Short stereoselective synthesis of α-substituted γ-lactams

Article abstract of DOI:10.1021/jo052212q

A concise, stereoselective synthesis of α-substituted γ-lactams is reported. γ-Lactam scaffolds 2 and 3, possessing an Evans' chiral auxiliary and two types of N substituents, were successfully alkylated with different electrophiles to give α-substituted

Full text of DOI:10.1021/jo052212q

current methods for the synthesis of R-substituted γ-lactams are
linear in their approach. Thus, there is a need for a more efficient
and versatile approach for such syntheses.
Short Stereoselective Synthesis of r-Substituted
γ-Lactams
Bhooma Raghavan and Rodney L. Johnson*
Department of Medicinal Chemistry, UniVersity of Minnesota,
308 HarVard Street Southeast, Minneapolis, Minnesota 55455
johns022@umn.edu
ReceiVed October 24, 2005
Recently, Palomo et al.9 constructed R-substituted â-lactams
in a stereoselective manner with template 1. We felt that such
an approach could be adapted to the more commonly used
γ-lactam scaffold, thereby providing a method for the stereo-
selective synthesis of the highly desirable R-substituted γ-lac-
tams. Such a method would greatly enhance the utility of the
γ-lactam scaffold in peptidomimetic design. Because the
synthetic approach used for template 1 was not deemed
applicable for the γ-lactam system, compounds 2 and 3 were
designed to serve as potential templates for the stereoselective
synthesis of R-alkylated γ-lactams.
In 2, the 4-methoxy-benzyl moiety was incorporated as the
lactam N substituent in our initial studies because of its ready
availability and its ease of removal. We recognized, however,
that template 2 suffered from the same drawback as template 1
in that for both lactam templates to serve as useful synthetic
dipeptide isosteres, the lactam N substituent first needed to be
removed before the lactam could be N alkylated with a suitable
carboxymethyl derivative. We felt that the versatility of a
template like 2 could be enhanced if the N substituent was a
masked carboxymethyl moiety that when unmasked would
provide a dipeptide isostere. The use of the 4-methyl-2,6,7-
trioxabicyclo[2.2.2]-oct-1-yl (OBO) ester10 in the synthetic
approach would fulfill this requirement and thus provide
template 3. The advantages of this functionality were viewed
to be (1) an ease of formation and cleavage, (2) a stability to
strong nucleophilic and basic conditions, and (3) an ability to
decrease the acidity of the R proton of the amino acid, making
it resistant to deprotonation, thus providing regioselectivity
during alkylation.
A concise, stereoselective synthesis of R-substituted γ-lac-
tams is reported. γ-Lactam scaffolds 2 and 3, possessing an
Evans’ chiral auxiliary and two types of N substituents, were
successfully alkylated with different electrophiles to give
R-substituted γ-lactams with reasonable diastereoselectivities.
The use of a masked carboxymethyl function off the lactam
nitrogen provided a convergent means to R-substituted
γ-lactam dipeptide isosteres.
γ-Lactams, with their ψ angle constrained, are important
constituents of â-turn peptidomimetics. Our ongoing research
on the synthesis of unsubstituted1,2 and substituted3 γ-lactam
peptide isosteres as Pro-Leu-Gly-NH2 mimics led us to
reinvestigate the existing synthetic methodologies to this scaf-
fold. Over the years, several approaches have been used for the
synthesis of peptidomimetics containing lactam scaffolds. One
method of obtaining the lactam is through a route established
by Freidinger et al.,4 involving the formation of a sulfonium
salt followed by a subsequent intramolecular cyclization. Other
widely used approaches are reductive amination followed by
thermal cyclization5 and an intramolecular Mitsunobu reaction.6
For R-substituted γ-lactams, the stereoselective synthesis of R,R-
dialkyl amino acids has to be achieved prior to their incorpora-
tion into the lactam by the above methods.5,7,8 In short, the
The synthesis of template 2 and its R-alkylation reaction is
outlined in Scheme 1. The starting material, 2,4-dibromobutyryl
chloride (4), was synthesized from γ-butyrolactone by a slight
modification of a reported procedure.11 This was then condensed
with 4-methoxy-benzylamine in the presence of NaOH and
tetrabutylammonium hydrogen sulfate as a phase-transfer cata-
lyst to give lactam 5.12 The bromolactam, after purification by
(1) Yu, K.; Rajakumar, G.; Srivastava, L. K.; Mishra, R. K.; Johnson,
R. L. J. Med. Chem. 1988, 31, 1430-1436.
(2) Sreenivasan, U.; Mishra, R. K.; Johnson, R. L. J. Med. Chem. 1993,
36, 256-263.
(3) Dolbeare, K.; Pontoriero, G. F.; Gupta, S. K.; Mishra, R. K.; Johnson,
R. L. J. Med. Chem. 2003, 46, 727-733.
(4) Freidinger, R. M.; Schwenk, D.; Veber, D. F. J. Org. Chem. 1982,
47, 104-109.
(8) Scheidt, K. A.; Roush, W. R.; McKerrow, J. H.; Selzer, P. M.;
Hansell, E.; Rosenthal, P. J. Bioorg. Med. Chem. 1998, 6, 2477-2494.
(9) Palomo, C.; Aizpurua, J. M.; Benito, A.; Miranda, J. I.; Fratila, R.
M.; Matute, C.; Domercq, M.; Gago, F.; Martin-Santamaria, S.; Linden,
A. Angew. Chem., Int. Ed. 1999, 38, 3056-3058.
(10) Corey, E. J.; Raju, N. Tetrahedron Lett. 1983, 24, 5555-5680.
(11) Ikuta, H.; Shirota, H.; Kobayashi, S.; Yamagishi, Y.; Yamada, K.;
Yamatsu, I.; Katayama, K. J. Med. Chem. 1987, 30, 1995-1998.
(5) Zydowsky, T. M.; Dellaria, J. F., Jr.; Nellans, H. N. J. Org. Chem.
1988, 53, 5607-5616.
(6) Genin, M. J.; Gleason, W. B.; Johnson, R. L. J. Org. Chem. 1993,
58, 860-866.
(7) Thaisrivongs, S.; Pals, D. T.; Turner, S. R.; Kroll, L. T. J. Med. Chem.
1988, 31, 1369-1376.
10.1021/jo052212q CCC: $33.50 © 2006 American Chemical Society
Published on Web 02/02/2006
J. Org. Chem. 2006, 71, 2151-2154
2151

SCHEME 1. Synthesis of γ-Lactam Template 2 and Its
r-Alkylated Derivatives
lized with CH2Cl2/MeOH/EtOAc. The stereochemistry of the
isomer was determined by X-ray crystallography to have the
predicted R stereochemistry about the R carbon of the γ lactam
(Figure 1 in Supporting Information).
In the alkylation of 2 with formaldehyde, it could be argued
that the alkylation might occur in a different stereochemical
fashion by virtue of a lithium-oxygen coordination. The results
of the NOESY and ROESY studies were inconclusive in
ascertaining the stereochemistry at the γ-lactam R carbon of
7c. The relative stereochemistry of this center was assigned as
R on the basis of (1) our belief that the formation of a six-
membered transition state comprised of formaldehyde, lithium,
and the carbonyl oxygen of the enolate would more likely form
on the si face, away from the steric bulk of the phenyl group
on the re face, (2) the X-ray structure of the benzyl derivative
7a , and (3) a previous report of the stereodirecting effects of
Evans’ auxiliary with the formaldehyde alkylation of enolates.18
HMPA and LiCl were added to several trials to determine
their effects on the alkylation diastereoselectivity. The presence
of HMPA in the trial with benzyl bromide as the electrophile
led to a reduction in the diastereomeric ratio of 7a and 8a to
3:2. When LiCl was used in the alkylation reaction with allyl
bromide, no change in the diastereomeric ratio of 7d and 8d
was seen.
On the basis of the alkylation results with template 2, we
decided to explore template 3. The synthesis of template 3 is
outlined in Scheme 2. This approach required the synthesis of
the OBO ortho ester derivative of glycine: compound 13. This
was accomplished by adapting literature procedures to Cbz-
glycine (9). Cbz-glycine was coupled to 3-methyl-3-oxetane
methanol (10) with DCC and catalytic amounts of 4-DMAP to
give the oxetane ester 11.19 The order of addition of the reagents,
that is, addition of small portions of acid 9 to the reaction
mixture containing DCC, 4-DMAP, and Cbz-glycine, was
important to minimize the formation of an imide between the
carbamate nitrogen and the acid function of another molecule
of glycine. The oxetane ester (11) was then treated with BF3‚
Et2O to give the compound 12.10 Hydrogenolysis of 12 yielded
the glycine OBO ester 13. The reaction of the amino ortho ester
13 with 2,4-dibromobutyryl chloride (4) yielded R-bromolactam
14. Initially, we used the same conditions that were used for
4-methoxy-benzylamine. However, the OBO group was cleaved
under these conditions, indicating the need for increased
equivalents of a base that was soluble in the reaction solvent.
The use of DBU and 4-DMAP led to the desired R-bromolactam
14, but over time or on standing, a SN2 attack was observed at
the R position. The nonnucleophilic, nonquaternizable base,
pentamethyl piperidine,20 was found to be much more suitable
for the reaction. After bromolactam 14 was purified on a Florisil
column, it was coupled with Evans' auxiliary 6 to give 3 as a
mixture of diastereoisomers.
TABLE 1. Yields and Diastereomeric Ratios Obtained upon the
Alkylation of Template 2 with Different Electrophiles
electrophile
yield (%)
ratio
PhCH2Br
CH3I
paraformaldehyde
HCHO
allyl bromide
PhCH2Br (HMPA, 1 equiv)
allyl bromide (LiCl, 10 equiv)
60
80
33
75
80
60
80
7a:8a ) 6:1
7b:8b ) 6:1
7c only
7c:8c ) 5:1
7d:8d ) 6:1
7a:8a ) 3:2
7d:8d ) 6:1
column chromatography, was coupled to Evans’ chiral auxiliary
(S)-4-phenyl-2-oxazolidinone (6)13-15 using NaH to give tem-
plate 2 as a mixture of diastereoisomers.
The lithium enolate of 2 in THF was subjected to alkylation
with different electrophiles to give R-alkylated γ lactams 7a-d
and 8a-d. The yields and diastereomeric ratios for these
alkylations are reported in Table 1. In most cases, both of the
diastereomers were isolated, with isomer 7 always predominat-
ing. The relative stereochemistry of 7 and 8 was predicted on
the basis of the known directing effects of the (S)-4-phenyl-2-
oxazolidinone chiral auxiliary.9,16,17 This was verified in the case
where benzyl bromide was used as the electrophile. The major
diastereomer of the benzyl alkylated product, 7a, was crystal-
The alkylation of 3 was carried out in a manner similar to
that used with 2. The results of the alkylation are shown in
Table 2. Although the yields of alkylation with benzyl bromide
were lower as compared to those of the alkylation of 2, the
diastereoselectivity was much greater. As in the alkylation of
2, the relative stereochemistries of 15 and 16 were predicted
(12) Abrecht, S. Preparation of R-bromolactams. Eur. Pat. Appl. EP
864564, 1998.
(13) Mackennon, M. J.; Meyers, A. I. J. Org. Chem. 1993, 58, 3568-
3571.
(14) Wu, Y.; Shen, X. Tetrahedron: Asymmetry 2000, 11, 4359-4363.
(15) Lewis, N.; McKillop, A.; Taylor, R. J. K.; Watson R. J. Synth.
Commun. 1995, 25, 561-568.
(18) Evans, D. A.; Urpi, F.; Somers, T. C.; Clark, J. S.; Bilodeau, M. T.
J. Am. Chem. Soc. 1990, 112, 8215-8216.
(19) Herdeis, C.; Kelm, B. Tetrahedron 2002, 59, 217-229.
(20) Sommer, H. Z.; Lipp, H. I.; Jackson, L. J. J. Org. Chem. 1971, 36,
824-828.
(16) Evans, D. A.; Ennis, M. D.; Mathre, D. J. J. Am. Chem. Soc. 1982,
104, 1737-1739.
(17) Evans, D. A. Aldrichimica Acta 1982, 15, 23-32.
2152 J. Org. Chem., Vol. 71, No. 5, 2006

SCHEME 2. Synthesis of γ-Lactam Template 3 and Its
r-Alkylated Derivatives
SCHEME 3. Conversion of 16b to the γ-Lactam Dipeptide
Isostere 18
electrophile. The use of LiCl in the reaction did not improve
the ratio significantly. When allyl bromide was used as the
electrophile, it was observed that the temperature at which the
enolate was formed played an important role in the diastereo-
selectivity. In comparison with the results seen with 2, the size
of the electrophile also seemed to be a determinant in the
diastereoselectivity seen with 3. A possible reason for the
generally consistent results seen in the alkylation of 2 could be
intramolecular stacking interactions between the phenyl groups,
thereby providing even greater steric hindrance to attack from
the bottom face.
To convert 15 and 16 to their dipeptide isosteres, which are
amenable to functionalization, the chiral auxiliary and the OBO
ortho ester have to be cleaved. In the present study, the OBO
ortho ester was readily converted to the desired carboxylic acid,
as illustrated by the treatment of 16b with TFA/CH2Cl2,
followed by exposure to 10% Cs2CO3 solution to obtain acid
17 (Scheme 3).21 The cleavage of Evans’ auxiliary from acid
9
17 was achieved by Li/NH3 to give the R-methyl-γ-lactam
dipeptide isostere 18.
In summary, we have devised a versatile and concise
stereoselective synthetic route to R-substituted γ lactams with
both the N- and the C-terminal ends of the lactam open to a
variety of modifications capable of providing lactam-based
peptidomimetics. Furthermore, this method potentially can be
extended to the six-membered lactams by the use of the higher
homologue of 4.
TABLE 2. Yields and Diastereomeric Ratios Obtained upon the
Alkylation of Template 3 with Different Electrophiles
electrophile
yield (%)
ratio
PhCH2Bra
45
80
80
80
50
15a:16a ) 19:1
15b:16b ) 3:1
15b:16b ) 3:1
15c:16c ) 4:1b; 7:1a
15d:16d ) 1:1
CH3Ib
CH3I (10 equiv LiCl)b
allyl bromide
HCHOb
Experimental Section
a Addition of a solution of 3 to a LDA solution at -78 °C. b Addition
of 3 as a solid to a LDA solution at -78 °C, stirring at -40 °C for 20 min
and then at -78 °C for 30 min before the addition of the electrophile.
Bromo-1-(4-methyl-2,6,7-trioxa-bicyclo[2.2.2]oct-1-ylmethyl)-
pyrrolidin-2-one (14). The glycine OBO ester (13, 4.5 g, 28.3
mmol) was dissolved in 200 mL of dry CH2Cl2 under nitrogen. To
this solution was added NaOH (4.5 g, 113.2 mmol), K2CO3 (7 g,
50 mmol), and pentamethyl piperidine (15 mL, 84.9 mmol). A
solution of 4 (7.9 g, 28.3 mmol) in 20 mL of CH2Cl2 was added
dropwise to the reaction with vigorous stirring over a period of 10
min. The reaction mixture started refluxing slightly. The reaction
was then refluxed overnight. The next day, ice was added to the
reaction, and the layers were separated. The aqueous layer was
washed with CH2Cl2 (2 × 100 mL). The combined organic layers
were dried over Na2SO4 and then concentrated under vacuum to
on the basis of the known directing effects of Evans' chiral
auxiliary. The predicted stereochemistry of the major isomer
formed with benzyl bromide as the electrophile; compound 15a,
was confirmed by X-ray crystallography to be the R configu-
ration about the R carbon of the γ lactam (Figure 2 in Supporting
Information).
A lower ratio of diastereoselectivity was seen with methyl
iodide and formaldehyde. The decrease in diastereoselectivity
with methyl iodide was comparable to that reported by Palomo
et al.9 The reason for this could be the smaller size of the
(21) Blaskovich, M. A.; Lajoie, G. A. J. Am. Chem. Soc. 1993, 115,
5021-5030.
J. Org. Chem, Vol. 71, No. 5, 2006 2153

give a reddish brown residue. The residue was then adsorbed onto
Florisil, which was then loaded on a Florisil column and eluted
with EtOAc/hexanes (1:1), followed by EtOAc/hexanes (2:1) to
give the product in a 60% yield as a white solid, which also had
some contamination with pentamethylpiperidine. TLC Rf 0.32
(EtOAc/hexanes, 2:1); 1H NMR (CDCl3, COSY assignment) δ 0.75
(s, 3H), 2.17-2.26 (m, 1H), 2.46-2.58 (m, 1H), 3.37 (d, 1H, J )
14.1 Hz), 3.55-3.62 (m, 2H), 3.55 (d, 1H, J ) 14.7 Hz), 3.83 (s,
6H), 4.36 (dd, 1H, J ) 2.85, 7.35 Hz); 13C NMR (CDCl3, HMQC
assignment) δ 14.8, 30.8, 30.9, 44.6, 46.7, 47.6, 72.8, 107.5, 171.3;
ESI HRMS (m/z) 328.0157 and 330.0140 [M + Na]+; C11H16NO4-
Br + Na+ requires 328.0160 and 330.0140.
and 16c). To a solution of diisopropylamine (0.13 mL, 1.07 mmol)
in 2 mL of THF under argon at -78 °C was added n-BuLi (2.56
M solution in hexanes, 0.32 mL, 0.79 mmol). The reaction was
stirred for 5 min at -78 °C and then warmed to 0 °C. After 15
min, the reaction mixture was cooled back to -78 °C. γ-Lactam 3
(200 mg, 0.5 mmol) was dissolved in 3 mL of THF, and this
solution was cooled to -78 °C and then added dropwise to the
solution containing LDA. The enolate formed had a yellow color.
The reaction was stirred at -78 °C for 30 min before the addition
of the allyl bromide (0.17 mL, 2 mmol). The next day, 5 mL of
saturated NH4Cl solution was added, and the mixture was extracted
with CH2Cl2 (2 × 25 mL). The organic layers were combined, dried
over MgSO4, and then concentrated under vacuum to give an oily
residue. The diastereoisomers were isolated by loading on a silica
gel column (2 × 4.6 cm) that had been pretreated with Et3N and
then eluting with EtOAc/hexanes (2:1), followed by CH2Cl2/MeOH
(20:1). The alkylation occurred with around 80% yield, and the
diastereoisomeric ratio was around 6:1. The diastereoisomers were
crystallized using CH2Cl2/ether. When the starting material was
added in one portion to LDA, the reaction was stirred for 15 min.
The reaction was warmed to -40 °C, and the color of the reaction
turned to bright yellow over a period of 30 min. After stirring at
-78 °C for an additional 20 min, allyl bromide was added. The
workup was the same as mentioned above. In this case, the
diastereoselectivity was more like 4:1. 15c (major isomer, 3R
configuration): TLC Rf 0.32 (EtOAc/hexanes, 4:1); [R]D +39.4 (c
0.8, CH3OH); mp 131-133 °C; 1H NMR (CD3OD, COSY
assignment) δ 0.78 (s, 3H), 1.68 (ddd, J ) 2.4, 8.4, 13.2 Hz, 1H),
2.25 (dd, 1H, J ) 9, 12.9 Hz), 2.38-2.48 (m, 1H, â-CH2), 2.63
(dd, 1H, J ) 5.7, 13.2 Hz), 3.0 (d, 1H, J ) 14.1 Hz), 3.26-3.33
(m, 1H), 3.39-3.48 (m, 1H), 3.85-3.89 (m, 7H), 4.10 (dd, 1H, J
) 3, 8.7 Hz), 4.71 (t, 1H, J ) 8.7 Hz), 4.97-5.09 (m, 2H), 5.17
(dd, 1H, J ) 3, 9 Hz), 5.72-5.86 (m, 1H), 7.34-7.44 (m, 5H);
13C NMR (CD3OD, HMQC assignment) δ 13.2, 29.9, 30.5, 40.3,
45.7, 47.5, 59.2, 63.8, 71.3, 72.4, 107.3, 119.0, 126.2, 128.7, 129.2,
131.4, 141.5, 157.9, 173.4; ESI HRMS (m/z) 429.2020 [M + H]+;
C2H28N2O6 + H+ requires 429.2026. 16c (minor isomer, 3S
configuration): TLC Rf ) 0.49 (EtOAc/hexanes, 4:1); [R]D +140
General Procedure for Templates 2 and 3. 3-[1-(4-Methyl-
2,6,7-trioxa-bicyclo[2.2.2]oct-1-ylmethyl)-2-oxo-pyrrolidin-3(R,S)-
yl]-4(S)-phenyl-oxazolidin-2-one (3). To a solution of 6 (3.19 g,
19.6 mmol) in THF at 0 °C under argon was added NaH (60%
dispersion in mineral oil, 784 mg, 19.6 mmol). A white precipitate
formed with the evolution of hydrogen. After vigorous stirring for
30 min, a solution of 14 (5 g, 16.3 mmol) in DMF (dried over
molecular sieves) was added dropwise. The reaction color changed
from orange to brown and then to gray overnight. The disappearance
of 14 was monitored by TLC. The next day, saturated NH4Cl
solution (20 mL) was added, and the solution color turned dark
brown. The reaction mixture was concentrated under vacuum, and
the residue partitioned between brine and CH2Cl2 (150 mL). The
aqueous layer was washed with CH2Cl2 (2 × 100 mL). The organic
layers were combined and dried over Na2SO4. After the removal
of the solvent under vacuum, an orange residue was obtained that
contained two diastereoisomers in the ratio 1:1. Xylenes were used
to azeotrope the DMF present in the residue. The diastereoisomers
were purified by column chromatography with EtOAc/hexanes (1:
1, 2:1, and 4:1) on a silica gel column (8 × 5 cm) that had been
pretreated with Et3N. The final elution was with CH2Cl2/MeOH
(20:1). The diastereoisomers were separable under chromatographic
conditions, and they were crystallized from CH2Cl2/ether. The
separated diastereoisomers were analyzed by NMR, but in each
case, a trace amount of the other diastereoisomer was observed by
TLC. The reaction went in a 40% yield (2.3 g of product). In
subsequent alkylation studies, the oxazolidinone was used as a
mixture of diastereoisomers. Diastereoisomer A: TLC Rf 0.30
(EtOAc/hexanes, 4:1); 1H NMR (CDCl3, COSY assignment) δ 0.80
(s, 3H), 1.32-1.46 (m, 1H), 2.03-2.13 (m, 1H), 2.96 (dt, 1H, J )
2.5, 9.6 Hz), 3.20 (d, 1H, J ) 13.8 Hz), 3.23-3.32 (m, 1H), 3.61
(d, 1H, J ) 14.1 Hz), 3.86 (s, 6H), 4.17-4.22 (m, 1H), 4.56 (t,
1H, J ) 9.45 Hz), 4.67 (t, 1H, J ) 9 Hz), 5.20 (dd, 1H, J ) 6.15,
9.15 Hz), 7.37-7.38 (m, 5H); 13C NMR (CDCl3, HMQC assign-
ment) δ 14.8, 24.6, 30.9, 45.4, 47.6, 54.9, 58.3, 70.9, 72.8, 107.4,
127.7, 129.2, 129.3, 139.6, 158.6, 170.2; ESI HRMS (m/z) 411.1526
[M + Na]+; C20H24N2O6 + Na+ requires 411.1532. Diastereoiso-
1
(c 0.93, CH3OH); mp 158-160 °C; H NMR (CD3OD, COSY
assignment) δ 0.75 (s, 3H), 2.16-2.25 (m, 1H), 2.27 (d, 1H, J )
14.1 Hz), 2.31-2.41 (m, 1H), 2.65-2.74 (m, 3H), 3.29-3.46 (m,
1H), 3.44 (d, 1H, J ) 14.1 Hz), 3.80 (s, 6H), 4.08 (dd, 1H, J )
3.15, 8.7 Hz), 4.63 (t, 1H, J ) 9 Hz), 5.08-5.19 (m, 3H), 5.73-
5.87 (m, 1H), 7.29-7.40 (m, 5H); 13C NMR (CD3OD, HMQC
assignment) δ 13.2, 29.2, 30.4, 39.9, 45.0, 46.9, 59.1, 63.6, 71.2,
72.4, 107.0, 118.8, 126.8, 128.5, 128.7, 132.6, 141.0, 158.4, 171.7;
ESI HRMS (m/z) 451.1850 [M + Na]+; C23H28N2O6 + Na+ requires
451.1845.
1
mer B: TLC Rf 0.22 (EtOAC/hexanes, 4:1); H NMR (CDCl3,
Acknowledgment. We thank Dr Victor Young, Jr. of the
Department of Chemistry’s Crystallographic Laboratory for the
X-ray structures of 7a and 15a and Swapna Bhagwanth for
synthesizing Evans' chiral auxiliary. This work was supported
by NIH Grant NS20036.
COSY assignment) δ 0.75 (s, 3H), 1.96-2.07 (m, 1H), 2.55-2.69
(m, 1H), 3.00 (d, 1H, J ) 14.4 Hz), 3.34-3.52 (m, 2H), 3.65 (t,
1H, J ) 9.6 Hz), 3.82 (s, 6H), 3.92 (d, 1H, J ) 14.7 Hz), 4.04 (t,
1H, J ) 8.7 Hz), 4.63 (t, 1H, J ) 8.85 Hz), 5.20 (t, 1H, J ) 9 Hz),
7.34-7.41 (m, 5H); 13C NMR (CDCl3, HMQC assignment) δ 14.8,
22.9, 30.9, 45.8, 47.6, 54.5, 63, 70.6, 72.8, 107.4, 127.6, 129.3,
129.4, 137.7, 157.7, 171.2; ESI HRMS (m/z) 389.1710 [M + H]+;
C20H24N2O6 + H+ requires 389.1713.
Supporting Information Available: Experimental procedures
and spectral data for 2, 5, 7, 8, 11-13, and 15-18. X-ray structure
data (ORTEP diagrams and CIF files) for 7a and 15a. This material
is available free of charge via the Internet at http://pubs.acs.org.
General Procedure for the Alkylation of Templates 2 and 3.
3-[3(R,S)-Allyl-1-(4-methyl-2,6,7-trioxa-bicyclo[2.2.2]oct-1-yl-
methyl)-2-oxo-pyrrolidin-3-yl]-4(S)-phenyl-oxazolidin-2-one (15c
JO052212Q
2154 J. Org. Chem., Vol. 71, No. 5, 2006