P-chiral o-phosphinophenol as a P/O hybrid ligand: Preparation and use in Cu-catalyzed asymmetric conjugate addition of diethylzinc to acyclic enones

Article abstract of DOI:10.1021/jo051034y

(S)-2-(tert-Butylmethylphosphino)phenol and its methyl ether were synthesized from tert-butyldichlorophosphine via optically active phosphine-boranes as the intermediates. The former compound was used as a P/O hybrid ligand in the Cu-catalyzed asymmetric

Full text of DOI:10.1021/jo051034y

ever, whereas most of the ligands provide excellent
enantioselectivity in the reactions of cyclic enones, the
reactions of acyclic enones result in relatively low enan-
tioselectivity, with only some ligands providing very high
enantioselectivity.3,4
P-Chiral o-Phosphinophenol as a P/O
Hybrid Ligand: Preparation and Use in
Cu-Catalyzed Asymmetric Conjugate
Addition of Diethylzinc to Acyclic Enones
We have previously prepared new P-chiral P/S and P/N
hybrid ligands and demonstrated their high enantioin-
duction ability in Pd-catalyzed asymmetric allylic alky-
lations.5 Of note was that in the reaction that used the
P/S hybrid ligands, the P-chirality controlled both the
conformation of the cyclic Pd complex and the configu-
ration of the creating S-stereogenic center, eventually
providing high enantioselectivity. These facts have in-
spired us to design and synthesize more electronically
different and rigid ligands that are applicable to Cu-
catalyzed conjugate additions. As one of the candidates,
we selected the o-phosphinophenol structure.6 This ligand
is expected to form a highly regulated asymmetric
environment based on the rigid o-phenylene backbone
and the P-stereogenic center possessing the bulky tert-
butyl group and the smallest alkyl group (methyl group).
It is also anticipated that the phenol hydroxy group
would coordinate more strongly to a copper atom as an
anionic donor site than the phenol ether oxygen atom.6b
We describe herein the synthesis of (S)-2-(tert-butyl-
methylphosphino)phenol and its methyl ether derivative
(3a and 3b in Scheme 1) and their enantioinduction
abilities in the Cu-catalyzed asymmetric conjugate ad-
dition of diethylzinc to acyclic enones.
Yukitoshi Takahashi,† Yoshikazu Yamamoto,†,‡
Kosuke Katagiri,†,‡ Hiroshi Danjo,‡
Kentaro Yamaguchi,‡ and Tsuneo Imamoto*,†
Department of Chemistry, Faculty of Science,
Chiba University, 1-33 Yayoi-cho,
Inage-ku, Chiba 263-8522, Japan, and Department of
Pharmaceutical Technology, Faculty of Pharmaceutical
Science at Kagawa Campus, Tokushima Bunri University,
1314-1 Shido, Sanuki, Kagawa 769-2193, Japan
imamoto@faculty.chiba-u.jp
Received May 23, 2005
(S)-2-(tert-Butylmethylphosphino)phenol and its methyl ether
were synthesized from tert-butyldichlorophosphine via opti-
cally active phosphine-boranes as the intermediates. The
former compound was used as a P/O hybrid ligand in the
Cu-catalyzed asymmetric conjugate addition of diethylzinc
to acyclic enones to achieve high enantioselectivity of up to
96%.
Synthesis of the desired P/O hybrid ligands was
accomplished using phosphine-boranes as the interme-
diates. The overall reaction sequence is shown in Scheme
1. tert-Butyldichlorophosphine was consecutively treated
with lithium (1R,2S,5R)-menthoxide, 2-(methoxy)methox-
yphenylmagnesium bromide, and borane-THF complex
to give phosphine-borane 1a in 73% yield as a mixture
Copper- or nickel-catalyzed asymmetric conjugate ad-
dition of alkylzinc reagents to R,â-unsaturated carbonyl
compounds is one of the most powerful strategies for
enantioselective carbon-carbon bond formation, and
great attention has been paid to the development of chiral
ligands for this reaction.1 Among a number of ligands
known to date, hybrid-type phosphine ligands, including
monodentate ones, have been proven to be effective for
this organic transformation, owing to their sterically and
electronically regulated asymmetric environment.2 How-
(3) For recent examples, see: (a) Hu, X.; Chen, H.; Zhang, X. Angew.
Chem., Int. Ed. Engl. 1999, 38, 3518-3521. (b) Shadakshari, U.;
Nayak, S. K. Tetrahedron 2001, 57, 8185-8188. (c) Mizutani, H.;
Degrado, S. J.; Hoveyda, A. H. J. Am. Chem. Soc. 2002, 124, 779-
781. (d) Wakimoto, I.; Tomioka, Y.; Kawanami, Y. Tetrahedron 2002,
58, 8095-8097. (e) Shintani, R.; Fu, G. C. Org. Lett. 2002, 4, 3699-
3702. (f) Wan, H.; Hu, Y.; Liang, Y.; Gao, S.; Wang, J.; Zheng, Z.; Hu,
X. J. Org. Chem. 2003, 68, 8277-8280. (g) Morimoto, T.; Mochizuki,
N.; Suzuki, M. Tetrahedron Lett. 2004, 45, 5717-5722. (h) Duncan,
A. P.; Leighton, J. L. Org. Lett. 2004, 6, 4117-4119.
(4) (a) Bolm, C.; Ewald, M.; Felder, M. Chem. Ber. 1992, 125, 1205-
1215. (b) de Vries, A. H. M.; Meetsma, A.; Feringa, B. L. Angew. Chem.,
Int. Ed. Engl. 1996, 35, 2374-2376. (c) Arnold, L. A.; Imbos, R.;
Mandoli, A.; de Vries, A. H. M.; Naasz, R.; Feringa, B. L. Tetrahedron
2000, 56, 2865-2878. (d) Reetz, M. T.; Gosberg, A.; Moulin, D.
Tetrahedron Lett. 2002, 43, 1189-1191. (e) Alexakis, A.; Benhaim, C.;
Rosset, S.; Human, M. J. Am. Chem. Soc. 2002, 124, 5262-5263. (f)
Zhou, H.; Wang, W.-H.; Fu, Y.; Xie, J.-H.; Shi, W.-J.; Wang, L.-X.; Zhou,
Q.-L. J. Org. Chem. 2003, 68, 1582-1584. (g) Alexakis, A.; Polet, D.;
Benhaim, C.; Rosset, S. Tetrahedron: Asymmetry 2004, 15, 2199-2203.
(5) (a) Sugama, H.; Saito, H.; Danjo, H.; Imamoto, T. Synthesis 2001,
2348-2353. (b) Danjo, H.; Higuchi, M.; Yada, M.; Imamoto, T.
Tetrahedron Lett. 2004, 45, 603-606.
† Chiba University.
‡ Tokushima Bunri University.
(1) For reviews, see: (a) Alexakis, A.; Benhaim, C. Eur. J. Org.
Chem. 2002, 3221-3236. (b) Krause, N.; Hoffmann-Ro¨der, A. Synthesis
2001, 171-196. (c) Feringa, B. L. Acc. Chem. Res. 2000, 33, 346-353.
(d) Sibi, M. P.; Manyem, S. Tetrahedron 2000, 56, 8033-8061. (e)
Rossiter, B. E.; Swingle, N. M. Chem. Rev. 1992, 92, 771-806.
(2) For recent examples, see: (a) de Vries, A. H. M.; Imbos, R.;
Feringa, B. L. Tetrahedron: Asymmetry 1997, 8, 1467-1473. (b)
Chataigner, I.; Gennari, C.; Piarulli, U.; Ceccarelli, S. Angew. Chem.,
Int. Ed. 2000, 39, 916-918. (c) Yin, Y.; Li, X.; Lee, D.-S.; Yang, T.-K.
Tetrahedron: Asymmetry 2000, 11, 3329-3333. (d) Tong, P.-E.; Li, P.;
Chan, A. S. C. Tetrahedron: Asymmetry 2001, 12, 2301-2304. (e)
Jensen, J. F.; Søtofte, I.; Sørensen, H. O.; Johannsen, M. J. Org. Chem.
2003, 68, 1258-1265. (f) Malkov, A. V.; Hand, J. B.; Kocovsky, P. Chem.
Commun. 2003, 1948-1949.
(6) For recent examples, see: (a) Serreqi, A. N.; Kazlauskas, R. J.
J. Org. Chem. 1994, 59, 7609-7615. (b) Heinicke, J.; He, M.; Dal, A.;
Klein, H.-F.; Hatche, O.; Keim, W.; Flo¨rke, U.; Haupt, H.-J. Eur. J.
Inorg. Chem. 2000, 431-440. (c) Sua´rez, A.; Me´ndez-Rojas, M. A.;
Pizzano, A. Organometallics 2002, 21, 4611-4621.
10.1021/jo051034y CCC: $30.25 © 2005 American Chemical Society
Published on Web 09/23/2005
J. Org. Chem. 2005, 70, 9009-9012
9009

TABLE 1. Cu-Catalyzed Asymmetric Conjugate
Addition of Diethylzinc to Chalcone with P-Chiral P/O
Ligands
SCHEME 1. Preparation of P-Chiral P/O Hybrid
Ligandsa
entry ligand
Cu
time (h) yielda (%) eeb (%)
1
2
3a
3b
3a
3b
3a
3b
3a
3b
3a
3b
3a
3b
3a
3b
3a
3b
Cu(OTf)2
Cu(OTf)2
Cu(OAc)2
Cu(OAc)2
Cu(OCOPh)2
Cu(OCOPh)2
Cu(acac)2
Cu(acac)2
CuCl2
0.3
0.3
0.5
0.3
0.3
0.2
0.3
0.3
0.3
0.5
0.8
84
81
64
79
82
79
81
84
77
43
54
5
77
61
77
40
81
40
81
19
81
22
74
4
3
4
5
6
7
8
9
10
11
12
13
14
15
16
CuCl2
CuCO3
CuCO3
24
CuOTf
0.3
0.3
0.5
3.5
83
80
73
27
82
54
80
7
CuOTf
CuI
CuI
a Isolated yield. b Determined by CSP-HPLC analysis.
a Reagents and conditions: (a) (i) lithium menthoxide, THF, -78
°C to rt, 6 h, (ii) 2-alkoxyphenylmagnesium bromide 0 °C to reflux,
15 h, (iii) BH3‚THF, 0 °C, 2 h; (b) (i) lithium naphthalenide, THF,
-40 °C, 2 h, (ii) CH3I, -40 °C, 1 h; (c) (i) HBF4‚OEt2, CH2Cl2, -20
°C to rt, 15 h, (ii) NaHCO3 aq, 0 °C, 1 h.
of diastereomers. Chromatographic separation of the
mixture on a silica gel column afforded each stereoisomer
in diastereomerically pure form. Reductive cleavage of
the P-O bond with lithium naphthalenide and subse-
quent addition of methyl iodide produced (2-(methoxy)-
methoxyphenyl)(tert-butyl)methylphosphine-borane (2a)
in 68% yield with retention of configuration at the
phosphorus atom.7 Simultaneous removal of the boranato
group and the methoxymethyl group was carried out by
successive treatments of 2a with tetrafluoroboric acid and
aqueous sodium bicarbonate to give optically active (S)-
tert-butyl(2-hydroxyphenyl)methylphosphine (3a) in 88%
yield.8 In a similar manner, (S)-tert-butylmethyl(2-meth-
oxyphenyl)phosphine (3b) was prepared from 1b via 2b.9
The absolute configuration of 2b was determined to be
S by X-ray crystallographic analysis.10 As 2a could be
converted into 2b by deprotection and subsequent me-
thylation of phenolic oxygen, the absolute configuration
of 2a should be S as well.
With these P-chiral P/O hybrid ligands in hand, we
tried to perform the highly stereoselective conjugate
addition of diethylzinc to R,â-unsaturated enones. Pre-
liminary catalyst screening was performed with various
copper salts. The reaction was carried out by mixing
chalcone with 1.1 equiv of diethylzinc in the presence of
1.0 mol % of copper salt and 1.2 mol % of chiral ligands
in diethyl ether at 0 °C. As shown in Table 1, phosphi-
FIGURE 1. Cu complexes of P-chiral P/O ligands.
nophenol 3a afforded the 1,4-adduct in 54-84% yield and
74-82% enantioselectivity within 1 h in combination
with each copper salt. The catalyst performance of the
Cu-3a system was not affected by the characteristics of
the counteranions of copper. This is rationally interpreted
by the formation of chelate complex 5 in which the
phenoxide moiety is coordinated to Cu(I) as an anionic
donor site, which would prevent the intervention of other
counteranions in the reaction (Figure 1). In contrast, the
reaction with phosphinoanisole 3b exhibited strong de-
pendence upon the characteristics of the counteranions.
The counteranion (X-) remained on the copper atom to
form complex 6, thereby affecting the reaction.4e
Solvent dependence was investigated as the second
screening step (Table 2). Ligand 3a gave high yield and
stereoselectivity in acyclic ethers (entries 1-3), hydro-
carbons (entries 4 and 5), and dichloromethane (entry
6). On the other hand, cyclic ethers gave poor enantio-
selectivity (entries 7-9). The use of acetonitrile, in
particular, resulted in the decrease of both reactivity and
selectivity (entry 10). The catalyst performance of the
system might be strongly affected by the coordination
ability of the solvent used.
The conjugate addition was next performed at various
temperatures (Table 3). It is worth noting that lowering
the temperature decreased the enantioselectivity, and
opposite enantioselectivity was observed at -78 °C when
3a was used as a ligand (entries 1-5). On the other hand,
ligand 3b afforded higher enantioselectivity at lower
temperatures (entries 6 and 7). A similar result was
observed when the monodentate phosphine ligand, (S)-
tert-butyl(methyl)phenylphosphine (4), was used (entries
(7) Oshiki, T.; Hikosaka, T.; Imamoto, T. Tetrahedron Lett. 1991,
32, 3371-3374.
(8) McKinstry, M.; Livinghouse, T. Tetrahedron Lett. 1994, 35,
9319-9322.
(9) Imamoto, T.; Matsuo, M.; Nonomura, T.; Kishikawa, K.; Yana-
gawa, M. Heteroatom Chem. 1993, 4, 475-486.
(10) CCDC-280439 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge via
www.ccdc.cam.ac.uk/conts/retrieving.html (or from the CCDC, 12
Union Road, Cambridge CB2 1EZ, UK.; fax: +44 1223 336033;
e-mail: deposit@ccdc.cam.ac.uk).
9010 J. Org. Chem., Vol. 70, No. 22, 2005

TABLE 2. Cu-Catalyzed Asymmetric Conjugate
Addition of Diethylzinc to Chalcone with P-Chiral P/O
Ligand 3a
TABLE 4. Cu-Catalyzed Asymmetric Conjugate
Addition of Diethylzinc to Various Enones with P-Chiral
P/O Ligands 3a
entry
solvent
time (h)
yielda (%)
eeb (%)
time yielda
eeb
(%)
entry
R1
R2
(h)
(%)
1
2
Et2O
DME
t-BuOCH3
toluene
hexane
CH2Cl2
THF
THP
dioxane
CH3CN
0.3
1.2
0.3
0.5
0.3
0.3
1
0.5
1
5
84
70
82
80
62
81
83
82
81
41
77
76
78
75
76
83
-7
39
26
7
1
2c
3
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
0.3
1.5
0.3
1
88
77
93
91
92
86
98
95
90
5
85 (R)
78 (R)
94 (R)
96 (-)
80 (R)
61 (+)
73 (+)
64 (-)
65 (+)
74 (-)
94 (+)
76 (+)
92 (-)
87 (-)
90 (-)
91 (-)
77 (S)
3
4
4-CH3OC6H4
4-(CH3)2NC6H4
4-ClC6H4
4-CF3C6H4
1-naphthyl
n-pentyl
5
4
6
5
1
7
6
0.5
0.3
1
1
24
8
7
9
8
10
9
iPr
t-Bu
a Isolated yield. b Determined by CSP-HPLC analysis.
10
11
12
13
14
15
16
17
4-CH3OC6H4 Ph
4-ClC6H4
0.5
1
0.5
1
1
0.2
5.0
84
90
94
90
97
77
63
Ph
TABLE 3. Cu-Catalyzed Asymmetric Conjugate
Addition of Diethylzinc to Chalcone with P-Chiral
Phosphine Ligands
iBu
Cy
Ph
Ph
n-hexyl
n-hexyl
Me
Ph
Me
n-pentyl
a Isolated yield. b Determined by CSP-HPLC analysis. c 0.1 mol
% of CuOTf and 0.12 mol % of 3a were used.
entry
ligand
T (°C)
time (h)
yielda (%)
eeb (%)
1
2
3
4
5
6
7
8
9
3a
3a
3a
3a
3a
3b
3b
4
-78
-40
-20
0
24
22
78
86
84
75
66
81
44
84
-13
49
64
77
77
80
61
41
26
slightly diminished stereoselectivity even with the use
of 0.1 mol % catalyst (entry 2). The stereoselectivity was
affected by the electronic nature of the substituent on
the â-phenyl group. The substitution with a methoxy or
a dimethylamino group at the para position led to an
increase in enantioselectivity (entries 3 and 4), whereas
a chloro or trifluoromethyl substitution decreased the
selectivity (entries 5 and 6). Alkyl substituents at the
â-position were responsible for the diminished stereose-
lectivity (entries 8 and 9). We also attempted to use
various aryl and alkyl ketones, including fully aliphatic
ketones, and high to excellent enantioselectivity was
obtained in each case (entries 11-17).
In conclusion, P-chiral phosphinophenol and phosphi-
noanisole were prepared as new chiral P/O hybrid ligands
and used in the Cu-catalyzed asymmetric conjugate
addition of diethylzinc to R,â-unsaturated carbonyl com-
pounds. It was revealed that the P-chiral phosphinophe-
nol exhibits high enantioselectivities up to 96% in the
reactions of various chalcone derivatives.
20
0.7
0.2
0.2
24
0.3
24
0.2
25
-78
0
-78
0
4
a Isolated yield. b Determined by CSP-HPLC analysis.
8 and 9). The unusual temperature dependence of the
enantioselectivities observed by the use of 3a cannot be
well understood, but we suggest that there might exist
more than two active catalyst species with different
stereoinduction modes or the reaction might be largely
controlled by entropy factor.
Using the conditions established as above, the conju-
gate additions of diethylzinc to various acyclic R,â-
unsaturated ketones were carried out, and the results
are summarized in Table 4.11 In almost all cases, the
reactions proceeded smoothly and were completed within
0.3-1.5 h to give the addition products in high to
excellent yields. In the conjugate addition to chalcone,
the best result was obtained by the use of copper(I)
triflate in dichloromethane, for which 1,3-diphenylpen-
tan-1-one was obtained in 88% yield and 85% enantiose-
lectivity (entry 1).12 The reaction proceeded smoothly with
Experimental Section
General experimental details can be found in the Supporting
Information.
Preparation of (S)-tert-Butyl((1R,2S,5R)-2-isopropyl-5-
methylcyclohexyloxy)(2-(methoxy)methoxyphenyl)phos-
phine-Borane (1a). Lithium (1R,2S,5R)-menthoxide (105
mmol, 90 mL of 1.16 M THF solution) was added dropwise
during 4 h into a solution of tert-butyldichlorophosphine (100
mmol, 15.9 g) in dry THF (200 mL) with stirring at -78 °C under
argon atmosphere. After addition, the cooling bath was removed,
and stirring was continued for 2 h. The mixture was cooled at 0
°C, and 2-(methoxy)methoxyphenylmagnesium bromide (110
mmol, 141 mL of 0.78 M THF solution) was slowly added. The
mixture was stirred for 15 h under reflux conditions. The
borane-THF complex (120 mmol, 104 mL of 1.15 M THF
solution) was added at 0 °C, and stirring was continued for 2 h.
The reaction mixture was carefully poured into a mixture of ice-
water containing HCl and diluted with diethyl ether. The organic
(11) As a representative cyclic enone, 2-cyclohexenone was used in
the conjugate addition. However, 3-ethylcyclohexanone of only 5% yield
and 8% ee was obtained even after 24 h with the Cu-3a system. By
contrast, 74% yield of the product was obtained by the use of 3b within
0.5 h, albeit with low selectivity (18% ee).
(12) The conjugate addition to cis-chalcone was examined next. The
reaction was completed within 20 min, and 82% ee (R) of the product
was obtained in 94% yield.
J. Org. Chem, Vol. 70, No. 22, 2005 9011

layer was separated, and the aqueous layer was extracted with
diethyl ether. The combined extracts were washed with satu-
rated NaHCO3 and brine and dried over Na2SO4. After filtration,
the filtrate was concentrated under reduced pressure. The
residue was subjected to column chromatography (hexane/ethyl
acetate ) 20/1) to give the diastereomeric mixture of phosphine-
borane, and the diastereomeric mixture was resolved by column
chromatography on silica gel (hexane/CHCl3 ) 4/1). 1H NMR
(500 MHz, CDCl3): δ 7.76 (ddd, J ) 11.1, 7.7, 1.8 Hz, 1H), 7.41
(dddd, J ) 8.4, 7.3, 1.8, 1.0 Hz, 1H), 7.17 (ddd, J ) 8.4, 4.1, 0.9
Hz, 1H), 7.04 (dddd, J ) 11.1, 7.3, 1.6, 0.9 Hz, 1H), 5.18 (d, J )
5.2 Hz, 1H), 5.10 (d, J ) 5.1 Hz, 1H), 4.29 (dq, J ) 4.7, 9.9 Hz,
1H), 3.50 (s, 3H), 2.24-2.18 (m, 1H), 1.79-1.70 (m, 1H), 1.67-
1.56 (m, 2H), 1.50-1.39 (m, 1H), 1.34-1.27 (m, 1H), 1.20-1.08
(m, 10H), 1.00-0.78 (m, 5H), 0.72 (d, J ) 7.0 Hz, 3H), 0.48 (d,
J ) 7.0 Hz, 3H). 13C NMR (125 MHz, CDCl3): δ 159.2, 135.0 (d,
J ) 10.0 Hz), 133.0 (d, J ) 2.0 Hz), 120.8 (d, J ) 10.0 Hz), 119.8
(d, J ) 50.0 Hz), 114.4 (d, J ) 5.0 Hz), 94.9, 79.9 (d, J ) 5.0
Hz), 56.4, 49.0 (d, J ) 4.0 Hz), 43.9 (d, J ) 2.0 Hz), 34.0, 33.7,
25.2, 25.2 (d, J ) 8 Hz), 22.6, 22.2, 21.1, 15.4. 31P NMR (202
MHz, CDCl3): δ 122.9 (d, J ) 78.9 Hz). IR (NaCl plates): 2955,
Preparation of (S)-tert-Butyl(2-hydroxyphenyl)meth-
ylphosphine (3a). An oven-dried 30 mL round-bottomed flask
was charged with phosphine-borane 2a (0.43 mmol, 109 mg)
and degassed CH2Cl2 (2 mL) under argon. To the solution was
added tetrafluoroboric acid in diethyl ether (6.46 mmol, 0.887
mL) at -20 °C. After the solution was stirred at room temper-
ature for 15 h, degassed saturated NaHCO3 was added at 0 °C.
After the solution was stirred at ambient temperature for 1 h,
the organic layer was separated, and the aqueous layer was
extracted with degassed diethyl ether three times. The combined
extracts were dried over Na2SO4 under argon. The solution was
passed through a column of silica gel using degassed diethyl
ether. The eluent was evaporated under reduced pressure to give
free phosphine as white crystal. 1H NMR (500 MHz, CDCl3): δ
7.30-7.25 (m, 2H), 6.95-6.90 (m, 2H), 1.30 (d, J ) 6.2 Hz, 3H),
1.02 (d, J ) 13.4 Hz, 9H). 13C NMR (125 MHz, CDCl3): δ 160.2
(d, J ) 21.0 Hz), 131.6 (d, J ) 3.0 Hz), 131.1, 119.9, 114.8, 29.0
(d, J ) 4.0 Hz), 26.7 (d, J ) 13.0 Hz), 4.2 (d, J ) 13.1 Hz). 31P
NMR (202 MHz, CDCl3): δ -43.8 (s). HRMS calcd for C11H17
-
OP [M]+ 196.1017, found 196.1013.
2390, 1590, 1475, 1155, 990 cm-1. [R]22 ) -101.4 (c ) 1.06,
General Procedure for Copper-Catalyzed Asymmetric
Conjugate Addition. A mixture of copper(I) triflate (0.03 mmol)
and phosphine 3 (0.036 mmol) in CH2Cl2 (3 mL) was stirred at
room temperature for 1 h under argon. The mixture was added
to the enone (3.0 mmol) and cooled to 0 °C. Diethylzinc (3.3
mmol, 3.3 mL of 1.0 M solution in hexane) wad added dropwise
and stirred at 0 °C until the starting enone had been completely
consumed by monitoring with thin-layer chromatography. The
reaction mixture was quenched with 1 M HCl, and the mixture
was extracted with diethyl ether. The combined organic layers
were washed with NaHCO3 and brine and dried over Na2SO4.
After filtration, the filtrate was concentrated under reduced
pressure, and the residue was purified by column chromatog-
raphy. The enantiomeric excess of the product was determined
by chiral GLC or HPLC.
D
CHCl3); HRMS calcd for C22H40BKO3P [M + K]+ 433.2445, found
433.2467.
Preparation of (S)-tert-Butyl(2-(methoxy)methoxyphe-
nyl)methylphosphine-Borane (2a). Lithium naphthalenide
(49 mmol, 49 mL of 1.0 M THF solution) was slowly added to a
solution of a phoshine-borane 1a (9.9 mmol, 3.92 g) in dry THF
(20 mL) at -40 °C under argon atmosphere. After the mixture
was stirred for 2 h, methyl iodide (49 mmol, 3.0 mL) was added,
and stirring was continued for an additional 1 h. The reaction
was quenched by the addition of 1 M HCl and diluted with
diethyl ether, and the organic layer was separated from the
aqueous solution. The aqueous layer was extracted with diethyl
ether. The combined extracts were washed with saturated
NaHCO3 and brine, and dried over Na2SO4. After filtration, the
filtrate was concentrated under reduced pressure, and the
residue was purified by column chromatography on silica gel
(hexane/ethyl acetate ) 20/1). 1H NMR (500 MHz, CDCl3): δ
7.88 (ddd, J ) 13.0, 7.6, 1.7 Hz, 1H), 7.44 (dddd, J ) 8.3, 7.3,
1.7, 1.1 Hz, 1H), 7.18 (ddd, J ) 8.3, 3.2, 0.9 Hz, 1H), 7.08 (dddd,
J ) 7.6, 7.3, 1.6, 0.9 Hz, 1H), 5.22 (d, J ) 6.7 Hz, 1H), 5.19 (d,
J ) 7.1 Hz, 1H), 3.49 (s, 3H), 1.71 (d, J ) 10.4 Hz), 1.15 (d, J )
14.1 Hz, 9H), 0.73 (br q, J ) 89.5 Hz, 3H). 13C NMR (125 MHz,
CDCl3): δ 159.8, 137.4 (d, J ) 13.1 Hz), 133.1, 121.7 (d, J )
11.0 Hz), 115.6 (d, J ) 46.1 Hz), 113.9 (d, J ) 4.0 Hz), 94.5,
56.5, 29.9 (d, J ) 33.1 Hz), 25.8 (d, J ) 3.0 Hz), 7.1 (d, J ) 39.1
Hz). 31P NMR (202 MHz, CDCl3): δ 28.0 (dd, J ) 52.5, 123.2
Hz). IR (KBr): 2375, 1475, 1155, 1070, 990, 765 cm-1. Mp )
Acknowledgment. This work was supported by a
Grant-in-Aid from the ministry of Education, Science,
Culture and Sports, Japan.
Supporting Information Available: Additional experi-
mental procedures, spectroscopic data for epi-1a, 3b, (S)-tert-
butyl(2-hydroxyphenyl)methylphosphine-borane (7), and 1,4-
adducts, copies of NMR spectra for all new phosphine
compounds, and X-ray crystallographic data for 2b (CIF). This
material is available free of charge via the Internet at
http://pubs.acs.org.
49-50 °C. [R]22 ) +30.0 (c ) 1.00, CHCl3). HRMS calcd for
D
C
13H24BKO2P [M + K]+ 293.1244, found 293.1242. Anal. Calcd
for C13H24BO2P: C, 61.44; H, 9.52. Found: C, 61.66; H, 9.49.
JO051034Y
9012 J. Org. Chem., Vol. 70, No. 22, 2005