ORGANIC

LETTERS

Synthetic Studies toward the C5−C20 2001

Vol. 3, No. 7
Domain of the Azaspiracids 975-978

Amy B. Dounay and Craig J. Forsyth*

Department of Chemistry, UniVersity of Minnesota, Minneapolis, Minnesota 55455

forsyth@[Link]

Received January 17, 2001

ABSTRACT

An approach toward the C5−C20 THF-fused trioxadispiroketal portion of the azaspiracids is reported. The highly substituted azaspiracid D
ring (C16−C19) was prepared by the one-pot conversion of a tetraol into a tetrahydrofuran. Efforts to establish the C10 and C13 spiroketal
centers via an oxonium-initiated bis-spiroketalization under both kinetic and thermodynamic conditions have yielded the (10R,13S)-
trioxadispiroketal 19 as the major product, which is diastereomeric with the (10R*,13R*) relative configuration assigned to the azaspiracids.

The marine natural product azaspiracid (1, Figure 1) was reported as well.2 The azaspiracids are structurally complex
isolated from the mussel Mytilus edulis and implicated as ω-amino acids that contain within their 40-carbon backbone
an unprecedented array of polycyclic, spiro-fused ring
systems.3 The structural complexity, stereochemical ambigu-
ity, biological activity, and scarcity of the azaspiracids have
stimulated considerable interest in the synthesis of these
natural products.4 A growing need for authentic samples for
environmental monitoring has emerged. Initial synthetic
efforts toward the C5-C20 THF-fused bis-spiroketal-
containing domain (4) of the azaspiracids are described
herein.
Synthetic Design. The original strategy for assembly of
the A-D ring system of azaspiracid relied upon the acid-
catalyzed bis-spiroketalization of 5 to form the A and B rings

(2) Ofuji, K.; Satake, M.; McMahon, T.; Silke, J.; James, K. J.; Naoki,
H.; Oshima, Y.; Yasumoto, T. Nat. Toxins 1999, 7, 99.
Figure 1. Azaspiracids. (3) For a review of bis-spiroketal natural products and their syntheses
see: (a) Brimble, M. A.; Farès, F. A. Tetrahedron 1999, 55, 7661. (b)
McCauley, J. A.; Nagasawa, K.; Lander, P. A.; Mischke, S. G.; Semones,
M. A.; Kishi, Y. J. Am. Chem. Soc. 1998, 120, 7647.
the causative toxin in human poisoning events beginning in (4) (a) Carter, R. G.; Weldon, D. J. Org. Lett. 2000, 2, 3913. (b) Aiguade,
J.; Hao, J.; Forsyth, C. J. Tetrahedron Lett. 2001, 42, 817. (c) Hao, J.;
The Netherlands in 1995.1 Two closely related analogues of Aiguade, J.; Forsyth, C. J. Tetrahedron Lett. 2001, 42, 821. (d) Aiguade,
1, azaspiracid-2 (2) and azaspiracid-3 (3), have recently been J.; Hao, J.; Forsyth, C. J. Org. Lett. 2001, 3, 979.
(5) A similar acid-triggered spiroketalization was employed to install
the dioxaspiro[4.5]nonane system of okadaic acid: Forsyth, C. J.; Sabes,
(1) Satake, M.; Ofuji, K.; Naoki, H.; James, K. J.; Furey, A.; McMahon, S. F.; Urbanek, R. A. J. Am. Chem. Soc. 1997, 119, 8381.
T.; Silke, J.; Yasumoto, T. J. Am. Chem. Soc. 1998, 120, 9967. (6) Numbering corresponds to that of 1-3.

10.1021/ol015570y CCC: $20.00 © 2001 American Chemical Society

Published on Web 03/16/2001
 a stereoselective bis-dihydroxylation of a diene using Sharp-
Scheme 1. Synthetic Strategy for the C5-C20 Domain of the less asymmetric dihydroxylation (SAD) methodology.
Azaspiracids Results and Discussion. Efforts toward the construction
of the C5-C20 domain of azaspiracid began with the
synthesis of the tetraol 8 (Scheme 2). The readily available

Scheme 2. Synthesis of C13-C20 Tetraol

(Scheme 1).5 Enone 5 would be derived from lactone 6, allylic alcohol (()-98 was acylated with propionyl chloride
which in turn could be obtained from diol 7 as a result of to provide allylic ester 10. Conversion of 10 to its tert-
regioselective protection, debenzylation, and oxidation. The butyldimethylsilyl ketene acetal followed by Ireland-Claisen
relative configuration at C146 would be established at the rearrangement9 gave the R-methyl TBS-silyl ester, which was
stage of lactone 6 as a result of equilibration of the methyl hydrolyzed to the carboxylic acid upon workup. In the same
group to the anticipated thermodynamically favored equato- manner, (S)-1010 was treated with LDA followed by TMSCl
rial position. in THF to give the corresponding (R)-R-methyl-carboxylic
The synthesis of the highly functionalized tetrahydrofuran acid in 70% yield and 75% ee. However, the C14 stereo-
7 would employ the use of a novel method for the one-pot center could ultimately be established more conveniently
conversion of a tetraol into a tetrahydrofuran. The envisioned from (()-9 via epimerization at a later stage. Reduction of
conversion of tetraol 8 to tetrahydrofuran 7 would involve the carboxylic acid with LiAlH4 followed by benzylation of
selective sulfonylation of the primary C20 hydroxyl group the resultant primary alcohol yielded diene 11 in excellent
of 8, followed by base-induced epoxide formation and overall yield.
intramolecular trans-etherification in a 5-exo mode to provide
Bis-dihydroxylation of diene 11 under standard SAD
7. This concept is based on the earlier development of a one-
conditions11 consistently provided a mixture of chromato-
pot conversion of vicinal diols into transient epoxides and
the in situ nucleophilic opening of the epoxides under graphically separable tetraols 8 and 12 as the result of the
carbanionic conditions.7 Tetraol 8 was expected to arise from highly diastereoselective dihydroxylation at the internal olefin
and a surprisingly low diastereoselectivity of terminal olefin
(7) Cink, R. D.; Forsyth, C. J. J. Org. Chem. 1995, 60, 8122. dihydroxylation.12 Use of enantiomerically enriched 11 in
(8) Compound 9 is commercially available from Aldrich Chemical Co., the SAD reaction also gave rise to a mixture of C19 epimers.
or it can be synthesized via addition of allylmagnesium bromide to acrolein.
(9) (a) Ireland, R. E.; Wipf, P.; Armstrong, J. D., III. J. Org. Chem. Attempts to optimize this stereorandom dihydroxylation with
1991, 56, 650. (b) Ireland, R. E.; Thompson, W. J. J. Org. Chem. 1979, the use of other ligands13 ((DHQ)2PYR and (DHQ)2AQN)
44, 3041. (c) Ireland, R. E.; Mueller, R. H.; Willard, A. K. J. Am. Chem.
Soc. 1976, 98, 2868. provided no improvements in diastereoselectivity. Neverthe-
(10) Either enantiomer of 9 is available in high % ee from the less, the high overall yield and brevity of this approach
enantioselective allylation of acrolein with the appropriate B-allyldiisopi-
nocampheylborane; see: Racherla, U. S.; Brown, H. C. J. Org. Chem. 1991, allowed for easy synthetic access to tetraol 8.
56, 401. Tetraol 8 was employed in a study of a novel, one-pot
(11) (a) Sharpless, K. B.; Amberg, W.; Bennani, Y. L.; Crispino, G. A.;
Hartung, J.; Jeong, K.-S.; Kwong, H.-L.; Morikawa, K.; Wang, Z.-M.; Xu, conversion of a tetraol into a tetrahydrofuran via a dihydroxy-
D.; Zhang, X.-L.; J. Org. Chem. 1992, 57, 2768. (b) For a review on epoxide intermediate (Scheme 3). Base-induced trans-etheri-
Sharpless asymmetric dihydroxylation: Kolb, H. C.; VanNieuwenhze, M.
S.; Sharpless, K. B. Chem. ReV. 1994, 94, 2483. fications of hydroxy epoxides have been successfully em-
(12) The diol intermediate resulting from dihydroxylation of the terminal ployed in the construction of heterocycles toward the
olefin prior to dihydroxylation of the 1,2-disubstituted olefin showed a ca.
1.5-1:1 dr by 1H NMR spectroscopic analysis. This suggests that the poor
diastereoselectivity does not simply result from intramolecular directing (13) Crispino, G. A.; Jeong, K.-S.; Kolb, H. C.; Wang, Z.-M.; Xu, D.;
effects of the internal diol. Sharpless, K. B. J. Org. Chem. 1993, 58, 3785.

976 Org. Lett., Vol. 3, No. 7, 2001

 provided the chromatographically separable lactones 6 and
Scheme 3. Base-Induced Epoxidation and Tetrahydrofuran 14 in moderate yield. Other oxidation conditions, including
Formation from Tetraol PCC and TEMPO, were explored, but these provided no
enhancement in yield. The overall yield of 6 was improved
by subsequent partial epimerization of 14 with DBU in CH3-
CN at 60 °C for 48 h. At this stage, the relative stereochem-
istry between C16 and C19 was verified using NOE studies.
Additionally, the configuration of the C14 methyl-bearing
stereocenter in lactones 6 and 14 was determined on the basis
of 1H-1H J-coupling values and NOE studies. X-ray
crystallography of the diol obtained by LiAlH4 reduction of
14 verified the stereochemical assignments.
Lactone 6 was elaborated into bis-spiroketalization precur-
sor 5 (Scheme 5). Treatment of 6 with 1 equiv of allylmag-

synthesis of complex polyether natural products.14 However,

the expediency and convenience of a one-pot conversion of Scheme 5. Synthesis of the C5-C20 Enone
a tetraol to a tetrahydrofuran without the intermediacy of an
isolated hydroxy epoxide is synthetically advantageous. After
extensive experimentation, it was found that treatment of the
tetraol with 1 equiv of KHMDS followed by slow addition
of 1 equiv of N-triisopropylsulfonylimidazole15 allowed for
selective sulfonylation of the primary alcohol. Subsequent
treatment with an additional equivalent of base provided the
diol-epoxide, which underwent base-induced tetrahydrofuran
formation upon treatment with excess KHMDS and warming
to room temperature. The one-pot protocol allowed for
conversion of tetraol 8 to substituted tetrahydrofuran 7 in
moderate yield.16 This transformation represents a remarkably
convenient and relatively efficient method for construction
of highly substituted tetrahydrofurans.
A short sequence of standard transformations allowed for
conversion of tetrahydrofuran 7 to lactone 6 (Scheme 4).

Scheme 4. Synthesis of C13-C20 Lactone

nesium bromide cleanly provided the hemiketal, which was

converted to mixed methyl ketal 15. Hydroboration-oxidation
of the olefin in 15 with 9-BBN/H2O2 gave the sensitive
primary alcohol, and oxidation with TPAP/NMO yielded
aldehyde 16. Addition of the magnesium acetylide of alkyne
1717 to aldehyde 16 provided propargylic alcohol 18. Lindlar
reduction of propargylic alcohol 18 generated the (Z)-allylic
alcohol, which was oxidized to enone 5 using TPAP/NMO
or MnO2.
(15) Corey, E. J.; Weigel, L. O.; Chamberlin, A. R.; Lipshutz, B. J. Am.
Chem. Soc. 1980, 102, 1439. Hicks, D. R.; Fraser-Reid, B. Synthesis 1974,
The primary alcohol of 7 was selectively protected as a 203.
TBDPS ether, and the benzyl ether was cleaved by hydro- (16) For convenience on a multigram scale, the mixture of 8 and 12
was typically used directly in the THF-ring formation step, at which stage
genolysis to provide diol 13. Oxidation using TPAP/NMO diol 7 was readily separated from its C19 epimer by column chromatog-
raphy.
(14) (a) Sasaki, M.; Inoue, M.; Takamatsu, K.; Tachibana, K. J. Org. (17) Alkyne 17 was derived from commercially available (R)-(+)-
Chem. 1999, 64, 9399. (b) Matsukura, H.; Morimoto, M.; Koshino, H.; glycidol in four steps: (i) PMBCl, NaH, TBAI, THF; (ii) trimethylsilyl-
Nakata, T. Tetrahedron Lett. 1997, 38, 5545. (c) Hoye, T. R.; Witowski, acetylene, n-BuLi, BF3.OEt2, THF; (iii) TBAF, THF; (iv) TESCl, Et3N,
N. E. J. Am. Chem. Soc. 1992, 114, 7291. DMAP, CH2Cl2.

Org. Lett., Vol. 3, No. 7, 2001 977

 Treatment of enone 5 under acidic conditions was expected results also suggest that 19 is kinetically more accessible
to yield the derived trioxadispiroketal as a result of C13 than 4 from enone 5 under the reaction conditions surveyed.
oxonium formation and spiroketalization accompanied by The observed kinetic selectivity for the (13S)-configuration
loss of the TES group (Scheme 6). Exposure of enone 5 to of 19 may be explained by the stereoelectronically favored
axial attack of the C10 keto-oxygen atom upon an initially
formed oxonium species at C13.
Conclusions. A synthesis of trioxadispiroketal (10R,13S)-
Scheme 6. Spiroketalization of the C5-C20 Enone 19 has been developed that begins with a novel method for
formation of the highly substituted tetrahydrofuran 7 and
subsequent oxonium-initiated bis-spiroketalization. Continued
studies will explore the scope and limitations of the polyol
etherification cascade that led to 7 and its applicability to
the synthesis of other cyclic ether-containing natural products.
The tetrahydrofuran 7 was elaborated into bis-spiroketaliza-
tion precursor 5. Thereafter, formation of the trioxadispiroket-
al system by intramolecular trapping of an oxonium species
generated at C13 gave the same major product [(10R,13S)-
numerous Brönsted and Lewis acids (e.g., PPTS, CSA, BF3.- 19] under thermodynamic and kinetic conditions. The
OEt2, TMSOTf) with a variety of solvents (e.g., benzene, corresponding (10R,13R)-intermediate 4, which appears to
THF, acetonitrile, dichloromethane) and reaction tempera- represent a contra-thermodynamic configurational array,
tures consistently resulted in the formation of trioxa- remains the target of ongoing synthetic studies.
dispiroketal 19 as the major product. Treatment of enone 5 Acknowledgment. This publication was made possible
with TMSOTf in CH3CN at -40 °C provided 19 in 85% by grant ES10615 from the National Institute of Environ-
yield, without the generaton of diastereomeric spiroketals. mental Health Sciences (NIEHS), NIH, and generous unre-
Enone 5 was also treated with CSA in various solvents at stricted grant support from Bristol-Myers Squibb. Its contents
room temperature to allow for equilibration to the thermo- are solely the responsibility of the authors and do not
dynamically favored trioxadispiroketal. Although 19 was the necessarily represent the official views of the NIEHS, NIH.
major product under all reaction conditions surveyed, a minor A.B.D. gratefully acknowledges graduate fellowships from
diastereomeric side product, 19*, was also formed under the the American Chemical Society Divisions of Medicinal
CSA conditions.18 The configurations at C10 and C13 of 19 Chemistry (sponsored by Parke-Davis) and Organic Chem-
were initially assigned on the basis of extensive NOE studies istry (sponsored by Organic Syntheses), and the University
and were verified by X-ray crystallography of the derived of Minnesota Stanwood Johnston Memorial Fund. We thank
alcohol 20. Molecular mechanics calculations indicate that Dr. V. Young and W. Brennessel (University of Minnesota)
the (10R,13S)-configurational array within the C5-C20 for X-ray analyses, Dr. L. Yao (University of Minnesota)
trioxadispiroketal, which experiences a double anomeric for assistance with NMR experiments, and Mr. J. Aiguade
stabilization due to the axial-type orientation of the B-ring and Mr. J. Hao for helpful discussions.
oxygen atom with respect to both the A- and C-ring pyrans,
is approximately 2-3 kcal/mol lower in energy than the Supporting Information Available: Experimental pro-
corresponding (10R,13R)-trioxadispiroketal. Experimental cedures and spectral data for compounds 5, 6, 7, 7a, 7b, 10,
10a, 10b, 11, 14, 15, 15a, 16, 18, 19. This material is
(18) Studies are underway to fully characterize 19*. The ratio of 19:19* available free of charge via the Internet at [Link]
obtained under various CSA conditions ranged from 4:1 (benzene, 24 h) to
7:3 (CH3CN, 24-48 h). OL015570Y

978 Org. Lett., Vol. 3, No. 7, 2001