Studies toward the synthesis of spirolides: Assembly of the elaborated E-ring fragment

Article abstract of DOI:10.1021/ol8027797

A stereoselective synthesis of the spiroimine fragment of spirolide C is described. The congested C7 and C29 tertiary and quaternary centers are constructed by a diastereoselective Ireland-Claisen rearrangement. The E ring is completed by means of an aldo

Full text of DOI:10.1021/ol8027797

ORGANIC
LETTERS
2009
Vol. 11, No. 4
839-842
Studies Toward the Synthesis of
Spirolides: Assembly of the Elaborated
E-Ring Fragment
Craig E. Stivala and Armen Zakarian*
Department of Chemistry and Biochemistry, UniVersity of California,
Santa Barbara, California 93106-9510
zakarian@chem.ucsb.edu
Received December 2, 2008
ABSTRACT
A stereoselective synthesis of the spiroimine fragment of spirolide C is described. The congested C7 and C29 tertiary and quaternary centers
are constructed by a diastereoselective Ireland-Claisen rearrangement. The E ring is completed by means of an aldol cyclocondensation.
Additional studies were preformed on the advanced intermediate to probe a future coupling strategy.
Spirolides belong to a family of marine toxins isolated from
the dinoflagellate Alexandrium ostenfeldii, collected from an
aquaculture site along the Atlantic coast of Nova Scotia by
Wright and co-workers.1 Spirolides possess a toxicity profile
comparable to that of other natural products bearing the
characteristic spiroimine moiety, including pinnatoxins,2
pteriotoxins,3 and gymnodimine.4 As established by Wright
and co-workers,1a the spirocyclic imine appears to be the
pharmacophore of these molecules. The absolute stereo-
chemistry of spirolides remains unconfirmed, and the relative
configuration of the stereogenic center at C4 has not been
assigned.1
The spiroimine natural products have generated a high
level of interest as targets for chemical synthesis. Several
total and one formal syntheses of pinnatoxins and pteriatoxins
have been accomplished,5 and significant progress toward
gymnodimine has been achieved.6 Within this class of natural
products, spirolides pose unique challenges for synthesis. In
(1) (a) Hu, T.; Burton, I. W.; Cemella, A. D.; Curtis, J. M.; Quilliam,
M. A.; Walter, J. A.; Wright, J. L. C. J. Nat. Prod. 2001, 64, 308–312. (b)
Hu, T.; Curtis, J. M.; Oshima, Y.; Quilliam, M. A.; Walter, J. A.; Watson-
Wright, W. M.; Wright, J. L. C. J. Chem. Soc., Chem. Commun. 1995,
215, 9–2161. (c) Falk, M.; Burton, I. W.; Hu, T.; Walter, J. A.; Wright,
J. L. C. Tetrahedron 2001, 57, 8659–8665.
(5) Pinnatoxins A, B, and C: (a) McCauley, J. A.; Nagasawa, K.; Lander,
P. A.; Mischke, S. G.; Semones, M. A.; Kishi, Y. J. Am. Chem. Soc. 1998,
120, 7647–7648. (b) Stivala, C. E.; Zakarian, A. J. Am. Chem. Soc. 2008,
130, 3774–3776. (c) Matsuuda, F.; Hao, J.; Reents, R.; Kishi, Y. Org. Lett.
2006, 8, 3327–3330. (d) Nakamura, S.; Kikuchi, F.; Hashimoto, S. Angew.
Chem., Int. Ed. 2008, 47, 7091–7094. (e) Sakamoto, S.; Sakazaki, H.;
Hagiwara, K.; Kamada, K.; Ishii, K.; Noda, T.; Inoue, M.; Hirama, M.
Angew. Chem., Int. Ed. 2004, 43, 6505–6510. Pteriatoxins: (f) Matsuura,
F.; Peters, R.; Anada, M.; Harried, S. S.; Hao, J.; Kishi, Y. J. Am. Chem.
Soc. 2006, 128, 7463–7465. (g) Hao, J.; Matsuura, F.; Kishi, Y.; Kita, M.;
Uemura, D.; Asai, N.; Iwashita, T. J. Am. Chem. Soc. 2006, 128, 7742–
7743.
(2) (a) Uemura, D.; Chuo, T.; Haino, T.; Nagatsu, A.; Fukuzawa, S.;
Zheng, S.; Chen, H. J. Am. Chem. Soc. 1995, 117, 1155–1156. (b) Chou,
T.; Kamo, O.; Uemura, D. Tetrahedron Lett. 1996, 37, 4023–4026. (c) Chou,
T.; Haino, T.; Kuramoto, M.; Uemura, D. Tetrahedron Lett. 1996, 37, 4027–
4030.
(3) (a) Takada, N.; Umemura, N.; Suenaga, K.; Chou, T.; Nagatsu, A.;
Haino, T.; Yamada, K.; Uemura, D. Tetrahedron Lett. 2001, 42, 3491–
3494. (b) Takada, N.; Umemura, N.; Suenaga, K.; Uemura, D. Tetrahedron
Lett. 2001, 42, 3495–3497.
(4) Seki, T.; Satake, M.; Mackenzie, L.; Kaspar, H.; Yasumoto, T.
Tetrahedron Lett. 1995, 36, 7093–7096.
10.1021/ol8027797 CCC: $40.75
Published on Web 01/26/2009
2009 American Chemical Society

addition to the 6,5,5-dispirotricyclic bisketal, which is only
partially stabilized by the anomeric effect, the methyl and
butenolide substituents on the double bond of the 6,7-
membered spiroimine add to other structural attributes that
make spirolides formidable synthetic targets. Several studies
aimed at the 6,5,5-dispiroketal portion of spirolides have been
described,7,8 yet progress to the intricate spiroimine fragment
has been extremely limited.9
stereoselectivity and to define the scope and utility of this
technique, we explored new bases, including the lithium
amides formed from benzylamines (S)-711 and (R)-7.12 Using
ester 5, we compared the stereoselectivity of the enolization
to that obtained with lithium amides (S)-6-Li and (R)-6-Li
produced from trifluoroethylamines (S)-6 and (R)-6, which
showed the highest stereocontrol previously.10 As depicted
in Table 1, (S)-7 and (R)-7 proved to be superior bases for
Our approach to the spiroimine fragment of spirolides is
based on the projected diastereoselective Ireland-Claisen
rearrangement of ester 4 followed by aldol cyclocondensation
to form the cyclohexene ring incorporating a tetrasubstituted
double bond (Scheme 1). Stereoselective generation of the
Table 1. Enolization Study
Scheme 1. General Synthesis Plan
entry
basea
LDA
(S)-6-Li
(S)-7-Li
(R)-6-Li
(R)-7-Li
(Z)-8:(E)-8b
1
2
3
4
5
67:33
8:92
2:98
92:8
96:4
a LDA ) lithium diisopropylamine. b The ratio of isomers was
1
determined by 500 MHz H NMR of the crude mixture of products.
stereoselective enolization of 5. Thus, switching from (S)-6
to (S)-7 improved selectivity from 92% to 98%, favoring
the (E)-enolate. In the (R)-series, moving from amine 6 to 7
improved Z-selectivity from 92% to 96%. These observations
demonstrate that the benzyl base 7 overall exerts a stronger
stereodirecting effect in both matched and mismatched cases.
Another practical advantage is that benzylamine 7 is
considerably more convenient in terms of preparation and
handling. It is a crystalline solid which requires benzylamine
rather than expensive trifluoroethylamine for its synthesis.
With these results at hand, the synthesis of ester 4
commenced with the preparation of allylic alcohol 10 from
commercially available (R)-(+)-methyl lactate (Scheme 2).
Protection of the hydroxyl group as tert-butyldimethylsilyl
ether followed by reduction of the methyl ester and olefi-
(Z)-enolate ((Z)-3) will be required for efficient chirality
transfer to the adjacent quaternary and tertiary stereocenters
at C29 and C7.
A method for stereoselective enolization of R-branched
esters has been recently developed in our laboratory.10
According to this method, chiral Koga-type bases or other
chiral lithium amides are used with stereodefined acyclic
R-branched esters to achieve highly stereoselective enoliza-
tions. As part of an ongoing investigation to improve
(6) Recent reports: (a) White, J. D.; Quaranta, L.; Wang, G. J. Org.
Chem. 2007, 72, 1717–1728. (b) Johannes, J. W.; Wenglowsky, S.; Kishi,
Y. Org. Lett. 2005, 7, 3997–4000. (c) Kong, K.; Moussa, Z.; Romo, D.
Scheme 2. Synthesis of Allylic Alcohol 10
Org. Lett. 2005, 7, 5127–5130
.
(7) (a) Meilert, K.; Brimble, M. A. Org. Lett. 2005, 7, 3497–3500. (b)
Furkert, D. P.; Brimble, M. A. Org. Lett. 2002, 4, 3655–3658. (c) Meilert,
K.; Brimble, M. A. Org. Biomol. Chem. 2006, 4, 2184–2192. (d) Brimble,
M. A.; Caprio, V.; Furkert, D. P. Tetrahedron 2001, 57, 4023–4034. (e)
Brimble, M. A.; Fares, F. A.; Turner, P. Aust. J. Chem. 2000, 53, 845–851
(8) Ishihara, J.; Ishizaka, T.; Suzuki, T.; Hatakeyama, S. Tetrahedron
Lett. 2004, 45, 7855–7858
.
.
(9) (a) Brimble, M. A.; Trzoss, M. Tetrahedron 2004, 60, 5613–5622.
(b) Trzoss, M.; Brimble, M. A. Synlett 2003, 2042–2046.
(10) (a) Qin, Y.-c.; Stivala, C. E.; Zakarian, A. Angew. Chem., Int. Ed.
2007, 46, 7466–7469.
840
Org. Lett., Vol. 11, No. 4, 2009

nation of the resulting aldehyde afforded ester 9.13 Reduction
of the ethyl ester to the allylic alcohol with i-Bu2AlH
followed by protection of the hydroxyl group as the tert-
butyldiphenylsilyl ether and selective ethanolysis of the TBS
protecting group with pyridinium p-toluenesulfonate deliv-
ered allylic alcohol 10 in six steps,14 in good yield, and with
only two chromatographic purifications.
recovered in quantitative yield by a simple extraction with
aqueous acid if desired.
Continuing with our synthetic studies toward spirolides,
the Ireland-Claisen rearrangement of ester 4 followed by
treatment of the crude product with (trimethylsilyl)diaz-
omethane afforded methyl ester 12 in 96% yield over the
two steps (Scheme 4).19 Chiral amine (S)-7 was recovered
Carboxylic acid 11 was prepared previously on a multi-
gram scale by a ten-step route starting from (S)-citronellic
acid (Scheme 3).15 After briefly exploring different reaction
Scheme 4. Synthesis of the E-Ring
Scheme 3
conditions for esterification of carboxylic acid 11 with allylic
alcohol 10 (EDC, DMAP, DMF, or CH2Cl2), we determined
that the Yamaguchi conditions were more effective in
delivering ester 4 in good yield.16
The studies on the Ireland-Claisen rearrangement of ester
4 revealed suprising results. As anticipated, the application
of the chiral lithum amides generated from either (S)-6 or
(S)-7 accomplished the desired rearrangement in high yield
and excellent diastereoselectivity. In accord with our previous
experience with esters of 4,5b,10 5 equiv of these bases is
required for complete enolization. Remarkably, when LDA
was employed the rearrangement also occurred with high
diastereoselectivity, albeit in significantly lower yields (Table
2). In this case, various quantities of carboxylic acid 11 were
Table 2. Enolization/Rearrangement Study
in quantitative yield by extraction with aqueous hydrochloric
acid.
Reduction of the methyl ester with i-Bu2AlH and protec-
tion of the primary alcohol delivered pivaloate 13. Oxidative
(11) (a) O’Brien, P.; Poumellec, P. Tetrahedron Lett. 1996, 37, 5619–
5622. (b) Curthbertson, E.; O’Brien, P.; Towers, T. D. Synthesis 2001, 5,
693–695.
entry
base
LDA
(S)-6-Li
(S)-7-Li
isolated yield
(12) (a) Saravanan, P.; Singh, V. K. Tetrahedron Lett. 1998, 39, 167–
170. (b) Saravanan, P.; Bisai, A.; Baktharaman, S.; Chandrasekhar, M.;
Singh, V. K. Tetrahedron 1998, 58, 4693–4706.
1
2
3
37%
84%
94%
(13) Massad, S. K.; Hawkins, L. D.; Baker, D. C. J. Org. Chem. 1983,
48, 5180–5182.
(14) Prakash, C.; Saleh, S.; Blair, I. A. Tetrahedron Lett. 1989, 30, 19–
22.
(15) Stivala, C. E.; Zakarian, A. Tetrahedron Lett. 2007, 48, 6845–6848.
(16) Inanaga, J.; Hirata, K.; Saeki, H.; Katsuki, T.; Yamaguchi, M. Bull.
Chem. Soc. Jpn. 1979, 52, 1989–1993.
recovered (25-35%), presumably because fragmentation of
the lithium enolate generated using LDA is competitive with
the O-silylation with Me3SiCl.17 Despite numerous attempts
under varying reaction conditions,18 the enolization-rearrange-
ment was consistently low yielding with LDA. On the other
hand, with the lithium amide of (S)-7, highly diastereose-
lective, efficient, scalable, and reproducible Ireland-Claisen
rearrangement was observed. Chiral amine (S)-7 can be
(17) (a) Sullivan, D. F.; Woodbury, R. P.; Rathke, M. W. J. Org. Chem.
1977, 42, 2038–2039. (b) Seebach, D.; Amstutz, R.; Laube, T.; Schweizer,
W. B.; Dunitz, J. D. J. Am. Chem. Soc. 1985, 107, 5403–5409.
(18) Varying concentration, number of equivalents of LDA, and reaction
time led to decomposition and/or incomplete reactions.
(19) For a recent review on (trimethylsilyl)diazomethane, see: Ku¨hnel,
E.; Laffan, D. D.; Lloyd-Jones, G. C.; del Campo, T. M.; Shepperson, I. R.;
Slaughter, J. L. Angew. Chem., Int. Ed. 2007, 46, 7075–7078.
Org. Lett., Vol. 11, No. 4, 2009
841

removal of the PMB protecting group with DDQ furnished
alcohol 14 in high yield. Ozonolysis of 14 directly to the
corresponding hydroxy aldehyde in the presence of N-
methylmorpholine20 followed by the addition of methyl-
magnesium bromide delivered diol 15 as a mixture of
diastereomers in good yield.
Double oxidation of the diol 15 to the corresponding keto
aldehyde set the stage for an aldol cyclo-condensation, which
was accomplished in the presence of piperidinium trifluo-
roacetate in toluene at 60 °C for 3 days, affording the desired
cyclized intermediate 16 in 85% yield over two steps.5b,21
Reduction of the enal with sodium borohydride and protec-
tion of the resulting primary alcohol as the methoxymethyl
ether completed the synthesis of the advanced intermediate
17.
a subsequent reoxidation of the addition product. Thus,
reductive cleavage of the pivaloate ester in 17 with i-Bu2AlH
followed by oxidation of the resulting primary alcohol
delivered the desired aldehyde 18 in good yield. Gratifyingly,
the organolithium reagent produced from 1-iodo-4-methyl-
4-pentene via iodine-lithium exchange underwent a smooth
addition to 18,22 delivering the secondary alcohols as a
mixture of diastereomers. Oxidation of the alcohols with
Dess-Martin periodinane provided ketone 19 in an 86%
overall isolated yield over the two steps (Scheme 5).23
Finally, the removal of the TBDPS group was accomplished
using TBAF, delivering 20 in 87% yield.
In summary, we have described an efficient, enantiose-
lective synthesis of the cyclohexene ring E of spirolides
incorporating the challenging adjacent tertiary and quaternary
stereocenters at C7 and C29. These stereogenic centers were
constructed with high stereocontrol by a single diastereose-
lective Ireland-Claisen rearrangement employing a method
recently developed in our laboratory. Aldol cyclocondensa-
tion proved to be a powerful tactic for the assembly of the
tetrasubstituted double bond in ring E. Subsequent studies
demonstrated viability of the future fragment coupling
strategy based on organolithium addition to aldehyde 18.
The subsequent transformations, illustrated in Scheme 5,
were carried out to explore the viability of the future fragment
Scheme 5
Acknowledgment. We thank Kristen A. McReynolds
(University of Hawaii) for carrying out some preliminary
experiments. Financial support for this work was provided
by the National Institutes of Health (National Institute of
General Medical Sciences, R01GM-077379).
Supporting Information Available: Detailed experimen-
1
tal procedures and copies of H and 13C NMR spectra for
compounds described in this report. This material is available
free of charge via the Internet at http://pubs.acs.org.
OL8027797
coupling en route to spirolides. We plan to achieve a
fragment union by a straightforward addition of an advanced
organolithium reagent to a hindered aldehyde such as 18 with
(21) Corey, E. J.; Danheiser, R. L.; Chandrasekaran, S.; Siret, R.; Keck,
G. E.; Gras, J.-L. J. Am. Chem. Soc. 1978, 100, 8031–8034.
(22) Larock, R. C.; Yang, H.; Weinreb, S. M.; Herr, R. J. J. Org. Chem.
1994, 59, 4172–4178.
(20) Schwartz, C.; Raible, J.; Mott, K.; Dussault, P. H. Org. Lett. 2006,
8, 3199–3201.
(23) (a) Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155–4156.
(b) Boeckman, R. K.; Shao, P.; Mullins, J. J. Org. Synth. 2000, 77, 141.
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Org. Lett., Vol. 11, No. 4, 2009