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Enzymatic Syntheses of Chiral Building Blocks from Racemates Preparation of (1R 3R)-Chrysanthemic -Permethrinic and -Caronic Acids from Racemic Diastereomeric Mixtures.

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[ 16lannulene structure does not contribute to its ground
state. Also, the percent resonance energy of 4 (0.87) is
larger than the aromatic criterion (0.50) defined by Aiharaf3].In view of these results, 4 is to be regarded as a peripheral 16%aromatic system.
The charge distribution on each C atom of 4 estimated
from the I3C-NMR spectrum is in accord with the calculated
charge distribution (MIND013, net charge density: C-1,13
-0.12, C-14,16 +0.02, C-15 -0.08, C-2,4 +0.16, C-3
- 0.09). These results demonstrate that the negative charge
is mainly distributed over C-1,13,15 and the positive
charge over C-2,4. We therefore conclude that 4 is stabilized by the resonance of two covalent structures (4a and
4b) and one polarized structure (4c) in which the fivemembered ring is similar to the cyclopentadienide anion
and three-membered ring, similar to the cyclopropenylium
cation[41.
4a
4b
By Manfred Schneider*, Norbert Engel, and
Heike Boensmann
The physiological activities of pyrethroid insecticides
derived from chrysanthemic acid (1R,3R)-la and permethrinic acid (lR,3R)-2a are closely related to their absolute
configurations, making the 1R-enantiomers interesting targets for organic synthesis. Important chiral building blocks
for the synthesis of optically active pyrethroids are also the
caronic acid derivatives (IR,3R)-3a and -3c to -3e"I. Simple methods for the preparation of (lR,3R)-la to -3a starting from readily available educts therefore provide an interesting synthetic challenge.
4c
The chemical properties of this system are consistent
with the n-configuration of 4. Thus, in agreement with no
contribution from the peripheral [16lannulene structure,
electrochemical or alkali metal reduction of 4 leads to decomposition, in marked contrast to [ 16lannulene which
gives the 1871 system by two electron reduction[5'. Also, the
HOMO energy level of 4 (MIND0/3) is extremely high
(-7.22 eV), suggesting that it should be a good electron
donor. On the other hand, although reaction of 4 with
NO :BFy and with CF,COOH affords undefined products (no characteristic absorption of calicene in IR spectra
at ca. 1800 and ca. 1550 cm-I), reaction of 4 with N-bromosuccinimide in dichloromethane proceeds smoothly to
afford the 6,7,8,14,15,16-hexabromo derivative (orange
crystals, m. p. = 222-225 "C (dec.), 80%). Nucleophilic
substitution of 2 with diethylamine in dichloromethane
gives the 3-tert-butylthio-1 I-diethylamino derivative 6
(dark reddish-purple crystals m.p. = 116- 117 "C, 36%).
Received: August 1, 1983;
revised: September 15, 1983 [Z 499 IE]
German version: Angew. Chem. 96 (1984) 75
CAS Registry numbers:
1, 72649-41-3; 2, 72649-42-4; 3, 73625-08-8; 4, 73091-52-8; 4 (hexabromo
deriv.), 88245-24-3;4 (3-ferf-butylthio-11-diethylamino deriv.), 88245-25-4; lithium cyclopentadienide, 16733-97-4;tributyltin hydride, 68-73-3.
[I] K. Hafner, R. Donges, E. Goedecke, R. Kaiser, Angew. Chem. 85 (1973)
362; Angew. Chem. Inf. Ed. Engl. 12 (1973) 337; K. Hafner, ibid. 75 (1963)
1041; 3 (1964) 165; K. Hafner, Pure Appl. Chem. 54 (1982) 939.
[2] Z. Yoshida, Pure Appl. Chem. 54 (1982) 1059.
[3] Private communication, see also J. Aihara, Pure Appl. Chem. 54 (1982)
1115.
[4] The 'H-NMR spectra of 4 did not show equilibration between 4a and 4b
until - 80°C. NMR measurements at temperatures lower than - 80°C
were difficult because 4 is sparingly soluble. For 4c it is suggested the
pentadienide polarization in the cyclopentadiene part (C-13,14,15,16,1)
and the ally1 cation polarization in the cyclopropene part (C-2,3,4) contribute to the ground state of 4.
[5] J. F. M. Oth, H. Baumann, J. M. Gilles, G. Schroder, J . Am. Chem. SOC.
94 (1972) 3498.
64
Enzymatic Syntheses of Chiral Building Blocks from
Racemates: Preparation of (lR,3R)-Chrysanthemic,
-Permethrinic and -Caronic Acids from Racemic,
Diastereomeric Mixtures**
0 Verlag Chemie CmbH, 0-6940 Weinheim,1984
(1R,3R)-3a; R
( lR, 3 R) - 3 b ; R
( 1 R , 3 R ) - 3 ~R;
(1Rj3R)-3d, R
(1R,3R)-3e, R
= CH,, H' = OH
= CH3, H'= OCH,
= CH3, R' = OtBu
= CH,, R' = H
= rBu, R' = H
4
In contrast to well documented asymmetric syntheses"]
and the resolution of racemic mixtures1'.'], the potential of
enzymatic reactions has never been tested in this context.
In fact diastereomeric, racemic mixtures of the methyl esters l b to 3b are readily hydrolyzed enzymatically in the
presence of porcine liver esterase (Scheme 1). l b to 3b
(10-200 mmol) are suspended in 0.1 M phosphate buffer
(pH 8 ) and mixed with the esterase [ca. 70 units (standard
ethyl butyrate) = 0.7 mg/g substrate]. The initial enzymatic
saponification is indicated by the decrease of pH, which is
maintained at pH 8 by the addition of 1 N NaOH solution
from an automatic buret. The reactions can be monitored
from the consumption of NaOH and can be interrupted
after the desired conversion (e.g. 50%). The unreacted esters are removed from the reaction mixtures by extraction
(Et20). The acids formed, which are present in the aqueous
phase as sodium salts, are isolated after acidification to pH
2 by continous extraction with Et20. Diastereomeric ratios
of all fractions were determined by gas chromatography,
and the enantiomeric ratios determined by 'H-NMR spectroscopy and/or gas chromatographic analysis of the diastereomeric (-)-menthy1 esters.
The products (lR,3R)-la to -3a can indeed be obtained
in good yields with the enantiomeric ratios listed in Table
[*] Prof. Dr. M. Schneider, Dr. N. Engel, H. Boensmann
FB 9-Organische Chemie der Universitat-GH
Gaussstrasse 20, D-5600 Wuppertal 1 (FRG)
[**I We thank the Deutsche Forschungsgemeinschaft and the Fonds der
Chemischen Industrie for financial support, Bayer AG for the determination of optical purities by 250 MHz NMR spectroscopy (Dr. J . Kurz)
and for generous gifts of chemicals, and Boehringer Mannheim for enzymes.
0570-0833/84/0101-0064 $02.50/0
Angew. Chem. l n t . Ed. Engl. 23 (1984) No. 1
(+)
- ciT- 1b,
2b
esterase
I
+
I
I(1S,3S)
(1R,3R.)
v
(+)- t r a n s - l b , 2 b
I
r=-cis- 3b
cis- 3b
4
.A
Me02C
cis-3b
COzMe
MeOzC
+
COzMe
(+) - ( 1S,3 S)- 3 b
i
(-)-(1R,3R)-3ae
I
organic phase
aqueous phase
Scheme 1. Diastereoselective enzymatic hydrolysis of l b [R'=CHI; (f)-cis-lb: (+)-trans-lb = 23 :77], 2b [R- CI: (f)-cis-2b :( k)-truns-2b = 14: 861 and 3b [cis3b :( i)-trans-3b =20 :80] as well as enantioselective enzymatic hydrolysis of trans-lb to -3b at 25°C. Enzyme: porcine liver esterase.
Table 1. Enzymatic hydrolysis of the methyl esters lb-3b.
Substrate
Conditions
[a1
cis,trans-1b
Product
(1R.3R)- l a
(1R. 3R)- l a
(IS,3S)-lb
(lR,3R)-la
(IR,3R)-la
(IR,3R)-2n
(1R,3R)-2a
(1R, 3R)-3a
(1R,3R)-3a
(1S,3S)-3b
(IR,3R)-3a
(1R,3R)-3a
trans-lb
trans-1 b
(+)-(IR,3R)-lb
cis, trans-2b
(+)-(IR,3R)-2a
cis,truns-3b
trans-3b
(-)-(lR,3R)-3a
(-)-(IR,3R)-3b
R : S [c]
90
85
80
75
75
90
65
85
85
90
65
70
70
73
30
80
: 30
: 27
: 70
: 20
85 : 15
90 : 10
98 : 2[d]
80 : 20
80 : 20
25 : 75
91 : 9[d]
97: 3
Product
250MHz 'H-NMR [el
(IR,3R)-la
1.16 (s, 3H, CHI), 1.31 (s, 3H, CHI), 1.40 (d, IH), 1.73 (m,
6 H , 2CHs), 2.11 (dd, IH), 4.92 (m, 1 H )
1.23 (s, 3H, CHI), 1.35 (s, 3H, CHI), 1.64 (d, l H ) , 2.30 (dd,
1 H), 5.65 (d, 1 H)
1.32 (s, 3H, CH2), 1.34 (s, 3H, CHI), 2.27 (AB, 2H), 3.72 (s,
3 H, C H d
(lR,3R)-2a
(1R23R)-3a
[a] A = enzymatic hydrolysis (% conversion): B = A with recycling after esterification (% conversion): C = recrystallisations from petroleum ether,
b.p.=60-9O0C.
Based on converted substrate. [cl Determined by 'HNMR (with (+)-(R)-a-methylbenzylamine or Eu(tfc)3) and G C (+5%). [d]
Determined by calibrated G C (+2%). [el &Values, solvent CDCII T=25 "C.
accepted by the enzyme as substrates. They can be recovered unchanged from the reaction mixtures. In contrast, trans-lb to -3b are readily saponified by the enzyme under these conditions. Complete conversions
therefore achieve a separation of the cis- and trans-cyclopropane derivatives (Scheme 1).
b) Enantioselective hydrolysis: Enzymatic hydrolysis of
trans-lb to -3b at lower conversions (e.g. SO%), produces, after removal of the unreacted (1S,3S)-lb to -3b,
the optically active acids (IR,3R)-la to -3a (Scheme 1,
Table 1). The desired 1R-enantiomers are saponified
much faster.
The, as yet non-optimized, enantiomeric ratios can be
further increased by the usual methods (lower conversion,
recycling, recrystallization; cf. examples in Table 1). Chrysanthemic acid (1R,3R)-la ([a1216, c 1.48, CHC13)can be
obtained from the enzymatic process in 70% ee. In contrast, permethrinic acid (lR,3R)-2a ([a]g 32.7, c 0.86,
CHC13), which is of particular commercial interest, can be
obtained almost enantiomerically pure (98 & 2% (GC), 96%
ee) after one recrystallization (petroleum ether) of the initial product (80% ee). Caronic acid monomethyl ester (-)(lR,3R)-3a is obtained almost enantiomerically pure
(97 f 2% (GC), 95% ee). This ester is not easily accessible
by other methods['.z1. It can also be converted into other
building blocks1'] such as (lR,3R)-3c ['H-NMR: 6 = 1.28
(~,6H,2CH3),1.46(~,9H,tBu),2.16(bs,2H),3.70(~,3H,
OCH3); [a]g-20.7, c 1.07, CHC13] and (1R,3R)-3d ['H1. Clearly, the enzymatic reactions are both diastereo- and
enantioselective:
a) Diastereoselective hydrolysis: At the enzyme concentrations used the cis-methyl esters (cis-lb to -3b) are not
Angew. Chem. Int. Ed. Engl. 23 (1984) NO.I
NMR: 6 ~ 1 . 3 2 ,1.35 (s, 3H, CH3), 2.49 (AB, 2H), 3.73 (s,
3H, OCH3), 9.66 (d, 1H); [@I" 15, c 1.43, CHC131.
(lR,3R)-3d can be converted via a known procedure[',*]
into 4, thereby allowing a synthetic entry into the corresponding cis-series.
0 Verlag Chemie GmbH, 0-6940 Weinheim, 1984
0570-0833/84/0101-0065 $02.50/0
65
The chosen reaction times (8-72 h) are dependent on the
amounts of substrate and enzyme and depent on the specific activities (lop6 mol min-' (mg enzyme)-') [(+)(1R,3R)-la: ca. 1.0 (+)-(lR,3R)-2a: ca. 1.7; ( - ) - ( l R , 3 R ) 3a : ca. 7; standard (ethyl butyrate): loo)] of the enzyme towards the substrates, which were determined with the enantiomerically pure (enriched) materials.
The studies are also interesting with respect to enzymesubstrate relations and "in vitro"-investigations of insecticide metabolism in mammals[31.
Received: June 30, 1983;
revised: November 18, 1983 [Z 436 IE]
German version: Angew. Chem. 96 (1984) 52
111 Review: D. Ark, M. Jautelat, R. Lantzsch, Angew. Chem. 93 (1981) 719;
Angew. Chem. Int. Ed. Engl. 20 (1981) 703.
[21 J. Mulzer, M. Kappert, Angew. Chem. 95 (1983) 60; Angew. Chem. Int.
Ed. Engl. 22 (1983) 63; Angew. Chem. Suppl. 1983, 23 and references
cited therein.
[31 D. M. Soderlund, J. E. Casida, Pestic. Biochem. Physiol. 7 (1977) 391.
Enzymatic Synthesis of Chiral Building Blocks
from Prochiral Substrates:
Enantioselective Synthesis of Monoalkyl
Malonates**
Table 1. Enzymatic hydrolysis of dialkyl malonates 1 to the monoalkyl esters
2.
By Manfred Schneider*, Norbert Engel, and
Heike Boensmann
Enantioselective conversion of the prochiral dialkyl malonates 1 into their chiral monoesters 2 would produce
versatile building blocks for numerous other optically active molecules. Selective transformations (derivatization,
degradations, reductions etc.) of the two, now chemically
distinguishable, functional groups at the chiral center in 2
would allow optional entry to both enantiomeric series of
potential target molecules. Optically active barbiturates 3
or a-amino acids 4/ent-4 (X = NH2) are examples of possible synthetic applications. A simple method for the enantioselective conversion of the readily accessible, prochiral
precursors 1 would therefore be very useful, regardless of
the resulting absolute configurations of the products 2.
1
I
2
differentiation"]. Hydrolytic enzymes from microorganisms were used several years ago to convert prochiral dialkyl glutarates into their chiral monoesters[21.Porcine liver
esterase was used in a similar way for a chemoenzymatic
synthesis of (R)-meval~nolactone[~~.
Since porcine liver esterase is easy to handlel41and conveniently accessible it seemed attractive to use this enzyme
for the conversions 1-2. The dialkyl malonates la-lf (1050 mmol) were suspended in 0.1 N phosphate buffer (pH 8)
and mixed with the esterase [70 units (standard: ethyl butyrate) = 0.7 mg/(g substrate)]. The initial enzymatic saponification is indicated by a decrease in pH, which is maintained at pH 8 by the addition of 1 N NaOH solution from
an automatic buret. Only one ester group is saponified and
the reaction terminates after the consumption of 1 equiv.
of NaOH; the reaction mixtures become homogeneous.
The monoesters 2a-2f formed, which are present as sodium salts in the aqueous phase, are isolated in good
yields after acidification to pH 2 by continous extraction
(Et20). The enantiomeric ratios were determined by NMR
spectroscopy of the crude products (Table 1).
a
b
C
d
e
f
R
R"
R
Enantiomer
ratio [a]
nBu
n Bu
Et
n Pr
Ph
Ph
MC
Et
Me
Et
Et
Et
Me
69 : 3 1
75 : 25
60 : 40
54 : 46
93: I
92: 8
4
COzH
From Table 1 it is clear that the enantioselectivities
are dependent on the substitution pattern at the chiral centers of 2a-2f and are largest when the difference in substituent size AR'R" reaches a maximum. Methyl esters, which
are preferable also due to their higher rates of hydrolysis,
appear to give somewhat higher enantiomeric purities than
ethyl esters. The best results from a synthetic point of view
were obtained with l e and If, which afforded the monoalkyl malonates 2e and 2f, respectively, in high enantiomeric ratios; these were further improved to > 97:3 (NMR)
by recrystallization.
H
Received: June 30, 1983;
revised: November 18, 1983 [ Z 438 IE]
German version: Angew. Chem. 96 (1984) 54
at
COIR
ent- 4
Enzymes are able to convert prochiral substrates enantioselectively into chiral molecules by enantiotopic group
[*] Prof. Dr. M. Schneider, Dr. N. Engel, H. Boensmann
[**I
66
MC
MC
Me
Et
[a] Determined by 250MHz 'H-NMR with (+)-(Rf-a-methylbenzylamine.
3
at
MC
FB 9-Organische Chemie der Universitat-GH
Gaussstrasse 20, D-5600 Wuppertal 1 (FRG)
Hydrolytic Enzymes in Organic Synthesis, Part 2. We thank the
Deutsche Forschungsgemeinschaft and the Fonds der Chemischen Industrie for financial support, Bayer AG for the determination of optical
purities by high field 'H-NMR spectroscopy (Dr. J . Kurz) and for generous gifts of chemicals, and Boehringer Mannheim for enzymes.-Part
1 : [4al.
0 Verlag Chemie GmbH, 0-6940 Weinheim, 1984
CAS Registry numbers:
la, 551 14-29-9; lb, 88253-94-5; lc, 2049-70-9: Id, 55898-43-6; le, 34009-615; If, 88253-95-6; (R)-Za, 88293-58-7; (S)-2a, 88293-59-8; (R)-Zb, 88253-96-7;
(S)-2b, 88253-97-8; (R)-Zc, 80226- 12-6; (S)-Zc, 42214-17-9: (R)-2d, 88253.989; (S)-Zd, 88253-99-0; (R)-Ze, 88254-00-6; (S)-2e, 88254-01-7; (R)-2f, 8825402-8; (S)-Zf, 88254-03-9; esterase, 9013-79-0.
[I] D. Seebach, E. Hungerbiihler, A. Fischli in R. Scheffold: Modern Synthetic Methods, Salle+ Sauerlander, Aarau 1980: J. B. Jones, c. J. Sih, D.
Perlman in A. Weissberger: Techniques of Chemistry, Vol. I , 2, Wiley,
New York 1975.
[2] H. Kosmol, K. Kieslich, H. Gibian, Justus Ann. Chem. 711 (1968) 38.
[3] F.-C. Huang, L. F. Hsu Lee, R. S. D. Mittal, P. R. Ravikumar, J. A. Chan,
C. J. Sih, E. Caspi, C. R. Eck, J. Am. Chem. SOC.97 (1975) 4144.
[4] M. Schneider, N. Engel, H. Boensmann, M. Schneider, N. Engel, P. HOnicke, G. Heinemann, H. Gorisch, Angew. Chem. 96 (1984) 52; Angew.
Chem. Int. Ed. Engl. 23 (1984) 64; ibid. 96 (1984) 5 5 ; 23 (1984) 67.
0570-0833/84/0101-0066 $02.50/0
Angew. Chem. Int. Ed. Engl. 23 (1984) No. I
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