Asymmetric N-heterocyclic carbene catalyzed addition of enals to nitroalkenes: Controlling stereochemistry via the homoenolate reactivity pathway to access δ-lactams

Article abstract of DOI:10.1021/ja403847e

An asymmetric intermolecular reaction between enals and nitroalkenes to yield δ-nitroesters has been developed, catalyzed by a novel chiral N-heterocyclic carbene. Key to this work was the development of a catalyst that favors the δ-nitroester pathway over the established Stetter pathway. The reaction proceeds in high stereoselectivity and affords the previously unreported syn diastereomer. We also report an operationally facile two-step, one-pot procedure for the synthesis of δ-lactams.

Full text of DOI:10.1021/ja403847e

Communication
pubs.acs.org/JACS
Asymmetric N‑Heterocyclic Carbene Catalyzed Addition of Enals to
Nitroalkenes: Controlling Stereochemistry via the Homoenolate
Reactivity Pathway To Access δ‑Lactams
Nicholas A. White, Daniel A. DiRocco, and Tomislav Rovis*
Department of Chemistry, Colorado State University, Fort Collins, Colorado 80523, United States
S
* Supporting Information
carbon. Differentiation between the acyl anion and homo-
ABSTRACT: An asymmetric intermolecular reaction
between enals and nitroalkenes to yield δ-nitroesters has
been developed, catalyzed by a novel chiral N-heterocyclic
carbene. Key to this work was the development of a
catalyst that favors the δ-nitroester pathway over the
established Stetter pathway. The reaction proceeds in high
stereoselectivity and affords the previously unreported syn
diastereomer. We also report an operationally facile two-
step, one-pot procedure for the synthesis of δ-lactams.
enolate is problematic, as the majority of electrophiles used in
homoenolate pathways have also been shown to be competent
acceptors in the acyl anion pathway.
Nitroalkenes represent attractive electophiles for the
homoenolate; the δ-nitroesters produced in this reaction are
useful synthons for δ-lactams and piperidines, common motifs
in drug targets and natural products.5 In 2009, Nair reported
the NHC-catalyzed homoenolate reaction between enals and
nitroalkenes. With the use of an achiral imidazolium precatalyst,
aromatic enals and nitrostyrene derivatives were coupled in
good yield and good anti selectivity.6 Recently, Liu and co-
workers rendered the reaction asymmetric by employing an
aminoindanol-based triazolium precatalyst. Liu’s work showed a
variety of enals, both aromatic and aliphatic, to be competent
coupling partners for aromatic nitrodienes, nitroenynes, and
nitrostryenes in excellent ee and good anti diastereoselectivity
(Figure 1).7 Herein we report our own concurrent studies on
this reaction that delivers complementary stereoselectivity and
allows coupling with aliphatic nitroalkenes.
ecently, N-heterocyclic carbenes (NHCs) have been
R
shown to be powerful catalysts for a variety of useful
transformations.1 NHC catalysis traditionally operates via the
acyl anion equivalent (Figure 1 A), and this manifold has
During the course of our previous investigations into the
asymmetric intermolecular Stetter reaction, we observed
homoenolate addition to nitroalkenes as a side product.8
Intrigued by this reactivity, we began our investigation with the
addition of cinnamaldehyde 1a to (E)-1-nitrobut-1-ene 2a. Our
exploration of chiral catalysts began with aminoindanol-derived
5a9 (Table 1) and found it provides the desired product with
excellent syn diastereoselectivity (17:1), but the yield and ee
were unsatisfactory (25% yield, 40% ee). The selective
formation of the syn diastereomer was unexpected in light of
Nair6 and Liu’s7 previous reports which delivered the anti
diastereomer. The incorporation of an aliphatic nitroalkene in
this reaction is also noteworthy, as only activated and aryl
nitroalkenes have been previously shown. We continued our
investigation by employing fluorinated precatalyst 5b8a and
were pleased to observe the product in 42% yield, 83% ee, and
excellent diastereoselectivity (17:1). Unfortunately this system
provides no preference for the homoenolate pathway, and a 1:1
mixture of the Stetter product 4 and desired nitroester 3a is
formed. Efforts to improve enantioselectivity with 5b via
reaction optimization proved fruitless, and the yield of 3a never
surpassed 50%. With these results in hand, we chose to focus
Figure 1. Background.
received a great deal of attention. When an enal is employed,
both the acyl anion and homoenolate pathways (Figure 1 B)
become accessible.2 In 2004, Bode and Glorius independently
reported the first NHC generated homoenolate in their
annulations between enals and aldehydes to synthesize γ-
lactones.3 Since those initial reports the application of the NHC
homoenolate has grown tremendously. A variety of annulations
have been developed to synthesize lactones, lactams, and
carbocycles.4 Despite these advances, challenges in stereo-
induction and differentiation between the acyl anion and
homoenolate pathways remain. Stereoinduction is challenging
due to the distal relationship between the NHC and the β-
Received: April 17, 2013
© XXXX American Chemical Society
A
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Journal of the American Chemical Society
Communication
a
a
Table 1. Chiral Catalyst Screen
Table 2. Nitroalkene Scope
b
c
d
entry
catalyst
3a:4
yield 3a (%)
dr (syn/anti)
ee (%)
1
2
3
4
5
6
5a
5b
5c
5d
5e
5f
2:1
1:1
25
42
70
60
16
49
17:1
17:1
2:1
−40
−83
−22
−30
95
5:1
6:1
15:1
17:1
17:1
>20:1
>20:1
93
a
Reactions were conducted with 1.5 equiv of 1 and 1.0 equiv of 2.
b
c
Isolated yield after chromatography. Diastereoselectivity determined
d
1
by H NMR of the unpurified reaction mixture. Enantiomeric excess
was determined by HPLC analysis on a chiral stationary phase.
on developing conditions to promote the homoenolate
pathway over the Stetter pathway.
We hypothesized that bulky substituents in the ortho/ortho′
position of the N-aryl ring of the NHC would shift product
distribution toward the desired nitroester by partially blocking
the acyl anion position. Precatalyst 5c was synthesized, and a
considerable increase in product selectivity (5:1 3a:4, 70%
yield) was observed, although the enantio- and diastereose-
lectivity suffered considerably (2:1 dr, 30% ee). Bis-
trifluoromethyl triazolium 5d showed good selectivity for the
nitroester (6:1 3a:4, 60% yield), and diastereoselectivity was
excellent (15:1) but enantioselectivity was low (22% ee).
Given the partial success with larger substituents on the aryl
side, we hypothesized that an increase in sterics on the alkyl
side of the azolium may deliver similar levels of selectivity
favoring the homoenolate product with the potential for
improved stereoselectivity. With that in mind, we examined
Ye’s bis-phenyl O-TMS triazolium precatalyst 5e which
provided excellent selectivity for the nitroester (>20:1 3a:4,
17% yield) and excellent stereoselectivity (17:1 dr, 95% ee).10
The remainder of the mass balance with catalyst 5e was enal,
suggesting the catalyst was either prohibitively slow or was
undergoing decomposition. We postulated that replacing the
bis-phenyl moiety with an aliphatic group may lead to a more
efficient catalyst. In pursuit of this belief we synthesized 5f and
were pleased to observe a substantial increase in yield while
product selectivity (>20:1 3a:4, 49% yield) and stereoselectivity
remained excellent (17:1 dr, 93% ee). A brief screen of bases
and base equivalents led us to our optimized conditions of 50
mol % sodium acetate (see Supporting Information).
a
b
See Table 1 footnotes a−d. 2.5 equiv of aldehyde 1a used.
(3a−3j). Sterically bulky nitroalkenes such as isopropyl are
tolerated, but tert-butyl does not participate (not shown).
Notably, acetal 3g and terminal olefin 3h are formed with
useful selectivities and provide valuable handles for further
manipulation. Enantio- and diastereoselectivities are typically
lower for aryl nitroalkenes (3k−3o), but the reactions proceed
in good yield. Heteroaromatic nitroalkenes participate as well
(3k, 3m, 3n).
Electron-withdrawing and -rich aryl enals provide product in
modest to good yield, Table 3. In the case of p-nitro-
cinnamaldehyde, the reaction delivers a modest yield of 3q,
with the remainder of the aldehyde starting material converted
to p-nitrodihydroethylcinnamate. In this highly electron-
withdrawing system, protonation of the homoenolate out-
competes addition to the nitroalkene.11 Use of trans-2-pentenal
in this reaction with catalyst 5f yields only the Stetter product.
This is unusual, as it is the only substrate that gives the Stetter
product in greater than trace amounts. However, the use of
fluorinated catalyst 5b at 50 °C delivers the desired product in
25% yield with the remainder of the mass balance as the Stetter
product 4.
A variety of aliphatic and aryl nitroalkenes are competent in
the reaction, Table 2. Aliphatic nitroalkenes typically provide
product in excellent stereoselectivity, albeit with moderate yield
Due to the orthogonality of the two ends of products 3, we
were motivated to explore manipulation of the nitro-ester
product to deliver valuable synthons. We found we could
B
dx.doi.org/10.1021/ja403847e | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
a
coupling with aliphatic nitroalkenes and provides access to the
syn diastereomer. We also report the operationally facile one-
pot two-step reaction sequence to arrive at synthetically useful
δ-lactams.
Table 3. Enal Scope
ASSOCIATED CONTENT
■
S
* Supporting Information
Full experimental details, spectroscopic data for all new
compounds, and crystallographic data (CIF). This material is
available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Author
rovis@lamar.colostate.edu
Funding Sources
NIGMS (GM72586).
Notes
a
b
See Table 1 footnotes a−d. Catalyst 5b was used, and the reaction
The authors declare no competing financial interest.
was run at 50 °C.
ACKNOWLEDGMENTS
generate the corresponding δ-lactams12 in good yield via a one-
pot two-step process (Table 4). Addition of zinc dust and acetic
■
This paper is dedicated to Professor Teruaki Mukaiyama in
celebration of the 40th anniversary of the Mukaiyama aldol
reaction. We thank NIGMS for support (GM72586). TR
thanks Amgen and Roche for unrestricted support. We thank
Derek M. Dalton (CSU) for solving the structure of S3.
a
Table 4. One-Pot Synthesis of δ-Lactams
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Scheme 1. Lactam Reduction
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