Synthesis of (+)-didemniserinolipid B via ketalization/ring-closing metathesis

Article abstract of DOI:10.1021/ol702454m

A modular synthesis of didemniserinolipid B is reported. Central to this synthesis was the use of a ketalization/ring-closing metathesis (K/RCM) strategy to establish the 6,8-dioxabicyclo[3.2.1]octane core. The C10 axial alcohol was established via a sele

Full text of DOI:10.1021/ol702454m

ORGANIC
LETTERS
2007
Vol. 9, No. 26
5357-5359
Synthesis of (+)-Didemniserinolipid B
via Ketalization/Ring-Closing Metathesis
Christopher C. Marvin, Eric A. Voight, and Steven D. Burke*
Department of Chemistry, UniVersity of WisconsinsMadison, 1101 UniVersity AVenue,
Madison, Wisconsin 53706-1322
burke@chem.wisc.edu
Received October 8, 2007
ABSTRACT
A modular synthesis of didemniserinolipid B is reported. Central to this synthesis was the use of a ketalization/ring-closing metathesis (K/
RCM) strategy to establish the 6,8-dioxabicyclo[3.2.1]octane core. The C10 axial alcohol was established via a selective epoxidation, followed
by reductive trans-diaxial epoxide opening. The serinol and unsaturated ester side chains were introduced by a Williamson etherification and
cross metathesis, respectively.
Didemniserinolipid B (1 in Figure 1) is one of three unusual
serinolipids isolated from a cytotoxic extract of the tunicate
Didemnum sp. by Jime´nez and co-workers.1 Ultimately, none
of these purified serinolipids possessed any cytotoxicity.
Subsequently, Faulkner and co-workers discovered a related
macrocycle-containing serinolipid, cyclodidemniserinol trisul-
fate, an inhibitor of HIV-1 integrase.2 A synthesis of
didemniserinolipid B has been reported by Ley and co-
workers.3 Their work resulted in both the elucidation of the
stereochemistry within the serinol fragment and in a structural
revision with the identification of an O-sulfate at C31.
formation via ring-closing alkene metathesis5 (K/RCM) is
that the use of protecting groups can be minimized. Fur-
Our interest in didemniserinolipid B was stimulated by
the central 6,8-dioxabicyclo[3.2.1]octane core. Traditional
routes to such bicyclic ketals involve intermolecular carbon-
carbon bond formation followed by intramolecular ketaliza-
tion via dehydration of a keto diol. Recently, we have
developed a nontraditional approach to these structures which
reverses this sequence.4 One advantage of intermolecular
ketalization followed by intramolecular carbon-carbon bond
(1) Gonza´lez, N.; Rodriguez, J.; Jime´nez, C. J. Org. Chem. 1999, 64,
5705.
(2) Mitchell, S. S.; Rhodes, D.; Bushman, F. D.; Faulkner, D. J. Org.
Lett. 2000, 2, 1605.
(3) Kiyota, H.; Dixon, D. J.; Luscombe, C. K.; Hettstedt, S.; Ley, S. V.
Org. Lett. 2002, 4, 3223.
Figure 1. Didemniserinolipid B structure and retrosynthesis.
10.1021/ol702454m CCC: $37.00
© 2007 American Chemical Society
Published on Web 11/30/2007

thermore, stereoselective functional group introduction is
facilitated by the rigid, facially biased dioxabicyclic core.
In the context of didemniserinolipid B, we felt that by first
constructing the bicyclic ketal core via K/RCM we could
develop an efficient and modular synthesis which could be
amenable to diversification of the chains appended to this
core for future analogue preparation.
3. Bicyclic ketal 3 would be directly accessible from a
K/RCM sequence involving ketone 5 and C2-symmetric
(R,R)-diene diol 6.10 While providing a rapid and convenient
route to 3, K/RCM has additional strategic advantages in
that the C2-symmetric diene diol 6 is desymmetrized, and
one of the vinyl groups is left unreacted and thus available
for later CM with 4.
Our retrosynthesis is shown in Figure 1. We imagined
installing the C1-C6 R,â-unsaturated ester fragment via an
alkene cross metathesis (CM) followed by saturation of the
isolated C6-C7 double bond. The axial C10 alcohol would
arise from a substrate-controlled epoxidation of the endocy-
clic alkene in 3,6 followed by hydride delivery via trans-
diaxial opening of the epoxide (Scheme 1).7 The C29-C31
Our synthesis commenced with the combination of ketone
5 and diene diol 6 with azeotropic removal of water to
provide ketal 9 in 87% yield (57% overall yield from 7).11
Two features of ketone 5 deserve comment. The γ-phenyl
group was essential, as it promoted a 5:1 mixture of â,γ- to
R,â-alkenes. Additionally, the mesylate served both as an
alcohol protecting group and as a reactive leaving group for
subsequent etherification.
Ketal 9 underwent RCM upon treatment with Grubbs’ first
generation metathesis catalyst (G1, Figure 2) to afford
Scheme 1. Synthesis of Bicyclic Ketal 3, Williamson
Etherification, and Installation of C10 Alcohol
Figure 2. Grubbs first and second generation metathesis catalysts.
bicyclic acetal 3 (53% isolated, 81% BORSM). Prolonged
reaction times led to decreased isolated yields due to
dimerization of 3 and the formation of significant amounts
of 10, resulting from cross metathesis of 3 with the styrene
byproduct of the RCM.
Etherification of 3 with the sodium alkoxide of 2 pro-
ceeded cleanly to yield 11 with only trace amounts (∼3%)
of elimination product. Bicyclic diene 11 underwent chemo-
and stereoselective epoxidation at the endocyclic double bond
upon treatment with 1 equiv of m-CPBA and warming from
0 to 4 °C overnight. After one recycle of recovered 11,
epoxide 12 could be obtained in 60% yield. trans-Diaxial
reductive epoxide opening was then achieved by treatment
of exo-epoxide 12 with LAH in THF, thus providing the C10
axial alcohol 13 in 86% yield.
serinol fragment would be installed via Williamson etheri-
fication8 involving known serinol derivative 29 and mesylate
(4) (a) Marvin, C. C.; Clemens, A. J. L.; Burke, S. D. Org. Lett. 2007,
9, 5353. (b) Voight, E. A.; Seradj, H.; Roethle, P. A.; Burke, S. D. Org.
Lett. 2004, 6, 4045. (c) Voight, E. A.; Rein, C.; Burke, S. D. J. Org. Chem.
2002, 67, 8489. (d) Keller, V. A.; Martinelli, J. R.; Strieter, E. R.; Burke,
S. D. Org. Lett. 2002, 4, 467. (e) Voight, E. A.; Rein, C.; Burke, S. D.
Tetrahedron Lett. 2001, 42, 8747. (f) Burke, S. D.; Voight, E. A. Org.
Lett. 2001, 3, 237. (g) Burke, S. D.; Mu¨ller, N.; Beaudry, C. M. Org. Lett.
1999, 1, 1827.
(5) For recent reviews, see: (a) Nicolaou, K. C.; Bulger, P. G.; Sarlah,
D. Angew. Chem., Int. Ed. 2005, 44, 4490. (b) Grubbs, R. H. Tetrahedron
2004, 60, 7117. (c) Deiters, A.; Martin, S. F. Chem. ReV. 2004, 104, 2199.
(d) Vernall, A. J.; Abell, A. D. Aldrichimica Acta 2003, 36, 93. (e) Connon,
S. J.; Blechert, S. Angew. Chem., Int. Ed. 2003, 42, 1900. (f) Trnka, T. M.;
Grubbs, R. H. Acc. Chem. Res. 2001, 34, 18. (g) Fu¨rstner, A. Angew. Chem.,
Int. Ed. 2000, 39, 3012.
(9) (a) Garner, P.; Park, J. M. J. Org. Chem. 1987, 52, 2361. (b) Dondoni,
A.; Perrone, D. Org. Synth. 2004, 10, 320.
(10) Burke, S. D.; Sametz, G. M. Org. Lett. 1999, 1, 71.
(11) 16-Hexadecanolide 7 was opened with lithiated dimethyl meth-
ylphosphonate to generate a â-ketophosphonate and immediately subjected
to Horner-Wadsworth-Emmons olefination with phenylacetaldehyde to
yield â,γ-unsaturated ketone 8. The presence of the phenyl ring promoted
isomerization of the double bond from the R,â- to the â,γ-position, which
was essential for the required RCM. Standard mesylation conditions
provided 5.
(6) For other selective epoxidations of endocyclic alkenes, see: (a)
Azzari, E.; Faggi, C.; Gelsomini, N.; Taddei, M. Tetrahedron Lett. 1989,
30, 6067. (b) Tchilibon, S.; Mechoulam, R. Org. Lett. 2000, 2, 3301. (c)
Hanus, L. O.; Tchilibon, S.; Ponde, D. E.; Breuer, A.; Fride, E.; Mechoulam,
R. Org. Biomol. Chem. 2005, 3, 1116.
(7) Fu¨rst, A.; Plattner, P. A. HelV. Chim. Acta 1949, 32, 275.
(8) (a) Williamson, W. Liebigs Ann. Chem. 1851, 77, 37. (b) Williamson,
W. J. Chem. Soc. 1852, 106, 229.
5358
Org. Lett., Vol. 9, No. 26, 2007

Completion of the synthesis of didemniserinolipid B
required elaboration of the vinyl group in 13 to the C1-C7
enoate-containing side chain. We initially explored the alkene
cross metathesis of 13 and 412 (proceeding in 57% yield,
not shown) but were unable to selectively hydrogenate the
generation Grubbs’ catalyst (G2).14 Although attempts to
reduce the C6-C7 alkene in 15 were unsuccessful with Pd/C
and 1 atm of hydrogen, 16 was obtained via diimide
reduction.15 Selenoxide elimination of 16 promoted by
m-CPBA introduced the R,â-unsaturation to provide 17.16
The serinol moiety was then liberated using 1 N HCl in EtOH
to afford 18, the HCl salt of Jime´nez’s originally proposed
didemniserinolipid structure. The final three steps to didem-
niserinolipid B followed those described in the Ley synthe-
sis.3 The amine was masked in nearly quantitative yield with
an Fmoc protecting group. Treatment of 19 with 1 equiv of
SO3•Py at 110 °C for 1 h under microwave irradiation,17
followed by Fmoc deprotection with piperidine, provided
(+)-didemniserinolipid B (1).18 Synthetic (+)-didemniser-
inolipid B thus obtained was identical with the natural
product by 1H and 13C NMR, MS, IR, and optical rotation.19
In summary, didemniserinolipid B has been prepared in
2.6% overall yield via a concise route with a longest linear
sequence (LLS) of 12 steps from ketone 5 and diene diol 6
(15 step LLS from commercially available materials). The
use of K/RCM to establish the central bicyclic ketal
facilitated a synthesis wherein the serinol and C1-C7 side
chains could be appended in a modular fashion. This total
synthesis further showcases the merits of a K/RCM strategy
in the construction of bicyclic ketals and their derivatives.4
∆
6,7 double bond without concomitant reduction of the R,â-
unsaturated ester. A successful alternative route to install the
correct C1-C7 functionality is shown in Scheme 2. In the
Scheme 2. Completion of Didemniserinolipid B
Acknowledgment. Financial support for this work from
NIH Grants GM069352 and CA108488 and NIH CBI
training Grant T32 GM008505 (C.C.M.) is gratefully ac-
knowledged, as is support of the departmental NMR facilities
by grants from the NIH 1 S10 RR0 8389-01 and NSF CHE-
9208463. We also thank Matt Dodge (University of
WisconsinsMadison) for obtaining the high-field 1H and 13C
NMR data for synthetic 1.
Supporting Information Available: Experimental pro-
cedures and NMR spectra for compounds 3, 5, 9-13, and
15-19 and comparison of 1 with literature data. This material
is available free of charge via the Internet at http://pubs.acs.org.
OL702454M
(14) Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett. 1999, 1,
953.
course of an isomigrastatin synthesis, Danishefsky reported
that selenides were compatible with RCM conditions.13 Cross
metathesis of 13 with racemic alkenyl selenide 1413 pro-
ceeded in 74% yield to give only the E isomer of 15 as an
inconsequential 1:1 diastereomeric mixture using second
(15) (a) Pasto, D. J.; Taylor, R. T. Org. React. 1991, 40, 91. (b) Wiberg,
N.; Fischer, G.; Bachhuber, H. Angew. Chem., Int. Ed. Engl. 1976, 15, 385.
(16) (a) Reich, H. J.; Wollowitz, S. Org. React. 1993, 44, 1. (b) Reich,
H. J. Acc. Chem. Res. 1979, 12, 22. (c) Reich, H. J.; Reich, I. L.; Renga,
J. M. J. Am. Chem. Soc. 1973, 95, 5813. (d) Sharpless, K. B.; Lauer, R. F.;
Teranishi, A. Y. J. Am. Chem. Soc. 1973, 95, 6137.
(17) Lidstro¨m, P.; Tierney, J.; Wathey, B.; Westman, J. Tetrahedron
2001, 57, 9225.
(12) Marshall, J. A.; Sabatini, J. J. Org. Lett. 2005, 7, 4819.
(13) Krauss, I. J.; Mandal, M.; Danishefsky, S. J. Angew. Chem., Int.
Ed. 2007, 46, 5576.
(18) Ley and co-workers reported a two-step yield of 49% for this
sequence. See ref 3.
(19) See the Supporting Information.
Org. Lett., Vol. 9, No. 26, 2007
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