Total Synthesis of (+)-Acutiphycin and (+)-trans-20,21-didehydroacutiphycin Wei Lin Literature Meeting Charette Group Dec. 5 th, 2006

Total Synthesis of (+)-Acutiphycin and (+)-trans-20,21-didehydroacutiphycin

Wei Lin

Literature Meeting

Charette Group

Dec. 5th, 2006

http://www.umontreal.ca/

Introduction

Isolated from the blue-green algae Oscillatoria acutissima in 1984 by Moore and co-workers.

Moore, R.E. et al., J.A.C.S. 1984, 106, 8193-8197.

Potent in vivo antineoplastic activity against murine Lewis lung carcinoma, significant cyctoxicity against KB and NIH/3T3 cell lines.

CYANOPHYTA: Blue-Green Algae

O

OH

O

OH

OO

OH H

*

*

**

**

Chemical Formula: C27H44O7

(+)- Acutiphycin

O

OH

O

OH

OO

OH H

*

*

* *

**

(+)- trans- 20,21-Didehydroacutiphycin

Chemical Formula: C27H42O7

macrolides family

Total Synthesis History

In 1995, first total synthesis by Smith Group from Pennsylvania.

In 1999, C10-epi seco acid derivative synthesized by Kiyooka group from Japan.

In 2001, C(9)- C(13) fragment was synthesized by Miftakhov and co-workers from Russia.

In 2002, C(1)- C(8) fragment was synthesized by Léger and co-workers from Merck Frosst center in Quebec

In 2006, second total synthesis by Jamison group from MIT.

O

OH

O

OH

OO

OH H

*

*

**

**

(+)- Acutiphycin

O

OH

O

OH

OO

OH H

*

*

* *

**

(+)- trans- 20,21-Didehydroacutiphycin

Amos B. Smith, III

Born in 1944

B.S.- M.S. Bucknell University (1966)

Ph.D. Rockefeller University (1972)

Research Associate, Rockefeller University (1972-73)

Rhodes-Thompson Professor of Chemistry (currently)

To date, more than 90 architecturally complex natural products have been prepared in his Laboratory.

Research -Completed and Ongoing NPCs

13-Deoxytedanolide (2003)

(-)-9-Prenylpaxilline Dactylolide(2002)

Salicylihalimide A(2001)

Spongistatin 1 & 2(2001)

Callystatin A (2001)

Phorboxazole A (2001)

Zampanolide (2001)

Emindole SA (2000)

Madinodoline A & B (2000)

Discodermolide (1999)

Penitrem D (1999)

Cylindrocyclophane A (1999)

Calyculin A (1998)

Macrolactin A (1996)

Smith Group Work-Retrosynthetic Analysis

J.A.C.S., 1995, 117, 12013-12014.J.A.C.S., 1997, 119, 10935-10946.

O

OH

O

OH

OO

OH H

R

*

*

**

**

(+)-Acutiphycin (1) R = n-Pr

(+)-trans-20,21-didehydroacutiphycin

(2) R =

O

OTES

O H

OMe H

OEtO

OBPS

+R

OTES

Br

R = n-Pr

R=

OMeOH

OBPS

OH

OMeOH

H

OBPS

O

OH

OO

OH

OHL- Malic acid

n-Pr

OTES

Br8 steps

n-Pr

OTES

Br 9 steps

Smith Group WorkOMeO

H

H

OBPS

O

Smith Group WorkO

OTES

O H

OMe H

OEtO

OBPS

Fukuyama* proposed mechanism

Smith Group Workn-Pr

OTES

Br

Smith Group WorkOTES

Br

HO

O OH

O

OH

L- Malic acid

3 steps

NN pTs

Smith Group Work

1) 4 (82%)or 6 (94%)

t-BuLi, MgBr2

2) Dess-Martin [O]a (94%); b (88%)

a R = n-Pr

b R =

a R = n-Pr

b R =

n-Pr

OTES

Br

OTES

Br

4

6

Smith Group Work

3 days

a R = n-Pr

b R =

Smith Group Work

The first total synthesis of (+)-Acutiphycin was accomplished in 38 steps with an overall yield of 0.12%.

Applied L-(-)-malic acid, chiral auxilliary AD-Mix-β, (+)-B-methoxy-(diisopinocamphenyl)borane and tetramethylammonium triacetoxyborohydride to build the chiral centers.

Kiyooka Group Work-chiral oxazaborolidinone-promoted asymmetric aldol reactions

Strategy: To construct linearly seco acid 2 by using a series of five aldol reactions at the carbon-carbon bond indicated with slant lines in 3.

Tetrahedron Lett., 1999, 40, 1161-1164.J.O.C., 1999, 64(15), 5511-5523.

12

34

567 8 9

A Chiral Oxazaborolidinone-Promoted Aldol Reaction

Syun-ichi Kiyooka et al., Tetrahedron Asymmetry, 1996, 7(8), 2181-2184.

Kiyooka Group Work-Promoters Used

Heteroatom Chem. 1997, 17, 245-270.

Kiyooka Group Work

1. 4, 6, CH2Cl2, -78oC, 8 h

(82%)

2. Ni2B- H2, EtOH(85%)

6

7

8

Opposite to the original target.

Explanation of the Unexpected Selectivity in the Aldol Reaction

Favored transition state

disfavored transition state

J.O.C., 1999, 64(15), 5511-5523.

8

Overcome the Problem of Unexpected Selectivity

16

33% + the recovered 16

After cyclization to the macrolactone, epimerization at C10 overcame the problem.

10

Kiyooka Group Work

83% de

Kiyooka Group Work

Highly selective synthesis of C10-epi seco acid derivative of (+)-

Acutiphycin was accomplished in 17 steps with an overall yield of 8.2%.

The six stereogenic centers were achieved form hexanal by using the chiral

oxazaborolidinone-promoted asymmetrical aldol reactions.

Which was opposite to the original target.

Miftakhov and Co-workers WorkC9-C13 segment of (+)-Acutiphycin

Russ. Chem. Bull., Int. Ed., 2001, 50(6), 1101-1106

levoglucosan




C9- C13 segment of (+)-Acutiphycin was accomplished from levoglucosan in 9 steps with an overall yield of 16.9%.

Léger and Co-workers Work C1-C8 fragment of (+)-Acutiphycin

Tetrahedron Lett., 2002, 43, 1147-1150.

Intramolecular Lewis acid-catalyzed reaction


69% ee


Lewis Acid: TiCl4 (65%)

C1-C8 segment of (+)-Acutiphycin was achieved in 11 steps with an overall yield of 17%.

Timothy F. Jamison

Born in in San Jose

B.S., University of California, Berkeley (1990)

Ph.D., Harvard University (Prof. Stuart L. Schreiber) (1991-1997).

P.D.F., Harvard University (Prof. Eric N. Jacobsen) (1997-1999)

Assistant Professor, MIT (1999-2004).

Associate Professor, MIT (2004-Now)

Research -Completed and Ongoing

Epoxide-opening cascades.

Carbon-carbon bond formation.

Target-oriented synthesis.

Timothy F. Jamison Nickel catalyzed carbon-carbon bond formation

Org. Lett. 2000, 2(26), 4221-4223.J.A.C.S.; 2004, 126, 4130-4131. J.A.C.S.; 2004, 126, 15342-15343. Org. Lett. 2006, 8(3), 455-458.Org. lett., 2005, 7(14), 2937-2940.

Org. Lett., 2005, 7(14), 3077-3080.Tetrahedron. 2003, 59, 8913-8917.Tetrahedron. 2005, 61, 11405-11417.Tetrahedron. 2006, 62, 7598-7610.Tetrahedron. 2006, 62, 11350-11359.

Angew. Chem. Int. Ed. 2003, 42(12), 1364-1367.Angew. Chem. Int. Ed. 2004, 43, 3941-3944.Adv. Synth. Catal. 2005, 347, 1533-1536.J.A.C.S., 2006, 128, 5362-5363.J.A.C.S., 2004, 126, 15342-15343.

H R

NR

O

RH

H

R R

HRR

RR

R

O

R

R

R

R

OH

R

R

R

OH

OR

R

R

R

HN

R

R

R

R OH

R

X3

RHO

R

R R

OH

R

R

R

R

OH

RR

R R

HO R

R

OSiR3

R

OSiR3

RR

R

OSiR3

R

Ni(cod)2

Jamison Nickel catalyzed carbon-carbon bond formation

Org. Lett. 2000, 2(26), 4221-4223.

Jamison Nickel catalyzed reductive coupling of aldehyde and

chiral 1,6-Enynes

Org. Lett. 2006, 8(3), 455-458.

Tetrahedron. 2006, 62, 7598-7610.

P

PCyp3

Jamison Nickel catalyzed reductive coupling of aldehyde and

1,6-Enynes

Proposed mechanism by Jamison

Org. Lett. 2006, 8(3), 455-458.

R'

3

RCHOCat. PCyp3

RCHO

>95: 5 regioselectivity

3

R'

R

OH

>95: 5 regioselectivity

Ni

R' L H

R

O

Ni

R'

Ni

R'

C-C bond formation

RH

3

R'

R

OH

A B

RCHO

type I

A

Ni

R' PCyp3

Ni

R' PCyp3

C-C bond formation

RCHO

type II

B

O

R

H

O Ni

R' PCyp3

OH

R

3

R'

R

OH

Ni(cod)2Et3B

Ni(cod)2Et3B

3

R'

R

OH

Jamison Group Work-Retrosynthetic Analysis

O

OH

O

OH

OO

OH H

Nickel Catalyzed Reductive Coupling

*

*

**

**


1

9

13

O

OH

O

OH

OO

OH H

*

*

**

**

(+)- Acutiphycin (1)

MeO O

O OTBDPS

1

OAc

n-Bu

Y

X

2: X= OTBS, Y= H;3: X= H, Y= OTBS

4O

OTBDPS

OTBSOO

OMe H

*

*

**

*

OTBS

**

OHOTBDPS

O

OMe

S/R

+


6 5


(5 steps)

Jamison Group Work

OTBS

OHO

MeO

O

TBDPS

S/R

Claisen condensation

MeO O

O OTBDPS

1

Y

X

2: X= OTBS, Y= H;3: X= H, Y= OTBS

+

(5 steps)


XHydroacylation

X

O

OH

O

OH

OO

OH H

*

*

**

**

or

O

OTBDPS

OTBSOO

OMe H

*

O

OTBDPS

OTBSOO

OMe H

*O

[O]

6

9 linear steps

Jamison Group Work

O

OH

O

OH

OO

OH H

*

*

**

**

Aldol condensation

X

Jamison Group Work -Retrosynthetic Analysis

MeO O

O OTBDPS

OEt

OMs

H

Et

O

O

OTES

On-Bu

3

4

2 (5 steps)

5 (5 steps)

6OTES

TESO

8 (5 steps)

O

OH

O

OH

OO

OH H

Wipf Coupling

Pd Coupling

SmI2 Reformatsky Reaction

Jamison-FunkEne-Macrolactonisation

Alkyne Addition*

*

**

**

Pd Catalyzed Couplinganti-homopropargylic alcohol

Proposed mechanism by Marshall.

Marshall, J. A. et al. J.O.C., 1999, 64, 5201-5204.

OMs

H

Et

O

O

3

4

OTESTESO

8

OTESTESO

Wipf Hydrozirconation-Transmetallation –Stereoselective Carbonyl Addition

Wipf., P. et al, Tetrahedron Lett., 1994, 35, 5197-5200.

Wipf., P. et al, J.Org. Chem., 1998, 63, 6454-6455.

MeO O

O OTBDPS

2

Jamison Group Work -Introduced the side chain

XMukaiyama aldol reaction

XHorner-Wadsworth-Emmons reaction

XCross- metathesis reaction

NBS

99%

OSiEt3

On-Bu

NBS

99%

5

Jamison Group Work -SmI2 Reformatsky reaction

For Reformatsky reaction, they tried Zn/Ag-graphite, no desired product generated. When switched to SmI2, they succeeded.

Fulvia Orsini, Elvira Maria Lucci, Tetrahedron Lett., 2005, 46, 1909-1911.

Richard J. Arhart, J. C. Martin, J.A.C.S., 1972, 94, 5003-5010.

Martin Sulfrane is specially used for dehydration of 2o and 3o

carbinols with excellent yield.

OSiEt3

On-Bu

5

Jamison Group WorkAlkyn addition

Ethoxyethyne and another OH group were introduced.

Jamison Group WorkJamison-Funk Ene-Macrolactonisation

Funk, R.L.; et al., Synlett., 1989, 36-37.

Jamison Group Work

O

OTBDPS

OH

OTES

OO

OMe H1. Citric acid, MeOH 2. TESOTf, 2,6-lutidineO

OTBDPS

OH

OH

OO

OMe H

Jamison Group Work

Highly convergent total synthesis of (+)-Acutiphycin was

accomplished in 18 steps with an overall yield of 3.1%.

Applied nickel catalyzed reductive coupling reaction was not successful in this total synthesis.

Richard E. TaylorUniversity of Notre Dame

Towards the total synthesis of (+)-Acutiphycin: utilization of homoaldol methodology in the preparation of enantioselective acetate aldol

1987 B.S. SUNY Oswego

1992 Ph.D. Rensselaer Polytechnic Institute Arthur G. Schultz

1992-1995 P.D.F, Stanford University,

1995-2001 Assistant Professor,

2001-2004 Associate Professor,

2004-present Professor

Richard E. Taylor

Documents

Total Synthesis of (+)-Acutiphycin and (+)-trans-20,21-didehydroacutiphycin Wei Lin Literature Meeting Charette Group Dec. 5 th, 2006