Stereoselective synthesis of spiro-β-lactams using d-(+)-glucose derived chiral pool: remarkable influence of the torquoelectronic effect

Article abstract of DOI:10.1016/j.tet.2007.06.073

Diastereoselective synthesis of spiro-β-lactams via [2+2] cycloaddition reaction of imines and chiral ketenes is described. The chiral ketene was prepared from commercially available, inexpensive d-glucose. Although, theoretically four diastereomers are p

Full text of DOI:10.1016/j.tet.2007.06.073

Tetrahedron 63 (2007) 9179–9187
Stereoselective synthesis of spiro-b-lactams using D-(D)-glucose
derived chiral pool: remarkable influence of the
torquoelectronic effect
P. M. Chincholkar,a Vedavati G. Puranikb and A. R. A. S. Deshmukhc,
*
aDivision of Organic Chemistry (Synthesis), National Chemical Laboratory, Pune 411008, India
bCentre for Materials Characterization, National Chemical Laboratory, Pune 411008, India
cEmcure Pharmaceuticals Limited, ARC-H, P-2, I.T.-B.T. Park, Phase-II, M.I.D.C., Hinjwadi, Pune 411057, India
Received 18 February 2007; revised 3 June 2007; accepted 21 June 2007
Available online 27 June 2007
Abstract—Diastereoselective synthesis of spiro-b-lactams via [2+2] cycloaddition reaction of imines and chiral ketenes is described. The
chiral ketene was prepared from commercially available, inexpensive D-glucose. Although, theoretically four diastereomers are possible,
the reaction yielded only two diastereomers stereoselectively in good to moderate yields. The stereochemical outcome of the reaction was
in accordance with the torquoelectronic model.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
found to act as poliovirus and human rhinovirus 3C-protein-
ases inhibitors.14 They have also found application as cho-
lesterol absorption inhibitors.15
b-Lactams, being a structural motif in most widely used
antibiotics,1 have occupied a pivotal position in medicinal
chemistry for almost a century now. With the microorgan-
isms retaliating the traditional antibiotics via b-lactamase
enzymes, the need for novel antibiotics prevails making syn-
thesis of newer b-lactams ever more important. Besides their
use as antibiotics, b-lactams are increasingly being used as
synthons for biologically important molecules.2 Apart
from this, the recent literature has seen a spurt in the number
of other diverse applications of the b-lactams. They have
been shown to increase the expression of glutamate trans-
porters through gene activation.3 b-Lactams have also
been found to act as cholesterol acyl transferase inhibitors,4
thrombin inhibitors,5 human cytomegalovirus protease
inhibitors,6 matrix metalloprotease inhibitors,7 human leu-
cocyte elastase,8 cysteine protease,9 and apoptosis induc-
tors10. Thus, owing to their ever growing applications,
synthesis of b-lactams remains a field of incessant activity.
In particular, spirocyclic b-lactams have attracted attention
as they have been shown to be b-turn mimetics11 and precur-
sors for a,a-disubstituted b-amino acids.12 The spiro-b-
lactam moiety forms a part of the chartelline, a family of
marine natural products.13 Spiro-b-lactams have also been
Several syntheses of spiro-b-lactams are available in the
literature.16 Many of them have employed the [2+2] cyclo-
condensation of ketenes and imines,17 better known as the
Staudinger reaction. The reason for the widespread use of
the Staudinger reaction is that it scores over other methods
in operational simplicity and the actual stereochemical out-
comes are often in good concordance with the predicted
ones. A large body of literature is available reporting the use
of carbohydrates as chiral starting materials for the synthesis
of b-lactams.18 Our group has also been engaged in the
stereoselective synthesis of b-lactams using carbohydrates
as a source of chirality.19 Herein, we wish to disclose our
work on synthesis of spirocyclic b-lactams using a D-(+)-glu-
cose derived chiral acid and the stereochemical implications
of the same. Spirocyclic b-lactams derived from carbohy-
drates can also be perceived to undergo other transformations
as the b-lactams are prone to amide bond cleavage.
2. Results and discussion
The commercially available D-(+)-glucose was used to pre-
pare aldehyde 4 in good yield by following a reported pro-
cedure20 (Scheme 1). This aldehyde was subjected to
oxidation21 using freshly prepared silver oxide to get the de-
sired chiral acid 5. It was converted to the corresponding
Keywords: Stereoselective synthesis; Staudinger reaction; Ketenes; Imines;
Spiro-b-lactams.
* Corresponding author. Tel.: +91 20 39821300; fax: +91 20 39821445;
e-mail: abdulrakeeb.deshmukh@emcure.co.in
0040–4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.06.073

9180
P. M. Chincholkar et al. / Tetrahedron 63 (2007) 9179–9187
O
O
H
OBn
O
O
O
OBn
O
OH
O
O
c
b
a
D (+) glucose
O
O
O
O
O
O
1
3 (95%)
2 (60%)
4 (78%)
OH
Cl
OBn
O
O
d
OBn
O
O
e
O
O
O
O
5 (89%)
6 (92%)
Scheme 1. Reagents and conditions: (a) dry acetone, anhyd CuSO4, concd H2SO4, rt, 48 h; (b) NaH, BnBr, dry DMF, 0 ꢁC to rt, 3 h; (c) (i) 75% CH3COOH,
70 ꢁC, 3 h; (ii) silica gel, 0.65 M, aq NaIO4, DCM, rt, 2 h; (d) AgNO3, aq KOH, HCl, rt, 1 h; (e) (COCl)2, dry DCM, reflux, 4 h.
acid chloride 6 by refluxing with oxalyl chloride in dichloro-
methane. This acid chloride 6 was then used as a ketene pre-
cursor in the Staudinger cycloaddition reaction (Scheme 2)
with imines. The reaction proceeded cleanly to afford a dia-
stereomeric mixture of spirocyclic b-lactams 7a–i and 8a–i
in good yields (Table 1). The 1H NMR spectrum of the crude
reaction product revealed a 70:30 mixture of two diastereo-
mers (7a and 8a). Although, theoretically four diastereomers
are possible, the formation of only two diastereomers clearly
indicates a high level of stereoselectivity in the cyclo-
addition reaction. Both the diastereomers were separated
by careful flash column chromatography. They exhibited
a band at around 1755 cmꢀ1 in the IR spectrum, typical of
a b-lactam carbonyl. In the 1H NMR spectrum of major iso-
mer 7a, the C-3 proton of the b-lactam ring resonated at
d 5.40, two singlets at d 1.35 and d 1.73 showed the presence
of acetonide group and the anomeric proton appeared as
a doublet at d 5.50 indicating the presence of carbohydrate
moiety in the molecule. Similarly, the minor isomer 8a
showed the b-lactam C-3 proton at d 4.82 along with other
signals for the carbohydrate moiety. The stereochemistry
of both the diastereomers 7a and 8a was elucidated with
the help of NOE experiments. In the major diastereomer
7a, the only proton on the b-lactam ring (C3H) showed
NOE interactions with C8H and the ortho protons of the aro-
matic ring (C3-PMP) on the same carbon (Figs. 1 and 3). In
the minor diastereomer 8a, C3H proton, apart from a strong
interaction (Figs. 1 and 3) with C8H and with the aromatic
protons similar to the major isomer 7a, also showed interac-
tion (Figs. 2 and 3) with one of the methyl protons from the
6,7-O-isopropylidene group, which was absent in the major
isomer 7a. This is indicative of the fact that the b-lactam C-3
of 8a is on the same side of the acetonide group. Hence,
based on the NOE results, structures 7(3R,4R) and
8(3S,4S) (Fig. 3) were assigned to the major and minor dia-
stereomers, respectively. Furthermore, we carried out C8-O-
debenzylation on some of the spiro-b-lactams. Gratifyingly,
we could get good crystals after C8-O-debenzylation of one
of the major isomers 7c. A single crystal X-ray diffraction
analysis22 of debenzylated product 12c (Fig. 4) confirmed
the stereochemistry inferred by NOE experiments.
Having elucidated the stereochemistry of the newly formed
stereocenters in both the diastereomers, we set out to account
for the observed stereochemical results. The mechanism of
the Staudinger reaction has been a subject of extensive inves-
tigation.23 It is believed that the imine attacks the ketene
from the less hindered side. Study of the literature brought
forth some reports providing a mechanistic rationale for
the stereochemistry of spiro-b-lactams obtained by the Stau-
dinger reaction.17d,24 In a report on proline derived spiro-b-
lactams,24 the observed stereochemistry of the b-lactams is
ascribed to the attack of imine taking place from the less hin-
dered side of ketene. In that case, the steric bulk on the nitro-
gen diverts the attack of the imine toward the less hindered
side of the ketene. During the study of the Staudinger reac-
tion of ketenes derived from 2- and 3-tetrahydrofuroyl
chloride,17d the torquoelectronic effect has been invoked to
explain the differences in stereochemical outcome. The ox-
ygen atom of the 2-tetrahydrofuroyl chloride derived ketene
prefers an outward position in the ring closure step, thereby
repelling the attack of imine toward the opposite side of the
ketene. Although this ketene exhibits torquoelectronic ef-
fects, the two sides of the ketene (–O–, –CH2–) are not
much differentiated sterically.
Table 1. Synthesis of spiro-b-lactams 7a–i and 8a–i
7 and 8
R1
R2
Yielda (%)
Isomersb (7:8)
A
B
C
D
E
F
G
H
I
PMP
Ph
Ph
PMP
4-Cl-Ph
Ph
PMP
4-Me-Ph
Ph
PMPc
PMP
Ph
Ph
Ph
Styryl
Styryl
Ph
65
71
62
62
59
69
67
72
70
70:30
72:28
70:30
68:32
65:35
71:39
68:32
64:36
64:36
R1
O
2 H
R
OBn
O
OBn
O
N
a
R1
N
R1
N
6
+
+
R2
11a-i
O
O
p-Tolyl
O
O
R2
H
O
a
Isolated yields of diastereomeric mixture.
Ratio of diastereomers was determined by 1H NMR.
PMP¼p-Methoxyphenyl.
7a-i
8a-i
b
c
Scheme 2. Reagents and conditions: (a) Et3N, dry DCM, ꢀ40 ꢁC to rt, 15 h.

P. M. Chincholkar et al. / Tetrahedron 63 (2007) 9179–9187
9181
ppm
1
ppm
1
2
3
4
5
6
7
2
3
4
5
6
7
8
ppm
ppm
8
7
6
5
4
3
2
1
7
6
5
4
3
2
1
Minor isomer 8a
Major isomer 7a
Figure 1. NOESY spectra for 7a (major) and 8a (minor) isomers.
In this context, it would be interesting to imagine a case
wherein the steric and torquoelectronic factors counter
each other. Our present study makes a case in point. Consid-
ering the starting imine to be having E configuration and the
approach toward the ketene to be from two different sides,
four products are possible. Figure 5 shows the approach of
the imine from all possible directions. In the case of path-
ways 1 and 2, the imine attacks from the opposite side of
the furanose oxygen delivering two products 7(3R,4R),
8(3S,4S) via a conrotatory ring closure (Fig. 5). Pathways
3 and 4 represent an attack of the imine from the side of
the furanose oxygen giving rise to compounds 9(3S,4R)
and 10(3R,4S). With the C8 bearing a benzyloxy group, ste-
ric factors state that attack of the imine should take place
from the opposite side (Fig. 5) resulting in formation of com-
pounds 9(3S,4R) and 10(3R,4S). Whereas, with the torquo-
electronic factors governing the course of reaction, attack
should happen from opposite side of the furanose oxygen
(pathways 1 and 2), delivering compounds 7(3R,4R) and
8(3S,4S). In pathway 1, after the initial attack of the imine
H3CO
O
H
H
OBn
OBn
O
H
R1
N
R1
N
O
O
H
R2
O
O
H
O
O
8a, R1, R2 = PMP
Figure 3. NOE interactions in major isomer 7a and minor isomer 8a.
7a, R1 = PMP
Figure 2. 2D NOESY spectra showing interaction of C3H with acetonide
group in minor isomer 8a (above) and absence of this interaction in major
isomer 7a (below).
Figure 4. ORTEP diagram of compound 12c.

9182
P. M. Chincholkar et al. / Tetrahedron 63 (2007) 9179–9187
OBn
R2
OBn
O
R2
-O
H
OBn
O
conrotatory
ring closure
-O
+
O
90° flip
R1
R2
H
N
N
+
O
O
N
O
R1
R1
O
O
H
O
O
7 (3R, 4R)
zwitterionic intermediate 1
OBn
Pathway-1
OBn
O
O
OBn
-O
conrotatory
ring closure
R1
O
-O
O
90° flip
N
R2
+
R1
N
+
O
O
R2
H
O
N
R2
R1
O
O
H
O
H
zwitterionic intermediate 2
H
Pathway-2
8 (3S, 4S)
2
H
OBn
O
R
H
R1
+
N
OBn
R2
OBn
+
conrotatory
ring closure
R1
R1
O
N
90° flip
O
N
R2
-O
O
-O
O
O
O
O
O
O
9 (3S, 4R)
Pathway-3
zwitterionic intermediate 3
O
R1
N
-O
OBn
O
R2
H
+
OBn
O
OBn
O
conrotatory
ring closure
R1
+
90° flip
N
R1
N
H
R2
-O
O
O
2
H
O
R
O
O
O
10 (3R, 4S)
Pathway-4
zwitterionic intermediate 4
Figure 5. Plausible mechanism for explaining the observed stereochemical outcomes.
resulting in formation of a zwitterionic intermediate 1, the
next step (90ꢁ flip) in which the imine part attains coplanar-
ity with the ketene should proceed with some resistance
from the benzyloxy substituent on the a-carbon (C-8) of
the ketene. This should divert the attack of the imine to the
other side (pathways 3 and 4) of the ketene; at least in
part, if not exclusively. But defying the steric constraints, re-
action showed strong inclination toward delivering products
governed by the torquoelectronic effect. With the structures
of the actual products found to be 7 and 8, it is pretty clear
that the torquoelectronic factor exerts a stronger effect in
the reaction. Each side of the ketene is additionally differen-
tiated into two faces: top face (pathways 1 and 3) and bottom
face (pathways 2 and 4). Among the two diastereomers, 7
(pathway 1) was found to be major and 8 was the minor
(pathway 2), although the diastereoselectivity was only
moderate (Table 1). This can be rationalized by proposing
that the bulky 6,7-O-isopropylidene moiety, to some extent,
prevents the attack of the imine from bottom face, so that the
zwitterionic intermediate 2 (pathway 2) is formed to a lesser
extent than the zwitterionic intermediate 1 (pathway 1) re-
sulting in the observed proportion of diastereomers.
with the imine attacking from the hindered side illustrating
the strong influence of the torquoelectronic effect. The facial
selectivity was moderate. Work to exploit the densely func-
tionalized nature of the product and cleavability of the lactam
to transform it into other heterocycles is underway.
4. Experimental section
4.1. General
1H NMR and 13C NMR spectra were recorded in CDCl3
solution on a Bruker AV 200 or AV 400 spectrometers and
chemical shifts are reported in parts per million downfield
1
from tetramethylsilane for H NMR. Infrared spectra were
recorded on a Perkin–Elmer Infrared Spectrophotometer,
Model 599-B or Shimadzu FTIR-8400 using sodium chlo-
ride optics. Melting points were determined on a Buchi melt-
ing point apparatus and are uncorrected. MS analyses were
performed on a Peseiex API QSTAR Pulsar with an electro-
spray ionization mass spectrometer (LC–MS), using MeOH
as a solvent (m/z, fragentor 70 V). The microanalyses were
performed on a Carlo-Erba, CHNS-O EA 1108 Elemental
analyzer. Optical rotations were recorded on an ADP-200
Polarimeter under standard conditions.
3. Conclusion
A stereoselective synthesis of spirocyclic b-lactams from a D-
(+)-glucose derived chiral acid has been achieved. The reac-
tion showed strong propensity toward following a course
governed bythe torquoelectroniceffect. Althoughfour diaste-
reomers are possible, only two diastereomers were obtained
4.2. (L)-(2S,3R,4R,5R)-3-Benzyloxy-4,5-O-isopropyl-
idene-tetrahydro-furan-2-carboxylic acid (5)
To the aldehyde 4 (0.566 g, 2.02 mmol) was added an aque-
ous solution of AgNO3 (0.588 M, 8.91 mL). To the resulting

P. M. Chincholkar et al. / Tetrahedron 63 (2007) 9179–9187
9183
emulsion was added aqueous KOH solution (0.91 M,
11.4 mL). A dark black precipitate was formed, which was
stirred for further an hour. It was then filtered through
a Buchner funnel. The filtrate was cooled to 0 ꢁC and acidi-
fied with approximately 6 M aqueous HCl to pH¼2. The
acidified solution was then extracted with dichloromethane
(3ꢂ20 mL). The combined organic extracts were washed
with brine (10 mL), dried over sodium sulfate, and concen-
trated under reduced pressure to give acid 5 (0.490 g, 82%)
as a white solid. Mp 140–141 ꢁC; [Found: C, 61.38; H, 6.05.
C15H18O6 requires: C, 61.21; H, 6.16%.] [a]2D6 ꢀ54.5 (c
1.76, CHCl3); nmax (CHCl3): 3300–2800, 1733 cmꢀ1; dH
(200 MHz, CDCl3): 1.26 (3H, s, CH3), 1.42 (3H, s, CH3),
4.25–4.81 (5H, m, C2–H, C3–H, C4–H, O–CH2–Ph), 6.02
(1H, d, J 3.6 Hz, C5–H), 7.16–7.29 (5H, m, Ar–H), 10.2 (1H,
br s, –COOH); dC (50 MHz, CDCl3): 26.2, 26.9, 72.5, 79.5,
81.8, 82.2, 105.7, 112.7, 127.7, 128.0, 128.4, 136.5, 171.8.
MS: m/z 295 (M+1).
114.3, 118.8, 125.3, 127.6, 128.1, 128.5, 129.0, 130.6,
136.9, 156.2, 159.6, 163.6; MS: m/z 518 (M+1).
4.4.2. (L)-(3S,4S,6R,7R,8R)-8-Benzyloxy-6,7-O-isopro-
pylidene-2,3-bis(4-methoxyphenyl)-5-oxa-2-aza-spiro-
[3.4]octan-1-one (8a). Yield 19%; white solid; mp 147–
148 ꢁC; [Found: C, 69.52; H, 5.87; N, 2.58. C30H31NO7 re-
quires: C, 69.62; H, 6.03; N, 2.71%.] Rf (20% ethyl acetate/
petroleum ether): 0.20; [a]2D6 ꢀ30.9 (c 1.1, CHCl3); nmax
(neat): 1753 cmꢀ1; dH (200 MHz, CDCl3): 1.03 (3H, s,
CH3), 1.23 (3H, s, CH3), 3.72 (3H, s, Ar–OCH3), 3.75 (3H,
s, Ar–OCH3), 4.40 (1H, d, J 1.2 Hz, C8–H), 4.60–4.70 (2H,
m, OCH2–Ph, C7–H), 4.81 (1H, d, J 12.4 Hz, 1ꢁCH02–Ph),
4.82 (1H, s, C3–H), 6.06 (1H, d, J 4.0 Hz, C6–H), 6.76
(2H, d, J 9.1 Hz, Ar–H), 6.83 (2H, d, J 8.7 Hz, Ar–H),
7.19–7.36 (9H, m, Ar–H); dC (50 MHz, CDCl3): 26.3,
26.7, 55.0, 55.3, 66.5, 72.4, 83.9, 85.4, 94.7, 106.2, 113.7,
113.8, 114.0, 114.3, 118.9, 125.2, 127.8, 128.4, 129.8,
130.3, 137.0, 156.2, 159.9, 163.3; MS: m/z 518 (M+1).
4.3. (L)-(2S,3R,4R,5R)-3-Benzyloxy-4,5-O-isopropyl-
idene-tetrahydro-furan-2-carboxylic acid chloride (6)
4.4.3. (L)-(3R,4R,6R,7R,8R)-8-Benzyloxy-6,7-O-isopro-
pylidene-3-(4-methoxyphenyl)-2-phenyl-5-oxa-2-aza-
spiro[3.4]octan-1-one (7b). Yield 45%; thick oil; [Found:
C, 71.38; H, 5.84; N, 2.98. C29H29NO6 requires: C, 71.44;
H, 5.99; N, 2.87%.] Rf (20% ethyl acetate/petroleum ether):
0.30; [a]2D6 ꢀ50 (c 1, CHCl3); nmax (neat): 1757 cmꢀ1; dH
(200 MHz, CDCl3): 1.27 (3H, s, CH3), 1.65 (3H, s, CH3),
3.71(3H, s, Ar–OCH3), 4.40 (1H, d, J 1.0 Hz, C8–H),
4.54–4.61 (2H, m, OCH2–Ph, C7–H), 4.75 (1H, d, J
11.6 Hz, OCH02–Ph), 5.35 (1H, s, C3–H), 5.44 (1H, d, J
4.0 Hz, C6–H), 6.77–7.03 (3H, m, Ar–H), 7.14–7.29 (11H,
m, Ar–H); dC (50 MHz, CDCl3): 25.8, 26.3, 55.4, 65.9,
72.0, 84.2, 85.1, 94.3, 105.4, 114.2, 117.3, 124.8, 125.4,
126.7, 127.8, 128.2, 128.7, 129.2, 129.8, 137.0, 137.1,
159.6, 163.9; MS: m/z 488 (M+1).
Acid 5 (0.500 g, 1.70 mmol) was dissolved in 10 mL anhy-
drous dichloromethane and cooled to 0 ꢁC. To the cooled
solution was added oxalyl chloride (0.215 g, 1.70 mmol)
dropwise. The resultant solution was refluxed for 5 h. After
5 h, the solution was cooled to room temperature and used
directly for preparation of spiro-b-lactams.
4.4. General procedure for the synthesis of spiro-b-
lactams
A solution of acid chloride 6 (0.259 g, 0.826 mmol) in anhy-
drous dichloromethane (10 mL) was added to a precooled
solution of imine 11a (0.116 g, 0.550 mmol) and anhydrous
triethylamine (0.344 mL, 2.47 mmol) in anhydrous di-
chloromethane (15 mL) at ꢀ40 ꢁC over a period of 15–
20 min. The reaction mixture was allowed to warm to
room temperature and stirred for 15 h. After completion of
reaction (TLC), the reaction mixture was diluted with di-
chloromethane and washed successively with water
(3ꢂ10 mL) and brine (10 mL). The organic layer was dried
over anhydrous sodium sulfate, filtered, and concentrated
under reduced pressure to get the crude product as a dark
brown viscous liquid (0.304 g, 71%). The crude reaction
mixture was purified using flash column chromatography
(20% ethyl acetate–petroleum ether) to get two diastereo-
mers 7a and 8a.
4.4.4. (L)-(3S,4S,6R,7R,8R)-8-Benzyloxy-6,7-O-isopro-
pylidene-3-(4-methoxyphenyl)-2-phenyl-5-oxa-2-aza-
spiro[3.4]octan-1-one (8b). Yield 20%; thick oil; [Found:
C, 71.58; H, 5.79; N, 2.80. C29H29NO6 requires: C, 71.44;
H, 5.99; N, 2.87%.] Rf (20% ethyl acetate/petroleum ether):
0.20; [a]2D6 ꢀ35.8 (c 0.78, CHCl3); nmax (neat): 1757 cmꢀ1
;
dH (200 MHz, CDCl3): 0.99 (3H, s, CH3), 1.18 (3H, s,
CH3), 3.69 (3H, s, Ar–OCH3), 4.35 (1H, d, J 1.1 Hz, C8–
H), 4.52–4.64 (2H, m, OCH2–Ph, C7–H), 4.73 (1H, d, J
12.4 Hz, OCH02–Ph), 4.80 (1H, s, C3–H), 6.01 (1H, d, J
3.9 Hz, C6–H), 6.76–7.01 (3H, m, Ar–H), 7.12–7.30 (11H,
m, Ar–H); dC (50 MHz, CDCl3): 26.4, 26.8, 55.1, 66.4,
72.6, 84.0, 85.5, 94.7, 106.3, 113.9, 117.7, 124.2, 125.1,
126.8, 127.9, 128.0, 128.5, 129.0, 129.8, 136.9, 137.0,
160.0, 164.1; MS: m/z 488 (M+1).
4.4.1. (L)-(3R,4R,6R,7R,8R)-8-Benzyloxy-6,7-O-isopro-
pylidene-2,3-bis(4-methoxyphenyl)-5-oxa-2-aza-spiro-
[3.4]octan-1-one (7a). Yield 52%; thick oil; [Found: C,
69.80; H, 6.09; N, 2.60. C30H31NO7 requires: C, 69.62; H,
6.03; N, 2.71%.] Rf (20% ethyl acetate/petroleum ether):
4.4.5. (L)-(3R,4R,6R,7R,8R)-8-Benzyloxy-6,7-O-isopro-
pylidene-2,3-diphenyl-5-oxa-2-aza-spiro[3.4]octan-1-one
(7c). Yield 43%; thick oil; [Found: C, 73.31; H, 6.10; N, 3.20.
C28H27NO5 requires: C, 73.50; H, 5.94; N, 3.06%.] Rf (20%
ethyl acetate/petroleum ether): 0.30 [a]2D6 ꢀ75 (c 1.44,
CHCl3); nmax (neat): 1753 cmꢀ1; dH (200 MHz, CDCl3):
1.29 (3H, s, CH3), 1.67 (3H, s, CH3), 4.43 (1H, d, J 1.0 Hz,
C8–H), 4.58–4.64 (2H, m, OCH2–Ph, C7–H), 4.79 (1H, d, J
11.6 Hz, OCH02–Ph), 5.43 (1H, s, C3–H), 5.46 (1H, d, J
4.1 Hz, C6–H), 6.98–7.33 (15H, m, Ar–H); dC (50 MHz,
CDCl3): 26.8, 26.9, 62.2, 72.7, 83.1, 83.7, 95.5, 105.5,
0.35; [a]2D6 ꢀ54.5 (c 1.1, CHCl3); nmax (neat): 1759 cmꢀ1
;
dH (200 MHz, CDCl3): 1.35 (3H, s, CH3), 1.73 (3H, s,
CH3), 3.75 (3H, s, Ar–OCH3), 3.80 (3H, s, Ar–OCH3),
4.47 (1H, d, J 1.2 Hz, C8–H), 4.62–4.68 (2H, m, OCH2–
Ph, C7–H), 4.83 (1H, d, J 11.6 Hz, OCH02–Ph), 5.40 (1H,
s, C3–H), 5.50 (1H, d, J 4.1 Hz, C6–H), 6.79 (2H, d, J
9.1 Hz, Ar–H), 6.87 (2H, d, J 8.7 Hz, Ar–H), 7.23–7.36
(9H, m, Ar–H); dC (50 MHz, CDCl3): 26.9, 27.0, 55.2,
55.4, 61.9, 72.7, 83.2, 83.9, 95.3, 105.3, 113.9, 114.2,

9184
P. M. Chincholkar et al. / Tetrahedron 63 (2007) 9179–9187
114.2, 117.4, 124.2, 127.5, 127.6, 128.1, 128.3, 128.4, 128.5,
128.9, 133.4, 136.7, 137.0, 164.2; MS: m/z 458 (M+1).
4.4.10. (L)-(3S,4S,6R,7R,8R)-8-Benzyloxy-2-(4-chloro-
phenyl)-6,7-O-isopropylidene-3-phenyl-5-oxa-2-aza-spiro-
[3.4]octan-1-one (8e). Yield 21%; thick oil; [Found: C,
68.48; H, 5.43; N, 2.72; Cl, 7.43. C28H26NO5Cl requires: C,
68.35; H, 5.32; N, 2.84; Cl, 7.20%.] Rf (20% ethyl acetate/
petroleum ether): 0.30; [a]2D6 ꢀ80.0 (c 0.9, CHCl3); nmax
(neat): 1755 cmꢀ1; dH (200 MHz, CDCl3): 1.27 (3H, s,
CH3), 1.44 (3H, s, CH3), 4.35 (1H, d, J 1.1 Hz, C8–H),
4.58–4.73 (2H, m, OCH2–Ph, C7–H), 4.83 (1H, d, J
12.3 Hz, OCH02–Ph), 4.84 (1H, s, C3–H), 6.0 (1H, d, J
4.1 Hz, C6–H), 7.15–7.27 (14H, m, Ar–H); dC (50 MHz,
CDCl3): 26.3, 26.8, 61.9, 73.1, 83.0, 83.9, 95.4, 105.7,
114.2, 118.7, 127.3, 128.1, 128.5, 128.6, 128.7, 129.0,
129.3, 133.1, 135.4, 136.7, 163.9; MS: m/z 492 (M+1).
4.4.6. (L)-(3S,4S,6R,7R,8R)-8-Benzyloxy-6,7-O-isopro-
pylidene-2,3-diphenyl-5-oxa-2-aza-spiro[3.4]octan-1-one
(8c). Yield 19%; thick oil; [Found: C, 73.59; H, 6.09; N, 3.14.
C28H27NO5 requires: C, 73.50; H, 5.94; N, 3.06%.] Rf (20%
ethyl acetate/petroleum ether): 0.20 [a]2D6 ꢀ42.1 (c 1.3,
CHCl3); nmax (neat): 1755 cmꢀ1; dH (200 MHz, CDCl3):
1.35 (3H, s, CH3), 1.52 (3H, s, CH3), 4.42 (1H, d, J 1.2 Hz,
C8–H), 4.61–4.67 (2H, m, OCH2–Ph, C7–H), 4.80 (1H, d, J
12.4 Hz, 1CH02–Ph), 4.81 (1H, s, C3–H), 6.02 (1H, d, J
4.0 Hz, C6–H), 7.01–7.33 (15H, m, Ar–H); dC (50 MHz,
CDCl3): 26.4, 26.9, 62.0, 72.9, 83.4, 84.0, 94.8, 104.4,
115.1, 117.7, 123.8, 127.5, 127.6, 128.5, 128.7, 128.8,
129.2, 129.4, 132.9, 136.7, 137.2, 165.5; MS: m/z 458 (M+1).
4.4.11. (L)-(3R,4R,6R,7R,8R)-8-Benzyloxy-6,7-O-isopro-
pylidene-2-phenyl-3-styryl-5-oxa-2-aza-spiro[3.4]octan-
1-one (7f). Yield 49%; thick oil; [Found: C, 74.70; H, 6.21;
N, 2.77. C30H29NO5 requires: C, 74.51; H, 6.04; N, 2.89%.]
Rf (20% ethyl acetate/petroleum ether): 0.35; [a]2D6 ꢀ16.6 (c
1.2, CHCl3); nmax (neat): 1756 cmꢀ1; dH (200 MHz, CDCl3):
1.31 (3H, s, CH3), 1.69 (3H, s, CH3), 4.38 (1H, d, J 1.2 Hz,
C8–H), 4.54 (1H, d, J 11.6 Hz, OCH2–Ph), 4.64 (1H, dd, J
3.9, 1.2 Hz, C7–H), 4.74 (1H, d, J 11.6 Hz, OCH02–Ph),
4.95 (1H, d, J 8.8 Hz, C3–H), 5.85 (1H, d, J 3.9 Hz, C6–
H), 6.28 (1H, dd, J 16.1, 8.8 Hz, Ph–CH]CH–CH–), 6.71
(1H, d, J 16.1 Hz, Ph–CH]CH–), 6.98–7.41 (15H, m, Ar–
H); dC (50 MHz, CDCl3): 26.8, 26.9, 61.5, 72.7, 83.2,
83.7, 95.6, 105.9, 114.4, 117.3, 123.7, 124.3, 126.7, 127.5,
128.1, 128.3, 128.5, 128.6, 129.0, 135.8, 136.3, 136.8,
137.6, 164.0; MS: m/z 484 (M+1).
4.4.7. (L)-(3R,4R,6R,7R,8R)-8-Benzyloxy-6,7-O-isopro-
pylidene-2-(4-methoxyphenyl)-3-phenyl-5-oxa-2-aza-
spiro[3.4]octan-1-one (7d). Yield 42%; thick oil; [Found:
C, 71.61; H, 5.81; N, 2.77. C29H29NO6 requires: C, 71.44;
H, 5.99; N, 2.87%.] Rf (20% ethyl acetate/petroleum ether):
0.30; [a]2D6 ꢀ80.0 (c 0.5, CHCl3); nmax (neat): 1755 cmꢀ1; dH
(200 MHz, CDCl3): 1.26 (3H, s, CH3), 1.63 (3H, s, CH3),
3.66 (3H, s, Ar–OCH3), 4.41 (1H, d, J 1.1 Hz, C8–H), 4.55–
4.60 (2H, m, OCH2–Ph, C7–H), 4.76 (1H, d, J 11.6 Hz,
OCH02–Ph), 5.36 (1H, s, C3–H), 5.41 (1H, d, J 4.0 Hz, C6–
H), 6.67–6.74 (2H, m, Ar–H), 7.14–7.30 (12H, m, Ar–H);
dC (50 MHz, CDCl3): 26.9, 27.0, 55.4, 62.3, 72.8, 83.2,
83.9, 95.5, 105.4, 114.3, 118.8, 126.4, 127.6, 127.7, 128.2,
128.3, 128.5, 128.6, 130.6, 133.6, 136.9, 156.3, 163.6; MS:
m/z 488 (M+1).
4.4.12. (L)-(3S,4S,6R,7R,8R)-8-Benzyloxy-6,7-O-isopro-
pylidene-2-phenyl-3-styryl-5-oxa-2-aza-spiro[3.4]octan-
1-one (8f). Yield 20%; white solid; mp 174–176 ꢁC; [Found:
C, 74.63; H, 5.89; N, 3.01. C30H29NO5 requires: C, 74.51; H,
6.04; N, 2.89%.] Rf (20% ethyl acetate/petroleum ether):
0.20; [a]2D6 ꢀ55.0 (c 2, CHCl3); nmax (neat): 1751 cmꢀ1; dH
(200 MHz, CDCl3): 1.30 (3H, s, CH3), 1.37 (3H, s, CH3),
4.40 (1H, d, J 1.0 Hz, C8–H), 4.53 (1H, d, J 8.9 Hz, C3–H),
4.55–4.64 (2H, m, OCH2–Ph, C7–H), 4.69 (1H, d, J
12.2 Hz, OCH02–Ph), 6.15 (1H, d, J 3.7 Hz, C6–H), 6.28
(1H, dd, J 15.9, 8.9 Hz, Ph–CH]CH–CH–), 6.75 (1H, d, J
15.9 Hz, Ph–CH]CH–), 7.10–7.50 (15H, m, Ar–H); dC
(50 MHz, CDCl3): 26.4, 26.7, 62.1, 71.9, 83.5, 83.7, 95.1,
105.3, 113.9, 116.9, 123.5, 124.2, 126.4, 127.4, 128.2,
128.3, 128.5, 128.6, 128.9, 135.5, 136.4, 136.8, 137.7, 166;
MS: m/z 484 (M+1).
4.4.8. (L)-(3S,4S,6R,7R,8R)-8-Benzyloxy-6,7-O-isopro-
pylidene-2-(4-methoxyphenyl)-3-phenyl-5-oxa-2-aza-
spiro[3.4]octan-1-one (8d). Yield 20%; thick oil; [Found:
C, 71.48; H, 6.10; N, 2.93. C29H29NO6 requires: C, 71.44;
H, 5.99; N, 2.87%.] Rf (20% ethyl acetate/petroleum ether):
0.20; [a]2D6 ꢀ71.2 (c 1.1, CHCl3); nmax (neat): 1756 cmꢀ1; dH
(200 MHz, CDCl3): 1.37 (3H, s, CH3), 1.54 (3H, s, CH3),
3.83 (3H, s, Ar–OCH3), 4.37 (1H, d, J 1.2 Hz, C8–H), 4.61–
4.72 (2H, m, OCH2–Ph, C7–H), 4.82 (1H, d, J 12.4 Hz,
OCH02–Ph), 4.90 (1H, s, C3–H), 6.01 (1H, d, J 4.0 Hz, C6–
H), 6.69–6.74 (2H, m, Ar–H), 7.17–7.32 (12H, m, Ar–H);
dC (50 MHz, CDCl3): 26.1, 26.4, 54.9, 62.5, 72.7, 83.2,
83.8, 95.4, 104.9, 114.1, 119.3, 126.8, 127.6, 127.7, 128.1,
128.3, 128.4, 128.7, 130.5, 133.7, 136.7, 156.5, 165.1;
MS: m/z 488 (M+1).
4.4.9. (L)-(3R,4R,6R,7R,8R)-8-Benzyloxy-2-(4-chloro-
phenyl)-6,7-O-isopropylidene-3-phenyl-5-oxa-2-aza-spiro-
[3.4]octan-1-one (7e). Yield 38%; thick oil; [Found: C,
68.51; H, 5.44; N, 2.68; Cl, 7.35. C28H26NO5Cl requires:
C, 68.35; H, 5.32; N, 2.84; Cl, 7.20%.] Rf (20% ethyl ace-
tate/petroleum ether): 0.40; [a]2D6 ꢀ63.6 (c 1.1, CHCl3);
nmax (neat): 1753 cmꢀ1; dH (200 MHz, CDCl3): 1.26 (3H,
s, CH3), 1.63 (3H, s, CH3), 4.40 (1H, d, J 1.1 Hz, C8–H),
4.54–4.60 (2H, m, OCH2–Ph, C7–H), 4.77 (1H, d, J
11.6 Hz, OCH02–Ph), 5.35 (1H, s, C3–H), 5.44 (1H, d, J
4.0 Hz, C6–H), 7.15–7.28 (14H, m, Ar–H); dC (50 MHz,
CDCl3): 26.8, 26.9, 62.5, 72.9, 83.2, 83.8, 95.8, 105.6,
114.4, 118.7, 127.6, 128.2, 128.5, 128.6, 128.7, 129.1,
129.4, 133.0, 135.5, 136.7, 164.2; MS: m/z 492 (M+1).
4.4.13. (L)-(3R,4R,6R,7R,8R)-8-Benzyloxy-6,7-O-isopro-
pylidene-2-(4-methoxyphenyl)-3-styryl-5-oxa-2-aza-spiro-
[3.4]octan-1-one (7g). Yield 45%; thick oil; [Found: C,
72.62; H, 6.24; N, 2.55. C31H31NO6 requires: C, 72.49; H,
6.08; N, 2.72%.] Rf (20% ethyl acetate/petroleum ether):
0.30; [a]2D6 ꢀ26.6 (c 0.5, CHCl3); nmax (neat): 1755 cmꢀ1
;
dH (200 MHz, CDCl3): 1.38 (3H, s, CH3), 1.75 (3H, s,
CH3), 3.76 (3H, s, Ar–OCH3), 4.45 (1H, d, J 1.0 Hz, C8–
H), 4.58–4.70 (2H, m, OCH2–Ph, C7–H), 4.80 (1H, d, J
11.7 Hz, OCH02–Ph), 4.98 (1H, d, J 8.8 Hz, C3–H), 5.91
(1H, d, J 3.7 Hz, C6–H), 6.35 (1H, dd, J 16.0, 8.8 Hz, Ph–
CH]CH–CH–), 6.83 (1H, d, J 16.0 Hz, Ph–CH]CH–),
7.20–7.42 (14H, m, Ar–H); dC (50 MHz, CDCl3): 26.9,
27.0, 55.4, 61.6, 72.7, 83.2, 83.8, 95.6, 105.8, 114.3, 114.4,

P. M. Chincholkar et al. / Tetrahedron 63 (2007) 9179–9187
9185
118.7, 123.9, 126.7, 127.5, 128.1, 128.3, 128.6, 131.1, 135.8,
136.3, 136.8, 156.3, 163.3; MS: m/z 514 (M+1).
95.3, 105.4, 114.2, 117.5, 124.1, 127.5, 127.6, 128.0, 128.5,
128.9, 129.2, 130.3, 136.8, 137.1, 138.1, 164.3. MS: m/z 472
(M+1).
4.4.14. (L)-(3S,4S,6R,7R,8R)-8-Benzyloxy-6,7-O-isopro-
pylidene-2-(4-methoxyphenyl)-3-styryl-5-oxa-2-aza-spiro-
[3.4]octan-1-one (8g). Yield 22%; thick oil; [Found: C,
72.55; H, 5.94; N; 2.84. C31H31NO6 requires: C, 72.49; H,
6.08; N, 2.72%.] Rf (20% ethyl acetate/petroleum ether):
4.4.18. (L)-(3S,4S,6R,7R,8R)-8-Benzyloxy-6,7-O-isopro-
pylidene-2-phenyl-3-p-tolyl-5-oxa-2-aza-spiro[3.4]octan-
1-one (8i). Yield 25%; thick oil; [Found: C, 74.04; H, 6.12;
N, 3.12. C29H29NO5 requires: C, 73.86; H, 6.19; N, 2.97%.]
Rf (20% ethyl acetate/petroleum ether): 0.20; [a]2D6 ꢀ28.3 (c
1.2, CHCl3); nmax (neat): 1755 cmꢀ1; dH (200 MHz, CDCl3):
1.31 (3H, s, CH3), 1.51 (3H, s, CH3), 2.32 (3H, s, Ar–CH3),
4.41 (1H, d, J 1.0 Hz, C8–H), 4.59–4.67 (2H, m, OCH2–Ph,
C7–H), 4.78 (1H, d, J 11.6 Hz, OCH02–Ph), 4.87 (1H, s, C3–
H), 6.06 (1H, d, J 4.0 Hz, C6–H), 7.01–7.39 (14H, m, Ar–H);
dC (50 MHz, CDCl3): 21.0, 26.3, 26.7, 61.9, 72.1, 83.5, 84.0,
95.5, 104.9, 114.7, 117.3, 124.1, 127.3, 127.6, 128.2, 128.6,
128.9, 129.3, 130.2, 136.7, 137.9, 138.1, 163.8. MS: m/z
472 (M+1).
0.25; [a]2D6 ꢀ45.0 (c 0.4, CHCl3); nmax (neat): 1757 cmꢀ1
;
dH (200 MHz, CDCl3): 1.30 (3H, s, CH3), 1.35 (3H, s, CH3),
3.77 (3H, s, Ar–OCH3), 4.36 (1H, d, J 1.0 Hz, C8–H), 4.57
(1H, d, J 8.7 Hz, C3–H), 4.64 (1H, d, J 12.4 Hz, OCH2–Ph),
4.72 (1H, dd, J 3.9, 1.0 Hz, C7–H), 4.77 (1H, d, J 12.4 Hz,
OCH02–Ph), 6.13 (1H, d, J 3.9 Hz, C6–H), 6.26 (1H, dd, J
15.9, 8.7 Hz, Ph–CH]CH–CH–), 6.71 (1H, d, J 15.9 Hz,
Ph–CH]CH–), 6.84 (2H, d, J 9.1 Hz, Ar–H), 7.23–7.43
(12H, m, Ar–H); dC (50 MHz, CDCl3): 26.1, 26.4, 55.4,
65.9, 72.5, 83.7, 85.6, 95.0, 106.6, 113.5, 114.3, 119.0,
123.8, 126.8, 127.9, 128.0, 128.3, 128.5, 128.6, 130.9,
135.8, 137.0, 138.0, 156.4, 162.5; MS: m/z 514 (M++1).
4.5. (L)-(3R,4R,6R,7R,8R)-8-Hydroxy-6,7-O-isopropyl-
idene-2,3-diphenyl-5-oxa-2-aza-spiro[3.4]octan-1-one
(12c)
4.4.15. (L)-(3R,4R,6R,7R,8R)-8-Benzyloxy-6,7-O-isopro-
pylidene-3-phenyl-2-p-tolyl-5-oxa-2-aza-spiro[3.4]octan-
1-one (7h). Yield 46%; thick oil; [Found: C, 74.02; H, 6.02;
N, 3.06. C29H29NO5 requires: C, 73.86; H, 6.19; N, 2.97%.]
Rf (20% ethyl acetate/petroleum ether): 0.3; [a]2D6 ꢀ56.6 (c
1.2, CHCl3); nmax (neat): 1755 cmꢀ1; dH (200 MHz,
CDCl3): 1.33 (3H, s, CH3), 1.71 (3H, s, CH3), 2.28 (3H, s,
Ar–CH3), 4.47 (1H, d, J 1.1 Hz, C8–H), 4.65 (1H, d, J
11.6 Hz, OCH2–Ph), 4.66 (1H, dd, J 4.1, 1.1 Hz, C7–H),
4.83 (1H, d, J 11.6 Hz, OCH02–Ph), 5.44 (1H, s, C3–H),
5.48 (1H, d, J 4.1 Hz, C6–H), 7.04 (2H, d, J 8.4 Hz, Ar–
H), 7.18–7.35 (12H, m, Ar); dC (50 MHz, CDCl3): 20.7,
26.7, 26.8, 62.0, 72.6, 83.0, 83.6, 95.4, 105.4, 114.1, 117.3,
127.5, 127.6, 128.0, 128.1, 128.3, 128.4, 129.4, 133.3,
133.8, 134.5, 136.7, 163.9. MS: m/z 472 (M+1).
O-benzylated spiro-b-lactam 7c (0.216 g, 0.472 mmol) was
dissolved in dry methanol (10 mL). Pd–C (10%, 0.050 g)
and ammonium formate (0.90 g, 1.416 mmol) were added
to it and the resulting solution was refluxed for 3 h. After
completion (TLC), the solution was filtered through a sin-
tered funnel and the residue was washed with methanol.
The filtrate was dried over anhydrous MgSO4 and concen-
trated in vacuo to furnish the crude product. The crude prod-
uct was recrystallized from ethyl acetate–petroleum ether to
obtain pale yellow crystals of debenzylated product 12c
(0.152 g, 88%), which were used for single crystal X-ray
analysis; mp 186–188 ꢁC; [Found: C, 68.61; H, 5.89; N,
3.72. C21H21NO5 requires C, 68.65; H, 5.76; N, 3.81%.] Rf
(40% ethyl acetate/petroleum ether): 0.20; [a]2D6 ꢀ123.52
(c 3.4, CHCl3); nmax (CHCl3): 1755, 3352 cmꢀ1; dH
(200 MHz, CDCl3): 1.30 (3H, s, CH3), 1.73 (3H, s, CH3),
4.42 (1H, d, J 1.1 Hz, C8–H), 4.64 (1H, dd, J 4.0, 1.1 Hz,
C7–H), 5.53 (1H, s, C3–H), 5.60 (1H, br s, –OH), 5.80
(1H, d, J 4.0 Hz, C6–H), 7.01–7.40 (10H, m, Ar–H); dC
(50 MHz, CDCl3): 26.5, 26.6, 61.9, 76.0, 86.3, 96.4, 105.6,
114.0, 117.5, 124.3, 127.7, 128.5, 128.7, 129.0, 133.4,
136.9, 164.8. MS: m/z 368 (M+1).
4.4.16. (L)-(3S,4S,6R,7R,8R)-8-Benzyloxy-6,7-O-isopro-
pylidene-3-phenyl-2-p-tolyl-5-oxa-2-aza-spiro[3.4]octan-
1-one (8h). Yield 26%; thick oil; [Found: C, 73.98; H, 6.33;
N, 2.81. C29H29NO5 requires: C, 73.86; H, 6.19; N, 2.97%.]
Rf (20% ethyl acetate/petroleum ether): 0.20; [a]2D6 ꢀ28.8 (c
0.9, CHCl3); nmax (neat): 1758 cmꢀ1; dH (200 MHz, CDCl3):
1.34 (3H, s, CH3), 1.50 (3H, s, CH3), 2.33 (3H, s, Ar–CH3),
4.42 (1H, d, J 1.1 Hz, C8–H), 4.57–4.66 (2H, m, OCH2–Ph,
C7–H), 4.79 (1H, d, J 12.3 Hz, OCH02–Ph), 4.87 (1H, s, C3–
H), 6.06 (1H, d, J 3.9 Hz, C6–H), 7.03 (2H, d, J 8.1 Hz, Ar–
H), 7.11–7.47 (12H, m, Ar–H); dC (50 MHz, CDCl3): 20.8,
26.3, 26.4, 66.6, 72.5, 82.5, 82.6, 94.6, 105.6, 113.9,
117.5, 127.5, 127.6, 127.9, 128.2, 128.3, 128.5, 129.4,
133.5, 133.9, 134.4, 136.7, 163.7. MS: m/z 472 (M+1).
Acknowledgements
The authors thank Department of Science and Technology
(DST), New Delhi for financial support. Dr. P. R. Rajmo-
hanan is gratefully acknowledged for his help in NOE stud-
ies. We also thank Mr. R. G. Gonnade for his timely help
during X-ray crystallographic analysis. P.M.C. thanks Uni-
versity Grants Commission (UGC), New Delhi for research
fellowship.
4.4.17. (L)-(3R,4R,6R,7R,8R)-8-Benzyloxy-6,7-O-isopro-
pylidene-2-phenyl-3-p-tolyl-5-oxa-2-aza-spiro[3.4]octan-
1-one (7i). Yield 45%; thick oil; [Found: C, 73.71; H, 6.38;
N, 2.92. C29H29NO5 requires: C, 73.86; H, 6.19; N, 2.97%.]
Rf (20% ethyl acetate/petroleum ether): 0.35; [a]2D6 ꢀ40.0 (c
0.3, CHCl3); nmax (neat): 1755 cmꢀ1; dH (200 MHz, CDCl3):
1.33 (3H, s, CH3), 1.71 (3H, s, CH3), 2.34 (3H, s, Ar–CH3),
4.46 (1H, d, J 1.0 Hz, C8–H), 4.61–4.71 (2H, m, OCH2–Ph,
C7–H), 4.83 (1H, d, J 11.6 Hz, OCH02–Ph), 5.42 (1H, s, C3–
H), 5.49 (1H, d, J 4.0 Hz, C6–H), 7.01–7.39 (14H, m, Ar–H);
dC (50 MHz, CDCl3): 21.1, 26.8, 26.9, 62.0, 72.7, 83.2, 83.8,
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22. X-ray diffraction data for compound 12c: single crystal X-ray
structure determination of C21H21NO5 was carried out using
Bruker SMART APEX CCD diffractometer with graphite-
˚
11. (a) Alonso, E.; Lopez-Ortiz, F.; del Pozo, C.; Peratta, E.;
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monochromatized (Mo Ka¼0.71073 A) radiation at room tem-
perature. The X-ray generator was operated at 50 kV and
30 mA. Data were collected with u scan width of 0.3ꢁ and
with three different settings of 4 (0ꢁ, 90ꢁ, and 180ꢁ) keeping
the sample-to-detector distance fixed at 6.145 cm and the de-
tector position (2q) fixed at ꢀ28ꢁ. The X-ray data collection
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14. Skiles, J. W.; McNeil, D. Tetrahedron Lett. 1990, 31, 7277.

P. M. Chincholkar et al. / Tetrahedron 63 (2007) 9179–9187
9187
SMART, Version 5.0, Bruker AXS, Madison, WI, USA, 1998).
All the data were corrected for Lorentzian, polarization, and
absorption effects using Bruker’s SAINT and SADABS pro-
grams (Bruker, SAINT (V6.45a), Bruker AXS, Madison, WI,
USA, 2004). SHELX-97 was used for structure solution and
full matrix least squares refinement on F2 (G. M. Sheldrick,
reflections, 2957 observed reflections, 247 refined parameters,
R1 [I>2s(I)]¼0.0352, wR2¼0.0769 (all data R¼0.0411,
wR2¼0.0794); goodness of fit, 1.098; Drmax
, Drmin
(eAꢀ3)¼0.130, ꢀ0.102. Crystallographic data of 12c have
been deposited with the Cambridge Crystallographic Data
Centre as supplementary publication no. CCDC-646016.
Copies of the data can be obtained free of charge on application
to CCDC, 12 Union Road, Cambridge CB21EZ, UK. The
perspective view of the molecule is shown in Figure 4.
23. (a) Hegedus, L. S.; Montgomery, J.; Narukawa, Y.; Snustad,
D. C. J. Am. Chem. Soc. 1991, 113, 5784; (b) Cossio, F. P.;
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Chem. Soc. 1993, 115, 995; (c) Lopez, R.; Sordo, T. L.;
Sordo, J. A.; Gonzalez, J. J. Org. Chem. 1993, 58, 7036; (d)
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Tetrahedron Lett. 1994, 35, 4465.
˚
€
SHELXS97, SHELXL97, University of Gottingen, Germany,
1997). Hydrogen atoms were included in the refinement as
per the riding model. ORTEP diagram was generated using
ORTEP-32 (M. N. Burnett, C. K. Johnson, ORTEPIII, Report
ORNL-6895, Oak Ridge National Laboratory, Oak Ridge,
Tennessee, USA, 1996). Crystal data for 12c: C21H21NO5;
M¼367.39; crystal size, 0.17ꢂ0.16ꢂ0.11 mm3; T¼297(2) K;
crystal system, orthorhombic; space group, P212121; a¼
3
˚
˚
5.7972(5), b¼10.6478(10), c¼30.579(3) A; V¼1887.6(3) A ;
Z¼4; F(000)¼776; d calcd [g cmꢀ3]¼1.293; m [mmꢀ1]¼
0.093; absorption correction, multi-scan, Tmin¼0.9846;
Tmax¼0.9898; 16,685 reflection collected, 3317 unique
24. Khasanov, A. B.; Ramirez-Weinhouse, M. M.; Webb, T. R.;
Thiruvazhi, M. J. Org. Chem. 2004, 69, 5766.