Asymmetric Organocatalysis (From Biomimetic Concepts to Applications in Asymmetric Synthesis) || Kinetic Resolution of Racemic Alcohols and Amines

12

Kinetic Resolution of Racemic Alcohols

and Amines

12.1

Acylation Reactions

This chapter covers the kinetic resolution of racemic alcohols by formation of es-

ters and the kinetic resolution of racemic amines by formation of amides [1]. The

desymmetrization of meso diols is discussed in Section 13.3. The acyl donors em-

ployed are usually either acid chlorides or acid anhydrides. In principle, acylation

reactions of this type are equally suitable for resolving or desymmetrizing the acyl

donor (e.g. a meso-anhydride or a prochiral ketene). Transformations of the latter

type are discussed in Section 13.1, Desymmetrization and Kinetic Resolution of

Cyclic Anhydrides, and Section 13.2, Additions to Prochiral Ketenes.

The organic acylation catalysts currently known are tertiary amines, N-heteroar-

omatic compounds (for example pyridine derivatives), or phosphines; they can be

of central, planar, and axial chirality. Finally, small peptides carrying N-methylhis-

tidine as the catalytically active subunit have also been employed; they also will be

discussed in this chapter.

The kinetic resolution of racemic alcohols is probably the most intensively

studied aspect of organocatalysis, and its beginnings can be traced back to the

1930s [2, 3]. In these early attempts naturally occurring alkaloids such as (�)-

brucine and (þ)-quinidine were used as catalysts. Synthetic chiral tertiary amines

also were introduced and examined, and enantiomeric excesses up to ca. 45% were

achieved up to the early 1990s [4, 5].

Significantly higher selectivity was reported for the first time in 1996 by Vedejs

et al. using either the C2-symmetric phosphines 1–4 [6, 8] (Scheme 12.1) or the

bicyclic systems 5 (Scheme 12.2) [7, 8]. For example, selectivity factors in the range

12–15 were observed when phosphine 2a was used in the acylation of aryl alkyl

carbinols with 3-chlorobenzoic anhydride (Scheme 12.1).

The chiral bicyclic phosphines 5 (and in particular 5a [7b]) are currently the

most active phosphorus-based acylation catalysts, enabling use of low reaction tem-

peratures. Under these conditions (i.e. �40 �C) selectivity factors as high as 370–

390 were achieved (Scheme 12.2). This is the best selectivity factor ever reported for

metal-free, non-enzymatic kinetic resolution. As a consequence, very good enantio-

meric purity of both the isobutyric esters 7 and the remaining alcohols 6 was ob-

tained, even at substrate conversions approaching 50% (Scheme 12.2) [7, 8].

Asymmetric Organocatalysis. Albrecht Berkessel and Harald GrogerCopyright 8 2005 WILEY-VCH Verlag GmbH & Co. KGaA, WeinheimISBN: 3-527-30517-3

323

P

PCH3

CH3

H3C

H3C

P-Ph

PPh2

PPh2

H3C

H3C

P-Ph

R

R

t-Bu

OH

t-Bu

OHH

t-Bu

HO

RO

12a: R = Me2b: R = Et2c: R = i-Pr

3 4

(R-CO)2O (2.5 eq.)

catalyst 2a (16 mol-%)

CH2Cl2, r.t.

at 25 % conversion

29 % ee 81 % eeR: 3-chlorophenyl

Scheme 12.1

PH3C CH3

CH3H

R'

Ar R

OH

Ar R

OH

Ar R

OCH3

O

CH3

5a: R' = 3,5-di-t-Bu-Ph5b: R' = Ph

catalyst:

rac-6

+

7(i-PrCO)2O (2.5 eq.)

catalyst 5 (2-12 mol-%)

heptane

6,7 Ar 6,7 R T [ oC] Conversion [%] % ee 6 % ee 7 s

rt

Catalyst (mol-%)

5a (4) 42 62 84 22

-20 5a (2.5) 38 93 42

rt 5a (4) 83 18

-40 5a (4) 87 57

rt 5b (4) 79 24

-40 5b (5) 93 67

2-Tolyl rt 5a (3) 90 39

5a (4) 95 145

Mesityl rt 5a (4) 79 15

5a (12) 44 79 99 370-390

2-Tolyl

1-Naphthyl rt 5a (3) 90 41

5a (4) 97 99

Mesityl

1-Naphthyl

-40

-40

-40

Ph Me

Ph Me

Ph n-Bu

Ph

Ph

Ph

Me

Me

Me

Me

n-Bu

t-Bu

t-Bu

Me

Me

6

29

5439

9351

8953

7946

7244

9550

5340

42 66

30 41

Scheme 12.2

324 12 Kinetic Resolution of Racemic Alcohols and Amines

Later, the chiral bicyclic phosphine catalyst 5a was also used for kinetic resolu-

tion of allylic alcohols with isobutyric anhydride [8, 9]. The best results were ob-

tained for trisubstituted allylic alcohols – selectivity factors ranged from 32 to 82

at �40 �C.The Vedejs group also reported the centrally chiral DMAP derivatives 8 and 9

[10, 11].

N

NMe2

t-Bu

OOMe

Cl3C

CH3H3C

O

N

NMe2

t-Bu

OOBn

O

CH3

CH3

CH3

ClCl

8 9

These chiral acyl donors can be used for quite effective kinetic resolution of

racemic secondary alcohols. For example, enantiomeric aryl alkyl ketones are es-

terified by the acyl pyridinium ion 8 with selectivity factors in the range 12–53

[10]. In combination with its pseudo-enantiomer 9, parallel kinetic resolution was

performed [11]. Under these conditions, methyl 1-(1-naphthyl)ethanol was resolved

with an ‘‘effective’’ selectivity factor > 125 [12]. Unfortunately, the acyl donors 8

and 9 must be preformed, and no simple catalytic version was reported. Further-

more, over-stoichiometric quantities of either MgBr2 or ZnCl2 are required to pro-

mote acyl transfer. In 2001, Vedejs and Rozners reported a catalytic parallel kineticresolution of secondary alcohols (Scheme 12.3) [13].

H3CH

O t-Bu

O

H3COH

H

O t-Bu

O

H3CH

OH

O

OOCH3

H3C CH3

H3CO

H

O

R

SR

S

ChiroCLEC (10) phosphine 5a

R-enantiomeric esterin solution, 94-97 % ee

S-enantiomeric esterbound to solid support, 91-93 % ee

racemic mixtureof starting alcohols

85-90 % conversion11

Scheme 12.3

12.1 Acylation Reactions 325

This quite remarkable process is based on simultaneous use of an insoluble li-

pase (ChiroCLEC, 10, Scheme 12.3) and vinyl pivaloate for conversion of one enan-

tiomer (R) of the substrate alcohol and of the solid-phase-bound anhydride 11 in

combination with the phosphine 5a for the conversion of the other enantiomer

(S). This system meets the requirement that the soluble acyl donor (vinyl pivaloate)

does not cross-react with the soluble catalyst (phosphine 5a). After completion of

the reaction the solid-phase-bound (S) enantiomer can easily be separated from

the (R) product which remains in solution. As summarized in Scheme 12.3, this

three-phase system affords remarkable yields and enantiomeric purity of the acy-

lated alcohols [13].

Other centrally chiral amine catalysts reported for kinetic resolution of alcohols

include the (S)-prolinol-derived dihydroisoindolines 12a,b (Scheme 12.4), devel-

R R'

OH

R R'

OH

R R'

O-Bz

NCH3

NH

OH

R

OH

Br R CH3

OH

NCH3

N CH3

H12acatalysts:

rac-13, 14 or 15

+(BzCl (0.75 eq.) Et3N (0.5 eq.)

catalyst 12a (0.3 mol-%)

4 Å MS, CH2Cl2, -78 oC

Yield (ee) of13, 14 or 15 [%]

racemicsubstrates: n

13 14 15

13, 14 or 15 16, 17 or 18

Substrate

rac -13a (n = 2; R = Ph)

Yield (ee) of16, 17 or 18 [%]

49 (96) (1S, 2R ) 48 (95) (1R, 2S ) 160

s

rac -13b (n = 1; R = Ph) 45 (89) (1S, 2R ) 42 (88) (1R, 2S ) 37

rac -13c (n = 4; R = Ph) 44 (95) 47 (79) 88

rac -13d (n = 2; R = CO2Et) 46 (85) 46 (90) 27

rac -13e (n = 2; R = CO2i-Pr) 48(84) 46 (90) 27

rac -13f (n = 2; R = Br) 47 (96) (1S, 2S ) 39 (95) (1R, 2R ) 130

rac -14 46 (97) (1S, 2S ) 43 (91) (1R, 2R ) 170

rac -15a (R = Ph) 43 (69) (S ) 41 (67) (R ) 9

rac -15b (R = 2-tolyl) 45 (82) 49 (78) 20

rac -15c (R = Bn) 49 (46) (S ) 39 (51) (R ) 4

12b

( )

Scheme 12.4


oped by Oriyama [14], the chiral DMAP analog 19a of Fuji and Kawabata [15],

and the a-methylproline derivative 19b of Campbell et al. (Scheme 12.5) [16]. The

Oriyama catalyst 12a is quite remarkable in that it can be applied at very low load-

ings (0.3 mol%) and still affords excellent selectivity (selectivity factors up to 170,

Scheme 12.4). The related catalyst 12b was also shown to differentiate between

enantiomeric alcohols quite effectively (e.g. rac-13a, 5 mol% catalyst 12b, selectivity

factor 200). Because 12a is significantly more reactive, however, in practice catalyst

loadings can be kept lower than for 12b.

The DMAP derivative 19a was tested for kinetic resolution of a variety of mono

esters of cyclic cis diols (rac-20a–i) (Scheme 12.5) [15]. Catalyst 19a afforded selec-

tivity factors up to 12.3 and highly enantioenriched mono esters 20 with conver-

sions of 65–73%. For this type of reaction the selectivity of the Campbell catalyst

19b was similar (selectivity factor 13.2, Scheme 12.5) [16a]. The latter catalyst was

identified by screening of a 31-mer library prepared from the parent N-(4-pyridyl)-

a-methylproline and a variety of amines [16a]. The solid-phase-bound forms of

N-(4-pyridyl)-a-methylproline, as reported by Anson et al. [16b], are easily recy-

clable acylation catalysts affording selectivity factors up to 11.9 in the kinetic

resolution of the secondary alcohol rac-20b (Scheme 12.5). In the kinetic resolution

of N-acylated amino alcohols, selectivity factors up to 21 were achieved by use of

the Kawabata–Fuji catalyst 19a, and up to 18.8 by use of the Campbell system

19b (Scheme 12.5) [15, 16a].

Quite efficient nucleophilic catalysts with planar (21a–c) and axial (22a–d) chir-

ality were recently developed by Fu et al. [17–22] and Spivey et al. [23–25]. The

ferrocene-derived catalysts developed by Fu (21a–c) were first tested in the kinetic

resolution of aryl alkyl carbinols with diketene as the acyl donor.

N

CH2OTES

CH3H3C

H3C CH3

CH3

N

NMe2

Ph Ph

PhPh

Ph

N

NMe2

H3C CH3

CH3H3C

CH3

Fe Fe Fe

N

NEt2Ph

N

RMeN CH3

H3C

CH3

H3C

21a 21b 21c

22a: R = Me22b: R = Ph

22c: R =

22d

Fu's catalysts

Spivey's catalysts


OH

OCOR

N

N

OH

H

H

OH

OCOR

OCO-i-Pr

OCOR

N

N

CH3

O

NH

O

catalysts:

rac-20+

(i-PrCO)2O (0.7 - 1.4 eq.)

catalyst 19a,b (5 mol-%)

toluene, rt

Conversion ofrac -20 [%]

racemicsubstrates:

n

rac-20

20

Substrate ee ofremaining 20 [%]

s

rac -20a (n = 2; R = t-Bu) 68 94 8.3

rac -20b (n = 2; R = 4-Me2NC6H4) 62 95 13.2

19a

rac -20c (n = 1; R = 4-Me2NC6H4) 71 97 8.3

rac -20d (n = 3; R = 4-Me2NC6H4) 70 92 6.5

rac -20e (n = 4; R = 4-Me2NC6H4) 73 92 5.8

19b

rac -20b (n = 2; R = 4-Me2NC6H4) 65 97 12.3

Catalyst

19a

19a

19b

19a

19a

19a

( )

OH

NH-R

R1

R2 OH

NH-R3

OH

NH-R

OH

NH-R

R1

R2 OH

NH-R3 R1

R2 O-CO-i-Pr

NH-R3

OH

NH-R

OH

NH-R

MeONH

R

O

OH

R: NMe2

O

Kinetic resolution of acylated amino alcohols using the catalysts 19a and 19b:

catalyst 19a: s > 12

+(i-PrCO)2O (0.6-0.7 eq.)

catalyst 19a,b (5 mol-%)

collidine (1 eq.), toluene, rt

racemic mixture

catalyst 19a: s > 18catalyst 19b: s = 18.8

catalyst 19a: s = 17catalyst 19b: s = 9 catalyst 19a: s = 21

catalyst 19a: s = 10

catalyst 19a: s = 6.8catalyst 19b: s > 12

n( ) n( )

Scheme 12.5


High reactivity was observed for 21b, and 21a was found to be the most selective.

In the presence of 10 mol% 21a selectivity factors as high as 6.5 were observed

with racemic 1-(1-naphthyl)ethanol as substrate (Scheme 12.6) [18]. The TBS ana-

log of 21a was found to be good catalyst for asymmetric addition of methanol to

a variety of prochiral aryl alkyl ketenes [18]. The catalytic asymmetric addition of

achiral alcohols to prochiral ketenes is discussed in Section 13.2.

Later studies focused on the planar chiral DMAP derivative 21c as catalyst and

use of acetic anhydride as an inexpensive and readily available acyl donor [19].

Under these conditions (2 mol% catalyst loading, r.t.) kinetic resolution of several

racemic alcohols could be achieved with selectivity factors up to 52 (Scheme 12.7).

As a consequence, enantiomerically highly enriched alcohols (b95% ee) could be

obtained at conversions only slightly above 50%.

Significant further improvement of this process resulted from solvent screening.

It was found that acylations proceed faster and with even higher selectivity in tert-amyl alcohol [20]. Scheme 12.8 illustrates the impressive performance of this easy-

to-handle kinetic resolution which works almost perfectly even at catalyst loadings

as low as 0.5 mol% [20].

As summarized in Schemes 12.9 and 12.10, kinetic resolution of propargylic [21]

and allylic [22] alcohols work equally well. The DMAP–ferrocene hybrid 21c was

also used for kinetic resolution of racemic diols and for the desymmetrization of

meso diols [20]. These two applications are discussed in Section 13.3.

The axially chiral DMAP derivatives 22a–d were developed by Spivey et al. [23–

25]. In these catalysts the chiral axis is positioned meta to the pyridyl nitrogen

N

CH2OTES

CH3H3C

H3C CH3

CH3

Fe

CH3

OH

O

O

CH3

ORH

CH3

OH

CH3

HRO

O

O

CH3

OHH

CH3

HHO

CH3

O O

R:

catalyst 21a

+s = 3.7

10 mol-% 21abenzene, r.t.

53 % ee at 58 % conversion

+s = 6.5

10 mol-% ent-21abenzene, r.t.

87 % ee at 67 % conversion

+

+

Scheme 12.6


atom. The rationale behind this type of structure is to maintain the high reactivity

of unsubstituted DMAP and thus to enable use of low reaction temperatures and

high selectivity. As shown in Scheme 12.11, selectivity factors less than ca. 5 were

observed in initial experiments with the azaindolines 22a–c [23, 24]. When the

N,N-diethylpyridine catalyst 22d (Scheme 12.11) was used, however, selectivity fac-

tors up to 29 were achieved. In the resolution of 1-(1-naphthyl)ethanol with isobu-

N

NMe2

Ph Ph

PhPh

Ph

Fe

R1 R2

OH

H3C O CH3

O O

R1 R2

HAcO

R3

OHH

R4

Ph CH3

R5

OHH

Me

OHH

R1 R2

OHH

Conversion ofracemate [%]

Remaining alcohol(major enantiomer)

ee ofremaining alcohol [%]

62 95.2 14

s

62 98.8 20

55 97.7 36

51 92.2 52

69 98.9 12

64 99.2 18

60 94.5 22

67 99.1 14

61 99.0 22

catalyst 21c

R1: aryl, vinyl; R2: alkyl

+ 2 mol-% 21c

NEt3, Et2O, r.t.

R3 = Me; R4 = H

R3 = Et; R4 = H

R3 = i-Pr; R4 = H

R3 = t-Bu; R4 = H

R3 = CH2Cl; R4 = H

R3 = Me; R4 = F

R3 = Me; R4 = OMe

R5 = H

R5 = Me

63 99.7 22

+

Scheme 12.7


tyric anhydride in toluene at �78 �C the (R)-ester could be obtained with an ee of

91% [25].

Jeong, Kim et al. reported use of the chiral DMAP derivative 22e, which was

synthesized from 3-amino-DMAP, Kemp’s triacid, and N-acetyl-2,2 0-diamino-1,1 0-binaphthyl [26]. As summarized in Scheme 12.11, selectivity factors up to 21 were

observed with 1 mol% modular catalyst 22e in the kinetic resolution of a variety of

secondary alcohols with acetic anhydride in tert-amyl alcohol as solvent, conditions

first described by Fu et al. [20].

In addition to phosphines and pyridines, N-alkylated imidazoles are also known

to act as a nucleophilic catalysts in acylation reactions [1]. In the approach by

Miller et al. short oligopeptides incorporating N-alkylhistidine derivatives were

used as enantioselective acylation catalysts [27]. The design of, e.g., the tripeptide

N

NMe2

Ph Ph

PhPh

Ph

Fe

R1 R2

OH

H3C O CH3

O O

R3

OHH

R4

Me

OHH

Me

OHH

CH3

R1 R2

HAcO

R1 R2

OHH

Conversion ofracemate [%]

Remaining alcohol(major enantiomer)

ee ofremaining alcohol [%]

55 99 43

s

51 96 95

56 98 32

54 99 68

catalyst 21c

R1: aryl; R2: alkyl

+ 1 mol-% 21c

NEt3, t-amyl alcohol, 0 oC

R3 = Me; R4 = H

R3 = t-Bu; R4 = H

R3 = CH2Cl; R4 = H

R3 = Me; R4 = F

52 95 65

53 99 71

+

Scheme 12.8


N

NMe2

Ph Ph

PhPh

Ph

Fe

R1

R2

OH

R1

R2

H OH

R1

R2

HAcO

Me

H OH

Me

O

Me

H OH

Me

H2C

Me

H OH

n-Bu

Ac2O

Conversion ofracemate [%]Substitution pattern ee of

remaining alcohol [%]s

catalyst 21c

+1 mol-% ent-21c

t-amyl alcohol, 0 oC

58 96 20

63 93 11

R1 = Me; R2 = Ph

86 95 3.8

60 94 14

71 99 10

65 97 13

58 94 18

+

R1 = Et; R2 = Ph

R1 = i-Pr; R2 = Ph

R1 = t-Bu; R2 = Ph

R1 = Me; R2 = 4-MeO-Ph

R1 = Me; R2 = 4-CF3-Ph

R1 = Me; R2 = 4-F-Ph

65 95 12

69 94 7.9

66 95 10

Scheme 12.9


23a [28] and the tetrapeptide 23b [29] (Scheme 12.12) incorporates an N-alkylated

and catalytically active His derivative, a Pro–Aib sequence to induce proper folding-

back of the catalyst, and further elements of chirality (phenethylamine in 23a and a

fourth amino acid in 23b).

The design of the peptide implies that interaction of the catalyst with its sub-

strate relies heavily on hydrogen bonding. Initial studies indeed revealed that, in

particular, N-acyl amino alcohols such as 25 and ent-25 were efficiently differenti-

ated whereas both enantiomers of 1-(1-naphthyl)ethanol were acetylated at identi-

cal rates [28]. Catalyst 23b, shown in Scheme 12.12, was the most efficient from a

series of ten peptides. For best performance, proper matching of the sense of chir-

ality of all three chiral amino acids is necessary, and the type of amino acid present

at the carbon terminus enables further tuning (for example, l-Phe was found to be

better than, e.g., l-Val, selectivity factor 21) [29].

N

NMe2

Ph Ph

PhPh

Ph

Fe

R1

OH

R3 R4

R2

R1

R3 R4

R2OAcH

R1

R3 R4

R2HHO

Ac2O

Conversion ofracemate [%]Substitution pattern ee of

remaining alcohol [%]s

catalyst 21c

+1 - 2.5 mol-% 21c

NEt3, t-amyl alcohol, 0 oC

53 98 80

+

59 99 29

R1 = R2 = Me; R3 = Ph; R4 = H

R1 = i-Pr; R2 = R3 = R4 = Me

55 94 25R1 = i-Pr; R2 = n-Bu; R3 = R4 = H

60 97 18R1 = i-Pr; R2 = H; R3 = R4 = Me

58 93 17R1 = i-Pr; R2 = Me; R3 = R4 = H

59 93 14R1 = i-Pr; R2 = Ph; R3 = R4 = H

66 97 12R1 = n-pentyl; R2 = H; R3 = R4 = Me

63 93 11R1 = Et; R2 = Me; R3 = R4 = H

63 92 10R1 = R2 = i-Pr; R3 = R4 = H

54 99 64R1 = Me; R2 = H; R3 = Ph; R4 = H

75 92 5.4R1 = i-Pr; R2 = H; R3 = n-Pr; R4 = H

73 90 5.3R1 = i-Pr; R2 = H; R3 = H; R4 = n-Bu

77 90 4.7R1 = n-pentyl; R2 = i-Pr; R3 = R4 = H

Scheme 12.10


N

NEt2Ph

N

RMeN

CH3

H3C

CH3

H3C

R1 R2

OH

R3 O R3

O O

R1 R2

HO

R3

OR1 R2

OHH

3

1 mol-% catalyst

NEt3, toluene, -78 oC

(t-amyl alcohol, 0 oC for 22e)

22a: R = Me22b: R = Ph

22c: R =

The Spivey-catalysts 22a-d and the Jeong-Kim-catalyst 22e:

Conversion ofracemate

[%]

Substrate,acylating agent

ee ofremainingalcohol [%]

35.0 9.1 1.5

s

+

R1 = Ph; R2 = R3 = Me

+

ee ofester[%]

19.6

Catalyst

22a

26.0 11.6 2.2R1 = Ph; R2 = R3 = Me 33.022b

18.3 9.0 2.5R1 = 1-naphthyl; R2 = R3 = Me 40.1

17.6 13.1 4.761.222c

22b

R1 = 1-naphthyl; R2 = R3 = Me

17.2 18.6 2189.322dR1 = 1-naphthyl; R2 = Me; R3 = i-Pr

22.3 26.3 2991.422dR1 = 1-naphthyl; R2 = Me; R3 = i-Pr

39.0 46.9 1378.122dR1 = Ph; R2 = Me; R3 = i-Pr

41.4 60.7 2586.022dR1 = o-tolyl; R2 = Me; R3 = i-Pr

17.5 18.8 2088.822dR1 = Ph; R2 = t-Bu; R3 = i-Pr

22d

22eR = N-acetyl-2,2'-diamino-

1,1'-binaphthyl

22a-c

59 90 13.36422eR1 = Ph; R2 = t-Bu; R3 = Me

72 98 8.33822eR1 = 1-naphthyl; R2 = R3 = Me

63 95 12.45722eR1 = 1-naphthyl; R2 = t-Bu; R3 = Me

77 99 8.1R1 = Ph; R2 = i-Pr; R3 = Me 3122e

62 99 21.06222etrans-2-phenylcyclohexanol; R3 = Me

H3C

H3CCH3

N

OO

N

Me2N

O NHR

Scheme 12.11


Kawabata et al. found that peptides 24a–c containing a 4-pyrrolidinopyridine

(PPY) unit afford selectivity factors in the range 5.6–7.6 in the kinetic resolution

of the N-acylated amino alcohol rac-26 with iso-butyric anhydride (Scheme 12.12)

[30]. In further studies by Miller et al. the octapeptide 27 was identified as even

more enantioselective [31]. As shown in Scheme 12.13, selectivity factors as high

as 51 were achieved.

The modular structure of peptides and the well-established methods for their as-

sembly enable the rapid synthesis of many structurally diverse catalyst candidates.

For rapid screening of these Miller et al. developed the indicator 28 which becomes

fluorescent on protonation (Scheme 12.14). In other words, catalyst candidates are

usually incubated with acetic anhydride, the proton sensor 28 [32], and the two in-

dividual substrate enantiomers in separate microtiter plates. A related assay based

on pH color indicators was developed by Davis et al. [34b].

Substrate acylation/liberation of acetic acid from the acylating agent results

in fluorescence of 28, and the relative rate of fluorescence increase is equal to

R1 R2

OH

i-Pr O I-Pr

O O

R1 R2

HO

i-Pr

OR1 R2

OHH

O

OH

O

X

O

OH

O

R

OH

CH3

OH

1 mol-% catalyst 22d

NEt3, toluene, -78 oC

Conversion ofracemate

[%]

Racemicsubstrate

ee ofremainingalcohol [%]

64.0 97.7 19.7

s

++

ee ofester[%]

64.8

18.0 17.9 16.186.4

11.0 8.2 5.567.2

69.0 85.3 5.739.1

51.0 75.4 14.272.8

34.0 37.0 8.471.0

X = H

X = NMe2

X = CN

X = NO2

54.0 61.4 5.952.8

16.0 14.3 9.378.0

R = Br

R = Ph

Scheme 12.11 (cont.)


N HBOC-NH

NN

O

NH

O

HNO

CH3H3C

Ph H

CH3

N

H

BOC-NH

NN

O

HN

HNO

CH3CH3

H

H3C

O

OCH3

O

NHAcHO

NHAcAcO NHAcAcONHAcHO

NHAcHO

HNHO

O

NMe2

N

N

OR

OHN

O NHCO2MeH

HNH-BOCN

N

Me

NH-Z

HN

NH-BOCN

N

Me

O

HN

tripeptide 23a tetrapeptide 23b

5 mol-% catalyst 23a

Ac2O,

toluene, 0 oC

major product enantiomer84 % ee at 10 % conversion

s = 12.6

2-5 mol-% catalyst 23b

Ac2O,

toluene, 25 oC

major product enantiomer,73 % ee at

58 % conversion

recovered ent-25,98 % ee at

58 % conversion

s = 28

+25 ent-25

racemic mixture

26racemic mixture

Kawabata-Fuji-catalysts 24a-c:

24a: R :

24c: R =

Miller-catalysts 23a,b:

24b: R :

s = 6.3 s = 5.6

s = 7.6

24a-c

Scheme 12.12


BOC-NH

NN

O

H3C

NH

L-Val

L-Val

N

H HN

HNO

CH3CH3

OO

L-Leu

L-Val

L-Val

CO2CH3

HO

NHAc

HO NHAc

HONHAc

octapeptide 27

racemic substrates:

s = 27

s = 51

s = 15

Scheme 12.13

N

OCH3

ON

OCH3

OH

R OH R OAc

HO NHAc

N

H

BOC-NHO

HN

HNO

CH3CH3

HO

NHO

H3CO

NN

CH3OH

OAc

Ac2O,catalyst,solvent

non-fluorescent

28 fluorescent

s = 46

pentapeptide 29Scheme 12.14


the selectivity factor. By use of this method peptides 29 and 30 were identified from

a 60-mer library comprising tetrapeptides and pentapeptides [35]. Whereas 29 dis-

tinguishes between the enantiomers of trans-2-acetaminocyclohexanol with a selec-

tivity factor of 46 (Scheme 12.14), the pentapeptide 30 enables kinetic resolution of

a series of tertiary alcohols with selectivity factors up to >50 (Scheme 12.15) [35].

All the peptide catalysts discussed are selective for alcohol substrates that carry

additional hydrogen bonding substituents (for example NHAc). In their search for

catalysts that distinguish non-H-bonding substrates (for example 1-phenylethanol)

Copeland and Miller screened a highly diverse 7:5� 106-mer split-and-pool library

of solid-phase-bound octapeptides, using the ‘‘sensor on the bead’’ method [33,

36]. Further optimization using a directed split-and-pool library afforded catalyst 31

which enables kinetic resolution of rather diverse ‘‘non-H-bonding’’ secondary al-

cohols with good to excellent (> 50) selectivity factors (Scheme 12.16).

By screening in solution Miller et al. identified the pentapeptide 32 as a catalyst

for kinetic resolution of the alcohol rac-33 (selectivity factor 27, Scheme 12.17). rac-33 was an intermediate in their synthesis of enantiomerically pure mitosane 34

[37].

For all the substrates discussed so far the peptide catalysts employed had to dif-

ferentiate between enantiomeric substrate molecules. Miller et al. subsequently

screened peptide libraries for members able to selectively functionalize enantio-

topic hydroxyl groups of meso inositols. In particular, they were able to convert

myo-inositol 35 to either monophosphorylated d-myo-inositol-1-phosphate 37 or d-myo-inositol-3-phosphate ent-37 in high yield and excellent ee (98%; Scheme

12.18) [38, 39]. This remarkable result was achieved by use of either of the penta-

N

H

BOC-NHO

HN

HNO

HO

HNO

H3CO

NN

CH3OH

R

NHAcOHH3C

R

pentapeptide 30

racemic substrate alcohols

s (temp. [oC])

20 (4); 40 (-23)

4-Me-Ph 22 (4); > 50 (-23)

15 (4); 32 (-23)

5,6,7,8-tetrahydro-2-naphthyl

20 (4); 39 (-23)

cyclohexyl 9 (4); 19 (-23)

1-naphthyl 14 (4); 40 (-23)

Ph

4-NO2-Ph

Scheme 12.15


BOC-HN

HN

NH

HN

NH

HN

NH

HN

O

O

O

O

O

O

NN

CH3

CONH(trt)

H3C CH3

N

NH3C CH3

trt

H3C CH3

OOCH3

O

CH3

CH3

OH

R

CH3

OAc

R

t-Bu

OH

t-Bu

OAc

CH3

OH

CH3

OAc

CH3

OH

CH3

OAc

CH3

OHCH3

OAc

H3CCH3

OH

H3CCH3

OAc

OHPh

OAcPh

octapeptide 31

Racemic secondarysubstrate alcohols

Predominantly formedproduct enantiomer s

20

30

11

9

> 50

16R = OCH3

R = H

R = F

8.2

4.0

(trans )

> 50

Scheme 12.16


peptides 38 or 39 as catalyst. In other words, peptides 38 and 39 are highly selective

and complementary low-molecular-weight kinase mimics whereas the peptide

catalysts already discussed have acylase activity. It is, furthermore, interesting

to note that the opposite enantioselectivity of catalysts 38 and 39 could hardly

have been predicted on the basis of the type and sequence of the amino acids

involved.

Catalytic kinetic resolution of amines has been a typical domain of enzymatic trans-

formations. Attempts to use low-molecular-weight catalysts have notoriously been

frustrated by the rapid uncatalyzed background reaction of the amine substrate

with the acyl donor [40]. The first solution to this problem was recently developed

by Fu, who used the planar chiral catalyst 21d and O-acyl azlactone 40 as the acyl

donor (Scheme 12.19) [41]. In this process, the acyl transfer from the azlactone 40

to the nucleophilic catalyst 21d is rapid relative to both direct transfer to the sub-

strate and to the transfer from the acylated catalyst to the substrate amine. Under

these conditions, which implies use of low reaction temperatures, selectivity factors

as high as 27 were achieved (Scheme 12.19) [41].

Conclusions

Recent years have seen enormous advances in the field of catalytic asymmetric

acylations. Most of the work has been devoted to the kinetic resolution of racemic

alcohols. For this application the most efficient catalysts currently available are

N

OO

OH

BOC

N NH

OOCH3

N

H

BOC-NHO

HN

HNO

H

HO

NHO

H3CO

NN

CH3OH

33 34

pentapeptide 32

from rac-33 using catalyst 32 (s = 27)

8 steps

Scheme 12.17


the bicyclic phosphines introduced by Vedejs, the planar-chiral DMAP derivatives

developed by Fu, and the peptide catalysts introduced by Miller. High selectivity

has also been achieved with the chiral tertiary amine catalysts developed by

Oriyama. All of these nucleophilic catalysts are well suited to practical applications.

Practical selectivity is also achieved by use of the axially chiral DMAP derivatives of

Spivey.

HNBOC-NH

NN

O

HN

HNO

H3C

O

OO

NH(trt)

O

N

N

t-Bu

NHO

OCH3

O

CH3

N HBOC-NH

NN

O

NH

O

HNO

H3C

t-BuO

NH

OCH3

O

O O-t-Bu

OBnOHHO

OHOBnBnO

OHOHHO

OHOHHO

OBnOPO(OPh)2HO

OHOBnBnO

OHOPO3H2HO

OHOHHO

OBnOH(PhO)2OPO

OHOBnBnO

OHOHH2O3PO

OHOHHO

2 mol-% catalyst 38

ClPO(OPh)2, NEt3toluene, 0 oC

2.5 mol-% catalyst 39

ClPO(OPh)2,

toluene, 25 oC

pentapeptide 38 pentapeptide 39

3635

65 %, >98 % ee

Li, NH3, THF

37, 96 %

56 %, >98 % ee

Li, NH3, THF

ent-37, > 95 %

15

3 135

Scheme 12.18


It is especially worth noting that a method for non-enzymatic resolution of

amines by acylation has also been developed. It is hoped that selectivity factors and

ease of operation achieved in the kinetic resolution of alcohols will soon by possi-

ble with amines also.

12.2

Redox Reactions

Kinetic resolution relies on enantiospecific conversion of one enantiomer present

in a racemic mixture while the other remains unchanged (except for parallelkinetic resolution in which both enantiomers are transformed but to different prod-ucts). For secondary alcohols enantiospecific conversion might consist in oxida-

tion of one enantiomer to a ketone while the other remains unchanged (Scheme

12.20).

N

N

H3C CH3

CH3H3C

CH3

R1 R2

NH2

R1 R2

HNH OCH3

O

Fe

R1 R2

HH2N

NO

O O

O

t-Bu

2-naphthyl

CH3

CH3

NH2

CH3

NH2CH3

CH3

NH2

H3CO

CH3

NH2

F3C

CH3

NH2

H3COEt

NH2

CH3

NH2

CH3

NH2

H2N

Oc-hexyl

O

R1: aryl ; R2: alkyl

+ 10 mol-% 21d

CHCl3, -50 oC

+

catalyst 21d

40

s = 12

substrate amines and s-factors:

s = 16 s = 11 s = 13

s = 22 s = 16 s = 27 s = 11

Scheme 12.19


R1 R2

OHH

R1 R2

OHH

R1 R2

O

R1 R2

OHHR1 R2

OHH+

racemic mixture

+separation

pureenantiomer

chiraloxidationcatalyst

Scheme 12.20

Tab. 12.1

mol-% 87 Recovered alcohol ee (%) Conversion (%) S

0.5

1.0 CH3

OH

R

81

98

69

87

5.0

7.1

1.0 CH3

OHH3C

R73 58 6.8

1.0 CH3

OHCl

R89 70 6.0

1.0 CH3

OH

H3CR

64 58 5.1

1.0

OHCH3

R57 59 3.9

0.5 CH3

OH

R57 56 4.5

0.5 c-C6H11

C5H11

OH

S41 66 2.2

0.5C5H11

O

HO2S, 3R

19 58 1.5

12.2 Redox Reactions 343

Oxidation of alcohols to carbonyl compounds using the stable nitroxyl radical

TEMPO (41) as catalyst is a well-known preparative method [42, 43]. Hypochlorite

or peracetic acid is usually used as the final oxidizing agent and ca. 1 mol% of the

catalyst 41 is used. In 1996 Rychnovsky et al. reported the synthesis of the chiral,

binaphthyl-derived TEMPO analog 42 [44]. Table 12.1 lists the results obtained

with 0.5–1 mol% of catalyst 42 [44]. In these oxidation reactions 0.6–0.7 equiva-

lents of sodium hypochlorite were used as the final oxidizing agent (plus 0.1 equiv.

potassium bromide) in a two-phase system containing substrate and catalyst 42 in

dichloromethane at 0 �C. As shown, the best selectivity factors (b5) were observed

for 1-phenylethanol and its derivatives as substrates.

N

CH3

CH3

H3C

H3C

O N

CH3

CH3

CH3

CH3

O

O

OO

OO

H3CCH3

CH3H3C

O

41 42 43

Whereas the chiral TEMPO analog 42 was used to resolve racemic secondary al-

cohols the d-fructose-derived ketone 43 [45] proved useful for oxidative resolution

of racemic diols (Table 12.2) [46, 47]. Persulfate in the form of Oxone, Curox, etc.,

serves as the final oxidizing agent, and the dioxirane generated from the ketone 43

is the chiral active species. Because of the relatively low conversions (except for the

unsubstituted dihydrobenzoin) at which the stated ee were achieved, the method

currently seems to be of limited practical value. Three equivalents of ketone 43

were typically used [46, 47].

Tab. 12.2

Starting racemic diol Conversion (%) Product hydroxy ketone ee (%)

OH

OH

R

R

R ¼ H 51

OH

O

R

R

S

65

R ¼ CH3 12 61

R ¼ F 31 69

R ¼ Cl 11 70

R ¼ Br 10 74

R ¼ CN 6 75

H3C OH

O

H3C

OH

O

S

S

44

H3C

OH

OH

2069


Conclusions

In principle, oxidative kinetic resolution of racemic alcohols can be achieved by

using chiral oxidation catalysts such as TEMPO derivatives or dioxiranes. The se-

lectivity achieved by use of these methods is, however, less than that observed in

acylation reactions (Section 12.1).

References

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Asymmetric Organocatalysis (From Biomimetic Concepts to Applications in Asymmetric Synthesis) || Kinetic Resolution of Racemic Alcohols and Amines