Flexible molecules with defined shape XI[≠]. - Conformer equilibria in 2,4-disubstituted pentane derivatives

Article abstract of DOI:10.1002/(sici)1099-0690(199911)1999:11<2915::aid-ejoc2915>3.0.co;2-r

2,4-Disubstituted penfanes are molecules which adopt essentially only two conformations. Substituents have been varied in order to find those which lead to a strong preference of the conformer equilibrium. Studying 2- substituted 4-methylpentanes 3 and 4-benzyloxypentanes 12, it has been shown that substituent effects on the conformer equilibria are not additive, as would be expected on the grounds of steric effects alone. Rather, interactions between polar groups reinforce the bias of the conformer equilibria. When applied to 2,4-disubstituted pentanes, substituents such as chloro or phthalimido shift the conformer equilibrium to the side of the gg conformer with preferences exceeding 90%.

Full text of DOI:10.1002/(sici)1099-0690(199911)1999:11<2915::aid-ejoc2915>3.0.co;2-r

FULL PAPER
Flexible Molecules with Defined Shape XI[°]
Conformer Equilibria in 2,4-Disubstituted Pentane Derivatives
Reinhard W. Hoffmann,*[a] Dirk Stenkamp,[a] Thomas Trieselmann,[a] and Richard Göttlich[a]
Keywords: Conformational analysis / Conformational isomerism / Isotopic labeling / 2,4-Disubstituted pentanes
2,4-Disubstituted pentanes are molecules which adopt
essentially only two conformations. Substituents have been
on the grounds of steric effects alone. Rather, interactions
between polar groups reinforce the bias of the conformer
varied in order to find those which lead to
a strong equilibria. When applied to 2,4-disubstituted pentanes,
preference of the conformer equilibrium. Studying 2- substituents such as chloro or phthalimido shift the
substituted 4-methylpentanes 3 and 4-benzyloxypentanes
12, it has been shown that substituent effects on the
conformer equilibria are not additive, as would be expected
conformer equilibrium to the side of the gg conformer with
preferences exceeding 90%.
Many examples of compounds which have a flexible mo- undertaken. We hoped to identify in this manner, substitu-
lecular backbone but nevertheless adopt certain preferred ents X which most strongly influence the conformer equilib-
conformations are found in nature.[2] Local segments in rium of 2.
some of these compounds can be identified as derivatives
Determinations of the position of the conformer equilib-
1
of 2,4-dimethylpentane (1), which itself has two enantio- rium of 2 are based on vicinal H,1H-NMR coupling con-
3
morphous low energy conformations comprising > 90% of stants. The measured JH,H coupling constants for the pro-
the conformer population.[3] Conformation design[4] (by tons HAHB, HAHC, HBHD, HCHD represent the population
nature or by man) could be based on structural modifi- weighted average of the values for the individual (low en-
cations of 1, i.e. the introduction of heteroatom substituents ergy) conformers of 2. MM3* calculations were carried out
X, cf. 2. This should shift the conformer equilibrium of the in order to identify the low energy conformers, and to pre-
2,4-disubstituted pentane skeleton to one side, hopefully dict conformer populations. E.g. for (R*,R*)-dimeth-
rendering the skeleton “monoconformational”.
oxypentane (2, X ϭ OCH3) the calculations predict the ra-
tio of the gg; tt; gt conformer populations to be 80:7:9, i.e.
there should be a significant contribution of the gt con-
former to the conformer population, in addition to the ex-
pected gg and tt conformers. The gt conformer is destabil-
ized relative to the most stable gg conformer by a 1,3-paral-
lel oxygen/methyl interaction[7] amounting to 0.8
kcal·molϪ1. It is at present not clear whether the gt con-
former really contributes towards the conformer equilib-
rium to such a large extent, or whether this prediction is
merely a reflection of an inadequate parameterization of
the force field. Vicinal coupling constants for the individual
conformers of 2 (gg, tt, tg) were calculated based on a
Karplus relationship implemented in the MACROMODEL
program.[8] This routine takes into account effects of the
electronegativity of the substituents X on the size of the
individual coupling constants. Interpolation[9] of the meas-
ured coupling constants between the values calculated for
the gg and tt conformers of 2 then allows for a crude esti-
mate of the position of the conformer equilibrium.[4] In this
manner the gg/tt conformer ratio for (R*,R*)-2,4-dimeth-
oxypentane (2, X ϭ OCH3) is estimated to be 2.3:1.
Scheme 1
For instance, for (R*,R*)-2,4-dimethoxypentane (2, X ϭ
OCH3), the equilibrium favors the gg conformer.[5] The
shift in the conformer equilibrium is attributed to the fact
that the methoxy group in 2 has a smaller van der Waals
radius than a methyl group.[6] The destabilizing interaction
between the hydrogen atom HA at C-2 and the methoxy
group at C-4 in the gg conformer is therefore smaller than
the interaction between HA at C-2 and the methyl group at
C-4 in the tt conformer. This favors the gg conformer in the
equilibrium. But aside from this purely steric argument,
there may be other factors influencing the conformer equili-
bria.[7] In order to learn more on how substituents affect
the conformer equilibrium of 2, the present study was
[°] Part X: Ref.[1]
2-Substituted 4-Methylpentanes
[a]
Fachbereich Chemie, Philipps-Universität Marburg,
Hans-Meerwein-Straße, D-35032 Marburg
Fax: (internat.) ϩ 49-(0)6421/28-8917
E-mail: rwho@ps1515.chemie.uni-marburg.de
The steric effects of substituents on the conformer equili-
bria can easily be assessed by studying the conformer popu-
Eur. J. Org. Chem. 1999, 2915Ϫ2927
WILEY-VCH Verlag GmbH, D-69451 Weinheim, 1999
1434Ϫ193X/99/1111Ϫ2915 $ 17.50ϩ.50/0
2915

R. W. Hoffmann, D. Stenkamp, T. Trieselmann, R. Göttlich
FULL PAPER
lations of 2-substituted 4-methylpentanes 3, in which dipo-
For the alcohol 4, lanthanide-induced shifts in the NMR
leϪdipole interactions may be neglected. A qualitative spectra have been interpreted in terms of a preference for
analysis of the steric effects reveals two limiting cases: If the the t conformation.[13] MM3* calculations suggest, how-
substituent X in 3 is a methyl group, i.e., the situation pre- ever, a preference for the g conformation. This discrepancy
sent in 1, a 1:1 conformer equilibrium prevails; if the sub- could be explained by the fact that oxygen coordinated to
stituent is reduced in size (it may not become smaller than europium is larger than a methyl group, whereas a hydroxy
a hydrogen atom, i.e. 3, X ϭ H), MM3* calculations predict group is not.[11]
a conformer ratio of 4:1. Substituents that have a size inbe-
In order to get a clear picture, we calculated the con-
tween that of a hydrogen atom and a methyl group should former populations and measured the NMR coupling con-
then lead to conformer preferences for the g conformer stants for the compounds 4؊11, cf. Table 1. In order to
which fall between the values 1:1 and 4:1. If the substituent avoid any ambiguities in identifying the predominant con-
X in 3 becomes larger than a methyl group, the t conformer former, in several instances we assigned the individual
of 3 should be favored.
coupling constants by specific deuterium labeling. To this
We previously reported data[10] for compounds 3 in end, (Z)-4-methyl-2-pentene was hydroborated with BD3 to
which the substituent X is a vinyl, phenyl, formyl or alkoxy- give deuterio-4 and the regioisomer, which were separated
carbonyl group. These compounds showed moderate con- by chromatography.
former preferences of up to 2:1 for the g conformer. This is
in line with the idea[11] that sp2-hybridized carbon atoms
are smaller than methyl groups. Here we consider com-
pounds 3, in which the substituent X is a heteroatom.
Scheme 2
There are already some reports regarding the conformer
preferences of hetero-substituted compounds of the type 3:
For the chloro compound 11 (and the corresponding bromo
compound), IR studies[12] indicate a clear preference for the
gauche conformer.
Scheme 3
Table 1. Experimentally derived and calculated conformer populations for 2-substituted 4-methylpentanes
a) The numbers do not add up to 100%, due to the presence of conformations not corresponding to g, t or gЉ. For the force field
used in MACROMODEL see ref.[32] Ϫ b) Coupling constants have been assigned by specific deuterium labeling. Ϫ c) The calculated
(MACROMODEL) gauche coupling constants involving the hydrogen atom α to oxygen for the individual conformers depended on the
spatial arrangement of the OR group. These couplings were not used when estimating the gg:tt ratios.
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Flexible Molecules with Defined Shape XI
FULL PAPER
The deuterated alcohol was then converted into the prising, since the sp2-hybridized nitrogen atom of the phthal-
phthalimide (deuterio-10), which was the precursor to the imido group should be smaller than the sp3-hybridized nitro-
specifically deuterated amines 6 and 9.
gen atom in the amines 6, 8, and 9.
Inspection of the data in Table 1 shows that the conformer
But with more polar substituents, steric effects may not
preferences are small. The alcohol 4 displays a preference for be the only factor affecting the conformer equilibria. It ap-
the gauche conformer 4g. In view of the similarity of the pears that polar effects may be of similar importance in
coupling constants, we believe that this also holds for the favoring the gauche conformer, since 1-halopropanes[14] and
methoxy compound 5. MM3* predicted a preference for the 1-propanol[15] prefer a conformation, in which the CϪX
gauche conformation for all the amines 6, 8, and 9. This, bond is gauche to the CϪC-bond, a situation not induced
however, is contradicted by the NMR spectra recorded for by steric effects. This finding has been attributed to a stabil-
the dimethylamino compound 9. Here, the trans conformer izing σCϪH Ϫ σ*CϪX interaction, for which an antiperi-
was found to be favored. MM3* correctly predicted the shift planar arrangement of the interacting orbitals is a pre-
of the preferred conformation from gauche to trans on pro- requisite.[16] This interaction would be possible in 3g but
tonation of the amine 6. From both the MM3* calculations not in 3t, provided that a CϪH bond is a better σ-donor
and the NMR spectra, it can be concluded that the phthali- than a CϪC bond.[17] The conformational preferences in
mido compound 10 has the strongest preference for the g the halopropanes has also been discussed in terms of in-
conformation of all the compounds studied. This is not sur- duced dipoleϪdipole interactions.[18][19]
Table 2. Experimentally derived and calculated conformer populations for 2-substituted 4-benzyloxypentanes
a) The calculated (MACROMODEL) gauche coupling constants involving the hydrogen atom α to oxygen for the individual conformers
depended on the spatial arrangement of the OR group. These couplings were not used when estimating the gg:tt ratios. b) For the force
field used in MACROMODEL see ref.[32]
Eur. J. Org. Chem. 1999, 2915Ϫ2927
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R. W. Hoffmann, D. Stenkamp, T. Trieselmann, R. Göttlich
FULL PAPER
With the aid of the results in Table 2, we may now evalu-
ate whether the substituent effects recorded for monosubsti-
tuted pentanes 3 may be used to predict the position of the
conformer equilibria of the disubstituted pentanes 12. Two
examples will be given: Multiplication of the conformer ra-
tios found for the disubstituted pentanes 5 and 13 (which is
equivalent to adding the ∆G values of the conformer equili-
bria) leads to a predicted value for the position of the con-
former equilibrium in the disubstituted pentane 12e which
is in fair agreement with the NMR-derived result. In the
second example, two polar substituents are involved. When
the conformer ratios of 5 and 11 are multiplied, the con-
former ratio predicted for 12c is clearly smaller than the
experimentally derived value. This difference can be attri-
buted to a mutual interaction between the substituents in
12c which affects the position of the conformer equilibrium.
Scheme 4
2-Substituted 4-Benzyloxypentanes
We then addressed the question of whether substituent
effects on conformer equilibria are additive on going from
the monosubstituted derivatives 3, to disubstituted deriva-
tives 2. For simplicity, we first studied a series of com-
pounds 12 in which we kept one substituent (the benzyloxy
group) constant. The results compiled in Table 2 show mod-
erate to marked conformational preferences. The predomi-
nance of the gg conformer was ascertained for 12b, 12c, and
12l by determination of JC,H coupling constants.[20] In the
In previous studies on 1,3-difluoropropane[19] and
3
other cases, the assignment of the predominant conformer (R*,R*)-2,4-dichloropentane,[21] the nature of this interac-
is tentative, and is based on MM3* calculations.
tion has been ascribed to 1,3-dipoleϪdipole interactions,
Scheme 5
Table 3. Experimentally derived and calculated conformer populations for 2,4-disubstituted pentanes
a)
d)
For the force field used in MACROMODEL see ref.[32]
Ϫ
b) Values from ref.[5] Ϫ c) Values from ref.[22]
Ϫ
The calculated (MACRO-
MODEL) gauche coupling constants involving the hydrogen atom α to oxygen for the individual conformers depended on the spatial
arrangement of the OR group. These couplings were not used when estimating the gg:tt ratios. Ϫ e) Calculated for ϪCϵCϪC(CH3)3 sub-
stituents.
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Flexible Molecules with Defined Shape XI
FULL PAPER
approximated by simulation[23] of the higher order mul-
tiplets. In turn, the accuracy of the values of the coupling
constants is rather low (± 0.2 Hz). The predominance of
the gg conformer has been established in the case of the
Scheme 6
3
dibromo compound 2d by determining the JC,C-coupling
constant to be 3.8 Hz. Assignments in the other cases were
made only on the basis of MM3* calculations.
which would additionally stabilize the gg conformer of 12c
over the tt conformer.
Our results for the dichloro 2c and dibromo 2d match
those reported earlier in the literature.[24][25] The dichloro
compound 2c, especially has been the focus of attention as
a model compound for the local conformations in syndio-
tactic polyvinyl chloride.[26]
Comparison of the data in Table 3 and Table 1 again shows
that the effects of polar substituents on the conformer popu-
lation are not additive. Thus, the dichloro compound 2c shows
a much larger conformational preference than predicted on
the basis of the mono-halo compound 11 in Table 1.
Our aim was to identify substituents, which when placed
Other 2,4-Disubstituted Pentanes
The finding that there are cooperative effects between
substituents on the conformer equilibria in 2,4-disubsti-
tuted pentanes, is of importance for conformation design.
The aim of this study was to identify specific substituents,
which, when placed in the 2,4-positions of a pentane chain,
would lead to a strong shift in the conformer equilibrium.
The data collected in Table 1 and Table 2 suggest that the
best candidates are chloro substituents, phthalimido groups,
alkynes or azido groups. Therefore, the next round of
experiments focussed on pentane derivatives having two of in the 2,4-positions of pentane, led to a strong confor-
those substituents in the 2,4-positions. The compounds in- mational preference of the pentane backbone. The dihalo
vestigated, and the position of the conformer equilibria, as compounds 2b, 2c and, most prominently, the diphthalim-
1
estimated from the H-NMR coupling constants, are sum- ido compound 2e, meet these criteria. It should therefore
marized in Table 3.
become possible to construct larger backbone sequences
Since most of the compounds in Table 3 are C2-sym- with a preferred conformation, such as 14, based on these
3
metric, the relevant JH,H coupling constants could only be substituents.
Scheme 7
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R. W. Hoffmann, D. Stenkamp, T. Trieselmann, R. Göttlich
FULL PAPER
Scheme 8
Syntheses
Experimental Section
All temperatures quoted are not corrected. Ϫ Reactions were car-
ried out under dry nitrogen or argon. Ϫ Boiling range of petroleum
The compounds referred to in Table 1 were partly com-
mercially available and partly prepared by procedures given
in the literature. The compounds referred to in Tables 2 and
3 were prepared following the routes outlined in Schemes 7
and 8.
1
ether: 40Ϫ60°C. Ϫ H, 13C NMR: Bruker AC 200, AC 300, AM
400, and AMX 500. Spectra were recorded at 20°C in CDCl3 (99%
D), which was also used as internal standard. Ϫ Buffer of pH ϭ
7: NaH2PO4 ϫ 2 H2O (56.2 g) and Na2HPO4 ϫ 2 H2O (213.3 g) in
In order to gain access to the bisalkyne 2g, bidirectional 1.0 L of water. Ϫ Column chromatography: Silica gel Si60 (63Ϫ200
µm), E. Merck AG, Darmstadt. Ϫ Flash chromatography: Silica
gel Si60 (40Ϫ63 µm), E. Merck AG, Darmstadt. Ϫ HPLC: Gilson/
Abimed 305/306, LiChrosorb Si 60 (7 µm) Knauer, Berlin.
routes were explored. Due to low yields, however, this ap-
proach was abandoned in favor of the more lengthy routes
shown in Scheme 9.
1. (2S*,3R*)-3-Deuterio-4-methylpentan-2-ol (deuterio-4): Sodium
borodeuteride (600 mg, 14.4 mmol) was added to a solution of (Z)-
4-methyl-2-pentene (1.5 mL, 12.0 mmol) in diethyl ether (50 mL).
The suspension was cooled to Ϫ78°C and boron trifluorideϪdie-
thyl ether (2.2 mL, 18.0 mmol) was added slowly over 3 h. The
mixture was allowed to reach room temperature. Aqueous NaOH
(6 mL, 3 ) and H2O2 (6 mL, 30% in water) were slowly added
and the mixture was stirred for 2 h. The phases were separated
and the aqueous phase was extracted with ether (3 ϫ 15 mL). The
combined extracts were dried (MgSO4) and concentrated. The resi-
due was subjected to flash chromatography with ether/pentane 1:4
to give the alcohol deuterio-4 (185 mg, 15%) and its regioisomer.
1
Ϫ deuterio-4: H NMR (200 MHz, CDCl3): δ ϭ 0.84 (d, J ϭ 6.6
Hz, 6 H), 1.11 (d, J ϭ 6.2 Hz, 3 H), 1.37 (m, 1 H), 1.40 (br. s, 1
H), 1.68 (m, 1 H), 3.84 (m, 1 H). Ϫ 13C NMR (50 MHz, CDCl3):
δ ϭ 22.3, 23.1, 23.9, 24.8, 48.6 (triplet due to attached deuterium),
66.1. The undeuterated alcohol showed 1H NMR (500 MHz,
CDCl3): δ ϭ 0.87 (d, J ϭ 6.6 Hz, 3 H), 0.88 (d, J ϭ 6.6 Hz, 3 H),
1.14 (d, J ϭ 6.2 Hz, 3 H), 1.19 (ddd, J ϭ 13.6, 8.2, and 4.9 Hz, 1
H), 1.37 (ddd, J ϭ 13.6, 8.2, and 4.9 Hz, 1 H), 1.70 (m, 1 H), 3.84
(m, 1 H).
2. (2R*,3R*)-3-Deuterio-4-methyl-2-phthalimidopentane (deuterio-
10): deuterio-4 and its regioisomer were prepared as above from
NaBD4 (100 mg, 2.4 mmol), BF3Ϫdiethyl ether (370 µL, 3.0
mmol), and (Z)-4-methyl-2-pentene (750 µL, 6.0 mmol). The mix-
Scheme 9
2920
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Flexible Molecules with Defined Shape XI
FULL PAPER
ture of alcohols obtained (207 mg, 2.0 mmol) was dissolved in THF ded dropwise at 0°C to a solution of (4R*,6R*)-4,6-dimethyl-2-
(15 mL). Phthalimide (403 mg, 2.74 mmol) and triphenylphos-
phane (698 mg, 2.66 mmol) were added and the mixture was cooled
phenyl-1,3-dioxane (15)[27] (1.47 g, 7.6 mmol) in dichloromethane
(15.0 mL). After stirring for 2 h at 0°C, and for one day at room
to 0°C. Diethyl azodicarboxylate (456 mg, 2.62 mmol) was then temperature, ethyl acetate (50 mL) was added at 0°C. After stirring
added dropwise. After stirring at room temperature for 12 h, the
mixture was concentrated and the residue was absorbed on silica
gel (3 g). This was purified by flash chromatography, eluted with
tert-butyl methyl ether/pentane 1:9 to give a 4:1 mixture of regio
isomers (333 mg, 72%). This mixture was separated by preparative
HPLC (2% tert-butyl methyl ether in pentane). Ϫ 1H NMR (200
for 0.5 h, aqueous NaOH (3 , 90 mL) and tert-butyl methyl ether
(40 mL) were added. The phases were separated and the aqueous
phase was extracted with tert-butyl methyl ether (4 ϫ 40 mL). The
combined organic phases were washed with brine (50 mL), dried
(MgSO4) and concentrated. Flash chromatography of the residue
with mixtures of petroleum ether and tert-butyl methyl ether vary-
MHz, CDCl3): δ ϭ 0.81 (d, J ϭ 6.2 Hz, 3 H), 0.84 (d, J ϭ 6.0 Hz, ing from 10:1 to 1:1 furnished 17 (1.35 g, 91%) as a colorless oil.
1
3 H), 1.37 (d, J ϭ 7.0 Hz, 3 H), 1.38 (m, 2 H), 4.38 (m, 1 H), 7.61
(m, 2 H), 7.74 (m, 2 H). Ϫ 13C NMR (50 MHz, CDCl3): δ ϭ 19.0, J ϭ 11.6 Hz, 1 H), 4.47 (d, J ϭ 11.6 Hz, 1 H), 4.13 (m, 1 H), 3.87
21.9, 22.9, 25.3, 42.2 (triplet due to the attached deuterium) 45.4, (m, 1 H), 2.85 (s, 1 H), 1.73Ϫ1.59 (m, 2 H), 1.27 (d, J ϭ 6.2 Hz, 3
123.0, 132.0, 133.7, 168.5. Ϫ C14H16DNO2: Mϩ found 232.1329, H), 1.19 (d, J ϭ 6.3 Hz, 3 H). Ϫ 13C NMR (50 MHz, CDCl3):
calcd. 232.1322. The undeuterated compound showed 1H NMR
δ ϭ 19.1, 23.5, 44.5, 64.5, 70.5, 72.6, 127.5, 127.6, 128.3, 138.4. Ϫ
Ϫ H NMR (300 MHz, CDCl3): δ ϭ 7.36Ϫ7.26 (m, 5 H), 4.63 (d,
(500 MHz, C6D6): δ ϭ 0.88 (d, J ϭ 6.5 Hz, 3 H), 0.97 (d, J ϭ 6.6 C12H18O2 (194.3): calcd. C 74.19, H 9.34; found C 73.91, H 9.40.
Hz, 3 H), 1.42 (ddd, J ϭ 13.9, 10.3, and 4.8 Hz, 1 H), 1.44 (d, J ϭ
6. (2S*,4R*)-4-Benzyloxy-2-pentanol (18): (2s*,4R*,6S*)-4,6-Di-
6.9 Hz, 3 H), 1.48 (m, 1 H), 2.30 (ddd, J ϭ 13.9, 9.9, and 4.8 Hz,
1 H), 4.63 (m, 1 H), 6.05 (m, 2 H), 7.60 (m, 2 H).
methyl-2-phenyl-1,3-dioxane (16)[27] (1.96 g, 10.2 mmol) was al-
lowed to react as described under 5. to give 1.57 g (79%) of the
3. (2R*,3R*)-2-Amino-3-deuterio-4-methylpentane (deuterio-6): Hy-
drazine hydrate (144 µL, 80% in water, 2.97 mmol) was added to a
solution of deuterio-10 (266 mg, 1.14 mmol) in methanol (3 mL).
After heating under reflux for 5 h, the mixture was cooled to room
temperature, diluted with dichloromethane (10 mL) and absorbed
onto an ion exchange column (Dowex Hϩ, 50 WX, 50Ϫ100 mesh).
The resin was washed with water/methanol (1:1, 3 ϫ 10 mL), and
dichloromethane (3 ϫ 10 mL). The amine was eluted with aqueous
ammonia (12.5%, 3 ϫ 10 mL). The combined ammonia solutions
were extracted with dichloromethane (3 ϫ 10 mL). Removal of the
solvent led to the amine deuterio-6 (85 mg, 73%). Ϫ 1H NMR (400
MHz, [D6]DMSO): δ ϭ 0.82, (d, J ϭ 6.6 Hz, 3 H), 0.83 (d, J ϭ
6.6 Hz, 3 H), 0.92 (d, J ϭ 6.2 Hz, 3 H), 1.02 (m, 1 H), 1.63 (m, 1
H), 2.77 (m, 1 H). Ϫ 13C NMR (100 MHz, [D6]DMSO): δ ϭ 22.4,
23.0, 24.4, 25.0, 44.5, 49.8 (triplet due to attached deuterium). Un-
product as a colorless oil. Ϫ 1H NMR (300 MHz, CDCl3): δ ϭ
1.12 (d, J ϭ 6.2 Hz, 3 H), 1.21 (d, J ϭ 6.1 Hz, 3 H), 1.51 (dt, J ϭ
14.5 and 9.5 Hz, 1 H), 1.68 (dt, J ϭ 14.5 and 9.5 Hz, 1 H), 3.62
(s, 1 H), 3.78 (m, 1 H), 3.95 (m, 1 H), 4.39 (d, J ϭ 11.4 Hz, 1 H),
4.63 (d, J ϭ 11.5 Hz, 1 H), 7.23Ϫ7.32 (m, 5 H). Ϫ 13C NMR (50
MHz, CDCl3): δ ϭ 19.5, 23.4, 46.6, 67.5, 70.2, 75.7, 127.6, 127.7,
128.4, 138.0. Ϫ C12H18O2 (194.3): calcd. C 74.19, H 9.34; found C
73.91, H 9.47.
7. (2R*,4R*)-2-Benzyloxy-4-methoxypentane (12a): Sodium hydride
(80% in white oil, 0.96 mmol) was added in small portions to a
solution of (2R*,4R*)-4-benzyloxy-2-pentanol (17, 124 mg, 0.64
mmol) in dimethylformamide (1.6 mL) at 0°C. After stirring for 30
min, methyl iodide (0.89 mL, 9.6 mmol) was added dropwise and
the suspension was stirred for 1.5 h at 0°C, and for 2 h at room
temperature. Saturated aqueous NaHCO3 solution (20 mL) was ad-
ded; the phases were separated and the aqueous phase was ex-
tracted with tert-butyl methyl ether (3 ϫ 30 mL). The combined
organic phases were washed with brine (20 mL), dried (MgSO4)
and concentrated. Flash chromatography of the residue (138 mg)
1
deuterated 6 showed H NMR (500 MHz, [D6]DMSO): δ ϭ 0.82
(d, J ϭ 6.6 Hz, 3 H), 0.83 (d, J ϭ 6.6 Hz, 3 H), 0.92 (d, J ϭ 6.3
Hz, 3 H), 1.02 (ddd, J ϭ 13.2, 7.8, and 5.9 Hz. 1 H), 1.11 (ddd,
J ϭ 13.2, 7.8, and 6.4 Hz, 1 H), 1.64 (m, 1 H), 2.78 (m, 1 H).
4. (2R*,3R*)-2-(Dimethylamino)-3-deuterio-4-methylpentane (deut-
erio-9): A solution of the deuterated amine 6 (128 mg, 0.93 mmol),
formic acid (178 µL, 4.65 mmol), and formaldehyde (37% in water,
208 µL, 2.79 mmol) were stirred at 80°C for 17 h. After cooling to
room temperature, hydrochloric acid (4 , 5 mL) was added. The
phases were separated and the aqueous phase was extracted with
ether (5 mL). The ether phase was discarded and the aqueous phase
was concentrated to leave a white solid. This was dissolved in water
(5 mL), the solution was cooled to 0°C and solid NaOH was added
to obtain a pH of 12. The solution was extracted with ether (4 ϫ
2 mL) and the combined extracts were dried (K2CO3) and concen-
trated at 0°C, leaving the amine deuterio-9 (91 mg, 75%). Ϫ 1H
NMR (200 MHz, CDCl3): δ ϭ 0.84 (d, J ϭ 6.5 Hz, 3 H), 0.88 (d,
J ϭ 6.4 Hz, 3 H), 0.91 (d, J ϭ 6.5 Hz, 3 H), 1.07 (m, 1 H), 1.55
(m, 1 H), 2.19 (s, 6 H), 2.59 (m, 1 H). Ϫ 13C NMR (125 MHz,
CDCl3): δ ϭ 13.3, 22.1, 23.3, 25.0, 40.1, 42.1 (triplet due to at-
1
furnished the product 12a (114 mg, 86%) as a colorless oil. Ϫ H
NMR (300 MHz, CDCl3): δ ϭ 1.12 (d, J ϭ 6.2 Hz, 3 H), 1.20 (d,
J ϭ 6.1 Hz, 3 H), 1.57 (m, 2 H), 3.26 (s, 3 H), 3.53 (m, 1 H), 3.75
(m, 1 H), 4.42 (d, J ϭ 11.6 Hz, 1 H), 4.61 (d, J ϭ 11.6 Hz, 1 H),
7.24Ϫ7.35 (m, 5 H). Ϫ 13C NMR (100 MHz, CDCl3): δ ϭ 19.4,
20.1, 45.3, 56.1, 70.8, 71.8, 73.6, 127.5, 127.9, 128.4, 139.1. Ϫ
C13H20O2 (208.3): calcd. C 74.96, H 9.68; found C 74.82, H 9.75.
8. (2R*,4R*)-2-Benzyloxy-4-chloropentane (12c): Triphenylphos-
phane (176 mg, 0.6 mmol) was added at room temperature to a
solution of (2S*,4R*)-4-benzyloxy-2-pentanol (18) (97 mg, 0.5
mmol) in acetonitrile (0.5 mL) and CCl4 (0.5 mL). After stirring
for 5 h, saturated aqueous NaHCO3 solution (3 mL) was added,
the phases were separated and the aqueous phase was extracted
with tert-butyl methyl ether (2 ϫ 30 mL). The combined organic
phases were washed with brine (10 mL), dried (MgSO4) and con-
centrated. Flash chromatography of the residue with pentane fol-
lowed by 1% tert-butyl methyl ether in pentane furnished the prod-
uct 12c (101 mg, 95%) as a colorless oil. Ϫ 1H NMR (500 MHz,
CDCl3): δ ϭ 1.23 (d, J ϭ 6.1 Hz, 3 H), 1.52 (d, J ϭ 6.6 Hz, 3 H),
1.73 (ddd, J ϭ 14.7, 10.7, and 2.6 Hz, 1 H), 1.88 (ddd, J ϭ 14.7,
10.0, and 2.8 Hz, 1 H), 3.87 (m, 1 H), 4.36 (m, 1 H), 4.46 (d, J ϭ
11.2 Hz, 1 H), 4.63 (d, J ϭ 11.2 Hz, 1 H), 7.26Ϫ7.37 (m, 5 H). Ϫ
2
tached deuterium), 56.6. Ϫ H NMR (61 MHz, CDCl3): δ ϭ 1.34
1
s. Undeuterated 9 showed H NMR (500 MHz, CDCl3): δ ϭ 0.84
(d, J ϭ 6.6 Hz, 3 H), 0.86 (d, J ϭ 6.6 Hz, 3 H), 0.99 (d, J ϭ 6.6
Hz, 3 H), 1.05 (ddd, J ϭ 13.4, 8.0, and 5.7 Hz, 1 H), 1.30 (ddd,
J ϭ 13.4, 7.9, and 6.3 Hz, 1 H), 1.61 (m, 1 H), 2.37 (s, 3 H), 2.55
(m, 1 H), 5.26 (s, 6 H).
5. (2R*,4R*)-4-Benzyloxy-2-pentanol (17): A solution of diisobutyl-
aluminium hydride (1.0  in petroleum ether, 15.2 mmol) was ad- 13C NMR (75 MHz, CDCl3): δ ϭ 19.6, 25.8, 48.2, 55.6, 71.2, 72.4,
Eur. J. Org. Chem. 1999, 2915Ϫ2927
2921

R. W. Hoffmann, D. Stenkamp, T. Trieselmann, R. Göttlich
127.5, 127.8, 128.3, 138.7. Ϫ C12H17ClO (212.7): calcd. C 67.76, H 7.7, and 6.4 Hz, 1 H), 2.92 (s, 3 H), 3.61 (m, 1 H), 4.39 (d, J ϭ
FULL PAPER
8.06; found C 67.49, H 7.76.
11.7 Hz, 1 H), 4.59 (d, J ϭ 11.7 Hz, 1 H), 4.93 (m, 1 H), 7.25Ϫ7.34
(m, 5 H). Ϫ 13C NMR (100 MHz, CDCl3): δ ϭ 19.4, 21.1, 38.4,
43.6, 70.1, 71.1, 77.6, 127.5, 127.6, 128.3, 138.3. Ϫ C13H20O4S
(272.4): calcd. C 57.33, H 7.40; found C 57.48, H 7.67.
9. (2R*,4R*)-2-Benzyloxy-4-bromopentane (12d): CBr4 (229 mg,
0.69 mmol) was added to a solution of (2S*,4R*)-4-benzyloxy-2-
pentanol (18, 96 mg, 0.49 mmol) in dichloromethane (0.4 mL). The
solution was cooled to Ϫ20°C and a solution of triphenylphos-
13. (2R*,4R*)-2-Azido-4-benzyloxypentane (12k): Sodium azide (46
phane (181 mg, 0.69 mmol) in dichloromethane (1.0 mL) was ad- mg, 0.70 mmol) was added to a solution of (1R*,3S*)-3-benzyloxy-
ded dropwise. After 1 d at room temperature, silica gel (0.7 g) was
added and the mixture was concentrated. The residue was purified
by flash chromatography using pentane and 0.7% tert-butyl methyl
ether in pentane to furnish the product 12d (105 mg, 88%) as a
colorless oil. Ϫ 1H NMR (500 MHz, CDCl3): δ ϭ 1.24 (d, J ϭ 6.1
1-methyl-butyl methanesulfonate (20) (147 mg, 0.54 mmol) in di-
methylformamide (1.8 mL). The mixture was stirred for 12 h at
50°C. Saturated aqueous NaHCO3 solution (3 mL) was added and
the phases were separated. The aqueous phase was extracted with
tert-butyl methyl ether (2 ϫ 30 mL) and the combined organic
Hz, 3 H), 1.72 (d, J ϭ 6.7 Hz, 3 H), 1.84 (ddd, J ϭ 15.0, 10.4, and phases were washed with brine (10 mL), dried (MgSO4) and con-
3.0 Hz, 1 H), 1.90 (ddd, J ϭ 15.0, 9.4, and 3.2 Hz, 1 H), 3.86 (m,
1 H), 4.45 (m, 1 H), 4.46 (d, J ϭ 11.3 Hz, 1 H), 4.64 (d, J ϭ 11.2
centrated. Flash chromatography of the residue (134 mg) with pen-
tane and 1.5% tert-butyl methyl ether in pentane furnished the
Hz, 1 H), 7.28Ϫ7.37 (m, 5 H). Ϫ 13C NMR (75 MHz, CDCl3): product 12k (99 mg, 84%) as a colorless oil. Ϫ 1H NMR (300 MHz,
δ ϭ 19.5, 27.0, 48.9, 49.0, 71.3, 73.5, 127.6, 127.9, 128.4, 138.7. Ϫ
C12H17BrO (257.2): calcd. C 56.05, H 6.66; found C 56.34, H 6.70.
CDCl3): δ ϭ 1.12 (d, J ϭ 6.1 Hz, 3 H), 1.16 (d, J ϭ 6.6 Hz, 3 H),
1.39 (ddd, J ϭ 14.4, 10.4, and 3.0 Hz, 1 H), 1.55 (ddd, J ϭ 14.4,
9.9, and 3.3 Hz, 1 H), 3.66 (m, 2 H), 4.33 (d, J ϭ 11.3 Hz, 1 H),
4.53 (d, J ϭ 11.3 Hz, 1 H), 7.18Ϫ7.28 (m, 5 H). Ϫ 13C NMR (75
MHz, CDCl3): δ ϭ 19.7, 20.1, 44.3, 55.0, 70.8, 71.8, 127.6, 127.8,
128.3, 138.6. Ϫ C12H17N3O (219.3): calcd. C 65.73, H 7.81, N
19.16; found C 65.50, H 8.00, N 19.11.
10. (2R*,4R*)-2-Benzyloxy-4-phthalimidopentane (12j): Phthali-
mide (106 mg, 0.72 mmol) and triphenylphosphane (180 mg, 0.68
mmol) were added sequentially at 0°C to a solution of (2S*,4R*)-
4-benzyloxy-2-pentanol (18) (100 mg, 0.51 mmol) in THF (2.6 mL).
After cooling to 0°C diethyl azodicarboxylate (105 µL, 0.67 mmol)
was added dropwise, the mixture was allowed to reach room tem-
perature. After 12 h, silica gel (0.7 g) was added and the suspension
was concentrated. Flash chromatography of the residue with pen-
tane and 10% tert-butyl methyl ether in pentane furnished the prod-
14. (2R*,4R*)-2-Benzyloxy-4-(phenylthio)pentane (12b): n-Butyl-
lithium (1.36  in hexane, 0.86 mmol) was added dropwise at
Ϫ78°C to a solution of thiophenol (103 µL, 1.0 mmol) in THF
(2.0 mL). After stirring for 20 min at Ϫ78°C, a solution of (1R*,
uct 12j (141 mg, 86%) as a colorless oil. Ϫ 1H NMR (500 MHz, 3S*)-3-benzyloxy-1-methylbutyl methanesulfonate (20) (151 mg,
CDCl3): δ ϭ 1.20 (d, J ϭ 6.1 Hz, 3 H), 1.45 (d, J ϭ 7.0 Hz, 3 H),
1.79 (ddd, J ϭ 14.6, 9.4, and 3.8 Hz, 1 H), 2.46 (ddd, J ϭ 14.6,
0.58 mmol) in THF (1.0 mL) was added by means of a canula. The
solution was allowed to stir for 36 h at room temperature. Saturated
11.0, and 2.8 Hz, 1 H), 3.40 (m, 1 H), 4.28 (d, J ϭ 10.9 Hz, 1 H), aqueous NaHCO3 solution (5 mL) was added and the phases were
4.44 (d, J ϭ 10.9 Hz, 1 H), 4.75 (m, 1 H), 7.18Ϫ7.34 (m, 5 H), separated. The aqueous phase was extracted with tert-butyl methyl
7.66 (m, 2 H), 7.78 (m, 2 H). Ϫ 13C NMR (75 MHz, CDCl3): δ ϭ ether (2 ϫ 30 mL). The combined organic phases were washed with
19.25, 19.31, 40.5, 43.9, 70.8, 72.2, 122.9, 127.3, 127.9, 128.1, 132.0,
brine (10 mL), dried (MgSO4), and concentrated. Flash chromatog-
133.6, 138.4, 168.4. Ϫ C20H21NO3 (323.4): calcd. C 74.28, H 6.55, raphy of the residue with pentane and 2% tert-butyl methyl ether
N 4.33; found C 74.22, H 6.73, N 4.64.
in pentane furnished the product 12b (137 mg, 83%) as a colorless
oil. Ϫ 1H NMR (300 MHz, CDCl3): δ ϭ 1.21 (d, J ϭ 6.0 Hz, 3
H), 1.29 (d, J ϭ 6.8 Hz, 3 H), 1.60 (ddd, J ϭ 14.5, 9.6, and 3.6
Hz, 1 H), 1.81 (ddd, J ϭ 14.5, 9.2, and 4.6 Hz, 1 H), 3.48 (m, 1
H), 3.89 (m, 1 H), 4.36 (d, J ϭ 11.4 Hz, 1 H), 4.58 (d, J ϭ 11.4
Hz, 1 H), 7.20Ϫ7.38 (m, 10 H). Ϫ 13C NMR (75 MHz, CDCl3):
δ ϭ 19.8, 22.7, 40.5, 44.7, 70.8, 72.9, 126.6, 127.4, 127.8, 128.3,
128.7, 132.0, 135.3, 138.9. Ϫ C18H22OS (286.4): calcd. C 75.48, H
7.74; found C 75.20, H 7.62.
11. (2R*,4S*)-2-Benzyloxy-4-phthalimidopentane (19): (2S*,4S*)-4-
Benzyloxy-2-pentanol (17, 400 mg, 2.06 mmol) was allowed to re-
act with phthalimide (424 mg, 2.88 mmol) and triphenylphosphane
(718 mg, 2.74 mmol) essentially as described under 10. to give 19
1
(570 mg, 86%) as a colorless oil. Ϫ H NMR (300 MHz, CDCl3):
δ ϭ 1.21 (d, J ϭ 6.1 Hz, 3 H), 1.42 (d, J ϭ 7.0 Hz, 3 H), 1.84
(ddd, J ϭ 14.1, 5.9, and 5.1 Hz, 1 H), 2.41 (ddd, J ϭ 14.2, 8.8, and
7.9 Hz, 1 H), 3.51 (m, 1 H), 4.27 (d, J ϭ 11.7 Hz, 1 H), 4.48 (d,
J ϭ 11.6 Hz, 1 H), 4.54 (m, 1 H), 7.08Ϫ7.16 (m, 5 H), 7.57Ϫ7.63 15. (2R*,4S*)-4-Phthalimido-2-pentanol (21): Palladium hydroxide
(m, 2 H), 7.67Ϫ7.73 (m, 2 H). Ϫ 13C NMR (75 MHz, CDCl3): δ ϭ
on carbon (20%, 13 mg) was added to a solution of (2S*,4R*)-2-
18.8, 19.6, 40.3, 44.8, 70.0, 72.9, 122.8, 127.0, 127.3, 128.0, 132.0, benzyloxy-4-phthalimidopentane (19) (567 mg, 1.75 mmol) in
133.5, 138.5, 168.3. Ϫ C20H21NO3 (323.4): calcd. C 74.28, H 6.55, methanol (17.5 mL). The mixture was stirred for 20 h under hydro-
N 4.33; found C 74.19, H 6.46, N 4.57.
gen. The mixture was filtered through a pad of Kieselgur and the
filtrate was concentrated. The residue (408 mg) was purified by
flash chromatography with gradients of petroleum ether and tert-
butyl methyl ether varying from 4:1 to 1:2, giving the product 21
12. (1R*,3S*)-3-Benzyloxy-1-methylbutyl Methanesulfonate (20):
Triethylamine (0.38 mL, 2.37 mmol) was added at Ϫ20°C to a solu-
tion of (2S*,4R*)-4-benzyloxy-2-pentanol (18) (408 mg, 2.10
mmol) in dichloromethane (8.4 mL). Methanesulfonyl chloride
(0.19 mL, 2.42 mmol) was added and the solution was stirred for
25 min at room temperature. Saturated aqueous NaHCO3 solution
(10 mL) was added and the phases were separated. The aqueous
phase was extracted with tert-butyl methyl ether (3 ϫ 30 mL), the
combined organic phases were washed with brine (20 mL) and
dried (MgSO4). Concentration of the solution furnished the prod-
1
(387 mg, 95%) as a colorless oil. Ϫ H NMR (300 MHz, CDCl3):
δ ϭ 1.21 (d, J ϭ 6.2 Hz, 3 H), 1.43 (s, 1 H), 1.49 (d, J ϭ 7.0 Hz,
3 H), 1.89 (ddd, J ϭ 14.1, 6.3, and 4.7 Hz, 1 H), 2.18 (dt, J ϭ 14.1
and 8.4 Hz, 1 H), 3.83 (m, 1 H), 4.53 (m, 1 H), 7.66Ϫ7.69 (m, 2
H), 7.78Ϫ7.81 (m, 2 H). Ϫ 13C NMR (75 MHz, CDCl3): δ ϭ 18.7,
24.1, 42.6, 45.0, 66.3, 123.0, 132.1, 133.8, 168.6. Ϫ C13H15NO3
(233.3): calcd. C 66.94, H 6.48, N 6.00; found C 66.72, H 6.32,
N 6.27.
1
uct 20 (572 mg, 100%) as a colorless oil. Ϫ H NMR (300 MHz,
CDCl3): δ ϭ 1.26 (d, J ϭ 6.1 Hz, 3 H), 1.37 (d, J ϭ 6.3 Hz, 3 H), 16. (2R*,4R*)-2,4-Bis(phthalimido)pentane (2e): (2R*,4S*)-4-
1.67 (ddd, J ϭ 14.1, 6.9, and 5.2 Hz, 1 H), 2.11 (ddd, J ϭ 14.1,
Phthalimido-2-pentanol (21, 125 mg, 0.54 mmol), phthalimide (118
2922
Eur. J. Org. Chem. 1999, 2915Ϫ2927

Flexible Molecules with Defined Shape XI
mg, 0.80 mmol), triphenylphosphane, (187 mg, 0.71 mmol) and 22. (2R*,4R*)-2,4-Dichloropentane (2c): (2S*,4S*)-2,4-Pentanediol
FULL PAPER
diethyl azodicarboxylate (110 µL, 0.70 mmol) were allowed to react
as described under 10. Flash chromatography with pentane/tert-
butyl methyl ether ϭ 2:1 to 1.5:1 furnished the product 2e (85 mg,
(1.50 g, 14.4 mmol) and CCl4 (9.0 mL) were allowed to react as
described under 8. Distillation of the crude product at 14 mbar,
30°C furnished the product 2c (1.21 g, 60%) as a colorless oil. Ϫ
43%) followed by a 4:7 mixture of 2e and diethyl azodicarboxylate: 1H NMR (300 MHz, CDCl3): δ ϭ 1.55 (d, J ϭ 6.6 Hz, 6 H), 1.96
1H NMR (300 MHz, CDCl3): δ ϭ 1.42 (d, J ϭ 6.8 Hz, 6 H), 2.69 (m, 2 H), 4.32 (m, 2 H) cf. ref.[25]
(m, 2 H), 4.24 (m, 2 H), 7.69Ϫ7.72 (m, 4 H), 7.78Ϫ7.82 (m, 4 H). δ ϭ 25.5, 50.5, 55.8.
13C NMR (75 MHz, CDCl3): δ ϭ 19.0, 36.4, 44.2, 123.0, 132.0,
Ϫ
13C NMR (75 MHz, CDCl3):
Ϫ
23. (2S)-2-Benzyloxy-1-iodopropane: To
a
solution of tri-
133.8, 168.5. Ϫ C21H18N2O4 (362.4): calcd. C 69.60, H 5.01, N
phenylphosphane (956 mg, 3.6 mmol) in dichloromethane (10 mL),
were added imidazole (310 mg, 4.55 mmol), iodine (1.04 g, 4.10
mmol) and a solution of (2S)-2-benzyloxypropanol[29] (505 mg,
3.04 mmol) in dichloromethane (6 mL). After stirring for 1 d at
room temperature, silica gel (6.0 g) was added. The mixture was
concentrated and the residue was purified by flash chromatography
with pentane/tert-butyl methyl ether varying from 80:1 to 40:1 to
give the product (799 mg, 95%) as a colorless oil. Ϫ [α]D20 ϭ ϩ 8.0
7.73; found C 69.70, H 5.24, N 7.50.
17. (2R*,4R*)-2-Chloro-4-phthalimidopentane (2h): (2R*,4S*)-4-
Phthalimido-2-pentanol (21, 96 mg, 0.41 mmol), CCl4 (0.43 mL)
and triphenylphosphane (157 mg, 0.60 mmol) were allowed to react
as described under 8. resulting in the product 2h (99 mg, 95%) as
1
a colorless oil. Ϫ H NMR (300 MHz, CDCl3): δ ϭ 1.43 (d, J ϭ
6.9 Hz, 3 H), 1.48 (d, J ϭ 6.6 Hz, 3 H), 1.90 (ddd, J ϭ 14.8, 10.7,
and 4.0 Hz, 1 H), 2.74 (ddd, J ϭ 14.8, 10.9, and 2.9 Hz, 1 H), 3.81
(m, 1 H), 4.69 (m, 1 H), 7.67Ϫ7.71 (m, 2 H), 7.78Ϫ7.81 (m, 2 H).
1
(c ϭ 6.368, CHCl3). Ϫ H NMR (200 MHz, CDCl3): δ ϭ 1.30 (d,
J ϭ 6.2 Hz, 3 H), 3.26 (m, 2 H), 3.50 (m, 1 H), 4.52 (d, J ϭ 11.6
Hz, 1 H), 4.58 (d, J ϭ 11.6 Hz, 1 H), 7.27Ϫ7.36 (m, 5 H). Ϫ 13C
NMR (50 MHz, CDCl3): δ ϭ 11.4, 20.3, 70.9, 73.9, 127.7, 128.4,
138.1. Ϫ C10H13IO (369.5): calcd. C 43.50, H 4.75; found C 43.58,
H 4.93.
Ϫ
13C NMR (75 MHz, CDCl3): δ ϭ 19.1, 25.5, 43.4, 44.9, 55.2,
123.1, 131.9, 133.9, 168.3. Ϫ C13H14ClNO2 (251.7): calcd. C 62.03,
H 5.61, N 5.56; found C 61.93, H 5.31, N 5.54.
18. (1R*,3S*)-1-Methyl-3-phthalimidobutyl Methanesulfonate (22):
(2S*,4R*)-4-Phthalimido-2-pentanol (21, 90 mg, 0.39 mmol) and
methanesulfonyl chloride (39 µL, 0.49 mmol) were allowed to react
as described under 12. to give 22 (121 mg, 100%) as a colorless oil
which was characterized only by the NMR spectra. Ϫ 1H NMR
(300 MHz, CDCl3): δ ϭ 1.43 (d, J ϭ 6.3 Hz, 3 H), 1.47 (d, J ϭ
6.9 Hz, 3 H), 2.09 (ddd, J ϭ 14.4, 6.7, and 6.0 Hz, 1 H), 2.47 (dt,
J ϭ 14.4 and 7.8 Hz, 1 H), 2.94 (s, 3 H), 4.46 (m, 1 H), 4.75 (m, 1
H), 7.67Ϫ7.70 (m, 2 H), 7.76Ϫ7.80 (m, 2 H). Ϫ 13C NMR (75
MHz, CDCl3): δ ϭ 18.5, 21.3, 38.6, 40.3, 43.7, 77.1, 123.1, 131.8,
134.0, 168.2.
24. (2S,4S)-4-Benzyloxy-N-[(1R,2R)-2-hydroxy-1-methyl-2-phenyl-
ethyl]-N,2-dimethylpentanamide (24): A solution of diisopropylam-
ine (9.2 mL, 65 mmol) in THF (47 mL) was added to dried lithium
chloride (7.9 g, 190 mmol) and the mixture was cooled to Ϫ78°C.
A solution of n-butyllithium (1.54  in hexane, 61 mmol) was ad-
ded dropwise. Stirring was continued for 10 min at Ϫ78°C, and for
15 min at 0°C. The mixture was recooled to Ϫ78°C and a solution
of (1R,2R)-N-(2-hydroxy-1-methyl-2-phenylethyl)-N-methylpropi-
onic amide[33] (6.9 g, 31 mmol) in THF (108 mL) was added, and
the yellow suspension was stirred for 1 h at Ϫ78°C, 20 min at 0°C
and 5 min at room temperature. The mixture was cooled to 0°C
and (2S)-2-benzyloxy-1-iodopropane (4.5 g, 16 mmol) was added
dropwise. After stirring for 30 min at 0°C, and for 2 d at 45°C, the
mixture was cooled to 0°C and hydrolyzed by the addition of aque-
ous semisaturated NH4Cl solution (100 mL). The phases were sepa-
rated and the aqueous phase was extracted with tert-butyl methyl
ether (5 ϫ 100 mL). The combined organic phases were washed
with brine (75 mL), dried (MgSO4) and concentrated. Flash chro-
matography of the residue (10.5 g) with mixtures of pentane and
tert-butyl methyl ether varying from 2:1 to 1:10 furnished the prod-
19. (2R*,4R*)-2-Azido-4-phthalimidopentane (2i): (2S*,4R*)-1-
Methyl-3-phthalimidobutyl methanesulfonate (22) (121 mg, 0.39
mmol) and sodium azide (35 mg, 0.54 mmol) were allowed to react
for 20 h at 40°C, as described under 13. to give the product 2i (93
1
mg, 92%) as a colorless oil. Ϫ H NMR (300 MHz, CDCl3): δ ϭ
1.25 (d, J ϭ 6.6 Hz, 3 H), 1.43 (d, J ϭ 7.0 Hz, 3 H), 1.66 (ddd,
J ϭ 14.4, 10.3, and 4.1 Hz, 1 H), 2.35 (ddd, J ϭ 14.3, 10.8, and
3.3 Hz, 1 H), 3.30 (m, 1 H), 4.55 (m, 1 H), 7.67Ϫ7.69 (m, 2 H),
7.77Ϫ7.81 (m, 2 H). Ϫ 13C NMR (75 MHz, CDCl3): δ ϭ 19.0,
19.5, 39.6, 44.3, 55.3, 123.1, 131.8, 133.9, 168.3. Ϫ C13H14N4O2
(258.3): calcd. C 60.45, H 5.46, N 21.69; found C 60.31, H 5.16,
N 21.52.
20
uct 24 (5.1 g, 84%) as a colorless oil. Ϫ [α]D ϭ Ϫ18.4 (c ϭ 1.155,
CHCl3). Ϫ The NMR spectra were complex due to the presence of
amide rotamers. Ϫ C23H31NO3 (369.5): calcd. C 74.76, H 8.46, N
3.79; found C 74.60, H 8.74, N 3.92.
20. (2R*,4R*)-2,4-Diazido-pentane (2f): (2R*,4R*)-2,4-Pentanediol
(100 mg, 0.96 mmol) and methanesulfonyl chloride (0.17 mL, 2.2
mmol) were converted into the dimesylate 23 (244 mg, 98%) as
described under 12. The latter was dissolved in DMF (3.0 mL) and
sodium azide (156 mg, 2.4 mmol) was added. The mixture was held
for 9 h at 50°C. Workup as described under 13. furnished the prod-
uct 2f (121 mg, 85%) which was characterized by the NMR spectra
only in view of its high energetic nature. Ϫ 1H NMR (300 MHz,
CDCl3): δ ϭ 1.23 (d, J ϭ 6.5 Hz, 6 H), 1.46 (m, 2 H), 3.66 (m, 2
H). Ϫ 13C NMR (75 MHz, CDCl3): δ ϭ 19.7, 43.1, 54.9.
25. (2S,4S)-4-Benzyloxy-2-methylpentanol (26): n-Butyllithium
(1.54  in hexane, 16.2 mmol) was added dropwise at Ϫ78°C to a
solution of diisopropylamine (2.5 mL, 17 mmol) in THF (17.4 mL).
After stirring for 10 min at Ϫ78°C and 15 min at 0°C, boraneϪam-
monia complex (90%, 0.57 g, 16.6 mmol) was added and the sus-
pension was stirred for 15 min at 0°C. A solution of (2S,4S)-4-
benzyloxy-N-[(1R,2R)-2-hydroxy-1-methyl-2-phenylethyl]-N,2-
dimethylpentanoic amide (24) (1.54 g, 4.2 mmol) in THF (12.7 mL)
was added slowly as the mixture was stirred for 2.5 h at room tem-
21. (2R*,4R*)-2,4-Dibromopentane (2d): (2S*,4S*)-2,4-Pentanediol
(120 mg, 1.15 mmol) was allowed to react with CBr4 (1.07 g, 3.2 perature. Hydrochloric acid (3 , 140 mL) was added at 0°C and
mmol) as described under 9. Flash chromatography with pentane the solution was stirred for 30 min. The phases were separated and
and 1% tert-butyl methyl ether in pentane resulted in a 1:1 mixture the aqueous phase was extracted with tert-butyl methyl ether (3 ϫ
of bromoform and the product 2d (246 mg), and analytically pure
product (77 mg) as a colorless oil. Ϫ 1H NMR (300 MHz, CDCl3):
δ ϭ 1.72 (d, J ϭ 6.7 Hz, 6 H), 2.08 (m, 2 H), 4.35 (m, 2 H). Ϫ 13C
NMR (75 MHz, CDCl3): δ ϭ 26.5, 49.7, 51.7, cf. ref.[28]
70 mL). The combined organic phases were washed with hydro-
chloric acid (3 , 20 mL), aqueous NaOH (2 , 20 mL), brine (20
mL), dried (MgSO4) and concentrated. Flash chromatography of
the crude product (0.87 g) with pentane/tert-butyl methyl ether va-
Eur. J. Org. Chem. 1999, 2915Ϫ2927
2923

R. W. Hoffmann, D. Stenkamp, T. Trieselmann, R. Göttlich
FULL PAPER
rying from 4:1 to 1:1 furnished the product 26 (0.82 g, 95%) as a
colorless oil. Ϫ [α]D ϭ ϩ 28.4 (c ϭ 3.830, CHCl3). Ϫ H NMR
temperature. Saturated aqueous NaHCO3 solution (5 mL) was ad-
ded, the phases were separated and the aqueous phase was ex-
20
1
(400 MHz, CDCl3): δ ϭ 0.91 (d, J ϭ 6.8 Hz, 3 H), 1.23 (d, J ϭ tracted with tert-butyl methyl ether (3 ϫ 20 mL). The combined
6.2 Hz, 3 H), 1.56 (m, 2 H), 1.89 (m, 1 H), 2.55 (s, 1 H), 3.42 (m, organic phases were washed with brine (10 mL), dried (MgSO4)
2 H), 3.70 (m, 1 H), 4.45 (d, J ϭ 11.6 Hz, 1 H), 4.60 (d, J ϭ 11.6 and concentrated. Flash chromatography of the residue with pen-
Hz, 1 H), 7.23Ϫ7.34 (m, 5 H). Ϫ 13C NMR (100 MHz, CDCl3): tane followed by 2% tert-butyl methyl ether in pentane furnished
δ ϭ 17.5, 19.3, 32.2, 40.7, 68.0, 70.3, 72.9, 127.6, 127.7, 128.4, the product 12l (74 mg, 95%) as a colorless oil. Ϫ [α]D20 ϭ ϩ 137.9
1
138.4. Ϫ C13H20O2 (208.3): calcd. C 74.96, H 9.68; found C 74.75,
(c ϭ 0.580, CHCl3). Ϫ H NMR (200 MHz, CDCl3): δ ϭ 1.19 (d,
J ϭ 7.0 Hz, 3 H), 1.22 (d, J ϭ 6.1 Hz, 3 H), 1.49 (ddd, J ϭ 13.7,
11.0, and 3.0 Hz, 1 H), 1.64 (ddd, J ϭ 13.7, 9.9, and 4.3 Hz, 1 H),
2.02 (d, J ϭ 11.3 Hz, 1 H), 2.80 (m, 1 H), 3.83 (m, 1 H), 4.46 (d,
J ϭ 11.3 Hz, 1 H), 4.62 (d, J ϭ 11.3 Hz, 1 H), 7.26Ϫ7.37 (m, 5
H). Ϫ 13C NMR (100 MHz, CDCl3): δ ϭ 19.9, 21.4, 22.6, 44.7,
68.4, 71.1, 73.3, 88.8, 127.4, 127.8, 128.3, 138.9. Ϫ C14H18O
(202.3): calcd. C 83.12, H 8.97; found C 82.92, H 8.86.
H 9.61.
26. (2S,4S)-4-Benzyloxy-2-methylpentanal (27): To a solution of
(2S,4S)-4-benzyloxy-2-methylpentanol (26) (307 mg, 1.47 mmol) in
dichloromethane (3.0 mL) was added molecular sieves (4 A, 750
mg), N-methylmorpholine oxide (259 mg, 2.21 mmol) and tetra-N-
propylammonium perruthenate (26 mg, 0.07 mmol). After stirring
for 30 min at room temperature, the mixture was transferred to a
chromatography column and purified by elution with pentane/tert-
butyl methyl ether mixtures from 10:1 to 4:1. The product 27 (248
mg, 82%) was obtained as a colorless oil and immediately used in
further transformations.
˚
30. (3S,5S)-5-Benzyloxy-3-methyl-1-trimethylsilylhexyne (12m):
(3S,5S)-5-Benzyloxy-1,1-dibromo-3-methylhexene (28, 111 mg,
0.31 mmol) was allowed to react as described under 29. The mix-
ture was quenched with chlorotrimethylsilane (0.16 mL, 1.23
mmol) and the solution was transferred by means of a canula to
an aqueous pH7-buffer solution (10 mL). The phases were sepa-
rated and the aqueous phase was extracted with tert-butyl methyl
ether (3 ϫ 20 mL). After purification as described under 29. the
product (12m, 78 mg, 93%) was obtained as a colorless oil. Ϫ
27. (3S,5S)-5-Benzyloxy-3-methylhexene (12e): n-Butyllithium solu-
tion (1.54  in hexane, 0.48 mmol) was added dropwise to a solu-
tion of methyltriphenylphosphonium bromide (187 mg, 0.52 mmol)
in ether (2.0 mL). The resulting yellow suspension was cooled to
Ϫ78°C, a solution of (2S,4S)-4-benzyloxy-2-methylpentanal (27)
(83 mg, 0.40 mmol) in THF (1.0 mL) was slowly added and the
mixture was allowed to reach room temperature overnight. Silica
gel (0.35 g) was added and the mixture was concentrated. Flash
chromatography of the residue with pentane followed by 1% of tert-
butyl methyl ether in pentane furnished the product 12e (67 mg,
20
[α]D ϭ ϩ 147.2 ( c ϭ 1.130, CHCl3). Ϫ 1H NMR (400 MHz,
CDCl3): δ ϭ 0.06 (s, 9 H), 1.08 (d, J ϭ 7.0 Hz, 3 H), 1.14 (d, J ϭ
6.1 Hz, 3 H), 1.39 (ddd, J ϭ 13.6, 10.8, and 3.2 Hz, 1 H), 1.55
(ddd, J ϭ 13.6, 9.8, and 4.5 Hz, 1 H), 2.75 (m, 1 H), 3.74 (m, 1
H), 4.38 (d, J ϭ 11.3 Hz, 1 H), 4.53 (d, J ϭ 11.3 Hz, 1 H),
7.18Ϫ7.30 (m, 5 H). Ϫ 13C NMR (100 MHz, CDCl3): δ ϭ 0.26,
20.0, 21.3, 23.8, 44.8, 71.3, 73.7, 84.4. 111.7, 127.4, 127.8, 128.3,
139.0.
20
82%) as a colorless oil. Ϫ [α]D ϭ ϩ 72.0 (c ϭ 1.495, CHCl3). Ϫ
1H NMR (200 MHz, CDCl3): δ ϭ 0.99 (d, J ϭ 6.8 Hz, 3 H), 1.19
(d, J ϭ 6.1 Hz, 3 H), 1.31 (ddd, J ϭ 14.0, 9.5, and 4.0 Hz, 1 H),
1.62 (ddd, J ϭ 14.0, 8.9, and 4.9 Hz, 1 H), 2.42 (m, 1 H), 3.56 (m,
1 H), 4.39 (d, J ϭ 11.4 Hz, 1 H), 4.58 (d, J ϭ 11.5 Hz, 1 H), 4.88
(m, 1 H), 4.94 (m, 1 H), 5.64 (m, 1 H), 7.25Ϫ7.36 (m, 5 H). Ϫ 13C
NMR (50 MHz, CDCl3): δ ϭ 19.9, 21.0, 34.6, 44.5, 70.5, 73.0,
113.0, 127.4, 127.8, 128.3, 139.0, 144.4. Ϫ C14H20O (204.3): calcd.
C 82.30, H 9.87; found C 82.40, H 9.67.
31. (3S,5S)-5-Benzyloxy-3-methyl-2-hexanone (12g): A solution of
methyllithium (1.6  in ether, 3.04 mmol) was slowly added at
Ϫ78°C to a solution of (2S,4S)-4-benzyloxy-N-[(1R,2R)-2-hydroxy-
1-methyl-2-phenylethyl]-N,2-dimethylpentanoic amide (24, 468 mg,
1.27 mmol) in ether (13.0 mL). After stirring for 15 min at Ϫ78°C,
diisopropylamine (179 µL, 1.27 mmol) was added at 0°C and stir-
ring was continued for 15 min. Acetic acid (20% in ether, 4.4 mL)
was added, resulting in the formation of a white precipitate. Satu-
rated aqueous NH4Cl solution (20 mL) was added and the phases
were separated. The aqueous phase was extracted with tert-butyl
methyl ether (3 ϫ 30 mL). The combined organic phases were
washed with brine (20 mL), dried (MgSO4) and concentrated.
Flash chromatography of the residue (305 mg) with pentane/tert-
butyl methyl ether varying from 50:1 to 10:1 furnished the product
28. (3S,5S)-5-Benzyloxy-1,1-dibromo-3-methylhexene (28): A solu-
tion of CBr4 (564 mg, 1.70 mmol) in dichloromethane (0.7 mL)
was added by means of a canula to a solution of triphenylphos-
phane (893 mg, 3.40 mmol) in dichloromethane (1.5 mL). After
stirring for 50 min at 0°C, a solution of (2S,4S)-4-benzyloxy-2-
methyl-pentanal (27) (180 mg, 0.87 mmol) in dichloromethane (1.0
mL) was added dropwise at Ϫ20°C. The suspension was allowed
to reach room temperature. Silica gel (3.0 g) was added and the
suspension was concentrated. Flash chromatography of the residue
20
12g (253 mg, 91%) as a colorless oil. Ϫ [α]D ϭ ϩ51.6 (c ϭ 4.350,
CHCl3). Ϫ 1H NMR (200 MHz, CDCl3): δ ϭ 1.07 (d, J ϭ 7.2 Hz,
3 H), 1.19 (d, J ϭ 6.1 Hz, 3 H), 1.55 (ddd, J ϭ 14.1, 8.7, and 4.5
Hz, 1 H), 1.87 (ddd, J ϭ 14.1, 8.9, and 3.8 Hz, 1 H), 2.05 (s, 3 H),
2.80 (m, 1 H), 3.50 (m, 1 H), 4.31 (d, J ϭ 11.6 Hz, 1 H), 4.53 (d,
J ϭ 11.4 Hz, 1 H), 7.21Ϫ7.34 (m, 5 H). Ϫ 13C NMR (50 MHz,
CDCl3): δ ϭ 17.2, 19.7, 28.2, 40.2, 43.1, 70.4, 72.6, 127.5, 127.8,
128.3, 138.6, 212.5. Ϫ C14H20O2 (208.3): calcd. C 76.33, H 9.15;
found C 76.04, H 9.04.
with pentane/tert-butyl methyl ether varying from 100:1 to 20:1 fur-
20
nished the product 28 (262 mg, 83%) as a colorless oil. Ϫ [α]D
ϭ
1
ϩ 62.9 (c ϭ 7.895, CHCl3). Ϫ H NMR (200 MHz, CDCl3): δ ϭ
1.00 (d, J ϭ 6.8 Hz, 3 H), 1.19 (d, J ϭ 6.1 Hz, 3 H), 1.38 (ddd,
J ϭ 14.1, 9.8, and 3.4 Hz, 1 H), 1.65 (ddd, J ϭ 14.1, 9.2, and 4.3
Hz, 1 H), 2.81 (m, 1 H), 3.47 (m, 1 H), 4.43 (d, J ϭ 11.3 Hz, 1 H),
4.57 (d, J ϭ 11.3 Hz, 1 H), 6.19 (d, J ϭ 9.5 Hz, 1 H), 7.28Ϫ7.36
(m, 5 H). Ϫ 13C NMR (50 MHz, CDCl3): δ ϭ 19.7, 19.9, 35.2,
43.9, 70.7, 73.0, 87.6, 127.4, 127.8, 128.3, 138.7, 144.1.
C14H18Br2O (362.1): calcd. C 46.44, H 5.01; found C 46.56, H 5.01.
Ϫ
32. (3S,5S)-5-Benzyloxy-2,3-dimethylhexene (12f): A solution of di-
methyltitanocene (1.0  in THF, 1.17 mmol) was added dropwise
to a solution of (3S,5S)-5-benzyloxy-3-methyl-2-hexanone (12g,
29. (3S,5S)-5-Benzyloxy-3-methylhexyne (12l): n-Butyllithium (1.54
 in hexane, 0.81 mmol) was added dropwise to a solution of 103 mg, 0.47 mmol) in toluene (2.4 mL). The mixture was stirred
(3S,5S)-5-benzyloxy-1,1-dibromo-3-methylhexene (28) (140 mg, in the dark for 16 h at 70°C. Silica gel (0.5 g) was added and the
0.39 mmol) in THF (3.9 mL) at Ϫ78°C. After stirring for 3 h, water suspension was concentrated. Flash chromatography of the residue
(0.2 mL) was added and the mixture was allowed to reach room
with pentane, followed by 2% tert-butyl methyl ether in pentane
2924
Eur. J. Org. Chem. 1999, 2915Ϫ2927

Flexible Molecules with Defined Shape XI
FULL PAPER
furnished the product 12f (77 mg, 76%) as a colorless oil. Ϫ
phy of the residue with ether furnished the diol (2.45 g, 92%) as a
20
1
[α]D ϭ ϩ 38.3 (c ϭ 2.940, CHCl3). Ϫ 1H NMR (200 MHz, colorless oil. Ϫ H NMR (300 MHz, CDCl3): δ ϭ 0.87 (d, J ϭ 6.7
CDCl3): δ ϭ 1.00 (d, J ϭ 7.0 Hz, 3 H), 1.18 (d, J ϭ 6.1 Hz, 3 H), Hz, 6 H), 1.20 (t, J ϭ 6.8 Hz, 2 H), 1.74 (sext, J ϭ 6.6 Hz, 2 H),
1.46 (ddd, J ϭ 14.1, 9.3, and 4.1 Hz, 1 H), 1.57 (ddd, J ϭ 14.1, 2.08 (s, 2 OH), 3.44 (d, J ϭ 6.6 Hz, 4 H). Ϫ 13C NMR (75 MHz,
8.5, and 5.3 Hz, 1 H), 1.63 (broad s, 3 H), 2.47 (m, 1 H), 3.47 (m, CDCl3): δ ϭ 16.4, 32.8, 36.7, 68.8. Ϫ C7H16O2 (132.2): calcd. C
1 H), 4.38 (d, J ϭ 11.4 Hz, 1 H), 4.55 (d, J ϭ 11.4 Hz, 1 H), 4.69 63.60, H 12.20; found C 63.80, H 12.39
(m, 2 H), 7.24Ϫ7.35 (m, 5 H). Ϫ 13C NMR (50 MHz, CDCl3): δ ϭ
36. (2R*,4R*)-5-(tert-Butyldimethylsilyloxy)-2,4-dimethylpentanol
(29): Sodium hydride (80% in white oil, 6.84 mmol) was added in
small portions to a solution of (2R*,4R*)-2,4-dimethyl-1,5-pen-
tanediol (861 mg, 6.51 mmol) in THF (10.9 mL) at 0°C. After
18.5, 19.9, 20.3, 37.8, 42.7, 70.6, 73.2, 110.0, 127.3, 127.7, 128.3,
139.1, 149.6. Ϫ C15H22O (218.3): calcd. C 82.52, H 10.16; found C
82.20, H 10.35.
33. (2S,4S)-4-Benzyloxy-2-methylpentanoic Acid (12h): Methanesul-
fonic acid (69 µL, 1.07 mmol) was added dropwise to a solution of
(2S,4S)-4-benzyloxy-N-[(1R,2R)-2-hydroxy-1-methyl-2-
phenylethyl]-N,2-dimethylpentanoic amide (274 mg, 0.74 mmol) in
THF (3 mL). After heating at reflux for 1 h, the mixture was cooled
to 0°C and a solution of lithium tetrahydroboranate (24.0 mg, 1.11
mmol) in THF (1.6 mL) was added dropwise. Aqueous NaOH (1
stirring for 40 min at room temperature, tert-butylchlorodimethylsi-
lane (50% in toluene, 6.84 mmol) was added and the mixture was
stirred for 1 d. Saturated aqueous NaHCO3 solution (10 mL) was
added, the phases were separated and the aqueous phase was ex-
tracted with tert-butyl methyl ether (2 ϫ 50 mL). The combined
organic phases were washed with brine (20 mL), dried (MgSO4),
and concentrated. Flash chromatography of the residue (1.62 g)
, 3.63 mmol) was added and the solution was stirred for 8 h at with pentane/tert-butyl methyl ether ϭ 10:1 to 4:1 resulted in the
room temperature. Dichloromethane (20 mL) and water (20 mL)
were added and the phases were separated. The aqueous phase was
product 29 (1.203 g, 75%) as a colorless oil. Ϫ 1H NMR (300 MHz,
CDCl3): δ ϭ 0.03 (s, 6 H), 0.83 (d, J ϭ 6.7 Hz, 3 H), 0.87 (s, 9 H),
extracted with dichloromethane (20 mL) and acidified with hydro- 0.87 (m, 3 H), 1.15 (m, 2 H), 1.70 (m, 2 H), 1.83 (s, 1 H), 3.41 (m,
chloric acid (2 ) to pH ϭ 2. The aqueous phase was extracted
with dichloromethane (3 ϫ 30 mL). The extracts were dried
(MgSO4) and concentrated to leave the acid 12h (126 mg, 77%) as
a colorless oil. Ϫ [α]D20 ϭ ϩ 74.5 (c ϭ 2.515, CHCl3). Ϫ 1H NMR
(200 MHz, CDCl3): δ ϭ 1.19 (d, J ϭ 7.2 Hz, 3 H), 1.20 (d, J ϭ
6.0 Hz, 3 H), 1.63 (ddd, J ϭ 14.2, 9.0, and 4.5 Hz, 1 H), 1.84 (ddd,
J ϭ 14.2, 9.5, and 3.7 Hz, 1 H), 2.78 (m, 1 H), 3.61 (m, 1 H), 4.40
(d, J ϭ 11.4 Hz, 1 H), 4.56 (d, J ϭ 11.4 Hz, 1 H), 7.26Ϫ7.33 (m,
5 H), 10.8 (broad s, 1 H). Ϫ 13C NMR (50 MHz, CDCl3): δ ϭ
17.9, 19.7, 36.0, 40.9, 70.7, 72.9, 127.4, 127.8, 128.3, 138.5, 183.1.
Ϫ C13H18O3 (222.3): calcd. C 70.24, H 8.16; found C 70.28, H 8.31.
4 H). Ϫ 13C NMR (75 MHz, CDCl3): δ ϭ Ϫ5.4, 16.4, 16.6, 18.3,
25.9, 33.0, 33.1, 36.8, 68.9, 69.0. Ϫ C13H30O2Si (246.5): calcd. C
63.35, H 12.27; found C 63.11, H 12.28.
37.
(3R*,5R*)-1,1-Dibromo-6-(tert-butyldimethylsilyloxy)-3,5-di-
methylhexene (30): A solution of dimethyl sulfoxide (1.33 mL, 18.7
mmol) in dichloromethane (7.0 mL) was added at Ϫ78°C to a solu-
tion of oxalyl chloride (0.80 mL, 9.4 mmol) in dichloromethane
(8.0 mL). After stirring for 5 min a solution of (2R*,4R*)-5-(tert-
butyldimethylsilyloxy)-2,4-dimethylpentanol (29, 1.54 g, 6.23
mmol) in dichloromethane (10 mL) was added and stirring was
continued for 20 min at Ϫ78°C. Triethylamine (3.9 mL, 27 mmol)
was added dropwise and the solution was allowed to reach 0°C
over 2 h. Saturated aqueous NH4Cl solution (50 mL) was added,
the phases were separated and the aqueous phase was extracted
with dichloromethane (3 ϫ 70 mL). The combined organic phases
were washed with brine (50 mL), dried (MgSO4) and concentrated.
34. Methyl (2S,4S)-4-Benzyloxy-2-methylpentanoate (12i): A solu-
tion of diazomethane in ether (ca. 1.5 mL) was added to a solution
of (2S,4S)-4-benzyloxy-2-methylpentanoic acid (12h) (81 mg, 0.36
mmol) in ether (2 mL) at 0°C until the yellow color persisted. The
mixture was stirred for 1 h at 0°C. Saturated aqueous NH4Cl solu-
tion (20 mL) was added and the phases were separated. The aque- Filtration of the residue with pentane/tert-butyl methyl ether, 12:1,
ous phase was extracted with tert-butyl methyl ether (3 ϫ 20 mL). over a short column of silica gel furnished the aldehyde (1.49 g,
The combined organic phases were washed with brine (10 mL), 98%) as a colorless oil. Ϫ A solution of CBr4 (3.94 g, 11.9 mmol)
dried (MgSO4), and concentrated. Flash chromatography of the
residue (99 mg) with pentane/tert-butyl methyl ether 10:1 to 4:1
in dichloromethane (5 mL) was added by means of a canula to a
solution of triphenylphosphane (6.24 g, 23.8 mmol) in dichloro-
methane (10.9 mL). After stirring for 1 h at 0°C, this solution was
20
furnished the ester 12i (82 mg, 95%) as a colorless oil. Ϫ [α]D
ϭ
1
ϩ 76.5 (c ϭ 1.820, CHCl3). Ϫ H NMR (200 MHz, CDCl3): δ ϭ cooled to Ϫ20°C and a solution of the above aldehyde (1.49 g,
1.18 (m, 6 H), 1.61 (ddd, J ϭ 14.1, 8.9, and 4.4 Hz, 1 H), 1.84 6.1 mmol) in dichloromethane (6.5 mL) was added. The resulting
(ddd, J ϭ 14.1, 9.7, and 3.7 Hz, 1 H), 2.78 (m, 1 H), 3.53 (m, 1
suspension was stirred for 30 min at Ϫ20°C. Pentane (50 mL) was
H), 3.60 (s, 3 H), 4.37 (d, J ϭ 11.4 Hz, 1 H), 4.55 (d, J ϭ 11.4 Hz, added and the solution was filtered through Kieselgur and concen-
1 H), 7.25Ϫ7.34 (m, 5 H). Ϫ 13C NMR (50 MHz, CDCl3): δ ϭ trated. The residue was extracted with dichloromethane (3 ϫ 20
18.0, 19.7, 35.9, 41.2, 51.4, 70.6, 72.9, 127.4, 127.8, 128.2, 138.7,
177.2. Ϫ C14H20O3 (236.3): calcd. C 71.16, H 8.53; found C 70.97,
H 8.66.
mL) and pentane (20 mL). The extracts were filtered through Kie-
selgur and were concentrated. Flash chromatography of the residue
with pentane followed by 1% tert-butyl methyl ether in pentane
furnished the product 30 (1.89 g, 77%) as a colorless oil. Ϫ 1H
NMR (300 MHz, CDCl3): δ ϭ 0.04 (s, 6 H), 0.89 (d, J ϭ 6.7 Hz,
3 H), 0.90 (s, 9 H), 0.98 (d, J ϭ 6.7 Hz, 3 H), 1.12 (dt, J ϭ 13.5
and 7.5 Hz), 1 H), 1.43 (m, 1 H), 1.61 (m, 1 H), 2.53 (m, 1 H),
3.42 (m, 2 H), 6.19 (d, J ϭ 9.4 Hz, 1 H). Ϫ 13C NMR (75 MHz,
CDCl3): δ ϭ Ϫ5.4, 17.2, 18.3, 19.2, 26.0, 33.4, 36.1, 39.5, 67.6,
87.1, 144.7. Ϫ C14H28Br2OSi (400.3): calcd. C 42.01, H 7.05; found
C 41.90, H 6.85.
35. (2R*,4R*)-2,4-Dimethyl-1,5-pentanediol:[30] BoraneϪdimethyl
sulfide (4.4 mL, 0.044 mol) was added dropwise at 0°C to a solu-
tion of (2R*,4R*)-dimethyl glutarate.[31] After stirring for 3 h at
room temperature, methanol (10 mL) was added carefully at 0°C.
After the vigorous reaction had ceased, the solvents were removed
in vacuo. The residue was taken up in methanol (20 mL) and the
solution was again concentrated in vacuo. The residue was par-
titioned between ether (20 mL) and aqueous saturated K2CO3 solu-
tion (20 mL). The phases were separated and the aqueous phase 38.
was extracted with ether (5 ϫ 10 mL). The combined organic
phases were dried (MgSO4) and concentrated. Flash chromatogra-
(3R*,5R*)-6-(tert-Butyldimethylsilyloxy)-3,5-dimethyl-1-tri-
methylsilyl-1-hexyne (31): n-Butyllithium (1.95  in hexane, 5.00
mmol) was added dropwise to a solution of (3R*,5R*)-1,1-di-
Eur. J. Org. Chem. 1999, 2915Ϫ2927
2925

R. W. Hoffmann, D. Stenkamp, T. Trieselmann, R. Göttlich
FULL PAPER
[1]
[2]
A. Gil de Oliveira Santos, W. Klute, J. Torode, V. P. W. Böhm,
E. Cabrita, J. Runsink, R. W. Hoffmann, New. J. Chem. 1998,
993Ϫ997.
bromo-6-(tert-butyldimethylsilyloxy)-3,5-dimethylhexene (30, 909
mg, 2.27 mmol) in THF (22.7 mL at Ϫ78°C). After stirring for 3
h, chlorotrimethylsilane (1.15 mL, 9.08 mmol) was added. The mix-
ture was allowed to reach room temperature overnight, and was
transferred by means of a canula to a pH7-buffer solution (80 mL).
The phases were separated, and the aqueous phase was extracted
with tert-butyl methyl ether (3 ϫ 100 mL). The combined organic
phases were washed with brine (40 mL), dried (MgSO4), and con-
centrated. Flash chromatography of the residue with pentane fol-
lowed by 10% tert-butyl methyl ether in pentane furnished the
product 31 (700 mg, 99%) as a colorless oil. Ϫ 1H NMR (300 MHz,
CDCl3): δ ϭ 0.03 (s, 6 H), 0.12 (s, 9 H), 0.88 (s, 9 H), 0.90 (d, J ϭ
6.7 Hz, 3 H), 1.12 (d, J ϭ 6.8 Hz, 3 H), 1.26 (ddd, J ϭ 13.4, 8.7,
and 6.6 Hz, 1 H), 1.44 (m, 1 H), 1.81 (m, 1 H), 2.51 (m, 1 H), 3.39
(dd, J ϭ 9.8 and 6.2 Hz, 1 H), 3.47 (dd, J ϭ 9.8 and 5.2 Hz, 1 H).
R. W. Hoffmann, Angew. Chem. 1992, 104, 1147Ϫ1157; Angew.
Chem. Int. Ed. Engl. 1992, 31, 1124Ϫ1134.
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S. Sykora, Collect. Czech. Chem. Commun. 1968, 33,
3514Ϫ3527. Ϫ [3b] P. L. Luisi, Naturwiss. 1977, 64, 569Ϫ574. Ϫ
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W. C. Still, D. Cai, D. Lee, P. Hauck, A. Bernardi, A. Ro-
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P. Picard, J. Moulines, Tetrahedron 1978, 34, 671Ϫ676. Ϫ
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1995, 107, 489Ϫ490; Angew. Chem. Int. Ed. Engl. 1995, 34,
448Ϫ449.
Ϫ
13C NMR (75 MHz, CDCl3): δ ϭ Ϫ5.4, 0.3, 17.4, 18.3, 21.2,
[7]
[8]
E. Kleinpeter, R. Meusinger, C. Duschek, R. Borsdorf, Magn.
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cf. the A-values: J. A. Hirsch, Top. Stereochem. 1967, 1,
199Ϫ222.
24.7, 26.0, 33.8, 40.7, 67.7, 83.8, 112.5. Ϫ C17H36OSi2 (312.6):
calcd. C 65.31, H 11.61; found C 65.56, H 11.79.
39.
(3R*,5R*)-3,5-Dimethyl-6-hydroxy-1-trimethylsilyl-1-hexyne
[9]
(32): Acetic acid (8.1 mL) was added to a solution of (3R*,5R*)-
6-(tert-butyldimethylsilyloxy)-3,5-dimethyl-1-trimethylsilyl-1-
hexyne (31) (450 mg, 1.44 mmol) in THF (2.7 mL) and water (2.7
mL). After stirring for 18 h, saturated aqueous NaHCO3 solution
(50 mL) was added in small portions. The phases were separated
and the aqueous phase was extracted with tert-butyl methyl ether
(3 ϫ 50 mL). The combined organic phases were washed with brine
(40 mL), dried (MgSO4), and concentrated. Flash chromatography
of the residue (570 mg), with pentane followed by 10% tert-butyl
methyl ether in pentane furnished the product 32 (266 mg, 93%) as
[10]
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K. L. Williamson, D. R. Clutter, R. Emch, M. Alexander, A.
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1
a colorless oil. Ϫ H NMR (300 MHz, CDCl3): δ ϭ 0.11 (s, 9 H),
[15]
0.93 (d, J ϭ 6.8 Hz, 3 H), 1.13 (d, J ϭ 6.9 Hz, 3 H), 1.31Ϫ1.50
(m, 2 H), 1.66 (s, 1 H), 1.82 (m, 1 H), 2.53 (m, 1 H), 3.46 (dd, J ϭ
10.7 and 5.9 Hz, 1 H), 3.53 (dd, J ϭ 10.7 and 5.6 Hz, 1 H). Ϫ 13C
NMR (75 MHz, CDCl3): δ ϭ 0.2, 17.1, 21.1, 24.4, 33.6, 40.4, 67.5,
84.2, 112.3. Ϫ C11H22OSi (198.4): calcd. C 66.60, H 11.18; found
C 66.40, H 11.03.
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D. Parker, K. Senanayake, J. Vepsailainen, S. Williams, A.
S. Batsanov, J. A. K. Howard, J. Chem. Soc., Perkin Trans. 2
[16b]
1997, 1445Ϫ1452. Ϫ
T. K. Brunck, F. Weinhold, J. Am.
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Chem. Soc. 1979, 101, 1700Ϫ1709. Ϫ
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Jacques, J. Am. Chem. Soc. 1987, 109, 2616Ϫ2623. Ϫ
N.
40. (3R*,5R*)-7,7-Dibromo-3,5-dimethyl-1-trimethylsilylhept-6-en-
1-yne (33): (3R*,5R*)-3,5-Dimethyl-6-hydroxy-1-trimethylsilyl-1-
hexyne (32) (237 mg, 1.19 mmol) was converted into the dibromo
compound (65%) as described under 37. Ϫ 1H NMR (300 MHz,
CDCl3): δ ϭ 0.13 (s, 9 H), 1.02 (d, J ϭ 6.8 Hz, 3 H), 1.14 (d, J ϭ
6.9 Hz, 3 H), 1.37 (ddd, J ϭ 13.4, 9.6, and 5.0 Hz, 1 H), 1.50 (ddd,
J ϭ 13.3, 10.1, and 4.6 Hz, 1 H), 2.44 (m, 1 H), 2.77 (m, 1 H), 6.15
(d, J ϭ 9.5 Hz, 1 H). Ϫ 13C NMR (75 MHz, CDCl3): δ ϭ 0.2,
19.5, 21.3, 25.1, 36.7, 43.5, 84.8, 88.2, 111.2, 143.6. Ϫ C12H20Br2Si
(352.2): calcd. C 40.93, H 5.72; found C 40.99, H 5.83.
D. Epiotis, R. L. Yates, J. R. Larson, C. R. Kirmaier, F.
Bernardi, J. Am. Chem. Soc. 1977, 99, 8379Ϫ8388.
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[17b] P. R. Ratlen, R. W. Hoffmann, D. A. Hrovat, W. T. Border,
J. Chem. Soc., Perkin Trans. 2, 1999, 1719Ϫ1726.
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G. J. Szasz, J. Chem. Phys. 1955, 23, 2449Ϫ2450.
[19]
K.-M. Marstokk, H. Mollendal, Acta Chem. Scand. 1997, 51,
1058Ϫ1065.
[20]
3
12b JCϪH (Hz): HB3-Me1 4.4; HCϪMe1 4.1; HBϪMe2 4.2;
HCϪMe2 3.2. Ϫ 12c JCϪH (Hz): HBϪMe1 2.4; HCϪMe1 2.7;
3
HBϪMe2 3.0; HCϪMe2 1.8. Ϫ 12l JCϪH (Hz): HBϪMe1 3.1;
HCϪMe1 3.1; HBϪMe2 3.1; HCϪMe2 2.2.
T. Shimanouchi, M. Tasumi, Spectrochim. Acta 1961, 17,
755Ϫ760.
[21]
[22]
[23]
41. (3R*,5R*)-3,5-Dimethyl-1,7-bis(trimethylsilyl)-1,6-heptadiyne
(2g): (3R*,5R*)-7,7-Dibromo-3,5-dimethyl-1-trimethylsilyl-hept-6-
en-1-yne (33, 209 mg, 0.59 mmol) was converted into the bis(trime-
thylsilyl)alkyne (90%) as described under 39. Ϫ 1H NMR (300
MHz, CDCl3): δ ϭ 0.05 (s, 18 H), 1.16 (d, J ϭ 6.9 Hz, 6 H), 1.44
(m, 2 H), 2.68 (m, 2 H). Ϫ 13C NMR (75 MHz, CDCl3): δ ϭ
0.3, 21.4, 25.6, 44.5, 84.4, 111.4. Ϫ C15H28Si2: calcd. C 264.1730:
found 264.1731.
D. Doskocilova, B. Schneider, Coll. Czech. Chem. Commun.
1964, 29, 2290Ϫ2308.
Simulations were carried out with the program XSIM; R.R.
Sebastian, University of Manitoba, Canada.
[24] [24a]
P. E. McMahon, R. L. McCullough, Trans. Faraday Soc.
[24b]
1964, 60, 2089. Ϫ
P. E. McMahon, Trans. Faraday Soc.
[24c]
1965, 61, 197. Ϫ
B. Schneider, J. Stokr, D. Doskocilova,
S. Sykora, J. Jakes, M. Kolinsky, J. Polym. Sci., Ser. C 1969,
[24d]
1073Ϫ1084. Ϫ
T. Moritani, Y. Fujiwara, J. Chem. Phys.
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[26]
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[28]
P. E. McMahon, W. C. Tincher, J. Molec. Spectrosc. 1965, 15,
Acknowledgments
180Ϫ198.
T. Shimanouchi, S. Tsuchiya, S. Mizushima, J.Chem. Phys.
1959, 30, 1365Ϫ1366.
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We thank the Volkswagenstiftung and the Fonds der Chemischen
Industrie for support of this study. D. S. and R. G. are grateful to
the latter institution for granting them fellowships. We thank also
M. Dauber, T. Brandl, and A. Burton for help in the synthesis of
the deuterium-labeled compounds.
2926
Eur. J. Org. Chem. 1999, 2915Ϫ2927

Flexible Molecules with Defined Shape XI
FULL PAPER
N. L. Allinger, Y. H. Yuh, J. H. Lii, J. Am. Chem. Soc. 1989,
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From the dissertation of U. Rolle, Universität Marburg, 1993.
N. Gruenfeld, J. L. Stanton, A. M. Yuan, F. H. Ebetino, L. J.
A. G. Myers, B. H. Yang, H. Chen, L. McKinstry, D. J. Ko-
pecky, J. L. Gleason, J. Am. Chem. Soc. 1997, 119, 6496Ϫ6511.
Received March 5, 1999
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Eur. J. Org. Chem. 1999, 2915Ϫ2927
2927