Synthesis of the C1-C52 fragment of amphidinol 3, featuring a β-alkoxy alkyllithium addition reaction

Article abstract of DOI:10.1021/ol7020934

(Chemical Equation Presented) An advanced intermediate for the synthesis of amphidinol 3 has been prepared. A cross-metathesis reaction was used to couple the C1-C12 and C13-C26 segments. An unusual β-alkoxy alkyllithium reagent was generated from this se

Full text of DOI:10.1021/ol7020934

ORGANIC
LETTERS
2007
Vol. 9, No. 23
4757-4760
Synthesis of the C1
Amphidinol 3, Featuring a
Alkyllithium Addition Reaction
−
C52 Fragment of
â
-Alkoxy
John R. Huckins, Javier de Vicente, and Scott D. Rychnovsky*
Department of Chemistry, 1102 Natural Sciences II, UniVersity of California,
IrVine, California 92697-2025
srychnoV@uci.edu
Received August 24, 2007
ABSTRACT
An advanced intermediate for the synthesis of amphidinol 3 has been prepared. A cross-metathesis reaction was used to couple the C1
and C13 C26 segments. An unusual -alkoxy alkyllithium reagent was generated from this segment and added to a Weinreb amide to assemble
the C1 C52 section of amphidinol 3. These compounds represent some of the most advanced intermediates reported to date for the synthesis
−C12
−
â
−
of amphidinol 3.
The amphidinols are a fascinating group of metabolites
isolated from the marine dinoflagellates Amphidinium klebsii
and Amphidinium carterae.1 Amphidinol 3 (1) exhibits potent
hemolytic activity against human erythrocytes as well as
antifungal activity against Aspergillus niger.1 A variety of
amphidinols have been reported, along with the structurally
similar compounds luteophanol A and lingshuiol A and B.2
Common structural features of these natural products are two
highly substituted tetrahydropyran (THP) rings, a long, irreg-
ular polyol domain, and a skipped polyene chain. Among
this family of natural products, only the configuration of am-
phidinol 3 has been assigned. The absolute stereochemistry
of amphidinol 3 was elucidated by Murata and co-workers
using a new and powerful J-based NMR spectroscopic tech-
nique.3 Amphidinol 3 has emerged as an important synthetic
target, and a number of groups, including our own,4 have
reported progress toward its synthesis.5 Herein, we describe
the synthesis of the fully protected C1-C52 fragment.
Our retrosynthetic analysis for amphidinol 3 is illustrated
in Figure 1. The three components are a bis-tetrahydropyran
2, a polyene sulfone 3, and the protected polyol 4. The bis-
THP 2 is similar to and derived from an intermediate we
have previously reported.4 Synthesis and coupling reactions
with the polyene sulfone have also been described.4a The
synthesis of protected polyol phenylthio ether 4 and strategies
for its coupling will be the focus of this discussion.
(1) Murata, M.; Matsuoka, S.; Matsumori, N.; Paul, G. K.; Tachibana,
K. J. Am. Chem. Soc. 1999, 121, 870-871.
(3) Matsumori, N.; Kaneno, D.; Murata, M.; Nakamura, H.; Tachibana,
K. J. Org. Chem. 1999, 64, 866-876.
(2) (a) Paul, G. K.; Matsumori, N.; Murata, M.; Tachibana, K. Tetra-
hedron Lett. 1995, 36, 6279-6282. (b) Satake, M.; Murata, M.; Yasumoto,
T.; Fujita, T.; Naoki, H. J. Am. Chem. Soc. 1991, 113, 9859-9861. (c)
Houdai, T.; Matsuoka, S.; Murata, M.; Satake, M.; Ota, S.; Oshima, Y.;
Rhodes, L. L. Tetrahedron 2001, 57, 5551-5555. (d) Paul, G. K.;
Matsumori, N.; Konoki, K.; Murata, M.; Tachibana, K. J. Mar. Biotechnol.
1997, 5, 124-128. (e) Echigoya, R.; Rhodes, L.; Oshima, Y.; Satake, M.
Harmful Algae 2005, 4, 383-389. (f) Doi, Y.; Ishibshi, M.; Nakamichi,
H.; Kosaka, T.; Ishikawa, T.; Kobayashi, J. i. J. Org. Chem. 1997, 62, 3820-
3823. (g) Huang, X.-C.; Zhao, D.; Guo, Y.-W.; Wu, H.-M.; Trivellone, E.;
Cimino, G. Tetrahedron Lett. 2004, 45, 5501-5504.
(4) (a) de Vicente, J.; Huckins, J. R.; Rychnovsky, S. D. Angew. Chem.,
Int. Ed. 2006, 45, 7258-7262. (b) De Vicente, J.; Betzemeier, B.;
Rychnovsky, S. D. Org. Lett. 2005, 7, 1853-1856.
(5) (a) BouzBouz, S.; Cossy, J. Org. Lett. 2001, 3, 1451-1454. (b)
Flamme, E. M.; Roush, W. R. Org. Lett. 2005, 7, 1411-1414. (c) Hicks,
J. D.; Flamme, E. M.; Roush, W. R. Org. Lett. 2005, 7, 5509-5512. (c)
Chang, S.-K.; Paquette, L. A. Synlett 2005, 2915-2918. (d) Paquette, L.
A.; Chang, S.-K. Org. Lett. 2005, 7, 3111-3114. (e) Dubost, C.; Marko, I.
E.; Bryans, J. Tetrahedron Lett. 2005, 46, 4005-4009. (f) Bedore, M. W.;
Chang, S.-K.; Paquette, L. A. Org. Lett. 2007, 9, 513-516.
10.1021/ol7020934 CCC: $37.00
© 2007 American Chemical Society
Published on Web 10/18/2007

Figure 1. Retrosynthetic analysis of amphidinol 3
The key coupling reaction between phenylthio ether 4 and
Weinreb amide 2 was envisioned as an addition of the alkyl-
lithium reagent derived from 4 to the amide 2. The resulting
â-hydroxy ketone would be suitable for stereoselective reduc-
tion. Elimination of the C25 oxygen would be avoided by
masking it as a lithium alkoxide. Such â-alkoxy alkyllithium
reagents are known. They have been prepared by mercury-
lithium exchange,6 reductive lithiation of chlorohydrins,7 re-
ductive lithiation of oxiranes,8 and from â-hydroxy phenyl-
thio ethers.9 Several reasonably complex â-alkoxy alkyl-
lithium reagents have been prepared by reduction of oxi-
ranes,10 but these reagents have not been used to couple
complex fragments.
TBAF treatment selectively removed the primary TBS group,
and oxidation gave the expected C31 aldehyde. Additions
to this aldehyde were very problematic, perhaps because of
the steric crowding. A 2-propenyllithium addition failed, and
the corresponding Grignard addition gave only trace quanti-
ties of the expected allylic alcohol products. Finally, a
Nozaki-Hiyama-Kishi reaction12 with 2-bromopropene led
to the desired alcohol diastereomers in good yield, and
acylation gave ester 10. Ireland-ester Claisen rearrangement13
using Nakai’s in situ method for generating the silyl ketene
acetal14 produced the expected unsaturated silyl ester in good
yield. Hydrolysis of the silyl ester and coupling with
N-methoxy-N-methylamine produced the Weinreb amide 2
as a single alkene isomer.
A model coupling reaction was investigated as outlined
in Scheme 1. The â-hydroxy phenyl sulfide 5 was prepared
The C14-C26 segment of amphidinol 3 was prepared
from (S)-glyceraldehyde acetonide (11) as illustrated in
Scheme 3. The syn-crotyl adduct 12 was prepared by Roush’s
procedure.15 A set of standard transformations led to the
phenyltetrazole sulfone 13, which was coupled with aldehyde
Scheme 1. Model Coupling of â-Alkoxy Alkyllithium 6 with
Weinreb Amide 7
(6) (a) Barluenga, J.; Fananas, F. J.; Yus, M. J. Org. Chem. 1979, 44,
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46, 1281-1283.
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F.; Soler, T.; Yus, M. Tetrahedron: Asymmetry 2000, 11, 2063-2066. (c)
Yus, M.; Soler, T.; Foubelo, F. Tetrahedron: Asymmetry 2001, 12, 801-
810.
and deprotonated with n-BuLi. Addition of lithium di-tert-
butylbiphenylide (LiDBB)11 at low temperature generated
the â-alkoxy alkyllithium 6. Subsequent addition of the
Weinreb amide 7 produced the desired â-hydroxy ketone 8
in 69% yield. The encouraging outcome of this model study
emboldened us to move forward with the amphidinol 3
synthesis.
(11) Freeman, P. K.; Hutchinson, L. L. J. Org. Chem. 1980, 45, 1924-
1930.
(12) Wessjohann, L. A.; Scheid, G. Synthesis 1999, 1-36.
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1976, 98, 2868-2877.
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Lett. 1996, 37, 3005-3008.
The synthesis of Weinreb amide 2 from the bis-THP
intermediate4a 9 is presented in Scheme 2. Low-temperature
4758
Org. Lett., Vol. 9, No. 23, 2007

alkene or diol diastereomers. Sharpless asymmetric dihy-
droxylation led to a single diastereomer by 1H NMR
analysis.17 Protection of the diol, selective deprotection of
the primary TBS ether,18 and oxidation delivered the alde-
hyde 16 in excellent overall yield. The enone 17 was
prepared by addition of vinylmagnesium bromide to the
aldehyde and oxidation. Both 16 and 17 were plausible
intermediates for the C14-C26 segment of amphidinol 3.
Scheme 2. Synthesis of the C27-C52 Weinreb Amide 2
Initially, we planned to add a C1-C13 organozinc reagent
to aldehyde 16 to assemble the C1-C26 fragment.19 We
prepared the protected polyol 18 using a modification of
Cossy’s elegant metathesis route (Scheme 4).5a,20 Unfortu-
nately, numerous attempts to prepare a dialkylzinc reagent
from 18 failed; the hydroboration was successful, but the
transmetalation was not. Ultimately, the successful coupling
strategy used a cross-metathesis reaction (Scheme 4).21 Enone
17 was combined with triene 18 in a 1:1 molar ratio and
exposed to the Grubbs-Hoveyda catalyst (10 mol %).22 The
reaction produced enone 19 in 69% yield. Stereoselective
reduction of the C14 ketone was accomplished using the CBS
reagent23 to deliver the required C14-R diastereomer with
17:1 selectivity in 92% yield. Following Roush’s precedent,5b
hydroxyl-directed reduction using Noyori’s catalyst24 satu-
rated the C12-C13 alkene and produced the C1-C26
segment 20 after protection. The proposed dialkylzinc
strategy would have required fewer steps, but the metathesis
route was very effective.
To set up the coupling between the bis-THP fragment and
the C1-C26 polyol segment, the phenyl sulfide needed to
be introduced and the protecting groups adjusted. Selective
hydrolysis of the acetonide was accomplished by enol ether
formation and hydrolysis.25 Removal of the benzyl ether,
epoxide formation, SEM protection, and treatment with
thiophenol and base delivered the desired C1-C26 synthon
4 in good overall yield.
14 using the Julia-Kocienski method16 to produce the (E)-
alkene 15 as a single isomer. The reaction was optimized
(KHMDS, DME, Barbier conditions) to produce high E/Z
selectivity to avoid subsequent problematic separations of
Scheme 3. Synthesis of the C14-C26 Aldehyde 16 and
Enone 17
The final segment coupling between protected polyol 4
and bis-THP 2 is illustrated in Scheme 4. Deprotonation of
(15) Roush, W. R.; Adam, M. A.; Walts, A. E.; Harris, D. J. J. Am.
Chem. Soc. 1986, 108, 3422-3434.
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Lett. 1991, 32, 1175-1178. (b) Blakemore, P. R.; Cole, W. J.; Kocienski,
P. J.; Morley, A. Synlett 1998, 26-28. (c) Blakemore, P. R. J. Chem. Soc.,
Perkin Trans. 1 2002, 2563-2585.
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1994, 94, 2483-2547.
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8550.
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P.; Singer, R. D. Chem. ReV. 1993, 93, 2117-2188. (c) Lutz, C.; Knochel,
P. J. Org. Chem. 1997, 62, 7895-7898.
(20) Preparation of triene 18 is presented in the Supporting Information.
(21) Chatterjee, A. K.; Choi, T. L.; Sanders, D. P.; Grubbs, R. H. J. Am.
Chem. Soc. 2003, 125, 11360-11370.
(22) Kingsbury, J. S.; Harrity, J. P. A.; Bonitatebus, P. J.; Hoveyda, A.
M. J. Am. Chem. Soc. 1999, 121, 791-799.
(23) (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.
(24) Takaya, H.; Ohta, T.; Sayo, N.; Kumobayashi, H.; Akutagawa, S.;
Inoue, S.-I.; Kasahara, I.; Noyori, R. J. Am. Chem. Soc. 1987, 109, 1596-
1597.
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7222. (b) Rychnovsky, S. D.; Kim, J. Tetrahedron Lett. 1991, 32, 7223-
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5576.
Org. Lett., Vol. 9, No. 23, 2007
4759

Scheme 4. Coupling Fragments to Assemble the C1-C52 Segment of Amphidinol 3
the C25 alcohol with n-BuLi, followed by reductive lithiation
with LiDBB, generated the â-alkoxy alkyllithium 23. The
bis-THP Weinreb amide 2 was added to the alkyllithium
solution in THF at -78 °C, and the reaction was allowed to
proceed for 21 h at that temperature. The â-hydroxy ketone
24 was isolated in 59% yield. A 4-fold excess of the
C1-C26 segment was used in the coupling, but this ratio
was largely dictated by the relative abundance of the two
coupling partners. Model studies to prepare ketone 8 used a
3-fold excess, but neither of these ratios were optimized.
Synthesis of the C1-C52 segment of amphidinol 3 was
completed by hydroxyl-directed reduction of the C27 ketone
using Prasad’s conditions,26 followed by alcohol protection
to produce the amphidinol 3 intermediate 25.
We have developed an efficient construction of an
advanced intermediate for the synthesis of amphidinol 3. The
route features segment coupling reactions using a cross-
metathesis and a â-alkoxy alkyllithium addition to a Weinreb
amide. These validated coupling strategies will undoubtedly
be useful in the synthesis of other complex natural products.
Acknowledgment. This work was supported by the
National Institute of General Medical Sciences (GM-65338)
and by a generous donation from the Schering Plough
Research Institute. J.d.V. acknowledges the Spanish Ministry
of Education and Science for a postdoctoral fellowship.
Supporting Information Available: Preparation and
characterization of compounds 2-4 and 10-25 are de-
scribed. This material is available free of charge via the
Internet at http://pubs.acs.org.
(26) Chen, K.-M.; Hardtman, G. E.; Prasad, K.; Repic, O.; Shapiro, M.
J. Tetrahedron Lett. 1987, 28, 155-158.
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