Application of the lewis acid-lewis base bifunctional asymmetric catalysts to pharmaceutical syntheses: Stereoselective chiral building block syntheses of human immunodeficiency virus (HIV) protease inhibitor and β3- adenergic receptor agonist

Article abstract of DOI:10.1248/cpb.51.702

Chiral building block syntheses of promising drugs were achieved using two types of catalytic stereoselective cyanosilylations of aldehydes promoted by Lewis acid-Lewis base bifunctional catalysts 1 and 2 as the key steps (diastereoselective cyanosilylation of amino aldehyde and enantioselective cyanosilylation). In the first part of this article, syntheses of chiral building blocks (6) of Atazanavir (3: human immunodeficiency virus (HIV) protease inhibitor) using the bifunctional catalyst 2 are discussed. The reaction of Boc-protected phenylalaninal 21 in the presence of 1 mol% catalyst 2 selectively afforded the anti isomer 22 as the major product (diastereomeric ratio=97:3), which was successively converted to the corresponding epoxide 6 in six steps. In the second part, we describe a chiral building block synthesis of β₃-adrenergic receptor agonists. The enantioselective cyanosilylation of 3-chlorobenzaldehyde (38) with 9 mol% catalyst 1 gave the chiral cyanohydrin 39, which was converted to β-hydroxyethylamine 40 by reduction. Moreover, the chiral ligand of catalyst 1 could be recovered without column chromatography and reused without decreasing its activity.

Full text of DOI:10.1248/cpb.51.702

702
Chem. Pharm. Bull. 51(6) 702—709 (2003)
Vol. 51, No. 6
Application of the Lewis Acid–Lewis Base Bifunctional Asymmetric
Catalysts to Pharmaceutical Syntheses: Stereoselective Chiral Building
Block Syntheses of Human Immunodeficiency Virus (HIV) Protease
b
Inhibitor and -Adenergic Receptor Agonist
3
Hiroyuki NOGAMI, ,a Motomu KANAI,b and Masakatsu SHIBASAKI
b
*
a Chemicals Development Laboratories, Mitsubishi Rayon Co., Ltd.; Daikoku-cho, Tsurumi-ku, Yokohama, Kanagawa
230–0053, Japan: and b Graduate School of Pharmaceutical Sciences, The University of Tokyo; Hongo, Bunkyo-ku, Tokyo
113–0033, Japan. Received March 10, 2003; accepted March 20, 2003
Chiral building block syntheses of promising drugs were achieved using two types of catalytic stereoselective
cyanosilylations of aldehydes promoted by Lewis acid–Lewis base bifunctional catalysts 1 and 2 as the key steps
(diastereoselective cyanosilylation of amino aldehyde and enantioselective cyanosilylation). In the first part of
this article, syntheses of chiral building blocks (6) of Atazanavir (3: human immunodeficiency virus (HIV) pro-
tease inhibitor) using the bifunctional catalyst 2 are discussed. The reaction of Boc-protected phenylalaninal 21
in the presence of 1 mol% catalyst 2 selectively afforded the anti isomer 22 as the major product (diastereomeric
ratio؍97 : 3), which was successively converted to the corresponding epoxide 6 in six steps. In the second part, we
describe a chiral building block synthesis of b3-adrenergic receptor agonists. The enantioselective cyanosilylation
of 3-chlorobenzaldehyde (38) with 9 mol% catalyst 1 gave the chiral cyanohydrin 39, which was converted to b-
hydroxyethylamine 40 by reduction. Moreover, the chiral ligand of catalyst 1 could be recovered without column
chromatography and reused without decreasing its activity.
Key words bifunctional asymmetric catalyst; cyanosilylation; asymmetric catalysis; human immunodeficiency virus (HIV) pro-
tease inhibitor; b3 adrenergic receptor agonist
The synthesis of optically pure compounds is important in are highly efficient for the asymmetric synthesis of chiral
the development of pharmaceuticals, agrochemicals, and building blocks of an human immunodeficiency virus (HIV)
their intermediates.1—4) Catalytic asymmetric reaction is an protease inhibitor (Atazanavir) and a b3-adrenergic receptor
ambitious and powerful method for the synthesis of chiral agonist.
compounds in terms of atom economy. Therefore, the devel-
opment of new enantioselective catalysts has been exten- Results and Discussion
sively investigated.5—7) We recently succeeded in developing
Building Block Syntheses of Atazanavir30—33)
chiral bifunctional catalysts 18—11) and 212,13) based on the Atazanavir (3) is an azapeptide HIV-1 protease inhibitor class
concept of bifunctional catalysis (Fig. 1). Based on mecha- and is currently in phase III clinical trials (Fig. 2).34,35)
nism studies, such as IR studies, kinetic profiles, and ab- Fässler et al. reported that Atazanavir is obtained using four
solute configuration of the products, the catalysts promote fragments (tert-leucine-derivative 4, amino epoxide 6, biaryl
the cyanosilylation reaction via a simultaneous dual activa- compound 8, and hydrazine 9).31) Thus, first, biaryl com-
tion of the substrate by the Lewis acid (aluminum metal) and pound 8 was synthesized using a nickel(II)-catalyzed Ku-
the Lewis base (oxygen atom of the phosphine oxide) at de- mada reaction of the Grignard reagent prepared from 4-bro-
fined positions in the transition state. This dual activation mobenzaldehyde dimethyl acetal and 2-bromopyridine, fol-
mechanism affords high stereoselectivity from a wide variety lowed by acidic hydrolysis. Next, the reaction of 8 with hy-
of substrates.
drazine 9 afforded hydrazone, which was reduced to hy-
Cyanohydrins are highly versatile intermediates that can drazine 7. Condensation of 7 with amino epoxide 6 and full
be easily converted into important chiral building blocks, in- deprotection resulted in the addition product 5. Finally, 5 was
cluding a-hydroxy carbonyl derivatives, b-hydroxyethyl- condensed with tert-leucine derivative 4 to give Atazanavir.
amine, a-amino acids, etc.14—20) Catalyst 1 promotes the cat-
Of the above fragments, we previously reported that tert-
alytic asymmetric cyanosilylation of various aldehydes8—11) leucine could be synthesized by an enantioselective Strecker-
as well as of imines21,22) with high enantioselectivity and sub- type reaction as a key step in the presence of 9 mol% of cata-
strate generality. On the other hand, catalyst 2 is applied to lyst 1 and 20 mol% of PhOH as a proton source.21,22,36) This
the asymmetric addition of TMSCN to aldehydes and ace- time, we expected that the amino epoxide 6 would be ob-
tophenone,12) and can also efficiently promote a variety of
catalytic diastereoselective cyanosilylations of aminoaldehy-
des with excellent stereoselectivity.13) Because enantioselec-
tive cyanosilylation is a key step in the synthesis of important
intermediates of many pharmaceuticals, catalysts 1 and 2 are
very useful. We previously demonstrated the synthesis of
several biologically significant compounds using catalytic
enantioselective cyanosilylation promoted by these catalysts,
as a key step.23—29) Herein, we report that catalysts 1 and 2
Fig. 1
* To whom correspondence should be addressed. e-mail: nogami_hi@mrc.co.jp
© 2003 Pharmaceutical Society of Japan

June 2003
703
Fig. 2
Fig. 3
Chart 1
Amprenavir (13)49) and Saquinavir (14)50,51) are therapeuti-
cally useful HIV protease inhibitors.52—56)
tained via asymmetric cyanosilylation of aminoaldehyde
using bifunctional catalyst 2, and biaryl 8 would be synthe-
sized via a one-step Suzuki–Miyaura reaction. Thus, we
planned to synthesize these fragments of Atazanavir.
For synthesis of the essential chiral building blocks of
these compounds, considerable research effort has been di-
rected towards the diastereoselective cyanation of chiral
amino aldehydes.57—59) A stoichiometric or excess amount of
promoters or reagents, however, is usually used, and the di-
astereoselectivity is not always high. Therefore, we investi-
gated the cyanosilylation of N-protected chiral aminoaldehy-
des in the presence of bifunctional catalyst 2 instead of achi-
ral promoters, and succeeded in the anti- and syn-selective
The Chiral Amino Epoxide (6)37—40) Pseudopeptides,
containing 3-amino-2-hydroxycarboxylic acids 10 or 3-
amino-2-hydroxyamines 11, are essential components in
many medicinally important compounds (Fig. 3). For exam-
ple, Bestatin (12) is an aminopeptidase inhibitor that exhibits
immunostimulatory as well as cytotoxic activity and is used
clinically as an anticancer agent.41—48) On the other hand,

704
Vol. 51, No. 6
Chart 2
Table 1. Synthesis of Biaryl Compound 8
cyanosilylation reactions with excellent yield and high di-
astereoselectivity (Chart 1).13) For example, the syn isomer
16 (93% yield, diastereomeric ratio; anti : synϭ7 : 93) was
obtained as the major product using dibenzyl protected L-
phenylalaninal 15.60) In addition, the anti isomer 19 (100%
yield, diastereomeric ratio; anti : synϭ96 : 4) was obtained in
the case of Boc-protected L-phenylalaninal 18. Also, the anti
isomer 22 (100% yield, diastereomeric ratio; anti : synϭ
97 : 3) was obtained from the Boc-protected D-aminoalde-
hyde 21.
Using syn- and anti-selective cyanosilylations, effective
syntheses of some useful chiral building blocks were
achieved. One was a short-step synthesis of Corey’s interme-
diate of Amprenavir 13.49) The other was a practical synthe-
sis of the important building block of Bestatin 12, achieved
in 5-g scale.
Catalyst
(mol%)
Time Yield
Entry
Solvent
Base
(h)
(%)
1
2
3
4
5
6
7
8
Ni(PPh3)n (3)
NiCl2(PPh3)2 (3)
NiCl2(PPh3)2 (3)
DME
DME
DME
LiOH
15
0
0
Na2CO3 15
K3PO4
K3PO4
K3PO4
15
15
15
7
0
NiCl2(PPh3)2 (3), PPh3 (15) DME
20
32
55
96
92
Ni(dppf)Cl2 (3), nBuLi (12) DME
PdCl2(cod) (3)
Pd(PPh3)4 (3)
Pd(PPh3)4 (0.3)
DME–H2O Na2CO3
DME–H2O Na2CO3 10
DME–H2O Na2CO3 12
a) Isolated yield.
These initial promising results led us to attempt the syn-
thesis of a pharmaceutically important intermediate 6 from
22 as follows (Chart 2). Acid hydrolysis of 22 with 6 N HCl
followed by recrystallization from MeOH–Et2O gave the di-
astereomerically pure b-amino-a-hydroxy acid 23.61,62) Com-
pound 23 was protected with (Boc)2O to give compound
24,63—65) which was esterified with MeI–K2CO3 to compound
25.63) Then, the ester group was reduced with NaBH4–LiCl to
give diol 26.40,66) Selective mesylation of 26 followed by sub-
sequent intramolecular cyclization gave the expected epoxide
6. The diastereomeric ratio remained high (anti : synϭ99 : 1)
through six steps.
2-(4-Formylphenyl)pyridine (8) Classic biaryl coupling
procedures (e.g., Ullmann reaction, or Grignard reaction)
often lack selectivity or give moderate yields. Keeping in
mind the compatibility with reactive functionality and the
toxicity of the reagent, a transition-metal-catalyzed cross
coupling between an electrophile (e.g., aryl halide and
pseudo aryl halide) and an organoborane in the presence of
an aqueous base, the so-called Suzuki–Miyaura reaction, is
one of the most efficient and versatile tools for the synthesis
of biaryls.67—69) Aryl bromide, iodide, and triflate are effi-
ciently activated by a palladium complex, and are therefore
often employed for the Suzuki–Miyaura reaction. On the
other hand, aryl chloride substrates are less reactive but more
attractive than the corresponding bromide, iodide, and triflate
because they are readily available and inexpensive. Nickel-
complexes often have higher reactivity toward aryl chloride
than palladium-complexes, thus we elaborated the cross-cou-
pling reaction of 2-chloropyridine (27) with 4-formylboronic
acid (28) for the synthesis of 8 in our first approach (Table
1).
1, entry 1—3).70) Excess addition of PPh3 to NiCl2 improved
the reaction little (Table 1, entry 4).71) The nickel complex
(0), prepared in situ by treating the nickel chloride with
nBuLi at room temperature, resulted in 32% yield (Table 1,
entry 5).72) Although the reason is not clear, these results
suggest that 2-chloropyridine (27) is strongly resistant to
nickel-catalyzed coupling.73)
Next, we investigated the cross coupling reaction using a
palladium-complex, which is often a superior catalyst for
certain aryl chlorides.74—76) The coupling reaction resulted in
a slightly reduced yield in the presence of 3 mol%
PdCl2(cod) (Table 1, entry 6). When the mixture was heated
to 80 °C for 10 h using 3 mol% Pd(PPh3)4 under basic condi-
tions, however, the target compound 8, accompanied by less
than 1% of the homo-coupling product, was obtained in 96%
yield. Also, a small amount of the homo-coupling product
was also completely separated after simple acidic extraction.
Moreover, the reaction was also completed using 0.3 mol%
Pd(PPh3)4 in 12 h (Table 1, entry 8).
As described above, we successfully prepared the three
fragments (4, 6, 8) using two types of catalytic stereoselec-
tive cyanosilylations promoted by Lewis acid–Lewis base bi-
functional catalysts and the Suzuki–Miyaura reaction. These
reactions are practical, and thus can be applied to a large
scale synthesis of Atazanavir.
(2R)-2-(3-Chlorophenyl)-2-hydroxyethylamine
(40)
Obesity causes significant complications such as type 2 dia-
betes mellitus, high blood pressure, coronary heart disease,
and hyperlipidemia.77) Recently, the b3-adrenergic receptor
(AR) was isolated and characterized as the third b AR sub-
type.78) b3 AR is suggested to have a significant role in the
The reaction, unfortunately, did not take place at all (Table

June 2003
705
Fig. 4
Fig. 5
Table 2. Catalytic Asymmetric Cyanosilylation of 3-Chlorobenzaldehyde
38
control of lipolysis and thermogenesis in brown adipose tis-
sue of rodents and humans. Thus, b3 AR-stimulating agents
have attracted attention for the treatment of obesity and type
2 diabetes.79) On the other hand, b1 AR-stimulating drugs are
clinically used as a cardiac function promoter or vasopressor,
and b2 AR-stimulating drugs are used as bronchodilators.
The structural similarity of b3 AR to known b AR agonists
has led to studis to develop a drug with selective b3 AR ago-
nist activity. There are currently many compounds with this
type of activity, such as AJ-9677 (29), FR-149175 (30), SR-
59062A (31), and BMS-187413 (32) (Fig. 4).79)
These compounds contain 2-(3-chlorophenyl)-2-hydroxy-
ethylamine (33) as a common chiral building block. There-
fore, we focused on the synthesis of this moiety via a cat-
alytic asymmetric cyanosilylation of 3-chlorobenzaldehyde
(38) using the bifunctional catalyst (S)-1.
Entry
Additive
Temp (°C) Time (h) Yield (%)a) ee (%)b)
1
2
3
4
5
6
7
8
—
—
—
MeOH
iPrOH
tBuOH
PhOH
MeOH
Ϫ40
Ϫ30
Ϫ50
Ϫ40
Ϫ40
Ϫ40
Ϫ40
Ϫ40
91
64
64
72
72
72
72
96
82
68
25
73
85
70
72
98
80
80
82
88
86
87
87
90c)
First, we attempted a catalytic asymmetric cyanosilylation
a) Isolated yield. b) Determined by HPLC analysis after convention to ethyl car-
of 38 (30 mg scale) at Ϫ40 °C for 96 h in the presence of bonate. c) TMSCN pre-mixed MeOH was slowly added over 8 h.
9 mol% of the catalyst (S)-1, and the product 39 was obtained
A beneficial role of the proton is proposed in Fig.
in 98% yield with 80% ee (Table 2, entry 1). When this cat-
alytic asymmetric cyanosilylation was applied to a larger
scale reaction (60 mg scale), however, the reaction rate was
retarded. Intensive investigation indicated that the addition of
a catalytic amount of a proton source (MeOH) had an impor-
tant role in reproducing the results of the smaller scale reac-
tions (Table 2, entry 4).
5.9,21,22,28) Namely, HCN generated from TMSCN and MeOH
should protonate the aluminum alkoxide 35, facilitating re-
generation of the active catalyst 1.80—83) The resulting free
cyanohydrin 36 was immediately silylated under the reaction
conditions to give the TMS protected form 37. Because HCN
should be regenerated from TMSCN and the free cyanohy-

706
Vol. 51, No. 6
drin, only a catalytic amount of MeOH was required for the tant for catalytic asymmetric synthesis in terms of atom
catalytic cycle. economy and the cost of the process. Solid-supported cata-
The kinetic profile of this reaction was investigated to gain lysts are very important in terms of easy separation of the
further insight into the reaction mechanism using benzalde- product, and the potential to reuse the catalyst in subsequent
hyde as a substrate. The reaction at Ϫ40 °C was monitored reactions. Although we developed a recyclable solid-sup-
by NMR spectroscopy by observing the disappearance of the ported catalyst 41 for an asymmetric Strecker-type reaction
aldehyde proton. The initial reaction rate was 1.4 times faster (Chart 4),84) 41 did not catalyze the catalytic asymmetric
in the presence of the proton source than in its absence (Fig. cyanosilylation of aldehydes. Therefore, we developed an al-
6).
So, we investigated the effect of different protic sources to
ternative method to recover chiral ligand 42 (Fig. 7).
After cyanosilylation was performed, the ligand was recov-
improve the yield on a gram scale reaction. MeOH afforded a ered as follows. The reaction mixture was quenched by the
higher yield and the highest enantiomeric excesses, although addition of HCl, and the extracted organic layer, including
other alcohols gave only slightly lower enantioselectivity the product and the ligand, was evaporated. Ether was added
(Table 2, entry 5—7). Treatment of 38 with TMSCN pre- to the residue and the slurry was stirred for 1 h at 0 °C. The
mixed with 5 mol% of MeOH in the presence of 9 mol% of precipitation was filtered and the ligand was recovered al-
the catalyst (S)-1 at Ϫ40 °C for 96 h led to the efficient for- most quantitatively. Recrystallization of the recovered ligand
mation of cyanohydrin 39 in 98% yield with 88% ee. There from CH2Cl2–Et2O successfully gave purified ligand 42 (re-
was further improvement when TMSCN pre-mixed with covery 96%). Moreover, 42 could be reused without any loss
5 mol% of MeOH was added slowly to the reaction mixture, of activity or enantioselectivity.
giving 39 in 98% yield with 90% ee (Table 2, entry 8). These
results demonstrate that the addition of a catalytic amount of Conclusion
a proton source is very important for this asymmetric induc-
We report the synthesis of some medically important chi-
tion. Having optimized the reaction conditions, the corre- ral building blocks via stereoselective cyanosilylations using
sponding cyanohydrin 39 was successfully performed on a the bifunctional catalysts 1 and 2. These reactions are practi-
gram scale.
cal and were successfully applied to efficient catalytic asym-
Subsequent reduction of TMS-protected cyanohydrin 39 metric syntheses of chiral building blocks. In addition, we
with BH3·SMe2 provided the expected b-hydroxyamine 33. demonstrated that ligand 42 of catalyst 1 can be easily recov-
To avoid chromatographic purification, compound 33 was ered without column chromatography and reused without any
obtained as a crystalline HCl salt with HCl–MeOH treat- loss of the activity or enantioselectivity. These results
ment. Recrystallization from MeOH–MTBE (methyl tert- demonstrate that future pilot scale syntheses of chiral
butyl ether) afforded the enantiomerically and chemically cyanohydrins using catalysts 1 and 2 might be possible.
pure salt 40 (Chart 3).
Recycling of the Catalyst Establishment of a recycling
method for asymmetric catalysts (or ligands) is very impor-
Chart 3
Fig. 6. Initial Reaction Rate of Benzaldehyde in the Absence and in the
Presence of 5 mol% of MeOH
The disappearance of benzaldehyde was traced by 1H-NMR: the reaction in the ab-
sence (᭹) and in the presence (᭜) of 5 mol% of MeOH.
Chart 4
Fig. 7. Recycling of the Catalyst

June 2003
707
1H), 3.05 (br s, 1H), 2.89 (d, Jϭ7.56 Hz, 2H), 1.39 (s, 9H); 13C-NMR
(CDCl3) d: 156.8, 138.0, 129.2, 128.5, 126.4, 79.7, 71.5, 63.9, 52.6, 38.2,
28.3; IR (neat) n: 3355, 1692, 1521, 1173 cmϪ1; MS (EI) m/z 282 (MϩϩH);
HR-MS Calcd for C15H24NO4 282.1705, Found 282.1708; [a]D20 Ϫ37°
(cϭ1.0, CHCl3).
Experimental
General Experimental Procedures NMR spectra were recorded on a
JEOL GX-270 spectrometer, operating at 270 MHz for 1H-NMR and
67.5 MHz for 13C-NMR. Chemical shifts were reported in ppm on the d
1
scale relative to TMS (dϭ0.00 ppm for H-NMR) or using residual CDCl3
1
(dϭ7.24 for H-NMR and dϭ77.0 for 13C-NMR) or CD3OD (dϭ3.30 for
(2R,3S)-N-(tert-Butoxycarbonyl)-3-amino-1,2-eopxy-4-phenylbutane
(6) Product 26 (30.1 mg, 0.107 mmol) was dissolved in toluene (1 ml).
MsCl (9 ml, 0.12 mmol) and Et3N (20 ml, 0.143 mmol) were added dropwise
to the mixture at 0 °C. The mixture was then warmed to room temperature
and stirred for 2 h. Saturated NaHCO3 was added to quench and the aqueous
layer was extracted with toluene. The combined organic layer was washed
with brine. The solvent was evaporated in vacuo and the resulting residue
was used for the next step without further purification. Toluene (2 ml) was
added to the residue, and 20% NaOH (2 ml) was added at 0 °C. The solution
was stirred at room temperature until the reaction completed. The reaction
mixture was extracted with toluene. The combined organic layer was washed
with water, brine, and then dried over Na2SO4. The crude product was puri-
fied by flash chromatography, giving 6 (22.5 mg, 80%, 99% de). Diastere-
omeric excess was determined by HPLC (column; DAICEL CHIRALCEL
OD-H, hexane/iPhOH 98/2, 1 ml/min) tR 9.1 and 10.5 min. Analytical data
indicated that the product was identical with the reported compound: 1H-
NMR (CDCl3) d: 7.20—7.33 (m, 5H), 4.49 (m, 1H), 4.12 (m, 1H), 2.84—
3.03 (m, 3H), 2.69 (m, 1H), 2.59 (m, 1H), 1.39 (s, 9H); 13C-NMR (CDCl3)
d: 155.4, 137.2, 129.4, 128.5, 126.7, 79.5, 52.6, 50.5, 44.5, 39.8, 28.2; IR
(neat) n: 3339, 1685, 1650, 1247, 1165 cmϪ1; MS (EI) m/z: 264 (MϩϩH);
HR-MS Calcd for C15H22NO3 264.1600, Found 264.1605; [a]D21 ϩ3°
(cϭ1.6, CHCl3).
1H-NMR and dϭ49.0 for 13C-NMR) as an internal reference. Infrared (IR)
spectra were recorded on a PERKIN ELMER 1600 fourier transform in-
frared spectrophotometer. EI mass spectra were measured on a HEWLETT
PACKARD G1800A GCD system or a JEOL JMS-SX102A system. HR
mass spectra were measured on a JEOL JMS-SX102A system. Optical rota-
tions were measured on a HORIBA SEPA-200 polarimeter. Flash column
chromatography was performed with silica gel Merck 60 (230—400 mesh
ASTM). Enantiomeric excess (ee) was determined by HPLC analysis. HPLC
analysis was performed on JASCO HPLC systems consisting of the follow-
ing: pump, 880-PU; detector, 875-UV, measured at 254 nm or 200 nm; col-
umn, Daicel CHIRALCEL OD-H or CROWNPAK CR(ϩ). In general, the
reactions were performed in dried solvents under an argon atmosphere, un-
less noted otherwise. Diethylaluminum chloride in hexane (0.93 M) was pur-
chased from Kanto Chemical Co., Inc., Tokyo. Starting materials were com-
mercially available or synthesized by the reported procedure.
(2R,3S)-N-(tert-Butoxycarbonyl)-3-amino-2-trimethylsilyloxy-4-
phenylbutanenitrile(22) Et2AlCl in hexane solution (0.93 M, 0.2 mmol)
was added to a solution of ligand 2 (66 mg, 0.2 mmol) in CH2Cl2 (3.5 ml) at
ambient temperature. After 30 min, a solution of aldehyde 21 (5.00 g,
20.0 mmol) in CH2Cl2 (50 ml) and TMSCN (3.2 ml, 24 mmol in 3.2 ml of
CH2Cl2) were added dropwise at Ϫ60 °C. The reaction was completed in
15 h in this scale. H2O was added for quenching and the product was ex-
tracted with ethyl acetate. The combined organic layer was washed with
brine, then dried over Na2SO4. Further purification was performed by flash
chromatography on silica gel to afford product 22 (6.99 g, 100%). Diastere-
omeric excess was determined by NMR: 1H-NMR (CDCl3) d: 7.14—7.30
(m, 5H), 4.78 (d, Jϭ7.3 Hz, 1H), 4.51 (d, Jϭ3.0 Hz, 1H), 4.01—4.08 (m,
1H), 3.00 (dd, Jϭ13.9, 6.3 Hz, 1H), 2.75 (dd, Jϭ14.0, 8.6 Hz, 1H), 1.36 (s,
9H), 0.20 (s, 9H); 13C-NMR (CDCl3) d: 154.9, 136.6, 128.9, 128.6, 126.8,
118.3, 80.1, 63.0, 55.0, 35.8, 28.3, Ϫ0.3; IR (neat) n: 2225, 1714,
1120 cmϪ1; MS (EI) m/z 349 (MϩϩH); high resolution (HR)-MS m/z Calcd
for C18H29N2O3Si 349.1947, Found 349.1975; [a]D25 Ϫ70° (cϭ2.0, CHCl3).
(2R,3S)-3-Amino-2-hydroxy-4-phenylbutanoic Acid Hydrochloride
(23) Product 22 was treated with 6 N HCl (50 ml) at 60 °C and the reaction
mixture was stirred for 48 h. Then the solution was washed in CH2Cl2. The
aqueous layer was evaporated, followed by recrystallization of the residue
2-(4-Formylphenyl)pyridine (8) The flask was charged with Pd(PPh3)4
(77.7 mg, 76.8 mmol) and 28 (5.00 g, 33.3 mmol) and then flushed with
argon. DME (55 ml), 10% Na2CO3 (55 g, 53.2 mmol), and 27 (2.42 ml,
25.6 mmol) were added at room temperature. The mixture was stirred at
80 °C for 12 h. The product was extracted with toluene and washed with 5%
NaHCO3. The biaryl 8 was purified as follows: 8 was extracted from the
toluene layer with 2 N HCl, then the aqueous layer was washed with toluene.
After neutralization with 10% NaOH, 8 was extracted with toluene, washed
with brine, and dried over Na2SO4. Concentration gave 8 in 4.33 g (92%), in
1
good agreement with previously reported data: H-NMR (CDCl3) d: 10.08
(s, 1H), 8.74 (dt, Jϭ4.86, 1.35 Hz, 1H), 8.16—8.24 (m, 2H), 7.96—8.01 (m,
2H), 7.80—7.82 (m, 2H), 7.31 (q, Jϭ4.59 Hz, 1H); 13C-NMR (CDCl3) d:
191.8, 155.7, 149.9, 144.8, 136.9, 136.3, 130.1, 127.4, 123.0, 121.1; IR
(KBr) n: 1712, 1573, 1550 cmϪ1; MS (EI) m/z: 183 (Mϩ); HR-MS Calcd for
C12H9NO 183.0684, Found 183.0690.
1
from MeOH–Et2O to give 3.47 g pure 23 (75% yield). H-NMR (CDCl3) d:
(2R)-2-(3-Chlorophenyl)-2-trimethylsilyloxyacetonitrile (39) The chi-
ral ligand (560 mg, 0.784 mmol) and MeP(O)Ph2 (644 mg, 2.98 mmol) were
placed in a flame-dried flask and dissolved in 14 ml of CH2Cl2. Et2AlCl
(0.80 ml, 744 mmol, 0.93 M in hexane) was added to this solution under
argon. The resulting mixture was stirred at room temperature for 1 h to give
a clear solution. Then 38 (936 ml, 8.27 mmol) was added to this solution at
Ϫ40 °C. TMSCN (1.32 ml, 9.92 mmol) pre-mixed with MeOH (17 ml,
0.41 mmol) in 4.0 ml of CH2Cl2 was slowly added over 8 h. The reaction
mixture was stirred for 96 h. Saturated Rochelle salt was added for quench-
ing and the product was extracted with ethyl acetate. The combined organic
layer was washed with brine and dried over Na2SO4. Purification was per-
formed by flash chromatography on SiO2 to afford 39 (1.94 g, 98% yield).
1H-NMR (CDCl3) d: 7.20—7.36 (m, 4H), 5.35 (s, 1H), 0.14 (s, 9H); 13C-
NMR (CDCl3) d: 138.0, 134.8, 130.1, 129.4, 126.3, 124.2, 118.6, 62.9,
Ϫ0.2; IR (neat) n: 2244, 1111, 1083 cmϪ1; MS (EI) m/z 239 (Mϩ); HR-MS
Calcd for C11H14ClNOSi 239.0533, Found 239.0535; [a]D20 ϩ76° (cϭ2.0,
CHCl3). The enantiomeric excess was determined by HPLC after conversion
13.01 (br s, 1H), 8.13 (br s, 2H), 7.15—7.53 (m, 5H), 3.90 (d, Jϭ2.7 Hz,
1H), 3.59 (m, 1H), 3.02 (dd, Jϭ13.4, 5.0 Hz, 1H), 2.89 (dd, Jϭ13.5, 9.5 Hz,
1H); 13C-NMR (CDCl3) d: 172.4, 136.0, 129.2, 128.4, 126.8, 67.3, 53.8,
35.2; IR (neat) n: 3379, 3130, 1730, 1594, 1491 cmϪ1; MS (EI) m/z 232
(MϩϩH); HR-MS m/z Calcd for C10H14ClNO3 231.0662, Found 231.0669;
[a]D24 Ϫ10° (cϭ0.5, 1 N HCl).
(2R,3S)-N-(tert-Butoxycarbonyl)-3-amino-2-hydroxy-4-phenylbu-
tanoic Acid (24) (Boc)2O (460 ml, 2.00 mmol) and Na2CO3 (212 mg,
2.00 mmol) were successively added to a solution of 23 (232 mg, 1.00 mmol)
in dioxane (2 ml)Ϫ10% NaOH (2 ml) at 0 °C. The reaction mixture was
stirred for 8 h at room temperature, then neutralized with 1 N HCl to pH 7.
The water layer was extracted with CH2Cl2 and the combined organic layer
was washed with brine, then dried over Na2SO4. Further purification was
performed by flash chromatography on silica gel to afford the product 24 as
a white solid (251 mg, 85%). 1H-NMR (CDCl3) d: 7.22—7.30 (m, 5H), 5.00
(m, 1H), 4.08—4.22 (m, 2H), 2.94 (m, 2H), 1.37 (s, 9H); 13C-NMR (CDCl3)
d: 174.8, 154.8, 138.9, 129.2, 128.1, 125.9, 78.9, 77.8, 54.8, 37.4, 28.2; IR
(neat) n: 3335, 1701 cmϪ1; MS (EI) m/z 278 (MϩϪOH); HR-MS m/z Calcd
for C15H20NO4 278.1392, Found 278.1388; [a]D22 Ϫ135° (cϭ2.0, CHCl3).
(2R,3S)-N-(tert-Butoxycarbonyl)-3-amino-2-hydroxy-4-phenylbutanol
(26) NaBH4 (15 mg, 0.39 mmol) was added to a solution of 25 (120 mg,
0.388 mmol) in MeOH (1 ml) at 0 °C. After stirring for 30 min at the same
temperature, LiCl (17 mg, 0.39 mmol) was added to this suspension. This
suspension was gradually warmed to room temperature. After completion of
the reaction, saturated NH4Cl was added, and most of the MeOH was re-
moved in vacuo. The residue was carefully extracted with ethyl acetate. The
combined organic layer was washed with brine. After removal of the solvent,
purification was performed by flash chromatography to give 26 (92.5 mg,
85%). Analytical data indicated that this product was identical with the re-
ported compound: 1H-NMR (CDCl3) d: 7.17—7.31 (m, 5H), 4.96 (d,
Jϭ8.91 Hz, 1H), 3.91 (m, 1H), 3.64 (m, 1H), 3.48—3.58 (m, 2H), 3.31 (br s,
1
to the ethylcarbonate derivative: H-NMR (CDCl3) d: 7.52 (s, 1H), 7.35—
7.36 (m, 3H), 6.21 (s, 1H), 4.23—4.34 (m, 2H), 1.34 (t, Jϭ7.16 Hz, 3H);
13C-NMR (CDCl3) d: 153.1, 135.2, 132.9, 130.8, 130.5, 127.8, 125.8, 115.2,
65.9, 65.5, 14.2; IR (neat) n: 2256, 1759, 1248 cmϪ1; MS (EI) m/z 239
(Mϩ); HR-MS Calcd for C11H10ClNO3 239.0349, Found 239.0352; [a]D25
ϩ7° (cϭ0.77, CHCl3) (90% ee). HPLC (DAICEL CHIRALCEL OD-H,
hexane/iPhOH 95/5, 0.5 ml/min) tR 18.9 and 21.3 min.
(2R)-2-(3-Chlorophenyl)-2-hydroxyethylamine Hydrochloride (40)
BH3·SMe2 (160 ml, 1.68 mmol) was added to a solution of 39 (98.5 mg,
0.41 mmol) in THF (1 ml) at an ambient temperature under argon. The reac-
tion mixture was stirred for 4 h at 60 °C, and then 10% NaOH (1 ml) was
added to the reaction mixture and the mixture stirred for 30 min at the same
temperature. The separated aqueous layer was extracted with CH2Cl2 and the
combined organic layer was washed with brine and dried over Na2SO4. The
solvent was evaporated in vacuo and HCl–MeOH was added to the residue

708
Vol. 51, No. 6
at ambient temperature. Removal of excessive HCl–MeOH under reduced 16) Belokon’ Y. N., Caveda-Cepas S., Green B., Ikonnikov N. S.,
pressure gave the crystalline HCl salt 40, which was recrystallized from
MeOH–MTBE to afford 40 (63.6 mg, 75% yield, 99% ee). 1H-NMR
(CD3OD) d: 7.48 (s, 1H), 7.29—7.38 (m, 3H), 4.92 (dd, Jϭ12.69, 3.24 Hz,
Khrustalev V. N., Larichev V. S., Moscalenko M. A., North M., Orizu
C., Tararov V. I., Tasinazzo M., Timofeeva G. I., Yashkina L. V., J. Am.
Chem. Soc., 121, 3968—3973 (1999).
1H), 3.18 (dd, Jϭ12.69, 3.24 Hz, 1H), 2.98 (dd, Jϭ12.69, 9.72 Hz, 1H); 13C- 17) Liang S., Bu X. R., J. Org. Chem., 67, 2702—2704 (2002).
NMR (CD3OD) d: 144.7, 135.5, 131.1, 129.1, 126.9, 125.3, 70.1, 47.1; IR 18) North M., Synlett, 1993, 807—820 (1993).
(KBr) n: 3353, 3006, 1600, 1522 cmϪ1; MS (EI) m/z 172 (MϩϪCl); HR-MS 19) Effenberger F., Angew. Chem. Int. Ed. Engl., 33, 1555—1564 (1994).
Calcd for C8H11Cl2NO 207.0218, Found 207.0216; [a]D25 ϩ46° (cϭ1.04, 1 N
20) Gregory R. J. H., Chem. Rev., 99, 3649—3682 (1999).
HCl) (99% ee). HPLC (DAICEL CROWNPAK CR(ϩ), aq. HClO4 (pH 2), 21) Takamura M., Hamashima Y., Usuda H., Kanai M., Shibasaki M.,
0.5 ml/min) tR 18.1 and 21.5 min. Angew. Chem. Int. Ed. Engl., 39, 1650—1652 (2000).
Procedure for Recovery and Reuse the Bifunctional Ligand 42 After 22) Takamura M., Hamashima Y., Usuda H., Kanai M., Shibasaki M.,
completion of the asymmetric cyanosilylation of benzaldehyde, the reaction
was quenched by adding 1 N HCl. The mixture was stirred vigorously at
room temperature for 1 h, then the product was extracted with ethyl acetate.
The combined organic layer was washed with brine and dried over Na2SO4.
The solvents were removed in vacuo and diethyl ether was added to the re-
Chem. Pharm. Bull., 48, 1586—1592 (2000).
23) Sawada D., Shibasaki M., Angew. Chem. Int. Ed. Engl., 39, 209—213
(2000).
24) Sawada D., Kanai M., Shibasaki M., J. Am. Chem. Soc., 122, 10521—
10532 (2000).
sulting residue. The suspended residue was filtered and washed with diethyl 25) Funabashi K., Ratni H., Kanai M., Shibasaki M., J. Am. Chem. Soc.,
ether to afford ligand 42. The ligand was purified by recrystallization from
CH2Cl2–Et2O (96% yield).
Procedures for Kinetic Studies Samples for kinetic studies were pre-
pared as followed:
123, 10784—10785 (2001).
26) Yabu K., Masumoto S., Yamasaki S., Hamashima Y., Kanai M., Du W.,
Curran D. P., Shibasaki M., J. Am. Chem. Soc., 123, 9908—9909
(2001).
(a) In the Case of the Cyanosilylation in the Absence of the Protic Addi-
tive: Well-dried ligand 42 (26 mg, 36.4 mmol), MeP(O)Ph2 (29.8 mg,
27) Takamura M., Funabashi K., Kanai M., Shibasaki M., J. Am. Chem.
Soc., 123, 6801—6808 (2001).
138 mmol), and 0.70 ml of CD2Cl2 were placed in a dried 5-mm NMR tube. 28) Takamura M., Yanagisawa H., Kanai M., Shibasaki M., Chem. Pharm.
Et2AlCl (38 ml, 35.4 mmol, 0.93 M in hexane) was added under argon atmos-
phere at room temperature and the mixture was allowed to stand for 1 h. The
resulting solution was cooled down to Ϫ40 °C, followed by the addition of
Bull., 50, 1118—1121 (2002).
29) Masumoto S., Suzuki M., Kanai M., Shibasaki M., Tetrahedron Lett.,
43, 8647—8651 (2002).
benzaldehyde (39.0 ml, 0.384 mmol) and TMSCN (62 ml, 0.46 mmo1) in 30) Atazanavir is also known by the experimental name BMS-232632 or
0.2 ml of CD2Cl2. The sample was quickly loaded into an NMR machine, CGP-73547, see ref. 31—33.
then the reaction rate was measured by comparison of the integration ratio 31) Bold G., Fässler A., Capraro H.-G., Cozens R., Klimkait T., Lazdins J.,
between the aldehyde proton and the methine proton of the product.
(b) Cyanosilylation in the Presence of the Protic Additive: A solution of
TMSCN (62 ml, 0.46 mmo1) and MeOH (0.80 ml, 19.2 mmol) in 0.2 ml of
Mestan J., Poncioni B., Rosel J., Stover D., Tintelnot-Blomley M.,
Acemoglu F., Ucci-Stoll K., Wyss D., Lang M., J. Med. Chem., 41,
3387—3401 (1998).
CD2Cl2 was used instead of the above mentioned TMSCN solution. These 32) Rabasseda X., Silvestre J., Castaner J., Drugs Fut., 24, 375—380
kinetic studies indicated an apparent difference of the initial rates between
two the reactions (a, b) as follows.
(1999).
33) Xu Z., Singh J., Schwinden M. D., Zheng B., Kissick T. P., Patel B.,
Humora M. J., Quiroz F., Dong L., Hsieh D.-M., Heikes J. E.,
Pudipeddi M., Lindrud M. D., Srivastava S. K., Kronenthal D. R.,
Mueller R. H., Org. Process Res. Dev., 6, 323—328 (2002).
34) Currier J. S., Havlir D. V., Topics in HIV Medicine, 10, 11—17 (2002).
35) Wilkin T. J., Hay C. M., Hogan C. M., Hammer S. M., Topics in HIV
Medicine, 10, 18—35 (2002).
a; va,initialϭ1.26ϫ10Ϫ2
b; vb,initialϭ1.80ϫ10Ϫ2
kadditive/kno-additiveϭvb,initial/va,initial
ϭ1.80ϫ10Ϫ2/1.26ϫ10Ϫ2ϭ1.43
36) We successfully demonstrated the catalytic asymmetric Strecker-type
reaction of various N-fluorenyl aldimines in the presence of 9 mol% of
catalyst (R)-1 and 20 mol% of PhOH as a proton source. Pivalaldehyde
imine could give the corresponding the D-aminonitrile in 44 h in 97%
yield with 78% ee, and then be converted to D-tert-leucine through
three steps in high yield and without racemization. L-tert-Leucine was
obtained by the same methods as described above, using 9 mol% of the
catalyst (S)-1. L-tert-Leucine was treated with methyl chloroformate
and gave the methyl carbamate 4 in 80% yield with 77% ee, and then
enantiomerically pure 4 was produced by recrystallization from
iPrOH–hexane, see ref. 21, 22.
Acknowledgments We gratefully acknowledge Prof. Miyaura, Hokkaido
University, for advice on the synthesis of the biaryl 8. Financial support was
provided by CREST, The Japan Science and Technology Corporation (JST),
and RFTF of Japan Society for the Promotion of Science.
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