Three-component coupling reactions of silyl glyoxylates, vinyl grignard reagent, and nitroalkenes: An efficient, highly diastereoselective approach to nitrocyclopentanols

Article abstract of DOI:10.1002/anie.201003470

Quick and easy: A regio- and stereoselective three-component coupling reaction generates functionalized (Z)-silyl enol ethers through a vinylation/[1,2]-Brook rearrangement/vinylogous Michael reaction cascade. These adducts can then undergo a diastereosel

Full text of DOI:10.1002/anie.201003470

Communications
DOI: 10.1002/anie.201003470
Multicomponent Reactions
Three-Component Coupling Reactions of Silyl Glyoxylates, Vinyl
Grignard Reagent, and Nitroalkenes: An Efficient, Highly
Diastereoselective Approach to Nitrocyclopentanols**
Gregory R. Boyce and Jeffrey S. Johnson*
The efficient synthesis of highly substituted cyclopentanols is
an important task given the prevalence of this class of
compounds in nature. Nitrocyclopentanols are of particular
value due to the rich chemistry associated with the nitro
group[1] and their potential use as aminocyclopentitol pro-
genitors.[2] Aminocyclopentitols have generated considerable
attention because of their significant biological activity and
synthetic challenges presented by their often dense function-
ality and contiguous chiral centers. As such, the development
of a flexible synthesis of functionalized nitrocyclopentanols
would be a welcome addition to the synthetic toolbox. Herein
we report the three-component coupling of silyl glyoxylates,
=
CH2 CHMgBr, and nitroalkenes that selectively affords (Z)-
silyl enol ether products through a unique vinylogous Michael
cascade. The resulting functionality enables the immediate
implementation of a second-stage Henry cyclization for the
expeditious, diastereoselective synthesis of functionalized
nitrocyclopentanols.
Scheme 1. Divergent silyl glyoxylate reactivity.
Silyl glyoxylates are conjunctive reagents for the union of
complementary nucleophilic and electrophilic partners linked
at a protected glycolic acid junction.[3] The use of these
reagents in coupling reactions with alkide and hydride
nucleophiles[4] and carbonyl secondary electrophiles has
been documented. We endeavoured to expand the utility of
silyl glyoxylate chemistry to include Michael acceptors as the
secondary electrophile. Nitroalkenes were chosen by virtue of
their highly electrophilic character and the synthetic versa-
tility of the nitro functionality. The proposed transformation
outlined in Scheme 1 involves the addition of vinyl Grignard
to the silyl glyoxylate 1 to reveal, after [1,2]-Brook rearrange-
ment,[5] the (Z)-metallodienolate 2.[4a,c] This intermediate
could act as a transient secondary nucleophile capable of
engaging the nitroalkene 4 in a vinylogous Michael addition
to provide enolsilane 6. As such, the combination of 1 and
=
CH2 CHMgBr would function as the synthetic equivalent of
the unusual a-keto ester homoenolate synthon, perhaps by
way of the C-metalated tautomer 3 of the (Z)-metallodieno-
late (Scheme 2).[6]
Scheme 2. Proposed access to the a-ketoester homoenolate synthon.
An open question at the outset of this inquiry was whether
a/g selectivity would exhibit electrophile dependence. Pre-
vious silyl glyoxylate-based couplings predominantly pro-
vided a-selectivity from metallodienolate intermediates.[4a,c]
Moreover, the vinylogous Michael reaction of metallodieno-
lates is infrequently deployed due to an innate kinetic
preference for a-addition: evaluation of frontier-orbital
densities and HOMO coefficients establish the a-carbon as
the more nucleophilic site.[7] While some exceptions exist,[8]
successful vinylogous Michael reactions frequently require
considerable prefunctionalization to control selectivity and
are almost exclusively performed with butenolide deriva-
tives[9] and a,a-dicyanoolefins.[10] A second challenge lies in
the management of the relevant rate constants. Stepwise
[*] G. R. Boyce, Dr. J. S. Johnson
Department of Chemistry
The University of North Carolina at Chapel Hill
Chapel Hill, NC 27599 (USA)
Fax: (+1)919-962-2388
E-mail: jsj@unc.edu
Homepage: http://www.unc.edu/jsjgroup/
[**] This project was supported by Award Number R01 GM084927 from
the National Institute of General Medical Sciences. Additional
support from Novartis and Amgen is gratefully acknowledged.
Glyoximide 10 was generously provided by Prof. Richard Hsung and
Dr. Ziyad Al-Rashid. X-ray crystallography was performed by Dr.
Peter White.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201003470.
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Table 1: Substrate scope for three-component coupling.
reagent introduction was viewed as untenable in light of the
known nucleophile-initiated oligomerization of 1 in the
absence of a secondary electrophile.[4a,c] The one-pot coupling
=
would be efficient only if CH2 CHMgBr exhibited high
chemoselectivity for 1 over 4 and the derived intermediate 3
manifested the opposite preference.
Product[a]
R
Yield [%]
Initial experiments with tert-butyl dimethylsilyl glyoxy-
late, b-nitrostyrene, and vinyl Grignard at À788C provided
the desired vinylogous Michael reactivity albeit in an unsat-
isfactory 43% yield for the (Z)-silyl enol ether product with
silyl glyoxylate oligomers as the major byproducts. The (Z)-
geometry was determined by NOESY analysis of enolsilane
and confirmed by NOESY analysis of the derived silyloxyep-
oxide. This observed (Z)-selectivity is consistent with the
Kuwajima-type intermediate 3;[6] a Diels–Alder pathway
through the s-cis conformer of 2 would have given the (E)-
enolsilane. This result also demonstrates that vinyl Grignard
does act as a discriminating nucleophile with a strong
preference for the silyl glyoxylate over the nitroalkene. The
predominance of the vinylogous reactivity in this reaction is
likely due to steric hindrance congesting the a-addition
pathway in conjunction with g-preference of the (Z)-metal-
lodienolate based on the hard/soft character of the electro-
phile.[7] Such an analysis provides a plausible explanation for
divergence from previous silyl glyoxylate coupling reactions
that have thus far been limited to hard electrophiles.
Optimization of the reaction conditions required 50%
excess of silyl glyoxylate and vinyl Grignard to compensate
for the partial oligomerization of the silyl glyoxylate. A
temperature of À788C or lower was required since the
[1,2]-Brook rearrangement and subsequent reactivity leads to
decomposition at higher temperatures. The silyl group was
also varied to determine its effect on the reaction. The
triethylsilyl (TES) and tert-butyldimethylsilyl (TBS) groups
were found to provide similar yields, with the bulkier
triisopropylsilyl (TIPS) group providing a diminished yield
(54%) and the trimethylsilyl (TMS) group performing the
poorest (30%). The triethylsilyl glyoxylate was chosen for the
substrate scope over the tert-butyldimethylsilyl glyoxylate due
to its more facile deprotection and functionalization. The
optimized conditions for the coupling involved dropwise
addition of vinyl Grignard to a solution of the silyl glyoxylate
and the nitroalkene at À788C followed by warming to room
temperature to afford the desired product 8a in a 72% yield
based on b-nitrostyrene.[11]
8a
8b
8c
8d
8e
8 f
8g
8h
8i
Ph
72[b]
70[b]
65[b]
64[b]
66[b]
57[c]
58[b]
53[c]
36[c]
4-Cl-C6H4
2-thienyl
2-furyl
(E)-CH CH-C6H5
H
n-pentyl
iPr
tBu
=
=
[a] Reagents: Silyl glyoxylate (1.5 equiv), nitroalkene (1 equiv), CH2
CHMgBr (1.5 equiv), [4]0 =0.1m in C7H8; [b] Yield of isolated product.
[c] Yields were determined by H NMR spectroscopy of crude product
compared to an internal standard of mesitylene.
1
conditions to reveal the latent nitroketone functionality
thereby enabling in situ Henry cyclization. Various depro-
tection methods were screened for the desired cascade using
the substrate 8a. Fluoride-based deprotections accomplished
the desired transformation; however, the diastereomeric
ratios were inconsistent, and mixtures of the acyclic a-
ketoester and the desired nitrocyclopentanol 9a were isolated
in varying ratios. Substituting the fluoride deprotections for a
basic methanol deprotection at À58C provided the desired
adduct 9a in 78% yield with a greater than 20:1 diastereo-
selection.[13]
We then examined the scope of the Henry cyclization for
the enolsilanes 8a–i (Table 2). Yields ranged from 58–94%
with alkyl, aryl, and heteroaryl substituents all being well
tolerated. The diastereomeric ratio was controlled by the
identity of the side chain. The branched substrates containing
aryl, heteroaryl, iPr, and tBu groups provided the highest
diastereoselectivies (ꢀ 20:1) while the products with
Table 2: Substrate scope for deprotection/diastereoselective Henry
cyclization cascade.
An examination of various alkyl, aryl, and heteroaryl
nitroalkenes was conducted with the results summarized in
Table 1. The yields ranged from 36–72% with aryl and
heteroaryl nitroalkenes outperforming the alkyl substrates.
The efficiency of the reaction for the alkyl examples tended to
decrease with the increasing steric hindrance from a-branch-
ing on the R group.
The silyl enol ethers 8a–i are assembled in the correct
oxidation state to enable a deprotection/Henry cyclization
cascade to furnish nitrocyclopentanols with three contiguous
stereocenters. The intramolecular Henry reaction is an
infrequently utilized transformation due to the difficulty in
synthesizing the requisite bifunctional nitrocarbonyl precur-
sors.[12] Our next set of experiments evaluated optimal
Product[a]
R
t [h]
Yield [%]
d.r.
9a
9b
9c
9d
9e
9 f
9g
9h
9i
Ph
3
7
3
78
69
94
54
64
70
58
56
59
>20:1
20:1
20:1
4-Cl-C6H5
2-thienyl
2-furyl
(E)-CH CH-C6H4
H
n-pentyl
iPr
tBu
3
20:1
=
12
12
12
16
16
3:1
1.5:1
5:1
>20:1
>20:1
[a] Reagents: Silyl enol ether 8a–i (1 equiv), NaOH (1.2 equiv), [8]0 =
0.01m in (1:1) MeOH:CH2Cl2. [b] Stereostructures were determined
through NOESY experiments and X-ray crystallography.
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unbranched R groups such as styryl (9e), hydrogen (9 f), and
n-pentyl (9g) were obtained with diminished diastereoselec-
tion.
Experimental Section
The silyl glyoxylate (123 mg, 0.5 mmol, 1.5 equiv) and b-nitrostyrene
(50 mg, 0.33 mmol, 1.0 equiv) were added to an oven-dried vial. The
vial was then purged with N2 and toluene (3.3 mL) was added. The
resulting solution was cooled to À788C using an acetone and dry ice
bath. Vinylmagnesium bromide (0.5 mL, 0.5 mmol, 1.5 equiv) was
added dropwise to the solution. Once the addition was complete the
reaction was allowed to warm to room temperature, diluted with ethyl
acetate (5 mL), and quenched with saturated ammonium chloride
(5 mL). The resulting mixture was stirred for 10 min. The layers were
separated, and the aqueous layer was extracted with ethyl acetate (3 ꢀ
5 mL). The organic extracts were combined, washed with brine
(5 mL), dried with magnesium sulfate, and concentrated in vacuo. The
crude mixture was purified by flash chromatography eluting with
2.5% EtOAc/hexanes to yield 102 mg (72%) of the desired product
8a as a yellow oil. Additional details and full characterization data are
presented in the Supporting Information.
This intramolecular Henry cascade provides a comple-
mentary method to that recently reported by Zhong et al. in
their synthesis of nitrocyclopentanols through an organo-
catalytic Michael/Henry domino reaction.[14] Where the
Zhong work provides a tertiary benzylic alcohol, the present
chemistry installs a tertiary glycolic acid moiety, the reduced
form of which is present in numerous cyclopentanol natural
products including trehazolin[15] and pactamycin.[16] This
method also addresses one of the few limitations of their
published methodology, which is the requirement of aryl and
heteroaryl nitroalkenes. Since the three-component coupling
reaction can employ a wide variety of nitroalkenes, it arrives
at nitrocyclopentanols with reasonable flexibility in the side
chain identity. Moreover, utilization of the nucleophilicity of
the silyl enol ether moiety prior to cyclization could enable
the synthesis of tetrasubstituted cyclopentanols.
Received: June 7, 2010
Revised: August 17, 2010
Published online: October 14, 2010
Lastly, we sought to develop an asymmetric variant of this
three-component coupling. We examined silyl glyoximides, a
new class of reagents recently synthesized by Hsung and co-
workers in conjunction with ynamide oxidation studies.[17]
Exposing silyl glyoximide 10 to the three-component coupling
conditions with vinyl Grignard and b-nitrostyrene gratifyingly
provided the desired product 11 in 75% yield and 20:1
diastereoselection (Scheme 3). The absolute configuration of
the product was determined by conversion to the known
nitroaldehyde by ozonolysis.[18] Studies are underway to
determine the potential of silyl glyoximides as a new class
of conjunctive reagents and to understand this remarkable
long-range stereochemical transmission.[19]
Keywords: Brook rearrangement · multicomponent reactions ·
nitroalkenes · nitrocyclopentanols · silyl glyoxylates
.
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Scheme 3. Diastereoselective silyl glyoximide coupling.
In summary, a sequential vinylation/[1,2]-Brook rear-
rangement/vinylogous Michael reaction incorporating silyl
glyoxylates, vinyl Grignard, and nitroalkenes has been
developed that provides (Z)-silyl enol ether products. This
marks the first use of a Michael acceptor as the secondary
electrophile in silyl glyoxylate-based cascades and is unique
due to the vinylogous reactivity of the (Z)-metallodienolate
that diverges from previous silyl glyoxylate couplings. The
silyl enol ether products were utilized in a merged depro-
tection/Henry cyclization sequence that furnishes nitrocyclo-
pentanols with three contiguous stereocenters in two steps
from readily available starting materials. We further demon-
strated that electrophile facial selectivity is possible in the title
coupling through the application of a chiral auxiliary.
[11] Certain substrates required alterations in procedure. See the
Supporting Information for details.
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X-ray crystallography and NMR analysis. CCDC 788056 con-
tains the supplementary crystallographic data for this paper.
These data can be obtained free of charge from The Cambridge
Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_
request/cif.
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