Chemo enzymatic synthesis of Rengyol and Isorengyol

Article abstract of DOI:10.1016/j.tet.2006.03.012

Cyanohydrins 2 of O-protected 4-hydroxycyclohexanones 1 are excellent starting compounds for the synthesis of Isorengyol (I) and Rengyol (II). The cyano group of the O-benzyl derivative 2d is first converted into the corresponding aldehyde 4, which via Wi

Full text of DOI:10.1016/j.tet.2006.03.012

Tetrahedron 62 (2006) 4823–4828
Chemo enzymatic synthesis of Rengyol and Isorengyol*
y
*
Christoph Kobler and Franz Effenberger
Institut fur Organische Chemie der Universitat Stuttgart, Pfaffenwaldring 55, D-70569 Stuttgart, Germany
¨
¨
Received 17 November 2005; revised 22 February 2006; accepted 3 March 2006
Available online 3 April 2006
Abstract—Cyanohydrins 2 of O-protected 4-hydroxycyclohexanones 1 are excellent starting compounds for the synthesis of Isorengyol (I)
and Rengyol (II). The cyano group of the O-benzyl derivative 2d is first converted into the corresponding aldehyde 4, which via Wittig olefi-
nation led to the vinyl compound 6. Hydroboration of the trans-derivative (trans-6) leads, after debenzylation, to Isorengyol, whereas hydro-
boration and debenzylation of the cis-isomer (cis-6) gives Rengyol. With hydroxynitrile lyases (HNLs) as catalysts the stereoselective
preparation of cis- as well as trans-cyanohydrin 2d is possible, which enables the selective preparation of Isorengyol or Rengyol, respectively.
The trans-configuration of Isorengyol and the cis-configuration of Rengyol were secured by X-ray crystal structure analysis.
Ó 2006 Elsevier Ltd. All rights reserved.
1. Introduction
In 1996 Sun et al. isolated and characterized Cleroindicin A
(III) from Clerodendrum indicum, which can be derived
from Rengyol by intramolecular ether formation (Scheme
1).10 Until today only one synthesis of Cleroindicin A is de-
scribed in literature.9
In 1984 Endo and Hikino have first isolated and character-
ized Rengyol (I) and Isorengyol (II) from the fruits of For-
sythia suspensa Vahl (Scheme 1).2 In traditional Chinese
medicine these fruits, commonly called ‘Rengyo’, are widely
used because of their anti-inflammatory, antibactericidal,
and antiemetic properties.3 Isorengyol was not only found
in Forsythia but also in the plants Isoplexis chalcantha,4
Millingtonia hortensis,5 and Eurya tigang.6 Soon after its
discovery chemical syntheses of Rengyol and Isorengyol
have been developed.7 The first stereoselective synthesis of
Rengyol was performed by Hikino et al.8 Starting from glu-
copyranosyl bromide, Rengyol was obtained in six steps and
a total yield of 4%.8 A completely different route was devel-
oped by the group of Ogasawara.9 Starting from ethyl-2-(1-
hydroxy-4-oxo-cyclohexa-2,5-dienyl)acetate Rengyol was
obtained in 12 and Isorengyol in 16 steps.9
The natural products I–III, contain a common 1,4-di-
hydroxy-cyclohexane substructure with an additional alkyl
substituent in the 1-position (Scheme 1). In our methodically
oriented investigations related to applications of hydroxy-
nitrile lyases (HNL) in stereoselective organic syntheses, we
have recently published the HNL-catalyzed addition of HCN
to 4-substituted cyclohexanones.11 Unexpectedly we ob-
served trans-selectivity in the (R)-PaHNL-catalyzed addi-
tions and cis-selectivity with (S)-MeHNL as catalyst.11
Since the transformation of a cyano group into a b-hydroxy-
ethyl moeity can be achieved easily, cyanohydrins of
4-hydroxy-cyclohexanones should be ideal starting com-
pounds for the syntheses of Rengyol, Isorengyol, and
Cleroindicin A.
O
HO
OH
HO
OH
2. Results and discussion
OH
OH
OH
In the publication mentioned above, the HNL-catalyzed re-
actions of O-protected 4-hydroxy-cyclohexanones 1 with
hydrogen cyanide are described.11b With (R)-PaHNL from
almonds (Prunus amygdalus) as catalyst the HCN addition
preferentially gives the trans-products trans-2, with (S)-
MeHNL from cassava (Manihot esculenta) as catalyst the
cis-isomers cis-2 are the major products (Scheme 2).11b
In the nonenzymatic chemical addition of HCN to the
cyclohexanones 1a–e the isomeric cyanohydrins, cis-2a–e
and trans-2a–e are obtained in almost equal amounts.11b
Therefore, in the latter case a selective synthesis of either
cis- or trans-1,4-substituted cyclohexanones is not possible.
I: Rengyol
II: Isorengyol
III: Cleroindicin A
Scheme 1.
* See Ref. 1.
Keywords: Rengyol; Isorengyol; Hydroxynitrile lyase; Cyanohydrins; cis/
trans-Selectivity.
* Corresponding author. Tel.: +49 711 685 4265; fax: +49 711 685 4269;
e-mail: franz.effenberger@oc.uni-stuttgart.de
Part of dissertation, Universitat Stuttgart, 2004.
¨
y
0040–4020/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2006.03.012

4824
C. Kobler, F. Effenberger / Tetrahedron 62 (2006) 4823–4828
CN
OH
OH
CN
O
PaHNL
MeHNL
RO
RO
RO
HCN
+
i Pr2O, rt
i Pr2O, rt
trans-2
1
cis-2
1, 2
a
b
c
d
e
R =
Me i -Bu allyl benzyl acetyl
Scheme 2.
ꢀ
For the further transformations of the cyanohydrins 2 into
Rengyol and Isorengyol, we have selected the benzyl pro-
tected cyanohydrin 2d as educt for two reasons. The rela-
tively high cis/trans-stereoselectivity of the HCN addition
to 1d with both the enzymes (cis/trans¼2:98 with PaHNL
and cis/trans¼82:18 with MeHNL),11b and the mild reaction
conditions for removal of the benzyl group by hydrogeno-
lysis. For the synthesis of either Isorengyol or Rengyol the
pure stereoisomers trans-2d and cis-2d, respectively, are re-
quired. However, since a separation of the cis/trans-isomers
can be achieved without problems in a later stage in the syn-
thesis, we first followed up reactions with the crude cyano-
hydrins obtained in the HNL-catalyzed reactions.
diborane in THF at 0 C overnight and subsequent treatment
of the reaction mixture with an alkaline solution of hydrogen
peroxide (30%) at room temperature leads to the O-benzyl
protected products trans-6 and cis-6, respectively, which
are isolated and purified.16 The debenzylation to the natural
products Isorengyol (II) and Rengyol (I) was performed via
Pd/C catalyzed transfer hydrogenation using cyclohexene in
abs EtOH (Scheme 4). Both Isorengyol and Rengyol are ob-
tained quantitatively as colorless solids, which are recrystal-
lized from acetone.
HO
OH
HO
OH
OH
1. B2H6, THF
Pd/C, EtOH
cyclohexene
99 %
-
2. H2O2, OH
In Scheme 3 the synthesis of 4-benzyloxy-1-vinylcyclo-
hexanol (6) starting from trans-2d is shown. Although the
(R)-PaHNL-catalyzed HCN addition to 1d using organic sol-
vents and the enzyme supported on cellulose gives almost
exclusively the trans-cyanohydrin, trans-2d,11b we have re-
sorted to a two-phase reaction system,12 which is easier to
handle with defatted almond meal as enzyme source. This
way 2d was obtained as a cis/trans-mixture with a ratio of
25:75. Protection of the OH-function with a trimethylsilyl
group13 and hydrogenation with DIBAL-H14 leads, after
aqueous work up, to the corresponding (protected) aldehyde
4 (cis/trans¼26:74). Wittig olefination of 4 results in the for-
mation of the vinyl compound 5.15 The TMS-protecting
group is removed by the treatment with n-Bu4NF in THF
leading to 6 (Scheme 3). At this stage the separation of the
cis/trans-isomers was performed via chromatography on
silica with PE/EE (7:1) to give pure trans-6 and pure cis-6,
respectively.
57 %
OH
Isorengyol (II)
OBn
trans-7
OBn
trans-6
HO
OH
HO
OH
HO
1. B2H6, THF
Pd/C, EtOH
-
cyclohexene
99 %
2. H2O2, OH
62 %
OH
OBn
cis-7
OBn
Rengyol (I)
cis-6
Scheme 4.
The cis/trans-isomer ratio of the starting cyanohydrin 2d
(Scheme 3) has been assigned by the chemical shift of the
C-4 atom in 13C NMR spectra. The absolute configuration
of the 4-substituted cyclohexanone cyanohydrins has been
determined earlier by X-ray crystallography of a correspond-
ing 4-nitrobenzoyloxy derivative.11b
O
NC OH
NC OTMS
In none of the reactions performed (Schemes 3 and 4) iso-
merizations are to be expected. Thus structure assignments
for the intermediates 3–6 are acceptable. The X-ray crystal-
lographic structure of Isorengyol (II) (Fig. 1) confirms
Me3SiCl
PaHNL
+
HCN
OBn
OBn
OBn
1d
trans-2d
3
H
OTMS
-
OH
OTMS
+
O
Ph3PMe Br
1. DIBAL-H
+
KOtBu
THF
2. H2O, H
OBn
OBn
OBn
4
5
6
Scheme 3.
In Scheme 4 the straightforward transformations of trans-6
to Isorengyol and cis-6 to Rengyol are summarized. Hydro-
boration of the vinyl compounds trans-6 and cis-6, with
Figure 1. ORTEP plot of the trans-configurated Isorengyol (II).

C. Kobler, F. Effenberger / Tetrahedron 62 (2006) 4823–4828
4825
Figure 2. ORTEP plot of cis-4-benzyloxy-1-(2-hydroxyethyl)cyclohexane-1-ol (cis-7)—the O-benzyl derivative of Rengyol (I).
unambiguously the assigned trans-configuration.17 The
cis-configuration of Rengyol (I) is supported by the X-ray
structure of the O-benzyl derivative cis-7 (Fig. 2).17
they obtained Isorengyol in 14 steps and a total yield of
3.64%. We obtained Isorengyol in seven steps and a total
yield of 8.9%.
This comparison confirms the advantage of our approach if
one combines the number of reaction steps and total yields,
especially for the synthesis of Isorengyol.
3. Conclusions
Rengyol (I) and Isorengyol (II), isolated from F. suspensa,
possess a variety of interesting biological activities, thus
justifying that stereoselective chemical syntheses of these
natural products are of great interest and importance.
Cyanohydrins of 4-hydroxycyclohexanones are ideal start-
ing materials for these naturally occurring 1,4-dihydroxy-
cyclohexanones. O-Protected 4-hydroxycyclohexanones 1
are excellent substrates for hydroxynitrile lyase (HNL)
catalyzed HCN additions leading to the corresponding cya-
nohydrins 2 for which an unexpected high cis- or trans-
selectivity is observed.11 With (R)-PaHNL from almonds
the trans-1,4-dihydroxycyclohexanones are almost exclu-
sively (ꢁ98%) obtained, whereas with (S)-MeHNL from
cassava high yields (ꢁ82%) of the corresponding cis-com-
pounds are obtained. The chemical transformations of the
cyanohydrins 2 to the final products, i.e., Isorengyol (II)
and Rengyol (I), are straightforward and can be performed
without problems. By using almond meal as enzyme catalyst
in a two-phase system, the cis/trans-ratio of the cyanohy-
drins 2d is only 25:75. Nevertheless, the chemical transfor-
mations of this cis/trans-mixture of 2d can be performed
without difficulties. Separation of the cis/trans-isomers is
best achieved via column chromatography of the vinyl com-
pounds trans-6 and cis-6, respectively. The last two steps to
the final products Isorengyol (II) and Rengyol (I) are then
performed separately with the pure isomers trans-6 and
cis-6, respectively.
4. Experimental
4.1. Materials and methods
Melting points were determined on a Buchi SMP-20 and are
¨
uncorrected. Unless otherwise stated, 1H and 13C NMR
spectra were recorded on a Bruker AC 250 F (250 MHz)
and ARX 500 (500 MHz) in CDCl3 with TMS as internal
standard. 13C NMR multiplicities were determined with
DEPT experiments. Chromatography was performed using
silica gel, grain size 0.040–0.063 mm (Fluka). cis/trans-
Ratios: GC separations were conducted using capillary glass
columns (20 m) with OV 1701, carrier gas 0.4–0.6 bar
hydrogen. 4-Benzyloxycyclohexanone (1d) was prepared
according to literature procedures.18 All solvents were dried
and distilled. Yields are not optimized.
4.1.1. 4-Benzyloxy-1-hydroxycyclohexanecarbonitrile
(2d).11b (a) HNL-catalyzed reactions in organic solvents:
the O-protected 4-hydroxycyclohexanone cyanohydrins
2a–e were prepared according to Effenberger et al.12 (b)
HNL-catalyzed reactions in the two-phase system: to a vigor-
ously stirred two-phase system of 24.51 g (120 mmol) 1d18
in 120 mL diisopropylether and 200 mL of an aqueous solu-
tion of crude (R)-PaHNL12 (42,200 U), 300 mL of a solution
of 6.48 g (240 mmol) HCN, prepared in situ,12 in 300 mL
diisopropylether was added. To determine the conversion
rate and the cis/trans-ratio, 2 mL of the reaction mixture
was diluted with 2 mL of diisopropylether and dried
(Na2SO4). The organic phase was decanted and concentrated
under reduced pressure. The residue was dissolved in 1 mL
anhydrous CH2Cl2 and 100 mL acetic anhydride and 20 mg
DMAP were added. After 48 h of stirring at room tempera-
A comparison of the syntheses of Rengyol and Isorengyol
published already, with the procedures described in this
paper, shows the following.
The synthesis of Rengyol by Hikino et al. was performed in
six steps, starting from glucopyranosyl bromide, in 4% total
yield. Ogasawara et al. synthesized Rengyol in 10 steps,
starting from ethyl-2(1-hydroxy-4-oxo-cyclohexa-2.5-dienyl)
acetate, in 14% total yield. Starting from 4-benzyloxy-cyclo-
hexanone, we obtained Rengyol in seven steps and a total
yield of 9.7%. The effort for the syntheses of the starting
compounds in the three procedures cited is comparable.
ture the reaction mixture was filtered through a Buchner
¨
funnel and washed several times with diisopropylether.
The combined organic layers were dried (Na2SO4) and
concentrated in vacuo to give 26.21 g (94% yield) 2d as a
pale yellow oil, cis/trans-ratio¼25:75. cis-2d: 1H NMR
(250 MHz, CDCl3) d 1.71–2.07 (m, 8H, 8CH), 3.39 (br s,
1H, OH), 3.73–3.78 (m, 1H, C4H), 4.51 (s, 2H, CH2Ph),
7.26–7.38 (m, 5H, HPh). cis-2d: 13C NMR (63 MHz,
For Isorengyol only one synthesis was published by Ogasa-
wara et al. From the same starting compound as for Rengyol

4826
C. Kobler, F. Effenberger / Tetrahedron 62 (2006) 4823–4828
CDCl3) d 26.74 (C3H2, C5H2), 33.30 (C2H2, C6H2), 68.85
(C1), 69.96 (CH2Ph), 71.63 (C4H), 121.76 (CN), 127.44,
127.56, 128.40, 138.47 (CPh). trans-2d: 1H NMR
(250 MHz, CDCl3) d 1.67–1.81 (m, 4H, 4CH), 1.95–2.03
(m, 2H, C3Heq, C5Heq), 2.19–2.29 (m, 2H, C2Heq, C6Heq),
2.93 (br s, 1H, OH), 3.45–3.54 (m, 1H, C4H), 4.53 (s, 2H,
CH2Ph), 7.28–7.39 (m, 5H, HPh). trans-2d: 13C NMR
(63 MHz, CDCl3) d 26.54 (C3H2, C5H2), 33.99 (C2H2,
C6H2), 68.34 (C1), 70.17 (CH2Ph), 73.27 (C4H), 121.87
(CN), 127.46, 127.63, 128.45, 138.48 (CPh).
cis-C4H), 3.60–3.63 (m, 0.75H, trans-C4H), 4.51 (s,
1.45H, trans-CH2Ph), 4.56 (s, 0.55H, cis-CH2Ph), 7.25–
7.36 (m, 5H, HPh), 9.49 (s, 0.75H, trans-CHO), 9.54 (s,
0.25H, cis-CHO).13C NMR (126 MHz, CDCl3) d 2.25
(Si(CH3)3), 25.13 (trans-C3H2, trans-C5H2), 26.53 (cis-
C3H2, cis-C5H2), 27.77 (trans-C2H2, trans-C6H2), 30.41
(cis-C2H2, cis-C6H2), 69.87 (trans-CH2Ph), 69.96 (cis-
CH2Ph), 72.67 (trans-C4H), 75.38 (cis-C4H), 79.31 (cis-
C1), 79.69 (trans-C1), 127.36, 127.40, 127.49, 127.53,
128.34, 128.38, 138.82, 138.96 (CPh), 202.89 (trans-CHO),
203.73 (cis-CHO). Anal. Calcd for C17H26O3Si (306.48):
C, 66.62; H, 8.55. Found: C, 66.34; H, 8.63.
4.1.2. 4-Benzyloxy-trimethylsilyloxycyclohexanecar-
bonitrile (3).13,14b To a stirred solution of 15.74 g
(224.82 mmol) imidazole in 280 mL dry DMF 1ꢀ4.25 g
(131.15 mmol) chloro-trimethylsilane was added at 0 C un-
der an atmosphere of nitrogen. After stirring for 15 min, a so-
lution of 26.00 g (112.41 mmol) 2d in 50 mL dry DMF was
added dropwise and the mixture was allowed to warm up
slowly to room temperature with continued stirring for a fur-
ther 1 h. Then 560 mL of water was added and the resulting
mixture was extracted with diethyl ether (3ꢂ100 mL). The
combined extracts were dried (Na2SO4) and concentrated
under reduced pressure. The crude cis/trans-mixture was pu-
rified by chromatography on SiO2 using petroleum ether–
EtOAc (7:1) as eluant (Rf¼0.56) to afford 28.51 g (84%
4.1.4. (4-Benzyloxy-1-vinyl-cyclohexyloxy)trimethyl-
silane (5).15 To a stirred solution of 4.79 g (42.68 mmol)
potassium tert-butoxide in 100 mL dry THF 16.06 g
(44.81 mmol) methyl-triphenylphosphonium bromide was
added under nitrogen atmosphere at room temperature.
The bright yellow reaction mixture was stirred for 0.5 h,
and then a solution of 7.40 g (24.14 mmol) 4 in 100 mL
dry THF was added dropwise. After stirring for 2 h, the pre-
cipitate was filtered off and washed with Et2O. The com-
bined filtrates were quenched with water and extracted
with Et2O. The organic phase was dried over Na2SO4 and
concentrated under reduced pressure. The crude cis/trans-
mixture was purified by chromatography on SiO2 using
a short column with petroleum ether–EtOAc (3:1) as eluant
1
yield) 3 as a colorless oil, cis/trans-ratio¼25:75. cis-3: H
NMR (500 MHz, CDCl3) d 0.25 (s, 9H, Si(CH3)3), 1.71–
2.01 (m, 6H, 4CH, C3Heq, C5Heq), 2.02–2.16 (m, 2H,
C2Heq, C6Heq), 3.53–3.55 (m, 1H, C4H), 4.50 (s, 2H,
CH2Ph), 7.29–7.34 (m, 5H, HPh). cis-3: 13C NMR
(126 MHz, CDCl3) d 1.40 (Si(CH3)3), 26.90 (C3H2, C5H2),
34.82 (C2H2, C6H2), 69.87 (C1), 69.98 (CH2Ph), 71.90
(C4H), 121.82 (CN), 127.43, 127.54, 128.39, 138.62 (CPh).
trans-3: 1H NMR (500 MHz, CDCl3) d 0.24 (s, 9H,
Si(CH3)3), 1.64–2.11 (m, 6H, 4CH, C3Heq, C5Heq), 2.15–
2.25 (m, 2H, C2Heq, C6Heq), 3.41–3.47 (m, 1H, C4H), 4.52
(s, 2H, CH2Ph), 7.29–7.34 (m, 5H, HPh). trans-3: 13C
NMR (126 MHz, CDCl3) d 1.30 (Si(CH3)3), 26.91 (C3H2,
C5H2), 35.60 (C2H2, C6H2), 69.43 (C1), 70.10 (CH2Ph),
73.54 (C4H), 121.80 (CN), 127.41, 127.54, 128.40, 138.64
(CPh). Anal. Calcd for C17H25NO2Si (303.48): C, 67.28;
H, 8.30; N, 4.62. Found: C, 67.40; H, 8.30; N, 4.45.
1
to give 2.25 g (31% yield) 5 as a colorless oil. H NMR
(500 MHz, CDCl3) d 0.09 (s, 6.4H, trans-Si(CH3)3), 0.10
(s, 2.6H, cis-Si(CH3)3), 1.26–1.49 (m, 8H, 8CH), 3.27–
3.38 (m, 0.3H, cis-C4H), 3.54–3.62 (m, 0.7H, trans-C4H),
4.50 (s, 2H, trans-CH2Ph), 4.56 (s, 0.6H, cis-CH2Ph),
4.99–5.21 (m, 1.4H, CH]CH2), 5.75–5.98 (m, 1H,
CH]CH2), 7.22–7.38 (5H, m, HPh). 13C NMR (126 MHz,
CDCl3) d 2.53 (cis-Si(CH3)3), 2.56 (trans-Si(CH3)3), 26.62
(trans-C3H2, trans-C5H2), 27.48 (cis-C3H2, cis-C5H2)cis,
33.47 (trans-C2H2, trans-C6H2), 35.39 (cis-C2H2, cis-
C6H2), 69.79 (trans-CH2Ph), 69.83 (cis-CH2Ph), 73.34
(cis-C1), 73.96 (trans-C4H), 74.24 (trans-C1), 76.64 (cis-
C4H), 112.27 (cis-CH]CH2), 113.00 (trans-CH]CH2),
127.29, 127.38, 127.54, 128.30, 128.33, 139.15, 139.24
(CPh), 145.10 (trans-CH]CH2), 145.56 (cis-CH]CH2).
HRMS (EI, 70 eV) calcd for C18H28O2Si+: 304.1859.
Found: 304.1850.
4.1.3. 4-Benzyloxy-1-trimethylsilyloxycyclohexanecar-
baldehyde (4).14 To a vigorously stirred solution of
15.50 g (51.07 mmol) 3 in 125 mL dry n-hexane 86.8 mL
of a DIBAL-H solution (1 M in n-hexane) was added drop-
4.1.5. 4-Benzyloxy-1-vinylcyclohexan-1-ol (6). To a solu-
tion of 2.19 g (7.19 mmol) 5 in 36 mL dry THF a solution
of 2.50 g (7.92 mmol) n-Bu4NF in 8 mL dry THF was added
ꢀ
wise at ꢃ45 C under an inert gas atmosphere. Thenꢀthe re-
ꢀ
action mixture was allowed to warm up slowly to 15 C and
stirring at this temperature was continued for 5 h. The mix-
ture was diluted with CH2Cl2 (100 mL) and quenched with a
saturated aqueous solution of NH4Cl (100 mL) and 0.5 M
aqueous H2SO4 (250 mL). After vigorous stirring for 12 h
slowly at 0 C. The mixture was stirred for 0.5 h. Then
42 mL H2O and 56 mL CH2Cl2 were added, the organic
layer separated, and the aqueous layer was extracted twice
with CH2Cl2 (2ꢂ25 mL). The combined organic phase
was dried (Na2SO4) and concentrated under reduced pres-
sure. The crude cis/trans-mixture was purified and separated
by chromatography on SiO2 with petroleum ether–EtOAc
(7:1) as eluant to give two main fractions as colorless oils:
0.55 g (33% yield) cis-6 and 0.76 g (45% yield) trans-6.
cis-6: IR (neat) 2928, 2855, 1453, 1363, 1252, 1229, 1068,
ꢀ
at 15 C, the organic layer was separated and the aqueous
layer was extracted with CH2Cl2 (3ꢂ100 mL). The com-
bined organic layers were dried (Na2SO4) and concentrated
under reduced pressure. The crude cis/trans-mixture was
purified by chromatography on SiO2 using petroleum
ether–EtOAc (10:1) as eluant (Rf (cis-4)¼0.54, Rf (trans-
4)¼0.57) to afford 7.54 g (48% yield) of 4 as a colorless
1
1028, 993, 959, 920, 841, 734, 695. H NMR (500 MHz,
CDCl3) d 1.36 (br s, 1H, OH), 1.48–1.54 (m, 2H, 2CH),
1.69–1.81 (m, 4H, 4CH), 1.86–1.91 (m, 2H, C2Heq,
C6Heq), 3.34–3.40 (m, 1H, C4H), 4.57 (s, 2H, CH2Ph),
5.04 (dd, 2J(HC, HB)¼1.3 Hz, cis-3J(HC, HA)¼10.8 Hz,
1
oil, cis/trans-ratio¼26:74. H NMR (500 MHz, CDCl3)14b
d 0.14 (s, 6.9H, trans-Si(CH3)3), 0.15 (s, 2.1H, cis-
Si(CH3)3), 1.41–2.04 (m, 8H, 8CH), 3.37–3.40 (m, 0.25H,

C. Kobler, F. Effenberger / Tetrahedron 62 (2006) 4823–4828
4827
1H, CHA]CHCHB), 5.26 (dd, 1H, 2J(HB, HC)¼1.3 Hz,
trans-3J(HB, HA)¼17.5 Hz, 1H, CHA]CHCHB), 5.93 (dd,
cis-3J(HA, HC)¼10.8 Hz, trans-3J(HB, HA)¼17.5 Hz, 1H,
CHA]CHCHB), 7.25–7.42 (m, 5H, HPh). 13C NMR
(126 MHz, CDCl3) d 27.40 (C3H2, C5H2), 35.24 (C2H2,
C6H2), 69.77 (CH2Ph), 70.93 (C1), 76.14 (C4H), 111.85
(CH]CH2), 127.39, 127.49, 128.34, 139.05 (CPh), 145.46
(CH]CH2). HRMS (MH+) calcd for C15H21O2: 233.1542.
Found: 233.1538.
1004, 973, 940, 731, 695, 648. 1H NMR (500 MHz,
CDCl3) d 1.49–1.54 (m, 2H, 2CH), 1.61–1.80 (m, 2H,
2CH), 1.74–1.80 (m, 2H, 2CH), 1.76 (t, 3J¼5.8 Hz,
CH2CH2OH), 1.84–1.90 (m, 2H, 2CH), 3.14 (br s, 2H,
C1OH, CH2CH2OH), 3.56–3.60 (m, 1H, C4H), 3.87 (t,
3J¼5.7 Hz, 2H, CH2CH2OH), 4.51 (s, 2H, CH2Ph), 7.24–
7.35 (m, 5H, HPh). 13C NMR (126 MHz, CDCl3) d 26.47
(C3H2, C5H2), 33.19 (C2H2, C6H2), 41.18 (CH2CH2OH),
59.30 (CH2CH2OH), 69.91 (CH2Ph), 72.35 (C1), 74.08
(C4H), 127.41, 127.52, 128.34, 139.03 (CPh). Anal. Calcd
for C15H22O3 (250.34): C, 71.97; H, 8.86. Found: C,
71.80; H, 8.93.
trans-6: IR (neat) 2931, 2860, 1453, 1360, 1089, 1063, 1027,
968, 920, 907, 847, 732, 696. H NMR (500 MHz, CDCl3)
1
d 1.30 (br s, 1H, OH), 1.41–1.49 (m, 2H, 2CH), 1.72–1.78
(m, 2H, 2CH), 1.85–1.92 (m, 4H, C3Heq, C5Heq, C2Heq,
C6Heq), 3.61–3.63 (m, 1H, C4H), 4.52 (s, 2H, CH2Ph),
5.07 (dd, 2J(HC, HB)¼1.3 Hz, cis-3J(HC, HA)¼10.8 Hz,
1H, CHA]CHCHB), 5.27 (dd, 1H, 2J(HB, HC)¼1.3 Hz,
trans-3J(HB, HA)¼17.3 Hz, 1H, CHA]CHCHB), 6.01 (dd,
cis-3J(HA, HC)¼10.8 Hz, trans-3J(HB, HA)¼17.3 Hz, 1H,
CHA]CHCHB), 7.25–7.36 (m, 5H, HPh). 13C NMR
(126 MHz, CDCl3) d 26.14 (C3H2, C5H2), 32.84 (C2H2,
C6H2), 69.85 (CH2Ph), 71.64 (C1), 73.35 (C4H), 111.91
(CH]CH2), 127.38, 128.33, 139.14 (CPh), 145.58
(CH]CH2). HRMS (MH+) calcd for C15H21O2: 233.1542.
Found: 233.1535. Anal. Calcd for C15H20O2 (232.32): C,
77.55; H, 8.68. Found: C, 77.40; H, 8.83.
4.1.8. Rengyol (cis-1-(2-hydroxyethyl)cyclohexane-1,4-
diol) (I).8,9 To a solution of 86.8 mg (0.35 mmol) cis-7 in
7 mL abs EtOH and 0.75 mL freshly distilled cyclohexene,
20 mg 10% Pd/C (Degussa Type E) was added. The suspen-
sion was stirred under reflux for 1 h. The mixture was al-
lowed to cool down and was then filtered through Celite.
The filtrate was concentrated under reduced pressure. The
residue was recrystallized from acetone to afford 55.3 mg
(99% yield) Rengyol (I) as a white amorphous solid: mp
ꢀ
120 C. IR (neat) 2931, 2439, 2405, 1125, 1090, 1063,
1019, 959, 930, 907, 735, 666. 1H NMR (500 MHz, metha-
nol-d4) d 1.37–1.43 (m, 2H, C2Hax, C6Hax), 1.60–1.73 (m,
6H, C3Hax, C5Hax, C3Heq, C5Heq, C2Heq, C6Heq), 1.68 (t,
3J¼7.2 Hz, 2H, CH2CH2OH), 3.52 (tt, 3J (C4Hax, C3Hax)¼3J
(C4Hax, C5Hax)¼9.9 Hz, 3J (C4Hax, C3Heq)¼3J (C4Hax,
C5Heq)¼4.4 Hz, 1H, C4H), 3.73 (t, 3J¼7.2 Hz, 2H,
CH2CH2OH). 1H NMR (300 MHz, pyridine-d5)5b,19
d 1.51–1.61 (m, 2H, C2Hax, C2Hax), 2.01–2.12 (m, 4H,
C2Heq, C6Heq, C3Heq, C5Heq), 2.04 (t, 3J¼6.6 Hz, 2H,
CH2CH2OH), 2.24–2.38 (m, 2H, C3Hax, C5Hax), 3,94 (tt,
3J (C4Hax, C3Hax)¼3J (C4Hax, C5Hax)¼10.1 Hz, 3J (C4Hax,
C3Heq)¼3J (C4Hax, C5Heq)¼4.0 Hz, 1H, C4H), 4.22 (t,
3J¼6.6 Hz, 2H, CH2CH2OH). 13C NMR (126 MHz, metha-
nol-d4) d 31.28 (C3H2, C5H2), 36.04 (C2H2, C6H2), 45.57
(CH2CH2OH), 59.15 (CH2CH2OH), 70.76 (C4H, C1). 13C
NMR (126 MHz, pyridine-d5)5b,19 31.86 (C3H2, C5H2),
36.26 (C2H2, C6H2), 45.21 (CH2CH2OH), 58.86
(CH2CH2OH), 69.80 (C1), 70.03 (C4H). Anal. Calcd for
C8H16O3 (160.21): C, 59.98; H, 10.07. Found: C, 59.92;
H, 9.96.
4.1.6. cis-4-Benzyloxy-1-(2-hydroxyethyl)cyclohexan-
1-ol (cis-7).16 To 480.9 mg (2.07 mmol) cis-6 in 6 mL dry
THF 4.5 mL of a 1 M solution of B2H6 in THF was added
ꢀ
dropwise at 0 C under nitrogen atmosphere and the mixture
ꢀ
stirred overnight at 0 C. The reaction mixture was oxidized
by careful addition of 3.5 mL NaOH (3 M) and 0.78 mL
30% H2O2 and allowed to warm up slowly to room temper-
ature. Stirring was continued for 30 min and then the mix-
ture was extracted with CH2Cl2 (3ꢂ8 mL). The organic
layer was dried (Na2SO4) and concentrated under reduced
pressure. The crude product was purified by chromatography
on SiO2 with petroleum ether–EtOAc (1:3) as eluant to af-
ford 320.0 mg (62% yield) cis-7 as a white amorphous solid,
recrystallized from iPr2O (colorless prismatic crystals): mp
ꢀ
102 C. IR (neat) 3331, 2929, 2973, 1453, 1362, 1165,
1102, 1070, 1050, 1019, 962, 937, 741, 697. 1H NMR
(500 MHz, CDCl3) d 1.33–1.38 (m, 2H, 2CH), 1.68–1.75
(m, 2H, 2CH), 1.69 (t, 3J¼5.7 Hz, CH2CH2OH), 1.83–1.85
4.1.9. Isorengyol (trans-1-(2-hydroxyethyl)cyclohexane-
1,4-diol) (II).9 To a solution of 242.2 mg (0.97 mmol)
trans-7 in 20 mL abs EtOH and 2.1 mL freshly distilled cy-
clohexene, 50 mg 10% Pd/C (Degussa Type E) was added.
The suspension was stirred under reflux for 1 h. The mixture
was allowed to cool down and was then filtered through Cel-
ite. The filtrate was concentrated under reduced pressure.
Recrystallization from acetone afforded 153.8 mgꢀ (99%
yield) Isorengyol (II) as colorless crystals: mp 109 C. IR
(neat) 3272, 2945, 2925, 2434, 1021, 979, 839, 730, 699,
3
(m, 4H, 4CH), 2.74 (br s, 1H, C1OH), 2.96 (t, J¼4.6 Hz,
1H, CH2CH2OH), 3.33–3.39 (m, 1H, C4H), 3.86 (dt,
3Jd¼4.6 Hz, 3Jt¼5.6 Hz, 2H, CH2CH2OH), 4.56 (s, 2H,
CH2Ph), 7.25–7.36 (m, 5H, HPh). 13C NMR (126 MHz,
CDCl3) d 27.28 (C3H2, C5H2), 35.09 (C2H2, C6H2), 42.21
(CH2CH2OH), 59.51 (CH2CH2OH), 69.79 (CH2Ph), 71.55
(C1), 76.20 (C4H), 127.42, 127.51, 128.35, 138.98 (CPh).
Anal. Calcd for C15H22O3 (250.34): C, 71.97; H, 8.86.
Found: C, 71.93; H, 8.86.
1
672. H NMR (500 MHz, methanol-d4) d 1.42–1.51 (m,
4H, 4CH), 1.74–1.87 (m, 4H, 4CH), 1.78 (t, J¼7.1 Hz,
3
4.1.7. trans-4-Benzyloxy-1-(2-hydroxyethyl)cyclohexan-
1-ol) (trans-7).16 For reaction conditions and workup see
above for cis-7. 598.0 mg (2.57 mmol) of trans-6, 7.4 mL
dry THF, and 5.6 mL B2H6 (1 M in THF). Purification by
column chromatography (SiO2) with petroleum ether–
EtOAc (1:3) as eluant affording 365.0 mg ꢀ(57% yield)
trans-7 as a white amorphous solid: mp 38 C. IR (neat)
3324, 3271, 2939, 2922, 1440, 1250, 1087, 1066, 1029,
2H, CH2CH2OH), 3.74–3.79 (m, 1H, C4H), 3.75 (t,
1
3J¼7.1 Hz, 2H, CH2CH2OH). H NMR (500 MHz, pyri-
dine-d5)5b,19
d 1.83–1.89 (m, 4H, 4CH), 2.15 (t,
3J¼6.5 Hz, 2H, CH2CH2OH), 2.18–2.29 (m, 4H, 4CH),
4.20–4.26 (m, 1H, C4H), 4.25 (t, 3J¼6.5 Hz, 2H,
CH2CH2OH). 13C NMR (126 MHz, methanol-d4) d 30.69
(C3H2, C5H2), 34.22 (C2H2, C6H2), 43.03 (CH2CH2OH),

4828
C. Kobler, F. Effenberger / Tetrahedron 62 (2006) 4823–4828
58.98 (CH2CH2OH), 68.52 (C4H), 72.00 (C1). 13C NMR
(126 MHz, pyridine-d5)5b,19 d 31.24 (C3H2, C5H2), 34.59
(C2H2, C6H2), 43.26 (CH2CH2OH), 58.81 (CH2CH2OH),
67.41 (C1), 71.29 (C4H). Anal. Calcd for C8H16O3
(160.21): C, 59.98; H, 10.07. Found: C, 60.11; H, 9.98.
9. Honzumi, M.; Kamikubo, T.; Ogasawara, K. Synlett 1998,
1001–1003.
10. (a) Tian, J.; Zhao, Q. S.; Lin, Z. W.; Sun, H. D. Chin. Chem.
Lett. 1996, 7, 279–282; (b) Yang, H.; Hou, A.-J.; Mei, S.-X.;
Sun, H.-D.; Che, C.-T. J. Asian Nat. Prod. Res. 2002, 4, 165–
169.
11. (a) Effenberger, F.; Roos, J.; Kobler, C. Angew. Chem., Int. Ed.
2002, 41, 1876–1879; (b) Effenberger, F.; Roos, J.; Kobler, C.;
Acknowledgments
Buhler, H. Can. J. Chem. 2002, 80, 671–679.
¨
12. (a) Buhler, H. Dissertation, Universitat Stuttgart, 2000; (b)
¨
¨
Kirschbaum, B.; Gotz, W.; Effenberger, F.; Brand, S.; Fromm,
This work was supported by the Fonds der Chemischen
Industrie and the Degussa AG. The authors thank Dr. Wolf-
gang Frey for X-ray crystallographic analyses.
¨
A.; Buhler, H. Patent EP 1203814 A2, 08.05.2002. The crude
¨
solution of (R)-PaHNL is obtained by extraction of 50 g defat-
ted almond meal with 250 mL of 0.02 M sodium citrate buffer
(pH 3.5) overnight. The suspension was centrifugated and the
buffer, containing the extracted enzyme, was decanted and
used for the reaction. In situ preparation of HCN: to a stirred
two-phase system of 53.4 g (255 mmol) citric acid monohy-
drate in 75 mL water and 300 mL diisopropylether a solution
of (240 mmol) 15.63 g KCN in 30 mL water was added drop-
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