Regiocontrolled Synthetic Approach to α,α′-Disubstituted Unsymmetrical Ketones

Full text of DOI:10.1021/jo991559o

J . Org. Chem. 2000, 65, 245-248
245
Notes
Ta ble 1. P r ep a r a tion of th e P r ecu r sor s 3 by Tw o
Su ccessive Alk yla tion s of â-Keto P h osp h on a tes 1
Regiocon tr olled Syn th etic Ap p r oa ch to
r,r′-Disu bstitu ted Un sym m etr ica l Keton es
Shi Yong Lee, Chi-Wan Lee, and Dong Young Oh*
Department of Chemistry, Korea Advanced Institute of
Science and Technology, 373-1, Kusong-dong,
Yusong-gu, Taejon, 305-701, Korea
Received October 7, 1999
The regiospecific alkylation of ketones is a time-
honored thesis in organosynthetic chemistry as a result
of its difficulty arising from polyalkylation, nonregio-
selectivity, self-condensation, etc.1 Many efforts have
been made to seek efficient methods for the alkylation,
many of which involve the introduction of a blocking
group,1a,b the use of regioselective enol ethers as intermedi-
ates,2-4 the employment of nitrogen derivatives of ke-
tones,5 or the utilization of a temporary activating
group.1a,6 Our research has focused on a potential pro-
cedure for the regiospecific R-alkylation of unsymmetrical
ketones that relies upon phosphonate as an activating
group.7 We herein report the first synthetic approach to
R,R′-disubstituted unsymmetrical ketones, whose four
R-substituents are different from each other, via sequen-
tial alkylations and dephosphonylation of â-keto phos-
phonates as outlined in Scheme 1.
product:
entry
substrate: R1, R2, (R3)
R3Br/R4X
yield (%)a
1
2
3
4
5
6
7
8
9
1a : n-Bu, Me
1b: allyl, Et
1c: Me, Et
1d : n-Pr, Ph
1e: -(CH2)3-
2a : n-Bu, Me, prenyl
2a
Me2CdCHCH2Br
PhCHdCHCH2Br
PhCH2Br
CH2dCHCH2Br
PhCHdCHCH2Br
PhCH2Br
2a : 88
2b: 91
2c: 74
2d b: 66
2e: 83c
3a : 95d
3b: 86d
3c: 87e
3d : 89e
3e: 80e
3ff: 94d
3g: 68d
EtI
2b: allyl, Et, cinnamyl
2b
Me2CdCHCH2Br
4-MePhCH2Br
MeCHdCHCH2Br
10
11
12
2c: Me, Et, Bn
2d b: n-Pr, Ph, allyl (R4) PhCHdCHCH2Br
2e: -(CH2)3-, cinnamyl MeI
a
b
Yield of isolated product after chromatography. The unusual
product has the allyl group at the γ-position. c NaHMDS was used
instead of NaH as a base. NaHMDS was used as a base. e LDA
d
was used as a base. f The unusual product has the cinnamyl group
at the R-position.
First, for preparation of the precursors to our desired
ketone products, two consecutive alkylations8 of â-keto
phosphonates9 were carried out step by step. Although
it is possible to selectively alkylate the γ-carbon of the
â-keto phosphonate first via the dianion with the active
R-carbon left just as it is,10 we selected the sequence of
alkylating the R-carbon prior to the γ-carbon for higher
yields. As a base, NaH was used for the R-alkylation, and
NaHMDS (sodium hexamethyldisilazane) or LDA was
used for the γ-alkylation. The R- and γ-alkylation reac-
tions under the conditions of THF, room temperature,
and 2-5 h gave 2 and 3, respectively, in good yields
(Table 1).11 Products of O-alkylation were not obtained
in any case.
* Tel: 82-42-869-2819. Fax: 82-42-869-2810. E-mail: dyoh@
sorak.kaist.ac.kr.
(1) For reviews, see: (a) House, H. O. Modern Synthetic Reactions,
2nd ed.; W. A. Benjamin: Menlo Park, CA, 1972; Chapter 9. (b)
Carruthers, W. Some Modern Methods of Organic Synthesis, 3rd ed.;
Cambridge University Press: New York, 1986; pp 12-38. (c) Caine,
D. In Comprehensive Organic Synthesis; Trost, B. M., Fleming, I.,
Pattenden, G., Eds.; Pergamon Press: Oxford, 1991; Vol. 3, pp 1-63.
(d) d’Angelo, J . Tetrahedron 1976, 32, 2979.
(2) For silyl enol ethers, see: (a) Rasmussen, J . K. Synthesis 1977,
91. (b) House, H. O.; Czuba, L. J .; Gall, M.; Olmstead, H. D. J . Org.
Chem. 1969, 34, 2324. (c) Kuwajima, I.; Nakamura, E.; Shimizu, M.
J . Am. Chem. Soc. 1982, 104, 1025. (d) Corey, E. J .; Gross, A. W.
Tetrahedron Lett. 1984, 25, 495.
Use of excess alkyl halides with equivalent bases
resulted in shortening of the reaction times and height-
ening of the yields without formation of side products
resulting from dialkylation. The γ-phenyl group of sub-
strate 1d activates the γ-carbon as well, and therefore
the formation of R-enolate competes with that of γ-enolate
on treatment with base. Actually, the first alkylation
(3) For enol acetates, see: (a) House, H. O.; Trost, B. M. J . Org.
Chem. 1965, 30, 2502. (b) House, H. O.; Gall, M.; Olmstead, H. D. J .
Org. Chem. 1971, 36, 2361.
(4) For enoxyborates, see: (a) Negishi, E.-i.; Idacavage, M. J .
Tetrahedron Lett. 1979, 845. (b) Negishi, E.-i.; Chatterjee, S. Tetra-
hedron Lett. 1983, 24, 1341.
(5) (a) Whitesell, J . K.; Whitesell, M. A. Synthesis 1983, 517. (b)
Hickmott, P. W. Tetrahedron 1982, 38, 1975 and 3363. (c) Kuehne, M.
E. Synthesis 1970, 510. (d) Smith, J . K.; Newcomb, M.; Bergbreiter,
D. E.; Williams, D. R.; Meyers, A. I. Tetrahedron Lett. 1983, 24, 3559.
(6) (a) Stowell, J . C. Carbanions in Organic Synthesis; Wiley: New
York, 1979; Chapter 6. (b) Krapcho, A. P. Synthesis 1982, 893. (c)
Kurth, M. J .; O’Brien, M. J . J . Org. Chem. 1985, 50, 3846. (d) Fujii,
M.; Nakamura, K.; Mekata, H.; Oka, S.; Ohno, A. Bull. Chem. Soc.
J pn. 1988, 61, 495.
(9) For the preparation of the starting â-keto phosphonates, see: (a)
Savignac, P.; Mathey, F. Tetrahedron Lett. 1976, 17, 2829. (b) Calog-
eropoulou, T.; Hammond, G. B.; Wiemer, D. F. J . Org. Chem. 1987,
52, 4185.
(7) (a) Hong, J . E.; Shin, W. S.; J ang, W. B.; Oh, D. Y. J . Org. Chem.
1996, 61, 2199. (b) Lee, S. Y.; Hong, J . E.; Shin, W. S.; Oh, D. Y.
Tetrahedron Lett. 1997, 38, 4567. (c) Lee, S. Y.; Lee, C.-W.; Oh, D. Y.
J . Org. Chem. 1999, 64, 7017.
(8) For the R-alkylation of â-keto phosphonates, see: (a) Clack, R.
D.; Kozar, L. G.; Heathcock, C. H. Synthesis 1975, 635. (b) Ruder, S.
M.; Kulkarni, V. R. Synthesis 1993, 945.
(10) Grieco, P. A.; Pogonowski, C. S. J . Am. Chem. Soc. 1973, 95,
3071.
(11) With phenylselenenyl bromide as an alkylating agent, the
R-phenylselenenyl â-keto phosphonate was successfully obtained as a
product of the first R-alkylation in 68% yield. However, treatment of
this product with base for the second alkylation resulted in decomposi-
tion of it, yielding a complicated mixture.
10.1021/jo991559o CCC: $19.00 © 2000 American Chemical Society
Published on Web 12/15/1999

246 J . Org. Chem., Vol. 65, No. 1, 2000
Notes
Sch em e 1
Ta ble 2. Dep h osp h on yla tion of 3 in to Keton es 4
slowly. The mixture was stirred until hydrogen evolution had
ceased and the solution was homogeneous (ca. 1 h). Addition of
the proper alkyl bromide (4.0 mmol) was followed by stirring of
the reaction mixture for 2-4 h. An aqueous ammonium chloride
solution (2 mL) was added, and the resulting solution was
extracted with diethyl ether (30 mL × 3). The combined organic
extracts were washed with water (5 mL × 2) and dried over
magnesium sulfate. After evaporation of the solvent, the residue
was chromatographed on a silica gel column using an EtOAc/
hexane mixture as eluent to give the pure product 2 as a colorless
oil.
P h osp h on a te 2a . Using the general procedure described
above and a reaction time of 4 h, 2a was obtained (0.585 g, 88%)
from 1a (0.529 g, 2.0 mmol) and prenyl bromide (0.48 mL, 4.0
mmol) after chromatography (EtOAc/hexane, 35/65): 1H NMR
(300 MHz, CDCl3) δ 0.85 (t, J ) 7.1 Hz, 3H), 1.00 (t, J ) 7.2 Hz,
3H), 1.06-1.15 (m, 1H), 1.20-1.39 (several peaks, 9H), 1.61 (s,
3H), 1.65 (s, 3H), 1.80-1.90 (m, 2H), 2.57-2.68 (several peaks,
4H), 4.01-4.12 (m, 4H), 5.05 (br t, J ) 6.6 Hz, 1H); 13C NMR
(75 MHz, CDCl3) δ 8.1, 13.8, 16.4 (d, J ) 5.9 Hz), 17.9, 23.3,
26.0, 26.5 (d, J ) 7.8 Hz), 29.2, 30.7 (d, J ) 3.9 Hz), 33.0, 58.3
(d, J ) 126.6 Hz), 62.3 (dd, J ) 3.7, 7.3 Hz), 118.9 (d, J ) 35.7
Hz), 133.9, 208.8.
P h osp h on a te 2b. Using the general procedure described
above and a reaction time of 2 h, 2b was obtained (0.689 g, 91%)
from 1b (0.525 g, 2.0 mmol) and cinnamyl bromide (0.813 g, 4.0
mmol) after chromatography (EtOAc/hexane, 35/65): 1H NMR
(300 MHz, CDCl3) δ 0.89 (t, J ) 7.3 Hz, 3H), 1.28 (t, J ) 7.0 Hz,
6H), 1.59 (sextet, J ) 7.3 Hz, 2H), 2.64-2.88 (several peaks,
6H), 4.05-4.15 (m, 4H), 5.07-5.14 (m, 2H), 5.72-5.85 (m, 1H),
6.13-6.24 (m, 1H), 6.43 (d, J ) 15.8 Hz, 1H), 7.15-7.31 (m, 5H);
13C NMR (75 MHz, CDCl3) δ 13.7, 16.4 (d, J ) 5.8 Hz), 17.1,
34.4, 35.5, 42.0, 58.3 (d, J ) 127.3 Hz), 62.5 (d, J ) 7.2 Hz),
118.7, 125.1 (d, J ) 8.6 Hz), 126.0, 127.1, 128.4, 132.9 (d, J )
9.8 Hz), 133.4, 137.3, 206.9.
P h osp h on a te 2c. Using the general procedure described
above and a reaction time of 3 h, 2c was obtained (0.483 g, 74%)
from 1c (0.473 g, 2.0 mmol) and benzyl bromide (0.48 mL, 4.0
mmol) after chromatography (EtOAc/hexane, 50/50): 1H NMR
(300 MHz, CDCl3) δ 0.84 (t, J ) 7.3 Hz, 3H), 1.27-1.37 (several
peaks, 9H), 1.52 (sextet, J ) 7.3 Hz, 2H), 2.25-2.36 (m, 1H),
2.60-2.71 (m, 1H), 2.83 (dd, J ) 10.4, 13.4 Hz, 1H), 3.67 (dd, J
) 7.8, 13.5 Hz, 1H), 4.06-4.19 (m, 4H), 7.03-7.06 (m, 2H), 7.16-
7.24 (m, 3H); 13C NMR (75 MHz, CDCl3) δ 13.5, 16.4 (d, J ) 5.6
Hz), 16.5 (d, J ) 5.2 Hz), 16.9, 38.5 (d, J ) 4.7 Hz), 42.4, 55.0
(d, J ) 125.6 Hz), 62.8 (dd, J ) 7.4, 19.2 Hz), 126.7, 128.1, 130.4,
136.3 (d, J ) 15.4 Hz), 208.4.
P h osp h on a te 2d . Using the general procedure described
above and a reaction time of 4 h, unusually γ-alkylated 2d was
obtained (0.465 g, 66%) from 1d (0.625 g, 2.0 mmol) and allyl
bromide (0.35 mL, 4.0 mmol) after chromatography (EtOAc/
hexane, 35/65): 1H NMR (300 MHz, CDCl3) δ 0.46-0.49 (m, 3H),
0.77-0.90 (m, 1H), 1.13-1.35 (several peaks, 7H), 1.39-1.50 (m,
1H), 1.84-1.95 (m, 1H), 2.42-2.52 (m, 1H), 2.73-2.83 (m, 1H),
3.22 (ddd, J ) 3.1, 10.9, 25.4 Hz, 1H), 4.01-4.15 (m, 5H), 4.87-
5.01 (m, 2H), 5.55-5.68 (m, 1H), 7.15-7.31 (m, 5H); 13C NMR
(75 MHz, CDCl3) δ 13.2, 16.4 (d, J ) 6.2 Hz), 20.6 (d, J ) 15.1
Hz), 27.7, 35.9, 50.6 (d, J ) 122.0 Hz), 59.8, 62.6 (t, J ) 7.0 Hz),
116.4, 127.6, 128.9, 128.9, 135.7, 136.9, 203.6.
P h osp h on a t e 2e.7c To a stirred solution of diethyl 2-oxo-
cyclohexylphosphonate (1e; 0.468 g, 2.0 mmol) in dry THF (8
mL) under N2 at 0 °C was added NaHMDS (2.0 mL of a 1.0 M
solution in THF, 2.0 mmol) dropwise. After being stirred for 1
h, the mixture was allowed to warm slowly to room temperature.
Cinnamyl bromide (0.813 g, 4.0 mmol) was added, and the
reaction mixture was stirred for 4 h. Hereafter, the same workup
and purification by chromatography (EtOAc/hexane, 50/50) as
for the general procedure gave pure 2e (0.582 g, 83%): 1H NMR
(300 MHz, CDCl3) δ 1.27-1.34 (m, 6H), 1.52-1.71 (m, 2H), 1.80-
product:
substrate
R1
R2
R3
R4
yield (%)a
3a
3b
3c
3d
3e
3f
n-Bu
n-Bu
allyl
allyl
Me
n-Pr
-(CH2)3-
Me
Me
Et
Et
Et
prenyl
prenyl
Bn
Et
prenyl
4-MeBn
crotyl
allyl
4a : 71b
4b: 43b
4c: 53c
4d : 62c
4e: 45c
4f: 73b
4g: 55b
cinnamyl
cinnamyl
Bn
cinnamyl
cinnamyl
Ph
3g
Me
a
b
Yield of isolated product after chromatography. NaHMDS
was used as a base. c LiHMDS was used as a base.
occurred at the γ-carbon unusually (entry 4). Further-
more, on being treated with base for the second alkylation
(entry 11), 2d underwent R-deprotonation although a
γ-hydrogen remained, leading to R-alkylation against our
expectation.
Dephosphonylation of the resultant precursors 3 af-
fording the corresponding ketones 4 was accomplished
by treatment of their sodium or lithium enolates with
LAH (lithium aluminum hydride) followed by acidic
quenching (Table 2). Compared with our previous re-
sults,7 not only were the yields somewhat low but also
the choice of the base was important. NaHMDS or
LiHMDS was successfully employed as a base, but use
of more common bases such as n-BuLi and LDA led to
decomposition of 3 to give a complicated mixture. All of
the ketone products except 4g2c have four R-substituents
that are different from each other. These substituents
can be readily varied to the extent that â-keto phospho-
nates9,10 and alkylating agents are available.
In conclusion, we have developed a regiocontrollable
synthetic route to R,R′-disubstituted unsymmetrical ke-
tones involving temporary use of phosphonate as an
activating group. The procedure, containing two succes-
sive alkylations and dephosphonylation of â-keto phos-
phonates, is a complement of existing methods for the
regiospecific alkylation of unsymmetrical ketones and
furnishes ready access to structures not previously avail-
able in ketones.
Exp er im en ta l Section
Gen er a l. All reactions were conducted under an atmosphere
of nitrogen in oven-dried glassware with magnetic stirring. THF
was dried over and distilled from sodium metal with benzophe-
none as the indicator. 1H and 13C NMR spectra were recorded
in CDCl3 using TMS (0 ppm), residual CHCl3 (7.24 ppm), or
solvent (77.0 ppm) as an internal standard. The starting â-keto
phosphonates were prepared as described in the literature with
minor modification.
Gen er a l P r oced u r e for th e r-Alk yla tion of â-Keto P h os-
p h on a tes. To a suspension of sodium hydride (0.060 g, 80%,
2.0 mmol) in dry THF (5 mL) under N2 at room temperature
was added â-keto phosphonate 1 (2.0 mmol) in dry THF (5 mL)

Notes
J . Org. Chem., Vol. 65, No. 1, 2000 247
2.02 (m, 2H), 2.07-2.34 (m, 2H), 2.38-2.53 (m, 2H), 2.78-2.89
(m, 1H), 2.94-3.05 (m, 1H), 4.04-4.20 (m, 4H), 6.04-6.15 (m,
1H), 6.37 (d, J ) 15.8 Hz, 1H), 7.15-7.32 (m, 5H); 13C NMR (75
MHz, CDCl3) δ 16.4 (t, J ) 6.1 Hz), 21.5 (d, J ) 2.4 Hz), 25.8,
31.9 (d, J ) 4.4 Hz), 36.6 (d, J ) 3.7 Hz), 41.2, 55.7 (d, J ) 124.8
Hz), 62.7 (d, J ) 7.1 Hz), 125.4 (d, J ) 9.8 Hz), 126.1, 127.2,
128.4, 133.6, 137.2, 208.4.
Gen er a l P r oced u r e for th e γ-Alk yla tion of â-Keto P h os-
p h on a tes. To a stirred solution of phosphonate 2 (1.0 mmol) in
dry THF (8 mL) under N2 at -78 °C was added NaHMDS (1.0
mL of a 1.0 M solution in THF, 1.0 mmol) or LDA (0.50 mL of
125.0 (d, J ) 8.0 Hz), 126.0 (d, J ) 1.4 Hz), 127.1, 128.4, 128.9
(d, J ) 2.7 Hz), 129.1 (d, J ) 1.5 Hz), 133.1 (d, J ) 8.6 Hz),
133.3 (d, J ) 5.3 Hz), 135.6 (d, J ) 2.8 Hz), 136.7 (d, J ) 5.9
Hz), 137.3 (d, J ) 8.0 Hz), 209.9 (d, J ) 2.5 Hz).
P h osp h on a te 3e. Using the general procedure described
above, with a reaction time of 3 h and LDA as a base, 3e was
obtained (0.304 g, 80%) from 2c (0.326 g, 1.0 mmol) and crotyl
bromide (0.24 mL, 2.0 mmol) after chromatography (EtOAc/
hexane, 35/65): 1H NMR (300 MHz, CDCl3) δ 0.53-0.59 (m, 3H),
1.00-1.23 (m, 2H), 1.28-1.34 (m, 6H), 1,46 (d, J ) 17.9 Hz, 3H),
1.59 (d, J ) 6.1 Hz, 3H), 2.05-1.13 (m, 1H), 2.23-2,31 (m, 1H),
2.80 (dd, J ) 10.3, 13.3 Hz, 2H), 3.70 (dd, J ) 8.1, 13.2 Hz, 1H),
4.05-4.19 (m, 4H), 5.27-5.46 (m, 2H), 7.10-7.23 (m, 5H); 13C
NMR (75 MHz, CDCl3) δ 10.8, 16.4 (d, J ) 5.2 Hz), 16.5, 17.9,
23.4, 33.9, 37.7 (d, J ) 4.4 Hz), 48.3, 55.6 (d, J ) 123.1 Hz),
62.8 (d, J ) 7.5 Hz), 126.5, 126.6, 127.8, 128.8, 131.1, 136.6 (d,
J ) 14.6 Hz), 210.7.
P h osp h on a te 3f. Using the general procedure described
above, with a reaction time of 2 h and NaHMDS as a base,
unusually R-alkylated 3f was obtained (0.440 g, 94%) as a
mixture of diastereomeric isomers (de 20% determined by NMR
analysis) from 2d (0.352 g, 1.0 mmol) and cinnamyl bromide
(0.406 g, 2.0 mmol) after chromatography (EtOAc/hexane, 25/
75): 1H NMR (300 MHz, CDCl3) δ 0.48 (t, J ) 6.4 Hz, 3 × 2/5H),
0.82 (t, J ) 7.2 Hz, 3 × 3/5H), 1.12-1.34 (several peaks, 8H),
1.12-1.41 (m, 2H), 2.52-2.93 (several peaks, 4H), 3.97-4.18 (m,
4H), 4.43-4.52 (m, 1H), 4.84-4.95 (m, 2H), 5.49-5.61 (m, 1H),
5.80-5.90 (m, 3/5H), 6.08-6.18 (m, 2/5H), 6.17 (d, J ) 15.9 Hz,
3/5H), 6.39 (d, J ) 15.9 Hz, 2/5H), 7.12-7.30 (several peaks,
10H); 13C NMR (75 MHz, CDCl3) δ 14.0, 14.6, 16.3 (d, J ) 5.7
Hz), 17.4 (d, J ) 8.3 Hz), 32.6, 33.0, 33.7, 34.3, 39.9, 40.0, 54.7,
59.7 (d, J ) 126.7 Hz), 59.7 (d, J ) 126.7 Hz), 60.1 (d, J ) 127.2
Hz), 62.4 (d, J ) 7.3 Hz), 116.5, 116.6, 124.8 (d, J ) 8.3 Hz),
126.0, (d, J ) 2.3 Hz), 126.9, 127.0 (d, J ) 4.9 Hz), 128.3 (d, J
) 7.4 Hz), 128.5 (d, J ) 14.3 Hz), 132.6, 132.8, 135.6 (d, J ) 7.0
Hz), 137.1, 137.5, 138.2, 206.8 (d, J ) 21.1 Hz).
P h osp h on a te 3g. Using the general procedure described
above, with a reaction time of 5 h and NaHMDS as a base, 3g
was obtained (0.247 g, 68%) as a mixture of diastereomeric
isomers (de 25% determined by NMR analysis) from 2e (0.350
g, 1.0 mmol) and methyl iodide (0.25 mL, 4.0 mmol) after
chromatography (EtOAc/hexane, 40/60): 1H NMR (300 MHz,
CDCl3) δ 1.02-1.06 (m, 3H), 1.20-1.37 (several peaks, 7H),
1.53-2.09 (several peaks, 4H), 2.20-2.38 (m, 2H), 2.42-2.54 (m,
1H), 3.00-3.12 (m, 1H), 4.00-4.19 (m, 4H), 5.95-6.15 (m, 1H),
6.37 (dd, J ) 15.8, 6.3 Hz, 1H), 7.15-7.31 (m, 5H); 13C NMR
(75 MHz, CDCl3) δ 15.1, 16.4 (d, J ) 5.7 Hz), 18.4, 21.8, 27.6,
30.0 (d, J ) 3.7 Hz), 32.8 (d, J ) 4.3 Hz), 35.0, 36.9, 37.8, 39.4
(d, J ) 4.5 Hz), 44.4, 45.1, 55.8 (d, J ) 123.3 Hz), 62.6 (d, J )
6.8 Hz), 125.0, 126.0, 126.1, 127.1, 127.3, 128.4, 128.5, 133.5,
134.0, 137.1, 137.4, 209.4.
Gen er a l P r oced u r e for th e Dep h osp h on yla tion of Tet-
r a su bstitu ted â-Keto P h osp h on a tes. NaHMDS (0.50 mL of
a 1.0 M solution in THF, 0.50 mmol) or LiHMDS (0.50 mL of a
1.0 M solution in THF, 0.50 mmol) was added dropwise to a
stirred solution of phosphonate 3 (0.50 mmol) in dry THF (3 mL)
under N2 at -78 °C. The mixture was allowed to warm slowly
to 0 °C, and then LiAlH4 (1.5 mL of a 1.0 M solution in THF,
1.5 mmol) was added. The cooling bath was removed, and the
reaction mixture was stirred at room temperature for 1 h. An
aqueous H2SO4 solution (5 N, 2 mL) was added, and the resulting
solution was extracted with diethyl ether (20 mL × 3). The
combined organic extracts were washed with saturated NaHCO3
solution (2 mL) and water (3 mL × 2), dried over magnesium
sulfate, and concentrated. Purification of the residue by flash
silica gel chromatography furnished the ketone 5 as a colorless
oil.
a
2.0 M solution in heptane/THF/ethylbenzene, 1.0 mmol)
dropwise. The mixture was allowed to warm slowly for about 1
h to -40 °C, and then alkyl halide (2.0 mmol) was added. The
cooling bath was removed, and the mixture was stirred at room
temperature for 2-5 h. An aqueous ammonium chloride solution
(2 mL) was added, and the resulting solution was extracted with
diethyl ether (20 mL × 3). The combined organic extracts were
washed with water (5 mL × 2), dried over magnesium sulfate,
and concentrated. The residue was chromatographed on a silica
gel column using an EtOAc/hexane mixture as eluent to give
the pure product 3 as a colorless oil.
P h osp h on a te 3a . Using the general procedure described
above, with a reaction time of 5 h and NaHMDS as a base, 3a
was obtained (0.313 g, 95%) from 2a (0.259 g, 0.78 mmol) and
benzyl bromide (0.19 mL, 1.6 mmol) after chromatography
(EtOAc/hexane, 30/70): 1H NMR (300 MHz, CDCl3) δ 0.84 (dt,
J ) 2.0, 7.1 Hz, 3H), 0.96 (dd, J ) 2.4, 6.6 Hz, 3H), 1.03-1.16
(m, 1H), 1.19-1.40 (several peaks, 9H), 1.60 (s, 3H), 1.66 (s, 3H),
1.79-1.95 (m, 2H), 2.43-2.66 (several peaks, 3H), 2.90-2.98 (m,
1H), 3.43-3.53 (m, 1H), 4.06-4.16 (m, 4H), 5.03 (br dt, J ) 26.0,
6.5 Hz, 1H), 7.15-7.28 (m, 5H); 13C NMR (75 MHz, CDCl3) δ
13.8, 16.4, 17.5 (d, J ) 10.0 Hz), 18.0, 23.3 (d, J ) 4.6 Hz), 25.9,
26.4 (d, J ) 6.5 Hz), 28.6 (d, J ) 14.3 Hz), 30.1, 40.2 (d, J ) 7.0
Hz), 43.8, 58.9 (d, J ) 126.8 Hz), 62.3 (d, J ) 6.9 Hz), 118.9 (d,
J ) 9.2 Hz), 126.1, 128.3, 129.3, 133.7 (d, J ) 14.6 Hz), 139.9
(d, J ) 3.2 Hz), 211.9.
P h osp h on a te 3b. Using the general procedure described
above, with a reaction time of 5 h and NaHMDS as a base, 3b
was obtained (0.233 g, 86%) from 2a (0.249 g, 0.75 mmol) and
ethyl iodide (0.12 mL, 1.5 mmol) after chromatography (EtOAc/
hexane, 25/75): 1H NMR (300 MHz, CDCl3) δ 0.86 (t, J ) 7.5
Hz, 6H), 1.01 (d, J ) 6.6 Hz, 3H), 1.07-1.18 (m, 1H), 1.19-1.43
(several peaks, 10H), 1.54-1.61 (m, 1H), 1.61 (s, 3H), 1.65 (s,
3H), 1.76-1.94 (m, 2H), 2.58-2.65 (m, 2H), 3.01-3.09 (m, 1H),
4.03-4.13 (m, 4H), 5.03-5.09 (m, 1H); 13C NMR (75 MHz,
CDCl3) δ 11.5 (d, J ) 4.4 Hz), 13.9, 16.4 (d, J ) 5.7 Hz), 17.0,
18.0, 23.3, 26.0, 26.5, 27.0, 28.7, 30.1, 43.2, 58.7 (d, J ) 126.6
Hz), 62.2, 119.1 (d, J ) 9.3 Hz), 133.6 (d, J ) 4.0 Hz), 212.5.
P h osp h on a te 3c. Using the general procedure described
above, with a reaction time of 5 h and LDA as a base, 3c was
obtained (0.276 g, 87%) from 2b (0.269 g, 0.71 mmol) and prenyl
bromide (0.18 mL, 1.4 mmol) after chromatography (EtOAc/
hexane, 25/75): 1H NMR (300 MHz, CDCl3) δ 0.85 (dt, J ) 3.5,
7.4 Hz, 3H), 1.21-1.30 (m, 6H), 1.40-1.52 (m, 1H), 1.56-1.74
(several peaks, 7H), 2.09-2.31 (several peaks, 2H), 2.69-2.90
(several peaks, 4H), 3.02-3.11 (m, 1H), 4.05-4.15 (m, 4H), 5.03-
5.13 (several peaks, 3H), 5.74-5.86 (m, 1H), 6.12-6.24 (m, 1H),
6.43 (d, J ) 15.8 Hz, 1H), 7.17-7.31 (m, 5H); 13C NMR (75 MHz,
CDCl3) δ 11.5 (d, J ) 2.7 Hz), 16.4 (d, J ) 5.9 Hz), 17.8, 24.7 (d,
J ) 2.6 Hz), 25.7 (d, J ) 4.9 Hz), 30.1, 34.2, 35.2, 49.0, 58.5 (d,
J ) 127.0 Hz), 62.4 (d, J ) 7.2 Hz), 118.5, 122.0 (d, J ) 8.1 Hz),
125.1 (d, J ) 7.7 Hz), 126.1, 127.1 (d, J ) 3.3 Hz), 128.4 (d, J )
1.9 Hz), 133.0, 133.1 (d, J ) 10.3 Hz), 133.3, 137.3, 210.2.
P h osp h on a te 3d . Using the general procedure described
above, with a reaction time of 5 h and LDA as a base, 3d was
obtained (0.339 g, 89%) from 2b (0.299 g, 0.79 mmol) and
4-methylbenzyl bromide (0.30 g, 1.6 mmol) after chromatography
(EtOAc/hexane, 25/75): 1H NMR (300 MHz, CDCl3) δ 0.80-0.88
(m, 3H), 1.24-1.31 (m, 6H), 1.40-1.50 (m, 1H), 1.60-1.69 (m,
1H), 2.23-2.28 (m, 3H), 2.43-2.85 (several peaks, 5H), 2.90-
2.98 (m, 1H), 3.32-3.41 (m, 1H), 4.08-4.15 (m, 4H), 4.97-5.11
(m, 2H), 5.67-5.80 (m, 1H), 6.04-6.15 (m, 1H), 6.37 (dd, J )
15.8, 23.8 Hz, 1H), 6.95-7.07 (m, 4H), 7.15-7.30 (m, 5H); 13C
NMR (75 MHz, CDCl3) δ 11.3, 16.3 (d, J ) 5.9 Hz), 20.9 (d, J )
3.7 Hz), 24.5, 34.0 (dd, J ) 3.1, 8.5 Hz), 35.2, 37.3 (d, J ) 10.1
Hz), 50.7, 58.4 (d, J ) 127.5 Hz), 62.4 (d, J ) 7.4 Hz), 118.4,
Keton e 4a . Using the general procedure described above and
NaHMDS as a base, 4a was obtained (0.102 g, 71%) as a mixture
of diastereomeric isomers (1:1 determined by NMR analysis)
from 3a (0.211 g, 0.50 mmol) after chromatography (EtOAc/
hexane, 1/40): 1H NMR (300 MHz, CDCl3) δ 0.77 (t, J ) 7.2 Hz,
3 × 1/2H), 0.84 (t, J ) 7.1 Hz, 3 × 1/2H), 0.93-1.03 (several
peaks, 4H), 1.08-1.33 (several peaks, 5H), 1.50 (s, 3 × 1/2H),
1.56 (s, 3 × 1/2H), 1.63 (d, J ) 3.2 Hz, 3H), 1.85-1.95 (m, 1H),
2.02 (sextet, J ) 7.2 Hz, 2H), 2.18-2.29 (m, 1H), 2.43-2.55 (m,
2H), 2.82-2.91 (m, 1H), 2.91-3.00 (m, 1H), 4.87 (tt, J ) 7.3,

248 J . Org. Chem., Vol. 65, No. 1, 2000
Notes
1.2 Hz, 1/2H), 4.98 (tt, J ) 7.3, 1.3 Hz, 1/2H), 7.13-7.27 (m,
5H); 13C NMR (75 MHz, CDCl3) δ 13.8, 13.9, 16.2, 16.3, 17.7,
22.8, 22.9, 25.7, 29.3, 29.7, 29.8, 30.5, 30.7, 38.4, 38.6, 48.2, 48.3,
51.6, 121.7, 121.9, 126.1, 128.3, 129.1, 133.1, 133.2, 140.1, 217.0;
HRMS m/z (M+) calcd for C20H30O 286.2297, found 286.2296.
Keton e 4b. Using the general procedure described above and
NaHMDS as a base, 4b was obtained (0.048 g, 43%) as a mixture
of diastereomeric isomers (1:1 determined by NMR analysis)
from 3b (0.180 g, 0.50 mmol) after chromatography (EtOAc/
hexane, 1/50): 1H NMR (300 MHz, CDCl3) δ 0.80-0.88 (several
peaks, 6H), 0.99 (t, J ) 7.1 Hz, 3H), 1.17-1.34 (several peaks,
7H), 1.53-1.69 (several peaks, 7H), 1.96-2.08 (m, 1H), 2.16-
2.27 (m, 1H), 2.43-2.50 (m, 1H), 2.53-2.61 (m, 1H), 4.98-5.06
(m, 1H); 13C NMR (75 MHz, CDCl3) δ 11.7, 11.8, 13.9, 15.4, 15.6,
17.7, 22.9, 25.3, 25.7, 29.7, 30.0, 30.1, 30.7, 30.9, 47.6, 51.1, 121.9,
133.0. 208.7; HRMS m/z (M+) calcd for C15H28O 224.2140, found
224.2136.
Keton e 4c. Using the general procedure described above and
LiHMDS as a base, 4c was obtained (0.082 g, 53%) as a mixture
of diastereomeric isomers (1:1 determined by NMR analysis)
from 3c (0.223 g, 0.50 mmol) after chromatography (EtOAc/
hexane, 1/40): 1H NMR (300 MHz, CDCl3) δ 0.78-0.86 (m, 3H),
1.34-1.46 (m, 1H), 1.52-1.65 (several peaks, 7H), 2.00-2.07 (m,
1H), 2.11-2.56 (several peaks, 6H), 2.70-2.79 (m, 1H), 4.96-
5.08 (several peaks, 3H), 5.63-5.77 (m, 1H), 6.01-6.13 (m, 1H),
6.38 (d, J ) 15.8 Hz, 1H), 7.12-7.29 (m, 5H); 13C NMR (75 MHz,
CDCl3) δ 11.8, 17.7, 23.4, 23.5, 25.7, 29.0, 33.9, 34.9, 51.2, 51.3,
53.4, 117.0, 117.1, 121.7, 121.9, 126.0, 127.1, 127.4, 128.4, 128.5,
132.1, 132.2, 133.2, 133.3, 135.6, 137.4, 215.2; HRMS m/z (M+)
calcd for C22H30O 310.2297, found 310.2265.
Keton e 4d . Using the general procedure described above and
LiHMDS as a base, 4d was obtained (0.107 g, 62%) as a mixture
of diastereomeric isomers (de 23% determined by NMR analysis)
from 3d (0.241 g, 0.50 mmol) after chromatography (EtOAc/
hexane, 1/40): 1H NMR (300 MHz, CDCl3) δ 0.81-0.90 (m, 3H),
1.37-1.50 (m, 1H), 1.56-1.70 (m, 1H), 1.93-2.21 (m, 2H), 2.23-
2.63 (several peaks, 7H), 2.78-2.92 (m, 2H), 4.87-4.94 (m, 1H),
4.98-5.06 (m, 1H), 5.43-5.55 (m, 5/13H), 5.61-5.73 (m, 1H),
6.00-6.12 (m, 8/13H), 6.22 (d, J ) 15.8 Hz, 5/13H), 6.36 (d, J )
15.8 Hz, 8/13H), 6.97-7.06 (m, 4H), 7.14-7.30 (m, 5H); 13C NMR
(75 MHz, CDCl3) δ 11.6, 21.0, 23.8, 23.9, 33.7, 34.4, 34.7, 36.0,
36.1, 51.5, 55.1, 117.0, 117.1, 126.0, 127.1, 127.4, 128.4, 128.5,
129.0, 132.0, 132.2, 135.4, 135.6, 135.7, 136.9, 137.3, 214.8;
HRMS m/z (M+) calcd for C25H30O 346.2297, found 346.2293.
Keton e 4e. Using the general procedure described above and
LiHMDS as a base, 4e was obtained (0.055 g, 45%) as a mixture
of diastereomeric isomers (1:1 determined by NMR analysis)
from 3e (0.190 g, 0.50 mmol) after chromatography (EtOAc/
hexane, 1/40): 1H NMR (300 MHz, CDCl3) δ 0.66 (t, J ) 7.4 Hz,
3 × 1/2H), 0.79 (t, J ) 7.4 Hz, 3 × 1/2H), 0.99-1.04 (m, 3H),
1.36-1.65 (several peaks, 5H), 1.85-1.96 (m, 1/2H), 1.97-2.11
(m, 1H), 2.17-2.28 (m, 1/2H), 2.46 (dd, J ) 7.4, 13.3 Hz, 2H),
2.78-2.90 (m, 1H), 2.91-3.02 (m, 1H), 4.98-5.52 (several peaks,
2H), 7.12-7.27 (m, 5H); 13C NMR (75 MHz, CDCl3) δ 11.5, 11.9,
16.2, 17.9, 23.6, 23.7, 33.8, 34.2, 38.7, 48.1, 48.2, 53.0, 126.1,
127.1, 128.3, 128.4, 129.1, 140.0, 216.6; HRMS m/z (M+) calcd
for C17H24O 244.1827, found 244.1828.
Keton e 4f. Using the general procedure described above and
NaHMDS as a base, 4f was obtained (0.121 g, 73%) as a mixture
of diastereomeric isomers (1:1 determined by NMR analysis)
from 3f (0.234 g, 0.50 mmol) after chromatography (EtOAc/
hexane, 1/50): 1H NMR (300 MHz, CDCl3) δ 0.57 (t, J ) 7.1 Hz,
3 × 1/2H), 0.89 (t, J ) 7.1 Hz, 3 × 1/2H), 1.17-1.64 (several
peaks, 4H), 2.05-2.15 (m, 1/2 H), 2.20-2.46 (several peaks, 2 +
1/2H), 2.65-2.84 (several peaks, 2H), 3.74 (dt, J ) 2.1, 7.5 Hz,
1H), 4.84-5.03 (m, 2H), 5.51-5.71 (several peaks, 1 + 1/2H),
6.03-6.14 (several peaks, 1H), 6.36 (d, J ) 15.7 Hz, 1/2H), 7.06-
7.31 (several peaks, 10H); 13C NMR (75 MHz, CDCl3) δ 13.8,
14.2, 20.0, 20.4, 32.6, 34.1, 35.9, 36.5, 50.6, 50.8, 59.0, 59.2, 116.6,
126.0, 126.8, 127.2, 127.3, 127.6, 128.2, 128.5, 128.7, 128.8, 131.3,
132.1, 135.9, 137.2, 137.4, 137.5, 211.4; HRMS m/z (M+) calcd
for C24H28O 332.2140, found 332.2148.
Keton e 4g.2c Using the general procedure described above
and NaHMDS as a base, 4g was obtained (0.063 g, 55%) from
3g (0.182 g, 0.50 mmol) after chromatography (EtOAc/hexane,
1/40): 1H NMR (300 MHz, CDCl3) δ 1.01 (d, J ) 6.4 Hz, 3H),
1.27-1.41 (m, 2H), 1.65-1.87 (m, 2H), 2.03-2.24 (several peaks,
3H), 2.35-2.47 (several peaks, 2H), 2.61-2.71 (m, 1H), 6.15-
6.25 (m, 1H), 6.37 (d, J ) 15.8 Hz, 1H), 7.15-7.19 (m, 1H), 7.24-
7.33 (m, 4H); 13C NMR (75 MHz, CDCl3) δ 14.5, 25.5, 33.0, 34.8,
37.3, 45.7, 50.9, 126.0, 126.9, 128.5, 128.8, 131.4, 137.6, 213.6;
HRMS m/z (M+) calcd for C16H20O 228.1514, found 228.1519.
Ack n ow led gm en t. This research was supported by
a grant from the Korea Advanced Institute of Science
and Technology.
Su p p or tin g In for m a tion Ava ila ble: Copies of 1H and 13C
NMR spectra of all compounds described in the Experimental
Section. This material is available free of charge via the
Internet at http://pubs.acs.org.
J O991559O