Conformational analysis of meso-2,3,4,5-tetramethylhexane and some of its derivatives

Article abstract of DOI:10.1002/1099-0690(200107)2001:14<2749::aid-ejoc2749>3.0.co;2-t

Compounds 12-15, meso-type 2,3,4,5,6,7-hexasubstituted octane derivatives, have been synthesized using solely substrate-based asymmetric induction. Thanks to the specific relative configurations at the six stereogenic centres, these compounds have a high tendency to populate the conformation with a fully extended zig-zag backbone chain.

Full text of DOI:10.1002/1099-0690(200107)2001:14<2749::aid-ejoc2749>3.0.co;2-t

FULL PAPER
Conformational Analysis of meso-2,3,4,5-Tetramethylhexane and Some of
Its Derivatives[‡]
Reinhard W. Hoffmann*[a] and Karsten Menzel[a]
Keywords: Conformational analysis / Hydrocarbons
Compounds 12−15, meso-type 2,3,4,5,6,7-hexasubstituted
octane derivatives, have been synthesized using solely sub- compounds have a high tendency to populate the conforma-
strate-based asymmetric induction. Thanks to the specific
tion with a fully extended zig-zag backbone chain.
relative configurations at the six stereogenic centres, these
We are interested in compounds with flexible molecular simultaneous creation of two syn-pentane interactions.
backbones that adopt a single distinct conformation.[2] Other groups[5] and we ourselves[6Ϫ8] have identified some
Such properties should result when every rotatable bond in substituent patterns for alkane chains (cf. 2Ϫ4) which meet
the compound in question has only a single low-energy these criteria.
local conformation and when all undesired conformations
are of substantially higher energy. In the case of saturated
alkane chains, this could come about as a result of a sub-
stituent pattern that creates destabilizing syn-pentane inter-
actions in each of the undesired conformers. The underlying
principle can be illustrated with reference to 2,2-dimethyl-
pentane (1), considering rotation about the C-3/C-4 bond.[3]
Of the three diamond lattice type conformations, only con-
formation 1a is free of syn-pentane interactions, whereas
the conformers 1b and 1c are destabilized by a syn-pent-
ane interaction.
This holds, for example, for the central bond in meso-
tetramethylhexane (3), the conformational properties of
which are discussed in this paper. The considerations men-
tioned above made us anticipate that 3 should populate the
conformation 3a with high preference, since this is the only
backbone conformation free of syn-pentane interactions.
Such a syn-pentane interaction results in a destabilization
of 1.8 to 2.5 kcal molϪ1, depending on how readily it can
relax into a non-diamond lattice conformation.[4] Adoption
of a single conformation at a rotatable bond causes a de-
crease in entropy, which has to be compensated by an en-
thalpy penalty. The enthalpy penalty of a single destabiliz-
ing syn-pentane interaction for forming an undesired rot-
amer may be sufficient to control the conformation of mole-
cules such as 1, with one or two rotatable bonds. When it
comes to larger molecules, however, this enthalpy penalty
may not be high enough to control the conformation at
several rotatable bonds simultaneously, or, put another way,
to enforce a high population of a single global conforma-
tion. For this reason, we were interested in identification of
alkane chain substituent patterns that would penalize un-
desired rotamers with a higher enthalpy penalty, such as by
However, force field calculations with the MM3* force
field implemented in the Macromodel program[9] indicated
that the conformational preference for 3a should amount
to only ca. 80%; the results are summarized in Table 1. The
higher energy conformers are pair-wise degenerate for
reasons of symmetry.
The low level of conformational preference can be attrib-
uted to the four methyl side groups present in 3, which give
rise to eight gauche interactions with the main chain even
in the desired conformer 3a. This results in a ca. 5 kcal
destabilization of the low-energy conformation and so re-
duces the decisive energy gap between 3a and the undesired
higher energy conformations. For this reason it appeared
futile to extend the concept to hexamethyloctane (5), in
which the most stable conformation 5a would have 12 de-
stabilizing gauche interactions. It turned out, however, that
Macromodel calculations predicted a higher conforma-
[‡]
Flexible Molecules with Defined Shape, XVI. Ϫ Part XV:
Ref.[1]
[a]
Fachbereich Chemie der Philipps-Universiät,
Hans Meerwein-Str. 35032 Marburg, Germany
Fax: (internat.) ϩ 49-(0)6421/282-8917
E-mail: rwho@chemie.uni-marburg.de
Eur. J. Org. Chem. 2001, 2749Ϫ2755
WILEY-VCH Verlag GmbH, 69451 Weinheim, 2001
1434Ϫ193X/01/0714Ϫ2749 $ 17.50ϩ.50/0
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R. W. Hoffmann, K. Menzel
FULL PAPER
Table 1. Relative enthalpy, population (25 °C) and backbone dihed-
ral angles for meso-2,3-dimethylbutane conformers calculated by
MM3*
Acid 7 was esterified (85%) and the alkene was ozonized to
give the aldehyde 8 (92%). Treatment of 8 with the (E)-
crotylboronate, followed by hydrolysis of the ester, fur-
nished the lactones 9 and 10 in a 5:1 ratio. At this point,
the major diastereomer 9 could be obtained (74%) diastere-
omerically pure by chromatography. The relative configura-
tion of 9 could not be established at this stage, but it was
assumed[12Ϫ14] to be the Cram product, a fact later shown
to be correct. The lactone group in 9 was reduced with DI-
BAH to the lactol 11. Since only a minute amount of free
aldehyde is in equilibrium with the lactol, the more reactive
(E)-crotyl-9-BBN[15] was chosen[16] to effect the second al-
lylmetallation. This produced a single diol in 72% yield. The
13C NMR spectrum proved it to have the symmetrical
structure 12.
tional preference (88%) for 5 than for 3. Apparently, the
steric crowding is felt more strongly in the bent conformers
of the larger molecule 5 than in those of 3.
A further improvement of the conformational preference
appeared possible in view of the magnitude of the indi-
vidual destabilizing gauche interactions. While gauche inter-
actions between alkyl groups are quite substantial, those
between an alkyl group and smaller heteroatom groups are
of significantly reduced magnitude.[10] Thus, modification
of 5 to a dihetero-substituted analogue 6, in which X is a
group sterically less demanding than a methyl group,
should reduce the magnitude of six of the twelve unfavour-
able gauche interactions present in the desired conformer
6a. We therefore initiated a study of compounds 6, in which
the X group is an oxygen functionality such as an ether or
an ester moiety.
Synthesis
Since compound 6 is a meso compound, the generation
of the stereogenic centres has to rely on substrate-based
asymmetric induction only. Because of the symmetry of 6,
a bidirectional approach appeared attractive. However, any
attempts along these lines met with failure, since the re-
acting ends of the synthetic intermediates were too close
to one another and interacted with one another. We were
therefore forced to use a stepwise approach, starting from
the unsymmetrically substituted core structure 7. The start-
ing material 7 was obtained as a 9:1 anti/syn mixture from
a Claisen rearrangement.[11]
2750
Eur. J. Org. Chem. 2001, 2749Ϫ2755

Conformational Analysis of meso-2,3,4,5-Tetramethylhexane
FULL PAPER
The key compound 12 was converted into the diacetate
13 and the bis(p-methoxybenzoate) 14. Ozonolysis of 14
with reductive workup furnished the diol 15, which was
converted into the diacetate 16. A similar sequence led from
12, through the silylated compounds 17 and 18, to the
tetraol 19. This last was converted into the bis-1,3-dioxane
20, and the bis(p-methoxybenzylidene acetal) 21.
Table 2. Vicinal coupling constants [Hz] along the backbone of
compounds 12 to 19
Conformational Analyses
Conformational analyses of the derivatives of 6 is based
on 3JH,H coupling constants along the molecular backbone;
a large degree of alteration (large/small/large) is character-
istic[17] of a preponderant population of the conformation
6a. The coupling constants 2-H/3-H ϭ 6-H/7-H and 3-H/
4-H ϭ 5-H/6-H can be directly derived from the spectra to
Ϯ0.1 Hz. Protons 4-H and 5-H are enantiotopic. Since they
are coupled across the symmetry centre of the molecule,
they give rise to a higher order multiplet, not amenable to
direct coupling constant analysis. One way to determine the
coupling constant between 4-H and 5-H is by inspection of
1
the 13C sidebands of the H NMR signal of 4-H ϭ 5-H.
1
Since the latter signal is overlapped with the H NMR sig-
nal of 2-H ϭ 7-H, a special 13C editing technique (SEL-
1
INCOR)[18] had to be used to record the unobscured H
NMR signal of 4-H ϭ 5-H. To simplify the coupling pat-
terns further we used a SELINCOR experiment in which
the 1H NMR signal of the methyl groups at positions 4 and
5 were homodecoupled. The coupling constants for 4-H, 5-
H listed in Table 2 were acquired in this manner, but be-
cause of line broadening their accuracy is Ϯ 0.3 Hz at best.
The simplest system is provided by compound 20, in 6a, as the coupling constants 2-H/3-H assume large values.
which rotation about the C-2/C-3 and the C-6/C-7 bonds The latter coupling constants are higher for the diol 15 than
is constrained by incorporation into the ring systems. The for the diacetate 16. As the X-ray structure of 15 indicates
coupling constants 3-H/4-H (Ͻ 1 Hz) and 4-H/5-H (9.4 Hz) (cf. Figure 1), the diol might adopt an internally hydrogen-
alternate and correspond to the values calculated (Macrom- bonded arrangement, further stabilizing the conformation
odel) for the conformation corresponding to 6a. In order to corresponding to 6a. When the backbone dihedral angles
check whether the predominant conformation is populated found in the X-ray structure of 15 are used, Macromodel
to Ͼ 95%, we looked at the temperature dependence of the calculates the following coupling constants: 10.7 Hz,
coupling constants. Indeed, the alteration of the coupling 1.1 Hz, and 12.4 Hz (JH2-H3, JH3-H4, JH4-H5), in close agree-
constants increased slightly on lowering the temperature. ment with those found (cf. Table 3). For 16, no such assist-
(The accuracy of the coupling constants determined at Ϫ70 ance from formation of internal hydrogen bonds is possible,
°C is lower, due to line broadening.) We therefore assume and this might be the reason for the differences in the coup-
that at room temperature compound 20 has a ca. 90% pref- ling constants between 16 and 15. In Table 3 there is a com-
erence for the fully extended conformation of the 6a type. parison of the backbone dihedral angles found in the crys-
The p-methoxybenzylideneacetal 21 showed coupling con- tal structure and those calculated with the MM3* force
stants rather similar to those of the acetonide 20.
field.
In compounds 20 and 21, the X groups (cf. 6) are ether
For the derivatives 12, 13, and 14, with terminal vinyl
oxygen atoms. On going to compounds 15 and 16, the X groups, a somewhat lower preference for the conformation
groups are modified to ester-type oxygen atoms, which have corresponding to 6a was found. This holds for the local
a stronger tendency to adopt positions lateral to the main conformer preference at any of the skeletal bonds C-2/C-3,
chain,[10] and therefore should reinforce the tendency to C-3/C-4, and C-4/C-5. This can be ascribed to the fact that
populate the 6a conformation. Indeed, the alteration of the a vinyl group does not have a high preference for posi-
coupling constants 3-H/4-H and 4-H/5-H found for com- tioning itself in the end-of-chain position, as it would have
pounds 15 and 16 is still somewhat larger than that found to be in the conformation corresponding to 6a (Figure 2).
for 20. There is, moreover, a substantial conformational In model compounds related to the halves of compound 12,
preference in the outer segments to adopt the conformation the vinyl group is oriented about 50% end-of-chain
Eur. J. Org. Chem. 2001, 2749Ϫ2755
2751

R. W. Hoffmann, K. Menzel
FULL PAPER
a marked tendency to adopt the fully extended conforma-
tion 6a.
Figure 2. X-ray crystal structure of compound 12
Experimental Section
1
General Remarks: All temperatures quoted are uncorrected. Ϫ H
NMR, 13C NMR: Bruker ARX 200, AC 300, AMX 500. Ϫ Boiling
range of petroleum ether: 40Ϫ60 °C. Ϫ Flash chromatography: SI
60 silica gel, E. Merck KGaA, Darmstadt, 40Ϫ63 µm. Buffer
(pH ϭ 7): NaH2PO4·2 H2O (56.2 g) and Na2HPO4·4 H2O (213.6 g)
made up to 1 L with water. Conformer populations were estimated
on the basis of force field calculations, using the MM3* force field
implemented in the MACROMODEL[9] program, versions 4.5 and
6.5. Conformers with energies of Ͻ 25 kJ above the minimum en-
ergy conformer were subjected to Boltzmann averaging for 298 K
to predict the conformer population.
Figure 1. X-ray crystal structure of compound 15
Table 3. Conformer population (25 °C) and backbone dihedral
angles for compound 15 calculated with MM3* compared to data
from the X-ray crystal structure
1. Methyl (2R*,3S*)-2,3-Dimethyl-4-pentenoate: p-Toluenesulfonic
acid monohydrate (608 mg, 3.20 mmol) was added to a solution of
(2R*,3S*)-2,3-dimethyl-4-pentenoic acid (7)[11] (87:13 diastereomer
mixture, 9.26 g, 72.3 mmol) in anhydrous methanol (50 mL). The
mixture was maintained under reflux for 12 h. Saturated aqueous
NaHCO3 solution (15 mL) was added and the phases were separ-
ated. The aqueous phase was extracted with tert-butyl methyl ether
(3 ϫ 20 mL). The combined organic phases were dried (MgSO4)
and concentrated. Distillation of the residue (11.3 g) at 40 mbar
provided the product (9.06 g, 88%) as a colourless liquid of b.p. 61
1
°C, 40 mbar. The diastereomer ratio was determined from the H
NMR spectrum as 87:13. Ϫ 1H NMR (200 MHz, CDCl3): δ ϭ 0.99
(d, J ϭ 6.7 Hz, 3 H), 1.07 (d, J ϭ 6.9 Hz, 3 H), 2.25Ϫ2.46 (m, 2
H), 3.65 (s, 3 H), 5.00Ϫ5.04 (m, 2 H), 5.55Ϫ5.67 (m, 1 H). Ϫ 13C
NMR (50 MHz, CDCl3): δ ϭ 13.6, 18.5, 41.2, 45.0, 51.5, 115.1,
141.0, 176.5. Ϫ C8H14O2 (142.2): Calcd. C 67.56, H 9.92; found C
67.54, H 9.96.
and 50% lateral to the chain.[19] In view of this, the con-
formational preferences found for compounds 12, 13, and
14 are surprisingly high, and show that these compounds
also have molecular backbones that probably populate the
extended conformation at more than 80%. The conforma-
tional preference of the diol 12 should be sensitive to solva-
2. (3S*,4R*,5R*)-3,4-Dimethyl-5-[(1R*)-1-methylprop-2-enyl]-4,5-
dihydrofuran-2(3H)-one (9): A stream of ozone in oxygen was
passed through a solution of methyl (2R*,3S*)-dimethylpentenoate
(4.30 g, 30.2 mmol) in dichloromethane (50 mL) at Ϫ78 °C. After
the solution had taken on a slight blue colour, excess ozone was
tion effects; solvation changes the effective size of a polar purged with nitrogen and triphenylphosphane (11.9 g, 45.4 mmol)
was added at Ϫ78 °C. After the mixture had reached room temper-
ature, the solvents were removed in vacuum and the residue was
subjected to flash chromatography on silica gel (30 g) with pentane
to give crude 8 (4.1 g, 95%), which was taken up in anhydrous THF
(15 mL). Ϫ (E)-2-Butene (8.40 g, 150 mmol) was added at Ϫ78 °C,
by cannula, to a solution of potassium tert-butoxide (5.03 g,
45.0 mmol) in THF (80 mL). After the mixture had been stirred
for 15 min, a solution of n-butyllithium (1.53  in hexane, 29.0 mL,
45.0 mmol) was added slowly over 2 h at Ϫ78 °C. After this mixture
had been stirred for 45 min at this temperature, B-isopropoxy-
group and, hence, the enthalpy term of gauche interactions
involving this group. For this reason, we determined the
coupling constants for 12 both in hydrogen bond donating
and in hydrogen bond accepting solvents (cf. Table 2). Thus,
there was a decrease in the conformational preference in
methanol, whereas in DMSO the conformational prefer-
ence was reinforced. These solvent effects remained small,
however. In this study we have shown that derivatives 6 of
hexamethyloctane (5), with the two methyl groups at C-3
and C-6 replaced by ‘‘slimmer’’ oxygen functionalities, have 4,4,5,5-tetramethyl-1,3-dioxaborolane (9.30 g, 50.0 mmol) was ad-
2752 Eur. J. Org. Chem. 2001, 2749Ϫ2755

Conformational Analysis of meso-2,3,4,5-Tetramethylhexane
FULL PAPER
ded over 1 h at Ϫ78 °C. BF3·OEt2 (6.73 mL, 55.0 mmol) was then as a single diastereomer (1.59 g, 72%) of m.p. 84 °C.[20] Ϫ 1H NMR
added rapidly, followed by the solution of the aldehyde 8 prepared (500 MHz, CDCl3): δ ϭ 0.92 (d, J ϭ 6.5 Hz, 6 H), 0.95 (d, J ϭ
above. The solution was stirred for 12 h at Ϫ78 °C. After reaching
6.6 Hz, 6 H), 1.73Ϫ1.76 (m, 2 H), 2.27 (tq, J ϭ 8.8 and 6.8 Hz, 2
room temperature, the mixture was poured into a buffer solution H), 3.42 (dd, J ϭ 9.3 and 1.2 Hz, 2 H), 5.12 (dd, J ϭ 10.2 and
(pH ϭ 7, 80 mL). The phases were separated and the aqueous 1.8 Hz, 2 H), 5.15 (dd, J ϭ 17.1 and 1.7 Hz, 2 H), 5.71 (ddd, J ϭ
phase was extracted with diethyl ether (3 ϫ 30 mL). The combined
organic phases were dried and concentrated to give crude 9 (3.90 g).
The material was added to a solution of LiOH (4.20 g, 101 mmol)
in dimethoxyethane/water (5:3, 150 mL) and was stirred for 30 min.
The mixture was acidified by addition of aqueous hydrochloric acid
(2 , 45 mL), stirred for 5 min and the phases were separated. The
aqueous phase was extracted with diethyl ether (3 ϫ 35 mL) and
the combined organic phases were dried (MgSO4) and concentrated
to give a 5:1 mixture of 9 and 10. Flash chromatography of the
residue with pentane/tert-butyl methyl ether ϭ 20:1 furnished
2.07 g (60%) of 9. Ϫ 1H NMR (200 MHz, CDCl3): δ ϭ 0.82 (d,
J ϭ 7.0 Hz, 3 H), 0.95 (d, J ϭ 6.8 Hz, 3 H), 1.09 (d, J ϭ 7.2 Hz,
3 H), 2.30Ϫ2.46 (m, 1 H), 2.47 (quintd, J ϭ 7.0 and 4.0 Hz, 1 H),
2.74 (quint, J ϭ 7.1 Hz, 1 H), 3.91 (dd, J ϭ 10.6 and 4.1 Hz, 1 H),
5.01 (d, J ϭ 10.4 Hz, 1 H), 5.05 (dt, J ϭ 17.3 and 1.2 Hz, 1 H),
5.82 (ddd, J ϭ 17.3, 10.4, and 6.7 Hz, 1 H). Ϫ 13C NMR (50 MHz,
CDCl3): δ ϭ 7.9, 9.8, 14.8, 36.8, 37.2, 41.2, 84.9, 115.1, 134.0,
178.9. Ϫ C10H16O2 (168.2): calcd. C 71.39, H 9.59; found C 71.11,
H 9.47.
17.2, 10.1, and 8.8 Hz, 2 H). Ϫ 13C NMR (125 MHz, CDCl3): δ ϭ
10.0, 16.6, 36.3, 43.2, 74.3, 116.6, 142.5. Ϫ C14H26O2 (226.4): calcd.
C 74.29, H 11.58; found C 74.10, H 11.42.
5. (3R*,4R*,5R*,6S*,7S*,8S*)-4,7-Diacetoxy-3,5,6,8-tetramethyl-
1,9-decadiene (13): A solution of n-butyllithium (1.44  in hexane,
320 µL, 0.46 mmol) was added dropwise to a solution of the diol
12 (50 mg, 0.22 mmol) in anhydrous THF (1 mL). Acetyl chloride
(33 µL, 0.46 mmol) was added after 15 min and the mixture was
stirred for 5 h. Saturated aqueous NH4Cl solution (2 mL) and
aqueous hydrochloric acid (2 , 1 mL) were added and the phases
were separated. The aqueous phase was extracted with tert-butyl
methyl ether (3 ϫ 10 mL), and the combined organic phases were
dried (MgSO4) and concentrated. Flash chromatography of the res-
idue with pentane/tert-butyl methyl ether ϭ 5:1 furnished 13
(28 mg, 45%) as a colourless solid of m.p. 87.5 °C. Ϫ 1H NMR
(300 MHz, CDCl3): δ ϭ 0.88 (d, J ϭ 6.8 Hz, 6 H), 0.88 (d, J ϭ
6.4 Hz, 6 H), 1.49Ϫ1.60 (m, 2 H), 2.00 (s, 6 H), 2.34Ϫ2.47 (m, 2
H), 4.86 (dd, J ϭ 8.8 and 1.7 Hz, 2 H), 4.88 (dd, J ϭ 10.1 and
1.8 Hz, 2 H), 4.92 (dd, J ϭ 17.1 and 1.5 Hz, 2 H), 5.54 (ddd, J ϭ
17.0, 10.0, and 8.9 Hz, 2 H). Ϫ 13C NMR (75 MHz, CDCl3): δ ϭ
11.4, 17.1, 21.4, 36.5, 41.7, 76.9, 115.2, 141.1, 170.9. Ϫ C18H30O4
(310.4): calcd. C 69.64, H 9.74; found C 69.56, H 9.61.
3. (3S*,4R*,5R*)-3,4-Dimethyl-5-[(1R*)-1-methylprop-2-enyl]tetra-
hydrofuran-2-ol (11): A solution of diisobutylaluminium hydride (1
) in petroleum ether (13 mL) was added dropwise at Ϫ78 °C to a
solution of 9 (2.07 g, 12.3 mmol) in anhydrous THF (50 mL). After
the mixture had been stirred for 1 h at Ϫ78 °C, methanol (10 mL)
was added. The mixture was allowed to come to room temperature
and saturated aqueous NH4Cl solution (40 mL) was added. The
phases were separated and the aqueous phase was extracted with
tert-butyl methyl ether (3 ϫ 60 mL). The combined organic phases
were dried (MgSO4) and concentrated, and the crude product
(2.18 g) was purified by flash chromatography with pentane/tert-
butyl methyl ether ϭ 5:1 to give 11 as a colourless liquid (1.72 g,
6.
(3R*,4R*,5R*,6S*,7S*,8S*)-4,7-Bis(p-methoxybenzoyloxy)-
3,5,6,8-tetramethyl-1,9-decadiene (14): n-Butyllithium (1.54  in
hexane, 1.20 mL, 1.86 mmol) was added at 0 °C to a solution of
the diol 12 (200 mg, 0.88 mmol) in anhydrous THF (3 mL). After
the mixture had been stirred for 5 min at 0 °C, p-methoxybenzoyl
chloride (252 µL, 1.86 mmol) was added, stirring was continued for
30 min at room temperature and saturated aqueous NH4Cl solu-
tion (2 mL) and aqueous hydrochloric acid (2 , 1 mL) were added.
The phases were separated and the aqueous phase was extracted
with tert-butyl methyl ether (3 ϫ 3 mL). The combined organic
phases were dried (MgSO4) and concentrated. Flash chromato-
graphy of the residue with pentane/tert-butyl methyl ether ϭ 4:1
furnished compound 14 (416 mg, 95%) as a slightly yellowish solid
1
82%). Ϫ H NMR (200 MHz, CDCl3): δ ϭ 0.78 (d, J ϭ 7.0 Hz, 3
H), 0.91 (d, J ϭ 6.5 Hz, 3 H), 1.02 (d, J ϭ 6.5 Hz, 3 H), 1.99Ϫ2.29
(m, 3 H), 3.87 (dd, J ϭ 10.3 and 3.3 Hz, 1 H), 3.98 (d, J ϭ 3.8 Hz,
1 H), 5.02 (ddd, J ϭ 10.3, 1.8, and 0.8 Hz, 1 H), 5.09 (ddd, J ϭ
17.3, 1.8, and 0.9 Hz, 1 H), 5.80 (ddd, J ϭ 17.4, 7.5, and 10.0 Hz,
1 H). Ϫ 13C NMR (50 MHz, CDCl3): δ ϭ 8.2, 12.0, 16.4, 38.6,
39.2, 45.5, 85.5, 103.8, 114.0, 142.4. Ϫ C10H18O2 (exact mass):
calcd. for [M ϩ H] 171.1386, found 171.1377.
1
of m.p. 143 °C. Ϫ H NMR (500 MHz, CDCl3): δ ϭ 0.93 (d, J ϭ
7.0 Hz, 6 H), 1.11 (d, J ϭ 6.3 Hz, 6 H), 1.65Ϫ1.79 (m, 2 H),
2.44Ϫ2.63 (m, 2 H), 3.86 (s, 6 H), 4.85 (dd, J ϭ 10.1 and 1.9 Hz,
2 H), 4.93 (dd, J ϭ 17.5 and 2.3 Hz, 2 H), 5.19 (dd, J ϭ 8.5 and
1.8 Hz, 2 H), 5.70 (ddd, J ϭ 17.1, 10.0, and 8.8 Hz, 2 H), 6.89Ϫ6.96
(m, 4 H), 7.94Ϫ8.01 (m, 4 H). Ϫ 13C NMR (75 MHz, CDCl3): δ ϭ
11.9, 17.2, 37.1, 41.7, 55.5, 77.2, 113.7, 115.3, 123.2, 131.7, 140.7,
163.3, 165.9. Ϫ C30H38O6 (494.6): calcd. C 72.85, H 7.74; found C
72.55, H 7.59.
4. (3R*,4R*,5R*,6S*,7S*,8S*)-3,5,6,8-Tetramethyl-1,9-decadiene-
4,7-diol (12): Precooled (E)-2-butene (4.50 g, 65.0 mmol) was added
at Ϫ88 °C by cannula to a solution of potassium tert-butoxide
(2.47 g, 22.0 mmol) in anhydrous THF (40 mL). n-Butyllithium in
hexane (1.53 , 14.4 mL, 22.0 mmol) was added dropwise over
1.5 h at Ϫ78 °C. A solution of B-methoxy-9-borabicyclononane (1 7.
 in THF, 22.0 mL) was then added dropwise at Ϫ78 °C over
45 min. After the mixture had been stirred for 30 min, BF3·OEt2
(2.65 mL, 25.0 mmol) was added rapidly. Finally, a solution of 11
(2R*,3S*,4R*,5S*,6R*,7S*)-3,6-Bis(p-methoxybenzoyloxy)-
2,4,6,7-tetramethyloctane-1,8-diol (15): A stream of ozone in oxy-
gen was passed at Ϫ45 °C through a solution of 14 (500 mg,
1.0 mmol) in dichloromethane (5 mL) and methanol (5 mL). After
(1.67 g, 9.8 mmol) in anhydrous THF (15 mL) was added at Ϫ88 the blue colour persisted, excess ozone was purged with nitrogen.
°C. After stirring for 12 h, the mixture was allowed to come to The mixture was cooled to Ϫ78 °C and NaBH4 (255 mg,
room temperature. Aqueous NaOH (3 , 50 mL) and aqueous 6.72 mmol) was added. After the mixture had reached room tem-
H2O2 (30%, 17 mL) were added, and the mixture was refluxed for perature, aqueous hydrochloric acid (2 , 6 mL) was added and the
1 h and cooled. Brine (20 mL) was added and the phases were sep-
arated. The aqueous phase was extracted with diethyl ether (3 ϫ
40 mL). The combined organic phases were dried (MgSO4) and
phases were separated and the aqueous phase was extracted with
tert-butyl methyl ether (3 ϫ 10 mL). The combined organic phases
were dried (MgSO4) and concentrated. Flash chromatography of
concentrated. The crude product (6.0 g) was purified by flash chro- the residue with pentane/tert-butyl methyl ether ϭ 2:1 furnished
matography with pentane/tert-butyl methyl ether ϭ 10:1 to give 12
compound 15 (160 mg, 33%) as a colourless solid of m.p. 174 °C.[20]
Eur. J. Org. Chem. 2001, 2749Ϫ2755
2753

R. W. Hoffmann, K. Menzel
1H NMR (500 MHz, CDCl3): δ ϭ 0.91 (d, J ϭ 6.8 Hz, 6 H), 40.9, 66.2, 76.0. Ϫ C24H54O4Si2 (462.8): calcd. C 62.28, H 11.76;
FULL PAPER
Ϫ
1.10 (broad d, J ϭ 5.8 Hz, 6 H), 1.62Ϫ1.73 (m, 2 H), 1.83Ϫ1.91
(m, 2 H), 3.39 (dd, J ϭ 12.2 and 2.5 Hz, 2 H), 3.51 (dd, J ϭ 12.2
and 2.8 Hz, 2 H), 3.86 (s, 6 H), 5.23 (broad d, J ϭ 10.5 Hz, 2 H),
6.94Ϫ6.97 (m, 4 H), 7.98Ϫ8.01 (m, 4 H). Ϫ 13C NMR (125 MHz,
CDCl3): δ ϭ 11.2, 14.1, 36.7, 37.4, 55.6, 63.9, 75.5, 114.0, 122.0,
132.0, 164.0, 167.8. Ϫ C28H38O8 (exact mass): calcd. 502.2566,
found 502.2532.
found C 62.33, H 11.78.
11. (4S*,5R*)-2,2,5-Trimethyl-4{(1R*,2S*)-1-methyl-2-[(4R*,5S*)-
2,2,5-trimethyl-1,3-dioxan-4-yl]propyl}-1,3-dioxane (20): HF (5% in
acetonitrile, 15 mL) was added to 18 (600 mg, 1.30 mmol) and the
resulting solution was stirred for 30 min. Saturated aqueous
NaHCO3 solution (5 mL) and sodium chloride (10 g) were added
and the solution was extracted with diethyl ether (3 ϫ 25 mL). The
combined organic phases were dried (MgSO4) and concentrated.
The residue (450 mg) was taken up in THF (2 mL). 2-Methoxypro-
pene (500 µL, 5.0 mmol) and p-toluenesulfonic acid (ca. 5 mg) were
added. After the mixture had been stirred for 12 h, saturated aque-
ous NaHCO3 solution (5 mL) was added and the phases were sep-
arated. The aqueous phase was extracted with diethyl ether (3 ϫ
5 mL) and the combined organic phases were dried (MgSO4) and
concentrated. Flash chromatography of the residue with pentane/
tert-butyl methyl ether ϭ 10:1 furnished compound 20 (40 mg,
10%) as a colourless solid of m.p. 113Ϫ114 °C. Ϫ 1H NMR
(500 MHz, CDCl3): δ ϭ 0.68 (d, J ϭ 6.7 Hz, 6 H), 0.86 (d, J ϭ
6.4 Hz, 6 H), 1.34 (s, 6 H), 1.41 (s, 6 H), 1.63 (m, 2 H), 1.82Ϫ1.91
(m, 2 H), 3.50 (t, J ϭ 11.2 Hz, 2 H), 3.63 (d, J ϭ 10.1 Hz, 2 H),
3.69 (dd, J ϭ 11.5 and 4.8 Hz, 2 H). Ϫ 13C NMR (75 MHz,
CDCl3): δ ϭ 10.5, 12.5, 19.0, 29.9, 31.0, 34.9, 66.8, 75.4, 98.1. Ϫ
C18H34O4 (314.5): calcd. C 68.75, H 10.90; found C 68.85, H 11.01.
8. (2R*,3S*,4R*,5S*,6R*,7S*)-1,8-Diacetoxy-3,6-bis(p-methoxy-
benzoyloxy)-2,4,5,7-tetramethyloctane (16): Acetic anhydride (38
µL, 0.40 mmol) was added dropwise to a solution of 15 (50 mg,
0.10 mmol) in dichloromethane (3 mL). 4-Dimethylaminopyridine
(ca. 3 mg) was added and the mixture was stirred for 16 h. Satur-
ated aqueous NaHCO3 solution (3 mL) was added and the phases
were separated. The aqueous phase was extracted with diethyl ether
(3 ϫ 10 mL). The combined organic phases were dried (MgSO4)
and concentrated. Flash chromatography of the residue with pent-
ane/tert-butyl methyl ether ϭ 1:2 furnished 16 (38 mg, 60%) as a
colourless oil. Ϫ 1H NMR (200 MHz, CDCl3): δ ϭ 0.88 (d, J ϭ
7.0 Hz, 6 H), 1.14 (d, J ϭ 6.0 Hz, 6 H), 1.59Ϫ1.73 (m, 2 H), 1.88
(s, 6 H), 3.86 (s, 6 H), 2.10Ϫ2.31 (m, 2 H), 3.94 (d, J ϭ 5.5 Hz, 2
H), 3.97 (d, J ϭ 4.5 Hz, 2 H), 5.27 (d, J ϭ 9.5 Hz, 2 H), 6.89Ϫ6.96
(m, 4 H), 7.95Ϫ8.02 (m, 4 H). Ϫ 13C NMR (50 MHz, CDCl3): δ ϭ
11.6, 14.4, 20.9, 35.4, 37.1, 55.6, 66.8, 75.5, 113.8. 122.6, 131.8,
163.6, 165.9, 171.1. Ϫ C32H42O10 (exact mass): calcd. 586.2778;
found 586.2774.
12. (4S*,5R*)-2-(p-Methoxyphenyl)-5-methyl-4-{(1R*,2S*)-1-meth-
yl-2-[(4R*,5S*)-2-(p-methoxyphenyl)-5-methyl-1,3-dioxan-4-yl]-
propyl}-1,3-dioxane (21): HF (5% in acetonitrile, 2 mL) was added
to 18 (80 mg, 0.17 mmol). After the mixture had been stirred for
30 min, saturated aqueous NaHCO3 solution (1 mL) and sodium
chloride (1 g) were added. The phases were separated and the aque-
ous phase was extracted with diethyl ether (6 ϫ 5 mL). The com-
bined organic phases were dried (MgSO4) and concentrated to
leave the crude tetraol 19 as a yellowish liquid (57 mg), which was
taken up in THF (5 mL). To this solution were added p-methoxy-
benzaldehyde dimethyl acetal (210 µL, 1.02 mmol) and p-tolu-
enesulfonic acid (ca. 5 mg). After the mixture had been stirred for
12 h, saturated aqueous NaHCO3 solution (1 mL) was added and
the phases were separated. The aqueous phase was extracted with
diethyl ether (3 ϫ 5 mL). The combined organic phases were dried
(MgSO4) and concentrated. Flash chromatography of the residue
with pentane/diethyl ether ϭ 10:1 furnished 21 (30 mg, 38%) as a
colourless solid of m.p. 185 °C. Ϫ 1H NMR (500 MHz, CDCl3):
δ ϭ 0.75 (d, J ϭ 5.7 Hz, 6 H), 1.07 (d, J ϭ 6.5 Hz, 6 H), 1.87Ϫ1.90
(m, 2 H), 2.10Ϫ2.14 (m, 2 H), 3.52 (t, J ϭ 11.1 Hz, 2 H), 3.63 (d,
J ϭ 9.7 Hz, 2 H), 3.83 (s, 6 H), 4.14 (dd, J ϭ 11.2 and 4.7 Hz, 2
H), 5.45 (s, 2 H), 6.90Ϫ6.93 (m, 4 H), 7.42Ϫ7.44 (m, 4 H). Ϫ 13C
NMR (125 MHz, CDCl3): δ ϭ 11.3, 12.3, 30.9, 35.2, 55.4, 73.5,
83.8, 101.1, 113.6, 127.4, 131.9, 160.4. Ϫ C28H38O6 (exact mass):
calcd. 470.2668; found 470.2674.
9. (3R*,4R*,5R*,6S*,7S*,8S*)-4,7-Bis(tert-butyldimethylsilyloxy)-
3,5,6,8-tetramethyl-1,9-decadiene (17): 2,6-Lutidine (290 µL,
2.5 mmol) was added under nitrogen to a solution of 12 (227 mg,
1.0 mmol) in dichloromethane (5 mL). After the mixture had been
stirred for 10 min, tert-butyldimethylsilyl trifluoromethanesulfon-
ate (700 µL, 3.0 mmol) was added dropwise. After this mixture had
been stirred for 3 h, saturated aqueous NaHCO3 solution (3 mL)
was added, the phases were separated and the aqueous phase was
extracted with tert-butyl methyl ether (3 ϫ 5 mL). The combined
organic phases were dried (MgSO4) and concentrated. Flash chro-
matography of the residue with pentane/tert-butyl methyl ether ϭ
20:1 furnished compound 17 (489 mg, 100%) as a colourless oil. Ϫ
1H NMR (300 MHz, CDCl3): δ ϭ 0.00 (s, 6 H), 0.20 (s, 6 H), 0.89
(d, J ϭ 5.5 Hz, 6 H), 0.90 (s, 18 H), 0.96 (d, J ϭ 6.9 Hz, 6 H),
1.49Ϫ1.53 (m, 2 H), 2.32 (quint, q, J ϭ 6.9 Hz, 2 H), 3.66 (d, J ϭ
6.2 Hz, 2 H), 4.93Ϫ5.00 (m, 4 H), 5.78 (ddd, J ϭ 17.1, 10.5, and
7.7 Hz, 2 H). Ϫ 13C NMR (75 MHz, CDCl3): δ ϭ Ϫ3.9, 1.2, 12.7,
16.9, 26.4, 38.3, 44.1, 55.9, 76.3, 114.3, 142.8. Ϫ C26H54O2Si2
(454.9): calcd. C 68.65, H 11.97; found C 68.50, H 11.78.
10. (2R*,3S*,4R*,5S*,6R*,7S*)-3,6-Bis(tert-butyldimethylsilyloxy)-
2,4,5,7-tetramethyloctane-1,8-diol (18): A stream of ozone in oxy-
gen was passed at Ϫ25 °C through a solution of 17 (150 mg,
0.33 mmol) in dichloromethane (1 mL) and methanol (1 mL).
When the blue colour persisted, excess ozone was purged with a
stream of nitrogen. The mixture was cooled to Ϫ80 °C and NaBH4
(100 mg, 2.64 mmol) was added. After the mixture had reached
room temperature, silica gel (4 g) was added, and the suspension
was concentrated. The material was placed on a chromatography
column and eluted with pentane/tert-butyl methyl ether ϭ 5:1 to
furnish 18 (126 mg, 82%) as a colourless solid of m.p. 113 °C. Ϫ
1H NMR (300 MHz, CDCl3): δ ϭ 0.07 (s, 6 H), 0.12 (s, 6 H),
0.88Ϫ0.93 (m, 30 H), 1.46Ϫ1.48 (m, 2 H), 1.74Ϫ1.83 (m, 2 H),
2.08 (broad s, 2 H), 3.54 (dd, J ϭ 10.7 and 5.1 Hz, 2 H), 3.66 (dd,
J ϭ 10.7 and 5.8 Hz, 2 H), 3.76 (d, J ϭ 7.5 Hz, 2 H). Ϫ 13C NMR
(75 MHz, CDCl3): δ ϭ Ϫ3.9, Ϫ3.3, 12.5, 14.9, 18.7, 26.3, 39.0,
Acknowledgments
We would like to thank the Deutsche Forschungsgemeinschaft and
the Fonds der Chemischen Industrie for support of this study. We
express our gratitude to Dr. K. Harms, Marburg, for carrying out
the X-ray structure analyses of compounds 12 and 15.
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R. W. Hoffmann, R. Göttlich, U. Schopfer, Eur. J. Org. Chem.,
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[3]
This conformational preference in 1 is commonly referred to
as the tert-butyl effect.[5,21Ϫ23]
2754
Eur. J. Org. Chem. 2001, 2749Ϫ2755

Conformational Analysis of meso-2,3,4,5-Tetramethylhexane
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2755