A new cysteine-derived ligand as catalyst for the addition of diethylzinc to aldehydes: The importance of a 'free' sulfide site for enantioselectivity

Article abstract of DOI:10.1055/s-2005-861801

New chiral sulfides and disulfides were synthesized from readily available and inexpensive cysteine by straightforward methods in order to elucidate the relative importance of the various donor atoms (N, O, S) available in free or alkylated form resulting in covalent or dative bonds to the metal, respectively. Their application in the addition of diethylzinc to aldehydes provides secondary alcohols with up to 99% ee, and S-configuration, when catalytic amounts of disulfide ligands with the ability to form an S-Zn bond were used. In contrast to this, benzyl alcohols with the opposite absolute configuration R could be achieved, albeit with decreased yield and enantioselectivity, by the use of alkylated sulfide ligands.

Full text of DOI:10.1055/s-2005-861801

588
PAPER
A New Cysteine-Derived Ligand as Catalyst for the Addition of Diethylzinc to
Aldehydes: The Importance of a ‘Free’ Sulfide Site for Enantioselectivity
New
Cysteine
Der
n
ived Ligand
t
as Cata
o
lyst
f
or the
A
n
ddition of
D
i
iethylz
o
inc to Aldehydes L. Braga,*a Elenilson F. Alves,a Claudio C. Silveira,a Gilson Zeni,a Helmoz R. Appelt,b
Ludger A. Wessjohann*c
a
Departamento de Química, Universidade Federal de Santa Maria, 97105-900, Santa Maria, RS Brazil
Fax +55(55)2208031; E-mail: albraga@quimica.ufsm.br
Centro Universitário Franciscano, Rua dos Andradas, 1614 – Centro, 97010-032, Santa Maria, RS Brazil
Leibniz Institute of Plant Biochemistry, Weinberg 3, 06120 Halle (Saale), Germany
b
c
Received 19 June 2004; revised 29 October 2004
and no asymmetric induction at all in diethyl zinc addi-
Abstract: New chiral sulfides and disulfides were synthesized from
readily available and inexpensive cysteine by straightforward meth-
ods in order to elucidate the relative importance of the various donor
atoms (N, O, S) available in free or alkylated form resulting in co-
tions.27 Further hints on the significance of the type of Zn-
S bond can be deduced from the extensive work of Mar-
tens et al.28–32 with alkylated thiolates compared to free
valent or dative bonds to the metal, respectively. Their application thiolates used e.g. by van Koten19,20 or us;36,37 or from
in the addition of diethylzinc to aldehydes provides secondary alco-
Gibsons work, where sterically hindered tertiary
thiolates23 gave considerably worse results than less hin-
hols with up to 99% ee, and S-configuration, when catalytic
amounts of disulfide ligands with the ability to form an S-Zn bond
were used. In contrast to this, benzyl alcohols with the opposite ab-
dered primary ones.25
The significance of a covalent Zn-S bond as well as the
importance of sulfur as donor in the most easily accessible
cysteine derived ligands with their additional amino and
alcohol moiety, however, remained unclear. In this paper
we try to elucidate the relative importance of the various
donors (N, O, S) available in cysteine-derived ligands in
free (donor-H) or alkylated (donor-R) form for the Zn-
alkyl addition, exemplified by the reaction of diethylzinc
with various aldehydes, predominantly with benzalde-
hyde as reference compound. Thus the cysteine modifica-
tions presented in this paper do not aim at the optimization
of enantiomeric excesses but at understanding the elec-
tronic effects in form of the individual donor contributions
in dative or ‘anionic’ form.
solute configuration R could be achieved, albeit with decreased
yield and enantioselectivity, by the use of alkylated sulfide ligands.
Key words: cysteine, disulfide, chiral ligands, dialkylzinc, asym-
metric synthesis
The development and functional understanding of chiral
ligands for catalytic asymmetric synthesis is of increasing
importance in modern synthetic chemistry.1–4 Chiral b-
amino alcohols have been shown to be versatile chiral
ligands for a variety of asymmetric reactions, including
the enantioselective addition of diorganozinc compounds
to aldehydes.4–38 In the last few years sulfur containing
ligands have gained more and more interest as catalysts in
these stereoselective reactions.16–41 They appear especial-
ly attractive in combination with soft metal ions or late
transition metals, where they are expected to either im-
prove the ligands association to the metal, e.g. for Zn-
complexation42,43 in the presence of titanium,16 or alter the
properties of the metal center altogether through their do-
nor properties.21,22 Recently, we and others described the
(combinatorial) synthesis and use of disulfide catalysts in
combination with dialkylzinc.17,18,22–26,36–38 Some cata-
lysts developed by us36–41 not only belong to the most eas-
ily available ones but also allowed the highly
enantioselective addition to usually ill-behaved non-aro-
matic aldehydes,15 but with a strong chain-length depen-
dence.36,37,41 Mechanistically it could be shown by
Kellogg and others that the disulfide is reduced by the
metal alkyl, and a stable Zn-S bond is formed.17,18 Ander-
son synthesized amino thiolates for which a phenyl pro-
tection of the free sulfide gave significantly lower yields
Recently, we have described the use of highly efficient
oxazol(id)ine type disulfide and diselenide catalysts for
Zn-, Cu-, and Pd-mediated reactions.36–41 The ox-
azol(id)ine thiols and disulfides are readily available from
natural (R)-cysteine.36–40,44 In order to gain some under-
standing of the (electronic) behavior of sulfur based cata-
lysts without being hampered by steric or ring constraints,
some simpler, linear, and more stable ligands were pre-
pared from cysteine (see Scheme 1) and tested as catalysts
in the diethylzinc addition to aldehydes.
The syntheses of disulfide 3 and sulfides 4 are shown in
Scheme 1: (R)-cysteine (1) was converted into N,N¢-
dibenzyl disulfide 2 by treatment with benzaldehyde fol-
lowed by NaBH4/I2-reduction and subsequent air oxida-
tion.36,44 The reaction of disulfide 2 with strong base and
four equivalents of methyl iodide yielded the N- and O-
methylated disulfide 3. The sulfide amino alcohols 4a–d
were obtained in good yields by reaction with NaBH4 and
NaOH followed by alkylation. Selective methylation of
these compounds gave the partially or fully methylated
sulfides 5–7 in moderate yields.
SYNTHESIS 2005, No. 4, pp 0588–0594
x
x
.
x
x
.2
0
0
5
Advanced online publication: 09.02.2005
DOI: 10.1055/s-2005-861801; Art ID: M04404SS
© Georg Thieme Verlag Stuttgart · New York

PAPER
New Cysteine-Derived Ligand as Catalyst for the Addition of Diethylzinc to Aldehydes
589
Scheme 1 Synthesis of sulfide and disulfide ligands.
The catalysts 3–7 were tested in the enantioselective addi- Table 1 Enantioselective Addition of Diethylzinc to Benzaldehyde
Using 2 mol% of the Chiral Ligands 3, 4a–d, 5a–d, 6a–d and 7a–da
tion of diethylzinc to benzaldehyde at room temperature
(Scheme 2, Table 1). The enantiomeric excesses for 1-
phenyl-1-propanol obtained with benzaldehyde ranged
from 0–88%, depending on the catalyst used.
Entry
1
Catalyst Yield (%)a ee (%) [config]b Free sitesc
2
56
70
67
28
29
27
43
62
55
83
33
47
32
15
59
13
41
21
–
OH, NH, S–Znc
2
3
88 [S(–)]
S–Zn (S–S)c
3
4a
4b
4c
4d
5a
5b
5c
5d
6a
6b
6c
6d
7a
7b
7c
7d
41 [R(+)]
OH, NH
OH, NH
OH, NH
OH, NH
OH
4
33 [R(+)]
Scheme 2 Enantioselective addition of diethylzinc to benzalde-
hyde.
5
30 [R(+)]
6
21 [R(+)]
A closer analysis reveals that the disulfide ligand 3 with
its potential to form covalent sulfide linkages to zinc pro-
vided much higher enantioselectivity than the S-methylat-
ed sulfide ligands 4–7, despite the fact that in 3 the O and
N atoms are fully methylated.
7
–
–
–
–
–
–
–
–
–
–
–
–
8
OH
9
OH
10
11
12
13
14
15
16
17
18
OH
Of the S-methyl protected ligands (4–7) only sulfides 4
without any N- or O-methylation, gave very moderate
enantiomeric excesses (21–41% ee, entries 3–6). In the
case of the additional N- and/or O-methylated catalysts 5–
7 no or only minimal excess of one enantiomer was ob-
tained (entries 7–18). With increasing alkylation of the
free sites the yields also decreased.
NH
NH
NH
NH
–
Also, the absolute configurations of the enriched sec-alco-
hols were not uniform. A predominant formation of (S)-1-
phenyl-propanol was observed in the presence of the di-
sulfide 3, whereas amino alcohols 4 gave the opposite
enantiomer preferentially. This appears logical if for 3 a
principal S–Zn bond is assumed, formed by reductive
cleavage of the labile S–S bond as reported previous-
ly.17,18,36 For compounds 4 a principal O–Zn bond should
be preferred,8,9 and thus, since the spatial ligand orienta-
tion in the transition state complex is inverted, a prefer-
ence for the opposite enantiomer is generated. Although
the actual catalytically active species are not determined
–
–
–
a Reactions were carried out in toluene at r.t. for 24 h.
b Determined by GC analysis of the N-tosyl-prolyl ester derivatives.
c Free sites refer to sites enabling covalent bonding to Zn with dialkyl-
zinc, i.e. X–H groups, or in case of sulfur also disulfides which are re-
ductively cleaved by dialkylzinc.17,18
Synthesis 2005, No. 4, 588–594 © Thieme Stuttgart · New York

590
A. L. Braga et al.
PAPER
for these ligands, the transition state models shown in second zinc (the one bound to the tertiary amine) com-
Figure 1 are suggested for the enantioselective catalysts, plexed efficiently by the sulfur atom through its d-orbitals
assuming the dinuclear Zn-complexes commonly accept- or because of its large radius; or (2) in complexes without
ed.4,40,45
Zn–S bond (4–7) the now free thioether sulfur competi-
tively destabilizes the dative bonds of ether and/or tertiary
amine, of which only the covalent N–Zn bond of the sec-
ondary amine and/or the covalent O–Zn bond of the pri-
mary alcohol in 4 can compete to some extent, giving rise
to low ee’s of inverse orientation. Other effects like the
modification of Lewis acidity of the zinc ion,21,22 other
electronic donor effects,45 or pH-dependent equilibria for
ligand formation and stability42,43 may contribute to the
extent of enantioselection, but except for the latter can
hardly explain a change of preference towards the other
enantiomer.
Obviously, thiolate-complexation also provides improved
stability and/or enhanced differences in DG of the diaste-
reomeric transition state complexes, thus resulting in bet-
ter enantiomeric excess – despite the fact that the second
metal binding atom of the chelate ligand can only provide
donor bonds, either in form of a tertiary amine or an ether-
oxygen. N and O donor bonds might not add sufficient
additional binding strength to give good ligand fixation in
combination with thio-ether donors. i.e. of the S-alkylated
ligands, only ligands 4 with their simultaneously free NH-
and OH-groups, able to form covalent N–Zn and O–Zn
bonds, give noteworthy ee’s. Neither ligands 5 (the O A special case is ligand 2 with all heteroatoms as ‘free’
equivalent of 3 with tertiary amine) nor 6 (with ether-ox- sites, which does give 0% ee36 (entry 1). Several explana-
ygen) appear to be able to force a definite ligand geogra- tions can account for this behavior: (a) This ligand can
phy that will result in enantio-differentiation.
adapt both transition states ts-3 and ts-4 equally well. (b)
The primary sulfur coordination gives two transition
states, one with oxygen as second point of coordination
(6-membered complex) and one with nitrogen as second
donor (cf. ts-3). Like in the former case, this leads to op-
posing stereoselection. If both transition states form
equally well, or scramble rapidly, racemization results.46
(c) Triple complexation, e.g., by expulsion of the remain-
ing axial ethyl of the central zinc, gives a reactive com-
plex that is either unable to enantio-differentiate or does
not even bind the aldehyde at all.
Two reasons may account for this behavior of the thiolate
complexes and at this moment both are very speculative:
(1) Either in ts-3 there is an additional stabilization of the
The enantioselective addition of diethylzinc to various ar-
omatic and aliphatic aldehydes using the most successful
ligand, disulfide 3, was examined more closely and the re-
sults are reported in Table 2. Most aromatic aldehydes
give acceptable yields and enantiomeric ratios (entries 1–
Figure 1 Tentative transition state models ts-3 and ts-4 for ligands 3
and 4, respectively. (The benzyl group is not shown in an conforma-
tionally ideal position but in one which allows graphical clarity).
Table 2 Addition of Diethylzinc to Various Aldehydes in the Presence of 2 mol% of Catalyst 3
Entry
Aldehyde
Time (h)
48
T (°C)
0
Yield (%)
ee (%) [config]a
92 [S(–)]
1
2
Benzaldehyde
4-Tolualdehyde
4-Tolualdehyde
4-Anisaldehyde
4-Anisaldehyde
Phenylacetaldehyde
Phenylacetaldehyde
hexanal
77
67
53
74
43
62
51
92
63
86
55
24
r.t.
0
81 [S(–)]
3
48
84 [S(–)]
4
24
r.t.
0
81 [S(–)]
5
48
> 99 [S(–)]
81 [S(+)]
6
24
r.t.
0
7
48
91 [S(+)]
8
24
r.t.
0
88b [S(+)]
81b [S(+)]
80b [S(+)]
69b [S(+)]
9
hexanal
48
10
11
decanal
24
r.t.
0
decanal
48
a Assigned by comparison with the optical rotations reported.5,9,
b By chiral GC analysis of the N-tosyl-prolyl-ester derivatives.
Synthesis 2005, No. 4, 588–594 © Thieme Stuttgart · New York

PAPER
New Cysteine-Derived Ligand as Catalyst for the Addition of Diethylzinc to Aldehydes
591
complete addition, the reaction mixture was heated to reflux for 20
h and then cooled to r.t. MeOH was added until a clear solution was
obtained which was stirred under air for several minutes. The sol-
vent was removed in vacuo and the residue was dissolved in a 20%
aq K2CO3 solution (70 mL), stirring thereafter for 4 h at r.t. The
mixture was extracted with CH2Cl2 (3 × 30 mL) and the organic lay-
er dried with MgSO4 and filtered, the solvent was removed in vac-
uo. Yield: 75%; mp 106 °C; [a]D20 –29.0 (c = 1.0, CH3OH).
1H NMR (400 MHz, DMSO-d6): d = 7.30–7.17 (m, 10 H), 3.74 (s,
4 H), 3.44–3.37 (m, 4 H), 2.90–2.74 (m, 6 H).
13C NMR (50 MHz, DMSO-d6): d = 40.90, 50.31, 57.90, 61.82,
126.53, 127.90, 128.07.
5; yield 43–77%; ee 81% to > 99%); most above values
were obtained with other S/N or S/O ligands.16–38
Although for most aromatic aldehydes these values are
not yet competitive to those from sulfur-free catalysts, we
believe that the functional information presented here can
significantly aid the development of problem adapted and
more stable ligands, based on cheap starting materials like
cysteine, penicillamine etc. In addition, the findings may
allow developing catalysts for the synthesis of both enan-
tiomeric products based on non-racemic starting material
with only one natural configuration available.
Anal. Calcd for C20H28N2O2S2: C, 61.19; H, 7.19. Found: C, 61.45;
H, 7.08.
Again, a very interesting feature was observed with ali-
phatic aldehydes, which are normally much less well be-
haved with traditional Noyori-type catalysts. Our non-
optimized catalyst 3 furnished good chemical yields and
even competitive enantioselectivities (entries 6–11; 80–
91% ee). For the purely aliphatic aldehydes an inverse
temperature-effect was observed (cf. entries 8–11, higher
ee at higher temperature), but no detailed study of this un-
common but not unknown47,48 behavior was done to allow
a generalization, e.g. for other alkanals or temperature
profiles.
(R,R¢)-Bis[2-(N-benzyl-N-methyl-amino)-3-methoxy-pro-
pyl]disulfide (3)
To a suspension of NaH (48 mg, 2 mmol) in anhyd THF (10 mL),
(R,R)-N,N¢-dibenzylcystinol (2, 392 mg, 1 mmol) was added at 0 °C
under Ar atmosphere. After 15 min, methyl iodide (568 mg, 4
mmol) was added and the mixture was stirred for 6 h at r.t. Then,
water (10 mL) was added and the resulting solution extracted with
CH2Cl2 (3 × 15 mL). The organic layer was dried with MgSO4 and
the solvent evaporated under reduced pressure. The crude product
was purified by flash chromatography (hexane–EtOac, 9:1) to give
the N/O-methylated disulfide 3 as a yellow oil (215 mg, 48%);
[a]D20 –33 (c = 0.72, CH2Cl2).
We have demonstrated the ready synthesis of a set of eas-
ily accessible ligands from natural cysteine, which are
useful to probe the importance of the S-, O-, or N-binding
site(s). This was demonstrated for the diethylzinc addition
to aldehydes, in which a covalent donor-Zn bond proved
to be crucial, and where a thiolate S–Zn bond was manda-
tory for good enantioselectivity. Although there is no im-
mediate need for more standard ligands for dialkyl zinc
additions, there is always a demand to improve the con-
cept of ligand design, to rationalize the process in addition
to evident steric requirements,45 for ligands with ready
and cheap synthetic access,37,40 and for ligands with spe-
cial properties, e.g. ligands which can selectively bind to
zinc in the presence of other metal ions16 as is the case
with thiolates. We expect that the results of this study will
help to direct and support the development of even better,
readily available, sulfur (and selenium) based ligands,
which will also be applicable for other reactions involving
late transition metals.39,40,49
IR (neat): 2924, 1452, 1117, 734, 698 cm–1.
1H NMR (200 MHz, CDCl3): d = 7.34–7.21 (m, 10 H), 3.70–3.59
(m, 6 H), 3.53–3.47 (m, 2 H), 3.34 (s, 6 H), 3.16–3.29 (m, 4 H), 2.82
(dd, J = 12.6, 6.9 Hz, 2 H), 2.22 (s, 6 H).
13C NMR (50 MHz, CDCl3): d = 37.13, 38.23, 58.30, 58.48, 61.36,
71.23, 126.45, 127.8, 128.29, 139.52.
Anal. Calcd for C24H36N2O2S2: C, 64.25; H, 8.09. Found: C, 63.84;
H, 8.04.
S-Alkyl-N-benzyl (R)-Cysteinols 4; General Procedure
To a solution of disulfide 2 (1.0 g, 2.55 mmol) in EtOH (10 mL),
NaOH (204 mg, 5.1 mmol) and NaBH4 (208 mg, 5.5 mmol) were
added at 0 °C. After 30 min the alkyl halide, e.g. methyl iodide (852
mg, 6 mmol) was added and the mixture was stirred for approx 4 h
at r.t. The exact reaction time depends on the alkylating agent and
can be determined by TLC. The solvent was removed in vacuo and
the residue dissolved in water (10 mL) and CH2Cl2. After the mix-
ture was extracted with CH2Cl2 (3 × 20 mL) and the organic layer
dried with MgSO4, the solvent was evaporated under reduced pres-
sure. The crude product was purified by flash chromatography (hex-
ane–EtOAc, 9:1).
Optical rotations were measured on a Perkin-Elmer 341 Polarime-
1
ter. The H and 13C NMR spectra were registered on Bruker DPX
4a (R = Me, from MeI)
200 and Bruker DPX 400 spectrometers using TMS as an internal
standard. Elemental analyses (C, H) were performed on a Vario El
and Perkin-Elmer CHN 2400 analyzer. Gas chromatography (GC)
was performed using a Varian 3800 gas chromatograph with (2,6-
Me-3-Pe)-b-cyclodextrin column as chiral stationary phase for ee
determination of the secondary alcohols obtained.37
Yield: 91%; [a]D20 –12 (c = 1.0, CH2Cl2).
IR (neat): 3315, 2915, 1454 cm–1.
1H NMR (200 MHz, CDCl3): d = 7.35–7.26 (m, 5 H), 3.81–3.83 (m,
2 H), 3.77 (dd, J = 11.0, 3.9 Hz, 1 H), 3.43 (dd, J = 11.0, 4.5 Hz, 1
H), 2.91–2.8 (m, 1 H), 2.67–2.59 (m, 2 H), 2.22–2.09 (m, 2 H), 2.0
(s, 3 H).
13C NMR (50 MHz, CDCl3): d = 15.30, 35.79, 50.73, 55.87, 62.06,
126.79, 127.81, 128.13, 139.44.
(R,R¢)-N,N¢-Dibenzylcystinol (2)
In a 100 mL two necked round-bottomed flask equipped with a re-
flux condenser and an addition funnel, anhyd THF (85 mL), NaBH4
(3.24 g, 85.5 mmol) and 2-phenyl-thiazolidin-4-carboxylic acid
(34.2 mmol), obtained from (R)-cysteine and benzaldehyde,44 were
introduced under Ar atmosphere. Under stirring, iodine (8.68 g,
34.2 mmol) dissolved in THF (30 mL) was added slowly. After
Anal. Calcd for C11H17NOS: C, 62.52; H, 8.11. Found: C, 62.17; H,
8.33.
Synthesis 2005, No. 4, 588–594 © Thieme Stuttgart · New York

592
A. L. Braga et al.
PAPER
4b (R = Propyl, from PrI)
2.47 (t, J = 7.3 Hz, 2 H), 2.38–2.27 (m, 1 H), 2.22 (s, 3 H), 1.62–
1.55 (sext, J = 7.3 Hz, 2 H), 0.98 (t, J = 7.3 Hz, 3 H).
Yield: 78%; [a]D20 –42 (c = 0.56, CH2Cl2).
IR (neat): 3315, 2959, 1454 cm–1.
13C NMR (50 MHz, CDCl3): d = 13.32, 22.71, 27.87, 34.89, 35.62,
58.17, 60.67, 63.17, 127.16, 128.32, 128.69, 138.68.
1H NMR (200 MHz, CDCl3): d = 7.31–7.2 (m, 5 H), 3.85–3.66 (m,
3 H), 3.41 (dd, J = 10.0, 4.7 Hz, 1 H), 2.74–2.66 (m, 2 H), 2.40–2.33
(m, 3 H), 2.36 (t, J = 7.3 Hz, 2 H), 1.55 (sext, J = 7.3 Hz, 2 H), 0.94
(t, J = 7.3 Hz, 3 H).
Anal. Calcd for C14H23NOS: C, 66.36; H, 9.15. Found: C, 66.15; H,
9.21.
5c (R = Bn)
13C NMR (50 MHz, CDCl3): d = 13.23, 22.69, 33.92, 34.21, 50.92,
Yield: 54%; [a]D20 +44 (c = 1.04, CH2Cl2).
56.61, 62.29, 126.95, 127.97, 128.29. 139.66.
IR (neat): 3435, 2927, 1452, 1028 cm–1.
Anal. Calcd for C13H21NOS: C, 65.23; H, 8.84. Found: C, 65.44; H,
8.61.
1H NMR (200 MHz, CDCl3): d = 7.39–7.37 (m, 10 H), 3.77 (m, 4
H), 3.61–3.42 (m, 2 H), 3.27 (s, 1 H), 3.11–2.98 (m, 1 H), 2.79–2.75
(m, 1 H), 2.41–2.30 (m, 1 H), 2.23 (s, 3 H).
13C NMR (50 MHz, CDCl3): d = 27.86, 36.30, 37.34, 58.60, 61.21,
63.62, 127.68, 128.89, 129.01, 129.24, 129.41, 137.05, 139.10.
4c (R = Benzyl, from BnBr)
Yield: 85%; [a]D20 –33 (c = 1.34, CH2Cl2).
IR (neat): 3390, 3028, 2924, 1953, 1453 cm–1.
1H NMR (200 MHz, CDCl3): d = 7.23–7.15 (m, 10 H), 3.69–3.44
(m, 5 H), 3.33 (dd, J = 11.0 Hz, J = 4.9 Hz, 1 H), 2.79–2.63 (m, 3
H), 2.50–2.47 (m, 2 H).
Anal. Calcd for C18H23NOS: C, 71.72; H, 7.69. Found: C, 71.28; H,
7.21.
5d (R = CH2SPh)
13C NMR (50 MHz, CDCl3): d = 32.78, 35.97, 50.62, 56.23, 62.07,
Yield: 60%; [a]D20 +84 (c = 1.1, CH2Cl2).
126.70, 126.76, 127.82, 128.12, 128.50, 137.78, 139.51.
IR (neat): 3437, 2931, 1479, 1025, 736 cm–1.
Anal. Calcd for C17H21NOS: C, 71.04; H, 7.36. Found: C, 71.28; H,
7.14.
1H NMR (200 MHz, CDCl3): d = 7.41–7.18 (m, 10 H), 3.96 (s, 2 H),
3.77–3.65 (m, 3 H), 3.63–3.59 (m, 1 H), 3.07–2.93 (m, 3 H), 2.51–
2.39 (m, 1 H), 2.20 (s, 3 H).
13C NMR (50 MHz, CDCl3): d = 27.16, 35.63, 38.47, 58.10, 60.50,
62.45, 126.91, 127.10, 128.26, 128.62, 128.82, 130.46, 134.69,
138.48.
4d (R = CH2SPh, from ClCH2SPh)
Yield: 80%; [a]D20 –11 (c = 1.08, CH2Cl2).
IR (neat): 3306, 3059, 2916, 1479 cm–1.
1H NMR (200 MHz, CDCl3): d = 7.34–7.11 (m, 10 H), 3.84–3.58
(m, 5 H), 3.43–3.36 (m, 1 H), 2.83–2.71 (m, 5 H).
13C NMR (50 MHz, CDCl3): d = 32.82, 37.62, 50.55, 56.26, 62.06,
126.48, 126.70, 127.77, 128.04, 128.54, 129.91, 134.58, 139.37.
Anal. Calcd for C18H23NOS2: C, 64.83; H, 6.95. Found: C, 64.71; H,
7.17.
S-Alkyl-N-Benzyl-O-methyl-(R)-cysteinol (6); General Proce-
dure
Anal. Calcd for C17H21NOS2: C, 63.91; H, 6.63. Found: C, 63.59; H,
6.75.
To a suspension of THF (10 mL) and NaH (24 mg, 1 mmol), sulfide
4 (1 mmol) was added at 0 °C under Ar atmosphere. After 15 min,
methyl iodide (142 mg, 1 mmol) was added and the mixture was
stirred for approx 6 h at r.t. Then, water (10 mL) was added and the
resulting solution extracted with CH2Cl2 (3 × 15 mL). The organic
layer was dried with MgSO4 and the solvent evaporated under re-
duced pressure. The crude product was purified by flash chromatog-
raphy (hexane–EtOAc, 9:1).
S-Alkyl-N-benzyl-N-methyl-(R)-cysteinols 5; General Proce-
dure
To sulfide 4 (1 mmol) in anhyd THF (10 mL), methyl iodide (142
mg, 1 mmol) was added under Ar atmosphere. The mixture was
stirred for 6 h at r.t. Then, water (10 mL) was added and the result-
ing solution extracted with CH2Cl2 (3 × 15 mL). The organic layer
was dried with MgSO4 and the solvent evaporated under reduced
pressure. The crude product was purified by flash chromatography
(hexane–EtOAc, 9:1).
6a (R = Me)
Yield: 38%; [a]D20 –26 (c = 1.4, CH2Cl2).
IR (neat): 2917, 1453, 1117, 698 cm–1.
5a (R = Me)
Yield: 78%; [a]D20 –12 (c = 0.90, CH2Cl2).
1H NMR (200 MHz, CDCl3): d = 7.33–7.22 (m, 5 H), 3.84 (s, 2 H),
3.45 (d, J = 5.2 Hz, 2 H), 3.33 (s, 3 H), 2.96–2.75 (m, 1 H), 2.73–
2.53 (m, 2 H), 2.0 (s, 4 H).
13C NMR (50 MHz, CDCl3): d = 15.92, 36.28, 51.40, 55.27, 58.89,
73.96, 126.90, 128.08, 128.32, 140.06.
IR (neat): 3424, 2915, 1452 cm–1.
1H NMR (200 MHz, CDCl3): d = 7.06–6.95 (m, 5 H), 3.52–3.42 (m,
2 H), 3.32–3.06 (m, 2 H), 2.74–2.64 (m, 2 H), 2.49 (dd, J = 13.0, 4.6
Hz, 1 H), 2.02 (dd, J = 13.0, 9.2 Hz, 1 H), 1.93 (s, 3 H), 1.80 (s, 3 H).
Anal. Calcd for C12H19NOS: C, 63.96; H, 8.50. Found: C, 64.22; H,
8.31.
13C NMR (50 MHz, CDCl3): d = 16.29, 30.21, 35.68, 58.21, 60.67,
62.71, 127.30, 128.44, 128.81, 138.
Anal. Calcd for C12H19NOS: C, 63.96; H, 8.50. Found: C, 64.11; H,
8.32.
6b (R = Pr)
Yield: 37%; [a]D20 –20 (c = 1.16, CH2Cl2).
IR (neat): 2924, 1454, 1117, 698 cm–1.
5b (R = Pr)
Yield: 61%; [a]D20 –8 (c = 0.88, CH2Cl2).
1H NMR (200 MHz, CDCl3): d = 7.33–7.22 (m, 5 H), 3.83 (s, 2 H),
3.44 (d, J = 5.2 Hz, 2 H), 3.33 (s, 3 H), 2.91–2.83 (m, 1 H), 2.74–
2.54 (m, 2 H), 2.41 (t, J = 7.3 Hz, 2 H), 2.27 (s, 1 H), 1.56 (sext,
J = 7.3 Hz, 2 H), 0.95 (t, J = 7.3 Hz, 3 H).
13C NMR (50 MHz, CDCl3): d = 13.41, 22.93, 34.11, 34.63, 51.51,
55.85, 58.93, 74.12, 126.91, 128.13, 128.36, 140.22.
IR (neat): 3454, 2960, 1453, 1029 cm–1.
1H NMR (200 MHz, CDCl3): d = 7.29–6.86 (m, 5 H), 3.82–3.73 (m,
2 H), 3.61–3.36 (m, 2 H), 3.04–2.97 (m, 2 H), 2.85–2.76 (m, 1 H),
Synthesis 2005, No. 4, 588–594 © Thieme Stuttgart · New York

PAPER
New Cysteine-Derived Ligand as Catalyst for the Addition of Diethylzinc to Aldehydes
593
Anal. Calcd for C14H23NOS: C, 66.36; H, 9.15. Found: C, 66.70; H,
9.34.
7c (R = Bn)
Yield: 48%; [a]D20 +23 (c = 1.1, CH2Cl2).
IR (neat): 2923, 1681, 1264 cm–1.
6c (R = Bn)
1H NMR (200 MHz, CDCl3): d = 7.24–7.18 (m, 10 H), 3.62–3.58
(m, 4 H), 3.51 (dd, J = 10.0, 6.4 Hz, 1 H), 3.38 (dd, J = 10.0, 4.8 Hz,
1 H), 3.24 (s, 3 H), 2.94–2.8 (m, 1 H), 2.6 (dd, J = 13.0, 6.6 Hz, 1
H), 2.46 (dd, J = 13.0, 7.4 Hz, 1 H), 2.14 (s, 3 H).
13C NMR (50 MHz, CDCl3): d = 30.73, 37.04, 37.35, 58.71, 58.84,
61.71, 72.0, 126.77, 126.8, 128.15, 128.42, 128.69, 128.88, 138.59.
139.98.
Yield: 40%; [a]D20 +15 (c = 1.1, CH2Cl2).
IR (neat): 3027, 2917, 1454, 1028 cm–1.
1H NMR (200 MHz, CDCl3): d = 7.28–7.20 (m, 10 H), 3.82–3.50
(m, 4 H), 3.38 (d, J = 5.3 Hz, 2 H), 3.28 (s, 3 H), 2.90–2.78 (m, 1
H), 2.65–2.53 (m, 2 H), 2.12–2.07 (m, 1 H).
13C NMR (50 MHz, CDCl3): d = 33.27, 36.55, 51.30, 55.49, 58.79,
73.98, 126.79, 126.85, 127.03, 127.99, 128.25, 128.33, 128.61,
128.75, 138.23, 140.22.
Anal. Calcd for C19H25NOS: C, 72.34; H, 7.99. Found: C, 71.96; H,
7.78.
Anal. Calcd for C18H23NOS: C, 71.72; H, 7.69. Found: C, 71.61; H,
7.47.
7d (R = CH2SPh)
Yield: 52%; [a]D20 +19 (c = 1.90, CH2Cl2).
6d (R = CH2SPh)
IR (neat): 2922, 1152, 1116, 736 cm–1.
Yield: 35%; [a]D20 +9 (c = 1.14, CH2Cl2).
1H NMR (200 MHz, CDCl3): d = 7.42–7.19 (m, 10 H), 4.06–3.93
(m, 2 H), 3.68–3.61 (m, 2 H), 3.59 (dd, J = 9.8, 5.8 Hz, 1 H), 3.44
(dd, J = 9.8, 5.8 Hz, 1 H), 3.31 (s, 3 H), 3.03–2.92 (m, 1 H), 2.80–
2.75 (m, 2 H), 2.24 (s, 3 H).
13C NMR (50 MHz, CDCl3): d = 30.70, 37.12, 38.52, 58.55, 58.67,
61.54, 71.65, 126.65, 127.99, 128.52, 128.69, 130.26, 135.25,
139.50.
IR (neat): 2919, 1454, 1113, 738, 696 cm–1.
1H NMR (200 MHz, CDCl3): d = 7.40–7.24 (m, 10 H), 3.98–3.81
(m, 4 H), 3.44–3.41 (m, 2 H), 3.31 (s, 3 H), 2.98–2.78 (m, 3 H),
2.07–2.03 (m, 1 H).
13C NMR (50 MHz, CDCl3): d = 37.41, 38.43, 58.58, 58.82, 61.67,
71.53, 126.76, 128.11, 128.34, 128.62, 139.0.
Anal. Calcd for C18H23NOS2: C, 64.83; H, 6.95. Found: C, 64.74; H,
6.78.
Anal. Calcd for C19H25NOS2: C, 65.67; H, 7.25. Found: C, 65.49; H,
7.18.
S-Alkyl-N-benzyl-N,O-dimethyl-(R)-cysteinols (7); General
Procedure
Asymmetric Addition of Diethylzinc to Benzaldehyde; General
Procedure
To a suspension of THF (10 mL) and NaH (24 mg, 1 mmol), sulfide
4 (1 mmol) was added at 0 °C under argon atmosphere. After 15
min, methyl iodide (284 mg, 2 mmol) was added and the mixture
was stirred for 6 h at r.t. Then, water (10 mL) was added and the re-
sulting solution extracted with CH2Cl2 (3 × 15 mL). The organic
layer was dried with MgSO4 and the solvent evaporated under re-
duced pressure. The crude product was purified by flash chromatog-
raphy (hexane–EtOAc, 9:1).
In a 25 mL flask with anhyd toluene (7 mL), benzaldehyde (3
mmol) and catalyst 2–7 (60 mmol; 2 mol%) and a 1 M hexane solu-
tion of diethyl zinc (5 mL; 5 mmol) were slowly injected under con-
stant stirring. Stirring was continued for 24 h at r.t. Finally the
temperature was adjusted to 0 °C (ice bath) and 1 N HCl (5 mL) was
slowly added (10 min) with continuous stirring. The organic layer
was separated and washed with 1 N HCl (2 × 8 mL). After drying
over Na2SO4 and filtration the toluene was removed under reduced
pressure. The crude alcohol was purified by bulb-to-bulb distillation
under reduced pressure (ca. 0.1 mbar).
7a (R = Me)
Yield: 45%; [a]D20 –15 (c = 1.36, CH2Cl2).
IR (neat): 2916, 1452, 1117, 698 cm–1.
Acknowledgment
1H NMR (200 MHz, CDCl3): d = 7.37–7.06 (m, 5 H), 3.70 (s, 2 H),
3.63 (dd, J = 9.9, 6.2 Hz, 1 H), 3.5 (dd, J = 9.9, 6.2 Hz, 1 H), 3.34
(s, 3 H), 3.07–2.98 (m, 1 H), 2.74 (dd, J = 12.9, 6.4 Hz, 1 H), 2.59
(dd, J = 12.9, 7.5 Hz, 1 H), 2.27 (s, 3 H), 2.08 (s, 3 H).
13C NMR (50 MHz, CDCl3): d = 16.20, 33.52, 37.38, 58.64, 58.79,
61.45, 71.90, 126.71, 128.07, 128.59, 139.88.
The authors wish to thank CAPES and the DAAD (German Acade-
mic Exchange Service) for travel grants as part of PROBRAL, and
CNPq, FAPERGS and Degussa AG for financial support and gifts
of chemicals, respectively.
References
Anal. Calcd for C13H21NOS: C, 65.23; H, 8.84. Found: C, 64.86; H,
8.69.
(1) Gawley, R. E.; Aube, J. Principles of Asymmetric Synthesis;
Pergamon: London, 1996.
(2) Seyden-Penne, J. Chiral Auxiliaries and Ligands in
Asymmetric Synthesis; Wiley: New York, 1995.
(3) Noyori, R. Asymmetric Catalysis in Organic Synthesis;
Wiley: New York, 1994.
(4) Noyori, R.; Kitamura, M. Angew. Chem., Int. Ed. Engl.
1991, 30, 49; Angew. Chem. 1991, 103, 34.
(5) Kitamura, M.; Okada, S.; Suga, S.; Noyori, R. J. Am. Chem.
Soc. 1989, 111, 4028.
7b (R = Pr)
Yield: 43%; [a]D20 –28 (c = 0.90, CH2Cl2).
IR (neat): 2951, 1435, 1040, 699 cm–1.
1H NMR (200 MHz, CDCl3): d = 7.30–7.13 (m, 5 H), 3.7–3.59 (m,
2 H), 3.55 (dd, J = 10.0, 6.3 Hz, 1 H), 3.43 (dd, J = 10.0, 4.8 Hz, 1
H), 3.27 (s, 3 H), 2.98–2.85 (m, 1 H), 2.69 (dd, J = 12.0, 6.3 Hz, 1
H), 2.51 (dd, J = 12.0, 7.6 Hz, 1 H), 2.39 (t, J = 7.4 Hz, 2 H), 2.2 (s,
3 H), 1.52 (sext, J = 7.4 Hz, 2 H), 0.89 (t, J = 7.4 Hz, 3 H).
13C NMR (50 MHz, CDCl3): d = 13.45, 22.94, 31.11, 34.9, 37.45,
58.68, 58.82, 61.92, 71.97, 126.74, 128.11, 128.66, 139.93.
(6) Yamakawa, M.; Noyori, R. J. Am. Chem. Soc. 1995, 117,
6327.
(7) Kitamura, M.; Suga, S.; Oka, H.; Noyori, R. J. Am. Chem.
Soc. 1998, 120, 9800.
Anal. Calcd for C15H25NOS: C, 67.37; H, 9.42. Found: C, 67.56; H,
9.71.
Synthesis 2005, No. 4, 588–594 © Thieme Stuttgart · New York

594
A. L. Braga et al.
PAPER
(8) Kitamura, M.; Yamakawa, M.; Oka, H.; Suga, S.; Noyori, R.
Chem.–Eur. J. 1996, 2, 1173.
(9) Kitamura, M.; Oka, H.; Noyori, R. Tetrahedron 1999, 55,
3605.
(31) Kossejans, M.; Martens, J. Tetrahedron: Asymmetry 1998,
9, 1409.
(32) Trentmann, W.; Mehler, T.; Martens, J. Tetrahedron:
Asymmetry 1997, 12, 2033.
(10) Bolm, C.; Hildebrand, J. P.; Muniz, K.; Hermanns, N.
Angew. Chem. Int. Ed. 2001, 40, 3284; Angew. Chem. 2001,
113, 3284.
(33) Cho, B. T.; Chun, Y. S. Synth. Commun. 1999, 29, 521.
(34) Huang, H. L.; Lin, Y. C.; Chen, S. F.; Wang, C. L. J.; Liu, L.
T. Tetrahedron: Asymmetry 1996, 7, 3067.
(11) Rudolph, J.; Rasmussen, T.; Bolm, C.; Norrby, P.-O. Angew.
Chem. Int. Ed. 2003, 42, 3002; Angew. Chem. 2003, 115,
3110.
(12) Bolm, C.; Hermanns, N.; Hildebrand, J. P.; Muñiz, K.
Angew. Chem. Int. Ed. 2000, 39, 3465; Angew. Chem. 2000,
112, 3607.
(13) Bolm, C.; Schlingloff, G.; Harms, K. Chem. Ber. 1992, 125,
1191.
(14) Bringmann, G.; Breuning, M. Tetrahedron: Asymmetry
1998, 9, 667.
(35) Nakano, H.; Kumagai, N.; Matsuzaki, H.; Kabuto, C.;
Hongo, H. Tetrahedron: Asymmetry 1997, 8, 1391.
(36) Braga, A. L.; Appelt, H. R.; Schneider, P. H.; Silveira, C. C.;
Wessjohann, L. A. Tetrahedron: Asymmetry 1999, 10, 1733.
(37) Braga, A. L.; Appelt, H. R.; Schneider, P. H.; Rodrigues, O.
E. D.; Silveira, C. C.; Wessjohann, L. A. Tetrahedron 2001,
57, 3291.
(38) Braga, A. L.; Appelt, H. R.; Silveira, C. C.; Wessjohann, L.
A.; Schneider, P. H. Tetrahedron 2002, 58, 10413.
(39) (a) Braga, A. L.; Silva, S.; Lüdtke, D. S.; Drekener, R.;
Silveira, C. C.; Rocha, J. B.; Wessjohann, L. A. Tetrahedron
Lett. 2002, 43, 7329. (b) Braga, A. L.; Paixão, M. V.;
Lüdtke, D. S.; Silveira, C. C.; Rodrigues, O. E. D. Org. Lett.
2003, 5, 2635.
(40) Schrekker, H. S.; Schneider, P. H.; Wessjohann, L. A.;
Silveira, C. C.; Braga, A. L. Eur. J. Org. Chem. 2004, 2715.
(41) Braga, A. L.; Rubim, R. M.; Schrekker, H. S.; Wessjohann,
L. A.; de Bolster, M. W. G.; Zeni, G.; Sehnem, J. A.
Tetrahedron: Asymmetry 2003, 14, 3291.
(42) Gelinsky, M.; Vogler, R.; Vahrenkamp, H. Inorg. Chim.
Acta 2003, 334, 230.
(15) Cho, B. T.; Chun, Y. S. Tetrahedron: Asymmetry 1998, 9,
1489.
(16) Hulst, R.; Heres, H.; Fitzpatrick, K.; Peper, N. C. M. W.;
Kellogg, R. M. Tetrahedron: Asymmetry 1996, 9, 2755.
(17) Fitzpatrick, K.; Hulst, R.; Kellogg, R. M. Tetrahedron:
Asymmetry 1995, 6, 1861.
(18) Hof, R. P.; Poelert, M. A.; Peper, N. C. M. W.; Kellogg, R.
M. Tetrahedron: Asymmetry 1994, 5, 31.
(19) Rijnberg, E.; Hovestad, N. J.; Kleij, A. W.; Jastrzebski, J. T.
B. H.; Boersma, J.; Janssen, M. D.; Spek, A. L.; van Kroten,
G. Organometallics 1997, 16, 2847.
(20) Rijnberg, E.; Jastrzebski, J. T. B. H.; Janssen, M. D.;
Boersma, J.; van Koten, G. Tetrahedron Lett. 1994, 35,
6521.
(21) Kang, J.; Lee, J. W.; Kim, J. I. J. Chem. Soc., Chem.
Commun. 1994, 2009.
(22) Kang, J.; Kim, D. S.; Kim, J. I. Synlett 1994, 842.
(23) Gibson, C. L. Tetrahedron: Asymmetry 1999, 10, 1551.
(24) Fulton, D. A.; Gibson, C. L. Tetrahedron Lett. 1997, 38,
2019.
(25) Gibson, C. L. Chem. Commun. 1996, 645.
(26) Anderson, J. C.; Cubbon, R.; Harding, M.; James, D. S.
Tetrahedron: Asymmetry 1998, 9, 3461.
(27) Anderson, J. C.; Harding, M. Chem. Commun. 1998, 393.
(28) Kossenjans, M.; Pennemann, H.; Martens, J.; Juanes, O.;
Rodrigues-Ubis, J. C.; Brunet, E. Tetrahedron: Asymmetry
1998, 9, 4123.
(29) Kossenjans, M.; Soeberdt, M.; Wallbaum, S.; Harms, K.;
Martens, J.; Aurich, H. G. J. Chem. Soc., Perkin Trans. 1
1999, 2353.
(30) Juanes, O.; Rodriguez-Ubis, J. C.; Brunet, E.; Pennemann,
H.; Kossejans, M.; Martens, J. Eur. J. Org. Chem. 1999,
3323.
(43) Gockel, P.; Vogler, R.; Gelinsky, M.; Meißner, A.; Albrich,
H.; Vahrenkamp, H. Inorg. Chim. Acta 2001, 323, 16.
(44) (a) Confalone, P. N.; Pizzolato, G.; Baggiolini, E. G.; Lollar,
D.; Uskoković, M. R. J. Am. Chem. Soc. 1977, 99, 7020.
(b) McKennon, M. J.; Meyers, A. I. J. Org. Chem. 1993, 58,
3568.
(45) Casey, M.; Smith, M. P. Synlett 2003, 102.
(46) We thank a referee for pointing out the likely possibility of a
transition state with 6-membered S/O-zinc-coordination to
ligand 2. This explanation is based on the importance of a
free sulfide site and its strength for primary binding. Would
thioether-binding be sufficiently stable as sole first
coordination point, ligands 5 and 6 should give
stereoinduction with opposing signs of rotation. This was
not observed.
(47) Soai, K.; Ookawa, A.; Ogawa, K.; Kaba, T. J. Chem. Soc.,
Chem. Commun. 1987, 467.
(48) Eilers, J.; Wilken, J. Tetrahedron: Asymmetry 1996, 7, 2343.
(49) Masdeu-Bulstó, A. M.; Diégues, M.; Martin, E.; Gómez, M.
Coord. Chem. Rev. 2003, 242, 159.
Synthesis 2005, No. 4, 588–594 © Thieme Stuttgart · New York