Lipase mediated preparation of differently protected homochiral 2-aryl- 2-fluoro-1,3-propanediols

Article abstract of DOI:10.1016/S0957-4166(98)00181-5

Lipase mediated asymmetric monohydrolysis of 2-aryl-2-fluoromalonic acid diesters or monoacetylation of 2-aryl-2-fluoro-1,3-propanediols affords chiral fiuorinated polyfunctionalized C₃ synthons in excellent enantiomeric excess and acceptable chemical yields.

Full text of DOI:10.1016/S0957-4166(98)00181-5

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 9 (1998) 1859–1862
Lipase mediated preparation of differently protected homochiral
2-aryl-2-fluoro-1,3-propanediols
Giuseppe Guanti,∗ Enrica Narisano ∗ and Renata Riva
Dipartimento di Chimica e Chimica Industriale dell’Università & C.N.R., Centro di Studio per la Chimica dei Composti
Cicloalifatici ed Aromatici,† Via Dodecaneso 31, I-16146 Genova, Italy
Received 24 April 1998; accepted 6 May 1998
Abstract
Lipase mediated asymmetric monohydrolysis of 2-aryl-2-fluoromalonic acid diesters or monoacetylation of 2-
aryl-2-fluoro-1,3-propanediols affords chiral fluorinated polyfunctionalized C3 synthons in excellent enantiomeric
excess and acceptable chemical yields. © 1998 Published by Elsevier Science Ltd. All rights reserved.
2-Substituted-1,3-propanediols are simple but very versatile units that can be used as starting materials
in the synthesis of many biological targets.1,2 Moreover, if the two hydroxyl groups are protected
differentially, these compounds are chiral and thanks to their enantiodivergency3 both enantiomers of
a given target can be achieved starting from the same homochiral precursor.
Enzymes, and particularly lipases, have been shown to be very efficient catalysts for obtaining these
compounds in optically active form.2 Using this methodology, some of these chiral building blocks have
been prepared and then used as precursors in many synthetic applications.2,4
Fluorine containing compounds are extremely rare in nature, however many ‘man made’ organofluoro
derivatives are known.5 It has been shown that the introduction of fluorine into a compound can
significantly affect its behaviour and that, in the case of optically active derivatives, strong differences of
activity between the two enantiomers can occur.6 Biological tools have also been used in the preparation
of fluorine compounds, but asymmetrization of prochiral or meso fluorinated compounds with hydrolytic
enzyme catalysis are reported to occur successfully only in a limited number of cases.5b,7
In connection with our standing interest in the synthesis of small, highly functionalized chiral building
blocks through biological strategies,4 we report here some preliminary results on the chemoenzymatic
synthesis of some differentially protected 2-aryl-2-fluoro-1,3-propanediols. The reasons that prompted
us to undertake this research are: (a) the aim of achieving some new versatile homochiral units to be
used as precursors to fluorinated analogues of aromatic targets; and (b) interest in studying the effect of
fluorine on the arrangement of the substrate in the active site of the enzyme. Recently, on the basis of
†
∗
Associated to the National Institute of C.N.R. for the Chemistry of Biological Systems.
Corresponding authors. E-mail: guanti@chimica.unige.it and narisano@chimica.unige.it
0957-4166/98/$19.00 © 1998 Published by Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(98)00181-5

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some results collected by us and others on the PPL catalysed hydrolysis of non-fluorinated derivatives,
we proposed a model for the active site of this enzyme.3
The asymmetrized diols 4 and thence 5 have been prepared from corresponding malonic diesters
through two convergent pathways: (a) enzymatic asymmetrization of malonic diesters, followed by
stepwise reduction and protection of the two oxygenated branches; and (b) reduction of malonic diesters
to 1,3-propanediols and enzymatic acylation.
The compounds 18 were synthesised from commercially available (for 1a) or from known (for 1b and
1c)4a arylmalonates through fluorination under basic conditions,9 and then submitted to lipase catalysed
hydrolysis, using enzymes of both microbial (lipase Amano AY, from Candida, AYL) or animal (lipase
from porcine pancreas supported on Celite,10 S-PPL) origin. The most significant results are reported in
Table 1. Enantiomeric excess was always measured by converting monoacids 2 into diastereoisomeric
amides, using either (R)- or (S)-α-methylbenzylamine, and analysing both 1H and 19F NMR spectra.11
Table 1
Lipase catalysed asymmetrization of arylfluoromalonic acid diesters (1a–c)a
Diesters 1a and 1c were easily asymmetrized in very high enantiomeric excess (e.e.) using supported
PPL (entries 1 and 4), while some trouble was encountered in the hydrolysis of 1b. As a matter of fact,
monoesters 2 turned out to be rather prone to decarboxylate to corresponding substituted fluoroacetates;
in particular, 2c is quite stable, while 2a decarboxylated on silica gel or in very acidic aqueous solution
(pH≤1) and 2b decarboxylated even at pH 3, so that it was always isolated in a very poor yield and mixed
with the decarboxylation product, ethyl 2-fluoro-2-(2-naphthyl)acetate.
Since the chiral synthon 4b and hence 5b could not be obtained via this route (see entry 3), we turned
to the alternative asymmetrization of 2-aryl-2-fluoro-1,3-propanediols, which can also afford the same
type of chiral building block (Scheme 1).
The new 2-aryl-2-fluoro-1,3-propanediols 3a and 3b12 were synthesised via hydride reduction of the
corresponding diethyl 2-aryl-2-fluoromalonates, while unsatisfactory results were obtained when the
same protocol was applied to the synthesis of 3c. Since the chiral building block 5c could be conveniently
obtained from the enzyme catalysed hydrolysis of diester 1c, no further effort was made to synthesise 3c.
The enzymatic asymmetrization of diols 3 was run in diisopropyl ether as solvent, using vinyl acetate
as an ‘irreversible’ acetylating agent.10 Lipase from Pseudomonas (PSL), from Candida cyclindracea
(CCL) and Novozym, from Candida antarctica (CAL) were tested, in addition to S-PPL, already used
for malonic acid diesters. Most significant results are reported in Table 2. Enantiomeric excess was always
measured by converting monoalcohols 4 into diastereoisomeric Mosher’s esters, using either (R)- or (S)-
MTPA-chlorides, and analysing 1H NMR spectra.11

G. Guanti et al. / Tetrahedron: Asymmetry 9 (1998) 1859–1862
1861
Scheme 1.
Table 2
Lipase catalysed asymmetrization of 2-aryl-2-fluoro-1,3-propanediols (3a–b)a
As already found for the asymmetrization of non-fluorinated 1,3-diols,4 both 3a and 3b gave satisfact-
ory chemical and optical results using PPL, despite the presence of a highly hydrophilic fluorine atom
instead of a hydrogen atom. Different batches of S-PPL gave different reaction rates, but consistantly
very high enantiomeric excesses (the minor enantiomer could scarcely be detected by NMR techniques).
CAL gave very fast acetylation, but poor enantiomeric excess. The reactions of 3b are sensibly slower,
as it appeared to be for the non-fluorinated analogues in the hydrolysis reaction,4a but nevertheless they
afford the desired chiral building block.
In order to test the synthetic utility of new chiral building blocks 2 and 413 and to define their absolute
configuration, we performed selective manipulation of the two oxygenated branches (Scheme 2).
Reduction of the acidic moiety of 2a (from S-PPL catalysed monohydrolysis of 1a), followed by
hydroxyl function protection and reduction of the ester moiety, led to monoprotected diol 5a (R=TBDMS
or Bn). Further manipulation of 5a (R=Bn) gave dextrorotatory 2-fluoro-2-phenyl-1-propanol 6, which
is known to possess the (S) configuration,14 thus allowing us to establish the (S) configuration for

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G. Guanti et al. / Tetrahedron: Asymmetry 9 (1998) 1859–1862
Scheme 2.
monoester 2a. The chemical correlation between monoester 2a and monoacetate 4a (from S-PPL
catalysed monoacetylation of diol 3a), through monoprotected diol 5a (R=TBDMS), allowed the (S)
configuration for monoacetate 4a to be established. This means that, in our case, the model previously
proposed by us for the acetylation/deacetylation reaction catalysed by PPL3 is still followed when
fluorine replaces hydrogen.
Further manipulations of chiral monoesters 2 and monoacetates 4, as well as full experimental details
on their achievement15 will be reported in due course.
Acknowledgements
We thank MURST and C.N.R. (Progetto Strategico) for financial support.
References
1. Banfi, L.; Guanti, G. Synthesis 1993, 1029–1056.
2. Schoffers, E.; Golebiowski, A.; Johnson, C. R. Tetrahedron 1996, 52, 3769–3826 and references therein.
3. Guanti, G.; Banfi, L.; Narisano, E. J. Org. Chem. 1992, 57, 1540–1554.
4. (a) Guanti, G.; Narisano, E.; Podgorski, T.; Thea, S.; Williams, A. Tetrahedron 1990, 46, 7081–7092. (b) Guanti, G.;
Brusco, S.; Narisano, E. Tetrahedron: Asymmetry 1994, 5, 537–540. (c) Guanti, G.; Narisano, E.; Riva, R. Tetrahedron:
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8. Only 1a was a known compound (Banks, R. E.; Besheesh, M. K.; Tsiliopoulos, E. J. Fluorine Chem. 1996, 78, 39–42). 1H
NMR11: 1.32 (t, J 7.1, 6H, 2×CH3), 4.35 (q, J 7.1, 4H, 2×CH2), 7.48–7.57 (m, 2H) and 7.68 (app dd, J 1.8 and 8.8, 1H)
and 7.83–7.91 (m, 3H) and 8.08 (app d, J 1.8, 1H) (ArH) for 1b; 1.32 (t, J 7.1, 6H, 2×CH3), 4.34 (q, J 7.1, 4H, 2×CH2),
7.25–7.38 (m, 2H) and 7.58–7.60 (m, 1H) (ArH) for 1c. 19F NMR11 (CDCl3, CF3CO2H): 84.40 (s) for 1b, 78.53 (s) for
1c.
9. (a) Lal, G. S. J. Org. Chem. 1993, 58, 2791–2796. (b) Banks, R. E.; Lawrence, N. J.; Popplewell, A. L. J. Chem. Soc.,
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11. Spectra were recorded in CDCl3, using TMS (for 1H) or CF3COOH (for 19F) as the internal standard.
1
12. H NMR (CDCl3, TMS, after exchanging with D2O) for 3a: 3.96 and 4.04 (AB part of an ABX system, J 12.8 and 17.8
and 22.5, 4H, 2×CH2OH), 7.35–7.41 (m, 5H, Ph). 19F NMR:11 93.66–94.76 (m) for 3a, 96.70–97.76 (m) for 3b.
13. 19F NMR:11 84.09 (s) for 2a, 84.21 (s) for 2b, 78.31 (s) for 2c, 94.57–95.64 (m) for 4a, 93.80–94.94 (m) for 4b.
14. Goj, O.; Burchardt, A.; Haufe, G. Tetrahedron: Asymmetry 1997, 8, 399–408.
15. Every new compound was fully characterised and gave satisfactory analytical data.