Convergent assembly of the spiroacetal subunit of didemnaketal B

Article abstract of DOI:10.1021/ol1024713

A highly convergent synthesis of the C9-C28 spiroacetal subunit of didemnaketal B has been accomplished. Assembly of the C9-C15 alkylborate and C16-C21 enol phosphate by means of Suzuki-Miyaura coupling and acid-catalyzed cyclization of the derived dihydroxy enol ether enabled a rapid and efficient construction of the spiroacetal subunit. The C22-C28 side chain was incorporated via Nozaki-Hiyama-Kishi coupling to complete the synthesis.

Full text of DOI:10.1021/ol1024713

ORGANIC
LETTERS
2010
Vol. 12, No. 22
5354-5357
Convergent Assembly of the Spiroacetal
Subunit of Didemnaketal B
Haruhiko Fuwa,* Sayaka Noji, and Makoto Sasaki
Graduate School of Life Sciences, Tohoku UniVersity, 2-1-1 Katahira, Aoba-ku,
Sendai 980-8577, Japan
hfuwa@bios.tohoku.ac.jp
Received October 12, 2010
ABSTRACT
A highly convergent synthesis of the C9-C28 spiroacetal subunit of didemnaketal B has been accomplished. Assembly of the C9-C15
alkylborate and C16-C21 enol phosphate by means of Suzuki-Miyaura coupling and acid-catalyzed cyclization of the derived dihydroxy enol
ether enabled a rapid and efficient construction of the spiroacetal subunit. The C22-C28 side chain was incorporated via Nozaki-Hiyama-Kishi
coupling to complete the synthesis.
Didemnaketals A and B (1 and 2, respectively, Figure 1)
were isolated from the magenta ascidian Didemnum sp.
collected at Auluptagel island, Palau, by Faulkner and co-
workers.1 The gross structure of 1 and 2 including relative
stereochemistry of the spiroacetal subunit was established
on the basis of extensive 2D NMR analysis. These terpenoids
have been shown to exhibit potent HIV-1 protease inhibitory
activity (IC50 2-10 µM) presumably via a dissociative
mechanism. Faulkner et al. later found that the actual
metabolite of the ascidian was didemnaketal C (3).2 It was
hence assumed that 1 and 2 were produced from 3 during
prolonged storage of the ascidian sample in methanol. The
complete stereostructure of 2 and 3 was finally determined
by a combination of degradation and derivatization of the
natural sample, application of the modified Mosher method,3
and spectroscopic comparison with reference compounds.4,5
The densely functionalized complex molecular structure and
interesting biological property of didemnaketals stimulated
considerable interest within the synthetic community.6-8 As
a part of our efforts toward the total synthesis of didemna-
ketals, we describe herein a highly convergent synthesis of
the C9-C28 subunit of didemnaketal B, which features
Suzuki-Miyaura coupling9 and Nozaki-Hiyama-Kishi
(NHK) coupling10 as key fragment assembly processes.
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10.1021/ol1024713  2010 American Chemical Society
Published on Web 10/28/2010

Figure 1. Structures of didemnaketals A-C.
Our synthesis plan toward the C9-C28 subunit 4 of
didemnaketal B is summarized in Scheme 1. We envisioned
thermodynamic conditions. In turn, 7 could be synthesized
via Suzuki-Miyaura coupling of alkylborate 8 generated
from iodide 9 and enol phosphate 10.11,12
The synthesis of the C9-C15 iodide 9 commenced with
Mitsunobu coupling13 of the known alcohol 1114 with 1-phenyl-
1H-tetrazole-5-thiol (95%) followed by mCPBA oxidation
(100%) to give sulfone 12 (Scheme 2). Julia-Kocienski
olefination15 of 12 with the known aldehyde 1316 required
optimization, but we eventually found that deprotonation of
12 with KHMDS in THF/DMPU (7:1) at -78 °C followed
by addition of 13 and warming the reaction mixture to room
temperature afforded olefin 14 in 82% yield as an inseparable
mixture of E/Z isomers (E/Z ) ca. 16:1). Sharpless asym-
metric dihydroxylation17 of 14 under standard conditions
using (DHQ)2PHAL as a chiral ligand provided 1,2-diol 15
in 81% yield after removal of the minor diastereomer by
recrystallization (see the Supporting Information for details
on stereochemical assignment of the major diastereomer).
Bis-silylation of 15 (TIPSOTf, 2,6-lutidine, 100%) and
oxidative removal of the MPM group (DDQ, 89%) gave
alcohol 16, which was converted to iodide 9 via tosylation
and displacement with NaI (98% for the two steps).
Scheme 1. Synthesis Plan for the C9-C28 Subunit 4
The C16-C21 enol phosphate 10 was prepared from the
known epoxide 1718 (Scheme 3). Regioselective epoxide
opening with vinylMgBr/CuI gave a homoallylic alcohol,
which was acylated with acryloyl chloride to deliver diene
18 in 95% yield (two steps). Ring-closing metathesis19 of
18 under the influence of the Grubbs second-generation
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.
that the C22-C28 side chain could be incorporated via NHK
coupling of aldehyde 5 and vinyl iodide 6. The spiroacetal
moiety of 5 was planned to be constructed by means of
acid-catalyzed cyclization of dihydroxy enol ether 7 under
(13) Mitsunobu, O. Synthesis 1981, 1–28.
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Org. Lett., Vol. 12, No. 22, 2010
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of the newly generated stereogenic center at C18 was
confirmed by an NOE experiment as shown. Finally, treat-
ment of 20 with KHMDS in the presence of (PhO)2P(O)Cl
furnished the C16-C21 enol phosphate 10.
Scheme 2. Synthesis of the C9-C15 Iodide 9
The C22-C28 vinyl iodide 6 was synthesized from the
known alkyne 218 (Scheme 4). Regioselective silylcupration
Scheme 4. Synthesis of the C22-C28 Vinyl Iodide 6
of 21 with (Me2PhSi)2Cu(CN)Li2 (THF, -78 to 0 °C)23 gave
vinylsilane 22 with approximately 7:1 regioselectivity. Io-
dodesilylation of vinylsilane 22 (NIS, CH3CN/THF)24 was
accompanied with a partial erosion of the double bond
geometry to deliver vinyl iodide 23 (E/Z ) ca. 6:1 for the
major regioisomer). Subsequent cleavage of the TBDPS ether
with TBAF delivered alcohol 24 in 57% overall yield from
21, after removal of the minor products. A two-stage
oxidation of 24 to the corresponding carboxylic acid followed
by esterification with TMSCHN2 afforded the C22-C28
vinyl iodide 6 in 97% overall yield.
Scheme 3. Synthesis of the C16-C21 Enol Phosphate 10
Completion of the synthesis of the C9-C28 subunit 4 is
illustrated in Scheme 5. Treatment of iodide 9 with t-BuLi
in the presence of B-MeO-9-BBN (Et2O, -78 °C; then add
THF, room temperature)25 generated alkylborate 8. Without
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catalyst (G-II)20 (Ti(Oi-Pr)421 (30 mol %), CH2Cl2 (10 mM),
reflux) afforded R,ꢀ-unsaturated lactone 19 in 95% yield.
Stereoselective 1,4-addition of Me2CuLi gave lactone 20 in
72% yield as a single stereoisomer.22 The stereochemistry
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Trans. 1 1981, 2527–2532. (b) Fuwa, H.; Ebine, M.; Bourdelais, A. J.;
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Org. Lett., Vol. 12, No. 22, 2010

aqueous Cs2CO3 in DMF at 50 °C to afford endocyclic enol
ether 25 in 81% yield. Desilylation of the TIPS groups with
TBAF led to dihydroxy enol ether 7, which was exposed to
PPTS in CH2Cl2 at room temperature to furnish spiroacetal
26 as a sole isolable product in 84% yield (two steps). The
stereochemistry of the newly created stereogenic centers was
established by NOE experiments on 26 as shown.
Scheme 5. Completion of the Synthesis of 4 and 21-epi-4
Protection of the hydroxy group within 26 as its TBS ether
(TBSOTf, 2,6-lutidine, 96%), removal of the MPM group
(DDQ, 87%), and subsequent Dess-Martin oxidation26 of
the derived alcohol (99%) led to aldehyde 5. Finally, NHK
coupling of 5 with vinyl iodide 6 under standard conditions
(NiCl2, CrCl2, DMSO, room temperature) afforded an
approximately 1.4:1 separable mixture of the C9-C28
subunit 4 and its C21 epimer 21-epi-4 in 81% combined
yield. The stereochemistry of the C21 stereogenic center of
the major isomer was determined by application of the
modified Mosher method (see the Supporting Information
for details).3 Although the NHK coupling proceeded with
only moderate diastereoselectivity, we found, after extensive
investigation, that 21-epi-4 could be efficiently transformed
into the desired 4 via an oxidation/reduction sequence;
oxidation of 21-epi-4 with Dess-Martin periodinane gave
an enone quantitatively, which was reduced with L-selectride
to provide the desired 4 in 82% yield as a single stereoisomer.
In conclusion, a highly convergent assembly of the fully
functionalized C9-C28 spiroacetal subunit 4 of didemnaketal
B (2) has been accomplished by exploiting Suzuki-Miyaura
coupling and NHK coupling. The present synthesis proceeded
with only 15 linear steps from the known alcohol 11. Further
studies toward the total synthesis of didemnaketals are
currently ongoing and will be reported in due course.
Acknowledgment. This work was supported by a Grant-
in-Aid for Scientific Research from MEXT, Japan.
Supporting Information Available: Detailed experimen-
tal procedures, spectroscopic data, and copies of 1H and 13
C
NMR spectra for all new compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
OL1024713
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isolation, this was coupled with enol phosphate 10 by the
action of PdCl2(dppf)·CH2Cl2 catalyst (10 mol %) and
Org. Lett., Vol. 12, No. 22, 2010
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