Synthesis of the bis-tetrahydropyran core of amphidinol 3

Article abstract of DOI:10.1021/ol1015898

A convergent synthesis of the C31-C52 bis-tetrahydropyran core of the natural product amphidinol 3 is reported. A common intermediate was synthesized from d-tartaric acid utilizing an asymmetric glycolate alkylation/ring-closing metathesis sequence to construct the THP rings. Differential elaboration of the common intermediate allowed the synthesis of two distinct coupling partners which were joined through a modified Horner-Wadsworth-Emmons olefination to provide the bis-tetrahydropyran core.

Full text of DOI:10.1021/ol1015898

ORGANIC
LETTERS
2010
Vol. 12, No. 17
3890-3893
Synthesis of the Bis-tetrahydropyran
Core of Amphidinol 3
Michael T. Crimmins,* Timothy J. Martin, and Theodore A. Martinot
Kenan and Caudill Laboratories of Chemistry, UniVersity of North Carolina at Chapel
Hill, North Carolina 27599
crimmins@email.unc.edu
Received July 9, 2010
ABSTRACT
A convergent synthesis of the C31-C52 bis-tetrahydropyran core of the natural product amphidinol 3 is reported. A common intermediate
was synthesized from D-tartaric acid utilizing an asymmetric glycolate alkylation/ring-closing metathesis sequence to construct the THP rings.
Differential elaboration of the common intermediate allowed the synthesis of two distinct coupling partners which were joined through a
modified Horner-Wadsworth-Emmons olefination to provide the bis-tetrahydropyran core.
Amphidinol, isolated from Amphidinium klebsii, was dis-
covered in 1991 by Yasumoto and co-workers and
determined to be the first member of a new class of
polyketide metabolites.1 The amphidinols, unlike poly-
cyclic ethers isolated from other dinoflagellates, are mainly
characterized by long carbon chains with multiple hy-
droxyl groups and polyolefins. Amphidinol 3 (1, Scheme
1) was discovered in 1996 from the same organism and
is reported to have the greatest antifungal and hemolytic
activity of any of the amphidinols reported to date.2 The
67-carbon backbone contains 25 stereocenters, a highly
oxygenated bis-tetrahydropyran core (C31-C51), a heavily
unsaturated region featuring a unique (E,E,E)-triene
(C52-C67), and a polyol domain consisting of repeating
1,5-diol moieties (C1-C30).3 In 2008, Murata published
a revised structure, in which the absolute configuration
at C2 had been changed to R.4
Because of its biological activity and challenging
structure, amphidinol 3 has garnered much attention from
the synthetic community. Although no total syntheses have
been reported to date, fragment syntheses have been
reported by several laboratories4-10 including contributions
from Marko´,6 Oishi,7 Paquette,8 Roush,9 and Rychnovsky10
toward the synthesis of the tetrahydropyran core.
(5) (a) BouzBouz, S.; Cossy, J. Org. Lett. 2001, 3, 1451–1454. (b) Cossy,
J.; Tsuchiya, T.; Ferrie, L.; Reymond, S.; Kreuzer, T.; Colobert, F.; Jourdain,
P.; Marko, I. E. Synlett 2007, 2286–2288. (c) Colobert, F.; Kreuzer, T.;
Cossy, J.; Reymond, S.; Tsuchiya, T.; Ferrie, L.; Marko, I. E.; Jourdain, P.
Synlett 2007, 2351–2354
.
(6) Dubost, C.; Marko´, I. E.; Bryans, J. Tetrahedron Lett. 2005, 46,
4005–4009
.
(7) Kanemoto, M.; Murata, M.; Oishi, T. J. Org. Chem. 2009, 74, 8810–
(1) Satake, M,; Murata, M.; Yasumoto, T.; Fujita, T.; Naoki, H. J. Am.
Chem. Soc. 1991, 113, 9859–9861.
8813
.
(8) (a) Chang, S. K.; Paquette, L. A. Org. Lett. 2005, 7, 3111–3114. (b)
(2) Paul, G. K.; Matsumori, N.; Konoki, K.; Sasaki, M.; Murata, M.;
Tachibana, K. In Harmful and Toxic Algal Blooms, Proceedings of the
Seventh International Conference on Toxic Phytoplankton; UNESCO:
Sendai, Japan, 1966; p 503.
Bedore, M. W.; Chang, S. K.; Paquette, L. A. Org. Lett. 2007, 9, 513–516.
(9) (a) Flamme, E. M.; Roush, W. R. Org. Lett. 2005, 7, 1411–1414.
(b) Hicks, J. D.; Flamme, E. M.; Roush, W. R. Org. Lett. 2005, 7, 5509–
5512. (c) Hicks, J. D.; Roush, W. R. Org. Lett. 2008, 10, 681–684
.
(3) Murata, M.; Matsuoka, S.; Matsumori, N.; Paul, G. K.; Tachibana,
K. J. Am. Chem. Soc. 1999, 121, 870.
(10) (a) Huckins, J. R.; de Vicente, J.; Rychnovsky, S. D. Org. Lett.
2007, 9, 4757–4760. (b) Huckins, J. R.; de Vicente, J.; Rychnovsky, S. D.
Angew. Chem., Int. Ed. 2006, 45, 7258–7262. (c) de Vicente, J.; Betzemeier,
(4) Oishi, T.; Kanemoto, M.; Swasono, R.; Matsumori, N.; Murata, M.
Org, Lett. 2008, 10, 5203–5206.
B.; Rychnovsky, S. D. Org. Lett. 2005, 7, 1853–1856
.
10.1021/ol1015898  2010 American Chemical Society
Published on Web 08/12/2010

Scheme 1. Retrosynthetic Analysis
Scheme 2. Synthesis of Tetrahydropyran 5 and Elaboration to ꢀ-Ketophosphonate 3
On the basis of the retrosynthetic plan illustrated in
Scheme 1, bis-tetrahydropyran core 2 was established as the
initial target. Our strategy focused on exploitation of the
symmetry of the C31-C39 and C44-C52 tetrahydropyran
moieties to access the core bis-tetrahydropyran unit. A
Horner-Wadsworth-Emmons olefination would introduce
the desired C40-41 bond as an enone that could be further
elaborated. Tetrahydropyran 5 would be obtained utilizing
the asymmetric glycolate alkylation/ring-closing metathesis
strategy developed in our laboratories.11
Synthesis of tetrahydropyran 5 is illustrated in Scheme 2.
Known aldehyde 6 was accessed via D-tartaric acid, following
a four-step protocol (Scheme 2).12 Several conditions for the
vinyl addition to aldehyde 6 were tested, and ultimately
Felkin-Ahn controlled divinyl zinc addition was deterem-
ined to deliver allylic alcohol 7 as a 9:1 ratio of inseparable
Org. Lett., Vol. 12, No. 17, 2010
3891

Scheme 3. Synthesis of Aldehyde 4 and Fragment Coupling
diastereomers in 80% yield. Alkylation of alcohol 7 with
Having accessed tetrahydropyran 5, NOESY analysis
revealed the desired trans ring fusion of the major product.
This is in agreement with the expected Felkin addition of
the divinyl zinc reagent, as well as the chiral auxiliary
directed glycolate alkylation. 2D NMR analysis of the
intermediate dihydropyran also supports the assignment of
trans ring fusion. NOESY analysis was further employed to
determine the structure of the major diastereomer obtained
as a result of the dihydroxylation of the dihydropyran.
With common intermediate 5 in hand, our attention turned
to the synthesis of the two coupling partners, ꢀ-ketophos-
phonate 3 and aldehyde 4. Synthesis of the C41-C52
tetrahydropyran coupling partner 3 was initiated by metha-
nolysis of the acetate followed by Swern oxidation14 to
access aldehyde 12 (Scheme 2). A glycolate anti aldol
reaction15 between aldehyde 12 and N-glycolyl oxazolidi-
nethione 13 introduced the C43 and C44 stereocenters as a
10:1 ratio of separable diastereomers in 44% yield. Varying
the amount of Lewis acid used in the reaction in an attempt
to increase the yield resulted in decomposition or decreased
selectivities. Simple conversion of aldol adduct 14 to the
desired coupling partner, ꢀ-ketophosphonate 3, was effected
by protection of the alcohol as the TBS ether and direct
displacement of the auxiliary with lithiated dimethyl meth-
ylphosphonate16 in 89% yield.
bromoacetic acid afforded acid 8, which could be coupled
with a valine-derived oxazolidinone to afford N-glycolyl
oxazolidinone 9. At this point the two diastereomers could
be readily separated by chromatography.
Alkylation of the sodium enolate of 9 with allyl iodide
introduced a key stereocenter with excellent diastereoselectivity
(>95:5).11 Reductive removal of the auxiliary followed by
protection of the resultant alcohol afforded diene 11. The
alkylation could be performed on 20 g scale and carried forward
without purification to diene 11. From diene 11, a ring-closing
metathesis followed by a dihydroxylation would provide the
requisite functionality of common intermediate 5.
Thus, direct exposure of the unpurified RCM product to
sodium periodate followed by protection of the diol as an
acetonide provided tetrahydropyran 5. As shown previously
in the literature,13 addition of a Lewis acid decreased the
amount of undesired overoxidation during dihydroxylation.
Following this procedure, tetrahydropyran 5 could be ob-
tained in up to 73% yield over three steps as a 5:1 mixture
of diastereomers in multigram quantities. The selectivity of
this sequence is comparable to other conditions explored for
dihydroxylation and requires no chromatography between
reactions. Although the sequence could be performed with
the primary alcohol unprotected, it was found that conversion
of the primary alcohol to an acetate was required to facilitate
separation of the diastereomers.
As a consequence of utilizing a common intermediate for
the synthesis of both coupling partners, the two primary
alcohols at C32 and C52 were both protected as benzyl
ethers. However, differential protection of the two primary
(11) (a) Crimmins, M. T.; Emmitte, K. A. Org. Lett. 1999, 1, 2029–
2032.
(12) Mukaiyama, T.; Suzuki, K.; Yamada, T.; Tabusa, F. Tetrahedron
1990, 46, 265.
(14) Huang, S. L.; Swern, D. J. Org. Chem. 1978, 43, 4537–4538.
(15) Crimmins, M. T.; McDougall, P. J. Org. Lett. 2003, 5, 591–594.
(16) Delamarche, I.; Mosset, P. J. Org. Chem. 1994, 59, 5453–5457.
(13) Beligny, S.; Eibauer, S.; Maechling, S.; Blechert, S. Angew. Chem.,
Int. Ed. 2006, 45, 1900–1903.
3892
Org. Lett., Vol. 12, No. 17, 2010

alcohols is required for the selective introduction of the
polyene and polyol domains of amphidinol 3. To this end,
before completing aldehyde 4 from common intermediate
5, the benzyl ether was cleaved, and the resulting primary
alcohol was protected with TBSCl to afford silyl ether 16
(Scheme 3).
Removal of the acetate protecting group afforded alcohol
17, which was oxidized under Swern conditions. Various
conditions were tested to introduce the C39 stereocenter;
however, a stereoselective vinyl addition remained elusive.
The allylic alcohol was obtained at best in 86% yield as a
3.5:1 mixture of diastereomers. Addition of nucleophiles to
similar aldehydes has been previously reported with com-
parable results.8,10
In light of these difficulties, an alternative oxidation/
stereoselective reduction sequence was pursued. Oxidation
of the mixture of allylic alcohols derived from 18 with
Dess-Martin periodinane17 provided enone 19, which upon
CBS reduction18 afforded a single diastereomer of allylic
alcohol 20. Advanced Mosher ester analysis19 was used
to determine that the stereocenter at C39 was indeed the
desired R configuration. With the stereochemistry con-
firmed, the allylic alcohol was then protected as a
methoxymethyl ether to afford alkene 21. Several oxida-
tion conditions to access aldehyde 4 were tested, including
ozonolysis and oxidative cleavage with ruthenium chloride
and sodium periodate. However, it was found that the
Johnson-Lemieux oxidation utilized by Paquette8b pro-
vided the best yields of aldehyde 4.
mixture of E:Z isomers. Switching to the MOM ether saw
an increase in yield and a decrease in reaction times.
Treatment of ꢀ-ketophosphonate 3 with barium hydroxide
followed by addition of aldehyde 4 afforded the desired
enone 22 in 74% yield and granted access to the carbon
backbone of the C31-C52 domain of amphidinol 3.
To complete the synthesis of the fragment, reduction of
the C40-C41 alkene and formation of the 1,1-disubstituted
alkene at C42 remained. A conjugate reduction was per-
formed on enone 18 utilizing methyl copper and di-
isobutylaluminum hydride21 to provide ketone 23. Subse-
quent transformation of ketone 23 to the bis-tetrahydropyran
core 2 via a methylene Wittig reaction22 proved inconsistent
and low yielding on a variety of similar systems. Treatment
of ketone 23 with the Tebbe reagent23 at lower temperatures
resulted in recovered starting material, even after prolonged
reaction, however it was found that heating the reaction
mixture for six hours resulted in formation of the 1,1-
disubstituted alkene in 73% yield, providing the fully
assembled bis-tetrahydropyran core 2 of amphidinol 3 (1).
In conclusion, we report the convergent synthesis of the
C31-C52 bis- tetrahydropyran core 2 of amphidinol 3
utilizing our asymmetric glycolate alkylation/ring-closing
metathesis strategy. This approach allows for the synthesis
of the C31-C40 and C41-C52 tetrahydropyrans from a
common intermediate (5) that is accessible on multigram
scale. Future work will focus on the synthesis of the polyol
and polyene domains and their union with the bis-tetrahy-
dropyran core.
With both coupling partners in hand, a modified Horner-
Wadsworth-Emmons reaction20 was pursued (Scheme 3).
Initial attempts at union of the two fragments were carried
out with the C39 hydroxyl group protected as a TBS ether
instead of the MOM ether. It was found that the desired
enone could be accessed in 52% yield, as an inconsequential
Acknowledgment. Financial support from the National
Institute of General Medical Sciences (GM60567) is grate-
fully acknowledged.
Supporting Information Available: Experimental details
and spectral data for new compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
(17) Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155–4156.
(18) (a) Corey, E. J.; Bakshi, K.; Shibata, S. J. Am. Chem. Soc. 1987,
109, 5551–5553. (b) Corey, E. J.; Helal, C. J. Angew. Chem., Int. Ed. 1998,
37, 1986–2012.
OL1015898
(19) (a) Dale, J. A.; Mosher, H. S. J. Am. Chem. Soc. 1973, 95, 512–
519. (b) Hoye, T. R.; Jefferson, C. S.; Feng, S. Nat. Protoc. 2007, 10, 2451–
2458.
(21) Tsuda, T.; Hayashi, T.; Satomi, H.; Kawamoto, T.; Saegusea, T. J.
Org. Chem. 1986, 51, 537–540.
(22) Wittig, G.; Haag, W. Chem. Ber. 1955, 88, 1654–1666.
(23) Tebbe, F. N.; Parshall, G. W.; Reddy, G. S. J. Am. Chem. Soc.
1978, 100, 3611–3613.
(20) Alvarezibarra, C.; Arias, S.; Banon, G.; Fernandez, M. J.; Rodriguez,
M.; Sinisterra, V. J. J. Chem Soc., Chem. Commun. 1987, 1509–1511.
Org. Lett., Vol. 12, No. 17, 2010
3893