Single and double diastereoselection in azomethine ylide cycloaddition reactions with unsaturated chiral bicyclic lactams

Article abstract of DOI:10.1021/jo9600870

Double diastereoselectivity data were analyzed to provide insight into the structural features that influence π-facial selectivity in 1,3-dipolar cycloadditions of chiral and achiral azomethine ylides to chiral, unsaturated bicyclic lactams. Three major steric contributions to the differences in stability (ΔΔG(≠)) between competing cycloaddition transition states were identified. The first major set of steric interactions involve that between the dipoles and the substituents on the left hemisphere (R₂) and concave faces of the bicyclic lactams. This effectively hindered both α- and β-approaches in the nonextended transition states. The second major steric interaction was provided by the nonbonded interactions (i) between the R₁ angular substituent on the bicyclic lactam and the π-system of the dipole. This interaction was shown to be very significant, causing reversal in π-facial attack of chiral and achiral dipoles when the angular substituent is changed from phenyl or methyl to hydrogen. The high diastereoselectivity observed now opens a route to highly substituted chiral, nonracemic pyrrolidines.

Full text of DOI:10.1021/jo9600870

3362
J . Org. Chem. 1996, 61, 3362-3374
Sin gle a n d Dou ble Dia ster eoselection in Azom eth in e Ylid e
Cycloa d d ition Rea ction s w ith Un sa tu r a ted Ch ir a l Bicyclic
La cta m s†
Andrew H. Fray and A. I. Meyers*
Department of Chemistry, Colorado State University, Fort Collins, Colorado 80523
Received J anuary 12, 1996X
Double diastereoselectivity data were analyzed to provide insight into the structural features that
influence π-facial selectivity in 1,3-dipolar cycloadditions of chiral and achiral azomethine ylides
to chiral, unsaturated bicyclic lactams. Three major steric contributions to the differences in stability
(∆∆Gq) between competing cycloaddition transition states were identified. The first major set of
steric interactions involve that between the dipoles and the substituents on the left hemisphere
(R2) and concave faces of the bicyclic lactams. This effectively hindered both R- and â-approaches
in the nonextended transition states shown in Figure 1. The second major steric interaction was
provided by the nonbonded interactions (i) between the R1 angular substituent on the bicyclic lactam
and the π-system of the dipole as shown in Figures 3 and 4. This interaction was shown to be very
significant, causing reversal in π-facial attack of chiral and achiral dipoles when the angular
substituent is changed from phenyl or methyl to hydrogen. The high diastereoselectivity observed
now opens a route to highly substituted chiral, nonracemic pyrrolidines.
Sch em e 1
The intermolecular 1,3-dipolar cycloaddition reaction
of azomethine ylides with olefins represents an efficient
and convergent method for the construction of the pyr-
rolidine structural unit.1,2 Since 1985, interest in the
asymmetric synthesis of substituted pyrrolidine deriva-
tives by this process has led to the development of
cycloaddition reactions in which chirality resides on one
of the two reaction partners. The level of stereoselectivity
provided by these bimolecular reactions has been variable
and empirically dependent upon the proper combination
of chiral dipolarophile3 or chiral dipole.4 In contrast,
employing a chiral dipole (A) and a chiral dipolarophile
(B) for the enhancement of diastereoselection in azo-
methine ylide cycloadditions has only been demonstrated,
to date, by Garner5,6 and briefly from these laboratories.7
The former reported excellent diastereofacial selectivity
for 1,3-dipolar cycloaddition reactions of a photochemi-
cally generated chiral azomethine ylide with a chiral
acryloyl sultam.
† Dedicated to Professor Rolf Huisgen on the occasion of his 75th
birthday.
X Abstract published in Advance ACS Abstracts, May 1, 1996.
(1) Lown, J . W. In 1,3-Dipolar Cycloaddition Chemistry; A. Padwa,
Ed.; Wiley-Interscience: New York, 1984; Vol. 1; p 686.
(2) Tsuge, O.; Kanemasa, S. In Advances in Heterocyclic Chemistry;
Katritzky, A., Ed.; 1989; Vol. 45; p 232.
(3) For recent results concerning intermolecular 1,3-dipolar cyclo-
addition of achiral azomethine ylides to chiral dipolarophiles, see
Takahashi, T.; Kitano, K.; Hagi, T.; Nihonmatsu, H.; Koizumi, T. Chem.
Lett. 1989, 597. Wee, A. G. H. J . Chem. Soc., Perkin Trans. 1 1989,
1363. Annunziata, R.; Cinquini, M.; Cozzi, F.; Raimondi, L.; Pilati, T.
Tetrahedron: Asymmetry 1991, 2, 1329. Coulter, T.; Grigg, R.; Malone,
J . F.; Sridharan, V. Tetrahedron Lett. 1991, 32, 5417. Kanemasa, S.;
Hayashi, T.; Tanaka, J .; Yamamoto, H.; Sakurai, T. J . Org. Chem.
1991, 56, 4473.
(4) For recent results concerning intermolecular 1,3-dipolar cyclo-
addition of chiral azomethine ylides to achiral dipolarophiles, see
Padwa, A.; Chen, Y.-Y.; Chiacchio, U.; Dent, W. Tetrahedron 1985, 41,
3529. Garner, P.; Sunitha, K.; Ho, W. B.; Youngs, W. J .; Kennedy, V.
O.; Djebli, A. J . Org. Chem. 1989, 54, 2041. Anslow, A. S.; Harwood,
L. M.; Phillips, H.; Watkin, D.; Wong, L. F. Tetrahedron: Asymmetry
1991, 2, 1343. Deprez, P.; Rouden, J .; Chiaroni, A.; Riche, C.; Royer,
J .; Husson, H. P. Tetrahedron Lett. 1991, 32, 7531. Deprez, P.; Royer,
J .; Husson, H.-P. Tetrahedron: Asymmetry 1991, 2, 1189. Chastanet,
J .; Fathallah, H.; Negron, G.; Roussi, G. Heterocycles 1992, 34, 1565.
Negron, G.; Roussi, G.; Zhang, J . Heterocycles 1992, 34, 293. Williams,
R. M.; Zhai, W.; Aldous, D. J .; Aldous, S. C. J . Org. Chem. 1992, 57,
6527.
We envisaged chiral bicyclic lactams such as B to be
useful templates for the study of the factors controlling
π-facial selectivity since the substituents (R1, R2, X) can
be systematically varied.8 Moreover, the regioselective
elaboration of the latent ketone (aminal) functionality on
B would allow for a wide variety of substituents (R3, R4)
at the 3- and 4-positions of pyrrolidine ring (C). In a
preliminary study,7 we described substituent effects that
influenced diastereoselectivity in the reaction of chiral,
unsaturated bicyclic lactams (1) with simple achiral (2)
and chiral (3) azomethine ylides derived from benzyl-
amine and enantiomerically pure (R) and (S) R-methyl-
benzylamines, respectively. The levels of single and
double diastereoselection9 in the production of tricyclic
lactams 4 and 5 were modest to good (70-88% de);
(5) Garner, P.; Ho, W. B. J . Org. Chem. 1990, 55, 3973.
(6) Garner, P.; Ho, W. B.; Grandhee, S. K.; Youngs, W. J .; Kennedy,
V. O. J . Org. Chem. 1991, 56, 5893.
(8) Romo, D.; Meyers, A. I. Tetrahedron 1991, 47, 9503.
(9) Masamune, S.; Petersen, J . S.; Sita, L. R. Angew. Chem., Int.
Ed. Engl. 1985, 24, 1.
(7) Fray, A. H.; Meyers, A. I. Tetrahedron Lett. 1992, 33, 3575.
S0022-3263(96)00087-4 CCC: $12.00 © 1996 American Chemical Society

Azomethine Ylide Cycloaddition Reactions
J . Org. Chem., Vol. 61, No. 10, 1996 3363
Ta ble 1. P r ep a r a tion of Dip ola r op h iles 1a -m fr om
Sa tu r a ted Bicyclic La cta m s 1′a -m
Sch em e 2
lactam
R1
R2
X
electrophile
% yield
1a
1b
1c
1d
1e
1f
1g
1h
1i
Me
Me
H
Me
Me
H
i-Pr
Ph
Ph
i-Pr
i-Pr
Ph
Ph
Ph
Ph
H
H
H
H
NH4Cl
NH4Cl
NH4Cl
ClCO2Me
Boc2O
p-TolSO2Cl
(BrCCl2)2
NIS
(BrCCl2)2
NH4Cl
82
82
78
66
43
71
84
55
75
17
77
80
69
CO2Me
CO2t-Bu
Cl
Br
I
Br
H
Me
Sch em e 3a
H
H
Me
Me
Me
Me
Ph
1j
1k
1la
1m
i-Pr
t-Bu
i-Pr
MeI
NH4Cl
ClCO2Me
H
CO2Me
a
This was prepared using LDA (see ref 8).
however, we felt the necessity of increasing the dia-
stereoselection in these cycloaddition processes while
gathering additional support for a steric model for the
origin of the stereoselectivity. We now report that
R-halo-unsaturated bicyclic lactams (1, X ) halogen)
exhibit significantly improved diastereoselection relative
to the lactams previously studied (1 X ) H, CO2R).
after oxidation as shown in Table 1. Unsaturated lac-
tams 1g-i were also prepared via a halogenation-
dehydrohalogenation sequence in similar yields.12
P r ep a r a tion of Ach ir a l a n d Ch ir a l Azom eth in e
Ylid e P r ecu r sor s. As shown in Scheme 2, simple
achiral (2) and chiral (3) azomethine ylide precursors
were derived from benzylamine and enantiomerically
pure (R) and (S)-R-methylbenzylamines according to
Padwa.13 Thus, alkylation of benzylamine or R-methyl-
benzylamine (3 equiv) with (chloromethyl)trimethylsilane
gave the corresponding secondary amines (6 or 7) in 70-
80% yields.
Conversion of the latter to the corresponding achiral
(2) and chiral (3) dipole precursors was accomplished by
treatment of the appropriate amine with aqueous form-
aldehyde, followed by the addition of MeOH and solid
K2CO3 (as water scavenger). Optimum parameters for
cycloaddition were achieved by allowing the azomethine
precursors 2 or 3 to react with the unsaturated bicyclic
lactams utilizing conditions described by Achiwa (cata-
lytic TFA in CH2Cl2).14
Resu lts a n d Discu ssion
P r ep a r a tion of Ch ir a l Dip ola r op h iles. The two
general routes to the dipolarophile precursors used in this
study are illustrated in Scheme 1. Typically, when the
angular substituent (R1) on bicyclic lactam 1′ was an
alkyl or aryl substituent, route A was employed, which
involved the cyclocondensation reaction between a chiral
amino-alcohol10 and a keto-acid.8 Alternatively, route B
was used for the preparation of angular hydrogen (R1 )
H) bicyclic lactams 1′. In this process, condensation of
an amino alcohol (R2 ) i-Pr, Ph) with succinimide gave
an intermediate chiral imide. Partial reduction of the
imide to give an intermediate hydroxy lactam, followed
by acid-catalyzed ring closure, afforded the desired
angular hydrogen bicyclic lactam 1′ (R1 ) H).11
Sequential treatment of the saturated lactams 1′ with
base (2.0 equiv) followed by the addition of phenyl-
selenenyl bromide (1.0 equiv) gave R-selenenyl enolates
that were quenched by a variety of electrophiles. The
unsaturated lactams 1a -m were obtained in good yields
Role of An gu la r Su bstitu en t. Scheme 3 clearly
shows that the nature of the substituent (R1) attached
(12) Newhouse, B. J .; Meyers, A. I.; Sirisoma, N. S.; Braun, M. P.;
J ohnson, C. J . Synlett 1993, 573. For a recent, convenient procedure
to reach these unsaturated lactams 1 (X ) H), see Resek, J .; Meyers,
A. I. Tetrahedron Lett. 1995, 36, 7051.
(13) (a) Padwa, A.; Dent, W. J . Org. Chem. 1987, 52, 235. (b) Vedejs,
E.; Larson, S.; West, F. G. J . Org. Chem. 1985, 50, 2171 and earlier
references cited.
(10) For a convenient conversion of amino acids to amino alcohols,
see McKennon, M. J .; Meyers, A. I.; Drauz, K.; Schwarm, M. J . Org.
Chem. 1993, 58, 3568 and Varma, R. S.; Kabalka, G. W. Synth. Comm.
1985, 15 (9), 843, and references therein.
(11) Meyers, A. I.; Lefker, B. A.; Sowin, T. J .; Westrum, L. J . Org.
Chem. 1989, 54, 4243.
(14) Achiwa, K.; Imai, N.; Motoyama, T.; Sekiya, M. Chem. Lett.
1984, 2041.

3364 J . Org. Chem., Vol. 61, No. 10, 1996
Fray and Meyers
Sch em e 4a
a
Reagents and Conditions: (a) (i) (S)-phenylglycinol (1 equiv), THF, rt, 1 h, (ii) Ac2O, NaOAc, reflux; (b) 2 N HClEtOH, reflux, 2 h; (c)
MeMgBr (3 equiv), THF, rt, 3.3 h; (d) TFA, CH2Cl2, rt, 12 h.
Ta ble 2. Effect of Str u ctu r e on F a cia l Selectivity
lactam 1
ylide 2
ylide (R)-3
(R)-4:5a
ylide (S)-3
(S)-4:5a
entry
R2
R1
X
lactam
(A)-4:5a
1
2
3
4
5
6
i-Pr
Ph
Ph
i-Pr
i-Pr
i-Pr
Me
Me
H
Me
Me
Ph
H
H
H
1a
1b
1c
1d
1e
1m
91:9
94:6
17:83
71:29
72:28
74:26
94:6
91:9
19:81
87:13
92:8
91:9
92:8
16:84
59:41
51:49
69:31
CO2Me
CO2t-Bu
CO2Me
87:13
a
(A)-4:5 refers to adducts derived from the N-benzyl (achiral) ylide; (R)-4:5 and (S)-4:5 refer to adducts from the R and S R-benzylamine
ylides, respectively.
to the angular carbon in 1b and 1c determined the
overall direction of cycloaddition. Predominant approach
of the dipole to the R-face is seen when the angular
substituent is large (R1 ) Me) whereas predominant
approach to the â-face occurs when the angular substitu-
ent is small (R1 ) H). Thus, reaction of 2 equiv of achiral
dipole precursor 2 with angular methyl lactam 1b af-
forded a 16:1 mixture of cycloadducts (A)-4b along with
the minor isomer (A)-5b in quantitative yield. Stereo-
chemical assignments, made on the basis of 13C NMR,
supported the structure of the major isomer (A)-4b,
arising from predominant approach of the dipole to the
“bottom” or R-face of unsaturated lactam 1b. Crystalline,
diastereomerically pure (A)-4b was obtained from the
crude mix in 56-69% yields. In contrast, reaction of
precursor 2 with the angular hydrogen lactam 1c af-
forded only a 5:1 mixture of cycloadducts with (A)-5c
predominating. This is the result of preferential ap-
proach of the dipole to the “top” or â-face of 1c.
With the goal of obtaining sufficient minor isomer (A)-
5b for unambiguous structural characterization, an
alternative synthesis of the tricyclic lactams (A)-4b and
(A)-5b was developed (Scheme 4). In situ cycloaddition
of 2 with maleic anhydride (7) provided the bicyclic
anhydride 8 which was treated with (S)-phenylglycinol,
followed by acetic anhydride, necessary to produce the
crude chiral imide 9. Hydrolysis of the resulting acetate
9 gave the alcohol 10 in 19% overall yield. Addition of
methylmagnesium bromide proceeded nonstereoselec-
tively to provide hydroxy lactams 11, which were con-
verted to a 1:1 mixture (42%) of tricyclic lactams (A)-4b
and (A)-5b using TFA. Chromatography produced pure
(A)-5b for structural comparisons.
Role of X-Su bstitu en t. Dou ble Dia ster eoselec-
tion . Double asymmetric synthesis9 of the tricyclic
cycloadducts was explored in the hope of obtaining
greater levels of diastereoselection in cycloadditions with
chiral dipole equivalents (R)-3 and (S)-3.
Table 2 summarizes the results of the addition to chiral
lactams 1a -e,m by achiral 2 and chiral dipoles (R)-3 and
(S)-3. In cases where the R-substituent, X, was hydrogen
(entries 1-3), it was observed that the π-facial selectivi-
ties were insensitive to the configuration at the benzylic
carbon of the dipole. In contrast, where X was larger
than hydrogen (entries 4-6, X ) CO2Me or CO2t-Bu),
significantly enhanced selectivity was observed for cy-
cloadditions with the dipole (R)-3, compared to the ratios
provided by the achiral 2 and the dipole (S)-3.
Tr a n sition Sta te Mod el. Transition state structural
insight was derived from the data summarized in Table
2 to allow the construction of a preliminary predictive
model for the origin of diastereoselectivity in these 1,3-
dipolar cycloadditions. Stereospecificity is well known

Azomethine Ylide Cycloaddition Reactions
J . Org. Chem., Vol. 61, No. 10, 1996 3365
F igu r e 2. Transition states for reactions of angular methyl
bicyclic lactams with (R)-3.
F igu r e 1. Four competing trajectories of the dipole to the
chiral bicyclic lactam.
to be a characteristic of concerted 1,3-dipolar reactions.15
For example, Padwa13 has demonstrated that methoxy-
methylsilylamine 2 adds to dimethyl fumarate and
maleate with complete stereospecificity, giving rise to
cycloadducts 12 and 13, respectively.
dipole during the cycloaddition. With regard to reactions
of π-systems vicinal to asymmetric centers, Houk19 has
shown that the favored approach of another reacting
species is generally anti to the largest group perpendicu-
lar to the π-system since this trajectory represents the
minimum of unfavorable repulsive interactions between
vicinal bonds.
Starting with the assumption that azomethine ylide
cycloadditions to unsaturated bicyclic lactams may occur
with concerted bond formation, four competing transition
state orientations can be proposed (Figure 1). These
orientations allow the π-systems of the two reaction
partners to approach each other within two parallel
planes.16
The trajectories indicated in Figure 1 as extended
transition orientations are proposed to be more favored
than the nonextended orientations.17 As stated earlier,
when X ) H, the magnitudes of the diastereoselection
were insensitive to the configuration at the dipole (Table
2, entries 1-3). This observation is consistent with poor
stereochemical “communication” or induction between the
sites of asymmetry (*) of the chiral unsaturated lactams
and that of the chiral azomethine ylides. The extended
models are therefore consistent with the maximization
of distance between sites of asymmetry and the minimi-
zation of nonbonded interactions between dipole and
dipolarophile.
Better insight into the nature of the favored confor-
mational preference of the chiral dipole was gained when
Newman projections 14a and 14b were evaluated with
respect to the double diastereoselectivity data collected
in Table 2. The observed trends in diastereoselection
were best rationalized using transition state models in
Figure 2 employing projection 14a . In this model,
approach of the dipolarophile occurs antiperiplanar to the
phenyl group that is oriented perpendicular to the
π-system of the dipole. Consequently, as shown in Table
2 (entries 4 and 5), the intrinsic π-facial selectivity of
bicyclic lactams 1d and 1e (∼40% de, as measured by
their reactions with achiral dipole 2) was due primarily
to gauche interactions (i) between the π-system of the
dipole and the angular methyl substituent. However, the
enhanced selectivity (74-84% de) for R-approach of the
dipole derived from (R)-3 to lactams 1d or 1e was
probably due to increased steric interaction (ii) between
substituents X and R3 in the unfavored transition state
for â-approach.
The model in Figure 2 also explains the decreased
diastereofacial preferences observed when lactams 1d or
1e were allowed to react with (S)-3. As shown in Figure
3, R-approach is subject to steric interactions (iii) between
the methyl substituent of the (S)-dipole (R3) and the ester
moiety (X ) CO2R) of unsaturated lactams 1d or 1e. This
interaction would tend to destabilize this transition state
relative to that for â-approach and may account for the
poor selectivities (2-18% de) observed for this pair of
reactants.
Furthermore, since the magnitudes of the diastereo-
selection was related to the configuration at the dipole
when X ) CO2Me or CO2t-Bu (Table 2, entries 4 and 5),
the model was further refined to take this observation
into account. Padwa proposed that two Felkin18 model
conformations (14a or 14b) could be adopted by the chiral
(15) Huisgen, R. In 1,3-Dipolar Cycloaddition Chemistry; Padwa,
A., Ed.; Wiley-Interscience: New York, 1984; Vol. 1.
(16) Houk, K. N.; Yamaguchi, K. In 1,3-Dipolar Cycloaddition
Chemistry; Padwa, A., Ed.; Wiley-Interscience: New York, 1984; Vol.
2; p 431.
(17) Some ambiguity may be caused by the use of the traditional
terms exo and endo for describing the relative orientations of the dipole
and dipolarophile in these cycloaddition transition states. Therefore,
regardless of π-facial orientation, the extended transition states refer
to the cases where the N-alkyl substituent on the dipole is directed
away from the bulk of the unsaturated bicyclic lactam; whereas the
nonextended transition states refer to orientations where the substit-
uents of the dipole and bicyclic lactam are disposed toward each other
as illustrated in Figure 1.
(18) Cherest, M.; Felkin, H.; Prudent, N. Tetrahedron Lett. 1968,
18, 2199.
(19) Caramella, P.; Rondan, N. G.; Paddon-Row, M. N.; Houk, K.
N. J . Am. Chem. Soc. 1981, 103, 2438.

3366 J . Org. Chem., Vol. 61, No. 10, 1996
Fray and Meyers
Ta ble 3. Effect of Ha logen Su bstitu en t in Rea ction s of
An gu la r Meth yl Bicyclic La cta m s 1b a n d 1i w ith Ach ir a l
a n d Ch ir a l Dip olesa
tricyclic
products
entry lactam
X
dipole
4:5c
1
2
3
4
1b
1i
1i
1i
H
(R)-3 or (S)-3 or 2 ∼94:6 (R),(S),(A)b4b,5b
Br (S)-3
Br (R)-3
Br
91:9 (S)-4i, 5i
>98:2 (R)-4i
∼96:4d (A)-4i
2
a
Reactions were performed by adding TFA (0.1 equiv) to a
solution of dipolarophile (1 equiv, 0.2 M) and dipole precursor (2
b
equiv) in CH2Cl2. For designations (A), (R), and (S)-4 or -5 see
F igu r e 3. Transition states for reactions of angular methyl
bicyclic lactams with 2 (R3 ) H) or (S)-3.
footnote in Table 2. c The ratios of 4 to 5 were determined by 1H
NMR analysis of the crude product mixtures. The crude ratios
d
could not be determined due to complexity of the 1H NMR
spectrum. Accordingly, the crude mixture was subjected to
reductive dehalogenation (NaBH4, Ni(OAc)2) to give the chromato-
graphically inseparable mixture of (A)-4b and (A)-5b. This crude
mixture was partially purified through a plug of silica gel (1:4
EtOAc/hexanes) to give the ratio 96:4 by 1H NMR analysis.
This model is also consistent with the observation that
the magnitude of the diastereoselection observed in 1,3-
dipolar reactions with R-unsubstituted lactams 1a -c (X
) H) was insensitive to the configuration at the dipole
(Table 2, entries 1-3). From the model it follows that
interactions ii and iii (cf. Figures 2 and 3) would be
minor unless both R3 and X substituents are larger than
hydrogen.
A self-consistent scenario was not obtained when
approach of the dipolarophile was assumed to occur
antiperiplanar to the methyl group oriented perpendicu-
lar to the π-system of the dipole (projection 14b). Ap-
parently, the phenyl group is the “large” group with
respect to the unique nonbonded interactions encoun-
tered in the approach of the chiral dipole to the R-sub-
stituted chiral unsaturated bicyclic lactams. This asser-
tion is reasonable when one compares the relative
A-values of methyl and phenyl groups (1.7420 and 2.8721
kcal/mol, respectively).
r-Ha lobicyclic La cta m s. Based on the above, we
next sought to increase the levels of diastereoselection
in cycloadditions with angular methyl (R1 ) Me) and
angular hydrogen (R1 ) H) bicyclic lactams 1 (cf. Table
2). If the model in Figure 2 is valid, then the intrinsic
π-facial selectivities of unsaturated bicyclic lactams
should be augmented by increasing steric interaction ii
to destabilize the transition state leading to the minor
cycloadduct. Since the destabilizing effect of interaction
ii would necessarily depend upon the nature of X, we felt
that a halogen may fulfill the expected criteria for high
selectivity since it is larger than hydrogen and not
excessively electron-withdrawing. Concern for synthetic
utility also dictated that the halogen be readily remov-
able.
An gu la r Meth yl La cta m s 1 (R1 ) Me). According
to the model depicted in Figure 2, the use of (R)-3 in
cycloaddition reactions with R-halo lactams 1 (R1 ) Me,
X ) halogen) was expected to afford high selectivity for
R-approach of the dipole as a consequence of selective
destabilization (ii) of the transition state for â-approach.
As shown in Table 3, cycloadduct (R)-4i was obtained as
a single diastereomer when R-bromo lactam 1i was
reacted with (R)-3 (entry 3, matched case); whereas
significantly decreased selectivity (82% de) was observed
in the reaction of 1i with (S)-3 (entry 2, mismatched
case).
F igu r e 4. Transition states for reactions of angular hydrogen
bicyclic lactams (1, X ) halogen) with (S)-3.
ture, proceeding to only 51-76% conversions after 48 h.
However, the use of excess dipole (2-4 equiv) and higher
reaction temperature (37 °C) markedly decreased reac-
tion times (2-3 h) and improved the isolated yields of
tricyclic product without detectable loss of diastereo-
selectivity. Presumably, the lower reactivity of 1i (rela-
tive to 1b) may be attributed to the slow approach of the
dipole due to the combined presence of the large bromine
atom and the angular methyl group.
An gu la r Hyd r ogen La cta m s 1 (R1 ) H). In contrast
to the reactivity and selectivity of the angular methyl
lactams 1 (R1 ) Me), the angular hydrogen lactams 1
(R1 ) H) were found to be more reactive (reactions were
typically complete within 1 h) and less selective. For
example, the intrinsic diastereofacial selectivity of 1c (X
) H) is moderate (∼66% de), favoring the cycloadduct
derived from â-approach of the dipole (Table 2, entry 3).
In contrast to the model describing the angular methyl
lactams (Figure 2), the (S)-3 dipole equivalent was
predicted to exhibit greater selectivity (Figure 4) for
â-approach. This was assumed to be a consequence of
greater nonbonded interactions (ii) in the transition state
for R-approach.
The results of additions with several angular hydrogen
lactams 1c,f-h are summarized in Table 4. As predicted
by the model in Figure 4, the (S)-dipole produced the
highest selectivities when the stereochemical control
element X was halogen (entries 2-4). In spite of the
increase in halogen size, the diastereoselection observed
with (S)-3 was identical, within experimental error (90-
94% de). However, the steric effect of the halogens is
likely to be attenuated by the increasing halogen polar-
izabilities and carbon-halogen bond lengths (Cl < Br <
I). The fact that these halogens show similar A values
(0.47-0.53 kcal/mole)22 makes this a reasonable assump-
tion. The diastereoselectivities observed in reactions
Compared to the reactivity of R-unsubstituted lactam
1b, the R-bromo lactam 1i reacted sluggishly with the
achiral and chiral azomethine ylides at room tempera-
(20) Booth, H.; Everett, J . R. J . Chem. Soc., Chem Commun. 1976,
278.
(21) Eliel, E. L.; Manoharan, M. J . Org. Chem. 1981, 46, 1959.

Azomethine Ylide Cycloaddition Reactions
J . Org. Chem., Vol. 61, No. 10, 1996 3367
Ta ble 4. Effect of Ha logen Su bstitu en t in Rea ction s of
An gu la r Hyd r ogen La cta m s 1c,f-h w ith Ach ir a l a n d
Ch ir a l Dip oles
with the achiral dipole 2 (R3 ) H) were insensitive to
the nature of X on the bicyclic lactams (Table 4, entries
1-4). This observation is consistent with the expectation
that interaction ii (Figure 3) would be minor unless both
R3 and X substituents are larger than hydrogen.
Rem ova l of Ha logen Ster eocon tr ol Elem en t. For
the sake of synthetic versatility it was necessary to
demonstrate that the R-halo substituent could be easily
removed. Initial attempts to effect the removal of the
halogen from tricyclic lactams (S)-5g and (A)-4i proved
to be problematic. For example, reaction of R-bromo
tricyclic lactam (S)-5g with zinc in acetic acid or activated
zinc-copper couple23 gave 64-72% yields of the corre-
sponding dehalogenated product ((S)-5c) accompanied by
4-14% yields of ring opened product 15. Lowering the
reaction temperature merely decreased the reduction rate
without decrease of 15. Use of samarium diiodide24,25
under conditions described by Curran26 and Imamoto27
gave incomplete reduction of the halogen in 5g. Incom-
plete dehalogenation of (S)-5g was also observed with
tributyltin hydride28 and with magnesium powder.
Since transition metals are known to catalyze a
number of hydride reductions,29 the reaction conditions
described by Goto and Kishi30 were explored. Although
both (S)-5g and (A)-4i remained essentially unreactive
in the presence of excess NaBH4 in MeOH, complete
dehalogenation was observed for both halogen adducts
within 30 min in the presence of 10% by weight nickel(II)
acetate and excess NaBH4 (10 eq.) in yields of 78-95%.
angular
hydrogen
lactam
achiral 2:
(A)-4:5a
(R)-3:
(R)-4:5
(S)-3:
(S)-4:5
entry
X
1
2
3
4
H
1c
1f
1g
1h
17:83
18:82
18:82
18:82
19:81
21:79
22:78
23:77
16:84
5:95
4:96
3:97
Cl
Br
I
a
See footnote on Table 2.
F igu r e 5.
F igu r e 6.
Ster eoch em ica l Assign m en ts. The stereochemical
assignments for the cycloadducts derived from the an-
gular methyl lactams (1, R1 ) Me, Table 1) are based
upon difference NOE experiments and 13C NMR chemical
shift correlations. For example, 2-D HETCOR experi-
ments on (R)-4d and (R)-5d allowed correlations between
13C and 1H NMR signals that provided unambiguous
structural assignment of the methine hydrogen signals
corresponding to each isomer.
The results of NOE experiments (CDCl3) on the major
((R)-4d )) and minor ((R)-5d )) cycloadducts are shown in
Figure 5. The major cycloadduct (R)-4d is assigned the
R-configuration based on the 5.7% enhancement ob-
served for the H methine hydrogen resonance (δ 2.94)
when the angular methyl hydrogen resonance at δ 1.55
was irradiated. For the minor isomer, irradiation of the
angular methyl hydrogen resonance at δ 1.27 caused a
0.9% enhancement for the methine hydrogen resonance
at δ 2.93.
Significant diagnostic differences in 13C chemical shift
existed between the angular methyl signals correspond-
ing to the major (4) and minor (5) diastereomers. For
example, higher shielding was observed for the methyl
signal in the minor cycloadducts relative to the corre-
sponding signal in the major cycloadducts. Since the
minor cycloadducts 5 exhibited upfield methyl signals (δ
19-23), they were assigned the â-configuration. Simi-
larly, the major tricyclic cycloadducts 4 were assigned
the R-configuration since these compounds exhibited
downfield angular methyl signals (δ 27-29).
Stereochemical assignments for the angular hydrogen
tricyclic lactams 4 and 5c,f-h are based on the ob-
served magnitude of the coupling (1H NMR) between the
angular H and the adjacent H methine hydrogens cor-
responding to each isomer (4 and 5). As shown in Figure
6, the observation of a singlet (J ) 0) for the angular
hydrogen of the major isomer is consistent with a ∼90°
dihedral angle or trans configuration between the two
hydrogens.31
(22) J ensen, F. R.; Bushweller, C. H. J . Am. Chem. Soc. 1969, 91,
344.
(23) LeGoff, E. J . Org. Chem. 1964, 29, 2048.
(24) Molander, G. A.; Hahn, G. J . Org. Chem. 1986, 51, 1135.
(25) Soderquist, J . A. Aldrichim. Acta 1991, 24, 15.
(26) Hasegawa, E.; Curran, D. P. J . Org. Chem. 1993, 58, 5008.
(27) Imamoto, T.; Ono, M. Chem. Lett. 1987, 501.
(28) Smith, A. B., III; Hale, K. J .; McCauley, J . P., J r. Tetrahedron
Lett. 1989, 30, 5579.
(29) For examples of transition metal-catalyzed hydride reductions
see: Bosin, T. R.; Raymond, M. G.; Buckpitt, A. R. Tetrahedron Lett.
1973, 47, 4699; Ashby, E. C.; Lin, J . J . Tetrahedron Lett. 1977, 51,
4481. Satoh, T.; Mitsuo, N.; Nishiki, M.; Nanba, K.; Suzuki, S. Chem.
Lett. 1981, 1029.
(31) Farina, F.; Martin, M. V.; Paredes, M. C. Heterocycles 1988,
27, 365.
(30) Goto, T.; Kishi, Y. Tetrahedron Lett. 1961, 513.

3368 J . Org. Chem., Vol. 61, No. 10, 1996
Fray and Meyers
Gen er a l Selen en yla tion /Oxid a tion P r oced u r e for th e
P r ep a r a tion of La cta m s 1. To a -78 °C solution (0.1 M) of
bicyclic lactam 1′ (1.0 equiv) in THF was added a 1.0 M
solution of LiN(TMS)2 (2.0 equiv) in THF, and the pale yellow
solution was allowed to stir 30 min. A 0.3 M THF solution of
PhSeBr (1.1 equiv) was added dropwise followed by, after 5
min, the dropwise addition of a 0.3 M THF solution of
electrophile (1.1 equiv). After 15 min, a saturated aqueous
NH4Cl solution was added to the -78 °C reaction mixture
which was then allowed to warm to rt. The mixture was
extracted with Et2O, and the organic extracts were concen-
trated under reduced pressure.
Con clu sion
Evidence for a predictive transition state picture
describing diastereoselective dipolar cycloadditions of
simple azomethine ylides to a structurally variable chiral
template has been presented. It is hoped that the steric
models presented here would provide insight for the
rational control of stereoselection in these processes,
especially for the preparation of nonracemic 3,4-di-
substituted pyrrolidine-containing building blocks. The
latter will be described in a future article.
To a CH2Cl2 solution (∼0.05 M) of the above phenylselenyl-
ated products, at 0 °C, was added a 30% H2O2 (3 equiv) solution
. The resulting heterogeneous mixture was allowed to warm
to rt while stirring vigorously for 6 h. The aqueous phase was
extracted with CH2Cl2, and the organic extracts were combined
and washed successively with 1 N HCl and saturated aqueous
NaHCO3. The organic phase was dried (Na2SO4) and concen-
trated under reduced pressure to afford a crude oil which was
purified as indicated below.
Un sa tu r a ted Bicyclic La cta m 1a . The bicyclic lactam
1a ′ (2.0 g, 0.011 mol), derived from (S)-valinol and levulinic
acid,33,11 was subjected to the above general selenenylation/
oxidation procedure using saturated aqueous NH4Cl as the
electrophile to afford 1.6 g (82%) of 1a as a pale orange liquid
after bulb to bulb vacuum distillation (115 °C, 1.5 mmHg). An
analytical sample was prepared by crystallization with hex-
Exp er im en ta l Section
N-Ben zyl-N-(m eth oxym eth yl)-N-(tr im eth ylsilyl)m eth -
yla m in e (2). The procedure described by Padwa32 for the
synthesis of N-benzyl-N-(trimethylsilyl)methylamine (6) was
followed with the exception that the crude secondary amine
was purified by flash chromatography through silica gel (7:1
silica gel/crude) saturated with 5:95 Et3N/EtOAc. This pro-
cedure easily allows the more polar excess benzylamine (Rf
0.14, 5:95 Et3N/EtOAc) to be separated from the less polar
desired secondary amine. Final purification of the secondary
amine was accomplished via short-path vacuum distillation
through a 15 cm Vigreux column. This method provided pure
secondary amine 6 (73%) as a clear colorless liquid: bp 70-
71 °C (0.7 mmHg) (lit.38 bp 89-90 °C (5 mmHg)); Rf 0.59 (5:95
anes to give white needles: Rf 0.41 (1:1 EtOAc/hexanes); mp
1
Et3N/EtOAc); H NMR (300 MHz, CDCl3) δ 7.30 (s, 5H), 3.79
(s, 2H), 2.04 (s, 2H), 1.10 (br s, 1H), 0.03 (s, 9H).
1
39-42 °C; [R]25 +48.7 (c 1.51, acetone); H NMR (300 MHz,
D
CDCl3) δ 6.99 (d, 1H, J ) 5.8), 5.98 (d, 1H, J ) 5.8), 4.27 (dd,
1H, J ) 7.3, 8.9), 4.05 (dd, 1H, J ) 5.9, 8.9), 3.48 (ddd, 1H, J
) 6.0, 7.3, 10.2), 1.74 (m, 1H), 1.53 (s, 3H), 1.06 (d, 3H, J )
6.7), 0.90 (d, 3H, J ) 6.6); IR (film) ν 1716 cm-1. Anal. Calcd
for C10H15NO2: C, 66.27; H, 8.34. Found: C, 66.08; H, 8.38.
Un sa tu r a ted Bicyclic La cta m 1b. The saturated bicyclic
lactam 1b′ was prepared in the following manner. A solution
of (S)-phenylglycinol (3.52 g, 0.0257 mol) and levulinic acid
(2.98 g, 0.0257 mol) in toluene (100 mL) was heated at reflux
and stirred overnight with azeotropic removal of water.
Toluene was removed under reduced pressure, and the result-
ing solids were recrystallized from hot EtOAc/hexanes. This
process yielded 4.55 g (82%) of the saturated bicyclic lactam
1b′ as yellow-white needles: mp 127-129 °C, Rf 0.25 (1:1
EtOAc/hexanes), [R]25D +147 (c 1.08, CCl4); 1H NMR (300 MHz,
CDCl3) δ 7.30 (m, 5H), 5.15 (t, 1H, J ) 7.5), 4.59 (app t, 1H, J
) 8.5), 4.08 (dd, 1H, J ) 7.0, 8.8), 2.86 (dt, 1H, J ) 9.8, 17.2),
2.57 (ddd, 1H, J ) 5.2, 7.6, 12.8), 2.27 (m, 2H), 1.43 (s, 3H);
13C NMR (75.5 MHz, CDCl3) δ 178.9 (s), 140.0 (s), 128.6 (d),
127.4 (d), 125.5 (d), 100.4 (s), 73.2 (t), 57.6 (d), 33.8 (t), 33.1
The procedure described by Padwa for the synthesis of 213
was followed with the exception that 6 (8.4 g, 0.043 mol) was
added by syringe dropwise over 45 min to a pH 7, 37% aqueous
formaldehyde solution (4.5 mL, 0.065 mol) at 0 °C. Distillation
provided 2 as a clear, colorless liquid in 81% yield: bp 77-80
1
°C (0.1 mmHg) (lit.13 bp 78-80 °C (5 mmHg)); H NMR (300
MHz, CDCl3) δ 7.31 (m, 5H), 3.99 (s, 2H), 3.75 (s, 2H), 3.23 (s,
3H), 2.18 (s, 2H), 0.04 (s, 9H); 13C NMR (75.5 MHz, CDCl3) δ
139.7 (s), 128.7 (d), 128.1 (d), 126.8 (d), 88.4 (t), 59.5 (t), 55.4
(q), 42.9 (t), -1.5 (q).
(R)-N-(1-P h en yleth yl)-N-(m eth oxym eth yl)-N-(tr im eth -
ylsilyl)m eth yla m in e ((R)-3). Using the procedure described
above for the synthesis of 6, (R)(+)-R-methylbenzylamine (10.4
g, 0.0860 mol) was heated with (chloromethyl)trimethylsilane
(3.5 g, 0.029 mol) to provide 3.2 g (94%) of recovered (R)(+)-
3-methylbenzylamine (Rf 0.25, 5:95 Et3N/EtOAc) and 5.0 g
(84%) of the known13 secondary amine (R)-7 as a clear, colorless
liquid after distillation: bp 64-70 °C (0.5 mmHg), Rf 0.64 (5:
95 Et3N/EtOAc), [R]25D +46.6 (c 1.06, CCl4); 1H NMR (300 MHz,
CDCl3) δ 7.28 (m, 5H), 3.62 (q, 1H, J ) 6.6), 1.87 (ABq, 2H, J
) 13.6, ∆ν ) 21.8), 1.30 (d, 3H, J ) 6.4), 1.00 (br s, 1H), 0.01
(t), 24.2 (q); IR (film) ν 1721 cm-1
. Anal. Calcd for C13H15-
NO2: C, 71.87; H, 6.96; N, 6.45. Found: C, 71.95; H, 7.01; N,
6.44.
(s, 9H); IR (film) ν 3083, 1603, 1492 cm-1
. Anal. Calcd for
C12H21NSi: C, 69.49; H, 10.21; N, 6.75. Found: C, 69.76; H,
10.32; N, 6.91.
Bicyclic lactam 1b′ (2.35 g, 0.0108 mol) was subjected to the
general selenenylation/oxidation procedure using saturated
aqueous NH4Cl as the electrophile. This procedure afforded
1.62 g (70%) of 1b as a pale yellow powder after flash
chromatography: Rf 0.43 (1:1 EtOAc/hexanes); mp 83-85 °C;
[R]25D +114 (c 1.54, acetone); 1H NMR (300 MHz, CDCl3) δ 7.30
(m, 5H), 7.10 (d, 1H, J ) 5.6), 6.08 (d, 1H, J ) 5.8), 5.06 (app
t, 1H, J ) 7.0), 4.66 (app t, 1H, J ) 8.5), 4.30 (dd, 1H, J ) 6.4,
8.8), 1.53 (s, 3H); 13C NMR (75.5 MHz, CDCl3) δ 177.9 (s), 151.0
(d), 139.7 (s), 128.7 (d), 128.0 (d), 127.5 (d), 125.8 (d), 101.0
Using the procedure described above for the synthesis of 2,
(R)-7 (5.42 g, 0.261 mol) was added by syringe dropwise over
45 min to a pH 7, 37% aqueous formaldehyde solution (2.95
mL, 0.0392 mol) at 0 °C. This procedure provided 5.42 g (83%)
of (R)-3 as a clear, colorless liquid: bp 82-84 °C (0.2 mmHg),
1H NMR (300 MHz, CDCl3) δ 7.35 (m, 5H), 4.11 (ABq, 2H, J
) 9.2, ∆ν ) 59.2), 3.98 (q, 1H, J ) 6.7), 3.18 (s, 3H), 2.12 (ABq,
2H, J ) 14.6, ∆ν ) 32.0), 1.36 (d, 3H, J ) 6.7), -0.14 (s, 9H);
13C NMR (75.5 MHz, CDCl3) δ 145.3 (s), 128.0 (d), 127.5 (d),
126.6 (d), 85.9 (t), 61.8 (d), 54.6 (q), 39.9 (t), 19.2 (q), -1.4 (q);
IR (film) ν 3084, 1071 cm-1. Anal. Calcd for C14H25NOSi: C,
66.88; H, 10.02; N, 5.57. Found: C, 67.08; H, 10.04; N, 5.75.
(S)-N-(1-P h en yleth yl)-N-(m eth oxym eth yl)-N-(tr im eth -
ylsilyl)m eth yla m in e ((S)-3). Using the procedure described
above for the synthesis of (R)-3, (S)(-)-R-methylbenzylamine
(s), 75.9 (t), 58.3 (d), 21.8 (q); IR (film) ν 1720 cm-1
. Anal.
Calcd for C13H13NO2: C, 72.54; H, 6.09. Found: C, 72.27; H,
6.07.
Un sa tu r a ted Bicyclic La cta m 1c. The bicyclic lactam 1c′
(106 mg, 0.522mmol), derived from (S)-phenylglycinol and
succinic anhydride,11 was subjected to the above general
selenenylation/oxidation procedure using saturated aqueous
NH4Cl as the electrophile. This procedure afforded 81.6 mg
(78%) of 1c as a white powder after radial chromatography:
was converted to secondary amine (S)-7 ([R]25 -46.9 (c 1.05,
D
CCl4)), which was then converted to (S)-3 ([R]25D -20.5 (c 2.45,
Rf 0.46 (1:1 benzene/Et2O); mp 74-75 °C; [R]25 +116 (c 1.55,
CCl4)).
D
acetone); 1H NMR (300 MHz, CDCl3) δ 7.30 (m, 5H), 7.20 (dd,
1H, J ) 1.5, 5.9), 6.22 (d, 1H, J ) 5.9), 5.65 (d, 1H, J ) 0.8),
4.96 (app t, 1H, J ) 7.2), 4.73 (dd, 1H, J ) 7.4, 8.8), 4.07 (dd,
(32) Padwa, A.; Chen, Y.-Y.; Dent, W.; Nimmesgern, H. J . Org.
Chem. 1985, 50, 4006.

Azomethine Ylide Cycloaddition Reactions
J . Org. Chem., Vol. 61, No. 10, 1996 3369
1H, J ) 7.3, 8.8); 13C NMR (75.5 MHz, CDCl3) δ 176.7 (s), 145.6
mol), and K2CO3 (2 g) in toluene (50 mL) was heated at reflux
for 36 h. The mixture was diluted with CH2Cl2 and filtered
through a sintered glass funnel. The filtrate was concentrated
under reduced pressure, and the resulting liquid was vacuum
distilled (71-73 °C, 1 mmHg) to afford 3.86 g (40%) of (()-1j′
as clear, colorless liquid. For the known35,36 racemic saturated
bicyclic lactam ((()-1j′) (7aRS)-5-oxo-7a-methyl-2,3,5,6,7,7a-
hexahydropyrrolo[2,1-b]oxazole: Rf 0.14 (1:1 EtOAc/hexanes);
bp 71-73 °C, 1 torr; 1H NMR (300 MHz, CDCl3) δ 3.94 (m,
3H), 3.13 (m, 1H), 2.68 (m, 1H), 2.45 (m, 1H), 2.16 (m, 2H),
1.40 (s, 3H).
Bicyclic lactam (()-1j′ (113 mg, 0.800 mmol) was subjected
to the general selenenylation/oxidation procedure using satu-
rated aqueous NH4Cl as the electrophile. This procedure
afforded 19.4 mg (17%) of (()-1j as a pale yellow oil after
partial purification via radial chromatography (1:1
EtOAc/hexanes): Rf 0.47 (EtOAc); 1H NMR (300 MHz, CDCl3)
δ 7.06 (d, 1H, J ) 5.8), 5.99 (d, 1H, J ) 5.7), 4.13 (m, 1H),
3.91 (m, 2H), 3.24 (m, 1H), 1.49 (s, 3H); 13C NMR (75.5 MHz,
CDCl3) δ 177.6 (s), 151.3 (d), 127.7 (d), 99.9 (s), 69.5 (t), 42.5
(t), 22.2 (q).
(d), 139.3 (s), 131.5 (d), 128.8 (d), 127.7 (d), 126.0 (d), 93.9 (d),
78.3 (t), 57.9 (d); IR (film) ν 1716 cm-1. Anal. Calcd for C12H11
NO2: C, 71.63; H, 5.51. Found: C, 71.59; H, 5.53.
-
Un sa tu r a ted Bicyclic La cta m 1d . Bicyclic lactam 1a ′
(506 mg, 2.76 mmol), derived from (S)-valinol and levulinic
acid,33,11 was subjected to the above general selenenylation/
oxidation procedure using methyl chloroformate as the elec-
trophile to afford unsaturated lactam 1d 34 in 66% yield.
Un sa tu r a ted Bicyclic La cta m 1e. Bicyclic lactam 1a ′ (1.0
g, 5.5 mmol), derived from (S)-valinol and levulinic acid,33,11
was subjected to the above general selenenylation/oxidation
procedure using di-tert-butyl dicarbonate as the electrophile
to afford unsaturated lactam 1e34 in 43% yield.
Un sa tu r a ted Bicyclic La cta m 1f. Bicyclic lactam 1c′
(103 mg, 0.507mmol), derived from (S)-phenylglycinol and
succinic anhydride,11 was subjected to the above general
selenenylation/oxidation procedure using p-toluenesulfonyl
chloride (102 mg, 0.535 mmol) as the electrophile. This
procedure afforded 84.3 mg (71%) of 1f as a tan powder after
radial chromatography: Rf 0.63 (Et2O); mp 84-89 °C; [R]25
D
+161 (c 0.99, acetone); 1H NMR (300 MHz, CDCl3) δ 7.32 (m,
5H), 7.11 (d, 1H, J ) 1.8), 5.60 (d, 1H, J ) 1.9), 5.00 (app t,
1H, J ) 7.4), 4.77 (dd, 1H, J ) 7.5, 9.0), 4.07 (dd, 1H, J ) 7.4,
8.9); 13C NMR (75.5 MHz, CDCl3) δ 170.3 (s), 138.5 (s), 137.8
(d), 134.9 (s), 128.9 (d), 127.9 (d), 126.0 (d), 90.8 (d), 77.9 (t),
Un sa tu r a ted Bicyclic La cta m 1k . Bicyclic lactam 1a ′
(500 mg, 2.73 mmol), derived from (S)-valinol and levulinic
acid,33,11 was subjected to the above general selenenylation/
oxidation procedure using methyl iodide as the electrophile
to afford the known8 unsaturated lactam 1k in 77% yield.
Un sa tu r a ted Bicyclic La cta m 1m . Bicyclic lactam 1m ′
(500 mg, 2.03 mmoles), derived from (S)-valinol and 3-benzoyl-
propionic acid,37 was subjected to the above general selenenyl-
ation/oxidation procedure using methyl chloroformate as the
electrophile to afford unsaturated lactam 1m as a very light
yellow powder in 69% yield: Rf 0.40 (4:5 Et2O/hexanes); mp
58.5 (d); IR (film) ν 1725, 1604 cm-1. Anal. Calcd for C12H10
ClNO2: C, 61.16; H, 4.28. Found: C, 61.02; H, 4.20.
-
Un sa tu r a ted Bicyclic La cta m 1g. Bicyclic lactam 1c′
(202 mg, 0.994mmol), derived from (S)-phenylglycinol and
succinic anhydride,11 was subjected to the above general
selenenylation/oxidation procedure using 1,2-dibromotetra-
chloroethane (358 mg, 1.09 mmol) as the electrophile. This
procedure afforded 233 mg (84%) of 1g as a pale yellow powder
after radial chromatography: Rf 0.31 (1:4 EtOAc/hexanes); mp
101-104 °C; [R]25D +154 (c 1.57, acetone); 1H NMR (300 MHz,
CDCl3) δ 7.28-7.38 (m, 6H), 5.57 (d, 1H, J ) 1.8), 5.00 (app t,
1H, J ) 7.3), 4.75 (dd, 1H, J ) 7.4, 9.0), 4.07 (dd, 1H, J ) 7.3,
9.0); 13C NMR (75.5 MHz, CDCl3) δ 170.8 (s), 142.6 (d), 138.5
(s), 128.8 (d), 127.9 (d), 125.9 (d), 124.8 (s), 92.3 (d), 77.8 (t),
58.5 (d); IR (film) ν 3081, 1713, 1679, 1641 cm-1. Anal. Calcd
for C12H10BrNO2: C, 51.45; H, 3.60. Found: C, 51.40; H, 3.64.
Un sa t u r a t ed Bicyclic La ct a m 1h . Bicyclic lactam 1c′
(102 mg, 0.499 mmol), derived from (S)-phenylglycinol and
succinic anhydride,11 was subjected to the above general
selenenylation/oxidation procedure using N-iodosuccimide (124
mg, 0.549 mmol) as the electrophile. This procedure afforded
89.0 mg (55%) of 1h as a pale yellow powder after radial
1
77-79 °C; [R]D ) +197 (c 1.01, acetone); H NMR (300 MHz,
CDCl3) δ 7.60 (s, 1H), 7.49 (m, 2H), 7.36 (m, 3H), 4.47 (dd,
1H, J ) 7.4, 8.8), 3.81 (t, 1H, J ) 8.1), 3.81 (s, 3H), 3.62 (dt,
1H, J ) 7.4, 10.3), 1.31 (m, 1H), 1.05 (d, 3H, J ) 6.6), 0.71 (d,
3H, J ) 6.6); 13C NMR (75.5 MHz, CDCl3) δ 172.5 (s), 161.5
(s), 155.5 (d), 136.0 (s), 129.3 (d), 129.2 (d), 128.9 (d), 126.0
(d), 99.6 (s), 75.3 (t), 62.5 (d), 52.3 (q), 32.3 (d), 20.7 (q), 18.8
(q); IR (film) ν 1766, 1737, 1635 cm-1. Anal. Calcd for C17H19
NO4 C, 67.76; H, 6.36. Found: C, 67.71; H, 6.34.
-
Azom eth in e Ylid e Cycloa d d ition s to Un sa tu r a ted Bi-
cyclic La cta m s. Gen er a l P r oced u r e. Using the conditions
of Achiwa,38 a 0.2 M CH2Cl2 solution of a mixture of unsatu-
rated bicyclic lactam (1.0 equiv) and dipole precursor 2, (R)-
3, or (S)-3 (2.0-4.0 equiv) was treated with trifluoroacetic acid
(0.1 equiv). After complete consumption of starting lactam was
indicated by TLC, the mixture was quenched with saturated
aqueous NaHCO3, extracted with CH2Cl2, dried (Na2SO4), and
concentrated under reduced pressure. The crude product
mixture was analyzed by 1H NMR to determine the diastereo-
meric ratios. Purification was then accomplished via column,
radial, or preparative thin-layer chromatography.
chromatography: Rf 0.65 (Et2O); mp 74-76 °C; [R]25 +147 (c
D
1
1.00, CHCl3); H NMR (300 MHz, CDCl3) δ 7.56 (d, 1H, J )
1.8), 7.25-7.40 (m, 5H), 5.58 (d, 1H, J ) 1.7), 5.02 (app t, 1H,
J ) 7.2), 4.73 (dd, 1H, J ) 7.4, 8.9), 4.09 (dd, 1H, J ) 7.1,
8.9); 13C NMR (75.5 MHz, CDCl3) δ 172.5 (s), 150.9 (d), 138.7
(s), 128.8 (d), 127.8 (d), 125.9 (d), 100.2 (s), 94.5 (d), 77.8 (t),
58.6 (d); IR (film) ν 1706 cm-1. Anal. Calcd for C12H10INO2:
C, 44.04; H, 3.09; N, 4.28. Found: C, 44.18; H, 3.04; N, 4.23.
Un sa tu r a ted Bicyclic La cta m 1i. Bicyclic lactam 1b′
(200 mg, 0.921 mmol), derived from (S)-phenylglycinol and
levulinic acid (see preparation for 1b), was subjected to the
general selenenylation/oxidation procedure using 1,2-dibromo-
tetrachloroethane (329 mg, 1.01 mmol) as the electrophile. This
procedure afforded 204 mg (75%) of 1i as a white solid after
Cycloa d d u cts (A)-4a a n d (A)-5a . Using the above general
procedure, a 0 °C solution of lactam 1a (50.0 mg, 0.276 mmol)
and 2 (134 mg, 0.552 mmol) in CH2Cl2 was treated with a 0.13
M solution of TFA in CH2Cl2 (0.21 mL, 0.028 mmol) and was
immediately allowed to warm to rt with stirring for 2.7 h.
Integration of the resolved signals corresponding to the major
isomer ((A)-4a : δ 1.02, 1.45) and the minor isomer ((A)-5a : δ
1.07, 1.35) indicated a ratio of 91:9. Column chromatography
(1:9 to 1:1 EtOAc/hexanes) of the crude mixture afforded 86.7
mg (99.9%) of an inseparable mixture of (A)-4a and (A)-5a as
a clear, colorless syrup.
radial chromatography: Rf 0.66 (Et2O); mp 98-101 °C; [R]25
D
+130 (c 1.55, acetone); 1H NMR (300 MHz, CDCl3) δ 7.26-
7.39 (m, 5H), 7.23 (s, 1H), 5.11 (app t, 1H, J ) 7.1), 4.68 (dd,
1H, J ) 7.9, 8.9), 4.29 (dd, 1H, J ) 6.5, 9.0), 1.53 (s, 3H); 13C
NMR (75.5 MHz, CDCl3) δ 172.1 (s), 148.0 (d), 139.0 (s), 128.8
(d), 127.7 (d), 125.7 (d), 121.5 (s), 99.8 (s), 75.7 (t), 59.0 (d),
21.9 (q); IR (film) ν 1715 cm-1. Anal. Calcd for C13H12BrNO2:
C, 53.08; H, 4.11; N, 4.76. Found: C, 53.16; H, 4.15; N, 4.70.
Un sa tu r a ted Bicyclic La cta m (()-1j. A solution of
ethanolamine (4.2 g, 0.069 mol), ethyl levulinate (9.9 g, 0.069
1
For (A)-4a : Rf 0.46 (EtOAc); H NMR (300 MHz, CDCl3) δ
7.25 (m, 5H), 4.08 (dd, 1H, J ) 7.3, 8.0), 3.87 (dd, 1H, J ) 4.8,
8.3), 3.66 (m, 1H), 3.52 (ABq, 2H, J ) 13.3, ∆ν ) 49.2), 3.23
(m, 2H), 3.09 (dd, 1H, J ) 3.0, 9.6), 2.69 (td, 1H, J ) 3.1, 8.4),
(35) Vainiotalo, P.; Savolainen, P.-L.; Ahlgren, M.; Malkonen, P. J .;
Vepsalainen, J . J . Chem. Soc., Perkin Trans. 2 1991, 735.
(36) Wedler, C.; Schick, H.; Schargenberg-Pfeiffer, D.; Reck, G.
Liebigs Ann. Chem. 1992, 29.
(37) Meyers, A. I.; Wallace, R. H.; Harre, M.; Garland, R. J . Org.
Chem. 1990, 55, 3137.
(38) Terao, Y.; Kotaki, H.; Imai, N.; Achiwa, K. Chem. Pharm. Bull.
1985, 33, 2762.
(33) Meyers, A. I.; Wanner, K. T. Tetrahedron Lett. 1985, 26, 2047.
(34) Busacca, C. A.; Meyers, A. I. J . Chem. Soc., Perkin Trans. 1
1991, 2299.

3370 J . Org. Chem., Vol. 61, No. 10, 1996
Fray and Meyers
2.34 (dd, 1H, J ) 6.7, 9.1), 2.20 (dd, 1H, J ) 5.1, 9.0), 1.69 (m,
1H), 1.44 (s, 3H), 1.02 (d, 3H, J ) 6.7), 0.89 (d, 3H, J ) 6.6);
13C NMR (75.5 MHz, CDCl3) δ 180.0 (s), 138.8 (s), 128.3 (d),
128.2 (d), 126.8 (d), 98.3 (s), 71.4 (t), 62.1 (d), 59.1 (t), 57.0 (t),
54.1 (t), 49.8 (d), 47.6 (d), 32.7 (d), 28.2 (q), 20.2 (q), 19.3 (q);
47.4 (d), 27.3 (q); IR (film) ν 3086, 3061, 3028, 2974, 1712, 1604
cm-1. Anal. Calcd for C22H24N2O2: C, 75.83; H, 6.94; N, 8.04.
Found: C, 75.80; H, 6.98; N, 8.00. GCMS (70 eV) of a 93.5:
6.5 mixture of (A)-4b and (A)-5b: One peak, tR 13.8 min; 348
(21 M+), 229 (6.7), 227 (33.6), 158 (36.2), 91 (100), 77 (8.9), 65
(19), 42 (24). For (A)-5b: Rf 0.53 (EtOAc); 1H NMR (300 MHz,
CDCl3) δ 7.30 (m, 10H), 5.24 (app t, 1H, J ) 7.7), 4.58 (app t,
1H, J ) 8.5), 3.99 (dd, 1H, J ) 6.9, 8.4), 3.61 (ABq, 2H, J )
12.9, ∆ν ) 79.8), 3.33 (d, 1H, J ) 9.5), 3.22 (app t, 1H, J )
9.5), 3.05 (d, 1H, J ) 10.3), 2.87 (dd, 1H, J ) 6.7, 9.3), 2.39
(app t, 1H, J ) 9.2), 2.16 (dd, 1H, J ) 6.7, 10.3), 1.24 (s, 3H);
13C NMR (67.9 MHz, CDCl3) δ 182.5 (s), 140.8 (s), 138.7 (s),
128.6 (d), 128.5 (d), 128.3 (d), 127.22 (d), 127.15 (d), 125.3 (d),
102.1 (s), 71.4 (t), 59.2 (t), 58.8 (d), 57.2 (t), 55.5 (t), 48.6 (d),
46.1 (d), 19.2 (q).
IR (film) for a 91:9 mixture of (A)-4a and (A)-5a : ν 1709 cm-1
.
Anal. for a 91:9 mixture of (A)-4a and (A)-5a ; calcd for
C19H26N2O2: C, 72.58; H, 8.34; N, 8.91. Found: C, 72.44; H,
8.40; N, 9.00. GCMS (70 ev) for a 91:9 mixture of (A)-4a and
(A)-5a ; for (A)-4a : tR 11.9 min; 314 (100 M+), 284 (62), 269
(15), 223 (58), 158 (29), 128 (8), 91 (85), 42 (48); for (A)-5a : tR
12.1 min; 314 (100 M+), 284 (15), 269 (5), 223 (31), 158 (19),
128 (25), 91 (39), 42 (14).
Cycloa d d u cts (S)-4a a n d (S)-5a . Employing the above
general procedure, a 0 °C solution of lactam 1a (46.7 mg, 0.258
mmol) and (S)-3 (162 mg, 0.645 mmol) in CH2Cl2 was treated
with TFA (1 drop) and was immediately allowed to warm to
rt with stirring for 24 h. Integration of the resolved signals
corresponding to the major isomer ((S)-4a : δ 1.03, 0.90) and
the minor isomer ((S)-5a : δ 1.06, 0.87) indicated a ratio of 91:
9. Radial chromatography (1:1 EtOAc/hexanes) of the crude
mixture afforded 84.6 mg (93.1%) of an inseparable mixture
of (S)-4a and (S)-5a as a clear, colorless oil. For (S)-4a : Rf
0.59 (EtOAc); 1H NMR (300 MHz, CDCl3) δ 7.30 (m, 5H), 4.07
(app t, 1H, J ) 8.1), 3.85 (dd, 1H, J ) 4.9, 7.8), 3.68 (m, 1H),
3.40 (d, 1H, J ) 8.9), 3.23 (app t, 1H, J ) 7.7), 3.10 (q, 1H, J
) 6.7), 2.93 (dd, 1H, J ) 2.5, 9.7), 2.62 (td, 1H, J ) 2.4, 8.4),
2.26 (app t, 1H, J ) 7), 2.07 (m, 1H), 1.68 (m, 1H), 1.41 (s,
3H), 1.30 (d, 3H, J ) 6.4), 1.03 (d, 3H, J ) 6.5), 0.90 (d, 3H, J
) 6.6); 13C NMR (75.5 MHz, CDCl3) δ 180.3 (s), 145.4 (s), 128.2
(d), 127.4 (d), 126.9 (d), 98.4 (s), 71.4 (t), 64.5 (d), 62.0 (d), 55.3
(t), 53.5 (t), 49.6 (d), 47.2 (d), 32.8 (d), 28.3 (q), 23.3 (q), 20.3
(q), 19.3 (q); IR (film) of a 91:9 mixture of (S)-4a and (S)-5a :
ν 1711, 1601 cm-1. Anal. of a 91:9 mixture of (S)-4a and (S)-
5a ; Calcd for C20H28N2O2: C, 73.14; H, 8.59. Found: C, 72.96;
H, 8.64. GCMS (70 ev) of a 91:9 mixture of (S)-4a and (S)-5a ;
for (S)-4a : tR 12.1 min, 328 (22, M+), 314 (23), 313 (100), 251
(4), 223 (4), 178 (5), 158 (3), 137 (2), 110 (3), 105 (15), 103 (4),
94 (2), 91 (4), 79 (5), 77 (5), 68 (5), 43 (15), 41 (12); for (S)-5a :
tR 12.3 min, 328 (14, M+), 314 (22), 313 (100), 251 (8), 223 (3),
158 (2), 137 (2), 105 (10), 91 (2), 79 (4), 77 (3), 43 (6), 41 (7).
Cycloa d d u cts (A)-4b a n d (A)-5b. Using the above general
procedure, a 0 °C solution of lactam 1b (500 mg, 2.32 mmol)
and 2 (1.10 g, 4.65 mmol) in CH2Cl2 (12 mL) was treated with
neat TFA (17.7 mL, 0.23 mmol) and was immediately allowed
to warm to rt with stirring for 7.5 h. Integration of the
resolved signals corresponding to the major isomer ((A)-4b: δ
1.40) and the minor isomer ((A)-5b: δ 1.24) indicated a ratio
of 93.7:6.3. Column chromatography (1:4 to 100:0 EtOAc/
hexanes) of the crude mixture afforded 800 mg (99%) of a
mixture of (A)-4b and (A)-5b as a clear, colorless syrup.
Column chromatography (1:50 MeOH/CH2Cl2) of an aliquot
of the 88% de mixture afforded essentially pure (A)-4b (98.6%
de) as a white crystalline solid. For (A)-4b: Rf 0.54 (5:95
MeOH/CH2Cl2). For (A)-5b: Rf 0.67 (5:95 MeOH/CH2Cl2).
Pure (A)-4b could be obtained directly from the crude product
mixture in 56-69% yields by using the following procedure.
The crude product mixture, obtained by the reaction of 1b (1.60
g, 7.43 mmol), 2 (3.52 g, 14.8 mmol), and TFA (57 mL, 0.74
mmol) in CH2Cl2 (20 mL), was diluted with 1:4 Et2O/hexanes
and cooled to -78 °C under a blanket of argon. A pure seed
crystal of (A)-4b was added and the mixture was allowed to
warm to rt while scratching the sides of the flask with a glass
rod. Crystallization occurred and the collected solids were
triturated with cool 1:4 Et2O/hexanes to give 1.78 g (69%) of
pure (A)-4b as a white powder.
Alter n a tive Syn th esis of (A)-4b a n d 5b fr om 10. To a
rt solution of imide 10 (138 mg, 0.394 mmol) in THF (3 mL)
was added a 3.0 M solution of methylmagnesium bromide in
Et2O (0.39 mL, 1.18 mmoles) dropwise. The clear, brown
solution was allowed to stir at rt for 3.3 h. TLC analysis
(EtOAc) revealed complete consumption of starting material.
The mixture was quenched with saturated, aqueous NH4Cl
and was extracted into Et2O. The organic extracts were dried
(MgSO4) and concentrated to afford the crude mixture of
intermediate hydroxy lactams 11 (Rf 0.33 and 0.10, EtOAc).
Hydroxy lactam mixture 11 was diluted with CH2Cl2 (20 mL),
treated with TFA (0.10 mL, 1.3 mmoles), and allowed to stir
for 18 h at rt. The resulting clear, yellow solution was poured
into a solution of saturated, aqueous NaHCO3, and the aqueous
layer was washed thoroughly with CH2Cl2. The combined
organic extracts were dried (MgSO4) and concentrated to afford
a yellow oil that was partially purified by radial chromatog-
raphy (1:1 EtOAc/hexanes). The first lot corresponded to pure
(A)-5b (5 mg, Rf 0.53, EtOAc), and the second lot corresponded
to a ∼1:1 mixture of (A)-5b and (A)-4b (52.7 mg, Rf 0.53 and
Rf 0.48, EtOAc) to afford a yield of 42% for the tricyclic lactams
derived from imide 10.
Red u ctive Deh a logen a tion of (A)-4i To Give (A)-4b. To
a 0 °C suspension of bromotricycle (A)-4i (45.6 mg, 0.107 mmol)
and Ni(OAc)2‚4H2O (4.5 mg, 0.018 mmol) in MeOH (2 mL) was
added NaBH4 (40 mg, 1.1 mmoles) in one portion, forming a
dark brown mixture with vigorous gas evolution. The mixture
was allowed to warm immediately to rt and was stirred for 33
min. The reaction mixture was partitioned between saturated
Na2EDTA (10 mL) and Et2O (10 mL). The aqueous phase was
extracted with Et2O (3 × 10 mL), and the ethereal extracts
were combined, dried (Na2SO4), and concentrated to afford
white solids. Dilution with CH2Cl2 gave a gellike insoluble
material which was filtered through a plug of MgSO4 and
concentrated. Radial chromatographic purification of the
residue (1:1 EtOAc/hexanes) afforded 29.2 mg (78.3%) of an
inseparable mixture of (A)-4b and (A)-5b as a clear, colorless
oil. Integration of the resolved signals corresponding to the
major isomer ((A)-4b: δ 1.40 (s, 3H)) and the minor isomer
((A)-5b: δ 1.25 (s, 3H) indicated a ratio of 96.0:4.0.
Cycloa d d u cts (R)-4b a n d (R)-5b. Using the above gen-
eral procedure, a 0 °C solution of lactam 1b (20.6 mg, 0.0957
mmol) and (R)-3 (50.4 mg, 0.200 mmol) in CH2Cl2 was treated
with a 0.13 M solution of TFA in CH2Cl2 (0.10 mL, 0.013 mmol)
and was immediately allowed to warm to rt with stirring for
24 h. Integration of the resolved signals corresponding to the
major isomer ((R)-4b: δ 3.07, 4.59) and the minor isomer ((R)-
5b: δ 3.99) indicated a ratio of 92.0:8.0. No further charac-
terization data was obtained.
Cycloa d d u cts (S)-4b a n d (S)-5b. Using the above general
procedure, a 0 °C solution of lactam 1b (21.8 mg, 0.101 mmol)
and (S)-3 (53.9 mg, 0.214 mmol) in CH2Cl2 was treated with a
0.13 M solution of TFA in CH2Cl2 (0.10 mL, 0.013 mmol) and
was immediately allowed to warm to rt with stirring for 24 h.
Integration of the resolved signals corresponding to the major
isomer ((S)-4b: δ 2.73, 3.47) and the minor isomer ((S)-5b: δ
4.60) indicated a ratio of 91.1:8.9. Radial chromatography (1:4
EtOAc/hexanes) of the crude mixture gave 26.8 mg (73%) of
an inseparable mixture of (S)-4b and (S)-5b as a clear,
colorless film.
For (A)-4b: mp 58-60 °C; Rf 0.32 (1:1 EtOAc/hexanes);
1
[R]25 +120 (c 1.02, CCl4); H NMR (300 MHz, CDCl3) δ 7.30
D
(m, 10H); 5.24 (app t, 1H, J ) 6.7); 4.54 (app t, 1H, J ) 7.9);
4.19 (dd, 1H, J ) 5.9, 8.5); 3.58 (ABq, 2H, J ) 13.3, ∆ν ) 50.8);
3.38 (ddd, 1H, J ) 1.4, 6.9, 8.3); 3.30 (app d, 1H, J ) 9.4);
3.21 (dd, 1H, J ) 3.0, 9.7); 2.80 (app td, 1H, J ) 3.0, 8.3); 2.41
(dd, 1H, J ) 6.9, 9.0); 2.26 (app t, 1H, J ) 9.1); 1.40 (s, 3H);
13C NMR (75.5 MHz, CDCl3) δ 180.1 (s), 139.9 (s), 138.8 (s),
128.5 (d), 128.3 (d), 128.2 (d), 127.4 (d), 126.9 (d), 125.8 (d),
98.9 (s), 73.1 (t), 59.0 (t), 57.8 (d), 56.9 (t), 54.0 (t), 50.0 (d),

Azomethine Ylide Cycloaddition Reactions
J . Org. Chem., Vol. 61, No. 10, 1996 3371
1
For (S)-4b: Rf 0.58 (EtOAc); H NMR (300 MHz, CDCl3) δ
forming a dark brown mixture with vigorous gas evolution.
The mixture was allowed to warm immediately to rt and was
stirred for 1 h. The reaction mixture was partitioned between
saturated Na2EDTA (10 mL) and Et2O (10 mL). The aqueous
phase was extracted with Et2O (3 × 10 mL), and the ethereal
extracts were combined, dried (Na2SO4), and concentrated to
a residue. Dilution with CH2Cl2 gave a gellike insoluble
material which was filtered through a plug of MgSO4 and
concentrated to afford 34.5 mg (95%) of (S)-5c as a white
semisolid that was judged greater than 95% pure by 1H NMR.
Cycloa d d u cts (A)-4d a n d (A)-5d . Using the above gen-
eral procedure, a 0 °C solution of lactam 1d (22.0 mg, 0.0919
mmol) and 2 (33 mg, 0.139 mmol) in CH2Cl2 was treated with
a 0.09 M solution of TFA in CH2Cl2 (0.10 mL, 0.009 mmol)
and was immediately allowed to warm to rt with stirring for
2 h. Integration of the resolved signals corresponding to the
major isomer ((A)-4d : δ 1.03, 1.52, 2.53) and the minor isomer
((A)-5d : δ 1.08, 1.37, 2.75) indicated a ratio of 71.1:28.9.
Column chromatography (1:9 to 1:1 Et2O/hexanes) of the crude
mixture afforded 31.5 mg (92%) of a mixture of (A)-4d and
(A)-5d as a clear, colorless film. Additional prep-TLC (1:1
EtOAc/hexanes) of the mixture gave 19.1 mg of (A)-4d and
8.9 mg of (A)-5d , both as clear, colorless films.
7.30 (m, 10H), 5.26 (app t, 1H, J ) 8.0), 4.52 (app t, 1H, J )
8.2), 4.18 (dd, 1H, J ) 5.8, 8.4), 3.45 (d, 1H, J ) 9.1), 3.37 (m,
1H), 3.15 (m, 1H), 3.03 (dd, 1H, J ) 2.9, 9.9), 2.73 (m, 1H),
2.33 (m, 1H), 2.14 (m, 1H), 1.36 (m, 6H); 13C NMR (75.5 MHz,
CDCl3 one accidental degeneracy present.) δ 180.4 (s), 145.3
(s), 140.0 (s), 128.6 (d), 128.2 (d), 127.4 (d), 126.9 (d), 125.8
(d), 98.9 (s), 73.1 (t), 64.5 (d), 57.8 (d), 55.3 (t), 53.4 (t), 49.8
(d), 47.1 (d), 27.3 (q), 23.4 (q); IR (film) of a 91:9 mixture of
(S)-4b and (S)-5b: ν 3027, 2973, 2789, 1711, 1602, 1493, 1029,
700 cm-1. For (S)-5b, selected 1H NMR signals: δ 4.60 (app
t, 1H, J ) 8.5), 4.02 (dd, 1H, J ) 6.9, 8.4), 3.26 (q, 1H, J )
6.6), 2.89 (dd, 1H, J ) 5.8, 8.6), 2.24 (m, 1H); GCMS (70 eV)
of a 91:9 mixture of (S)-4b and (S)-5b: one peak, tR 17.1 min;
362 (13 M+), 347 (55), 285 (6), 257 (7), 200 (7), 173 (5), 158
(45), 131 (27), 130 (20), 105 (100), 103 (30), 91 (38), 90 (23), 77
(42), 68 (10).
Cycloa d d u cts (A)-4c a n d (A)-5c. Using the above general
procedure, a 0 °C solution of lactam 1c (74.9 mg, 0.372 mmol)
and 2 (177 mg, 0.744 mmol) in CH2Cl2 was treated with neat
TFA (3 mL, 0.04 mmol) and was immediately allowed to warm
to rt with stirring for 12 h. Integration of the resolved signals
corresponding to the major isomer ((A)-5c: δ 4.90 (s, 1H)) and
the minor isomer ((A)-4c: δ 5.36 (d, 1H, J ) 6.8)) indicated a
ratio of 83:17. Column chromatography (1:9 to 1:1 EtOAc/
hexanes) of the crude mixture afforded 118 mg (95%) of an
inseparable mixture of (A)-5c and (A)-4c as a pale yellow-white
solid. Trituration of this mixture with 1:1 Et2O/hexanes gave
46.7 mg of a white solid which was enriched significantly (93:
7) in (A)-5c.
For (A)-4d : Rf 0.11 (1:1 Et2O/hexanes); [R]25 38.3 (c 1.68,
D
CCl4); 1H NMR (300 MHz, CDCl3) δ 7.20 (m, 5H); 4.11 (dd,
1H, J ) 7.1, 8.3); 3.88 (dd, 1H, J ) 4.9, 8.4); 3.73 (s, 3H); 3.69
(ddd, 1H, J ) 5.0, 7.1, 11.0); 3.50 (ABq, 2H, J ) 13.3, ∆ν )
35.3); 3.49 (d, 1H, J ) 9.1); 3.27 (app d, 1H, J ) 9.7); 2.91 (dd,
1H, J ) 1.9, 8.4); 2.52 (d, 1H, J ) 9.1); 2.22 (app t, 1H, J )
9.0); 1.71 (m, 1H); 1.51 (s, 3H); 1.02 (d, 3H, J ) 6.7), 0.89 (d,
3H, J ) 6.6); 13C NMR (75.5 MHz, CDCl3) δ 175.2 (s), 170.0
(s), 138.3 (s), 128.3 (d), 128.2 (d), 127.0 (d), 97.7 (s), 71.5 (t),
66.6 (s), 62.5 (d), 60.6 (t), 58.8 (t), 54.4 (t), 52.8 (q), 52.1 (d),
32.7 (d), 27.8 (q), 20.2 (q), 19.2 (q); IR (film) ν 2961, 2874, 2800,
1741, 1714, 1495 cm-1. Anal. Calcd for C21H28N2O4: C, 67.72;
H, 7.58; N, 7.52. Found: C, 67.82; H, 7.63; N, 7.58.
For (A)-5c: mp 77-83 °C; Rf 0.33 (Et2O); [R]25D +41 (c 0.97,
CCl4 for 87% de); 1H NMR (300 MHz, CDCl3) δ 7.20-7.45 (m,
10H), 5.12 (app t, 1H, J ) 7.4), 4.90 (s, 1H), 4.55 (app t, 1H,
J ) 8.2), 3.74 (app t, 1H, J ) 7.3), 3.65 (ABq, 2H, J ) 13.2, ∆ν
) 39.0), 3.19 (m, 2H), 2.97 (d, 1H, J ) 9.6), 2.85 (app t, 1H, J
) 7.0), 2.40 (m, 2H); 13C NMR (75.5 MHz, CDCl3 one accidental
degeneracy present in aryl region) δ 181.0 (s), 139.8 (s), 138.6
(s), 128.8 (d), 128.3 (d), 127.6 (d), 127.1 (d), 125.7 (d), 99.0 (d),
74.2 (t), 58.5 (t), 58.0 (t), 58.0 (d), 56.7 (t), 48.6 (d), 42.1 (d); IR
(film) ν 3061, 3028, 2958, 1711, 1604 cm-1. Anal. for a 93.5:
6.5 mixture of (A)-5c and (A)-4c; calcd for C21H22N2O2: C,
75.42; H, 6.63; N, 8.38. Found: C, 75.35; H, 6.65; N, 8.35.
Cycloa d d u cts (R)-4c a n d (R)-5c. Using the above general
procedure, a 0 °C solution of lactam 1c (23.0 mg, 0.114 mmol)
and (R)-3 (48.0 mg, 0.191 mmol) in CH2Cl2 was treated with
a 0.13 M solution of TFA in CH2Cl2 (0.10 mL, 0.011 mmol)
and was immediately allowed to warm to rt with stirring for
24 h. Integration of the resolved signals corresponding to the
major isomer ((R)-5c: δ 4.80 (s, 1H) and the minor isomer ((R)-
4c: δ 5.40 (d, 1H, J ) 6.8)) indicated a ratio of 81.4:18.6. No
further characterization data was obtained.
For (A)-5d : Rf 0.07 (1:1 Et2O/hexanes); [R]25D -13.6 (c 1.07,
CCl4); 1H NMR (300 MHz, CDCl3) δ 7.20 (m, 5H); 4.21 (app t,
1H, J ) 8.0); 3.71 (s, 3H); 3.43-3.79 (m, 4H); 3.38 (d, 1H, J )
9.8); 3.01 (m, 2H); 2.75 (d, 1H, J ) 9.9); 2.20 (dd, 1H, J ) 6.6,
10.4); 1.68 (m, 1H); 1.36 (s, 3H); 1.07 (d, 3H, J ) 6.6); 0.86 (d,
3H, J ) 6.6); 13C NMR (75.5 MHz, CDCl3) δ 178.2 (s), 170.8
(s), 138.4 (s), 128.5 (d), 128.3 (d), 127.2 (d), 100.3 (s), 77.2 (s),
69.9 (t), 64.5 (d), 60.0 (t), 59.0 (t), 55.1 (t), 53.0 (q), 51.6 (d),
34.2 (d), 20.9 (q), 19.8 (q), 19.0 (q); IR (neat) ν 2959, 2873, 1741,
1711, 1453 cm-1
.
Cycloa d d u cts (R)-4d a n d (R)-5d . Using the above gen-
eral procedure, a 0 °C solution of lactam 1d (102.7 mg, 0.429
mmol) and (R)-3 (162 mg, 0.644 mmol) in CH2Cl2 was treated
with TFA (4 µL) and was immediately allowed to warm to rt
with stirring for 3.0 h. Integration of the resolved signals
corresponding to the major isomer ((R)-4d : δ 0.93, 1.03) and
the minor isomer ((R.)-5d : δ 1.11) indicated an average ratio
of 86.8:13.2. Column chromatography (1:1 Et2O/hexanes)
purification of the crude mixture afforded 155 mg (93.4%) of a
mixture of (R)-4d and (R)-5d as a clear, colorless film.
For (R)-4d : Rf 0.56 (1:1 EtOAc/hexanes); [R]25D +52.2 (c 1.64,
CCl4); 1H NMR (300 MHz, CDCl3) δ 7.20 (m, 5H), 4.18 (dd,
1H, J ) 6.8, 8.1), 3.96 (dd, 1H, J ) 4.3, 8.2), 3.73 (m, 1H),
3.69 (s, 3H), 3.48 (app d, 1H, J ) 9.5), 3.28 (d, 1H, J ) 9.3),
3.15 (q, 1H, J ) 6.6), 2.94 (dd, 1H, J ) 2.1, 8.5), 2.36 (d, 1H,
J ) 9.3), 2.27 (app t, 1H, J ) 9.0), 1.75 (m, 1H), 1.55 (s, 3H),
1.27 (d, 3H, J ) 6.6), 1.03 (d, 3H, J ) 6.7), 0.93 (d, 3H, J )
6.6); 13C NMR (75.5 MHz, CDCl3) δ 175.0 (s), 170.0 (s), 144.5
(s), 128.4 (d), 127.0 (d), 126.8 (d), 97.8 (s), 71.5 (t), 66.2 (s),
64.0 (d), 62.7 (d), 59.4 (t), 52.8 (q), 52.8 (t), 52.0 (d), 32.3 (d),
28.1 (q), 22.9 (q), 20.1 (q), 19.3 (q); IR (film) ν 3084, 3065, 2970,
1738, 1715, 1601 cm-1. Anal. for a 86.6:13.5 mixture of (R)-
4d and (R)-5d; Calcd for C22H30N2O4: C, 68.37; H, 7.82; N, 7.25.
Found: C, 68.43; H, 7.83; N, 7.28.
Cycloa d d u cts (S)-4c a n d (S)-5c. Using the above general
procedure, a 0 °C solution of lactam 1c (22.3 mg, 0.111 mmol),
and (S)-3 (53.7 mg, 0.214 mmol) in CH2Cl2 was treated with a
0.13 M solution of TFA in CH2Cl2 (0.10 mL, 0.011 mmol) and
was immediately allowed to warm to rt with stirring for 12 h.
Integration of the resolved signals corresponding to the major
isomer ((S)-5c: δ 4.97 (s, 1H) and the minor isomer ((S)-4c: δ
5.33 (d, 1H, J ) 6.8)) indicated a ratio of 84.2:15.8.
For (S)-5c: Rf 0.35 (1:1 EtOAc/hexanes); 1H NMR (300 MHz,
CDCl3) δ 7.30 (m, 10H), 5.12 (app t, 1H, J ) 7.4), 4.97 (s, 1H),
4.57 (app t, 1H, J ) 8.3), 3.77 (dd, 1H, J ) 7.2, 8.6), 3.32 (q,
1H, J ) 6.6), 3.12 (m, 2H), 2.96 (app d, 1H, J ) 9.7), 2.87 (app
t, 1H, J ) 6.7), 2.43 (dd, 1H, J ) 6.6, 9.3), 2.33 (app t, 1H, J
) 9.1), 1.39 (d, 3H, J ) 6.6); 13C NMR (75.5 MHz, CDCl3) δ
181.1 (s), 144.7 (s), 139.9 (s), 128.8 (d), 128.4 (d), 127.5 (d),
127.0 (d), 126.8 (d), 125.6 (d), 99.1 (d), 74.2 (t), 63.4 (d), 57.8
(d), 56.1 (t), 55.6 (t), 48.3 (d), 42.0 (d), 22.8 (q); IR (film) for a
97:3 mixture of (S)-5c and (S)-4c: ν 3061, 3029, 1713, 1603,
1065, 1029 cm-1. Anal. for a 97:3 mixture of (S)-5c and (S)-
4c; calcd for C22H24N2O2: C, 75.83; H, 6.94. Found: C, 75.80;
H, 6.91.
For (R)-5d : Rf 0.48 (1:1 EtOAc/hexanes); [R]25D -15.5 (c 1.13,
CCl4); 1H NMR (300 MHz, CDCl3) δ 7.30 (m, 5H), 4.19 (app t,
1H, J ) 8.0), 3.72 (s, 3H), 3.72 (d, 1H, J ) 15.3), 3.66 (m, 1H),
3.60 (d, 1H, J ) 9.9), 3.17 (q, 1H, J ) 6.5), 2.93 (d, 1H, J )
15.3), 2.75 (d, 2H, J ) 9.7), 2.05 (dd, 1H, J ) 6.8, 10.6), 1.70
(m, 1H), 1.34 (d, 3H, J ) 6.5), 1.27 (s, 3H), 1.11 (d, 3H, J )
Red u ctive Deh a logen a tion of (S)-5g To Give (S)-5c. To
a 0 °C suspension of bromotricycle (S)-5g (44.3 mg, 0.104
mmol) and Ni(OAc)2‚4H2O (4.3 mg, 0.017 mmol) in MeOH (2
mL) was added NaBH4 (45 mg, 1.2 mmol) in one portion,

3372 J . Org. Chem., Vol. 61, No. 10, 1996
Fray and Meyers
6.6), 0.87 (d, 3H, J ) 6.6); 13C NMR (75.5 MHz, CDCl3) δ 178.6
(s), 170.9 (s), 144.9 (s), 128.4 (d), 127.2 (d), 126.9 (d), 100.4 (s),
69.8 (t), 64.9 (d), 64.6 (d), 64.4 (s), 58.3 (t), 54.7 (t), 53.0 (q),
51.2 (d), 34.1 (d), 22.7 (q), 21.0 (q), 19.7 (q), 18.9 (q); IR (film)
ν 2962, 1742, 1712, 1453 cm-1. Anal. Calcd for C22H30N2O4:
C, 68.37; H, 7.82. Found: C, 68.38; H, 7.87.
J ) 6.5), 2.80 (dd, 1H, J ) 2.3, 8.5), 2.42 (d, 1H, J ) 9.3), 2.28
(app t, 1H, J ) 9), 1.73 (m, 1H), 1.54 (s, 3H), 1.14 (s, 9H), 1.26
(d, 3H, J ) 6.6), 1.03 (d, 3H, J ) 6.7), 0.92 (d, 3H, J ) 6.6);
13C NMR (75.5 MHz, CDCl3) δ 175.6 (s), 168.9 (s), 144.8 (s),
128.3 (d), 126.9 (d), 126.8 (d), 97.7 (s), 82.2 (s) 71.6 (t), 67.1
(s), 64.0 (d), 62.3 (d), 58.9 (t), 52.8 (t), 52.7 (d), 32.5 (d), 27.9
(q), 22.9 (q), 20.0 (q), 19.3 (q), 18.4 (q); IR (film) ν 3062, 2972,
Cycloa d d u cts (S)-4d a n d (S)-5d ): Using the above general
procedure, a 0 °C solution of lactam 1d (49.6 mg, 0.207 mmol),
and (S)-3 (79.8 mg, 0.317 mmol) in CH2Cl2 was treated with
a 0.13 M solution of TFA in CH2Cl2 (0.14 mL, 0.018 mmol)
and was immediately allowed to warm to rt with stirring for
2.5 h. Integration of the resolved signals corresponding to the
major isomer ((S)-4d : δ 2.49, 1.29) and the minor isomer ((S)-
5d : δ 2.56, 1.34) indicated a ratio of 59.3:40.7. Prep-TLC (1:1
Et2O/hexanes) purification of the crude mixture afforded 73.6
mg (92%) of a mixture of (S)-4d and (S)-5d as a clear, colorless
film. Additional prep-TLC of the mixture gave 36 mg of (S)-
4d and 28.6 mg of (S)-5d , both as clear, colorless films.
1738, 1732, 1714, 1602 cm-1
.
Cycloa d d u cts (S)-4e a n d (S)-5e. Using the above general
procedure, a 0 °C solution of lactam 1e (50.0 mg, 0.178 mmol)
and (S)-3 (67.1 mg, 0.267 mmol) in CH2Cl2 was treated with a
0.13 M solution of TFA in CH2Cl2 (0.14 mL, 0.018 mmol) and
was immediately allowed to warm to rt with stirring for 3.5
h. Integration of the resolved signals corresponding the
isomers (S)-4e and (S)-5e indicated a ratio of 51:49. Column
chromatography (1:5 Et2O/hexanes) of the crude mixture
afforded 64.3 mg (84.5%) of an inseparable mixture of (S)-4e
and (S)-5e as a clear, colorless syrup.
1
For (S)-4d : Rf 0.28 (1:1 Et2O/hexanes); [R]25 29.6 (c 1.25,
For a 1:1 mixture of (S)-4e and (S)-5e, selected resolved H
D
CCl4); 1H NMR (300 MHz, CDCl3) δ 7.20 (m, 5H); 4.12 (dd,
1H, J ) 7.2, 8.3); 3.86 (dd, 1H, J ) 5.1, 8.3); 3.75 (s, 3H); 3.70
(m, 2H); 3.10 (m, 2H); 2.83 (dd, 1H, J ) 1.7, 8.5); 2.49 (d, 1H,
J ) 8.9); 2.07 (app t, 1H, J ) 8.9); 1.68 (m, 1H); 1.47 (s, 3H);
1.28 (d, 3H, J ) 6.6); 1.03 (d, 3H, J ) 6.7); 0.90 (d, 3H, J )
6.6); 13C NMR (75.5 MHz, CDCl3) δ 175.3 (s), 170.1 (s), 144.8
(s), 128.1 (d), 127.0 (d), 126.9 (d), 97.7 (s), 71.4 (t), 66.5 (s),
64.1 (t), 62.3 (d), 58.8 (t), 53.8 (t), 52.8 (q), 51.6 (d), 32.9 (d),
27.6 (q), 23.0 (q), 20.3 (q), 19.2 (q); IR (film) ν 3062, 3027, 2970,
NMR signals: δ 4.20 (app t, 1H, J ) 8.2), 4.13 (app t, 1H, J )
7.8), 2.11 (app t, 1H, J ) 10.1), 2.05 app t, 1H, J ) 14.6), 1.46
(s, 9H), 1.38 (s, 9H), 1.33 (d, 3H, J ) 6.6), 1.28 (d, 3H, J )
6.6), 1.07 (d, 3H, J ) 6.7), 1.04 (d, 3H, J ) 6.7), 0.91 (d, 3H, J
) 6.6), 0.88 (d, 3H, J ) 6.6).
Cycloa d d u cts (A)-4f a n d (A)-5f. Using the above general
procedure, a 0 °C solution of lactam 1f (21.8 mg, 0.0925 mmol)
and 2 (44.9 mg, 0.189 mmol) in CH2Cl2 was treated with a
0.13 M solution of TFA in CH2Cl2 (0.10 mL, 0.011 mmol) and
was immediately allowed to warm to rt with stirring for 24 h.
Integration of the resolved signals corresponding to the major
isomer ((A)-5f: δ 4.82 (s, 1H) and the minor isomer ((A)-4f: δ
5.48 (d, 1H, J ) 6.7)) indicated a ratio of 81.9:18.1. No further
characterization data was obtained.
Cycloa d d u cts (R)-4f a n d (R)-5f. Using the above general
procedure, a 0 °C solution of lactam 1f (22.3 mg, 0.0946 mmol)
and (R)-3 (48.7 mg, 0.194 mmol) in CH2Cl2 was treated with
a 0.13 M solution of TFA in CH2Cl2 (0.10 mL, 0.011 mmol)
and was immediately allowed to warm to rt with stirring for
24 h. Integration of the resolved signals corresponding to the
major isomer ((R)-5f: δ 4.72 (s, 1H) and the minor isomer ((R)-
4f: δ 5.52 (d, 1H, J ) 6.6)) indicated a ratio of 79.0:21.0. No
further characterization data was obtained.
1743, 1715, 1602 cm-1
.
For (S)-5d : Rf 0.16 (1:1 Et2O/hexanes); [R]25D -39.4 (c 1.19,
1
CCl4) H NMR (300 MHz, CDCl3) δ 7.20 (m, 5H), 4.22 (app t,
1H, J ) 8.4), 3.77 (dd, 1H, J ) 6.9, 8.6), 3.67 (s, 3H), 3.61
(ddd, 1H, J ) 7.1, 10.9, 14.7), 3.35 (d, 1H, J ) 10.2), 3.25 (q,
1H, J ) 6.5), 3.07 (m, 2H), 2.56 (d, 1H, J ) 10.1), 2.26 (dd,
1H, J ) 6.4, 10.1), 1.69 (m, 1H), 1.55 (s, 3H), 1.34 (d, 3H,J )
6.5), 1.06 (d, 3H, J ) 6.6), 0.87 (d, 3H, J ) 6.5); 13C NMR (75.5
MHz, CDCl3) δ 178.1(s), 170.8 (s), 144.6 (s), 128.5 (d), 127.1
(d), 126.7 (d), 100.3 (s), 69.9 (t), 64.2 (d), 64.1 (s), 63.7 (d), 59.0
(t), 53.0 (t), 52.9 (q), 51.3 (d), 34.2 (d), 22.8 (q), 20.9 (q), 19.7
(q), 19.0 (q); IR (film) ν 3061, 3028, 2965, 1745, 1713, 1668,
1602 cm-1. Anal. Calcd for C22H30N2O4 C, 68.37; H, 7.82; N,
7.25. Found: C, 68.15; H, 7.85; N, 7.17.
Cycloa d d u cts (A)-4e a n d (A)-5e. Using the above general
procedure, a 0 °C solution of lactam 1e (50.0 mg, 0.178 mmol)
and 2 (63.2 mg, 0.266 mmol) in CH2Cl2 was treated with a
0.13 M solution of TFA in CH2Cl2 (0.14 mL, 0.018 mmol) and
was immediately allowed to warm to rt with stirring for 3.4
h. Integration of the resolved signals corresponding to the
major isomer ((A)-4e: δ 1.45) and the minor isomer ((A)-5e:
δ 1.41) indicated a ratio of 72.1:27.9. Column chromatography
(1:9 to 1:1 Et2O/ hexanes) of the crude mixture afforded 37.1
mg (50%) of an inseparable mixture of (A)-4e and (A)-5e as a
clear, colorless film.
Cycloa d d u cts (S)-4f a n d (S)-5f. Using the above general
procedure, a 0 °C solution of lactam 1f (23.4 mg, 0.0993 mmol),
and (S)-3 (51.7 mg, 0.206 mmol) in CH2Cl2 was treated with a
0.13 M solution of TFA in CH2Cl2 (0.10 mL, 0.013 mmol) and
was immediately allowed to warm to rt with stirring for 12 h.
Integration of the resolved signals corresponding to the major
isomer ((S)-5f: δ 4.90 (d, 1H, J ) 0.83)) and the minor isomer
((S)-4f: δ 5.44 (d, 1H, J ) 6.6)) indicated a ratio of 95.2:4.8.
Radial chromatography (1:4 EtOAc/hexanes) of the crude
mixture afforded 33.5 mg (88%) of an inseparable mixture of
(S)-5f and (S)-4f as a white powder.
For (A)-4e, selected 1H NMR signals: δ 4.12 (dd, 1H, J )
7.2, 8.2), 3.27 (d, 1H, J ) 9.7), 2.57 (d, 1H, J ) 9.2), 1.80 (d,
3H, J ) 6.6), 1.52 (s, 3H), 1.45 (s, 9H), 1.08 (d, 3H, J ) 6.6),
For (S)-5f: Rf 0.35 (1:4 EtOAc/hexanes); 1H NMR (300 MHz,
CDCl3) δ 7.30 (m, 10H), 5.21 (app t, 1H, J ) 7.4), 4.90 (s, 1H),
4.63 (app t, 1H, J ) 8.3), 3.82 (app t, 1H, J ) 8.1), 3.42 (m,
2H), 3.32 (app d, 1H, J ) 9.4), 2.99 (app d, 1H, J ) 5.7), 2.74
(dd, 1H, J ) 6.0, 9.4), 2.50 (app d, 1H, J ) 10.3), 1.39 (d, 3H,
J ) 6.4); 13C NMR (75.5 MHz, CDCl3) δ 175.2 (s), 143.8 (s),
139.2 (s), 129.0 (d), 128.6 (d), 127.8 (d), 127.4 (d), 126.7 (d),
125.6 (d), 96.0 (d), 74.2 (t), 72.2 (s), 65.2 (t), 62.7 (d), 58.5 (d),
54.6 (t), 53.0 (d), 22.2 (q); IR (film) ν 3063, 3026, 1727, 1641,
1
0.90 (d, 3H, J ) 6.6). For (A)-5e, selected H NMR signals: δ
4.18 (app t, 1H, J ) 8.2), 3.33 (d, 1H, J ) 9.9), 2.71 (d, 1H, J
) 9.8), 1.41 (s, 9H), 1.34 (s, 3H), 1.08 (d, 3H, J ) 6.6), 1.03 (d,
J ) 6.7), 0.87 (d, 3H, J ) 6.5). Anal. for a 72.1:27.9 mixture
of (A)-4e and (A)-5e; calcd for C24H34N2O4: C, 69.54; H, 8.27;
N, 6.76. Found: C, 69.37; H, 8.32; N, 6.76.
1604 cm-1
.
Cycloa d d u cts (R)-4e a n d (R)-5e. Using the above general
procedure, a 0 °C solution of lactam 1e (50.0 mg, 0.178 mmol)
and (R)-3 (67.1 mg, 0.267 mmol) in CH2Cl2 was treated with
a 0.13 M solution of TFA in CH2Cl2 (0.14 mL, 0.018 mmol)
and was immediately allowed to warm to rt with stirring for
3.5 h. Integration of the resolved signals corresponding to the
major isomer ((R)-4e: δ 3.42, 0.92) and the minor isomer ((R)-
5e: δ 3.53 (d, 1H, J ) 9.6), 1.12 (d, 3H, J ) 6.6)) indicated a
ratio of 91.6:8.4. Column chromatography (1:5 Et2O/ hexanes)
of the crude mixture afforded 71.5 mg (94%) of an inseparable
mixture of (R)-4e and (R)-5e as a clear, colorless syrup.
For (R)-4e: 1H NMR (300 MHz, CDCl3) δ 7.21 (m, 5H), 4.17
(dd, 1H, J ) 8.1, 6.9), 3.94 (dd, 1H, J ) 4.3, 8.2), 3.72 (m, 1H),
3.42 (dd, 1H, J ) 2.1, 9.5), 3.18 (d, 1H, J ) 9.4), 3.15 (q, 1H,
Cycloa d d u cts (A)-4g a n d (A)-5g. Using the above general
procedure, a 0 °C solution of lactam 1g (21.8 mg, 0.0778 mmol)
and 2 (39.0 mg, 0.164 mmol) in CH2Cl2 was treated with a
0.13 M solution of TFA in CH2Cl2 (0.10 mL, 0.011 mmol) and
was immediately allowed to warm to rt with stirring for 24 h.
Integration of the resolved signals corresponding to the major
isomer ((A)-5g: δ 4.86 (s, 1H) and the minor isomer ((A)-4g:
δ 5.49 (d, 1H, J ) 6.6)) indicated a ratio of 82.0:18.0. No
further characterization data was obtained.
Cycloa d d u cts (R)-4g a n d (R)-5g. Using the above general
procedure, a 0 °C solution of lactam 1g (23.1 mg, 0.0825 mmol)
and (R)-3 (35.2 mg, 0.140 mmol) in CH2Cl2 was treated with
a 0.13 M solution of TFA in CH2Cl2 (0.10 mL, 0.011 mmol)

Azomethine Ylide Cycloaddition Reactions
J . Org. Chem., Vol. 61, No. 10, 1996 3373
and was immediately allowed to warm to rt with stirring for
24 h. Integration of the resolved signals corresponding to the
major isomer ((R)-5g: δ 4.76 (s, 1H) and the minor isomer ((R)-
4g: δ 5.53 (d, 1H, J ) 6.6)) indicated a ratio of 78.1:21.9. No
further characterization data was obtained.
Cycloa d d u cts (S)-4g a n d (S)-5g. Using the above general
procedure, a 0 °C solution of lactam 1g (24.1 mg, 0.0860 mmol)
and (S)-3 (34.2 mg, 0.136 mmol) in CH2Cl2 was treated with a
0.13 M solution of TFA in CH2Cl2 (0.10 mL, 0.013 mmol) and
was immediately allowed to warm to rt with stirring for 17 h.
Integration of the resolved signals corresponding to the major
isomer ((S)-5g: δ 4.94 (s, 1H)) and the minor isomer ((S)-4g:
δ 5.44 (d, 1H, J ) 6.5)) indicated a ratio of 96.2:3.7. Radial
chromatography (1:4 EtOAc/hexanes) of the crude mixture
afforded 33.1 mg (90%) of an inseparable mixture of (S)-5g
and (S)-4g as a white powder.
For (S)-5g: Rf 0.39 (1:4 EtOAc/hexanes); mp 168-174 °C
(91.2% d.e); 1H NMR (300 MHz, CDCl3) δ 7.30 (m, 10H); 5.21
(app t, 1H, J ) 7.3); 4.93 (s, 1H); 4.62 (dd, 1H, J ) 7.8, 8.5);
3.83 (dd, 1H, J ) 6.8, 8.6); 3.42 (m, 2H); 3.19 (d, 1H, J ) 9.5),
3.12 (d, 1H, J ) 6.3); 2.73 (dd, 1H, J ) 6.3, 9.4); 2.64 (d, 1H,
J ) 10.3); 1.38 (d, 3H, J ) 6 .6); 13C NMR (75.5 MHz, CDCl3)
δ 175.6 (s), 143.7 (s), 139.3 (s), 129.0 (d), 128.6 (d), 127.8 (d),
127.4 (d), 126.7 (d), 125.6 (d), 96.5 (d), 74.1 (t), 65.6 (t), 62.7
(d), 61.9 (s), 58.8 (d), 54.8 (t), 53.2 (d), 22.2 (q); IR (film) for a
95.6:4.4 mixture of (S)-5g and (S)-4g: ν 3025, 2971, 2930, 1723,
1603 cm-1. Anal. for a 95.6:4.4 mixture of (S)-5g and (S)-4g;
calcd for C22H23BrN2O2 C, 61.83; H, 5.43; N, 6.56. Found: C,
61.86; H, 5.46; N, 6.47.
Cycloa d d u cts (A)-5h a n d (A)-4h . Using the above gen-
eral procedure, a 0 °C solution of lactam 1h (23.4 mg, 0.0715
mmol) and 2 (34.8 mg, 0.147 mmol) in CH2Cl2 was treated with
a 0.13 M solution of TFA in CH2Cl2 (0.10 mL, 0.011 mmol)
and was immediately allowed to warm to rt with stirring for
24 h. Integration of the resolved signals corresponding to the
major isomer ((A)-5h : δ 4.93 (s, 1H) and the minor isomer ((A)-
4h : δ 5.49 (d, 1H, J ) 6.6)) indicated a ratio of 82.1:17.9. No
further characterization data was obtained.
Cycloa d d u cts (R)-5h a n d (R)-4h . Using the above gen-
eral procedure, a 0 °C solution of lactam 1h (17.4 mg, 0.0532
mmol) and (R)-3 (27.2 mg, 0.108 mmol) in CH2Cl2 was treated
with a 0.13 M solution of TFA in CH2Cl2 (0.10 mL, 0.011 mmol)
and was immediately allowed to warm to rt with stirring for
24 h. Integration of the resolved signals corresponding to the
major isomer ((R)-5h : δ 4.82 (s, 1H) and the minor isomer
((R)-4h : δ 5.52 (d, 1H, J ) 6.5)) indicated a ratio of 77.3:22.7.
No further characterization data was obtained.
Cycloa d d u cts (S)-5h a n d (S)-4h . Using the above general
procedure, a 0 °C solution of lactam 1h (19.6 mg, 0.0599 mmol),
and (S)-3 (36.5 mg, 0.145 mmol) in CH2Cl2 was treated with a
0.13 M solution of TFA in CH2Cl2 (0.10 mL, 0.013 mmol) and
was immediately allowed to warm to rt with stirring for 12 h.
Integration of the resolved signals corresponding to the major
isomer ((S)-5h : δ 5.01 (s, 1H)) and the minor isomer ((S)-4h :
δ 5.44 (d, 1H, J ) 6.7)) indicated a ratio of 96.6:3.4. Radial
chromatography (1:4 EtOAc/hexanes) of the crude mixture
afforded 23.0 mg (81%) of an inseparable mixture of (S)-5h
and (S)-4h as a pale yellow semisolid.
(84.5%) of (A)-4i as a colorless film: Rf 0.37 (5:95 Et2O/CH2Cl2);
[R]25 +92.6 (c Et2O/CH2Cl2); 1H NMR (300 MHz, CDCl3) δ
D
7.2-7.4 (m, 10), 4.54 (dd, 1H, J ) 7.7, 8.6), 4.22 (dd, 1H, J )
5.9, 8.6), 3.67 (m, 1H), 3.60 (ABq, 2H, J ) 13.3, ∆ν ) 43.6),
3.34 (dd, 1H, J ) 1.7, 9.7), 2.94 (dd, 1H, J ) 2.1, 8.8), 2.63 (d,
1H, J ) 9.1), 2.47 (app t, 1H, J ) 9.3), 1.51 (s, 3H); 13C NMR
(75.5 MHz, CDCl3 one accidental degeneracy present in aryl
region) δ 175.4 (s), 139.0 (s), 137.6 (s), 128.7 (d), 128.3 (d), 127.6
(d), 127.2 (d), 125.8 (d), 97.5 (s), 73.3 (t), 64.9 (t), 59.8 (s), 58.4
(t), 57.8 (d), 57.0 (d), 53.6 (t), 27.2 (q); IR (film) ν 3086, 3061,
3028, 2976, 2802, 1721, 1678, 1642, 1604 cm-1. Anal. Calcd
for C22H23BrN2O2: C, 61.83; H, 5.43; N, 6.56. Found: C, 61.95;
H, 5.45; N, 6.51.
Cycloa d d u ct (R)-4i. To a rt solution of 1i (40.7 mg, 0.138
mmol) and (R)-3 (132 mg, 0.525 mmol) in CH2Cl2 (2.0 mL) was
added TFA (10 mL, 0.014 mmol). The resulting solution was
heated to 37 °C and was stirred for 2 h. The reaction mixture
was quenched with excess saturated, aqueous NaHCO3. The
aqueous phase was extracted with CH2Cl2, and the organic
extracts were dried (Na2SO4) and concentrated. The crude
residue was purified by radial chromatography (5:95 Et2O/
CH2Cl2) to give 60.6 mg (99.5%) of (R)-4i as a pale yellow oil.
An analytical sample was prepared by inducing crystallization
(Et2O/hexanes), followed by trituration, to afford a pale yellow
crystalline powder: Rf 0.61 (1:1 EtOAc/hexanes); mp 100-108
1
°C; [R]25 +103 (c 3.40, CCl4); H NMR (300 MHz, CDCl3) δ
D
7.30 (m, 10H), 5.27 (app t, 1H, J ) 6.4), 4.61 (app t, 1H, J )
7.9), 4.29 (dd, 1H, J ) 5.7, 8.5), 3.49 (m, 2H), 3.28 (q, 1H, J )
6.6), 2.94 (dd, 1H, J ) 2.2, 8.7), 2.50 (t, 1H, J ) 9.1), 2.49 (d,
1H, J ) 9.3), 1.54 (s, 3H), 1.32 (d, 3H, J ) 6.5); 13C NMR (75.5
MHz, CDCl3) δ 175.6 (s), 144.2 (s), 139.3 (s), 129.1 (d), 128.8
(d), 128.0 (d), 127.5 (d), 127.1 (d), 126.1 (d), 97.9 (s), 73.8 (t),
63.91 (d), 63.88 (t), 60.1 (s), 58.2 (d), 57.3 (d), 52.4 (t), 27.6 (q),
22.7 (q); IR (film) ν 3062, 3029, 2975, 1724, 1603 cm-1. Anal.
Calcd for C23H25BrN2O2: C, 62.59; H, 5.71; N, 6.35. Found:
C, 62.69; H, 5.95; N, 6.19.
Cycloa d d u ct (S)-4i. To a rt solution of 1i (32.2 mg, 0.109
mmol) and (S)-3 (54.8 mg, 0.218 mmol) in CH2Cl2 (0.5 mL)
was added a 0.13 M solution of TFA in CH2Cl2 (0.10 mL, 0.013
mmol). The resulting solution was stirred for 46 h at 25 °C.
The reaction mixture was quenched with excess saturated,
aqueous NaHCO3. The aqueous phase was extracted with
CH2Cl2, and the organic extracts were dried (Na2SO4) and
concentrated. Integration of the resolved signals correspond-
ing to the major isomer ((S)-4i: δ 4.21 (dd, 1H, J ) 5.7, 8.5))
and the minor isomer ((S)-5i: δ 4.08 (dd, 1H, J ) 6.6, 8.4))
indicated a ratio of 91.5:8.5. The crude residue was purified
by radial chromatography (5:95 Et2O/CH2Cl2) to give 37.9 mg
(78.8%) of (S)-4i as an off-white solid. For (S)-4i: Rf 0.44 (5:
95 Et2O/CH2Cl2); mp 100-103 °C; 1H NMR (300 MHz, CDCl3)
δ 7.2-7.5 (m, 10H), 5.28 (app t, 1H, J ) 6.0), 4.49 (app t, 1H,
J ) 8.4), 4.21 (dd, 1H, J ) 5.7, 8.5), 3.86 (d, 1H, J ) 8.9), 3.26
(q, 1H, J ) 6.6), 3.13 (d, 1H, J ) 10.0), 2.87 (dd, 1H, J ) 1.8,
8.8), 2.62 (d, 1H, J ) 8.9), 2.33 (app t, 1H, J ) 9.4), 1.47 (s,
3H), 1.33 (d, 3H, J ) 6.6); 13C NMR (75.5 MHz, CDCl3) δ 175.7
(s), 144.1 (s), 139.0 (s), 128.7 (d), 128.3 (d), 127.6 (d), 127.2
(d), 126.9 (d), 125.8 (d), 97.6 (s), 73.2 (t), 63.7 (d), 63.3 (t), 59.8
(s), 57.8 (d), 56.7 (d), 53.0 (t), 27.3 (q), 22.8 (q); IR (film) ν 3061,
3029, 2975, 1723, 1604 cm-1. Anal. Calcd for C23H25BrN2O2:
C, 62.59; H, 5.71; N, 6.35. Found: C, 62.49; H, 5.59; N, 6.36.
For (S)-5h : Rf 0.30 (1:4 EtOAc/hexanes); 1H NMR (300 MHz,
CDCl3) δ 7.30 (m, 10H), 5.19 (app t, 1H, J ) 7.2), 5.00 (s, 1H),
4.59 (app t, 1H, J ) 8.0), 3.82 (dd, 1H, J ) 6.7, 8.2), 3.40 (m,
2H), 3.22 (app d, 1H, J ) 6.7), 3.11 (app d, 1H, J ) 9.6), 2.74
(app d, 1H, J ) 9.4), 2.69 (partially obscured dd, 1H, J ) 6.8,
9.4), 1.37 (d, 3H, J ) 6.6); 13C NMR (75.5 MHz, CDCl3) δ 177.6
(s), 143.8 (s), 139.5 (s), 129.0 (d), 128.6 (d), 127.8 (d), 127.3
(d), 126.7 (d), 125.7 (d), 97.3 (d), 73.9 (t), 67.9 (t), 62.5 (d), 59.2
(d), 55.2 (t), 54.5 (d), 37.4 (s), 22.3 (q); IR (film) for a 97:3
Cycloa d d u cts (A)-4m a n d (A)-5m . Using the above
general procedure, a 0 °C solution of lactam 1m (56.0 mg, 0.186
mmol) and 2 (73.0 mg, 0.307 mmol) in CH2Cl2 was treated with
a 0.13 M solution of TFA in CH2Cl2 (0.14 mL, 0.018 mmol)
and was immediately allowed to warm to rt with stirring for
11 h. Integration of the resolved signals corresponding to the
major isomer ((A)-4m : δ 0.68, 2.61, 4.33) and the minor isomer
((A)-5m : δ 0.62, 2.67, 4.19) indicated an average ratio of 74.3:
25.7. Column chromatography (1:1 Et2O/hexanes) of the crude
mixture afforded 73.5 mg (91%) of an inseparable mixture of
(A)-4m and (A)-5m as a clear, colorless, foamy film.
mixture of (S)-5h and (S)-4h : ν 3060, 3029, 1718, 1604 cm-1
.
Cycloa d d u ct (A)-4i. To a rt solution of 1i (51.0 mg, 0.173
mmol) and 2 (85 mg, 0.36 mmol) in CH2Cl2 (2.5 mL) was added
TFA (1 drop). The resulting solution was heated to 37 °C and
was stirred for 2 h. The reaction mixture was quenched with
excess saturated, aqueous NaHCO3. The aqueous phase was
extracted with CH2Cl2, and the organic extracts were dried
(Na2SO4) and concentrated. The crude residue was purified
by radial chromatography (5:95 Et2O/CH2Cl2) to give 62.6 mg
1
For (A)-4m , selected H NMR signals: δ 4.33 (app t, 1H, J
) 7.8), 2.61 (d, 1H, J ) 9.2), 0.68 (d, 3H, J ) 6.2). For (A)-
5m , selected 1H NMR signals: δ 4.19 (app t, 1H, J ) 8.1),
2.67 (d, 1H, J ) 9.6), 0.62 (d, 3H, J ) 6.1). Anal. for a 74.3:

3374 J . Org. Chem., Vol. 61, No. 10, 1996
Fray and Meyers
25.7 mixture of (A)-4m and (A)-5m ; calcd for C26H30N2O4: C,
71.87; H, 6.96; N, 6.45. Found: C, 71.80; H, 6.94; N, 6.38.
Cycloa d d u cts (R)-4m a n d (R)-5m . Using the above
general procedure, a 0 °C solution of lactam 1m (33.1 mg, 0.110
mmol) and (R)-3 (33.9 mg, 0.135 mmol) in CH2Cl2 was treated
with a 0.13 M solution of TFA in CH2Cl2 (0.14 mL, 0.018 mmol)
and was immediately allowed to warm to rt with stirring for
10 h. Integration of the resolved signals corresponding to the
major isomer ((R)-4m : δ 0.69, 2.43, 4.36) and the minor isomer
((R)-5m : δ 0.62, 2.72, 4.16) indicated an average ratio of 87.3:
12.7. Radial chromatography (1:4 EtOAc/hexanes) of the crude
mixture afforded 38.8 mg (79%) of pure (R)-4m as a white
crystalline solid.
For (R)-4m : Rf 0.22 (1:1 (Et2O/hexanes); mp 183-185 °C;
[R]D ) +17.6 (c 1.16, CCl4); 1H NMR (300 MHz, CDCl3 the
signals indicated by * show non-first-order behavior (virtual
coupling)) δ 7.45-7.50 (m, 2H), 7.15-7.40 (m, 8H), 4.36 (dd,
1H, J ) 7.4, 8.2), 3.7-3.8 (m, 2H), 3.68 (s, 3H), 3.59 (dd, 1H,
J ) 6.6, 8.3), 3.31 (d, 1H, J ) 9.3), 3.22 (q, 1H, J ) 6.5), 3.01
(dd, 1H, J ) 1.8, 8.1), 2.43 (d, 1H, J ) 9.3), 2.28 (app t, 1H, J
) 8.8), 1.33 (d, 3H, J ) 6.6), 1.13 (m, 1H), 1.04 (d, 3H, J )
6.2)*, 0.70 (d, 3H, J ) 6.4)*. 13C NMR (75.5 MHz, CDCl3 one
accidental degeneracy is present) δ 176.7 (s), 170.3 (s), 144.7
(s), 144.0 (s), 128.4 (d), 128.0 (d), 127.0 (d), 126.8 (d), 125.1
(d), 99.7 (s), 71.7 (t), 66.0 (s), 63.7 (d), 62.7 (d), 59.4 (t), 53.1
(d), 52.8 (q), 52.7 (t), 32.2 (d), 22.8 (q), 20.6 (q), 18.7 (q); IR
(film) ν 2969, 1723, 1452, 1342, 1235, 962, 808 cm-1. Anal.
Calcd for C27H32N2O4: C, 72.30; H, 7.19; N, 6.25. Found: C,
72.05; H, 7.25; N, 6.17.
Cycloa d d u cts (S)-4m a n d (S)-5m . Using the above
general procedure, a 0 °C solution of lactam 1m (20.0 mg,
0.0664 mmol), and (S)-3 (25.0 mg, 0.0994 mmol) in CH2Cl2 was
treated with a 0.13 M solution of TFA in CH2Cl2 (0.14 mL,
0.018 mmol) and was immediately allowed to warm to rt with
stirring for 3 h. Integration of the resolved signals corre-
sponding to the major isomer ((S)-4m : δ 2.07, 2.57, 3.52) and
the minor isomer ((S)-5m : δ 1.97, 2.46, 3.32) indicated an
average ratio of 69.1:30.9. Preparatory thin-layer chromatog-
raphy (4:5 Et2O/hexanes) of the crude mixture afforded 27.4
mg (92%) of separable mixture of (S)-4m (white crystalline
solid) and (S)-5m (oil).
10.0), 1.10 (m, 4H), 0.92 (d, 3H, J ) 6.6), 0.63 (d, 3H, J ) 6.4)*;
13C NMR (75.5 MHz, CDCl3) δ 179.8 (s), 170.5 (s), 144.6 (s),
138.0 (s), 128.8 (d), 128.6 (d), 128.5 (d), 127.1 (d), 126.7 (d),
125.8 (d), 103.9 (s), 77.2 (s), 70.1 (t), 65.6 (d), 64.0 (d), 59.3 (t),
54.2 (t), 53.0 (q), 51.1 (d), 32.2 (d), 22.4 (q), 21.0 (q), 18.6 (q);
IR (film) ν 2970, 1747, 1722 cm-1
.
P r ep a r a tion of Im id e 10. To a rt mixture of maleic
anhydride (200 mg, 2.04 mmoles) and dipole precursor 2 (726
mg, 3.06 mmol) was added THF (2 mL). After a few seconds,
an exotherm was observed; apparently, the presence of trace
acid was sufficient to catalyze the dipolar cycloaddition reac-
tion. After 15 min, a solution of (S)-phenylglycinol (280 mg,
2.04 mmol) in THF (2 mL) was added dropwise to the originally
clear, colorless reaction mixture to give a pale yellow gel-
atinous precipitate that was allowed to stir for 1 h. This
precipitate was diluted with Ac2O (20 mL) and NaOAc (0.3 g),
and the mixure was heated to reflux for 2 h. The excess Ac2O
was removed by short-path distillation at atmospheric pres-
sure, and the residue was diluted with 2 N ethanolic HCl (25
mL) and was heated to reflux for 2 h. The mixture was poured
into saturated aqueous NaHCO3 solution (150 mL) and was
extracted with EtOAc. The organic extracts were combined,
dried (MgSO4), and concentrated to a dark brown residue that
was purified by column chromatography (1:4 to 100:0 EtOAc/
hexanes) to afford semipure material. Repurification of this
material by radial chromatography (1:4 to 100:0 EtOAc/
hexanes) afforded 138 mg (19%) of 10 as a light brown film:
1
Rf 0.50 (EtOAc); H NMR (300 MHz, CDCl3) δ 7.30 (m, 10H),
5.12 (dd, 1H, J ) 4.5, 9.0), 4.52 (app t, 1H, J ) 10.7), 4.06 (dd,
1H, J ) 4.8, 12.1), 3.54 (ABq, 2H, J ) 13.1, ∆ν ) 17.8), 3.28
(d, 2H, J ) 9.8), 3.16 (m, 3H), 2.35 (m, 2H); 13C NMR (75.5
MHz, CDCl3) δ 180.3 (s), 179.8 (s), 137.7 (s), 135.9 (s), 128.5
(d), 128.3 (d), 128.2 (d), 127.9 (d), 127.4 (d), 127.2 (d), 61.6 (t),
58.3 (t), 58.1 (d), 56.7 (t), 56.6 (t), 44.2 (d), 44.1 (d); IR (film) ν
3454, 3087, 3063, 3031, 2964, 1954, 1770, 1694, 1651, 1633
cm-1
.
Red u ctive Deh a logen a tion of (S)-5g w ith Zin c. Freshly
prepared zinc-copper couple (78 mg, ∼1.2 mmol) was added
to a rt suspension of (S)-5g (102 mg, 0.239 mmol) and NH4Cl
(13 mg, 0.243 mmol) in MeOH (5 mL). After 20 min of stirring,
TLC analysis indicated complete consumption of (S)-5g. The
reaction mixture was quenched with saturated, aqueous
NaHCO3 to give an emulsion which was repeatedly extracted
with CH2Cl2. The organic extracts were dried (Na2SO4) and
concentrated under reduced pressure to afford, after radial
chromatography (1:1 EtOAc/hexanes), 59.7 mg (71.7%) of (S)-
5c and 9.4 mg of 15 as an oil.
For (S)-4m : mp 166.5-167 °C; Rf 0.53 (4:5 Et2O/hexanes);
1H NMR (300 MHz, CDCl3 the signals indicated by * show
non-first-order behavior (virtual coupling)) δ 7.41 (m, 2H), 7.27
(m, 8H), 4.33 (dd, 1H, J ) 7.6, 8.3), 3.74 (m, 2H), 3.74 (s, 3H),
3.51 (dd, 1H, J ) 7.0, 8.4), 3.39 (d, 1H, J ) 9.5), 3.17 (q, 1H,
J ) 6.6), 2.91 (dd, 1H, J ) 1.2, 8.0), 2.56 (d, 1H, J ) 8.9), 2.07
(dd, 1H, J ) 8.2, 9.5), 1.31 (d, 3H, J ) 6.6), 1.07 (m, 4H), 0.68
(d, 3H, J ) 6.2)*; 13C NMR (75.5 MHz, CDCl3 one accidental
degeneracy is present) δ 177.1 (s), 170.3 (s), 145.2 (s), 143.7
(s), 128.4 (d), 128.2 (d), 128.0 (d), 126.9 (d), 125.1 (d), 99.8 (s),
71.6 (t), 66.1 (s), 64.1 (d), 62.7 (d), 58.8 (t), 53.9 (t), 52.9 (q),
52.8 (d), 32.4 (d), 23.6 (q), 20.7 (q), 18.6 (q); IR (film) ν 2972,
1
For 15: Rf 0.14 (1:1 EtOAc/hexanes); H NMR (300 MHz,
CDCl3) δ 7.30 (m, 10H), 6.11 (d, 1H, J ) 2.8), 5.38 (d, 1H, J )
2.4), 5.15 (app t, 1H, J ) 7.4), 5.09 (s, 1H), 4.56 (app t, 1H, J
) 8.5), 3.84 (dd, 1H, J ) 7.1, 8.7), 3.79 (q, 1H, J ) 6.6), 2.98
(m, 1H), 2.86 (dd, 1H, J ) 5.0, 11.9), 2.64 (dd, 1H, J ) 8.8,
11.9), 1.55 (br s, D2O exch.), 1.36 (d, 3H, J ) 6.6).
1747, 1721, 1453 cm-1
.
For (S)-5m : Rf 0.45 (4:5 Et2O/hexanes); 1H NMR (300 MHz,
CDCl3 the signal indicated by * shows non-first-order behavior
(virtual coupling)) δ 7.44 (m, 10H), 4.21 (dd, 1H, J ) 7.7, 8.1),
3.71 (s, 3H), 3.66 (m, 1H), 3.31 (dd, 1H, J ) 7.4, 8.4), 3.22 (d,
1H, J ) 6.7), 3.21 (d, 1H, J ) 9.9), 3.01 (q, 1H, J ) 6.6), 2.44
(d, 1H, J ) 9.9), 2.32 (d, 1H, J ) 9.9), 1.96 (dd, 1H, J ) 7.0,
Ack n ow led gm en t. The authors are grateful to the
National Institutes of Health for financial support of
this work.
J O9600870