Stereoselective assembly of a 1,3-diene via coupling between an allenic acetate and a (B)-alkylborane: Synthetic studies on amphidinolide B1

Article abstract of DOI:10.1021/ol051175m

(Chemical Equation Presented) The preparation of three fragments for the total synthesis of amphidinolide B1 has been described. The C16 stereochemistry was set by asymmetric allylic alkylation. C21 and C25 stereogenic centers were set by an enantioselect

Full text of DOI:10.1021/ol051175m

ORGANIC
LETTERS
2005
Vol. 7, No. 17
3645-3648
Stereoselective Assembly of a 1,3-Diene
via Coupling between an Allenic Acetate
and a (B)-Alkylborane: Synthetic
Studies on Amphidinolide B1
Amit K. Mandal,† John S. Schneekloth, Jr.,‡ and Craig M. Crews*,†,‡,§
Departments of Chemistry, Molecular, Cellular, and DeVelopmental Biology, and
Pharmacology, Yale UniVersity, New HaVen, Connecticut 06520-8103
craig.crews@yale.edu
Received May 18, 2005
ABSTRACT
The preparation of three fragments for the total synthesis of amphidinolide B1 has been described. The C16 stereochemistry was set by
asymmetric allylic alkylation. C21 and C25 stereogenic centers were set by an enantioselective/diastereoselective double allylation reaction.
The C9 configuration was set by an asymmetric heteroene reaction. A differentially substituted stereodefined 1,3-diene iodide was synthesized
by iodide-mediated SN2′ reaction. A novel stereoselective method to assemble a 1,3-diene by coupling an allenic acetate and (B)-alkylborane
is also reported.
Amphidinolide B1 1, a polyketide-based 26-membered
macrolide, was isolated from a culture of the symbiotic
marine dinoflagellate Amphidinium sp. (strain Y-5) in 1987
by Kobayashi et al.1 Compound 1 exhibits potent and
selective cytotoxicity against L1210 murine leukemia and
KB human epidermoid carcinoma cell lines in vitro (IC50
0.00014 and 0.0042 µg/mL, respectively).1,2 The relative
stereochemistry of the nine stereogenic centers in amphi-
dinolide B1 was determined by X-ray crystallographic
analysis,3 and the absolute stereochemistry was assigned on
the basis of the chemical synthesis of the C22-C26
segment.4 Due to its potent cytotoxic activity and topological
complexities, amphidinolide B1 1 has attracted the attention
of synthetic chemists for over 15 years.5 There have been
several efforts toward the total synthesis of this natural
product; however, no completed total synthesis has yet been
reported. Both Pattenden et al. and Kobayashi et al. reported
elegant approaches toward 1.5d,6 Nishiyama, Chakraborty,
Myles, Lee, and Carter have also reported partial syntheses
toward 1.7 In our chemical biology program, we are interested
in developing natural products as biological probes to identify
novel proteins for therapeutic intervention (target validation)
(4) Ishibashi, M.; Ishiyama, H.; Kobayashi, J. Tetrahedron Lett. 1994,
35, 8241.
† Department of Molecular, Cellular, and Developmental Biology.
‡ Department of Chemistry.
(5) (a) Kobayashi, J.; Ishibashi, M. Chem. ReV. 1993, 93, 1753. (b)
Chakraborty, T.; Das, S. Curr. Med. Chem.: Anti-Cancer Agents 2001, 1,
131. (c) Kobayashi, J.; Shimbo, K.; Kubota, T.; Tsuda, M. Pure Appl. Chem.
2003, 75, 337. (d) Kobayashi, J.; Tsuda, M. Nat. Prod. Rep. 2004, 21, 77.
(6) (a) Cid, M. B.; Pattenden, G. Synlett 1998, 540. (b) Cid, M. B.;
Pattenden, G. Tetrahedron Lett. 2000, 41, 7373. (c) Ishiyama, H.; Takemura,
T.; Tsuda, M.; Kobayashi, J. Tetrahedron 1999, 55, 4583. (d) Ishiyama,
H.; Takemura, T.; Tsuda, M.; Kobayashi, J. J. Chem. Soc., Perkin Trans.
1 1999, 1163.
§ Department of Pharmacology.
(1) Ishibashi, M.; Ohizumi, Y.; Hamashima, M.; Nakamura, H.; Hirata,
Y.; Sasaki, T.; Kobayashi, J. J. Chem. Soc., Chem. Commun. 1987, 1127.
(2) Kobayashi, J.; Ishibashi, M.; Nakamura, H.; Ohizumi, Y.; Yamasu,
T.; Hirata, Y.; Sasaki, T.; Ohta, T.; Nozoe, S. J. Nat. Prod. 1989, 52, 1036.
(3) Bauer, I.; Maranda, L.; Shimizu, Y.; Peterson, R. W.; Cornell, L.;
Steiner, J. R.; Clardy, J. J. Am. Chem. Soc. 1994, 116, 2657.
10.1021/ol051175m CCC: $30.25
© 2005 American Chemical Society
Published on Web 07/27/2005

and the exploration of cell biology (chemical genetics). As
amphidinolide B1 1 is a highly potent anticancer agent, it
can be useful as a tool for understanding more about cancer
biology. As a result of our interest in the biology of this
molecule, we initiated a program directed toward completing
the total synthesis of amphidinolide B1 1.
Our proposed synthetic route to 1 is based on a highly
convergent disconnection of the 26-membered macrolide
ring: Mitsunobu-type esterification,8 Suzuki-Miyaura cou-
pling9 between C12 and C13, aldol reaction10 between C18
and C19, and Horner-Wadsworth-Emmons reaction across
C2-C3 (Scheme 1).
factors, although steric effects tend to predominate. Electron-
rich, unhindered olefins generally react rapidly. It is docu-
mented that the 2-propenyl group undergoes hydroboration
600 times faster than a disubstituted internal trans double
bond.11b We hope to take advantage of this differential
hydroboration rate to preferentially hydroborate the 2-pro-
penyl group, yielding the requisite (B)-alkylborane for
Suzuki-Miyaura coupling. Though Evans and co-workers
reported â-alkyl-directed diastereoselective hydroboration in
an acyclic system,12 to the best of our knowledge there is
little precedent for â-alkoxy- or â-silyloxy-directed successful
diastereoselective hydroboration in acyclic systems.13 In this
letter, we describe the synthesis of fragments 2, 3, and 4 as
well as validation of the 1,3-diene iodide fragment 3 as a
coupling partner. We also discuss a new stereoselective and
regioselective synthesis of a highly substituted 1,3-diene by
joining an allenic acetate and an (B)-alkylborane in the
presence of a palladium catalyst.
Scheme 1. Retrosynthetic Analysis
The key step in the synthesis of fragment 2 is based on
the enantioselective/diastereoselective double allylboration
reaction to prepare 1,5-syn-diol 8. Adopting Roush’s proto-
col,14 we hydroborated allenylboronate 6 using (-)-Ipc2BH15
to produce 1,3-boryl-substituted allylborane 7.
Scheme 2. Synthesis of Fragment 2
Use of a 1,3-diene iodide system such as fragment 3 as a
substrate for Suzuki-Miyaura coupling is unprecedented in
the literature.11 We hope to attain a high level of stereo-
induction to install the C11 stereogenic center by proper
choice of hydroborating agent and fine-tuning of the protect-
ing groups of the C8 and C9 hydroxyl groups to generate
the borane from fragment 4. It is shown that rate of
hydroboration is sensitive to electronic as well as steric
(7) (a) Ohi, K.; Shima, K.; Hamada, K.; Saito, Y.; Yamada, N.; Ohba,
S.; Nishiyama, S. Bull. Chem. Soc. Jpn. 1998, 71, 2433. (b) Ohi, K.;
Nishiyama, S. Synlett 1999, 573. (c) Ohi, K.; Nishiyama, S. Synlett. 1999,
571. (d) Chakraborty, T. K.; Thippeswamy, D.; Suresh, V. R.; Jayaprakash,
S. Chem. Lett. 1997, 563. (e) Chakraborty, T. K.; Thippeswamy, D. Synlett
1999, 150. (f) Chakraborty, T. K.; Thippeswamy, D.; Jayaprakash, S. J.
Ind. Chem. Soc. 1998, 75, 741. (g) Chakraborty, T. K.; Suresh, V. R.;
Vayalakkada, R. Chem. Lett. 1997, 565. (h) Eng, H. M.; Myles, D. C.
Tetrahedron Lett. 1999, 40, 2275. (i) Eng, H. M.; Myles, D. C. Tetrahedron
Lett. 1999, 40, 2279. (j) Lee, D.-H.; Lee, S.-W. Tetrahedron Lett. 1997,
38, 7909. (k) Lee, D.-H.; Rho, M.-D. Bull. Korean Chem. Soc. 1998, 19,
386. (l) Lee, D.-H.; Rho, M.-D. Tetrahedron Lett. 2000, 41, 2573. (m)
Zhang, W.; Carter, R. G.; Yokochi, A. F. T. J. Org. Chem. 2004, 69, 2569.
(8) Mitsunobu, O. Synthesis 1981, 1.
The allylborane 7 was reacted with benzyloxyacetaldehyde
first at -78 °C for 2 h, followed by treatment with
acetaldehyde at -78 °C for 2 h and at room temperature for
24 h to produce 1,5-syn-diol 8 in 95% yield and g95% ee
(9) Miyaura, N.; Ishiyama, T.; Sasaki, H.; Ishikawa, M.; Satoh, M.;
Suzuki, A. J. Am. Chem. Soc. 1989, 111, 314.
(10) Evans, D. A.; Carter, P. H.; Carreira, E. M.; Charette, A. B.; Prunet,
J. A.; Lautens, M. J. Am. Chem. Soc. 1999, 121, 7540.
(11) (a) Miyaura, M.; Suzuki, A. Chem. ReV. 1995, 95, 2457. (b) Chemler,
S. R.; Trauner, D.; Danishefsky, S. J. Angew. Chem., Int. Ed. 2001, 40,
4544.
(12) Evans, D. A.; Bartroli, J.; Godel, T. Tetrahedron Lett. 1982, 23,
4577.
(13) Morimoto, Y.; Mikami, A.; Kuwabe, S.-i.; Shirahama, H. Tetra-
hedron Lett. 1991, 32, 2909.
(14) Flamme, E. M.; Roush, W. R. J. Am. Chem. Soc. 2002, 124, 13644.
(15) Brown, H. C.; Singaram, B. J. Org. Chem. 1984, 49, 945.
3646
Org. Lett., Vol. 7, No. 17, 2005

alcohol 15 was converted to methyl ketone 16 using common
functional group transformations. Chelation-controlled ad-
dition of ethynylmagnesium bromide to methyl ketone 16
produced the ethynyl carbinol (dr 90:10), which was ho-
mologated using (CH2O)n/i-Pr2NH/CuBr in refluxing dioxane
to afford allenic alcohol 17.18 Acetylation of 17 proved to
be nontrivial. Powerful acetylation protocols such as Ac2O/
catalytic TMSOTf19 and Ac2O/catalytic Sc(OTf)320 were not
successful. However, acetylation was achieved using Ac2O/
4-pyrrolidinopyridine in reproducible, albeit 40-50% yield.
Exposure of the acetate 18 to acetic acid and lithium iodide
exclusively produced (E)-1,3-diene iodide fragment 3.21 The
olefin geometry was verified by NOE experiments.
Scheme 3. Synthesis of Fragment 3
We believe that the diastereomeric acetates lead exclu-
sively to the (E)-product by SN2′ attack of the iodide
nucleophile on the central allenic carbon anti to the acetate
leaving group on the lowest energy conformation of each
diastereomer (B and D). Due to severe 1,3-allylic strain, anti
SN2′ attack of the iodide nucleophile was not favorable on
conformations (A and C), leading to the (Z)-isomer.22
based on MTPA ester analysis. Thus, the C21 and epi-C25
hydroxy group (which would be inverted during Mitsunobu
esterification) were installed efficiently. We hoped that
matched allylic and homoallylic hydroxy-directed epoxida-
tion would afford good selectivity.16 However, diastereo-
selective epoxidation using VO(acac)2/t-BuOOH gave poor
selectivity. Gratifyingly, epoxidation with mCPBA in CH2Cl2
furnished epoxy alcohol 9 in an 8:1 diastereoisomeric ratio
based on the crude 500 MHz NMR. Bis-silyl protection with
TBSOTf/2,6-lutidine was followed by regioselective and
stereoselective opening of the epoxide with Me4AlLi/Me3Al
in refluxing hexane. Further silyl protection provided com-
pound 11, which was converted to fragment 2 using
straightforward functional group manipulations. Stereochem-
istry at the newly generated hydroxyl-bearing stereocenter
was verified by NOE analysis of the acetonide obtained by
TBAF deprotection of 10 and subsequent treatment with 2,2-
dimethoxypropane (Supporting Information).
The synthesis of fragment 3 began with commercially
available racemic isoprene monoxide 12. Palladium- and
boron-cocatalyzed dynamic kinetic asymmetric transforma-
tion (DYKAT) using (S,S)-ligand-13 and p-methoxybenzyl
alcohol as the nucleophile provided differentially protected
alcohol 14 in a highly regio- and enantioselective fashion
(90% yield and 94% ee).17 Application of a hydroboration
and oxidation sequence furnished the diol. The less sterically
hindered of the two primary alcohols was selectively
protected as its mono-TBDPS ether to yield alcohol 15. The
Figure 1. Stereochemical rationale for SN2′ reaction.
The synthesis of fragment 4 takes advantage of Evans’
Cu(II)-Box-catalyzed enantioselective heteroene reaction
between iso-butene and ethyl glyoxalate 19 to produce
homoallylic alcohol 20 in 60% yield and 93% ee (Scheme
4).23 The free alcohol was protected as its corresponding TBS
ether and converted to the Weinreb amide 21. In parallel,
vinyl iodide 23 was prepared from commercially available
pentyn-1-ol 22 via two steps24 in 50% overall yield. Addition
of the vinyl iodide 23 to the Weinreb amide 21 smoothly
produced R,â-unsaturated ketone 24 in 86% yield. Diastereo-
(18) Searles, S.; Li, Y.; Nassim, B.; Lopes, M.-T. R.; Tran, P. T.; Crabbe´,
P. J. Chem. Soc., Perkin Trans. 1 1984, 747.
(19) Procopiou, P. A.; Baugh, S. P. D.; Flack, S. S.; Inglis, G. G. A. J.
Org. Chem. 1998, 63, 2342.
(20) Ishihara, K.; Kubota, M.; Kurihara, H.; Yamamoto, H. J. Am. Chem.
Soc. 1995, 117, 4413.
(21) Horva´th, A.; Ba¨ckvall, J.-E. J. Org. Chem. 2001, 66, 8120.
(22) This hypothesis is supported by our observation that the (E)-
selectivity diminishes slightly as the bulk of RL decreases (unpublished
results).
(16) Hoveyda, A. H.; Evans, D. A.; Fu, G. C. Chem. ReV. 1993, 93,
1370.
(23) Evans, D. A.; Tregay, S. W.; Burgey, C. S.; Paras, N. A.; Vojkovsky,
T. J. Am. Chem. Soc. 2000, 7936.
(17) Trost, B. M.; McEachern, E. J.; Toste, F. D. J. Am. Chem. Soc.
1998, 120, 12702.
(24) Reich, H. J.; Eisenhart, E. K.; Olson, R. E.; Kelly, M. J. J. Am.
Chem. Soc. 1986, 108, 7791.
Org. Lett., Vol. 7, No. 17, 2005
3647

complex 27 is formed by anti oxidative addition on the
allenic central carbon. The formed π-allyl complex 27
presumably then isomerizes to the thermodynamically more
stable (E)-complex 28 via an η3-η1-η3 rearrangement. This
isomerization is presumably faster than the product formation
because no identifiable (Z)-isomer was observed. More
detailed studies on this coupling will be published in due
course.
Scheme 4. Synthesis of Fragment 4
Scheme 5. Stereoselective Synthesis of Stereodefined
1,3-Diene
selective reduction using Luche conditions produced an
alcohol, which was protected as a TIPS ether to provide
fragment 4. Stereochemical assignment was corroborated on
NOE experiment of the corresponding acetonide (Supporting
Information).
With all three fragments securely in hand, we next
concentrated our efforts on the key Suzuki-Miyaura cou-
pling. The viability of fragment 3 for use as a coupling
partner was demonstrated by its successful coupling with
the (B)-alkylborane derived from styrene to furnish 26.
Encouraged by this result, we next investigated the possibility
of using allenic acetate 18 as a coupling partner to a (B)-
alkylborane. This would increase the efficiency in the context
of our present study and also would provide a novel
technology to stereoselectively assemble the highly substi-
tuted 1,3-diene. We were aware that allenic carbonates can
be used to generate vinylpalladium species.25 However, to
the best of our knowledge, this reaction had not been
explored in the context of setting a differentially substituted
1,3-diene. We reasoned that we might be able to generate a
vinylpalladium species such as 25 directly from allenic
acetate 18 by treating it with a palladium source and couple
it with a (B)-alkylborane. We treated allenic acetate 18 with
[Pd(dppf)Cl2], K3PO4, H2O, and the (B)-alkylborane derived
from styrene and gratifyingly isolated the coupled product
26 in 47% unoptimized yield. The geometry of the 1,3-diene
was confirmed on the basis of NOE experiments. This is
the first example of the synthesis of a highly substituted
stereodefined 1,3-diene in this fashion. In catalytic reactions,
a (π-allyl)palladium intermediate can be generated from an
allylic carboxylate.26 We postulate that a (π-allyl)palladium
In conclusion, we have accomplished efficient synthetic
routes to all the requisite fragments for amphidinolide B1 1.
Our studies document that a SN2′ reaction can be used to
prepare highly substituted stereodefined 1,3-diene iodide 3.
We have also demonstrated that an allenic acetate 18 derived
(π-allyl)palladium species can be coupled with a (B)-
alkylborane to stereoselectively and regioselectively assemble
a 1,3-diene. Our continued investigation into the chemical
problems posed by amphidinolide B1 1 and our investigation
of its intracellular mode of action will be reported in due
course.
Acknowledgment. We gratefully acknowledge financial
support from NIH (GM062120). J.S.S. acknowledges the
American Chemical Society, Division of Medicinal Chem-
istry, and Aventis Pharmaceuticals for a predoctoral fellow-
ship. We thank Professor John Wood for his help during
the preparation of this manuscript.
Supporting Information Available: Experimental pro-
cedures, characterization data, and stereochemical proofs.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(25) Moriya, T.; Furuuchi, T.; Miyaura, N.; Suzuki, A. Tetrahedron 1994,
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In ComprehensiVe Organic Synthesis; Trost, B. M., Fleming, I., Shammel-
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OL051175M
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