Baker's yeast-mediated approach to (-)-cis- and (+)-trans-Aerangis lactones

Article abstract of DOI:10.1016/S0957-4166(01)00314-7

The first enantioselective synthesis of natural (-)-cis-Aerangis lactone (-)-1a and its (+)-trans-diastereoisomer (+)-1b is described. The key steps in the synthesis are: (i) the enantiospecific and 100% diastereoselective baker's yeast reduction of 1,4-keto acid 2, to afford enantiopure trans-cognac lactone (+)-10; (ii) the regioselective PPL-mediated hydrolysis of the primary acetate moiety of diacetate (+)-(3S,4R)-3, obtained from (+)-10. Chain elongation by one carbon atom via cyanide substitution, and inversion of the configuration of C(5) in nitrile derivative (+)-21a are also required to complete the synthetic route to (-)-1a.

Full text of DOI:10.1016/S0957-4166(01)00314-7

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 12 (2001) 1871–1879
Baker’s yeast-mediated approach to (−)-cis- and
(+)-trans-Aerangis lactones
Elisabetta Brenna,* Claudia Dei Negri, Claudio Fuganti and Stefano Serra
Dipartimento di Chimica del Politecnico, Centro CNR per lo Studio delle Sostanze Organiche Naturali, Via Mancinelli 7,
I-20131 Milan, Italy
Received 13 June 2001; accepted 9 July 2001
Abstract—The first enantioselective synthesis of natural (−)-cis-Aerangis lactone (−)-1a and its (+)-trans-diastereoisomer (+)-1b is
described. The key steps in the synthesis are: (i) the enantiospecific and 100% diastereoselective baker’s yeast reduction of 1,4-keto
acid 2, to afford enantiopure trans-cognac lactone (+)-10; (ii) the regioselective PPL-mediated hydrolysis of the primary acetate
moiety of diacetate (+)-(3S,4R)-3, obtained from (+)-10. Chain elongation by one carbon atom via cyanide substitution, and
inversion of the configuration of C(5) in nitrile derivative (+)-21a are also required to complete the synthetic route to (−)-1a.
© 2001 Elsevier Science Ltd. All rights reserved.
1. Introduction
stereoisomer of Aerangis lactone present in the scent of
living, white flowering orchids (Aerangis confusa). The
fragrance of (4S,5S)-1a was described3 to be typical for
the lactonic odour of A. confusa and A. kirkii, and
identical to the olfactory qualities of natural Aerangis
lactone. Its enantiomer (4R,5R)-1a was found to be
reminiscent of d-decalactone and cocos, and with a
fragrance intensity much lower than (4S,5S)-1a.
cis-Aerangis lactone 1a (cis-4-methyl-5-decanolide) was
described by Kaiser in 1993 as the main odour compo-
nent of the African ‘moth orchids’ Aerangis confusa J.
Stewart and Aerangis kirkii (Rolfe) Schltr.1 ( )-1a was
first obtained as a 1:1 mixture with the trans-
diastereoisomer 1b by hydrogenation of dihydrojas-
mone and subsequent Baeyer–Villiger oxidation.2 The
two diastereoisomers were separated by preparative GC
and characterised. The cis isomer was found to have a
very pleasant and room-filling odour, reminiscent both
of the smell of tuberose and gardenia, and of the
fragrance of caramel, condensed milk and coconut.2
The trans isomer exhibited similar, but somewhat
weaker, olfactory properties. In 1995, Mosandl, Kaiser
et al.3 obtained samples of all four stereoisomers of
Aerangis lactone, (4S,5S)- and (4R,5R)-1a and
(4S,5R)- and (4R,5S)-1b, as homochiral compounds by
chiral high performance liquid chromatography. These
latter derivatives were reduced to the corresponding
1,5-diols, in order to derive their absolute configuration
from the 1H NMR spectra of the corresponding di-
MTPA esters, according to Mosher’s procedure. Opti-
cal rotation values for the four lactones were not
reported in the work. By means of enantioselective
multi-dimensional capillary GC the authors found that
(4S,5S)-cis-4-methyl-5-decanolide 1a was the sole
O
O
O
O
(4S,5S)-1a
(-)-cis-aerangis lactone
(4R,5R)-1a
(+)-cis-aerangis lactone
O
O
O
O
(4S,5R)-1b
(+)-trans-aerangis lactone
(4R,5S)-1b
(-)-trans-aerangis lactone
O
OAc
OH
OAc
O
2
(+)-3
In the present work we describe the first enantioselec-
tive synthesis of natural Aerangis lactone (−)-1a, and of
* Corresponding author. Tel.: +39 02 23993073; fax: +39 02
23993080; e-mail: brenna@dept.chem.polimi.it
0957-4166/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(01)00314-7

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E. Brenna et al. / Tetrahedron: Asymmetry 12 (2001) 1871–1879
its epimer (+)-1b. Key steps are the enantiospecific and
completely diastereoselective reduction of keto acid 2
mediated by Baker’s yeast (BY), and the regioselective
lipase-catalysed hydrolysis of the primary acetate moi-
ety of derivative (+)-3, followed by suitable chain
homologation by one carbon atom via cyanide substitu-
tion. This work on Aerangis lactone gave us the chance
to carry out a study of the mode of BY reduction of
various 1,5-, 1,4- and 1,3- difunctionalised synthons.
The results of this investigation are reported herein.
BY reductions of various 1,5-, 1,4-, and 1,3-difunction-
alised synthons (Scheme 1). The C(5)-O fragment of
Aerangis lactone could most likely be derived from the
enantioselective reduction of a carbonyl group, while
the C(4) centre, bearing the methyl group, could be
involved in a double bond in the chosen precursor.
2.1. 1,5-Keto acid synthons
In the past we had been involved in the study of the
mode of BY reduction of methyl substituted g- and
d-keto acids.4 We had noticed that the outcome of the
reaction was almost unpredictable: the enzymatic sys-
tem of baker’s yeast was so complex, that it could
transform structurally similar substrates in different
ways. Nonetheless, one of the main results of that work
was that enantiopure methyl substituted d-lactones,
showing high diastereoisomeric excess (d.e.), could be
generally obtained by baker’s yeast reduction of the
corresponding keto acids. We thus tried to exploit this
approach for the synthesis of natural Aerangis lactone
(4S,5S)-1a, starting from a 1,5-difunctionalised syn-
thon, such as derivative 4 (Scheme 2).
2. Results and discussion
With the aim of finding the most convenient and useful
access to natural 1a and eventually achieving the syn-
thesis of the other stereoisomers, we investigated the
For a preliminary investigation of the behaviour of
keto acid 4 under BY treatment, we prepared it through
a simple and quick route, starting from commercial
2-methyl-glutaric acid, and affording even regioisomer
5. When the 2:1 mixture (GC/MS) of substrates 4 and
5 was submitted to BY reduction, a 1:3 mixture of
Aerangis lactones and 2-methyl regioisomers was
obtained. Derivative 5 was readily and efficiently con-
verted into the corresponding diastereoisomeric lac-
tones cis-6a and trans-6b (1:1 ratio, GC/MS).
Reduction of derivative 4 was much slower, and gave
Scheme 1. 1,5-, 1,4- and 1,3-Difunctionalised synthons stud-
ied in this work as precursors of Aerangis lactone.
O
O
COOH
COOH
+
4
5
+
+
+
R
O
O
R
O
O
R
O
O
R
O
O
trans-6b
(4R,5R)-1a
(4S,5R)-1b
cis-6a
e.e. = >99%
e.e. = >99%
d.e. = 0
d.e. = 0
O
Ph
Ph
COOH
ref.4
ref.4
Ph
e.e. = 99%, d.e. = 76%
O
O
7
O
COOH
Ph
O
O
e.e. = 99%, d.e. = 74%
8
Scheme 2. BY reductions of 1,5-difunctionalised substrates.

E. Brenna et al. / Tetrahedron: Asymmetry 12 (2001) 1871–1879
1873
enantiopure (chiral GC) diastereoisomeric lactones cis-
(4R,5R)-1a and trans-(4S,5R)-1b in a 1:1 ratio. The
carbon bearing the hydroxyl function in all four lac-
tones was tentatively assigned (R)-configuration on the
basis of previous experience.4 This assumption was
confirmed for Aerangis lactones 1a and 1b by chiral GC
analysis at the end of the synthesis.
GC analysis, using a sample of racemic cis- and trans-
cognac lactone (prepared by NaBH4 reduction and
saponification of ester 9) as a reference. While we were
preparing this work a paper appeared in this journal
describing, among other results, the preparation of
(+)-trans-cognac lactone through the same synthetic
procedure.6a
We thus found that the steric course of the reaction was
different from the one we had described in the past for
BY treatment of structurally similar 1,5-keto acids 7
and 8, which were reduced to afford the corresponding
trans-enantiopure lactones with good d.e.s (Scheme 2).
(+)-trans-cognac lactone was also obtained by BY
reduction of unsaturated 1,4-keto acid 11. The same
behaviour was observed for 1,4-keto acid 12, affording
a single whisky lactone diastereoisomer, namely (+)-
(3S,4R)-trans-whisky lactone.5
An exception to this general rule of 1,4-synthons was
found when the unsaturated 1,4-keto ester 13 was
treated with yeast, in order to generate the stereocentre
at C(5) under the control of BY. A 7:3 mixture of the
allylic alcohol 14 and saturated keto ester 9 was
obtained. The enantiomeric excess of this latter deriva-
tive was established by means of chiral shift reagents,
and e.e. of 60% was evaluated. No allylic alcohol was
formed when the same reaction was carried on in the
presence of non-polar resins. A 3:1 mixture of starting
material 13 and of chiral derivative 9 was recovered
after 48 h. The keto ester 9 resulted to be enantiomeri-
cally pure (chiral shift reagents), but recovery yields
were too low to allow a practical application of the
procedure.
2.2. 1,4-Keto acid synthons
The absolute lack of diastereoselectivity in the BY
reduction of 4 led us to investigate the behaviour of
1,4-keto acid 2, having one carbon atom less, in order
to find an efficient route to the desired Aerangis lactone
(Scheme 3). Derivative 2 was prepared by saponifica-
tion of the corresponding ethyl ester 9, obtained by
reaction of n-hexanal with methyl crotonate in the
presence of benzoyl peroxide.5 Upon BY reduction keto
acid 2 afforded the substituted g-lactone 10, known as
‘cognac lactone’, in good yields after 48 h. This deriva-
tive was found to be the single diastereoisomer, (+)-
(3S,4R)-10.6a–h The assignment of trans relative
1
stereochemistry was based on the H NMR spectrum:
lH C(4)Htrans=4.01 ppm,6b C(4)Hcis=4.44 ppm.7 The
absolute configuration was established by the sign of
the optical rotation, [h]2D0=+72, c=2.4, CH2Cl2 (lit.
6a–h). The enantiomeric and diastereoisomeric purity of
(+)-trans-cognac lactone 10 was confirmed by chiral
2.3. 1,3-Keto acid synthons
Our investigation was then directed to 1,3-difunction-
alised synthons of the type 15 (Scheme 4). This choice
O
COOH
2
O
C5H11
O
O
(3S,4R)-10
(e.e. = 99%, d.e. = 99%)
COOH
COOH
11
O
O
C4H9
O
(3S,4R)-whisky lactone
(e.e. = 99%, d.e. = 99%)
12
O
OH
+
COOEt
COOEt
O
9
14
e.e. = 60%
COOEt
O
13
COOEt
9
e.e. = 99%
Scheme 3. BY reductions of 1,4-difunctionalised substrates.

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E. Brenna et al. / Tetrahedron: Asymmetry 12 (2001) 1871–1879
O
O
OEt
OEt
OEt
OH
15
16
OH
OH OEt
OEt
OH
+
OH
(±)-17
18
19
Scheme 4. BY reductions of 1,3-difunctionalised substrates.
was based on some literature reports, describing the BY
reduction of the double bond of structurally similar
substrates, such as 2-substituted acrolein acetals,8 4,4%-
dimethoxy crotonate derivatives,9 and a-methylene
ketones.10 Unfortunately, yeast treatment of our sub-
strate gave vinyl ethyl ether derivative 16. The forma-
tion of this compound could be justified by loss of
ethanol from the primary product of reduction of the
double bond. Once again, a subtle modification of the
substrate structure induces a great difference in the
reaction outcome.
2.4. Synthesis of natural Aerangis lactone (Scheme 5)
After this investigation we decided that the most conve-
nient approach to natural Aerangis lactone was that
based on the BY reduction of 1,4-keto acid 2 to lactone
(+)-10. (+)-trans-Cognac lactone was then employed as
starting material for the preparation of both (+)-1b, and
(−)-1a.
Reduction of (+)-10 with lithium aluminum hydride
gave, after treatment with acetic anhydride in pyridine,
diacetate (+)-(3R,4S)-3. This was submitted to regiose-
lective hydrolysis in water–THF in the presence of
Porcine pancreatic lipase, keeping the pH constant at
7.8 by addition of 0.5 M aqueous NaOH. Mono alco-
hol mono acetate (+)-20 was obtained, and converted,
via tosylate derivatisation and cyanide treatment, into
the nitrile derivative (+)-21a. Basic hydrolysis of (+)-21a
in ethylene glycole with 10% KOH gave directly (+)-
trans Aerangis lactone, after acid work-up (Scheme 5).
The configuration of C(5) in (+)-21a was inverted via
acetate displacement: hydrolysis of (+)-21a with KOH
in methanol gave alcohol (+)-22 which was converted
We then submitted alcohol derivative ( )-17 to yeast
treatment, with the aim of performing a form of kinetic
resolution by BY reduction. A 1:1 mixture of saturated
diol 18 and unsaturated derivative 19 was obtained.
However, diol 18 was found to be a 2:1 mixture of two
possible trans and cis diastereoisomers (GC/MS). Treat-
ment with tosyl chloride and chain elongation by one
carbon atom via cyanide reaction afforded, after
saponification, a 4:1 mixture of (+)-trans-cognac lac-
tone (e.e.=65%) and ( )-cis-cognac lactone (chiral
GC).
O
OAc
OAc
OR
iii,iv
ii
vi, vii
OH
v
OAc
O
O
O
9 R = Et
2 R = H
(+)-(3S,4R)-20
i
(3S,4R)-10
(+)-trans-cognac lactone
(+)-(3S,4R)-3
OAc
OH
OAc
vi,ix
viii
i
CN
CN
CN
O
O
(+)-(4S,5R)-21a
(+)-(4S,5R)-22
(-)-(4S,5S)-21b
(4S,5S)-1a
(-)-cis-aerangis lactone
viii
O
O
(4S,5R)-1b
(+)-trans-aerangis lactone
Scheme 5. (i) KOH, MeOH; (ii) Baker’s yeast; (iii) LiAlH4, THF; (iv) Ac2O, pyridine; (v) PPL, THF–water, pH 7.8, NaOH 0.5
M; (vi) tosyl chloride, pyridine; (vii) NaCN, DMSO; (viii) KOH 10%, ethylene glicole; (ix) AcONa, DMF.

E. Brenna et al. / Tetrahedron: Asymmetry 12 (2001) 1871–1879
1875
into the corresponding tosylate derivative. This latter
was treated with sodium acetate in DMF, to afford
nitrile (−)-21b. The diastereoisomeric purity of this
derivative was determined via GC/MS: d.e.=73%, tR
21a=19.12 min, tR 21b=18.81 min. Nucleophile substi-
tution of acetate anion on the tosylate derivative did
not proceed totally with configuration inversion: a par-
tial contribution of a mechanism other than SN2 should
be hypothesised. Nitrile (−)-21b was submitted to basic
hydrolysis to afford natural Aerangis lactone (−)-1a:
e.e.=99%, d.e.=70%. Both e.e. and d.e. values were
determined by chiral GC analysis, as we could find the
conditions for a baseline-peak separation of the four
stereoisomers of Aerangis lactone on a b-cyclodextrine
based column. Following the same route, a reference
sample of 1:1 ( )-1a and ( )-1b was prepared from a
1:1 mixture of the two possible racemic diastereoiso-
mers of diacetate 3.
Besides the successful synthesis of natural Aerangis
lactone and of its trans-diastereoisomer (+)-1b, we have
reported in this work the results of our broader
research on the BY treatment of various substrates,
which underline once again the unpredictability of BY
reactions.
4. Experimental
Porcine pancreatic lipase (PPL type II, Sigma) was
employed in this work. Chiral GC analyses of whisky
and cognac lactones were performed on a Chirasil DEX
CB, 25 m×0.25 mm column (Chrompack), installed on
a DANI HT 86.10 gas chromatograph, with the follow-
ing temperature program: 70°C (3%)–3.5°C/min–140°C–
8°C/min–180°C (1%). Chiral GC analyses of Aerangis
lactone were performed on a DeTBuSiBETA (086) 25
m×0.25 mm column (Mega, Italy), installed on a DANI
GC 1000 gas chromatograph, with the following tem-
perature program: 120°C (5%)–0.8°C/min–180°C (5%).
GC–MS analyses were performed on a HP 6890 gas–
chromatograph equipped with a 5973 mass-detector,
using a HP-5MS column (30 m×0.25 mm×0.25 mm).
The following temperature program was employed:
60°C (1 min)/6°/min/150° (1 min)/12°/min/280° (5 min).
1H NMR spectra were recorded in CDCl3 solutions at
room temperature unless otherwise stated, on a Bruker
AC-250 spectrometer (250 MHz 1H). The chemical shift
scale was based on internal tetramethylsilane. Coupling
constant (J) values are in Hz. Optical rotations were
measured on a Dr. Kernchen Propol digital automatic
polarimeter. TLC analyses were performed on Merck
Kieselgel 60 F254 plates. All the chromatographic sepa-
rations were carried out on silica gel columns.
3. Conclusions
The first enantioselective synthesis of enantiopure natu-
ral Aerangis lactone (−)-1a and the trans-diastereoiso-
mer (+)-1b is reported. We took advantage of the BY
reduction of 1,4-keto acid 2, affording a single enan-
tiopure diastereoisomer of trans-cognac lactone, (+)-10.
This substrate was then manipulated through unexcep-
tional reactions, to afford directly (+)-1b and, after
inversion of configuration, (−)-1a.
This work on Aerangis lactone gave us the chance to
further investigate the BY mode of reduction of various
1,5-, 1,4- and 1,3-difunctionalised synthons, we found
that:
(i) Reduction of the carbonyl function of 1,5-keto acids
in substrates 4 and 5 was enantiospecific, but barely
diastereoselective. A kinetic preference for the reduc-
tion of the less hindered carbonyl in derivative 5 was
also noticed. Structurally similar substrates, such as 7
and 8, were reduced with higher diastereoselectivity4
(d.e.=76 and 74%, respectively).
4.1. Synthesis of Aerangis lactones (−)-1a and (+)-1b
4.1.1. Ethyl 3-methyl-4-oxononanoate 9.6a Derivative 9
(22.5 g, 70%) was prepared from ethyl crotonate (17.1
g, 0.15 mol) and hexanal (90 g, 0.9 mol), in the presence
of benzoyl peroxide (29.0 g, 0.12 mol) according to the
procedure described by Gu¨nther and Mosandl for the
preparation of 3-methyl-4-oxooctanoate ethyl ester.5 1
H
(ii) Reduction of 1,4-keto acids, such as 2 and 12, took
an unexpectedly different steric course: only one
diastereoisomer of the corresponding enantiopure
trans-g-lactone was recovered. In the presence of a
conjugated double bond, such as in 1,4-keto ester 13,
the double bond and the carbonyl moiety were reduced
separately, to afford a mixture of 9 and 14. In the
presence of non-polar resins, the double bond was
preferentially reduced, and the corresponding keto ester
9 was obtained in enantiopure form.
NMR: l 4.08 (2H, q, J=7, COOCH2), 2.98 (1H, m,
H-C(3)), 2.75 (1H, dd, J=17, 9, H-C(2)), 2.50 (2H, m,
2H-C(5)), 2.25 (1H, dd, J=17, 5.4, H-C(2)), 1.57 (2H,
quintuplet, J=7.3, 2H-C(6)), 1.27 (4H, m, 2CH2), 1.22
(3H, s, COOCH2CH3), 1.10 (3H, d, J=7.3, CH3-C(3)),
0.87 (3H, t, J=7, CH2CH3); GC/MS tR=16.04 min;
m/z: 55 (17), 71 (70), 99 (100), 112 (65), 158 (52), 169
(50), 214 (0.1)
4.1.2. 3-Methyl-4-oxononanoic acid 2.6a Ester 9 (21.4 g,
0.10 mol) was hydrolysed with KOH (8.40 g, 0.15 mol)
in methanol (100 mL) to afford acid 2 (17.7 g, 95%):
GC/MS tR=16.09 min m/z: 55 (13), 71 (55), 99 (100),
130 (30), 168 (5), 186 (5).
(iii) Yeast treatment of the 1,3-difunctionalised deriva-
tive 15 did not effect reduction of the double bond, as
expected on the base of literature reports.8–10 The achi-
ral enol ether 16 was obtained. Double bond reduction
was observed when racemic alcohol derivative 17 was
submitted to treatment with BY: the reaction proceeded
with low diastereoselectivity and modest enantio-
selectivity.
4.1.3. (+)-(3S,4R)-3-Methyl-4-nonanolide ((+)-trans-
cognac lactone) (+)-10.6a–h Keto acid 2 (17.0 g, 0.091
mol) was submitted to baker’s yeast according to the
general procedure reported hereafter, to afford lactone

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E. Brenna et al. / Tetrahedron: Asymmetry 12 (2001) 1871–1879
(+)-10 (6.03 g, 39%): [h]2D0=+72 (c 2.4, CH2Cl2) (lit.
Ref. 6a [h]2D0=+73 (c 0.2, MeOH); Ref. 6b [h]2D0=+82.2
(c 0.71, MeOH); Ref. 6d [h]2D0=+83.2 (c 0.69, MeOH);
Ref. 6e [h]2D0=+78 (c 1.12, CH2Cl2); Ref. 6f [h]2D0=+48.3
(c 0.79, CH2Cl2); Ref.6g [h]2D0=+72 (c 1.0, CH2Cl2);
Ref. 6h [h]2D0=+79.5 (CH2Cl2)); e.e. and d.e.=>99%
chiral GC tR=24.72 min; d.e.=>99% by GC/MS tR=
According to the same procedure a sample of a 1:1
mixture of the two racemic (3SR,4RS)- and (3RS,4RS)-
diastereoisomers was prepared from the corresponding
mixtures of diacetates. The two diastereoisomers could
not be distinguished by GC/MS, but had different
signals in the 1H NMR spectra: (3RS,4RS)-
diastereoisomer 4.88 (1H, m, H-C(4)), 2.05 (3H, s,
CH3COO), 0.92 (3H, d, J=7.1, CH3CH).
1
14.76 min; H NMR: l 4.00 (1H, m, H-C(4)), 2.67 (1H,
m), 2.18 (2H, m), 1.75–1.25 (8H, m), 1.12 (3H, d,
J=6.4, CH3C(3)), 0.86 (3H, t, J=6.8, CH3CH2); m/z
(GC/MS): 71 (28), 83 (11), 99 (100), 128 (8), 142 (4),
170 (1).
4.1.6. (+)-(4S,5R)-5-Acetoxy-4-methylnonanonitrile (+)-
21a. To a solution of alcohol (+)-20 (4.40 g, 0.020 mol)
in pyridine (20 mL), 4-toluenesulphonyl chloride (5.81
g, 0.030 mol) was added at 0°C. After the usual work-
up, the residue was dissolved in DMSO (20 mL) and
NaCN (1.47 g, 0.030 mol) was added. The mixture was
heated at 50°C for 3 h, then diluted with water and
extracted with methylene chloride. The organic phase
was dried, and concentrated. The residue was purified
by columnn chromatography, eluting with hexane/ethyl
acetate 9:1, to afford (+)-21a (3.38 g, 75%): [h]2D0=+7.4
A 1:1 mixture of ( )-trans- and cis-cognac lactones,7 to
be used as a reference sample, was prepared by NaBH4
reduction and saponification of keto ester 9: GC/MS tR
(trans-cognac lactone)=14.76 min, tR (cis-cognac lac-
tone)=15.44 min, m/z (cis): 71 (25), 83 (20), 99 (100),
128 (8), 142 (8), 170 (1).); chiral GC: tR (+)-10=24.72
min, tR (−)-10=23.31 min, tR cis-cognac lactone=25.82
min, tR cis-cognac lactone=25.98 min.
1
(c 1.4, CH2Cl2); d.e.=>99% GC/MS tR=19.12 min; H
NMR: l 4.79 (1H, m, H-C(5)), 2.36 (2H, m, CH2CN),
2.06 (3H, s, CH3COO), 1.88 (2H, m), 1.50 (4H, m), 1.27
(5H, m), 0.92 (3H, d, J=7.1, CH3CH), 0.87 (3H, t,
J=7.1, CH3CH2); m/z GC/MS: 55 (75), 83 (100), 113
(57), 154 (68), 182 (23).
4.1.4. (+)-(3S,4R)-1,4-Dihydroxy-3-methylnonane diac-
etate (+)-3. trans-Cognac lactone (+)-10 (6.0 g, 0.035
mol) was treated with lithium aluminium hydride (1.99
g, 0.053 mol) in THF (50 mL). After the usual work-up,
the diol was treated with acetic anhydride and pyridine
in excess, to afford (+)-3 (6.59 g, 73%): [h]2D0=4.16 (c
According to the same procedure a sample of a 1:1
mixture of the two racemic diastereoisomers
(4SR,5RS)- 21a and (4RS,5RS)-21b was prepared from
the corresponding mixtures of alcohols. Derivatives 21a
and 21b could be distinguished by GC/MS: tR (21b)=
18.81 min.
1
2.55, CH2Cl2); de >99% (GC/MS) tR=19.29 min; H
NMR: l 4.78 (1H, m, H-C(4)), 4.09 (2H, m, CH2OAc),
2.03 (3H, s, CH3COO), 2.01 (3H, s, CH3COO), 1.78
(2H, m), 1.57–1.34 (3H, m), 1.26 (6H, m), 0.90 (3H, d,
J=6.4, CH3CH), 0.86 (3H, t, J=6.8, CH3CH2); m/z
(GC/MS): 56 (86), 72 (83), 85 (100), 98 (60), 155 (44),
172 (0.08), 215 (0.04).
4.1.7. (+)-(4S,5R)-4-Methyl-4-decanolide (+)-1b.2,3
A
solution of nitrile (+)-21a (0.800 g, 3.56 mmol) in
ethylene glycole (10 mL) in the presence of KOH 10%
(2 mL) was heated at 100°C for 8 h. The reaction
mixture was diluted with water, acidified with HCl
10%, and extracted with ethyl acetate. The residue was
bulb to bulb distilled to afford (+)-1a (0.445 g, 68%):
[h]2D0=+45 (c 0.3, CH2Cl2); e.e. and d.e.=>99% by
chiral GC tR=27.00 min; d.e.=>99% by GC/MS tR=
A 1:1 mixture of racemic (3SR,4RS) and (3RS,4RS)
diacetates, to be used as a reference sample, was pre-
pared by LiAlH4 reduction of keto ester 2 and acetyla-
tion with Ac2O and pyridine: GC/MS tR (3SR,4RS)
diastereosiomer=19.29 min, tR (3RS,4RS) diastereoiso-
mer=19.19 min, m/z (3RS,4RS) diastereoisomer: 56
(82), 72 (76), 85 (100), 98 (56), 155 (44), 172 (1.5), 215
1
1
(0.03). The H NMR spectrum was similar to that of
17.68 min; H NMR: l 3.93 (1H, m, H-C(5)); 2.61 (1H,
the single diastereoisomer (+)-3.
ddd, J=17, 7, 5, CHHCOO), 2.44 (1H, ddd, J=17, 10,
7, CHHCOO), 1.89 (1H, m), 1.70 (2H, m), 1.63–1.26
(8H, m), 1.00 (3H, d, J=6.5, CH3-C(4)), 0.89 (3H, t,
J=7, CH3CH2). m/z GC/MS: 56 (100), 84 (69), 113
(90), 128 (12), 184 (0.1).
4.1.5. (+)-(3S,4R)-4-Acetoxy-3-methylnonan-1-ol (+)-20.
A solution of diacetate (+)-3 (6.50 g, 0.026 mol) in THF
(5 mL) was added to a suspension of PPL (3 g) in water
(100 mL) at pH 7.8. The reaction was monitored with a
pH-stat with continuous addition of aqueous 0.5 M
NaOH. After 24 h, the enzyme was removed by filtra-
tion and the filtrate was extracted with ethyl acetate.
The organic phase was dried (Na2SO4), and concen-
trated under reduced pressure to give a residue, which
was chromatographed on a silica gel column, using
hexane/ethyl acetate 4:1. Derivative (+)-20 (4.41 g, 81%)
According to the same procedure, a sample of a 1:1
mixture of the two racemic diastereoisomers 1a and 1b
was prepared from the corresponding mixtures of
nitriles. Derivatives 1a and 1b could be distinguished by
GC/MS: tR 1a=18.15 min, tR 1b=17.68 min. The four
stereoisomers could be separated by chiral GC analysis:
tR (+)-1b=27.00 min, tR (−)-1b=27.31 min, tR (−)-1a=
29.43 min, tR (+)-1a=30.22 min.
1
was obtained: [h]D20=+9.6 (c 1, CH2Cl2); H NMR: l
4.81 (1H, dt, J=5.6, 7.2, H-C(4)), 3.69 (2H, m,
CH2OH), 2.06 (3H, s, CH3COO), 1.88 (1H, m), 1.65
(1H, m), 1.57–1.19 (9H, m), 0.91 (3H, d, J=7.1,
CH3CH), 0.88 (3H, t, J=7.1, CH3CH2); GC/MS tR=
17.25 min m/z: 56 (78), 85 (100), 155 (14), 173 (10).
4.1.8. (+)-(4S,5R)-5-Hydroxy-4-methylnonanonitrile (+)-
22. A solution of nitrile (+)-21a (2.50 g, 0.011 mol) was
treated with KOH (0.933 g, 0.017 mol) in methanol (20
mL). After the usual work-up, the residue was purified

E. Brenna et al. / Tetrahedron: Asymmetry 12 (2001) 1871–1879
1877
by column chromatography, eluting with hexane/ethyl
acetate 7:3, and alcohol (+)-22 (1.85 g, 92%) was
4.2.3. Ethyl 3-methyl-4-hydroxy-2-nonenoate 14. To a
solution of pentyl magnesium bromide, prepared from
pentyl bromide (15.1 g, 0.10 mol) and magnesium (2.28
g, 0.095 mol), in THF (300 mL) a solution of zinc(II)
bromide (10.7 g, 0.048 mol) in THF (30 mL) was added
under nitrogen, maintaining the temperature below
20°C. To the resulting greyish mixture a solution of
3-formyl crotonic acid ethyl ester (14.2 g, 0.10 mol) was
added at 20°C. The reaction mixture was quenched
with ice, acidified with diluted HCl, and extracted with
diethyl ether. The organic phase was washed with brine,
dried (Na2SO4) and concentrated under reduced pres-
sure. The residue was chromatographed eluting with
hexane/ethyl acetate 9:1, to afford derivative 14 (12.4 g,
1
obtained. [h]2D0=2 (c 1.1, CH2Cl2); H NMR: l 3.42
(1H, m, H-C(5)); 2.45 (1H, ddd, J=16, 8, 6, CHHCN),
2.34 (1H, dt, J=16, 8, CHHCN), 1.91 (1H, m), 1.69–
1.21 (10H, m), 0.94 (3H, d, J=6.5, CH3-C(4)), 0.89
(3H, t, J=7, CH3CH2); GC/MS tR=17.63 min m/z: 55
(95), 83 (100), 101 (60), 112 (32), 141 (18), 182 (0.01).
4.1.9. (−)-(4S,5S)-5-Acetoxy-4-methylnonanonitrile (−)-
21b. Alcohol (+)-22 (1.80 g, 0.01 mol) was converted
into the tosylate derivative, according to the procedure
described for (+)-20. This was dissolved in DMF (20
mL), and AcONa (1.23 g, 0.015 mol) was added. The
reaction mixture was stirred for 3 h, diluted with water
and extracted with ethyl acetate. The residue was chro-
matographed, eluting with hexane/ethyl acetate 9:1, to
give a 1:1 mixture of acetate (−)-21b and of the corre-
sponding (4S,5S) formate derivative (1.71 g); [h]2D0=−6
(c 0.7, CH2Cl2); d.e.=73% by GC/MS, tR (−)-21b=
1
61%): H NMR: l 5.91 (1H, s; H-C(2)), 4.16 (2H, q,
J=7, COOCH2), 4.08 (1H, m, H-C(4)), 2.11 (3H, s,
CH3-C(3)), 1.65–1.31 (8H, m), 1.28 (3H, s,
COOCH2CH3), 0.89 (3H, t, J=7, CH2CH3); m/z GC/
MS tR=18.87 min: 69 (25), 87 (50), 115 (100), 143 (63),
169 (17), 196 (2).
1
18.81 min, tR (formate ester)=18.27 min; H NMR: l
4.2.4. Ethyl 3-methyl-4-oxo-2-nonenoate 13. A mixture
of allylic alcohol 14 (12.0 g, 0.056 mol) and mangane-
se(IV) oxide (1.5 equiv.) in methylene chloride (200 mL)
was stirred under reflux for 4 h. The reaction mixture
was filtered and the filtrate was concentrated under
reduced pressure. The residue was chromatographed,
eluting with hexane:ethyl acetate 19:1, to give keto ester
8.11 (1H, s, CHO), 5.02 (1H, m, H-C(5)), 4.88 (1H, m,
H-C(5)), 2.40 (4H, m, CH2CN of acetate and formate),
2.06 (3H, s, CH3COO), 1.96–1.40 (22H, m), 0.97 (3H,
d, J=7, CH3CH), 0.95 (3H, d, J=7, CH3CH), 0.89
(6H, t, J=7, CH3CH2); m/z (GC/MS) 21b: 55 (68), 83
(100), 113 (55), 154 (60), 182 (23); m/z (GC/MS) for-
mate ester: 55 (90), 83 (100), 101 (64), 141 (32), 166 (8),
182 (2).
1
13 (9.14 g, 77%): H NMR: l 6.52 (1H, m; H-C(2)),
4.23 (2H, q, J=7, COOCH2), 2.68 (2H, t, J=7.3,
CH2CO), 2.22 (3H, d, J=1.5, CH3-C(3)), 1.62 (2H,
quintuplet, J=7.3, CH2CH2CO), 1.32 (7H, m+t, J=
4.1.10. (−)-(4S,5S)-4-Methyl-4-decanolide (−)-1a.2,3
According to the procedure described for the prepara-
tion of (+)-1b, the 1:1 mixture of nitrile (−)-21b and of
the corresponding formate (1.71 g) was converted in
natural Aerangis lactone (−)-1a (1.05 g, 57% from
alcohol (+)-22): [h]D20=−35 (c 0.9, CH2Cl21); e.e. >99%,
d.e.=70% by chiral GC tR=29.43 min; H NMR: l
4.27 (1H, m, H-C(5)); 2.53 (2H, t, J=7, CH2COO),
2.03 (3H, m), 1.67 (2H, m), 1.60–1.20 (6H, m), 0.95
(3H, d, J=6.5, CH3-C(4)), 0.89 (3H, t, J=7, CH3CH2).
m/z GC/MS: 56 (100), 84 (62), 113 (52), 128 (7), 184
(0.1).
7.3,
2
CH2+COOCH2CH3), 0.89 (3H, t, J=7,
CH2CH3); m/z GC/MS tR=17.67 min: 85 (31), 110
(100), 139 (100), 167 (40), 183 (4).
4.2.5. 2-Diethoxymethyl-oct-1-en-3-ol 17. Derivative 17
was prepared (55.2 g, 80%) from hexanal (30 g, 0.30
mol) and 2-bromo-3,3-diethoxy-propene (81.5 g, 0.39
mol) according to the literature:11 1H NMR: l 5.17
(2H, s, C=CH2), 4.81 (1H, s, CH(OEt)2), 4.04 (1H, t,
J=6.2, CHOH), 3.66–3.32 (4H, m, 2OCH2CH3), 1.58–
1.14 (14H, m), 0.90 (3H, t, J=7, CH2CH3); m/z GC/
MS tR=16.36 min: 85 (65), 103 (100), 113 (83), 185
(23).
4.2. Synthesis of the substrates
4.2.6. 2-Diethoxymethyl-oct-1-en-3-one 15. Derivative 15
was prepared (25.8 g, 65%) from alcohol 17 (40.0 g,
0.17 mol) by Swern oxidation:11 1H NMR: l 5.97 (1H,
m, C=CH), 5.92 (1H, m, C=CH), 5.19 (1H, s,
CH(OEt)2), 3.65–3.35 (4H, m, 2OCH2CH3), 2.59 (2H,
t, J=7, CH2CO), 1.68–1.21 (6H, m), 1.17 (6H, t, J=7,
2OCH2CH3), 0.92 (3H, t, J=7, CH2CH3); m/z GC/MS
tR=15.48 min: 85 (65), 103 (100), 113 (83), 185 (23).
4.2.1. 4-Methyl-5-oxo-decanoic acid 4 and 2-methyl-5-
oxo decanoic acid 5. The 2:1 mixture of derivatives 4
and 5 was prepared from 2-methyl glutaric acid,
according to the procedure already reported in Ref. 4.
The two corresponding methyl esters could be distin-
guished by GC/MS: methyl ester of 4 tR=16.92 min,
m/z: 55 (35), 71 (58), 99 (100), 126 (51), 158 (31), 183
(24), 214 (4); methyl ester of 5 tR=17.05 min, m/z: 55
(66), 71 (79), 99 (100), 126 (95), 158 (77), 183 (38), 214
(0.5).
4.3. Yeast reduction
A suspension of baker’s yeast (2.5 kg) and
D-glucose
4.2.2. 3-Methyl-4-oxo-octanoic acid 12. This derivative
was prepared (16.5 g, 96%) by saponification with
KOH (8.4 g, 0.15 mol) in methanol (100 mL) of the
corresponding ethyl ester (20 g, 0.1 mol) prepared
according to Ref. 5.
(2.0 kg) in tap water (7.5 l) was stirred for 30 min at
32°C. A solution of the substrate (0.15 mol) in ethanol
(20 mL) was then added. After stirring the mixture for
48 h at rt Celite (1 kg) was added, and the reaction
mixture filtered, washing the Celite pad with ethyl

1878
E. Brenna et al. / Tetrahedron: Asymmetry 12 (2001) 1871–1879
acetate. The filtrate was adjusted to pH 4 with aqueous
2N HCl, and extracted with ethyl acetate. The organic
layer was dried (Na2SO4) and concentrated under
reduced pressure. The residue was chromatographed on
a silica gel column.
4.4.4. BY reduction of derivative 15. Reduction of 15 (7
1
g, 0.021 mol) gave derivative 16 (2 g, 52%): H NMR:
l 7.15 (1H, m, C=CH), 4.03 (2H, q, J=7, OCH2CH3),
2.39 (2H, t, J=7, CH2CO), 1.64 (3H, d, J=1.25, CH3-
C=), 1.65–1.20 (9H, m), 0.92 (3H, t, J=7, CH2CH3);
m/z GC/MS tR=15.48 min: 55 (55), 69 (100), 83 (92),
101 (40), 140 (5).
4.4. Reduction products
4.4.5. BY reduction of derivative 17. Reduction of 17 (10
g, 0.043 mol) gave a 1:1 mixture of derivatives 18 and
19 (2.65 g). In order to recover the desired unsaturated
diol 18, the reaction mixture was oxidised with MnO2
in methylene chloride. After the usual work-up, the
residue was chromatographed, using hexane:ethyl ace-
tate 7:3 as an eluent, to recover derivative 18 (1.5 g,
22%) as a 2:1 mixture (GC/MS) of the two possible
trans and cis-diastereoisomer: GC/MS tR (trans)=
13.19 m/z: 55 (60), 71 (35), 83 (100), 101 (65); tR
4.4.1. BY reduction of derivatives 4 and 5. The 2:1
mixture of 4 and 5 (20.0 g, 0.10 mol) gave a mixture
(GC/MS) of 4-methyl decanolides and of the 2-methyl
regioisomers (7.72 g, 42%). The mixture was analysed
by GC/MS: cis-6a and trans-6b tR=17.27 and 17.56
min (not assigned), tR 1b=17.68 min, tR 1a=18.15 min
Aerangis lactones were separated from the 2-methyl
regioisomers by column chromatography, eluting with
hexane/ethyl acetate 9:1. The two 1:1 Aerangis lactones
were identified by chiral GC/MS: (+)-1b tR=27.00 min,
e.e.=>99%; (+)-1a tR=30.22 min, e.e.=>99%.
1
(cis)=13.12 m/z: 55 (67), 71 (39), 83 (100), 101 (65); H
NMR: l 3.68 (3H, m), 1.89–1.08 (12H, m), 0.89 (3H, t,
J=7, CH2CH3).
The relative configuration of the diastereoisomers and
their enantiomeric purity was assessed converting diol
18 into cognac lactone, via tosylate derivatisation, cya-
nide substitution, and alkaline hydrolysis. A 4:1 mix-
ture of trans- and cis-cognac lactones was obtained
(GC/MS). Chiral GC analysis: (+)-trans-cognac e.e.=
65% and ( )-cis-cognac lactone.
4.4.2. BY reduction of keto acid 12. Keto acid 12 (16.0
g, 0.094 mol) gave (+)-(3S,4R)-3-methyl-4-octanolide5
((+)-trans-whisky lactone) (5.57 g, 38%): [h]2D0=+90 (c
0.5, MeOH) (lit. Ref. 5 [h]2D0=96 (c 1, MeOH); e.e. and
d.e.=>99% chiral GC tR=21.64 min; d.e.=>99% by
GC/MS tR=12.47 min; 1H NMR: l 4.00 (1H, m,
H-C(4)), 2.66 (1H, m), 2.18 (2H, m), 1.70–1.20 (6H, m),
1.14 (3H, d, J=6.4, CH3C(3)), 0.92 (3H, t, J=6.8,
CH3CH2); m/z (GC/MS): 71 (25), 87 (15), 99 (100), 114
(1), 156 (0.5).
Acknowledgements
COFIN-Murst is acknowledged for financial support.
References
A 1:1 mixture of racemic trans- and cis-whisky lac-
tones, to be used as a reference sample, was prepared
by NaBH4 reduction of keto acid 12: GC/MS tR (trans-
whisky lactone)=12.47 min, tR (cis-whisky lactone)=
13.10 min, m/z (cis): 69 (23), 87 (20), 99 (100), 114 (7),
156 (3); chiral GC: tR (+)-trans-whisky lactone=21.64
min, tR (−)-trans-whisky lactone=22.77 min, tR cis-
whisky lactone=23.35 min, tR cis-whisky lactone=
23.53 min.
1. Kaiser, R. The Scent of Orchids, Olfactory and Chemical
Investigations; Editions Roche, F. Hoffmann La Roche:
AG Basel, 1993.
2. Kaiser, R. US patent US 005248792A.
3. Bartschat, D.; Lehmann, D.; Dietrich, A.; Mosandl, A.;
4.4.3. BY reduction of derivative 13. Unsaturated keto
ester 13 (9.0 g, 0.042 mol) gave a 7:3 mixture (GC/MS)
of allylic alcohol 14 and keto ester 9 (3.5 g). The desired
keto ester 9 was isolated by column chromatography,
eluting with hexane:ethyl acetate 19:1. Keto ester 9
(1.12 g, 12%): [h]D20=23.8, c 1.9, CH2Cl2; e.e.=60% by
1H NMR in the presence of chiral shift reagents
(Eu(hfc)3): signal of the major enantiomer 4.25 ppm (q,
COOCH2); signal of the minor enantiomer 4.26 ppm,
Dl=0.01 ppm.
Kaiser, R. Phytochem. Anal. 1995, 6, 130.
4. Fronza, G.; Fuganti, C.; Grasselli, P.; Terreni, M. Tetra-
hedron 1992, 48, 7363.
5. Gu¨nther, C.; Mosandl, A. Liebigs Ann. Chem. 1986, 2112.
6. (a) Benedetti, F.; Forzato, C.; Nitti, P.; Pitacco, G.;
Valentin, E.; Vicario, M. Tetrahedron: Asymmetry 2001,
12, 505. Other syntheses of (+)-trans-cognac lactone: (b)
Takahata, H.; Uchida, Y.; Momose, T. J. Org. Chem.
1995, 60, 5628; (c) Takahata, H.; Uchida, Y.; Momose,
T. Tetrahedron Lett. 1994, 35, 4123; (d) Ebata, T.; Mat-
sumoto, K.; Yoshikoshi, H.; Koseki, K.; Kawakami, H.
Heterocycles 1993, 36, 1017; (e) Miyata, O.; Shinada, T.;
Kawakami, N.; Taji, K.; Ninomiya, I. Chem. Pharm.
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Matsumoto, K.; Yoshikoshi, H.; Koseki, K.; Kawakami,
H.; Matsushita H. Heterocycles 1993, 36, 1017.
When derivative 13 (9.0 g, 0.042 mol) was reduced by
BY in the presence of resin XAD 1180,12 a 3:1 mixture
(1H NMR) of starting material 13 and saturated keto
ester 9 was obtained (4.32 g). The two derivatives could
not be separated by column chromatography. Keto
ester 9 (impure of 13): [h]2D0=27.8, c 2.8, CH2Cl2;
1
e.e.=95% by H NMR in the presence of chiral shift
reagents.

E. Brenna et al. / Tetrahedron: Asymmetry 12 (2001) 1871–1879
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