Donor-acceptor substituted cyclopropane to butanolide and butenolide natural products: Enantiospecific first total synthesis of (+)-hydroxyancepsenolide

Article abstract of DOI:10.1021/ol503246k

An oxygen substituted donor-acceptor cyclopropane (DAC) is used as a common intermediate in the enantiospecific collective total synthesis of butanolide- and butenolide-based natural products like (+)-juruenolide C and D, (+)-blastmycinone, (+)-antimycino

Full text of DOI:10.1021/ol503246k

Letter
pubs.acs.org/OrgLett
Donor−Acceptor Substituted Cyclopropane to Butanolide and
Butenolide Natural Products: Enantiospecific First Total Synthesis of
(+)-Hydroxyancepsenolide
Santosh J. Gharpure,*,† Laxmi Narayan Nanda,† and Manoj Kumar Shukla‡
†Department of Chemistry, Indian Institute of Technology Bombay, Powai, Mumbai 400076, India
‡Department of Chemistry, Indian Institute of Technology Madras, Chennai 600036, Tamil Nadu, India
S
* Supporting Information
ABSTRACT: An oxygen substituted donor−acceptor cyclopropane
(DAC) is used as a common intermediate in the enantiospecific
collective total synthesis of butanolide- and butenolide-based natural
products like (+)-juruenolide C and D, (+)-blastmycinone, (+)-anti-
mycinone, and (+)-ancepsenolide. Enantiospecific first total syntheses
of (+)-hydroxyancepsenolide and its acetate are achieved confirming
their absolute stereochemistry.
substituted γ-butyrolactone or butanolide moiety bearing
(2b and 2c) were found in the latter.3 The marine natural
product butanolide 2d, its dehydration product butenolide 3,
(+)-ancepsenolide (4), and (+)-hydroxyancepsenolide (5) of the
ancepsenolide family were isolated from the Caribbean
gorgonian Pterogorgia anceps and are involved in the defensive
mechanism of the species. While ancepsenolides (4 and 5a) were
also isolated from Pterogorgia citrina as well as from Pterogorgia
guadalupensis, (+)-hydroxyancepsenolide acetate (5b) was
isolated only from former.4 (+)-Ancepsenolide (4) represents
one of the first butenolide acetogenins, plant metabolites that
have shown interesting antitumoral, antimalarial, immunosup-
pressive, as well as pesticidal activities. Varied biological activity
of butanolide and butenolide natural products coupled with
structural diversity has attracted significant attention from
synthetic chemists, and many of these natural products have
succumbed to their total synthesis.5−7
A
three contiguous stereocenters is found in many natural
products (Figure 1).1 Its unsaturated counterpart, namely,
Despite significant progress in this area, a general approach for
their collective total synthesis is still uncommon. Further, there is
no report on the total synthesis of lactones 2a, 2d,
(+)-juruenolide D (2c), or (+)-hydroxyancepsenolide (5a).
While semisynthesis of (+)-hydroxyancepsenolide acetate (5b)
has been described, its total synthesis is still not documented.4 In
continuation of our interest in donor−acceptor substituted
cyclopropanes (DAC),8 herein we disclose an approach for the
collective total synthesis of butanolide and butenolide natural
products 1−5 starting from a common precursor 6.9
Figure 1. Butanolide- and butenolide-based natural products.
butenolide, is also ubiquitous in nature with Annonaceous
acetogenins being the most celebrated family of natural products
bearing this moiety. (+)-Blastmycinone (1a) and (+)-anti-
mycinone (1b) isolated from Streptomyces sp. are the hydrolysis
products of antimycin A3 and A1 and display antifungal and
antitumor activities.2 The γ-lactone polyketides are widely
distributed in Iryanthera sp. and Virola surinamensis with lactone
2a being isolated from the former, whereas juruenolides C and D
Over the years, DACs have come to the fore as versatile
synthons in organic chemistry.10 We envision that the butanolide
and butenolide natural products could all be assembled starting
Received: November 8, 2014
© XXXX American Chemical Society
A
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Letter
from DAC 6. Our retrosynthetic plan is delineated in Scheme 1.
Butenolide 7 could be readily prepared from the corresponding
Table 1. Synthesis of Butanolide Natural Products and
Epimers
Scheme 1. Retrosynthetic Analysis for Butanolide and
Butenolide Natural Products
butanolide 2 by dehydration. Butanolide 2 bearing three
contiguous stereocenters could be obtained by hydrogenation
followed by oxidation of the acetal 8, which in turn could be
readily assembled by the Wittig reaction of an appropriate ylide 9
with lactol 10. The lactol 10 can be derived from the DAC 6
through the intermediate 11 bearing differentially oxidized
lactone moieties. We have already described stereoselective
synthesis of DAC 6 starting from (S)-ethyl lactate.8a It was also
noted that butanolide natural products like (+)-blastmycinone
(1a) and (+)-antimycinone (1b) can be prepared from the
appropriate butanolide 2 by epimerization of the C-2 stereo-
center.
The synthesis began with the conversion of the DAC 6 into the
lactol 10, which is a common intermediate for the synthesis of all
butanolide and butenolide natural products 1−5. Thus, chemo-
and stereoselective reduction of the ketone moiety in DAC 6
with LiAlH4 furnished the alcohol 12 (Scheme 2).8a Treatment
a
For the synthesis of ylide 9f, KHMDS was used as base and reaction
was carried out in pet. ether:THF (1:1).
was obtained in 76% yield as a mixture of diastereomers. No
effort was made to separate the diastereomers at this stage as in
the subsequent steps; the acetal would be oxidized to lactone.
Thus, catalytic hydrogenation of the olefin 8a using 10% Pd/C in
MeOH furnished the acetal 13a. Finally, the acetal functional
group in 13a was chemoselectively oxidized employing m-CPBA
and TMSOTf to obtain (+)-2-epi-blastmycinolactol (2e) in good
yield. Repetition of the same reaction sequence starting with
ylide 9b furnished (+)-2-epi-NFX-2 (2f) in good overall yield
(Table 1, entry 2). It is worth noting that this is the first
enantiospecific synthesis of epimers of natural products
blastmycinolactol (2e′) and NFX-2 (2f′). This strategy proved
to be quite general and starting with appropriate ylides (9c,d),
butanolide natural products lactone (+)-2a [[α]2D5 = +2.7 (c 0.16,
MeOH), lit.3c [α]2D5 = +2.0 (c 0.16, MeOH)], (+)-juruenolide C
(2b) [[α]2D5 = +24.8 (c 0.2, MeOH), lit.6 [α]2D5 = +26.0 (c 0.3,
MeOH)], and (+)-juruenolide D (2c) [[α]2D4 = +11.6 (c 0.16,
MeOH), lit.3d [α]2D5 = +12.0 (c 0.1, MeOH)] could be assembled
in excellent overall yields (Table 1, entries 3−5). It is pertinent to
mention here that in the total synthesis of natural product
lactone (+)-2d [[α]D26 = +9.0 (c 0.9, CHCl3), lit.4f [α]D20 = +7.0 (c
1.1, CHCl3)], in the Wittig olefination reaction step, ylide 9f had
to be prepared using KHMDS as the base and petroleum ether−
THF (1:1) as a solvent for efficient reaction. Spectral data for all
these butanolide natural products 2a−d were in good agreement
with those reported. It should be noted that these are
enantiospecific first total syntheses of butanolide (+)-2a,
Scheme 2. Synthesis of the Common Intermediate Lactol 10
of the alcohol 12 with a catalytic amount of concd H2SO4 in
MeOH led to the lactone 11 via a tandem regioselective
cyclopropane ring opening−trapping of the oxonium ion with a
MeOH−intramolecular lactonization sequence. Reduction of
the lactone 11 with DIBAL-H gave the requisite advanced
intermediate lactol 10.
Attention was next turned toward using this lactol 10 in the
divergent synthesis of butanolide natural products 1 and 2. A
three-step protocol of Wittig olefination, hydrogenation, and
chemoselective oxidation was used to achieve this (Table 1).
When a simple Wittig reaction of the ylide 9a derived from
ethyltriphenylphosphonium bromide in the presence of n-BuLi
with the lactol 10 was performed, the corresponding olefin 8a
B
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(+)-juruenolide D (2c), and butanolide (+)-2d, thus establishing
their absolute stereochemistry.
hydrogenated using 10% Pd/C as the catalyst to furnish the
acetal 20, which upon Lewis acid mediated oxidation gave the
bis-lactone 16, albeit in only 15% overall yield (Scheme 5). The
At this juncture, having epimers (+)-2-epi-blastmycinolactol
(2e) and (+)-2-epi-NFX-2 (2f) in hand, attention was turned
toward total synthesis of (+)-blastmycinone (1a) and (+)-anti-
mycinone (1b). Toward this end, lactone 2e was subjected to
treatment with sodium methoxide, which resulted in partial
epimerization of the C-2 stereocenter. Since the separation of
epimers 2e and 2e′ was found to be difficult, they were subjected
to acylation with isovaleryl chloride to furnish (+)-blastmycinone
(1a) [[α]2D5 = +8.7 (c 0.5, CHCl3), lit.5b [α]2D0 = +11.2 (c 0.7,
CHCl3)] and (+)-2-epi-blastmycinone (14a) [[α]2D5 = +25.0 (c
0.6, CHCl3)], which were separated by silica gel column
chromatography (Scheme 3). In a similar manner, the (+)-2-
Scheme 5. Double-Wittig Reaction Based Approach to the
Synthesis of Bis-butanolide 16
Scheme 3. Total Synthesis of (+)-Blastmycinone (1a) and
(+)-Antimycinone (1b)
major stumbling block in this approach was double-Wittig
reaction. All our efforts to optimize this reaction by changing
reaction conditions or reagents failed, and hence, an alternate
approach was explored for the synthesis of bis-lactone natural
products 4 and 5.
In an alternate approach, a cross-metathesis−homodimeriza-
tion reaction was planned as key reaction to assemble bis-
butanolide 16. Thus, Wittig reaction of the lactol 10 with the
ylide 21 generated from the pentenylphosphonium bromide
(22), and n-BuLi furnished the olefin 23 in 92% yield (Scheme
6). It was gratifying to see that the olefin 23 underwent a
Scheme 6. Cross-Metathesis Homodimerization Based
Approach to Bis-butanolide 16
epi-NFX-2 (2f) was used to synthesize (+)-antimycinone (1b)
[[α]2D5 = +8.0 (c 0.5, CHCl3), lit.5b [α]D20 = +10.6 (c 1.0, CHCl3)]
and (+)-2-epi-antimycinone (14b) [[α]2D5 = +103.0 (c 0.5,
CHCl3)].
Attention was next turned toward synthesis of butenolide
natural product 3. To this end, the butanolide 2d was treated
with MsCl in the presence of Et3N to obtained the mesylate 15,
which was found to be unstable. The crude reaction mixture was
therefore subjected to treatment with TBAF to give the
butenolide 3 in 90% yield (over two steps) [[α]2D3 = +22 (c 1.0,
CHCl3), lit.4f [α]D20 = +22 (c 1.1, CHCl3)] (Scheme 4).
Scheme 4. Total Synthesis of (+)-Butenolide 3
regioselective homodimerization by cross-metathesis reaction in
the presence of Grubbs’ first-generation catalyst (G-1) to furnish
the corresponding bis-acetal olefin 24 as a mixture of
diastereomers in excellent yield.11 Subsequent hydrogenation
and Lewis acid mediated oxidation proceeded smoothly, and bis-
lactone 16 was obtained in good overall yield.
With the bis-butanolide 16 in hand, the stage was set for the
total synthesis of ancepsenolides. The bis-butanoilde 16 was
treated with excess MsCl in the presence of Et3N and DMAP in
CH2Cl2 to obtain (+)-ancepsenolide (4) [[α]2D5 = +41.8 (c 0.4,
CHCl3), lit.7d [α]D25 = +39.6 (c 0.4, CHCl3)] in 76% yield. On the
other hand, when the bis-lactone 16 was exposed to 1 equiv of
For the synthesis of bis-lactone natural products (+)-ancep-
senolide (4), (+)-hydroxyancepsenolide (5a), and (+)-hydrox-
yancepsenolide acetate (5b) of the ancepsenolide family, bis-
butanolide 16 was identified as a common precursor. For the
synthesis of this bis-butanolide 16, to begin with, a double-Wittig
reaction based strategy was conceived. The synthesis com-
menced by the double-Wittig reaction of the lactol 10 with the
ylide 17 (generated using bis-phosphonium salt 18 and
KHMDS), which led to the bis-acetal olefin 19 as a mixture of
diastereomers. The diastereomeric mixture of olefin 19 was then
C
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MsCl in the presence of Et3N and DMAP in CH2Cl2, only one of
the hydroxy group was eliminated and the (+)-hydroxyanceps-
nolide (5a) [[α]D20 = +20.4 (c 0.6, CHCl3), lit.4f [α]2D0 = +20.0 (c
0.59, CHCl3)] was obtained in 55% yield (along with 30% of
unreacted lactone 16) constituting the enantiospecific first total
synthesis and establishing its absolute configuration. Acylation of
(+)-hydroxyancepsenolide (5a) with Ac2O in pyridine in the
presence of catalytic amount of DMAP furnished (+)-hydrox-
yancepsenolide acetate (5b) [[α]2D1 = +18.5 (c 0.6, CHCl3), lit.4d
[α]2D5 = +3.7 (c 2.2, CHCl3)] (Scheme 7). Their structures were
confirmed by the comparison of spectral data with those reported
in the literature.
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ASSOCIATED CONTENT
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AUTHOR INFORMATION
Corresponding Author
■
*E-mail: sjgharpure@iitb.ac.in.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the Department of Science and Technology (DST)
and the Council of Scientific and Industrial Research (CSIR),
New Delhi, for financial support. We are grateful to CSIR, New
Delhi, for the award of research fellowships to LNN.
DEDICATION
■
Dedicated to Professor U. V. Varadaraju, IIT Madras, on the
occasion of his 60th birthday.
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