds a large degree of complexity in one transformation
! Novel avenues of research, new reaction development
! A tandem reaction is a reaction in which several bonds are formed in sequence without
isolating intermediates, changing reaction conditions, or adding reagents.
A Definition:
Polyene Cationic Cyclization
CF3CO2H
CH3CHF2
-30 ºC
Me
Me
HOMe
OO
O
O
O
O+
H
Me
H
H
H
Me
Johnson, W.S. Angew. Chem. Int. Ed. Engl. 1976, 15, 9.Fish, P.V.; Johnson, W.S. J. Org. Chem. 1994, 59, 2324.
Me
H2O
MeMe
+
MeMe
OO
O+
O
O
O
O
H
Me
H
H
H
Me
! Acetals and allylic alcohols are good initiators
! Only one out of 32 possible diastereomers formed
! Double bond geometry controls stereochemistry of
product
! Vinyl fluorides can increase yield by stabilizing
intermediate carbcations
H2O
65% yield
Mannich-Cation Olefin Cyclization
N
SO2Ar
NH
TMS
CH2O
40 ºC
63% yield
NN
H
H
NN
H
H
O
H
(±)-Yohimbone
6 steps
N
SO2Ar
N
TMS
N
SO2Ar
N
TMS
+ +
Grieco, P.A.; Fobare, W.F. J. Chem. Soc. Chem. Commun. 1987, 185.
! Allylsilanes are common
terminators of cationic olefin
cyclizations
! This is the first example of an
iminium ion as the initiator
Cascade Polyether Cyclization
O
BnO
Me
Me
OBz
MeOMe H
O
O
DEIPS
O
MeO
Me
Me
O
OPMB
OO
O
HO
Me
O
OH
MeOH
OBz
Me
BnO
Me
Me
Me
OPMB
OO
O
HO
Me
O
OH
Me
OBz
Me
BnO
Me
Me
Me
OPMB
OMe H
C1 - C22 of Etheromycin
HCl
30% yield
PPTS(MeO)3CH
MeOH
51% yield
R
OR3Si
O O
Me
OMe
+OMe
OPMB
H
Paterson, I.; Tillyer, R.D.; Smaill, J.B. Tet. Lett. 1993, 34, 7137.Review: Koert, U. Synthesis 1995, 115.
DEIPS = diethylisopropylsilyl
! Stereochemistry of epoxide determines the stereochemistry of the polyether
Diastereoselective Ugi Reaction
Linderman, R.J.; Binet, S.; Petrich, S.R. J. Org. Chem. 1999, 64, 336.
N
C
OTBS +ZnCl2, THF, -78 °C, 3 d
O
OPivPivO
NH2PivO
OPiv
TBSO
NH
O
R
NSug* CHO
O
O
R
NH3ClNH3Cl
HO
O
R
NH3Cl
H+
31-99% yield
d.r. yield
Ph
CH2CH(CH3)2
(CH2)4CO2CH3
Bn
(CH2)2CF=CHC6H5
90 : 10
97 : 3
98 : 2
98 : 2
98 : 2
61%
80%
80%
85%
65%
! The opposite enantiomer can be accessed by using
a different sugar auxiliary. Diastereoselectivities are
similar (90:10 - 96:4); yields are lower (48 - 76%).
Ugi Coupling
+ HCO2H
RCHO
R
Ugi Reaction Mechanism
Linderman, R.J.; Binet, S.; Petrich, S.R. J. Org. Chem. 1999, 64, 336.Ugi, I. Angew. Chem. Int. Ed. Engl. 1962, 1, 8.
ArNC
HCO2-
R H
OH2N Sug*+
R H
NSug*
ZnCl2
R H
NSug*
HNSug*
RN
ArO
HN
Sug* R
N
Ar
O
HN
O
RH
Sug*
NAr
O
N
N
O
Ar
RH
Sug*
H
O~H+ N
NH
O
Ar
R
H
O
Sug*
N
C
OTBS +ZnCl2, THF, -78 °C, 3 d
O
OPivPivO
NH2PivO
PivO
TBSO
NH
O
R
NSug* CHO
+ HCO2H
TBSO
NH
O
R
NSug* CHO
Cl2Zn
+H+
Tandem Knoevenagel Diels-Alder Reaction
O
O C5H11
MeMe
Me
CHO
O
O C5H11Me Me
Me
100 °C
65% yield
O
C5H11
Me
Me
O
Me
O C5H11
O
Me
H
H
Me
MeO C5H11
OH
Me
H
H
Me
Me
i) LDA, PhSeBr
ii) MCPBA
+ Knoevenagel
[4+2]
46% yield
(+)-Hexahydrocannabol
Tietze, L.F.; Kiedrowski, G.; Berger, B. Angew. Chem. Int. Ed. Engl. 1982, 21, 221.
! The Diels-Alder reaction is controlled by the chiral center in citronellal.
! The product is a 2:1 (!:") mixture of diastereomers at the alkyl chain.
RCHO
Tethered Biginelli Condensation
McDonald, A.I.; Overman, L.E. J. Org. Chem. 1999, 64, 1520.Coffey, D.S.; McDonald, A.I.; Overman, L.E.; Rabinowitz, M.H.; Renhowe, P.A. J. Am. Chem. Soc. 2000, 122, 4893.
R Me
NH
O
H2N Me i) O3, Me2S
ii) morpholine-HOAc (1:1.1)
Na2SO4, 70 °C
MeR1O2C
O OTBS
N
NH
OTBSCO2R1
O
R
HH Ptilomycalin A
Crambescidin 657
Neofoliispates 2
Crambescidin 800
RO
NH
O
H2N
H
CO2R1
ONH
NH2O
alkyl~H+
N
R
R
H HCO2R1
NH2
OO
alkyl
-H2ON
NH
alkyl
CO2R1
O
R
HH
O3, Me2S
uncharacterized
complex mixture
! Both cis and trans product can be accessed
based on rxn conditions and guanidine
equivalent
!
Knoevenagel
NH
X NH2
R When X=NH2+, trans product is formed
When X=O, cis product is formed
Tandem Radical Cyclization
Curran, D.P.; Kuo, S.C. J. Am. Chem. Soc. 1986, 108, 1106.
OO
MeMe
Br
MeBu3SnH
! The stereochemistry of the
vinyl bromide does not affect
reaction outcome
! Direct cyclization of the !,"-
unsaturated ketone is possible,
but favors the !-methyl
diastereomer 3:1. The cyclic
acetal shields the endo face of the
bicyclic system and favors the "-
methyl diastereomer.
OO
Me
Me
Me
OO
Me
Me
OOHMe
Me
OOHBu3Sn H
2.5 : 1 d.r.
65% yield
Me
Me H
Me
Me
Me
Me
Me
Me
1) H3O+
2) NH2NH2
66 - 80% yield?
(±)-Siliphiperfol-6-ene
A Biomimetic Cyclization
Me
Me
Me
BnO
HO
HO
H
i) Swern
ii) NH3
iii) HOAc, 70 ºC
82% yield MeHN
Me
OBn
Swern
Me
Me
Me
BnO
O
O
H
NH3
Me
Me
Me
BnO
N
H HOAc
r.t
MeN
Me
Me
OBn
70 ºC
Imino-ene reaction
Isolated intermediates
Heatchcock, C.H. Angew. Chem. Int. Ed. Engl. 1992, 31, 665.
Diels-Alder
H
H
Tandem Michael Reaction
NHBnHO
O2NMe
r.t.
quant. yield+
NBn
HO NH
HO2C
MeHO2CEtO2C Me
O2N
(-)-!-Kainic Acid
Formal
Synthesis
NH
HO
CO2Et
NMe
Bn
O
O-
+
N
Bn
EtO2C
CO2Et
-H+Me
N
O
O-
-
+
+H+
Barco, A.; Benetti, S.; Pollini, G.P.; Spalluto, G.; Zanirato, V. J. Chem. Soc. Chem. Comm. 1991, 390.
! Nitro group used as a
removable electron-withdrawing
group
BrMgO
Tandem Alkylation, Oxy-Cope, Cyclization
O
CO2Me
O
PMB
5
Me
BrMg Me
OO
OMOM
O
O
OPMB
Me
5
OMOM
Me
O
O2
53% yield
Chen, C.; Layton, M.E.; Sheehan, S.M.; Shair, M.D. J. Am. Chem. Soc. 2000, 122, 7424.
OPMB
Me
5
RMeO O
Oxy-Cope
BrMgOOPMB
Me
5
RMeO O
Grignard addition Dieckmann cyclization
! Grignard addition sets up an anion-accelerated oxy-Cope which rearranges through a chair transition state
! The enolate resulting from the oxy-Cope spontaneously cyclizes onto the methyl ester
Tandem Fries rearrangement, Cyclization, Deprotection
O
O
Me
5
OMOM
Me
O
O2
Chen, C.; Layton, M.E.; Sheehan, S.M.; Shair, M.D. J. Am. Chem. Soc. 2000, 122, 7424.
! This intermediate was elaborated iinto (+)-CP-263,114.
O
OMOM
MeO
O
TMSOTf
(MeO)3CH
O
O
Me
5
OMOM
Me
O
O2
O
OMOM
TMSOMe
O
O
OMe
5
2
O
O
MeOOO
MeO
OMeTMS
O
MeO
TMS
OMe
5
2
O
OH
MeOO
O
Fries-like
rearrangement
OO
MeO2CMeO2C
MeO2C MeO2C
Tandem Diels-Alder Retro Diels-Alder
136 °C
N
O
O
Me
Me
Me
MeO
Me N
O Me
OMe
Me
MeMeO
O
O
Me
OMe
Me
Me
O
OH
Me
O
Me
Me
O
poor formal
synthesis
136 °C
(±)-Paniculide-A
Jacobi, P.A.; Kaczmarek, C.S.R.; Udodong, U.E. Tet. Lett. 1984, 25, 4859.
- CH3CN
! Intramolecular Diels-Alder reaction assures regiocontrol over
product
! The rest of the synthesis involves several oxidation-reduction
and deprotonation-reprotonation sequences.
Me
Oxy-Cope, Diels-Alder, Retro Diels-Alder
O
O
N
O
MeOH
MeO
Me
O
O
160 ºC O
N
O
Me
Me
Me
O
O
H
N
O
O
Me
HO
MeO
Me
MeMe
O
O
Me
HO
Me O
Me
!-Me 45% yield of Gnididione
"-Me 57% yield of Isognididone
[3,3]
Jacobi, P.A.; Selnick, H.G. J. Am. Chem. Soc. 1984, 106, 3041.
Diels-Alder
Retro
Diels-Alder
- HCN
Me
HO
Me O
MeO
hydrolysis
! Note: Each olefin geometry (E and Z) was prepared selectively and subjected to the reaction conditions
! Oxy-Cope rearrangement proceeds through a chair transition state, possibly stabilized by intramolecular hydrogen bonding.
Analysis of crude reaction mixtures indicated that less than 2% of material rearranged through the boat conformation.
! Regiocontrol over the Diels-Alder reaction was established by geometrical constraints, and the retro Diels-Alder was
entropically favored.
H
N
O
Tandem Oxy-Cope Claisen
O OTIPS
Me
MeMe
[3,3]O OTIPS
Me
MeMe
200 ºC
Me
Me
O
OTIPS
Me
Me
Me
O
OTIPS
Me
Me
Me
O
OMe
Me
1) KF-2H2O
2) CH2N2[3,3]
Me
MeO
OMe
H
(+)-dihydrocostunolide
30% yield
7 steps
Raucher, S.; Chi, K.W.; Hwang, K.J.; Burks, J.E. J. Org. Chem. 1986, 51, 5503.
! Rearrangement shows no evidence of silyl migration. When TBS is the silyl group, the rearrangement is complicated
by silyl migration.
! Both [3,3] rearrangements occur through chair transition states.
Aza-Cope Mannich Reaction
NMe
O
Bn C9H19
Me
NMe
Bn C9H19
O
Me
NMe
Bn C9H19
HO
3 steps
(+)-Preussin
NMe
O
Bn C9H19
MeN C9H19
OH
MeBn
N
C9H19
MeBn
OH
N
MeN
N
MeN
Bn
C9H19
HO
Me
Me
Me
MeOH
MeBn C9H19
OH
MeBn
Me
C9H19
BnHO
MeC9H19
H+
H+
[3,3]
[3,3]
C-C
rotation
C-C
rotation
NMe
Bn C9H19
O
Me
NMe
Bn C9H19
O
Me
NMe
Bn C9H19
O
Me
NMe
Bn C9H19
O
Me
Mannich
Mannich
Mannich
Mannich
80% ee
Deng, W.; Overman, L.E. J. Am. Chem. Soc. 1994, 116, 11241.
favored favored
favored
disfavored
CSA
CF3CH2OH
61 - 68% yield
Tandem Claisen-Ene Reaction
MeO
OMe
PO
HOMe
CO2Me
P = Si
Me
Me
Me
Me
Me
Me
180 ºC
60 h
O
CHOMe
CO2Me
H
H
76% yield
after hydrolysis
+
MeO
O
MePO
MeO2C
OMe
POR
OMe
PO CO2Me
H
H
HPO
H
O
MeCO2Me
H
H
PO
Mikami, K.; Takahashi, K.; Nakai, T. J. Am. Chem. Soc. 1990, 112, 4035.Mikami, K.; Takahashi, K.; Nakai, T.; Uchimaru, T. J. Am. Chem. Soc. 1994, 116, 10948.
MeCO2Me
! Claisen rearrangement proceeds through a chair transition state--evidinced by high 8,14 syn selectivity and the 14S configuration
! Ene rearrangement proceeds through the bicyclic transition state with the A,B ring at a pseudo-equatorial position
8
14
Cascade Aromatic Annulation
Danheiser, R.L.; Cha, D.D. Tet. Lett. 1990, 31, 1527.
MeON2
O
OTIPS
+
OMe
OTIPS
OH
nBu99
nBu
h! O2, TBAF
54% yield 67% yield
OMe
OH
O
nBu9O
O
HMeO
O R
OTIPSMeO
OOMe
R
OTIPS
photochemical Wolff
rearrangement
[2+2] 4 electron electrocyclic
ring opening
Maesanin
6 electron ring closure
and tautomerization
Tandem [2,3] Rearrangement, Diels-Alder
OH
Me
Me
Me
PhSCl
Et3NO
Me
Me
Me
S
Ph
Me
Me
SPh
O
Me
Me
Me
SPh O
Me
S
Me
Me
Ph
O
Me
H
r.t.
38 h
H
H [2,3]
[4+2]
Me
Me
Me
H
H
(+)-Sterpurene70% yield
1) MeMgBr, Ni(dppp)Cl22) Na, NH3, tBuOH
43% yield
Gibbs, R.A.; Okamura, W.H. J. Am. Chem. Soc. 1988, 110, 4062.
! Chirality of secondary alcohol is effectively transferred to the axial chirality of the allene intermediate
! The intramolecular Diels-Alder sets two stereocenters enatio- and diastereoselectively from the allene intermediate
H
Pericyclic Domino Reaction
Iglesias, B.; Torrado, A.; de Lera, A.R. J. Org. Chem. 2000, 65, 2696.
Me
Me Me
MeOH
Me R
Me
S(O)Ph
Me
PhSCl
Et3N
61% yield
OTBS
OTBS
R
Me
O
Me
OTBS
S
Ph
R
Me
Me
OTBS
S(O)PhR
PhS
Me
Me
OTBSO
R
Me
Me
OTBS
OS
Ph
R
R
Me
S(O)PhMe
OTBS
H
A
A
! [2,3]-allyl sulfenate and [2,3]-allyl sulfoxide shifts are reversible. The [1,5] sigmatropic hydride migration is the
stereodifferentiating step in this reaction sequence.
= R
CoCp
CoCp
Cobalt-Mediated [2+2+2] Cycloaddition
N
NHAc
O
CpCo(C2H4)2
C2H4, THF, 0 °C
47% yieldN
O
H
NHAc
CoCp
Eichberg, M.J.; Dorta, R.L.; Lamottke, K.; Vollhardt, K.P.C. Org. Lett. 2000, 2, 2479.
N
N
OH
H
H
Strychnine
8 steps
N
NHAc
O
TMS OMe
CpCo(CO)2
46% yieldN
O
H
TMS
OMe
NHAc
N
BnN
O
CpCo(CO)2
40% yield
1:1 syn:anti
N
O
H
BnN
! Cyclization tolerates a wide range of
functionality as olefin equivalents
C C C CC N
C O N C O
Nickel-Catalyzed [2+2+2] Cyclizations
O
Ph Ph
O
Me
HPh
O
Me
O
Ph
75% yield
Ni
H
Ph
O
Ph
O
Me
Ni
Ph
HPh
O
Me O
L
L
20 mol% Ni(COD)2
100 mol% PPh3
Montgomery, J.; Seo, J. Tetrahedron 1998, 54, 1131.Seo, J.; Chui, H.M.; Heeg, M.J.; Mongomery, J. J. Am. Chem. Soc. 1999, 121, 476.
Ni
PhO PhLnLn
O
Ph
10 mol% Ni(COD)2
tBuLi, ZnCl2
HPh
O
52% yield
+
! Radical mechanism eliminated as a possibility due to high stereoselectivities of products in model systems.
! E and Z enones yield same product stereochemistry.
H
NiOPh Ln
Ph
Nickel-Catalyzed Cyclization
O X
O
N
O
OTBS
NO
O
MeMe
Ni
N
O
O
X
O
OTBS
Ln
N
O
O
LnNi OTBSMe2AlO
X
Me
N
O
O
Me OTBSO
X 4 steps
NH
Me
HO2C
HO2C
(+)-!-allokainic acid
AlMe3
Ni(COD)2
10 mol% Ni(COD)2
300 mol% AlMe3
Chevliakov, M.V.; Montgomery, J. J. Am. Chem. Soc. 1999, 121, 11139.Seo, J.; Fain, H.; Blanc, J.B.; Mongomery, J. J. Org. Chem. 1999, 64, 6060.
73% yield
>97:3 d.r.
! Metallocycle formation proceeds through a transitions state with all substituents in a pseudo-equatorial configuration
! Unsaturated acyl oxazolidinones show greater reactivity and selectivity than unsaturated esters.
COX
NOTBS
H
O
O
NiLn
Palladium Polyene Cyclization
PhO2S
PhO2S
OMe
OMe
PhO2S
PhO2S
HPd(OAc)(SbPh3)2
PhO2S
PhO2S
OMe
PdHLn
R
PhO2S
PhO2S
H
OMe
PdLn
R
OMe
PhO2S
PhO2SR
PdLn H PdLn
2.5 mol% (dba)3Pd2CHCl310 mol% HOAc
10 mol% SbPh3
65 °C
77% yield
Trost, B.M.; Shi, Y. J. Am. Chem. Soc 1993, 115, 9421.Review: Overman, L.E.; Abelman, M.M.; Kucera, D.J.; Tran, V.D.; Ricca, D.J. Pure Appl. Chem. 1992, 64, 1813.
6
! The geometry of the double bonds controls the ring-fusion geometry. 1,1-disubstituted olfins form spiro ring systems - 1,2-disubstituted olefins form fused ring systems.
! The two new bonds formed with the "-system are cis to one another due to the syn addition of the Pd species.
! This tandem cyclization process can be initiated by an alkyne in the presence of HOAc or by a vinyl halide.
= X
Enantioselective Heck-Anion Addition
OTf
Me
2.5 mol% [Pd(allyl)Cl]26 mol% (S)-BINAP
200 mol% NaBr
77% yield
87% ee
TBDPSO CO2Et
CO2Et
-
Na+
H
Me
CO2EtEtO2C OTBDPS
8 stepsH
Me
MeMe
H
H
(-)-Capnellene
Me
Pd
PP
*H
MePdLn*
R R
-
! Heck reaction is
enantiodifferentiating
! Nucleophile adds to less hindered
carbon
! Wide range of soft nucleophiles will
add to the !-allyl Pd species
Oshima, T.; Kagechika, K.; Adachi, M.; Sodeoka, M.; Shibasaki, M. J. Am .Chem. Soc. 1996, 118, 7108.
H
Me
PdLn*
Na+
Enantioselective Michael Aldol
O
BnO2C CO2Bn
Me
O
HCO2Me
5
5 mol% catalyst4.5 mol% NaOtBu O
O
O
OAl
Li
catalyst
O
CMe(CO2Bn)2
HCO2Me
OH
5
84% yield
92% ee
6 : 1 - 17 : 1 d.r
O
O
O
OAl
Li
O
Nu
Na
O
O
O
OAl
Li
O
Nu
Na
Yamada, K.; Arai, T.; Sasai, H.; Shibasaki, M. J. Org. Chem. 1998, 63, 3666.
! Enantioselectivity is determined in the Michael addition.
! When simple malonates were used as nucleophiles, low yields resulted.
Enantioselective Tandem Mukaiyama Aldol Reaction
OTBS
Me
O
H CO2Me2
10 mol% TiCl2(OiPr)2
10 mol% (R)-BINOL
CH2Cl20 ºC, 3 h
+MeO2C CO2Me
OH OHO
1 : 4 E : Z
MeO2C CO2Me
OH OHOTBS
77% yield
>99% de
>99% ee
HCl
MeOH
OTBS
Me
MeO2C
OH OTBS
MeO2C
OH OTBS
(S)
MeO2C CO2Me
OH OHO
MeO2C CO2Me
OH OHO
MeO2C CO2Me
OH OHO
(R,R)
meso
(S,S)
kR = 129
kS = 1
kR,R = 3.4
kR,S = 0.1
kS,R = 17
kS,S = 1
Mikami, K.; Matsukawa, S.; Nagashima, M.; Funabashi, H.; Morisima, H. Tet. Lett. 1997, 38, 579.
! ee of major product of
first reaction amplified
! minor product of first
aldol converted into
meso product
preferentially
Tandem Sakurai Ene Reaction
MeOtBu
Me
TMS
O
Me
d.r. 1:1:1:0.1
TMSOTfMe
OtBu
MeMe
O
H
TMS
TMS
Me
OtBu
MeMe
O
H
TMS
TMS
Me
OtBu
MeMe
O
H
TMS ~H+
OtBu
Me
OMe
OtBu
Me
OMe
H
TMS
Me OtBu
H
H
H
TMS
HMe
HO
Sakurai
52% yield
Ene
Tietze, L.F.; Rischer, M. Angew. Chem. Int. Ed. Engl. 1992, 31, 1221.
! High diastereoselectivity of the tandem sequence was observed when a mixture of all four olefin isomers was
submitted to the reaction conditions.
(R)
Prins-Pinacol Reaction
CHO
TIPSO
Me
Me
Me
HO
OH
TMS
p-TsOH•H2O
MgSO4
76% yield
Me
Me
Me
O
O
TMSTIPSO
+10 mol% SnCl4
88% yield
O
Me
CHMe2
O
Me
OTIPS
TMS
Cl4Sn
O
Me
CHMe2
O
Me
OTIPS
TMS
Cl4Sn
O
Me
Me
MeHOHC
Me
OTIPSTMS
HH
O
Me
MeH H
O
H H
Me
Me
HO
alleged structure of
Sclerophytin AOverman, L.E.; Pennington, L.D. Org. Lett., 2000, 2, 2683.for a previous example: MacMillan, D.W.C.; Overman, L.E. J. Am. Chem. Soc. 1995, 117, 10391.
Prins Pinacol
! Diastereomeric mixture yielded only one diastereomer of the product under reaction conditions.
! no olefin isomerization was observed
Tandem Acyl-Claisen Rearrangement
ClR2
O10 mol% Yb(OTf)3
i-Pr2EtN, CH2Cl2N
N
R1
O
O
+
excess
N N
O
R2
R1
R2
O
O O
R1
Me
Cl
CN
SPh
OBz
Me
Me
Me
yield
97%
96%
81%
70%
86%
98%
97%
100%
d.r.
97:3
>95:5
>95:5
93:7
91:9
95:5
97:3
94:6
R2
Me
Me
Me
Me
Me
NPhth
OPv
Bn
Dong, V.M.; MacMillan, D.W.C. unpublished results.
! The tandem acyl claisen tolerates a wide range of functionality with excellent yields and diastereocontrol.
Tandem Acyl–Claisen Rearrangement: Stereocontrol
ClMe
O 10 mol% Yb(OTf)3
i-Pr2EtN, CH2Cl2N
N
Me
O
O
! Rearrangment via the trans morpholine is favored in the first rearrangement
N
LAO Me
+O
NR2
Me
[3,3]+
N
O
Me
Me
O
N
O
syn
N N
O
Me
Me
Me
O
O O
syn-anti isomer
N N
O
Me
Me
Me
O
O O
syn-syn isomerdisfavored
N
OLAMe
+
OMe
H
NR2O
Me
H
N
LAO Me
+O
favored
HMe
Me
O
NR2favored
intermediate
ClMe
O
2nd equiv.
! A1,2 strain controls the second rearrangement
Amino-Thio Tandem Acyl-Claisen
O
N
Me
Me
SiPr
O
ClR
20 mol% TiCl4, iPr2EtN
-30 °C, 1 d
N
O
Me
SiPr
RCl4TiO
Me
N SiPr
O
O
R
Me
Me
O
ClOTBDPS
5 eq. Me2AlCl, iPr2EtN
-50 °C, 4 d
N
O
O
SiPr
O
R
Me
OTBDPS
Me
Seo, J.; MacMillan, D.W.C. unpublished results."Felkin-Anh" control in a [3,3] rearrangement: Hatakeyama, S.; Saijo, K.; Takano, S. Tet. Lett. 1985, 26, 865.
yield d.r. (syn, anti, anti):(syn, syn, anti)
Me
OTBDPS
OBn
83%
80%
80%
12 : 1
9 : 1
7 : 1
Me
R(iPr)
HS
Me Me
R(iPr)
H MeS
OLATBDPSO
LAO
iPr
OTBDPS
favored disfavored
! Stereochemistry of first rearrangement is controlled by a chair transition state
! Stereochemistry of second rearrangement is dictated by "Felkin-Anh" type control
! When the OTBDPS group on the second acid chloride is substituted with a smaller substituent, the
diastereoselectivity decreases
iPr
R
The Conclusion Slide
! There are many tandem reaction sequences, grouping together almost any pair of reactions with compatable reaction
conditions.
! Tandem reactions are typically calssified by the mechanism of each step.
! There are few enantioselective tandem reactions.
! Tandem reaction sequences can quickly build significant complexity into a molecule.
