Novel sparteine-mediated enantio-dichotomic formal synthesis of (R)-(-)- and (S)-(+)-curcuphenol

Article abstract of DOI:10.1021/jo001485c

High and opposite enantiodiscriminations were observed between tertiary amides and secondary amides in the sparteine-mediated lateral metalation-allylation of 2-ethyl-m-toluamide derivatives (2a, 2e). The results described above have been applied for the formal synthesis of both enantiomers of curcuphenol. The brief mechanistic studies suggested that stereoinformation was introduced after the deprotonation step.

Full text of DOI:10.1021/jo001485c

2700
J . Org. Chem. 2001, 66, 2700-2704
Novel Sp a r tein e-Med ia ted En a n tio-Dich otom ic F or m a l Syn th esis
of (R)-(-)- a n d (S)-(+)-Cu r cu p h en ol
Tetsutaro Kimachi* and Yoshiji Takemoto
Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku 606-8501, Kyoto, J apan
tkimachi@pharm.kyoto-u.ac.jp
Received October 17, 2000
High and opposite enantiodiscriminations were observed between tertiary amides and secondary
amides in the sparteine-mediated lateral metalation-allylation of 2-ethyl-m-toluamide derivatives
(2a , 2e). The results described above have been applied for the formal synthesis of both enantiomers
of curcuphenol. The brief mechanistic studies suggested that stereoinformation was introduced
after the deprotonation step.
Ta ble 1. Op p osite En a n tioselectivity betw een Ter tia r y
Am id es (2a , 2b) a n d Secon d a r y Am id es (2c-e) in th e
Sp a r tein e-Med ia ted La ter a l Meta la tion Su bstitu tion s
In tr od u ction
The recent progress in various aspects of chiral ligand-
mediated organometallic chemistry has brought great
benefits to the asymmetric synthesis of optically active
compounds including natural products and related bio-
logically active compounds.1 In general, one of the two
antipodal chiral ligands produces adducts with either an
(R) or (S) configuration, although there are a few
exceptional examples affording both enantiomers of ad-
ducts by only one of the two antipodal ligands.2 In
previous study, we reported that the opposite enantiose-
lectivity was observed between N,N-diisopropyl o-ally-
loxymethylbenzamide and N,N-diethyl o-allyloxymeth-
ylbenzamide on the (-)-sparteine-mediated enantio-
selective [2,3]-Wittig rearrangement of N,N-dialkyl o-
allyloxymethylbenzamides.3 We presently report on the
moderate to high and opposite enantiodiscrimination
between tertiary amides and secondary amides in the (-)-
sparteine-mediated lateral metalation-substitution reac-
tions (Table 1, Scheme 1). We applied these findings for
the formal synthesis of both enantiomers of curcuphenol
(1 and ent-1). The findings of a brief mechanistic study
suggested that an enantiodetermining step in both
sequences (2a f 4a , 2e f 4e in Scheme 1) occurred after
deprotonation. This method makes it possible to carry
out a preparation of a pair of optically active compounds
with opposite configurations at the stereogenic center.
In medicinal chemistry, the high optical purity of each
target molecule is of course crucial and preparations of
both of the (R) and (S) enantiomers of the molecules are
often needed. A pair of enantiomers showing these factors
is curcuphenol (1 and ent-1).
en- prod-
try uct
yield ee
R
R′
solventa
pentane
pentane
pentane/MTBE (10/1)
(%) (%) [R]D
1b 3a
i-Pr i-Pr
66
43
55
31
51
92 +9.39
25 +2.2
16 -1.56
15 -1.3
44 -5.5
2
3b
Et
H
H
H
Et
i-Pr
3c 3c
4c 3d
5c 3e
c-Hex pentane/MTBE (5/1)
n-Oct pentane
a
MTBE ) tert-butyl methyl ether. bWith 2.2 equiv of sec-BuLi,
c
55% of 3a with 48% ee was obtained. 3.3 Equivalents of n-BuLi
and (-)-sparteine were used for effective metalation.
Sch em e 1. En a n tioselective
Meta la tion -Allyla tion of 2a , 2b, 2c
Even though much attention has been paid to these
bisabolane sesquiterpenes which showed different activi-
ties between each enantiomers,4 only two enantioselective
(1) For reviews, see: (a) Noyori, R.; Kitamura, M. Angew. Chem.,
Int. Ed. Engl. 1991, 30, 49. (b) Schlosser, M. Tetrahedron 1994, 50. (c)
Hoppe, D.; Hense, T. Angew. Chem., Int. Ed. Engl. 1997, 36, 2282. (d)
Tomioka, K. Synthesis 1990, 541. (e) Beak, P.; Basu, A.; Gallagher, D.
J .; Park, Y. S.; Thayumanavan, S. Acc. Chem. Res. 1996, 29, 552. (f)
Tsukazaki, M.; Tinkl, M.; Roglans, A.; Chapell, B. J .; Taylor, N. J .;
Snieckus, V. J . Am. Chem. Soc. 1996, 118, 685.
(2) Schlosser, M.; Limat, D. J . Am. Chem. Soc. 1995, 117, 12342.
(b) Thayumanavan, S.; Lee, S.; Liu, C.; Beak, P. J . Am. Chem. Soc.
1994, 116, 9755. (c) Thayumanavan, S.; Basu, A.; Beak, P. J . Am.
Chem. Soc. 1997, 119, 8209.
syntheses of curcuphenol have been reported.4c,4d In the
present study, we attempted to synthesize both enanti-
omers of curcuphenol by the (-)-sparteine-mediated
enantioselective lateral metalation-substitution reac-
tions of o-ethylbenzamide derivatives, following prece-
dents developed by Beak et al.2
(3) Kawasaki, T.; Kimachi, T. SYNLETT 1998, 1429. (b) Kawasaki,
T.; Kimachi, T. Tetrahedron 1999, 55, 6847.
10.1021/jo001485c CCC: $20.00 © 2001 American Chemical Society
Published on Web 03/20/2001

Synthesis of (R)-(-)- and (S)-(+)-Curcuphenol
J . Org. Chem., Vol. 66, No. 8, 2001 2701
Ch a r t 1. Str u ctu r e of Cu r cu p h en ol
Sch em e 2. Ap p lica tion for th e F or m a l Syn th esis
of (R)-(-)-Cu r cu p h en ol
Resu lts a n d Discu ssion s
Our initial goal of preparing both enantiomers of
curcuphenol envisioned an enantioselective introduction
of a side chain and a stereogenic center in a single step
(Table 1). According to Beak’s procedure, lithiation of a
series of o-ethylbenzamide derivatives (2a -e) with n-
BuLi in the presence of (-)-sparteine at -78 °C and
careful treatment with 5-bromo-2-methyl-2-pentene af-
forded the optically active intermediates (3a -e) in
moderate to high enantiomeric ratios (Table 1).
The N,N-diisopropyl carbamyl group resulted in highly
enantioselective alkylation to afford 3a (92% ee) (entry
1), but the subsequent conversions of the N,N-diisopropyl
carbamyl group to a hydroxyl group by way of acidic or
basic hydrolysis or reduction with DIBAH, or cleavage
with La(OTf)3-MeLi5-mediated alkylation, MeLi, or n-
BuLi6 could not be realized. It is noted that 2a and 2b
showed a similar configurational selectivity in this alky-
lation and afforded the products with similar signs of
optical rotation (see entries 2, 3), while the substrates
with one N-alkyl group afforded the products with an
opposite sign of optical rotation compared with those of
3a and 3b (entries 3-5). These findings differ from our
enantioselective [2,3]-Wittig rearrangement analogy.7
The results in Table 1 (entries 3-5) also show that the
N-octyl group was the most suitable director in all three
N-alkyl groups because it could form the most enantio-
enriched product in all three. From these preliminary
results, we reexamined the strategy for the synthesis of
curcuphenol and carried out an alternative approach
shown in Scheme 1, Scheme 2, and Scheme 3. Presently,
we attempted to obtain enantiomerically enriched 8 and
ent-6 to complete the formal synthesis of both enanti-
omers of curcuphenol. Compound 8 is an enantiomer of
a reported intermediate and is known to have an (R)-
configuration.4d
Sch em e 3. Ap p lica tion for th e F or m a l Syn th esis
of (S)-(+)-Cu r cu p h en ol
(5a , 5b) (Scheme 2). The % ee of 5b (60%) was obtained
by HPLC analysis using a CHIRALCEL OD column.
Although the % ee of 5a was not found at this stage, it
was found to be 88% when 5a was converted to 6 by
excess amounts of n-BuLi (Scheme 2).
Metalation of N,N-diisopropyl-2-ethyl-m-toluamide (2a)
and N,N-diethyl-2-ethyl-m-toluamide (2b) at -78 °C in
the presence of (-)-sparteine followed by the careful
treatment with allyl chloride afforded optically active
allyl adducts (4a , 4b). The compounds (4a , 4b) were
subsequently exposed to ozonolysis and in situ reduction
by sodium borohydride to afford optically active alcohols
Baeyer-Villiger oxidation of 6 by trifluoroperacetic
acid (TFPAA) and successive hydrolysis afforded a phenol
(7) in moderate yields (31%). Conversion by MeI/K2CO3
gave a desired substituted anisole (8). The absolute
configuration of 8 was found to be (R) by the comparison
of the optical rotation reported by Serra et al.4d Next, (-)-
sparteine-mediated lateral metalation-substitution of
N-octylbenzamide derivative (2e) was carried out. Meta-
lation at -78 °C with 3.3 equiv of n-BuLi-(-)-sparteine
mixture, and the following careful treatment with allyl
chloride afforded an adduct (4e) in 56% yields (80% ee)
(Scheme 1). The adduct 4e was converted to an N-methyl-
N-octylamide derivative (9) which led to 5e that was
further converted to an ent-6 by alkylation with n-BuLi
(Scheme 3).
(4) Wright, A. E.; Pomponi, S. A.; McConnell, O. J .; Kohmoto, S.;
McCarthy, P. J . J . Nat. Prod. 1987, 50, 976. (b) Ghisalberti, E. L.;
J efferies, P. R.; Stuart, A. D. Aust. J . Chem. 1979, 32, 1627. (c)
Synthesis of both enantiomers of curcuphenol by enzymatic resolution
of the racemic intermediates: Ono, M.; Oguta, Y.; Hatogai, K.; Akita,
H. Tetrahedron: Asymmetry 1995, 6, 1829. (d) Synthesis of (S)-
curcuphenol by the enzymatic reduction of the appropriate precursor
for the introduction of the stereogenic center: Fuganti, C.; Serra, S.
Synlett 1998, 1252.
(5) Collins, S.; Hong, W. Tetrahedron Lett. 1987, 28, 4391. (b) Collins,
S.; Hong, Y.; Hoover, G. J .; Veit, J . R. J . Org. Chem. 1990, 55, 3565.
(6) Comins, D. L.; Brown, J . D. J . Org. Chem. 1986, 51, 3566.
(7) In the case of the (-)-sparteine-mediated [2,3]-Wittig rearrange-
ment of N,N-dialkyl and N-alkyl o-allyloxymethylbenzamides, an
opposite enantioselectivity was observed between the N,N-diisopropyl
carbamyl group and the N,N-diethyl carbamyl group, and the N,N-
diethyl carbamyl group showed the same selectivity as the N-isopropyl
carbamyl group.
According to the same experimental procedures used
in the synthesis of 8, ent-6 can be transformed to ent-8.
In conclusion, we achieved the (-)-sparteine-mediated

2702 J . Org. Chem., Vol. 66, No. 8, 2001
Kimachi and Takemoto
at -78 °C, and then 0.27 mL (2.0 mmol) of 5-bromo-2-methyl-
2-pentene in 5 mL of pentane was added. After the reaction
was completed, methanol was added to the reaction mixture,
and then the mixture was treated with saturated aqueous NH4-
Cl and then separated. The aqueous layer was extracted twice
with ethyl acetate. The combined organic layer was washed
with 5% HCl, water, and then brine. The organic layer was
dried over MgSO4 and concentrated to a small volume.
Purification by flash chromatography afforded a pure com-
pound (3a ) as a colorless oil (108 mg, 66% yield); [R]D +9.4 (c
1.64 in CHCl3). 1H NMR (270 MHz, CDCl3) δ 1.06-1.26 (m,
9H), 1.56-1.66 (m, 14H), 1.90 (m, 2H), 2.30 (s, 3H), 2.75 (m,
1H), 3.46 (m, 1H), 3.73 (m, 1H), 5.12 (m, 1H), 6.87 (d, 1H, J )
7.59 Hz), 7.17(dd, 1H, J ) 1.98 Hz, J ) 7.59 Hz). 13C NMR
(67.8 MHz, CDCl3) δ 17.5, 20.3, 20.4, 20.7, 20.8, 20.9, 22.4,
25.6, 25.9, 34.9, 35.8, 45.5, 50.4, 124.1, 125.1, 126.1, 129.0,
131.1, 135.3, 136.9, 139.8, 170.4. Anal. Calcd for C22H35NO:
C, 80.24; H, 10.64; N, 4.26. Found: C, 79.95; H, 10.65; N, 4.17.
The enantiomeric excess was found to be 92% and was
obtained by HPLC on a Chiralcel OD column (250 × 4.6 mm,
i.d.) from Daicel Co., using n-hexane/isopropyl alcohol 200/1
as eluent (flow rate 0.5 mL/min) at 254 nm. The major
enantiomer was eluted after 11.5 min, and the minor enanti-
omer was eluted after 15.8 min.
Syn th esis of Op tica lly Active 3b fr om 2b According to
the typical procedure for the synthesis of 3a , the reaction was
carried out using 0.5 mmol (109 mg) of N,N-diethyl-2-ethyl-
5-methylbenzamide (2b), (-)-sparteine (0.25 mL, 1.1 mmol),
and n-BuLi (0.76 mL, 1.1 mmol). The resulting burgundy
solution was stirred for 1 h at -78 °C and then quenched with
0.27 mL (2.0 mmol) of 5-bromo-2-methyl-2-pentene in 5 mL
of pentane. Purification by flash chromatography afforded a
pure compound (3b) as a colorless oil; 64 mg (43%). [R]20D +2.2
(c 2.7 CHCl3). 1H NMR (270 MHz, CDCl3) δ 1.01-1.33 (m, 9H),
1.55(s, 3H), 1.67 (s, 3H), 1.63 (m, 2H), 1.90 (m, 2H), 2.31 (s,
3H), 2.71 (m, 1H), 3.01-3.20 (m, 2H), 3.35 (m, 1H), 3.83 (m,
1H), 5.08 (m, 1H), 6.93 (s, 1H), 7.15 (m, 1H). 13C NMR (67.8
MHz, CDCl3) δ 12.8, 14.0, 17.6, 20.7, 22.7, 25.6, 26.3, 34.7,
38.1, 42.3, 43.3, 124.4, 125.5, 126.1, 130.1, 131.3, 135.6, 136.5,
140.0, 172.2. HRMS (FAB+) Calcd for C20H31NO (302.24856,
MH+); Found: 302.2483. The enantiomeric excess was found
to be 25% and was obtained by HPLC on a Chiralcel OD
column (250 × 4.6 mm, i.d.) from Daicel Co., using n-hexane/
isopropyl alcohol 100/1 as eluent (flow rate 0.5 mL/min) at 254
nm. The major enantiomer was eluted after 23.5 min, and the
minor enantiomer was eluted after 29 min.
Syn th esis of 3c fr om 2c According to the typical procedure
for the synthesis of 3a , the reaction was carried out using 1.46
mmol (300 mg) of 2c, (-)-sparteine (1.1 mL, 4.8 mmol), and
n-BuLi (3.4 mL, 4.8 mmol) in freshly distilled pentane/MTBE
(10/1) (30 mL). The resulting burgundy solution was stirred
for 1 h at -78 °C and then quenched with 0.8 mL (6.0 mmol)
of 5-bromo-2-methyl-2-pentene in 5 mL of solvent. Purification
by flash chromatography afforded a pure compound (3c) as a
white solid; 231 mg (55%). [R]21D -1.34 (c 0.9 CHCl3). 1H NMR
(270 MHz, CDCl3) δ 1.26 (m, 9H), 1.51 (s, 3H), 1.64 (s, 3H),
1.59 (m, 2H), 1.90 (m, 2H), 2.32 (s, 3H), 3.08 (m, 1H), 4.27 (m,
1H), 5.07 (m, 1H), 5.51 (m, 1H), 7.07 (m, 1H), 7.17 (m, 2H).
13C NMR (67.8 MHz, CDCl3) δ 17.5, 20.7, 22.5, 22.6, 22.7, 25.6,
26.3, 34.6, 38.1, 41.6, 124.3, 126.1, 126.8, 130.3, 131.2, 135.0,
137.0, 142.0, 170.0. Anal. Calcd for C19H29NO: C, 79.38; H,
10.17; N, 4.87. Found: C, 79.28; H, 10.08; N, 4.73. The
enantiomeric excess was found to be 16% and was obtained
by HPLC on a Chiralcel OD column (250 × 4.6 mm, i.d.) from
Daicel Co., using n-hexane/isopropyl alcohol 100/1 as eluent
(flow rate 0.5 mL/min) at 254 nm. The major enantiomer was
eluted after 34 min, and the minor enantiomer was eluted after
24 min.
enantioselective formal synthesis of both enantiomers of
curcuphenol because the efficient synthesis of ent-1 from
ent-8 in four steps is known.4d
To interpret the opposite configurational result s in this
sparteine-mediated lateral metalation-substitution, the
following experiment was carried out. (-)-Sparteine (3.3
equiv) was added to a solution of racemic lithiated 2e
followed by quenching with allyl chloride. As a result,
the enantioenriched product (4e) in 54% yields (68% ee)
with an (S) configuration was formed. This result indi-
cates that stereoinformation is transferred after depro-
tonation. This result is also consistent with that of Beak’s
mechanistic studies of sparteine-mediated lateral meta-
lation-substitution of N,N-dialkyl o-ethylbenzamides.
However, further investigations are required to confirm
whether enantioenrichment in the sequence with lithi-
ated 2e-(-)-sparteine arises from a dynamic kinetic
resolution or a dynamic thermodynamic resolution.
Exp er im en ta l Section
1H NMR spectra were recorded on a J EOL J NM-FX-270
spectrometer using tetramethylsilane (TMS) as an internal
standard. Chemical shifts are reported in parts per million
(ppm) relative to TMS. When peak multiplicities are given,
the following abbreviations are used: s, singlet; d, doublet; t,
triplet; q, quartet; dd, doublet of a doublet; m, multiplet; b,
broad. 13C NMR spectra were proton decoupled and recorded
on a J EOL-FX-270 spectrometer using a carbon signal of the
deuterated solvents as an internal standard. Mass spectra
(MS) were obtained on J MS-HX/HX-110A instruments. El-
emental analyses were performed by the Center for Organic
Elemental Microanalysis in Kyoto University. Optical rotations
were measured on
a DIP 360 (J apan Spectroscopic Co.)
polarimeter at the sodium D-line and ambient temperature.
Analytical HPLC was performed on a Waters 510/486 unit,
and the wavelength detector was operated at 254 nm. Chiral
HPLC analyses were performed using CHIRALCEL OD
columns at room temperature unless stated otherwise. Enan-
tiomeric purity assays using chiral HPLC columns were
completed with both racemic and enantioenriched materials
and repeated at least once to ensure accuracy of the method
used. Melting points were measured on a Yanagimoto micro
melting point apparatus without correction. Flash chroma-
tography was performed with silica gel (C-200) obtained from
Wakenyaku Co. Analytical thin-layer chromatography was
performed on Merck Silica gel 60 F254 aluminum sheets and
the visualization was accomplished using a UV lamp. THF was
distilled from sodium/benzophenone under an argon atmo-
sphere. Pentane and diethyl ether were distilled from calcium
hydride under an argon atmosphere. Toluene was distilled
from sodium. (-)-Sparteine and N,N,N,N-tetramethylethyl-
enediamine (TMEDA) were distilled from calcium hydride
under nitrogen and stored under argon. Solution of n-BuLi in
hexane and sec-BuLi in cyclohexane were obtained from
KANTO CHEMICAL CO. or Aldrich and titrated periodically
according to the method of Watson and Eastham.9 A -78 °C
bath refers to a mixture of dry ice in acetone.
Syn th esis of 3a . Typ ica l P r oced u r e (sp a r tein e-m ed i-
a ted la ter a l m eta la tion -su bstitu tion ). To a solution of (-)-
sparteine (0.25 mL, 1.1 mmol) in freshly distilled pentane (15
mL) at -78 °C was added n-BuLi (0.76 mL, 1.1 mmol). The
reaction mixture was stirred for 10 min, and then a precooled
solution of N,N-diisopropyl-2-ethyl-5-methylbenzamide (2a )
(123 mg, 0.5 mmol) in pentane (15 mL) was added via a
cannula. The resulting burgundy solution was stirred for 1 h
Syn th esis of 3d fr om 2d According to the typical proce-
dure for the synthesis of 3a , the reaction was carried out using
1 mmol (245 mg) of 2d , (-)-sparteine (0.76 mL, 3.3 mmol) and
n-BuLi (2.3 mL, 3.3 mmol) in freshly distilled pentane/MTBE
(5/1) (25 mL) at -78 °C. The resulting burgundy solution was
stirred for 1 h at -78 °C and then 0.67 mL (5.0 mmol) of
5-bromo-2-methyl-2-pentene in 5 mL of pentane was added.
(8) Sparteine-mediated lateral metalation-substitutions of o-eth-
ylbenzamides are known to proceed via an asymmetric substitution
pathway (dynamic kinetic resolution), and this suggested that the
stereoinformation of 4a and 4b are also determined after deprotonation
of 2a and 2b, respectively. See ref 2c.
(9) Watson, S. C.; Eastham, J . F. J . Organomet. Chem. 1967, 9, 165.

Synthesis of (R)-(-)- and (S)-(+)-Curcuphenol
J . Org. Chem., Vol. 66, No. 8, 2001 2703
Purification by flash chromatography afforded a pure com-
pound (3d ) as a white solid; 100 mg (31%). [R]D25 -1.84 (c 0.87
CHCl3). 1H NMR (270 MHz, CDCl3) δ 1.16 (d, 3H, J ) 6.93
Hz), 1.44 (s, 3H), 1.57 (s, 3H), 1.10-2.20 (m, 14H), 2.23 (s,
3H), 2.98 (m, 1H), 3.88 (m, 1H), 4.98 (m, 1H), 5.50 (m, 1H),
6.99 (s, 1H), 7.10 (m, 2H). 13C NMR (67.8 MHz, CDCl3) δ 17.6,
20.8, 22.7, 24.8, 24.8, 25.5, 25.7, 26.3, 33.1, 33.2, 34.7, 38.1,
48.4, 124.4, 126.2, 126.9, 130.4, 131.3, 135.1, 137.1, 142.0,
169.7. Anal. Calcd for C22H33NO: C, 80.67; H, 10.16; N, 4.28.
Found: C, 80.83; H, 10.45; N, 4.25. The enantiomeric excess
was found to be 15% and was obtained by HPLC on a Chiralcel
OD column (250 × 4.6 mm, i.d.) from Daicel Co., using
n-hexane/isopropyl alcohol 50/1 as eluent (flow rate 0.7 mL/
min) at 254 nm. The major enantiomer was eluted after 28
min, and the minor enantiomer was eluted after 16 min.
Syn th esis of 3e fr om 2e According to the typical procedure
for the synthesis of 3a , the reaction was carried out using 1
mmol (275 mg) of 2e, (-)-sparteine (0.77 mL, 3.3 mmol) and
n-BuLi (2.3 mL, 3.3 mmol) in freshly distilled pentane (20 mL)
at -78 °C. The resulting clear green solution was stirred for
1 h at -78 °C and then quenched with 0.67 mL (5.0 mmol) of
5-bromo-2-methyl-2-pentene. Purification by flash chromatog-
raphy afforded a pure compound (3e) as a colorless oil; 182
mg (51%). [R]20D -5.5 (c 2.2 CHCl3). 1H NMR (270 MHz, CDCl3)
δ 0.88 (m, 3H), 1.22 (d, 3H, J ) 6.93 Hz), 1.28 (m, 11H), 1.50
(s, 3H), 1.65 (s, 3H), 1.56 (m, 3H), 1.89 (m, 2H), 2.31 (s, 3H),
3.05 (m, 1H), 3.41 (m, 2H), 5.07 (m, 1H), 5.69 (m, 1H), 7.08 (s,
1H), 7.18 (m, 2H). 13C NMR (67.8 MHz, CDCl3) δ 14.1, 17.6,
20.8, 22.6, 22.8, 25.6, 26.3, 27.0, 29.0, 29.2, 29.3, 29.7, 31.8,
34.7, 38.1, 39.8, 124.5, 126.2, 127.0, 130.5, 131.3, 135.1, 137.0,
142.0, 170.5.Anal. Calcd for C24H39NO: C, 80.60; H, 11.00; N,
3.92. Found: C, 80.50; H, 11.04; N, 3.82. The enantiomeric
excess was found to be 44% and was obtained by HPLC on a
Chiralcel OD column (250 × 4.6 mm, i.d.) from Daicel Co.,
using n-hexane/isopropyl alcohol 100/1 as eluent (flow rate 0.5
mL/min) at 254 nm. The major enantiomer was eluted after
59 min, and the minor enantiomer was eluted after 42 min.
N,N-Diisop r op yl-2-(1-a llyl)et h yl-5-m et h ylb en za m id e
(4a ) To a -78 °C solution of n-BuLi (0.56 mL, 0.9 mmol, 1.6
M solution in hexane) and (-)-sparteine (0.21 mL, 0.9 mmol)
in pentane (15 mL) was added 2a (124 mg, 0.5 mmol) in
pentane (15 mL) via a cannula. (2a in pentane was precooled
to -40 °C before cannulation.) The resulting purple solution
was kept under -50 °C for 1.5 h and then cooled to -78 °C
and quenched with allyl chloride (0.082 mL, 1.0 mmol) in
pentane (allyl chloride solution was cooled to -78 °C before
cannulation) at this temperature. The mixture was stirred for
5 h at -78 °C. When the solution turned colorless, methanol
was added to the resulting colorless solution followed by
extractive work up with ethyl acetate and NH4Cl aq. The
aqueous layer was extracted twice with ethyl acetate, and the
organic layers were combined. The organic layer was washed
with 5% HCl, brine, dried over MgSO4, and then concentrated.
The crude product was purified by flash chromatography to
afford pure N,N-Diisopropyl-2-(1-allyl)ethyl-5-methylbenza-
47 mg (77%) of pure 5a as a colorless oil; [R]25 -99 (c 2.92
D
CHCl3). 1H NMR (270 MHz, CDCl3) δ 1.13 (d, 6H, J ) 6.93
Hz), 1.25 (d, 3H, J ) 6.93 Hz), 1.57 (m, 6H), 1.94 (m, 1H),
2.32 (s, 3H), 2.94 (m, 1H), 3.14 (m, 1H), 3.41-3.56 (m, 2H),
3.78 (m, 1H), 4.50 (m, 1H), 6.86 (s, 1H), 7.16 (m, 2H). 13C NMR
(67.8 MHz, CDCl3) δ 20.2, 20.3, 20.7, 20.8, 20.9, 23.4, 31.7,
42.4, 46.2, 51.2, 59.2, 124.7, 126.5, 129.8, 135.7, 138.0, 139.3,
172.4. HRMS (FAB+) Calcd for C18H30NO2 (292.2278, MH+);
Found: 292.2286.
(-)-2-(1-Hydr oxyeth yl)eth yl-5-m eth ylvaler oph en on e (6)
To a solution of 5a (370 mg, 1.27 mmol) in 20 mL of hexane in
-78 °C was slowly added n-BuLi (3.6 mL, 5.1 mmol, 1.4 M
solution in hexane). A white precipitate was formed, and the
reaction mixture was continuously stirred for 16 h at room
temperature. The reaction mixture was worked up with
saturated NH4Cl aq and then separated. The aqueous layer
was extracted twice with ethyl acetate. The combined organic
layers were washed with water and brine, dried over MgSO4,
and concentrated to a small volume. Purification by flash
chromatography afforded 202 mg (64%) of the desired 2-(1-
hydroxyethyl)ethyl-5-methylvalerophenone (6) as a colorless
1
oil; [R]21 -44.0 (c 0.38 CHCl3). H NMR (270 MHz, CDCl3) δ
D
0.93 (t, 3H, J ) 7.26 Hz), 1.20 (d, 3H, J ) 6.93 Hz), 1.38 (m,
2H), 1.68 (m, 3H), 1.95 (m, 1H), 2.36 (s, 3H), 2.87 (m, 2H),
3.25 (m, 2H), 3.48 (m, 1H), 7.24 (m, 3H). 13C NMR (67.8 MHz,
CDCl3) δ 13.9, 20.9, 22.3, 23.7, 26.5, 30.2, 41.8, 42.7, 60.1,
127.3, 127.4, 132.0, 135.2, 139.1, 141.9, 208.8. HRMS (FAB+)
Calcd for C16H25O2 (249.18555, MH+); Found: 249.1860. The
enantiomeric excess was found to be 88% and was obtained
by HPLC on a Chiralcel OD column (250 × 4.6 mm, i.d.) from
Daicel Co., using n-hexane/isopropyl alcohol 100/1 as eluent
(flow rate 0.5 mL/min) at 254 nm. The major enantiomer was
eluted after 48 min, and the minor enantiomer was eluted after
43 min.
2-(1-Hyd r oxyeth yl)eth yl-5-m eth ylp h en ol (7). 2-(1-Hy-
droxyethyl)ethyl-5-methylvalerophenone (6) (100 mg, 0.4 mmol)
in chloroform (2.5 mL) was added at 0 °C to a solution of
trifluoroperacetic acid (TFPAA) in chloroform. (TFPAA was
prepared by adding trifluoroacetic anhydride (0.56 mL, 4
mmol) to 30% aq H2O2 (0.6 mL) in chloroform (3.7 mL) at 0
°C.) The mixture was stirred at room temperature for 1 h and
then poured into 2% aqueous potassium carbonate and ex-
tracted with chloroform. The extract was vigorously stirred
with a few drops of 10% NaOH at 0 °C for 5 min and then
acidified with 5% HCl. The chloroform layer was separated
and washed with water and brine and then dried over MgSO4.
Concentration in vacuo and purification by flash chromatog-
raphy afforded pure 7 (21 mg, 31%) as a pale yellow oil; [R]21
D
1
-24 (c, 2.3, CHCl3). H NMR (270 MHz, CDCl3) δ 1.32 (d, 3H,
J ) 6.93 Hz), 1.53 (m, 1H), 2.03 (m, 1H), 2.27 (s, 3H), 2.72 (m,
1H), 3.26-3.43 (m, 2H), 3.68 (m, 1H), 6.67(s, 1H), 6.74 (d, 1H,
J ) 7.59 Hz), 7.05 (d, 1H, J ) 7.59 Hz). HRMS (FAB+) Calcd
for C11H16O2 (180.11508, MH+); Found; 180.1152.
2-(1-Hydr oxyeth yl)eth yl-5-m eth ylan isole (8) To a stirred
solution of 7 (23 mg, 0.14 mmol) in acetone (3 mL) were added
potassium carbonate (100 mg) and iodomethane (50 µL). The
mixture was refluxed for 3 h and then filtered. The filtrate
was concentrated in vacuo, and the residue was diluted with
ethyl acetate, washed with Na2S2O3 aq, water, and brine, and
then dried over MgSO4. Solvent was removed in vacuo and
purified by flash chromatography to afford 19 mg (75%) of 2-(1-
hydroxyethyl)ethyl-5-methylanisole (8) as a colorless oil. The
absolute configuration of this compound was determined as
mide (4a ) as a colorless oil (111 mg, 78%); [R]22 +6.8 (c 3.02
D
CHCl3). 1H NMR (270 MHz, CDCl3) δ 1.10 (d, 6H, J ) 6.6 Hz),
1.22 (m, 3H), 1.55 (d, 3H, J ) 6.93 Hz), 1.56 (d, 3H, J ) 6.93
Hz), 2.30 (s, 3H), 2.10-2.52 (m, 2H), 2.85 (m, 1H), 3.48 (m,
1H), 3.72 (m, 1H), 5.0 (m, 2H), 5.73 (m, 1H), 6.88 (s, 1H), 7.09-
7.26 (m, 2H). 13C NMR (67.8 MHz, CDCl3) δ 20.1, 20.4, 20.5,
20.6, 20.7, 20.8, 35.0, 41.4, 45.5, 50.4, 115.8, 125.1, 125.9, 128.9,
135.1, 137.0, 137.7, 140.0, 170.4. HRMS (FAB+) Calcd for
C
19H30NO (288.2329, MH+); Found: 288.2323.
1
(R) by the negative sign of an optical rotation value. H NMR
N,N-Diisopr opyl-2-(1-h ydr oxyeth yl)eth yl-5-m eth ylben -
(270 MHz, CDCl3) δ 1.25 (d, 3H, J ) 6.26 Hz), 1.64 (m, 1H),
1.90 (m, 1H), 2.0 (m, 1H), 2.33 (s, 3H), 3.31-3.57 (m, 3H), 3.82
(s, 3H), 6.76 (s, 1H), 6.77 (d, 1H, J ) 7.91 Hz), 7.08 (d, 1H, J
) 7.91 Hz). [R]20D -16 (c 1.58 CHCl3). LRMS (FAB+) m/z (M+)
194. The enantiomeric excess was found to be 88% and was
obtained by HPLC on a Chiralcel OD column (250 × 4.6 mm,
i.d.) from Daicel Co., using n-hexane/isopropyl alcohol 100/1
as eluent (flow rate 0.7 mL/min) at 254 nm. The R-enantiomer
was eluted after 66 min, and the S-enantiomer was eluted after
59 min.
za m id e (5a ) To a -78 °C solution of N,N-diisopropyl-2-(1-
allylethyl)-5-methylbenzamide (4a ) (61 mg, 0.21 mmol, [R]D
+6.8) in MeOH (15 mL), O3 gas was passed through for 30
min. After the reaction was completed, excess amounts of
NaBH4 (500 mg) was added at -10 °C. Saturated NH4Cl aq
was added to the reaction mixture, and the mixture was
concentrated in vacuo. The aqueous layer was extracted twice
with ethyl acetate. The combined organic layer was washed
with 5% HCl, water, and brine and concentrated after drying
over MgSO4. Purification by flash chromatography afforded

2704 J . Org. Chem., Vol. 66, No. 8, 2001
Kimachi and Takemoto
N,N-Dieth yl-2-(1-a llyl)eth yl-5-m eth ylben za m id e (4b).
According to the procedure described in the synthesis of N,N-
diisopropyl-2-(1-allyl)ethyl-5-methylbenzamide (4a ), 200 mg
(0.91 mmol) of N,N-diethyl-2-ethyl-5-methylbenzamide (2b )
was lithiated in toluene instead of hexane at -78 °C and 113
layer was washed with water and brine and dried over MgSO4.
Concentration and purification by flash chromatography af-
1
forded 28.5 mg (80%) of 9; [R]21 -7.5 (c 2.8 CHCl3). H NMR
D
(270 MHz, CDCl3) δ 0.89 (m, 3H), 1.14-1.70 (m, 15H), 2.30
(s, 3H), 2.35 (m, 2H), *2.78 and *3.08 (s, totally 3H), 3.41-
3.66 (m, 2H), 4.95 (m, 2H), 5.70 (m, 1H), 6.92 (s, 1H), 7.16 (m,
2H). Asterisks indicate the separated singlet methyl proton
signals of diastereomers at the N atom. HRMS (FAB+) Calcd
for C22H36NO (330.27988, MH+); Found: 330.2793.
mg (48%) of 4b was obtained; [R]26 +7.8 (c 2.2, CHCl3). 1H
D
NMR (270 MHz, CDCl3) δ 0.85-1.37 (m, 9H), 2.15-2.55 (m,
2H), 2.31 (s, 3H), 2.79 (m, 1H), 3.03-3.42 (m, 3H), 3.80 (m,
1H), 4.91-5.03 (m, 2H), 5.71 (m, 1H), 6.93 (m, 1H), 7.17 (m,
2H). 13C NMR (67.8 MHz, CDCl3) δ 12.4, 13.6, 20.0, 22.3, 34.8,
37.9, 41.3, 42.6, 115.7, 125.5, 125.8, 129.2, 135.0, 136.1, 136.6,
139.7, 170.5. Anal. Calcd for C17H25NO: C, 78.76; H, 9.65; N,
5.41. Found: C, 78.48; H, 9.83; N, 5.22.
N,N-Diet h yl-2-(1-h yd r oxyet h yl)et h yl-5-m et h ylb en za -
m id e (5b) According to the procedure described in the
synthesis of 5a , 70 mg (0.27 mmol) of 4b was exposed to
ozonolysis and the following reduction by NaBH4 to afford 68
N-Met h yl-N-oct yl-2-(1-h yd r oxyet h yl)et h yl-5-m et h yl-
ben za m id e (5e). According to the procedure for the synthesis
of 5a , a -78 °C solution of N-methyl-N-octyl-2-(1-allyl)ethyl-
5-methylbenzamide (9) (26 mg, 0.08 mmol, [R]D -7.5) in MeOH
(15 mL) was exposed to O3 and then reduced by NaBH4. The
resulting residue after workup was purified by flash chroma-
tography to provide 15.4 mg (60%) of 5e as a colorless oil; [R]21
D
1
+80.4 (c 1.54 CHCl3). H NMR (270 MHz, CDCl3) δ 0.88 (m,
mg (98%) of N,N-diethyl-2- (1-hydroxethyl)ethyl-5-methyl-
3H), 1.23 (d, 3H, J ) 6.93 Hz), 1.21-1.93 (m, 14H), 2.32 (s,
3H), 2.83 and 3.09 (s, 3H), 2.90 (m, 1H), 3.15 (m, 2H), 3.56
(m, 2H), 6.91 (m, 1H), 7.18 (m, 2H). HRMS (FAB+) Calcd for
1
benzamide (5b) was obtained; [R]26 -61.6 (c 1.48 CHCl3). H
D
NMR (270 MHz, CDCl3) δ 1.03-1.36 (m, 10H), 1.88 (m, 1H),
2.34 (s, 3H), 2.84 (m, 1H), 3.07-3.90 (m, 7H), 6.91 (s, 1H), 7.18-
(m, 2H). 13C NMR (67.8 MHz, CDCl3) δ 12.8, 14.0, 20.9, 23.2,
31.7, 39.1, 42.4, 43.3, 59.3, 125.5, 126.5, 130.1, 135.6, 1365,
139.6, 172.3. HRMS (FAB+) Calcd for C16H26NO2 (264.19648,
MH+); Found: 264.1961. The enantiomeric excess was found
to be 60% and was obtained by HPLC on a Chiralcel OD
column (250 × 4.6 mm, i.d.) from Daicel Co., using n-hexane/
isopropyl alcohol 400/3 as eluent (flow rate 0.7 mL/min) at 254
nm. The major enantiomer was eluted after 77.5 min, and the
minor enantiomer was eluted after 68.5 min.
C
21H36NO2 (334.2748, MH+); Found: 334.2750.
(S)-(+)-2-(1-H yd r oxyet h yl)et h yl-5-m et h ylva ler op h e-
n on e (en t-6). To a solution of 5e (15 mg, 45 µmol) in 1 mL of
hexane at -78 °C was slowly added n-BuLi (0.1 mL, 0.16
mmol, 1.6 M solution in hexane). White precipitates were
formed, and the reaction mixture was continuously stirred for
4 h at room temperature. The reaction mixture was worked
up with saturated NH4Cl aq and then separated. The aqueous
layer was extracted twice with ethyl acetate. The combined
organic layers were washed with water and brine, dried over
MgSO4, and concentrated to a small volume. Purification by
preparative thin-layer chromatography (20 × 20 cm) (hexane:
ethyl acetate ) 4:1) afforded 8.3 mg (71%) of desired ent-6.
The absolute configuration was determined as (S) from the
N-Octyl-2-(1-a llyl)eth yl-5-m eth ylben za m id e (4e). Ac-
cording to the procedure described in the synthesis of 4a , with
3.3 equiv of n-BuLi and (-)-sparteine, 200 mg (0.7 mmol) of
N-octyl-2-ethyl-5-methylbenzamide (2e) was lithiated in pen-
tane at -78 °C and 126 mg (56%) of 4e was obtained; [R]21
positive sign of the optical rotation value; [R]21 +37 (c 0.83
D
D
1
-6 (c 3.9 CHCl3). H NMR (270 MHz, CDCl3) δ 0.88 (m, 3H),
CHCl3). 1H NMR (270 MHz, CDCl3) δ 0.93 (t, 3H, J ) 7.26
Hz), 1.20 (d, 3H, J ) 6.93 Hz), 1.38 (m, 2H), 1.68 (m, 3H),
1.95 (m, 1H), 2.36 (s, 3H), 2.87 (m, 2H), 3.25 (m, 2H), 3.48 (m,
1H), 7.24 (m, 3H). LRMS (FAB+) m/z (MH+) 249. The
enantiomeric excess was found to be 80% and was obtained
by HPLC on a Chiralcel OD column (250 × 4.6 mm, i.d.) from
Daicel Co., using n-hexane/isopropyl alcohol 100/1 as eluent
(flow rate 0.5 mL/min) at 254 nm.
1.23 (d, 3H, J ) 6.6 Hz), 1.28 (m, 10H), 1.57 (m, 2H), 2.30 (s,
3H), 2.36 (m, 2H), 3.16 (m, 1H), 3.39 (m, 2H), 4.93 (m, 2H),
5.6-5.79 (m, 2H), 7.08 (bs, 1H), 7.18 (m, 2H). 13C NMR (67.8
MHz, CDCl3) δ 13.9, 20.7, 21.8, 22.5, 26.8, 29.0, 29.1, 29.5,
31.7, 34.7, 39.7, 42.4, 115.9, 126.2, 127.0, 130.3, 135.1, 136.7,
137.1, 141.2, 170.4. HRMS (FAB+) Calcd for C21H34NO (MH+,
316.26422); Found: 316.2630. The enantiomeric excess was
found to be 80% and was obtained by HPLC on a Chiralcel
OD column (250 × 4.6 mm, i.d.) from Daicel Co., using
n-hexane/isopropyl alcohol 400/3 as eluent (flow rate 0.5 mL/
min) at 254 nm. The R-enantiomer was eluted after 76.5 min,
and the S-enantiomer was eluted after 83 min.
Ack n ow led gm en t . We thank Professor Victor
Snieckus (Department of Chemistry, Queen’s Univer-
sity, Canada) for informative discussions and advice.
N -Me t h y l-N -o c t y l-2-(1-a lly l)e t h y l-5-m e t h y lb e n za -
m id e (9). To a 0 °C suspension of NaH (8 mg, 0.2 mmol, 60%
oil suspension) in 0.5 mL of DMF was slowly added 4e (35
mg, 0.1 mmol) in DMF, and the mixture was stirred for 30
min at room temperature. Iodomethane (25 mL, 0.4 mmol) was
added, and the mixture was continuously stirred for 12 h. The
reaction mixture was poured into NH4Cl aq with ice and then
extracted three times with diethyl ether. The combined ether
Su p p or tin g In for m a tion Ava ila ble: Detailed description
of experimental procedures and 1H NMR, 13C NMR spectral
data, and analytical data for N,N-dialkyl-2,5-dimethylbenza-
mides, N-alkyl-m-toluamides, 2a , 2b, 2c, 2d , and 2e. This
material is available free of charge via the Internet at
http://pubs.acs.org.
J O001485C