Highly selective palladium catalyzed kinetic resolution and enantioselective substitution of racemic allylic carbonates with sulfur nucleophiles: Asymmetric synthesis of allylic sulfides, allylic sulfones, and allylic alcohols

FULL PAPER

Highly Selective Palladium Catalyzed Kinetic Resolution and

Enantioselective Substitution of Racemic Allylic Carbonates

with Sulfur Nucleophiles:Asymmetric Synthesis of Allylic Sulfides,

Allylic Sulfones, and Allylic Alcohols

Hans-Joachim Gais,* Thomas Jagusch, Nicole Spalthoff, Frank Gerhards, Michael Frank,

[

a]

and Gerhard Raabe

Abstract: We describe the highly selec-

tive palladium catalyzed kinetic resolu-

tions of the racemic cyclic allylic carbo-

nates rac-1a ± c and racemic acyclic

allylic carbonates rac-3aa and rac-3ba

through reaction with tert-butylsulfinate,

tolylsulfinate, phenylsulfinate anions

and 2-pyrimidinethiol by using N,N'-

nates and sulfinate anions and thiols,

respectively, in the presence of BPA.

Synthesis of the E-configured allylic

sulfides 6aa, 6ab, 6ac and 6bb was

accompanied by the formation of minor

amounts of the corresponding Z iso-

mers. The analogous synthesis of allylic

tert-butylsulfides from allylic carbonates

and tert-butylthiol by using BPA could

not be achieved. Reaction of the cyclo-

pentenyl esters rac-1da and rac-1db

with 2-pyrimidinethiol gave the allylic

sulfide 5c having only a low ee value.

Similar results were obtained in the case

of the reaction of the cyclohexenyl

carbonate rac-1a and of the acyclic

carbonates rac-3aa and rac-3ba with

2-pyridinethiol and lead to the forma-

tion of the sulfides 5ab, 6ab, and 6bb,

respectively. The low ee values may be

ascribed to the operating of a ™memory

effect∫, that is, both enantiomers of the

substrate give the substitution product

with different enantioselectivities. How-

ever, in the reaction of the racemic

carbonate rac-1a as well as of the highly

enriched enantiomers 1a (ꢀ99% ee)

and ent-1a (ꢀ99% ee) with 2-pyrimidi-

nethiol the ee values of the substrates

and the substitution product remained

constant until complete conversion.

Similar results were obtained in the

reaction of the cyclic carbonates rac-

1a, ent-1a (ꢀ99% ee) and ent-1c

(ꢀ99% ee) with lithium tert-butylsulfi-

nate. Thus, in the case of rac-1a and

2-pyrimidinthiol and tert-butylsulfinate

anion as nucleophiles the enantioselec-

tivity of the substitution step is, under

the conditions used, independent of the

chirality of the substrate; this shows that

no ™memory effect∫ is operating in this

case. Hydrolysis of the carbonates ent-

1a ± c, ent-3aa and ent-3ba, which were

obtained through kinetic resolution, af-

forded the enantiomerically highly en-

riched cyclic allylic alcohols 9a ± c

(ꢀ99% ee) and acyclic allylic alcohols

10a (ꢀ99% ee) and 10b (99% ee),

respectively.

(

1R,2R)-1,2-cyclohexanediylbis[2-(di-

phenylphosphino)-benzamide] (BPA)

as ligand. Selectivities are expressed in

yields and ee values of recovered sub-

strate and product and in selectivity

factors S. The reaction of the cyclohex-

enyl carbonate 1a (ꢀ99% ee) with

2-pyrimidinethiol in the presence of

BPA was shown to exhibit, under the

conditions used, an overall pseudo-zero

order kinetics in regard to the allylic

substrate. Also described are the highly

selective palladium catalyzed asymmet-

ric syntheses of the cyclic and acyclic

allylic tert-butylsulfones 2aa, 2b, 2c, 2d

and 4a ± c, respectively, and of the cyclic

and acyclic allylic 2-pyrimidyl-, 2-pyrid-

yl-, and 4-chlorophenylsulfides 5aa, 5b,

Keywords: allylic compounds

¥

asymmetric catalysis ¥ asymmetric

synthesis

¥

kinetic resolution

¥

5

ab, 6aa ± ac, 6ba and 6bb, respectively,

palladium

from the corresponding racemic carbo-

riched compounds,^[¹^]particularly on an industrial scale.^[¹^d^,^e^]

Especially attractive resolution methods are those based on

enantiomer selective reactions (kinetic resolution) employing

Introduction

The separation of the enantiomers of a racemate (resolution)

is an important technique for the attainment of enantioen-

chiral catalysts.^[While catalytic kinetic resolution has been

1, 2]

for a long time the domain of enzymes,^[

1q,r]

much progress has

[

a] Prof. Dr. H.-J. Gais, Dipl.-Chem. T. Jagusch, Dr. N. Spalthoff,

Dr. F. Gerhards, Dr. M. Frank, Dr. G. Raabe

Institut f¸r Organische Chemie der

been made in the last decade towards the development of

transition metal and small-molecule catalysts.^[

1h,m,n]

In this

context particularly interesting is the palladium-catalyzed

Rheinisch-Westf‰lischen Technischen Hochschule (RWTH) Aachen

Prof.-Pirlet-Strasse 1, 52056 Aachen (Germany)

Fax: ( 49)241-8092665

reaction of racemic allylic esters with nucleophiles

3]

(

Scheme 1),^[which can not only provide an asymmetric

E-mail: Gais@RWTH-Aachen.de

synthesis of allylic compounds with complete conversion of

4202

¹ 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

DOI:10.1002/chem.200204657

Chem. Eur. J. 2003, 9, 4202 ± 4221

4

202±4221

preliminary observations,^[⁷^,⁹^]we have been interested in the

general synthetic and selectivity aspects of both the kinetic

resolution and the enantioselective substitution of cyclic and

acyclic substrates by using sulfur nucleophiles, as for example

thiols and sulfinate anions, and BPA as ligand because of the

following reasons. First, chiral allylic alcohols are synthetically

highly useful^[

3a, 12]

and the development of new methods for

their kinetic resolution is currently a topic of much inter-

est.^[

1h,m,n,q, 13]

Following the invention of the highly efficient

kinetic resolution of allylic alcohols through titanium-cata-

[14]

lyzed epoxidation by Sharpless et al., a number of catalytic

methods using transition-metal catalysts,^[enzymes,

15]

[16]

en-

zymes in combination with an achiral transition-metal cata-

lyst,^[and small-molecule catalysts have been described.

However, methods which provide for high selectivities in the

kinetic resolution of both cyclic and acyclic allylic alcohols are

17]

[18]

[19]

[20]

still scarce. Second, allylic sulfides and allylic sulfones are

valuable intermediates in organic synthesis^[and the devel-

opment of a method for the catalytic asymmetric synthesis of

21]

allylic sulfides and the widening of the scope of the palladium

catalyzed asymmetric synthesis of allylic sulfones^[

7, 22±24]

should

greatly enhance the synthetic utility of these allylic sulfur

compounds. For example, they could find interesting applica-

Scheme 1. Simplified mechanistic Scheme of the palladium(0) catalyzed

reaction of racemic allylic substrates with nucleophiles (X leaving group,

Nu nucleophile, M metal).

tions as for example in sigmatropic rearrangement, transition

metal mediated substitution with organometallics^[

19, 20]

and

synthesis of chiral nonracemic sulfur stabilized allylic carban-

ions.^[Third, it was of interest to see whether thiols can

generally function as nucleophiles in the palladium catalyzed

allylic substitution in the presence of chiral ligands including

BPA and POX. Because of the pronounced thiophilicity of

the palladium atom, coordination of the thiol to the palladium

atom of the p-allyl intermediate^[could occur leading to a

retardation or even blocking of the catalytic cycle. The

literature on the feasibility of a palladium catalyzed allylic

substitution with thiols is ambiguous.^[While several groups

25]

the substrate but, in principle, also kinetic resolution of the

latter. According to a simplified mechanistic scheme^[both

enantiomers of a symmetrically disubstituted substrate^[are

converted by a chiral palladium(0) catalyst to the same set of

equilibrating p-allyl palladium(ii) intermediates;^[its reac-

4a]

4b]

4c]

26]

tion with the nucleophile affords the substitution product and

the catalyst.^[

3, 5]

While the second step, the enantioselective

substitution, has been intensively studied,^[it was only in the

recent years that the first step, the kinetic resolution, has

received attention. Kinetic resolution in palladium catalyzed

allylic substitution was described for the first time by Hayashi

et al. in 1986.^[Reaction of an unsymmetrically disubstituted

allylic ester with a carbon nucleophile in the presence of a

chiral ferrocenylphosphane based palladium catalyst was

found to proceed with a medium selective kinetic resolution.

We reported in 1998^[about the observation of high

selectivities in both kinetic resolution and enantioselective

substitution in the reaction of 1,3-diphenylpropenyl carbonate

3]

27]

have described the successful utilization of thiols in the

presence of achiral phosphanes,^[

27c±g]

others reported about

6]

[27a,b]

the failure to achieve an allylic substitution with thiols.

Fourth, BPA was selected as ligand for the palladium atom

because it provided high enantioselectivities in the substitu-

tion of a range of cyclic and acyclic substrates with various

7]

[3]

[7, 9, 22, 23, 28±30]

nucleophiles including those based on sulfur.

In this paper we describe both the highly selective kinetic

resolution of cyclic and acyclic racemic allylic carbonates in

reactions with sulfinate anions and thiols by using BPA and

POX containing palladium catalysts, leading for example to

highly enantioenriched allylic alcohols and the asymmetric

with lithium tert-butylsulfinate by using the chiral phosphi-

nooxazoline ligand POX.^[

8, 3e,f]

Determination of the stereo-

chemical course of both processes revealed k > k and k > k .

1

2

3

4

Shortly afterwards we found^[that the reaction of racemic

9]

[31]

synthesis of allylic sulfides and allylic sulfones.

2

-cyclohexenyl carbonate with 2-pyrimidinethiol in the pres-

[10, 3d]

ence of the chiral bisphosphinoamide ligand BPA

also

proceeds with high enantioselectivities in both kinetic reso-

lution and substitution and takes a similar stereochemical

course. At the same time and subsequently several other

groups also encountered kinetic resolution in the reaction of

allylic substrates with carbon and oxygen nucleophiles by

using chiral phosphanes including BPA.^[These studies were

mainly conducted in connection with the design of new chiral

ligands for the palladium atom and were thus limited to

certain substrates and nucleophiles. Based on our previous

Results and Discussion

Kinetic resolution

Sulfinates and racemic allylic carbonates: The investigation of

the kinetic resolution of allylic esters in their reaction with

sulfinate anions was carried out with the racemic cyclo-

hexenyl, cycloheptenyl and cyclooctenyl carbonates rac-1a,

rac-1b and rac-1c, respectively (Schemes 2 and 3) and the

11]

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H.-J. Gais et al.

FULL PAPER

nucleophiles. The reactions were carried out at 08C at a

1

0 mmol scale under argon in a two-phase system composed

of CH Cl and water, containing Hex NBr (THAB) as a phase

2

4

transfer catalyst, by using 2 equiv of the sulfinate salt,

.5 mol% [Pd (dba) ] ¥ CHCl

1

(dba dibenzylideneace-

2

3

[33]

tone) and 4.5 mol% BPA. The precatalyst and BPA were

dissolved at 08C in CH Cl and after a preformation time the

2

allylic substrate was added. Then a cold solution of the

sulfinate salt in a mixture of degassed water and CH Cl ,

2

1

containing THAB, was added. After GC analysis or H NMR

spectroscopy revealed an approximately 50% conversion of

the allylic substrates, the reactions were terminated by phase

separation and stirring of the organic phase under air in order

to destroy the catalyst. Carbonates and the sulfones were

separated by chromatography and their ee values were

determined either by GC or HPLC analysis using chiral

1

stationary phase containing columns or by H NMR spectro-

scopy in the presence of a chiral shift reagent.

As revealed by Table 1 both the kinetic resolution and the

enantioselective substitution of the cyclic carbonates rac-1a ±

c in the reaction with lithium tert-butylsulfinate proceeded

with high selectivities and afforded the highly enantioen-

Scheme 2. Palladium-catalyzed kinetic resolution of cyclic carbonates with

lithium tert-butylsulfinate.

Table 1. Palladium-catalyzed kinetic resolution of the cyclic carbonates rac-

a ± c with lithium tert-butylsulfinate.^[

a]

1

Substrate

t

Conv Carbonate Yield ee

Sulfone Yield ee

[

h]

[%]

rac-1a

rac-1b

rac-1c

0.75 54

ent-1a

ent-1b

ent-1c

34

33

34

ꢀ 99 2aa

94 2b

ꢀ 99 2c

49

46

48

98

95

96

4

53

58

24

[

a] 1.5 mol% [Pd

2

3 3

(dba) ] ¥ CHCl and 4.5 mol% BPA.

riched carbonates ent-1a ± c and sulfones 2aa, 2b and 2c,

respectively, in good yields (cf. Scheme 2). The selectivity of

the kinetic resolution of the cyclooctenyl carbonate rac-1c

was the highest. After an approximately 50% conversion of

the carbonate, the reaction with the sulfinate salt came

practically to a complete halt (see below). The kinetic

resolution of carbonate rac-1c was carried out with similar

results on a 30 mmol and a 50 mmol scale by using only

Scheme 3. Palladium-catalyzed kinetic resolution of cyclic carbonates with

aromatic sulfinate anions.

racemic acyclic carbonate rac-3aa (Scheme 4). Carbonates

were chosen instead of acetates because of their higher

_r_e_a_c_t_i_v_i_t_y_i_n_p_a_l_l_a_d_i_u_m_-_c_a_t_a_l_y_z_e_d_s_u_b_s_t_i_t_u_t_i_o_n_.[

3a,g]

Because of

0

.9 mol% [Pd (dba) ] ¥ CHCl and 3 mol% BPA. We note

their different steric size and because of synthetic reasons,

_t_e_r_t_-_b_u_t_y_l_s_u_l_f_i_n_a_t_e_,[32] tolylsulfinate and phenylsulfinate anions

2 3 3

that the faster reacting enantiomers of the carbonates rac-

1

a ± c and the preferentially formed sulfones 2aa, 2b and 2c

were used. Most of the reactions studied were run with the

tert-butylsulfinate anion because of 1) our interest in the

utilization of enantioenriched allylic tert-butylsulfones as

starting material for the synthesis of the corresponding chiral

_n_o_n_r_a_c_e_m_i_c_a_l_l_y_l_i_c_a_-_s_u_l_f_o_n_y_l_c_a_r_b_a_n_i_o_n_s[25] and 2) the desire

to determine the scope and limitation of sulfinate anions as

[7]

have the same absolute configuration.

In addition to lithium tert-butylsulfinate, sodium tolylsulfi-

nate which is commercially available and sodium phenyl-

sulfinate were applied as nucleophiles in the kinetic resolution

of carbonate rac-1a (cf. Scheme 3). Table 2 shows that the

kinetic resolution and enantioselective substitution of carbo-

Table 2. Palladium-catalyzed kinetic resolution of the cyclic carbonate rac-

a with sodium tolylsulfinate and sodium phenylsulfinate.^[

a]

1

Sulfinate t [h] Conv Carbonate Yield ee

Sulfone Yield ee

salt

[%]

NaO

2

STol 0.5 68

ent-1a

24

27

ꢀ 99 2ab

ꢀ 99 2ac

60

56

ꢀ 99

SPh 0.5 62

(dba)

Scheme 4. Palladium-catalyzed kinetic resolution of a acyclic carbonate

with lithium tert-butylsulfinate.

[a] 1.5 mol% [Pd

2

3

] ¥ CHCl and 4.5 mol% BPA.

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Chem. Eur. J. 2003, 9, 4202 ± 4221

Palladium Catalyzed Kinetic Resolution

4202±4221

nate rac-1a by using the tolylsulfinate anion occurred with

high selectivities and gave the highly enantioenriched carbo-

nate ent-1a and sulfone 2ab in good yields. Not surprisingly

similar results were recorded by using sodium phenylsulfinate.

Here too both the carbonate ent-1a and the sulfone 2ac were

obtained highly enantioenriched in good yields. These results

show that the intermediate cyclic p-allyl-palladium complexes

are readily substituted by sulfinate anions irrespective of their

steric bulkiness.

It should be noted that sulfinate anions are ambident

nucleophiles, which can react with the p-allyl intermediate not

only at the sulfur atom with formation of an allylic sulfone but

also at the oxygen atom with formation of an allylic sulfinate.

Scheme 5. Palladium-catalyzed kinetic resolution of cyclic carbonates with

thiols.

However, the latter reaction is reversible and thus sulfinic

esters are normally not isolated.^[

24, 34, 35]

We were interested to

see whether the reaction of the p-allyl intermediate with the

sulfinate anion with formation of the sulfone is reversible.

Therefore the racemic tolylsulfone rac-2ab was treated with

lithium tert-butylsulfinate in the presence of [Pd (dba) ] ¥

2

3

CHCl and BPA under the same conditions used above. Even

3

after a prolonged reaction time at room temperature or at

refluxtemperature formation of the tert-butylsulfone 2aa

could not be detected and tolylsulfone rac-2ab was recovered.

After having observed high selectivities in the kinetic

resolution and enantioselective substitution of the cyclic

carbonates rac-1a ± c in reactions with sulfinate anions, the

kinetic resolution of the acyclic carbonate rac-3aa by using

lithium tert-butylsulfinate in the presence of BPA was studied

under similar conditions (cf. Scheme 4). As revealed by

Table 3 kinetic resolution and enantioselective substitution

also occurred in this case with high selectivities and gave the

highly enantioenriched carbonate ent-3aa and sulfone 4a in

good yields.

Scheme 6. Palladium-catalyzed kinetic resolution of acyclic carbonates

with thiols.

Table 3. Palladium-catalyzed kinetic resolution of the acyclic carbonate

rac-3aa with lithium tert-butylsulfinate.^[^a^]

2

^T^h^e^r^e^a^c^tⁱ^oⁿ^s^w^e^r^e^c^a^r^rⁱ^e^d^o^u^t^a^t^r^o^o^m^t^e^m^p^e^r^a^t^u^r^eⁱⁿ^C^H^C^l2

under argon on a 10 mmol scale in substrate by using 2.5 or

Carbonate ent-3aa

Sulfone 4a

5

mol% [Pd (dba) ] ¥ CHCl , 5 or 11 mol% BPA and equi-

2 3 3

t [min]

Conv [%]

Yield [%]

ee [%]

Yield [%]

ee [%]

molar amounts of the thiol and they were terminated at

approximately 50% conversion by filtration of the reaction

mixture through Celite and stirring of the liquid phase under

air. Carbonates and sulfides were separated by chromatog-

raphy and their ee values were determined by GC or HPLC

analysis on chiral stationary phases containing columns.

Higher amounts of catalyst were required in all reactions

with thiols as compared to those with sulfinate anions. The

reactions of carbonates rac-1a and rac-1b with 2-pyrimidine-

thiol were highly selective in regard to the kinetic resolution

and afforded the highly enantioenriched carbonates ent-1a

and ent-1b, respectively and the enantioenriched sulfides 5aa

and 5b, respectively, in good yields (cf. Scheme 5) (Table 4,

entries 1 and 2). It should be noted that the ee values of the

sulfides 5aa and 5b are significantly lower than that of the

corresponding sulfones 2aa and 2. Kinetic resolution and

substitution of the acyclic carbonates rac-3aa and rac-3ba

with the thiol under the same condition used above proceeded

with similar high selectivities and gave the highly enantioen-

riched carbonates ent-3aa and ent-3ba, respectively, and the

enantioenriched sulfides 6aa and 6ba, respectively, in good

5

24

36

73

53

46

19

33

51

ꢀ 99

21

32

68

98

96

1

2

0

5

[

2 3 3

a] 1.5 mol% [Pd (dba) ] ¥ CHCl and 4.5 mol% BPA.

2-Pyrimidinethiol and racemic allylic carbonates: A study of

the palladium-catalyzed resolution of allylic substrates with

thiols was undertaken in order to see whether they can

function as nucleophiles and whether there is dependency of

the selectivity of the kinetic resolution on the nucleophile. For

the investigations the cyclic carbonates rac-1a and rac-1b and

the acyclic carbonates rac-3aa and rac-3ba were selected as

substrates and 2-pyrimidinethiol as nucleophile (Schemes 5

and 6). We had previously observed that 2-pyrimidinethiol is

capable to act as a nucleophile in the palladium catalyzed

allylic substitution in the presence of BPA in CH Cl (see

2

below).^[

22]

2-Pyrimidinethiol has only

a

low solubility

À1

(

4.6 mmolL ) in CH Cl at room temperature. Thus, in all

2

reactions with 2-pyrimidinethiol in CH Cl undissolved thiol

was present until nearly all of the substrate was consumed.

2

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H.-J. Gais et al.

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Table 4. Palladium-catalyzed kinetic resolution of the cyclic allylic carbonates

rac-1a and rac-1b and of the acyclic allylic carbonates rac-3aa and rac-3ba with

2

-pyrimidinethiol.

Entry Substrate

t

Conv Carbonate Yield ee

Sulfide Yield ee

[h] [%]

[%]

a]

1

2

3

4

rac-1a^[

rac-1b

1.5 50

3.5 50

ent-1a

41

39

36

28

ꢀ 99 5aa

97 5b

46

38

36

44

84

93

92

[

b]

ent-1b

ent-3aa

ent-3ba

[

a]

rac-3aa

20

48

50

ꢀ 99 6aa

[

b]

rac-3ba

ꢀ 99 6ba

[

a] 2.5 mol% [Pd

2

(dba)

3

3 2 3

] ¥ CHCl and 5.5 mol% BPA. [b] 5 mol% [Pd (dba) ] ¥

3

CHCl and 11 mol% BPA.

yields (entries 3 and 4). NMR spectroscopy of the crude

reaction mixtures indicated in no case the formation of side

products. Deviations in the yields of carbonates and sulfides

from the maximum yield of 50% are most likely due to losses

during work-up because of their volatility. The reactions of the

cyclic carbonates rac-1a and rac-1b went to 50% conversion

of the substrates in much shorter reaction times as compared

to the acyclic carbonates rac-3aa and rac-3ba.

Formation of sulfides 5aa, 5b, 6aa and 6ba rather than the

isomeric N-allylic thiopyrimidones in the reaction of the

allylic carbonates rac-1a, rac-1b, rac-3aa and rac-3ba with

2

-pyrimidinethiol was revealed by an analysis of their

C NMR data in comparison with those of 2-(alkylthio)-

1

3

Scheme 7. Asymmetric synthesis of cyclic sulfones.

pyrimdines/2-(alkylthio)-pyridines and the corresponding N-

alkyl-thiopyrimidinones/N-alkyl-thiopyridones, which show

characteristic differences.^[

27e,f, 36]

Table 5. Palladium-catalyzed asymmetric synthesis of ayclic allylic S-tert-

butylsulfones.^[

a]

Asymmetric synthesis

Entry

Carbonate

t [h]

Sulfone

Yield [%]

ee [%]

1

2

3

4

rac-1a

rac-1b

rac-1c

rac-1d

19

6

52

24

2aa

2b

2c

95

89

50

76

94

93

94

89

Allylic sulfones: After having shown that in the reactions of

the cyclic and acyclic carbonates with sulfinate anions in the

presence of BPA the substitution of the corresponding p-allyl

intermediates proceed with high enantioselectivities, it was of

interest to see whether an asymmetric synthesis of the cyclic

sulfones 2aa, 2b, 2c and 2d (Scheme 7) and of the acyclic

sulfones 4a ± c (Schemes 8 ± 11) could be achieved, requiring a

complete transformation of the racemic substrates. Emphasis

was placed on the asymmetric synthesis of tert-butylsulfones.

The reactions of the cyclic carbonates rac-1a ± c and rac-1da

with lithium tert-butylsulfinate were carried out at room

temperature on a 1 ± 5 mmol scale in CH Cl /H O, containing

2d

[

2 3 3

a] 1.5 mol% [Pd (dba) ] ¥ CHCl and 4.5 mol% BPA.

lithium tert-butylsulfinate gave sulfone 2d with 89% ee in

76% yield (entry 4).

The reactions of the acyclic carbonates rac-3aa and rac-3ba

with lithium tert-butylsulfinate were carried out in a similar

way as those of the cyclic carbonates (Scheme 8). The acyclic

2

THAB, by using 1.5 mol% [Pd (dba) ] ¥ CHCl , 4.5 mol%

2

3

BPA and 2 equiv of the sulfinate salt under otherwise the

same conditions used in the corresponding kinetic resolutions.

1

After TLC, H NMR spectroscopy or GC analysis indicated

complete conversion of the carbonate, the reaction mixture

was exposed to air and the sulfone was isolated by chroma-

tography. As shown by Table 5 the highly enantioenriched

cyclohexenyl- and cycloheptenyl sulfones 2aa and 2b, re-

spectively, were obtained in high yields (entries 1 and 2). In

the case of the cyclooctenyl carbonate rac-1c the selectivity of

the kinetic resolution was so high that even after a prolonged

reaction time the conversion of the allylic substrate did not

exceed 53% (entry 3). Thus, the highly enantioenriched

sulfone 2c was isolated in only 44% yield and the highly

enantioenriched (ꢀ99% ee) carbonate ent-1c in 34% yield.

The reaction of the cyclopentenyl carbonate rac-1da with

Scheme 8. Asymmetric synthesis of acyclic sulfones from carbonates.

carbonates showed a higher reactivity than the cyclic carbo-

nates rac-1a ± d. After the complete conversion of the

substrates the highly enantioenriched sulfones 4a and 4b

were isolated in high yields (Table 6, entries 1 and 2).

Formation of the corresponding (Z)-configured allylic sul-

fones was not observed. Occasionally, in palladium catalyzed

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Chem. Eur. J. 2003, 9, 4202 ± 4221

Palladium Catalyzed Kinetic Resolution

4202±4221

Table 6. Palladium-catalyzed asymmetric synthesis of acyclic allylic S-tert-butylsulfones.

Entry

Substrate

Precatalyst, mol%

Ligand, mol%

Solvent

t [h]

Conv [%]

Sulfone

Yield [%]

ee [%]

1

2

3

4

5

6

7

8

rac-3aa

rac-3ba

rac-3ab

rac-3bb

rac-3ab

rac-3bb

rac-3cb

[Pd

[Pd(C

[Pd

2

(dba)

3

] ¥ CHCl

3

, 1.5

BPA, 4.5

POX, 11

POX, 6

CH

THF

CH

2

Cl

2

, H

2

O, THAB

2

6

100

48

70

48

100

68

53

55

4a

4b

4a

98

97

96

51

43

55

60

58

98

97

96

98

96

58

61

84

3

H

5

)Cl]

2

, 3

2

(dba)

3

] ¥ CHCl

3

, 1.5

, 2

4b

ent-4a

ent-4b

4c

, 1.5

68

70

[Pd(C

3

H

5

)Cl]

2

, 1.5

BPA, 6

2

Cl

2

, H

2

O, THAB

asymmetric synthesis of allylic sulfones and kinetic resolution

the palladium-catalyzed reaction of racemic 1,3-diphenylpro-

penyl carbonate and acetate with lithium tert-butylsulfinate in

THF in the presence of POX was highly enantioselective and

gave the corresponding sulfone of 93% ee.^[The reaction of

acetates rac-3ab and rac-3bb with lithium tert-butylsulfinate

in THF by using 2 or 1.5 mol% [Pd (dba) ] ¥ CHCl and 11 or

6 mol% POX could not be brought to completion and gave

sulfones ent-4a and ent-4b only with 58 and 61% ee,

respectively (entries 6 and 7). Thus, not only the substitutions

of racemic alkyl substituted allylic substrates with tolylsulfi-

nate anion but also those with tert-butylsulfinate anion

catalyzed by the POX based palladium(0) catalyst show

significantly lower enantioselectivities than those catalyzed by

the BPA based catalyst. Because of the low enantioselectivity

of the substitution, we did not investigate whether the low

conversion was due at least in part to a kinetic resolution or to

the low solubility of lithium tert-butylsulfinate in THFat room

temperature (0.047m).

by using [Pd (dba) ] ¥ CHCl as precatalyst separation of the

2

3

substrate and the product or isolation of the product by

chromatography was hampered by the presence of dibenzy-

lideneacetone stemming from the precatalyst. Therefore the

reaction of the carbonate rac-3ba with lithium tert-butylsulfi-

nate was studied by using as precatalyst 3 mol%

24]

2

3

[

37]

[

Pd(C H )Cl] (C H allyl)

and 4.5 mol% BPA under

3

5

2

3

5

otherwise the same conditions used above. As indicated by

Table 6 the reaction time for 100% conversion was longer but

sulfone 4b could be isolated with the same high ee value and

in almost the same high yield (entry 3).

As noted previously^[acetates rac-3ab and rac-3bb showed

a much lower reactivity than the corresponding carbonates in

the substitution with tert-butylsulfinate anion and a complete

conversion of the substrates could not be achieved even after

a longer reaction time (Scheme 9). Thus, at 68 and 53%

conversion of rac-3ab and rac-3bb the yields of the sulfones

7]

4

a and 4b, respectively, were only 51 and 43%, respectively

A substitution of the branched carbonate rac-3ca with tert-

butylsulfinate anion by using either 1.5 mol% [Pd (dba) ] ¥

(

entries 4 and 5). The enantioselectivities of the substitution

2

3

were, however, the same as with the carbonates.

CHCl₃or 1.5 mol% [Pd(C H )Cl] as precatalyst and

3 5 2

4

.5 mol% BPA or 4.5 mol% POX as ligand could not be

achieved (Scheme 11). However, reaction of chloride rac-3cb

with lithium tert-butylsulfinate in the presence of 1.5 mol%

[

Pd(C H )Cl] and 6 mol% BPA led to a 70% conversion of

3 5 2

the allylic substrate and the branched sulfone 4c of 84% ee

was isolated in 58% yield (entry 8). The lower ee value of 4c

as compared to 4a and 4b was not due to a competing and

hence non-selective uncatalyzed reaction of rac-3cb with the

sulfinate anion as revealed by a control experiment. Another

limitation of the palladium catalyzed allylic alkylation of

Scheme 9. Asymmetric synthesis of acyclic sulfones from acetates.

For comparison purposes the reaction of the acetates rac-

3

ab and rac-3bb with the tert-butylsulfinate anion in the

presence of POX as ligand for the palladium atom was

investigated (Scheme 10). We had previously observed that

Scheme 10. Asymmetric synthesis of acyclic sulfones by using POX as

ligand.

Scheme 11. Asymmetric synthesis of branched sulfones.

Chem. Eur. J. 2003, 9, 4202 ± 4221

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4207

H.-J. Gais et al.

FULL PAPER

sulfinate anions was apparent in the case of the branched

racemic carbonate rac-3d where a substitution with formation

of sulfone 4d could be accomplished neither with BPA nor

with POX as ligand.

Allylic sulfides: After having recorded high enantioselectiv-

ities in the second step (cf. Scheme 1) of the reaction of

racemic carbonates with 2-pyrimidinethiol in the presence of

BPA, we investigated the asymmetric synthesis of the cyclic

sulfides 5aa and 5ab (Scheme 12) and of the acyclic sulfides

Scheme 13. Asymmetric synthesis of acyclic sulfides.

enantioenriched pyrimidyl sulfide 5aa could be isolated in

medium to good yield (entry 1). Interestingly, the correspond-

ing pyridyl sulfide 5ab derived from the reaction of rac-1a

with 2-pyridinethiol had a much lower ee value (entry 2),

which was not caused by a partial racemization of the sulfide

during work-up as revealed by a control experiment. The

reactions of the cycloheptenyl carbonate rac-1b with 2-pyr-

imidinethiol afforded the sulfide 5b in a similar yield as in the

cyclohexenyl case but with a lower ee value (entry 3).

Scheme 12. Asymmetric synthesis of cyclic sulfides.

6

aa, 6ab, 6ac, 6ba and 6bb (Scheme 13), which requires a

complete transformation of the corresponding racemic sub-

strates. 2-Pyridinethiol and 4-chlorothiophenol were also

included in this study, since we had observed previously that

these two thiols are capable to act as nucleophiles in the

palladium catalyzed allylic substitution in the presence of

BPA as ligand. The reactions of the cyclohexenyl carbonate

rac-1a with 2-pyrimidinethiol and 2-pyridinethiol were car-

ried out on a 1-5 mmol scale in CH Cl by using 5 mol%

Surprising results were obtained in the reaction of the

cyclopentenyl esters rac-1da and rac-1db with 2-pyrimidine-

Table 7. Palladium-catalyzed asymmetric synthesis of cyclic and acyclic allylic

sulfides.^[

a]

Entry Substrate Thiol

t

Sulfide E:Z

Yield ee

[

h]

[%]

2

1

2

3

4

5

6

7

8

9

rac-1a^[

rac-1a

rac-1b

a]

2-pyrimidinethiol

2-pyridinethiol

2-pyrimidinethiol

24

27

24

0.5 5c

5aa

5ab

5b

±

63

64

61

80

96

84

55

84

34

36

89

68

90

91

50

[

Pd (dba) ] ¥ CHCl , 11 mol% BPA and 1 equiv of the thiol

2 3 3

[a]

under otherwise the same conditions used in the kinetic

resolution. In contrast to 2-pyrimidinethiol, 2-pyridinethiol

and 4-chlorothiophenol were completely soluble in CH Cl

[a]

rac-1da[b] 2-pyrimidinethiol

[

b]

rac-1db

2-pyrimidinethiol

2-pyridinethiol

4-chlorothiophenol 48

2-pyrimidinethiol

2-pyridinethiol

2

[

c]

a]

d]

rac-3aa

rac-3aa^[

48

6aa

6ab

6ac

6ba

6bb

29:1 72

15:1 87

10:1 73

ꢀ 99:1 64

16:1 24

under the conditions used. In order to achieve a complete

conversion of both enantiomers of the carbonates, larger

amounts of the precatalyst and the ligand were required as

compared to the analogous reactions with sulfinate anions.

After TLC indicated the complete conversion of the carbo-

nate, the reaction mixture was exposed to air and the sulfide

isolated by chromatography. As shown by Table 7 the

[a]

rac-3ba

72

c]

10

rac-3ba^[

[

a] 5 mol% [Pd

2

(dba)

and 5.5 mol% BPA. [c] 5 mol% [Pd

(dba) ] ¥ CHCl and 13 mol% BPA.

3

] ¥ CHCl

3

and 11 mol% BPA. [b] 2.5 mol% [Pd

2 3

(dba) ] ¥

CHCl

3

2

(dba) ] ¥ CHCl and 10 mol% BPA.

3

[d] 5 mol% [Pd

2

3

4208

¹ 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

www.chemeurj.org

Chem. Eur. J. 2003, 9, 4202 ± 4221

Palladium Catalyzed Kinetic Resolution

4202±4221

thiol (entries 4 and 5). Not only were the reaction times much

shorter compared with the reaction of the cyclohexenyl

analogues but also the ee values of the sulfide 5c, which was

isolated in high yields, were much lower.

symmetrically substituted substrate ought to be converted by

the Pd ¥ BPA complexto the same set of equilibrating p-allyl

0

palladium intermediates (see below). Thus the ee of the

substitution product should be independent of the absolute

configuration of the starting material. However, it has been

reported that with BPA as ligand and certain racemic

substrates, particularly cyclopentenyl esters, the two enan-

tiomers of the substrate may give the substitution product of

different ee values, a phenomenon termed as ™memory

effect∫.^[Knowledge of the origins of this effect is of

significant importance not only under mechanistic consider-

ations but also for the application of palladium catalyzed

allylic substitution in asymmetric synthesis, where a complete

conversion of the racemic substrate to the product of high ee

value is desired. The low ee values of sulfides 5ab, 5c, 6ab and

6bb, which were obtained through reaction of the cyclic esters

rac-1a, rac-1da and rac-1db and of the acyclic esters rac-3aa

and rac-3ba, respectively, with 2-pyrimidinethiol and 2-pyr-

idinethiol, respectively, at higher catalyst loading could be

ascribed to the operation of this effect. This would be

supported by our observation that in the reaction of the

racemic cyclopentenyl acetate with the thioacetate anion,

which also proceeds under kinetic resolution, the faster

reacting enantiomer gives the substitution product with high

and the slow reacting enantiomer with low enantioselectiv-

ity.^[Several explanations have been advanced as to the

origins of the ™memory effect∫, which are, however, still a

The reactions of the acyclic carbonates rac-3aa and rac-3ba

with 2-pyrimidinethiol, 2-pyridinethiol and 4-chlorothiophe-

nol were carried out in a similar way as those of the cyclic

carbonate (cf. Scheme 13). Table 7 shows that whereas

pyrimidyl sulfides 6aa and 6ba were formed with high ee

values (entries 6 and 9) the pyridyl sulfides 6ab and 6bb were

obtained with low ee values (entries 7 and 10). Interestingly,

the (E)-configured sulfides 6aa, 6ab and 6bb contained minor

amounts of the corresponding (Z)-configured isomers.^[In

the case of the sulfide 6ba a contamination by the corre-

sponding Z isomer could not be detected. Therefore the

racemic Z isomer of 6ba was prepared through reaction of

carbonate rac-3ba with 2-pyrimidinethiol in the presence of

40]

9]

[

Pd (dba) ] ¥ CHCl and bis(diphenylphosphane)propane in

2 3 3

CH Cl at reflux, which yielded a mixture of rac-6ba and its Z

2

isomer in a ratio of 9:1 in 55% yield. Both isomers were

obtained pure by HPLC. Formation of the Z isomers of the

allylic sulfides points to the existence of an equilibrium

between the corresponding (syn,syn)- and (anti,syn)-config-

ured p-allyl complexes (cf. Scheme 1), which are perhaps

interconverting by a p ± s ± p-isomerization mechanism.^[

The palladium catalyzed asymmetric synthesis of allylic tert-

butylsulfides from tert-butylthiol by using BPA as ligand

failed. No sulfide formation was observed upon treatment of

the carbonates rac-1a and rac-3aa with tert-butylthiol in

CH Cl in the presence of 5 mol% [Pd (dba) ] ¥ CHCl and

38]

30]

[40]

matter of debate. Recent investigations of the structures of

0

the Pd ¥ BPA and symmetrically substituted p-allyl palladiu-

m(ii) ¥ BPA complexes had revealed in both cases monomer±

2

3

1

1 mol% BPA at room temperature. Formation of the allylic

oligomer equilibria, the components of which feature a P,P- as

[39a]

[40c,d]

sulfides with pyrimidinethiol (pK 7.13 ), 4-chlorothiophe-

nol (pK 7.06 ) and 2-pyridinethiol (pK 9.81 ) but not

with tert-butylthiol (pK 11.05^[³⁹^d^]) may be related to their

different acidity. The thiols are expected to react with the

leaving group MeOCO₂(pK 5.61 ) under deprotonation

to give the corresponding thiolates, which ought to be the

more reactive nucleophiles [Eq. (1)].

Furthermore the equilibrium between the leaving group

and the thiol could be shifted to the side of the thiolate

because of a decomposition of methyl carbonate with

well as a P,O-coordination of the palladium atom.

It has

a

[39b]

[39c]

been suggested that in the case of BPA as ligand for the

palladium atom the ™memory effect∫ may be mainly due to

1) a combination of a difference in reactivity of the mono-

meric and oligomeric palladium(0) complexes towards the

enantiomers of the substrate and 2) a difference in enantio-

a

À

[39e]

a

selectivity of the reaction of the monomeric and oligomeric p-

allyl intermediates with the nucleophile.^[

40c,d,f]

This ™oligome-

rization scheme∫ would also accommodate the observation

that the catalyst concentration has an effect upon the ee value

[

39e]

[40d,e]

formation of carbon dioxide and methanol [Eq. (2)].

of the substitution product.

In order to shed more light on

the reaction of the racemic cyclic esters^[with the sulfur

nucleophiles, the time dependencies of the conversion of the

substrate and of the ee values of the substitution product in

the reaction of the cyclohexenyl carbonate rac-1a with lithium

tert-butylsulfinate (Figure 1, Table 8) (cf. Scheme 2) were

followed by GC analysis according to the method of internal

standard^[and by NMR spectroscopy and by GC analysis on

chiral stationary phase containing columns, respectively. In

11i]

À

H RS^À

MeOCO

2

RSH > MeOCO

MeOH

2

(1)

(2)

2

H ! CO

2

Thus, because of a much lower acidity of tert-butylthiol,

equilibrium may be unfavorable in this. Alternatively, reac-

tion of a thiol with the BPA containing p-allyl intermediate

could lead to the formation of an p-allyl ± palladium complex

containing the thiolate ligand at the palladium atom, whose

stability in the case of tert-butylthiolate may be such as to

prevent a catalytic cycle.

41a]

addition to these two methods the method of enantiomer

labeling,^[

41b±d]

which does not require an internal standard, was

also used for the determination of the concentration of the

remaining substrate. This was done by the measurement of the

ee values of the substrate before and after the addition of a

certain amount of rac-1a by GC using a chiral stationary

phase containing column.

Aspects of kinetics

™

Memory effect∫: Although BPA displays in solution time-

average C symmetry, its p-allyl palladium complexes do not

While the ee value of the cyclohexenyl sulfone 2aa

remained practically constant until 50% conversion, that of

2

cf. Scheme 1).^[

40d,h]

Nevertheless, both enantiomers of the

(

Chem. Eur. J. 2003, 9, 4202 ± 4221

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¹ 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

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H.-J. Gais et al.

FULL PAPER

values of carbonate ent-1a and sulfone 2aa remained

constant. The reaction of cyclooctenyl carbonate ent-1c with

the sulfinate anion was very slow and only after a reaction

time of 4 d could the formation of 4% of the S configured

sulfone 2c be detected by GC analysis. However, both the

carbonate ent-1c and ulfone 2c had an ee value of 99%. The

observation of a constant ee value of the sulfone 2aa up to

5

0% conversion of rac-1a and 100% conversion of ent-1a

indicates that the enantioselectivity of the substitution step is

independent of the chirality of the substrate, that is, no

™

memory effect∫ is operating. In a final experiment sulfone 2c

of 96% ee was treated with lithium tert-butylsulfinate in the

presence of the precatalyst and BPA, which led to its recovery

with 96% ee. Thus, once sulfone 2c is formed through reaction

of rac-1c with the sulfinate anion it does not suffer a partial

racemization during the course of the reaction.

Figure 1. Time dependencies of c and ee (X) in the palladium-catalyzed

kinetic resolution of carbonate rac-1a with lithium tert-butylsulfinate.

Table 8. Selectivity of the palladium-catalyzed kinetic resolution of the

cyclic carbonate rac-1a with lithium tert-butylsulfinate.

The reactions of the racemic carbonate rac-1a and of the

enantiomeric carbonates 1a and ent-1a with 2-pyrimidinethiol

in CH Cl were studied next (cf. Schemes 5 and 15). The time

Entry

t [min]

Conv rac-1a [%]

ee ent-1a [%]

S

2

1

2

3

4

5

6

2

4

5

10

15

20

23

34

38

49

51

54

29

50

60

90

95

90

110

173

95

81

61

ꢀ 99

carbonate ent-1a increased and reached 96% at approxi-

mately 50% conversion. Having obtained these results,

cyclohexenyl carbonate ent-1a of ꢀ99% ee and cyclooctenyl

carbonate ent-1c of ꢀ99% ee, both of which are the slow

reacting enantiomers in the kinetic resolution of rac-1a and

rac-1c, respectively, were submitted to the palladium-cata-

lyzed reaction with lithium tert-butylsulfinate in the presence

of BPA (Scheme 14). A complete conversion of the cyclo-

hexenyl carbonate ent-1a to the S configured sulfone 2aa of

Scheme 15. Palladium catalyzed substitution of enantioenriched sub-

strates with 2-pyrimidinethiol.

91% ee took place. During the substitution reaction the ee

dependencies of the conversion of the substrates and of the ee

values of the substrates and the sulfide were determined by

GC analysis by the method of internal standard and GC

analysis using a chiral stationary phase containing column,

respectively (Table 9). As revealed by Figure 2 the ee value of

sulfide 5aa remained practically constant throughout the

reaction and that of carbonate ent-1a increased with increas-

ing conversion reaching at 50% conversion a value of 99%. In

two further experiments the highly enantioenriched 1a

(

ꢀ99% ee) and ent-1a (ꢀ99% ee), which were prepared

Table 9. Selectivity of the palladium-catalyzed kinetic resolution of the

cyclic carbonate rac-1a with 2-pyrimidinethiol.

Entry

t [min]

Conv rac-1a [%]

ee ent-1a [%]

S

1

2

3

4

5

6

7

10

15

20

25

30

35

40

29

36

40

46

48

52

53

40

51

64

77

89

97

ꢀ 99

141

34

95

46

164

76

Scheme 14. Palladium catalyzed substitution of enantioenriched sub-

strates with lithium tert-butylsulfinate.

80

4210

¹ 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

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Chem. Eur. J. 2003, 9, 4202 ± 4221

Palladium Catalyzed Kinetic Resolution

4202±4221

particularly appropriate given that a major aim of this work

was the synthetic exploitation of the palladium catalyzed

kinetic resolution. In principle the efficiency of a kinetic

resolution can also be described by the selectivity factor S, the

ratio of the rate constants for the reactions of the enantiomers

of the substrate with the catalyst.^[

1a,b, 42a]

For a palladium

catalyzed kinetic resolution of an allylic substrate obeying

first-order kinetics with regard to the reaction of the substrate

with the catalyst (unimolecularity) S can be calculated

according to Equation (3), which contains as variables the

[42b, 43]

conversion (c) and the ee value of the substrate (ee ).

s

Application of Equation (3) requires, however, a determina-

tion of c and ee of the substrate with a precision not easily to

obtain.^[

Figure 2. Time dependencies of c and ee (X) in the palladium-catalyzed

kinetic resolution of carbonate rac-1a with 2-pyrimidinethiol.

1a,o, 44]

S ln[(1 À c)(1 À ee

s

)]

/

ln[(1 À c)(1 ee

s

)] (0 < c < 1, 0 < ee

s

< 1

(3)

through kinetic resolution of rac-1a by employing BPA and

ent-BPA, were submitted separately to the reaction with the

thiol in the presence of BPA. Both substitution reactions led

to the formation of sulfide 5aa of 87% ee. The ee values of

sulfide 5aa and carbonates 1a and ent-1a remained practically

constant throughout the reaction (Figure 3). These results

show that not only in the reaction of the cyclohexenyl

carbonate rac-1a with tert-butylsulfinate anion but also with

Small errors in the determination of ee and c can lead to

major apparent changes of S with conversion, particularly in

the case of high S values,^[a problem which is often

underestimated or even neglected in the measurement of S.

However, the overall error can be reduced by analysis of a

series of ee versus c values (see below).^[

Calculation of S for the kinetic resolution of the cyclo-

hexenyl carbonate rac-1a with 2-pyrimidinethiol and lithium

tert-butylsulfinate (cf. Figures 1 and 2) according to Equa-

tion (3) gave large values for pairs of ee versus c (cf. Tables 8

and 9); this indicates a high selectivity. This is in accordance

with the isolation of ent-1a with high ee at approximately 50%

conversion in the preparative experiments (cf. Tables 1, 2 and

45]

11m]

2

-pyrimidinethiol no significant ™memory effect∫ is operating.

This is in contrast to the palladium-catalyzed reaction of rac-

a with thioacetate anion in the presence of BPA, where a

1

[30]

powerful ™memory effect∫ was observed. However, in this

case the catalyst loading was much higher.

4

). However, Tables 8 and 9 also reveal major and irregular

changes of S with conversion. Since our measurements of ee

and c had a precision of only Æ0.5 and Æ1.0%, respectively,

we ascribe the change of S with conversion mainly to errors in

[

46]

the determination of both values.

(

Nonlinear regression

Origin 6.1) of S^[

11m]

(Tables 8 and 9) gave S 74 Æ 7 for the

kinetic resolution of rac-1a with lithium tert-butylsulfinate and

S 77 Æ 11 for the kinetic resolution of rac-1a with 2-

pyrimidinethiol.

Overall kinetics: We have investigated the reactions of the

enantiomerically highly enriched carbonates 1a (ꢀ99% ee)

and ent-1a (ꢀ99% ee) with 2-pyrimidinethiol in order to

determine the dependency of the rate of the overall reaction

on the concentration of the substrate. In the case of a first-

order dependency on the substrate measurement of the rate

constants would allow an alternative and direct determination

of the selectivity factor S. Reactions were run in CH Cl at

Figure 3. Time dependencies of ee in the palladium catalyzed reaction of

1

a and ent-1a with 2-pyrimidinethiol.

In summary, it seems that the magnitude of the ™memory

effect∫ depends not only on the substrate and the concen-

tration of the catalyst but also on the nucleophile. Particularly

illustrative examples are the reactions of the cyclopentenyl

ester rac-1da with 2-pyrimidinethiol at higher (cf. Table 7,

entry 4) and with tert-butylsulfinate anion (cf. Table 5) at

lower catalyst concentration. While the reaction with the thiol

delivered sulfide 5c of 34% ee, that with the sulfinate ion gave

sulfone 2d of 89% ee.

2

258C under argon with 1 mmol of carbonate (c

o

À1

250 mmolL ),

0.025 mmol

[Pd (dba) ] ¥ CHCl

3

(c

2

3

À1

6.25 mmolL ), 0.055 mmol of BPA (c 13.75 mmolL )

and 1 mmol 2-pyrimidinethiol. Because of the low solubility

À1

of the thiol (c 4.6 mmolL ), solid thiol was present and

only at the very end of the reaction was a homogenous

mixture formed. Therefore it is assumed that the concen-

tration of the thiol in solution was not only rather low but also

remained constant until nearly all of the substrate had been

consumed. The progress of the reactions was monitored by

Selectivity factor: All of the kinetic resolutions described

above have been characterized in terms of the yields and ee

values of the recovered substrate and the product. This seems

GC using tetradecane as an internal standard. A plot of c/c of

o

Chem. Eur. J. 2003, 9, 4202 ± 4221

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H.-J. Gais et al.

FULL PAPER

the substrate versus logt^[⁴⁷^](Figure 4) and a plot of c versus t

the acyclic sulfides 6aa, 6ba, 6ac, 6ba and 6bb (see below) all

have the same sign of optical rotation, the R configuration was

also assigned to the later sulfides. The absolute configuration

of the cyclohexenyl sulfide 5aa had been assigned previously

by chemical correlation.^[The S configuration was assigned

to the cyclic sulfides 5b and 5ab (see below) on the basis that

(

Figure 5) for four half-lives of the reaction of 1a indicated a

pseudo-zero order kinetics in regard to the allylic substrate

under the special conditions used, where the concentration of

28b]

Figure 4. Time dependency of c of 1a in the palladium catalyzed reaction

with 2-pyrimidinethiol (c/c vs logt).

o

Scheme 16. Determination of absolute configuration.

both have the same sign of optical rotation as 5aa and the

formation of the (S)-configured sulfones in the reaction of

carbonates rac-1a and rac-1b with sulfinate anions (see

below).

Figure 5. Time dependency of c of 1a in the palladium catalyzed reaction

with 2-pyrimidinethiol (c vs t).

The absolute configuration of cyclooctenyl sulfone 4c was

determined by X-ray crystal structure analysis (Figure 6). By

assuming that the substitution of carbonates rac-1a ± c with

tert-butylsulfinate anion in the presence of BPA all proceed

with the same sense of asymmetric induction we assigned the

S configuration to all of the sulfones 2aa, 2ab, 2ac,^[2b and

the catalyst and the nucleophile remained constant. Thus in

this particular case the rate of the overall catalytic reaction is

independent of the substrate concentration. The reaction of

ent-1a with 2-pyrimidinethiol, which was carried out under

the same conditions as in the case of 1a because of

comparison, could be followed only for less than 1 half-live

because of its slowness. Therefore the kinetic data obtained in

this experiment did not allow for a determination of the order

of the reaction of ent-1a with 2-pyrimidinethiol. The obser-

vation of a pseudo-zero order regime in the allylic substrate

for the overall reaction of 1a with 2-pyrimidinethiol implies

that the rate-limiting step involves attack of the thiolate on

23a]

2

c.

[5a]

the p-allyl intermediate. Both, pseudo-zero order

and

pseudo-first order kinetics^[

11c]

with regard to the allylic

substrate had been previously observed in palladium cata-

lyzed allylic substitution with C-nucleophiles in the presence

of chiral ligands other than BPA.

Figure 6. Structure of sulfone 2c in the crystal.

Determination of absolute configuration

The absolute configuration of sulfide 6aa was determined by

Synthesis of highly enantioenriched allylic alcohols

chemical correlation as shown in Scheme 16.^[Reduction of

48]

sulfide 6aa with diimide gave the saturated sulfide 7. The (R)-

was converted via

mesylate 8b to the saturated sulfide ent-7 of 96% ee. Since

The completion of the partial conversion of the racemic allylic

alcohols rac-1a ± c, rac-3aa and rac-3ba to the corresponding

enantioenriched allylic alcohols via palladium-catalyzed res-

configured alcohol 8a of 96% ee^[

49]

4212

¹ 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

www.chemeurj.org

Chem. Eur. J. 2003, 9, 4202 ± 4221

Palladium Catalyzed Kinetic Resolution

4202±4221

olution required the hydrolysis of the corresponding enan-

tioenriched carbonates (Scheme 17). The reaction of the

cyclic carbonates ent-1a ± c and of the acyclic carbonates ent-

Conclusion

The palladium-catalyzed reactions of symmetrically disubsti-

tuted racemic allylic carbonates, being either cyclic or acyclic,

with sulfinate anions and 2-pyrimidinethiol in the presence of

BPA as ligand proceed with excellent levels of enantioselec-

tivity in both kinetic resolution and substitution. The effi-

ciencies of the kinetic resolutions are described in terms of ee

values and yields of recovered substrates and substitution

products rather than by the selectivity factors. This seems to

be more appropriate given the problems associated with the

accurate experimental measurement of the later. The state-

ment of a selectivity factor based on the measurement of a

single ee versus c pair and without error analysis may lead to

questionable results, in particular in the case of high

selectivities. However, a more reliable S value can be obtained

by measurement and analysis of a series of ee versus c pairs. In

accordance with previous observations the faster reacting

enantiomer of the substrate and the preferentially formed

substitution product have the same absolute configuration.

While the kinetic resolution allows for the synthesis of

enantiomerically highly enriched cyclic and acyclic allylic

alcohols, the substitution provides for an asymmetric synthesis

of enantiomerically highly enriched allylic sulfones, bearing

various groups at the sulfur atom and allylic sulfides, carrying

an aromatic group at the sulfur atom. The allylic substitutions

with thiols required higher amounts of palladium catalyst as

compared to those with sulfinate anions. Furthermore, sulfide

formation in the presence of BPA was observed only with

3

aa and ent-3ba with NaOH in water led to the isolation of

[50a]

[50b]

the highly enantioenriched alcohols 9a ± c,

10a

and

50c]

1

0b,^[respectively, in medium to high yields (Table 10). It

should be noted that because of the high selectivity of the

kinetic resolution of the racemic carbonates and because of

2

-pyrimidinethiol, 2-pyridinethiol and 4-chlorophenylthiol

but not with tert-butylthiol. While the different pK values

a

of the thiols used may play a decisive role, it can not be

excluded that the formation of p-allyl palladium thiolate

complexes is also an important factor in the palladium

catalyzed allylic substitution with thiols. An equilibrium

between a palladium thiolate complexand an p-allyl thiolate

ion pair could perhaps account for the higher amount of

catalyst required.

According to experiments with racemic and enantioen-

riched cyclohexenyl carbonate and tert-butylsulfinate anion

and 2-pyrimidinethiol the ee value of the substitution product

is independent of the chirality of the substrate, that is, no

Scheme 17. Synthesis of enantiomerically highly enriched cyclic and

acyclic allylic alcohols.

Table 10. Synthesis of highly enantioenriched cyclic and acyclic allylic

alcohols.

Carbonate Alcohol Yield [%] ee [%] [a]²²

D

ent-1a

ent-1b

ent-1c

ent-4a

ent-4b

9a

9b

9c

10a

10b

65

94

75

90

94

ꢀ 99

99

110.8 (c 1.20, CH

28.2 (c 1.03, CH

À 52.4 (c 1.46, CH

À 18.5 (c 1.05, CH

4.0 (c 0.99, CH

2

Cl

2

Cl

2

Cl

2

Cl

2

Cl

2

)

™

memory effect∫ is operating. However, a ™memory effect∫

seems to operate in the case of the reaction of the cyclo-

hexenyl ester with 2-pyridinethiol and, in particular, in that of

the cyclopentenyl esters with 2-pyrimidinethiol. Whether the

formation of equilibrium mixtures of monomers and oligom-

0

II

ers of the Pd ¥ BPA and p-allyl Pd ¥ BPA complexes are

mainly responsible for the ™memory effect∫ remains to be

seen.

principle the alcohols 9a ± c, 10a and 10b, can be obtained in

an enantiomeric purity not easily attainable by the known

methods of asymmetric synthesis.^[The absolute configura-

tions of the alcohols 9a ± c and 10a and thus of the carbonates

ent-1a ± c and ent-3aa, respectively, were determined by

13]

Experimental Section

comparison of their chiroptical data with those reported in

General: All reactions were carried out in absolute solvents under an argon

atmosphere with syringe and Schlenk techniques in oven-dried glassware.

_t_h_e_l_i_t_e_r_a_t_u_r_e_.[50] Determination of the absolute configuration

2 2 2

Cl was distilled under argon from CaH

. The ligands POX^[and

53]

CH

of alcohol 10b and thus of carbonate ent-3ba was achieved

through its hydrogenation to the corresponding saturated

alcohol.^[

BPA,^[the precatalysts [Pd

10]

(dba)

] ¥ CHCl

[33]

3 5 2

and [Pd(C H )Cl]

,^[³⁷^]and

lithium tert-butylsulfinate were prepared according to the literature. H

and ¹³C NMR spectra were recorded on a Varian VXR 300, Varian Gemini

2

3

[32]

1

51, 52]

Chem. Eur. J. 2003, 9, 4202 ± 4221

www.chemeurj.org

¹ 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

4213

H.-J. Gais et al.

FULL PAPER

3

(

00, Varian Inova 400 and Varian Unity 500 spectrometer. Chemical shifts

bar and the flask was evacuated and refilled with argon. Then the

precatalyst and the ligand were dissolved under stirring through addition of

CH Cl or THF. The solution of [Pd (dba) ] ¥ CHCl and BPA initially

2 2 2 3 3

1

13

H, C) are reported relative to Me

4

Si (d 0 ppm). Splitting patterns in

1

the H NMR spectra are designated as s, singlet; d, doublet; dd, double

doublet; t, triplet; q, quartet; quin, quintet; m, multiplet. ¹³C NMR spectra

are denoted as (u) for carbons with zero or two attached protons or (d) for

carbons with one or three attached protons, as determined from ATP pulse

sequence. IR spectra were recorded with a Perkin ± Elmer PE 1759-FT

instrument. GC analyses were performed by using Chrompack CP-9000

attained a dark violet color which gradually changed to bright red-orange

(approximately 15 min). Then the substrate was added. Stirring of the

mixture was continued until the color of the solution had changed from red-

orange to yellow (approximately 15 min). The sulfinate salt and THAB

were placed in a second Schlenk flask which was evacuated and refilled

with argon. Then the salt and the phase transfer catalyst were dissolved

through addition of degassed water. Alternatively, a suspension of the

sulfinate salt in THF was prepared in the same way. Both the solution

containing the sulfinate salt and the solution containing the substrate were

cooled in an ice bath and the solution or suspension of the sulfinate salt was

added under argon with a syringe to the solution containing the catalyst and

the substrate. Subsequently, the reaction mixture was either stirred at 08C

or warmed to room temperature and stirred at this temperature for the time

given and the progress of the reaction was monitored by TLC, GC or

[

DB-5 (30 m, 0.32 mm; 50 kPa H

2,3-O-dipentyl-6-O-methyl)-g-cyclodextrin (25 m, 0.25 mm; 100 kPa H

Macherey ± Nagel LipodexE: octakis-(2,6-di- O-pentyl-3-O-butyryl)-g-cy-

clodextrin (25 m, 0.25 mm; 100 kPa H )] and Carlo Erba Mega Series 5300

CP-Chirasil-Dex-CB (CP-bI-CB): permethyl-b-cyclodextrin (25 m,

2

); Macherey ± Nagel Lipodex g: octakis-

(

2

);

2

[

0

6

.25 mm; 100 kPa H

-O-tert-butyldimethylsilyl)-b-cyclodextrin (25 m, 0.25 mm, 100 kPa H

2

); Hydrodex-b-6-TBDM: heptakis(2,3-di-O-methyl-

)]

2

instruments. GC-MS analyses were run on a Magnum Finnigan (HT-5:

5 m, 0.25 mm; 50 kPa He, CI, 40 eV, MeOH). HPLC analyses were

2

1

performed on a Waters 600 (UV 485; RI 410) instrument with a Baker

Chiralcel OD-H column. MS spectra were recorded on a Varian MAT 212S

H NMR spectroscopy. Then saturated aqueous NaCl was added and the

mixture was stirred at room temperature under exposure to air for 1 h.

(

EI, 70 eV) instrument. Only decisive signals of the MS spectra and those

Then CH

2

Cl

2

was added and the aqueous phase was extracted with CH

2 2

Cl .

with an intensity higher than 10% are listed. Column chromatography was

carried out on Merck silica gel 60, 0.063 ± 0.200 mm. TLC was done with

Merck silica gel 60 F254 aluminum plates. Elementary analyses were carried

out by the microanalytical laboratories of the Institut f¸r Organische

Chemie at the RWTH Aachen. Optical rotary powers were measured on a

Perkin ± Elmer 241 instrument at approximately 228C.

The combined organic phases were dried (MgSO

4

) and concentrated in

vacuo. Chromatography or kugelrohr distillation gave the sulfone and the

allylic substrate. In kinetic resolution experiments stirring of the mixture

under exposure to air was omitted.

Kinetic resolution of carbonate rac-1a with lithium-tert-butylsulfinate: (S)-

3

-(2-methyl-propan-2-sulfonyl)-cyclohexene (2aa) and (R)-carbonic acid

cyclohex-2-enyl methyl ester (ent-1a): Following GP1, a mixture of

carbonate rac-1a (1.57 g, 10 mmol), [Pd (dba) ] ¥ CHCl (155 mg,

.15 mmol) and BPA (311 mg, 0.45 mmol) in CH Cl (10 mL) was treated

under stirring at 08C successively with a suspension of LiO StBu (2.56 g,

0 mmol) and THAB (360 mg, 0.8 mmol) in CH Cl (15 mL) and degassed

X-ray Analyses: The crystal data and the most salient experimental

parameters used in the X-ray measurement and in the crystal structure

analysis are reported in Table 11. The crystal structure was solved using

direct methods as implemented in the XTAL3.7 package of crystallo-

2

3

0

2

[

54a]

graphic routines.

The molecular structure was visualized with the

2

[

54b,c]

program SCHAKAL 92.

Figure 6 has been determined by the method of Flack^[

The absolute configuration of 2c as shown in

water (8 mL). Quenching of the mixture after stirring it at 08C for 45 min

54d]

(cabs 0.01(4)).

gave a mixture of carbonate ent-1a and sulfone 2aa in a ratio of 46:54

1

(

H NMR). Chromatography (hexane/EtOAc 7:1, 1% NEt

3

) afforded

1

sulfone 2aa (999 mg, 49%) of 98% ee { H NMR, 400 MHz, CDCl

3

,

Table 11. Crystal data and parameters of data collection for 2c.

formula

3

0 mol%, [Eu(hfc)

3

]}: d (tBu) (2aa) 1.78, d (tBu) (ent-2aa) 1.80] as a

12 22 2

C H O S

colorless solid and carbonate ent-1a (536 mg, 34%) of 99% ee [GC,

M

r

230.37

LipodexE, t

R

(ent-1a) 13.3 min, t

R

(1a) 13.8 min] as a colorless oil.

Cl ); m.p. 558C; the spectro-

color and habit

crystal size [mm], ca.

crystal system

space group

a [ä]

colorless, irregular

0.3 Â 0.3 Â 0.3

Sulfone 2aa: [a]²

scopic data were identical to those reported in the literature.

0

À177.0 (c 1.01, CH

D

2

[

7]

orthorhombic

Carbonate ent-1a: [a]²

CHCl

): d 1.56 ± 2.16 (m, 6H), 3.77 (s, 3H), 5.09 ± 5.14 (m, 1H), 5.78 (ddt,

J 10.0, 3.7, 2.0 Hz, 1H), 5.97 (dtd, J 10.0, 3.7, 1.3 Hz, 1H); C NMR

(75 MHz, CHCl

0

168.0 (c 1.73, CH

1

P2

1

2

1

2

1

(19)

2 2

Cl ); H NMR (300 MHz,

D

6.051(2)

3

1

3

b [ä]

15.205(1)

27.643(3)

2543.3(9)

c [ä]

): d 18.6 (u), 24.9 (u), 28.2 (u), 54.5 (d), 71.9 (d), 125.0

3

V [ä ]

(d), 133.3 (d), 155.5 (u); IR (neat): nÄ 3084 (w), 3061 (w), 3030 (w), 2983

[

a]

Z

2 Â 4

(w), 2937 (w), 1744 (s), 1496 (m), 1450 (m), 1371 (m), 1305 (m), 1255 (s),

À3

À1

1

calcd [gcm

]

1.203

2.098

1005 (m), 991 (m), 964 (m), 789 (m), 748 (m), 697 (m), 541 cm (m); MS:

À1

m [mm

]

m/z (%): 156 (11) [M ], 111 (11), 97 (26), 84 (12), 81 (41), 80 (55), 79 (74),

diffractometer

T [K]

radiation

l [ä]

CDA4 Enraf-Nonius

150

CuKa

1.54179

w/2q

74.9

6278

I > 2s(I)

on F

271

77 (14), 74 (59), 59 (100), 53 (11), 46 (18), 45 (73); elemental analysis calcd

(%) for C

Kinetic resolution of carbonate rac-1b with lithium tert-butylsulfinate: (S)-

-(2-methyl-propan-2-sulfonyl)-cycloheptene (2b) and (R)-carbonic acid

cyclohept-2-enyl methyl ester (ent-1b): Following GP1, a mixture of

carbonate rac-1b (1.77 g, 10 mmol), [Pd (dba) ] ¥ CHCl (155 mg,

.15 mmol) and BPA (311 mg, 0.45 mmol) in CH Cl (10 mL) was treated

under stirring at 08C successively with a suspension of LiO StBu (2.56 g,

0 mmol) and THAB (360 mg, 0.8 mmol) in CH Cl (15 mL) and degassed

8 12 3

H O : C 61.52, H 7.74; found: C 61.34, H 7.79.

3

scan method

V

max [8]

[

b]

2

3

no. of data coll.

obsn criterion

refinement

0

2

no. params refd

no. data obsd in refmnt

water (8 mL). Quenching of the mixture after stirring it at 08C for 4 h gave

4803

1

a mixture of carbonate ent-1b and sulfone 2b in a ratio of 47:53 ( H NMR).

[

c]

R, R

w

0.058/0.073

À 0.57/ 0.79

2.627

Chromatography (hexane/EtOAc 7:1, 1% NEt

3

) afforded sulfone 2b

, 30 mol%,

À3

D(1) [eä

]

1

(

993 mg, 46%) of 95% ee { H NMR, 400 MHz, CDCl

3

GOF

[

Eu(hfc)

(ent-2b) 35.07 min, t

carbonate ent-1b (580 mg, 33%) of 94% ee [GC, LipodexE,

1b) 20.78 min, t

3

]}: d (tBu) (2b) 2.06, d (tBu) (ent-2b) 2.21; GC, Lipodex-E,

[

a] Two symmetrically independent species. [b] Friedel pairs col-

t

R

(2b) 34.58 min] as a colorless solid and

2

0.5

t

(ent-

lected. [c] RSjjF

o

jÀjF

c

jj/SjF

o

j ;

R

w

[Sw(jF

o

jÀjF

c

j) /SwjF

o

j ]

;

R

2

(1b) 20.93 min] as a colorless oil. Sulfone 2b: [a]

20

w1/s (F

o

) where F

o

and F

c

are observed and calculated structure factors.

R

D

À95.4 (c 1.01, CH

2

Cl

2

); m.p. 488C; the spectroscopic data were identical

[

7]

to those reported in the literature.

Carbonate ent-1b: [a]² 33.2 (c 1.29, CH Cl ); H NMR (400 MHz,

0

1

General procedure for the asymmetric synthesis of allylic sulfones and

kinetic resolution of allylic carbonates with sulfinate anions (GP1): The

precatalyst and ligand were placed in a Schlenk flask containing a stirring

D

2

CDCl ): d 1.34 ± 2.30 (m, 8H), 3.77 (s, 3H), 5.26 (br d, J 7.7 Hz, 1H),

3

1

3

5.56 ± 5.76 (m, 1H), 5.79 ± 5.90 (m, 1H); C NMR (100 MHz, CDCl ): d

3

4214

¹ 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

www.chemeurj.org

Chem. Eur. J. 2003, 9, 4202 ± 4221

Palladium Catalyzed Kinetic Resolution

4202±4221

mixture was stirred at room temperature for 20 min and then cooled to 08C.

2

1

6.5 (u), 26.6 (u), 28.5 (u), 32.8 (u), 54.5 (d), 78.2 (d), 131.8 (d), 133.1 (d),

In a second Schlenk flask were placed under argon LiO

2

StBu (2.62 g,

55.4 (u); IR (neat): nÄ 2930 (m), 2857 (w), 1747 (s), 1444 (s), 1356 (w),

2

0 mmol), THAB (300 mg, 0.7 mmol) and CH Cl (20 mL) and the mixture

2

À1

326 (m), 1268 (s), 1203 (w), 1127 (w), 977 (m), 944 (m), 794 cm (m); MS:

was cooled to 08C and treated with degassed water (10 mL). Than the

solution of the sulfinate salt was added to the solution containing the

catalyst and the resulting mixture was treated with carbonate rac-1a

m/z (%): 170 (2) [M ], 95 (7), 94 (15), 79 (29), 77 (4), 67 (5), 59 (5), 55 (7);

elemental analysis calcd (%) for C

H 8.26.

8 12 3

H O : C 63.51, H 8.29; found: C 63.30,

(

1.77 g, 11 mmol). The mixture was stirred at 08C and samples of the

organic phase (0.1 mL) were withdrawn with a syringe after 2, 4, 5, 10, 15,

0 and 30 min under exposure to air and analyzed by GC. After a total

Kinetic resolution of carbonate rac-1c with lithium-tert-butylsulfinate: (S)-

-(2-methyl-propan-2-sulfonyl)-cyclooctene (2c) and (R)-carbonic acid

3

2

cyclooct-2-enyl methyl ester (ent-1c)

reaction time of 45 min phases were separated and the aqueous phase was

extracted with CH Cl . The combined organic phases were dried (MgSO )

On a 9.3 mmol scale: Following GP1, a mixture of carbonate rac-1c (1.71 g,

2

4

9

.3 mmol), [Pd

2

(dba)

Cl

3

] ¥ CHCl

(10 mL) was treated under stirring at 08C succes-

StBu (2.56 g, 20 mmol) and THAB

(15 mL) and degassed water (8 mL).

3

(145 mg, 0.14 mmol) and BPA (288 mg,

and concentrated in vacuo. Chromatography (hexane/EtOAc 7:1) afforded

1

0

.42 mmol) in CH

2

sulfone 2aa (990 mg, 45%) of 96% ee [ H NMR, 400 MHz, CDCl ,

3

sively with a suspension of LiO

220 mg, 0.5 mmol) in CH Cl

2

30 mol%, Eu(hfc) ] as a colorless solid and carbonate ent-1a (498 mg,

3

(

2

29%) of ꢀ99% ee (GC, LipodexE) as a colorless oil.

Substitution of carbonate ent-1a with lithium tert-butylsulfinate: Following

Quenching of the mixture after stirring it successively at 08C for 4 h and

at room temperature for 20 h gave a mixture of carbonate ent-1c and

sulfone 2c in a ratio of 42:58 ( H NMR). Chromatography (hexane/EtOAc

GP1, BPA (16 mg, 2.3 mmol), [Pd

carbonate ent-1a (79 mg, 0.5 mmol) of ꢀ99% ee in CH

treated with LiO StBu (128 mg, 1 mmol) and THAB (13 mg, 2.99 mmol) in

CH Cl (3 mL) and degassed water (4 mL). Then the mixture was stirred at

2

(dba)

3

] ¥ CHCl

3

(8 mg, 0.77 mmol) and

1

2

Cl (3 mL) were

2

1

0:1, 1% NEt

3

) furnished sulfone 2c (1.03 g, 48%) of 96% ee [GC, Lipodex

(2c) 134.96 min] as a colorless solid and

(ent-

2

E, t

R

(ent-2c) 134.63 min, t

R

2

carbonate ent-1c (584 mg, 34%) of ꢀ99% ee [GC, LipodexE,

t

R

room temperature for 18 h. Chromatography (hexane/EtOAc 7:1) afforded

1

c) 21.97 min, t

R

0

(1c) 23.63 min] as a colorless oil.

135.4 (c 1.99, CH Cl

); m.p. 558C; ¹H NMR

): d 1.27 ± 1.38 (m, 2H), 1.42 (s, 9H), 1.44 ± 1.58 (m,

H), 1.71 ± 1.85 (m, 4H), 2.01 ± 2.11 (m, 1H), 2.17 ± 2.27 (m, 2H), 4.16 ± 4.23

1

sulfone 2aa (88 mg, 87%) of 91% ee [ H NMR, 400 MHz, CDCl

3

,

Sulfone 2c: [a]²

D

2

3

0 mol% Eu(hfc)

Substitution of carbonate ent-1c with lithium tert-butylsulfinate: Following

GP1, BPA (31 mg, 0.045mmol), [Pd (dba) ] ¥ CHCl (15 mg, 0.015 mmol)

and carbonate ent-1c (194 mg, 1.05 mmol) of 99% ee in CH Cl (3 mL)

were treated with LiO StBu (250 mg, 2.1 mmol) and THAB (22 mg,

.05 mmol) in CH Cl (3 mL) and degassed water (2 mL). Then the mixture

3

] as a colorless solid.

(

400 MHz, CDCl

3

1

3

2

3

(

m, 1H), 5.70 (m, 1H), 5.92 (m, 1H); C NMR (75 MHz, CDCl

3

): d 24.09

2

(

u), 24.31 (d), 26.87 (u), 27.33 (u), 27.40 (u), 29.24 (u), 55.35 (d), 61.02 (u),

2

1

25.46 (d), 132.80 (d); GC-MS (EI, 70 eV) m/z (%): 231 (1.5) [M ], 123

0

2

(

100), 109 (18); IR (KBr): nÄ 2925 (s), 2857 (s), 1479 (m), 1450 (m), 1395

was stirred at room temperature for 4 d. GC showed formation of 4.5%

sulfone 2c of 99% ee (GC, LipodexE) and 95% carbonate ent-1c of 99%

ee (GC, LipodexE).

w), 1371 (w), 1305 (s), 1286 (s), 1263 (s), 1244 (s), 1222 (m), 1197 (m), 1110

s), 1011 (w), 975 (w), 961 (w), 942 (w), 891 (w), 873 (w), 802 (w), 762 (m),

À1

7

24 (m), 664 (s), 583 cm (s); elemental analysis calcd (%) for C12

H

22

O

2

S:

C 62.58, H 9.63; found: C 62.55, H 9.64.

Kinetic resolution of carbonate rac-1a with sodium p-tolylsulfinate: (S)-3-

(tolyl-sulfonyl)-cyclohexene (2ab) and (R)-carbonic acid cyclohex-2-enyl

methyl ester (ent-1a): Following GP1, BPA (63 mg, 0.09 mmol),

_e_n_t_-₁_c_:_[_a_]₂0

1

D

À78.4 (c 1.02, CH

2 2 3

Cl ); H NMR (400 MHz, CDCl

): d

1

.35 ± 1.45 (m, 1H), 1.47 ± 1.75 (m, 6H), 1.94 ± 2.03 (m, 1H), 2.09 ± 2.18 (m,

H), 2.20 ± 2.30 (m, 1H), 3.77 (s, 3H), 5.48 ± 5.56 (m, 2H), 5.66 ± 5.73 (m,

_H₎_;₁3C NMR (100 MHz, CDCl

2 3 3

[Pd (dba) ] ¥ CHCl (31 mg, 0.03 mmol) and rac-1a (313 mg, 2.0 mmol) in

): d 23.27 (u), 25.82 (u), 26.36 (u), 28.80

CH Cl (6 mL) were treated with NaO STol (713 mg, 4 mmol) and THAB

2

3

(

2

1

u), 34.99 (u), 54.56 (d), 76.42 (d), 130.12 (d), 130.13 (d), 155.34 (u); GC-MS

(45 mg, 0.1 mmol) in CH

2

Cl

2

(6 mL) and degassed water (3 mL). After

stirring the mixture at 08C for 30 min a mixture of carbonate ent-1a and

sulfone 2ab in a ratio of 32:68 was isolated. Chromatography (hexane/

EtOAc 7:1) afforded sulfone 2ab (234 mg, 60%) of ꢀ99% ee (HPLC, OD-

H column) as a colorless solid and carbonate ent-1a (74 mg, 24%) of

ꢀ99% ee (GC, LipodexE) as a colorless oil. Sulfone 2ab: m.p. 588C;

CI, 70 eV): m/z (%): 184 [M ], 109 (100), 107 (17), 75; IR (capillary): nÄ

930 (s), 2858 (m), 1747 (s), 1443 (s), 1333 (m), 1305 (m), 1271 (s), 1149 (w),

À1

135 (w), 1021 (m), 993 (w), 950 (s), 794 (m), 757 (m), 723 cm (w);

elemental analysis calcd (%) for C10

H 8.63.

16 3

H O : C 65.19, H 8.75; found C 65.21,

2

0

1

[

1

a]

D

À133.7 (c 1.02, CH

2

Cl

2

); H NMR (400 MHz, CDCl

3

): d 1.44 ±

On a 30 mmol scale: Following GP1, a mixture of carbonate rac-1c (5.70 g,

1.0 mmol), [Pd (dba) ] ¥ CHCl (310 mg, 0.30 mmol) and BPA (830 mg,

.2 mmol) in CH Cl (10 mL) was treated under stirring at 08C successively

with a suspension of LiO StBu (7.70 g, 60 mmol) and THAB (650 mg,

.5 mmol) in CH Cl (50 mL) and degassed water (20 mL). Quenching of

.56 (m, 1H), 1.72 ± 1.91 (m, 2H), 1.94 ± 2.03 (m, 3H), 2.45 (s, 3H), 3.73 (m,

3

2

3

1

H), 5.79 (dq, J 10.1, 2.4 Hz, 1H), 6.06 (dq, J 10.1, 2.2 Hz, 1H), 7.32 ±

1

2

1

3

7.38 (pseudo-d, 2H), 7.74 (pseudo-d, 2H); C NMR (100 MHz, CDCl ):

2

d 19.51 (u), 21.62 (d), 22.69 (u), 24.34 (u), 61.74 (d), 118.52 (d), 128.98 (d),

1

2

1

29.41 (d), 134.18 (u), 134.94 (d), 144.36 (u); MS: 236 (0.3) [M ], 157 (39),

the mixture after stirring it at room temperature for 26 h gave a mixture of

carbonate ent-1c and sulfone 2c in a ratio of 42:58 ( H NMR). Chroma-

1

91 (7), 82 (10), 81 (100), 80 (13), 79 (22), 65 (7), 53 (6); IR (KBr): nÄ 3038

(

m), 2941 (m), 2864 (m), 2837 (m), 1596 (m), 1497 (m), 1449 (m), 1405 (w),

tography (hexane/EtOAc 10:1, 1% NEt

4%) of 97% ee (GC, LipodexE) as a colorless solid and carbonate ent-1c

2.34 g, 41%) of 95% ee (GC, LipodexE) as a colorless oil.

On a 50 mmol scale: Following GP1, a mixture of carbonate rac-1c (9.80 g,

3.0 mmol), [Pd (dba) ] ¥ CHCl (530 mg, 0.50 mmol), BPA (1.05 g,

.5 mmol) and tetradecane (1.25 g, 6.3 mmol) in CH Cl (50 mL) was

treated under stirring at 08C successively with a suspension of LiO StBu

10.0 g, 78 mmol) and THAB (1.086 g, 2.5 mmol) in CH Cl (75 mL) and

3

) furnished sulfone 2c (3.14 g,

1

8

288 (s), 1211 (w), 1185 (w), 1144 (s), 1086 (s), 1044 (m), 984 (m), 960 (w),

94 (m), 872 (m), 819 (s), 727 (w), 800 (m), 772 (w), 735 (m), 710 (s);

4

(

16 2

elemental analysis calcd (%) for C13H O S: C 66.07, H 6.82; found: C

6

5.90, H 6.91.

5

2

3

Kinetic resolution of carbonate rac-1a with sodium phenylsulfinate: (S)-3-

phenyl-sulfonyl)-cyclohexene (2ac) and (R)-carbonic acid cyclohex-2-

enyl methyl ester (ent-1a): Following GP1, BPA (60 mg, 0.09 mmol),

Pd (dba) ] ¥ CHCl (31 mg, 0.03 mmol) and rac-1a (316 mg, 2.0 mmol) in

CH Cl (6 mL) were treated with NaO SPh (656 mg, 4 mmol) and THAB

(40 mg, 0.09 mmol) in CH Cl (6 mL) and degassed water (4 mL). After

1

2

(

2

(

2

[

2

3

degassed water (30 mL). Quenching of the mixture after stirring it at room

temperature for 48 h gave a mixture of carbonate ent-1c and sulfone 2c in a

2

1

ratio of 42:58 ( H NMR). Chromatography (hexane/EtOAc 10:1, 1%

NEt ) furnished sulfone 2c (5.86 g, 48%) of 89% ee (GC LipodexE).

Crystallization from hexane/ethyl acetate gave sulfone 2c (4.88 g, 40%) of

2

stirring the mixture at 08C for 30 min a mixture of carbonate ent-1a and

sulfone 2ac in a ratio of 38:62 was isolated. Chromatography (hexane/

EtOAc 7:1) afforded sulfone 2ac (252 mg, 56%) of ꢀ99% ee [GC, Lipodex

3

2

0

ꢀ

99% ee (GC, LipodexE); [ a]

D

148.3 (c 2.81, CH

2 2

Cl )) as a colorless

E, t

R

(3b) 27.0 min, t

R

(3b) 26.57, t (ent-3b) 27.64 min] as a colorless

R

solid. Besides sulfone 2c carbonate ent-1c (3.81 g, 39%) of ꢀ99% ee (GC,

oil and carbonate ent-1a (85 mg, 27%) of ꢀ99% ee (GC, LipodexE).

LipodexE) was isolated as a colorless oil.

2

0

1

Determination of the conversion in the kinetic resolution of carbonate rac-

Sulfone 2ac: [a]

CDCl

): d 1.26 ± 1.56 (m, 1H), 1.70 ± 2.01 (m, 5H), 3.76 (m, 1H), 5.7 ±

5.82 (dq, J 10.0, 2.35 Hz, 1H), 6.05 ± 6.13 (m, 1H), 7.53 ± 7.69 (m, 3H),

D

À134.7 (c 1.02, CH

2 2

Cl ); H NMR (300 MHz,

1

a in the reaction with lithium tert-butylsulfinate by the method of internal

standard: BPA (311 mg, 0.45 mmol), [Pd (dba) ] ¥ CHCl (155 mg,

.15 mmol) and tetradecane (253 mg, 1.27 mmol) were placed under argon

in a Schlenk flask. Subsequently CH Cl (10 mL) was added and the

3

2

3

1

3

0

7.86 ± 7.90 (m, 2H); C NMR (75 MHz, CDCl

3

): d 19.55 (u), 22.75 (u),

2

24.43 (u), 61 85 (d), 118.53 (d), 129.08 (d), 129.20 (d), 133.76 (d), 135.43 (d).

Chem. Eur. J. 2003, 9, 4202 ± 4221

www.chemeurj.org

¹ 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

4215

H.-J. Gais et al.

FULL PAPER

Kinetic resolution of carbonate rac-3aa with lithium tert-butylsulfinate:

(30), 59 (10), 57 (15), 53 (28), 52 (16); elemental analysis calcd (%) for

(

R,E)-4-(2-methyl-propan-2-sulfonyl)-2-pentene (4a) and (S,E)-carbonic

C

9

H

12

N

2

S: C 59.97, H 6.71, N 15.54; found: C 59.76, H 6.95, N 15.22.

acid pent-2-enyl methyl ester (ent-3aa): Following GP1, BPA (315 mg,

20

Carbonate ent-3aa: [a]

D

À64.48 (c 1.04, CHCl

3

).

0

9

1

.45 mmol), [Pd

.92 mmol) in CH

9.5 mmol) and THAB (380 mg, 0.87 mmol) in CH

2

(dba)

3

] ¥ CHCl

(10 mL) were treated with LiO

Cl

3

(150 mg, 0.15 mmol) and rac-3aa (1.43 g,

Kinetic resolution of carbonate rac-3ba with 2-pyrimidinethiol: 2-((R,E)-1-

ethyl-pent-2-enylsulfanyl)-pyrimidine (6ba) and (S)-carbonic acid 1-ethyl-

pent-2-enyl methyl ester (ent-3ba): Following GP2, a mixture of carbonate

rac-3ba (1.76 g, 10.3 mmol), [Pd

BPA (760 mg, 1.1 mmol) in CH Cl

nethiol (1.12 g, 10 mmol) in CH Cl

2

Cl

2

StBu (2.50 g,

2

(20 mL) and

degassed water (3 mL). Termination of the reaction after stirring the

mixture at room temperature for 25 min gave a mixture of carbonate ent-

2

(dba)

(20 mL) was treated with 2-pyrimidi-

(20 mL) in CH Cl (20 mL). After 2 d

3 3

] ¥ CHCl (517 mg, 0.5 mmol) and

2

3

aa and sulfone 4a in a ratio of 27:73. Chromatography (hexane/EtOAc

2

1

0:1) afforded sulfone 4a (1.28 g, 68%) of 96% ee [GC, LipodexE,

t

R

conversion of carbonate rac-3ba was approximately 50%. Purification by

flash chromatography (pentane/diethyl ether 7:1 ! 3:1) gave sulfide 6ba

(

4a) 32.70 min, t

R

(ent-4a) 33.73 min] as a colorless solid and carbonate

ent-3aa (270 mg, 19%) of ꢀ99% ee [GC, LipodexE, t

R

(3aa) 5.95 min, t

R

(

962 mg, 44%) of 92% ee [HPLC, Chiralcel OD-H column, hexane/iPrOH

2

0

(

ent-3aa) 6.42 min] as a colorless oil. Carbonate ent-3aa: [a]

D

À64.38

9

5:5, t (6ba) 10.13 min, t

492 mg, 28%) of ꢀ99% ee [GC, Hydrodex-b-6-TBDM, t

6.49 min].

R

(ent-6ba) 8.99 min] and carbonate ent-3ba

1

c 0.90, CH

2

Cl

2

); H NMR (300 MHz, CDCl

3

): d 1.35 (d, J 6.7 Hz,

(

2

R

(ent-3ba)

3

1

2

1

8

H), 1.69 (ddd, J 6.4, 1.7, 0.7 Hz, 3H), 3.76 (s, 3H), 5.15 (quin, J 6.4 Hz,

H), 5.50 (ddq, J 15.1, 6.4, 1.7 Hz, 1H), 5.77 (dqd, J 15.4, 6.4, 1.0 Hz,

Sulfide 6ba: [a]² 209.4 (c 2.11, CHCl ). H NMR (400 MHz, CDCl ):

0

1

H); ¹³C NMR (75 MHz, CDCl

): d 17.7 (d), 20.4 (d), 54.5 (d), 75.5 (d),

D

3

d 0.95 (t, J 7.4 Hz, 3H), 1.02 (t, J 7.4, 3H), 1.80 ± 1.94 (m, 2H), 1.97 ±

29.1 (d), 130.3 (d), 155.2 (u); IR (neat): nÄ 2983 (m), 2958 (m), 2922 (w),

857 (w), 1747 (s), 1678 (w), 1585 (w), 1444 (s), 1380 (m), 1330 (m), 1270 (s),

172 (w), 1142 (w), 1125 (w), 1087 (w), 1038 (s), 1009 (w), 966 (m), 940 (m),

97 (m), 864 (m), 793 cm (m); MS (EI): m/z (%): 144 (8) [M ], 112 (10),

5 (28), 69 (100), 68 (24), 67 (32), 59 (17), 55 (16), 53 (13); elemental

2

.08 (m, 2H), 4.31 (td, J 8.2, 6.0 Hz, 1H), 5.46 (ddt, J 15.1, 8.5, 1.7 Hz,

H), 5.77 (dtd, J 15.4, 6.4, 0.7 Hz, 1H), 6.93 (t, J 4.8 Hz, 2H), 8.49 (d,

1

3

À1

J 5.0 Hz, 1H); C NMR (100 MHz, CDCl ): d 11.7 (d), 13.6 (d), 25.4

3

(

u), 27.8 (u), 48.7 (d), 116.3 (d), 128.2 (d), 134.5 (d), 157.1 (d), 172.5 (u); IR

neat): nÄ 2964 (m), 2932 (m), 2873 (w), 1565 (s), 1547 (s), 1460 (m), 1426

analysis calcd (%) for C

7

H

12

O

3

: C 58.32, H 8.39; found: C 58.51, H 8.51.

À11.2 (c 2.81, CH Cl ). Following GP1, BPA (66 mg,

(dba) ] ¥ CHCl (33 mg, 0.03 mmol) and rac-3aa (303 mg,

Cl (3 mL) were treated with LiO StBu (517 mg, 4 mmol)

Cl (3 mL) and degassed water

3 mL). Terminated of the reaction after stirring the mixture at room

À1

w), 1382 (s), 1187 (s), 965 (w), 798 (w), 774 (m), 750 (m), 631 cm (w); MS

Sulfone 4a: [a]²⁰

D

2

EI): m/z (%): 208 (7) [M ], 175 (19), 165 (35), 113 (30), 97 (11), 96 (19), 81

22), 67 (11), 55 (100), 53 (14); elemental analysis calcd (%) for C11

C 63.42, H 7.74, N 13.45; found: C 63.38, H 7.70,N 13.29.

0

2

.09 mmol), [Pd

.1 mmol) in CH

2

3

16 2

H N S:

2

and THAB (45 mg, 0.1 mmol) in CH

(

2

Carbonate ent-3ba: [a]²

CDCl

0

À60.28 (c 1.31, CHCl

): d 0.91 (t, J 7.4 Hz, 3H), 0.99 (t, J 7.6 Hz, 3H), 1.55 ± 1.80 (m,

H), 2.06 (quinm, J 7.5 Hz, 2H), 3.76 (s, 3H), 4.95 (q, J 7.0 Hz, 1H),

.40 (ddt, J 15.4, 7.9, 1.7 Hz, 1H), 5.81 (dtd, J 15.4, 6.4, 0.7 Hz, 1H);

1

D

3

); H NMR (300 MHz,

temperature for 5 min gave a mixture of carbonate ent-3aa and sulfone 4a

in a ratio of 76:24. Chromatography (hexane/EtOAc 10:1) afforded sulfone

3

2

5

4

a (85 mg, 21%) of 98% ee (GC, LipodexE) as a colorless solid and

1

3

C NMR (75 MHz, CDCl

3

): d 9.5 (d), 13.2 (d), 25.2 (u), 27.6 (u), 54.5 (d),

carbonate ent-3aa (161 mg, 53%) of 33% ee (GC, LipodexE) as a colorless

oil.

8

2

9

0.7 (d), 126.5 (d), 136.9 (d), 155.4 (u); IR (neat): nÄ 2967 (m), 2937 (m),

879 (w), 2854 (w), 1749 (s), 1443 (s), 1383 (w), 1348 (m), 1265 (s), 1076 (w),

General procedure for the kinetic resolution of allylic carbonates with

thiols (GP2): The precatalyst and the ligand were placed in a Schlenk flask

containing a stirring bar and the flask was evacuated and refilled with

argon. Then precatalyst and ligand were dissolved under stirring by

À1

69 (m), 948 (s), 923 (m), 793 cm (m); GC-MS (EI): m/z (%): 172 (3)

M ], 143 (10), 99 (26), 97 (36), 96 (25), 81 (83), 79 (12), 71 (25), 69 (24), 68

[

(

17), 67 (95), 59 (38), 57 (18), 55 (100), 54 (15), 53 (18), 45 (10); elemental

analysis calcd (%) for C : C 62.77, H 9.36; found: C 62.56, H 9.65.

Determination of the conversion in the kinetic resolution of carbonate rac-

a in the reaction with 2-pyrimidinethiol by the method of internal

standard: 2-((S)-cyclohex-2-enylsulfanyl)-pyrimidine (5aa) and (R)-car-

bonic acid cyclohex-2-enyl methyl ester (ent-1a): Following GP2, a mixture

9

16 3

H O

2 2

addition of CH Cl . Stirring was continued until the color of the solution

had changed from dark violet to bright red-orange (approximately 15 min).

Then the substrate was added. Stirring of the mixture was continued until

the color of the solution had changed from red-orange to yellow

1

(

approximately 15 min). The thiol (and tetradecane as internal standard

of carbonate rac-1a (1.52 g, 9.7 mmol), [Pd

.25 mmol) and BPA (380 mg, 0.55 mmol) containing tetradecane

252 mg, 1.27 mmol) in CH Cl (20 mL) was treated with 2-pyrimidinethiol

1.12 g, 10 mmol) in CH Cl (20 mL). Samples (0.1 mL) were taken with a

2 3 3

(dba) ] ¥ CHCl (259 mg,

in the case to determine the conversion) were placed in a second Schlenk

flask and the flask was evacuated and refilled with argon. Then the thiol

was suspended by the addition of CH Cl . The mixture containing the

2 2

catalyst and the substrate were added under argon and stirring with a

cannula to the suspension of the thiol. The reaction mixture was stirred at

room temperature for the time given and the reaction progress was

monitored by TLC or GC. For work-up the mixture was filtered through

0

(

2

syringe after 10, 15, 20, 25, 30, 35, 40, 45, 50 and 55 min and filtered under

exposure to air through Celite. The Celite was washed with CH Cl (2 mL)

2

and the filtrate was analyzed by GC. After 60 min conversion of carbonate

rac-1a was 50%. Purification by flash chromatography (pentane/diethyl

ether 7:1 ! 3:1) gave sulfide 5aa (860 mg, 46%) of 84% ee [GC, CP-bI-CB,

2 2

Celite and washed with CH Cl and concentrated in vacuo. Chromatog-

raphy gave the sulfide and the carbonate.

t

R

(5aa) 58.88, t

R

(ent-5aa) 58.72 min] as a colorless oil and the

Kinetic resolution of carbonate rac-3aa with 2-pyrimidinethiol: 2-((R,E)-1-

methyl-but-2-enylsulfanyl)-pyrimidine (6aa) and (S)-carbonic acid methyl

carbonate ent-1a (614 mg, 41%) of ꢀ99% ee (GC, LipodexE) as a

colorless oil.

1

-methyl-but-2-enyl ester (ent-1a): Following GP2, a mixture of carbonate

rac-3aa (1.44 g, 10 mmol), [Pd (dba) ] ¥ CHCl (259 mg, 0.25 mmol) and

BPA (380 mg, 0.55 mmol) in CH (20 mL) was treated with 2-pyrimi-

dinethiol (1.12 g, 10 mmol) in CH (20 mL). After 20 h conversion of

Sulfide 5aa: [a]²

0

À124.8 (c 1.14, CHCl

1

D

3 3

); H NMR (300 MHz, CDCl ):

2

3

d 1.63 ± 1.76 (m, 1H), 1.79 ± 1.99 (m, 2H), 2.03 ± 2.16 (m, 3H), 4.53 ± 4.56

2

Cl

2

(

m, 1H), 5.78 ± 5.92 (m, 2H), 6.96 (t, J 5.0 Hz, 1H), 8.51 (d, J 5.0 Hz,

13

2

Cl

2

1

2

1

H); C NMR (75 MHz, CDCl

3

): d 19.8 (u), 24.9 (u), 29.1 (u), 40.8 (d),

carbonate rac-3aa was approximately 50% and the reaction was termi-

nated. Purification by flash chromatography (pentane/diethyl ether 20:1 !

16.4 (d), 126.3 (d), 131.0 (d), 157.2 (d), 172.5 (u); IR (neat): nÄ 2932 (m),

858 (w), 2834 (w), 1564 (s), 1547 (s), 1444 (m), 1428 (m), 1381 (s), 1255 (w),

3

:1) gave sulfide 6aa (649 mg, 36%) of 93% ee [GC, Lipodex g, t

R

(6aa)

À1

189 (s), 871 (w), 799 (w), 774 (m), 748 (m), 724 (w), 628 cm (m); MS (EI):

6.02 min, t

R

(ent-6aa) 36.08 min] and carbonate ent-3aa (519 mg, 36%)

m/z (%): 192 (39) [M ], 159 (87), 131 (16), 113 (96), 84 (13), 81 (63), 80

of ꢀ99% ee (GC, LipodexE).

(

66), 79 (100), 77 (26), 53 (28), 52 (12); elemental analysis calcd (%) for

Sulfide 6aa: [a]²

0

188.1 (c 1.06, CHCl

1

D

3 3

); H NMR (400 MHz, CDCl ):

C

10

H

12

N

2

S: C 62.47, H 6.29, N 14.57; found: C 62.18, H 6.39, N 14.60.

d 1.51 (d, J 7.0 Hz, 3H), 1.69 (dm, J 5.7 Hz, 3H), 4.47 (quin, J

Carbonate ent-1a: [a]²

0

166.7 (c 1.10, CHCl

D

3

).

6

.7 Hz, 1H), 5.64 (ddq, J 15.4, 7.0, 1.3 Hz, 1H), 5.74 (dqd, J 15.1, 5.7,

1

3

1

.0 Hz, 1H), 6.94 (t, J 4.7 Hz, 1H), 8.52 (d, J 4.7 Hz, 2H); C NMR

Kinetic resolution of carbonate rac-1b with 2-pyrimidinethiol: 2-((S)-

cyclohept-2-enylsulfanyl)-pyrimidine (5b) and (R)-carbonic acid cyclo-

hept-2-enyl methyl ester (ent-1b): Following GP2, a mixture of carbonate

(

100 MHz, CDCl

3

): d 17.8 (d), 20.4 (d), 41.7 (d), 116.3 (d), 126.4 (d), 131.7

d), 157.2 (d), 172.5 (u); IR (neat): nÄ 3027 (w), 2965 (w), 2924 (w), 1565

s), 1547 (s), 1450 (m), 1426 (w), 1382 (s), 1188 (s), 1017 (w), 965 (w), 798

rac-1b (828 mg, 4.9 mmol), [Pd

BPA (380 mg, 1.1 mmol) in CH

nethiol (560 mg, 5 mmol) in CH

2

(dba)

3

] ¥ CHCl

3

(259 mg, 0.25 mmol) and

À1

w), 774 (m), 749 (m), 630 cm (w); GC-MS (EI): m/z (%): 180 (10) [M ],

51 (99), 147 (57), 113 (20), 112 (39), 84 (18), 79 (14), 69 (100), 68 (24), 67

2

Cl

2

(10 mL) was treated with 2-pyrimidi-

1

2

Cl

2

(10 mL). After 3.5 h conversion of

4216

¹ 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

www.chemeurj.org

Chem. Eur. J. 2003, 9, 4202 ± 4221

Palladium Catalyzed Kinetic Resolution

4202±4221

carbonate rac-1b was approximately 50%. Purification by flash chroma-

tography (pentane/diethyl ether 7:1) gave sulfide 5b (380 mg, 38%) of

temperature for 4 h. Chromatography (hexane/EtOAc 3:1) afforded

sulfone 4a (186 mg, 98%) of 98% ee (GC, LipodexE) as a colorless oil.

8

4% ee [GC, CP-bI-CB, t

R

(5b) 47.92, t

R

(ent-5b) 47.67 min] as a

From acetate rac-3ab in the presence of BPA: Following GP1, a mixture of

colorless oil and carbonate ent-1b (324 mg, 39%) of 97% ee (GC, Lipodex

E) as a colorless oil. Sulfide 5b: [a]

acetate rac-3ab (130 mg, 1.0 mmol), [Pd

.015 mmol) and BPA (31.4 mg, 0.045 mmol) CH

with a solution of THAB (70.0 mg, 0.16 mmol) and LiO

.0 mmol) in water (10 mL) and the mixture was stirred at room temper-

2

(dba)

3

] ¥ CHCl

(5 mL) was treated

StBu (260 mg,

3

(15.5 mg,

2

0

1

D

À157.5 (c 1.42, CHCl

3

); H NMR

0

2

Cl

2

(

400 MHz, CDCl

m, 2H), 6.94 (t, J 4.7 Hz, 1H), 8.51 (d, J 4.7 Hz, 2H); C NMR

100 MHz, CDCl

3

): d 1.50 ± 2.27 (m, 8H), 4.67 ± 4.71 (m, 1H), 5.82 ± 5.93

2

1

3

2

3

): d 27.2 (u), 27.2 (u), 28.4 (u), 32.3 (u), 44.9 (d), 116.3

ature for 94 h. Chromatography (hexane/EtOAc 3:1) afforded sulfone 4a

d), 131.7 (d), 134.0 (d), 157.2 (d), 172.5 (u); GC-MS (EI): m/z (%): 206 (19)

20

(

98 mg, 51%) of 98% ee (GC, LipodexE) as a colorless oil: [ a]

c 1.00, EtOH).

D

À11.2

[

M ], 174 (11), 173 (77), 163 (17), 145 (15), 137 (16), 114 (11), 113 (100), 112

(

35), 95 (57), 94 (79), 91 (17), 84 (20), 80 (14), 79 (83), 77 (29), 67 (88), 65

21), 57 (20), 55 (34), 53 (36), 52 (30); elemental analysis calcd (%) for

From acetate rac-3ab in the presence of POX: Following GP1, a mixture of

acetate rac-3ab (2.00 g, 15.6 mmol), [Pd (dba) ] ¥ CHCl (403 mg,

.39 mmol) and POX (640 mg, 1.72 mmol) in THF (50 mL) was treated

2

3

C

11

H

14

N

2

S: C 64.04, H 6.84, N 13.58; found: C 64.14, H 6.75, N 13.83.

Carbonate ent-1b: [a]²⁰

34.18 (c 0.99, CHCl ).

Determination of the conversion of carbonate 1a in the reaction with

-pyrimidinethiol by the method of internal standard: 2-((S)-cyclohex-2-

0

D

3

2

with a suspension of NaO StBu (4.50 g, 31.2 mmol) in THF (60 mL) and the

mixture was stirred at room temperature for 48 h. Chromatography

(hexane/EtOAc 4:1) gave sulfone ent-4a (1.62 g, 55%) of 58% ee (GC,

2

0

enylsulfanyl)-pyrimidine (5aa) and (S)-carbonic acid cyclohex-2-enyl

methyl ester (1a): Following GP2, a mixture of carbonate 1a (156 mg,

1

LipodexE) as a colorless oil: [ a]

R,E)-5-(2-Methyl-propan-2-sulfonyl)-3-heptene (4b)

From carbonate rac-3ba in the presence of BPA: Following GP1, a mixture

of carbonate rac-3ba (172 mg, 1.0 mmol), [Pd (dba) ] ¥ CHCl (15.5 mg,

.015 mmol) and BPA (31.4 mg, 0.045 mmol) CH Cl (10 mL) was treated

StBu (256 mg, 2.0 mmol) and THAB (70 mg,

D

4.3 (c 1.30, EtOH).

(

mmol) of ꢀ99% ee, [Pd

2

(dba)

Cl

.33 mmol) was treated with 2-pyrimidinethiol (112 mg, 1 mmol) in CH

3

] ¥ CHCl

(2 mL) containing tertradecane (65 mg,

Cl

3

(25.9 mg, 0.025 mmol) and BPA

(

38.0 mg, 0.055 mmol) in CH

2

3

0

2

0

2

(

9

2 mL) and samples were taken with a syringe after 20, 30, 40, 50, 60, 70, 80,

0, 100 and 110 min and filtered under exposure to air through Celite. The

Celite was washed with CH Cl (2 mL) and the filtrate was analyzed by GC.

Determination of the conversion of carbonate ent-1a in the reaction with

-pyrimidinethiol by the method of internal standard: 2-((S)-cyclohex-2-

enylsulfanyl)-pyrimidine (5aa) and (R)-carbonic acid cyclohex-2-enyl

methyl ester (ent-1a): Following GP2, mixture of carbonate 1a

156 mg, 1 mmol) ꢀ99% ee, [Pd (dba) ] ¥ CHCl (25.9 mg, 0.025 mmol)

and BPA (38.0 mg, 0.055 mmol) in CH Cl (2 mL) containing tetradecane

65 mg, 0.33 mmol) was treated with 2-pyrimidinethiol (112 mg, 1 mmol) in

CH Cl (2 mL) and samples were taken with a syringe after 20, 30, 40, 50,

0, 70, 80, 90, 100 and 110 min and filtered under exposure to air through

with a solution of LiO

2

0

.16 mmol) in water (5 mL) and the mixture was stirred at room temper-

2

ature for 2 h. Chromatography (silica gel, hexane/EtOAc 3:1) afforded

sulfone 4b (214 mg, 97%) of 97% ee [GC, LipodexE,

t

R

(ent-4b)

2

20

3

1.60 min, t

R

(4b) 31.86 min] as a colorless oil: [a]

D

À31.4 (c 1.00,

1

EtOH); H NMR (300 MHz, CDCl

3

): d 0.94 (t, J 7.4 Hz, 3H), 1.03 (t,

a

J 7.4 Hz, 3H), 1.42 (s, 9H), 1.68 (m, 1H), 2.14 (m, 2H), 2.22 (m, 1H), 3.55

(

2

3

(

1

dt, J 3.3, 10.1 Hz, 1H), 5.45 (ddt, J 9.9, 15.6, 1.6 Hz, 1H), 5.75 (dt, J

2

5.6, 6.3 Hz, 1H); C NMR (75 MHz, CDCl

13

): d 11.35 (d), 13.58 (d),

3

(

2

0.97 (u), 25.10 (d), 26.13 (u), 62.20 (u), 65.34 (d), 124.46 (d), 139.48 (d); MS

2

(

EI, 70 eV) m/z: 219 (1) [M ], 162 (5), 125 (5), 124 (5), 123 (100), 69 (6), 57

6

5); IR (capillary): nÄ 2980 (s), 2940 (s), 1460 (m), 1280 (s), 1115 (s), 1015

Celite. The Celite was washed with CH

analyzed by GC.

2

Cl

2

(2 mL) and the filtrate was

À1

m), 975 (m), 800 (w), 720 (m), 660 cm (m); elemental analysis calcd (%)

for C11

From carbonate rac-3ba in the presence of BPA and [Pd(C

Following GP1, a mixture of carbonate rac-3ba (172 mg, 1.0 mmol),

Pd(C )Cl] (6.8 mg, 0.03 mmol) and BPA (31.4 mg, 0.045 mmol) in

CH Cl (10 mL) was treated with a solution of LiO StBu (256 mg,

.0 mmol) and THAB (70 mg, 0.16 mmol) in water (5 mL) and the mixture

was stirred at room temperature for 6 h. Chromatography (hexane/EtOAc

22 2

H O S: C 60.51, H 10.16; found: C 60.62, H 10.48.

(

S)-3-(2-Methyl-propan-2-sulfonyl)-cyclopentene (2d): Following GP1, a

mixture of carbonate rac-1da (130 mg, 0.93 mmol), [Pd (dba) ] ¥ CHCl

15 mg, 0.014 mmol) and BPA (31 mg, 0.045 mmol) in CH Cl (2 mL)

was treated under stirring at 08C with a suspension of LiO StBu (256 mg,

mmol) und THAB (24 mg, 0.055 mmol) in CH Cl (3 mL). Then degassed

3

5 2

H )Cl] :

2

3

(

2

[

3

H

5

2

water (3 mL) was added and the mixture was stirred at room temperature

for 24 h. Chromatography (hexane/EtOAc 5:1) gave sulfone 2d (133 mg,

3

:1) furnished sulfone 4b (210 mg, 96%) of 96% ee (GC, LipodexE) as a

7

3

2

6%) of 89% ee [GC, LipodexE,

t

R

(2d) 33.63 min, t

R

(ent-2d)

20

D

colorless oil: [a]

À31.2 (c 1.32, EtOH).

1

3.78 min; { H NMR, CDCl

3

, 30 mol% [Eu(hfc)

3

]}: d (tBu) (ent-2d)

From acetate rac-3bb in the presence of BPA: Following GP1, a mixture of

acetate rac-3bb (157 mg, 1.0 mmol), [Pd (dba) ] ¥ CHCl (15.5 mg,

.015 mmol) and BPA (31.4 mg, 0.045 mmol) in CH Cl (10 mL) was

StBu (256 mg, 2.0 mmol) and THAB (70 mg,

2

0

.50, d (tBu) (2d) 2.47] as a colorless solid. M.p. 588C; [a]

Cl ).

S)-3-(2-Methyl-propan-2-sulfonyl)-cyclohexene (2aa): Following GP1, a

(dba) ] ¥ CHCl

77 mg, 0.075 mmol) and BPA (155 mg, 0.22 mmol) in CH Cl (30 mL)

was treated under stirring at 08C with a suspension of LiO StBu (1.28 g,

0 mmol) und THAB (109 mg, 0.25 mmol) in CH Cl (30 mL). Then

D

À192.6

2

3

(

c 1.02, CH

2

0

2

(

treated with a solution of LiO

2

mixture of carbonate rac-1a (781 mg, 5.0 mmol), [Pd

(

2

3

0

.16 mmol) in water (5 mL) and the mixture was stirred at room temper-

2

ature for 48 h. Chromatography (hexane/EtOAc 3:1) afforded sulfone 4b

20

2

(

95 mg, 43%) of 96% ee (GC, LipodexE) as a colorless oil: [ a]

c 1.00, EtOH).

À31.4

D

1

2

degassed water (10 mL) was added and the mixture was successively stirred

at 08C for 1 h and at room temperature for 18 h. Chromatography (hexane/

EtOAc 7:1, 1% NEt

Sulfone ent-4b from acetate rac-3bb in the presence of POX: Following

GP1, a mixture of acetate rac-3bb (156 mg, 1.0 mmol), [Pd (dba) ] ¥ CHCl

15.5 mg 0.015 mmol) and POX (22.0 mg, 0.06 mmol) in THF (10 mL) was

2

3

) afforded sulfone 2aa (960 mg, 95%) of 94% ee

, 30 mol% [Eu(hfc) ]) as a colorless solid.

(

1

(

400 MHz H NMR, CDCl

3

2

treated with a suspension of LiSO tBu (250 mg, 2.0 mmol) in THF (10 mL)

and the mixture was stirred at room temperature for 70 h. Chromatography

(

S)-3-(2-Methyl-propan-2-sulfonyl)-cycloheptene (2b): Following GP1, a

(dba) ] ¥ CHCl

15 mg, 0.015 mmol) and BPA (31.3 mg, 0.045 mmol) in CH Cl (3 mL)

was treated under stirring at 08C with a suspension of LiO StBu (256 mg,

mmol) und THAB (25 mg, 0.057 mmol) in CH Cl (3 mL). Then degassed

water (3 mL) was added and the mixture was successively stirred at 08C for

h and at room temperature for 4 h under ultrasonication. Chromatog-

raphy (hexane/EtOAc 7:1, 1% NEt ) afforded sulfone 2b (192 mg, 89%) of

3% ee (GC, LipodexE) as a colorless solid.

R,E)-4-(2-Methyl-propan-2-sulfonyl)-2-pentene (4a)

From carbonate rac-3aa in the presence of BPA: Following GP1, a mixture

of carbonate rac-3aa (144 mg, 1.0 mmol), [Pd (dba) ] ¥ CHCl (15.5 mg,

.015 mmol) and BPA (31.4 mg, 0.045 mmol) in CH Cl (5 mL) was treated

with a solution of THAB (70.0 mg, 0.16 mmol) and LiO StBu (260 mg,

.0 mmol) in water (10 mL) and the resulting mixture was stirred at room

mixture of carbonate rac-1b (172 mg, 1.0 mmol), [Pd

2

3

(

hexane/EtOAc 3:1) gave sulfone ent-4b (130 mg, 60%) of 61% ee (GC,

(

2

20

LipodexE) as a colorless oil: [ a]

D

14.6 (c 1.15, THF).

2

(

S,E)-2,6-Dimethyl-5-(2-methyl-propan-2-sulfonyl)-3-heptene (4c): Fol-

2

lowing GP1,

a

mixture of chloride rac-3cb (364 mg, 2.27 mmol),

(15.0 mg, 0.034 mmol) and BPA (94.0 mg, 0.136 mmol) in

(20 mL) was treated with a solution of LiSO tBu (600 mg,

.56 mmol) and THAB (160 mg, 0.36 mmol) in water (15 mL) and the

mixture was stirred at room temperature for 120 h. Chromatography

hexane/EtOAc 3:1) gave sulfone 4c (330 mg, 58%) of 84% ee [GC,

[

Pd(C

3 5 2

H )Cl]

2

CH Cl

2

3

4

9

(

LipodexE, t

R

(ent-4c) 76.13 min, t

R

(4c) 76.30 min] as a colorless oil:

2

0

1

2

3

[a]

D

À6.35 (c 1.15, THF); H NMR (400 MHz, CDCl

3

): d 0.93 (d,

0

2

J 7.1 Hz, 3H), 1.03 (d, J 6.9 Hz, 3H), 1.04 (d, J 6.6 Hz, 6H), 1.4 (s,

9H), 2.41 (m, 1H), 2.71 (dh, J 6.9, 2.8 Hz, 1H), 3.55 (m, 1H), 5.59 (m,

2

1

3

2

2H); C NMR (100 MHz, CDCl

3

): d 17.73 (d), 21.62 (d), 22.00 (d), 22.39

Chem. Eur. J. 2003, 9, 4202 ± 4221

www.chemeurj.org

¹ 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

4217

H.-J. Gais et al.

FULL PAPER

(

d), 24.71 (d), 27.49 (d), 31.65 (d), 62.36 (u), 66.42 (d), 119.31 (d), 145.26 (d);

53 (13), 52 (10); elemental analysis calcd (%) for C

N 15.71; found: C 60.34, H 5.80, N 15.99.

9 10 2

H N S: C 60.64, H 5.65,

IR (capillary): nÄ 2970 (s), 2930 (s), 1460 (s), 1280 (s), 1190 (m), 1120 (s),

À1

9

80 (m), 800 (m), 695 (m), 635 (m), 560 (m), 490 cm (w); MS (EI, 70 eV)

From rac-1db: Following GP3, a mixture of ester rac-1db (243 mg,

.02 mmol), [Pd (dba) ] ¥ CHCl (25.8 mg, 0.025 mmol, 2.5 mol%) and

BPA (37.9 mg, 0.055 mmol, 5.5 mol%) in CH Cl (2 mL) was treated with

-pyrimidinethiol (112 mg, 1 mmol) in CH Cl (2 mL). After 30 min the

m/z: 247 (2) [M ], 126 (18), 125 (100), 124 (29), 109 (10), 95 (8), 83 (17), 69

(

C 63.10, H 10.91.

1

2

3

11); elemental analysis calcd (%) for C13

26 2

H O S: C 63.37, H 10.64; found:

2

reaction was complete. Purification by flash chromatography (hexane/

EtOAc 7:1) gave sulfide 5c (174 mg, 96%) of 36% ee (GC, Hydrodex-b-6-

General procedure for the asymmetric synthesis of sulfides by Pd-catalyzed

allylic substitution of carbonates with thiols (GP3): The precatalyst and the

ligand were placed in a Schlenk flask containing a stirring bar and the flask

was evacuated and refilled with argon. Then precatalyst and ligand were

dissolved under stirring by addition of CH Cl . The thiol was placed in a

2 2

second Schlenk flask and the flask was evacuated and refilled with argon,

then the carbonate was added. The thiol and carbonate were dissolved or

suspended by the addition of CH Cl . Both solutions were degassed by

2 2

three freeze-thaw cycles. Stirring was continued until the color of the

solution had changed from dark violet to bright red-orange (approximately

2

0

TBDM): [a]

-((R,E)-1-Methyl-but-2-enylsulfanyl)-pyrimidine (6aa): Following GP3, a

mixture of carbonate rac-3aa (173 mg, 1.2 mmol), [Pd (dba) ] ¥ CHCl

51.8 mg, 0.05 mmol) and BPA (69.1 mg, 0.10 mmol) in CH Cl (2.5 mL)

was treated with 2-pyridinethiol (112 mg, 1 mmol) in CH Cl (2.5 mL).

After 2 d the reaction was stopped. Purification by flash chromatography

hexane/EtOAc 10:1) gave sulfide 6aa (129 mg, 72%) of 89% ee [GC,

D

À43.2 (c 1.13, CHCl

3

).

2

3

(

2

(

Lipodex g, t

R

(6aa) 36.02 min, t

R

(ent-6aa) 36.08 min] and a E/Z ratio of

1

5 min). The solution containing the catalyst and ligand was added under

20

2

9:1 (GC) as a colorless oil: [a]

D

155.2 (c 2.02, CHCl

3

).

argon with a cannula to the solution or suspension of the thiol and the

carbonate. This solution was stirred at the desired temperature. For work-

up the reaction mixture was concentrated in vacuo and the sulfide was

isolated by chromatography.

2

-((R,E)-1-Ethyl-pent-2-enylsulfanyl)-pyrimidine (6ba): Following GP3, a

(dba) ] ¥ CHCl

51.8 mg, 0.05 mmol) and BPA (75.9 mg, 0.11 mmol) in CH Cl (2.5 mL)

was treated with 2-pyrimidinethiol (112 mg, 1 mmol) in CH Cl (2.5 mL).

mixture of carbonate rac-3ba (207 mg, 1.2 mmol), [Pd

(

2

3

2

-((S)-Cyclohex-2-enylsulfanyl)-pyrimidine (5aa): Following GP3, a mix-

ture of carbonate rac-1a (187 mg, 1.2 mmol), [Pd (dba) ] ¥ CHCl (51.8 mg,

.05 mmol) and BPA (75.9 mg, 0.11 mmol) in CH Cl (2.5 mL) was treated

with 2-pyridinethiol (111 mg, 1 mmol) in CH Cl (2.5 mL). After 24 h the

After 3 d the reaction was stopped. Purification by flash chromatography

(hexane/EtOAc 10:1) gave sulfide 6ba (134 mg, 64%) of 91% ee [HPLC,

2

3

0

2

Chiralcel OD-H-column, hexane/iPrOH 95:5, t (6ba) 10.13 min, t_R(ent-

R

2

0

2

6ba) 8.99 min]: [a]

D

210.9 (c 0.97, CHCl

3

).

reaction was stopped. Purification by flash chromatography (hexane/

EtOAc 10:1) gave sulfide 5aa (121 mg, 63%) of 84% ee (GC, CP-bI-CB).

2

-((RS,Z)-1-Ethyl-pent-2-enylsulfanyl)-pyrimidine (rac-6ab): Following

GP3, a mixture of carbonate rac-3ba (310 mg, 1.8 mmol), [Pd (dba) ] ¥

CHCl (31.1 mg, 0.03 mmol) and dppp (49.5 mg, 0.12 mmol) in CH

2.5 mL) was treated with 2-pyrimidinethiol (168 mg, 1.5 mmol) in CH

2

3

2

Cl

2

-((S)-Cyclohex-2-enylsulfanyl)-pyrimidine (5ab): Following GP3, a mix-

ture of carbonate rac-1a (182 mg, 1.2 mmol), [Pd (dba) ] ¥ CHCl (51.8 mg,

.05 mmol) and BPA (75.9 mg, 0.11 mmol) in CH Cl (2.5 mL) was treated

with 2-pyridinethiol (111 mg, 1 mmol) in CH Cl (2.5 mL). After 27 h the

reaction was stopped. Purification by flash chromatography (hexane/

(

2

3

2.5 mL) and the mixture was heated at reflux for 3 d. Purification by

0

2

chromatography (hexane/EtOAc 10:1) gave a mixture of rac-6ab and its Z

isomer (173 mg, 55%) in a ratio of 9:1. HPLC (Merck, LiChrosorb, Si 60,

2

5

mm, hexane/EtOAc 9:1) afforded rac-6ab (100 mg) and its Z isomer

EtOAc 40:1) gave sulfide 5ab (122 mg, 64%) of 55% ee [GC, CP-bI-CB, t

R

1

2

0

(17 mg) as colorless oils. Z isomer: H NMR (CDCl , 300 MHz): d 0.99 (t,

(

5ab) 26.05 min,

t

R

(ent-5ab) 25.95 min]: [a]

D

À60.9 (c 1.82,

3

1

J 7.6 Hz, 3H), 1.01 (t, J 7.4 Hz, 3H), 1.60 ± 1.75 (m, 1H), 1.84 ± 1.99 (m,

CHCl

3

); H NMR (300 MHz, CDCl

3

): d 1.62 ± 1.74 (m, 1H), 1.78 ± 1.95

1

H), 2.16 ± 2.32 (m, 2H), 4.58 ± 4.66 (m, 1H), 5.33 (ddt, J 10.6, 10.6,

(

2

1

m, 2H), 2.02 ± 2.14 (m, 3H), 4.56 ± 4.62 (m, 1H), 5.77 ± 5.90 (m, 2H), 6.96

ddd, J 7.4, 5.0, 1.0 Hz, 1H), 7.15 (dm, J 8.0 Hz, 1H), 7.45 (td, J 7.7,

1

.7 Hz, 1H), 5.77 (dtd, J 10.7, 7.0, 0.7 Hz, 1H), 6.95 (t, J 4.8 Hz, 2H),

1

3

1

3

8.49 (d, J 5.0 Hz, 1H); C NMR (CDCl , 75 MHz): d 11.74 (d), 14.15

.0 Hz, 1H), 8.43 (dm, J 5.0 Hz, 1H); C NMR (75 MHz, CDCl

3

): d

3

(

d), 21.23 (u), 28.47 (u), 44.15 (d), 116.28 (d), 128.50 (d), 134.49 (d), 157.06

9.8 (u), 24.9 (u), 29.3 (u), 39.9 (d), 119.4 (d), 122.4 (d), 126.9 (d), 130.5 (d),

35.9 (d), 149.4 (d), 159.2 (u); MS (EI): m/z (%): 191 (28) [M ], 159 (10),

58 (91), 130 (14), 112 (100), 111 (27), 81 (40), 80 (37), 79 (65), 78 (31), 77

(d), 172.51 (u); MS (EI): m/z: 208 (10) [M ], 175 (22), 165 (42), 113 (42),

1

12 (10), 97 (11), 96 (24), 81 (32), 79 (13), 67 (13), 55 (100), 53 (16); IR

(

1

capillary): nÄ 3306 (w), 2965 (s), 2932 (m), 2873 (m), 1565 (s), 1547 (s),

(

20), 67 (27), 53 (15), 51 (16); IR (neat): nÄ 3026 (m), 2993 (w), 2932 (s),

À1

461 (m), 1426 (w), 1382 (s), 1188 (s), 798 (m), 774 (m), 749 (m), 631 cm

2

1

7

858 (m), 2833 (m), 1579 (s), 1555 (s), 1453 (s), 1430 (m), 1414 (s), 1280 (w),

255 (w), 1205 (w), 1146 (m), 1123 (s), 1041 (m), 997 (w), 986 (m), 871 (m),

(

w).

-((R,E)-1-Methyl-but-2-enylsulfanyl)-pyridine (6ab): Following GP3, a

mixture of carbonate rac-3aa (173 mg, 1.2 mmol), [Pd (dba) ] ¥ CHCl

51.8 mg, 0.05 mmol), BPA (75.9 mg, 0.11 mmol) and nBu NF (31.5 mg,

(2.5 mL) was treated with 2-pyridinethiol (111 mg,

(2.5 mL). After 2 d the reaction was stopped.

À1

56 (s), 724 (s), 638 (w), 619 cm (w).; elemental analysis calcd (%) for

2

C

11

H

13NS: C 69.07, H 6.85, N 7.32; found: C 68.83, H 6.75, N 7.60.

-((S)-Cyclohept-2-enylsulfanyl)-pyrimidine (5b): Following GP3, a mix-

ture of carbonate rac-1b (170 mg, 1 mmol), [Pd (dba) ] ¥ CHCl (51.8 mg,

.05 mmol) and BPA (75.9 mg, 0.11 mmol) in CH Cl (2 mL) was treated

(2 mL). After 24 h the

2

3

(

0

1

4

2

.098 mmol) in CH

2 2

Cl

2

3

mmol) in CH Cl

2

0

2

Purification by flash chromatography (hexane/EtOAc 40:1) gave sulfide

2 2

with 2-pyrimidinethiol (112 mg, 1 mmol) in CH Cl

6

ab (157 mg, 87%) of 68% ee [GC, LipodexE,

t

R

(6ab) 60.72 min, t

R

reaction was stopped. Purification by flash chromatography (pentane/

diethyl ethyl 7:1) gave sulfide 5b (125 mg, 61%) of 84% ee (HPLC,

Chiralcel OD-H column, hexane/iPrOH 98:2).

1

(

ent-6ab) 60.33 min] and a E/Z ratio of 15:1 ( H NMR) as a colorless oil:

2

0

1

[

a]

J 6.7 Hz, 3H), 1.66 (d, J 6.7 Hz, 3H), 4.46 (quin, J 6.8 Hz, 1H), 5.59

dd, J 15.5, 7 Hz, 1H), 5.66 (dq, J 15.5, 5.8 Hz, 1H), 6.97 (ddd, J 7.3,

.7, 1.0 Hz, 1H), 7.16 (d, J 8.1 Hz, 1H), 7.46 (td, J 7.4, 2.0 Hz, 1H), 8.43

D

100.0 (c 2.52, CHCl

3

); H NMR (300 MHz, CDCl

3

): d 1.47 (d,

2

-((S)-Cyclopent-2-enylsulfanyl))-pyrimidine (5c)

From rac-1da: Following GP3, a mixture of carbonate rac-1da (146 mg,

.03 mmol), [Pd (dba) ] ¥ CHCl (25.8 mg, 0.025 mmol, 2.5 mol%) and

BPA (37.9 mg, 0.055 mmol) in CH

dinethiol (112 mg, 1 mmol) in CH

(

4

1

3

(

dm, J 4.7 Hz, 1H), C NMR(75 MHz, CDCl

3

): d 17.7 (d), 20.7 (d), 41.4

1

2

3

(

d), 119.5 (d), 123.1 (d), 126.0 (d), 132.3 (d), 135.8 (d), 149.4 (d), 159.8 (u);

2

Cl

2

(2 mL) was treated with 2-pyrimi-

2

(2 mL). After 35 min the reaction

IR (capillary): nÄ 3067 (w), 3044 (w), 3025 (w), 2964 (m), 2920 (m), 2866

2

(

w), 1578 (s), 1556 (s), 1452 (s), 1414 (s), 1377 (w), 1280 (w), 1148 (m), 1124

s), 1088 (w), 1044 (m), 1017 (m), 985 (m), 964 (m), 758 (s), 725 (m), 620

was complete. Purification by flash chromatography (hexane/EtOAc 7:1)

gave sulfide 5c (146 mg, 80%) of 34% ee [GC, Hydrodex-b-6-TBDM, t

R

À1

2

0

(w), 481 cm (w); GC-MS (EI): m/z (%): 179 (9) [M ], 151 (10), 150 (100),

(

ent-5c) 59.99 min, t

R

(5c) 60.26 min]: [a]

D

À42.1 (c 1.41, CHCl

3

).

1

146 (30), 131 (14), 112 (19), 11 (43), 83 (12), 78 (23), 69 (58), 68 (12), 67 (51),

H NMR (500 MHz, CDCl

3

): d 1.91 ± 1.98 (m, 1H), 2.30 ± 2.53 (m, 3H),

5

3 (13), 52 (10), 51 (22); elemental analysis calcd (%) for C10

H 7.32, N 7.81; found: C 66.96, H 7.40, N 8.04.

2-((R,E)-1-Ethyl-pent-2-enylsulfanyl)-pyridine (6bb): Following GP3, a

mixture of carbonate rac-3ba (207 mg, 1.2 mmol), [Pd (dba) ] ¥ CHCl

(51.8 mg, 0.05 mmol) and BPA (69.0 mg, 0.10 mmol) in CH Cl (2.5 mL)

was treated with 2-pyridinethiol (112 mg, 1 mmol) in CH Cl (2.5 mL).

After 3 d the reaction was stopped. Purification by flash chromatography

H13NS:C 67.00,

4

.78 (m, 1H), 5.81 (m, 1H), 5.89 (m, 1H), 6.88 (t, J 4.9 Hz, 1H), 8.44 (d,

1

3

J 4.6 Hz, 2H); C NMR (125 MHz, CDCl

3

): d 31.58 (u), 31.77 (u),

5

0.37 (d), 116.53 (d), 130.74 (d), 134.63 (d), 157.39 (d), 173.41 (u); IR

(

capillary): nÄ 3056 (w), 2933 (m), 2849 (m), 1564 (s), 1546 (s), 1454 (w),

2

3

1

9

1

427 (w), 1381 (s), 1347 (w), 1293 (w), 1254 (w), 1190 (s), 1018 (m), 980 (w),

2

À1

10 (w), 799 (m), 773 (s), 747 (s), 630 (w), 475 cm (w); MS (CI): m/z (%):

2

78 (46) [M ], 145 (65), 113 (91), 112 (59), 69 (10), 67 (100), 66 (47), 65 (26),

4218

¹ 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

www.chemeurj.org

Chem. Eur. J. 2003, 9, 4202 ± 4221

Palladium Catalyzed Kinetic Resolution

4202±4221

(

hexane/EtOAc 40:1) gave sulfide 6bb (50 mg, 24%) of 50% ee [GC,

10a (155 mg, 90%) of ꢀ99% ee [GC, LipodexE, t

R

(10a) 3.47 min] as a

2

0

Lipodex g, t

of 16:1 (GC): [a]

R

(6bb) 67.22 min, t

R

(ent-6bb) 66.97 min] and a E/Z ratio

colorless oil: [a]

D

À18.57 (c 1.05, CH

2 2

Cl ).

2

0

1

D

88.8 (c 1.26, CHCl

3

); H NMR (500 MHz, CDCl

3

):

(

S,E)-Hept-4-en-3-ol (10b): NaOH (600 mg, 0.015 mol) in water (6 mL)

d 0.90 (t, J 7.5 Hz, 3H), 1.01 (t, J 7.5 Hz, 3H), 1.72 (dquin, J 21.3,

was added to a solution of carbonate ent-3ba (344 mg, 2 mmol) of 99% ee.

The mixture was stirred at room temperature for 4 d after which time TLC

indicated the complete consumption of the carbonate. The mixture was

extracted with diethyl ether and the combined organic phases were dried

7

5

1

.6 Hz, 1H), 1.78 ± 1.87 (m, 1H), 1.95 ± 2.02 (m, 2H), 4.22 (td, J 8.3,

.8 Hz, 1H), 5.39 (ddt, J 15.3, 8.5, 1.5 Hz, 1H), 5.65 (dt, J 15.3, 6.4 Hz,

H), 6.97 (ddd, J 7.3, 4.9, 1.1 Hz, 1H), 7.17 (dm, J 8.2 Hz, 1H), 7.47 (dt,

1

3

J 7.7, 1.9 Hz, 1H), 8.44 (dm, J 4.9 Hz, 1H); C NMR (125 MHz,

(

4

MgSO ). Concentration of the organic phase in vacuo and afforded

CDCl

3

): d 11.8 (d), 13.6 (d), 25.4 (u), 27.9 (u), 48.9 (d), 119.6 (d), 123.6 (d),

alcohol 10b (214 mg, 94%) of 99% ee [GC, Hydrodex-b-6-TBDM, t

R

1

2

1

28.8 (d), 134.3 (d), 135.8 (d), 149.3 (d), 159.0 (u); IR (neat): nÄ 3029 (w),

20

D

(

10b) 26.93 min, t

R

(ent-10b) 27.16 min] as a colorless oil: [a]

4.04

963 (s), 2931 (s), 2872 (m), 1564 (s), 1546 (s), 1459 (m), 1425 (w), 1381 (s),

c 0.99, CH Cl ).

2

À1

254 (w), 1187 (s), 964 (m), 797 (m), 774 (s), 749 (m), 630 cm (m); MS

(

EI): m/z (%): 207 (14) [M ], 192 (16), 178 (12), 174 (28), 164 (79), 112 (43),

1

6

11 (42), 97 (16), 96 (23), 83 (12), 81 (41), 79 (13), 78 (31), 74 (36), 73 (13),

7 (33), 61 (33), 59 (46), 55 (100), 53 (10), 51 (11), 45 (41); elemental

Acknowledgement

analysis calcd (%) for C12

H 8.34, N 6.97.

H17NS: C 69.52, H 8.26, N 6.776; found: C 69.59,

We thank the Deutsche Forschungsgemeinschaft (SFB 380 ™Asymmetric

Synthesis With Chemical and Biological Methodes∫) for financal support,

Cornelia Vermeeren for the GC analyses, Dr. Guy C. Lloyd-Jones for

helpful discussions and a referee for valuable suggestions.

1

-Chloro-4-((R,E)-1-methyl-but-2-enylsulfanyl)-benzene (6ac): Following

GP3, a mixture of carbonate rac-3aa (144 mg, 1 mmol), [Pd (dba) ] ¥ CHCl

51.8 mg, 0.05 mmol) and BPA (90 mg, 0.13 mmol) in CH Cl (2.5 mL) was

treated with 4-chlorothiophenol (188 mg, 1.3 mmol) in CH Cl (2.5 mL).

After 2 d the reaction was stopped. Purification by flash chromatography

hexane/EtOAc 40:1) gave sulfide 15c (155 mg, 73%) of 90% ee [GC,

2

3

(

2

[

1] a) H. B. Kagan, J. C. Fiaud, Top. Stereochem. 1988, 18, 249; b) C. J. Sih,

S.-H. Wu, Top. Stereochem. 1989, 19, 63; c) J. Jacques, A. Collet, S. H.

Wilen, Enantiomers, Racemates, and Resolutions, Krieger, Malabar,

(

Lipodex g, t

R

(6ac) 49.62 min, t

R

(ent-6ac) 49.44 min] and a E/Z ratio of

1

20

D

1

0:1 ( H NMR) as a colorless oil: [a]

35.7 (c 1.45, CHCl

3

); H NMR

1

991; d) Chirality in Industry (Eds.: A. N. Collins, G. N. Sheldrake, J.

(

300 MHz, CDCl

.68 (quin, J 6.7 Hz, 1H), 5.28 ± 5.46 (m, 2H), 7.22 ± 7.37 (m, 4H);

3

): d 1.34 (d, J 7.0 Hz, 3H), 1.61 (d, J 5.3 Hz, 3H),

Crosby), Wiley, New York, 1992; e) R. A. Sheldon, Chirotechnology,

Marcel Dekker, New York, 1993; f) E. L. Eliel, S. H. Wilen, Stereo-

chemistry of Organic Compounds, Wiley, New York, 1994; g) R. S.

Ward, Tetrahedron: Asymmetry 1995, 6, 1475; h) A. H. Hoveyda,

M. T. Didiuk, Curr. Org. Chem. 1998, 2, 489; i) A. Collet, Enantiomer

1999, 4, 157; j) T. O. Lukas, C. Girard, D. R. Fenwick, H. B. Kagan, J.

Am. Chem. Soc. 1999, 121, 9299; k) D. W. Johnson, Jr., D. A.

Singleton, J. Am. Chem. Soc. 1999, 121, 9307; l) D. Wistuba, V. J.

Schurig, J. Chromatogr. A 2000, 875, 255; m) G. R. Cook, Curr. Org.

Chem. 2000, 4, 869; n) J. M. Keith, J. F. Larrow, E. N. Jacobsen, Adv.

Synth. Catal. 2001, 343, 5; o) D. G. Blackmond, J. Am. Chem. Soc.

3

1

C NMR(75 MHz, CDCl

3

): d 17.6 (d), 20.6 (d), 46.2 (d), 126.3 (d), 128.7

(

1

(

d), 132.5 (d), 133.1 (u), 133.6 (u), 134.2 (d); IR (CHCl ): nÄ 3023 (w), 2970

m), 2922 (m), 2866 (w), 1573 (w), 1476 (s), 1448 (s), 1389 (m), 1377 (m),

261 (w), 1201 (m), 1095 (s), 1044 (w), 1013 (s), 963 (s), 821 (s), 746 (m), 554

3

À1

37

m), 502 cm (m); MS (CI): m/z (%): 215 ( Cl) (35) [M H], 214 ( Cl)

35 35

19) [M ], 213 ( Cl) (100) [M H], 212 ( Cl) (18) [M ], 201 (22);

elemental analysis calcd (%) for C11

H13ClS: C 62.11, H 6.16; found: C 61.89,

H 6.21.

(

R)-Cyclohex-2-en-1-ol (9a): NaOH (5 g, 0.125 mol) in water (25 mL) was

added to a solution of carbonate ent-1a (350 mg, 2.24 mmol) of ꢀ99% ee in

MeOH (2 mL). The mixture was stirred at room temperature for 4 d after

which time TLC indicated the complete consumption of the carbonate. The

mixture was extracted with diethyl ether and the combined organic phases

2

001, 123, 545; p) H. B. Kagan, Tetrahedron 2001, 57, 2449; q) H.-J.

Gais, F. Theil in Enzyme Catalysis in Organic Synthesis, Vol. II (Eds.:

K. Drauz, H. Waldmann), Wiley-VCH, Weinheim, 2002, p. 335; r) A.

Bommarius in Enzyme Catalysis in Organic Synthesis, Vol. II (Eds.: K.

Drauz, H. Waldmann), Wiley-VCH, Weinheim, 2002, p. 741.

4

were dried (MgSO ) and concentrated in vacuo. Chromatography (pen-

tane/diethyl ether 7:1) afforded alcohol 9a (143 mg, 65%) of ꢀ99% ee

[

2] While resolution by classical methods and by chromatography

generally gives access to both enantiomers, kinetic resolution yields

one enantiomer of the starting material and a product which may or

may not be readily convertible to the other enantiomer of the starting

material. Illustrative examples for the later aspect are the hydrolase

catalyzed resolution of the acetates of racemic alcohols giving a

mixture of the alcohol and the acetate^[and the transition metal

catalyzed oxidative resolution of benzylic alcohols yielding a mixture

of the alcohol and the ketone.^[

[

GC, LipodexE, t

R

(9a) 26.58 min, t

R

(ent-9a) 25.57 min] as a colorless

2

0

oil: [a]

D

110.8 (c 1.20, CH Cl ).

2

(

R)-Cyclohept-2-en-1-ol (9b): NaOH (10 g, 0.25 mol) in water (50 mL) was

added to a solution of carbonate ent-1b (200 mg, 1.17 mmol) of ꢀ 99% ee

in MeOH (3 mL). The mixture was stirred at room temperature for 4 d

after which time TLC indicated the complete consumption of the

carbonate. The mixture was extracted with diethyl ether and the combined

1q]

1n]

organic phases were dried (MgSO

tography (pentane/diethyl ether 7:1) afforded alcohol 9b (126 mg, 94%) of

99% ee [GC, Lipodex g, t (9b)

(7b) 12.36 min; Lipodex g, t

3.95 min, t 28.2 (c

(ent-9b) 14.06 min] as a colorless oil: [a]

.03, CH Cl

4

) and concentrated in vacuo. Chroma-

[

3] a) J. Tsuji, Palladium Reagents and Catalysts, Wiley, New York, 1997;

b) S. J. Sesay, J. M. J. Williams, Adv. Asymmetric Synth. 1998, 3, 235;

c) A. Heumann in Transition Metals for Organic Synthesis, Vol. 1

ꢀ

R

2

0

1

R

D

(

Eds.: M. Beller, C. Bolm), Wiley-VCH, Weinheim, 1998, p. 251;

1

2

).

d) B. M. Trost, C. Lee in Catalytic Asymmetric Synthesis (Ed.: I.

Ojima), Wiley-VCH, Weinheim, 2000; e) G. Helmchen, A. Pfaltz,

Acc. Chem. Res. 2000, 33, 336; f) G. Helmchen, J. Organomet. Chem.

(

R)-Cyclooct-2-en-1-ol (9c): NaOH (10 g, 0.25 mol) in water (50 mL) was

added to a solution of carbonate ent-1c (600 mg, 3.25 mmol) of ꢀ99% ee in

MeOH (3 mL). The mixture was stirred at room temperature for 4 d after

which time TLC indicated the complete consumption of the carbonate. The

mixture was extracted with diethyl ether and the combined organic phases

1

999, 576, 203; g) M. Moreno-Ma nƒ as, R. Pleixats in Handbook of

Organopalladium Chemistry for Organic Synthesis, Vol. 2 (Eds.: E.

Negishi, A de Meijere), Wiley, New York, 2002, p. 1707; h) L.

Acemoglu, J. M. J. Williams in Handbook of Organopalladium

Chemistry, Vol. 2 (Eds.: E. Negishi, A. de Meijere), Wiley, New York,

were dried (MgSO

tane/diethyl ether 7:1) afforded alcohol 9c (308 mg, 75%) of ꢀ99% ee

GC, Lipodex-g, t

4

) and concentrated in vacuo. Chromatography (pen-

[

R

(9c) 11.36 min; GC, LipodexE:

(9c) 11.47 min, t (ent-9c) 12.04 min] as a colorless

Cl ).

t

R

(9c) 8.44 min,

2

002, p. 1945.

GC, Lipodex-g, t

oil: [a]²

R

[

4] a) Although Scheme 1 shows only symmetrically substituted acyclic

substrates, it is in priciple also valid for symmetrically substituted

cyclic and for unsymmetrically substituted substrates. Scheme 1 is a

simplified representation of the palladium-catalyzed allylic substitu-

tion because of the omission of the syn,syn- and anti,syn-isomerism of

the p-allyl complexes as well as of the formation of contact ion pairs

and the coordination of the leaving group or the nucleophile to the

palladium atom with formation of neutral complexes; b) symmetri-

0

D

À52.4 (c 1.46, CH

2

(

S,E)-Pent-3-en-2-ol (10a): NaOH (600 mg, 0.015 mol) in water (6 mL) was

added to a solution of carbonate ent-3aa (288 mg, 2 mmol) of ꢀ99% ee.

The mixture was stirred at room temperature for 2 d after which time TLC

indicated the complete consumption of the carbonate. The mixture was

extracted with diethyl ether and the combined organic phases were dried

(

MgSO

4

). Concentration of the organic phase in vacuo afforded alcohol

Chem. Eur. J. 2003, 9, 4202 ± 4221

www.chemeurj.org

¹ 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

4219

H.-J. Gais et al.

FULL PAPER

cally disubstituted allylic substrates are the most popular ones in

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1b,q]

Received: December 10, 2002 [F4657]

Chem. Eur. J. 2003, 9, 4202 ± 4221

www.chemeurj.org

¹ 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

4221

Article Doi

Highly selective palladium catalyzed kinetic resolution and enantioselective substitution of racemic allylic carbonates with sulfur nucleophiles: Asymmetric synthesis of allylic sulfides, allylic sulfones, and allylic alcohols

DOI: 10.1002/chem.200204657

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