Synthesis of Amphidinolide T1 via Catalytic, Stereoselective Macrocyclization

Article abstract of DOI:10.1021/ja039716v

Two nickel-catalyzed reductive coupling reactions of alkynes were instrumental in a modular, stereoselective synthesis of amphidinolide T1 (1). The C13-C21 fragment was prepared from two simple starting materials that were joined in a catalytic alkyne-epo

Full text of DOI:10.1021/ja039716v

Published on Web 01/09/2004
Synthesis of Amphidinolide T1 via Catalytic, Stereoselective Macrocyclization
Elizabeth A. Colby, Karen C. O’Brien, and Timothy F. Jamison*
Massachusetts Institute of Technology, Department of Chemistry, Cambridge, Massachusetts 02139
Received November 20, 2003; E-mail: tfj@mit.edu
Since the isolation of amphidinolide A by Kobayashi in 1986,1
the structural complexity, effects upon biological systems, and
scarcity of the amphidinolide natural products have stimulated
intense research efforts in several disciplines.2 A significant feature
common to all 35 members of this ever-growing family of
molecules is a highly oxygenated and stereochemically rich
macrocycle, ranging in size from 12 to 29 atoms. A small fraction
of these otherwise diverse natural products have been prepared by
total synthesis.3
Scheme 1. Enantioselective Synthesis of the C13-C21 (3)
Fragment of 1 Using a Nickel-Catalyzed Alkyne-Epoxide
Reductive Coupling
Herein we describe a stereoselective synthesis of amphidinolide
T14 (Figure 1, 1), whereby an intramolecular, transition metal-
catalyzed reductive alkyne-aldehyde coupling related to methods
developed in our laboratories5,6 and in the Montgomery group7
assembles the 19-membered macrocycle by formation of the C12-
C13 carbon-carbon bond (red f). In contrast to all previous
amphidinolide syntheses,3 the macrocyclization also addresses a
stereochemical issue in the same operation, in this case installation
of the C13 stereogenic center (with very high stereocontrol).
An enantioselective Brown (Z)-crotyl addition to aldehyde 413
(93% ee) established the C7-C8 syn relationship,14 and straight-
forward functional group manipulation provided 5.11 Stereoselective
installation of the PhCtCCH2 group was best accomplished by
Lewis acid-promoted allenylsilane addition to hemiacetal 5, in
analogy to Danheiser’s method for allenyl addition to aldehydes
and acyclic acetals.15 Warming to ambient temperature effected
concomitant removal of the TBS protective group, giving 6 in 40%
overall yield and high diastereoselectivity, mirroring the levels of
stereoselection observed by Woerpel in a recent series of investiga-
tions.11,12 Because the remaining stereogenic center in this fragment
lay remote to those of the tetrahydrofuran, a diastereoselective
alkylation using the pseudoephedrine-based chiral auxiliary devel-
oped by Myers proved to be the best course of action.16 In this
way, the fully elaborated C1-C12 fragment, carboxylic acid 7, was
afforded in 65% overall yield from 6 (>95:5 dr).
Figure 1. Amphidinolide T1 (1). Asterisks indicate carbon-carbon bonds
formed using a nickel-catalyzed reductive alkyne-aldehyde (red f,
intramolecular) or alkyne-epoxide (blue f, intermolecular) coupling.
Scheme 2. Synthesis of the C1-C12 Fragment (7) of
Amphidinolide T1
The catalytic, stereoselective macrocyclization strategy we
employed also enabled preparation of the entire C13-C21 fragment
(3) of the target in only four steps, one of which was another nickel-
catalyzed reductive coupling reaction developed in our group: that
of an alkyne and an epoxide (Figure 1 (blue f) and Scheme 1).8
The construction of nearly half of amphidinolide T1 was thus
reduced to the synthesis of two enantiomerically pure coupling
partners: an epoxide and an alkyne.
Jacobsen’s (salen)Co(III)-catalyzed hydrolytic kinetic resolution
efficiently solved the first of these problems, affording (R)-n-
propyloxirane in >99% ee (Scheme 1).9 An Evans oxazolidinone
auxiliary was used to prepare the requisite alkyne (2), by way of
a diastereoselective propargylation with 3-bromo-1-phenyl-1-
propyne.10 The Ni-catalyzed, alkyne-epoxide reductive coupling
smoothly united these two building blocks, completing the synthesis
of this fragment (3) of amphidinolide T1 in an average yield of
87% per step and with >95:5 regioselectivity with respect to both
epoxide ring opening and addition to the alkyne.
As summarized in Scheme 2, three of the four stereogenic centers
in the C1-C12 fragment (7) were established in a reagent-controlled
fashion, whereas the other capitalized on a strong stereochemical
bias11 in an addition reaction to an oxocarbenium species derived
from a lactol (5).12
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10.1021/ja039716v CCC: $27.50 © 2004 American Chemical Society

C O M M U N I C A T I O N S
Scheme 3. Synthesis of Amphidinolide T1 (1) via Stereoselective
Macrocyclization: Intramolecular, Nickel-Catalyzed
Alkyne-Aldehyde Reductive Coupling
ance. E.A.C. and K.C.O., respectively, thank the American Society
for Engineering Education (NDSEG Fellowship) and the Thomas
A. Spencer Endowed UROP Fund (MIT). We also thank the
National Institute of General Medical Sciences (GM-063755), NSF
(CAREER CHE-0134704), Merck Research Laboratories, Johnson
& Johnson, Boehringer Ingelheim, Amgen, Pfizer, and Glaxo-
SmithKline for generous financial support. The NSF (CHE-9809061
and DBI-9729592) and NIH (1S10RR13886-01) provided partial
support for the MIT Department of Chemistry Instrumentation
Facility.
Supporting Information Available: Experimental procedures and
1
data and H NMR spectra of 1, 3, and 6-9 (PDF). This material is
available free of charge via the Internet at http://pubs.acs.org.
References
(1) Kobayashi, J.; Ishibashi, M.; Nakamura, H.; Ohizumi, Y. Tetrahedron
Lett. 1986, 27, 5755-5758.
(2) (a) Kobayashi, J.; Ishibashi, M. Chem. ReV. 1993, 93, 1753-1769. (b)
Kobayashi, J. In ComprehensiVe Natural Products Chemistry; Mori, K.,
Ed.; New York: Elsevier, 1999; Vol. 8, pp 619-634. (c) Kobayashi, J.;
Shimbo, K.; Kubota, T.; Tsuda, M. Pure Appl. Chem. 2003, 75, 337-
342.
(3) Macrolactonization: (a) Amphidinolide J: Williams, D. R.; Kissel, W.
S. J. Am. Chem. Soc. 1998, 120, 11198-11199. (b) P: Williams, D. R.;
Myers, B. J.; Mi, L. Org. Lett. 2000, 2, 945-948. (c) K: Williams, D.
R.; Meyer, K. G. J. Am. Chem. Soc. 2001, 123, 765-766. (d) T1: Ghosh,
A. K.; Liu, C. J. Am. Chem. Soc. 2003, 125, 2374-2375. (e) A (proposed),
Stille coupling: Lam, H. W.; Pattenden, G. Angew. Chem., Int. Ed. 2002,
41, 508-511. Ring-closing metathesis: (f) A (proposed): Maleczka, R.
E.; Terrell, L. R.; Geng, F.; Ward, J. S., III. Org. Lett. 2002, 4, 2841-
2844. (g) T4: Fu¨rstner, A.; A¨ıssa, C.; Riveiros, R.; Ragot, J. Angew.
Chem., Int. Ed. 2002, 41, 4763-4766. (h) T1: A¨ıssa, C.; Riveiros, R.;
Ragot, J.; Fu¨rstner, A. J. Am. Chem. Soc. 2003, 125, 15512-15520. (i)
A (proposed), Ru-catalyzed alkene-alkyne coupling: Trost, B. M.;
Chisholm, J. D.; Wrobleski, S. T.; Jung, M. J. Am. Chem. Soc. 2002,
124, 12420-12421.
(4) (a) Tsuda, M.; Endo, T.; Kobayashi, J. J. Org. Chem. 2000, 65, 1349-
1352. (b) Kobayashi, J.; Kubota, T.; Endo, T.; Tsuda, M. J. Org. Chem.
2001, 66, 134-142. (c) Kubota, T.; Endo, T.; Tsuda, M.; Shiro, M.;
Kobayashi, J. Tetrahedron 2001, 57, 6175-6179.
(5) (a) Miller, K. M.; Huang, W.-S.; Jamison, T. F. J. Am. Chem. Soc. 2003,
125, 3442-3443. (b) Chan, J.; Huang, W.-S.; Jamison, T. F. Org. Lett.
2000, 2, 4221-4223.
(6) (a) Colby, E. A.; Jamison, T. F. J. Org. Chem. 2003, 68, 156-166. (b)
Synthesis of (-)-terpestacin via intermolecular alkyne-aldehyde reductive
coupling based on ref 6a: Chan, J.; Jamison, T. F. J. Am. Chem. Soc.
2003, 125, 11514-11515.
(7) Ni-catalyzed alkynal cyclizations (five- and six-membered rings): (a)
Oblinger, E.; Montgomery, J. J. Am. Chem. Soc. 1997, 119, 9065-9066.
(b) Tang, X.-Q.; Montgomery, J. J. Am. Chem. Soc. 1999, 121, 6098-
6099. (c) Lozanov, M.; Montgomery, J. J. Am. Chem. Soc. 2002, 124,
2106-2107.
Fragment coupling via ester formation between alcohol 3 and
carboxylic acid 7 and conversion of C13 to an aldehyde set the
stage for a nickel-catalyzed reductive macrocyclization of (1,19)-
alkynal 8. To our delight, allylic alcohol 9 was obtained with
complete selectivity for the desired configuration of the C13
carbinol,17 thus completing both assembly of the 19-membered ring
and installation of all of the stereogenic centers of amphidinolide
T1 (Scheme 3).
Two other features of this stereoselective macrocyclization are
noteworthy and compensate for the moderate yield. That the
undesired C13 diastereomer was undetectable was surprising
because intermolecular couplings of closely related compounds were
nearly nonstereoselective (1.5:1). Further, even if the intermolecular
coupling were perfectly selective, the catalytic macrocyclization
led to a significantly shorter synthesis because it obviated protection
(and subsequent unmasking) of carboxylic acid 7 and the free
hydroxyl group in 3.
With the macrocycle in hand, the only remaining task was
conversion of the C12 and C16 benzylidene groups to a ketone
and methylidene, respectively. After investigation of several end-
game strategies, we found that protection of the C13 hydroxyl,
global ozonolysis, selective methylenation at C16 using a modifica-
tion of Takai’s method,18 and finally HF-pyridine removal of the
TBS protective group afforded amphidinolide T1 (1), whose
spectroscopic and spectrometric data were identical in every respect
to those reported by Kobayashi for the naturally occurring enan-
tiomer.4
In conclusion, two nickel-catalyzed, carbon-carbon bond-
forming reactions were instrumental in an enantioselective synthesis
of amphidinolide T1 (1). A catalytic alkyne-epoxide reductive
coupling (intermolecular) completed the preparation of one half of
1, and a catalytic alkyne-aldehyde reductive coupling (intra-
molecular) simultaneously assembled the macrocycle and estab-
lished the configuration of a stereogenic center with complete
selectivity in the desired fashion. This is the most direct synthesis
of an amphidinolide T natural product to date, in terms of both
longest linear sequence (16 steps from 4) and total number of
synthetic operations (20).3d,g,h We are currently developing an analo-
gous, modular strategy for the synthesis of the other amphidinolide
T natural products.4b,c
(8) Molinaro, C.; Jamison, T. F. J. Am. Chem. Soc. 2003, 125, 8076-8077.
(9) (a) Tokunaga, M.; Larrow, J. F.; Kakiuchi, F.; Jacobsen, E. N. Science
1997, 277, 936-938. (b) Schaus, S. E.; Brandes, B. D.; Larrow, J. F.;
Tokunaga, M.; Hansen, K. B.; Gould, A. E.; Furrow, M. E.; Jacobsen, E.
N. J. Am. Chem. Soc. 2002, 124, 1307-1315.
(10) (a) Evans, D. A.; Ennis, M. D.; Mathre, D. J. J. Am. Chem. Soc. 1982,
104, 1737-1739. (b) Alkylation using 1-bromo-2-butyne: Savignac, M.;
Durand, J.-O.; Geneˆt, J.-P. Tetrahedron: Asymmetry 1994, 5, 717-722.
(11) Larsen, C. H.; Ridgway, B. H.; Shaw, J. T.; Woerpel, K. A. J. Am. Chem.
Soc. 1999, 121, 12208-12209.
(12) Schmitt, A.; Reissig, H.-U. Synlett 1990, 40-42.
(13) Marshall, J. A.; Shearer, B. G.; Crooks, S. L. J. Org. Chem. 1987, 52,
1236-1245.
(14) Brown, H. C.; Bhat, K. S. J. Am. Chem. Soc. 1986, 108, 5919-5923.
(15) Danheiser, R. L.; Carini, D. J. J. Org. Chem. 1980, 45, 3925-3927.
(16) Myers, A. G.; Yang, B. Y.; Chen, H.; McKinstry, L.; Kopecky, D. J.;
Gleason, J. L. J. Am. Chem. Soc. 1997, 119, 6496-6511.
(17) Assignment based on Mosher ester analysis of 9 and conversion to 1.
(18) (a) Takai, K.; Kakiuchi, T.; Kataoka, Y.; Utimoto, K. J. Org. Chem. 1994,
59, 2668-2670. (b) Zirconium alkylidene reagents: Hartner, F. W.;
Schwartz, J.; Clift, S. M. J. Am. Chem. Soc. 1983, 105, 640-641.
Acknowledgment. We thank Anna K. Hirsch (Cambridge
University-MIT Exchange Program) for experimental assist-
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