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Enzymatic Synthesis of Selectively Protected Glycals.

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[2] E. R. H. Walker, Chem. SUC.Rev. 5 (1976) 23.
[3]H. C. Brown, S. Narasimhan, J . Org. Chem. 49 (1984)3891.
[4]T.Sato, S. Suzuki, Y . Suzuki, Y. Miyaji, Z. Imai, Tetrahedron Lett. 1969.
455s.
[S] S . W. Heinzman, B. Ganem, J . Am. Chern. SOC.104 (1982)6801.
[6] Obtainable from Aldrich or easily prepared according to H. C . Brown,
Y . M. Choi, S. Narasimhan, Inorg. Chem. 20 (1981)4456.
[7] M. S . Mourad, R. S. Varma, G. W. Kabalka, Synth. Cummun. 14 (1984)
1099.
[S]R. S. Varma, G. W. Kabalka, Synth. Cummun. 15 (1985)843.
[9]Using NaBH4/Me2SiCIZ, we were able to reduce benzyl cyanide to 2phenylethylamine in 86% yield.
[lo] 0. W. Steward, 0. R. Pierce, J. Am. Chem. SUC.83 (1961)1916.
stirring the resulting mixture for 45 minutes. With lipase P,
on the other hand, the 3,6-di-O-acetyI derivatives 4a and
4 b were obtained in 92% and 75% yield, respectively.
LCC
2
la, b
3a. b
P
1a.b
Enzymatic Synthesis
of Selectively Protected Glycals**
+
2
4a, b
By E. Wolfgang HoNa*
Glycals and their esters are versatile chiral building
blocks.[’I They can be obtained in good yields from the
corresponding saturated carbohydrates;[’] however, because of their overfunctionalization with hydroxyl groups
and because of the absence of strategically valuable functional groups such as C=C and C=O bonds, these are in
many cases unsuitable for direct conversion into the target
molecules. The directed chemical linkage or transformation of glycals such as la and lb at the hydroxyl groups
usually requires tedious, multistep protection and deprotection procedures. Regioselective acetylations of D-glucal
la and D-galactal lb and deacetylations of the triacetates
5c, 5d have so far never been reported.[31This prompted us
to investigate lipase-catalyzed acetyl transfer reactions [Eq.
(a)-( c)].[~]
+ y R‘COOR”
+Gly(OCOR’),(OH), + x R’COOH
+Gly(OH),(OCOR’), + yR”0H
+ yR’COOCH=CH2
+Gly(OH),(OCOR‘),
Gly(OCOR’),+,
Gly(OH),
+y
Gly(OH),+,
+xH~O
+ yCH3CHO
In the present communication we report some novel, efficient and facile enzymatic syntheses of partially protected
as well as fully hydroxyl-differentiated glucals and galactals.
Of primary interest was the realization of enzymatic
transacetylations in nonaqueous organic media. Reversible
transesterifications [Eq. (b)], however, generally result in
unsatisfactory conversions. This problem can be overcome
by using vinyl esters[51[Eq. (c)]. An especially suitable reagent for irreversible enzymatic acetyl transfer is the inexpensive vinyl acetate 2. For carrying out the reactions the
glycals are either stirred with the enzyme in pure 2 at room
temperature or are previously taken up in small amounts
of a cosolvent and finally treated with 2 and the lipase
(Table 1). The enzymes employed are commercially available lipases from Candida cylindracea (LCC) and Pseudomonas fluorescens (P).[“’ Especially suitable for the selective acetylation of the primary hydroxyl groups of la and
lb are the Candida lipases (Scheme 1, Table 1). Thus, the
reaction of la in 2/ethyl acetate in presence of the lipase
O F afforded, in 24 hours, 6-O-acetyl-~-glucal3a in 90%
yield. The galactal derivative 3b was obtained by dissolving lb in a little water, addition of 2 and lipase S-VII, and
1’1 Dr. E. W. Holla
Hoechst Aktiengesellschaft
Postfach 800320,D-6230 Frankfurt am Main 80 (FRG)
[**II am grateful to Frau A. Weber for carrying out some of the preparative
work.
220
0 VCH Verlagsgesellschaji mbH, D-6940 Weinheim. 1989
Scheme 1. Lipase-catalyzed acetylations and deacetylations.
Table 1. Enzymatic acetyl transfer reactions with o-glucal la, D-galactal lb
and 3,4,6-tri-0-aCetyI-D-gluCal5c.
Starting
Cpd.
Enzyme [6][a]
Reaction
conditions [b]
Product
Isolated
Yield [Yo] [c]
la
lb
la
OF,0.4 g
2 [d], 24 h
S-VII, 0.8 g
P, 0.25 g
P, 1.0 g
P, 1.0 g
2 [el, 45 min
2 [d], 48 h
2 [el, 20 h
buffer [g],5-7 h
3a
3b
4a
4b
6c
90
93
92
75 14
90
(a)
(b)
(c)
Ib
5c
[a] The quoted amounts of enzyme refer to 1.Og of starting compound; the
enzymes can be used several times. [b]All reactions at room temperature. [c]
After flash chromatography. [d] 20-25 vo!-% ethyl acetate. [el 1-4 vol-Yo water, 2 g of powdered molecular sieve 4 A. [fl Approx. 10% of regioisorner
found. [gI 10 mL 0.25 M potassium phosphate buffer, p H = 7 .
After completion of the reactions the insoluble enzymes
can be recovered by membrane filtration and used again in
further transformation^.[^^
Especially interesting with regard to the regiochemistry
is the deacetylation of tri-0-acetyl-D-glucal 5c. The lipaseP-catalyzed ester cleavage in weakly buffered solution
without pH-control affords 4,6-di-O-acetyl-~-glucal6c in
90% yield. In the case of the tri-0-acetyl-D-galactal 5d, on
the other hand, the formation of a complex mixture of 6d
and several di- and monoacetates is observed.
For the synthesis of completely hydroxyl-differentiated
glycals we investigated the enzymatic transfer of benzoyl
and chloroacetyl groupsLs1by using vinyl esters 7 and 9 ,
respectively (Scheme 2, Table 2). Lipase AY-20 and, contrary to expectation, lipase P are suitable for the selective
benzoylation of the 6-hydroxy groups of la and lb with 7.
With tetrahydrofuran or water as cosolvent, the monobenzoates 8a,b are obtained in about 70% yield.[’] Regioselective chioroacetylation of 3a,b and 8a,b with 9/lipase P
and acetylation of 8a,b with 2Aipase P gave the completely differentiated glycals lOa,b, lla,b, and 12a,b in good
yields.“”’
0570-0833/89/0202-0220 $ 02.50/0
Angew. Chem. Int. Ed. Engl. 28 (1989) Nu. 2
J. Chem. 29 (1976) 381; d) W. Kinzy, R. R. Schmidt, Tetrahedron Lett.
R2
0
28 (1987) 1981; e) T. Maki, S. Tejima, Chem. Pharm. Bull. 15 (1967)
1367.
[4] Lipase-catalyzed acetyl transfer reactions of saturated monosaccharides
according to Equations (a) and (b) have already been described; see a)
J.-F. Shaw, A. M. Klibanov, Biotechnol. Bioeng. 29 (1987) 648; b) A. L.
Fink, G. W. Hay, Can. J . Biochem. 4711969) 353; c) J. Zemek, S. Kucar,
D. Anderle, Collect. Czech. Chem. Commun. 52 (1987) 2347; d) H. M.
Sweers, C.-H. Wong, J . Am. Chem. SOC.108 (1986) 6421; e) M. Kloostermann, E. W. J. Mosmuller, H. E. Schoemaker, E. M. Meijer, Tetruhedron
L e f t 28 (1987) 2989; 0 M. Therisod, A. M. Klibanov, J. Am. Chem. SOC.
108 (1986) 5638.
[5] a) M. Degueil-Castaing, B. De Jeso, S. Drouillard, B. Maillard, Tetruhedron Left. 28 (1987) 953; b) Y.-F. Wang, C.-H. Wong, J . Org. Chem. 53
(1988) 3127.
[6] The following lipases from Cundidu cyiindruceu (LCC) were employed:
L-1754 Type VII from Sigma Chemie GmbH (“S-VII”), lipase AY-20
from Amano Pharmaceutical Co.; lipase O F from Meito Sangyo Co.,
Ltd.; lipase P from Pseudomonus fluorescens was supplied by Amano
Pharmaceutical Co.
[7] The lipases were used up to ten times; the decrease in enzymatic activity
is dependent on the type of lipase and reaction. The retention of enzymatic activity is currently under investigation.
[S] For the chemoselective cleavage of acetates, benzoates and chloroacetates see T. W. Greene: Protective Groups in Organic Synthesis, Wiley,
New York 1981.
191 For comparison: Treatment of l a with 1 equivalent of C6H5COCl/pyridine at 0°C gave 8a in only 29% yield [3c].
[lo] Acyl-group migrations were not observed in any of the reactions. All the
given structures are consistent with the spectroscopic data.
7
+
CH2OH
8a, b
la, b
P
+
9
3a, b
1Oa. b
P
+
9
‘OACH20COC,H5
I
1la.b
8a, b
P
+
2
8a, b
12a, b
a,
R1
= OH,
R2 = H; b, R’
7 = &OCOC,H,;
= H,
R2 = OH
9 = bCOCH,CI
Scheme 2. Lipase-catalyzed synthesis of completely hydroxyl-differentiated
glycals.
Table 2. Enzymatic acylations (benzoylation, chloroacetylation and acetylation) of glycals.
Starting
Cpd.
Enzyme [6] [a]
la
lb
lb
3a
3b
88
8b
AY-20
AY-20
P
P
P
P
P
P
P
8a
8b
Reaction
conditions [b]
Product
8a
8b
8b
10a
10b
lla
llb
12a
12b
Isolated
yield [c]
[04
70 [el
67
66
83 [el
80 [el
82
80
92
80
~
[a] One gram of enzyme used per gram of starting compound; the enzymes
can be used several times. [b] All reactions at room temperature. [c] After
flash chromatography. [d] 30-40 vol-% tetrahydrofuran. [el 5-10 vol-% rfgioisomer found. [fl 5-10 vol-% water, 3 g of powdered molecular sieve 4 A. [g]
20-30 vol-% dirnethoxyethane.
Our results show that the enzymatic acetylations and
chloroacetylations of glucal l a and galactal l b as well as
the lipase-catalyzed benzoylations first described by us
provide versatile and efficient routes to useful monosaccharide synthetic building blocks.
Received: August 28, 1988 [Z 2934 IE]
German version: Angew. Chem. I 0 1 (1989) 222
[ I ] S. Hanessian: Tofu1 Synthesis of Natural Products: The ’Chiron Approuch’, Pergamon, Oxford 1983; N. L. Holder, Chem. Rev. 82 (1982)
287; T. D. Inch, Tetrahedron 40 (1984) 3161.
[2] W. Roth, W. Pigman, Methods Curbohydr. Chem. 2 (1963) 405.
13) Concerning the problems of the regioselective acetylation and deacetylation of carbohydrates see a) A. H. Haines, Adv. Curbohydr. Chem. 33
(1976) 11; b) ibid. 39 (1981) 13; for differentiation of the OH groups of
l a and l b see c) I. D. Blackburne, P. M. Fredericks, R. D. Guthrie, Aust.
Angew. Chem. In!. Ed. Engl. 28 (1989) No. 2
Bis(trifluoromethy1)sulfene (CF3)2C=S02,
Isolated as Adduct
By Uwe Hartwig, Hans Pritzkow, Klaus RaN, and
Wolfgang Sundermeyer*
Dedicated to Professor Heinrich Noth on the occasion of
his 60th birthday
Sulfenes R2C=S02(thione S,S-dioxides) have so far not
been isolated but only detected as unstable intermediates
by (in most cases) cycloaddition reactions.[’] Of particular
interest for investigations on the synthesis and stabilization
of small reactive molecules are compounds with double
bonds between main group elements of the second and
third periods. Such species containing, for example,
C=Si,”] N=SiI3] and C=SF, bondsr4]have been isolated or
stabilized as a d d ~ c t d ~and
. ~ ] characterized by structural
analyses.
In reactions previously carried out with a-H-sulfonyl
chlorides in the presence of suitable tertiary amines no
symmetrically substituted sulfenes R2C=S02 could be isolated, but, after further reaction, only sulfonylsulfenes,”] as
was recently demonstrated by us with the isolation of the
amine-stabilized species
XCH2-S02-C(X)=S02+N(CHzCH2)3CH
A,
X = H, CI, Br, CF3
A completely different route now led to the successful
synthesis of bis(trifluoromethy1)sulfene 2, namely via the
symmetrical cleavage of 1,3-dithietane S-oxides.”] The
thermolysis of tetrakis(trifluoromethyl)-1,3-dithietane
1,1,3-trioxide
already gave an indication of the existence of 2 [Eq. (a)], as did also the reaction of the corre~~
[*I Prof. Dr. W. Sundermeyer, Dr. U. Hartwig, Dr. H. Pritzkow,
DipLChem. K. Rall
Anorganisch-chemisches lnstitut der Universitat
Im Neuenheimer Feld 270, D-6900 Heidelberg 1 (FRG)
0 VCH Verlugsgesellschuji mbH, 0-6940 Weinheim, 1989
0570-0833/89/0202-0221 $ 02.50/0
22 1
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