Conformation of isobutyl, 2,2-dibromoethyl, and 2-methoxypropyl side chains on cyclohexane and tetrahydropyran ring systems

Article abstract of DOI:10.1002/1099-0690(200105)2001:10<1857::AID-EJOC1857>3.0.CO;2-4

An isobutyl group placed equatorially in the 2-position of a 1-equatorially substituted cyclohexane adopts a preferred conformation (cf. 5). This also holds when it is placed in the 2-position on a 3-equatorially substituted tetrahydropyran (cf. 6). The same conformational preference is found for 2-methoxypropyl residues in the 2-position of 3-substituted tetrahydropyrans (cf. 8 and 10). The latter compounds chelate lithium cations as analogues of 1,2-dimethoxyethane. Through this complexation, it is possible to effect a change in the side chain conformation.

Full text of DOI:10.1002/1099-0690(200105)2001:10<1857::AID-EJOC1857>3.0.CO;2-4

FULL PAPER
Conformation of Isobutyl, 2,2-Dibromoethyl, and 2-Methoxypropyl Side
Chains on Cyclohexane and Tetrahydropyran Ring Systems[‡]
Reinhard W. Hoffmann,*[a] B. Colin Kahrs,[a] Philipp Reiß,[a] Thomas Trieselmann,[a]
Hans-Christian Stiasny,[a] and Werner Massa[a]
Keywords: Conformational analysis / Li complexation
An isobutyl group placed equatorially in the 2-position of a
1-equatorially substituted cyclohexane adopts a preferred
conformation (cf. 5). This also holds when it is placed in the
methoxypropyl residues in the 2-position of 3-substituted
tetrahydropyrans (cf. 8 and 10). The latter compounds che-
late lithium cations as analogues of 1,2-dimethoxyethane.
2-position on a 3-equatorially substituted tetrahydropyran Through this complexation, it is possible to effect a change
(cf. 6). The same conformational preference is found for 2-
in the side chain conformation.
Introduction
3 is to use the anullated ring system 4. To evaluate the mag-
nitude and scope of this conformational induction, we
studied a number of derivatives of 4. The results of these
studies are reported in this paper.
2,4-Dimethylpentane (1) populates two enantiomorphous
conformations, 1a and 1b, equally.[2Ϫ5] In the heteroatom
analogs 2,[6,7] the conformer equilibrium may be shifted to
favor the a conformer on the basis of steric or polar effects.
Results
Derivatives of Isobutylcyclohexane and 2-
Isobutyltetrahydropyran
Synthetic accessibility inclined us to study the hydrocar-
bon 5 (available from menthone, see below) rather than the
simple hydrocarbon 4. In order to evaluate the folding of
the isobutyl side chain (cf. 4a and 4b), the vicinal coupling
constants between the diastereotopic protons at C-1Ј and
the tertiary protons at C-2 and C-2Ј had to be determined.
As the relevant signals are obscured by overlaying in the 1H
NMR spectrum of 5, we intended to extract the character-
istic coupling constants using the SELINCOR technique,[10]
with the aid of the 13C NMR signal of C-2Ј.
Another potential way to influence the conformer equi-
librium of 1 is to introduce an ‘‘inductor’’ group, which
selectively destabilizes one of the two conformers 1a and
1b.[8,9] For instance, placement of a substituent ⌼ antiper-
iplanar to the C-2-methyl group in 3 will only slightly desta-
bilize conformer 3a, through a single gauche interaction, but
will destabilize conformer 3b by creating a syn-pentane in-
teraction. Therefore, the conformer equilibrium should be
shifted in favor of 3a, due to the presence of the inductor
group.
In the 13C NMR spectrum of 5, signals for carbon atoms
carrying two hydrogen atoms appear at δ ϭ 24.4, 35.4, 41.4,
and 42.7; one of these must be the signal of C-1Ј. In order
to identify this, the deuterated compound 5-D2 was pre-
pared. The deuterium substitution significantly lessened the
intensity of the signal at δ ϭ 42.7, which we therefore assign
One way to guarantee the spatial arrangement of the in-
ductor group antiperiplanar to the C-2-methyl group in unit
[‡]
Flexible Molecules with Defined Shape, XIV. Ϫ
Part XIII: Ref.[1]
[a]
1
to C-1Ј. Using the SELINCOR technique,[10] the H NMR
Fachbereich Chemie der Philipps-Universität,
Hans-Meerwein-Strasse, 35032 Marburg, Germany
Fax: (internat.) ϩ 49-(0)6421/282-8917
signal of the protons attached to C-1Ј were recorded. One
of these protons resonated at δ ϭ 0.82 as a ddd (J ϭ 13.0,
E-mail: rwho@chemie.uni-marburg.de
Eur. J. Org. Chem. 2001, 1857Ϫ1864
WILEY-VCH Verlag GmbH, 69451 Weinheim, 2001
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1857

R. W. Hoffmann, B. C. Kahrs, P. Reiß, T. Trieselmann, H.-C. Stiasny, W. Massa
3
FULL PAPER
10.4, and 3.3 Hz). The other proton signal appeared at δ ϭ
The JH,H coupling constants obtained are in line with
1.33, also as a ddd (J ϭ 12.9, 10.4, and 4.0 Hz). The vicinal the presence of a single conformer, which should be the one
coupling constants 10.4 and 3.3 Hz, together with 10.4 and shown in 7. This corresponds to the conformation found in
4.0 Hz, demonstrate the substantial preference for a distinct the crystal structure of 7 (Figure 1).
conformation of the isobutyl side chain in 5. We infer this
to be the one depicted, since force-field calculations for
compound 4 predicted a 89% preference for conformation
4a.[8] Nature uses this type of conformational preorganiza-
tion of side chains in certain acid components of antibiotics
such as L-156,602[11] or polyoxypeptin,[12] whereby a hydro-
phobic part of the pharmacophore is held in a distinct
shape.
It therefore appeared worthwhile to investigate the be-
havior of an oxygen analog of 4. We chose the tetrahy-
dropyran derivative 6. The change from cyclohexane to
tetrahydropyran allows conformers such as 6b and 6c, in-
volving a 1,3-parallel arrangement[13] between the side
chain methyl group and the oxygen atom, to be significantly
populated, since an oxygen substituent is smaller than a
CH2 group. Compound 6 additionally contains an axial
Figure 1. X-ray crystal structure of compound 7
methyl group. This has a small conformation-reinforcing ef-
The change from the pure hydrocarbon 5 to the monoox-
ygenated analog 6 resulted in a (small) decrease in the
population of the preferred conformation 6a, and increased
populating of conformation 6b. One might expect on this
fect, as it destabilizes some of the higher energy conformers
of the side chain even further.[9,14] Thus, MACROMO-
DEL[15] predicts the following conformer population.
basis that introduction of a further oxygen atom, as in com-
pound 8, should diminish the conformer preference further.
However, force-field calculations predict a high (92%) pref-
erence for populating the conformation 8a. Conformation
8b should be rather sparsely populated (5%), while con-
formation 8c should contribute only marginally to the con-
former equilibrium. Therefore, the force-field calculations
suggest that the conformer preference in 8 should be in-
creased relative to that in 6, probably as a consequence of
polar interactions.[7]
The synthesis of 6 was straightforward (see below). The
relevant 3JH,H coupling constants show the alteration char-
acteristic of the presence of a predominant conformer. The
larger difference between the coupling constants along the
C-2ϪC-1Ј bond, compared to the C-1ЈϪC-2Ј bond, is in
line with a minor presence of conformer 6b in the equilib-
rium.
Another compound, 7, related to 6, was available from a
previous study. In compound 7 a 2,2-dibromoethyl group
takes the position of the isobutyl side chain in 6.[16] Because
of the similar sizes of a methyl group and a bromine sub-
stituent, the effects on the conformer population should be
1
similar. Since the H NMR spectra of 7 showed a higher
order splitting, due to an accidental coincidence of the
chemical shifts of the 1Ј-H protons, the coupling constants
had to be approximated by simulation of the splitting pat-
tern.
This is indeed borne out by the coupling constants re-
corded for 8. The possible contribution by polar interac-
tions suggests that the conformer population might depend
on the solvent polarity. The coupling constants recorded for
solutions of 8 in various solvents, however, show that there
are only minor changes on going from toluene to acetonitr-
ile.
1858
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Conformation of Side Chains on Cyclohexane and Tetrahydropyran Ring Systems
FULL PAPER
The related dioxane derivative 9 was studied as well. It change in the conformer population. Complexation-in-
showed coupling constants (in toluene) very similar to those duced changes in the conformation of ligands have been the
found for 8.
object of many investigations; for some recent examples, see
refs.[22Ϫ25] A case related to the systems 8Ϫ10 is given in
the complexation of C-sucrose with Ca ions.[26] Such com-
plexation-induced conformational changes are of interest in
the context of signal transduction across membranes.[27]
For this reason, we looked at the interaction of com-
pound 8 with Li cations. NMR titration of 8 with LiBPh4
in CD3NO2 revealed significant changes in the 13C NMR
1
chemical shifts, as well as in the splitting pattern of the H
NMR signal of 2Ј-H (cf. Figure 2). The change in the major
conformer from 8a to 8c attendant with Li ion com-
plexation is most easily seen with an NOE experiment: Un-
complexed 8 shows no NOE between 2-H and 3Ј-CH3, but
such an NOE effect is observed upon addition of 1.6 equiv.
of LiBPh4.
Since the polar and steric effects may act in concert to
give high conformer preferences in 8 and 9, the diastereom-
eric compound 10 might then be expected to be a mis-
matched system. In fact, force-field calculations predict a
significantly reduced preference for conformation 10a, with
attendant higher contributions of the conformations 10b
and 10c in the conformer equilibrium.
Figure 2. NMR titration of compound 8 with LiBPh4; changes in
the 13C NMR chemical shifts
Nevertheless, the NMR spectra of 10 show vicinal coup-
ling constants which again indicate a strong preference for
a single conformation. Moreover, the data show that this
preference does not depend on the polarity of the solvent.
That conformer 10a, and not conformer 10c, is the pre-
ferred one follows from a strong NOE contact between 3Ј-
CH3 and 2-H.
The changes in the 13C NMR chemical shifts induced by
the addition of LiBPh4 (cf. Figure 2) can be reproduced by
numerical simulation,[28] suggesting complexation constants
of ca. 580 L·molϪ1 for an 8·Li complex and of ca. 30
L2·molϪ2 for an (8)2·Li complex.
As a common feature in the set of compounds 6Ϫ10, we
anticipated that the gem-dimethyl inductor group of the
THP ring would guarantee a high preference for an antiper-
We then initiated a similar study with the diastereomeric
[17Ϫ20]
iplanar orientation
of C-2Ј to the gem-dimethyl
ligand 10. Again, addition of LiBPh4 to a solution of 10 in
group. Regarding the C-1ЈϪC-2Ј-bond, the conformer pref-
erence was in all cases found to be higher than that calcu-
lated by the MM3* force-field. When comparing com-
pounds 6Ϫ10 with 2,4-dimethoxypentane, which has only a
low conformational preference,[21] the high conformational
preference found for the compounds 8Ϫ10 is gratifying.
1
CD3NO2 resulted in significant changes in the H and 13C
NMR spectra. In this case, however, complexation was ac-
companied by considerable line broadening of the NMR
signals, precluding an NMR titration of sufficient quality
to allow the determination of complexation constants. That
complexation to Li cations induced a conformation change
from 10a to 10b could, nevertheless, be established by re-
sorting to NOE experiments.
Complexation Studies
The fact that the conformational preferences calculated
for compounds 8Ϫ10 are high (ca. 90%), but not exceed-
ingly high, opens up the possibility of changing the con-
former population by external action. We imagined that
complexation with a bidentate Lewis acid should lead to a
Eur. J. Org. Chem. 2001, 1857Ϫ1864
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R. W. Hoffmann, B. C. Kahrs, P. Reiß, T. Trieselmann, H.-C. Stiasny, W. Massa
FULL PAPER
Uncomplexed 10 (ϭ 10a) shows an NOE contact be- shows a methyl signal at δ ϭ 15 (i.e. Ͻ 20), diagnostic of
tween 2-H and 3Ј-CH3 and no NOE contact between 2-H an isopropyl group flanked by an equatorial substituent.[32]
and 2Ј-H. Upon addition of ca. 5 equiv. of LiBPh4, the
former NOE contact vanishes, while a new one appears be-
tween 2-H and 2Ј-H.
Encouraged by these results, we took a brief look at the
complexation behavior of the bis(tetrahydropyranyl)me-
thane 11.[14] Initial experiments with 11 in toluene solution
3
showed that the JH,H coupling constants characteristic of
11a (9.4 and 2.7 Hz) changed to 8.0 and 3.5 Hz upon addi-
tion of LiClO4. NMR titration with LiBPh4 in CD3NO2
was complicated by the precipitation of a complex Ϫ prob-
We then transformed 14 into the tertiary bromo com-
ably the (11)2·Li complex Ϫ in an intermediate concentra-
pound 15[31] (77%). Reduction with Bu3SnH and AIBN
tion range. The complex redissolved upon further addition
gave a 1.4:1 mixture of 5/epi-5. The highest ratio of 5 to
of LiBPh4. The complexation constant for the formation of
epi-5 (3.6:1) was reached when 15 was reduced with sodium
the 11·Li and (11)2·Li complexes have been approximated
metal in refluxing THF followed by protonation with meth-
by simulation and turned out to be of the same magnitude
anol at Ϫ78 °C. The mixture of 5/epi-5 obtained (93%) was
as the complexation constants found for 8.
used as such to determine the characteristic NMR data of
5.
For the synthesis of 6, isovaleraldehyde was converted[33]
into the homoallylic alcohol 16 (74%). The latter compound
was subjected to hydroformylation, followed by ionic reduc-
tion of the tetrahydropyranol intermediate. This sequence
furnished the tetrahydropyran 6 in 87% yield.
Finally, when the bis(dioxane) compound 12[29] was
treated with LiBPh4 in CD3NO2, only very small (Ͻ
0.5 ppm, but systematic) changes occurred in the 13C NMR
chemical shifts. These show that the complexation con-
stants are only of the order of 1Ϫ2 L·molϪ1. This is in line
The acetonide 7 was obtained by acetalization of the diol
17, available from another study.[34]
with the reduced basicity of oxygen atoms in acetals, com-
pared to those in an ether function.[30] Kishi reported[26]
a
related observation concerning the complexing abilities of
O-sucrose versus C-sucrose towards Ca ions. These results
are noteworthy in that very similar structural entities, such
as 11 and 12, can be activated (11) or deactivated (12) to-
wards conformational switching by cation complexation.
The synthesis of 8 and 10 began with the prenylation[33]
of β-methoxybutyraldehyde (18).[35] This produced a 1:2
mixture of the epimeric alcohols 19 and 20. Separation of
the epimers by flash chromatography was possible, but we
found it more convenient to convert 19 and 20 into the silyl
ethers 21 and 22, which allowed for easy chromatographic
separation.
Syntheses
The synthesis of 5 started from menthone. Addition of
isobutyllithium in the presence of CeCl3 at Ϫ78 °C fur-
nished 54% of the alcohol 14. A single diastereomer was
isolated. We assume that the hydroxy group in 14 is in the
axial position, but this is not proven. When ionic reduction
(Ph3SiH, CF3COOH; or Et3SiH, CF3COOH) was used to
convert 14 into 5, product mixtures of 5 and epi-5 were
obtained, with epi-5 predominating. The assignment is
based on the 13C NMR spectra, in which we attribute the
set of signals with a larger number of signals shifted upfield
in the δ ϭ 20Ϫ50 range to epi-5, which bears an axial iso-
butyl group.[31] Moreover, only one of these compounds
1860
Eur. J. Org. Chem. 2001, 1857Ϫ1864

Conformation of Side Chains on Cyclohexane and Tetrahydropyran Ring Systems
FULL PAPER
omethane (5 ϫ 10 mL). The combined organic phases were dried
(MgSO4) and concentrated. Flash chromatography of the residue,
using petroleum ether/tert-butyl methyl ether (25:1), furnished 14
The alcohols 19 and 20 were then obtained individually
by hydrolysis of the separated silyl ethers 21 and 22. The
relative configurations of 19 and 20 were assigned on the
basis of chemical shift values of the oxygen-bearing carbon
atoms [δ ϭ 78.5, 78.6 (syn); 74.3, 74.8 (anti)].[36] The homo-
allylic alcohol 19 was converted into the tetrahydropyran
10 (82%) by a sequence of hydroformylation and ionic re-
duction. Likewise, the alcohol 20 furnished 66% of 8.
Finally, for the synthesis of 9 the aldehyde 18 was allowed
to react with the ketene acetal 23[37] under TiCl4 cata-
lysis.[38] This furnished the hydroxy ester 24 with a 4:1 anti/
syn selectivity. Diastereomer assignment was again based
on the 13C NMR signal positions[36] [δ ϭ 75.5, 77.5 (syn);
72.4, 73.9 (anti)].
1
as a colorless oil (0.831 g, 54%). Ϫ H NMR (200 MHz, CDCl3):
δ ϭ 0.75Ϫ1.15 (m, 19 H), 1.25Ϫ1.55 (m, 4 H), 1.55Ϫ1.85 (m, 4
H), 2.12 (qd, J ϭ 7.0 and 1.8 Hz, 1 H). Ϫ 13C NMR (50 MHz,
CDCl3): δ ϭ 18.1, 20.6, 22.6, 23.6, 23.7, 24.6, 25.3, 25.5, 28.1, 35.1,
47.0, 49.4, 49.8, 75.5. Ϫ [α]D20 ϭ Ϫ10.0 (c ϭ 1.55, diethyl ether). Ϫ
C14H28O (212.4): calcd. C 79.18, H 13.29; found C 78.91, H 13.05.
2. (1R,2RS,4S)-2-Isobutyl-1-isopropyl-4-methylcyclohexane (5): A
stream of hydrogen bromide was slowly introduced into a flask
containing (1R,2R,5S)-1-isobutyl-2-isopropyl-5-methylcyclohexa-
nol (14) (167 mg, 0.79 mmol). After ca. 45 min, two phases formed.
TLC indicated that the reaction was complete after 1.5 h. The mix-
ture was diluted with ether (8 mL). The resulting solution was
washed with aqueous NaHCO3 solution (5 mL) and brine (5 mL).
The solution was dried (MgSO4) and concentrated to give a color-
less oil (167 mg), which appeared to be a single diastereomer. Ϫ
13C NMR (50 MHz, C6D6): δ ϭ 17.6, 20.7, 22.3, 23.2, 25.2, 25.4,
32.4, 32.7, 33.5, 37.4, 38.1, 40.9, 42.7, 89.6. Ϫ The bromo com-
pound obtained (50 mg, ca. 0.18 mmol) was taken up in THF
(1.5 mL) and sodium (122 mg, 5.3 mmol) was added in small
pieces. This mixture was heated to reflux for 2 h and cooled to
room temperature. The remaining sodium pieces were removed and
the solution was cooled to Ϫ78 °C. Methanol (0.5 mL) was added
slowly over 1 h. The mixture was allowed to come to room temper-
ature and was extracted with pentane (3 ϫ 4 mL). The combined
organic phases were dried (MgSO4) and concentrated. Flash chro-
matography of the residue with petroleum ether furnished 5 and
epi-5 (33 mg, 93%) as a colorless oil. The diastereomer ratio was
estimated to be 3.6:1 by integrating the 13C NMR signals at δ ϭ
47.9 and 48.3. Ϫ 5: 13C NMR (100 MHz, CDCl3): δ ϭ 15.1, 21.3,
21.7, 22.9, 24.4, 24.5, 24.8, 26.2, 32.8, 35.4, 36.6, 41.4, 42.7, 47.9.
Ϫ HRMS: C14H28: required for [Mϩ] 196.2191, found 196.2197.
The mixture of esters 24 was reduced to a mixture of
diastereomeric diols 25, which were immediately converted
into the acetonides 9 and epi-9. Flash chromatography pro-
vided 9 in 57% yield.
Experimental Section
3. 3,3,6-Trimethyl-1-hepten-4-ol (16): Prenyl bromide (12.5 g,
83.6 mmol), sodium iodide (20.9 g, 139 mmol), and SnCl2·2H2O
(23.6 g, 104 mmol) were added slowly to a solution of isovaleral-
dehyde (6.00 g, 69.7 mmol) in dimethylformamide (140 mL) at 0 °C
in such a manner that the temperature did not rise above 30 °C.
The resulting suspension was stirred for 2 d. The mixture was
poured into aqueous NH4F solution (15%, 100 mL), the phases
were separated, and the aqueous phase was extracted with tert-
butyl methyl ether (4 ϫ 100 mL). The combined organic phases
were dried (Na2SO4) and concentrated. Distillation of the residue
furnished 16 (15.35 g, 74%) as a colorless liquid of b.p. 69 °C/
30 mbar. Ϫ 1H NMR (200 MHz, CDCl3): δ ϭ 0.89 (d, J ϭ 6.8 Hz,
3 H), 0.93 (d, J ϭ 6.8 Hz, 3 H), 0.99 (s, 6 H), 1.24 (m, 2 H), 1.76
(m, 1 H), 3.47 (m, 1 H), 5.0 (m, 2 H), 5.81 (m, 1 H). These data
correspond to those given in ref.[39]
1
General Remarks: All temperatures quoted are uncorrected. Ϫ H
NMR, 13C NMR: Bruker ARX-200, AC-300, WH-400, AM-400,
AMX 500. Ϫ Boiling range of petroleum ether: 40Ϫ60 °C. Ϫ Flash
chromatography: SI 60 silica gel, Merck KGaA, Darmstadt, 40Ϫ63
µm. Conformer populations were estimated on the basis of force-
field calculations using the MM3* force-field implemented in the
MACROMODEL[15] program, versions 4.5 and 6.5. Conformers
with energies of Ͻ 25 kJ above the minimum energy conformer
were subjected to Boltzmann averaging for 298 K to predict the
conformer population.
1. (1R,2R,5S)-1-Isobutyl-2-isopropyl-5-methylcyclohexanol (14):
CeCl3 (2.52 g, 9.83 mmol) was dried at 10Ϫ3 Torr and 140 °C for
1.5 h. The material was subsequently suspended in THF (30 mL).
The suspension was cooled to Ϫ78 °C and a solution of isobutylli-
thium (12.6 mL, 0.72  in Et2O, 9.43 mmol) was added dropwise. 4. 2-Isobutyl-3,3-dimethyltetrahydropyran (6): Triphenylphosphane
After the mixture had been stirred for 1 h, (R,R)-menthone (1.12 g,
7.25 mmol) was added and the suspension was stirred for a further
1.5 h at Ϫ78 °C. Saturated aqueous NH4Cl solution (10 mL) was
added, and after the mixture had reached room temperature, water
was added until a homogenous solution resulted. The phases were
separated and the aqueous phase was extracted with dichlorome-
(2.4 g, 9.0 mmol) was added to a solution of (acetylacetonato)-
dicarbonylrhodium (31 mg, 0.12 mmol) in methyl acetate (2 mL), re-
sulting in a strong gas evolution. After stirring for 30 min, this
solution was transferred into an autoclave which contained a solu-
tion of 3,3,6-trimethyl-1-hepten-4-ol (16) (1.0 g, 6.0 mmol) in
methyl acetate (23 mL). The contents of the autoclave were stirred
thane (5 ϫ 30 mL). The combined organic phases were dried for 48 h at 100 °C under 30 bar of CO/H2. The contents of the
(MgSO4) and concentrated. To reduce residual menthone, the re-
maining yellowish oil was added at 0 °C to a solution of NaBH4
(70 mg) in methanol (8 mL). After the mixture had been stirred at
room temperature overnight, water (5 mL) was added, the phases
were separated, and the aqueous phase was extracted with dichlor-
autoclave were concentrated and the residue was taken up in pent-
ane/ethyl acetate (4:1) (50 mL) and filtered through silica gel (50 g).
The filtrate was concentrated and the residue was taken up in
dichloromethane (20 mL). Triethylsilane (1.3 mL, 8.0 mmol) and
trifluoroacetic acid (1.3 mL, 17 mmol) were added at 0 °C. The
Eur. J. Org. Chem. 2001, 1857Ϫ1864
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R. W. Hoffmann, B. C. Kahrs, P. Reiß, T. Trieselmann, H.-C. Stiasny, W. Massa
FULL PAPER
solution was heated to reflux for 18 h. Aqueous ammonia (25%)
was added until the mixture was basic. The phases were separated
and the aqueous phase was extracted with tert-butyl methyl ether
(4 ϫ 50 mL). The combined organic phases were dried (Na2SO4)
and concentrated. Flash chromatography of the residue with pent-
ane/tert-butyl methyl ether (9:1) furnished 0.89 g (87%) of 6 as a
H), 1.72 (ddd, J ϭ 13.4, 9.3, and 4.2 Hz, 1 H), 3.25Ϫ2.34 (m, 5
H), 4.95 (dd, J ϭ 17.2 and 1.4 Hz, 1 H), 4.97 (dd, J ϭ 11.1 and
1.4 Hz, 1 H), 5.80 (dd, J ϭ 17.2 and 11.1 Hz, 1 H). Ϫ 13C NMR
(75 MHz, CDCl3): δ ϭ 0.86, 18.9, 22.5, 24.1, 39.9, 41.9, 55.8, 75.1,
77.5, 111.9, 145.8. Ϫ C13H28O2Si (244.4): calcd. C 63.88, H 11.55,
found C 63.70, H 11.69.
1
colorless liquid. Ϫ H NMR (500 MHz, CD3NO2): δ ϭ 0.80 (s, 3
(4R*,6S*)-6-Methoxy-3,3-dimethyl-4-trimethylsilyloxy-1-heptene
(22): 1H NMR (300 MHz, CDCl3): δ ϭ 0.11 (s, 9 H), 1.03 (s, 6 H),
1.08 (d, J ϭ 6.0 Hz, 3 H), 1.27 (ddd, J ϭ 14.3, 10.2, and 2.3 Hz, 1
H), 1.53 (ddd, J ϭ 14.3, 10.3, and 1.6 Hz, 1 H), 3.28 (s, 3 H),
3.35Ϫ3.49 (m, 1 H), 3.66 (dd, J ϭ 10.2 and 1.6 Hz, 1 H), 4.87Ϫ4.99
(m, 2 H), 5.73Ϫ5.91 (m, 1 H). Ϫ 13C NMR (75 MHz, CDCl3): δ ϭ
0.95, 19.1, 22.7, 24.1, 40.8, 41.5, 55.1, 72.9, 76.6, 111.6, 146.1. Ϫ
C13H28O2Si (244.4): calcd. C 63.88, H 11.55, found C 63.89, H
11.72.
H), 0.87 (d, J ϭ 6.6 Hz, 3 H), 0.88 (s, 3 H), 0.89 (d, J ϭ 6.6 Hz, 3
H), 1.16 (ddd, J ϭ 14.0, 10.1, and 2.0 Hz, 1 H), 1.24 (ddd, J ϭ
14.0, 10.1, and 2.0 Hz, 1 H), 1.36 (m, 2 H), 1.46 (m, 1 H), 1.73 (m,
2 H), 3.03 (dd, J ϭ 10.1 and 2.0 Hz, 1 H), 3.31 (ddd, J ϭ 12.5,
11.1, and 2.4 Hz, 1 H), 3.88 (dddd, J ϭ 11.1, 4.9, 1.7, and 1.7 Hz,
1 H). Ϫ 13C NMR (100 MHz, CDCl3): δ ϭ 19.0, 21.5, 23.2, 23.9,
24.7, 27.6, 32.6, 38.8, 39.3, 68.8, 83.7. Ϫ C11H22O (170.3): calcd. C
77.58, H. 13.02; found C 77.30, H 12.60.
5. (4R*,6S*)-4,6-Bis(2Ј,2Ј-dibromoethyl)-2,2,5,5-tetramethyl-1,3-di-
oxane (7): p-Toluenesulfonic acid (40 mg, 0.20 mmol) was added to
a solution of (3S*,5R*)-1,1,7,7-tetrabromo-3,5-dihydroxy-4,4-di-
methylheptane (17) (683 mg, 1.44 mmol) in 2,2-dimethoxypropane
(10 mL). After the mixture had been stirred for 1 d, triethylamine
(5 drops) was added and the mixture was concentrated. Flash chro-
matography of the residue with pentane/tert-butyl methyl ether
(10:1) furnished 7 (682 mg, 92%) as a colorless solid of m.p.
162Ϫ165 °C[40] Ϫ 1H NMR (300 MHz, CDCl3): δ ϭ 0.81 (s, 3 H),
0.89 (s, 3 H), 1.34 (s, 3 H), 1.42 (s, 3 H), 2.35Ϫ2.51 (m, 4 H),
3.71Ϫ3.78 (m, 2 H), 5.69Ϫ5.76 (m, 2 H). Simulation of the spec-
trum is compatible with the following assignments: δ ϭ 2.425 (ddd,
J ϭ 14.4, 11.2, and 2.4 Hz, 1 H), 2.448 (ddd, J ϭ 14.4, 9.8, and
2.5 Hz, 1 H), 3.74 (ddd, J ϭ 9.8, 2.4, and Ϫ0.2 Hz, 1 H), 5.72 (ddd,
J ϭ 11.2, 2.5, and Ϫ0.2 Hz, 1 H). Ϫ 13C NMR (75 MHz, CDCl3):
δ ϭ 14.0, 19.3, 20.0, 29.8, 34.6, 43.7 (2C), 45.1 (2C), 76.2 (2C), 99.3.
Ϫ C12H20Br4O2 (515.9): calcd. C 27.94, H 3.91; found C 28.04, H
3.84.
7. (4R*,6R*)-4-Hydroxy-6-methoxy-3,3-dimethyl-1-heptene (19):
(4R*,6R*)-6-Methoxy-3,3-dimethyl-4-trimethylsilyloxy-1-heptene
(21) (1.58 g, 6.45 mmol) in ethanol (30 mL) was stirred with aque-
ous NH4F solution (15%, 20 mL) for 12 h. The mixture was ex-
tracted with tert-butyl methyl ether (3 ϫ 50 mL). The combined
organic phases were dried (MgSO4) and concentrated. Flash chro-
matography of the residue with petroleum ether/ether (1:1) fur-
1
nished 19 (945 mg, 85%) as a colorless oil. Ϫ H NMR (400 MHz,
CDCl3): δ ϭ 1.00 (s, 6 H), 1.15 (d, J ϭ 6.0 Hz, 3 H), 1.40Ϫ1.58
(m, 2 H), 3.33 (s, 3 H), 3.47 (ddd, J ϭ 10.1, 1.5, and 1.5 Hz, 1 H),
3.47Ϫ3.56 (m, 1 H), 3.73 (d, J ϭ 1.5 Hz, 1 H), 4.99 (dd, J ϭ 17.3
and 1.5 Hz, 1 H), 5.00 (dd, J ϭ 11.1 and 1.5 Hz, 1 H), 5.86 (dd,
J ϭ 17.3 and 11.1 Hz, 1 H). Ϫ 13C NMR (100 MHz, CDCl3): δ ϭ
19.1, 22.0, 23.2, 38.3, 41.2, 55.8, 78.5, 78.6, 112.1, 145.7. Ϫ
C10H20O2 (172.3): calcd. C 69.72, H 11.70; found C 69.52, H 11.84.
8. (4R*,6S*)-4-Hydroxy-6-methoxy-3,3-dimethyl-1-heptene (20):
(4R*,6S*)-6-Methoxy-3,3-dimethyl-4-trimethylsilyloxy-1-heptene
(22) (3.12 g, 12.8 mmol) was deprotected as described under 7 to
give 20 as a colorless oil (1.93 g, 88%). Ϫ 1H NMR (400 MHz,
CDCl3): δ ϭ 0.99 (s, 3 H), 1.00 (s, 3 H), 1.17 (d, J ϭ 6.2 Hz, 3 H),
1.43Ϫ1.57 (m, 2 H), 2.44 (broad s, 1 H), 3.31 (s, 3 H), 3.56Ϫ3.66
(m, 2 H), 5.01 (dd, J ϭ 17.5 and 1.5 Hz, 1 H), 5.04 (dd, J ϭ 10.9
and 1.5 Hz, 1 H), 5.84 (dd, J ϭ 17.5 and 10.9 Hz, 1 H). Ϫ 13C
NMR (100 MHz, CDCl3): δ ϭ 18.6, 22.5, 22.8, 37.4, 41.2, 56.2,
74.3, 74.8, 112.8, 145.5. Ϫ C10H20O2 (172.3): calcd. C 69.72, H
11.70; found C 69.66, H 11.72.
6. 6-Methoxy-3,3-dimethyl-4-trimethylsilyloxy-1-heptenes (21 and
22): 3-Methoxybutanal (18)[35] (10.0 g, 97.9 mmol), prenyl bromide
(17.52 g, 117.6 mmol), and sodium iodide (30.0 g, 200 mmol) were
dissolved in dimethylformamide (200 mL). SnCl2·2H2O (33.0 g,
146 mmol) was added under nitrogen, in such a manner that the
temperature did not exceed 30 °C. The mixture was stirred for 2 d,
aqueous NH4F solution (20%, 600 mL) was added, the phases were
separated, and the aqueous phase was extracted with tert-butyl
methyl ether (3 ϫ 200 mL). The combined organic phases were
concentrated. Zinc powder (ca. 100 mg) was added and the suspen-
sion was stirred for 10 min. tert-Butyl methyl ether (200 mL) was
added, together with MgSO4 (ca. 0.5 g). The suspension was fil-
tered and the filtrate was concentrated. Distillation furnished a ca.
2:1 mixture of the alcohols 19 and 20 as a colorless liquid of b.p.
60Ϫ64 °C at 1 mbar. Separation of the mixture by flash chromato-
graphy is possible, using diethyl ether/pentane (1:1). The mixture
of 19 and 20 (5.35 g, 31.1 mmol) was taken up in dichloromethane
(150 mL). Triethylamine (5.8 mL, 42 mmol), 4-(dimethylamino)py-
ridine (ca. 100 mg), and chlorotrimethylsilane (4.0 g, 37 mmol)
were added at 0 °C. The mixture was stirred for 12 h at room tem-
perature. Water (100 mL) and ether (150 mL) were added. The
phases were separated and the aqueous phase was extracted with
ether (2 ϫ 50 mL). The combined organic phases were dried
(MgSO4) and concentrated. Flash chromatography of the residue
with petroleum ether/dichloromethane (1:1) furnished 22 (4.20 g,
55%) and 21 (1.81 g, 24%) as colorless liquids.
9.
(2R*,2ЈS*)-2-(2Ј-Methoxypropyl)-3,3-dimethyltetrahydropyran
(8): Compound 20 (1.03 g, 6.00 mmol) was transformed essentially
as described for compound 6, to give 8 as a colorless oil (734 mg,
66%). Ϫ 1H NMR (500 MHz, CD3NO2): δ ϭ 0.80 (s, 3 H), 0.87
(s, 3 H), 1.08 (d, J ϭ 6.2 Hz, 3 H), 1.23 (ddd, J ϭ 14.4, 10.3, and
3.1 Hz, 1 H), 1.30Ϫ1.40 (m, 2 H), 1.42Ϫ1.49 (m, 1 H), 1.54 (ddd,
J ϭ 14.4, 9.4, and 1.5 Hz, 1 H), 1.68Ϫ1.82 (m, 1 H), 3.15 (dd, J ϭ
10.3 and 1.5 Hz, 1 H), 3.26 (s, 3 H), 3.32 (ddd, J ϭ 12.3, 11.1, and
2.1 Hz, 1 H), 3.43 (m, 1 H, decoupling at δ ϭ 1.08 revealed dd,
J ϭ 9.4 and 3.1 Hz), 3.88 (dddd, J ϭ 11.1, 4.9, 1.6, and 1.6 Hz, 1
H). Ϫ 13C NMR (100 MHz, CD3NO2): δ ϭ 19.5, 20.2, 24.4, 28.1,
33.5, 38.8, 40.3, 56.5, 69.6, 75.2, 83.3. Ϫ C11H22O2 (186.3): calcd.
C 70.92, H 11.90; found C 70.80, H 11.65.
10. (2R*,2ЈR*)-2-(2Ј-Methoxypropyl)-3,3-dimethyltetrahydropyran
(10): Compound 19 (1.0 g, 6.0 mmol) was converted into the tetra-
hydropyran as described for compound 6, to give 10 (0.92 g, 82%)
1
as a colorless liquid. Ϫ H NMR (500 MHz, CD3NO2): δ ϭ 0.81
(4R*,6R*)-6-Methoxy-3,3-dimethyl-4-trimethylsilyloxy-1-heptene
(21): 1H NMR (300 MHz, CDCl3): δ ϭ 0.11 (s, 9 H), 0.95 (s, 6 H),
1.10 (d, J ϭ 6.0 Hz, 3 H), 1.40 (ddd, J ϭ 13.4, 9.3, and 2.3 Hz, 1
(s, 3 H), 0.90 (s, 3 H), 1.10 (d, J ϭ 6.1 Hz, 3 H), 1.30Ϫ1.41 (m, 3
H), 1.44Ϫ1.50 (m, 1 H), 1.62 (ddd, J ϭ 13.9, 10.4, and 3.0 Hz, 1
H), 1.70Ϫ1.83 (m, 1 H), 3.00 (dd, J ϭ 10.4 and 1.9 Hz, 1 H), 3.25
1862
Eur. J. Org. Chem. 2001, 1857Ϫ1864

Conformation of Side Chains on Cyclohexane and Tetrahydropyran Ring Systems
FULL PAPER
(s, 3 H), 3.29 (ddd, J ϭ 12.2, 11.1, and 2.2 Hz, 1 H), 3.36Ϫ3.45
(m, 1 H), 3.86 (dddd, J ϭ 11.1, 4.8, 1.7, and 1.7 Hz, 1 H). Ϫ 13C
after each addition of 20 µL of a 0.708  solution of lithium tetra-
phenylborate in CD3NO2. The chemical shifts recorded were plot-
NMR (125 MHz, CDCl3): δ ϭ 18.7, 19.0, 23.0, 27.5, 32.6, 35.9, ted against the equivalents of lithium tetraphenylborate added. The
39.1, 55.8, 68.7, 74.7, 82.5. Ϫ C11H22O2 (186.3): calcd. C 70.92, H
11.90, found C 70.62, H 11.84.
resulting curves were simulated by considering formation of 1:1 and
2:1 ligand/lithium complexes. This provided an approximation of
the equilibrium constants.
11. Ethyl 3-Hydroxy-5-methoxy-2,2-dimethylhexanoate (24): A so-
lution of 3-methoxybutanal (18)[35] (2.16 g, 21.2 mmol) in dichloro-
methane (30 mL) was stirred for 20 min with molecular sieves (4
˚
A, 1 g). The solution was cooled to Ϫ78 °C. TiCl4 (2.4 mL,
Acknowledgments
22 mmol) was added. After the mixture had been stirred for 15
We express our gratitude to the Deutsche Forschungsgemeinschaft
(Graduierten-Kolleg ‘‘Metallorganische Chemie’’) for fellowships
to B. C. K. and to H. C. S. We thank the Fonds der Chemischen
Industrie and the VW-Stiftung for support of this study.
min,
1-ethoxy-2-methyl-1-trimethylsilyloxy-1-propene
(23)[37]
(4.02 g, 21.4 mmol) was added dropwise. After stirring for 2 h at
Ϫ78 °C, the mixture was allowed to come to 0 °C. Water (10 mL)
and ether (50 mL) were added, the phases were separated, and the
aqueous phase was extracted with ether (3 ϫ 50 mL). The com-
bined organic phases were washed with saturated aqueous
NaHCO3 solution (10 mL), dried (MgSO4), and concentrated.
Bulb-to-bulb distillation of the residue at 60 °C/1 mbar furnished
the ester 24 (2.62 g, 57%) as a diastereomer mixture. Ϫ C11H22O4
(218.3): calcd. C 60.52, H 10.16; found C 60.44, H 10.30. Ϫ Major
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1
Diastereomer (anti): H NMR (300 MHz, CDCl3): δ ϭ 0.94Ϫ1.16
(m, 12 H), 1.30Ϫ1.40 (m, 2 H), 3.20 (s, 3 H), 3.44Ϫ3.58 (m, 1 H),
3.70 (broad s, 1 H), 3.76Ϫ3.88 (m, 1 H), 3.94Ϫ4.08 (m, 2 H). Ϫ
13C NMR (75 MHz, CDCl3): δ ϭ 13.8, 18.5, 20.3, 21.4, 38.1, 46.5,
55.8, 60.2, 72.4, 73.9, 177.3. Ϫ Minor Diastereomer (syn): The fol-
[5]
[6]
[7]
1
lowing signals could be recorded. Ϫ H NMR (300 MHz, CDCl3):
δ ϭ 3.21 (s, 3 H). Ϫ 13C NMR (75 MHz, CDCl3): δ ϭ 18.7, 20.5,
[8]
38.2, 46.7, 55.5, 60.1, 75.5, 77.5, 176.8.
[9]
12. (2ЈR*,4S*)-4-(2Ј-Methoxypropyl)-2,2,5,5-tetramethyl-1,3-diox-
ane (9): Compound 24 (2.40 g, 11.0 mmol) was added to a solution
of LiAlH4 (0.50 g, 13 mmol) in THF (20 mL) under argon. After
15 h of reflux, the mixture was cooled to 0 °C. Excess LiAlH4 was
decomposed by the dropwise addition of saturated aqueous NH4F
solution (20 mL). The phases were separated and the aqueous
phase was extracted with tert-butyl methyl ether (4 ϫ 50 mL). The
combined organic phases were dried (MgSO4) and concentrated.
Chromatography of the residue with petroleum ether/ethyl acetate
(1:2) furnished the mixture of the diastereomeric diol 25 (592 mg,
31%) as a colorless oil. Ϫ Major Diastereomer (anti): 13C NMR
(75 MHz, CDCl3): δ ϭ 18.4, 18.8, 22.2, 37.4, 37.9, 56.0, 71.9, 74.7,
75.0. Ϫ Minor Diastereomer (syn): 13C NMR (75 MHz, CDCl3):
δ ϭ 18.7, 19.0, 22.3, 37.9, 38.0, 55.6, 71.3, 78.6, 79.4. Ϫ The diols
obtained (570 mg, 3.23 mmol) were taken up in dichloromethane
(10 mL). 2,2-Dimethoxypropane (1.3 mL) and camphorsulfonic
acid (ca. 50 mg) were added. The mixture was stirred for 3 h at
room temperature and poured into saturated aqueous NaHCO3
solution (10 mL). The phases were separated and the aqueous
phase was extracted with ether (3 ϫ 50 mL). The combined organic
phases were dried (MgSO4) and concentrated. Flash chromato-
graphy with dichloromethane/ethyl acetate (10:1) furnished the ma-
jor diastereomer 9 (401 mg, 57%) as a colorless oil. Ϫ 1H NMR
(500 MHz, [D8]toluene): δ ϭ 0.530 (s, 3 H), 1.009 (s, 3 H), 1.023
(d, J ϭ 6.2 Hz, 3 H), 1.314 (ddd, J ϭ 13.9, 10.3, and 2.6 Hz, 1 H),
1.364 (s, 1 H), 1.459 (ddd, J ϭ 13.9, 10.0, and 1.4 Hz, 1 H), 1.477
(s, 1 H), 3.181 (s, 3 H), 3.192 (d, J ϭ 10.7 Hz, 1 H), 3.40Ϫ3.49 (m,
2 H), 3.845 (dd, J ϭ 10.3 and 1.4 Hz, 1 H). Ϫ 13C NMR (125 MHz,
[D8]toluene): δ ϭ 18.3, 19.1, 19.5, 21.5, 30.1, 32.5, 37.9, 56.1, 72.3,
73.1, 73.5, 98.6. Ϫ C12H24O3 (216.3): calcd. C 66.63, H 11.18,
found C 66.65, H 11.24.
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spectra of this solution were recorded and new spectra measured
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Eur. J. Org. Chem. 2001, 1857Ϫ1864
1863

R. W. Hoffmann, B. C. Kahrs, P. Reiß, T. Trieselmann, H.-C. Stiasny, W. Massa
FULL PAPER
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Crystallographic data (excluding structural factors) for the
structure reported in this paper have been deposited with the
Cambridge Crystallographic Data Centre as supplementary
publication number CCDC-157271. Copies of the data can be
obtained free of charge on application to CCDC, 12 Union
Road, Cambridge, CB2 1EZ, UK [Fax: (internat.) ϩ 44-1223/
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Received November 24, 2000
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[O00597]
1864
Eur. J. Org. Chem. 2001, 1857Ϫ1864