A new methodology for synthesis of a chiral phosphinocarboxylic acid through michael cyclization-aldol tandem reaction of chiral α,β,χ,ψ-unsaturated bisphosphine oxide and application in palladium-catalyzed asymmetric allylic alkylation

Article abstract of DOI:10.1021/jo025725v

Upon successive treatment with lithium diisopropylamide and then benzaldehyde, a chiral α,β,ψ,ω- unsaturated bisphosphine oxide underwent Michael cyclization-aldol tandem reaction to afford the corresponding endo- α,β-unsaturated cyclic bisphosphine oxides. Sequential stereoselective reduction and Horner-Wadsworth-Emmons olefination gave the corresponding monophosphine oxide. Oxidative conversion of an olefin moiety into a carboxyl group and subsequent deoxygenation of an oxide gave the corresponding chiral phosphinocarboxylic acid, which was successfully applied as a chiral and functionalized monophosphine ligand in a palladium-catalyzed asymmetric allylic alkylation.

Full text of DOI:10.1021/jo025725v

SCHEME 1. Selective Cycliza tion -Ald ol Ta n d em
Rea ction
A New Meth od ology for Syn th esis of a
Ch ir a l P h osp h in oca r boxylic Acid th r ou gh
Mich a el Cycliza tion -Ald ol Ta n d em
Rea ction of Ch ir a l r,â,ø,ψ-Un sa tu r a ted
Bisp h osp h in e Oxid e a n d Ap p lica tion in
P a lla d iu m -Ca ta lyzed Asym m etr ic Allylic
Alk yla tion
Hideki Inoue, Yasuo Nagaoka,† and Kiyoshi Tomioka*
Graduate School of Pharmaceutical Sciences,
Kyoto University,Yoshida, Sakyo-ku, Kyoto 606-8501, J apan
tomioka@pharm.kyoto-u.ac.jp
Received March 15, 2002
Abstr a ct: Upon successive treatment with lithium diiso-
propylamide and then benzaldehyde, a chiral R,â,ψ,ω-
unsaturated bisphosphine oxide underwent Michael cycliza-
tion-aldol tandem reaction to afford the corresponding endo-
R,â-unsaturated cyclic bisphosphine oxides. Sequential
stereoselective reduction and Horner-Wadsworth-Emmons
olefination gave the corresponding monophosphine oxide.
Oxidative conversion of an olefin moiety into a carboxyl
group and subsequent deoxygenation of an oxide gave the
corresponding chiral phosphinocarboxylic acid, which was
successfully applied as a chiral and functionalized mono-
version to a chiral diphosphine, which was applied as a
chiral ligand in a catalytic asymmetric hydrogenation of
dehydroamino acid derivatives.8 Because lithiated phos-
phine oxide 4a , the intermediate of the tandem cycliza-
tion reaction, might be potentially applicable as a car-
bonucleophile, we designed a synthesis of a chiral
monophosphine bearing both a phosphino- and an ad-
ditional functional group such as a carboxyl.9 We describe
herein the successful synthesis of a chiral phosphinocar-
boxylic acid 12 and its application in a palladium-
catalyzed asymmetric allylic alkylation of 1,3-diphenyl-
2-propenyl acetate 13 with malonate.
phosphine ligand in
allylic alkylation.
a palladium-catalyzed asymmetric
In tr od u ction
Allylic substitution reactions rank among the most
intensively studied catalytic transformations. Since the
reports by Tsuji1 and Trost,2 this area has seen fast
developments in catalyst structure and ligand design for
asymmetric version.3 In our program aimed at develop-
ment of an efficient and versatile catalytic asymmetric
reaction,4,5 we have been involved in a conjugate addi-
tion-intramolecular Michael tandem cyclization reaction
of achiral R,â,ψ,ω-unsaturated bisphosphonates that
were potential synthetic precursors of bisphosphine
ligands.6 More recently the methodology has been suc-
cessfully extended to selective lithiation7-intramolecular
Michael tandem cyclization of chiral C2 symmetric R,â,ψ,ω-
unsaturated bisphosphine oxide 1 and subsequent con-
Resu lts a n d Discu ssion
Mich a el-Ald ol Ta n d em Rea ction . In our previous
work C2 symmetric chiral bisphosphine oxide 110 has been
treated with LDA in THF at -78 °C to give 2 and
subsequent cyclization through 3 gave 4b in 60% isolated
yield, which was a protonation product of lithiated
phosphine oxide 4a .8 In this study, 4a and its diastere-
omer were treated with benzaldehyde to give a cyclized
alcohol 5 and its diastereoisomer 6 in 54% and 8%
isolated yields, respectively (Scheme 1). The stereochem-
istry of the newly created asymmetric center on a
cyclopentene ring of 5 and 6 was assigned by NMR-
NOESY analysis. The major product 5 corresponds to a
benzaldehyde-aldol product derived from 4a . It is note-
worthy that the aldol reaction of 4a and its diastereomer
proceeded in a high degree of stereoselectivity to afford
† Present address: Department of Biochemistry, Faculty of Engi-
neering, Kansai University, Suita, Osaka, 564-8680, J apan.
(1) Tsuji, J . Acc. Chem. Res. 1969, 2, 144.
(2) Trost, B. M.; Verhoeven, T. R. J . Am. Chem. Soc. 1976, 98, 630.
(3) Pfaltz, A.; Lautens, M. Comprehensive Asymmetric Catalysis;
Springer: New York, 1999; Vol. 2, Chapter 24, p 834,
(4) (a) Fujihara, H.; Nagai, K.; Tomioka, K. J . Am. Chem. Soc. 2000,
122, 12055. (b) Nagai, K.; Fujihara, H.: Kuriyama, M.; Yamada, K.;
Tomioka, K. Chem. Lett. 2002, 8.
(5) Reviews for external chiral ligand-mediated asymmetric reac-
tions, see: (a) Tomioka, K. Synthesis 1990, 541. (b) Noyori, R.
Asymmetric Catalysis in Organic Synthesis; J ohn Wiley and Sons: New
York, 1994. (c) Lagasse, F.; Kagan, H. B. Chem. Pharm. Bull. 2000,
48, 315.
(6) (a) Nagaoka, Y.; Tomioka, K. Org. Lett. 1999, 1, 1467. (b)
Nagaoka, Y.; Tomioka, K. J . Org. Chem. 1998, 63, 6428. (c) Inoue, H.;
Tsubouchi, H.; Nagaoka, Y.; Tomioka, K. Tetrahedron 2002, 58, 83.
(7) Minami, T.; Okauchi, T.; Kouno, R. Synthesis 2001, 349.
(8) (a) Nagaoka, Y.; Inoue, H.; El-Koussi, N.; Tomioka, K. Chem.
Commun. 2002, 122. (b) Nagaoka, Y.; El-Koussi, N.; Uesato, S.;
Tomioka, K. Tetrahedron Lett. 2002, 43, 4355.
(9) Tandem cyclization has been one of recent topics. (a) Wang, L.-
C.: Luis, A. L.; Agapiou, K.; J ang, H. Y.; Krische, M. J . J . Am. Chem.
Soc. 2002, 124, 2404. (b) Frank, S. A.; Mergott, D. J .; Roush, W. R. J .
Am. Chem. Soc. 2002, 124, 2404, and references therein.
(10) Prepared from dimethyl ether of diethyl L-tartrate through
DIBALH reduction followed by Horner-Wadsworth-Emmons olefi-
nation with methylene(phosphonate)phosphine oxide in 48% overall
yield.
10.1021/jo025725v CCC: $22.00 © 2002 American Chemical Society
Published on Web 07/11/2002
5864
J . Org. Chem. 2002, 67, 5864-5867

TABLE 1. Asym m etr ic Allylic Alk yla tion Usin g 11 a n d
12
SCHEME 2. Syn th esis of P h osp h in oca r boxylic
Acid 12
x
y
time yield ee
entry (mol %) (mol %) phosphine temp
(h)
(%) (%)
1
2
3
4
1
1
1
3
2
2
2
6
11
12
12
12
rt
rt
reflux
rt
24
20
2
0
46
97
77
0
91
60
93
24
of the most useful and fundamental carbon-carbon bond
forming reactions. Among them, chiral phosphinocar-
boxylic acids developed by Minami14 and Helmchen15
have been reported to be moderately effective in pal-
ladium-catalyzed allylic alkylation. In our study we
examined our new phosphinocarboxylic acid 12 and its
ester 11 in the palladium-catalyzed allylic alkylation of
1,3-diphenyl-2-propenyl acetate 13 with dimethyl mal-
onate.
A palladium complex catalyst was generated in situ
by mixing a chiral ligand 11 or 12 with palladium acetate.
The reaction of 13 with sodium dimethyl malonate was
carried out at room temperature in THF using 1 mol %
of palladium acetate and 2 mol % of an ester ligand 11.
However, the alkylation product 14 was not obtained and
13 was recovered unchanged (Table 1, Entry 1). Fortu-
nately, (R)-14 was obtained in 46% yield and 91% ee by
using phosphinocarboxylic acid 12 instead of 11 (Entry
2). Improvement of the chemical yield was possible by
enforcing the reaction conditions under reflux for 2 h,
giving 14 in 97% yield but in unsatisfactory enantiose-
lectivity of 60% (Entry 3). Finally we found that the
reaction was catalyzed by 3 mol % of palladium acetate
and 6 mol % of 12 at room temperature for 24 h giving
14 in 93% ee and 77% yield (Entry 4). All these observa-
tions suggest that the phosphinocarboxylic acid 12 forms
a O,P-chelate coordination to palladium rather than only
one point coordination by a phosphorus atom.
only two diastereomers 5 and 6. The compounds 5 and 6
were obtained as a single stereoisomer, respectively. The
relative configuration at the aldol reaction sites of 5 is
related to that giving E-double bond by olefination
through Horner-Wadsworth-Emmons syn-elimination.
Syn th esis of P h osp h in e Liga n d s. Treatment of 5
with Super-Hydride in THF at 0 °C for 20 min underwent
highly stereoselective 1,4-reduction to afford thermody-
namically stable trans-7 in 75% yield (Scheme 2). The
corresponding cis-product was not detected. Subsequent
Horner-Wadsworth-Emmons reaction with potassium
hydride in THF gave a monophosphine oxide 8 in 82%
yield. The stereochemistry of an olefin moiety was
unequivocally assigned to be purely E by NMR analysis,
indicating the fixed relative configuration of the aldol
reaction sites. The ozonolysis of an olefin moiety of 8 and
following potassium permanganate oxidation gave a
carboxylic acid 9 in 75% yield. The phosphine oxide
moiety of 9 failed to be directly converted to the requisite
phosphinocarboxylic acid 12. Therefore the carboxylic
acid of 9 was once converted under acid-catalyzed esteri-
fication conditions to its methyl ester 10 in 95% yield and
was then subjected to reduction with trichlorosilane11 in
benzene at 110 °C for 24 h readily giving the phosphine
11 in 93% yield. Then hydrolysis of 11 with sodium
hydroxide in aqueous THF afforded the requisite chiral
phosphinocarboxylic acid 12 in nearly quantitative yield.
Asym m etr ic Allylic Alk yla tion . Development of a
new chiral phosphine ligand for a metal catalyst has
attracted considerable interest in the past 30 years.
Several kinds of chiral phosphines have made significant
contributions to the development of palladium-catalyzed
asymmetric allylic substitution,12,13 which constitutes one
In summary, the new methodology was proved to be
effective for the synthesis of chiral monophosphines
through Michael-aldol tandem reaction of chiral R,â,ψ,ω-
unsaturated bisphosphine oxide as a key step. Successful
(12) For other reviews on Pd(0)-catalyzed asymmetric allylic sub-
stitution, see: (a) Frost, C. G.; Howarth, J .; Williams, J . M. J .
Tetrahedron: Asymmetry 1992, 3, 1089. (b) Tsuji, J . Palladium
Reagents and Catalysis, Innovations in Organic Synthesis; Wiley &
Sons: New York, 1995. (c) Williams, J . M. J . Synlett 1996, 705. (d)
Trost, B. M. Acc. Chem. Res. 1996, 29, 355. (e) Trost, B. M.; Van
Vranken, D. L. Chem. Rev. 1996, 96, 395. (f) Hayashi, T. J . Organomet.
Chem. 1999, 576, 195. (g) Helmchen, G. J . Organomet. Chem. 1999,
576, 203. (h) Trost, B. M. Chem. Pharm. Bull. 2002, 50, 1.
(13) For recent impressive reports, see: (a) Saitoh, A.; Achiwa, K.;
Tanaka, K.; Morimoto. T. J . Org. Chem. 2000, 65, 4227. (b) Hashizume,
T.; Yonehara, K.; Ohe, K.; Uemura, S. J . Org. Chem. 2000, 65, 5197.
(c) Nakano, H.; Okuyama, Y.; Yanagida, M.; Hongo, H. J . Org. Chem.
2001, 66, 620. (d) Nettekoven, U.; Widhalm, M.; Kalchhauser, H.;
Kamer, P. C. J .; van Leeuwen, P. W. N. M.; Lutz, M.; Spek, A. L. J .
Org. Chem. 2001, 66, 759. (e) Uozumi, Y.; Shibatomi, K. J . Am. Chem.
Soc. 2001, 123, 2919.
(14) Okada, Y.; Minami, T.; Umezu, Y.; Nishikawa, S.; Mori, R.;
Nakayama, Y. Tetrahedron: Asymmetry 1991, 2, 667.
(11) Segall, Y.; Granoth, I.; Kalir, A. J . Chem. Soc., Chem. Commun.
1974, 501.
(15) Knu¨hl, G.; Sennhenn, P.; Helmchen, G. J . Chem. Soc., Chem.
Commun. 1995, 1845.
J . Org. Chem, Vol. 67, No. 16, 2002 5865

56.4, 57.1, 74.3, 84.4 (d, J ) 7.2 Hz), 86.3 (dd, J ) 3.1, 9.3 Hz),
127.1(d, J ) 4.1 Hz), 128.06 (d, J ) 11.4 Hz), 128.08, 128.2 (d,
J ) 11.4 Hz), 128.3 (d, J ) 11.4 Hz), 128.7 (d, J ) 11.4 Hz),
130.9, 131.3 (d, J ) 9.3 Hz), 131.5 (d, J ) 9.3 Hz), 131.7 (d, J )
9.3 Hz), 131.8 (d, J ) 9.3 Hz), 130.4 (d, J ) 96.2 Hz), 132.7 (d,
J ) 96.2 Hz), 134.1 (d, J ) 96.2 Hz), 135.3 (d, J ) 96.2 Hz),
142.3 (d, J ) 7.2 Hz). 31P NMR: 34.4, 36.2. IR (Nujol): 3200,
1190 cm-1. FABMS m/z: 651 (M+H+). HRMS Calcd for
application of the phosphinocarboxylic acid in a pal-
ladium-catalyzed asymmetric allylic alkylation is the
clear evidence of the usefulness of the methodology.
Exp er im en ta l Section 16
2-(Dip h en ylp h osp h or yl)-2-[(1R,4S,5S)-2-(d ip h en ylp h os-
p h or yl)-4,5-d im eth oxy-2-cyclop en ten -1-yl]-1-p h en yleth a -
n ol (5) an d 2-(Diph en ylph osph or yl)-2-[(1S,4S,5S)-2-(diph en -
ylp h osp h or yl)-4,5-d im eth oxy-2-cyclop en ten -1-yl]-1-p h en -
yleth a n ol (6). A solution of bisphosphine oxide 18 (2.71 g, 5
mmol) in THF (75 mL) was added dropwise over a period of 5
min to a solution of LDA (10 mmol) in THF (175 mL) at -78 °C.
The mixture was stirred for 10 min at -78 °C. Benzaldehyde
(1.55 mL, 15 mmol) was added, and then the mixture was stirred
for 20 min at -78 °C. The mixture was added with MeOH (5
mL) and satd NH4Cl (100 mL) and then was extracted with
EtOAc. The extract was washed with satd NaCl and dried over
Na2SO4. Concentration and recrystallization (EtOAc) gave 5
C
39H41O5P2: 651.2429. Found: 651.2432.
{(1S ,2S ,3S ,4S )-3,4-Dim e t h oxy-2-[2-p h e n yle t h e n yl]cy-
clop en tyl}d ip h en ylp h osp h in e Oxid e (8). A solution of 7 (567
mg, 0.87 mmol) in THF (4 mL) was added to a suspension of
KH (100 mg, 0.87 mmol) in THF (4 mL) at -78 °C. The mixture
was allowed to warm to room temperature over 0.5 h. The
mixture was quenched with satd NH4Cl (3 mL) and extracted
with benzene. The organic layer was washed with brine and then
dried over Na2SO4. Concentration and chromatography (EtOAc/
MeOH ) 100/1) gave 8 (307 mg, 82%) as a colorless solid of mp
178-179 °C and [R]25 +83.0 (c 1.00, CHCl3). 1H NMR: 1.84
D
(1H, m), 2.30 (1H, dddd, J ) 6.4, 9.5, 11.9, 13.7 Hz, CH2), 2.85
(1H, dq, J ) 1.8, 9.5 Hz, CH), 3.08 (1H, ddd, J ) 5.8, 8.9, 15.3
Hz, CH), 3.35 and 3.37 (each 3H, s, OMe), 3.58 (1H, dd, J ) 4.0,
5.8 Hz, CH), 3.80 (1H, m), 5.79 (1H, dd, J ) 8.9, 15.6 Hz, CH),
5.86 (1H, d, J ) 15.6 Hz, CH), 6.96-7.84 (15H, m, Ph). 13C
NMR: 29.6, 39.6 (d, J ) 75.5 Hz), 47.2, 56.8, 57.8, 84.4 (d, J )
8.3 Hz), 91.3 (d, J ) 8.3 Hz), 126.0, 127.0, 128.0, 128.2 (d, J )
11.4 Hz), 128.6 (d, J ) 11.4 Hz), 130.6, 130.7, 130.8, 131.2 (d, J
) 9.3 Hz), 131.3 (d, J ) 9.3 Hz), 131.5, 132.0 (d, J ) 96.2
Hz), 133.0 (d, J ) 96.2 Hz), 136.8. 31P NMR: 31.5. IR (Nujol):
1600, 1180 cm-1. FABMS m/z: 433 (M+H+). HRMS Calcd
for C27H30O3P: 433.1933. Found: 433.1941. Anal. Calcd for
(1.75 g, 54%) as colorless needles of mp 227-228 °C and [R]25
D
-52.2 (c 1.00, CHCl3) and 6 (259 mg, 8%) as colorless needles of
mp 234-235 °C and [R]25 +33.5 (c 1.00, CHCl3).
D
5: 1H NMR: 3.13 (3H, s, OMe), 3.19 (1H, brs, CH), 3.45 (3H,
s, OMe), 4.07 (1H, brs, CH), 4.35 (1H, m), 4.48 (1H, brs, OH),
4.70 (1H, brs, CH), 5.24 (1H, m), 5.60 (1H, d, J ) 11.2 Hz, CH),
6.89-8.11 (25H, m, Ph). 13C NMR: 48.5 (d, J ) 68.3 Hz), 50.4
(d, J ) 9.3 Hz), 56.8, 57.6, 74.1 (d, J ) 4.1 Hz), 89.8 (dd, J )
5.2, 7.2 Hz), 90.2 (d, J ) 15.5 Hz), 126.6, 126.7, 127.6 (d, J )
12.4 Hz), 127.7, 128.1 (d, J ) 12.4 Hz), 128.3 (d, J ) 12.4 Hz),
128.7 (d, J ) 12.4 Hz), 129.2, 130.4, 130.6 (d, J ) 9.3 Hz), 130.7,
131.1 (d, J ) 9.3 Hz), 131.5 (d, J ) 9.3 Hz), 131.97 (d, J ) 2.1
Hz), 132.03 (d, J ) 2.1 Hz), 132.9 (d, J ) 9.3 Hz), 134.0 (d, J )
90.0 Hz), 135.6 (d, J ) 99.3 Hz), 140.1 (d, J ) 96.2 Hz), 142.0
(d, J ) 6.2 Hz), 144.4 (d, J ) 9.3 Hz). 31P NMR: 25.7, 33.6. IR
(Nujol): 3200, 1590, 1180 cm-1. FABMS m/z: 649 (M + H+).
HRMS Calcd for C39H39O5P2: 649.2273. Found: 649.2283.
6: 1H NMR: 3.14 and 3.36 (each 3H, s, OMe), 3.51 (1H, m),
3.61 (1H, brs, CH), 3.92 (1H, d, J ) 7.0 Hz, CH), 4.46 (1H, d, J
) 10.7 Hz, CH), 5.23 (1H, d, J ) 8.5 Hz, CH), 5.41 (1H, d, J )
11.3 Hz, CH), 6.64-8.44 (25H, m, Ph). 13C NMR: 46.0 (d, J )
67.2 Hz), 47.4 (d, J ) 6.2 Hz), 56.3, 57.2, 71.5, 85.0 (dd, J ) 3.1,
8.3 Hz), 88.9 (d, J ) 15.5 Hz), 125.1, 126.6, 127.3 (d, J ) 12.4
Hz), 127.6, 128.3 (d, J ) 12.4 Hz), 128.6 (d, J ) 12.4 Hz), 128.7
(d, J ) 12.4 Hz), 129.5, 130.7, 130.9 (d, J ) 9.3 Hz), 131.3, 131.5
(d, J ) 9.3 Hz), 131.6 (d, J ) 9.3 Hz), 131.79 (d, J ) 90.0 Hz),
131.84 (d, J ) 9.3 Hz), 134.5 (d, J ) 99.3 Hz), 135.7 (d, J ) 96.2
Hz), 140.7 (d, J ) 96.2 Hz), 141.0 (d, J ) 12.4 Hz), 144.5 (d, J
) 11.4 Hz). 31P NMR: 26.5, 34.8. IR (Nujol): 3300, 1600, 1170
cm-1. FABMS m/z: 649 (M + H+). HRMS Calcd for C39H39O5P2:
649.2273. Found: 649.2264.
C
27H29O3P: C, 74.96; H, 6.76. Found: C, 74.78; H, 6.75.
(1R,2S,3S,5S)-5-(Dip h en ylp h osp h or yl)-2,3-d im eth oxycy-
clop en ta n eca r boxylic Acid (9). Ozone was passed through a
solution of 8 (130 mg, 0.30 mmol) in dry MeOH (1.5 mL) at -78
°C for 2 h. Argon gas was passed through the mixture. The
mixture was concentrated at 0 °C and was added to a mixture
of formic acid (90%, 1 mL) and hydrogen peroxide (30%, 0.5 mL).
The mixture was stirred at 40 °C for 1 h and at 70 °C for 1 h
and then concentrated. To the solution of the residue in acetone
(8 mL) was added dropwise a solution of KMnO4 (100 mg) in
water (4 mL) at room temperature. After the mixture was stirred
for 1 day, concentrated HCl was added to the mixture until a
clear solution was obtained. The mixture was extracted with
CHCl3. The organic layer was washed with water and then dried
over Na2SO4. Concentration and recrystallization (Et2O) gave 9
(84 mg, 75%) as a white powder of mp 163-164 °C and [R]20
D
+54.6 (c 1.0, CHCl3). 1H NMR: 1.92-2.02 (2H, m), 3.12 (1H,
ddd, J ) 4.0, 9.5, 16.5 Hz, CH), 3.28 and 3.31 (each 3H, s, OMe),
3.46 (1H, q, J ) 9.5 Hz, CH), 3.58 (1H, m), 4.21 (1H, m), 7.43-
7.84 (10H, m, Ph). 13C NMR: 30.8, 37.0 (d, J ) 74.5 Hz), 50.3,
56.6, 56.7, 84.5 (d, J ) 7.2 Hz), 88.4 (d, J ) 7.2 Hz), 128.2 (d, J
) 11.4 Hz), 128.4 (d, J ) 11.4 Hz), 131.4 (d, J ) 9.3 Hz), 131.6
(d, J ) 9.3 Hz), 132.18 (d, J ) 83.8 Hz), 132.24, 178.9. 31P
NMR: 39.7. IR (Nujol): 1720, 1150 cm-1. FABMS m/z: 375 (M
+ H+). HRMS Calcd for C20H24O5P: 375.1361. Found: 375.1352.
2-(Diph en ylph osph or yl)-2-[(1S,2S,3S,5S)-5-(diph en ylph os-
p h or yl)-2,3-d im eth oxycyclop en tyl]-1-p h en yleth a n ol (7). To
a solution of 5 (5.26 g, 8.11 mmol) in THF (312 mL) was added
Super-Hydride (1.0 M, 24.8 mL) in THF at 0 °C. The mixture
was stirred at 0 °C for 20 min, quenched with MeOH (4 mL)
and satd NH4Cl (260 mL), and then extracted with EtOAc. The
organic layer was washed with brine and then dried over Na2-
SO4. Concentration and chromatography (EtOAc/MeOH ) 100/
1) gave 7 (3.97 g, 75%) as colorless plates of mp 196-197 °C
Met h yl (1R,2S,3S,5S)-5-(Dip h en ylp h osp h or yl)-2,3-d i-
m eth oxycyclop en ta n eca r boxyla te (10). A solution of 9 (225
mg, 0.6 mmol) and concentrated H2SO4 (0.03 mL) in methanol
(7.2 mL) was heated under reflux for 12 h and was then treated
with aq Na2CO3. The mixture was extracted with CHCl3. The
organic layer was washed with brine and then dried over Na2-
SO4. Concentration and chromatography (EtOAc/MeOH ) 100/
1) gave 10 (222 mg, 95%) as a white solid of mp 88-90 °C and
(DME) and [R]25 -25.5 (c 1.00, CHCl3). 1H NMR: 1.50-1.68
D
(2H, m), 2.45 (1H, m), 3.175 and 3.184 (each 3H, s, OMe), 3.22-
3.33 (2H, m), 3.89 (1H, m), 3.95 (1H, brs, OH), 4.37 (1H, dd, J
) 4.3, 7.9 Hz, CH), 5.19 (1H, m), 7.13-8.04 (25H, m, Ph). 13C
NMR: 30.7, 35.2 (d, J ) 74.5 Hz), 43.9, 47.7 (d, J ) 67.2 Hz),
[R]20 +13.3 (c 1.02, CHCl3). 1H NMR: 1.87 (1H, m), 2.29 (1H,
D
(16) 1H, 13C, and 31P NMR spectra were taken at 500, 126, and 202
MHz in CDC13. Chemical shift values are expressed in ppm relative
to internal tetramethylsilane and external 85% H3PO4 for 31P. Ab-
breviations are as follows: s, singlet; d, doublet; t, triplet; m, multiplet.
Purification was carried out using silica gel column chromatography
unless otherwise noted. TLC analyses were performed on Merck silica
gel 60 F254. Column chromatography was carried out with silica gel,
Fuji Silysia BW820. All reactions were carried out under an argon
atmosphere unless otherwise stated.
m), 3.15 (1H, ddd, J ) 5.8, 9.5, 15.3 Hz, CH), 3.25, 3.31, and
3.35 (each 3H, s, OMe), 3.45 (1H, dq, J ) 1.5, 9.5 Hz, CH), 3.77
(1H, m), 3.91 (1H, dd, J ) 4.3, 5.8 Hz, CH), 7.41-7.85 (10H, m,
Ph). 13C NMR: 29.4, 36.8 (d, J ) 75.5 Hz), 47.8, 51.9, 56.9, 57.5,
84.4 (d, J ) 7.2 Hz), 89.6 (d, J ) 7.2 Hz), 128.3 (d, J ) 11.4 Hz),
128.7 (d, J ) 11.4 Hz), 130.8 (d, J ) 8.3 Hz), 131.2 (d, J ) 8.3
Hz), 131.7, 131.8 (d, J ) 2.1 Hz), 132.3 (d, J ) 71.4 Hz), 173.8.
31P NMR: 31.6. IR (Nujol): 1735, 1190 cm-1. FABMS m/z: 389
5866 J . Org. Chem., Vol. 67, No. 16, 2002

(M + H+). Anal. Calcd for C21H25O5P: C, 64.94; H, 6.49. Found:
128.29 (d, J ) 8.3 Hz), 128.35 (d, J ) 8.3 Hz), 128.9 (d, J ) 23.8
Hz), 133.4 (d, J ) 19.7 Hz), 133.7 (d, J ) 19.7 Hz), 136.7 (d, J
) 13.4 Hz), 136.8 (d, J ) 13.4 Hz), 178.8 (d, J ) 3.1 Hz). 31P
NMR: -3.20. IR (neat): 1730 cm-1. FABMS m/z: 359 (M + H+).
HRMS Calcd for C20H24O4P: 359.1412. Found: 359.1400.
P a lla d iu m -Ca ta lyzed Asym m etr ic Allylic Alk yla tion of
1,3-Dip h en yl-2-p r op en yl Aceta te 13 (Ta ble 1. En tr y 4). A
mixture of 12 (7.8 mg, 0.022 mmol) and Pd(OAc)2 (2.4 mg, 0.011
mmol) in THF (1.1 mL) was stirred at room temperature for 0.5
h. After addition of a solution of 13 (92 mg, 0.36 mmol)17 in THF
(0.7 mL), the mixture was stirred for 0.5 h at room temperature.
A solution of sodium dimethyl malonate (0.54 mmol) in THF
(1.8 mL) was added to the mixture. The mixture was stirred at
room temperature for 24 h and quenched with 2 N HCl and then
extracted with AcOEt. The organic layer was washed with water
and brine, and then dried over Na2SO4. Concentration and
chromatography (hexane/AcOEt ) 9/1) gave (R)-14 (91 mg, 77%)
as a colorless oil of [R]20D +20.5 (c 0.8, CHCl3). The enantiomeric
excess was determined to be 93% by HPLC analysis (Daicel
Chiralcel AD, hexane/2-propanol ) 95/5, 254 nm, 1.0 mL/min:
major peak 19.3 min, minor peak 27.1 min). The absolute
configuration was determined to be (R) by the optical rotation.18
C, 64.67; H, 6.42.
Met h yl
(1R,2S,3S,5S)-5-(Dip h en ylp h osp h in o)-2,3-d i-
m eth oxycyclop en ta n eca r boxyla te (11). Trichlorosilane (2.0
mL, 20 mmol) was added to a stirred mixture of 10 (400 mg,
1.03 mmol) and triethylamine (2.8 mL, 20 mmol) in dry benzene
(40 mL) under an argon atmosphere at 0 °C in a sealed tube.
The mixture was stirred at 110 °C for 24 h. The mixture was
added to 30% aq NaOH (90 mL) at 0 °C and stirred at 60 °C for
0.5 h. The mixture was extracted with benzene. The organic
layer was washed with brine and then dried over Na2SO4.
Concentration and chromatography (EtOAc) gave 11 (356 mg,
93%) as a white solid of mp 59-61 °C and [R]25 +26.9 (c 1.10,
D
CHCl3). 1H NMR: 1.81-2.01 (2H, m), 2.68 (1H, ddd, J ) 6.4,
9.2, 11.9 Hz, CH), 3.26 (1H, m), 3.28, 3.31 and 3.35 (each 3H, s,
OMe), 3.69 (1H, m), 3.92 (1H, dd, J ) 4.3, 6.4 Hz, CH), 7.30-
7.53 (10H, m, Ph). 13C NMR: 33.4 (d, J ) 15.5 Hz), 34.4 (d, J )
10.3 Hz), 51.7, 52.7 (d, J ) 20.7 Hz), 57.0, 57.8, 85.0 (d, J ) 6.2
Hz), 90.0 (d, J ) 6.2 Hz), 128.2 (d, J ) 8.3 Hz), 128.4 (d, J ) 8.3
Hz), 129.0 (d, J ) 23.8 Hz), 133.2 (d, J ) 20.7 Hz), 133.9 (d, J
) 20.7 Hz), 136.2 (d, J ) 13.4 Hz), 136.7 (d, J ) 13.4 Hz), 174.2
(d, J ) 3.1 Hz). 31P NMR: -3.55. IR (Nujol): 1730 cm-1. FABMS
m/z: 373 (M + H+). HRMS Calcd for C21H26O4P: 373.1569.
Found: 373.1571. Anal. Calcd for C21H25O4P‚1/4H2O: C, 66.92;
H, 6.82. Found: C, 66.87; H, 6.77.
Ack n ow led gm en t. This research was supported by
a Grant-in-Aid for Scientific Research on Priority Areas
(A) “Exploitation of Multi-Element Cyclic Molecules”
from the Ministry of Education, Culture, Sports, Science
and Technology, J apan.
(1R,2S,3S,5S)-5-(Dip h en ylp h osp h in o)-2,3-d im eth oxycy-
clop en ta n eca r boxylic a cid (12). To a solution of 11 (54 mg,
0.15 mmol) in THF (0.75 mL) was added a solution of NaOH
(29 mg, 0.73 mmol) in water (0.75 mL). The mixture was stirred
at 50 °C for 12 h. After the mixture was neutralized with 2 N
HCl, the mixture was extracted with CH2Cl2. The organic layer
was washed with water and dried over Na2SO4. Concentration
and chromatography (benzene/EtOAc ) 1/4) gave 12 (51 mg,
98%) as a colorless oil of [R]25D +25.6 (c 0.75, CH2Cl2). 1H NMR:
1.80-2.05 (2H, m), 2.69 (1H, ddd, J ) 5.1, 8.2, 12.8 Hz, CH),
3.29 (1H, m), 3.31 and 3.38 (each 3H, s, OMe), 3.72 (1H, m),
3.94 (1H, dd, J ) 3.4, 5.1 Hz, CH), 7.26-7.51 (10H, m, Ph). 13C
NMR: 32.9 (d, J ) 12.4 Hz), 34.2 (d, J ) 12.4 Hz), 53.0 (d, J )
18.6 Hz), 57.0, 57.3, 85.4 (d, J ) 5.2 Hz), 89.5 (d, J ) 5.2 Hz),
Su p p or tin g In for m a tion Ava ila ble: Spectroscopic data
(NMR) of the products. This material is available free of charge
via the Internet at http://pubs.acs.org/.
J O025725V
(17) Leung, W.; Cosway, S.; J ones, R. H. V.; McCann, H.; Wills, M.
J . Chem. Soc., Perkin Trans. 1 2001, 2588.
(18) Sprinz, J .; Helmchen, G. Tetrahedron Lett. 1993, 34, 1769.
J . Org. Chem, Vol. 67, No. 16, 2002 5867