Total synthesis of (-)-dihydroprotolichesterenic acid via diastereoselective conjugate addition to a chiral fumarate

Article abstract of DOI:10.1016/j.tetlet.2013.02.014

A diastereoselective conjugate addition of a variety of monoorganocuprates, Li[RCuI], to chiral fumarates to provide funtionalized succinates has been developed. The utility of this reaction is demonstrated in a concise total synthesis of (-)-dihydroprotolichesterenic acid that required only four steps and proceeded in an overall 31% yield.

Full text of DOI:10.1016/j.tetlet.2013.02.014

Tetrahedron Letters 54 (2013) 2074–2076
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Tetrahedron Letters
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Total synthesis of (À)-dihydroprotolichesterenic acid via diastereoselective
conjugate addition to a chiral fumarate
⇑
J. Caleb Hethcox, Charles S. Shanahan, Stephen F. Martin
Department of Chemistry and Biochemistry, The University of Texas at Austin, Austin, TX 78712, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
A diastereoselective conjugate addition of a variety of monoorganocuprates, Li[RCuI], to chiral fumarates
to provide funtionalized succinates has been developed. The utility of this reaction is demonstrated in a
concise total synthesis of (À)-dihydroprotolichesterenic acid that required only four steps and proceeded
in an overall 31% yield.
Received 10 January 2013
Revised 31 January 2013
Accepted 4 February 2013
Available online 11 February 2013
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Conjugate addition
Total synthesis
Chiral auxiliary
Butyrolactone
Succinate
Functionalized succinic acid derivatives and compounds that
may be derived therefrom are structural motifs that are commonly
found in biologically active molecules of natural and non-natural
origin. Some notable examples include the matrix metalloprotein-
ase inhibitor BB-1101 (1),1 the antifungal and antibacterial agent
dihydroprotolichesterenic acid (2),2 the glaucoma drug pilocarpine
(3),3 and the anti-inflammatory and antiviral agent antrodin D (4)
(Fig. 1).4
Because of the obvious importance of the functionalized, four-
carbon building blocks found in these and other compounds, there
has been considerable interest in developing efficient methods for
enantioselective and stereoselective synthesis of substituted succi-
nates.5 Toward this end, three general diastereoselective ap-
proaches using chiral auxiliaries have been reported. These
include alkylations of enolates,6 oxidative cross couplings of eno-
lates,7 and radical mediated conjugate additions to unsaturated
carbonyl compounds (Scheme 1).8 However, these methods typi-
cally suffer from low stereoselectivity or production of toxic stoi-
chiometric byproducts. Furthermore, none of the current
strategies to access the succinate core enable access to any desired
diastereomer from a single starting material.
can be reversed by varying Lewis acid additives and solvents, thus
enabling a single starting material 5 to be converted into the two
diastereomeric products 6 and 7 (Scheme 2).10 Prior to this discov-
ery, the only tactic that could be used to direct an organometallic
reagent to the other face of the carbon–carbon double bond of a
crotonate derivative was to employ an enantiomorphic chiral aux-
iliary on the starting material.
In the context of work directed toward the stemofoline alka-
loids, we had an occasion to expand the utility of the Bergdahl
chemistry to c
-alkoxy crotonates,11 and we then queried whether
it might also be extended to fumarate derivatives such as 10. If the
Diastereoselective conjugate additions that are directed by chi-
ral oxazolidinones have been extensively explored since their ini-
tial report in 1993.9 In a useful advance in the area, Bergdahl and
co-workers reported that the diastereofacial selectivity of copper-
mediated conjugate additions to chiral N-crotonyl oxazolidinones
⇑
Corresponding author. Tel.: +1 (512) 471 3915; fax: +1 (512) 471 4180.
E-mail address: sfmartin@mail.utexas.edu (S.F. Martin).
Figure 1. Biologically active molecules accessible through succinate derivatives.
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.02.014

J. C. Hethcox et al. / Tetrahedron Letters 54 (2013) 2074–2076
2075
reagents, Li[RCuI], to 10 required little optimization. Indeed, reac-
tion of 10 with the monomethylcuprate Li[MeCuI] derived from
methyllithium and (CuI)4(DMS)3 in the presence of TMSI pro-
ceeded with a high degree of regio- and diastereoselectivity to fur-
nish the mono substituted succinate 11a (R = Me) in 89% yield and
19:1 dr (Table 1, entry 1). None of the regioisomeric addition prod-
uct was detected in the NMR spectrum of the reaction mixture. The
absolute stereochemistry of 11a was established by its subsequent
conversion into 2 (vide infra).
The observed regioselectivity in the reaction of 10 with a
monomethylcuprate reagent is consistent with other conjugate
additions that proceed via different mechanistic pathways.8,12
The enhanced reactivity at the carbon atom b to the imide moiety
of 10 can be attributed to its greater electropositive character that
is reflected by the relative chemical shifts of the two olefinic car-
bon atoms in the 13C NMR spectrum of 10.14 Namely, the chemical
shift of the carbon atom b to the imide moiety (d = 133.4 ppm) is
Scheme 1. Diastereoselective routes to access succinates.
1.5 ppm further downfield than the carbon atom
a to the imide
(d = 131.9 ppm). The presence of TMSI, which is proposed to inter-
act selectively with the oxygen atom of the imide carbonyl group,10
in the reaction mixture would be expected to further increase the
electropositive character of this carbon atom.
Toward elucidating the scope of this process, the reactions of
the chiral fumarate 10 with monoorganocuprates derived from
several other alkyllithium reagents were examined (Table 1). In
each case, the additions proceeded with high regio- and diastere-
oselectivity to give 11b–d. The absolute stereochemistry of 11b–
d was assigned based on analogy with 11a. Although monoorgano-
cuprates derived from organolithium species and (CuI)4(DMS)3
added smoothly to 10 in the presence of TMSI, efforts to switch
the diastereoselectivity of this reaction according to the Bergdahl’s
protocol have thus far been unsuccessful. We have examined a
number of alternate reaction conditions. For example, use of alkyl-
cuprates derived from Grignard reagents, MgBr[RCuI], as described
by Bergdahl and co-workers did not give detectable amounts of
any conjugate addition product.10 Reactions in which various che-
lating Lewis acids such as MgBr2, ZnCl2, and MnCl2 were used with
monoorganocuprates, Li[RCuI], gave only small amounts of prod-
ucts arising from 1,4-addition. Hence, the ability to control the dia-
stereofacial selectivity in cuprate additions to chiral fumarate
derivatives by the simple expedient of changing conditions as
was done for 5 remains an unsolved problem.
Scheme 2. Bergdahl’s switchable conjugate addition.10
Having established the underlying feasibility of inducing highly
regio- and diastereoselective additions to 10, we sought to exem-
plify the utility of the process by applying it to a synthetic problem.
We thus identified (À)-dihydroprotolichesterinic acid (2), a mem-
ber of the paraconic acid family of natural products,15 as a suitable
Scheme 3. Preparation of chiral fumarate 10.
regio- and stereoselective additions of organometallic reagents to
fumarates could be controlled, it would be possible to access a vari-
ety of useful succinate derivatives. However, we could not be cer-
tain of the regiochemical outcome of cuprate additions to 10
because two carbon atoms are b to an activating carbonyl group.
Curran and Sibi had each shown that radical additions proceeded
b to the imide moiety of such compounds,8 and Evans et al. had
found that Mukaiyama–Michael reactions with chiral fumarates
also occurred at the carbon atom b to the imide moiety.12 However,
there was no guiding precedent for the reactions of such substrates
with organocuprate-derived reagents.
In order to probe the feasibility of inducing addition to chiral
fumarates at the carbon atom distal to the chiral auxiliary, we pre-
pared the chiral fumarate 10 in 78% yield from commercially avail-
able monomethyl fumarate 8 and oxazolidinone 9 in the presence
of pivaloyl chloride, lithium chloride, and triethylamine (Scheme
3).13
Table 1
Diastereoselective conjugate addition
Entry
Alkyllithium
Yieldb (%)
drc
a
b
c
MeLi
EtLi
n-BuLi
PhLi
89
72
83
82
19:1
19:1
19:1
19:1
d
a
b
c
13C NMR spectrum chemical shifts (ppm) for 10.
Isolated yields after purification by flash column chromatography.
Based on HPLC analysis using a chiralcel OD-H column.
We quickly found that implementing Bergdahl’s conditions for
the TMSI-mediated conjugate addition of monoorganocuprate

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J. C. Hethcox et al. / Tetrahedron Letters 54 (2013) 2074–2076
Acknowledgments
We thank the National Institutes of Health (GM 25439) and the
Robert A. Welch Foundation (F-0652) for generous support of this
research. We would also like to thank Dr. Vincent Lynch (The Uni-
versity of Texas) for obtaining X-ray data for compound 2.
Supplementary data
Supplementary data (experimental procedures and spectral
data for all new compounds) associated with this article can be
found, in the online version, at http://dx.doi.org/10.1016/j.
tetlet.2013.02.014.
Scheme 4. Synthesis of (À)-dihydroprotolichesterenic acid.
References and notes
target. (À)-Dihydroprotolichesterenic acid has been synthesized
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pure form.16d,e However, we envisioned that a more concise enan-
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2 could be achieved using our
With the key intermediate 11a in hand, all that remained to
complete a synthesis of 2 was a diastereoselective aldol reaction,
which we envisioned would proceed with concomitant lactone for-
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tion of a substrate similar to 11a had been reported,17 use of those
conditions for 11a gave 12 in only 24% yield. After some experi-
mentation, we discovered that enolization of 11a at a higher con-
centration (0.9 M) with n-Bu2BOTf (1.5 equiv) in the presence of
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in 12 under standard conditions delivered (À)-dihydroprotoliche-
sterenic acid (2) in 85% yield, thereby completing a four step, enan-
tioselective synthesis of 2 that proceeded in 31% overall yield (56%
based upon recovered starting material). The structure of synthetic
2 was confirmed by X-ray crystallography,18 and it also gave 1H
and 13C NMR spectra and optical rotation data consistent with
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18. Crystallographic data (excluding structure factors) for the structures in this
Letter have been deposited with the Cambridge Crystallographic Data Centre as
supplementary publication No. CCDC 918018. Copies of the data can be
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CB2 1EZ, UK. Fax: +44 (0)1223 336033 or e-mail: deposit@ccdc.cam.ac.Uk.
In summary, we report the first diastereoselective conjugate
addition of alkyl and aryl monoorganocuprates, Li[RCuI], to chiral
fumarates, thereby providing a rapid and stereoselective entry to
substituted succinate derivatives. The practical utility of the meth-
od was demonstrated by its application to the concise, enantiose-
lective synthesis of (À)-dihydroprotolichesterinic acid (2).