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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
Marie-Celine Frantz @ Wipf Group Page 1 of 11 4/26/2010
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
Marie-Celine Frantz @ Wipf Group Page 2 of 11 4/26/2010
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.
Marie-Celine Frantz @ Wipf Group Page 3 of 11 4/26/2010
(‒)-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
Marie-Celine Frantz @ Wipf Group Page 4 of 11 4/26/2010
(‒)-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)
Marie-Celine Frantz @ Wipf Group Page 5 of 11 4/26/2010
(‒)-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)
Marie-Celine Frantz @ Wipf Group Page 6 of 11 4/26/2010
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
+
Marie-Celine Frantz @ Wipf Group Page 7 of 11 4/26/2010
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
Marie-Celine Frantz @ Wipf Group Page 8 of 11 4/26/2010
(‒)-Polycavernoside A Total Synthesis: Title Paper
Woo, S. K.; Lee, E. J. Am. Chem. Soc. 2010, 132, 4564.
(enantiomer)
Marie-Celine Frantz @ Wipf Group Page 9 of 11 4/26/2010
(‒)-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
Marie-Celine Frantz @ Wipf Group Page 10 of 11 4/26/2010
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
Marie-Celine Frantz @ Wipf Group Page 11 of 11 4/26/2010