One step synthesis of optically active diazabicyclo-[3.3.0] octanones or diazabicyclo [4.3.0] nonanones by asymmetric conjugate addition of cyclic hydrazine

Article abstract of DOI:10.3987/COM-12-12442

Asymmetric conjugate addition-cyclization of lithium amide of 6-membered hydrazine 4, piperidazine, (or 5-membered hydrazine 6, pyrazolidine) to N-(E)-cinnamoyl-(1S)-2,10-camphorsultam (1S)-3 afforded β-amino acid derivative (S)-1 {or (S)-2} for the synthesis of polyamine alkaloids in good yield with good stereoselectivity (up to 86% ee).

Full text of DOI:10.3987/COM-12-12442

HETEROCYCLES, Vol. 85, No. 5, 2012
1045
HETEROCYCLES, Vol. 85, No. 5, 2012, pp. 1045 - 1052. © 2012 The Japan Institute of Heterocyclic Chemistry
Received, 8th February, 2012, Accepted, 19th March, 2012, Published online, 23rd March, 2012
DOI: 10.3987/COM-12-12442
ONE STEP SYNTHESIS OF OPTICALLY ACTIVE DIAZABICYCLO-
[3.3.0]OCTANONES OR DIAZABICYCLO[4.3.0]NONANONES BY
ASYMMETRIC CONJUGATE ADDITION OF CYCLIC HYDRAZINE
Chigusa Seki,* Masafumi Hirama, Takeshi Sato, Saya Takeda, Yoshihito
Kohari, Kazuhiro Ishigaki, Masafumi Ohuchi, Kiyoshi Yokoi, Hiroto Nakano,
Koji Uwai, Nobuhiro Takano, Kazuyuki Umemura,# and Haruo Matsuyama*
Department of Applied Chemistry, Graduate School of Engineering, Muroran
Institute of Technology, 27-1 Mizumoto, Muroran, Hokkaido 050-8585, Japan
#Course of Life Science, College of Science and Engineering, Iwaki Meisei
University, 5-5-1 Chuodai-Iino, Iwaki, Fukushima 970-8551, Japan
e-mail: hmatsuya@mmm.muroran-it.ac.jp and chigusa@mmm.muroran-it.ac.jp
Abstract
–
Asymmetric conjugate addition-cyclization of lithium amide of
6-membered hydrazine 4, piperidazine, (or 5-membered hydrazine 6, pyrazolidine) to
N-(E)-cinnamoyl-(1S)-2,10-camphorsultam (1S)-3 afforded -amino acid derivative
(S)-1 {or (S)-2} for the synthesis of polyamine alkaloids in good yield with good
stereoselectivity (up to 86% ee).
A number of -amino acids have been isolated in free form and show interesting pharmacological
properties.1 In addition, many classes of natural products contain -amino acid derivatives as
fragments. Macrocyclic lactams containing a biogenetic base such as spermine or spermidine alkaloids,
which have a framework of -amino acid such as -phenyl--alanine, are particularly interested as
synthetic targets in view of their broad biological activity, antibiotics, and antihypertensives.2,3 The
conjugate addition of nitrogen anion such as lithium amide reagents (R2N- Li+) to -unsaturated ester
derivatives is one of the most versatile synthetic methods for the introduction of a new asymmetric
center at the -position of the carbonyl containing motif. Yamamoto et al. have reported nucleophilic
reactions of R2NM, such as conjugate addition to enoates, and asymmetric synthesis of -lactams was
accomplished using amide cuprate reagents as a new class of nitirogen nucleophiles.4 The introduction
of chirality using a chiral auxiliary is a useful way of producing a wide variety of optically active

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HETEROCYCLES, Vol. 85, No. 5, 2012
organic compounds. (1S)-(–)-2,10-camphorsultam and its antipode, accessible from inexpensive (–)-
and (+)-camphorsulfonic acid in two simple operations, were introduced by Oppolzer et al.5 and rank
today among the most practical auxiliaries. Almost all of their N-acyl derivatives are stable and can be
1
(1) readily purified by crystallization, (2) directly analyzed by H NMR to determine their
stereochemical purity, and (3) cleaved (e.g. with LiAlH4, LiOH, etc.) under mild conditions without loss
of the induced chirality and with excellent recovery of the auxiliary. Our continuing interest in the
development of synthetic pathway to the polyamine macrocycles prompted us to investigate the
synthesis of optically active bicyclic lactam, (S)-(–)-9-pheny-1,6-diazabicyclo[4.3.0]nonan-7-one (1)
and (S)-(–)-4-phenyl-1,5-diazabicyclo[3.3.0]octan-2-one (2). Starting from (S)-1, naturally occurring
(S)-celacinnine6 could be synthesized via nine-membered azalactam7 and the synthesis of
(S,S)-homaline8 could be achieved starting from (S)-2 via eight-membered azalactam. We investigated
asymmetric conjugate addition of lithium amide of 6-membered hydrazine 4 (or 5-membered hydrazine
6) to N-(E)-cinnamoyl-(1S)-2,10-camphorsultam (1S)-3 to afford -amino acid derivative (S)-1 {or
(S)-2} in good yield with good stereoselectivity.
O
O
O
O
N
N
H
N
N
Na
H
N
H
N
liq. NH3
Ph
N
H
Ph
Ph
Ph
(S)-9-membered
(S)-1
(S)-celacinnine
azalactam
O
O
Me
Ph
O
N
Ph
Me
NH
N
N
N
Na
N
N
liq. NH3
O
Ph
HN
Ph
(S)-8-membered
(S)-2
(S,S)-homaline
azalactam
Figure 1. Spermidine and spermine alkaloids: (S)-celacinnine and (S,S)-homaline
N-(E)-cinnamoyl-(1S)-2,10-camphorsultam (1S)-3 was obtained in 91% yield by deprotonation of (1S)-
(–)-2,10-camphorsultam (1S)-5 with NaH in anhydrous toluene, followed by addition of (E)-cinnamoyl
chloride and a catalytic amount of copper(I) chloride.9 The conjugate addition of 6-membered
o
hydrazine 4 (5 equiv), piperidazine, to (1S)-3 (1 equiv) proceeded at 0 C in THF (10 mL) as a solvent
to afford cyclization product (S)-9-pheny-1,6-diazabicyclo[4.3.0]nonan-7-one (S)-1 in 80% yield with
44% ee and (1S)-(–)-2,10-camphorsultam (1S)-5 (Table 1, entry 1). The conjugate addition of lithium
o
amide of 4 (3 equiv) to (1S)-3 (1 equiv) proceeded successfully at 0 C in THF to give (S)-1 in 79%
yield with 57% ee and (1S)-5 (entry 2). It is found that increasing the amount of lithium amide of
6-membered hydrazine 4, from 3 equiv to 5 equiv, the chemical yield and stereoselectivity of (S)-1 was
increased up to 84% yield with 66% ee and (1S)-5 (entry 3).

HETEROCYCLES, Vol. 85, No. 5, 2012
1047
Table 1.
-1
4a)
Effect of selectivity of (S) using lithium amide of cyclic hydrazine
O
n-BuLi/ THF
N
N
O
HN
HN
+
0 oC, 24 h
then rt, 24 h
NH
N
Ph
S
S
O2
O2
(1S)-5
Ph
(1S)-3
(S)-1
4
% eeb)
Entry
n-BuLi/ equiv
Yield of (S)-1/%
1
2
3
none
3
80
79
84
44
57
66
5
a)
-3
4
The amount of reactants: (1S) (1.0 mmol), 6-membered hydrazine (5.0 mmol), THF (10 mL).
b) The enantiomeric excess (% ee) of (S)-1 was determined by HPLC analysis using a Chiralpak AD-H;
3.5% 2-propanol/ n-hexane, f low rate 1.0 mL/min, tR= 17 min (major, S), tR= 21 min (minor, R).
Then we have investigated the optimization of the reaction conditions for the conjugate addition of
lithium amide reagent of 6-membered hydrazine 4 (5 equiv) to (1S)-3 (1 equiv) in the several solvents
and the chemical yields of (S)-1 are moderate to good (64-85%) (Table 2, entries 1-5). The
stereoselectivity of (S)-1 is summarized in Table 2 as follows: THF (66% ee), tert-butyl methyl ether
(76% ee), Et2O (86% ee), cyclopentyl methyl ether (CPME) (74% ee) or toluene (75% ee) (Table 2,
o
entries 1-5). The results of Table 2 show that using Et2O as a solvent at 0 C was the better reaction
conditions and (S)-1 was obtained in 83% yield with 86% ee (entry 3).10 The good stereoselectivity of
(S)-1 in Et2O might be dependent on the aggregation state of lithium amide of 4, because solvated
structures of dimeric or higher aggregate lithium amides can be estimated in Et2O.
Similarly, the conjugate addition of lithium amide of 5-membered hydrazine 6 (5 equiv), pyrazolidine,
o
to N-(E)-cinnamoyl-2,10-camphorsultam (1S)-3 (1 equiv) at 0 C also proceeded successfully to give
cyclization product (S)-4-phenyl-1,5-diazabicyclo[3.3.0]octan-2-one (S)-2 and (1S)-(–)-2,10-
camphorsultam (1S)-5 (Scheme 1). The chemical yield and steroselectivity of conjugate addition of
lithium amide reagent of 5-membered hydrazine 6 to (1S)-3 was examined in the several solvents and
the results are shown in Tabel 2. The stereoselectivity of (S)-2 is as follows: THF (70% ee), tert-butyl
methyl ether (76% ee), Et2O (77% ee),11 cyclopentyl methyl ether (CPME) (77% ee) or toluene (75% ee)
o
(Table 2, entries 6-10). The results of Table 2 show that using Et2O (or CPME) as a solvent at 0 C
was the better reaction conditions and (S)-2 was obtained in 90% yield with 77% ee (or 69% yield with
77% ee) (entries 8 and 9).

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HETEROCYCLES, Vol. 85, No. 5, 2012
O
O
n-BuLi (5 equiv)
N
N
N
N
O
NH
NH
NH
or
or
NH
solvent (10 mL)
0 oC, 24 h then rt, 24 h
N
Ph
NH
S
S
Ph
Ph
O2
O2
(1S)-3
4
6
(S)-1
(S)-2
(1S)-5
-
+
-
+
Li
N
N Li
1 equiv
5 equiv
5 equiv
or
NH
NH
Scheme 1. Conjugate addition-cyclization of lithium amide of cyclic hydrazine 4 (or 6)
to N-(E)-cinnamoyl-(1S)-2,10-camphorsultam (1S)-3
Table 2. Synthesis of -amino acid derivatives (S)-1 and (S)-2
a
b)
Entry
solvent (mL)
4 or 6 Product
Yield / % % ee
(S)-1
THF (10)
84
1
66
76
86
74
4
t-BuOMe (10)
(S)-1
2
3
4
64
83
Et O (10)
2
(S)-1
4
c)
(S)-1
4
CPME (5)
85
67
81
67
4
d)
(S)-1
(S)-2
(S)-2
5
6
7
8
4
toluene (5)
75
THF (10)
70
76
6
6
t-BuOMe (10)
Et O (10)
2
(S)-2
6
90
77
77
75
9
6
6
CPME (10)
toluene (10)
(S)-2
(S)-2
69
65
10
a) The amount of reactants: (1S)-3 (1.0 mmol), 6-membered 4 or 5-membered hydrazine 6 (5.0 mmol).
b) The enantiomeric excess (% ee) of (S)-1 was determined by HPLC analysis using a Daicel Chiralpak AD-H
column; eluent 3.5% 2-propanol/n-hexane, flow rate 1.0 mL/min, tR = 17 min (major, S), tR= 21 min (minor, R).
The enantiomeric excess (% ee) of (S)-2 was determined by HPLC analysis using a Daicel Chiralpak AD-H
column; eluent 10% ethanol/n-hexane, flow rate 1.0 mL/min, tR = 15 min (minor, R), tR= 21 min (major, S).
d)
c) Cyclopentyl methyl ether
Reaction temperature: -78 oC (24 h) then rt (24 h).
The conjugate addition of 5-membered hydrazine 6 was further studied using other cinnamoyl substrates
7a-e containing electron-donating (R = OMe, Me) and electron–withdrawing substituents (R= NO2, F, Cl)
on the aromatic ring. The conjugate addition of 6 (5 equiv) to (1S)-7a-e (1 equiv) underwent in
Et2O-THF at room temperature, however, the stereoselectivities of 8a-e are moderate (46% ee - 64% ee)
(Scheme 2). The conjugate addition of lithium amide of 6 (5 equiv) to (1S)-7a (R = OMe) (1 equiv)
underwent smoothly at 0 oC in diethyl ether to give (S)-8a (R = OMe) in 88% yield with 64% ee (Scheme
2). It was found that the reaction of lithium amide of 6 (5 equiv) and (1S)-7b (R = NO2) (1 equiv) also

HETEROCYCLES, Vol. 85, No. 5, 2012
1049
afforded (S)-8b (R = NO2) in 70% yield with 86% ee.12 The electron-deficient cinnamoyl substrate
(1S)-7b (R = NO2) showed better stereoselectivity on the conjugate addition of lithium amide of 6.
O
N
Et2O/THF
rt, 48 h
N
O
NH
NH
+
N
S
O2
R
R
6
(1S)-7a: R = OMe
(1S)-7b: R = NO2
(1S)-7c: R = Me
(S)- 8a: R = OMe 12% yield (61% ee)
(S)- 8b: R = NO2 84% yield (46% ee)
(S)- 8c: R = Me
(S)- 8d: R = F
(S)- 8e: R = Cl
72% yield (64% ee)
92% yield (56% ee)
82% yield (50% ee)
(1S)-7d: R = F
(1S)-7e: R = Cl
O
N
N
n-BuLi/ Et2O
0 oC, 24 h then rt, 24 h
O
NH
NH
+
N
S
O2
R
R
6
(1S)-7a: R = OMe
(1S)-7b: R = NO2
(S)- 8a: R = OMe 88% yield (64% ee)
(S)- 8b: R = NO2 70% yield (86% ee)
Scheme 2. Conjugate addition-cyclization of cyclic hydrazine 6 to (1S)-7
Based on the X-ray structure of N-crotonoyl-(1S)-2,10-camphorsultam reported by Oppolzer et al.13 and
good enentioselectivity (up to 86% ee) of the -amino acid derivatives (S)-1 obtained from the reaction of
(1S)-3 and 4, the asymmetric conjugate addition course was proposed as follows (Figure 2). Due to the
bulky camphorsultam group in (1S)-3, the nitrogen nucleophile (lithium amide of 4) may attack on the
-carbon atom of the double bond of (1S)-3 from the down side of the plane (si-face). Then cyclization
of -amino acid derivative took place successfully to afford (S)-1 and (1S)-5.
conjugate
addition
O
O
cyclization
(S)
(S)-1
O S
O
O S
O
N
N
Si-face
attack
(up to 86% ee)
N
N
Li
(1S)-3
Li
N
4
NH
Figure 2. Plausible conjugate addition-cyclization course of lithium amide of 4 to (1S)-3
In summary, we could accomplish the synthesis of -amino acid derivative (S)-1 {or (S)-2} for the
synthesis of polyamine alkaloids in good yield with good stereoselectivity (up to 86% ee) by asymmetric

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HETEROCYCLES, Vol. 85, No. 5, 2012
conjugate addition-cyclization of lithium amide of 6-membered hydrazine 4 (or 5-membered hydrazine 6)
to N-(E)-cinnamoyl-(1S)-2,10-camphorsultam (1S)-3.
REFERENCES AND NOTES
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2. For reviews of polyamine alkaloids, see: (a) U. Bachrach, ‘Function of Naturally Occuring
Polyamines’, Academic press, New York, 1973; (b) M. Hesse and N. Schmid, ‘Macrocyclic
Spermidine and Spermine Alkaloids’, Int Reviews of Science, ed. by H. D. Hey and K. Wiesner,
Butterworth, London, 1976, Organic Chemistry Series II, Vol. 9, p. 265; (c) M. M. Badawi, K.
Bernauer, P. Van den Broek, D. Groger, A. Gueggisberg, S. Johne, I. Kompis, F. Schneider, H.-J.
Veith, M. Hesse, and H. Schmid, Pure Appl. Chem., 1973, 33, 81; (d) H. H. Wasserman and J. S. Wu,
Heterocycles, 1982, 17, 581; (e) R. A. Campbell, D. R. Morris, and D. Bartos, ‘Advances in
Polyamine Research’, Raven press, New York, 1978, Vols. 1 and 2; (f) B. Ganem, Acc. Chem. Res.,
1982, 15, 290; (g) H. H. Wasserman and R. P. Robinson, Heterocycles, 1984, 21, 279.
3. For polyamine alkaloids, see: (a) P. Kuehne, A. Linden, and M. Hesse, Helv. Chim. Acta, 1996, 79,
1085; (b) K. Schultz and M. Hesse, Helv. Chim. Acta, 1996, 79, 1295; (c) U. A. Hausermann, A.
Linden, J. Song, and M. Hesse, Helv. Chim. Acta, 1996, 79, 1995; (d) P. Kuehne, A. Guggisberg, and
M. Hesse, Helv. Chim. Acta, 1997, 80, 1802; (e) A. Horni, A. Linden, and M. Hesse, Helv. Chim.
Acta, 1998, 81, 1303; (f) K. Drandarov, A. Guggisberg, A. Linden, and M. Hesse, Helv. Chim. Acta,
1998, 81, 1773; (g) L. Nezbedova, K. Drandarov, C. Werner, and M. Hesse, Helv. Chim. Acta, 2000,
83, 2953; (h) A. Guggisberg, K. Drandarov, and M. Hesse, Helv. Chim. Acta, 2000, 83, 3035.
4. (a) Y. Yamamoto, N. Asao, and T. Uyehara, J. Am. Chem. Soc., 1992, 114, 5427; (b) S. G. Davies, A.
C. Garner, R. L. Nicholson, J. Osborne, E. D. Savory, and A. D. Smith, Chem. Commun., 2003, 2134;
(c) T. Sakai, H. Doi, Y. Kawamoto, K. Yamada, and K. Tomioka, Tetrahedron Lett., 2004, 45, 9261.
5. (a) W. Oppolzer, C. Chapuis, and G. Bernardinelli, Helv. Chim. Acta, 1984, 67, 1397; (b) W.
Oppolzer, Tetrahedron, 1987, 43, 1969; (c) W. Oppolzer, Tetrahedron, 1987, 43, 4057; (d) W.
Oppolzer, Pure Appl. Chem., 1990, 62, 1241.

HETEROCYCLES, Vol. 85, No. 5, 2012
1051
6. For spermidine alkaloid (S)-(–)-celacinnine, see: (a) H. Matsuyama, N. Itoh, A. Matsumoto, N. Ohira,
K. Hara, M. Yoshida, and M. Iyoda, J. Chem. Soc., Perkin Trans. 1, 2001, 2924; (b) Y. Kuroki, K.
Ishihara, N. Hanaki, S. Ohara, and H. Yamamoto, Bull. Chem. Soc. Jpn., 1998, 71, 1221; For
(+)-celacinnine, see: (c) J. S. McManis and B. Ganem, J. Org. Chem., 1980, 45, 2041; (d) H. H.
Wasserman, R. P. Robinson, and H. Matsuyama, Tetrahedron Lett., 1980, 21, 3493; (e) H. Yamamoto
and K. Maruoka, J. Am. Chem. Soc., 1981, 103, 6133; For (+)-dihydroperiphylline, see: (f) H.
Matsuyama, A. Kurosawa, T. Takei, N. Ohira, M. Yoshida, and M. Iyoda, Chem. Lett., 2000, 1104;
(g) T. Kaseda, T. Kikuchi, and C. Kibayashi, Tetrahedron Lett., 1989, 30, 4539; (h) K. Ishihara, Y.
Kuroki, and H. Yamamoto, Synlett, 1995, 41.
7. (a) N. Itoh, H. Matsuyama, M. Yoshida, N. Kamigata, and M. Iyoda, Heterocycles, 1995, 41, 415; (b)
H. H. Wasserman, R. P. Robinson, and H. Matsuyama, Tetrahedron Lett., 1980, 21, 3493; (c) H.
Matsuyama, M. Kobayashi, and H. H. Wasserman, Heterocycles, 1987, 26, 85; (d) M. J. Begley, L.
Crombie, D. Haigh, R. C. F. Jones, S. Osborn, and R. A. B. Webster, J. Chem. Soc., Perkin Trans. 1,
1993, 2027.
8. (a) M. Pais, R. Sarfati, and F.–X. Jarreau, Bull. Soc. Chim. Fr., 1973, 331; (b) M. Pais, R. Sarfati,
F.–X. Jarreau, and R. Goutarel, Tetrahedron, 1973, 29, 1001, and references cited their in; natural
24
homaline, ]D –34 (c 1, CHCl3). For the synthesis of (S,S)-homaline, see: (c) N. Itoh, H.
Matsuyama, M. Yoshida, N. Kamigata, and M. Iyoda, Bull. Chem. Soc. Jpn., 1995, 68, 3121; (d) H. H.
Wasserman, G. D. Berger, and K. R. Cho, Tetrahedron Lett., 1982, 23, 465; (e) H. H. Wasserman and
G. D. Berger, Tetrahedron, 1983, 39, 2459; (f) L. Crombie, R. C. F. Jones, Ab. Rasid Mat-Zin, and S.
Osborne, J. Chem. Soc., Chem. Commun., 1983, 960; (g) L. Crombie, D. Haigh, R. C. F. Jones, and
Ab. Rasid Mat-Zin, J. Chem. Soc., Perkin Trans. 1, 1993, 2047.
9. (a) W. Oppolzer and J.-P. Barras, Tetrahedron, 1986, 42, 4035; (b) D. P. Curran and T. A. Heffner,
J. Org. Chem., 1990, 55, 4585; (c) X. Cao, F. Liu, W. Lu, G. Chen, G.-A. Yu, and S. H. Liu,
Tetrahedron, 2008, 64, 5629; (d) S. Hajra, M. Bhowmick, and D. Sinha, J. Org. Chem., 2006, 71,
9237.
10. Conjugate addition of lithium amide of 6-membered hydrazine 4 to (1S)-3 (Table 2, entry 3): (1S)-3:
white solid (recrystallized from n-hexane), mp 186-187 C; []D24 –98 (c 1.02, CHCl3). To the
o
anhydrous Et2O (5 mL) solution of 4 (5.0 mmol) was added dropwise n-BuLi (1.6M in n-hexane, 3.2
o
mL, 5.0 mmol) at 0 C under nitrogen and the solution was stirred for 30 min. Then the anhydrous
Et2O (5 mL) solution of (1S)-3 (345 mg, 1.0 mmol) was added and the solution was stirred at 0 oC for
24 h, and then at room temperature for 24 h. To this solution was added ammonium chloride (200
mg) and then water was added. The product was extracted with AcOEt and the organic layer was
dried (Na2SO4). After purification of crude product by flash column chromatography on silica gel

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HETEROCYCLES, Vol. 85, No. 5, 2012
(50% AcOEt in n-hexane), (S)-1 was obtained in 83% yield (180 mg, 0.83 mmol) with 86% ee and
(1S)-5 in 96% yield (207 mg, 0.96 mmol). (S)-1: oil; Rf = 0.10 (AcOEt/n-hexane = 2/1); []D24 –140
(c 0.50, CHCl3, 86% ee), lit.,6a []D24 –167 (c 1.30, CHCl3, 99% ee). IR (CHCl3) 1677 cm-1 (C=O); 1H
o
NMR [ppm] (500 MHz, CDCl3, 20 C):  1.37-1.48 (1H, m, 4-CH), 1.59-1.67 (1H, m, 4-CH),
1.70-1.79 (2H, m, 3-CH2), 2.26 (1H, td, J = 11.2, 2.4 Hz, 2-CH), 2.52 (1H, dd, J = 16.4, 11.4 Hz,
8-CH), 2.88 (1H, dd, J = 16.4, 8.8 Hz, 8-CH), 2.98 (1H, dd, J = 12.4, 11.6 Hz, N(CO)CH, 5-CH),
3.06 (1H, d, J = 10.0 Hz, 2-CH), 3.85 (1H, dd, J = 11.2, 8.3 Hz, PhCH, 9-CH), 4.17 (1H, d, J = 11.2
o
Hz, C(O)NCH, 5-CH), 7.29-7.41 (5H, m, Ph); 13C NMR [ppm] (125 MHz, CDCl3, 20 C): 22.7
(4-C), 23.9 (3-C), 39.9 (8-C), 42.0 (5-C), 55.4 (2-C), 67.4 (9-C), 128.1 (p-phenyl-C), 127.5 and 128.7
(o- and m-phenyl-C), 139.0 (phenyl C), 168.5 (C=O); m/z 216 (M+); HRMS Calcd for C13H16N2O: M,
216.1263. Found: m/z, 216.1273 (M+).
11. The conjugate addition of 5-membered hydrazine 6 (5.0 mmol) to (1S)-3 (1.0 mmol) was
investigated (Table 2, entry 8): purification by flash column chromatography on silica gel (10%
MeOH in CHCl3) gave (S)-2 in 90% yield (182 mg, 0.90 mmol) with 77% ee and (1S)-5 in 94%
yield (202 mg, 0.94 mmol). (S)-2: oil; Rf= 0.49 (CHCl3/MeOH = 19/1); []D24 –163 (c 1.23, CHCl3,
77% ee), lit.,8c []D24 –177 (c 1.90, CHCl3, 87% ee); IR (CHCl3) 1650 cm-1 (C=O); H NMR
1
[ppm] (500 MHz, CDCl3, 20 oC):  2.32-2.42 (2H, m, 7-CH), 2.44 (1H, q, J = 8.3 Hz, 6-CH), 2.97
(2H, d, J = 8.3 Hz, 3-CH2), 3.21 (1H, t, J = 8.3 Hz, 6-CH), 3.35 (1H, ddd, J = 11.2, 8.3, 4.9 Hz,
N(CO)CH, 8-CH), 3.75 (1H, dt, J = 11.2, 7.8 Hz, N(CO)CH, 8-CH), 4.11 (1H, t, J = 9.8 Hz, PhCH,
4-CH), 7.25-7.45 (5H, m, Ph); 13C NMR [ppm] (125 MHz, CDCl3, 20 oC): 27.5 (7-C), 23.9 (3-C),
39.5 (8-C), 43.9 (3-C), 53.3 (6-C), 69.0 (4-C), 126.9 (p-phenyl-C), 128.1 and 128.8 (o- and
m-phenyl-C), 139.1 (phenyl C), 165.9 (C=O); m/z 202 (M+); HRMS Calcd for C12H14N2O: M,
202.1106. Found: m/z 202.1079 (M+).
12. (1S)-7a (R= OMe): mp 148-149 oC, ]D25 –93 (c 0.50, CHCl3); (1S)-7b (R = NO2): mp 243-245 oC,
]D23 –93 (c 0.37, CHCl3); (1S)-7c (R= Me): mp 205-206 oC, ]D25 –97 (c 0.50, CHCl3); (1S)-7d
(R = F): mp 188-191 oC, ]D23 –96 (c 0.50, CHCl3); (1S)-7e (R= Cl): mp 211-213 oC, ]D23 –88 (c
23
0.50, CHCl3); (S)-8a (R = OMe): ]D25 –110 (c 1.03, CHCl3; 64% ee); (S)-8b (R = NO2): ]D
–180 (c 0.38, CHCl3; 86% ee); (S)-8c (R = Me): ]D25 –133 (c 0.78, CHCl3; 64% ee); (S)-8d (R =
F): ]D23 –121 (c 1.02, CHCl3; 56% ee); (S)-8e (R= Cl): ]D23 –113 (c 0.97, CHCl3; 50% ee).
13. The X-ray analysis of N-crotonoyl (1S)-2,10-camphorsultam has been reported: W. Oppolzer, I.
Rodriguez, J. Blagg, and G. Bernardinelli, Helv. Chim. Acta, 1989, 72, 123.