(R)-(+)-[VCD(-)984]-4-Ethyl-4-methyloctane: A cryptochiral hydrocarbon with a quaternary chiral center. (1) synthesis of the enantiopure compound and unambiguous determination of absolute configuration

Article abstract of DOI:10.1002/ejoc.201000777

Enantiopure (R)-(+)-[VCD(-)984]-4-ethyl-4-methyloctane (1), a cryptochiral hydrocarbon with a quaternary chiral center, was synthesized by the use of 2-methoxy-2-(1-naphthyl)propionate (Mα NP) and (-)-camphorsultam dichlorophthalic (CSDP) acid methods. The diastereomeric Mα NP and CSDP acid esters prepared from racemic 2-butyl-2-methyl-1-tetralols, were effectively separated by HPLC on silica gel, and their absolute configurations were unambiguously determined by X-ray crystallographic analysis and ¹H NMR anisotropy methods. The recovered enantiopure 2-butyl-2-methyl-1-tetralol [(1S,2S)-(+)-cis-9] was then converted into the hydrocarbon (+)-1, the R absolute configuration of which was unambiguously determined for the first time. The structure of hydrocarbon 1 was also confirmed by NMR HSQC-TOCSY analysis. Copyright

Full text of DOI:10.1002/ejoc.201000777

FULL PAPER
DOI: 10.1002/ejoc.201000777
(R)-(+)-[VCD(–)984]-4-Ethyl-4-methyloctane: A Cryptochiral Hydrocarbon
with a Quaternary Chiral Center. (1) Synthesis of the Enantiopure Compound
and Unambiguous Determination of Absolute Configuration
Takuma Fujita,[a] Kazuhiro Obata,[a] Shunsuke Kuwahara,[a,b] Atsufumi Nakahashi,[c]
Kenji Monde,[c] John Decatur,[d] and Nobuyuki Harada*[a,d]
Keywords: Alkanes / Chirality / Configuration determination / Resolution / X-ray diffraction / NMR anisotropy
Enantiopure (R)-(+)-[VCD(–)984]-4-ethyl-4-methyloctane (1),
a cryptochiral hydrocarbon with a quaternary chiral center,
was synthesized by the use of 2-methoxy-2-(1-naphthyl)pro-
pionate (MαNP) and (–)-camphorsultam dichlorophthalic
(CSDP) acid methods. The diastereomeric MαNP and CSDP
acid esters prepared from racemic 2-butyl-2-methyl-1-tet-
ralols, were effectively separated by HPLC on silica gel, and
their absolute configurations were unambiguously deter-
mined by X-ray crystallographic analysis and 1H NMR an-
isotropy methods. The recovered enantiopure 2-butyl-2-
methyl-1-tetralol [(1S,2S)-(+)-cis-9] was then converted into
the hydrocarbon (+)-1, the R absolute configuration of which
was unambiguously determined for the first time. The struc-
ture of hydrocarbon 1 was also confirmed by NMR HSQC-
TOCSY analysis.
Introduction
The science of stereochemistry started when L. Pasteur
first succeeded in the so-called “optical resolution” of race-
mic tartaric acid in 1848, and then the theory of “tetra-
hedral carbon atom” was proposed independently by J. H.
van’t Hoff and J. A. Le Bel in 1874 to explain the enantio-
meric structures of optically active compounds. Com-
pounds having a tetrahedral carbon atom substituted with
four different groups represent the fundamental structure of
molecular chirality. 4-Ethyl-4-methyloctane (1) is one such
fundamental chiral molecule; it contains a simple chiral
saturated hydrocarbon with a quaternary chiral center, to
which four different, unbranched alkyl groups (methyl,
ethyl, propyl, and butyl groups), are bonded (Figure 1). Un-
like chiral compounds with functional groups, compound 1
is an alkane without any polarizable group, and all four
alkyl groups are similar to each other. Therefore, its optical
rotation would be extremely small, falling in the category
of so-called cryptochirality.[1]
Figure 1. Absolute configuration of 4-ethyl-4-methyloctane 1 deter-
mined in this study.
In 1980, H. Wynberg and a co-worker first reported the
synthesis of both enantiomers (–)-1 (95% ee) and (+)-1
(85% ee), which showed small specific rotations, [α]578
=
–0.198 and [α]578 = +0.185 (neat), respectively (Scheme 1);
in this approach, menthyl ester 2 was resolved by recrystalli-
zation, and carboxylic acid 3 was resolved with cinchon-
idine.[2] It was thus difficult to obtain the synthetic precur-
sors of hydrocarbon 1 in an enantiopure form by recrystalli-
zation. In addition, the absolute configuration of 1 re-
mained undetermined. In 1988, L. Lardicci and co-workers
reported the synthesis and absolute configurational assign-
ment of (+)-1,[3] where acetylene tert-alcohol 4 was resolved
[a] Institute of Multidisciplinary Research for Advanced Materials, as its phthalate half-ester/brucine salt, and then the reco-
Tohoku University,
2-1-1 Katahira, Aoba, Sendai 980-8577, Japan
vered chiral alcohol 4 was converted into hydrocarbon (+)-
1 through bromo-allene 6 (Scheme 1). However, although
the absolute configuration of acetylene tert-alcohol 4 was
determined by applying the CD exciton chirality method[4]
to its benzoate 5, the observed CD (λext = 230 nm, ∆ε =
+0.8)[3] is too small to make a clear assignment. Therefore,
it remains an intriguing challenge to synthesize enantiopure
hydrocarbon 1 with cryptochirality and to determine its ab-
E-mail: n2harada@tagen.tohoku.ac.jp
[b] Department of Chemistry, Toho University,
2-2-1 Miyama, Funabashi 274-8510, Japan
[c] Frontier Research Center for Post-Genome Science and
Technology, Faculty of Advanced Life Science, Hokkaido
University,
Kita 21 Nishi 11, Sapporo 001-0021, Japan
[d] Department of Chemistry, Columbia University,
3000 Broadway, New York, NY 10027, USA
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(R)-(+)-[VCD(–)984]-4-Ethyl-4-methyloctane
solute configuration in an unambiguous manner.[5] We re- ence to the CSDP acid moiety as an internal reference. The
port here, in Part 1 of a two-part paper, the synthesis of enantiopure alcohol with established absolute configuration
enantiopure (+)-1 and make the first unambiguous absolute could be subsequently recovered by hydrolysis.[8]
configurational assignment by 1H NMR anisotropy and by
X-ray crystallographic analysis.[6] In the following paper,
Part 2, the vibrational circular dichroism (VCD)[7] charac-
terization of hydrocarbon [VCD(–)984]-1 and the indepen-
dent absolute configurational assignment by ab inito calcu-
lation of the VCD spectra will be discussed.
Figure 2. Chiral acids used for the enantioresolution of racemic
alcohols and the determination of absolute configurations.
The CSDP acid method is thus useful for enantioresolu-
tion and absolute configurational assignment. However, it
is not always possible to obtain single crystals suitable for
X-ray crystallographic analysis. If X-ray analysis is not pos-
sible, the absolute configuration cannot be determined. For
such cases, we have recently developed the 2-methoxy-2-(1-
naphthyl)propionate (MαNP) ester method[8b–8f,9] using
chiral MαNP acid (Figure 2) as an alternative, which is very
powerful for enantioresolution of racemic alcohols, espe-
cially aliphatic alcohols, and simultaneous determination of
1
their absolute configurations by H NMR anisotropy. The
method has been successfully applied to various
alcohols.[8b–8f,9] In this approach, racemic alcohol is esteri-
fied with enantiopure (S)-(+)-MαNP acid, yielding dia-
stereomeric esters that can be effectively separated by
HPLC on silica gel. The application of the 1H NMR anisot-
ropy method to the separated, enantiopure, diastereomeric
MαNP esters leads to the absolute configurational assign-
ment of the alcohol moiety. Single crystals are thus unnec-
essary for this method and, therefore, it is applicable to
1
most secondary alcohols. Although the H NMR anisot-
ropy method is an empirical rule, we have never encoun-
Scheme 1. Syntheses of chiral hydrocarbon 1 previously reported.
Recently, we have developed the (–)-camphorsultam
tered any exception, which is a great advantage of the
MαNP ester method. The solvolysis of the separated MαNP
ester yields the enantiopure alcohol with an established ab-
solute configuration.[8b–8f,9]
Although the MαNP/1H NMR anisotropy method does
dichlorophthalic (CSDP) ester method[8] using CSDP acid not require crystallization, MαNP esters can sometimes be
(Figure 2), which is very useful for the enantioresolution of obtained as single crystals, which can be subjected to X-
racemic aromatic alcohols and determination of their abso- ray crystallographic analysis.[9f] In these cases, the absolute
lute configurations by X-ray crystallographic analysis. In configuration of the alcohol part can be unambiguously de-
this approach, the racemic alcohol is esterified with termined, because the absolute configuration of the MαNP
enantiopure (–)-CSDP acid, yielding diastereomeric esters, acid part is known. The absolute configuration of the
1
which are separated well by HPLC on silica gel. If the dia- MαNP ester can thus be doubly determined by both H
stereomeric CSDP esters are base-line-separated by HPLC, NMR anisotropy and X-ray crystallographic methods. We
the separated esters are guaranteed to be enantiopure. This have never experienced any exceptional case showing a dis-
is an advantage of the CSDP acid method by using HPLC, agreement between these NMR and X-ray methods.[9f]
compared to resolution by recrystallization. Some CSDP These CSDP acid and MαNP acid methods were applied to
esters are obtained as single crystals that are suitable for the synthesis of enantiopure hydrocarbon 1 to unambigu-
X-ray crystallographic analysis and, therefore, its absolute ously determine its absolute configuration as described be-
configuration can be unambiguously determined by refer- low.
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N. Harada et al.
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determined by the observation of an NOE (7.5%) corre-
lation between the methylene protons of 2-butyl group and
the 1-methine proton, as shown in Scheme 3.
Results and Discussion
Synthetic Strategy and Absolute Configurational
Assignment
We adopted the synthetic strategy and absolute configu-
rational assignment as shown in Scheme 2, in an approach
that is generally applicable to acyclic chiral compounds
with a quaternary chiral center.
Scheme 3. Preparation of racemic 2-butyl-2-methyl-1-tetralols: (a)
LDA, THF, HMPA, –78 °C, then MeI, –40 °C (88%). (b) tBuOK,
THF, reflux, then BuI (72%). (c) LiAlH4, THF (69% for cis-9, 31%
for trans-9).
The major alcohol (Ϯ)-cis-9 was esterified with (–)-
CSDP acid to give the diastereomeric esters, which sepa-
rated well by HPLC on silica gel (hexane/EtOAc, 6:1; sepa-
ration factor α = 1.17; resolution factor Rs = 1.51), afford-
ing the first-eluted CSDP ester (–)-cis-10a (yield 50%) and
the second-eluted CSDP ester (+)-cis-10b (47%)
(Scheme 4). It should be noted that the two diastereoiso-
meric CSDP esters 10a/10b were base-line-separated, as
shown in Figure 3 (a) and, hence, the separated esters were
enantiopure.
Scheme 2. General synthetic strategy for acyclic chiral compounds
with a quaternary chiral center and their absolute configurational
assignment.
As a starting material, a racemic cyclic secondary alcohol
was chosen in which the relative stereochemistry of groups
R1 and R2 could be determined by NOE experiments. The
racemic alcohol can be enantioresolved as the CSDP ester
and/or the MαNP ester as described above, and their abso-
1
lute configurations can be determined by H NMR anisot-
ropy and/or X-ray crystallographic analysis. The recovered
enantiopure alcohol can then be subjected to a ring-open-
ing reaction and then converted into the desired acyclic
compound with a quaternary chiral center. The reason we
selected the cyclic alcohol as a starting material is as fol-
lows. Even if single crystals of CSDP ester or MαNP ester
could not be obtained, the relative configuration could still
be determined by NOE experiments, and the absolute con-
figuration by 1H NMR anisotropy. In this strategy, the chi-
rality of the quaternary stereogenic center is always kept
unchanged and, therefore, the synthetic reactions lead to
unambiguous absolute configurational assignment of the
target compound.
Application of the CSDP Acid Method
Tetralone was converted into 2-methyltetralone (7) by a
modification of the reported procedure,[10] and then into 2-
butyl-2-methyl-1-tetralone (8), which was reduced with
LiAlH4 yielding cis-2-butyl-2-methyl-1-tetralol (9; 69%)
and trans-alcohol (9; 31%) (Scheme 3). The relative config-
uration of cis-9 was determined by observation of an NOE
(4.8%) correlation between the 2-methyl group and the 1-
Scheme 4. Preparation of CSDP esters of cis-alcohol (Ϯ)-9, HPLC
separation, and recovery of enantiopure alcohol (1R,2R)-(–)-cis-9:
(a) DCC, DMAP, CH2Cl2. (b) HPLC on silica gel (hexane/EtOAc,
6:1), yield (1S,2S)-(–)-cis-10a, 50%, and (1R,2R)-(+)-cis-10b, 47%.
methine proton. The configuration of trans-9 was similarly (c) KOH, MeOH (88%).
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(R)-(+)-[VCD(–)984]-4-Ethyl-4-methyloctane
Figure 3. HPLC separation of diastereomeric esters on silica gel
(22ϫ300 mm): theoretical plate number N = 9300–10800; detector:
UV, 254 nm; flow rate: 10 mL/min; α = separation factor; Rs
=
resolution factor. (a) CSDP esters (1S,2S)-(–)-cis-10a and (1R,2R)-
(+)-cis-10b: sample injected, 10 mg; hexane/EtOAc, 6:1. (b) MαNP
esters (S:1S,2S)-(–)-cis-12a and (S:1R,2R)-(–)-cis-12b: sample in-
jected 25 mg; hexane/EtOAc, 15:1.
Figure 4. X-ray crystal structure establishing the absolute configu-
ration: (a) CSDP ester (1R,2R)-(+)-cis-10b; (b) MαNP ester
(S:1R,2R)-(–)-cis-12b taken from S. Kuwahara et al.[9f]
When CSDP ester (+)-cis-10b was recrystallized from
EtOH/CH2Cl2, single crystals were obtained as expected,
and subjected to X-ray analysis [orthorhombic, P212121
(#19); R/Rw = 0.0598/0.0740; R/Rw for the mirror image =
0.0719/0.0899].
From the X-ray crystal structure of (+)-cis-10b shown in
Figure 4 (a), the relative configuration was clearly deter-
mined to be cis, confirming the NOE assignment. The abso-
lute configuration of (+)-cis-10b was also unambiguously
determined to be (1R,2R) by reference to the absolute con-
figuration of the CSDP acid moiety. In addition, the
(1R,2R) absolute configuration was confirmed by the
anomalous dispersion effect of the chlorine and sulfur
atoms, as indicated above. The CSDP ester (+)-cis-10b was
easily hydrolyzed to yield the enantiopure alcohol (1R,2R)-
(–)-cis-9.
Racemic trans-alcohol (Ϯ)-trans-9 was similarly esterified
with (–)-CSDP acid, giving diastereomeric esters that were
also separated by HPLC on silica gel (hexane/EtOAc, 6:1;
separation factor α = 1.12; resolution factor Rs = 1.10) af-
fording the first-eluted CSDP ester (–)-trans-11a (50%) and
the second-eluted CSDP ester (+)-trans-11b (50%)
(Scheme 5). Compared to the cis-CSDP esters 10a/10b, the
HPLC separation of 11a/11b was less effective, as indicated Scheme 5. Preparation of CSDP esters of trans-alcohol (Ϯ)-9,
HPLC separation, and recovery of enantiopure alcohol (1R,2S)-
by the separation factor α = 1.12; however, pure esters were
(–)-trans-9: (a) DCC, DMAP, CH2Cl2. (b) HPLC on silica gel, hex-
obtained by repeated HPLC separation. Although both
ane/EtOAc, 6:1, yield (1S,2R)-(–)-trans-11a, 50%, and (1R,2S)-(+)-
CSDP esters 11a and 11b were obtained as colorless solids,
trans-11b, 50%. (c) KOH, MeOH (96%).
no single crystals suitable for X-ray crystallographic analy-
sis could be obtained. Therefore, at this point, the absolute
configurations of the alcohol moieties in CSDP esters 11a
and 11b could not be determined (they were later unambig-
Application of the MαNP Acid Method
uously determined as shown in Scheme 5 by chemical corre-
Alcohol (Ϯ)-cis-9 was esterified with (S)-(+)-MαNP acid
lation as discussed below). From the second-eluted ester giving diastereomeric esters that separated well by HPLC
(+)-trans-11b, enantiopure alcohol (1R,2S)-(–)-trans-9 was on silica gel (hexane/EtOAc, 15:1; separation factor α =
recovered.
1.81; resolution factor Rs = 5.97), affording the first-eluted
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MαNP ester (S:1S,2S)-(–)-cis-12a (yield 49%) and the
second-eluted MαNP ester (S:1R,2R)-(–)-cis-12b (48%)
(Scheme 6). It should be emphasized that MαNP esters 12a/
12b are very well separated as shown in Figure 3 (b) (sepa-
ration factor α = 1.81). Such a large separation enables
larger amount of sample to be separated by HPLC, which
is a significant advantage of the MαNP ester method over
the CSDP ester method.
1
Figure 5. H NMR anisotropy values ∆δ [= δ(2nd fr.) – δ(1st fr.)]
in ppm (CDCl3) and the determination of absolute configuration:
(a) first-eluted MαNP ester (S:1S,2S)-(–)-cis-12a; (b) first-eluted
MαNP ester (S:1S,2R)-(–)-trans-13a.
0.0425/0.0423)]. Since the ester (–)-cis-12b has no heavy
separation, and recovery of enantiopure alcohol (1S,2S)-(+)-cis-9: atom, only the relative configuration was determined by X-
Scheme 6. Preparation of MαNP esters of cis-alcohol (Ϯ)-9, HPLC
(a) DCC, DMAP, CSA, CH2Cl2, reflux. (b) HPLC on silica gel,
ray crystallography; however, because the S absolute config-
hexane/EtOAc, 15:1, yield (S:1S,2S)-(–)-cis-12a, 49%, and
uration of the MαNP acid part was known, the (1R,2R)
(S:1R,2R)-(–)-cis-12b, 48%. (c) NaOMe, MeOH, reflux (84%). (d)
absolute configuration of the alcohol part could be unam-
PCC, Celite, CH2Cl2 (92%).
biguously determined.
Recovery of the enantiopure alcohol from the MαNP es-
To determine the absolute configurations of MαNP es- ter generally requires treatment with a stronger base (e.g.,
ters 12a and 12b by using the 1H NMR anisotropy method, NaOMe) than required to cleave the CSDP ester. Thus, a
1
the H NMR spectroscopic data of both esters were care- mixture of MαNP ester (S:1S,2S)-(–)-12a and NaOMe in
fully analyzed and assigned as listed in the Experimental MeOH was heated to reflux to yield the enantiopure
Section. The anisotropy factor ∆δ is defined as ∆δ = alcohol (1S,2S)-(+)-cis-9 in good yield. It should be noted
δ(R,X) – δ(S,X), where R and S are the absolute configura- that enantiopure (S)-(+)-MαNP acid could be recovered
tions of MαNP acids used, and X is the absolute configura- from the solvolysis/hydrolysis and subsequently reused.
tion of the alcohol to be determined. When the racemic
The 1H and 13C NMR spectroscopic data for the
alcohol is enantioresolved with (S)-(+)-MαNP acid, the an- enantiopure alcohol (1R,2R)-(–)-cis-9 obtained from the
isotropy factor ∆δ is defined as ∆δ = δ(R,X) – δ(S,X) = CSDP ester (+)-cis-10b (Scheme 4) were in complete agree-
δ(S,–X) – δ(S,X) = δ(2nd fr.) – δ(1st fr.), where X is the ment with those of alcohol (1S,2S)-(+)-cis-9 recovered from
absolute configuration of the alcohol part in the first-eluted the MαNP ester (–)-cis-12a (Scheme 6); however, they were
MαNP ester. The ∆δ values obtained are shown in Figure 5 opposite in the sign of specific rotation. The absolute con-
(a), in which the protons on the right side have positive ∆δ figurational assignments by the CSDP and MαNP methods
values, and the protons on the left side have negative values. are thus consistent with each other.
Based on the ∆δ results and on the relative cis configura-
Alcohol (Ϯ)-trans-9 was esterified with (S)-(+)-MαNP
tion, the absolute configuration of the first-eluted ester (–)- acid, giving diastereomeric esters, which were similarly well
cis-12a was determined to be (S:1S,2S), and that of the sec- separated by HPLC on silica gel (hexane/EtOAc, 15:1; sepa-
ond-eluted ester (–)-cis-12b was (S:1R,2R).
ration factor α = 1.59; resolution factor Rs = 4.23) affording
The (S:1R,2R) absolute configuration of the second- the first-eluted MαNP ester (S:1S,2R)-(–)-trans-13a (yield
eluted ester (–)-cis-12b was also established by X-ray crys- 47%) and the second-eluted MαNP ester (S:1R,2S)-(–)-
tallographic analysis [Figure 4 (b)]; single crystals were ob- trans-13b (48%) (Scheme 7). It should be noted that MαNP
tained by recrystallization from hexane/EtOAc, and sub- esters 13a/13b were also effectively separated with a large
jected to X-ray analysis [monoclinic, C2 (#5); R/Rw
=
separation factor (α = 1.59).
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(R)-(+)-[VCD(–)984]-4-Ethyl-4-methyloctane
Scheme 7. Preparation of MαNP esters of trans-alcohol (Ϯ)-9,
HPLC separation, and recovery of enantiopure alcohol (1S,2R)-
(+)-trans-9: (a) DCC, DMAP, CSA, CH2Cl2, reflux. (b) HPLC on
silica gel, hexane/EtOAc, 15:1, yield (S:1S,2R)-(–)-trans-13a, 47%,
and (S:1R,2S)-(–)-trans-13b, 48%. (c) NaOMe, MeOH, reflux
(81%). (d) PCC, Celite, CH2Cl2 (96%).
Figure 6. CD and UV spectra of aromatic ketones (S)-(+)-8 and
(R)-(–)-8 in EtOH.
The absolute configurations of MαNP esters 13a and 13b
were similarly determined by the 1H NMR anisotropy
method. As shown in Figure 5 (b), the ∆δ values of the pro-
tons on the right side are positive, whereas those of the
protons on the left side are negative. Therefore, the results
led to the assignment of (S:1S,2R) for the absolute configu-
Synthesis of Enantiopure (R)-(+)-[VCD(–)984]-4-Ethyl-4-
methyloctane
We first synthesized racemic hydrocarbon (Ϯ)-1 and
ration of the first-eluted ester (–)-trans-13a and (S:1R,2S) adopted the synthetic procedure and reaction conditions
configuration for the second-eluted ester (–)-trans-13b. shown in Scheme 8. Accordingly, enantiopure 4-ethyl-4-
From the first-eluted MαNP ester (–)-trans-13a, enantio- methyloctane (R)-(+)-1 was synthesized as follows. Enantio-
pure alcohol (1S,2R)-(+)-trans-9 was recovered in good pure alcohol (1S,2S)-(+)-cis-9 was reduced with NaBH4/
yield.
AlCl3 yielding 2-butyl-2-methyltetralin [(S)-(+)-14], the op-
The absolute configuration of alcohol (–)-trans-9 ob- tical rotation of which was very small {[α]2D9 = +1.5 (c =
tained from CSDP ester (+)-trans-11b (Scheme 5) was de- 1.06, CHCl3)}. To cleave the benzene ring, tetralin (S)-(+)-
termined to be (1R,2S) by comparison with the 1H and 13
C
14 was subjected to oxidation with HIO4/RuCl3, affording
NMR spectra, and the specific rotation data of alcohol 3-butyl-3-methyladipic acid, which was isolated as dimethyl
(1S,2R)-(+)-trans-9 recovered from the MαNP ester 3-butyl-3-methyladipate {(S)-(–)-15; [α]2D4 = –2.4 (c = 1.05,
(S:1S,2R)-(–)-trans-13a (Scheme 7). The absolute configu- CHCl3)}.
rations of the compounds in Scheme 5 were thus assigned
as shown by analyzing the 1H NMR anisotropy and chemi- +0.54 (c = 1.53, CHCl3), [α]2D6 = –0.33 (c = 2.31, EtOH)}.
cal correlation. It is interesting that the specific rotation of diol 16 changes
Diester (S)-(–)-15 was reduced to diol (S)-(+)-16 {[α]D25
=
To confirm the absolute configuration of trans-alcohol 9 its sign depending on the solvent, although the absolute
further, enantiopure alcohol (1S,2S)-(+)-cis-9 was oxidized values are very small. Diol (S)-(+)-16 was subjected to bro-
with pyridinium chlorochromate (PCC) to yield 2-butyl-2- mination with CBr4 and PPh3 followed by reduction of the
methyl-1-tetralone (S)-(+)-8 (Scheme 6). trans-Alcohol dibromide with NaBH4 in HMPA. This furnished the target
(1S,2R)-(+)-trans-9 was similarly converted into ketone (R)- hydrocarbon, 4-ethyl-4-methyloctane {(R)-(+)-1; [α]D25
=
23
(–)-8 (Scheme 7). The CD spectra obtained for both ketones +0.19 (neat, ρ = 0.7565) and [α]
= +0.70 (neat, ρ =
365
were mirror images of each other, as shown in Figure 6. The 0.7565), where the density
ρ was taken from the
absolute configuration of trans-alcohol 9 was thus estab- literature[2]}. The observed [α]D and [α]365 values agreed
lished by chemical correlation and by X-ray crystallo- well with the data reported by the groups of Wynberg[2]
graphic analysis.
and Lardicci.[3] We have thus succeeded in the synthesis of
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N. Harada et al.
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Scheme 8. Synthesis of enantiopure (R)-(+)-4-ethyl-4-methyloctane
[(R)-(+)-1]: (a) NaBH4, AlCl3, THF, reflux (89%). (b) RuCl3,
HIO4/CCl4, CH3CN, H2O. (c) MeI, K2CO3, DMF (52%). (d) Li-
AlH4, THF (95%). (e) CBr4, PPh3, CH2Cl2. (f) NaBH4, HMPA
(77%).
enantiopure 4-ethyl-4-methyloctane [(R)-(+)-1] and have,
for the first time, unambiguously assigned its absolute con-
figuration.
Direct Determination of the Structure of 4-Ethyl-4-
methyloctane
Figure 7. HSQC–TOCSY spectrum of hydrocarbon (Ϯ)-1:
500 MHz, CDCl3, mixing time = 25 ms. There is no cross peak at
δC = 34.8 ppm (where the quaternary carbonatom, C-4, would be
expected to resonate).
As described above, our synthesis of enantiopure 4-ethyl-
4-methyloctane [(R)-(+)-1] is straightforward, and its abso-
lute configurational assignment is very clear. However, we
have found a strange fact that the 13C NMR spectroscopic
data of (Ϯ)-1 and (+)-1 synthesized here disagreed with
those reported by L. Lardicci and co-workers.[3] Unfortu-
connectivity of C-1, C-2, and C-3 was similarly determined,
together with their chemical-shift data. From the HSQC
data, the methylene protons, 2-H2 and 3-H2, could also be
assigned.
nately, H. Wynberg and a co-workers did not report the 13
C
NMR spectroscopic data of (–)-1.[2]
The disagreement in the 13C NMR spectroscopic data
prompted us to determine the structure of 1 again by
various NMR spectroscopic methods, including 1H, 13C,
1H–1H COSY, HMBC, and HSQC, whereby the structure
was confirmed to be as shown. In addition, we conducted
an HSQC–TOCSY analysis, which proved to be a much
simpler and more powerful technique for the unambiguous
and full assignment of the carbon and proton signals, as
1
The 13C and H NMR signals of the ethyl group were
assigned in a similar way. The triplet signal at δ =
0.755 ppm showed two cross peaks in the HSQC–TOCSY
spectrum, indicating the presence of the ethyl group; the C-
10, C-9, 10-H3, and 9-H2 signals were thus determined. The
singlet signal at δ = 0.762 ppm, showing one cross peak in
the HSQC–TOCSY spectrum could clearly be assigned as
the methyl group at the 4-position. The 13C NMR signal at
δ = 34.8 ppm showed no cross peak in the HSQC–TOCSY
spectrum, and was hence assigned to the quaternary carbon
atom, C-4. In consequence, all the 1H and 13C NMR signals
were fully assigned as shown in Figure 7 and detailed in the
Experimental Section, establishing the structure of 4-ethyl-
4-methyloctane (1).[11] It should be emphasized that
HSQC–TOCSY analysis is clearly a very powerful tech-
nique for solving the structure of compounds with complex
NMR spectra.
1
shown in Figure 7. For example, the H triplet signal at δ =
0.89 ppm, corresponding to one of the terminal methyl
groups, showed four cross peaks in the HSQC–TOCSY
spectrum, which were measured using mixing times of 12,
25, and 80 ms. The results indicate that this terminal methyl
group is part of the butyl group; the C-8 and 8-H3 signals
could be thus assigned. From the time dependence of the
cross-peak intensity, the connectivity of C-8, C-7, C-6, and
C-5 could be clearly determined, together with their chemi-
cal shift data. From the cross peaks in the HSQC, the meth-
ylene protons, 7-H2, 6-H2, and 5-H2, could also be assigned.
On the other hand, the triplet signal at δ = 0.87 ppm
showed three cross peaks in the HSQC–TOCSY spectrum,
indicating that this methyl group is part of the propyl
Conclusions
We have succeeded in the synthesis of enantiopure (R)-
group; the C-1 and 1-H3 signals could thus be assigned. (+)-4-ethyl-4-methyloctane (1), which is the simplest chiral
From the time dependence of the cross-peak intensity, the saturated hydrocarbon with a quaternary chiral center, and
6378
www.eurjoc.org
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 6372–6384

(R)-(+)-[VCD(–)984]-4-Ethyl-4-methyloctane
silica gel (hexane/EtOAc, 20:1) and HPLC on silica gel (hexane/
EtOAc, 50:1) yielding (Ϯ)-7 (0.993 g, 88%); colorless oil. IR (neat):
conducted the first unambiguous determination of its abso-
lute configuration by X-ray crystallographic analysis, 1H
NMR anisotropy, and chemical correlation. The methodol-
ogies described here would be generally applicable to a
range of chiral compounds containing a quaternary chiral
center.
ν
max = 3066, 2963, 2932, 2861, 1685, 1602, 1455, 1376, 1359, 1323,
˜
1268, 1228, 968, 907, 803, 776, 740 cm–1. 1H NMR (400 MHz,
CDCl3): δ = 1.28 (d, J = 6.8 Hz, 3 H, 2-CH3), 1.89 (dddd, J = 13.3,
12.0, 11.1, 4.8 Hz, 1 H, 3-Hax), 2.20 (dddd, J = 13.3, 4.5, 4.5,
4.4 Hz, 1 H, 3-Heq), 2.60 (ddq, J = 12.0, 4.4, 6.8 Hz, 1 H, 2-H),
2.97 (br. ddd, J = 16.8, 4.8, 4.5 Hz, 1 H, 4-Heq), 3.05 (br. ddd, J =
16.8, 11.1, 4.5 Hz, 1 H, 4-Hax), 7.23 (br. d, J = 7.5 Hz, 1 H), 7.30
(br. dd, J = 7.8, 7.5 Hz, 1 H), 7.46 (ddd, J = 7.5, 7.5, 1.3 Hz, 1 H),
As will be discussed in Part 2 of this two-part paper,[12]
VCD (i.e., the CD spectrum in the IR region) of hydro-
carbon (R)-(+)-1 showed a negative Cotton effect at
984 cm–1. Therefore, the absolute configuration of hydro- 8.04 (dd, J = 7.8, 1.3 Hz, 1 H) ppm. 13C NMR (100 MHz, CDCl3):
δ = 15.34, 28.82, 31.35, 42.62, 126.53, 127.38, 128.69, 132.37,
133.06, 144.18, 200.80 ppm. C11H12O (160.21): calcd. C 82.46, H
7.55; found C 81.97, H 7.60.
carbon 1 can be fully designated as (R)-(+)-[VCD(–)984],
which indicates that the enantiomer showing a negative
VCD band at 984 cm–1 has an R absolute configuration.
Preparation of (؎)-2-Butyl-2-methyl-1-tetralone (8): A mixture of
2-methyl-1-tetralone (Ϯ)-7 (2.81 g, 17.5 mmol) and tBuOK (3.21 g,
26.3 mmol) in THF (50 mL) was heated to reflux for 2 h. After
cooling to r.t., 1-iodobutane (3.99 mL, 26.3 mmol) was added, and
the mixture was stirred for 1 h. Aqueous saturated NH4Cl was
added and the mixture was extracted with EtOAc. The organic
layer was washed with aqueous NaHCO3, water, and brine, dried
with anhydrous MgSO4, and then concentrated to dryness. The
crude product was purified by short column chromatography on
silica gel (hexane/EtOAc, 20:1) and by HPLC on silica gel (hexane/
EtOAc, 50:1) yielding (Ϯ)-8 (2.79 g, 74%); colorless oil. IR (neat):
Experimental Section
General Methods: IR spectra were obtained either neat, as a film
on KBr, or as KBr disks, with a Jasco FT/IR-410 spectrophotome-
ter. 1H NMR spectra were recorded with a Jeol JNM-LA400
(400 MHz), a Bruker DMX 500 (500 MHz), and/or a Jeol JNM-
LA600 (600 MHz) spectrometer. 13C NMR spectra were obtained
with
a Jeol JNM-LA400 (100 MHz), a Bruker DMX 500
(125 MHz), and/or a Jeol JNM-LA600 (150 MHz) spectrometer.
All NMR spectroscopic data of CDCl3 and CD2Cl2 solutions are
reported in ppm (δ) downfield from TMS. HR mass spectra were
measured with a Jeol JMS-700TZ instrument with inlet GC (r.t.,
3.53 min) operated in the EI ion mode. Optical rotations [α]D were
measured with a Jasco DIP-1000 spectropolarimeter. Silica gel 60
F254 precoated plates on glass from Merck Ltd. were used for thin
layer chromatography (TLC). HPLC separation and purification
were performed using a prepacked glass column (22ϫ300 mm, or
25ϫ400 mm) of silica gel (particle size 5–10 µm) from Kusano Co.
Ltd., equipped with a UV/RI detector (Shimamura YRU-880). The
purities of the title compounds were shown to be Ն99% by 1H
NMR, TLC, HPLC, and/or elemental analysis.
ν
max = 2961, 2932, 2860, 1683, 1601, 1455, 1376, 1302, 1221, 1155,
˜
1100, 965, 900, 741 cm–1. 1H NMR (400 MHz, CDCl3): δ = 0.88
(br. t, J = 7.0 Hz, 3 H, terminal CH3), 1.18 (s, 3 H, 2-CH3), 1.21–
1.34 (m, 4 H), 1.50 (m, 1 H), 1.64 (m, 1 H), 1.92 (ddd, J = 13.7,
8.4, 5.2 Hz, 1 H, 3-Hax), 2.08 (ddd, J = 13.7, 6.8, 5.1 Hz, 1 H, 3-
Heq), 2.93 (br. ddd, J = 17.3, 6.8, 5.2 Hz, 1 H, 4-Heq), 3.00 (br.
ddd, J = 17.3, 8.4, 5.1 Hz, 1 H, 4-Hax), 7.21 (br. d, J = 7.5 Hz, 1
H), 7.30 (br. dd, J = 7.9, 7.4 Hz, 1 H), 7.45 (ddd, J = 7.5, 7.4,
1.3 Hz, 1 H), 8.04 (dd, J = 7.9, 1.3 Hz, 1 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 14.02, 22.16, 23.33, 25.38, 26.14, 33.65,
36.09, 44.63, 126.54, 127.95, 128.60, 131.72, 132.88, 143.29,
202.78 ppm. C15H20O (216.32): calcd. C 83.28, H 9.32; found C
83.07, H 9.13.
X-ray Crystallography: The diffraction measurements were carried
out with a Mac Science MXC18 automated four-circle dif-
fractometer: radiation: Cu-Kα (1.54178 Å); monochromator: graph-
ite crystal. The structure was solved by direct methods and success-
ive Fourier syntheses. Some hydrogen atoms were placed in calcu-
lated positions. Full-matrix least-squares refinement of positional
and thermal parameters, including anomalous scattering factors of
chlorine, sulfur, oxygen, nitrogen, and carbon atoms, led to the
final convergence with R value. The absolute configuration was de-
termined by using the CSDP acid moiety as the internal reference
for the absolute configuration. The result was also supported by
the anomalous dispersion effect of chlorine and sulfur atoms.
Preparation of (؎)-2-Butyl-2-methyl-1-tetralols (cis-9 and trans-9):
To a solution of ketone (Ϯ)-8 (1.38 g, 6.40 mmol) in THF (20 mL)
cooled to 0 °C, was added portion-wise, LiAlH4 (0.239 g,
6.28 mmol), and the mixture was stirred at r.t. overnight. The ex-
cess hydride was quenched by the dropwise addition of aqueous
diethyl ether, and the organic layer was separated from the precipi-
tate, which was washed with diethyl ether. The combined organic
layers were dried with anhydrous MgSO4, and the solvents were
evaporated to dryness. The epimeric alcohols formed were purified
by short column chromatography on silica gel (hexane/EtOAc,
10:1) and then separated by HPLC on silica gel (hexane/EtOAc,
15:1) yielding (Ϯ)-cis-9 (0.962 g, 69%) and (Ϯ)-trans-9 (0.431 g,
31%).
Preparation of (؎)-2-Methyl-1-tetralone (7): The reported pro-
cedure[10] was modified; to
a solution of diisopropylamine
(1.34 mL, 10.3 mmol) in THF (20 mL) cooled to 0 °C, was added
dropwise, n-butyllithium (1.56  in hexane, 5.7 mL, 8.9 mmol). Af-
ter cooling to –78 °C, hexamethylphosphoramide (HMPA, 5 mL)
was added, and the mixture was stirred for 2 h. A solution of 1-
tetralone (1.04 g, 7.08 mmol) in THF (5 mL) was added dropwise,
and the mixture was stirred at –78 °C for 2 h. After addition of
iodomethane (0.64 mL, 10 mmol), the mixture was stirred at –40 °C
overnight. The reaction was quenched with aqueous NH4Cl, and
the mixture was extracted with EtOAc. The organic layer was
washed with aqueous NaHCO3, water, and brine, dried with anhy-
drous MgSO4, and the solvents were evaporated to dryness. The
crude product was purified by a short column chromatography on
(؎)-cis-Alcohol 9: Colorless oil. IR (neat): νmax = 3396, 2955, 2931,
˜
2860, 1456, 1378, 1020, 946, 771, 739 cm–1. 1H NMR (400 MHz,
CDCl3): δ = 0.89 (s, 3 H, 2-CH3), 0.93 (br. t, J = 7.1 Hz, 3 H,
terminal CH3), 1.25–1.52 (m, 8 H), 1.85 (ddd, J = 13.7, 8.1, 7.3 Hz,
1 H, 3-Hax), 2.75 (br. ddd, J = 18.0, 8.1, 6.5 Hz, 1 H, 4-Hax), 2.80
(br. ddd, J = 18.0, 7.3, 5.8 Hz, 1 H, 4-Heq), 4.29 (br. d, J = 5.8 Hz,
1 H, 1-H), 7.11 (m, 1 H), 7.17–7.22 (m, 2 H), 7.39 (m, 1 H) ppm.
1H NMR NOE (400 MHz, CDCl3): irradiation of H with signal at
δ = 4.29 ppm =Ͼ +4.8% NOE of Me signal at δ = 0.89 ppm. 13C
NMR (100 MHz, CDCl3): δ = 14.23, 21.28, 23.67, 25.53, 25.72,
29.34, 35.76, 36.02, 75.93, 126.12, 127.43, 128.80, 129.37, 136.29,
Eur. J. Org. Chem. 2010, 6372–6384
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
6379

N. Harada et al.
FULL PAPER
138.26 ppm. C15H22O (218.33): calcd. C 82.52, H 10.16; found C
82.33, H 10.04.
7.8, 7.5 Hz, 1 H), 7.13 (br. d, J = 7.8 Hz, 1 H), 7.21 (br. ddd, J =
7.5, 7.4, 1.3 Hz, 1 H), 7.31 (br. d, J = 7.4 Hz, 1 H), 7.49 (s, 1 H),
8.07 (s, 1 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 14.13, 20.04,
20.97, 21.19, 23.49, 25.44, 25.64, 26.47, 29.66, 32.93, 36.01, 36.21,
37.65, 44.79, 47.72, 48.45, 52.91, 65.54, 78.60, 126.01, 128.00,
128.39, 128.64, 130.29, 131.04, 131.61, 133.81, 134.59, 135.07,
136.74, 136.77, 162.91, 165.17 ppm. UV (EtOH): λmax (ε) = 295.2
(800), 244.2 (12700), 215.2 (43100 Lmol–1 cm–1) nm. CD (EtOH):
(؎)-trans-Alcohol 9: Colorless solid. IR (film): ν
= 3383, 2956,
˜
max
1
2929, 2859, 1491, 1455, 1378, 1040, 1009, 772, 737 cm–1. H NMR
(400 MHz, CDCl3): δ = 0.89 (br. t, J = 7.1 Hz, 3 H, terminal CH3),
0.97 (s, 3 H, 2-CH3), 1.22–1.35 (m, 6 H), 1.56 (br. ddd, J = 13.5,
6.8, 6.5 Hz, 1 H, 3-H), 1.64 (m, 1 H), 1.78 (ddd, J = 13.5, 7.5,
6.3 Hz, 1 H, 3-H), 2.71 (br. ddd, J = 17.8, 7.5, 6.8 Hz, 1 H, 4-H),
2.79 (br. ddd, J = 17.8, 6.5, 6.3 Hz, 1 H, 4-H), 4.30 (br. d, J =
5.6 Hz, 1 H, 1-H), 7.10 (m, 1 H), 7.16–7.22 (m, 1 H), 7.44 (m, 1
H) ppm. 1H NMR NOE (400 MHz, CDCl3): irradiation of H with
λext (∆ε)
=
241.8 (–2.8), 220.2 (–16.2 Lmol–1 cm–1) nm.
C33H39Cl2NO5S (632.64): calcd. C 62.65, H 6.21, Cl 11.21, N 2.21,
S 5.07; found C 62.51, H 6.15, Cl 11.79, N 2.21, S 5.02.
signal at δ = 4.30 ppm =Ͼ +7.5% NOE of 2 H signal at δ = 1.22– X-ray Data of CSDP Ester (1R,2R)-(+)-cis-10b: Crystallized from
1.35 ppm. 13C NMR (100 MHz, CDCl3): δ = 14.15, 19.81, 23.56,
EtOH/CH2Cl2; crystal dimension: 0.38ϫ 0.37ϫ 0.32 mm; crystal
25.74, 25.80, 28.96, 36.33, 37.46, 75.64, 126.12, 127.26, 128.68, system: orthorhombic; space group: P212121 (#19);
a
=
128.99, 136.06, 138.58 ppm. C15H22O (218.33): calcd. C 82.52, H
10.16; found C 82.43, H 10.00.
11.306(2) Å, b = 25.590(5) Å, c = 11.250(3) Å; V = 3255(1) Å3; Z
= 4; Dcalcd. = 1.291 g/cm3; Dobsd = 1.285 g/cm3; no. of independent
reflections: Fo Ͼ 3.0σ(Fo), 3135; no. of variables: 443; R/Rw
=
Preparation and Separation of CSDP Esters (1S,2S)-(–)-cis-10a and
(1R,2R)-(+)-cis-10b: To a mixture of racemic alcohol (Ϯ)-cis-9
(0.052 g, 0.24 mmol), (–)-CSDP acid (0.206 g, 0.477 mmol), 4-(di-
methylamino)pyridine (DMAP; 0.018 g, 0.15 mmol), and 1,3-dicy-
clohexylcarbodiimide (DCC; 0.120 g, 0.582 mmol) cooled to 0 °C,
was added CH2Cl2 (1 mL), and the mixture was stirred at r.t. over-
night. The excess DCC was hydrolyzed with a small amount of
water and, after addition of anhydrous MgSO4, the mixture was
filtered through Celite, and the filtrate was concentrated to dryness.
The diastereomeric CSDP esters were purified by short column
chromatography on silica gel (hexane/EtOAc, ca. 1:1) and then sep-
arated by HPLC on silica gel (hexane/EtOAc, 6:1; α = 1.17, Rs =
1.51) yielding (1S,2S)-(–)-cis-10a (0.078 g, 50%) and (1R,2R)-(+)-
cis-10b (0.074 g, 47%).
0.0598/0.0740; R/Rw for the mirror image = 0.0719/0.0899. CCDC-
753557 contains the supplementary crystallographic data for this
paper. These data can be obtained free of charge from The Cam-
bridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/
data_request/cif.
Preparation and Separation of CSDP Esters (1S,2R)-(–)-trans-11a
and (1R,2S)-(+)-trans-11b: The CSDP esters were prepared and
separated as described above for the cis esters: HPLC on silica gel
(hexane/EtOAc, 6:1; α = 1.12, Rs = 1.10) yielded (1S,2R)-(–)-trans-
11a (50%) and (1R,2S)-(+)-trans-11b (50%).
CSDP Ester (1S,2R)-(–)-trans-11a: Colorless solid. [α]2D5 = –163 (c
= 1.06, CHCl ). IR (film): ν
= 2959, 1720, 1686, 1588, 1553,
˜
3
max
1457, 1376, 1337, 1298, 1142, 1116, 1094, 1064, 974, 909, 768, 733,
649, 540 cm–1. 1H NMR (400 MHz, CDCl3): δ = 0.87 (br. t, J =
6.8 Hz, 3 H, terminal CH3), 0.98 (s, 3 H), 0.99 (s, 3 H), 1.24–1.46
(m, 11 H), 1.62 (m, 1 H), 1.88–1.94 (m, 3 H), 1.98 (br. ddd, J =
13.9, 10.4, 6.4 Hz, 1 H, 3-Hax), 2.14 (m, 1 H), 2.52 (m, 1 H), 2.80
(br. ddd, J = 17.7, 10.4, 6.7 Hz, 1 H, 4-Hax), 2.88 (br. ddd, J =
17.7, 6.4, 4.7 Hz, 1 H, 4-Heq), 3.37 (d, J = 13.8 Hz, 1 H), 3.43 (d,
CSDP Ester (1S,2S)-(–)-cis-10a: Colorless plates; m.p. 142–144 °C.
[α]2D5 = –122 (c = 1.07, CHCl ). IR (film): νmax = 2959, 1722, 1687,
˜
3
1587, 1553, 1457, 1376, 1337, 1298, 1264, 1245, 1168, 1142, 1116,
1094, 1064, 972, 910, 758, 733, 649, 540 cm–1. 1H NMR (400 MHz,
CDCl3): δ = 0.89 (br. t, J = 6.8 Hz, 3 H, terminal CH3), 0.93 (s, 3
H), 0.98 (s, 3 H), 1.24–1.47 (m, 11 H), 1.65 (br. ddd, J = 13.7, 7.1,
6.0 Hz, 1 H, 3-H), 1.92–2.01 (m, 3 H), 1.98 (br. ddd, J = 13.7, 7.7, J = 13.8 Hz, 1 H), 3.92 (m, 1 H), 5.90 (s, 1 H, 1-H), 7.13 (br. dd,
6.2 Hz, 1 H, 3-H), 2.14 (m, 1 H), 2.52 (m, 1 H), 2.82 (br. ddd, J =
17.7, 7.7, 7.1 Hz, 1 H, 4-H), 2.91 (br. ddd, J = 17.7, 6.2, 6.0 Hz, 1
H, 4-H), 3.37 (d, J = 13.9 Hz, 1 H), 3.42 (d, J = 13.9 Hz, 1 H),
J = 7.6, 7.0 Hz, 1 H), 7.15 (br. d, J = 7.0 Hz, 1 H), 7.23 (br. ddd,
J = 7.7, 7.6, 1.4 Hz, 1 H), 7.28 (br. d, J = 7.7 Hz, 1 H), 7.52 (s, 1
H), 7.92 (s, 1 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 14.10,
3.96 (m, 1 H), 5.90 (s, 1 H, 1-H), 7.10–7.15 (m, 2 H), 7.19–7.27 (m, 20.04, 20.82, 21.58, 23.38, 25.59, 25.79, 26.47, 29.96, 33.02, 35.86,
2 H), 7.53 (s, 1 H), 7.96 (s, 1 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 14.16, 20.06, 20.83, 21.35, 23.48, 25.40, 26.50, 29.55,
35.89, 37.47, 44.68, 47.74, 48.39, 53.05, 65.51, 78.09, 126.11,
128.12, 128.77, 128.97, 130.67, 131.05, 131.27, 133.65, 134.65,
33.02, 35.58, 35.88, 37.50, 44.68, 47.75, 48.43, 53.06, 65.54, 134.98, 136.52, 136.74, 163.10, 165.25 ppm. UV (EtOH): λmax (ε)
78.84, 126.08, 127.96, 128.72, 128.91, 129.85, 131.09, 131.28,
133.82, 134.70, 135.04, 136.58, 136.74, 163.06, 165.24 ppm.
= 297.0 (600), 244.0 (13700), 215.0 (46000 Lmol–1 cm–1) nm. CD
(EtOH): λext (∆ε) = 249.2 (–18.3), 218.8 (+38.1 Lmol–1 cm–1) nm.
C33H39Cl2NO5S (632.64): calcd. C 62.65, H 6.21, Cl 11.21, N 2.21,
S 5.07; found C 62.03, H 6.18, Cl 11.17, N 2.14, S 5.12.
UV (EtOH): λmax (ε)
= 295.4 (700), 244.2 (13000), 215.0
(44200 Lmol–1 cm–1) nm. CD (EtOH): λext (∆ε) = 250.2 (–16.6),
219.4 (+41.9 Lmol–1 cm–1) nm. C33H39Cl2NO5S (632.64): calcd. C
62.65, H 6.21, Cl 11.21, N 2.21, S 5.07; found C 61.48, H 6.30, Cl
9.92, N 2.11, S 4.44.
CSDP Ester (1R,2S)-(+)-trans-11b: Colorless solid. [α]2D5 = +33.2
(c = 1.11, CHCl ). IR (film): ν
= 2959, 1722, 1687, 1588, 1553,
˜
3
max
1457, 1377, 1337, 1299, 1244, 1168, 1142, 1116, 1094, 1064, 974,
909, 768, 734, 651, 539 cm–1. 1H NMR (400 MHz, CDCl3): δ =
0.85 (t, J = 7.1 Hz, 3 H, terminal CH3), 0.96 (s, 3 H), 0.99 (s, 3 H),
1.17–1.38 (m, 11 H), 1.67 (br. ddd, J = 13.7, 6.1, 5.7 Hz, 1 H, 3-
CSDP Ester (1R,2R)-(+)-cis-10b: Colorless prisms; m.p. 190–
191 °C (EtOH/CH2Cl2). [α]2D5 = +21.0 (c = 1.02, CHCl3). IR (film):
ν
max = 2958, 1722, 1686, 1553, 1458, 1337, 1299, 1244, 1168, 1142,
˜
1116, 1093, 1064, 972, 909, 733, 652, 538 cm–1. 1H NMR Heq), 1.88–1.92 (m, 3 H), 1.96 (br. ddd, J = 13.7, 9.2, 6.1 Hz, 1 H,
(400 MHz, CDCl3): δ = 0.86 (t, J = 7.0 Hz, 3 H, terminal CH3),
0.93 (s, 3 H), 0.96 (s, 3 H), 1.23–1.45 (m, 11 H), 1.67 (br. ddd, J =
3-Hax), 2.14 (br. dd, J = 13.7, 8.1 Hz, 1 H), 2.54 (m, 1 H), 2.81 (br.
ddd, J = 17.7, 9.2, 6.1 Hz, 1 H, 4-Hax), 2.88 (br. ddd, J = 17.7, 6.1,
13.7, 6.4, 6.0 Hz, 1 H, 3-Heq), 1.89–1.95 (m, 3 H), 1.99 (br. ddd, J 5.7 Hz, 1 H, 4-Heq), 3.26 (d, J = 13.6 Hz, 1 H), 3.40 (d, J = 13.6 Hz,
= 13.7, 8.1, 6.1 Hz, 1 H, 3-Hax), 2.15 (m, 1 H), 2.53 (m, 1 H), 2.83 1 H), 3.87 (m, 1 H), 5.97 (s, 1 H, 1-H), 7.13 (br. dd, J = 7.3, 7.2 Hz,
(br. ddd, J = 17.6, 8.1, 6.4 Hz, 1 H, 4-Hax), 2.90 (br. ddd, J = 17.6,
6.1, 6.0 Hz, 1 H, 4-Heq), 3.27 (d, J = 13.7 Hz, 1 H), 3.40 (d, J =
13.7 Hz, 1 H), 3.91 (m, 1 H), 5.96 (s, 1 H, 1-H), 7.12 (br. dd, J =
1 H), 7.14 (br. d, J = 7.2 Hz, 1 H), 7.22 (br. ddd, J = 7.4, 7.3,
1.6 Hz, 1 H), 7.28 (br. d, J = 7.4 Hz, 1 H), 7.47 (s, 1 H), 8.08 (s, 1
H) ppm. 13C NMR (100 MHz, CDCl3): δ = 14.08, 20.00, 20.93,
6380
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© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 6372–6384

(R)-(+)-[VCD(–)984]-4-Ethyl-4-methyloctane
21.32, 23.35, 25.58, 25.73, 26.41, 29.09, 32.88, 36.17, 36.28, 37.60,
44.76, 47.67, 48.39, 52.86, 65.48, 78.04, 125.98, 128.01, 128.34,
128.62, 130.60, 130.97, 131.63, 133.72, 134.56, 135.01, 136.71,
136.73, 162.92, 165.15 ppm. UV (EtOH): λmax (ε) = 297.0 (600),
244.2 (13700), 215.0 (46000 Lmol–1 cm–1) nm. CD (EtOH): λext (∆ε)
81.80, 124.42, 125.22, 125.24, 125.38, 125.41, 126.23, 127.47,
128.16, 128.29, 129.12, 129.74, 131.17, 133.32, 133.85, 135.02,
136.22, 173.32 ppm. UV (EtOH): λmax (ε) = 294.0 (4600), 282.2
(6700), 272.6 (5800), 224.8 (59500), 222.8 (56300 Lmol–1 cm–1) nm.
CD (EtOH): λext (∆ε)
=
282.0 (+0.8), 224.8 (–43.3 L
=
262.0 (–1.8), 240.0 (–2.8), 220.4 (–15.7 Lmol–1 cm–1) nm. mol–1 cm–1) nm. C29H34O3 (430.58): calcd. C 80.89, H 7.96; found
C33H39Cl2NO5S (632.64): calcd. C 62.65, H 6.21, Cl 11.21, N 2.21, C 80.81, H 8.13.
S 5.07; found C 62.13, H 6.19, Cl 11.46, N 2.16, S 5.26.
MαNP Ester (S;1R,2R)-(–)-cis-12b: Colorless prisms (hexane/
EtOAc). [α]2D5 = –7.7 (c = 1.11, CHCl ). IR (KBr): ν
= 2933,
Recovery of Enantiopure 2-Butyl-2-methyl-1-tetralol (1R,2R)-(–)-cis-
9 from CSDP Ester (1R,2R)-(+)-cis-10b: A mixture of (1R,2R)-(+)-
cis-10b (0.730 g, 1.15 mmol) in saturated KOH/MeOH solution
(16 mL) was stirred at r.t. overnight. After addition of water, the
mixture was extracted with diethyl ether. The organic layer was
dried with anhydrous MgSO4, and the solvents were evaporated to
dryness. The crude product was purified by short column
chromatography on silica gel (hexane/EtOAc, 10:1) yielding alcohol
(1R,2R)-(–)-cis-9 (0.221 g, 88%) as a colorless oil. [α]2D9 = –11.6 (c
˜
3
max
1744, 1457, 1367, 1245, 1134, 971, 920, 805, 781 cm–1. 1H NMR
(600 MHz, CDCl3): δ = 0.28 (ddd, J = 13.1, 12.7, 4.7 Hz, 1 H, 9-
H), 0.36 (ddd, J = 13.1, 12.7, 4.0 Hz, 1 H, 9-H), 0.42 (m, 1 H, 11-
H), 0.50 (s, 3 H, 13-H3), 0.59 (m, 4 H, 11-H, 12-H3), 0.68 (m, 1 H,
10-H), 0.79 (ddddd, J = 16.8, 12.7, 4.7, 4.7, 4.7 Hz, 1 H, 10-H),
1.23 (dddd, J = 13.4, 6.0, 5.0, 0.9 Hz, 1 H, 3-Heq), 1.38 (ddd, J =
13.4, 9.2, 6.9 Hz, 1 H, 3-Hax), 1.80 (s, 3 H, CH3), 2.63–2.67 (br.
ddd, J = 17.5, 9.2, 6.0 Hz, 2 H, 4-H2), 3.04 (s, 3 H, OCH3), 5.61
(br. s, 1 H, 1-H), 7.06 (br. d, J = 7.6 Hz, 1 H, 5-H), 7.12 (br. ddd,
J = 7.6, 7.5, 1.1 Hz, 1 H, 7-H), 7.20 (br. ddd, J = 7.6, 7.5, 1.3 Hz,
1
= 1.31, CHCl3). The IR, H NMR, and 13C NMR were identical
with those of racemate (Ϯ)-cis-9. UV (EtOH): λmax (ε) = 272.8
(300), 265.4 (400), 212.4 (8900 Lmol–1 cm–1) nm. CD (EtOH): λext 1 H, 6-H), 7.34 (br. dd, J = 7.6, 1.3 Hz, 1 H, 8-H), 7.41 (dd, J =
(∆ε) = 272.4 (+0.10), 264.8 (+0.08 Lmol–1 cm–1) nm. C15H22O
(218.33): calcd. C 82.52, H 10.16; found C 82.23, H 10.21.
8.1, 7.1 Hz, 1 H), 7.44 (m, 1 H), 7.48 (dd, J = 7.1, 1.2 Hz, 1 H),
7.56 (m, 1 H), 7.81 (br. d, J = 8.1 Hz, 1 H), 7.83 (m, 1 H), 8.56
(m, 1 H) ppm. 13C NMR (150 MHz, CDCl3): δ = 14.08, 20.19,
21.35, 22.88, 24.93, 25.45, 29.27, 35.15, 36.38, 50.61, 77.13, 81.45,
124.52, 125.72, 125.75, 125.84, 125.98, 126.55, 127.87, 128.45,
128.62, 129.40, 130.14, 131.61, 133.97, 134.24, 134.77, 136.63,
173.20 ppm. UV (EtOH): λmax (ε) = 293.6 (5100), 282.2 (7300),
272.8 (6400), 224.8 (70300), 222.0 (65400 Lmol–1 cm–1) nm. CD
(EtOH): λext (∆ε) = 293.4 (–2.8), 282.4 (–4.2), 271.0 (–2.8), 226.2
(+5.3), 209.6 (–24.1 Lmol–1 cm–1) nm. C29H34O3 (430.58): calcd. C
80.89, H 7.96; found C 80.81, H 8.13.
Recovery of Enantiopure 2-Butyl-2-methyl-1-tetralol (1R,2S)-(–)-
trans-9 from CSDP Ester (1R,2S)-(+)-trans-11b: CSDP ester
(1R,2S)-(+)-trans-11b was treated as described for the cis ester,
yielding (1R,2S)-(–)-trans-9 (96%) as a colorless oil. [α]2D9 = –9.7 (c
1
= 1.02, CHCl3). The IR, H NMR, and 13C NMR were identical
with those of racemate (Ϯ)-trans-9. UV (EtOH): λmax (ε) = 272.8
(300), 265.4 (400), 213.4 (8800 Lmol–1 cm–1) nm. CD (EtOH) was
almost silent. C15H22O (218.33): calcd. C 82.52, H 10.16; found C
82.20, H 10.26.
Preparation and Separation of MαNP Esters (S:1S,2R)-(–)-trans-
13a and (S:1R,2S)-(–)-trans-13b: The MαNP esters were prepared
and separated as described above for the cis esters: HPLC on silica
gel (hexane/EtOAc, 15:1; α = 1.59, Rs = 4.23) yielded (S:1S,2R)-
(–)-trans-13a (47%) and (S:1R,2S)-(–)-trans-13b (48%).
Preparation and Separation of MαNP Esters (S:1S,2S)-(–)-cis-12a
and (S:1R,2R)-(–)-cis-12b: To a mixture of racemic alcohol (Ϯ)-
cis-9 (0.875 g, 4.01 mmol), (S)-(+)-MαNP acid (1.10 g, 4.80 mmol),
DMAP (1.01 g, 8.28 mmol), 10-camphorsulfonic acid (CSA;
0.812 g, 3.75 mmol), and DCC (2.49 g, 12.1 mmol) cooled to 0 °C,
was added CH2Cl2 (10 mL), and the mixture was heated gently to
reflux overnight. The excess DCC was hydrolyzed by addition of a
small amount of water. After addition of anhydrous MgSO4, the
mixture was filtered through Celite, and the filtrate was concen-
trated to dryness. The diastereomeric MαNP esters were purified
by short column chromatography on silica gel (hexane/EtOAc, ca.
1:1) and then separated by HPLC on silica gel (hexane/EtOAc,
15:1; α = 1.81, Rs = 5.97) yielding (S:1S,2S)-(–)-cis-12a (0.853 g,
49%) and (S:1R,2R)-(–)-cis-12b (0.830 g, 48%).
MαNP Ester (S:1S,2R)-(–)-trans-13a: Colorless solid. [α]2D7 = –86.9
(c = 1.13, CHCl ). IR (film): ν
= 3051, 2933, 2860, 1743, 1600,
˜
3
max
1510, 1494, 1456, 1378, 1344, 1241, 1180, 1134, 1051, 993, 966,
936, 805, 779 cm–1. 1H NMR (600 MHz, CDCl3): δ = 0.77 (s, 3 H,
13-H3), 0.83 (br. t, J = 7.1 Hz, 3 H, 12-H3), 1.14 (m, 2 H, 9-H2),
1.19 (m, 2 H, 11-H2), 1.23 (m, 2 H, 10-H2), 1.43 (dd, J = 7.3,
6.2 Hz, 2 H, 3-H2), 2.03 (s, 3 H, CH3), 2.43 (dt, J = 17.4, 6.2 Hz,
1 H, 4-Heq), 2.52 (dt, J = 17.4, 7.3 Hz, 1 H, 4-Hax), 3.11 (s, 3 H,
OCH3), 5.69 (br. s, 1 H, 1-H), 6.50 (br. d, J = 7.6 Hz, 1 H, 8-H),
6.63 (br. ddd, J = 7.6, 7.5, 1.0 Hz, 1 H, 7-H), 6.82 (br. d, J =
7.5 Hz, 1 H, 5-H), 6.96 (br. ddd, J = 7.5, 7.5, 1.3 Hz, 1 H, 6-H),
7.34 (ddd, J = 8.6, 6.9, 1.5 Hz, 1 H), 7.34 (dd, J = 8.1, 7.3 Hz, 1
H), 7.42 (ddd, J = 8.1, 6.9, 1.2 Hz, 1 H), 7.52 (dd, J = 7.3, 1.0 Hz,
1 H), 7.74 (br. d, J = 8.1 Hz, 1 H), 7.78 (br. dd, J = 8.1, 1.5 Hz, 1
H), 8.38 (br. dd, J = 8.6, 1.2 Hz, 1 H) ppm. 13C NMR (150 MHz,
CDCl3): δ = 14.07, 20.90, 21.95, 23.39, 25.22, 25.55, 29.18, 35.86,
36.74, 50.97, 77.34, 81.89, 124.51, 125.30, 125.43, 125.51, 125.56,
126.34, 127.27, 128.13, 128.42, 129.20, 129.33, 131.31, 133.61,
133.94, 134.92, 136.05, 173.48 ppm. UV (EtOH): λmax (ε) = 294.0
(4400), 282.2 (6500), 272.8 (5700), 224.8 (58200), 222.0
(54100 Lmol–1 cm–1) nm. CD (EtOH): λext (∆ε) = 284.4 (+0.6),
224.2 (–47.8 Lmol–1 cm–1) nm. C29H34O3 (430.58): calcd. C 80.89,
H 7.96; found C 80.32, H 7.99.
MαNP Ester (S:1S,2S)-(–)-cis-12a: Colorless solid. [α]2D5 = –87.7 (c
= 1.09, CHCl ). IR (film): ν
= 2934, 1861, 1727, 1600, 1510,
˜
3
max
1494, 1457, 1380, 1344, 1248, 1180, 1134, 1052, 970, 915, 805, 778,
1
732 cm–1. H NMR (600 MHz, CDCl3): δ = 0.78 (s, 3 H, 13-H3),
0.86 (br. t, J = 7.0 Hz, 3 H, 12-H3), 1.04 (m, 1 H, 9-H), 1.17 (m, 5
H, 9-H, 10-H2, 11-H2), 1.31 (dddd, J = 13.5, 6.6, 5.7, 0.8 Hz, 1 H,
3-Heq), 1.41 (ddd, J = 13.5, 8.7, 6.7 Hz, 1 H, 3-Hax), 2.00 (s, 3 H,
CH3), 2.35 (br. ddd, J = 17.5, 6.7, 5.7 Hz, 1 H, 4-Heq), 2.51 (br.
ddd, J = 17.5, 8.7, 6.6 Hz, 1 H, 4-Hax), 3.07 (s, 3 H, OCH3), 5.65
(br. s, 1 H, 1-H), 6.73 (br. ddd, J = 7.5, 7.3, 1.2 Hz, 1 H, 7-H), 6.76
(dd, J = 7.5, 1.7 Hz, 1 H, 8-H), 6.79 (br. d, J = 7.4 Hz, 1 H, 5-H),
6.98 (ddd, J = 7.4, 7.3, 1.7 Hz, 1 H, 6-H), 7.23 (ddd, J = 8.7, 6.9,
1.5 Hz, 1 H), 7.34 (dd, J = 8.2, 7.3 Hz, 1 H), 7.36 (ddd, J = 8.2,
6.9, 1.2 Hz, 1 H), 7.50 (dd, J = 7.3, 1.1 Hz, 1 H), 7.73 (br. d, J =
8.2 Hz, 1 H), 7.75 (br. dd, J = 8.2, 1.5 Hz, 1 H), 8.24 (br. dd, J =
8.7, 1.2 Hz, 1 H) ppm. 13C NMR (150 MHz, CDCl3): δ = 14.14,
20.97, 21.84, 23.48, 25.10, 25.25, 29.70, 35.57, 36.38, 50.92, 77.61,
MαNP Ester (S:1R,2S)-(–)-trans-13b: Colorless solid. [α]2D7 = –8.6
(c = 1.06, CHCl ). IR (KBr): ν
= 3053, 2932, 2857, 1744, 1600,
˜
3
max
1509, 1494, 1456, 1367, 1238, 1181, 1137, 1053, 992, 938, 805,
Eur. J. Org. Chem. 2010, 6372–6384
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
6381

N. Harada et al.
FULL PAPER
780 cm–1. H NMR (600 MHz, CDCl3): δ = 0.00 (s, 3 H, 13-H3), Lmol–1 cm–1) nm. CD (EtOH): λext (∆ε) = 354.4 (–0.22), 341.4
1
0.67 (ddd, J = 13.5, 12.1, 4.3 Hz, 1 H, 9-H), 0.71 (t, J = 6.8 Hz, 3 (–0.26), 328.2 (–0.14), 309.8 (+0.06), 286.8 (–0.89), 245.6 (+2.40),
H, 12-H3), 0.75 (ddd, J = 13.5, 12.0, 4.4 Hz, 1 H, 9-H), 0.88 (m, 1
H, 10-H), 0.91 (ddq, J = 6.8, 6.8, 6.8 Hz, 2 H, 11-H2), 0.97 (m, 1
H, 10-H), 1.26 (ddd, J = 13.6, 6.9, 6.1 Hz, 1 H, 3-Heq), 1.29 (ddd,
J = 13.6, 8.1, 6.1 Hz, 1 H, 3-Hax), 1.90 (s, 3 H, CH3), 2.57 (br. ddd,
J = 17.4, 8.1, 6.9 Hz, 1 H, 4-Hax), 2.62 (br. ddd, J = 17.4, 6.1,
6.1 Hz, 1 H, 4-Heq), 3.08 (s, 3 H, OCH3), 5.66 (br. s, 1 H, 1-H),
7.05 (br. d, J = 7.4 Hz, 1 H, 5-H), 7.13 (br. ddd, J = 7.5, 7.5,
1.3 Hz, 1 H, 7-H), 7.18 (ddd, J = 7.5, 7.4, 1.4 Hz, 1 H, 6-H), 7.26
(br. d, J = 7.5 Hz, 1 H, 8-H), 7.41 (dd, J = 8.1, 7.3 Hz, 1 H), 7.45
(m, 1 H), 7.46 (m, 1 H), 7.50 (dd, J = 7.3, 1.1 Hz, 1 H), 7.81 (br.
d, J = 8.1 Hz, 1 H), 7.83 (m, 1 H), 8.58 (m, 1 H) ppm. 13C NMR
(150 MHz, CDCl3): δ = 14.02, 19.79, 21.42, 23.09, 25.39, 25.43,
28.92, 35.39, 36.10, 50.66, 76.98, 81.51, 124.53, 125.72, 125.83,
125.89, 126.01, 126.55, 127.64, 128.42, 128.60, 129.38, 129.62,
131.71, 133.95, 134.44, 134.82, 136.59, 173.53 ppm. UV (EtOH):
λmax (ε) = 293.2 (4600), 282.2 (6700), 272.6 (5800), 224.6 (62700),
222.4 (59200 Lmol–1 cm–1) nm. CD (EtOH): λext (∆ε) = 283.4
(–2.0), 281.2 (–3.2), 270.6 (–2.5), 236.6 (+2.0), 218.6 (–20.2 Lmol–1
cm–1) nm. C29H34O3 (430.58): calcd. C 80.89, H 7.96; found C
80.13, H 7.94.
210.8 (–5.45 Lmol–1 cm–1) nm. C15H20O (216.32): calcd. C 83.28,
H 9.32; found C 83.01, H 9.30.
Preparation of Enantiopure 2-Butyl-2-methyl-1-tetralone (R)-(–)-(8)
from Alcohol (1S,2R)-(+)-trans-9: Alcohol (1S,2R)-(+)-trans-9 was
treated as described for cis alcohol, yielding ketone (R)-(–)-8 (96%)
as a colorless oil. [α]3D0 = –8.4 (c = 1.19, CHCl3). The IR, 1H NMR,
and 13C NMR spectra were identical with those of racemate (Ϯ)-
8. UV (EtOH): λmax (ε) = 290.2 (1700), 247.0 (12100), 206.0
(26300 Lmol–1 cm–1) nm. CD (EtOH): λext (∆ε) = 354.0 (+0.22),
340.8 (+0.26), 329.2 (+0.14), 310.6 (–0.07), 287.4 (+0.87), 245.6
(–2.52), 211.2 (+5.07 Lmol–1 cm–1) nm. C15H20O (216.32): calcd. C
83.28, H 9.32; found C 83.08, H 9.65.
Preparation of Enantiopure 2-Butyl-2-methyltetralin (S)-(+)-14: A
mixture of alcohol (1S,2S)-(+)-cis-9 (0.536 g, 2.46 mmol), NaBH4
(0.513 g, 13.6 mmol), anhydrous AlCl3 (1.56 g, 11.6 mmol), and
THF (26 mL) was gently heated to reflux for 2 h. After the reaction
was quenched with water at 0 °C, the mixture was diluted with
EtOAc, and the organic layer was dried with anhydrous MgSO4,
and the solvents were evaporated to dryness. The crude product
was purified by short column chromatography on silica gel (hex-
ane) and HPLC on silica gel (hexane) to yield (S)-(+)-2-butyl-2-
methyltetralin (14; 0.443 g, 89%) as a colorless oil. [α]2D9 = +1.5 (c
Recovery of Enantiopure 2-Butyl-2-methyl-1-tetralol (1S,2S)-(+)-cis-
9 from MαNP Ester (S:1S,2S)-(–)-cis-12a: A mixture of (S:1S,2S)-
(–)-cis-12a (0.325 g, 0.755 mmol) and NaOMe/MeOH solution
(28%, 5 mL) was gently heated to reflux overnight. After the reac-
tion was quenched with water, the mixture was extracted with di-
ethyl ether three times, and the organic layer was dried with anhy-
drous MgSO4, and the solvents were evaporated to dryness. The
crude product was purified by short column chromatography on
silica gel (hexane/EtOAc, 5:1) and HPLC on silica gel (hexane/
EtOAc, 20:1) yielding alcohol (1S,2S)-(+)-cis-9 (0.139 g, 84%) as a
= 1.06, CHCl ). IR (neat): ν
= 2956, 2927, 2870, 1495, 1456,
˜
3
max
1377, 741 cm–1. H NMR (400 MHz, CDCl3): δ = 0.90 (br. t, J =
7.0 Hz, 3 H, terminal CH3), 0.92 (s, 3 H, 2-CH3), 1.20–1.33 (m, 6
H), 1.54 (ddt, J = 13.1, 1.1, 6.6 Hz, 1 H, 3-H), 1.60 (dt, J = 13.1,
6.6 Hz, 1 H, 3-H), 2.48 (d, J = 16.2 Hz, 1 H, 1-H), 2.57 (d, J =
16.2 Hz, 1 H, 1-H), 2.77 (br. t, J = 6.6 Hz, 2 H, 4-H2), 7.01–7.10
(m, 4 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 14.21, 23.61,
24.63, 25.86, 26.18, 31.84, 33.89, 40.83, 42.33, 125.29, 125.42,
128.69, 129.56, 136.08, 136.44 ppm. UV (EtOH): λmax (ε) = 273.2
(600), 266.2 (600), 212.2 (8400 Lmol–1 cm–1) nm. CD (EtOH): λext
(∆ε) = 273.0 (–0.05), 265.2 (–0.06 Lmol–1 cm–1) nm. C15H22
(202.34): calcd. C 89.04, H 10.96; found C 88.49, H 11.10.
1
colorless oil. [α]2D8 = +10.8 (c = 1.26, CHCl3). The IR, H NMR,
1
and 13C NMR spectra were identical with those of racemate (Ϯ)-
cis-9. UV (EtOH): λmax (ε) = 272.8 (300), 264.8 (400), 213.2
(8800 Lmol–1 cm–1) nm. CD (EtOH): λext (∆ε) = 272.8 (–0.10),
264.8 (–0.07 Lmol–1 cm–1) nm. C15H22O (218.33): calcd. C 82.52,
H 10.16; found C 82.14, H 10.21. The addition of 2  HCl to the
aqueous layer gave a white precipitate, which was collected by fil-
tration and dried yielding (S)-(+)-MαNP acid (0.134 g, 77%).
Preparation of Enantiopure Dimethyl 3-Butyl-3-methyladipate (S)-
(–)-15: To a mixture of 2-butyl-2-methyltetralin (S)-(+)-14 (0.496 g,
2.45 mmol), CCl4 (4.9 mL), CH3CN (4.9 mL), and water (7.4 mL),
was added HIO4/2H2O (8.23 g, 36.1 mmol), and the mixture was
stirred until it became a clear solution. RuCl3/hydrate (0.017 g,
0.081 mmol) was added to give a brown solution, which was stirred
at r.t. overnight. The reaction mixture was extracted with EtOAc
three times, and the organic layer was dried with anhydrous
MgSO4, and the solvents were evaporated to dryness to give the
crude dicarboxylic acid (0.131 g). A mixture of the crude dicar-
boxylic acid, K2CO3 (11.3 g, 81.4 mmol), N,N-dimethylformamide
(DMF; 15 mL), and iodomethane (5.5 mL, 88 mmol) was stirred
at r.t. overnight. After addition of diethyl ether, the mixture was
filtered through Celite, and the filtrate was concentrated to dryness.
The yellow oil obtained was dissolved in diethyl ether, and the solu-
Recovery of Enantiopure 2-Butyl-2-methyl-1-tetralol (1S,2R)-(+)-
trans-9 from MαNP Ester (S:1S,2R)-(–)-trans-13a: Ester (S:1S,2R)-
(–)-trans-13a was treated as described for the cis ester, yielding
alcohol (1S,2R)-(+)-trans-9 (81%) as a colorless oil. [α]2D6 = +9.4 (c
= 1.06, CHCl3). The IR, 1H NMR, and 13C NMR spectra were
identical with those of racemate (Ϯ)-trans-9. UV (EtOH): λmax (ε)
= 272.8 (300), 264.8 (400), 213.2 (8800 Lmol–1 cm–1) nm. CD
(EtOH) was almost silent. C15H22O (218.33): calcd. C 82.52, H
10.16; found C 82.20, H 10.26. (S)-(+)-MαNP acid (96%) was reco-
vered from the aqueous layer.
Preparation of Enantiopure 2-Butyl-2-methyl-1-tetralone (S)-(+)-(8)
from Alcohol (1S,2S)-(+)-cis-9: A mixture of alcohol (1S,2S)-(+)- tion was dried with anhydrous MgSO4, filtered, and the solvents
cis-9 (0.056 g, 0.26 mmol) and pyridinium chlorochromate (PCC;
0.177 g, 0.819 mmol) in CH2Cl2 (2.5 mL) was stirred at r.t. for 8 h.
After addition of diethyl ether, the mixture was filtered through
Celite, and the solvents were evaporated to dryness. The crude
product was purified by short column chromatography on silica gel
(hexane/EtOAc, 20:1) and HPLC on silica gel (hexane/EtOAc,
50:1) to give ketone (S)-(+)-8 (0.052 g, 92%) as a colorless oil.
were evaporated to dryness. The crude ester product was purified
by HPLC on silica gel (hexane/EtOAc, 15:1) to yield dimethyl 3-
butyl-3-methyladipate (S)-(–)-15 (0.309 g, 52%) as a colorless oil.
[α]2D4 = –2.4 (c = 1.05, CHCl ). IR (neat): ν
= 2956, 2873, 1739,
˜
3
max
1437, 1382, 1237, 1198, 1168, 1017 cm–1. 1H NMR (400 MHz,
CDCl3): δ = 0.90 (br. t, J = 6.7 Hz, 3 H, terminal CH3), 0.97 (s, 3
H, 3-CH3), 1.18–1.30 (m, 6 H), 1.68 (m, 2 H), 2.21 (br. s, 2 H),
2.30 (m, 2 H), 3.65 (s, 3 H, OCH3), 3.67 (s, 3 H, OCH3) ppm. 13C
NMR (100 MHz, CDCl3): δ = 14.04, 23.33, 24.66, 25.66, 28.96,
34.10, 35.33, 39.00, 43.45, 51.20, 51.60, 172.38, 174.38 ppm.
1
[α]3D2 = +7.9 (c = 1.45, CHCl3). The IR, H NMR, and 13C NMR
spectra were identical with those of racemate (Ϯ)-8. UV (EtOH):
λmax (ε)
=
289.8 (1600), 247.0 (11900), 206.0 (26000
6382
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Eur. J. Org. Chem. 2010, 6372–6384

(R)-(+)-[VCD(–)984]-4-Ethyl-4-methyloctane
Preparation of Enantiopure 3-Butyl-3-methyl-1,6-hexanediol (S)-(+)-
16: To a solution of dimethyl 3-butyl-3-methyladipate (S)-(–)-15
(0.239 g, 0.978 mmol) in THF (10 mL) cooled to 0 °C, was added
LiAlH4 (0.053 g, 1.4 mmol), and the mixture was stirred at r.t. over-
night. After the reaction was quenched with diethyl ether/water, the
organic layer was dried with anhydrous MgSO4, and the solvents
were evaporated to dryness giving the crude product, which was
purified by HPLC on silica gel (hexane/EtOAc/iPrOH, 10:20:2) to
yield 3-butyl-3-methyl-1,6-hexanediol (S)-(+)-16 (0.174 g, 95%) as
a colorless solid. [α]2D5 = +0.54 (c = 1.53, CHCl3). [α]2D6 = –0.33 (c
Acknowledgments
The authors thank Dr. George A. Ellestad and Prof. Koji Nakani-
shi, Department of Chemistry, Columbia University, for their valu-
able suggestions. This work was supported in part by grants from
the Japan Society for Promotion of Science Scientific Research (B)
(to N. H.), the Nissan Science Foundation (to S. K.), the Mazda
Foundation (to S. K.), and the Inamori Foundation (to S. K.).
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[6] Some data were reported as a short communication, see: T.
Fujita, K. Obata, S. Kuwahara, N. Miura, A. Nakahashi, K.
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= 2.31, EtOH). IR (film): ν
= 3320, 2931, 2863, 1457, 1373,
˜
max
1054, 1014, 672 cm–1. H NMR (400 MHz, CDCl3): δ = 0.87 (s, 3
H, 3-CH3), 0.90 (br. t, J = 7.0 Hz, 3 H, terminal CH3), 1.19–1.56
(m, 12 H), 3.62 (t, J = 6.5 Hz, 2 H), 3.68 (br. t, J = 7.7 Hz, 2
H) ppm. 1H NMR (400 MHz, [D6]DMSO): δ = 0.79 (s, 3 H, 3-
CH3), 0.87 (t, J = 7.2 Hz, 3 H, terminal CH3), 1.10–1.36 (m, 12
H), 3.31–3.38 (m, 2 H), 3.39 (br. dt, J = 5.1, 7.8 Hz, 2 H), 4.22 (t,
J = 5.1 Hz, 1 H, OH), 4.36 (t, J = 5.1 Hz, 1 H, OH) ppm. 13C
NMR (100 MHz, CDCl3): δ = 14.11, 23.52, 25.21, 25.68, 26.87,
34.21, 35.45, 39.47, 41.90, 59.46, 63.63 ppm.
1
Preparation of Enantiopure 4-Ethyl-4-methyloctane (R)-(+)-1: To a
solution of 3-butyl-3-methyl-1,6-hexanediol (S)-(+)-16 (0.139 g,
0.740 mmol) and triphenylphosphane (PPh3; 0.815 g, 3.11 mmol)
in CH2Cl2 (2 mL) cooled to 0 °C, was added CBr4 (0.723 g,
2.18 mmol), and the mixture was stirred at 0 °C for 0.5 h and then
at r.t. for 2 h. The reaction mixture was directly subjected to short
column chromatography on silica gel (hexane) to yield the crude
dibromoalkane (0.367 g) as a colorless oil. To a mixture of the
crude dibromoalkane (0.367 g) and HMPA (2 mL), was added
NaBH4 (0.266 g, 7.03 mmol), and the mixture was stirred at r.t. for
2 h. The reaction mixture was directly subjected to a short column
chromatography on silica gel, which was eluted with pentane
(60 mL), and the eluent was concentrated under atmospheric pres-
sure to yield 4-ethyl-4-methyloctane (R)-(+)-1 (0.089 g, 77%) as a
23
colorless liquid. [α]2D5 = +0.19 (neat, ρ = 0.7565), [α]
= +0.70
365
1
(neat, ρ = 0.7565). H NMR (400 MHz, CD2Cl2): δ = 0.76 (t, J =
7.4 Hz, 3 H), 0.77 (s, 3 H), 0.87 (t, J = 7.0 Hz, 3 H), 0.89 (t, J =
7.2 Hz, 3 H), 1.10–1.30 (m, 12 H) ppm. 13C NMR (100 MHz,
CD2Cl2): δ = 8.10, 14.35, 15.25, 17.04, 24.12, 24.70, 26.12, 31.90,
35.15, 38.99, 41.90 ppm. HRMS: m/z calcd. for C11H24 [M]+
156.1878; found 156.1863.
Preparation of Racemic 4-Ethyl-4-methyloctane (؎)-1: Starting
from racemic alcohol (Ϯ)-cis-9, racemic 4-ethyl-4-methyloctane
(Ϯ)-1 was synthesized as described above as a colorless liquid; b.p.
183–184 °C. IR (neat): ν
= 2961, 2928, 2857, 1459 cm–1. 1H
˜
max
NMR (400 MHz, CDCl3): δ = 0.76 (t, J = 7.6 Hz, 3 H), 0.76 (s, 3
H), 0.87 (t, J = 7.1 Hz, 3 H), 0.89 (t, J = 7.2 Hz, 3 H), 1.09–1.30
(m, 12 H) ppm. 1H NMR (400 MHz, CD2Cl2): δ = 0.76 (t, J =
7.6 Hz, 3 H), 0.77 (s, 3 H), 0.87 (t, J = 7.0 Hz, 3 H), 0.90 (t, J =
7.2 Hz, 3 H), 1.10–1.31 (m, 12 H) ppm. 1H NMR (600 MHz,
CDCl3): δ = 0.76 (t, J = 7.5 Hz, 3 H, 10-H3), 0.76 (s, 3 H, 11-H3),
0.87 (t, J = 7.2 Hz, 3 H, 1-H3), 0.89 (t, J = 7.2 Hz, 3 H, 8-H3), 1.11
(t, J = 7.2 Hz, 2 H, 3-H2), 1.14 (m, 2 H, 6-H2), 1.14 (m, 2 H, 5-
H2), 1.20 (tq, J = 7.2, 7.2 Hz, 2 H, 2-H2), 1.20 (q, J = 7.5 Hz, 2 H,
9-H2), 1.26 (m, 2 H, 7-H2) ppm. 13C NMR (100 MHz, CDCl3): δ
= 7.93 (C-10), 14.17 (C-8), 15.07 (C-1), 16.64 (C-2), 23.68 (C-7),
24.52 (C-11), 25.72 (C-6), 31.50 (C-9), 34.82 (C-4), 38.61 (C-5),
41.51 (C-3) ppm. 13C NMR (100 MHz, CD2Cl2): δ = 8.10, 14.35,
15.25, 17.04, 24.11, 24.69, 26.12, 31.90, 35.15, 38.99, 41.90 ppm.
13C NMR (150 MHz, CDCl3): δ = 7.99 (C-10), 14.23 (C-8), 15.13
(C-1), 16.71 (C-2), 23.74 (C-7), 24.58 (C-11), 25.79 (C-6), 31.58 (C-
9), 34.89 (C-4), 38.69 (C-5), 41.59 (C-3) ppm.
1
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© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
6383

N. Harada et al.
FULL PAPER
Kasai, T. Fujita, K. Noro, K. Shimanuki, M. Akagi, M. Wat-
anabe, T. Matsumoto, M. Watanabe, A. Ichikawa, N. Harada,
Eur. J. Org. Chem. 2007, 1827–1840; g) J. Naito, H. Taji, S.
Sekiguchi, M. Watanabe, S. Kuwahara, M. Watanabe, N. Har-
ada, Chirality 2007, 19, 335–343; h) S. Sekiguchi, M. Akagi, J.
Naito, Y. Yamamoto, H. Taji, S. Kuwahara, M. Watanabe, Y.
Ozawa, K. Toriumi, N. Harada, Eur. J. Org. Chem. 2008, 2313–
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group had made an error in interpreting the13C NMR spectro-
scopic data. Namely, they had misassigned the signal at δ =
7.9 ppm to be the TMS peak and, therefore, their chemical
shift data should be corrected by addition of 7.9 ppm. If this
is the case, their data agree well with ours except for the last,
lowest-field peak, which may arise from some impurity.
[12] S. Kuwahara, K. Obata, T. Fujita, N. Miura, A. Nakahashi,
K. Monde, N. Harada, Eur. J. Org. Chem., DOI: 10.1002/
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[10] M. Adamczyk, D. S. Watt, D. A. Netzel, J. Org. Chem. 1984,
49, 4226–4237.
Received: May 30, 2010
Published Online: October 12, 2010
[11] After the publication of our short communication,[6] we re-
ceived private information from a third party that the Lardicci
6384
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Eur. J. Org. Chem. 2010, 6372–6384