Synthesis of enantiomerically pure 2-amino alcohols from amino acids mediated by sulfoxides

Article abstract of DOI:10.1016/S0957-4166(00)00264-0

Enantiomerically pure (R₁,S₂)- and (S₁,S₂)-2-amino alcohols can be easily synthesized by stereodivergent reduction of α'-(N-Boc)amino β-keto sulfoxides (easily synthesized from readily available N-Boc amino este

Full text of DOI:10.1016/S0957-4166(00)00264-0

Tetrahedron: Asymmetry 11 (2000) 3079±3090
Synthesis of enantiomerically pure 2-amino alcohols from
amino acids mediated by sulfoxides
Francisco Yuste,a,* Benjamin Ortiz,a Alejandra Carrasco,a Martha Peralta,b
Leticia Quintero,b Ruben Sanchez-Obregon,a Fernando Wallsa
and Jose L. Garcõa Ruanoc,*
a
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Instituto de Quõmica, Universidad Nacional Autonoma de Mexico, Circuito Exterior, Cd. Universitaria,
Â
Coyoacan 04510, Mexico DF
Â
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Centro de Investigacion, Facultad de Ciencias Quõmicas, Benemerita Universidad Autonoma de Puebla,
72570 Puebla, Mexico
b
Â
Â
Â
Â
c
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Departamento de Quõmica Organica (C-1), Universidad Autonoma de Madrid, Cantoblanco, 28049 Madrid, Spain
Â
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Received 30 May 2000; accepted 5 July 2000
Abstract
Enantiomerically pure (R1,S2)- and (S1,S2)-2-amino alcohols can be easily synthesized by stereodivergent
reduction of a0-(N-Boc)amino b-keto sulfoxides (easily synthesized from readily available N-Boc amino
ester hydrochlorides) with DIBAH (de 82±92%) and DIBAH/ZnBr2 (de 80%), followed by hydrogenolysis
of the C±S bond of the resulting hydroxy sulfoxides and ®nal hydrolysis of the N-Boc protecting group.
# 2000 Elsevier Science Ltd. All rights reserved.
1. Introduction
The importance of enantiopure 2-amino alcohols is well recognized due to their signi®cance as
building blocks in the synthesis of drugs and natural products, ligands for asymmetric catalysis,
and chiral auxiliaries.1 These compounds are usually obtained by resolution of racemates,2
synthesis from optically pure precursors,3a and asymmetric synthesis.1a,b,4 The more general
synthetic routes to chiral 2-amino alcohols include reduction of a-amino acids or a-amino carbonyl
compounds,1,5 ring opening of epoxides,1,6 cyclic carbonates,7 sulfates8a or sul®tes8b with
amines1,6 or amine precursors,1,6c,7,8 diasteroselective formation of the central C±C bond by
several procedures,9 asymmetric aminohydroxylation of ole®ns10 and oxa Michael addition to
nitro alkenes.11
* Corresponding authors. E-mail: yustef@servidor.unam.mx; joseluis.garcia.ruano@uam.es
0957-4166/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(00)00264-0

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Concerning the use of natural amino acids as readily available starting materials, primary
2-amino alcohols containing one stereogenic center have been obtained by reduction of the parent
amino acid or amino ester salts.1b,5a The preparation of secondary 2-amino alcohols with two
stereogenic centers has been restricted essentially to the steroselective reduction of a-amino
ketones1,5 and the stereoselective addition of organometallic reagents to N-protected a-amino
aldehydes,1,3 which in turn are accessible from the corresponding amino acids. These two
approaches often provide complementary product stereochemistries but the preparation of both
diastereoisomers requires the synthesis of di€erent precursors as starting materials. On the other
hand, the generation of high levels of diastereoselectivity and the stability of the a-amino
carbonyl compounds have sometimes been problems inherent to these methods.1a They have been
minimized by using N,N-dibenzyl a-amino aldehydes3 but the removal of the benzyl groups may
be troublesome under some conditions.1a Concerning reduction reactions5 stereodivergent
reduction of a-N-phenyl¯uorenyl ketone to either the syn- or anti-amino alcohols have been
reported5c but it is not clear to what an extent the scope of this particular reaction is general
(other examples of similar reductions provide the anti-isomer).5d,e
Nucleophilic additions to enantiomerically pure b-keto sulfoxides have been widely used in
asymmetric synthesis of carbinols.12 Alkylation13 and hydrocyanation14 reactions of these
compounds with aluminium reagents have been reported to synthesize tertiary alcohols and
cyanohydrins respectively, but the most used reaction has been the stereoselective reduction of
b-keto sulfoxides15 with DIBAH and DIBAH/ZnX2 to yield secondary alcohols.16 These reagents
can also be used on b-imino sulfoxides (easily obtained from b-keto sulfoxides)17 a€ording
enantiomerically pure amines.18 Other functional groups such as epoxides, can be obtained by
conversion of the hydroxy sulfoxides resulting from these reactions,19 which can be subsequently
opened with nucleophiles.5,20 As b-keto sulfoxides are easily obtained by reaction of esters with
enantiomerically pure methyl p-tolyl sulfoxide,21 we envisioned the synthesis of a large variety of
1,2-amino alcohols (and occasionally 1,2-diamino derivatives) making use of the above-mentioned
reactions on the a-sul®nyl-a0-amino ketones 3 (or their imino derivatives), derived from
commercial amino ester hydrochlorides (Scheme 1).
Herein we report the synthesis and DIBAH and DIBAH/ZnX2 reductions of b-keto sulfoxides
3, derived from readily available (S)-alanine, (R)-phenylglycine and (S)-proline methyl ester
hydrochlorides. The obtained results suggest this method can be used as a general stereodivergent
procedure to synthesize (S,R)- and (S,S)-1,2-amino alcohols starting from (S)-N-Boc amino
esters, the desired con®guration at the hydroxylic carbon being obtained by choosing the suitable
reducing system. The transformation of the resulting hydroxy sulfoxides into the corresponding
enantiomerically pure 3-amino-2-alkanols without signi®cant racemization is also described.
Scheme 1.

F. Yuste et al. / Tetrahedron: Asymmetry 11 (2000) 3079±3090
3081
2. Results and discussion
Taking into account that the stereoselectivity of the b-keto sulfoxides reduction with DIBAH
and DIBAH/ZnX2 seems to be related to the ability of the sul®nyl oxygen to become associated
with metals,16b as a previous step of the attack of the hydride, presumably the presence of any
basic center at the substrate could interfere in the stereochemical course of these reactions. This
assumption was evidenced for b-keto sulfoxides bearing oxygenated functions able to compete
with the sul®nyl one for their association with the metal, which evolve with lower stereo-
selectivity.22 In order to avoid this problem in the case of b-keto sulfoxides derived from natural
amino acids, the protection of the amino group as N-Boc derivative, which decreases the ability
of the nitrogen to become associated to the metal thus minimizing its ability to compete with the
sul®nyl group for the aluminum, seemed to be reasonable.
The synthetic sequence to obtain a-sul®nyl-a0-amino ketone derivatives, 3, is depicted in
Scheme 2. The amino acid methyl ester hydrochlorides 1 reacted with di-tert-butyl dicarbonate in
methanol in the presence of triethylamine, resulting in the carbamates 2. The synthesis of the
b-keto sulfoxides 3 was performed by reaction of 2 with (R)-(+)-methyl p-tolyl sulfoxide and
LDA at ^78ꢀC (^25ꢀC, in the case of 3a), according to the procedure reported by Solladie.21
Diastereoisomeric excesses of b-keto sulfoxides were determined by 300 MHz 1H NMR. Crude 3a
was obtained as a 95:5 diasteroisomeric mixture, epimers at the stereogenic carbon vicinal to the
nitrogen moiety probably due to the excess of base and/or anion used in its preparation. The
puri®cation of the major epimer was carried out by crystallization of the crude product to provide
diasteroisomerically pure 3a (de >97%) in 61% yield. On the other hand, the keto sulfoxides 3b
and 3c were obtained with high diasteroisomeric excesses (>97%) and satisfactory chemical
yields (75 and 78%, respectively) and their absolute con®guration was unequivocally established
as (1R,RS) for 3b (Fig. 1) and (2S,RS) for 3c23 by X-ray di€raction studies.
Scheme 2. (i) Et3N, Boc2O, MeOH, rt, 24 h; (ii) p-Tol-SO-Me, LDA, THF, ^78ꢀC (or ^25ꢀC), 3±4 h
The reduction of b-keto sulfoxides 3 with DIBAH15 at ^78ꢀC gave the b-hydroxy sulfoxides 4
and 40 (Table 1) with high stereoselectivity (de 82±92%). An excess of DIBAH (5 equiv.) was
required to achieve the complete transformation of the starting products and to get high yields.
The major b-hydroxy sulfoxides were puri®ed by crystallization (4a) or by chromatography (4b
and 4c) to give diasteroisomerically pure products (de >97%) in yields ranging between 64 and
1
75%. Con®gurational assignment of the obtained diastereoisomers was deduced from their H
NMR, taking into account the well-known behavior of diastereoisomeric b-sul®nyl carbinols,24
which agrees with the predictions made on the basis of the stereochemical model proposed to
explain the DIBAH reduction of b-keto sulfoxides.15b The absolute con®guration of 4a was
con®rmed by a X-ray di€raction study (Fig. 1). The observed stereoselectivity is not complete
(de 82% for 4a, 86% for 4b, and 92% for 4c) suggesting some interferences of the nitrogen

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F. Yuste et al. / Tetrahedron: Asymmetry 11 (2000) 3079±3090
function in the stereochemical course of the reaction, which became less important by increasing
the steric hindrance of the nitrogenated carbon or the substitution at the nitrogen. Nevertheless,
the stereoselectivity of the reduction is high enough for synthetic purposes, which demonstrates
the eciency of the N-Boc group to avoid the competing of the amino and sul®nyl groups for the
aluminum. Additionally, we must remark the fact that the same con®guration at the hydroxylic
carbon is obtained from compounds 3a and 3b, both di€ering in con®guration at the nitrogenated
carbon, which suggests that the stereochemical course of these reductions is exclusively controlled
by the sul®nyl group.
Figure 1. X-Ray structures for compounds 3b and 4a
Table 1
Results obtained in DIBAH and DIBAH/ZnBr2 reduction of b-keto sulfoxides 3
The synthesis of the carbinols with the opposite con®guration at the hydroxylic carbon could
be achieved by reduction of the b-keto sulfoxides 3 with DIBAH in the presence of ZnBr2.15 In
these reactions, the inversion of the stereoselection has been justi®ed by assuming the formation
of a chelated species between the sul®nyl and the carbonyl oxygens with ZnBr2 previous to the

F. Yuste et al. / Tetrahedron: Asymmetry 11 (2000) 3079±3090
3083
hydride attack.15b,c As the nitrogen in compounds 3 could compete with the oxygens for the
metal, thus a€ecting the usual stereochemical pathway, it was necessary to check whether its
protection as N-Boc derivative was enough to eliminate such possible competitiveness. In this
sense, we have investigated the evolution of 3a with DIBAH/ZnBr2 (Table 1), because this is the
substrate presumably more prone to form such a chelate due to its lower steric hindrance around
the nitrogen atom. As expected, the reduction proceeds with high stereoselectivity but the
hydroxy sulfoxide 40a was now obtained as the major compound. The obtained de (80%, entry 4)
is similar to that observed in the reduction of (MeO)2CH-CO-CH2SOTol,21b which suggests that
the ability of the NHBoc group to form chelates is not signi®cant and equivalent to that of the
acetal group at C-a0. These results show the eciency of the N-Boc to minimize the ability of the
amino group to compete with the sul®nyl one in both DIBAH and DIBAH/ZnBr2 reductions of
compounds 3,25 thus allowing the synthesis of the epimeric carbinols by stereodivergent reduction
of compounds 3.
The cleavage of the C±S bond of b-hydroxy sulfoxides 4 with Raney nickel yields the
corresponding N-Boc protected 2-amino alkanols 5 in high yields (Scheme 3). Partial racemization
of the hydroxylated chiral carbon, observed in some desul®nylations of hydroxy sulfoxides with
Raney nickel,26 was not detected in these reactions. Finally, acidic hydrolysis of the N-Boc
protecting group proceeded in good yields by treatment of 5a, 50a and 5b with a saturated
solution of hydrochloric acid in ethyl acetate at room temperature for 2 h producing the hydro-
chlorides 6a, 60a, and 6b. Ecient deprotection of the amino group of 5c required its reaction
with tri¯uoroacetic acid, a€ording 6c after basi®cation with ammonium hydroxide and extractive
work-up.
Scheme 3. (i) Raney nickel, MeOH, rt, 1 h; (ii) HCl±EtOAc, rt, 2 h; (iii) (1) CF3CO2H, rt, 0.5 h; (2) NH4OH, rt, 5 min
The absolute con®guration and optical purity of the 2-amino alcohols 6b and 6c were
determined by comparison of the speci®c optical rotation of the samples obtained here with those
previously reported,27,28 whereas 6a and 60a had to be transformed into their N-acetyl
derivatives29 for their chemical correlation.
In summary, we have shown that both diastereoisomers of chiral 2-amino alcohols can be
easily synthesized in high optical purity from the readily available N-Boc-protected amino ester
hydrochlorides 2 by a four-step sequence involving formation of the b-keto sulfoxides 3 by
reaction of 2 with (+)-Me-SOTol/LDA, followed by stereodivergent reduction of 3 with DIBAH
or DIBAH/ZnBr2 (yielding the hydroxy sulfoxides 4 and 40, respectively), hydrogenolysis of the
C±S bond to produce the N-Boc protected amino alcohols 5, and ®nal acid hydrolysis of the
protecting group.

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F. Yuste et al. / Tetrahedron: Asymmetry 11 (2000) 3079±3090
3. Experimental
3.1. General methods
Melting points were determined in a Culatti melting point apparatus. All moisture sensitive
reactions were performed in ¯ame-dried glassware equipped with rubber septa under a positive
pressure of argon and monitored by TLC. Solvents were dried according to literature procedures.
Optical rotations were measured on a Jasco DIP-360 digital polarimeter at 20ꢀC (concentration
in g/100 ml). The IR spectra were recorded on a Nicolet-5SX spectrophotometer. The 1H and 13
C
NMR spectra were obtained either on a Varian Gemini-200 or Unity-300 spectrometer at room
temperature in deuteriochloroform using TMS as internal standard. Mass spectra were measured on a
Jeol AX-505 mass spectrometer at 70 eV and 190ꢀC. The diastereoisomeric excesses were determined
by 300 MHz 1H NMR spectroscopy. The two di€erent sets of signals in the NMR spectra (assigned as
Z and E) in compounds 2c and 3c resulted by the observable rotamers of the N-Boc group.
3.2. Preparation of N-(tert-butoxycarbonyl)methyl esters 2
To a solution of the corresponding methyl ester hydrochloride 1 (24 mmol) in 30 ml of dry
methanol, triethylamine (36 mmol) and di-tert-butyl dicarbonate (36 mmol) were added. The
mixture was stirred at room temperature for 24 h. The volatiles were removed under vacuum and
the residue was dissolved in 30 ml of CHCl3. The organic phase was washed with 10% aqueous
citric acid (2Â20 ml), dried and concentrated.
3.2.1. (S)-N-(tert-Butoxycarbonyl)alanine methyl ester 2a
Obtained from l-alanine methyl ester hydrochloride. White crystals, mp 30ꢀC, 91% yield; [ꢀ]D
1
^44 (c 1, MeOH). IR (CHCl3) ꢁmax: 3443, 2983, 1741, 1710, 1504, and 1452 cm^1; H NMR
(CDCl3, 200 MHz): ꢂ 1.38 (d, J=7.2 Hz, 3H), 1.44 (s, 9H), 3.75 (s, 3H), 4.33 (m, 1H), 5.15 (bd,
1H); 13C NMR (CDCl3, 75 MHz): ꢂ 18.5, 28.2, 49.1, 52.2, 80.0, 155.0, 173.8; EIMS m/z 203 (1%,
M+), 144 (55), 88 (40), 57 (100), 44 (68).
3.2.2. (R)-N-(tert-Butoxycarbonyl)phenylglycine methyl ester 2b
Obtained from d-phenylglycine methyl ester hydrochloride. White crystals, mp 104ꢀC, 98%
yield; [ꢀ]D ^130 (c 1, CHCl3). IR (CHCl3) ꢁmax: 3439, 2984, 1743, 1712, 1494, 1367 and 1165 cm^1;
1H NMR (CDCl3, 300 MHz): ꢂ 1.43 (s, 9H), 3.71 (s, 3H), 5.32 (d, J=7.5 Hz, 1H), 5.55 (m, 1H),
7.30±7.40 (m, 5H); 13C NMR (CDCl3, 75 MHz): ꢂ 28.2, 52.6, 57.6, 80.1, 127.1, 128.4, 128.9,
136.9, 154.8, 171.6; EIMS m/z 265 (1%, M+), 206 (71), 150 (100), 106 (88), 104 (15), 57 (83).
3.2.3. (S)-N-(tert-Butoxycarbonyl)proline methyl ester 2c
Obtained from l-proline methyl ester hydrochloride. Oil, pb 135ꢀC/16 mm, 54% yield; [ꢀ]D
1
^61.5 (c 0.34, MeOH). IR (CHCl3) ꢁmax: 3394, 2981, 1746, 1689, 1406 cm^1; H NMR (CDCl3,
200 MHz) (Z, 60%): ꢂ 1.46 (s, 9H), 1.80±2.05 (m, 3H), 2.15±2.30 (m, 1H), 3.35±3.60 (m, 2H), 3.72
(s, 3H), 4.34 (dd, J=7.9 and 3.4 Hz, 1H); (E, 40%): ꢂ 1.41 (s, 9H), 1.80±2.05 (m, 3H), 2.15±2.30
(m, 1H), 3.35±3.60 (m, 2H), 3.72 (s, 3H), 4.22 (dd, J=8.3 and 3.9 Hz, 1H); 13C NMR (CDCl3,
75 MHz) (Z): ꢂ 24.2, 28.3, 29.8, 46.4, 51.9, 58.6, 79.7, 153.7, 173.6; (E): ꢂ 3.5, 28.1, 30.7, 46.2,
51.8, 58.9, 79.7, 154.3, 173.6; EIMS m/z 230 (5%, M+), 229 (4), 170 (65), 128 (65), 114 (93), 70
(100), 57 (96), 41(54).

F. Yuste et al. / Tetrahedron: Asymmetry 11 (2000) 3079±3090
3085
3.3. Preparation of ꢃ-keto sulfoxides 3
3.3.1. (3S,RS)-N-(tert-Butoxycarbonyl)-3-amino-1-(p-tolylsul®nyl)-2-butanone 3a
A solution of (R)-(+)-methyl p-tolyl sulfoxide (6.16 g, 40 mmol) in 10 ml of THF was added
dropwise to a solution of LDA (40 mmol) in 100 ml of THF at ^78ꢀC. The mixture was stirred at
^78ꢀC for 1.5 h. Then a solution of 2a (4.06 g, 20 mmol) in 10 ml of THF was added and the
resulting mixture was stirred at ^25ꢀC for 3.5 h. The reaction mixture was decomposed with 100
ml of saturated ammonium chloride solution and extracted with CH2Cl2 (2Â50 ml). The organic
phase was washed with brine, dried and evaporated. The crystalline residue (de 90%) was
recrystallized from CH2Cl2±hexane to give 2.74 g (42%) of 3a as white crystals, mp 106ꢀC; [ꢀ]D
+189 (c 1, CHCl3), de >97%. The mother liqueurs were puri®ed by silica gel column chromatography
eluting with hexane:EtOAc, 35:65, to produce, additionally, 1.23 g (19% yield) of 3a, mp 106ꢀC,
1
de >97%; IR (CHCl3) ꢁmax: 3437, 2984, 2931, 1706, 1496, 1370, and 1054 cm^1; H NMR
(CDCl3, 300 MHz), major diasteroisomer: ꢂ 1.24 (d, J=7.2 Hz, 3H), 1.43 (s, 9H), 2.42 (s, 3H),
3.78 and 4.13 (AB system, J=13.8 Hz, 2H), 4.20 (m, 1H), 5.25 (m, 1H, interchangeable with
D2O), 7.34±7.57 (AA0BB0 system, 4H); minor diasteroisomer: ꢂ 1.27 (d, J=7.2 Hz, 3H), 1.43 (s,
9H), 2.42 (s, 3H), 3.86 and 4.01 (AB sy0stem, J=13.8 Hz, 2H), 4.20 (m, 1H), 5.25 (m, 1H,
interchangeable with D2O), 7.34±7.57 (AA BB0 system, 4H); 13C NMR (CDCl3, 75 MHz), major
diasteroisomer: ꢂ 16.1, 21.4, 28.3, 56.0, 65.5, 80.3, 124.1, 130.1, 140.2, 142.4 155.0, 201.5; EIMS
m/z 326 (2%, M++1), 144 (100), 140 (74), 88 (36), 57 (98), 44 (84); CIMS m/z 326 (50%, M++1),
270 (100), 226 (18), 130 (45), 86 (95).
3.3.2. (1R,RS)-N-(tert-Butoxycarbonyl)-1-amino-1-phenyl-3-(p-tolylsul®nyl)-2-propanone 3b
A solution of (R)-(+)-methyl p-tolyl sulfoxide (0.308 g, 2 mmol) in 5 ml of THF was added
dropwise to a solution of LDA (4 mmol) in 20 ml of THF at ^78ꢀC. The mixture was stirred at
^78ꢀC for 1 h. Then a solution of 2b (0.530 g, 2 mmol) in 10 ml of THF was added and the
resulting mixture was stirred at ^78ꢀC for 3 h. The reaction mixture was decomposed with 20 ml
of saturated ammonium chloride solution and extracted with Et2O (2Â25 ml). The organic phase
was washed with brine, dried and concentrated. The residue was puri®ed by silica gel column
chromatography eluting with hexane:EtOAc, 30:70. White crystals, mp 177ꢀC (petroleum ether),
75% yield; [ꢀ]D ^67 (c 1, CHCl3), de >97%; IR (CHCl3) ꢁmax: 3427, 2984, 2930, 1708, 1491, 1369
1
and 1166 cm^1; H NMR (CDCl3, 300 MHz): ꢂ 1.39 (s, 9H), 2.41 (s, 3H), 3.71 and 3.92 (AB
system, J=13.8 Hz, 2H), 5.19 (d, J=6 Hz, 1H), 5.75 (s, 1H, interchangeable with D2O), 7.23±7.48
(m, 9H); 13C NMR (CDCl3, 75 MHz): ꢂ 21.5, 28.2, 64.9, 65.4, 80.1, 124.1, 128.2, 128.9, 129.4,
130.1, 137.0, 139.0, 142.4, 154.6, 197.0; CIMS m/z 388 (72%, M++1), 332 (83), 288 (10), 248 (20),
192 (86), 174 (19), 148 (100).
3.3.3. (2S,RS)-1-(tert-Butoxycarbonyl)-2-(20-p-tolylsul®nyl)acetylpyrrolidine 3c
A solution of (R)-(+)-methyl p-tolyl sulfoxide (1.30 g, 8.5 mmol) in 5 ml of THF was added
dropwise to a solution of LDA (17 mmol) in 50 ml of THF at ^78ꢀC. The mixture was stirred at
^78ꢀC for 1 h. Then a solution of 2c (1.3 g, 5.7 mmol) in 5 ml of THF was added and the resulting
mixture was stirred at ^78ꢀC for 4 h. The reaction mixture was decomposed with 100 ml of
saturated ammonium chloride solution and extracted with Et2O (3Â20 ml). The organic phase
was washed with brine, dried and concentrated. The oily residue was puri®ed by silica gel column
chromatography eluting with hexane:EtOAc, 30:70. White crystals, mp 92±93ꢀC (ether±hexane),
78% yield; [ꢀ]D +80 (c 1, MeOH), de >97%; IR (CHCl3) ꢁmax: 2981, 2883, 1722, 1683, 1396, 1163

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F. Yuste et al. / Tetrahedron: Asymmetry 11 (2000) 3079±3090
and 1037 cm^1; 1H NMR (CDCl3, 300 MHz) (Z): ꢂ 1.37 (s, 9H), 1.80 (m, 3H), 2.15 (m, 1H), 2.41
(s, 3H), 3.42 (m, 1H), 3.58 (m, 1H), 3.63±4.04 (AB system, J=14.4 Hz, 2H), 4.27 (m, 1H), 7.35
and 7.57 (AA0BB0 system, 4H); (E): ꢂ 1.42 (s, 9H), 1.80 (m, 3H), 2.15 (m, 1H), 2.42 (s, 3H), 3.42
(m, 1H), 3.58 (m, 1H), 3.85±3.99 (AB system, J=15 Hz, 2H), 4.36 (m, 1H), 7.31 and 7.57
(AA0BB0 system, 4H); 13C NMR (CDCl3, 75 MHz) (Z): ꢂ 21.4, 23.8, 27.7, 28.4, 46.9, 65.4, 66.1,
80.4, 124.1, 130.0, 140.6, 142.0, 153.7, 201.9; (E): ꢂ 21.4, 24.6, 28.4, 28.6, 47.0, 66.1, 66.6, 80.9,
124.2, 130.2, 140.6, 142.3, 154.4, 201.9; EIMS m/z 352 (5%, M++1), 170 (60), 140 (25), 114 (100),
70 (98), 57 (60).
3.4. Preparation of ꢃ-hydroxy sulfoxides 4
DIBAH reduction: To a solution of b-keto sulfoxide 3 (1 equiv.) in THF (5 ml/mmol) at ^78ꢀC
a 1.5 M solution of DIBAH in toluene (5 equiv.) was added dropwise. The reaction mixture was
stirred for 10±15 min to completion and the excess of DIBAH was decomposed by adding MeOH
(2 ml/mmol). The solvents were removed under vacuum and the residue was treated with a 5%
HCl solution (10 ml/mmol) and extracted with Et2O (3Â10 ml/mmol). The organic phase was
washed with brine, dried and evaporated.
3.4.1. (2S,3S,RS)-N-(tert-Butoxycarbonyl)-3-amino-1-(p-tolylsul®nyl)-2-butanol 4a
Obtained from 1.97 g (6.06 mmol) of 3a (de >97%). The crystalline crude product (1.93 g, de
82%) was puri®ed by crystallization from CH2Cl2/hexane to give 1.27 g (64% yield) of 4a as
white crystals, mp 116±118ꢀC; [ꢀ]D +160.4 (c 1, CHCl3), de >97%; IR (CHCl3) ꢁmax: 3440, 3003,
2983, 2933, 1704, 1500, 1165, and 1027 cm^1; 1H NMR (CDCl3, 300 MHz): ꢂ 1.13 (d, J=6.9 Hz,
3H), 1.40 (s, 9H), 2.43 (s, 3H), 2.64 (dd, J=1.8 and 13.5 Hz, 1H), 3.06 (dd, J=10.2 and 13.5 Hz,
1H), 3.62 (bs, 1H), 4.08 (ddd, J=1.8, 4.5 and 10.5 Hz), 4.42 (s, 1H, interchangeable with D2O),
4.71 (s, 1H, interchangeable with D2O), 7.35 and 7.51 (AA0BB0 system, 4H); 13C NMR (CDCl3,
75 MHz): ꢂ 15.7, 21.4, 28.3, 50.5, 58.5, 69.7, 79.7, 124.0, 130.1, 139.5, 141.7, 155.5; EIMS m/z 327
(5%, M+), 254 (15), 205 (20), 183 (45), 139 (95), 132 (80), 88 (35), 71 (20), 57 (100), 44 (57), 43
(28).
3.4.2. (1R,2S,RS)-N-(tert-Butoxycarbonyl)-1-amino-1-phenyl-3-(p-tolylsul®nyl)-2-propanol 4b
Obtained from 0.774 g (2 mmol) of 3b (de >97%). The crude product (0.701 g, de 86%) was
puri®ed by silica gel column chromatography eluting with hexane:EtOAc, 35:65, to produce
0.552 g (71% yield) of 4b as white crystals, mp 180ꢀC (acetone/hexane); [ꢀ]D +203.5 (c 1, CHCl3),
de >97%; IR (CHCl3) ꢁmax: 3440, 2931, 1711, 1494 and 1166 cm^1; 1H NMR (CDCl3, 300 MHz):
ꢂ 1.39 (s, 9H), 2.42 (s, 3H), 2.69 (dd, J=1.8 and 13.5 Hz, 1H), 3.22 (dd, J=10.2 and 13.8 Hz, 1H),
4.10 (m, 1H, interchangeable with D2O), 4.40 (m, 1H), 4.53 (m, 1H), 5.52 (m, 1H, interchangeable
with D2O), 7.18±7.50 (m, 9H); 13C NMR (CDCl3, 75 MHz): ꢂ 21.4, 28.3, 58.5, 59.2, 69.6, 79.9,
124.0, 126.7, 127.6, 128.6, 130.1, 139.2, 139.9, 141.7, 155.8; EIMS m/z 389 (1%, M+), 206 (28),
183 (60), 150 (95), 139 (75), 106 (100), 91 (15), 57 (72).
3.4.3. (10S,2S,RS)-1-(tert-Butoxycarbonyl)-2-(20-p-tolylsul®nyl-10-hydroxy)ethylpyrrolidine 4c
Obtained from 0.704 g (2 mmol) of 3c (de >97%). The crude product (0.630 g, de 92%) was
puri®ed by silica gel column chromatography eluting with hexane:EtOAc, 35:65, to produce
0.528 g (75% yield) of 4c as white crystals, mp 123±124ꢀC (acetone/hexane); [ꢀ]D +23 (c 0.4,
1
MeOH), de >97%; IR (CHCl3) ꢁmax: 3394, 2979, 1661, 1408, 1323, 1121 and 1033 cm^1; H

F. Yuste et al. / Tetrahedron: Asymmetry 11 (2000) 3079±3090
3087
NMR (CDCl3, 300 MHz): ꢂ 1.41 (s, 9H), 1.75 (m, 3H), 2.00 (m, 1H), 2.42 (s, 3H), 2.75 (m, 2H),
3.11 (m, 1H), 3.42 (m, 1H), 4.02 (m, 1H), 4.21 (m, 1H), 7.33 and 7.53 (AA0BB0 system, 4H); 13C
NMR (CDCl3, 75 MHz): ꢂ 21.4, 23.8, 28.3, 29.7, 47.8, 61.6, 62.5, 68.8, 80.4, 124.0, 130.0, 141.3,
156.3; EIMS m/z 354 (3%, M++1), 170 (43), 158 (36), 139 (35), 114 (100), 70 (97), 57 (55); CIMS
m/z 354 (30%, M++1), 298 (8), 282 (11), 255 (25), 254 (100), 158 (15), 114 (10).
3.4.4. (2R,3S,RS)-N-(tert-Butoxycarbonyl)-3-amino-1-(p-tolylsul®nyl)-2-butanol 40a
DIBAH/ZnBr2 reduction of 3a: A solution of b-keto sulfoxide 3a (0.163 g, 0.5 mmol) in 3 ml of
THF was added to a cooled solution of ZnBr2 (0.124 g, 0.55 mmol) in 10 ml of THF at 0ꢀC under
argon and the resulting mixture was stirred at this temperature for 1.5 h. Then the solution was
cooled at ^78ꢀC and a 1.5 M solution of DIBAH in toluene (1.5 mmol) was added dropwise. The
reaction mixture was stirred at ^78ꢀC for 1 h and the excess of DIBAH was decomposed by
adding 2 ml of MeOH. Once the solution reached room temperature, the volatiles were removed
under vacuum and the residue was treated with 15 ml of saturated ammonium chloride and
extracted with CH2Cl2 (3Â10 ml). The organic phase was washed with brine, dried and evapo-
rated. The crystalline crude product (0.16 g, de 80%) was puri®ed by crystallization from
CH2Cl2/hexane to give 0.116 g (71% yield) of 40a as white crystals, mp 126ꢀC; [ꢀ]D +138 (c 1,
CHCl3), de >97%; IR (CHCl3) ꢁmax: 3440, 2997, 2982, 2933, 1703, 1499, 1165, and 1013 cm^1;
1H NMR (CDCl3, 300 MHz): ꢂ 1.25 (d, J=6.9 Hz, 3H), 1.39 (s, 9H), 2.42 (s, 3H), 2.85 (dd, J=2.7
and 13.5 Hz, 1H), 2.99 (dd, J=9.3 and 13.5 Hz, 1H), 3.54 (s, 1H, interchangeable with D2O), 3.77
(bs, 1H), 4.27 (ddd, J=2.1, 2.7 and 9.3 Hz, 1H), 4.87 (s, 1H, interchangeable with D2O), 7.34 and
7.53 (AA0BB0 system, 4H); 13C NMR (CDCl3, 75 MHz): ꢂ 18.1, 21.4, 28.3, 50.4, 60.6, 71.1, 79.4,
123.9, 130.1, 140.3, 142.0, 155.9; EIMS m/z 327 (5%, M+), 254 (13), 183 (37), 139 (65), 132 (100),
88 (39), 57 (83), 44 (64).
3.5. Desulfurization of sul®nyl alcohols
To a suspension of Raney nickel (ca. 300 mg) in 5 ml of MeOH a solution of sul®nyl hydroxy
compound 4 (1 mmol) in 5 ml of MeOH was added. The mixture was stirred at room temperature
for 1 h. The catalyst was removed by ®ltration over Celite and washed with MeOH. The
evaporation of the solvent produced the corresponding N-(tert-butoxycarbonyl)amino alcohol 5.
3.5.1. (2R,3S)-N-(tert-Butoxycarbonyl)-3-amino-2-butanol 5a
White crystals, mp 73±74ꢀC, 92% yield; [ꢀ]D ^3.8 (c 1, MeOH); IR (CHCl3) ꢁmax: 3624, 3445,
1
2982, 1704, 1504, 1367 and 1168 cm^1; H NMR (CDCl3, 300 MHz): ꢂ 1.09 (d, J=6.6 Hz, 3H),
1.14 (d, J=6.6 Hz, 3H), 1.45 (s, 9H), 1.75 (bs, 1H, interchangeable with D2O), 3.70 (bs, 1H), 3.85
(qd, J=3.0 and 6.6 Hz, 1H), 4.63 (bs, 1H, interchangeable with D2O); 13C NMR (CDCl3, 75
MHz): ꢂ 15.0, 18.5, 28.4, 51.7, 70.6, 80.1, 155.2; CIMS m/z 190 (90%, M++1), 134 (100), 116 (24),
90 (83).
3.5.2. (1R,2R)-N-(tert-Butoxycarbonyl)-1-amino-1-phenyl-2-propanol 5b
White solid, mp 93ꢀC, 82% yield; [ꢀ]D ^36.5 (c 1, MeOH); IR (CHCl3) ꢁmax: 3591, 3444, 2982,
2932, 1709, 1496 and 1166 cm^1; 1H NMR (CDCl3, 300 MHz): ꢂ 1.19 (d, J=6.3 Hz, 3H), 1.41 (s,
9H), 2.19 (s, 1H, interchangeable with D2O), 4.00 (bs, 1H), 4.54 (bs, 1H), 5.38 (bd, 1H,
interchangeable with D2O), 7.22±7.37 (m, 5H); 13C NMR (CDCl3, 75 MHz): ꢂ 20.2, 28.3, 60.3,
71.1, 79.7, 126.5, 127.4, 128.6, 140.7, 156.2; EIMS m/z 252 (1%, M++1), 206 (27), 150 (100), 135

3088
F. Yuste et al. / Tetrahedron: Asymmetry 11 (2000) 3079±3090
(10), 106 (87), 57 (68); CIMS m/z 252 (15%, M++1), 206 (20), 196 (84), 178 (49), 152 (44), 135
(100), 106 (18).
3.5.3. (10R,2S)-1-(tert-Butoxycarbonyl)-2-(10-hydroxy)ethylpyrrolidine 5c
Oil, 81% yield; [ꢀ]D ^59.8 (c 1, MeOH); IR (CHCl3) ꢁmax: 3365, 2978, 1668, 1409, 1166 and
1
1110 cm^1; H NMR (CDCl3, 300 MHz): ꢂ 1.09 (d, J=6.3 Hz, 3H), 1.47 (s, 9H), 1.60±2.10 (m,
4H), 3.18±3.32 (m, 1H), 3.43±3.60 (m, 1H), 3.80±4.10 (m, 2H), 4.50 (bs, 1H, interchangeable with
D2O); 13C NMR (CDCl3, 75 MHz): ꢂ 17.7, 24.1, 28.5, 29.7, 48.0, 63.5, 69.7, 80.0, 156.5; EIMS m/z
216 (3%, M++1), 215 (2), 170 (25), 114 (90), 70 (100), 57 (75).
3.5.4. (2S,3S)-N-(tert-Butoxycarbonyl)-3-amino-2-butanol 50a
Oil, 92% yield; [ꢀ]D ^3.7 (c 1.08, MeOH); IR (®lm) ꢁmax: 3356, 2976, 2933, 1689, 1519, 1367
and 1169 cm^1; 1H NMR (CDCl3, 300 MHz): ꢂ 1.16 (d, J=6.9 Hz, 3H), 1.18 (d, J=6.3 Hz, 3H),
1.45 (s, 9H), 2.47 (bs, 1H, interchangeable with D2O), 3.56 (bs, 1H), 3.69 (qd, J=4.5 and 6.3 Hz,
1H), 4.78 (bs, 1H, interchangeable with D2O); 13C NMR (CDCl3, 75 MHz): ꢂ 18.0, 20.2, 28.3,
51.9, 71.0, 79.4, 156.3; CIMS m/z 190 (100%, M++1), 134 (49), 116 (9), 90 (42), 88 (8).
3.6. Hydrolysis of N-(tert-butoxycarbonyl)amino alcohols
A saturated hydrogen chloride solution in ethyl acetate (5 ml) was added to N-(tert-Boc)amino
alcohols 5a, 50a or 5b (0.5 mmol). The resulting solution was stirred at room temperature for 2 h.
The volatiles were removed under vacuum and the solid residue was triturated with ethyl acetate.
3.6.1. (2R,3S)-3-Amino-2-butanol hydrochloride 6a
White solid, mp 106±107ꢀC, 81% yield; [ꢀ]D ^11.1 (c 0.22, MeOH); IR (Nujol) ꢁmax: 3396,
1
2924, 2854, 1609, 1458, 1216, 1057 and 1026 cm^1; H NMR (D2O, 300 MHz): ꢂ 1.09 (d, J=6.6
Hz, 3H), 1.12 (d, J=6.9 Hz, 3H), 3.27 (qd, J=3.3 and 6.9 Hz, 1H), 3.90 (qd, J=3.3 and 6.6 Hz,
1H); 13C NMR (D2O, 75 MHz): ꢂ 12.5, 18.1, 53.0, 67.8 [lit.:29 13C NMR (D2O): ꢂ 12.18, 17.79,
52.57, 67.32]; CIMS m/z 90 (65%, M++1^HCl), 73 (15), 72 (100), 55 (5). The (2R,3S)-3-acetamido-
2-acetoxybutane was prepared from 6a (acetic anhydride, pyridine, 4-(dimethylamino)pyridine,
CH2Cl2, room temperature, 12 h), mp 61ꢀC, 65% yield; [ꢀ]D ^31 (c 2.5, 2-butanone) [lit.:29 mp
62±63ꢀC, [ꢀ]D ^33.0 (c 0.5, 2-butanone)]; 1H NMR (CDCl3, 300 MHz): ꢂ 1.13 (d, J=6.9 Hz, 3H),
1.22 (d, J=6.6 Hz, 3H), 1.98 (s, 3H), 2.08 (s, 3H), 4.14 (qd, J=3.6 and 6.9 Hz, 1H), 4.90 (qd,
J=3.6 and 6.6 Hz, 1H), 5.79 (sa, 1H, interchangeable with D2O)
3.6.2. (1R,2R)-1-Amino-1-phenyl-2-propanol hydrochloride 6b
White solid, mp 195ꢀC, 75% yield; [ꢀ]D ^24 (c 0.9, H2O) [lit.:27 mp 192±193ꢀC, [ꢀ]D +26 (c 0.9,
H2O) for (1S,2S)-enantiomer]; IR (KBr) ꢁmax: 3421, 2993, 2920, 1615, 1526, 1454 and 1096 cm^1;
1H NMR (CDCl3+CD3OD, 300 MHz): ꢂ 1.07 (d, J=6.0 Hz, 3H), 3.93 (d, J=9.6 Hz, 1H), 4.08±
4.20 (m, 1H), 7.44 (s, 5H); 13C NMR (CDCl3+CD3OD, 75 MHz): ꢂ 20.3, 62.9, 68.7, 128.1, 129.7,
129.9, 134.9; CIMS m/z 152 (75%, M++1^HCl), 135 (100), 134 (20), 106 (18).
3.6.3. (10R,2S)-2-(10-Hydroxy)ethylpyrrolidine 6c
To 5c (0.2 mmol) tri¯uoroacetic acid (0.2 ml) was added. The solution was stirred at room
temperature for 0.5 h. The volatiles were removed under a nitrogen stream and the residue was
evaporated to dryness under vacuum. The residue was treated with 1 ml of concentrated

F. Yuste et al. / Tetrahedron: Asymmetry 11 (2000) 3079±3090
3089
ammonium hydroxide and stirred at room temperature for 5 min. The aqueous phase was
extracted with CH2Cl2 (3Â2 ml). The organic phase was dried with anhydrous potassium
carbonate and the solvent was removed under vacuum to give a white solid: mp 82ꢀC, 75% yield;
[ꢀ]D ^35.3 (c 1, MeOH) [lit.:28 mp 86ꢀC, [ꢀ]D ^36.4 (c 1, MeOH)]; IR (CHCl3) ꢁmax: 3351, 2957,
1
2924, 2853, 2272 and 1462 cm^1; H NMR (CDCl3, 300 MHz): ꢂ 1.18 (d, J=6.0 Hz, 3H), 1.50±
2.00 (m, 4H), 2.71 (m, 2H), 2.90±3.25 (m, 3H), 3.78 (m, 1H).
3.6.4. (2S,3S)-3-Amino-2-butanol hydrochloride 60a
Oil, 89% yield; [ꢀ]D +15 (c 1.46, MeOH); IR (®lm) ꢁmax: ca. 3600±2200 (b), 1727, 1603, 1505,
1
1391, and 1104 cm^1; H NMR (D2O, 300 MHz): ꢂ 1.10 (d, J=6.3 Hz, 3H), 1.12 (d, J=6.0 Hz,
3H), 3.04 (qd, 1H), 3.61 (qd, 1H); 13C NMR (D2O, 75 MHz): ꢂ 15.4, 19.6, 54.1, 69.2 [lit.:30 13
C
NMR (D2O): ꢂ 15.56, 19.47, 53.92, 68.93]. The (2S,3S)-3-Acetamido-2-acetoxybutane was
prepared from 60a (acetic anhydride, pyridine, 4-(dimethylamino)pyridine, CH2Cl2, room
temperature, 12 h), oil, 58% yield; [ꢀ]D ^33 (c 1.46, 2-butanone) [lit.:29 mp 15±16ꢀC, [ꢀ]D +35 (c
0.503, 2-butanone) for the (2R,3R)-enantiomer]; IR (®lm) ꢁmax: 3291, 2982, 2938, 1737, 1652,
1
1548, 1449, 1374, 1242, and 1023 cm^1; H NMR (CDCl3, 300 MHz): ꢂ 1.12 (d, J=6.9 Hz, 3H),
1.21 (d, J=6.6 Hz, 3H), 2.01 (s, 3H), 2.08 (s, 3H), 4.15 (qd, 1H), 4.90 (qd, J=4.2 and 6.6 Hz, 1H),
5.65 (sa, 1H, interchangeable with D2O); 13C NMR (CDCl3, 75 MHz): ꢂ 17.3, 18.1, 21.1, 23.3, 48.4,
72.9, 169.6, 170.6; EIMS m/z 173 (1%,M+), 129 (10), 113 (17), 86 (76), 72 (13), 44 (100), 43 (43).
Acknowledgements
We thank M. I. Chavez, R. Gavino, W. Matus, R. Patino, M. A. Pena, J. Perez, B. Quiroz, H.
Rõos, R. A. Toscano and L. Velasco for their technical assistance, and the Consejo Nacional de
Ciencia y Tecnologõa (CONACYT-Mexico) for partial ®nancial support (Project 26375-E). We
also thank DGICYT, Spain (Project PB98-078) for ®nancial support.
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