Stereocontrol in the EtAlCl2-induced cyclization of chiral γ,δ-unsaturated methyl ketones to form cyclopentanones

Article abstract of DOI:10.1021/jo034561v

EtAlCl₂-induced cyclization of chiral γ,δ-unsaturated ketones 11c and 17b takes place mainly from the expected face. The selectivity is modest for 11c (60:40) in which the large substituent is a primary alkyl group and the medium substituent is a methyl group and excellent for 17b (93:7) in which the large substituent is a cyclohexyl group and the medium substituent is a methyl group. The cyclization of 17a is anomalous, suggesting that the phenyl group has more than a simple steric effect.

Full text of DOI:10.1021/jo034561v

SCHEME 1
Ster eocon tr ol in th e EtAlCl2-In d u ced
Cycliza tion of Ch ir a l γ,δ-Un sa tu r a ted
Meth yl Keton es To F or m Cyclop en ta n on es
Barry B. Snider,* Mercedes Lobera, and
Tracy P. Marien
Department of Chemistry, MS 015, Brandeis University,
Waltham, Massachusetts 02454-9110
snider@brandeis.edu
Received April 30, 2003
Abstr a ct: EtAlCl2-induced cyclization of chiral γ,δ-unsatur-
ated ketones 11c and 17b takes place mainly from the
expected face. The selectivity is modest for 11c (60:40) in
which the large substituent is a primary alkyl group and
the medium substituent is a methyl group and excellent for
17b (93:7) in which the large substituent is a cyclohexyl
group and the medium substituent is a methyl group. The
cyclization of 17a is anomalous, suggesting that the phenyl
group has more than a simple steric effect.
We recently reported the EtAlCl2-induced cyclization
of γ,δ-unsaturated methyl ketone 1 to give cyclopen-
tanone 3, which was used for the synthesis of (()-
guanacastepene A (see eq 1).1,2 Ketone 1 reacts with 1.5
equiv of EtAlCl2 to give a very electrophilic R2CdOAlEt2
cation that cyclizes to give tertiary cation 2 as the AlCl4
salt. A 1,2-hydride shift followed by a 1,2-methyl shift
gives cyclopentanone 3 stereospecifically as a single
diastereomer. The relative stereochemistry may be con-
trolled by the preferential addition to give the larger
OAlEt2 substituent on the less hindered side of the
cyclopentane with the adjacent hydrogen. Alternatively,
the cyclization may be reversible with the stereochem-
istry controlled by the preference for the two migrating
substituents to be trans in the Wagner-Meerwein shifts.
oriented perpendicular to the π-bond, the small substitu-
ent is oriented toward the double bond, and the electro-
phile adds from the face opposite to the large substitu-
ent.3 In the 1,3-allylic strain model, the hydrogen is
eclipsed with the cis substituent on the alkene.3 The
electrophile adds preferentially from the face with the
medium methyl substituent rather than the large R
substituent. Both of these models predict that cyclization
of 4‚(EtAlCl2)2 should occur preferentially from the
bottom face to give 5bot, which should rearrange to 6bot.
Assigning the stereochemistry of 6bot and 6top is not
trivial. We therefore decided to examine the cyclization
of 4 with R ) (CH2)3CHMe2 and with R1 as a substituent
that can be converted to either the methyl ketone of 7a
We report here the stereochemical effect of a chiral
center adjacent to the double bond as in 4 (see Scheme
1). The stereochemistry of additions to R-chiral alkenes
has been much less studied and is more poorly under-
stood than additions to R-chiral carbonyl compounds
(Cram or Felkin-Anh rule).3 Additions to alkenes are
more complex than additions to carbonyl compounds
because the addition may be either electrophilic or
nucleophilic, and there are substituents on both ends of
an alkene. In the Houk model, the large substituent is
* To whom correspondence should be addressed. Fax: 781-736-2516.
(1) (a) Snider, B. B.; Hawryluk, N. A. Org. Lett. 2001, 4, 569-572.
(b) Shi, B.; Hawryluk, N. A.; Snider, B. B. J . Org. Chem. 2003, 68,
1030-1042.
(2) For earlier studies on the synthesis of bicyclic systems, see: (a)
Snider, B. B.; Kirk, T. C. J . Am. Chem. Soc. 1983, 105, 2364-2368. (b)
Snider, B. B.; Cartaya-Marin, C. P. J . Org. Chem. 1984, 49, 153-157.
(3) (a) Mengel, A.; Reiser, O. Chem. Rev. 1999, 99, 1191-1223. (b)
Fleming, I. J . Chem. Soc., Perkin Trans. 1 1992, 3363-3369. (c)
Hoffmann, R. W. Chem. Rev. 1989, 89, 1841-1860.
10.1021/jo034561v CCC: $25.00 © 2003 American Chemical Society
Published on Web 07/08/2003
J . Org. Chem. 2003, 68, 6451-6454
6451

SCHEME 2
SCHEME 3
double bond for successful cyclization to give a cyclopen-
tanone.
We then examined the cyclization of 11c that would
give 2-(phenethyl)cyclopentanone 12bot and 12top that
can be converted to acids 13 and 7b, respectively, by
oxidative cleavage of the benzene ring (see Scheme 3).
The benzene ring of 11c is much less reactive toward
electrophiles than the double bonds of 11a and 11b and
should therefore not participate in the cyclization. We
were delighted to find that treatment of 11c with 1.6
equiv of EtAlCl2 in CH2Cl2 for 19 h at 25 °C afforded a
difficultly separable mixture of the expected major prod-
uct 12bot (42%) and minor product 12top (28%). Oxida-
tion of a mixture rich in the minor isomer 12top with
RuO4 afforded mainly the known keto acid 7b, with H
and 13C NMR spectral data identical to those previously
reported.4b,c A similar oxidation of a mixture rich in the
major isomer 12bot afforded mainly keto acid 13 with
distinctly different spectral data.
These results indicate that cyclization of 11c with
EtAlCl2 occurred with 60:40 selectivity in the expected
direction. This selectivity is good considering that the
large (primary alkyl) and medium (methyl) substituents
are very similar in size. Cyclization of 11d with a butyl
side chain gave a 73% yield of a 66:33 mixture of
cyclopentanones. Comparison of spectral data9 indicated
that the major isomer corresponded to 12bot, indicating
that in this case (vide infra) the phenyl substituent has
at most a modest effect on the stereochemistry of the
cyclization.
We next turned our attention to the cyclization of 17a
and 17b, in which the large substituent is either a phenyl
or a cyclohexyl group. Aldehydes 14a and 14b10 were
converted to 17a and 17b as shown in Scheme 4
analogously to the preparation of 11a -d . To our surprise,
cyclization of 17a with 1.8 equiv of EtAlCl2 in CH2Cl2
for 24 h at 25 °C afforded only 18% of the expected major
or the carboxylic acid of 7b. Both 7a and 7b have been
fully characterized because these compounds are inter-
mediates in the syntheses of Grundmann’s ketone and
vitamin D3.4 The (CH2)3CHMe2 side chain was also
synthetically attractive because the requisite γ,δ-unsat-
urated ketone 11 can be easily prepared from (R)-
citronellol.
Reaction of (R)-3,7-dimethyloctanal (8)5 with formalin,
piperidine, and hydrochloric acid6 afforded 98% of (R)-
3,7-dimethyl-2-methyleneoctanal,7 which was treated
with 3-butenyllithium, allylmagnesium bromide, phen-
ethylmagnesium bromide, or n-BuLi to give 9a -d as a
mixture of diastereomers (see Scheme 2). J ohnson ortho
ester Claisen rearrangement of 9a -d with triethyl
orthoacetate and propionic acid at reflux afforded ethyl
ester 10a -d as an 87:13 Z/ E mixture. Hydrolysis with
KOH in aqueous MeOH and reaction of the resulting acid
with 2 equiv of MeLi afforded ketone 11a -d .
The cyclization of 1 to give 2-(4-pentenyl)cyclopen-
tanone 3 established that a terminal double bond is
compatible with these very acidic conditions if three
methylene groups separate it from the cyclopentanone.
We therefore first investigated the cyclization of 11a that
would give a 2-(3-butenyl)cyclopentanone that could be
converted to methyl ketone 7a by a Wacker oxidation.
However, treatment of 11a with EtAlCl2 did not afford
any cyclopentanone, possibly because the cationic inter-
mediate analogous to 2 can cyclize to the double bond
to give a cyclohexyl cation. We then investigated the
cyclization of 11b that would give a 2-(2-propenyl)cyclo-
pentanone that could be converted to acid 7b by hydro-
boration and oxidation. As with 11a , no cyclopentanone
was formed on treatment of 11b with EtAlCl2. This
indicates that at least three methylene groups must be
between a terminal double bond and the trisubstituted
8
1
(8) Carlsen, P. H. J .; Katsuki, T.; Martin, V. S.; Sharpless, K. B. J .
Org. Chem. 1981, 46, 3936-3938.
(4) For 7a , see: (a) Duhamel, P.; Dujardin, G.; Hennequin, L.;
Poirier, J .-M. J . Chem. Soc., Perkin Trans. 1 1992, 387-396. For 7b,
see: (b) Nemoto, H.; Kurobe, H.; Fukumoto, K.; Kametani, T. J . Org.
Chem. 1986, 51, 5311-5320. (c) Grzywacz, P.; Marczak, S.; Wicha, J .
J . Org. Chem. 1997, 62, 5293-5298.
(9) The methyl doublet of the major diastereomer from 11d absorbs
at δ 0.85-0.90. The methyl doublet of the minor diastereomer absorbs
downfield at δ 0.98. The analogous methyl doublet of the minor
diastereomer 12top (δ 1.05) is also downfield from that of the major
isomer 12bot (δ 0.92). The differences between the carbon spectra of
the diastereomers in the two series are similarly analogous.
(10) Aldehyde 14b was prepared by reduction of 14a with NaBH4
(93%), hydrogenation (60 psi) of the alcohol over Rh/Al2O3 (86%), and
PCC oxidation (83%). Hydrogenation of 14a over Rh/Al2O3 was unsuc-
cessful, suggesting that the catalyst was poisoned by decarbonylation.
(5) Tietze, L. F.; Schiemann, K.; Wegner, C.; Wulff, C. Chem. Eur.
J . 1996, 2, 1164-1172.
(6) Riehs, G.; Urban, E. Tetrahedron 1996, 52, 1221-1230.
(7) Blumenthal, J . H. Fr. Patent 1,508,854, 1968; Chem. Abstr. 1969,
70, 37191j.
6452 J . Org. Chem., Vol. 68, No. 16, 2003

SCHEME 4
control in this cyclization when the large substituent is
a secondary alkyl group and the medium substituent is
a methyl group.
The formation of 18top as the major isomer in the
cyclization of 17a may indicate that interactions with the
phenyl group are more complex. The intermediate cation
is a stabilized phenethyl cation. The phenyl group can
also act as a Lewis base and bind to either the Lewis
acid or the ketone-Lewis acid complex. Alternatively, the
planar phenyl substituent might be smaller than the
methyl group in this particular addition reaction. Al-
though Ph is larger than cyclohexyl in the reduction of
PhMeCHCOR and (C6H11)MeCHCOR,11 a flat phenyl
group is smaller than a cyclohexyl group in some aldol
reactions.12
In conclusion, we have shown that in favorable cases
such as 17b, the chiral center in the unsaturated ketone
controls almost completely the newly formed chiral
centers on the cyclopentanone with the expected orienta-
tion. Modest stereocontrol is obtained with 11c in which
the large primary alkyl substituent is similar in size to
the medium methyl substituent. We have also estab-
lished that the phenyl groups of 11c and 17a are
compatible with these cyclizations.
product 18bot and 31% of the expected minor product
18top (see Scheme 5). The remaining material was
recovered 17a and 5-(1-phenylethylidene)nonan-2-one
formed by protonation of the double bond and loss of a
proton to form the styrene.
The structure of 18 was established by NOE experi-
ments. The vicinal coupling constant between the ben-
zylic methine and the cyclopentane methine hydrogens
is 11.0 Hz in both isomers. This established that these
molecules exist largely in the conformations shown with
these hydrogens anti-periplanar. The configuration was
established by an NOE between the methyl singlet and
the phenyl protons in 18bot and the methyl singlet and
the methyl doublet in 18top . In addition, one of the butyl
methylene hydrogens in 18bot is shielded by the adjacent
phenyl ring and absorbs upfield at δ 0.19.
Exp er im en ta l Section
Gen er a l P r oced u r es. NMR spectra were recorded at 400
MHz in CDCl3 unless otherwise indicated; chemical shifts are
reported in δ, coupling constants in Hz, and IR spectra in cm-1
.
(2S,3S)- a n d (2R,3R)-3-(1R,5-Dim eth ylh exyl)-2-m eth yl-
2-p h en eth ylcyclop en ta n on e (12bot a n d 12top ). EtAlCl2
(0.53 mL of a 1.0 M solution in hexanes, 0.53 mmol) was added
dropwise to a solution of ketone 11c as a 93:7 Z/E mixture (105
mg, 0.33 mmol) in CH2Cl2 (7 mL) at 0 °C. The reaction was
stirred at 25 °C for 19 h and poured into an ice-water mixture,
which was extracted with CH2Cl2. The combined extracts were
washed with brine, dried (MgSO4), and concentrated under
reduced pressure to yield 102 mg (97%) of a 3:2 mixture of
diastereomers 12bot and 12top and the recovered minor E-
isomer of 11c. Careful chromatography on Bakerbond Octadecyl
40 µm Prep LC packing (15% H2O-MeOH) yielded a trace of
pure 12bot, 33 mg of a 3:1 mixture of 12bot and 12top , 30 mg
of a 1:1 mixture of 12bot and 12top , 7 mg of a 1:2.2 mixture of
12bot and 12top , and a trace of pure 12top . 13C NMR data were
determined from the mixtures. The optical rotations for both
diastereomers were calculated from the measurements of the
3:1 mixture ([R]20D +10.7 (c 0.205, CHCl3)) and the 1:2.2 mixture
SCHEME 5
([R]20 -7.3 (c 0.250, CHCl3)); HRMS(DEI) calcd for C22H34
O
D
(M+) 314.2610, found 314.2598.
Data for 12bot: 1H NMR (CDCl3) 7.29-7.25 (m, 2), 7.19-
7.15 (m, 3), 2.60 (dt, 1, J ) 4.9, 12.8), 2.40-2.22 (m, 2), 2.16-
1.94 (m, 4), 1.73 (dt, 1, J ) 4.9, 13.5), 1.65-1.37 (m, 5), 1.32-
1.14 (m, 4), 0.95 (s, 3), 0.92 (d, 3, J ) 6.7), 0.88 (d, 6, J ) 6.7);
13C NMR 223.88, 142.26, 128.4 (2 C), 128.3 (2 C), 125.81, 52.2,
46.9, 40.1, 39.2, 37.57, 36.1, 33.5, 31.2, 28.0, 24.8, 22.7, 22.59,
22.45, 18.22, 17.3; IR (CH2Cl2) 1737 cm-1; [R]20 +20.9 (calcu-
D
lated from the rotations of the mixtures).
Data for 12top : 1H NMR (CDCl3) 7.29-7.25 (m, 2), 7.19-
7.15 (m, 3), 2.62 (dt, 1, J ) 4.9, 12.8), 2.40-2.23 (m, 2), 2.16-
1.94 (m, 4), 1.77 (dt, 1, J ) 4.9, 14.0), 1.65-1.37 (m, 5), 1.32-
1.14 (m, 4), 1.05 (d, 3, J ) 6.7), 0.94 (s, 3), 0.894 (d, 3, J ) 6.7),
0.889 (d, 3, J ) 6.7); 13C NMR 223.90, 142.28, 128.4 (2 C), 128.3
(2 C), 125.79, 52.3, 47.0, 40.0, 39.4, 37.62, 34.5, 34.1, 31.4, 28.0,
On the other hand, cyclization of 17b with 1.6 equiv
of EtAlCl2 in CH2Cl2 for 24 h at 25 °C was very selective,
providing 55% of the expected major product 19bot and
<3% of the expected minor product 19top . The structures
were established by hydrogenation (60 psi) of 18bot and
18top over 5% Rh/Al2O3 to afford 19bot and 19top ,
respectively. Thus, there is a very high degree of stereo-
24.0, 23.5, 22.8, 22.5, 18.4, 18.18; IR (CH2Cl2) 1737 cm-1; [R]20
D
-19.9 (calculated from the rotations of the mixtures).
(11) Cherest, M.; Prudent, N. Tetrahedron 1980, 36, 1599-1606.
(12) (a) Gennari, C.; Vieth, S.; Comotti, A.; Vulpetti, A.; Goodman,
J .; Paterson, I. Tetrahedron 1992, 48, 4439-4458. (b) Hoffmann, R.
W.; Stu¨rmer, R.; Harms, K. Tetrahedron Lett. 1994, 35, 6263-6266.
J . Org. Chem, Vol. 68, No. 16, 2003 6453

(2S,3S)- a n d (2R,3R)-3-[2-(1R,5-Dim eth ylh exyl)-1-m eth -
yl-5-oxocyclop en tyl]p r op a n oic Acid (13 a n d 7b). A solution
of the 3:1 mixture of cyclopentanones 12bot and 12top (5 mg,
0.016 mmol) and RuCl3‚3H2O (0.2 mg, 0.001 mmol) in CCl4
(0.064 mL) and CH3CN (0.064 mL) was treated with a solution
of NaIO4 (70 mg, 0.32 mmol) in H2O (0.32 mL) and stirred at 25
°C for 19 h. The reaction mixture was then diluted with H2O
and extracted with CH2Cl2. The combined extracts were con-
centrated under reduced pressure to yield a green residue that
was dissolved in Et2O. The ether solution was extracted with
2% aqueous KOH. The combined aqueous extracts were acidified
with 6 N HCl and extracted with EtOAc. The combined EtOAc
extracts were washed with brine, dried (MgSO4), and concen-
trated under reduced pressure to yield 3 mg (70%) of a 3:1
mixture of acids 13 and 7b.
NOEs to the benzylic methine at δ 2.7 and the methyl doublet
at δ 1.35. Irradiation of the benzylic methine at δ 2.7 showed
NOEs to the aromatic protons at δ 7.23-7.20, the methyl singlet
at δ 1.00, and the methyl doublet at δ 1.35.
Partial data for 5-(1-phenylethylidene)nonan-2-one was de-
termined from the mixture: 1H NMR 7.07 (d, 2, J ) 7.9), 2.58
(t, 2, J ) 7.3), 2.43 (t, 2, J ) 7.3), 2.20 (s, 3), 1.93 (s, 3), 1.83 (t,
2, J ) 7.3), 0.79 (t, 3, J ) 7.3).
A solution of the 1.4:1 mixture of 18bot and 17a (8 mg), and
NaBH4 (0.29 mg, 7.74 × 10-3 mmol), in EtOH (3 mL) was stirred
for 30 min.13 The reaction mixture was concentrated, diluted
with water, and extracted with Et2O. The combined extracts
were washed with brine, dried (MgSO4), and concentrated to
yield 6.2 mg (77%) of 18bot and 5-(1-phenylethyl)-5E-decen-2-
ol. Flash chromatography (95:5 hexanes/EtOAc) gave 3 mg of
pure 18bot: 1H NMR 7.30-7.26 (m, 2), 7.23-7.18 (m, 3), 2.75
(dq, 1, J ) 11.0, 6.7), 2.43-2.37 (m, 2), 2.25 (ddd, 1, J ) 12.2,
9.8, 6.1), 2.04 (ddd, 1, J ) 18, 12.2, 9.2), 1.56 (dddd, 1, J ) 12.2,
12.2, 12.2, 8.5), 1.4-1.26 (m, 2), 1.26-1.17 (m, 1), 1.29 (d, 3, J
) 6.7), 1.05-0.70 (m, 2), 0.89 (s, 3), 0.68 (t, 3, J ) 6.7), 0.19
(ddd, 1, J ) 12.8, 12.8, 3.7); 13C NMR 224.3, 146.4, 128.3 (2 C),
127.2 (2 C), 126.3, 52.4, 46.9, 41.3, 37.8, 35.5, 26.5, 24.4, 22.9,
21.6, 19.3, 13.8. Irradiation of the aromatic hydrogens at δ 7.2
in a 1D NOESY experiment showed NOEs to the methyl doublet
at δ 1.29 and the methyl singlet at δ 0.89. Irradiation of the
benzylic methine at δ 2.75 showed NOEs to the methyl singlet
at δ 0.89, and the methyl doublet at δ 1.29 and the aromatic
protons at δ 7.2. Irradiation of H4a at δ 2.25 showed NOEs to
the methyl doublet at δ 1.29, H4b at δ 1.56, and H5a at δ 2.43.
(2R,3R)-2-Bu tyl-3-(1R*-cycloh exyleth yl)-2-m eth ylcyclo-
p en ta n on e (19bot). EtAlCl2 (0.69 mL of a 1.0 M solution in
hexanes, 0.69 mmol) was added dropwise to a solution of ketone
17b (121 mg, 0.457 mmol) in CH2Cl2 (16.9 mL) at 0 °C. The
reaction was stirred at 25 °C for 24 h and worked up as described
for the cyclization of 11c yielding 112 mg (93%) of a 93:7 mixture
of 19bot and 19top as determined by integration of the δ 2.3-
2.4 region. Flash chromatography (99.7:0.3 hexanes/EtOAc)
yielded 66.5 mg (55%) of 19bot containing a trace of 19top : 1H
NMR 2.32 (dd, 1, J ) 8.6, 17.1), 2.14-1.92 (m, 3), 1.80-1.73
(m, 2), 1.70-1.56 (m, 3), 1.56-1.37 (m, 5), 1.34-0.98 (m, 9), 0.88
(s, 3), 0.87 (t, 3, J ) 7.3), 0.83 (d, 3, J ) 6.7); 13C NMR 224.5,
52.0, 43.6, 41.6, 38.6, 38.1, 37.5, 31.8, 27.8, 27.1, 26.8, 26.72,
A similar experiment sequence was carried out with 5 mg of
the 1:2.2 mixture of 12bot and 12top , yielding 3 mg (70%) of a
1:2.2 mixture of acids 13 and 7b.
1H NMR and 13C NMR data were determined from the
mixtures. The optical rotations for both diastereomers were
calculated from the measurements of the 3:1 mixture ([R]20
D
+20.4 (c 0.200, CHCl3)) and the 1:2.2 mixture ([R]20 -19.6 (c
D
0.100, CHCl3)); HRMS(DEI) calcd for C17H31O3 (MH+) 283.2273,
found 283.2261.
Data for 13: 1H NMR (CDCl3) 2.46-2.30 (m, 2), 2.24-1.96
(m, 4), 1.86-1.70 (m, 2), 1.60-1.09 (m, 9), 0.99 (d, 3, J ) 6.7),
0.94 (s, 3), 0.88 (d, 3, J ) 6.7), 0.87 (d, 3, J ) 6.7); 13C NMR
223.25, 177.5, 51.1, 47.7, 39.1, 37.1, 36.2, 33.3, 32.0, 29.0, 28.0,
24.7, 22.65, 22.58, 22.1, 17.6, 17.1; IR (CH2Cl2) 1732, 1712 cm-1
;
[R]20 +43.0.
D
Data for 7b: 1H NMR (CDCl3) 2.46-2.30 (m, 2), 2.24-1.96
(m, 4), 1.86-1.70 (m, 2), 1.60-1.09 (m, 9), 0.99 (d, 3, J ) 6.7),
0.94 (s, 3), 0.88 (d, 3, J ) 6.7), 0.87 (d, 3, J ) 6.7); 13C NMR
223.25, 177.53, 51.1, 47.8, 39.3, 37.1, 34.3, 33.9, 31.9, 29.6, 27.9,
24.0, 23.2, 22.7, 22.5, 18.5, 17.5; IR (CH2Cl2) 1732, 1712 cm-1
;
1
[R]20 -47.5 (lit.4c -42.3; c 0.85). The H and 13C NMR spectral
D
data are identical to those previously reported.4b,c
(2S,3S)- a n d (2R,3R)-3-(1R,5-Dim eth ylh exyl)-2-m eth yl-
2-bu tylcyclop en ta n on e. EtAlCl2 (0.23 mL of a 1.0 M solution
in hexanes, 0.23 mmol) was added dropwise to a solution of 11d
(40 mg, 0.15 mmol) in CH2Cl2 (3 mL) at 0 °C. The reaction
mixture was stirred for 24 h at 25 °C and worked up as described
above for the cyclization of 11c to yield 39 mg (98%) of crude
cyclopentanones. Flash chromatography (9/1 hexanes/EtOAc)
gave 29 mg (73%) of a 2:1 mixture of (2S,3S)- and (2R,3R)-
diastereomers: 1H NMR (600 MHz, CDCl3) 2.47-2.27 (m, 1),
2.10-1.99 (m, 2), 1.96-1.87 (m, 1), 1.72-1.39 (m, 5), 1.38-1.08
(m, 10), 0.98 (d, 3 × 0.33, J ) 6.4), 0.90-0.85 (m, 12 + 3 × 0.67);
13C NMR (major) 52.1, 46.5, 39.2, 37.70, 37.65, 35.9, 33.4, 28.1,
27.0, 24.6, 23.2, 22.64, 22.62, 22.4, 18.3, 17.3, 14.0; (minor) 52.0,
46.8, 39.4, 37.7, 37.6, 34.5, 34.1, 28.0, 27.2, 24.1, 23.23, 23.20,
22.8, 22.5, 18.2 (2 C), 14.0 (the ketone carbonyls were not
observed).
(2R,3R)- a n d (2S,3S)-2-Bu tyl-2-m eth yl-3-(1R*-p h en yleth -
yl)cyclop en ta n on e (18bot a n d 18top ). EtAlCl2 (0.22 mL of a
1.0 M solution in hexanes, 0.22 mmol) was added dropwise to a
solution of ketone 17a (30 mg, 0.12 mmol) in CH2Cl2 (5 mL) at
0 °C. The reaction was stirred for 24 h and worked up as
described above for the cyclization of 11c to give 43 mg of crude
18. Flash chromatography (99.5:0.5 hexanes/EtOAc) gave 6 mg
of pure 18top , followed by 6 mg of a 4:2.2:1 mixture of 18top ,
5-(1-phenylethylidene)nonan-2-one, and 18bot, and 8 mg of a
1.4:1 mixture of 18bot and recovered 17a . The calculated yields
of 18top and 18bot are 9.3 mg (31%) and 5.5 mg (18%),
respectively. This ratio is consistent with the NMR spectrum of
the crude mixture.
26.68, 23.5, 23.2, 18.5, 13.9, 13.4; HRMS(DEI) calcd for C18H32
264.2453, found 264.2448.
O
Hyd r ogen a tion of 18bot. Cyclopentanone 18bot (2.0 mg,
7.56 × 10-3 mmol), 5% Rh/Al2O3 (12 mg), acetic acid (66 µL),
and EtOH (1.1 mL) were combined and shaken under H2 (60
psi) for 24 h. The reaction mixture was filtered through Celite
1
and concentrated to give 2.0 mg (98%) of 19bot, whose H NMR
spectrum is identical to that obtained from the cyclization of 17b.
(2S,3S)-2-Bu tyl-3-(1R*-cycloh exyleth yl)-2-m eth ylcyclo-
p en ta n on e (19top ). Cyclopentanone 18top (4.0 mg, 1.54 × 10-2
mmol), 5% Rh/Al2O3 (2.3 mg), and acetic acid (60 µL) in EtOH
(1.0 mL) were combined and shaken under H2 (60 psi) for 24 h.
The reaction mixture was filtered through Celite and concen-
trated under reduced pressure to yield 4 mg of 19top : 1H NMR
2.36 (dd, 1, J ) 8.5, 18.3), 2.10-1.95 (m, 3), 1.78-1.56 (m, 6),
1.56-1.19 (m, 12) 1.06-0.98 (m, 1), 0.88 (d, 3, J ) 5.5), 0.87 (s,
3), 0.86 (t, 3, J ) 7.3); 13C NMR 224.7, 52.0, 43.7, 39.4, 38.0,
37.7, 32.2, 29.7, 27.3, 27.2, 26.9, 26.8, 25.7, 24.2, 23.2, 18.5, 13.9,
13.0.
Ack n ow led gm en t. We thank the NIH (GM50151)
for generous financial support.
Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
cedures for the preparation of 11c and 17a ,b. Copies of 1H
and 13C NMR spectra. This material is available free of charge
via the Internet at http://pubs.acs.org.
Data for 18top : 1H NMR 7.34-7.30 (m, 2), 7.23-7.20 (m, 3),
2.70 (dq, 1, J ) 11.0, 6.7), 2.34-2.20 (m, 2), 1.95-1.81 (m, 2),
1.64-1.56 (m, 1), 1.50-1.24 (m, 5), 1.35 (d, 3, J ) 6.7), 1.00 (s,
3), 1.00-0.87 (m, 1), 0.92 (t, 3, J ) 7.3); 13C NMR 224.1, 146.8,
128.5 (2 C), 127.3 (2 C), 126.2, 52.0, 47.4, 42.5, 37.9, 37.5, 27.4,
25.5, 23.3, 21.0, 18.5, 14.0; IR (neat) 1731 cm-1; HRMS(DEI)
calcd for C18H26O (M+) 258.1984, found 258.1980. Irradiation of
the methyl singlet at δ 1.00 in a 1D NOESY experiment showed
J O034561V
(13) The cyclopentanone is very hindered, so that treatment of the
inseparable mixture with NaBH4 reduces 17a to the more polar alcohol
without reducing 18bot.
6454 J . Org. Chem., Vol. 68, No. 16, 2003