Optimization of the catalytic asymmetric addition of nitroalkanes to cyclic enones with trans-4,5-methano-L-proline

Article abstract of DOI:10.1021/ol0618407

(Chemical Equation Presented) The conjugate addition of symmetrical 2-nitroalkanes to 2-cycloalkenones catalyzed by trans-4,5-methano-L-proline proceeds with >99% ee and excellent chemical yields. 1-Nitroalkanes afford diastereomeric syn/anti products tha

Full text of DOI:10.1021/ol0618407

ORGANIC
LETTERS
2006
Vol. 8, No. 21
4787-4790
Optimization of the Catalytic
Asymmetric Addition of Nitroalkanes to
Cyclic Enones with
trans-4,5-Methano- -proline
L
Stephen Hanessian,* Zhihui Shao, and Jayakumar S. Warrier
Department of Chemistry, UniVersite´ de Montre´al, P.O. Box 6128, Station Centre-Ville,
Montre´al, QC H3C 3J7, Canada
stephen.hanessian@umontreal.ca
Received July 25, 2006
ABSTRACT
The conjugate addition of symmetrical 2-nitroalkanes to 2-cycloalkenones catalyzed by trans-4,5-methano-
L
-proline proceeds with >99% ee
and excellent chemical yields. 1-Nitroalkanes afford diastereomeric syn/anti products that can be separated with good individual
enantioselectivities. Proline hydroxamic acid and its trans-4,5-methano - -proline hydroxamic acid are also effective organocatalysts in the
addition of 2-nitropropane to 2-cyclohexenone (75% and 81% ee, respectively).
L
The base-catalyzed addition of nitroalkanes to cyclic enones
is a fundamentally important preparative route to â-substi-
tuted cycloalkanones.1 Formally grouped under Michael
addition reactions, the resulting nitroalkyl appendages in
these compounds can be chemically transformed into a
variety of functionally useful compounds, which can also
benefit from the rich chemistry of the resident carbonyl
group.2
cycloheptanone were obtained in 59% and 79% ee, respec-
tively. Enantioselectivities were substantially lower with
nitromethane and 2-cyclohexenone (45% ee).
Subsequent studies in our laboratory revealed that the use
of 3-7 mol % equiv of L-proline (1) in the presence of
achiral trans-2,5-dimethylpiperazine as an additive led to the
3R-nitroalkyl cyclohexanone adduct in 93% ee with 2-ni-
tropropane, 1-nitrocyclopentane, and 1-nitrocyclohexane as
nucleophiles.4 Contrary to the case of Rb prolinate, this
reaction exhibited a very unusual nonlinear effect,5 especially
with trans-2,5-dimethylpiperazine as the additive,4,6 Since
then, the catalytic asymmetric Michael addition of 2-nitro-
propane to 2-cyclohexenone has been reported in the
The first example of a preparatively useful metal-free
catalytic asymmetric addition of 2-nitropropane to 2-cyclo-
hexenone was achieved in the presence of rubidium L-
prolinate by Yamaguchi and co-workers in 1994.3 Thus, 3-(2-
nitropropan-2-yl)cyclohexanone and the corresponding
(3) (a) Yamaguchi, M.; Igarashi, Y.; Reddy, R. S.; Shiraishi, T.; Hirama,
M. Tetrahedron 1997, 53, 11223. (b) Yamaguchi, M.; Shiraishi, T.; Igarashi,
Y.; Hirama, M. Tetrahedron Lett. 1994, 35, 8233
(4) Hanessian, S.; Pham, V. Org. Lett. 2000, 2, 2975.
(5) For a review, see: Girard, C.; Kagan, H. Angew. Chem., Int. Ed.
Engl. 1998, 37, 2923
(6) For a review on additives and cocatalysts in asymmetric reactions,
see: Vogel, E. M.; Gro¨ger, H.; Shibasaki, M. Angew. Chem., Int. Ed. Engl.
1999, 38, 1570.
(1) For pertinent reviews and monographs, see: (a) Ballini, R.; Bosica,
G.; Fiorini, D.; Palmieri, A.; Petrini, M. Chem. ReV. 2005, 105, 933. (b)
Leonard J. Contemp. Org. Synth. 1994, 1, 387. (c) Perlmutter, P. Conjugate
Additions Reactions in Organic Synthesis; Pergamon: Oxford, UK, 1992.
(2) For reviews, see: (a) Ono, N. The Nitro Group in Organic Synthesis;
Wiley-VCH: New York, 2001; Chapter 3, p 30. (b) Luzzio, F. A.
Tetrahedron 2001, 57, 915. (c) Ballini, R.; Petrini, M. Tetrahedron 2004,
60, 1017.
10.1021/ol0618407 CCC: $33.50
© 2006 American Chemical Society
Published on Web 09/19/2006

presence of a peptide catalyst and trans-2,5-dimethylpipera-
zine as additive (80% yield, 77% ee).7 Using an optimized
N-spiro C2-symmetrical chiral quaternary ammonium bro-
mide catalyst, Maruoka and co-workers8 reported the con-
jugate addition of various 1-nitroalkanes with good to
excellent syn/anti selectivities and 82-93% ee for the syn-
isomers depending on the enone and the nature of the
nucleophile. The anti-diastereomers, usually obtained as
minor components, exhibited poor to modest enantioselec-
tivities (37-57% ee for 1-nitropropane). The rationale for
the selectivity was attributed to transition-state models
favoring syn-addition of a N-spiro ammonium alkyl nitronate
salt to 2-cyclohexenone.9
In a recent paper we showed that the high stereodiffer-
entiation in the catalytic asymmetric addition of 2-nitropro-
pane to 2-cyclohexenone in the presence of 5-10 mol %
L-proline was not subject to variations in the chirality of the
added 2,5-dialkylpiperazine.10 We also reported the first use
of L-proline hydroxamic 411 as an effective catalyst to achieve
75% ee of adduct.
Herein we report on the use of trans-4,5-methano-L-proline
212as an optimized, metal-free organocatalyst13 for the
asymmetric conjugate addition of symmetrical and nonsym-
metrical nitroalkanes to 2-cycloalkenones (reaction scheme
in Table 1). The results of reactions catalyzed by L-proline
(1), trans-4,5-methano-L-proline (2), and cis-4,5-methano-
L-proline (3) for 2-nitropropane, 1-nitrocyclopentane, and
1-nitrocyclohexane with 2-cyclopentenone, 2-cyclohexenone,
and 2-cycloheptenone, respectively, reveal a preference for
higher enantioselectivities when using the trans-isomer 2 as
a catalyst in all cases. Thus, with 2-cyclohexenone and
2-cycloheptenone, only the 3R-adduct is formed with 2
(Table 1, entries 2, 22, 25, and 28). Unprecedented enantio-
selectivity is shown in the case of 2-cyclopentenone at 80-
87% ee with 2-nitropropane, 1-nitrocyclopentane, and 1-ni-
trocyclohexane (Table 1, entries 13, 16, and 19, respectively).
It should be noted that none of the previous reports3,7,8 include
2-cyclopentenone as a substrate. Using Yamaguchi’s Rb
prolinate as a catalyst for the addition of 2-nitropropane to
2-cyclopentenone gave the adduct with 12% ee.
Table 1. Catalytic Enantioselective Addition of Nitroalkanes to
Cyclic R,â-Unsaturated Ketones Catalyzed by Proline (1) and
Proline Analogues (2-5)
entry
n
(R)
catalyst time (h) yielda (%) eeb (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
1
CH3
1
2
3
4
5
1
2
3
1
2
3
1
2
3
1
2
3
1
2
3
1
2
3
1
2
3
1
2
3
72
140
146
162
216
72
141
149
78
140
157
71
96
146
72
98
144
71
96
144
80
144
144
76
144
144
84
83
92
52
78
65
79
93
50
83
91
40
72
87
40
74
90
47
59
84
23
60
57
15
65
56
22
49
50
8
89c
99
75
75
81
90
99
76
92
99
74
69
80
66
76
87
73
77
83
76
84
99
60
86
99
59
85
99
61
1
1
0
0
0
2
2
2
(CH2)4
(CH2)5
CH3
(CH2)4
(CH2)5
CH3
(CH2)4
(CH2)5
144
144
With trans-4,5-methano-L-proline hydroxamic acid 5 as
a catalyst, the addition product of 2-nitropropane to 2-cy-
clohexenone showed an ee of 81% compared to 75% with
a Isolated yield. b By 13C NMR analysis of the corresponding ketal with
(2R,3R)-2,3-butanediol (average of three runs). See the Supporting Informa-
tion. c ee values of 89-92% were obtained on average of three runs.
(7) (a) Tsogoeva, S. B.; Jagtap, S. B.; Ardemasove, Z. A.; Kalikhevich,
V. Eur. J. Org. Chem. 2004, 4014. (b) Tsogorva, S. B.; Jagtap, S. B. Synlett
2004, 2624.
(8) Ooi, T.; Takada, S.; Fujioka, S.; Maruoka, K. Org. Lett. 2005, 7,
5143.
(9) For the use of chiral quaternary ammonium salts and related reagents
as catalysts in Michael additions of nitroalkanes to acyclic R,â-enones,
see: (a) Corey; E. J.; Zhang, F.-Y. Org. Lett. 2000, 2, 4257. (b) Kim, D.
Y.; Hu, S. C. Tetrahedron 2001, 57, 8933. (c) Halland, N.; Hazell, R. G.;
Jørgensen, K.-A. J. Org. Chem. 2002, 67, 8331. (d) Itoh, K.; Kanemasa, S.
J. Am. Chem. Soc. 2002, 124, 13394. (e) Nakulya, B.; Varges, B.; Csa´mpai,
A.; Soo´s, T. Org. Lett. 2005, 7, 1967 and references therein.
(10) Hanessian, S.; Govindan, S.; Warrier, J. S. Chirality 2005, 7, 5143.
(11) Pirrung, M. C.; Chan, J. H. L. J. Org. Chem. 1995, 60, 8084.
(12) Hanessian, S.; Reinhold, U.; Gentile, G. Angew. Chem., Int. Ed.
1997, 36, 1881.
L-proline hydroxamic acid 410 (Table 1, entry 5). Extension
of the addition reactions to nitromethane and 2-cyclohex-
enone or 2-cyclopentenone under the same conditions gave
the corresponding 3R-nitromethyl adducts as major isomers
(74% and 61% ee, respectively) (Table 2, entries 2 and 6).
The highest reported ee for 2-cyclohexenone and ni-
tromethane was 58% ee in the presence of a peptide catalyst
and trans-2,5-dimethylpiperazine as an additive.7 In the case
of 1-nitropent-4-ene, the diastereomeric addition products
with catalyst 2 (Table 2, entry 4) were separable by column
chromatography. The less polar compound corresponds to
the anti-(R,R) diastereomer (87% ee) while the more polar
compound corresponds to the syn-(R,S)-isomer (77% ee). A
notable difference in comparison with Maruoka’s results is
(13) For reviews on asymmetric organocatalysis, see: (a) Berkessel, A.;
Gro¨ger, H. In Metal-Free Organic Catalyst in Asymmetric Synthesis; Wiley-
VCH: Weinheim, Germany, 2004. (b) Dalko, P. I.; Moisan, L. Angew.
Chem., Int. Ed. 2004, 43, 5138.
4788
Org. Lett., Vol. 8, No. 21, 2006

Table 2. Diastereoselective Addition of 1-Nitroalkanes to
Cyclic R,â-Unsaturated Ketones Catalyzed by 1 and 2
reaction
entry
n
2 (R)
catalyst time (h) yielda (%) ee (%)
1
2
3
1
1
1
H
H
1
2
1
72
142
86
69
80
77 (2:3)b
71
74
CH2CH(CH2)2
84c
70d
87
4
1
CH2CH(CH2)2
2
144
94 (2:3)b
77d
57
5
6
7
0
0
0
H
H
1
2
1
71
143
82
40
50
84
61
CH2CH(CH2)2
70c
50d
76c
60d
85c
72d
91c
74d
8
9
0
1
1
CH2CH(CH2)2
CH3CH2
2
1
2
144
72
91
80 (1:2)b
89 (1:2)b
Figure 1. Possible catalytic cycle for trans-4,5-methano-L-proline,
2-cyclohexenone, and 2-nitropropane.
10
CH3CH2
144
a Isolated yield. b Diastereomeric ratio. c Less polar isomer (anti-R,R-
isomer). d More polar isomer (syn-R,S-isomer).
left in the case of the cis-isomer 3. No reaction was observed
with L-proline alone, and only trace amounts of racemic
product were seen in the presence of the piperazine without
L-proline as controls.
the relatively high ee of the anti-diastereomer in the addition
to 2-cyclohexenone catalyzed by 2. In the case of 2-cyclo-
pentenone (Table 2, entry 8), the ratios were 76% and 60%
ee for anti- and syn-isomers, respectively. Although enan-
tioselectivies of individual products are still modest, these
are the first examples of additions of unsymmetrical 1-ni-
troalkanes to cyclopentenone. Compared to Maruoka’s results
with 1-nitropropane and 2-cyclohexenone (syn-major, 91%
ee; anti-minor 57% ee), catalysis with 2 gave anti/syn
enantioselectivities of 91% and 74% ee, respectively, and a
1:2 diastereomeric ratio of separable 3-nitropropyl adducts
(Table 2, entry 10). The preponderance of higher enantiose-
lectivity for anti-isomers in all cases is also noteworthy.
A plausible catalytic cycle representing the prototypical
addition of 2-nitropropane to 2-cyclohexenone in the pres-
ence of 2 as a catalyst is shown in Figure 1. Thus, iminium
carboxylate intermediate A undergoes face selective addition
of the piperazinium nitronate anion in an anti-trajectory
relative to the carboxylate group, to give the enamine adduct
B. The cycle continues with the formation of a second
iminium carboxylate C, which leads to the hemiaminal D.
Release of the amino acid into the medium together with
the adduct allows for the catalytic cycle to continue. An
analogous mechanism can be suggested for 1 and 3 resulting
in products having 89-92% ee and 75% ee, respectively.
The reaction time with L-proline is roughly half compared
to that of 2 and 3. There is considerable unreacted material
It is not immediately obvious why catalyst 2 should surpass
1 and its cis-isomer counterpart 3 in its ability to significantly
bias the enantioselectivities of the conjugate addition reac-
tions products. A priori, based on steric arguments, the results
are counterintuitive, since the pro-R face of the 2-cyclohex-
enone should be more accessible to attack by the 2-nitro-
propane anion with its associated bulky base in the case of
the cis-isomer 3. In comparison to L-proline (1) as a catalyst,
there must be an intrinsic bias in favor of 2 that leads to the
exclusive formation of the enantiopure R-adduct with sym-
metrical 1-nitroalkanes and 2-nitrocycloalkanes.
The solid-state crystal structure of 3 reveals a boatlike
conformation with the carboxylate out-of-plane (Figure 2).14
Torsional effects involving the cyclopropane ring in 3 will
favor a boat conformation.15,16 However, a pseudoaxial
carboxyl17 group that is normally favored due to minimization
of A1,3 strain18 (as in Ia compared to Ib, Figure 2) will not
be favored due to a steric interaction with the cyclopropane
ring. The combination of these two effects may account for
(14) See the Supporting Information.
(15) Cheong, P. H.-Y.; Houk, K. N.; Warrier, J. S.; Hanessian, S. AdV.
Catal. 2004, 346, 1111.
(16) (a) Kang, P.; Choo, J.; Jeong, M.; Kwou, Y. J. Med. Struct. 2000,
519, 75. (b) Mastryukov, V. S.; Osina, E. L.; Vilkov, L. V.; Hildebrandt,
R. L. J. Am. Chem. Soc. 1977, 99, 6855. (c) Cook, R. L.; Malloy, T. B., Jr.
J. Am. Chem. Soc. 1974, 96, 1703. (d) Grostic, M. F.; Duchamp, D. J.;
Chidester, C. G. J. Org. Chem. 1971, 36, 2929.
Org. Lett., Vol. 8, No. 21, 2006
4789

addition of symmetrical 2-nitroalkanes to 2-cycloalkenones.
Hitherto unreported additions to 2-cyclopentenone afford
products with enantioselectivities surpassing 80% ee. While
the ratios of the two syn- and anti-isomers in the case of
1-nitroalkanes are low, the products can be easily separated,
and each exhibits good enantioenrichment favoring the anti-
isomer, contrary to when quaternary bases are used.8 These
results are of interest, since efforts to extend such conjugate
additions of nitroalkanes to ring-substituted analogues of
proline have not been successful in the past.3,21
In addition to their recent versatile applications as proline
analogues in prototypical enzyme inhibitors,22-24 4,5-meth-
anoprolines are also useful organocatalysts that can surpass
the venerable proline in conjugate additions of nitroalkanes
to cyclic enones in many cases. Trans-4,5-methano-L-proline
hydroxamic acid 5 is also an effective catalyst albeit with
modest enantioselectivity in a model reaction.
Figure 2. (Top) X-ray structure of 3;. (Bottom) Torsional (Ia)
and A1,3 strain (Ib) effects in iminium ion derived from 3.
Acknowledgment. We thank NSERC for generous
financial assistance.
the sluggish progress of the reaction and the lower enantio-
selectivity in the case of 3. We have previously shown that
in the solid state, N-Boc-4,5-trans-methano-L-proline is
considerably flatter compared to the cis-isomer (rms 0.003
and 0.013 Å, respectively).12,19 It is therefore possible that
formation of the iminium ion A from 2 (Figure 1) requires
less geometrical reorganization compared to 3 (Ia, Figure
2).20
Supporting Information Available: Representative ex-
perimental procedures, 13C NMR spectra, and X-ray data of
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
OL0618407
(20) The iminium ion A may also benefit from a through space interaction
with the electron-rich cyclopropane ring.
(21) For the use of a pyrrolidine 3-carboxylic acid derivative as a catalyst
in Mannich reactions, see: Mitsumori, S.; Zhang, H.; Cheong, P. H. T.;
Houk, K. N.; Tanaka, F.; Barbas, C. F., III J. Am. Chem. Soc. 2006, 128,
1040.
(22) Magnin, D. R.; Robl, J. A.; Sulsky, R. B.; Augeri, D. J.; Huang,
Y.; Simpkins, L. M.; Taunk, P. C.; Betebener, D. A.; Robertson, J. G.;
Abbao-Offei, B. E.; Wang, A.; Cap, M.; Xin, L.; Tao, L.; Sitkoff, D. F.;
Malley, M. F.; Gougoutas, J. Z.; Khanna, A.; Huang, Q.; Han, S.-P.; Parker,
R. A.; Haman, L. G. J. Med. Chem. 2004, 47, 2583.
(23) Hanessian, S.; Reinhold, U.; Saulnier, M.; Claridge, S. Bioorg. Med.
Chem. Lett. 1998, 8, 2123.
In conclusion, we have shown that trans-4,5-methano-L-
proline 2 is an optimal catalyst for the asymmetric conjugate
(17) See for example: (a) Overman, L. E.; LeSuisse, D.; Hashimoto M.
J. Am. Chem. Soc. 1983, 105, 5373. (b) Brown, J. D.; Foley, M.; Comins,
D. L. J. Am. Chem. Soc. 1988, 110, 7445. (c) Beak, P.; Zajdel, W. J. Am.
Chem. Soc. 1984, 106, 1010. (d) Hart, D. J. J. Am. Chem. Soc. 1980, 102,
397. See also: (e) Hanessian, S.; Tremblay, M.; Marzi, M.; Del Valle, J. J.
Org. Chem. 2005, 70, 5070 and references therein.
(18) Hoffmann, R. W. Chem. ReV. 1989, 89, 1841.
(19) The cyclopropane C-C bonds toward its apex extending from C-4
and C-5 are significantly longer in N-Boc 2 compared to N-Boc 3, indicating
a relatively less rigid ring (ref 12).
(24) Reichelt, A.; Martin, S. F. Acc. Chem. Res. 2006, 39, 433.
4790
Org. Lett., Vol. 8, No. 21, 2006