Synthesis of chiral C/N-functionalized morpholine alcohols: Study of their catalytic ability as ligand in asymmetric diethylzinc addition to aldehyde

Article abstract of DOI:10.1016/j.tetasy.2005.12.027

A broad variety of chiral C/N-functionalized morpholine alcohols sharing a common structural motif in the 3-(hydroxymethyl)morpholine 6 were prepared from enantiomerically pure serine for the purpose of studying their catalytic ligand properties. The asym

Full text of DOI:10.1016/j.tetasy.2005.12.027

Tetrahedron: Asymmetry 17 (2006) 388–401
Synthesis of chiral C/N-functionalized morpholine alcohols:
study of their catalytic ability as ligand in asymmetric
diethylzinc addition to aldehyde
*
´
Rajesh Dave and N. Andre Sasaki
Institut de Chimie des Substances Naturelles, CNRS, Avenue de la Terrasse, 91198 Gif-sur-Yvette, France
Received 9 December 2005; accepted 28 December 2005
Available online 2 February 2006
Abstract—A broad variety of chiral C/N-functionalized morpholine alcohols sharing a common structural motif in the 3-(hydroxy-
methyl)morpholine 6 were prepared from enantiomerically pure serine for the purpose of studying their catalytic ligand properties.
The asymmetric addition of diethylzinc to benzaldehyde in the presence of 10 mol % of chiral C/N-functionalized morpholine alco-
hols gave 1-phenyl-1-propanol in 59–81% yield with 10–30% ee. The addition of 10 mol % of n-butyl lithium to the reaction mixture
resulted in a significant enhancement of the stereoselectivity in the case of ligands bearing the two geminal phenyl substituents on the
backbone. In the presence of n-butyl lithium and using (S)-3-(hydroxydiphenylmethyl)morpholine (S)-19 as the chiral promoter, (S)-
1-phenyl-1-propanol was obtained in 81% yield with 76% ee. The geminal diphenyl-class of morpholine ligands was examined for the
diethylzinc addition to four different aldehydes in the presence of n-butyl lithium. (S)-N-Benzyl-3-(hydroxydiphenylmethyl)mor-
pholine (S)-27 was found to be most enantioselective in the case of 4-methoxybenzaldehyde to give (R)-alcohol in 87% yield with
80% ee. Catalysts (S)-19 and its N-methyl derivative (S)-26 gave alcohols with an (S)-absolute configuration while the N-benzylated
derivative (S)-27 gave the opposite enantiomeric products. The tentative transition state models to account for the observed product
stereoselectivity with morpholine ligands holding the geminal diphenyl group on the b-amino alcohol segment are proposed.
ꢀ 2006 Elsevier Ltd. All rights reserved.
1. Introduction
aldehydes. A common feature of these catalysts is the
presence of an achiral morpholine ring moiety with the
stereodirecting stereogenic center on the appended seg-
ment of the amine. To the best of our knowledge, there
has not been a report on the synthesis of morpholine-
based b-amino alcohols with chirality on the heterocy-
clic ring.4 It is thus of interest to synthesize and study
the stereoinducing ability of the morpholine-based b-
amino alcohol ligands with the stereocontrolling stereo-
genic center on the heterocyclic ring. Previously, we have
reported5 the enantioselective synthesis of O-protected
trans-3,5-bis(hydroxymethyl)morpholines with the objec-
tive of understanding the influence of the oxygen atom
of the morpholine ring on the ligand catalytic properties.
Even until today, the asymmetric addition1 of diethyl-
zinc to aldehydes is considered as a classical test for
the design of new ligands, particularly chiral amino
alcohols for catalytic enantioselective syntheses. The
reaction allows access to chiral alcohols that are ubiqui-
tous in the structures of natural products and drug
compounds. Generally, it is assumed that six-membered
azacycloalkanes are less efficient chiral catalysts in com-
parison with the corresponding smaller ring compounds,
due to the ring flexibility. However, if the six-membered
ring contains a heteroatom, such as an oxygen atom in
morpholine, then the presence of an extra coordination
site in the catalyst may influence its ligand catalytic
properties. Recently, Seto et al.2 and Nugent3 have
reported morpholine based b-diamines, and b-amino
alcohols, respectively, as efficient chiral promoters for
the enantioselective addition of organozinc reagents to
Herein, we report the synthesis of a variety of chiral C/N-
functionalized morpholine alcohols bearing a common
3-(hydroxymethyl)morpholine structural motif from the
commercially available optically active serine (Fig. 1).
The catalytic ability of these chiral morpholine ligands
was studied in the asymmetric addition of diethylzinc
addition to benzaldehyde. The addition reaction was also
studied in the presence of an n-butyl lithium additive.
*
Corresponding author. Tel.: +33 1 69 823101; fax: +33 1 69
077247; e-mail: andre.sasaki@icsn.cnrs-gif.fr
0957-4166/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2005.12.027

R. Dave, N. A. Sasaki / Tetrahedron: Asymmetry 17 (2006) 388–401
389
R1 R2 R3
R4
R1 R2 R3
R4
O
R2
R2
5
H
H
H
H
H
H
H
H
H
H
H
H
allyl
15
H
H
CH2OBn
COC2H5
CH2C(Ph)2OH
H
CH3
10
11
14
CH2OBn
CH2OTBDPS
CH2OBn
18 Bn
H
CH2OBn
R3
N
R4
21
28
29
H
H
H
Ph
Ph
Ph
H
H
H
OR1
Bn
Figure 1. Design of chiral ligands with 3-(hydroxymethyl)morpholine as a common structural unit.
These investigations would be informative for the future
design of the morpholine-based ligand catalyst.
We felt that if (S)-6 can share the benzyl/tert-butyldi-
phenylsilyloxymethyl structural motif at the C-5 posi-
tion in a trans stereo-fashion then the resulting ligand
may give valuable information on the influence of such
substituents on the catalyst’s chirality inducing proper-
ties in the asymmetric reactions. Thus, (3S,5S)-3-(benz-
yloxymethyl)-5-(hydroxymethyl)morpholine (3S,5S)-8
and (3R,5S)-3-(tert-butyldiphenylsilyloxymethyl)-5-(hydr-
oxymethyl)morpholine (3R,5S)-9 were prepared from
(3S,5R)-3-(benzyloxymethyl)-5-(tert-butyldiphenylsilyl-
oxymethyl)morpholine5 (3S,5R)-7 by selective cleavage
of the O-tert-butyldiphenylsilyl, and O-benzyl group,
respectively. (3S,5R)-7 on treatment with 1 M TBAF
in THF gave (3S,5S)-3-(benzyloxymethyl)-5-(hydroxy-
methyl)morpholine (3S,5S)-8 in 87% yield. Initially,
debenzylation of (3S,5R)-7 by the palladium catalyzed
hydrogenation failed to give the desired (3R,5S)-3-
(tert-butyldiphenylsilyloxymethyl)-5-(hydroxymethyl)-
morpholine (3R,5S)-9. Later, cleavage of O-benzyl
group was achieved8 in dichloromethane with 1 M solu-
tion of boron trichloride in dichloromethane to afford
(3R,5S)-9 in 83% yield (Scheme 2).
2. Results and discussion
2.1. Synthesis of C/N-functionalized morpholine-based
b-amino alcohols
The synthesis of (S)-3-(hydroxymethyl)morpholine,6
(S)-6 was envisaged from L-serine by involving coupling
of a serinol derivative with tert-butyl bromoacetate as a
key step.7 One of the coupling components, (2R)-2-(tert-
butoxycarbonylamino)-3-(tert-butyldiphenylsilyloxy)-
propan-1-ol 1, was obtained5 from L-N-Boc-serine
methyl ester in 87% yield over two steps. Compound 1
was coupled with tert-butyl bromoacetate in a mixture
of toluene and 30% aq NaOH containing catalytic TBAI
to give ester 2 in 87% yield. LiAlH4 reduction of 2 fur-
nished alcohol 3 in only 45% yield, in an irreproducible
manner in a large scale.
This problem was circumvented when a two-pot reduc-
tion procedure was employed to convert 2 to alcohol 3
in 85% yield. 2 was first reduced with DIBAL-H in
DCM and the resulting crude aldehyde was further
reduced to 3 with LiBH4 in ether. 3 was converted to
morpholine derivative 5 by the three-step sequence of
O-mesylation, removal of the Boc-group from mesylate
derivative 4, and finally base-mediated cyclization at
reflux in methanol (Scheme 1). Removal of silyl group
from 5 with TBAF in THF gave (S)-6 in 87% yield.
The overall yield of (S)-6 starting from 1 was 50%.
To understand the significance of the trans-stereochem-
istry of the substituents in (3R,5S)-9 in an asymmetric
reaction, we synthesized the cis-isomer of 9 from
(3S,5S)-3-(benzyloxymethyl)-5-(tert-butyldiphenylsilyl-
oxymethyl)morpholine (3S,5S)-7 by debenzylation with
boron trichloride in 83% yield. Compound (3S,5S)-7
was prepared from D-N-Boc-serine methyl ester (R)-10
and (S)-2,3-O-isopropylideneglycerol triflate (S)-11 in
42% overall yield following our standard5 protocol
(Scheme 3).
CO2But
O
Toluene, 30% aq. NaOH,
BrCH2CO2But, TBAI
OH
1. DCM, DIBAL-H
TBDPSO
TBDPSO
2. Et2O, LiBH4
NHBoc
NHBoc
87%
85%
1
2
O
OH
O
OMs
DCM, Et3N,
MsCl
1. DCM, TFA
TBDPSO
TBDPSO
TBDPSO
2. MeOH, DIEA,
reflux
NHBoc
NHBoc
93%
3
4
83%
O
O
THF, 1M TBAF
87%
HO
N
H
(S)-6
N
H
5
Scheme 1. Revised synthesis of (S)-6.

390
R. Dave, N. A. Sasaki / Tetrahedron: Asymmetry 17 (2006) 388–401
O
DCM, 1M BCl3
O
O
THF, 1M TBAF
in DCM
OTBDPS
HO
OH
OTBDPS
BnO
BnO
N
H
87%
83%
N
H
N
H
(3S,5S)-8
(3S,5R)-7
(3R,5S)-9
Scheme 2. Synthesis of (3S,5S)-8 and (3R,5S)-9.
O
DCM, 1M BCl3
in DCM
OH
ref 5
O
O
TfO
OTBDPS
BnO
+
N
H
BocHN
83%
CO2CH3
(3S,5S)-7
(R)-10
(S)-11
O
OTBDPS
HO
N
H
(3S,5S)-9
Scheme 3. Synthesis of (3S,5S)-9.
N-Derivatized morpholine ligands are useful for evalu-
ating the steric role of the tertiary N-substituent on the
transition state models in asymmetric reactions.
Attempts to alkylating the morpholine nitrogen of
(3S,5R)-7 with methyl iodide and benzyl bromide/iodide
in the presence of a base such as NaH, K2CO3, n-butyl
lithium, etc. failed to give any N-alkylated product due
to steric reasons. However, the use of allyl iodide in the
presence of K2CO3 in DMF gave N-allylated derivative
of (3S,5R)-7 in 93% yield. Subsequent cleavage of the
silyl protecting group with TBAF afforded (3S,5S)-N-
allyl-3-(benzyloxymethyl)-5-(hydroxymethyl)morpholine
(3S,5S)-12 in 87% yield (81% yield over two steps). It
was observed that the N-acylation of (3S,5R)-7 in the
presence of base was facile. Using propionyl chloride
in the presence of triethylamine, N-propionylation of
(3S,5R)-7 and the subsequent removal of silyl protecting
group from the resulting N-propionyl derivative with
TBAF, furnished (3S,5S)-N-propionyl-3-(benzyloxy-
methyl)-5-(hydroxymethyl)morpholine (3S,5S)-13 in 83%
yield over two steps (Scheme 4).
The C2-symmetric ligands obtained from the chiral
scaffold of cyclic amines (azetidine and pyrrolidine) are
known9 to be excellent candidates for the enantioselec-
tive diethylzinc addition to aldehydes. The C2-symmetric
(3S,5S)-N-(2,2-diphenyl-2-hydroxyethyl)-3,5-bis(benzyl-
oxymethyl)morpholine (3S,5S)-16 was prepared from
the chiral scaffold, (3S,5S)-3,5-bis(benzyloxymethyl)-
morpholine (3S,5S)-14 in two steps. The coupling of
(3S,5S)-14 with ethyl bromoacetate in the presence of
K2CO3 in DMF gave ester 15 in 91% yield. The addition
of phenylmagnesium bromide to 15 in ether gave (3S,5S)-
16 in 83% yield (Scheme 5).
In the literature,10 there are several examples of ligands,
which share a flat/bulky phenyl structural motif, and
promote asymmetric reactions. In this aspect, the syn-
thesis of (R)-3-(hydroxydiphenylmethyl)morpholine11
(R)-19 was attempted by using the most obvious
approach12 from (S)-6 (Scheme 6). The amino group
of (S)-6 was protected with Boc2O, and the resulting
N-Boc derivative of (S)-6 was subjected to TEMPO-
O
O
O
1. DMF, K CO
1. DCM, Et N,
2
3
3
allyl iodide
OH C H COCl
BnO
2
5
OH
BnO
OTBDPS
N
BnO
N
N
2. THF 1M TBAF
in THF
2. THF 1M TBAF
in THF
H
O
(3S,5R )-7
81%
83%
(3S,5S )-12
(3S,5S )-13
Scheme 4. Synthesis of (3S,5S)-12 and (3S,5S)-13.
O
O
N
O
DMF, K2CO3,
Et2O, 3M PhMgBr
in Et2O
OBn
CO2C2H5
OBn
BnO
BnO
BrCH2CO2C2H5
N
OBn
BnO
Ph
Ph
(3S,5S)-16
N
H
91%
83%
HO
15
(3S,5S)-14
Scheme 5. Synthesis of (3S,5S)-16.

R. Dave, N. A. Sasaki / Tetrahedron: Asymmetry 17 (2006) 388–401
391
1. MeOH, Et3N,
Boc2O
O
DMF, K2CO3,
CH3I
O
O
Et2O, 3M PhMgBr
in Et2O
HO
HO
HO2C
N
H3CO2C
2. Acetone, 5% aq.
NaHCO3,TEMPO,
NaOCl,
89%
N
H
(S)-6
N
Boc
Boc
17
18
81%
O
N
Boc
Ph
Ph
(R)-19
Scheme 6. Attempted synthesis of (R)-19 from (S)-6.
mediated oxidation to afford acid 17 in 81% yield over
two steps.
acid and coupling of the resulting alcohol 22 with tert-
butyl bromoacetate in a mixture of toluene and 30% aq
NaOH solution gave ester 23. LiAlH4 reduction of 23
in THF gave alcohol 24 in 91% yield. The standard three
step protocol of mesylation, deprotection of the amino
group, and base-mediated cyclization gave (S)-19 in
76% yield over three steps (Scheme 7).
Esterification of 17 with methyl iodide in DMF in the
presence of K2CO3 gave ester 18 in 89% yield. Unfortu-
nately, the addition of phenylmagnesium bromide to
ester 18 failed to give the desired (R)-19 under various
reaction conditions.
To examine the role of the tertiary amine component of
these ligands in the asymmetric reactions, N-substituted
derivatives of (S)-19 were prepared. Unlike 3,5-disubsti-
tuted morpholine, (S)-19 underwent N-methylation with
methyl iodide in the presence of potassium carbonate
smoothly to give (S)-26 in 87% yield. Similarly, when
using benzyl bromide as an alkylating agent, (S)-19
was converted to (S)-N-benzyl-3-(hydroxydiphenyl-
methyl)morpholine14 (S)-27 in 81% yield (Scheme 8).
Failure of the above approach to access (R)-19 prompted
us to utilize a known addition reaction13 of phenylmag-
nesium bromide to (S)-methyl N-(tert-butoxycarbonyl)-
2,2-dimethyloxazolidine-4-carboxylate 20 to obtain
(S)-19. Addition of phenylmagnesium bromide to 20
in ether gave N-(tert-butoxycarbonyl)-2,2-dimethyl-4-
(hydroxydiphenylmethyl)oxazolidine 21 in 83% yield.
Cleavage of the oxazolidine moiety with 80% aq acetic
Ph
Ph
CO2CH3
NBoc
Ph
Ph
Toluene, 30% aq. NaOH,
BrCH2CO2But, TBAI
Et2O, 3M PhMgBr
in Et2O
80% aq. AcOH
rt, 24 hrs
OH
OH
O
O
NBoc
89%
HO
NHBoc
91%
83%
20
22
21
Ph
Ph
Ph
OH
Ph
Ph
Ph
DCM, Et3N,
MsCl
OH
OH
Et2O, LiAlH4
91%
1. DCM, TFA
O
NHBoc
O
NHBoc
2. MeOH, DIEA,
reflux
O
NHBoc
94%
ButO2C
23
24
OH
81%
25
OMs
O
Ph
Ph
N
H
HO
(S)-19
Scheme 7. Synthesis of (S)-19.
O
O
O
DMF, K2CO3,
PhCH2Br
DMF, K2CO3,
CH3I
OH
N
OH
OH
N
N
81%
Ph
H
Ph
Ph
Ph
Ph
Ph
87%
Ph
(S)-26
(S)-19
(S)-27
Scheme 8. Synthesis of (S)-26 and (S)-27.

392
R. Dave, N. A. Sasaki / Tetrahedron: Asymmetry 17 (2006) 388–401
2.2. Enantioselective diethylzinc addition
wise, with C2-symmetric morpholine-based amino alco-
hol, (3S,5S)-16, although it yielded the product in 81%
yield, the ee was only 16% (entry 8). All the tertiary
amine morpholine ligands, (3S,5S)-12, (3S,5S)-13, and
(3S,5S)-16 led to crossover in the product configuration.
The promising ligand candidate (S)-19, with flat/bulky
geminal phenyl substituents on the backbone, gave alco-
hol in 79% yield with just 14% ee (entry 8). Even, the N-
methylated derivative, (S)-26, was equally less efficient
(entry 9) in this catalytic reaction. Both (S)-19 and
(S)-26 gave alcohol with (S) absolute configuration.
2.2.1. Enantioselective diethylzinc addition to benzalde-
hyde catalyzed by chiral morpholine-based b-amino
alcohols. To begin with, ligands (S)-6, (3S,5S)-8,
(3R,5S)-9, (3S,5S)-9, (3S,5S)-12, (3S,5S)-13, (3S,5S)-
16, (S)-19, (S)-26, and (S)-27 were tested for the asym-
metric diethylzinc reaction with benzaldehyde as the
reference substrate (Fig. 2). The results from these
experiments are shown in Table 1.
O
OH
2 eq. Et2Zn, toluene
Interestingly, the N-benzylated ligand, (S)-27, was the
best amongst the current series of morpholine ligands
tested for the reaction. It led to a crossover in product
configuration with 30% ee and 78% yield (entry 10). It
is noteworthy that the sense of stereo-induction
observed15 for the product with (S)-19 was reversed in
comparison with that observed for (S)-6. This implies
that the reaction involving the geminal diphenyl-class
of morpholine ligand and (S)-6 proceeds through differ-
ent transition states.
10 mol% chiral
Ph
H
Ph
morpholine alcohol,
ο
0 C-rt, 48 h
Figure 2. Diethylzinc addition to benzaldehyde catalyzed by b-amino
alcohols bearing a morpholine moiety.
Table 1. Diethylzinc addition to benzaldehyde catalyzed by b-amino
alcohol bearing chiral morpholine
Entry Catalyst
Yield Enantioselective ee
Config. of
(%)a
ratio (R:S)
(%)b alcoholc
The widely accepted mechanism16 for this addition reac-
tion involves the reaction of a b-amino alcohol with a
molecule of diethylzinc to form ethylzinc-alkoxide che-
late A, which subsequently coordinates with both the
aldehyde and a second molecule of diethylzinc, allowing
the addition of the ethyl group to the aldehyde carbonyl
in a stereoselective manner. Monomeric zinc-alkoxide
chelate A is the actual catalyst, which bears a Lewis acid
site (Zn atom) to activate the aldehyde and a Lewis base
site (O atom) to activate the zinc reagent (Fig. 3). Thus,
the catalyst positions the two partners in close proximity
and with the correct relative geometry, facilitating the
reaction in a synergistic manner similar to catalysis by
enzymes.
1
2
3
(S)-6
(3R,5S)-8 71
(3R,5S)-9 75
80
40:60
43:57
36:64
37:63
55:45
56:44
58:42
43:57
42:58
65:35
20
14
28
26
10
12
16
14
16
30
S
S
S
S
R
R
R
S
S
R
4
(3S,5S)-9
74
5
6
7
(3S,5S)-12 61
(3S,5S)-13 59
(3S,5S)-16 81
8
9
10
(S)-19
(S)-26
(S)-27
79
77
78
a Isolated yield.
b HPLC analyses chiralcel OD column (10 lm, 4.6 · 250 mm), hexane/
2-propanol 97.5/2.5, 1 ml/min, tR = 11.9 (R) and 13.7 (S) min.
c Assigned from the sign of the specific rotation and from the elution
order in HPLC analysis.
R
N
HO
R
N
RCHO, Et2Zn
H
*
Zn
O
O
Zn
When benzaldehyde (1 mmol) was reacted with diethyl-
zinc (2 mmol) in the presence of (S)-6 (10 mol %) in
toluene at room temperature for 48 h, (S)-1-phenylpro-
pan-1-ol was obtained in 80% yield with 20% ee (entry 1).
Zn
O
R
O
O
A
Figure 3. Mechanism for the addition of diethylzinc to aldehyde
catalyzed by b-amino alcohol.
The enantiomeric excess (ee) of the products was deter-
mined by chiral HPLC analysis and the absolute configu-
ration of the major enantiomer assigned based on the
sign of optical rotations and from the elution order in
HPLC analysis. Compounds (3R,5S)-8 and (3R,5S)-9,
bearing benzyloxymethyl and tert-butyldiphenylsilyl-
oxymethyl group, respectively, in a stereo-defined trans
fashion when used as ligand, gave an alcohol with an
(S)-configuration. Compound (3R,5S)-9 with bulky
TBDPS group yielded product with higher ee in com-
parison to (3R,5S)-8 with a benzyl group (compare
entries 2 and 3). Further, reversing the configuration of
the stereogenic center bearing a tert-butyldiphenylsilyl-
oxymethyl group (cis-form) did not show any significant
change on the catalytic properties (entry 4). The tertiary
amino alcohols, (3S,5S)-12 and (3S,5S)-13, were rela-
tively less efficient promoters in terms of both chemical
yield as well as enantioselectivity (entries 5 and 6). Like-
Similar bifunctional catalysts, such as lithium-alkoxide
chelate,16a,17 prepared from the reaction of a b-amino
alcohol with n-butyl lithium are also known to catalyze
the nucleophilic addition of organozinc reagent to alde-
hydes. Motivated by this precedence, the catalytic dieth-
ylzinc addition to benzaldehyde was reinvestigated in
the presence of n-butyl lithium additive.
2.2.2. Enantioselective diethylzinc addition to benzalde-
hyde catalyzed by chiral morpholine-based b-amino alco-
hols in the presence of n-butyl lithium. Enantioselective
diethylzinc addition to benzaldehyde catalyzed by chiral
morpholine-based b-amino alcohols was studied in the
presence of n-butyl lithium. First, to a toluene solution
of (S)-6 (1 mmol), n-butyl lithium (10 mol %), and dieth-
ylzinc (2 mmol) were sequentially added at ꢀ30 ꢁC. The

R. Dave, N. A. Sasaki / Tetrahedron: Asymmetry 17 (2006) 388–401
393
mixture was warmed to 0 ꢁC and after stirring for
30 min, benzaldehyde (1 mmol) was added. After 48 h
of stirring at room temperature, (S)-1-phenylpropan-1-
ol was isolated in 77% yield with 32% ee (Table 2, entry
1). With the monolithiated (S)-6, the sense of stereo-
induction for product was same and there was no signifi-
cant change in the chemical yield. Interestingly, the
degree of stereoselectivity had enhanced by almost
50%. Following the same procedure, ligands (3S,5S)-8,
(3R,5S)-9, (3S,5S)-9, (3S,5S)-12, (3S,5S)-13, (3S,5S)-
16, (S)-19, (S)-26, and (S)-27 were tested for asymmetric
diethylzinc addition to the benzaldehyde in the presence
of n-butyl lithium. The results from these experiments
are summarized in Table 2.
N-Derivatized ligands, (3S,5S)-12 and (3S,5S)-13 were also
poor promoters for the diethylzinc addition to benzalde-
hyde in the presence of n-butyl lithium (entries 5 and 6).
However, the interesting observation was that the
configuration of the resulting alcohol was reversed.
The C2-symmetric morpholine-based amino alcohol,
(3S,5S)-16 was a better catalyst in its monolithiated
form. The product was obtained in 74% yield with
22% ee (entry 7). Notably, ligands bearing a geminal
diphenyl group on the backbone showed a dramatic
enhancement in the ee of the product in the presence
of n-butyl lithium. Compound (S)-19 in the monolithi-
ated form was the best amongst the series of morpholine
ligands evaluated for the asymmetric diethylzinc addi-
tion to benzaldehyde and (S)-19 gave the alcohol in
81% yield with 76% ee (entry 8). N-Methylated deriva-
tive, (S)-26, was relatively less efficient and afforded
product in 73% yield with 46% ee (entry 9). As before,
the use of N-benzylated derivative, (S)-27, as the ligand
led to the reversal in the sense of stereoinduction, yield-
ing 79% of product in 68% ee with R absolute configu-
ration (entry 10). It is noteworthy that the sense of
stereoinduction for the product with the morpholine
ligands [except for (3S,5S)-12 and (3S,5S)-13] was the
same as with the case in the absence of n-butyl lithium
additive.
Table 2. Diethylzinc addition to benzaldehyde catalyzed by b-amino
alcohol bearing morpholine moiety in the presence of 10 mol % n-butyl
lithium
Entry Catalyst
Yield Enantioselective ee
Config. of
(%)a
ratio (R:S)
(%)b alcoholc
1
2
3
4
5
6
7
8
9
(S)-6
(3S,5S)-8
77
55
34:66
47:53
38:62
39:61
44:56
43:57
61:39
12:88
27:73
84:16
32
6
S
S
S
S
S
S
R
S
S
R
(3R,5S)-9 71
(3S,5S)-9 67
(3S,5S)-12 35
(3S,5S)-13 69
(3S,5S)-16 74
(S)-19
(S)-26
(S)-27
24
22
12
14
22
76
46
68
81
73
79
2.2.3. Diethylzinc addition to aldehydes catalyzed by
morpholine-based diphenyl-class of ligands, (S)-19, (S)-
26, and (S)-27, in the presence of 10 mol % n-butyl
lithium. Observing the significant enhancement in the
ee of the product in the presence of n-butyl lithium addi-
tive, the use of diphenyl-class of ligands, (S)-19, (S)-26,
and (S)-27 was extended to the asymmetric ethylation of
other aromatic, aliphatic, and a,b-unsaturated alde-
hydes (Table 3). The yields and enantioselectivites were
71–88% and 43–80%, respectively. Ligand (S)-19, which
was the most enantioselective amongst the ligands tested
for the benzaldehyde, was less efficient with other alde-
hydes except a,b-unsaturated aldehydes. It gave the best
results for 3-phenylpropionaldehyde and trans-cinna-
maldehyde, yielding the products with 68% ee (Table 3,
10
a Isolated yield.
b HPLC analyses chiralcel OD column (10 lm, 4.6 · 250 mm), hexane/
2-propanol 97.5/2.5, 1 ml/min, tR = 11.9 (R) and 13.7 (S) min.
c Assigned from the sign of the specific rotation and from the elution
order in HPLC analysis.
Compound (3S,5S)-8 was an inefficient catalyst as it
gave the product in 55% yield but with only 6% ee (entry
2). The presence of n-butyl lithium did not have any sig-
nificant influence on the ligand catalytic properties of
(3R,5S)-9 and (3S,5S)-9, as product ee values and chem-
ical yields were nearly the same as in the absence of the
additive (compare entries 3 and 4 in Tables 1 and 2).
Table 3. Diethylzinc addition to aldehydes catalyzed by morpholine-based diphenyl-class of ligands, (S)-19, (S)-26, and (S)-27, in the presence of
10 mol % n-butyl lithium
Entry
Aldehyde
Catalyst
Yield (%)a
Enantioselective ratio R:S
ee (%)b
Config. of alcoholc
1
2
3
4
5
6
7
8
4-Methoxybenzaldehyde
4-Methoxybenzaldehyde
4-Methoxybenzaldehyde
2-Naphthaldehyde
2-Naphthaldehyde
2-Naphthaldehyde
3-Phenylpropionaldehyde
3-Phenylpropionaldehyde
3-Phenylpropionaldehyde
trans-Cinnamaldehyde
trans-Cinnamaldehyde
trans-Cinnamaldehyde
(S)-19
(S)-26
(S)-27
(S)-19
(S)-26
(S)-27
(S)-19
(S)-26
(S)-27
(S)-19
(S)-26
(S)-27
79
83
87
78
84
88
71
73
79
80
74
76
18:82
20:80
90:10
18:82
24:76
87:13
16:84
21:79
87:13
16:84
21:79
82:18
64
60
80
64
52
74
68
58
74
68
58
64
S
S
R
S
S
R
S
S
R
S
S
R
9
10
11
12
a Isolated yield.
b HPLC analyses chiralcel OD column.
c Assigned from the sign of the specific rotation and from the elution order in HPLC analysis.

394
R. Dave, N. A. Sasaki / Tetrahedron: Asymmetry 17 (2006) 388–401
entries 7 and 10). It also catalyzed the ethylation of cin-
namaldehyde better than the other ligands tested (Table
3, compare entries 10–12). N-Methylated ligand, (S)-26,
was a poor promoter in the ethylation reaction of the
aldehydes. With 4-methoxybenzaldehyde, it gave the
product with 60% ee in 83% yield (Table 3, entry 2).
For 2-naphthaldehyde, 3-phenylpropionaldehyde, and
trans-cinnamaldehyde, the ees were 52%, 58% and
58%, respectively (Table 3, entries 5, 8, and 11). The
N-benzylated ligand, (S)-26, was the most enantioselec-
tive among the geminal diphenyl-class of catalyst for all
the aldehydes, except trans-cinnamaldehyde. It catal-
yzed the diethylzinc addition to 4-methoxybenzalde-
hyde to furnish the (R)-configured alcohol in 87%
yield with 80% ee (Table 3, entry 3). However, for 2-
naphthaldehyde and 3-phenylpropionaldehyde, the
enantioselection was lower, that is 74% for both (Table
3, entries 6 and 9). Cinnamaldehyde was a poor sub-
strate for the (S)-26 catalyzed ethylation reaction, giving
the product with 64% ee (Table 3, entry 12).
product. However, with N-methylated tertiary amine
ligand (S)-26, the smaller methyl group is less effective
in generating the steric interaction and thus the sense of
stereoinduction is determined by model A.
The higher enantioselectivity with the lithiated morpho-
line ligand, may be attributed to the stronger hard acid
character of lithium compared to zinc.19 Thus, the lith-
ium can more easily coordinate with the oxygen atom
(hard base) of the approaching aldehyde than zinc.17b
Such a coordination of the lithium cation may control
the steric course of the reaction to afford higher
enantioselectivity.
3. Conclusion
In conclusion, a broad variety of chiral C/N functional-
ized morpholine catalysts sharing a common structural
motif with 3-(hydroxymethyl)morpholine 6 were pre-
pared from optically active serine in an efficient manner.
The key step in the building of the chiral morpholine
unit was the base-mediated coupling of the serinol deriv-
ative with tert-butyl bromoacetate or chiral 2,3-O-iso-
propylideneglycerol triflate. These morpholine-based
b-amino alcohols in 10 mol % concentration catalyze
the diethylzinc addition to benzaldehyde to afford
1-phenyl-1-propanol in 59–81% yield with 10–30% ee.
Interestingly, the addition of 10 mol % of n-butyl lith-
ium to the reaction mixture dramatically enhanced the
ee of the product in the case of ligands bearing geminal
diphenyl group on the backbone. In the presence of
n-butyl lithium, the use of (R)-3-(hydroxydiphenyl-
methyl)morpholine (S)-19 as a catalyst gave (S)-1-phen-
yl-1-propanol in 81% yield with 75% ee for the
benzaldehyde. The ee amplification of the product with
the 10 mol % of n-butyl lithium additive in the case of
geminal diphenyl-class of ligands was 220–580% for
benzaldehyde. Principally, such a dramatic improve-
ment in the product enantioselectivity could not be
explained by only considering the strong hard acid char-
acter of lithium atom of the lithiated morpholine ligand.
It seems that there may be some sort of coordination of
the oxygen atom of the morpholine ring with the lithium
atom, thereby imparting rigidity to the catalyst system.
To gain a precise understanding, parallel studies with
the corresponding piperidine class of ligands need to
be conducted. N-Benzylated morpholine ligand, (S)-27
was found to be the most efficient catalyst among the
diphenyl-class of ligands tested against other aldehydes
except cinnamaldehyde. With 4-methoxybenzaldehyde,
it gave an (R)-configured alcohol in 87% yield with
80% ee. Interestingly, catalyst (S)-19 and its N-methyl
derivative (S)-26 gave alcohols with an (S)-configuration
while the N-benzylated derivative (S)-27 gave the oppo-
site enantiomeric products for all the aldehydes. The
transition state models proposed could explain this
crossover in the product configuration. Experiments
are currently underway to refine our proposed model,
and to probe the role of the a-substituents on the
hydroxymethylene group of the morpholine unit. For
this purpose, the synthesis of (1S,3R)-3-(1-hydroxy-
ethyl)morpholine from L-threonine is under progress.
The asymmetric addition of the organozinc reagent to
the aldehyde in the presence of the b-amino alcohol is
a well-documented reaction and several models explain-
ing the sense of stereoinduction have been proposed.18
The tentative transition state models for the reaction
catalyzed by morpholine ligands bearing the geminal
diphenyl group on the backbone was defined to explain
the observed product configuration. The two chair-like
transition states A and B, which account for the interac-
tion of the N-substituent (X) with the morpholine ring
segment, by reinforcement of the a-substituents (gemi-
nal phenyl groups), seem to be operational in the reac-
tion (Fig. 4). This interaction dictates the approach
and coordination of the aldehyde to the metal atom.
In reactions with (S)-19, model A is operative. In this
ligand, the geminal phenyl groups create a more crowded
bottom face of the metallocycle. This allows for the
coordination of the aldehyde from the top face and a
re face ethyl addition to give the alcohol with an (S)-
configuration. Model B becomes operative in the case
of tertiary amine ligand (S)-27 to neutralize the steric
interaction of the N-substituent (benzyl) with the
approaching aldehyde. In this complex, coordination
of the aldehyde to the Lewis acid (metal atom) occurs
on the less hindered bottom face while si face ethyl addi-
tion accounts for the observed (R)-configuration of the
H
O
X
X
O
O
M
R
N
O
N
R
M
Zn
Zn
O
O
H
M = Li/ZnEt
R = aryl/alkylaryl
X = Bn
X = H/Me
A re face addition
B si face addition
Figure 4. Transition state models for the diethylzinc reaction with
benzaldehyde catalyzed by geminal diphenyl-class of morpholine
ligands.

R. Dave, N. A. Sasaki / Tetrahedron: Asymmetry 17 (2006) 388–401
395
Such a ligand having an extra chirality on the methylene
carbon holding the hydroxyl group could provide more
information on the design of new catalysts. We also plan
to screen the morpholine ligands presented in this article
against a variety of other aliphatic and aromatic alde-
hydes as substrates using various zinc reagents.
4.1.2. (R)-2-(2-(tert-Butoxycarbonylamino)-3-(tert-butyl-
diphenylsilyloxy)propoxy)ethanol 3. solution of
A
DIBAL-H (1.5 M) in toluene (21 ml) was added dropwise
to a stirred solution of 2 (8.745 g, 15.6 mmol) in DCM
(25 ml) at ꢀ78 ꢁC and left to stir for 1 h. The solution
was warmed to 0 ꢁC and stirred for 2 h. Then, the mix-
ture was again cooled toꢀ78 ꢁC and diluted with cold
MeOH (3 ml) and cold 1 M HCl (30 ml). The DCM
layer was separated and the aq layer extracted with
DCM (2 · 25 ml). Combined DCM extract was washed
with 5% aq NaHCO3 (25 ml), brine (25 ml) and dried
over Na2SO4. Evaporation of the solvent under vacuum
gave the yellow residue (7.4 g), which was subjected to
further reduction with LiBH4 in ether without
purification.
4. Experimental
4.1. General considerations
Tetrahydrofuran was distilled from sodium benzophe-
none ketyl and methylene chloride from P2O5 imme-
diately prior to use. All reagents obtained from
commercial sources were used without purification,
unless otherwise mentioned. Diethylzinc (1 M in hexanes)
and n-butyl lithium (1.6 M in hexanes) were supplied by
Aldrich. Flash column chromatography was performed
using Kieselgel 60 (230–400 mesh, E. Merck) and a step-
wise solvent polarity gradient elution method was
employed. Optical rotations and Infrared (IR) spectra
were recorded on a JASCO P-1010 polarimeter and
Perkin Elmer Spectrum BX spectrometer, respectively.
High resolution mass spectra (HRMS) were run on
Waters Micromass LCT with an electrospray source
(ZQ) in positive mode ionization (ESI). Proton nuclear
magnetic resonance (dH) spectra and carbon nuclear
magnetic resonance spectra were recorded on Brucker
AM-300. HPLC analyses were carried out on an Alli-
ance (Waters 2695) using PDA detector (2996). Melting
points were determined on a Buchi melting point appa-
ratus and are uncorrected.
To a stirred solution of the above yellow residue in
anhydrous ether (50 ml), LiBH4 (0.34 g, 15.6 mmol)
was added at 0–5 ꢁC under argon. The cooling-bath
was removed and stirring continued at room tempera-
ture for 12 h. The mixture was again cooled to 0–5 ꢁC
and quenched with water (40 ml) containing 6 M HCl
(5 ml). The ether layer was separated and the aqueous
layer was extracted with ether (2 · 25 ml). The combined
ether layer was dried over Na2SO4 and evaporated to
give a yellow residue, which on silica gel flash column
chromatographic (40% EtOAc in heptanes) purification
23
afforded 3 (6.275 g, 85%) as a colorless oil: ½aꢁD ¼ þ1:9
(c 1.9, CHCl3); IR (neat) 3445, 3070, 3048, 2930, 2857,
1710, 1695, 1589, 1499, 1472, 1427, 1390, 1364, 1313,
1246, 1170, 1111, 1058, 1029, 1007, 997, 969, 936, 884,
852, 823, 739, 700, 613 cmꢀ1 1H NMR (300 MHz,
;
CDCl3) d 1.06 (9H, s, SiC(CH3)3), 1.44 (9H, s,
NCO2C(CH3)3), 2.18 (1H, br s, OH), 3.54 (2H+Ha, m,
H2COCHaHb), 3.68 (4H+Hb, m, COCHaHb, SiOCH2,
CH2-hydroxyl), 3.88 (1H, m, NCH), 5.03 (1H, d,
J = 7.7 Hz, NH), 7.41 (6H, m, PhH), 7.66 (4H, m,
PhH); 13C NMR (75.5 MHz, CDCl3) d 19.3, 26.9,
28.4, 51.2, 61.8, 62.7, 69.9, 72.4, 79.5, 127.8, 129.8,
133.2, 135.6, 155.6; MS (ESI) m/z 496 [M+Na]+; HRMS
(ESI) (M+Na)+: m/z calcd for C26H39NNaO5Si
496.2490, found 496.2477.
4.1.1. (R)-tert-Butyl 2-(2-(tert-butoxycarbonylamino)-3-
a
(tert-butyldiphenylsilyloxy)propoxy)acetate 2. To
stirred solution of 1 (4.08 g, 9.5 mmol) in toluene
(50 ml), 30% aq NaOH solution (50 ml), tert-butyl bro-
moacetate (2.8 ml, 19 mmol), and TBAI (1.736 g,
4.7 mmol) were sequentially added at 0–5 ꢁC. After stir-
ring for 3 h, the toluene layer was separated and the aq
layer diluted with water (100 ml) before extracting with
toluene (3 · 25 ml). The combined toluene layer was
washed with 1 M HCl (25 ml), and brine (20 ml). Drying
over Na2SO4 and evaporation of the solvent gave a res-
idue, which on silica gel flash column chromatographic
4.1.3. (R)-(2-tert-Butoxycarbonylamino-3-(tert-butyldi-
phenylsilyloxy)propoxy)-2-(methanesulfonyloxy)ethane 4.
To a stirred mixture of 3 (1.514 g, 3.2 mmol) and tri-
ethylamine (1.3 ml, 9.6 mmol) in DCM (25 ml), methane-
sulfonyl chloride (0.4 ml, 4.8 mmol) was added at
ꢀ30 ꢁC under argon. After addition, the cooling-bath
was removed and the mixture stirred at room tempera-
ture for 2 h. The mixture was diluted with DCM
(20 ml) and washed successively with water (10 ml),
1 M HCl (10 ml), satd aq NaHCO3 solution (10 ml),
and brine (10 ml). Drying over Na2SO4 and evaporation
of the solvent gave a yellow residue, which on silica gel
flash column chromatographic (5% EtOAc in DCM)
purification (15% EtOAc in heptanes) afforded 2
23
(4.49 g, 87%) as a colorless oil: ½aꢁD ¼ þ4:7 (c 1.1,
CHCl3); IR (neat) 3444, 3071, 2976, 2930, 2856, 1747,
1714, 1588, 1499, 1473, 1427, 1391, 1366, 1308, 1228,
1167, 1133, 1112, 1059, 1029, 997, 939, 885, 846, 824,
780, 740, 702, 691, 613 cmꢀ1 1H NMR (300 MHz,
;
CDCl3) d 1.05 (9H, s, SiC(CH3)3), 1.42 (9H, s,
NCO2C(CH3)3), 1.47 (9H, s, CO2C(CH3)3), 3.61 (Ha,
dd, J = 9.3, 5.4 Hz, COCHaHb), 3.72 (2Hb, m,
COCHaHb, SiOCHaHb), 3.79 (Ha, dd, J = 10, 4.3 Hz,
SiOCHaHb), 3.88 (1H, m, NCH), 3.92 (2H, s, OCH2-
CO2), 5.03 (1H, d, J = 7.6 Hz, NH), 7.37 (6H, m, PhH),
7.65 (4H, m, PhH); 13C NMR (75.5 MHz, CDCl3) d
19.3, 26.9, 28.1, 28.4, 51.4, 62.5, 68.9, 70, 79.2, 81.8,
127.7, 129.7, 133.3, 135.6, 155.5, 169.5; MS (ESI) m/z
566 [M+Na]+; HRMS (ESI) (M+Na)+: m/z calcd for
C30H45NNaO6Si 566.2908, found 566.2916.
purification afforded 4 (1.64 g, 93%) as a colorless oil:
27
½aꢁD ¼ þ2:2 (c 1.5, CHCl3); IR (neat) 3390, 3070,
2957, 2930, 2856, 1711, 1588, 1503, 1471, 1454, 1427,
1390, 1353, 1311, 1246, 1173, 1111, 1059, 1021, 997,
970, 921, 852, 823, 803, 741, 702, 690, 620, 612 cmꢀ1
;
1H NMR (300 MHz, CDCl3) d 1.06 (9H, s, SiC(CH3)3),
1.44 (9H, s, NCO2C(CH3)3), 2.95 (3H, s, SCH3), 3.55

396
R. Dave, N. A. Sasaki / Tetrahedron: Asymmetry 17 (2006) 388–401
(Ha, dd, J = 9.3, 6.1 Hz, COCHaHb), 3.67 (2H+2Hb, m,
COCHaHb, SiOCHaHb, COCH2), 3.76 (Ha, dd, J = 10,
4 Hz, SiOCHaHb), 3.87 (1H, m, NCH), 4.29 (2H, dd,
J = 4.6, 4.5 Hz, CH2OMs), 4.85 (1H, d, J = 7.7 Hz,
NH), 7.41 (6H, m, PhH), 7.65 (4H, m, PhH); 13C
NMR (75.5 MHz, CDCl3) d 19.3, 26.9, 28.4, 37.6,
51.1, 62.6, 68.8, 69.9, 79.5, 127.8, 129.8, 133.1, 135.5,
155.4; MS (ESI) m/z 574 [M+Na]+; HRMS (ESI)
(M+Na)+: m/z calcd for C27H41NNaO7SSi 574.2265,
found 574.2250.
MeOD) d 44.2, 57.3, 59.2, 64.7, 66.8; MS (ESI) m/z
118 [M+H]+; HRMS (ESI) (M+H)+ HRMS (ESI)
(M+H)+: m/z calcd for C5H12NO2 118.0863, found
118.0865.
4.1.6. (3S,5S)-3-(Benzyloxymethyl)-5-(hydroxymethyl)-
morpholine (3S,5S)-8. (3S,5R)-7 was desilylated with
TBAF using the previously described procedure to fur-
26
nish (3S,5S)-8 as a colorless oil in 87% yield: ½aꢁD
¼
þ3:7 (c 1.0, MeOH); IR (neat) 3304, 2856, 1495, 1453,
1365, 1335, 1206, 1097, 1047, 925, 853, 796, 736, 696,
1
4.1.4. (R)-3-(tert-Butyldiphenylsilyloxymethyl)morphol-
ine 5. To a stirred ice-cold solution of 4 (1.322 g,
2.4 mmol) in anhydrous DCM (20 ml), trifluoroacetic
acid (5 ml) was added under argon. The cooling-bath
was removed and the mixture stirred at room tempera-
ture for 1 h, after which TLC revealed the completion
of the reaction. The mixture was concentrated under
vacuum and the resulting residue was treated with satd
aq NaHCO3 solution (25 ml). The mixture was extracted
with DCM (3 · 10 ml) and the combined DCM layer
was dried (Na2SO4) and evaporated to give a yellow
residue.
609 cmꢀ1; H NMR (300 MHz, MeOD) d 2.97 (1H, m,
NCH), 3.17 (1H, m, NCH), 3.51 (2H+Ha, m, COCH2,
CHaHbOBn), 3.58 (2H+Hb, m, COCH2, CHaHbOBn),
3.74 (2H, d, J = 11.6 Hz, CH2-hydroxyl), 4.54 (Ha, d,
J = 12.2 Hz, PhCHaHb), 4.57 (Hb, d, J = 12.2 Hz,
PhCHaHb), 7.31 (1H, m, PhH), 7.36 (4H, m, PhH);
13C NMR (75.5 MHz, DMSO-d6) d 49.3, 51.4, 60.9,
68.1, 68.2, 69.6, 72.2, 127.3, 127.4, 128.2, 138.4; MS
(ESI) m/z 260 [M+Na]+, 238 [M+H]+; HRMS (ESI)
(M+Na)+: m/z calcd for C13H19NNaO3 260.1257, found
260.1255.
4.1.7.
(3R,5S)-3-(tert-Butyldiphenylsilyloxymethyl)-5-
The residue was dissolved in MeOH (15 ml) and triethyl-
amine (1 ml, 7.2 mmol) and N,N-diisopropylethylamine
(1.3 ml, 7.2 mmol) added at room temperature. The
mixture was refluxed at 80 ꢁC under stirring for 4 h.
The mixture was cooled, concentrated under vacuum,
and treated with water (30 ml). The mixture was
extracted with EtOAc (3 · 10 ml) and the combined
EtOAc layer washed with brine (10 ml), dried over
Na2SO4, and evaporated to give a yellow residue. Silica
gel flash column chromatographic (EtOAc) purification
(hydroxymethyl)morpholine (3R,5S)-9. To a stirred
solution of (3S,5R)-7 (1.283 g, 2.7 mmol) in DCM
(6 ml), 1 M solution of boron trichloride in DCM
(5.4 ml, 5.4 mmol) was added at 0–5 ꢁC under argon
over a period of 10 min. The cooling-bath was removed
and the mixture stirred at room temperature for 30 min.
The mixture was quenched with MeOH (2 ml) and con-
centrated under vacuum. The resulting residue was
diluted with DCM (25 ml, cooled to 0 ꢁC and basified
with triethylamine (1.9 ml). The mixture was concen-
trated under vacuum and the resulting brown residue
was purified by silica gel flash column chromatography
of the residue afforded 5 (0.707 g, 83%) as a colorless oil:
25
½aꢁD ¼ ꢀ0:3 (c 1.2, CHCl3); IR (neat) 3069, 3048, 2954,
2930, 2891, 2854, 1588, 1486, 1461, 1471, 1427, 1389,
1360, 1348, 1329, 1310, 1263, 1188, 1155, 1104, 1030,
1007, 997, 971, 956, 935, 883, 839, 823, 797, 740, 701,
(EtOAc) to afford (3R,5S)-9 (0.863 g, 83%) as a colorless
24
oil: ½aꢁD ¼ þ11:5 (c 1.1, MeOH); IR (neat) 3315, 3070,
2929, 2856, 2358, 2337, 1589, 1470, 1427, 1390, 1360,
690, 622, 608 cmꢀ1
;
1H NMR (300 MHz, CDCl3) d
1336, 1110, 998, 969, 932, 823, 740, 700, 614 cmꢀ1; H
1
1.06 (9H, s, SiC(CH3)3), 2.01 (1H, br s, NH), 2.96
(3H, m, NCH2, NCH), 3.26 (Ha, dd, J = 11.1, 9.6 Hz,
COCHaHb), 3.53 (2H+Hb, m, SiOCH2, COCHaHb),
3.77 (Hc, t, J = 3.2 Hz, COCHcHd), 3.81 (Hd, t, J =
3.4 Hz, COCHcHd), 7.41 (6H, m, PhH), 7.65 (4H, m,
PhH); 13C NMR (75.5 MHz, CDCl3) d 19.3, 26.9,
45.6, 56.2, 64.7, 67.8, 69.6, 127.8, 129.8, 133.3, 135.5;
MS (ESI) m/z 378 [M+Na]+, 356 [M+H]+, 278, 200;
HRMS (ESI) (M+H)+: m/z calcd for C21H30NO2Si
356.2040, found 356.2037.
NMR (300 MHz, DMSO-d6) d 1 (9H, s, SiC(CH3)3),
2.77 (1H, m, NCH), 2.96 (1H, m, NCH), 3.29
(2H+Ha, m, HaHbCOCHcHd), CH2-hydroxyl), 3.42
(Hc, dd, J = 10.9, 5.1 Hz, HaHbCOCHcHd), 3.59
(2H+Hb+Hd, m, SiOCH2, HaHbCOCHcHd), 4.56 (1H,
br s, NH), 7.46 (6H, m, PhH), 7.63 (4H, m, PhH); 13C
NMR (75.5 MHz, DMSO-d6) d 18.8, 26.7, 51.3, 61.1,
63.3, 67.7, 68.4, 127.9, 129.8, 133, 135; MS (ESI) m/z
408 [M+Na]+, 386 [M+H]+, 308, 230; HRMS (ESI)
(M+Na)+: m/z calcd for C22H31NNaO3Si 408.1965,
found 468.1964.
4.1.5. (S)-3-(Hydroxymethyl)morpholine (S)-6. Com-
pound 5 was desilylated with TBAF using the previously
4.1.8. (3S,5S)-3-(Benzyloxymethyl)-5-(tert-butyldiphenyl-
silyloxymethyl)morpholine (3S,5S)-7. (3S,5S)-7 was
prepared from D-N-Boc-serine methyl ester (R)-10 and
described procedure to afford (S)-6 as a colorless solid in
27
87% yield: mp 112 ꢁC; ½aꢁD ¼ ꢀ17:2 (c 1.4, 1 M HCl);
IR (neat) 3347, 2945, 2496, 1613, 1449, 1307, 1202,
(S)-2,3-O-isopropylideneglycerol triflate (S)-11 employ-
24
1101, 1046, 988, 944, 863, 669, 648, 613 cmꢀ1
;
1H
ing our standard protocol:5 ½aꢁD ¼ þ2:2 (c 1.0, CHCl3);
NMR (300 MHz, MeOD) d 3.25 (2H, m, NCH2), 3.38
(1H, m, NCH), 3.62 (Ha, dd, J = 8.1, 2.2 Hz, HaHb-
COCHcHd), 3.66 (Ha, dd, J = 8, 2 Hz, CHaHb-hydroxyl),
3.74 (Hb+Hc, m, CHaHb-hydroxyl, HaHbCOCHcHd),
3.94 (Hd, t, J = 3.4 Hz, HaHbCOCHcHd), 3.98 (Hb, t,
J = 3.3 Hz, HaHbCOCHcHd); 13C NMR (75.5 MHz,
IR (neat) 3069, 2929, 2854, 1588, 1471, 1453, 1427, 1389,
1361, 1336, 1308, 1240, 1209, 1101, 1028, 998, 968, 940,
822, 787, 737, 698, 641 cmꢀ1 1H NMR (300 MHz,
;
CDCl3) d 1.04 (9H, s, SiC(CH3)3), 3.14 (4H, m, NCH,
NCH, COCH2), 3.32 (Ha, m, BnOCHaHb), 3.52
(Hb+2H, m, BnOCHaHb, SiOCH2), 3.81 (2H, m,

R. Dave, N. A. Sasaki / Tetrahedron: Asymmetry 17 (2006) 388–401
397
COCH2), 4.49 (Ha, d, J = 11.9 Hz, PhCHaHb), 4.53 (Hb,
d, J = 11.9 Hz, PhCHaHb), 7.35 (11H, m, PhH), 7.64
(4H, m, PhH); 13C NMR (75.5 MHz, CDCl3) d 19.3,
26.8, 54.4, 56, 64.9, 69.4, 69.7, 71.1, 73.5, 127.8, 128.4,
129.8, 133.3, 135.6, 138; MS (ESI) m/z 476 [M+H]+;
HRMS (ESI) (M+H)+: m/z calcd for C29H38NO3Si
476.2615, found 476.2610.
CCHN), 3.19 (Ha, ddt, J = 14.1, 7.2, 1.1 Hz, NCHaHb),
3.46 (Hb, ddt, J = 14.2, 5.6, 1.5 Hz, NCHaHb), 3.53 (Ha,
dd, J = 11.3, 3.8 Hz, CHaHb-hydroxyl), 3.64 (4H, m,
SiOCCH2, COCH2), 3.76 (2H+Hb, m, COCH2,
CHaHb-hydroxyl), 4.47 (Ha, d, J = 12.1 Hz, PhCHaHb),
4.53 (Hb, d, J = 12.1 Hz, PhCHaHb), 5.13 (Ha, ddd,
J = 10.2, 3.8, 1.5 Hz, C@CHaHb), 5.21 (Hb, ddd,
J = 17.2, 3, 1.7 Hz, C@CHaHb), 5.84 (1H, m, CCH=C),
7.31 (5H, m, PhH); 13C NMR (75.5 MHz, CDCl3) d
52.4, 54.6, 55.8, 58.8, 66.1, 67.7, 68.2, 73.4, 117.5,
127.7, 128.4, 135.8, 138.1; MS (ESI) m/z 300
[M+Na]+, 278 [M+H]+; HRMS (ESI) (M+H)+: m/z
calcd for C16H24NO3 278.1751, found 278.1721.
4.1.9.
(3S,5S)-3-(tert-Butyldiphenylsilyloxymethyl)-5-
(hydroxymethyl)morpholine (3S,5S)-9. (3S,5S)-7 was
debenzylated with 1 M boron trichloride solution in
DCM using the previously described procedure to give
26
(3S,5S)-9 as a colorless oil in 83% yield: ½aꢁD ¼ ꢀ0:6
(c 1.4, MeOH); IR (neat) 3304, 3069, 2929, 2854, 1588,
1470, 1461, 1426, 1389, 1360, 1335, 1240, 1209, 1103,
4.1.11. (3S,5S)-N-Propionyl-3-(benzyloxymethyl)-5-(hydr-
oxymethyl)morpholine (3S,5S)-13. To a stirred ice-cold
solution of (3S,5R)-7 (2.134 g, 4.5 mmol) in anhydrous
DCM (45 ml), triethylamine (1.3 ml, 9 mmol), and
propionyl chloride (0.6 ml, 6.7 mmol) were sequentially
added under argon. After addition, the cooling-bath
was removed and stirring continued at room tempera-
ture for 30 min. The mixture was diluted with DCM
(50 ml) and washed subsequently with satd aq NaHCO3
solution (20 ml) and brine (20 ml). Drying over Na2SO4
and evaporation of the solvent gave a yellow residue,
which on silica gel flash column chromatographic
purification (10% EtOAc in heptanes) afforded the
1
1006, 997, 937, 821, 788, 738, 699, 689, 621 cmꢀ1; H
NMR (300 MHz, DMSO-d6) d 1 (9H, s, SiC(CH3)3),
2.76 (1H, m, NCH), 2.92 (3H, m, NCH, COCH2),
3.22 (2H, m, CH2-hydroxyl), 3.48 (2H, m, SiOCH2),
3.72 (Ha, dd, J = 10.5, 2.9 Hz, COCHaHb), 3.79 (Hb,
d, J = 7.4 Hz, COCHaHb), 4.58 (1H, br s, NH), 7.45
(6H, m, PhH), 7.61 (4H, m, PhH); 13C NMR
(75.5 MHz, DMSO-d6) d 18.8, 26.6, 55.7, 56.1, 62.1,
64.9, 69.3, 69.4, 127.9, 129.9, 132.8, 132.9, 135; MS
(ESI) m/z 408 [M+Na]+, 386 [M+H]+; HRMS (ESI)
(M+Na)+: m/z calcd for C22H31NNaO3Si 408.1965,
found 468.1964.
N-propionyl derivative of (3S,5R)-7 (2.2 g, 92%) as a
29
4.1.10. (3S,5S)-N-Allyl-3-(benzyloxymethyl)-5-(hydroxy-
methyl)morpholine (3S,5S)-12. To
colorless oil: ½aꢁD ¼ þ40:8 (c 1.0, CHCl3); IR (neat)
a
solution of
2930, 2856, 1650, 1471, 1426, 1407, 1272, 1152, 1111,
1
(3S,5R)-7 (1.662 g, 3.5 mmol) in DMF (10 ml), K2CO3
(0.967 g, 7 mmol), and allyl iodide (0.5 ml, 5.3 mmol)
were added at room temperature under argon. After
stirring for 3 h, the mixture was diluted with EtOAc
(100 ml), filtered, and the filtrate washed sequentially
with water (15 ml), 1 M HCl (15 ml), satd NaHCO3
(15 ml), and brine (15 ml). Drying over Na2SO4 and
evaporation of solvent gave a residue, which on silica
gel flash column chromatographic purification (DCM)
1028, 997, 824, 739, 701, 614 cmꢀ1; H NMR (300 MHz,
DMSO-d6) d 0.86 (3H, t, J = 7.3 Hz, CH3), 0.99 (9H,
s, SiC(CH3)3), 2.24 (2H, br hump, COCH2Me), 3.79
(10H, m, 4 · COCH2, 2 · NCH), 4.51 (2H, s, PhCH2),
7.32 (5H, m, PhH), 7.46 (6H, m, PhH), 7.62 (4H, m,
PhH); 13C NMR (75.5 MHz, MeOD) d 10.1, 20.1,
27.3, 27.6, 52.7, 54.4, 55.9, 64.4, 65.1, 70.3, 71.8, 74.2,
128.8, 129.1, 129.5, 131.2, 134.3, 136.7, 136.8, 139.6,
176.9; MS (ESI) m/z 554 [M+Na]+; HRMS (ESI)
(M+Na)+: m/z calcd for C32H41NNaO4Si 554.2697,
found 554.2692.
afforded N-allyl derivative of (3S,5R)-7 (1.677 g, 93%)
28
as a colorless oil: ½aꢁD ¼ þ49:8 (c 2.0, CHCl3); IR (neat)
3069, 2928, 2854, 1588, 1471, 1453, 1427, 1360, 1111,
997, 919, 822 cmꢀ1
;
1H NMR (300 MHz, CDCl3) d
The N-propionyl derivative of (3S,5R)-7 was desilylated
1.03 (9H, s, SiC(CH3)3), 2.88 (2H, m, 2 · NCH), 2.99
(Ha, dd, J = 14.3, 7.5 Hz, NCHaHb), 3.35 (Hb, ddt,
J = 14.3, 5.1, 1.7 Hz, NCHaHb), 3.48 (2H, d,
J = 5.8 Hz, BnOCH2), 3.72 (6H, m, SiOCH2,
H2COCH2), 4.43 (Ha, d, J = 11.9 Hz, PhCHaHb), 4.49
(Hb, d, J = 12.1 Hz, PhCHaHb), 5.02 (2H, m, C@CH2),
5.74 (1H, m, HCC@C), 7.33 (11H, m, PhH), 7.65 (4H,
m, PhH); 13C NMR (75.5 MHz, CDCl3) d 19.2, 26.8,
53.5, 55.2, 57, 60, 67, 68.6, 69.1, 73.4, 116.8, 127.7,
128.4, 129.7, 133.5, 135.6, 136.2, 138.1; MS (ESI) m/z
538 [M+Na]+, 516 [M+H]+; HRMS (ESI) (M+H)+:
m/z calcd for C32H42NO3Si 516.2928, found 516.2916.
with TBAF using previously described procedure to
afford (3S,5S)-13 as a colorless oil in 90% yield (two
24
rotamers): ½aꢁD ¼ þ22:2 (c 1.6, CHCl3); IR (neat) 3407,
3030, 2936, 2874, 1636, 1495, 1454, 1419, 1283, 1147,
1098, 1076, 1053, 947, 908, 843, 817, 740, 698, 634,
1
602 cmꢀ1; H NMR (300 MHz, MeOD) d 1.09 (3H, t,
J = 7.2 Hz, CH3), 2.47 (2H, q, J = 7.5 Hz, COCH2Me),
3.89 (10H, m, 4 · COCH2, 2 · NCH), 4.57 (2H, s,
PhCH2), 7.34 (5H, m, PhH); 13C NMR (75.5 MHz,
MeOD) d 9.5, 10, 27.2, 27.6, 52.9, 54.8, 56, 62.4, 65.6,
70.3, 70.7, 74.2, 128.6, 128.8, 129.2, 129.3, 129.5,
130.5, 136, 139.6, 177.6; MS (ESI) m/z 316 [M+Na]+;
HRMS (ESI) (M+Na)+: m/z calcd for C16H23NNaO4
316.1519, found 316.1484.
The N-allyl derivative of (3S,5R)-7 was desilylated with
TBAF using previously described procedure to afford
26
(3S,5S)-12 as a colorless oil in 87% yield: ½aꢁD ¼ þ47
4.1.12. (3S,5S)-N-Ethoxycarbonylmethyl-3,5-bis(benzyl-
oxymethyl)morpholine 15. To a solution of (3S,5S)-14
(1.9 g, 5.8 mmol) in DMF (20 ml), K2CO3 (1.204 g,
8.71 mmol), and ethyl bromoacetate (0.8 ml, 7.0 mmol)
were added at room temperature under argon. After
(c 1.3, CHCl3); IR (neat) 3418, 2856, 1641, 1495, 1454,
1418, 1306, 1129, 1094, 1075, 1047, 921, 737,
698 cmꢀ1; H NMR (300 MHz, CDCl3) d 2.32 (1H, br
1
s, OH), 2.81 (1H, m, BnOCCHN), 3.09 (1H, m, SiO-

398
R. Dave, N. A. Sasaki / Tetrahedron: Asymmetry 17 (2006) 388–401
26
stirring for 12 h, the mixture was diluted with EtOAc
(200 ml), filtered, and the filtrate washed sequentially
with water (25 ml), 1 M HCl (25 ml), satd NaHCO3
(25 ml), and brine (25 ml). Drying over Na2SO4 and
evaporation of the solvent gave a residue, which on sil-
ica gel flash column chromatographic purification (25%
mp 80 ꢁC; ½aꢁD ¼ þ60:4 (c 1.1, CHCl3); IR (neat)
3448, 2974, 2862, 1692, 1454, 1411, 1365, 1297, 1277,
1236, 1169, 1122, 1054, 968, 912, 862, 710, 620,
606 cmꢀ1; H NMR (300 MHz, CDCl3) d 1.47 (9H, s,
1
OC(CH3)3), 2.22 (1H, br s, OH), 3.17 (Ha, td,
J = 12.7, 3.2 Hz, NCHaHb), 3.46 (Ha, td, J = 11.8,
3 Hz, COCHaHb), 3.57 (Hb, dd, J = 11.9, 3.6 Hz,
COCHaHb), 3.87 (5H+Hb, m, COCH2, NCH, CH2-
hydroxyl, NCHaHb); 13C NMR (75.5 MHz, CDCl3) d
28.4, 40.1, 52.2, 60.5, 66.4, 66.7, 80.5, 155.7; MS (ESI)
m/z 240 [M+Na]+, 184; HRMS (ESI) (M+Na)+: m/z
calcd for C10H19NNaO4 240.1206, found 240.1210.
EtOAc in heptanes) afforded 15 (2.183 g, 91%) as a col-
23
orless oil: ½aꢁD ¼ þ26:9 (c 1.2, CHCl3); IR (neat) 2856,
1745, 1495, 1453, 1366, 1177, 1134, 1091, 1057, 933,
734, 697 cmꢀ1 1H NMR (300 MHz, CDCl3) d 1.14
;
(3H, t, J = 7.2 Hz, CH3) 3.17 (2H, m, 2 · NCH), 3.62
(10H, m, NCH2, 2 · BnOCH2, 2 · COCH2), 3.99 (2H,
m, CO2CH2), 4.45 (4H, s, 2 · PhCH2), 7.31 (10H, m,
PhH); 13C NMR (75.5 MHz, CDCl3) d 14.1, 54.2,
56.3, 60.4, 68.1, 69.1, 73.3, 127.6, 128.4, 137.6, 172.2;
MS (ESI) m/z 382 [M+Na]+, 360 [M+H]+, 342, 167;
HRMS (ESI) (M+Na)+: m/z calcd for C24H31NNaO5
436.2094, found 436.2086.
To a solution of the N-Boc derivative of (S)-6 (4 g,
18.4 mmol) in acetone (20 ml), an aq 5% solution of
NaHCO3 (62 ml) was added at room temperature. The
heterogeneous mixture was cooled to 0 ꢁC and treated
sequentially with KBr (219 mg, 1.8 mmol) and TEMPO
(3.163 g, 20.2 mmol). An aq 5% solution of sodium
hypochlorite (27.4 ml, 18.4 mmol) was then added drop-
wise while the mixture was vigorously stirred and main-
tained at 0 ꢁC. After 1 h, additional 5% aq NaOCl
solution (27.4 ml, 18.4 mmol) was added and stirring
was continued at 0 ꢁC for another 1 h followed by addi-
tion of 5% aq NaHCO3 solution. Acetone was removed
under vacuum and the aq layer washed with ether
(2 · 25 ml), acidified to pH 6 with 1 M KHSO4 solution
and extracted with EtOAc (3 · 50 ml). Drying over
Na2SO4 and evaporation of EtOAc extract gave a pale
yellow solid, which on silica gel flash column chromato-
graphic purification (50% EtOAc in heptanes) afforded
4.1.13.
(3S,5S)-N-(2,2-Diphenyl-2-hydroxyethyl)-3,5-
bis(benzyloxymethyl)morpholine (3S,5S)-16. To a solu-
tion of 15 (1.2 g, 2.9 mmol) in THF (25 ml), 1 M
solution of PhMgBr in THF (11.6 ml, 11.6 mmol) was
added at ꢀ20 ꢁC under argon over a period of 10 min.
The mixture was warmed to room temperature and stir-
red for 3 h. Reaction was quenched with aq satd NH4Cl
solution (50 ml) and then extracted with ether
(3 · 20 ml). Ether layer was washed with brine, dried
over Na2SO4, and evaporated under reduced pressure
to give a yellow oil, which on silica gel flash column
chromatographic purification (20% EtOAc in heptanes)
afforded (3S,5S)-16 (1.259 g, 83%) as a colorless oil:
17 (3.536 g, 83%, two rotamers) as a colorless solid:
23
24
½aꢁD ¼ þ35:2 (c 1.0, CHCl3); IR (neat) 3416, 3058,
mp 181 ꢁC; ½aꢁD ¼ þ73 (c 1.1, MeOH); IR (neat) 3458,
3027, 2856, 1596, 1493, 1447, 1364, 1311, 1204, 1088,
3400–2700, 1730, 1745, 1694, 1680, 1650, 1476, 1454,
1392, 1367, 1324, 1300, 1267, 1255, 1226, 1164, 1113,
1074, 1027, 1012, 953, 909, 778, 734, 694, 646 cmꢀ1
;
1H NMR (300 MHz, CDCl3) d 1.59 (1H, br s, OH),
2.71 (2H, m, 2 · NCH), 3.54 (Ha+ 8H, m, 2 · BnOCH2,
2 · COCH2, NCHaHb), 3.82 (Hb, d, J = 14 Hz,
NCHaHb), 4.36 (2Ha, d, J = 11.6 Hz, 2 · PhCHaHb),
4.44 (2Hb, d, J = 12.2 Hz, 2 · PhCHaHb), 5.25 (1H, br
s, NH), 7.27 (16H, m, PhH), 7.48 (2H, d, J = 7.3 Hz,
PhH), 7.53 (2H, d, J = 7.3 Hz, PhH); 13C NMR
(75.5 MHz, CDCl3) d 56, 58.6, 67.8, 68.1, 73.2, 74.7,
125.9, 126.1, 126.6, 126.7, 127.7, 128, 128.1, 128.4,
137.9, 147, 147.2; MS (ESI) m/z 546 [M+Na]+, 524
[M+H]+, 506; HRMS (ESI) (M+H)+: m/z calcd for
C34H38NO4 524.2795, found 524.2798.
1066, 1022, 981, 950, 871, 834, 775, 754, 629 cmꢀ1; H
1
NMR (300 MHz, DMSO-d6) d 1.37, 1.47 (9H, two s,
OC(CH3)3), 2.99 (Ha, td, J = 12.7, 3.7 Hz, NCHaHb),
3.17 (0.5Ha, td, J = 12.4, 3.3 Hz, NCHaHb), 3.37 (Ha,
m, COCHaHb), 3.55 (2Hb, m, COCHaHb, NCHaHb),
3.78 (Hc, td, J = 14.7, 3.3 Hz, COCHcHd), 4.15 (Hd, t,
J = 11.6 Hz, COCHcHd), 4.31 (1H, dd, J = 15.2,
2.7 Hz, NCH); 13C NMR (75.5 MHz, DMSO-d6) d
27.8, 27.9, 38.7, 40.3, 53.4, 54.8, 65.5, 65.8, 66.8, 67.3,
79.3, 79.5, 154.8, 171.4, 171.6; MS (ESI) m/z 254
[M+Na]+, 198, 154; HRMS (ESI) (M+Na)+: m/z calcd
for C10H17NNaO5 254.0999, found 254.1033.
4.1.14. (R)-N-tert-Butoxycarbonyl morpholine-3-carbox-
ylic acid 17. To a stirred ice-cold solution of (S)-6
(3.7 g, 31.6 mmol) in methanol (35 ml), triethylamine
(5.3 ml, 37.9 mmol), and di-tert-butyl dicarbonate
(9.644 g, 44.2 mmol) were added under argon. The cool-
ing-bath was removed and the mixture stirred at room
temperature for 1 h. The mixture was concentrated under
vacuum and the resulting residue was quenched with
water (50 ml). The mixture was extracted with EtOAc
(3 · 25 ml) and the combined EtOAc extract was washed
with 1 M KHSO4 (15 ml) and brine (15 ml). Drying over
Na2SO4 and evaporation of the solvent gave a residue,
which on silica gel flash column chromatographic puri-
fication (30% EtOAc in heptanes) afforded the N-Boc
derivative of (S)-6 (6.654 g, 97%) as a colorless solid:
4.1.15. (R)-Methyl N-tert-butoxycarbonyl morpholine-3-
carboxylate 18. To a solution of 17 (4 g, 17.3 mmol) in
DMF (20 ml), K2CO3 (3.589 g, 26 mmol), and methyl
iodide (1.6 ml, 26 mmol) were added at room tempera-
ture under argon. After stirring for 12 h, the mixture
was diluted with EtOAc (100 ml), filtered, and the fil-
trate washed sequentially with water (15 ml), 1 M HCl
(15 ml), satd NaHCO3 (15 ml), and brine (15 ml). Dry-
ing over Na2SO4 and evaporation of the solvent gave
a residue, which on silica gel flash column chromato-
graphic purification (15% EtOAc in heptanes) afforded
18 (3.774 g, 89%, two rotamers) as a pale yellow oil:
24
½aꢁD ¼ þ78:9 (c 1.2, CHCl3); IR (neat) 2975, 1747,
1699, 1454, 1395, 1365, 1328, 1299, 1267, 1220, 1198,
1
1166, 1109, 1067, 1027, 982, 872, 776 cmꢀ1; H NMR

R. Dave, N. A. Sasaki / Tetrahedron: Asymmetry 17 (2006) 388–401
399
(300 MHz, CDCl3) d 1.44, 1.48 (9H, two s, OC(CH3)3),
3.19 (0.5Ha, td, J = 12.8, 3 Hz, NCHaHb), 3.32 (0.5Ha,
td, J = 12.6, 3 Hz, NCHaHb), 3.48 (Ha, t, J = 11.9 Hz,
COCHaHb), 3.73 (2Hb+Hc, m, HcHdCOCHaHb,
NCHaHb), 3.78 (3H, s, OCH3), 4.36 (0.5H+Hd, m,
NCH, COCHcHd), 4.59 (0.5H, m, NCH); 13C NMR
(75.5 MHz, CDCl3) d 28.3, 40.7, 41.9, 52.4, 54, 55.4,
66.4, 66.8, 67.3, 67.8, 80.7, 155.6, 155.8, 170.4, 170.7;
MS (ESI) m/z 268 [M+Na]+, 212, 168; HRMS (ESI)
(M+Na)+: m/z calcd for C11H19NNaO5 268.1155, found
268.1136.
(Hb, dd, J = 9.6, 2.5 Hz, COCHaHb), 3.86 (Hb, d,
J = 15.8 Hz, CHaHbCO2), 4.78 (1H, d, J = 8.9 Hz,
NCH), 5.2 (1H, s, OH), 5.58 (1H, d, J = 8.7 Hz, NH),
7.24 (6H, m, PhH), 7.53 (4H, m, PhH); 13C NMR
(75.5 MHz, CDCl3) d 28.1, 28.3, 54.5, 69.4, 72.9, 79.5,
81.1, 82.4, 125.2, 125.6, 126.7, 126.8, 128.1, 128.4,
144.6, 145.8, 155.8, 168.8; MS (ESI) m/z 480
[M+Na]+, 424, 368; HRMS (ESI) (M+Na)+: m/z calcd
for C26H35NNaO6 480.2357, found 480.2350.
4.1.19. (S)-2-(2-(tert-Butoxycarbonylamino)-3-hydroxy-
3,3-diphenylpropoxy)ethanol 24. To an ice-cold stirred
solution of 23 (2.67 g, 7.5 mmol) in ether (50 ml), LiAlH4
(0.425 g, 11.2 mmol) was added under argon over a per-
iod of 30 min. After addition, the cooling-bath was
removed and the mixture was stirred at room
temperature for 2 h. The mixture was again cooled to
0 ꢁC and water (0.44 ml), 15% aq NaOH solution
(0.44 ml) and again water (1.32 ml) were added sequen-
tially. The mixture was stirred for 10 min and filtered
through Celite. The filtrate was evaporated under vac-
uum and the resulting residue was subjected to silica
gel flash column chromatographic purification (30%
4.1.16. (S)-N-tert-Butoxycarbonyl-4-(hydroxydiphenyl-
methyl)-2,2-dimethyloxazolidine 21. Compound 21 was
obtained as a colorless solid in 83% yield from 20 using
the previously described procedure, except that 3 M
PhMgBr solution in ether was used instead of 1 M solu-
25
tion in THF: mp 127 ꢁC; ½aꢁD ¼ ꢀ8:5 (c 1.1, CHCl3); IR
(neat) 3290, 2976, 1696, 1656, 1478, 1446, 1395, 1364,
1249, 1205, 1168, 1113, 1069, 1046, 850, 813, 756, 699,
632, 616 cmꢀ1 1H NMR (300 MHz, CDCl3) d 1.19
;
(3H, s, OCCH3), 1.35 (9H, s, NCO2C(CH3)3), 1.43
(3H, s, OCCH3), 4.02 (Ha, dd, J = 9.9, 1.8 Hz,
OCHaHb), 4.11 (Hb, dd, J = 9.9, 7.1 Hz, OCHaHb),
4.96 (H, dd, J = 7, 1.7 Hz, NCH), 6.26 (1H, br s, OH),
7.31 (8H, m, PhH), 7.49 (2H, m, PhH); 13C NMR
(75.5 MHz, CDCl3) d 23.8, 25.6, 28.1, 65.5, 66.2, 81.2,
81.3, 95.4, 127.1, 127.5, 127.9, 128, 143.6, 145.3, 154.8;
MS (ESI) m/z 406 [M+Na]+; HRMS (ESI) (M+Na)+:
m/z calcd for C23H29NNaO4 406.1989, found 406.1994.
EtOAc in heptanes) to give 24 (2.642 g, 91%) as a color-
25
less solid: mp 141 ꢁC; ½aꢁD ¼ ꢀ55:7 (c 1.2, CHCl3); IR
(neat) 3425, 2976, 1681, 1494, 1448, 1391, 1366, 1249,
1
1167, 1120, 1063, 889, 858, 750, 702, 664, 642 cmꢀ1; H
NMR (300 MHz, CDCl3) d 1.36 (9H, s, NCO2C(CH3)3),
2.42 (1H, br s, OH), 3.26 (Ha, m, COCHaHb), 3.41 (Hb,
dt, J = 10.6, 4.2 Hz, COCHaHb), 3.81 (2H+Ha, m,
NCCHaHb, CH2-hydroxyl), 3.73 (Hb, dd, J = 9.9,
2.4 Hz, NCCHaHb), 4.79 (1H, d, J = 9 Hz, NCH), 4.91
(1H, br s, OH), 5.69 (1H, d, J = 9.2 Hz, NH), 7.26 (6H,
m, PhH), 7.51 (4H, m, PhH); 13C NMR (75.5 MHz,
CDCl3) d 28.3, 54.6, 61, 72.5, 72.9, 79.6, 81.3, 125,
125.5, 126.9, 127, 128.2, 128.5, 144.4, 145.6, 155.9; MS
(ESI) m/z 410 [M+Na]+, 354; HRMS (ESI) (M+Na)+:
m/z calcd for C22H29NNaO5 410.1938, found 410.1932.
4.1.17.
(S)-2-tert-Butoxycarbonylamino-1,1-diphenyl-
propane-1,3-diol 22. A suspension of 21 (1.456 g,
3.8 mmol) in 80% aq acetic acid (20 ml) was stirred at
room temperature for 24 h. The mixture was concen-
trated under vacuum below 50 ꢁC and the resulting res-
idue was purified by silica gel flash column
chromatography (50% EtOAc in heptanes) to afford 22
(1.186 g, 91%) as
a
colorless oil: mp 123 ꢁC;
28
½aꢁD ¼ ꢀ63:9 (c 1.4, CHCl3); IR (neat) 3399, 2977,
4.1.20. (S)-(2-tert-Butoxycarbonylamino-3-hydroxy-3,3-
diphenylpropoxy)-2-(methanesulfonyloxy)ethane
1681, 1503, 1449, 1392, 1366, 1247, 1166, 1061, 965,
25.
Compound 24 was mesylated with methanesulfonyl
887, 853, 749, 701, 663, 640 cmꢀ1
;
1H NMR
(300 MHz, CDCl3) d 1.36 (9H, s, OC(CH3)3), 2.24
(1H, br s, OH), 3.71 (Ha, ddd, J = 11.3, 5.2, 2.5 Hz,
CHaHb), 3.83 (Hb, dt, J = 10.7, 3 Hz, CHaHb), 4.61
(1H, s, OH), 4.67 (1H, d, J = 7.3 Hz, NCH), 5.43 (1H,
d, J = 8.3 Hz, NH), 7.25 (6H, m, PhH), 7.49 (4H, m,
PhH); 13C NMR (75.5 MHz, CDCl3) d 28.3, 55.5,
63.9, 79.8, 81.7, 125.1, 125.4, 126.9, 127, 128.2, 128.5,
144.6, 145.4, 156; MS (ESI) m/z 366 [M+Na]+; HRMS
(ESI) (M+Na)+: m/z calcd for C20H25NNaO4 366.1676,
found 366.1652.
chloride following the previously described procedure
to afford 25 as a colorless solid in 94% yield: mp
27
161 ꢁC; ½aꢁD ¼ ꢀ43:3 (c 1.2, CHCl3); IR (neat) 3443,
2976, 1704, 1494, 1449, 1352, 1250, 1172, 1127, 1063,
1
1021, 970, 923, 858, 807, 751, 704, 662, 642 cmꢀ1; H
NMR (300 MHz, CDCl3) d 1.35 (9H, s, NCO2C(CH3)3),
3.05 (3H, s, CH3), 3.44 (Ha, m, COCHaHb), 3.57 (2Hb,
m, COCHaHb, NCCHaHb), 3.73 (Ha, dd, J = 9.7,
2.4 Hz, NCCHaHb), 4.29 (2H, dd, J = 5.1, 3.8 Hz,
CH2OMs), 4.44 (1H, s, OH), 4.77 (1H, d, J = 8.9 Hz,
NCH), 5.48 (1H, d, J = 9 Hz, NH), 7.25 (6H, m,
PhH), 7.49 (4H, m, PhH); 13C NMR (75.5 MHz,
CDCl3) d 28.3, 37.7, 54.6, 67.8, 69.4, 72.9, 79.7, 81.1,
124.9, 125.5, 126.9, 127, 128.2, 128.5, 144.2, 145.4,
155.8; MS (ESI) m/z 488 [M+Na]+, 432; HRMS (ESI)
(M+Na)+: m/z calcd for C23H31NNaO7S 488.1713,
found 488.1718.
4.1.18. (S)-tert-Butyl 2-(2-(tert-butoxycarbonylamino)-3-
hydroxy-3,3-diphenylpropoxy)acetate 23. Compound
22 was coupled with tert-butyl bromoacetate using pre-
viously described procedure to furnish 23 as a colorless
25
solid in 89% yield: mp 148 ꢁC; ½aꢁD ¼ ꢀ23:3 (c 1.5,
CHCl3); IR (neat) 3439, 2976, 1705, 1492, 1391, 1366,
1
1246, 1163, 1126, 1054, 846, 749, 703 cmꢀ1; H NMR
(300 MHz, CDCl3) d 1.34 (9H, s, NCO2C(CH3)3), 1.47
(9H, s, CO2C(CH3)3), 3.47 (Ha, dd, J = 9.5, 2 Hz,
COCHaHb), 3.59 (Ha, d, J = 15.6 Hz, CHaHbCO2), 3.81
4.1.21. (S)-3-(Hydroxydiphenylmethyl)morpholine (S)-
19. Compound (S)-19 was obtained from 25 as a
colorless solid in 81% yield following the previously

400
R. Dave, N. A. Sasaki / Tetrahedron: Asymmetry 17 (2006) 388–401
25
described procedure: mp 140 ꢁC; ½aꢁD ¼ ꢀ105:5 (c 1.7,
CHCl3); IR (neat) 3434, 2852, 1596, 1492, 1449, 1350,
1316, 1172, 1143, 1106, 1058, 1032, 993, 963, 938, 893,
131.7, 138.3, 148.8; MS (ESI) m/z 382 [M+Na]+, 360
[M+H]+, 342, 167; HRMS (ESI) (M+H)+: m/z calcd
for C24H26NO2 360.1964, found 360.1956.
848, 813, 747, 703, 665, 635 cmꢀ1
;
1H NMR
(300 MHz, CDCl3) d 1.73 (1H, br s, OH), 2.81 (Ha,
ddd, J = 11.4, 2.4, 1.1 Hz, NCHaHb), 3.05 (Hb, td,
J = 11.3, 3.4 Hz, NCHaHb), 3.46 (2Ha+Hb, m, HbHa-
COCHaHb), 3.75 (Hb, ddd, J = 11.3, 3.3, 1.1 Hz,
COCHaHb), 3.85 (H, dd, J = 8.5, 4.9 Hz, NCH), 4.25
(1H, s, NH), 7.26 (6H, m, PhH), 7.48 (2H, m, PhH),
7.59 (2H, m, PhH); 13C NMR (75.5 MHz, CDCl3) d
45.6, 59.3, 66.9, 68, 77.1, 125.2, 125.7, 126.8, 127.2,
128.2, 128.7, 142.8, 145.6; MS (ESI) m/z 270 [M+H]+,
252; HRMS (ESI) (M+H)+: m/z calcd for C17H20NO2
270.1489, found 270.1483.
4.2. Typical reaction procedure for Et2Zn addition to
benzaldehyde in the presence of catalytic morpholine-
based b-amino alcohol
To
a
solution/suspension of b-amino alcohol
(0.38 mmol) in toluene (4 ml), diethylzinc (7.6 mm,
7.6 ml of 1 M hexane solution) was added at 0 ꢁC under
argon. After stirring for 30 min, benzaldehyde (403 mg,
3.8 mmol) was added and the reaction mixture stirred
for 3 h at 0 ꢁC. The cooling-bath was removed and the
mixture stirred at room temperature for another 45 h.
The reaction was quenched with 3% aq HCl solution
(15 ml) and the organic product was extracted with
EtOAc (3 · 25 ml). Combined EtOAc layer was dried
(Na2SO4) and evaporated under vacuum. The resulting
residue was purified by silica gel flash column
chromatography (8% EtOAc in heptanes) to afford
1-phenyl-1-propanol as a colorless oil. The product was
4.1.22.
(S)-N-Methyl-3-(hydroxydiphenylmethyl)mor-
pholine (S)-26. Compound (S)-26 was obtained from
(S)-19 in 87% yield as a colorless solid using the previ-
ously described procedure: mp 213 ꢁC (decomp.);
29
½aꢁD ¼ ꢀ157:2 (c 0.9, CHCl3); IR (neat) 3382, 2854,
2804, 1593, 1487, 1444, 1340, 1294, 1167, 1154, 1125,
1059, 1042, 1030, 988, 959, 899, 870, 789, 758, 748,
1
characterized by H NMR and the enantiomeric excess
713, 696, 662 cmꢀ1
;
1H NMR (300 MHz, CDCl3) d
was determined by HPLC. The absolute configuration
of the major enantiomer was assigned based on the sign
of optical rotations and from the elution order in HPLC
analysis.
1.95 (3H, s, NCH3), 2.63 (Ha, td, J = 11.6, 3.6 Hz,
NCHaHb), 2.73 (Hb, ddd, J = 12, 2.5, 1.9 Hz,
NCHaHb), 3.12 (Ha, dd, J = 12.2, 10.5 Hz, HdHcCO-
CHaHb), 3.31 (Hb, ddd, J = 12.1, 4, 1.1 Hz, HdHcCO-
CHaHb), 3.48 (Hc+1H, m, HdHcCOCHaHb, NCH),
3.76 (Hd, m, HdHcCOCHaHb), 7.22 (6H, m, PhH), 7.5
(2H, m, PhH), 7.7 (2H, m, PhH); 13C NMR
(75.5 MHz, CDCl3) d 46.5, 55.3, 65.1, 66.5, 68.5, 75.5,
124.7, 125.4, 126.4, 128.1, 128.2, 144.6, 149.4; MS
(ESI) m/z 266 [(MꢀH2O)+H]+, 167; HRMS (ESI)
[(MꢀH2O)+H]+: m/z calcd for C18H20NO 266.1539,
found 266.1525.
4.3. Typical reaction procedure for Et2Zn addition to
aldehydes in the presence of lithiated ligand
To a stirred solution of b-amino alcohol (0.38 mmol) in
toluene (4 ml), n-butyl lithium (0.38 mm, 0.2 ml of 1.6 M
hexane solution) was added under argon at ꢀ30 ꢁC. The
mixture was warmed to 0 ꢁC and stirred for 10 min. The
mixture was again cooled to ꢀ30 ꢁC and diethylzinc
(7.6 mm, 7.6 ml of 1 M hexane solution) was added over
a period of 5 min. The mixture was warmed to 0 ꢁC, stir-
red for 30 min and the aldehyde (3.8 mmol) was added.
The reaction mixture was then stirred at room tempera-
ture for 48 h. The reaction mixture was quenched with
1 M aq HCl solution (15 ml) and the organic product
extracted with EtOAc (3 · 25 ml). The combined EtOAc
layer was dried over Na2SO4 and evaporated under vac-
uum. The resulting residue was purified by silica gel flash
column chromatography (8% EtOAc in heptanes) to
afford alcohol as a colorless oil. The product was char-
4.1.23. (S)-N-Benzyl-3-(hydroxydiphenylmethyl)morphol-
ine (S)-27. To a solution of (S)-19 (1.076 g, 4 mmol) in
DMF (15 ml), K2CO3 (1.106 g, 8 mmol) and benzyl bro-
mide (0.7 ml, 6.0 mmol) were added at room tempera-
ture under argon. After stirring for 18 h, the mixture
was diluted with EtOAc (100 ml), filtered, and the fil-
trate washed sequentially with water (20 ml), 1 M HCl
(20 ml), satd NaHCO3 (20 ml), and brine (20 ml). Dry-
ing over Na2SO4 and evaporation of the solvent gave
a residue, which on silica gel flash column chromato-
graphic purification (20% EtOAc in heptanes) afforded
1
acterized by H NMR and the ee was determined by
(S)-27 (1.164 g, 81%) as a colorless solid: mp 102 ꢁC;
HPLC. The absolute configuration of the major enan-
tiomer was assigned based on the sign of optical rota-
tions and from the elution order in HPLC analysis.
28
½aꢁD ¼ ꢀ81:4 (c 1.0, CHCl3); IR (neat) 3304, 3027,
2855, 1595, 1493, 1448, 1376, 1298, 1171, 1130, 1114,
1058, 1026, 1009, 956, 906, 875 cmꢀ1
;
1H NMR
(300 MHz, CDCl3) d 2.38 (Ha, ddd, J = 12.9, 9.4,
3.5 Hz, NCHaHb), 2.87 (Ha, d, J = 13.2 Hz,
NCHaHbPh), 2.88 (Hb, m, NCHaHbC), 3.31 (Ha, dd,
J = 12.2, 9.1 Hz, HdHcCOCHaHb), 3.45 (Hb+Hc, m,
HdHcCOCHaHb), 3.71 (Hd, dt, J = 11.4, 3.6 Hz,
HdHcCOCHaHb), 3.76 (1H, dd, J = 9.1, 4.4 Hz,
NCH), 3.88 (Hb, d, J = 13 Hz, NCHaHbPh), 5.38 (1H,
br s, OH), 7.11 (4H, m, PhH), 7.26 (7H, m, PhH),
7.55 (2H, m, PhH), 7.72 (2H, m, PhH); 13C NMR
(75.5 MHz, CDCl3) d 49.9, 60.5, 63.7, 66, 68, 77.2,
124.9, 125.6, 126.5, 126.6, 127.2, 128.2, 128.4, 128.8,
4.4. Determination of alcohol enantiomeric excesses
Unless otherwise mentioned, ee values of ethylation
products were determined by HPLC analysis using Chi-
ralcel OD column (10 lm, 4.6 · 250 mmol) as the chiral
stationary phase. For 1-phenyl-1-propanol tR = 11.9
and tS = 13.7 min, flow 1.0 ml/min, hexane/2-propanol
97.5/2.5; 1-(4-methoxyphenyl)-1-propanol tR = 11.8
and tS = 13.3 min, flow 1.0 ml/min, hexane/2-propanol
96/4; 1-(2-naphthyl)-1-propanol tR = 10.4 and tS =
9.2 min, flow 1.0 ml/min, hexane/2-propanol 90/10;

R. Dave, N. A. Sasaki / Tetrahedron: Asymmetry 17 (2006) 388–401
401
8. Williams, D. R.; Brown, D. L.; Benbow, J. W. J. Am.
Chem. Soc. 1989, 111, 1923–1925.
1-phenyl-3-pentanol tR = 13.0 and tS = 20.6 min, flow
1.0 ml/min, hexane/2-propanol 97/3; 1-phenyl-1-pen-
ten-3-ol tR = 11.7 and tS = 19.6 min, flow 1.0 ml/min,
hexane/2-propanol 95/5.
9. (a) Shi, M.; Jiang, J.-K. Tetrahedron: Asymmetry 1999, 10,
1673–1679; (b) Shi, M.; Satoh, Y.; Makihara, T.; Masaki,
Y. Tetrahedron: Asymmetry 1995, 6, 2109–2112.
10. (a) Lawrence, C. F.; Nayak, S. K.; Thijs, L.; Zwanenburg,
B. Synth. Lett. 1999, 1571–1572; (b) Behnen, W.; Mehler,
T.; Martens, J. Tetrahedron: Asymmetry 1993, 4, 1413–
1416; (c) Shibata, T.; Tabira, H.; Soai, K. J. Chem. Soc.,
Perkin Trans. 1 1998, 177–178; (d) 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,
7078–7082.
11. ( )3-(Hydroxydiphenylmethyl)morpholine is known as a
hydrochloride salt: Winthrop, S. O.; Humber, L. G. J.
Org. Chem. 1960, 26, 2834–2836.
12. Rao, A. V. R.; Gurjar, M. K.; Sharma, P. A.; Kaiwar, V.
Tetrahedron Lett. 1990, 31, 2341–2344.
Acknowledgments
´ `
We thank Marie-Therese Adeline for technical assis-
tance in HPLC analyses and Institut de Chimie des Sub-
stances Naturelles (CNRS, Gif-sur-Yvette) for financial
assistance to R.D.
References
1. Pu, L.; Yu, H.-B Chem. Rev. 2001, 101, 757–824.
2. (a) Sprout, C. M.; Seto, C. T. J. Org. Chem. 2003, 68,
7788–7794; (b) Richmond, M. L.; Seto, C. T. J. Org.
Chem. 2003, 68, 7505–7508; (c) Sprout, C. M.; Richmond,
M. L.; Seto, C. T. J. Org. Chem. 2004, 69, 6666–6673.
3. (a) Nugent, W. A. Org. Lett. 2002, 4, 2133–2136; (b)
Nugent, W. A. Chem. Commun. 1999, 1369–1370; (c)
Nugent, W. A. Patent No. US6187918, February 13, 2001
4. For a recent review article see: Wijtmans, R.; Vink, M. K.
S.; Schoemaker, H. E.; van Delft, F. L.; Blaauw, R. H.;
Rutjes, F. P. J. T. Synthesis 2004, 641–662.
5. Dave, R.; Sasaki, N. A. Org Lett. 2004, 6, 15–18.
6. Although, (S)-3-(hydroxymethyl)morpholine (S)-6 is cited
in the following patents, there is no information on
analytical data; (a) Bradbury, R. H.; Hennequin, L. F. A.;
Kettle, J. G. Patent No. WO2005026152, March 03, 2005.;
(b) Heron, N. M.; Pasquet, G. R.; Mortlock, A. A.; Jung,
F. H. Patent No. WO2004094410, November 04, 2004.; (c)
Miyake, H.; Take, K.; Shigenaga, S.; Azami, H.; Sasaki,
H.; Eikyu, Y.; Nakai, K.; Ishida, J.; Manabe, T.; Konishi,
N.; Terasaka, T. Patent No. WO9857954, December 23,
1998.; (d) Fukuda, Y.; Shimazawa, R.; Oomori, Y.;
Terashima, S. Patent No. WO9832757, July 30, 1998.
Tyger Scientific Inc., NJ, USA, is a commercial vendor of
(S)-3-(hydroxymethyl)morpholine (price is $1500/g).
7. During the initial synthesis, when chloroacetyl chloride
was used as the coupling agent instead of tert-butyl
bromoacetate, (S)-6 was obtained in four steps in 12%
overall yield starting from 1; Nozulak, J.; Vigouret, J. M.;
Jaton, A. L.; Hofmann, A.; Dravid, A. R.; Weber, H. P.;
Kalkman, H. O.; Walkinshaw, M. D. J. Med. Chem. 1992,
35, 480–489.
13. Koskinen, A. M. P.; Hassila, H.; Myllymaki, V. T.;
Rissanen, K. Tetrahedron Lett. 1995, 36, 5619–5622.
14. (S)-N-Benzyl-3-(hydroxydiphenylmethyl)morpholine
is
reported by Ogata et al. in racemic form: Ogata, M.;
Matsumoto, H.; Kano, H. Kogyo Kagaku Zasshi 1969, 72,
195–196.
15. If the reaction with (S)-19 and (S)-26 involves the same
transition state as with (S)-6 then the expected absolute
configuration of the product is (R).
16. (a) Noyori, R.; Kitamura, M. Angew. Chem., Int. Ed.
Engl. 1991, 30, 49–69; (b) Yamakawa, M.; Noyori, R. J.
Am. Chem. Soc. 1995, 117, 6327–6335; (c) Kitamura, M.;
Suga, S.; Oka, H.; Noyori, R. J. Am. Chem. Soc. 1998,
120, 9800–9809.
17. (a) Corey, E. J.; Hannon, F. J. Tetrahedron Lett. 1987, 28,
5233–5236; (b) Soai, K.; Ookawa, A.; Kaba, T.; Ogawa,
K. J. Am. Chem. Soc. 1987, 109, 7111–7115; (c) de Vries,
E. F. J.; Brussee, J.; Kruse, C. C.; van der Gen, A.
Tetrahedron: Asymmetry 1993, 4, 1987–1990; (d) Vidal-
Ferran, A.; Moyano, A.; Pericas, M. A.; Riera, A. J. Org.
Chem. 1997, 62, 4970–4982; (e) Mehler, T.; Martens, J.
Tetrahedron: Asymmetry 1994, 5, 207–210.
18. (a) Yamakawa, M.; Noyori, R. Organometallics 1999, 18,
128–133; (b) Soai, K.; Niwa, S. Chem. Rev. 1992, 92, 833–
856; (c) Vyskocil, S.; Jacarz, S.; Smrcina, M.; Hanus, V.;
Polasek, M.; Kocovsky, P. J. Org. Chem. 1998, 63, 7727–
7737; (d) Watanabe, M.; Araki, S.; Butsugan, Y.; Uemura,
M. J. Org. Chem. 1991, 56, 2218–2224; (e) Goldfuss, B.;
Houk, K. N. J. Org. Chem. 1998, 63, 8998–9006.
19. Ho, T.-L. Hard and Soft Acids and Bases Principle in
Organic Chemistry; Academic: New York, 1977; Chapter
2.