Total synthesis of apoptolidinone

Article abstract of DOI:10.1002/anie.200461469

The complex macrolide apoptolidinone (1) was synthesized in 19 steps (longest linear sequence) from (S)-malic acid. Key reactions include A) two stereoselective aldol reactions, B) a late-stage Grubbs cross-metathesis reaction to install a trisubstituted

Full text of DOI:10.1002/anie.200461469

Angewandte
Chemie
Natural Products
mitochondrial F0F1-ATPase.[7a] Although evaluation of the
cytotoxicity of select analogues has suggested the three
hexose sugars of apoptolidin to contribute significantly to
the overall cytotoxicity of 2,[3c,5e,8] biological evaluation of the
aglycone, apoptolidinone (1), has not been reported. We
describe herein the total synthesis of apoptolidinone.
Total Synthesis of Apoptolidinone**
Bin Wu, Qingsong Liu, and Gary A. Sulikowski*
Besides the synthetic approach to apoptolidin (2) de-
scribed by Toshima and co-workers,[6a] all previous synthetic
strategies directed towards apoptolidin have relied on a linear
approach in which the seco acid was assembled and sub-
sequently subjected to a macrolactonization. To develop a
more convergent assembly we retrosynthetically divided
apoptolidinone into four fragments (4–7, Scheme 1). We
planned to couple the four fragments through a combination
of two diastereoselective aldol reactions, a Grubbs cross-
metathesis reaction, and an intramolecular Suzuki–Miyaura
cross-coupling reaction.
Dedicated to Professor Amos B. Smith, III
on the occasion of his 60th birthday.
Polyketide-derived secondary metabolites have long served
as a source of structurally diverse and biologically active
natural products.[1] In the course of screening soil micro-
organisms for cell-specific apoptosis-inducing agents, Hay-
akawa and co-workers isolated the polyketide natural product
apoptolidin (2) from Nocardiopsis sp.[2] Apoptolidin induces
Construction of fragment 4 started from (S)-malic acid
(8), which was converted into 3-methoxy-g-butyrolactone (9)
through a known four-step reaction sequence.[9] Reduction of
lactone 9 with DIBAL-H afforded lactol 10, which on
condensation with 1,3-propanedithiol afforded dithiane 11.
Swern oxidation of primary alcohol 11 provided aldehyde 12
in near quantitative yield. A five-carbon unit was introduced
to aldehyde 12 by chelation-controlled addition of the
Grignard reagent derived from bromide 13 to provide
secondary alcohol 14 as a single isomer (Scheme 2). Bromide
13 was prepared from dihydrofuran according to the Kocien-
programmed cell death in E1A-transformed
cells but not in normal cells.[2a] Khosla, Salomon,
and co-workers later correlated this cell-specific
activity to the inhibition of mitochondrial F0F1-
ATPase by apoptolidin as well as other polyke-
tide natural products.[3] Structurally, apoptolidin
features an unsaturated 20-membered macro-
lide, a six-membered hemiketal, and three
hexose sugars.[2b] In 2001 Koert and co-workers
reported the synthesis of apoptolidinone (1) and
later the same year Nicolaou and co-workers
described the total synthesis of apoptolidin.[4–6]
Scheme 1. Retrosynthetic analysis of apoptolidinone (1). TES=triethylsilyl, TBS=tert-butyl-
The latter total synthesis and other recent work
has demonstrated that apoptolidin is a rather
labile compound that undergoes a base-induced
dimethylsilyl.
acyl migration from the C19 to C20 hydroxy group to produce
ski procedure described by Koert and co-workers in their
reported synthesis of apoptolidinone.[4a,10] A solution of 14 in
dichloromethane was treated sequentially with iodine, trie-
thylchlorosilane, and imidazole in one pot to provide vinyl
iodide 16 in 90% overall yield from 14. The dithiane group of
16 was hydrolyzed efficiently by using the Fetizon–Jurion
procedure to provide aldehyde 17 in 68% yield (as well as
recovered 16 (19%)).[11]
Homoallylic silyl ether 18 was produced by the asymmet-
ric addition of the diisopropyl tartrate ester derived (Z)-
crotylboronate reagent developed by Roush et al.[12] to the
pinacol ester of 3-boronoacrolein,[13] followed by silylation
(TESOTf, 2,6-lutidine) of the crude crotylation product. The
syn homoallylic ether 18 (single diastereomer, 80% ee) was
isoapoptolidin,[7] a compound that is less active against
[*] B. Wu, Q. Liu, Prof. G. A. Sulikowski
Department of Chemistry, Vanderbilt University
7920 Stevenson Center, Nashville, TN 37235 (USA)
Fax: (+1)615-343-1234
E-mail: gary.a.sulikowski@vanderbilt.edu
[**] We gratefully acknowledge support by the National Institutes of
Health (CA 59515-09) and the Robert A. Welch Foundation (A-
1230). The National Science Foundation (CHE-0077917) is
acknowledged for providing funds for the purchase of NMR
instrumentation.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
Angew. Chem. Int. Ed. 2004, 43, 6673 –6675
DOI: 10.1002/anie.200461469
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Communications
obtained in 43% yield over two steps. Suzuki–Miyaura cross-
coupling between vinyl iodide 17 and vinyl boronate 18
provided diene 4 in 70% yield (Scheme 2).[14]
The stereochemical relationship between C19 and C20
(see 20) was established by a diastereoselective Mukaiyama
aldol condensation between aldehyde 4 and enol silane (Z)-19
(derived from 1,2-butanediol in three steps) to afford ketone
20 as the major product with a 4:1 ratio of isomers
(Scheme 3). The assigned C19–C20 relative stereochemistry
rested on the observed coupling constant of the aldol product
(J19,20 = 3.5 Hz) and the 1,3-asymmetric induction model
proposed by Evans and co-workers for b-methoxyalde-
hydes.[15] Yamaguchi esterification of 20 with carboxylic acid
5 led to isolation of dienoate 21 in 83% yield.[16] Kinetic
deprotonation (LHMDS, HMPA, THF, ꢀ788C) of 21 fol-
lowed by aldol condensation with aldehyde 6[17] afforded syn
aldol product 22 as a single isomer in 41% yield (plus 30%
recovered 21).[18] After silylation of 22 to give 23 we examined
a series of cross-metathesis reactions with propenyl boronate
to provide vinyl boronate 25.[19] The Grubbs second-gener-
ation catalyst 24 provided 25 in up to 30% yield (plus 30%
recovered alkene 23). Remarkably, this reaction provided 25
as a single isomer that was immediately subject to an
intramolecular Suzuki–Miyaura cross-coupling to give macro-
lactone 3 in 47–60% yield. Exhaustive desilylation of 3
provided apoptolidinone (1) in 61% yield. Our synthetic
apoptolidinone matched, in all respects, the spectral data
reported by Koert and co-workers for their synthetic sam-
ple.[4a]
Scheme 2. Synthesis of fragment 4. a) DIBAL-H, THF, ꢀ788C; b) 1,3-
propanedithiol, BF3·OEt2, CH2Cl2, 288C, 60% from 9; c) (COCl)2,
DMSO, iPr2NEt, ꢀ78!08C, 98%; d) 13, Mg, 1,2-dibromoethane, Et2O,
ꢀ788C, 68%; e) I2, CH2Cl2, 08C; f) TESCl, ImH, CH2Cl2, 288C, 90%
from 14; g) MeI (excess), K2CO3, MeCN/pH 7 buffer (4:1), 288C, 68%
(plus 19% recovered 16); h) 18, [Pd(Ph3P)4], TlOH, THF/H2O (3:1),
288C, 70%. DIBAL-H=diisobutylaluminum hydride, DMSO=dimethyl
sulfoxide, ImH=imidazole.
Scheme 3. Synthesis of apoptolidinone (1). a) BF3·OEt2, CaH2, CH2Cl2, ꢀ948C, 50% (plus 34% recovered 4); b) 5, 2,4,6-trichlorobenzoyl chloride,
Et3N, DMAP, toluene, ꢀ78!288C, 83%; c) LHMDS, THF, HMPA, ꢀ788C, 2 h; then 6, THF, 41% (plus 30% recovered 21); d) TESOTf, 2,6-luti-
dine, CH2Cl2, 08C, 81%; e) 24, isopropenyl pinacol boronic ester (18 equiv), CH2Cl2, reflux, 6 h, 30% (plus 30% recovered 23); f) [Pd(Ph3P)4],
Tl(OEt), THF/H2O (3:1), 288C, 30 min, 60%; g) HF·py, THF, ꢀ108C, 12 h; then ꢀ58C, 5 h, 61%. DMAP=4-(dimethylamino)pyridine,
LHMDS=lithium hexamethyldisilazide, HMPA=hexamethylphosphoramide, Tf=trifluoromethanesulfonyl.
6674
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In summary, apoptolidinone was synthesized from 3-
methoxy-g-butyrolactone (9) in 14 steps (longest linear
sequence). Key steps of the synthesis include two diastereo-
selective aldol reactions, a cross-metathesis reaction, and two
Suzuki–Miyaura cross-coupling reactions. We anticipate that
this synthesis will provide access to modified derivatives of
apoptolidin for utilization in studies on the cell-specific
cytotoxicity of the parent natural product.[20]
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[17] The preparation of aldehyde 6 is described in the Supporting
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Received: July 28, 2004
Keywords: aldol reaction · diastereoselectivity · metathesis ·
.
natural products · total synthesis
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