Asymmetric synthesis of protected 1,2-amino alcohols using tert-butanesulfinyl aldimines and ketimines

Article abstract of DOI:10.1021/jo0156868

tert-Butanesulfinyl aldimines and ketimines bearing an α-benzyloxy or α-silyloxy substituent serve as precursors in the synthesis of protected 1,2-amino alcohols in high yields and diastereoselectivities. General protocols are described for the addition of unbranched alkyl, branched alkyl, and aryl organometallic reagents to N-sulfinyl aldimines 1 and 2 and ketimines 5 and 6. Furthermore, the selective N- or O-deprotection of sulfinamide products 3, 4, 7, and 8 is described, enabling further synthetic transformations of the reaction products.

Full text of DOI:10.1021/jo0156868

8772
J . Org. Chem. 2001, 66, 8772-8778
Asym m etr ic Syn th esis of P r otected 1,2-Am in o Alcoh ols Usin g
ter t-Bu ta n esu lfin yl Ald im in es a n d Ketim in es
Tony P. Tang, Steven K. Volkman, and J onathan A. Ellman*
Department of Chemistry, University of California, Berkeley, Berkeley, California 94720-1460
jellman@uclink.berkeley.edu
Received April 14, 2001
tert-Butanesulfinyl aldimines and ketimines bearing an R-benzyloxy or R-silyloxy substituent serve
as precursors in the synthesis of protected 1,2-amino alcohols in high yields and diastereoselec-
tivities. General protocols are described for the addition of unbranched alkyl, branched alkyl, and
aryl organometallic reagents to N-sulfinyl aldimines 1 and 2 and ketimines 5 and 6. Furthermore,
the selective N- or O-deprotection of sulfinamide products 3, 4, 7, and 8 is described, enabling
further synthetic transformations of the reaction products.
Ta ble 1. Op tim iza tion of Rea ction Con d ition s for th e
In tr od u ction
Ad d ition of t-Bu MgCl to Ald im in e 1
Enantiopure â-amino alcohols are commonly utilized
as building blocks for biologically active compounds,
chiral auxiliaries, and ligands for asymmetric catalysis.1,2
Although several methods exist for the construction of
this structural motif, including the reduction of R-amino
acids,3 asymmetric aminohydroxylation,4 and catalytic
asymmetric ring opening of epoxides,2 highly stereo-
selective methods that enable the incorporation of diverse
substituents are still needed.
Previously, we have reported the utility of tert-butane-
sulfinyl imines for the synthesis of R-branched and R,R-
dibranched amines,5,6 â-amino acids,7 and R,R-disubsti-
tuted R-amino acids.8 Prompted by a recent publication
by Barrow et al.,9 we now report our own efforts toward
the highly diastereoselective synthesis of â-amino alco-
hols utilizing the tert-butanesulfinyl chiral directing
group.
entry
T (°C)
solvent
additive
yielda (%)
drb,c
1
2
3
4
5
6
7
8
-48
-78
-78
-78
-78
-78
-78
-78
CH2Cl2
CH2Cl2
toluene
toluene
CH2Cl2
toluene
CH2Cl2
toluene
-
95
90
84
86
77
23
75
98
80:20
90:10
97:3
87:13
97:3
99:1
98:2
99:1
-
-
MgBr2
BF3‚OEt2
BF3‚OEt2
AlMe3
AlMe3
a
Yields determined by mass balance of purified material.
Ratios determined by HPLC-MS of crude reaction mixtures after
b
workup. c Absolute configuration determined by deprotection and
comparison of optical rotation to literature values.
and (tert-butyldimethylsilyloxy)acetaldehyde afforded N-
sulfinyl imines 1 and 2 in 97 and 96% yields, respectively
(eq 1).9
Resu lts a n d Discu ssion
We envisioned the synthesis of â-amino alcohols via
nucleophilic additions to tert-butanesulfinyl imines (1 and
2) bearing an R-alkoxy or R-silyloxy substitutent. Under
standard CuSO4-mediated conditions,10 the condensation
of tert-butanesulfinamide11 with benzyloxyacetaldehyde
Addition of tert-butylmagnesium chloride to 1 was
initially examined using our previously reported condi-
tions (Table 1, entry 1), which resulted in high conversion
but uncharacteristically low diastereoselectivity.11 How-
ever, upon lowering the temperature from -48 to -78
°C and using toluene as the reaction solvent, increased
selectivities were observed. We have previously observed
that Lewis acid additives increased the yields and
selectivities for additions to alkyl and aryl N-sulfinyl
ketimines.12 Evaluation of Lewis acid additives for ad-
ditions to 1 (eq 2) revealed that the highest yields and
(1) Ager, D. J .; Prakash, I.; Schaad, D. R. Chem. Rev. 1996, 96, 835-
875.
(2) J acobsen, E. N., Pfaltz, A., Yamamoto, H., Eds. Comprehensive
Asymmetric Catalysis; 1st ed.; Springer: Berlin, 1999.
(3) McKennon, M. J .; Meyers, A. I.; Drauz, K.; Schwarm, M. J . Org.
Chem. 1993, 58, 3568-3571.
(4) Demko, Z. P.; Bartsch, M.; Sharpless, K. B. Org. Lett. 2000, 2,
2221-2223.
(5) Cogan, D. A.; Liu, G. C.; Ellman, J . Tetrahedron 1999, 55, 8883-
8904.
(6) Borg, G.; Cogan, D. A.; Ellman, J . A. Tetrahedron Lett. 1999,
40, 6709-6712.
(7) Tang, T. P.; Ellman, J . A. J . Org. Chem. 1999, 64, 12-13.
(8) Borg, G.; Chino, M.; Ellman, J . A. Tetrahedron Lett. 2001, 42,
1433-1436.
(9) Barrow, J . C.; Ngo, P. L.; Pellicore, J . M.; Selnick, H. G.;
Nantermet, P. G. Tetrahedron Lett. 2001, 42, 2051-2054.
(10) Liu, G. C.; Cogan, D. A.; Owens, T. D.; Tang, T. P.; Ellman, J .
A. J . Org. Chem. 1999, 64, 1278-1284.
(11) Liu, G. C.; Cogan, D. A.; Ellman, J . A. J . Am. Chem. Soc. 1997,
119, 9913-9914.
10.1021/jo0156868 CCC: $20.00 © 2001 American Chemical Society
Published on Web 11/29/2001

Protected 1,2-Amino Alcohols Asymmetric Synthesis
J . Org. Chem., Vol. 66, No. 26, 2001 8773
Ta ble 2. Ad d ition of Va r iou s Or ga n om eta llic Rea gen ts
to Ald im in es 1 in Tolu en e
Ta ble 3. Or ga n om eta llic Ad d ition s to N-Su lfin yl Im in e 2
entry
compd
RM
yielda (%)
drb
entry compd
RM
additive yielda (%)
drb
1
2
3
4
5
6
7
8
4a
EtMgCl
EtMgBr
96
91
85
89
88
90
92
95
88:12
91:9
1
2
3
4
5
6
7
8
9
10
11
12
13
14
3a c
EtMgBr
EtMgBr
n-BuMgCl
n-BuMgCl AlMe3
n-BuLi
85
90:10
90:10
90:10
90:10
75:25
97:3
90:10
99:1
97:3
AlMe3
81
80
84
81
87
88
85
84
98
99
95
92
96
4b
n-BuMgCl
n-BuLi/AlMe3
i-PrMgCl
t-BuMgCl
Ph-t-MgBr
PhMgBr
83:17 (91:9)d
91:9
3bc
4c
96:4
96:4
4d c
4e
n-BuLi
AlMe3
AlMe3
AlMe3
AlMe3
AlMe3
90:10 (77:23)d
96:4 (91:9)e
3c
i-PrMgCl
i-PrMgCl
t-BuMgCl
t-BuMgCl
PhMgBr
PhMgBr
PhLi
4fc
a
Yields determined by mass balance of purified material.
Ratios determined by HPLC-MS of crude reaction mixtures after
3d c
3ec
b
99:1
workup. c Absolute configuration determined by deprotection and
93:7 (75:25)d
98:2
d
comparison of optical rotation with literature values. Performed
by Barrow et al.9 with Et2O as solvent. e Performed by Barrow et
al.9 with CH2Cl2 as solvent.
80:20 (81:19)e
96:4
PhLi
a
Yields determined by mass balance of purified material.
diastereoselectivities was observed. Barrow et al. exam-
ined similar Grignard additions (parenthetical references
in entry 3, 7, and 8) using Et2O and CH2Cl2 as reaction
solvents, resulting in comparable drs.9
b
Ratios determined by HPLC-MS of crude reaction mixtures after
workup. c Absolute configuration determined by deprotection and
d
comparison of optical rotation to literature values. Performed by
Barrow et al. with CH2Cl2 as solvent.9 e Performed by Barrow et
al. with hexane as solvent.9
Conversion of products 3a ,13 3b,14 3d , 3e,15 4d ,14 and
4f9 to the respective 1,2-amino alcohols or O-benzyl 1,2-
amino alcohols and comparison to literature optical
rotation values revealed that the sense of induction for
additions to R-benzyloxy or R-silyloxy N-sulfinyl aldi-
mines is opposite from that previously observed for
additions to alkyl and aryl substituted N-sulfinyl imines.5
This reversal of selectivity for N-sulfinyl aldimines
bearing an R-coordinating group has ample precedent.9,16
For Grignard additions to alkyl and aryl N-sulfinyl
aldimines, attack occurs exclusively from the Si face of
the imine (eq 5), where the reaction is postulated to occur
through a six-membered transition state resulting from
the coordination of the E-imine with the incoming nu-
cleophile.5 To explain the reversal in selectivity, Barrow
et al. proposed a transition state in which the Z-imine is
stabilized via coordination of the R-chelating group with
the metal of the incoming nucleophile, which correctly
translates to the observed diastereoselectivity (eq 6, top).
Alternatively, Davis proposed an open transition state
where the six-membered chelate is disrupted by chelation
of the incoming nucleophiles to the R-coordinating group.
The Cram product correctly translates to the observed
diastereoselectivity (eq 6, bottom). Although these two
diastereoselectivites were obtained in the presence of
AlMe3 (Table 1, entry 8). The scope and generality of
organometallic additions to 1 was then examined with
toluene as solvent, with or without AlMe3.
The addition of various Grignard reagents to 1 (Table
2, entries 1, 3, 7, 9, and 11) proceeded in high yields and
diastereoselectivities (90:10 to 99:1), with modest or no
effect observed when the additions were performed in the
presence of AlMe3 (Table 2, entries 2, 4, 8, 10, and 12).
Organolithiums could also be added to imine 1 (Table 2,
entries 5 and 13); however, AlMe3 was required to achieve
high diastereoselectivities (Table 2, entries 6 and 14; eq
3). Barrow et al. also examined the additions of PhMgBr
and PhLi to 1. In their studies, CH2Cl2 provided the
highest diastereoselectivity for PhMgBr addition to 1
(75:25) and hexane provided the highest diastereoselec-
tivity for PhLi addition (81:19).9 Notably, Barrow et al.
did not examine toluene as a solvent.
To determine the effect of the alcohol protecting group
on yield and diastereoselectivity, organometallic addi-
tions to tert-butyldimethylsilyl (TBS) protected imines 2
were examined (Table 3; eq 4). Additions of Grignard
reagents to 2 (Table 3, entries 1-3 and 5-8) proceeded
in high yields (88-96%) and generally high diastereo-
selectivities (83:17 to 96:4). A significant improvement
in diastereoselectivity was observed for 4b (entry 4) using
BuLi with AlMe3 as an additive. AlMe3 was also exam-
ined for other organolithium and Grignard additions to
2; however, no significant enhancement in yields or
mnemonics accurately predict the stereochemistry of
additions to N-sulfinyl aldimines 1 and 2, the actual
(13) Brown, E. Acros Org. Acta 1996, 2, 23.
(14) Segat-Dioury, F.; Lingibe, O.; Graffe, B.; Sacquet, M. C.;
Lhommet, G. Tetrahedron 2000, 56, 233-248.
(15) Ince, J .; Ross, T. M.; Shipman, M.; Ennis, D. S. Tetrahedron:
Asymmetry 1996, 7, 3397-3406.
(12) Cogan, D. A.; Ellman, J . A. J . Am. Chem. Soc. 1999, 121, 268-
269.

8774 J . Org. Chem., Vol. 66, No. 26, 2001
Tang et al.
Ta ble 4. Or ga n om eta llic Ad d ition s to N-Su lfin yl
Ta ble 5. Or ga n om eta llic Ad d ition s to N-Su lfin yl
Ketim in e 6
Ketim in e 5
entry
compd
R1
R2M
yielda (%)
dr
entry compd
LA
R1
R2M
yielda (%)
dr
1
2
3
4
7a
Bn
Bn
Bn
Bn
n-BuLi
n-BuMgCl
PhLi
52
50
42
46
85:15b
82:18b
72:28c
85:15c
1
2
3
4
5
6
7
8
9
10
11
12
13
14
8a d
8b
TBS EtMgCl
83
70
40
85
54
89
91:9c
AlMe3 TBS EtMgCl
AlMe3 TBS EtMgBr
TBS n-BuMgCl
AlMe3 TBS n-BuMgCl
AlMe3 TBS n-BuLi
TBS i-PrMgCl
AlMe3 TBS i-PrMgCl
TBS t-BuMgCl
AlMe3 TBS t-BuMgCl
AlMe3 TBS t-BuLi
TBS PhMgBr
88:12c
68:32c
88:12c
98:2c
7bd
PhMgBr
a
Yields determined by mass balance of purified material.
Ratios determined by 1H NMR integration of crude reaction
95:5c
b
8c
8d
products after workup. c Ratios determined by HPLC-MS of crude
20
96:4c
d
reaction products after workup. Absolute configuration deter-
mined by deprotection and comparison of optical rotation with
literature values.
36
40
93
76
88:12c
60:40b
96:4b
8ed
AlMe3 TBS PhMgBr
AlMe3 TBS PhLi
origin of the stereochemical bias cannot at this point be
ascertained.
78:22b,e
a
The direct synthesis of â,â-disubstituted â-amino al-
cohols could also be achieved by additions to N-sulfinyl
ketimines bearing an R-alkoxy or R-silyloxy substituent.
Standard Ti(OEt)4 mediated condensation of tert-butane-
sulfinamide11 with benzyloxyacetone and ((tert-butyldi-
methylsilyl)oxy)acetone afforded N-sulfinyl ketimines 5
and 6 in 67 and 63% yield, respectively (eq 7).10
Yields determined by mass balance of purified material.
Ratios determined by 1H NMR integration of crude reaction
b
products after workup. c Ratios determined by HPLC-MS of crude
d
reaction products after workup. Absolute configuration deter-
mined by deprotection and comparison of optical rotation with
literature values. e PhLi is only available as a solution in cyclo-
hexane/Et2O; the presence of Et2O may affect diastereoselectivi-
ties.
the difficulty in synthesizing these highly substituted and
hindered amino alcohol derivatives with current methods.
To our knowledge, there has been only one other report
of nuclephilic additions to ketimines to afford â,â-disub-
stituted amino alcohols, and in this study, additions of
unstabilized Grignard reagents were not reported.17
Conversion of products 7b,17 8a ,18 and 8e17 to their
respective amino alcohols and comparison to literature
optical rotation values revealed that the sense of induc-
tion for additions to R-benzyloxy or R-silyloxy N-sulfinyl
ketimines is the same as previously observed for addi-
tions to alkyl and aryl N-sulfinyl ketimines.12 Interest-
ingly, the presence of R-chelating groups does not reverse
the face selectivity of additions to N-sulfinyl ketimines,
as was observed with N-sulfinyl aldimines possessing
R-chelating groups (vide supra).
The N-tert-butanesulfinyl group is orthogonal to the
benzyl ether and TBS ether. Therefore, sulfinamides 3,
4, 7, and 8 can be selectively deprotected at the nitrogen
or oxygen for subsequent organic transformations. For
addition products 3 and 7, the O-benzyl amino alcohol
may be readily accessed by treatment with HCl in MeOH.
For example, treatment of 3d with HCl in MeOH resulted
in the quantitative cleavage of the N-sulfinyl group,
affording O-benzylamine 9 in 97% yield. Deprotection of
the O-benzyl group was achieved via hydrogenolysis,
affording the fully deprotected amino alcohol 10 in 88%
yield (eq 8).
Previously described organolithium additions to N-
sulfinyl ketimines required the use of AlMe3 to activate
the imine toward addition and minimize side reactions.12
Under these conditions, organometallic additions to O-
benzyl imine 5 afforded disubstituted products 7 in
moderate yields and diastereoselectivities (Table 4).
Additions to TBS-protected imine 6 resulted in an
overall increase in diastereoselectivities in the formation
of disubstituted products 8 (Table 5). Unbranched alkyl
Grignard additions to imine 6 proceeded in high yields
and diastereoselectivities with no Lewis acid additives
(Table 5, entries 1 and 4). For aromatic and more
sterically hindered organometallic reagents, however,
activation with a Lewis acid additive was required (Table
5, entries 8 and 13). For aliphatic organolithium reagents,
high diastereoselectivity was observed using AlMe3 ac-
tivation (Table 5, entries 6 and 11).
The lower isolated yields for additions to N-sulfinyl
ketimines can be attributed to two competing side reac-
tions. First, R-deprotonation and self-condensation is
prevalent for the more hindered nucleophiles (i-PrMgCl
and t-BuMgCl). Second, a competitive methyl transfer
from the AlMe3 additive to give 8 (R2 ) Me) occurs in
reactions that proceed with low isolated yield of desired
product (Table 5, entries 3, 5, 8, 10). Despite the moderate
to low yields for these substrates, it is significant to note
Conversely, the TBS group of sulfinamides 4 and 8 can
be selectively removed by treatment with HF in pyridine
(16) Fujisawa, T.; Kooriyama, Y.; Shimizu, M. Tetrahedron Lett.
1996, 37, 3881-3884. Davis, F. A.; Srirajan, V.; Fanelli, D. L.;
Portonovo, P. J . Org. Chem. 2000, 65, 7663-7666. Davis, F. A.;
McCoull, W. J . Org. Chem. 1999, 64, 3396-3397. Heathcock, C. H.
Aldrichim. Acta 1990, 23, 99-111.
(17) Steinig, A. G.; Spero, D. M. J . Org. Chem. 1999, 64, 2406-2410.
(18) Richter, W. J .; Korte, E. H. Ber. Bunsen-Ges. Phys. Chem. 1978,
82, 812-814.

Protected 1,2-Amino Alcohols Asymmetric Synthesis
J . Org. Chem., Vol. 66, No. 26, 2001 8775
formed by the University of California, Berkeley Microana-
lytical Laboratory and MHW Laboratories (Phoenix, AZ).
Gen er a l P r oced u r e for th e Con d en sa tion of Ald e-
h yd es w ith (RS)-ter t-Bu ta n esu lfin a m id e. To a 0.500 M
solution of (RS)-tert-butanesulfinamide (1.10 equiv) in CH2Cl2
was added 2.50 equiv of anhydrous CuSO4 and the aldehyde
(1.00 equiv). The mixture was stirred at room temperature for
24 h. The reaction mixture was filtered through a pad of Celite,
and the filter cake was washed with CH2Cl2 and the filtrate
concentrated.
with no N-sulfinyl cleavage. For example, treatment of
TBS-protected sulfinamide 4d with 14% HF/pyridine in
THF afforded the N-sulfinyl â-amino alcohol 11 in 77%
yield (eq 9).
Furthermore, the simultaneous removal of both the
nitrogen and oxygen protecting groups for sulfinamides
4 and 8 can be readily accomplished. Treatment of TBS-
protected sulfinamide 4d with HCl in MeOH resulted in
the conversion to amino alcohol 10 in 87% yield (eq 10).
(RS)-Ben zyloxyeth yliden e-N-ter t-bu tan esu lfin am ide (1).
The general procedure was followed using (RS)-tert-butane-
sulfinamide (2.66 g, 22.0 mmol, 1.10 equiv), CuSO4 (7.98 g,
50.0 mmol), and benzyloxyacetaldehyde (3.00 g, 20.0 mmol,
1.00 equiv). Pure 1 was obtained (4.92 g, 97.0%) as a clear,
colorless oil after chromatography of the residue (20% EtOAc/
Hex to 50% EtOAc/Hex): [R]23D ) -212 (c ) 1.00, CHCl3); IR
1736, 1632, 1084 cm-1; 1H NMR (400 MHz) δ 1.23 (s, 9H), 4.39
(dd, 1H, J ) 16.3, 3.3), 4.44 (dd, 1H, J ) 16.3, 3.2), 4.65 (s,
2H), 7.32-7.37 (m, 5H), 8.14 (t, 1H, J ) 3.2); 13C NMR (100
MHz) δ 22.31, 56.87, 71.18, 73.20, 127.78, 127.96, 128.47,
137.47, 166.61. Anal. Calcd for C13H19NO2S: C, 61.63; H, 7.56;
N, 5.53. Found: C, 61.48; H, 7.53; N, 5.30.
(RS)-2-Meth ylp r op a n e-2-su lfin ic Acid [2-(ter t-Bu tyld i-
m eth ylsila n yloxy)eth ylid en e]a m id e (2). The general pro-
cedure was followed using (RS)-tert-butanesulfinamide (2.66
g, 22.0 mmol, 1.10 equiv), CuSO4 (7.98 g, 50.0 mmol), and (tert-
butyldimethylsilyloxy)acetaldehyde (3.00 g, 20.0 mmol, 1.00
equiv). Pure 2 was obtained (4.72 g, 85.0%) as a white solid
after chromatography of the residue (10% EtOAc/Hex to 30%
EtOAc/Hex): mp 19 °C; [R]23D ) -187 (c ) 1.00, CHCl3); IR
1087, 1123, 1702 cm-1; 1H NMR (400 MHz) δ 0.10 (s, 6H), 0.91
(s, 9H), 1.20 (s, 9H), 4.54 (d, 2H, J ) 3.2), 8.06 (t, 1H, J )
3.2); 13C NMR (100 MHz) δ -5.43, -5.40, 22.25, 25.65, 56.72,
65.47, 110.40, 168.64. Anal. Calcd for C12H27NO2SSi: C, 51.94;
H, 9.81; N, 5.05. Found: C, 51.76; H, 9.75; N, 4.91.
Con clu sion
We have demonstrated the use of N-tert-butanesulfinyl
imines bearing an R-benzyloxy or R-silyloxy substituent
toward the synthesis of protected mono- and disubsti-
tuted 1,2-amino alcohols. Excellent yields and diastereo-
selectivities for a wide range of nucleophiles were ob-
served. These products can be enriched to diastereomeric
purity with standard chromatography and selectively
deprotected for use in subsequent organic transforma-
tions.
Gen er a l P r oced u r e for th e Con d en sa tion of Keton es
w ith (RS)-ter t-Bu ta n esu lfin a m id e. A 0.5 M solution of Ti-
(OEt)4 (distilled, 2.5 equiv) and ketone (1.0 equiv) in THF was
prepared under a nitrogen atmosphere. To the solution was
then added tert-butanesulfinamide (1.0 equiv), and the flask
was heated to 70 °C. Conversion was followed by TLC, and
the mixture cooled upon reaction completion. Once at room
temperature, the mixture was poured into an equal volume of
brine while being stirred rapidly. The resulting suspension was
filtered through a plug of Celite, and the filter cake was
washed with EtOAc. The filtrate was transferred to a sepa-
ratory funnel, where the aqueous layer was extracted (3 ×
EtOAc). The organic layers were combined, washed with brine,
dried, and concentrated.
Exp er im en ta l Section
Gen er a l P r oced u r e. Unless otherwise noted, all reagents
were obtained from commercial suppliers and were used
without further purification. A solution of 1.0 M AlMe3 in
toluene was prepared from neat AlMe3, obtained from Aldrich
Chemical Co. Grignard reagents were obtained as solutions
in ether, n-BuLi in hexanes, PhLi in cyclohexane/Et2O, and
t-BuLi in pentane. A 14% solution of HF in pyridine was
prepared from 70% HF in pyridine, obtained from Aldrich.
CuSO4 was obtained from Aldrich and flame-dried in vacuo
before use. Ti(OEt)4 was obtained from Strem and distilled
before use. (RS)-tert-Butanesulfinamide was prepared accord-
ing to previously published protocols.11 All solvents were
distilled under N2 from the following drying agents im-
mediately before use: tetrahydrofuran (THF) was distilled
from sodium/benzophenone ketyl, and dichloromethane (CH2-
Cl2) and toluene were distilled from CaH2. Unless otherwise
noted, all reactions were carried out in flame-dried glassware
under an inert N2 atmosphere. Chromatography was carried
out using Merck 60 Å 230-400 mesh silica gel. Reaction
progress was monitored with thin-layer chromatography on
Merck 60 F254 0.25 µm silica plates. Unless otherwise noted,
all organic layers were dried over anhydrous MgSO4, and all
solvents were removed with a rotary evaporator equipped with
a KNF Neuberger dry vacuum pump. IR spectra of liquids
were recorded as thin films on NaCl plates, and IR spectra of
solids were recorded as KBr pellets; only partial data are listed.
Unless otherwise noted, NMR spectra were obtained in CDCl3
at room temperature with either a Bruker AM-400 or Bruker
DRX-500. Chemical shifts in NMR spectra are expressed in
parts per million, and all coupling constants expressed in
hertz. Unless otherwise noted, diastereoselectivity was deter-
mined via HPLC-MS with an Agilent 1100 LC-MS equipped
with a C8 Zorbax 2.1 µm × 150 mm column, monitored at 210
and 220 nm. Optical rotations were measured on a Perkin-
Elmer Model 241 polarimeter. Elemental analyses were per-
(RS)-N-(2-(1-Ben zyloxy)p r op ylid en e-2-m eth ylp r op a n e-
su lfin a m id e (5). The general procedure was followed with
665 mg of (RS)-tert-butanesulfinamide (1.00 equiv, 5.48 mmol),
1.00 g of benzyloxyacetone (1.00 equiv, 5.48 mmol) and 2.92
mL of Ti(OEt)4 (2.50 equiv, 13.7 mmol), and 13.0 mL of THF.
Pure 5 was obtained (980 mg, 67.0% yield) as a clear, colorless
oil after column chromatography (15% EtOAc/Hex to 40%
EtOAc/Hex): [R]23D ) -123 (c ) 1.00, CHCl3); IR 1077, 1629,
1732 cm-1 1H NMR (400 MHz) δ 1.26 (s, 9H), 2.37 (s, 3H),
;
4.14 (s, 2H), 4.58 (s, 2H), 7.30-7.39 (m, 5H); 13C NMR (100
MHz) δ 19.23, 22.15, 56.65, 72.97, 75.47, 127.67, 127.86,
128.40, 137.30, 181.91. Anal. Calcd for C14H21NO2S: C, 62.89;
H, 7.92; N, 5.24. Found: C, 62.73; H, 7.84; N, 5.09.
(RS)-2-Meth ylp r op a n e-2-su lfin ic Acid [2-(ter t-Bu tyld i-
m eth ylsilan yloxy)-1-m eth yleth yliden e]am ide (6). The gen-
eral procedure was followed with 500 mg of (RS)-tert-butane-
sulfinamide (1.00 equiv, 4.13 mmol), 0.800 mL of (tert-
butyldimethylsilyloxy)acetone (1.00 equiv, 4.13 mmol), 2.20 mL
of Ti(OEt)4 (2.50 equiv, 10.3 mmol), and 9.00 mL of THF. Pure
6 was obtained (770 mg, 63.0% yield) as a brown oil after
column chromatography (5% EtOAc/Hex to 35% EtOAc/Hex):
[R]23D ) -146 (c ) 1.00, CHCl3); IR 1079, 1361, 1631 cm-1
;
1H NMR (400 MHz) δ 0.03 (s, 6H), 0.86 (s, 9H), 1.18 (s, 9H),
2.28 (s, 3H), 4.18 (s, 2H).; 13C NMR (100 MHz) δ -5.56, -5.66,
18.09, 18.71, 22.02, 24.84, 56.40, 69.40, 183.98. Anal. Calcd

8776 J . Org. Chem., Vol. 66, No. 26, 2001
Tang et al.
for C13H29NO2SSi: C, 53.56; H, 10.03; N, 4.80. Found: C, 53.25;
H, 10.10; N, 4.72.
3H, J ) 6.84), 1.19 (s, 9H), 1.91-1.96 (m, 1H), 3.09-3.13 (m,
1H), 3.57-3.62 (m, 2H), 3.65 (d, 1H, J ) 7.97), 4.43 (d, 1H, J
) 11.82), 4.55 (d, 1H, J ) 11.80), 7.22-7.39 (m, 5H); 13C NMR
(100 MHz) δ 18.55, 18.97, 22.64, 29.89, 55.90, 61.37, 70.83,
Gen er a l P r oced u r e for th e Gr ign a r d /Or ga n olith iu m
Ad d it ion s t o N-ter t-Bu t a n esu lfin yl Im in es. To a flame-
dried flask was added imine 1, 2, 5, or 6 (1.0 equiv) in toluene
(0.20 M) and the solution cooled to -78 °C. To this solution
was slowly added the organometallic reagent (1.5 equiv) and
the solution stirred until the reaction was complete as deter-
mined by TLC (1-3 h). Excess organometallic reagent was
quenched with a solution of Na2SO4 (saturated) The resulting
mixture was then warmed to room temperature, dried, filtered
through Celite, and concentrated. The residue was purified
via flash chromatography to afford sulfinamides 3, 4, 7, or 8
(for yields and diastereoselectivities, see Tables 1-5).
Gen er a l P r oced u r e for AlMe3-Med ia ted Or ga n om e-
ta llic Ad d ition s to N-ter t-Bu ta n esu lfin yl Im in es. To a
flame-dried flask was added imine 1, 2, 5, or 6 (1.0 equiv) in
toluene (0.50 M) and the solution cooled to -78 °C. To this
solution was added a solution of AlMe3 in toluene (1.0 M, 1.1
equiv) and the resulting solution stirred for 30 min. This
solution was then slowly transferred over 10 min to a -78 °C
solution of the organometallic reagent (1.5 equiv) in toluene
(0.50 M). The resulting solution was stirred at -78 °C until
the reaction was complete as determined by TLC (1-3 h). A
solution of Na2SO4 (saturated) was then slowly added until
the cessation of gas evolution. The resulting mixture was then
warmed to room temperature, dried, filtered through Celite,
and concentrated. The residue was purified via flash chroma-
tography to afford sulfinamides 3, 4, 7, or 8 (for yields and
diastereoselectivities, see Tables 1-5).
(RS, 1R)-2-Meth ylp r op a n e-2-su lfin ic Acid (1-(Ben zyl-
oxym eth yl)p r op yl)a m id e (3a ). Pure 3a was obtained as a
clear, colorless oil after flash chromatography (50% EtOAc/
Hex to 70% EtOAc/Hex) with yields and diastereoselectivities
given in Table 2: HPLC-MS (70-95% MeOH/H2O over 3 min
at 1 mL/min) tR(major) ) 5.01 min, tR(minor) ) 4.78 min; [R]23D
) -52.7 (c ) 1.00, CHCl3); IR 1069, 1097, 2960 cm-1; 1H NMR
(400 MHz) δ 0.91 (t, 3H, J ) 7.41), 1.22 (s, 9H), 1.57-1.64 (m,
2H), 3.31-3.38 (m, 1H), 3.44 (dd, 1H, J ) 9.38, 5.14), 3.62-
3.65 (m, 2H), 4.48 (d, 1H, J ) 11.9), 4.60 (d, 1H, J ) 11.9),
7.27-7.37 (m, 5H); 13C NMR (100 MHz) δ_10.14, 22.57, 25.75,
55.63, 57.01, 72.75, 72.96, 127.55, 127.63, 128.28, 138.03. Anal.
Calcd for C15H25NO2S: C, 63.56; H, 8.89; N, 4.94. Found: C,
63.78; H, 8.97; N, 4.73.
72.97, 127.53, 127.63, 128.25, 137.99. Anal. Calcd for C16H27
-
NO2S: C, 64.60; H, 9.15; N, 4.71. Found: C, 64.43; H, 9.22;
N, 4.65.
(RS,1R)-2-Met h ylp r op a n e-2-su lfin ic Acid (1-(Ben zyl-
oxym eth yl)-2,2-d im eth ylp r op yl)a m id e (3d ). Pure 3d was
obtained as a clear, colorless oil after column chromatography
(50% EtOAc/Hex to 70% EtOAc/Hex), with yields and diaste-
reoselectivities given in Tables 1 and 2: HPLC-MS (70-95%
MeOH/H2O over 3 min at 1 mL/min) tR(major) ) 5.06 min,
tR(minor) ) 4.61 min; [R]23D ) -47.3 (c ) 1.00, CHCl3); IR
1
1072, 1604 cm-1; H NMR (400 MHz) δ 0.95 (s, 9H), 1.26 (s,
9H), 3.01-3.05 (m, 1H), 3.67 (dd, 1H, J ) 9.93, 4.24), 3.81 (dd,
1H, J ) 9.89, 3.24), 3.97 (d, 1H, J ) 8.52), 4.45 (d, 1H, J )
11.82), 4.61 (d, 1H, J ) 11.81), 7.31-7.35 (m, 5H); 13C NMR
(100 MHz) δ 22.80, 27.21, 35.08, 56.16, 64.27, 70.93, 73.09,
127.40, 127.53, 128.21, 138.20. Anal. Calcd for C17H29NO2S:
C, 65.55; H, 9.38; N, 4.50. Found: C, 65.70; H, 9.49; N, 4.37.
Deter m in a tion of Absolu te Con figu r a tion th r ou gh
Com p a r ison w ith (S)-ter t-Leu cin ol Ben zyl Eth er . (S)-tert-
Leucinol (1.00 equiv, 168 mg) was added to a slurry of NaH
(1.10 equiv, 63.2 mg) in 7.00 mL of THF (0.200 M). After
cessation of gas evolution, the solution was transferred via
filter cannula to a flask containing BnBr (0.175 mL, 1.00 equiv)
in 7.00 mL of THF (0.200 M) and the solution stirred for 6 h.
Concentration and chromatography afforded (S)-tert-leucinol
benzyl ether in 78% yield after column chromatography (CH2-
Cl2 to 10% MeOH/CH2Cl2): [R]23D ) -14.0 (c ) 1.00, CHCl3).
Refer to procedure for 9 for sulfinyl cleavage of 3d : [R]23D )
+17.0 (c ) 1.00, CHCl3).
(RS,1R)-2-Meth ylp r op a n e-2-su lfin ic Acid (2-Ben zyloxy-
1-p h en yleth yl)a m id e (3e). Pure 3e was obtained as a clear,
colorless solid after column chromatography (50% EtOAc/Hex
to 70% EtOAc/Hex), with yields and diastereoselectivities given
in Table 2: mp 73 °C; HPLC-MS (70-95% MeOH/H2O over 3
min at 1 mL/min) tR(major) ) 4.43 min, tR(minor) ) 4.24 min;
[R]23D ) -124 (c ) 1.00, CHCl3); IR 1071, 1603 cm-1; 1H NMR
(400 MHz) δ 1.24 (s, 9H), 3.58-3.68 (m, 2H), 4.25 (s, 1H), 4.53
(d, 1H, J ) 11.95), 4.64 (d, 1H, J ) 11.94), 4.71-4.75 (m, 1H),
7.29-7.40 (m, 10 H); 13C NMR (100 MHz) δ 22.50, 55.40, 57.21,
72.62, 74.01, 127.79, 127.77, 127.89, 128.00, 128.40, 128.42,
137.55, 138.48. Anal. Calcd for C19H25NO2S: C, 68.85; H, 7.60,
N, 4.23. Found: C, 68.80; H, 7.67; N, 4.07.
Absolute configuration was determined through sulfinyl
group cleavage, affording (R)-1-(benzyloxymethyl)propyl-
amine: [R]23D ) -16.2 (c ) 1.00, CHCl3) [lit.: [R]23D ) -18.0
(no conditions given)].13
Absolute configuration was determined through sulfinyl
group cleavage to afford (R)-2-benzyloxy-1-phenylethyl-
amine: [R]23D ) -24.6 (c ) 1.00, CHCl3) [lit.: [R]23D ) -28.3°
(c ) 1.10, CHCl3)].15
(RS,1R)-2-Met h ylp r op a n e-2-su lfin ic Acid (1-(Ben zyl-
oxym eth yl)p en tyl)a m id e (3b). Pure 3b was obtained as a
clear, colorless oil after column chromatography (50% EtOAc/
Hex to 70% EtOAc/Hex), with yields and diastereoselectivities
given in Table 2: HPLC-MS (70-95% MeOH/H2O over 3 min
at 1 mL/min) tR(major) ) 4.44 min, tR(minor) ) 4.24 min; [R]23D
) -44.0 (c ) 1.00, CHCl3); IR 1069, 1604 cm-1; 1H NMR (400
MHz) δ 0.89 (m, 3H), 1.19 (s, 9H), 1.22-1.35 (m, 4H), 1.49-
1.61 (m, 2H), 3.30-3.41 (m, 1H), 3.49 (dd, 1H, J ) 9.35, 5.01),
3.61 (dd, 1H, J ) 9.37, 4.37), 3.66 (d, 1H, J ) 7.15), 4.45 (d,
1H, J ) 11.88), 4.56 (d, 1H, J ) 11.87), 7.24-7.31 (m, 5H);
13C NMR (100 MHz) δ 13.90, 22.40, 22.53, 27.80, 32.48, 55.59,
55.68, 72.94, 73.12, 127.52, 127.62, 128.25, 138.02. Anal. Calcd
for C17H29NO2S: C, 65.55; H, 9.38; N, 4.50. Found: C, 65.50;
H, 9.23; N, 4.36.
(RS,1R)-2-Meth ylp r op a n e-2-su lfin ic Acid [1-((ter t-Bu t-
yld im eth ylsila n yloxy)m eth yl)p r opyl]a m ide (4a ). The gen-
eral procedure was followed with 52 mg of 2 (0.19 mmol), 1.0
mL of toluene, and 0.10 mL of EtMgBr (3.0 M solution in Et2O,
0.29 mmol). Pure 4a (53 mg, 91%) was obtained as a clear,
colorless oil after column chromatography (20% EtOAc/Hex to
60% EtOAc/Hex), with a dr (crude) of 91:9: HPLC-MS (70-
95% MeOH/H2O over 10 min at 1 mL/min) tR(major) ) 11.85
min, tR(minor) ) 11.44 min; [R]23D ) -57.0 (c ) 1.00, CHCl3);
IR 1056, 1077, 1104, 1472 cm-1; 1H NMR (400 MHz) δ 0.05 (s,
3H), 0.06 (s, 3H), 0.88 (s, 9H), 0.88-0.90 (m, 3H), 1.21 (s, 9H),
1.52-1.59 (m, 2H), 3.19-3.23 (m, 1H), 3.57-3.59 (m, 1H),
3.71-3.77 (m, 2H); 13C NMR (100 MHz) δ -5.61, -5.48, 10.08,
18.09, 22.55, 25.25, 25.73, 55.46, 58.33, 65.58. Anal. Calcd for
Absolute configuration was determined through sulfinyl
group and benzyl group cleavage, affording (R)-2-aminohexan-
1-ol: [R]23D ) -12.0 (c ) 1.00, CHCl3) [lit.: [R]23D ) -12.3 (c
) 1.00, CHCl3)].14
C
14H33NO2SSi: C, 54.67; H, 10.81; N, 4.55. Found: C, 54.38;
H, 10.91; N, 4.65.
(RS,1R)-2-Meth ylp r op a n e-2-su lfin ic Acid [1-((ter t-Bu t-
yld im eth ylsila n yloxy)m eth yl)p en tyl]a m id e (4b). Pure 4b
(53 mg, 85%) was obtained as a clear, colorless oil after column
chromatography (20% EtOAc/Hex to 60% EtOAc/Hex), with
yields and diastereoselectivities given in Table 3: HPLC-MS
(70-95% MeOH/H2O over 10 min at 1 mL/min) tR(major) )
13.25 min, tR(minor) ) 12.90 min; [R]23D ) -46.4 (c ) 1.00,
CHCl3); IR 1057, 1075, 1106 cm-1; 1H NMR (400 MHz) δ 0.05
(s, 3H), 0.06 (s, 3H), 0.88 (s, 9H), 1.20 (s, 9H), 1.27-1.36 (m,
(RS,1R)-2-Met h ylp r op a n e-2-su lfin ic Acid (1-(Ben zyl-
oxym eth yl)-2-m eth ylp r op yl)a m id e (3c). Pure 3c was ob-
tained as a clear colorless oil after column chromatography
(50% EtOAc/Hex to 70% EtOAc/Hex), with yields and diaste-
reoselectivities given in Table 2: HPLC-MS (70-95% MeOH/
H2O over 3 min at 1 mL/min) tR(major) ) 5.12 min, tR(minor)
) 4.71 min; [R]23D ) -43.7 (c ) 1.00, CHCl3); IR 1069, 1604
cm-1 1H NMR (400 MHz) δ 0.86 (d, 3H, J ) 6.82), 0.88 (d,
;

Protected 1,2-Amino Alcohols Asymmetric Synthesis
J . Org. Chem., Vol. 66, No. 26, 2001 8777
5H), 1.50-1.64 (m, 2H), 3.19-3.28 (m, 1H), 3.54-3.60 (m, 2H),
3.71-3.74 (m, 2H), 3.75-3.77 (m, 1H); 13C NMR (100 MHz) δ
-5.61, -5.48, 13.89, 18.09, 22.50, 22.54, 25.73, 27.73, 32.01,
55.43, 56.91. Anal. Calcd for C16H37NO2SSi: C, 57.26; H, 11.11;
N, 4.17. Found: C, 56.99; H, 11.21; N, 4.10.
0.07 (s, 3H), 0.91 (s, 9H), 1.23 (s, 9H), 3.59-3.64 (m, 1H), 3.78
(dd, 1H, J ) 10.1, 4.1), 4.29 (m, 1H), 4.51-4.55 (m, 1H), 7.28-
7.36 (m, 5H); 13C NMR (100 MHz) δ -5.61, -5.42, 18.07, 22.47,
25.72, 55.23, 59.25, 67.76, 110.40, 127.95, 128.32, 138.45. Anal.
Calcd for C18H33NO2SSi: C, 60.79; H, 9.35; N, 3.94. Found:
C, 60.40; H, 9.58; N, 3.73.
Absolute determination was determined through deprotec-
tion of 4e, affording (R)-phenylglycinol: [R]23D ) -29.1 (c )
0.750, 1.00 N HCl) [lit.: [R]23D ) -26.7 (c ) 0.075, 1.00 N
HCl)].9
(RS,1R)-2-Meth ylp r op a n e-2-su lfin ic Acid [1-((ter t-Bu t-
yldim eth ylsilan yloxy)m eth yl)-2-m eth ylpr opyl]am ide (4c).
The general procedure was followed with 52 mg of 2 (0.19
mmol), 1.0 mL of toluene, and 0.15 mL of i-PrMgCl (2.0 M
solution in Et2O, 0.29 mmol). Pure 4c (53 mg, 88%) was
obtained as a clear, colorless oil after column chromatography
(20% EtOAc/Hex to 60% EtOAc/Hex), with a dr (crude) of 96:
4: HPLC-MS (70-95% MeOH/H2O over 10 min at 1 mL/min)
tR(major) ) 12.63 min, tR(minor) ) 12.12 min; [R]23D ) -37.1
(RS,1S)-2-Met h ylp r op a n e-2-su lfin ic Acid (1-(Ben zyl-
oxym eth yl)-1-m eth ylp en tyl)a m id e (7a ). Pure 7a was ob-
tained as a clear, colorless oil after column chromatography
(50% EtOAc/Hex to 70% EtOAc/Hex) with yields and diaste-
reoselectivities given in Table 4. (Diastereomeric ratio deter-
mined through comparison of integration of doublets (major)
at 3.26 and 3.40 ppm with doublet at 3.34 ppm: [R]23D ) -57.1
(c ) 1.00, CHCl3); IR 1069 cm-1; 1H NMR (400 MHz) δ 0.90 (t,
3H, J ) 6.9), 1.18-1.19 (m, 12H), 1.21-1.34 (m, 4H), 1.68-
1.72 (m, 2H), 3.26 (d, 1H, J ) 8.9), 3.40 (d, 1H, J ) 8.9), 3.61
(s, 1H), 4.50 (d, 1H, J ) 12), 4.55 (d, 1H, J ) 12), 7.26-7.36
(m, 5H); 13C NMR (100 MHz) δ 13.96, 22.51, 23.04, 23.08,
25.85, 37.80, 55.39, 58.03, 73.10, 76.83, 127.46, 127.49, 128.22,
138.23. Anal. Calcd for C18H31NO2S: C, 66.42; H, 9.60; N, 4.30.
Found: C, 66.60; H, 9.49; N, 4.19.
(RS,1S)-2-Meth ylp r op a n e-2-su lfin ic Acid (2-Ben zyloxy-
1-m eth yl-1-p h en yleth yl)a m id e (7b). Pure 7b was obtained
as a clear, colorless oil after column chromatography (50%
EtOAc/Hex to 70% EtOAc/Hex) with yields and diastereose-
lectivities given in Table 4: HPLC-MS (60.0-97.5% MeOH/
H2O over 20 min at 1 mL/min) tR(major) ) 11.36 min, tR(minor)
) 11.69 min; [R]23D ) -30.9 (c ) 1.00, CHCl3); IR 1068, 1602
cm-1; 1H NMR (400 MHz) δ 1.21 (s, 9H), 1.64 (s, 3H), 3.76 (d,
1H, J ) 9.0), 3.87 (d, 1H, J ) 9.0), 4.09 (d, 1H, J ) 2.8), 4.51
(d, 1H, J ) 12), 4.59 (d, 1H, J ) 12), 7.26-7.43 (m, 8H), 7.49-
7.51 (m, 2H); 13C NMR (100 MHz) δ 22.58, 26.54, 55.87, 60.75,
73.20, 77.53, 126.65, 127.22, 127.50, 127.55, 128.12, 128.24,
137.99, 143.48. Anal. Calcd for C20H27NO2S: C, 69.53; H, 7.88;
N, 4.05. Found: C, 69.37; H, 7.94; N, 3.89.
(c ) 1.00, CHCl3); IR 1077, 1104, 1472 cm-1 1H NMR (400
;
MHz) δ 0.04 (s, 3H), 0.05 (s, 3H), 0.87 (s, 9H), 0.87-0.90 (m,
6H), 1.20 (s, 9H), 1.87-1.94 (m, 1H), 2.93-3.01 (m, 1H), 3.69
(d, 1H, J ) 7.9), 3.73 (d, 2H, J ) 4.5); 13C NMR (100 MHz) δ
-5.65, -5.55, 18.02, 18.51, 18.94, 22.62, 25.70, 29.51, 55.69,
62.63, 63.51. Anal. Calcd for C15H35NO2SSi: C, 56.02; H, 10.97;
N, 4.36. Found: C, 55.97; H, 10.99; N, 4.29.
(RS,R)-2-Meth ylp r op a n e-2-su lfin ic Acid [1-((ter t-Bu t-
yld im eth ylsila n yloxy)m eth yl)-2,2-d im eth ylp r op yl]a m id e
(4d ). The general procedure was followed with 52 mg of 2 (0.19
mmol), 1.0 mL of toluene, and 0.15 mL of t-BuMgCl (2.0 M
solution in Et2O, 0.29 mmol). Pure 4d (57 mg, 90%) was
obtained as a clear, colorless oil after column chromatography
(20% EtOAc/Hex to 60% EtOAc/Hex), with a dr (crude) of 96:
4: HPLC-MS (70-95% MeOH/H2O over 10 min at 1 mL/min)
tR(major) ) 13.38 min, tR(minor) ) 12.50 min; [R]23D ) -80.8
(c ) 1.00, CHCl3); IR 1077, 1111, 1472 cm-1 1H NMR (400
;
MHz) δ 0.05 (s, 3H), 0.06 (s, 3H), 0.88 (s, 9H), 0.92 (s, 9H),
1.23 (s, 9H), 2.84-2.87 (m, 1H), 3.77 (dd, 1H, J ) 10.3, 4.2),
3.94 (dd, 1H, J ) 10.3, 1.8), 4.10 (d, 1H, J ) 7.5); 13C NMR
(100 MHz) δ -5.71, -5.67, 17.93, 22.78, 25.70, 27.27, 35.17,
55.91, 63.29, 64.91. Anal. Calcd for C16H37NO2SSi: C, 57.26;
H, 11.11; N, 4.17. Found: C, 57.14; H, 11.31; N, 4.09. Refer to
details for compound 10 for assignment of absolute configu-
ration.
Deter m in a tion of Absolu te Con figu r a tion of 7b. The
representative procedures were followed for conversion of
O-benzyl sulfinamides 7 to amino alcohols, affording (S)-2-
amino-2-phenylpropan-1-ol (8.6 mg, 70%): [R]23D ) +7.40 (c
) 0.500, EtOH) [lit.: [R]23D ) +14.3 (c ) 0.980, EtOH)].17
(RS,1S)-2-Meth ylp r op a n e-2-su lfin ic Acid [1-((ter t-Bu t-
yldim eth ylsilan yloxy)m eth yl)-1-m eth ylpr opyl]am ide (8a).
Pure 8a was obtained as a clear, colorless oil after column
chromatography (30% EtOAc/Hex to 70% EtOAc/Hex) with
yields and diastereoselectivities given in Table 5: HPLC-MS
(70-95% MeOH/H2O over 10 min at 1 mL/min) tR(major) )
10.45 min, tR(minor) ) 10.69 min; [R]23D ) -43.6 (c ) 1.00,
(RS,R)-2-Meth ylp r op a n e-2-su lfin ic Acid [1-((ter t-Bu t-
yldim eth ylsilan yloxy)m eth yl)-3-ph en ylpr op-2-yn yl]am ide
(4e). Phenylacetylmagnesium bromide was first prepared
according to a modified procedure by Poncini:19 To a 25 mL
Schlenk tube with sidearm under a N2 atmosphere was added
a solution of EtMgBr (0.32 mL, 0.97 mmol, 3.0 M) in Et2O. To
this solution was then added phenylacetylene (0.61 mL, 0.54
mmol). The valve was then closed and the tube heated to 60
˚C for 6 h. The valve was then opened and the solvent
evaporated under a stream of nitrogen for 45 min. To the
residue was added 1.5 mL of toluene and the suspension cooled
to -78 ˚C. To this mixture was added a solution of 2 (75 mg,
0.27 mmol) in 1.5 mL of toluene. Pure 4e (63 mg, 90%) was
obtained as a clear, colorless oil after column chromatography
(30% EtOAc/Hex to 60% EtOAc/Hex), with a dr (crude) of 90:
10: HPLC-MS (70-95% MeOH/H2O over 10 min at 1 mL/
CHCl3); IR 1077, 1463 cm-1 1H NMR (400 MHz) δ 0.06 (s,
;
3H), 0.06 (s, 3H), 0.86-0.94 (m, 3H), 0.90 s, 9H), 1.14 (s, 3H),
1.19 (s, 9H), 1.73 (q, 2H, J ) 7.4), 3.32 (d, 1H, J ) 9.4), 3.51
(d, 1H, J ) 9.4), 3.66 (s, 1H); 13C NMR (100 MHz) δ -5.76,
-5.72, 8.32, 18.08, 21.71, 22.52, 25.71, 30.61, 55.35, 58.77,
69.27. Anal. Calcd for C15H35NO2SSi: C, 56.02; H, 10.97; N,
4.36. Found: C, 55.98; H, 10.99; N, 4.30.
Deter m in a tion of Absolu te Con figu r a tion of 8a . The
general procedure was followed for conversion of TBS protected
sulfinamides 8 to amino alcohols, affording (S)-2-amino-2-
methylbutan-1-ol (9.1 mg, 74%): [R]23D ) -4.40 (c ) 0.500,
EtOH) [lit.: (R)-enantiomer [R]23D ) +3.40 (c not reported,
EtOH)].18
(RS,1S)-2-Meth ylp r op a n e-2-su lfin ic Acid [1-((ter t-Bu t-
yldim eth ylsilan yloxy)m eth yl)-1-m eth ylpen tyl]am ide (8b).
Pure 8b was obtained as a clear, colorless oil after column
chromatography (30% EtOAc/Hex to 70% EtOAc/Hex) with
yields and diastereoselectivities given in Table 5: HPLC-MS
(70-95% MeOH/H2O over 10 min at 1 mL/min) tR(major) )
11.55 min, tR(minor) ) 11.76 min; [R]23D ) -46.5 (c ) 1.00,
CHCl3); IR 1072, 1104, 1471 cm-1; 1H NMR (400 MHz) δ 0.05
(s, 3H), 0.06 (s, 3H), 0.90 (s, 9H), 0.90 (m, 3H), 1.19 (s, 9H),
1.24 (s, 3H), 1.29 (m, 2H), 1.66-1.70 (m, 4H), 3.32 (d, 1H, J )
9.4), 3.51 (d, 1H, J ) 9.4), 3.68 (s, 1H); 13C NMR (100 MHz) δ
1
min) tR(major) ) 9.982 min, tR(minor) ) 10.87 min; H NMR
(400 MHz) δ 0.09 (s, 3H), 0.10 (s, 3H), 0.91 (s, 9H), 1.24 (s,
9H), 3.70-3.77 (m, 1H), 3.80-3.87 (m, 2H), 7.27-7.30 (m, 3H),
7.40-7.44 (m, 2H); 13C NMR (100 MHz) δ -5.45, -5.39, 18.19,
22.49, 25.73, 50.03, 56.18, 66.86, 85.61, 86.44, 128.09, 128.14,
128.27, 131.68. Barrow et al. previously prepared this com-
pound.9
(RS,1R)-2-Meth ylp r op a n e-2-su lfin ic Acid [2-(ter t-Bu t-
yld im eth ylsila n yloxy)-1-p h en yleth yl]a m id e (4f). The gen-
eral procedure was followed with 52 mg of 2 (0.19 mmol), 1.0
mL of toluene, and 0.10 mL of PhMgBr (3.0 M solution in Et2O,
0.29 mmol). Pure 4f (63 mg, 95%) was obtained as a clear,
colorless oil after column chromatography (20% EtOAc/Hex to
60% EtOAc/Hex), with a dr (crude) of 96:4: HPLC-MS (60.0-
97.5% MeOH/H2O over 20 min at 1 mL/min) tR(major) ) 16.70
min, tR(minor) ) 16.45 min; [R]23D ) -111 (c ) 1.00, CHCl3);
IR 1069, 1077, 1630 cm-1; 1H NMR (400 MHz) δ 0.05 (s, 3H),
(19) Poncini, L. J . Org. Chem. 1984, 49, 2031-2032.

8778 J . Org. Chem., Vol. 66, No. 26, 2001
Tang et al.
-5.68, -5.62, 13.99, 18.08, 22.07, 22.52, 23.09, 25.71, 26.16,
37.80, 55.32, 58.53, 69.54. Anal. Calcd for C17H39NO2SSi: C,
58.40; H, 11.24; N, 4.01. Found: C, 58.20; H, 11.13; N, 3.89.
(RS,1S)-2-Meth ylp r op a n e-2-su lfin ic Acid [1-((ter t-Bu t-
yld im eth ylsila n yloxy)m eth yl)-1,2-d im eth ylp r op yl]a m id e
(8c). Pure 8c was obtained as a clear, colorless oil after column
chromatography (30% EtOAc/Hex to 70% EtOAc/Hex) with
yields and diastereoselectivities given in Table 5: HPLC-MS
(70-95% MeOH/H2O over 10 min at 1 mL/min) tR(major) )
11.02 min, tR(minor) ) 11.57 min; [R]23D ) -29.8 (c ) 0.500,
(50% EtOAc/Hex to elute sulfur-containing impurities then
10% MeOH/CH2Cl2): [R]23D ) +17.0 (c ) 1.00, CHCl3), IR 1602
cm-1 1H NMR (400 MHz) δ 0.90 (s, 9H), 1.59 (s, 2H), 2.74
;
(dd, 1H, J ) 9.2, 2.9), 3.25 (t, 2H, J ) 9.1), 3.64 (dd, 1H, J )
9.0, 2.9), 4.51 (d, 1H, J ) 12), 4.53 (d, 1H, J ) 12); 13C NMR
(100 MHz) δ 26.44, 32.94, 59.49, 72.52, 73.21, 127.53, 127.57,
128.35, 138.36. Anal. Calcd for C13H21NO: C, 75.32; H, 10.21;
N, 6.76. Found: C, 75.05; H, 10.23; N, 6.66.
Rep r esen ta tive P r oced u r e for th e Hyd r ogen a tion of
Bn P r otected Am in o Alcoh ols. (R)-ter t-Leu cin ol (10). To
a solution of 9 (32.1 mg, 0.156 mmol) in MeOH (0.500 M) was
added a slurry of dry Pd/C (50.0 mg, 10% Pd) in EtOAc and
then 0.400 mL of HCl/dioxane (10.0 equiv, 1.56 mmol). The
mixture was briefly purged with a stream of H2 and then
stirred overnight under a H2 atmosphere (balloon). The reac-
tion mixture was then filtered through Celite and concen-
trated. The residue was then dissolved in EtOAc and washed
with 5.00 mL of 4 N NaOH. The aqueous layer was extracted
3× with EtOAc, and the combined organic layers were dried
and evaporated to afford pure 10 (16.0 mg, 88.0%). Spectro-
scopic data were consistent with those previously observed.14
Rep r esen ta tive P r oced u r e for th e Dep r otection of
TBS P r otected Su lfin a m id es 4 a n d 8. (R)-ter t-Leu cin ol
(10). To a solution of 4d (50.0 mg, 0.143 mmol) in MeOH (0.300
mL) was added 0.360 mL of 4 N HCl/dioxane (1.43 mmol). The
solution was stirred for 30 min at room temperature and then
concentrated in vacuo. The residue was then dissolved in
EtOAc and washed with 5.00 mL of 4 N NaOH. The aqueous
layer was extracted 3× with EtOAc, and the combined organic
layers were dried and evaporated. Pure 10 (14.6 mg, 87.0%)
was obtained as a clear, colorless oil after column chromatog-
raphy (50% EtOAc/Hex to elute sulfur-containing impurities
then 10% MeOH/CH2Cl2). Spectroscopic data was consistent
with that previously observed: [R]23D ) -34.0 (c ) 1.00, EtOH)
[lit.: (S)-enantiomer [R]26D ) +37.2 (c ) 3.00, EtOH)].14
(RS,R)-2-Meth ylp r op a n e-2-su lfin ic Acid (1-(Hyd r oxy-
m eth yl)-2,2-d im eth ylp r op yl)a m id e (11). In a polypropylene
centrifuge tube was added a solution of 4d (50.0 mg, 0.143
mmol) in THF (0.715 mL) and the solution cooled to 0 ˚C. To
this solution was added 0.715 mL of 14% HF/pyridine. The
solution was stirred at room temperature for 24 h and then
poured into a separatory funnel containing 10.0 mL of NaHCO3
(saturated) and 10.0 mL of EtOAc. The separatory funnel was
agitated until cessation of gas evolution, and then the aqueous
layer was extracted 3× with EtOAc. The organic layers were
washed with brine (1×), dried, and then concentrated. Pure
11 (24.4 mg, 77.0%) was obtained as a clear, colorless oil after
column chromatography (50% EtOAc/Hex): [R]23D ) -30.4 (c
) 0.500, CHCl3); IR 1071 cm-1; 1H NMR (400 MHz) δ 0.95 (s,
9H), 1.29 (s, 9H), 2.98 (m, 1H), 3.43 (m, 1H), 3.94 (m, 1H),
4.59 (m, 1H); 13C NMR (100 MHz) δ 22.80, 26.85, 29.58, 57.07,
64.90, 69.57. Anal. Calcd for C10H23NO2S: C, 54.26; H, 10.47;
N, 6.33. Found: C, 54.01; H, 10.44; N, 6.29.
CHCl3); IR 1072, 1105 cm-1 1H NMR (500 MHz) δ 0.05 (s,
;
3H), 0.06 (s, 3H), 0.90 (s, 9H), 0.94 (d, 3H, J ) 6.9), 0.98 (d,
3H, J ) 3.9), 1.10 (s, 3H), 1.19 (s, 9H), 2.02-2.08 (m, 1H),
3.38 (d, 1H, J ) 9.6), 3.59 (d, 1H, J ) 9.5), 3.69 (s, 1H); 13C
NMR (125 MHz) δ -5.68, -5.63, 17.26, 17.65, 18.09, 19.27,
22.63, 25.76, 33.69, 55.58, 60.98, 68.82. Anal. Calcd for C16H37
-
NO2SSi: C, 57.26; H, 11.11; N, 4.17. Found: C, 57.22; H, 10.98;
N, 4.12.
(RS,1S)-2-Meth ylp r op a n e-2-su lfin ic Acid [1-((ter t-Bu t-
yldim ethylsilanyloxy)m ethyl)-1,2,2-tr im eth ylpr opyl]am ide
(8d ). Pure 8d was obtained as a clear, colorless oil after column
chromatography (30% EtOAc/Hex to 70% EtOAc/Hex) with
yields and diastereoselectivities given in Table 5: HPLC-MS
(70-95% MeOH/H2O over 10 min at 1 mL/min) tR(major) )
10.78 min, tR(minor) ) 11.52 min; [R]23D ) -35.2 (c ) 0.500,
CHCl3); IR 1073, 1432 cm-1 1H NMR (400 MHz) d 0.06 (s,
;
3H), 0.07 (s, 3H), 0.91 (s, 9H), 1.04 (s, 9H), 1.18 (s, 3H), 1.21
(s, 9H), 3.43 (d, 1H, J ) 10), 3.72 (d, 1H, J ) 10), 3.77 (m,
1H); 13C NMR (100 MHz) δ -5.76, -5.72, 14.09, 19.02, 22.61,
25.74, 26.50, 37.14, 55.87, 62.46, 69.31. Anal. Calcd for C17H39
-
NO2SSi: C, 58.40; H, 11.24; N, 4.01. Found: C, 58.32; H, 11.25;
N, 3.87.
(RS,1S)-2-Meth ylp r op a n e-2-su lfin ic Acid [2-(ter t-Bu t-
yldim eth ylsilan yloxy)-1-m eth yl-1-ph en yleth yl]am ide (8e).
Pure 8e was obtained as a clear, colorless oil after column
chromatography (30% EtOAc/Hex to 70% EtOAc/Hex) with
yields and diastereoselectivities given in Table 5. Diastereo-
meric ratio determined through comparison of integration of
doublets (major) at 3.75 and 3.85 ppm with doublets at 3.47
and 3.80 ppm: [R]23D ) -33.8 (c ) 1.00, CHCl3); IR 1071, 1252,
1472 cm-1; 1H NMR (400 MHz) δ -0.09 (s, 3H), -0.04 (s, 3H),
0.83 (s, 9H), 1.24 (s, 9H), 1.62 (s, 3H), 3.75 (d, 1H, J ) 9.5),
3.85 (d, 1H, J ) 9.5), 4.19 (s, 1H), 7.23-7.27 (m, 1H), 7.31-
7.33 (m, 2H), 7.49-7.51 (m, 2H); 13C NMR (100 MHz) δ -5.83,
-5.77, 18.04, 22.59, 25.64, 56.17, 63.21, 71.46, 110.39, 126.89,
127.91, 144.10. Anal. Calcd for C19H35NO2SSi: C, 61.74; H,
9.54; N, 3.79. Found: C, 61.65; H, 9.49; N, 3.75.
Deter m in a tion of Absolu te Con figu r a tion of 8e. The
general procedure was followed for conversion of TBS protected
sulfinamides 8 to amino alcohols, affording 2-amino-2-phenyl-
propan-1-ol (9.1 mg, 70%): [R]23D ) +11.6 (c ) 0.500, EtOH)
[lit.: (S)-enantiomer [R]23D ) +14.3 (c ) 0.980, EtOH)].17
Rep r esen ta tive P r oced u r e for th e Su lfin yl Gr ou p
Clea va ge for Su lfin a m id es 7, (R)-1-(Ben zyloxym eth yl)-
2,2-d im eth ylp r op yla m in e (9). To a 0.160 M solution of
sulfinamide 3d (50.0 mg, 0.161 mmol) in MeOH (1.00 mL) was
added 0.400 mL of 4.00 N HCl/dioxane (10.0 equiv, 1.61 mmol).
The solution was stirred for 30 min at room temperature and
then concentrated in vacuo. Pure 9 (32.1 mg, 97%) was
obtained as a clear, colorless oil after column chromatography
Ack n ow led gm en t. J .A.E. gratefully acknowledges
the support of the NSF. T.P.T. thanks Pharmacia for a
graduate fellowship.
J O0156868