Probing the abilities of synthetically useful serine proteases to discriminate remote stereocenters. Chiral naphthyl aldehyde inhibitors

Article abstract of DOI:10.1021/ja9708777

The capacities of subtilisin Carlsberg (SC) and α-chymotrypsin (CT), which are representative of synthetically useful serine proteases, to discriminate between R- and S-configurations of stereocenters remote from the catalytic site have been further explo

Full text of DOI:10.1021/ja9708777

10260
J. Am. Chem. Soc. 1997, 119, 10260-10268
Probing the Abilities of Synthetically Useful Serine Proteases
To Discriminate Remote Stereocenters. Chiral Naphthyl
Aldehyde Inhibitors
Taekyu Lee and J. Bryan Jones*
Contribution from the Department of Chemistry, UniVersity of Toronto, 80 St. George Street,
Toronto, Ontario, Canada M5S 1A1
ReceiVed March 19, 1997X
Abstract: The capacities of subtilisin Carlsberg (SC) and R-chymotrypsin (CT), which are representative of
synthetically useful serine proteases, to discriminate between R- and S-configurations of stereocenters remote from
the catalytic site have been further explored using chiral naphthyl aldehyde transition state analog inhibitors as probes.
The inhibitors evaluated were (3R)- and (3S)-3-(1-naphthyl and 2-naphthyl)butanal and (4R)- and (4S)-4-(1-naphthyl
and 2-naphthyl)pentanal, for which the methyl groups at the C-3 and C-4 stereocenters, respectively, are significantly
removed from the aldehyde functionality that interactswith the catalytic serine residue. Each aldehyde was a
competitive inhibitor for both enzymes, with CT being significantly more powerfully inhibited than SC. While only
low levels of stereoselectivity were observed with SC, significant stereocenter discrimination was manifest for CT
within this series of inhibitors with, encouragingly, the similar degrees of stereoselectivity (up to 3.9-fold) being
observed between the enantiomers of the naphthylaldehyde inhibitors bearing both C-3 and C-4 remote methyl
substituents. Furthermore, CT consistently favored the S-enantiomers within this series of inhibitor structures, which
represents a reversal of the stereoselectivity observed previously for inhibition by the analogous phenyl substituted
aldehydes. Molecular mechanics and molecular dynamics calculations were performed to identify the binding and
orientation differences responsible for the R- and S-enantiomer binding discriminations observed.
Introduction
Subtilisin Carlsberg (SC, EC 3.4.21.14) and R-chymotrypsin
(CT, EC 3.4.21.1) were selected as representative hydrolases
for our initial studies, being commercially available serine
proteases that have been applied synthetically4 and for which
high resolution X-ray crystal structures are available.5 These
enzymes have an extended active site binding region composed
of several subsites, of which the S1-pocket6 dominates, particu-
larly in the binding of hydrophobic groups. Our initial
investigations7 on the remote stereocenter-sensing question
Enzymes are highly efficient biocatalysts that are now widely
exploited in organic syntheses, largely because of the exceptional
asymmetric synthetic advantages that they offer.1 Among the
enzymes that are synthetically useful, hydrolases are currently
receiving the most attention because of their ease of use and of
their abilities to embrace of a wide range of substrate structures.
However, for one-stereocenter, or prochiral, substrates, asym-
metric transformations by hydrolases have overwhelmingly
focussed on the introduction or selection of stereocenters located
adjacent to the site of catalysis.1 Very few examples have been
reported where the stereocenter of interest is three or more bonds
removed from the carbonyl group of the ester function under-
going hydrolysis.2 However, since the whole of an enzyme’s
active site is chiral, an enzyme has the potential to discriminate
of any substrate stereocenter, no matter how remotely it is
located from the catalytic site. The asymmetric synthetic
promise that enzymic methods offer in this regard is significant,
because control of the configurations of stereocenters remote
from the chiral auxiliaries or catalysts applied in nonenzymic
methodology remains an unsolved problem.3 However, the
meager literature database on this topic does not permit any
conclusion to be drawn as to the scope and limitations of the
remote stereocenter discriminating potentials of enzymes.
X Abstract published in AdVance ACS Abstracts, October 1, 1997.
(1) (a) Biotransformations in PreparatiVe Organic Chemistry, 2nd ed.;
Faber, K., Ed.; Springer-Verlag: New York, 1995. (b) Enzymes in Synthetic
Organic Chemistry; Wong, C.-H., Whitesides, G. M., Eds.; Pergamon: New
York, 1994. (c) PreparatiVe Biotransformations; Roberts, S. M., Ed.;
Wiley: New York, 1993.
(2) (a) Hughes, D. L.; Bergan, J. J.; Amato, J. S.; Bhupathy, M.; Leazer,
J. L.; McNamara, J. M.; Sidler, D. R.; Reider, P. J.; Grabowski, E. J. J. J.
Org. Chem. 1990, 55, 6252. (b) Ladner, W. E.; Whitesides, G. M. J. Am.
Chem. Soc. 1984, 106, 7250. (c) Jones, J. B.; Marr, P. W. Tetrahedron
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ska, K.; Gawronski, J. K. HelV. Chim. Acta 1983, 66, 2501. (e) Cohen, S.
G.; Weinstein, S. Y. J. Am. Chem. Soc. 1964, 86, 725.
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Koskinen, A., Ed.; Wiley: New York, 1993. (d) Transition Metals in the
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Can. J. Chem. 1990, 960. (h) Frigerio, F.; Coda, A.; Pugliese, L.; Lionetti,
C.; Menegatti, E.; Amiconi, G.; Schnebli, H. P.; Ascenzi, P.; Bolognesi,
M. J. Mol. Biol. 1992, 225, 107. (i) Ricca, J. M.; Crout, D. H. J. Chem.
Soc., Perkin Trans. I 1989, 2126. (j) Kitaguchi, H.; Fitzpatrick, P. A.;
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Brieva, R.; Rebelleo, F.; Gotor, V. Chem. Commun. 1990, 1386. (l) Gutman,
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S0002-7863(97)00877-9 CCC: $14.00 © 1997 American Chemical Society

Abilities of Serine Proteases to Discriminate Remote Stereocenters
J. Am. Chem. Soc., Vol. 119, No. 43, 1997 10261
1
Chart 1
of diastereomeric imidazolidines exhibited H and 13C NMR
chemical shifts sufficiently different to permit diastereomeric
excess levels of g95% to be confirmed in each case.11
Each pure imidazolidine diastereomer was then hydrolyzed
with wet Si gel of precisely controlled acidity to generate the
R- and S-enantiomers of each of 6, 8, 10, and 12. In each case,
g95% ee values were reconfirmed by reforming the corre-
sponding imidazolidine diastereomers and repeating the NMR
percent de analysis. Absolute configurations were assigned on
the basis of comparisons of optical rotations with those of
literature compounds of established stereochemistry.
The kinetic evaluations of the inhibitory effects of each
naphthyl aldehyde on CT and SC were determined by the
method of Waley,12 using suc-Ala-Ala-Pro-Phe-PNA as the
standard substrate. The results, which showed competitive
inhibition of both enzymes in every case, are recorded in Table
1. For convenient comparison, the KI values for inhibition of
CT and SC by the analogous phenylalkyl aldehydes 1-4
obtained previously7 are also included.
Since the aldehyde inhibitors will be moderately hydrated in
the aqueous assay solutions,13 the observed KI values, which
derive from the free aldehyde concentrations, thus represent
maximum values that underestimate the inhibitory power. The
true aldehyde KI’s are therefore somewhat lower, which goes
part of the way to explain the unexpectedly high, mM rather
than µM range, KI’s of many of the Table 1 inhibitors. While
the hydrated forms may also be capable of acting as a
competitive inhibitors, we were unable to make any predictions
in this regard and did not attempt any corrections for hydration
effects in our kinetic analyses.
Each of the aldehydes 5-12 was a significantly more potent
inhibitor of CT than of SC, generally by about an order of
magnitude. In view of the similarities of all the SC-KI’s, the
following discussion focusses only on CT, for which was
observed the strongest inhibition, by the achiral 3-(1-naphthyl)-
propanal (5) with its KI of 45 µM. Introduction of a C-3 methyl
substituent into 5 is clearly deleterious, with the KI’s of R-6
and S-6 being 10- and 2.7-fold higher, respectively, than that
of the achiral parent. Within the 1-naphthyl series, introduction
of an extra methylene group, as in 7, also results in weaker
binding, with the KI of 7 being 5-fold higher than that of its
lower homolog 5. In contrast, creation of a remote stereocenter
by inserting a C-4 methyl group now has a beneficial effect on
binding, with the KI’s of R-8 and S-8 becoming lower than that
of 7 by factors of 4. The CT-binding differences between the
inhibitors of the 2-naphthyl series 9-12 are somewhat smaller,
with the maximum KI variation being 6-fold between R-10
and S-12, compared with the 1-naphthyl series with its 10.4-
fold KI difference between 5 and R-6. However, CT is evi-
dently responsive to minor constitutional isomerism changes
in that the achiral 2-naphthylpropanal (9) binds 9-fold worse
than its 1-naphthyl isomer 5. Furthermore, the introduction of
a C-4 methyl group, as in S-8 and R-8, now becomes only
marginally beneficial. Another contrast between the 1- and
2-naphthyl series is that the achiral 2-naphthyl aldehyde 11, with
its extra methylene group, now binds 3-fold better than its lower
homolog 9.
focussed on the interactions of SC and CT with the chiral
phenylalkylaldehyde, transition state analog8 inhibitors 2 and 4
and their achiral parents 1 and 3. In this paper, the investigation
has been extended to the 1- or 2-naphthylalkylaldehyde struc-
tures 5-12, selected as suitable probes for S1-site specificity
by graphics analyses based on the X-ray structures of SC and
CT.5 For these naphthyl inhibitors, remote â- or γ-stereocenter
and structural specificity selectivities quite different from those
of their phenyl analogs 1-4 become manifest.
Results and Discussion
Aldehyde structures were selected since they are well-known
to be good transition state analog competitive inhibitors of serine
proteases9 and, due to the formation of hydrates,10 usually have
sufficient aqueous solubility for kinetics to be performed in
water or with minimal organic cosolvent requirements. The
achiral aldehydes 5, 7, 9, and 11 and their respective racemic
chiral derivatives 6, 8, 10, and 12 were prepared by unexcep-
tional routes that are fully described in the Experimental Section.
Resolutions of the racemates 6, 8, 10, and 12 into their individual
enantiomers were accomplished by their conversions into the
corresponding diastereomeric imidazolidines with (1R,2R)-N,N′-
dimethyl-1,2-diphenylethylenediamine.11 These were chro-
matographically separable into their individual diastereomers
in excellent yields. Moreover, the methyl groups of each pair
Examination of the stereoselectivity differences reveals that
for CT, regardless of the 1- or 2-naphthyl substitution or whether
(8) (a) Lienhard, G. E. Science 1973, 180, 149. (b) Wolfenden, R. V.
Acc. Chem. Res. 1972, 5, 10. (c) Koehler, K. A.; Lienhard, G. E.
Biochemistry 1971, 10, 2477. (d) Wolfenden, R. V.; Radzicka, A. Curr.
Opin. Struct. Biol. 1991, 1, 780.
(9) (a) Rawn, J. D.; Lienhard, G. E. Biochemistry 1974, 13, 3124. (b)
Tatsuta, K.; Mikami, N.; Fujimoto, K.; Umezawa, S.; Umezawa, H.; Aoyagi,
T. J. Antibiot. (Tokyo), Ser. A. 1973, 26, 625. (c) Ito, A.; Tokawa, K.;
Shimizu, B. Biochem. Biophys. Res. Comm. 1972, 49, 343.
(11) (a) Mangeney, P.; Tejero, T.; Alexakis, A.; Grosjean, F.; Normant,
J. Synthesis 1988, 255. (b) Mangeney, P.; Grojean, F.; Alexakis, A.;
Normant, J. F. Tetrahedron Lett. (c) Mangeney, P.; Alexakis, A.; Normant,
J. F. Tetrahedron Lett. 1988, 29, 2677.
(12) Waley, S. G. J. Biochem. 1982, 205, 631.
(10) Keeffe, J. R.; Kresge, A. J. In The Chemistry of Enols; Rappoport,
Z., Ed.; John Wiley & Sons: Toronto, 1990, p 399.
(13) (a) Lewis, C. A., Jr.; Wolfenden, R. Biochemistry 1977, 16, 4886.
(b) Lewis, C. A., Jr.; Wolfenden, R. Biochemistry 1977, 16, 4895.

10262 J. Am. Chem. Soc., Vol. 119, No. 43, 1997
Lee and Jones
Table 1. Inhibition of R-Chymotrypsin and Subtilisin Carlsberg by the 1- and 2-Naphthyl Aldehydes 5-12, with Their Phenyl Aldehyde
Analogs 1-4 for Comparisona
a KI values for both enzymes were determined7,12 in duplicate at pH 7.5 at 25 °C in 0.1 M NaH2PO4, 0.5 M NaCl, 0.25 mM of substrate, 5%
DMSO (v/v), and enzyme concentrations of 4.5 nM (SC) and 16 nM (CT). b From ref 7.
the remote stereocenter is at the C-3 or C-4 position, the
S-enantiomers are somewhat preferred over their R counterparts.
However, even in the best case of inhibitors R- and S-6, where
the S-enantiomer binds 4-fold better than the R, the stereose-
lectivity difference is well below that required for the effective
resolution of a structurally analogous substrate. This contrasts
the more favorable stereoselectivity situation with the phenyl
aldehydes, where the R-2 over S-2 discrimination by CT is a
very healthy 88-fold. In fact, there are several interesting
variations in the patterns of CT inhibition between the phenyl
aldehydes 1-4 and their 1- and 2-naphthyl counterparts 5-12,
while for SC the variations between the different inhibitor
structures are minor and unremarkable, and with the KI values
in the weakly inhibiting mM range almost throughout. Despite
its greater potential for hydrophobic interaction with the S1-
pocket, the naphthyl group evidently does not confer better
binding properties, nor does it elicit improved stereorecognition
benefits.
their achiral analogs 5 and 7, respectively. In contrast, for CT,
the presence of either an R- or S-center methyl substituent in
R-6 or S-6 exerts a negative influence, with the KI of the
unsubstituted parent 5 being 10.4- and 2.7-fold lower than those
of R-6 and S-6, respectively. On the other hand, the R-center
methyl substituent of (3R)-3-phenylbutanal (R-2) is highly
beneficial to good binding, since it binds 61- and 16-fold more
strongly than its unsubstituted parent 1 with CT and SC,
respectively.7 In contrast, the presence of similar R-center
methyl substituent in the 1-naphthyl aldehydes R-6 and S-6 does
not bestow a similarly advantageous binding contribution, and
this deficiency may well be responsible for the observed
stereoselectivity reversal for these inhibitors. Moreover, for the
isomeric 2-naphthyl probes 9-12, the reversals of stereoselec-
tivity relative to the phenyl analogs are also attributable to
negative contributions binding by R-methyl substituents com-
pared with the neutral effect on KI’s of introducing an
S-configuration methyl group.
The differences in the degree of stereoselectivity between the
phenyl and naphthyl inhibitors is not the only interesting
observation. In addition, the direction of stereoselectivity is
different for the two series. For the phenyl cases studied
previously, CT-binding of the R- over the S-enantiomers was
significantly favored for 2 and 4,7 whereas for the naphthyl
analogs 6, 10, and 12, the S-enantiomers now become the
preferred inhibitors, albeit to a much lesser degree.
The questions posed by the observed differences and reversals
of stereoselectivity for the naphthyl and phenyl inhibitors are
intriguing. For the 1-naphthyl probes 5-8, SC appears to be
unresponsive to the presence of a methyl substituent that creates
a remote stereocenter of either R- or S-configuration, with the
KI’s of R-6, S-6, R-8, and S-8 being very similar to those of
Similar reversals of CT stereoselectivity induced by replacing
phenyl by naphthyl have also been detected with boronic acid
inhibitors.14 In this case it was suggested that a contributing
factor was the fact that the naphthyl groups could be bound in
different conformations not available to their CV-symmetric
phenyl analogs. The molecular modeling performed supported
this hypothesis, with the caveat that the calculations could not
take into account any E1 complexation involving boron-
histidine bonds.15 Fortunately, for aldehyde E1 complexes, there
is no corresponding evidence for histidine adducts. Thus the
(14) Martichonok, V.; Jones, J. B. J. Am. Chem. Soc. 1996, 118, 950.
(15) (a) Tsilikounas, E.; Kettner, C. A.; Bachovchin, W. W. Biochemistry
1993, 32, 12651. (b) Zhong, S.; Haghjoo, K.; Kettner, C.; Jordan, F. J.
Am. Chem. Soc. 1995, 117, 7048.

Abilities of Serine Proteases to Discriminate Remote Stereocenters
J. Am. Chem. Soc., Vol. 119, No. 43, 1997 10263
Figure 1. Superimposed energy-minimized E1 complexes of (3R)-
and (3S)-3-(1-naphthyl)butanals, R-6 (boldface s) and S-6 (boldface
- -), respectively, in the active site of CT. The oxyanions of the
tetrahedral complexes derived from R-6 and S-6 are located in the
oxyanion hole, and are stabilized by hydrogen-bonding (‚‚‚) with the
peptide NH’s of Ser195 (O--N, 3.12 and 3.15 Å respectively for R-6
and S-6) and Gly193 (O--N, 2.89 and 2.88 Å respectively for R-6
and S-6). The methyl group at the stereocenter of the better inhibitor
S-6 is located more deeply inside of the S2 pocket than that of R-6,
thereby eliciting the better hydrophobic interaction manifest in the lower
KI of S-6.
Figure 2. Superimposed energy-minimized E1 complexes of (3R)- and
(3S)-3-(1-naphthyl)butanals, R-6 (boldface s) and S-6 (boldface - -),
respectively, in the active site of SC. The negative charges of the
oxyanions of the tetrahedral complexes derived from R-6 and S-6 are
again stabilized to similar degrees by the oxyanion hole, by hydrogen-
bonding (‚‚‚) with the peptide NH of Ser221 (O--N, 2.80 and 2.91 Å,
respectively, for R-6 and S-6) and the side chain -NH2 of Asn155
(O--N, 2.81 and 2.82 Å, respectively, for R-6 and S-6). The methyl
groups at the stereocenters of R-6 and S-6 are directed outside of the
active site and do not contribute to binding. Furthermore, the naphthyl
moieties of both R-6 and S-6 are oriented very similarly in the
hydrophobic S1-pocket. The absence of significant binding differences
is in accord with the comparable inhibitory powers of R-6 and S-6
measured experimentally.
search for an explanation of the KI and stereoselectivity dif-
ferences Via molecular modeling based on transition state analog
formation by addition of the active site serine nucleophiles is
considerably more secure.
Molecular modeling was performed as described previously7
for the representative pairs of inhibitors R-6, S-6, R-10, and
S-10, using X-ray structures of CT and SC energy-minimized
by molecular mechanics. Each inhibitor was individually
docked into the active site, with the naphthyl moieties in the
S1-subsite, and with the aldehyde carbonyl carbon covalently
bonded to the active site serine-CH2OH oxygen to form a
transition state-like tetrahedral intermediate. Each E1-complex
was then subjected to energy-minimization by molecular
mechanics calculations, and the optimized conformations and
the free energies of each R- and S-pair of E1 complexes
compared. The results are depicted in Figures 1-4.
In each minimized E1 complex, there were strong interac-
tions between the oxyanion of the tetrahedral intermediate
and the oxyanion hole H-bonding residues of the peptide
backbone NH’s of Ser195 and Gly193 of CT and the backbone
NH of Ser221 and the side chain NH2 of Asn155 of SC,
respectively. Accordingly, it is apparent that the KI variations
manifest in Table 1 reflect the active site differences between
the naphthyl and methyl group interactions and orientations of
each inhibitor.
Figure 1 shows that the 1-naphthyl moieties of R-6 and S-6
adopt very different orientations in the hydrophobic S1 pocket
of CT. As a result, the methyl group at the stereocenter of the
S-enantiomer is directed more deeply into the S2 pocket and
thus elicits a stronger hydrophobic interaction than does the
corresponding methyl group of R-6. This accounts for the 3.9-
fold lower KI of S-6 than R-6. Furthermore, the calculated ∆∆G
value (1.8 Kcal/mol) between the two E1 complexes ap-
proximates the experimental value16 of 0.82 kcal/mol.
The corresponding picture for SC is depicted in Figure 2.
For both E1 complexes of R-6 and S-6, the naphthyl groups
penetrate adequately, and almost equivalently, into S1 to provide
good hydrophobic binding contributions. In addition, now the
methyl groups at the stereocenters of both enantiomers are
Figure 3. Superimposed energy-minimized E1 complexes of (3R)- and
(3S)-3-(2-naphthyl)butanal, R-10 (boldface s) and S-10 (boldface - -),
respectively, in the active site of CT. The oxyanions of the tetrahedral
complexes derived from R-10 and S-10 are located in the oxyanion
hole, stabilized by hydrogen-bonding (‚‚‚) with the peptide NH’s of
Gly193 (O--N, 2.75 and 2.79 Å, respectively, for R-10 and
S-10), but having weak interaction with the peptide NH’s of Ser195
(O--N, 3.45 and 3.85 Å, respectively, for R-10 and S-10). While the
methyl group at the stereocenter of R-10 must occupy a sterically
unfavorable location very close to the peptide bond of Trp215, that of
S-10 is more agreeably positioned outside of the active site. This factor,
together with the deeper penetration of the 2-naphthyl groups of S-10
into the S1 hydrophobic pocket, explains the lower KI of the S-
enantiomer.
oriented toward the outside of the active site and do not make
any binding contributions. Thus the overall binding efficiencies
of R-6 and S-6 with SC are comparable, as reflected by their
almost equivalent KI’s and by the virtually indistinguishable
calculated free energy values of the minimized E1 complexes
for R-6 (-1285.9 Kcal/mol) and S-6 (-1286.1 Kcal/mol). In

10264 J. Am. Chem. Soc., Vol. 119, No. 43, 1997
Lee and Jones
mol equiv) in CH2Cl2 (18 mL) was added N-methoxy-N-methyl-2-
(triphenylphosphoranylidine)acetamide18 (10.2 g, 28.0 mmol, 2.0 mol
equiv) at 20 °C. The reaction mixture was stirred for 2 days at 20 °C
and then concentrated in Vacuo. The crude product was chromato-
graphed on a Si gel column (hexanes/EtOAc, 80/20 elution) to give
N-methoxy-N-methyl-3-(1-naphthyl)prop-2-enamide (3.30 g, 98%) as
a white solid: mp 66-67 °C; IR (cm-1) 1656, 1611; 1H NMR (CDCl3)
δ 3.35 (3H, s), 3.78 (3H, s), 7.11 (1H, d, J ) 15.5 Hz), 7.45-7.60
(3H, m), 7.76-7.90 (3H, m), 8.20-8.30 (1H, m), 8.57 (1H, d, J )
13.5 Hz).
N-Methoxy-N-methyl-3-(1-naphthyl)prop-2-enamide (1.66 g, 6.9
mmol) in EtOAc (24 mL) containing 10% Pd/C (60 mg) was stirred
under H2 (1 atm) at 20 °C for 20 h. The reaction mixture was filtered
through Celite and then Si gel and then concentrated in Vacuo to give
N-methoxy-N-methyl-3-(1-naphthyl)propanamide (1.60 g, 96%) as
colorless oil: IR (cm-1) 1737, 1663; 1H NMR (CDCl3) δ 2.86 (2H, t,
J ) 7.4 Hz), 3.21 (3H, s), 3.38-3.50 (2H, m), 3.57 (3H, s), 7.35-
7.55 (4H, m), 7.70-7.90 (2H, m), 8.06-8.10 (1H, m).
Figure 4. Superimposed energy-minimized E1 complexes of (3R)- and
(3S)-3-(2-naphthyl)butanal, R-10 (boldface s) and S-10 (boldface - -),
respectively, in the active site of SC. Again, good oxyanion hole
stabilization is seen for both tetrahedral complexes derived from R-10
and S-10, involving hydrogen-bonding (‚‚‚) with the peptide NH of
Ser221 (O--N, 2.82 and 2.99 Å, respectively, for R-10 and S-10) and
the side chain -NH2 of Asn155 (O--N, 2.77 and 2.78 Å, respectively,
for R-10 and S-10). The comparable KI’s of R-10 and S-10 are in
agreement with the similar orientations of both naphthyl groups in S1
and the external-to-active-site locations of each methyl group that
preclude stereocenter discrimination differences.
To a solution of N-methoxy-N-methyl-3-(1-naphthyl)propanamide
(243 mg, 1.0 mmol, 1.0 mol equiv) in THF (10 mL) was added LiAlH4
(48 mg, 1.2 mmol, 1.2 mol equiv) at -78 °C under a N2 atmosphere.
Stirring was continued for 20 min at -78 °C, and the mixture then
poured into 5% ethanolic HCl (10 mL) at 0 °C and partitioned between
brine (10 mL) and ether:CH2Cl2 (1:1). The organic layer was dried
(MgSO4), filtered, and concentrated in Vacuo and 3-(1-naphthyl)-
propanal19 (5, 146 mg, 79%) isolated by radial TLC (Chromatotron,
1
hexanes/EtOAc, 90/10) as a colorless oil: IR (cm-1) 1721; H NMR
(CDCl3) δ 2.92 (2H, t, J ) 7.5 Hz), 3.42 (2H, t, J ) 8.1 Hz), 7.30-
8.00 (7H, m), 9.88 (1H, t, J ) 1.2 Hz).
(3R)- and (3S)-3-(1-Naphthyl)butanal (R-6 and S-6) [General
Procedure B]. To 1-naphthaldehyde (3.0 g, 19.2 mmol, 1.0 mol equiv)
in CH2Cl2 (18 mL) was added methyl 2-(triphenylphosphoranylidine)-
acetate (7.68 g, 23.1 mmol, 1.2 mol equiv) at 20 °C. The reaction
mixture was stirred for 15 h at 20 °C and then concentrated in Vacuo,
and the crude product chromatographed on Si gel column (hexanes/
EtOAc, 90/10 elution) to give methyl 3-(1-naphthyl)prop-2-enoate (4.11
g, 99%) as a colorless oil: 1H NMR (CDCl3) δ 3.85 (3H, s), 6.52 (1H,
d, J ) 15.8 Hz), 7.45-7.62 (3H, m), 7.73 (1H, d, J ) 7.3 Hz), 7.85-
7.95 (2H, m), 8.15-8.25 (1H, m), 8.53 (1H, d, J ) 15.7 Hz); 13C NMR
δ 52.3, 120.9, 123.9, 125.5, 126.0, 126.7, 127.4, 129.2, 131.0, 131.9,
132.2, 134.2, 142.4, 167.8.
To a slurry of CuI (3.77 g, 19.8 mmol, 1.2 mol equiv) in Et2O (80
mL), ethereal MeLi (1.4 M, 28.3 mL, 39.6 mmol, 2.4 mol equiv) was
added dropwise during 5 min at 0 °C under N2 atmosphere. The
reaction mixture was stirred for 10 min at 0 °C then cooled to -25 °C.
A solution of methyl 3-(1-naphthyl)prop-2-enoate (3.50 g, 16.5 mmol,
1.0 mol equiv) in Et2O (20 mL) was injected into the reaction mixture
at -25 °C. The reaction mixture was stirred for an additional 1 h at
-25 °C and then quenched with saturated aqueous NH4Cl (50 mL).
The resulting mixture was stirred until the solid had dissolved and the
aqueous layer had turned deep blue. The organic layer was separated,
and the aqueous phase extracted with Et2O (2 × 50 mL). The combined
organic layers were washed with brine (50 mL), dried (MgSO4), filtered,
and concentrated in Vacuo, and the crude product purified by radial
TLC (Chromatotron, hexanes/EtOAc, 90/10) to yield methyl (()-3-
(1-naphthyl)butanoate (1.50 g, 40%) as a colorless oil: IR (cm-1) 1740;
1H NMR δ 1.45 (3H, d, J ) 6.8 Hz), 2.63 (1H, d of d J ) 15.3,
9.3 Hz), 2.87 (1H, d of d, J ) 15.2, 5.3 Hz), 3.67 (3H, s), 4.13-4.28
(1H, m), 7.35-7.60 (4H, m), 7.74 (1H, d, J ) 8.1), 7.85-7.92
(1H, m), 8.19 (1H, d, J ) 8.4 Hz); 13C NMR δ 21.7, 31.3, 42.8, 52.1,
122.8, 123.5, 126.0, 126.1, 126.6, 127.4, 129.5, 131.6, 134.5, 142.2,
173.5.
the isomeric 2-naphthyl aldehyde series, the interpretations of
the molecular modeling results on the E1 complexes of R-10
and S-10 were carried out similarly. In these cases, the KI-
differences for inhibition of CT (1.8-fold) and SC (1.1-fold) by
the enantiomers are very small. This is reflected in the
molecular modeling results (Figures 3 and 4), which reveal only
minor differences in the active site positions and orientations
of the R-10 and S-10 in both CT and SC.
While the levels of remote stereocenter stereoselectivity
achieved in the present study are modest, the data demonstrate
that the use of chiral competitive inhibitors as probes, in
conjunction with molecular modeling, is clearly an effective
strategy. Our eventual goal is to establish that molecular
modeling prior to experimental work can provide an effective
filter which will identify the structures with the highest R-to-S
discrimination potential and thereby eliminate the need for more
time consuming experimental or kinetic screening. In this
regard, the results to date are very encouraging, in that when
little positional or free energy differences are seen between the
modeled E1 complexes of enantiomeric inhibitors, the KI
variations are small, and there will be little stereocenter
configuration discrimination. On the other hand, when there
is a large KI separation, such as the potentially preparatively
significant 88-fold factor between R- and S-2, clearly discernible
differences between the active site orientations of the two
enantiomers are evident, particularly with respect to the ste-
reocenter region, with the more favorable position of the lower
energy complex clearly identifiable.7
Experimental Section
To methyl (()-3-(1-naphthyl)butanoate (1.00 g, 4.38 mmol, 1.0 mol
equiv) in Et2O (5 mL) was added LiAlH4 (116 mg, 2.63 mmol, 2.4 H-
mol equiv) at 0 °C under N2. The reaction mixture was stirred for 5
min at 0 °C, then warmed to 20 °C, and stirred for an additional 30
min. It was then diluted with EtOAc (5 mL), and the reaction then
quenched by the slow addition of brine (5 mL). The organic layer
was separated, dried (MgSO4), filtered, and concentrated in Vacuo, and
The materials and suppliers, equipment, and analytical methods used
were as described previously.7 When needed, solvents were dried by
standard methods.17
1-Naphthyl Series. 3-(1-Naphthyl)propanal (5) [General Pro-
cedure A]. To a solution of 1-naphthaldehyde (2.2 g, 14.0 mmol, 1.0
(16) Calculated from ∆∆G ) -RT ln[(KI)S/(KI)R].
(17) Perrin, D. D.; Armarego, W. L. F.; Perrin, D. R. Purification of
Laboratory Chemicals; Pergamon Press: New York, 1980.
(18) Evans, D. E.; Kaldor, S. W.; Jones, T. K.; Clardy, J.; Stout, T. J. J.
Am. Chem. Soc. 1990, 112, 7001.

Abilities of Serine Proteases to Discriminate Remote Stereocenters
J. Am. Chem. Soc., Vol. 119, No. 43, 1997 10265
(()-3-(1-naphthyl)butan-1-ol (820 mg, 94%) was purified by radial
TLC (Chromatotron, hexanes/EtOAc, 80/20) as a colorless oil: 1H
NMR δ 1.43 (3H, d, J ) 6.8 Hz), 1.85-2.20 (2H, m), 3.53-3.73
(2H, m), 3.75-3.90 (2H, m), 7.36-7.55 (4H, m), 7.68-7.75 (1H, m),
7.80-7.90 (1H, m), 8.15-8.23 (1H, m); 13C NMR δ 22.4, 30.5, 41.1,
61.7, 123.1, 123.6, 125.9, 126.1, 126.3, 127.0, 129.5, 132.1, 134.5,
143.6.
H2SO4 (250 µL) gave (3S)-3-(1-naphthyl)butanal (S-6, 88 mg, 89%,
>95% ee) as a colorless oil: [R]24 +21.0° (c 0.3, Et2O); lit.20 [R]20
D
D
+2.0° (c 0.1, EtOH, 35% ee); HRMS, calcd for M+ C14H14O m/e
198.1045, found m/e 198.1046, spectroscopically identical to the
racemate ((()-6).
4-(1-Naphthyl)butanal (7) [General Procedure C]. Jones oxida-
tion21 of 3-(1-naphthyl)propanal (5, 130 mg, 0.71 mmol) in acetone (3
mL) gave 3-(1-naphthyl)propanoic acid (124 mg, 88%) as a light yellow
solid: 1H NMR δ 2.83 (2H, t, J ) 7.7 Hz), 3.45 (2H, t, J ) 8.3 Hz),
7.35-7.60 (4H, m), 7.70-7.80 (1H, m), 7.85-7.92 (1H, m), 8.02-
8.10 (1H, m), 10.8-11.1 (1H, br).
DMSO (703 mg, 9.0 mmol, 2.4 mol equiv) in CH2Cl2 (2.0 mL) was
added dropwise at -60 °C under N2 atmosphere to a solution of
oxalylchloride (571 mg, 4.5 mmol, 1.2 mol equiv) in CH2Cl2 (10 mL).
The reaction mixture was stirred for 3 min then (()-3-(1-naphthyl)-
butan-1-ol (750 mg, 3.75 mmol, 1.0 mol equiv) in CH2Cl2 (4.0 mL)
was added dropwise at -60 °C. The reaction mixture was stirred for
15 min, and Et3N (1.82 g, 17.9 mmol, 5.0 mol equiv) was then added
at -60 °C. After the reaction mixture was stirred for 5 min at -60
°C, it was warmed to 20 °C, the reaction quenched by the addition of
brine (10 mL), the organic layer separated, and the aqueous phase
extracted with CH2Cl2 (2 × 10 mL). The combined organic layers
were washed with water (10 mL), then with brine (10 mL), dried
(MgSO4), filtered, and concentrated in Vacuo. The crude product was
purified by radial TLC (Chromatotron, hexanes/EtOAc, 90/10) to give
(()-3-(1-naphthyl)butanal ((()-6, 722 mg, 97%) as a colorless oil: IR
3-(1-Naphthyl)propanoic acid (95 mg, 0.48 mmol) in SOCl2 (283
mg, 5.0 mmol) was refluxed for 2 h under an N2 atmosphere, the excess
SOCl2 was then removed under reduced pressure, and the crude product
Kugelrohr-distilled to give 3-(1-naphthyl)propanoyl chloride as a
colorless oil. This was dissolved immediately in Et2O (1.0 mL) and
added dropwise at 0 °C to a solution of CH2N2 prepared from Diazald
(520 mg, 2.4 mmol, 5.0 mol equiv) in Et2O (6.5 mL), and the reaction
mixture was then stirred at 20 °C for 3 h. The reaction mixture was
then concentrated under reduced pressure, and the crude product purified
by radial TLC (Chromatotron, hexanes/EtOAc, 90/10) to give 1-diazo-
4-(1-naphthyl)butan-2-one (78 mg, 73% from acid) as a yellow oil:
1
IR (cm-1) 1645; H NMR δ 2.71 (2H, 7, J ) 7.0 Hz), 3.40 (2H, t, J
1
(cm-1) 1724; H NMR δ 1.46 (3H, d, J ) 6.9 Hz), 2.70-3.00 (2H,
) 8.1 Hz), 5.11 (1H, s), 7.25-7.55 (4H, m), 7.65-7.89 (2H, m), 7.99
(1H, d, J ) 7.2 Hz); 13C NMR δ 27.8, 41.4, 54.6, 123.3, 125.3, 125.5,
125.8, 126.0, 127.0, 128.8, 131.5, 133.8, 136.6, 193.8.
m), 4.15-4.32 (1H, m), 7.32-7.60 (4H, m), 7.73 (1H, d, J ) 8.0 Hz),
7.85-7.93 (1H, m), 8.10-8.20 (1H, m), 9.77 (1H, t, J ) 1.8 Hz); 13
C
NMR δ 22.1, 29.0, 51.8, 123.2, 123.3, 126.1, 126.2, 126.7, 127.6, 129.6,
To 1-diazo-4-(1-naphthyl)butan-2-one (75 mg, 0.33 mmol) in MeOH
(2.5 mL) at 60 °C was added a catalytic amount of Ag2O. After N2
evolution ceased (5 min), the reaction mixture was stirred for an
additional 30 min at 60 °C, Norit added, and the reaction mixture
filtered, concentrated under reduced pressure, and purified by radial
TLC (Chromatotron, hexanes) to give methyl 4-(1-naphthyl)butanoate
131.5, 134.5, 141.8, 202.3.
The above racemate was resolved as follows: To (()-3-(1-naphthyl)-
butanal ((()-6, 6.70 mg, 3.38 mmol, 1.0 mol equiv) in Et2O (30 mL)
was added molecular sieves (7.0 g) followed by (1R,2R)-N,N′-dimethyl-
1,2-diphenyl-ethylenediamine11 (812 mg, 3.38 mmol, 1.0 mol equiv)
at 20 °C under N2. The reaction mixture was stirred for 15 h at 20 °C
and then filtered through Celite. The filtrate was concentrated in Vacuo,
and the diastereomeric imidazolidines separated by column chroma-
tography on Si gel (hexanes/EtOAc, 90/10 elution) to give diastereo-
merically pure R,R,R-N,N′-dimethyl-4,5-diphenyl-2-[2-(1-naphthyl)-
1
(67 mg, 89%) as a colorless oil: IR (cm-1) 1736; H NMR δ 2.07
(2H, q, J ) 7.6 Hz), 2.40 (2H, t, J ) 7.3 Hz), 3.10 (2H, t, J ) 7.3 Hz),
3.66 (3H, s), 7.31-7.55 (4H, m), 7.71 (1H, d, J ) 8.4 Hz), 7.80-7.89
(1H, m), 8.06 (1H, d, J ) 9.0 Hz); 13C NMR δ 25.7, 32.2, 33.6, 51.4,
123.7, 125.4, 125.5, 125.8, 126.1, 126.8, 128.7, 131.8, 133.9, 137.4,
173.8.
propyl]-1,3-imidazolidine (less polar, 600 mg, 85%, >95% de): [R]24
D
-53.0° (c 0.6, CHCl3); IR (cm-1) 3033, 2964, 2792, 1454; 1H NMR δ
1.49 (3H, d, J ) 7.0 Hz), 1.95-2.15 (1H, m), 2.11 (3H, s), 2.27 (3H,
s), 2.40-2.55 (1H, m), 3.56 (2H, d of d, J ) 39.0, 8.4 Hz), 3.85-3.95
(1H, m), 4.05-4.25 (1H, m), 7.10-7.34 (10H, m), 7.43-7.56 (4H,
m), 7.70-7.80 (1H, m), 7.85-7.94 (1H, m), 8.29 (1H, d, J ) 8.9 Hz);
13C NMR δ 24.4, 29.8, 34.8, 37.2, 41.3, 76.0, 79.6, 83.1, 122.5, 123.2,
125.3, 125.6, 125.8, 126.4, 127.1, 127.3, 127.6, 128.0, 128.1, 128.2,
129.0, 131.6, 134.1, 139.8, 141.0, 143.2, and R,R,S-N,N′-dimethyl-4,5-
diphenyl-2-[2-(1-naphthyl)propyl]-1,3-imidazolidine (more polar, 610
Using general procedure B above, methyl 4-(1-naphthyl)butanoate
(63 mg, 0.28 mmol, 1.0 mol equiv) and LiAlH4 (6.7 mg, 0.15 mmol,
2.2 H- mol equiv) gave 4-(1-naphthyl)butan-1-ol (50 mg, 91%) as a
1
colorless oil: IR (cm-1) 3600-3200 (br); H NMR δ 1.25 (1H, s),
1.65-1.95 (4H, m), 3.12 (2H, t, J ) 7.0 Hz), 3.65-3.75 (2H, m), 7.30-
7.55 (4H, m), 7.72 (1H, d, J ) 8.1 Hz), 7.82-7.90 (1H, m), 8.01-
8.10 (1H, m).
4-(1-Naphthyl)butan-1-ol (49 mg, 0.25 mmol, 1.0 mol equiv), oxalyl
chloride (37 mg, 0.29 mmol, 1.2 mol equiv), DMSO (46 mg, 0.59
mmol, 2.4 mol equiv) and Et3N (124 mg, 1.23 mmol, 5.0 mol equiv)
gave 4-(1-naphthyl)butanal19 (7, 37 mg, 77%) as a colorless oil: IR
mg, 86%, >95% de): [R]24 -85.2° (c 0.5, CHCl3); IR (cm-1) 3030,
D
1
2967, 2793, 1452; H NMR δ 1.56 (3H, d, J ) 6.8 Hz), 1.95-2.30
(2H, m), 2.19 (3H, s), 2.54 (3H, s), 3.54 (2H, d of d, J ) 22.9, 8.7
Hz), 4.05-4.20 (2H, m), 7.02-7.10 (2H, m), 7.15-7.30 (8H, m), 7.45-
7.65 (4H, m), 7.70-7.80 (1H, m), 7.88-7.96 (1H, m), 8.52 (1H, d, J
) 9.1 Hz); 13C NMR δ 20.5, 29.3, 34.6, 40.5, 41.8, 75.4, 80.0, 82.8,
122.6, 123.8, 125.4, 125.6, 125.8, 126.3, 127.2, 128.0, 128.1, 128.9,
131.4, 134.0, 139.6, 140.5, 144.5.
1
(cm-1) 1726; H NMR δ 2.11 (2H, q, J ) 7.6 Hz), 2.55 (2H, t, J )
7.1 Hz), 3.13 (2H, t, J ) 7.3 Hz), 7.30-7.55 (4H, m), 7.74 (1H, d,
J ) 8.8 Hz), 7.82-7.89 (1H, m), 8.02-8.11 (1H, m), 9.79 (1H, t,
J ) 1.5 Hz).
The preparations of aldehydes R-8 and S-8 were carried out in the
same manner, as follows.
Each diastereomer was converted back to its aldehyde component
as follows: To Si gel (1.7 g, Si gel 60, Merck, 70-230 mesh) in
CH2Cl2 (6 mL) was added 15% H2SO4 (170 µL). After 5 min, the
water phase disappeared due to absorption on the Si gel surface. A
solution of R,R,R-N,N′-dimethyl-4,5-diphenyl-2-[2-(1-naphthyl)propyl]-
1,3-imidazolidine (140 mg, 0.34 mmol) in CH2Cl2 (1.5 mL) was then
added at 20 °C, and the reaction mixture was stirred for 30 min at 20
°C. The solid phase was separated by suction filtration, and the solid
was washed several times with CH2Cl2. The filtrate was dried (MgSO4),
filtered, and concentrated in Vacuo to give (3R)-3-(1-naphthyl)butanal
(R-6, 60 mg, 90%, >95% ee) as a colorless oil: [R]24D -21.0° (c 0.3,
(4R)-4-(1-Naphthyl)pentanal (R-8). (3R)-3-(1-Naphthyl)butanal
(R-6, 105 mg, 0.53 mmol), Jones reagent, and acetone (2 mL) gave
(3R)-3-(1-naphthyl)butanoic acid (103 mg, 91%) as a light yellow
solid: mp 64-67 °C; [R]25D -4.5° (c 0.27, CHCl3); IR (cm-1) 3540-
3046 (br), 1707; 1H NMR δ 1.46 (3H, d, J ) 6.8 Hz), 2.58-2.75 (1H,
m), 2.85-2.98 (1H, m), 4.05-4.25 (1H, m), 7.33-7.60 (4H, m), 7.73
(1H, d, J ) 7.7 Hz), 7.82-7.91 (1H, m), 8.16 (1H, d, J ) 9.1 Hz),
10.23-11.48 (1H, br); 13C NMR δ 21.1, 30.5, 42.1, 122.3, 122.9, 125.5,
125.6 126.1, 127.0, 129.0, 131.0, 134.0, 141.3, 179.0.
(19) Stokker, G. E.; Hoffman, W. F.; Alberts, A. W.; Cragoe, E. J.;
Deana, A. A.; Gilfillan, J. L.; Huff, J. W.; Novello, F. C.; Prugh, D. J.;
Smith, R. L.; Willard, A. K. J. Med. Chem. 1985, 28, 347.
(20) Berlan, J.; Besace, Y.; Pourcelot, G.; Cresson, P. Tetrahedron 1986,
42, 2675.
(21) Bowers, A.; Halsall, T. G.; Jones, E. R. H.; Lemin, A. J. J. Chem.
Soc. 1953, 2548.
Et2O); lit.20 [R]20 -3.0° (c 0.1, EtOH, 55% ee), spectroscopically
D
identical to the racemate ((()-6). HRMS, Calcd for M+ C14H14O m/e
198.1045, found m/e 198.1041.
Similarly, R,R,S-N,N′-dimethyl-4,5-diphenyl-2-[2-(1-naphthyl)pro-
pyl]-1,3-imidazolidine (210 mg, 0.50 mmol), Si gel (2.5 g), and 15%

10266 J. Am. Chem. Soc., Vol. 119, No. 43, 1997
Lee and Jones
(3R)-3-(1-Naphthyl)butanoic acid (41 mg, 0.19 mmol, 1.0 mol equiv)
and SOCl2 (164 mg, 1.38 mmol, 7.3 mol equiv) gave (3R)-3-(1-
naphthyl)butanoyl chloride as a colorless oil, which on treatment with
ethereal CH2N2 (large excess) gave (4R)-1-diazo-4-(1-naphthyl)pentan-
(4S)-4-(1-Naphthyl)pentan-1-ol (95 mg, 0.44 mmol, 1.0 mol equiv),
oxalyl chloride (68 mg, 0.53 mmol, 1.2 mol equiv), DMSO (84 mg,
1.07 mmol, 2.4 mol equiv), Et3N (225 mg, 2.2 mmol, 5.0 mol equiv),
and CH2Cl2 (3.5 mL) gave (4S)-4-(1-naphthyl)pentanal (S-8, 86 mg,
91%) as a colorless oil: [R]25D -24.7° (c 0.30, Et2O), spectroscopically
identical to the R-enantiomer. HRMS, calcd for M+ C15H16O m/e
212.1201, found m/e 212.1206.
2-one (34 mg, 76% from acid) as a yellow oil: [R]23 +1.5° (c 0.20,
D
CH2Cl2); IR (cm-1) 1635; 1H NMR δ 1.44 (3H, d, J ) 6.8 Hz), 2.52-
2.68 (1H, m), 2.82 (1H, d of d J ) 15.0, 5.1 Hz), 4.22 (1H, se, J ) 7.2
Hz), 5.15 (1H, s), 7.33-7.60 (4H, m), 7.72 (1H, d, J ) 7.4 Hz), 7.82-
7.90 (1H, m), 8.18 (1H, d, J ) 7.7 Hz); 13C NMR δ 21.0, 30.7, 48.8,
55.1, 122.4, 123.0, 125.4, 125.5, 126.1, 126.9, 128.9, 131.1, 133.9,
141.8, 193.6.
2-Naphthyl Series. 3-(2-Naphthyl)propanal (9). Using general
procedure A, 2-naphthaldehyde (3.60 g, 23 mmol, 1.0 mol equiv), and
N-methoxy-N-methyl-2-(triphenylphosphoranylidine)acetamide (16.8 g,
46.0 mmol, 2.0 mol equiv) gave N-methoxy-N-methyl-3-(2-naphthyl)-
prop-2-enamide (5.25 g, 95%) as a white solid: mp 85-86 °C; IR
(4R)-1-Diazo-4-(1-naphthyl)pentan-2-one (30 mg, 0.126 mmol),
Ag2O (catalytic amount), and MeOH (1.0 mL) gave methyl (4R)-4-
1
(cm-1) 1654, 1613; H NMR (CDCl3) δ 3.34 (3H, s), 3.81 (3H, s),
(1-naphthyl)pentanoate22,23 (26 mg, 87%) as a colorless oil: [R]25
7.15 (1H, d, J ) 14.5 Hz), 7.45-7.55 (2H, m), 7.70-8.00 (6H, m).
N-Methoxy-N-methyl-3-(2-naphthyl)prop-2-enamide (564 mg, 2.34
mmol) and 10% Pd/C (20 mg) gave N-methoxy-N-methyl-3-(2-
D
+20.5° (c 0.34, CH2Cl2); IR (cm-1) 1736; H NMR δ 1.40 (3H, d, J
1
) 6.9 Hz), 2.00-2.37 (4H, m), 3.62 (3H, s), 3.68 (1H, se, J ) 7.0
Hz), 7.38-7.55 (4H, m), 7.72 (1H, d, J ) 7.3 Hz), 7.84-7.91 (1H,
m), 8.10-8.16 (1H, m); 13C NMR δ 21.5, 32.1, 32.6, 32.9, 51.4, 122.5,
123.0, 125.3, 125.6, 125.8, 126.6, 128.9, 131.7, 134.0, 142.3, 174.1.
Methyl (4R)-4-(1-naphthyl)pentanoate (25 mg, 0.103 mmol, 1.0 mol
equiv), LiAlH4 (3.0 mg, 0.071 mmol, 2.7 H- mol equiv), and Et2O
(0.5 mL) gave (4R)-4-(1-naphthyl)pentan-1-ol (18 mg, 82%) as a
naphthyl)propanamide (544 mg, 96%) as a colorless oil: IR (cm-1
)
1
1662, 1603; H NMR (CDCl3) δ 2.83 (2H, t, J ) 8.1 Hz), 3.13 (2H,
t, J ) 8.4 Hz), 3.19 (3H, s), 3.61 (3H, s), 7.35-7.50 (3H, m), 7.68
(1H, s), 7.75-7.85 (3H, m).
N-Methoxy-N-methyl-3-(2-naphthyl)propanamide (237 mg, 0.97
mmol, 1.0 mol equiv) and LiAlH4 (47 mg, 1,17 mmol, 1.2 mol equiv)
gave 3-(2-naphthyl)propanal25 (9, 158 mg, 89%) as white crystals, mp
colorless oil: [R]24 +20.4° (c 0.25, CHCl3); IR (cm-1) 3600-3150
D
1
1
41.5-42.3 °C; IR (cm-1) 1722; H NMR (CDCl3) δ 2.87 (2H, t, J )
(br); H NMR δ 1.32 (1H, s), 1.39 (3H, d, J ) 6.9 Hz), 1.50-1.95
(4H, m), 3.53-3.70 (3H, m), 7.38-7.55 (4H, m), 7.68-7.72 (1H, m),
7.82-7.89 (1H, m), 8.07-8.16 (1H, m); 13C NMR δ 21.9, 30.9, 33.4,
33.8, 63.1, 122.5, 123.0, 125.2, 125.6, 125.7, 126.3, 128.9, 131.6, 133.9,
143.3.
7.9 Hz), 3.13 (2H, t, J ) 7.7 Hz), 7.28-7.50 (3H, m), 7.63 (1H, s),
7.73-7.85 (3H, m), 9.86 (1H, t, J ) 1.4 Hz).
(3R)- and (3S)-3-(2-Naphthyl)butanal (R-10 and S-10). To a
slurry of NaH (0.50 g, 20.8 mmol, 1.04 mol equiv) in 1,2-dimethoxy-
ethane (35 mL) was added dropwise triethyl phosphonoacetate (4.5 g,
20.0 mmol, 1.0 mol equiv) at 20 °C under N2. The reaction mixture
was stirred for 1 h until gas evolution had ceased. To this yellow
solution was added dropwise a solution of 2-acetonaphthone (3.4 g,
20.0 mmol, 1.0 mol equiv) in 1,2-dimethoxyethane (5 mL), during the
addition the temperature at <25 °C. The reaction mixture was then
stirred for 30 min at 20 °C and then quenched with water (50 mL), the
organic layer separated, and the aqueous layer was extracted with Et2O
(2 × 50 mL). The combined organic layer was dried (MgSO4), filtered,
and concentrated in Vacuo, and the crude product purified by column
chromatography on Si gel (hexanes/EtOAc, 90/10 elution) to give ethyl-
(4R)-4-(1-Naphthyl)pentan-1-ol (18 mg, 0.084 mmol, 1.0 mol equiv),
oxalyl chloride (12.8 mg, 0.101 mmol, 1.2 mol equiv), DMSO (15.4
mg, 0.20 mmol, 2.4 mol equiv), Et3N (425 mg, 0.42 mmol, 5.0 mol
equiv), and CH2Cl2 (0.7 mL) gave (4R)-4-(1-naphthyl)pentanal (R-8,
16 mg, 89%) as a colorless oil: [R]24D +25.5° (c 0.24, Et2O); IR (cm-1
)
1717; 1H NMR δ 1.37 (3H, d, J ) 6.9 Hz), 1.95-2.15 (2H, m),
2.30-2.41 (2H, m), 3.64 (1H, se, J ) 7.0 Hz), 7.30-7.55 (4H,
m), 7.70 (1H, d, J ) 8.0 Hz), 7.78-7.89 (1H, m), 8.07 (1H, d,
J ) 7.6 Hz), 9.64 (1H, t, J ) 1.4 Hz); 13C NMR δ 21.7, 29.6, 32.7,
41.9, 122.5, 122.9, 125.3, 125.5, 125.8, 126.6, 128.9, 131.6, 133.9,
142.1, 202.1; HRMS, calcd for M+C15H16O m/e 212.1201, found m/e
212.1194.
3-(2-naphthyl)but-2-enoate (3.5 g, 73%) as a colorless oil: IR (cm-1
)
1
(4S)-4-(1-Naphthyl)pentanal (S-8). (3S)-3-(1-Naphthyl)butanal (S-
6, 160 mg, 0.81 mmol), Jones reagent, and acetone (1.2 mL) gave (3S)-
3-(1-naphthyl)butanoic acid (165 mg, 95%) as a light yellow solid:
1709; H NMR δ 1.33 (3H, t, J ) 7.2 Hz), 2.68 (3H, s), 4.24 (2H, q,
J ) 7.1 Hz), 6.28 (1H, s), 7.40-7.60 (3H, m), 7.75-7.95 (4H, m); 13
C
NMR δ 14.3, 17.8, 59.8, 117.5, 123.9, 125.9, 126.4, 126.6, 127.5, 128.1,
128.4, 133.1, 133.4, 139.3, 155.1, 166.8.
mp 65-68.5 °C; lit.24 mp 63-68 °C; [R]25 +4.7° (c 0.27, CHCl3);
D
lit.25 [R]25 +16.6° (c 11.0, Me2CO), spectroscopically identical to
365
To ethyl-3-(2-naphthyl)but-2-enoate (1.36 g, 2.1 mmol) in EtOAc
(21 mL) was added 10% Pd/C (52 mg), and the reaction mixture stirred
under H2 (1atm) for 15 h at 20 °C. The reaction mixture was filtered
through Celite and then concentrated in Vacuo to give (()-ethyl-3-(2-
naphthyl)butanoate (1.36 g, 99%) as a colorless oil: IR (cm-1) 1736;
1H NMR δ 1.16 (3H, t, J ) 7.1 Hz), 1.39 (3H, d, J ) 7.0 Hz), 2.56-
2.78 (2H, m), 3.46 (1H, hex, J ) 7.3 Hz), 4.07 (2H, q, J ) 7.2 Hz),
7.35-7.50 (3H, m), 7.66 (1H, s), 7.75-7.85 (3H, m); 13C NMR δ 14.1,
21.7, 36.6, 42.8, 60.2, 124.9, 125.3, 125.4, 125.9, 127.5, 127.6, 128.1,
132.3, 133.5, 143.1, 172.2.
The subsequent reduction and oxidation reactions were carried by
general procedure B as follows: (()-Ethyl-3-(2-naphthyl)butanoate (1.0
g, 4.13 mmol, 1.0 mol equiv) and LiAlH4 (100 mg, 2.27 mmol, 2.2
H- mol equiv) gave (()-3-(2-naphthyl)butan-1-ol (808 mg, 98%) as a
colorless oil: 1H NMR δ 1.32 (3H, d, J ) 7.0 Hz), 1.65 (1H, s), 1.90
(2H, q, J ) 6.8 Hz), 3.02 (1H, se, J ) 7.1 Hz), 3.45-3.60 (2H, m),
7.30-7.50 (3H, m), 7.60 (1H, s), 7.70-7.85 (3H, m); 13C NMR δ 22.3,
36.5, 40.7, 61.0, 125.1, 125.2, 125.5, 125.9, 127.4, 127.5, 128.0, 132.2,
133.6, 144.2.
(()-3-(2-Naphthyl)butan-1-ol (700 mg, 3.5 mmol, 1.0 mol equiv),
oxalyl chloride (533 mg, 4.2 mmol, 1.2 mol equiv), DMSO (656 mg,
8.4 mmol, 2.4 mol equiv) and Et3N (1.77 g, 17.5 mmol, 5.0 mol equiv)
gave (()-3-(2-naphthyl)butanal ((()-10, 606 mg, 87%) as a colorless
oil: IR (cm-1) 1719; 1H NMR δ 1.40 (3H, d, J ) 7.0 Hz), 2.65-2.95
(2H, m), 3.52 (1H, se, J ) 7.3 Hz), 7.35-7.50 (3H, m), 7.64 (1H, s),
7.75-7.85 (3H, m), 9.73 (1H, t, J ) 1.9 Hz); 13C NMR δ 22.1, 34.4,
51.6, 125.0, 125.4, 125.5, 126.1, 127.5, 127.6, 128.4, 132.3, 133.5,
142.8, 201.7.
the R-enantiomer.
(3S)-3-(1-Naphthyl)butanoic acid (160 mg, 0.75 mmol, 1.0 mol
equiv) and SOCl2 (656 mg, 5.51 mmol, 7.4 mol equiv) gave (3S)-3-
(1-naphthyl)butanoyl chloride as a colorless oil which on treatment with
ethereal CH2N2 (large excess) gave (4S)-1-diazo-4-(1-naphthyl)pentan-
2-one (143 mg, 81% from acid) as a yellow oil: [R]25D -2.4° (c 0.20,
CH2Cl2), spectroscopically identical to the R-enantiomer.
(4S)-1-Diazo-4-(1-naphthyl)pentan-2-one (140 mg, 0.59 mmol, Ag2O
(catalytic amount), and MeOH (4.0 mL) gave methyl (4S)-4-(1-
naphthyl)pentanoate (134 mg, 94%) as a colorless oil: [R]25 -19.6°
D
(c 0.45, CH2Cl2), spectroscopically identical to the R-enantiomer.
Methyl (4S)-4-(1-naphthyl)pentanoate (130 mg, 0.54 mmol, 1.0 mol
equiv), LiAlH4 (13.0 mg, 0.30 mmol, 2.3 H- mol equiv), and Et2O
(1.0 mL) gave (4S)-4-(1-naphthyl)pentan-1-ol (102 mg, 89%) as a
colorless oil: [R]24D -20.9° (c 0.46, CHCl3), spectroscopically identical
to the R-enantiomer.
(22) Since the analogous homologation method, which applied to the
chiral aldehydes with phenyl groups, proceeded without any racemiza-
tions,7,23 the enantiomeric excesses of the homologated chiral aldehydes
R-4, S-4, R-8, and S-8 were deemed to be >95% ee. This assumption was
supported by the absolute values of optical rotation of each chiral aldehyde
pair R-4, S-4 and R-8, S-8 being identical, within experimental error.
(23) (a) Arndt, F.; Eistert, B. Ber. 1935, 68, 200. (b) Bachmann, W. E.;
Struve, W. S. In Organic Reactions; Florkin, M., Stotz, E. H., Ed.; Wiley
and Sons Inc.: New York, 1965; Vol. 1, pp 38-62.
(24) Menicagli, R.; Piccolo, O.; Lardicci, L.; Wis, M. L. Tetrahedron
1979, 35, 1301.
(25) Grissom, J. W.; Klingberg, D. J. Org. Chem. 1993, 58, 6559.

Abilities of Serine Proteases to Discriminate Remote Stereocenters
J. Am. Chem. Soc., Vol. 119, No. 43, 1997 10267
The resolution of 3-(2-naphthyl)butanal ((()-10) was carried out
by using general procedure C as follows: (()-3-(2-Naphthyl)butanal
((()-10, 576 mg, 2.91 mmol, 1.0 mol equiv), (1R,2R)-N,N′-dimethyl-
1,2-diphenylethylenediamine (698 mg, 2.91 mmol, 1.0 mol equiv) and
molecular sieves gave R,R,R-N,N′-dimethyl-4,5-diphenyl-2-[2-(2-naph-
thyl)propyl]-1,3-imidazolidine (less polar, 560 mg, 92%, >95% de)
J ) 7.7 Hz), 7.30-7.50 (3H, m), 7.52 (1H, s), 7.72-7.85 (3H, m),
10.00-10.50 (1H, br); 13C NMR δ 21.8, 36.2, 42.4, 124.9, 125.3, 125.4,
126.0, 127.5, 127.6, 128.2, 132.3, 133.5, 142.8, 178.7.
(3R)-3-(2-Naphthyl)butanoic acid (120 mg, 0.56 mmol, 1.0 mol
equiv) and SOCl2 (490 mg, 4.13 mmol, 7.4 mol equiv) gave (3R)-3-
(2-naphthyl)butanoyl chloride as a colorless oil which with ethereal
CH2N2 (large excess) gave (4R)-1-diazo-4-(2-naphthyl)pentan-2-one
[[R]25 -43.0° (c 0.44, CHCl3); IR (cm-1) 3043, 2956, 2787, 1451;
D
1H NMR δ 1.46 (3H, d, J ) 7.0 Hz), 1.85-2.00 (1H, m), 2.22 (3H, s),
2.25-2.40 (1H, m), 2.32 (3H, s), 3.33-3.50 (1H, m), 3.55 (2H, d of
d, J ) 29.3, 8.4 Hz), 3.75-3.85 (1H, m), 7.10-7.30 (10H, m), 7.40-
7.53 (3H, m), 7.73 (1H, s), 7.78-7.89 (3H, m); 13C NMR δ 24.6, 34.8,
36.2, 38.1, 41.5, 76.1, 79.9, 83.2, 125.2, 125.4, 125.9, 127.1, 127.4,
127.6, 127.9, 128.0, 128.2, 132.3, 133.8, 140.1, 141.1, 145.0] and R,R,S-
N,N′-dimethyl-4,5-diphenyl-2-[2-(2-naphthyl)propyl]-1,3-imidazoli-
(100 mg, 75% from acid) as a yellow solid: mp 82.0-83.3 °C; [R]23
D
-153.4° (c 0.37, CH2Cl2); IR (cm-1) 1645; 1H NMR δ 1.35 (3H, d, J
) 7.0 Hz), 2.50-2.80 (2H, m), 3.46 (1H, se, J ) 7.0 Hz), 5.03 (1H,
s), 7.30-7.50 (3H, m), 7.63 (1H, s), 7.72-7.83 (3H, m); 13C NMR δ
21.7, 36.6, 49.0, 55.0, 124.9, 125.2, 125.3, 125.9, 127.5, 127.6, 128.2,
132.2, 133.4, 143.1, 193.5.
(4R)-1-Diazo-4-(2-naphthyl)pentan-2-one (93 mg, 0.39 mmol), Ag2O
(catalytic amount), and MeOH (3.0 mL) gave methyl (4R)-4-(2-
naphthyl)pentanoate (84 mg, 89%) as a colorless oil: [R]25D -27.1° (c
dine (more polar, 560 mg, 92%, >95% de) as a viscous oil: [[R]25
D
+20.0° (c 0.44, CHCl3); IR (cm-1) 3041, 2962, 2780, 1456; 1H NMR
δ 1.47 (3H, d, J ) 6.9 Hz), 2.01-2.11 (2H, m), 2.28 (3H, s), 2.32
(3H, s), 3.30-3.45 (1H, m), 3.56 (2H, d of d, J ) 58.9, 8.1 Hz), 3.75
(1H, t, J ) 6.2), 7.05-7.30 (10H, m), 7.40-7.55 (3H, m), 7.75-7.90
(4H, m); 13C NMR δ 22.3, 35.5, 36.2, 39.3, 40.2, 76.2, 79.6, 83.2,
125.2, 125.4, 125.8, 125.9, 127.2, 127.5, 127.6, 127.8, 128.0, 132.3,
133.8, 140.4, 140.9, 145.5].
1
0.33, CH2Cl2); IR (cm-1) 1731; H NMR δ 1.34 (3H, d, J ) 6.9 Hz),
1.92-2.10 (2H, m), 2.17-2.30 (2H, m), 2.87 (1H, se, J ) 7.2 Hz),
3.58 (3H, m), 7.30-7.50 (3H, m), 7.59 (1H, s), 7.75-7.87 (3H, m);
13C NMR δ 22.0, 32.2, 33.0, 39.5, 51.3, 125.2, 125.3, 125.4, 125.8,
127.5, 127.6, 128.1, 132.3, 133.6, 143.6, 173.9.
Methyl (4R)-4-(2-naphthyl)pentanoate (82 mg, 0.34 mmol, 1.0 mol
equiv), LiAlH4 (11.0 mg, 0.26 mmol, 3.0 H- mol equiv), and Et2O
(1.5 mL) gave (4R)-4-(2-naphthyl)pentan-1-ol (70 mg, 95%) as a
R,R,R-N,N′-Dimethyl-4,5-diphenyl-2-[2-(2-naphthyl)propyl]-1,3-imi-
dazolidine (378 mg, 0.93 mmol), Si gel (4.6 g), and 15% H2SO4 (460
µL) gave (3R)-3-(2-naphthyl)butanal (R-10, 162 mg, 89%, >95% ee)
colorless oil: [R]24 -19.4° (c 0.31, CHCl3); IR (cm-1) 3600-3150
D
as a colorless oil: [R]25 -41.8° (c 0.3, Et2O), spectroscopically
1
(br); H NMR δ 1.32 (2H, d, J ) 6.9 Hz), 1.40-1.80 (5H, m), 2.84
D
identical to the racemate ((()-10). HRMS, calcd for M+ C14H14O m/e
(1H, se, J ) 7.0 Hz), 3.53 (2H, t, J ) 7.1 Hz), 7.28-7.45 (3H, m),
7.59 (1H, s), 7.72-7.82 (3H, m), 13C NMR δ 22.3, 30.9, 34.2, 39.9,
62.9, 125.1, 125.2, 125.6, 125.8, 127.5, 127.6, 127.9, 132.2, 133.6,
144.7.
198.1044, found m/e 198.1043.
R,R,S-N,N′-dimethyl-4,5-diphenyl-2-[2-(2-naphthyl)propyl]-1,3-imi-
dazolidine (390 mg, 0.93 mmol), Si gel (4.6 g) and 15% H2SO4 (460
µL) yielded (3S)-3-(2-naphthyl)butanal (S-10, 162 mg, 88%, >95%
(4R)-4-(2-Naphthyl)pentan-1-ol (67 mg, 0.31 mmol, 1.0 mol equiv),
oxalyl chloride (48 mg, 0.38 mmol, 1.2 mol equiv), DMSO (59 mg,
0.75 mmol, 2.4 mol equiv), Et3N (158 mg, 1.57 mmol, 5.0 mol equiv),
and CH2Cl2 (0.7 mL) gave (4R)-4-(2-naphthyl)pentanal (R-12, 59 mg,
89%) as a colorless oil: [R]24D -20.7° (c 0.57, Et2O); IR (cm-1) 1712;
1H NMR δ 1.35 (3H, d, J ) 6.9 Hz), 1.90-2.10 (2H, m), 2.27-2.40
(2H, m), 2.88 (1H, se, J ) 6.8 Hz), 7.28-7.50 (3H, m), 7.58 (1H, s),
7.75-7.85 (3H, m), 9.66 (1H, t, J ) 1.5 Hz); 13C NMR δ 22.2, 30.1,
39.4, 42.1, 125.2, 125.3, 125.4, 126.0, 127.5, 127.6, 128.2, 132.3, 133.5,
143.4, 202.2; HRMS, calcd for M+ C15H16O m/e 212.1201, found m/e
212.1198.
(4S)-4-(2-Naphthyl)pentanal (S-12). (3S)-3-(2-Naphthyl)butanal
(S-10, 127 mg, 0.64 mmol), Jones reagent, and acetone (2.5 mL) gave
(3S)-3-(2-naphthyl)butanoic acid (125 mg, 91%) as a light yellow
solid: mp 67.0-69.0 °C; [R]25D +38.0° (c 0.30, EtOH), spectroscopi-
cally identical to the R-enantiomer.
ee) as a colorless oil: [R]25 +40.4° (c 0.2, Et2O), spectroscopically
D
identical to the racemate ((()-10); HRMS, calcd for M+ C14H14O m/e
198.1044, found m/e 198.1037.
4-(2-Naphthyl)butanal (11). Using general procedure C, 3-(2-
naphthyl)propanal (9, 133 mg, 0.72 mmol), Jones reagent, and acetone
(3 mL) gave 3-(2-naphthyl)propanoic acid (132 mg, 92%) as a light
yellow solid: 1H NMR δ 2.78 (2H, t, J ) 7.2 Hz), 3.14 (2H, t, J ) 7.1
Hz), 7.30-7.60 (3H, m), 7.66 (1H, s), 7.73-7.85 (3H, m), 9.83-10.41
(1H, br).
3-(2-Naphthyl)propanoic acid (97 mg, 0.48 mmol, 1.0 mol equiv)
and SOCl2 (490 mg, 4.13 mmol, 8.5 mol equiv) gave 3-(2-naphthyl)-
propanoyl chloride as a colorless oil which with ethereal CH2N2 (large
excess) gave 1-diazo-4-(2-naphthyl)butan-2-one (52 mg, 48% from acid)
1
as a yellow solid: IR (cm-1) 1638; H NMR δ 2.70 (2H, t, J ) 7.5
Hz), 3.11 (2H, t, J ) 7.3 Hz), 5.15 (1H, s), 7.30-7.57 (3H, m), 7.62
(1H, s), 7.70-7.91 (3H, m); 13C NMR δ 31.6, 42.6, 55.2, 125.9, 126.6,
127.0, 127.5, 128.0, 128.1, 128.7, 132.6, 134.1, 138.6, 194.4.
1-Diazo-4-(2-naphthyl)butan-2-one (30 mg, 0.13 mmol), Ag2O
(catalytic amount) and MeOH (1.0 mL) yielded methyl 4-(2-naphthyl)-
butanoate (25 mg, 83%) as a colorless oil: IR (cm-1) 1731; 1H NMR
δ 2.05 (2H, q, J ) 7.2 Hz), 2.37 (2H, t, J ) 7.1 Hz), 2.82 (2H, t, J )
7.3 Hz), 3.66 (3H, s), 7.30-7.90 (7H, m).
(3S)-3-(2-Naphthyl)butanoic acid (121 mg, 0.59 mmol, 1.0 mol
equiv) and SOCl2 (490 mg, 4.13 mmol, 7.0 mol equiv) gave (3S)-3-
(2-naphthyl)butanoyl chloride as a colorless oil which with ethereal
CH2N2 (large excess) gave (4S)-1-diazo-4-(2-naphthyl)pentan-2-one (94
mg, 67% from acid) as a yellow solid: mp 81.5-82.5 °C; [R]25
D
+154.0° (c 0.32, CH2Cl2), spectroscopically identical to the R-
enantiomer.
(4S)-1-Diazo-4-(2-naphthyl)pentan-2-one (90 mg, 0.38 mmol), Ag2O
(catalytic amount), and MeOH (3.0 mL) gave methyl (4S)-4-(2-
naphthyl)pentanoate (85 mg, 93%) as a colorless oil: [R]25D +25.8° (c
0.33, CH2Cl2), spectroscopically identical to the R-enantiomer.
Methyl (4S)-4-(1-naphthyl)pentanoate (80 mg, 0.33 mmol, 1.0 mol
equiv), LiAlH4 (10.3 mg, 0.25 mmol, 3.0 H- mol equiv), and Et2O
(1.5 mL) gave (4S)-4-(2-naphthyl)pentan-1-ol (70 mg, 98%) as a
colorless oil: [R]24D +19.1° (c 0.32, CHCl3), spectroscopically identical
to the R-enantiomer.
(4S)-4-(2-Naphthyl)pentan-1-ol (68 mg, 0.32 mmol, 1.0 mol equiv),
oxalyl chloride (53 mg, 0.42 mmol, 1.3 mol equiv), DMSO (65 mg,
0.83 mmol, 2.6 mol equiv), Et3N (175 mg, 1.73 mmol, 5.0 mol equiv),
and CH2Cl2 (2.5 mL) gave (4S)-4-(2-naphthyl)pentanal (S-12, 63 mg,
93%) as a colorless oil: [R]25D +19.6° (c 0.57, Et2O), spectroscopically
identical to the R-enantiomer; HRMS, calcd for M+ C15H16O m/e
212.1201, found m/e 212.1202.
Methyl 4-(2-naphthyl)butanoate (22 mg, 0.096 mmol, 1.0 mol equiv)
and LiAlH4 (3.0 mg, 0.072 mmol, 3.0 H- mol equiv) gave 4-(2-
naphthyl)butan-1-ol (19 mg, 94%): IR (cm-1) 3600-3200 (br); 1H
NMR δ 1.32 (1H, s), 1.60-1.87 (4H, m), 2.81 (2H, t, J ) 7.2 Hz),
3.67 (2H, t, J ) 6.3 Hz), 7.30-7.50 (3H, m), 7.62 (1H, s), 7.73-7.85
(3H, m).
4-(2-Naphthyl)butan-1-ol (18 mg, 0.090 mmol, 1.0 mol equiv), oxalyl
chloride (18 mg, 0.14 mmol, 1.5 mol equiv), DMSO (21 mg, 0.27
mmol, 3.0 mol equiv), Et3N (46 mg, 0.45 mmol, 5.0 mol equiv), and
CH2Cl2 (0.7 mL) gave 4-(2-naphthyl)butanal25 (11, 16 mg, 89%) as a
1
colorless oil: IR (cm-1) 1721; H NMR δ 2.05 (2H, q, J ) 7.4 Hz),
2.49 (2H, t, J ) 7.3 Hz), 2.82 (2H, t, J ) 7.3 Hz), 7.30-7.52 (3H, m),
7.61 (1H, s), 7.72-7.88 (3H, m), 9.77 (1H, t, J ) 1.5 Hz).
(4R)-4-(2-Naphthyl)pentanal (R-12). (3R)-3-(2-Naphthyl)butanal
(R-10, 130 mg, 0.66 mmol), Jones reagent, and acetone (2.5 mL) gave
(3R)-3-(2-naphthyl)butanoic acid (130 mg, 93%) as a light yellow
solid: mp 68.0-69.5 °C; lit.25 67-69 °C; [R]25D -37.5° (c 0.30, EtOH);
lit.25 [R]25D -35.0° (c 0.93, EtOH); IR (cm-1) 3540-3020 (br), 1697;
1H NMR δ 1.45 (3H, d, J ) 6.9 Hz), 2.55-2.82 (2H, m), 3.50 (1H, se,
Enantiomeric Excess Determinations of R- and S-6, 8, 10, and
12. The same general procedure was applied in each case, as follows:
To a solution of R- or S-aldehyde (1.0 mol equiv) in Et2O was added

10268 J. Am. Chem. Soc., Vol. 119, No. 43, 1997
Lee and Jones
molecular sieves followed by (1R,2R)-N,N′-dimethyl-1,2-diphenyl-
ethylenediamine (1.3 mol equiv) at 20 °C under N2. The reaction
mixture was stirred for 5 h at 20 °C and then filtered through Celite.
The filtrate was concentrated in Vacuo, and the 13C NMR spectrum of
the residue was taken. The integrations of the peaks for the methyl
groups at the stereocenters of each aldehyde (e.g., 24.4 ppm for R-6,
20.5 ppm for S-6) were used to determine the enantiomeric excesses.
In each case, the materials were seen to be enantiomerically pure, within
the (5% confidence limits of the NMR method.
Kinetic Measurements. The enzyme kinetic procedures applied
were exactly as described previously,7 except that 10-40 µL of the
inhibitor solutions (0.03-0.08 M in DMSO) were employed. The
inhibition constants are recorded in Table 1.
described previously.7 The minimized complexes of CT and SC with
R- and S-6 and -12 are depicted in Figures 1-4.
Acknowledgment. Support from the Natural Sciences and
Engineering Research Council of CAnada and the award of
University of Toronto Open Scholarships (to T.L.), are gratefully
acknowledged.
Supporting Information Available: 1H and 13C NMR
spectra of R-6, S-6, R-8, S-8, R-10, S-10, R-12, and S-12. (16
pages). See any current masthead page for ordering and Internet
access instructions.
Computational Methods. The protocols for the system setup,
docking, and energy minimization of E1 complexes were exactly as
JA9708777