Comparative Strategies in Natural Products Synthesis

Bordeaux I University Stéphane Quideau, Ph.D.Centre de Recherche en Chimie Moléculaire Laboratoire de Chimie des Substances végétales

1

Comparative Strategies in Natural Products Synthesis

Université Bordeaux 1Master de Chimie (CO-3)

Stéphane Quideau, Ph.D.Institut Européen de Chimie et Biologie

&Laboratoire de Chimie des Substances Végétales

Centre de Recherche en Chimie MoléculaireUniversité Bordeaux 1

[email protected] : 05-40-00-30-10Cel : 06-62-91-65-51

The objective of this course is to provide graduate students majoring in chemistry with a strengthenedknowledge of organic synthesis. The student will utilize his/her knowledge of organic reactions,mechanisms, and controls to critically and comparatively study the challenges of natural productssynthesis. Toward this objective, total syntheses of various targets accomplished by different researchgroups over the years will be discussed. The different synthetic strategies will be compared via aretrosynthetic analysis approach (i.e., topological disconnection path to starting materials). The differenttactics (i.e., choice of reactions and combinations thereof) will be discussed by highlighting the key steps ofthe actual syntheses.

Targets: Camptothecin, Biotin, Denticulatins, Dynemycin A , Dysidiolide, Epothilones, FK-506,Quadrone, Strychnine, Zaragozic Acids, Taxol.

Suggested Readings and Reference Sources:• E. J. Corey and Xue-Min Cheng, The Logic of Chemical Synthesis, Wiley.• K. C. Nicolaou and E. J. Sorensen, Classics in Total Synthesis, VCH.• Tse-Lok Ho, Tactics of Organic Synthesis, Wiley.• A. Koskinen, Asymmetric Synthesis of Natural Products, Wiley.• S. Warren, Designing Organic Synthesis, Wiley.• S. Warren, Organic Synthesis, The Disconnection Approach, Wiley


2

• Strategies and Tactics in Organic Synthesis (volume series).


3

General Guidelines

A. Convergent / linear synthesis

9

92 20vs.

better not so good

The overall yield is a function of the yield of every steps !

eg, 10 steps95% each 0.9510 = 60%90% each 0.9010 = 34%70% each 0.7010 = 3%

B. Timing of bad risky steps early middle late1 3 2

C. sp2 centers vs. sp3 centers available less available, but stereogenic centers ⇒ Diels-Alder

ClaisenCarbonyl addition

D. Intra/intermolecular reactions

Intramolecular bond forming reaction have entropic and stereochemical/conformational advantages!

E. Double diastereodifferentiation

RO

HMe

OMR'

OH+

Si/Re5/1 (inherent preference)

Si/Re1/5

R

Me

OHR'

Me OH

O

R

Me

R'

OH

O

reflects both inherent preferences

+ 25/1

OH

Me

NB: This estimate does not take into account kinetic resolution


4

F. Enantiomeric excess

definition = (d% - l% / d% + l%) x 100

Coupling chiral, scalemic (not racemic) fragments

A + B → C ee?

90% ee

90% ee

95/5 d/l

dd 0.95 x 0.95 = 0.90dl 0.95 x 0.05 = 0.05 (separable diast.)ld 0.05 x 0.95 = 0.05 (separable diast.)ll 0.05 x 0.05 = 0.0025

⇒ ee = 90/025 ⇒ 360/1 ⇒ 99.4%

NB: This estimate does not take into accountkinetic resolution

G. Natural and unnatural polarization of functional groups

Synthetic target may be viewed in terms of their ionic components

R

O

α

β

γ

Nu

R

Oα α carbon is negative!

R

O β

E

β carbon is positive!

Nu

R

O

γ

δ

δ

δ

δ

δδ

δ

Michael 1,4-addition

γ carbon is negative!

BaseR

O

γ

E

Arrays of alternate negative/positive centers are easier to construct!

O

O

δ

δ

δ

δ not so trivial to put together!

Umpolung chemistry, i.e., polarity reversal ⇒ synthetic equivalent with unnatural polarity


5

R

O

acyl anion(not accessible!)

S S

R

S S

R HR

O

HE

H. Topological disconnections to simplify structures ⇒ Retrosynthetic analysis

• E. J. Corey, JACS 1975, 97, 6116 (strategic bond disconnections).• E. J. Corey and Xue-Min Cheng, The Logic of Chemical Synthesis, Wiley.

Perception of strategic bondsThe most desirable bond disconnections in the antithetic manipulation of structure are those in which thefollowing structural features are minimized:

(i) appendages(ii) appendages carrying chiral centers(iii) rings of medium or large size(iv) bridged ringsStrategic bonds (to break in the retrosynthetic manipulation) vs. core bonds (not to break!)

Analysis of Bridged Polycyclic Molecular Networks

Me OH

a b

c d

a b

cd

Me OH Me OH

Me OH Me OH

*

**

*

*

*

**

Rule #1A strategic bond must be in a four-, five-, six- or seven-membered “primary” ring (relatively easy to form)

a secondary six-membered ringenvelope of two fused four membered-ring

A primary ring is one which cannot be expressed as the envelope of two or more smaller rings bridged orfused to one another.


6

Rule #2

A strategic bond must be directly attached to another ring (exo to another ring, except three-membered rings)because a ring disconnection which produces two functionalized appendages leads to a more complex systemthan a ring disconnection that lead to one or no functionalized appendages.

⇒ mimimize appendages on rings!

A1

2

Out of six bonds in ring A, only bonds 1 and 2 can be strategic

Rule #3

To achieve maximal simplification of the cyclic system, strategic bonds should be in the ring (or rings) whichexhibits the greatest degree of bridging.

central four-membered ringof maximum bridging

Disconnection of any bond in that central four-membered ring produces a major network simplification to adecalin system.

The maximum bridging ring is selected from the set of “synthetically significant rings” (all primary rings— Rule #1— plus all secondary rings less than eight membered, ie, those that can be formed from a pair ofsmaller primary rings)

Maximum bridging rings of a molecule are those rings which are bridged at the greatest number of sites.

** *

*How many sitesbridged at?

Rule #4

To avoid the formation of rings having greater than seven members, any bond common to a pair of bridged orfused rings whose envelop is > eight-membered cannot be considered strategic.

The bonds that are eliminated from further consideration by this rule are termed core bonds

a core bondDO NOT BREAK!


7

Exception : when the two fused or bridged rings being examined are directly joined elsewhere by anotherbond.

core bond?No, breaking does not lead to a ten-membered ring, butto two fused six-membered rings!

Rule #5

Bonds within aromatic rings are not considered to have potential strategic character.

Rule #6

If a cyclic arc linking a pair of common atoms (fusion atoms, bridgeheads, or spiro ring junction atoms)contains a chiral carbon atom, then none of the bonds in the cyclic arc may be considered strategic.

⇒ mimimize appendages with chiral centers!

Don’t!

This situation is undesirable because it is difficult to control stereochemistry efficiently at centers onappendages as opposed to centers in rings.

Exception : A bond directly attached to a chiral center can be broken if that center is the only chiral one onthe arc linking the two common atoms

OK!(but again don’t if center 3 is chiral!

Rule #7 : The C-Heterobond Procedure

To the set of strategic bonds determined by rules 1-6, C-X bonds (X = O, N, S) are added!

OHH

1 23

4OHH

* *

12

34

O2NHO

12

34

O2NO


8

“One-Group Transforms”

“Two-Group Transforms”

NB: This analysis is limited to one-bond disconnections. Keep in mind the possibility of bond-pairdisconnecting transforms ⇒ applications of powerful ring transforms [4+2], [2+2], [2+1]

Ref: EJ Corey, JACS, 1974, 96, 7724

O

OH

O

OH

eliminated by rule 2 (not exocyclic)kept by the C-Heterobond procedure

O

FGA 1-GRP

OLG

alkylation

FGA

O

FGI

O OH

2-GRP

aldolO CHO

FGI

O

FGI

O

O

2-GRP

Michael

O

O


9

0Quadrone - “The Taxol of its time”

A. General

• Sesquiterpene (i.e., 15 carbon skeleton) isolated from Aspergillus terreus in 1978• This quadicyclic ketone was viewed as “a popular test of design and execution” for synthetic organic chemists • Four rings, 5 contiguous steregenic centers:

one cis-fused bicyclo[3.3.0]octane subunitone bicyclo[3.2.1]octane subunit4 neopentyl and 1 quaternary (C-1) asymmetric carbonC-1 is common to each four rings!

• Shows cell-growth inhibitory activity:somewhat surprising, since quadrone is devoid of the electrophilicfunctionality common in sesquiterpene antitumor agents

quadrone is actually the progenitor of the α-methyleneketone, terrecyclic acid A

• Antitumor activity against:human epidermoid carcinoma; ED50 = 1.3 µg/mLlymphocytic leukemia in mice; LD50 > 340 mg/kg

NB: quadrone and terrecyclic acid A are the only twonatural products known to possess such a carbon skeleton

B. References

Burke, JACS 1984, 106, 4558See also: Strategies and Tactics in Organic Synthesis , Volume 2, Chapters 2 (Burke) and 5 (Helquist)Kende, JACS 1982, 104, 5808 Danishefsky, JACS 1981, 103, 4136Magnus, JOC 1987, 52, 1483 Wender, JOC 1985, 50, 4418Yoshii, JACS 1983, 105, 563 Wender, Org. Photochem. 1989, 10, 439Schlessinger, JOC1983, 48, 1147 Smith,JACS 1991, 113, 3533

O

O

O

H

13 28

45

6

9

7

10

1211

1314 15

(+)-quadrone

CO2H

O

H

terrecyclic acid Agreater acute toxicity than quadrone itself!


10

C. Retrosynthetic Analysis and Synthesis

Topological disconnection in bridged polycyclic framework (E.J. Corey, JACS 1975, 97, 6116):

1) Identify rings with maximum bridging:look for bridgehead carbons to identify the ring of maximum bridging

2) Identify strategic bonds vs. core bonds:• A strategic bond (i.e., most desirable to break in retrosynthetic analysis) must be within a ring of

maximum bridging• A core bond (i.e., not to be broken in retrosynthetic analysis)

O

O

core bondDo Not Break !

O

• Breaking this core bond would lead to a nine-membered ring ⇒ need for a medium-size ringformation synthetic step (difficult!)

• Any non-core bonds in maximally-bridged ring can be a strategic bond!

O

O

Burke

O

O

CHO

O

O

Kende

O

O

Magnus

CO2Et

TMSO

R

acyclic!

O O O

core bond broken!

O

O

bridging

bridge head bridge head

O

O

O

H

O

O

ring with maximum bridging!

O O


11

The Burke routeJACS 1984, 106, 4558

All new carbon-carbon bonds are formed via intramolecular deliveryRetrosynthetic analysis


12

This is actually (ent)-quadrone

O

O

CHO

O

OO

OO

1

O

CHO

O

key starting materialwith correct stereo. at spiro center!

spiro[4,5]decadienoneBurke, JOC 1981, 46, 2400

Aldol

CHO

O

O

O

O

CHO

O

OH

O

OHC

H

axial! ⇒ contrathermodynamic ⇒ kinetic control

E Nu

retro-Aldol

thermoneutral+ 5 Kcal/mol

E Nu

1

core bond

convexe

concave

retro-Michael

downhill- 20 Kcal/mol

i.e.,

This plan involves a bond formation through the convexe face ⇒ difficult!This was in the first Burke's grant proposal; a referee claimed that such a bond was impossible to make!Burkeet al. found a way (more than 50 sets of conditions were tried...

O

O

CHOMichael

Nu centers = -E centers = +

+

+

+ + We shall see how Burke et al. controlled this reaction!

exo-orientation of CHO, as exo-face slightlyless hindered (not obvious! Burke was concerned about the possibility of having formed the endo-product, for Aldol was difficult to achieve

convexe/exo-face is less hindered!

Synthesis


13

O O

O

CHO

O

O

O

CHO

O

CHO

O

OO

O

electron-rich alkenecould use electrophilic ozone,but degradation problems!

HO

1. OsO4 cat., N-methyl morpholine N-oxide2. NaIO4

TsOH, PhH

O

TiCl4, R4N OCOCF3

H

A

CO2MeH

A

B

B

C

KOH, PhH, refluxdibenzo-18-crown-6

95%

92%

96%remains to build lactone!

not so trivial due to difficulties in forming C-5 enolate regioselectively

HO

TsOH, morpholinePhH, reflux

OO

50 trials withdifferent condition sets

JACS 1984, 106, 4558

O

Danishefsky's intermediateJACS 1981, 103, 4136

axial ⇒ contrathermodynamic: this is not so easy, but Burke provided a solution to complete his formal total synthesis

add 1C

Wharton fragmentationJOC 1961, 26, 3615

H

OO

1. HOCH2CH2OH, TsOH2. t-BuOOH, NaOH, aq. MeOH (epoxidation at α-face because β-face is blocked by the ethano bridge)

H2NNH2.xH2OMeOH–AcOH

OH

5

92%

O

i.e. allylic transposition from enone

Hg(OAc)2, i-Pr2NEt, xylene, Δ


14

O

12

3

1 2

3

allyl vinyl ether ⇒ [3,3] Claisen with sterecontrol!

α-face

[3,3]

CHO

α-faceH2, Pd/C

CHO

axialO

O OO O

O

Danishefsky'sintermediate

56

contains all the target carbons!

formal total Σ total Σ

need to:1. form C5–C6 bond

2. reduce C-6, oxidize C-73. disconnect C-6 and C-7,

then reattach through oxygen togive lactone

7

total synthesis completion

1. aq. HCl2. HOAc–H2SO4 (Aldol)

CHOOO O

AcO 79% (4:1)

400 °Csealed tube

O

O

+

61%

33%

TBSO OHOH

Ag2CO3 – CeliteFetizon's reagent

O

XO

YA: X = O, Y = H, HB: X = H, H, Y = O

92% (1:1)

Jones

(+)-quadrone

19 steps and 6.2% overall yield from spiro [4,5]decadienone


15

The Kende routeJACS 1982, 104, 5808

Pd(II)-mediated cycloalkenylation

Retrosynthetic analysis

CO2MeO

H


O

O

O

CO2Et

TMSO

Synthesis

O O

CO2Me

CO2Et TMSO CO2Et

CO2Et

TMSO HOMe3Si

EtO2C

Pd

OEtO

O

O

O O

1. LiOH (selective ester hydrolysis + decarboxylation)

Pd(OAc)2, CH3CN, rt"Pd"

2. 0.95 equiv. LDA, THF, - 78 °C → - 0 °C(thermo enolate), TMSCl

β-hydrideelimination

oxidationNaH, PhCH3 hydroboration


16

CO2HO

H

O

H

O O

3:1O

CO2H

H

terrecyclic acid A

H melting point!!! quadrone

isoquadrone

O

CO2H

H

HO

mp was for isoquadrone, not quadrone!!!mp changed on second measure ⇒ quadrone!!! (ouf!!!)

14 steps, 2.4% overall

Danishefsky

LDA (3 equiv.), CH2O gas62%

H2, Pd-C

O

CO2H

H

HO

100%

190 -195°C5 min

The Sclessinger routeJOC1983, 48, 1147

Intramolecular Diels-AlderRetrosynthetic analysis

O

CO2HH

O

OO

OH

O

OH

O

O

(+)-quadrone Danishefsky'sintermediate

1 23

4

5

23

45

1 remove 1C

cyclohexene⇒ D.A.

core bond

core bond

Synthesis


17

O

MeO2CI

O

MeO2C

O

OH

NHN

O

OHOO

CO2HO

O

CO2H

H

OH

NN

Cr

OO

OH

O

N

HN

Cr

OOH

ON

NCr

OHOH

O

regioselectivity of allylic oxidation?more stable trisubstituted olefin product !? (thermo control !)Also complex attacks less hinderedface (hydrogen) of molecule!

O

[2,3]

Salmond et al., JOC 1978, 43, 2057-2059

1. LDA (2 equiv.), TMSCl (2 equiv.)2. O3, then NaIO4, CrO3

Hase and McCoySynth. Commun. 1979, 9, 63

"remove 1C"


13 steps, 6% overall

Base (2 equiv.) 1,3-diCO dianion alkylation

1. LiCl, DMSO/H2O (decarboxylation)2. [(CH3)2N]2CHOt-Bu (Brederick's reagent)3. Dibal-H

Diels-Alderprecursor

NaH, xylene, Δ

NN

Cr

OHO

OO

Chem. Ber. 1968, 101, 41

OH

PhCH3, CH3CN120 °C

48%

trans-decalin system!⇒ need to epimerize

to cis-decalin

CrO3

O

"Cr(VI)""Cr(IV)"

"Cr(VI)"

CrOH

OH

"Cr(VI)" O

allylic oxidation via 3,5-dimethylpyrazole•CrO3 complex

NN

break 2 πC=C ⇒ 2x70 Kcal/molgain 2 σC–C⇒ 2x90 Kcal/mol⇒ downhill by 40 Kcal/mol

"Cr(IV)"

HO

cannot collapse to ketone, since no hydrogen to remove!

or "Cr(V)" O

O

[3,3]

nice 1,3-diaxial dispostion for [3,3]i.e., 6-membered TS


18

The Wender routesJOC 1985, 50, 4418

Intramolecular Diels-Alder / Ring Expansion SequenceRetrosynthetic analysis

terrecyclic acidi A

CO2t-BuOCO2H

H

Oring

expansion

CO2t-Bu

OMeCl

LG

cycloaddition

OMe

MeO2C

t-BuO2C

core bond broken!

form core bond!

Synthesis of (+)-desdimethylquadroneOrg. Photochem. 1989, 10, 439

Alkene-Arene Photochemical Coupling - “The Home Run Approach”NB: Only novel development of carbon-carbon bond forming reaction (with Stille coupling)

in the past 25-30 years!Background Analysis

Possibilities of photocycloadditions

ortho para

weird, but so clever!meta


19

mechanism?

hν*

exciplexSynthesis

MeO2C MeO2C MeO2C MeO2CH

H

HMeO2C

H

H

H

HMeO2C

MeO2C

H

H

H

MeO2C HHH

intramolecular meta photocycloaddition

HH

21

H

CO2Me

hν via exciplex3

45

2,66

slightly favored!gives rise to CO2Me in less sterically

favored axial orientation in cycloadduct

1,3

1,5

+ epimer

poor regio- and diastereoselectivity,but highly expeditous synthesis!

versus

exciplex 1

MeO2C

NB: regio- and diastereoselectivity improves when ester group is replaced by more bulky alcohol group (via reduction)

H

H

exciplex 2

2

H3

[1,5]

CO2H

H

5

O

4

OO1

Δ

(+)-desdimethylquadrone


20

Strychnine

A. General

Strychnos alkaloid (poison / rain forest)first isolated from Strychnos ignatii by Pelletier and Caventou (1818)

complex heptacyclic structure (24 skeletal atoms):6 contiguous assymetric carbon centers5 of those are included within one saturated six-membered ring1 is quaternary!7-membered oxygen heterocyclic motif

“For its molecular size it is the most complex substance known”(Sir Robert Robinson, 1952)

B. References

Robinson, Chem. Ind. 1953, 245. Overman, JACS 1993, 115, 9293Woodward, JACS 1954, 76, 4749. Kuehne, JOC 1993, 58, 7490.Wooddward, Tetrahedron 1963, 19, 247. Beifuss, Angew Chem. IEE 1994, 22, 1144.Magnus, JACS 1992, 114, 4403. Rawal, JOC 1994, 61, 7873.Overman, Acc. Chem. Res. 1992, 25, 352 Martin, JACS 1996, 118, 9804.


N

O

N

HO

H

N

O

N

HHO

N

O

N

HO

H

NH

N

HO

H

HO

no obvious disconnection!

Woodward(1954)

First

N

O

N

HO

H

isostrychnine I

"Best"

NNH

corynantheoid alkaloid skeleton

conjugate addition

Biomimetic

OH

Overman(1993)

MeO2C

Wieland-Gumlich aldehyde

H

H

2C introductionlactamization

Martin(1996)

N

O

N

HO

H


21

The Woodward RouteTetrahedron 1963, 19, 247

JACS 1954, 76, 4749.

7-membered ether ring last!Retrosynthetic Analysis

N

O

N

HO

HN

O

N

HHO

isostrychnine I

conjugate addition

N

O

N

HO

H

N

O

N

HO

allylic rearrangement

N

O

N O

O

diastereoselectiveorganometallic

addition

H attack at ketonefrom convex face

amide C=O

ketone C=O

dehydrostrychninone

lactamization

N

O

NH

CHO

Oglyoxal

H

N

O

NH

OH

oxidationneeds epimerization!

N

O

NP

OMe

O

OH Dieckmann

N

CO2R

O

NP

OMe

O1,3-diC=O(enol form)

H H

needs epimerization!

NP

CO2R

NP

CO2Me

Hlactamization

CO2Me

trans

cis

NP

CO2R

NP

OMe

OMe

veratryloxidative cleavage

C–C spiral bondformation

N OMe

OMe

NCO2R

X–P

B

H N OMe

OMeH

OMe

OMeNHNH2

O

+Fischer indolesynthesis

2C/N + 2Cintroduction

phenylhydrazine

acetoveratrone


22

Synthesis

OMe

OMe

NHNH2O

+ Fischer indolesynthesis

phenylhydrazine acetoveratrone

PPA

N OMe

OMeH2

3blocked!

2-veratrylindole

CH2O, Me2NH

Schiff base

aq. AcOHNH

N OMe

OMeH

NMe2

N OMe

OMeH

N

1. MeI2. NaCN, DMF (97% over 2 steps)3. LAH, THF, Δ (85%)4. Ethyl glyoxylate, PhH (92%)

92%

CO2Etp-TsCl, pyr.

Nu E

N

CO2Et

NSO2Ar

OMe

OMe

N

CO2Et

NSO2Ar

OMe

OMe

vs.

not formed!only product (64%)close spatial relationshipbetween two sites of

complementary reactivity! 1. NaBH4, EtOH2. Ac2O (84% over 2 steps)3. O3, aq. AcOH (regioselective but only 29% )

NAc

CO2Et

NSO2Ar

CO2Me

H

MeO2C

MeOH, HCl, Δ

3 transforms in one steps:acetate cleavage

lactamizationepimerization

cannot lactamize here!

N

CO2Et

O

NSO2Ar

OMe

O

H

aromatic!

H

hydride attack at sp2 center from less hindered α face (not critical

since stereogenic center subsequently destroyed!

need epimerization to allow Dieckmann cyclization!

N

CO2Me

O

NAc

OMe

O

H

Tosyl group incompatibility ⇒ 3 extra steps!

75%

NaOMe, MeOH, ΔDieckmann

N

O

NAc

OMe

O

OHH

88%

N

O

NH

OH

several steps


23

N

O

NH

OHN

O

NH

CHO

OH N

O

NH

CHO

OH

N

O

N O

ONa, THF (53%)

N

O

N

HHO

N

O

N O

OH

N

O

N O

OH

SeO2, EtOH

H

trans-glyoxal cis-glyoxal

can cyclize!

dehydrostrychninone

1. cyclize2. oxidise

1. HBr, AcOH (allylic bromide formation)2. aq. H2SO4, Δ (allylic isomerization, 13%)

isostrychnine I

21

concavetop face

convexbottom face

attack at less hindered face

N

O

N

HO

1. H2, Lindlar catalyst, i.e., Pd-CaCO3-PbO (86%)2. LAH, Et2O (30%)

intramolecular hydride deliveryfrom C21 aluminum alkoxide

to C8 β face!

8

218

N

O

N

HO

HKOH, EtOH strychnine


24

The Overman RouteJACS 1993, 115, 9293

“Domino aza-Cope/Mannich transform”

NR

HO [3,3]

aza-Cope NR

HOMannich

NR

OHC

3-formylpyrrolidine

1 2 3

321

1

23

32

1

N

O

N

HO

H

Wieland-Gumlich aldehyde

one step to strychnine !Robinson (1953)

NH

N

HO

H

HO

lactonization

NH

N

MeO2C OH

CarboxymethylationImine formationtautomerization

N

Ot-Bu

ONP2

NR2

N

tBuO

HO

look for the3-formylpyrrolidine

motif!

NR2

N

tBuO

HO

aza-Cope Mannich

NR2

HN

tBuO

HO

epoxide opening

R2N

O

PHN

OtBu

olefinationepoxidationcarbonylative Stille

R2NI

TIPSO

OtBu

Bu3Sn+

AcOOAc

prochiral meso1,4-diacetoxycyclopent-2-ene

1

2

34

567

8910

11

12

3

4 5

6

7

89

10

11


25

Synthesis

Overman, JACS 1993, 115, 9293See also: Classics, 646-653

AcO

OAcAcO

OH

AcOO

OOMe

EtO2CO

Ot-Bu

AcOO

CO2EtH

AcOOH

CO2EtH

O TiLn

CO2Et

R

H

H OH

CH2Ot-Bu

R H

CO2Et

O

Ot-Bu Ot-Bu

Ot-Bu

TIPSO

Me3SnOt-Bu

TIPSO

97%MeOCOCl, pyr.

electric eelacetylcholinesterase

Ph

O

Ph

NaH, Pd2(dba)3 (1%)PPh3 (15%), THF, rt 1:1 (91%)

displacement of allylic carbonatevia π-allyl Pd species

NaCNBH3, TiCl4 anti:syn >20:1

CH2Ot-Bu

NI

H

Felkin-Ahn

NN

O

4 steps 1. L-Selectride, PhNTf2, THF-78 °C → 0 °C

L-Selectride =

dba =

N-phenyltriflimide

2. Me6Sn2, Pd(Ph3P)4 (10%)LiCl, THF, 60 °C

conjugate reduction

lithium tri-sec-butylborohydrideLiB[CH(CH3)CH2CH3]3H

NO

vinylstannane

triazone-protectedortho-iodoanilinePd-catalyzed

carbonylative Stille

Overman, JACS 1993,115, 3966NMP =

N-methyl-2-pyrrolidinone

R2N

O

TIPSO

OtBu

Pd2(dba)3 (2.5%), Ph3As (22%)CO, LiCl, NMP, 70 °C

Triton B = N-benzyltrimethylammonium hydroxide

80%


26

NR2

HN

tBuO

HOR2N

O

TIPSO

OtBu

1. t-BuOOH, Triton B2. Ph3P=CH2, THF3. TBAF

Key aza-Cope/Mannich

rearrangement substrate

4. MsCl, i-Pr2NEt5. LiCl, DMF6. NH2COCF3, NaH, DMF7. NaH, PhH, 100 °C8. KOH, EtOH-H2O

43% over these 8 steps!!!

(CH2O)n, Na2SO4MeCN, 80 °C

N

Ot-Bu

ONR2

98% (crystalline !)

N

O

N

HO

H

strychninevia Wieland-Gumlich

aldehyde


27

The Martin RouteJACS 1996, 118, 9804

“biomimetic base-mediated rearrangement of corynantheoid skeletoninto strychnoid skeleton”

N

O

N

HO

HNH

N

MeO2C OR

NNH

OBnMeO2CH

H

NNH

OHMeO2CH

H

Cl

NN

OBnH

H

MeO2C

NNH

OH

HO

OBn

NNH H

O

OOBn

H

NNH

R = H (Overman's intermediate)R = Bn (Martin's intermediate, cannot deprotect!!!)

corinantheoidskeleton

OTMS

Hetero DA

+OBn

COCl+

vinilogous Mannich

6-membered ring from acyclic prec.with regio and stereocontrol!

H

SynthesisJACS 1996, 118, 9804


28

Epothilones

A. General

• Macrolides isolated from myxobacteria of the genus sorangium 16-membered macrocyclic polyketides featuring: methyl/hydroxyl triads (polyketide trademark) an aromatic thiazole ring (⇒ cysteine) an oxirane ring a gem-dimethyl group 7 stereogenic centers Multigram-scale supply from single batch fermentation! • Antitumor agents with antimitotic activity via stabilization of microtubules (Taxol-like activity!): broad activity against eukaryotic cells; epothilone B is twice as active as epothilone A epothilone B ⇒ apoptosis of mouse fibroblasts (L929) within three days at an IC50 dose of 2 ng/ml in vitro activity against breast and colon tumor cell epothilones and taxol probably occupy different but possibly overlapping binding sites on microtubules 1000 to 5000 times more active against multiple drug-resistant tumor cell lines 30 times more soluble in water

NB: the microtubule-stabilizing activity of the epothilones and taxol is shared by only one other naturalproduct ⇒ discodermolide

B. References

Höfle et al., Angew. Chem. IEE 1996, 35, 1567 (isolation, manuscript received on March 26)Danishefsky et al., Angew. Chem. IEE 1996, 35, 2801 (epothilone A, manuscript received on October 17)Danishefsky et al., Angew. Chem. IEE 1997, 36, 757 (epothilone B)Danishefsky et al., JACS 1997, 119, 10073 (the full story!)Nicolaou et al., Angew. Chem. IEE 1997, 36, 166 (epothilone A, manuscript received on November 25, 1996)Nicolaou et al., JACS 1997, 119, 7960 and 7974 (epothilones A and B, the full story!)Schinzer et al., Angew. Chem. IEE 1997, 36, 523 (epothilone A)Schinzer et al., Chem. Eur. J 1996, 2, 1477Wessjohann, Angew. Chem. IEE 1997, 36, 715 (highlights)

O

S

N

O

O

OH

R

OH O

epothilone A ⇒ R = Hepothilone B ⇒ R = Me


29

C. Analysis

O

S

N

O

O

OH

R

OH O

O

S

N

O

OH

OH O

R

Aldol

esterification

Wittig

Three major fragments:one thiazole unittwo aldol components

disconnectionorder vary

Epoxidation is the last step in all syntheses

Variations ⇒ disconnection strategies and tactics to synthesis each fragment, especially in the northern half!

Northern half

Southern half

Possible macrocyclization strategies:macrolactonizationmacroaldolizationring-closing olefin metathesis

NB: Danishefsky implemented them all!

The Danishefsky’s routeJACS 1997, 119, 10073

First Syntheses of Epothilones A and Bvia Suzuki Coupling and Macroaldolization

Retrosynthetic analysis

O

S

N

O

OH

OH O

R

OH

S

N

R

X

X

O

OP

OP

B-alkyl Suzuki

Xmacroaldolization

+

esterificationA

B


30

SynthesisA

+

OP

OPX

TBSO OTPSOMeOMe

BnO

OMe

OTMS

O

H

1. TiCl4, CH2Cl2, -78°C2. CSA, PhH, rt

O

O

OBn* ***

chelation-controlled facially selectivediene-aldehyde cyclocondensation

triad

JACS 1985, 107, 1256JACS 1987, 109, 862Aldrichimica Acta 1986, 19, 59

"dihydropyrone"

8 possible triads!

87%

L.a.

O

H

BnO

reactive conformer

Z ⇒ syn

attack at C=O from less hindered α-face

chelated Cram control of diastereofacial selectivity ⇒ anti Cram–Felkin product

ideal for the synthesis of polypropionate-based natural products, such as polyketides

O

O

OBn O

OH

OBn

H I

1. NIS, MeOH2. n-BU3SnH, AIBN cat.PhH, reflux3. Ph3SiCl, imidazole

O

OTPS

OBn

OMe

cyclopropane solvolysis

TBSO OTPSOMeOMe A

2 steps

6 steps

OH

S

N

R

X

B

OAc

S

N

R

I


31

O

S

N

O

OTBS

OTPS3. p-TsOH, aq. dioxane

R

O

O

S

N

O

OTBS

OTPS

R

OH

71%, R = H77%, R = Me

KHMDS, THF, -78°C

R = H ⇒ 6:1 (51%)R = Me ⇒ 2:1 (60%)

A2. "Pd(II)",

1. 9-BBN, THF, rt

O

oxidation-reduction sequence to epimerize undesired isomer

S

N

O

OTBS

R

OH

B

deprotection + Dess–Martin O

Suzuki

DMD

epothilone A ⇒ >16:1 (49%)epothilone B ⇒ >20:1 (97%)

non-enolizable aldehyde!

Suzuki Coupling and MacrolactonizationRetrosynthetic Analysis

O

S

N

O

OH

OH O

R

OH

S

N

R

X

OP

O

B-alkyl Suzuki

OP

+C

B

macrolactonization O

HO


32

Synthesis

TBSO OTPSOMeOMe

ATBSO O O

OTBS

OR

R = TBS

a more advanced intermediate already containing the C1–C2 acetyl moiety of epothilones

6 steps1 2

S

N OTBS

TBSO

B C+

R = H

OHO2C

1. Suzuki2. K2CO3, aq. MeOH

OHYamaguchi's conditions

2,4,6-trichlorobenzoyl chloride,TEA, DMAP, CH2Cl2, rt

O

S

N

O

OTBS

OR OR = TBS

macrolactonization

epothilone A88%

intermediate in macroaldolization route!

NB: Danishefsky and his co-workers also developped a route to epothilones based on ring-closing olefinmetathesis to achive macrocyclization (JACS 1997, 119, 10073).


33

The Nicolaou’s routeJACS 1997, 119, 7960 and 7974

Macrolactonization-Based Strategy

Retrosynthetic Analysis

O

S

N

O

OH

OH O

R

OH

S

N

O

OP

OP O

R

HO

OP

S

NO OP O

R

HOO

Aldol

macrolactonization

OP

S

N

asymmetric allylboration

R

OP

+

PPh3IEnders alkylation

Wittig

O

a phosphonium salt(ylide)

+OP

S

N

O


Synthesis

Thiazole unit:

1. (+)-Ipc2B(allyl)

2. TBSCl, imidazole OTBS

S

N

S

N O Et2O, -100°C

asymmetric allylboration 1. OsO42. Pb(OAc)43. NaBH4

OTBS

S

N

OH 1. I2, Ph3P2. Ph3P

OTBS

S

N

PPh3I


34

(+)-Diisopinocampheyallylborane

OH

S

N

S

N O

B

O

BH

R

BO

H

R

Et2O, -100°C2

JACS 1957, 79, 1920

favored complex

H. C. Brown's Chemistrye.g., JACS 1986, 108, 5919

1.

2. TBSCl, imidazole

allyl transfer


Zimmerman–Traxler TS

OR

96%, ee > 97%

Aldehyde/ketone Unit:

Enders alkylation

H

NN OMe

Enders' chiral hydrazoneform SAMP = (S)-1-amino-2-(methoxymethyl)pyrrolidine

LDA, I(CH2)4OBN

H

NN

OMe

OBn

Tetrahedron 1995, 51, 10699

TBSOO

For epothilone A

1. MeMgBr2. TPAP, NMO TBSO O

For epothilone B

NMO = 4-methylmorpholine N-oxideO

NO

TPAP = tetrapropylammonium perruthenate (CH3CH2CH2CH2)4NRuO4


35

HO2CTBSO O

OTBS

S

N R

OTBS

PPh3I

O

NaHMDS

OTBS

S

N

R

OTBS

R = H : THF, 0°C, 15 min ⇒ 77% (Z:E = 9:1)R = Me : THF, - 20°C, 12h ⇒ 73% (Z:E = 1:1)

1. CSA (selective desilylation of primary hydroxyl group2. SO3•Pyr (oxidation)

OTBS

S

N

R

O

LDA (3 equiv), THF, -78°CTBSO

S

N

R

OH

OTBSOHO2C

+ diastereomer (1:1)

sodium hexamethyldisilazaneTMS

NTMS

Na

HO

S

N

R

OTBS

OTBSOHO2C

1. Yamaguchi macrolactonization2. desilylation

CF3

O O3.epothilone A (α:β epoxide = 2:1)epothilone B (α:β epoxide = 1:1)

The Olefin Metathesis Approach to Epothilone A


O

S

N

O

OH

OP O

O

S

N

O

OH

OP O

olefin metathesis

esterification


36

OH

S

N

O

OH

OP O

HO

O OP O

HOO

OP O O O

+

Wittig

+

Aldolasymmetric allylboration


Synthesis

S NO O

O

S NO O

OO

HO2CTBSO O

HO2CTBSO O

HO2C

OH

TBSO O

OHOH

S

N

1. LAH2. TPAP, NMONaHMDS, C5H9I

Oppolzer's acylated sultam chiral auxiliaryTetrahedron Lett. 1989, 30, 5603

O

LDA

S

N +

O

OH

OP OEDC, DMAP

3:2

+ diastereomer(31%)

EDC = 1-ethyl-3-((dimethylamino)propyl)carbodiimide HCl52% from keto acid

A

A


37

O

S

N

O

OH

OP O

CHPhClCl

PCy3

PCy3

O

S

N

O

OH

OP O

CHPh RuPh

RuRu

Ph

O

S

N

O

OH

OP O

Ru

ring-closing olefin metathesis

AAIEE 1995, 34, 2039JACS 1996, 118, 6634JACS 1996, 118, 100ACR 1995, 28, 446

Grubbs' chemistry

[2 + 2]Ru

Z (46%)

+ E isomer (39%)

remove

P = TBSP = TBS

P = TBS

1. TFA2. methyl(trifluoromethyl)dioxirane epothilone A

[2 + 2]

The Schinzer’s routeAngew. Chem. Int. Ed. Engl. 1997, 36, 523

Double Diastereodifferentiating Aldol and Ring-closing Metathesis


O

S

N

O

OH

OH O

OH

S

N

O O O

Oolefin metathesis

esterification

Aldol

A

B


38

Synthesis

POS

N

OH OH O OTBS BIpc2 OTBS

OH

MgBr

TBSO OH

TBSOO

OTBS

OEtOEt S

N OH

OTBS

1.2. Sharpless resolution

B

1. NaH, TBSCl2. Swern

1. Me2CO, H+, CuSO42. NaIO4, OsO4 cat.3. EtMgBr4. TPAP, NMO

1. TBSCl, imidazole2. ozonolysis

BuLi, THF

1.

1. Dess–Martin2. Wittig3. TBAF

A

2. HF, MeCN, a few splinters of glass(catalysis by H2SiF6)

O O O OO O O OH

TBSO O OTBSHO2C

O

NO

OO

HO

+B

Anti–Cram Aldol

LDA, THF, -78°C

oxazolidinone-based Evans' chiral auxiliary

How would you make this chiral aldehyde?

This a case of double diasteredifferentitionoverruling Cram selectivity (mismatched chiral pair)

+ NaHMDS, MeI

hept-6-enoic acid

asymmetric alkylation

70%


39

TBSO O OTBSHO2C

OH

S

N

A

+DCC, DMAP

O

S

N

O

OTBS

OP O

P = TBS

80% via ring-closing metathesisepothilone A


40

Dynemicin A

A. General

• Enediyne isolated from fermentation broth ofMicromonospora chersina(Konishi, 1989)

• Antitumor antibiotichigh levels of invitro antitumor activity comparable to those of two other enediyne natural products, calicheamicin andesperamicin (show overhead!)

• Only members of the natural enediynes to possess an anthraquinone, astructural feature also common to the anthracycline antibiotics.

No carbohydrate moiety (affect DNA binding properties)Strained epoxy (Z)-enediyne bridge across bicyclic ring system

• Bergman cycloaromatization of enediynes:H

H

H

H

ΔBergman cyclization

H

H

H

H

highly unstable1,4-dehydrobenzene

a biradical species!

Natural enediynes are thought to display their antitumor activity via Bergman cycloaromatization of theirenediyne unit; the resulting biradical species being capable of inducing double-stranded DNA cleavage! Thiswas a novel biomechanism of action for antitumor agents!

• Biomechanism of action of dynemicin A:1) the anthraquinone unit functions as a DNA intercalating agent (i.e., delivery system), and as the initial site of reduction in the activation of dynemicin A.2) base-mediated epoxide opening to a quinone methide followed by trapping with a bionucleophile (i.e., triggering device: sp2 → sp3) causes the two triple bonds of the otherwise inactive enediyne unit (i.e., warhead) to come close enough together to undergo Bergman cyclization.3) Bergman cyclization: biradical product abstracts DNA hydrogen ⇒ DNA cleavage!

HNOH

OH

O

O OH

OOMe

CO2H bioreduction

3.54 Å

HNOH

OH

O

OH OH

OOMe

CO2HHB

HNOH

OH

O

OH OH

HOOMe

CO2H

a quinone methide!

BioNu

HNOH

OH

OH

OH OH

HOOMe

CO2H

Nu

3.17 Å

Bergman!

HNOH

OH

O

O OH

OOMe

CO2H


41

B. References

Hoffmann, American Scientist 1993, 81, 324 (of what use enediynes)Bergman, Acc. Chem. Res. 1973, 6, 25 (Bergman cyclization)Konishi et al., J. Antibiot. 1989, 42, 1449 (isolation)Schreiber et al., JACS 1993, 115, 10378Myers, A. G.et al., JACS 1997, 119, 6072, and Chem. & Biol. 1995, 2, 33Danishefsky, JACS 1996, 118, 9509

NB: For a non radical but polar cycloaromatization alternative pathway to biological activity, see:Magnus et al., JACS 1993, 115, 12627.


The Myers’s routeJACS 1997, 119, 6072

Chem. & Biol. 1995, 2, 33

Highly Convergent Route Allowing for the Synthesis of Dynemicin Analogs


isobenzofuran 4π component

F

F

+

+

" "

a stable quinone imineas 2π component

HNOH

OH

O

O OH

OOMe

CO2HN

O

OOMe

CO2ROH

OH

O

OH

OH

HNA

D

O

O OH

O

N

O

OA

D

O

X

Y

B

C

analogs

loci of chirality!

B

CE

[4π + 2π]

angucycline chemistry

E

NB: reactive anthraquinone unit is introduced at the later stage of the synthesis! Synthetic problem is reducedto the preparation of the quinone imine Diels-Alder component ⇒ easy access to various analogs!


42

N

O

OOMe

CO2RN

OTBS

H

O

O

OH

OMeOMe

oxidation to quinone imineFGI within A ring

A

HN

OMe

O

OMe

a quinolone

down to one stereogenic center !need syn addition of (Z)-enediyne unit!

B(OH)2NH

OMe

O

O

+

Suzuki

TfO

O

OMe

O

Synthesis

O

O OO

OEtO

O

O O500 g scale (94 %)2. recrystallization

(benzene)

1.

O

O

O OMeMeO

NHBOC

B(OH)2

36 %

KO-t-Bu, t-BuOH, reflux

Enantioselective Synthesis of Quinone Imine

Michael-Dieckman

A. G. Myers, M. E. Fraley, N. J. TomJACS, 1994, 116, 11556-11557

1. NaH, (TfO)2O, - 78 °C, Et2O2. Pd(PPh3)4, Na2CO3dioxane, reflux

dry MeOH, CSA

regioselectively in 71 %

rt, 12 h

Suzuki

O

O

OMeMeO

NHBOC86 %

HN

O

OMe

OMe

180 °C30 min

84 %4-chlorophenol(weakly acidic solvent)

desired quinolone!

removal BOC groupwithout cleaving methyl enol ether,and lactamization


43

N

OMe

OMe

OMe

OH

N

OMe

OTBS

OMe

OH

N

OMe

OTBS

OMe

OH

1. (TfO)2, 2,6-di-t-BuPyr, CH2Cl2 (triflate in 86 %)2. m-CPBA, MeOH, reflux (α alcohol in 67 %) 3. formic acid, Et3N, Pd(PPh3)4, dioxane, reflux(reductive cleavage of triflate to quinoline in 97 %)

TBS

Me-TMS exchange

O

O

EtMgBr, 0°C → reflux, THF

9 g scale89 %

> 25:1

1. m-CPBA (88 %)2. TBAF (100 %)3. TBSCl, imidazole (93 %)4. Swern secondary alcohol (92 %)5. KHMDS (deprotonate acetylide),CeCl3

HN

O

OMe

OMe TL 1986, 27, 5541

will control syn adition of acetylide

3 steps

would require harshconditions for removal

65 %

NTBSO

H

O

H

OMe

OMe

Me

H

MgX

half-chair

H

magnesium chelation with methoxyl oxygenscauses the alkoxide to adopt a half-chair conformation in which the methyl group is placedin a pseudoequatorial position!

axial mode of entry for the acetylide!

cis

TBS

H

EtMgBr, -78°C → 0°C, THFO

O Cl

Yamaguchi reaction

TL 1983, 24, 1801

N

OTBS

O

OHOMeOMe

O

O

94 %

1. p-TsOH.H2O, acetone (hydrolyse ketal in 83 %)2. 1,1'-thiocarbonyl-diimidazole, DMAP (85 %) N

OTBS

O

O

O

OO

S

a thionocarbonate


44

1. 3HF.Et3N (91%)2. TfOSi(i-Pr)3, imidazole (69 %)

89 %

Bu3SnH, cat. Pd(PPh3)2Cl2, wet CH2Cl2

49 %

60 %

2. KOtBu, Et2O, then MeOTf, toluene

3. iodosobenzene, MeOH(oxidize phenol, MeOH trapping)

cleave Alloc, eliminate MeOH!

N

OTBS

O

O

O

OO

S

N

OTBS

O

O

O

OH

N

OTBS

O

O

O

OMeH

CO2HN

O

O

O

O

OMeH

CO2Si(i-Pr)3

MeO

N

O

OOMe

H

CO2R

Bu3SnH, AIBN

97 %

1. CO2, MgBr2, Et3N, acetonitrile(α-keto acid formation as per Rathke))

O

OHN(TMS)2, cat, H2SO4

N

O

O

quinone imine

isobenzofuran

OH

OH

O

OTMSO

OTMS H

O

OTMSTMSO

OTMS

CO2R

OMe

THF, reflux, 30 min

oxygenated phthalide(all oxygens required to access

desired anthraquinone are in place !)

100 %

N

O

OOMe

OTMS

TMSO

O

KN(TMS)2, THF

Base

+

TMSO

TMSCl trappingof enolate

R = Si(i-Pr)3

55 °C

exo

CO2R

dienophile

diene

Diels-Alder

70-80%


45

3HF•Et3N

(+)-dynemicin A53 %

F

N

O

OCO2Si(i-Pr)3

OMe

OTMS

TMSO

O

HNOH

OH

O

O OH

OOMe

CO2H

OSiMe3

MnO2

THF, rt, 9 min

The Schreiber’s routeJACS 1993, 115, 10378

Regioselective Friedel–Crafts CouplingRetrosynthetic Analysis

HNOMe

OMe

O

O OMe

OOMe

CO2Me

OMe

OMe

O

O

Br

N

OMe

OH

CO2MeO

OMeO2C

N

OMe

O

MeO

CO2H

N

OMe

O

MeO

H

O

H

O+

retro

N

OMe

many steps!

1

2 OP

OH

Friedel–Crafts

FGI retro

N Br

OMe

Diels-Alder

weaknessof tactic

Stille

3-alkenylquinoline 3-alkenyl-6-methoxyquinoline

H

N

OMe

OMe

CO2Me

MeO OMe

OO

O

OMeO2C

Synthesis


46

1.

N

OMe

O

MeO

H

O

Yamaguchi reaction

early!

H

H O

N

OMe

OTBS SiMe2thexyl

MgBrCl

O

OMe

N

OMe

OH

O

MeO

H

Br

O

OH

2. TBAF

first stereogenic

center(axial)

60%

!?

JACS 1990, 112, 7410

50%

DBUepimerization

N

OMe

OH

O

MeO

Johnson, Chem. Rev. 1968, 375Allylic A1,3 strain!

CO2H

Pd(PPh3)4, CuI

Cl Cl

Cl O

Cl

ideal for subsequentcyclization!

1.

2. LiOH DMAP, toluene, rt

Yamaguchi macrolactonization conditions

N

OMe

O

O

MeO

O

N

OMe

O

MeO

H

O

H

H O

or PyBroP, Et3N

involve benzylic oxidation with CAN to oxygenate at C-11

N

OMe

O

O

OH

O

H

H O

OBzbase-labile

via β-elimination

113

4

need to reposition C3–C4 olefin,while controlling stereo at C4

JACS 1992, 114, 5898

direct hydride introdution at C4 withconcommitant deoxygenation at C11 of the allylic alcohol moiety to repositionthe olefin with desired stereochemistry at C4did not work ⇒ allylic diazene rearrangement!

1. MeAlCl2, CH2Cl22. MesNHNH2

N

OMe

O

RO

N

O

H

H ON H

stereoselectivesigmatropic [1,5] shift


47

N

OMe

O

RO O

H

H O

11 steps N

OMe

O

O

butyrolactone vinylogous carbonate

CO2Me

OH

OMe

OMe

O

O

Br

Friedel–Crafts

1. anhydrous AgOTf, 1 min 2. Me2SO4, K2CO3

N

OMe

OMe

CO2Me

MeO OMe

OO

O

OMeO2C

MeO2C

H 57% (1:1)

CO2HNOMe

OMe OMe

OMe

CO2Me

MeAlCl2, Et3SiHO

OR

NOMe

OMe OMe

OMe

CO2MeO

OR

1. SOCl22. TMSOTf3. DDQ

51%OH

O1. m-CPBA (epoxidation)2. DBU (removal of carbamate via β-elimination)3. CAN (oxidation to target)

HNOMe

OMe

O

O OMe

OOMe

CO2Me


48

The Danishefsky’s routeJACS 1996, 118, 9509

Stille-mediated Ethylene Interpolation


HNOH

OH

O

O OH

OOMe

CO2H

ZZHN

OP

X

Y

W W

V

U

TT

ZZN

OP

X

Y

V

U

ZZN

OP

V

U WintramolecularReissert coupling

intermolecularethylene interpolation

2 4

7

stereochemically more demandingsince need to control cis relationships between C2, C4 and C7!

need to control cis stereochemistryat C4 and C7, cis stereochemistry at C2 would be fixed by cyclization

unsuccessful?

successful!

Popp, Chem. Heterocycl. Comp. 1982, 32, 353

Yamaguchi reaction-like

Synthesis

OCHO

OMe

ZnCl2, CH2Cl2, rt

endo-selectiveDiels–Alder O

OMe

H

H CHO60%

hemiacetal formationpossible since reactive centersare both on the α-face ⇒ would not be possible with exo-cycloadduct!

racemate!

CAN

O

O

H

O

HO

47

control of C4–C7 cis relatioship!

4

7

1. NH4OAc, AcOH, 100 °C2. TBSCl, imidazole

90%

N

OTBSOTBS

desired quinoline!

87%


49

N

OTBSOTBS

N

OTBSOTBS

OH

OH

N

TBSO

OTBSH

HO

O

W

W

N

OTBSOTBS

O

O

PhPh BrMg TIPS

O

O

Cl

N

OTBSOTBS

O

O

PhPh

O

O

TIPS

N

OTBS

O

O

PhPh

O

O

TIPS

Danishefsky's solution fi render the α-face even more hindered than the β-face:

TMS O

O

N

2

OTBS

undesired attack sterically prevented

OH

OH

80% (9:1)

TEOC

I

1. Ph2C(OMe)2, H2SO4, CH2Cl22. TBSCl, imidazole

83%

I

THF, -20°C

difficult task of the ethylene interpolation route: an ethynyl group must be introduced at C2 cis to both C4 and C7, that is onto the already sterically hindered β-face

Me3Sn SnMe3

OsO4, NMO

90%

47

N

OTBS

TEOC

DMF, 75 oC

O

O

2

5% Pd(PPh3)4

OH

OH

1. conc. HCl, THF2. Swern oxidation3. Corey–Fuchs (TL 1972, 13, 3769)

81%

TEOC =


50

N

O

OCO2MOM

OMe

OMOM

MOMO

O

O

O

LHMDSN

O

OCO2MOM

OMe

OMOM

MOMO O

3 steps

(rac)-dynemicin A


51

Dysidiolide

A. General

• sesterterpene (i.e., C25) γ-hydroxybutenolide isolated from the marine sponge Dysidea etheria de Laubenfels • Antimitotic activity; it is the only known natural inhibitor of cdc25A, a signaling

protein phosphatase known to activate the G2/M transition of the cell cycle:

inhibition of cdc25A ⇒ cell cycle arrestation ⇒ cell division prevention⇒ applications for cancer treatment

micromolar activity against A-549 human lung carcinoma and P388murine leukemia cancer cells

Is this cancer cell growth inhibition due to the inhibition of cdc25A by dysidiolide?

• Unusual rearranged carbon skeleton with two fused six-membered rings possessing four stereogeniccenters, plus two functionalized appendages.

B. References

Isolation: Gunasekera, Clardy et al., JACS, 1996, 118, 8759First synthesis: E.J. Corey and Roberts, JACS, 1997, 119, 12425 (December 24) (-)-dysidiolideSecond synthesis: Boukouvalas et al., JOC, 1998, 63, 228 (January 8) ent-dysidiolideThird synthesis: Danishefsky et al., JACS, 1998, 120, 1615 (February 5) rac-dysidiolide


H

OOHO

HO (-)-dysidiolide


52

H

OH

O

OO

O

O

O

Corey Boukouvalas

O

Hagiwara, JOC, 1988, 53, 2308

H

Danishefsky

+

asymmetric Robinson-like cyclization

OBn

+CHO

EtO2C

TIPSO

OH

+O

O

OTBDPS

different strategy same strategy, different tactics

The Corey’s routeJACS, 1997, 119, 12425

Biomimetic cationic rearrangementSynthesis


53

O

OO

O

OO

O

OOTMS

HO

O

O

Li-NH3, isopreneallyl bromide

82%single diastereomer (more stable trans-decalin)Hagiwara, Perkin 1 1995, 757

1. LDA (2 equiv.), HMPA-THF2. PhSSPh3. m-CPBA

TMS

4. (MeO)3P, PhH, reflux5. TMSLi, HMPA-Et2O

H

HTBDPSO

O

TMS

7 steps

M

did not work!

1. allylMgBr, Et2O, -78°C → rt (stereospecific, equatorial attack!)2. Hydroboration–oxidation (→ primary-tertiary diol)3. TBSCl, DMAP

HTBDPSO

TMS91 %

OH

OTBS

BF3 gas, CH2Cl2, -78°C

Key cationic rearrangement step

HTBDPSO

TMS

OTBS

(σ → p)π

β−hyperconjudation effect stabilizing CHOBF3 HOBF2 + F

[1,2]

PPTS (1 equiv.), EtOHselective removal of TBS

H

TBDPSO

H

HO

1. I2, Ph3P, imidazole2. Br

, t-BuLi, CuI

iodine displaced by in situ generated vinyl cuprate

H

TBDPSO

H

1. TBAF2. Dess–Martin

OI

O

AcO

OAcOAc

periodinane


54

H

OH

1.O

Li, THF

2. O2, hν, rose bengali-Pr2NEt, CH2Cl2, -78°C

(–)-dysidiolide

Photochemical oxidation of the furan moiety

O+ O O

singlet (excited state)

[4 + 2]O

O OH

Base

O OO OOO H

Kerman and Faulkner, JOC 1988, 53, 2773

O

ClClCl

Cl CO2NaI

O

I

NaOII

The Boukouvalas’s routeJOC, 1998, 63, 228

Diels-Alder cycloadditionSynthesis

OH

OBn

CHO

EtO2C

TIPSO

+

OBn

OCO2Me

both enantiomers are commercially availabled'Angelo et al., Tetrahedron Asym. 1992, 3, 459

1. LAH, THF2. NaH, BnBr, THF3. TPAP, NMO, 4 Å sieves

O

OBn1. CH2=CHMgBr, CeCl32. CuSO4, PhH, reflux (dehydration)

diene

BA

A


55


56

OTIPS

CHO

TIPSO

EtO2C

BnO

CO2EtO

H

OTIPS

H

BnO

CO2EtO

H

OTIPS

H

H

OBn

CHO

OTIPS

EtO2C

H

OBn

EtO2CCHO

H

TIPSO

OBn

EtO2CCHO

TIPSO

H

CO2EtO

OTIPS

H

OBn

dienophile

1. EtMgBr, THF, ClCO2Et2. CH2=CHLi, CuI, THF

H

CO2EtO

A

OTIPS

+ B

B

H

3 variable stereogenic centers⇒ 8 possible stereoadducts! only 2 observed!

OBn

3. O3, MeOH, CH2Cl2, then Me2S

BnO

+

H

1:2.3

TIPSO

Diels-Alder

EtO2C CHO

EtAlCl2CH2Cl2, -94°C

diastereofacial selectivitydieneophile approach fromless hindered diene face!

role of EtAlCl2 ⇒ only activation!?

endo

endo


57

OBn

TIPSO

LiEt3BH

OH

HO

1. MeLi, (Me2N)2PCl (Ireland et al., JACS 1972, 94, 5098 2. Li, EtNH2 (Benkeser reduction with debenzylation)

O OH

TIPSO

via diphosphoramidate

CHO

4 steps

85%OTIPSO

Ti(Oi-Pr)3

, Et2O, -78°C

OHO

TIPSO+ epimer (14%)

58%

1. DMD, acetone2. Amberlyst-15/H2O(+)-dysidiolide

longest linear sequence = 15 steps5.26% overall yield

The Danishefsky’s routeJACS, 1998, 120, 1615

Dioxolenium-mediated Diels-Alder Reaction

NB: most concise route !Synthesis


58

+

OH

O

O

OTBDPSA B

an allylic acetal as activated dienophilevia dioxolenium ion !

Gassman's chemistry:see refs in JACS, 1998, 120, 1615

diene

LiO I

DME, HMPA

O

a racemate!49%

1. Tf2O, base2. CH2=CHSnBu3, Pd(PPh3)4, LiCl

StilleA


59

dienophile

O

O

OTBDPS

BO

O 1. Me2CuLi, ICH2CO2Et2. reduction, silylation

TBDPSO

O

O

Diels-Alder

Lewis acid mediation

TBDPSO

O OTMS

TMSOTf Lewis acid-activateddienophile ⇒ vinyl oxolenium ion

secondary orbital interactions between oxolenium LUMO and diene HOMO ⇒ endo

dienophile approaches from lesshindered diene α-face ⇒ diastereofacialcontrol !

β-face is more hindered ⇒ clever usage of the differing steric demand of fully appended precursor

CH2Cl2, -90°C

TBDPSO OO

1. Montmorillonite K102. Wolff-Kishner reduction3. TPAP, NMO (Aldehyde!)4. 3-lithiofuran

OHO

+ epimerHow to epimerize ?1. oxidation, reduction2. Mitsunobu, reduction

singlet O2

OHO

O

HO


60

Documents

Comparative Strategies in Natural Products Synthesis