First generation cysteine- and methionine-derived oxazolidine and thiazolidine ligands for palladium-catalyzed asymmetric allylations

Article abstract of DOI:10.1002/ejoc.200300675

A new series of enantiopure oxazolidine-thioether and thiazolidine-alcohol ligands have been synthesized from L-cysteine, S-methyl-L-cysteine, and L-methionine in a straightforward manner that allows numerous structural variations to be formed. These types of ligands have not previously been used in asymmetric palladium-catalyzed allylations and their efficacy was explored in the reaction of rac-1,3-diphenyl-2-propenyl acetate with dimethyl malonate. The reaction proceeds in excellent yield and with good enantioselectivity. The palladium catalyst derived from N-benzyl-2,2-dimethyl-4-(2-thiapropyl) oxazolidine (12) provides the allylation product in a quantitative yield and with an enantiomeric excess of 94%. Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2004.

Full text of DOI:10.1002/ejoc.200300675

FULL PAPER
First Generation Cysteine- and Methionine-Derived Oxazolidine and
Thiazolidine Ligands for Palladium-Catalyzed Asymmetric Allylations
Paulo H. Schneider,[a] Henri S. Schrekker,[b] Claudio C. Silveira,[a] Ludger A. Wessjohann,[b]
and Antonio L. Braga*[a]
Keywords: Allylic alkylation / Homogeneous catalysis / Palladium / Oxazolidine / Asymmetric catalysis
A new series of enantiopure oxazolidine-thioether and thia-
zolidine-alcohol ligands have been synthesized from -cyst-
eine, S-methyl- -cysteine, and -methionine in a straightfor-
ward manner that allows numerous structural variations to
be formed. These types of ligands have not previously been
used in asymmetric palladium-catalyzed allylations and their
efficacy was explored in the reaction of rac-1,3-diphenyl-2-
ceeds in excellent yield and with good enantioselectivity.
The palladium catalyst derived from N-benzyl-2,2-dimethyl-
4-(2-thiapropyl)oxazolidine (12) provides the allylation prod-
uct in a quantitative yield and with an enantiomeric excess
of 94%.
L
L
L
( Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
propenyl acetate with dimethyl malonate. The reaction pro- Germany, 2004)
Introduction
stabilize palladium();[5] C2-symmetric bidentate nitrogen-
containing ligands have also been investigated extensively.[6]
The second class of ligands induces enantioselectivity by
another principle. In the presence of a C1-symmetric ligand,
two different (π-allyl)palladium complexes may be ob-
tained, with each one having the possibility of being at-
tacked by the nucleophile at two different sites, leading to
four possible transition states in this case. Two effects are
responsible for the stereochemical outcome.[7] (1) The elec-
tronic effect: if the two donor atoms exhibit sufficiently dif-
ferent donorϪacceptor strengths the number of possible
transition states is reduced.[8] In general, nucleophilic attack
is directed trans to the donor atom with the largest π-ac-
ceptor strength. (2) The steric effect: the final stereoselectiv-
ity is determined by the chiral moiety of the ligand favoring
one of the two π-allyl conformations. Various chiral biden-
tate ligands with two different heterodonor atoms and dif-
ferent donorϪacceptor strengths, like (phosphanyl)oxazol-
Palladium-catalyzed reactions have allowed many unique
routes to CϪC bond formation to be developed, of which
a major one is the allylic allylation of carbon nucleophiles.[1]
The asymmetric allylic allylation is a widely applied process
in which racemic or achiral allylic substrates can be con-
verted into optically active products and has been studied
extensively in recent years.[2] Widespread application of this
process to the synthesis of small molecules and in the total
synthesis of natural products has proven its usefulness.[3]
The catalytic activity and enantioselectivity of the reaction
is highly dependent on the properties of the chiral ligand,
and consequently the design of efficient chiral ligands has
become one of the most intensively studied areas of re-
search. In particular, two classes of bidentate ligands, C2-
and C1-symmetric ones, have been identified. The C2-sym-
metric ligands lead to the formation of only one (π-allyl)-
palladium complex when a symmetric allylic substrate is
used. Nucleophilic attack will take place preferentially at
the site at which the allyl functionality has the strongest
steric interaction with the ligand. The asymmetric reaction
was initially developed by using bidentate ligands with
phosphorus as the donor atoms.[4] Many other examples
were found due to the excellent ability of phosphorus to
ines,[9]
(phosphanyl)imines,[10]
(phosphanyl)amines,[11]
phosphite-oxazolines,[12] phosphaferrocene-oxazolines,[13]
phosphane-phosphites,[14] (thio)oxazolines,[15] (thio)pyrid-
ines,[16] thioglucose-oxazolines,[17] phosphanyl sulfoxides,[18]
and phosphito-thioethers,[19] form effective catalysts with
palladium to induce high enantioselectivities. To our sur-
prise, heterobidentate sulfur-nitrogen ligands have received
little attention in the search for an effective catalyst.
In the course of our work in the field of asymmetric ca-
talysis, we have reported bis(oxazolidinylmetyl) disulfide 4a
(Scheme 1) to be a highly efficient ligand in the enantiose-
lective addition of diethylzinc[20] or alkynylzinc com-
pounds[21] to aldehydes. This ligand affords optically active
alcohols, often with excellent enantioselectivity (up to Ͼ
99% ee).
[a]
´
Departamento de Quımica, Universidade Federal de Santa
Maria,
97105-900 Santa Maria, RS, Brazil
Fax: (internat.) ϩ 55-55-220-8031
E-mail: albraga@quimica.ufsm.br
Leibniz-Institute of Plant Biochemistry,
Weinberg 3, 06120 Halle (Saale), Germany
E-mail: wessjohann@ipb-halle.de
[b]
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DOI: 10.1002/ejoc.200300675
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P. H. Schneider, H. S. Schrekker, C. C. Silveira, L. A. Wessjohann, A. L. Braga
FULL PAPER
Scheme 1. The enantioselective addition of diethylzinc to benzaldehyde using the disulfide (R,R)-4a
The disulfide 4a is an attractive catalyst for several re-
asons. It is derived from cheap -cysteine, and can be pre-
Results and Discussion
pared in an easy three-step synthesis (see Scheme 2) in an
overall yield of ca. 60%.[20a] Most important, oxazolidines
with high structural diversity can be readily generated,
which is important for systematic optimization of the cata-
lyst’s structure. This type of disulfide is an excellent starting
point in the synthesis of a variety of sulfur-oxazolidine li-
gands by a general combinatorial approach (Figure 1).[22]
The objective of this work was to screen the catalytic poten-
tial of sulfur-containing ligands in various homogeneous
catalytic reactions. Owing to the soft nature of the sulfur
atom we focused our efforts on the reactions of the late
transition metals. The palladium-catalyzed allylic alkylation
attracted our attention because the use of C1 bidentate li-
gands with an oxazoline unit as the chiral modifier in this
reaction has been investigated extensively, and proved to be
very successful. In contrast, to the best of our knowledge,
heterobidentate ligands with a similar oxazolidine unit have
not yet been investigated.
The successful results that were obtained with the disulfide
4a prompted us to explore the potential of 4 and some first-
generation derivatives. A series of new heterobidentate sul-
fur-oxazolidine ligands with variations in R1 and R2 (B and
D, Figure 1), derived from the disulfides 4, were synthesized
to enable a systematic improvement of the ligand’s structure
(Scheme 2).[23] A simple transformation of 4a into the thioe-
thers 5a (93% yield) and 6 (64% yield) was achieved by
NaBH4 reduction under basic conditions and consecutive al-
kylation with MeI and benzyl chloride, respectively. By using
the N-(1-naphthylmethyl) derivative 4b, an analogous pro-
cedure can be followed to give 5b in 69% yield. Reduction of
bis(oxazolidinylmethyl) disulfide 4a with NaBH4 under neu-
tral conditions, however, gave the thiazolidine alcohol 7 ex-
clusively in 80% yield and not the expected free thiol. Meth-
ylation of 7 with sodium hydride and methyl iodide resulted
in the methyl thiazolidinylmethyl ether 8 in 47% yield.
Another, more efficient strategy was developed to obtain
variations in R and n (A and C, Figure 1). Starting from -
methionine or S-methyl--cysteine, instead of -homocys-
teine and -cysteine, reduces the number of steps in the syn-
thesis of (S)-methyloxazolidines with one- and two-carbon
tethers (Scheme 3). Reduction, followed by benzylation and
cyclization, resulted in an overall yield of 56% of 11. Thio-
ether 12, an analogue of thioether 5a with more steric hin-
drance at the 2-position of the oxazolidine, was obtained in
a similar three-step synthesis (Scheme 3) in a moderate
overall yield of 31%.
Figure 1. General combinatorial approach to the synthesis of sul-
fur-oxazolidine ligands with the variables R and n (AϪD)
Scheme 2. Synthesis of sulfur-oxazolidine ligands by the general combinatorial approach
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Oxazolidine and Thiazolidine Ligands for Palladium-Catalyzed Asymmetric Allylations
FULL PAPER
Scheme 3. Synthesis of ligands with variations in R or n (A and C, Figure 1)
The reaction of rac-1,3-diphenyl-2-propenyl acetate with ligand/palladium ratio was increased because it is known
dimethyl malonate as the nucleophile is the standard reac- that heterobidentate sulfur-nitrogen ligands do not always
tion that is used to test the potential of a ligand in the bind efficiently to palladium, and competition for coordi-
asymmetric palladium-catalyzed allylic alkylation. The re- nation of the solvent might result if the ligand concen-
action was performed with dimethyl sodiomalonate, [Pd(η3- tration is insufficient.[14] However, in our system, an in-
C3H5)Cl]2 (2.5 mol %), disulfide 4a (10 mol %), and THF creased ratio of 2:1, apparently has only a small influence,
as solvent at room temperature. Unfortunately, the reaction resulting in only a slightly improved enantiomeric excess of
with this ligand was not successful; a moderate 63% yield 71% (Table 1, Entry 3); this implies good binding of 5a to
of an almost racemic product was obtained (Table 1, Entry palladium. The decrease in enantioselectivity that occurs
1). Sulfur-sulfur coordination to palladium might be the re- with a 3:1 ratio (Table 1, Entry 4) might be caused by a
ason for the low enantioselectivity.[9a]
change in the mode of coordination of the ligands to pal-
ladium; two monodentate coordinating ligands instead of a
single bidentate coordinating ligand is a possible expla-
nation.
Table 1. Asymmetric palladium-catalyzed allylic alkylation
The screening process was continued by using the opti-
mum 2:1 ratio (ligand/palladium) and benzyl thioether 6
(Table 1, Entry 6) in order to study the influence of a
slightly bulkier substituent at the sulfur atom (D, Figure 1).
The reactions with benzyl thioether 6 (70% ee) and methyl
thioether 5a (71% ee) resulted in the same enantiomeric ex-
cess. This indicates that the oxazolidine moiety is mainly
responsible for the enantioselectivities that are obtained.
The 1-naphthylmethyl derivative 5b was tested in an at-
tempt to increase the steric bulk around the nitrogen donor
(B, Figure 1). Unfortunately, this variation did not result
(97% yield, 69% ee) in any significant change in the proper-
ties of the respective palladium complex (Table 1, Entry 5).
The enantiomeric excesses were the same with the thio-
ethers 5 and 6. Obviously other or more dramatic structural
changes are required at the nitrogen or sulfur atom to in-
crease the enantiomeric excess that can be obtained with
this type of ligand.
Reactions with thiazolidinylmethanol 7 and thiazolidinyl-
methyl ether 8 enable the influence of the donor-atom dis-
tribution in the ligand to be studied. The alkylation prod-
ucts had the same absolute (S) stereochemistry as was ob-
tained with thioethers 5 and 6, but with an increased enanti-
omeric excess of 81% with alcohol 7 (Table 1, Entry 8) and
a decreased enantiomeric excess of 31% with ether 8
(Table 1, Entry 10). Thiazolidines 7 and 8 probably also act
as bidentate ligands and form oxygen-nitrogen complexes
Entry[a]
Ligand
Time [h]
Yield [%][b]
ee [%][c]
1
2
3
4
5
6
7
8
9
4a (10 mol %)
5a (5 mol %)
5a (10 mol %)
5a (15 mol %)
5b (10 mol %)
6 (10 mol %)
7 (5 mol %)
7 (10 mol %)
7 (15 mol %)
8 (10 mol %)
11 (10 mol %)
12 (10 mol %)
48
20
12
15
15
63
84
96
94
97
96
43
52
61
59
87
96
6 (S)
62 (S)
71 (S)
60 (S)
69 (S)
70 (S)
Ϫ
81 (S)
74 (S)
31 (S)
6 (S)
15
168
168
169
64
24
12
10
11
12
81 (S)
[a] NaH (1.5 equiv.), dimethyl malonate (2 equiv.), and 1,3-diphenyl-
2-propenyl acetate (1 equiv.).
HPLC using a Daicel Chiralcel OD-H column; solvent: hexane/2-
propanol (99:1); flow rate: 0.5 mL·minϪ1; UV detection: 254 nm.
The absolute configuration of the product was assigned by com-
parison of the sign of the specific rotations with literature data.[9b]
[b]
[c]
Isolated yield.
Determined by
This prompted us to screen oxazolidine-thioether 5a. A with palladium. However, the direction of the nucleophilic
5 mol % loading of 5a, which corresponds to a 1:1 ratio attack is different compared with that at the nitrogen-sulfur
of bidentate ligand/palladium, resulted in 84% yield and a palladium complexes. Coincidentally, the increase in enantio-
modest enantiomeric excess of 62% (Table 1, Entry 2). The selectivity with 7 was achieved by using 10 mol % of the
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P. H. Schneider, H. S. Schrekker, C. C. Silveira, L. A. Wessjohann, A. L. Braga
FULL PAPER
ligand (2:1 ratio) (Table 1, Entry 8). However, when a 1:1
The successful application of heterobidentate ligands in
ratio of bidentate ligand/palladium was used, a racemic this reaction originates from steric and electronic effects
product was observed in only 43% yield. This indicates that (Figure 3). The enantiodifferentiation step in palladium-cat-
this ligand probably does not bind strongly to the metal alyzed allylic alkylations is the substitution of (allyl)Pd
atom. The decrease in enantioselectivity observed with a 3:1 complexes by incoming nucleophiles. Nucleophilic attack
ratio (Table 1, Entry 9) was similar to that obtained when occurs predominantly at the allyl terminus trans to the bet-
the heterobidentate sulfur-nitrogen ligand 5a was used ter π-acceptor. The sulfur donor has a greater trans influ-
(Table 1, Entry 4). The large difference between the ence (greater π-acceptor capacity) than the nitrogen donor,
donorϪacceptor strengths of oxygen and sulfur explains and therefore directs the incoming nucleophile cis to the
the poor yields and long reaction times of 7 compared with nitrogen atom.[25] This electronic effect is supported by the
the complete conversion that occurred with thioether 5a enantioselectivities observed with thioethers 5a and 6, and
after 12 h.
implies that the oxazolidine unit controls the enantioselec-
The low catalytic activity of the thiazolidinylmethanol li- tivity (steric effect). With alcohol 7 and ether 8 the opposite
gands led us to develop the oxazolidine-thioether ligand absolute stereochemistry would be expected if oxygen was
structure further. The importance of the bite angle (Fig- a stronger π-acceptor than nitrogen. This is not the case,
ure 2, complexes 14 and 15) in the asymmetric palladium- and the nitrogen donor directs nucleophilic attack cis to the
catalyzed allylic alkylation has been generally accepted as oxygen donor, which explains why the absolute configura-
the chiral environment of the ligand has to reach over the tions of the alkylation products are the same for thiazolid-
palladium atom in order to interact with the allylic unit. ine-oxygen and oxazolidine-sulfur ligands. The strongly di-
Increased interactions between the ligand and allylic unit minished enantioselectivity obtained with methyl ether 8
can result in greater enantioselectivity. An increase in the might be the result of a less pronounced difference between
tether length between the two donor atoms of the bidentate the π-acceptor strengths of the thiazolidine-nitrogen and
ligand can increase the bite angle. A three- instead of a the ether-oxygen, such that the incoming nucleophile exerts
two-carbon tether was highly favorable for the oxazoline- less directional preference.
thioether ligands described previously (C2: ee ϭ 56%: C3:
ee ϭ 88%).[15c] Unfortunately, the larger bite angle had an
opposite effect in our case; the enantiomeric excess de-
creased to 6% with the larger oxazolidine-thioether 11. This
low enantioselectivity might be explained by the lower
rigidity of the oxazolidine ring compared to the oxazoline
ring. Other explanations are possible, such as the ability to
form additional chiral centers at the nitrogen and sulfur
atoms when complexed to the palladium center,[17,24] and
the higher flexibility of the benzyl substituent on the oxazo-
lidine unit compared to the phenyl substituent on the ox-
azoline ligands that have been studied (Figure 2, complexes
15 vs. 16).
The stereochemical course of the reaction with oxazolid-
ine ligands can proceed via the two diastereomeric (allyl)-
palladium complexes 17 and 18 (Figure 3). The (S) enanti-
omer is formed in excess, which could be the result of nucle-
ophilic attack trans to the oxazolidine moiety in the M-
shaped complex 17 or trans to the thioether in the W-
shaped complex 18. From previous results, it can be con-
cluded that the nucleophilic attack most likely occurs via
complex 18, trans to the thioether. The M-shaped complex
17 suffers from steric hindrance between the rather rigid
oxazolidine moiety and the phenyl group of the allylic sub-
strate. In the W-shaped complex 18 there is less steric hin-
drance between the allylic phenyl and the more flexible
benzyl group. As a consequence alterations at the oxazolid-
ine moiety should allow the stereochemical outcome of the
allylic alkylation to be controlled.
With this in mind we tested the 2,2-dimethyloxazolidine
12, an analogue of thioether 5a with more steric crowding
of the oxazolidine ring. As expected, a significant increase
in enantioselectivity to 81% ee was observed, together with
complete conversion after 12 h (Table 1, Entry 12).
Figure 2. The bite angle effect
Figure 3. Diastereomeric (allyl)palladium complexes; enantioselectivity as a result of steric and electronic effects
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Oxazolidine and Thiazolidine Ligands for Palladium-Catalyzed Asymmetric Allylations
FULL PAPER
Substitution of the previously used dimethyl sodiomalon- ing preliminary results from asymmetric palladium-cata-
ate procedure by a facile one-pot procedure with N,O-bi- lyzed allylic alkylations have been obtained, and these re-
s(trimethylsilyl)acetamide (BSA) and potassium acetate, led sults will allow the design of improved ligands of this type,
to an increase in the rate of the reaction as well as in chiral adapted for application in palladium-catalyzed reactions,
induction.[15d,15e] The potential of disulfide 4a seems to be including carbonϪcarbon and carbonϪheteroatom bond
somewhat higher under these conditions with an ee of 20% formations. Subtle changes in the ligand’s structure made it
(Table 2, Entry 1), but is still very poor compared with the possible to clarify the mode of action, determine a ligand
high enantioselectivities obtained with this ligand in the ad- structureϪcatalyst efficiency relationship, and to undertake
dition of organozinc compounds to aldehydes. An increased a rational improvement of the ligand’s structure. This shows
catalytic activity was observed with the ligands 5a, 5b, 7 the importance of a flexible synthetic strategy for systematic
and 12, which might be explained by the better solubility optimization of the catalyst’s structure, and an enantiomeric
of the in situ generated nucleophile relative to dimethyl so- excess of 94% was obtained by increasing the steric bulk at
diomalonate. A general effect on the enantiomeric excess the 2-position of the oxazolidine. Interestingly, for thiaz-
was not observed. There was no effect on the enantioselec- oline-oxygen ligands, nucleophilic attack does not need to
tivity with ligands 5 and 6. The enantioselectivity of 11 in- take place near the chiral modifier to obtain enantioselec-
creased substantially, but is still very low. A significant de- tive reactions.
crease in ee from 81% to 59% was observed with thiazolidi-
nylmethanol 7 (Table 2, Entry 5), and from 31% to 21% for
Experimental Section
thiazolidinylmethyl ether 8 (Table 2, Entry 6). Fortunately,
this catalytic system had a positive effect on thioether 12,
with an enantiomeric excess of 94% (Table 2, Entry 8), the
highest obtained with these oxazolidinylmethyl thioether li-
gands.
General: The reagents and solvents were purchased from
SigmaϪAldrich and used without purification. All reactions were
performed under argon unless otherwise stated. Silica gel (230Ϫ400
mesh) was used as the stationary phase in flash chromatography.
Optical rotations were measured with a PerkinϪElmer 341 polar-
imeter. The NMR spectra were recorded with a Varian Mercury
300 or 400 MHz spectrometer using TMS as the internal standard.
Chemical shifts δ are quoted in parts per million (ppm), and coup-
ling constants J are given in Hertz (Hz). IR spectra were recorded
in the range of 4000Ϫ600 cmϪ1 using a Nicolet Magna 550 spec-
trometer, and were measured as KBr or as neat oils. HPLC analyses
were carried out with a Shimadzu SCL-10 AVP chromatograph
using a Diacel Chiralcel OD column; solvent: hexane/2-propanol
(99:1); flow rate: 0.5 mL·minϪ1; UV detection: 254 nm. Elemental
analyses were performed with a Leco CHNS-932 analyzer. High-
resolution mass spectra were recorded with a Bruker BioApex 70e
FT-ICR (Bruker Daltonics, Billerica, USA) instrument in ESI
mode and with a GCT (Micromass, Manchester, UK) instrument
in EI mode (70 eV). The spectral data of the known compounds 2a,
3a, 4a,[20a] and 12, 17[15e] are in accordance with the literature data.
Table 2. One-pot asymmetric palladium-catalyzed allylic substi-
tution of rac-1,3-diphenyl-2-propenyl acetate with dimethyl malon-
ate
Entry[a]
Ligand
Time [h]
Yield [%][b]
ee [%][c]
1
2
3
4
5
6
7
8
4a
5a
5b
6
24
6
8
15
48
64
15
10
28
96
96
95
48
56
93
98
20 (S)
68 (S)
69 (S)
68 (S)
59 (S)
21 (S)
17 (S)
94 (S)
General Procedure for the Allylic Alkylation of 1,3-Diphenyl-2-pro-
penyl Acetate with Dimethyl Sodiomalonate: A THF (1 mL) solu-
tion of [Pd(η3-C3H5)Cl]2 (9 mg, 25 µmol, 2.5 mol %), and ligand
(1, 3Ϫ6, 10 mol %) was stirred for 30 min under argon and then
rac-1,3-diphenyl-2-propenyl acetate (252 mg, 1.0 mmol) was added.
The mixture was stirred for 10 min and a solution of dimethyl
sodiomalonate, prepared from dimethyl malonate (264 mg,
2.0 mmol) and sodium hydride (36 mg, 1.5 mmol) in THF (3 mL),
was added at room temperature. The mixture was stirred at room
temperature for the time given in Table 1. The reaction was
quenched with saturated NH4Cl (aq.) and extracted with CH2Cl2
(3 ϫ 15 mL). The combined organic layers were dried with MgSO4.
The solvent was evaporated and the crude product purified by flash
chromatography on silica gel (230Ϫ400 mesh) with hexane/ethyl
acetate (98:2) as eluent.
7
8
11
12
[a]
N,O-Bis(trimethylsilyl)acetamide (BSA, 3 equiv.), dimethyl ma-
lonate (3 equiv.), KOAc (0.06 mmol), and acetate (1 equiv.). [b] Iso-
lated yield. Determined by HPLC using a Daicel Chiralcel OD-
[c]
H
column; solvent: hexane/2-propanol (99:1); flow rate: 0.5
mL·minϪ1; UV detection: 254 nm. The absolute configuration of
the product was assigned by comparison of the sign of the specific
rotations with literature data.[9b]
Conclusions
General Procedure for the Allylic Alkylation of 1,3-Diphenyl-2-pro-
penyl Acetate with Dimethyl Malonate: A solution of [PdCl(η3-
C3H5)]2 (18 mg, 50 µmol, 5 mol %), and chiral ligand (0.1 mmol,
10 mol %) in dichloromethane (1.5 mL) was stirred for 30 min at
room temperature. Subsequently, a solution of rac-1,3-diphenyl-2-
In summary, some new, enantiopure oxazolidinylmethyl
thioether and thiazolidinylmethanol ligands have been ef-
ficiently synthesized from readily available amino acids, like
-cysteine, S-methyl--cysteine, and -methionine. Promis- propenyl acetate (252 mg, 1.0 mmol), dimethyl malonate (480 mg,
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P. H. Schneider, H. S. Schrekker, C. C. Silveira, L. A. Wessjohann, A. L. Braga
FULL PAPER
3.0 mmol), N,O-bis(trimethylsilyl)acetamide (BSA) (608 mg, 1354, 1154, 1094, 1039, 871, 805 cmϪ1
.
1H NMR (400 MHz,
3.0 mmol), and KOAc (3 mg, cat. quantity) in dichloromethane [D6]DMSO): δ ϭ 8.30Ϫ8.28 (m, 2 H), 7.90Ϫ7.81 (m, 4 H),
(0.8 mL) were added. The reaction mixture was stirred for the time
presented in Table 2. Satd. NH4Cl (aq.) was then added to quench
7.50Ϫ7.38 (m, 8 H), 4.30 (d, J ϭ 5.9 Hz, 2 H), 4.15Ϫ4.00 (m, 8
H), 3.98Ϫ3.36 (m, 4 H), 2.71 (dd, J ϭ 13.3, 6.5 Hz, 2 H), 2.57 (dd,
the reaction, followed by extraction with dichloromethane (3 ϫ J ϭ 13.3, 6.8 Hz, 2 H) ppm. 13C NMR (100.6 MHz, [D6]DMSO):
15 mL). The combined organic layers were dried with MgSO4. The
solvent was removed in vacuo and the product purified by flash
chromatography on silica gel (230Ϫ400 mesh) with hexane/ethyl
acetate (98:2) as eluent.
δ ϭ 134.02, 133.70, 131.95, 128.32, 128.21, 127.28, 126.18, 125.85,
124.99, 124.60, 85.40, 68.96, 62.75, 57.02, 41.83 ppm. HRMS-EI:
m/z calcd. for C15H16NOS2 291.0714 [M Ϫ C15H16NO]ϩ; found
291.0733. [α]2D5 ϭ Ϫ24.95 (c ϭ 0.413, CHCl3).
(4R)-2-Naphthyl-1,3-thiazolidine-4-carboxylic Acid (2b): 1-Naph-
thaldehyde (4.68 g, 30 mmol) diluted in ethanol (30 mL) was added
to a solution of (R)-cysteine (3.63 g, 30 mmol) in water (40 mL).
The product thiazolidine 2b soon began to drop out of solution.
The reaction was kept at 25 °C for 3 h and at 0 °C for an additional
3 h. The product was filtered, washed with ethanol, and dried to
afford 6.78 g (88%) of a diastereomeric mixture of 2b as a white
(4R)-N-Benzyl-4-[(methylthio)methyl]-1,3-oxazolidine (5a): NaBH4
(114 mg, 3.00 mmol) was added in portions to a solution of disulf-
ide 4a (630 mg, 1.50 mmol) and NaOH (114 mg, 2.85 mmol) in dry
ethanol (10 mL) at room temperature. The reaction mixture was
stirred for 30 min and then MeI (374 µL, 6.00 mmol) was added.
After 2 h, the ethanol was evaporated and the residue dissolved in
CH2Cl2 (30 mL), washed with water, and dried with MgSO4. Re-
moval of the solvent in vacuo and purification by flash chromatog-
raphy on silica gel (230Ϫ400 mesh) with hexane/ethyl acetate
(85:15) as eluent afforded 622 mg (93%) of 5a as an oil. IR (film):
powder. IR (KBr): ν˜ ϭ 1609, 1554, 1367, 774 cmϪ1 1H NMR
.
(300 MHz, [D6]DMSO, isomer A): δ ϭ 8.20 (d, J ϭ 8.06 Hz, 1 H),
7.98Ϫ7.47 (m, 6 H), 6.29 (s, 1 H), 4.11 (dd, J ϭ 8.78, 7.13 Hz, 1
H), 3.47 (dd, J ϭ 9.97, 7.13 Hz, 1 H), 3.15 (m, 1 H); isomer B: δ ϭ
8.14 (d, J ϭ 8.24 Hz, 1 H), 7.98Ϫ7.47 (m, 6 H), 6.45 (s, 1 H), 4.29
(dd, J ϭ 6.32, 6.32 Hz, 1 H), 3.33 (dd, J ϭ 10.16, 6.32 Hz, 1 H),
3.15 (m, 1 H) ppm. 13C NMR (75.5 MHz, [D6]DMSO): δ ϭ 172.71
(172.10), 136.92, 134.36, 133.17, 133.02, 130.50, 130.27, 128.42,
128.29, 127.62, 126.17, 125.99, 125.76, 125.59, 125.32, 125.21,
123.42, 123.37, 123.21, 122.16, 67.91 (68.25), 64.95 (65.18), 37.81
(37.99) ppm. HRMS-ESI : m/z calcd. for C14H14NO2S 260.0739
[M ϩ Hϩ]; found 260.0725. C14H13NO2S (259.3): calcd. C 64.84,
H 5.05; found C 64.80, H 5.09. [α]2D5 ϭ Ϫ159.1 (c ϭ 0.6, CH3OH).
1
ν˜ ϭ 2915, 2860, 1495, 1454, 1356, 1247, 1154, 744, 699 cmϪ1. H
NMR (400 MHz, CDCl3): δ ϭ 7.40Ϫ7.20 (m, 5 H), 4.35 (d, J ϭ
5.7 Hz, 1 H), 4.32 (d, J ϭ 5.7 Hz, 1 H), 4.10 (dd, J ϭ 7.0, 8.4 Hz,
1 H), 3.82 (d, J ϭ 13.0 Hz, 1 H), 3.75 (d, J ϭ 13.0 Hz, 1 H), 3.54
(dd, J ϭ 5.2, 8.4 Hz, 1 H), 3.20 (m, 1 H), 2.64 (dd, J ϭ 5.8, 13.1 Hz,
1 H), 2.44 (dd, J ϭ 8.5, 13.1 Hz, 1 H) ppm. 13C NMR (100.6 MHz,
CDCl3): δ ϭ 138.7, 128.7, 128.3, 127.2, 86.0, 69.4, 62.7, 59.0, 37.9,
15.8 ppm. HRMS-ESI: m/z calcd. for C12H17NOSNa 246.0924 [M
ϩ Na]ϩ; found 246.0923. C12H17NOS (223.3): calcd. C 64.53, H
7.67; found C 64.47, H 7.81. [α]2D5 ϭ Ϫ39.7 (c ϭ 1.12, CH3OH).
Bis[(2R)-2-{[(1-naphthyl)methyl]amino}-3-hydroxypropyl] Disulfide
(3b): A solution of iodine (5.08 g, 20.0 mmol) in THF (20 mL) was
added slowly to a suspension of 2b (5.18 g, 20.0 mmol) and NaBH4
(1.90 g, 50.0 mmol) in THF (50 mL) at room temperature. After
the addition was complete, the reaction mixture was refluxed for
20 h and then cooled to room temperature. Methanol was added
to the mixture until a clear solution was obtained. The solvent was
removed in vacuo and the residue dissolved in 20% K2CO3 (aq.)
(50 mL). The mixture was stirred at room temperature for 4 h.
After extraction with dichloromethane (3 ϫ 30 mL), the combined
organic layers were dried with MgSO4. The solvent was removed
in vacuo. The crude product was crystallized from methanol/diethyl
ether to yield 5.20 g (53%) of 3b as a white powder. IR (KBr): ν˜ ϭ
(4R)-4-[(Methylthio)methyl]-3-[(1-naphthyl)methyl]-1,3-oxazolidine
(5b): The experimental procedure that was used to prepare 5a was
applied but by using disulfide 4b (774 mg, 1.50 mmol) instead of
4a. Oxazolidine 5b was obtained as an oil in 63% yield (493 mg).
IR (film): ν˜ ϭ 2914, 2865, 1596, 2509, 1151, 1096, 1000, 792, 777
cmϪ1 1H NMR (300 MHz, CDCl3): δ ϭ 8.37 (dd, J ϭ 7.96,
.
1.00 Hz, 1 H), 7.86Ϫ7.78 (m, 2 H), 7.57Ϫ7.25 (m, 4 H), 4.43 (d,
J ϭ 5.95 Hz, 1 H), 4.29 (d, J ϭ 5.95 Hz, 1 H), 4.24Ϫ4.14 (m, 3 H),
3.56 (dd, J ϭ 8.42, 5.21 Hz, 1 H), 3.36 (m, 1 H), 2.62 (dd, J ϭ
13.08, 6.13 Hz, 1 H), 2.44 (dd, J ϭ 13.08, 8.38 Hz, 1 H), 2.01 (s, 3
H) ppm. 13C NMR (75.5 MHz): δ ϭ 134.18, 133.69, 131.99, 128.33,
128.23, 127.23, 125.89, 125.66, 125.00, 124.58, 85.52, 69.46, 63.41,
57.33, 38.12, 16.10 ppm. HRMS-ESI: m/z calcd. for C16H19NOSNa
296.1081 [M ϩ Na]ϩ; found 296.1079. C16H19NOS (273.4): calcd.
C 70.29, H 7.00; found C 70.07, H 6.97. [α]2D5 ϭ Ϫ18.35 (c ϭ 0.5,
CHCl3).
3294, 2911, 2850, 791, 775 cmϪ1
.
1H NMR (400 MHz,
[D6]DMSO): δ ϭ 8.17 (m, 2 H), 7.88 (m, 2 H), 7.79 (d, J ϭ 7.8 Hz,
2 H), 7.52Ϫ7.38 (m, 8 H), 4.71 (m, 2 H), 4.21 (d, J ϭ 13.1 Hz, 2
H), 4.15 (d, J ϭ 13.1 Hz, 2 H), 3.57Ϫ3.46 (m, 4 H), 2.97Ϫ2.90 (m,
6 H), 2.06 (br. s, 2 H) ppm. 13C NMR (100.6 MHz, [D6]DMSO):
δ ϭ 136.2, 133.1, 131.2, 128.1, 127.1, 125.7, 125.6, 125.4, 125.2,
124.0, 61.9, 58.7, 48.5, 41.0 ppm. HRMS-ESI: m/z calcd. for
(4R)-3-Benzyl-4-[(benzylthio)methyl]oxazolidine (6): An experimen-
tal procedure identical to that used for the preparation of 5a was
applied using benzyl bromide instead of methyl iodide and disulfide
4a (630 mg, 1.50 mmol). Product 6 was obtained as an oil in a yield
of 69% (309 mg). IR (film): ν˜ ϭ 3027, 2866, 1494, 1453, 1005, 695
cmϪ1. 1H NMR (400 MHz, CDCl3): δ ϭ 7.35Ϫ7.00 (m, 10 H), 4.13
C28H33N2O2S2 493.1977 [M ϩ Hϩ]; found 493.1975. [α]2D5
Ϫ99.98 (c ϭ 0.50, CHCl3).
ϭ
Bis[{(4R)-3-[(1-naphthyl)methyl]-1,3-oxazolidin-4-yl}methyl] Disulf-
ide (4b): Benzene (30 mL), 3b (1.50 g, 3.05 mmol), paraformal- (s, 2 H), 3.85 (dd, J ϭ 7.2, 8.2 Hz, 1 H), 3.58 (d, J ϭ 13.0 Hz, 1
dehyde (275 mg, 9.15 mmol), and p-toluenesulfonic acid (cat. H), 3.52 (d, J ϭ 13.0 Hz, 1 H), 3.45 (s, 2 H), 3.31 (dd, J ϭ 5.2,
amount) were added to a 50-mL round-bottomed flask equipped
with a DeanϪStark apparatus. The mixture was refluxed for 5 h
and then cooled to room temperature. The benzene was removed
in vacuo, the residue dissolved in dichloromethane (30 mL), and
washed with 0.5  NaOH (aq.). The organic layer was dried with
MgSO4, filtered, and the solvent removed in vacuo to afford 1.48 g
8.2 Hz, 1 H), 2.94 (m, 1 H), 2.40 (dd, J ϭ 5.9, 13.1 Hz, 1 H), 2.18
(dd, J ϭ 8.6, 13.1 Hz, 1 H) ppm. 13C NMR (100.6 MHz, CDCl3):
δ ϭ 138.8, 138.3, 128.8, 128.7, 128.4, 128.3, 127.3, 126.9, 86.1, 68.9,
62.4, 58.7, 36.0, 34.4 ppm. HRMS-EI: m/z calcd. for C18H21NOS
299.1344 [Mϩ]; found 299.1408. C18H21NOS (299.4): calcd. C
72.20, H 7.07; found C 72.07, H 7.08. [α]2D5 ϭ ϩ28.74 (c ϭ 0.526,
(94%) of 4b as a brown oil. IR (film): ν˜ ϭ 2923, 2868, 1514, 1454, CHCl3).
2720  2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim www.eurjoc.org
Eur. J. Org. Chem. 2004, 2715Ϫ2722

Oxazolidine and Thiazolidine Ligands for Palladium-Catalyzed Asymmetric Allylations
FULL PAPER
[(4R)-3-Benzyl-1,3-thiazolidin-4-yl]methanol (7): A solution of dis-
ulfide 4a (420 mg, 1.0 mmol) in dry ethanol (10 mL) was cooled to
0 °C. NaBH4 (114 mg, 3.0 mmol) was added and the reaction mix-
ture stirred at room temperature for 1 h. The reaction was
1153, 1010, 698 cmϪ1 1H NMR (300 MHz, CDCl3):
. δ ϭ
7.37Ϫ7.22 (m, 5 H), 4.34 (d, J ϭ 6.03 Hz, 1 H), 4.29 (d, J ϭ
6.03 Hz, 1 H), 4.08 (dd, J ϭ 7.87, 7.13 Hz, 1 H), 3.73 (s, 2 H), 3.35
(dd, J ϭ 8.05, 4.94 Hz, 1 H), 3.20 (m, 1 H), 2.60Ϫ2.38 (m, 2 H),
quenched with brine, followed by extraction with CH2Cl2. The or- 2.03 (s, 3 H), 1.77 (m, 1 H), 1.57 (m, 1 H) ppm. 13C NMR
ganic layer was washed with brine and dried with MgSO4. The
solvent was evaporated and the crude product purified by distil-
(75.5 MHz, CDCl3): δ ϭ 138.85, 128.78, 128.18, 127.11, 85.49,
69.12, 62.22, 59.22, 33.01, 31.25, 15.51 ppm. HRMS-ESI: m/z
lation (100 °C, 4 Torr), which afforded alcohol 7 as an oil in 80% calcd. for C13H20NOS 238.1259 [M ϩ H]ϩ; found 238.1260.
yield (334 mg). IR (film): ν˜ ϭ 3408, 2940, 2879, 1045, 1025, 733, C13H19NOS (237.4): calcd. C 65.78, H 8.07; found C 65.64, H 7.81.
1
692 cmϪ1. H NMR (400 MHz, CDCl3): δ ϭ 7.30Ϫ7.05 (m, 5 H), [α]2D5 ϭ Ϫ26.81 (c ϭ 0.593, CHCl3).
3.85 (d, J ϭ 10.3 Hz, 1 H), 3.75 (d, J ϭ 10.3 Hz, 1 H), 3.50 (d, J ϭ
(2R)-2-(Benzylamino)-3-(methylthio)propan-1-ol (10b): An exper-
13.0 Hz, 1 H), 3.45 (m, 1 H), 3.38 (d, J ϭ 13.0 Hz, 1 H), 3.24Ϫ3.10
imental procedure identical to that used for the preparation of 10a
(m, 2 H), 2.86 (dd, J ϭ 6.9, 10.7 Hz, 1 H), 2.44 (dd, J ϭ 1.8,
was applied using compound 9b (229 mg, 1.9 mmol), methanol
10.7 Hz, 1 H) ppm. 13C NMR (100.6 MHz, CDCl3): δ ϭ 138.0,
(5 mL), benzaldehyde (0.24 mL, 2 mmol) and NaBH4 (158 mg,
128.8, 128.3, 127.4, 69.8, 61.5, 58.2, 56.9, 31.3 ppm. HRMS-ESI:
4 mmol). Product 10b was obtained as an oil in a yield of 96%
m/z calcd. for C11H16NOS 210.0947 [M ϩ H]ϩ; found 210.0942.
(386 mg). IR (film): ν˜ ϭ 2915, 2866, 1494, 1453, 1436, 1114, 1046,
971, 742, 699. H NMR (300 MHz, CDCl3): δ ϭ 7.37Ϫ7.24 (m, 5
[α]2D5 ϭ Ϫ84.96 (c ϭ 0.453, CHCl3).
1
(4R)-3-Benzyl-4-(methoxymethyl)-1,3-thiazolidine (8): NaH (72 mg,
3.0 mmol) was added in portions to a solution of alcohol 7
(627 mg, 3.0 mmol) at 0 °C. The mixture was stirred at room temp.
for 15 min and MeI (374 µL, 6.0 mmol) was then added. After 2 h,
brine was added, followed by extraction with CH2Cl2. The organic
layer was dried with MgSO4 and the solvent removed in vacuo. The
crude product was purified by column chromatography (silica; ethyl
acetate/hexane, 15:85) to afford 47% (314 mg) of 8 as an oil. IR
(film): ν˜ ϭ 2927, 2881, 2813, 1452, 1109, 733, 692 cmϪ1. 1H NMR
(300 MHz, CDCl3): δ ϭ 7.39Ϫ7.23 (m, 5 H), 4.08 (d, J ϭ 10.07 Hz,
1 H), 3.98 (d, J ϭ 10.06 Hz, 1 H), 3.69Ϫ3.57 (m, 3 H), 3.37 (dd,
J ϭ 9.52, 6.22 Hz, 1 H), 3.33 (s, 3 H), 3.22 (dd, J ϭ 9.52, 7.50 Hz,
1 H), 3.04 (dd, J ϭ 10.61, 6.40 Hz, 1 H), 2.87 (dd, J ϭ 10.61,
2.74 Hz, 1 H) ppm. 13C NMR (75.5 MHz, CDCl3): δ ϭ 138.08,
128.81, 128.23, 127.21, 73.17, 67.66, 58.94, 58.82, 58.18, 31.99 ppm.
HRMS-EI: m/z calcd. for C12H17NOS 223.1031 [M]ϩ; found
223.1072. [α]2D5 ϭ Ϫ97.01 (c ϭ 0.513, CHCl3).
H), 3.84 (d, J ϭ 13.17 Hz, 1 H), 3.76 (d, J ϭ 13.17 Hz, 1 H), 3.67
(dd, J ϭ 10.98, 3.93 Hz, 1 H), 3.41 (dd, J ϭ 10.89, 4.57 Hz, 1 H),
2.84 (m, 1 H), 2.65 (d, J ϭ 6.59 Hz, 2 H), 2.00 (s, 3 H) ppm.
13C NMR (75.5 MHz, CDCl3): δ ϭ 139.68, 128.38, 127.97, 127.40,
127.05, 126.80, 65.16, 62.32, 55.88, 51.04, 36.47, 15.72 ppm.
HRMS-ESI: m/z calcd. for C11H18NOS 212.1101 [M ϩ H]ϩ; found
212.1103. [α]2D5 ϭ Ϫ41.36 (c ϭ 0.360, CHCl3).
(4R)-3-Benzyl-2,2-dimethyl-4-[(methylthio)methyl]oxazolidine (12):
A solution of the amino alcohol 10b (1.0 g, 4.74 mmol) and p-tolu-
enesulfonic acid monohydrate (120 mg, 0.6 mmol) in 2,2 dimeth-
oxypropane (11.7 mL, 96 mmol) was heated at reflux for 3 h. The
solvent was removed in vacuo, the residue dissolved in ethyl acetate
and washed with NaHCO3 (2 ϫ 20 mL). The organic layer was
dried with MgSO4 and the solvent removed in vacuo. The crude
product was purified by column chromatography (silica, ethyl acet-
ate/hexane, 1:9) to afford 41% (483 mg) of 12 as an oil. IR (film):
ν˜ ϭ 2989, 2916, 2827, 1462, 1454, 1379, 1368, 1212, 1183, 1151,
1084, 1078, 850, 734, 698 cmϪ1. 1H NMR (300 MHz, CDCl3): δ ϭ
7.36Ϫ7.23 (m, 5 H), 3.88 (dd, J ϭ 16.60, 13.42 Hz, 1 H), 3.85 (dd,
J ϭ 16.60, 13.30 Hz, 1 H), 3.48 (m, 2 H), 2.87 (m, 1 H), 2.69 (dd,
J ϭ 13.43, 5.98 Hz, 1 H), 2.60 (dd, J ϭ 13.43, 6.72 Hz, 1 H), 2.03
(s, 3 H), 1.33 (s, 6 H) ppm. 13C NMR (75.5 MHz, CDCl3): δ ϭ
140.17, 128.19, 127.9, 126.73, 126.69, 99.86, 62.03, 55.38, 51.45,
36.70, 24.42, 15.97 ppm. HRMS-ESI: m/z calcd. for C14H22NOS
252.1415 [M ϩ H]ϩ; found 252.1426. [α]2D5 ϭ Ϫ25.04 (c ϭ 0.366,
CHCl3).
(2R)-2-(Benzylamino)-4-(methylthio)butan-1-ol (10a): Benzaldehyde
(1.3 mL, 11.2 mmol) was added to a cooled solution of amino al-
cohol 9a (1.5 g, 11.1 mmol) in dry methanol (15 mL). The reaction
mixture was stirred at room temp. for 1 h, cooled to 0 °C and
NaBH4 (850 mg, 22.4 mmol) was added in portions over 30 min.
Next, 4  HCl (aq.) (15 mL) and diethyl ether (20 mL) were added.
The organic layer was washed twice with 4  HCl (aq.). The com-
bined aqueous layers were extracted with diethyl ether and the
combined ethereal layers were discarded. The aqueous layer was
neutralized with NaHCO3 and extracted three times with diethyl
ether. The organic layers were combined and dried with MgSO4
and the solvent removed in vacuo to afford pure 10a as an oil in
77% (1.92 g) yield. IR (KBr): ν˜ ϭ 3261, 2915, 2852, 1451, 1061,
Acknowledgments
The authors are grateful to CAPES and DAAD (German Aca-
demic Exchange Service) for travel grants as part of a PROBRAL-
project, and to CNPq and FAPERGS for financial support.
1
733, 699 cmϪ1. H NMR (300 MHz, CDCl3): δ ϭ 7.35Ϫ7.23 (m,
5 H), 3.84 (d, J ϭ 12.99 Hz, 1 H), 3.78 (d, J ϭ 12.99 Hz, 1 H),
3.67 (dd, J ϭ 10.98, 3.84 Hz, 1 H), 3.39 (dd, J ϭ 10.98, 5.86 Hz, 1
H), 2.85 (m, 1 H), 2.63 (br. s, 2 H), 2.53 (m, 2 H), 2.09 (s, 3 H),
1.79 (m, 2 H) ppm. 13C NMR (75.5 MHz, CDCl3): δ ϭ 139.33,
128.38, 128.09, 127.14, 62.49, 57.46, 50.86, 30.86, 30.70, 15.62 ppm.
HRMS-ESI: m/z calcd. for C12H20NOS 226.1260 [M ϩ H]ϩ; found
226.1257. C12H19NOS (225.3): calcd. C 63.96, H 8.50; found C
63.47, H 8.21. [α]2D5 ϭ ϩ25.49 (c ϭ 0.453, CHCl3).
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was applied using amino alcohol 10a (1.35 g, 6.0 mmol), paraform-
aldehyde (270 mg, 9.0 mmol), benzene (80 mL) and p-toluenesul-
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Eur. J. Org. Chem. 2004, 2715Ϫ2722
www.eurjoc.org
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
2721

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 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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