Mendeleev Commun., 2002, 12(2), 59–60
Superacidic cyclisation–lipase-mediated kinetic resolution as a short route from
achiral linear isoprenoid alcohols to scalemic cyclic isomers
Edward P. Serebryakov,*a Galina D. Gamalevich,a Veacheslav N. Kulcitki,b Nicon D. Ungurb and Pavel F. Vlad*b
a N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, 119991 Moscow, Russian Federation.
Fax: +7 095 135 5328
b Institute of Chemistry, Academy of Sciences of Republic of Moldova, MD 2028 Kishinev, Republic of Moldova.
Fax: + 373 2 73 9775
10.1070/MC2002v012n02ABEH001566
( )-α-Cyclogeraniol and ( )-drim-7-en-11-ol acetates obtained via the FSO3H-induced cyclisation of geraniol and (E)-farnesol and
subsequent acetylation were hydrolysed in the presence of hog pancreas lipase (PPL) to afford (R)-(+)-α-cyclogeraniol (ee ~30%
at the optimal conversion C = 20 2%) and (5R,9R,10R)-(+)-drim-7-en-11-ol (ee 78.5% at C = 30%), respectively; ( )-15-acetoxy-
isoagath-12-ene, obtained similarly from all-E-geranylgeraniol, is resistant to PPL-mediated hydrolysis, but is hydrolysed in the
presence of lipase from Candida cylindracea to afford (10S,14R)-(–)-isoagath-12-en-15-ol of 69–80% ee in ~3% yield.
Cyclic isoprenoids with a common structure and common
relative configuration can occur in the nature in both enantio-
meric forms. Typically, the species abundant in one or another
enantiomer belong to rather remote taxons. To study the bio-
medical properties of enantiomeric terpenoids and, all the more
so, to convert the latter into chiral building blocks, considerable
amounts of both enanitomers are needed, but it is not always
easy to obtain each of the two from natural sources or by
chemical synthesis.
However, both enantiomers of certain cyclic isoprenoids could
be obtained in only three steps via a stereodivergent protocol
that includes (i) the stereospecific superacid-induced cyclisation of
geometrically pure achiral alcohols of the type H[CH2C(Me)=
CHCH2]nOH into racemic cyclic isomers, (ii) the acetylation of
the latter to produce the corresponding ( )-acetates, and (iii) the
subsequent lipase-mediated kinetic resolution of the acetates into
differently functionalised (+)- and (–)-enantiomers by partial
hydrolysis. Cyclisation of the lower members of the above type
(n = 2–4) is well known,1 while enzymatic optical resolution of
chiral alcohols or esters is such an obvious solution,2 that one
can only wonder, (or just not wonder) why this protocol has not
been actuated so far.†
This work demonstrates the feasibility of stereodivergent trans-
formation of geraniol 1 and (E,E)-farnesol 2 into scalemic
α-cyclogeraniols [(R)-3, (S)-3] and drim-7-en-11-ols [(all-R)-4,
(all-S)-4]. Similar transformation of all-E geranylgeraniol 5 into
(–)-isoagath-12-en-15-ol [(10S,14R)-6] is also reported. By means
of superacidic cyclisation alcohols 1, 2 and 5 were converted
into corresponding cyclic isomers ( )-3, ( )-4, and ( )-6,‡ from
which acetates ( )-3a, ( )-4a and ( )-6a were prepared§ and
subjected to partial hydrolysis in the presence of hog pancreas
lipase (PPL) or lipase from Candida rugosa (º C. cylindracea,
CCL). In order to attain the highest possible ee of scalemic
alcohols 3 and 4 without sacrificing too much the yield, conver-
sions of ( )-3a and ( )-4a were arrested at C £ 30%. Acetate
( )-6a could not be hydrolysed in the presence of PPL even
upon repetitive addition of the enzyme up to a twofold excess
(w/w). The scalemic form of alcohol 6 was obtained only using
CCL as the catalyst.¶
The PPL-mediated hydrolysis of ( )-3a proceeded with low
enantioselectivity. In the best variant (C = 20% in 32 h), it
afforded in a 20% yield a specimen of (+)-α-cyclogeraniol
[(R)-3] with [a]D20 +34.6° (c 0.96, EtOH), which corresponds to
~30% ee. For the specimens of 3 with ee ~100%, [a]2D5 +122°
(EtOH)4(a) for the R enantiomer and –116° or –109.2° (EtOH)
for its S antipode were reported.4(b),(c) Mild alkaline hydrolysis
of the fraction of unconverted acetate gave a specimen of alcohol
(S)-3 with [a]D20 –10.4% (c 1.05, EtOH), which corresponds to
ee ~10%.
The hydrolysis of ( )-4a was quicker (C = 30% in 22 h) and
more selective. The isolated drim-7-en-11-ol with all-R con-
figuration [(R)-4] had [a]D21 +13.1° (c 1.1, PhH), which corre-
sponds to ee 78.5%. Lit., [a]D25 +15.8° (PhH)5(a) for a specimen
of (R)-4 with ee 88% and [a]Drt –18° or –18.2° (PhH)5(a),(b) for
the specimens of all-S drim-7-en-11-ol [(S)-4] of ~100% ee. The
fraction of unconverted acetate upon alkaline hydrolysis gave
alcohol (S)-4 with [a]2D0 –5.81° (c 0.89, PhH), which corresponds
to ee ~32% (Scheme 1). The enhanced hydrolysis enantioselec-
tivity in the case of ( )-4a was considered earlier.6
The transition from ( )-4a to ( )-6a resulted in a dramatical
deceleration of the PPL-catalysed hydrolysis, the recovery of
acetate ( )-6a after 96 h of incubation being almost quantita-
tive. The hydrolysis of ( )-6a in the presence of CCL was also
very slow (C ~10% after 148 h). The reaction mass was worked-
up as usual and chromatographed twice, first on SiO2 and then
on Florisil®, to give an alcohol in 3% yield with [a]D21 –7.2°
(c 0.23, CHCl3). It was identical to the (–)-enantiomer of 6
1
with the 10S,14R configuration in H and 13C NMR spectra,
GC MS data7(a),(b) and the sign of [a]D. Specimens of the latter
with ~100% ee, obtained earlier from natural sources7(a),(b) or by
partial synthesis from grindellic acid7(a) and sclareol7(c), displayed
[a]Drt –9 to –10.5° (CHCl3).7 Consequently, the ee of this speci-
†
¶
A conceptually similar approach to Ambrox®‚ from farnesyl acetate via
Powdered PPL (48 units per mg protein, Olainfarm, Latvia) or CCL
lipase-mediated kinetic resolution of ( )-drimane-8,10-diol3 is unsuitable
for obtaining unsaturated cyclic alcohols with unambiguously positioned
double bonds.
(type VII with lactose, 1200 units per mg solid, Sigma) and a substrate
(1:2, w/w) were suspended in a 0.1 M aqueous phosphate buffer solution
[pH 6.5 for PPL or 7.0 for CCL, 1–3 ml per 0.25 mmol of ( )-acetate]
and vigorously stirred at 20–22 °C. The duration of stirring for ( )-3a,
( )-4a and ( )-6a was 28–32 and 22 h (using PPL), or 148 h (using
CCL), respectively. After standard work-up the only products of PPL-
mediated hydrolysis, the required alcohol and acetate (TLC monitoring),
were separated by column chromatography on SiO2 [in the case of CCL-
mediated hydrolysis of ( )-6a this was followed by additional chromato-
graphy on Florisil®] and identified spectroscopically. The enantioselec-
tivity of hydrolysis was estimated by comparing the signs and magnitudes
of [a]D of chromatographically pure alcohols obtained at C £ 30% with
those reported in the literature for the same alcohols of ~100% ee. The
fractions of unconverted acetates left after the hydrolysis of ( )-3a or
( )-4a were saponified (1 N NaOH/MeOH–H2O, ~20 °C, 2–4 h) to give
alcohols with the opposite signs of [a]D.
‡
Starting alcohols 1–3 were cyclised on treatment with fluorosulfonic
acid (20 equiv.) in 2-nitropropane at –78°C, the reaction mass was
neutralised with NEt3, washed with water, extracted with Et2O, dried
(Na2SO4), and concentrated. The remainder was subjected to column
chromatography on SiO2 using hexane–Et2O gradient elution (80:20 ®
0:100) to give, in agreement with known procedures, ( )-α-cyclogeraniol
[( )-3, yield 73%],1(a) ( )-drim-7-en-15-ol [( )-4, yield 71%]1(b) and
( )-isoagath-12-en-15-ol [( )-6, yield 72%].1(c)
§
The solutions of ( )-4, ( )-5 and ( )-6 (0.25 mmol in hexane) were
treated with Ac2O–Py (1:1, v/v; ~20 °C, 12–18 h) in the presence of
4-DMAP (4–5 mg). After standard work-up the acetates were purified
by column chromatography on SiO2 to give ( )-3a, ( )-4a and ( )-6a in
92, 94 and 79% yields, respectively.
– 59 –
Serebryakov, Edward P.
