Efficient synthesis of the C7-C20 subunit of amphidinolides C and F

Article abstract of DOI:10.1039/b916744g

Synthesis of the C₇-C₂₀ subunit of amphidinolides C and F has been accomplished utilizing a Me₃Al-mediated ring opening of a vinyl iodide/allylic epoxide to establish the C_12,13anti stereochemistry, an organolit

Full text of DOI:10.1039/b916744g

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C. Nájera and J. M. Sansano
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Efficient synthesis of the C7–C20 subunit applications to the synthesis of
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Efficient synthesis of the C7-C20 subunit of amphidinolides C and F†
Subham Mahapatra and Rich G. Carter*
Received 13th August 2009, Accepted 7th September 2009
First published as an Advance Article on the web 16th September 2009
DOI: 10.1039/b916744g
Synthesis of the C7-C20 subunit of amphidinolides C and
F has been accomplished utilizing a Me3Al-mediated ring
opening of a vinyl iodide/allylic epoxide to establish the C12,13
anti stereochemistry, an organolithium coupling/olefination
sequence to construct the C9-C11 diene moiety and a sulfone
alkylation/hydroxylation strategy to join the C7-C14 and
C15-C20 fragments.
C14,15 bond. The C25-C26 alkene should be accessible via a Julia-
Kocienski olefination—thereby allowing access to both natural
products 1 and 2 through a common intermediate. The C-O
linkage of the macrolactone could be constructed via standard
Yamaguchi-type cyclization.4,5 The most difficult of these three
dissection points is the C14-C15 bond. The proposed route requires
a challenging alkylation of an a-branched halide6 followed by
hydroxylation of the resultant sulfone coupled product with
in situ decomposition to the corresponding ketone.7 While these
types of oxidative desulfurizations have been known for some
time, this transformation has found only limited application in
complex molecule synthesis.8,9 Any strategy must also take care to
avoid furan formation between the C15 and C18 carbonyl motifs.
Finally, the C9-C11 diene moiety should be accessible via an
organolithium addition of vinyl iodide 6 to Weinreb amide 7
followed by methylenation.
The C9-C11 diene motif is worthy of additional comment.
These types of highly substituted dienes have proven challenging
to construct. One illustration of this point is the fact that no
method for preparing the C9-C11 diene in amphidinolides C and
F has been reported. A structurally related diene is present
in amphidinolides B, G and H. While these compounds have
attracted significantly more synthetic attention,10–12 proportionally
limited success has been achieved for accessing the key diene
motif—likely due to the challenging nature of the metal-mediated
cross coupling reaction (e.g. Suzuki or Stille reaction) commonly
envisioned to form dienes.12,13 While both Fu¨rstner and Nelson
have separately disclosed the ability to construct highly substituted
dienes via Suzuki couplings, it is important to note that these
conditions require extremely high catalyst loadings (up to 70 mol%
Pd).11m,12,14 Consequently, our group has invested considerable
effort to develop alternate pathways for constructing these types
of structures.10
The amphidinolide natural products have generated considerable
attention since their initial discovery in the 1980’s by Kobayashi
and co-workers.1 Two of the most complicated members of this
family are amphidinolides C (1) and F (2) (Scheme 1).2 While most
of the amphidinolides have attracted sizable synthetic interest from
numerous researchers, macrolides 1 and 2 have been significantly
underexplored and remain unconquered synthetic targets.3 We
were drawn particularly to amphidinolide C (1) as it is one of
the most potent members of this natural product family against
a range of cancer cell lines.2 Additionally, the macrocyclic core
of both 1 and 2 possesses significant synthetic challenges: (a) 11
stereogenic centers, (b) two separate substituted THF rings, (c)
the sensitive C15,C18-diketone moiety and (d) the C9-C11 highly
substituted diene. Herein, we detail a unified synthesis of the entire
C7-C20 western portion of amphidinolides C and F.
Our retrosynthetic strategy for macrolides 1 and 2 is shown
in Scheme 1. The three main disconnections are at the C25,26
alkene sidearm, the C-O bond of the macrolactone and the
Department of Chemistry, Oregon State University, 153 Gilbert
Hall, Corvallis, OR 97331, USA. E-mail: rich.carter@oregonstate.edu;
Fax: +1 541-737-9496; Tel: +1 541-737-9486
† Electronic supplementary information (ESI) available: Complete exper-
imental procedures are provided, including 1H and 13C spectra, of all new
compounds. See DOI: 10.1039/b916744g
Scheme 1 Retrosynthesis of amphidinolides C and F.
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The synthesis of the Weinreb amide subunit is shown in
Scheme 2. Amide 7 was readily accessible from the known Ley
ester 10, which in turn was constructed from D-mannitol (8).15
Ley has shown that these diacetal derivatives of glyceraldehyde are
significantly more robust than traditional acetonide analogues. We
did find that the order of addition (LDA was added to the ester 9)
for the key epimerization of equatorial ester 9 into axial ester 10
was critical to the success of the experiment—use of the alternate
order of addition led to a significant reduction in yield (<20%).
Scheme 2 Synthesis of the Weinreb amide.
Synthesis of the C7-C14 subunit is shown in Scheme 3. The
vinyl iodide 12 was available from diester 11 through a known
procedure.16 After Sharpless epoxidation to cleanly provide the
epoxide 13,17 the first major challenge in this sequence was
selective opening of the epoxide at C12 with inversion by a methyl
nucleophile. Despite the wealth of research on the reactivity of
allylic electrophiles, surprisingly few examples of this type of
transformation have been reported.18 Furthermore, no reported
examples of accomplishing this transformation on an allylic vinyl
iodide have been disclosed. After some experimentation, we were
pleased to find that Me3Al-mediated epoxide ring opening19 at C12
cleanly provided product 15 in good diastereoselectivity (>20:1
dr) at -78 ◦C. The temperature proved to be critical to the success
of this transformation. If the epoxide opening was conducted at
-50 ◦C, significant erosion in the C12 stereochemistry was observed
(3.5:1 dr).20 The absolute stereochemistry of 15 was established by
degradation to a known compound and by matching the optical
rotation data.21 With the key vinyl halide 15 in hand, silylation
followed by halogen-metal exchange and addition to the Weinreb
amide 7 cleanly generated the enone 16. Methylenation of ketone
16 using the Petasis reagent generated the diene. Alternate methyle-
nation conditions (e.g. Wittig, Lombardo’s reagent) were unsuc-
cessful. Finally, selective desilylation at C14 OTBS ether followed
by conversion to the iodide generated the key coupling subunit 5.
The synthesis of the sulfone subunit 4 is detailed in Scheme 4.
Starting from the known iodide 18,22 halogen/metal exchange
followed by addition of the aldehyde 1923 generated the alcohol 20
as an inconsequential mixture of isomers at C18. TPAP oxidation24
of the C18 alcohol followed by Noyori ketalization25 generated the
dimethyl ketal 21. Careful debenzylation with Freeman’s LiDBB
reagent26 followed by sulfide formation provided compound 23.
Finally, sulfide oxidation using TPAP27 provided the C15-C20
subunit 4.
Scheme 3 Synthesis of the C7-C14 subunit
Scheme 4 Synthesis of the C15-C20 subunit
With the subunits in hand, efforts turned towards the critical
coupling sequence (Scheme 5). Treatment of sulfone 4 with
LiHMDS followed by the addition of iodide 5 smoothly provided
the C14,15 coupled material.6 Next, treatment of sulfone 24 under
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Scheme 5 Completion of the C7-C20 fragment of amphidinolides C
and F.
our previously developed hydroxylation conditions28 (NaHMDS,
TMSOOTMS, THF) led to no reaction. Fortunately, modification
of the base to LDA led to clean formation of the ketone 3 via the
presumed intermediate 25. Key to these reactions is the relative sta-
bility of silyloxy sulfone 25 to decomposition to the ketone 3. This
two-step sequence (sulfone alkylation/oxidation) circumvents any
problematic furan formation (between C15 and C18) and can be
viewed as a viable alternative to traditional dithiane chemistry.29
In conclusion, synthesis of the C7-C20 fragment of am-
phidinolides C and F has been disclosed. A diastereoselective
ring opening of vinyl iodide/allylic epoxide provided access
to the anti-stereochemistry. An efficient Weinreb amide cou-
pling/methylenation sequence was used to access the key C9-C11
diene motif. Sulfone alkylation was used to join the C7-C14 and
C15-C20 subunits. Finally, a hydroxylation/desulfurization process
incorporated the C15 ketone. Further application towards the
synthesis of amphidinolides will be reported in due course.
Financial support was provided by the National Institutes
of Health (NIH) (GM63723). National Science Foundation
(CHE-0722319) and the Murdock Charitable Trust (2005265)
are acknowledged for their support of the NMR facility. Mr.
Jun Xie (OSU) is acknowledged for his early work towards the
synthesis of amide 7. The authors would like to thank Professor
Max Deinzer and Dr. Jeff Morre´ (OSU) for mass spectra data.
Finally, the authors are grateful to Dr. Roger Hanselmann (Rib-X
Pharmaceuticals) for their helpful discussions.
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