Chemoenzymatic synthesis of 2-substituted 2-fluoro-1,3-dioxygenated chiral building blocks

Article abstract of DOI:10.1016/S0957-4166(99)00088-9

A series of 2-substituted-2-fluoro-1,3-dioxygenated chiral building blocks are synthesized via a chemoenzymatic route using either (i) lipase catalyzed monohydrolysis of suitably functionalized malonic diesters, or (ii) lipase catalyzed monoacetylation of suitably functionalized 1,3-propanediols.

Full text of DOI:10.1016/S0957-4166(99)00088-9

Pergamon
Tetrahedron: Asymmetry 10 (1999) 1223–1242
Chemoenzymatic synthesis of 2-substituted 2-fluoro-
1,3-dioxygenated chiral building blocks
Enrica Narisano ∗ and Renata Riva †
Dipartimento di Chimica e Chimica Industriale dell’Università and C.N.R. Centro di Studio per la Chimica dei Composti
Cicloalifatici ed Aromatici,‡ Via Dodecaneso 31, I-16146 Genova, Italy
Received 15 January 1999; accepted 8 March 1999
Abstract
A series of 2-substituted-2-fluoro-1,3-dioxygenatedchiral building blocks are synthesized via a chemoenzymatic
route using either (i) lipase catalyzed monohydrolysis of suitably functionalized malonic diesters, or (ii) lipase
catalyzed monoacetylation of suitably functionalized 1,3-propanediols. © 1999 Elsevier Science Ltd. All rights
reserved.
1. Introduction
Chiral highly functionalized small molecules are very attractive building blocks thanks to their usually
high versatility, which allows them to be used in the synthesis of very different complex molecules.
Among them, asymmetrized 2-substituted 1,3-propanediols1,2 are particularly interesting because they
combine high versatility and enantiodivergency,3 i.e. both enantiomers can be prepared starting from the
same homochiral precursor.
Asymmetrization of 2-substituted 1,3-propanediols or their equivalents can be conveniently obtained
via an enzymatic route,2 in particular when using lipases. Lipases have found broad application in organic
chemistry as chiral catalysts, since they can usually be easily obtained, stored and manipulated, are cheap
and usually have a low substrate selectivity, i.e. they accept ‘unnatural’ substrates, with very profound
modifications in structure and functionality. They have proved to be really powerful instruments in
allowing the chiral arsenal of chemists to be enriched.
Asymmetrization of prochiral diols via a hydrolytic enzyme catalyzed reaction can usually be conduc-
ted either via monoacylation of the diol itself or via monohydrolysis of the corresponding diacetate.
∗
†
‡
Corresponding author. E-mail: narisano@chimica.unige.it
E-mail: riva@chimica.unige.it
Associated to the Istituto Nazionale per la Chimica dei Sistemi Biologici.
0957-4166/99/$ - see front matter © 1999 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(99)00088-9

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In recent years we have been engaged in successfully applying this method to different 2-substituted
1,3-propanediols: for example, asymmetrized 2-aryl-1,3-propanediols have been used as precursors of
2-arylpropionic acids (antiinflammatory drugs)4a and of 11-deoxyanthracyclinones (aglycone portion of
some antibiotics),4b while 2-heterocyclic-1,3-propanediols are precursors of quinuclidine drugs,4c but
surely the most impressive result has been the asymmetrization of 2-alkenyl-1,3-propanediols, which
are precursors of asymmetrized tris(hydroxymethyl)methane (THYM*),3 which in turn has been used in
the synthesis of very different targets: top and bottom fragments of talaromicin A;4d a key intermediate
for carbapenem synthesis;4e open-chain phosphonomethoxy analogues of nucleotides;4f an intermediate
for the synthesis of lasalocide A;4g and an intermediate for the synthesis of hypocholesterolemic agent
1233A.4h
Fluorine containing organic compounds are almost xenobiotic: that is, they are scarcely present in
nature, however introduction of a fluorine atom at a specific site in organic molecules is of considerable
interest because fluorine can deeply modify biological activity and allow fluorinated substrates to be used
in biomedical chemistry as drugs or in the study of bioorganic processes.5 For this reason many fluorine-
containing new compounds have been synthesized, with particular attention to chirality, since strong
differences in activity between the two enantiomers have been observed.6 Nevertheless, only sparse
reports have been found on enantioselective fluorination of optically inactive materials or asymmetriza-
tion of compounds having a fluorine atom at the stereogenic center.5b Recently, chemoenzymatic routes
to monofluorinated analogues of anti-inflammatory agents via lipase mediated resolutions of racemic
materials have been reported,7a,b as well as the resolution of 4-fluoroglutamic acids using acylases.7c
To the best of our knowledge, asymmetrization of fluorinated prochiral or meso-compounds through
enzyme-catalyzed reactions is reported as occurring only in a very limited number of cases.8
2. Results and discussion
In connection with our ongoing interest in the synthesis of small, highly-functionalized chiral building
blocks via biochemical strategies, we report here our results on the asymmetric synthesis of 2-substituted
2-fluoro-1,3-dioxygenated C3 fragments 1.9 Synthesis of these very versatile building blocks can be
realized by following at least three different convergent pathways (Scheme 1): (i) enzymatic asymme-
trization of 2-substituted 2-fluoromalonic diesters 2; (ii) enzymatic asymmetrization of 2-substituted
2-fluoro-1,3-propanediols 3 via monoacylation; or (iii) enzymatic asymmetrization of 2-substituted 2-
fluoro-1,3-diacetoxypropanes 4 via monohydrolysis. A suitable stepwise reduction strategy, along with
protection/deprotection of hydroxy groups, should lead in each case to the same type of chiral building
block. Of course, routes (ii) and (iii) should give the two opposite enantiomeric forms of monoacetate
6, but thanks to the enantiodivergency of these molecules this should be neither an advantage nor a
drawback.
2.1. Synthesis of prochiral fluorinated malonic diesters 2, 1,3-propanediols 3, and 1,3-diacetoxyprop-
anes 4
Compounds 2 were synthesized from commercially available (for 2a and 2e) or from known (for
2b,c4a and for 2d10) 2-substituted malonates, through fluorination under basic conditions.11 In our

E. Narisano, R. Riva / Tetrahedron: Asymmetry 10 (1999) 1223–1242
1225
Scheme 1.
hands, diethyl 2-methoxymalonate, the starting material for 2d, was better prepared from dimethyl 2-
methoxymalonate via transesterification under classical acidic conditions than via ethoxycarbonylation
of ethyl methoxyacetate10 (large quantities of ethyl 2,4-dimethoxy-3-oxobutanoate were always formed).
Having 2-fluoromalonates 2 in hand, the most straightforward route to diols 3 appeared to be the
reduction of the malonates themselves. This reaction proved to be more troublesome than expected. As a
matter of fact, conditions that were suitable for non-fluorinated analogues (i.e. lithiumaluminumhydride
in tetrahydrofuran),4a when applied to 2a led only to traces of diol 3a. Low yields10 or difficulties when
using too active hydride sources12 had already been observed in similar reactions.
Using 2a as a probe, a variety of reductive conditions were assayed: diisobutylaluminum hydride13
in toluene at −78°C (traces of 3a, extensive decomposition); Red-Al14 in toluene at 0°C (extensive
decomposition); and sodium borohydride15 in dimethylsulfoxide at high temperature (60°C or 150°C).16
Acceptable yields17 were at last obtained using in situ generated calcium borohydride.15,18 When the
same conditions were applied to 2b, diol 3b was obtained in moderate yield, while neither 2c nor 2d
gave the corresponding diols. By treatment with sodium borohydride in dimethylsulfoxide, 2c, as could
be expected from results obtained using 2a, gave 2-fluoro-2-(3-thienyl)-1-ethanol. Since chiral building
blocks of type 1 with X=3-thienyl or methoxy could be obtained from route (i) (Scheme 1) (vide infra),
no further attempt to synthesize diols 3c,d was made.
An attempt to synthesize diacetate 4a under conditions (acetic anhydride, Et3N) that were suitable
for its non-fluorinated counterpart,4a afforded the desired product only in low yield, probably due to
instability of diol 3a under basic conditions.17 Diacetate 4a was better synthesized via enzyme catalyzed
acetylation, using lipase from Candida antarctica (CAL) (vide infra). The same enzyme catalyzed
acetylation was also applied to the synthesis of 4b.
2.2. Enzyme catalyzed asymmetrization of 2-substituted 2-fluoromalonic acid diesters 2a–d
Several reports on enzyme catalyzed asymmetrization of 2-substituted malonic acid diesters have
appeared,2,8 and usually satisfactory chemical yield and enantiomeric excess are obtained, provided
that no acidic α-proton (prone to racemization) is present8,19 in the malonate to be hydrolyzed or that
anhydrous conditions are used for the enzymatic transesterification.20 Recently, some papers reporting
enzymatic asymmetrization under aqueous conditions of 2-monosubstituted malonates showing no21 or

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slow22 racemization have appeared. Esterases,19,21 aminoacylases,22 and lipases8,20 of both microbial
and mammalian origin have been used at times. The efficiency of a lipase in catalyzing hydrolysis
or transesterification of malonates seems strongly dependent on the substitution pattern and reaction
conditions; for example, diethyl 2-fluoro-2-methylmalonate is a substrate for PPL (lipase from porcine
pancreas) in the hydrolytic reaction,8a while dimethyl 2-methylmalonate is not in the transesterification
process.20 A study on the active site of PLE has been conducted using 2-aryl-2-methylmalonic acid
diester19d as probes.
We assayed a series of lipases of both microbial (Amano AY, AYL, from Candida; CAL, from Candida
antarctica) and mammalian (PPL, from porcine pancreas, from which S-PPL, supported on Celite,23 was
prepared) origin. The aim was (i) to obtain new small functionalized fluorinated building blocks and (ii)
to gain more information on PPL (on the basis of some results collected by us and others on the PPL
catalyzed hydrolysis of non-fluorinated derivatives, we have proposed a model for the active site of this
enzyme3), studying the effects of introducing fluorine instead of hydrogen.
The most significant results are listed in Table 1. Particular attention should be devoted to workup
of crude reaction mixtures from enzymatic hydrolysis, since at pH 7 only non-acidic materials (namely
unreacted diester and by-products) could be extracted from an aqueous layer using an organic solvent
(ethyl acetate). It is necessary to lower pH at values ≤3 in order to extract monoesters 5a–e from the
aqueous layer, but too low a pH caused the monoesters themselves to decarboxylate, giving 2-substituted
2-fluoroacetic acid esters. In particular, 5a (X=Ph) completely decarboxylates to probably optically
inactive19a ethyl 2-fluoro-2-phenylacetate at pH 1, but it is reasonably stable at pH 3 (workup of reaction
mixture should be very rapid), while 5c–e (X=3-thienyl, MeO) are fairly stable at pH 3 and 5b (X=2-
naphthyl) is quite unstable even at pH 3 [only a poor quantity of 5b is obtained from a crude reaction
mixture of enzymatic hydrolysis, along with a sensible amount of ethyl 2-fluoro-2-(2-naphthyl)acetate].
An attempt to purify 5a using flash chromatography resulted in complete decarboxylation, so that
monoesters 5 were always isolated, characterized, and further reacted as crude products. Formation of
a decarboxylated by-product has been previously observed in PLE catalyzed monohydrolysis of a 2,2-
disubstituted malonate:19f in our case, maybe decarboxylation is due to the presence, on the same carbon
atom between the two carboxylic groups, of two additional ‘acidifying’ substituents, such as the highly
electronegative fluorine and an aromatic group. 2-Fluoro-2-substituted malonic acids were never detected
in the reaction mixture: they are either too unstable or too water-soluble to be isolated under the employed
workup conditions.
A perusal of Table 1 indicates that, in the case of 2-aryl-2-fluoromalonates 2a and 2c, satisfactory
results, both in terms of chemical yield and enantiomeric excess, can be achieved using S-PPL (entries 1
and 6), which seems to be somewhat superior (at least in terms of reaction rate) to unsupported enzyme
(cf. entries 1 and 3). The microbial lipase Amano AY is also effective, producing the opposite enantiomer,
but in lower enantiomeric excess (entry 4). Diester 2b was a substrate for PPL (entry 5), notwithstanding
its low reaction rate, but unfortunately monoester 5b, as already stated, is very unstable even at pH 3 and
was always isolated in very low yield (enantiomeric excess was not measured). Since a chiral buinding
block 1, having X=2-naphthyl, can be conveniently obtained from route (ii) of Scheme 1, no particular
effort was made in order to isolate 5b in acceptable yield. As for 2-fluoro-2-methoxymalonic acid diesters
2d,e, initial runs were performed on dimethyl ester 2e, more directly obtained from commercial material
(see above), but results proved to be quite disappointing, both with S-PPL and lipases of microbial origin
(AYL, CAL) (entries 10–12). A ‘blank’ run (identical reaction conditions to enzymatic hydrolysis, but
in the absence of any added lipase) showed that chemical hydrolysis plays a major role in the process,
thus lowering the enantiomeric excess of the monoester. A similar problem of hydrolysis under very mild
conditions of a methyl ester having an electronegative fluorine atom in the α position had already been

E. Narisano, R. Riva / Tetrahedron: Asymmetry 10 (1999) 1223–1242
1227
Table 1
Lipase catalyzed asymmetrization of 2-substituted 2-fluoromalonic acid diesters (2a–e)a
observed.7c Fortunately, use of the diethyl ester minimized chemical hydrolysis, and good results were
obtained when AYL was used as a catalyst (entry 8). It should be noted that AYL showed, with any
substrate tested in Table 1, the opposite enantiomeric preference with respect to S-PPL (cf. entries 1 and
4, 7 and 8, 10 and 11).
Enantiomeric excess of 5a, 5c, and 5d could not be determined simply by running 1H NMR spectra of
these monoacids in the presence of a chiral amine, such as (S)- or (R)-α-methylbenzylamine.19 a,f,24 We
had to react monoacids themselves with the chiral amine, in order to obtain diastereoisomeric amides.8b
The ratio of diastereoisomeric amides could be determined either via gas-chromatographic techniques
(for 5a and 5c) or via 1H or 19F NMR analysis (for 5a, 5c–e).
The absolute configuration was determined for levorotatory 5a, via chemical correlation (vide infra)
to the already known levorotatory (R)-2-fluoro-2-phenyl-1-propanol7b and assessed to be (S). The
same absolute configuration was also tentatively assigned to monoester 5c, with the assumption that
an arrangement of substrate in the active site of an enzyme does not alter when changing aromatic
substituents.
The monoethyl ester of 2-fluoro-2-methylmalonic acid had already been obtained with (S)-
configuration from MYL (from Candida cyclindracea) catalyzed monohydrolysis of diester.8b

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Table 2
Lipase catalyzed asymmetrization of 2-aryl-2-fluoro-1,3-propanediols (3a–b)a
2.3. Enzyme catalyzed asymmetrization of 2-aryl-2-fluoro-1,3-propanediols 3a–b
Compounds 2-aryl-2-fluoro-1,3-propanediols 3a–b were subjected to irreversible enzyme catalyzed
monoacetylation, under already reported experimental conditions.23 More significant results are reported
in Table 2.
As already found for a series of 2-monosubstituted 1,3-propanediols, S-PPL gave very satisfactory
results both for 3a (entry 1) and for 3b (entry 6). Reaction of 3b was slower, as already observed in
the hydrolysis of the corresponding non-fluorinated diacetates;4a nevertheless, it gave monoacetate 6b in
very good enantiomeric excess. Lipase from Pseudomonas (PSL) gave monoacetate 6a in good chemical
yield, comparable to S-PPL, but a somewhat inferior enantiomeric excess (entry 5), while lipases from
Candida (CCL, CAL) gave 6a in very poor enantiomeric excess (entries 2–4). In particular, CAL gave
very fast reactions that did not stop at the monoacetate but went further to the diacetate: indeed, CAL
catalyzed acetylation was used to prepare diacetates 4a,b (entries 3 and 7) in good chemical yield, since
classical acetylation conditions failed (see above). The same enantiomeric preference was steadily found
for every tested enzyme.
The absolute configuration was determined for dextrorotatory 6a to be (S), via chemical correlation
to levorotatory 5a, whose absolute configuration had in turn been ascertained by chemical correlation
(see above) and found to be (S). These results are in accord with an earlier model proposed by us3 for
the catalytic site of PPL: it is apparent that hydrogen-replacing fluorine in the prochiral center takes the
place of hydrogen in the proposed model. Also, the absolute configuration of 6b is tentatively assigned
as (S), on the basis of enzyme selectivity.
The enantiomeric excess of the monoacetates was determined either by gas-chromatographic analysis
using a chiral stationary phase (for 6a) or by converting the monoacetates into diastereoisomeric esters,

E. Narisano, R. Riva / Tetrahedron: Asymmetry 10 (1999) 1223–1242
1229
using either (R) or (S) Mosher’s acid chloride (for 6a and 6b). The two enantiomers of 6a were also
1
distinguishable in the H NMR spectra in the presence of the chiral shift reagent Eu(hfc)3 {europium
tris[(3-heptafluoropropylhydroxymethylene)-(+)-camphorate]}, but rapid racemization (catalyzed by the
same shift reagent) made this analytical method impracticable.
A preliminary attempt to hydrolyze diacetate 4a under standard working conditions, using PPL as
catalyst, gave very disappointing results (good chemical yield, but very low enantiomeric excess). Since
route (iii) gives no improvement with respect to route (ii), but on the contrary is a step longer and requires
a more difficult and time-consuming workup, no further efforts were made.
2.4. Determination of absolute configuration of monoester 5a and monoacetate 6a and synthetic mani-
pulation of these C3 polyfunctionalized chiral building blocks
In order to test synthetic applications of chiral building blocks obtained from enzymatic reactions,
selective independent manipulation of the two oxygenated branches of both 5a,d,e and 6a were perfor-
med, as shown in Scheme 2. At the same time, some of these transformations allowed us to determine
absolute configuration of both (−)-5a and (+)-6a, via chemical correlation to 2-fluoro-2-phenyl-1-
propanol,7b as summarized in detail in Scheme 3.
Scheme 2. Reagents and conditions: (a) (COCl)2, DMF, then NaBH4; 60% for 10a, 33% for 10d, 27% for 10e. (b) TBDMS-OTf,
2,6-lutidine, CH2Cl2; 92% for 11a, 22% for 11d. (c) BnBr, NaH, DMF, 58%. (d) NaBH4, DMSO, 110°C; 20% for 7, 61% for
9. (e) TIPS-OTf, 2,6-lutidine, CH2Cl2. (f) NaOH, THF, MeOH, H2O; 90% for 7, 47% for 8 (two steps from 6a). (g) (COCl)2,
DMSO, i-Pr2EtN, −78°C, quantitative yield for 13 and 15; −20°C, 76% for 14. (h) NaBH4, EtOH, quantitative yield
Initial selective reduction of malonate 5a was attempted using both basic (NaBH4 reduction of
activated carboxylic acid moiety)8b,19f,g and acidic (BH3)19f,g,20 conditions: using the latter conditions,
both the reduction of either the acidic moiety20 or the ester one19f,g in malonic monoesters has been
reported. In our hands, borane reduction of 5a gave extensive decomposition, while NaBH4 reduction of
the activated carboxylic acid moiety gave the desired hydroxy ester 10a in acceptable yield. When the
same reduction conditions were applied to 5d and 5e, hydroxy esters 10d,e were obtained in somewhat
lower yield: as a matter of fact, they appeared to be even more base-sensitive than 10a. Protection of the
hydroxyl function of 10a,d as silyl or benzyl ether run under usual conditions allowed, in turn, 11a,d or
12 to be obtained. Further reduction of the remaining ester function afforded monoprotected diol 7 (from
11a) or 9 (from 12). The same monoprotected diols can, in principle, be obtained via protection of the
hydroxyl of 6a, followed by acetyl removal. As a matter of fact, compound 7, along with the analogous
silylated compound 8, was obtained from 6a in very good yield, while direct synthesis of 9 from 6a
was not useful, since, as for the non-fluorinated analogue, this reaction results in a completely racemic
product, probably via acetyl group exchange under strongly basic conditions.3 Monoprotected diols 7–9

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Scheme 3. Reagents and conditions: (a) See Scheme 2. (b) TsCl, Et3N, DMAP, CH2Cl2, 81% for 16. (c) NaBH4 DMSO, 150°C,
75% (two steps from 8). (d) H2, 10% Pd/C, CaCO3, MeOH, 50%
were in turn transformed into the corresponding aldehydes 13–15 (14 required positively more vigorous
conditions that both 13 and 15). Aldehyde 13 was also reverted to 7, in order to confirm the preservation
of stereochemical integrity during these manipulations.
Convergent synthesis of monoprotected diol 7, both from 5a and 6a, was important, since it allowed
stereochemical correlation between the malonic acid monoester and the monoprotected diol. As a matter
of fact, 7 showed a specific rotation close to zero when derived from both (−)-5a and (+)-6a, but synthesis
and NMR spectrometric analysis of the corresponding Mosher’s ester showed that in both cases 7 had
the same enantiomeric excess as the starting material and that the same enantiomer was obtained from
both (−)-5a and (+)-6a, thus indicating that they should have the same configuration (Scheme 3).
Activation of the alcoholic group of 7 as a tosylate ester afforded diprotected diol 16, which proved
to be very resistant to the reductive removal of the sulfonate function, even when subjected to prolonged
heating with NaBH4 in DMSO.4a On the contrary, monoprotected diol 8, obtained from (−)-5a, could
be easily transformed into the corresponding activated tosylate ester, which was in turn reduced to the
protected alcohol 17. Catalytic hydrogenation gave dextrorotatory 2-fluoro-2-phenyl-1-propanol,7b thus
establishing the (S)-configuration of (−)-5a and, as a consequence, of (+)-6a.
In an attempt to shorten the transformation from 5a to 17, the hydroxy group of 10a was activated as
a tosylate ester, which was then subjected to reduction using NaBH4 in DMSO at high temperature, but
unfortunately this reaction stopped at the stage of monotosylated diol (2-fluoro-2-phenyl-3-tosyloxy-1-
propanol), resistant to any further reduction. It is possible that the neighboring ionized alcohol function
prevents the tosylate from undergoing nucleophilic attack by hydride.
3. Conclusions
In conclusion, we have shown a possible enzymatic route to 2-fluorinated-1,3-dioxygenated chiral
building blocks 1. In detail, synthetic equivalents of 1a and 1b could be obtained both from (i)
enzyme catalyzed monohydrolysis of malonic acid diesters and (ii) enzyme catalyzed monoacetylation
of corresponding 1,3-propanediols, while 1c and 1d could be conveniently obtained from route (i).

E. Narisano, R. Riva / Tetrahedron: Asymmetry 10 (1999) 1223–1242
1231
Effective independent manipulation of the two oxygenated branches, which also means the possibility
to obtain both enantiomeric forms of a given diol such as 7–9 through suitable sequential introductions
of protecting groups, has also been shown. For example, the enantiomer of 16, obtained from (−)-5a or
(+)-6a as shown in Schemes 2 and 3, was obtained from (+)-6a by protection of the hydroxy group of
monoacetate as a tosylate ester, hydrolysis of acetate ester, and final protection of the second hydroxy
group as silyl ether.
Further manipulation of aldehydes 13–15, as well as of monoesters 5 and 6, for example in the
synthesis of fluorinated analogs of antiinflammatory arylpropionic acids,4a,7a,b will be reported in due
course.
4. Experimental
4.1. General
1H and 13C NMR spectra were recorded as CDCl3 solutions on a Varian Gemini 200 spectrometer
at 200 MHz (1H) and 50 MHz (13C) using tetramethylsilane (TMS) as the internal standard; 19F NMR
spectra were recorded as CDCl3 solutions on a Varian FT-80 (80 MHz) spectrometer using CF3COOH
as the internal standard; chemical shifts (δ) are in ppm, coupling constants (J) are in hertz; a ‘*’ means
that the value was obtained through double resonance experiments. Designation of 13C signals was also
made with the aid of DEPT and HETCOR experiments. Optical rotatory powers ([α]D) were measured
with a JASCO DIP 181 polarimeter as CHCl3 (containing 0.75% EtOH) solutions. Melting points were
taken using a Büchi 535 apparatus. GC–MS was carried out on an HP-5971A instrument, using an HP-1
column (12 m long, 0.2 mm wide), electron impact at 70 eV, and a mass temperature of about 175°C.
Unless otherwise stated, analyses were performed with a constant helium flow (0.9 ml/min), starting at
60°C for 2 min and then raising the temperature by 20°C/min up to 280°C (10 min). Gas-chromatographic
(GC) analyses were performed on a Carlo Erba HRGC 5300 instrument, using a chiral capillary column
Dmet.Terbut.SBeta (Mega) (stationary phase: persilylated β-cyclodextrin; 25 m long, 0.25 mm wide) and
helium as a carrier gas (unless otherwise stated: Tinjector=200°C, Tdetector=220°C).
‘Usual workup’ means that the given reaction mixture was extracted three times (Et2O or AcOEt
or CH2Cl2), the organic layer was dried (Na2SO4), filtered and evaporated to dryness under reduced
pressure.
Tetrahydrofuran (THF) was always freshly distilled from K/Ph2CO; CH2Cl2, Et2O, N,N-
dimethylformamide (DMF), dimethylsulfoxide (DMSO), and hexamethylphosphorous triamide
(HMPA) were purchased as dry solvents from Aldrich and stored over 4 Å molecular sieves. Petroleum
ether (PE) refers to the fraction boiling in the range 40–60°C.
F-TEDA-BF4 stands for 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoro-
borate),11 Tf for trifluoromethanesulfonyl (triflyl), Ts for p-toluenesulfonyl (tosyl), TBDMS for
t-butyldimethylsilyl, TIPS for triisopropylsilyl, Bn for benzyl, MTPA for α-methoxy-α-(trifluoro-
methyl)phenylacetyl.
All reactions requiring dry conditions were run under an inert atmosphere (N2).
TLC analyses were carried out on silica gel plates, which were observed under UV (254 nm) light and
developed by dipping into a solution of 21 g of (NH4)4MoO4·4H2O and 1 g of Ce(SO4)2·4H2O in 31 ml
H2SO4 and 469 ml H2O or a 2% aqueous solution of potassium permanganate and warming. Rfs were
measured after an elution of 7–9 cm. Column chromatographies were run following the method of ‘flash
chromatography’, using 230–400 mesh silica gel (Merck).

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All compounds gave satisfactory spectroscopic and chromatographic data: an extensive selection of
this data is reported. Diesters 2a11,25 and 2e,26 as well as racemic monoprotected diol 7,27 were already
known compounds.
PPL (lipase from porcine pancreas), from which S-PPL23 was prepared, and CCL (lipase from Candida
cylindracea) were purchased from Sigma; lipases AYL (from Candida) and PSL (from Pseudomonas)
were kindly donated by Amano; CAL (lipase from Candida antarctica) was a kind gift from Novo
Nordisk.
4.2. Dialkyl 2-substituted 2-fluoromalonates 2a–e
To an oil-free suspension of NaH (1.2 mmol) in dry THF (2 ml) a THF (7 ml) solution of 2-
substituted malonate (1.0 mmol) and 2 ml of dry DMF were added at room temperature. After stirring
for 20 min at the same temperature, F-TEDA-BF4 (1.3 mmol) was added as a solid and stirring
continued overnight. The reaction mixture was cooled to 0°C and 5% H2SO4 was added. The product
was extracted using Et2O, and the organic phase was washed with saturated aqueous NaHCO3, dried
(Na2SO4), filtered and evaporated to dryness. In the case of 2-fluoro-2-methoxymalonates 2d,e, the
reaction mixture was quenched using water instead of 5% H2SO4 and washing with NaHCO3 obviously
omitted. Chromatographic purification (PE:AcOEt, 9:1, for 2a–c, 8:2 for 2d,e) afforded 2-substituted
2-fluoromalonates 2a–e as yellow oils.
4.2.1. Diethyl 2-fluoro-2-phenylmalonate 2a11,25
This product was obtained in 94% yield.
4.2.2. Diethyl 2-fluoro-2-(2-naphthyl)malonate 2b
Yield: 90%; Rf=0.35 (PE:AcOEt, 9:1); 1H NMR and 19F NMR: see literature;9 13C NMR: 13.95 (Me),
63.07 (CH2), 94.27 (d, J 199.8, CF), 123.06 (d, J 7.3), 125.17 (d, J 10.4), 126.55, 127.05, 127.61, 128.10,
128.59, 130.52 (d, J 21.8), 133.03 (d, J 44.4) (ArC), 165.64 (d, J 25.6, C_O); GC–MS: Rt=10.5 min,
m/z (%) 304 (M+, 45), 231 (100), 203 (37), 159 (17), 155 (20), 127 (9).
4.2.3. Diethyl 2-fluoro-2-(3-thienyl)malonate 2c
Yield: 78%; Rf=0.40 (PE:AcOEt, 9:1); 1H NMR and 19F NMR: see literature;9 13C NMR: 13.86 (Me),
62.98 (CH2), 92.52 (d, J 197.6, CF), 124.19 (d, J 8.8), 125.99 (d, J 4.9), 126.04, 133.64 (d, J 24.0) (ArC),
165.12 (d, J 25.8, C_O); GC–MS: Rt=7.9 min, m/z (%) 260 (M+, 20), 187 (100), 159 (35), 131 (55), 115
(39).
4.2.4. Diethyl 2-fluoro-2-methoxymalonate 2d
1
Yield: 72%; Rf=0.47 (PE:AcOEt, 8:2); H NMR: 1.34 (t, J 7.1, 6H, 2×MeCH2), 3.59 (d, J 1.4, 3H,
MeO), 4.36 (q, J 7.1, 4H, 2×CH2); 13C NMR: 13.91 (MeCH2), 53.25 (d, J 3.1, MeO), 63.08 (CH2),
104.52 (d, J 239.7, CF); 19F NMR: 48.67 (bs); GC–MS: Rt=5.2 min, m/z (%) 178 (M+−30, 6), 135 (100),
121 (15), 107 (10), 93 (10).
4.2.5. Dimethyl 2-fluoro-2-methoxymalonate 2e26
This product was obtained in 86% yield.

E. Narisano, R. Riva / Tetrahedron: Asymmetry 10 (1999) 1223–1242
1233
4.3. General procedure for the synthesis of 2-aryl-2-fluoro-1,3-propanediols 3a,b
To a suspension of anhydrous CaCl2 (6.0 mmol) in dry EtOH:THF 1:1 (2 ml), cooled to 0°C, NaBH4
(10.0 mmol) was added as a solid. After stirring for 20 min, a solution of diethyl 2-aryl-2-fluoromalonate
(1.0 mmol) in THF (10 ml) was added and stirring continued for 2 h. The reaction mixture was quenched
(1 N HCl) and worked up as usual (Et2O). Flash chromatography (CH2Cl2:Et2O, 1:1) afforded pure diols
as white solids.
4.3.1. 2-Fluoro-2-phenyl-1,3-propanediol 3a
Yield: 47%; m.p. 67–68.5°C; Rf=0.47 (Et2O); 1H NMR: 2.65 (bt, J 5.0, 2H, 2×OH; disappeared after
exchanging with D2O), 3.87–4.16 [m, 4H, 2×CH2OH; after exchanging with D2O: 3.96 and 4.04 (AB
as part of an ABX system, JAB 12.8, JAX 17.8, JBX 22.5], 7.35–7.41 (m, 5H, Ph); 13C NMR: 66.40 (d, J
25.3, CH2), 98.76 (d, J 175.6, CF), 124.77 (d, J 9.4), 128.47 (d, J 12.8), 128.61, 137.74 (d, J 20.9) (Ph);
19F NMR: 93.66–94.76 (m); GC–MS: Rt=6.8 min, m/z (%) 170 (M+, 0.3), 122 (100), 91 (68).
4.3.2. 2-Fluoro-2-(2-naphthyl)-1,3-propanediol 3b
1
Yield: 30%; m.p. 69–70.5°C; Rf=0.40 (PE:Et2O, 2:8); H NMR: 2.11 (bs, 2H, 2×OH; disappeared
after exchanging with D2O), 4.03–4.34 [m, 4H, 2×CH2OH; after exchanging with D2O: 4.10 and 4.18
(AB as part of an ABX system, JAB 13.1, JAX 18.2, JBX 21.5], 7.46–7.56 (m, 3H) and 7.83–7.92 (m, 4H)
(ArH); 13C NMR: 66.49 (d, J 25.4, CH2), 99.14 (d, J 175.4, CF), 122.29 (d, J 8.9) and 124.37 (d, J 10.5)
and 126.58 and 127.65 and 128.23 and 128.55 and 128.59 and 132.99 (d, J 1.8) and 146.95 (ArC); 19
F
NMR: 96.70–97.76 (m); GC–MS: Rt=9.8 min, m/z (%) 220 (M+, 8), 182 (9), 172 (14), 149 (100), 141
(51), 115 (11).
4.4. General procedure for the synthesis of 2-aryl-2-fluoro-1,3-diacetoxypropanes 4a,b
4.4.1. Chemical acetylation
To a solution of diol 3a (1.0 mmol) in dry CH2Cl2 (6 ml), cooled to 0°C, triethylamine (5.0 mmol),
Ac2O (2.5 mmol), and DMAP (0.1 mmol) were sequentially added. After stirring for 1.5 h at the
same temperature, the reaction was quenched (saturated aqueous NH4Cl) and worked up (Et2O). Flash
chromatography (PE:AcOEt, 9:1 -→ 8:2) afforded diacetate 4a (10%) as an oil: Rf=0.34 (PE:AcOEt, 8:2);
1H NMR: 2.04 (s, 6H, 2×Me), 4.47 and 4.53 (AB as part of an ABX system, JAB 12.4, JAX 20.6, JBX 20.3,
4H, 2×CH2), 7.39 (bs, 5H, Ph); 13C NMR: 20.66 (Me), 60.67 (d, J 25.7, CH2), 95.44 (d, J 181.1, CF),
124.84 (d, J 9.3) and 128.57 and 128.62 (d, J 4.9) and 136.68 (d, J 21.6) (Ph), 170.33 (C_O); 19F NMR:
85.65–86.75 (m); GC–MS (temperature was raised at a rate of 10°C/min): Rt=12.1 min, m/z (%) 254
(M+, 1), 181 (11), 122 (100).
4.4.2. Enzymatic acetylation
To a solution of diols 3a or 3b (1.0 mmol) in diisopropyl ether (17 ml) and vinyl acetate (23
ml), in the presence of a small amount of 3 Å molecular sieves, CAL was added. The reaction was
stopped by filtering off the enzyme on a Celite pad and washing with Et2O. Evaporation of solvent and
chromatographic purification (PE:AcOEt, 9:1 -→ 7:3 for 4b) afforded diacetates 4a or 4b (see Table 2 for
temperatures, enzyme quantities, times and yields).
4b: oil; Rf=0.53 (PE:AcOEt, 7:3); 1H NMR: 2.04 (s, 6H, 2×Me), 4.58 and 4.62 (AB as part of an ABX
system, JAB 12.4, JAX 20.4, JBX 20.7, 4H, 2×CH2), 7.44–7.58 (m, 3H), 7.85–7.92 (m, 4H) (ArH); 13C
NMR: 20.67 (Me), 65.75 (d, J 25.2, CH2), 95.71 (d, J 181.4, CF), 122.24 (d, J 8.8), 124.52 (d, J 10.2),

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E. Narisano, R. Riva / Tetrahedron: Asymmetry 10 (1999) 1223–1242
126.61, 126.73, 127.66, 128.32, 128.44, 132.92, 133.10, 134.02 (d, J 29.0) (ArC), 170.36 (C_O); 19F
NMR: 91.21–92.27 (m); GC–MS: Rt=10.5 min, m/z (%) 304 (M+, 52), 231 (39), 189 (14), 172 (100),
141 (36), 115 (4).
4.5. General procedure for the enzymatic synthesis of 2-substituted 2-fluoromalonic acid monoesters
5a–e
To a suspension of 2-substituted 2-fluoromalonic acid diester (1.0 mmol) in a 0.01 M pH 7 phosphate
buffer (40 ml), lipase was added at room temperature and under vigorous stirring. Addition of 0.1 M
NaOH via a pH-stat apparatus allowed the pH to be kept constant and to monitor the hydrolysis. The
reaction was stopped by filtering off the enzyme through a Celite pad and washing with AcOEt. The
organic phase was separated from the aqueous layer and the latter was extracted twice with AcOEt (this
organic phase contained unreacted diester and decarboxylated by-products), then acidified (diluted HCl)
to pH 3, and extracted (three times) with AcOEt. Anhydrification and evaporation of this organic phase
yielded almost pure 2-substituted 2-fluoromalonic acids monoesters 5a–e as yellow oils. Temperatures,
enzymes (type and quantities), times, optical rotatory powers, chemical yields, and enantiomeric excesses
are reported in detail in Table 1. When reactions were scaled up, 1 N instead of 0.01 N NaOH was used
to titrate the hydrolysis. Analytical data for ethyl 2-fluoro-2-(naphthyl)acetate, the main product isolated
from hydrolysis of 2b (see entry 5 of Table 1), are also reported.
4.5.1. Monoethyl 2-fluoro-2-phenylmalonate 5a
1
Rf=0.33 (AcOEt:EtOH, 7:3); H NMR: 1.30 (t, J 7.1, 3H, Me), 4.33 (q, J 7.1, 2H, CH2), 7.39–7.42
(m, 3H), 7.58–7.63 (m, 2H) (Ph), 9.21 (s, 1H, OH; disappeared after exchanging with D2O); 13C NMR:
13.79 (Me), 63.48 (CH2), 93.68 (d, J 199.7, CF), 125.55 (d, J 9.0), 128.41, 129.67, 132.55 (d, J 21.9)
(Ph), 165.53 (d, J 25.4, CO2Et), 159.53 (d, J 26.4, CO2H); 19F NMR: 84.09 (s).
4.5.2. Monoethyl 2-fluoro-2-(2-naphthyl)malonate 5b
1
Rf=0.28 (AcOEt:EtOH, 7:3); H NMR: 1.33 (t, J 7.1, 3H, Me), 4.35 (q, J 7.1, 2H, CH2), 7.51–8.09
(m, 7H, ArH); 13C NMR: 13.96 (Me), 63.10 (CH2); 19F NMR: 84.21 (s).
4.5.3. Monoethyl 2-fluoro-2-(3-thienyl)malonate 5c
Rf=0.28 (AcOEt:EtOH, 7:3); 1H NMR: 1.33 (t, J 7.1, 3H, Me), 4.36 (q, J 7.1, 2H, CH2), 7.28 (app dd,
J 1.4 and 5.2, 1H), 7.34–7.39 (m, 1H), 7.60–7.62 (m, 1H) (ArH), 10.71 (s, 1H, OH; disappeared after
exchanging with D2O); 13C NMR: 13.87 (Me), 63.63 (CH2), 92.22 (d, J 198.8, CF), 124.58 (d, J 8.5),
128.84 (d, J 5.2), 126.47, 132.90 (d, J 24.8) (ArC), 165.03 (d, J 25.6, CO2Et), 169.64 (d, J 26.9, CO2H);
19F NMR: 78.31 (s).
4.5.4. Monoethyl 2-fluoro-2-methoxymalonate 5d
Rf=0.20 (AcOEt:EtOH, 7:3); 1H NMR: 1.36 (t, J 7.1, 3H, MeCH2), 3.61 (d, J 1.4, 3H, MeO), 4.38 (q,
J 7.1, 2H, CH2), 8.44 (bs, 1H, OH; disappeared after exchanging with D2O); 13C NMR: 13.80 (MeCH2),
53.67 (d, J 3.4, MeO), 63.61 (CH2), 104.28 (d, J 240.2, CF), 162.95 (d, J 34.6, CO2Et), 166.12 (d, J
34.6, CO2H).

E. Narisano, R. Riva / Tetrahedron: Asymmetry 10 (1999) 1223–1242
1235
4.5.5. Monomethyl 2-fluoro-2-methoxymalonate 5e
Rf=0.20 (AcOEt:EtOH, 7:3); 1H NMR: 3.61 (d, J 1.4, 3H, MeOCF), 3.92 (s, 3H, MeOCO), 6.39 (bs,
1H, OH; disappeared after exchanging with D2O); 13C NMR: 53.71–53.84 (m, MeOCF and MeOCO),
104.36 (d, J 244.2, CF), 163.46 (d, J 34.4, CO2Me), 165.77 (d, J 35.1, CO2H); 19F NMR: 48.65 (bs).
4.5.6. Ethyl 2-fluoro-2-(2-naphthyl)acetate
1
Oil; Rf=0.59 (PE:AcOEt, 8:2); H NMR: 1.26 (t, J 7.1, 3H, Me), 4.17–4.38 (m, 2H, CH2), 5.94 (d,
J 47.6, 1H, HCF), 7.51–7.55 (m, 3H), 7.84–7.95 (m, 4H) (ArH); 13C NMR: 14.25 (Me), 62.11 (CH2),
89.76 (d, J 184.9, CF), 123.69 (d, J 5.2), 126.17, 126.82, 127.13, 127.98, 128.42, 128.95, 131.79 (d, J
19.8), 133.69 (d, J 39.0) (ArC), 168.83 (d, J 22.5, C_O); 19F NMR: 96.61 (d).
4.6. General procedure for the enzymatic synthesis of 3-acetoxy-2-aryl-2-fluoro-1-propanols 6a–b
To a solution of diol 3a or 3b (1.0 mmol) in diisopropyl ether (17 ml) and vinyl acetate (23 ml), in
the presence of a small amount of 3 Å molecular sieves, lipase was added. The reaction was stopped
by filtering off the enzyme on a Celite pad and washing with Et2O. Evaporation of the solvent and
chromatographic purification (PE:AcOEt, 7:3) afforded monoacetates 6a or 6b as oils. Temperatures,
enzymes (type and quantities), times, optical rotatory powers, chemical yields and enantiomeric excesses
are reported in detail in Table 2.
4.6.1. 3-Acetoxy-2-fluoro-2-phenyl-1-propanol 6a
1
Rf=0.33 (PE:AcOEt, 7:3); H NMR: 2.05 (s, 3H, Me), 3.97 [dd, J 5.9 and 19.1, 2H, CH2OH; after
exchanging with D2O: 3.97 (d, J 19.2)], 4.52 and 4.57 (AB as part of an ABX system, JAB 11.9, JAX 18.6,
JBX 21.7, 2H, CH2OAc), 7.39–7.43 (m, 5H, Ph); 13C NMR: 20.70 (Me), 65.60 (d, J 25.4), 65.68 (d, J
26.0) (CH2OH and CH2OAc), 97.28 (d, J 177.5, CF), 124.89 (d, J 9.6), 128.57, 137.19 (d, J 21.0) (Ph),
170.76 (C_O); 19F NMR: 94.57–95.64 (m); GC–MS: Rt=8.3 min, m/z (%) 212 (M+, 0.02), 182 (2), 122
(100), 91 (22); GC (P=150 kg/cm2, Toven=145°C): Rt=14.1 min for the (S)-enantiomer and 14.7 min for
the (R)-enantiomer.
4.6.2. 3-Acetoxy-2-fluoro-2-(2-naphthyl)-1-propanol 6b
1
Rf=0.32 (PE:AcOEt, 7:3); H NMR: 2.04 (s, 3H, Me), 2.13 (bt, J 5.6, 1H, OH; disappeared after
exchanging with D2O), 4.05 [dd, J 5.2 and 19.0, 2H, CH2OH; after exchanging with D2O: 4.05 (d, J
19.0)], 4.62, 4.67 (AB as part of an ABX system, JAB 12.5, JAX 21.3, JBX 20.7, 2H, CH2OAc), 7.46–7.56
(m, 3H), 7.83–7.91 (m, 4H) (ArH); 13C NMR: 20.70 (Me), 65.40–65.90 (m, CH2OH and CH2OAc),
97.56 (d, J 177.7, CF), 122.34 (d, J 8.5), 124.50 (d, J 10.1), 126.55, 126.62, 127.64, 128.27, 128.45 (d,
J 1.8), 132.95, 133.04, 134.55 (d, J 21.0) (ArC), 170.83 (C_O); 19F NMR: 93.80–94.94 (m); GC–MS:
Rt=10.2 min, m/z (%) 262 (M+, 22), 231 (7), 189 (9), 172 (100), 141 (51), 128 (11), 115 (8).
4.7. Synthesis of hydroxy esters 10a,d,e
These hydroxy esters were prepared from the corresponding half-esters according to a reported
procedure,7b except that the reaction temperature of the reduction step was kept for 3 h at −78°C. Pure
products were obtained after chromatographic purification (PE:AcOEt, 9:1 -→ 7:3).

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E. Narisano, R. Riva / Tetrahedron: Asymmetry 10 (1999) 1223–1242
4.7.1. Ethyl 2-fluoro-3-hydroxy-2-phenylpropanoate 10a
1
Yield: 60%, white solid, mp 38.0–39.5°C; Rf=0.47 (PE:AcOEt, 7:3); H NMR: 1.30 (t, J 7.1, 3H,
Me), 4.02 and 4.33 (AB as part of an ABX system, JAB 12.6, JAX 15.7, JBX 29.4, 2H, CH2OH), 4.30 (q,
J 7.1, 2H, MeCH2), 7.38–7.55 (m, 5H, Ph); 13C NMR: 14.00 (Me), 62.33 (MeCH2), 67.52 (d, J 22.5,
CH2OH), 97.62 (d, J 188.7, CF), 124.71 (d, J 9.0), 128.62, 129.04, 134.69 (d, J 21.8) (Ph), 168.93 (d,
J 26.6, C_O); 19F NMR: 94.76–95.39 (m); GC–MS: Rt=7.2 min, m/z (%) 182 (M+−30, 100), 154 (53),
119 (41), 91 (79).
4.7.2. Ethyl 2-fluoro-3-hydroxy-2-methoxypropanoate 10d
1
Yield: 27%, oil; Rf=0.35 (PE:AcOEt, 7:3); H NMR: 1.36 (t, J 7.1, 3H, MeCH2), 1.6 (bs, 1H, OH;
disappeared after exchanging with D2O), 3.49 (d, J 1.1, 3H, MeO), 3.82–3.90 (m, 2H, CH2OH), 4.34 (q,
J 7.1, 2H, CH2Me).
4.7.3. Methyl 2-fluoro-3-hydroxy-2-methoxypropanoate 10e
Yield: 33%, oil; Rf=0.32 (PE:AcOEt, 7:3); 1H NMR: 2.22 (bt, 1H, OH; disappeared after exchanging
with D2O), 3.49 (d, J 0.9, 3H MeOCF), 3.83–3.92 (m, 2H, CH2), 3.89 (s, 3H, MeOCO); 13C NMR: 29.41
(d, J 40.9, CH2), 52.98 (MeOCO), 64.65 (d, J 28.0, MeOCF), 110.56 (d, J 23.1, CF), 166.53 (d, J 39.8,
C_O).
4.8. Ethyl 3-(t-butyldimethylsilyloxy)-2-fluoro-2-phenylpropanoate 11a
To a solution of 10a (1.0 mmol) in dry CH2Cl2 (20 ml), cooled to 0°C, 2,6-lutidine (3.0 mmol) and
TBDMS-OTf (2.0 mmol) were sequentially added. Stirring was continued at room temperature overnight,
then the reaction mixture was cooled again to 0°C, quenched (saturated aqueous NH4Cl), and worked up
as usual (AcOEt). Chromatographic purification (PE:Et2O, 95:5 -→ 9:1) afforded 11a (82%, 92% based
1
on unrecovered substrate) as an oil. Rf=0.79 (PE:AcOEt, 8:2); H NMR: 0.07 and 0.08 (2s, 3H each,
Me2Si), 0.89 (s, 9H, Me3C), 1.31 (t, J 7.1, 3H, MeCH2), 3.94 and 4.35 (AB as part of an ABX system,
JAB 11.5, JAX 15.9, JBX 32.1, 2H, CH2OSi), 4.24 and 4.31 (AB as part of an ABX system, JAB 7.1,
J
AX 2.2, JBX 2.4, 2H, CH2Me), 7.33–7.44 (m, 3H), 7.54–7.59 (m, 2H) (Ph); 13C NMR: −5.50 and −5.42
(Me2Si), 14.11 (MeCH2), 18.24 (CSi), 25.70 (Me3C), 61.82 (CH2Me), 68.51 (d, J 21.7, CH2OSi), 97.52
(d, J 193.8, CF), 125.00 (d, J 9.1), 128.37, 128.75, 135.43 (d, J 21.8) (Ph), 168.96 (d, J 25.5, C_O);
19F NMR: 100.06–102.43 (m); GC–MS: Rt=9.1 min, m/z (%) 311 (M+−15, 0.4), 269 (35), 197 (14), 177
(47), 151 (64), 123 (30), 103 (41), 91 (60), 77 (100).
4.9. Ethyl 3-(t-butyldimethylsilyloxy)-2-fluoro-2-methoxypropanoate 11d
The same procedure described above for the synthesis of 11a was applied, but with a reaction
temperature of −15°C and timed for 1 h; 11d was obtained as an oil (32%) after chromatographic
purification (PE:AcOEt, 95:5). Rf=0.76 (PE:AcOEt, 8:2); 1H NMR: 0.04 and 0.05 (2s, 3H each, Me2Si),
0.86 (s, 9H, Me3C), 1.33 (t, J 7.1, 3H, MeCH3), 3.42 (d, J 0.7, 3H MeO), 3.80, 3.94 (AB as part of an
ABX system, JAB 10.9, JAX 10.5, JBX 23.3, 2H, CH2OSi), 4.30 (q, J 7.1, 2H, CH2Me); 13C NMR: −5.60
and −5.51 (Me2Si), 14.17 (MeCH2), 18.77 (Me3C), 25.64 (Me3C), 52.54 (MeO), 61.98 (CH2Me), 65.61
(d, J 27.1, CH2OSi), 111.08 (d, J 233.8, CF), 166.10 (d, J 40.3, C_O); 19F NMR: 56.19–56.77 (m);
GC–MS: Rt=6.6 min, m/z (%) 265 (M+−15, 0.2), 223 (40), 151 (14), 131 (70), 116 (44), 89 (33), 77 (78),
73 (100).

E. Narisano, R. Riva / Tetrahedron: Asymmetry 10 (1999) 1223–1242
1237
4.10. Ethyl 3-(benzyloxy)-2-fluoro-2-phenylpropanoate 12
To a solution of 10a (1.0 mmol) in dry DMF (1.5 ml), cooled to 0°C, benzyl bromide (2.0 mmol)
and NaH (50% dispersion in mineral oil) (2.0 mmol) were sequentially added. After stirring at room
temperature for 2 h, the reaction mixture was again cooled to 0°C, quenched (saturated aqueous NH4Cl),
and worked up as usual (AcOEt). Chromatographic purification (PE:AcOEt, 95:5) afforded 12 (58%) as
an oil. Rf=0.54 (PE:AcOEt, 8:2); 1H NMR: 1.29 (t, J 7.1, 3H, MeCH3), 3.78–4.34 (m, 4H, CH2OBn and
CH2Me), 4.55–4.74 (m, 2H, CH2Ph), 7.28–7.56 (m, 10H, 2×Ph); 13C NMR: 14.05 (MeCH2), 62.13,
67.55, 74.18 (d J 20.7) (CH2OCH2Ph and CH2Me), 97.13 (d, J 193.0, CF), 124.94 (d, J 9.1), 127.70,
128.04, 128.39, 128.52, 128.90, 135.28 (d, J 21.9), 137.71 (2×Ph), 168.83 (d, J 27.1, C_O); 19F NMR:
91.68–92.84 (m).
4.11. 3-(t-Butyldimethylsilyloxy)-2-fluoro-2-phenyl-1-propanol 7
4.11.1. From compound 11a
To a solution of 11a (1.0 mmol) in dry DMSO (10 ml) NaBH4 (8.0 mmol) was added as a solid and
the reaction mixture was heated for 3 h to 110°C. After cooling to room temperature, saturated aqueous
NH4Cl was added and the reaction mixture was worked up as usual (Et2O). Chromatographic purification
1
(PE:EtOAc, 9:1) afforded 7 (20%) as an oil. Rf=0.60 (PE:AcOEt, 8:2); H NMR: see literature;27 13
C
NMR: −5.64 and −5.58 (Me2Si), 18.23 (CSi), 25.76 (Me3C), 66.20 (d, J 24.5), 67.44 (d, J 28.1) (CH2OSi
and CH2OH), 98.06 (d, J 177.3, CF), 124.94 (d, J 9.8), 128.11, 128.32 (d, J 1.8), 138.56 (d, J 21.0) (Ph);
19F NMR: 96.09 (app quintuplet, J 20.8).
4.11.2. From compound 6a
4.11.2.1. Silylation. A dry CH2Cl2 solution of 6a was sequentially treated with 2,6-lutidine and
TBDMS-OTf as described above in the synthesis of 11a. The usual workup afforded crude 1-acetoxy-
3-(t-butyldimethylsilyloxy)-2-fluoro-2-phenylpropane (oil), which was used as such in the subsequent
reaction. Rf=0.84 (PE:AcOEt, 8:2).
4.11.2.2. Saponification. A solution of crude acetate (1.0 mmol) in THF:MeOH, 10:1 (11 ml) was
treated with 1 N NaOH (1.5 ml) at room temperature for 30 min. Saturated aqueous NH4Cl was added
and the reaction mixture worked up as usual (AcOEt). Chromatographic purification afforded pure 7.
When synthesized from (+)-6a, having an e.e.≥96% (see entry 1 of Table 2), (R)-7 showed [α]D=−1.0 (c
1.1); 1H NMR analysis of Mosher’s esters showed an e.e.≥96%.
4.11.3. From aldehyde 14
To a solution of aldehyde 14 in 95% EtOH (1.0 mmol in 6 ml), cooled to 0°C, NaBH4 (1.1 mmol)
was added as a solid. After stirring for 5 min, the reaction mixture was quenched with saturated aqueous
NH4Cl and most of the solvent was evaporated under reduced pressure; the residue was kept using AcOEt
and the reaction worked up as usual (AcOEt) to give 7 in quantitative yield.
4.12. 3-Benzyloxy-2-fluoro-2-phenyl-1-propanol 9
Applying to 12 the same procedure described above for the synthesis of 7 from 11a, monoprotected
diol 9 was obtained (61%) as an oil after chromatographic purification (PE:AcOEt, 9:1). Rf=0.28
(PE:AcOEt, 8:2); 1H NMR: 2.18 (bt, J 6.7, 1H, OH), 3.89 (d, J 20.1, 2H), 3.87–4.21 (m, 2H) (CH2OBn,

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E. Narisano, R. Riva / Tetrahedron: Asymmetry 10 (1999) 1223–1242
CH2OH), 4.62, 4.58 (AB system, JAB 12.1, 2H, CH2Ph), 7.27–7.43 (m, 10H, 2×Ph); 13C NMR: 66.48
(d, J 25.0), 73.25 (d, J 26.2), 73.84 (CH2OCH2Ph, CH2OH), 98.16 (d, J 176.7, CF), 124.93 (d, J
9.5), 127.72, 127.86, 128.22, 128.44, 128.48, 137.58, 138.41 (d, J 21.4) (2×Ph); 19F NMR: 94.28 (app
quintuplet, J 20.6); GC–MS: Rt=10.0 min, m/z (%) 260 (M+, 1), 210 (1), 199 (2), 139 (7), 122 (35), 119
(23), 91 (100). When synthesized starting from (−)-5a, having an e.e.≥96% (see entry 1 of Table 1), (R)-9
showed [α]D=−20.2 (c 0.3); GC (P=250 kg/cm2, Toven=160°C): Rt=40.0 min for the (S)-enantiomer and
41.7 min for the (R)-enantiomer] showing an e.e.≥96%.
4.13. 2-Fluoro-3-(triisopropylsilyloxy)-2-phenyl-1-propanol 8
4.13.1. Silylation
A dry CH2Cl2 solution of 6a (1.0 mmol in 13 ml), cooled to 0°C, was sequentially treated with 2,6-
lutidine (3.0 mmol) and TIPS-OTf (2.0 mmol). Stirring was continued at room temperature overnight,
then the reaction mixture was cooled again to 0°C, quenched (saturated aqueous NH4Cl), and worked up
as usual (Et2O).
4.13.2. Saponification
Crude acetate was dissolved in THF:MeOH, 1:1 (1.0 mmol in 25 ml) and treated with 1 N NaOH (1 ml)
at room temperature for 2 h. Saturated aqueous NH4Cl was added; the usual workup and chromatographic
purification (PE:AcOEt, 85:15) afforded pure 8 as an oil (47%, two steps from 6a). Rf=0.43 (PE:AcOEt,
1
9:1); H NMR: 1.01–1.25 (m, 21H, 3×CHMe2), 2.36 (bt, J 6.6, 1H, OH), 3.93–4.31 (m, 4H, CH2OH
and CH2OSi), 7.32–7.46 (m, 5H, Ph); 13C NMR: 11.90 and 12.33 (Me2CH), 17.76 (d, J 6.5, Me2CH),
66.24 (d, J 24.5), 67.91 (d, J 28.8) (CH2OH and CH2OSi), 98.18 (d, J 176.3, CF), 125.01 (d, J 9.7),
128.15 (d, J 11.4), 128.27, 138.75 (d, J 20.1) (Ph). When synthesized starting from (+)-6a, having an
e.e.≥96% (see entry 1 of Table 2), (R)-8 showed [α]D=−0.4 (c 1.0).
4.14. General procedure for the synthesis of O-protected 3-hydroxyaldehydes 13–15 from corresponding
monoprotected diols 7–9
To 1.1 ml (2.6 mmol) of a 2.4 M solution of (COCl)2 in dry CH2Cl2, cooled to −78°C, 3.5 ml (3.5
mmol) of a 1 M solution of DMSO in CH2Cl2 were added; the reaction mixture was stirred for 15 min
at the same temperature, then 1.0 mmol of 7 or 9 was added as a CH2Cl2 (10 ml) solution and, after
an additional 15 min, 8.0 mmol of i-Pr2NEt was added. After stirring overnight at −78°C, a 5% (w/w)
aqueous solution of NH4H2PO4 and 1 N HCl were added to neutral pH. The usual workup (CH2Cl2)
afforded the desired aldehyde as an oil.
The same procedure was also applied to monoprotected diol 8, but the reaction was stirred, after the
addition of the amine, for 3 days at −20°C before quenching; aldehyde 14 was isolated as an oil which
crystallized on freezing.
4.14.1. 3-(t-Butyldimethylsilyloxy)-2-fluoro-2-phenylpropanal 13
Quantitative yield; Rf ∼0.60 (PE:AcOEt, 8:2) (elongated spot); 1H NMR: 0.05 and 0.06 (2s, 3H each,
Me2Si), 0.86 (s, 9H, Me3C), 3.96 and 4.31 (AB as part of an ABXM system, JAB 11.8, JAX 16.6, JBX 31.0,
JAM 1.4, 2H, CH2), 7.28–7.49 (m, 5H, Ph), 9.81 (dd, J 1.4 and 5.6, 1H, H–C_O); 13C NMR: −5.57 and
−5.52 (Me2Si), 18.27 (Me3C), 25.70 (Me3C), 67.87 (d, J 21.4, CH2), 100.93 (d, J 185.3, CF), 124.91 (d,
J 9.7), 128.68, 128.89, 133.24 (d, J 21.4) (Ph), 198.60 (d, J 43.7, C_O); 19F NMR: 89.48–90.18 (m).

E. Narisano, R. Riva / Tetrahedron: Asymmetry 10 (1999) 1223–1242
1239
4.14.2. 2-Fluoro-3-(triisopropylsilyloxy)-2-phenylpropanal 14
1
Yield: 76%; white crystals, mp 29.5–30°C; Rf ∼0.58 (PE:AcOEt, 9:1) (elongated spot); H NMR:
1.04–1.27 (m, 21H, 3×CHMe2), 3.99–4.51 (m, 2H, CH2), 7.16–7.49 (m, 5H, Ph), 9.84 (dd, J 1.4 and
5.6, 1H, H–C_O); 13C NMR: 11.89 (CSi), 17.80 (Me), 68.56 (d, J 21.5, CH2OSi), 100.97 (d, J 185.6,
C–F), 124.92 (d, J 14.2), 128.64 (d, J 1.7), 128.85, 133.36 (d, J 21.7) (ArC), 198.78 (d, J 42.4, C_O);
19F NMR: 97.57–98.26 (m); GC–MS (temperature was raised at a rate of 10°C/min): Rt=15.4 min, m/z
(%) 281 (M+−43, 2), 233 (23), 211 (10), 105 (33), 103 (32), 77 (100).
4.14.3. 3-(Benzyloxy)-2-fluoro-2-phenylpropanal 15
Yield: 92%; Rf ∼0.46 (PE:AcOEt, 9:1) (elongated spot); 1H NMR: 3.78–4.26 (m, 2H, CH2CF), 4.60
(s, 2H, CH2Ph), 7.25–7.43 (m, 10H, 2×Ph), 9.80 (dd, J 1.4 and 5.3, 1H, HC_O); 13C NMR: 73.34 (d,
J 20.6, CH2CF), 73.95 (CH2Ph), 100.61 (d, J 185.12, CF), 124.90 (d, J 9.3), 127.74, 127.91, 128.47,
128.81, 129.06, 132.99 (d, J 22.1), 137.27 (2×Ph), 197.65 (d, J 42.1, C_O).
4.15. 1-(t-Butyldimethylsilyloxy)-2-fluoro-2-phenyl-3-(p-toluenesulfonyloxy)propane 16
To a solution of 7 (1.0 mmol) in dry CH2Cl2 (35 ml), cooled to 0°C, Et3N (6.0 mmol), p-
toluenesulfonyl chloride (4.4 mmol), and DMAP (2.0 mmol) were sequentially added. After stirring at
room temperature for 3 h, the reaction mixture was quenched with saturated aqueous NH4Cl and worked
up as usual (CH2Cl2). Chromatographic purification (PE:AcOEt, 95:5) gave pure 16 (81%) as an oil.
Rf=0.42 (PE:AcOEt, 9:1); 1H NMR: −0.04 and −0.02 (2s, 3H each, Me2Si), 0.82 (s, 9H, Me3C), 2.44 (s,
3H, MeAr), 3.81 and 3.91 (AB as part of an ABX system, JAB 11.1, JAX 19.1, JBX 13.8, 2H, CH2OSi),
4.37 and 4.48 (AB as part of an ABX system, JAB 10.8, JAX 21.3, JBX 19.1, 2H, CH2OTs), 7.28–7.32 (m,
7H), 7.68–7.73 (m, 2H) (ArH); 13C NMR: −5.64 (Me2Si), 18.19 (Me3C), 21.68 (MeAr), 25.73 (Me3C),
66.06 (d, J 29.5), 70.43 (d, J 25.6) (CH2OSi, CH2OTs), 96.00 (d, J 181.4, CF), 125.05 (d, J 9.7), 128.07,
128.32 (d, J 1.8), 128.44, 129.81, 132.61, 137.10 (d, J 21.1), 144.86 (ArC); 19F NMR: 93.02–94.00 (m).
4.16. 1-Benzyloxy-2-fluoro-2-phenylpropane 17
4.16.1. Tosylation
Monoprotected alcohol 8 was tosylated as described above for the synthesis of 16.
Chromatographic purification (PE:AcOEt, 95:5) afforded pure 1-benzyloxy-2-fluoro-2-phenyl-3-
1
(p-toluenesulfonyloxy)propane (95%) as an oil. Rf=0.52 (PE:AcOEt, 8:2); H NMR: 2.42 (s, 3H,
MeAr), 3.77 and 3.82 (AB as part of an ABX system, JAB 10.8, JAX 18.9, JBX 16.4, 2H, CH2OBn),
4.37 and 4.47 (AB as part of an ABX system, JAB 10.9, JAX 20.0, JBX 20.0, 2H, CH2OTs), 4.53 (s, 2H,
CH2Ph), 7.23–7.33 (m, 12H), 7.69 (app d, J 8.3, 2H) (ArH); 13C NMR: 22.10 (MeAr), 71.27 (d, J 26.4),
72.57 (d, J 27.2) (CH2OBn and CH2OTs), 74.27 (CH2Ph), 96.20 (d, J 180.7, CF), 125.48 (d, J 9.4),
128.08, 128.29, 128.44, 128.90, 129.03, 130.27, 137.38 (d, J 21.4), 137.92, 145.34 (ArC); 19F NMR:
90.95–91.94 (m); GC–MS: Rt=9.9 min, m/z (%) 279 (M+−135, 0.06), 223 (4), 205 (3), 149 (100).
4.16.2. Reduction
1-Benzyloxy-2-fluoro-2-phenyl-3-(p-toluenesulfonyloxy)propane was dissolved in dry DMSO (1.0
mmol in 8 ml) and NaBH4 (5.0 mmol) was added as a solid. After heating at 150°C for 5 h, the reaction
mixture was cooled to room temperature, quenched (saturated aqueous NH4Cl), and worked up as usual
(PE:AcOEt, 1:1). Chromatographic purification (PE:AcOEt, 95:5) afforded pure 1-benzyloxy-2-fluoro-
2-phenylpropane 17 (68%, 79% based on unrecovered substrate) as an oil. Rf=0.30 (PE:AcOEt, 95:5);

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E. Narisano, R. Riva / Tetrahedron: Asymmetry 10 (1999) 1223–1242
1H NMR: 1.73 (d, J 22.9, 3H, Me), 3.64 and 3.71 (AB as part of an ABX system, JAB 11.1, JAX 24.5, JBX
17.7, 2H, CH2OBn), 4.56 and 4.63 (AB system, JAB 12.2, 2H, CH2Ph), 7.25–7.38 (m, 10H, 2×Ph); 13
C
NMR: 24.08 (d, J 24.6, Me), 74.07 and 76.78 (d, J 25.3) (CH2OCH2Ph), 97.59 (d, J 173.5, CF), 125.04
(d, J 9.2), 128.07, 128.68, 128.83, 138.55, 142.32 (d, J 21.3) (ArC).
4.17. (S)-(+)-2-Fluoro-2-phenyl-1-propanol
A solution of 1.0 mmol of 17 (obtained starting from levorotatory 5a) in 96% MeOH (30 ml) was
hydrogenated at room temperature and ambient pressure in the presence of a small amount of CaCO3 and
10% Pd/C. After 7 h, the solid residue was filtered off and the solvent evaporated to give dextrorotatory
2-fluoro-2-phenyl-1-propanol7b (50%).
4.18. Synthesis and reduction of ethyl 2-fluoro-2-phenyl-3-(p-toluenesulfonyloxy)propanoate
4.18.1. Tosylation
Hydroxy ester 10a was tosylated as described above for the synthesis of 16. Chromatographic puri-
fication (PE:AcOEt, 9:1 -→ 8:2) afforded ethyl 2-fluoro-2-phenyl-3-(p-toluenesulfonyloxy)propanoate
1
(71%) as an oil: Rf=0.44 (PE:AcOEt, 8:2); H NMR: 1.27 (t, J 7.1, 3H, MeCH2), 2.45 (s, 3H, MeAr),
4.25 (q, J 7.1, 2H, CH2Me), 4.36 and 4.72 (AB as part of an ABX system, JAB 11.1, JAX 15.8, JBX 27.9,
2H, CH2OTs), 7.31–7.47 (m, 7H), 7.75 (app d, J 8.3, 2H) (ArH); 13C NMR: 13.93 (MeCH2), 21.67
(MeAr), 62.75, 71.61 (d, J 21.7) (CH2OTs, CH2Me), 94.44 (d, J 196.1, CF), 124.65 (d, J 8.9), 128.00,
128.79 (d, J 1.8), 129.55, 129.86, 132.49, 133.26 (d, J 21.5), 145.11 (ArC), 167.09 (d, J 26.3, C_O).
4.18.2. Reduction
Applying to ethyl 2-fluoro-2-phenyl-3-(p-toluenesulfonyloxy)propanoate the same reduction condi-
tions described above for the synthesis of 7 from 11a, 2-fluoro-2-phenyl-3-(p-toluenesulfonyloxy)-1-
propanol (78%) was obtained as a white solid after chromatographic purification (PE:AcOEt, 8:2 -→ 1:1).
1
Rf=0.17 (PE:AcOEt, 8:2); H NMR: 2.01 (bt, J 7.0, 1H, OH; disappeared after exchanging with D2O),
2.45 (s, 3H, Me), 3.97 [app dd, J 6.0 and 18.8, 2H, CH2OH; after exchanging with D2O: 3.95 (d, J 18.7)],
4.27–4.55 (m, 2H, CH2OTs), 7.27–7.34 (m, 7H), 7.72 (app d, J 8.3, 2H) (ArH); 13C NMR: 21.68 (Me),
65.14 (d, J 26.0), 70.48 (d, J 27.0) (CH2OTs, CH2OH), 96.52 (d, J 179.3, CF), 124.90 (d, J 9.4), 127.97,
128.63, 128.72, 129.00, 132.55, 136.30 (d, J 20.9), 145.13 (ArC).
4.19. Diastereoisomeric amides from monoesters 5a,c–d
The two diastereoisomeric amides were synthesized, according to the procedure reported in the
literature,8b using either (R)- or (S)-α-methylbenzylamine. Some selected analytical data for each
diastereoisomer are reported here. Retention times (Rt) refers to GC (P=150 kg/cm2, Tinjector=250°C,
T
detector=300°C, Toven=210°C) on chiral column (see Section 4.1).
4.19.1. Amides from 5a [(S)-enantiomer, from entry 1 of Table 1]
PE:AcOEt, 97:3 -→ 9:1 (for chromatographic purification), 8:2 (for TLC); diastereoisomer A [from
1
(S)-amine]: Rf=0.41; H NMR: 1.25 (d, J 7.0, MeCH; s, irradiating at 5.14 ppm); 19F NMR: 80.70 (s);
Rt=17.7 min; diastereoisomer B [from (R)-amine]: Rf=0.46; 1H NMR: 1.30 (d, J 7.0, MeCH; s, irradiating
at 5.14 ppm); 19F NMR: 70.08 (s); Rt=16.8 min.

E. Narisano, R. Riva / Tetrahedron: Asymmetry 10 (1999) 1223–1242
1241
4.19.2. Amides from 5c
PE:AcOEt, 95:5 -→ 8:2 (for chromatographic purification), 7:3 (for TLC); diastereoisomer A: Rf=0.32;
1H NMR: 1.25 (t, J 7.1, MeCH2; s, irradiating at 4.30 ppm), 4.39* (s, CH2Me, irradiating at 1.28 ppm),
1
7.59–7.62 (m, ArH); Rt=18.0 min; diastereoisomer B: Rf=0.37; H NMR: 1.32 (t, J 7.1, MeCH2; s,
irradiating at 4.30 ppm), 4.44* (s, CH2Me, irradiating at 1.28 ppm), 7.50–7.53 (m, ArH); Rt=17.6 min.
4.19.3. Amides from 5d
PE:AcOEt, 9:1 -→ 8:2 (for chromatographic purification), 7:3 (for TLC); diastereoisomer A: Rf=0.33;
1H NMR: 3.43 (d, J 1.3, MeO); diastereoisomer B: Rf=0.39; 1H NMR: 3.48 (d, J 1.5, MeO).
4.19.4. Amides from 5e
PE:AcOEt, 9:1 -→ 8:2 (for chromatographic purification), 7:3 (for TLC); diastereoisomer A: Rf=0.29;
1
1H NMR: 3.52 (d, J 1.4, MeOCF), 3.86 (s, MeOCO); diastereoisomer B: Rf=0.24; H NMR: 3.55 (d, J
1.4, MeOCF), 3.88 (s, MeOCO).
4.20. Diastereoisomeric Mosher’s esters from monoacetates 6a,b and from monoprotected diol 7
The two diastereoisomeric Mosher’s esters were always synthesized,28 using either (R)- or (S)-MTPA-
Cl. Some selected analytical data for each diastereoisomer are reported here.
4.20.1. Esters from 6a [(S)-enantiomer, from entry 1 of Table 2]
Chromatographic purification: PE:AcOEt, 9:1; diastereoisomer A [from (R)-chloride]: 1H NMR: 2.04
(s, MeCO), 3.38 (app bd, J 1.0, MeO); diastereoisomer B [from (S)-chloride]: 1H NMR: 2.06 (s, MeCO),
3.40 (app bd, J 1.1, MeO).
4.20.2. Esters from 6b
1
Chromatographic purification: PE:AcOEt, 9:1; diastereoisomer A: H NMR: 2.04 (s, MeCO), 3.37
(app bd, J 1.2, MeO); diastereoisomer B: 1H NMR: 2.06 (s, MeCO), 3.39 (app bd, J 1.1, MeO).
4.20.3. Esters from 7
1
Chromatographic purification: PE:AcOEt, 95:5; diastereoisomer A: H NMR: 3.40 (app bd, J 0.9,
MeO); diastereoisomer B: 1H NMR: 3.37 (app bd, J 1.0, MeO).
Acknowledgements
We are grateful to Amano Pharmaceuticals and to Novo Nordisk for a generous gift of some enzymes
(see Experimental). This work was supported by MURST (Ministero dell’Università e della Ricerca
Scientifica) and CNR (Consiglio Nazionale delle Ricerche) of Italy. We also wish to thank Mr. Marco
Delmonte and Miss Patrizia Larghero for their valuable collaboration on this project.
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