Concise asymmetric synthesis of β-hydroxy α-amino acids using the sulfinimine-mediated asymmetric strecker synthesis: Phenylserine and β-hydroxyleucine

Full text of DOI:10.1021/jo000559h

J . Org. Chem. 2000, 65, 7663-7666
7663
As a continuation of our studies of the sulfinimine
mediated asymmetric Strecker synthesis5,16,17 and its
application to the enantioselective synthesis of â-substi-
tuted R-amino acids, we describe a general route to
â-hydroxy R-amino acids. The overall strategy is il-
lustrated in Scheme 1 and involves the conversion of an
enantiopure R-substituted aldehyde to an R-substituted
sulfinimine. Addition of HCN affords the R-amino nitrile,
which is hydrolyzed to the amino acid. This general
approach has recently been employed in the asymmetric
synthesis of â-fluoro R-amino acids5 and (2R,3S)-alloiso-
leucine.17 In these studies it was established that the
sulfinyl group controlled the stereoselective addition of
cyanide to the imine. However, there was no assurance
that similar stereocontrol would be observed for â-hy-
droxy sulfinimines because of the better coordinating
ability of oxygen. Herein we report concise asymmetric
syntheses of all four stereoisomers of phenylserine and
(2R,3S)-â-hydroxy leucine.
(R)-(-)- and (S)-(+)-2-[(tert-Butyldimethylsilyl)oxy]-2-
phenylethanal (1) were prepared from commercially
available mandelic acid in 80% yield using a literature
procedure.19 Treatment of these protected aldehydes with
commercially available (S)-(+)- and (R)-(-)-p-toluene-
sulfinamide (2) in the presence of 6 equiv of Ti(OEt)4 in
CH2Cl2 for 2 h gave the corresponding sulfinimines 3 and
4 in 47-73% yield (Scheme 2).20 The modest yields of 3
and 4 may reflect some deprotection of the TBDMS group
during the course of the reaction, because yields generally
exceed 80%.20
Con cise Asym m etr ic Syn th esis of
â-Hyd r oxy r-Am in o Acid s Usin g th e
Su lfin im in e-Med ia ted Asym m etr ic Str eck er
Syn th esis: P h en ylser in e a n d
â-Hyd r oxyleu cin e
Franklin A. Davis,* Vaidyanathan Srirajan,
Dean L. Fanelli, and Padma Portonovo
Department of Chemistry, Temple University,
Philadelphia, Pennsylvania 19122
fdavis@astro.ocis.temple.edu
Received April 13, 2000
â-Hydroxy R-amino acids are an important class of
amino acids that are found in nature (threonine, serine,
and â-hydroxy proline) and as constituents of more
complex natural products. For example, â-hydroxy ty-
rosine and â-hydroxyphenylalanine derivatives are found
in clinically important glycopeptide antibiotics, which
include teicoplanin, ristocetin, actaplanin (A4696), and
(A33512b).1 â-Hydroxyleucine is found in lysobactin2 and
MeBmt in cyclosporin.3 These densely functionalized
amino acids are also useful building blocks for the
asymmetric synthesis of â-lactams,4 â-fluoro R-amino
acids,5 and sugars.6 As a consequence of the essential role
played by these amino acids in biological systems and
their utility as synthetic building blocks, a number of
useful strategies have been devised for their preparation.7
Recent methods include Sharpless AE,8 Sharpless AD,9
electrophilic amination10 and hydroxylation,11 stereose-
lective hydrolysis of aziridine carboxylate esters,12 aldol
condensation13 from oxazolidinone intermediates,14 and
others.15
Next, the sulfinimines were treated with ethylalumi-
num cyanoisopropoxide [EtAl(O-i-Pr)CN], generated in
situ by addition of 1.0 equiv of i-PrOH to 1.5 equiv of
diethylaluminum cyanide (Et2AlCN) (Scheme 3). If the
sulfinyl group controls the stereoselectivity according to
TS-1 then re face addition of CN to sulfinimines (SS,2R)-
(+)-3 and (SS,2S)-(+)-4 is predicted to give (SS,2R,3R)-
(+)-5 and (SS,2R,3S)-(+)-6, respectively, and was con-
firmed in the synthesis of phenylserine (2S,3R)-7 and
(2S,3S)-8 of known absolute configurations. In a similar
(1) Rao, A. v. R.; Gurjar, M. K.; Reddy, K. L.; Rao, A. S. Chem. Rev.
1995, 95, 2135.
(2) Nagamitsu, T.; Sunazuka, T.; Tanaka, H.; Omura, S.; Sprengeler,
P. A.; Smith, A. B., III. J . Am. Chem. Soc. 1996, 118, 3584.
(3) Evans, D. A.; Weber, A. E. J . Am. Chem. Soc. 1986, 108, 6757.
(4) (a) Miller, M. J . Acc. Chem. Res. 1986, 19, 49. (b) Lotz, B. T.;
Miller, J . J . J . Org. Chem. 1993, 58, 618.
(5) For leading references see: Davis, F. A.; Srirajan, V.; Titus, D.
D. J . Org. Chem. 1999, 64, 6931.
(6) (a) Fuganti, G.; Grasselli, P.; Pedrocchi-Fantoni, G. J . Org. Chem.
1983, 48, 909. (b) Garner, P.; Ramakanth, S. J . Org. Chem. 1986, 51,
2609. (c) Maurer, P. J .; Knudsen, C. G.; Palkowitz, A. D.; Rapoport,
H. J . Org. Chem. 1985, 50, 325. (d) Boutin, R. H.; Rapoport, H. J . Org.
Chem. 1986, 51, 5320.
(7) For leading references see: (a) Blaskovich, M. A.; Evindar, G.;
Rose, N. G. W.; Wilkinson, S.; Luo, Y.; Lajoie, G. A. J . Org. Chem.
1998, 63, 3631. (b) Williams, R. M. Synthesis of Optically Active
R-Amino Acids; Pergamon: Oxford, U.K., 1989. (c) Duthaler, R. O.
Tetrahedron 1994, 50, 1539.
(8) (a) Reference 2. (b) Caldwell, C. G.; Bondy, S. S. Synthesis 1990,
34. (c) J ung, M. E.; J ung, Y. H. Tetrahedron Lett. 1989, 30, 6637.
(9) Shao, H.; Rueter, J . K.; Goodman, M. J . Org. Chem. 1998, 63,
5240. (b) Shao, H.; Goodman, M. J . Org. Chem. 1996, 61, 2582. (c)
Rao, A. V. R.; Chakraborty, T. K.; Reddy, J . L.; Rao, A. S. Tetrahedron
Lett. 1994, 35, 5043. (d) Hale, K. J .; Manaviazar, S.; Delisser, V. M.
Tetrahedron Lett. 1994, 35, 9181.
(14) (a) Laib, T.; Chastanet, J .; Zhu, J . Tetrahedron Lett. 1997, 38,
1771. (b) Williams, L.; Zhang, Z.; Shao, F.; Carroll, P. J .; J oullie, M.
M. Tetrahedron 1996, 52, 11673. (c) Kanemasa, S.; Mori, T.; Tat-
sukawa, A. Tetrahedron Lett. 1993, 34, 8293. (d) Cardani, S.; Bernardi,
A.; Colombo, L.; Gennari, C.; Scolastico, C.; Venturini, I. Tetrahedron
1988, 44, 5563.
(15) (a) Adams, Z. M.; J ackson, R. F. W.; Palmer, N. J .; Rami, H.
K.; Wythes, M. J . J . Chem. Soc., Perkin Trans. 1 1999, 937. (b) Morgan,
A. J .; Masse, C. E.; Panek, J . S. Org. Lett. 1999, 1, 1949. (c) J ackson,
R. F. W.; Palmer, N. J .; Wythes, M. J .; Clegg, W.; Elsegood, M. R. J . J .
Org. Chem. 1995, 60, 6431. (d) Boger, D. L.; Zhou, J .; Borzilleri, R.
M.; Nukui, S.; Castle, S. L. J . Org. Chem. 1997, 62, 2054. (e) Girard,
A.; Greck, C.; Ferroud, D.; Genet, J . P. Tetrahedron Lett. 1996, 36,
6803. (f) Zandbergen, P.; Brussee, J .; van der Gen, A. Tetrahedron:
Asymmetry 1992, 3, 769.
(16) (a) Davis, F. A.; Fanelli, D. L. J . Org. Chem. 1998, 63, 1981.
(b) Davis, F. A.; Portonovo, P. S.; Reddy, R. E.; Chiu, Y.-H. J . Org.
Chem. 1996, 61, 440.
(17) Portonovo, P.; Liang, B.; J oullie, M. M. Tetrahedron: Asymmetry
1999, 10, 1451.
(10) Guanti, G.; Banfi, L.; Narisano, E. Tetrahedron 1988, 44, 5553.
(11) Fernandez-Meria, E.; Paz, M. M.; Sardina, F. J . J . Org. Chem.
1994, 59, 7643.
(12) (a) Tomashini, C.; Vecchione, A. Org. Lett. 1999, 1, 2153. (b)
Davis, F. A.; Liu, H.; Reddy, G. V. Tetrahedron Lett. 1996, 37, 5473.
(c) Davis, F. A.; Reddy, G. V. Tetrahedron Lett. 1996, 37, 4349. (c)
Davis, F. A.; Zhou, P.; Reddy, R. E. J . Org. Chem. 1994, 59, 3243. (e)
Davis, F. A.; Zhou, P. Tetrahedron Lett. 1994, 35, 7525.
(13) Blaser, D.; Seebach, D. Liebigs Ann. Chem. 1991, 1067.
(18) Davis, F. A.; Srirajan, V. J . Org. Chem. 2000, 65, 3248.
(19) (a) Kobayashi, Y.; Takemoto, Y.; Kamijo, T.; Harada, H.; Ito,
Y.; Terashima, S. Tetrahedron 1992, 48, 1853. (b) Andreoli, P.; Cainelli,
G.; Panunzio, M.; Bandini, E.; Martelli, G.; Spunta, G. J . Org. Chem.
1991, 56, 5984.
(20) (a) Davis, F. A.; Zhang, Y.; Andemichael, Y.; Fang, T.; Fanelli,
D. L.; Zhang, H. J . Org. Chem. 1999, 64, 1043. (b) Fanelli, D. L.;
Szewczyk, J . M.; Zhang, Y.; Reddy, G. V.; Burns, D. M. Davis, F. A.
Org. Synth. 1999, 77, 50.
10.1021/jo000559h CCC: $19.00 © 2000 American Chemical Society
Published on Web 10/04/2000

7664 J . Org. Chem., Vol. 65, No. 22, 2000
Notes
Sch em e 1
Sch em e 3
Sch em e 2
Sch em e 4
manner Si face addition to (RS,2R)-(-)-4 and (RS,2S)-
(-)-3 gave (RS,2S,3R)-(-)-6 and (RS,2S,3S)-(-)-5, respec-
tively.
The diastereoselectivities for addition of EtAl(O-i-Pr)-
CN to pseudoenantiomers (+)-3/(-)-3 was 87% and 74%
de, respectively, while for (+)-4/(-)-4 the de was >96%
(Scheme 3). These results suggest the operation of a
double stereo-differentiation effect where the chirality of
the resident hydroxyl moiety influences the asymmetric
induction. In this context (+)-4/(-)-4 would be considered
a “matched pair”, while (-)-3/(+)-3 would be the “mis-
matched pair”. However, the effect is weak, and the chi-
rality of the sulfinyl group overrides any influence
that the R-hydroxyl group may have and controls the
asymmetric induction. It is interesting to note for chiral
R-methyl and R-fluoro groups (Scheme 1) a double
stereo-differentiation effect was not detected.5,18 The fact
that one is observed here may reflect the bulkiness of
the TBDMS protecting group, because silyl ethers are
generally considered to be weak Lewis bases.21 The
R-amino nitrile diastereoisomers were readily separated
by chromatography or crystallization to give the yields
of the major pure diastereoisomers as indicated in
Scheme 3.
Hydrolysis of the diastereomeric pure R-amino nitriles
(+)-5/(-)-5 and (-)-6/(+)-6 was accomplished by refluxing
with 3 N HCl for 4 h. Ion-exchange chromatography
(Dowex-50) gave phenylserines 7 and 8 in 46-88% yield
(Scheme 4). They were identified by comparison with
literature, which indicated that they were >95% enan-
tiomerically pure.22
(2R,3S)-3-Hydroxyleucine (11), a popular target,2,8b,c,9d,23
was readily prepared as before from (S)-(+)-2-(benzyloxy)-
3-methylbutanal (8) synthesized according to the method
of J oullie et al. from L-valine (Scheme 5).23 Thus addition
(22) These reaction conditions have been previously estabilished not
to lead to racemization.5,16,17 If epimerization of one to the stereocenters
had occurred in the hydrolysis process the diastereoisomers would been
detected by NMR.
(21) Overman, L. E.; McReaday, R. T. Tetrahedron Lett. 1982, 23,
2355. Hale, M. R.; Hoveyda, A. H. J . Org. Chem. 1992, 56, 1643.

Notes
J . Org. Chem., Vol. 65, No. 22, 2000 7665
(R S ,2S)-(-)-N -[(t er t -Bu t yld im e t h ylsilyl)oxy]-2-p h e n -
yla cetylid en e]-p-tolu en esu lfin a m id e (3). Chromatography
Sch em e 5
(hexane/EtOAc, 90:10) gave 0.255 g (65%) of (-)-3 as a gel: [R]20
D
-184.3 (c 0.7, CHCl3); 1H NMR (CDCl3) δ 0 (s, 3H), 0.15 (s, 3H),
0.9 (s, 9H), 2.4 (s, 3H), 5.47 (d, J ) 5.5 Hz, 1H), 7.2-7.3 (m,
7H), 7.42 (d, J ) 8.4 Hz, 2H), 8.1 (d, J ) 5.1 Hz, 1H); 13C NMR
(CDCl3) δ -0.45, -0.4, 18.5, 22.0, 26.8, 77.0, 126.0, 127.0, 129.2,
130.1, 131.2, 139.2, 141.9, 142.4, 166.9; IR 1620 cm-1; HRMS
calcd for C21H29NO2SSi (M + Na) 410.1586, found 410.1586.
(R S ,2R )-(-)-N -[(t er t -Bu t yld im e t h ylsilyl)oxy]-2-p h e n -
yla cetylid en e]-p-tolu en esu lfin a m id e (4). Chromatography
(hexane/EtOAc, 90:10) afforded 0.285 g (73%) of (-)-4 as an oil;
[R]20 -173.8 (c 0.85, CHCl3); 1H NMR (CDCl3) δ -0.1 (2s, 6H),
D
0.8 (s, 9H), 2.4 (s, 3H), 5.4 (d, J ) 5.9 Hz, 1H), 7.3-7.5 (m, 7H),
7.55 (d, J ) 6.6 Hz, 2H), 8.0 (d, J ) 5.9 Hz, 1H); 13C NMR
(CDCl3) δ -4.0, 18.7, 21.9, 26.3, 76.7, 125.1, 126.8, 128.8, 129.2,
130.3, 139.7, 142.3, 166.7; IR: 1624 cm-1. Anal. Calcd for C21H29
-
NO2SSi: C, 65.07; H, 7.54; N, 3.61. Found: C, 64.60; N, 7.67;
N, 3.26.
of EtAl(O-i-Pr)CN to sulfinimines (-)-9 afforded the
R-amino nitrile 10 in 94% yield and 74% de. Hydrolysis
of the major diastereoisomer and isolation gave (2R,3S)-
(+)-11 in 64% isolated yield and >95% ee.
(S S ,2R )-(+)-N -[(t er t -Bu t yld im e t h ylsilyl)oxy]-2-p h e n -
yla cetylid en e]-p-tolu en esu lfin a m id e (3). Chromatography
(hexane/Et0Ac, 90:10) provided 0.34 g (66%) of ( + )-3: mp 60-
61 °C; [R]20 79.5 (c 4.3, CHCl3); 1H NMR (CDCl3) δ 0.67 (2s,
D
6H), 0.9 (s, 9H), 2.39 (s, 3H), 5.46 (d, J ) 5.2 Hz, 1H), 7.21-
7.39 (m, 7H), 7.42 (d, J ) 8.1 Hz, 2H), 8.1 (d, J ) 5.2 Hz, 1H);
13C NMR (CDCl3) δ -4.3, -3.9, 1.6, 18.9, 22.1, 24.7, 29.3, 77.0,
125.3, 126.9, 128.7, 129.1, 130.4, 139.4, 1141.9, 142.3, 166.8. IR:
1623. Anal. Calcd for C21H29NO2SSi: C, 65.07; H, 7.54; N, 3.61.
Found: C, 65.01; H, 7.38; N, 3.58.
In summary, enantiopure R-hydroxy aldehydes are
efficiently transformed, in good yield and high diaste-
reoselectivity, to â-hydroxy R-amino acids via the sulfin-
imine-mediated asymmetric Strecker synthesis.
Gen er a l P r oced u r e for th e Ad d ition of Et2AlCN/i-P r OH
to th e Su lfin im in es. (SS,2R,3S)-(+)-N-(p-Tolu en esu lfin yl)-
2-a m in o-[(ter t-bu tyl-d im eth ylsilyl)oxy]-3-p h en ylp r op ion i-
tr ile (6). In an oven dried two neck 100 mL round-bottom flask
fitted with a magnetic stir bar and an argon balloon was placed
a solution of (+)-4 (0.31 g, 0.8 mmol) in THF (15 mL), and the
mixture was cooled to -78 °C. In a separate one neck round-
bottom flask equipped with a magnetic stir bar under argon,
was placed a solution of diethyl aluminum cyanide (1.2 mL, 1.2
mmol) in THF (10 mL). The reaction mixture was cooled to 0
°C, and i-PrOH (0.08 mL) was added via syringe, stirred at this
temperature for 10-15 min, and then cannulated to the sulfin-
imine solution at -78 °C. The reaction mixture was allowed to
warm to room temperature, stirred for 8 h, cooled to -78 °C,
and quenched with a saturated NH4Cl solution (10 mL). The
solution was filtered through Celite and washed with EtOAc (2
× 15 mL), and the combined organic phases were washed with
brine (15 mL), dried (MgSO4), and concentrated. Flash chroma-
tography (hexane/EtOAc, 85:15) afforded 0.34 g (93% of major
Exp er im en ta l Section
Gen er a l P r oced u r e. Column chromatography was per-
formed on silica gel, Merck grade 60 (230-400 mesh). Analytical
and preparative thin-layer chromatography was performed on
precoated silica gel plates (250 and 1000 µm) purchased from
Analtech Inc. TLC plates were visualized with UV in an iodine
chamber or with phosphomolybdic acid unless noted otherwise.
THF was freshly distilled under nitrogen from a purple solution
of sodium and benzophenone.
Unless stated otherwise, all reagents were purchased from
commercial sources and used without additional purification.
Dichloromethane was distilled over calcium hydride under an
inert atmosphere. THF and ether were freshly distilled under
nitrogen from a purple solution of sodium and benzophenone
ketyl. (S)-(+)-2-[(tert-Butyldimethylsilyl)oxy]-2-phenylethanal (1)
and (R)-(-)-2-[(tert-butyldimethylsilyl)oxy]-2-phenylethanal (1)24
and (S)-(+)-2-(benzyloxy)-3-methylbutanal (8)23 prepared as
previously described.
Gen er a l P r oced u r e for th e Syn th esis of Su lfin im in es.
(SS,2S)-(+)-N-[(ter t-Bu tyldim eth ylsilyl)oxy]-2-ph en ylacetyl-
id en e-p-tolu en esu lfin a m id e (4). In an oven dried 100 mL
single neck round-bottom flask equipped with a magnetic stir
bar under argon was placed a solution of (S)-tert-butyldimeth-
ylsilyloxy phenylethanal (0.525 g, 2.1 mmol) in CH2Cl2 (10 mL).
A solution of (S)-(+)-p-toluenesulfinamide (2) (0.355 g, 2.3 mmol)
in CH2Cl2 (10 mL) and titanium tetraethoxide (2.6 mL, 6 equiv)
was added, and the reaction mixture was stirred at room
temperature for 2 h. After completion, monitored by TLC, the
reaction mixture was cooled to 0 °C, quenched with ice-cold water
(15 mL), filtered through Celite, and washed with EtOAc (3 ×
25 mL). The combined organic phases were washed with brine
(20 mL), dried (MgSO4), and concentrated. Flash chromatogra-
phy (hexane/EtOAc, 10:90) provided 0.38 g (47%) of (+)-4 as an
oil: [R]20D 147.4 (c 0.5, CHCl3); 1H NMR (CDCl3) δ -0.09 (s, 3H),
-0.06 (s, 3H), 0.85 (s, 9H), 2.4 (s, 3H), 5.4 (d, J ) 5.9 Hz, 1H),
7.25-7.40 (m, 7H), 7.55 (d, J ) 8 Hz, 2H), 8.05 (d, J ) 5.9 Hz,
1 H); 13C NMR (CDCl3) δ -4.0, 18.8, 22.1, 26.4, 76.8, 125.2, 126.9,
128.9, 129.3, 130.4, 139.8, 142.1, 142.3, 166.7; IR 2932, 1620
cm-1; HRMS calcd for C21H29NO2SSi (M + Na) 410.1586, found
410.1585.
diastereoisomer) of (+)-6 as an oil: [R]20 66.6 (c 0.45 CHCl3);
D
1H NMR (CHCl3) δ -1.5 (s, 3H), 0.2 (s, 3H), 1.0 (s, 9H), 2.4 (s,
3H), 4.1 (dd, J ) 9.1 & 3.3 Hz, 1H), 5.0 (d, J ) 3.3 Hz, 1H), 5.05
(d, J ) 9.2 Hz, 1H), 7.3-7.4 (m, 7H), 7.57 (d, J ) 8 Hz, 2H); 13
C
NMR (CHCl3) δ -5.1, -4.7, 17.9, 21.1, 25.6, 50.9, 76.8, 116.1,
125.9, 126.4, 128.4, 128.7, 129.8, 138.4, 139.7, 141.9; IR: 3443-
2584, 2249 cm-1; HRMS calcd for C22H30N2O2SSi (M + Na)
437.1694, found 437.1695.
(SS,2S,3R)-(-)-N-(p-Tolu en esu lfin yl)-2-a m in o-[(ter t-bu -
tyld im eth yl-silyl)oxy]-3-p h en ylp r op ion itr ile (6). Chroma-
tography (hexane/EtoAc, 85:15) provided 0.210 g (100% of major
diastereoisomer) of (-)-6 in 96% de as an oil: [R]20 -72.32 (c
D
0.43, CHCl3); IR 2247 cm-1
;
1H NMR (CDCl3) δ -0.1 (s, 3H),
0.19 (s, 3H), 0.95 (s, 9H), 2.4 (s, 3 H), 4.1 (d, J ) 3.3 & 9.2 Hz,
1 H), 5.0 (d, J ) 3.3 Hz, 1H), 5.0 (d, J ) 9.2 Hz, 1H), 7.25-7.39
(m, 7 H), 7.58 (d, J ) 8 Hz, 2H); 13C NMR (CDCl3) δ -4.3, -3.9,
18.8, 21.9, 26.4, 51.9, 77.6, 117.0, 126.7, 127.3, 129.2, 129.6,
130.7, 139.3, 140.4, 142.9. Anal. Calcd for C22H30N2O2SSi: C,
63.73; H, 7.29; N, 6.76. Found: C, 63.42; H, 7.40; N, 6.42.
(RS,2S,3S))-(-)-N-(p-Tolu en esu lfin yl]-2-a m in o-[(ter t-bu -
tyld im eth yl-silyl)oxy]-3-p h en ylp r op ion itr ile (5). Chroma-
tography (hexane/EtOAc, 85:15) gave 0.14 g (72% of major
diastereoisomer) of (-)-5 as a gel: [R]20 -11.4 (c 0.57, CHCl3);
D
1H NMR (CDCl3) δ -0.1 (s, 3H), 0.1 (s, 3H), 0.9 (s, 9H), 2.4 (s,
3H), 4.2 (m, 1H), 4.5 (d, J ) 9.2 Hz, 1H), 4.99 (d, J ) 5.1 Hz,
1H); 7.26-7.5 (m, 9H); 13C NMR (CDCl3) δ -5.3, -5.0, 17.9, 21.3,
25.5, 49.4, 74.7, 116.8, 125.9, 127.3, 128.5, 128.9, 129.8, 137.6,
139.4, 142.2; IR: 3588-3090, 2245 cm-1; HRMS calcd for
(23) Li, W.-R.; Ewing, W. R.; Harris, B. D.; J oullie, M. M. J . Am.
Chem. Soc. 1990, 112, 7659.
(24) (a) Andreoli, P.; Cainelli, G.; Panunzio, M.; Bandini, E.; Martelli,
G.; Spunta, G. J . Org. Chem. 1991, 56, 5984. (b) Kobayashi, Y.;
Takemoto, Y.; Kamijio, T.; Harada, H.; Ito, Y.; Terashima, S. Tetra-
hedron 1992, 48, 1853.
C
22H30N2O2SSi (M + Na) 437.1694, found 437.1694.

7666 J . Org. Chem., Vol. 65, No. 22, 2000
Notes
(SS,2R,3R)-(+)-N-(p-Tolu en esu lfin yl]-2-a m in o-[(ter t-bu -
tyld im eth yl-silyl)oxy]-3-p h en ylp r op ion itr ile (5). Chroma-
tography (hexane/EtOAc, 85:15) provided 0.22 g (76% of major
diastereoisomer) of (+)-5 in as an oil: [R]20D 189.6 (c 1.1, CHCl3);
1H NMR (CDCl3) δ -0.10 (s, 3H), 0.6 (s, 3H), 0.87 (s, 9H), 2,43
(s, 3H), 4.21 (dd, J ) 5.1 & 9 Hz, 1H), 4.5 (d, J ) 9 Hz, 1H), 4.98
(d, J ) 5.1 Hz, 1H), 7.33-7.54 (m, 9H); 13C NMR (CDCl3) δ -4.4,
-4.1, 18.7, 22.1, 26.3, 50.0, 75.4, 117.5, 126.8, 128.0, 129.3, 129.7,
130.6, 138.2, 140.1, 143.0. IR: 3600-3000, 2247. Anal. Calcd
for C22H30N2O2SSi: C, 63.73; H, 7.29; N, 6.76. Found: C, 63.71;
H, 7.22; N, 6.68.
(2S,3R)-(-)-P h en ylser in e (7): 0.08 g (77%); mp 184 °C (dec)
(lit.25a 184-86 °C) (dec); [R]20D -48.2 (c 2.2, 6 N HCl) [lit.27 [R]20
D
-50.2 (c 2, 6 N HCl); [R]20D -32.8 (c 0.10, H2O) [lit.27 [R]20D -31.5
(c 0.1 H2O]; 1H NMR (D2O) δ 4.18 (d, J ) 5.86 Hz, 1 H), 4.88 (d,
J ) 5.86 Hz, 1H), 7.35-7.45 (m, 5 H). Other spectral properties
are in agreement with literature values.
(RS,2S)-(-)-N-[(O-ben zyloxy)-isovela r ylid en e]-p-tolu en e-
su lfin a m id e (9). Chromatography (hexane/EtoAc, 90:10) gave
0.39 g (59%) of (-)-9 as an oil: [R]20 -304 (c 0.5, CHCl3); 1H
D
NMR (CDCl3) δ 0.82 (d, J ) 6.97 Hz, 3H), 0.92 (d, J ) 6.97 Hz,
3H), 2.0 (m, 1H), 2.4 (s, 3H), 3.8 (t, J ) 6.2 Hz, 1H), 4.4 & 4.6
(d, J ) 11.63 Hz, 1 H), 7.2-7.4 (m, 7H), 7.6 (d, J ) 6.6 Hz, 2H),
8.16 (d, J ) 5.5 Hz, 1 H); 13C NMR (CDCl3) δ 18.7, 18.9, 22.0,
32.6, 72.7, 85.4, 125.0, 128.5, 128.6, 129.0, 130.5, 138.4, 142.4,
167.5; IR: 1624 cm-1; HRMS calcd for C19H23NO2S (M + H)
330.1479, found 330.1520.
Gen er a l P r oced u r e for th e Syn th esis of P h en ylser in es.
(2S,3S)-(+)-P h en ylser in e (8). In a single neck 25 mL round-
bottom flask was placed (+)-6 (0.08 g, 0.2 mmol) in 3 N HCl (10
mL), and the solution was refluxed for 4 h. The reaction mixture
was cooled to room temperature and loaded in a DOWEX-50 ion-
exchange resin column, and the column was eluted with distilled
water (70 mL) until the pH became neutral. At this time the
column was eluted with 10% NH4OH (150 mL), and the eluant
was concentrated to afford 0.018 g (52%) of (+)-8: mp 172-174
(R S,2S,3S)-(+)-(N-p -Tolu en esu lfin yl)-2-a m in o-(O-b en z-
yloxy)-3-isovela r on it r ile (10). Chromatography (hexane/
EtOAc, 80:20) gave 0.21 g (94%) of (+)-10 in 74% de as an oil:
1
[R]20 18.9 (c 0.38, CHCl3); H NMR (CDCl3) δ 0.97 (d, J ) 6.6
D
°C (dec) [lit.25a 175 °C (dec)]; [R]20 60.7 (c 0.4, 6 N HCl), [lit.25b
Hz, 3H), 1.1 (d, J ) 6.6 Hz, 3H), 2.0 (m, 1H), 2.45 (s, 3H), 3.37
(dd, J ) 2.2 & 8.8 Hz, 1H), 4.2 (dd, J ) 1.8 & 7.3 Hz, 1H), 4.7
& 4.9 (d, J ) 10.6 Hz, 1H), 5.15 (d, J ) 7.7 Hz, 1H), 7.2-7.4 (m,
7H), 7.6 (d, J ) 6.6 Hz, 2H); 13C NMR (CDCl3) δ 18.0, 18.6, 20.9,
29.7, 41.8, 74.7, 84.7, 118.8, 125.5, 127.9, 128.0, 129.5, 136.8,
139.4, 141.7; IR 3150, 2245, 1595 cm-1; HRMS calcd for
D
[R]20 66.0 (1.07 5 N HCl)]; 1H NMR (D2O) δ 4.1 (d, J ) 5.5 Hz,
D
1H), 4.87 (d, J ) 5.5 Hz, 1H), 7.4 (m, 5H).
(2R,3R)-(-)-P h en ylser in e (8): 0.022 g (46%); mp 174 °C
(dec) [R]20 -63.2 (c 0.65, 6 N HCl); [lit.25b [R]20 -66.0 (c 1.07,
D
D
1
5 N HCl)]; H NMR (D2O) δ 4.09 (d, J ) 5.5 Hz, 1H); 4.87 (d, J
) 5.5 Hz, 1H); 7.4-7.5 (m, 5H). Other spectral properties are
in agreement with literature values.
C
20H24N2O2S (M + Na) 379.1455, found 379.1456.
(2R,3S)-(+)-3-Hyd r oxyleu cin e (11): mp 212-213 °C (lit.2
213-14 °C); [R]20 2.7 (c 0.8, H2O); [R]20 3.5 (c 1, H2O). It has
D
D
(2R,3S)-(+)-P h en ylser in e (7): 0.027 g (88%); mp 182-184
spectral properties identical with literature values.2
26a
°C (lit.
183-186 °C); [R]20 48.7 (c 2.5, 6 N HCl) [lit.27 [R]20
D
D
50.2 (c 2, 6 N HCl)]; [R]20 30.6 (c 0.7, H2O) [lit.27 [R]20 30.2 (c
0.62 H2O]; H NMR (D2O) δ 4.15 (d, J ) 5.86 Hz, 1H); 4.86 (d,
J ) 5.87 Hz, 1H); 7.41-7.44 (m, 5H). Other spectral properties
are in agreement with literature values.
D
D
1
Ack n ow led gm en t. This work was supported by the
National Institutes of Health (GM57870).
Su p p or tin g In for m a tion Ava ila ble: 1H, 13C, and IR
spectra for compounds (-)-3, (+)-4, (-)-5, (+)-6, (-)-9, and (+)-
10. This material is available free of charge via the Internet
at http://pubs.acs.org.
(25) (a) Blaskovich, M. A.; Lajoie, G. A. J . Am. Chem. Soc. 1993,
115, 5021. (b) Harada, K. J . Org. Chem. 1966, 31, 1407.
(26) (a) Herberet, R. B.; Wilkinson, B.; Ellames, G. T. Can. J . Chem.
1994, 72, 114.
(27) Vogler, V. K. Helv. Chim. Acta 1950, 33, 2111.
J O000559H