Synthesis of optically active α-amino esters via dynamic kinetic resolution: A mechanistic study

Article abstract of DOI:10.1021/jo9811625

Synthesis of N-protected optically active α-amino esters from racemic α-halo esters via dynamic kinetic resolution (DKR) will be described. This methodology is general in nature and provides the desired optically active N- protected amino esters in 70-95% yield with diastereomeric excesses in the range of 85 to >98%. Applications and mechanistic aspects will be discussed.

Full text of DOI:10.1021/jo9811625

7700
J . Org. Chem. 1999, 64, 7700-7706
Syn th esis of Op tica lly Active r-Am in o Ester s via Dyn a m ic Kin etic
Resolu tion : A Mech a n istic Stu d y
Robert N. Ben† and Tony Durst*,‡
Department of Chemistry, The State University of New York at Binghamton, P.O. Box 6016,
Binghamton, New York 13902-6016, Department of Chemistry, University of Ottawa,
Ottawa, Ontario, Canada K1N 6N5
Received J une 17, 1998 (Revised Manuscript Received February 18, 1999)
Synthesis of N-protected optically active R-amino esters from racemic R-halo esters via dynamic
kinetic resolution (DKR) will be described. This methodology is general in nature and provides the
desired optically active N-protected amino esters in 70-95% yield with diastereomeric excesses in
the range of 85 to >98%. Applications and mechanistic aspects will be discussed.
In tr od u ction
Resu lts a n d Mech a n istic Asp ects
Kinetic resolutions have been known and utilized by
synthetic organic chemists for many decades and have
found widespread use in the separation of enantiomeric
mixtures.1 While many variations of kinetic resolutions
have been reported, they all have one feature in common.
In order for such a reaction to be effective, there must
exist a significant difference in the rate of reaction of one
isomer over the other. Even under such conditions, the
maximum yield of the desired isomer (starting from a
racemate) is 50%. This aspect tends to make kinetic
resolution a costly process since half of the starting
material must be discarded or recycled.
In contrast to the above, a dynamic kinetic resolution
(DKR) is potentially much more efficient. In a DKR
process the slower reacting isomer is converted into the
faster one in situ. As a result, it is possible in ideal
situations to obtain the desired isomer in yields ap-
proaching 100%. Reactions of this type are relatively rare
in the literature. Several examples have been reported
which utilize enzymes.2 A classic example of DKR not
involving enzymes is Noyori’s catalytic hydrogenation of
2-substituted-3-keto esters.3 Classic resolutions under
conditions in which one of the diastereomers is converted
to the other while one of the diastereomeric salts crystal-
lizes preferentially have also been described.4
Our serendipitous discovery of this DKR process oc-
curred while we were developing a synthesis of N-
benzylproline derivatives from optically active R-halo-(R)-
pantolactone esters. As shown, it was anticipated that
reaction of 1 with benzylamine would preferentially
furnish the desired N-benzyl-(R)-proline derivative, 3. In
the event, the product, obtained in 78% yield, was a 7:1
mixture of diastereomers in which the major product was
2 possessing the (S,R) configuration instead of the
expected (R,R) configuration.6
There are two possible explanations to account for this
unexpected result: (i) the products (2 and 3) are not
configurationally stable under the reaction conditions,
and 2 is significantly more stable than 3, or (ii) the
starting materials are interconverted under the reaction
conditions. Since it was shown that 2 and 3 are configu-
rationally stable, the major isomer, 2, must therefore
result from a sequence of two inversion reactions. The
first is an inversion of the (S,R)-diastereomer of 1 into
the (R,R)-diastereomer by bromide released after a small
amount of displacement reaction with benzylamine has
taken place.7 The second SN2 involves reaction of the
(R,R)-diastereomer of 1 with benzylamine to give the
major observed product. This displacement reaction is
necessarily slower than epimerization of the (S,R)-1 to
(R,R)-1 but more rapid than the conversion of (S,R)-1 to
3 with benzylamine (Scheme 1). It should be noted that
epimerization of 1 might be catalyzed by triethylamine
instead of bromide or iodide ion, but subsequent experi-
ments have shown that 1 is configurationally stable in
the presence of triethylamine. The practical consequence
of Scheme 1 is that a 1:1 mixture of the diastereomers 1
can lead to enantiomerically pure product 2 in greater
than 50% chemical yield. Several examples of this process
resulting in the formation of both bicyclic and acyclic
R-amino esters in >60% yield and with >98% enantio-
meric purity have been reported by us.5
Several years ago we described a DKR process which
was the basis for a synthesis of highly enantiomerically
enriched R-amino esters starting from racemic R-halo
esters.5 Since that time, some insight has been gained
with respect to the scope, generality and mechanism of
this useful reaction through a number of studies. In this
paper we describe these findings.
* To whom correspondence should be addressed. Phone: (613) 562-
5800 (ext 6072). E-mail: tdurst@science.uottawa.ca.
† The State University of New York at Binghamton.
‡ University of Ottawa.
(1) Kagan, H. B.; Fiaud, J . C. Top. Stereochem. 1988, 18, 249.
(2) Meijer, E. M.; Boestan, W. H. J .; Schoemaker, H. E.; Van Blaken,
J . A. M. In Biocatalysis in Organic Synthesis; Tramper, J ., Van der
Plas, H. C., Linko, P., Eds.; Elsevier Publishing: Amsterdam, 1985; p
135.
(3) Noyori, R.; Ikeda, T.; Ohkuma, T.; Widhalm, M.; Kitamura, M.;
Takaya, H.; Sayo, N.; Saito, T.; Taketomi, T.; Kumobayashi, H. J . Am.
Chem. Soc. 1989, 111, 9134.
(4) Sheih, W-C; Carlson, J . A.; Zaunius, G. M. J . Org. Chem. 1997,
62, 8271.
(6) Durst, T.; Koh, K. Tetrahedron Lett. 1992, 33, 6799.
(7) It has been proposed that the oxygen of the lactone carbonyl may
participate in displacement of the bromide. The resulting bicyclic
oxonium ion could then undergo reaction with benzylamine to furnish
products 2 and 3. This reaction pathway is not likely since diastereo-
merically enriched mixtures of products would not be expected or
obtained.
(5) Koh, K.; Ben, R. N.; Durst, T. Tetrahedron Lett. 1993, 34, 4473.
10.1021/jo9811625 CCC: $18.00 © 1999 American Chemical Society
Published on Web 09/21/1999

Synthesis of Optically Active R-Amino Esters
J . Org. Chem., Vol. 64, No. 21, 1999 7701
Sch em e 1
Ta ble 1. Effects of Va r iou s Ch ir a l Au xilia r ies a n d Sid e
Ch a in R1 on Dia ster eoselectivitya
(A) Th e Effect of Oth er Ch ir a l Au xilia r ies on
Dia ster eoselectivity. A survey of alternate chiral aux-
iliaries was undertaken to gain insight into the mecha-
nism of this reaction, to improve product diastereoselec-
tivities, and to increase yields such that this process
might become synthetically more useful. The initial
auxiliary, (R)-pantolactone 4, has thus far given the best
results among all of the alcohol auxiliaries tested. (4S)-
tert-Butyl-1-methyl-2-oxoimidazolidine-4-carboxylate, 5,
is a superior chiral auxiliary for the SN2-DKR process
involving R-halo acids, giving generally higher ee’s than
(R)-pantolactone. The induced chirality is opposite for
these two auxiliaries, and the dynamic aspect of the DKR
process using 5 as described by Nunami8 involves a base-
catalyzed isomerization rather than the halide ion in-
duced epimerization described by us. In addition, the
preferred conformation of these imides is quite different
from that of the (R)-pantolactone esters. As a conse-
quence, this system will not be discussed in this paper.
(R)-Pantolactone was initially chosen by us because it
showed superior diastereofacial selectivity in additions
to unsymmetrically substituted ketenes.9 It is also known
to be an efficient chiral auxiliary in a variety of reaction
types including the rhodium-catalyzed cyclopropana-
tions10 and metal-coordinated Lewis acid catalyzed
Diels-Alder reactions.11
a
Products 7a -l were shown to be configurationally stable under
these reaction conditions. SR/RS ratio. c SR/RR ratio.
b
A number of other auxiliaries having the R-hydroxy
motif found in (R)-pantolactone with the 2-bromobutyrate
6h or R-bromophenylacetic ester 6i as probes gave
decreased the product diastereoselectivity (entries 5-7).
The use of an open chain auxiliary such as methyl-(S)-
mandelate (entry 1) or a bicycloketo alcohol (entry 4)
afforded only a 2:1 product ratio. Chiral alcohols having
non-R-carbonyl substituents such as trans-2-phenylcy-
clohexanol (entry 2) or D-glucose diacetonide (entry 3)
gave excellent displacement yields but only a 2:1 dia-
stereomeric ratio. Evans’ auxiliary, (4R)-isopropyl-1,3-
oxazolidin-2-one (entry 12), gave a 5:1 diastereomeric
ratio when tested with R-bromophenylacetic acid.
inferior results, Table 1. For example, replacement of the
gem-dimethyl groups in 4 by either hydrogen or phenyl
(B) Effect of Size Ch a n ges in th e Nu cleop h ile a n d
th e Su bstr a te on th e DKR P r ocess. As anticipated for
an SN2 process, an increase in the size of the nucleophile
decreased the rate of reaction and also increased the
selectivity (Table 2). For example, reaction of the R-bromo
ester 6i (R1 ) phenyl) with dibenzylamine or benzhydryl-
amine afforded the (S)-R-amino-substituted products 8a
and 8c in 70% and 74% yields, respectively, with greater
than 96% de (entries 1 and 3). In contrast, anisidine
(8) Kubo, A.; Kubota, H.; Takahashi, M.; Nunami, K. J . Org. Chem.
1997, 62, 5830. Kubota, H.; Kubo, A.; Nunami, K. Tetrahedron Lett.
1994, 35, 3107. Nunami, K.; Kubota, H.; Kubo, A. Tetrahedron Lett.
1994, 35, 8639. Kubota, H.; Kubo, A.; Takahashi, M.; Shimizu, R.; Da-
te, T.; Okamura, K.; Nunami, K. J . Org. Chem. 1995, 60, 6776.
(9) Larsen, R. D.; Corley, E. G.; Davis, P.; Reider, P. J .; Grabowski,
E. J . J . Am. Chem. Soc. 1989, 111, 7650.
(10) Davies, H. M. L.; Cantrell, W. R. Tetrahedron Lett. 1991, 32,
6509.
(11) Poll, T.; Sobczak, A.; Hartmann, H.; Helmchen, G. Tetrahedron
Lett. 1985, 26, 3095.

7702 J . Org. Chem., Vol. 64, No. 21, 1999
Ben and Durst
Ta ble 2. Effect of Differ en t Nitr ogen Nu cleop h ilesd
F igu r e 1. A qualitative free energy diagram for the DKR
process.
Ta ble 3. Solven t Effect on th e F or m a tion of 8
a
Diastereomeric ratios of 8 (SR/RR) were determined using
500 MHz 1H NMR. Significant amounts of elimination product
b
were also obtained under these reaction conditions. c No reaction.
d
Products 8a -h were shown to be configurationally stable under
these reaction conditions.
(4-methoxyaniline), 4-aminophenol, and pyrrolidine gave
diastereomer ratios of 98:2, 12:1, and 4:1, respectively
(entries 7-9), demonstrating that the relative nucleo-
philicity of the amine may have a profound effect upon
stereoselectivity. Similar results were observed in the
reaction of 6h (R1 ) ethyl); the diastereomer ratio
increased from 7:1 to 12:1 when the nucleophile was
changed from benzyl- to dibenzylamine (entry 2). Inter-
estingly, both (S)- and (R)-1-phenylethylamine gave the
same chirality at the R-carbon, showing that the stere-
ochemistry of the major product is dominated by the
asymmetry of the chiral auxiliary and not that of the
incoming nucleophile (entries 5 and 6).
Limited results indicate that the size and nature of the
R1 group attached to the reacting center also affect both
the rate of reaction and product formation. For example,
the product diastereomer ratio with PhCH2NH2 increases
from 7:1 to 10:1 in going from 6h to 6i (Table 1, entries
8 and 9). In this case, the rate of reaction is also
accelerated since reaction is occurring at a benzylic
carbon as opposed to an aliphatic carbon.
(C) Solven t Effects. Highest chemical yields and
product diastereomer ratios were observed with solvents
such as THF (Table 3). n-Hexylammonium bromide or
iodide has significant solubility in this solvent and, thus,
allows Br- or I- to epimerize the starting materials. The
more polar solvent DMF resulted in a diminished product
diastereomer ratio. Methanol or ethanol was an unsuit-
able solvent from the points of view of both chemical
yields and diastereoselectivities.
Or igin of th e Selectivity. On the basis of the results
described above and others introduced during this dis-
cussion, we propose that the scheme and free energy
diagram shown in Figure 1 is operative. Isomerization
experiments show that the diastereomeric starting esters
have approximately the same free energies. Thus, reac-
tion of a 10:1 mixture of SR:RR of the ester 6h with
Bu4N+I- in THF at rt gave a 1.1:1 mixture within 1 h.
Similarly, 1:1 mixtures of a number of other R-halo-(R)-
pantolactone esters when stirred with the corresponding
halide for one day in THF showed only slight changes in
composition as determined by NMR. The diastereomeric
products, as reported earlier, are not interconverted
under our reaction conditions. Finally, the observed
product ratios which are typically about 7:1 in the
reaction with benzylamine at 20 °C translate to a free
energy difference of about 1 kcal/mol in the transition
states for the reaction of the two diastereomers. In the
case of the more hindered nucleophiles such as dibenzy-
lamine the difference in the Gq* value must exceed 3 kcal/
mol to account for the >96% diastereomeric excesses.
The probable structure of the two transition states
must be addressed to understand why one of the dia-
stereomers reacts significantly faster than the other. To
begin this process, we have examined the preferred
conformations of the two R-bromo-(R)-pantolactone es-
ters.
X-ray structure determination of several R-amino
products and the R-bromo esters showed consistently that
the ester function exists in the cisoid conformation.12
Theoretical calculations by Houk et al.13 confirmed this
(12) Ben, R. N.; Durst, T. Unpublished results.
(13) Loncharich, R. T.; Schwartz, T. R.; Houk, K. N. J . Am. Chem.
Soc. 1987, 109, 14. Wiberg, K. B.; Laidig, K. E. J . Am. Chem. Soc.
1987, 109, 5935.

Synthesis of Optically Active R-Amino Esters
J . Org. Chem., Vol. 64, No. 21, 1999 7703
and indicate a 7 kcal/mol preference for this arrange-
ment. The two carbonyl groups in all relevant X-ray
structures were nearly perpendicular to each other. This
leads to a dihedral angle of near 0° between the panto-
lactone methine CsH bond and the plane of the OsCd
O group. Semiempirical molecular modeling using PC-
Model confirmed this observed small dihedral angle.
When such calculations were carried out on the R-keto
ester 6d (Table 1, entry 4), the relevant dihedral angle
was found to be nearly 60°. Reaction of 6d with benzy-
lamine under the usual DKR reaction conditions gave
poor diastereoselectivity, thus indicating the importance
of this angle. These results suggested that the structures
of the pantolactone esters are quite rigid and only
conformational changes due to rotation about the C1-
C2 bond are allowed. Taken together, these data point
to ground-state structures such as 9 and 10 for the (R,R)-
and the (S,R)-diastereomers.
F igu r e 2. Energy minima for the faster reacting diastereo-
mer 9.
diastereomer where R ) methyl were also in agreement
with this precedent. Figure 2 depicts the energy profile
as the dihedral angle between the methyl group and
carbonyl group of the ester function is rotated through
360°. As shown, conformation I that begins to ap-
proximate 9′ is at an energy minimum while II, (ap-
proximately 10′) is about 1.5 kcal/mol higher in energy.
We therefore propose that the origin of the diastereo-
selectivity is due essentially to the fixed conformation of
the pantolactone ester. It is because of this that a strong
preference for attack of the nucleophile from the same
side as the lactone carbonyl group (anti to the gem-
dimethyl group) exists. In addition, the preferential
eclipsing of the R group compared to hydrogen with the
acyl rather than the alkyl oxygen of the ester in the
transition state facilitates formation of the (S,R)-diaste-
reomer as a major product. Our experimental results
reviewed in the previous sections are in agreement with
this conclusion.
In the transition states leading to displacement of
bromide ion, it is assumed that the Br atom is perpen-
dicular to the ester carbonyl group since it has been
shown experimentally that a halogen fixed in this
conformation is displaced much more rapidly than one
which cannot attain perpedicularity.14 This effect has
been called the “neighboring orbital overlap” effect.
We assume that the geminal dimethyl group on the
lactone ring effectively blocks attack by the nucleophile
from the rear. In contrast, delivery of the nucleophile
from the front side can be aided by hydrogen bonding to
the lactone carbonyl group (see below). Thus, the relevant
transition states shown in 9′ and 10′ can be considered.
As predicted, more sterically demanding amines show
a greater diastereoselectivity (Table 2). Thus, the (SR/
RR)-product ratio increases from 4:1 to >98:2 when the
nucleophile is pyrrolidine and dibenzylamine, respec-
tively, with the R-bromophenylacetate as probe. A similar
trend is observed with the R-bromobutyrate esters (R1 )
ethyl). The large nucleophiles are likely blocked from
attacking the same side as the gem-dimethyl groups in
9′ or 10′, thereby allowing attack only as shown in 9′ and
10′. Interestingly, both (R)- and (S)-R-methylbenzylamine
give the same (S)-stereochemistry at the R-carbon in the
product, both with >98:2 selectivity. Not surprisingly, the
rate of the SN2 reaction decreases with the increasing
size of the nucleophile. Small nucleophiles such as azide
gave only modest selectivity (1.5:1). Good diastereoselec-
tivities have been observed with sodium phenoxides16 and
with the stabilized carbanions derived from dimethyl
malonate and malononitrile.17
The transition state 9′ which leads to the (S,R)-product
has two eclipsing interactions. One involves the R group
and the carbonyl oxygen, and in the other, the H atom
eclipses the alkyl oxygen. This situation is more favorable
than the alternate arrangement found in 10′. Support
for this comes from ab initio calculation on 2-butanone
by Allinger et al.15 who demonstrated that the conforma-
tion in which the methyl group partially eclipses the
carbonyl oxygen is favored by 2.8 kcal/mol over that in
which hydrogen eclipses the carbonyl group. Our own
calculations using AM1 on the faster reacting (RR)-
An increase in the size of the R group on the R-carbon
increases the observed product diastereoselectivity (Table
1). However, elimination reactions may dominate (i.e.,
R1 ) CH2Ph). Thus, this route is not practical for the
preparation of phenylalanine or analogues.
(14) Streitwieser, A. Solvolytic Displacement Reactions; McGraw-
Hill Book Company Inc.: New York, 1962; p 26.
(15) Allinger, K. B.; Kuchsiang, C.; Rahman, M.; Pathiaseril, A. J .
Am. Chem. Soc. 1991, 113, 4505.
(16) Koh, K.; Durst, T. J . Org. Chem. 1994, 59, 4683.
(17) Koh, K.; Durst, T. Unpublished results.

7704 J . Org. Chem., Vol. 64, No. 21, 1999
Ben and Durst
ture procedure19) in dry THF was added dropwise to a solution
of triethylamine and the desired alcohol (2.0 equiv each) in
THF at 0 °C over a 1 h period. The reaction mixture was then
quenched with H2O and subjected to extractive workup. The
combined organic layers were dried over MgSO4 and evapo-
rated under reduced pressure. Crude products were then
purified by column chromatography using the appropriate
solvent system and fully characterized.
Ta ble 4. Effect of Am id e-Der ived Ch ir a l Au xilia r ies
P r oced u r e B. The appropriate alcohol, R-bromo carboxylic
acid (1.0 equiv), DCC (1.0 equiv), and DMAP (0.1 equiv) were
dissolved in dry CH2Cl2 and stirred at room temperature under
a nitrogen atmosphere until TLC verified that the alcohol had
been consumed. The precipitate was filtered off, and the
organic phase was washed with 3 × 20 mL of H2O and 1 × 20
mL of 10% HCl. The organic layer was dried over MgSO4 and
evaporated under reduced pressure to furnish the crude
product that was purified via column chromatography.
Gen er a l P r oced u r e for th e Dyn a m ic Kin etic Resolu -
tion . The appropriate R-halo ester was dissolved in 5-10 mL
of dry THF. Triethylamine (2.0 equiv), tetrahexylammonium
iodide (0.2 equiv), and the desired amine (1.05 equiv) were
added to the solution. The reaction mixture was stirred under
a nitrogen atmosphere until TLC verified that all of the
starting materials had been consumed. After addition of 20-
30 mL of ether, the precipitate was filtered off and the filtrate
was evaporated under reduced pressure to furnish the crude
product. At this point, a proton NMR was taken of the crude
mixture to determine the diastereomeric ratio, and the crude
product was then purified via column chromatography.
Meth yl-(S)-O-(2-br om obu tyr yl)m a n d ela te (6a ). Com-
pound 6a was prepared using procedure A. The crude product
was purified via column chromatography using hexane-EtOAc
(10:1) as elutant to furnish 6a in 91% yield as a colorless oil:
IR (CH2Cl2) 2948, 1750, 1748, 1497, 1145, 1033 cm-1; 1H NMR
(200 MHz, CDCl3) δ 1.05 (m, 3H), 2.10 (m, 2H), 3.70 (s, 3H),
4.30 (m, 1H), 5.94 (s, 1H), 7.40 (m, 5H); 13C NMR (75 MHz,
CDCl3) δ 11.6, 28.4, 52.3, 75.2, 75.4, 127.5, 128.8, 129.4, 133.0,
133.1, 168.5, 168.8; CIMS (ether) m/ e (relative intensity) 389
(0.6), 317 (17), 315, (17), 297 (100).
It was suggested above that hydrogen bonding between
the nucleophile and the lactone carbonyl group should
favor the attack as shown in 9′ or 10′. To verify this
hypothesis, the ester of (S)-mandelate was converted to
an amide (Table 4). It was anticipated that the increased
basicity of the amide versus ester carbonyl oxygen would
enhance hydrogen bonding. Indeed, an increase in dias-
tereoselectivity was observed for the open chain amide
vs the corresponding ester (Tables 1 and 4).
Syn th etic Ap p lica tion s. A number of applications of
our DKR of (R)-pantolactone ester of R-bromo acids have
been described in preliminary form. These include the
synthesis of a number of (S)-N-benzyl-R-amino acids,5
N-carboxylalkylamino acids, and (S,S)-pyrrolidine-2,5-
dicarboxylic acids.18 The DKR approach is particularly
useful for the preparation of N-substituted R-amino acids.
For example, a variety of N-aryl-R-amino acid derivatives
were obtained in good to excellent yields according to
eq 1.
(1R,2S)-2-Br om obu tyr yloxy-1-p h en ylcycloh exa n e (6b).
Compound 6b was prepared via procedure A. The crude
product was obtained as a colorless oil in 60% yield after
column chromatography using hexane-EtOAc (5:1): IR (CH2-
The formation of the N-substituted azetidine-2-car-
boxylates as a 15:1 SR to RR mixture in 75% isolated
yield starting from the 2,4-dibromobutanoate ester 13
also illustrates the versatility of the DKR approach.
Compounds such as 14 have been patented as possible
anti-Parkinson’s agents.
Cl2) 2980, 1720, 1328, 1032, 852 cm-1 1H NMR (200 MHz,
;
CDCl3) δ 0.60 (m, 3H), 1.30-2.20 (m, 10H), 3.85 (m, 1H), 4.80
(m, 1H), 5.00 (m, 1H), 7.20 (m, 5H); CIMS (ether) m/ e (relative
intensity) 327 (4), 325 (4), 249 (11), 171 (14.2). Anal. Calcd for
C
16H21O2Br: C, 59.26; H, 6.52. Found: C, 59.14; H, 6.54.
3-(2-Br om ob u t yr yl)-1,2,5,6-d iisop r op ylid e n e -O-glu -
cose (6c). R-Bromo ester 6c was prepared via procedure A,
and the crude product was purified via column chromatogra-
phy on silica using hexane-EtOAc (5:1). Compound 9c was
isolated in 63% yield as a yellow oil: IR (CH2Cl2) 3479, 2913,
1743, 1206, 1156, 1080, 1026 cm-1; 1H NMR (200 MHz, CDCl3)
δ 1.00 (t, 3H, J ) 8.2 Hz), 1.27 (s, 3H), 1.28 (s, 3H), 1.35 (s,
3H), 1.50 (s, 3H), 2.0 (m, 2H), 3.90-4.20 (m, 5H), 4.45 (t, 1H,
J ) 4.2 Hz), 5.31 (br s, 1H), 5.87, 5.89 (both s, total 1H); 13C
NMR (50 MHz, CDCl3) δ 11.6, 11.7, 25.1, 26.1, 26.5, 26.6, 28.1,
49.5, 47.0, 60.1, 67.3, 67.4, 71.9, 72.1, 76.5, 79.8, 79.9, 82.7,
82.8, 167.8, 168.1; CIMS (ether) m/ e (relative intensity) 411
(38), 409 (39), 393 (12), 351 (100), 293 (20).
Exp er im en ta l Section
Microanalyses were performed at the University of Ottawa
or by M-H-W Laboratories, Phoenix, AZ.
2-(2-Br om ob u t yr yloxy)-3,3-d ip h en yl-γ-b u t yr ola ct on e
(6f). Compound 6f was prepared using procedure B and was
purified via column chromatography on silica using hexane-
EtOAc (3:1). The desired product was obtained in 52% yield
as a colorless oil: IR (CH2Cl2) 2930, 1802, 1752, 1498, 1074,
Chromatographic separations were performed using 230-
400 mesh SiO2 from Terochem Laboratories in the solvent
systems specified. All solvents were dried and distilled prior
to utilization; THF was distilled over sodium-benzophenone,
and methylene chloride was distilled over P2O5.
Gen er a l P r oced u r es for th e P r ep a r a tion of r-Br om o
Ester s. P r oced u r e A. A solution of the appropriate R-bro-
moacyl halide (obtained commercially or prepared via litera-
1
1016 cm-1; H NMR (200 MHz, CDCl3) δ 0.90 (m, 3H), 1.50-
2.20 (m, 2H), 4.10 (m, 1H), 4.50, 4.60 (both d, total 1H, J )
9.6 Hz), 5.15 (d, 1H, J ) 9.6 Hz), 6.39, 6.41 (both s, total 1H),
7.25 (m, 10H); 13C NMR (75 MHz, CDCl3) δ 11.2, 11.3, 27.4,
27.8, 54.9 (2), 55.4, 55.5, 73.7, 126.1, 127.4, 127.6, 128.1 (2),
(18) O’Meara, J . A.; Gardee, N.; J ung, M.; Ben, R. N.; Durst, T. J .
Org. Chem. 1998, 63, 3117. Koh, K.; Ben, R. N.; Durst, T. Tetrahedron
Lett. 1994, 35, 375.
(19) Harpp, D. W.; Black, C. J .; Gleason, J . G.; Smith, R. A. J . Org.
Chem. 1975, 40, 3420.

Synthesis of Optically Active R-Amino Esters
J . Org. Chem., Vol. 64, No. 21, 1999 7705
128.9, 137.8, 140.6, 167.5, 168.2, 170.0, 170.1; EIMS m/ e
(relative intensity) 404 (4), 402 (4), 291 (3), 236 (4), 211 (39);
HRMS calcd for C20H19O4Br (M+) 402.0466, found 402.0461.
2-(2-Br om o-2-p h en yla cet oxy)-3,3-d ip h en yl-γ-b u t yr o-
la cton e (6g). Compound 6g was prepared using procedure B
and was obtained in 56% yield after purification by column
chromatography using hexane-EtOAc (3:1): IR (CH2Cl2) 2930,
1802, 1752, 1498, 1136, 1073 cm-1; 1H NMR (200 MHz, CDCl3)
δ 4.50, 4.54 (both d, total 1H, J ) 9.6 Hz), 5.10, 5.40 (both d,
total 1H, J ) 9.6 Hz), 5.30, 5.35 (both s, total 1H), 6.35, 6.40
(both s, 1H), 6.80-7.50 (m, 15H); 13C NMR (75 MHz, CDCl3)
δ 44.5, 46.5, 73.3, 73.8, 126.0, 126.2, 127.4, 127.5, 128.0, 128.1,
128.3, 128.5, 128.6, 128.9, 129.0, 129.1, 166.3, 169.8, 169.9;
EIMS m/ e (relative intensity) 452 (2), 450 (2), 371 (25), 325
(21); HRMS calcd for C24H19O4Br (M+) 450.0466, found 450.0452.
(R)-O-(2-Br om o-2-p h en yl)a cetylp a n tola cton e (6i). Com-
pound 6i was prepared using procedure B and was purified
via column chromatography using hexane-EtOAc (3:1). The
desired product was obtained in 72% yield as a colorless oil
which solidified on standing in a freezer: mp 143-144 °C; IR
3H), 1.50 (s, 3H), 1.75 (m, 1H), 3.20 (m, 1H), 3.60 (d, 1H, J )
12.3 Hz), 3.80 (d, 1H, J ) 12.3 Hz), 3.95 (m, 6H), 4.35, 4.36
(both d, total 1H, J ) 3.5 Hz), 5.29, 5.35 (both d, total 1H, J
) 3 Hz), 5.80, 5.82 (both d, total 1H, J ) 4 Hz), 7.25 (m, 5H);
13C NMR (75 MHz, CDCl3) δ 10.2, 25.0, 25.1, 25.2, 26.1, 26.4,
26.6, 26.7, 26.8, 51.2, 52.0, 61.8, 67.4, 67.7, 72.1, 72.3, 75.9,
80.0, 81.2, 83.2, 83.4, 85.0, 105.0, 105.2, 127.1, 128.2, 128.3,
139.5, 173.9. Anal. Calcd for C23H32NO7: C, 63.57; H, 7.42.
Found: C, 63.72; H, 7.60.
2-(2-Phenylmethylamino)butyryloxy-3,3-diphenyl-γ-butyro-
la cton e (7f). Compound 7f was synthesized according to the
general procedure. The crude product showed a 3:1 mixture
of diastereomers which were isolated together via column
chromatography using hexane-EtOAc (3:1) in 93% yield: IR
(CH2Cl2) 2912, 1799, 1746, 1376, 1073, 1015, 870 cm-1 1H
;
NMR (200 MHz, CDCl3) δ 0.90 (m, 3H), 1.60 (m, 2H), 1.90 (br
s, 1H), 3.20 (m, 1H), 3.50, 3.60 (both d, total 1H, J ) 10.2 Hz),
3.80 (d, 1H, J ) 10.2 Hz), 4.46, 4.52, (both d, total 1H, J ) 9.6
Hz), 5.15 (d, 1H, J ) 9.6 Hz), 6.48, 6.52 (both s, total 1H), 7.2
(m, 15H); 13C NMR (75 MHz, CDCl3) δ 9.9, 10.0, 25.9, 26.3,
51.6, 55.2, 61.6, 62.0, 71.7, 71.9, 74.3, 74.5, 126.5, 126.8, 127.1,
127.8, 127.9, 128.0, 128.1, 128.2, 128.3, 128.4, 128.7, 129.3,
138.8, 141.1, 170.9, 173.7; CIMS (isobutylene) m/ e (relative
intensity) 430 (100), 237 (42), 194 (81), 148 (100). Anal. Calcd
for C27H27NO4: C, 75.50; H, 6.33. Found: C, 75.61; H, 6.35.
2-[(2-P h en ylm eth ylam in o)-2-ph en yl]acetoxy-3,3-diph en -
yl-γ-bu tyr ola cton e (7g). Compound 7g was obtained accord-
ing to the general procedure. Analysis of the reaction mixture
by proton NMR revealed that the crude product contained a
mixture of diastereomers in a 3.5:1 ratio and was purified as
a white solid in 97% yield via column chromatography using
hexane-EtOAc (2:1) which was recrystallized from ether-
hexanes to furnish the major diastereomer: mp 101 °C; IR
(CH2Cl2) 3014, 1800, 1762, 1076, 1136 cm-1 1H NMR (200
;
MHz, CDCl3) δ 0.88, 1.10, 1.15, 1.23 (all s, total 6H), 3.98, 4.05
(both s, total 2H), 5.34, 5.36 (both s, total 1H), 5.48, 5.51 (both
s, total 1H), 7.25-7.60 (m, 5H); 13C NMR (75MHz, CDCl3) δ
20.1, 20.3, 23.2, 23.4, 40.2 (2), 45.6 (2), 47.3 (2), 77.8 (2), 78.4
(2), 128.5, 128.7, 129.1, 129.6, 130.1, 135.3, 136.1, 167.8, 168.3,
172.1; CIMS (ether) m/ e (relative intensity) 329 (34), 327 (34),
283 (9), 247 (100). Anal. Calcd for C14H15O4Br: C, 51.40; H,
4.62. Found: C, 51.61; H, 4.70.
(4S)-(2-Br om o-2-p h en yla cetyl)-4-isop r op yl-2-oxa zolid i-
n on e (6l). Compound 6l was obtained as a yellow oil in 75%
yield after purification by column chromatography using
hexane-EtOAc (5:1): IR (CH2Cl2) 2946, 1780, 1706, 1379,
1197, 1101, 972 cm-1; 1H NMR (200 MHz, CDCl3) δ 0.50-1.40
(m, 6H), 2.10-2.60 (m, 1H), 4.00-4.50 (m, 3H), 6.82, 6.90 (both
s, total 1H), 7.40 (m, 5H); 13C NMR (75 MHz, CDCl3) δ 14.2,
14.4, 17.5, 44.1, 45.8, 58.5, 63.1, 63.2, 128.3, 128.5, 128.9, 129.0,
129.2, 129.3, 134.7, 135.2, 152.9, 166.8, 167.2; EIMS m/ e
(relative intensity) 327 (75), 325 (75), 246 (100), 196 (100), 198
(100), 170 (100); HRMS calcd for C14H16NO3Br (M+) 325.0310,
found 325.0333.
(CH2Cl2) 3450, 2840, 1800, 1751, 1496, 1132, 1074, 869 cm-1
;
1H NMR (200 MHz, CDCl3) δ 1.40 (br s, 1H), 3.70 (s, 2H), 4.36
(s, 1H), 4.45 (d, 1H, J ) 9.6 Hz), 5.08 (d, 1H, J ) 9.6 Hz), 6.32
(s, 1H), 6.70 (m, 4H), 7.20 (m, 16H); 13C NMR (75 MHz, CDCl3)
δ 50.8, 54.5, 63.8, 72.3, 73.2, 73.3, 125.8, 126.5, 126.7, 127.1,
127.4, 127.6, 127.9, 128.1, 128.2, 128.4, 128.5, 128.7, 136.9,
137.7, 138.8, 140.5, 170.3, 171.4; CIMS (isobutylene) m/ e
(relative intensity) 478 (100), 237 (5), 196 (50), 106 (21).
(R)-O-[(2-P h en ylm eth yla m in o)-2-p h en yl]a cetylp a n to-
la ct on e (7i). A proton NMR of the crude reaction mixture
revealed that 7i was formed as a 10:1 mixture of diastereo-
mers. After purification by column chromatography using
hexane-EtOAc (3:1) the mixture of diastereomers was ob-
tained in 85% yield as a colorless oil: IR (CH2Cl2) 2949, 1784,
1780, 1109, 1007 cm-1; 1H NMR (200 MHz, CDCl3) δ 0.40, 0.92,
1.00, 1.18 (all s, total 6H), 2.40 (br s, 1H), 3.75, 3.90, 3.92,
4.00 (all s, total 4H), 4.55, 4.56 (both s, total 1H), 5.46, 5.47
(both s, total 1H), 7.20-7.50 (m, 5H); 13C NMR (50 MHz,
CDCl3) δ 18.9, 22.4, 40.1, 50.9, 63.7, 74.9, 75.8, 126.9, 127.4,
128.1, 128.2, 128.4, 128.5, 137.5, 138.9, 171.8, 171.9; CIMS
(isobutylene) m/ e (relative intensity) 260 (70), 247 (90), 226
(10), 131 (100). Anal. Calcd for C21H23O4N: C, 71.36; H, 6.55.
Found: C, 71.21; H, 6.45.
Meth yl-(S)-O-(2-a m in obu tyr yl)m a n d ela te (7a ). Ester 7a
was prepared according to the general procedure. The crude
product was obtained as a 2:1 mixture (SS/RS) of diastereo-
mers and was purified via column chromatography using
toluene-acetone (17:1) in 60% yield as a colorless oil: IR (CH2-
1
Cl2) 3527, 2945, 1739, 1680, 1495, 1092, 1067 cm-1; H NMR
(200 MHz, CDCl3) δ 0.95, 1.05 (both t, total 3H, J ) 7.8 Hz),
1.60-1.92 (m, 2H), 3.40 (m, 1H), 3.60-3.92 (m, 5H), 6.00, 6.01
(both s, total 1H), 7.10-7.50 (m, 10H); 13C NMR (75 MHz,
CDCl3) δ 9.7, 9.8, 26.1, 26.2, 51.5, 51.6, 52.3, 52.4, 61.4, 74.2,
74.3, 126.8, 127.4, 128.1, 128.2, 128.5, 128.6, 128.7, 129.0,
133.4, 139.2, 168.9, 174.4; CIMS (isobutylene) m/ e (relative
intensity) 342 (100), 194 (11), 148 (100), 106 (12). Anal. Calcd
for C20H23O4N: C, 70.36; H, 6.79. Found: C, 70.52; H, 6.83.
(1R,2S)-(2-P henylmethylamino)butyryloxy-1-phenylcyclo-
h exa n e (7b). The general procedure using 6b with benzy-
lamine produced compound 7b in a diastereomeric ratio of 2:1,
which was isolated in 92% yield as a pale yellow oil: IR (CH2-
(R)-O-[(2-Bisp h en ylm eth yla m in o)-2-p h en yl]a cetylp a n -
tola cton e (8a ). Compound 8a which was obtained as a single
diastereomer was purified on silica using hexane-EtOAc (3:
1) and was obtained in 70% yield as a pale orange solid: mp
83 °C; IR (CH2Cl2) 2931, 1794, 1748, 1127, 1077 cm-1; 1H NMR
(300 MHz, CDCl3) δ 0.95 (s, 3H), 1.27 (s, 3H), 3.78 (ABq, 4H,
J ) 9.6 Hz), 4.05 (s, 2H), 4.70 (s, 1H), 5.60 (s, 1H), 7.20-7.40
(m, 15H); 13C NMR (75 MHz, CDCl3) δ 19.6, 22.7, 39.8, 53.7,
65.2, 74.7, 75.9, 127.7, 128.0, 128.1, 128.3, 128.4, 128.7, 135.9,
138.9, 170.5, 171.7; CIMS (isobutylene) m/ e (relative intensity)
444 (1), 443 (1), 288 (2), 286 (55), 91 (100). Anal. Calcd for
1
Cl2) 2936, 1725, 1494, 1188, 1013 cm-1; H NMR (200 MHz,
CDCl3) δ 0.50, 0.70 (both t, total 3H, J ) 8.1 Hz), 1.10-2.40
(m, 11H), 2.60-3.52 (m, 4H), 5.10 (m, 1H), 7.20 (m, 10H); 13
C
NMR (75 MHz, CDCl3) δ 9.4, 10.0, 24.7, 25.8, 26.2, 26.6, 32.4,
32.6, 34.1, 34.3, 49.8, 49.9, 51.4, 51.2, 61.8, 62.1, 75.9, 76.2,
126.5, 126.7, 127.4, 127.6, 128.2 (2), 128.3, 139.8, 143.1, 174.7,
174.8; CIMS 17 (isobutylene) m/ e (relative intensity) 352 (100),
194 (18), 159 (40), 148 (94), 106 (14). Anal. Calcd for C23H29
NO2: C, 78.59; H, 8.32. Found: C, 78.25; H, 8.09.
-
C
28H29O4N: C, 75.82; H, 6.59. Found: C, 75.42; H, 6.58.
3-(2-P h en ylm eth yla m in o)bu tyr yloxy-1,2:5,6-d iisop r o-
p ylid en e-O-glu cose (7c). Compound 7c was prepared ac-
cording to the general procedure. The crude product was
obtained as a 2:1 mixture of diastereomers and was isolated
as such in 83% yield as a yellow oil: IR (CH2Cl2) 2917, 1740,
1378, 1164, 1076, 1024, 848 cm-1; 1H NMR (200 MHz, CDCl3)
δ 0.90 (t, 3H, J ) 7.8 Hz), 1.23 (s, 3H), 1.24 (s, 3H), 1.40 (s,
(R)-O-2-(Bisp h en ylm eth yla m in o)bu tyr ylp a n tola cton e
(8b). Compound 8b which was obtained as a 12:1 mixture of
diastereomers was purified via column chromatography using
hexane-EtOAc (3:1) and isolated in 30% yield as a colorless
oil: IR (CH2Cl2) 2810, 1782, 1740, 1325, 1072, 1010, 850 cm-1
;
1H NMR (200 MHz, CDCl3) δ 0.90 (t, 3H, J ) 8.0 Hz), 1.10,
1.11, 1.20, 1.22 (all s, total 6H), 1.80 (m, 2H), 3.35 (t, 1H, J )

7706 J . Org. Chem., Vol. 64, No. 21, 1999
Ben and Durst
8.2 Hz), 3.60, 3.62 (both d, 2H, J ) 12 Hz), 3.95, 3.98 (both d,
total 2H, J ) 12 Hz), 4.05 (s, 2H), 5.45, 5.50 (both s, total 1H),
7.30 (m, 10H); 13C NMR (75 MHz, CDCl3) δ 10.8, 20.2, 22.8,
22.9, 40.1, 54.2, 62.1, 74.8, 76.2, 126.9, 128.2, 128.9, 139.5,
171.6, 172.1; CIMS (isobutylene) m/ e (relative intensity) 396
(100), 304 (2), 238 (84), 234 (8). Anal. Calcd for C24H29O4N:
C, 72.88; H, 7.39. Found: C, 72.92; H, 7.32.
CDCl3) δ 18.7, 19.7, 22.3, 22.7, 22.9, 23.0, 29.8, 40.1, 51.2, 52.1,
72.5, 73.1, 74.4, 74.8, 75.6, 75.7, 128.0, 128.1, 128.3, 136.2,
170.4, 171.3; CIMS (isobutylene) m/ e (relative intensity) 318
(100), 316 (9), 160 (92). Anal. Calcd for C18H23NO4: C, 68.11;
H, 7.30. Found: C, 68.32; H, 7.41.
(1S)-[P h en yl(pyr r olid in eca r bon yl)m eth yl]-2-br om obu -
ta n oa te (11a ). Compound 11a which was synthesized using
procedure B was purified by column chromatography using
hexane-EtOAc (1:1) to furnish the desired compound in 70%
yield as a white solid: IR (CH2Cl2) 2865, 1743, 1712, 1363,
(R)-O-[(2-Dip h en ylm eth yla m in o)-2-p h en yl]a cetylp a n -
tola cton e (8c). Compound 8c was obtained as a single
diastereomer and was isolated by column chromatography
using hexane-EtOAc (3:1) in 74% yield as a colorless oil: IR
1
1221, 1099, 844 cm-1; H NMR (200 MHz, CDCl3) δ 0.90 (q,
(CH2Cl2) 2915, 1793, 1749, 1352, 1075, 1019, 850 cm-1
;
1H
3H, J ) 7.2 Hz), 1.60-2.20 (m, 6H), 3.00 (m, 1H), 3.30 (m,
1H), 3.50 (m, 2H), 4.20 (q, 1H, J ) 7.2 Hz), 5.92, 5.95 (both s,
total 1H), 7.40 (m, 5H); 13C NMR (75 MHz, CDCl3) δ 11.7, 23.7,
25.9, 28.4, 28.5, 45.8, 45.9, 46.2, 47.5, 47.6, 128.5, 128.6, 128.7
(2), 128.8, 128.9, 129.3, 129.4, 133.0, 133.2, 165.5, 165.6, 169.1,
169.6; EIMS m/ e (relative intensity) 355 (1), 353 (1), 317 (2),
274 (2), 187 (6); HRMS calcd for C16H20NO3Br (M+) 353.0627,
found 353.0599.
NMR (200 MHz, CDCl3) δ 0.60 (s, 3H), 0.95 (s, 3H), 2.70 (br s,
1H), 3.90 (s, 2H), 4.50 (s, 1H), 5.40 (s, 1H), 7.30 (m, 15H); 13
C
NMR (75 MHz, CDCl3) δ 18.9, 22.5, 40.1, 62.2, 64.2, 75.3, 75.8,
127.2, 127.4, 127.6, 128.3, 128.4, 128.5, 128.7, 128.9, 129.0,
132.1, 140.1, 141.2, 171.2, 172.0, 172.3; EIMS m/ e (relative
intensity) 429 (3), 352 (14), 316 (9), 272 (99), 182 (100); HRMS
calcd for C27H27O4N (M+) 429.1941, found 429.1932.
(R)-O-[2-((1S)-P h en yl(eth ylam in o))-2-ph en yl]acetylpan -
tola cton e (8d ). Compound 8d was isolated as a single
diastereomer by column chromatography using hexane-EtOAc
(3:1) in 84% yield as a colorless oil: IR (CH2Cl2) 2914, 1793,
1748, 1371, 1144, 1077, 1012 cm-1; 1H NMR (200 MHz, CDCl3)
δ 0.70 (s, 3H), 0.95 (s, 3H), 1.40 (d, 3H, J ) 8.1 Hz), 2.30 (br
s, 1H), 3.90 (q, 1H, J ) 8.1 Hz), 3.95 (s, 2H), 4.35 (s, 1H), 5.40
(s, 1H), 7.30 (m, 10H); 13C NMR (75 MHz, CDCl3) δ 19.3, 22.7,
24.5, 40.2, 56.4, 62.8, 75.2, 76.0, 127.0, 127.1, 128.1, 128.2,
128.4, 128.7, 138.1, 144.4, 171.8, 173.0; CIMS (isobutylene)
m/ e (relative intensity) 368 (100), 320 (16), 264 (80), 249 (10),
210 (67). Anal. Calcd for C22H25O4N: C, 71.91; H, 6.83.
Found: C, 71.52; H, 6.80.
(1S)-[P h en yl(p yr r olid in eca r bon yl)m eth yl]-2-br om o-2-
p h en yla ceta te (11b). Compound 11b which was synthesized
using procedure B was purified by column chromatography
using hexane-EtOAc (1:1) to furnish the desired compound
in 40% yield as a colorless oil: IR (CH2Cl2) 2896, 1748, 1711,
1356, 1137, 1024, 849 cm-1; 1H NMR (200 MHz, CDCl3) δ 1.70
(m, 4H), 3.05 (m, 1H), 3.20-3.60 (m, 3H), 5.40 (s, 1H), 5.95,
6.00 (both s, total 1H), 7.40 (m, 10H); 13C NMR (75 MHz,
CDCl3) δ 23.7, 24.9, 26.0, 33.8, 45.9, 46.3, 75.8, 75.9, 128.4,
128.5, 128.7 (2), 128.8, 128.9, 129.0, 129.2, 129.4, 129.5, 131.1,
135.3, 135.6, 165.5, 167.9, 168.2; CIMS (isobutylene) m/ e
(relative intensity) 404 (20), 402 (20), 352 (11), 324 (79).
(1S)-[P h en yl(p yr r olid in eca r bon yl)m eth yl]-2-(p h en yl-
m eth yla m in o)bu ta n oa te (12a ). Compound 12a was ob-
tained as a 4:1 mixture of diastereomers and was purified via
column chromatography using hexane-EtOAc (1:1) to furnish
the desired product as a pale yellow oil in 82% yield: IR (CH2-
(R)-O-[2-(4-Met h oxyp h en yla m in o)p h en yl]a cet ylp a n -
tola cton e (8f). Compound 8f which was obtained as a single
diastereomer was purified by column chromatography using
hexane-EtOAc (3:1) and isolated in 75% yield as needle-like
crystals: mp 118-120 °C; IR (CH2Cl2) 2929, 1795, 1753, 1514,
1
Cl2) 2908, 1747, 1656, 1492, 1170, 1031 cm-1; H NMR (200
1161, 1075 cm-1
;
13C NMR (75 MHz, CDCl3) δ 19.1, 22.6, 40.4,
MHz, CDCl3) δ 0.80, 0.90 (both t, total 3H, J ) 8.0 Hz), 1.50-
2.00 (m, 8H), 3.00 (m, 1H), 3.20-3.80 (m, 5H), 5.92, 5.98 (both
s, total 1H), 7.10-7.40 (m, 10H); 13C NMR (75 MHz, CDCl3) δ
10.0, 10.2, 23.7, 26.0, 26.3, 45.8, 46.2, 51.8, 51.9, 61.7, 61.8,
74.3, 74.4, 126.7, 126.8, 128.2, 128.3 (2), 128.4, 128.6, 128.9,
129.2, 133.8, 139.9, 166.0, 175.1; CIMS (isobutylene) m/ e
(relative intensity) 381 (100), 275 (13), 190 (50).
55.6, 62.0, 75.7, 76.0, 115.0, 121.1, 127.4, 127.6, 128.1, 128.5,
128.8, 128.9, 129.0, 129.1, 130.4, 131.8; EIMS m/ e (relative
intensity) 369 (10), 212 (100), 210 (13), 196 (4), 77 (9); HRMS
calcd for C21H23O5N (M+) 369.1570, found 369.1595.
(R)-O-[2-(4-H yd r oxyp h en yla m in o)p h en yl]a cet ylp a n -
tola cton e (8g). Compound 8g was obtained as a 12:1 mixture
of diastereomers and isolated by column chromatography using
hexane-EtOAc (1:1) in 75% yield as a colorless oil: IR (CH2-
Cl2) 3586, 2900, 1794, 1749, 1515, 1376, 1165, 1075, 1007, 822
(1S)-[P h en yl(p yr r olid in eca r bon yl)m eth yl]-2-(p h en yl-
m eth yla m in o)bu ta n oa te (12b). Compound 12b which was
obtained as a 10:1 diastereomeric mixture was purified by
column chromatography using hexane-EtOAc (1:1) to furnish
the desired product as a colorless oil in 80% yield: IR (CH2-
1
cm-1; H NMR (200 MHz, CDCl3) δ 0.70, 0.80, 0.90, 1.10 (all
s, total 6H), 3.95, 4.00 (both s, total 2H), 4.55, 4.60 (both d,
total 1H, J ) 6.3 Hz), 5.20, 5.25 (both d, total 1H, J ) 6.3 Hz),
5.40, 5.45 (both s, total 1H), 6.50 (d, 2H, J ) 7.0 Hz), 6.80 (d,
2H, J ) 7.0 Hz), 7.30-7.60 (m, 5H); 13C NMR (75 MHz, CDCl3)
δ 18.3, 18.8, 19.4, 22.2, 22.5, 30.5, 40.1, 61.3, 61.5, 75.3, 75.4,
75.7, 75.9, 114.0, 115.0, 115.8, 126.7, 127.1, 128.1, 128.3, 128.5,
128.6, 137.2, 139.5, 147.9, 171.1; EIMS m/ e (relative intensity)
355 (7), 198 (100), 196 (12); HRMS calcd for C20H21O5N (M+)
355.1420, found 355.1430.
1
Cl2) 2901, 1747, 1656, 1497, 1176, 1032 cm-1; H NMR (200
MHz, CDCl3) δ 1.70 (m, 4H), 2.15 (br s, 1H), 3.05 (m, 1H), 3.30
(m, 1H), 3.50 (m, 2H), 3.70, 3.76 (both s, total 1H), 4.45, 4.50
(both s, total 1H), 5.92, 5.98 (both s, total 1H), 7.25 (m, 15H);
13C NMR (75 MHz, CDCl3) δ 23.5, 25.7, 45.6, 46.0, 51.1, 63.8,
74.6, 126.7, 127.3, 127.7, 128.0, 128.3, 128.4, 128.9, 133.2,
137.3, 139.2, 165.8, 172.6; CIMS (isobutylene) m/ e (relative
intensity) 429 (44), 323 (9), 242 (18), 196 (72), 188 (21), 160
(31), 106 (34). Anal. Calcd for C27H28N2O3: C, 75.67; H, 6.58.
Found: C, 75.82; H, 6.62.
(R)-O-[2-(1-P yr r olid yl)-2-p h en yla cet yl]p a n t ola ct on e
(8h ). Compound 8h which was obtained as a 4:1 mixture of
diastereomers was purified using column chromatography with
hexane-EtOAc (3:1) to furnish a colorless oil in 87% yield:
IR (CH2Cl2) 2907, 1787, 1756, 1471, 1131, 1010, 856 cm-1; 1H
NMR (200 MHz, CDCl3) δ 0.60, 0.90, 1.00, 1.10 (all s, total
6H), 2.80 (br s, 4H), 2.30-2.70 (m, 4H), 3.80-4.10 (m, 3H),
5.25, 5.35 (both s, total 1H), 7.35 (m, 5H); 13C NMR (75 MHz,
Ack n ow led gm en t. We gratefully acknowledge the
Natural Sciences and Engineering Research Council
(NSERC) of Canada for supporting this work.
J O9811625