Chiral ligands derived from abrine. Part 6: Importance of a bulky N-alkyl group in indole-containing chiral β-tertiary amino alcohols for controlling enantioselectivity in addition of diethylzinc toward aldehydes

Article abstract of DOI:10.1016/S0957-4166(00)00189-0

A number of chiral β-amino alcohols possessing a 3-indolylmethyl group have been synthesized from the alkaloid, (S)-abrine and elucidated for potency in the catalytic enantioselective ethylation of PhCHO with Et₂Zn. In general, the secondary amines 15a-d bearing a dialkylhydroxymethyl group induced (R)-1-phenyl-1-propanol, whereas 15e-g and 18 bearing a diarylhydroxymethyl group favored the (S)-enantiomer. In contrast, the β-tertiary amino alcohols 20b-d and 21 produced (R)-1-phenyl-1-propanol, regardless of the substituents at the carbon bearing the hydroxy group. Enantiomeric excess of 87.5% was obtained for (R)-1-phenyl-1-propanol using ligand 21 as the promoter. Eleven substituted benzaldehydes and naphthaldehydes were examined for enantioselective ethylation by using 21 and the chiral alcohols were obtained in 93-97% ee, except for o-BrC₆H₄CHO and p-Me₂NC₆H₄CHO. Excellent enantioselectivity was also observed in the ethylation of cyclohexanecarboxaldehyde (94.8% ee) and 2-thiophenecarboxaldehyde (94.9% ee) by using catalytic 21. The anti 5/4/4-fused tricyclic TS I was proposed to rationalize the asymmetric induction. The diethylhydroxymethyl and N-2-t-butylethyl groups are believed to enforce the preference for the anti-TS(R) I and it results in high enantioselectivity. Copyright (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0957-4166(00)00189-0

Tetrahedron: Asymmetry 11 (2000) 2315±2337
Chiral ligands derived from abrine. Part 6: Importance of a
bulky N-alkyl group in indole-containing chiral b-tertiary
amino alcohols for controlling enantioselectivity in addition
of diethylzinc toward aldehydes
Wei-Min Dai,a,* Hua-Jie Zhua and Xiao-Jiang Haob
aDepartment of Chemistry, The Hong Kong University of Science and Technology, Clear Water Bay, Kowloon,
Hong Kong, China
bKunming Institute of Botany, The Chinese Academy of Sciences, Heilongtan, Kunming 650204, Yunnan, China
Received 16 March 2000; accepted 10 May 2000
Abstract
A number of chiral b-amino alcohols possessing a 3-indolylmethyl group have been synthesized from the
alkaloid (S)-abrine and elucidated for potency in the catalytic enantioselective ethylation of PhCHO with
Et2Zn. In general, the secondary amines 15a±d bearing a dialkylhydroxymethyl group induced (R)-1-
phenyl-1-propanol, whereas 15e±g and 18 bearing a diarylhydroxymethyl group favored the (S)-enantiomer.
In contrast, the b-tertiary amino alcohols 20b±d and 21 produced (R)-1-phenyl-1-propanol, regardless of
the substituents at the carbon bearing the hydroxy group. Enantiomeric excess of 87.5% was obtained for
(R)-1-phenyl-1-propanol using ligand 21 as the promoter. Eleven substituted benzaldehydes and naphth-
aldehydes were examined for enantioselective ethylation by using 21 and the chiral alcohols were obtained
in 93±97% ee, except for o-BrC6H4CHO and p-Me2NC6H4CHO. Excellent enantioselectivity was also
observed in the ethylation of cyclohexanecarboxaldehyde (94.8% ee) and 2-thiophenecarboxaldehyde
(94.9% ee) by using catalytic 21. The anti 5/4/4-fused tricyclic TS I was proposed to rationalize the asymmetric
induction. The diethylhydroxymethyl and N-2-t-butylethyl groups are believed to enforce the preference for
the anti-TS(R) I and it results in high enantioselectivity. # 2000 Elsevier Science Ltd. All rights reserved.
1. Introduction
The organic molecules isolated from the extracts of plants have been extremely valuable to
humans in curing diseases such as cancer.1,2 Because the molecules produced through plant bio-
synthesis are commonly homochiral, natural products are also the most important source of the
homochiral ligands and auxiliaries used in contemporary asymmetric synthesis.3 A well-known
* Corresponding author. E-mail: chdai@ust.hk
0957-4166/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(00)00189-0

2316
W.-M. Dai et al. / Tetrahedron: Asymmetry 11 (2000) 2315±2337
example is the use of the alkaloids, dihydroquinidine and dihydroquinine, and their derivatives in
the catalytic asymmetric dihydroxylation.4 Recently, we were able to isolate the alkaloid, (S)-
abrine 1b,5 the N-methylated a-amino acid of (S)-tryptophan 1a in multi-gram quantity from the
red beans (Rosary pea or Xiang Si Zi in Chinese) of Abrus precatorius L., which were collected in
the Yunnan Province located in the southwestern part of China. We were particularly interested
in exploring the application of (S)-abrine in catalytic enantioselective reactions by taking advan-
tage of the indole moiety and the N-methyl group. After searching the literature, we found only a
small number of precedents in utilizing (S)-tryptophan derivatives as the chiral ligands in catalytic
enantioselective reactions (Fig. 1). The Zn(II) complex formed from (S)-tryptophan ethyl ester
and Zn(NO3)2 6H2O was used to catalyze the asymmetric aldol reaction.6a Inoue and co-workers
.
reported that the chiral Ti(IV) species derived from the dipeptide 2 and Ti(Oi-Pr)4 promoted the
addition of HCN to aldehydes in up to 90% ee.6b A number of chiral oxazaborolidines obtained
from N-tosyl-(S)-tryptophan 3a and N-tosyl-(aS,bR)-b-methyltryptophan 3b and boron com-
pounds were demonstrated to be excellent catalysts for asymmetric Diels±Alder reaction.6c e
Various 2-substituted 2,3-dihydro-4H-pyran-4-ones were prepared in 67±82% ee via the aldol
reaction catalyzed by the chiral oxazaborolidine of 3a followed by treatment with CF3CO2H.6f
The chiral oxazaborolidine formed from 3b and (p-chlorophenyl)dibromoborane catalyzed the
enantioselective ring cleavage of 1,3-dioxolanes with enol silyl ethers in 86±93% ee.6g Very
recently, Engberts and co-workers reported the (S)-abrine±Cu(II) complex that catalyzed the
Diels±Alder reaction of 3-phenyl-1-(2-pyridyl)-2-propen-1-one with cyclopentadiene in 74% ee.7
It was suggested that both the 3-indolylmethyl and the N-methyl groups in (S)-abrine are
important for stereochemistry control in the transition state.7
Figure 1. Chiral indole-containing ligands used in catalytic enantioselective reactions
Enantioselective addition of dialkylzincs to aldehydes in the presence of a chiral promoter, such
as chiral b-amino alcohols, has been shown to be an attractive and synthetically useful carbon±
carbon bond-forming reaction.8 A vast number of chiral promoters including b-amino alcohols,
b-amino thiols, diamines, and diols has been accumulated since the ®rst report by Oguni and Omi
in 1984,8a some representative chiral b-amino alcohols and the ee percentages of the ethylation of
PhCHO with Et2Zn are given in Fig. 2.9 In general, enantioselectivities of 90±100% ee can be
achieved for aromatic aldehydes using dialkylzincs. Starting from (S)-abrine, we prepared three
classes of chiral ligands possessing an indole moiety, and examined their catalysis in the ethylation
of aldehydes with Et2Zn.10 They are secondary and tertiary b-amino alcohols,10a 2,4-cis-substituted
1,3-oxazolidines,10b,d and 1,2,3,4-tetrahydro-b-carbolines.10c In this article, we disclose a full
account of the synthesis and catalysis of chiral acyclic b-secondary and b-tertiary amino alcohols
possessing a 3-indolylmethyl group. Emphasis will be put on the elucidation of the e€ect of a
bulky N-alkyl chain on the enantioselectivity. A crystalline b-tertiary amino alcohol 21 has been
found to promote the addition of Et2Zn to aldehydes in high ee's.

W.-M. Dai et al. / Tetrahedron: Asymmetry 11 (2000) 2315±2337
2317
Figure 2. The con®guration and ee percentage of 1-phenyl-1-propanol formed from ethylation of PhCHO promoted
by chiral ligands 4±14
2. Results and discussion
2.1. Secondary amino alcohols
An examination on the chiral ligands illustrated in Fig. 2 revealed that both secondary and
tertiary amines were used. A diphenylhydroxymethyl group was found in 10±13a,b and
14a.9d,j m,o,q,r Because of the enhanced stereoselectivity in catalytic reactions, the `diarylhydroxy-
methyl group' is called the `magic group' in catalyst design and synthesis and has been used with
increasing frequency in recent years.11a In contrast, chiral ligands possessing a dialkylhydroxy-
methyl group rarely provide high enantioselectivity.11b In 1995, we disclosed the chiral compound
21 (vide infra) containing the diethylhydroxymethyl group for use in the ethylation of aromatic
aldehydes with >90% ee's.10a Very recently, several groups also demonstrated the e€ect of the
dialkylhydroxymethyl group in chiral compounds 8b,9g 13c,9p 14b,9p and others9k,m,r t on enantio-
selectivity. It is known that b-secondary amino alcohols 5 and 12 possessing a bicyclic skeleton
and 10 having an additional chelating site induce high enantioselectivity, whereas 11a9l and
others9g,r t usually give low enantioselectivity. Chiral amino alcohol 13a9o gives an impressively
high level of ee and this encouraged us to undertake the following investigations.
Our initial e€ort was to design and synthesize a number of b-secondary amino alcohols 15a±g
bearing either a di-n-alkylhydroxymethyl or diarylhydroxymethyl group (Scheme 1). Conversion
of (S)-abrine 1b into the methyl ester 1c was achieved by treatment of 1b with excess SOCl2 in
MeOH in 95% yield. Addition of various Grignard reagents (in excess) to the ester 1c provided the
tertiary alcohols 15a±g in 50±78% yield. An analogous compound 18 of 13a was also synthesized
for comparison of the e€ect of the 3-indolylmethyl group in 18 with the benzyl group in 13a.
Treatment of (S)-tryptophan methyl ester hydrochloride 16 with large excess PhMgCl in THF
gave the alcohol 17 in 60% yield. Selective acylation of the primary amino group in 17 with isovaleryl

2318
W.-M. Dai et al. / Tetrahedron: Asymmetry 11 (2000) 2315±2337
chloride±Et3N at room temperature formed the corresponding amide in 69% yield. Finally, the
amide was reduced by excess LiAlH4 in re¯uxing THF to furnish the b-secondary amino alcohol
18 in 56% yield (Scheme 1).
Scheme 1.
Catalysis of the above synthesized chiral ligands 15a±g and 18 was examined with PhCHO as
the substrate under the standard conditions (entries 1±8 in Table 1). The ethylation was carried
out in dry PhMe:hexanes (2:1) in the presence of 10 mol% chiral ligand at room temperature, and
the reaction mixture was then quenched by 5% aqueous HCl in an ice±water bath. The product,
1-phenyl-1-propanol 19, was isolated by extraction and puri®ed by column chromatography over
silica gel and the ee was determined by HPLC analysis using a chiral stationary phase. In general,
the chiral ligands 15a±d possessing a di-n-alkylhydroxymethyl group produced (R)-19 as the
major enantiomer, whereas the chiral ligands 15e±g and 18, having a diarylhydroxymethyl group,
induced (S)-19 preferentially. This ®nding is of interest in the mechanistic consideration. In
addition to the low enantioselectivity, the reaction time was signi®cantly longer, the yield of the
product was moderate, and benzyl alcohol was formed as the result of reduction by Et2Zn. All
these aspects indicated that the b-secondary amino alcohols 15a±g and 18 were not the ecient
ligands. In particular, the diminished enantioselectivity induced by 18 compared to 13a±b
suggested that the 3-indolylmethyl group interfered with the functioning of the amino alcohol
moiety. Because of the acidity of indole (pKa 21.0 in DMSO),12 a plausible zinc amide10d,13 might
be formed through deprotonation of the indole moiety in 18 and competed for catalysis via multi-
component complexation.14 The less steric demand of the N-methyl group might be another fac-
tor for the ineciency of the chiral ligands 15a±g in stereochemical control.
The e€ect of the n-alkyl chain length on enantioselectivity was observed in the chiral ligands
15a±d possessing a di-n-alkylhydroxymethyl group. As shown in Fig. 3, the % ee of (R)-19 varied
regularly with the length of the n-alkyl chain to form a `zigzag' curve. The peaks were found for the
chain length of odd number carbon. A maximum value of 44.9% ee was obtained with the n-propyl
group. A similar phenomenon was noted in the chiral oxazolidine-catalyzed addition of Et2Zn to
PhCHO.10d One can assume that this e€ect originates from the van der Waals interaction and re¯ects
the conformational preference of the n-alkyl chain. The e€ect of the N-n-alkyl group in (1S,2R)-
N,N-di-n-alkylnorephedrines15a and the polymer-supported (1S,2R)-N-n-alkylnorephedrines15b

W.-M. Dai et al. / Tetrahedron: Asymmetry 11 (2000) 2315±2337
2319
Table 1
Addition of Et2Zn to PhCHO promoted by chiral amino alcohols 15a±g, 18, 20a±d and 21a
was examined, and the carbon number of the n-alkyl group for inducing the maximum % ee
di€ered with the catalyst type and the substrate structure.
2.2. Tertiary amino alcohols
Next, we turned our attention to the synthesis of alcohols bearing a tertiary amino group.
Because of the enhanced Lewis basicity of tertiary amines compared with the corresponding sec-
ondary ones, many known chiral ligands such as 4, 6, 7, 8b, 9, 11b and 14a,b given in Fig. 2 are
tertiary amines and contain either a ring structure or two identical alkyl groups. As the result of
less accessibility and complication in a complex formation, tertiary amines having three di€erent
substituents are seldom used in chiral ligands. Several tertiary amines having an N-methyl group
were synthesized from ephedrine and pseudoephedrine.8d,16 High enantioselectivity in catalyzing
Et2Zn addition toward aldehydes was observed for these b-amino alcohols. We prepared the
tertiary amines 20a±d and 21 as shown in Scheme 2. Selective acylation of 15f with various
RCOCl in the presence of Et3N gave the amides which were reduced to the tertiary amines 20a±d
by LiAlH4 in re¯uxing THF in 34±56% yield. Similarly, the crystalline b-tertiary amino alcohol
21 was prepared in 67% overall yield from 15b.
Addition of Et2Zn toward PhCHO was carried out using 10 mol% chiral ligand 20a±d and 21,
respectively. The results are listed in Table 1, entries 9±13. It is interesting to note that chiral
ligand 20a still induced (S)-19, whereas 20b±d produced the antipodal enantiomer. In addition,

2320
W.-M. Dai et al. / Tetrahedron: Asymmetry 11 (2000) 2315±2337
Scheme 2.
the % ee of (R)-19 increased with increasing bulkiness of the N-alkyl group in the following order: 20b
(PhCH2CH2)<20c (i-PrCH2CH2)<20d (t-BuCH2CH2). A plot of the % ee against the bulkiness of
p
the N-alkyl group in 15f and 20a±d gave the ` ' shaped curve (Fig. 3). The ligand 20d containing the
N-2-t-butylethyl group produced (R)-19 in 57.9% ee. This is a much better result compared to the
ligand 14a (22% ee) shown in Fig. 2. Introduction of this `magic' 2-t-butylethyl group into 15b to form
ligand 21 signi®cantly improved the asymmetric induction from 7.1 to 87.5% ee for (R)-19. Chiral
ligand 21 features some unique functional groups: a diethylhydroxymethyl group, a 3-indolylmethyl
group, and an N-2-t-butylethyl group. It is readily synthesized from (S)-abrine 1b in four steps and in
41% overall yield. Compound 21 is a crystalline compound and is easy for puri®cation and handling.
Figure 3. E€ects of the alkyl group(s) in chiral ligands 15a±d,f and 20a±d on the rotation sign and the ee of 19 formed
via the ligand-promoted addition of Et2Zn toward PhCHO in PhMe:hexanes (2:1) at 20ꢀC
2.3. Catalysis of 21 in Et2Zn addition toward aldehydes
With the ligand 21 in hand, we examined a number of aldehydes for the enantioselective ethyl-
ation with Et2Zn (Table 2). In general, high enantioselectivity of >93% ee was obtained for

W.-M. Dai et al. / Tetrahedron: Asymmetry 11 (2000) 2315±2337
2321
naphthaldehydes and p-, and m-substituted benzaldehydes, except for o-bromobenzaldehyde and
p-dimethylaminobenzaldehyde. The former aldehyde may be a€ected by the bulky ortho bromine
atom. For the latter substrate, the basic dimethylamino group in the substrate and the product
(R)-22g may contribute to some minor catalytic pathways. It then reduces the overall enantio-
selectivity. This argument is supported by the observation that (R)-1-phenyl-1-propanol (R)-19
underwent autoinduction in the addition of Et2Zn toward benzaldehyde in the presence of a
catalytic amount of achiral amine.14a Low enantioselectivity (40% ee) was observed previously
for p-dimethylaminobenzaldehyde catalyzed by an axially chiral pyridylphenol and was explained
by the electronic e€ect of the para substituent.17a We tried to make the Hammett plots of log[(R)-
22/(S)-22)] versus substituent constants ꢀ+p, ꢀp, or ꢀI for p-Me2N, p-MeO, p-Me, p-Cl, p-Br, and
Table 2
Addition of Et2Zn to RCHO promoted by 21a

2322
W.-M. Dai et al. / Tetrahedron: Asymmetry 11 (2000) 2315±2337
p-H,18 respectively. But the linearity of the plots is very poor. The data suggested that the stereo-
chemistry of the ethylation catalyzed by chiral ligand 21 is not only determined by the electronic
e€ect.17b
A high enantioselectivity (94.8% ee) was obtained for (R)-22m formed from a saturated aldehyde,
cyclohexanecarboxaldehyde. trans-Cinnamaldehyde gave a reasonably high ee of 81.3% for (R)-
22l. The heterocyclic aromatic aldehydes, 2-furaldehyde and 2-thiophenecarboxaldehyde provided
(R)-22q (78.0% ee) and (R)-22r (94.9% ee) in good to excellent enantioselectivity. However,
pyridinecarboxaldehydes were the poorest substrates of the ethylation reaction giving 5.4 to
24.3% ee.19a The results are interpreted by the competitive side catalytic cycle involving the basic
heteroatom. In fact, autocatalysis of the nitrogen-containing aromatic aldehydes was investigated
extensively by the Soai's group.19b i For example, 3-pyridinecarboxaldehyde was converted into
(^)-1-(3-pyridyl)-1-propanol (S)-22o of 14% ee in the presence of 20 mol% of (S)-22o possessing
56% ee.19b In general, the ee of the product is much lower than the ee of the initially used promoter,
except for the cases where the ee of the product is high (or higher than the ee of the initial catalyst)
using a bulky i-Pr2Zn.19b i Because of the proximity of the nitrogen atom to the reacting center,
2-pyridinecarboxaldehyde failed to give chiral 1-(2-pyridyl)-1-propanol in the chiral ligand-catalyzed
ethylation.20 Another possibility is worthy of mentioning. Because of the bulkiness of the tertiary
amino group in 21, complexation of the nitrogen atom with metal species is rather weak and can be
easily replaced by other Lewis bases. This argument agrees well with the enhanced ee in (R)-22n,q,r
according to the diminished Lewis basicity of the heteroatoms: pyridine>furan>thiophene.
Therefore, in the presence of a stronger Lewis base, the chiral ligand 21 cannot function properly
and gives a low ee of the product.
We examined the autocatalysis of (R)-22q and (R)-22r shown in Scheme 3. Compound (R)-22q
with 82.0% ee was obtained from the ethylation of 2-furaldehyde in 85% yield in the presence of
the chiral ligand 23, previously synthesized by us from (S)-abrine (1b).10c Using this chiral alcohol
Scheme 3.

W.-M. Dai et al. / Tetrahedron: Asymmetry 11 (2000) 2315±2337
2323
(R)-22q (82.0% ee) as the promoter (7.6 mol%), the addition of Et2Zn to 2-furaldehyde in
PhMe:hexanes (2:1) completed within 96 h and (R)-22q was isolated in 92% yield and in 27.6%
ee.21 Similarly, addition of Et2Zn to 2-thiophenecarboxaldehyde in the presence of 7.9 mol%
(R)-22r (94.9% ee) a€orded (R)-22r (13.9% ee)21 in 69% yield with 87% conversion of the
aldehyde. The newly formed product ee induced by (R)-22q (82.0% ee) and (R)-22r (94.9% ee) is
calculated to be 23.1 and 3.1% ee, respectively.21 It is evident that (R)-1-(20-furyl)-1-propanol
(R)-22q is a much more ecient promoter than (R)-1-(20-thienyl)-1-propanol (R)-22r in terms of
reactivity and asymmetric autocatalysis. As a result of the autocatalysis by (R)-22q, a relatively
low enantioselectivity (78.0% ee) was obtained for the chiral ligand 21 promoted ethylation of
2-furaldehyde.
2.4. Transition state consideration
Noyori and co-workers investigated the chirality ampli®cation phenomenon in the chiral b-amino
alcohol promoted alkylation of aldehydes with dialkylzincs and demonstrated the existence of an
equilibrium among monomeric and dimeric Zn±ligand complexes.22 Recently, they con®rmed
that the alkylation occurs through the monomeric alkylzinc aminoalkoxide as the catalytic
species.23 In the product-forming transition state (TS), a dinuclear Zn complex with the chiral
ligand and the aldehyde substrate was proposed.24a Based on the molecular orbital calculations at
the restricted Hartree±Fock (RHF) level, the 5/4/4±fused tricyclic transition states were estab-
lished and the alkyl migration was predicted to take place with retention of con®guration.24a,25 27
Among the two possible stereoisomeric m-O TS', the anti-TS is 2.9 kcal/mol much more stable
than the syn-TS.24a These results have recently been reproduced by Houk and Goldfuss in the
PM3 and ONIOM(RHF/LanL2DZ:UFF) TS models.24b,c For the fenchone derivatives, the m-O
syn-TS may dominate compared to the m-O anti-TS depending on the nature of the donor
group.24c
According to these theoretical studies, we use the anti-TS(R) and syn-TS(S) I and II to explain
the stereochemistry induced by the chiral ligands 15a±g, 18, 20b±d, and 21 (Fig. 4).28 Because of the
gem disubstituents at the hydroxymethyl group, the chirality at the carbon bearing the 3-indolyl-
methyl group controls the stereochemical course of the alkylation. In both TS' I and II, the
3-indolylmethyl group points away from the Zn2O2 ring to minimize the steric interaction. For
the anti-TS(R) I, there may be a repulsive intereaction among the X1 and the passive ethyl group
Etp. The two substituents on the nitrogen atom should be arranged with RL being opposite to the
3-indolylmethyl group. In the case of b-tertiary amino alcohols 20b±d and 21, the bulky groups
[3-indolylmethyl, N-CH2CH2X (X=Ph, i-Pr, t-Bu), and Zna-Et] on the ®ve-membered chelate
align with each other in the 1,2-trans relationship. The ethyl group EtT is transferred from the
re-face of the aldehyde to form the R enantiomer. The electron-rich diethylhydroxymethyl group
in 21 should increase the Lewis basicity of the alkoxide and enhances the rigidity of the ®ve-
membered chelate. It gives a higher preference for the anti-TS(R) I and results in a better stereo-
chemical control. This accounts for the excellent performance of the chiral ligand 21 described
above, as well as the remarkably improved enantioselectivity of 14b over 14a (Fig. 2). It has been
known that the b-secondary amino alcohols 13a±c induced the S alcohols,9o,p and a zinc mono-
alkoxide was proposed as the catalytic species.9o We suggest the syn-TS(S) II for the asymmetric
induction of 15e±g and 18. With RS being H, steric repulsion between RS and the transferring
ethyl group EtT is less demanding. Thus, TS II becomes much more stable than I and the S product
is formed predominantly.24c A similar TS of the type II can be proposed for the catalysis of 13a±c.

2324
W.-M. Dai et al. / Tetrahedron: Asymmetry 11 (2000) 2315±2337
The higher ee observed for 13a±c compared to 18 may be rationalized by considering the possible
catalysis of an indole zinc amide of 18.10d For the ligands 15a±d, a reversal in asymmetric
induction was observed. It may result from the preference of anti-TS(R) I over syn-TS(S) II where
the steric repulsion between X2 (alkyl) and EtT causes destabilization. It seems reasonable that the
electronic e€ect of the alkoxide should enhance the rigidity of the ®ve-membered chelate and
bring the X2 (alkyl) closer to EtT in syn-TS(S) II. Moreover, an alkyl group may have a larger
`e€ective size' than an aryl group. Thus, both electronic and steric e€ects of the dialkylhydroxy-
methyl group in the b-secondary amino alcohols 15a±d destabilizes the syn-TS(S) II. However, it
must be mentioned that the energy di€erence between anti-TS(R) I and syn-TS(S) II may be
within 3 kcal/mol according to reported calculations.24 It is not surprising to see the preference
for the TS switched over with a minor modi®cation on the catalyst structure.
Figure 4. 5/4/4-Fused tricyclic transition states for chiral ligand-promoted ethylation of aldehydes
3. Conclusion
We have synthesized a novel series of chiral b-amino alcohols 15a±g, 20a±d, and 21 from the
alkaloid, (S)-abrine, isolated from the red beans of Abrus precatorius L. Enantioselective ethylation
of aldehydes with Et2Zn was investigated in the presence of a catalytic amount of the chiral
b-amino alcohols and the e€ects of the ligand structures on the enantioselectivity were examined.
As a result of our e€orts, a chiral ligand 21 was discovered. This promoted the ethylation of a
number of naphthaldehydes, p- and m-substituted benzaldehydes, cyclohexanecarboxaldehyde,
and 2-thiophenecarboxaldehyde in >93% ee. An anti 5/4/4±fused tricyclic TS I was proposed to
rationalize the asymmetric induction. Unlike the known cyclic b-amino alcohols, such as the
pyrrolidine derivatives 10±12, and b-amino alcohols attached to a ring skeleton, such as the camphor
derivatives 4 and 5, acyclic b-amino alcohols are relatively ¯exible for positioning the N-alkyl
groups in the aminoalkoxide±zinc chelate. Particularly, unsymmetrical tertiary amines can form
two possible chelates and reduce the stereochemical control in the TS. The success of the chiral
ligand 21 relies on the larger steric di€erence among the N-methyl and the N-2-t-butylethyl
groups. In combination with the electron-rich diethylhydroxylmethyl group, a well-de®ned and
rigid TS I operates for the 21-promoted ethylation. The 3-indolylmethyl group does not seem to
be absolutely necessary and other bulky arylmethyl substituents should act in a similar manner.9p

W.-M. Dai et al. / Tetrahedron: Asymmetry 11 (2000) 2315±2337
2325
We believe that the results described above are very helpful in a novel chiral ligand design for
enantioselective catalysis. The current study provides another good example for the use of natural
products as a source of chiral ligands.
4. Experimental
4.1. General methods
1
1H and 13C NMR spectra were recorded in CDCl3 (300, 400, or 500 MHz for H and 75, 100,
or 125 MHz for 13C, respectively) with CHCl3 as the internal reference. IR spectra were taken on
a FT-IR spectrophotometer. Mass spectra (MS) were measured by CI or FAB method. Both high
resolution mass spectra (HRMS, measured by EI or FAB method) and elemental analysis were
performed by Kunming Institute of Botany, The Chinese Academy of Sciences. All reactions
were carried out under a nitrogen atmosphere and monitored by thin-layer chromatography on
0.25 mm E. Merck silica gel plates (60 F-254) using UV light, or 7% ethanolic phosphomolybdic
acid and heating as the visualizing methods. E. Merck silica gel (60, particle size 0.040±0.063 mm)
was used for ¯ash column chromatography. Yields refer to chromatographically and spectro-
scopically (1H NMR) homogeneous materials. (S)-Abrine was isolated from the extract of the
seeds of Abrus precatorius collected in the Yunnan Province of China.5 Et2Zn (1.0 M in hexanes)
and other reagents were obtained commercially and used as received. Room temperature is
around 20ꢀC.
4.2. (S)-Abrine methyl ester 1c
To methanol (20 mL) in a 250 mL round-bottomed ¯ask cooled to ^20± ^15ꢀC was added
dropwise SOCl2 (1.0 mL). After stirring for 15 min, (S)-abrine 1b (1.50 g, 6.88 mmol) was added
followed by stirring at room temperature for 48 h. The reaction mixture was condensed under
reduced pressure, water was added to the residue, and the aqueous solution was adjusted to pH
9±10 using saturated aqueous Na2CO3. The resultant aqueous solution was extracted with
CH2Cl2 (3Â40 mL), and the organic layer was washed with brine, dried over anhydrous MgSO4,
1
®ltrated, and condensed under reduced pressure to give 1c (1.52 g, 95%): pale yellow oil; H
NMR (300 MHz, CDCl3) ꢁ 8.88 (br s, 1H), 7.65 (d, J=7.7 Hz, 1H), 7.30 (d, J=8.1 Hz, 1H),
7.28±7.13 (m, 2H), 6.97 (s, 1H), 3.71 (s, 3H), 3.64 (t, J=6.9 Hz, 1H), 3.26 (dd, J=14.4, 5.8 Hz,
1H), 3.17 (dd, J=14.4, 7.2 Hz, 1H), 2.42 (s, 3H); 13C NMR (75 MHz, CDCl3) ꢁ 175.0, 136.2,
127.2, 123.0, 121.7, 119.1, 118.4, 111.2, 110.4, 63.7, 51.6, 34.6, 29.0; HRMS (+EI) calcd for
C13H16N2O2 (M+): 232.1212; found: 232.1195.
4.3. Synthesis of secondary amino alcohols from 1c; general procedure
To a solution of 1c (1.00 g, 4.3 mmol) in dry THF (20 mL) cooled in an ice±water bath (ca.
0ꢀC) was added a THF solution of RMgBr or ArMgBr (6 mol equiv.) followed by stirring at
room temperature for 15 h. The reaction mixture was quenched by saturated aqueous NH4Cl and
extracted with EtOAc (3Â50 mL). The combined organic layer was washed with brine, dried over
anhydrous MgSO4, ®ltered, and concentrated in vacuo. The residue was puri®ed by ¯ash column
chromatography (silica gel, 5% MeOH±CH2Cl2) to give the alcohols.

2326
W.-M. Dai et al. / Tetrahedron: Asymmetry 11 (2000) 2315±2337
4.3.1. 3-(30-Indolyl)-1,1-dimethyl-(2S)-(N-methylamino)-1-propanol 15a
20
D
Prepared from 1c in 78% yield; pale yellow foam; ‰ꢂŠ ^48.2 (c=1.05, MeOH); IR (KBr) 3332,
3224 (br), 1457, 1359, 1171 cm^1; 1H NMR (400 MHz, CDCl3) ꢁ 9.03 (br s, 1H), 7.54 (d, J=7.44
Hz, 1H), 7.32 (d, J=8.12 Hz, 1H), 7.14 (t, J=7.08 Hz, 1H), 7.06 (t, J=7.56 Hz, 1H), 7.03 (s, 1H),
3.28 (br s, 2H), 3.02 (d, J=12.48 Hz, 1H), 2.70±2.61 (m, 2H), 2.11 (s, 3H), 1.33 (s, 3H), 1.17 (s,
3H); 13C NMR (100 MHz, CDCl3) ꢁ 136.5, 127.2, 122.4, 121.8, 119.0, 118.4, 112.7, 111.3, 72.0,
68.9, 37.0, 27.5, 26.8, 23.8; MS (+FAB) m/z (relative intensity) 233 (M+H+, 100); HRMS (+FAB)
calcd for C14H21N2O (M+H+): 233.1654; found: 233.1664.
4.3.2. 1,1-Diethyl-3-(30-indolyl)-(2S)-(N-methylamino)-1-propanol 15b
20
D
Prepared from 1c in 64% yield; pale yellow foam; ‰ꢂŠ ^51.9 (c=2.24, CHCl3); IR (KBr) 3420
1
(br), 1460, 1360, 1110 cm^1; H NMR (300 MHz, CDCl3) ꢁ 8.20 (br s, 1H), 7.64 (d, J=7.8 Hz,
1H), 7.38 (d, J=8.1 Hz, 1H), 7.24±7.12 (m, 2H), 7.04 (d, J=2.1 Hz, 1H), 3.07 (dd, J=10.8, 3.6
Hz, 1H), 2.80 (dd, J=14.1, 3.6 Hz, 1H), 2.65 (dd, J=14.7, 10.8 Hz, 1H), 2.11 (s, 3H), 1.74±1.51
(m, 4H), 1.00 (t, J=7.5 Hz, 6H); 13C NMR (75 MHz, CDCl3) ꢁ 136.5, 127.6, 122.2, 122.1, 119.4,
118.7, 113.8, 111.3, 74.9, 65.0, 38.2, 28.7, 27.0, 26.6, 8.0, 7.9; MS (+CI) m/z (relative intensity) 261
(M+H+, 100); HRMS (+FAB) calcd for C16H25N2O (M+H+) 261.1967; found: 261.1977; anal.
calcd for C16H24N2O: C, 73.81; H, 9.29; N, 10.76; found: C, 73.85; H, 9.37; N, 10.48.
4.3.3. 3-(30-Indolyl)-(2S)-(N-methylamino)-1,1-di-n-propyl-1-propanol 15c
20
D
Prepared from 1c in 60% yield; pale yellow foam; ‰ꢂŠ ^13.0 (c=1.02, MeOH); IR (KBr) 3264
1
(br), 1459, 1436, 1354 cm^1; H NMR (500 MHz, CDCl3) ꢁ 8.15 (br s, 1H), 7.56 (d, J=7.88 Hz,
1H), 7.39 (d, J=8.12 Hz, 1H), 7.20±7.13 (m, 2H), 7.11 (t, J=7.05 Hz, 1H), 3.56 (br s, 2H), 3.09
(dd, J=14.77, 2.76 Hz, 1H), 2.94 (dd, J=10.86, 3.16 Hz, 1H), 2.80 (dd, J=14.72, 11.02 Hz, 1H),
2.10 (s, 3H), 1.75±1.40 (m, 8H), 0.98 (t, J=7.06 Hz, 3H), 0.96 (t, J=7.06 Hz, 3H); 13C NMR (125
MHz, CDCl3) ꢁ 136.6, 127.0, 123.2, 121.8, 119.1, 118.2, 111.5 (Â2), 75.0, 66.4, 39.3, 37.3, 37.1,
29.6, 25.8, 16.6, 14.7, 14.6; MS (+FAB) m/z (relative intensity) 289 (M+H+, 57); HRMS (+FAB)
calcd for C18H29N2O (M+H+): 289.2280; found: 289.2194.
4.3.4. 1,1-Di-n-butyl-3-(30-indolyl)-(2S)-(N-methylamino)-1-propanol 15d
20
D
Prepared from 1c in 63% yield; pale yellow foam; ‰ꢂŠ ^11.7 (c=0.32, MeOH); IR (KBr) 3467,
1
3415, 3309 (br), 1458 cm^1; H NMR (500 MHz, CDCl3) ꢁ 8.12 (br s, 1H), 7.62 (d, J=7.70 Hz,
1H), 7.37 (d, J=8.10 Hz, 1H), 7.21 (t, J=7.00 Hz, 1H), 7.14 (t, J=7.05 Hz, 1H), 7.06 (d, J=1.95
Hz, 1H), 3.06 (ddd, J=14.63, 3.61, 0.92 Hz, 1H), 2.79 (dd, J=10.68, 3.64 Hz, 1H), 2.66 (dd,
J=14.64, 10.70 Hz, 1H), 2.11 (s, 3H), 1.70±1.25 (m, 12H), 0.95 (t, J=7.23 Hz, 3H), 0.92 (t,
J=7.17 Hz, 3H); 13C NMR (125 MHz, CDCl3) ꢁ 136.5, 127.6, 122.3, 122.2, 119.4, 118.7, 113.8,
111.3, 74.8, 65,8, 38.2, 36.9, 35.0, 26.7, 25.8, 25.75, 23.7, 23.5, 14.2 (Â2); MS (+FAB) m/z (relative
intensity) 317 (M+H+, 100); HRMS (+FAB) calcd for C20H33N2O (M+H+): 317.2593; found:
317.2539.
4.3.5. 3-(30-Indolyl)-(2S)-(N-methylamino)-1,1-diphenyl-1-propanol 15e
20
D
Prepared from 1c in 52% yield; pale yellow foam; ‰ꢂŠ ^14.5 (c=2.11, CHCl3); IR (KBr) 3395
(br), 1450 cm^1; 1H NMR (300 MHz, CDCl3) ꢁ 8.04 (br s, 1H), 7.79±7.70 (m, 4H), 7.61 (d, J=7.5
Hz, 1H), 7.38±7.13 (m, 9H), 6.99 (d, J=1.8 Hz, 1H), 3.98 (dd, J=10.8, 3.0 Hz, 1H), 3.30±2.55 (br
s, 2H), 2.92 (dd, J=15.3, 2.4 Hz, 1H), 2.63 (dd, J=15.3, 10.8 Hz, 1H), 1.83 (s, 3H); 13C NMR (75
MHz, CDCl3) ꢁ 147.9, 145.3, 136.5, 128.2, 128.1, 127.5, 126.5, 126.4, 125.9, 125.6, 122.4, 122.2,

W.-M. Dai et al. / Tetrahedron: Asymmetry 11 (2000) 2315±2337
2327
119.5, 118.9, 113.2, 111.3, 77.8, 66.4, 37.1, 27.1; MS (+CI) m/z (relative intensity) 357 (M+H+,
100); HRMS (+FAB) calcd for C24H25N2O (M+H+): 357.1967; found: 357.1908; anal. calcd for
C24H24N2O: C, 80.87; H, 6.79; N, 7.86; found: C, 80.75; H, 6.96; N, 7.77.
4.3.6. 3-(30-Indolyl)-(2S)-(N-methylamino)-1,1-di(400-methylphenyl)-1-propanol 15f
20
D
Prepared from 1c in 59% yield; pale yellow foam; ‰ꢂŠ ^12.5 (c=1.94, CHCl3); IR (KBr) 3400
(br), 1450 cm^1; 1H NMR (300 MHz, CDCl3) ꢁ 8.10 (br s, 1H), 7.67±7.59 (m, 5H), 7.34 (d, J=8.1
Hz, 1H), 7.24±7.12 (m, 6H), 6.97 (d, J=1.5 Hz, 1H), 3.94 (dd, J=10.5, 2.7 Hz, 1H), 3.60±2.50 (br
s, 2H), 2.95 (dd, J=15.3, 2.1 Hz, 1H), 2.62 (dd, J=15.3, 10.8 Hz, 1H), 2.32 (s, 3H), 2.31 (s, 3H),
1.85 (s, 3H); 13C NMR (75 MHz, CDCl3) ꢁ 145.1, 142.6, 136.5, 135.9, 135.8, 128.9, 128.8, 127.5,
125.8, 125.5, 122.4, 122.1, 119.4, 118.9, 113.4, 111.2, 77.8, 66.4, 37.2, 27.2, 20.9, 20.8; MS (+CI)
m/z (relative intensity) 385 (M+H+, 100); HRMS (+FAB) calcd for C26H29N2O (M+H+):
385.2280; found: 385.2242; anal. calcd for C26H28N2O: C, 81.21; H, 7.34; N, 7.29; found: C,
81.50; H, 7.43; N, 7.01.
4.3.7. 3-(30-Indolyl)-(2S)-(N-methylamino)-1,1-di(200-methylphenyl)-1-propanol 15g
20
D
Prepared from 1c in 50% yield; pale yellow foam; ‰ꢂŠ ^45.6 (c=2.27, CHCl3); IR (KBr) 3398
1
(br), 1452 cm^1; H NMR (300 MHz, CDCl3) ꢁ 8.01 (br s, 1H), 7.81 (br d, J=6.0 Hz, 1H), 7.68
(dd, J=7.7, 1.8 Hz, 1H), 7.57 (d, J=7.7 Hz, 1H), 7.35 (dd, J=7.0, 1.0 Hz, 1H), 7.25±7.10 (m,
7H), 7.05 (d, J=7.4 Hz, 1H), 6.82 (d, J=1.8 Hz, 1H), 4.06 (dd, J=9.6, 3.3 Hz, 1H), 3.05 (dd,
J=15.6, 3.0 Hz, 1H), 2.62 (dd, J=15.3, 9.6 Hz, 1H), 2.22 (s, 3H), 2.16 (s, 6H); 13C NMR (75
MHz, CDCl3) ꢁ 143.4, 142.1, 138.8, 136.4, 132.8, 132.2, 128.4, 127.5, 127.3, 127.0, 126.8, 124.8,
124.5, 122.1, 122.0, 119.4, 118.7, 113.7, 111.2, 81.0, 64.0, 36.5, 28.1, 22.4, 22.0; MS (+CI) m/z
(relative intensity) 385 (M+H+, 100); HRMS (+FAB) calcd for C26H29N2O (M+H+): 385.2280;
found: 385.2253; anal. calcd for C26H28N2O: C, 81.21; H, 7.29; N, 7.29; found: C, 81.57; H, 7.50;
N, 6.98.
4.4. (2S)-Amino-3-(30-indolyl)-1,1-diphenyl-1-propanol 17
To a solution of l-tryptophan methyl ester hydrochloride (16, 1.05 g, 3.93 mmol) in dry THF
(20 mL) cooled in an ice±water bath (ca. 0ꢀC) was added a solution of PhMgCl (15.0 mL, 2.0 M in
THF, 30.0 mmol) followed by stirring at room temperatue for 19 h. The reaction mixture was
quenched by saturated aqueous NH4Cl and extracted with Et2O (3Â30 mL). The combined organic
layer was washed with brine, dried over anhydrous MgSO4, ®ltered, and concentrated in vacuo. The
residue was puri®ed by ¯ash column chromatography (silica gel, MeOH:CH2Cl2:hexane=1:10:10)
to give 17 (852 mg, 60%): pale yellow foam; 1H NMR (300 MHz, CDCl3) ꢁ 8.05 (br s, 1H), 7.67
(t, J=8.7 Hz, 4H), 7.52 (d, J=7.5 Hz, 1H), 7.45±7.15 (m, 9H), 7.03 (d, J=1.8 Hz, 1H), 4.30 (dd,
J=10.2, 3.0 Hz, 1H), 2.75 (dd, J=14.7, 2.7 Hz, 1H), 2.66 (dd, J=14.4, 10.5 Hz, 1H), 2.10±1.40
(br s, 2H); 13C NMR (75 MHz, CDCl3) ꢁ 147.1, 144.5, 136.6, 128.5, 128.3, 127.3, 126.7, 126.6,
125.8, 125.4, 122.6, 122.2, 119.4, 118.9, 113.4, 111.3, 78.5, 56.4, 26.3.
4.5. 3-(30-Indolyl)-(2S)-(isovalerylamino)-1,1-diphenyl-1-propanol
To a solution of 17 (340 mg, 0.99 mmol) in dry THF (5 mL) cooled in an ice±water bath was
added Et3N (0.18 mL, 1.29 mmol) and isovaleryl chloride (0.14 mL, 1.15 mmol) followed by
stirring at room temperature for 6 h. The precipitate was ®ltered o€ through Celite with rinsing

2328
W.-M. Dai et al. / Tetrahedron: Asymmetry 11 (2000) 2315±2337
by Et2O (3Â20 mL). The combined organic layer was washed with brine, dried over anydrous
MgSO4, ®ltered, and condensed under reduced pressure. The residue was puri®ed by ¯ash column
chromatography (silica gel, 25% EtOAc±hexane) to give the amide of 17 (295 mg, 69%): pale
yellow foam; IR (KBr) 3410, 3320 (br), 1640, 1450 cm^1; 1H NMR (300 MHz, CD3CN) ꢁ 8.87 (br
s, 1H), 7.56±7.51 (m, 2H), 7.43±7.38 (m, 2H), 7.25±7.14 (m, 2H), 7.09±7.00 (m, 4H), 6.96±6.88 (m,
2H), 6.84 (d, J=2.4 Hz, 1H), 6.79 (ddd, J=8.1, 6.9, 1.2 Hz, 1H), 6.40 (d, J=8.8 Hz, 1H), 5.57 (br
s, 1H), 4.73 (ddd, J=11.9, 8.7, 2.1 Hz, 1H), 2.91 (dd, J=14.7, 11.1 Hz, 1H), 2.57 (ddd, J=14.7,
2.1, 0.6 Hz, 1H), 11.55±1.41 (m, 3H), 0.35 (d, J=6.6 Hz, 3H), 0.29 (d, J=6.0 Hz, 3H); 13C NMR
(75 MHz, CD3CN) ꢁ 172.9, 147.0, 146.3, 136.4, 128.3, 127.7, 126.6, 126.3, 125.8, 125.6, 123.1,
121.1, 118.6, 118.3, 112.3, 111.2, 80.5, 58.8, 45.2, 25.6, 24.4, 21.4, 21.2; MS (+CI) m/z (relative
intensity) 427 (M+H+, 8), 409 (M+^H2O, 11), 280 (100); HRMS (+FAB) calcd for C28H31N2O2
(M+H+): 427.2386; found: 427.2470; anal. calcd for C28H30N2O2: C, 78.84; H, 7.09; N, 6.57;
found: C, 78.59; H, 7.42; N, 6.30.
4.6. 3-(30-Indolyl)-(2S)-(300-methylbutylamino)-1,1-diphenyl-1-propanol 18
To a suspension of LiAlH4 (76 mg, 2.00 mmol) in dry THF (10 mL) cooled in an ice±water
bath (ca. 0ꢀC) was added a solution of the amide obtained above from 17 (200 mg, 0.47 mmol) in
dry THF (5 mL). The resultant mixture was then heated at re¯uxing temperature for 43 h. After
cooled to ca. 0ꢀC in an ice±water bath, the reaction mixture was quenched by 5% aqueous NaOH
(4 mL) and ®ltered through Celite with rinsing by EtOAc. The ®ltrate was extracted with EtOAc
(3Â20 mL), and the combined organic layer was washed with brine, dried over anhydrous
MgSO4, ®ltered, and condensed in vacuo. The residue was puri®ed by ¯ash column chromatography
20
D
(silica gel, 20% EtOAc±hexane) to give 18 (109 mg, 56%): pale yellow foam; ‰ꢂŠ ^23.4 (c=2.18,
CHCl3); IR (KBr) 3420 (br), 1450, 1350 cm^1; 1H NMR (300 MHz, CDCl3) ꢁ 8.01 (br s, 1H), 7.78
(t, J=8.1 Hz, 4H), 7.65 (d, J=7.5 Hz, 1H), 7.40±7.17 (m, 9H), 6.95 (d, J=1.5 Hz, 1H), 5.60±5.05
(br s, 2H), 4.04 (dd, J=10.8, 2.7 Hz, 1H), 2.95 (dd, J=15.3, 2.7 Hz, 1H), 2.56 (dd, J=15.3, 11.1
Hz, 1H), 1.98 (dt, J=11.4, 6.9 Hz, 1H), 1.85 (dt, J=11.4, 6.9 Hz, 1H), 1.10 (sept., J=6.6 Hz,
1H), 0.90±0.75 (m, 2H), 0.53 (d, J=6.6 Hz, 3H), 0.43 (d, J=6.6 Hz, 3H); 13C NMR (75 MHz,
CDCl3) ꢁ 148.2, 145.5, 136.6, 128.1, 128.0, 127.5, 126.4, 126.3, 126.0, 125.7, 122.2, 122.1, 119.4,
118.9, 113.5, 111.2, 77.6, 64.5, 47.7, 39.2, 27.4, 25.1, 22.3, 22.0; MS (+CI) m/z (relative intensity)
413 (M+H+, 100); HRMS (+FAB) calcd for C28H33N2O (M+H+): 413.2593; found: 413.2506;
anal. calcd for C28H32N2O: C, 81.51; H, 7.82; N, 6.79; found: C, 81.41; H, 7.98; N, 6.66.
4.7. Synthesis of amides of 15b and 15f; general procedure
To a solution of 15b or 15f (3.03 mmol) in dry THF (30 mL) cooled in an ice±water bath was
added Et3N (0.50 mL, 3.59 mmol) and the acyl chloride (3.60 mmol) followed by stirring at room
temperature for 17 h. The precipitate was ®ltered o€ through Celite with rinsing by Et2O (3Â30 mL).
The combined organic layer was washed with brine, dried over anydrous MgSO4, ®ltered, and
condensed under reduced pressure. The residue was puri®ed by ¯ash column chromatography
(silica gel, EtOAc:hexane:CH2Cl2=1:3:3) to give the amide.
4.7.1. 1,1-Diethyl-3-(30-indolyl)-(2S)-(N-methyl-N-300,300-dimethylbutyrylamino)-1-propanol
Prepared from 15b in 94% yield; pale yellow foam; IR (KBr) 3250 (br), 1600, 1450, 1355 cm^1;
1H NMR (300 MHz, CDCl3) ꢁ 8.26 (br s, 1H), 7.56 (d, J=7.8 Hz, 1H), 7.37 (d, J=7.8 Hz, 1H),

W.-M. Dai et al. / Tetrahedron: Asymmetry 11 (2000) 2315±2337
2329
7.19 (t, J=7.2 Hz, 1H), 7.11 (t, J=7.2 Hz, 1H), 6.95 (s, 1H), 6.42 (s, 1H), 3.64 (dd, J=14.7, 12.0
Hz, 1H), 3.34 (dd, J=12.0, 3.0 Hz, 1H), 3.08 (dd, J=14.7, 2.4 Hz, 1H), 2.41 (s, 3H), 2.19 (d,
J=14.4 Hz, 1H), 2.01 (d, J=14.7 Hz, 1H), 1.90±1.30 (m, 3H), 1.05 (s, 9H), 1.00 (t, J=7.5 Hz,
3H), 0.90 (t, J=7.5 Hz, 3H); 13C NMR (75 MHz, CDCl3) ꢁ 174.6, 136.4, 127.5, 122.8, 121.9,
119.3, 118.4, 113.6, 111.4, 75.8, 73.8, 46.7, 43.0, 31.6, 30.1, 28.4, 27.9, 21.0, 8.8, 7.8; MS (+CI) m/z
(relative intensity) 359 (M+H+, 1), 156 (100); HRMS (+FAB) calcd for C22H35N2O2 (M+H+):
359.2699; found: 359.2735; anal. calcd for C22H34N2O2: C, 73.70; H, 9.56; N, 7.81; found: C,
73.50; H, 9.70; N, 7.58.
4.7.2. (2S)-(N-Benzoyl-N-methylamino)-3-(30-indolyl)-1,1-di(400-methylphenyl)-1-propanol
Prepared from 15f in 60% yield; pale yellow foam; IR (KBr) 3420 (br), 1600, 1450, 1360 cm^1;
1H NMR (300 MHz, CDCl3) ꢁ 8.36 (br s, 1H), 8.14 (s, 1H), 7.80 (d, J=8.1 Hz, 2H), 7.64±7.01 (m,
14H), 6.77 (d, J=6.9 Hz, 2H), 4.56 (dd, J=11.7, 2.4 Hz, 1H), 4.04 (dd, J=15.0, 12.3 Hz, 1H),
3.16 (dd, J=14.7, 2.1 Hz, 1H), 2.40 (s, 3H), 2.29 (s, 3H), 2.13 (s, 3H); 13C NMR (75 MHz,
CDCl3) ꢁ 173.7, 144.0, 142.5, 136.4, 136.3, 135.9, 129.3, 129.1, 128.4, 128.2, 127.4, 126.0, 125.7,
125.3, 122.9, 122.0, 119.4, 118.7, 113.2, 111.4, 79.9, 74.4, 44.3, 21.8, 20.9, 20.8; MS (+CI) m/z
(relative intensity) 489 (M+H+, 100); HRMS (+FAB) calcd for C33H33N2O2 (M+H+): 489.2542;
found: 489.2565; anal. calcd for C33H32N2O2: C, 81.12; H, 6.60; N, 5.73; found: C, 80.80; H, 6.83;
N, 5.41.
4.7.3. 3-(30-Indolyl)-(2S)-(N-methyl-N-phenylacetylamino)-1,1-di(400-methylphenyl)-1-propanol
Prepared from 15f in 96% yield; pale yellow foam; IR (KBr) 3390 (br), 1600, 1450, 1350 cm^1;
1H NMR (300 MHz, CDCl3) ꢁ 8.14 (br s, 1H), 8.08 (s, 1H), 7.73 (d, J=8.1 Hz, 2H), 7.46±7.01 (m,
13H), 6.76 (s, 1H), 6.75 (d, J=6.6 Hz, 2H), 4.38 (d, J=9.6 Hz, 1H), 3.78 (dd, J=14.7, 12.0 Hz,
1H), 3.44 and 3.33 (AB q, J=15.0 Hz, 2H), 3.01 (d, J=14.7 Hz, 1H), 2.36 (s, 3H), 2.30 (s, 6H);
13C NMR (75 MHz, CDCl3) ꢁ 173.4, 144.4, 143.0, 136.2, 135.6, 133.0, 129.0, 128.5, 128.4, 127.4,
126.5, 125.6, 125.2, 122.5, 121.9, 119.4, 118.6, 113.6, 111.3, 79.6, 76.7, 43.1, 42.5, 21.7, 20.9; MS
(+CI) m/z (relative intensity) 503 (M+H+, 100); HRMS (+FAB) calcd for C34H35N2O2 (M+H+):
503.2699; found: 503.2703; anal. calcd for C34H34N2O2: C, 81.24; H, 6.82; N, 5.57; found, C,
81.01; H, 6.99; N, 5.26.
4.7.4. 3-(30-Indolyl)-(2S)-(N-isovaleryl-N-methylamino)-1,1-di(400-methylphenyl)-1-propanol
1
Prepared from 15f in 83% yield; pale yellow foam; IR (KBr) 3420 (br), 1610, 1450 cm^1; H
NMR (300 MHz, CDCl3) ꢁ 8.27 (br s, 1H), 8.23 (s, 1H), 7.73 (d, J=8.1 Hz, 2H), 7.44±7.10 (m,
8H), 7.03 (d, J=8.1 Hz, 2H), 6.92 (d, J=1.8 Hz, 1H), 4.36 (dd, J=11.7, 2.4 Hz, 1H), 3.78 (dd,
J=15.0, 11.7 Hz, 1H), 3.00 (dd, J=15.0, 2.1 Hz, 1H), 2.36 (s, 3H), 2.27 (s, 3H), 2.24 (s, 3H),
1.89±1.77 (m, 3H), 0.81 (d, J=6.0 Hz, 3H), 0.67 (d, J=6.0 Hz, 3H); 13C NMR (75 MHz, CDCl3)
ꢁ 174.9, 144.5, 143.1, 136.2, 135.6, 129.0, 128.3, 125.6, 125.3, 122.4, 121.9, 119.4, 118.7, 114.0,
111.2, 79.7, 76.6, 43.9, 42.9, 25.2, 22.5, 22.3, 21.7, 20.9, 20.8; MS (+CI) m/z (relative intensity) 469
(M+H+, 100); HRMS (+FAB) calcd for C31H37N2O2 (M+H+): 469.2855; found: 469.2832; anal.
calcd for C31H36N2O2: C, 79.45; H, 7.74; N, 5.98; found: C, 79.11; H, 7.99; N, 5.67.
4.7.5. 3-(30-Indolyl)-(2S)-(N-methyl-N-300,300-dimethylbutyrylamino)-1,1-di(4000-methylphenyl)-1-
propanol
Prepared from 15f in 85% yield; pale yellow foam; IR (KBr) 3300 (br), 1610, 1450, 1370 cm^1;
1H NMR (300 MHz, CDCl3) ꢁ 8.32 (br s, 1H), 8.20 (s, 1H), 7.73 (d, J=8.1 Hz, 2H), 7.46±7.10 (m,

2330
W.-M. Dai et al. / Tetrahedron: Asymmetry 11 (2000) 2315±2337
8H), 7.02 (d, J=8.1 Hz, 2H), 6.92 (d, J=2.1 Hz, 1H), 4.39 (dd, J=11.7, 2.7 Hz, 1H), 3.80 (dd,
J=15.0, 11.7 Hz, 1H), 2.97 (dd, J=14.7, 2.4 Hz, 1H), 2.35 (s, 3H), 2.29 (s, 3H), 2.22 (s, 3H), 1.97
and 1.85 (AB q, J=14.1 Hz, 2H), 0.75 (s, 9H); 13C NMR (75 MHz, CDCl3) ꢁ 174.5, 144.6, 143.2,
136.1, 135.6, 129.0, 128.4, 127.4, 125.5, 125.3, 122.5, 121.9, 119.4, 118.7, 113.9, 111.2, 79.6, 76.6,
46.7, 43.8, 31.4, 29.6, 21.4, 20.9, 20.8; MS (+CI) m/z (relative intensity) 483 (M+H+, 100); HRMS
(+FAB) calcd for C32H39N2O2 (M+H+): 483.3012; found: 483.3044; anal. calcd for C32H38N2O2:
C, 79.63; H, 7.94; N, 5.80; found: C, 79.35; H, 8.10; N, 5.56.
4.8. Synthesis of tertiary amino alcohols by LiAlH4 reduction of amides; general procedure
To a suspension of LiAlH4 (217 mg, 5.72 mmol) in dry THF (10 mL) cooled in an ice±water
bath (ca. 0ꢀC) was added a solution of the amide obtained above from 15b or 15f (2.79 mmol) in
dry THF (20 mL). The resultant mixture was then heated at re¯uxing temperature for 12 h. After
cooled to ca. 0ꢀC in an ice±water bath, the reaction mixture was quenched by 5% aqueous NaOH
(4 mL) and ®ltered through Celite with rinsing by EtOAc. The ®ltrate was extracted with EtOAc
(3Â20 mL), and the combined organic layer was washed with brine, dried over anhydrous
MgSO4, ®ltered, and condensed in vacuo. The residue was puri®ed by ¯ash column chromato-
graphy (silica gel, MeOH:CH2Cl2:hexane=1:8:16) to give the product.
4.8.1. (2S)-(N-Benzyl-N-methylamino)-3-(30-indolyl)-1,1-di(400-methylphenyl)-1-propanol 20a
20
D
Prepared from the corresponding amide in 70% yield; pale yellow foam; ‰ꢂŠ ^10.2 (c=2.10,
1
CHCl3); IR (KBr) 3410 (br), 1450, 1340 cm^1; H NMR (300 MHz, CDCl3) ꢁ 8.15 (br s, 1H),
7.59±7.49 (m, 5H), 7.36 (d, J=8.1 Hz, 1H), 7.23±7.17 (m, 9H), 7.04±6.99 (m, 3H), 4.23 (dd,
J=9.3, 4.5 Hz, 1H), 3.52 (d, J=13.2 Hz, 1H), 3.30 (d, J=13.2 Hz, 1H), 3.24±3.21 (m, 2H), 2.38
(s, 3H), 2.37 (s, 3H), 1.98 (s, 3H); 13C NMR (75 MHz, CDCl3) ꢁ 143.1, 141.2, 139.4, 136.7, 136.4,
136.2, 128.7, 128.6, 128.5, 128.3, 128.2, 128.0, 127.4, 127.2, 126.9, 122.5, 122.0, 119.3, 119.1,
114.3, 111.2, 78.5, 72.0, 61.5, 38.3, 23.6, 21.0; MS (+CI) m/z (relative intensity) 475 (M+H+, 100);
HRMS (+FAB) calcd for C33H35N2O (M+H+: 475.2749; found: 475.2785; anal. calcd for
C33H34N2O: C, 83.51; H, 7.22; N, 5.90; found: C, 83.60; H, 7.29; N, 5.69.
4.8.2. 3-(30-Indolyl)-(2S)-(N-methyl-N-200-phenylethylamino)-1,1-di(4000-methylphenyl)-1-propanol
20b
20
D
Prepared from the corresponding amide in 35% yield; pale yellow foam; ‰ꢂŠ +37.6 (c=1.20,
1
CHCl3); IR (KBr) 3420 (br), 1500, 1450, 1350 cm^1; H NMR (300 MHz, CDCl3) ꢁ 7.97 (br s,
1H), 7.51±7.46 (m, 5H), 7.35 (d, J=8.1 Hz, 1H), 7.22±7.11 (m, 9H), 6.95 (s, 1H), 6.86 (d, J=6.9
Hz, 2H), 4.06 (br s, 1H), 3.11 (d, J=7.2 Hz, 2H), 2.65±2.25 (m, 4H), 2.41 (s, 3H), 2.35 (s, 3H),
2.08 (s, 3H); 13C NMR (75 MHz, CDCl3) ꢁ 143.0, 141.0, 139.7, 136.8, 136.4, 136.3, 128.8, 128.7,
128.3, 128.1, 127.6, 127.2, 126.0, 122.4, 122.0, 119.4, 119.1, 114.4, 111.2, 78.2, 73.0, 58.1, 39.7,
35.4, 23.5, 21.0; MS (+CI) m/z (relative intensity) 489 (M+H+, 42), 211 (100); HRMS (+FAB)
calcd for C34H37N2O (M+H+): 489.2906; found: 489.2972; anal. calcd for C34H36N2O: C, 83.57;
H, 7.43; N, 5.73; found: C, 83.40; H, 7.45; N, 5.51.
4.8.3. 3-(30-Indolyl)-(2S)-(N-methyl-N-300-methylbutylamino)-1,1-di(4000-methylphenyl)-1-propanol
20c
20
D
Prepared from the corresponding amide in 67% yield; pale yellow foam; ‰ꢂŠ +40.0 (c=1.03,
1
CHCl3); IR (KBr) 3380 (br), 1450, 1350 cm^1; H NMR (300 MHz, CDCl3) ꢁ 8.09 (br s, 1H),

W.-M. Dai et al. / Tetrahedron: Asymmetry 11 (2000) 2315±2337
2331
7.56±7.49 (m, 5H), 7.32±7.11 (m, 7H), 6.96 (d, J=1.8 Hz, 1H), 4.06 (dd, J=10.8, 3.3 Hz, 1H),
3.18 (dd, J=15.3, 2.7 Hz, 1H), 3.09 (dd, J=15.3, 11.1 Hz, 1H), 2.40 (s, 3H), 2.37 (s, 3H), 2.35±
2.05 (m, 2H), 2.02 (s, 3H), 1.33±1.25 (m, 2H), 1.20±1.05 (m, 1H), 0.70 (d, J=6.3 Hz, 3H), 0.69 (d,
J=6.6 Hz, 3H); 13C NMR (75 MHz, CDCl3) ꢁ 143.1, 141.3, 136.7, 136.3, 136.1, 129.1, 128.7,
128.2, 128.1, 127.6, 127.2, 126.4, 122.4, 121.9, 119.2, 119.1, 114.3, 111.1, 77.7, 72.3, 55.0, 39.2,
37.8, 26.0, 23.5, 22.8, 22.3, 21.0; MS (+CI) m/z (relative intensity) 455 (M+H+, 11), 211 (100);
HRMS (+FAB) calcd for C31H39N2O (M+H+): 455.3062; found: 455.3115; anal. calcd for
C31H38N2O: C, 81.89; H, 8.42; N, 6.16; found: C, 81.93; H, 8.53; N, 5.93.
4.8.4. 3-(30-Indolyl)-(2S)-(N-methyl-N-300,300-dimethylbutylamino)-1,1-di(4000-methylphenyl)-1-
propanol 20d
20
D
Prepared from the corresponding amide in 65% yield; pale yellow foam; ‰ꢂŠ +48.4 (c=1.39,
1
CHCl3); IR (KBr) 3310 (br), 1470, 1370 cm^1; H NMR (300 MHz, CDCl3) ꢁ 8.08 (br s, 1H),
7.57±7.50 (m, 5H), 7.33 (d, J=8.1 Hz, 1H), 7.21±7.08 (m, 6H), 6.96 (d, J=1.8 Hz, 1H), 6.60±6.05
(br s, 1H), 4.08 (dd, J=10.5, 3.0 Hz, 1H), 3.21±3.06 (m, 2H), 2.40 (s, 3H), 2.37 (s, 3H), 2.33±2.07
(m, 2H), 2.04 (s, 3H), 1.34±1.06 (m, 2H), 0.69 (s, 9H); 13C NMR (75 MHz, CDCl3) ꢁ 143.2, 141.3,
136.7, 136.4, 136.1, 128.7, 128.2, 128.1, 127.6, 127.3, 122.4, 121.9, 119.2, 119.1, 114.4, 111.1, 77.6,
72.1, 52.0, 42.3, 40.0, 29.3, 23.6, 21.0; MS (+CI) m/z (relative intensity) 469 (M+H+, 8), 211 (100);
HRMS (+FAB) calcd for C32H41N2O (M+H+): 469.3219; found: 469.3242; anal. calcd for
C32H40N2O: C, 82.01; H, 8.60; N, 5.98; found: C, 81.82; H, 8.77; N, 5.77.
4.8.5. 1,1-Diethyl-3-(30-indolyl)-(2S)-(N-methyl-N-300,300-dimethylbutylamino)-1-propanol 21
Prepared from the corresponding amide in 71% yield; colorless solid; mp 122±123.5ꢀC
20
D
1
(EtOAc±hexane); ‰ꢂŠ ^17.8 (c=2.29, CHCl3); IR (KBr) 3240 (br), 1440, 1350 cm^1; H NMR
(300 MHz, CDCl3) ꢁ 8.27 and 8.15 (br s, 1H), 7.65 (d, J=7.8 Hz, 1H), 7.37 (d, J=7.8 Hz, 1H),
7.26±7.11 (m, 2H), 7.03 (d, J=1.8 Hz, 1H), 4.68 (br s, 1H), 3.29 (br d, J=10.2 Hz, 1H), 3.13 (dd,
J=15.0, 10.8 Hz, 1H), 2.86 (dd, J=15.0, 3.3 Hz, 1H), 2.55±2.28 (m, 2H), 2.34 (s, 3H), 1.90±1.78
(m, 1H), 1.68±1.49 (m, 2H), 1.47±1.14 (m, 3H), 1.00 (t, J=7.2 Hz, 3H), 0.98 (t, J=7.5 Hz, 3H),
0.74 (s, 9H); 13C NMR (75 MHz, CDCl3) ꢁ 136.4, 127.3, 122.4, 121.9, 119.2, 118.8, 114.7, 111.2,
73.8, 67.4, 42.6, 29.5, 29.3, 28.8, 28.1, 21.4, 8.0; MS (+CI) m/z (relative intensity) 345 (M+H+,
100); HRMS (+FAB) calcd for C22H37N2O (M+H+): 345.2906; found: 345.2906; anal. calcd for
C22H36N2O: C, 76.69; H, 10.53; N, 8.13; found: C, 76.63; H, 10.91; N, 8.08.
4.9. The chiral ligand-promoted addition of Et2Zn to aldehydes; general procedure
To a solution of the chiral ligand 21 (0.18 mmol) in dry PhMe (8 mL) under a nitrogen atmosphere
cooled in an ice±water bath (ca. 0ꢀC) was added a solution of Et2Zn (4 mL, 1 M in hexanes) via a
syringe. After stirring for 10 min, freshly distilled benzaldehyde (0.20 mL, 1.80 mmol) was added
into the mixture via another syringe. The resultant mixture was allowed to warm up to room
temperature and stirred for 96 h at the same temperature. The reaction mixture was cooled in an
ice±water bath and quenched by 5% HCl aqueous solution. The mixture was extracted with Et2O
(3Â20 mL), washed with brine, dried over anhydrous MgSO4, and condensed under reduced
pressure. The residue was puri®ed by ¯ash column chromatography (silica gel, 10% EtOAc in
hexane) to give (R)-19 in 70% yield. For other chiral ligands, the reaction time, yield, and
enantiomeric excess are summarized in Tables 1 and 2.

2332
W.-M. Dai et al. / Tetrahedron: Asymmetry 11 (2000) 2315±2337
4.10. General conditions for HPLC analysis of chiral alcohols
Method A: Chiralcel OD column eluted with hexane:2-propanol (97.5:2.5) at 1.0 mL/min using
UV detector at 254 nm.
Method B: Chiralcel OD column eluted with hexane:2-propanol (96:4) at 0.5 mL/min using UV
detector at 254 nm.
Method C: Chiralcel OD column eluted with hexane:2-propanol (97:3) at 0.5 mL/min using
UV detector at 254 nm.
Method D: Chiralcel OD column eluted with hexane:2-propanol (85:15) at 0.5 mL/min using
UV detector at 254 nm.
Method E: Chiralcel OD column eluted with hexane:2-propanol (95:5) at 1.0 mL/min using UV
detector at 254 nm.
Method F: Chiralcel OD column eluted with hexane:2-propanol (90:10) at 0.5 mL/min using
UV detector at 254 nm.
Method G: two Chiralcel OD columns eluted with hexane:2-propanol (96:4) at 0.6 mL/min
using UV detector at 254 nm.
Method H: two Chiralpak AD columns eluted with hexane:2-propanol (99.6:0.4) at 1.0 mL/
min using UV detector at 230 nm.
Method I: two Chiralpak AD columns eluted with hexane:2-propanol (98:2) at 1.0 mL/min
using UV detector at 230 nm.
Method J: Chiralcel OD column eluted with hexane:2-propanol (99.8:0.2) at 1.0 mL/min using
UV detector at 230 nm.
Method K: Chiralpak AD column eluted with hexane:2-propanol (98:2) at 1.0 mL/min using
UV detector at 230 nm.
4.10.1. (R)-1-Phenyl-1-Propanol (R)-19
20
‰ꢂŠ +42.9 (c=3.58, CHCl3) {lit.29 [ꢂ]D +45.6 (CHCl3)}; 87.5% ee by HPLC analysis using
D
Method A: tR=14.9 min for (R)-19 and tR=16.9 min for (S)-19.
4.10.2. (R)-1-(40-Chlorophenyl)-1-propanol (R)-22a
20
22
D
‰ꢂŠ +26.4 (c=5.27, PhH) {lit.30 (S)-22a, ‰ꢂŠ ^28.2 (c=5.01, PhH), 100% ee}; 96.9% ee by
D
HPLC analysis using Method A: tR=11.7 min for (R)-22a and tR=10.9 min for (S)-22a.
4.10.3. (R)-1-(30-Chlorophenyl)-1-propanol (R)-22b
20
D
analysis using Method B: tR=14.6 min for (R)-22b and tR=14.0 min for (S)-22b.
‰ꢂŠ +26.6 (c=2.36, PhH) {lit.16a (R)-22b, [ꢂ]D +24.2 (PhH), 78% ee}; 97.0% ee by HPLC
4.10.4. (R)-1-(40-Bromophenyl)-1-propanol (R)-22c
20
20
D
‰ꢂŠ +16.5 (c=1.07, PhH) {lit.31 (R)-22c, ‰ꢂŠ +13.33 (c=1.0, PhH), 76% ee}; 95.7% ee by
D
HPLC analysis using Method B: tR=15.5 min for (R)-22c and tR=14.8 min for (S)-22c.
4.10.5. (R)-1-(20-Bromophenyl)-1-propanol (R)-22d
20
D
HPLC analysis using Method G: tR=22.4 min for (R)-22d and tR=23.5 min for (S)-22d.
‰ꢂŠ +54.2 (c=2.46, PhH) {lit.32 (R)-22d, [ꢂ]D +52.4 (c=1.3, PhH), >99% ee}; 85.1% ee by

W.-M. Dai et al. / Tetrahedron: Asymmetry 11 (2000) 2315±2337
2333
4.10.6. (R)-1-(40-Methylphenyl)-1-propanol (R)-22e
20
D
25
D
‰ꢂŠ +39.3 (c=3.65, PhH) {lit.33 (S)-22e, ‰ꢂŠ ^39.3 (c=5.0, PhH), 91% ee}; 95.7% ee by
HPLC analysis of the corresponding benzoate using Method K: tR=6.9 min for (R)-22e and
tR=9.5 min for (S)-22e.
4.10.7. (R)-1-(40-Methoxyphenyl)-1-propanol (R)-22f
20
25
D
‰ꢂŠ +35.4 (c=4.84, PhH) {lit.33 (S)-22f, ‰ꢂŠ ^34.6 (c=5.0, PhH), 90% ee}; 95.8% ee by
D
HPLC analysis using Method A: tR=16.5 min for (R)-22f and tR=19.3 min for (S)-22f.
4.10.8. (R)-1-(40-Dimethylaminophenyl)-1-propanol (R)-22g
20
D
HPLC analysis using Method E: tR=11.6 min for (R)-22g and tR=14.1 min for (S)-22g.
‰ꢂŠ +31.3 (c=2.22, PhH) {lit.34 (S)-22g, [ꢂ]D ^45.85 (c=5.0, CHCl3),35 14% ee}; 80.0% ee by
4.10.9. (R)-1-(30,50-Dichlorophenyl)-1-propanol (R)-22h
20
D
using the Method J: tR=11.4 min for (R)-22h and tR=12.6 min for (S)-22h.
‰ꢂŠ +28.8 (c=2.21, CHCl3);36 94.9% ee by HPLC analysis of the corresponding benzoate
4.10.10. (R)-1-(30,50-Dimethoxyphenyl)-1-propanol (R)-22i
20
23
D
‰ꢂŠ +19.4 (c=2.46, CHCl3) {lit.37 (R)-22i, ‰ꢂŠ +24.1 (c=0.6, CHCl3), 75% ee}; 94.1% ee by
D
HPLC analysis using Method C: tR=21.2 min for (R)-22i and tR=32.0 min for (S)-22i.
4.10.11. (R)-1-(10-Naphthyl)-1-propanol (R)-22j
20
23
‰ꢂŠ +52.6 (c=2.55, CHCl3) {lit.37 (R)-22j, ‰ꢂŠ +45.5 (c=0.8, CHCl3), 74% ee}; 93.5% ee by
D
D
HPLC analysis using Method D: tR=19.4 min for (R)-22j and tR=12.4 min for (S)-22j.
4.10.12. (R)-1-(20-Naphthyl)-1-propanol (R)-22k
20
22
D
‰ꢂŠ +27.5 (c=3.80, PhH) {lit.30 (S)-22k, ‰ꢂŠ ^26.6 (c=3.35, PhH), 97% ee}; 96.1% ee by
D
HPLC analysis using Method F: tR=18.8 min for (R)-22k and tR=17.7 min for (S)-22k.
4.10.13. (R)±(E)-1-Phenyl-1-penten-3-ol (R)-22l
20
22
‰ꢂŠ +5.2 (c=1.91, CHCl3) {lit.38 (S)-22l, ‰ꢂŠ ^6.6 (c=3.2, CHCl3), 75% ee}; 81.3% ee by
D
HPLC analysis using Method E: tR=11.9 min for (R)-22l and tR=20.0 min for (S)-22l.
D
4.10.14. (R)-1-Cyclohexyl-1-propanol (R)-22m
20
20
D
24
D
‰ꢂŠ +6.35 (c=3.00, CHCl3) {lit.39a (R)-22m, ‰ꢂŠ +8.1 (CHCl3), 100% ee; lit.39b (S)-22m, ‰ꢂŠ
D
^6.39 (c=1.05, CHCl3), 97% ee}; 94.8% ee by HPLC analysis of the corresponding benzoate
using Method H: tR=15.9 min for (R)-22m and tR=18.4 min for (S)-22m.
4.10.15. (R)-1-(20-Pyridyl)-1-propanol (R)-22n
20
25
D
‰ꢂŠ +5.7 (c=2.25, MeOH) {lit.40 (R)-22n, ‰ꢂŠ +38.0 (c=1.68, MeOH), 52.1% ee}; 5.4% ee by
D
HPLC analysis using Method E: tR=7.5 min for (R)-22n and tR=8.0 min for (S)-22n.
4.10.16. (R)-1-(30-Pyridyl)-1-propanol (R)-22o
20
28
‰ꢂŠ +9.1 (c=2.16, MeOH) {lit.20 ‰ꢂŠ ^41.4 (c=2.1, MeOH), 88% ee};41 24.3% ee by HPLC
D
D
analysis using Method E: tR=21.1 min for (R)-22o and tR=20.0 min for (S)-22o.

2334
W.-M. Dai et al. / Tetrahedron: Asymmetry 11 (2000) 2315±2337
4.10.17. (R)-1-(40-Pyridyl)-1-propanol (R)-22p
20
29
D
‰ꢂŠ +2.6 (c=2.34, MeOH) {lit.20 ‰ꢂŠ ^41.1 (c=2.0, MeOH), 83% ee};41 7.5% ee by HPLC
D
analysis using Method C: tR=26.8 min for (R)-22p and tR=25.2 min for (S)-22p.
4.10.18. (R)-1-(20-Furyl)-1-propanol (R)-22q
20
D
25
D
‰ꢂŠ +14.3 (c=2.20, CHCl3) {lit.42a (R)-22q, ‰ꢂŠ +12.6 (c=2.09, CHCl3), 95% ee; lit.42b (S)-
22
578
22q, [ꢂ] ^17.9 (c=1.75, CHCl3), 91% ee;}; 78.0% ee by HPLC analysis of the corresponding
benzoate using Method I: tR=10.4 min for (R)-22q and tR=11.6 min for (S)-22q.
4.10.19. (R)-1-(20-Thienyl)-1-propanol (R)-22r
20
D
25
D
‰ꢂŠ +25.3 (c=2.24, CHCl3) {lit.43a (R)-22r, ‰ꢂŠ +25.9 (c=2.1, CHCl3); lit.43b (S)-
25
22, ‰ꢂŠ ^25.3 (c=1.6, CHCl3), >99% ee}; 94.9% ee by HPLC analysis of the corresponding
D
benzoate using Method I: tR=12.1 min for (R)-22r and tR=15.4 min for (S)-22r.
4.11. Autocatalysis of (R)-1-(20-furyl)-1-propanol (R)-22q
To a solution of the chiral alcohol (R)-22q (82.0% ee, 19.2 mg, 0.152 mmol) in dry PhMe (8
mL) under a nitrogen atmosphere cooled in an ice±water bath (ca. 0ꢀC) was added a solution of
Et2Zn (4 mL, 1 M in hexanes) via a syringe. After stirring for 10 min, 2-furaldehyde (165.5 mL,
2.00 mmol) was added into the mixture via another syringe. The resultant mixture was allowed to
warm up to room temperature and stirred for 96 h at the same temperature. The reaction mixture
was cooled in an ice±water bath and quenched by 5% HCl aqueous solution. The mixture was
extracted with ethyl ether (3Â20 mL), washed with saturated aqueous NaHCO3 and brine, dried
over anhydrous MgSO4, and condensed under reduced pressure. The residue was puri®ed by ¯ash
column chromatography (silica gel, MeOH:EtOAc:hexane=1:10:50) to give (R)-22q (250.0 mg,
20
92% yield): ‰ꢂŠ +5.45 (c=2.40, CHCl3); 27.6% ee by HPLC analysis of the corresponding
D
benzoate using Method I. The ee of the newly formed product was calculated to be 23.1% ee.21
4.12. Autocatalysis of (R)-1-(20-thienyl)-1-propanol (R)-22r
To a solution of the chiral alcohol (R)-22r (94.9% ee, 22.4 mg, 0.158 mmol) in dry PhMe (8
mL) under a nitrogen atmosphere cooled in an ice±water bath (ca. 0ꢀC) was added a solution of
Et2Zn (4 mL, 1 M in hexanes) via a syringe. After stirring for 10 min, 2-thiophenecarboxaldehyde
(187 mL, 2.00 mmol) was added into the mixture via another syringe. The resultant mixture was
allowed to warm up to room temperature and stirred for 96 h at the same temperature. The
reaction mixture was cooled in an ice±water bath and quenched by 5% HCl aqueous solution.
The mixture was extracted with ethyl ether (3Â20 mL), washed with saturated aqueous NaHCO3
and brine, dried over anhydrous MgSO4, and condensed under reduced pressure. The residue was
puri®ed by ¯ash column chromatography (silica gel, MeOH:EtOAc:hexane=1:10:50) to give
20
2-thiophenecarboxaldehyde (30.0 mg, 13% recovery) and (R)-22r (191.0 mg, 68% yield): ‰ꢂŠ
D
+3.51 (c=2.56, CHCl3); 13.9% ee by HPLC analysis of the corresponding benzoate using
Method I. The ee of the newly formed product was calculated to be 3.1%.21
Acknowledgements
This work was supported by the Department of Chemistry, HKUST and a research grant from
the Science and Technology Commission of the Yunnan Province of China.

W.-M. Dai et al. / Tetrahedron: Asymmetry 11 (2000) 2315±2337
2335
References
1. For the anticancer alkaloid, Taxol1, see: (a) Nicolaou, K. C.; Dai, W.-M.; Guy, R. K. Angew. Chem., Int. Ed.
Engl. 1994, 33, 15. (b) Taxane Anticancer Agents, Basic Science and Current Status, ACS Symposium Series 583;
Georg, G. I.; Chen, T. T.; Ojima, I.; Vyas, D. M., Eds.; American Chemical Society: Washington, DC, 1995.
2. For the anticancer alkaloid, camptothecin, see: Wall, M. E.; Wani, M. C. In Cancer Chemotherapeutic Agents;
Foye, W. O., Ed.; ACS: Washington, DC, 1995; pp. 293±310.
3. (a) Catalytic Asymmetric Synthesis; Ojima, I., Ed.; VCH Publishers: New York, 1993. (b) Noyori, R. Asymmetric
Catalysis in Organic Synthesis; John Wiley & Sons: New York, 1994. (c) Enantioselective Synthesis; Gladysz, J. A.;
Michl, J., Eds.; Chem. Rev. 1992; Vol. 92, No. 5. (d) Seyden-Penne, J. Chiral Auxiliaries and Ligands in
Asymmetric Synthesis; John Wiley & Sons: New York, 1995. (e) Advances in Catalytic Processes; Doyle, M. P.,
Ed.; JAI Press: Greenwich, 1995. (f) Handbook of Enantioselective Catalysis; Brunner, H.; Zettlmeier, W., Eds.;
VCH Publishers: New York, 1993; Vols. 1±2.
4. Johnson, R. A.; Sharpless, K. B. In Catalytic Asymmetric Synthesis; Ojima, I., Ed.; VCH Publishers: New York,
1993; pp. 227±272.
5. Dictionary of Organic Compounds, 5th ed.; Buckingham, J., Ed.; Chapman and Hall: New York, 1982; p. 4084.
6. For chiral indole-containing ligands for catalytic enantioselective reactions, see: (a) Nakagawa, M.; Nakao, H.;
Watanabe, K. Chem. Lett. 1985, 391. (b) Nitta, H.; Yu, D.; Kudo, M.; Mori, A.; Inoue, S. J. Am. Chem. Soc.
1992, 114, 7969. (c) Corey, E. J.; Loh, T.-P. J. Am. Chem. Soc. 1991, 113, 8966. (d) Corey, E. J.; Loh, T.; Roper,
T. D.; Aziminoara, M. C.; Noe, M. C. J. Am. Chem. Soc. 1992, 114, 8290. (e) Corey, E. J.; Loh, T.-P. Tetrahedron
Lett. 1993, 34, 3979. (f) Corey, E. J.; Cywin, C. L.; Roper, T. D. Tetrahedron Lett. 1992, 33, 6907. (g) Kinugasa,
M.; Harada, T.; Oku, A. J. Org. Chem. 1996, 61, 6772.
7. For (S)-Abrine±Cu(II)-catalyzed Diels±Alder reaction, see: (a) Otto, S.; Boccaletti, G.; Engberts, J. B. F. N. J. Am.
Chem. Soc. 1998, 120, 4238. (b) Otto, S.; Engberts, J. B. F. N. J. Am. Chem. Soc. 1999, 121, 67988.
8. (a) Oguni, N.; Omi, T. Tetrahedron Lett. 1984, 25, 2823. (b) Kitamura, M.; Suga, S.; Kawai, K.; Noyori, R. J. Am. Chem.
Soc. 1986, 108, 6071. For reviews, see: (c) Noyori, R.; Kitamura, M. Angew. Chem., Int. Ed. Engl. 1991, 30, 49. (d) Soai,
K.; Niwa, S. Chem. Rev. 1992, 92, 833. (e) Ref. 3b, pp. 255±297. (f) Oguni, N. Kikan Kagaku Sosetsu 1993, 19, 143.
9. For selected chiral b-amino alcohols for enantioselective addition of Et2Zn to aldehydes for 4, see: Ref. 8b and (a)
Noyori, R.; Suga, S.; Kawai, K.; Okada, S.; Kitamura, M.; Oguni, N.; Hayashi, M.; Kaneko, T.; Matsuda, Y.
J. Organomet. Chem. 1990, 382, 19. For 5, see: (b) Tanaka, K.; Ushio, H.; Suzuki, H. J. Chem. Soc., Chem.
Commun. 1989, 1700. For 6, see: Ref. 8b and (c) Hayashi, M.; Kaneko, T.; Oguni, N. J. Chem. Soc., Perkin Trans.
1 1991, 25. For 7 and 11b, see: (d) Soai, K.; Ookawa, A.; Ogawa, K.; Kaba, T. J. Chem. Soc., Chem. Commun.
1987, 4678. (e) Soai, K.; Ookawa, A.; Kaba, T.; Ogawa, K. J. Am. Chem. Soc. 1987, 109, 7111. (f) Niwa, S.; Soai,
K. J. Chem. Soc., Perkin Trans. 1 1990, 25. For 8a,b, see: (g) Peper, V.; Martens, J. Chem. Ber. 1996, 129, 691. For
9, see: (h) Soai, K.; Niwa, S.; Yamada, Y.; Inoue, H. Tetrahedron Lett. 1987, 28, 4841. (i) Soai, K.; Yokoyama, S.;
Ebihara, K.; Hayasaka, T. J. Chem. Soc., Chem. Commun. 1987, 1690. For 10, see: (j) Corey, E. J.; Yuen, P.;
Hannon, F. J.; Wierda, D. A. J. Org. Chem. 1990, 55, 784. For analogues of 11b, see: (k) Yang, X.; Shen, J.; Da,
C.; Wang, R.; Choi, M. C. K.; Yang, L.; Wong, K.-Y. Tetrahedron: Asymmetry 1999, 10, 133. For 11a and 12, see:
(l) Wallbaum, S.; Martens, J. Tetrahedron: Asymmetry 1993, 4, 637. For gem-dialkyl analogues of 12, see: (m)
Wilken, J.; Kossenjans, M.; Groger, H.; Martens, J. Tetrahedron: Asymmetry 1997, 8, 2007. For 13a,b and 14a,
see: (o) Soai, K.; Watanabe, M.; Yamamoto, A.; Yamashita, T. J. Mol. Catal. 1991, 64 L27. For 13c and 14b, see:
(p) Beliczey, J.; Gi€els, G.; Kragl, U.; Wandrey, C. Tetrahedron: Asymmetry 1997, 8, 1529. For other chiral
amines possessing a diphenylhydroxymethyl or dialkylhydroxymethyl group, see: (q) Sola, L.; Reddy, K. S.; Vidal-
Ferran, A.; Moyano, A.; Pericas, M. A.; Riera, A.; Alvarez-Larena, A.; Piniella, J.-F. J. Org. Chem. 1998, 63,
7078. (r) Guijarro, D.; Pinho, P.; Andersson, P. G. J. Org. Chem. 1998, 63, 2530. (s) Kossenjans, M.; Pennemann,
H.; Martens, J.; Juanes, O.; Rodrõguez-Ubis, J. C.; Brunet, E. Tetrahedron: Asymmetry 1998, 9, 4123. (t) Liu, G.;
Ellman, J. A. J. Org. Chem. 1995, 60, 7712.
10. (a) Dai, W.-M.; Zhu, H. J.; Hao, X.-J. Tetrahedron: Asymmetry 1995, 6, 1857. (b) Dai, W.-M.; Zhu, H. J.; Hao,
X.-J. Tetrahedron: Asymmetry 1996, 7, 1245. (c) Dai, W.-M.; Zhu, H. J.; Hao, X.-J. Tetrahedron Lett. 1996, 37,
5971. (d) Zhu, H.-J.; Zhao, B.-T.; Dai, W.-M.; Zhou, J.; Hao, X.-J. Tetrahedron: Asymmetry 1998, 9, 2879.
11. (a) Braun, M. Angew. Chem., Int. Ed. Engl. 1996, 35, 519. (b) For an early study on the chiral ligands containing
the dialkylhydroxymethyl group in enantioselective addition of RLi to aldehydes, see: Mukaiyama, T.; Soai, K.;
Sato, T.; Shimizu, H.; Suzuki, K. J. Am. Chem. Soc. 1979, 101, 1455.
12. Bordwell, F. G.; Drucker, G. E.; Fried, H. E. J. Org. Chem. 1981, 46, 632.

2336
W.-M. Dai et al. / Tetrahedron: Asymmetry 11 (2000) 2315±2337
13. For zinc amides of secondary amines, see: (a) Chelucci, G.; Falorni, M.; Giacomelli, G. Tetrahedron: Asymmetry
1990, 1, 843. (b) Chelucci, G.; Conti, S.; Falorni, M.; Giacomelli, G. Tetrahderon 1991, 47, 8251. (c) Prasad,
K. R. K.; Joshi, N. N. J. Org. Chem. 1997, 62, 3770. (d) Asami, M.; Inoue, S. Bull. Chem. Soc. Jpn. 1997, 70, 1687.
(e) Asami, M.; Watanabe, H.; Honda, K.; Inoue, S. Tetrahedron: Asymmetry 1998, 9, 4165. For reports against
the formation of zinc amides from secondary amines and Et2Zn, see: (f) Tanaka, K.; Oshio, H.; Suzuki, H.
J. Chem. Soc., Chem. Commun. 1989, 1700. (g) Pini, D.; Mastantuono, A.; Uccello-Barretta, G.; Iuliano, A.;
Salvadori, P. Tetrahedron 1993, 49, 9613.
14. For an amine±alcohol two-component combination as the promoter in Et2Zn addition to aldehydes, see: (a) Li, S.;
Jiang, Y.; Mi, A.; Yang, G. J. Chem. Soc., Perkin Trans. 1 1993, 885. Also, see: (b) Ding, K.; Ishii, A.; Mikami, K.
Angew. Chem., Int. Ed. 1999, 38, 497.
15. (a) Soai, K.; Yokoyama, S.; Hayasaka, T. J. Org. Chem. 1991, 56, 4264. (b) Soai, K.; Niwa, S.; Watanabe, M.
J. Chem. Soc., Perkin Trans. 1 1989, 109.
16. For tertiary amines of ephedrine and pseudoephedrine, see: Ref. 15b and (a) Chaloner, P. A.; Perera, S. A. R.
Tetrahedron Lett. 1987, 28, 3013. (b) Chaloner, P. A.; Longadianon, E. Tetrahedron Lett. 1990, 31, 5185. (c)
Corey, E. J.; Hannon, F. J. Tetrahedron Lett. 1987, 28, 5233 and 5237. (d) Muchov, G.; Vannonoorenberghe, Y.;
Buono, G. Tetrahedron Lett. 1987, 28, 6163. (e) Soai, K.; Nishi, M.; Ito, Y. Chem. Lett. 1987, 2405. (f) Soai, K.;
Niwa, S.; Watanabe, M. J. Org. Chem. 1988, 55, 927. (g) Watanabe, M.; Araki, S.; Butsugan, Y.; Uemura, M.
Chem. Express 1990, 5, 761.
17. (a) Zhang, H.; Xue, F.; Mak, T. C. W.; Chan, K. S. J. Org. Chem. 1996, 61, 8002. (b) Suggestion for dependence
of ee on the basicity of the functional group in the aromatic aldehyde was mentioned in the ethylation catalyzed by
the chiral hydroxy sulfamide±modi®ed titanium(IV) species; see Ref. 34.
18. The Hammett constants ꢀ+p, ꢀp, and ꢀI are taken from the book by: Exner, O. Correlation Analysis of Chemical
Data; Plenum Press: New York, 1988.
19. Addition of Et2Zn to 3-pyridinecarboxaldehyde using N,N-dibutylnorphedrine with 74% ee was reported: (a)
Soai, K.; Hori, H.; Niwa, S. Heterocycles 1989, 29, 2065. For autocatalysis in dialkylzincs addition to
pyridinecarboxaldehydes, see: (b) Soai, K.; Niwa, S.; Hori, H. J. Chem. Soc., Chem. Commun. 1990, 982. (c)
Shibata, T.; Morioka, H.; Tanji, S.; Hayase, T.; Kodaka, Y.; Soai, K. Tetrahedron Lett. 1996, 37, 8783. To
quinolinecarboxaldehydes, see: (d) Shibata, T.; Choji, K.; Morioka, H.; Hayase, T.; Soai, K. Chem. Commun.
1996, 751. (e) Shibata, T.; Choji, K.; Hayase, T.; Aizu, Y.; Soai, K. Chem. Commun. 1996, 1235. To
pyrimidinecarboxaldehydes, see: (f) Soai, K.; Shibata, T.; Morioka, H.; Choji, K. Nature 1995, 378, 767. (g)
Shibata, T.; Morioka, H.; Hayase, T.; Choji, K.; Soai, K. J. Am. Chem. Soc. 1996, 118, 471. (h) Shibata, T.;
Hayase, T.; Yamamoto, J.; Soai, K. Tetrahedron: Asymmetry 1997, 8, 1717. (i) Shibata, T.; Yonekubo, S.; Soai, K.
Angew. Chem., Int. Ed. 1999, 38, 659. Also, see: Alberts, A. H.; Wynberg, H. J. Am. Chem. Soc. 1989, 111, 7265.
20. Ishizaki, M.; Hoshino, O. Chem. Lett. 1994, 1337.
21. These are the ee values of the total amount of the initially used promoter and the forming product. The ee of the
newly formed product (eepdt) in the reaction is calculated according to the following formula: for R-enantiomer being
the major product, eepdt=[(WpRdt WpSdt)/(WRpdt‡WSpdt)]Â100%, where WRpdt ˆ WiRso WiRnit and WpSdt ˆ WSiso WiSnit
.
WiRnit and WSinit are the weights of the initially used R- and S-enantiomers in the reaction as the promoter, WRiso and
WiSso are the total weights of the R- and S-enantiomers isolated from the reaction, and WRpdt and WpSdt are the
calculated weights of the newly formed R- and S-enantiomers in the reaction, respectively.
22. (a) Kitamura, M.; Suga, S.; Niwa, M.; Noyori, R. J. Am. Chem. Soc. 1995, 117, 4832. (b) Kitamura, M.;
Yamakawa, M.; Oka, H.; Suga, S.; Noyori, R. Chem. Eur. J. 1996, 2, 1173. (c) Kitamura, M.; Suga, S.; Oka, H.;
Noyori, R. J. Am. Chem. Soc. 1998, 120, 9800. Also see: Oguni, N.; Matsuda, Y.; Kaneko, T. J. Am. Chem. Soc.
1988, 110, 7877.
23. Kitamura, M.; Oka, H.; Noyori, R. Tetrahedron 1999, 55, 3605.
24. For computational modelings on TS, see: (a) Yamakawa, M.; Noyori, R. J. Am. Chem. Soc. 1995, 117, 6327. (b)
Goldfuss, B.; Houk, K. N. J. Org. Chem. 1998, 63, 8998. (c) Goldfuss, B.; Steigelmann, M.; Khan, S. I.; Houk,
K. N. J. Org. Chem. 2000, 65, 77.
25. For the original proposals of the reaction mechanism, see: (a) Itsuno, S.; Frechet, J. M. J. J. Org. Chem. 1987, 52,
4140. (b) Evans, D. A. Science 1988, 240, 420. (c) Corey, E. J.; Hannon, F. J. Tetrahedron Lett. 1987, 28, 5233 and
5237. (d) Corey, E. J.; Yuen, P.-W.; Hannon, F. J.; Wierda, D. A. J. Org. Chem. 1990, 55, 784. (e) Kitamura, M.;
Okada, S.; Suga, S.; Noyori, R. J. Am. Chem. Soc. 1989, 111, 4028.
26. For the related 4/4-fused bicyclic structure in the reaction of trimethylaluminum with benzophenone, see: (a)
Je€ery, E. A.; Mole, T.; Saunders, J. K. Aust. J. Chem. 1968, 21, 649. (b) Je€ery, E. A.; Mole, T. Aust. J. Chem.

W.-M. Dai et al. / Tetrahedron: Asymmetry 11 (2000) 2315±2337
2337
1970, 23, 715. For theoretical studies on reaction of MeLi with aldehydes in vaccum and in solution, see: (c)
Kaufmann, E.; Schleyer, P. von R.; Houk, K. N.; Wu, Y.-D. J. Am. Chem. Soc. 1985, 107, 5560. (d) Nakamura,
M.; Nakamura, E.; Koga, N.; Morokuma, K. J. Am. Chem. Soc. 1993, 115, 11016.
27. (a) Matteson, D. S. Organomet. Chem. Rev. Sect. A 1969, 4, 263. (b) Matteson, D. S. Organometallics Reaction
Mechanism on the Nontransition Elements; Academic: New York, 1974; pp. 146±147.
28. For similar 5/4/4-fused tricyclic TS0, see: Vidal-Ferran, A.; Moyano, A.; Pericas, M. A.; Riera, A. Tetrahedron
Lett. 1997, 38, 8773.
29. Soai, K.; Watanabe, M. Tetrahedron: Asymmetry 1991, 2, 97.
30. Watanabe, M.; Araki, S.; Butsugan, Y.; Uemura, M. J. Org. Chem. 1991, 56, 2218.
31. Chaloner, P. A.; Perena, S. A. R. J. Chem. Soc., Perkin Trans. 1 1991, 2731.
32. Nakano, H.; Kumagai, N.; Matsuzaki, H.; Kabuto, C.; Hongo, H. Tetrahedron: Asymmetry 1997, 8, 1391.
33. Ishizaki, M.; Fujita, K.; Shimamoto, M.; Hoshino, O. Tetrahedron: Asymmetry 1994, 5, 411.
34. Ramon, D. J.; Yus, M. Tetrahedron: Asymmetry 1997, 8, 2479.
35. The speci®c rotation value of ^45.85 for 14% ee of (S)-22g does not seem to be correct.
36. The absolute con®guration of (+)-22h was assigned by comparison with the speci®c rotation data of (R)-22b.
37. Williams, D. R.; Fromhold, M. G. Synlett 1997, 523.
38. Sato, T.; Gotoh, Y.; Wakabayashi, Y.; Fujisawa, T. Tetrahedron Lett. 1983, 24, 4123.
39. (a) Burrows, E. P.; Welch, F. J.; Mosher, H. S. J. Am. Chem. Soc. 1960, 82, 880. (b) Asami, M.; Watanabe, H.;
Honda, K.; Inoue, S. Tetrahedron: Asymmetry 1998, 9, 4165.
40. Ohno, A.; Nakai, J.; Nakamura, K. Bull. Chem. Soc. Jpn. 1981, 54, 3482.
41. The absolute con®gurations of (±)-22o,p were not assigned in Ref. 20. By comparison of the longer retention times
on the Chiralcel OD column with the reported data for 2-methyl-1-(30-pyridyl)-1-propanol (Ref. 19b), the absolute
con®guration of (+)-22o,p is assigned as R.
42. (a) Kametani, T.; Tsubuki, M.; Tatsuzaki, Y.; Honda, T. J. Chem. Soc., Perkin Trans. 1 1990, 639. (b) Oeveren,
A. V.; Menge, W.; Feringa, B. L. Tetrahedron Lett. 1989, 30, 6427.
43. (a) Fujiwara, M.; Mori, K. Agric. Biol. Chem. 1986, 50, 2925. (b) Kang, S.-K.; Jeon, J.-H.; Yamaguchi, T.; Kim,
J.-S.; Ko, B.-S. Tetrahedron: Asymmetry 1995, 6, 2139.