On the unexpected stereochemical outcome of the magnesium in methanol - Conjugate reduction of an exocyclic α,β-unsaturated ester

Article abstract of DOI:10.1002/(sici)1099-0690(199908)1999:8<1803::aid-ejoc1803>3.0.co;2-l

The conjugate reduction of the exocyclic α,β-unsaturated ester 9 with magnesium in methanol gives a mixture of diastereoisomers containing predominantly the less stable 10a. Eventual structural identification rests on the X-ray diffraction analysis of tosylate 18.

Full text of DOI:10.1002/(sici)1099-0690(199908)1999:8<1803::aid-ejoc1803>3.0.co;2-l

FULL PAPER
On the Unexpected Stereochemical Outcome of the Magnesium in Methanol ؊
Conjugate Reduction of an Exocyclic ␣,β-Unsaturated Ester
[a]
[a]
[a]
[a]
¨
Stefan Gabriels, Dirk Van Haver, Maurits Vandewalle, Pierre De Clercq,*
and Davide Viterbo[b]
Keywords: Magnesium–methanol reduction / Reductions / α,β-Unsaturated esters / Stereoselectivity / (R)-(–)-Carvone /
Analogs of 1α,25-(OH)2-vitamin D3 / Steroids
The conjugate reduction of the exocyclic α,β-unsaturated
ester 9 with magnesium in methanol gives a mixture of
diastereoisomers containing predominantly the less stable
10a. Eventual structural identification rests on the X-ray
diffraction analysis of tosylate 18.
Next to its role in calcium homeostasis, the secosteroid are characterized by profound structural modifications in
hormone 1α,25-dihydroxyvitamin D3 (1), the physiologi- the central part.[5]
cally active form of vitamin D3, has been shown to induce
cellular differentiation and to inhibit cellular prolifer-
ation.[1] Its therapeutic utility in the treatment of certain
cancers and skin diseases is, however, limited because effec-
tive doses provoke hypercalcemia. As a consequence in re-
cent years analogs of vitamin D that would possess a high
cell differentiating ability but a low calcemic activity have
been actively sought.[2]
In the context of structure-function relationship it has
become clear from several studies that the relative orien-
tation of the side chain is important.[6] In this respect the
natural hormone 1 and its (20S)-epimer 2 are of particular
interest since the latter has been shown to be more efficient
than 1 in the inhibition of cellular proliferation and induc-
tion of cell differentiation.[7] A representation of the confor-
mational behaviour of the side chain of both derivatives is
shown in Figure 1. In this approach force field calculations
In a first approximation the structure of 1 consists of
a central rigid hydrophobic CD-ring system to which are
are performed so as to generate within a given energy win-
dow all possible local minimum energy conformations that
connected two flexible moieties, the side chain at C17 and
the side chain may adopt; the orientation in space is further
the seco-B,A-ring part at C8, each carrying one of the
defined by a dot that corresponds to the position of the 25-
hydroxy groups, i.e. the 1α-OH and 25-OH groups, that
have been shown to be essential for recognition by the re-
ceptor protein.[3] With regard to the flexible parts of the
molecule successful structural modifications that led to the
desired dissociation of activities include e.g. 19-nor deriva-
tives, 22-oxa, 23-yne, 24-homo, 26,27-bishomo, 20-epi, and
combinations thereof.[4] In contrast our laboratory has fo-
cussed in recent years on the development of analogs that
oxygen atom in that particular conformation.[8] The re-
spective top views nicely show how in 1 the side chain is
oriented in a “north-east” direction and in 2 in the “north-
west” region.
The present work aims at the development of 6D-analogs
in which, as a consequence of a particular substitution pat-
tern on the six-membered D-ring, specific orientations are
enforced on the side chain.[5f] 6D-analogs as e.g. 3 are
characterized by the absence of a C-ring and by the pres-
ence of a conformationally well defined chair six-membered
D-ring. In particular analog 4 is designed so as to enforce
the above north-west orientation of the side chain. This
conformational preference, as illustrated in the dot map of
Figure 2, is the result of the absence of the gem-dimethyl
[a]
Department of Organic Chemistry, University of Gent,
Krijgslaan 281 (S4), B-9000 Gent, Belgium
Fax: (internat.) ϩ 32-9/2644998
E-mail: pierre.declercq@rug.ac.be
[b]
`
Dipartimento di Chimica Inorganica, Universita degli Studi di
Torino,
Via P. Giuria 7, I-10125 Torino, Italy
Eur. J. Org. Chem. 1999, 1803Ϫ1809
WILEY-VCH Verlag GmbH, D-69451 Weinheim, 1999
1434Ϫ193X/99/0808Ϫ1803 $ 17.50ϩ.50/0
1803

S. Gabrie¨ls, D. Van Haver, M. Vandewalle, P. De Clercq, D. Viterbo
FULL PAPER
Figure 1. Dot-map representation of the side-chain conformation of 1 (left) and 2 (right) in side and perpendicular views (the line drawing
represents the global energy minimum conformation)
Tosylate 7 is a key intermediate in the synthesis of 4.
Indeed, using known methodology[9] both the classical side
chain (substitution process) and the seco-B,A-ring part
(Horner reaction) can be introduced. The projected enan-
tioselective synthesis of 7 is summarized in Scheme 1. Start-
ing from (R)-(Ϫ)-carvone a derivative as 5 is first developed
in which the three substituents in the six-membered D-ring
possess the more stable equatorial orientation. Subsequent
introduction of the 20-methyl group in the required (S)-
configuration as in 6 occurs via stereoselective alkylation of
the corresponding enolate from the least hindered si-face.
Subsequent standard transformations would lead to tosyl-
ate 7, and further to analog 4.
We now wish to describe the synthesis of tosylate 18, a
derivative that, compared with the desired 7, is epimeric at
C14 and C17,[10] and was obtained because of the unexpec-
ted stereochemical outcome of the magnesium in methanol
conjugate reduction of the α,β-unsaturated ester 9.
The synthesis of 18 is shown in Schemes 2 and 3. The
route that was expected to lead uneventfully to a 1,2,4-tri-
substituted all-equatorial derivative, with absolute and rela-
Figure 2. Dot-map representation of the side-chain conformation
tive configurations as shown for 6 and 7, in practice led to
of 4 in side and perpendicular views (the line drawing represents
the all-cis derivative 15. The conjugate reduction of (R)-
(Ϫ)-carvone with sodium dithionite under phase transfer
conditions led, as described, to trans-cyclohexanone 8.[11a]
The corresponding cis-isomer (not shown) was isolated as
the minor isomer and found to isomerize in base (sodium
methoxide) to the more stable 8.[11b]
the global energy minimum conformation)
substitution at C13 (compare 3) and the presence of the α-
oriented methyl group at C16.
In a following stage the methoxycarbonylmethyl substitu-
ent was introduced. First a Peterson olefination gave an un-
separable mixture of the (E,Z)-isomers 9a and 9b (ratio 2:3,
respectively). The preferred formation of the (Z)-derivative
is in line with the result obtained for 2-methylcyclohexa-
none.[12] The identification of both isomers rests on 1H-
NMR analysis.[13] The subsequent conjugate reduction of
the α,β-unsaturated ester 9 (both isomers) with magnesium
in methanol was expected to yield ester 10b with the more
stable all-equatorial-stereochemistry. Magnesium in meth-
anol has been promoted as reducing agent for the CϪC
double bond in α,β-unsaturated nitriles, amides, and es-
ters.[14] To the best of our knowledge there are only a few
examples in which the stereochemical outcome at the β-cen-
tre (i.e., C17) has been addressed, and, not unexpectedly,
Scheme 1. Synthesis plan
1804
Eur. J. Org. Chem. 1999, 1803Ϫ1809

On the Unexpected Stereochemical Outcome of the Magnesium in Methanol
FULL PAPER
in THF) with iodomethane which led to 11 as an unsepa-
rable mixture of three diastereomers in high yield (ratio
5:4:1 of unidentified isomers).[16] Subsequent reduction
with lithium aluminum hydride gave alcohol 12 which was
directly converted into acetate 13. At this point a 7:3 mix-
1
ture (from H-NMR analysis) of isomers is obtained.
The further sequence calls for the oxidative cleavage of
the double bond in 13 so that in a subsequent step the A-
ring and s-trans diene may be introduced in a classical way
via Horner reaction.[17] Cleavage using osmium tetraoxide
and potassium periodate led to ketone 14 as an isomericaly
pure compound, in isolated yield of 58%; presumably the
minor isomer in 13 was also converted into the correspond-
ing ketone and was discarded through the chromatograph-
ical process. Ketone 14 was then further converted into al-
cohol 15. During this step occurred the isomerization at
C14 leading to the cis-relation of the two larger equatorial
1
substituents. Indeed, careful analysis of the H-NMR spec-
tra reveals an axial orientation of the acetyl group in 14
[δ(H14) ϭ 2.59 (ΣJvic ϭ 16 Hz)] and an equatorial orien-
tation in 15 [δ(H14) ϭ 2.32 (tt, J ϭ 12.2, 3.6 Hz)].
Scheme 2. Synthesis of 15
the more stable orientation was obtained.[15] However when
the mixture of 9a and 9b was subjected to the same re-
duction conditions (Mg, MeOH, reflux), a very high yield
of a 85:15 mixture of the two saturated esters 10a and 10b,
isomeric at C17, was obtained in which we expected the all-
equatorial isomer 10b to be the major isomer. This pre-
sumption however turned out to be erroneous and was only
discovered after the X-ray structural determination of tosyl-
ate 18 (see later)! Reinvestigation of this particular re-
duction step using other dissolving metal conditions, i.e.,
lithium in liquid ammonia (ether/dimethoxyethane), led to
a 3:7 mixture of 10a and 10b, respectively, now in favour of
the more stable isomer (56% yield).
Scheme 3. Synthesis of 18
The final conversion of 15 into 18 is shown in Scheme 3.
Acetalisation led to 16a, the tosylate of which did not give
adequate crystals for X-ray analysis. After oxidation to the
corresponding aldehyde 17a, isomerization in base led to a
ca 1:1 mixture of aldehydes isomeric at C20. After re-
duction of this mixture, alcohol 16b could be isolated
(47%), which upon tosylation afforded 18. By slow evapo-
In the illusion that the major isomer possessed the all- ration from dichloromethane/isooctane (1:1) solutions of 18
equatorial-configuration, the further sequence was pursued. crystals (m.p. 93 °C) appropriate for crystal structure analy-
This involved alkylation of the ester enolate (obtained from sis were obtained. The X-ray molecular structure[18] is
the mixture of 10a and 10b with lithium diisopropylamide shown in Figure 3, together with the adopted atomic label-
Eur. J. Org. Chem. 1999, 1803Ϫ1809
1805

S. Gabrie¨ls, D. Van Haver, M. Vandewalle, P. De Clercq, D. Viterbo
FULL PAPER
Figure 3. X-ray crystal structure of tosylate 18 with atomic labeling
applied to the rotatable CϪC bonds of the side chain, while the 25-
OH was rotated with increments of 120°. The so generated starting
conformations were minimized using the MM2* force field im-
plementation of MacroModel and the conformations within 20 kJ/
mol of the minimum energy form were retained. Using a PC com-
puter program all conformations of each compound were then
overlaid using C13 as common origin (x, y, z ϭ 0), C14 was posi-
tioned in the yz-plane (x ϭ 0) and C18 was made to coincide with
the positive y-axis (x, z ϭ 0). A line drawing was generated of the
minimum energy conformation and the position of O25 in each
of the local energy minima within the given energy window was
represented by a dot to obtain the dot maps shown in Figures 1
and 2.
ing scheme. It may be clearly seen that in tosylate 18 all
three cyclohexane substituents point towards the same face
(all-cis), with equatorial acetal and the tosylated propanol
moieties and axial methyl group. Needless to say that great
was our surprise when the relative configuration of the de-
rivative appeared to correspond to the one shown for 18.
Clearly, an in depth study of the magnesium in methanol
reduction of exocyclic α,β-unsatured esters is in order.
Experimental Section
General: Thin-layer chromatography was performed on Merck sil-
ica gel 60F-254 TLC plates. All products were purified by flash
chromatography (Merck silica gel 60F254) or High Performance
Liquid Chromatography (HPLC): Waters 4000, Kontron 420/422.
Ϫ [α]D20(CHCl3): PerkinϪElmer 241. Ϫ IR (NaBr): PerkinϪElmer
(2R,5R)-5-Isopropenyl-2-methylcyclohexanone (8): A mixture of R-
(Ϫ)-carvone (10 g, 66.569 mmol), phase transfer catalyst (Adogen
464 , 3.59 g, 19.974 mmol) and sodium bicarbonate (100.66 g) in
toluene (500 mL) and water (500 mL) was stirred vigorously under
argon. Sodium dithionite (104.306 g, 559.116 mmol) was added
and the mixture heated in an oil bath at 110 °C for 3 h. After cool-
ing, the aqueous layer was separated and extracted with diethyl
ether. The combined organic extracts were washed with water, dried
(MgSO4), and the solvent removed in vacuo. Flash chromatography
(hexane/diethyl ether, 85:15) and HPLC (hexane/ethyl acetate, 96:4)
of the residue afforded 8 (8.209 g, 81%). Ϫ Rf ϭ 0.38 (hexane/
1
1600 series. Ϫ H NMR (CDCl3): 500 MHz - Bruker AN-500 (in-
ternal TMS as reference). Ϫ 13C NMR (CDCl3): 50 MHz - Varian
Gemini-200 (with DEPT program.). Ϫ MS: Finnigan 4000 or Hew-
lettϪPackard 5988A.
X-Ray Crystal Structure Analysis. ؊ Crystal Data: C21H32O5S;
M ϭ 396.53 g/mol; orthorombic space group P212121, a ϭ 8.035(2),
3
˚
˚
b ϭ 8.274(2), c ϭ 32.025(9) A, V ϭ 2129(1) A , Z ϭ 4, dcalcd.
ϭ
20
diethyl ether, 8:2). Ϫ [α]D ϩ15.87, (c ϭ 1.21, CHCl3), ref.[11b]
1.237 Mg/m3. Ϫ Data Collection: Siemens P4 diffractometer, Mo-
Kα radiation (λ ϭ 0.71069 A), graphite monochromator; crystal
ϩ17.5. Ϫ IR (NaBr): ν˜ ϭ 2968 cmϪ1, 2931, 1713, 1646, 1449, 1376,
˚
1
size 0.6 ϫ 0.3 ϫ 0.3 mm3, µ ϭ 0.180 mmϪ1; ω scan mode, θ range:
1.3Ϫ25°, index ranges 0 Յ h Յ 9, 0 Յ k Յ 9, 0 Յ l Յ38, reflections
collected: 2185, independent reflections: 2185, observed reflec-
tions[I > 2σ(I)]: 1414. Ϫ Structure Solution and Refinement: solu-
tion by direct methods; refinement by full-matrix least-squares on
F2, non-H atoms with anisotropic displacement parameters, H
atoms could be located in a difference Fourier map, but were geo-
metrically positioned and treated as riding atoms; data/parameters
ratio in the final refinement: 2185/244; R ϭ 0.0546 (observed data),
Rw(F2) ϭ 0.1784 (all data). Programs used: P3/PC,[19] SIR92,[20]
SHELXL/PC IRIS,[21] SHELXL-97,[22] MOLDRAW.[23]
1218, 1184, 1142, 1057, 891, 730. Ϫ H NMR (500 MHz, CDCl3):
δ ϭ 4.75 (1 H, m), 4.73 (1 H, m), 2.45 (1 H, dt, J ϭ 11.3, 2.4 Hz),
2.25Ϫ2.40 (3 H), 2.13 (1 H, dq, J ϭ 13.3, 2.8 Hz), 1.94 (1 H, dq,
J ϭ 13.2, 3.2 Hz), 1.73 (3 H, s), 1.62 (1 H, tq, J ϭ 12.3, 1.7 Hz),
1.37 (1 H, qd, J ϭ 12.3, 1.7 Hz), 1.03 (3 H, d, J ϭ 6.5 Hz). Ϫ 13C
NMR/DEPT (50 MHz, CDCl3): δ ϭ 212.5 (CϭO), 147.5 (Cϭ),
109.5 (CH2ϭ), 46.9 (CH), 46.8 (CH2), 44.7 (CH), 34.8 (CH2), 30.7
(CH2), 20.4 (CH3), 14.2 (CH3). Ϫ MS; m/z (%): 152 (13) [Mϩ], 137
(9), 123 (3), 110 (16), 109 (28), 95 (63), 82 (44), 79 (13), 67 (100),
55 (44), 41 (58). Ϫ C10H16O (152.24): calcd. C 78.89, H 10.60;
found C 78.85, H 10.61.
Conformational Analysis and Molecular Modeling: Conformational
Methyl [(2R,5R)-5-Isopropenyl-2-methylcyclohexylidene]acetate (9a,
analysis of the side chain of compounds 1, 2, and 4 was carried b): To a solution of diisopropylamine (5.53 mL, 42.186 mmol) in
out using the MacroModel molecular modeling program of Still[24]
tetrahydrofuran (60 mL) was added a 2.5 molar solution of n-butyl-
run on a Digital VAXstation 4000Ϫ90A or SiliconGraphics lithium in hexane (26.37 mL, 42.186 mmol) at 0 °C under argon
Octane. Molecular mechanics calculations were carried out on
model compounds in which the A-ring and diene system up to C6
atmosphere. The solution of lithium diisopropylamide was stirred
at 0 °C for 10 min, cooled to Ϫ78 °C and treated dropwise with
were replaced by a H atom. Rotations with 60° increments were ethyl (trimethylsilyl)-acetate (6.93 mL, 42.186 mmol). The resultant
1806 Eur. J. Org. Chem. 1999, 1803Ϫ1809

On the Unexpected Stereochemical Outcome of the Magnesium in Methanol
FULL PAPER
mixture was stirred at Ϫ78 °C for 30 min, treated dropwise with
ketone 8 (5.340 g, 35.155 mmol) and then stirred for an additional 181 (6), 164 (4), 149 (6), 136 (87), 107 (24), 88 (100), 67 (47), 41
1264, 1194, 1159, 1082, 887. Ϫ MS; m/z (%): 224 (3) [Mϩ], 209 (1),
2 h at Ϫ78 °C. On warming to room temperature the reaction mix-
ture was quenched with a saturated aqueous solution of am-
monium chloride and extracted with diethyl ether. The combined
ether extracts were dried with magnesium sulfate, filtered, and con-
centrated in vacuo. Flash chromatography (hexane/diethyl ether,
98:2) and HPLC (hexane/ethyl acetate, 98:2) afforded 9 (a/b, 2:3)
(7.038 g, 96%). Ϫ Rf ϭ 0.23 (hexane/ethyl acetate, 98:2). Ϫ IR
(NaBr): ν˜ ϭ 2934 cmϪ1, 1720, 1644, 1434, 1387, 1336, 1237, 1192,
(63). Ϫ C14H24O2 (224.34): calcd. C 74.94, H 10.79; found C 75.00,
H 10.94.
2-[(2R,5R)-5-Isopropenyl-2-methylcyclohexyl]propan-1-ol (12): To a
solution of 11 (1.333 g, 5.942 mmol) in dry tetrahydrofuran
(15 mL) at 0 °C under an argon atmosphere was added lithium
aluminum hydride (0.450 g, 11.883 mmol). After being stirred for
4 h at room temperature, the suspension was cooled in an ice bath
and water (0.45 mL) was added dropwise followed by a 15% aque-
ous solution of sodium hydroxide (0.45 mL) and water (1.35 mL).
After 15 min, the granular suspension was filtered and the filter
cake washed with diethyl ether. The combined filtrates were evapo-
rated under reduced pressure. Flash chromatography (pentane/ace-
tone, 9:1) and HPLC (isooctane/acetone, 85:15) afforded 12 as a
mixture of three isomers (1.076 g, 92%). Ϫ Rf ϭ 0.28 (hexane/ethyl
acetate, 6:4). Ϫ IR (NaBr): ν˜ ϭ 3312 cmϪ1, 2922, 2875, 1644, 1454,
1376, 1031, 887. Ϫ MS; m/z (%): 196 (3) [Mϩ], 165 (6), 153 (5),
137 (42), 109 (26), 82 (100), 67 (71), 41 (91). Ϫ C13H24O (196.33):
calcd. C 79.53, H 12.32; found C 79.53, H 12.34.
1
1161, 1140, 1014, 891, 668. Ϫ H NMR (500 MHz, CDCl3): δ ϭ
5.62 (1 H of 9b, m), 5.59 (1 H of 9a, m), 4.83 (1 H of 9b, m), 4.78
(1 H of 9b, m), 4.74 (1 H of 9a, m), 4.73 (1 H of 9a, m), 4.00 (1 H
of 9a, ddd, J ϭ 12.6, 9.0, 2.4), 3.85 (1 H of b, m), 3.70 (3 H of 9a,
s), 3.67 (3 H of 9b, s), 2.64 (1 H of 9b, ddd, J ϭ 14.8, 6.7, 2.1 Hz),
2.47 (1 H of 9b, m), 2.32 (1 H of 9b, d, J ϭ 14.8 Hz), 2.16 (1 H of
a, m), 2.04 (1 H of 9a, tt, J ϭ 12.3, 3.3 Hz), 1.97 (1 H of 9a, ddd,
J ϭ 13.0, 7.2, 4.0 Hz), 1.76 (3 H of 9a, s), 1.70 (3 H of 9b, s), 1.48
(1 H of 9b, qd, J ϭ 12.7, 3.9 Hz), 1.33 (1 H of 9b, ddd, J ϭ 13.8,
7.9, 3.6 Hz), 1.17 (3 H of 9b, d, J ϭ 7.1 Hz), 1.06 (3 H of 9a, d,
J ϭ 6.5 Hz). Ϫ MS; m/z (%): 208 (52) [Mϩ], 193 (18), 176 (64), 135
(100), 148 (52), 133 (61), 119 (41), 93 (71), 67 (54), 55 (63). Ϫ
C13H20O2 (208.30): calcd. C 74.95, H 9.68; found C 74.93, H 9.51.
A solution of 12 (3.528 g, 17.970 mmol) in anhydrous pyridine
(30 mL) and acetic anhydride (13.34 mL, 141.140 mmol) was
stirred at room temperature for 15 h. The reaction mixture was
then evaporated to dryness in vacuo. The residue, dissolved in ethyl
acetate, was successively washed with 1  hydrochloric acid, water,
2  potassium bicarbonate and finally with brine. After the mixture
was dried (MgSO4) and the solvent was evaporated, flash chroma-
tography and HPLC (hexane/ethyl acetate, 85:15) of the residue
afforded 13 as a 7:3 mixture of two isomers (3.470 g, 81%). Rf ϭ
Methyl [(2R,5R)-5-Isopropenyl-2-methylcyclohexyl]acetate (10a, b):
To a stirred solution of 9a,b (2.911 g, 13.975 mmol) in dry meth-
anol (60 mL) was added magnesium powder (0.798 g,
32.836 mmol) through a reflux condenser. After a short time, an
exothermic reaction occurred which resulted in boiling of the reac-
tion mixture. When the metal was consumed, a second portion of
magnesium (0.798 g, 32.836 mmol) was added and then the ad-
dition was repeated twice (total consumption of Mg: 3.193 g,
131.365 mmol). After all the magnesium had been consumed, the
reaction mixture was cooled to room temperature and HOAc
(15 mL) was added in one portion (exothermic reaction) followed
by water (70 mL). The reaction mixture was extracted with diethyl
ether and the ether layer washed with brine, dried with magnesium
sulfate, and concentrated in vacuo. Flash chromatography (hexane/
ethyl acetate, 97:3) and HPLC (isooctane, 97:3) of the residue af-
forded 10 (a/b, 85:15) (2.854 g, 97%). Ϫ Rf ϭ 0.38 (hexane/ethyl
acetate, 96:4). IR (NaBr): ν˜ ϭ 2922 cmϪ1, 2848, 1740, 1644, 1436,
0.45 (pentane/ethyl acetate, 96:4). Ϫ IR (NaBr): ν˜ ϭ 2928 cmϪ1
,
1
1742, 1453, 1372, 1236, 1033, 886. Ϫ H NMR (500 MHz, CDCl3)
(signals of the major isomer are printed in italics): δ ϭ 4.83 (1 H,
m), 4.76 (1 H, m), 4.66 (2 H, m), 4.15 (1 H, dd, J ϭ 10.8, 4.0 Hz),
3.95 (2 H), 3.80 (1 H, dd, J ϭ 10.8 Hz, 7.6 Hz), 2.06 (3 H, s), 2.05
(3 H, s), 1.72 (3 H, s), 1.70 (3 H, s), 0.98 (3 H, d, J ϭ 6.7 Hz), 0.94
(3 H, d, J ϭ 7.1 Hz), 0.89 (3 H, d, J ϭ 6.3 Hz), 0.80 (3 H, d, J ϭ
7.0 Hz). Ϫ MS; m/z (%): 238 (< 1) [Mϩ], 223 (1), 194 (1), 178 (15),
163 (7), 149 (4), 135 (35), 121 (20), 93 (42), 82 (67), 67 (34), 43
(100). Ϫ C15H26O2 (238.37): calcd. C 75.57, H 11.00; found C
75.52, H 11.11.
1
1376, 1286, 1254, 1158, 887. Ϫ H NMR (500 MHz, CDCl3) (only
signals of the major isomer are given): δ ϭ 4.67 (2 H, m), 3.67
(3 H, s), 1.69 (3 H, s), 0.87 (3 H, d, J ϭ 6.9 Hz). Ϫ MS; m/z (%):
210 (4) [Mϩ],195 (2), 167 (8), 150 (12), 136 (100), 121 (38), 93 (65),
81 (36), 67 (47), 41 (63). Ϫ C13H22O2 (210.32): calcd. C 74.24, H
10.54; found C 74.12, H 10.53.
Acetate
of
1-{(1R,3S,4R)-3-[(1R)-2-hydroxy-1-methylethyl]-4-
solution of 13 (0.258 g,
methylcyclohexyl}ethanone (14):
A
1.082 mmol) in a 1:1 mixture of tetrahydrofuran/water (18 mL) was
combined with a 1% aqueous solution of osmium tetraoxide
(0.25 mL) and finely pulverized potassium periodate (0.800 g,
3.478 mmol) and stirred vigorously for 24 h at 45 °C. Most of the
tetrahydrofuran was then evaporated in vacuo and the residue di-
luted with water and extracted with ethyl acetate. The combined
organic extracts were washed with 1  aqueous sodium bisulfite,
followed by water, 2  aqueous sodium bicarbonate, and brine.
After the mixture was dried (MgSO4) and the solvents were evapo-
rated, flash chromatography and HPLC (pentane/ethyl acetate, 9:1)
Methyl
2-[(2R,5R)-5-Isopropenyl-2-methylcyclohexyl]propionate
(11): The ester 10a, b (2.439 g, 11.600 mmol) was added to a 1
molar tetrahydrofuran solution of lithium diisopropylamide [pre-
pared by treatment of diisopropylamine (1.52 mL, 11.600 mmol)
with n-butyllithium (7.25 mL, 11.600 mmol) at 0 °C for 15 min] at
Ϫ78 °C. The ester enolate was allowed to form over a period of
30 min and iodomethane (0.79 mL, 12.760 mmol) dissolved in 1,3-
dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU) (1.4 mL,
afforded 14 (0.151 g, 58%). Ϫ Rf ϭ 0.26 (pentane/ethyl acetate, 9:1).
20
11.600 mmol) was added at Ϫ78 °C. After stirring for 30 min, the Ϫ [α]D Ϫ27.14 (c ϭ 1.05, CHCl3). Ϫ IR (NaBr): ν˜ ϭ 2939 cmϪ1
,
1
mixture was treated with aqueous ammonium chloride and ex-
tracted with diethyl ether. The ether solution was washed with
water, saturated aqueous sodium chloride, and dried with mag-
nesium sulfate. After concentration in vacuo, flash chromatography
(hexane/ethyl acetate, 96:4) and HPLC (isooctane/ethyl acetate,
1737, 1708, 1441, 1367, 1238, 1174, 1032. Ϫ H NMR (500 MHz,
CDCl3): δ ϭ 4.13 (1 H, dd, J ϭ 10.9, 3.9 Hz), 3.80 (1 H, dd, J ϭ
10.9, 7.2 Hz), 2.59 (1 H, m), 2.15 (3 H, s), 2.05 (3 H, s), 2.02 (1 H,
m), 1.89 (2 H, m), 1.68 (1 H, tdd, J ϭ 13.5, 5.4, 4.0 Hz), 1.56 (2 H,
m), 1.40 (3 H, m), 0.99 (3 H, d, J ϭ 6.7 Hz), 0.90 (3 H, d, J ϭ
97:3) of the residue afforded 11 as a mixture of three isomers (ratio 7.1 Hz). Ϫ 13C NMR/DEPT (50 MHz, CDCl3): δ ϭ 211.1 (CϭO),
5:4:1, 2.370 g, 91%). Ϫ Rf ϭ 0.26 (hexane/ethyl acetate, 96:4). Ϫ
171.2 (OϪCϭO), 67.6 (CH2), 47.5 (CH), 38.5 (CH), 34.0 (CH),
29.8 (CH2), 29.4 (CH), 27.7 (CH3), 24.6 (CH2), 21.0 (CH2), 20.8
IR (NaBr): ν˜ ϭ 2924 cmϪ1, 2857, 2359, 1739, 1644, 1453, 1376,
Eur. J. Org. Chem. 1999, 1803Ϫ1809
1807

S. Gabrie¨ls, D. Van Haver, M. Vandewalle, P. De Clercq, D. Viterbo
FULL PAPER
(CH3), 15.4 (CH3), 12.3 (CH3). Ϫ MS; m/z (%): 180 (6), 165 (3), (1 H), 1.26 (3 H, s), 1.02Ϫ1.64 (5H), 1.07 (3 H, d, J ϭ 6.9 Hz), 0.87
137 (23), 123 (5), 107 (5), 95 (19), 67 (10), 43 (100). Ϫ C14H24O3 (3 H, d, J ϭ 7.1 Hz). Ϫ 13C NMR/DEPT (50 MHz, CDCl3): δ ϭ
(240.34): calcd. C 69.96, H 10.07; found C 69.80, H 10.07.
205.8 (CϭO), 111.9 (OϪCϪO), 65.1 (OϪCH2ϪCH2ϪO), 49.7
(CH), 47.3 (CH), 41.9 (CH), 33.6 (CH2), 30.4 (CH), 24.1 (CH2),
21.4 (CH2), 21.3 (CH3), 12.8 (CH3), 12.7 (CH3). Ϫ MS m/z (%):
225 (1), 200 (1), 182 (1), 169 (1), 149 (1), 129 (2), 128 (2), 95 (3),
87 (100), 67 (3), 43 (30). Ϫ C14H24O3 (240.34).
1-{(1S,3S,4R)-3-[(1R)-2-Hydroxy-1-methylethyl]-4-methylcyclo-
hexyl}ethanone (15): To a solution of 14 (0.985 g, 4.098 mmol) in
dry methanol (14 mL) was added potassium carbonate (0.680 g,
4.918 mmol). After stirring for 40 h at room temperature, diethyl
ether was added, the mixture filtered over silica and the solvents
evaporated. HPLC (pentane/acetone, 8:2) afforded 15 (0.780 g,
(2S)-2-[(1S,2R,5S)-2-Methyl-5-(2-methyl[1,3]dioxolan-2-yl)cyclo-
hexyl]propan-1-ol (16b): To a solution of 17a (0.533 g, 2.218 mmol)
in dry methanol (20 mL) and dry tetrahydrofuran (20 mL) was ad-
ded sodium methoxide (0.300 g, 5.554 mmol). After stirring for
24 h, the reaction mixture was poured into saturated aqueous so-
dium chloride, extracted with diethyl ether, dried with magnesium
sulfate, and concentrated in vacuo. Flash chromatography and
HPLC (pentane/acetone, 93:7) of the residue afforded a 1:1 mixture
17a, b (0.522 g, 2.172 mmol, 98%) which was then subjected to re-
duction as described for 12. The desired epimeric alcohol 16b
(0.247 g, 47%) could be isolated by flash chromatography and
HPLC (pentane/acetone, 85:15). Ϫ Rf ϭ 0.42 (pentane/acetone,
20
96%). Ϫ Rf ϭ 0.31 (pentane/acetone, 8:2). Ϫ [α]D Ϫ3.51 (c ϭ
1.26, CHCl3). Ϫ IR (NaBr): ν˜ ϭ 3428 cmϪ1, 2933, 1704, 1464,
1
1381, 1357, 1175, 1032. Ϫ H NMR (500 MHz, CDCl3): δ ϭ 3.65
(1 H, dd, J ϭ 10.7, 3.7 Hz), 3.50 (1 H, dd, J ϭ 10.5, 5.6 Hz), 2.32
(1 H, tt, J ϭ 12.2, 3.6 Hz), 2.14 (3 H, s), 2.01 (1 H, m), 1.73 (1 H,
dm, J ϭ 13.2 Hz), 1.66 (2 H, m), 1.20Ϫ1.60 (6H), 0.98 (3 H, d, J ϭ
6.7 Hz), 0.86 (3 H, d, J ϭ 7.2 Hz). Ϫ 13C NMR/DEPT (50 MHz,
CDCl3): δ ϭ 212 (CϭO), 65.7 (CH2ϪO), 52.1 (CH), 41.3 (CH),
37.1 (CH), 33.0 (CH2), 28.9 (CH), 27.9 (CH3), 25.2 (CH2), 22.4
(CH2), 15.1 (CH3), 12.1 (CH3). Ϫ MS; m/z (%): 198 (2) [Mϩ], 180
(3), 168 (5), 151 (3), 137 (12), 136 (7), 110 (7), 97 (16), 95 (49), 81
(40), 55 (38), 43 (100). Ϫ C12H22O2 (198.31): calcd. C 72.68, H
11.18; found C 72.75, H 11.32.
20
8:2). Ϫ [α]D Ϫ4.91 (c ϭ 1.13, CHCl3). Ϫ IR (NaBr): ν˜ ϭ 2433
cmϪ1, 2876, 1446, 1382, 1216, 1165, 1115, 1042, 992, 948, 864. Ϫ
1H NMR (500 MHz, CDCl3): δ ϭ 3.91 (4 H, m), 3.70 (1 H, dd,
J ϭ 10.5, 2.4 Hz), 3.54 (1 H, dd, J ϭ 10.3, 6.2 Hz), 1.98 (1 H, m),
1.73 (1 H, dm, J ϭ 13.8 Hz), 1.64 (1 H, dq, J ϭ 13.0, 2.9 Hz),
1.00Ϫ1.65 (7H), 0.97 (3 H, d, J ϭ 6.7 Hz), 0.82 (3 H, d, J ϭ
(2R)-2-[(1S,2R,5S)-2-Methyl-5-(2-methyl[1,3]dioxolan-2-yl)-
cyclohexyl]propan-1-ol (16a): To a solution of 15 (0.236 g,
1.190 mmol) in toluene (10 mL) was added 1,2-ethanediol
(0.66 mL, 11.900 mmol) and pyridinium tosylate (0.060 g,
0.238 mmol). The mixture was refluxed with water separation by a
DeanϪStark trap until the starting ketone had been completely
used (12 h). The solvent was then removed in vacuo, diethyl ether
was added and the mixture was washed with sodium bicarbonate
and saturated aqueous sodium chloride solution. The organic
phase was dried with magnesium sulfate and the solvent removed
under reduced pressure. HPLC (pentane/acetone, 86:14) afforded
7.1 Hz).
Ϫ δ ϭ 111.7
13C NMR/DEPT (50 MHz, CDCl3):
(OϪCϪO), 66.3 (CH2ϪO), 64.6 (OϪCH2ϪCH2ϪO), 46.8 (CH),
41.5 (CH), 37.7 (CH), 33.3 (CH2), 28.2 (CH), 24.7 (CH2), 21.1
(CH2), 20.9 (CH3), 14.9 (CH3), 11.9 (CH3). Ϫ MS m/z (%): 227 (2),
202 (1), 181 (1), 165 (1), 141 (2), 128 (2), 107 (2), 87 (100), 67 (4),
43 (32). Ϫ C14H26O3 (242.36).
(2S)-[(1S,2R,5S)-2-Methyl-5-(2-methyl[1,3]dioxolan-2-yl)cyclo-
hexyl]propyl Toluene-4-sulfonate (18): To a solution of 16b (0.247 g,
1.019 mmol) in dichloromethane (4.5 mL) at 0 °C was added tri-
ethylamine (0.57 mL, 4.110 mmol), a solution of p-tosyl chloride
(0.392 g, 2.055 mmol) in dichloromethane (2.7 mL) and a trace of
4-dimethylaminopyridine (DMAP). After stirring for 20 h at room
temperature, the reaction mixture was concentrated partially, fil-
tered and then evaporated in vacuo. Flash chromatography and
HPLC (pentane/acetone, 86:14) afforded 18 (0.331 g, 82%), color-
20
16a (0.277 g, 96%). Ϫ Rf ϭ 0.38 (pentane/acetone, 8:2). Ϫ [α]D
Ϫ7.20 (c ϭ 0.96, CHCl3). Ϫ IR (NaBr): ν˜ ϭ 3415 cmϪ1, 2939,
1467, 1382, 1217, 1174, 1114, 1042, 949, 862. Ϫ 1H NMR
(500 MHz, CDCl3): δ ϭ 3.92 (4 H, m), 3.66 (1 H, dd, J ϭ 10.7,
3.6 Hz), 3.48 (1 H, dd, J ϭ 10.6, 6.1 Hz), 1.96 (1 H, m), 1.70 (1 H,
dm, J ϭ 13.0 Hz), 1.26 (3 H, s), 1.20Ϫ1.60 (9H), 0.98 (3 H, d, J ϭ
6.7 Hz), 0.86 (3 H, d, J ϭ 7.1 Hz). Ϫ 13C NMR/DEPT (50 MHz,
CDCl3): δ ϭ 111.7 (OϪCϪO), 66.0 (CH2ϪO), 64.6 (OϪCH2Ϫ
CH2ϪO), 47.0 (CH), 41.8 (CH), 37.5 (CH), 33.4 (CH2), 29.2 (CH),
24.4 (CH2), 21.1 (CH2), 21.0 (CH3), 15.2 (CH3), 12.4 (CH3). Ϫ MS
m/z (%): 227 (2), 212 (1), 180 (1), 165 (1), 149 (1), 137 (2), 107 (1),
87 (100), 67 (4), 43 (28). Ϫ C14H26O3 (242.36): calcd. C 69.38, H
10.81; found C 69.36, H 10.88.
less crystals, m.p. 93 °C. Ϫ Rf ϭ 0.32 (pentane/acetone, 9:1). Ϫ
20
[α]D ϩ9.07 (c ϭ 0.70, CHCl3). Ϫ IR (NaBr): ν˜ ϭ 2944 cmϪ1
,
1467, 1360, 1177, 1098, 1042, 960, 837, 815, 668. 1H NMR
(500 MHz, CDCl3): δ ϭ 7.78 (2 H, d, J ϭ 8.2 Hz), 7.3 (2 H, d, J ϭ
8.2 Hz), 4.08 (1 H, dd, J ϭ 9.4, 3.3 Hz), 3.90 (5 H), 2.44 (3 H, s),
1.92 (1 H, m), 1.61 (1 H, dq, J ϭ 13.2, 2.9 Hz), 1.50Ϫ1.58 (4 H),
1.45 (1 H, tt, J ϭ 12.2, 3.5 Hz), 1.42 (1 H, tt, J ϭ 13.8, 3.8 Hz),
1.20Ϫ1.30 (2 H), 1.20 (3 H, s), 0.91 (3 H, d, J ϭ 6.8 Hz), 0.76 (3 H,
d, J ϭ 7.11 Hz). Ϫ 13C NMR/DEPT (50 MHz, CDCl3): δ ϭ 144.5
(2R)-2-[(1S,2R,5S)-2-Methyl-5-(2-methyl[1,3]dioxolan-2-yl)cyclo-
hexyl]propionaldehyde (17a): To
a solution of 16a (0.643 g,
2.653 mmol) and DMSO (20 mL) in dichloromethane (12 mL) at (ArϪC), 133.2 (ArϪC), 129.8 (ArϪCH), 127.9 (ArϪCH), 111.5
Ϫ12 °C was slowly added a solution of SO3/pyridine (1.056 g,
6.633 mmol), triethylamine (1.12 mL) and DMSO (10.08 mL) in di-
chloromethane (5 mL). After 2 h stirring (temperature slowly in-
(OϪCϪO), 74.1 (CH2ϪO), 64.7 (2 ϫ CH2ϪO), 46.6 (CH), 41.4
(CH), 35.4 (CH), 33.1 (CH2), 28.1 (CH2), 24.5 (CH2), 21.6 (CH3),
21.1 (CH3), 20.8 (CH2), 14.9 (CH3), 11.7 (CH3). Ϫ MS m/z (%):
creased to Ϫ6 °C), the reaction mixture was poured into a brine/ 381 (3), 366 (1), 278 (1), 259 (1), 209 (1), 155 (3), 88 (22), 87 (100).
diethyl ether mixture, and the water phase was extracted with ether.
The combined organic extracts were dried (MgSO4) and the sol-
Ϫ C21H32O5S (396.54). Ϫ Relevant torsion angles [°] of tosylate 18
(for the atomic numbering, see Figure 3): O(1)ϪC(1)ϪC(4)ϪC(5)
vents were evaporated. Flash chromatography and HPLC (pentane/ 168.1, O(1)ϪC(1)ϪC(4)ϪC(9) Ϫ65.6, O(1)ϪC(1)ϪC(4)ϪH(4) 51,
acetone, 93:7) afforded 17a (0.568 g, 89%). Ϫ Rf ϭ 0.35 (pentane/
O(2)ϪC(1)ϪC(4)ϪC(5) 53.4, C(10)ϪC(1)ϪC(4)ϪC(5) Ϫ71.4,
C(10)ϪC(1)ϪC(4)ϪH(4) 172, C(10)ϪC(1)ϪO(1)ϪC(2) 117.4,
C(4)ϪC(9)ϪC(8)ϪC(7) 54.6, C(9)ϪC(8)ϪC(7)ϪC(6) Ϫ53.9,
20
acetone, 93:7). Ϫ [α]D Ϫ11.81 (c ϭ 1.41, CHCl3). Ϫ IR (NaBr):
ν˜ ϭ 2943 cmϪ1, 2877, 1724, 1459, 1384, 1219, 1112, 1043, 872. Ϫ
1H NMR (500 MHz, CDCl3): δ ϭ 9.58 (1 H, d, J ϭ 4.0 Hz), 3.93 C(8)ϪC(7)ϪC(6)ϪC(5) 57.2, C(5)ϪC(4)ϪC(9)ϪC(8) Ϫ55.1,
(4 H, m), 2.24 (1 H, dqd, J ϭ 9.5, 6.9, 4.0 Hz), 1.87 (1 H, m), 1.73
(1 H, ddt, J ϭ 12.5, 9.4, 3.6 Hz), 1.70 (1 H, dm, J ϭ 11.6 Hz), 1.30
C(7)ϪC(6)ϪC(5)ϪC(4) Ϫ59.1, C(6)ϪC(5)ϪC(4)ϪC(9) 56.5,
C(9)ϪC(8)ϪC(7)ϪC(11) 71.0, C(5)ϪC(6)ϪC(7)ϪC(11) Ϫ70.1,
1808
Eur. J. Org. Chem. 1999, 1803Ϫ1809

On the Unexpected Stereochemical Outcome of the Magnesium in Methanol
FULL PAPER
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C(12)ϪC(8)ϪC(7)ϪC(11) Ϫ55.6, C(13)ϪC(12)ϪC(8)ϪC(7) Ϫ545,
C(14)ϪC(12)ϪC(8)ϪC(7) 179.4, C(14)ϪC(12)ϪC(8)ϪC(9) 53.5,
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Acknowledgments
Financial support by the FWO-Vlaanderen (G.0051.98), the Minis-
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Received February 11, 1999
[99079]
Eur. J. Org. Chem. 1999, 1803Ϫ1809
1809