Amphidinolide A Isolation: 1. Kobayashi, J. et al. Tetrahedron Lett. 1986, 27, 5755. 2. Kobayashi,...

Amphidinolide A

Isolation:

1. Kobayashi, J. et al. Tetrahedron Lett. 1986, 27, 5755.

2. Kobayashi, J. et al. J. Nat. Prod. 1991, 54, 1435.

HO

HOO

O

O

HO

HO

Biological Activity:

L1210 murine leukemia cellshuman epidermoid carcinoma KB cellsrabbit skeletal muscle actomysion ATPaseKobayashi, J. et al. J. Nat. Prod. 1991, 54, 1435.

Amphidinolide A: Pattenden’s Retrosynthesis

Lam, H. W.; Pattenden, G. Angew. Chem., Int. Ed. 2002, 41, 508–511.

For Stille Reaction Review See: Farina, V.; Krishnamurthy, V.; Scott, W. J. Organic Reactions 1997, 50, 1–652.

Stille rxn

Stille rxn

HO

HOO

O

O

HO

HO

O

BnO

OMeOBn

O O

OO

I

AcO

TESO

TESO

TESO

TESO

SnBu3

SnBu3

A'

BC

AOTBS

CHO

AcO

B

S

S

O O

C

Amphidinolide A: Trost’s Retrosynthesis

Trost, B. M.; Chisholm, J. D.; Wrobleski, S. J.; Jung, M. J. Am. Chem. Soc. 2002, 124, 12420–12421.

HO

HOO

O

O

HO

HO

Ru-cat.alkene-alkyne

coupling


coupling

O

O

O

O

O

O

O

OOH

O

O

O

O

OOH

O

O

O

O

OOFm

A BAB

C

ABC

Amphidinolide A: Our Retrosynthesis

Maleczka, R. E., Jr.; Terrell, L. R.; Geng, F.; Ward, J. S., III Org. Lett. 2002, 4, 2841–2844.

HO

PMBO

TBSO

PMBO

O

OO

Stille rxn

RCMHO

HOO

O

O

HO

HO

O

OO

I

HO

PMBO

TBSO

PMBO

SnBu3

AB'

CD

CHO

PivO

PMBO

PMBO

AHO

O

C

O

OHI

D

TMS

Br

B

MgBr

Synthesis of Fragment A

HO

HOO

O

O

HO

HO

A

CHO

PivO

PMBO

PMBO ?

Synthesis of Fragment A

p-TSA, DMF40 °C, 3h

(quantitative)

1. SO3•pyr., DMSO, i-Pr2NEt

2. Ph3P=CH2 (90%; 2 steps)

D-arabitol

OH OH

OH

Et Et

MeO OMe

OH

O

OO

O

Et

EtEt

Et

OH OH

10% HCl, MeOH

(> 95%)

1. TIPSCl, Et3N, DMAP,CH2Cl2 (35%)

OH

HO

HO

HOO

OO

O

Et

EtEt

Et

2. 1 eq. PivCl, pyr. (77%)

(cat.) TrClO4(83%)

PivO

HO

TIPSO

HO

A

PMBO CCl3

NHPivO

PMBO

TIPSO

PMBO1. TBAF (96%)

2. Dess-Martin (95%, crude)

CHO

PivO

PMBO

PMBO

Synthesis of Fragment C

?

OHO

C

HO

HOO

O

O

HO

HO

Synthesis of Fragment C

N N

O O

PhMe

1. NaHMDS, -78 °C;

2. H2, Pd/C

(84%, 2 steps)

BrN N

O O

PhMe

LiBH4,H2O

(85%)

1. Swern [O]2. Ph3P=CHCO2Et3. DIBAL (85%, 3 steps)

4. CMD [O] (96%)

Me MeHO

CMD oxidation: Aoyama, T.;et. al. Synlett 1998, 35.

OH

O Xc

Abiko, A.; Liu, J.-F.; Masamune, S. J. Am. Chem. Soc. 1997, 119, 2586

2. DIBAL (83%)3. TsCl, Et3N DMAP (75%)

TBSO

TsOLi

EDA complex,

DMSO(82%)

OHC NSO2Mes

O

O

Me

Ph

Bn

(c-Hex)2BOTf, Et3N;MeOH, H2O2, pH 7(65%; ds 91: 9 : 6)

1. TBSOTf, 2,6-lut., 0°C

(94%)

OHO

C

In(0), )))

42 °C (80%)TBSO TBSO

2. Sharpless(89%)

Br

Ranu, B.C.; Majee, A. J. Chem. Soc., Chem. Commun. 1997, 1225.

1. TBAF•1/2 HOAc(89%)

Coupling of Fragments C and D

I OH

Me O

O

OO

DIAD, Ph3P

(79%) I

DC

D

O

C

HO+

For an example synthesis of Fragment D see:Thibonnet, J. et. al. Tetrahedron Lett. 1998, 39, 4277.

Chelation Controlled Additions

HO

HO

HO

O

OO

HO

chelationcontrolledaddition

Stille

ring closingmetathesis

Mitsunobuesterification

chelation controlledaddition

CHO

PivO

PMBO

PMBO

A

TMS

Br

B

MgBr

O

OO

I

DC


HO

HO

HO

O

OO

HO


Stille




CHOPMBO

PMBO

A

TMS

Br

B

MgBr

O

OO

I

DC

OPiv


TMS H

BrBr

50 oC

1. EtMgBr, 0 oC to 50 oC2. CuBr, RT3.

HO

HO

HO

O

OO

HO


Stille




CHOPMBO

PMBO

A

TMS

Br

B

MgBr

O

OO

I

DC

OPiv

Elaboration of the AB Subunit

SiMe3

BrMg

(70%)SiMe3

PivO

PMBO

HO

PMBO

CHO

PivO

PMBO

PMBO

A

B'

SiMe3

HO

PMBO

TBSO

PMBO

1. TBSOTf (80%)

2. LiEt3BH; glycerol, NH4Cl (88%)

Dess-Martin [O]

(98%, crude)

MgBr2•Et2OEt2O, CH2Cl2,PhH (3:1:1)

Bu3SnFRed-Sil

cat. TBAF

(Ph3P)2PdCl2(73%)

HO

PMBO

TBSO

PMBO

SnBu3

Br

HO

PMBO

TBSO

PMBO

1. MgBr2•Et2O, vinyl MgBr 0 oC (70%)

2. NBS, AgNO3 (92%)

CHO

SiMe3

PMBO

TBSO

PMBO

Elaboration of the AB Subunit

For leading Red-Sil references see:(a) Reed-Mundell, J. J.; Nadkarni, D. V.; Kunz, J. M., Jr.; Fry, C. W.; Fry, J. L. Chem. Mater. 1995, 7, 1655-1660.(b) Kini, A. D.; Nadkarni, D. V.; Fry, J. L. Tetrahedron Lett. 1994, 35, 1507-1510. (c) Fry, J. L.; Nadkarni, D. V. U. S. Patent 5,281,440, 1994.

Bu3SnFRed-Sil,

cat. TBAF

cat. (Ph3P)2PdCl2,Et2O(73%)

HO

PMBO

TBSO

PMBO

SnBu3

Br

HO

PMBO

TBSO

PMBO

HO

PMBO

TBSO

PMBO

SnBu3

Br

Red-Sil = Si

O

O

O HBu3SnFTBAF

Si

O

O

O

H

F

Bu3Sn–HSiO2 SiO2

The Union

O

OO

I

DC

HO

PMBO

TBSO

PMBO

SnBu3

+

AB

Pd2dab3 AsPh3, NMP,45 oC, 18 hours

or

NMP,25 °C, 30 min

(62%)

S CO2Cu

OH

PMBO

TBSO

PMBO

O

OO

RCM ?

The RCM

HO

PMBO

TBSO

PMBO

O

OO

HO

RO

R'O

RO

O

OO

Ru

Ph

P(Cy)3

Cl

Cl

NN mesitylmesityl

0.2 eq. addeddropwise over 4 hrCH2Cl2 (0.001 M)

40 °C, 10 hr(35%)

PMBO

TBSO

PMBO

O

OO

(40%) + starting material (40%)

O

Note: Employing thebis-phosphine catalystssolely affords themethyl ketone

See: Hoye, T. R.; Zhao, H. Org. Lett. 1999, 1, 1123-1125.

Ru

Ph

P(Cy)3

P(Cy)3

Cl

Cl

High Yielding Highly Selective RCM is possible

OH

PMBO

TBSO

PMBO OO

O

OO

OH

TBSO

PMBO

O

OPMB

only the E-isomer observed

Ru

Ph

P(Cy)3

Cl

Cl

NN mesitylmesityl


40 °C, 10 hr

(88%)

The Total Synthesis of Amphidinolide A?

HO

PMBO

TBSO

PMBO

O

OO

HO

RO

R'O

RO

O

OO

Ru

Ph

P(Cy)3

Cl

Cl

NN mesitylmesityl


40 °C, 10 hr(35%)

1. TBSOTf, 2,6-lut. 0 °C, 12 hr (50%)

2. DDQ, CH2Cl2, t-BuOH, pH 7 buffer, 4 hr (35%)3. TBAF•HOAc, THF, rt, 4.5 hr (50%)

HO

HO

HO

HO

O

OO

amphidinolide A?

H

H

H

H

Presumed Amphidinolide A


Possible Reasons for the Discrepancy:

(1) We screwed up.

(2) Trace contamination affecting NMR data.

(3) Misidentification of natural product.

HO

HOO

O

O

HO

HO

Spectroscopic datainconsistent with thoseof the natural product!

35 steps from article of commerce with

a longest linearsequence of 23 steps

from L-(-)-ephedrine. Stille rxn

RCMHO

HOO

O

O

HO

HO

Presumed Amphidinolide A


Possible Reasons for the Discrepancy:

(1) We screwed up.

(2) Trace contamination affecting NMR data.

(3) Misidentification of natural product.

Spectroscopic datainconsistent with thoseof the natural product!

35 steps from article of commerce with

a longest linearsequence of 23 steps

from L-(-)-ephedrine. Stille rxn

RCMHO

HOO

O

O

HO

HO

OO

OH

TBSO

PMBO

O

OPMB

Amphidinolide A: Pattenden’s Retrosynthesis


For Stille Reaction Review See: Farina, V.; Krishnamurthy, V.; Scott, W. J. Organic Reactions 1997, 50, 1–652.

Stille rxn

Stille rxn

HO

HOO

O

O

HO

HO

O

BnO

OMeOBn

O O

OO

I

AcO

TESO

TESO

TESO

TESO

SnBu3

SnBu3

A'

BC

AOTBS

CHO

AcO

B

S

S

O O

C

Pattenden’s Epoxide Synthesis


OH

AcOS

S

O O

C

1. KHMDS; then A (78%)

2. HF • pyr (98%)

3:1 E/Z

Pattenden’s Epoxide Synthesis


OH

AcOS

S

O O

C

1. KHMDS; then A (78%)

2. HF • pyr (98%)

OH

AcO

t-BuOOH, Ti(OiPr)4

CH2Cl2 OH

AcO

O O+

(46%) (39%)(1.2:1)

Pattenden’s Synthesis


O

OO

I

NOT amphidinolide A

HO

HO

HO

HO

O

OO

AcO

TESO

TESO

TESO

TESO

SnBu3

SnBu3

1. Pd2dba3, Ph3As, THF, 60°C, 4h (51%)2. PPTS, MeOH, CH2Cl2, rt, 6h (60%)

3. Pd2dba3, Ph3As, LiCl, cyclohexane, D, 3h (51%)

Pattenden’s Synthesis


O

OO

I

NOT amphidinolide A

HO

HO

HO

HO

O

OO

AcO

TESO

TESO

TESO

TESO

SnBu3

SnBu3

As before

Amphidinolide A: Trost’s Retrosynthesis


HO

HOO

O

O

HO

HO


coupling


coupling

O

O

O

O

O

O

O

OOH

O

O

O

O

OOH

O

O

O

O

OOFm

A BAB

C

ABC

46%

58%

Presumed Amphidinolide A: Trost’s Syntheses

Trost, B. M.; Harrington, P. E.J. Am. Chem. Soc. 2004, 126, 5028–5029.


HO

HOO

O

O

HO

HO


coupling


coupling

11 isomers

Presumed Amphidinolide A: Trost’s Syntheses

Trost, B. M.; Harrington, P. E.J. Am. Chem. Soc. 2004, 126, 5028–5029.

OH

HO

HO

HOO

O

O

natural amphidinolide A


HO

HOO

O

O

HO

HO


coupling


coupling

Amphidinolide A: Another Possibility?

HO

HOO

O

O

HO

HO


Ishiyama, H.; Nakamura, Y.; Kobayashi, J.Tetrahedron 2006,62, 166–170.

HO

HOO

O

O

HO

HO

Trost, B. M.; et al. J. Am. Chem. Soc. 2005, 126, 13589–13610.

OH

HO

HO

HOO

O

O

natural amphidinolide A

Amphidinolide A Isolation: 1. Kobayashi, J. et al. Tetrahedron Lett. 1986, 27, 5755. 2. Kobayashi,...

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