Synthesis of the ABC ring system of Azaspiracid. 2. A systematic study into the effect of C(16) and C(17) substitution on bis-spirocyclization.

Article abstract of DOI:10.1021/ol026034o

[reaction: see text] A systematic study into the effect of C(16) and C(17) substitution on the stereochemical outcome of bis-spirocyclization to form the ABC ring system of azaspiracid is disclosed. Successful construction of the natural 10R,13R bis-spirocyclic stereochemistry has been accomplished on the C(16) benzyloxy-containing precursor.

Full text of DOI:10.1021/ol026034o

ORGANIC
LETTERS
2002
Vol. 4, No. 13
2181-2184
Synthesis of the ABC Ring System of
Azaspiracid. 2. A Systematic Study into
the Effect of C and C Substitution on
16
17
Bis-spirocyclization†
,‡
Rich G. Carter,* David E. Graves,§ Melissa A. Gronemeyer,§ and
Gregory S. Tschumper§
Department of Chemistry, Oregon State UniVersity, CorVallis, Oregon 97331, and
Department of Chemistry and Biochemistry, UniVersity of Mississippi,
UniVersity, Mississippi 38677
rich.carter@oregonstate.edu
Received April 17, 2002
ABSTRACT
A systematic study into the effect of C16 and C17 substitution on the stereochemical outcome of bis-spirocyclization to form the ABC ring
system of azaspiracid is disclosed. Successful construction of the natural 10R,13R bis-spirocyclic stereochemistry has been accomplished on
the C16 benzyloxy-containing precursor.
The azaspiracids are an intriguing class of recently isolated
natural products that possess a complex structural framework
Scheme 1. Potential Combinations for Substitution Patterns at
as well as considerable biological activity.1-3 As discussed
C16 and C17
in the previous paper,4 the D ring appears to exert consider-
able influence on the bis-spirocyclization. Based on these
results, our efforts shifted toward the construction of selected
substrates containing substitution at C16 or C17 (Scheme 1).
The C17 series appeared more attractive as inspection of the
potential chair conformations of bis-spiroketals 2 and 34
revealed that the transoidal and the cisoidal structures were
both capable of placing the C17 allyl substituent equatorial
on the basis of the proposed conformation for bis-spiroketals
5 and 6.
† This work was performed at the University of Mississippi. The
corresponding author’s present address is Department of Chemistry, Oregon
State University, Corvallis, OR 97331.
‡ Oregon State University.
§ University of Mississippi.
(1) MacMahon, T.; Silke, J. Harmful Algae News 1996, 14, 2.
(2) Ofuji, K.; Satake, M.; McMahon, T.; Silke, J.; James, K. J.; Naoki,
H.; Oshima, Y.; Yasumoto, T. Nat. Toxins 1999, 7, 99.
(3) Ofuji, K.; Satake, M.; McMahon, T.; James, K. J.; Naoki, H.; Oshima,
Y.; Yasumoto, T. Biosci. Biotechnol. Biochem. 2001, 65, 740.
(4) Carter, R. G.; Bourland, T. C.; Graves, D. E. Org. Lett. 2002, 4,
2177 (ol026033w).
10.1021/ol026034o CCC: $22.00 © 2002 American Chemical Society
Published on Web 06/05/2002

C17 Substitution. Spirocyclization of previously described
keto sulfone 104 using our preferred conditions for keto
sulfone substrates (CSA, MeCN)5 led to a mixture of
stereoisomers (Scheme 2). Treatment of the spirocycle 11
resents, to the best of our knowledge, a unique strategy for
the effective construction of highly labile enol ethers (e.g.,
14).
C16 Substitution. The synthesis of the required benzyloxy
aldehyde 21 began with the known Evans alkylation product
158 (Scheme 3). Conversion to its benzyl ester 16 followed
Scheme 2. Bis-spirocyclization of C17 Allyl Substratea
Scheme 3. Synthesis of the C16 Benzyloxy-Substituted
Aldehydea
a Key: (i) BnOLi, PMBOH, THF, 99%; (ii) AD mix R, NaHCO3,
t-BuOH, H2O; (iii) TIPSOTf, 2,6-lutidine, CH2Cl2, -78 °C, 66%
overall yield from 16 (3:1 d.s.); (iv) LiBH4, MeOH, THF, 0 °C,
99%; (v) PivCl, Et3N, DMAP, CH2Cl2, 66%; (vi) NaH, BnBr, DMF,
-50 °C to -10 °C; (vii) TBAF, THF, 79% (over two steps); (viii)
TESCl, DMAP, Et3N, CH2Cl2, 95%; (ix) LiBH4, saturated aqueous
NH4Cl, THF, 0 °C to rt, 99%; (x) TPAP, NMO, CH2Cl2, molecular
sieves, 87%.
a Key: (i) CSA, MeCN, 90%; (ii) n-BuLi, THF, -78 °C, 70%;
(iii) TPAP, NMO, CH2Cl2, mol. sieves, 96%; (iv) (+)-Ipc2Ballyl,
Et2O, pentane, 70%, >20:1 d.s.; (v) 5% Na/Hg, Na2HPO4, MeOH,
THF, -10 °C; (vi) CSA, t-BuOH, PhMe, 76% (over two steps).
by Sharpless asymmetric dihydroxylation,9 in situ lacton-
ization, and TIPS protection yielded the lactone 17, in overall
66% yield from 16, as a separable 3:1 ratio at C16 favoring
the desired stereochemistry.10 While the diastereomeric
selectivity in the dihydroxylation is less than optimum (3:1
d.s.), direct dihydroxylation of the chiral oxazolidinone-
containing alkene 15 provided inferior results (1.5:1 d.s.).
This observation is consistent with our previous findings with
other oxazolidinone-containing alkenes.11 Subsequent reduc-
tion using LiBH4 provided the diol 18. Next, sequential
protection at C13 and C16 produced the fragment 19, along
with a small amount of impurities derived from migration
of the pivaloate and silyl protecting groups. Removal of the
TIPS ether under standard conditions allowed for easy
purification. The C17 hydroxyl was reprotected as its TES
ether 20. Cleavage of the C13 pivaloate protecting group did
with n-BuLi induced â-elimination to yield the elaborate enol
ether 12 in 70% yield, along with 10% of the presumed C10
epimer. The strategy allowed for the protection of the C13
carbonyl function while selectively revealing the C17 hy-
droxyl group. Oxidation at C17 followed by Brown allylation6
yielded the homoallylic alcohol 13 in greater than 20:1 d.s.
Removal of the sulfone functionality revealed the highly
labile enol ether 14, which rapidly underwent spirocyclization
under the standard conditions (0.04 M CSA, t-BuOH/PhMe,
14-18 h) to give the bis-spiroketal 6 as a single diastereomer.
Unfortunately, NOESY and COSY NMR experiments (CDCl3)
confirmed the cisoidal 10R,13S relationship of the bis-
spiroketal. While it is important to point out that the enol
ether spirocyclization precursor 14 is structurally different
than ketone 4, previous work in our laboratory has shown
that the C10 ketal is readily ionized under acidic conditions,5
thereby ensuring formation of comparable spirocyclization
intermediates from both precursors. It is interesting to note,
however, that the sulfone moiety once again provided added
stability,7 as 13 was indefinitely stable in the freezer. Also,
our ketalization/â-elimination/desulfonylation strategy rep-
(7) We have consistently observed an increased stabilization in substrates
containing the sulfone function versus their corresponding desulfonylated
counterparts, which are prone to elimination at C10,11 to the corresponding
enol ether.
(8) Evans, D. A.; Ennis, M. D.; Mathre, D. J. J. Am. Chem. Soc. 1982,
104, 1737.
(9) Kolb, H. C.; VanNieuwenhze, M. S.; Sharpless, K. B. Chem. ReV.
1994, 94, 2483.
(10) A small, inseparable bi-product was present in 17. Fleming and co-
workers recently reported the presence of an n-propyl silyl impurity in
selected TIPS protection protocols. As silylation as alternate silyl protecting
groups (such as TBS or TES) did not lead to a similar impurity, it would
appear that the n-propyl silyl species is a reasonable explanation. Barden,
D. J.; Fleming, I. Chem Commun. 2001, 2366.
(5) Carter, R. G.; Graves, D. E. Tetrahedron Lett. 2001, 42, 6035.
(6) Racherla, U. S.; Brown, H. C. J. Org. Chem. 1991, 56, 401.
(11) Carter, R. G.; Weldon, D. J. Org. Lett. 2000, 2, 3913.
2182
Org. Lett., Vol. 4, No. 13, 2002

prove problematic with DIBAL-H;12 however, the use of
LiBH4, in the presence of a small amount of saturated
aqueous NH4Cl, cleanly provided the desired alcohol in 99%
yield. Finally, TPAP oxidation yielded the target aldehyde
21.
Lithiation of sulfone A with LDA followed by addition
of the aldehyde 21 provided the hydroxy sulfone adduct as
a labile mixture13 of all four diastereomers (Scheme 4).
lack of signal can be explained by the placement of the C13
furan oxygen and the C14 methyl substituents in axial
orientations within the pyran C ring. Further NMR evidence
supports this hypothesis: (1) a strong NOE is observed
between the C14 methyl and the C16 hydrogen and (2) the
coupling constants between the C16 and C17 hydrogens match
the predicted data for the proposed C ring, chair conformation
using the Karplus correlation.14 Furthermore, the alternate
chair conformer (with the C13 furan oxygen and the C14
methyl substituent in equatorial orientations) is significantly
higher in energy (3.4 kcal/mol) using the B3LYP density
functional and a 6-31G(d) basis set. It should also be noted
that the observed NOE and coupling constant data would
not be expected for the alternate non-natural transoidal bis-
spirocycle.5 Finally, the proposed conformation of transoidal
spirocycle 8 is in contrast to the previously discussed
transoidal spirocycle 2, which appeared to place the C13 furan
oxygen and the C14 methyl substituents in equatorial orienta-
tions.
Scheme 4. Bis-spirocyclization of C16 Benzyloxy Substratea
To further study the nature of the bis-spiroketalization,
the reaction with ketone 7 was performed at lower temper-
atures (-10 to +4 °C, 21 h) and reduced molarity of the
acid catalyst (0.003 M) under otherwise identical reaction
conditions (1:1 t-BuOH/PhMe). We were intrigued to
discover that the predominate product was the cisoidal bis-
spirocycle 9. Gratifyingly, further warming of the reaction
to room temperature for an additional 48 h resulted in the
previously observed (3:5 ratio of 8:9) equilibrium mixture.15
It would appear from these observations that the cisoidal bis-
spirocycle 9 is the result of kinetic control while the
transoidal bis-spirocycle 8 can be accessed under thermo-
dynamic conditions. With one equilibration cycle, a 50%
overall yield of the desired transoidal bis-spirocycle 8 can
be obtained. Finally, use of Nicolaou and co-workers’
conditions16 for equilibration of their cisoidal bis-spirocycle
to the natural transoidal species (3 equiv of TFA, CH2Cl2)
provided inferior results for the conversion of 9 to 8
(approximately 1:3 ratio for 8:9).17
a Key: (i) LDA, THF, -78 °C then 21; (ii) TPAP, NMO,
CH2Cl2, molecular sieves 60% (over two steps); (iii) 5% Na/Hg,
Na2HPO4, MeOH, THF, -10 °C; (iv) CSA, PhMe/t-BuOH, 80%,
3:5 ratio (8/9).
Immediate oxidation to the ketone sulfone 22 was ac-
complished with TPAP in a 60% yield over two steps.
Desulfurization under standard conditions followed by bis-
spirocyclization (0.04 M CSA, t-BuOH/PhMe, 14-18 h)
gave two spiroketals in a 3:5 ratio (8/9) in an overall 80%
yield. After careful separation of the two isomers, the
stereochemistry of the more polar isomer was determined
to be the cisoidal ketal 9 (2D NMR, CDCl3). We were
gratified to find, however, that the less polar spirocycle 8
possessed the natural transoidal stereochemistry at C10 and
C13 as established by ROESY and COSY correlations
(C6D5N). While the NOE between the C9 alkene to C17
hydrogen was previously observed in the transoidal product
2 from the D ring truncated series,4 the NOE between the
C6 hydrogen and the methyl at C14 was not present. This
The first systematic study into the effect of substituents
on the bis-spirocyclization of a series of precursors has been
presented. The C16 oxygen substitution facilitated formation
of a nearly equal mixture of the cisoidal and transoidal bis-
spirocycles while C17 allyl substitution provided sole access
to the cisoidal species. Our continuing progress toward the
total synthesis will be reported in due course.
Acknowledgment. We thank the National Institutes of
Health (GM63723) and the University of Mississippi for
partial support of this work. In addition, we thank Dr. Jeff
Morre´ and Professor Max Dienzer (Oregon State University)
(14) Karplus, M. J. Phys. Chem. 1959, 30, 11.
(15) The same ratio (3:5, 92% overall yield) can also be observed by
resubmission of the cisoidal bis-spirocycle 9 to the standard conditions (0.04
M CSA, t-BuOH/PhMe, 14-18 h).
(12) It is unclear at this juncture as to the exact nature of the problem;
however, the experimental data is consistent with silyl migration of the
C17 TES protecting group.
(13) The Julia adduct appeared to be prone to rapid spirocyclization of
the C13 hydroxyl moiety onto a corresponding C10 oxonium ion. This
problem could be easily circumvented by the immediate oxidation of the
hydroxy sulfone intermediate (without purification or storage) to the
corresponding keto sulfone 22.
(16) Nicolaou, K. C.; Qian, W.; Bernal, F.; Uesaka, N.; Pihko, P. M.;
Hinrichs, J. Angew. Chem., Int. Ed. 2001, 40, 4068.
(17) While this protocol appeared to reach equilibrium in a similar time
frame to Nicolaou and co-workers (4 h), the TFA/CH2Cl2 conditions led to
a significantly more complex crude reaction mixture, presumably due to
decomposition.
Org. Lett., Vol. 4, No. 13, 2002
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for mass spectral data. Finally, we thank Dr. Roger Hansel-
mann (Rib-X Pharmaceuticals) for his helpful discussions.
material is available free of charge via the Internet at
http://pubs.acs.org.
Supporting Information Available: Experimental pro-
cedures and spectral characterization are provided. This
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