Total synthesis of dolabelide D

Article abstract of DOI:10.1021/ja058692k

The first total synthesis of dolabelide D (or of any of the closely related dolabelides) has been achieved with a longest linear sequence of 17 steps. Key features of the synthesis include an application of the catalytic asymmetric silane alcoholysis, the

Full text of DOI:10.1021/ja058692k

Published on Web 02/09/2006
Total Synthesis of Dolabelide D
Peter K. Park, Steven J. O’Malley, Darby R. Schmidt, and James L. Leighton*
Department of Chemistry, Columbia UniVersity, New York, New York 10027
Received December 22, 2005; E-mail: leighton@chem.columbia.edu
Scheme 1
In 1995, researchers reported the isolation and structural
characterization of two new 22-membered macrolides they termed
dolabelides A and B from Japanese specimens of the sea hare
Dolabella auricularia.1 These compounds exhibited cytotoxic
activity against HeLa-S3 cells with IC50’s of 6.3 and 1.3 µg/mL,
respectively. Two years later, two new members of this class of
natural products, dolabelides C and D, were reported.2 These 24-
membered macrolides are also cytotoxic against HeLa-S3 cells with
IC50’s of 1.9 and 1.5 µg/mL, respectively. This biological activity
and the interesting stereostructure of these natural products have
combined to elicit attention from synthetic chemists,3 including our
own group.4 Herein we describe our investigations that have led to
the first total synthesis of dolabelide D, by way of the synthesis
and coupling of fragments 2 and 3 by esterification and ring-closing
metathesis (Scheme 1).
The synthesis of fragment 24 commenced with an application of
our recently developed catalytic asymmetric silane alcoholysis5 with
alcohol 4 and tert-butyl-cis-crotylsilane to provide 5 as the major
component of a 4:1 mixture of diastereomers in 95% yield (Scheme
2). Rhodium-catalyzed tandem silylformylation-crotylsilylation6
proceeded stereospecifically to provide, after quenching with
methyllithium, a 4:1 mixture of diastereomers favoring 1,5-syn-
diol 6 in 56% yield. Selective protection of the less-hindered alcohol
as its triethylsilyl (TES) ether led, after separation of the diaster-
eomers, to the isolation of 7 in 74% yield. Treatment of alcohol 7
with n-BuLi and then CuBr‚SMe2 and DMPU initiated a Brook-
like 1,4-carbon (sp2) to oxygen silane migration,7 and the resulting
vinylcopper species was then alkylated with MeI to provide 8 in
92% yield. This sequence illustrates the power of the tandem
silylformylation chemistry to provide access to different function-
alities and substitution patterns in the 1,5-diol products. In addition,
it is noteworthy that the tert-butylsilane serves multiple purposes
before being morphed into the desired tert-butyldimethylsilyl (TBS)
ether. A Wacker oxidation was optimized for concurrent removal
of the TES ether, and the resulting alcohol 9 was acetylated to
provide 10 in 78% overall yield (two steps). Asymmetric aldol
coupling8 with 5-hexenal then gave aldol 11 in 85% yield and with
>10:1 diastereoselectivity. Anti diastereoselective (>10:1 dr)
â-hydroxyketone reduction9 then gave 12 in 91% yield. Protection
of the diol as a cyclopentylidene ketal10 gave 13, and TBS removal
provided fragment 2 in 50% yield (two steps from 12). The
synthesis of 2 was thus achieved in 10 steps and 11% overall yield
from 4.
Scheme 2 a
a (a) 4 mol % CuCl, 4 mol % NaO-t-Bu, 4 mol % (R,R)-BDPP, PhH.
(b) i. 2 mol % [Rh(acetone)2-(P(OPh)3)2]BF4, CO, PhH, 60 °C; ii. MeLi,
Et2O, -78 to 23 °C. (c) TESCl, Et3N, CH2Cl2, -20 °C. (d) n-BuLi, THF,
-78 °C; CuBr‚Me2S, DMPU, 23 °C; MeI, -78 to 23 °C. (e) 25 mol %
PdCl2, CuCl, DMF, THF, H2O, O2. (f) Ac2O, pyridine, DMAP, CH2Cl2.
(g) (+)-(ipc)2BCl, Et3N, 5-hexenal, Et2O, -78 to 23 °C. (h) Me4NBH(OAc)3,
AcOH, CH3CN, THF, -40 to -20 °C. (i) 1,1-Dimethoxycyclopentane,
PPTS, CH2Cl2. (j) n-Bu4NF, THF.
Allylation of aldehyde 14 with our recently developed reagent
1511 proceeded smoothly to provide 16 in 80% yield and 98% ee
(Scheme 3). Protection of the alcohol as its p-methoxybenzyl (PMB)
ether gave 17 in 95% yield and was followed by a Wacker oxidation
to give ketone 18 in 81% yield. Crotylation of methacrolein with
crotylsilane ent-19,12 followed by protection of the resultant alcohol
as its PMB ether, produced 20 in 53% yield (based on ent-19, two
steps) and 88% ee. Hydroformylation in the presence of 2,2-
dimethoxypropane proceeded smoothly and selectively to give acetal
21 in 72% yield. Still-Barrish hydroboration13 gave alcohol 22
with 13:1 dr. A four-step oxidation-oxidation-protection-depro-
tection sequence then provided aldehyde 23 in 79% overall yield.
9
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J. AM. CHEM. SOC. 2006, 128, 2796-2797
10.1021/ja058692k CCC: $33.50 © 2006 American Chemical Society

C O M M U N I C A T I O N S
Scheme 3 a
Scheme 4 a
a (a) Et3N, DMAP, toluene, -78 to 0 °C. (b) PPTS, MeOH. (c) DDQ,
CH2Cl2, pH 7 buffer. (d) 25 mol % 31, CH2Cl2, reflux.
catalytic asymmetric silane alcoholysis and tandem silylformyla-
tion-crotylsilylation methods. That the pathway from alcohol 4 to
dolabelide D comprises just 14 linear steps (the longest linear
sequence is from methacrolein to dolabelide D in 17 steps) is
testament to the efficiency of these methods.
Acknowledgment. The NIH (NIGMS GM58133) is acknowl-
edged for their generous support of this work and for a postdoctoral
fellowship to D.R.S. P.K.P. is supported by the NIH Medical
Scientist Training Program. We thank Bristol-Myers Squibb for a
graduate fellowship to S.J.O.
a (a) 15, CH2Cl2, -20 °C. (b) NaH, PMBBr, THF, reflux. (c) 25 mol %
PdCl2, CuCl, DMF, H2O, O2. (d) ent-19, CH2Cl2. (e) 2 mol % Rh(acac)-
(CO)2, 10 mol % PPh3, H2/CO, 2,2-dimethoxypropane, PPTS, 60 °C. (f)
9-BBN, THF, -78 to 23 °C; H2O2, NaOH. (g) (COCl)2, DMSO, Et3N,
CH2Cl2, -78 °C. (h) NaClO2, NaH2PO4, 2-methyl-2-butene, t-BuOH, H2O.
(i) K2CO3, CH2dCHCH2Br, acetone, reflux. (j) PPTS, acetone, H2O, reflux.
(k) n-Bu2BOTf, i-Pr2NEt, Et2O, -110 °C. (l) TESCl, imidazole, CH2Cl2.
(m) L-Selectride, CH2Cl2, -78 °C. (n) Ac2O, pyridine, DMAP, CH2Cl2.
(o) 10 mol % Pd(PPh3)4, morpholine, THF.
Supporting Information Available: Experimental procedures,
characterization data, and stereochemical proofs. This material is
available free of charge via the Internet at http://pubs.acs.org.
References
1,5-Anti selective aldol coupling14 of ketone 18 and aldehyde 23
proceeded smoothly to give aldol 24 in 79% yield as a 10:1 mixture
of diastereomers. Protection of the alcohol as a TES ether gave 25
in 94% yield and was followed by a diastereoselective (∼5:1) ketone
reduction with L-Selectride to give 26. Following acetylation, the
diastereomers were separated, and 27 was isolated in 51% yield.
Finally, deprotection of the allyl ester gave the target acid 28 in
92% yield. The synthesis of 28 was carried out with a longest linear
sequence of 13 steps from methacrolein in 9% overall yield.
Esterification of alcohol 2 with acid 28 proceeded smoothly to
give 29 in 74% yield (Scheme 4). Methanolysis of the TES ether
and cyclopentylidene ketal-protecting groups was followed by
oxidative cleavage of the PMB ether groups to provide pentaol 30
in 70% overall yield (two steps). Initial attempts at macrocyclization
by ring-closing metathesis with the “second-generation” Grubbs
catalyst 31 were plagued not only by (not unexpected) low
stereoselectivity (∼1.3:1 E:Z), but also by significant amounts of
byproducts presumably derived from olefin isomerization path-
ways.15 Despite these setbacks, dolabelide D could be isolated in
31% yield. Although a sample of the natural product was unavail-
able, comparison (1H and 13C NMR, IR, HRMS, [R]D) to published
data confirmed the identity of our synthetic material.
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The first synthesis of dolabelide D (and of any of the dolabelides)
has been achieved. Methodologically, the four-step sequence that
converts alcohol 4 into protected diol fragment 8 is especially
noteworthy and serves as a demonstration of the power of the
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