Synthesis of the C1-C27 portion of the aplyronines

Article abstract of DOI:10.1016/j.tetlet.2004.04.159

This manuscript describes the use of the anti,anti-diastereoselective aldol reaction of an efficiently generated dipropionate equivalent to construct the C₅-C₁₄-portion of the aplyronines. This portion was then coupled with a compound corresponding to C₁₅-C₂₀ of the targets. Further elaboration and an additional coupling led to an intermediate containing C₁-C₂₇ with appropriate stereochemistry and functionalization for eventual conversion into the aplyronines.

Full text of DOI:10.1016/j.tetlet.2004.04.159

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 4847–4850
Synthesis of the C1–C27 portion of the aplyronines
Michael A. Calter* and Jianguang Zhou
Department of Chemistry, University of Rochester, Rochester, NY 14627-0216, USA
Received 22 January 2004; accepted 28 April 2004
Available online
Abstract—This manuscript describes the use of the anti,anti-diastereoselective aldol reaction of an efficiently generated dipropionate
equivalent to construct the C5–C14-portion of the aplyronines. This portion was then coupled with a compound corresponding to
C15–C20 of the targets. Further elaboration and an additional coupling led to an intermediate containing C1–C27 with appropriate
stereochemistry and functionalization for eventual conversion into the aplyronines.
Ó 2004 Elsevier Ltd. All rights reserved.
The aplyronine family of polyketide natural products
contains three members (Fig. 1).1 These compounds
share a common carbon skeleton, including a twenty-
four-membered macrolactone, but differ in the position
of various aminoesters. Aplyronine A exhibits sub-
nanomolar activity toward a variety of cancer lines. This
activity perhaps stems from the ability of these mole-
cules to depolymerize actin filaments.2
covered that ketoester 2, derived from 1 in two simple
steps, selectively affords the anti,anti-dipropionate aldol
product under appropriate conditions (Scheme 1).7 We
realized that this aldol adduct possessed the stereo-
chemical relationships necessary for the synthesis of the
C7–C10-dipropionate portion of the aplyronine, and
therefore we initiated a synthesis of a C5–C14-precursor.
We report here the completion of this synthesis, along
One total synthesis of a member of the aplyronine
3
family has appeared, along with several subunit syn-
theses.4 We recently reported the preparation of the
aplyronine C21–C34 subunit starting with methylketene
dimer 1.5 As 1 is available from propionyl chloride in
one step via asymmetric catalysis, we hoped to use this
synthon in the synthesis of the remaining propionate
portions of the aplyronine skeleton.6 We recently dis-
Figure 1. The aplyronines.
* Corresponding author. Tel.: +1-585-275-1626; fax: +1-585-506-0205;
e-mail: calter@chem.rochester.edu
Scheme 1.
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.04.159

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M. A. Calter, J. Zhou / Tetrahedron Letters 45 (2004) 4847–4850
Scheme 3.
Scheme 2.
with coupling of the newly synthesized precursor to
other subunits to yield an intermediate containing C1–
C27 of the aplyronines.
Our synthesis of the C5–C14-precursor began with the
anti,anti-aldol adduct 3 (Scheme 2).8 anti-Reduction of
3, followed by ketalization, afforded acetonide 4. Ester
hydrolysis and iodination afforded iodide 5.9 Finally, the
use of 5 to alkylate a phosphonate dianion yielded C5–
C14-precursor 6.10
Scheme 4.
(Scheme 5). Reduction of 11 with lithium 4,40-di-t-
butylbiphenylate (LDBB) accomplished deprotection of
the C5-hydroxyl.15 Several hydrogenation-based condi-
tions for benzyl ether removal either failed to afford any
reaction or also led to significant hydrogenation of the
alkene. Oxidation of primary alcohol 12,16 followed by
reaction with an allylic phosphonate,17 led to formation
of E,E-dienoate 14 in moderate yield. Although removal
of the silyl group under standard conditions led to
extensive decomposition, the use of ‘buffered’ TBAF led
to clean desilylation.18 Oxidation of the resulting pri-
mary alcohol yielded aldehyde 16,19 corresponding to
C1–C20. We also prepared C5–C20 equivalent 17 by
desilylation of 11, followed by oxidation.
We next prepared a C15–C20-precursor beginning with
known lactone 7, available in four steps and 54% overall
yield from D
-glutamic acid (Scheme 3).11 Opening of the
lactone to the Weinreb amide,12 followed by methyla-
tion, gave methyl ether 8.13 Reduction of the amide,
Wittig reaction of the resulting aldehyde, and hydrolysis
gave aldehyde 9.
Our assembly of 6 and 9 into a C5–C20-precursor pro-
ceeded in a similar fashion to that used by Paterson et al.
(Scheme 4).4d Horner–Wadsworth–Emmons reaction of
6 with 9 yielded enone 10. Corey–Itsuno reduction14 and
methylation afforded the C5–C20-precursor 11.
We next prepared a C21–C27-precursor, starting with
primary alcohol 18 (Scheme 6). We had previously
reported the preparation of 18 from the enantiomer of 1
We next converted 11 into two electrophiles suitable for
coupling to the remaining portion of the aplyronines

M. A. Calter, J. Zhou / Tetrahedron Letters 45 (2004) 4847–4850
4849
Scheme 7.
Sulfone 20 was then coupled to both 16 and 17 (Scheme
7). We confirmed the result of Kocienski and co-workers
that the stereoselectivity of this type of reaction
depended moderately on solvent, with the reaction in
dimethoxyethane (DME) giving higher E-selectivity
than the one in THF.21 Compound 16 reacted in slightly
lower yield 17, perhaps reflecting some lability of the
dienoate. However, the convergency gained by incor-
poration of the dienoate into the coupling partner more
than outweighs the slightly lower yield.
Scheme 5.
In summary, we have prepared intermediate 21, corre-
sponding to C1–C27 of the aplyronines. We assembled
this compound in an efficient manner by coupling of C1–
C20-aldehyde 16 with C21–C27-sulfone 20. This synthesis
benefited from the ready availability of dipropionate
equivalents for the dimerization of methylketene. We
are currently exploring removal of the acetonide and
methyl ester protecting groups from 21 as a prelude to
macrolactonization. We are also preparing a fully
homologated sulfone for synthesis of the full carbon
skeleton of the aplyronines.
Acknowledgements
We thank the NIH for support of this work.
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