Synthesis of enantiomerically pure bicyclic condensed δ-lactones via microbial reduction and enzymic resolution strategies

Article abstract of DOI:10.1016/S0957-4166(00)00218-4

The formation of enantiopure δ-lactones condensed with alicyclic rings has been achieved either by reduction with baker's yeast of the corresponding δ-keto esters and δ-keto acids or by enzymic resolution of the former compounds. The absolute configuratio

Full text of DOI:10.1016/S0957-4166(00)00218-4

Tetrahedron: Asymmetry 11 (2000) 2599±2614
Synthesis of enantiomerically pure bicyclic condensed
d-lactones via microbial reduction and enzymic
resolution strategies
Erica Fogal, Cristina Forzato, Patrizia Nitti, Giuliana Pitacco and Ennio Valentin*
Á
Dipartimento di Scienze Chimiche, Universita di Trieste, via Licio Giorgieri 1, I-34127 Trieste, Italy
Received 4 May 2000; accepted 30 May 2000
Abstract
The formation of enantiopure d-lactones condensed with alicyclic rings has been achieved either by
reduction with baker's yeast of the corresponding d-keto esters and d-keto acids or by enzymic resolution
of the former compounds. The absolute con®gurations of the lactones were determined by means of CD
spectroscopy, using the correlation method. # 2000 Elsevier Science Ltd. All rights reserved.
1. Introduction
Biological methods which make use of whole cell microorganisms or puri®ed enzymes are
widely present in the literature for the synthesis of chiral building blocks.1 Among the biocatalysts
used for the asymmetric reduction of prochiral carbonyl groups, baker's yeast plays the most
traditional and useful role,2 although stereoselectivity this is not always satisfactory and needs
improvement by thermal pretreatment,3 addition of inhibitors,4 presence of organic solvent,5
immobilization on a solid phase6 and eventually isolation of reductases from the microorganism.7
Keto acids and esters are excellent substrates for baker's yeast. Although there are not as
many examples as for the bioreductions of b-keto esters and acids,1d,3,5b,6c,8a,9 bioreductions of
a-,4a,c,5b,8,7b g-10 and d-keto esters and acids10a,b,g,h,11 have also been reported.
The use of 5-oxoalkanoic acids of the C8±C12 chain as substrates for baker's yeast reduction for
the production of d-lactones was ®rst reported by Tuynenburg Muys and co-workers.10a Later,
Francke11a studied the reduction of 5-oxodecanoic acid and proposed a mechanism for its stereo-
speci®c conversion. However, in neither case was data reported either on the enantiomeric excess
or on the absolute con®gurations of the products. A systematic study was undertaken by Utaka
* Corresponding author. Tel: +39-040-6763917; fax: +39-040-6763903; e-mail: valentin@dsch.univ.trieste.it
0957-4166/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(00)00218-4

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and co-workers10b on the reduction by fermenting baker's yeast of 5-oxoalkanoic acids and esters
of C6±C10, C13, and C16 chains. Apart from the ®rst member of the series, all substrates furnished
the corresponding d-lactones with an R con®guration in low to good yields and with >98% e.e.s.
In a chemoenzymic synthesis of Leukotriene B4, Sih and co-workers11b prepared a chiral 5-hydroxy
ester intermediate by reduction with baker's yeast under non-fermenting conditions of t-butyl
5-oxo-5-(1,3-dithian-2-yl)pentanoate. In this case, the product with an S con®guration was iso-
lated in good yield and high enantiomeric excess (>97%). On the contrary, the analogous methyl
ester derivative underwent hydrolyses by esterases of baker's yeast but the resulting 5-oxo-5-(1,3-
dithian-2-yl)pentanoic acid was not reduced under the same conditions. A 5-oxopentanoic ester
of a similar structure, i.e. functionalized at C5 with a thiazole group, was subjected to bioreduction
with fermenting baker's yeast to furnish the corresponding 5-hydroxy acid in S con®guration,
with >95% e.e. and good yield, as a result of a parallel hydrolysis of the methyl ester function.10h
On reduction with non-fermenting baker's yeast, a series of 5-oxoalkanoic acids bearing a methyl
group either at C2 or C3 a€orded the corresponding d-lactones with 100% e.e. and also with high
diastereomeric excess.11c
From the above short survey on bioreductions of 5-oxoalkanoic acids and esters with baker's
yeast it is shown that no trend was evident, which is surely related to the multienzymic nature of
baker's yeast and to the reaction conditions. As a consequence, the stereoselective outcome of the
reactions is absolutely unpredictable, as it is the possibility of isolating the 5-hydroxy derivative
intermediates and also whether a di€erence exists between the reduction of d-keto acids and that
of d-keto esters.
Other enzyme-assisted syntheses of d-lactones, having fairly good enantiomeric excesses, were
also reported. Thus, enantiomerically pure d-lactones were obtained by enzymic resolution of
their racemic forms by lipases12 and also by the nucleophilic ring opening of enantiomerically
pure alkyl oxiranes, obtained by enzyme-catalyzed kinetic resolutions.13
In our previous paper14 we reported on the baker's yeast reduction of some d-keto esters, by
which enantiomerically pure condensed bicyclic d-lactones, having excellent enantiomeric excesses,
were prepared. Also, diastereoselectivity was high, allowing the use of mixtures of distereomeric
esters as substrates.
Owing to the fact that d-valerolactones condensed to a cycloalkane ring are widely present as
structural subunits of polycyclic naturally occurring products, in the present paper we extend our
study to other d-keto esters derived from cycloalkanones and also to their d-keto acid analogs,
with the aim of making a comparison between the two systems.
2. Results and discussion
2.1. Synthesis of the substrates
Like the d-keto esters 2a15 and 2b,14 2c and 2d (Scheme 1) were also prepared by alkylation
reaction of the corresponding enamines 1c and 1d with ethyl acrylate and successive hydrolysis.
When R was di€erent from hydrogen, the resulting cis and trans diastereomeric mixtures of
thermodynamic formation were inseparable, the cis:trans ratio being 90:10 for 2b and 85:15 for
2c. By hydrolysis under basic conditions, the corresponding d-keto acids 3a±d were obtained. In
the case of 3c, the cis:trans ratio was slightly di€erent from that of the corresponding d-keto esters
2c, namely 95:5.

E. Fogal et al. / Tetrahedron: Asymmetry 11 (2000) 2599±2614
2601
Scheme 1.
2.2. Chemical reduction of the ꢀ-keto esters 2c,d and ꢀ-keto acids 3a±d
The most signi®cant results of the chemical and biological reductions of the d-keto esters 2a±d
and d-keto acids 3a±d are listed in Table 1, while the structures of the products are shown in
Schemes 2 and 3. Although the data concerning the reductions of 2a and 2b had already been
described in a previous paper,14 they are reported here for comparison. On reduction with sodium
cyanoborohydride, 2a furnished a 1:4 mixture of the corresponding bicyclic cis- and trans-fused
d-lactones 4a and 5a, (Scheme 2 and Table 1), while 2b, which was a 9:1 mixture of cis and trans
diastereomers, furnished 4b, 5b and 6b in the ratio of 18:72:10 (Scheme 3 and Table 1).
Table 1

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E. Fogal et al. / Tetrahedron: Asymmetry 11 (2000) 2599±2614
Scheme 2.
Scheme 3.
The reduction of the 85:15 mixture of cis and trans-2c was more complex. In fact, four lactones
were identi®ed in the reaction mixture after acidic treatment, namely 4c, 5c, 6c and 7c in the ratio
of 10:70:8:12, respectively (Scheme 3). The stereochemical assignments were made on the basis of
the chemical shift values observed for the proton at C-8a and the methyl group at C-6 in their 1H
and 13C NMR spectra, respectively (Table 2). Table 2 also lists the resonances of H-8a for the
other bicyclic d-lactones 4a, 4b, 5a, 5b and 6b for a comparison.
Compounds 4c and 5c, derived from cis-2c, while 6c and 7c derived from trans-2c, as shown in
Scheme 3. In fact, the major product 5c (70%) must be formed from cis-2c which was the major
component in the parent mixture (85%). Since the signal of its proton at C-8a is characteristic of
an axial proton (WH=28.0 Hz), the fusion between the rings must be trans and the methyl group
at C-6 equatorial (21.6 ppm). The methyl group at C-6 is also equatorial in 4c (22.3 ppm) as it has
its proton at C-8a (WH=7.1 Hz). Therefore, lactone 4c must also be derived from cis-2c. As a
consequence, compounds 6c and 7c must be formed from trans-2c. Since H-8a in 7c showed
the same chemical shift value and pattern as the same proton in 5c, the fusion between the rings
must be cis in 6c and trans in 7c. Attempts to separate the four diastereomeric lactones by ¯ash-
chromatography resulted in the isolation of the only major compound 5c.
Chemical reduction of the d-keto ester 2d under the same conditions used for 2a±c a€orded a
4:1 mixture of the cis- and trans-fused lactones 4d and 5d, respectively. This attribution was made
on the basis of the chemical shift values found for H-9a for the two stereoisomers.16 The high
frequency value (4.58 ppm) was attributed to the cis-fused system 4d and the low frequency value
(4.01 ppm) to the trans-fused lactone 5d. Chemical reductions of the d-keto acids 3a±d a€orded
mixtures of the corresponding lactones of about the same compositions as those found for the
d-keto esters 2a±d (Table 1). Reductions of both the d-keto esters and acids a€orded the corres-
ponding trans-fused lactone 5 as the major product. The exception was the reduction of the 2d
and its acid 3d which furnished the cis-fused lactone 4d as the major product.17

E. Fogal et al. / Tetrahedron: Asymmetry 11 (2000) 2599±2614
2603
Table 2
The most relevant NMR data for d-lactones
2.3. Baker's yeast reductions of the ꢀ-keto esters 2c, 2d and the ꢀ-keto acids 3a±d
A few di€erent reaction conditions were checked for bioreductions of the d-keto esters 2 and d-keto
acids 3, namely the use of untreated raw and dry baker's yeast, pretreatment of the former at 50ꢀC
for 30 min and 1 h, as well as di€erent baker's yeast:substrate ratios, when dry baker's yeast was
used. In Table 1 we report only the results obtained when raw baker's yeast preincubated at 50ꢀC for
30 min was used, since no relevant di€erences were found when the other conditions were used.
Baker's yeast reduction of the keto ester 2a had already been found14 to be highly diastereo-
and enantioselective, since the only product obtained was the d-lactone (^)-4a having the cis
fusion between the rings. On the contrary, bioreduction of the corresponding keto acid 3a was by
no means diastereoselective, as both lactones (^)-4a and 5a were obtained. Furthermore, the
enantiomeric excess was satisfactory only for the cis-fused lactone (^)-4a. Just with the aim of
shifting the reaction towards the formation of the trans-fused lactones 5a, several other reaction
conditions were checked, including the use of inhibitors such as methyl vinyl ketone,3 allyl bromide,
ethyl chloroacetate and phenacylchloride,4b but unsuccessfully.
As to the comparison between the reductions of the d-keto esters 2 and d-keto acids 3, the most
striking di€erence was found for the system b. In fact, in the case of the acid 3b, conversion was
so low (5%) even after days, as to prevent the use of the reaction for a preparative scale. Probably
this inhibition may be ascribed to the presence of the t-butyl group. In fact, no di€erence was
found between the bioreductions of 2c and 3c, in which the t-butyl group was substituted for a
methyl group. The diastereoselectivity was poor (mixtures of cis- and trans-fused lactones 4c and
5c, respectively, was always obtained), although enantioselectivity was in general high. In some
cases, pretreatment of baker's yeast enhanced both the diastereoselectivity and the enantio-

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E. Fogal et al. / Tetrahedron: Asymmetry 11 (2000) 2599±2614
selectivity but no trend could be evidenced. Interestingly, the formation of the cis-fused lactone 4c
was favoured over that of the trans-fused one 5c, but the isolation of the former, which was
shown by chiral HRGC analysis to have >99% e.e. was not possible.
As to the systems 2d and 3d, a lower conversion was observed for the d-keto acid, although the
diastereoselectivity of the reaction was fairly high (50% d.e.).
From the crude reaction mixtures also, the unreacted d-keto esters (+)-cis-2c and (+)-2d, having
93 and 86% e.e., respectively, were recovered. The latter value was obtained indirectly, since racemic
2d was not separable on the chiral columns available. Therefore, (+)-2d was reduced with sodium
cyanoborohydride and the resulting d-hydroxy esters were cyclized to the corresponding d-lactones
(+)-4d and (+)-5d, whose enantiomeric excesses were determined by HRGC on a chiral column.
2.4. Enzymic hydrolyses
Since baker's yeast reductions of both d-keto esters 2c,d and d-keto acids 3a d a€orded, in
most cases, mixtures of products, and also conversions were unsatisfactory, an alternative
approach was used for the synthesis of enantiomerically pure d-lactones, namely the kinetic
resolution of the d-keto esters by hydrolytic enzymes.
The 9:1 mixture of racemic d-keto esters cis- and trans-2b was resolved with Lipase PS, by
which the corresponding d-keto acid cis-(^)-3b with 70% e.e. was obtained. Candida rugosa lipase
(CRL) also hydrolyzed the ester group but with lower e.e. (51%) and porcine pancreatic lipase
(PPL), a-chymotrypsin (a-CT) and Pseudomonas ¯uorescens lipase (PFL) were not e€ective. Pig
liver esterase (PLE), Mucor miehei lipase (MML), porcine liver acetone powder (PLAP), and
horse liver acetone powder (HLAP) showed very poor enantioselectivities.
Better results were obtained with the 85:15 mixture of racemic cis- and trans-2c. Of the various
enzymes which exhibited a high E value (Table 3), a-CT was the most ecient, rapidly a€ording
the d-keto acid cis-(^)-3c with 92% d.e. and 98% e.e. Other lipases and esterases, such as PLE,
MML, PLAP, HLAP and CRL were also e€ective in hydrolyzing the ester group but with low or
no enantioselectivity.
On the contrary, enzymic resolution of the d-keto ester 2d was by no means satisfactory. In fact all
the enzymic systems checked were characterized by a low E value. However, a-CT and PPL (E=5
and 4, respectively) a€orded the corresponding d-keto acid 3d with 66 and 57% e.e., respectively,
while MML, PLAP and HLAP showed very poor enantioselectivity. The enantiomeric excesses of
the unreacted ester 2d and acid 3d were not determined by HRGC, because neither 2d nor its
methyl ester analogue, obtained from 3d by treatment with diazomethane, were separable on
chiral chromatographic columns. Therefore, 2d and 3d were reduced with sodium cyanoborohydride,
with the aim of determining the e.e.'s of their corresponding lactones. It should be noted, however,
that the acidic conditions required for the reduction with NaBH3CN (reductions with other
reducing agents were unsatisfactory) are likely to racemize partially the substrates.
2.5. Determination of the absolute con®guration of the ꢀ-lactones (^)-4c, (^)-4d, (^)-5d
The absolute con®gurations of the d-lactones (^)-4c and (^)-4d, obtained by reduction of the
corresponding d-keto esters cis-2c and 2d with baker's yeast, were determined by analysis of
the CD spectra of their respective unreacted d-keto esters cis-(+)-2c and (+)-2d, recovered from the
bioreductions. A comparison of their CD spectra with that of the already known14 d-keto ester
(1S,5S)-(^)-2b (Fig. 1) would indicate the same con®guration of C-1, that is 1S for cis-(+)-2c and
1R for (+)-2d, the di€erent notation being due to a di€erent priority sequence in the two lactones.

E. Fogal et al. / Tetrahedron: Asymmetry 11 (2000) 2599±2614
2605
Table 3
Enzymic resolution of the 85:15 mixture of (þ)-cis and trans-2c
Figure 1. CD spectra of the d-keto esters (^)-2b, (+)-2c and (+)-2d
Therefore, since cis-(S)-(+)-2c was recovered unreacted, the d-lactone cis-(^)-4c, which was the
main product (71%) of the bioreduction, must be derived from cis-(R)-(^)-2c. As a consequence,
its absolute con®guration is 4aR,6R,8aS. In a similar manner, the absolute con®guration of (^)-4d
was assigned as 4aS,9aS. This latter assignment was con®rmed by the analysis of its CD curve.
However, since lactone (^)-4d was inseparable from its diastereomer (^)-5d, the separation was
e€ected in accordance with a literature procedure,18 as follows. The diastereomeric mixture was

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E. Fogal et al. / Tetrahedron: Asymmetry 11 (2000) 2599±2614
treated with KOH in methanol to open their respective lactone rings and the resulting carboxylate
groups were esteri®ed with isopropylbromide (Scheme 4). The isopropyl d-hydroxy esters cis-(^)-8
and trans-8 thus obtained were separated on ¯ash chromatography. However, only the cis
diastereomer was obtained as pure compound, whereas the trans one was contaminated by 15%
of the former. On heating, both hydroxy esters were reconverted separately into the correspond-
ing d-lactones (^)-4d and (^)-5d, this latter in admixture with the former (15%).
Scheme 4.
Although the size of the fused carbocyclic ring is di€erent, the CD spectrum of (^)-4d was
compared with those of the other cis-fused lactones (^)-4a and (^)-4b, whose absolute con®gura-
tions had already been determined,14 and with that of (^)-4c, whose absolute con®guration has
been assigned above. The curves were almost superimposable and therefore the absolute con®g-
uration of (^)-4d was assigned as 4aS,9aS. (Fig. 2)
Figure 2. CD spectra of the cis-fused d-lactones (^)-4a, (^)-4b, (^)-4c and (^)-4d
Since (^)-5d was isolated from the bioreduction of 2d in admixture with (^)-4d, its absolute
con®guration is likely to be 4aR,9aS, di€ering from that of (^)-4d only for the con®guration
around C-4a. This attribution will be con®rmed later by comparing the CD spectrum of (^)-5d
with that of the trans-fused lactone (+)-5c, obtained from the d-keto acid cis-(^)-3c.

E. Fogal et al. / Tetrahedron: Asymmetry 11 (2000) 2599±2614
2607
The acid cis-(^)-3c, isolated in high optical purity from the enzymic resolution of racemic cis-
2c, was assigned the 1S,5S absolute con®guration by comparing its CD spectrum with that of its
ethyl ester cis-(+)-2c, whose absolute con®guration was determined above to be S. In fact both
compounds exhibited a positive Cotton e€ect for the n!p* transition around 290 nm.
The d-keto acid cis-(^)-3c was then reduced with both K-SelectrideTM and sodium cyanoboro-
hydride, which are known19 to show opposite diastereopreference (Scheme 5). From the former
reduction, a 9:1 mixture of (+)-4c and (+)-5c was obtained and from the latter a 15:85 mixture of
the same d-lactones. Separation by ¯ash chromatography of the two mixtures allowed for the
isolation of both diastereomers (+)-4c and (+)-5c; the former, however, contaminated with 9% of
the latter.
Scheme 5.
The absolute con®guration of (+)-4c is known from the previous determination made on (^)-4c
to be 4aS,6S,8aR and therefore that of (+)-5c, which di€ers from (+)-4c for the con®guration
around C-8a, is 4aS,6S,8aS.
The trans-fused lactones (^)-5b, (+)-5c and (^)-5d exhibited CD curves which were practically
superimposable (Fig. 3). As a consequence, the absolute con®guration of (^)-5d was assigned to
be 4aR,9aS.
Figure 3. CD spectra of the trans-fused d-lactones (^)-5b, (+)-5c and (^)-5d

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E. Fogal et al. / Tetrahedron: Asymmetry 11 (2000) 2599±2614
3. Conclusions
d-Keto acids are not as good for baker's yeast as the corresponding d-keto ester substrates, in
particular as far as conversions are concerned. This result might be related to a type of poisoning
of the yeast occurring when the concentrations of 5-oxo acids or 5-hydroxy acids or both
increase, as already reported by Francke11a for linear systems. Also, diastereoselectivity and
enantioselectivity of the reactions were lower. No evidence was found which would account for
the hydrolysis of the d-keto esters to the corresponding d-keto acids in the reaction medium prior
to reduction, as suggested by some authors for the bioreduction of long chain 5-keto esters and
acids.10b On the contrary, because our d-keto acids are such bad substrates for baker's yeast, we
are in favour of the intermediacy of d-hydroxy esters when d-keto esters are reduced. In any case,
there is no general trend. Some molecules are better reduced as d-keto esters, others as d-keto
acids. However, since in general bioreductions were not diastereoselective, enzyme-catalyzed
kinetic resolutions of chiral racemic 5-keto esters are more advantageous, in particular when
mixtures of diastereomers are to be used as substrates.
4. Experimental
4.1. General
1
IR spectra were recorded on a Jasco FT/IR 200 spectrophotometer. H NMR and 13C NMR
spectra were run on a Jeol EX-400 spectrometer (400 MHz for proton), using deuteriochloroform
as a solvent and tetramethylsilane as the internal standard. Coupling constants and WH's are
given in Hz. Optical rotations were determined on a Perkin±Elmer Model 241 polarimeter. CD
spectra were obtained on a Jasco J-700A spectropolarimeter (0.1 cm cell) using CH3OH as a
solvent. GLC analyses were run on a Carlo Erba GC 8000 instrument and on a Shimadzu GC-
14B instrument, the capillary columns being EC-WAX (30 mÂ0.32 mm) (carrier gas He, 40 KPa)
and a ChiraldexTM type G-TA, tri¯uoroacetyl g-cyclodextrin (40 mÂ0.25 mm) (carrier gas He,
180 KPa) or DiMePe b-cyclodextrin (25 mÂ0.25 mm). Enzymic hydrolyses were performed using
a pH-stat Controller PHM290 Radiometer Copenhagen. Mass spectra were recorded on a Hewlett±
Packard 5971-A GC±MS instrument by the electron-impact mode. TLCs were performed on
Polygram1 Sil G/UV254 silica gel pre-coated plastic sheets (eluant: light petroleum:ethyl acetate).
Flash chromatography was run on silica gel 230±400 mesh ASTM (Kieselgel 60, Merck). Light
petroleum refers to the fraction with b.p. 40±70ꢀC and ether to diethyl ether.
4.2. Synthesis of the substrates 2c and 2d
The d-keto esters 2c were prepared by reacting 1-pyrrolidinyl-4-methylcyclohexene 1c with
ethyl acrylate in re¯uxing dioxane for 3 h, according to the literature procedure.15 Water was
added and the mixture was re¯uxed for 1 h. After the usual workup, an inseparable mixture of
cis-2c and trans-2c in the ratio of 85:15 was obtained.
In the same manner, the d-keto ester 2d was prepared starting with 1-pyrrolidinylcycloheptene
1d.20
The spectroscopic data for compounds (+)-2c and (+)-2d recovered in 20% yield from their
respective bioreductions, are given.

E. Fogal et al. / Tetrahedron: Asymmetry 11 (2000) 2599±2614
2609
4.2.1. Ethyl (1S,5S)-(+)-3-(2-oxo-5-methylcyclohexyl)propionate cis-2c
IR, (®lm) cm^1: 1710 (CˆO), 1735 (CO2); 1H NMR, ꢀ, ppm: 4.12 (2H, q, J=7.3 Hz, OCH2CH3),
2.36 (5H, m), 2.02 (4H, m), 1.50 (1H, m), 1.35 (1H, m), 1.25 (3H, t, J=7.3 Hz, OCH2CH3), 1.12
(1H, m), 1.00 (3H, d, J=6.4 Hz, CH3); 13C NMR, ꢀ, ppm: 212.3 (s, CˆO), 173.3 (s, O±CˆO), 59.9
(t, OCH2CH3), 48.3 (d, C-1), 42.1 (t), 41.3 (t), 35.7 (t), 31.7 (d, C-4), 31.5 (t), 24.3 (t), 21.0 (q, CH3),
14.0 (q, OCH2CH3); m/z: 212 (M+Á, 5%), 167 (32), 166 (60), 139 (17), 138 (26), 125 (13), 124 (25),
112 (12), 111 (10), 99 (11), 97 (16), 96 (27), 95 (17), 83 (16), 82 (12), 81 (20), 70 (20), 69 (18), 67 (15),
60 (10), 55 (100), 53 (15); 93% e.e. (HRGC, b-CDX), ‰ꢁŠ2D5=+8.1 (c 0.32, CH3OH), [Â]290=+1129.
4.2.2. Ethyl trans-3-(2-oxo-5-methylcyclohexyl)propionate trans-2c
Although the spectra were run on the mixture, the most signi®cant peaks are given separately.
1H NMR, ꢀ, ppm: 4.12 (2H, q, J=7.3 Hz, OCH2CH3), 2.36 (3H, m), 2.02 (3H, m), 1.75±1.50 (4H,
m), 1.25 (3H, t, J=7.3 Hz, OCH2CH3), 1.06 (3H, d, J=6.2 Hz, CH3); 13C NMR, ꢀ, ppm: 60.0 (t,
OCH2CH3), 46.8 (d, C-2), 39.6 (t), 37.6 (t), 33.9 (t), 26.4 (d, C-4), 25.7 (t), 19.4 (q, CH3), 14.0 (q,
OCH2CH3); m/z: 212 (M+Á, 4%), 167 (30), 166 (56), 139 (15), 138 (24), 125 (14), 124 (25), 112 (11),
111 (10), 99 (11), 97 (16), 96 (28), 95 (17), 83 (17), 82 (13), 81 (20), 70 (18), 69 (15), 67 (17), 60 (11),
56 (14), 55 (100), 54 (10), 53 (16).
4.2.3. Ethyl (R)-(+)-3-(2-oxocycloheptyl)propionate 2d
1
IR, H NMR and 13C NMR data were identical with the reported values:21 m/z: 212 (M+Á, 4),
167 (32), 166 (39), 139 (16), 138 (37), 125 (14), 112 (15), 98 (19), 97 (14), 96 (13), 95 (14), 88 (18),
84 (14), 82 (13), 81 (15), 70 (13), 69 (16), 68 (13), 67 (23), 61 (11), 60 (16), 55 (100), 54 (18), 53 (14);
e.e. ꢁ86% (determined after reduction with NaBH3CN and chiral HRGC g-CDX analysis of the
lactones obtained) ‰ꢁŠD25=+27.3 (c 0.11, CH3OH), [Â]290=+2886.
4.3. General procedure for the hydrolysis of the ꢀ-keto esters 2a±d
The d-keto ester (1 mmol) was added to a solution of KOH (2 mmol) in methanol (1.6 ml). The
mixture was stirred for 2 days, acidi®ed with 2N HCl and extracted with ether, after evaporation
of the methanol.
4.3.1. 3-(2-Oxocyclohexyl) propionic acid 3a
All spectroscopic data are in accordance with the literature.22
4.3.2. (1S,5S)-(^)-3-(2-Oxo-5-(1,1-dimethylethyl)cyclohexyl)propionic acid23 cis-3b
The keto acid cis-(^)-3b was recovered from enzymic hydrolysis with Lipase PS in 20% yield.
Oil; IR, cm^1 (®lm): 1725, 1710 (CˆO); 1H NMR, ꢀ, ppm: 10.45 (1H, bs, OH), 2.40 (5H, m), 2.10
(3H, m), 1.53 (3H, m), 1.19 (1H, m), 0.91 (9H, s); 13C NMR, ꢀ, ppm: 213.2 (s, CˆO), 179.6 (s,
COOH), 48.5 (d), 46.9 (d), 41.5 (t), 35.3 (t), 32.3 (s, C (CH3)3), 31.6 (t), 28.7 (t), 27.5 (q, (CH3)3),
+Á
24.5 (t); m/z: 208 (M±H2O)e , 72), 193 (24), 165 (19), 152 (20), 151 (22), 137 (24), 124 (69), 123
(38), 109 (20), 96 (100), 95 (46), 79 (27), 67 (41), 57 (72), 55 (51); 70% e.e. (determined by chiral
HRGC b-CDX, after esteri®cation with CH2N2), ‰ꢁŠ2D5=^3.4 (c 0.32, CH3OH), [Â]288=+663.
4.3.3. (1S,5S)-(^)-3-(2-Oxo-5-methylcyclohexyl)propionic acid24 cis-3c
The keto acid cis-(^)-3c was recovered from enzymic hydrolysis with a-CT in 24% yield (in
1
admixture with 4% of trans-3c). IR, cm^1 (®lm): 1725, 1710 (CˆO); H NMR, ꢀ, ppm: 9.44 (1H,

2610
E. Fogal et al. / Tetrahedron: Asymmetry 11 (2000) 2599±2614
s, OH), 2.41 (5H, m), 2.02 (4H, m), 1.48 (1H, m), 1.38 (1H, m), 1.11 (1H, m), 1.00 (3H, d, J=6.2
Hz, CH3); 13C NMR, ꢀ, ppm: 213.0 (s), 179.4 (s), 48.3 (d), 42.2 (t), 41.4 (t), 35.8 (t), 31.9 (d), 31.4
(t), 24.2 (t), 21.1 (q); m/z:184 (M+Á, 3), 166 (M±H2O+Á, 89), 138 (36), 124 (44), 109 (14), 96 (96), 95
(36), 81 (100), 68 (22), 67 (44), 55 (38); 98% e.e. (determined by chiral HRGC b-CDX, after
esteri®cation with CH2N2), ‰ꢁŠ2D5=^3.8 (c 0.13, CH3OH), [Â]289=+1479.
4.3.4. trans-3-(2-Oxo-5-methylcyclohexyl)propionic acid trans-3c
1H NMR, ꢀ, ppm: 9.44 (1H, s, OH), 2.40 (5H, m), 1.95 (3H, m), 1.60 (4H, m), 1.00 (3H, d,
J=7.0 Hz, CH3); 13C NMR, ꢀ, ppm: 214.4 (s), 178.8 (s), 46.7 (d), 39.6 (t), 37.7 (t), 33.9 (t), 31.6
(t), 26.5 (d), 25.5 (t), 19.5 (q).
4.3.5. 3-(2-Oxocycloheptyl)propionic acid21,25 3d
IR, cm^1 (®lm): 1725,1705 (CˆO); 1H NMR, ꢀ, ppm: 9.30 (1H, s, OH), 2.60 (1H, m), 2.49 (2H,
m), 2.35 (2H, m), 1.97 (1H, m), 1.85 (4H, m), 1.64 (2H, m), 1.36 (3H, m); 13C NMR, ꢀ, ppm:
216.0 (s, CˆO), 178.7 (s, COOH), 50.7 (d, C-10), 42.6 (t, C-30), 31.4 (t, C-2), 31.3 (t, C-20), 29.0 (t,
C-3), 28.3 (t, C-40), 26.7 (t, C-50), 24.0 (t, C-60); m/z:184 (M+Á, 3), 166 (M±H2Oe , 100), 138 (93),
+Á
123 (14), 112 (17), 110 (33), 109 (40), 96 (37), 95 (40), 82 (36), 81 (84), 68 (41), 67 (75), 55 (51).
4.4. Reductions with baker's yeast
To a stirred suspension of 100 g of raw baker's yeast (preincubated or not) or dry baker's yeast
purchased from Sigma-Aldrich (4 g/mmol or 20 g/mmol) in 200 ml of water was added the d-keto
ester (10. 0 mmol) at room temperature. The course of the reaction was monitored by HRGC. At
the end of the reaction, brine was added and the broth was continuously extracted with ether for
48 h. The organic phase was dried and evaporated.
4.5. General procedure for enzymic hydrolyses
The following enzymes were used: a-Chymotrypsin (a-CT, 51.8 U/mg), Pseudomonas ¯uorescens
lipase (PFL, 42.5 U/mg), and Mucor miehei lipase (MML) were purchased from Fluka; porcine
pancreatic lipase type II (PPL), pig liver acetone powder (PLAP), horse liver acetone powder
(HLAP), Candida rugosa lipase type VII (CRL, 700-1500 U/mg), pig liver esterase (PLE, sus-
pension in 3.2 M (NH4)2SO4 solution 20 mg/ml, 230 U/mg), and lipase type XII from Pseudo-
monas species (Lipase PS, 27 U/mg) were purchased from Sigma.
To a solution of 1.0 mmol of the d-keto ester in 10 ml of phosphate bu€er (pH 7.4) was added
the enzyme, under vigorous stirring. The course of the reaction was monitored with a pH-STAT,
with continuous addition of 1.0N NaOH. At 20% conversion, the reaction mixture was extracted
with ether to separate the unreacted d-keto ester. The mother liquors were acidi®ed with 5% HCl
and extracted with ether. The organic phase was dried on Na2SO4 and treated with diazomethane
to esterify the carboxylic group before the HRGC analysis.
4.6. Reduction of cis-(^)-3c with K-SelectrideTM26,27
The keto acid cis-(^)-3c (1.0 mmol) in anhydrous THF (2 ml) was added dropwise to a stirred
1.0 M solution of K-SelectrideTM (1.2 equiv.) in THF, at ^35ꢀC, under an argon atmosphere.
After 1.5 h, water (0.16 ml) and ethanol (0.6 ml) were added and the temperature was allowed to

E. Fogal et al. / Tetrahedron: Asymmetry 11 (2000) 2599±2614
2611
warm to 0ꢀC. The solution was then added with 6 M NaOH (0.4 ml) and 30% H2O2 (0.6 ml),
saturated with K2CO3 and extracted with diethyl ether. Evaporation of the solvent furnished the
d-lactone (+)-4c, which was puri®ed on ¯ash chromatography.
4.6.1. (4aS,6S,8aR)-(+)-6-Methyl-octahydro-2H-1-benzopyran-2-one 4c
1
The title compound was obtained in 20% yield as an oil. IR, cm^1 (®lm): 1740 (CˆO); H
NMR, ꢀ, ppm: 4.47 (1H, m, WH 7.1, H-8a), 2.51 (2H, t, J=6.0 Hz, H-3), 2.08 (2H, m), 1.91 (1H,
m), 1.51 (5H, m), 1.24 (1H, m), 1.08 (1H, q, J=13.7 Hz), 0.92 (3H, d, J=6.0 Hz, CH3); 13C
NMR, ꢀ, ppm: 172.7 (s, CˆO), 77.2 (d), 34.6 (t), 32.7 (d), 31.6 (d), 30.4 (t), 27.8 (t), 26.4 (t), 24.9
(t), 22.3 (q, CH3); m/z: 168 (M+Á, 1), 124 (2), 111 (15), 96 (25), 95 (100), 83 (28), 82 (26), 81 (53), 68
(30), 67 (37), 55 (52); 99% e.e. (by chiral HRGC g-CDX), ‰ꢁŠ2D5=+17.9 (c 0.08, CH3OH) (in
admixture with 9% of (+)-5c), [Â]192=+5039, [Â]214=+4205.
4.7. Reduction of 3c with NaBH3CN
4.7.1. (4aS,6S,8aS)-(+)-6-Methyl-octahydro-2H-1-benzopyran-2-one 5c
Compound (+)-5c was obtained by reduction of (^)-3c with NaBH3CN in 20% yield after
1
puri®cation by ¯ash-chromatography. IR, cm^1 (®lm): 1740 (CˆO); H NMR, ꢀ, ppm: 3.79
(1H, ddd, J1=11.9, J2 9.9, J3 4.4 Hz, H-8a), 2.59 (1H, part A of an ABMX system, J1=18.0, J2
7.3, J3 4.0 Hz, H-3), 2.46 (1H, part B of an ABMX system, J1=18.0, J2 9.5, J3 8.2 Hz, H-3), 2.02
(1H, dq, J1=12.6, J2=J3=J4=3.7 Hz, H-8eq), 1.84±1.70 (3H, m, H-4, H-5, H-7), 1.53±1.38 (4H,
m, H-4, H-4a, H-6, H-8ax), 0.95 (1H, m, H-7), 0.85 (3H, d, J=6.6 Hz, CH3), 0.74 (1H, m, H-5);
13C NMR, ꢀ, ppm: 171.5 (s, CˆO), 83.2 (d, C-8a), 39.3 (t, C-5), 38.1 (d, C-4a), 32.3 (t, C-7), 31.9
(t, C-8), 31.6 (d, C-6), 29.6 (t, C-3), 26.2 (t, C-4), 21.6 (q, CH3); m/z:168 (M+Á, 1), 124 (4), 111 (8),
96 (26), 95 (39), 83 (41), 82 (27), 81 (100), 68 (19), 67 (32), 55 (63); 98% e.e. (by chiral HRGC
g-CDX), ‰ꢁŠ2D5=+4.6 (c 0.33, CH3OH), [Â]236=+193, [Â]209=^385, [Â]195=^894.
4.7.2. cis-6-Methyl-octahydro-2H-1-benzopyran-2-one 6c and trans-6-methyl-octahydro-2H-1-
benzopyran-2-one 7c28
Since the mixture of lactones 4c, 5c, 6c and 7c could not be completely separated, only a few
signals were identi®ed in the 1H and 13C NMR spectra of 6c and 7c.
Compound 6c: 1H NMR, ꢀ, ppm (CDCl3+C6D6): 4.20 (1H, m, WH=18.9); 13C NMR, ꢀ, ppm:
80.0 (d), 20.5 (q).
Compound 7c: 1H NMR, ꢀ, ppm (CDCl3): 3.79 (1H, m); 13C NMR, ꢀ, ppm: 83.9 (d), 17.7 (q).
4.8. Separation of the ꢀ-lactones 4d and 5d
The 80:20 mixture of lactones 4d and 5d (0.7 g, 4.2 mmol), obtained from the reduction of the
d-keto ester 2d with baker's yeast, was dissolved in methanol (20 ml), KOH (0.7 g, 12.6 mmol)
and the mixture was stirred at room temperature for 72 h. Evaporation of methanol left an oil
which was dissolved in anhydrous DMF (5 ml) and added of isopropylbromide (3.0 ml, 25.2
mmol). The mixture was then stirred at room temperature for 24 h. When the reaction was over,
water (14 ml) was added and the mixture was extracted three times with ether. The combined
organic extracts were washed with water and dried over Na2SO4. The crude reaction mixture
(50% yield), containing the d-hydroxy esters cis-8 and trans-8, was separated by ¯ash chromato-
graphy (eluant: light petroleum:ethyl acetate, gradient from 99:1 to 88:12) furnishing the d-

2612
E. Fogal et al. / Tetrahedron: Asymmetry 11 (2000) 2599±2614
hydroxy ester cis-8 as a pure compound and a mixture of 4d, 5d and trans-8 in the ratio of
17:17:66. Evidently, silica was acid enough as to recyclize, albeit partially, the d-hydroxy esters.
The d-hydroxy ester cis-8 and the mixture of products containing trans-8 were lactonized
separately in re¯uxing benzene with p-toluensulfonic acid as a catalyst for 30 min. The former
reaction furnished (^)-4d as pure compound and the latter gave a 15:85 mixture of (^)-4d and
(^)-5d.
4.8.1. Methylethyl (1S,2S)-(^)-3-(2-hydroxycycloheptyl)propionate cis-8
1
Oil; IR, cm^1 (®lm): 1730 (COO), 3460 (OH); H NMR, ꢀ, ppm: 5.01 (1H, sept, J=6.4 Hz,
CH(CH3)2), 3.91 (1H, bs, CHOH), 2.33 (2H, m), 1.87±1.35 (14H, m), 1.23 (6H, d, J=6.4 Hz,
CH3); 13C NMR, ꢀ, ppm: 173.8 (s), 72.3 (d), 67.6 (d), 44.2 (d), 35.4 (t), 33.0 (t), 28.2 (t), 27.8 (t),
27.2 (t), 26.6 (t), 21.8 (2q), 21.8 (t); m/z: 168 (9), 150 (12), 112 (75), 111 (46), 108 (17), 98 (100), 97
(55), 96 (85), 95 (57), 94 (16), 93 (21), 84 (56), 83 (80), 82 (63), 81 (58), 80 (24), 79 (35), 77 (11), 70
(21), 69 (20), 68 (42), 67 (75), 66 (11), 57 (14), 56 (14), 55 (98), 54 (38), 53 (30); >99% e.e.,
‰ꢁŠ2D5=^20.0 (c 0.30, CH3OH), [Â]212=^1665.
4.8.2. Methylethyl trans-3-(2-hydroxycycloheptyl)propionate trans-8
1H NMR, ꢀ, ppm: 5.01 (1H, sept, J=6.3 Hz, CH(CH3)2), 3.46 (1H, dt, J1=J2=7.4 Hz, J3=3.7
Hz, CHOH), 2.35 (2H, m), 1.87±1.35 (14H, m), 1.24 (6H, d, J=6.3 Hz, CH3); 13C NMR, ꢀ, ppm:
173.8 (s), 76.4 (d), 67.6 (d), 46.8 (d), 36.3 (t), 32.2 (t), 29.5 (t), 28.9 (t), 28.8 (t), 26.6 (t), 22.3 (t),
21.8 (2q).
4.8.3. (4aS,9aS)-(^)-Octahydro-2(3H)-cyclohepta[b]pyran-2-one 4d
1
IR, cm^1 (®lm): 1765 (CˆO); H NMR ꢀ, ppm: 4.58 (1H, dt, J1=J2=4.6 Hz, J3=8.9 Hz, H-
9a), 2.45 (2H, t, J=6.8 Hz, H-3), 2.16 (3H, m), 1.80±1.62 (2H, m), 1.52±1.25 (4H, m); 13C NMR,
ꢀ, ppm: 172.3 (s), 81.8 (d), 36.6 (d), 32.3 (t), 29.2 (t), 28.4 (t), 27.8 (t), 27.1 (t), 26.4 (t), 21.6 (t); m/
z: 168 (M+Á, 5%), 112 (40), 111 (24), 98 (54), 97 (34), 96 (48), 95 (35), 83 (56), 82 (46), 81 (42), 79
(25), 77 (10), 68 (38), 67 (67), 55 (100), 54 (43), 53 (28); >99% e.e. (by chiral HRGC g-CDX),
‰ꢁŠ2D5=^41.7 (c 0.24, CH3OH), [Â]212=^3651.
4.8.4. (4aR,9aS)-(^)-Octahydro-2(3H)-cyclohepta[b]pyran-2-one 5d (in admixture with 15% of
(^)-4d)
1
Only a few signals could be identi®ed in the H NMR spectrum, ꢀ, ppm: 4.01 (1H, dt,
J1=J2=9.3, J3=5.2 Hz, H-9a), 2.61 (1H, m), 2.48 (1H, m), 2.07 (1H, m), 1.90±1.25 (12H, m); 13
C
NMR, ꢀ, ppm: 171.9 (s, CˆO), 85.8 (d), 40.1 (d), 34.0 (t), 30.1 (t), 29.0 (t), 27.5 (t), 26.3 (t), 25.3
(t), 21.5 (t); m/z: 168 (M+Á, 4%), 112 (36), 111 (16), 98 (46), 97 (26), 96 (45), 95 (26), 93 (10), 84
(37), 83 (57), 81 (54), 80 (14), 79 (22), 70 (13), 69 (16), 68 (30), 67 (60), 56 (12), 55 (100), 54 (29),
53 (24); e.e. >99% (by chiral HRGC g-CDX), ‰ꢁŠ2D5=^31.9 (c 0.26, CH3OH); [Â]236=+359,
[Â]205=^862.
Acknowledgements
Financial support by the MURST, CNR (Rome) and the University of Trieste are gratefully
acknowledged.

E. Fogal et al. / Tetrahedron: Asymmetry 11 (2000) 2599±2614
2613
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