Enantioselective palladium-catalyzed [3 + 2] cycloadditions of trimethylenemethane with nitroalkenes

Article abstract of DOI:10.1021/ol2030179

Nitroalkenes readily undergo palladium-catalyzed [3 + 2] cycloaddition with trimethylenemethane to generate nitrocyclopentanes in excellent yield and enantioselectivity. Furthermore, the products thus formed are highly versatile synthetic intermediates an

Full text of DOI:10.1021/ol2030179

ORGANIC
LETTERS
2012
Vol. 14, No. 1
234–237
Enantioselective Palladium-Catalyzed [3 þ 2]
Cycloadditions of Trimethylenemethane with
Nitroalkenes
Barry M. Trost,* Dustin A. Bringley, and Pamela S. Seng
Department of Chemistry, Stanford University, Stanford, California 94305-5080,
United States
*bmtrost@stanford.edu
Received November 8, 2011
ABSTRACT
Nitroalkenes readily undergo palladium-catalyzed [3 þ 2] cycloaddition with trimethylenemethane to generate nitrocyclopentanes in excellent
yield and enantioselectivity. Furthermore, the products thus formed are highly versatile synthetic intermediates and provide convenient access to
both cyclopentylamines and cyclopentenones.
The palladium-catalyzed cycloaddition of trimethylene-
methane (TMM) represents a powerful method for the
construction of carbo- and heterocycles and proceeds with
high chemo-, regio-, and diastereoselectivity.1 First de-
scribed over 30 years ago as a racemic method,2 a general,
asymmetric protocol was only recently achieved with the
discovery that phosphoramidites bearing bulky 2,5-diaryl-
pyrrolidines were effective chiral ligands.3a Using these
ligands, we have demonstrated asymmetric [3 þ 2] cy-
cloadditions with several olefins,3 imines,4 and aldehydes.5
Although electron-deficient olefins were among the first
substrates demonstrated in the asymmetric TMM reac-
tion, the examples to date are nearly completely restricted
to alkenes activated by functional groups bearing a
carbonyl. The lone exception is the reaction of cinnamyl
nitrile,3a which proceeded in moderate enantioselectivity
under the reaction conditions. During the course of these
studies, however, we identified nitroalkenes (2, Scheme 1)
as attractive substrates for the asymmetric TMM reaction.
The substrates themselves are widely available and have
been demonstrated in racemic TMM cycloadditions;6
however, the known sensitivity of the asymmetric method
tochanges in the electron-withdrawing group3,4 make their
success far from certain. Furthermore, the nitrocyclopen-
tanes (3) thus formed would possess considerable synthetic
utility.7 Simple reduction of the nitro group would provide
access to cyclopentylamines (4), which have been the focus
of synthetic efforts and represent potential therapeutic
(6) Ikeda, M.; Okano, M.; Kosaka, K.; Kido, M.; Ishibashi, H.
Chem. Pharm. Bull. 1993, 41, 276. (b) Holzapfel, C. W.; van der Merwe,
T. L. Tetrahedron Lett. 1996, 37, 2307.
(7) Noboru, O. The Nitro Group in Organic Synthesis; Wiley-VCH:
New York, 2001.
(8) Zhou, J. (S.); Hartwig, J. F. J. Am. Chem. Soc. 2008, 130, 12220.
(b) Bournaud, C.; Chung, F.; Luna, A. P.; Pasco, M.; Errasti, G.;
Lecourt, T.; Micouin, L. Synthesis 2009, 6, 869. (c) Noonan, G. M.;
Cobley, C. J.; Lebl, T.; Clarke, M. L. Chem.;Eur. J. 2010, 16, 12788.
(9) Kurteva, V. B.; Afonso, C. A. Chem. Rev. 2009, 109, 6809.
(10) Chand, P.; Kotian, P. L.; Dehghani, A.; El-Kattan, Y.; Lin, T.-H.;
Hutchinson, T. L.; Babu, Y. S.; Bantia, S; Elliott, A. J.; Montgomery, J. A.
J. Med. Chem. 2001, 44, 4379. (b) De Clercq, E. Nat. Rev. Drug Discovery
2006, 5, 1015.
(1) Chan, D. M. T. Recent Advances in Palladium-Catalyzed
Cycloadditions Involving Trimethylenemethane and its Analogs. In
Cycloaddition Reactions in Organic Synthesis; Kobayashi, S., Jorgensen,
K. A., Eds.; Wiley-VCH: Weinheim, Germany, 2002; pp 57ꢀ83.
(2) Trost, B. M.; Chan, D. M. T. J. Am. Chem. Soc. 1979, 101, 6429.
(3) Trost, B. M.; Stambuli, J. P.; Silverman, S. M.; Schworer, U.
J. Am. Chem. Soc. 2006, 128, 13328. (b) Trost, B. M.; Cramer, N.;
Silverman, S. M. J. Am. Chem. Soc. 2007, 129, 12396.
(4) Trost, B. M.; Silverman, S. M.; Stambuli, J. P. J. Am. Chem. Soc.
2007, 129, 12398. (b) Trost, B. M.; Silverman, S. M. J. Am. Chem. Soc.
2010, 132, 8238.
(5) Trost, B. M.; Bringley, D. A.; Silverman, S. M. J. Am. Chem. Soc.
2011, 133, 7664.
r
10.1021/ol2030179
Published on Web 12/16/2011
2011 American Chemical Society

Table 1. Initial Optimization with trans-β-Nitrostyrenea
Scheme 1. Synthesis and Derivatization of Nitrocyclopentanes
entry
ligand
solvent
% yield
% ee
1
2
3
4
5
6
7
L1
L2
L3
L4
L5
L5
L5
toluene
toluene
toluene
toluene
toluene
dioxane
THF
85
70
79
79
93
79
57
ꢀ3
18
53
84
87
85
91
agents.8,9 For example, peramivir, an antiviral currently
under development for the treatment of influenza, pos-
sesses a cyclopentylamine core.10 Alternatively, oxidation
of the nitro group to a ketone (the Nef reaction) generates
an enantioenriched cyclopentenone (5), a widely studied
and important intermediate in organic synthesis.11,12
a All reactions were conducted at 0.15 M in the indicated solvent, at
50 °C, with 1.6 equiv of 1a, 5% Pd(dba)2, and 10% ligand. Yields are
isolated values; ee’s were determined by chiral HPLC.
enantioselectivity (entries 1ꢀ5). A reaction temperature of
50 °C was adequate for most substrates, although a lower
temperature gave improved ee’s in select cases with mini-
mal impact on the yield.
Disubstituted nitrostyrenes could also be used, as seen in
the reactions of both 1- and 2-naphthyl-substituted ni-
troalkenes (entries 6 and 7, respectively). 3,4-Methylene-
dioxy-β-nitrostyrene was previously used in a racemic
Table 2. Reaction Scope with Nitroalkene Derivativesa
Figure 1. Chiral ligands used in this study.
To evaluate the viability of nitroalkenes as a substrate
class, we began our studies using trans-β-nitrostyrene.
Although ligands L1 and L2 (Figure 1) gave cycloaddition
with nitrostyrene in good yield, the ee was poor (Table 1,
entries 1 and 2). Consistent with our earlier reports,
phosphoramidites bearing a pyrrolidine gave higher ee’s.
Bis-p-biphenyl L3 and bis-1-naphthyl L4 led to a signifi-
cant improvement, but bis-2-naphthyl L5 proved best,
yielding the nitrocyclopentane in 93% yield and 87% ee.
Briefly examining other solvents (entries 6ꢀ7) gave no
advantage over toluene; while selectivity was highest in
THF, the yield was only moderate.
Various types of trans-β-substituted nitroalkenes were
successfully utilized under these optimized condi-
tions (Table 2). Both electron-rich and -poor nitrostyrene
derivatives, possessing various substitution patterns,
gave the nitrocyclopentanes in good yield and excellent
T,
%
%
entry
R =
product
°C
yield
ee
1
2
3
4
5
6
7
8
3-bromophenyl
4-chlorophenyl
2-methylphenyl
4-methylphenyl
4-methoxyphenyl
1-naphthyl
7
50
50
23
50
23
23
50
50
63
65
91
82
72
67
82
80
94
95
93
89
94
92
93
91
8
9
10
11
12
13
14
2-naphthyl
3,4-methylene-
dioxyphenyl
2-furyl
9
15
16
17
18
19
20
21
22
23
50
23
50
50
50
50
50
66
58
75
91
88
97
97
53
88
87
91
86
83
93
88
93
10
11
12
13
14
15
16
3-furyl
2-thiophenyl
N-Boc-3-indolyl
n-propyl
cyclohexyl
tert-butyl
(E)-styrenyl
(11) Gibson, S. E.; Lewis, S. E.; Mainolfi, N. J. Organomet. Chem.
2004, 689, 3873. (b) Frontier, A. J.; Collison, C. Tetrahedron 2005, 61,
7577. (c) Pellissier, H. Tetrahedron 2005, 61, 6479.
(12) Lee, H.-W.; Kwong, F.-Y. Eur. J. Org. Chem. 2010, 789.
(b) Shibata, T. Adv. Synth. Catal. 2006, 348, 2328.
a All reactions were conducted at 0.15 M in toluene with 1.6 equiv of
1a, 5% Pd(dba)2, and 10% L5. Yields are isolated values; ee’s were
determined by chiral HPLC.
Org. Lett., Vol. 14, No. 1, 2012
235

TMM reaction but gave the product as a mixture of
diastereomers.6a Under the asymmetric conditions, how-
ever, the product was isolated as a single diastereomer in
80% yield and 91% ee (entry 8). Interestingly, this product
was used in the synthesis of (()-cephalotaxine, the major
alkaloid from the Cephalotaxus species (Scheme 2). Our
asymmetric synthesis therefore constitutes a formal synth-
esis of cephalotaxine, albeit as the unnatural enantiomer
when using (R,R,R)-L5, a situation easily rectified by
switching to the (S,S,S) enantiomer of L5.13
Scheme 3. Generation of Cyclopentylamine 23 and Its Conver-
sion to Mandelamide 24
Scheme 2. Formal Synthesis of (þ)-Cephalotaxine
Nitroalkenes bearing heterocyclic rings or aliphatic
groups could also be used. For reactions with the former,
heterocycles such as furans, thiophenes, and indoles were
all found to be compatible with the reaction conditions
(Table 2, entries 9ꢀ10, 11, and 12, respectively). Notably,
the substrates bearing the nitroalkene at the 2-position of
the heterocycle gave lower selectivity than the correspond-
ing 3-substituted heterocycles, and a lower reaction tem-
perature was therefore required (compare, for example,
entries 9 and 10). In the reactions with the latter, several
alkyl substituents were tolerated, such as primary, second-
ary, and tertiary groups (entries 13, 14, and 15, respectively).
Interestingly, the conjugated nitrodiene derived from cinna-
maldehyde gave a reaction exclusively at the double bond
proximal to the nitro group (entry 16). Although the yield
was only moderate, the enantioselectivity remained high.
Having demonstratedthatarangeof nitrocyclopentanes
could be easily synthesized, we were pleased to discover
that the products could be readily functionalized. For
example, reduction to cyclopentylamine 23 was accom-
plished with zinc in acidic methanol (Scheme 3). Convert-
ing this amine to either the (R)- or (S)-mandelamide
allowed for the determination of absolute configuration
by 1H NMR analysis.14 Alternatively, X-ray crystal ana-
lysis of the (R)-mandelamide (Figure 2) provided for an
unambiguous assignment of absolute stereochemistry, and
all other cycloadducts are proposed by analogy.
Figure 2. X-ray based ORTEP drawing of mandelamide 24.
Spheres are drawn at the 50% probability level.
the product ketone would contain an R-stereocenter that
could easily epimerize.15 Despite a wide variety of known
conditions for accomplishing the Nef reaction,7 most
synthetic protocols gave either no reaction or complete
decomposition of the nitrocyclopentane. An encouraging
lead was identified using the conditions of Palomo,16
involving formation of the trimethylsilyl nitronate fol-
lowed by oxidation with m-chloroperoxybenzoic acid. In
contrasttoPalomo’sreport, however, werecovered notthe
ketone but gem-chloro-nitrocyclopentane 27 in reasonable
yield as a single diastereomer. This unusual result has been
observed previously,17 and the structure of 27 has been
unambiguously assigned by X-ray crystal analysis (Figure
3). The propensity for the peroxy acid to react not with the
silyl nitronate, but with the chloride counterion demon-
strated a need for a more reactive nitronate species. The
high reactivity of potassium nitronates18 prompted us to
test the conditions of Zhao, using potassium tert-butoxide
to generate the nitronate anion followed by oxidation with
dimethyldioxirane.19 Gratifyingly, use of these conditions
gave cyclopentenone 28 in 86% yield with only minimal
racemization. This impressive result is further highlighted
The nitro group also serves as a handle for further
alkylation (Scheme 4). Both palladium-catalyzed prenyla-
tion and Michael addition, giving nitrocyclopentanes 25
and 26, respectively, proceeded with excellent diastereos-
electivity and good yield and provide access to cyclopen-
tanes with a tetrasubstituted stereocenter.
(15) Bures, J.; Isart, C.; Vilarrasa, J. Org. Lett. 2009, 11, 4414.
(16) Aizpurua, J. M.; Oiarbide, M.; Palomo, C. Tetrahedron Lett.
1987, 28, 5361.
Converting the nitro group into a carbonyl (the Nef
reaction) proved to be more challenging, in part because
(17) Zschiesche, R.; Hafner, T.; Reissig, H.-U. Liebigs Ann. Chem.
1988, 1169.
(13) Teichert, J. F.; Feringa, B. L. Synthesis 2010, 7, 1200.
(14) Trost, B. M.; Bunt, R. C.; Pulley, S. R. J. Org. Chem. 1994, 59,
4202.
(18) Hwu, J. R.; Josephraja, T.; Tsay, S.-C. Synthesis 2006, 19, 3305.
(19) Adam, W.; Makosza, M.; Saha-Moller, C. R.; Zhao, G.-G.
Synlett 1998, 1335.
236
Org. Lett., Vol. 14, No. 1, 2012

Scheme 4. Synthetic Utility of Nitrocyclopentanes
Figure 3. X-ray based ORTEP drawing of gem-chloronitrocy-
clopentane 27. Spheres are drawn at the 50% probability level.
Acknowledgment. We thank the NSF and the NIH
(GM 033049) for their generous support of our programs.
Additional financial support was provided by the W.S.
Johnson Graduate Fellowship (D.A.B.) and the Bing
Summer Fellowship (P.S.S.). We thank Dr. Victor G.
Young, Jr. and the X-ray Crystallographic Laboratory
(University of Minnesota), and Dr. Allen Oliver (Notre
Dame) for XRD analysis. Palladium salts were a generous
gift from Johnson Matthey.
by the rate at which the exocyclic methylene isomerizes; no
trace of the product bearing the nonisomerized product is
detected, yet the cyclopentenone is isolated with high ee.
To conclude, we have demonstrated a highly enantiose-
lective palladium-catalyzed cycloaddition of TMM with
nitroalkenes. The reaction tolerates a wide variety of
nitroalkenes and gives products as single diastereomers
in high yield and ee. The functionalization of these cy-
cloadducts proceeds with excellent diastereoselectivity and
minimal racemization where applicable, allowing for rapid
access to several important synthetic intermediates such as
cyclopentylamines, cyclopentenones, and cyclopentanes
bearing tetrasubstituted stereocenters.
Supporting Information Available. Experimental de-
tails and spectral data for all unknown compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
Org. Lett., Vol. 14, No. 1, 2012
237