Stereoselective alkylations in rigid systems. Effect of remote substituents on π-facial additions to lactam enolates. Stereoelectronic and steric effects

Article abstract of DOI:10.1021/ja980614s

A series of chiral bicyclic lactams has been studied by both experiment and ab initio molecular orbital calculations, The facial selectivity of the alkylation of their enolates shows a high degree of endo or exo entry, depending upon certain substituents and their positions in the lactams. The suggested reasons for the exo or endo selectivity for alkylation were determined to be purely electronic or purely steric in certain instances, The results of the selectivity study now allow the asymmetric synthesis of various ketones, acids, and pyrrolidines in either enantiomeric form based on the choice of lactam employed.

Full text of DOI:10.1021/ja980614s

J. Am. Chem. Soc. 1998, 120, 7429-7438
7429
Stereoselective Alkylations in Rigid Systems. Effect of Remote
Substituents on π-Facial Additions to Lactam Enolates.
Stereoelectronic and Steric Effects
A. I. Meyers,*,† Mark A. Seefeld,† Bruce A. Lefker,‡ James F. Blake,‡ and
Paul G. Williard§
Contribution from the Department of Chemistry, Colorado State UniVersity, Fort Collins, Colorado 80523,
Pfizer Central Research, Groton, Connecticut 06340, and Department of Chemistry, Brown UniVersity,
ProVidence, Rhode Island 02912
ReceiVed February 23, 1998
Abstract: A series of chiral bicyclic lactams has been studied by both experiment and ab initio molecular
orbital calculations. The facial selectivity of the alkylation of their enolates shows a high degree of endo or
exo entry, depending upon certain substituents and their positions in the lactams. The suggested reasons for
the exo or endo selectivity for alkylation were determined to be purely electronic or purely steric in certain
instances. The results of the selectivity study now allow the asymmetric synthesis of various ketones, acids,
and pyrrolidines in either enantiomeric form based on the choice of lactam employed.
Chiral bicyclic lactams 1 are highly useful templates for the
asymmetric construction of compounds containing quaternary
carbon centers 3-5.1 The cornerstone of this methodology has
Unfortunately, a satisfactory and consistent rationale has not
yet been forthcoming to explain these observed reversals in
selectivity.
Herein we report a series of experimental results and ab initio
molecular orbital calculations which seem to support the
hypothesis that an electronic preference for alkylation anti to
the nitrogen lone pair (endo alkylation) is in competition with
steric factors which have the potential to reverse the selectivity
and thus favor exo alkylation. Additionally, we report the X-ray
structure of the lithium enolate of lactam 6 (R ) i-Pr). This
enolate structure 12 (Figure 1A,B) provides information about
the configuration and facial accessibility of this reactive species.
We chose to first investigate these stereoselective alkylations
by focusing on the electronic aspects of lactam alkylation. We
recently reported experimental and theoretical studies6 on the
monocyclic (()-1,5-dimethylpyrrolidinone (9). Those studies
been the ability to alkylate 1 in a highly endo-selective manner.
In the majority of cases, the preferred endo approach was 10-
50:1 to give 2.
This is in stark contrast to a number of bicyclic lactams 6-8
that have been reported to alkylate in an exo-selective fashion.2-5
provided evidence that the nitrogen lone pair of the lactam
enolate may introduce an electronic preference for alkylation
anti to the nitrogen lone pair (R-entry). In this simple system,
which is devoid of any significant steric biases, selectivities of
(2) Lefker, B. A. Ph.D. Thesis, Colorado State University, 1988.
(3) Thottathil, J. K.; Moniot, J. L.; Mueller, R. H.; Yong, M. K. Y.;
Kissick T. P. J. Org. Chem. 1986, 51, 3140.
(4) (a) Brown, K. L.; Damm, L.; Dunitz, J. D.; Eschenmoser, A.; Hobl,
R.; Kratky, C. HelV. Chim. Acta 1978, 61, 3108. (b) Damm, L. G.;
Eschenmoser, A. Ph.D. Dissertation, Eidgenossischen Technischen Hoch-
scule, Zurich, Switzerland, 1979.
(5) Meyers, A. I.; Seefeld, M. A.; Lefker B. A. J. Org. Chem. 1996, 61,
5712. See also: Roth, G.; Leonard, S. F.; Tong L. J. Org. Chem. 1996, 61,
5710.
A combination of steric and electronic effects may be operative
in defining the preferred trajectory for the incoming electrophile.
† Colorado State University.
‡ Pfizer Central Research.
§ Brown University.
(1) (a) Romo, D.; Meyers, A. I. Tetrahedron 1991, 47, 9503. (b) Meyers,
A. I.; Brengel, G. P. Chem. Commun. 1997, 1.
(6) Meyers, A. I.; Seefeld, M. A.; Lefker, B. A.; Blake, J. F. J. Am.
Chem. Soc. 1997, 119, 4565.
S0002-7863(98)00614-3 CCC: $15.00 © 1998 American Chemical Society
Published on Web 07/18/1998

7430 J. Am. Chem. Soc., Vol. 120, No. 30, 1998
Meyers et al.
Figure 1. (A, top) Computer-generated X-ray structure of simplified lithium enolate 12 (from lactam 6) with TMEDA complex. Only one-half
of the dimer is shown; a complete structure is given in part B. Complete data are given in the Supporting Information. (B, bottom) ORTEP X-ray
structure of dimeric lithium enolate‚TMEDA (12).
Table 1. Effect of Exo Substituents on Endo/Exo Benzylation
Ratios
substituents do impart some steric bias for endo alkylation.
Systematic replacement of the exo alkyl and aryl substituents
(A and B, Table 1) on bicyclic lactam 1 with hydrogen results
in an erosion of endo alkylation selectivity from 98:2 down to
69:31. However, endo alkylation is still preferred even when
both A and B are hydrogens (entry f, Table 1). Thus, exo
substituents (A and B) may be assumed to be only a minor factor
in the determination of diastereofacial alkylation selectivity. This
residual preference for endo alkylation in entry f can likely be
attributed to an electronic effect or some yet to be observed
steric factor. In an effort to further define this electronic effect,
computational methodology similar to that described for the
monocyclic (()-dimethyl lactam 9 was applied.
entry
A
B
%2n (endo)a
%2x (exo)a
a
b
c
d
e
f
i-Pr
t-Bu
i-Pr
i-Pr
H
Me
Me
Ph
H
Me
H
97
98
98
80
70
69
3
2
2
20
30
31
A ground-state conformation for the lithium enolate of lactam
1 was calculated from X-ray parameters (Figure 1A), and the
highly convex enolate structure 14 (Figure 2) appears to offer
H
a Ratios detemined by NMR and are accurate to (2%.
99:1 for compounds 10:11 were observed. Ab initio molecular
orbital calculations on the â and R SN2 transition states also
predicted that R-face alkylation on this monocyclic lactam would
be favored.
If a similar electronic effect can be extended to bicyclic
lactams and alkylation anti to the nitrogen lone pair (endo) is
mainly electronic in origin, then clearly additional steric and/
or electronic factors are influencing the alkylation of bicyclic
lactams 6-8.
significantly less access to the endo face than would have been
predicted from the lactam structure prior to enolization. In an
earlier study, we determined, in a prototypical system (lactam
Previous studies1 measuring alkylation selectivity in bicyclic
lactams 1 have suggested that the angularly placed exo

StereoselectiVe Alkylations in Rigid Systems
J. Am. Chem. Soc., Vol. 120, No. 30, 1998 7431
Figure 2. Exo addition is favored experimentally for 12, as the endo face is encumbered by H atom. Endo addition is favored experimentally for
14, although the exo face also appears to be unencumbered.
9), that the alkylation selectivity could be predicted via location
of the SN2 transition-state structures corresponding to the two
modes (R and â) of attack.6 This methodology has now been
applied to the alkylation reaction involving enolate 14. The
transition-state structures corresponding to the endo and exo
alkylation products of methyl bromide were determined (Figure
2). As with the enolate of lactam 9, the endo mode of addition
to 14 was predicted to be favored by ca. 1.26 kcal/mol,
consistent with the results reported in Table 1 (entry a). It is
interesting that the high endo selectivity displayed in this system
is retained despite the concave nature of the bicyclic system.
Clearly, the driving force for addition anti to the nitrogen lone
pair is operative in this system.
anti to the angular methyl or trifluoromethyl (endo face) suggest
that the Cieplak effect10 is probably not applicable to this system.
In contrast to results obtained on alkylations with lactams 1,
the enolate 12 from lactam 6 (R ) i-Pr) was reported3 previously
to alkylate with high exo selectivity. This reversal was
surprising considering the only difference between enolates 12
and 14 is the position of the ring oxygen. To further our
understanding about the factors governing selectivity, we chose
to examine the specific configuration of the enolate 12. To
achieve this goal, the lithium enolate was successfully crystal-
lized and studied by X-ray analysis. The structure of enolate
12 (Figure 1A,B) reveals a surprisingly convex bicyclic species
which crystallized as a dimeric 1:1 complex with TMEDA. The
plane designated by the three carbon atoms attached to nitrogen
is 0.5 Å removed from the bridgehead nitrogen of the enolate
structure. This indicates a substantial increase in pyramidal-
ization from the starting bicyclic lactams 1 and 6 (0.1-0.3 Å)
as determined from earlier X-ray analyses.1 Alkylation of the
lithio TMEDA/enolate 12 proceeded with the same selectivity
as that observed in the absence of TMEDA. This is similar to
earlier observations where addition of TMEDA or HMPA,
altering the solvent polarity, or varying the counterion charac-
ter7,8 did not effect the facial alkylation selectivity of lactams
1. In addition, the similar behaviors of lactams 1 and 139
wherein the electrophile entered the corresponding lithio enolates
Examination of the HOMO of the enolate 12 reveals a larger
orbital coefficient on the endo face (Figure 3A), and thus, based
on electronics alone, endo-facial alkylation for both lactam
enolates might be expected. Similarly, the HOMO of enolate
14 reveals the larger orbital coefficient on the endo face (Figure
3B). Furthermore, the transition states for exo and endo attack
on enolate 14 reveal no visible steric inhibition from either face
(Figure 3C). However, comparison of the transition states for
endo and exo alkylation reveals a reversal in the predicted ster-
eoselectivity from 14, with the exo addition product now favored
by 0.94 kcal/mol (Figure 2). This result is in agreement with the
earlier observed experimental preference for exo alkylation.2,3
Overlap of enolate 12 with the calculated enolate lactam 14
reveals only a 0.074 Å rms difference in structure between the
non-hydrogen atoms forming the core enolate rings (Figure 4).
A more meaningful analysis of this exo/endo paradox might be
found by directly comparing the transition-state profiles for
enolates 12 and 14.
A comparison of the stereostructures of the valinol-derived
enolate 14 with that of enolate 12 provides some interesting
insight into endo-facial steric bias. The two structures are
largely superimposable (Figure 4). The main structural differ-
ences lie in the position of their ether oxygens and their adjacent
methylene groups. Calculations for the approach of methyl
(7) Liotta, D.; Durkin, K. A. J. Am. Chem. Soc. 1990, 112, 8162.
(8) Meyers, A. I.; Wallace, R. H.; Romo, D. Unpublished results.
(9) Meyers, A. I.; Wallace, R. H. J. Org. Chem. 1989, 54, 2509.
(10) Cieplak, A. S. J. Am. Chem. Soc. 1981, 103, 4540.

7432 J. Am. Chem. Soc., Vol. 120, No. 30, 1998
Meyers et al.
Figure 3. (A, top left) Electron density isosurface of the HOMO enolate 12. (B, top right) Electron density isosurface of the HOMO of enolate
14. (C, bottom) Calculated transition states for endo and exo approach of CH3Br to enolate 14.
Figure 4. Overlapping enolates 12 (green) and 14 (gray) and their respective CH3Br (green and gray) approach vectors for endo (left) and exo
(right) entry.
bromide to enolate 12 indicate a difference in transition-state
energies of 0.94 kcal/mol in favor of the exo approach model
(Figure 2). Likewise, similar calculations predict a favored endo
transition state for enolate 14 by 1.26 kcal/mol (Figure 2).
Presumably some steric component, and one not present on the
exo face of the bicyclic lactam 12, must be overriding the
electronic effect.
The approach vectors of methyl bromide to superimposed
stereomodels of enolates 12 and 14 (Figure 4) indicate no visible
steric bias on the exo faces of either of these enolates. In fact,
the approach vectors to the exo face seem to be identical.
However, the trajectory of the electrophile (CH3Br) toward the
endo face of enolate 12 is altered 10° relative to that of the
valinol-derived enolate 14. It appears the endo-methylene
hydrogens of enolate 12 are interfering with the electrophile
approach. By analogy, the deoxylactam 7 should show similar
behavior on the basis of its endo hydrogens similarly protruding
into the concave region, and exo entry was found to indeed be
the case.4
Recently, we and others5 reported that additional substitution
on the endo face of related bicyclic lactams 8 could reverse the
direction of entry and induce high levels of exo-facial alkylation.
We concluded that a steric component provided by the newly
placed endo substituent was responsible for this reversal in
stereofacial alkylation. To test this hypothesis, racemic lactams
8, each containing an endo substituent in the position â to the

StereoselectiVe Alkylations in Rigid Systems
J. Am. Chem. Soc., Vol. 120, No. 30, 1998 7433
Table 2. Alkylation of Sutstituted Bicyclic Lactams
entry
R1
R2
R3
R4
R5
R′
RX
R
R′
T (°C)
% yieldb
exo:endoc
a
b
c
d
e
f
H
H
Me
H
H
H
H
H
H
H
Me
H
H
H
H
H
H
H
Me
Me
Me
Me
Me
Me
Me
Me
H
Bn
H
Bn
Bn
H
Bn
Bn
BnBr
allyBr
BnBr
allylBr
allylBr
BnBr
allylBr
allylBr
H
allyl
Bn
allyl
allyl
Bn
allyl
allyl
Bn
Bn
H
Bn
Bn
H
-78
-78
-78
-78
0
-78
-78
0
86
89
91
93
90
94
95
90
1:99d
99:1d
96:4
Me
i-Pr
i-Pr
i-Pr
Ph
Ph
Ph
Me
i-Pr
i-Pr
i-Pr
Ph
Ph
Ph
99:1d
99:1d
94:6e
99:1d
99:1d
g
h
Bn
Bn
i
j
H
H
H
H
H
H
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
CH2O-TBDPS
CH2O-TBDPS
CH2O-TBDPS
CH2O-TBDPS
CH2O-TBDPS
CH2O-TBDPS
Ph
H
H
H
H
H
H
H
H
Me
Me
Me
Me
H
H
Me
Me
CH3
Bn
allyl
allyl
H
Bn
H
BnBr
allylBr
BnBr
BnBr
BnBr
allylBr
allylBr
BnBr
Bn
allyl
Bn
Bn
Bn
allyl
allyl
Bn
CH3
Bn
allyl
allyl
H
Bn
H
-78
-78
-78
0
-78
-78
-78
-78
91
87
88
77
85
90
92
93
94:6
98:2
k
l
m
n
o
p
99:1d
99:1d
91:9
99:1d
99:1d
99:1d
Ph
allyl
allyl
a Similar diastereomeric ratios and yields were also observed using LDA in THF. b Isolated yield of both diastereomers. c Diastereomeric ratio
1
1
was determined by H NMR at 300 MHz. d No minor diastereomer could be detected in the H NMR spectrum. e Epimerization noted.
quaternary angular center, were prepared from levulinic acid
To further substantiate the relative stereoselectivities which
were assigned to 18 on the basis of anisotropic shielding of the
angular substituent, chiral nonracemic lactams were constructed
that could be further carried on to previously known, chiral,
nonracemic products. To perform this task, lactam 21 was
synthesized by condensing the commercially available amino
diol (+)-19 and levulinic acid to afford chiral lactam (+)-20.
The hydroxyl group in the latter was silylated smoothly with
TBDPS-Cl in 85% yield. Lactam (+)-21, on being subjected
to the usual enolate formation, also exhibited a strong preference
for exo alkylation to 18 at both -78 and 0 °C (Table 2, entries
i-n) when alkyl halides were sequentially introduced.
(16) and their respective vicinal amino alcohols 15.11
Alkylation of the lithium enolate of lactams 17 (Table 2,
entries c and f) with benzyl bromide proceeded with high levels
of exo selectivity. The exo-benzyl product gave rise to a
diagnostic anisotropic shielding effect on the angular methyl
1
substituent which was discernible by H NMR. In two cases,
complete exo selectivity was also observed at temperatures as
high as 0 °C (Table 2, entries 18e,h). Interestingly, the achiral
lactam 17 containing gem-dimethyl substituents adjacent to
nitrogen (entry a) displayed complete preference for endo
alkylation. This is consistent with substituents adjacent to
nitrogen in the enolates of 17 not interfering with the endo
alkylation trajectory as much as substituents placed â to the
ring nitrogen. In every instance shown in Table 2 where an
endo substituent (R2) was other than H, complete (or nearly
so) exo alkylation occurred (entries 18b-p).
The absolute stereochemistry for these systems was verified
by chemical correlation as follows. Subjecting both lactam 21
and valinol-derived lactam 1 (R ) i-Pr) separately to reverse-
order alkylations followed by heating in butanol and H2SO4
resulted in the formation of an identical ketoester 22.12 Further
stereochemical confirmation was provided by the conversion
of 1 and 21 into the same cyclopentenone (-)-23 when both
substituents were introduced in reverse order to 21 and 1,
(11) Evans, D. A.; Carroll, G. L.; Truesdale, L. K. J. Org. Chem. 1974,
39, 914.
(12) Meyers, A. I.; Harre, M.; Garland, R. J. Am. Chem. Soc. 1984, 106,
1146.

7434 J. Am. Chem. Soc., Vol. 120, No. 30, 1998
Meyers et al.
Figure 5. Calculated transition states for exo approach to enolates 24 and 25.
respectively.13 This clearly showed that (+)-21, with an endo-
phenyl substituent alkylated on the exo face, whereas (+)-1,
with no endo substituent, alkylated on the endo face. Since a
reverse sequence of electrophiles was employed, both modes
of alkylation gave identical stereochemical results.
To rationalize the exo entry as the main mode of alkylation
on the lactams in Table 2 (17h-p), stereomodels of the
corresponding enolates 24 and 25 were studied as their transition
shown in Table 2 (17b-18b; 17i-18i) where, in every case, a
substituent (R2) projected down into the endo face.
It was now desirable to assess the feasibility of having ready
access to a chiral nonracemic bicyclic lactam which is closely
related to 1, except it will selectively alkylate on the exo face.
This was implemented by using (S)-phenylglycinate as the chiral
auxiliary. Thus, chiral, nonracemic lactam (-)-17o was con-
structed in two steps from phenylmagnesium bromide and (S)-
2-phenylglycine methyl ester (26) followed by simple reflux
with levulinic acid in toluene. The enantiopurity of the lactam
was determined from chiral HPLC analysis and found to be
>99% ee. As with all the other similarly substituted lactams,
the highly crystalline lactam 17o displayed excellent exo
alkylation selectivity when metalated and alkylated sequentially
with allyl and benzyl bromide to give 18 (entries o and p, Table
2).
In an earlier report14 we described the use of the bicyclic
lactams in the preparation of chiral pyrrolidines.1b In this regard,
it was deemed necessary to have access to a chiral lactam which
would also alkylate exo and therefore lead to the enantiomeric
series of pyrrolidines. We, therefore, prepared the angular
hydrogen-substituted lactam 17m which was constructed by
heating amino diol 19 and succinic anhydride in xylenes. After
recrystallization, the enantiomerically pure succinamide 28 was
reduced with NaBH4 followed by formic acid mediated cy-
clization and silylation to afford the crystalline lactam 17m.
states toward alkylation. They clearly show the effect of having
a substituent on the endo face (Figure 5). The transition-state
energies of lactam enolates 24 and 25 with respect to the
approach of methyl bromide should reflect the preference for
exo alkylation, and this was indeed found to be the case.
Racemic lactam enolate 24 is favored to give exo alkylation
(0.93 kcal/mol), and the chiral lactam enolate 25 is also favored
to provide exo alkylated products (0.49 kcal/mol). This is
consistent with the experimental results for exo alkylation as
(13) Meyers, A. I.; Wanner, K. Th. Tetrahedron Lett. 1985, 26, 2047.
(14) Westrum, L. J.; Meyers, A. I. Tetrahedron Lett. 1994, 35, 973.

StereoselectiVe Alkylations in Rigid Systems
J. Am. Chem. Soc., Vol. 120, No. 30, 1998 7435
entropies of each molecule at 195.15 K. Electron correlation energies
were computed via third-order Møller-Plesset perturbation theory
(MP3) with the 6-31+G(d) basis set. All energetic values reported
herein are given as enthalpies at 195.15 K computed from the MP3
(MP2 for 25)/6-31G+(d) energies.17
Summary
Through ab initio molecular orbital calculations and experi-
mentation, we have determined the basis of diastereofacial
alkylation for a series of bicyclic lactams, which appears to be
governed by electronics and/or steric control. We have also
prepared a number of easily accessible chiral, nonracemic
bicyclic lactams that display excellent exo alkylation and should
be of complementary use in the asymmetric construction of
quaternary compounds and chiral pyrrolidines and piperidines.
Further investigations into the application of chiral bicylic
lactams toward asymmetric syntheses are continuing.
Experimental Section
The latter also alkylated in high exo-diastereofacial selectivity
at both -78 and 0 °C (entries 18m,n, Table 2). This suggests
that the angular substituent in the bicyclic lactams (H vs Me)
has little effect on the approach trajectory of the electrophile
and the major factor in determining facial entry still remains
the substituent R2 in 17 (Table 2).
General Experimental Procedures. All reactions were carried out
under argon in septum-stoppered flasks. Unless otherwise noted,
reagents were added by syringe and organic extracts were dried over
anhydrous Na2SO4, filtered through a fritted glass funnel, and concen-
trated with a rotary evaporator at aspirator pressure (20-40 mm). Flash
chromatography was performed with ASA (200-400 mesh) silica gel.
Thin-layer chromatography (TLC) was performed with Merck F-254
silica gel plates.
Unless otherwise noted, starting materials were obtained from
commercial suppliers and used without further purification. Tetrahy-
drofuran (THF) and ether were distilled under N2 from sodium/
benzophenone immediately prior to use. Dichloromethane (CH2Cl2)
and toluene were distilled from CaH2 immediately prior to use.
Microanalyses were performed by Atlantic Microlab, Inc., Norcross,
GA.
General Procedure for Pyrrolidinone Dialkylation. Lactam (10).
Lactam 9 (2.26 g, 20.00 mmol) was dissolved in THF (30 mL) and
cooled to -78 °C. s-BuLi (18.0 mL, 1.1 M in hexane) was added
dropwise over 5 min to the solution. After 1 h benzyl bromide (3.60
g, 21.0 mmol) was added to the stirred -78 °C solution. Thirty minutes
after the addition of benzyl bromide, the solution was quenched with
saturated aqueous NH4Cl solution (10 mL). Ethyl acetate (20 mL) was
added to the mixture, and the resulting solution was separated, dried,
and concentrated. Filtration through silica (hexanes/EtOAc, 1:1)
afforded 3.86 g of a crude colorless oil. The crude dried oil (2.40 g,
11.8 mmol) was dissolved in THF (20 mL) and cooled to -78 °C.
s-BuLi (10.9 mL, 1.1 M in hexane) was added dropwise to the solution.
After 1 h, allyl bromide (1.80 g, 15.0 mmol) was added dropwise, and
after an additional 15 min, the solution was quenched by the addition
of saturated aqueous NH4Cl solution (10 mL). Ethyl acetate (30 mL)
was added to the mixture, and the resulting solution was separated,
dried, and concentrated. Purification on silica (hexanes/EtOAc, 2:1)
gave lactam 10 (2.72 g, 95%) as a light yellow oil. IR (neat) 3027,
Computational Methods
Restricted Hartree-Fock calculations were carried out for the endo
and exo alkylation reactions of enolates 12, 14, 24, and 25 with methyl
bromide. The geometries for each series of molecules were fully
optimized by means of analytical energy gradients with the 6-31+G-
(d) basis set. The ab initio molecular orbital calculations were carried
out with the Gaussian 94 series of programs on a Silicon Graphics
computer.15 Vibrational frequencies were calculated at the 6-31+G-
(d) level for all stationary structures. The existence of transition states
or minima was confirmed by the presence of either one or zero negative
eigenvalues in the analytical second-derivative matrix. The scaled
vibrational frequencies16 were used to compute the enthalpies and
2966, 1686 cm-1 1H NMR (300 MHz): δ 0.77 (d, J ) 6.3, 3H), 1.57
.
(dd, J ) 13.2, 6.7, 1H), 2.11 (dd, J ) 13.4, 8.1, 1H), 2.25 (dd, J )
13.4, 8.4, 1H), 2.58 (dd, J ) 13.4, 6.4, 1H), 2.66 (d, J ) 13.4, 1H),
2.80 (s, 3H), 3.20 (dd, J ) 13.4, 1H), 3.41 (m, 1H), 5.15 (d, J ) 9.9,
1H), 5.20 (d, J ) 18.0, 1H), 5.83 (ddd, J ) 18.0 9.9, 5.3, 1H), 7.24-
7.37 (m, 5H). 13C NMR (75 MHz): δ 20.1, 27.5, 34.6, 43.2, 43.4,
49.9, 52.6, 118.7, 126.6, 128.3, 130.6, 134.1, 138.3, 177.2. MS
(FAB+): m/z 243 [(M + H)+], 202, 152. HRMS calcd for C16H21NO:
[(M + H)+] 243.1623. Found: 243.1616.
(15) Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Gill, P. M. W.;
Johnson, B. G.; Robb, M. A.; Cheeseman, J. R.; Keith, T.; Petersson, G.
A.; Montgomery, J. A.; Raghavachari, K.; Al-Laham, M. A.; Zakrzewski,
V. G.; Ortiz, J. V.; Foresman, J. B.; Peng, C. Y.; Ayala, P. Y.; Chen, W.;
Wong, M. W.; Andres, J. L.; Replogle, E. S.; Gomperts, R.; Martin, L.;
Fox, D. J.; Binkley, J. S.; Defrees, D. J.; Baker, J.; Stewart, J. P.; Head-
Gordon, M.; Gonzalez, C.; Pople, J. A. Gaussian 94, ReVision B.3; Gaussian,
Inc.: Pittsburgh, PA, 1995.
(16) A scale factor of 0.91 was applied to all vibrational frequencies.
Scaled vibrational frequencies below 500 cm-1 were treated as classical
rotations, while imaginary frequencies were ignored. Grev, R. S.; Janssen,
C. L.; Schaefer, H. F., III. J. Chem. Phys. 1991, 95, 5128.
Lactam (11). Isolated as a light yellow oil. IR (neat): 3027, 2966,
1685 cm-1 1H NMR (300 MHz): δ 1.02 (d, J ) 6.0, 3H), 1.54 (dd,
.
J ) 12.0, 7.1, 1H), 2.14 (m, 2H), 2.33 (dd, J ) 13.0, 8.7, 1H), 2.55
(m, 1H), 2.60 (s, 3H), 3.07 (d, J ) 12.9, 1H), 5.15 (d, J ) 10.1, 1H),
5.18 (d, J ) 17.1, 1H), 5.80 (ddd, J ) 17.1, 10.1, 5.9, 1H), 7.18-7.33
(17) For a detailed discussion of this procedure, see: Hehre, W. J.;
Radom, L.; Schleyer, P. v. R.; Pople, J. A. Ab Initio Molecular Orbital
Theory; Wiley: New York, 1986.

7436 J. Am. Chem. Soc., Vol. 120, No. 30, 1998
Meyers et al.
(m, 5H). 13C NMR (75 MHz): δ 20.3, 27.2, 35.7, 42.7, 43.8, 49.4,
52.1, 118.4, 126.6, 127.9, 129.8, 134.2, 137.6, 177.3. MS (FAB+):
m/z 243 [(M + H)+], 202, 152. HRMS calcd for C16H21NO [(M +
H)+]: 243.1623. Found: 243.1616.
suspension which was stirred an additional 3 h at room temperature.
The mixture was quenched by the addition of 125 mL of saturated
NaHCO3 solution and then extracted with 3 × 75 mL of EtOAc. The
combined extracts were dried (K2CO3), and the solvent was removed
to give a yellow oil. The crude oil was dissolved in CH2Cl2 (300 mL)
to which 88% formic acid (6 mL) was added with stirring. After 16
h the reaction was quenched by the addition of saturated NaHCO3
solution. The organics were separated off, dried, and concentrated.
Silyl ether formation (TBDPS) as in the preceding procedure followed
by recrystallization (hexane/EtOAc) afforded lactam (17m) as a
colorless solid in 60% yield from 19, mp ) 90-91 °C (hexane/EtOAc).
General Procedure for Bicyclic Lactam Formation. Lactam
(17a). 2-Amino-2-methyl-1-propanol (2.45 g, 27.0 mmol) and levulinic
acid (3.13 g, 27.0 mmol) were dissolved in toluene (50 mL). The flask
was equipped with a Dean-Stark trap, and the solution was heated to
reflux. After 16 h the solution was cooled, washed with saturated
aqueous NaHCO3, dried, and concentrated. Chromatography on silica
gel (hexane/EtOAc, 1:1) afforded 3.83 g (84%) of lactam 17a as a
colorless solid, mp ) 37-38 °C (hexanes/EtOAc). IR (neat): 2975,
[R]23D: +28.2 (c 1.5, EtOH). IR (neat): 2930, 1719 cm-1 1H NMR
.
1698 cm-1 1H NMR (300 MHz): δ 1.39 (s, 3H), 1.47 (s, 3H), 1.54
.
(300 MHz): δ 1.06 (s, 9H), 2.17 (m, 1H), 2.37 (m, 1H), 2.60 (m, 2H),
3.78 (m, 1H), 3.95 (m, 2H), 5.15 (d, J ) 5.8, 2H), 5.36 (dd, J ) 6.1,
2.1, 1H), 7.16-7.42 (m, 11H), 7.61 (m, 4H). 13C NMR (75 MHz): δ
19.2, 24.3, 26.9, 31.3, 63.5, 63.9, 82.6, 93.1, 126.3, 127.8, 127.9, 128.3,
128.6, 129.8, 129.9, 133.0, 135.6, 135.7, 139.1, 179.3. Anal. Calcd
for C29H34SiNO2: C, 73.85; H, 7.05. Found: C, 73.72; H, 7.08.
Bicyclic Lactam (17o). (S)-2-Phenylglycine methyl ester (26) (10.0
g, 60.6 mmol) was dissolved in THF (250 mL) and cooled to 0 °C.
Phenylmagnesium bromide (61 mL, 3 M in ether) was added to the
solution dropwise over 20 min with vigorous stirring. After the addition
was complete the cooling bath was removed and the reaction stirred
for 18 h at room temperature under Ar. The reaction slurry was
quenched at 0 °C by careful addition of saturated NH4Cl solution (100
mL), extracted with EtOAc (3 × 100 mL), dried, and concentrated to
give a yellow oil. This oil was immediately reacted with levulinic
acid using the general lactam procedure, providing, after chromatog-
raphy on silica (EtOAc), lactam (17o) as a light yellow solid in 63%
yield, mp 126-128 °C (hexane/EtOAc). [R]23D: -118.2 (c 1.1, EtOH).
(s, 3H), 2.04 (m, 2H), 2.43 (m, 1H), 2.65 (m, 1H), 3.94 (d, J ) 8.6,
1H), 4.02 (d, J ) 8.6, 1H). 13C NMR (75 MHz): δ 23.4, 24.2, 26.5,
35.5, 36.0, 57.9, 81.7, 101.0, 172.9. Anal. Calcd for C9H15NO2: C,
63.88; H, 8.93. Found: C, 63.65; H, 8.90.
Lactam (8, R ) Me). Isolated as yellow oil in 89% yield. IR
(neat): 2974, 1713 cm-1 1H NMR (300 MHz): δ 0.98 (s, 3H), 1.24
.
(s, 3H), 1.30 (s, 3H), 2.06 (m, 2H), 2.37 (m, 1H), 2.53 (m, 1H), 2.81
(d, J ) 11.6, 1H), 3.74 (d, J ) 11.6, 1H). 13C NMR (75 MHz): δ
26.6, 27.7, 28.0, 32.3, 34.8, 52.8, 81.3, 99.4, 177.4. Anal. Calcd for
C9H15NO2: C, 63.88; H, 8.93. Found: C, 63.95; H, 8.97.
Lactam (17c). Isolated as light yellow oil in 90% yield. IR
(neat): 2974, 1713 cm-1 1H NMR (300 MHz): δ 0.79 (d, J ) 6.7,
.
3H), 0.83 (d, J ) 6.7, 3H), 0.90 (d, J ) 6.7, 3H), 0.95 (d, J ) 6.7,
3H), 1.42 (s, 3H), 1.76 (m, 1H), 2.03 (m, 1H), 2.15 (m, 2H), 2.36 (m,
1H), 2.61 (m, 1H), 2.95 (d, J ) 12.2, 1H), 3.72 (d, J ) 12.2, 1H). 13
C
NMR (75 MHz): δ 17.9, 18.0, 18.4, 18.6, 27.0, 32.7, 33.3, 33.8, 35.8,
44.0, 92.2, 99.4, 175.0. Anal. Calcd for C13H23NO2: C, 69.30; H,
10.29. Found: C, 69.19; H, 10.34.
IR (neat): 3060, 1713 cm-1 1H NMR (300 MHz): δ 1.69 (s, 3H),
.
1.75 (m, 1H), 1.93 (m, 1H), 1.97 (d, J ) 12.5, 1H), 2.46 (m, 1H), 6.17
(s, 1H), 6.94 (m, 10H), 7.17 (m, 1H), 7.27 (t, J ) 7.0, 2H), 7.54 (d, J
) 7.3, 2H). 13C NMR (75 MHz): δ 27.9, 33.0, 37.2, 64.9, 93.8, 101.6,
127.0, 127.1, 127.2, 127.3, 127.7, 127.8, 128.0, 128.7, 129.0, 137.3,
142.4, 144.7, 177.7. Anal. Calcd for C25H23NO2: C, 81.27; H, 6.27.
Found: C, 81.19; H, 6.30.
Lactam (17f). Isolated as colorless solid in 87% yield, mp 95-96
.
°C (hexane/EtOAc). IR (neat): 2977, 1716 cm-1 1H NMR (300
MHz): δ 1.47 (s, 3H), 2.09 (m, 3H), 2.48 (m, 1H), 3.41 (d, J ) 12.3,
1H), 4.90 (d, J ) 12.3, 1H), 7.11-7.33 (m, 10H). 13C NMR (75
MHz): δ 27.1, 32.8, 34.6, 53.0, 89.0, 101.0, 126.1, 126.8, 127.7, 128.0,
128.80, 128.82, 144.1, 145.3, 177.7. Anal. Calcd for C19H19NO2: C,
77.79; H, 6.53. Found: C, 77.66; H, 6.61.
General Procedure for Bicyclic Lactam Alkylation. Lactam
(18a). Lactam 17a (280 mg, 1.66 mmol) was dissolved in THF (20
mL) and cooled to -78 °C. s-BuLi (1.50 mL, 1.1 M in hexane) was
added dropwise to the solution over 5 min. After 2 h benzyl bromide
(0.31 g, 1.82 mmol) was added dropwise over 5 min to the stirred
-78 °C solution. The reaction solution was quenched after an
additional 2 h by addition of saturated aqueous NH4Cl solution (4 mL).
Ethyl acetate (20 mL) was added to the mixture, and the resulting
solution was separated, dried, and concentrated. Purification on silica
(hexanes/EtOAc, 1:1) afforded 370 mg (86%) of 18a as a colorless
Lactam (20). Isolated as colorless crystals in 76% yield, mp 89-
90 °C (hexanes/EtOAc). [R]23D: +65.3° (c 1.4, EtOH). IR (neat):
3407, 2978, 1686 cm-1 1H NMR (300 MHz): δ 1.65 (s, 3H), 2.39
.
(m, 2H), 2.60 (m, 1H), 2.85 (m, 2H), 3.70 (m, 1H), 3.76 (m, 2H), 5.14
(d, J ) 7.6, 1H), 7.35 (m, 5H). 13C NMR (75 MHz): δ 24.8, 33.4,
35.3, 63.1, 65.0, 82.9, 100.1, 126.3, 128.7, 128.8, 178.6. Anal. Calcd
for C14H17NO3: C, 68.00; H, 6.93. Found: C, 68.12; H, 6.97.
General Silylation Procedure. Lactam (21). To a CH2Cl2 solution
(100 mL) of lactam 20 (8.0 g, 33.7 mmol) and TBDPS-Cl (11.1 g,
40.5 mmol) was added neat imidazole (2.8 g, 41.0 mmol) with stirring.
After 24 h at 25 °C the slurry was filtered through Celite and
concentrated. Recrystallization from hexanes/ethyl acetate afforded
lactam 21 (13.9 g, 28.6 mmol) in 85% yield as colorless crystals, mp
127-128 °C (hexanes/EtOAc). [R]23D: +38.7 (c 2.0, EtOH). IR
oil. IR (neat): 2974, 1698 cm-1 1H NMR (300 MHz): δ 1.45 (s,
.
6H), 1.54 (s, 3H), 1.81 (app t, J ) 11.9, 1H), 2.13 (m, 1H), 2.68 (dd,
J ) 13.7, 9.5, 1H), 3.06 (m, 1H), 3.27 (dd, J ) 13.8, 4.3, 1H), 3.92 (d,
J ) 8.5, 1H), 4.03 (d, J ) 8.5, 1H), 7.19-7.35 (m, 5H). 13C NMR
(75 MHz): δ 23.6, 24.7, 26.6, 36.6, 42.7, 48.2, 58.3, 81.6, 98.6, 126.5,
128.7, 129.3, 139.6, 173.9. MS (FAB+): m/z 260 [(M + H)+], 244,
182. HRMS calcd for C16H22NO2 [(M + H)+]: 260.1651. Found:
260.1655.
(neat): 3409, 2976, 1687 cm-1 1H NMR (300 MHz): δ 1.00 (s, 9H),
.
1.53 (s, 3H), 2.23 (m, 2H), 2.49 (m, 1H), 2.74 (m, 1H), 3.75 (m, 1H),
3.87 (m, 2H), 5.30 (d, J ) 6.7, 1H), 7.30 (m, 9H), 7.61 (m, 6H). 13C
NMR (75 MHz): δ 19.5, 25.3, 26.8, 27.1, 33.6, 34.9, 63.9, 64.0, 83.1,
100.5, 126.8, 127.9, 128.0, 128.5, 128.8, 129.8, 130.0, 130.1, 133.1,
133.3, 135.0, 135.8, 135.9, 139.3, 178.3. Anal. Calcd for C19H19-
NO2: C, 74.19; H, 7.26. Found: C, 74.04; H, 7.31.
Lactam (17m). Succinic anhydride (5.2 g, 51.5 mmol) and (+)-
2-amino-1-phenyl-1,3-propanediol (19) (8.6 g, 51.5 mmol) were
dissolved in xylenes (1 L), and the mixture was heated to reflux for 1
h. Triethylamine (15 mL) was added, and the reaction mixture was
further heated for 36 h, after which the volatiles were removed by
atmospheric distillation. The resulting colorless oil was triturated with
EtOH/EtOAc to give a colorless solid 28. The crude colorless
compound was dissolved in ethanol (100 mL) and cooled to 0 °C.
NaBH4 (9.5 g, 250 mmol) was added with stirring. Hydrochloric acid
(2 M) in ethanol was added (∼0.15 mL per minute) over a 3-h period
until 1 equiv of acid was added (51.5 mmol). The solution was acidified
to a pH of 1-3 by addition of 2 M HCl in ethanol, affording a white
Lactam (18b). Isolated as a colorless oil in 89% yield. IR (neat):
2976, 1707 cm-1 1H NMR (300 MHz): δ 0.61 (s, 3H), 1.30 (s, 3H),
.
1.44 (s, 3H), 1.98 (d, J ) 13.7, 1H), 2.40 (m, 2H), 2.75 (d, J ) 13.7,
1H), 2.94 (d, J ) 11.5, 1H), 3.04 (d, J ) 13.4, 1H), 3.81 (d, J ) 11.7,
1H), 5.17 (m, 2H), 5.84 (m, 1H), 7.21 (m, 5H). 13C NMR (75 MHz):
δ 27.7, 28.6, 42.0, 42.3, 43.4, 52.8, 53.2, 80.7, 96.9, 119.2, 126.7, 128.3,
131.4, 133.8, 137.4, 180.4. MS (FAB+): m/z 300 [(M + H)+], 284.
HRMS calcd for C19H26NO2 [(M + H)+]: 300.1964. Found: 300.1967.
Lactam (18c). Isolated as a colorless oil in 91% yield. IR (neat):
2965, 1707 cm-1 1H NMR (300 MHz): δ 0.88 (app t, J ) 7.0, 6H),
.
0.99 (app t, J ) 7.0, 6H), 1.23 (s, 3H), 1.81 (m, 1H), 2.05 (m, 2H),
2.43 (dd, J ) 14.0, 10.1, 1H), 3.01 (m, 4H), 3.89 (d, J ) 12.2, 1H),
7.27 (m, 5H). 13C NMR (75 MHz): δ 17.9, 18.1, 18.5, 18.6, 28.8,
33.4, 33.6, 37.5, 38.7, 45.3, 46.9, 91.3, 98.5, 126.5, 128.4, 129.1, 138.6,
178.1. MS (FAB+) m/z 316 [(M + H)+]: 272. HRMS calcd for
C20H30NO2 [(M + H)+]: 316.2276. Found: 316.2269.

StereoselectiVe Alkylations in Rigid Systems
J. Am. Chem. Soc., Vol. 120, No. 30, 1998 7437
Lactam (18d). Isolated as a colorless solid in 93% yield, mp 65-
H)+]: 574. HRMS calcd for C40H46NO3Si [(M + H)+]: 616.3247.
Found: 616.3247.
66 °C (hexanes). IR (neat): 2962, 1709 cm-1 1H NMR (300 MHz):
.
δ 0.53 (d, J ) 6.7, 3H), 0.74 (d, J ) 6.7, 3H), 0.95 (m, 6H), 1.50 (s,
3H), 2.02 (m, 2H), 2.32 (d, J ) 13.4, 1H), 2.47 (m, 2H), 2.74 (d, J )
13.7, 1H), 2.96 (d, J ) 11.9, 1H, 3.05 (d, J ) 13.7, 1H), 3.84 (d, J )
11.9, 1H), 5.20 (m, 2H), 5.93 (m, 1H), 7.25 (m, 5H). 13C NMR (75
MHz): δ 17.0, 19.1, 19.2, 28.2, 31.8, 34.6, 40.3, 42.8, 44.0, 45.2, 52.9,
90.5, 96.2, 118.8, 126.4, 128.0, 131.2, 133.6, 137.3, 179.0. Anal. Calcd
for C23H33NO2: C, 77.70; H, 9.36. Found: C, 77.89; H, 9.34.
Lactam (18f). Isolated as a yellow oil in 94% yield. IR (neat):
Lactam (18m). Isolated as a colorless solid in 85% yield, mp 109-
110 °C (hexane/EtOAc). [R]23D: ) +8.2 (c 0.8, EtOH). IR (neat):
3029, 2930, 1716 cm-1 1H NMR (300 MHz): δ 1.06 (s, 9H), 2.07
.
(m, 1H), 2.25 (m, 1H), 2.80 (dd, J ) 13.7, 9.1, 1H), 3.04 (m, 1H),
3.19 (dd, J ) 13.7, 4.5, 1H), 3.78 (m, 1H), 3.90 (m, 1H), 4.05 (m,
1H), 5.06 (d, J ) 6.1, 1H), 5.14 (dd, J ) 4.6, 1.2, 1H), 7.20 (m, 10H),
7.34 (m, 6H), 7.64 (d, J ) 6.5, 4H). 13C NMR (75 MHz): δ 19.1,
26.8, 29.3, 37.7, 44.2, 63.5, 64.5, 82.3, 91.5, 126.2, 126.5, 127.7, 128.1,
128.4, 128.5, 128.9, 129.7, 129.8, 132.8, 135.5, 138.3, 139.1, 181.4.
Anal. Calcd for C36H39NO3Si: C, 76.97; H, 7.00. Found: C, 76.63;
H, 6.95.
3026, 2978, 1714 cm-1 1H NMR (300 MHz): δ 1.24 (s, 3H), 1.91
.
(dd, J ) 14.3, 4.8, 1H), 2.40 (m, 1H), 2.62 (m, 1H), 2.79 (m, 1H),
2.95 (dd, J ) 13.5, 4.8, 1H), 3.57 (d, J ) 12.2, 1H), 4.98 (d, J ) 11.9,
1H), 7.09-7.38 (m, 15H). 13C NMR (75 MHz) δ 27.3, 37.0, 37.2,
44.9, 53.9, 87.7, 99.3, 125.5, 126.0, 126.4, 127.1, 127.3, 128.1, 128.3,
129.0, 138.3, 144.0, 145.0, 180.3. MS (FAB+) m/z 384 [(M + H)+]:
201. HRMS calcd for C26H26NO2 [(M + H)+]: 384.1963. Found:
384.1959.
Lactam (18n). Isolated as a yellow oil in 90% yield. [R]23D: )
+60.0 (c 1.0, EtOH). IR (neat): 3069, 2929, 1706 cm-1 1H NMR
.
(300 MHz): δ 1.02 (s, 9H), 2.20 (m, 3H), 2.50 (dd, J ) 13.4, 6.4,
1H), 2.63 (d, J ) 13.4, 1H), 3.15 (d, J ) 13.4, 1H), 3.65 (m, 2H), 3.91
(dd, J ) 10.7, 3.6, 1H), 5.05 (d, J ) 6.5, 1H), 5.11 (m, 2H), 5.81 (m,
1H), 6.73 (dd, J ) 7.9, 2.1), 7.10-7.38 (m, 16H), 7.60 (m, 4H). 13C
NMR (75 MHz): δ 19.3, 26.9, 33.9, 42.5, 44.0, 53.7, 62.9, 63.7, 82.5,
90.3, 119.1, 126.3, 126.5, 127.8, 127.9, 128.2, 128.4, 128.5, 129.9,
130.0, 131.1, 132.9, 133.4, 135.6, 135.7, 137.6, 139.0, 179.9. MS
(FAB+) m/z 602 [(M + H)+]: 544, 524, 135. HRMS calcd for C39H44-
NO3Si [(M + H)+]: 602.3090. Found: 602.3087.
Lactam (18 g). Isolated as a yellow oil in 95% yield. IR (neat):
3027, 2977, 1712 cm-1 1H NMR (300 MHz): δ 1.54 (s, 3H), 1.79
.
(d, J ) 11.8, 1H), 1.86 (d, J ) 12.0, 1H), 2.15 (m, 1H), 2.40 (dd, J )
13.5, 6.4, 1H), 2.52 (d, J ) 14.0, 1H), 2.67 (d, J ) 13.7, 1H), 3.58 (d,
J ) 11.9, 1H), 5.11 (m, 2H), 5.76 (m, 1H), 7.03 (m, 2H), 7.19-7.48
(m, 13H). 13C NMR (75 MHz): δ 27.3, 41.5, 41.8, 42.8, 51.3, 52.9,
87.8, 97.8, 118.8, 125.5, 126.4, 126.6, 127.2, 127.5, 128.0, 128.30,
128.33, 130.5, 133.9, 137.2, 143.7, 145.3, 181.4. MS (FAB+) m/z 424
[(M + H)+]: 241. HRMS calcd for C29H30NO2 [(M + H)+]; 424.2277.
Found: 424.2278.
Lactam (18o). Isolated as a light yellow solid in 92% yield, mp
118-119 °C (hexane/EtOAc). [R]23D: -114.5 (c 0.4, CHCl3). IR
(neat): 3062, 1713 cm-1 1H NMR (300 MHz): δ 1.81 (s, 3H), 1.96
.
(d, J ) 13.3, 1H), 2.13-2.30 (m, 3H), 2.50 (m, 1H), 5.02 (d, J ) 4.9,
1H), 5.08 (s, 1H), 5.69 (m, 1H), 6.34 (s, 1H), 7.07 (m, 10H), 7.27 (t,
J ) 6.9, 1H), 7.35 (t, J ) 7.0, 2H), 7.66 (d, J ) 7.4, 2H). 13C NMR
(75 MHz): δ 31.0, 36.2, 40.2, 43.6, 66.1, 93.0, 99.8, 117.2, 126.9,
127.0, 127.2, 127.4, 127.6, 127.7, 128.3, 129.0, 135.3, 136.8, 142.1,
144.3, 181.0. MS (FAB+) m/z 410 [(M + H)+]: 227. HRMS calcd
for C28H28NO2 [(M + H)+]: 410.2120. Found: 410.2113.
Lactam (17j). Isolated as colorless oil in 91% yield. [R]23D: -35.1
(c 1.1, EtOH). IR (neat): 1711 cm-1 1H NMR (300 MHz): δ 0.64
.
(s, 3H), 1.08 (s, 9H), 1.72 (app t, J ) 11.9, 1H), 2.01 (m, 1H), 2.47
(dd, J ) 11.9, 10.3, 1H), 2.91 (m, 1H), 3.30 (dd, J ) 14.1, 4.0, 1H),
3.82 (dd, J ) 9.2, 7.7, 1H), 3.93 (dd, J ) 9.4, 7.6, 1H), 4.30 (app q,
J ) 7.6, 1H), 4.96 (d, J ) 7.6, 1H), 7.11-7.44 (m, 16H), 7.74 (m,
4H). 13C NMR (75 MHz): δ 19.1, 19.4, 23.4, 26.7, 27.0, 36.5, 42.3,
46.3, 59.8, 67.9, 76.0, 97.9, 126.3, 126.6, 127.4, 127.6, 127.7, 127.8,
127.9, 128.1, 128.5, 128.8, 129.5, 129.6, 129.8, 133.2, 133.7, 134.9,
135.5, 136.0, 136.1, 139.5, 139.8, 178.4. MS (FAB+) m/z 576 [(M +
H)+]: 519, 498, 135. HRMS calcd for C37H42NO3Si [(M + H)+]:
576.2934. Found: 576.2928.
Lactam (18p). Isolated as a light yellow solid in 93% yield, mp
155-156 °C (hexane/EtOAc). [R]23D: -131.2 (c 0.4, CHCl3). IR
(neat): 3062, 3029, 1712 cm-1 1H NMR (300 MHz) δ 1.25 (s, 3H),
.
2.19 (dd, J ) 13.9, 7.5, 1H), 2.27 (d, J ) 14.2, 1H), 2.51 (d, J ) 14.2,
1H), 2.93 (d, J ) 13.4, 1H), 3.20 (d, J ) 13.4, 1H), 5.01 (dd, J )
17.0, 1.2, 1H), 5.12 (dd, J ) 10.0, 1.2, 1H), 5.56 (m, 1H), 6.57 (s,
1H), 7.00 (d, J ) 7.3, 2H), 7.17-7.29 (m, 8H), 7.41-7.56 (m, 6H),
7.62 (t, J ) 7.7, 2H), 7.93 (d, J ) 7.3, 2H). 13C NMR (75 MHz): δ
29.2, 41.9, 42.7, 43.8, 52.0, 66.4, 93.1, 98.0, 118.9, 126.7, 127.2, 127.5,
127.6, 127.8, 128.3, 128.4, 128.5, 130.7, 133.3, 137.1, 137.5, 141.8,
144.3, 182.2. MS (FAB+) m/z 500 [(M + H)+]: 317. HRMS calcd
for C35H34NO2 [(M + H)+]: 500.2590. Found: 500.2595.
Lactam (18i). Isolated as a colorless oil in 91% yield. [R]23
:
D
-66.2 (c 1.5, EtOH). IR (neat): 3069, 2962, 1711 cm-1 1H NMR
.
(300 MHz): δ 1.05 (s, 9H), 1.06 (s, 3H), 1.37 (s, 3H), 2.00 (d, J )
14.0, 1H), 2.31 (d, J ) 14.0, 1H), 2.65 (d, J ) 13.5, 1H), 3.10 (d, J )
13.4, 1H), 3.52 (m, 1H), 4.25 (dd, J ) 11.2, 3.6, 1H), 4.70 (dd, J )
11.6, 4.6, 1H), 4.98 (d, J ) 8.3, 1H), 7.05-7.72 (m, 20H). 13C NMR
(75 MHz): δ 19.1, 26.9, 27.4, 43.8, 49.3, 58.3, 64.5, 82.2, 97.2, 126.3,
126.7, 127.7, 127.8, 128.3, 128.4, 129.7, 129.8, 130.5, 133.0, 133.3,
135.8, 135.9, 137.8, 139.6, 179.0. MS (FAB+) m/z 590 [(M + H)+]:
532, 512. HRMS calcd for C38H44NO3Si [(M + H)+]: 590.3090.
Found: 590.3087.
Lactam (2, R ) i-Pr, R1 ) Bn, R2 ) CH3). Isolated as a colorless
oil in 91% yield. [R]23D: -74.2 (c 1.2, EtOH). IR (neat): 2960, 1710
cm-1 1H NMR (300 MHz): δ 0.73 (s, 3H), 0.81 (d, J ) 6.7, 3H),
.
1.03 (d, J ) 6.7, 3H), 1.25 (s, 3H), 1.47 (m, 1H), 1.97 (d, J ) 14.1,
1H), 2.15 (d, J ) 14.1, 1H), 2.55 (d, J ) 13.1, 1H), 3.05 (d, J ) 13.4,
3H), 3.60 (m, 2H), 4.11 (m, 1H), 7.14-7.29 (m, 5H). 13C NMR (75
MHz): δ 18.9, 20.7, 23.8, 27.1, 34.3, 43.5, 45.2, 49.1, 62.5, 70.0, 96.6,
126.7, 128.2, 130.3, 137.6, 183.9. MS (FAB+) m/z 288 [(M + H)+]:
272. HRMS calcd for C18H26NO2 [(M + H)+]: 288.1964. Found:
288.1964.
Lactam (18j). Isolated as a colorless oil in 87% yield. [R]23
:
D
+63.8 (c 1.9, EtOH). IR (neat): 3067, 2965, 1709 cm-1 1H NMR
.
(300 MHz): δ 1.12 (s, 9H), 1.60 (s, 3H), 2.09 (d, J ) 13.8, 1H), 2.60
(m, 4H), 3.24 (d, J ) 13.4, 1H), 3.81 (m, 2H), 3.94 (m, 1H), 5.15 (d,
J ) 6.7, 1H), 5.23 (m, 2H), 5.93 (m, 1H), 6.81 (d, J ) 8.0, 2H), 7.19-
7.44 (m, 14H), 7.71 (m, 4H). 13C NMR (75 MHz): δ 19.3, 26.3, 27.0,
41.2, 41.7, 44.1, 53.5, 64.0, 64.9, 81.6, 97.3, 119.3, 126.5, 127.9, 128.0,
128.2, 128.5, 128.6, 129.9, 130.0, 131.3, 133.0, 133.2, 133.7, 135.7,
135.8, 135.9, 137.7, 139.3, 181.7. MS (FAB+) m/z 616 [(M + H)+]:
574. HRMS calcd for C40H46NO3Si [(M + H)+]: 616.3247. Found:
616.3245.
Ketoester (22). Isolated as a colorless oil in 71% yield from lactam
(21). [R]23D: -5.3 (c 1.1, CHCl3). IR (neat): 2960, 1718, 1684 cm-1
.
1H NMR (300 MHz): δ 0.91 (t, J ) 7.4, 3H), 1.22 (s, 3H), 1.30 (m,
2H), 1.55 (m, 2H), 2.09 (s, 3H), 2.55 (d, J ) 18.0, 1H), 2.79 (d, J )
18.0, 1H), 2.92 (m, 2H), 4.05 (t, J ) 6.4, 2H), 7.06 (m, 2H), 7.26 (m,
3H). 13C NMR (75 MHz): δ 13.6, 19.1, 22.2, 30.5, 44.2, 44.6, 50.3,
64.4, 126.6, 128.0, 130.3, 137.0, 176.3, 206.2. MS (FAB+) m/z 277
[(M + H)+]: 203. HRMS calcd for C17H25O3 [(M + H)+]: 277.1804.
Found: 277.1809.
Lactam (18k). Isolated as a colorless oil in 88% yield. [R]23
:
D
+11.8 (c 1.3, EtOH). IR (neat): 3067, 2965, 1709 cm-1 1H NMR
.
(300 MHz): δ 0.87 (s, 3H), 1.05 (s, 9H), 2.06 (d, J ) 14.4, 1H), 2.27
(m, 1H), 2.44 (d, J ) 14.3, 1H), 2.59 (m, 1H), 2.65 (d, J ) 13.5, 1H),
3.08 (d, J ) 13.4, 1H), 3.71-3.98 (m, 3H), 5.05 (d, J ) 7.0, 1H), 5.15
Cyclopentenone (23). To a -78 °C THF solution (60 mL) of lactam
(21) (4.02 g, 6.54 mmol) was added Red-Al (1.95 mL, 3.4 M in toluene)
over 15 min. The -78 °C bath was replaced with a 0 °C cooling bath,
and the reaction was monitored for the disappearance of starting material
by TLC. After 6 h the reaction was quenched by the addition of
methanol (1.5 mL), concentrated, extracted with EtOAc (3 × 50 mL),
(m, 2H), 5.73 (m, 1H), 7.19 (m, 10H), 7.35 (m, 6H), 7.68 (m, 4H). 13
C
NMR (75 MHz): δ 19.1, 24.8, 26.7, 40.7, 43.2, 44.0, 53.2, 63.8, 64.9,
80.9, 97.3, 119.3, 126.2, 126.7, 127.7, 128.0, 128.1, 128.3, 129.7, 130.4,
132.8, 133.9, 135.5, 137.0, 139.3, 182.1. MS (FAB+) m/z 616 [(M +

7438 J. Am. Chem. Soc., Vol. 120, No. 30, 1998
Meyers et al.
washed with 10% aqueous NaOH and H2O, then dried and concentrated.
The resulting crude residue was dissolved in EtOH (125 mL) and
aqueous 1 M Bu4NH2PO4 solution (125 mL) and stirred at room
temperature for 36 h. The reaction solution was concentrated, extracted
with ether, dried, and concentrated. The resulting yellow oil was
dissolved in 100 mL of THF, and 1.5 mL of 1 M KOH in ethanol was
added. After 2 h the reaction solution was diluted with ether (75 mL),
washed with H2O, dried, and concentrated. Purification on silica
(hexane/EtOAc, 4:1) afforded cyclopentenone (23) as a colorless oil
MS (FAB+) m/z 213 [(M + H)+]: 171. HRMS calcd for C25H16O
[(M + H)+]:213.1279. Found: 213.1278.
Acknowledgment. This paper is dedicated to Professor E.
J. Corey on the occasion of his 70th birthday. A.I.M. and M.A.S.
are grateful to the National Institutes of Health and the National
Science Foundation for financial support of this study.
Supporting Information Available: 1H NMR and 13C NMR
spectra for all compounds, complete X-ray structural parameters
(bond angles, etc.) for 12, and chiral HPLC of lactam 17o, both
enantiomers (62 pages, print/PDF). See any current masthead
page for ordering information and Web access instructions.
23
in 69% yield. [R]23D: -62.6 (c 1.7, EtOH), (lit.13 [R]D -64.1). IR
(neat): 3028, 2916, 1714 cm-1 1H NMR (300 MHz): δ 2.27 (d, J )
.
1.5, 2H), 2.30 (m, 2H), 2.77 (d, J ) 3.4, 1H), 2.90 (d, J ) 3.4, 1H),
5.06 (m, 2H), 5.65 (m, 1H), 6.04 (d, J ) 5.8, 1H), 7.07 (m, 2H), 7.25
(m, 3H), 7.44 (d, J ) 5.8, 3H). 13C NMR (75 MHz): δ 42.8, 44.6,
45.3, 49.1, 119.3, 126.7, 128.2, 130.3, 133.2, 133.4, 136.7, 170.2, 213.0.
JA980614S