An enantioselective total synthesis of (+)-peloruside A

Article abstract of DOI:10.1002/anie.201002177

Short and sweet: Chiral epoxides, prepared using (salen)cobalt-catalyzed ring-opening reactions, and a chromium catalyst controlled hetero-Diels-Alder reaction were used to set most of the stereocenters in the total synthesis of the microtubule-stabilizing agent peloruside A. The overall highly convergent route required only 20 steps in the longest linear sequence. MOM=methoxymethyl, TBS=tert-butyldimethylsilyl.

Full text of DOI:10.1002/anie.201002177

Angewandte
Chemie
DOI: 10.1002/anie.201002177
Total Synthesis
An Enantioselective Total Synthesis of (+)-Peloruside A**
Meredeth A. McGowan, Christian P. Stevenson, Matthew A. Schiffler, and Eric N. Jacobsen*
Peloruside A (1), a potent microtubule stabilizer that acts in a
manner synergistic to that of paclitaxel, was first isolated in
2000 by Northcote and co-workers from a marine sponge of
the Pelorus Sound in New Zealand.[1a] The absolute stereo-
chemistry of 1 was established in De Brabander and co-
workers’ initial total synthesis in 2003,[2] and since then three
other total syntheses have been reported.[3–5]
Herein, we describe a convergent total synthesis of
peloruside A in which three different enantioenriched epox-
ides (8, 9, and 11; Figure 1), obtained using asymmetric
catalytic methodologies, serve as the key building blocks for
the stereochemically complex macrocyclic framework. A
second key strategic feature is a chiral-catalyst-controlled
diastereoselective hetero-Diels–Alder reaction for the con-
struction of intermediate 7. The application of direct catalyst
control is complementary to the previous synthetic
approaches to peloruside A, which relied primarily on
substrate- and auxiliary-based diastereocontrol to establish
the relative and absolute stereochemical features of the
natural product.[2–5]
Dissection of the seco ester form of peloruside A into
fragments of roughly equal size and complexity suggested
aldehyde 3 and enone 4 as potentially useful late-stage
intermediates (Figure 1).[6] The synthesis of enone 4 began
with a highly enantioselective Payne rearrangement of meso-
epoxy diol 12, available in one step from commercial cis-2,3-
butenediol, into enantioenriched terminal epoxide 14
(Scheme 1).[7] This transformation was catalyzed by oligo-
meric cobalt salen catalyst 13,[8] which established an equi-
librium that favored terminal epoxide 14 over meso epoxide
12 in a 7:3 ratio. Epoxide 14 was unstable to purification, but
protection as the primary silyl ether in situ and subsequent
Figure 1. Retrosynthetic analysis of peloruside A.
[*] M. A. McGowan, C. P. Stevenson, M. A. Schiffler,
Prof. Dr. E. N. Jacobsen
Department of Chemistry and Chemical Biology, Harvard University
12 Oxford St., Cambridge, MA 02138 (USA)
Fax: (+1)617-496-1880
E-mail: jacobsen@chemistry.harvard.edu
[**] This work was supported by the NIH (GM-59316 and GM-43214).
We are grateful to Dr. Dieter Muri, Dr. Kristine Nolin, Ms. Tavꢀ van
Zyl, and Mr. Charles Goodhue for key experimental contributions,
and to Prof. D. A. Evans, Prof. J. K. De Brabander, Dr. D. S. Welch,
and Mr. A. W. S. Speed for helpful discussions.
Scheme 1. Asymmetric Payne rearrangement and elaboration. Reagents
and conditions: a) CuBr (10 mol%), vinyl magnesium bromide,
À408C, 2 h; then HMPA, Me2SO4, RT, 48 h; b) O3, CH2Cl2, À788C;
then PPh3, RT, 3 h; c) CuBr (10 mol%), vinyl magnesium bromide,
À408C, 2 h; then HMPA, Me2SO4, 48C, 48 h; d) O3, CH2Cl2, À788C;
then PPh3, RT, 3 h. DIPEA=diisopropylethylamine, TBSCl=tert-butyldi-
methylsilyl chloride, MOMCl=methoxymethyl chloride, HMPA=hexa-
methylphosphoramidite, PPh3 =triphenylphosphine.
Supporting information for this article, including full experimental
details, is available on the WWW under http://dx.doi.org/10.1002/
anie.201002177.
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alkylation of the secondary alcohol provided the functionally
rich bis-protected epoxide 11 in good overall yield.[9]
Epoxide 11 was subjected to a one-pot vinyl cuprate
addition/methylation, followed by ozonolysis to provide
aldehyde 15 in 66% overall yield. In an analogous manner,
enantiopure aldehyde 16 was obtained from racemic epoxide
9 using a high-yielding hydrolytic kinetic resolution (HKR)/
vinylation/alkyation/ozonolysis sequence.
Aldehyde 15 was then engaged in a hetero-Diels–Alder
(HDA) reaction with trioxy-substituted diene 10, available in
two steps from methyl benzyloxyacetate (Scheme 2; for
Scheme 3. Elaboration of the hetero-Diels–Alder adduct 7 to enone 4.
Reagents and conditions: a) Pd/C, iPrOH, pH 7 buffer, H2 (200 psi),
48 h; b) KBr, TEMPO, NaOCl, pH 7 buffer, CH2Cl2, 08C, 90 min;
c) N,O-dimethylamine hydrochloride, AlMe3, toluene, À108C, 90 min;
d) TBSOTf, 2,6-lutidine, CH2Cl2, À788C, 2 h; e) isopropenyl-magne-
sium bromide, THF, 5 h; f) TBSOTf, 2,6-lutidine, CH2Cl2, À108C, 4 h.
TEMPO=2,2,6,6-Tetramethylpiperidine-1-oxyl (free radical), THF=te-
trahydrofuran, TBSOTf=tert-butyldimethylsilyl trifluoromethanesulfo-
nate.
idation[14]/hydrolytic kinetic resolution (HKR) sequence.[15]
Epoxide 8 was then opened stereospecifically and regiose-
lectively at the propargylic position, and the resulting primary
alcohol was protected as the triisopropylsilyl ether to provide
alkyne 25 in 72% yield over two steps (Scheme 4). This
strategy of opening a terminal epoxy-alkyne at the internal
position with a simple Grignard reagent provides a concise
and convenient method for the stereocontrolled synthesis of
homopropargylic primary alcohols.
Scheme 2. Diastereoselective hetero-Diels–Alder Reaction. TBME=
tert-butyl methyl ether.
further details, see the Supporting Information). Diene 10
was highly sensitive to decomposition in the presence of
strong Lewis acids, but cycloadditions catalyzed by (Schiff-
base)chromium complexes were found to proceed cleanly.
The degree of intrinsic substrate diastereocontrol was poor, as
reaction with achiral chromium catalyst 17 afforded cyclo-
adduct in a 1:2 diastereomeric ratio, favoring the undesired
isomer. However, the chiral chromium–Schiff-base complex
(1R,2S)-18[10] catalyzed the formation of the desired product 7
in good yield and 7:1 d.r., favoring the desired isomer.
Conversely, the enantiomeric catalyst (1S,2R)-18 provided the
undesired diastereomer in high (1:11) selectivity. This result
represents one of the most demanding applications reported
to date of the use of catalyst 18 in a HDA reaction between
stereochemically and functionally complex substrates.[11]
Hydrogenation of hetero-Diels–Alder adduct 7 took place
diastereoselectively, and concomitant hydrogenolysis of the
O-benzyl acetal provided 19 in 69% yield and in 10:1 d.r.
(Scheme 3).[12] Oxidation of lactol 19 and opening of the
resulting lactone with N,O-dimethylamine hydrochloride
afforded Weinreb amide 20, which was protected as a
secondary TBS ether. Addition of isopropenylmagnesium
bromide occurred with cleavage of the C8 acetate ester to
provide hydroxyenone 21, which was purified chromato-
graphically to > 20:1 d.r. The C8 hydroxy group was then
reprotected as the TBS ether to provide aldol coupling
partner 4.
Scheme 4. Synthesis of key aldehyde fragment 3. Reagents and con-
ditions: a) 22 (5.0 mol%), NaOCl, CH2Cl2, 08C, 6.5 h; b) 23 (0.50
mol%), H2O, Et2O, 08C to RT, 24 h; c) ethylmagnesium chloride, THF,
À788C to rt, 4 h; d) TIPSCl, imidazole, DMF, RT, 16 h; e) catecholbor-
ane, 40 to 508C, 48 h; then bromine, CH2Cl2, À788C, 10 min.; then
TBAF, THF, 408C, 2.5 h; f) 2-benzyloxy-1-methylpyridinium triflate,
MgO, trifluorotoluene, 838C, 24 h; g) sec-butyllithium, THF, Et2O,
À788C; then 16, THF, À788C to RT, 16 h; h) PMBBr, NaH, DMF, RT,
2 h; i) acetic acid, H2O, THF, RT, 16 h; j) Dess–Martin periodinane,
CH2Cl2, RT, 4 h. DMF=N,N-dimethylformamide, TBAF=tetrabutylam-
monium fluoride, TIPSCl=triisopropylsilyl chloride, PMBBr=
p-methoxybenzyl bromide.
In the approach to aldehyde 3, epoxide 8 was prepared in
high ee from enyne 24, available in two steps from commercial
3-pentyn-1-ol,[13] using a (salen)manganese-catalyzed epox-
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Silyl ether 25 was further elaborated to vinyl bromide 5 by
one-pot hydroboration/bromination/elimination/silyl-
drew direct inspiration from the Evans approach to pelor-
a
uside A, employing a similarly protected seco acid,[5] wherein
differentiation between free hydroxy groups at C11 and C15
was also observed. Finally, the benzyl protecting group at the
C20 hydroxy group was removed under transfer hydrogenol-
ysis conditions, and a subsequent global removal of the
remaining protecting groups under strongly acidic condi-
tions[18] afforded (+)-peloruside A (1), isolated in 57% yield,
with characterization data matching those reported for the
natural product.[1]
deprotection sequence (Scheme 4).[16] Protection of the
resultant primary alcohol as the benzyl ether provided
compound 5 in 69% overall yield from 25.[17] This protecting
group exchange on the C20 hydroxy group was advantageous
because a large silyl protecting group was required for
attaining high regioselectivity (9:1) in the hydroboration of
compound 25, whilst the presence of a benzyl protecting
group led to improved diastereoselctivity in the addition of
the vinyl lithium reagent (derived from 5) to aldehyde 17. In
this manner, alcohol 26 was obtained in 5:1 d.r. and isolated in
64% yield following chromatographic purification. In con-
trast, analogous silyl-protected vinyl bromides (TIPS,
TBDPS) led to their corresponding allylic alcohols in only
2:1 d.r. Alcohol 26 was then protected as the paramethox-
ybenzyl ether, and the primary alcohol was selectively
unmasked and oxidized with the Dess–Martin periodinane
to provide aldehyde 3 in 58% yield over the three steps.
Enone 4 and aldehyde 3 were coupled using a reductive
aldol reaction, similar to that utilized in the Ghosh synthesis
of peloruside A,[4] to afford 2 in 1.7:1 d.r. Despite the modest
stereoselectivity in this step, 2 could be isolated in diastereo-
merically pure form in 52% yield following chromatographic
purification (Scheme 5). The primary TBS ether was then
removed selectively using buffered HF·pyridine and the
resulting alcohol was oxidized into aldehyde 27 in 74%
yield over the two steps. Aldehyde 27 was then oxidized into
the corresponding acid, and the crude reaction mixture was
subjected to pH 7-buffered DDQ to cleave the C15 PMB
ether and afford the macrolaconization substrate. The seco
acid was subjected without purification to Yamaguchi con-
ditions to provide macrolactone 28 in 52% yield for the three
steps from aldehyde 27. This macrolactonization strategy
This convergent synthesis of (+)-peloruside A required 20
steps in the longest linear sequence from commercially
available materials. This approach relies on the availability
of both simple (e.g., 8 and 9) and relatively complex (i.e., 11)
terminal epoxides from (salen)Co-catalyzed ring-opening
reactions, and on chiral-catalyst-induced diastereocontrol in
a key hetero-Diels–Alder cycloaddition reaction between
advanced intermediates. This route provides a useful illus-
tration of the applicability of modern asymmetric catalytic
methods in the total synthesis of stereochemically complex
polyketides.
Received: April 13, 2010
Revised: May 13, 2010
Published online: June 28, 2010
Keywords: asymmetric catalysis · epoxidation ·
.
kinetic resolution · natural products · total synthesis
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4n HCl, THF, RT, 3.5 h. DDQ=2,3-dichloro-5,6-dicyano-1,4-bezoqui-
none, DMAP=4-(dimethylamino)pyridine.
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