Diastereoselective synthesis of β-substituted-α,γ- diaminobutyric acids and pyrrolidines containing multichiral centers

Article abstract of DOI:10.1021/jo8023076

A convenient and efficient way for the highly diastereoselective synthesis of β-substituted-α,γ-diaminobutyric acids and pyrrolidines containing multichiral centers has been well-developed. Michael addition of chiral tricyclic iminolactones 1 and 2 to nit

Full text of DOI:10.1021/jo8023076

Diastereoselective Synthesis of ꢀ-Substituted-r,γ-Diaminobutyric
Acids and Pyrrolidines Containing Multichiral Centers
Yan Huang,†,‡ Qiong Li,† Tian-Liang Liu,† and Peng-Fei Xu*,†
State Key Laboratory of Applied Organic Chemistry, College of Chemistry and Chemical Engineering,
Lanzhou UniVersity, Lanzhou 730000, Gansu, People’s Republic of China, and College of Chemistry and
Chemical Engineering, Xinjiang UniVersity, Urumqi 830046, Xinjiang, People’s Republic of China
xupf@lzu.edu.cn
ReceiVed October 14, 2008
A convenient and efficient way for the highly diastereoselective synthesis of ꢀ-substituted-R,γ-
diaminobutyric acids and pyrrolidines containing multichiral centers has been well-developed. Michael
addition of chiral tricyclic iminolactones 1 and 2 to nitroalkenes afforded the adducts in good yields (up
to 95%) and excellent diastereoselectivities (up to dr > 99:1) when titanium(IV) isopropoxide was used.
Configuration of the second new stereocenter was decided by the substitution of nitroalkene. Selective
reduction and hydrolysis of the Michael adducts furnished the desired ꢀ-substituted-R,γ-diaminobutyric
acids in good yields and high enantiomeric excesses (>99% ee). Synthesis of pyrrolidines containing
multichiral centers has also been accomplished in good to excellent yields and diastereoselectivities under
mild conditions via Michael-Mannich tandem reactions using Cu(OTf)2 or AgOTf as an activating reagent
for aliphatic nitroalkenes.
Introduction
Lathyrus latifolius by Ressler et al.,4 who demonstrated its acute
neurotoxicity in rats. O’Neal et al.5 discovered that DABA, a
lower homologue of ornithine, induced ammonia toxicity in rats
by inhibiting the liver enzyme ornithine transcarbamylase and
disrupting the urea cycle. DABA appeared to be found in the
chick brain and excreta6 to have antitumor activities in vitro
and in vivo against mouse fibrosarcoma cells.7 3-Amino-2-
pyrrolidones are derivatives of R,γ-diaminobutyric acids and
are of interest as pharmaceutically important peptides.8 Although
R,γ-diaminobutyric acids possess wide biological activities, little
Optically active nonproteinogenic amino acids have received
considerable attention for their nutritional, biological, and
chemical importance.1,2 As a member of this class of com-
pounds, R,γ-diaminobutyric acid (DABA) was first identified
in Polygonatum multiflorum3 and subsequently isolated from
† Lanzhou University.
‡ Xinjiang University.
(1) (a) Clausen, V.; Frydenvang, K.; Koopmann, R.; Jorgensen, L. B.; Abbiw,
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H.; Komiyama, S.; Hasegawa, Y.; Kobayashi, S. J. Am. Chem. Soc. 2000, 122,
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1252 J. Org. Chem. 2009, 74, 1252–1258
10.1021/jo8023076 CCC: $40.75 2009 American Chemical Society
Published on Web 12/29/2008

Synthesis of ꢀ-Substituted-R,γ-Diaminobutyric Acids
attention was paid probably due to the lack of a general method
for their syntheses.
Pyrrolidines are of the important class of five-membered
heterocycles, which not only are common structural subunits
present in natural and unnatural products9 but also are widely
used as chiral auxiliaries in asymmetric organic synthesis.10
Depending on the substitution pattern and functionalization,
pyrrolidines have been reported to possess different important
biological activities. They can act as antibacterials,11 neuroex-
citatory agents,12 glycosidase inhibitors,13 and fungicides.14
However, their construction with predictable regio- and stereo-
control still constitutes a challenge in organic chemistry.
Michael addition of electron-deficient olefins is without
question one of the most classical and fundamental car-
bon-carbon bond formation reactions.15,16 Nitroalkenes have
been attracting continuous attention as electron acceptors
because the nitro group can only lead to 1,4-addition as a result.
This reaction and its similar variants have been extensively used
in organic synthesis.17 Thus, it is not surprising that the
development of enantioselective catalytic protocols for this
reaction has received much attention.16d-k The chiral auxiliary
methods are attractive approaches to stereocontrolling in such
reactions. Important examples involved the stereocontrolled
Michael addition of chiral glycine-derived enolates to electron-
poor olefins.18 Tricyclic iminolactones19a could act as effective
equivalents of chiral amino acids in Michael addition reactions
to nitroalkenes, thus allowing the convenient synthesis of
enantiomerically enriched R,γ-diaminobutyric acids after sub-
sequent manipulation of the nitro group and removal of the
camphor-based protecting group. This process leads to the
generation of up to two new stereogenic centers in the product.
FIGURE 1. Tricyclic iminolactones 1 and 2.
In this study, we focused our attention on the convenient
asymmetric synthesis of the optically active ꢀ-substituted-R,γ-
diaminobutyric acids via Michael addition followed by hydroly-
sis. In addition, high diastereoselectivity was obtained in the
synthesis of pyrrolidines containing multichiral centers via
Michael-Mannich tandem reaction in the presence of Cu(OTf)2
or AgOTf.
Results and Discussion
Recently, we reported the synthesis of two novel chiral
tricyclic iminolactones, (1S,2R,8R)-8,11,11-trimethyl-3-oxa-6-
azatricyclo[6.2.1.02,7]undec-6-en-4-one (1) and (1R,2S,8S)-
1,11,11-trimethyl-3-oxa-6-azatricyclo[6. 2.1.02,7]undec-6-en-4-
one (2), prepared from (1R)-(+)-camphor as glycine equivalents,
which have been successfully applied to the asymmetric
synthesis of R-monosubstituted-R-amino acids, R,R-disubsti-
tuted-R-amino acids, and R,ꢀ-diamino acids.19 Nitroalkenes,20
as electron-deficient alkenes, were easily prepared via Henry
reaction and subsequent dehydration procedure, which could
be ideal acceptors for these two iminolactones 1 and 2 to prepare
R,γ-diaminobutyric acids (Figure 1).
In order to find the experimental conditions most suitable
for Michael addition, chiral tricyclic iminolactone (1) as the
nucleophile and trans-ꢀ-nitrostyrene (a) as the Michael acceptor
were selected at first for our model reactions. Representative
results are listed in Table 1. To maximize diastereoselectivity,
we performed the reaction at -78 °C as we did before.19
Considering the solvent effect,21 different solvents in the
presence of LiCl and LDA were examined initially. The results
showed that THF gave good diastereoselectivity and conversion
rate compared with dichloromethane and toluene (entries 1-3).
The effects of base and additives were also investigated.
Specifically, both n-BuLi and LHMDS in THF afforded poor
diastereoselectivities (dr 62:38 in LHMDS and dr 59:41 in
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J. Org. Chem. Vol. 74, No. 3, 2009 1253

Huang et al.
TABLE 1. Optimization on the Asymmetric Michael Addition of Tricyclic Iminolactone (1) to trans-ꢀ-Nitrostyrene (a)
entry
solvent
additive
base
LDA
LDA
LDA
LHMDS
n-BuLi
LDA
LDA
LDA
conversion (%)a
dra
1
2
3
4
5
6
7
8
9
THF
LiCl (6 equiv)
LiCl (6 equiv)
LiCl (6 equiv)
LiCl (6 equiv)
100
32
50
100
59
92
78
63
100
98:2
45:55
33:67
62:38
59:41
93:7
96:4
74:26
>99:1
CH2Cl2
toluene
THF
THF
THF
THF
THF
THF
LiCl (6 equiv)
LiCl (10 equiv)
ZnCl2 (3 equiv)
MgBr2 (1.2 equiv)
Ti (O-iPr)4 (2.5 equiv)
LDA
a
1
By 400 MHz H NMR of the crude products.
TABLE 2. Michael Addition of Tricyclic Iminolactones 1 and 2 to Aromatic Nitroalkenes
entry
R
adducts
dr (syn/anti)a
yield (%)b
>adducts
dr (syn/anti)a
yield (%)b
1
2
3
4
5
6
7
8
9
Ph
p-Cl-Ph
p-OCH3-Ph
o-Cl-Ph
o-OCH3-Ph
p-N(Me)2-Ph
p-CH3-Ph
o-CH3-Ph
m-Cl-Ph
1a
1b
1c
1d
1e
1f
1g
1h
1i
>99:1
>99:1
98:2
>99:1
98:2
>99:1
>99:1
>99:1
96:4
90
77
88
77
79
72
91
76
74
2a
2b
2c
2d
2e
2f
2g
2h
2i
>99:1
96:4
>99:1
98:2
98:2
97:3
>99:1
>99:1
98:2
90
77
95
82
78
79
82
79
78
a
By 400 MHz H NMR of the crude products. b Yield of the major products after silica gel column chromatography.
1
n-BuLi, entries 4 and 5). As a metal-mediated reaction, we
reasoned that the metal chelation could be used as a way to
control stereoselectivity. Lithium enolate might often serve as
a chelating metal cation in ethereal solvents at relatively low
temperature. In an effort to enhance the stability of the chelate,
we examined other common metal cations such as Zn(II),
Mg(II), and Ti(IV).22 On the basis of the experiments, readily
accessible titanium(IV) isopropoxide [Ti(O-iPr)4] emerged as
an effective additive (entries 6-9). Finally, entry 9 gave the
optimum conditions for this Michael addition.
aromatic nitroalkene acceptors were treated with chiral
tricyclic iminolactones 1 and 2. Observations of the reactions
are summarized in Table 2. Compared with the aromatic
nitroalkenes, the reaction system is relatively complex when
treated with aliphatic substrates in the normal feeding order.
As a result, we change the addition order of the reagents to
improve the effectiveness of the target Michael addition
reaction, satisfactory diastereoselectivity and yield were
obtained as a result according to the optimum conditions used
in entry 9 (Table 1) except feeding order. The results are
listed in Table 3. Compared with the aromatic nitroalkenes,
the reaction system is relatively complex when treated with
aliphatic substrates. So we only changed the feeding order
in order to improve the effectiveness of the target Michael
addition reaction. Satisfactory diastereoselectivity and yield
were obtained when we conducted the reaction with reversed
feeding order (the reaction mixture was added into solution
of nitroalkene). The results are listed in Table 3.
With the optimum conditions in hand, the scope of the
reaction was investigated and a range of readily prepared
(21) (a) Enders, D.; Seki, A. Synlett 2002, 26–28. (b) Alexakis, A.; Andrey,
O. Org. Lett. 2002, 4, 3611–3614. (c) Betancort, J. M.; Sakthivel, K.;
Thayumanavan, R.; Tanaka, F.; Barbas, C. F., III Synthesis 2004, 1509–1521.
(d) Mase, N.; Thayumanavan, R.; Tanaka, F.; Barbas, C. F., III Org. Lett. 2004,
6, 2527–2530. (e) Andrey, O.; A Alexakis; Tomassini, A.; Bernardinelli, G. AdV.
Synth. Catal. 2004, 346, 1147–1168. (f) Kotrusz, P.; Toma, S.; Schmalz, H.-G.;
Adler, A. Eur. J. Org. Chem. 2004, 1577–1583. (g) Zu, L.; Li, H.; Wang, J.;
Yu, X.; Wang, W. Tetrahedron Lett. 2006, 47, 5131–5134. (h) Zu, L.; Wang,
J.; Li, H.; Wang, W. Org. Lett. 2006, 8, 3077–3079. (i) Mase, N.; Watanabe,
K.; Yoda, H.; Takabe, K.; Tanaka, F.; Barbas, C. F., III J. Am. Chem. Soc.
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Angew. Chem. 2006, 118, 6130-6133; Angew. Chem., Int. Ed. 2006, 45,
59845987. For a recent review on asymmetric Michael additions to nitroalkenes,
see: (k) Berner, O. M.; Tedeschi, L.; Enders, D. Eur. J. Org. Chem. 2002, 1877–
1894.
The configurations of the major Michael adducts, such as
compounds 1a, 2a, 2g, 2h, and 2i, which were obtained from
aromatic substituted nitroalkenes, were unambiguously con-
firmed by X-ray crystallographic determination and obtained
by recrystallization from a mixture of ethyl acetate and hexane
(22) Busch, K.; Groth, U. M.; Ku¨hnle, W.; Scho¨llkopf, U. Tetrahedron 1992,
48, 5607–5618.
1254 J. Org. Chem. Vol. 74, No. 3, 2009

Synthesis of ꢀ-Substituted-R,γ-Diaminobutyric Acids
TABLE 3. Michael Addition of Tricyclic Iminolactones 1 and 2 to Aliphatic Nitroalkenes
dr (anti/syn)b c
yield (%)b
,
entry
R
adducts
1
2
3
4
5
6
7
(CH2)5
1m
1k
2j
2k
2l
2m
2n
>99:1
94:6
95:5
93
76
83
71
92
92
78
C(CH3)3
CH(CH3)2
C(CH3)3
(S)-2,2-dimethyl-1,3-dioxolane-4-yl
(CH2)5
93:7
>99:1
>99:1
94:6
cyclohexyl
a By 400 MHz 1H NMR of the crude products. b Yield of the major products after silica gel column chromatography. c Reversed addition (see
Experimental Section).
FIGURE 2. X-ray structure of compound 1a.
FIGURE 4. Proposed mechanism of Michael addition of 1 with
aromatic and aliphatic nitroalkenes.
addition of tricyclic iminolactone to (E)-nitroalkene was pro-
posed to involve a chelated eight-membered transition state.
Similar concepts were proposed by Heathcock’s group,24 Ley’s
group,16c and Schollkopf’s group.22
In our studies, the extremely high endo/exo ratio at the C5
position in the tricyclic iminolactone is presumably due to the
steric hindrance of C12-methyl substitution and/or the interaction
FIGURE 3. X-ray structure of compound 2i.
between the lone-pair electron of the imine and the electrophile,
which effectively hinders the orientation from the exo face and
thus favors the attack of the electrophile from the endo face of
the enolate (endo/exo > 99:1).19 Noticeably, syn adducts (R )
aromatic group) and anti adducts (R ) aliphatic group) were
obtained with high diastereoselectivities in our experiments. The
reason for the difference probably can be described as the
proposed mechanisms in Figure 4. There is π-π interaction
between the aromatic group of the acceptor and the π-system
of NdC in the donor, so the syn adducts were favored for
aromatic nitroalkenes. The mechanism can be further supported
by the chemical shift of C2-H in tricyclic iminolactone. The
shielding effect of the aromatic ring makes the C2-H of the
Michael adduct shift to a higher field compared with that in
compounds 1 and 2. However, there is no π-π interaction in
the case of aliphatic nitroalkene, thus the anti adduct was
correspondingly generated in order to reduce the steric interaction.
The ultimate goal of most applications of nitroalkane
chemistry involves further conversion of the nitro unit, most
commonly by reduction to give a primary amine. Reductive
manipulation of the nitro group is necessary to confirm the
effectiveness of this reaction as an asymmetric method for the
(Figures 2 and 3).23 Thus, compound 1 has a (5S,14S)-
configuration, and compound 2 has a (5R,14R)-configuration.
The configuration of aliphatic substituted Michael adducts was
determined by the crystal structure of compound 2′j because
there was no configuration transformation at C14 in the reaction
of compound 2j to compound 2′j. Compared to the R-
configuration at C14 in compound 2′j, we can deduce that the
compound 2j has the S-configuration at C14 according to the
CIP sequence rules (see Scheme 3). Thus, compound 2j has a
(5R,14S)-configuration.
On the basis of these observations, there are strong correla-
tions between the enolate geometries and the adduct stereo-
structures. Predominantly syn adducts were obtained when R
substitution was an aryl group, which is in agreement with the
results of other workers in this field.16b,j On the other hand,
anti adducts were preferentially formed when aliphatic nitroalk-
enes were used. To our satisfaction, good to excellent diaster-
eomeric ratios were obtained. The mechanism for the Michael
(23) The X-ray crystallographic structures of compounds 1a, 2a, 2g, 2h, and
2i have been submitted to the Cambridge Crystallographic Data Centre. The
CCDC numbers for compounds 1a, 2a, 2g, 2h, and 2i are CCDC 678006, CCDC
678011, CCDC 678012, CCDC 678007, and CCDC 678013, respectively.
(24) Oare, D. A.; Heathcock, C. H. J. Org. Chem. 1990, 55, 157–172.
J. Org. Chem. Vol. 74, No. 3, 2009 1255

Huang et al.
SCHEME 1. Reductive Manipulation of Michael Adducts to
3a-3i and 4a-4i
addition (Scheme 3). The structures and the configurations of
compounds were confirmed by X-ray crystallographic determi-
nation.28 The observation from crystal structures of compound
2′j showed that the partially eclipsed conformations were
obtained at C5-C14 and C14-C15 in the pyrrolidine structure
for the interpretation of the rigid structure of the fused rings
(see Supporting Information). As a result, compound 2′R has a
(5R,14R)-configuration and 2′R′ has a (5R,14S)-configuration.
Although pyrrolidines are very useful, a direct approach to
synthesize multichiral pyrrolidine is rather limited. Consquently,
searching for an efficient Michael-Mannich tandem reaction
to carry out the conversion of Michael adducts to multichiral
pyrrolidine is still a very significant work. Up to now,
considerable attention has been mainly focused on [3 + 2]
annulations29 or 1,3-dipolar cycloadditions30 for pyrrolidine
constructions. In order to obtain pyrrolidines from Michael
adducts directly, a series of experiments were carried out by
optimizing the experimental conditions in our laboratory,
including the use of Et3N, K2CO3, Triton B, NaH, DBU, and
t-BuLi as base under different conditions. Unfortunately,
pyrrolidines could not be synthesized successfully in the above-
mentioned conditions.
SCHEME 2. Manipulation of Michael Adducts to
γ-Lactams 7 and 8a
We finally considered that the nonactivated imine group in
tricyclic iminolactone might be the problem. Investigation results
of recent literature relevant to catalytic nitro-Mannich reactions
revealed that the use of chiral catalysts31 or Lewis acid activated
method32 might be very helpful for this asymmetric Mannich-
type reaction. Gratifyingly, the use of Cu(OTf)2 or AgOTf as
the activating reagent for an imine provided the expected
Michael-Mannich tandem reaction product with almost quan-
titative yield and high diastereoselectivity (Scheme 4).
a Reaction conditions: (a) NiCl2 ·6H2O/NaBH4, THF/MeOH, 0 °C to rt;
(b) TMSOTf, i-Pr2EtN, CH2Cl2, 0 °C; (c) 2 N HCl/THF, 50-60°C.
synthesis of R,γ-diaminobutyric acids while not affecting on
the imine group in tricyclic iminolactone. The majority of such
reductive procedures involves a transition metal catalyst, usually
palladium, and a source of hydrogen, usually hydrogen gas.25,26
Unfortunately, these reductions usually proceed slowly, thereby
resulting in loss of stereochemical integrity and degradation of
the substrate. It was eventually found that the most reliable way
to reduce the nitro group with little effect on the imine was
one-pot nickel borohydride reduction by carefully controlling
the reaction temperature followed by the addition of di-tert-
butyldicarbonate (Boc2O) to the reaction system (Scheme 1).27
Before Boc2O was added to the reduction system, we
monitored the γ-lactam 6 in addition to the amino compound 5
when the reaction mixture was allowed to warm to room
temperature. The equilibrium could not be destroyed until
TMSOTf was added as a protecting reagent. The compound 7
was obtained in almost quantitative yield (Scheme 2).
Conclusion
In summary, an efficient way for the synthesis of enantioen-
riched ꢀ-substituted-R,γ-diaminobutyric acids and their deriva-
tives has been well-developed via Michael addition of chiral
tricyclic iminolactones 1 and 2 as glycine equivalents to
(28) The X-ray crystallographic structures of compounds 2′j and 2′j′ have
been submitted to the Cambridge Crystallographic Data Centre. The CCDC
numbers for compounds 2′j and 2′j′ are CCDC 678009 and CCDC 709779,
respectively.
(29) (a) Pandey, G.; Banerjee, P.; Gadre, S. R. Chem. ReV. 2006, 106, 4484–
4517. (b) Restorp, P.; Fischer, A.; Somfai, P. J. Am. Chem. Soc. 2006, 128,
12646–12647. (c) Romero, A.; Woerpel, K. A. Org. Lett. 2006, 8, 2127–2130.
(30) Selected examples for construction of pyrrolidines via 1,3-dipolar
cycloadditions: (a) Waldmann, H.; Blaeser, E.; Jansen, M.; Letschert, H. P.
Angew. Chem. 1994, 106, 717-719; Angew. Chem., Int. Ed. 1994, 33, 683-
685. (b) Trost, B. M.; Marrs, C. M. J. Am. Chem. Soc. 1993, 115, 6636–6645.
(c) Li, G.-Y.; Chen, J.; Yu, W.-Y.; Hong, W.; Che, C. -M. Org. Lett. 2003, 5,
2153–2156. (d) Morita, Y.; Tokuyama, H.; Fukuyama, T. Org. Lett. 2005, 7,
4337–4340. (e) Hata, H.; Kamimura, Y.; Shinokubo, H.; Osuka, A. Org. Lett.
2006, 8, 1169–1172. (f) Garner, P.; Kaniskan, H. U.; Hu, J.; Youngs, W. J.;
Panzner, M. Org. Lett. 2006, 8, 3647–3650.
(31) For reviews, see: (a) Kobayashi, S.; Ishitani, H. Chem. ReV. 1999, 99,
1069–1094. (b) Kleinman, E. F. In ComprehensiVe Organic Synthesis; Trost,
B. M., Fleming, I., Eds.; Pergamon Press: Oxford, 1991;,Vol. 2, pp 893-951.
(c) Arend, M.; Westermann, B.; Risch, N. Angew. Chem. 1998, 110, 1096-
1122; Angew. Chem., Int. Ed. 1998, 37, 1044-1070. (d) Arend, M. Angew. Chem.
1999, 111, 3047-3049; Angew. Chem. Int. Ed. 1999, 38, 2873-2874. (e)
Akiyama, T.; Itoh, J.; Yokota, K.; Fuchibe, K. Angew. Chem. 2004, 116, 1592-
1594; Angew. Chem., Int. Ed. 2004, 43, 1566-1568. (f) Yoon, T. P.; Jacobsen,
E. N. Angew. Chem. 2005, 117, 470-472; Angew. Chem., Int. Ed. 2005, 44,
466-468. (g) Bode, C. M.; Ting, A.; Schaus, S. E. Tetrahedron 2006, 62, 11499–
11505.
Removal of the chiral auxiliary was achieved by hydrolysis
of 3 and 4 in 4 N HCl solution at 50 °C for 2 h, which afforded
the corresponding ꢀ-substituted-R,γ-diaminobutyric acids 9a,
9c, 9g, 10a, 10c, and 10g in good yields and excellent
enantiomeric excesses (Table 4). The corresponding γ-lactam
8a was also given after similar hydrolysis (Scheme 2).
Noticeably, pyrrolidine structures were detected simulta-
neously when aliphatic nitroalkenes were used in Michael
(25) (a) Hudlicky´, M. Reductions in Organic Chemistry, 2nd ed.; ACS
Monograph, 1996. (b) Scriven, E. F. V. Chem. ReV. 1988, 88, 297–368.
(26) Recent review: (a) Pae, A. N.; Cho, Y. S. Curr. Org. Chem. 2002, 6,
715–737. (b) Yadav, J. S.; Reddy, B. V. S.; Reddy, M. M. Tetrahedron Lett.
2000, 41, 2663–2665. (c) Ranu, B. C.; Dutta, J.; Guchhait, S. K. J. Org. Chem.
2001, 66, 5624–5626. (d) Ranu, B. C.; Samanta, S.; Guchhait, S. K. J. Org.
Chem. 2001, 66, 4102–4103. (e) Ranu, B. C.; Dutta, P.; Sarkar, A. J. Chem.
Soc., Perkin Trans. 1 1999, 1139–1140. (f) Park, L.; Keum, G.; Kang, S. B.;
Kim, K. S.; Kim, Y. J. Chem. Soc., Perkin Trans. 1 2000, 4462–4463. (g) Shin,
J. A.; Choi, K. I.; Pae, A. N.; Koh, H. Y.; Kang, H.-Y.; Cho, Y. S. J. Chem.
Soc., Perkin Trans. 1 2001, 946–948.
(32) (a) Asao, N.; Yudha, S. S.; Nogami, T.; Yamamoto, Y. Angew. Chem.
2005, 117, 5662-5664; Angew. Chem., Int. Ed. 2005, 44, 5526-5528. (b)
Anderson, J. C.; Blake, A. J.; Howell, G. P.; Wilson, C. J. Org. Chem. 2005,
70, 549–555. (c) Qian, C.; Gao, F.; Chen, R. Tetrahedron Lett. 2001, 42, 4673–
4675.
(27) (a) Ganem, B.; Osby, J. O. Chem. ReV. 1986, 86, 763–780. (b) Adderley,
N. J.; Buchanan, D. J.; Dixon, D. J.; Laine´, D. I. Angew. Chem. 2003, 115,
4373-4376; Angew. Chem., Int. Ed. 2003, 42, 4241-4244.
1256 J. Org. Chem. Vol. 74, No. 3, 2009

Synthesis of ꢀ-Substituted-R,γ-Diaminobutyric Acids
SCHEME 3. Pyrrolidines Detected in the Aliphalic Nitroalkene-Mediated Michael Addition
TABLE 4. Hydrolysis of the Derivatives of Michael Adducts to
g, 1.0 mmol) in dry THF (10.0 mL) was added dropwise over a
period of 10 min to the above freshly prepared LDA solution via
a syringe at -30 °C. A solution of Ti(O-iPr)4 (0.370 mL, 2.5 mmol,
2.5 equiv) in dry THF (2.0 mL) was added after the reaction mixture
was cooled to -78 °C. A solution of nitroalkenes (1.05 mmol, 1.05
equiv) in dry THF (10.0 mL) was then added via a syringe over 10
min. The well-stirred reaction was kept at -78 °C for 2 h. The
reaction was quenched at -78 °C by the addition of saturated
NH4Cl (2.0 mL). The reaction mixture was then allowed to warm
to room temperature and filtered. The filtrate was extracted with
EtOAc (3 × 15.0 mL), and the combined extracts were washed
with water (3 × 3.0 mL) and brine (3 × 3.0 mL), dried over
anhydrous MgSO4, and then concentrated to give the crude product.
The crude product was purified by flash column chromatography
to yield the desired compound.
ꢀ-Substituted-r,γ-Diaminobutyric Acids 9 and 10
entry
substrate
R
product
yield (%)a
ee (%)b
1
2
3
4
5
6
3a
3c
3g
4a
4c
4g
Ph
9a
9c
9g
10a
10c
10g
82
78
68
65
79
67
>99
>99
>99
>99
>99
>99
p-OCH3-Ph
p-CH3-Ph
Ph
p-OCH3-Ph
p-CH3-Ph
(1S,2R,5S,8R)-5-((S)-1-Phenyl-2-nitroethyl)-8,11,11-trimethyl-
3-oxa-6-azatricyclo[6.2.1.02,7]undec-6-en-4-one (1a): Purified by
chromatography (EtOAc/petroleum ) 1/4), white solid, mp 208-210
°C; [R]20 ) +48 (c ) 0.85, CH2Cl2); FT-IR (KBr) 3380 (br),
D
1728 (s), 1694 (m), 1549 (vs), 1377 (m), 1029 (m) cm-1; 1H NMR
(400 MHz, CDCl3) δ 7.37-7.32 (m, 3H), 7.17-7.14 (m, 2H),
5.18-5.07 (m, 2H), 4.77 (d, J ) 4.0 Hz, 1H), 4.07-4.02 (m, 1H),
2.37(s, 1H), 1.85 (d, J ) 4.8 Hz, 1H), 1.82-1.76 (m, 1H),
1.63-1.56 (m, 1H), 1.33-1.26 (m, 1H), 1.02 (s, 3H), 0.84 (s, 3H),
0.68 (s, 3H), 0.65-0.61 (m, 1H) ppm; 13C NMR (100 MHz, CDCl3)
δ 183.4, 169.4, 134.5, 129.3, 129.0, 128.4, 79.2, 76.4, 63.8, 52.9,
48.3, 47.2, 45.3, 28.8, 25.8, 19.9, 19.4, 10.1 ppm; MS m/z 356
(M+, 1.9), 341 (1.3), 328 (2.5), 312 (1.3), 297 (2.2), 284 (2.1), 266
(2.1), 252 (1.5), 238 (2.3), 206 (13.6), 178 (100.0), 162 (12.0), 150
(23.6), 110 (37.4), 104 (66.5), 91 (52.0), 77 (45.5), 69 (79.0), 55
(29.1), 41 (76.6); HRMS (ESI) calcd for C20H25N2O4 [M + H]+
357.1809, found 357.1805.
a Isolated yield. b Enantiomeric excess (%) values are determined by
HPLC analysis utilizing a CR(+) column.
SCHEME 4. Cu(OTf)2 as Lewis Acid in the Synthesis of
Pyrrolidines
General Procedure for the Michael Addition of Tricyclic
Iminolactones to Aliphatic Nitroalkenes (1m and 2j-2n): Metal
chelate’s formation was the same as the above procedure, and it
was then slowly transferred to a solution of nitroalkene in dry THF
in a long-necked flask under stirring at -78 °C with a double-
sided needle. The well-stirred reaction was kept at -78 °C for 2 h
and then worked up as above. The crude product was purified by
flash column chromatography to yield the desired compound.
2j (5R,14S): Purified by chromatography (EtOAc/petroleum )
1:10-1:6), white solid, mp 144-146 °C, [R]20D ) -148 (c ) 0.49,
CH2Cl2); 1H NMR (400 MHz, CDCl3) δ 4.83 (d, J ) 7.6 Hz, 1H),
4.73 (s, 1H), 3.58 (s, 1H), 2.61 (br, 1H), 2.59 (s, 1H), 2.04 (d, J )
4.0 Hz, 1H), 1.68-1.60 (m, 1H), 1.57-1.50 (m, 1H), 1.40-1.34
(m, 1H), 1.17 (s, 3H), 1.02 (s, 3H), 1.00-0.97 (m, 1H), 0.95 (s,
9H), 0.88 (s, 3H) ppm; 13C NMR (100 MHz, CDCl3) δ 172.1, 89.1,
83.1, 72.6, 57.5, 56.9, 52.1, 50.5, 50.1, 33.4, 33.3, 26.4, 22.9, 21.5,
20.4, 10.6 ppm; HRMS (ESI) calcd for C17H27N2O4 [M + H]+
323.1965, found 323.1969.
nitroalkenes with subsequent hydrolysis of Michael adducts.
Addition of titanium(IV) isopropoxide, instead of lithium
chloride, yielded better selectivity. Moreover, it was noticed
that the configurations of the products depended on the
substitutions of nitroalkenes. On the basis of the above reaction,
pyrrolidines containing multichiral centers via Michael-Mannich
tandem reaction have also been accomplished using Cu(OTf)2
or AgOTf as the activating reagent. Good to excellent yields
and diastereoselectivities were obtained under mild conditions.
Studies on Lewis acid catalytic Michael-Mannich tandem
reactions to construct the pyrrolidines by applying other imines
are in progress.
Experimental Section
General Procedure for the Michael Addition of Tricyclic
Iminolactones to Aromatic Nitroalkenes (1a-1i and 2a-2i):
Diisopropylamine (0.156 mL, 1.1 mmol, 1.1 equiv) was added to
a solution of dry THF (1.0 mL) and n-BuLi (1.6 M, 0.688 mL, 1.1
mmol, 1.1 equiv) at -30 °C, and the mixture was stirred for 30
min under an argon atmosphere. A solution of iminolactone (0.207
General Procedure for the Michael-Mannich Tandem Reac-
tion to Generate Pyrrolidines (1′m and 2′j-2′n): The crude
Michael adduct was dissolved in THF (5.0 mL) and cooled to -20
°C. Cu(OTf)2 (10% mmol) was added with efficient stirring under
J. Org. Chem. Vol. 74, No. 3, 2009 1257

Huang et al.
argon flow protection to result in a green solution. Then Et3N (1.0
equiv) was added after 30 min, and the reaction mixture was stirred
at -20 °C for 2 h before allowing it to warm to room temperature.
The catalyst was removed by filtration, and the crude product after
concentration was purified by flash column chromatography
(petroleum/ethyl acetate ) 30:1-12:1) to get the desired compound.
2′j (5R,7S,14R,15S): Purified by chromatography (EtOAc/
1.58-1.46 (m, 1H), 1.39 (s, 9H), 1.29-1.23 (m, 1H), 0.99 (s, 3H),
0.81 (s, 3H), 0.66 (s, 3H), 0.59-0.54 (m, 1H) ppm; 13C NMR (100
MHz, CDCl3) δ 182.2, 170.1, 155.7, 137.6, 128.8, 127.9, 79.3, 79.0,
63.8, 52.6, 48.1, 47.7, 47.3, 42.0, 29.0, 28.3, 25.8, 19.9, 19.3, 10.1
ppm; HRMS (ESI) calcd for C25H35N2O4 [M + H]+ 427.2591, found
427.2594.
General Procedure for Preparation of 9 and 10: Compound
3 or 4 (0.14 mmol) was dissolved in 4 N HCl (1.0 mL) in a sealed
tube with a Teflon screw cap and heated at 50 °C for 2 h. After the
mixture was cooled to room temperature, water (1.0 mL) was added,
and the mixture was extracted with diethyl ether. The aqueous layer
was evaporated under reduced pressure, and the residue was
dissolved in EtOH (1.0 mL). Propylene oxide (0.5 mL) was then
added, and the mixture was stirred at room temperature for 30 min
during which time the white solid started to precipitate. The
precipitate was collected by filtration and washed successively with
cold EtOH and Et2O to afford the desired amino acid.
petroleum ) 1:30-1:12), white solid, mp 211-213 °C, [R]20
)
D
-85.0 (c ) 1.14, CH2Cl2); 1H NMR (400 MHz, CDCl3) δ 5.05 (d,
J ) 8.8 Hz, 1H), 3.81 (m, 1H), 3.59 (d, J ) 5.2 Hz, 1H), 3.38 (s,
1H), 2.22-2.16 (m, 1H), 1.91-1.85 (m, 1H), 1.82 (d, J ) 4.0 Hz,
1H), 1.77-1.68 (m, 1H), 1.63-1.57 (m, 1H), 1.54 (s, 1H), 1.25
(s, 3H), 1.08 (d, J ) 8.4 Hz, 3H), 1.01 (s, 3H), 0.93 (d, J ) 8.4
Hz, 3H), 0.89 (s, 3H) ppm; 13C NMR (100 MHz, CDCl3) δ 170.0,
93.5, 89.3, 61.7, 56.1, 50.7, 49.7, 49.1, 34.3, 28.6, 22.9, 22.4, 22.2,
21.9, 21.6, 10.6 ppm; HRMS (ESI) calcd for C17H27N2O4 [M +
H]+ 323.1965, found 323.1968.
General Procedure for the Selective Reduction of Michael
Adducts (3a-3i and 4a-4i): The nitro compound (1a-1i or
2a-2i, 0.1 mmol) was dissolved in THF (1.5 mL) and MeOH (0.7
mL) at ambient temperature, and NiCl2 ·6H2O (48 mg, 0.2 mmol,
2 equiv) was added under argon flow. After the mixture was stirred
for 20 min, it was cooled to 0 °C. Then NaBH4 (24 mg, 0.6 mmol,
6 equiv) was added in small portions to result in a black solution,
and the mixture was stirred at 0 °C for 3 h before the addition of
Boc2O (66 mg, 0.3 mmol, 3 equiv). The solution was allowed to
warm to room temperature and stirred for 16 h. The mixture was
filtered through a short silica gel column eluting with EtOAc to
remove the black precipitate. The eluent was concentrated, and the
residue was purified by flash column chromatography to give the
desired compound.
(1S,2R,5S,8R)-5-((S)-N-tert-Butoxycarboxyl-1-phenyl-2-ami-
noethyl)-8,11,11-trimethyl-3-oxa-6-aza-tricyclo[6.2.1.02,7]undec-
6-en-4-one (3a): Purified by chromatography (EtOAc/petroleum
) 1:4-1:3), colorless oil, [R]20D ) +21.0 (c ) 1.31, CH2Cl2); 1H
NMR (400 MHz, CDCl3) δ 7.28 (m, 3H), 7.09 (m, 2H), 5.05 (br
s, 1H), 4.84 (d, J ) 3.6 Hz, 1H), 3.81-3.71 (m, 2H), 3.41 (m,
1H), 2.29 (s, 1H), 1.81 (d, J ) 3.6 Hz, 1H), 1.79-1.70 (m, 1H),
(2S,3S)-2,4-Diamino-3-phenylbutanoic Acid (9a): White solid,
mp 232 °C (dec.); [R]20D ) -11.0 (c ) 0.25, H2O); 1H NMR (400
MHz, D2O) δ 7.18 (m, 3H), 7.05 (m, 2H), 3.70 (d, J ) 4.8 Hz,
1H), 3.49 (dd, J ) 8.4 Hz, J ) 12.8 Hz, 1H), 3.29 (dd, J ) 4.4,
12.8 Hz, 1H), 3.21 (m, 1H) ppm; HRMS (ESI) calcd for C10H15N2O2
[M + H]+ 195.1128, found 195.1128. Ee >99%, determined by
HPLC.
Acknowledgment. We are grateful for the financial support
of the National Natural Science Foundation of China (NSFC,
20772051, 20572039), the Program for NCET-05-0880, and the
Doctoral Funds from the Chinese Ministry of Education of the
People’s Republic of China.
Supporting Information Available: X-ray structure of 1a,
2a, 2g, 2h, 2i, and 2′j (major) (CIF), synthesis, characterization,
copies of 1H and 13C NMR spectra for all new compounds, and
HPLC results. This material is available free of charge via the
Internet at http://pubs.acs.org.
JO8023076
1258 J. Org. Chem. Vol. 74, No. 3, 2009