Lipase-mediated resolution of the hydroxy-cyclogeraniol isomers: application to the synthesis of the enantiomers of karahana lactone, karahana ether, crocusatin C and γ-cyclogeraniol

Article abstract of DOI:10.1016/j.tetasy.2009.05.013

A comprehensive study on the lipase PS-mediated resolution of different hydroxy-geraniol isomers is reported. A number of α-, β- and γ-isomers bearing a 2-, 3- or 4-hydroxy functional group were synthesised regioselectively and then submitted to the lipase-mediated kinetic acetylation. The latter experiments showed that the 2-hydroxy isomers 4, 5 and 14 (α, γ and β, respectively) as well as cis-3-hydroxy α-cyclogeraniol 7 and cis-4-hydroxy γ-cyclogeraniol 10 could be easily resolved by this procedure. The enantiomeric purity of the main part of these compounds was increased by recrystallisation and the enantiopure diols obtained were used as building blocks for the synthesis of the natural terpenoids karahana lactone, karahana ether and crocusatin C and for the preparation of the synthetic intermediate γ-cyclogeraniol. The absolute configurations of the enantiomers of the diols 7, 10, 14 and 19 were determined by chemical correlation with the known compounds 40, 41, 39 and 41, respectively.

Full text of DOI:10.1016/j.tetasy.2009.05.013

Tetrahedron: Asymmetry 20 (2009) 1319–1329
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Lipase-mediated resolution of the hydroxy-cyclogeraniol isomers: application
to the synthesis of the enantiomers of karahana lactone, karahana ether,
crocusatin C and
c-cyclogeraniol
b
b
Stefano Serra a, , Francesco G. Gatti , Claudio Fuganti
*
a C.N.R. Istituto di Chimica del Riconoscimento Molecolare, Via Mancinelli 7, 20131 Milano, Italy
b Dipartimento di Chimica, Materiali ed Ingegneria Chimica del Politecnico, Via Mancinelli 7, 20131 Milano, Italy
a r t i c l e i n f o
a b s t r a c t
Article history:
A comprehensive study on the lipase PS-mediated resolution of different hydroxy-geraniol isomers is
Received 22 April 2009
Accepted 12 May 2009
Available online 8 June 2009
reported. A number of
synthesised regioselectively and then submitted to the lipase-mediated kinetic acetylation. The latter
experiments showed that the 2-hydroxy isomers 4, 5 and 14 ( and b, respectively) as well as cis-3-
hydroxy -cyclogeraniol 7 and cis-4-hydroxy -cyclogeraniol 10 could be easily resolved by this proce-
a-, b- and c-isomers bearing a 2-, 3- or 4-hydroxy functional group were
a, c
a
c
dure. The enantiomeric purity of the main part of these compounds was increased by recrystallisation
and the enantiopure diols obtained were used as building blocks for the synthesis of the natural terpe-
noids karahana lactone, karahana ether and crocusatin C and for the preparation of the synthetic inter-
mediate c-cyclogeraniol. The absolute configurations of the enantiomers of the diols 7, 10, 14 and 19
were determined by chemical correlation with the known compounds 40, 41, 39 and 41, respectively.
Ó 2009 Elsevier Ltd. All rights reserved.
1
1. Introduction
6 R'
R = Hydroxy, ether, keto
functionality
2
3
1
R
The cyclohexene ring of general structure 1 (Fig. 1) is a very
common moiety belonging to the frameworks of a variety of natu-
ral products. The most relevant class of these compounds is that of
the oxygenated carotenoids1 bearing a polyenic side chain at the
6-position and a hydroxyl group on the cyclohexenic ring. In addi-
tion, a large number of biologically active terpenoids (often carot-
enoid derivatives) with shorter side chains and different degrees of
functionalization have been isolated from natural sources. All these
compounds share a difficult accessibility by the chemical synthesis
of their single isomeric forms. Since the biological properties of
these molecules depend on their stereochemistry, this aspect is
especially demanding for compounds bearing at least one stereo-
centre. Due to the extensive industrial production of carotenoids/
retinoics from inexpensive ionone isomers, the synthetic require-
ment was settled on the stereospecific preparation of oxygenated
ionone derivatives.2 Otherwise, for compounds with less than thir-
teen carbon atoms, there is not an exclusive pathway; these kinds
of terpenoids were synthesised by a variety of stereospecific ap-
proaches. In this context, we envisaged that the enantioenriched
diols of general structure 2 could be useful chiral building blocks
for the synthesis of all compounds of type 1.
5
18
R' = from C1 to C31 substituent
4
Δ4,5 α-isomer
OH
Δ5,6 β-isomer
Δ5,18 γ-isomer
(carotenoid
numbering)
HO
2
Figure 1. Structures and numbering of general framework 1 and of hydroxy-
cyclogeraniol isomers 2.
Since a number of racemic diol isomers 2 are easily available
by chemical synthesis we set our study on the resolution ap-
proach. We have previously reported the enzyme-mediated reso-
lution of different terpenic alcohols,3 diols4 and hydroxy-ionone
derivatives.5 By taking advantage of this acquired experience,
we extended this method to the resolution of hydroxy-cycloger-
aniol isomers. Herein, we report a comprehensive study on the
lipase PS-mediated acetylation of the latter compounds. We
found that the use of the aforementioned acetylation or its use
in combination with fractional crystallisation of the obtained
enantioenriched diols was an effective resolution protocol. By
these means we prepared the enantiomers of the 2-hydroxy
cyclogeraniol isomers 4, 5 and 14 (
as well as cis-3-hydroxy -cyclogeraniol 7 and cis-4-hydroxy
-cyclogeraniol 10. The latter compounds are valuable chiral
building blocks as demonstrated by their use in the synthesis of
a-, c- and b-, respectively)
a
c
* Corresponding author. Tel.: +39 02 2399 3076; fax: +39 02 2399 3180.
E-mail address: stefano.serra@polimi.it (S. Serra).
0957-4166/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2009.05.013

1320
S. Serra et al. / Tetrahedron: Asymmetry 20 (2009) 1319–1329
the natural terpenoids such as karahana lactone,6 karahana ether
and crocusatin C7 and for the preparation of the relevant
ing isomerisation of the oxirane ring to an allylic alcohol was
performed using LDA as a strong, non-nucleophilic base.5c By these
means, diol 10 was obtained in a satisfactory yield and, due to its
crystalline nature, in a regioisomerically pure form. Concerning
the b-hydroxycyclogeraniol isomers, they could exist in only three
isomeric forms which we synthesised as described in Scheme 2.
synthetic intermediate c
-cyclogeraniol.8
2. Results and discussion
2.1. Preparation of the racemic diols
O
O
Diols of type 2, showing a secondary hydroxy group at the 2-, 3-
or 4-position and a double bond in one of the three different
O
11
12
6
isomeric positions (a-, b- or c-), could exist in overall 13 different
isomeric forms. Our study on their resolutions first required a valu-
able amount of regioisomerically pure racemic starting materials.
Indeed, it is mandatory to investigate both the enantioselectivity
and the regioselectivity of the enzyme-mediated acetylation using
a single isomeric form of each hydroxy-cyclogeraniol isomer.
Therefore, we selected some synthetic methods that would allow
their regiospecific preparation in a straightforward fashion and
starting from easily available materials. According to these general
requirements, seven representative diols were prepared as de-
scribed below.
i, ii 57%
v
O
O
CO2Et
I
15
HO
HO
vi 62% from 6
iii 79%
O
O
O
CO2Et
OH
16
18
13
The
a- and c-cis-2-hydroxy-cyclogeraniol isomers 4 and 5,
O
respectively (Scheme 1), were synthesised from epoxygeraniol 3,
which in turn is obtainable on a multigram scale from geraniol
by a hydrobromination-elimination protocol.9 The SnCl4-catalysed
cyclisation10 of the trimethylsilyl ether of 3 afforded a mixture of
products from which the regioisomerically pure diol 4 was easily
separated by crystallization. Otherwise, diol 5 was prepared from
4 by a photochemical double bond isomerization reaction previ-
vii 74%
iv, v 81%
viii, ix, v 67%
HO
OH
OH
OH
14
17
19
HO
OH
ously developed by us.11,5d,e The cis-
a-diol 4 was protected as a
Scheme 2. Synthesis of racemic diols 14, 17 and 19. Reagents and conditions: (i)
NH2NH2, Et3N, EtOH, reflux; (ii) DBN, I2, ether; (iii) BuLi, THF then formaldehyde;
(iv) THF/H2O, HClO4 cat.; (v) NaBH4, MeOH; (vi) NaOEt, EtOH, reflux; (vii) LiAlH4,
ether; (viii) O3, CH2Cl2/MeOH, ꢀ78 °C then Ph3P; (ix) DBU, CH2Cl2.
diacetate and then irradiated in an isopropanol/xylene solution
with high-pressure Hg lamps light. Almost complete transforma-
tion was necessary since diol 5 is a liquid compound, and hence
not purifiable by crystallisation, and was not separable from 4 by
Diol 14 was prepared starting from ketone 11 that was obtained
on a large scale by the regioselective ketalisation of 2,2,4-tri-
methylcyclohexane-1,3-dione.14 The C1 unit was introduced by a
two-step sequence. The reaction of 11 with hydrazine gave the cor-
responding hydrazone15 which was converted into iodide 12 by
treatment with iodine and DBN according to Barton’s protocol.16
The vinyl iodide was metallated with BuLi and the organo-lithium
derivative obtained was quenched with formaldehyde to afford
alcohol 13. The hydrolysis of the ketal functionality followed by
NaBH4 reduction of the intermediate keto-alcohol gave diol 14.
The 3-hydroxycyclogeraniol isomer 17 was prepared starting from
3,5,5-trimethyl-2-cyclohexen-1-one-4-carboxylic acid ethyl ester
chromatography. Deprotection by saponification gave pure cis-c-
diols 5. The 3,5,5-trimethyl-2-cyclohexen-1-one-4-carboxylic acid
ethyl ester 6 is available in large scale by condensation of mesityl
oxide with ethyl acetoacetate.12 Its reduction with LiAlH4 gave
mainly cis-diol 7 that could be purified both by chromatography
and by fractional crystallisation. Otherwise,
a-cyclogeraniol 8 is
the precursor of cis-c-diol 10. Oxidation of 8 with 3-chloroperben-
zoic acid in CH2Cl2 gave epoxide 9 as a single isomer.13 The follow-
6. The NaBH4 reduction afforded hydroxy-ester 15 whose
a double
OH
COOEt
bond was isomerised at the b-position by NaOEt catalysis. The
LiAlH4 reduction of the obtained 16 gave diol 17. Otherwise, 4-hy-
droxy-cyclogeraniol isomer 19 was prepared by degradation of
OH
3
O
6
8
O
epoxy-ionone 18. Racemic
a
-ionone is an inexpensive starting
vii, iii 53%
viii 94%
ii,
i, iii 41%
material whose
a-double bond could be selectively epoxidised.
Thus, according to a reported procedure,17 compound 18 was trea-
ted with ozone and the intermediate epoxy-aldehyde was isomer-
ised to 4-hydroxy-b-cyclogeranial in the presence of catalytic DBU.
The following NaBH4 reduction afforded diol 19.
HO
OH
OH
OH
4
HO
9
7
O
iv, v, vi 76%
HO
ix, iii 60%
2.2. Enzyme-mediated acetylation of the obtained diols
To the best of our knowledge, no enzyme-mediated resolutions
of hydroxy-geraniol isomers have been reported until now. Some
studies have investigated the stereoselectivity of the lipase-cata-
OH
OH
5
10
OH
lysed acetylation of a c
-cyclogeraniol,13,18 -cyclogeraniol,19 3-5b
and 4-hydroxy-ionone5a,c derivatives. It should be noted that the
enantioselectivities in the primary alcohol esterification were very
low with the exception of the lipase PS-catalysed acetylation of
Scheme 1. Synthesis of racemic diols 4, 5, 7 and 10. Reagents and conditions: (i)
Me3SiCl, Et3N; (ii) SnCl4, toluene; (iii) crystallization from hexane/ether; (iv) Ac2O,
Py; (v) xylene, i-PrOH, high-pressure Hg lamp light; (vi) NaOH, MeOH; (vii) LiAlH4,
ether; (viii) MCPBA, CH2Cl2; (ix) LDA, THF, reflux.
a
-cyclogeraniol.13 Moreover, the enzyme-mediated resolution of

S. Serra et al. / Tetrahedron: Asymmetry 20 (2009) 1319–1329
1321
3- and 4-hydroxy-ionone derivatives was possible by using the
( )-10
( )-19
same kind of lipase. Therefore, we settled on the employment of
the lipase PS as the enzyme of choice for our study. Accordingly,
we performed seven different acetylation experiments. Each diol
was treated with vinyl acetate in t-butyl-methyl ether in the pres-
ence of the aforementioned enzyme. The reactions were inter-
rupted when the wanted conversion was achieved; all the
compounds were separated and characterised. The results are de-
scribed in Schemes 3–5, and are summarised in Table 1. The first
examined diols are the 2-hydroxy-cyclogeraniol isomers 4, 5 and
14. All of these compounds afforded 2-acetoxy derivatives with a
high preference for the (2R)-configuration allowing the prepara-
tion of diacetates 21, 24 and 26 with high enantiomeric purity
(Scheme 3). Interestingly, both the enantioselectivity and the ki-
netic of the acetylation of the primary alcohol changed consider-
i
i
OH
(+)-10
OAc
OH
35
36
OH
+
OH
OAc
+
ii, iii, iv, v
76%
OAc
OH
(−)-32
(+)-37
OAc
OAc
+
OAc
(+)-33
ably shifting the double bond from the
a- to
c-position. Indeed,
OH
+
( )-4
( )-5
( )-14
OAc
(−)-34
i
i
i
OAc
HO
HO
HO
HO
HO
OH
OH
OAc
Scheme 5. Lipase PS-mediated acetylation of diols 10 and 19. Reagents: (i) lipase
PS, t-BuOMe, vinyl acetate; (ii) Dess–Martin periodinane, CH2Cl2; (iii) DBU, CH2Cl2;
(iv) NaBH4, MeOH; (v) Ac2O, Py.
(−)-4
(+)-5
(−)-25
+
+
+
+
AcO
HO
OAc
OAc
OAc
compound 4 was easily converted into (2R,6S)-monoacetate 20
with modest enantioselectivity and did not afford any 2-acetoxy-
cyclogeraniol derivative, clearly indicating that the acetylation of
the secondary alcohol is the rate-determining step. Otherwise, diol
5 gave both (6R)-monoacetate 22 and the (6S)-2-acetoxy-cycloger-
aniol derivative 23 with modest and good enantioselectivity,
respectively. This is likely due to the combination of two factors:
the rate and the enantioselectivity of the acetylation of the two hy-
droxy groups. The acetylation rates of the two hydroxyl groups are
very similar whereas the transformation of the secondary alcohol
showed higher enantioselectivity.
(+)-20
(+)-22
(−)-26
ii
+
+
AcO
AcO
OAc
OH
OH
(+)-21
(−)-23
(+)-14
AcO
OAc
(−)-24
Regarding the transformations of the 3-hydroxy-cyclogeraniol
isomers 7 and 17, we observed different behaviours (Scheme 4).
Again, the acetylation of the two hydroxyl groups of diol 7 pro-
ceeded with similar ratios allowing the formation of both 3-acet-
oxy-cyclogeraniol 27 and 3-hydroxy-cyclogeraniol acetate 28
with very low and modest enantiomeric purity, respectively. This
indicates a corresponding very low and modest enantioselectivity
in the acetylation of the secondary and primary alcohol, respec-
tively. Nevertheless, both diacetate 29 and the unreacted diol
(ꢀ)-7 showed high enantiomeric excesses. We can explain this ef-
fect by considering that the lipase catalyses the acetylation of the
(6R) and (3S) primary and secondary alcohol functionalities of this
diol, respectively. Since the relative configuration of cis diol 7 is
(3SR,6RS), both acetylation steps must work in a ‘matching’ fashion
to afford the diacetate and hence the unreacted diol with high ee.
This hypothesis is also supported by two further observations. As
Scheme 3. Lipase PS-mediated acetylation of diols 4, 5 and 14. Reagents: (i) lipase
PS, t-BuOMe, vinyl acetate; (ii) NaOH, MeOH.
( )-7
( )-17
i
i
OH
OAc
(−)-7
(+)-30
HO
HO
+
+
+
+
OH
OAc
(−)-27
AcO
AcO
(−)-31
described above, the
28 with the same stereochemical preference at C6, again the same
as that described for the PS-mediated resolution of -cyclogerani-
a-diols 4 and 7 gave monoacetates 20 and
OAc
a
(+)-28
HO
ol. In addition, the results obtained in the acetylation of 3-hydroxy-
b-cyclogeraniol 17 confirmed that the enzyme catalyses this trans-
formation with the same stereochemical preference at C3.
Indeed, racemic 17 was converted into diacetate 31 and mono-
acetate 30 having the (3R)- and (3S)-configurations, respectively,
both with very low enantiomeric purity. At the reported conver-
sion, only traces of diol and 2-acetoxy-cyclogeraniol derivative
were detected in the reaction mixture, clearly indicating that the
OAc
AcO
(+)-29
Scheme 4. Lipase PS-mediated acetylation of diols 7 and 17. Reagents: (i) lipase PS,
t-BuOMe, vinyl acetate.

1322
S. Serra et al. / Tetrahedron: Asymmetry 20 (2009) 1319–1329
Table 1
Results of the lipase PS-mediated acetylation of racemic diols 4, 5, 7, 10, 14, 17 and 19
Diol
Diacetatea (%) configuration (ee)
Monoacetatea (%) configuration (ee)
Unreacted diola (%) configuration (ee)
7-Acetoxy
7-Hydroxy
( )-4
(+)-21 (10)
(+)-20 (51)
(2R,6S) (37% ee)
(+)-22 (15)
(ꢀ)-4 (39)
(2R,6S) (96% ee)
(ꢀ)-24 (7)
(2S,6R) (57% ee)
(+)-5 (60)
( )-5
(ꢀ)-23 (18)
(2R,6S) (89% ee)
Trace
(2R,6S) (99% ee)
(ꢀ)-26 (24)
(2S,6R) (32% ee)
(ꢀ)-25 (76)
(2S,6R) (22% ee)
( )-14
( )-7
(2R) (99% ee)
(+)-29 (11)
(2S) (30% ee)
(+)-28 (39)
(ꢀ)-27 (3)
(3R,6S) (7% ee)
Trace
(ꢀ)-7 (47)
(3R,6S) (93% ee)
Trace
(3S,6R) (94% ee)
(ꢀ)-31 (39)
(3S,6R) (52% ee)
(+)-30 (61)
(3S) (10% ee)
(+)-33 (10)
(4S,6R) (90% ee)
35 + 36 (61)
( )-17
( )-10
( )-19
(3R) (27% ee)
(ꢀ)-34 (12)
(ꢀ)-32 (46)
(+)-10 (32)
(4S,6R) (>99% ee)
(4R,6S) (92% ee)
(+)-37 (39)
(4R,6S) (76% ee)
(4R) (19% ee)
a
Molar percentage of the compound in the reaction mixture.
acetylation of the primary alcohol proceeds much faster than that
of the secondary one.
without any racemisation starting from enantiopure (+)- and (ꢀ)-
4 by the photoisomerization procedure described above. We have
experimentally verified these aspects by carrying out the large-
scale preparation of the enantiomeric forms of all these diols.
It should be noted that the enantioselective synthesis of diols 4
and 5 and their use in the preparation of natural terpenoids such as
The transformations of the 4-hydroxy-cyclogeraniol isomers 10
and 19 showed further interesting insights (Scheme 5). The acety-
lation of the two hydroxy groups of the diol 10 proceeds with sim-
ilar ratios allowing the formation of both 4-acetoxy-cyclogeraniol
32 and 4-hydroxy-cyclogeraniol acetate 33. Moreover, both the
diacetate 34 and the unreacted diol (+)-10 showed good and very
good enantiomeric purity, respectively. These results, seen to dem-
onstrate that the enzyme catalyses the acetylation of the hydroxide
groups of the isomers showing (4R)- and (6S)-configuration with
high and low enantioselectivity, respectively. At the reported con-
version, the (4R,6S)-diol was completely transformed and the unre-
acted diol (+)-10 was isolated in its enantiopure form. Otherwise,
the low enantioselectivity in the acetylation of primary alcohols al-
lowed the formation of the (6R)-acetate 33 whose configuration
and enantiomeric purity arose from the conversion of the remain-
ing (4S,6R)-diol. Interestingly, the acetylation of the diol 19 showed
a preference for the (4R)-enantiomer as demonstrated by chemical
correlation of the obtained diacetate 37 with compound (ꢀ)-32.
Indeed, the latter compound was oxidised with Dess–Martin
periodinane20 and the obtained aldehyde was treated with DBU
a
- and c-ionones, a- and c-damascone, karahana ether and karah-
ana lactone have been already described.6a,b,23 As a demonstration
of the usefulness of our resolution protocol, we report here
(Scheme 6) a further preparation of karahana ether and a new
short synthesis of karahana lactone that is itself a relevant chiral
building block for the synthesis of several natural compounds.25
Accordingly, we converted diacetate (ꢀ)-24 into diol (ꢀ)-5 which
(−)-24
(−)-4
(99% ee)
(57% ee)
O
iv
i
40%
ii
ii
v, vi, i
78%
(−)-5
(+)-38
(+)-5
(−)-4
(99% ee)
83%
85%
(−)-Karahana ether 38
iii 89%
O
iii 90%
in order to achieve
c–b double bond isomerisation. Next, NaBH4
O
reduction followed by acetylation gave (+)-37 showing the same
configuration and higher enantiomeric purity than the material ob-
tained by enzymic acetylation of 19. In the latter instance, the re-
corded enantio- and regioselectivity were very low. Indeed, the
diacetate 37 showed only 19% ee (c 0.39), whereas monoacetylated
derivatives were obtained as an inseparable mixture of compounds
35 and 36.
vii, viii, ix
51%
(+)-39
(−)-14
(−)-Karahana lactone 39
x
x
OH
( )-7
−
(+)-7
(99% ee)
(+)-40
80%
81%
(99% ee)
2.3. Resolution of diols 4, 5, 14, 7 and 10, assignation of their
absolute configuration and evaluation of their synthetic utility
O
(-)-crocusatin C 40
iv 85%
i, iv 90%
(−)-7
(+)-29
Although the enzymic transformations described above ever
afforded enantioenriched compounds, not all are suitable for
large-scale preparation of the enantiopure hydroxy-cyclogeraniol
isomers. This is the case for diols 1721 and 1922 whose lipase PS-
mediated acetylation afforded diacetate derivatives with a very
low enantiomeric purities. In contrast, the transformations of diols
4, 5, 14, 7 and 10 afforded derivatives with high enantiomeric ex-
cess that could be considered, useful chiral building blocks. In addi-
tion, both the racemates and the single enantiomeric forms of the
diols 4,10,23 14,22 722 and 1024 are crystalline compounds whose
enantiomeric purity could be increased by fractional crystallisa-
tion. Moreover, the enantiomers of liquid diol 5 were obtained
(93% ee)
(94% ee)
v
xi, i
(+)-34
xi, i
OH
(+)-10
(99% ee)
(−)-34
(+)-41
82%
84%
(−)-γ-cyclogeraniol 41
Scheme 6. Synthesis of the enantiomeric forms of karahana ether, karahana
lactone, crocusatin and -cyclogeraniol. Reagents and conditions: (i) NaOH,
MeOH; (ii) TsCl, Py; (iii) BAIB, TEMPO cat., CH2Cl2; (iv) crystallisation from hexane/
ether; (v) Ac2O, Py; (vi) xylene, i-PrOH, high-pressure Hg lamp light; (vii) DIBAH,
toluene, ꢀ78 °C; (viii) NaOMe, MeOH; (ix) NaBH4, MeOH; (x) MnO2, CH2Cl2; (xi)
Et3N, HCO2H, (Ph3P)2PdCl2 cat., Ph3P cat., THF, reflux.
C
c

S. Serra et al. / Tetrahedron: Asymmetry 20 (2009) 1319–1329
1323
was treated with TsCl and an excess of pyridine to give (ꢀ)-karah-
4. Experimental
ana ether 38. Then, oxidation of the same diol with bis-acetoxyiod-
obenzene (BAIB) in the presence of a catalytic amount of 2,2,6,
6-tetramethylpiperidinooxy (TEMPO)26 gave directly (ꢀ)-karahana
lactone 39 in good yield. The opposite enantiomers of the latter
compounds were prepared starting from diol (ꢀ)-4 (57% ee) whose
enantiomeric purity was easily increased to 99% ee by fractional
crystallisation. The diol obtained was then converted into enantio-
pure (+)-5 by means of protection as a diacetate, photoisomeriza-
tion and saponification. Next, this diol was transformed into the
(+)-karahana ether and the (+)-karahana lactone following the
methods described above. It should be noted that (+)-karahana lac-
tone was also employed for the determination of the absolute con-
figuration of the enantiomers of diol 14 which were unknown until
now. The reduction of (+)-39 with DIBAH at low temperature affor-
ded the corresponding lactol which was treated with sodium
methylate in order to achieve double bond isomerisation from
4.1. General experimental
All moisture-sensitive reactions were carried out under a static
atmosphere of nitrogen. All reagents were of commercial quality.
The photoisomerization experiments were carried out using a Ray-
onet photochemical reactor equipped with 12 ꢁ 8 W high pressure
mercury (Hg) lamps. Geraniol epoxide 3 was prepared by hydro-
bromination of geraniol acetate with NBS/H2O followed by NaOH
treatment of the obtained bromohydrin.9 Keto-ester 6 was pre-
pared by zinc chloride-catalysed condensation of mesityl oxide
with ethyl acetoacetate.12
LiAlH4 reduction of ethyl
a
-Cyclogeraniol 8 was prepared by
a
-cyclogeraniate in turn obtained by
SnCl4-catalysed cyclization28 of 3,7-dimethyl-octa-2,6-dienoic acid
ethyl ester. Iodide 1215 was prepared via I2/DBN-16 mediated
decomposition of the hydrazone of mono ethylene glycol ketal
11. The latter compound was obtained by the regioselective ketal-
isation of 2,2,4-trimethylcyclohexane-1,3-dione, which in turn was
synthesised by the condensation of 3-pentanone with ethyl acry-
the
pure (ꢀ)-14 whose configuration was unambiguous (2S). Subse-
quently, we exploited the use of diols and 10 for the
c- to the b-position. Next, the NaBH4 reduction gave enantio-
7
late followed by iodomethane alkylation.14 Epoxy-
was obtained as a 4:1 mixture of cis/trans isomers, respectively,
by means of MCPBA treatment of the commercially available -io-
a-ionone 18
preparation of additional natural compounds. The enantiomeric
purity of diols (ꢀ)- and (+)-7 was increased to 99% by crystallisa-
tion. Then, the following MnO2 oxidation of the secondary alcohol
functionality gave (ꢀ)- and (+)-crocusatin 40,7 respectively, whose
enantiospecific syntheses have not been reported before. The latter
compound is a natural monoterpenoid that can be found either free
a
none. Lipase from Pseudomonas cepacia (PS), Amano Pharmaceuti-
cals Co., Japan, 30 units/mg was employed in this work. TLC:
Merk Silica Gel 60 F254 plates. Column chromatography (CC): silica
gel. GC–MS analyses: HP-6890 gas chromatograph equipped with a
5973 mass detector, using a HP-5MS column (30 m ꢁ 0.25 mm,
or as b-D
-glucoside27 in the pollen of Crocus sativus and in the fruit
of Gardenia jasminoides. Since the absolute configuration of natural
(ꢀ)-crocusatin was described as (6S) by mean of a circular dichro-
ism study,27b we assigned the (3R,6S) configuration to diol (ꢀ)-7.
Similarly, the configuration of the enantiomers of diol 10, also still
unknown, was assigned by chemical correlation. Accordingly, we
submitted diacetate (+)- and (ꢀ)-34 to reductive elimination of
the allylic acetate group by treatment with triethylammoniun
formate in the presence of catalytic (Ph3P)2PdCl2. We obtained
0.25 lm firm thickness; Hewlett Packard) with the following temp.
program: 60° (1 min)ꢀ6°/minꢀ150° (1 min)ꢀ12°/minꢀ280°
(5 min); carrier gas, He; constant flow 1 ml/min; split ratio, 1/30;
tR given in min: tR(4) 16.75, tR(5) 16.42, tR(7) 15.54, tR(9) 12.79,
tR(10) 16.11, tR(13) 19.97, tR(14) 16.58, tR(15) 17.17 and 17.74,
tR(16) 16.22, tR(17) 14.39, tR(19) 15.92, tR(20) 18.77, tR(21) 20.37,
tR(22) 18.84, tR(23) 18.24, tR(24) 19.92, tR(25) 19.25 tR(26) 20.73,
tR(27) 18.58, tR(28) 18.21, tR(29) 19.16, tR(30) 17.12, tR(31) 19.24,
tR(32) 18.19, tR(33) 18.47, tR(34) 20.10, tR(35) 16.83, tR(36) 16.72,
tR(37) 20.32, tR(38) 8.98, tR(39) 14.12, tR(40) 17.82, tR(41) 11.05;
mass spectra: m/z (rel.%). Chiral GC analyses: DANI-HT-86.10 gas
chromatograph; enantiomer excesses determined on a CHIRASIL
DEX CB-Column with the following temp. program: com-
pound 24: 70° (1 min)ꢀ2°/minꢀ100° (0 min)ꢀ0.3°/minꢀ105°
(0 min)ꢀ30°/minꢀ180° (0 min); tR given in min: tR((+)-24) 28.7,
tR((ꢀ)-24) 29.2; compound 26: 65° (0 min)ꢀ1°/minꢀ94°
(0 min)ꢀ0.3°/minꢀ110° (0 min)ꢀ30°/minꢀ180° (0 min); tR given
in min: tR((+)-26) 50.9, tR((ꢀ)-26) 51.5; compound 29: 80°
(ꢀ)-(R)- and (+)-(S)-
regioselectivity and without any racemisation. These transforma-
tions are noteworthy since -cyclogeraniol isomers are suitable
starting materials for the preparation of relevant fragrances such
c-cyclogeraniol, respectively, with very good
c
as c-ionone and c
-damascone6a,8b and for the synthesis of the tri-
terpene ambrein.8a Moreover, by these means we assigned the
absolute configuration of diol (+)- and (ꢀ)-10 as (4S,6R) and
(4R,6S), respectively. In addition, since acetate (ꢀ)-32 was
chemically correlated with diacetate (+)-37 (Scheme 5), the latter
compound is the (4R)-enantiomer.
(0 min)ꢀ1°/minꢀ100°
(0 min)ꢀ0.5°/minꢀ115°
(0 min)ꢀ30°/
3. Conclusions
minꢀ180° (0 min); tR given in min: tR((+)-29) 28.8, tR((ꢀ)-29)
29.6; compounds 31 and 37: 60° (2 min)ꢀ1°/minꢀ95°
(0 min)ꢀ0.5°/minꢀ120° (0 min)ꢀ30°/minꢀ180° (0 min); tR given
in min: tR((+)-31) 62.3, tR((ꢀ)-31) 63.7, tR((+)-37) 57.9, tR((ꢀ)-37)
58.4; compound 34: 80° (0 min)ꢀ1°/minꢀ100° (1 min)ꢀ0.3°/
minꢀ105° (0 min)ꢀ30°/minꢀ180° (0 min); tR given in min: tR((ꢀ)-
34) 29.2, tR((+)-34) 29.7; compound 39: 70° (1 min)ꢀ1.5°/minꢀ90°
(1 min)ꢀ0.5°/minꢀ95° (0 min)ꢀ30°/minꢀ180° (0 min); tR given in
min: tR((+)-39) 17.8, tR((ꢀ)-39) 18.6. Enantiomer excesses of com-
pounds 4, 20 and 21 were determined by measurement of the spe-
cific rotation value of the corresponding diols and comparison with
that of enantiopure 4. Optical rotations: Jasco-DIP-181 digital polar-
imeter. 1H and 13C Spectra: CDCl3 solns. at rt; Bruker-AC-400 spec-
trometer at 400 and 100 MHz, respectively; chemical shifts in
ppm rel to internal SiMe4 (=0 ppm), J values in hertz. IR spectra were
The study described above is a comprehensive investigation
on the lipase PS-mediated resolution of hydroxy-cyclogeraniol
isomers. Some representative members of this class of com-
pounds were synthesised regioselectively and the following
experiments showed many relevant results. We found that the
2-hydroxy isomers 4, 5 and 14 (
a
,
c
and b, respectively) as well
-cycloger-
as cis 3-hydroxy -cyclogeraniol 7 and cis-4-hydroxy
a
c
aniol 10 can be easily resolved by a straightforward procedure
consisting of a combination of a lipase-mediated kinetic acetyla-
tion with a fractional crystallisation. The enantiopure diols ob-
tained are suitable building blocks for the synthesis of many
natural terpenoids such as karahana lactone, karahana ether
and crocusatin C and for the preparation of the synthetic inter-
mediate
c-cyclogeraniol. Further studies on the use of the latter
recorded on a Perkin-Elmer 2000 FT-IR spectrometer;
Melting points were measured on a Reichert apparatus, equipped
with a Reichert microscope, and are uncorrected.
m .
in cmꢀ1
enantiopure diols as starting materials for the preparation of
hydroxylated carotenoids are still in progress and will be re-
ported in due course.

1324
S. Serra et al. / Tetrahedron: Asymmetry 20 (2009) 1319–1329
4.2. Procedures for the preparation of racemic diols
4.2.1. cis-2-Hydroxy -cyclogeraniol 4
layer was separated, washed with brine, dried (Na2SO4) and the
solvent evaporated in vacuo. The residue was chromatographed
with hexane/diethyl ether (9:1ꢀ2:1) as eluent to give 7 contami-
nated with trans isomers. Crystallisation of the latter oil (hexane/
diethyl ether, ꢀ20 °C) afforded pure 7 (21.5 g, 53%, 98% of chemical
purity by GC), mp 92–94 °C; 1H NMR (400 MHz, CDCl3) d 5.63 (s,
1H), 4.20–4.11 (m, 1H), 3.81–3.71 (m, 2H), 2.65 (br s, 1H), 2.23
(br s, 1H), 1.77 (t, J = 1.3 Hz, 3H), 1.62 (d, J = 8.4 Hz, 2H), 1.55 (s,
1H), 1.05 (s, 3H), 0.89 (s, 3H). 13C NMR (100 MHz) d 135.0, 128.0,
66.2, 60.9, 51.9, 42.2, 34.0, 28.3, 28.1, 22.4. IR (nujol, cmꢀ1) 3355,
1039, 1007, 987, 828. GC–MS m/z (rel intensity) 170 (M+, 1), 155
(26), 152 (17), 137 (37), 121 (48), 107 (100), 96 (88), 91 (56), 81
(31), 69 (31), 55 (12), 41 (19).
a
Chlorotrimethylsilane (56 mL, 441 mmol) was added dropwise
to a cooled (0 °C) solution of geraniol epoxide 3 (50 g, 294 mmol)
in ether (500 mL) and triethylamine (90 mL, 646 mmol). The reac-
tion was stirred for 4 h at rt, the precipitated salt was removed by
filtration and the filtrate was washed with brine. The organic phase
was dried (Na2SO4) and the solvent evaporated in vacuo. The resi-
due was diluted with toluene (350 mL) and cooled (0 °C). Tin tetra-
chloride (1 M in toluene, 150 mL) was added dropwise and the
reaction was stirred for 2 h followed by quenching with a saturated
solution of NH4Cl aq (300 mL). The mixture was extracted with
ether (300 mL) and the organic layers were washed with brine,
dried (Na2SO4) and concentrated under reduced pressure. The res-
idue was chromatographed with hexane/diethyl ether (9:1ꢀ2:1) as
4.2.4. cis-4-Hydroxy
c-cyclogeraniol 10
A solution of -cyclogeraniol 8 (35 g, 227 mmol) in CH2Cl2
a
eluent to give 4 contaminated with the corresponding
c
isomers.
(350 mL) was treated with MCPBA (43 g, 249 mmol) stirring at
0 °C until no more starting 8 was detected by TLC analysis (2 h).
The MCBA was eliminated by filtration and the solution was
washed in turn with saturated NaHCO3 solution (100 mL) and 5%
aq Na2SO3 (100 mL). The organic layer was dried (Na2SO4), concen-
trated under reduced pressure and the residue was chromato-
graphed with hexane/ethyl acetate (9:1ꢀ2:1) as eluent to give
pure 9 (36.5 g, 94%, 96% of chemical purity by GC) as a colourless
oil; 1H NMR (400 MHz, CDCl3) d 3.97 (dd, J = 11.3, 3.8 Hz, 1H),
3.80 (dd, J = 11.3, 6.2 Hz, 1H), 3.01 (s, 1H), 2.61 (br s, 1H), 1.98
(ddt, J = 15.4, 6.2, 1.7 Hz, 1H), 1.92–1.82 (m, 1H), 1.63–1.52 (m,
1H), 1.50–1.44 (m, 1H), 1.40 (s, 3H), 0.98–0.88 (m, 1H), 0.95 (s,
3H), 0.90 (s, 3H). 13C NMR (100 MHz) d 62.2, 60.4, 59.6, 47.6,
30.5, 28.6, 28.2, 26.9, 25.4, 21.7. IR (film, cmꢀ1) 3447, 1448, 1366,
1090, 1049, 902. GC–MS m/z (rel intensity): 170 (M+, 1), 155
(93), 137 (35), 125 (21), 109 (27), 95 (28), 87 (100), 81 (30), 69
(35), 55 (40), 43 (72).
Crystallisation of the latter oil (hexane/diethyl ether, ꢀ20 °C) affor-
ded pure 4 (20.4 g, 41%, 99% of chemical purity by GC), mp 95–
96 °C; 1H NMR (400 MHz, CDCl3) d 5.44 (s, 1H), 4.45 (br s, 2H),
3.79–3.71 (m, 2H), 3.37 (d, J = 4.5 Hz, 1H), 2.36 (dm, J = 18.3 Hz,
1H), 2.11 (d, J = 18.3 Hz, 1H), 1.75 (s, 3H), 1.71 (br s, 1H), 1.10 (s,
3H), 0.94 (s, 3H). 13C NMR (100 MHz) d 131.5, 120.3, 71.3, 58.7,
51.0, 37.0, 32.1, 28.5, 24.1, 22.4. IR (nujol, cmꢀ1) 3221, 1490,
1374, 1318, 1163, 1085, 1032, 974, 909. GC–MS m/z (rel intensity)
152 (M+ꢀH2O, 6), 140 (4), 122 (52), 107 (100), 91 (16), 81 (17), 72
(9), 55 (8), 43 (12).
4.2.2. cis-2-Hydroxy c-cyclogeraniol 5
A sample of diol 4 (5 g, 29.4 mmol) was treated with pyridine
(20 mL) and Ac2O (10 mL) and set aside at rt until acetylation
was complete (12 h). The mixture was concentrated under reduced
pressure and the residue was dissolved in isopropanol (320 mL)
and xylene (80 mL). The obtained solution was flushed with nitro-
gen, sealed in quartz vessels and irradiated in a Rayonet photo-
chemical reactor equipped with 12 8-W high-pressure Hg lamps.
The reaction was monitored by GC analysis and the irradiation
was interrupted until starting compound became less than 1% of
the mixture (10 days). The solution was then concentrated under
reduced pressure to afford oil that was dissolved in methanol
(50 mL) and treated with a solution of NaOH (4 g, 100 mmol) in
methanol (50 mL). The mixture was stirred at rt until no more
starting acetate was detected by TLC analysis, then was diluted
with water (200 mL) and extracted with diethyl ether
(3 ꢁ 100 mL). The combined organic phases were washed with
brine, dried (Na2SO4) and concentrated. The residue was purified
by chromatography eluting with hexane/diethyl ether (9:1ꢀ2:1)
as eluent to give 5 (3.8 g, 76%, 97% of chemical purity by GC) as a
colourless oil; 1H NMR (400 MHz, CDCl3) d 4.92 (s, 1H), 4.73 (s,
1H), 3.92 (dd, J = 10.8, 7.0 Hz, 1H), 3.68 (dd, J = 10.8, 3.4 Hz, 1H),
3.44 (dd, J = 5.4, 3.4 Hz, 1H), 2.93 (br s, 2H), 2.55–2.45 (m, 1H),
2.08 (dt, J = 13.7, 5.4 Hz, 1H), 2.01–1.95 (m, 1H), 1.91–1.79 (m,
1H), 1.64 (dq, J = 13.7, 5.4 Hz, 1H), 1.00 (s, 3H), 0.96 (s, 3H). 13C
NMR (100 MHz) d 147.8, 110.3, 74.6, 62.3, 55.0, 38.8, 30.8, 29.3,
27.5, 20.8. IR (film, cmꢀ1) 3291, 1646, 1445, 1386, 1365, 1160,
1087, 1013, 991, 956, 890. GC–MS m/z (rel intensity) 170 (M+, 1),
152 (M+ ꢀH2O, 7), 134 (4), 122 (89), 107 (100), 93 (33), 79 (38),
67 (27), 55 (21), 43 (29).
BuLi (45 ml of a 10 M solution in hexane) was added dropwise
to a cooled (ꢀ78 °C) solution of iPr2NH (50 g, 494 mol) in dry
THF (350 mL) under nitrogen. The mixture was stirred at this tem-
perature for 30 min, then a solution of the epoxy-a-cyclogeraniol 9
(34 g, 200 mmol) in dry THF (80 ml) was added dropwise. The reac-
tion was gradually warmed to rt (1 h) and then heated at reflux un-
til no more starting epoxide was detected by TLC analysis (3 h).
After cooling to rt, the mixture was poured into a mixture of
crushed ice and 10% HCl soln (500 ml) and extracted with EtOAc
(2 ꢁ 300 mL). The organic phase was successively washed with
satd aq NH4Cl soln (100 mL), brine, dried over Na2SO4 and concen-
trated under reduced pressure. The residue was chromatographed
with hexane/ethyl acetate (4:1ꢀ1:1) as eluent and the obtained
diol was further purified by crystallisation (hexane/ether) to give
pure 10 (20.5 g, 60%, 99% of chemical purity by GC), mp 95–
96 °C; 1H NMR (400 MHz, CDCl3) d 5.20 (s, 1H), 4.88 (s, 1H), 4.12
(dd, J = 5.9, 4.5 Hz, 1H), 3.89 (dd, J = 10.7, 8.7 Hz, 1H), 3.73 (dd,
J = 10.7, 3.9 Hz, 1H), 2.90 (br s, 1H), 2.58 (br s, 1H), 2.03 (dd,
J = 8.7, 3.9 Hz, 1H), 1.90–1.80 (m, 1H), 1.75–1.66 (m, 1H), 1.65–
1.55 (m, 1H), 1.26 (ddd, J = 13.5, 7.6, 4.5 Hz, 1H), 0.95 (s, 3H),
0.87 (s, 3H). 13C NMR (100 MHz) d 149.2, 110.7, 72.2, 61.7, 54.1,
34.5, 34.1, 31.4, 28.7, 24.3. IR (nujol, cmꢀ1) 3365, 1653, 1368,
1350, 1114, 1066, 1024, 901, 869. GC–MS m/z (rel intensity) 170
(M+, 1), 152 (M+ꢀH2O, 5), 139 (30), 122 (82), 107 (100), 93 (52),
79 (40), 70 (22), 55 (34), 41 (24).
4.2.3. cis-3-Hydroxy
a-cyclogeraniol 7
4.2.5. 2-Hydroxy b-cyclogeraniol 14
A solution of 3,5,5-trimethyl-2cyclohexen-1-one-4-carboxylic
acid ethyl ester 6 (50 g, 238 mmol) in dry ether (200 mL) was
added dropwise to a stirred suspension of LiAlH4 (10 g, 263 mmol)
in dry ether (250 mL). The mixture was heated at reflux for 2 h,
then cooled (0 °C) and quenched by dropwise addition of water
(10 mL) and a 20% aqueous solution of NaOH (50 mL). The ether
BuLi (13 mL of a 10 M solution in hexane) was added dropwise
to a cooled (ꢀ78 °C) solution of iodide 12 (35 g, 114 mmol) in dry
THF (200 mL) under nitrogen. The mixture was stirred at this tem-
perature for 20 min., then the cooling bath was removed and a
stream of formaldehyde (obtained by thermal depolymerisation
of solid formaldehyde) was bubbled into the solution. The reaction

S. Serra et al. / Tetrahedron: Asymmetry 20 (2009) 1319–1329
1325
mixture was diluted with ether (300 mL) and quenched by the
addition of saturated NH4Cl (200 mL). The layers were separated
and the organic phase was concentrated. The residue was chro-
matographed eluting with hexane/diethyl ether (8:1ꢀ2:1) as elu-
ent to give 13 (19.1 g, 79%, 95% of chemical purity by GC), as a
thick oil; 1H NMR (250 MHz, CDCl3) 4.15 (br s, 2H), 4.05–3.94 (m,
4H), 2.24–2.12 (m, 2H), 1.84–1.68 (m, 2H), 1.78 (s, 3H), 1.11 (s,
6H). 13C NMR (62.8 MHz) d 136.8, 132.3, 89.2, 65.0, 59.1, 42.5,
30.7, 26.7, 22.8, 19.2. GC–MS m/z (rel intensity) 212 (M+, 5), 194
(M+ꢀH2O, 3), 179 (3), 169 (3), 151 (2), 137 (2), 121 (4), 107 (8),
99 (10), 93 (19), 86 (100), 79 (6), 67 (4), 55 (7). Compound 13
(15 g, 70.6 mmol) was dissolved in THF (80 mL) and stirred at rt
with water (20 mL) and 70% HClO4 (0.5 mL). After complete hydro-
lysis of the ketal functionality (TLC analysis), the mixture was par-
titioned between a saturated NaHCO3 solution (100 mL) and ethyl
acetate (200 mL). The organic phase was concentrated under re-
duced pressure and the residue, dissolved in MeOH (100 mL),
was treated at 0 °C with NaBH4 (1.4 g, 37 mmol). The reaction
was then quenched by addition of 1 M aq HCl solution (200 mL)
and ethyl acetate (200 mL). The phases were separated and the
aqueous phase was extracted with ethyl acetate (100 mL). The or-
ganic layers were concentrated and the residue was purified by
chromatography (hexane/Et2O 2:1) and crystallisation (hexane/
ether) to afford pure diol 14 (9.8 g, 81%, 97% of chemical purity
by GC), mp 98–100 °C; 1H NMR (400 MHz, CDCl3) 4.20–4.10 (m,
2H), 3.52 (dd, J = 9.0, 3.1 Hz, 1H), 2.19–2.02 (m, 2H), 1.87–1.77
(m, 1H), 1.76 (s, 3H), 1.76–1.65 (m, 1H), 1.57 (br s, 2H), 1.12 (s,
3H), 1.05 (s, 3H). 13C NMR (100 MHz) d 135.9, 132.8, 75.6, 58.9,
39.1, 29.8, 26.5, 26.3, 21.7, 19.3. IR (film, cmꢀ1) 3287, 1313, 1196,
1145, 1075, 1039, 1012, 995. GC–MS m/z (rel intensity) 170 (M+,
3), 152 (M+ꢀH2O, 50), 137 (32), 123 (50), 109 (84), 93 (100), 81
(32), 67 (34), 55 (29), 43 (26).
NMR (100 MHz) d 137.4, 130.7, 64.9, 58.2, 48.2, 42.2, 36.8, 29.3,
28.6, 19.4. IR (nujol, cmꢀ1) 3291, 1657, 1373, 1363, 1074, 1039,
1020, 998. GC–MS m/z (rel intensity) 170 (M+, 12), 152
((M+ꢀH2O, 45), 137 (53), 119 (100), 109 (59), 95 (50), 81 (28), 67
(46), 55 (30), 41 (36).
4.2.7. 4-Hydroxy b-cyclogeraniol 19
A solution of the epoxy-a-ionone 18 (30 g, 144 mmol) in CH2Cl2
(200 mL) and MeOH (50 mL) was treated with a stream of ozone at
ꢀ78 °C until the appearance of a persistent blue colour. Nitrogen
was then bubbled through the solution until it turned colourless
and the reaction was treated with a solution of Ph3P (42 g,
160 mmol) in CH2Cl2 (100 mL). The obtained solution was gradu-
ally warmed at rt and then concentrated at reduced pressure.
The residue was diluted with CH2Cl2 (300 mL) and washed with
water (100 mL), dried (Na2SO4) and concentrated under reduced
pressure to a final volume of about 100 mL. The solution was then
treated with DBU (4.4 g, 28.9 mmol) stirring at rt until complete
isomerisation to the b-isomer (12 h, TLC analysis). The reaction
was then quenched by addition of 1 M aq HCl solution (100 mL),
the phases were separated and the aqueous phase was extracted
with CH2Cl2 (100 mL). The combined organic layers were concen-
trated under reduced pressure and the residue was dissolved in
MeOH (100 mL) and treated with NaBH4 (2.7 g, 71.4 mmol). The
reaction mixture was then partitioned between a 1 M aq HCl solu-
tion (300 mL) and ethyl acetate (200 mL). The phases were sepa-
rated and the aqueous phase was extracted with ethyl acetate
(100 mL). The organic layers were concentrated, the residue was
chromatographed with hexane/ethyl acetate (4:1ꢀ1:1) as eluent
and the obtained diol was further purified by crystallisation (hex-
ane/CHCl3) to give pure 19 (16.6 g, 67%, 98% chemical purity by
GC), mp 112–113 °C, Ref. 17b mp 109 °C; 1H NMR (400 MHz,
CDCl3) d 4.19–4.09 (m, 2H), 3.95 (brt, J = 4.8 Hz, 1H), 1.95–1.83
(m, 2H), 1.88 (s, 3H), 1.72–1.59 (m, 2H), 1.44 (br s, 1H), 1.43–
1.35 (m, 1H), 1.10 (s, 3H), 1.01 (s, 3H). 13C NMR (100 MHz) d
141.2, 134.3, 69.9, 58.7, 34.5, 28.6, 28.1, 27.2, 16.4. IR (nujol,
cmꢀ1) 3269, 1377, 1150, 1044, 1032, 1001, 971. GC–MS m/z (rel
intensity) 152 (M+ꢀH2O, 48), 139 (100), 123 (28), 109 (61), 95
(46), 81 (46), 67 (37), 55 (24), 43 (43).
4.2.6. 3-Hydroxy b-cyclogeraniol 17
A cooled (0 °C) solution of 3,5,5-trimethyl-2cyclohexen-1-one-
4-carboxylic acid ethyl ester
6 (40 g, 190 mmol) in MeOH
(200 mL) was treated under stirring with NaBH4 (3.6 g, 95 mmol).
Until complete reduction of the starting ketone (1 h), the reaction
mixture was then partitioned between 1 M aq HCl solution
(500 mL) and ethyl acetate (400 mL). The organic phase was
washed with brine, dried over Na2SO4 and concentrated under re-
duced pressure to give crude 15 as a 3:2 mixture of diastereoiso-
mers. The latter oil was dissolved in ethanol (250 mL) and
treated with NaOEt (14 g, 206 mmol) stirring at reflux for 24 h.
The mixture was then cooled, poured into a mixture of crushed
ice and 5% HCl soln (250 mL) and extracted with ethyl acetate
(2 ꢁ 200 ml). The organic phase was washed with brine, dried over
Na2SO4 and concentrated under reduced pressure. The residue was
chromatographed with hexane/ethyl acetate (5:1ꢀ2:1) as eluent to
give pure 16 (25.1 g, 62%, 95% chemical purity by GC) as a colour-
less oil; 1H NMR (400 MHz, CDCl3) d 4.28–4.18 (m, 2H), 4.10–3.99
(m, 1H), 2.36 (ddd, J = 17.1, 5.8, 1.3 Hz, 1H), 2.00 (ddd, J = 17.1, 9.6,
1.1 Hz, 1H), 1.74 (ddd, J = 12.0, 3.7, 1.7 Hz, 1H), 1.70 (s, 3H), 1.68 (br
s, 1H), 1.46 (t, J = 12.0 Hz, 1H), 1.32 (t, J = 7.1 Hz, 3H), 1.22 (s, 3H),
1.08 (s, 3H). GC–MS m/z (rel intensity) 212 (M+, 14), 197 (26), 179
(34), 167 (59), 151 (100), 139 (33), 121 (75), 107 (32), 95 (21), 79
(18), 67 (12), 55 (13), 43 (13). The latter compound was then re-
duced with LiAlH4 (9 g, 237 mmol) using the same conditions de-
scribed for the preparation of 7. The crude diol obtained was
chromatographed with hexane/diethyl ether (8:1ꢀ2:1) as eluent
to give 17 as a thick oil (14.8 g, 74%, 97% of chemical purity by
GC) that crystallised on standing, mp 123–125 °C; 1H NMR
(400 MHz, CDCl3) d 4.18 (d, J = 11.6 Hz, 1H), 4.09 (d, J = 11.6 Hz,
1H), 4.01–3.91 (m, 1H), 2.33 (ddd, J = 16.8, 5.5, 1.7 Hz, 1H), 2.02
(dd, J = 16.8, 9.6 Hz, 1H), 1.78 (s, 3H), 1.74 (ddd, J = 12.0, 3.5,
2.1 Hz, 1H), 1.46 (t, J = 12.0 Hz, 1H), 1.13 (s, 3H), 1.06 (s, 3H). 13C
4.3. Lipase PS-mediated diols resolution
4.3.1. General procedure
A
solution of the suitable hydroxy-cyclogeraniol (5 g,
29.4 mmol), lipase PS (5 g), vinyl acetate (15 mL) and t-BuOMe
(60 mL) was stirred at rt and the formation of the acetylated com-
pounds was monitored by TLC analysis. The reaction was stopped
at the reported conversion (see Table 1) by filtration of the enzyme
and evaporation of the solvent at reduced pressure. The residue
was then purified by chromatography using hexane–diethyl ether
(95:5–2:1) as eluent.
4.3.2. Resolution of cis 2-hydroxy a-cyclogeraniol 4
The general procedure afforded:
Diacetate (+)-21: colourless oil, ½a D20
¼ þ8:5 (c 2.5, CHCl3), 98%
ꢂ
chemical purity by GC, 96% ee, 1H NMR (400 MHz, CDCl3) d 5.38–
5.32 (m, 1H), 4.71 (t, J = 5.5 Hz, 1H), 4.44 (dd, J = 11.6, 4.9 Hz,
1H), 4.15 (dd, J = 11.6, 5.3 Hz, 1H), 2.32 (dm, J = 18.5 Hz, 1H),
2.13–1.98 (m, 2H), 2.05 (s, 6H), 1.75 (br s, 3H), 0.99 (s, 3H), 0.96
(s, 3H). 13C NMR (100 MHz) d 170.8, 170.4, 133.5, 119.3, 75.6,
64.1, 48.6, 35.7, 28.6, 25.8, 22.4, 21.0, 21.0, 19.6. IR (film, cmꢀ1
)
1739, 1661, 1372, 1238, 1049. GC–MS m/z (rel intensity) 151
(<1), 134 (99), 119 (100), 107 (13), 91 (10), 81 (7), 72 (6), 55 (3).
Monoacetate (+)-20: colourless oil, ½a D20
¼ þ26:1 (c 2, CHCl3),
ꢂ
97% chemical purity by GC, 37% ee, 1H NMR (400 MHz, CDCl3) d
5.43–5.36 (m, 1H), 4.45 (dd, J = 11.7, 4.1 Hz, 1H), 4.15 (dd,

1326
S. Serra et al. / Tetrahedron: Asymmetry 20 (2009) 1319–1329
J = 11.7, 4.4 Hz, 1H), 3.49–3.40 (m, 1H), 2.32 (dm, J = 17.7 Hz, 1H),
2.10–1.96 (m, 3H), 2.04 (s, 3H), 1.72 (br s, 3H), 1.02 (s, 3H), 0.97
(s, 3H). 13C NMR (100 MHz) d 170.6, 132.6, 120.4, 73.4, 63.3,
48.4, 37.1, 31.8, 26.6, 22.2, 21.0, 19.2. IR (film, cmꢀ1) 3447, 1738,
1438, 1386, 1366, 1243, 1030, 971, 909. GC–MS m/z (rel intensity)
152 (M+ꢀAcOH, 98), 137 (38), 123 (43), 119 (44), 107 (100), 91
(30), 81 (72), 72 (23), 55 (15).
Diacetate (ꢀ)-26: colourless oil, ½a D20
¼ ꢀ2:9 (c 2.5, CHCl3), 96%
ꢂ
of chemical purity by GC, 99% ee by chiral GC; 1H NMR (400 MHz,
CDCl3) 4.78 (dd, J = 8.9, 3.3 Hz, 1H), 4.66–4.55 (m, 2H), 2.17–2.10
(m, 2H), 2.06 (s, 3H), 2.05 (s, 3H), 1.89–1.69 (m, 2H), 1.70 (s, 3H),
1.02 (s, 3H), 1.02 (s, 3H). 13C NMR (100 MHz) d 171.2, 170.8,
135.4, 130.5, 77.4, 60.8, 37.9, 29.9, 25.8, 23.4, 22.3, 21.2, 21.0,
19.5. IR (film, cmꢀ1) 1738, 1368, 1242, 1021, 954. GC–MS m/z
(rel intensity) 194 (M+ꢀAcOH, 1), 151 (2), 134 (68), 119 (100),
105 (11), 93 (17), 79 (6), 67 (4), 55 (4).
Diol (ꢀ)-4: colourless crystals, ½a D20
¼ ꢀ31:5 (c 2, CH2Cl2), 97%
ꢂ
chemical purity by GC, 57% ee, 1H NMR, 13C NMR, IR and MS: in
accordance with those of racemic diol. The diol (ꢀ)-4 was recrys-
tallised twice from hexane/ether and its specific rotation value in-
Acetate (ꢀ)-25: colourless oil, ½a D20
¼ ꢀ8:9 (c 2, CHCl3), 96% of
ꢂ
chemical purity by GC, 30% ee by chiral GC; 1H NMR (400 MHz,
CDCl3) d 4.65–4.57 (m, 2H), 3.53 (dd, J = 8.9, 3.1 Hz, 1H), 2.22–
2.07 (m, 2H), 2.04 (s, 3H), 1.89–1.79 (m, 1H), 1.79–1.66 (m, 1H),
1.70 (s, 3H), 1.07 (s, 3H), 1.02 (s, 3H). 13C NMR (100 MHz) d
170.8, 134.9, 130.0, 74.9, 60.5, 38.6, 29.4, 25.8, 25.4, 21.1, 20.6,
19.0. GC–MS m/z (rel intensity) 194 (M+ꢀH2O, <1), 152 (M+ꢀAcOH,
55), 137 (34), 123 (44), 119 (50), 109 (72), 93 (100), 81 (26), 67
(23), 55 (15).
creased to ½a 2D0
¼ ꢀ57:4 (c 2, CH2Cl2), mp 120–122 °C; Ref. 23
ꢂ
½
a 2D0
ꢂ
¼ ꢀ51:7 (c 2, CH2Cl2), mp 131–132 °C.
The diacetate (+)-21 was saponified with NaOH in methanol.
The product was purified by chromatography and crystallisation
from hexane/ether to give diol (+)-4: colourless crystals,
½
a 2D0
ꢂ
¼ þ57:8 (c 2, CH2Cl2), mp 122–123 °C; Ref. 10 ½a D20
¼ þ45:8
ꢂ
(c 1.93, CHCl3), mp 113–114 °C.
Diacetate (ꢀ)-26 was saponified with NaOH in methanol. The
product was purified by chromatography and crystallisation from
4.3.3. Resolution of cis-2-hydroxy c-cyclogeraniol 5
hexane/ether to give diol (+)-14: colourless crystals, ½a D20
¼ þ23:8
ꢂ
The general procedure afforded:
(c 1, CHCl3); mp 126–127 °C.
Diacetate (ꢀ)-24: colourless oil, ½a D20
¼ ꢀ20:1 (c 1, CHCl3), 96%
ꢂ
chemical purity by GC, 99% ee by chiral GC, 1H NMR (400 MHz,
CDCl3) d 4.90 (s, 1H), 4.70 (dd, J = 7.1, 3.7 Hz, 1H), 4.67 (s, 1H),
4.40 (dd, J = 11.2, 9.8 Hz, 1H), 4.30 (dd, J = 11.2, 4.1 Hz, 1H), 2.42–
2.31 (m, 1H), 2.20 (dd, J = 9.8, 4.1 Hz, 1H), 2.14–2.00 (m, 1H),
2.08 (s, 3H), 2.02 (s, 3H), 1.90–1.79 (m, 1H), 1.72–1.57 (m, 1H),
1.01 (s, 3H), 0.91 (s, 3H). 13C NMR (100 MHz) d 171.0, 170.3,
144.9, 110.9, 77.5, 62.3, 51.3, 38.0, 29.5, 27.9, 26.3, 21.2, 21.0,
19.6. IR (film, cmꢀ1) 1739, 1649, 1442, 1369, 1236, 1026, 960,
895. GC–MS m/z (rel intensity) 212 (<1), 194 (M+ꢀAcOH, 2), 152
(2), 134 (100), 119 (78), 107 (27), 93 (18), 79 (14), 71 (15), 55 (6).
4.3.5. Resolution of cis 3-hydroxy
a-cyclogeraniol 7
The general procedure afforded:
Diacetate (+)-29: colourless oil, ½a D20
ꢂ ¼ þ17:9 (c 2, CHCl3), 97% of
chemical purity by GC, 94% ee by chiral GC; 1H NMR (400 MHz,
CDCl3) d 5.49 (s, 1H), 5.33–5.24 (m, 1H), 4.29 (dd, J = 11.8, 5.5 Hz,
1H), 4.08 (dd, J = 11.8, 3.4 Hz, 1H), 2.04 (s, 3H), 2.03 (s, 3H), 1.83–
177 (m, 1H), 1.80 (t, J = 1.6 Hz, 3H), 1.69 (dd, J = 13.1, 7.2 Hz, 1H),
1.58 (dd, J = 13.1, 9.3 Hz, 1H), 1.01 (s, 3H), 0.98 (s, 3H). 13C NMR
(100 MHz) d 170.8, 170.7, 137.8, 122.6, 69.4, 63.2, 49.1, 37.1,
33.8, 27.9, 27.7, 22.6, 21.3, 21.0. IR (film, cmꢀ1) 1736, 1445, 1366,
1238, 1022, 975, 932, 836. GC–MS m/z (rel intensity) 194
(M+ꢀAcOH, 10), 169 (9), 152 (53), 137 (77), 119 (100), 109 (40),
96 (47), 91 (29), 79 (11), 69 (6), 55 (4).
Mono acetate (+)-22: colourless oil, ½a D20
¼ þ2:5 (c 2, CHCl3),
ꢂ
98% chemical purity by GC, 32% ee by chiral GC, 1H NMR
(400 MHz, CDCl3) d 4.89 (s, 1H), 4.63 (s, 1H), 4.39 (dd, J = 11.3,
9.3 Hz, 1H), 4.33 (dd, J = 11.3, 4.2 Hz, 1H), 3.45 (dd, J = 8.4, 3.8 Hz,
1H), 2.41 (dt, J = 13.6, 5.8 Hz, 1H), 2.13 (dd, J = 9.3, 4.2 Hz, 1H),
2.11–1.98 (m, 1H), 2.02 (s, 3H), 1.91–1.81 (m, 1H), 1.62–1.50 (m,
2H), 1.07 (s, 3H), 0.85 (s, 3H). 13C NMR (100 MHz) d 171.1, 145.6,
109.8, 76.1, 62.6, 50.7, 39.2, 31.4, 30.9, 26.0, 21.0, 17.4. IR
(film, cmꢀ1) 3464, 1736, 1649, 1443, 1384, 1367, 1252, 1078,
1025, 892. GC–MS m/z (rel intensity) 152 (M+ꢀAcOH, 51), 134
(77), 119 (100), 110 (67), 107 (68), 93 (61), 81 (56), 71 (36), 67
(43), 55 (25).
Mono acetate (ꢀ)-27: colourless oil, ½a D20
¼ ꢀ8 (c 2, CHCl3),
ꢂ
94% of chemical purity by GC, 7% ee by chiral GC; 1H NMR
(400 MHz, CDCl3) d 5.59 (s, 1H), 5.33–5.24 (m, 1H), 3.83–3.73
(m, 2H), 2.03 (s, 3H), 1.86–1.62 (m, 4H), 1.80 (t, J = 1.6 Hz, 3H),
1.08 (s, 3H), 0.96 (s, 3H). 13C NMR (100 MHz) d 170.9, 137.7,
123.6, 69.8, 61.2, 52.0, 37.7, 33.8, 28.1, 28.1, 22.5, 21.3. IR (film,
cmꢀ1) 3449, 1735, 1649, 1376, 1243, 1023. GC–MS m/z (rel inten-
sity) 212 (M+, <1), 194 (M+ꢀH2O, <1), 170 (6), 152 (17), 137 (23),
121 (74), 107 (100), 96 (66), 91 (42), 81 (21), 67 (9), 60 (7), 53
(6).
Mono acetate (ꢀ)-23: colourless oil, ½a D20
¼ ꢀ52:5 (c 2, CHCl3),
ꢂ
98% of chemical purity by GC, 89% ee by chiral GC, 1H NMR
(400 MHz, CDCl3) d 5.01 (s, 1H), 4.81 (s, 1H), 4.70 (dd, J = 5.8,
3.5 Hz, 1H), 3.86 (t, J = 10.8 Hz, 1H), 3.74 (dd, J = 10.8, 3.9 Hz, 1H),
2.40–2.30 (m, 1H), 2.15–2.04 (m, 2H), 2.06 (s, 3H), 1.91–1.80 (m,
1H), 1.69 (dq, J = 13.8, 5.8 Hz, 1H), 1.48 (br s, 1H), 1.01 (s, 3H),
0.89 (s, 3H). 13C NMR (100 MHz) d 170.2, 145.8, 111.8, 77.1, 59.9,
55.8, 37.7, 28.2, 27.7, 26.9, 21.2, 20.7. IR (film, cmꢀ1) 3446, 1736,
1649, 1443, 1373, 1240, 1053, 1023, 896. GC–MS m/z (rel intensity)
212 (M+ <1), 195 (<1), 152 (M+ꢀAcOH, 8), 134 (8), 121 (100), 107
(62), 93 (23), 81 (20), 79 (20), 67 (13), 55 (10).
Mono acetate (+)-28: colourless oil, ½a D20
¼ þ49:6 (c 2, CHCl3),
ꢂ
98% of chemical purity by GC, 52% ee by chiral GC; 1H NMR
(400 MHz, CDCl3) d 5.55 (br s, 1H), 4.22 (dd, J = 11.8, 5.7 Hz,
1H), 4.21–4.13 (m, 1H), 4.09 (dd, J = 11.8, 3.3 Hz, 1H), 2.04 (s,
3H), 1.79 (t, J = 1.6 Hz, 3H), 1.80–1.69 (m, 2H), 1.65 (ddt,
J = 12.8, 6.9, 1.4 Hz, 1H), 1.44 (dd, J = 12.8, 9.7 Hz, 1H), 1.00 (s,
3H), 0.93 (s, 3H). 13C NMR (100 MHz) d 170.8, 135.5, 127.0,
66.2, 63.6, 49.1, 41.4, 33.9, 28.1, 27.5, 22.6, 21.0. IR (film, cmꢀ1
)
3402, 1740, 1672, 1471, 1447, 1382, 1366, 1235, 1026, 941,
838. GC–MS m/z (rel intensity) 169 (3), 152 (M+ꢀAcOH, 10),
137 (100), 119 (25), 109 (51), 96 (45), 84 (10), 77 (7), 69 (21),
55 (6), 43 (34).
Diol (+)-5: colourless oil, ½a D20
¼ þ19:9 (c 1.5, CHCl3), 99% of
ꢂ
chemical purity by GC, 22% ee by chiral GC, 1H NMR, 13C NMR, IR
and MS: in accordance with those of racemic diol.
The diacetate (ꢀ)-24 was saponified with NaOH in methanol.
Diol (ꢀ)-7: ½a 2D0
¼ ꢀ70:6 (c 2, CHCl3), 98% chemical purity by
ꢂ
The product was purified by chromatography to give diol (ꢀ)-5:
GC, 93% ee by chiral GC, 1H NMR, 13C NMR, IR and MS: in accor-
dance with those of racemic diol. The diol (ꢀ)-7 was recrystallised
from hexane/ether and its specific rotation value increased to:
colourless oil, ½a D20
ꢂ
¼ ꢀ47:2 (c 2, CHCl3); Ref. 6b ½a D20
¼ ꢀ54:0 (c
ꢂ
1, CHCl3).
½
a 2D0
ꢂ
¼ ꢀ76:1 (c 2, CHCl3), 99% ee by chiral GC.
Diacetate (+)-29 was saponified with NaOH in methanol. The
product was purified by chromatography and crystallised from
4.3.4. Resolution of 2-hydroxy b-cyclogeraniol 14
The general procedure afforded:

S. Serra et al. / Tetrahedron: Asymmetry 20 (2009) 1319–1329
1327
hexane/ether to give diol (+)-7: ½a D20
ꢂ
¼ þ77:1 (c 2, CHCl3), 99% ee
Diacetate (ꢀ)-34 was saponified with NaOH in methanol. The
product was purified by chromatography and crystallisation from
hexane/ether to give diol (ꢀ)-10: colourless crystals,
by chiral GC.
4.3.6. Lipase-mediated acetylation of 3-hydroxy b-cyclogeraniol
17
½
a 2D0
ꢂ
¼ ꢀ28:9 (c 2, CH2Cl2); mp 114–116 °C, 99% ee by chiral GC.
The general procedure afforded:
4.3.8. Lipase-mediated acetylation of 4-hydroxy b-cyclogeraniol
19
Diacetate (ꢀ)-31: colourless oil, ½a D20
ꢂ
¼ ꢀ20:8 (c 1, MeOH), Ref.
21a ½a 2D0
ꢂ
¼ ꢀ50:0 (c 1.02, MeOH); 97% of chemical purity by GC,
The general procedure afforded:
27% ee by chiral GC; 1H NMR (400 MHz, CDCl3) d 5.09–4.99 (m,
1H), 4.57 (s, 2H), 2.44 (dd, J = 17.1, 5.5 Hz, 1H), 2.12 (dd, J = 17.1,
9.6 Hz, 1H), 2.07 (s, 3H), 2.06 (s, 3H), 1.76 (ddd, J = 12.3, 3.5,
2.1 Hz, 1H), 1.70 (s, 3H), 1.59 (t, J = 12.3 Hz, 1H), 1.08 (s, 3H),
1.06 (s, 3H). 13C NMR (100 MHz) d 171.1, 170.6, 132.7, 132.2,
68.1, 60.2, 43.8, 38.3, 36.3, 28.8, 28.2, 21.3, 20.9, 19.5. IR (film,
Diacetate (+)-37: colourless oil, ½a D20
¼ þ18:6 (c 2, CHCl3), 98% of
ꢂ
chemical purity by GC, 19% ee by chiral GC; 1H NMR (400 MHz,
CDCl3) d 5.21 (t, J = 5.1 Hz, 1H), 4.65–4.56 (m, 2H), 2.08 (s, 3H),
2.06 (s, 3H), 1.97–1.87 (m, 1H), 1.78–1.55 (m, 2H), 1.66 (s, 3H),
1.48–1.39 (m, 1H), 1.06 (s, 3H), 1.00 (s, 3H). 13C NMR (100 MHz)
d 171.1, 170.8, 138.4, 133.1, 72.1, 60.5, 34.7, 34.4, 27.7, 26.8,
25.3, 21.2, 20.9, 16.2. IR (film, cmꢀ1) 1736, 1370, 1230, 1023,
964, 870. GC–MS m/z (rel intensity) 194 (M+ꢀAcOH, 4), 152
(100), 137 (18), 119 (25), 109 (11), 91 (9), 79 (5), 67 (3), 55 (3).
A mixture of monoacetate 35 and 36 (6:4 ratio, respectively); 1H
NMR (400 MHz, CDCl3) d 5.19 (t, J = 5.0 Hz, 1H), 4.63–4.54 (m, 2H),
4.20–4.14 (m, 2H), 3.98 (t, J = 5.0 Hz, 1H), 2.07 (s, 3H), 2.05 (s, 3H),
1.96–1.84 (m, 2H), 1.80 (s, 3H), 1.75 (s, 3H), 1.76–1.57 (m, 6H),
1.46–1.37 (m, 2H), 1.12 (s, 3H), 1.05 (s, 3H), 1.04 (s, 3H), 0.98 (s,
3H). GC–MS m/z (rel intensity):
1
cmꢀ ) 1736, 1365, 1240, 1024, 957. GC–MS m/z (rel intensity)
194 (M+ꢀAcOH, 13), 152 (3), 134 (34), 119 (100), 105 (10), 91
(10), 79 (4), 67 (3), 55 (3).
Mono acetate (+)-30: colourless oil, ½a D20
¼ þ15:6 (c 0.5, CHCl3),
ꢂ
98% chemical purity by GC, 10% ee by chiral GC; 1H NMR (400 MHz,
CDCl3) d 4.58 (s, 2H), 4.04–3.93 (m, 1H), 2.36 (ddd, J = 16.8, 5.5,
1.7 Hz, 1H), 2.09–2.00 (m, 1H), 2.04 (s, 3H), 1.75 (ddd, J = 12.1,
3.5, 2.1 Hz, 1H), 1.70 (s, 3H), 1.60 (br s, 1H), 1.48 (t, J = 12.1 Hz,
1H), 1.06 (s, 3H), 1.04 (s, 3H). 13C NMR (100 MHz) d 171.3, 133.3,
132.1, 64.8, 60.3, 48.1, 42.3, 36.8, 29.0, 28.5, 21.0, 19.6. IR (film,
cmꢀ1) 3391, 1736, 1365, 1233, 1023, 955. GC–MS m/z (rel inten-
sity) 152 (M+ꢀAcOH, 93), 137 (55), 119 (100), 109 (45), 93 (34),
81 (15), 67 (26), 55 (14).
tR(36) 16.72: 194 (M+ꢀH2O, 1), 152 (100), 139 (22), 121 (27),
107 (32), 95 (16), 81 (12), 67 (9), 55 (7), 43 (28).
tR(35) 16.83: 194 (M+ꢀH2O, 1), 152 (100), 137 (59), 124 (41),
109 (60), 96 (37), 81 (21), 67 (23), 55 (16), 43 (55).
4.3.7. Resolution of cis 4-hydroxy
c-cyclogeraniol 10
4.4. Conversion of enantiopure diol 4 into enantiopure diol 5
The general procedure afforded:
Diacetate (ꢀ)-34: colourless oil, ½a D20
ꢂ
¼ ꢀ16:7 (c 2, CHCl3), 97%
The photoisomerization procedure described for the conversion
of racemic 4 into racemic 5 was used also for the transformation of
the corresponding enantiopure compounds. Accordingly, diol (ꢀ)-4
chemical purity by GC, 92% ee by chiral GC; 1H NMR (400 MHz,
CDCl3) d 5.18 (dd, J = 8.6, 4.7 Hz, 1H), 5.13 (s, 1H), 4.80 (s, 1H),
4.32 (dd, J = 10.9, 4.7 Hz, 1H), 4.21 (dd, J = 10.9, 9.4 Hz, 1H), 2.25
(dd, J = 9.4, 4.7 Hz, 1H), 2.07 (s, 3H), 2.00 (s, 3H), 1.93–1.79 (m,
1H), 1.70–1.55 (m, 2H), 1.47–1.36 (m, 1H), 1.02 (s, 3H), 0.86 (s,
3H). 13C NMR (100 MHz) d 171.0, 169.8, 143.3, 110.5, 73.9, 62.7,
50.3, 35.7, 34.1, 28.8, 28.6, 23.2, 21.2, 20.9. IR (film, cmꢀ1) 1743,
1651, 1369, 1238, 1040, 970, 903. GC–MS m/z (rel intensity) 194
(M+ꢀAcOH, 10), 179 (2), 152 (68), 134 (100), 119 (77), 107 (28),
91 (29), 79 (19), 67 (7), 55 (9).
(½a 2D0
¼ ꢀ57:4 (c 2, CH2Cl2)) gave diol (+)-5 (yield 78%,
ꢂ
½
a 2D0
ꢂ
¼ þ46:9 (c 2, CHCl3)) and diol (+)-4 (½a D20
¼ þ57:8 (c 2,
ꢂ
CH2Cl2)) gave diol (–)-5 (yield 75%, ½a D20
¼ ꢀ48:1 (c 2, CHCl3));
ꢂ
Ref. 6a ½a 2D0
ꢂ
¼ þ46:6 (c 1.02, CH2Cl2), Ref. 6b ½a D20
¼ ꢀ54:0 (c 1,
ꢂ
CHCl3).
4.5. Synthesis of karahana ether and karahana lactone
Mono acetate (+)-33: colourless oil, ½a D20
ꢂ
¼ þ28:1 (c 2, CHCl3),
p-Toluenesulphonyl chloride (0.92 g, 4.8 mmol) was added por-
96% of chemical purity by GC, 90% ee by chiral GC; 1H NMR
(400 MHz, CDCl3) d 5.18 (br s, 1H), 4.76 (br s, 1H), 4.38 (dd,
J = 11.1, 9.4 Hz, 1H), 4.29 (dd, J = 11.1, 4.5 Hz, 1H), 4.06 (dd,
J = 8.3, 4.5 Hz, 1H), 2.15 (dd, J = 9.4, 4.5 Hz, 1H), 2.06 (br s, 1H),
2.02 (s, 3H), 1.93–1.83 (m, 1H), 1.62–1.49 (m, 2H), 1.44–1.31 (m,
1H), 1.01 (s, 3H), 0.83 (s, 3H). 13C NMR (100 MHz) d 171.3, 148.5,
107.9, 72.7, 63.1, 50.4, 36.7, 34.5, 31.9, 28.9, 22.7, 21.0. IR (film,
cmꢀ1) 3452, 1733, 1368, 1239, 1036, 903. GC–MS m/z (rel inten-
sity) 194 (M+ꢀH2O, 4), 152 (M+ꢀAcOH, 90), 137 (61), 123 (40),
119 (50), 109 (73), 96 (52), 91 (38), 83 (100), 70 (42), 55 (47).
tion-wise to a stirred solution of diol (ꢀ)-5 (½a D20
¼ ꢀ47:2 (c 2,
ꢂ
CHCl3), 99% ee by chiral GC, 0.8 g, 4.7 mmol) in pyridine (20 mL).
After 5 h, the mixture was diluted with ether (100 mL) and washed
in turn with 1 N aq HCl solution (200 mL), saturated NaHCO3 solu-
tion (50 mL) and brine. The organic phase was dried (Na2SO4) and
concentrated in vacuo. The residue was bulb-to-bulb distilled to
give pure (ꢀ)-38 (0.61 g, 85%), ½a D20
¼ ꢀ79:9 (c 0.6, CH2Cl2), Ref.
ꢂ
6b ½a 2D0
ꢂ
¼ ꢀ68:0 (c 1, pentane), 97% chemical purity by GC, 1H
NMR (400 MHz, CDCl3) d 4.64 (t, J = 2.2 Hz, 1H), 4.55 (t, J = 2.2 Hz,
1H), 4.02 (dd, J = 8.2, 4.6 Hz, 1H), 3.80 (d, J = 8.2 Hz, 1H), 3.75 (d,
J = 3.9 Hz, 1H), 2.48–2.35 (m, 1H), 2.31 (d, J = 4.6 Hz, 1H), 2.12
(dd, J = 15.5, 6.9 Hz, 1H), 1.79–1.70 (m, 1H), 1.70–1.59 (m, 1H),
1.08 (s, 3H), 0.96 (s, 3H). 13C NMR (100 MHz) d 149.0, 107.4,
82.4, 71.1, 54.0, 42.2, 28.6, 25.8, 25.4, 20.8. IR (film, cmꢀ1) 3072,
1646, 1446, 1388, 1368, 1240, 1066, 1035, 979, 911, 885, 874.
GC–MS m/z (rel intensity) 152 (M+, 3), 134 (4), 121 (57), 107
(100), 95 (15), 93 (22), 91 (24), 81 (17), 79 (35), 67 (18), 53 (10),
41 (17).
Mono acetate (ꢀ)-32: colourless oil, ½a D20
¼ ꢀ14:9 (c 2, CHCl3),
ꢂ
98% of chemical purity by GC, 76% ee by chiral GC; 1H NMR
(400 MHz, CDCl3) d 5.24 (br s, 1H), 5.21 (dd, J = 7.0, 4.5 Hz, 1H),
4.96 (br s, 1H), 3.81–3.75 (m, 2H), 2.15–2.07 (m, 1H), 2.08 (s,
3H), 1.92–1.81 (m, 1H), 1.74–1.64 (m, 1H), 1.65–1.55 (m, 1H),
1.48 (br s, 1H), 1.34 (ddd, J = 13.8, 7.9, 4.5 Hz, 1H), 0.99 (s, 3H),
0.86 (s, 3H). 13C NMR (100 MHz) d 169.9, 143.9, 112.8, 74.3, 60.5,
54.6, 34.6, 33.9, 28.5, 24.1, 21.3. IR (film, cmꢀ1) 3446, 1743, 1652,
1368, 1243, 1043, 901. GC–MS m/z (rel intensity) 182 (3), 152
(M+ꢀAcOH, 5), 139 (30), 122 (100), 107 (91), 93 (47), 79 (28), 67
(10), 55 (11).
A solution of the above described diol (ꢀ)-5 (0.9 g, 5.3 mmol) in
CH2Cl2 (50 mL) was treated with bis-acetoxyiodobenzene (BAIB,
5 g, 15.5 mmol) and 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO,
0.2 g, 1.3 mmol) and stirred at rt until no more starting material
was detected by TLC analysis (4 h). The mixture was then poured
in ice (100 g), treated with satd aq Na2S2O3 soln (100 mL) and
Diol (+)-10: ½a 2D0
¼ þ29:7 (c 2, CHCl3), mp 116–117; 98% of
ꢂ
chemical purity by GC, >99% ee by chiral GC, 1H NMR, 13C NMR,
IR and MS: in accordance with those of racemic diol.

1328
S. Serra et al. / Tetrahedron: Asymmetry 20 (2009) 1319–1329
extracted with Et2O (2 ꢁ 150 mL). The combined organic phases
were washed with satd aq NaHCO3 soln (100 mL) and brine, dried
(Na2SO4) and concentrated under reduced pressure. The residue
was purified by chromatography eluting with hexane/ether
(95:5ꢀ4:1) as eluent to afford pure (ꢀ)-39 (0.78 g, 89%) as a col-
9:1) and bulb-to-bulb distillation to give (ꢀ)-41 as a cyclogeraniol
isomeric mixture (0.67 g, 82%, 98% of chemical purity) with the fol-
lowing composition: ratio
c/a
/b = 97/ 2.9/0.1; ½a D20
¼ ꢀ21:3 (c 2,
ꢂ
CHCl3), Ref. 8b ½a D20
ꢂ
¼ ꢀ25:0 (c 0.017, CHCl3); 1H NMR (400 MHz,
CDCl3) 4.95 (br s, 1H), 4.75 (br s, 1H), 3.76–3.67 (m, 1H), 3.62 (t,
J = 10.7 Hz, 1H), 2.12 (t, J = 6.5 Hz, 2H), 2.04 (dd, J = 10.7, 4.6 Hz,
1H), 1.65–1.49 (m, 2H), 1.47–1.38 (m, 1H), 1.37 (br s, 1H), 1.27
(dt, J = 13.5, 4.6 Hz, 1H), 0.96 (s, 3H), 0.87 (s, 3H). 13C NMR
(100 MHz) d 147.5, 111.5, 59.6, 56.4, 36.4, 33.9, 31.9, 28.5, 26.4,
23.1. IR (film, cmꢀ1) 3371, 1648, 1441, 1029, 889. GC–MS m/z
(rel intensity) 154 (M+, 1), 136 (46), 121 (80), 109 (53), 93 (100),
81 (72), 69 (99), 55 (28), 41 (44).
ourless oil that crystallised on standing, ½a D20
¼ ꢀ288:1 (c 1, CHCl3),
ꢂ
mp 55–56 °C, 98% ee by chiral GC; Ref. 6b ½a D20
¼ ꢀ295:0 (c 1,
ꢂ
CHCl3), mp 57.5–58.5 °C, 98% chemical purity by GC, 1H NMR
(400 MHz, CDCl3) d 4.90 (br s, 1H), 4.83 (br s, 1H), 4.33 (d,
J = 4.0 Hz, 1H), 2.75 (s, 1H), 2.46–2.32 (m, 1H), 2.32 (dd, J = 15.8,
7.5 Hz, 1H), 2.04–1.94 (m, 1H), 1.87–1.75 (m, 1H), 1.17 (s, 3H),
1.00 (s, 3H). 13C NMR (100 MHz) d 176.6, 139.8, 112.6, 85.2, 59.3,
42.4, 25.5, 25.1, 24.5, 20.0. IR (film, cmꢀ1) 1781, 1653, 1394,
1374, 1340, 1293, 1253, 1137, 1035, 945. GC–MS m/z (rel intensity)
166 (M+, 1), 137 (2), 122 (24), 107 (100), 91 (35), 79 (39), 67 (8), 53
(5), 41 (7), 38 (8).
The diacetate (ꢀ)-34 (½a D20
¼ ꢀ16:7 (c 2, CHCl3)) was reduced as
ꢂ
described above to give (+)-41 as a cyclogeraniol isomeric mixture
(84% yield, 98% of chemical purity) with the following composi-
tion: ratio
c
/
a
/b = 96.6/ 3.3/0.1; ½a D20
¼ þ20:1 (c 2, CHCl3), Ref. 8a
ꢂ
Following the procedures described above, diol (+)-5
½
a 2D0
ꢂ
¼ þ23:7 (c 0.31, CHCl3).
(½a 2D0
¼ þ46:9 (c 2, CHCl3), 99% ee by chiral GC) was converted into
ꢂ
(+)-karahana ether 38 (yield 83%, ½a D20
ꢂ
¼ þ78:1 (c 1, CH2Cl2), Ref. 6a
4.8. Chemical correlation of 32 with 37
½
a 2D0
ꢂ
¼ þ76:6 (c 0.88, CH2Cl2)) and into (+)-karahana lactone 39
(yield 90%, ½a 2D0
ꢂ
¼ þ277:5 (c 1, CHCl3), Ref. 6a ½a D20
ꢂ
¼ þ260:5 (c
A solution of monoacetate diol (ꢀ)-32 {½a D20
¼ ꢀ14:9 (c 2,
ꢂ
0.9, CH2Cl2)).
CHCl3)}, 76% ee by chiral GC, 0.12 g, 0.56 mmol) in CH2Cl2 (5 mL)
was added dropwise to a stirred solution of Dess–Martin period-
inane (0.36 g, 0.85 mmol) in CH2Cl2 (10 mL). After complete oxida-
tion (30 min), the reaction mixture was diluted with ether (80 mL)
and treated with 10% Na2S2O3 solution (50 mL) and saturated NaH-
CO3 solution (50 mL) stirring vigorously for 15 min. The layers
were separated and the organic phase was washed with saturated
NaHCO3 and brine then was dried (Na2SO4) and concentrated un-
der reduced pressure. The residue was dissolved in CH2Cl2
(10 mL) and stirred at rt with DBU (0.1 g, 0.66 mmol). After com-
plete isomerization (6 h, TLC analysis), the reaction was diluted
with further CH2Cl2 (60 mL) and washed with water. The organic
layer was concentrated and the residue was dissolved in MeOH
(10 mL). The obtained solution was cooled (0 °C) and treated with
NaBH4 (25 mg, 0.66 mmol). The reaction mixture was then parti-
tioned between a 1 M aq HCl solution (50 mL) and ethyl acetate
(50 mL). The phases were separated and the aqueous phase was
extracted with ethyl acetate (30 mL). The organic layers were con-
centrated and the residue, dissolved in pyridine (10 mL) and acetic
anhydride (5 mL), was set aside at rt for 12 h. The solvent was then
removed in vacuo and the obtained diacetate was purified by chro-
matography (hexane/Et2O 9:1) and bulb-to-bulb distillation to af-
4.6. Synthesis of crocusatin C
A sample of diol (ꢀ)-7 (½a D20
¼ ꢀ76:1 (c 2, CHCl3), 99% ee by chi-
ꢂ
ral GC, 0.4 g, 2.3 mmol) was dissolved in CH2Cl2 (25 mL) and trea-
ted with MnO2 (2 g, 23 mmol) stirring at rt for 4 h. The mixture
was then filtered, the organic phase concentrated under reduced
pressure and the residue was purified by chromatography (hex-
ane/Et2O from 9:1 to 2:1) to afford pure (ꢀ)-crocusatin C 40
(0.31 g, 80%) as a thick oil that crystallised on standing, mp 78–
80 °C, ½a 2D0
ꢂ
¼ ꢀ99:1 (c 1, MeOH), Ref. 7 ½a D20
¼ ꢀ63 (c 0.06, MeOH),
ꢂ
98% of chemical purity by GC; 1H NMR (400 MHz, CDCl3) d 5.96 (s,
1H), 3.99–3.85 (m, 2H), 2.63 (d, J = 17.1 Hz, 1H), 2.11 (dd, J = 6.6,
4.5 Hz, 1H), 2.04 (d, J = 1.2 Hz, 3H), 2.03 (d, J = 17.1 Hz, 1H), 2.00
(br t, J = 3.8 Hz, 1H), 1.15 (s, 3H), 1.04 (s, 3H). 13C NMR
(100 MHz) d 199.9, 161.4, 127.3, 61.4, 53.6, 48.5, 35.3, 29.2, 27.0,
23.9. IR (nujol, cmꢀ1) 3335, 1640, 1377, 1364, 1276, 1068, 889.
GC–MS m/z (rel intensity) 168 (M+, 39), 153 (8), 138 (12), 123
(100), 111 (46), 97 (23), 91 (8), 82 (16), 67 (20), 55 (12).
The diol (+)-7 (½a D20
¼ þ77:1 (c 2, CHCl3), 99% ee by chiral GC)
ꢂ
was oxidised as described above to give pure (+)-crocusatin C 40,
mp 78–80 °C; ½a 2D0
ꢂ
¼ þ99:8 (c 1, MeOH).
-cyclogeraniol
ford pure (+)-37 {½a D20
¼ þ62:4 (c 2, CHCl3)}, 97% chemical purity
ꢂ
by GC, 0.11 g, 76%) as a colourless oil.
4.7. Chemical correlation of 10 with
c
4.9. Chemical correlation of karahana lactone with 14
A sample of diol (+)-10 (½a D20
¼ þ29:7 (c 2, CHCl3), 99% ee by
ꢂ
chiral GC, 0.9 g, 5.3 mmol) was treated with pyridine (20 mL) and
Ac2O (10 mL) and set aside at rt until acetylation was complete
(8 h). The mixture was concentrated under reduced pressure and
the residue was dissolved in dry THF (30 mL). The solution ob-
tained was refluxed under a static nitrogen atmosphere in the
presence of formic acid (0.75 g, 16.3 mmol), Et3N (1.65 g,
16.3 mmol), (PPh3)2PdCl2 (140 mg, 0.2 mmol) and triphenylphos-
phine (0.25 g, 0.9 mmol). After the reaction was complete (6 h,
TLC analysis), the mixture was diluted with ether (100 mL) and
washed with water (50 mL), 5% HCl soln (50 mL), satd aq NaHCO3
soln (50 mL) and brine. The organic phase was concentrated under
reduced pressure. The obtained acetate was then dissolved in
methanol (10 mL) and treated with NaOH (2 g, 50 mmol) in meth-
anol (10 mL) stirring at rt until no more starting material was de-
tected by TLC analysis. The mixture was diluted with water
(60 mL) and extracted with diethyl ether (3 ꢁ 50 mL). The organic
phase was washed with brine, dried (Na2SO4) and concentrated in
vacuo. The residue was purified by chromatography (hexane/Et2O
Diisobutylaluminium hydride (2.3 mL of 1.2 M solution in tolu-
ene, 2.76 mmol) was added dropwise under nitrogen to a cooled
(ꢀ78 °C) solution of (+)-karahana lactone {½a D20
¼ þ286:6 (c 1,
ꢂ
CHCl3)}, 0.4 g, 2.41 mmol) in toluene (30 mL). The reaction mixture
was stirred for 1 h at this temperature, quenched by addition of
1 M aq HCl solution (50 mL) and diluted with ether (100 mL).
The layers were separated and the organic phase was washed with
brine, dried (Na2SO4) and concentrated under reduced pressure.
The residue was dissolved in MeOH (40 mL) and stirred at rt in
the presence of NaOMe (390 mg, 7.22 mmol). After 2 h, the isomer-
ization reaction was cooled (0 °C) and quenched by dropwise addi-
tion of 1 N aq. HCl solution (7.2 mL). To the resulting mixture,
NaBH4 (100 mg, 2.64 mmol) was added portion-wise stirring at
0 °C for further 1 h. The reaction was then poured into a mixture
of crushed ice and 5% HCl soln (50 mL) and extracted with EtOAc
(2 ꢁ 100 mL). The organic phase was washed with brine, dried
(Na2SO4) and concentrated under reduced pressure. The residue
was chromatographed with hexane/ethyl acetate (3:1ꢀ1:1) as

S. Serra et al. / Tetrahedron: Asymmetry 20 (2009) 1319–1329
1329
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ꢂ
¼ ꢀ24:3 (c 1, CHCl3), 1H NMR,
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