Polycavernoside A:

The Prins Macrocyclization Approach

Sang Kook Woo and Eun Lee

Seoul National University, Seoul, Korea

J. Am. Chem. Soc. 2010, 132, 4564–4565

Marie-Céline Frantz

Wipf Group - Current Literature

April 24, 2010

OO

MeO

OMe

O

O

HOOMe

OMe

O

OO

OO

HO

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Polycavernoside A

• Isolated by Yasumoto from the edible red alga Polycavernosa

tsudai in Guam in 1991.

• Responsible for sudden and fatal human intoxication in Guam

in 1991 and in the Philippines in 2002.

• Symptoms: gastrointestinal (vomiting, diarrhea) and

neurological (scratching, muscle spasms, paralysis) disorders.

• Cyanobacterial origin speculated.

• Group of macrolides with:

– structurally unique 13-membered central lactone ring

– disaccharide and trienyl side chains.

• Polycavernoside A analogs also isolated:

• Estimated LD99 in mice (ip) of PA and PB: 200-400 µg/kg.

• SAR: macrocyclic core and iPr-polyene side chain required

for high toxicity.

• Hydrolysis of the disaccharide in the stomach would deliver

the aglycone bioactive form.

• Postulated mechanism of action: triggers an initial

extracellular calcium entry into the cytosol, resulting in

membrane depolarization.

Yotsu-Yamashita, M.; Haddock, R. L.; Yasumoto, T. J. Am. Chem. Soc. 1993, 115, 1147. Yotsu-Yamashita, M.; Yasumoto, T.; Yamada, S.; Bajarias, F. F.

A.; Formeloza, M. A.; Romero, M. L.; Fukuyo, Y. Chem. Res. Toxicol. 2004, 17, 1265. Yotsu-Yamashita, M.; Seki, T.; Paul, V. J.; Naoki, H.; Yasumoto, T.

Tetrahedron Lett. 1995, 36, 5563. Yotsu-Yamashita, M.; Abe, K.; Seki, T.; Fujiwara, K.; Yasumoto, T. Tetrahedron Lett. 2007, 48, 2255. Barriault, L.;

Boulet, S. L.; Fujiwara, K.; Murai, A.; Paquette, L. A.; Yotsu-Yamashita, M. Bioorg. Med. Chem. Lett. 1999, 9, 2069. Cagide, E.; Louzao, M. C.; Ares, I. R.;

Vieytes, M. R.; Yotsu-Yamashita, M.; Paquette, L. A.; Yasumoto, T. Cell. Phys. Biochem. 2007, 19, 185.

OO

R2

OMe

O

O

R3OMe

OMe

O

O

R1

OO

MeO OH

Polycavernosides C

diene

triene

PC2 OMe

R2R1

OMe

R3

OMediene

triene

PC OAc

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Polycavernoside A: Structure Determination & Synthesis

• Yasumoto (1993): determination (1D/2D NMR) of the partial relative structure of:

– each sugar component,

– bottom (C1-C8) and upper (C9-C15) halves of the macrolactone part.

• Murai (1995): determination (synthetically) of the relative configuration of the sequence of the

fucose-xylose bottom half of the macrolactone.

• Murai (1998): 1st total synthesis & determination of the absolute configuration.

Yotsu-Yamashita, M.; Haddock, R. L.; Yasumoto, T. J. Am. Chem. Soc. 1993, 115, 1147. Fujiwara, K.; Amano, S.; Murai, A. Chem. Lett. 1995, 855.

Fujiwara, K.; Murai, A.; Yotsu-Yamashita, M.; Yasumoto, T. J. Am. Chem. Soc. 1998, 120, 10770. Paquette, L. A.; Barriault, L.; Pissarnitski, D. J. Am.

Chem. Soc. 1999, 121, 4542. Paquette, L. A.; Barriault, L.; Pissarnitski, D.; Johnston, J. N. J. Am. Chem. Soc. 2000, 122, 619. White, J. D.;

Blakemore, P. R.; Browder, C. C.; Hong, J.; Lincoln, C. M.; Nagornyy, P. A.; Robarge, L. A.; Wardrop, D. J. J. Am. Chem. Soc. 2001, 123, 8593.

Blakemore, P. R.; Browder, C. C.; Hong, J.; Lincoln, C. M.; Nagornyy, P. A.; Robarge, L. A.; Wardrop, D. J.; White, J. D. J. Org. Chem. 2005, 70, 5449.

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(‒)-Polycavernoside A: Murai's synthesis (1998)

Fujiwara, K.; Murai, A.; Yotsu-Yamashita, M.; Yasumoto, T. J. Am. Chem. Soc. 1998, 120, 10770.

35 steps

(longest

linear

sequence)

O

OH

(R)-(+)-Glycidol

OH OBn

CO2Me

O

Stereoselective intramol.Michael cyclization

OBn

OH CO2Me

t-BuOK

91%

O

OBn

OTBSSEtEtS

O

14 steps 7 stepsHO OH

17 steps

O OOMe

OBn

PMBO

PMBO OTBS

O

OH

HO

OH

OO

O

OBn

OOMeO

1. Swern2. PMB cleavage3. Pinnick4. Cl3PhCOCl, Et3N;

DMAP; >75%

Yamaguchimacrolactonization

O

OO

OO

HO

OH

I1. Dihydroxylation2. Oxidative cleavage3. PG manipulation4. Takai iodovinylation5. TFA/H2O/THF, >95%

Acid-mediated acetalrearrangement

1. Glycosidation2. Bn cleavage3. Cross-coupling

O

MgBr

OH

1. TsCl2. NaNH2

Z/E sep.I

Cp2ZrCl2LiEt3BH;

I2

Hg

t-BuLi;HgCl2

2

PMBO OTBS

OH

O

OBn

TBSO

PMBO OTBS

OH

O

OBn

TBSO

EtS SEt

O

SEt

OO

MeO

OMe

O

O

HOOMe

OMe

O

OO

OO

HO

( )-Polycavernoside A

LDA; then

+

46%33%

TsOH,MeOH/(MeO)3CH

- Thio/sulfinyl gps removal- TBS cleavage- Cyclic Me acetal formation

65-68%

OBnO

HO

CO2Me

+

Sulfoxideanion addition

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(‒)-Polycavernoside A: Paquette's synthesis (1999)

Paquette, L. A.; Barriault, L.; Pissarnitski, D. J. Am. Chem. Soc. 1999, 121, 4542.

Paquette, L. A.; Barriault, L.; Pissarnitski, D.; Johnston, J. N. J. Am. Chem. Soc. 2000, 122, 619.

32 steps

(longest

linear

sequence)

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(‒)-Polycavernoside A: White's synthesis (2001)

White, J. D.; Blakemore, P. R.; Browder, C. C.; Hong, J.; Lincoln, C. M.; Nagornyy, P. A.; Robarge, L. A.; Wardrop, D. J. J. Am. Chem. Soc. 2001,

123, 8593. Blakemore, P. R.; Browder, C. C.; Hong, J.; Lincoln, C. M.; Nagornyy, P. A.; Robarge, L. A.; Wardrop, D. J.; White, J. D. J. Org.

Chem. 2005, 70, 5449.

25 steps

(longest

linear

sequence)

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The Prins Reaction

Crosby, S. R.; Harding, J. R.; King, C. D.; Parker, G. D.;Willis, C. L. Org. Lett. 2002, 4, 577. Barry, C. S. J.; Crosby, S. R.; Harding, J. R.; Hughes,

R. A.; King, C. D.; Parker, G. D.; Willis, C. L. Org. Lett. 2003, 5, 2429. Jasti, R.; Anderson, C. D.; Rychnovsky, S. D. J. Am. Chem. Soc. 2005,

127, 9939. Jasti, R.; Rychnovsky, S. D. J. Am. Chem. Soc. 2006, 128, 13640.

Selectivity of nucleophilic capture at C4 dependent on reactivity:

- Highly reactive nucleophile (e.g.: Br-) and electrophile: axial attack

- Less reactive nucleophile (e.g.: AcO-, TFA-) and electrophile:

equatorial attack

Prins cyclization vs competing oxonia-Cope rearrangement Cyclization of (E)- and (Z)-Homoallylic Alcohols

Stereochemical outcome for Prins cyclizations

Excellent stereocontrol.

All the substituents in the equatorial position.

OH

OTBS

O

Cl OTBS

38% (40% r.s.m.)

EtCHO, EtAlCl2

DCM

OH O

Cl OTBS

1 : 3 (36%)

EtCHO, EtAlCl2

DCM

OTBS

9:1 Z/E

O

Cl OTBS

+

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The Prins Reaction: Application in Total Synthesis

• Application in the total synthesis of (‒)-Blepharocalyxin D (Lee, 2007)

– Optimization of the conditions of Willis & coworkers

• Application of the intramolecular Prins macrocyclization in the total synthesis of (+)-Neopeltolide

(Lee, 2008)

Ko, H. M.; Lee, D. G.; Kim, M. A.; Kim, H. J.; Park, J.; Lah, M. S.; Lee, E. Org. Lett. 2007, 9, 141.

Ko, H. M.; Lee, D. G.; Kim, M. A.; Kim, H. J.; Park, J.; Lah, M. S.; Lee, E. Tetrahedron 2007, 63, 5797.

Woo, S. K.; Kwon, M. S.; Lee, E. Angew. Chem., Int. Ed. 2008, 47, 3242.

HO

O

O

OH

OH

OH

H

( )-Blepharocalyxin D

OH

OAc

MeO

OAc

O

OAc

MeO

OAc

OAc

OMe

CHO

OMe

(1.2 equiv.)

TESOTf (4.0 equiv.)TMSOAc (1.0 equiv.)

AcOH (40 equiv.)rt, 1 h, 60%

single diastereomer

H

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(‒)-Polycavernoside A Total Synthesis: Title Paper

Woo, S. K.; Lee, E. J. Am. Chem. Soc. 2010, 132, 4564.

(enantiomer)

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(‒)-Polycavernoside A Total Synthesis: Title Paper

Woo, S. K.; Lee, E. J. Am. Chem. Soc. 2010, 132, 4564.

OTBS

OH O O

OEt

OEtOH

OAc O O

OEt

OEt

1. Ac2ODMAP

2. HF py

90%

TESOTfTMSOAcAcOH

85%

*

O

O

OO

OO

HO

O

O

OAc

OAc

O

O

OAc

6:1 d.r.

O3;PPh3

79%

O

O

OAc

O

O

CrCl2CHI3

Complexproductmixture

OH

OH O O

OEt

OEt

HF py 81%

TESOTf (10 equiv)TMSOAc (15 equiv)AcOH

*

O

O

O

OH

OAc

69%

5.5:1 d.r.

OO

O

OAc

O

PtO2, COK2CO3;4 A MS OO

O

OAc

OOMe

1. DMDO;PPTS, MeOH

2. TPAP, NMO4 A MS

72% (3 steps)

1. O3; PPh32. CrCl2, CHI33. K2CO3

OH

I

54%

O

OO

MeO

OMe

O

O

HOOMe

OMe

O

OO

OO

HOO

OMeO

OMe

SPh

O

BnOOMe

OMe

Bu3Sn

1. NBS, 4 A MS

2. DDQ3. PdCl2

23%

( )-Polycavernoside A

Prins

Prins6-endo intramol.alkyne hydration

Fortuitous rearrangementupon prolonged exposureto Takai conditions

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Conclusion and Perspectives

• Novel approach for the total synthesis of (‒)-Polycavernoside A.

• Use of a Prins macrocyclization strategy to build chemical complexity in a single step:

– 2 new rings

– 3 new stereocenters

• Comparison of synthetic routes to the macrocycle:

• Perspectives: further applications of the Prins macrocyclization strategy in the synthesis of complex

natural products.

5.34.71.52.6Overall yield (%)

19222932Longest linear sequence (steps)

LeeWhitePaquetteMurai

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