Investigating the π-facial discrimination phenomenon in the conjugate addition of amines to chiral crotonates: A convenient basis for the rational design of chiral auxiliaries

Article abstract of DOI:10.1021/jo951414r

This paper is concerned with the nature of the chiral inducer in the high pressure-induced conjugate addition of amines to auxiliary-tethered crotonates. Almost complete stereocontrol was obtained in the addition of diphenylmethanamine to crotonates derived from the "arylmenthol" auxiliaries 18a, 18c, and 4 bearing an o-methoxyphenyl, p-phenoxyphenyl, or β-naphthyl substituent, respectively. This high efficiency has been attributed to the predominance of stacked conformations in such crotonates, a hypothesis supported by the ¹H NMR spectra, calculated energy of conformational optima of the corresponding crotonates, and X-ray crystal structure of 5a. The arene and enoate appendages are roughly coplanar, separated by 3.4-4 A. In contrast, only moderate selectivities could be achieved using various trans-2-arylcyclohexanols (27, 28, 2c, 29) as auxiliaries. In these cases the efficiency appears to be seriously compromised by the "widening V" arrangement exhibited by the two π-systems, as shown in the X-ray crystal structures of crotonates 5h and 5k. The sense of stereochemical induction of this conjugate addition has been determined by condensing diphenylmethanamine with enantiopure crotonate (+)-5a. The adduct 9a was converted to amino alcohol (S)-11, of known configuration. This correlation is consistent with the preferential attack of the amine to the less sterically hindered enoate π-face of (+)-5a, in its s-trans conformation. Finally, the stereochemistry of the proton transfer was determined by adding N,N-dideuteriodiphenylmethanamine to crotonate (±)-5a. The stereochemical outcome of this addition is consistent with the anti-addition of the incoming nitrogen nucleophile and the deuterium atom.

Full text of DOI:10.1021/jo951414r

J . Org. Chem. 1996, 61, 2293-2304
2293
In vestiga tin g th e π-F a cia l Discr im in a tion P h en om en on in th e
Con ju ga te Ad d ition of Am in es to Ch ir a l Cr oton a tes: A Con ven ien t
Ba sis for th e Ra tion a l Design of Ch ir a l Au xilia r ies
Franc¸oise Dumas,* Brahim Mezrhab, and J ean d’Angelo*
Laboratoire de Chimie Organique associe´ au CNRS, Universite´ Paris Sud,
Centre d’Etudes Pharmaceutiques, 5, rue J .-B. Cle´ment, 92296 Chaˆtenay-Malabry, France
Claude Riche and Ange`le Chiaroni
Institut de Chimie des Substances Naturelles, CNRS, Avenue de la Terrasse, 91198 Gif-sur-Yvette, France
Received August 1, 1995X
This paper is concerned with the nature of the chiral inducer in the high pressure-induced conjugate
addition of amines to auxiliary-tethered crotonates. Almost complete stereocontrol was obtained
in the addition of diphenylmethanamine to crotonates derived from the “arylmenthol” auxiliaries
18a , 18c, and 4 bearing an o-methoxyphenyl, p-phenoxyphenyl, or â-naphthyl substituent,
respectively. This high efficiency has been attributed to the predominance of stacked conformations
in such crotonates, a hypothesis supported by the 1H NMR spectra, calculated energy of
conformational optima of the corresponding crotonates, and X-ray crystal structure of 5a . The
arene and enoate appendages are roughly coplanar, separated by 3.4-4 Å. In contrast, only
moderate selectivities could be achieved using various trans-2-arylcyclohexanols (27, 28, 2c, 29)
as auxiliaries. In these cases the efficiency appears to be seriously compromised by the “widening
V” arrangement exhibited by the two π-systems, as shown in the X-ray crystal structures of
crotonates 5h and 5k . The sense of stereochemical induction of this conjugate addition has been
determined by condensing diphenylmethanamine with enantiopure crotonate (+)-5a . The adduct
9a was converted to amino alcohol (S)-11, of known configuration. This correlation is consistent
with the preferential attack of the amine to the less sterically hindered enoate π-face of (+)-5a , in
its s-trans conformation. Finally, the stereochemistry of the proton transfer was determined by
adding N,N-dideuteriodiphenylmethanamine to crotonate (()-5a . The stereochemical outcome of
this addition is consistent with the anti-addition of the incoming nitrogen nucleophile and the
deuterium atom.
Ch a r t 1
In tr od u ction
After decades of exploratory studies, the field of asym-
metric synthesis attained a high degree of sophistication
when several teams succeeded in elaborating efficient
and practical chiral auxiliaries. The first auxiliary that
furnished important levels of asymmetric induction in a
great variety of condensations was (-)-8-phenylmenthol
(1a ) (Chart 1), introduced by Corey in 1975.1 The much
higher efficiency of 8-phenylmenthol, compared to men-
thol itself, clearly indicates that phenyl groups (and more
generally the aryl substituents) act as powerful stereo-
directing steric barriers. Ten years ago, fine tuning of
8-phenylmenthyl esters led Whitesell to propose trans-
2-phenylcyclohexanol (2a ) as a substantially simplified
substitute (bearing only two stereogenic centers) for
8-phenylmenthol (1a ).2 We have shown that auxiliaries
1b,c and 2b-d , obtained by replacing the phenyl ring
in 1a or 2a with more bulky aromatic substituents, led
to a notable enhancement of the degree of diastereodif-
ferentiation, compared to parent compounds 1a or 2a ,
in the Michael addition of amines to chiral crotonates,3
in the catalytical hydrogenation of chiral â-acetamido-
crotonates,4a and in the aldol condensation of chiral silyl
enol esters with aldehydes.4b We have also demonstrated
that 2,2-diphenylcyclopentanol (3), although containing
a single stereogenic center, is a powerful chiral auxiliary,
as efficient as 8-phenylmenthol in the aforementioned
hydrogenation reaction.4a
On the other hand, we have established that “simpli-
fied” auxiliary 4 (Chart 2, the analogous structure of 8-â-
naphthylmenthol (1c), lacking only the methyl substit-
uent on the cyclohexane ring) is a highly efficient chiral
inducer, as potent as parent 1c.5 Thus, high pressure-
mediated addition of diphenylmethanamine, in methanol,
to the corresponding crotonate 5a led to the expected
conjugate adduct with a very high de (98%), a remarkable
X Abstract published in Advance ACS Abstracts, March 1, 1996.
(1) (a) Corey, E. J .; Ensley, H. E. J . Am. Chem. Soc. 1975, 97, 6908-
6909.
(2) Whitesell, J . K.; Chen, H. H.; Lawrence, R. M. J . Org. Chem.
1985, 50, 4663-4664.
(3) (a) d’Angelo, J .; Maddaluno, J . J . Am. Chem. Soc. 1986, 108,
8112-8114. (b) Potin, D.; Dumas, F.; Maddaluno, J . Synth. Commun.
1990, 20, 2805-2813.
(4) (a) Potin, D.; Dumas, F.; d’Angelo, J . J . Am. Chem. Soc. 1990,
112, 3483-3486. (b) Vasconcellos, M. L.; Desmae¨le, D.; Costa, P. R.
R.; d’Angelo, J . Tetrahedron Lett. 1992, 33 4921-4922. For related
“simplified” chiral auxiliaries derived from â-pinene: Vasconcellos, M.
L.; d’Angelo, J ; Desmae¨le, D.; Costa, P. R. R.; Potin, D. Tetrahedron:
Asymmetry 1991, 2, 353-356.
(5) Mezrhab, B.; Dumas, F.; d’Angelo, J .; Riche, C. J . Org. Chem.
1994, 59, 500-503.
0022-3263/96/1961-2293$12.00/0 © 1996 American Chemical Society

2294 J . Org. Chem., Vol. 61, No. 7, 1996
Dumas et al.
Sch em e 1
F igu r e 1. (Left) plot of the X-ray crystal structure of crotonate
5a , viewing the molecule perpendicularly to the naphthalene
plane (hydrogens are omitted). (Right) space-filling diagram
concentrating on the π-system region.
excesses observed in the high pressure-promoted addi-
tions of diphenylmethanamine or benzylamine to 8-phe-
nylmenthyl crotonate, in methanol, were 60% and 20%,
respectively. Methanol was used as solvent, since it
significantly enhanced the rate of these addition reac-
tions, as well as the diastereoselectivities (no de was
obtained in the absence of this alcohol). The role of the
high pressure is crucial to the stereoselectivity: thus,
addition of diphenylmethanamine to crotonate 5a , under
atmospheric pressure (5 days at 40 °C in MeOH), fur-
nished the expected â-amino ester with a 50% yield, but
with a very low de (10%) (when this addition was
performed under 14 kbar, a 98% de was observed).5
Incidentally, an intriguing effect of the pressure on the
chemoselectivity was noted with crotonate 5b. Thus,
while the â-amino ester 9b derived from conjugate
addition of diphenylmethanamine was the only product
obtained under high pressure (vide infra: Table 3, entry
3), surprisingly, the conjugate addition of methanol to
furnish â-methoxy ester 6 in low de (30%) was the only
reaction observed at atmospheric pressure (Scheme 1).
Ster eoch em ica l Sen se of In d u ction of th e Mich a el
Ad d ition ; th e Qu estion of th e Con for m a tion a l P r ef-
er en ce of th e Cr oton a te F r a gm en t. We have previ-
Ch a r t 2
selectivity for a reaction in which the nearest stereogenic
center of the inducer is located four bonds away from the
site of C-N bond formation, in an apparently conforma-
tionally mobile substrate.5 This high stereoselectivity
has been attributed to the fact that in crotonate 5a , the
enoate side chain, and the naphthalene nucleus (which
plays the role of a “stereoblocking group”) have a stacked
conformation.6 This hypothesis was strongly supported
by the X-ray crystal structure of crotonate 5a which
shows that the two π-systems are roughly coplanar, with
a separation distance in the range of 3.4-4 Å (Figure 1).
The purpose of this paper is to report new chemical
experiments in the addition of amines to auxiliary-
tethered crotonates.7 In order to gain a better under-
standing of the forces which affect the π-facial discrimi-
nation phenomenon, and consequently to improve the
design of the chiral auxiliary component, the X-ray
crystal structures of trans-2-arylcyclohexyl crotonates 5h
and 5k have also been determined (vide infra). On the
basis of these findings, it is highly likely that the high
facial selectivity exhibited by crotonate 5a originates from
the stacked geometry of the arene and enoate moieties.
In contrast, crotonates 5h and 5k , in which these two
π-systems lie in a “widening V” arrangement (Figures 3
and 4), furnish low levels of diastereodifferentiation.
1
ously proposed, on the basis of the H NMR analysis of
the adduct, that the high-pressure-induced addition of
diphenylmethanamine, in the presence of methanol, to
racemic crotonate 5a proceeded essentially (98% de) to
the less sterically congested enoate π-face, in its s-trans
conformation.5 In order to ascertain the stereochemical
sense of induction, the addition of diphenylmethanamine
to enantiopure 5a , followed by chemical correlation of the
adduct with a compound of known configuration, was
undertaken. Recently, Comins and Salvador claimed to
have resolved auxiliary 4 by means of an enzymatic
esterification procedure.9 However, in spite of extensive
experimentation, all attempts at reproducing this work
were invariably unsuccessful.10 We therefore turned to
a chemical resolution, by using commercially available
(+)-Naproxene [(S)-6-methoxy-R-methyl-2-naphthalene-
acetic acid], as resolving agent. To our delight, a great
solubility difference between the crystalline diastereo-
meric esters formed by condensing (()-4 with naproxen
acid chloride was observed. Isomer 7 (Chart 3) was found
to be the less soluble one in a methanol-hexane mixture,
thereby allowing a facile and nearly quantitative resolu-
tion. Furthermore, the X-ray crystal structure determi-
nation of 7 has been made (Figure 2), establishing
unambiguously the 1S,2R configuration of the alcohol
component. All attempts at direct hydrolysis of 7, under
a variety of conditions (KOH, 12 h in refluxing EtOH;
NaOH, 18 h in refluxing dioxane; LiOH, H2O2, 24 h at
20 °C), failed; this ester was cleaved by reduction with
Resu lts a n d Discu ssion
Since the present Michael reaction constitutes an
enantioselective approach to â-amino esters,8 diphenyl-
methanamine was used as an “ammonia equivalent”,
through the hydrogenolysis of the adducts. This amine
was preferred over benzylamine since better regioselec-
tivities (1,4- versus 1,2-addition) and diastereoselectivi-
ties were obtained. For instance, the diastereomeric
(6) Review: J ones, G. B.; Chapman, B. J . Synthesis 1995, 475-497.
(7) For recent examples of conjugate addition of lithium amides to
enoates, see: Costello, J . F.; Davies, S. G.; Ichihara, O. Tetrahedron:
Asymmetry 1994, 5, 1999-2008. Enders, D.; Bettray, W.; Raabe, G.;
Runsink, J . Synthesis 1994, 1322-1326. Tsukada, N.; Shimada, T.;
Gyoung, Y. S.; Asao, N.; Yamamoto, Y. J . Org. Chem. 1995, 60, 143-
148. Bunnage, M. E.; Burke, A. J .; Davies, S. G.; Goodwin, C. J .
Tetrahedron: Asymmetry 1995, 6, 165-176. J enner, G. Tetrahedron
Lett. 1995, 36, 233-236. Davies, S. G.; Fenwick, D. R. J . Chem. Soc.,
Chem. Commun. 1995, 1109-1110.
(9) Comins, D. L.; Salvador, J . M. J . Org. Chem. 1993, 58, 4656-
4661.
(10) We are indebted to Dr. Robert Azerad (CNRS, Universite´ Rene´
Descartes, Paris) for these experiments.
(8) Reviews: Cole, D. C. Tetrahedron 1994, 50, 9517-9582. J uaristi,
E.; Quintana, D.; Escalante, J . Aldrichim. Acta 1994, 27 (1), 3-11.

Rational Design of Chiral Auxiliaries
J . Org. Chem., Vol. 61, No. 7, 1996 2295
F igu r e 3. X-ray crystal structure of crotonate 5h : space-
filling diagram.
F igu r e 2. X-ray crystal structure of ester 7.
Ch a r t 3
F igu r e 4. X-ray crystal structure of crotonate 5k : space-
filling diagram.
Ta ble 1. Va r ia ble-Tem p er a tu r e 400 MHz 1H NMR Stu d y
of 5a in (CD3)2CO
Ch a r t 4
T, °C
δ Ha
δ Hb
δ Hc
+45
+25
-1
1.26
1.22
1.17
1.05
4.96
4.95
4.90
4.87
6.08
6.04
5.92
5.73
-31
uncomplexed enoates,12 indicate a marked s-cis confor-
mational preference in the solid state. In view of the fact
that high-pressure addition of diphenylmethanamine to
5a , in methanol, implicates almost exclusively the s-trans
conformer, we decided to examine the conformational
preference of this crotonate in solution, bearing in mind
that, according to the Curtin-Hammett principle, the
product ratio does not necessarily reflect the population
of these conformers in the ground state.13 For this
purpose, a variable-temperature 1H NMR study of 5a was
first undertaken. The chemical shifts of the enoate
hydrogens moved upfield upon cooling in the range of +45
°C f -31 °C, by 0.10 (R-vinylic proton), 0.35 (â-vinylic
proton), and 0.20 ppm (Me protons) (Table 1). As
previously pointed out by Dussault,14 this can be inter-
preted in terms of a conformational equilibrium that is
shifted toward the s-trans isomer at lower temperature;
however, this experiment offers no information regarding
the quantitative determination of conformers. Seeing
that the presence of methanol in conversion (5a f 9a )
appears to be critical to gain a good diastereoselection
LiAlH4, delivering quantitatively the desired enantiopure
alcohol (1S,2R)-(+)-4. In a similar fashion, the more
soluble diastereomer 8 was converted into (1R,2S)-(-)-
4.
Diphenylmethanamine was then added to crotonate
(1S,2R)-(+)-5a , derived from alcohol (1S,2R)-(+)-4. This
addition (14 kbar, 12 h at 20 °C in MeOH, 67% yield)
gave â-amino ester 9a with a de of 98%. The S config-
uration at the newly created stereogenic center in 9a was
established through LiAlH4 reduction to (S)-(+)-10, which
upon hydrogenolysis [H2/Pd(OH)2] produced amino alco-
hol (S)-(+)-11 of known configuration.11 This stereo-
chemical correlation was consistent with attack of the
amine preferentially from the less sterically hindered (Si)
enoate π-face of (+)-5a , in its s-trans conformation (arrow,
Chart 4).
At this stage the crucial problem of the s-cis/ s-trans
stereochemistry of the crotonate 5a arose, since X-ray
analyses of this ester (Figure 1), of related crotonates 5h
and 5k (Figures 3 and 4, vide infra), as well as most
(12) Shida, N.; Kabuto, C.; Niwa, T.; Ebata, T.; Yamamoto, Y. J .
Org. Chem. 1994, 59, 4068-4075.
(13) For the Curtin-Hammett principle, see: Stereochemistry of
Organic Compounds; Eliel, E. L., Wilen, S. H., Eds.; J ohn Wiley: New
York, 1994; pp 647-655.
(11) Kinas, R.; Pankiewicz, K.; Stec, W. J .; Farmer, P. B.; Foster,
A. B.; J arman, M. J . Org. Chem. 1977, 42, 1650-1652.
(14) Dussault, P. H.; Woller, K. R.; Hillier, M. C. Tetrahedron 1994,
50, 8929-8940.

2296 J . Org. Chem., Vol. 61, No. 7, 1996
Dumas et al.
Ta ble 2. Solven t Effect in th e 1H NMR of 5a (a t 25 °C)
Ch a r t 5
solvent
δ Ha
δ Hb
δ Hc
CDCl3
CD3CN
CD3OD
1.15
1.17
1.09
4.83
4.83
4.77
5.98
5.96
5.87
(thus, no selectivity was observed when this addition was
performed under high pressure in a MeCN/Et2O mix-
ture), the solvent effect in the NMR study of crotonate
5a was also investigated (Table 2). However, only a
minute effect was observed by changing CD3OD for CD3-
CN, thus reflecting no significant alteration in the
conformational equilibrium, under atmospheric pressure.
At first sight, the dramatic solvent effect on the
stereoselectivity seems to be consistent with a kinetically
controlled addition in methanol, while equilibration,
leading to the thermodynamic product (equimolar mix-
ture of diastereomers), possibly occurred in MeCN/Et2O.
Equilibration of â-amino esters, under thermal condi-
tions, was actually evidenced by Hawkins.15 However,
seeing that pressurization in MeCN/Et2O (14 kbar, 70 h
at 60 °C, in the presence of a catalytical amount of Ph2-
CHNH2) of enamino ester 9a having a 98% de, returned
quantitatively the unchanged starting material, it is clear
that the addition reaction of PhCHNH2 to crotonate 5a
in MeCN/Et2O is not reversible under the conditions used
and that its steric course is therefore kinetically deter-
mined.
Ch a r t 6
molecule; consequently, the 1H NMR spectrum of this
amino alcohol could be analyzed on the basis of a pseudo-
six-membered ring, in its energetically preferred chairlike
conformation (Me group adopting an “equatorial” posi-
tion). Thus, after selective decoupling of the geminal
methyl signal, proton Ha exhibited a residual coupling
constant with the vicinal proton Hb of 9.0 Hz, unequivo-
cally assigned to a J anti, the corresponding proton in the
similarly decoupled NMR spectrum of the nondeuterated
parent compound 10 exhibiting by comparison two cou-
pling constants, of 8.7 Hz (J anti between Ha and Hb) and
3.8 Hz (J gauche between Ha and Hc). These NMR experi-
ments established unambiguously the relative configu-
ration of the deuterium atom and the amine moiety in
13 (and therefore in 12), a stereochemical outcome
consistent with the anti-addition of the incoming nucleo-
phile and the deuterium atom to crotonate 5a . This
stereochemical result may be interpreted as MeOD-
mediated deuteron transfer, a view reinforced by the
observation that methanol plays a critical role in the
present Michael addition.17b It should be noted that the
stereochemical course (syn or anti) in the conjugate
addition of neutral nucleophiles to electrophilic alkenes,
although not well documented, appears to be substrate
dependent.18
In any case, this remarkable solvent effect can be
compared to theoretical calculations made by Houk on
enoates.16 Thus, when in the ground state, it has been
established that the s-cis conformer of methyl acrylate
is more stable than the s-trans isomer by 0.7 kcal mol-1
,
while the reverse was found with the protonated form of
this ester, the s-trans conformer being preferred by 3.6
kcal mol-1 over the s-cis isomer. The critical role of
methanol might be therefore interpreted in terms of
hydrogen-bond formation between this solvent and the
crotonate moiety, a phenomenon favored under high
pressure, because of the decrease in atomic distance and
suppression of thermal motions.17ab
Another essential aspect of this Michael addition was
the stereochemistry of the proton transfer, which was
determined as follows. A solution of crotonate 5a and
Ph2CHND2 (prepared by stirring 1 h at 20 °C Ph2CHNH2
with a MeOD-D2O mixture) in MeOD was pressurized
for 12 h under 14 kbar at 20 °C to furnish deuterated
adduct 12, which was then reduced (LiAlH4) to 13 (Chart
5). Careful examination of the spectral data of 13 reveals
the presence of an intramolecular hydrogen bond, re-
stricting considerably the degrees of freedom of the
Mod ifica tion of th e Ch ir a l Au xilia r y. The influ-
ence of the nature of the chiral auxiliary component was
investigated in the high-pressure addition of diphenyl-
methanamine to auxiliary-tethered crotonates 5 (Scheme
2). The diastereoselectivity in the resulting adducts 9
was determined by H and 13C NMR spectroscopy.
1
The chiral auxiliaries studied can be classified into two
categories: cyclohexanols of type 4, in which the aryl
moiety is connected to the cyclohexane ring by means of
a one-carbon spacer, and trans-2-arylcyclohexanols 2, in
which the aryl substituent is directly attached to the
(15) Hawkins, J . M.; Fu, G. C. J . Org. Chem. 1986, 51, 2820-2822.
(16) Loncharich, R. J .; Schwartz, T. R.; Houk, K. N. J . Am. Chem.
Soc. 1987, 109, 14-23.
(17) (a) Thus, for example, the volume change upon hydrogen-bond
formation between phenol and ethyl acetate is -4.2 mL mol-1: Organic
Synthesis at High Pressure; Matsumoto, K., Acheson, R. M., Eds.; J ohn
Wiley: New York, 1991; pp 22-24. (b) Mechanistic studies by Stirling
on the addition of amines to vinyl sulfones and sulfoxides showed that
these reactions were first order in MeOH, amine, and vinyl sulfone
(sulfoxide) and probably involved a methanol molecule in the transition
state that was H-bonded to both the amine and the vinyl sulfone
(sulfoxide): Abbott, D. J .; Colonna, S.; Stirling, C. J . M. J . Chem. Soc.,
Perkin Trans. 1 1976, 492-498.
(18) Thus, for example, in the condensation of thiophenol to isomeric
amides 14, in the presence of catalytic amounts of LiSPh, the anti-
addition adduct predominates from E-substrate, while the syn-addition
product predominates from the Z-isomer; both processes proceeded
with the same degree of stereoselectivity (90% de) (Chart 6): Miyata,
O.; Shinada, T.; Ninomiya, I.; Naito, T. Tetrahedron Lett. 1991, 32,
3519-3522.

Rational Design of Chiral Auxiliaries
J . Org. Chem., Vol. 61, No. 7, 1996 2297
Sch em e 2
Sch em e 5a
Sch em e 3
a
Key: (a) Me2CuLi, Et2O, 0 °C, 40 min then TMSCl, Et3N,
HMPA, 0 °C, 15 min, 88% yield; (b) MeLi, Et2O, 0 °C then
2-naphthaldehyde, -78 °C, 3 h, 20% yield; (c) 1.5 bar of H2, Pd/C,
AcOEt-AcOH, 4 h, 70% yield; (d) NaBH4, CeCl3, 30 min, 20 °C in
MeOH, then separation of epimers, 90% combined yield.
(60% de, entry 2, Table 3), almost complete stereocontrol
was obtained with chiral inducers 18a , 18c, and 4
bearing an o-methoxyphenyl, p-phenoxyphenyl, or â-naph-
thyl group, respectively (entries 3, 4, and 5). Among
these auxiliaries, 18a , which was tailored with the aid
of computational modeling,20 deserves a special comment.
On the basis of semiempirical calculations, Giessner-
Prettre and co-workers made the prediction that the
presence of a methoxy substituent on the phenyl ring,
by increasing the stabilization of the stacked geometry
in the corresponding crotonate (an effect particularly
marked for the o-methoxy derivative), would lead to a
notable enhancement of efficiency of the auxiliary.20
Thus, alcohol 18a constitutes indisputably one of the first
successful examples of a priori application of molecular
mechanics in the de novo design of chiral inducers.21 In
this respect, with the exception of 18c, a nearly perfect
agreement was observed between predicted and experi-
mental stereoselectivities, thereby providing feedback
information about the reliability of the SIBFA calculation
procedure used here. In other respects, this excellent
accord between calculation and experiment supports the
implicit hypothesis that the product ratio reflects the
population of the crotonate conformers (“stacked”, “trans”,
and “axial”; for a definition of these terms, see Table 3,
footnote b) in the ground state. Furthermore, this set of
results clearly indicates that the stacked conformation
of chiral crotonates plays a crucial role in the π-facial
discrimination,6 a view strengthened by the 1H NMR data
of crotonates derived from 18b, 18a , 18c, and 4. Indeed,
a significant shielding of the protons of the enoate moiety
(particularly Hb and Hc) was observed (entries 2-5,
Table 3), compared to the menthyl parent compound
(entry 1, Table 3). Another critical aspect in the design
of these inducers is the necessary presence of two methyl
substituents at the “benzylic” center, as a dramatic
decrease in diastereoselectivitiy was observed with aux-
iliary 21, which lacked this gem dimethyl group (compare
entries 6 and 5 of Table 3). That this drop in selectivity
results from a radical conformational change was con-
Sch em e 4
cyclohexane. Auxiliaries of the first category were pre-
pared as follows. Coupling of silyl enol ether 15 with
tertiary chlorides 16, in the presence of zinc chloride, led
to ketones 17 with a 93-96% yield, which were then
reduced (Na, i-PrOH) to the desired trans alcohols 18,
which were separated from the minor cis epimers by
fractional crystallization (Scheme 3).19 Because the
naphthalene nucleus was partially reduced under the
preceding reduction conditions, auxiliaries 4 and 21 were
obtained by condensing cyclohexene oxide 19 with orga-
nometallics 20 (Scheme 4).9 Auxiliary 26 was prepared
from the following reaction sequence. Addition of Me2-
CuLi to 3-methylcyclohexenone (22), followed by enolate
trapping with TMSCl, led to silyl enol ether 23. The
regiospecific lithio enolate, generated by MeLi cleavage
of 23, was then added to 2-naphthaldehyde, furnishing
ketol 24, albeit in a low yield (20%). Catalytic reduction
(H2, Pd/C) of 24 then afforded ketone 25 which was finally
reduced (NaBH4, CeCl3) to an equimolar mixture of the
desired trans alcohol 26 and its cis epimer, which were
easily separated by flash chromatography on silica gel
(Scheme 5).
The results of the addition of diphenylmethanamine
to crotonates derived from the preceding “arylmenthol”
auxiliaries are gathered in Table 3. To help rationalize
the origin of the facial selectivity, 1H NMR data and
calculated energy for conformational optima (SIBFA
procedure)20 of the chiral crotonates are also presented
in Table 3.
1
firmed by H NMR spectrum analysis of the crotonate
derivative: all enoate proton resonances are close to those
in menthyl crotonate (compare entries 6 and 1 of Table
While, as expected, phenyl-substituted auxiliary 18b
furnished the same selectivity as 8-phenylmenthol (1a )3a
(19) Whitesell, J . K.; Lawrence, R. M. Chimia 1986, 40, 318-321.
(20) Maddaluno, J . F.; Gresh, N.; Giessner-Prettre, C. J . Org. Chem.
1994, 59, 793-802.
(21) Reviews: Eksterowicz, J . E.; Houk, K. N. Chem. Rev. 1993, 93,
2439-2461. Lipkowitz, K. B.; Peterson, M. A. Ibid. 1993, 93, 2463-
2486.

2298 J . Org. Chem., Vol. 61, No. 7, 1996
Dumas et al.
Ta ble 3. Ch ir a l Cr oton a tes Der ived fr om “Ar ylm en th ol-Typ e” Au xilia r ies: 1H NMR Da ta , Ca lcu la ted En er gy for
Con for m a tion a l Op tim a , a n d d e in th e Con ju ga te Ad d ition of Dip h en ylm eth a n a m in e
3), a view reinforced by the fact that the three conformers
of trans-2-benzylcyclohexyl crotonate were found to be
nearly isoenergetic by computational analysis.20 In light
of the preceding observation, we reasoned that the
presence of an additional gem-dimethyl group on the
cyclohexane ring, in the R-position to the naphthylmethyl
substituent of alcohol 26, by engendering unfavorable
(Me-naphthyl) pseudo-1,3-diaxial interactions in both
“trans” and “axial” conformers of the corresponding
crotonate, can force the naphthalene nucleus to adopt the
“stacked” orientation in order to minimize strain, hence
possibly restoring the efficiency of the auxiliary. To our
delight, this prediction proved correct from all points of
view: an important shielding of the enoate protons of the
crotonate derived from auxiliary 26 was indeed observed,
while, concomitantly, excellent stereoselectivity was again
obtained in the addition of Ph2CHNH2 to this crotonate
(entry 7, Table 3).
The auxiliaries of the second category, namely trans-
2-arylcyclohexanols 27, 28, 2c, and 29, were prepared by
condensing the aryl Grignard reagents in the presence
of cuprous chloride22 or the aryl lithiocuprate complexes23
with cyclohexene oxide. Addition of diphenylmetha-
(22) Huynh, C.; Derguini-Bouchemal, F.; Linstrumelle, G. Tetrahe-
dron Lett. 1979, 17, 1503-1506.

Rational Design of Chiral Auxiliaries
J . Org. Chem., Vol. 61, No. 7, 1996 2299
Ch a r t 7. tr a n s-2-Ar ylcycloh exa n ols a n d Rela ted
assistance of several complementary tools: chemical
experiment, NMR spectroscopy, X-ray crystallography,
and molecular mechanics. In this regard, the a priori
application of the latter tool in the fascinating area of
design of chiral auxiliaries looks highly promising.21
Au xilia r iesa
Exp er im en ta l Section
Gen er a l Meth od s. Melting points were recorded on a
Kofler bench. Infrared (IR) spectra were obtained as neat films
between NaCl plates or KBr pellets. The 1H NMR spectra and
13C NMR spectra were recorded in CDCl3, unless otherwise
stated. Optical rotations were measured at 589 nm in a 1 dm
cell at specified temperature. Mass spectra were recorded by
electron impact at 70 eV. Analytical thin-layer chromatogra-
phy was performed on Merk silica gel 60F254 glass precoated
plates (0.25 mm layer). All liquid chromatography separations
were performed using Merck silica gel 60 (230-400 mesh
ASTM). Diethyl ether and tetrahydrofuran (THF) were dis-
tilled from Na-benzophenone ketyl. Methanol was dried over
magnesium and distilled. Toluene, CH2Cl2, HMPA, and DMF
were distilled from calcium hydride, under a nitrogen atmo-
sphere. All reactions involving air- or water-sensitive com-
pounds were routinely conducted in glassware which was
flame-dried under a positive pressure of nitrogen. Organic
layers were dried over anhydrous MgSO4. Chemicals obtained
from commercial suppliers were used without further purifica-
tion, except in the case of diphenylmethanamine, which was
purified by liquid chromatography prior to use. Elemental
analyses were obtained from the Service de microanalyse,
Centre d’Etudes Pharmaceutiques, Chaˆtenay-Malabry, France.
High-pressure-mediated reactions were performed in a piston-
cylinder apparatus of 13 mm internal diameter for pressure
up to 20 kbar. For reactions performed at temperatures higher
than 20 °C, an external electric heating jacket was used.
Pyrex-made cylindrical cells (1.5 mm wall-thickness, fitted
with a 1 mm inner diameter capillary inlet), in which the
reaction mixtures were introduced and removed by means of
a syringe, were immersed in hexane, used as piezotransmitter
liquid, contained in the high pressure-vessel, this being closed
on the bottom side with a steel stopper. The mobile piston,
equiped with Bridgman triple seals (rubber, teflon and bronze),
was then inserted, and the whole assembly was placed between
the pistons of the hydraulic press. The pressure was raised
to an extent depending on the reaction conditions used in each
case. After stabilization of the pressure, the heater was
eventually swithched on, whereupon the temperature was
raised to the desired value (up to 65 °C). The reaction mixture
was kept under these conditions for a convenient time and then
cooled to room temperature before depressurization. X-ray
crystallographic intensity data of 7, 5h , and 5k were measured
using graphite-monochromated Cu KR radiation, and the (θ-
2θ) scan technique up to given θ. The structure was solved
by direct methods using SHELXS8626 and refined by full-
matrix least-squares with SHELX76,27 minimizing the function
∑w(Fo - |Fc|)2. The hydrogen atoms, located in difference
Fourier maps, were introduced in theoretical position (d(C-
H) ) 1.00 Å) and assigned an isotropic thermal factor
equivalent to that of the bonded carbon atom, plus 10%.
Convergence was reached at given R and Rw (with Rw ) [∑w(Fo
a
The de (%) obtained in the conjugate addition of Ph2CHNH2
to the corresponding crotonates are in parentheses.
namine to crotonates derived from the preceding alcohols,
as well as the two related auxiliaries 3024 and 3,4a was
then examined. Only disappointing stereoselectivities
were obtained with these chiral inducers (Chart 7). In
order to determine the cause of this modest selectivity,
the X-ray crystal structures of crotonates 5h and 5k ,
derived from alcohols 28 and 2c, respectively, were
undertaken. Examination of these structures reveals
that, in sharp contrast with crotonate 5a , where the
arene and enoate appendage are roughly coplanar (Figure
1, vide supra), the two π-systems in crotonates 5h and
5k lie in a “widening V” arrangement14 (Figures 3 and
4). These crystallographic data show clearly that both
enoate π-faces of 5h and 5k are now subject to nucleo-
philic attack; thus, these crotonates are expected to have
a much lower degree of facial selectivity.
Con clu d in g Com m en ts
The ability of cyclohexyl-based chiral auxiliaries to
control the interaction of reagents with tethered sub-
strates has been extensively exploited for asymmetric
synthesis.25 Through this work, we have shown that an
almost complete stereocontrol can be obtained in the
conjugate addition of diphenylmethanamine to chiral
crotonates derived from certain “arylmenthol-type” aux-
iliaries. This high efficiency has been attributed to the
predominance, in such crotonates, of stacked conforma-
tions. We have also demonstrated that, in contrast, only
moderate selectivities can be achieved with trans-2-
arylcyclohexanols as auxiliaries. In that case the ef-
ficiency appears to be seriously compromised by the
“widening V” arrangement exhibited by the arene and
enoate side chain in the corresponding crotonates, hence
excluding any stacking contribution to the observed
selectivity. Thus, the presence of a one-carbon spacer
substituted by a dimethyl group, between the aryl
nucleus and the cyclohexane ring in the chiral auxiliary
component, is crucial in order to gain a good facial
selectivity. Finally, it must be pointed out that the
proper choice of auxiliaries has been guided by the
2
1/2
- |Fc|)2/∑wFo
]
and w ) 1/[σ2(Fo) + given Fo2]).28
P r ep a r a tion of th e Ter tia r y Ch lor id es 16. Ter tia r y
Alcoh ols. Gen er a l P r oced u r e. To MeMgBr (3 M in diethyl
ether, 52 mL, 0.15 mol) in diethyl ether (35 mL) at 0 °C was
added the aromatic ketone (0.13 mol) in diethyl ether (100 mL).
After the mixture was stirred for 3 h at rt, a slight excess of
1 N HCl was slowly added at 0 °C. The aqueous layer was
(26) Scheldrick, G. SHELSX86. Program for crystal structure
determination: University of Go¨ttingen: Germany, 1985.
(27) Scheldrick, G. SHELSX76. Program for crystal structure
determination: University of Cambridge: United Kingdom, 1976.
(28) The authors have deposited atomic coordinates for 7, 5h , and
5k with the Cambridge Crystallographic Centre. The coordinates can
be obtained, on request, from the Director, Cambridge Crystallographic
Data Centre, 12 Union Road, Cambridge, CB2 1EZ, UK.
(23) Alexakis, A.; J achiet, D.; Normant, J . F. Tetrahedron 1986, 42,
5607-5619.
(24) Esser, P.; Buschmann, H.; Meyer-Stork, M.; Scharf, H.-D.
Angew. Chem., Int. Ed. Engl. 1992, 31, 1190-1192.
(25) Review: Whitesell, J . K. Chem. Rev. 1992, 92, 953-964.

2300 J . Org. Chem., Vol. 61, No. 7, 1996
Dumas et al.
separated and extracted with diethyl ether (3 × 150 mL). The
combined organic layers were washed with a saturated aque-
ous NaHCO3 solution (2 × 100 mL) and brine (2 × 50 mL),
dried, concentrated, and used without any further purification.
2-(2-Meth oxyp h en yl)-2-h yd r oxyp r op a n e: 20.84 g, 96%
acetate 20:1) to give 24 (2.3 g, 20% yield) as a white solid: mp
142 °C (diethyl ether); IR (neat) 3502, 1694 cm-1
;
1H NMR
(200 MHz, CDCl3) δ 7.90-7.73 (m, 4H), 7.86-7.53 (m, 3H),
5.17 (dd, J ) 9.5, 2.8 Hz, 1H), 4.72 (d, J ) 9.5 Hz, 1H), 2.76
(d, J ) 2.8 Hz, 1H), 2.38-2.20 (m, 2H), 2.0-1.82 (m, 2H), 1.80-
1.55 (m, 2H), 1.20 (s, 3H), 1.15 (s, 3H); 13C NMR (50 MHz,
CDCl3) δ 168.8 (C), 142.3 (C), 133.2 (C), 132.5 (C), 127.9 (2CH),
127.5 (CH), 126.0 (CH), 125.6 (CH), 124.6 (CH), 124.3 (CH),
71.9 (CH), 65.2 (CH), 43.0 (CH2), 40.9 (C), 40.7 (CH2), 30.2
(CH3), 23.2 (CH2), 23.0 (CH3). Anal. Calcd for C19H22O2: C,
80.81, H, 7.85. Found: C, 80.70, H, 7.80.
yield; oil; IR (neat) 3458, 1584 cm-1 1H NMR (200 MHz,
;
CDCl3) δ 7.69 (dd, J ) 7.0, 2.0 Hz, 1H), 7.60 (dt, J ) 9.0, 1.2
Hz, 1H), 7.34-7.26 (m, 2H), 4.53 (br s 1H), 4.24 (s, 3H), 1.99
(s, 6H); 13C NMR (50 MHz, CDCl3) δ 156.8 (C), 135.8 (C), 128.1
(CH), 125.7 (CH), 120.9 (CH), 111.2 (CH), 72.5 (C), 55.2 (CH3),
29.6 (2 CH3).
2-(4-P h en oxyp h en yl)-2-h yd r oxyp r op a n e: 28.8 g, 97%
yield; white solid; mp 30-31 °C (petroleum ether); IR (neat)
3415, 1590 cm-1; 1H NMR (200 MHz, CDCl3) δ 7.48-7.13 (m,
4H), 7.10-6.96 (m, 5H), 1.88 (br s, 1H), 1.59 (s, 6H); 13C NMR
(50 MHz, CDCl3) δ 157.4 (C), 155.9 (C), 144.2 (C), 129.9 (2 CH),
126.1 (2 CH), 123.3 (CH), 118.9 (2 CH), 118.6 (2 CH), 72.4 (C),
31.9 (2 CH3).
Ter tia r y Ch lor id es 16. To 0.1 mol of tertiary alcohol in
dichloromethane (20 mL) at 0 °C was slowly added 12 N
hydrochloric acid (100 mL). After the mixture was stirred for
1 h at 20 °C, the organic phase was diluted with CH2Cl2 (200
mL), separated, concentrated under reduce pressure (0.1 Torr)
at 20 °C, and used immediately without further purification.
2-(2-Meth oxyp h en yl)-2-ch lor op r op a n e (16a ): 17.8 g,
96% yield; viscous oil; IR (neat) 1600, 1582 cm-1; 1H NMR (200
MHz, CDCl3) δ 7.66-7.51 (m, 2H), 7.30-7.22 (m, 2H), 4.22 (s,
3H), 1.93 (s, 6H); 13C NMR (50 MHz, CDCl3) δ 157.0 (C), 136.0
(C), 128.2 (CH), 125.9 (CH), 121.0 (CH), 111.4 (CH), 72.6 (C),
55.3 (CH3), 29.8 (2 CH3).
2-(4-P h en oxyp h en yl)-2-ch lor op r op a n e (16c): 23.1 g,
94% yield; viscous oil; IR (neat) 1613, 1592 cm-1; 1H NMR (200
MHz, CDCl3) δ 7.50-7.38 (m, 2H), 7.34-7.18 (m, 2H), 7.08-
6.81 (m, 5H), 1.90 (s, 6H).
P r ep a r a tion of Keton es 17. Compounds 17a -c were
prepared according to the procedure reported by Whitesell,19
starting from the tertiary chloride (0.045 mol).
2-[1-(2-Me t h oxyp h e n yl)-1-m e t h yle t h yl]c yc loh e xa -
n on e (17a ): 7.8 g, 75% yield; viscous oil, bp 155 °C (1 Torr);
IR (neat) 1709 cm-1; 1H NMR (200 MHz, CDCl3) δ 7.25 (dd, J
) 7.7, 1.7 Hz, 1H), 7.1 (dt, J ) 7.7, 1.7 Hz, 1H), 6.89-6.77 (m,
2H), 3.74 (s, 3H), 3.51 (dd, J ) 11.8, 4.7 Hz, 1H), 2.24-2.1 (m,
2H), 2.0-1.84 (m, 1H), 1.55-1.1 (m, 5H), 1.45 (s, 3H), 1.34 (s,
3H); 13C NMR (50 MHz, CDCl3) δ 212.8 (C), 157.8 (C), 137.3
(C), 128.0 (CH), 127.0 (CH), 120.5 (CH), 111.8 (CH), 55.5 (CH3),
55.2 (CH), 44.1 (CH2), 39.8 (C), 30.4 (CH2), 28.3 (CH2), 26.2
(CH2), 25.0 (CH3), 23.9 (CH3).
3,3-Dim eth yl-2-(2-n aph th ylm eth yl)cycloh exan on e (25).
A solution of aldol 24 (0.70 g, 2.5 mmol) in ethyl acetate (3
mL) and acetic acid (3 mL) was stirred in the presence of 10%
Pd/C (200 mg) for 4 h under 1.5 bar of hydrogen. The catalyst
was filtered off, and the product was chromatographed over
silica gel (cyclohexane:ethyl acetate 20:1) to yield pure ketone
25 (0.52 g, 78% yield) as a white solid: mp 82 °C (methanol);
1
IR (neat) 1708 cm-1; H NMR (200 MHz, CDCl3) δ 7.80-7.15
(m, 3H), 7.70 (s, 1H), 7.48-7.30 (m, 3H), 3.27 (dd, J ) 13.6,
9.6 Hz, 1H), 2.76 (dd, J ) 13.6, 2.2 Hz, 1H), 2.60 (dd, J ) 9.6,
2.2 Hz, 1H), 2.41-2.14 (m, 2H), 2.0-1.55 (m, 4H), 1.24 (s, 3H),
0.89 (s, 3H); 13C NMR (50 MHz, CDCl3) δ 211.8 (C), 139.6 (C),
133.5 (C), 131.8 (C), 127.8 (CH), 127.7 (CH), 127.5 (CH), 127.4
(CH), 127.1 (CH), 125.8 (CH), 125.1 (CH), 63.3 (CH), 41.8
(CH2), 40.5 (C), 40.0 (CH2), 30.0 (CH3), 29.7 (CH2), 23.3 (CH2),
21.3 (CH3). Anal. Calcd for C19H22O: C, 85.66, H, 8.32.
Found: C, 84.97, H, 8.31.
Ch em ica l R esolu t ion of (1R*,2S*)-2-[1-(2-Na p h t h yl)-
1-m et h ylet h yl]cycloh exa n ol (4):
(2S,1′R,2′S)- a n d
(2S,1′S,2′R)-6-Meth oxy-2-m eth yl-2-n aph th alen eacetic Acid
2′-[1-(2-Na p h th yl)-1-m eth yleth yl]cycloh exyl Ester s (7)
a n d (8). Pyridine (3.4 mL, 42.2 mmol), followed by 4-(dim-
ethylamino)pyridine (0.6 g, 5 mmol) and racemic alcohol 49
(7.5 g, 27.9 mmol) dissolved in CH2Cl2 (30 mL), were added
dropwise to naproxen acid chloride (10.5 g, 42.2 mmol) in CH2-
Cl2 (150 mL) at 0 °C. The mixture was stirred for 4 h at 20
°C, concentrated under vacuum, diluted with diethyl ether (250
mL), and washed with 1 N HCl (2 × 70 mL), a solution of
saturated aqueous NaHCO3 (50 mL), and brine (50 mL). The
organic layer was concentrated and chromatographed over
silica gel (cyclohexane:ethyl acetate 9:1) to give 12.3 g of pure
naproxen esters 7 and 8 as pale yellow crystals (92% yield).
After one crystallization in MeOH/hexane (1:1), 6.0 g of 7 (44%
yield) (de 87% by 1H NMR spectroscopy) was obtained; after a
second crystallization, 4.5 g of 7 (de g 99%) was isolated (34%
yield). The mother liquors were concentrated, and the crude
was crystallized twice from hexane at 0 °C to give diastereomer
8 (4 g, 30% yield, de 95%). (2S,1′S,2′R)-6-Meth oxy-2-m eth yl-
2-n a p h t h a len ea cet ic a cid 2′-[1-(2-n a p h t h yl)-1-m et h yl-
eth yl]cycloh exyl ester (7): white solid; mp 134 °C (MeOH:
2-[1-(4-P h e n oxyp h e n yl)-1-m e t h yle t h yl]c yc loh e xa -
n on e (17c): 10.4 g, 75% yield; mp 90 °C (methanol); IR (neat)
1
1710 cm-1; H NMR (200 MHz, CDCl3) δ 7.36-7.25 (m, 4H),
7.11-6.68 (m, 5H), 2.64 (dd, J ) 12.1, 4.5 Hz, 1H), 2.27-2.14
(m, 2H), 2.0-1.89 (m, 1H), 1.84-1.69 (m, 2H), 1.65-1.27 (m,
3H), 1.40 (s, 3H), 1.34 (s, 3H); 13C NMR (50 MHz, CDCl3) δ
212.1 (C), 158.6 (C), 154.9 (C), 144.7(C), 129.8 (2CH), 127.2
(2CH), 123.1 (CH), 118.9 (2CH), 118.3 (2CH), 60.6 (CH), 44.3
(CH2), 39.0 (C), 30.4 (CH2), 28.6 (CH2), 26.8 (CH3), 26.1 (CH2),
24.3 (CH3). Anal. Calcd for C21H24O2: C, 81.78, H, 7.84.
Found: C, 81.69, H, 7.84.
hexane 1:1); IR (neat, KBr) 1725, 1635,1610 cm-1 1H NMR
;
(200 MHz, CDCl3) δ 7.82-7.63 (m, 5H), 7.55 (s, 1H), 7.5-7.38
(m, 4H), 7.24 (dd, J ) 8.7, 2.0 Hz, 1H), 7.15-7.09 (m, 2H),
4.85 (dt, J ) 9.9, 3.7 Hz, 1H), 3.90 (s, 3H), 3.21 (q, J ) 6.8 Hz,
1H), 2.13 (dt, J ) 11.5, 3.7 Hz, 1H), 2.3-1.9 (m, 1H), 1.74-
0.85 (m, 7H), 1.31 (d, J ) 6.8 Hz, 3H), 1.20 (s, 3H), 1.18 (s,
3H); 13C NMR (50 MHz, CDCl3) δ 173.8 (C), 157.5 (C), 148.6
(C), 135.4 (C), 133.6 (C), 133.3 (C), 131.5 (C), 129.2 (CH), 128.8
(C), 128.0 (CH), 127.3 (CH), 127.2 (CH), 126.8 (CH), 126.5
(CH), 126.3 (CH), 125.7 (CH), 125.2 (CH), 125.0 (CH), 123.0
(CH), 118.7 (CH), 105.6 (CH), 75.5 (CH), 55.2 (CH3), 50.4 (CH),
45.6 (CH), 40.3 (C), 33.3 (CH2), 27.5 (CH2), 27.2 (CH3), 25.9
(CH2), 25.6 (CH3),24.7 (CH2), 19.0 (CH3). X-ray crystal-
lographic analysis: C33H36O3, Mw ) 480.65, crystal of 0.25 ×
0.50 × 0.50 mm, orthorhombic, space group P212121, Z ) 4, a
) 11.455(5) Å, b ) 14.826(7) Å, c ) 16.288(9) Å, V ) 2766(2)
Å3, dcalc ) 1.15 g cm-3, F(000) ) 1032, l (Cu KR) ) 1.5418 Å,
µ ) 0.53 mm-1; θ ) 66°. Of the 3209 collected reflections (-7
e h e 13, k: 0-17, l: 0-19), 3093 were unique (Rint ) 0.063)
and 2801 were considered as observed having I g 3σ(I). Cell
parameters were refined from 25 well-centered reflections with
10.2 e θ e 18.0°. Convergence was reached at R ) 0.046 and
Rw ) 0.052 (0.0001Fo2). The residual electron density in the
final difference map was located between -0.26 and 0.30 e
P r ep a r a tion of Keton e 25. 3,3-Dim eth yl-2-[1-(2-n a p h -
th yl)-1-h ydr oxym eth yl]cycloh exan on e (24). 3,3-Dimethyl-
1-[(trimethylsilyl)oxy]cyclohexene (23)29 (9 g, 45.3 mmol) in
diethyl ether (30 mL) was added dropwise in 20 min to
methyllithium (37 mL of a 1.6 M solution in diethyl ether, 59
mmol) at 0 °C. After the mixture was stirred for 2 h at 0 °C,
2-naphthaldehyde (10 g, 64 mmol) in diethyl ether (20 mL)
was added in 15 min at -78 °C and allowed to stir for 3 h at
this temperature. A solution of saturated aqueous NH4Cl (50
mL) was added all at once at -78 °C, and the mixture was
allowed to warm to 20 °C. The aqueous layer was separated
and extracted with diethyl ether (3 × 150 mL). The combined
organic phases were washed with a saturated solution of
NaHCO3 and brine, dried, and concentrated, and the resulting
oil was purified by column chromatography (cyclohexane:ethyl
(29) Plamondon, J .; Canonne, P. Tetrahedron Lett. 1991, 32, 589-
592.

Rational Design of Chiral Auxiliaries
J . Org. Chem., Vol. 61, No. 7, 1996 2301
Å3. (2S,1′R,2′S)-6-Meth oxy-2-m eth yl-2-n a p h th a len ea ce-
t ic a cid , 2′-[1-(2-n a p h t h yl)-1-m et h ylet h yl]cycloh exyl
ester (8): white solid; mp 110 °C (hexane); IR (neat, KBr)
1723, 1635, 1610 cm-1; 1H NMR (200 MHz, CDCl3) δ 7.9-7.82
(m, 3H), 7.67 (s, 1H), 7.6-7.45 (m, 5H), 7.13-7.05 (m, 3H),
6.94 (dd, J ) 8.7, 1.9 Hz, 1H), 4.82 (dt, J ) 10.5, 4.3 Hz, 1H),
3.88 (s, 3H), 2.4 (q, J ) 6.8 Hz, 1H), 2.13 (dt, J ) 11.1, 3.7 Hz,
1H), 1.9-1.75 (m, 1H), 1.7-0.75 (m, 7H), 1.45 (s, 3H), 1.30 (s,
3H), 1.08 (d, J ) 6.8 Hz, 3H); 13C NMR (50 MHz, CDCl3) δ
173.6 (C), 157.3 (C), 149.5 (C), 136.1 (C), 133.4 (C), 133.3 (C),
131.5 (C), 129.1 (CH), 128.7 (C), 127.9 (CH), 127.2 (2 CH),
126.7 (CH), 125.9 (CH), 125.7 (CH), 125.5 (CH), 125.2 (2 CH),
122.6 (CH), 118.5 (CH), 105.5 (CH), 74.4 (CH), 55.2 (CH3), 50.3
(CH), 44.6 (CH), 39.8 (C), 32.5 (CH2), 28.4 (CH3), 26.8 (CH2),
25.8 (CH2), 24.4 (CH2), 23.8 (CH3), 17.7 (CH3).
trated under vacuum. The two diastereomeric alcohols (1:1
by 1H NMR) were purified by column chromatography over
silica gel (cyclohexane:ethyl acetate 20:1). trans-Alcohol 26:
142 mg, 42% yield; white solid; mp 110 °C (petroleum ether);
1
IR (CCl4) 3616, 1633, 1597 cm-1; H NMR (200 MHz, CDCl3)
δ 7.85-7.7 (m, 4H), 7.50-7.36 (m, 3H), 3.67 (dt, J ) 10.5, 4.3
Hz, 1H), 3.06 (dd, J ) 14.3, 3.1 Hz, 1H), 2.82 (dd, J ) 14.3,
6.8 Hz, 1H), 1.96 (dt, J ) 10.5, 6.8 Hz, 1H), 1.63-1.06 (m,
7H), 1.07 (s, 3H), 0.94 (s, 3H); 13C NMR (50 MHz, CDCl3) δ
141.7 (C), 133.7 (C), 131.9 (C), 128.0 (CH), 127.8 (CH), 127.6
(CH), 127.4 (CH), 126.7 (CH), 125.9 (CH), 125.1 (CH), 74.1
(CH), 56.1 (CH), 41.4 (CH2), 36.3 (CH2), 35.6 (CH2), 35.5 (C),
31.2 (CH3), 20.7 (CH3), 20.5 (CH2). Anal. Calcd for C19H24O:
C, 85.02, H, 9.01. Found: C, 84.96, H, 8.98.
(1R*,2S*)-2-(2-Na p h th ylm eth yl)cycloh exa n ol (21). n-
Butyllithium (40 mL of a 2.5 M solution in hexanes, 0.1 mol)
was added to TMEDA (15.1 mL) at 0 °C. After 15 min at this
temperature, 2-methylnaphthalene (14.2 g, 0.1 mol), diluted
in THF (100 mL), was added dropwise. The mixture was
warmed to 20 °C and stirred for 24 h. Cyclohexene oxide (12.2
mL, 0.12 mol) was added dropwise, and the mixture was
stirred for 1 day, poured into 0.1 N hydrochloric acid (100 mL)
and ice (100 g), and extracted with diethyl ether (3 × 150 mL).
The combined organic phases were washed with brine, dried,
and concentrated. The crude alcohol was crystallized from cold
pentane:diethyl ether (1:1) to give 21 (18 g, 75% yield) as a
white solid; mp 82 °C (pentane:diethyl ether 1:1); IR (neat)
(1R,2S)-(-)- a n d (1S,2R)-(+)-2-[1-(2-Na p h th yl)-1-m eth -
yleth yl]cycloh exa n ols (4). Ester 7 or 8 (3.8 g, 7.9 mmol) in
diethyl ether (35 mL) was added dropwise to LiAlH4 (600 mg,
15.8 mmol) in diethyl ether (5 mL) at 0 °C. After the mixture
was strirred for 0.5 h at 20 °C, it was hydrolyzed at 0 °C with
0.5 N NaOH (0.5 mL). The precipited solid was filtered off,
the filtrate was concentrated under vacuum, and the crude
product was chromatographed over silica gel (cyclohexane:
ethyl acetate 1.5:1). (1S,2R)-2-[1-(2-Na p h th yl)-1-m eth yl-
eth yl]cycloh exa n ol ((+)-4): 2.0 g, 95% yield; white solid; mp
74-75 °C (petroleum ether); [R]20 +25.4 (c 2.1, MeOH) [lit.9
D
mp 71-74 °C; [R]23 +12.0 (c 2, MeOH), 99.40% ee by chiral
D
HPLC analysis]. (1R,2S)-2-[1-(2-Na p h th yl)-1-m eth yleth yl]-
cycloh exa n ol ((-)-4): 1.9 g, 93% yield; white solid; mp 73
3397, 1634,1602 cm-1
;
1H NMR (200 MHz, CDCl3) δ 7.85-
7.77 (m, 3H), 7.65 (s, 1H), 7.48-7.35 (m, 3H), 3.37 (m, 1H),
3.36 (dd, J ) 13.2, 3.2 Hz, 1H), 2.54 (dd, J ) 13.2, 9.0 Hz,
1H), 2.01 (dt, J ) 8.2, 4.8 Hz, 1H), 1.88-1.52 (m, 5H), 1.45-
0.83 (m, 4H); 13C NMR (50 MHz, CDCl3) δ 138.2 (C), 133.3
(C), 131.7 (C), 127.9 (CH), 127.3 (3 CH), 127.1 (CH), 125.5
(CH), 124.8 (CH), 74.1 (CH), 46.7 (CH), 38.8 (CH2), 35.5 (CH2),
29.7 (CH2), 24.1 (CH2), 24.7 (CH2).
°C (petroleum ether); [R]20 -21.9 (c 3.4, MeOH).
D
P r ep a r a tion of th e Ch ir a l Au xilia r ies. Alcoh ols 18a
a n d 18c (fr om Keton es 17a ,c). A solution of ketone (22.3
mmol) in 2-propanol (17 mL)was slowly added to molten
sodium (3.8 g, 0.165 mol) in refluxing toluene (145 mL). The
mixture was stirred for 21 h at 110 °C. The mixture was cooled
to 20 °C and was poured into cold 6 N hydrochloric acid (30
mL). The aqueous phase was separated and extracted with
toluene (3 × 100 mL). The combined organic phases were
washed with a saturated solution of NaHCO3 (2 × 60 mL) and
brine (50 mL), dried, and concentrated under vacuum.
(1R*,2S*)-2-[1-(2-Meth oxyp h en yl)-1-m eth yleth yl]cyclo-
h exa n ol (18a ). The yield was 5.2 g (95% yield) as a mixture
P r ep a r a tion of tr a n s-2-Ar ylcycloh exa n ols. Alcohols 28
and 29 were prepared according to the literature,4 starting
from cyclohexene oxide (0.15 mol).
(1R*,2S*)-2-(2-Na p h th yl)cycloh exa n ol (28): 89% yield;
white solid; mp 90 °C (diisopropyl ether); IR (neat) 3374, 1600
1
cm-1; H NMR (200 MHz, CDCl3) δ 7.86-7.77 (m, 3H), 7.71
(s, 1H), 7.52-7.38 (m, 3H), 3.79 (dt, J ) 9.9, 4.4 Hz, 1H), 2.61
(dt, J ) 9.9, 3.8 Hz, 1H), 2.17 (m, 1H), 2.02-1.32 (m, 8H); 13
C
1
of trans and cis alcohols (9:1 by H NMR), from which 4.2 g of
NMR (50 MHz, CDCl3) δ 140.7 (C), 133.5 (C), 132.4 (C), 128.2
(CH), 127.5 (2 CH), 126.5 (CH), 125.9 (CH), 125.8 (CH), 125.4
(CH), 74.0 (CH), 53.2 (CH), 34.4 (CH2), 33.2 (CH2), 25.9 (CH2),
24.9 (CH2).
the trans isomer was separated by fractional crystallization
from petroleum ether (76% yield) as a white solid: mp 69-70
°C; IR (neat, KBr) 3312, 1597, 1581 cm-1; 1H NMR (200 MHz,
CDCl3) δ 7.17-7.0 (m, 2H), 6.82-6.67 (m, 2H), 3.67 (s, 3H),
3.51 (dt, J ) 10.0, 4.4 Hz, 1H), 2.31 (dt, J ) 11.4, 3.5 Hz, 1H),
1.77-1.46 (m, 5H), 1.23 (s, 3H), 1.17 (s, 3H), 1.17-0.75 (m,
4H); 13C NMR (50 MHz, CDCl3) δ 157.5 (C), 138.8 (C), 127.5
(CH), 126.2 (CH), 120.8 (CH), 112.2 (CH), 73.5 (CH), 55.1
(CH3), 49.6 (CH), 40.2 (C), 36.5 (CH2), 26.9 (CH2), 26.4 (CH2),
26.0 (CH3), 25.1 (CH2), 24.6 (CH3). Anal. Calcd for C16H24O2:
C, 77.37, H, 9.74. Found: C, 77.39, H, 9.78.
(1R*,2S*)-2-(4-P h en oxyp h en yl)cycloh exa n ol (29): 69%
1
yield; amorphous solid; IR (neat) 3412, 1592 cm-1; H NMR
(200 MHz, CDCl3) δ 7.28-6.86 (m, 9H), 3.53 (dt, J ) 10.1, 4.6
Hz, 1H), 2.32 (dt, J ) 12.8, 3.2 Hz, 1H), 2.04 (dt, J ) 9.1, 4.6
Hz, 1H), 1.86-1.56 (m, 4H), 1.5-1.2 (m, 4H); 13C NMR (50
MHz, CDCl3) δ 157.1 (C), 156.0 (C), 137.9 (C), 129.6 (2 CH),
128.9 (3 CH), 123.1 (CH), 118.9 (3 CH), 74.4 (CH), 52.4 (CH),
34.4 (CH2), 33.4 (CH2), 26.0 (CH2), 25.0 (CH2).
(1R*,2S*)-2-[1-(4-P h en oxyp h en yl)-1-m eth yleth yl]cyclo-
h exa n ol (18c). The yield was 6.6 g (95% yield) as a mixture
of trans and cis alcohols (24:1 by 1H NMR) from which 5.2 g of
the trans isomer was separated by fractional crystallization
from methanol at 0 °C (75% yield); amorphous solid; IR (neat)
P r ep a r a tion of Ch ir a l Cr oton a tes 5: Gen er a l P r oce-
d u r e. To a stirred solution of chiral alcohol (4 mmol), crotonic
acid (688 mg, 8 mmol), and DMAP (244 mg, 2 mmol) in CH2
-
Cl2 (10 mL), at 0 °C, was added dropwise a solution of DCC
(1.65 g, 8 mmol) in CH2Cl2 (2 mL). After 14 h at rt, the excess
DCC was consumed with methanol (0.5 mL) and the dicyclo-
hexylurea was filtered off and washed with hexanes. The
filtrate was washed successively with 0.5 N hydrochloric acid
(50 mL), a saturated aqueous solution of NaHCO3 (50 mL),
1
3588, 3453, 1590 cm-1; H NMR (200 MHz, CDCl3) δ 7.34-
7.17 (m, 4H), 7.07-6.84 (m, 5H), 3.41 (dt, J ) 9.7, 4.4 Hz, 1H),
1.82-1.56 (m, 5H), 1.34 (s, 3H), 1.21 (s, 3H), 1.27-0.86 (m,
5H); 13C NMR (50 MHz, CDCl3) δ 157.4 (C), 155.2 (C), 146.0
(C), 129.6 (2 CH), 127.0 (2 CH), 123.0 (CH), 118.7 (2 CH), 118.6
(2 CH), 73.4 (CH), 54.5 (CH), 39.5 (C), 36.7 (CH2), 28.7 (CH3),
26.8 (CH2), 26.2 (CH2), 25.0 (CH2), 24.5 (CH3). Anal. Calcd
for C21H26O2: C, 81.24, H, 8.44. Found: C, 81.60, H, 8.02.
(1R*,2S*)-3,3-Dim eth yl-2-(2-n a p h th ylm eth yl)cycloh ex-
a n ol (26). A solution of ketone 25 (0.34 g, 1.27 mmol) and
cerium trichloride heptahydrate (950 mg, 2.54 mmol) in
methanol (4 mL) was stirred at room temperature for 1 h.
Sodium borohydride (100 mg, 2.6 mmol) was then added in
small portions. The mixture was stirred for 15 min, treated
with 1 N hydrochloric acid, and extracted twice with diethyl
ether. The combined organic phases were washed with a
saturated solution of NaHCO3 and brine, dried, and concen-
and brine (30 mL), dried over MgSO4
, and concentrated.
Chromatography of the crude product (cyclohexane:ethyl
acetate 20:1) afforded pure crotonates 5.
(1S,2R)-2-[1-(2-Naph th yl)-1-m eth yleth yl]cycloh exyl (E)-
2-bu ten oa te ((+)-5a ): 90% yield; white solid; mp 89 °C
1
(hexane); [R]20 +26.2 (c 7.8, EtOH); H NMR and 13C NMR
D
spectra were found to be identical to those of rac-5a .5
(1R*,2S*)-2-[1-(2-Meth oxyp h en yl)-1-m eth yleth yl]cyclo-
h exyl (E)-2-bu ten oa te (5b): 1.1 g, 87% yield; viscous oil; IR
(neat) 1714, 1661, 1597 cm-1; H NMR (200 MHz, CDCl3) δ
1
7.16-7.05 (m, 2H), 6.84-6.74 (m, 2H), 6.49 (dq, J ) 15.5, 6.8
Hz, 1H), 5.28 (dq, J ) 15.5, 1.6 Hz, 1H), 4.78 (dt, J ) 10.4, 4.4

2302 J . Org. Chem., Vol. 61, No. 7, 1996
Dumas et al.
Hz, 1H), 3.82 (s, 3H), 2.71 (dt, J ) 11.8, 3.4 Hz, 1H), 1.88 (m,
1H), 1.69-1.5 (m, 3H), 1.67 (dd, J ) 6.8, 1.6 Hz, 3H), 1.33-
0.81 (m, 4H), 1.28 (s, 3H), 1.20 (s, 3H); 13C NMR (50 MHz,
CDCl3) δ 165.8 (C), 158.1 (C), 143.3 (CH), 139.5 (C), 126.4 (CH),
126.2 (CH), 123.3 (CH), 120.6 (CH), 111.7 (CH), 74.7 (CH), 55.2
(CH3), 46.3 (CH), 40.2 (C), 33.4 (CH2), 27.4 (CH3), 26.3 (CH2),
25.5 (CH3), 25.2 (CH3), 24.9 (CH2), 17.7 (CH3).
125.8 (CH), 125.6 (CH), 125.1 (CH), 122.7 (CH), 75.4 (CH), 49.7
(CH), 34.1 (CH2), 32.3 (CH2), 25.8 (CH2), 24.7 (CH2), 17.6 (CH3).
X-ray crystallographic analysis: C20H22O2, Mw ) 294.39,
crystal of 0.14 × 0.40 × 0.46 mm, monoclinic, space group P21/
c, Z ) 4, a ) 12.927(9) Å, b ) 5.748(6) Å, c ) 22.829(15) Å, â
) 101.66(5)°, V ) 1661(2) Å3, dcalc ) 1.18 g cm-3, F(000) )
632, λ (Cu KR) ) 1.5418 Å, µ ) 0.55 mm-1; θ ) 64°. Of the
2834 collected reflections (-15 e h e 14, k: 0-6, l: 0-26),
2753 were unique (Rint ) 0.028) and 1957 were considered as
observed having I g 2.5σ(I). Cell parameters were refined
from 25 well-centered reflections with 12.2 e θ e 24.8°.
Convergence was reached at R ) 0.075 and Rw ) 0.112
(0.0013Fo2). The residual electron density in the final differ-
ence map was located between -0.25 and 0.76 e Å3.
(1R*,2S*)-2-(1-P h en yl-1-m eth yleth yl)cycloh exyl (E)-2-
bu ten oa te (5c): 980 mg, 86% yield; viscous oil; IR (neat)-
1
1715, 1661, 1600 cm-1; H NMR (200 MHz, CDCl3) δ 7.23-
7.13 (m, 4H), 7.11-7.0 (m, 1H), 6.37 (dq, J ) 15.5, 6.9 Hz,
1H), 5.25 (dq, J ) 15.5, 1.6 Hz, 1H), 4.73 (dt, J ) 10.6, 4.4 Hz,
1H), 2.02 (dt, J ) 10.6, 3.0 Hz, 1H), 1.92-1.80 (m, 1H), 1.68-
1.52 (m, 3H), 1.65 (dd, J ) 6.9, 1.6 Hz, 3H), 1.35-0.94 (m,
4H), 1.23 (s, 3H), 1.13 (s, 3H); 13C NMR (50 MHz, CDCl3) δ
165.7 (C), 151.8 (C), 143.9 (CH), 128.1 (2 CH), 125.5 (2 CH),
124.8 (CH), 123.3 (CH), 74.5 (CH), 51.2 (CH), 40.0 (C), 33.5
(CH2), 27.7 (CH3), 27.2 (CH2), 26.2 (CH2), 25.4 (CH3), 24.9
(CH2), 17.9 (CH3).
(1R*,2S*)-2-(4-P h en oxyp h en yl)cycloh exyl
(E)-2-
bu ten oa te (5i): 1.2 g, 87% yield; viscous oil; IR (neat) 1722,
1659, 1591 cm-1; 1H NMR (200 MHz, CDCl3) δ 7.34-6.88 (m,
9H), 6.80 (dq, J ) 15.3, 6.7 Hz, 1H), 5.63 (dq, J ) 15.3, 1.7
Hz, 1H), 4.96 (dt, J ) 10.1, 4.4 Hz, 1H), 2.68 (dt, J ) 11.6, 3.5
Hz, 1H), 2.17 (m, 1H), 2.1-1.19 (m, 7H), 1.78 (dd, J ) 6.7, 1.7
Hz, 3H); 13C NMR (50 MHz, CDCl3) δ 165.6 (C), 157.4 (C),
155.2 (C), 143.9 (CH), 138.1 (C), 129.5 (2 CH), 128.6 (2 CH),
122.8 (2 CH), 118.7 (2 CH), 118.3 (2 CH), 75.6 (CH), 48.9 (CH),
33.7 (CH2), 32.2 (CH2), 25.7 (CH2), 24.6 (CH2), 17.6 (CH3).
(1R*,2S*)-2-ter t-Bu tylcycloh exyl (E)-2-bu ten oa te (5j):
(1R*,2S*)-2-[1-(4-P h en oxyp h en yl)-1-m eth yleth yl]cyclo-
h exyl (E)-2-bu ten oa te (5d ): 1.3 g, 87% yield; viscous oil; IR
1
(neat) 1715, 1661, 1591 cm-1; H NMR (200 MHz, CDCl3) δ
7.21-6.98 (m, 4H), 6.96-6.68 (m, 5H), 6.35 (dq, J ) 15.5, 6.9
Hz, 1H), 5.25 (dq, J ) 15.5, 1.5 Hz, 1H), 4.63 (dt, J ) 10.2, 4.4
Hz, 1H), 1.93-1.45 (m, 5H), 1.61 (dd, J ) 6.9, 1.5 Hz, 3H),
1.27-0.82 (m, 4H), 1.12 (s, 3H), 1.04 (s, 3H); 13C NMR (50
MHz, CDCl3) δ 165.5 (C), 157.4 (C), 154.2 (C), 146.5 (C), 143.9
(CH), 129.5 (2 CH), 126.6 (2 CH), 123.0 (CH), 122.8 (CH), 118.5
(2 CH), 118.2 (2 CH), 74.3 (CH), 51.1 (CH), 39.5 (C), 33.3 (CH2),
27.6 (CH3), 27.1 (CH2), 25.9 (CH2), 25.5 (CH3), 24.7 (CH2), 17.8
(CH3).
1
770 mg, 86% yield; viscous oil; IR (neat) 1719, 1662 cm-1; H
NMR (200 MHz, CDCl3) δ 6.95 (dq, J ) 15.5, 6.9 Hz, 1H), 5.82
(dq, J ) 15.5, 1.6 Hz, 1H), 4.78 (dt, J ) 10.1, 4.5 Hz, 1H), 1.94
(m, 1H), 1.87 (dd, J ) 6.9, 1.6 Hz, 3H), 1.77-1.62 (m, 2H),
1.49-0.86 (m, 6H), 0.90 (s, 9H); 13C NMR (50 MHz, CDCl3) δ
165.6 (C), 144.0 (CH), 123.6 (CH), 74.9 (CH), 50.5 (CH), 33.3
(CH2), 32.8 (C), 29.1 (3 CH3), 26.9 (CH2), 25.9 (CH2), 24.7 (CH2),
18.0 (CH3).
(1R*,2S*)-2-(2-Na p h t h ylm et h yl)cycloh exyl
(E)-2-
bu ten oa te (5e): 1 g, 86% yield; viscous oil; IR (neat) 1716,
1
1659, 1602 cm-1; H NMR (200 MHz, CDCl3) δ 7.75-7.66 (m
(1R*,2S*)-2-(4-Bip h en ylyl)cycloh exyl (E)-2-bu ten oa te
(5k ): 1 g, 84% yield; white solid; mp 85 °C (methanol); IR
3H), 7.48 (s, 1H), 7.43-7.28 (m, 2H), 7.21 (dd, J ) 7.9, 1.6 Hz,
1H), 6.82 (dq, J ) 15.5, 6.9 Hz, 1H), 5.72 (dq, J ) 15.5, 1.7
Hz, 1H), 4.61 (dt, J ) 9.9, 4.3 Hz, 1H), 3.0 (dd, J ) 13.4, 4.2
Hz, 1H), 2.37 (dd, J ) 13.4, 9.1 Hz, 1H), 2.05-0.9 (m, 9H),
1.73 (dd, J ) 6.9, 1.7 Hz, 3H); 13C NMR (50 MHz, CDCl3) δ
165.2 (C), 143.3 (CH), 137.1 (C), 132.6 (C), 131.1 (C), 126.9
(CH), 126.7 (CH), 126.6 (CH), 126.4 (2 CH), 124.9 (CH),124.1
(CH), 122.2 (CH), 75.7 (CH), 42.9 (CH), 38.3 (CH2), 31.0 (CH2),
29.3 (CH2), 24.2 (CH2), 23.6 (CH2), 16.9 (CH3).
(KBr) 1710, 1650, 1597 cm-1 1H NMR (200 MHz, CDCl3) δ
;
7.55-7.13 (m, 9H), 6.68 (dq, J ) 15.5, 6.8 Hz, 1H), 5.54 (dq, J
) 15.5, 1.6 Hz, 1H), 4.98 (dt, J ) 10.4, 4.4 Hz, 1H), 2.68 (dt,
J ) 11.5, 3.6 Hz, 1H), 2.12 (m, 1H), 1.98-1.22 (m, 7H), 1.67
(dd, J ) 6.8, 1.6 Hz, 3H); 13C NMR (50 MHz, CDCl3) δ 166.0
(C), 144.2 (CH), 142.6 (C), 142.0 (C), 139.2 (C), 128.9 (2 CH),
128.0 (2 CH), 127.1 (5 CH), 123.1 (CH), 75.7 (CH), 49.5 (CH),
34.3 (CH2), 32.6 (CH2), 26.1 (CH2), 25.0 (CH2), 18.0 (CH3). X-ray
crystallographic analysis: C22H24O2, Mw ) 320.43, crystal of
0.08 × 0.53 × 0.60 mm, monoclinic, space group C2/c, Z ) 8,
a ) 25.262(23) Å, b ) 5.694(5) Å, c ) 25.405(22) Å, â ) 92.14-
(4)°, V ) 3651(5) Å3, dcalc ) 1.17 g cm-3, F(000) ) 1376, λ (Cu
KR) ) 1.5418 Å, µ ) 0.53 mm-1; θ ) 65°. Of the 3188 collected
reflections (-29 e h e 29, k: 0-6, l: 0-29), 3105 were unique
(Rint ) 0.018) and 2094 were considered as observed having I
g 3σ(I). Cell parameters were refined from 25 well-centered
reflections with 12.9 e θ e 19.2. Convergence was reached
at R ) 0.054 and Rw ) 0.070 (0.000 74Fo2). The residual
electron density in the final difference map was located
between -0.18 and 0.17 e Å3.
(1R *,2S *)-3,3-Dim e t h yl-2-(2-n a p h t h ylm e t h yl)cyclo-
h exyl (E)-2-bu ten oa te (5f): 1.2 g, 87% yield; viscous oil; IR
1
(neat) 1714, 1659, 1602 cm-1; H NMR (200 MHz, CDCl3) δ
7.8-7.67 (m, 3H), 7.52 (s, 1H), 7.45-7.3 (m, 3H), 6.19 (dq, J
) 15.5, 6.8 Hz, 1H), 5.2 (dq, J ) 15.5, 1.2 Hz, 1H), 4.97 (dt, J
) 10.5, 4.3 Hz, 1H), 3.06 (dd, J ) 14.2, 1.8 Hz, 1H), 2.53 (dd,
J ) 14.2, 8.0 Hz, 1H), 2.3-1.83 (m, 2H), 1.68-1.08 (m, 5H),
1.34 (dd, J ) 6.8, 1.2 Hz, 3H), 1.12 (s, 3H), 0.99 (s, 3H); 13C
NMR (50 MHz, CDCl3) δ 166.0(C), 143.9 (CH), 140.9 (C), 133.6
(C), 131.6 (C)127.4 (CH), 127.3 (CH), 127.2 (CH), 126.6 (CH),
125.6 (CH), 124.7 (2 CH), 122.6 (CH), 75.9 (CH), 52.2 (CH),
41.1 (CH2), 35.6 (C), 35.5 (CH2), 32.7 (CH2), 31.0 (CH3), 20.4
(CH3), 20.2 (CH2), 17.3 (CH3).
r a c-2,2-Dip h en ylcyclop en tyl (E)-2-bu ten oa te (5l): 1.1
g, 85% yield; white solid; mp 167 °C (hexane); IR (KBr) 1712,
1659 cm-1; 1H NMR (200 MHz, CDCl3) δ 7.38-7.09 (m, 10H),
6.88 (dq, J ) 15.8, 6.4 Hz, 1H), 6.44 (d, J ) 4.7 Hz, 1H), 5.72
(dq, J ) 15.8, 1.7 Hz, 1H), 3.16 (m, 1H), 2.94-2.68 (m, 2H),
2.40-2.15 (m, 3H), 1.80 (dd, J ) 7.0, 1.8 Hz, 3H); 13C NMR
(20 MHz, CDCl3) δ 165.7 (C), 145.6 (C), 145.0 (C), 144.1 (CH),
128.3 (2 CH), 127.9 (2 CH), 127.7 (2 CH), 126.5 (2 CH), 126.0
(CH), 125.7 (CH), 122.9 (CH), 79.2 (CH), 59.0 (C), 35.2 (CH2),
30.5 (CH2), 20.3 (CH2), 17.7 (CH3). Anal. Calcd for C21H22O2:
C, 82.31, H, 7.23. Found: C, 82.40, H, 7.32.
(1R*,2S*)-2-(2,4,6-Tr im eth ylp h en yl)cycloh exyl (E)-2-
bu ten oa te (5g): 1.2 g, 86% yield; viscous oil; IR (neat) 1715,
1
1660, 1613 cm-1; H NMR (200 MHz, CDCl3) δ 6.80 (s, 1H),
6.76 (s, 1H), 6.71 (dq, J ) 15.6, 6.8 Hz, 1H), 5.58 (dq, J ) 15.6,
1.8 Hz, 1H), 5.51 (dt, J ) 10.0, 4.2 Hz, 1H), 3.23 (dt, J ) 11.6,
3.9 Hz, 1H), 2.46-1.1 (m, 8H), 2.46 (s, 3H), 2.36 (s, 3H), 2.22
(s, 3H), 1.76 (dd, J ) 6.8, 1.8 Hz, 3H); 13C NMR (50 MHz,
CDCl3) δ 165.6 (C), 143.3 (CH), 136.9 (C), 135.7 (C), 135.2 (C),
134.8 (C), 131.0 (CH), 128.8 (CH), 122.9 (CH), 73.3 (CH), 45.3
(CH), 33.3 (CH2), 29.0 (CH2), 26.5 (CH2), 24.8 (CH2), 21.8 (CH3),
21.5 (CH3), 20.5 (CH3), 17.8 (CH3).
(1R*,2S*,3R*)- a n d (1R*,2S*,3S*)-2-[1-(2-Meth oxyp h e-
n yl)-1-m eth yleth yl]cycloh exyl 3-Meth oxybu tyr a te (6). A
solution of crotonate 5b (250 mg, 0.8 mmol) and diphenyl-
methanamine (500 µL, 2.9 mmol) in methanol (150 µL) was
stirred for 72 h at 20 °C. The solvent was removed under
vacuum, and the residue was chromatographed, affording 6
(1R*,2S*)-2-(2-Na p h t h yl)cycloh exyl (E)-2-b u t en oa t e
(5h ): 1.3 g, 88% yield; white solid; mp 90 °C (diethyl ether);
IR (KBr) 1719, 1662, 1603 cm-1; 1H NMR (200 MHz, CDCl3) δ
7.73-7.65 (m, 3H), 7.56 (s, 1H), 7.42-7.23 (m, 3H), 6.63 (dq,
J ) 15.5, 6.8 Hz, 1H), 5.47 (dq, J ) 15.5, 1.6 Hz, 1H), 5.08 (dt,
J ) 10.3, 4.4 Hz, 1H), 2.81 (dt, J ) 11.4, 3.7 Hz, 1H), 2.14 (m,
1H), 2.0-1.17 (m, 7H), 1.60 (dd, J ) 6.8, 1.6 Hz, 3H); 13C NMR
(50 MHz, CDCl3) δ 165.7 (C), 143.9 (CH), 140.7 (C), 133.5 (C),
132.3 (C), 127.7 (CH), 127.5 (CH), 127.4 (CH), 125.9 (CH),
(257 mg, 93% yield) as an oil: IR (neat) 1730, 1598, 1582 cm-1
;
1H NMR (200 MHz, CDCl3) δ major diastereomer 7.17-7.09
(m, 2H), 6.88-6.80 (m, 2H), 4.77 (dt, J ) 10.5, 4.7 Hz, 1H),
3.85 (s, 3H), 3.38 (m, 3H), 3.23 (s, 3H), 2.75 (dt, J ) 11.7, 3.5

Rational Design of Chiral Auxiliaries
J . Org. Chem., Vol. 61, No. 7, 1996 2303
Hz, 1H), 2.05-1.60 (m, 6H), 1.39-1.0 (m, 4H), 1.33 (s, 3H),
1.26 (s, 3H), 1.03 (d, J ) 6.4 Hz, 3H), minor diastereomer 3.50
(m, 1H), 1.06 (d, J ) 6.4 Hz, 3H); 13C NMR (50 MHz, CDCl3)
δ major diastereomer 170.7 (C), 158.1 (C), 139.4 (C), 126.4
(CH), 120.3 (CH), 111.6 (CH), 74.7 (CH), 73.4 (CH), 56.1 (CH3),
55.0 (CH3), 45.9 (CH), 41.6 (CH2), 40.0 (C), 33.2 (CH2), 27.0
(CH2), 26.1 (CH2), 25.7 (CH3), 24.7 (CH2), 24.5 (CH3), 19.0
(CH3), minor diastereomer 170.8 (C), 139.5 (C), 126.0 (CH),
74.6 (CH), 73.3 (CH), 41.2 (CH2), 19.1 (CH3).
P r ep a r a tion of â-Am in o Ester s (9). Gen er a l P r oce-
d u r e. A solution of chiral crotonate 5 (3 mmol) and diphe-
nylmethanamine (2.4 mL, 12 mmol) in methanol (300 µL) was
introduced by means of a syringe through the capillary inlet
of a Pyrex cell and pressurized under 14 kbar at 20 °C for 18
h. After depressurization, the solvent was removed and the
residue chromatographed over silica gel (cyclohexane:ethyl
acetate 20:1) to yield pure aminobutyrate 9.
44.5 (CH), 42.5 (CH), 42.2 (CH2), 32.5 (CH2), 30.6 (CH2), 25.5
(CH2), 20.5 (CH3), minor diastereomer 76.7 (CH), 44.4 (CH),
42.1 (C), 20.7 (CH3).
(1R*,2S*,3R*)- a n d (1R*,2S*,3S*)-3′,3′-Dim eth yl-2′-(2-
n a p h t h ylm et h yl)cycloh exyl 3-(d ip h en ylm et h yla m in o)-
bu tyr a te (9f): 55% yield; viscous oil; IR (neat) 3343, 1726,
1
1602 cm-1; H NMR (200 MHz, CDCl3) δ major diastereomer
7.82-7.12 (m, 17H), 4.98 (dt, J ) 10, 4.1 Hz, 1H), 4.64 (s, 1H),
3.04 (dd, J ) 14.6, 1.8 Hz, 1H), 2.62 (dd, J ) 14.6, 6.5 Hz,
1H), 2.60 (m, 1H), 2.02-0.74 (m, 10H), 1.08 (s, 3H), 0.99 (s,
3H), 0.83 (d, J ) 6.4 Hz, 3H), minor diastereomer 4.73 (s, 1H),
0.76 (d, J ) 6.4 Hz, 3H); 13C NMR (50 MHz, CDCl3) δ major
diastereomer 171.8 (C), 144.1 (C), 143.8 (C), 140.8 (C), 133.5
(C), 131.7 (C), 128.4 (CH), 128.3 (CH), 128.2 (3 CH), 127.5
(CH), 127.4 (2 CH), 127.3 (CH), 127.2 (2 CH), 126.8 (CH),-
126.7 (CH), 126.6 (CH), 125.9 (CH), 125.8 (CH), 125.0 (CH),
76.1 (CH), 63.6 (CH), 51.8 (CH), 47.1 (CH), 41.0 (2 CH2), 35.6
(CH2), 32.7 (CH2), 31.0 (CH3), 26.9 (C), 20.5 (CH3), 20.1 (CH2),
20.0 (CH3), minor diastereomer 172.2 (C) 44.2 (C), 143.6 (C),
140.8 (C), 131.9 (C), 75.8 (CH), 63.7 (CH), 51.6 (CH), 47.6 (CH),
41.2 (CH), 35.4 (CH2).
(1R*,2S*,3R*)-2-[1-(2-Meth oxyp h en yl)-1-m eth yleth yl]-
cycloh exyl 3-(d ip h en ylm eth yla m in o)bu tyr a te (9b): 69%
yield, single diastereomer by 1H and 13C NMR spectroscopy;
1
viscous oil; IR (neat) 3343, 1721, 1598, 1582 cm-1; H NMR
(400 MHz, CD3COCD3) δ 7.42 (d, J ) 7.3 Hz, 4H), 7.30-7.28
(m, 4H), 7.27-7.06 (m, 4H), 6.94 (dd, J ) 8.1, 1.2 Hz, 1H),
6.82 (dt, J ) 7.7, 1.2 Hz, 1H), 4.94 (s, 1H), 4.73 (dt, J ) 10.4,
4.4 Hz, 1H), 3.82 (s, 3H), 2.80-2.74 (m, 2H), 2.0 (dd, J ) 10.3,
3.0 Hz, 1H), 1.90 (dd, J ) 10.3, 3.2 Hz, 1H), 1.88-1.84 (m,
1H), 1.84-1.80 (m, 3H), 1.30-0.98 (m, 5H), 1.33 (s, 3H), 1.25
(s, 3H), 1.00 (d, J ) 6.4 Hz, 3H); 13C NMR (50 MHz, CDCl3) δ
171.8 (C), 158.4 (C), 144.6 (C), 144.2 (C), 139.7 (C), 128.3 (4
CH), 127.7 (2 CH), 127.5 (2 CH), 127.1 (2 CH), 126.7 (CH),
126.5 (CH), 120.7 (CH), 112.0 (CH), 75.1 (CH), 64.0 (CH), 55.4
(CH3), 47.7 (CH), 46.2 (CH), 41.6 (CH2), 40.4 (C), 33.7 (CH2),
27.4 (CH2), 26.4 (CH2), 26.0 (CH3), 26.1 (CH2), 25.1 (CH3), 20.6
(CH3).
(1R*,2S*,3R*)- an d (1R*,2S*,3S*)-2-(2,4,6-Tr im eth ylph e-
n yl)cycloh exyl 3-(d ip h en ylm eth yla m in o)bu tyr a te (9g):
70% yield; viscous oil; IR (neat) 3340, 1721, 1612, 1601 cm-1
;
1H NMR (200 MHz, CDCl3) δ major diastereomer 7.40-7.05
(m, 10H), 6.58 (s, 1H), 6.52 (s, 1H), 5.36 (dt, J ) 11.5, 4.2 Hz,
1H), 4.76 (s, 1H), 3.03 (dt, J ) 11.5, 3.9 Hz, 1H), 2.53 (m, 1H),
2.33-1.47 (m, 6H), 2.33 (s, 3H), 2.1 (s, 3H), 2.0 (s, 3H), 1.45-
1.18 (m, 5H), 0.54 (d, J ) 6.3 Hz, 3H), minor diastereomer
6.64 (s, 1H), 6.6 (s, 1H), 4.71 (s, 1H), 2.71 (m, 1H), 2.10 (s,
3H), 0.64 (d, J ) 6.4 Hz, 3H); 13C NMR (50 MHz, CDCl3) δ
major diastereomer 171.4 (C), 144.5 (C), 144.3 (C), 137.5 (C),
136.1 (C), 135.4 (2 C), 131.3 (CH), 129.3 (CH), 128.6 (CH),
127.6 (2 CH), 127.5 (2 CH), 127.1 (2 CH), 73.8 (CH), 64.2 (CH),
48.0 (CH), 45.3 (CH), 42.2 (CH2), 33.4 (CH2), 29.9 (CH2), 26.6
(CH2), 25.0 (CH2), 21.7 (CH3), 20.8 (2 CH3), 19.8 (CH3), minor
diastereomer 171.6 (C), 64.3 (CH), 47.9 (CH), 45.5 (CH), 21.8
(CH3), 20.0 (CH3).
(1R*,2S*,3R*)- a n d (1R*,2S*,3S*)-2-(1-P h en yl-1-m eth -
ylet h yl)cycloh exyl 3-(d ip h en ylm et h yla m in o)b u t yr a t e
(9c): 66% yield; viscous oil; IR (neat) 3312, 1721, 1600 cm-1
;
1H NMR (200 MHz, CDCl3) δ 7.34-6.98 (m, 15H), 4.80 (s, 1H),
4.68 (dt, J ) 10.3, 4.4 Hz, 1H), 2.72 (m, 1H), 2.0-1.50 (m, 8H),
1.32-0.9 (m, 4H), 1.22 (s, 3H), 1.12 (s, 3H), 0.93 (d, J ) 6.4
Hz, 3H); 13C NMR (50 MHz, C6D6) δ major diastereomer 171.3
(C), 152.2 (C), 145.6 (C), 145.0 (C), 127.8 (4 CH), 127.4 (2 CH),
127.2 (2 CH), 126.8 (2 CH), 125.3 (2 CH), 124.9 (2 CH), 124.8
(CH), 74.8 (CH), 64.7 (CH), 51.4 (CH), 48.2 (CH), 42.2 (CH2),
40.4 (C), 34.2 (CH2), 28.2 (CH3), 27.6 (CH2), 26.5 (CH2), 25.9
(CH3), 25.2 (CH2), 20.8 (CH3); minor diastereomer 171.5 (C),
74.6 (CH), 48.4 (CH), 42.0 (CH2), 28.0 (CH3), 20.9 (CH3).
(1R*,2S*,3R*)- a n d (1R*,2S*,3S*)-2-[1-(4-P h en oxy-
p h en yl)-1-m et h ylet h yl]cycloh exyl 3-(d ip h en ylm et h y-
la m in o)bu tyr a te (9d ): 83% yield; viscous oil; IR (neat) 3346,
(1R*,2S*,3R*)- a n d (1R*,2S*,3S*)-2-(2-Na p h th yl)cyclo-
h exyl 3-(d ip h en ylm eth yla m in o)bu tyr a te (9h ): 70% yield;
viscous oil; IR (neat) 3348, 1730, 1602 cm-1 1H NMR (200
;
MHz, CDCl3) δ major diastereomer 7.75-7.63 (m, 3H), 7.5 (s,
1H), 7.42-7.11 (m, 13H), 5.04 (dt, J ) 10.3, 4.2 Hz, 1H), 4.72
(s, 1H), 2.73 (dt, J ) 11.8, 3.7 Hz, 1H), 2.67 (m, 1H), 2.2-1.23
(m, 11H), 0.46 (d, J ) 6.6 Hz, 3H), minor diastereomer 5.1
(dt, J ) 10.3, 4.2 Hz, 1H), 4.70 (s, 1H), 0.54 (d, J ) 6.4 Hz,
3H); 13C NMR (50 MHz, CDCl3) δ major diastereomer 171.8
(C), 144.2 (C), 143.9 (C), 137.8 (C), 133.4 (C), 132.4 (C), 128.3
(4 CH), 127.8 (CH), 127.5 (2 CH), 127.4 (2 CH), 127.3 (2 CH),
126.8 (2 CH), 126.1 (CH), 125.9 (CH), 125.8 (CH), 125.2 (CH),
76.9 (CH), 63.8 (CH), 47.6 (CH), 43.6 (CH), 41.5 (CH2), 33.8
(CH2), 31.8 (CH2), 30.0 (CH2), 25.0 (CH2), 24.5 (CH2), 19.7
(CH3), minor diastereomer 171.9 (C), 41.6 (CH2).
1
1724, 1591 cm-1; H NMR (200 MHz, CDCl3) δ major diaste-
reomer 7.34-6.76 (m, 19H), 4.83 (s, 1H), 4.68 (dt, J ) 10.0,
4.2 Hz, 1H), 2.78 (m, 1H), 2.04-1.74 (m, 4H), 1.70-1.48 (m,
4H), 1.26-0.88 (m, 4H), 1.21 (s, 3H), 1.12 (s, 3H), 0.98 (d, J )
6.4 Hz, 3H), minor diastereomer 4.84 (s, 1H), 0.96 (d, J ) 6.4
Hz, 3H); 13C NMR (50 MHz, CDCl3) δ major diastereomer 171.2
(C), 157.4 (C), 154.4 (C), 146.5 (C), 144.3 (C), 143.7 (C), 129.6
(2 CH), 128.3 (4 CH), 127.4 (2 CH), 127.2 (2 CH), 126.8 (2 CH),
126.6 (2 CH), 122.9 (CH), 118.6 (2 CH), 118.2 (2 CH), 74.6
(CH), 63.8 (CH), 50.7 (CH), 47.3 (CH), 41.8 (C), 39.4 (CH2),
33.3 (CH2), 27.9 (CH3), 27.0 (CH2), 25.9 (CH2), 25.3 (CH3), 24.6
(CH2), 20.3 (CH3), minor diastereomer 73.8 (CH), 47.5 (CH),
41.5 (C), 26.7 (CH2).
(1R*,2S*,3R*)- a n d (1R*,2S*,3S*)-2-(4-P h en oxyp h en yl)-
cycloh exyl 3-(d ip h en ylm eth yla m in o)bu tyr a te (9i): 73%
1
yield; viscous oil; IR (neat) 3400, 1731, 1592 cm-1; H NMR
(200 MHz, CDCl3) δ major diastereomer 7.35-7.19 (m, 2H),
7.17-6.68 (m, 17H), 4.87 (dt, J ) 10.1, 4.5 Hz, 1H), 4.72 (s,
1H), 2.68 (m, 1H), 2.22 (dt, J ) 11.5, 3.4 Hz, 1H), 2.17-1.86
(m, 3H), 1.67-0.6 (m, 8H), 0.63 (d, J ) 6.2 Hz, 3H), minor
diastereomer 4.70 (s, 1H), 2.78 (m, 1H), 0.66 (d, J ) 5.5 Hz,
3H); 13C NMR (50 MHz, CDCl3) δ major diastereomer 171.9
(C), 144.3 (C), 143.7 (C), 137.8 (C), 133.4 (C), 131.9 (C), 128.4
(4 CH), 127.8 (CH), 127.7 (CH), 127.5 (CH), 127.4 (3 CH), 127.3
(2 CH), 127.2 (2 CH), 127.1 (CH), 126.9 (CH), 126.8 (CH), 125.8
(CH), 125.1 (CH), 76.9 (CH), 64.0 (CH), 47.7 (CH), 43.5 (CH),
41.6 (CH2), 39.2 (CH2), 31.9 (CH2), 25.0 (CH2), 24.4 (CH2), 20.4
(CH3), minor diastereomer 171.8 (C), 127.8 (CH), 41.9 (CH2),
30.1 (CH2), 26.8 (CH2).
(1R*,2S*,3R*)- a n d (1R*,2S*,3S*)-2-ter t-Bu tylcycloh ex-
yl 3-(d ip h en ylm eth yla m in o)bu tyr a te (9j): 82% yield; vis-
cous oil; IR (neat) 3342, 1726, 1600 cm-1; 1H NMR (200 MHz,
CDCl3) δ major diastereomer 7.4-7.2 (m, 10H), 4.97 (s, 1H),
4.73 (dt, J ) 10.2, 4.1 Hz, 1H), 3.1 (m, 1H), 2.58-2.26 (m, 2H),
2.07-1.64 (m, 5H), 1.42-0.87 (m, 5H), 1.13 (d, J ) 6.4 Hz,
3H), 0.88 (s, 9H), minor diastereomer 4.72 (dt, J ) 10.2, 4.1
(1R*,2S*,3R*)- a n d (1R*,2S*,3S*)-2-(2-Na p h th ylm eth -
yl)cycloh exyl 3-(diph en ylm eth ylam in o)bu tyr ate (9e): 84%
1
yield; viscous oil; IR (neat) 3483, 1743, 1602 cm-1; H NMR
(200 MHz, CDCl3) δ major diastereomer 7.82-7.72 (m, 3H),
7.52 (s, 1H), 7.46-7.13 (m, 13H), 4.96 (s, 1H), 4.64 (dt, J )
10.4, 4.9 Hz, 1H), 3.06 (dt, J ) 11.2, 3.82 Hz, 1H), 3.03 (dd, J
) 12.8, 4.6 Hz, 1H), 2.5-2.23 (m, 3H), 2.05 (m, 1H), 1.92-
1.53 (m, 7H), 1.42-0.98 (m, 2H), 1.10 (d, J ) 6.3 Hz, 3H),
minor diastereomer 1.13 (d, J ) 6.8 Hz, 3H); 13C NMR (50
MHz, CD3COCD3) δ major diastereomer 172.0 (C), 145.8 (C),
145.3 (C), 140.6 (C), 137.3 (C), 134.4 (C), 133.1 (CH), 129.0 (4
CH), 128.6 (CH), 128.5 (2 CH), 128.3 (4 CH), 128.2 (2 CH),
126.6 (2 CH), 125.9 (CH), 76.8 (CH), 64.6 (CH), 48.6 (CH2),

2304 J . Org. Chem., Vol. 61, No. 7, 1996
Dumas et al.
Hz, 1H), 0.87 (s, 9H); 13C NMR (50 MHz, CDCl3) δ major
diastereomer 171.3 (C), 144.3 (C), 143.6 (C), 128.3 (4 CH), 127.3
(2 CH), 127.2 (2 CH), 126.8 (2 CH), 75.3 (CH), 63.9 (CH), 50.2
(CH), 47.4 (C), 42.3 (CH), 33.2 (CH2), 32.7 (CH2), 29.0 (3 CH3),
26.7 (CH2), 25.8 (CH2), 24.5 (CH2), 20.2 (CH3), minor diaste-
reomer 64.0 (CH), 47.6 (CH2), 42.1 (CH), 20.4 (CH3).
the presence of 20% Pd(OH)2/C (150 mg) for 5 h under 4 bar
of hydrogen. The catalyst was filtered off and carefully washed
with MeOH (6 × 5 mL). The filtrate was concentrated under
vacuum to yield a crude product (258 mg, 99% yield) that
contained only amino alcohol (S)-(+)-11 and diphenylmethane
(estimated respective weights by 1H NMR spectroscopy: 89
(1R*,2S*,3R*)- a n d (1R*,2S*,3S*)-2-(4-Bip h en yl)cyclo-
h exyl 3-(d ip h en ylm eth yla m in o)bu tyr a te (9k ): 73% yield;
mg of 11 and 169 mg of diphenylmethane): [R]20 +16.3 (c
D
4.5, EtOH) (lit.11 [R]20 +10.5 (c 5.1, EtOH)]; IR (neat) 3376,
D
viscous oil; IR (neat) 3342, 1721, 1600 cm-1
;
1H NMR (200
1602 cm-1; 1H NMR (200 MHz, CD3OD) δ 7.3-7.02 (m, 10H),
5.0 (br s, 3H), 3.87 (s, 2H), 3.86-3.53 (m, 2H), 3.5-3.3 (m,
1H), 2.0-1.52 (m, 2H), 1.28 (d, J ) 6.6 Hz, 3H).
MHz, CDCl3) δ major diastereomer 7.58-7.0 (m, 19H), 4.91
(dt, J ) 10.6, 5.2 Hz, 1H), 4.76 (s, 1H), 2.84 (m, 1H), 2.58 (dt,
J ) 11.4, 3 Hz, 1H), 2.28-1.97 (m, 3H), 1.88-0.80 (m, 8H),
0.60 (d, J ) 6.5 Hz, 3H), minor diastereomer 4.74 (s, 1H), 2.95
(m, 1H), 0.63 (d, J ) 6.5 Hz, 3H); 13C NMR (50 MHz, CDCl3)
δ major diastereomer 171.4 (C), 144.2 (C), 144.0 (C), 142.2 (C),
141.0 (C), 139.3 (C), 128.7 (2 CH), 128.4 (5 CH), 127.9 (2 CH),
127.4 (2 CH), 127.3 (2 CH), 127.0 (6 CH), 76.1 (CH), 63.9 (CH),
49.5 (CH), 47.8 (CH), 41.6 (CH2), 33.8 (CH2), 32.4 (CH2), 25.8
(CH2), 24.8 (CH2), 19.8 (CH3), minor diastereomer 171.5 (C),
75.9 (CH), 64.0 (CH), 47.6 (CH), 41.1 (CH2), 34.1 (CH2).
(1R*,3R*)- a n d (1R*,3S*)-2,2-Dip h en ylcyclop en t yl
3-(d ip h en ylm eth yla m in o)bu tyr a te (9l): 72% yield; viscous
Ster eoch em istr y of th e P r oton Tr a n sfer . N,N-Did eu -
ter iod ip h en ylm eth a n a m in e. A mixture of diphenylmetha-
namine (2 g, 10.9 mmol), CH3OD (1 mL), and D2O (3 mL) was
vigorously stirred for 1 h at 20 °C. The deuterated amine was
extracted with dry diethyl ether (3 × 10 mL), and the organic
layer was dried over MgSO4 and concentrated under vacuum.
A ratio of ca. 90% of deuterium incorporation was measured
by 1H NMR spectroscopy: IR (neat) 2516, 2424 cm-1; 1H NMR
(200 MHz, C6D6) δ 7.25 (m, 4H), 7.14-6.9 (m, 10H), 4.72 (s,
1H), 1.1 (br s, ca. 0.1H).
(()-2-Deu ter io-3-(d ip h en ylm eth yla m in o)bu ta n ol (13).
A solution of racemic crotonate 5a (403 mg, 1.2 mmol) and
N,N-dideuteriodiphenylmethanamine (1.13 g, 6.2 mmol) in
CH3OD (300 µL) was pressurized under 14 kbar at 25 °C for
19 h. After depressurization, the solvent was removed and
the crude adduct 12 was diluted in diethyl ether (4 mL) and
directly added dropwise to LiAlH4 (67 mg, 1.7 mmol) in diethyl
ether (1 mL) at 0 °C. The mixture was strirred for 0.5 h at 20
°C and then hydrolyzed at 0 °C with 0.5 N NaOH (0.5 mL).
The precipitated solid was filtered off and washed with diethyl
ether, and the filtrate was concentrated under vacuum. The
crude product was chromatographed over silica gel (cyclohex-
ane:ethyl acetate, 1.5:1) to yield pure amino alcohol 13 (197
mg, 64% yield) as a white solid: mp 62 °C (petroleum ether);
1H NMR (400 MHz, C6D6) δ 7.42 (d, J ) 7.6 Hz, 2H), 7.33 (d,
J ) 7.6 Hz, 2H), 7.3-7.19 (m, 6H), 5.04 (s, 1H), 3.74 (dd, J )
10.8, 4.5 Hz, 1H), 3.67 (dd, J ) 10.8, 8.5 Hz, 1H), 2.62 (dq, J
) 9.0, 6.3 Hz, 1H), 2.6 (br s, 2H), 1.39 (m, 1H), 0.76 (d, J )
6.3 Hz, 3H); 13C NMR (50 MHz, C6D6) δ 144.8 (C), 143.7 (C),
128.8 (4 CH), 127.9 (2 CH), 127.5 (2 CH), 127.3 (2 CH), 64.5
(CH), 61.9 (CH2), 50.7 (CH2), 38.7 (t, J ) 18.5 Hz, CHD), 20.1
(CH3); MS (C17DH20NO, FW 256) m/z 256 M+ (13), 210 (29),
167 (100), 165 (12), 106 (18).
oil; IR (neat) 3345, 1728, 1600 cm-1 1H NMR (200 MHz,
;
CDCl3) δ major diastereomer 7.37-7.05 (m, 20H), 6.07 (dd, J
) 6.6, 1.9 Hz, 1H), 4.85 (s, 1H), 2.71 (m, 1H), 2.54-2.4 (m,
2H), 2.31-2.04 (m, 3H), 1.93-1.45 (m, 4H), 0.86 (d, J ) 6.6
Hz, 3H), minor diastereomer 6.1 (dd, J ) 6.6, 1.9 Hz, 1H), 2.83
(m, 1H), 0.87 (d, J ) 6.3 Hz, 3H); 13C NMR (50 MHz, CDCl3)
δ major diastereomer 171.2 (C), 145.3 (C), 144.6 (C), 144.1 (C),
143.8 (C), 128.2 (6 CH), 127.8 (CH), 127.7 (4 CH), 127.3 (2
CH), 127.2 (CH), 127.1 (CH), 126.8 (CH), 126.4 (2 CH), 125.9
(CH), 125.6 (CH), 79.4 (CH), 63.9 (CH), 59.0 (CH2), 47.4 (CH),
41.5 (C), 34.9 (CH2), 30.6 (CH2), 20.3 (CH2), 20.1 (CH3), minor
diastereomer 171.4 (C), 145.2 (C), 144.7 (C), 126.3 (CH), 79.5
(CH), 41.2 (CH), 20.0 (CH3).
Ch em ica l Cor r ela tion of Ad d u ct 9a to (S)-3-Am in obu -
ta n ol ((+)-11). (1S,2R,3S)-2-[1-(2-Na p h th yl)-1-m eth yleth -
yl]cycloh exyl 3-(Dip h en ylm eth yla m in o)bu tyr a te (9a ). A
solution of crotonate (1S,2R)-(+)-5a (820 mg, 2.4 mmol) and
diphenylmethanamine (1 mL, 5.7 mmol) in methanol (300 µL)
was pressurized under 14 kbar at 20 °C for 18 h. After
depressurization, the solvent was removed and the residue
chromatographed over silica gel (cyclohexane:ethyl acetate 20:
1) to give â-amino ester 9a (826 mg, 66% yield). 1H NMR and
13C NMR spectra were found to be identical to those of rac-
9a .5
(S)-3-(Dip h en ylm eth yla m in o)bu ta n ol ((+)-10). Amino
ester 9a (0.74 g, 1.42 mmol) in diethyl ether (6 mL) was added
dropwise to LAH (110 mg, 2.84 mmol) in diethyl ether (2 mL)
at 0 °C. After the mixture was stirred for 0.5 h at 20 °C, it
was hydrolyzed at 0 °C with 0.5 N NaOH (0.5 mL). The solid
was filtered off, the filtrate was concentrated under vacuum,
and the residue was chromatographed over silica gel (cyclo-
hexane:ethyl acetate 1.5:1) to give pure amino alcohol (S)-(+)-
10 (308 mg, 85% yield) as a white solid: mp 64 °C (petroleum
ether); [R]20D +42.4 (c 4.37, MeOH); IR (neat) 3334, 1600, 1588
cm-1; 1H NMR (400 MHz, C6D6) δ 7.4 (d, J ) 7.8 Hz, 2H), 7.25
(d, J ) 7.8 Hz, 2H), 7.15-6.97 (m, 6H), 4.84 (s, 1H), 3.75 (ddd,
J ) 11.9, 5.2, 4.2 Hz, 1H), 3.64 (ddd, J ) 11.9, 7.1, 4.3 Hz,
1H), 2.61 (ddq, J ) 8.7, 6.3, 3.8 Hz, 1H), 2.35 (br s, 2H), 1.35-
1.24 (m, 2H), 0.77 (d, J ) 6.3 Hz, 3H); 13C NMR (50 MHz,
CDCl3) δ 143.9 (C), 142.6 (C), 128.6 (4 CH), 127.5 (2 CH), 127.2
(2 CH), 126.9 (2 CH), 64.1 (CH), 62.5 (CH2), 51.3 (CH), 38.3
(CH2), 20.2 (CH3). Anal. Calcd for C17H21NO: C, 79.96, H,
8.29, N, 5.48. Found: C, 79.99, H, 8.30, N, 5.44.
Ack n ow led gm en t. We thank Dr. J acqueline Mahu-
teau (Centre d’Etudes Pharmaceutiques, Chaˆtenay-
Malabry) for valuable assistance with NMR studies, Dr.
Robert Azerad (CNRS, Universite´ Rene´ Descartes,
Paris) for performing enzymatic experiments and sug-
gesting to us the use of naproxen as the resolving agent,
Dr. Alexandre Alexakis (CNRS, Universite´ Paris 6) for
providing us with a sample of auxiliary 27, and Drs.
Claude Giessner-Prettre (CNRS, Universite´ Paris 6),
Nohad Gresh (CNRS, Universite´ Rene´ Descartes, Paris),
and J acques Maddaluno (CNRS, Universite´ de Rouen)
for their contributions to the computational modeling,
in particular the accurate prediction of auxiliary 18a .
1
Su p p or tin g In for m a tion Ava ila ble: Copies of H NMR
spectra (36 pages). This material is contained in libraries on
microfiche, immediately follows this article in the microfilm
version of the journal, and can be ordered from the ACS; see
any current masthead page for ordering information.
(S)-3-Am in obu ta n ol ((+)-11). A solution of the amino
alcohol 10 (260 mg, 1 mmol) in MeOH (4 mL) was stirred in
J O951414R