Novel asymmetric phenylselenium-induced lactamizations of olefinic amides: Stereoselective routes to α- and β-amino acids

Article abstract of DOI:10.1039/a705390h

Organoselenium-induced cyclofunctionalization of the (S)-N-(α,β-unsaturated) acylprolinamides 1, 7 and 14 has been found to produce the 7-membered bislactam products 2 and 15, or the 6-membered phenylselenolactam products 8 and 9 depending on the substitution pattern of the enone moiety of the starting material. The structural identities and stereochemistry of the cyclized products have been determined by X-ray diffraction, and the diastereoselectivity in the formation of the 7-membered ring bislactam product was found to be 91.6% de. The mechanism of the cyclolactamization is discussed.

Full text of DOI:10.1039/a705390h

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Novel asymmetric phenylselenium-induced lactamizations of olefinic
amides: stereoselective routes to á- and â-amino acids
Sung-Kee Chung,* Tae-Heum Jeong and Dong-Ho Kang
Department of Chemistry, Pohang University of Science & Technology, Pohang, 790-784,
Korea
Organoselenium-induced cyclofunctionalization of the (S)-N-(á,â-unsaturated) acylprolinamides 1, 7
and 14 has been found to produce the 7-membered bislactam products 2 and 15, or the 6-membered
phenylselenolactam products 8 and 9 depending on the substitution pattern of the enone moiety of
the starting material. The structural identities and stereochemistry of the cyclized products have been
determined by X-ray diffraction, and the diastereoselectivity in the formation of the 7-membered ring
bislactam product was found to be 91.6% de. The mechanism of the cyclolactamization is discussed.
ii
Introduction
Electrophilic heteroatom cyclizations of olefinic compounds
H
H
leading to a variety of 5- and 6-membered ring heterocycles
have been extensively investigated. For example, halogeno-
lactonization of alkenes with an intramolecular carboxylate
nucleophile and various cyclofuntionalizations of olefins with
internal hydroxy, amino, sulfur and phosphorus functional
groups are well-studied.1 The successful application of these
methods to the synthesis of specific target molecules requires
appropriate combinations of substrate geometry,2 nucleo-
philic functionality and the activating electrophile, the most
frequently used electrophiles being halogenium, HgII and
phenylselenium ions.3
O
O
NH
Ph
O
(S)
(S)
N
N
N
i
+
NH
NH2
(R)
O
O
O
Ph
H
H
PhSe
PhSe
Ph
1
2
3
v
iii
iv
O
O
O
NH
Ph
In the cyclofunctionalization of olefinic amides promoted by
a number of electrophiles, the predominant product is usually
not the lactam, but the imino ether which subsequently
hydrolyses to the corresponding lactone, i.e. the oxygen atom
instead of the nitrogen in the amide functionality preferentially
attacks the developing electrophilic centre.3c,4 The only reported
exceptions include halogenocyclization of N-sulfonyl, N-butyl,
N-isoxazolyl and N-thiazoyl olefinic amides.5 In order to cyclo-
functionalize olefinic amides to lactams, it is normally necessary
to utilize the protected forms of amide functionality such as
bis-silylated imidate, thioimidate and O-acylhydroxamate.6 We
have studied the asymmetric version of the organoselenium-
induced cyclization of olefinic amides as a potential route to
chiral α- or β-amino acids, and here report novel lactamizations
with high degrees of chirality transfer.7
(S)
(S)
(S)
N
N
N
vi
NH
NH
(R)
(S)
O
O
O
Ph
Ph
H
H
4
6
5
Scheme 1 Cyclofunctionalization of 1 and subsequent conversions to
()-and ()-β-AA derivatives. Reagents: i, PhSeBr, AgOTf, DMF,
CH3CN; ii, PhSeBr, AgOTf, DMF, CH3CN, 70%; iii, H2O2 (30%), THF,
77%; iv, NiCl2ؒ6H2O, NaBH4, THF, MeOH, 88%; v, NiCl2ؒ6H2O,
NaBH4, THF, MeOH, 87% (5:6 = 22.8:1); vi, Pd᎐C, H2, MeOH, 89%
(5:6 = 1:4.56).
shown that the initial product was 2 by converting the isolated
pure product 2 into product 3 in 70% yield under identical
reaction conditions, or in ca. 30% yield upon treatment with
PhSeBr in DMF and Me3CN (runs 5 and 7). It was also found
that the reaction of 1 with PhSeBr (1.8 equiv.), AgOTf (2
equiv.) and DMF (20 equiv.) in dry Me3CN at room temper-
ature under Ar for 12 h gave almost exclusively product 2 (73%
isolated yield) together with trace amounts of 1 and 3 (run 4). It
is to be emphasized that without DMF, the cyclization reaction
rarely proceeded, but the role of DMF has yet to be clarified.
Addition of NaH instead of DMF to the reaction mixture gave
a mixture of 2 and 4 (run 6).
The products 2 and 3 showed similar polarities on a TLC
plate, but the UV spectra indicated a distinct difference between
them. While the UV spectrum of 2 shows only bands at 224 (ε,
3311, E-band of Ph) and 266 nm (ε, 712, B-band of Ph), the
spectrum of 3 contains a main band at 210 nm (ε, 7875, E-band
of Ph), whose intensity and position vary with the degree of co-
planarity and conjugation of double bond in addition to the
characteristic subsidiary maxima at 258 (ε, 4170, π → π*;
K-band) and 320 nm (ε, 1453, n → π*; R-band). The 1H
NMR spectrum of 2 displayed three 1H signals at 4.71 [d,
Results and discussion
The required substrate, (S)-N-cinnamoylprolinamide 1 was effi-
ciently prepared from (S)-proline by successive reactions with
(i) cinnamoyl chloride and NaOH in aqueous acetone at 0 ЊC,
(ii) methyl chloroformate and triethylamine and (iii) ammo-
nium hydroxide at Ϫ10 ЊC. After considerable experimentation
with a number of electrophiles under a variety of reaction con-
ditions, benzeneselenenyl bromide (PhSeBr), silver triflate
(AgOTf)8 and DMF in Me3CN was found to be most suitable
for the desired cyclofunctionalization of 1 (Scheme 1).
Thus, treatment of compound 1 with PhSeBr (3 mol equiv.),
AgOTf (3 mol equiv.) and DMF (20–30 mol equiv.) in dry
Me3CN at room temperature under Ar, gave a mixture of the
cyclic products 2 and 3 in a varying ratio depending on the
reaction time (Table 1). For instance, after 12 h compound 2
was isolated in 31% yield together with the starting material 1
(65%), whereas after 48 h products 2 (5%) and 3 (72%) were
obtained along with a trace amount of 1 (runs 1–3). It could be
J. Chem. Soc., Perkin Trans. 1, 1998
969

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Table 1 Phenylselenolactamization
Conditionsa
Products (%)b
Run
Substrate
PhSeBr (equiv.)
AgOTf (equiv.)
DMF (equiv.)
Time (h)
1
2
3
4
1
2
3
4
5
6
7
1
1
1
1
2
1
2
3
3
3
1.8
3.3
1.8
3
3
3
3
2
3
2
—
30
30
20
20
12
24
48
12
48
12
48
65
31
—
5
73
—
30
6
—
57
72
Trace
70
—
29
—
—
—
—
—
34
6
38
NDc
NDc
—
20
1.2d
30
NDc
—
a All reactions were carried out in dry acetonitrile under argon at room temperature. b Isolated yield by column chromatographt on SiO2. c Identified
by TLC but not determined. d NaH was used instead of DMF; runs with NaH, SiO2, PhSeBr, AgOTf in CH2Cl2 at 0 ЊC gave similar results.
THF–MeOH9 to give compound 5. An HPLC analysis of the
crude product 5 (Alltech RP-18; 4.6 × 250 mm; 25% Me3CN in
water; 1.5 ml minϪ1; detection at 208 nm) indicated that the
diastereoisomeric ratio at this stage was ca. 22.8:1, equivalent
to ca. 91.6% de. Similarly, compound 3 was deselenenylated to 4
in 88% yield by the nickel boride procedure. Alternatively, the
oxidative elimination of compound 2 with H2O2 (30%) in
THF10 was carried out in 77% yield to provide 4, which was
hydrogenated over Pd–C in MeOH to give a diastereoisomeric
mixture of 5 and 6 in the ratio of 1:4.56 (% de = 64.0) on the
basis of HPLC analysis. It is noteworthy that in the catalytic
hydrogenation of both compound 4 and the exocyclic double
bond in the diketopiperazine derivatives,11 derived from
(S)-proline and α-keto acids, the catalyst-bound hydrogen
approaches from the convex side of the molecules, i.e. the
same side as the chiral hydrogen of the (S)-proline auxiliary,
Fig. 1 X-Ray crystal structure of compound 2
although the 1,4 chirality transfer efficiency appears to be
slightly higher in the 6-membered ring than in the 7-membered
ring (4).
In its UV spectrum, 4 as a solution in MeOH showed λm
at 206 (ε 15 739, E-band of Ph), 228 (ε, 14 768, B-band of
cinnamoyl moiety) and 278 nm (ε, 9990, K-band of cinnamoyl
moiety), whereas the diastereoisomeric pair 5 and 6 showed
only the E-band at 208 nm (ε, 3311) because of destruction of
the conjugated system. The 1H NMR chemical shifts of 5 were
1
assigned on the basis of H-1H homonuclear correlation spec-
1
troscopy (COSY). The H NMR signals appear at δ 2.76, 3.20
[C(O)CH2] and 4.82 (CHPh) for compound 5, and at δ 2.95, 3.14
[C(O)CH2] and 4.94 (CHPh) for compound 6. The specific
optical rotations of 5 and 6 were Ϫ92.40 and 8.54, respectively,
whilst other spectroscopic features (high resolution mass, UV
and IR) were very similar.
The conversion of compound 2 into 3 represents an overall
trans dehydrogenation, and might be occurring through the
initial N-phenylselenation followed by the elimination of a
‘phenylselenol equivalent’ to give an imine, which isomerizes to
3 (Scheme 2). Similarly, the production of 4 from compound 2
might be explicable in terms of the diphenyldiselenium species
and an intramolecular elimination (see Scheme 2).
Fig. 2 X-Ray crystal structure of compound 3
J 8.7 Hz, 1H, C(O)CHSePh], 4.82 (dd, J 8.7, 4.4 Hz, 1H,
NHCHPh) and 6.24 (d, J 4.4 Hz, 1H, NH), thus revealing the
connectivity pattern of the structure. However, a more defini-
tive structural elucidation together with stereochemical assign-
ments for the products 2 and 3 were made on the basis of single-
crystal X-ray diffraction studies (Figs. 1 and 2). It is clear from
the X-ray structure of 2 that the amide nitrogen has attacked
the β-position of the cinnamoylamide moiety thus generating a
7-membered system, and that the electrophile-promoted add-
ition occurs in an anti fashion with an R-absolute configuration
at the new chiral centre of C*-NH. However, the reason for the
exclusive formation of the lactam product as opposed to the
usual lactone via imino ether species is not at present clear,
although it is currently speculated that the hard/soft-ness of the
effective electrophiles and the transition state geometry may be
playing important roles.
When another substrate, (S)-N-crotonoylprolinamide 7, pre-
pared from (S)-proline and crotonyl chloride, was subjected to
the phenylselenium-induced lactamization under the similar
conditions, i.e. PhSeBr (1.8 equiv.), AgOTf (2 equiv.) and DMF
(20 equiv.) in dry Me3CN, somewhat different results were
obtained (Scheme 3). While the lactamization of 7 was found to
be very sluggish and gave the 6-membered diketopiperazine
compounds 8 (13.2%) and 9 (4.2%), the simple addition of phe-
nylselenium ion to the olefinic moiety of 7 followed by trapping
with water gave a predominance of apparently diastereoiso-
meric products 10 (46%) and 11 (19.4%). The structures of the
6-membered bislactam diastereoisomers (8 and 9) were again
ascertained by single-crystal crystallography (Figs. 3 and 4).
Despite the low yields, formation of the 6-membered diketopi-
perazine products 8 and 9 was observed for the first time in this
phenylselenolactamization. Compounds 8 and 9, in principle,
The crude product 2 was deselenenylated in 87% yield with
nickel boride generated in situ from NiCl2ؒ6H2O and NaBH4 in
970
J. Chem. Soc., Perkin Trans. 1, 1998

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O
O
O
SePh
SePh
+
2PhSe+
–(PhSe)2
–HBr
N
N
N
NH
N
N
O
O
O
Ph
Ph
Ph
H
PhSe
PhSe
PhSe
Br–
2
PhSeBr
O
O
O
N
N
N
–(PhSe)2
–HBr
NH
NH
NH
O
O
O
Ph
H
Ph
Ph
+
PhSe
PhSe
PhSe
4
3
Scheme 2 A proposed mechanism for the conversion of 2 into 3 and 4
H
O
Fig. 3 X-Ray crystal structure of compound 8
(S)
N
PhSeBr, AgOTf, DMF, MeCN
NH2
O
CH3
7
H
H
O
H
O
O
(S)
(S)
N
(S)
N
N
NH2
NH
NH
+
H
+
O
O
O
SePh
H
PhSe
Me
PhSe
Me
Me
HO
H
H
8
10, 11
9
H
O
Ac2O, Pyr, CH2Cl2
(S)
N
10, 11
NH2
O
SePh
Me
AcO
Fig. 4 X-Ray crystal structure of compound 9
12, 13
MeOH). The 7-membered ring structure was clearly indicated
by the 1H NMR spectrum of deselenenylated product 18, which
exhibited two isolated methyl groups and two diastereotopic
protons at 2.47 and 3.07 ppm with the geminal coupling J 14.1
Hz).
Scheme 3 Cyclofunctionalization of 7
could be used as precursors of the unnatural α-(R)-amino acid
and α-(S)-amino acid, respectively. The simple PhSe-added
diastereoisomers incorporated the hydroxy group as nucleo-
phile, perhaps most likely due to the hydrolysis during the aq.
NaHCO3 work-up, after the initial trapping of the carbocati-
onic intermediates with the trifluoromethanesulfonate anion.
The presence of the secondary hydroxy groups in 10 and 11
That the phenylselenolactamization of 1 and 14 afforded the
7-membered bislactam product 2 and 15, whereas the lactamiz-
ation of 7 gave the 6-membered diketopiperazines 8 and 9,
clearly suggest that the electronic factors around the double
bond and the geometry of the initial intermediates generated by
addition of the phenylselenium ion to the double bond may
play important roles. Comparison of the reaction rates, chem-
ical yields and the product structures observed in the above
cyclofunctionalizations also suggest that compound 1 shows a
higher reactivity towards the phenylselenium electrophile than
do 7 and 14. The fact that (monoaryl- or dialkyl-substituted
α,β-unsaturated)acylprolines 1 and 14 gave the 7-membered
ring products 2 and 15, while (monoalkyl substituted α,β-
unsaturated)acylproline 7 afforded the 6-membered phenyl-
selenolactams 8 and 9 suggest that an effective cation-stabilizing
substituent at the β-position is needed for the formation of the
7-membered ring. Otherwise, the formation of a 6-membered
ring product is favoured, although the overall reaction rate
is rather low. In this connection it is interesting to note the
α-substituent effect on the mode of the cyclization. A prelimin-
1
could be confirmed by analysing the H NMR spectra of the
acetylated compounds 12 and 13. Large chemical-shift changes
for the CHCH3 signals in 1H NMR spectra (>ϩ1 ppm) between
the starting materials (10 and 11) and the products (12 and 13)
indicate that the hydroxy group is bonded to the CHCH3
moiety.
Next, the cyclofunctionalization of (S)-N-(β-methylcrotonyl)-
prolinamide 14 was examined under similar reaction condi-
tions. In this case, the only cyclized product was found to be the
7-membered lactam 15 (22.4%). In addition, two apparent dias-
tereoisomeric PhSe-added alcohols 16 (49%) and 17 (13.3%)
were obtained again as the simple electrophilic addition prod-
ucts (Scheme 4). In order to elucidate the structure of 15, the
reductive deselenenylation was carried under the same condi-
tions as described above (NiCl2ؒ6H2O and NaBH4 in THF–
J. Chem. Soc., Perkin Trans. 1, 1998
971

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the internal carboxamide nucleophile in an SN2 or SN1 fashion.
H
O
In the direct SN2 type cyclization, both 6-exo-trig and 7-endo-
(S)
N
trig modes would be expected to be possible.2
PhSeBr, AgOTf, DMF, MeCN
NH2
In summary, it has been demonstrated that the cyclofunc-
tionalization (S)-N-(α,β-unsaturated)acylprolinamides should
provide an efficient route to both (S)- and (R)-β-amino acids,13
since the diastereoisomeric cyclic dipeptides such as 5 and 6 can
be easily purified and hydrolysed to the corresponding chiral
β-amino acids and the chiral auxiliary which can be recycled.11c
In spite of the low chemical yields, the possibility that (S)- and
(R)-α-amino acids could also be synthesized by the cyclo-
functionalization has been shown in the cases where the sub-
strate includes an electron-deficient olefin moiety. A study to
define the generality and scope of this cyclolactamization route
and the possible control of the cyclization mode is currently in
progress.
O
Me
Me
14
H
H
O
O
(S)
N
(S)
N
H
NH2
NH
+
O
SePh
O
Me
Me
Me
Me
PhSe
OH
16, 17
15
NiCl2•6H2O, NaBH4
THF, MeOH.
Experimental
General
Melting points were determined on a Thomas-Hoover melting
point apparatus and are uncorrected. IR spectra were obtained
on a BOMEM model FT-IR M100-C15 spectrometer for liquid
O
(S)
N
films. Optical rotations, recorded as 10Ϫ1 deg cm2 Ϫ1, were
g
NH
Me
measured on a JASCO DIP-360 digital polarimeter at ambient
O
temperature and are reported as follows: [α]λ (c g 100 mlϪ1
,
Me
18
solvent). NMR spectra were determined on a Bruker AM 300
(300 MHz) spectrometer. Chemical shifts are reported in δ ppm
1
relative to SiMe4 for H and 13C NMR spectra. Coupling con-
Scheme 4 Cyclofunctionalization of 14
stants, J are reported in Hz. NMR multiplicities are reported
using the following abbreviations: s = singlet, d = doublet, t =
triplet, q = quartet, m = multiplet, br = broad. Assignments of
1H resonances were assisted by COSY spectral data. Elemental
analyses were performed by Galbraith laboratories, Inc.,
Knoxville, TN, USA. Mass spectra were determined on a
KRATOS MS 25 RFA (EI and FAB) system. High resolution
MS were performed by Korea Basic Science Center, Taejeon,
Korea. Selenium-containing compounds exhibited the charac-
teristic isotopic family in their mass spectra [74Se(1), 76Se(10),
77Se(9), 78Se(27), 80Se(57), 82Se(11)] but only the peaks due to the
most abundant isotope (80Se) are reported.
Analytical thin-layer chromatography was performed on
Merck 60 F254 silica gel plate (0.25 mm layer thickness) and
visualization was done with UV light, and/or a spray with 5%
phosphomolybdic acid in ethanol followed by charring with a
heat gun. Column chromatography was carried out on silica gel
60 (E. Merck, 70–230 mesh). HPLC was performed on RP 18
Alltech column (250 × 4.6 mm) using an SP 8800 ternary pump
and SP 8450 UV/Vis detector (λ = 208 nm). Relative peak areas
were determined by an SP 4290 integrator.
ary experiment with N-(2-methylpent-2-enoyl)prolinamide
showed that the 6-membered ring products were preferentially
formed in the cyclofunctionalization. This reaction could pro-
vide a convenient synthetic route to α,α-disubstituted α-amino
acids.12
According to the PM3 calculations, the s-cis structure 19 is
more stable than s-trans 20 by ca. 0.7–1.4 kcal molϪ1 (Scheme
5). Thus, the presumed bridged phenylselenium ion inter-
(S)
(S)
O
O
R
DEs(kcal mol–1
)
N
N
NH2
NH2
Ph
Me
ca. 0.7
ca. 1.4
O
O
R
R
(s-trans)
20
19 (s-cis)
O
O
N
N
All reactions were carried out under the argon atmosphere in
oven-dried glassware, all commercial chemicals were used as
obtained and all solvents were carefully dried and distilled by
standard methods prior to use. DMF was dried by storage over
MgSO4 and vacuum distilled. Dichloromethane and aceto-
nitrile were dried and distilled over P2O5.
NH2
NH2
O
+
O
SePh
R
Ph
Se
+
R
22
21
(S)-N-Cinnamolyprolinamide 1
A solution of (S)-proline (5.0 g, 43 mmol) in 2  aqueous
NaOH (26 ml, 52 mmol) was cooled in an ice-bath and diluted
with acetone (26 ml). An acetone solution (26 ml) of cinnamoyl
chloride (8.0 g, 48 mmol) and 2  aqueous NaOH (30 ml,
61 mmol) were simultaneously added over 40 min with good
stirring to the aqueous proline in an ice-bath. After 3 h at room
temperature, the mixture was evaporated in vacuo to remove the
acetone. The residual solution was washed with ether and acid-
ified (pH 2) with conc. hydrochloric acid. The acidic mixture,
after saturation with NaCl, was extracted with ethyl acetate,
and the combined extracts were washed with brine and evapor-
ated. Recrystallization of the crude product from methanol
gave pure (S)-cinnamoylproline (8.7 g, 82%).
O
O
N
N
NH
R
NH
H
O
O
PhSe
H H
PhSe
R
H
Scheme 5 Mode of cyclofunctionalization
mediates generated en route to the formation of bislactams
might actually be an equilibrium mixture of the two geometric-
ally different types (21 and 22). In the subsequent asymmetric
cyclofunctionalizations, the bridged phenylselenium ions (21
and 22) are attacked regioselectively at the α or β position by
972
J. Chem. Soc., Perkin Trans. 1, 1998

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To a solution of (S)-cinnamoylproline (6.4 g, 26 mmol) and
triethylamine (3.7 ml, 26 mmol) in CH2Cl2 (120 ml) at Ϫ20 ЊC,
methyl chloroformate (2.0 ml, 26 mmol) was added dropwise.
After the mixture had been stored for 1 h at Ϫ20 ЊC, 30%
aqueous NH4OH (25 ml, excess) was added to it dropwise.
Stirring was continued for 2 h at room temperature by which
time evolution of CO2 had subsided. The mixture was concen-
trated and neutralized (pH 7) with 1  hydrochloric acid.
The residual solution was extracted with CH2Cl2, and the
extract was dried and evaporated to give a crude product, which
was recrystallized from MeOH–hexane. Compound 1 (5.4 g,
85%), mp 175–178 ЊC; [α]D Ϫ218.0 (c 1.1, CHCl3); RF 0.1 (silica,
ethyl acetate); λmax(MeOH)/nm 208, 220 and 282; νmax(film)/
cmϪ1 3320, 2935, 1680, 1648, 1597, 1454, 1422 and 759;
δH(CDCl3) 1.80–2.10 (m, 3H, CHCH2CH2N), 2.52 (m, 1H,
CHCH2CH2N), 3.72 (m, 2H, CH2N), 4.76 (br d, J 8.1, 1H,
CHCH2CH2CH2N), 6.75 (d, J 15.6, 1H, CHPh), 7.37–7.55
(m, 5H, Ph) and 7.75 [d, J 15.6, 1H, C(O)CH]; δC(CDCl3)
25.56, 27.65, 48.11, 60.30, 118.41, 128.61, 129.48, 130.61,
135.50, 144.03, 166.83 and 174.11; m/z (EI) 244 (Mϩ).
216 ЊC; [α]D ϩ178.39 (c 1.05, CHCl3); RF 0.50 (silica, ethyl
acetate); λmax(MeOH)/nm 210, 258 and 320; νmax(film)/cmϪ1
3230, 1895, 1821, 1420 and 751; δH(CDCl3) 1.86–2.12 (m, 3H,
CHCH2CH2N), 2.71 (m, 1H, CHCH2CH2N), 3.26 (dt, J 11.8,
8.1, 1H, CH2N), 3.66 (m, 1H, CH2N), 4.25 (dd, J 7.5, 2.6, 1H,
CHCH2CH2CH2N) and 7.11–7.42 (m, 10H, Ph); δC(CDCl3)
23.86, 26.51, 47.31, 58.04, 117.41, 128.22, 129.33, 129.52,
129.61, 130.90, 131.86, 134.04, 137.59, 142.07, 168.97 and
170.77; m/z (EI) 398 (Mϩ); (FAB) 421 (M ϩ 23) and 399
(M ϩ 1).
(9aS)-3-Phenyl-1,2,7,8,9a-hexahydro-5H-pyrrolo[1,2-a][1,4]-
diazepine-1,5-dione 4
(A) To a solution of 2 (60 mg, 0.15 mmol) in THF (3 ml) at 0 ЊC
was added dropwise 30% aqueous H2O2 (0.1 ml), and the result-
ing mixture was stirred at 20 ЊC for 2 h. It was then diluted with
water (2 ml) and extracted with CH2Cl2. The combined extracts
were washed with 10% aqueous Na2CO3, dried and concen-
trated. Column chromatography of the residue afforded 4 (28.1
mg, 77.2%) as a white solid.
(B) To a solution of 3 (146 mg, 0.367 mmol) in THF (5 ml)
was added a solution of nickel() chloride hexahydrate (349
mg, 1.47 mmol) in MeOH (5 ml) at ambient temperature. The
solution was cooled in an ice-bath and treated with sodium
borohydride (167 mg, 4.41 mmol), added in small portions.
After an additional 10 min at 0 ЊC, the mixture was filtered
through Celite and chromatographed to give 4 (78.7 mg, 88.3%)
as a white solid, mp 187–188 ЊC; [α]D ϩ326.88 (c 1.00, CHCl3);
RF 0.28 (silica, ethyl acetate); λmax(MeOH)/nm 206, 228 and
278; νmax(film)/cmϪ1 3221, 1700, 1634, 1599, 1440 and 761;
δH(CDCl3) 1.88–2.10 (m, 3H, CHCH2CH2N), 2.76 (m, 1H,
CHCH2CH2N), 3.61 (m, 2H, CH2N), 4.27 (dd, J 8.1, 2.5, 1H,
CHCH2CH2CH2N), 6.04 (d, J 1.2, 1 H, CHPh) and 7.26–7.55
(m, 5H, Ph); δC(CDCl3) 24.13, 26.64, 47.30, 58.26, 110.22,
127.63, 129.75, 131.29, 136.62, 142.81, 166.77 and 170.11; m/z
(EI) 242 (Mϩ).
(3R,4R,9aS)-3-Phenyl-4-phenylselenooctahydropyrrolo[1,2-a]-
[1,4]diazepine-1,5-dione 2
To a solution of cinnamoylprolinamide 1 (200 mg, 0.82 mmol)
in acetonitrile (7 ml) were added silver trifluoromethane-
sulfonate (420 mg, 1.64 mmol) in acetonitrile (8 ml), and then
benzeneselenyl bromide (384 mg, 1.47 mmol) and dimethyl-
formamide (1.30 ml, 16.4 mmol) in acetonitrile (8 ml). The
resulting solution was stirred at ambient temperature for 12 h
after which it was treated with saturated aqueous NaHCO3 and
extracted with methylene dichloride. The extract was washed
with brine, dried and evaporated to give the crude product.
Column chromatography of this afforded 2 (240.0 mg, 73.4%)
as a white solid, recrystallization of which from CH2Cl2–hexane
gave colourless crystals, mp 194–195 ЊC; [α]D ϩ26.66 (c 1.015,
CHCl3); RF 0.51 (silica, ethyl acetate); λmax(MeOH)/nm 224 and
266; νmax(film)/cmϪ1 3140, 1683, 1652, 1432 and 749; δH(CDCl3)
m, 2H, CH2CH2N), 2.03 (m, 1H, CHCH2CH2N), 2.59 (m, 1H,
CHCH2CH2N), 3.60 (m, 2H, CH2N), 4.19 (dd, J 7.5, 6.2, 1H,
CHCH2CH2CH2N), 4.71 [d, J 8.7, 1H, C(O)CHSePh], 4.82 (dd,
J 8.7, 4.4, 1H, NHCHPh), 6.24 (d, J 4.4, 1H, NH) and 7.07–
7.32 (m, 10H, Ph); δC(CDCl3) 23.08, 29.29, 48.46, 52.40, 59.92,
60.95, 127.53, 128.55, 129.04, 129.33, 129.49, 135.59, 139.68,
168.97 and 170.77; m/z (EI) 400 (Mϩ) (Found C, 60.16; H, 5.07;
N, 7.05. Calc. for C20H20N2O2Se: C, 60.15; H, 5.05; N, 7.02%).
(3S,9aS)-3-Phenyloctahydropyrrolo[1,2-a][1,4]diazepine-1,5-
dione 5
To a solution of 2 (71.6 mg, 0.18 mmol) in THF (3 ml) was
added a solution of nickel() chloride hexahydrate (85.2 mg,
0.36 mmol) in MeOH (3 ml) at ambient temperature. The solu-
tion was cooled in an ice-bath and treated with sodium boro-
hydride (40.74 mg, 1.07 mmol), added in small portions. After
an additional 10 min at 0 ЊC, the mixture was filtered through
Celite and chromatographed to give a crude solid product 5
(38.2 mg, 87.2%). HPLC analysis indicated the ratio of 5 and 6
to be 22.8:1. Recrystallization of the crude product from ethyl
acetate–hexane gave colourless crystalline 5, mp 154–155 ЊC;
[α]D Ϫ92.40 (c 0.610, CHCl3); RF 0.26 (silica, ethyl acetate);
λmax(MeOH)/nm 210 and 286; νmax(film)/cmϪ1 3246, 1649,
1453 and 759; δH(300 MHz, CDCl3) 1.80 (m, 2H, CH2CH2N),
2.18 (m, 1H, CHCH2CH2N), 2.76 (m, 2H, CHCH2CH2N ϩ
C(O)CH2), 3.20 [app.t, J 13.3, 1H, C(O)CH2], 3.58 (t, J 6.8, 2H,
CH2N), 4.59 (dd, J 8.1, 4.4, 1H, CHCH2CH2CH2N), 4.82 (dd,
J 13.3, 1.5, 1H, CHPh), 5.83 (s, 1H, NH) and 7.26–7.41 (m, 5H,
Ph); δC(CDCl3) 23.98, 29.25, 44.30, 47.25, 57.36, 60.28, 126.38,
129.21, 129.87, 142.64, 169.43 and 170.62; m/z (EI) 244 (Mϩ)
[Found (HRMS, EI): m/z 244.1216. Calc. for C14H16O2N2:
244.1212].
(9aS)-3-Phenyl-4-phenylseleno-1,2,7,8,9,9a-hexahydro-5H-
pyrrolo[1,2-a][1,4]diazepine-1,5-dione 3
(A) To a solution of cinnamoylprolinamide 1 (150 mg, 0.61
mmol) in acetonitrile (6 ml) were added silver trifluoro-
methanesulfonate (474 mg, 1.84 mmol) in acetonitrile (8 ml),
and benzeneselenyl bromide (435 mg, 1.84 mmol) and dimethyl-
formamide (0.95 ml, 12.3 mmol) in acetonitrile (8 ml). The
resulting mixture was stirred at ambient temperature for 48 h
after which it was treated with saturated aqueous NaHCO3, and
extracted with methylene dichloride. The extract was washed
with brine, dried and evaporated to give the crude product.
Column chromatography of this afforded 2 (12.4 mg, 5.1%) and
3 (175.2 mg, 71.6%) as white solids, which were recrystallized
from CH2Cl2–hexane.
(B) To a solution of 2 (160.0 mg, 0.040 mmol) in acetonitrile
(1 ml) were added silver trifluoromethanesulfonate (30.8 mg,
0.12 mmol) in acetonitrile (1 ml) and benzeneselenyl bromide
(31.3 mg, 0.13 mmol) and dimethylformamide (0.093 ml, 1.2
mmol) in acetonitrile (2 ml). The resulting mixture was stirred
at ambient temperature for 48 h after which it was treated with
saturated aqueous NaHCO3 and extracted with methylene
dichloride. The extract was washed with brine, dried and evap-
orated to give the crude product, column chromatography of
which afforded 3 (11.2 mg, 70.4%) as a white solid, mp 215–
(3R,9aS)-3-Phenyloctahydropyrrolo[1,2-a][1,4]diazepine-1,5-
dione 6
A mixture of Pd–C (10 mg) and 4 (20 mg, 0.083 mmol) in
MeOH (1 ml) was stirred at ambient temperature under H2
(1 atm) for 20 h, after which it was filtered and evaporated to
give the crude product mixture (18.0 mg, 89.3%). This was
found to contain 5 and 6 in a ratio of 1:4.56 by HPLC analysis.
Repeated recrystallization of the crude product from ethyl
acetate–hexane gave 6 as colourless crystals, mp 150–152 ЊC;
J. Chem. Soc., Perkin Trans. 1, 1998
973

View Article Online
[α]D Ϫ17.27 (c 0.75, CHCl3); RF 0.24 (silica, ethyl acetate);
λmax(MeOH)/nm 208 and 285; νmax(film)/cmϪ1 3244, 1646, 1447
and 755; δH(CDCl3) 1.88 (m, 2H, CH2CH2N), 2.15 (m, 1H,
CHCH2CH2N), 2.70 (m, 1H, CHCH2CH2N), 2.95 [dd, J 16.5,
10.0, 1H, C(O)CH2], 3.14 [dd, J 16.5, 3.7, 1H, C(O)CH2], 3.61
(m, 2H, CH2N), 4.62 (dd, J 7.5, 6.2, 1H, CHCH2CH2CH2N),
4.94 (dt, J 10.0, 3.7, 1H, CHPh), 6.09 (s, 1H, NH) and 7.26–
7.43 (m, 5H, Ph); δC(CDCl3) 23.32, 29.16, 44.05, 48.46, 53.80,
58.42, 126.81, 129.45, 129.94, 139.81, 168.16 and 171.02; m/z
(EI) 244 (Mϩ) [Found (HRMS, EI): m/z 244.1207. Calc. for
C14H16O2N2: 244.1212].
J 7.7, 3.3, 1H, CHCH2CH2CH2N), 6.14 (s, 1H, NH), 6.85 (s,
1H, NH) and 7.27–7.63 (m, 5H, Ph); δC(CDCl3) 21.73, 24.94,
28.71, 47.98, 50.28, 60.49, 69.91, 127.64, 129.27, 129.59, 136.41,
171.93 and 174.26; m/z (FAB) 357 (Mϩ ϩ 1) (Found: C, 50.43;
H, 5.92; N, 7.54. Calc. for C15H20N2O3Se: C, 50.71; H, 5.67; N,
7.88%).
(S)-N-(3-Hydroxy-2-phenylselenobutanoyl)prolinamide 11
Mp 56–59 ЊC; [α]D Ϫ69.29 (c 0.89, CHCl3); RF 0.07 (silica, ethyl
acetate); νmax(film)/cmϪ1 3360, 3200, 2975, 2880, 1680, 1626,
1428 and 739; δH(CDCl3) 1.43 (d, J 6.3, 3H, CH3), 1.87–1.99 (m,
3H, CHCH2CH2N), 2.34 (m, 1H, CHCH2CH2N), 3.41 (m, 2H,
CH2N), 3.59 (d, J 7.8, 1H, HCSePh), 3.87 (1H, br s, OH), 4.23
(m, 1H, CHCH3), 4.59 (m, 1H, CHCH2CH2CH2N), 5.70 (s, 1H,
NH), 6.73 (s, 1H, NH) and 7.28–7.65 (m, 5H, Ph); δC(CDCl3)
21.14, 25.25, 27.74, 47.94, 49.28, 59.93, 69.07, 126.28, 129.42,
129.70, 136.54, 172.67 and 174.18; m/z (FAB) 357 (Mϩ ϩ 1)
(Found: C, 50.37; H, 5.89; N, 7.56. Calc. for C15H20N2O3Se: C,
50.71; H, 5.67; N, 7.88%).
(S)-N-Crotonylprolinamide 7
This compound was analogously prepared as described for 1;
mp 122–124 ЊC; [α]D Ϫ274.63 (c 1.11, CHCl3); RF 0.1 (silica,
ethyl acetate); νmax(film)/cmϪ1 3299, 3170, 1675, 1606, 1428, 965
and 753; δH(CDCl3) (dd, J 6.9, 1.9, 3H, CH3), 1.97–2.08 (m, 3H,
CHCH2CH2N), 2.37 (m, 1H, CHCH2CH2N), 3.60 (m, 2H,
CH2N), 4.64 (dd, J 8.0, 2.0, 1H, CHCH2CH2CH2N), 6.16 (dd,
J 15.0, 1.9, 1H, CH᎐CHCH ) and 6.96 (dq, J 15.0, 6.9, 1H,
᎐
3
CH᎐CHCH ); δ (CDCl ) 17.84, 24.58, 27.59, 47.08, 59.30,
Acetylation of (S)-N-(3-hydroxy-2-phenylselenobutanoyl)-
prolinamide 10 and 11
᎐
3
C
3
122.27, 142.18, 165.59 and 174.02; m/z (EI) 182 (Mϩ).
The reaction was carried out with acetic anhydride (1.1 equiv.)
and pyridine (1.1 equiv.) in CH2Cl2 to give 12 and 13 as colour-
less oils.
Cyclofunctionalization of (S)-N-crotonoylprolinamide 7
To a solution of (S)-N-crotonoylprolinamide 7 (725 mg, 4.0
mmol) in acetonitrile (50 ml) were added silver trifluorometh-
anesulfonate (3.37 g, 13.1 mmol) in acetonitrile (25 ml), and
then benzeneselenyl bromide (2.82 g, 11.9 mmol) and dimethyl-
formamide (9.2 ml, 119 mmol) in acetonitrile (25 ml). The
resulting mixture was stirred at ambient temperature for 12 h
after which it was treated with saturated aqueous NaHCO3, and
extracted with methylene dichloride. The organic layer was sep-
arated, washed with brine and evaporated to give the crude
product. Column chromatography of this afforded 8 (178.4 mg,
13.2%) and 9 (56 mg, 4.2%) as colourless crystals and 10 (649
mg, 46.9%) and 11 (274.8 mg, 19.4%) as white solids.
(S)-N-(3-Acetoxy-2-phenylselenobutanoyl)prolinamide
12.
[α]D Ϫ144.55 (c 0.855, CHCl3); RF 0.13 (silica, ethyl acetate);
νmax(film)/cmϪ1 3350, 3200, 2990, 1738, 1686, 1636, 1430 and
1237; δH(CDCl3) 1.49 (d, J 6.3, 3H, CHCH3), 1.88 [3H, s,
C(O)CH3], 2.00–2.21 (m, 3H, CHCH2CH2N), 2.33 (m, 1H,
CHCH2CH2N), 3.36–3.71 (m, 2H, CH2N), 4.01 (d, J 9.0, 1H,
HCSePh), 4.46 (dd, J 7.2, 1.8, 1H, CHCH2CH2CH2N), 5.33
(dq, J 9.0, 6.3, 1H, CHCH3), 5.91 (s, 1H, NH), 7.01 (s, 1H, NH)
and 7.28–7.64 (m, 5H, Ph); δC(CDCl3) 18.55, 21.24, 25.14,
27.60, 47.86, 48.72, 60.06, 71.93, 126.30, 129.37, 136.29, 169.97
and 170.24; m/z (FAB) 399 (Mϩ ϩ 1).
(S)-N-(3-Acetoxy-2-phenylselenobutanoyl)prolinamide
13.
(3R,9aS)-3-[(1ЈR)-1Ј-Phenylselenoethyl]-3-methyloctahydro-
pyrrolo[1,2-a][1,4]diazepine-1,5-dione 8
[α]D Ϫ13.12 (c 1.6, CHCl3); RF 0.15 (silica, ethyl acetate);
νmax(film)/cmϪ1 3360, 3200, 2980, 1738, 1686, 1636, 1429, 1238
and 749; δH(CDCl3) 1.55 (d, J 6.3, 3H, CH3), 1.91 [3H, s,
C(O)CH3], 2.00–2.18 (m, 3H, CHCH2CH2N), 2.32 (m, 1H,
CHCH2CH2N), 3.51 (m, 2H, CH2N), 3.92 (d, J 8.4, 1H,
HCSePh), 4.61 (dd, J 8.1, 1.6, 1H, CHCH2CH2CH2N), 5.33 (m,
1H, CHCH3), 5.92 (s, 1H, NH), 7.05 (s, 1H, NH) and 7.28–7.65
(m, 5H, Ph); δC(CDCl3) 18.65, 21.38, 25.30, 27.76, 47.91, 50.26,
61.13, 71.30, 125.16, 129.77, 136.18, 138.83, 174.52 and 178.02.
(S)-N-(â-Methylcrotonyl)prolinamide 14. This compound
was analogously prepared as described for 1. Mp 151–153 ЊC;
[α]D Ϫ209.82 (c 0.79, CHCl3); RF 0.1 (silica, ethyl acetate);
δH(CDCl3) 1.82 (s, 3H, CH3), 1.89 (s, 3H, CH3), 1.86–1.99 (m,
3H, CHCH2CH2N), 2.34 (m, 1H, CHCH2CH2N), 3.54 (m, 2H,
CH2N), 4.63 (dd, J 5.5, 2.5, 1H, CHCH2CH2CH2N) and 5.85 [s,
Mp 110–111 ЊC; [α]D Ϫ59.43 (c 0.655, CHCl3); RF 0.56 (silica,
ethyl acetate); λmax(MeOH)/nm 212 and 274; νmax(film)/cmϪ1
2935, 1756, 1673, 1458, 1373, 1194 and 742; δH(CDCl3) 1.60 (d,
J 7.2, 3H, CH3), 1.84 (m, 1H, CHCH2N), 1.96–2.10 (m,
2H, CHCH2CH2N ϩ CHCH2N), 2.45 (m, 1H, CHCH2CH2N),
3.41 (ddd, J 11.8, 9.1, 2.6, 1H, CHHN), 3.59–3.70 (m, 2H,
CHCH3 ϩ one of CHHN), 4.33 (dd, J 9.7, 6.7, 1H, CHCH2-
CH2CH2N), 4.89 [d, J 5.9, 1H, C(O)CHNH], 7.26–7.64 (m, 5H,
Ph); δC(CDCl3) 18.95, 22.28, 30.35, 41.19, 45.88, 57.53, 84.94,
128.75, 129.64, 135.19, 135.57, 162.78 and 167.53.
(3S,9aS)-3-[(1ЈS)-1Ј-Phenylselenoethyl]-3-methyloctahydro-
pyrrolo[1,2-a][1,4]diazepine-1,5-dione 9
Mp 139–140 ЊC; [α]D Ϫ221.77 (c 0.82, CHCl3); RF 0.56 (silica,
ethyl acetate); λmax(MeOH)/nm 208 and 268; νmax(film)/cmϪ1
2391, 1766, 1682, 1448, 1265 and 740; δH(CDCl3) 1.52 (d, J 7.1,
3H, CH3), 1.91 (m, 1H, CHCH2N), 2.03 (m, 1H, CHCH2N),
2.26 (m, 1H, CHCH2CH2N), 2.38 (m, 1H, CHCH2CH2N), 3.59
(m, 2H, CH2N), 3.99 (dq, J 7.1, 2.4, 1H, CHCH3), 4.20 (t, J 8.0,
1H, CHCH2CH2CH2N), 4.93 [d, J 2.4, 1H, C(O)CHNH] and
7.26–7.62 (m, 5H, Ph); δC(CDCl3) 16.62, 23.41, 28.79, 37.67,
45.61, 58.09, 81.80, 128.37, 129.64, 135.18, 163.77 and 168.80;
m/z (FAB) 339 (Mϩ ϩ 1).
1H, CH᎐C(CH ) ].
᎐
3 2
Cyclofunctionalization of (S)-N-(â-methylcrotonyl)prolin-
amide 14. To a solution of (S)-N-β-methylcrotonoyl)prolin-
amide 14 (398 mg, 2.0 mmol) in acetonitrile (15 ml) were added
silver trifluoromethanesulfonate (1.04 g, 4.0 mmol) in aceto-
nitrile (12 ml), and then benzeneselenyl bromide (0.85 g, 3.6
mmol) and dimethylformamide (3.1 ml, 40 mmol) in aceto-
nitrile (12 ml). The resulting mixture was stirred at ambient
temperature for 12 h, after which it was treated with saturated
aqueous NaHCO3, and extracted with methylene dichloride.
The extract was washed with brine, dried and evaporated to
give the crude product, column chromatography of which
afforded 15 (157.2 mg, 22.4%) as a yellow solid and 16 (364.8
mg, 49.4%) and 17 (98.6 mg, 13.3%) as colourless oils.
(S)-N-(3-Hydroxy-2-phenylselenobutanoyl)prolinamide 10
Mp 119–122 ЊC; [α]D Ϫ108.68 (c 0.85, CHCl3); RF 0.06 (silica,
ethyl acetate); νmax(film)/cmϪ1 3360, 3200, 2972, 2877, 1678,
1628, 1431 and 740; δH(CDCl3) 1.39 (d, J 6.3, 3H, CH3), 1.86–
1.99 (m, 3H, CHCH2CH2N), 2.13 (m, 1H, CHCH2CH2N), 3.27
(dd, J 16.8, 7.5, 1H, CHHN), 3.63 (m, 1H, CHHN), 3.78 (d,
J 8.2, 1H, HCSePh), 4.25 (dq, J 8.2, 6.3, 1H, CHCH3), 4.38 (dd,
(9aS)-3,3-Dimethyl-4-phenylselenooctahydropyrrolo[1,2-a]-
[1,4]diazepine-1,5-dione 15. Mp 190–191.5 ЊC; [α]D Ϫ14.54 (c
1.00, CHCl3); RF 0.77 (silica, MeOH–CH2Cl2, 1:10); νmax
-
(film)/cmϪ1 1649, 1437 and 735; δH(CDCl3) 1.27 (s, 3H, CH3),
974
J. Chem. Soc., Perkin Trans. 1, 1998

View Article Online
Table 2 Crystal data for compounds 2, 3, 8 and 9
Compound
2
3
8
9
Empirical formula
M
C20H20N2O2Se
399.34
C20H18N2O2Se
397.32
C15H18N2O2Se
337.27
C15H18N2O2Se
337.27
Crystal system
Space group
orthorhombic
P212121
monoclinic
P21
orthorhombic
P212121
orthorhombic
P212121
a/Å
b/Å
c/Å
8.783(1)
11.959(1)
17.288(1)
12.681(1)
5.523(2)
12.846(7)
92.88(3)
898.6(6)
2
5.3445(4)
10.4678(8)
26.549(3)
5.271(1)
10.181(2)
27.974(6)
β/Њ
V/Å3
1815.7(3)
4
1.460
20.83
1485.3
4
1.508
25.31
1501.2(5)
4
1.492
Z
Dc/g cmϪ3
1.469
21.05
µ/cmϪ1
25.04
F(000)
816
404
688
688
Crystal size
θ range for data collection
Index ranges
0.35 × 0.30 × 0.10 mm
2.07 to 23.97Њ
h = 0 → 10
k = 0 → 13
l = 0 → 19
1639
0.45 × 0.25 × 0.20 mm
1.59 to 24.97Њ
h = Ϫ15 → 15
k = 0 → 6
l = 0 → 15
1846
0.40 × 0.20 × 0.15 mm
1.53 to 22.95Њ
h = 0 → 5
k = 0 → 11
l = 0 → 29
1236
0.45 × 0.35 × 0.30 mm
2.13 to 21.99Њ
h = 0 → 5
k = 0 → 10
l = 0 → 29
1114
Reflections collected
Independent reflections
Refinement method
1639
1762
1236
1114
Full-matrix least squares
on F2
Data/parameters
1639/226
1.040
0.02(3)
R1 = 0.045, wR2 = 0.093
R1 = 0.063, wR2 = 0.103
0.276 and Ϫ0.357 e ÅϪ3
1762/226
1.034
0.01(2)
R1 = 0.044, wR2 = 0.092
R1 = 0.066, wR2 = 0.103
0.335 and Ϫ0.372 e ÅϪ3
1236/181
1.098
Ϫ0.11(6)
R1 = 0.072, wR2 = 0.167
R1 = 0.100, wR2 = 0.185
0.536 and Ϫ0.716 e ÅϪ3
1114/173
1.097
0.00(5)
R1 = 0.069, wR2 = 0.179
R1 = 0.088, wR2 = 0.196
0.382 and Ϫ0.905 e ÅϪ3
Goodness-of-fit on F2
Absolute structure parameter
Final R indices [I > 2σ(I)]
R Indices (all data)
Largest diff. Peak and hole
¹
2
R indicies; R1 = [Σ Fo| Ϫ |Fc ]/Σ|Fo| (based on F), wR2 = {[Σw(|Fo2 Ϫ Fc2|)2]/[Σw(Fo )2]}² (based on F2).
1.34 (s, 3H, CH3), 1.78 (m, 2H, CH2CH2N), 2.11 (m, 1H,
CHCH2CH2N), 2.55 m, 1H, CHCH2CH2N), 3.53 (m, 2H,
CH2N), 4.42 (dd, J 7.8, 4.9, 1H, CHCH2CH2CH2N), 4.46 [s,
1H, C(O)CHSePh] and 7.19–7.59 (m, 5H, Ph); δC(CDCl3)
22.84, 26.82, 28.97, 31.65, 47.09, 58.27, 58.72, 59.94, 127.76,
129.17, 130.48, 134.20, 167.41 and 169.51; m/z (EI) [Found
(HRMS, EI): m/z 352.0691. Calc. for C16H20N2O2Se: 352.0690].
(S)-N-(3-Hydroxy-3-ethyl-2-phenylselenobutanoyl)prolin-
amide 16. [α]D Ϫ107.04 (c 2.7, MeOH); RF 0.08 (silica, ethyl
acetate); δH(CDCl3) 1.37 (s, 3H, CH3), 1.50 (s, 3H, CH3), 1.60–
2.19 (m, 4H, CH2CH2CH2N), 2.79 (m, 1H, CHHN), 3.34 (m,
1H, CHHN), 3.93 (s, 1H, HCSePh), 4.40 (dd, J 7.8, 3.0, 1H,
CHCH2CH2CH2N), 4.95 (s, 1H, OH), 5.71 (s, 1H, NH), 6.94 (s,
1H, NH) and 7.28–7.72 (m, 5H, Ph); δC(CDCl3) 24.88, 28.55,
29.02, 48.21, 54.52, 55.43, 60.06, 72.55, 128.14, 129.27, 129.60,
136.72, 173.35 and 174.04; m/z (FAB) 371 (Mϩ ϩ 1).
1.34 (s, 3H, CH3), 1.36 (s, 3H, CH3), 1.83 (m, 2H, CH2CH2N),
2.16 (m, 1H, CHCH2CH2N), 2.47 [dd, J 14.1, 1.8, 1H,
C(O)CHH], 2.67 (m, 1H, CHCH2CH2N), 3.07 [d, J 14.1, 1H,
C(O)CHH), 3.56 (m, 2H, CH2N), 4.42 (dd, J 8.1, 4.8, 1H,
CHCH2CH2CH2N) and 5.83 (s, 1H, NH); δC(CDCl3) 23.30,
28.83, 29.77, 32.94, 46.45, 49.94, 53.34, 59.64, 168.61 and
169.40.
X-Ray crystal structure determinations of compounds 2, 3, 8 and
9
A crystal of each of the compounds 2, 3, 8 and 9 was sealed in a
Lindemann glass capillary tube and mounted on an Enraf-
Nonius CAD4 diffractometer equipped with graphite-
monochromated Mo-Kα (λ = 0.710 69 Å) radiation. Cell
parameters and an orientation matrix for data collection were
obtained from least-squares refinement, using the setting angles
of 25 reflections at 293 K. The intensities of 3 standard reflec-
tions, recorded every 3 h of X-ray exposure, showed no system-
atic changes. The crystal data for compounds 2, 3, 8 and 9 are
summarized in Table 2. The intensity data were corrected for
Lorentz and polarization effects. Empirical absorption correc-
tions were also applied (XABS2).14 Their structures were solved
by direct methods (SHELXS-86).15 For 9, the phenylselenyl
group was disordered over two sites and the sum of their
occupancies was fixed to 1 (0.493 ϩ 0.507). Full-matrix least-
squares refinement16 was employed with anisotropic thermal
parameters for all non-hydrogen atoms. Full crystallographic
details, excluding structure factor tables, have been deposited at
the Cambridge Crystallographic Data Centre (CCDC). For
details of the deposition scheme, see ‘Instructions for Authors’,
J. Chem. Soc., Perkin Trans. 1, available via the RSC Web
pages (http://www.rsc.org/authors). Any request to the CCDC
for this material should quote the full literature citation and the
reference number 207/176.
(S)-N-(3-Hydroxy-3-methyl-2-phenylselenobutanoyl)prolin-
amide 17
[α]D ϩ35.12 (c 0.885, CH3OH); RF 0.11 (silica, ethyl acetate);
δH(CDCl3) 1.37 (s, 3H, CH3), 1.56 (s, 3H, CH3), 1.66–1.95 (m,
3H, CHCH2CH2N ϩ CH2CH2N), 2.39 (m, 1H, CHCH2-
CH2N), 2.76 (m, 1H, CHHN), 3.14 (dd, J 17.0, 8.6, 1H,
CHHN), 3.75 (s, 1H, HCSePh), 4.67 (ad, J 6.1, 1H, CHCH2-
CH2CH2N), 4.90 (s, 1H, OH), 5.61 (s, 1H, NH), 6.87 (s, 1H,
NH) and 7.28–7.72 (m, 5H, Ph); δC(CDCl3) 25.15, 27.66, 28.72,
28.90, 48.9, 55.46, 59.54, 72.16, 126.30, 129.24, 129.77, 136.48,
172.97 and 174.79; m/z (FAB) 371 (Mϩ ϩ 1).
(9aS)-3,3-Dimethyloctahydropyrrolo[1,2-a][1,4]diazepine-
1,5-dione 18. To a solution of 15 (75.2 mg, 0.21 mmol) in THF
(3 ml) was added a solution of nickel() chloride hexahydrate
(101.8 mg, 0.42 mmol) in MeOH (3 ml) at ambient temperature.
The mixture was cooled in an ice-bath and treated with sodium
borohydride (48.6 mg, 1.28 mmol), added in small portions.
After an additional 10 min at 0 ЊC, the mixture was filtered
through Celite and chromatographed to give product 18 (42.0
mg, quantitative yield) as a white solid, mp 195–197 ЊC; [α]D
Ϫ120.33 (c 1.26, CHCl3); RF 0.44 (silica, MeOH–CH2Cl2,
1:10); νmax(film)/cmϪ1 1655, 1444, 1262 and 854; δH(CDCl3)
Acknowledgements
The authors are grateful to the Korea Science & Engineering
Foundation and POSCO for financial support of this work. We
J. Chem. Soc., Perkin Trans. 1, 1998
975

View Article Online
5 (a) A. J. Biloski, R. D. Wood and B. Ganem, J. Am. Chem. Soc.,
also thank Dr Dongmok Whang in the laboratory of Professor
Kimoon Kim for assistance in obtaining the X-ray crystal
structures.
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7 A preliminary account of this work was published. S. K. Chung,
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Paper 7/05390H
Received 25th July 1997
Accepted 3rd December 1997
976
J. Chem. Soc., Perkin Trans. 1, 1998