Lipase mediated desymmetrization of 1,2-bis(hydroxymethyl)ferrocene in organic medium: Production of both enantiomers of 2-acetoxymethyl-1-hydroxymethylferrocene

Terrahedron: ASY?UWIV Phcd in Great Britain

Lipase

WA. 3. NO. 6, m. 153-758.

WL?

09574166/92 S5.G0+.00 Pergamcm Press Lad

Mediated Desymmetrization of 1,2-Bis(hydroxymethyl)ferrocene Organic Medium: Production of Both Enantiomers of 2-Acetoxymethyl-1-hydroxymethylferrocene

in

Giovanni Nicolosi*, Raffaele Morrone, Angela Patti and Mario Piattelli Istituto CNR per lo Studio delle Sostanze Naturali di Interesse Alimentare e Chimico-farmaceutico Via de1 Santuario 110,

I-95028 Valverde

CT, Italy

(Received 29 April 1992)

- Both enantiomers of 2-acetoxymethyl-1-hydroxymethylferrocene have been obtained via enantiotoposelective irreversible acylation in organic medium of 1,2-bis(hydroxymethyl)ferrocene using vinyl acetate as acyl donor and a lipase as catalyst.

Abstract

INTRODUCTION

In the last decades chemistry of metallocenes has become the object of an ever increasing attention, at least in part due to the peculiarities of their stereochemistry (‘metallocene chirality’), and hundreds of optically active compounds of this class have been obtained so far. The use of biocatalysis in the preparation of chiral metallocenes, for long time hampered by the generally low solubility of organometallic compounds in water, has now become very attractive in consequence of the recent finding that enzymes can be used successfully in nonaqueous media.’ While 1,2-symmetrically substituted ferrocenes are meso forms, those 1,2-unsymmetrically substituted possess planar chirality and therefore can exist in two enantiomeric forms. In this paper we would like to report the desymmetrization of a meso compound, 1,2-bis(hydroxymethyl)ferrocene 1, by the aid of biocatalyzed acyl-transfer reaction in organic medium.

753

G. NICOLOSI et al.

154

RESULTS

AND

DISCUSSION

At the onset of this work we observed that Pseudomonas cepacea lipase (Amano PS) in benzene catalyzes the acetylation of 1 with vinyl acetate2 as acetyl donor to give (-)-2-acetoxymethyl-l-hydroxymethylferrocene (2a) of good enantiomeric purity (Table, entry 6). Further experiments with this same

CH20H

CH20H 2a

1

2b

3

enzyme immobilized on Hyflo Super Cel gave still better results and 2a could be obtained with good chemical yield and extremely high optical purity (entry 14). Its absolute configuration was established by the sequence of reactions outlined in the following scheme:

2a

Mn02

a

OH-

Fe

.

4

CHO

CHO

CH20Ac

Fe ba

CHzOH 5

Oxidation of 2a with activated MnO2 gave (-)-2-acetoxymethyl-I-formylferrocene on alkaline hydrolysis yielded (lS)-(-)-l-formyl-2-hydroxy(4)) which methylferrocene (5) with known absolute configuration.’ At this point we tried to obtain the antipodal (lR)-(+)-2-acetoxymethyl-l-hydroxymethylferrocene (2b) following an approch successfully used with prochiral aliphatic diols.4 The rationale of this approach is that an enzyme which catalyzes the acetylation of a substrate of this type to afford a chiral monoacyl derivative should give the enantiomer by enzymatic hydrolysis of the corresponding diacyl derivative, provided that in both instances the enantioselectivity of the enzyme remains the same. In our hands, attempts to obtain 2b by hydrolysis of

Desymmeuization of 1,2-bis(hydroxymethyI)ferrccene

diacetate

3

efforts

to

using 1,

met

with

achieve

the

n-butanol.

testing

series

in

an

proteases)t stereopreference The in

(entry

three 10)

lipases

gave

javanicus

lipases

and

3)

2b

purity

in

(entries

11-13)

lipases

gave

applies

in

organic

direct

the

medium

acetylation

enzymes (lipases,

them

to

of

potentially esterases

possessing

and

opposite

lipase. for

these

experiments

of

its

lipase,

of

are

shown

expense

operative

minor

of

chemical conclusion,

or

the

P.

cepacea

in

yield,

hydrolyzed in

the

chemical the

or

and

it

is the

behaviour

is

second kinetic to

be

diol

the to

acylation noted

that

2b, C.

affords

and

excess

the

enantiomeric time

to

the

the

the

fact

that

enantiomeric

fraction

preferential

of

enhanced removal

of

(enantiotoposelective

Although diacetate

this

implies

a

can

be

formed

recycled. by

acetylation

with

vinyl 2a

(lS)-(-)-2-acetoxymethyl-l-hydroxymethylferrocene

as optically viscosum

used

the

due

step5 the

Immobilized was

at

monoester

resolution).

and

enantiomeric

of

the

to

2b

time,

amplification of

latter

compared

yields.

and

(entries The

of

enzyme,

incubation

owing

Mucor purity,

as

optical

yield

cepacea,

optical

preparation

reached

purity yield,

P.

as

(entry

viscosum

diacetate

crude

well

only

R isomer.

being

1,2-bis(hydroxymethyl)ferrocene

benzene

antipode

This

optical

by

the

kinetic

from

lower

the

and

the

e.e.

germ

that

the

the in

chemical of

100% diol.

and

followed

than

the

reaction

the

form

chemical

increase

starting

enantiomer

transesterification recovered,

With

acyl-transfer

is

15-17).

as

wheat

Chromobacterium gave

esterase

adopted,

and to

liver

discrimination.

and

to

active

steadily,

condition

catalyst

to optimize more

(entries

the

and

as

porcine

of definitely

active

tendency

also

addition

however

chosen

much

increased

at

moderate

less

determined. 2b

in

cylindracea

was

the

enantiotopic

reasonably

undertaken

intervals

excess the

be

and

javanicus

screened,

S isomer,

Candida to

under

Rhizopus

perfect

the

lipase,

the

inactive

other

view

were

during

tested

essentially

disappearance

acetate

yield

the

were

of

In

optical

of

also 3

the

media

one

cepacea

an from

viscosum

the

least

P.

arrhizus,

cylindracea

at various of

of

hydrolytic

organic

and

completely

proved

experiments C.

of

in at

this

reconsider

available

find

Rhizopus

lipase

enzyme, C.

that chemical

were

Among

which while

to

and

alcoholysis to

reaction

proteases

from

7-9).

via

decided

any,

Table.

The

2

on

result

commercially

hope

to

data

the

of

the

if

we

acyl-transfer

in

success,

desired

Therefore,

a

effective

little

755

pure

lipase,

compounds, respectively.

using

as catalyst

immobilized

756

G. NICOLOSI et al.

Table.

Enzymatically

mediated

Entry

Enzyme

esterification

Yield

of

of

2(wb

Lipases

1,2-bis(hydroxymethyl)ferrocenea

Stereopreference

(%P

0

Aspergillus

2

Candida

3

Chromobacterium

4

Mucor

5

Porcine

6

Pseudomonas

7

Rhizopus

arrhizus

no

reaction

8

Rhizopus

javanicus

no

reaction

9

Wheat

no

reaction

no

reaction

no

reaction

no

reaction

no

reaction

54

R

75

46

20

R

15

-

80

javanicus

30

S

50

-

70

pancreas

c5

n.d.

n.d.

27

S

94

-

73

viscosum

cepacea

germ

liver

11

Bacillus

12

Papaya

13

Aspergillus

> 95

from licheniformis

Immobilized

oryzae lipases

14

Pseudomonas

15

Chromobacterium

viscosum

16

Chromobacterium

17

Chromobacterium

cepacea

determined;

of benzene,

80

S

100

-

20

(12h)

61

R

46

5

34

viscosum

(18h)

73

R

62

viscosum

(30h)

57

R

-

vinyl

1-13) or 40 mg (immobilized 1-13.

51

cylindracea

Porcine

48 h, others

mixture.

6

none

from

in 4 mL

Unreacted l(%)b

43

Esterase

= not

of

3(Wb

niger

Proteases

‘n.d.

Yield

from

1

10

e.e.

‘Determined

(12h)

indicates

acetate

trifluoro- 1-(9-anthryl)ethanol].

Experimental

(5 molar

equivalent),

on Hyflo

as indicated; from

absence.

chiral

Super Cel, entries

100

enzyme 14-17);

experiments

using

substrate

80 mg (raw, incubation

by ‘H-NMR

Pirkle’s

8

43

conditions:

40 ‘C, 300 rpm. bDetermined shift

19

alcohol

time:

20

mg

entries entries

of the crude [(R)-(-)-2,2.2-

757

Desymmetrization of 1,2-bis(hydroxymethyl)ferrocene

EXPERIMENTAL

General

Methods

Melting Optical and

point

is uncorrected

rotations ‘H-NMR

CDC13 ppm

a

were

Bruker

from

and

measured

spectra

using (6)

were

was

with

recorded

AC250

determined

a at

with

Perkin-Elmer 62.9

and 250 Chemical

spectrometer.

a Kofler

241

instrument. 13c_

polarimeter.

MHz, shifts

respectively, are reported

in as

TMS.

Materials All on

chemicals

3A

used

molecular

previously (AP6),

reported Mucor

(FAP-15)

and Co.

pancreas

Lipases

licheniformis used

C.

in

immobilized

of

Hyflo

procedure

Candida

for

Cel

enzyme

A known

enzymes,

amount

respectively)

The

suspension

the

reaction

the

solvent

was time was

kept (see

(80

vinyl at

40

mg) for

acetate

(5

‘C under

Table)

the at

reduced

of

the

the

determined

after

P.

and

in

dry

40 mg

for

stirring removed

of

were

(300 by

The

residue

the

unreacted

Pirkle’s

benzene

chiral

(4

immobilized

equivalents)

was and

lipases

previously.7

I

continuous pressure.

from enzymes

cepacea

reported

molar

products

addition

Lipase Crude

and

germ, Bacillus

and

Co.

of

niger

javanicus

wheat

papaya

dissolved

raw

catalyst

evaporated

for

as

was

mg

quantification

(‘H-NMR) e.e.

and

viscosum

as

International

arrhizus,

esterification

(20

of enzyme

Amano

Biochemicals.

prepared

catalyzed

Aspergillus

Chemical

C.

were

overnight

prepared

Rhizopus

from oryzae,

FinnSugar

dried was

from (PS),

Rhizopus

Sigma

from

experiments.

Super

were

Aspergillus

from was

the

Lipases

cylindracea,

from

1,2-Bis(hydroxymethyl)ferrocene mL).

was (1)

cepacea

liver

porcine

obtained

most

a1.6

Pseudomonas

proteases

viscosum

on

Benzene

grade.

et

Moise

from

from

were

analytical

(M-lo),

and

Chromobacterium

General

from

esterase

porcine

of

1,2-Bis(hydroxymethyl)ferrocene

javanicus

Enzyme

were

were

sieves.

added.

rpm).

After

filtration

and

was

analyzed and

diol, shift

reagent

[(R)-(-)-2,2,2-trifluoro-l-(9-anthryl)ethanol]. Determination The mg)

of

the

reaction

using

absolute

mixture P.

immobilized

gradient

of

ether

in

configuration

obtained cepacea

hexane

6

4.32

(bs;

H-3

and

of 2a a larger

lipase to

(2a),

methyl-1-hydroxymethylferrocene ‘H-NMR

from

H-5),

give orange 4.21

was 355 oil, (bs;

scale

acetylation

purified mg [cII],~’ H-4).

on of

Si

of gel

1

(400

with

a

(Id)-(-)-2-acetoxy-

-28.3 4.31

(c 0.12, and

EtOH);

4.57

(AB

758

G. NICOL~SI et al.

system,

J=ll

4.14

(s,

70.0,

68.8

product

The

stirring.

residue

ether

in 79

(dd,

J=1.5,

10.06

was

kept

filtered

(s,

aqueous the

for crude

were

5.21

(AB To

a

solution

of

2 h.

Extraction

product

afforded

identical

to

An

those

for

(c

J=ll

mg)

C&OAc), 80.1,

of

the

Mn02

Si

g)

in

gel

was

continuous

evaporated on

70.9,

obtained

(1.5

24 h under

solvent

0.1,

Hz, 4

added

vacua.

(gradient

of

of

reported

83.4,

and 5,

(dd,

mg) the

= (s,

75.4,

mixture ‘H-NMR

2.5

COC&), (5

left

4.69

1.5,

72.3,

EtOH

chromatographic

whose for

in

6

J

2.01

77.6,

(100

(4),

‘H-NMR

4.79

C&-OAc),

and

benzene

EtOH),

H-4),

170.7, of

mg

Hz;

87.1,

2-acetoxymethyl-1-formylferrocene Hz;

was 70

the

-34.2

193.2,

with

(300

activated

temperature

J=2.5

solution

J=12

171.3,

chromatography

system,

NaOH

6

and

and

of

(t.

system,

aliquot

mL)

off mg

6

13C-NMR 20.9.

21.0. (10

column

4.57

(AB

13C-NMR

[a]~”

H-3),

5.15

at room

270

hexane),

and

60.6,

by

give

Hz,

CEO);

temperature [a]~

(from

5.16

0.5N of

purified to

2.5

(5C),

59.0,

CH2C12

was

was

70.2

61.3, in

and

COC&);

catalyst

“C

H-5),

(s,

suspension

hexane)

m.p. Hz;

68.1,

dissolved

The

The

4.81

2.01

(5C),

was

added.

; C&OH),

Hz

H-l’-H-5’),

71.6, mL)

at

a

room

purification spectrum

and

(lS)-(-)-1-formyl-2-hydroxy-

methylferrocene.3

Aknowledgments - We are grateful to Dr. D. Bianchi (Istituto G. Donegani, Novara) for helpful discussion upon ferrocene chirality. We are also indebted to Amano International Enzyme Co. for kind supply of lipases. Thanks are due to CNR for financial assistence, under the scheme “Progetto Finalizzato per la Chimica Fine e Secondaria”. REFERENCES 1 Zaks, A.; Klibanov, A.M. Science, 1984, 224, 1249. Chen, C.-S.; Sih. J. C. Angew. Chem. Int. Ed. Engl. 1989. 28, 695. Klibanov, A.M. Act. Chem. Res., 1990, 23, 114. 2 Degueil-Castaing, M.; DeJesco, B.; Drouillard, S.; Maillard, B. Tetrahedron Let?. 1987, 28, 952 3 Yamazaki, Y.; Hosono, K. Tetrahedron Lett. 1988, 29, 5769. 4 Ramos Tombo, G. M.; Schar, H.-P.; Fernandez, X.; Busquets, I.; Ghisalba, 0. Tetrahedron Lett. 1986. 27, 5707. Hemmerle, H.; Gais, H.J. Tetrahedron Lett. 1987, 28, 3471. 5 Wang, Y.-F.; Chen, C.-S.; Girdaukas, G.; Sih, C. J. J. Am. Chem. Sot. 1984, 106, 3695. Kaslauskas. R.J. J. Am. Chem. Sot. 1989. 111, 4953. Guo. Z.-W.; Wu, S.-H.; Chen, C-S.; Girdaukas, G. Sih, C. J. J. Am. Chem. Sot. 1990, 112, 4942. Chen. C.-S.; Liu, Y. C. J. Org. Chem. 1991, 56, 1966. 6 Moise, C.; Tirouflet. J. Bull. Sot. Chim. Fr. 1969, 4, 1182. 7 Nicolosi, G.; Sanfilippo, C.; Piattelli, M. Tetrahedron, in press.