Stereoselective Synthesis of 1,2-Disubstituted β-Amino Alcohols by Nucleophilic Addition to N-tert-Butanesulfinyl α-Alkoxyaldimines

Article abstract of DOI:10.1021/jo035224p

N-tert-Butanesulfinyl α-alkoxyaldimines are readily prepared from protected (S)-lactals without epimerization at the α-stereocenter. Addition of ethyl and phenyl Grignard reagents, as well as the titanium enolate of methyl acetate, to the N-tert-butanesul

Full text of DOI:10.1021/jo035224p

Ster eoselective Syn th esis of 1,2-Disu bstitu ted â-Am in o Alcoh ols by
Nu cleop h ilic Ad d ition to N-ter t-Bu ta n esu lfin yl r-Alk oxya ld im in es
J ared W. Evans and J onathan A. Ellman*
Center for New Directions for Organic Synthesis, Department of Chemistry, University of California,
Berkeley, California 94720
jellman@uclink.berkeley.edu
Received August 20, 2003
N-tert-Butanesulfinyl R-alkoxyaldimines are readily prepared from protected (S)-lactals without
epimerization at the R-stereocenter. Addition of ethyl and phenyl Grignard reagents, as well as
the titanium enolate of methyl acetate, to the N-tert-butanesulfinyl aldimines provides 1,2-
disubstituted â-amino alcohols in good yields (73-98%) and with high diastereoselectivities. Either
syn- or anti-amino alcohol products can be obtained by the appropriate choice of alcohol protecting
groups and/or reaction conditions. Finally, deprotection of the addition products provides straight-
forward access to either syn- or anti-1,2-amino alcohols.
In tr od u ction
Resu lts a n d Discu ssion
P r ep a r a tion of th e N-Su lfin yl Im in es. The N-
sulfinyl aldimines 1a -c (eq 1) and 2a -c (eq 2) were
â-Amino alcohols are important structural motifs in
natural products, pharmacologically active compounds,
chiral auxiliaries, and ligands.1,2 Many methods for the
asymmetric synthesis of 1,2-disubstituted â-amino alco-
hols, such as the enantioselective aminohydroxylation of
alkenes or the reduction of protected R-amino ketones,3,4
rely on functional group interconversion.5 A more con-
vergent approach is the well-studied diastereoselective
addition of nucleophiles to protected, chiral amino alde-
hydes.6 In contrast, only a few reports have appeared on
the alternative convergent approach of nucleophilic ad-
dition to R-alkoxy imines.7 Recently, we have reported,
as have others, on the diastereoselective addition of
nucleophiles to N-tert-butanesulfinyl-R-alkoxyacetaldi-
mines for the expedient asymmetric synthesis of â-amino
alcohols.8 Here we describe the application of this meth-
odology to the synthesis of both syn- and anti-1,2-
disubstituted â-amino alcohols by the addition of nucleo-
philes to N-tert-butanesulfinyl aldimines prepared from
hydroxyl protected (S)-lactals.
prepared by the titanium-mediated condensation of the
corresponding protected (S)-lactals with either (SS)- or
(RS)-tert-butanesulfinamide, respectively.9 Both diaster-
eomers of the protected N-sulfinyl aldimines were syn-
thesized to probe the steric and electronic factors involved
in the addition reactions. Each enantiomer of tert-
butanesulfinamide condensed in good yields and with
comparable rates regardless of the hydroxyl protecting
group. While racemization has previously been reported
for the condensation of R-substituted aldehydes with
amines,10 no epimerization of the R-stereocenter of 1a -c
or 2a -c was detected by chiral HPLC analysis.11
(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, Germany, 1999.
(3) Andersson, M. A.; Epple, R.; Folkin, V. V.; Sharpless, K. B.
Angew. Chem., Int. Ed. 2002, 41, 472-475. Demko, Z. P.; Bartsch, M.;
Sharpless, K. B. Org. Lett. 2000, 2, 2221-2223.
(4) Hoffman, R. V.; Maslouh, N.; Cervantes-Lee, F. J . Org. Chem.
2002, 67, 1045-1056.
(5) For a recent review of asymmetric synthesis of vicinal amino
alcohols see: Bergmeier, S. C. Tetrahedron 2000, 56, 2561-2576.
(6) Reetz, M. Chem. Rev. 1999, 99, 1121-1162.
(7) (a) Ishimaru, K.; Tsuru, K.; Yabuta, K.; Wada, M.; Yamamoto,
Y.; Akiba, K. Tetrahedron 1996, 52, 13137-13144. (b) Cianelli, G.;
Giacomini, D.; Panunzio, M.; Zarantonello, P. Tetrahedron Lett. 1992,
33, 7783. (c) Zietlow, A.; Steckhan, E. J . Org. Chem. 1994, 59, 5658-
5661.
Ad d ition of n u cleop h iles to N-Su lfin yl Im in es. We
initially explored the addition of phenyl and ethyl Grig-
(8) (a) Barrow, J . C.; Ngo, P. L.; Pellicore, J . M.; Selnick, H. G.;
Nantermet, P. G. Tetrahedron Lett. 2001, 42, 2051-2054. (b) Tang, T.
P.; Volkman S. K.; Ellman, J . A. J . Org. Chem. 2001, 66, 8772-8778.
(9) Lui, G.; Cogan, D. A.; Owens, T. D.; Tang, T. P.; Ellman, J . A. J .
Org. Chem. 1999, 64, 1278-1284.
10.1021/jo035224p CCC: $25.00 © 2003 American Chemical Society
Published on Web 11/22/2003
9948
J . Org. Chem. 2003, 68, 9948-9957

Synthesis of 1,2-Disubstituted â-Amino Alcohols
TABLE 1. Or ga n om eta llic Ad d ition s to (RS,2S)
Ben zyloxysu lfin yl Ald im in e
TABLE 2. Or ga n om eta llic Ad d ition s to (SS,2S)
Silyloxysu lfin yl Ald im in e
yielda
(%)
drb
(syn:anti)
temp
(°C) solvent
yielda
drb
entry product R2MgBr
R1
(%) (syn:anti)
entry product
RM
solvent
1
2
3
4
5
6
7
3b
3c
4b
4c
PhMgBr TBDPS -48 CH2Cl2
80c
6:94
7:93
1
2
3
4
5
6
7
5a
PhMgBr toluene
PhMgBr toluene/AlMe3
PhMgBr THF
98
74
23:77
25:75
22:78
5:95
14:86
10:90
2:98
c
PhMgBr TBDPS -48 toluene 86c
PhMgBr TBS
-78 CH2Cl2
-78 toluene 89
73
EtMgBr TBDPS -48 toluene 90
EtMgBr TBS -78 toluene 94
95
75:25
40:60
10:90
17:83
92:8
PhMgBr TBS
PhMgBr THF/TMEDAd
EtMgBr toluene
80
93
93
86
EtMgBr TBDPS -48 CH2Cl2
6a
EtMgBr THF
EtMgBr THF/TMEDAd
a
Yields were determined by mass balance of purified material.
a
Yields were determined by mass balance of purified material.
Ratios were determined by 1H NMR analysis of crude reaction
b
b
Ratios were determined by HPLC-MS analysis of crude reaction
mixtures after workup. c Yield of major diastereomer was deter-
mined by mass balance of purified material.
mixtures after workup. c 1.1 equiv of AlMe3 was used. 2.1 equiv
of TMEDA was added to the Grignard reagent prior to the addition
to the aldimine.
d
entries 1 and 5). We have previously observed that
precomplexation of N-sulfinyl imines with the Lewis acid
AlMe3 can increase yields and diastereoselectivities for
the addition of organometallic reagents.8b However, ad-
dition of PhMgBr to sulfinyl imine 2a in the presence of
1.1 equiv of AlMe3 did not enhance selectivities in this
case (entry 2). Interestingly, greatly increased anti
selectivity (95:5) was observed for the addition of PhMgBr
in the presence of the Lewis base N,N,N,N-tetramethyl-
ethylenediamine (TMEDA) in THF (entry 4). Use of these
improved conditions for the addition of EtMgBr to 2a also
led to a higher level of selectivity (98:2) over additions
run in THF alone (entry 6 vs 7).
nard reagents as solutions in ether to the N-sulfinyl
aldimine (SS,2S)-1a (eq 3). The syn products were ob-
It is interesting to note that anti selectivity was
observed, which suggests that the diastereofacial selec-
tivity afforded by the N-sulfinyl group overrides the
selectivity predicted by the Cram chelate model (eq 4).12
The increased anti selectivity observed in the presence
of TMEDA could be rationalized if TMEDA disrupts the
chelate predicted by Cram’s model.13
To determine the effect of the alcohol protecting group
on the diastereofacial selectivity of the nucleophilic
additions, we examined the addition of the Grignard
reagents to silyl ether protected aldimines (SS,2S)-1b and
(SS,2S)-1c (Table 2). Phenyl Grignard reagent added to
the TBDPS protected imine 1b with high anti selectivities
when either CH2Cl2 or toluene was used as the solvent
(entries 1 and 2). In contrast, poor selectivities were
observed for the addition of PhMgBr to TBS protected
imine 1c regardless of whether CH2Cl2 or toluene was
employed (Table 2, entries 3 and 4). Addition of ethyl
Grignard reagent gave high anti selectivity for the
TBDPS protected imine 1b (Table 2, entries 5 and 6),
while high syn selectivity was observed for the TBS
protected imine 1c (Table 2, entry 7).14 A similarly
dramatic effect of the silyl protecting group (TBS vs TIPS)
tained in high yields and with high stereoselectivities for
both Grignard reagents. Significantly, no epimerization
of the R-stereocenter occurred under the reaction condi-
tions as determined by HPLC analysis.
The observed syn selectivity for the addition of these
nucleophiles to 1a is consistent with the Cram chelate
model for nucleophilic additions into R-alkoxyaldehydes,12
as well as the sense of induction previously observed for
additions to ether protected N-tert-butanesulfinyl R-hy-
droxyacetaldimines (eq 4).8b
The addition of the phenyl and ethyl Grignard reagents
to N-sulfinyl aldimine (RS,2S)-2a proceeded with only
modest diastereofacial selectivities in toluene (Table 1,
(10) Reetz, M. T.; Drewes, M. W.; Schmitz, A. Angew. Chem., Int.
Ed. Engl. 1987, 26, 1141-1143.
(11) For additions to R-aminosulfinyl aldimine see: Prakash, G. K.
S.; Mandal, M. J . Am. Chem. Soc. 2002, 124, 6538-6539. For an
addition to R-alkoxysulfinyl aldimine see: J ung, P. M. J .; Beaudegnies,
R.; De Mesmaeker, A.; Wendeborn, S. Tetrahedron Lett. 2003, 44, 293-
297.
(12) Cram, D. J .; Abd Elhafez, F. A. J . Am. Chem. Soc. 1952, 74,
5828. Stocker, J . H.; Benjamin, B. M.; Collins, C. J . J . Am. Chem. Soc.
1960, 82, 3913.
(13) Rutherford, J . L.; Hoffmann, D.; Collum, D. B. J . Am. Chem.
Soc. 2002, 124, 264-271.
(14) Addition of ethyl Grignard to (SS,2S) silyloxysulfinyl aldimines
1b and 1c in the presence of 2 equiv of TMEDA in THF reversed
diastereoselectivities of 5b from 90:10 (Table 2, entry 5) to 11:89 (anti:
syn), and in the case of 5c decreased selectivities from 92:8 (Table 2,
entry 7) to 69:31.
J . Org. Chem, Vol. 68, No. 26, 2003 9949

Evans and Ellman
TABLE 3. Or ga n om eta llic Ad d ition s to (RS,2S) Silyloxysu lfin yl Ald im in e
entry
product
R2MgBr
R1
temp (°C)
solvent
toluene
yielda (%)
88
drb (syn:anti)
1
2
3
4
5
6
7
8
9
5b
PhMgBr
PhMgBr
PhMgBr
PhMgBr
PhMgBr
EtMgBr
EtMgBr
EtMgBr
EtMgBr
TBDPS
TBDPS
TBDPS
TBS
-48
-78
-78
-78
-78
-48
-78
-78
-78
21:79
35:65
12:88
7:93
THF
THF/TMEDAe
toluene
72c
90
5c
6b
6c
TBS
THF/TMEDAe
toluene
78c
75
2:98d
65:35
2:98d
20:80
2:98d
TBDPS
TBDPS
TBS
THF/TMEDAe
toluene
93c
77
TBS
THF/TMEDAe
81c
a
b
Yields were determined by mass balance of purified material. Ratios were determined by 1H NMR analysis of crude reaction mixtures
after workup. c Yield of major diastereomer was determined by mass balance of purified material. Ratios were determined by HPLC-
MS analysis of crude reaction mixtures after workup. e 2.1 equiv of TMEDA was added to the Grignard reagent prior to the addition to
the aldimine.
d
TABLE 4. En ola te Ad d ition s to Su lfin yl Ald im in es 1
a n d 2
upon the diastereoselectivity for the addition of organo-
metallic reagents to R-alkoxyimines, previously reported
by Cainelli, was attributed to differential entropies of
activation.15
The anti selectivity that is observed, except for the
special cases of EtMgBr and PhMgBr additions to the
TBS protected lactal 1c (Table 2, entries 2, 3, and 7), is
consistent with both the Felkin Ahn16 and Conforth17
models for nucleophilic additions into R-alkoxy ketones
and aldehydes, and is opposite to the inherent selectivity
yielda
(%)
drb
(syn:anti)
provided by the sulfinyl group (eq 4).8b
entry
product
imine
R
Under optimized reaction conditions high anti selec-
tivities could also be achieved for the addition of nucleo-
philes to N-sulfinyl imines (RS,2S)-2b and (RS,2S)-2c
(Table 3). Addition of PhMgBr to the TBDPS protected
aldimine 2b provided only modest selectivities regardless
of the solvent employed (entries 1 and 2). However,
addition of PhMgBr in the presence of the TMEDA in
THF resulted in a significant improvement in diastereo-
selectivity to 88:12 (entry 3). Addition of PhMgBr to the
TBS protected aldimine 2c proceeded with high levels of
diastereoselectivity when toluene was used as solvent
(entry 4), and performing the addition reaction with
TMEDA in THF resulted in an even higher diastereose-
lectivity of 98:2 (entry 5). The addition of EtMgBr to the
TBPDS and TBS protected aldimines 2b and 2c, respec-
tively, proceeded with excellent selectivity (98:2) with
TMEDA in THF (entries 7 and 9), but with only modest
selectivities when toluene was employed as the solvent
(entries 6 and 8).
The anti selectivity observed for the addition of nu-
cleophiles to 2b and 2c is consistent with both Felkin
Ahn16 and Cornforth17 models, as well as the inherent
selectivity previously observed for nucleophilic additions
to N-sulfinyl R-silyloxyacetaldimines (eq 4).8b,18 The
increased diastereomeric ratios in the presence of
TMEDA suggests that the modest selectivities observed
in the absence of a Lewis base result from chelation to
the silyl ether.
1
2
3
4
5
6
7a
7b
7c
8a
8b
8c
1a
1b
1c
2a
2b
2c
Bn
TBDPS
TBS
Bn
TBDPS
TBS
96
12:88
9:91
5:95
26:74
90:10
57:43
74
87c
89
78
51c
a
Yields were determined by mass balance of purified material.
Ratios were determined by 1H NMR analysis of crude reaction
b
mixtures after workup. c Yield of major diastereomer was deter-
mined by mass balance of purified material.
evaluated (Table 4). Previous studies had clearly indi-
cated that the titanium counterion provides the highest
diastereoselectivities for additions to N-tert-butanesulfi-
nyl imines.19 As shown in Table 4, high anti stereoselec-
tivity was observed for the addition to imines (SS,2S)-
1a -c. In contrast, more modest anti selectivity (Table
4, entry 4) or even syn selectivity (entries 5 and 6) was
observed for addition to (RS,2S)-2a -c depending on the
alcohol protecting group.
Anti stereoselectivity observed for the titanium enolate
additions to imines 1a -c is consistent with the inherent
selectivity previously observed for enolate additions to
(15) Cianelli, G.; Giacomini, D.; Galletti, P. Eur. J . Org. Chem. 1999,
61-65.
(16) Ahn, N. T. Top. Curr. Chem. 1980, 88, 145.
(17) Evans, D. Angew. Chem., Int. Ed. 2003, 42, 1761-1765.
(18) Addition of EtMgBr to N-tert-butanesulfinyl-R-tert-butyldi-
methylsilyloxyacetaldimine in the presence of 2 equiv of TMEDA in
THF proceeded with 90:10 diastereoselectivity (88:12 diastereoselec-
tivity was reported for the same reaction in toluene).8b
(19) Tang, T. P.; Ellman, J . A. J . Org. Chem. 1999, 64, 12-13.
The addition of the titanium enolate of methyl acetate
to the benzyl protected sulfinyl imines 1a and 2a and
the silyl-protected imines 1b-c and 2b-c was also
9950 J . Org. Chem., Vol. 68, No. 26, 2003

Synthesis of 1,2-Disubstituted â-Amino Alcohols
R-alkoxy aldehydes,20 as well as enolate additions to
N-tert-butanesulfinyl imines (eq 5).21 For the titanium
subsequent hydrogenolysis (eq 10). Unfortunately, at-
tempts to concomitantly cleave both the sulfinyl group
and the TBPDS groups from 7b and 8b with HF/pyridine
were unsuccessful. However, selective cleavage of the
sulfinyl group with acidic methanolysis could be ac-
complished to afford amines 12 and 13 in high yields (eq
11). Concomitant removal of the sulfinyl and TBS groups
from methyl acetate addition product 7c and 8c could
be accomplished with HCl/MeOH to afford lactones 11
and 14, respectively, also in high yields (eq 12).
enolate additions to sulfinyl imines 2a -c, the inherent
selectivity provided by the sulfinyl group opposes the
selectivity provided by the Felkin Ahn16 and Conforth17
models, which explains the poor selectivity for 2a and
2c and the syn selectivity for 2b.
Dep r ot ect ion of t h e N-Su lfin yl Im in e Ad d it ion
P r od u cts. The N-sulfinyl imine addition products were
deprotected to provide the â-amino alcohols in good to
excellent yields. Treatment of the benzyloxy-protected
amino alcohols 3a and 5a with HCl/MeOH resulted in
removal of the sulfinyl groups, and after hydrogenolysis
of the benzyloxy ethers, the amine hydrochlorides of ami-
no alcohols 9 and 10 were isolated in 85% and 83% yields,
respectively (eqs 6 and 7).8b Treatment of the TBDPS eth-
ers 3b and 5b with 70% HF/pyridine effectively cleaved
both the silyl and sulfinyl groups with comparable rates
(eq 8). In contrast, global deprotection of the TBS ethers
3c and 5c could be accomplished in high yields (95 and
93%) simply by employing HCl/MeOH (eq 9).
Deter m in a tion of Rela tive Ster eoch em istr y of th e
Ad d ition P r od u cts. Stereochemical analysis was per-
formed on addition products 3a -c, 4a -c, 5a -c, and
6a -c to establish the relative stereochemistry. The
N-sulfinyl and alcohol protecting groups were removed
as previously described, and treatment of the resulting
free amino alcohols with triphosgene in the presence of
N,N-diisopropylethylamine cleanly provided oxazolidi-
nones 15-18.22 Stereochemical assignments of 15 and
16 were made by correlation with known literature
compounds,7c while the assignments of 17 and 18 were
determined by NMR based upon the observation of the
indicated NOE measurements.
The methyl acetate addition products 7a and 8a were
readily deprotected to afford lactone 11 in 95% and 94%
yields, respectively, by treatment with HCl/MeOH and
The relative stereochemistries of the methyl acetate
addition products 7a -c and 8a -c were established by
J . Org. Chem, Vol. 68, No. 26, 2003 9951

Evans and Ellman
as KBr pellets; only partial data are listed. Unless otherwise
noted, NMR spectra were obtained in CDCl3 at room temper-
ature. Chemical shifts in NMR spectra are expressed in parts
per million, and all coupling constants are expressed in hertz.
Unless otherwise noted, all chemical correlations to known
compounds were performed on the major diastereomer. Dias-
tereoselectivity was determined by HPLC-MS with an Agilent
1100 LC-MS equipped with a C18 Zorbax 2.1 mm × 150 mm
column, monitored at 210 and 254 nm, and by electronic
ionization. Optical rotations were measured on a Perkin-Elmer
Model 241 polarimeter.
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 N-ter t-Bu ta n esu lfin a m id e. A 0.5 M solution of
Ti(OEt)4 (2.5 equiv) and aldehyde (1.0 equiv) in THF was
prepared under a nitrogen atmosphere. To the solution was
added tert-butanesulfinamide (1.1 equiv), and conversion was
followed by TLC. Upon reaction completion, 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 separatory funnel, where the
aqueous layer was extracted with EtOAc (3×). The organic
layers were combined, washed with brine, dried, and concen-
trated to afford the crude product.
converting the addition products into the previously
reported lactones 19 and 20.23 Specifically, methyl acetate
addition products 7a , 7c, 8a , and 8c were transformed
to 11 and 14, as described previously, followed by N,N-
dibenzylation to afford 19 and 20. The methyl acetate
addition products 7b and 8b were transformed to 19 and
20, respectively, by cleavage of the sulfinyl group with
HCl/MeOH to afford 12 and 13. N,N-Dibenzylation,
subsequent deprotection of the TBDPS group with HF/
pyridine, and final cyclization produced lactones 19 and
20, respectively.
Con clu sion
N-tert-Butanesulfinyl aldimines 1a -c and 2a -c have
been prepared from protected (S)-lactals without epimer-
ization at the R-stereocenter. Grignard reagents and
enolates have been added to these N-tert-butanesulfinyl
aldimines in good yields and with high diastereoselec-
tivities. Either the syn or anti addition products can be
obtained by the appropriate choice of alcohol protecting
groups and/or reaction conditions. Finally, the addition
products were readily deprotected in high yields to
provide straightforward access to either syn- or anti-1,2-
amino alcohols.
(SS,2S)-2-Meth yl-p r op a n e-2-su lfin ic Acid (2-Ben zyloxy-
p r op ylid en e)-a m id e (1a ). The general procedure was fol-
lowed with use of 0.51 g (3.1 mmol) of (S)-2-benzyloxy propanal
for 3 h. Pure 1a (0.61 g, 75%) was obtained as a clear oil after
chromatography (35% EtOAc/hexanes). HPLC (Diacel Chiral-
pak OD column, 99:01 hexanes/IPA; 1.0 mL/min; 254 nm)
tR[(SS,2R)-1a ] ) 8.8 min, tR[(SS,2S)-1a ] ) 12.8 min; [R]21
D
+10.53 (c 0.70, CH2Cl2); IR 3063, 1626, 1087 cm-1; H NMR
1
(400 MHz) δ 1.21 (s, 9H), 1.38 (d, 3H, J ) 6.8), 4.31 (dq, 1H,
J ) 4.8, 6.8), 4.48 (d, 1H, J ) 11.6), 4.63 (d, 1H, J ) 11.6),
7.24-7.34 (m, 5H), 8.06 (d, 1H, J ) 4.8); 13C NMR (100 MHz)
δ 18.4, 22.3, 56.7, 71.4, 77.5, 127.6, 127.8, 128.4, 137.6, 170.3.
Anal. Calcd for C14H21NO2S: C, 62.89; H, 7.92; N, 5.24.
Found: C, 62.90; H, 8.23; N, 5.35.
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. ClTi(Oi-Pr)3 was fractionally
distilled and stored under N2 as a neat liquid, which solidified
upon standing. BnBr was filtered through a plug of basic
alumina (Brockman activity I, 60-325 mesh) prior to use.
N,N,N,N-Tetramethylethylenediamine (TMEDA) was distilled
under N2 from either n-BuLi or CaH2. tert-Butanesulfinamide
was prepared according to previously published protocols.24 All
solvents were distilled under N2 from the following drying
agents immediately before use: tetrahydrofuran (THF) was
distilled from sodium/benzophenone ketyl, and dichloromethane
(CH2Cl2), methanol (MeOH), 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 with use of 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 Na2SO4, and all solvents were removed with
a rotary evaporator. IR spectra of liquids were recorded as thin
films on NaCl plates, and IR spectra of solids were recorded
(RS,2S)-2-Meth yl-pr opan e-2-su lfin ic Acid (2-Ben zyloxy-
p r op ylid en e)-a m id e (2a ). The general procedure was fol-
lowed with use of 0.51 g (3.1 mmol) of (S)-2-benzyloxy propanal
for 3 h. Pure 2a (0.77 g, 93%) was obtained as a clear oil after
chromatography (35% EtOAc/hexanes). HPLC (Diacel Chiral-
pak OD column, 99:01 hexanes/IPA; 1.0 mL/min; 280 nm)
tR[(RS,2R)-2a ] ) 8.7 min, tR[(RS,2S)-2a ] ) 12.2 min; [R]21
D
-185.51 (c 0.60, CH2Cl2); IR 3061, 1620, 1084 cm-1; 1H NMR
(400 MHz) δ 1.21 (s, 9H), 1.39 (d, 3H, J ) 6.8), 4.35 (dq, 1H,
J ) 4.4, 6.8), 4.53 (d, 1H, J ) 12.0), 4.65 (d, 1H, J ) 12.0),
7.26-7.39 (m, 5H), 8.06 (d, 1H, J ) 4.4); 13C NMR (100 MHz)
δ 18.6, 22.4, 56.8, 71.5, 76.2, 127.7, 127.8, 129.3, 137.5, 175.2.
Anal. Calcd for C14H21NO2S: C, 62.89; H, 7.92; N, 5.24.
Found: C, 62.70; H, 8.15; N, 5.00.
(SS,2S)-2-Meth yl-p r op a n e-2-su lfin ic Acid [2-(ter t-Bu -
tyl-d ip h en yl-sila n yloxy)-p r op ylid en e]-a m id e (1b). The
general procedure was followed with use of 2.1 g (6.6 mmol)
of (S)-2-tert-butyl-diphenyl-silanyloxy propanal for 28 h. Pure
1b (2.3 g, 84%) was obtained as a clear oil after chromatog-
raphy (25% EtOAc/hexanes). HPLC (Diacel Chiralpak OD
column, 99:01 hexanes/IPA; 1.0 mL/min; 280 nm) tR[(SS,2R)-
1b] ) 5.1 min, tR[(SS,2S)-1b] ) 5.7 min; [R]21 +38.71 (c 1.00,
D
CH2Cl2); IR 3071, 1625, 1598, 1481, 1111, 1089 cm-1; 1H NMR
(400 MHz) δ 1.08 (s, 9H), 1.19 (s, 9H), 1.28 (d, 3H, J ) 6.4),
4.60 (dq, 1H, J ) 4.0, 6.4), 7.33-7.44 (m, 6H), 7.64-7.69 (m,
4H), 8.30 (d, 1H, J ) 4.0); 13C NMR (100 MHz) δ 19.3, 21.6,
22.4, 26.9, 56.7, 71.3, 127.7, 128.0, 129.87, 129.89, 133.2, 133.7,
135.8, 171.3. Anal. Calcd for C23H33NO2SSi: C, 66.46; H, 8.00;
N, 3.37. Found: C, 66.67; H, 8.24; N, 3.17.
(20) Reetz, M. T. Angew. Chem., Int. Ed. Engl. 1984, 23, 556-569.
Reetz, M. T.; Kesseler, K.; Schmidtberger, S.; Wenderoth, B.; Steinbach,
R. Angew. Chem., Int. Ed. Engl. 1983, 22, 989-990.
(21) Tang, T. P.; Ellman, J . A. J . Org. Chem. 2002, 67, 7819-7832.
(22) Andres, J . M.; de Elena, N.; Pedrosa, R.; Perez-Encabo, A.
Tetrahedron 1999, 55, 14137-14144.
(RS,2S)-2-Meth yl-p r op a n e-2-su lfin ic Acid [2-(ter t-Bu -
tyl-d ip h en yl-sila n yloxy)-p r op ylid en e]-a m id e (2b). The
general procedure was followed with use of 0.48 g (1.5 mmol)
of (S)-2-tert-butyl-diphenyl-silanyloxy propanal for 20 h. Pure
2b (0.63 g, 98%) was obtained as a clear oil after chromatog-
(23) Asao, N.; Shimada, T.; Sudo, T.; Tsukada, N.; Yazawa, K.;
Gyoung, Y. S.; Uyehara, T.; Yamamoto, Y. J . Org. Chem. 1997, 62,
6274-6282.
(24) Weix, D. J .; Ellman, J . A. Org. Lett. 2003, 5, 1317-1320.
9952 J . Org. Chem., Vol. 68, No. 26, 2003

Synthesis of 1,2-Disubstituted â-Amino Alcohols
1
raphy (25% EtOAc/hexanes). HPLC (Diacel Chiralpak AS
column, 99:01 hexanes/IPA; 1.0 mL/min; 280 nm) tR[(RS,2R)-
2b] ) 4.8 min, tR[(RS,2S)-2b] ) 6.4 min; [R]21D -296.97 (c 1.00,
CH2Cl2); IR 3071, 1626, 1462, 1111, 1088 cm-1; 1H NMR (400
MHz) δ 1.10 (s, 9H), 1.15 (s, 9H), 1.29 (d, 3H, J ) 6.4), 4.62
(dq, 1H, J ) 4.0, 6.4), 7.35-7.46 (m, 6H), 7.65-7.70 (m, 4H),
8.02 (d, 1H, J ) 4.0); 13C NMR (100 MHz) δ 19.0, 21.5, 22.2,
26.7, 56.5, 71.2, 127.56, 127.61, 129.7, 129.8, 132.9, 133.4,
135.5, 135.7, 171.3. Anal. Calcd for C23H33NO2SSi: C, 66.46;
H, 8.00; N, 3.37. Found: C, 66.31; H, 8.15; N, 3.23.
IR 3269, 3063, 1603, 1495, 1068 cm-1; H NMR (400 MHz) δ
1.04 (d, 3H, J ) 6.2), 1.13 (s, 9H), 3.66 (dq, 1H, J ) 6.2, 8.6),
4.29 (d, 1H, J ) 8.6), 4.42 (d, 1H, J ) 12.0), 4.52 (s, 1H), 4.71
(d, 1H, J ) 12.0), 7.27-7.37 (m, 10H); 13C NMR (100 MHz) δ
15.8, 22.6, 55.1, 63.0, 70.2, 78.6, 127.7, 127.8, 128.0, 128.36,
128.41, 128.7, 138.0, 138.8. Anal. Calcd for C20H27NO2S: C,
69.53; H, 7.88; N, 4.05. Found: C, 69.46; H, 7.94; N, 3.85.
(SS,2S)-2-Meth yl-p r op a n e-2-su lfin ic Acid [2-(ter t-Bu -
tyl-diph en yl-silan yloxy)-1-ph en yl-pr opyl]-am ide (3b). The
general procedure was followed with use of 0.089 g (0.21 mmol)
of 2a . Pure anti-3b (0.091 g, 86%) was obtained as a clear oil
after chromatography (35% EtOAc/hexanes to 45% EtOAc/
hexanes). syn-3b: 1H NMR (400 MHz) δ 0.82 (d, 3H, J ) 6.0),
1.09 (s, 9H), 1.17 (s, 9H), 4.09 (apparent pent, 1H, J ) 6.0),
4.35 (m, 1H), 4.52 (s, 1H), 7.24-7.30 (m, 3H), 7.36-7.46 (m,
8H), 7.65-7.76 (m, 4H); 13C NMR (100 MHz) δ 19.3, 20.5, 22.7,
27.1, 55.3, 65.3, 74.3, 125.4, 127.6, 127.8, 127.9, 128.3, 128.5,
(SS,2S)-2-Meth yl-p r op a n e-2-su lfin ic Acid [2-(ter t-Bu -
tyl-d im eth yl-sila n yloxy)-p r op ylid en e]-a m id e (1c). The
general procedure was followed with use of 0.85 g (4.5 mmol)
of (S)-2-tert-butyl-dimethyl-silanyloxy propanal for 13 h. Pure
1c (0.91 g, 70%) was obtained as a clear oil after chromatog-
raphy (35% EtOAc/hexanes). HPLC (Diacel Chiralpak AD
column, 99:01 hexanes/IPA; 1.0 mL/min; 280 nm) tR[(SS,2S)-
1c] ) 5.2 min, tR[(SS,2R)-1c] ) 5.8 min; [R]21 +25.38 (c 2.13,
128.8, 129.0, 129.78, 129.81, 135.8, 136.0. anti-3b: [R]21
D
D
CH2Cl2); IR 1640, 1089 cm-1; H NMR (400 MHz) δ 0.08 (s,
1
+23.80 (c 0.72, CH2Cl2); IR 3070, 1593, 1470, 1071 cm-1; H
1
3H), 0.09 (s, 3H), 0.90 (s, 9H), 1.19 (s, 9H), 1.35 (d, 3H, J )
6.4), 4.56 (dq, 1H, J ) 4.0, 6.4), 7.95 (d, 1H, J ) 4.0); 13C NMR
(100 MHz) δ -4.8, -4.7, 18.0, 21.4, 22.3, 25.7, 56.7, 70.5, 171.5;
HRMS calcd for C13H30NO2SSi 292.176654, found 292.176655.
NMR (400 MHz) δ 0.94 (d, 3H, J ) 6.0), 1.09 (s, 9H), 1.23 (s,
9H), 4.07 (d, 1H, J ) 7.2), 4.21 (dq, 1H, J ) 4.0, 6.0), 4.29 (dd,
1H, J ) 4.0, 7.2), 7.27-7.40 (m, 7H), 7.40-7.49 (m, 4H), 7.63
(d, 2H, J ) 6.6), 7.73 (d, 2H, J ) 6.6); 13C NMR (100 MHz) δ
19.2, 19.3, 22.5, 26.9, 56.2, 65.1, 73.0, 127.4, 127.5, 127.7, 128.1,
128.2, 129.6, 129.8, 133.2, 133.9, 135.77, 135.81, 139.4. Anal.
Calcd for C29H39NO2SSi: C, 70.54; H, 7.96; N, 2.84. Found:
C, 70.25; H, 8.18; N, 2.86.
(RS,2S)-2-Meth yl-p r op a n e-2-su lfin ic Acid [2-(ter t-Bu -
tyl-d im eth yl-sila n yloxy)-p r op ylid en e]-a m id e (2c). The
general procedure was followed with use of 1.3 g (6.9 mmol)
of (S)-2-tert-butyl-dimethyl-silanyloxy propanal for 13 h. Pure
2c (1.6 g, 80%) was obtained as a clear oil after chromatog-
raphy (35% EtOAc/hexanes). HPLC (Diacel Chiralpak AD
column, 99:01 hexanes/IPA; 1.0 mL/min; 280 nm) tR[(RS,2S)-
2c] ) 5.3 min, tR[(RS,2R)-2c] ) 5.9 min; [R]21D -210.60 (c 10.00,
(SS,2S)-2-Meth yl-p r op a n e-2-su lfin ic Acid [2-(ter t-Bu -
tyl-dim eth yl-silan yloxy)-1-ph en yl-pr opyl]-am ide (3c). The
general procedure was followed with use of 0.10 g (0.36 mmol)
of 1c. A mixture of syn- and anti-3c (0.13 g, 95% yield) was
obtained as a clear oil after chromatography (30% EtOAc/
hexanes to 40% EtOAc/hexanes). anti-3c: [R]21D +20.61 (c 4.67,
CH2Cl2); 1H NMR (400 MHz) δ 0.05 (s, 3H), 0.07 (s, 3H), 0.92
(s, 9H), 1.33 (d, 3H, J ) 6.0), 1.19 (s, 9H), 3.87 (dq, 1H, J )
6.0, 7.2), 4.18 (d, 1H, J ) 7.6), 4.69 (s, 1H), 7.27-7.36 (m, 5H);
13C NMR (100 MHz) δ -4.8, -4.2, 17.8, 20.6, 22.6, 25.7, 55.1,
1
CH2Cl2); IR 1626, 1092 cm-1; H NMR (400 MHz) δ 0.08 (s,
3H), 0.09 (s, 3H), 0.93 (s, 9H), 1.20 (s, 9H), 1.35 (d, 3H, J )
6.4), 4.60 (dq, 1H, J ) 3.6, 6.4), 7.98 (d, 1H, J ) 3.6); 13C NMR
(100 MHz) δ -4.8, -4.7, 18.2, 21.7, 22.4, 25.7, 56.7, 70.7, 171.8.
Anal. Calcd for C13H29NO2SSi: C, 53.56; H, 10.03; N, 4.80.
Found: C, 53.58; H, 10.30; N, 4.84.
64.8, 73.0, 127.8, 128.3, 128.6, 139.4. syn-3c: [R]21 +142.82
Gen er a l P r oced u r e for th e Gr ign a r d Ad d ition s to
N-ter t-Bu ta n esu lfin yl Im in es. To a flame-dried flask was
added the aldimine (1.0 equiv, 0.10 g) in appropriate solvent
(Tables 1-4, 0.20 M), and the solution was cooled. The
Grignard reagent (2.0 equiv, 3.0 M in ether) was added
dropwise to the solution and conversion was followed by TLC.
Upon reaction completion, excess organometallic reagent was
quenched with NH4Cl (saturated), and the mixture was
warmed to room temperature. The resulting suspension was
diluted with an equal portion of brine and extracted with
EtOAc (3×). The organic layers were combined, washed with
brine, dried, and concentrated to afford the crude product (for
yields and diastereoselectivities, see Tables 1-3).
Gen er a l P r oced u r e for th e Gr ign a r d Ad d ition s to
N-ter t-Bu ta n esu lfin yl Im in es w ith TMEDA. To a flame-
dried flask was added the aldimine (1.00 equiv, 0.10 g) in THF
(0.24 M), and the solution was cooled to -78 °C. In another
flask was added the Grignard reagent (2.0 equiv, 3.0 M in
ether) to a solution of TMEDA (2.05 equiv) in THF (2.0 M),
and this mixture was transferred dropwise via cannula to the
cooled aldimine solution. Upon reaction completion as deter-
mined by TLC, excess organometallic reagent was quenched
with NH4Cl (saturated), and the mixture was warmed to room
temperature. The resulting suspension was diluted with an
equal portion of brine and extracted with EtOAc (3×). The
organic layers were combined, washed with brine, dried, and
concentrated to afford the crude product (for yields and
diastereoselectivities, see Tables 1 and 3).
D
(c 3.11, CH2Cl2); IR 3200, 1603, 1462, 1062 cm-1; 1H NMR (400
MHz) δ 0.02 (s, 3H), 0.03 (s, 3H), 0.75 (s, 9H), 1.01 (d, 3H, J
) 6.0), 1.20 (s, 9H), 3.99 (d, 1H, J ) 7.2), 4.12-4.20 (m, 2H),
7.25-7.32 (m, 5H); 13C NMR (100 MHz) δ -4.9, -4.3, 17.9,
20.1, 22.5, 25.7, 56.2, 64.8, 71.7, 127.5, 128.0, 128.4, 139.4;
HRMS calcd for C19H36NO2SSi 370.223604, found 370.223605.
(SS,2S)-2-Meth yl-p r op a n e-2-su lfin ic Acid (2-Ben zyloxy-
1-eth yl-p r op yl)-a m id e (4a ). The general procedure was
followed with use of 0.094 g (0.35 mmol) of 1a . A mixture of
syn- and anti-4a (0.079 g, 75% yield) was obtained as a clear
oil after chromatography (40% EtOAc/hexanes to 55% EtOAc/
hexanes). HPLC-MS (60-95% MeOH/H2O over 15 min at 0.5
mL/min) tR(anti-4a ) ) 8.5 min, tR(syn-4a ) ) 9.2 min. anti-4a :
1H NMR (400 MHz) δ 1.03 (t, 3H, J ) 7.4), 1.18-1.20 (m, 12H),
1.52-1.55 (m, 1H), 1.62-1.71 (m, 1H), 3.17 (d, 1H, J ) 9.2),
3.21-3.30 (m, 1H), 3.55 (dq, 1H, J ) 4.0, 6.4), 4.48 (d, 1H, J
) 11.6), 4.58 (d, 1H, J ) 11.6), 7.27-7.35 (m, 5H). syn-4a :
[R]21 +32.00 (c 0.10, CH2Cl2); IR 1062 cm-1 1H NMR (400
;
D
MHz) δ 0.87 (t, 3H, J ) 7.2), 1.20 (s, 9H), 1.28 (d, 3H, J )
6.4), 1.50-1.53 (m, 1H), 1.71-174 (m, 1H), 3.11-3.15 (m, 1H),
3.59-3.65 (m, 1H), 3.77 (d, 1H, J ) 6.0), 4.40 (d, 1H, J ) 11.6),
4.65 (d, 1H, J ) 11.6), 7.26-7.35 (m, 5H); 13C NMR (100 MHz)
δ 9.6, 15.8, 22.7, 25.0, 55.7, 61.2, 70.3, 75.5, 127.5, 127.6, 128.3,
138.4. Anal. Calcd for C16H27NO2S: C, 64.61; H, 9.15; N, 4.71.
Found: C, 64.57; H, 9.24; N, 4.85.
(SS,2S)-2-Meth yl-p r op a n e-2-su lfin ic Acid [2-(ter t-Bu -
tyl-d ip h en yl-sila n yloxy)-1-eth yl-p r op yl]-a m id e (4b). The
general procedure was followed with use of 0.11 g (0.26 mmol)
of 1b. A mixture of syn- and anti-4b (0.10 g, 90% yield) was
obtained as a clear oil after chromatography (35% EtOAc/
hexanes to 45% EtOAc/hexanes). syn-4b: [R]21D +31.23 (c 1.29,
(SS,2S)-2-Meth yl-p r op a n e-2-su lfin ic Acid (2-Ben zyloxy-
1-p h en yl-p r op yl)-a m id e (3a ). The general procedure was
followed with use of 0.081 g (0.30 mmol) of 1a . A mixture of
syn- and anti-3a (0.095 g, 94% yield) was obtained as a clear
oil after chromatography (40% EtOAc/hexanes to 55% EtOAc/
hexanes). HPLC-MS (60-95% MeOH/H2O over 15 min at 0.5
mL/min) tR(syn-3a ) ) 9.2 min, tR(anti-3a ) ) 8.5 min. syn-3a :
1
CH2Cl2); H NMR (400 MHz) δ 0.78 (t, 3H, J ) 7.6), 1.07 (s,
9H), 1.16 (d, 3H, J ) 6.0), 1.26 (s, 9H), 1.44-1.50 (m, 1H),
1.51-1.60 (m, 1H), 2.90-2.95 (m, 1H), 3.94-3.98 (m, 2H),
J . Org. Chem, Vol. 68, No. 26, 2003 9953

Evans and Ellman
7.36-7.45 (m, 6H), 7.76-7.70 (m, 4H); 13C NMR (100 MHz) δ
10.4, 19.4, 20.5, 22.9, 26.5, 27.0, 55.8, 63.3, 77.8, 127.5, 127.7,
129.6, 129.8, 133.4, 134.0, 135.87, 135.91. anti-4b: [R]21D +2.75
Calcd for C19H35NO2SSi: C, 61.74; H, 9.54; N, 3.79. Found:
C, 61.56; H, 9.90; N, 3.77.
(RS,2S)-2-Meth yl-pr opan e-2-su lfin ic Acid (2-Ben zyloxy-
1-eth yl-p r op yl)-a m id e (6a ). The general procedure with
TMEDA was followed with use of 0.030 g (0.11 mmol) of 2a
and 0.035 mL (0.23 mmol, 2.1 eq) of TMEDA. Pure anti-6a
(0.029 g, 86% yield) was obtained as a clear oil after chroma-
tography (40% EtOAc/hexanes to 55% EtOAc/hexanes). HPLC-
MS (60-95% MeOH/H2O over 15 min at 0.5 mL/min) tR(anti-
6a ) ) 6.5 min, tR(syn-6a ) ) 8.2 min. syn-6a : 1H NMR (400
MHz) δ 0.94 (t, 3H, J ) 7.4), 1.20 (d, 3H, J ) 6.4), 1.21 (s,
9H), 1.73-1.79 (m, 2H), 2.97-3.05 (m, 1H), 4.47 (d, 1H, J )
10.0), 3.65 (dq, 1H, J ) 4.0, 6.4), 4.45 (d, 1H, J ) 11.2), 4.61
(d, 1H, J ) 11.6), 7.27-7.35 (m, 5H). anti-6a : IR 3035, 1555,
(c 4.14, CH2Cl2); IR 3041, 1591, 1469, 1108, 1055 cm-1 1H
;
NMR (400 MHz) δ 0.92 (t, 3H, J ) 7.2), 1.02 (d, 3H, J ) 6.4),
1.06 (s, 9H), 1.20 (s, 9H), 1.50-1.61 (m, 2H), 3.11-3.16 (m,
2H), 3.83 (dq, 1H, J ) 2.8, 6.4), 7.24-7.45 (m, 6H), 7.66-7.70
(m, 4H); 13C NMR (100 MHz) δ 10.7, 18.3, 19.2, 22.7, 25.0,
27.0, 55.9, 64.3, 72.0, 127.4, 127.6, 129.6, 129.7, 133.7, 134.2,
135.8, 135.9. Anal. Calcd for C25H39NO2SSi: C, 67.36; H, 8.82;
N, 3.14. Found: C, 67.17; H, 9.05; N, 3.06.
(SS,2S)-2-Meth yl-p r op a n e-2-su lfin ic Acid [2-(ter t-Bu -
tyl-d im eth yl-sila n yloxy)-1-eth yl-p r op yl]-a m id e (4c). The
general procedure was followed with use of 0.12 g (0.42 mmol)
of 1c. A mixture of syn- and anti-4c (0.13 g, 94% yield) was
obtained as a clear oil after chromatography (30% EtOAc/
hexanes to 40% EtOAc/hexanes). syn-4c: [R]21D +32.98 (c 4.85,
1
1472, 1066 cm-1; H NMR (400 MHz) δ 0.92 (t, 3H, J ) 7.2),
1.17 (d, 3H, J ) 7.2), 1.22 (s, 9H), 1.56 (apparent pent, 2H, J
) 7.2), 3.18 (dq, 1H, J ) 3.2, 7.2), 3.78 (d, 1H, J ) 7.2), 3.90-
3.95 (m, 1H), 4.52 (d, 1H, J ) 11.4), 4.56 (d, 1H, J ) 11.4),
7.26-7.35 (m, 5H); 13C NMR (100 MHz) δ 10.7, 15.4, 22.3, 22.6,
55.8, 61.1, 70.9, 77.4, 127.4, 127.8, 128.3, 138.6. Anal. Calcd
for C16H27NO2S: C, 64.60; H, 9.15; N, 4.71. Found: C, 64.39;
H, 9.32; N, 4.65.
1
CH2Cl2); IR 1074, 1053 cm-1; H NMR (400 MHz) δ 0.04 (s,
3H), 0.05 (s, 3H), 0.86-0.89 (m, 12H), 1.19-1.20 (m, 12H),
1.39-1.46 (m, 1H), 1.54-1.61 (m, 1H), 2.91-2.93 (m, 1H),
3.83-3.87 (m, 2H); 13C NMR (100 MHz) δ -4.2, -3.3, 10.3,
17.8, 20.7, 22.8, 25.7, 26.5, 55.7, 63.0, 69.5. Anal. Calcd for
C
15H35NO2SSi: C, 56.02; H, 10.97; N, 4.36. Found: C, 56.09;
(RS,2S)-2-Meth yl-p r op a n e-2-su lfin ic Acid [2-(ter t-Bu -
tyl-d ip h en yl-sila n yloxy)-1-eth yl-p r op yl]-a m id e (6b). The
general procedure with TMEDA was followed with use of 0.10
g (0. 24 mmol) of 2b and 0.075 mL (0.50 mmol, 2.1 equiv) of
TMEDA. Pure anti-6b (0.10 g, 93% yield) was obtained as a
clear oil after chromatography (25% EtOAc/hexanes to 35%
EtOAc/hexanes). HPLC-MS (60-95% MeOH/H2O over 20 min
at 0.4 mL/min) tR(anti-6b) ) 19.8 min, tR(syn-6b) ) 20.5 min.
H, 11.17; N, 4.42.
(RS,2S)-2-Meth yl-pr opan e-2-su lfin ic Acid (2-Ben zyloxy-
1-p h en yl-p r op yl)-a m id e (5a ). The general procedure with
TMEDA was followed with use of 0.020 g (0.075 mmol) of 2a
and 0.024 mL (0.16 mmol, 2.1 equiv) of TMEDA. Pure anti-
5a (0.021 g, 80% yield) was obtained as a clear oil after
chromatography (40% EtOAc/hexanes to 55% EtOAc/hexanes).
HPLC-MS (60-95% MeOH/H2O over 15 min at 0.5 mL/min)
anti-6b: [R]21 -53.38 (c 2.64, CH2Cl2); 1H NMR (400 MHz) δ
D
tR(syn-5a ) ) 10.3 min, tR(anti-5a ) ) 11.3 min. anti-5a : [R]21
0.79 (t, 3H, J ) 7.6), 0.95 (d, 3H, J ) 6.4), 1.06 (s, 9H), 1.24 (s,
9H), 1.37-1.44 (m, 1H), 1.66-1.75 (m, 1H), 3.07-3.15 (m, 1H),
3.91 (d, 1H, J ) 4.8), 4.13 (dq, 1H, J ) 3.2, 6.4), 7.35-7.44
(m, 6H), 7.68-7.70 (m, 4H); 13C NMR (100 MHz) δ 10.3, 17.6,
19.2, 22.7, 27.0, 33.6, 55.5, 61.5, 71.3, 127.5, 127.6, 129.6, 129.7,
D
-125.23 (c 2.30, CH2Cl2); IR 3278, 3031, 1603, 1494, 1068 cm-1
;
1H NMR (400 MHz) δ 1.05 (d, 3H, J ) 6.4), 1.27 (s, 9H), 3.86
(dq, 1H, J ) 4.0, 6.4), 4.11 (d, 1H, J ) 2.0), 4.59 (d, 1H, J )
11.6), 4.72 (d, 1H, J ) 11.6), 4.77 (dd, 1H, J ) 2.0, 4.0), 7.27-
7.41 (m, 10H); 13C NMR (100 MHz) δ 14.6, 22.6, 55.6, 59.3,
70.4, 77.7, 127.5, 127.7, 127.9, 128.1, 128.3, 128.4, 138.0, 138.3.
Anal. Calcd for C20H27NO2S: C, 69.53; H, 7.88; N, 4.05.
Found: C, 69.69; H, 8.04; N, 4.07.
133.2, 134.0, 135.76, 135.84. syn-6b : [R]21 -16.91 (c 5.21,
D
CH2Cl2); IR 3070, 1589, 1472, 1110, 1053 cm-1; 1H NMR (400
MHz) δ 0.86 (t, 3H, J ) 7.4), 1.05 (d, 3H, J ) 6.4), 1.17 (s,
9H), 1.20 (s, 9H), 1.61-1.68 (m, 1H), 1.77-1.85 (m, 1H), 2.86-
2.88 (m, 1H), 3.26 (d, 1H, J ) 8.4), 3.89 (dq, 1H, J ) 2.4, 6.4),
7.34-7.44 (m, 6H), 7.64-7.67 (m, 4H); 13C NMR (100 MHz) δ
10.8, 19.3, 19.8, 22.7, 26.0, 27.0, 56.1, 64.4, 70.2, 127.4, 127.7,
(RS,2S)-2-Meth yl-p r op a n e-2-su lfin ic Acid [2-(ter t-Bu -
tyl-diph en yl-silan yloxy)-1-ph en yl-pr opyl]-am ide (5b). The
general procedure with TMEDA was followed with use of 0.061
g (0.15 mmol) of 2b and 0.045 mL (0.30 mmol, 2.1 equiv) of
TMEDA. Pure anti-5b (0.052 g, 72% yield) was obtained as a
clear oil after chromatography (20% EtOAc/hexanes). syn-5b:
[R]21D -1.55 (c 1.80, CH2Cl2); 1H NMR (400 MHz) δ 0.97-0.98
(m, 12H), 1.24 (s, 9H), 4.22 (dq, 1H, J ) 2.8, 6.0), 4.32-4.33
(m, 2H), 7.25-7.43 (m, 13H), 7.61 (d, 2H, J ) 8.0). anti-5b:
[R]21D -90.82 (c 5.10, CH2Cl2); IR 3281, 3060, 1589, 1472, 1110,
1084 cm-1; 1H NMR (400 MHz) δ 0.92 (d, 3H, J ) 6.4), 1.12 (s,
9H), 1.31 (s, 9H), 4.05 (dq, 1H, J ) 4.0, 6.4), 4.24 (s, 1H), 4.46-
4.50 (m, 1H), 7.16 (d, 2H, J ) 7.6), 7.22-7.27 (m, 3H), 7.36-
7.49 (m, 6H), 7.66 (d, 2H, J ) 6.6), 7.70 (d, 2H, J ) 6.6); 13C
NMR (100 MHz) δ 16.9, 19.2, 22.7, 27.0, 55.5, 62.2, 72.9, 127.5,
127.6, 127.8, 128.0, 128.5, 129.7, 130.0, 133.0, 133.8, 135.8,
136.1, 138.1; HRMS calcd for C29H40NO2SSi 494.254904, found
494.254905.
129.6, 129.8, 133.2, 134.4, 135.7, 135.8; HRMS calcd for C29H40
NO2SSi 494.254904, found 494.254905.
-
(RS,2S)-2-Meth yl-p r op a n e-2-su lfin ic Acid [2-(ter t-Bu -
tyl-d im eth yl-sila n yloxy)-1-eth yl-p r op yl]-a m id e (6c). The
general procedure with TMEDA was followed with use of 0.15
g (0.52 mmol) of 2c and 0.16 mL (1.1 mmol, 2.1 equiv) of
TMEDA. Pure anti-6c (0.13 g, 81%) was obtained as a clear
oil after chromatography (30% EtOAc/hexanes to 40% EtOAc/
hexanes). HPLC-MS (60-95% MeOH/H2O over 25 min at 0.4
mL/min) tR(syn-6c) ) 19.5 min, tR(anti-6c) ) 20.4 min. syn-
6c: 1H NMR (400 MHz) δ 0.04 (s, 3H), 0.05 (s, 3H), 0.85 (s,
9H), 1.03 (t, 3H, J ) 6.0), 1.12 (d, 3H, J ) 6.0), 1.21 (s, 9H),
1.65-169 (m, 1H), 2.94-3.03 (m, 1H), 3.32 (d, 1H, J ) 7.2),
3.92 (dq, 1H, J ) 4.4, 6.0); 13C NMR (100 MHz) δ -4.9, -4.2,
10.9, 17.9, 20.7, 22.8, 25.8, 26.6, 56.3, 64.4, 68.7. anti-6c: [R]21
D
-35.92 (c 0.65, CH2Cl2); IR 1075 cm-1; H NMR (400 MHz) δ
1
(RS,2S)-2-Meth yl-p r op a n e-2-su lfin ic Acid [2-(ter t-Bu -
tyl-dim eth yl-silan yloxy)-1-ph en yl-pr opyl]-am ide (5c). The
general procedure with TMEDA was followed with use of 0.011
g (0.038 mmol) of 2c and 0.012 mL (0.077 mmol, 2.1 equiv) of
TMEDA. Pure anti-5c (0.011 g, 78% yield) was obtained as a
clear oil after chromatography (30% EtOAc/hexanes to 40%
EtOAc/hexanes). HPLC-MS (60-95% MeOH/H2O over 30 min
at 0.4 mL/min), tR(syn-5c) ) 22.7 min, tR(anti-5c) ) 23.3 min.
0.08 (s, 3H), 0.13 (s, 3H), 0.87 (s, 9H), 0.92 (t, 3H, J ) 7.2),
1.09 (d, 3H, J ) 6.4), 1.20 (s, 9H), 1.41-1.56 (br m, 2H), 3.02-
3.04 (m, 1H), 3.70 (d, 1H, J ) 7.2), 4.16 (dq, 1H, J ) 3.2, 6.4);
13C NMR (100 MHz) δ -4.7, -4.3, 10.7, 17.9, 19.2, 22.0, 22.8,
25.8, 55.8, 63.1, 70.8. Anal. Calcd for C15H35NO2SSi: C, 56.02;
H, 10.97; N, 4.36. Found: C, 55.89; H, 10.79; N, 4.48.
Gen er a l P r oced u r e for th e Ti En ola te Ad d ition to
N-ter t-Bu ta n esu lfin yl Ald im in es. A solution of i-Pr2NH
(2.20 equiv) in THF (0.70 M) was cooled to 0 °C. n-Butyllithium
(n-BuLi) (2.25 M, 2.10 equiv) was added via syringe and the
solution was stirred for 30 min. The solution was then cooled
to -78 °C and methyl acetate (2.00 equiv) was added via
syringe and the reaction solution was stirred for 30 min. To
anti-5c: [R]21 -82.56 (c 6.21, CH2Cl2); IR 3129, 1583, 1471,
D
1071 cm-1
;
1H NMR (400 MHz) δ 0.09 (s, 3H), 0.14 (s, 3H),
0.88 (s, 9H), 1.02 (d, 3H, J ) 6.0), 1.25 (s, 9H), 4.10 (dq, 1H,
J ) 4.0, 6.0), 4.13 (d, 1H, J ) 3.6), 4.45 (dd, 1H, J ) 3.6, 4.0),
7.25-7.33 (m, 5H); 13C NMR (100 MHz) δ -4.9, -4.5, 18.0,
22.6, 25.8, 55.6, 63.0, 71.9, 127.5, 128.1, 128.6, 138.4. Anal.
9954 J . Org. Chem., Vol. 68, No. 26, 2003

Synthesis of 1,2-Disubstituted â-Amino Alcohols
this solution was added ClTi(Oi-Pr)3 (4.20 equiv) in THF (5.00
M) and the orange-colored enolate solution was stirred for 30
min. A solution of the N-sulfinyl imine (1.00 equiv) in THF
(1.2 M) was slowly added via syringe and the solution was
stirred at -78 °C. Upon reaction completion, as determined
by TLC, a saturated aqueous solution of NH4Cl (10 equiv) was
added and the suspension was warmed to room temperature.
The mixture was diluted with H2O and vigorously stirred to
dissolve the Ti precipitate. The mixture was then decanted
into a separatory funnel, and the remaining solid was diluted
with equal parts of H2O and EtOAc and vigorously stirred for
15 min. The mixture was then added to the separatory funnel
and the organic layer was collected. The aqueous layer was
then extracted with EtOAc (3×). The combined organic layers
were washed with brine, dried, and concentrated to afford the
crude amino ester product.
(0.45 mmol) of sulfinylimine 2a according to the general
procedure yielded a mixture of syn- and anti-8a (0.14 g, 89%)
as a clear oil after chromatography (60% EtOAc/hexanes to
70% EtOAc/hexanes). HPLC-MS (60-95% MeOH/H2O over 15
min at 0.5 mL/min) tR(syn-8a ) ) 5.5 min, tR(anti-8a ) ) 6.4 min.
syn-8a : 1H NMR (400 MHz) δ 1.17 (s, 9H), 1.22 (d, 3H, J )
6.0), 2.56 (d, 2H, J ) 7.2), 3.64 (s, 3H), 3.65-3.78 (m, 1H),
3.95-4.04 (m, 2H), 4.47 (d, 1H, J ) 11.2), 4.60 (d, 1H, J )
11.2), 7.27-7.36 (m, 5H). anti-8a : [R]21 +16.87 (c 1.00,
D
CH2Cl2); IR 3070, 1738, 1069 cm-1
;
1H NMR (400 MHz) δ
1.21-1.23 (m, 12H), 2.79 (d, 2H, J ) 6.0), 3.62 (s, 3H), 3.62-
3.68 (m, 2H), 3.86 (d, 1H, J ) 9.6), 4.40 (d, 1H, J ) 11.6), 4.60
(d, 1H, J ) 11.6), 7.26-7.37 (m, 5H); 13C NMR (100 MHz) δ
16.0, 22.6, 37.9, 51.6, 56.3, 58.0, 70.9, 75.7, 127.6, 127.7, 128.3,
138.1, 172.2. Anal. Calcd for C17H27NO4S: C, 59.80; H, 7.97;
N, 4.10. Found: C, 59.59; H, 8.22; N, 3.93.
(SS,4S)-4-Ben zyloxy-3-(2-m eth yl-pr opan e-2-su lfin ylam i-
n o)-p en ta n oic Acid Meth yl Ester (7a ). Reaction of 0.10 g
(0.37 mmol) of sulfinylimine 1a according to the general
procedure yielded a mixture of syn- and anti-7a (0.12 g, 96%
yield) as a clear oil after chromatography (60% EtOAc/hexanes
to 70% EtOAc/hexanes). HPLC-MS (60-95% MeOH/H2O over
15 min at 0.5 mL/min) tR(syn-7a ) ) 4.1 min, tR(anti-7a ) ) 5.0
min. syn-7a : 1H NMR (400 MHz) δ 1.18 (s, 9H), 1.33 (d, 3H,
J ) 6.4), 2.58 (d, 2H, J ) 6.4), 3.64 (s, 3H), 3.65-3.79 (m, 3H),
4.42 (d, 1H, J ) 11.6), 4.65 (d, 1H, J ) 11.6), 7.27-7.36 (m,
(RS,4S)-4-(ter t-Bu tyl-d ip h en yl-sila n yloxy)-3-(2-m eth yl-
p r op a n e-2-su lfin yla m in o)-p en ta n oic Acid Meth yl Ester
(8b). Reaction of 0.11 g (0.27 mmol) of sulfinylimine 2b
according to the general procedure yielded a mixture of syn-
and anti-8b (0.10 g, 78%) as a clear oil after chromatography
(50% EtOAc/hexanes). anti-8b: [R]21D -74.63 (c 3.71, CH2Cl2);
1H NMR (400 MHz) δ 1.03 (d, 3H, J ) 6.4), 1.06 (s, 9H), 1.22
(s, 9H), 2.77 (dd, 1H, J ) 6.4, 16.4), 2.82 (dd, 1H, J ) 6.4,
16.4), 3.53-3.62 (m, 1H), 3.63 (s, 3H), 3.76 (d, 1H, J ) 9.2),
3.95 (dq, 1H, J ) 4.0, 6.4), 7.36-7.46 (m, 6H), 7.67-7.69 (m,
4H); 13C NMR (100 MHz) δ 19.2, 19.8, 22.7, 26.9, 37.9, 51.6,
56.2, 58.7, 71.2, 127.4, 127.7, 129.6, 129.9, 132.8, 134.0, 135.7,
5H). anti-7a : [R]21 +87.37 (c 0.64, CH2Cl2); IR 3032, 1728,
D
1071 cm-1; H NMR (400 MHz) δ 1.17 (s, 9H), 1.25 (d, 3H, J
1
) 6.4), 2.80 (dd, 1H, J ) 5.0, 16.4), 2.88 (dd, 1H, J ) 5.0, 16.4),
3.47-3.53 (m, 1H), 3.58-3.67 (m, 4H), 4.35-4.38 (m, 2H), 4.60
(d, 1H, J ) 11.6), 7.26-7.36 (m, 5H); 13C NMR (100 MHz) δ
16.6, 22.6, 35.8, 51.5, 55.9, 58.7, 70.9, 76.3, 127.6, 127.7, 128.3,
138.0, 172.1. Anal. Calcd for C17H27NO4S: C, 59.80; H, 7.97;
N, 4.10. Found: C, 59.77; H, 8.16; N, 4.13.
171.9. syn-8b: [R]21 -11.29 (c 2.36, CH2Cl2); IR 3070, 1724,
D
1480, 1130, 1083 cm-1; 1H NMR (400 MHz) δ 0.95 (d, 3H, J )
6.4), 1.07 (s, 9H), 1.16 (s, 9H), 2.58 (dd, 1H, J ) 4.4, 15.2),
2.69 (dd, 1H, J ) 9.4, 15.2), 3.65 (s, 3H), 3.64-3.75 (m, 1H),
4.00 (d, 1H, J ) 8.4), 4.24-4.32 (m, 1H), 7.70-7.72 (m, 6H),
7.40-7.46 (m, 4H); 13C NMR (100 MHz) δ 19.3, 19.8, 22.5, 27.0,
35.3, 51.6, 55.8, 59.5, 72.3, 127.5, 127.7, 129.6, 129.8, 132.8,
133.7, 135.7, 135.8, 172.0; HRMS calcd for C26H40NO4SSi
490.244734, found 490.244734.
(SS,4S)-4-(ter t-Bu tyl-d ip h en yl-sila n yloxy)-3-(2-m eth yl-
p r op a n e-2-su lfin yla m in o)-p en ta n oic Acid Meth yl Ester
(7b). Reaction of 0.10 g (0.24 mmol) of sulfinylimine 1b
according to the general procedure yielded a mixture of syn-
and anti-7b (0.087 g, 74% yield) as a clear oil after chroma-
(RS,4S)-4-(ter t-Bu tyl-d im eth yl-sila n yloxy)-3-(2-m eth yl-
p r op a n e-2-su lfin yla m in o)-p en ta n oic Acid Meth yl Ester
(8c). Reaction of 0.091 g (0.31 mmol) of sulfinylimine 2c
according to the general procedure yielded pure syn-8c (0.058
g, 51%) as a clear oil after chromatography (50% EtOAc/
hexanes). HPLC-MS (65-95% MeOH/H2O over 15 min at 0.4
mL/min) tR(anti-8c) ) 11.5 min, tR(syn-8c) ) 12.5 min. anti-
8c: 1H NMR (400 MHz) δ -0.09 (s, 3H), 0.14 (s, 3H), 0.90 (s,
9H), 1.15 (d, 3H, J ) 6.3), 1.17 (s, 9H), 2.45-2.55 (m, 2H),
3.55-3.70 (m, 1H), 3.66 (s, 3H), 3.81 (d, 1H, J ) 9.2), 4.23
(dq, 1H, J ) 3.0, 6.3); 13C NMR (100 MHz) δ -4.7, -4.4, 17.8,
tography (50% EtOAc/hexanes). syn-7b: [R]21 +6.31 (c 0.54,
D
CH2Cl2); 1H NMR (400 MHz) δ 1.08 (s, 9H), 1.16, 1.19 (m, 12H),
2.46 (dd, 1H, J ) 5.6, 15.2), 2.52 (dd, 1H, J ) 15.2, 8.4), 3.60-
3.62 (m, 4H), 3.94-3.96 (m, 2H), 7.37-7.46 (m, 6H), 7.64-
7.69 (m, 4H); 13C NMR (100 MHz) δ 19.3, 20.1, 22.6, 27.0, 38.9,
51.5, 55.8, 59.1, 70.9, 127.5, 127.7, 129.7, 129.9, 132.9, 134.6,
135.77, 135.80, 171.6. anti-7b: [R]21D +18.75 (c 5.42, CH2Cl2);
IR 3071, 1738, 1589, 1478, 1110, 1074 cm-1 1H NMR (400
;
MHz) δ 1.02 (d, 3H, J ) 7.6), 1.04 (s, 9H), 1.15 (s, 9H), 2.85
(dd, 1H, J ) 5.2, 16.8), 2.90 (dd, 1H, J ) 5.2, 16.8), 3.49-3.51
(m, 1H), 3.63 (s, 3H), 3.93-3.94 (m, 1H), 4.27 (d, 1H, J ) 9.6),
7.36-7.46 (m, 6H), 7.65-7.68 (m, 4H); 13C NMR (100 MHz) δ
19.2, 20.5, 22.5, 26.9, 35.7, 51.6, 55.8, 60.1, 72.1, 127.4, 127.7,
129.6, 129.7, 133.2, 134.0, 135.7, 135.8, 172.6. Anal. Calcd for
20.5, 22.5, 25.7, 34.6, 51.5, 55.8, 60.1, 71.0, 172.3. syn-8c: [R]21
D
-43.0 (c 1.00, CH2Cl2); IR 1734, 1078 cm-1; 1H NMR (400 MHz)
δ -0.03 (s, 3H), 0.02 (s, 3H), 0.82 (s, 9H), 1.11 (d, 3H, J )
6.3), 1.18 (s, 9H), 2.64 (dd, 1H, J ) 7.8, 16.4), 2.76 (dd, 1H, J
) 5.9, 16.4), 3.47-3.56 (m, 1H), 3.58-3.72 (m, 1H), 3.66 (s,
3H), 3.91 (dq, 1H, J ) 2.0, 6.3); 13C NMR (100 MHz) δ -5.2,
-4.5, 17.8, 20.5, 22.5, 25.6, 38.3, 51.5, 56.2, 58.6, 69.5, 172.5.
Anal. Calcd for C16H35NO4S: C, 52.56; H, 9.65; N, 3.83.
Found: C, 52.67; H, 9.79; N, 3.90.
C
26H39NO4SSi: C, 63.76; H, 8.03; N, 2.86. Found: C, 63.77;
H, 7.79; N, 2.91.
(SS,4S)-4-(ter t-Bu tyl-d im eth yl-sila n yloxy)-3-(2-m eth yl-
p r op a n e-2-su lfin yla m in o)-p en ta n oic Acid Meth yl Ester
(7c). Reaction of 0.10 g (0.34 mmol) of sulfinylimine 1c
according to the general procedure yielded pure anti-7c (0.11
g, 87%) as a clear oil after chromatography (45% EtOAc/
hexanes to 55% EtOAc/hexanes). HPLC-MS (60-95% MeOH/
H2O over 15 min at 0.5 mL/min) tR(syn-7c) ) 11.0 min, tR(anti-
Rep r esen ta tive P r oced u r e for th e Su lfin yl Gr ou p
Clea va ge of Su lfin a m id es (p r od u cts 1a -c to 8a -c). To a
0.10 M solution of protected amino alcohol 5a (0.097 g, 0.28
mmol) in MeOH was added 0.35 mL of 4.00 N HCl/dioxane
(5.0 equiv, 1.4 mmol). The solution was stirred for 1 h at room
temperature and was then concentrated in vacuo. The amine
hydrochloride was obtained as a white solid after precipitation
from MeOH with ether, and was used without further puri-
fication.
Rep r esen ta tive P r oced u r e for th e Hyd r ogen a tion of
Ben zyl P r otected Am in o Alcoh ols (p r od u cts 3-8a ). To a
solution of the crude amine hydrochloride resulting from the
sulfinyl deprotection of 5a (ca. 0.060 mmol) in 0.60 mL of
MeOH (0.10 M) was added dry Pd/C (0.005 g, 5% Pd/C dry)
and then 0.10 mL of 4 N HCl/dioxane (5.0 equiv, 0.35 mmol).
7c) ) 13.1 min. anti-7c: [R]21 +145.6 (c 0.61, CH2Cl2); IR
D
1740, 1076 cm-1; H NMR (400 MHz) δ -0.04 (s, 3H), -0.01
1
(s, 3H), 0.81 (s, 9H), 1.12 (d, 3H, J ) 7.2), 1.16 (s, 9H), 2.74 (d,
2H, J ) 4.8), 3.30-3.32 (m, 1H), 3.62 (s, 3H), 3.84 (apparent
pent, 1H, J ) 6.2), 4.32 (d, 1H, J ) 9.6); 13C NMR (100 MHz)
δ -5.1, -4.2, 17.9, 21.1, 22.7, 25.7, 35.4, 51.6, 55.9, 60.3, 70.5,
173.0. Anal. Calcd for C16H35NO4SSi: C, 52.56; H, 9.65; N,
3.83. Found: C, 52.42; H, 9.98; N, 3.88.
(RS,4S)-4-Ben zyloxy-3-(2-m eth yl-pr opan e-2-su lfin ylam i-
n o)-p en ta n oic Acid Meth yl Ester (8a ). Reaction of 0.12 g
J . Org. Chem, Vol. 68, No. 26, 2003 9955

Evans and Ellman
1
The mixture was purged with a stream of H2 and stirred
overnight under a H2 atmosphere (balloon). The reaction
mixture was filtered through Celite, the cake was washed with
MeOH (2×), and the solvent was evaporated. Pure amino
alcohol 9 (0.009 g, 83% two steps) was obtained as white solid
after precipitation from MeOH with ether.
Rep r esen ta tive P r oced u r e for th e Dep r otection of
TBDP S P r otected Eth er s (p r od u cts 3-8b). To a polypro-
pylene centrifuge tube containing a solution of 5b (0.048 g,
0.098 mmol) in THF (0.40 mL) was added 0.20 mL of 70%
HF/pyridine dropwise. The solution was stirred at room
temperature for 24 h and was then poured into a separatory
funnel containing 10 mL of NaHCO3 (saturated) and 10 mL
of EtOAc. The separatory funnel was agitated until cessation
of gas evolution, and the aqueous layer was extracted with
EtOAc (3×). The organic layers were dried and then concen-
trated. Pure 10 (0.014 g, 77%) was obtained as a white solid
after precipitation of the HCl salt from MeOH with ether.
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 (p r od u cts 3-8c). To a solu-
tion of 5c (0.087 mg, 0.24 mmol) in 2.4 mL of MeOH (0.10 M)
was added 0.30 mL of 4 N HCl/dioxane (5.0 equiv, 1.2 mmol).
The solution was stirred overnight at room temperature and
then concentrated in vacuo. The residue was then dissolved
in 10 mL of CH2Cl2 and washed with 5.0 mL of 2 N NaOH.
The aqueous layer was extracted with CH2Cl2 (3×), and the
combined organic layers were dried and concentrated. Free
amino alcohol 10 (0.035 g, 93%) was obtained as a white solid
after precipitation of the HCl salt from MeOH with ether.
Rep r esen ta tive P r oced u r e for th e F or m a tion of Ox-
a zolid in on es 15-18. To a solution of amino alcohol 10 (0.052
g, 0.32 mmol) and triphosgene (0.072 g, 0.24 mmol) in 1.6 mL
of CH2Cl2 was added N,N-diisopropylethylamine (0.13 mL, 0.71
mmol) dropwise at 0 °C. The mixture was allowed to warm to
room temperature over a period of 4 h. The solution was then
diluted with CH2Cl2 and washed with NaHCO3 (saturated).
The aqueous layer was extracted with CH2Cl2 (3×), and the
combined organic layers were dried and concentrated to afford
16 (0.040 g, 83%) as a clear oil.
Oxazolidinone 16: H NMR (400 MHz) δ 0.92 (d, 3H, J )
6.4), 4.91 (d, 1H, J ) 8.0), 5.00 (dq, 1H, J ) 6.4, 8.0), 6.52 (br,
1H), 7.32-7.43 (m, 5H).7c
Dep r otection a n d Deter m in a tion of Absolu te Ster eo-
ch em istr y of 3c. The general procedure for cleavage of TBS
protected ethers was followed with use of 0.055 g (0.15 mmol)
of 3c yielding free amine hydrochloride 10 (27 mg, 95%) as a
white solid after precipitation of the HCl salt from MeOH with
ether. Spectroscopic data are consistent with previously pub-
lished results (see deprotection of 3b).25
Dep r ot ect ion a n d Det er m in a t ion of t h e Ab solu t e
Ster eoch em istr y of 4a . The general procedure for sulfinyl
group cleavage was followed with use of 0.13 g (0.42 mmol) of
4a . After removal of the sulfur impurities in vacuo, the crude
HCl salt was hydrogenated following the general procedure
to afford the HCl salt of the free amino alcohol. Cyclization of
the crude amino alcohol by using the general procedure yielded
oxazolidinone 17 (48 mg, 87%, three steps). Spectroscopic data
are consistent with previously published results.22
Oxazolidinone 17: 1H NMR (400 MHz) δ 0.93 (t, 3H, J )
7.5), 1.39 (d, 3H, J ) 6.2), 1.48-1.62 (m, 1H), 3.32 (q, 1H, J )
6.2), 4.28 (pent, 1H, 6.2), 6.73, (br, 1H).
Dep r ot ect ion a n d Det er m in a t ion of t h e Ab solu t e
Ster eoch em istr y of 4b. To a polypropylene centrifuge tube
containing a solution of 4b (0.095 g, 0.21 mmol) in THF (0.40
mL) was added 0.20 mL of 70% HF/pyridine dropwise. After
the solution was stirred at room temperature for 24 h, 0.25
mL of MeOH, and 4 N HCl/dioxane (0.10 mL, 0.40 mmol) was
added, and the solution was stirred an additional 1 h. After
removal of the solvent and sulfur impurities in vacuo, the free
amine hydrochloride was obtained as a mixture with pyri-
dinium hydrochloride (16:1 pyridinium hydrochloride/amino
alcohol). Oxazolidinone 18 (0.017 g, 64% two steps) was
obtained as a clear oil by using the general cyclization
procedure with 20 equiv of N,N-diisopropylethylamine.
Oxazolidinone 18: [R]21 +15.5 (c 1.00, CH2Cl2); IR 1729,
D
1074 cm-1; 1H NMR (400 MHz) δ 0.95 (t, 3H, J ) 7.2), 1.32 (d,
3H, J ) 6.8), 1.41-1.57 (m, 1H), 3.67 (dt, 1H, J ) 4.8, 8.4),
4.76 (pent, 1H, 6.8), 6.43, (br, 1H). 13C NMR (100 MHz) δ 10.4,
14.6, 22.9, 57.3, 76.2, 159.8; HRMS calcd for C6H11NO2
129.078979, found 129.078979.
Dep r ot ect ion a n d Det er m in a t ion of t h e Ab solu t e
Ster eoch em istr y of 3a . The general procedure for sulfinyl
group cleavage was followed with use of 0.070 g (0.21 mmol)
of 3a . After removal of the sulfur impurities in vacuo, the crude
HCl salt was hydrogenated by using the general procedure and
precipitated from MeOH with ether to afford 9 (0.033 g, 85%)
as a white solid. A portion of amino alcohol 9 (0.014 g, 0.072
mmol) was cyclized following the general procedure to afford
pure oxazolidone 15 (11 mg, 86%) after column chromatogra-
phy (90% CHCl3/MeOH). Spectroscopic data are consistent
with previously published results.
Dep r ot ect ion a n d Det er m in a t ion of t h e Ab solu t e
Ster eoch em istr y of 4c. The general procedure for cleavage
of a TBS protected ether was followed with use of 0.026 g
(0.081 mmol) of 4c yielding the free amine hydrochloride (0.011
g, 97%) as a light yellow oil. Spectroscopic data of the crude
amine hydrochloride were consistent with those previously
observed for the precursor to oxazolidinone 17 (see deprotec-
tion of 4a ).22
Dep r ot ect ion a n d Det er m in a t ion of t h e Ab solu t e
Ster eoch em istr y of 5a . The general procedure for sulfinyl
group cleavage was followed with use of 21 mg (0.060 mmol)
of 5a . After removal of the sulfur impurities in vacuo, the crude
HCl salt was hydrogenated and precipitated from MeOH with
ether to afford amino alcohol 10 (9.3 mg, 83%). Spectroscopic
data were consistent with those previously observed (see
deprotection of 3b).25
Dep r ot ect ion a n d Det er m in a t ion of t h e Ab solu t e
Ster eoch em istr y of 5b. The general procedure for cleavage
of TBDPS protected ethers was followed with use of 48 mg
(0.097 mmol) of 5b. Pure 10 (14 mg, 77%) was obtained after
trituration of the amine hydrochloride with ether. Spectro-
scopic data were consistent with those previously observed (see
deprotection of 3b).25
Amino alcohol 9 (free base): 1H NMR (400 MHz) δ 1.04 (d,
3H, J ) 6.0), 3.56 (d, 1H, J ) 8.0), 3.76 (dq, 1H, J ) 6.0, 8.0),
7.25-7.36 (m, 5H).25
Oxazolidone 15: 1H NMR (400 MHz) δ 1.50 (d, 3H, J ) 6.4),
4.43 (dq, 1H, J ) 6.4, 8.0), 4.47 (d, 1H, J ) 8.0), 5.81 (br, 1H),
7.32-7.41 (m, 5H).7c
Dep r ot ect ion a n d Det er m in a t ion of t h e Ab solu t e
Ster eoch em istr y of 3b. The general procedure for cleavage
of TBDPS protected ethers was followed with use of 0.087 g
(0.18 mmol) of 3b. Pure 10 (0.021 g, 64%) was obtained after
trituration of the amine hydrochloride with ether. Amino
alcohol 10 (0.051 g, 0.27 mmol) was cyclized following the
general procedure to afford oxazolidinone 16 (40 mg, 83%) after
column chromatography (90% CHCl3/MeOH). Spectroscopic
data are consistent with previously published results.
Dep r ot ect ion a n d Det er m in a t ion of t h e Ab solu t e
Ster eoch em istr y of 5c. The general procedure for cleavage
of TBS protected ethers was followed with use of 74 mg (0.20
mmol) of 5c. Pure 10 (35 mg, 93%) was obtained after
trituration of the amine hydrochloride with ether. Spectro-
scopic data were consistent with those previously observed (see
Amino alcohol 10 (free base): 1H NMR (400 MHz) δ 1.05
(d, 3H, J ) 6.0), 3.89 (d, 1H, J ) 4.8), 3.93 (dq, 1H, J ) 4.8,
6.0), 7.25-7.37 (m, 5H).25
(25) Gelbcke, M.; Baudet, M.; Hoyois, J .; Van deVliedt, G.; Deleers,
M. Nouv. J . Chim. 1983, 7, 41-47.
25
deprotection of 3b).
9956 J . Org. Chem., Vol. 68, No. 26, 2003

Synthesis of 1,2-Disubstituted â-Amino Alcohols
Dep r ot ect ion a n d Det er m in a t ion of t h e Ab solu t e
Ster eoch em istr y of 6a . The general procedure for sulfinyl
group cleavage was followed with use of 54 mg (0.18 mmol) of
6a . After removal of the sulfur impurities in vacuo, the crude
material was hydrogenated following the general procedure
to afford the HCl salt of the free amino alcohol (23 mg, 92%
two steps). Spectroscopic data of the amino alcohol were
consistent with those previously observed for the precursor to
oxazolidinone 18 (see deprotection of 4b).
173.1; HRMS calcd for C22H32NO3Si 386.215147, found
386.215148.
Dep r ot ect ion a n d Det er m in a t ion of t h e Ab solu t e
Ster eoch em istr y of 7c. The general procedure for cleavage
of TBS protected ethers was followed with use of 0.043 g (0.12
mmol) of 7c yielding lactone 11 (0.014 g, 78%) as a white solid
after precipitation of the HCl salt from MeOH with ether. Spec-
troscopic data of 11 were consistent with those previously ob-
served for the precursor to lactone 19 (see deprotection of 7a ).23
Dep r ot ect ion a n d Det er m in a t ion of t h e Ab solu t e
Ster eoch em istr y of 8a . The general procedure for sulfinyl
group cleavage was followed with use of 82 mg (0.24 mmol) of
8a . The resulting amine hydrochloride was hydrogenated fol-
lowing the general procedure yielding lactone 11 (26 mg, 94%),
which was obtained as a clear, colorless oil after column chrom-
atography (9:1:0.1 MeOH/CH2Cl2/NH4OH). Spectroscopic data
of the lactone were consistent with those previously observed
for the precursor to lactone 19 (see deprotection of 7a ).23
Dep r ot ect ion a n d Det er m in a t ion of t h e Ab solu t e
Ster eoch em istr y of 8b. The general procedure for sulfinyl
group cleavage was followed with use of 0.68 g (1.4 mmol) of
8b, and after evacuation of the solvent, the crude material was
diluted with CH2Cl2 and washed with NaHCO3 (saturated).
The aqueous layer was washed with CH2Cl2 (3×), and the
combined organic layers were dried and concentrated. Free
amine 13 (0.50 g, 93%) was obtained as a clear oil after
purification (70% EtOAc/hexanes). 13 was added to a mixture
of K2CO3 (0.40 g, 2.9 mmol) and BnBr (0.34 mL, 2.9 mmol) in
CH2Cl2/H2O (3:1, 0.30 M) that had been cooled to 0 °C. The
solution was warmed to room temperature over a period of an
hour, and after an additional 16 h the mixture was concen-
trated. Deprotection of the silyl ether by using the general
deprotection procedure yielded the free alcohol, which was
dissolved in CH2Cl2 (0.20 mL) and added to 4 N HCl/dioxane,
(1.8 mL). The solution was placed in a sealed tube and after
16 h the solution was concentrated in vacuo to yield a 1:1
mixture of lactone 20 and free alcohol after chromatography
(20% EtOAc/hexanes). Spectral data from a pure sample of 20
are consistent with previously published results.23
Dep r ot ect ion a n d Det er m in a t ion of t h e Ab solu t e
Ster eoch em istr y of 6b. To a polypropylene centrifuge tube
containing a solution of the minor diastereomer of 6b (34 mg,
0.075 mmol) in THF (0.40 mL) was added 0.20 mL of 70%
HF/pyridine dropwise. After the solution was stirred at room
temperature for 24 h, 0.25 mL of MeOH and 4 N HCl/dioxane
(0.10 mL, 0.40 mmol) were added. After an additional 1 h, the
solvent and sulfur impurities were removed in vacuo, and the
free amine hydrochloride was obtained as a mixture with
pyridinium hydrochloride. Spectroscopic data of the mixture
were consistent with those previously observed for the precur-
sor to oxazolidinone 18 (see deprotection of 4b).
Dep r ot ect ion a n d Det er m in a t ion of t h e Ab solu t e
Ster eoch em istr y of 6c. The general procedure for cleavage
of TBS protected ethers was followed with use of 15 mg (0.046
mmol) of 6c yielding the free amine hydrochloride (6.2 mg,
96%) as a light yellow oil. Spectroscopic data of the amino
alcohol were consistent with those previously observed for the
precursor to oxazolidinone 18 (see deprotection of 4b).
Dep r ot ect ion a n d Det er m in a t ion of t h e Ab solu t e
Ster eoch em istr y of 7a . The general procedure for sulfinyl
group cleavage was followed with use of 4.5 mg (0.013 mmol)
of 7a . The resulting amine hydrochloride was hydrogenated
following the general procedure yielding lactone 11 (1.5 mg,
95%) after column chromatography (9:1:0.1 MeOH/CH2Cl2/
NH4OH). Lactone 11 (2.4 mg, 0.025 mmol) was N,N-dibenzy-
lated by treatment with BnBr (0.11 mL, 0.88 mmol) and K2CO3
(0.10 g, 0.76 mmol) in 0.38 mL of CH3CN at 50 °C. After 16 h,
the suspension was cooled, diluted with EtOAc, and washed
with brine. The aqueous layer was extracted with EtOAc (3×),
and the combined organic layers were dried and concentrated.
Pure 19 (3.1 mg, 44%) was obtained after chromatography
(20% EtOAc/hexanes) as a clear oil. Spectroscopic data are
consistent with previously published results.23
1
Amine 13: IR 3071, 1736, 1110 cm-1; H NMR (400 MHz)
δ 1.01 (d, 3H, J ) 6.0), 1.06 (s, 9H), 2.32 (dd, 1H, J ) 9.6,
15.6), 2.54 (dd, 1H, J ) 4.0, 15.6), 3.12 (dt, 1H, J ) 4.0, 9.6),
3.62 (s, 3H), 4.76 (dq, 1H, J ) 4.0, 6.0), 7.32-7.41 (m, 6H),
7.67-7.69 (m, 4H); 13C NMR (100 MHz) δ 19.0, 21.2, 26.8, 38.4,
51.2, 53.8, 72.1, 127.2, 127.4, 129.3, 129.5, 133.1, 134.0, 135.52,
135.54, 172.8; HRMS calcd for C22H32NO3Si 386.215147, found
386.215148.
Lactone 19: 1H NMR (400 MHz) δ 1.33 (d, 3H, J ) 6.4),
2.59 (dd, 1H, J ) 8.4, 18.0), 2.65 (dd, 1H, J ) 6.7, 18.0), 3.33-
3.38 (m, 1H), 3.50 (d, 2H, J ) 13.8), 3.74 (d, 2H, J ) 13.8),
4.63 (pent, 1H, J ) 6.4), 7.26-7.44 (m, 10H).
Lactone 20: 1H NMR (400 MHz) δ 1.56 (d, 3H, J ) 6.4),
2.46 (dd, 1H, J ) 8.0, 17.6), 2.71 (dd, 1H, J ) 4.8, 17.6), 3.49
(d, 2H, J ) 14.0), 3.55-3.60 (m, 1H), 3.73 (d, 2H, J ) 14.0),
4.71 (pent, 1H, J ) 6.4), 7.24-7.38 (m, 10H).23
Dep r ot ect ion a n d Det er m in a t ion of t h e Ab solu t e
Ster eoch em istr y of 7b. The general procedure for sulfinyl
group cleavage was followed with use of 0.16 g (0.33 mmol) of
7b. After evaporation of the solvent, the crude material was
diluted with CH2Cl2 and washed with NaHCO3 (saturated).
The aqueous layer was washed with CH2Cl2 (3×), and the
combined organic layers were dried and concentrated. Puri-
fication of the residue (70% EtOAc/hexanes) yielded free amine
12 (0.11 g, 85%). Amine 12 was added to a mixture of K2CO3
(0.10 g, 0.75 mmol) and BnBr (0.090 mL, 0.75 mmol) dissolved
in CH2Cl2/H2O (3:1, 0.30 M) at 0 °C. The solution was warmed
to room temperature over a period of an hour, and after an
additional 16 h the mixture was concentrated in vacuo.
Cleavage of the silyl ether by using the general deprotection
procedure yielded lactone 19 (18 mg, 22% two steps) after
chromatography (20% EtOAc/hexanes). Spectroscopic data
were consistent with those previously observed (see deprotec-
tion of 7a ).23
Dep r ot ect ion a n d Det er m in a t ion of t h e Ab solu t e
Ster eoch em istr y of 8c. The general procedure for cleavage
of TBS protected ethers was followed with use of 44 mg (0.12
mmol) of 8c yielding 14 (17 mg, 94%) as a white solid after
precipitation of the HCl salt from MeOH with ether. A portion
of lactone 14 (3.9 mg, 0.034 mmol) was N,N-dibenzylated by
treatment with BnBr (0.11 mL, 0.88 mmol) and K2CO3 (0.10
g, 0.76 mmol) in 0.38 mL of CH3CN at 50 °C. After 16 h, the
suspension was cooled, diluted with EtOAc, and washed with
brine. The aqueous layer was extracted with EtOAc (3×), and
the combined organic layers were dried and concentrated. Pure
20 (5.9 mg, 59%) was obtained after chromatography (20%
EtOAc/hexanes) as a clear oil. Spectroscopic data were consis-
tent with those previously observed (see deprotection of 8b).23
Ack n ow led gm en t. This work was supported by the
National Science Foundation. The Center for New
Directions for Organic Synthesis is supported by Bristol-
Myers Squibb as a Sponsoring Member and Novartis
Pharma as a Supporting Member.
1
Amine 12: IR 3065, 1733, 1111 cm-1; H NMR (400 MHz)
δ 0.98 (d, 3H, J ) 6.4), 1.05 (s, 9H), 2.28 (dd, 1H, J ) 10.0,
16.0), 2.45 (dd, 1H, J ) 4.0, 16.0), 3.20 (dt, 1H, J ) 4.0, 10.0),
3.62 (s, 3H), 3.75-3.84 (m, 1H), 7.35-7.44 (m, 6H), 7.65-7.68
(m, 4H); 13C NMR (100 MHz) δ 18.3, 19.4, 27.0, 37.7, 51.7,
53.9, 72.7, 127.6, 127.7, 129.7, 129.8, 133.6, 134.3, 135.8, 135.9,
J O035224P
J . Org. Chem, Vol. 68, No. 26, 2003 9957