Highly diastereoselective allylation and reduction of chiral camphor-derived α-ketoamides

Article abstract of DOI:10.1016/j.tetasy.2006.01.011

The diastereoselective allylation and reduction of camphor-derived α-ketoamides to give optically enriched α-hydroxyl amides with high to excellent stereoselectivities are described. Allylation was carried out using allyltributylstannane in the presence o

Full text of DOI:10.1016/j.tetasy.2006.01.011

Tetrahedron: Asymmetry 17 (2006) 336–346
Highly diastereoselective allylation and reduction of
chiral camphor-derived a-ketoamides
Neelesh A. Kulkarni, Shy-Guey Wang, Li-Chen Lee, Huei Ru Tsai,
Uppala Venkatesham and Kwunmin Chen*
Department of Chemistry, National Taiwan Normal University, Taipei 116, Taiwan, ROC
Received 14 November 2005; revised 17 January 2006; accepted 18 January 2006
Available online 20 February 2006
Abstract—The diastereoselective allylation and reduction of camphor-derived a-ketoamides to give optically enriched a-hydroxyl
amides with high to excellent stereoselectivities are described. Allylation was carried out using allyltributylstannane in the presence
of a stoichiometric amount of a Lewis acid to afford the desired homoallylic alcohols in relatively high chemical yields (up to 98%)
and stereoselectivities (up to 98% de). Diastereoselective reductions were performed with the relatively bulky hydride K-Selectride at
ꢀ78 ꢀC to give the corresponding a-hydroxy amides in excellent chemical yields (up to 98%) and stereoselectivities (up to 98% de).
The absolute configuration of the new stereogenic center of the major diastereomer was established by X-ray crystallographic anal-
ysis. Finally, stereochemical induction and the Lewis acid dependent reversal of stereoselectivity is described.
ꢁ 2006 Elsevier Ltd. All rights reserved.
1. Introduction
has been focused on the development of novel methods
for the preparation of two possible stereoisomers from a
single chiral material, a topic that is at the forefront of
synthetic organic chemistry.7
The allylmetal addition and hydride reduction of a car-
bonyl functionality has been extensively studied for over
the last few decades and has proven to be an enormously
successful method for the construction of carbon–car-
bon bonds. The enantioselective version of allylation,1
and hydride reduction,2 of C@O and C@N functional-
ities, to produce the corresponding optically enriched
alcohols and amines, have been documented in the liter-
ature. These utilities stimulated an important synergy
between the fundamental studies of the stereochemistry
and applications in target-oriented synthesis.3 On the
other hand, the diastereoselective allylation and reduc-
tion of an a-dicarbonyl functionality bearing a chiral
auxiliary provide an alternative route to the preparation
of important structural arrays.4 The diastereoselective
allylation of a-ketoamides to give homoallylic hydroxyl
acid derivatives can be readily used in further functional
group transformations.5 The diastereoselective reduc-
tion of a-ketoamides, to produce chiral a-hydroxyl acid
derivatives, which are fairly common structural units,
that are useful in complex bioactive natural products
synthesis, has been described.6 Considerable interest
In continuation of our research interest in the area of
asymmetric synthesis,8 we herein report a full account
of the diastereoselective allylation and hydride reduction
of a variety of a-ketoamides, derived from camphor-
based chiral auxiliaries (Xc = A–C) (Fig. 1) to give the
corresponding a-hydroxy amides in high to excellent
yields and diastereoselectivities. The stereochemical
course of the reaction and proposed mechanisms for
the reactions are discussed.
2. Results and discussion
The starting chiral a-ketoamides 1a–j were readily
prepared from the camphor-based chiral auxiliaries:
camphor N-phenyl pyrazolidinone A, camphor N-tosyl-
pyrazolidinone B,9 and camphorsultam C and the chem-
1
ical structures were unambiguously assigned by H, 13C
NMR, HRMS as well as X-ray crystallographic analysis
in some cases. A variety of aromatic, heteroaromatic
and aliphatic a-ketoamides were utilized in the diaste-
reoselective allylation and reduction reactions while
the results are summarized in Tables 1–3.
*
Corresponding author. Tel.: +886
2 89315831; fax: +886 2
29324249; e-mail: kchen@cc.ntnu.edu.tw
0957-4166/$ - see front matter ꢁ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2006.01.011

N. A. Kulkarni et al. / Tetrahedron: Asymmetry 17 (2006) 336–346
337
1a: Xc =A, R = H
1b: Xc =A, R = Ph
1c: Xc =A, R = Me
1d: Xc =A, R = Et
1f: Xc = C, R = Ph
1g: Xc = B, R = Ph
1h: Xc = B, R = Me
1i : Xc = B, R = Et
allyltributylstannane in the absence of a Lewis acid,
provided the desired product in 50% yield and low stereo-
selectivity (Table 1, entry 1). Various Lewis acids,
including Sn(OTf)2, Sc(OTf)3, Sm(OTf)3 and Yb(OTf)3,
were then employed and all the reactions led to only
modest stereoselection with good to high chemical yields
(entries 2–5). The reactivity was improved upon when
the reaction was carried out in the presence of Eu(OTf)3
in CH3CN (entry 6). The diastereoselectivity was deter-
O
Xc
R
O
1e: Xc =A, R = 2-thienyl 1j : Xc = B, R = 2-thienyl
Me
Me
Me
Me
Xc:
N
N
O
1
2
1
N
R
S
O
C
mined by H NMR analysis of the crude products as
O
judged by the integration of the C-2 methine proton
resonances (camphor numbering). The absolute configu-
ration of the major diastereomer was assigned as an
(S)-configuration based on a single crystal X-ray analy-
sis. Solvent effects were then examined and CH3CN
found to be the solvent of choice for the reaction (entries
7–9). The use of 0.5 equiv of a Lewis acid provided the
desired products in 91% yield, while the reaction pro-
ceeded sluggishly when 0.1 equiv of Lewis acid was used
(entries 10 and 11). It thus appeared that the use of a
stoichiometric amount of a Lewis acid in CH3CN was
A: R = Ph
B: R = Ts
Figure 1. Structures of various camphor-derived a-ketoamides 1a–j.
2.1. Asymmetric allylation
With various a-carbonyl amides in hand, we examined
the diastereoselective allylation reaction. Treatment of
camphor N-phenyl pyrazolidinone glyoxylate 1a,8a with
Table 1. Diastereoselective allylation of camphor N-phenylpyrazolidinone derived a-ketoamides 1a–e with allyltributylstannane in the presence of a
Lewis acida
Me
Me
Me
Me
HO
O
R
R
OH
N
N
N
N
O
O
O
Ph
Ph
2a-e
3a-e
a: R = H
b: R = Ph
c: R = Me
d: R = Et
e: R = 2-thienyl
Entry
Substrate
Lewis acid (equiv)
Solvent
Time/h
Yield (%)b
Dr (2:3)c
1
2
3
4
5
6
7
8
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1b
1b
1b
1c
1c
1ce
1c
1d
1e
—
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
THF
CH2Cl2
Toluene
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
168
50
<20
94
88
90
90
75
85
88
91
62
50
93
95
89
90
85
51
91
92
55:45
—
Sn(OTf)2 (1.0)
Sc(OTf)3 (1.0)
Sm(OTf)3 (1.0)
Yb(OTf)3 (1.0)
Eu(OTf)3 (1.0)
Eu(OTf)3 (1.0)
Eu(OTf)3 (1.0)
Eu(OTf)3 (1.0)
Eu(OTf)3 (0.5)
Eu(OTf)3 (0.1)
Eu(OTf)3 (1.0)
Zn(OTf)2 (1.0)
Sn(OTf)2 (1.0)
Sn(OTf)2 (1.0)
Zn(OTf)2 (1.0)
Zn(OTf)2 (1.0)
Eu(OTf)2 (1.0)
Sn(OTf)2 (1.0)
Sn(OTf)2 (1.0)
5 min
30 min
20 min
20 min
5 min
5
30 min
10 min
10 min
4
67:33
70:30
72:28
75d:25
43:57
42:58
43:57
71:29
70:30
72:28
96:04
99d:01
77:23
88:12
89:11
26:74
83:17
99:01
9
10
11
12
13
14
15
16
17
18
19
20
72
40 min
5 min
5 min
3
48
72
5 min
5 min
a Unless otherwise noted, all reactions were carried out at ambient temperature using 1 (0.16 mmol), allyltributylstannane (2.0 equiv), a Lewis acid
and the solvent indicated.
b Total isolated yield (2 + 3).
c Diastereomeric ratios was determined by 1H NMR analysis of the relevant peaks and/or HPLC analysis [(Daicel chiralcel chiral OD column: 2-
propanol/hexane = 05:95, 1.0 mL/min)] from the crude products.
d The absolute stereochemistry of the new stereogenic carbon center was determined by single crystal X-ray analysis.
e Reaction was performed at ꢀ30 ꢀC.

338
N. A. Kulkarni et al. / Tetrahedron: Asymmetry 17 (2006) 336–346
Table 2. Diastereoselective allylation of camphorsultam phenylglyoxylate 1f and camphor N-tosylpyrazolidinone 1g with allyltributylstannane in the
presence of a Lewis acida
Me
Me
Me
Me
Me
Me
Me
Me
O
O
HO
O
Ph
Ph
OH
N
N
N
O
N
O
Ph
OH
HO
Ph
N
N
S
S
O
O
O
Ts
Ts
O
O
7g
6g
4f
5f
Entry
Substrate
Lewis acid (equiv)
Solvent
Time/h
Yield (%)b
Dr (4f:5f)c
Dr (6g:7g)c
1
2
3
4
5
6
7
8
1f
1f
1f
1f
1fe
1f
1f
1f
1f
1f
1g
1g
Sn(OTf)2 (2.0)
Zn(OTf)2 (2.0)
ZnCl2 (2.0)
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
THF
Toluene
CH2Cl2
CH3CN
CH2Cl2
48
6
62
87
92
95
—
50
95
95
95
28
92
60
87d:13
14:86
14:86
12:88
—
13:87
11:89d
11:89
55:45
38:62
72
72
48
48
6
24
24
48
5 min
24
ZnI2 (2.0)
Zn(OTf)2 (0.5)
Zn(OTf)2 (1.0)
Zn(OTf)2 (3.0)
Zn(OTf)2 (3.0)
Zn(OTf)2 (3.0)
Zn(OTf)2 (3.0)
Sn(OTf)2 (2.0)
PdCl2 (2.0)
9
10
11f
12f
99d:01
06:94d
a Unless otherwise noted, all reactions were carried out at ambient temperature using 1 (0.16 mmol), allyltributylstannane (2.0 equiv), a Lewis acid
and the solvent indicated.
b Total isolated yield.
c Diastereomeric ratios was determined by1H NMR analysis of the relevant peaks of the crude products.
d The absolute stereochemistry of the newly generated stereogenic center was determined by single crystal X-ray analyses of 4f, 5f, 6g and 7g.
e Trace amount of the products were observed.
f See Ref. 9.
Table 3. Diastereoselective reduction of camphor N-phenyl and N-tosylpyrazolidinone-derived a-ketoamides 1b–e and 1g, i–j with various reducing
agentsa
Me
Me
Me
Me
Me
Me
Me
Me
HO
O
H
H
OH
R
HO
O
H
H
OH
R
N
N
N
N
R
R
N
N
N
N
O
O
O
O
O
O
Ph
Ph
Ts
Ts
9
8
10
11
g: R = Ph
i: R = Et
j: R = 2-thienyl
b: R = Ph
c: R = Me
d: R = Et
e: R = 2-thienyl
Reductant
NaBH4
Entry
Substrate
Solvent
Yield (%)b
Dr (8:9)c
Dr (10:11)c
1
2
3
4
5
6
7
8
1b
1b
1be
1b
1c
1c
1c
1d
1e
1g
1g
1i
MeOH
THF
THF
THF
MeOH
THF
THF
THF
THF
THF
THF
THF
THF
82
90
50
98
80
92
95
96
98
72
68
65
81
>99:01
>99:01
>99:01
>99d:01
>99:01
>99:01
>99:01
>99d:01
>99d:01
LiB(C2H5)3H
K-Selectride
K-Selectride
NaBH4
LiB(C2H5)3H
K-Selectride
K-Selectride
K-Selectride
K-Selectride
L-Selectride
L-Selectride
L-Selectride
9
10f
11
12
13
90:10d
97:03
97:03
97:03
1j
a Unless otherwise noted, all reactions were carried out at ꢀ78 ꢀC using 1 (0.26 mmol), metal hydride (0.26 mmol) and the solvent indicated.
b Isolated yields of the products.
c Diastereomeric ratios was determined by 1H NMR analysis of relevant peaks of the crude products.
d Absolute configuration of the newly generated stereogenic center was deduced from the X-ray crystallographic analysis 8b, 8d–e and 11g.
e Reaction was performed at 0 ꢀC.
f For entries 10–13, reactions were carried out at ꢀ78 ꢀC using (0.43 mmol), metal hydride (0.86 mmol) in THF.

N. A. Kulkarni et al. / Tetrahedron: Asymmetry 17 (2006) 336–346
339
SnBu3
optimal for the reaction (entry 6). We next investigated
SnBu3
Me
Me
Me
Me
the allylation of camphor N-phenyl pyrazolidinone
phenylglyoxylate 1b, under the developed conditions.
Treatment of a-ketoamide 1b under the same reaction
conditions gave the product in 50% yield and 44% de
(entry 12). Both the reactivity and stereoselectivity were
improved when Eu(OTf)3 was replaced with Zn(OTf)2
under similar conditions (entry 13). Interestingly, this
was further improved upon when Sn(OTf)2 was used
(entry 14). We then studied the substrate scope of
the allylation reaction under optimum conditions. To
this end, a high material yield and reasonable stereo-
selectivity were observed when camphor N-phenyl-
pyrazolidinone methylglyoxylate 1c was used (entry
15). However, the selectivity was improved to 76%
de when Zn(OTf)2 was employed instead of Sn(OTf)2
(entry 16). It is noteworthy that the stereoselectivity
was reversed when the reaction was carried out using
several different Lewis acids (compare entries 16 and
18). The allylation reactions of aliphatic and hetero aro-
matic backbone architectures 1d–e proceeded smoothly
to give the corresponding allylation products in good
to excellent stereoselectivities (entries 19 and 20).
ZnLn
O
O
O
Ph
N
O
N
O
S
Ph
S
O
Sn
Ln
O
O
B' (1f)
B (1f)
Figure 3. Proposed mechanism for the reaction of camphorsultam
phenyl glyoxylate 1f with allyltributylstannane in the presence of a
Lewis acid.
signals at d 160.60 and 189.40 ppm were shifted upfield
to d 160.47 and 189.22 ppm, respectively.11 These results
indicate that the Sn is strongly coordinated to dicarbonyl
oxygen atoms, resulting in the formation of the preferred
s-cis conformation. The major diastereoisomer is then
obtained when the allyl reagent approaches from the less
hindered bottom si face of the a-carbonyl group, to
afford the desired product.
We further investigated the scope of the chiral auxilia-
ries; these results are presented in Table 2. Camphorsul-
tam, one of the most widely used chiral auxiliaries, has
great versatility in organic synthesis. Treatment of
phenylglyoxylate 1f with allyltributystannane using
Sn(OTf)2 afforded the desired product in good stereose-
lectivity (Table 2, entry 1). The absolute stereochemistry
of the major diastereomer was assigned as an (R)-config-
uration by X-ray crystallographic analysis. It is interest-
ing to note that a reversal of stereoselectivity occurred
when Zn(OTf)2 was used in place of Sn(OTf)2 (entry
2). The influence of the Lewis acid in causing a reversal
in stereoselectivity deserves special attention. The use of
different Zn metals failed to improve the stereoselectivi-
ties (entries 3 and 4). The effects of the amount of Lewis
acid was then studied. It is interesting to note that for
camphor N-tosylpyrazolidinone B and camphorsultam
C derived substrates, the use of more than 1.0 equiv of
a Lewis acid was required to achieve high material yields
(Table 2, entries 5–7). The use of 3.0 equiv of Zn(OTf)2
provided 5f in high chemical yield and stereoselectivity
(entry 7). This may be due to the presence of the sulfone
functionality in the auxiliaries B and C. Studies of sol-
vent effects indicate that CH3CN is the most effective
solvent, affording the allylation product in 95% yield
(entries 7–10).
The stereochemical outcome can be rationalized by
invoking the conformational preferences of a-keto-
amides 1b–e in the transition state (Fig. 2).10 The pseu-
do-planar s-trans conformation (A) of the a-dicarbonyl
group in 1a–e is electronically favored over its s-cis con-
former (A0) in the solid state; this is supported by single
crystal X-ray analyses of 1b–e. This is due to the avoid-
ance of dipole–dipole repulsions of the two carbonyl
functionalities. However, the coordination of the Lewis
acid metal ion to the dicarbonyl oxygen atoms shifted
the reaction toward the formation of the s-cis conforma-
tion. The equilibrium between the different conforma-
tional states is highly dependent upon the type and
amount of Lewis acid used in the reaction. From the
data, we proposed that for strong Lewis acids, such as
Zn(OTf)3 and Sn(OTf)2, the metal coordinates to the
dicarbonyl oxygen atoms to give the desired major dia-
stereomer. On the other hand, Eu(OTf)3 coordinates to
dicarbonyl oxygen atoms in most substrates while
mono-coordinates to an oxygen atom in a specific sub-
strate (1c). Spectroscopic evidence for the dual coordina-
tion behavior of Sn(OTf)2 was obtained by 13C NMR
spectroscopy using camphor N-phenylpyrazolidinone
phenylglyoxylate 1b. The 100 MHz 13C NMR spectrum
of a mixture of Sn(OTf)2 and 1b (1:1) complex in CD3CN
at room temperature showed that the original dicarbonyl
We next investigated the allylation of camphor N-tos-
ylpyrazolidinone phenylglyoxylate 1g derived from chi-
ral auxiliary B.9 No reaction products were obtained
when 1g was treated with allyltributylstannane in the ab-
sence of a Lewis acid. Various metal triflates, including
Sc(OTf)3, Sm(OTf)3, Zn(OTf)2 and Eu(OTf)3, were sys-
tematically screened, but resulted in either low to moder-
ate chemical yields or low levels of diastereoselectivities
(data not shown). Excellent stereoselectivity was ob-
tained when the reaction was carried out in the presence
of Sn(OTf)2 in a 5 min reaction (entry 11).9 The diastereo-
selectivity was determined from the 1H NMR spectra of
relevant peaks and an HPLC analysis of crude products.
Me
Me
Me
Me
EuLn
Me
O
Ph
N
N
O
N
N
O
O
SnBu3
O
O
Ph
Ph
SnLn
EuLn
SnBu3
A (1c)
A' (1b)
Figure 2. Proposed mechanism for the reaction of a-ketoamide 1b and
1c with allyltributylstannane in the presence of a Lewis acid.

340
N. A. Kulkarni et al. / Tetrahedron: Asymmetry 17 (2006) 336–346
The absolute stereochemistry of the new stereogenic cen-
ter in the major diastereomer 6g was assigned as an (R)-
configuration, by means of X-ray crystallographic anal-
ysis. The reactivity decreased when the reaction was car-
ried out in the presence of PdCl2 with the major product
with the reversed stereochemistry (entry 12). The struc-
ture of the major diastereomer 7g was again confirmed
by X-ray crystallographic analysis. A careful study of
1H NMR spectra indicates that the characteristic C-2
methine proton (camphor numbering) appears at an up-
field position (3.16 ppm) for the (R)-isomer compared
with that of the counter (S)-product (4.32 ppm). The dia-
magnetic anisotropy effect of the aromatic substituent
may account for the shielding effect.
as an (S)-configuration by an X-ray crystallographic
analysis of 8b.
Substrate generality was then investigated for a wide
variety of a-ketoamides 1b–e under the optimized condi-
tions. The reduction of the aliphatic ketone 1c with
NaBH4 in MeOH provided the product in 80% material
yield, while the use of LiB(C2H5)3H and K-Selectride re-
sulted in excellent stereoselectivities (entries 5–7). The
reduction of 1d and a 2-thienyl substituent substrate
1e was examined and excellent material yields and stereo-
selectivities were obtained (entries 8 and 9). Finally, the
reduction of camphor N-phenylpyrazolidinone 3-indo-
loylglyoxylate with either NaBH4 or K-Selectride virtu-
ally failed to yield any detectable products. This was
presumably due to the presence of a ketone functionality
in conjugation with the nitrogen of an indole, which
could result in a decrease in the electrophilicity of the
carbonyl carbon, thus leading to a lower reactivity.
The reversal of stereoselectivity in the allylation of 1f
and 1g can be rationalized by the coordination of a
Lewis acid with different Lewis base atoms, as shown
in Figure 3. The results obtained for the allylation reac-
tion of 1f catalyzed by Sn(OTf)2 can be explained by the
formation of the chelated conformer B,12 which is sup-
ported by IR spectroscopic data. Upon the addition of
1 equiv of the Lewis acid Sn(OTf)2, the sulfonyl stretch-
ing band was shifted from 1042 to 1028 cmꢀ1. On the
other hand, the sulfonyl group absorbs at 1038 cmꢀ1
when complexed with 1 equiv of Zn(OTf)2. The use of
Zn(OTf)2 afforded the desired products, which can be
explained by the predominance of the chelated con-
former B0, leading to the formation of the desired prod-
uct. Additionally, the reversal of stereoselectivity in the
allylation of 1g was deduced from 13C NMR and FTIR
data.9 The coordination of the Sn(OTf)2 to the sulfonyl
group resulted in the rapid release of the nucleophilic
allyl group, which may account for the much faster reac-
tion in the presence of Sn(OTf)2 compared to the use of
PdCl2 (5 min vs 24 h). The allyl group then attacks the
a-carbonyl group from the bottom si face to afford the
desired product. In the case of PdCl2, the electron-rich
tosyl group prevents nucleophilic addition from the si
face, leading to the addition from the top re face.
Structural aspects of the chiral auxiliary were also inves-
tigated under the developed reaction conditions with the
camphor N-tosylpyrazolidinone derived a-ketoamides
1g–j (Table 3). Treatment of camphor N-tosylpyrazolid-
inone phenylglyoxylate 1g in THF with K-Selectride at
ꢀ78 ꢀC gave the desired product in 72% chemical yield
and good stereoselectivity (80% de) (entry 10). The dia-
stereoselectivity was further improved to 94% when
LiB(C2H5)3H was used (entry 11). The diastereomeric
1
excess was determined by H NMR analysis of the rele-
vant peaks of the crude products. The absolute configu-
ration of the newly generated stereogenic center in the
minor diastereomer 11g was determined to have an
(R)-configuration, as deduced from a single X-ray crys-
tal analysis. In the case of the methylglyoxylate deriva-
tive 1h, cleavage of the auxiliary was observed under
the conditions used for the reduction. High stereoselec-
tivities were achieved in the case of the ethyl and thienyl
derivatives 1i–j (entries 12 and 13).
The stereochemical outcome of the asymmetric reduc-
tion may be rationalized by the conformational prefer-
ence of pyrazolidinone derived a-ketoamides. The
pseudo-planar s-trans conformation of the a-dicarbonyl
group in 1b–e is electronically favored over its s-cis con-
former in the solid state as evidenced by X-ray crystallo-
graphic analyses (Fig. 4). This is due to the avoidance of
dipole repulsion between the two carbonyl functional-
ities. In the s-cis conformation, the carbonyls (amide
and carbonyl functionalities) are in close proximity,
which causes mutual electronic repulsions. To avoid
2.2. Asymmetric reduction
In the second aspect of the study, the diastereoselective
reduction of the a-ketoamides was carried out and the re-
sults of these experiments tabulated in Table 3. Various
chiral a-ketoamides were subjected to the reduction con-
ditions and camphor N-phenylpyrazolidinone phenylgly-
oxylate 1b was used as a model substrate. Treatment of
1b with NaBH4 in THF at 0 ꢀC resulted in cleavage of
the chiral auxiliary. Only a trace amount of the desired
products were obtained when the reaction was carried
out at ꢀ78 ꢀC. A significant improvement in the chemical
yield (82%) and excellent diastereoselectivity (>95% de)
was achieved when a protic solvent, such as MeOH,
was used at a lower temperature (entry 1). The material
yield was slightly improved when a sterically demanding
reducing reagent, such as LiB(C2H5)3H, was employed
(entry 2). The chemical yield decreased to 50% when
K-Selectride was employed at 0 ꢀC, but was improved
significantly when the same reaction was carried out at
ꢀ78 ꢀC (entries 3 and 4). The absolute stereochemistry
of the newly generated stereogenic center was assigned
Me
Me
Me
Me
O
O
R
H
N
N
R
N
N
O
O
O
O
Ph
Ts
H
D
C
Figure 4. Proposed mechanism for the asymmetric reduction of
a-ketoamides 1b–e (Xc = A) and 1g, i–j (Xc = B).

N. A. Kulkarni et al. / Tetrahedron: Asymmetry 17 (2006) 336–346
341
such repulsions at low temperatures, the carbonyls are
oriented anti to each other. The carbonyl group of the
amide is directed toward the phenyl ring of the pyrazol-
idinone moiety in 1b–e, while they are directed away
from the N-tosyl group in 1g–j. For the allylation, the
presence of a Lewis acid metal chelated to the dicar-
bonyl oxygen atoms, results in the formation of the pre-
ferred s-cis conformation. However, in the hydride
reduction reaction the metal cation predominantly mono-
coordinates to the carbonyl moiety with an s-trans con-
formation. The bulkier camphor moiety shields the top
face of the carbonyl group, thus permitting the hydride
to attack from the sterically less hindered re face for 1b–
d (si face for 1e). In the case of the camphor N-tosylpy-
razolidinone derived a-dicarbonyl, the hydride attacks
from the less hindered re face for 1g–i and the si face
for 1j. This leads to the formation of the desired a-
hydroxyl amides with a high level of stereoselectivity.
graphic Data Center and allocated a CCDC deposit
number.13
4.2. Procedure for the synthesis of (10,10-dimethyl-2-oxo-
3-phenyl-3,4-diaza-tricyclo[5.2.1.01,5]dec-4-yl)-oxo-acet-
aldehyde, 1a
Oxalyl chloride (3.3 mL, 34.7 mmol) was dissolved in
CH2Cl2 (10 mL) and added slowly to N-phenyl camp-
horpyrazolidinone 1 (1 g, 3.9 mmol) in CH2Cl2 (5 mL)
at ambient temperature. The mixture was stirred for
10 min and the solution concentrated in vacuo. The
resulting crude product was dissolved in benzene
(10 mL) and tributyl tinhydride (1.04 mL, 3.9 mmol)
then slowly added. The reaction mixture was allowed
to stir for 10 min at ambient temperature and quenched
with H2O (100 mL), extracted with EtOAc (3 · 75 mL).
The layers were separated and the combined organic ex-
tracts dried over anhydrous MgSO4 and concentrated.
The resulting crude product was further purified by sil-
ica gel flash column chromatography eluted with hex-
ane/EtOAc (2:1), to afford the pure product 1a (0.99 g;
3. Conclusions
1
The diastereoselective allylation and reduction reactions
of a-ketoamides derived from camphor-based chiral
auxiliaries are operationally simple and the products
can be obtained at synthetically useful level of chemical
yields (up to 98%) and stereoselectivities (up to 98% de).
The reversal of stereoselectivity was observed when
different Lewis acids were used for the asymmetric
allylation. For the asymmetric reduction of chiral
a-ketoamides, high to excellent diastereoselectivities
were generally obtained when a bulky hydride was used.
The stereochemical outcome can be explained based on
conformational preferences under the reaction condi-
tions employed.
82%) as a colorless oil: H NMR (400 MHz, CDCl3) d
9.32 (1H, s), 7.39–7.35 (2H, m), 7.24–7.22 (m, 3H),
4.54 (t, 1H, J = 5.3 Hz), 2.33–2.0 (m, 5H), 1.53–1.47
(m, 1H), 1.44–1.36 (m, 1H), 1.17 (s, 3H), 1.15 (s, 3H);
13C (100 MHz, CDCl3) d 186.2, 170.0, 156.8, 128.7,
126.6, 123.4, 122.2, 68.9, 59.1, 52.4, 46.9, 40.4, 28.3,
26.5, 20.4, 19.9; HRMS (EI) calcd for C18H20N2O3
312.1474. Found 312.1478.
4.3. Procedure for the synthesis of 1-(10,10-dimethyl-2-
oxo-3-phenyl-3,4-diaza-tricyclo[5.2.1.01,5]dec-4-yl)-2-phen-
yl-ethane-1,2-dione, 1b
Under a N2 atmosphere, a mixture of phenylglyoxylic
acid (0.64 g, 4.29 mmol) and thionyl chloride (10 mL,
137 mmol) was refluxed for 2 h at 75 ꢀC and concen-
trated. The resulting crude product was dissolved in
CH2Cl2 (5 mL). N-phenyl camphorpyrazolidinone 1
(1.0 g, 3.9 mmol) in CH2Cl2 (5 mL) was added, followed
by stirring for 10 min at ambient temperature. The reac-
tion mixture was quenched with H2O (50 mL) and ex-
tracted with CH2Cl2 (3 · 50 mL). The layers were
separated and the combined organic layers were dried
over anhydrous MgSO4. The resulting crude product
was further purified by silica gel flash column chroma-
4. Experimental methods
4.1. General methods
All reagents were used as purchased from commercial
suppliers without further purification. NMR spectra
were recorded on a Bruker Avance 400 NMR spectro-
meter (400 MHz for 1H, and 100 MHz for 13C). Chemical
shifts are reported in d ppm referenced to an internal
1
TMS standard for H NMR and chloroform-d (d 77.0)
for 13C NMR. Optical rotations were measured on a
JASCO P-1010 polarimeter. EI mass spectra were re-
corded on Finnigan TSQ-700 at an ionizing energy of
70 eV and HRMS spectra were recorded on JEOL SX-
102A. Routine monitoring of reactions was performed
using silica gel, glass-backed TLC plates (Merck Kiesel-
gel 60 F254) and visualized by UV light (254 nm). Solu-
tions were evaporated to dryness under reduced pressure
on a rotary evaporator and the residues purified by flash
column chromatography on silica gel (230–400 mesh)
with the indicated eluents. Air and/or moisture sensitive
reactions were performed under the usual inert atmo-
sphere conditions.
tography eluted with hexane/EtOAc (2:1) to give the
27
pure product 1b (1.28 g; 85%): ½aꢁD ¼ ꢀ144:8 (c 1,
1
CHCl3); H NMR (400 MHz, CDCl3) d 8.10 (d, 2H,
J = 8.1 Hz), 7.61–7.56 (m, 1H), 7.47–7.42 (m, 3H),
7.38–7.36 (m, 3H), 7.20 (br s, 1H), 4.51 (t, 1H,
J = 4.9 Hz), 2.28 (td, 1H, J = 12.0, 5.1 Hz), 2.06–1.86
(m, 4H), 1.52–1.47 (m, 1H), 1.32–1.29 (m, 1H), 1.26 (s,
3H), 1.14 (s, 3H); 13C NMR (100 MHz, CDCl3) d
187.5, 170.2, 158.7, 136.9, 134.8, 132.9, 130.3, 128.8,
128.5, 126.4, 121.9, 68.3, 59.1, 52.2, 47.0, 39.0, 28.3,
26.4, 20.4, 19.8; HRMS (EI) calcd for C24H24N2O3
388.1787. Found 388.1788; IR (neat, cmꢀ1): 3008,
2958, 2879, 1730, 1655, 1594, 1491, 1451, 1340, 1298,
1214, 1133, 962, 755; Crystal data for 1b (colorless crys-
tals, recrystallized from hexanes/EtOAc) at 25 ꢀC:
C24H24N2O3, M = 388.467, orthorhombic, P212121,
Crystallographic data for the structures in this paper
have been deposited with the Cambridge Crystallo-

342
N. A. Kulkarni et al. / Tetrahedron: Asymmetry 17 (2006) 336–346
˚
˚
˚
a = 10.1466 (3) A, b = 10.9048 (3) A, c = 18.8303 (7) A,
Dc = 1.285 Mg/m3, l = 0.183 mmꢀ1, 11172 reflections,
254 parameters, R = 0.0755, Rw = 0.1394.
3
V = 2083.51 (11) A , Z = 4, Dc = 1.238 Mg/m3,
˚
l = 0.082 mmꢀ1, 9170 reflections, 8137 parameters,
R = 0.052, Rw = 0.1267.
4.3.4. 1-(10,10-Dimethyl-3,3-dioxo-3v6-thia-4-aza-tricy-
clo[5.2.1.01,5]dec-4-yl)-2-phenyl-ethane-1,2-dione, 1f.
Yield 70%; 1H NMR (400 MHz, CDCl3) d 7.97 (d,
2H, J 7.5 Hz), 7.66 (t, 1H, J = 7.5 Hz), 7.51 (t, 2H,
J = 7.5 Hz), 4.07 (dd, 1H, J = 7.8, 4.8 Hz), 3.48 (d,
1H, J = 13.8 Hz), 3.42 (d, 1H, J = 13.8 Hz), 2.10–1.92
(m, 5H), 1.45 (t, 1H, J = 9.0 Hz), 1.35–1.33 (m, 1H),
1.20 (s, 3H), 0.97 (s, 3H); 13C (100 MHz, CDCl3) d
186.9, 165.0, 135.1, 132.3, 130.2, 129.0, 64.4, 52.6,
50.0, 48.0, 45.1, 38.2, 32.9, 26.3, 21.0, 19.9; MS (EI)
347 [M]+Æ, C18H21NO4S; Crystal data for 1f (colorless
crystals, recrystallized from hexanes/EtOAc) at 20 ꢀC:
C18H21NO4S, M 347.42, orthorhombic, P212121, a =
4.3.1.
1-(10,10-Dimethyl-2-oxo-3-phenyl-3,4-diaza-tri-
cyclo[5.2.1.01,5]dec-4-yl)-propane-1,2-dione, 1c. Yield
27
1
60%; ½aꢁD ¼ ꢀ52:3 (c 1, CHCl3); H NMR (400 MHz,
CDCl3) d 7.38–7.35 (m, 2H), 7.26–7.20 (m, 3H), 4.51
(t, 1H, J = 6.0 Hz), 2.41 (br s, 3H), 2.28 (td, 1H,
J = 11.8, 4.7 Hz), 2.04–1.99 (m, 4H), 1.52–1.46 (m,
1H), 1.42–1.37 (m, 1H), 1.17 (s, 3H), 1.15 (s, 3H); 13C
(100 MHz, CDCl3) d 195.9, 170.1, 158.3, 136.9, 128.6,
126.5, 122.2, 69.2, 59.1, 52.1, 46.9, 39.9, 28.3, 26.4,
26.1, 20.5, 19.7; HRMS (EI) calcd for C19H22N2O3
326.1630. Found 326.1626; IR (neat, cmꢀ1): 2998,
2963, 2919, 1740, 1715, 1660, 1594, 1490, 1457, 1418,
1387, 1345, 1320, 1306, 1205, 1115, 968, 759; Crystal
data for 1c (colorless crystals, recrystallized from hex-
anes/EtOAc) at 25 ꢀC: C19H22N2O3, M 326.396, ortho-
˚
˚
˚
7.6490 (2) A, b = 11.7760 (3) A, c = 19.0790 (5) A,
3
V = 1758.53 (8) A , Z = 4, Dc = 1.343 Mg/m3, l =
˚
0.210 mmꢀ1, 7515 reflections, 218 parameters, R =
0.0883, Rw = 0.1495.
˚
rhombic, P212121, a = 10.1656 (8) A, b = 11.6227
3
˚
˚
˚
(9) A, c = 15.2081 (13) A, V = 1796.9 (11) A , Z = 4,
Dc = 1.206 Mg/m3, l = 0.082 mmꢀ1, 2518 reflections,
6858 parameters, R = 0.0718, Rw = 0.1779.
4.4. For the experimental procedure for 1g–j, see Ref. 9.
4.5. Typical procedure for the synthesis of 4-(2S)-
(hydroxy-pent-4-enoyl)-10,10-dimethyl-3-phenyl-3,4-
diaza-tricyclo[5.2.1.01,5]decan-2-one, 2a
4.3.2.
cyclo[5.2.1.01,5]dec-4-yl)-butane-1,2-dione,
1-(10,10-Dimethyl-2-oxo-3-phenyl-3,4-diaza-tri-
1d. Yield
27
1
65%; ½aꢁD ¼ ꢀ55:7 (c 1, CHCl3); H NMR (400 MHz,
CDCl3) d 7.38–7.34 (m, 2H), 7.26–7.19 (m, 3H), 4.62
(m, 1H), 3.0 (br s, 1H), 2.66 (br s, 1H), 2.27 (td, 1H,
J = 11.8, 5.4 Hz), 2.03–1.98 (m, 4H), 1.51–1.45 (m,
1H), 1.40–1.34 (m, 1H), 1.17 (s, 3H), 1.14 (s, 3H), 1.10
(s, 3H); 13C (100 MHz, CDCl3) d 198.9, 170.0, 158.5,
137.0, 128.5, 126.4, 122.1, 69.0, 59.0, 52.0, 46.9, 39.6,
32.0, 28.3, 26.4, 20.4, 19.7, 6.9; HRMS (EI) calcd for
C20H24N2O3 340.1787. Found 340.1788; IR (neat,
cmꢀ1): 2961, 1724, 1661, 1595, 1495, 1457, 1303, 1281,
1103, 1071, 970, 756, 692; Crystal data for 1d (colorless
crystal, recrystallized from hexanes/EtOAc) at 25 ꢀC:
The N-glyoxyloyl N-phenyl camphorpyrazolidinone 1a
(50 mg, 0.16 mmol) was dissolved in CH3CN (2 mL)
and Eu(OTf)3 (96 mg, 0.16 mmol) and allyltributyltin
(0.1 mL, 0.32 mmol) were added. The resulting mixture
was stirred for 5 min at ambient temperature and
quenched with H2O (10 mL). The solution was extracted
with CH2Cl2 (3 · 10 mL), the layers were separated and
the organic extracts dried over anhydrous MgSO4. The
crude product was further purified by silica gel flash col-
umn chromatography eluted with hexane/EtOAc (1:1)
to afford the total amount of products (51.05 mg, 90%
yield), major diastereomer 2a; 1H NMR (400 MHz,
CDCl3) d 7.40–7.36 (m, 2H), 7.26–7.24 (m, 3H), 5.80–
5.70 (m, 1H), 5.16 (m, 1H), 5.12 (m, 1H), 4.30 (dd,
1H, J = 7.9, 5.0 Hz), 4.05 (m, 1H), 2.81–2.75 (m, 1H),
2.53–2.47 (m, 1H), 2.40–2.26 (m, 2H), 2.11 (dd, 1H,
J = 13.5, 7.9 Hz), 2.08–2.01 (m, 2H), 1.51–1.38 (m,
2H), 1.20 (s, 3H), 1.15 (s, 3H); 13C (100 MHz, CDCl3)
d 171.0, 169.1, 138.1, 132.7, 128.9, 126.8, 122.5, 118.7,
69.4, 68.5, 59.2, 52.2, 47.1, 38.9, 37.7, 28.9, 26.7, 20.4,
20.2; HRMS (EI) calcd for C21H26N2O3 354.1943.
Found 354.1939. Crystal data for 2a (colorless crystals,
recrystallized from hexanes/EtOAc) at 25 ꢀC:
C21H28N2O4, M = 372.465, orthorhombic, P212121,
C20H24N2O3,
M
340.41, orthorhombic, P212121,
˚
˚
a = 9.8270 (5) A, b = 12.2890 (7) A, c = 15.6450
3
3
˚
˚
(10) A, V = 1889.35 (19) A , Z = 4, Dc = 1.197 Mg/m ,
l = 0.081 mmꢀ1
,
6365 reflections, 227 parameters,
R = 0.0957, Rw = 0.1771.
4.3.3. 1-(10,10-Dimethyl-2-oxo-3-phenyl-3,4-diaza-tricy-
clo[5.2.1.01,5]dec-4-yl)-2-thiophen-2-yl-ethane-1,2-dione,
27
1
1e. Yield 82%; ½aꢁD ¼ ꢀ268:9 (c 1, CHCl3); H NMR
(400 MHz, CDCl3) d 8.09 (s, 1H), 7.80 (s, 1H), 7.38–
7.35 (m, 4H), 7.21–7.17 (m, 2H), 4.59 (t, 1H,
J = 5.2 Hz), 2.29 (td, 1H, J 12.0, 5.1 Hz), 2.17–2.13
(m, 1H), 2.03–1.93 (m, 3H), 1.54–1.48 (m, 1H), 1.41–
1.34 (m, 1H), 1.20 (s, 3H), 1.15 (s, 3H); 13C (100 MHz,
CDCl3) d 179.5, 170.1, 158.0, 139.2, 137.5, 137.0,
136.8, 128.8, 128.6, 126.4, 121.8, 69.2, 59.2, 52.0, 47.1,
39.3, 28.4, 26.5, 20.6, 19.7; HRMS (EI) calcd for
C22H22N2O3S 394.1351. Found 394.1350; IR (neat,
cmꢀ1): 3092, 3003, 2962, 1732, 1652, 1594, 1493, 1458,
1409, 1339, 1301, 1216, 1136, 1071, 1049, 753; Crystal
data for 1e (colorless crystals, recrystallized from hex-
anes/EtOAc) at 25 ꢀC: C22H22N2O3S, M 394.48, ortho-
˚
˚
˚
a = 9.6023 (3) A, b = 11.7053 (4) A, c = 17.4243 (7) A,
3
V = 1958.45 (12) A , Z = 4, Dc = 1.263 Mg/m3,
˚
l = 0.09 mmꢀ1, 10744 reflections, 7839 parameters, R =
0.0731, Rw = 0.1768.
4.5.1. 4-(2R)-(Hydroxy-2-phenyl-pent-4-enoyl)-10,10-di-
methyl-3-phenyl-3,4-diaza-tricyclo[5.2.1.01,5]decan-2-one,
2b. 1H NMR (400 MHz, CDCl3) d 7.58–7.56 (m, 2H),
7.39–7.29 (m, 7H), 7.14 (1H, m), 5.62–5.55 (1H, m), 5.31
(dd, 1H, J = 10.2, 1.8 Hz), 5.26 (d, 1H, J = 17.2 Hz),
3.36 (dd, 1H, J = 8.0, 5.0 Hz), 3.17 (dd, 1H, J = 13.4,
˚
˚
rhombic, P212121, a = 10.1420 (3) A, b = 12.3190 (4) A,
3
˚
˚
c = 16.3260 (6) A, V = 2039.76 (12) A , Z = 4,

N. A. Kulkarni et al. / Tetrahedron: Asymmetry 17 (2006) 336–346
343
6.1 Hz), 2.90 (s, 2H), 2.85–2.79 (m, 1H), 2.42 (dd, 1H,
J = 13.5, 8.5 Hz), 2.14–2.04 (m, 1H), 1.99 (dd, 1H,
J = 13.5, 8.0 Hz), 1.90–1.82 (m, 1H), 1.79 (t, 1H,
J = 4.0 Hz), 1.04 (s, 3H), 1.01 (s, 3H); 13C (100 MHz,
CDCl3) d 176.2, 169.6, 139.7, 139.2, 132.7, 128.5,
128.3, 128.1, 124.9, 124.6, 122.2, 120.3, 78.4, 66.4,
59.5, 54.9, 48.7, 45.2, 42.1, 27.8, 26.8, 20.5, 19.9; HRMS
(EI) calcd for C27H30N2O3 430.2256. Found 430.2255;
IR (neat, cmꢀ1): 3454, 2961, 1716, 1595, 1496, 1457,
1385, 1354, 1141, 1099, 1071, 922, 754; Crystal data
for 2b (colorless crystals, recrystallized from hexanes/
EtOAc) at 25 ꢀC: C27H30N2O3, M 430.53, orthorhom-
J = 10.6, 1.0 Hz), 4.02 (dd, 1H, J = 7.6, 4.8 Hz), 3.72
(s, 1H), 3.46 (d, 1H, J = 13.5 Hz), 3.41 (d, 1H,
J = 13.5 Hz), 3.31 (dd, 1H, J = 13.8, 6.2 Hz), 2.63 (dd,
1H, J = 13.8, 8.2 Hz), 1.90 (dd, 1H, J = 13.8, 6.2 Hz),
1.87–1.85 (m, 1H), 1.70–1.68 (m, 1H), 1.65 (m, 1H),
1.35–1.27 (m, 2H), 0.87 (s, 3H), 0.73 (s, 3H); 13C
(100 MHz, CDCl3) d 174.2, 140.1, 132.3, 128.1, 127.8,
125.2, 121.2, 80.0, 67.6, 54.2, 48.2, 47.4, 44.7, 44.5,
38.4, 33.2, 26.3, 20.5, 19.8; MS (EI) 372 ([MꢀOH]+Æ,
C21H27NO4S); IR (neat, cmꢀ1): 3581, 2951, 2878,
1677, 1478, 1450, 1414, 1334, 1272, 1215, 1168, 1129,
1067; Crystal data for 4f (colorless crystals, recrystal-
lized from hexanes/EtOAc) at ꢀ73 ꢀC: C22H30N2O4SSi,
˚
˚
bic, P212121, a = 8.8990 (2) A, b = 10.8260 (3) A,
3
˚
˚
˚
c = 24.2140 (9) A, V = 2340.55 (12) A , Z = 4,
Dc = 1.222 Mg/m3, l = 0.080 mmꢀ1, 7840 reflections,
290 parameters, R = 0.0653, Rw = 0.1225.
M 446.63, orthorhombic, P21P21P21, a = 8.87220 (2) A,
˚
˚
b = 14.4130 (3) A, c = 18.1900 (5) A, V = 2286.67
3
(9) A , Z = 4, Dc = 1.297 Mg/m3, l = 0.224 mmꢀ1
,
˚
14140 reflections, 272 parameters, R = 0.0720, Rw =
4.5.2. 4-(2S)-(Hydroxy-2-methyl-pent-4-enoyl)-10,10-di-
methyl-3-phenyl-3,4-diaza-tricyclo[5.2.1.01,5]decan-2-one,
2c. 1H NMR (400 MHz, CDCl3) d 7.37–7.30 (m, 4H),
7.20–7.16 (m, 1H), 5.72–5.70 (m, 1H), 5.24 (dd, 1H,
J = 10.0, 1.8 Hz), 5.18 (dd, 1H, J = 17.1, 1.8 Hz), 4.3
(dd, 1H, J = 8.0, 5.0 Hz), 2.76–2.73 (m, 1H), 2.68 (dd,
1H, J = 6.7, 3.8 Hz), 2.32–2.16 (m, 4H), 2.04–1.96
(m, 1H), 1.92 (t, 1H, J = 3.9 Hz), 1.46 (s, 3H), 1.45 (m,
1H), 1.39–1.32 (m, 1H), 1.14 (s, 3H), 1.10 (s, 3H); HRMS
(EI) calcd for C22H28N2O3 368.2100. Found 368.2106.
Crystal data for 2c (colorless crystals, recrystallized
0.1076.
4.5.6.
1-(10,10-Dimethyl-3,3-dioxo-3v6-thia-4-aza-tri-
cyclo[5.2.1.01,5]dec-4-yl)-(2S)-hydroxy-2-phenyl-pent-4-en-
1-one, 5f. 1H NMR (400 MHz, CDCl3) d 7.52–7.50
(m, 2H), 7.37–7.33 (m, 2H), 7.31–7.29 (m, 1H),
5.77–5.67 (m, 1H), 5.14 (dd, 1H, J = 10.6, 1.0 Hz),
5.10 (dd, 1H, J 16.8, 1.0 Hz), 4.31 (s, 1H), 4.00
(dd, 1H, J = 7.7, 4.9 Hz), 3.41 (d, 1H, J = 13.6 Hz),
3.28 (d, 1H, J = 13.6 Hz), 3.10 (dd, 1H, J = 13.9,
6.6 Hz), 2.62 (dd, 1H, J = 13.9, 7.7 Hz), 2.10–2.04
(dd, 1H, J = 13.9, 7.7 Hz), 1.96–1.84 (m, 4H), 1.37–
1.33 (m, 2H), 1.16 (s, 3H), 0.94 (s, 3H); 13C
from hexanes/EtOAc) at 25 ꢀC: C22H28N2O3,
M
˚
368.46, monoclinic, P21, a = 8.8760 (10) A, b =
3
˚
˚
˚
11.2330 (17) A, c = 10.9320 (19) A, V = 1011.1 (3) A ,
Z = 2, Dc = 1.210 Mg/m3, l = 1.210 mmꢀ1, 6214 reflec-
tions, 245 parameters, R = 0.0955, Rw = 0.2180.
(100 MHz, CDCl3) d 174.4, 139.2, 132.5, 128.1,
128.0, 125.5, 120.1, 80.6, 67.1, 53.3, 48.8, 47.8, 47.7,
44.7, 38.9, 33.0, 26.4, 21.0, 19.9; MS (EI) 372
([MꢀOH]+Æ, C21H27NO4S); IR (neat, cmꢀ1): 3581,
2951, 2878, 1677, 1478, 1450, 1414, 1334, 1272,
1215, 1168, 1129, 1067; Crystal data for 5f (color-
less crystals, recrystallized from hexanes/EtOAc) at
ꢀ73 ꢀC: C21H27NO4S, M 389.50, monoclinic, P21,
4.5.3.
4-(2S)-(Ethyl-2-hydroxy-pent-4-enoyl)-10,10-di-
methyl-3-phenyl-3,4-diaza-tricyclo[5.2.1.01,5]decan-2-one,
2d. Inseparable diastereomers; IR (neat, cmꢀ1): 3479,
2967, 2938, 2881, 1695, 1595, 1493, 1458, 1382, 1299,
1214, 918, 752.
˚
˚
a = 8.6320 (2) A, b = 11.4770 (4) A, c = 10.2410
3
3
˚
˚
(3) A, V = 997.72 (5) A , Z = 2, Dc = 1.297 Mg/m ,
4.5.4. 4-(2S)-(Hydroxy-2-thiophen-2-yl-pent-4-enoyl)-10,
10-dimethyl-3-phenyl-3,4-diaza-tricyclo[5.2.1.01,5]decan-
2-one, 2e. 1H NMR (400 MHz, CDCl3) d 7.35–7.29
(m, 4H), 7.25–7.24 (m, 1H), 7.15–7.10 (m, 1H), 7.03
(dd, 1H, J = 3.6, 1.0 Hz), 6.98 (dd, 1H, J = 4.8,
3.6 Hz), 5.68–5.57 (m, 1H), 5.33–5.25 (m, 2H), 3.78
(dd, 1H, J = 7.9, 5.2 Hz), 3.18 (br s, 1H), 3.12 (dd,
1H, J = 15.1, 8.0 Hz), 2.80–2.74 (m, 1H), 2.65 (dd, 1H,
J = 13.5, 8.0 Hz), 2.24–2.12 (m, 2H), 1.95–1.87 (m,
1H), 1.83 (t, 1H, J = 4.1 Hz), 1.26–1.20 (m, 2H), 1.06
(s, 3H), 1.04 (s, 3H); 13C (100 MHz, CDCl3) d 175.2,
169.5, 144.9, 138.9, 131.9, 128.3, 127.4, 125.1, 125.0,
124.2, 122.4, 120.5, 77.9, 67.32, 59.6, 54.7, 48.7, 45.3,
42.3, 27.9, 26.8, 20.4, 19.9; HRMS (EI) calcd for
C16H20N2O3 436.1821. Found 436.1817. IR (neat,
cmꢀ1): 3411, 3076, 3009, 2964, 2882, 1694, 1595, 1495,
1456, 1434, 1389, 1304, 1215, 1093, 754, 705.
l = 0.188 mmꢀ1
,
7040 reflections, 249 parameters,
R = 0.0704, Rw = 0.1756.
4.5.7. 4-(2R)-(Hydroxy-2-phenyl-pent-4-enoyl)-10,10-di-
methyl-3-(toluene-4-sulfonyl)-3,4-diaza-tricyclo[5.2.1.01,5]-
decan-2-one, 6g. Rf = 0.54 (2:1 hexanes/EtOAc);
27
½aꢁD ¼ þ142:0 (c 1, CHCl3); 1H NMR (400 MHz,
CDCl3) d 8.14 (d, 2H, J = 8.0 Hz), 7.54 (d, 2H,
J = 7.2 Hz), 7.37 (d, 2H, J = 8.0 Hz), 7.33–7.26
(m, 3H), 5.92 (m, 1H), 5.35 (d, 1H, J = 9.6 Hz), 5.28
(d, 1H, J = 16.8 Hz), 3.34 (dd, 1H, J = 13.2, 5.5 Hz),
3.15 (s, 1H), 3.02 (s, 1H), 2.76–2.73 (m, 1H), 2.46
(s, 3H), 2.46–2.42 (m, 1H), 2.00–1.94 (m, 1H), 1.81–
1.78 (m, 3H), 1.27 (s, 3H), 1.05 (s, 3H), 0.97–
0.91 (m, 1H), 0.86–0.81 (m, 1H); 13C NMR (100 MHz,
CDCl3) d 171.7, 153.0, 144.8, 139.5, 136.0, 132.6,
129.3, 129.1, 128.4, 128.0, 124.7, 122.1, 78.4, 67.5,
59.0, 55.1, 49.5, 46.3, 41.5, 28.0, 26.2, 21.7, 20.7,
19.7; HRMS (EI) calcd for C28H32N2O5S 509.2060.
Found 509.2053; Crystal data for 6g (colorless
crystals, recrystallized from hexanes/EtOAc) at
20 ꢀC: C28H32N2O5S, M 508.62, monoclinic, P21,
4.5.5.
1-(10,10-Dimethyl-3,3-dioxo-3v6-thia-4-aza-tri-
cyclo[5.2.1.01,5]dec-4-yl)-(2R)-hydroxy-2-phenyl-pent-4-en-
1-one, 4f. 1H NMR (400 MHz, CDCl3) d 7.56–7.54 (m,
2H), 7.37–7.33 (m, 2H), 7.29–7.26 (m, 1H), 5.79–5.70
(m, 1H), 5.23 (dd, 1H, J = 16.8, 1.0 Hz), 5.24 (dd, 1H,
˚
˚
˚
a = 8.6460 (2) A, b = 11.5040 (3) A, c = 13.4890 (3) A,

344
N. A. Kulkarni et al. / Tetrahedron: Asymmetry 17 (2006) 336–346
3
V = 1301.10 (5) A , Z = 2, Dx= 1.298 Mg/m3,
4.6.1. 4-(2S)-(Hydroxy-propionyl)-10,10-dimethyl-3-phen-
˚
22
l = 0.165 mmꢀ1
,
4476 reflections, 326 parameters,
R = 0.0652, Rw = 0.1377.
yl-3,4-diaza-tricyclo[5.2.1.01,5]decan-2-one, 8c. ½aꢁD
¼
ꢀ67:1 (c 1, CHCl3); 1H NMR (400 MHz, CDCl3) d
7.41–7.33 (m, 2H), 7.26–7.20 (m, 3H), 4.28 (dd, 1H,
J = 8.0, 5.1 Hz), 4.08 (m, 1H), 2.83–2.77 (m, 1H),
2.33–2.26 (m, 1H), 2.10 (dd, 1H, J = 13.7, 8.0 Hz),
2.06–2.03 (m, 2H), 1.51–1.36 (m, 2H), 1.33 (d, 3H,
J = 6.6 Hz), 1.21 (s, 3H), 1.16 (s, 3H). 13C (100 MHz,
CDCl3) d 171.7, 170.6, 138.4, 129.0, 126.7, 122.0, 77.7,
68.5, 66.0, 59.3, 52.3, 47.1, 37.3, 28.9, 26.7, 20.5, 20.3;
HRMS (EI) calcd for C19H24N2O3 328.1781. Found
328.1783; IR (neat, cmꢀ1): 3462, 2961, 1715, 1597,
1495, 1455, 1371, 1304, 1214, 1107, 1035, 756.
4.5.8. 4-(2S)-(Hydroxy-2-phenyl-pent-4-enoyl)-10,10-di-
methyl-3-(toluene-4-sulfonyl)-3,4-diaza-tricyclo[5.2.1.01,5]-
decan-2-one, 7g. Rf = 0.46 (2:1 hexanes/EtOAc);
27
½aꢁD ¼ ꢀ71:3 (c 1, CHCl3); 1H NMR (400 MHz,
CDCl3) d 8.08 (d, 2H, J = 7.8 Hz), 7.67 (d, 2H,
J = 7.8 Hz), 7.39–7.28 (m, 5H), 5.94 (m, 1H), 5.32
(d, 1H, J = 10.1 Hz), 5.26 (d, 1H, J = 17.2 Hz), 4.32
(t, 1H, J = 6.2 Hz), 3.27 (dd, 1H, J = 13.4, 6.2 Hz),
2.93 (br s, 1H), 2.66 (dd, 1H, J = 13.4, 8.4 Hz),
2.46 (s, 3H), 2.08–2.02 (m, 1H), 1.89–1.74 (m, 3H),
1.56 (s, 1H), 1.27–1.16 (m, 2H), 0.90 (s, 3H), 0.70
(s, 3H); 13C NMR (100 MHz, CDCl3) d 174.0,
172.9, 145.2, 140.2, 135.6, 133.0, 129.5, 128.9, 128.1,
127.6, 125.4, 121.9, 78.7, 72.5, 60.3, 51.7, 51.1, 47.0,
39.5, 29.1, 26.5, 21.8, 20.2, 19.5; HRMS (EI) calcd
for C28H32N2O5S 508.2026. Found 508.2009; Crystal
data for 7g (colorless crystals, recrystallized from hex-
anes/EtOAc) at ꢀ73 ꢀC: C28H32N2O5S, M 508.62,
4.6.2. 4-(2S)-(Hydroxy-butyryl)-10,10-dimethyl-3-phenyl-
22
3,4-diaza-tricyclo[5.2.1.01,5]decan-2-one,
8d. ½aꢁD ¼
ꢀ27:1 (c 1, CHCl3); 1H NMR (400 MHz, CDCl3) d
7.40–736 (m, 2H) 7.25–7.22 (m, 3H) 4.29 (dd, 1H,
J = 7.8, 5.2 Hz), 3.88 (br s, 1H), 3.01 (br s, 1H), 2.81–
2.74 (m, 1H), 2.35–2.27 (m, 1H), 2.10 (dd, 1H,
J = 13.6, 11.0 Hz), 2.07–2.02 (m, 2H), 1.82–1.73 (m,
1H), 1.54–1.40 (m, 3H), 1.2 (s, 3H), 1.15 (s, 3H), 0.94
(t, 3H, J = 7.4 Hz); 13C (100 MHz, CDCl3) d 171.3,
169.8, 138.2, 128.9, 126.8, 122.5, 71.0, 68.5, 59.2, 52.1,
47.1, 37.5, 28.9, 27.6, 26.6, 20.4, 20.2, 9.7; HRMS (EI)
calcd for C20H26N2O3 342.1938. Found 342.1939; IR
(neat, cmꢀ1): 3507, 2969, 2929, 2874, 1712, 1652, 1494,
1457, 1354, 1306, 1217, 1049, 758, 712; Crystal data
for 8d (colorless crystals, recrystallized from hexanes/
EtOAc) at 25 ꢀC: C20H27N2O3.5, M 351.44, orthorhom-
˚
orthorhombic, P212121, a = 6.3790 (2) A, b = 18.5760
3
˚
˚
˚
(6) A, c = 21.1690 (8) A, V = 2508.45 (15) A , Z = 4,
Dx = 1.347 Mg/m3, l = 0.172 mmꢀ1, 4409 reflections,
326 parameters, R = 0.1054, Rw = 0.1766.
4.6. Typical procedure for the synthesis of 4-(2S)-
(hydroxy-2-phenyl-acetyl)-10,10-dimethyl-3-phenyl-3,4-
diaza-tricyclo[5.2.1.01,5]decan-2-one, 8b
˚
˚
bic, P212121, a = 10.45480 (5) A, b = 10.7670 (5) A,
3
c = 16.0710 (9) A , Z = 4, Dc = 1.290 Mg/m3, l =
˚
Under a N2 atmosphere, N-phenyl camphorpyrazol-
idinone phenylglyoxylate 1b (100 mg, 0.26 mmol)
was dissolved in dry THF (5 mL) at ꢀ78 ꢀC. To
this solution, K-Selectride (0.26 mL, 1.0 M solution
in dry THF, 0.26 mmol) was added slowly. The reac-
tion mixture was stirred for 2 h at ꢀ78 ꢀC and
quenched with H2O (15 mL). The aqueous layer was
extracted with ethyl acetate (3 · 15 mL), the organic
layers separated, washed with saturated NaCl solution
(10 mL) and dried over anhydrous MgSO4. The
organic layer was concentrated to a solid residue,
which was purified by silica gel flash column chro-
matography using hexane/ethyl acetate (1:1) as the
0.088 mmꢀ1, R = 0.1087, Rw = 0.2161.
4.6.3. 4-(2R)-(Hydroxy-2-thiophen-2-yl-acetyl)-10,10-di-
methyl-3-phenyl-3,4-diaza-tricyclo[5.2.1.01,5]decan-2-one,
22
1
8e. ½aꢁD ¼ ꢀ10:2 (c 1, CHCl3); H NMR (400 MHz,
CDCl3) d 7.38–7.32 (m, 3H), 7.25–7.17 (m, 3H),
7.04–7.0 (m, 2H), 5.28 (s, 1H), 4.06 (m, 2H), 2.74–
2.72 (m, 1H), 2.22–2.18 (m, 1H), 2.2 (dd, 1H,
J = 12.8, 8.2 Hz), 2.03 (m, 2H), 1.36–1.26 (m, 2H),
1.08 (s, 3H), 0.99 (s, 3H); 13C (100 MHz, CDCl3) d
171.0, 167.0, 140.4, 138.1, 128.8, 127.0, 126.6, 126.5,
126.3, 121.9, 67.7, 67.6, 59.2, 52.5, 46.9, 38.0, 28.7,
26.7, 20.3, 19.5; HRMS (EI) calcd for C22H24N2O3S
396.1502. Found 396.1501; IR (neat, cmꢀ1): 3434,
2992, 2958, 2924, 1712, 1667, 1491, 1457, 1371,
1329, 1306, 1217, 1080, 1046, 769, 713. Crystal data
for 8e (colorless crystals, recrystallized from hex-
anes/EtOAc) at 25 ꢀC: C22H24N2O3S, M 396.49 ortho-
eluent to give the corresponding products as
a
colorless solid (99 mg, 98%), major diastereomer is
22
8b. ½aꢁD ¼ ꢀ11:5 (c 1, CHCl3); 1H NMR (400 MHz,
CDCl3) d 7.38–7.28 (m, 7H), 7.2 (t, 1H, J = 7.2 Hz),
7.04 (d, 2H, J = 7.2 Hz), 5.04 (s, 1H), 4.16 (br
s, 1H), 4.05 (t, 1H, J = 6.7 Hz), 2.75–2.72 (m,
1H), 2.25–2.11 (m, 2H), 2.02–1.98 (m, 2H), 1.33
(m, 2H) 1.07 (s, 3H), 0.91 (s, 3H); 13C (100 MHz,
CDCl3) d 171.2, 167.6, 138.2, 137.8, 129.0, 128.8,
128.7, 127.0, 126.5, 121.7, 72.3, 68.0, 59.3, 52.2,
47.0, 37.9, 28.7, 26.6, 20.3, 19.6; HRMS (EI) calcd
for C24H26N2O3 390.1938. Found 390.1945; IR
(neat, cmꢀ1): 3462, 2947, 1703, 1659, 1488, 1454,
1320, 1303, 1091, 1052, 912, 724; Crystal data for
8b (colorless crystals, recrystallized from hexanes/
EtOAc) at 25 ꢀC: C24H26N2O3, M 390.47, ortho-
˚
˚
rhombic, P212121, a = 10.5030 (3) A, b = 11.5270(4) A,
3
c = 16.7140 (6) A , Z = 4, Dc = 1.301 Mg/m3, l =
˚
0.185 mmꢀ1, R = 0.1549, Rw = 0.3304.
4.7. Typical procedure for the synthesis of 4-(2S)-
(hydroxy-2-phenyl-acetyl)-10,10-dimethyl-3-(toluene-4-
sulfonyl)-3,4-diaza-tricyclo[5.2.1.01,5]decan-2-one, 10g
Under a N2 atmosphere, N-tosylcamphorpyrazolidinone
phenylglyoxylate 1g (200 mg, 0.43 mmol) was dissolved
in dry THF (4 mL) at ꢀ78 ꢀC. To this solution was
added L-Selectride (0.86 mL, 1.0 M solution in THF,
0.86 mmol). The reaction mixture was stirred for
˚
rhombic, P212121, a = 10.4410 (3) A, b = 10.77760
(3) A, c = 16.8250(6) A , Z = 4, Dc = 1.254 Mg/m3,
3
˚
˚
l = 0.083 mmꢀ1, R = 0.1187, Rw = 0.1875.

N. A. Kulkarni et al. / Tetrahedron: Asymmetry 17 (2006) 336–346
345
45 min at ꢀ78 ꢀC and quenched with H2O (25 mL). The
aqueous layer was extracted with ethyl acetate
(3 · 25 mL), the organic layers separated, washed with
a saturated solution of NaCl (2 · 25 mL) and dried over
anhydrous MgSO4. The organic layer was concentrated
to a solid residue, which was purified by silica gel flash
column chromatography using hexane/ethyl acetate
(2:1) as the eluent to give the corresponding product
as a colorless solid (121 mg, 60%, major diastereomer
60.3, 52.1, 47.5, 34.2, 29.6, 26.8, 21.8, 20.1, 18.2; HRMS
(FAB) (M+H)+Æ calcd for C23H27N2O5S2 475.1361.
Found 475.1357.
Acknowledgements
This work was supported by the National Science Coun-
cil of the Republic of China (NSC 94-2113-M-003-003)
and National Taiwan Normal University (ORD 93-C).
Our gratitude is expressed to the Academic Paper Edit-
ing Clinic, NTNU. The collection and processing of the
X-ray crystal data by National Taiwan Normal Univer-
sity is gratefully acknowledged.
1
is 10g). H NMR (400 MHz, CDCl3) d 8.14 (m, 1H),
7.53–7.52 (m, 2H), 7.44–7.37 (m, 5H), 5.30 (br s, 1H),
3.89 (br s, 1H), 3.50 (br s, 1H), 2.46 (s, 3H), 2.21–2.17
(m, 2H), 1.94 (m, 1H), 1.86 (m, 1H), 1.78 (dd, 1H,
J = 13.3, 8.1 Hz), 1.25 (s, 2H), 1.19 (s, 3H), 1.10 (s,
3H); 13C (100 MHz, CDCl3) d 175.6, 171.1, 145.2,
138.7, 135.9, 129.3, 128.9, 128.7, 127.8, 71.7, 66.3,
59.0, 54.9, 46.9, 39.4, 27.9, 26.2, 21.7, 20.2, 19.7; HRMS
(FAB) (M+H)+Æ calcd for C25H29N2O5S 469.1797.
Found 469.1805.
References
1. Representative allylation references see: (a) Teo, Y.-C.;
Tan, K.-T.; Loh, T.-P. Chem. Commun. 2005, 1318–1320;
(b) V Vilaivan, T.; Winotapan, C.; Banphavichit, V.;
Shinada, T.; Ohfune, Y. J. Org. Chem. 2005, 70, 3464–
3471; (c) Lu, J.; Hong, M.-L.; Ji, S.-J.; Loh, T.-P. Chem.
Commun. 2005, 1010–1012; (d) Lee, J.-Y.; Miller, J. J.;
Hamilton, S. S.; Sigman, M. S. Org. Lett. 2005, 7, 1837–
1839; (e) Lu, J.; Ji, S.-J.; Teo, Y.-C.; Loh, T.-P. Org. Lett.
2005, 7, 159–161; (f) Hirama, L. C.; Gamsey, S.; Knuep-
pel, D.; Steiner, D.; DeLaTorre, K.; Singaram, B. Tetra-
hedron Lett. 2005, 46, 2315–2318; (g) Fernandes, R. A.;
Yamamoto, Y. J. Org. Chem. 2004, 69, 735–738; (h) Kim,
J. G.; Waltz, K. M.; Garcia, I. F.; Kwiatkowski, D.;
Walsh, P. J. J. Am. Chem. Soc. 2004, 126, 12580–12585.
2. Representative reduction references see: (a) Letondor, C.;
Humbert, N.; Ward, T. R. PNAS 2005, 102, 4683–4687;
(b) Chandrasekhar, S.; Hota, R. Tetrahedron: Asymmetry
2005, 16, 751–754; (c) Gosselin, F.; O’Shea, P. D.; Roy, S.;
Reamer, R. A.; Chen, C.-Y.; Volante, R. P. Org. Lett.
2005, 7, 355–358; (d) Ushio, H.; Mikami, K. Tetrahedron
Lett. 2005, 46, 2903–2906; (e) Lapis, A. A. M.; Fatima, A.
D.; Martins, J. E. D.; Costa, V. E. U.; Pilli, R. A.
Tetrahedron Lett. 2005, 46, 495–498; (f) Schlatter, A.;
Kundu, M. K.; Woggon, W.-D. Angew. Chem., Int. Ed.
2004, 43, 6731–6734; (g) Xu, J.; Wei, T.; Zhang, Q. J. Org.
Chem. 2004, 69, 6860–6866; (h) Ohno, K.; Kataoka, Y.;
Mashima, K. Org. Lett. 2004, 6, 4695–4697; (i) Xu, J.;
Wei, T.; Zhang, Q. J. Org. Chem. 2003, 68, 10146–10151;
(j) Nettles, S. M.; Matos, K.; Burkhardt, E. R.; Rouda, D.
R.; Corella, J. A. J. Org. Chem. 2002, 67, 2970–2976.
3. (a) Keck, G. E.; Truong, A. P. Org. Lett. 2005, 7, 2149–
2152; (b) Fatima, A. D.; Kohn, L. K.; Antonio, M. A.;
Carvalho, J. E. D.; Pilli, R. A. Bioorg. Med. Chem. 2005,
13, 2927–2933; (c) Keck, G. E.; Yu, T.; McLawa, M. D. J.
Org. Chem. 2005, 70, 2543–2550; (d) Atobe, M.; Yama-
zaki, N.; Kibayashi, C. Tetrahedron Lett. 2005, 46, 2669–
2773; (e) Faiz, A. K.; Rashmirekha, S.; Jyotirmayee, D.;
Savitha, G. J. Org. Chem. 2004, 69, 5295–5301; (f) Tosaki,
S.-Y.; Nemoto, T.; Ohshima, T.; Shibasaki, M. Org. Lett.
2003, 5, 495–498; (g) Ramachandran, P. V.; Liu, H.; Ram
Reddy, M. V.; Brown, H. C. Org. Lett. 2003, 5, 3755–
3757; (h) Ghosh, A. K.; Lei, H. J. Org. Chem. 2002, 67,
8783–8788; (i) Yamamoto, Y.; Asao, N. Chem. Rev. 1993,
93, 2207–2293; (j) Yamamoto, Y. Acc. Chem. Res. 1987,
20, 243–249.
4.7.1. 4-(2R)-(Hydroxy-2-phenyl-acetyl)-10,10-dimethyl-
3-(toluene-4-sulfonyl)-3,4-diaza-tricyclo[5.2.1.01,5]decan-
1
2-one, 11g. Minor diastereomer: H NMR (400 MHz,
CDCl3) d 7.85 (d, 2H, J = 8.0 Hz), 7.44 (d, 2H,
J = 7.0 Hz), 7.40 (d, 2H, J = 8.0 Hz), 7.31–7.23 (m,
3H), 5.82 (br s, 1H), 4.17 (br s, 1H), 3.76 (dd, 1H,
J = 7.8, 5.6 Hz), 2.52 (m, 1H), 2.48 (s, 3H), 1.78–1.74
(m, 3H), 1.65 (br s, 1H), 1.12–1.06 (m, 1H), 0.80 (s,
3H), 0.41 (m, 1H), 0.09 (s, 3H); 13C (100 MHz, CDCl3)
d 171.3, 146.8, 137.6, 134.2, 130.2, 129.5, 128.6, 128.5,
128.0, 72.0, 70.1, 60.4, 52.0, 47.5, 34.2, 29.6, 26.9,
21.8, 20.0, 18.5; HRMS (EI) (M+H)+Æcalcd for
C25H29N2O5S 469.1797. Found 469.1794. Crystal
data for 11g (colorless crystals, recrystallized from
hexanes/EtOAc) at 25 ꢀC: C25H28N2O5S, M 468.55
˚
˚
triclinic, P1, a = 9.6500 (2) A, b = 10.895 (2) A,
3
˚
˚
c = 12.9202 (3) A, V = 1163.11 (4) A , Z = 2, Dc =
1.338 Mg/m3, l = 0.179 mmꢀ1, 14805 reflections, 596
parameters, R = 0.0585, Rw = 0.1430.
4.7.2. 4-(2R)-(Hydroxy-butyryl)-10,10-dimethyl-3-(tolu-
ene-4-sulfonyl)-3,4-diaza-tricyclo[5.2.1.01,5]decan-2-one,
10i. 1H NMR (400 MHz, CDCl3) d 7.89 (d, 2H,
J = 7.0 Hz), 7.39 (d, 2H, J = 7.0 Hz), 7.28 (s, 1H), 4.55
(br s, 1H), 3.91 (br s, 1H), 3.08 (br s, 1H), 2.73 (d, 1H,
J = 13.7 Hz), 2.48 (s, 3H), 1.95–1.17 (m, 5H), 1.26–
1.20 (m, 2H), 1.06 (s, 3H), 1.04 (s, 3H), 1.03 (s, 3H);
13C (100 MHz, CDCl3) d 173.1, 146.5, 134.4, 130.0,
129.2, 71.0, 70.5, 60.5, 52.3, 47.6, 34.9, 29.6, 29.5, 26.8,
22.7, 20.3, 20.2, 9.8; HRMS (FAB) (M+H)+Æ calcd for
C21H29N2O5S 421.1797. Found 421.1806.
4.7.3. 4-(2S)-(Hydroxy-2-thiophen-2-yl-acetyl)-10,10-di-
methyl-3-(toluene-4-sulfonyl)-3,4-diaza-tricyclo[5.2.1.01,5]-
decan-2-one, 10j. 1H NMR (400 MHz, CDCl3) d 7.86
(d, 2H, J = 8.4 Hz), 7.41 (d, 2H, J = 8.4 Hz), 7.24 (d,
1H, J = 5.0 Hz), 7.15 (d, 1H, J = 3.2 Hz), 6.91 (dd,
J = 5.0, 3.2 Hz), 6.10 (br s, 1H), 4.06 (br s, 1H), 3.76
(dd, 1H, J = 8.3, 5.4 Hz), 2.58–2.54 (m, 1H), 2.49 (s,
3H), 1.86–1.79 (m, 3H), 1.75 (d, 1H, J = 8.3 Hz), 1.13–
1.08 (m, 1H), 0.86 (s, 3H), 0.47 (m, 1H), 0.33 (s, 3H);
13C (100 MHz, CDCl3) d 177.6, 170.2, 146.9, 140.5,
134.0, 130.2, 129.4, 127.4, 126.6, 126.3, 70.5, 67.7,
4. (a) Scafato, P.; Leo, L.; Superchi, S.; Rosini, S. Tetrahe-
dron 2002, 58, 153–159; (b) Loupy, A.; Monteux, D. A.
Tetrahedron 2002, 58, 1541–1549; (c) Fukuzawa, S.-I.;
Miura, M.; Matsuzawa, H. Tetrahedron Lett. 2001, 42,

346
N. A. Kulkarni et al. / Tetrahedron: Asymmetry 17 (2006) 336–346
4167–4169; (d) Shin, J. A.; Cha, J. H.; Pae, A. N.; Choi, K.
J.-C.; Lin, C.-H.; Chen, K. J. Org. Chem. 1999, 64, 6993–
6998; (f) Alvarez-Ibara, C.; Csaky, A. G.; Maroto, R.;
Quiroga, M. L. J. Org. Chem. 1995, 60, 7934–7940.
8. (a) Pan, J.-F.; Venkatesham, U.; Chen, K. Tetrahedron
Lett. 2004, 45, 9345–9347; (b) Wang, S.-G.; Tsai, H. R.;
Chen, K. Tetrahedron Lett. 2004, 45, 6183–6185; (c) Lee,
W.-D.; Chiu, C.-C.; Hsu, H.-L.; Chen, K. Tetrahedron
2004, 60, 6657–6664.
9. Chen, J.-H.; Venkatesham, U.; Lee, L.-C.; Chen, K.
Tetrahedron, in press.
10. Christofers, J.; Mann, A. Angew. Chem., Int. Ed. 2001, 40,
4591–4597.
I.; Koh, H. Y.; Kang, H.-Y. Tetrahedron Lett. 2001, 42,
5489–5492; (e) Bandopadhyaya, A. K.; Sangeetha, N. M.;
Radha, A.; Maitra, U. Tetrahedron: Asymmetry 2000, 11,
3463–3466; (f) Kiegiel, K.; Jurczak, J. Tetrahedron Lett.
1999, 40, 1009–1012; (g) Chen, C.-J.; Chu, Y.-Y.; Liao, Y.-
Y.; Tsai, Z.-H.; Wang, C. C.; Chen, K. Tetrahedron Lett.
1999, 40, 1141–1144; (h) Ghosh, A. K.; Chen, Y. Tetra-
hedron Lett. 1995, 36, 6811–6814; (i) Soai, K.; Ishizaki, M.
J. Org. Chem. 1986, 51, 3290–3295; (j) Hanessian, S. Total
Synthesis of Natural Product: The Chiron Approach;
Pergamon Press: New York, 1983; Chapter 2.
5. Corey, E. J.; Yu, C.-M.; Kim, S. S. J. Am. Chem. Soc.
1989, 111, 5495–5496.
11. (a) Bandini, M.; Cozzi, P. G.; Garelli, A.; Melchiorre, P.;
Umani-Ronchi, A. Eur. J. Org. Chem. 2002, 3243–3249;
(b) Ooi, T.; Takahashi, M.; Maruoka, K. J. Am. Chem.
Soc. 1996, 118, 11307–11308.
12. Similar seven-membered chelates were observed. See
references: (a) Jurczak, J.; Prokopowicz, P. Tetrahedron
Lett. 1998, 39, 9835–9838; (b) Garner, P.; Ramakanth, S.
J. Org. Chem. 1986, 51, 2609–2612.
13. 1b (CCDC 286444), 1c (CCDC 286443), 1d (CCDC
286447), 1e (CCDC 286446), 1f (CCDC 286451), 1g
(CCDC 281384), 1j (CCDC 281386), 2a (CCDC 287868),
2b (CCDC 247167), 2c (CCDC 247166), 4f (CCDC
286452), 5f (CCDC 286450), 6g (CCDC 281385), 7g
(CCDC 281388), 8b (CCDC 286445), 8d (CCDC 286447),
8e (CCDC 287869), 11g (CCDC 286453).
6. (a) Vedejs, E.; Ahmad, S.; Larsen, S. D.; Westwood, S. J.
J. Org. Chem. 1987, 52, 3937–3938; (b) White, J. M.;
Ohira, S. J. Org. Chem. 1986, 51, 5492–5494; (c) Hanes-
sian, S. Total Synthesis of Natural Product: The Chiron
Approach; Pergamon Press: New York, 1983; Chapter 2.
7. (a) Fan, C. L.; Lee, W.-D.; Teng, N.-W.; Sun, Y.-C.;
Chen, K. J. Org. Chem. 2003, 68, 9816–9818; (b) Sibi, M.
P.; Liu, M. Curr. Org. Chem. 2001, 5, 719–755; (c) Yabu,
K.; Masumoto, S.; Yamasaki, S.; Hamashima, Y.; Kanai,
M.; Du, W.; Curran, D. P.; Shibasaki, M. J. Am. Chem.
Soc. 2001, 123, 9908–9909; (d) Adam, W.; Pastor, A.;
Peters, K.; Peters, E.-M. Org. Lett. 2000, 2, 1019–1022;
(e) Chu, Y.-Y.; Yu, C.-S.; Chen, C.-J.; Yang, K.-S.; Lain,