Design, synthesis and structure of new chiral squaric acid monoaminoalcohols and diaminoalcohols and their use as catalysts in asymmetric reduction of ketones and diketones

Article abstract of DOI:10.1016/S0040-4020(01)00936-X

Many chiral squaric acid aminoalcohols and C₂-symmetric diaminoalcohols have been synthesized and their in situ formed chiral boron heterocycles have been used as catalysts for the enantioselective reduction of prochiral ketones and diketones by borane to give alcohols with up to 99% enantiomeric excess and 99% yield. The effects of solvent, catalyst-substrate ratio and temperature were also investigated.

Full text of DOI:10.1016/S0040-4020(01)00936-X

TETRAHEDRON
Pergamon
Tetrahedron 57 >2001) 9325±9333
Design, synthesis and structure of new chiral squaric acid
monoaminoalcohols and diaminoalcohols and their use as
catalysts in asymmetric reduction of ketones and diketonesq
Hai-Bing Zhou,a Ji Zhang,a Shou-Mao LuÈ,a Ru-Gang Xie,a,p Zhong-Yuan Zhou,b
c
Michael C. K. Choi,b Albert S. C. Chanb andTeng-Kuei Yang
aDepartment of Chemistry, Sichuan University, Chengdu 610064, People's Republic of China
bOpen Laboratory of Chirotechnology and Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic
University, Hong Kong, People's Republic of China
cDepartment of Chemistry, National Chung-Hsing University, Taichung, Taiwan, ROC
Received21 June 2001; revised29 August 2001; accepted20 September 2001
AbstractÐMany chiral squaric acidaminoalcohols and C2-symmetric diaminoalcohols have been synthesized and their in situ formed chiral
boron heterocycles have been used as catalysts for the enantioselective reduction of prochiral ketones and diketones by borane to give
alcohols with up to 99% enantiomeric excess and99% yield. The effects of solvent, catalyst±substrate ratio andtemperature were also
investigated. q 2001 Elsevier Science Ltd. All rights reserved.
1. Introduction
selective catalysts, we initiated a study to develop new
bifunctional ligands.
The reduction of ketones to enantiomerically enriched
alcohols remains a fundamental asymmetric transforma-
tion.2 Many asymmetric catalysts have been developed for
the reduction of ketones by borane, and the most signi®cant
catalyst, oxazaborolidines, have been extensively
reviewed.3 However, in this regard, most of the ligands
are derived from natural compounds such as amino acids,4
camphor5 etc. andin many cases these ligands are usually
basedon the basic amino alcohol skeleton andare incon-
venient to modify for a practical purpose. From a practical
point of view, it is important to develop effective and
versatile chiral ligands that are easy to modify so that highly
enantioselective catalysts can be screened. Recently, some
chiral aminoalcohols containing electron-withdrawing
groups such as phosphosphinamidoalcohols6 andsulfon-
amidoalcohols7 were developed and successfully used as
bifunctional catalysts8 in the enantioselective reduction of
ketones using borane. However, the reactive intermediate>s)
involvedin these catalytic reactions remain poorly under-
stoodandin most cases enantioselectivity needs a further
improvement. In order to ®nd highly effective and stereo-
Squaric acidhas long been known as an aromatic compound
with unique character andwide applications. 9 Basedon the
cyclobutenedione structure, the acidic hydroxyl groups can
be replacedby various functional groups so that versatile
chiral ligands can be conveniently prepared. However, to
the best of our knowledge, previous synthesis of chiral
derivatives of squaric acid was rare.10 Herein, we wish to
report our work on the synthesis of two types of versatile
new chiral ligands, monoaminoalcohols and C2-symmetric
diaminoalcohols of squaric acid, and a procedure for their
use as improvedcatalysts in asymmetric carbonyl reduction.
The advantages of the structures are that the rigid ring of
squaric acidcan be attachedto either one or two chiral
amino alcohols and, at the same time, the rigid ring moiety
provides an ef®cient chiral environment for coordination of
the substrate as well as the reagent in the reaction. The
squaric acidmonoaminoalcohols can serve as prototypical
examples of bifunctional catalysts, since the C-3 position of
the squaric acidring can be conveniently modi®edby intro-
ducing a second functional group, which can preferentially
coordinate with the borane. Furthermore, the intramolecular
delivery of hydride to the carbonyl group may proceed in a
highly selective manner by changing the size of the C-3
substituent. The C2-symmetric squaric aciddiaminoalcohols
have two catalytic centers, which may serve as bifunctional
catalysts for the reduction of prochiral ketones, especially
diketones.
q See Ref. 1.
Keywords: asymmetric synthesis; enantioselective reduction; squaric
aminoalcohol and diaminoalcohols; prochiral ketones and diketones.
p
Corresponding author. Fax: 186-28-5412285;
e-mail: schemorg@mail.sc.cninfo.net
0040±4020/01/$ - see front matter q 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020>01)00936-X

9326
H.-B. Zhou et al. / Tetrahedron 57 02001) 9325±9333
Scheme 1. Reaction conditions: >i) diester squarate/b-amino alcohols/Et3Nˆ1.1:1:1, EtOH. >ii) RNH2, EtOH. >iii) NaHS, HCl, EtOH. >iv) K2CO3, CH3I,
CH3COCH3. >v) 2N HCl, EtOH, re¯ux.
2. Results and discussion
5c, respectively. Unlike the ligands 3 and 6, the alkylthio
squaric acidaminoalcohol 8 couldnot be prepareddirectly
by reacting alkylthioalcohols with squaric acidamino-
2.1. Synthesis and characterization of ligands
11
alcohol esters, which only ledto a complex result.
An
alternative methodwas used, reactions of thio-sqauric acid
7 with methyl iodide in the presence of K2CO3 gave the
aminoalcohol 8. The squaric acids 4 and 7 were prepared
by the reactions of 2b and 5c with aqueous sodium thiolate
followed by the treatment with hydrochloric acid.
Two types of chiral squaric acidaminoalcohols were
derived from squaric acid diester 1 and b-amino alcohols
as shown in Scheme 1. Squaric acidaminoalcohols 2 and 5
were preparedby the reaction of chiral aminoalcohols with a
slight excess of squaric aciddiesters in the presence of
triethylamine in ethanol or ether at ambient temperature.
Aminoalcohol 5a was obtainedwhen the ester group of 5c
was hydrolyzed. In order to investigate the effect of the
substituent at C-3 of squaric acidon the reduction, we intro-
duced other heteroatoms such as nitrogen or sulfur to this
C2-symmetric squaric aciddiaminoalcohols 9±11 can be
conveniently preparedby the reaction of 2 equiv. of
b-amino alcohols with squaric aciddiester 1 >Scheme 2).
All of the new ligands were characterized by IR, 1H NMR,
MS andelemental analysis, the results conformedwell with
site. The amino substitutedsquaric acidaminoalcohols
and 6 can be preparedfrom the ammonolysis of 2b and
3
Scheme 2.

H.-B. Zhou et al. / Tetrahedron 57 02001) 9325±9333
9327
Figure 1. ORTEP drawing scheme and cell stacking for ligand 2b.
Figure 2. Crystal structure andcell packing of ligand>1 0R,20S)-5c.
the expectedstructures, in which the structures of ligands
0
>Fig. 1). Similar to the crystal structure of the ligands
>10R,20S)-5b, the structure determination >Fig. 2) of
>10R,20S)-5c reveals that the unit cell contains two
molecules with slightly different conformation. The
molecules are linkedby O±H´´´O andN±H´´´O hydrogen
bonds to form a two-dimensional network. While for
12
2b, >10R,20S)-5b, >10R,20S)-5c and>1 S,20R)-5e were also
con®rmedby X-ray analysis.
The main feature of the crystal packing in 2b is that every
two molecules are linked by O±H´´´O hydrogen bonds
Figure 3. Crystal structure andcell packing of ligand>1 0S,20R)-5e.

9328
H.-B. Zhou et al. / Tetrahedron 57 02001) 9325±9333
Table 1. The enantioselective catalytic reduction of prochiral ketones with
BH3´Me2S by using 10 mol% of ligands 5±8
compound 5e, in which the amino alcohol moiety has
opposite con®guration andhas a steric benzyl group at
C-3 of squaric acid, the crystal structure has a large
difference. The main feature of this crystal stacking is
that both layers were holdtogether through p±p stack-
ing effect of phenyls andsquaric acidmoieties. Every
four molecules were linkedby O±HO andN±HO
hydrogen bonds within a layer and form a supra-
molecular system >Fig. 3).
a
Entry
LigandSolvent
Ketone
ee %
Con®gurationb
1
2
3
4
5
6
7
8
>10R,20S)-5a Toluene PhCOCH2Br
>10R,20S)-5b Toluene PhCOCH2Br
>10R,20S)-5c Toluene PhCOCH2Br
>10S,20R)-5c Toluene PhCOCH2Br
>10R,20S)-5d Toluene PhCOCH2Br
>10S,20R)-5d Toluene PhCOCH2Br
>10R,20S)-5e Toluene PhCOCH2Br
>10S,20R)-5e Toluene PhCOCH2Br
58
61
75
75
82
82
52
52
62
62
76
57
25
69
52
49
22
61
40
52
63
52
R
R
R
S
R
S
R
S
2.1.1. Effect of the solvent. On observing the effect of
solvent on the reduction, it was found that toluene is the
best solvent for the reduction. Lower ees were obtained
when using dichloromethane or THF as solvent >Table 1,
entries 12±14 and16±18).
9
6a
6b
7
Toluene PhCOCH2Br
Toluene PhCOCH2Br
Toluene PhCOCH2Br
R
R
R
R
R
R
S
S
S
S
S
10
11
12
13
14
15
16
17
18
19
20
21
22
8
THF
PhCOCH2Br
8
8
CH2Cl2 PhCOCH2Br
Toluene PhCOCH2Br
>10R,20S)-5b Toluene PhCOMe
>10R,20S)-5c THF
PhCOMe
2.1.2. Effect of the temperature. We carriedout the reduc-
tion of ketones at various temperatures andthe results are
summarizedin Table 2. The results inidcate that the
temperature has a critical effect on the reduction. The opti-
mum reaction temperature was foundto be about 50 8C
>entries 2 and5). Either raising or lowering the temperature
might leadto a decrease of the ee.
>10R,20S)-5c CH2Cl2 PhCOMe
>10R,20S)-5c Toluene PhCOMe
>10R,20S)-5d Toluene PhCOMe
6a
7
8
Toluene PhCOMe
Toluene PhCOMe
Toluene PhCOMe
S
S
S
Unless otherwise noted, all experiments were conducted at 508C andthe
chemical yields were 85±100%.
2.1.3. Effect of the catalyst±substrate ratio. The molar
ratio of the ligandto the substrate was also an important
factor in¯uencing the enantioselectivity of the resulting
alcohol >Table 3), the optimum ligand-to-substrate ratio
was about 10 mol% for monoaminoalcohols >entries 3, 5
and8) and5 mol% for diaminoalcohols >entry 11). Further
increasing the amount of ligandledto a decrease of the ee.
The reasons for these phenomena are the possibility of
a
The ee values were determined by capillary GC analysis with a
CP-cyclodex >0.25 mm£25 m) column.
b
The product con®guration was determined by comparison with an
authentic sample.
Table 2. Effect of temperature on the enantioselective reduction of acetophenone
Entry
LigandTemperature >
>10R,20S)-5b >0.1)
>10R,20S)-5b >0.1)
>10R,20S)-5b >0.1)
>10R,20S)-5c >0.1)
>10R,20S)-5c >0.1)
>10R,20S)-5c >0.1)
8C)
Solvent
Ketone
ee %a
Con®gurationb
1
2
3
4
5
6
30
50
70
30
50
70
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
PhCOMe
PhCOMe
PhCOMe
PhCOMe
PhCOMe
PhCOMe
43
52
42
45
61
47
S
S
S
S
S
S
The chemical yields were 85±100%.
The ee values were determined by capillary GC analysis with a CP-cyclodex >0.25 mm£25 m) column.
a
b
The product con®guration was determined by comparison with an authentic sample.
Table 3. Effect of catalyst±substrate ratio on the enantioselective reduction of prochiral ketones
Entry
Ligand>equiv.)
Solvent
Ketone
ee % a
Con®gurationb
1
2
3
4
5
6
7
8
2a >0.025)
2a >0.05)
2a >0.1)
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
PhCOCH2Br
PhCOCH2Br
PhCOCH2Br
PhCOMe
PhCOMe
PhCOMe
PhCOCH2Br
PhCOCH2Br
PhCOCH2Br
PhCOCH2Br
PhCOCH2Br
PhCOCH2Br
92
97
99
47
61
45
72
82
72
84
92
84
S
S
S
S
S
S
R
R
R
R
R
R
>10R,20S)-5c >0.05)
>10R,20S)-5c >0.1)
>10R,20S)-5c >0.15)
>10R,20S)-5d >0.05)
>10R,20S)-5d >0.1)
>10R,20S)-5d >0.15)
9a >0.025)
9
10
11
12
9a >0.05)
9a >0.1)
Unless otherwise noted, all experiments were conducted at 508C andthe chemical yields were 85±100%.
The ee values were determined by capillary GC analysis with a CP-cyclodex >0.25 mm£25 m) column.
a
b
The product con®guration was determined by comparison with an authentic sample.

H.-B. Zhou et al. / Tetrahedron 57 02001) 9325±9333
9329
Table 4. The enantioselective catalytic reduction of prochiral ketones with
BH3´Me2S by using 10 mol% of ligands 2±4 at 508C in toluene
gave a slightly lower ee, in the reduction of v-bromo-
acetophenone, up to 94 and96% ee were obtainedby
using 3a and 3b, respectively >entries 3 and4).
Ligands 5±8 which possess ¯exible chiral 2-amino-1,2-
diphenylethanol moiety exhibited moderate to good
enantioselectivity in the reduction, and the substituents at
C-3 of squaric acidhave an effect on the ee of the resulting
alcohols. In ligands 5a±d, the ee values increase with the
chain length of the alkoxy group >Table 1, entries 1±6). The
lower ee by ligand 5e might be due to the steric repulsion
between the phenyl ring of ligandandthe aryl ketone, which
obstructs the latter from getting in close proximity to the
catalytic center >entries 7 and8). The use of butylamino
squaric acidaminoalcohols 6 ledto a decrease in ee >entries
9 and10). The thiohydroxy squaric acid 7 gave an ee value
comparable to 8, in which a methylthio group is on the C-3
position >entry 11 and14).
a
Entry
LigandKetone
ee %
Con®gurationb
1
2
3
4
5
6
7
8
2a
2b
3a
3b
4
2a
3b
4
PhCOCH2Br
99
98
94
96
99
97
94
95
S
S
S
S
S
R
R
R
PhCOCH2Br
PhCOCH2Br
PhCOCH2Br
PhCOCH2Br
PhCOMe
PhCOMe
PhCOMe
The chemical yields were 85±100%.
The ee values were determined by capillary GC analysis with a
CP-cyclodex >0.25 mm£25 m) column.
a
b
The product con®guration was determined by comparison with an
authentic sample.14
As expected, using the opposite enantiomers of the ligands
gave alcohols with opposite con®gurations andessentially
identical ees >Table 1, entries 3±8). The reduction of
v-bromo-acetophenone consistently gave higher ees as
comparedto the reduction of the acetophenone.
forming multinuclear aggregates of achiral catalysis in the
reaction system.13
2.2. Effect of the structure of ligands on the
enantioselectivity of the asymmetric reduction
The enantioselective reduction of prochiral ketones and
diketones catalyzed by bisoxazaborolidines is relatively
rare.15,16 Herein we report the results of our study of the
use of C2-symmetric squaric aciddiaminoalcohols 9±11
in this enantioselective reaction >Table 5). The diamino-
alcohols which have two catalytic centers seem particularly
favorable in the enantioselective reduction of prochiral
diketones: ees of up to 99% were obtained in the reduction
of 1,6-diphenyl-1,6-hexanedione with 10 mol% of ligands 9
and 11 >entries 8, 9 and13). In the reduction of v-bromo-
acetophenone, up to 92% ee was obtainedwith only 5 mol%
of ligands 9a and 9b >entries 1 and2). It is probably due to
the co-operative effect of a bifunctional catalyst with the
substrate or the enhancedrigideffect.
In order to examine the effect of the structure of the catalysts
on the reaction, enantioselective reduction of prochiral
ketones by borane were conducted at 508C in the presence
of a catalytic amount >10 mol%) of various squaric acid
aminoalcohols. Almost all catalysts afforded product
alcohols in over 90% synthetic yields. The results indicated
that the ligandstructure is critical for enantioselectivity
in the reduction. Catalysts 2±4 which possess a rigid
pyrrolidinylmethanol moiety always gave high enantio-
selectivities, up to 99% yieldand99% ee were obtained
in the reduction of v-bromo-acetophenone with ligands
2a, 2b and 4 >Table 4, entries 1, 2 and5). The ligands
3
Table 5. The enantioselective reduction of prochiral ketones and diketones with BH3´Me2S catalyzedby diaminoalcohols of squaric acid
Entry
Ligand>equiv.)
Ketone
[ a]D20 >c, MeOH)
Meso/>R,R1S,S)
ee %a
Con®gurationb
1
2
3
4
5
6
7
8
9a >0.05)
9b >0.05)
9a >0.05)
9a >0.1)
9b >0.05)
10 >0.1)
11 >0.1)
9a >0.1)
9b >0.1)
9a >0.1)
9b >0.1)
10 >0.1)
11 >0.1)
PhCOCH2Br
PhCOCH2Br
PhCOMe
PhCOCH2Br
PhCOMe
PhCOCH2Br
PhCOCH2Br
PhCO>CH2)4COPh
PhCO>CH2)4COPh
PhCO>CH2)3COPh
PhCO>CH2)3COPh
PhCO>CH2)4COPh
PhCO>CH2)4COPh
92a
92a
81a
84a
81a
35
R
S
S
R
R
S
R
>S,S)
>R,R)
>S,S)
>R,R)
>R,R)
>S,S)
82
213.87 >1.5)
113.57 >1.5)
213.57 >1.5)
113.87 >1.5)
17.87 >1.5)
213.87 >1.5)
3/97
3/97
8/92
8/92
18/82
3/97
99c
99c
86c
86c
61d
99d
9
10
11
12
13
Unless otherwise noted, all experiments were conducted at 508C andthe chemical yields were 85±100%.
The ee values were determined by capillary GC analysis with a CP-cyclodex >0.25 mm£25 m) column.
a
b
The product con®guration was determined by comparison with an authentic sample.
The ee% and meso% of chiral diols were determined by HPLC with Chiralpak AS column.
The ee% and meso% of chiral diol were determined by HPLC with Whelk-01 column.
c
d

9330
H.-B. Zhou et al. / Tetrahedron 57 02001) 9325±9333
repeatedthree times. Finally the alcohol was removed
under reduced pressure as dry as possible. The resulting
diesters were puri®ed by ¯ash chromatography >petroleum
ether/ethyl acetate, 6:1) or directly used in the following
procedure without puri®cation.
3.2. General procedure for the synthesis of ligands 2 and
5b±5e
To a solution of squaric aciddiester 1 >1.1 mmol) in dry
ethanol or ether >10 mL) was added slowly a solution of
b-amino alcohols >1.0 mmol) in ethanol or ether >10 mL)
over 2±3 h at room temperature in the presence of triethy-
lamine >1.0 mmol). The reaction was monitoredby TLC and
after completion >,24 h), the solvent was removedunder
reduced pressure. Further puri®cation was achieved by
either crystallization from ethanol >5b) or column chroma-
tography >petroleum ether/ethyl acetate, 1:1).
Figure 4. Postulatedreactive complexes.
2.3. Possible mechanisms
One reactive intermediate proposed by Corey14a couldbe a
clue to explain the mechanism of borane reduction
catalyzedby squaric aminoalcohols 5±8. The secondBH
3
molecule coordinates with the nitrogen atom on the
oxazaborolidine cycle to form the oxazaborolidine´BH3
complex. We postulate the reactive complexes as the
transition state model of the borane reduction catalyzed by
squaric prolinols 2±4 shown in Fig. 4. Two possibilities
such as A >Corey's mechanism14a) and B can be considered
andfurther studies are underway. In B, because there is no
hydrogen on the N atom of the prolinol and owing to the
steric block of the squaric ring, it is likely that the borane
molecule may combine with the heteroatom >such as nitro-
gen, oxygen or sulfur atom) at the C-3 position of the
ligands to form an eight-membered boron heterocycle
complex with both donor and acceptor groups which may
interact with a molecule of BH3 andketone. Then the car-
bonyl compoundwill orient itself anti to the prolinol portion
for steric reasons, the attack of hydride occurs through a six-
memberedcycle on the si face of the complexedketone
within a most reactive distance. So the absolute con®gura-
tion of the product alcohol may be estimated in advance.
3.2.1. 3-Ethoxy-4-[420S)-20-4diphenylhydroxymethyl) pyr-
rolidino]-3-cyclobutene-1,2-dione 2a. Colorless ¯ake.
20
65% yield. Mp 106±1078C. [a]D ˆ2175.3 >c 0.8,
CH2Cl2). IR n: 3403, 3032, 2966, 2885, 1799, 1707, 1608,
1585 cm21. dH >200 MHz, CDCl3): 1.33 >t, Jˆ7.2 Hz, 3H,
CH3), 2.04 >m, 2H, CH2), 2.76 >m, 3H, CH2), 3.33 >m, 2H,
CH2), 4.69 >q, Jˆ7.2 Hz, 2H, CH2O), 5.18 >s, 1H, CH),
7.24±7.54 >m, 10H, 2ArH). MS >EI) m/z 378 >M111, 30),
360, 195 >100). Anal. Calcdfor C 23H23NO4: C, 73.18, H,
6.15, N, 3.71. Found: C, 73.01, H, 6.11, N, 3.66.
3.2.2. 3-Butoxy-4-[420S)-20-4diphenylhydroxymethyl) pyr-
rolidino]-3-cyclobutene-1,2-dione 2b. Colorless ¯ake.
20
65% yield. Mp 162±1638C. [a]D ˆ2184.0 >c 0.5,
CH2Cl2): IR n: 3351, 3012, 2951, 2887, 1800, 1702,
1589 cm21. dH >300 MHz, CDCl3): 1.10 >m, 3H, CH3),
1.56 >m, 2H, CH2), 1.71±1.90 >m, 4H, 2CH2), 2.17±2.36
>m, 2H, CH2), 3.34 >br, 1H, OH), 3.61±3.80 >m, 2H, CH2),
4.85 >m, 2H, CH2O), 5.31 >m, 1H, CH), 7.38±7.48 >m, 10H,
2ArH). MS >EI) m/z: 406 >M111, 30), 332, 223, 166 >100).
Anal. Calcdfor C 25H27NO4: C, 74.04, H, 6.72, N, 3.46.
Found: C, 73.98, H, 6.68, N, 3.45.
3. Experimental
Melting points were taken on a micro-melting apparatus and
the data were uncorrected. Optical rotations were measured
on a WZZ-1 polarimeter. IR spectra were measuredon
FT-IR 16PC infraredspectrophotometer with KBr disc. 1H
NMR spectra were recorded at Bruker DPX-400 MHz,
Bruker DPX-300 MHz andBruker AC-E 200 MHz and
chemical shifts in ppm are reportedrelative to internal
Me4Si. Mass spectral data were recorded on a Finnigan
MAT 4510 spectrometer. Elemental analyses were
performedwith Carlo Erba 1106 instrument. Column
chromatography using SiO2 >230±400 mesh). Dichloro-
methane, tetrahydrofuran and toluene were puri®ed accord-
ing to the standard methods. All other chemicals and
reagents were obtainedcommercially andusedwithout
further puri®cation.
3.2.3. 3-Ethoxy-4-[410R,20S)-420-hydroxy-10,20-dipheny-
lethyl)amino]-3-cyclobutene-1,2-dione 5b. Colorless
20
¯ake. 75% yield. Mp 213±2158C. [a]D ˆ276.8 >c 1.0,
THF). IR n: 3392, 3262, 3012, 2963, 1807, 1694,
1605 cm21. dH >200 MHz, DMSO-d6): 1.31 >q, Jˆ7.5 Hz,
3H CH3), 3.44 >m, 1H, OH), 4.51±4.67 >m, 2H, CH2O), 4.84
>d, Jˆ10.4 Hz, 1H, CH), 5.23±5.61 >m, 1H, CH), 7.28±7.41
>m, 10H, 2ArH), 9.10 >2d, Jˆ9.7 Hz, 1H, NH). MS >EI) m/z:
406 >M111, 30), 332, 223, 166, 110. Anal. Calcdfor
C20H19NO4: C, 83.05, H, 5.68, N, 4.15. Found: C, 82.78,
H, 5.50, N, 3,97.
3.2.4. 3-Butoxy-4-[410R,20S)-420-hydroxy-10,20-diphenyl-
ethyl)amino]-3-cyclobutene-1,2-dione
5c.
Colorless
20
3.1. General procedure for the synthesis of diesters of
squaric acid 1
¯ake. 85% yield. Mp 104±1058C. [a]D ˆ2100.0 >c 1.0,
EtOH). IR n: 3437, 3232, 3018, 2963, 1804, 1691,
1610 cm21. dH >400 MHz, CDCl3): 0.92 >s, 3H, CH3),
1.33 >m, 2H, CH2), 1.67 >m, 2H, CH2), 3.31 >s, 1H, OH),
4.75 >m, 2H, CH2O), 4.93 >m, 1H, CH), 5.24 >d, Jˆ4.6 Hz,
1H, CH), 7.09±7.28 >m, 10H, 2ArH), 9.39±9.80 >m, 1H,
NH). MS >EI) m/z: 365 >M1, 15). Anal. Calcdfor
Squaric acid >1.1 mmol) was added to the alcohols >10 mL)
andthe mixture was re¯uxedfor 3 h. Alcohol was removed
to about 5 mL under vacuum and further alcohol >10 mL)
were added and re¯uxed for 0.5 h. This procedure was

H.-B. Zhou et al. / Tetrahedron 57 02001) 9325±9333
9331
C22H23NO4: C, 72.29, H, 6.35, N, 3.84. Found: C, 72.54, H,
6.48, N, 3.69.
graphy >petroleum ether/ethyl acetate, 1:4) and 7 was
obtainedby recrystallization from a mixture of ethanol
anddichloromethane.
3.2.5. 3-Butoxy-4-[410S,20R)-420-hydroxy-10,20-diphenyl-
ethyl)amino]-3-cyclobutene-1,2-dione
5c.
Colorless
3.3.1. 3-Butylamino-4-[420S)-20-4diphenylhydroxymethyl)
pyrrolidino]-3-cyclobutene-1,2-dione 3a. Colorless ¯ake.
20
¯ake. 87% yield. Mp 104±1058C. [a]D ˆ1102.0 >c 1.0,
EtOH). IR n: 3390, 3268, 3010, 2962, 1806, 1698,
1600 cm21. dH >400 MHz, CDCl3): 0.92 >s, 3H, CH3),
1.30 >m, 2H, CH2), 1.65 >m, 2H, CH2), 3.27 >s, 1H, OH),
4.73 >m, 2H, CH2O), 4.93 >m, 1H, CH), 5.23 >d, Jˆ4.6 Hz,
1H, CH), 7.08±7.28 >m, 10H, 2ArH), 9.36±9.81 >m, 1H,
NH). MS >EI) m/z: 365 >M1, 20). Anal. Calcdfor
C22H23NO4: C, 72.29, H, 6.35, N, 3.84. Found: C, 72.12,
H, 6.21, N, 3.47.
20
96% yield. Mp 62±648C. [a]D ˆ2159.7 >c 0.72, AcOEt).
1
IR n: 3279, 3075, 1791, 1662, 1566, 1512 cm21. H NMR
>CDCl3) dH: 0.93 >t, Jˆ7.3 Hz, 3H, CH3), 1.52±1.64 >m,
6H, ±CH2±), 3.68 >qd, Jˆ6.7, 2.0 Hz, 2H, ±CH2N±), 3.77
>t, Jˆ9.9 Hz, 2H, ±CH2N±), 5.10 >d, Jˆ7.1 Hz, 1H,
±CHN±), 5.86 >s, 1H, OH), 7.26±7.39 >m, 10H, ArH),
7.81 >d, Jˆ7.1 Hz, 1H, NH). MS >EI) m/z: 405 >M111,
95). Anal. Calcdfor C 25H28N2O3: C, 74.23, H, 6.98, N,
6.93. Found: C, 74.67, H, 6.87, N, 6.89.
3.2.6. 3-Hexyloxy-4-[410R,20S)-420-hydroxy-10,20-diphenyl-
ethyl)amino]-3-cyclobutene-1,2-dione 5d. Pale yellow oil.
3.3.2. 3-Benzylamino-4-[420S)-20-4diphenylhydroxymethyl)
pyrrolidino]-3-cyclobutene-1,2-dione 3b. Flake. 80%
20
85% yield. [a]D ˆ22.4 >c 2.5, CH2Cl2). IR n: 3402, 3265,
2931, 1805, 1704, 1600 cm21. dH >200 MHz, CDCl3): 0.86±
0.96 >m, 3H, CH3), 1.22±1.28 >br, 6H, 3CH2), 1.68 >m, 2H,
CH2), 2.51 >br, 1H, OH), 4.57±4.67 >m, 2H, CH2O), 4.90
>m, 1H, CH), 5.25 >d, Jˆ4.8 Hz, 1H, CH), 7.10±7.30 >m,
10H, 2ArH), 7.68 >m, 1H, NH). MS >EI) m/z: 394 >M111,
60). Anal. Calcdfor C 24H27NO4: C, 73.24, H, 6.92, N, 3.56.
Found: C, 73.16, H, 6.56, N, 3.78.
20
yield. Mp 172±1748C. [a]D ˆ2210 >c 1.15, CH2Cl2). IR
1
n: 3275, 1790, 1666, 1565, 1509 cm21. H NMR >DMSO-
d6) dH: 0.93 >d, Jˆ6.7 Hz, 2H, ±CH2±), 1.73±1.76 >m, 2H,
±CH2±), 1.89±2.14 >m, 2H, ±CH2N±), 3.67 >br, 2H,
±CH2N±), 4.69 >t, Jˆ7.6 Hz, 1H, ±CHN±), 5.92 >s, 1H,
OH), 7.12±7.49 >m, 15H, ArH), 7.71 >d, Jˆ9.8 Hz, 1H,
NH). MS >EI) m/z: 440 >M112, 20). Anal. Calcdfor
C28H26N2O3: C, 76.69, H, 5.98, N, 6.39. Found: C, 76.47,
H, 5.91, N, 6.29.
3.2.7. 3-Hexyloxy-4-[410S,20R)-420-hydroxy-10,20-diphenyl-
ethyl)amino]-3-cyclobutene-1,2-dione 5d. Pale yellow oil.
20
85% yield. [a]D ˆ12.4 >c 2.5, CH2Cl2). IR n: 3402, 3265,
3.3.3.
3-Butylamino-4-[410R,20S)-420-hydroxy-10,20-di-
phenylethyl)amino]-3-cyclobutene-1,2-dione 6a. White
2931, 1805, 1704, 1600 cm21. dH >200 MHz, CDCl3): 0.86±
0.96 >m, 3H, CH3), 1.22±1.28 >m, 6H, 3CH2), 1.68 >m, 2H,
CH2), 2.51 >br, 1H, OH), 4.57±4.67 >m, 2H, CH2), 4.90 >m,
1H, CH), 5.25 >d, Jˆ4.8 Hz, 1H, CH), 7.10±7.30 >m, 10H,
2ArH), 7.68 >br, 1H, NH). MS >EI) m/z: 394 >M111, 60).
Anal. Calcdfor C 24H27NO4: C, 73.24, H, 6.92, N, 3.56.
Found: C, 73.16, H, 6.56, N, 3.78.
20
solid. 82% yield. Mp 262±2648C. [a]D ˆ15.0 >c 0.5,
DMSO). IR n: 3410, 3185, 2941, 1800, 1646, 1558 cm21
.
dH >200 MHz, DMSO-d6): 0.91 >tr, Jˆ7.5 Hz, 3H, ±CH3),
1.25±1.60 >m, 3H, 2-CH2±), 3.40 >m, 3H, ±CH2±, OH),
5.03 >m, 1H, CH), 5.25 >m, 1H, CH), 7.12±7.28 >m, 10H,
±ArH), 7.40 >s, H, ±NH±), 7.80 >d, Jˆ8.4 Hz, 1H, ±NH±).
MS >EI) m/z: 365 >M111, 30). Anal. Calcdfor C 22H24N2O3:
C, 72.50, H, 6.64, N, 7.69. Found: C, 72.61, H, 6.73, N, 7.54.
3.2.8.
3-Benzyloxy-4-[410R,20S)-420-hydroxy-10,20-di-
phenylethyl)amino]-3-cyclobutene-1,2-dione 5e. Color-
20
less prism. 32% yield. Mp 177±1798C. [a]D ˆ294.3 >c
3.3.4. 3-Benzylamino-4-[410R,20S)-420-hydroxy-10,20-di-
phenylethyl)amino]-3-cyclobutene-1,2-dione 6b. White
0.5, EtOH). IR n: 3441, 3169, 3002, 1805, 1706,
1598 cm21. dH >200 MHz, CDCl3): 2.93 >br, 1H, OH),
4.89 >s, 2H, CH2), 5.17 >d, Jˆ4.5 Hz, 1H, CH), 5.62 >s,
1H, CH), 6.99±7.30 >m, 15H, 3ArH), 7.36 >m, 1H, NH).
MS >EI) m/z: 400 >M111, 5). Anal. Calcdfor C 25H21NO4:
C, 75.16, H, 5.30, N, 3.51. Found: C, 74.97, H, 5.15, N, 3.26.
20
solid. 80% yield. Mp 284±2868C. [a]D ˆ117.0 >c 0.5,
DMSO). IR n: 3412, 3182, 3052, 2936, 1794, 1638,
1569 cm21. dH >200 MHz, DMSO-d6): 2.48 >m, 1H, OH),
4.71 >d, Jˆ6.0 Hz, 2H, CH2), 5.08 >m, 1H, CH), 5.34 >m,
1H, CH), 7.22±7.33 >m, 15H, 3ArH), 7.88±8.00 >m, 2H,
2NH). MS >EI) m/z: 395 >M111, 100). Anal. Calcdfor
C25H22N2O3S: C, 75.36, H, 5.57, N, 7.03. Found: C,
75.48, H, 5.52, N, 7.08.
3.2.9.
3-Benzyloxy-4-[410S,20R)-420-hydroxy-10,20-di-
phenylethyl)amino]-3-cyclobutene-1,2-dione 5e. Color-
20
less prism. 37% yield. Mp 177±1798C. [a]D ˆ193.4 >c
0.7, EtOH). IR n: 3441, 3173, 3002, 1804, 1706,
1598 cm21. dH >200 MHz, CDCl3): 2.92 >br, 1H, OH),
4.88 >s, 2H, CH2), 5.16 >d, Jˆ4.5 Hz, 1H, CH), 5.60 >s,
1H, CH), 6.89±7.26 >m, 15H, 3ArH), 7.34 >m, 1H, NH).
MS >EI) m/z: 401 >M112, 5). Anal. Calcdfor C 25H21NO4:
C, 75.16, H, 5.30, N, 3.51. Found: C, 75.01, H, 5.01, N, 3.46.
3.4. General procedure for the synthesis of ligands 4 and
7
To a solution of 2b or 5c >1.0 mmol) in ethanol >10 mL) was
added aqueous sodium hydrosul®de >1.1 mmol) dropwise at
room temperature, the yellow solution was stirredfor 3 h
then treated with hydrochloric acid. The precipitate was
®lteredoff andrecrystallizedfrom idchloromethane to
afford 4 or 7 as pale yellow ¯akes.
3.3. General procedure for the synthesis of ligands 3 and
6
To a solution of 2b or 5c >1.0 mmol) in ethanol >10 mL) was
added amine >1.1 mmol) at room temperature for 24 h.
Further puri®cation of 3 was achievedby ¯ash chromato-
3.4.1. 3-Mercapto-4-[420S)-20-4diphenylhydroxymethyl)
pyrrolidino]-3-cyclobutene-1,2-dione 4. Pale yellow
¯ake. 55% yield. Mp 163±1658C. [a]D ˆ282.0 >c 0.7,
20

9332
H.-B. Zhou et al. / Tetrahedron 57 02001) 9325±9333
EtOH). IR n: 3446, 3064, 1774, 1662, 1563 cm21. 1H NMR
>DMSO-d6) dH: 1.98 >m, 2H, ±CH2±), 2.19 >m, 2H, ±CH2±
), 3.86 >s, 2H, ±CH2N±), 4.00 >m, 1H, SH), 5.27 >br, 1H,
±CHN±), 6.15 >s, 1H, OH), 7.18±7.50 >m, 10H, ArH). MS
>EI) m/z: 366 >M111, 37). Anal. Calcdfor C 21H19NO3S: C,
69.04, H, 5.21, N, 3.84. Found: C, 68.87, H, 5.28, N, 3.90.
presence of triethylamine >2.0 mmol) at room temperature
with stirring, andthe stirring was continueduntil the reac-
tion was completed>24 h TLC, silica gel, petroleum ether/
ethanol, 2:1). The precipitate was ®ltratedandrecrystallized
from a mixture of ethanol andTHF >1:1) to affordproduct as
colorless needles.
3.4.2.
3-Mercapto-4-[410R,20S)-420-hydroxy-10,20-di-
phenylethyl)amino]-3-cyclobutene-1,2-dione 7. Pale
3.7.1. 3,4-Bis[410R,20S)-420-hydroxy-10,20-diphenylethyl)-
amino]-3-cyclobutene-1,2-dione 9a. 85% yield. Mp 288±
20
20
yellow ¯ake. 50% yield. Mp 182±1838C. [a]D ˆ182.0
2898C >dec.). [a]D ˆ143.3 >c 0.6, DMSO). IR n: 3424,
3156, 3042, 1800, 1642, 1572 cm21. dH >400 MHz, DMSO-
d6): 5.03 >t, Jˆ4.6 Hz, 2H, 2OH), 5.26 >t, Jˆ4.4 Hz, 2H,
2CH), 5.83 >d, Jˆ4.4 Hz, 2H, 2CH), 7.07±7.26 >m, 20H,
4ArH), 8.18 >t, Jˆ4.8 Hz, 2H, NH). MS >EI) m/z: 505
>M111, 15). Anal. Calcdfor C 32H28N2O4: C, 76.16, H,
5.56, N, 2.78. Found: C, 76.45, H, 5.47, N, 2.99.
>c 0.7, EtOH). IR n: 3445, 3324, 3018, 1770, 1690,
1578 cm21. dH >200 MHz, C3D6O): 4.30 >s, 1H, SH), 4.94
>s, 1H, OH), 5.37 >s, 1H, CH), 5.59 >s, 1H, CH), 7.42±7.17
>m, 10H, 2ArH), 7.80 >s, 1H, NH). MS >EI) m/z: 326
>M111, 45), 219 >M2106, 75). Anal. Calcdfor
C18H15NO3S: C, 66.45, H, 4.65, N, 4.31. Found: C, 66.36,
H, 4.57, N, 4.29.
3.7.2. 3,4-Bis[410S,20R)-420-hydroxy-10,20-diphenylethyl)-
amino]-3-cyclobutene-1,2-dione 9b. 83% yield. Mp 286±
3.5. Procedure for the synthesis of ligand 8
20
2878C >dec.). [a]D ˆ242.5 >c 0.6, DMSO-d6). IR n: 3446,
3213, 3065, 1802, 1640, 1570 cm21. dH >400 MHz, DMSO-
d6): 5.02 >d, Jˆ3.8 Hz, 2H, 2OH), 5.22 >t, Jˆ4.6 Hz, 2H,
2CH), 5.83 >d, Jˆ3.8 Hz, 2H, 2CH), 7.08±7.33 >m, 20H,
4ArH), 8.17 >d, Jˆ9.3 Hz, 2H, NH). MS >EI) m/z: 505
>M111, 15). Anal. Calcdfor C 32H28N2O4: C, 76.16, H,
5.56, N, 2.78. Found: C, 75.98, H, 5.29, N, 2.61.
To a dry one-necked, round-bottomed ¯ask with 7
>1.0 mmol) was added acetone >10 mL), K2CO3
>0.5 mmol), the mixture was stirredat 40 8C until the
K2CO3 disappeared, then CH3I >1.1 mmol) was added and
the solution was stirredovernight at 40 8C. After ®ltration to
remove KI, the ®ltrate was evaporated under reduced
pressure andthe resultedresidue was subjectedto ¯ash
chromatography >petroleum ether/ethyl acetate, 2:1) to
afford 8 as pale yellow ¯akes.
3.7.3.
3,4-Bis[410R)-420-hydroxy-10-benzylthiomethyl-
10,20-diphenylethyl)amino]-3-cyclobutene-1,2-dione 10.
20
45% yield. Mp 2508C >dec.). [a]D ˆ2307 >c 0.4,
DMSO). IR n: 3420, 3151, 3026, 1800, 1573 cm21. dH
>400 MHz, DMSO-d6): 3.27 >br, 2H, 2OH), 3.65 >m, 4H,
2CH2), 3.77 >m, 4H, 2CH2), 5.77 >m, 2H, 2CH), 7.03±7.65
>m, 30H, 6ArH), 8.60 >m, 2H, 2NH). MS >EI) m/z: 778
>M112, 35). Anal. Calcdfor C 48H44N2O4S2: C, 74.20, H,
5.71, N, 3.61. Found: C, 74.97, H, 5.59, N, 3.67.
3.5.1.
3-Methylthio-4-[410R,20S)-420-hydroxy-10,20-di-
phenylethyl)amino]-3-cyclobutene-1,2-dione 8. Pale
20
yellow ¯ake. 75% yield. Mp 211±2128C. [a]D ˆ218.0
>c 0.7, EtOH). IR n: 3388, 3041, 2929, 1771, 1686,
1576 cm21. dH >200 MHz, DMSO-d6): 2.32 >s, 3H, CH3),
4.94 >s, 1H, OH), 5.34 >s, 1H, CH), 5.54 >s, 1H, CH), 7.09±
7.18 >m, 10H, 2ArH), 7.75 >s, 1H, NH). MS >EI) m/z: 340
>M111, 100). Anal. Calcdfor C 19H17NO3S: C, 67.24, H,
5.05, N, 4.13. Found: C, 67.47, H, 5.01, N, 4.19.
3.7.4. 3,4-Bis-[410R)-420-hydroxy-10,2020-triphenylethyl)-
amino]-3-cyclobutene-1,2-dione 11. 40% yield. Mp
20
2508C >dec.). [a]D ˆ1180 >c 0.5, DMSO). IR n: 3466,
3206, 3209, 2962, 1804, 1644, 1571, 1543 cm21. dH
>400 MHz, DMSO-d6): 2.15 >br, 2H, 2OH), 4.75 >m, 2H,
2CH), 5.13 >s, 1H, CH), 7.60 >m, 30H, 6ArH), 8.12 >m, 2H,
2±NH±). MS >EI) m/z: 657 >M111, 20). Anal. Calcdfor
C44H36N2O4: C, 80.45, H, 5.53, N, 4.27. Found: C, 79.98, H,
5.49, N, 4.61.
3.6. Procedure for the synthesis of ligand 5a
5c >1 mmol) in the mixture of ethanol >10 mL) and2N HCl
>5 mL) was heatedto re¯ux andthe reaction was monitored
by TLC. After completion >,10 h), the solvent was
removedandthe precipitate was recrystallizedfrom a
mixture of ethanol andidchloromethane >1:1) to afford
®ne colorless crystals.
3.8. A general procedure for the catalytic reduction of
prochiral ketones
3.6.1. 3-Hydroxy-4-[410S,20R)-420-hydroxy-10,20-diphenyl-
ethyl)amino]-3-cyclobutene-1,2-dione 5a. 65% yield. Mp
Under an argon atmosphere, to a solution of chiral ligand in
toluene was added BH3´Me2S at 08C. The reaction mixture
was stirredfor 3 h at ambient temperature to form an oxa-
zaborolidine catalyst and then was warmed to speci®ed
temperature andstirredfor another 1 h. The ketone was
added slowly over a period of 1.5 h and stirred for another
1 h. The reaction mixture was cooledto 0 8C andquenched
with 5 mL of 2N HCl solution. The organic layer was
extractedwith ethyl acetate >10 mL £3) andwashedwith
saturatedbrine solution. The organic layer was then concen-
tratedin vacuum andpassedthrough a short silica gel
column elutedwith petroleum ether andethyl acetate >6:1)
before being subjectedto GC analysis.
20
208±2108C. [a]D ˆ1108.4 >c 0.75, EtOH). IR n: 3360,
3221, 3086, 1808, 1671, 1593 cm21
. dH>200 MHz,
DMSO-d6): 4.40 >br, 1H, OH), 4.87 >d, Jˆ8.5 Hz, 1H,
CH), 5.03 >t, Jˆ8.5 Hz, 1H, CH), 7.21±7.41 >m, 10H,
2ArH), 8,74 >d, Jˆ9.7 Hz, 1H, NH), 10.17 >s, 1H, OH).
MS >EI) m/z: 310 >M111, 5). Anal. Calcdfor C 18H15NO4:
C, 69.88, H, 4.89, N, 4.53. Found: C, 69.79, H, 4.98, N, 4.77.
3.7. General procedure for the synthesis of ligands 9±11
To a solution of dibutyl squarate 1 >1.0 mmol) in dry ethanol
>10 mL) was added b-amino alcohols >2.1 mmol) in the

H.-B. Zhou et al. / Tetrahedron 57 02001) 9325±9333
9333
Yeung, C. H.; Chan, A. S. C.; Yang, T.-K. Tetrahedron:
Asymmetry 1999, 10, 759. >e) Santhi, V.; Rao, J. M.
Tetrahedron: Asymmetry 2000, 11, 3553.
Crystallographic data >excluding structure factors) for
0
compound>1 R,20S)-5c, >10S,20R)-5e and 2b have been
deposited with the Cambridge Crystallographic Data Centre
as supplementary publication numbers CCDC 161175±
161177, respectively. Copies of the data can be obtained,
free of charge, on application to CCDC, 12 Union Road,
Cambridge, CB2 1EZ, UK [fax: 144>0)-1223-336033 or
e-mail: deposit@ccdc.cam.ac.uk].
6. >a) Gamble, M. P.; Studley, J. R.; Wills, M. Tetrahedron Lett.
1996, 37, 2853. >b) Gamble, M. P.; Smith, A. R. C.; Wills, M.
J. Org. Chem. 1998, 63, 6068. >c) Burns, B.; King, N. P.; Tye,
H.; Studley, J. R.; Gamble, M.; Wills, M. J. Chem. Soc.,
Perkin Trans. 1 1998, 1027.
7. >a) Sibi, M. P.; Cook, G. R.; Liu, P. R. Tetrahedron Lett. 1999,
40, 2477. >b) Yang, G. S.; Hu, J. B.; Zhao, G.; Ding, Y.; Tang,
M. H. Tetrahedron: Asymmetry 1999, 10, 4307. >c) Hu, J. B.;
Zhao, G.; Ding, Z. D. J. Org. Chem. 2001, 66, 303. >d) Hu,
J. B.; Zhao, G.; Ding, Z. D. Angew. Chem., Int. Ed. Engl. 2001,
40, 1109. >e) Inoue, T.; Sato, D.; Komure, K.; Itsuno, S.
Tetrahedron Lett. 1999, 40, 5379.
Acknowledgements
The ®nancial support of The Hong Kong Polytechnic
University ASD Fund is gratefully acknowledged.
8. For a recent review on bifunctional catalysts see: Rowlands,
G. J. Tetrahedron 2001, 57, 1865.
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