Synthesis of the spirastrellolide A, B/C spiroketal: Enabling solutions for problematic au(I)-catalyzed spiroketalizations

Article abstract of DOI:10.1021/acs.orglett.5b00711

A synthesis of the spirastrellolide A, B/C-ring monounsaturated spiroketal is reported. The key step relies on a Au-catalyzed spiroketalization of a propargyl triol employing an acetonide as a regioselectivity regulator. Through observation and analysis, a set of conditions has been developed that facilitates the use of a mixture of diastereomeric substrates, obviating the need to control the stereochemistry of the propargyl stereocenter and enabling a convenient retrosynthetic disconnection. The key reaction proceeds in 80% yield in 1 min at ambient temperature with the Me₃PAuCl/AgOTf catalyst system. These conditions should be widely applicable for new synthetic endeavors as they appear to overcome all issues with the Au-catalyzed spiroketalization.

Full text of DOI:10.1021/acs.orglett.5b00711

Letter
pubs.acs.org/OrgLett
Synthesis of the Spirastrellolide A, B/C Spiroketal: Enabling Solutions
for Problematic Au(I)-Catalyzed Spiroketalizations
Barry B. Butler Jr., Jagadeesh Nagendra Manda, and Aaron Aponick*
Department of Chemistry, Center for Heterocyclic Compounds, University of Florida, Gainesville, Florida 32611, United States
S
* Supporting Information
ABSTRACT: A synthesis of the spirastrellolide A, B/C-ring
monounsaturated spiroketal is reported. The key step relies on
a Au-catalyzed spiroketalization of a propargyl triol employing
an acetonide as a regioselectivity regulator. Through
observation and analysis, a set of conditions has been
developed that facilitates the use of a mixture of diastereomeric
substrates, obviating the need to control the stereochemistry of
the propargyl stereocenter and enabling a convenient
retrosynthetic disconnection. The key reaction proceeds in 80% yield in 1 min at ambient temperature with the Me3PAuCl/
AgOTf catalyst system. These conditions should be widely applicable for new synthetic endeavors as they appear to overcome all
issues with the Au-catalyzed spiroketalization.
attention of the synthetic community with four total syntheses2
he Spirastrellolide natural products were first isolated from
and numerous approaches having been reported to date.3
Tthe marine sponge Spirastrella coccinea by Andersen and co-
workers in 2003.1 The family consists of several congeners
Our interest in these natural products stems from the densely
functionalized macrolide core of the molecules, consisting of
named spirastrellolides A−G (1−7) that display potent
saturated oxygen heterocycles. As part of a program aimed at
developing new Au-catalyzed methods for dehydrative trans-
biological activity. Spirastrellolide A methyl ester was reported
as a novel antimitotic agent (IC50 100 ng/mL)1a and was later
formations of unsaturated alcohols, we initiated method
shown to selectively inhibit protein phosphatase 2A (PP2A);
development studies for the formation of the requisite
(IC50 = 1 nM).1b In 2004, the revised structure of spirastrellolide
A appeared and is the basis for the assignment of the
stereochemistry of spirastrellolides A−G (Figure 1).1b The
absolute configuration was later determined in 2007.1c Due to
the potent biological activity and interesting and complex
molecular architecture, the spirastrellolides have attracted the
heterocycles.4 We felt that it was important to address the B/
C-ring system as an unsaturated spiroketal is also found in
okadaic acid,5 another potent phosphatase inhibitor, and thus
became interested in spirastrellolides A, D, E, and G. As can be
seen in Scheme 1, spirastrellolide A lends itself to disconnection
into the fragments containing tetrahydropyran, unsaturated
spiroketal, and bispiroketal motifs. Our initial report demon-
strated the use of Au catalysis for the formation of
tetrahydropyrans, and we reported an A-ring synthon in racemic
form that has now been prepared enantioselectively.4a To
complete the southern hemisphere, a B/C-ring unsaturated
spiroketal was necessary, but application of our Au-catalyzed
propargyl triol method4b proved to be problematic. Fortunately,
we were able to gain an understanding of the underlying
problems, and this led to the development of a mechanistic
rationale and eventually to a good solution to the spiroketaliza-
tion problem. Herein we report an efficient synthesis of the B/C-
ring fragment and describe the important details necessary for
successful spiroketalization.
As shown above, retrosynthetic analysis suggested that the B/
C-ring spiroketal 8 should be available by spiroketalization of an
alkyne precursor 9. This approach distinguishes itself from more
traditional spiroketalization methods as oxygenation at spiroketal
Received: March 11, 2015
Figure 1. Structures of spirastrellolides A−G.
© XXXX American Chemical Society
A
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15 and alkyne 16 were selected as synthetic intermediates
Scheme 1. Retrosynthetic Analysis of Spirastrellolide A
(Scheme 3).
Scheme 3. Retrosynthetic Analysis of Spiroketalization
Precursor 9
The synthesis of Weinreb amide 15 (Scheme 4) began with
known acid 17,8 forming the monoprotected β-ketoester 19 by
Scheme 4. Synthesis of Amide Fragment 15
C17 is introduced via addition to the alkyne C17 and the Δ15,16
olefin is produced by elimination of the C15 hydroxyl group. At
the outset, it was thought that the C15 hydroxyl group
stereochemistry in 9 should be inconsequential, but this was
somewhat in question. As seen in Scheme 2, the relative
Scheme 2. Problematic 1,3-syn-Diols for Spiroketalization
coupling with 18.9 The C13 stereochemistry was set in 97% ee by
Noyori reduction9 and the methyl group introduced by
alkylation10 to provide 21 in 25:1 dr after TBS protection. The
ester was then smoothly converted to the Weinreb amide 15 in
nearly quantitative yield.
Synthesis of the alkyne 16 commenced from O-allyl L-
arabinose 22,11 which contains the C20−22 stereotriad required
for spirastrellolide A, and proved to be a convenient starting
material (Scheme 5). This required chain extension at both
termini, which would be accomplished by Wittig olefination and
epoxide opening. In the event, selective formation of the six-
membered ketal and benzyl protection of the remaining hydroxyl
group were accomplished, forming 23 in 99% yield. Deallylation
and Wittig olefination then provided the olefin 24.12 Addition of
the alkyne moiety proved to be slightly more difficult. To achieve
this, the acetonide was first cleaved and the resulting primary
alcohol selectively activated as the tosylate. At this stage,
extensive efforts to form the epoxide and protect the ensuing C21
alcohol failed, resulting in decomposition. The C20,21 alcohols
needed to be differentiated as C20 bears a methyl ether in the
natural product and the C21 hydroxyl group is required for the
Au-catalyzed cyclization. It was found that the C20 alcohol could
be selectively protected, but all attempts to then protect the C21
alcohol provided unsatisfactory results. To overcome this issue,
stereochemistry of the indicated diols had a pronounced effect on
the spiroketalization with the 1,3-anti-diols 10 and 14 smoothly
providing the [6,6]-spiroketals (1,7-dioxaspiro[5.5]undecanes)
in high yields and the 1,3-syn-diols providing mixtures of [6,6]-
and [5,7]-spiroketals with virtually no selectivity.6
These data suggested that it may be important to control the
C15 stereochemistry, but the effect of the C14 methyl group was
unknown. This would later be borne out here (vide infra) and
also by Smith and co-workers.7 In anticipation of these
stereochemical consequences, triol 9 would be prepared by
selective ketone reduction if necessary, and thus Weinreb amide
B
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using the Echavarren catalyst (Table 1, entry 1), unfortunately,
the yield was low (50% isolated yield) and it appeared that one
Scheme 5. Synthesis of Alkyne Fragment 16
Table 1. Au(I) Spiroketalization Studies
a
entry
alkyne
catalyst system
yield
1
2
3
4
9a/b
JohnPhos Au(MeCN)SbF6
50%
9a/b
AuCl
50%
29a/b
29a/b
AuCl
decomp
50%
JohnPhos Au(MeCN)SbF6
a
Mixtures of 8 and [5,7]-spiroketals were observed.
diastereomer rapidly provided the product while the other
sluggishly reacted and formed a mixture of 8 and [5,7]-
spiroketals. Use of simple AuCl provided the same results
(entry 2). During our work on this system, Smith reported the
same observation and nicely determined that the 1,3-anti-
diastereomer was the one that was smoothly cyclizing in his
system.7 Forsyth provided a mechanistic rationale for this
phenomenon that was based on steric effects,6 and we recently
reported a method to overcome this issue using AuCl as catalyst
with acetonide substrates such as 29a,b.15 Unfortunately,
employing the optimized conditions (entry 3) only resulted in
decomposition. In an attempt to overcome this, the less Lewis
acidic Echavarren catalyst was employed (entry 4) and the
isolated yield improved to 50%, but this was still deemed
unacceptable.
the C20 alcohol was protected as the TBS ether, and a silyl
migration/epoxide formation sequence then nicely afforded
epoxide 26. To complete the synthesis of 16, the epoxide was
opened with a propargyl Grignard reagent prepared with catalytic
HgCl2 as an initiator,13 and the C20 methyl ether formed with
NaH and MeI.
Union of the two fragments was accomplished in 71% yield by
acetylide addition to the Weinreb amide to give the ketone 28
(Scheme 6). At this stage, it was decided to do a simple DIBAL-H
At this stage, it was hypothesized that the diastereomers 29a
and 29b follow similar reaction pathways (Scheme 7). The
process must begin with an initial anti-alkoxyauration to provide
30a and 30b, respectively. Examination of these σ-gold
Scheme 6. Synthesis of Spiroketalization Substrates
Scheme 7. Analysis of 1,3-syn- and 1,3-anti-Diols in Au-
Catalyzed Spiroketalization
reduction and explore the key spiroketal formation4b on a 2:1
mixture of diastereomers 9a,b thus obtained, with the goal of
overcoming the requirement for a specific diastereomer. The
material was also converted to the acetonides 29a,b, initially to
determine the relative stereochemistry14 and later for preparative
purposes. Conversion of the ketone 28 to the acetonides 29a,b
proceeded in 91% yield over three steps.
With a source of triols 9a,b in hand, Au-catalyzed
spiroketalization was attempted. While the reaction proceeded
C
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Notes
complexes reveals a syn-pentane interaction in the intermediate
30a, resulting from the C13,15-syn-diastereomer 29a, while such
an interaction would be greatly diminished in 30b, which results
from the C13,15-anti-diastereomer 29b. This was intriguing as it
may explain the reactivity problem of the anti diastereomers such
as 29b.4,6,7 To complete the transformation, what is needed is an
anti-elimination of the σ-gold complex to release acetone and
reveal the second hydroxyl group for cyclization. In both 30a and
30b, the proper anti-periplanar orientation required for this
elimination is achieved, and the leaving group is likely further
activated by hydrogen bonding, as was reported for similar
reactions on THP systems.16
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the James and Esther King Biomedical Research
Program (09KN-01) and the University of Florida Health
Cancer Center for their generous support. J.N.M. thanks the
University of Florida Graduate School for a Graduate Research
Fellowship. We thank Drs. Beranger Biannic (UF) and John M.
Ketcham (UF) for exploratory synthetic work, and Mr. Paulo
Paioti (UF) for helpful discussions regarding the spiroketaliza-
tion.
This hypothesis suggested that the rates of cyclization could be
modulated by changing either the substrate or the catalyst to
relieve the unfavorable syn-pentane interactions. The goal of this
method was to allow for either diastereomer to participate in the
spiroketalization and obviate the need for a stereoselective
substrate preparation. As such, it was postulated that a smaller
catalyst might facilitate this and suggested use of the smallest
Au−phosphine complex available, Me3PAuCl, in combination
with AgOTf. With these conditions, a rapid consumption of both
diastereomers was observed, providing a single diastereomer of
the B/C spiroketal in a reaction time of 1 min (Scheme 8). The
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ASSOCIATED CONTENT
* Supporting Information
■
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AUTHOR INFORMATION
Corresponding Author
■
*E-mail: aponick@chem.ufl.edu.
D
DOI: 10.1021/acs.orglett.5b00711
Org. Lett. XXXX, XXX, XXX−XXX