Stereochemistry of hydroxylation of some chiral spiro-[2,5]octan-4-ones

Article abstract of DOI:10.1016/j.molstruc.2012.03.052

Stereoselective oxidative alpha hydroxylation of (1R,5R,8R,3R)-1-aryl-5- isopropyl-8-methyl-3-spiro-[2,5]octan-4-ones has been found as a secondary process in the cyclopropanation of 2-arylidene isomenthanones with trimethylsulfoxonium iodide in DMSO/NaOH or DMF/NaOH system. Three stereoisomeric hydroxy ketones have been isolated from a reaction mixture of cyclopropanation reaction, but the reaction of oxidation carried out with isolated spiro-[2,5]octan-4-ones was stereoselective. The advantages of this method of stereoselective hydroxylation are room temperature of reaction and absence of expensive catalysts. The reduction of obtained hydroxy ketones was also stereoselective and gave the only trans-(4R,5S)-dioles. The structures have been confirmed with 1D and 2D ¹H and ¹³C NMR, MS spectra and for stereoisomeric hydroxy ketones with X-ray analysis also.

Full text of DOI:10.1016/j.molstruc.2012.03.052

Journal of Molecular Structure 1019 (2012) 120–129
Contents lists available at SciVerse ScienceDirect
Journal of Molecular Structure
journal homepage: www.elsevier.com/locate/molstruc
Stereochemistry of hydroxylation of some chiral spiro-[2,5]octan-4-ones
a
a
b
a
I.M. Gella a, T.G. Drushlyak a, , N.S. Pivnenko , R.I. Zubatyuk , A.V. Turov , I.S. Konovalova ,
⇑
N.B. Novikova a, O.V. Shishkin a,c
a SSI Institute for Single Crystals, National Academy of Sciences of Ukraine, 60 Lenin Ave., Kharkiv 61001, Ukraine
b T.G. Shevchenko Kiev National University, Vladimirskaya St. 4, Kiev 01033, Ukraine
c V.N. Karazin Kharkiv National University, 4 Svobody Sq., Kharkiv 61202, Ukraine
a r t i c l e i n f o
a b s t r a c t
Article history:
Stereoselective oxidative alpha hydroxylation of (1R,5R,8R,3R)-1-aryl-5-isopropyl-8-methyl-3-spiro-
[2,5]octan-4-ones has been found as a secondary process in the cyclopropanation of 2-arylidene isomen-
thanones with trimethylsulfoxonium iodide in DMSO/NaOH or DMF/NaOH system. Three stereoisomeric
hydroxy ketones have been isolated from a reaction mixture of cyclopropanation reaction, but the reac-
tion of oxidation carried out with isolated spiro-[2,5]octan-4-ones was stereoselective. The advantages of
this method of stereoselective hydroxylation are room temperature of reaction and absence of expensive
catalysts. The reduction of obtained hydroxy ketones was also stereoselective and gave the only trans-
(4R,5S)-dioles. The structures have been confirmed with 1D and 2D 1H and 13C NMR, MS spectra and
for stereoisomeric hydroxy ketones with X-ray analysis also.
Received 11 January 2012
Received in revised form 22 March 2012
Accepted 22 March 2012
Available online 2 April 2012
Keywords:
Chiral spiro-[2,5]octan-4-ones
Cyclopropanation
Hydroxylation
Stereoselective
Ó 2012 Elsevier B.V. All rights reserved.
Corey–Chaykovsky reaction
Conformational isomerism
1. Introduction
The most common oxidative procedures for a-hydroxyketone
obtaining are oxidation of O-sylil enolic ethers (epoxidation,
Rubottom oxidation) or enolates of carbonyl compounds [12] with
different oxidants. MoOPH or MoOPD [Ref. in 9] and dioxygen
[13,9], and also dibenzyl peroxydicarbonate [14], molybdenum
peroxide [15], osmium tetroxide/N-methylmorpholine-N-oxide
[16], m-chloroperbenzoic acid [17], chiral oxaziridines (N-sulpho-
nyloxaziridines) [9], nitroso and iodoso compounds [18], dioxir-
anes [19] were used predominately. Other ways include
oxidation of enamines with molecular oxygen [20] or metal-
catalyzed oxidation of olefins [21]. Last time strongly upcoming
The reaction of cyclopropanation with sulfur ylides (Corey–
Chaykovsky reaction) is attractive because of its potential for
simple procedures in obtaining of three-membered rings [1–4]
application-oriented in the synthesis of some biologically active
compounds. Peculiarities of this reaction in modern synthesis
remain the subject of studies [5–7]. Also, the substitution of double
bond in arylidene derivatives of isomenthone with a cyclopropane
cycle seems to be attractive for obtaining of photo stable chiral
dopants to nematic liquid crystals [8].
Corey–Chaykovsky reaction behavior for (1R,5R,8R,3R)-1-aryl-
5-isopropyl-8-methyl-3-spiro-[2,5]octan-4-ones and its accompa-
nying stereoselective oxidative alpha hydroxylation with dioxygen
in NaOH/DMSO and NaOH/DMF is described in this paper.
chemo-enzymatic reactions were applied to the synthesis of
droxy ketones [22] also. To improve an enantiomeric excess (ee) in
a synthesis of -hydroxy substituted ketones and aldehydes it was
proposed to pass oxygen through a reaction mixture at low tem-
peratures (ꢀ25 °C) and use triethyl phosphite for hydroperoxides
reduction [23–25], or to use amino acids as organocatalysts
[9,26,27].
a-hy-
a
a-Hydroxyketones, especially optically active, are interesting as
important intermediate products for synthesis of different bioac-
tive substances. Non-oxidative procedures for their obtaining are
known (see [9] for review) but they are limited to the synthesis
of acyclic derivatives. Recently, cesium formate using [10] and
In this investigation, we have obtained a-hydroxyketones with-
out reducing agents. We have separated intermediate hydroperox-
ide that confirms the mechanism of oxidative hydroxylation
reaction in concerned case. Also we have studied stereoselectivity
of this reaction and found configurations of new chiral centers.
Molecular structures of compounds studied have been confirmed
with 1D and 2D 1H and 13C NMR, MS, and for stereoisomeric hydroxy
ketones with X-ray analysis also.
a
-haloketones irradiation with ultra violet or micro-waves [11]
were proposed for the transformation of -haloketones to
-hydroxyketones.
a
a
⇑
Corresponding author. Tel.: +380 57 341 04 21; fax: +380 57 341 02 73.
E-mail addresses: igella@kharkov.ua (I.M. Gella), drushlyak@isc.kharkov.com
(T.G. Drushlyak).
0022-2860/$ - see front matter Ó 2012 Elsevier B.V. All rights reserved.
http://dx.doi.org/10.1016/j.molstruc.2012.03.052

I.M. Gella et al. / Journal of Molecular Structure 1019 (2012) 120–129
121
16.371, 15.587. MS, m/z 351 (M+.). Anal. Calcd. for C18H23BrO2: C,
61.55; H, 6.60, Br 22.75; found: C, 61.52; H, 6.63, Br 22.73.
(1R,5S,8R,3R)-1-(4-Chlorophenyl)-5-isopropyl-5-hydroxy-8-methyl-
3-spiro[2.5]octan-4-one (2c) (yield 76%). Mp 143–145 °C (ethanol,
hexane). 1H NMR, CDCl3: 7.334 (m., 4H), 5.217 (s., 1H), 2.894 (s.,
2H), 2.168 (dd., 1H), 1.987 (sept., 1H), 1.77 (m., 1H) 1.571 (m.,
1H), 1.110, 1.095 (d.m., 3H), 0.96 (d., 3H), 0.952 (d., 3H), 0.818
(m., 3H). 13C NMR, CDCl3 (HMQC): 137.015, 131.795, 130.399,
127.982, 80.833, 75.257, 32.930, 31.874, 30.688, 28.252, 24.731,
24.529, 19.017, 15.813, 11.899. MS, m/z 306 (M+.). Anal. Calcd.
for C18H23ClO2: C, 70.46; H, 7.56, Cl 11.55; found: C, 70.38; H,
7.60, Cl 11.51.
(1R,5S,8R,3R)-1-(4-Fluorophenyl)-5-isopropyl-5-hydroxy-8-methyl-
3-spiro[2.5]octan-4-one (2d) (yield 77%). Mp 126–128 °C (ethanol,
hexane). 1H NMR, DMSO-d6: 7.334 (Ar, 4H), 5.218 (s., 1H), 2.44
(s., 2H), 2.228 (dd., 2H), 1.754 (m., 1H), 1.515 (m., 1H), 1.077 (m.,
3H), 0.848 (m., 6H), 0.716 (m., 3H); MS, m/z 290 (M+.). Anal. Calcd.
for C18H23FO2: C, 74.45; H, 7.98, F 6.54; found: C, 74.43; H, 8.03, F
6.51. MS, m/z 290 (M+.). Anal. Calcd. for C18H23FO2: C, 74.45; H,
7.98, F 6.54; found: C, 74.43; H, 8.02, F 6.55.
(1R,5S,8R,3R)-1-(4-Methoxyphenyl)-5-isopropyl-5-hydroxy-8-me-
thyl-3-spiro[2.5]octan-4-one (2e) (yield 78%). Mp 96–97 °C (etha-
nol). 1H NMR, DMSO-d6: 7.030 (Ar, 4H), 5.161 (s., 1H), 3.712 (s.,
3H), 2.216 (m., 2H), 1.830 (m., 2H), 1.704 (m., 1H) 1.501 (m., 1H),
1.021 (m., 4H), 0.842 (dd., 7H), 0.714 (d., 4H)). MS, m/z 302
(M+.). Anal. Calcd. for C19H26O3: C, 75.46; H, 8.67; found: C,
75.43; H, 8.69.
(1R,5S,8R,3R)-1-(4-bromophenyl)-5-isopropyl-5-hydroperoxy-8-
methyl-3-spiro[2.5]octan-4-one (20b) was obtained in similar proce-
dure when reaction was carried in DMF. Yield 20%. Mp 158–160 °C
(ethanol). 1H NMR, DMSO-d6: 11.183, 7.478, 7.305, 5.239, 2.601,
2.390, 1.905, 1.671, 1.101, 0.886, 0.843, 0.808, 0.757, 0.723. 13C
NMR, CDCl3: 206.701, 135.989, 131.372, 131.166, 131.110,
131.026, 120.708, 88.011, 40.015, 35.337, 30.785, 26.452, 23.998,
22.147, 18.450, 18.024, 15.204, 13.943. MS, m/z 367 (M+.). Anal.
Calcd. for C19H26O3: C, 58.86; H, 6.31, Br 21.76; found: C, 58.78;
H, 6.38, Br 21.73.
2. Experimental
2.1. Preparation
The compounds described in this work and used synthetic pro-
cedures are shown in Fig. 1.
The syntheses of compounds 1 were described earlier [8]. Initial
benzylidene cyclohexanones (BC) were obtained using published
protocols [28].
2.1.1. (1R,5S,8R,3R)-1-Aryl-5-isopropyl-5-hydroxy-8-methyl-3-spiro
[2.5]octan-4-ones (2a–e)
To 8 mmol of compound 1 in 12 ml DMSO (or DMF) 960 mg
(24 mmol) of powdered sodium hydroxide was added and stirred
at room temperature in open vessel (using of protective tube some
reduce the oxygen transport and therefore reduce the reaction).
The reaction was completed usually during 24 h (control with thin
layer chromatography (TLC), silica gel/dichloroethane). Then the
reaction mixture was poured in water at 0 °C, neutralized with ace-
tic acid, filtered. The precipitate was washed with water, dried in
air and dissolved in DCM. Then solvent was evaporated with a ro-
tary evaporator and a residue was crystallized from ethanol or hex-
ane. All compounds (2a–e) were obtained as white solids. Finally,
reaction mixtures had 80–90% of products 2a–e (by HPLC).
(1R,5S,8R,3R)-1-(Biphenyl-4-yl)-5-isopropyl-5-hydroxy-8-methyl-
3-spiro[2.5]octan-4-one (2a1) (yield 78%). Mp 139–140 °C (ethanol).
1H NMR (DMSO d6), d: 7.416, 7.463 (both d, 2H each, H arom.,
3J = 8.2), 7.256 (t, 2H, m-H arom., 3J = 8.2 Hz); 7.186 (d, 2H, o-H
arom., 3J = 8.2 Hz); 7.155 (t, 1H, p-H arom., 3J = 8.2 Hz); 5.088 (s,
1H, OH); 2.312 (dd, 1H, H(1), 3J = 8.7 Hz, 3J = 7.1 Hz); 2.295 (sept,
1H, H(10), 3J = 7.0 Hz); 1.907 (m, 1H, H(7 trans), 2J = ꢀ13.2 Hz,
2J = 13.6 Hz, 2J = 3.6 Hz, 2J = 2.9 Hz); 1.884 (m, 1H, H(6 trans),
2J = ꢀ13.5 Hz, 3J = 13.6 Hz, 3J = 2.6 Hz); 1.812 (dd, 1H, cis-H(2),
2J = ꢀ4.7 Hz, 3J = 8.7 Hz); 1.606 (m, 1H, H(6), 2J = ꢀ13.5 Hz,
3J = 2.9 Hz, 3J = 2.5 Hz); 1.295 (m, 1H, H(8), 3J = 7.1 Hz,
3J = 3.6 Hz, 3J = 2.0 Hz); 1.184 (dd, 1H, trans-H(2), 2J = ꢀ4.7 Hz,
3J = 7.1 Hz); 1.156 (m, 1H, H(7), 2J = ꢀ13.2 Hz, 3J = 2.9 Hz,
3J = 2.5 Hz, 3J = 2.0 Hz); 0.967 (d, 3H, C(9)Me, 3J = 7.1 Hz); 0.828,
0.934 (both d, 3H each, C(11)Me, C(12)Me, 3J = 7.0 Hz). 13C NMR,
CDCl3: 213.105, 140.714, 139.701, 135.885, 129.845, 128.782,
127.272, 126.981, 126.900, 78.483, 38.229, 35.393, 32.556,
30.007, 27.162, 26.354, 19.094, 17.050, 16.641, 15.608. MS, m/z
348 (M+.). Anal. Calcd. for C24H28O2: C, 82.72; H, 8.10; found: C,
2.1.2. Isomeric 1-(4-phenyl)-phenyl-5-isopropyl-5-hydroxy-8(R)-
methyl-3(R)-spiro[2.5]octan-4-ones (2a1–2a3)
(3R,6R)-3-methyl-6-isopropyl-2-(4-phenyl)benzylidenecyclohe-
xanone (PBC) (1.9 g, 6 mmol) was dissolved in 20 ml DMSO and
0.6 g (15 mmol) of powdered NaOH was added to former. The
resulting mixture was stirred for 2 days at a room temperature
up to initial product disappearance on TLC. The mixture after reac-
tion completion was poured into water, and a precipitate obtained
was filtered and dried. Its crystallization from isopropanol yielded
1.4 g (78%) of 2a1 (data see in Section 2.1.1). According to TLC and
HPLC, a mother stock contained additively two more polar reaction
products. To obtain these products the solvent was removed, and
residue was separated by column chromatography on silica gel
82.69; H, 8.15; ½a D20
ꢁ
236.36° (C = 1.15 g/100 cm3, ethyl acetate).
(1R,5S,8R,3R)-1-(4-Bromophenyl)-5-isopropyl-5-hydroxy-8-methyl-
3-spiro[2.5]octan-4-one (2b) (yield 76%). Mp 135–137 °C (ethanol).
1H NMR, CDCl3: 7.295 (m., 4H), 5.216 (s., 1H), 2.758, 2.252, 2.125,
1.831, 1.740, 1.531, 1.392, 1.232, 0.910, 0.853, 0.711. 13C NMR,
CDCl3: 212.758, 135.918, 131.373, 131.110, 120.808, 78.519,
37.911, 34.383, 32.473, 30.163, 27.305, 26.367, 18.976, 16.956,
OH
OOH
5
OH
O
O
4
(R)
O
O
HO
(S)
(R)
(R)
(R)
(S)
(R)
(R)
3
NaBH 4
2
[O]
8
Me2S(O)CH 2
(R)
(R)
(R)
(R)
1
(R)
(R)
(R)
NaOH / DMSO
NaOH / DMF
NaOH / DMSO
NaOH / DMF
R
R
R
R
R
BC
1
2'
2
3
Fig. 1. Synthetical procedures used for obtaining spiro compounds, their hydroxylation and reduction.

122
I.M. Gella et al. / Journal of Molecular Structure 1019 (2012) 120–129
Table 1
Chemical shifts of protons (d, ppm) in 1H NMR spectra for compounds 2a1, 2a2, 2a3.
Compounds
H(8)
H(7a) H(7e) H(6a) H(6e) H(5)
H(10) Me(9) Me(11,12) Benzene ring
Ho Hm
Cyclopropane ring
H(1) H(2c) H(2t)
Isomeric 1-(4-phenyl)-phenyl-5-isopropyl-5-
hydroxy-8(R)-methyl-3(R)-
spiro[2.5]octan-4-ones
CDCl3
2a1
1.608 1.876 1.395 2.132 1.756 2.589 2.279 0.755
2.024 1.990 1.652 2.231 1.745 2.019 2.496 0.435
2.286 1.826 1.629 2.262 1.691 3.317 1.710 0.996
0.871;
0.916
0.892;
1.001
7.302 7.536 2.854 1.698 1.318
7.335 7.532 2.801 1.505 1.660
7.240 7.463 2.878 1.113 2.305
2a2
2a3
ꢀ0.470;
0.784
C6D6
2a1
1.408 1.781 1.044 1.884 1.592 1.312 2.226 0.612
1.677 1.883 1.369 1.980 1.614 1.315 2.433 0.331
0.816;
0.846
0.847;
0.924
7.159 7.422 2.794 1.775 0.999
7.113 7.374 3.024 1.517 1.247
2a2
DMSO-d6
2a1
1.244 1.884 1.100 1.858 1.569 5.197 2.295 0.758
1.687 2.340 1.443 1.872 1.628 4.884 2.297 0.461
0.868;
0.903
0.791;
0.869
7.383 7.671 2.312 1.784 1.128
7.303 7.517 3.105 1.156 1.590
2a2
Note. For 2a1 in CDCl3: dHo0 7.592, dHm0 7.433, dHp0 7.337, 2a1 in C6D6: dHo0 7.458, dHm0 7.212, dHp0 7.126.
For 2a2 in CDCl3: dHo0 7.597, dHm0 7.436, dHp0 7.340, 2a2 in C6D6: dHo0 7.464, dHm0 7.222, dHp0 7.135.
For 2a1 in DMSO2-d6: dHo0 7.622, dHm0 7.456, dHp0 7.351.
For 2a2 in DMSO2-d6: dHo0 7.595, dHm0 7.412, dHp0 7.301.
Table 2
Experimental values of vicinal coupling constants (J, Hz) in spectra 1H NMR of
compounds 2a1, 2a2 and 2a3 in different solvents.
2.1.3. (1R,3R,4R,5S,8R)-1-Aryl-5-isopropyl-8-methyl-3-
spiro[2.5]octan-4,5-dioles
(1R,3R,5S,8R)-1-aryl-5-isopropyl-5-hydroxy-8-methyl-3-spiro[2.5]
octan-4-one (2, 1 mmol) was dissolved in 2-propanol and NaBH4
(1 mmol) was added slowly to the mixture at room temperature.
The mixture was stirred for several hours up to initial substance
2 convert (control with TLC). Then the mixture was poured into
water, extracted using EtOAc, dried (anhydrous MgSO4), filtered,
and concentrated using rotary evaporator. The mixture was puri-
fied with column chromatography (silica gel, hexane–EtOAc, 2:1)
and furnished 3 after crystallization from methanol as white crys-
tals. Yields 60–70%.
(1R,3R,4R,5S,8R)-1-(Biphenyl-4-yl)-5-isopropyl-8-methyl-3-spiro
[2.5]octan-4,5-diole (3a). Yield 70%. Mp 127–129 °C. 1H NMR,
CDCl3: d., 2H 7.595, d. 2H, 7.513, m., 2H, 7.431, m., 3H, 7.339,
c.1H, 2.943 dd.1H, 2.943, m.1H, 2.257, 2.001, m.1H, 1.793, m., 2H,
1.599, m., 4H, 1.136, m., 6H, 0.982, m, 2H 0.918, dd, 1H 0.863;
13C NMR, CDCl3: 140.896, 138.860, 137.406, 129.398, 128.694,
126.924, 126.551, 80.926, 75.210, 32.888, 31.963, 30.940, 28.115,
24.687, 24.609, 19.038, 15.854, 11.817. MS, m/z 308 (M+). Anal.
Calcd. for C24H30O2: C 82.24%, H 8.63%; found: C 82.20%, H 8.70%.
(1R,3R,4R,5S,8R)-1-(4-Bromophenyl)-5-isopropyl-8-methyl-3-spiro
[2.5]octan-4,5-diole (3b). Yield 62%. Mp 110–111 °C. 1H NMR,
CDCl3: 7.38 (d., 2H),7.66 (d., 2H Ar), 2.893 (c. 1H), 2.150 (dd.,
1H), 1.987 (sept. 1H), 1.769 (m., 1H), 1.568 (m., 2H), 1.102, (d.,
3H, m., 1H), 0.959 (d., 3H), 0.951 (d., 3H), 0.816 (m., 3H); 13C
NMR, CDCl3: 137.563, 130.921, 130.819, 119.854, 80.809, 75.257,
32.919, 31.877, 30.755, 28.259, 24.726, 24.523, 19.025, 15.821,
Protons
J (H,H), Hz
2a1
2a2
2a3
CDCl3 C6D6
DMSO-d6 CDCl3 C6D6
DMSO-d6 CDCl3
8,7a
8,7e
4.3
6.9
7.6
3.8
3.7
9.8
4.5
5.4
5.9
3.8
3.7
10.8
3.6
2.2
13.6
2.9
2.9
2.4
3.4
7.3
7.9
3.6
3.8
8.9
3.5
6.5
6.9
3.9
3.6
10.2
3.4
2.7
13.2
2.8
3.3
2.3
3.1
12.6
2.8
2.7
2.9
13.3
ꢀ13.5
ꢀ13.5
6.8
6.6
8.8
7a,6a
7a,6e
7e,6a
7e,6e
7a,7e
6a,6e
8,9(CH3)
ꢀ13.7 ꢀ13.6 ꢀ13.2
ꢀ13.9 ꢀ13.8 ꢀ13.2
ꢀ13.7 ꢀ14.4 ꢀ13.5
ꢀ14.4 ꢀ13.7 ꢀ13.2
6.8
7.0
7.1
7.0
8.7
7.2
7.0
6.8
9.2
7.4
7.0
7.0
8.9
7.2
7.0
7.0
8.8
7.0
10,11,12(CH3) 6.9
6.9
1,2cis
1,20tr
2,20
9.0
9.0
7.1
7.4
6.8
ꢀ5.4
ꢀ4.7
ꢀ4.7
ꢀ4.7
ꢀ4.6
ꢀ4.4
ꢀ4.5
60 (Merck), gradient elution benzene–ethyl acetate. Crystallization
of fractions containing additional products from absolute isopropa-
nol gave isomer 2a2 (0.167 g, 8%), Mp. 178–179 °C, MS, m/z 348
(M+). Anal. Calcd. for C24H28O2: C, 82.72; H, 8.10; found: C,
82.67; H, 8.17; ½a D20
ꢁ
ꢀ187.75° (C = 0.81 g/100 cm3, ethyl acetate)
and isomer 2a3 (21 mg, 1%). Mp 205 °C, MS, m/z 348 (M+). Anal.
Calcd. for C24H28O2: C, 82.72; H, 8.10; found: C, 82.64; H, 8.15;
½
a 2D0 124.77° (C = 0.29 g/100 cm3, ethyl acetate). NMR spectral
ꢁ
characteristics of 2a2 and 2a3 are given in Tables 1–3.
Table 3
Chemical shifts in 13C NMR spectra for compounds 2a1, 2a2, 2a3.
Compounds
1
2
3
4
5
6,7
8
9
10
Me-11,12
Aryl
2a1
2a2
2a3
30.01
29.98
29.49
19.09
18.82
12.77
38.23
39.30
37.04
213.11
212.37
209.56
78.48
79.28
79.28
26.25; 27.16
27.76; 29.23
29.49; 29.23
35.39
34.45
34.36
15.61
15.79
17.02
32.56
32.67
30.88
16.64; 17.05
16.92; 17.28
14.31; 15.49
126.9–140.71
128.78–140.65
126.64–140.85

I.M. Gella et al. / Journal of Molecular Structure 1019 (2012) 120–129
123
11.868. MS, m/z 353 (M+). Anal. Calcd. for C18H25BrO2: C 61.19%, H
7.13%, Cl 22.62; found: C 61.16%, H 7.23%, Cl 22.59%.
unique (Rint = 0.021), refinement converged at wR2 = 0.101 (all data),
R1 = 0.038 (5232 reflections with I > 2 (I)), GooF = 1.02. Crystal data
r
(1R,3R,4R,5S,8R)-1-(4-Chlorophenyl)-5-isopropyl-8-methyl-3-spiro
[2.5]octan-4,5-diole (3c). Yield 68%. Mp 127–129 °C. 1H NMR,
CDCl3: 7.227 (Ar, 4H), 2.894 (s.1H), 2.168 (dd., 1H), 1.987 (sept.,
1H), 1.77 (m., 1H) 1.571 (m., 3H), 1.110, 1.095 (d.,m., 4H), 0.96
(d., 3H)), 0.952 (d., 3H), 0.818 (m., 3H); 13C NMR, CDCl3 (HMQC):
137.015, 131.795, 130.399, 127.982, 80.833, 75.257, 32.930,
31.874, 30.688, 28.252, 24.731, 24.529, 19.017, 15.813, 11.899.
MS, m/z 308 (M+). Anal. Calcd. for C18H25ClO2: C 70.00%, H 8.16%,
Cl 11.48; found: C 69.95%, H 8.36%, Cl 11.42%.
for 2a2: orthorhombic, space group P212121, a = 6.0342(6) Å,
b = 9.6532(12) Å, c = 33.580(15) Å, V = 1956.0(9) Å3, Z = 4,
dc = 1.18 g cmꢀ1 = 0.07 mmꢀ1, 11276 reflections were measured
, l
up to 2hmax = 50.0° of which 2031 were unique (Rint = 0.094), refine-
ment converged at wR2 = 0.109 (all data), R1 = 0.060 (1226 reflec-
tions with I > 2
orthorhombic, space group P212121, a = 6.2393(3) Å, b = 9.8272(4)
Å, c = 31.0724(13) Å, V = 1905.19(13) Å3, Z = 4, dc = 1.22 g cmꢀ1
= 0.08 mmꢀ1, 8928 reflections were measured up to 2hmax = 56.3°
of which 2507 were unique (Rint = 0.036), refinement converged at
wR2 = 0.087 (all data), R1 = 0.040 (2115 reflections with I > 2 (I)),
r(I)), GooF = 1.09. Crystal data for 2a3:
,
l
r
2.2. Physical measurements
GooF = 1.04. Crystallographic data have been deposited to the Cam-
bridge Crystallographic Data Center, deposition numbers are CCDC
854981–854983.
The 1H, 13C and 1H–13C correlation (2D COSY, NOESY and
HMQC) NMR spectra were obtained on a Varian Mercury 400
NMR spectrometer and Bruker AVANCE DRX 500 spectrometer.
The 1H chemical shifts were referred to SiMe4 as an internal stan-
dard. For 13C NMR spectra at 125 MHz CDCl3 was used both as a
solvent and the internal standard.
The high-pressure liquid chromatography (HPLC) analyses were
carried out using a Bischoff system, reversed-phase Prontosil 120-
3-C18–H column, UV detector, eluent acetonitrile–water 78:22 and
direct phase Prontosil 120-3-Si column, eluent 1.5% BuOAc in
heptane.
3. Results and discussion
3.1. Structures of the byproducts in cyclopropanation (Corey–
Chaykovsky) reaction
When we carried Corey–Chaykovsky reaction with (3R,6R)-3-
methyl-6-isopropylcyclohexanone (isomenthone) 2-arylidene
derivatives in NaOH/DMSO and NaOH/DMF systems with oxygen
admission, we detected more polar byproducts with chromatogra-
phy (HPLC, TLC) (Fig. 2).
Elemental analyses were carried out using Element Analyzer
EA-3000 (Eurovector, Italy).
The isolation of these byproducts with column chromatography
gave three stereoisomers, 1-aryl-5-hydroxy-5-isopropyl-8-methyl-
3-spiro-[2,5]octan-4-ones with (1R,3R,5S,8R), (1R,3S,5S,8R) and
(1S,3S,5S,8R) configurations. This hydroxylation was noticeably
slower than cyclopropanation, and a hydroxylation rate essentially
diminished when cyclopropanation was realized in inert
atmosphere.
FAB-mass-spectrometric analyses were performed in the liquid
matrix of the m-nitrobenzyl alcohol using a magnetic sector mass
spectrometer MI-1201E equipped with primary FAB ion source for
generating a bombarding beam of argon atoms. The region of
molecular ion is represented by ion-radical M+ and protonated
molecular ion [MH]+.
The specific optical rotation
measured using the Perkin Elmer-343 polarimeter and ethyl
acetate as a solvent.
½
a 2D0
for stereoisomers was
ꢁ
ꢂ When we put (1R,5R,8R,3R)-1-aryl-5-isopropyl-8-methyl-3-
spiro-[2,5]octan-4-ones 1 (the predominant products of cyclo-
propanation) to oxidation with atmospheric oxygen, we
obtained exclusively (1R,5S,8R,3R)-1-aryl-5-hydroxy-5-isopro-
pyl-8-methyl-3-spiro-[2,5]octan-4-ones 2.
Single crystals for X-ray diffraction study were grown from ethyl
acetate (isomer (2a1) and isopropyl alcohol (2a2 and 2a3). Diffrac-
tion data were collected on an ‘‘Xcalibur 3’’ diffractometer (graphite
monochromated MoKa, x scans) at room temperature for 2a1 and
2a2, and at 100 K for 2a3. Structures were solved by direct method
a refined against F2 in anisotropic approximation for all non-hydro-
gen atoms using SHELX-97 software [29]. Hydrogen atoms were re-
fined using ‘‘riding’’ model with Uiso = nUeq of parent atom (n = 1.5
for CH3 and OH, n = 1.2 for remaining H = atoms). As long as struc-
tures do not contain anomalously scattering atoms, Friedel equiva-
lents were merged. Crystal data for 2a1: orthorhombic, space group
P212121, a = 16.7112(3) Å, b = 17.1736(3) Å, c = 20.9216(4) Å,
3.1.1. NMR study of the 2a–2e compounds
The structures of obtained compounds 2 were proved with 1H
NMR and 13C NMR (Tables 1–3) and signal attributions have been
made on the base of their chemical shifts, scalar coupling constants
and 1H and 13C homo and heteronuclear correlation spectra
(HMQC, HMBC, COSY-45 and NOESY). Although the main products
of the oxidative hydroxylation reaction were products 2a1–2e, we
also studied isomers of 2a1 (2a2 and 2a3) to exclude errors in the
structure proving.
V = 6004.33(19) Å3, Z = 12, dc = 1.16 g cmꢀ1 = 0.07 mmꢀ1, 26166
, l
reflections were measured up to 2hmax = 55.5° of which 7011 were
OH
Ph
OH
OH
(S)
(S)
(S)
(R)
(S)
(S)
O
O
O
O
O
-
Me2S+(O)CH2
[O]
+
+
(S)
(R)
(R)
(R)
(R)
(R)
2a3
Ph
Ph
2a2
Ph
Ph
1a
2a1
PBC
Fig. 2. Isomers obtained by means of Corey–Chaykovsky reaction.

124
I.M. Gella et al. / Journal of Molecular Structure 1019 (2012) 120–129
Table 4
Correlations in 2D NMR for compound 2a1.
d, ppm
HMQC
HMBC
COSY
NOESY
7.59
7.53
7.43
7.34
7.30
2.85
2.28
2.13
1.87
1.76
1.70
1.61
1.40
1.31
0.91
0.87
0.75
127.2
127.1
129.0
127.5
130.1
35.6
32.6
27.3
26.6
27.3
16.9
30.2
26.6
16.9
17.3
15.8
19.3
139.9; 127.5
140.9; 136.1; 130.1; 127.1
140.9; 129.0
7.43
7.30
7.59; 7.34
7.43
7.53
1.70; 1.31
0.91; 0.87
1.87; 1.76; 1.40
2.13; 1.61; 1.40
2.13; 1.40
2.85; 1.31
1.87; 0.75
2.13; 1.87; 1.76
2.85; 1.70
2.28
127.1
139.9; 130.1; 127.1; 35.5
213.3; 130.1; 38.4; 16.9
27.3; 17.3; 15.8; 78.7
32.8; 30.2; 26.6; 78.7; 213.3
38.4; 30.2; 27.3; 19.3; 78.7
32.8; 30.2; 26.6; 213.3
38.4; 35.6; 30.2; 136.1; 213.3
38.4; 35.6; 27.3; 19.5; 213.3
38.4; 30.2; 78.7
2.85; 1.87; 1.61; 1.31; 0.75
1.70; 1.31; 7.30
0.91; 0.87; 1.40
1.87; 1.76; 1.40; 0.91; 0.75
2.13; 1.61; 1.40
2.13; 0.87; 1.40
2.87; 1.31
1.87; 1.40; 0.75
2.28; 2.13; 1.87; 0.91; 0.75
7.30; 1.75; 0.75
2.28; 2.13; 1.40
38.4; 35.6; 30.2; 136.1; 213.3
30.2; 15.8; 78.7
32.7; 17.3; 78.7
2.28
1.61
2.28; 1.76
2.13; 1.87; 1.61; 1.40; 1.31
38.4; 30.2; 26.6
Table 5
Correlations in 2D NMR for compound 2a2.
d, ppm
HMQC
HMBC
COSY
NOESY
7.59
7.53
7.44
7.34
2.80
2.50
2.23
2.02
1.75
1.66
1.51
1.00
0.89
0.43
127.1
127.0
129.0
129.7; 127.5
30.2
32.8
29.5
28.0; 34.7
29.5
28.0; 18.9
19.9
139.7; 127.5
140.8; 136.6; 129.7; 127.0
140.8; 129.0
139.7; 129.7; 127.1; 30.2
39.5; 18.9; 129.7; 212.7
29.5; 17.1; 16.0; 79.4; 212.7
34.6; 79.4; 212.7
7.44
7.34
7.60; 7.34
7.53; 7.44
1.66; 1.51
1.00; 0.89
2.02; 1.75;
2.23; 1.75; 1.66; 0.43
2.23; 1.66; 0.43
2.80; 2.02; 1.51
2.80; 1.66
2.50
1.51; 2.02; 2.80
1.66; 1.51
1.00; 0.89
1.75; 2.02; 1.00; 0.43
2.23; 1.75; 1.66; 0.43
2.23; 2.02
39.5; 29.5; 17.1
34.7; 32.8; 28.0; 79.4
39.5; 34.7; 29.5; 136.6; 212.7
39.5; 34.7; 30.1; 136.6; 212.7
32.8; 17.1; 79.4
32.8; 16.0; 79.4
39.5; 34.6; 28.0
2.80; 2.02; 1.51; 0.44
17.1
16.0
17.5
2.50; 2.23
2.50; 0.43
2.23; 2.02; 1.66; 1.51; 0.89
2.50
2.02
The isomeric structures of compounds 2a1–2a3 follow from the
analysis of spectral parameters for protons above. 1H NMR spectra
of compounds 2a1–2a3 contain proton signals of all their struc-
tural fragments. Cyclic methylene protons C8H, C7H0a, C7H0b,
C6H0a, C6H0b form five-spin system and become apparent as multi-
plets in 1.629–2.286 ppm region. Protons of biphenyl fragment
were found as multiplets at 7.26–7.62 ppm. It is visible and regular
that signals of cyclopropane protons of isomers 2a1–2a3 are differ-
ent in chemical shift values. Such differences are connected with
the influence of carbonyl position against cyclopropane protons
at their chemical shifts, owing to deshielding. In the same time
the position of biphenyl substituent in a cyclopropane ring is
important for chemical shift values of the methyl groups and, to
a lesser degree, for shielding of other protons.
Assignment for peaks was made also by the use of combined
analysis of correlations in HMQC, HMBC, COSY and NOESY experi-
ments (Tables 4 and 5, Figs. 3 and 4). So, proton signals of two
methyl groups in molecules of 2a1 have correlations HMBC with
carbon atom of neighboring CH group that absorb at 32.6 ppm.
That atom has
a HMQC correlation with proton signal at
2.28 ppm. So, proton at 2.28 ppm and 13C at 32.6 ppm bound with
chemical bond. This fact gives the assignment for signals of 1H and
13C in isopropyl group. All protons in isopropyl have HMBC corre-
lations with quaternary carbon at 78.7 ppm. So that atom is carbon
C5 in cyclohexanone ring bound with hydroxyl group.
The presence of correlation in COSY experiment for the methyl
(chemical shift 0.75 ppm) with signal at 1.61 ppm allows assign
this signal to H8. Signal at 1.87 ppm correlates in COSY with proton
H8 that permits assign this signal to axial proton in neighboring
methylene group. HMQC correlation between this signal and 13C
with chemical shift of 26.6 ppm proves this assignment also. Sim-
ilar reasoning may be used for 1H and 13C assignments in aromatic
ring and for other compounds.
For the identification of proton and methyl orientations at C-8
in cyclohexanone ring we used homonuclear decoupling experi-
ments with suppression of the signal of methyl substituent at
C-8 (to find necessary vicinal 1H–1H coupling constants). There
were some problems with solvent selection as we needed solution
where H–C8 signal would be separated. For 2a1 satisfying solvent
was benzene-d6 but for 2a2 it was DMSO-d6. The results are given
in Figs. 5 and 6.
Signals of almost all the protons in the 1H NMR spectra of
compounds 2a1–2a3 in DMSO-d6 are separated. Multiplets of all
protons of cyclohexane ring are similar to the same of their arylidene
precursors [30] that allows to suppose negligible changes in spatial
structure of that part of molecule. Signals of three protons in cyclo-
propane ring form three spin system and are solved because of its
typical multiplicity. Using of cross-peaks in 2D NMR spectroscopy
(COSY-45 and HQMC) and simulation of spin systems (with NUTs
program [31]) for protons of cyclohexanone and cyclopropane rings
has allowed complete solving of all proton multiplets. Obtained 1H
NMR parameters (chemical shifts, d, and coupling constants, J) for
compounds 2a1–2a3 are given in Tables 1 and 2. Chemical shifts
in 13C NMR spectra for compounds 2a1–2a3 are given in Table 3.

I.M. Gella et al. / Journal of Molecular Structure 1019 (2012) 120–129
125
7,34
7,44
(a) COSY
(a) COSY
ax
1,87
eq
1,40
ax
ax
0,75
2,13
CH3
2,23
7,34
1,75
eq
0,43
CH3
1,61
eq
1,31
2,02
HO
1,76
7,59
2,02
2,28
(CH3)2CH
0,87
1,66
7,53
7,43
1,70
2,50
(CH3)2CH
7,34
2,80
7,59
0,91
7,53
0,89
1,00
HO
2,55
7,30
2,85
O
1,51
1,66
O
(b) HMBC
7,34
127,5
ax
1,87
(b) HMBC
eq
129,0
ax
1,40
0,75
ax
2,13
7,44
CH3
140,8
2,23
127,5
7,34
eq
1,75
1,61
eq
127,1
7,59
0,43
26,6
1,76
2,02
15,8
139,7
127,0
CH3
1,31
140,9
30,2
27,3
129,0
7,43
2,28
17,3
2,02
136,6
35,6
1,66
16,0
29,5
(CH3)2CH
139,9
127,1
127,2
7,59
1,70
136,1
7,53
78,7
28,0
34,7
32,6
0,87
0,91
38,4
17,1
2,50
129,7
7,34
30,2
130,1
7,30
16,9
2,85
(CH3)2CH
213,3
7,53
39,5
79,4
2,80
HO
2,55
0,89
1,00
32,8
212,7
O
O
18,9 1,51
1,66
HO
(c) NOESY
ax
7,34
ax
eq
1,40
(c) NOESY
1,87
ax
0,75
2,13
CH3
7,34
7,44
eq
1,76
1,61
2,23
1,75
eq
0,43
CH3
2,02
1,31
1,70
2,28
(CH3)2CH
7,59
7,43
2,02
1,66
2,50
7,53
0,87 32,6
0,91
7,59
7,53
7,34
2,80
1,51
HO
2,55
(CH3)2CH
7,30
2,85
O
0,89
1,00
HO
Fig. 3. The main correlations in NMR experiments for compound 2a1 used in
assignments for signals.
1,66
O
Fig. 4. The main correlations in NMR experiments for compound 2a2 used in
assignments for signals.
As could be seen in Figs. 5 and 6 that in both cases proton H–C8
signal changes into triplet with vicinal coupling constants near
4 Hz. Equality of coupling constants of H–C8 with neighboring
methylene protons evidences proximity of corresponding dihedral
angles, and therefore equatorial orientation of H–C8 in both com-
pounds 2a1 and 2a2 in solutions. Similar analysis gives the same
orientation of methyl substituent in products 2b–e also.
NOESY experiments were useful for determination of biphenyl
substituent orientation. The most important correlations there
were cross-peaks between signals of aromatic protons and H–C8
ones (in cyclohexanone ring). Such correlations are in NOESY for
compounds 2a1 and 2a2. It indicates similar orientation of biphe-
nyl substituent relative to protons in cyclohexanone fragment
(Figs. 3 and 4). Downfield shift of the methyl substitute at C8 in
compound 2a2 in comparison with 2a1 takes place because of its
nearer disposition to nearby benzene ring in biphenyle and corre-
sponding shielding.
biphenyl groups. The upfield shift of isopropyl protons and inver-
sion of shifts of methylene protons in the cyclopropane ring adjust
with these facts. Also, in NOESY maximal interaction was observed
between 8-methyl group protons and cyclopropane proton H-1
(2.88 ppm) that demonstrates their approach. Molecular models
analysis (MOPAC, PM6 [32]) proves that geometry corresponds to
1(S),3(S)-configuration of cyclopropane fragment. Therefore, com-
pound 2a3 was formed as the result of rotation around C–C bond
in intermediate betaine in the cyclopropanation reaction, with fol-
lowing hydroxylation.
3.1.2. X-ray diffraction study
The structures of compounds 2a1, 2a2 and 2a3 as determined
by X-ray crystallography are shown in Figs. 7 and 8. All three com-
pounds crystallize in chiral P212121 space group. The structures do
not contain anomalously scattering atoms, which disallowed us to
determine absolute configuration directly from diffraction data.
Instead, absolute configuration was chosen as shown in Fig. 7.
The cyclohexane ring in molecules 2a1, 2a2 and 2a3 adopts
slightly deformed chair conformation with Zefirov-Palyulin [33]
puckering amplitude S of 0.93–1.03 and puckering angle h of
6.8–16.8°, whereas h should be zero for ideal chair conformation.
The signal of axial Me at C-8 in 2a2 compound is shifted at
0.32 ppm to high field as compared with 2a1. Such a shift may be
a result of a shielding from biphenyl group that is the only possible
if the cyclopropane fragment has (1R,3S)-configuration. Therefore
compound 2a2 is the result of hydroxylation not for a spiro product
1a but for its isomer obtained from a cyclopropanation of (3R,6R)-3-
methyl-6-isopropyl-2-(4-phenyl)benzylidenecyclohexanone (PBC)
through dimethyloxosulfonium methylide attack on enone system
from side opposite to axial 3R-methyl group.
ꢂ There are three symmetry unique molecules A–C in the crystal
structure of 2a1 (Fig. 7).
The doublet at ꢀ0.47 ppm in 1H NMR of compound 2a3 is at-
tached to methyl group of isopropyl radical with correlation spec-
tra 1H COSY that is possible only for cis-orientation of carbonyl and
Molecules A and B have similar conformation, which differs
only by orientation of the hydrogen atom of the hydroxy group
which is involved in intermolecular hydrogen bond. The molecule

126
I.M. Gella et al. / Journal of Molecular Structure 1019 (2012) 120–129
1.95
1.90
1.85
1.80
1.75
1.70
1.65
1.60
1.55
1.95
1.90
1.85
1.80
1.75
1.70
1.65
1.60
1.55
1.50
Fig. 5. Decoupling experiment with the suppression of methyl substituent at C-8 signal for compound 2a1 (solution in benzene-d6).
1.90
1.85
1.80
1.75
1.70
1.65
1.60
1.55
1.50
1.45
1.40
1.90
1.85
1.80
1.75
1.70
1.65
1.60
1.55
1.50
1.45
1.40
1.3
Fig. 6. Decoupling experiment with the suppression of methyl substituent at C-8 signal for compound 2a2 (solution in DMSO-d6).
C shows inverted conformation of cyclohexane ring. The hydroxy
and methyl substituents have axial orientation in molecules A
and B, and equatorial in molecule C (corresponding torsion angles:
C2–C1–C6–O2 86.7(2)° (A), 87.3(2)° (B), 170.16(19)° (C) and C1–
C2–C3–C7 83.2(3)° (A), 78.0(3)° (B), 163.9(2)° (C)). The isopropyl
substituent and methylene group of cyclopropane ring have equa-
torial orientation in molecules A and B, and axial in C (C2-C1-C6-
C8–154.5(2)° (A), ꢀ158.2(2)° (B), ꢀ72.7(3)° (C); C6–C1–C2–C12
179.6(2)° (A), ꢀ175.86(19)° (B), 104.6(2)° (C)). The molecules A, B
and C form hydrogen-bonded trimers (Fig. 7d, O2a–Hꢃ ꢃ ꢃO2b:
Hꢃ ꢃ ꢃO 1.99 E, O–Hꢃ ꢃ ꢃO 171°; O2b–Hꢃ ꢃ ꢃO1c: Hꢃ ꢃ ꢃO 2.07 E, O–Hꢃ ꢃ ꢃO
147°; O2c–Hꢃ ꢃ ꢃO1a: Hꢃ ꢃ ꢃO 2.17 E, O–Hꢃ ꢃ ꢃO 169°). Most probably,
intermolecular hydrogen bonds are the driving force for conforma-
tional isomerism observed in the crystal of 2a1.
inverted conformation of the cyclohexane ring like molecule C in
the crystal 2a1. In the molecule 2a2 hydroxy, methyl substituents
and methylene group of the cyclopropane ring have equatorial
conformation, isopropyl substituent have axial conformation, and
vice versa in 2a3 (corresponding torsion angles: C2–C1–C6–O2
162.3(3)° (2a2), 71.3(2)° (2a3); C1–C2–C3–C7 167.4(3)° (2a2),
76.5(2)° (2a3); C6–C1–C2–C12 176.1(3)° (2a2), ꢀ97.7(2)° (2a3);
C2-C1-C6-C8–78.3(4)° (2a2), ꢀ170.27(18)° (2a3)). In crystal mole-
cules 2a3 linked into zig-zag chains along (1 0 0) crystallographic
direction by intermolecular hydrogen bonds O2–Hꢃ ꢃ ꢃO1i [i:
ꢀS + x, S ꢀ y, ꢀz] (Hꢃ ꢃ ꢃO 2.03 E, O–Hꢃ ꢃ ꢃO 173°). In 2a2 hydroxy
group is involved into weak intermolecular hydrogen O2–Hꢃ ꢃ ꢃO1
(Hꢃ ꢃ ꢃO 2.16 E, O–Hꢃ ꢃ ꢃO 116°), thus no intermolecular hydrogen
bonds are formed in this crystal.
The molecules 2a2 and 2a3 have the same absolute configura-
tion of the cyclohexane ring atoms and differ only by configuration
of the C11 atom (Fig. 8). However, these two molecules also show
The trans-orientation of the biphenyl group with respect to the
carbonyl as could be seen both in Figs. 7a and 8a, but the biphenyl
group is in the cis-disposition relatively to methyl substituent in

I.M. Gella et al. / Journal of Molecular Structure 1019 (2012) 120–129
127
Fig. 8. Molecular structures for compounds 2a2 (a) and 2a3 (b) according to X-ray
diffraction study. Thermal ellipsoids are shown at 30% for 2a2 and 50% for 2a3
probability levels.
mixing an enolizable ketone in DMSO or DMF with powdered so-
dium hydroxide at room temperature till initial reagents disappear
(control with TLC). However for the hydroxylation reaction access
of oxygen is necessary whereas in the cyclopropanation reaction by
Corey–Chaykovsky oxygen does not take part. Also the cycloprop-
anation of 1a–e proceeds noticeably faster than hydroxylation
(20 min – 1 h for the first and 6–48 h for the last).
The hydroxylation of 1a and 1c–e both in DMF and DMSO gave
the only hydroxy ketones 2, but when hydroxylation of 1b was car-
ried in DMF we separate from reaction mixture two products, hy-
droxy ketone 2b and other product, 20b, different in melt points
(correspondingly 135–137 °C and 158–160 °C).
Peaks corresponding to hydroxyl removal (m/z 333/335) and
maximal peak was with m/z 307/309 (isopropyl removal for hy-
drated 2b) were detected in mass spectrum of 20b. The signal at
5.21 ppm (hydroxyl) was observed in 1H NMR spectrum of 2b (in
1
DMSO-d6) but it was absent in H NMR spectrum of product 20b.
However the signal at 11.18 ppm was observed for 20b that corre-
sponds to published values of chemical shift for hydroperoxy group
(near 10.3 ppm) [34,35]. It should be noted that we have found few
solved NMR data of hydroperoxides in literature, especially about
chemical shift of hydrogen in hydroperoxy group.
Fig. 7. Molecular structure of three symmetry unique molecules of 2a1 according to
X-ray diffraction study (a–c), with thermal ellipsoids at 30% probability level, and
asymmetric part of the unit cell showing hydrogen-bonded trimer (d).
Electron-withdrawing carbonyl group in
a-position to HOO
group makes a significant low field shift in our case. This fact
agrees with weak field shift of C-5 signal in 13C NMR from
78.519 ppm for 2b to 88.011 ppm for 20b. Maximal peak in MS
for 20b corresponding to removal of hydroperoxide (m/z 333/
335). The hydroperoxide formation unambiguously confirms that
the hydroxylation of enolates of 1a–e proceeds with dioxygen by
the way of intermediate hydroperoxide formation and its subse-
quent decomposition to tertiary hydroxy ketones. In other cases
peaks corresponding for hydroperoxides were detected by HPLC
but we could not separate relevant substances over their instability
at room temperature. The only enantiomerically pure tertiary
hydroxy ketones 2a1 and 2c–e were obtained. Probably, hydroper-
oxide 20b could be regarded as homochiral (enantiomerically pure)
since it transforms to enantiomerically pure hydroxy ketone
without additional chiral reagents. The only stereoisomer of this
the cyclohexanone ring. Thus, 2a2 is the trans–cis isomer with
respect to carbonyl and methyl groups in the cyclohexanone ring
correspondingly. The torsion angles determined show the molecu-
lar conformation in crystal of isomer 2a3 is chair with an equatorial
methyl and hydroxyl groups and axial isopropyl one. Like to NMR
analysis, this fact confirms that compound 2a3 is the cis–cis isomer
and it was formed as the result of rotation in intermediate beta-
ine in the previous cyclopropanation reaction, with following
hydroxylation.
3.1.3. The peculiarities and mechanism of oxidative hydroxylation
reaction
The hydroxylation of compounds 1a–e obtained previously was
carried in much the same way as the cyclopropanation reaction, by

128
I.M. Gella et al. / Journal of Molecular Structure 1019 (2012) 120–129
compound was detected in 1H NMR spectra and by HPLC. Corre-
sponding peaks for other analogs 20were detected by HPLC in reac-
tion mixtures, but we could not separate relevant substances
because of their instability at room temperature. So, hydroxylation
runs stereospecifically as the result of dioxygen axial attack on the
corresponding enolate with following decomposition of intermedi-
ate hydroperoxide. This action does not affect the C-5 configura-
tion. We can conclude that
carbonyl group, the (4R,5S)-dioles 3a–e formation in the reduction
of 2a1–e verifies their configuration at C-5.
The similar orienting axial hydroxyl effect was observed in the
reduction of tertiary
a-hydroxycyclohexanones [38,39] and
b-hydroxycarbonyl compounds [40].
4. Conclusions
We have found
ꢂ the ratio of stereoisomeric hydroxy ketones in the Corey–Chay-
kovsky reaction for 2-arylideneisomenthones with dim-
ethyloxosulfonium methylide in DMSO (DMF)/NaOH system
corresponds to the ratio of stereoisomeric spirooctanones.
ꢂ stereoselective oxidative alpha hydroxylation of (1R,5R,8R,3R)-
1-aryl-5-isopropyl-8-methyl-3-spiro-[2,5]octan-4-ones in
DMSO/NaOH (or DMF/NaOH) system to (1R,5S,8R,3R)-1-aryl-5-
isopropyl-5-hydroxy-8-methyl-3-spiro[2.5]octan-4-ones. We
have isolated three stereoisomeric hydroxyketones from a reac-
tion mixture of cyclopropanation reaction. But when reaction of
oxidation was carried out with isolated spiro-[2,5]octan-4-ones,
it was stereoselective. We have separated the intermediate
hydroperoxide that is argument of reaction mechanism as oxy-
We also quantify hydroperoxides in reaction mixtures of
hydroxylation like to [36] and found approximately 10% of hydro-
peroxides when conversion of initial spiro compounds 1 was 75–
85 % as the proof of proposed mechanism of hydroxylation.
ꢂ We have not found any traces of dimethylsulphide in reaction
mixtures with GC–MS, so DMSO was not oxidizing agent in
hydroxylation process.
gen addition in a-position.
ꢂ The reaction has been studied runs at room temperature and
does not need in expensive catalysts. We confirmed that
ꢂ
a-hydroxylated cyclohexanones with axial OH group in the
Apparently, this oxidation of spiroketones 1 is similar to ke-
tones and esters auto oxidation with dioxygen in a strong base
reaction of reduction with NaBH4 stereoselectively produce
trans-(4R,5S)-dioles similarly to known processes [37,38].
Thereby spirocycle even with bulky spatial substitute do not
affect stereochemistry of reduction with NaBH4.
media [37] that gives the formation of
by -hydroxy compounds formation. It should be noted that we
obtain nonenolisable -hydroxy ketones 2 with quite good yield
although -hydroxy ketones may be unstable due to various isom-
a-hydroperoxy, followed
a
a
a
Acknowledgements
erization and disproportion processes, for example, formation of
enols or hemiacetals followed by reactions of these products.
Authors thank National Academy of Science of Ukraine for the
financial support.
Also we are very appreciating to James J.P. Stewart (Stewart
Computational Chemistry) for kind accordance of MOPAC2009
using.
3.1.4. The reduction of hydroxy ketones with sodium borohydride
We also studied 2a–e compounds reduction with sodium boro-
hydride in isopropanol. The result of such reduction was exclu-
sively formation of trans-(4R,5S)-dioles 3a–e (Fig. 9).
Such conclusion has been made from NMR analysis. In 1H NMR
spectra of 3a–e in DMSO-d6 signals of two hydroxyl groups were
observed and an additional proton singlet was near 2.8 ppm (C-
4). NOE measurements demonstrated strong coupling for protons
at C-4 and C-1 (near 24%). Molecular modeling (MOPAC, PM6
[32]) showed that such effect is possible only for trans-4,5-dioles
with equatorial proton orientation at C-4. Cis-4,5-diole conformer
with inverted cyclohexane cycle, with axial isopropyl group and
equatorial methyl at C-8, may be considered as alternative. How-
ever results of calculations favors the trans conformer by
4.5 kcal/mol. In cis-conformer in the most favorable conformation
axial proton at C-9 would be the closest to H-4 (2.5 Å) but in exper-
imental NOE spectra such interactions were absent.
References
[1] E.J. Corey, M. Chaykovsky, J. Am. Chem. Soc. 8 (1962) 867;
B.V. Trost, L.S. Melvin, Sulfur Ylides, Emerging Synthetic Intermediates,
Academic Press, New York, 1975;
J.J. Li, Name Reactions: A Collection of Detailed Reaction Mechanisms, third ed.,
Springer, Berlin–Heidelberg–New York, 2006.
[2] B.M. Trost, I. Fleming, Comprehensive Organic Synthesis, vol. 8, Pergamon
Press, Elsevier Ltd., Oxford, UK, 2005.
[3] Yu.G. Gololobov, A.N. Nesmeyanov, L.P. Lysenko, I.E. Boldeskul, Tetrahedron 43
(1987) 2609.
[4] A.-H. Li, L.-X. Dai, V.K. Aggarwal, Chem. Rev. 97 (1997) 2341.
[5] R.J. Paxton, R.J.K. Taylor, Synlett (2007) 633.
[6] R. Robiette, J. Marchan-Brynaert, Synlett (2008) 517.
[7] M.G. Edwards, R.J. Paxton, D.S. Pugh, A.C. Whitwood, R.J.K. Taylor, Synthesis
(2008) 3279.
Because of the reaction direction for reduction with borohy-
dride is determined with orienting influence of axial hydroxyl at
C-5 that provide an intramolecular delivery of the hydride ion to
[8] I.M. Gella, N.S. Pivnenko, L.A. Kutulya, T.G. Drushlyak, A.Yu. Kulikov, N.B.
Novikova, Russ. Chem. Bull. 54 (2005) 2406.
[9] F.A. Davis, B.-C. Chen, Chem. Rev. 92 (1992) 919.
[10] F.F. Wong, P.-W. Chang, H.-Ch. Lin, B.-J. You, J.-J. Huang, Sh.-K. Lin, J.
Organomet. Chem. 694 (2009) 3452.
[11] C.A. Horiuchi, A. Takeda, W. Chai, K. Ohwada, S.-J. Ji, T.T. Takahashi,
Tetrahedron Lett. 44 (2003) 9307;
T. Tanaka, M. Kawase, S. Tani, Bioorg. Med. Chem. Lett. 12 (2004) 501.
[12] G.M. Rubottom, M.A. Vazquez, D.R. Pelegrina, Tetrahedron Lett. 49–50 (1974)
4319;
R. Myers, in: R.E. Krebs (Series Ed.), The Basics of Chemistry (Basics of the Hard
Sciences), Greenwood Press, Westport, Connecticut–London, 2003.
[13] V. Karnojitzky, Russ. Chem. Rev. (Engl. Transl.) 50 (1981) 888;
Jan-Erling Blckvall (Ed.), Modern Oxidation Methods, Wiley-VCH Verlag
GmbH@Co, KGaA, Weinheim, 2004.
NaBH4
[O]
Ar
Ar
O
Ar
O
OH
O
O
H
B
H
2a-e
1a-e
OH
[14] M.P. Gore, J.C. Vederas, J. Org. Chem. 51 (1986) 3700.
[15] E. Vedejs, J.E. Telschow, J. Org. Chem. 41 (1976) 740.
[16] J.P. McCormick, W. Tomasik, M.W. Johnson, Tetrahedron Lett. 22 (1981)
607.
Ar
OH
3a-e
[17] Y. Horiguchi, E. Nakamura, I. Kuwajima, Tetrahedron Lett. 30 (1989) 3323.
[18] B. Plietker, Tetrahedron: Asymmetry 16 (2005) 3453.
Fig. 9. Stereoselective formation of trans-4(R),5(S)-dioles 3a–e.

I.M. Gella et al. / Journal of Molecular Structure 1019 (2012) 120–129
129
[19] H. Wang, Y.W. Andemichael, F.G. Vogt, J. Org. Chem. 74 (2009) 478;
V. Farina, J.T. Reeves, Ch.H. Senanayake, J.J. Song, Chem. Rev. 106 (2006) 2734.
[20] T. Cuvigny, G. Valette, M. Larcheveque, H. Normant, J. Organomet. Chem. 155
(1978) 147.
[30] N.S. Pivnenko, T.G. Drushlyak, L.A. Kutulya, V.V. Vashchenko, A.O. Doroshenko,
J.W. Goodby, Magn. Reson. Chem. 40 (2002) 566.
[31] NUTS, NMR Data Processing Software for Microsoft Windows, Acorn NMR Inc.,
2009.
[21] S.I. Murahashi, T. Saito, H. Hanaoka, Y. Murakami, T. Naota, H. Kumobayashi, S.
Akutagawa, J. Org. Chem. 58 (1993) 2929.
[32] James J.P. Stewart, MOPAC2009, Stewart Computational Chemistry, Version
10.153W. <http://OpenMOPAC.net>.
[22] Cs. Paizs, M. Tosë, C. Majdik, V. Bydai, L. Nov,k, F.-D. Irimie, L. Poppe, J. Chem.
Soc. Perkin Trans. 1 (2002) 2400.
[23] J.N. Gardner, F.E. Carlon, O. Gnoj, J. Org. Chem. 33 (1968) 3294.
[24] E.J. Bailey, D.H.R. Barton, J. Elks, J.F. Templeton, J. Chem. Soc. (1962) 1578.
[25] D.M. Floyd, R.V. Moquin, K.S. Atwal, S.Z. Ahmed, S.H. Spergel, J.Z. Gougoutas,
M.F. Malley, J. Org. Chem. 55 (1990) 5572.
[26] M. Engqvist, Doctoral Dissertation, Stockholm University, 2005.
[27] A. Cyrdova, H. Sundqn, A. Bigevig, M. Johansson, F. Himo, Chem. Eur. J. 10
(2004) 3673.
[33] N.S. Zefirov, V.A. Palyulin, E.E. Dashevskaya, Stereochemical studies. XXXIV.
Quantitative description of ring puckering via torsional angles. The case of six-
membered rings, J. Phys. Org. Chem. 3 (1990) C147–C154.
[34] J.-C. Brunie, M. Costantini, N. Crenne and M. Jouffret, United States Patent
3726,916, 04/10/1973.
[35] R.K. Haynes, S.C. Vonwiller, United States Patent 5420,299, 05/30/1995.
[36] N.D. Cheronis, T.S. Ma, Organic Functional Group Analysis by Micro and
Semimicro Methods, Interscience Publishers, Advision of J. Wiley and Sons,
Inc., New York–London–Sydney, 1964.
[28] V. Vashchenko, L. Kutulya, A. Krivoshey, Synthesis 14 (2007) 2125.
[29] G.M. Sheldrick, SHELXTL PLUS, PC Version, A System of Computer Programs for
the Determination of Crystal Structure from X-ray Diffraction Data, Rev.5.1,
1998.
[37] H.R. Gersmann, A.F. Bickel, J. Chem. Soc. B (1971) 2230.
[38] Y. Senda, N. Kikuchi, A. Inui, H. Itoh, Bull. Chem. Soc. Jpn. 73 (2000) 237.
[39] D.A. Evans, K.T. Chapman, E.M. Carreira, J. Am. Chem. Soc. 110 (1988) 3560.
[40] Y. Senda, Chirality 14 (2002) 110.