Synthesis of chiral hydroxyl phospholanes from D-mannitol and their use in asymmetric catalytic reactions

Article abstract of DOI:10.1021/jo000066c

Chiral hydroxyl monophosphane 3 [(2S,3S,4S,5S)-3,4-dihydroxy-2,5-dimethyl-1-phenylphospholane] and bisphospholanes 5a [1,2-bis[(2S,3S,4S,5S)-3,4-dihydroxy-2,5-dimethylphospholanyl]benzene] and 5b [1,2-bis[(2S,3S,4S,5S)-2,5-diethyl-3,4-dihydroxyphospholanyl]benzene] were synthesized from readily available D-mannitol in high yields. Strategies for protection and deprotection of OH-groups in the presence of phosphines have been explored. Rate acceleration in the Baylis - Hillman reaction was observed when a hydroxyl phosphine was used as the catalyst. Rhodium complexes with chiral bisphospholanes are highly enantioselective catalysts for the asymmetric hydrogenation of various kinds of functionalized olefins such as dehydroamino acid derivatives, itaconic acid derivatives, and enamides. An interesting feature of the hydroxyl phospholane system is that hydrogenation of some substrates can be carried out in water with >99% ee and 100% conversion (e.g., itaconic acid).

Full text of DOI:10.1021/jo000066c

J . Org. Chem. 2000, 65, 3489-3496
3489
Syn th esis of Ch ir a l Hyd r oxyl P h osp h ola n es fr om D-m a n n itol a n d
Th eir Use in Asym m etr ic Ca ta lytic Rea ction s
Wenge Li, Zhaoguo Zhang, Dengming Xiao, and Xumu Zhang*
Department of Chemistry, The Pennsylvania State University, University Park, Pennsylvania 16802
Received J anuary 18, 2000
Chiral hydroxyl monophosphane 3 [(2S,3S,4S,5S)-3,4-dihydroxy-2,5-dimethyl-1-phenylphospholane]
and bisphospholanes 5a [1,2-bis[(2S,3S,4S,5S)-3,4-dihydroxy-2,5-dimethylphospholanyl]benzene]
and 5b [1,2-bis[(2S,3S,4S,5S)-2,5-diethyl-3,4-dihydroxyphospholanyl]benzene] were synthesized
from readily available D-mannitol in high yields. Strategies for protection and deprotection of OH-
groups in the presence of phosphines have been explored. Rate acceleration in the Baylis-Hillman
reaction was observed when a hydroxyl phosphine was used as the catalyst. Rhodium complexes
with chiral bisphospholanes are highly enantioselective catalysts for the asymmetric hydrogenation
of various kinds of functionalized olefins such as dehydroamino acid derivatives, itaconic acid
derivatives, and enamides. An interesting feature of the hydroxyl phospholane system is that
hydrogenation of some substrates can be carried out in water with >99% ee and 100% conversion
(e.g., itaconic acid).
In tr od u ction
plexes have shown broad utility for catalytic asymmetric
hydrogenation.5 We proposed to introduce hydroxyl groups
in the ligand framework as in monophospholane 3 and
bisphospholane 5 for achieving the following significant
goals: (1) to introduce a secondary interaction site
between the hydroxyl group and substrate, (2) to make
water-soluble ligands for carrying out reactions in aque-
ous media or to link the hydroxyl groups to a polymer
chain that can be separated easily from the reaction
mixture, and (3) to make ligands easily by using readily
available chiral materials. It is common to use D-mannitol
as a chiral auxiliary or ligand backbone.6 We have
learned from recent literature that the Borner, Brown,
and RajanBabu groups have independently pursued the
synthesis of chiral phospholanes derived from D-mannitol
during the course of our study.2c,6d-h The so-called
RoPhos, 1,2-bis[(2S,3S,4S,5S)-3,4-bis(benzyloxy)-2,5-di-
methylphospholanyl]benzene, by Borner is an excellent
ligand for Rh-catalyzed asymmetric hydrogenation reac-
tions.6d Borner’s results prompted us to disclose our
findings with the hydroxyl phospholanes 3 and 5 since
they are more amenable for ligand modification than
RoPhos. In addition, we envision that different diaste-
Transition metal-catalyzed asymmetric reactions are
one of the most efficient methods for preparing a wide
range of enantiomerically pure compounds.1 Design and
synthesis of new efficient chiral ligands is crucial for the
development of practical asymmetric catalytic reactions.
Of particular interest in ligand design is the development
of novel structural motifs or introduction of concepts such
as “hemi-labile ligands” and ligands with secondary
interactions with substrates.2 Recently, we introduced
several classes of structurally innovative bisphosphines
based on chiral 1,4-diols containing four stereogenic
centers (e.g., BICP and PennPhos), which have shown
excellent enantioselectivities in Rh- and Ru-catalyzed
hydrogenation of olefins and ketones.3 Naturally, we have
planned to make more chiral phosphines from a variety
of 1,4-diols, especially those from readily available ma-
terials such as sugars and tartaric acid derivatives.
Herein we report the synthesis of hydroxyl phospholanes
3 and 5 from D-mannitol as well as their application in
the asymmetric Baylis-Hillman reaction and asym-
metric hydrogenation of various functionalized olefins.4
Burk et al. have developed C2-symmetric bisphos-
pholanes DuPhos and BPE, and their rhodium(I) com-
(4) The preliminarily results of asymmetric hydrogenation of dehy-
droamino acid derivatives with Rh(I)-5a complex were reported. See:
Li, W.; Zhang, Z.; Xiao, D.; Zhang, X. Tetrahedron Lett. 1999, 40, 6701.
(5) (a) Burk, M. J . J . Am. Chem. Soc. 1991, 113, 8518. (b) Burk, M.
J .; Feaster, J . E.; Nugent, W. A.; Harlaw, R. L. J . Am. Chem. Soc. 1993,
115, 10125. (c) Burk, M. J .; Kalberg, C.; Pizzano, A. J . Am. Chem. Soc.
1998, 120, 4345. (d) Burk, M. J .; Bienewald, F.; Harris, M.; Zanotti-
Gerosa, A. Angew. Chem., Int. Ed. 1998, 37, 1931. (e) Burk, M. J .; Allen,
J . G.; Kiesman, W. J . Am. Chem. Soc. 1998, 120, 657. (f) Burk, M. J .
Casy, G.; J ohnson, N. J . Org. Chem. 1998, 63, 6084. (g) Burk, M. J .;
Bienewald, F.; Challenger, S.; Derrick, A.; Ransden, J . J . Org. Chem.
1999, 64, 3290.
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249. (b) Stoss, P.; Hemmer, R. Adv. Carbohydr. Chem. Biochem. 1992,
49, 93-173. (c) Reetz, M. T.; Neugebauer, T. Angew. Chem., Int. Ed.
1999, 38, 179. (d) Holz, J .; Quirmbach, M.; Schmidt, U.; Heller, D.;
Sturmer, R.; Borner, A. J . Org. Chem. 1998, 63, 8031. (e) Borner, A.;
Holz, J .; Voss, G.; Sturmer, R. DE 48 084 (18.06.1997). (f) Holz, J .;
Heller, D.; Sturmer, R.; Borner, A. Tetrahedron Lett. 1999, 40, 7059.
During the preparation of our full paper, RajanBabu reported synthesis
and applications of some ligands reported in our paper: (g) Yan, Y.-
Y.; RajanBabu, T. V. Org. Letter 2000, 2, 199. (h) Yan, Y.-Y.;
RajanBabu, T. V. J . Org. Chem. 2000, 65, 900.
(1) (a) Catalytic Asymmetric Synthesis; Ojima, I., Ed.; VCH: New
York, 1993. (b) Sheldon, R. A. Chirotechnology; Marcel Dekker: New
York, 1993. (c) Noyori, R. Asymmetric Catalysis In Organic Synthesis;
Wiley: New York, 1994.
(2) (a) Sawamura, M.; Ito, Y. Chem. Rev. 1992, 92, 857 and
references therein. (b) Holz, J .; Quirmbach, M.; Borner, A. Synthesis
1997, 983 and references therein. (c) Carmichael, D.; Doueet, H.;
Brown, J . M. Chem. Commun. 1999, 261. (d) Nomura, N,; J in, J .; Park,
H.; Rajanbabu, T. V. J . Am. Chem. Soc. 1998, 120, 459. (e) Rajanbabu,
T. V.; Nomura, N.; J in, J .; Radetich, B.; Park, H.; Nandi. M. Chem.
Eur. J . 1999, 5, 1963.
(3) (a) Zhang, X. US Provisional Patent, 60/019,938, filed J une 14,
1996, and PTC International Patent 96,2055-A, filed J une 13, 1997.
(b) Zhu, G.; Cao, P.; J iang, Q.; Zhang, X. J . Am. Chem. Soc. 1997, 119,
1799. (c) Zhu, G.; Zhang, X. J . Org. Chem. 1998, 63, 3133. (d) J iang,
Q.; J iang, Y.; Xiao, D.; Cao, P.; Zhang, X. Angew. Chem., Int. Ed. 1998,
37, 1100. (e) J iang, Q.; Xiao, D.; Zhang, Z.; Cao, P.; Zhang, X. Angew.
Chem., Int. Ed. 1999, 37, 516. (f) Zhang, Z.; Zhu, G.; J iang, Q.; Xiao,
D.; Zhang, X. J . Org. Chem. 1999, 64, 1774. (g) Cao, P.; Zhang, X. J .
Org. Chem. 1999, 64, 2127. (h) Cao, P.; Zhang, X. J . Am. Chem. Soc.
1999, 121, 7708.
10.1021/jo000066c CCC: $19.00 © 2000 American Chemical Society
Published on Web 05/04/2000

3490 J . Org. Chem., Vol. 65, No. 11, 2000
Li et al.
reoisomers of the 1,4-diols of our chiral hydroxyl phos-
pholanes are also available from D-mannitol, which could
potentially lead to opposite asymmetric induction in the
catalytic process.7
protective groups followed by selective tosylation of the
two primary hydroxymethyl groups and subsequent
reduction with LiAlH4 furnished the 1,4-diol 8.6d,11 In
basic medium, the ditosylate underwent an intramolecu-
lar SN2 reaction leading to diepoxide 9 with retention of
configuration at C2 and C5.7 Regioselective ring-opening
by attack of PhMgBr in the presence of CuI gave the 1,4-
diol 10 in high yield.12 Cyclic sulfate 11 was obtained
using esterification with thionyl chloride followed by
oxidation with RuCl3/NaIO4.13 Nucleophilic attack of 11
with phenylphosphine in the presence of n-BuLi afforded
1 as a colorless oil in high yield. For further purification,
phospholane 1 was converted in situ into the correspond-
ing phosphine borane adducts by treatment with a 1 M
THF solution of BH3.14 After flash chromatography, the
phosphines were liberated with 1,4-diazabicyclo[2,2,2]-
octane (DABCO) in toluene to afford the desired phos-
pholane 1.14 In the ketal route, selective hydrolysis of 1,2:
3,4:5,6-triacetonide D-mannitol gave 3,4-O-isopropylidene
D-mannitol 127 as a white solid that was transferred into
the ketal phosphine 2.
Our new hydroxyl phospholanes accelerate the Baylis-
Hillman reaction, which we believe is due to the second-
ary interactions between the hydroxyl group and the
enolate intermediate formed during the reaction. We are
also pleased to see that Rh(I) complexes of our new
bisphospholanes 5 afforded efficient catalysts for the
highly enantioselective hydrogenation of various unsat-
urated substrates such as dehydroamino acid derivatives,
itaconic acid derivatives, enamides, and enol acetates.
Another significant finding is that the hydrogenation
reaction can be carried out in water with high ee (e.g.,
itaconic acid, >99% ee).
In our experiments, all attempts to cleave the O-benzyl
ether groups of the 1a -borane adduct failed. In the
15
presence of excess BCl3 or BF3‚Et2O,16 the 1a -borane
adduct was debenzylated to give the derivatives bearing
one hydroxyl and one benzyl ethyl groups. The corre-
sponding phosphine oxide of 1a was formed under
hydrogenation conditions [Pd(OH)2/C, 30 atm of H2 or
H2NNH2‚H2O, Pd/C in CH3OH or ethanol with reflux].17
High temperature (50 °C) and H2 pressure (40 atm) led
to cleavage of the benzyl ether and reduction of the
phenyl group attached to phosphine to a cyclohexanyl
group. Although O-benzyl ether protection afford the
monophosphine 1 in high yield, we cannot get the desired
hydroxyl phosphine 3 from 1a . In contrast, the isopro-
pylidene group in 2 was smoothly removed by acid-
catalyzed hydrolysis (methanesulfonic acid/CH3OH,
refluxing).8b Based on these results, we selected the
isopropylidene protection strategy in the preparation of
hydroxyl phosphines. Compared with preparation of 8,
synthesis of the diol 15 is much easier because there is
no need to run column chromatography in all of the steps.
The bisphospholanes 4 and 5 were synthesized using
a similar procedure for preparation of 3. The phosphine
compounds 4 were formed as crystalline materials and
purified by recrystallization from ether/methanol. Com-
pounds 4 are air stable (e.g., their 31P NMR spectra
remain the same after 4 days). The easier synthesis and
air-stability of phosphines 4 and 5 are attractive for the
practical applications of these chiral phosphines.
Resu lts a n d Discu ssion
1. Liga n d P r ep a r a tion . There have been extensive
studies in preparing hydroxyl phosphines.8 The key step
is removal of the O-protecting group in the presence of
phosphine. Most of the known O-protective groups have
serious drawbacks due to attack by phosphide ions or to
problematic deprotection in the presence of incorporated
phosphine groups.9 Because Kagan’s (S)-1,2-bis(diphen-
ylphosphino)butane-4-ol was protected via benzyl ether8f
and (R,R)-1,4(diphenylphosphino)butane-2,3-diol was pro-
g-h
tected via isopropylidene ketal,8b,8
we started both
synthetic routes simultaneously for the purpose of com-
parison. The synthetic route is illustrated in Scheme 1.
For the benzyl ether protection route, commercially
available D-mannitol was selectively converted into the
1,2:5,6-di-O-isopropylidene derivative followed by O-
benzylation of the remaining alcoholic groups affording
3,4-di-O-benzyl ether 7.10 Acidic cleavage of the acetal
2. Asym m etr ic Ca ta lytic Ba ylis-Hillm a n Rea c-
tion . The Baylis-Hillman reaction is a convenient
(7) (a) Merver, Y. L.; Dureault, A.; Greck, C.; Micas-Languin, D.;
Gravier, C.; Depezay, J .-C. Heterocycles 1987, 25, 541. (b) Allevi, P.;
Anastasia, M.; Ciuffreda, P.; Sanvito, A. M. Tetrahedron: Asymmetry
1994, 5, 927.
(10) (a) J urczak, J .; Bauer, T.; Chmielewski, M. Carbohydr. Res.
1987, 164, 493. (b) Zou, W.; Szarek, W. A. Carbohydr. Res. 1994, 254,
25.
(11) Fitremann, J .; Dureault, A.; Depezay, J .-C. Tetrahedron 1995,
51, 9581.
(12) Ghosh, A. K.; Mckee, S. P.; Thompson, W. J . Tetrahedron Lett.
1991, 32, 5729.
(13) (a) Kim, B. M.; Sharpless, K. B. Tetrahedron Lett. 1989, 30,
655. (b) Gao, Y.; Sharpless, K. B. J . Am. Chem. Soc. 1988, 110, 7538.
(14) Ohff, M.; Holz, J .; Quirmbach, M.; Borner, A. Synthesis 1998,
1391.
(8) (a) Ward, J .; Borner, A.; Kagan, H. B. Tetrahedron: Asymmetry
1992, 3, 849. (b) Borner, A.; Ward, J .; Kortus, K.; Kagan, H. B.
Tetrahedron: Asymmetry 1993, 4, 2219. (c) Borner, A.; Kadyrov, R.;
Michalik, M.; Heller, D. J . Organomet. Chem. 1994, 470, 237. (d)
Borner, A.; Holz, J .; Ward, J .; Kagan, H. B. J . Org. Chem. 1993, 58,
6814. (e) Lopusinski, A.; Bernet, B.; Linden, A.; Vasella, A. Helv. Chim.
Acta 1993, 76, 94. (f) Borner, A.; Ward, J .; Ruth, W.; Holz, J .; Kless,
A.; Heller, D.; Kagan, H. B. Tetrahedron 1994, 50, 10419. (g) Desche-
neaux, R.; Stille, J . J . Org. Chem. 1985, 50, 2299. (h) Tamao, K.;
Nakamura, K.; Yamaguchi, S.; Shiro, M.; Saito, S. Chem. Lett. 1996,
1007.
(15) Nagaoka, H.; Schmid, G.; Iio, H.; Kishi, Y. Tetrahedron Lett.
1981, 22, 899.
(16) Fuji, K.; Ichikawa, K.; Node, M.; Fujita, E. J . Org. Chem. 1979,
44, 1661.
(9) Greene, T. W. Protective Groups in Organic Synthesis; Wiley &
Sons: New York, 1991.
(17) (a) Bieg, T.; Szeja, W. Synthesis 1986, 317. (b) Otvos, L.; Beres,
J .; Sagi, G.; Tomoskozi, I.; Gruber, L. Tetrahedron Lett. 1987, 28, 6381.

Synthesis of Chiral Hydroxyl Phospholanes
J . Org. Chem., Vol. 65, No. 11, 2000 3491
Sch em e 1a
a
Key: (a) (i) (CH3)2C(OCH3)2, PTS, DMSO, rt, (ii) BnBr, KOH, DMSO, rt, (iii) 70% HOAc-H2O, 40 °C; (b) (i) TsCl, pyridine, 0 °C, (ii)
LiAlH4, THF, (c) (i) SOCl2, Et3N, CH2Cl2, 0 °C, (ii) NalO4, RuCl3‚xH2O, 0 °C; (d) (i) TsCl, pyridine, 0 °C, (ii) K2CO3, CH3OH; (e) CuI,
PhMgBr, THF, -40 °C; (f) (i) PhPH2, n-BuLi, THF, (ii) n-BuLi, THF; (g) (i) acetone, H2SO4, (ii) 70% HOAc-H2O, 40 °C; (i) CuI, CH3MgBr,
THF, -40 °C, (ii) CH3OH, H2O, CH3SO3H, refluxing; (j) (i) 1,2-H2PC6H4PH2, n-BuLi, THF, (ii) n-BuLi, THF.
Ta ble 1. Asym m etr ic Ca ta lytic Ba ylis-Hillm a n
method for the preparation of â-hydroxy-R-methylene
ketones, nitriles, and esters via the condensation of an
aldehyde and corresponding R,â-unsaturated deriva-
tives.18 The reaction products bearing polyfunctional
groups are very useful for various organic transforma-
tions. Recently, much effort has been focused on the
development of an enantioselective Baylis-Hillman reac-
tion.19 However, only limited success has been reported.
A significant drawback is the requirement of high pres-
sure with a tertiary amine catalyst,20 and low reactivity
is observed with both amine and phosphine catalysts.21
The first step of the Baylis-Hillman reaction was
proposed as a Michael addition of tertiary amines or
phosphines to the activated alkene forming a transient
zwitterionic enolate.22 If this intermediate is stabilized
by interaction of an intramolecular hydrogen bond, the
Rea ction a
entry
catalyst
time (h)
yieldb (%)
eec (%)
1
2
3
4
1a
1b
3
70
94
9
29
18
83
56
19 (+)
2 (-)
17 (+)
18 (+)
20
31
a
The reaction was carried out at rt by mixing 1 mmol of
4-pyridinecarbonaldehyde, 1 mL of methyl acrylate, and 10%
b
catalyst under N2 atmosphere. Isolated yield. c % ee was deter-
mined by GC using a Supelco Chiral 1000 column.
reactivity increases.23 Based on this assumption, we
tested our hydroxyl phospholanes in the Baylis-Hillman
reaction using 4-pyridinecarboaldehyde and methyl acry-
late as the reactants.
The reaction was carried out by mixing the reactants
and phosphines under inert atmosphere in the absence
of solvent. The phospholane 1a catalyzed this reaction
with low conversion and moderate ee (19%) (Table 1,
entry 1). When the methyl group in 1a was replaced with
a benzyl group (1b), the ee dropped to 2% (entry 2). With
(18) For the recent progress of Baylis-Hillman reaction, see a
review: Basavaiah, D.; Rao, P. D.; Hyma, R. S. Tetrahedron 1996, 52,
8001.
(19) (a) Barrett, A. G. M.; Cook, A. S.; Kamimura, A. Chem.
Commun. 1998, 2533. (b) Barrett, A. G. M.; Kamimura, A. J . Chem.
Soc., Chem. Commun. 1995, 1755. (c) Ciganek, E. Org. React. 1997,
51, 201. (d) Brzezinski, L. J .; Rafel, S.; Leahy, J . W. J . Am. Chem.
Soc. 1997, 119, 4317.
(20) (a) Oishi, T.; Oguri, H.; Hirama, M. Tetrahedron: Asymmetry
1995, 6, 1241. (b) Marko, I. E.; Giles, P. R.; Hindley, N. J . Tetrahedron
1997, 53, 1015.
(21) Hayase, H.; Shibata, T.; Soai, K.; Wakatsuki, Y. Chem. Com-
mun. 1998, 1271.
(22) (a) Drewes, S. E.; Nijamela, O. L.; Emslie, N. D.; Ramesar, N.;
Field, J . S. Synth. Commun. 1993, 23, 2807. (b) Hill, J . S.; Isaacs, N.
S. J . Phys. Org. Chem. 1990, 3, 285. (c) Bode, M. L.; Kaye, P. T.
Tetrahedron Lett. 1991, 32, 5611. (d) Fort, Y.; Berthe, M. C.; Caubere,
P. Tetrahedron 1992, 48, 6371.
(23) (a) Drewes, S. E.; Freese, S. D.; Emslie, N. D.; Roos, G. H. P.
Synth. Commun. 1988, 18, 1565. (b) Ailey, M.; Marko, I. E.; Ollis, W.
D.; Rasmussen, P. R. Tetrahedron Lett. 1990, 31, 4509. (c) Basavaiah,
D.; Sarma, P. K. S. Synth. Commun. 1990, 20, 1611.

3492 J . Org. Chem., Vol. 65, No. 11, 2000
Li et al.
Sch em e 2
4-7) has no significant effect on the enantioselectivity.
The enantioselectivities obtained with these hydroxyl
phospholanes are comparable to those achieved with
Rh-DuPhos catalysts and higher than those reported with
a Rh-RoPhos catalyst.26
Extremely high enantioselectivities have been achieved
in hydrogenation of dehydroamino acid and ester deriva-
tives with the Rh-5b catalyst (Table 3). The catalyst can
tolerate substrates with thio (entries 11 and 12) and
halogen groups (entries 3, 4, and 7-10). A wide array of
ring-substituted phenylalanine derivatives were formed
with high enantioselectivity regardless of the substituent
or substitution position. The 2-naphthyl (entries 13 and
14) as well as N-benzoyl derivatives (entries 15 and 16)
were also hydrogenated with high enantioselectivities
(>99% ee).
the hydroxyl phospholane 3 as the catalyst, the reaction
was accelerated significantly [83% isolated yield in 9 h
(entry 3) vs 29% isolated yield in 70 h (entry 1)].
Unfortunately, the enantioselectivity was not enhanced
with the hydroxyl phospholane 3. This rate acceleration
may be explained by the hydrogen-bonding interaction
between a hydroxyl group and an enolate formed in the
reaction.
4. Asym m etr ic Hyd r ogen a tion of Ita con ic Acid in
Aqu eou s Med iu m . Enantioselective hydrogenation of
itaconic acid and its dimethyl ester was carried out (Table
4). The Rh-Et-phospholane 5b catalyst gave superior
enantioselectivities for both the acid and dimethyl ester
compared with Rh-Me-phospholane 5a . The mixture of
Rh(COD)2PF6 (2.1 mg, 0.0045 mmol) and 0.1 mL of 0.05
M 5b (0.005 mmol) in methanol was stirred for several
minutes followed by addition of 3 mL of water. A clear
yellowish solution was formed, which indicates that the
Rh(I)-5b complex is soluble in water. In this 97%/3%
water/MeOH solution, itaconic acid was hydrogenated
smoothly with 100% conversion and >99% ee. It is
exciting that this hydrogenation reaction can be carried
out in water without any decrease of enantioselectivity.
Further modification of the new hydroxyl phosphines will
focus on creating more water-soluble catalysts so two-
phase catalytic systems can be generated.
5. Asym m etr ic Hyd r ogen a tion of En a m id es a n d
En ola ceta tes. In many cases, high enantioselectivity
and reactivity are achieved only on electron-deficient
olefins. In contrast, electron-rich olefins such as simple
enamides and enolacetates are generally poor substrates
for asymmetric hydrogenation with most known sys-
tems.27 Since enamides and enolacetates upon asym-
metric hydrogenation can be converted to enantiomeri-
cally pure amines and alcohols, it would be extremely
desirable to have a general and efficient method for this
transformation. Therefore, we have investigated the
hydrogenation of several enamides with rhodium-5b
complex. The results of these studies are listed in Table
5. While high enantioselectivities were obtained, rela-
tively low reaction rates were observed compared with
DuPhos, PennPhos, and BICP.26
We also made the boron analogue (20) of phospholane
3 by mixing phenylboronic acid in methylene chloride at
-78 °C (Scheme 2).24 The product was used directly as
the catalyst after removing the solvent under vacuum.
We expected to achieve rate acceleration through second-
ary interaction between the substrate and boron Lewis
acid. Indeed, a moderate rate acceleration was achieved
with 20 compared with 1a (entry 4).
3. Asym m etr ic Hyd r ogen a tion of Deh yd r oa m in o
Acid Der iva tives. The demand of making enantiomeri-
cally pure R-amino acids has led to the development of
effective chiral diphosphine-rhodium catalysts for hy-
drogenation of R-(acylamino)acrylates.1,25 This reaction
has been extensively investigated, and high enantiose-
lectivities have been achieved using many chiral diphos-
phine-Rh catalysts. Thus, the hydrogenation of these
enamides has become a standard test reaction for new
chiral phosphine ligands. Using chiral chelating hydroxyl
phosphines as ligands, we have evaluated their effec-
tiveness in Rh-catalyzed asymmetric hydrogenation of
R-(acylamino)acrylates (Table 2 and Table 3).
The cationic Rh(I) complexes [Rh(COD)(phosphine)]X
(X ) PF6, BF4, SbF6, and OTf) were prepared in situ by
mixing the corresponding Rh(COD)2X with 1.1 molar
equiv of bisphospholane ligands under inert atmosphere.
Surprisingly, the isopropylidene-protected phospholane
4a does not work in the hydrogenation reaction. Under
3 atm of H2, no product was detected by chiral GC after
12 h. This is likely due to the steric hindrance of the
isopropylidene group in the two fused trans-five-mem-
bered rings, which blocks the substrate binding site to
the Rh. However, Rh complex with the corresponding
hydroxyl phospholane 5a is an excellent hydrogenation
catalyst.4 The more sterically hindered Et-phospholane
5b provided slightly higher enantiomeric excess com-
pared with Me-phospholane 5a (Table 2, entries 2 and
4). Furthermore, both acid and ester derivatives were
hydrogenated with high enantioselectivities. Changing
solvents (entries 4 and 8-11) and counteranions (entries
To further expand the utility of this asymmetric
hydrogenation, we have examined enantioselective hy-
drogenation of cyclic enamide 29 and some enolacetates
(26) (a) Borner, A.; Kless, A.; Kempe, R.; Heller, D.; Holz, J .;
Baumann, W. Chem. Ber. 1995, 128, 767. (b) Borns, S.; Kadyrov, R.;
Heller, D.; Baumann, W.; Spannenberg, A.; Kempe, R.; Holz, J .; Borner,
A. Eur. J . Inorg. Chem. 1998, 1291. (c) Borns, S.; Kadyrov, R.; Heller,
D.; Baumann, W.; Holz, J .; Borner, A. Tetrahedron: Asymmetry 1999,
10, 1425. (d) Kadyrov, R.; Borner, A.; Selke, R. Eur. J . Inorg. Chem.
1999, 705.
(27) (a) Chan, Y. Ng C.; Osborn, J . A. J . Am. Chem. Soc. 1990, 112,
9400. (b) Willoughby, C. A.; Buchwald, S. L. J . Am. Chem. Soc. 1994,
116, 8952. (c) Uematsu, N.; Fuji, A.; Hashiguchi, S.; Ikariya, T.; Noyori,
R. J . Am. Chem. Soc. 1996, 118, 4916. (d) Burk, M. J .; Wang, Y. M.;
Lee, R. J . J . Am. Chem. Soc. 1996, 118, 5241. (e) Zhang, F.-Y.; Pai,
C.-C.; Chan, A. S. C. J . Am. Chem. Soc. 1998, 120, 5808. (f) Zhu, G.;
Zhang, X. J . Org. Chem. 1998, 63, 9590. (g) Xiao, D.; Zhang, Z.; Zhang,
X. Org. Lett. 1999, 1, 1679.
(24) Fields, L. B.; J acobsen, E. N. Tetrahedron: Asymmetry 1993,
4, 2229.
(25) (a) Knowles, W. S. Acc. Chem. Res. 1983, 16, 106. (b) Koenig,
K. E. In Asymmetric Synthesis; Morrison, J . D., Ed.; Academic Press:
New York, 1985; Vol. 5, Chapter 3.

Synthesis of Chiral Hydroxyl Phospholanes
J . Org. Chem., Vol. 65, No. 11, 2000 3493
Ta ble 2. Rh od iu m Ca ta lyzed Asym m etr ic Hyd r ogen a tion of Deh yd r oa m in o Acid 21a
entry
substrate
cat.
ligand
solvent
eeb (%)
1
2
3
4
5
6
7
8
9
21a , R ) H
Rh(COD)2PF6
Rh(COD)2PF6
Rh(COD)2PF6
Rh(COD)2PF6
Rh(COD)2SbF6
Rh(COD)2BF4
Rh(COD)2OTf
Rh(COD)2PF6
Rh(COD)2PF6
Rh(COD)2PF6
Rh(COD)2PF6
5a
5a
5b
5b
5b
5b
5b
5b
5b
5b
5b
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
i-PrOH
CH2CL2
THF
>99c
98
21b, R ) CH3
21a
21b
21b
21b
21b
21b
21b
21b
21b
>99c
>99
>99
>99
>99
>99
>99
>99
>99
10
11
toluene
a
The reaction was carried out at rt under 3 atm of H2 for 9 h. The catalyst was prepared in situ by stirring a solution of Rh(COD)2X
(X ) PF6, SbF6, BF4, OTf) and 5 in a solvent (3 mL) [[substrate (0.5 mmol, 0.167 M)/[Rh]/5 ) 1:0.01:0.011]]. The reaction went with 100%
b
conversion. The S absolute configuration was assigned by comparison of optical rotation with reported data.6c Enantiomeric excesses
were determined by chiral GC using a Chirasil-VAL III FSOT column. c % ee was determined on the corresponding methyl ester.
Ta ble 3. Asym m etr ic Hyd r ogen a tion of Deh yd r oa m in o Acid Der iva tives by a Ca tion ic Rh od iu m -5b Com p lexa
entry
substrate
eec (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
Ar ) Ph, R ) H
>99d
>99
>99d
>99
99d,e
>99e
99d
Ar ) Ph, R ) CH3
Ar ) p-F-Ph, R ) H
Ar ) p-F-Ph, R ) CH3
Ar ) p-MeO-Ph, R ) H
Ar ) p-MeO-Ph, R ) CH3
Ar ) m-Br-Ph, R ) H
Ar ) m-Br-Ph, R ) CH3
Ar ) o-Cl-Ph, R ) H
>99
98d
Ar ) o-Cl-Ph, R ) CH3
Ar ) 2-thienyl, R ) H
Ar ) 2-thienyl, R ) CH3
Ar ) 2-naphthyl, R ) H
Ar ) 2-naphthyl, R ) CH3
Ar ) Ph, R ) H, N-benzoyl
Ar ) Ph, R ) CH3, N-benzoyl
98
>99d
>99
>99d
>99
>99d
>99
a
The reaction was carried out at rt under 3 atm of H2 for 12 h. The catalyst was made in situ by stirring a solution of Rh(COD)2PF6
and the ligand 5b in methanol (3 mL) [[substrate (0.5 mmol, 0.167 M)/[Rh]/5b ) 1:0.01:0.011]]. The reaction went with 100% conversion.
b The S absolute configuration was assigned by comparison of optical rotation with reported data.6c c Enantiomeric excesses were determined
d
by chiral GC using a Chirasil-VAL III FSOT column. Determined on the corresponding methyl ester. e The % ee was determined by
HPLC using a Daicel Chiralcel OJ column.
30-32. Under the same reaction conditions used for
hydrogenation of acyclic enamide substrates, hydrogena-
tion of cyclic enamide 29 gave the corresponding N-
acetylamine with 96.2% ee. Enolate 30 was hydrogenated
with 94.5% ee (48 h, 100% conversion). While enolates
31 and 32 were hydrogenated with high enantioselec-
tivities, low conversions [31 (37%) and 32 (31%)] were
achieved after 48 h.
observed that hydrogen-bonding interactions can acceler-
ate the Baylis-Hillman reaction. The readily accessible
chiral hydroxyl phosphines are likely to be useful for
many asymmetric catalytic reactions.
Exp er im en ta l Section
Gen er a l Meth od s. All reactions and manipulations were
performed in a nitrogen-filled glovebox or using standard
Schlenk techniques. All reagents were obtained from Aldrich
and used directly. Toluene, diethyl ether, tetrahydrofuran, and
hexanes were distilled from sodium benzophenone ketyl under
nitrogen. Methylene chloride was distilled from CaH2. Metha-
nol and isopropyl alcohol were distilled from Mg under
nitrogen. The phenylphosphine was purchased from Strem,
and 1,2-bis(phosphino)benzene was prepared by LiAlH4 reduc-
tion of 1,2-phenylenebis(phosphorodichloridite) from Digital
Specialty Chemicals, Inc. (Canada).
Su m m a r y
We have derived a practical route to synthesize chiral
hydroxyl mono- and bisphospholanes and developed a
highly enantioselective catalyst for asymmetric hydro-
genation of dehydroamino acids and their derivatives,
itaconic acid and its derivatives, enamides, and enolac-
etates. The Rh-5 complex can be used in water to
hydrogenate water-soluble substrates (e.g., itaconic acid)
without decrease of enantiomeric excesses. We also
Melting points were determined in sealed capillary tubes
under nitrogen and are uncorrected. GC analyses were carried
out on a Helwett-Packard 6890 gas chromatograph using chiral

3494 J . Org. Chem., Vol. 65, No. 11, 2000
Ta ble 4. Asym m etr ic Hyd r ogen a tion of Ita con ic Acid Der iva tives by a Rh od iu m -5 Com p lexa
Li et al.
entry
substrate
ligand
solvent
MeOH
MeOH
MeOH
eeb (%)
1
2
3
4
5
6
7
8
25a , R ) H
25b, R ) CH3
5a
5a
5b
5b
5b
5b
5b
5b
96c
98
25a
25b
25b
25b
25a
25a
>99c
>99
>99c
>99c
>99
>99
MeOH
MeOH/H2O (9:1)
MeOH/H2O (5:5)
MeOH/H2O (5:5)
MeOH/H2O (3:97)
a
The reaction was carried out at rt under 10 atm of H2 for 12 h. The catalyst was prepared in situ by stirring a solution of Rh(COD)2PF6
and the ligand 5 in a solvent (3 mL) [[substrate (0.5 mmol, 0.167 M)/[Rh]/5 ) 1:0.01:0.011]]. The reaction went with 100% conversion.
b
The R absolute configuration was assigned by comparison of optical rotation with reported data. Enantiomeric excesses were determined
by chiral GC using a gama-225 column. c % ee was determined on the corresponding methyl ester.
Ta ble 5. Asym m etr ic Hyd r ogen a tion of En a m id es by a Rh od iu m -5b com p lexa
entry
substrate
eec (%)
1
2
3
4
5
6
7
Ar ) Ph, R ) H
96
95
98
Ar ) p-MeO-Ph, R ) H
Ar ) p-F3C-Ph, R ) H
Ar ) p-Cy-Ph, R ) H
Ar ) 2-naphthyl, R ) H
Ar ) p-MeO-Ph, R ) CH3
Ar ) p-F3C-Ph, R ) CH3
98
99d
92d
91
a
The reaction was carried out at rt under 10 atm of H2 for 24 h. The catalyst was prepared in situ by stirring a solution of Rh(COD)2PF6
b
and 5b in methanol (3 mL) [[substrate (0.5 mmol, 0.167 M)/[Rh]/5b ) 1:0.01:0.011]]. The reaction went with 100% conversion. The S
absolute configuration was assigned by comparison of optical rotation with reported data. c % ee was determined by chiral GC using a
d
Supelco Chiral Select 1000 (0.25 mm × 15 m) column. % ee was determined by HPLC using a (R, R)-Poly Whelk-O1 column.
in dry THF (40 mL) was added 21.6 mL of PhMgBr (1.0 M in
THF, 21.6 mmol) over 30 min at -40 °C. The mixture was
stirred for an additional 30 min before a solution of diepoxide
9 (1.75 g, 5.37 mmol) in THF (20 mL) was added. After being
stirred at -40 °C for 4 h and then at room temperature for
additional 1 h, the reaction mixture was quenched with 50
mL of saturated NH4Cl aqueous solution. The aqueous layer
was separated and extracted with 3 × 30 mL of CH2Cl2. The
combined organic layer was dried over Na2SO4 and evaporated.
The residue was further purified via a silica gel column eluted
with hexanes/EtOAc (8:2) to give a colorless oil (2.51 g) in 97%
yield: [R]24D ) -6.8 (c 1.02, CHCl3); 1H NMR (360 MHz, CDCl3)
δ 7.53-7.34 (m, 20H), 4.87-4.75 (m, 4H) 4.40-4.34 (m, 2H),
3.91-3.85 (m, 2H), 3.12 (dd, J ) 3.74, 13.78 Hz, 2H), 3.0 (br,
capillary columns: Chirasil-Val III FOST (dimensions: 25 m
× 0.25 mm) for dehydroamino acid derivatives; Chiral Select
2H), 2.84 (dd, J ) 8.9, 17.78 Hz, 2H); 13C NMR (CDCl3) δ
138.43, 137.34, 129.33, 128.49, 128.45, 128.37, 128.04, 126.37,
1000 column (dimensions: 15 m × 0.25 mm) for enamides,
enolates, and Baylis-Hillman products; γ-225 (dimensions: 30
m × 0.25 mm) for itaconic acid derivatives. HPLC analysis
was carried out on a Waters 600 chromatograph with an (R,R)-
Poly Whelk-O1 column from Regis Technologies, Inc. [particle
size: 5.0 µm. column dimensions: 25 cm (length) × 0.46 cm
(i.d.)] for enamide derivatives; Daicel Chiralcel OJ column for
dehydroamino acid derivatives. 1H, 13C, and 31PNMR were
recorded on Bruker WM 360 spectrometer. Chemical shifts
were reported in ppm downfield from tetramethylsilane with
the solvent resonance as the internal standard or 85% H3PO4
as the external standard, respectively. Optical rotation was
obtained on a Perkin-Elmer 241 polarimeter.
79.72, 72.96, 72.25, 40.16; HRMS calcd for C32H34O4Na (MNa+)
505.2355, found 505.2391.
Syn th esis of 1,4-Diol Cyclic Su lfa tes. Cyclic sulfate 11a
was prepared according to the literature.6d
(4R,5S,6S,7R)-5,6-Bis(ben zyloxy)-4,7-d iben zyl[1,3,2]-d i-
oxa th iep a n e 2,2-Dioxid e (11b). To a solution of diol 10 (2.41
g, 5.0 mmol) and Et3N (1.4 mL, 10.0 mmol) in CH2Cl2 (30 mL)
was added dropwise a solution of SOCl2 (0.5 mL, 6.0 mmol) in
CH2Cl2 (10 mL) at 0 °C. After being stirred at 0 °C for 1 h, the
reaction mixture was quenched with 30 mL of brine. The
separated aqueous layer was then extracted with 3 × 30 mL
of CH2Cl2. The organic layer was dried over Na2SO4, evapo-
rated, and then dried via vacuum pump for 20 min. The
residue was dissolved in 20 mL of CCl4, 20 mL of CH3CN, and
30 mL of water. RuCl3‚xH2O (25 mg) and NaIO4 (1.33 g, 6.0
mmol) were added at 0 °C, and the mixture was stirred for 30
Syn th esis of Ch ir a l 1,4-Diols. The diols 8, 14, and 15 were
prepared according to reported procedures.6d,7
(2R ,3R ,4R ,5R )-1,6-Dip h e n yl-3,4-d i-O-b e n zylh e xa n e -
2,3,4,5-tetr ol (10). To a suspension of CuI (2.09 g, 10.8 mmol)

Synthesis of Chiral Hydroxyl Phospholanes
J . Org. Chem., Vol. 65, No. 11, 2000 3495
min. Brine (50 mL) was added, and the aqueous solution was
extracted with ether (3 × 50 mL). The combined extracts were
dried over Na2SO4 and evaporated. The residue was purified
by a silica gel column eluted with hexanes/EtOAc (9:1) to give
sulfate 11b as a white solid (2.58 g) in 95% yield: mp 81-3
31.60, 60.68 Hz), 29.81 (d, J ) 7.15 Hz); 31P NMR (CDCl3) δ
34.20; HRMS calcd for C38H40O2PB 569.2895, found 569.2862.
1b was liberated according to the procedure for 1a : 1H NMR
(360 MHz, CDCl3) δ 7.90-7.80 (m, 2H), 7.50-7.20 (m, 18H),
4.28-4.21 (m, 4H), 4.08-3.98 (m, 2H), 3.35-3.20 (m, 4H),
2.70-2.61 (m, 2H); 31P NMR (CDCl3) δ -0.31.
°C; [R]24 ) -4.5 (c 1.0, CHCl3); 1H NMR (360 MHz, CDCl3) δ
D
7.53-7.35 (m, 20H), 5.02-4.97 (m, 4H), 4.94-4.91 (m, 2H),
P h osp h in e 2. To a stirred solution of phenylphosphine
(440.4 mg, 4.0 mmol) in THF (80 mL) was added dropwise
n-BuLi (1.6 M n-hexane solution, 2.5 mL, 4.0 mmol) via a
syringe at -78 °C. Then the resulting pale yellow solution was
stirred for 2 h at room temperature. After the mixture was
cooled to -78 °C, cyclic sulfate 16a (1.01 g, 4.0 mmol) in THF
(40 mL) was added over 10 min. The resulting yellow solution
was warmed to room temperature and stirred for 4 h. After
the solution was cooled to -78 °C, n-BuLi (1.6 M solution in
n-hexane, 2.5 mL, 4.0 mmol) was added, and the reaction
mixture was stirred for an additional 20 h at room tempera-
ture. The color of the reaction mixture changed from orange
yellow to red and then became colorless. After removal of the
solvent under reduced pressure, the residue was dissolved in
40 mL of ethyl ether, and 30 mL of brine was added. The
aqueous layer was then washed with 3 × 30 mL of ethyl ether.
The combined organic layer was dried over Na2SO4 and
concentrated to afford a colorless oil. This oily compound (2)
was further purified by a short silica gel column eluted with
hexane/ether (9:1) (850 mg in 80% yield): 1H NMR (360, MHz,
CDCl3) δ 7.72-7.27 (m, 5H), 4.60-4.32 (m, 2H), 2.70-2.51 (m,
2H), 1.52 (s, 6H), 1.38-1.32 (m, 3H), 0.70-0.52(m, 3H); 31P
NMR (CDCl3) δ 50.2; HRMS calcd for C15H21O2P 265.1357,
found 265.1370.
P h osp h in e 3. The phosphine (2) (528 mg, 2.0 mmol)
obtained above was dissolved in 50 mL of methanol and 2 mL
of water. To this solution was added 0.05 mL of methane-
sulfonic acid, and the resulting mixture was refluxed for 10
h. The solvent was removed under reduced pressure, and the
residue was dissolved in 50 mL of methylene chloride. A
saturated aqueous solution of NaHCO3 (30 mL) was added,
and the two layers were separated. The aqueous layer was
washed with 3 × 40 mL of methylene chloride. The combined
organic layers were dried over Na2SO4 and concentrated to
give a white solid 3: mp 57-9 °C; 1H NMR (360 MHz, CDCl3)
δ 7.94-7.89 (m, 2H), 7.48-7.41 (m, 3H), 4.36-4.22 (m, 2H),
3.05-2.93 (m, 1H), 2.82-2.73 (m, 1H), 2.11 (br, 2H), 1.29 (dd,
J ) 7.46, 15.6 Hz, 3H), 0.92 (dd, J ) 7.38, 14.3 Hz, 3H); 31P
NMR (CDCl3) δ 4.69; HRMS calcd for C12H17O2P 225.1044,
found 225.1042.
3.92-3.88 (m, 2H), 3.55-3.50 (m, 2H), 3.02-2.95 (m, 2H). 13
C
NMR (CDCl3) δ 136.97, 135.06, 129.35, 128.56, 128.43, 128.06,
127.50, 126.97, 83.31, 82.62, 75.45, 37.47; HRMS calcd for
C
32H32O6SNa (MNa+) 567.1817, found 567.1762.
(4R,5S,6S,7R)-5,6-O-(1-Meth yleth yliden e)-4,7-dim eth yl-
[1,3,2]d ioxa th iep a n e 2,2-Dioxid e (16a ). Cyclic sulfate 16a
was prepared according to the procedure for 11b in 96%
yield: mp 70-1 °C; [R]24 ) +9.4 (c 1.01, CHCl3); 1H NMR
D
(360 MHz, CDCl3) δ 4.45-4.40 (m, 2H), 4.05-4.00 (m, 2H),
1.56 (d, J ) 7.6 Hz, 6H), 1.40 (s, 6H); 13C NMR (CDCl3) δ
110.64, 81.16, 80.45, 26.69, 18.35; HRMS calcd for C9H16O6SNa
275.0565, found 275.0568.
(4R,5S,6S,7R)-5,6-O-(1-Meth yleth ylid en e)-4,7-d ieth yl-
[1,3,2]d ioxa th iep a n e 2,2-Dioxid e (16b). Cyclic sulfate 16b
was prepared according to the similar procedure for 11b in
97% yield: mp 58-9 °C; [R]24 ) +35.2 (c 1.07, CHCl3); 1H
D
NMR (360 MHz, CDCl3) δ 4.27-4.22 (m, 2H), 4.07-4.04 (m,
2H), 2.01-1.88 (m, 4H), 1.41 (s, 6H), 1.08 (t, J ) 7.39 Hz, 6H);
13C NMR (CDCl3) δ 110.58, 86.06, 79.36, 26.76, 25.53, 9.16;
HRMS calcd for C11H20O6SNa 303.0878, found 303.0888.
Gen er a l Syn th etic P r oced u r e for Ma k in g Ch ir a l P h os-
p h in es. P h osp h in e 1a . To a stirred solution of phenylphos-
phine (220.2 mg, 2.0 mmol) in THF (50 mL) was added
dropwise n-BuLi (1.6 M n-hexane solution, 1.25 mL, 2.0 mmol)
via a syringe at -78 °C. The resulting yellow solution was
warmed to room temperature and stirred for 2 h. The mixture
was then cooled to -78 °C, and cyclic sulfate 11a (0.78 g, 2.0
mmol) in THF (30 mL) was added over 10 min. The resulting
brown solution was warmed to room temperature and stirred
for 4 h. After the solution was cooled back to -78 °C, n-BuLi
(1.6 M solution in n-hexane, 1.25 mL, 2.0 mmol) was added
and the reaction mixture was stirred for additional 20 h at
room temperature followed by addition of BH3-THF complex
(1 M solution in THF, 3.0 mL, 3.0 mmol) at 0 °C. After the
solution was stirred overnight, the solvent was evaporated
under reduced pressure and 30 mL of water was added. The
aqueous solution was extracted with CH2Cl2 (3 × 40 mL). The
combined organic layer was dried over Na2SO4 and concen-
trated to afford the crude phospholane-borane product.
Purification was performed by a silica gel column eluted with
hexanes/EtOAc (9:1) to give 1a -borane adduct as a white solid
(767 mg, 92%): mp 90-2 °C; 1H NMR (360 MHz, CDCl3) δ
7.96-7.91 (m, 2H), 7.43-7.24 (m, 13H), 4.65-4.53 (m, 4H),
4.10-3.95 (m, 2H), 2.87-2.81 (m, 2H), 1.29 (dd, J ) 7.33, 15.82
Hz, 3H), 0.94 (dd, J ) 7.38, 14.21 Hz, 3H), 1.23-0 (br, 3H,
BH3); 13C NMR (CDCl3) δ 137.91, 137.50, 134.26 (d, J ) 9.15
Hz), 130.96, 128.37-126.29 (m), 83.61 (d, J ) 2.71 Hz), 72.35
(d, J ) 24.54 Hz), 35,83 (dd, J ) 25.6, 33.8 Hz), 9,04 (t, J )
7.33 Hz); 31P NMR (CDCl3) δ 37.1 (br); HRMS calcd for
P h osp h in e 4a . To a stirred solution of 1,2-bis(phosphino)-
benzene (1.24 g, 8.72 mmol) in THF (200 mL) was added
dropwise n-BuLi (1.6 M n-hexane solution, 10.9 mL, 17.4
mmol) via a syringe at -78 °C. Then the resulting yellow
solution was stirred for 2 h at room temperature. After the
mixture was cooled to -78 °C, cyclic sulfate 16a (4.39 g, 17.4
mmol) in THF (50 mL) was added over 10 min. The solution
was then warmed to room temperature and stirred for 4 h.
The mixture was cooled to -78 °C, and n-BuLi (1.6 M solution
in n-hexane, 11.0 mL, 17.5 mmol) was added. After the mixture
was cooled at room temperature for another 20 h, the solvent
was removed under reduced pressure. The residue was dis-
solved in 50 mL of ethyl ether and washed with 50 mL of brine.
The aqueous layer was then extracted with 3 × 40 mL ethyl
ether. The combined organic layer was dried over Na2SO4 and
concentrated to afford a colorless crystalline solid. Recrystal-
lization from Et2O/MeOH gave the pure product (3.42 g, 87%
C
26H32O2PB 417.2269, found 417.2281.
The 1a -borane adduct was dissolved in 20 mL of toluene,
and 2 equiv of DABCO was added. The resulting mixture was
heated at 50 °C for 8 h. After removal of the solvent, the
residue was passed through a silica gel plug eluted with
hexane/ethyl acetate (9:1) to give phosphine 1a as a colorless
oil: 1H NMR (360 MHz, CDCl3) δ 7.56-7.52 (m, 2H), 7.17-
7.06 (m, 13H), 4.45-4.32 (m, 4H), 3.86-3.82 (m, 2H), 2.75-
2.67 (m, 2H), 1.15 (dd, J ) 7.57, 14.88 Hz, 3H), 0.68 (dd, J )
7.42, 17.2 Hz, 3H); 31P NMR (CDCl3) δ 5.95.
yield): mp 67-9 °C; [R]24 ) + 287.2 (c 0.85 CHCl3); 1H NMR
D
(360 MHz, CDCl3) δ 7.38-7.33 (m, 4H), 4.46-4.36 (m, 4H),
2.89-2.82 (m, 2H), 2.56-2.51 (m, 2H), 1.47 (s, 6H), 1.42 (s,
6H), 1.33-1.28 (m, 6H), 0.73-0.69 (m, 6H); 13C NMR (90 MHz,
CDCl3) δ 140.53, 130.59, 129.00, 117.44, 81.41, 80.51 (t, J )
6.5 Hz), 27.34, 27.30, 25.05 (t, J ) 10.3 Hz), 24.20, 13.74 (t, J
) 19.6 Hz), 12.15; 31P NMR (145 MHz, CDCl3) δ 45.1; HRMS
calcd for C24H37O4P2 (MH+) 451.2167, found 451.2164.
P h osp h in e 1b. The phosphine 1b was prepared according
to the procedure for the synthesis of 1a .
1b-BH3 adduct in 87% yield: mp 78-81 °C; 1H NMR (360
MHz, CDCl3) δ 8.28-8.22 (m, 2H), 7.71-7.15 (m, 18H), 4.59-
4.49 (m, 4H), 4.11-3.97 (m, 2H), 3.50-3.18 (m, 4H), 2.79-
2.76 (m, 2H), 1.30-0 (br, 3H, BH3); 13C NMR (CDCl3) δ 140.03,
137.82, 137.36, 134.32, 134.21, 131.27, 128.54-125.97 (m),
80.65 (d, J ) 49.17 Hz), 72.25 (d, J ) 18.1 Hz), 43.23 (dd, J )
P h osp h in e 5a . Compound 4a (451 mg, 1.0 mmol) was
dissolved in 100 mL of methanol and 2 mL of water. To this
solution 0.05 mL of methanesulfonic acid was added, and the
resulting mixture was heated at reflux for 10 h. After removal

3496 J . Org. Chem., Vol. 65, No. 11, 2000
Li et al.
of the solvent, the residue was passed through a short silica
gel plug by eluting with EtOAc/MeOH (95:5) to give pure
1 mmol) and 1 mL of methyl acrylate was degassed three times
by a freeze-pump-thaw method. The resulting solution was
transferred into another Schlenk tube, which contained the
phosphine catalyst (0.1 mmol). The solution was stirred at
room temperature, and the methyl acrylate was removed
under vacuum. The residue was purified by a silica gel column
eluted with hexanes/ethyl acetate (1:2). The enantiomeric
excess was measured by GC with a chiral capillary column.
Gen er a l P r oced u r e for Asym m etr ic Hyd r ogen a tion .
To a solution of [Rh(COD)2]PF6 (2.1 mg, 0.0045 mmol) in
methanol (3 mL) in a glovebox was added bisphospholane 5
(0.10 mL of 0.05 M solution in methanol, 0.005 mmol). After
the mixture was stirred for 10 min, substrate (0.5 mmol) was
added. The hydrogenation was performed at room temperature
under 3-10 atm of H2 for 12-48 h. After carefully releasing
the hydrogen, the reaction mixture was passed through a short
silica gel column to remove the catalyst. For hydrogenation of
dehydroamino acids and itaconic acid, the methanol was
removed under vacuum. A portion of the residue was dissolved
in THF and then treated with a diazamethane in ether to
provide the corresponding methyl ester. The enantiomeric
excesses were measured by GC or HPLC directly. The absolute
configuration of products was determined by comparing the
observed rotation with the reported value. When water was
used as the solvent for hydrogenation of dimethyl itaconate,
the product was extracted with 3 × 3 mL Et2O and dried over
Na2SO4. For hydrogenation of the itaconic acid, the solvent
was removed and a portion of the residue was treated with a
diazamethane solution in THF.
compound 5a as a colorless syrup (352 mg, 95% yield): [R]24
D
) + 373.1 (c 0.98 CH3OH); 1H NMR (360 MHz, CD3OD) δ
8.42-8.07 (m, 2H), 7.72-7.69 (m, 2H), 5.28 (br, 4H), 4.24-
4.17 (m, 4H), 3.31-3.28 (m, 2H), 3.16-3.13 (m, 2H), 1.37-
1.30 (m, 6H), 0.94-0.88 (m, 6H); 13C NMR (90 MHz, CD3OD)
δ 136.6 (t, J ) 3.4 Hz), 133.7, 133.6, 80.2, 80.0, 37.3, 35.4 (d,
J ) 10.0 Hz), 11.6 (d, J ) 6.5 Hz), 10.8; 31P NMR (145 MHz,
CD3OD) δ 11.9 (br); HRMS calcd for C18H29O4P2 (MH+)
371.1541, found 371.1523.
P h osp h in e 4b. Diethyl phosphine 4b was prepared accord-
ing to the procedure for the synthesis of 4a . Recrystallization
of crude 4b from Et2O/MeOH gave the pure product as a
colorless crystal in 83% yield: mp 55-7 °C; [R]24D ) +142.3 (c
0.84 CHCl3); 1H NMR (360 MHz, CDCl3) δ 7.41-7.32 (m, 4H),
4.50-4.37 (m, 4H), 2.62-2.61 (m, 2H), 2.22-2.20 (m, 2H),
2.19-2.17 (m, 2H), 1.50-1.44 (m, 2H), 1.47 (s, 6H), 1.32-1.30
(m, 2H), 0.99-0.95 (m, 6H), 0.88-0.86 (m, 2H), 0.79-0.75 (m,
6H); 13C NMR (90 MHz, CDCl3) δ 141.3, 131.1, 129.2, 117.1,
82.3, 81.4 (t, J ) 6.1 Hz), 33.0, 32.8 (t, J ) 9.6 Hz), 27.4, 27.3,
21.4, 21.1 (t, J ) 14.2 Hz), 14.6, 13.1 (t, J ) 5.1 Hz).; 31P NMR
(145 MHz, CDCl3) δ 34.5; HRMS calcd for C28H44O4P2 507.2793,
found 507.2777.
P h osp h in e 5b. Hydroxyl phospholane 5b was prepared as
a colorless syrup according to the procedure for the synthesis
1
of 4b (94% yield): [R]24 ) +195.4 (c 0.75 CH3OH); H NMR
D
(360 MHz, CD3OD) δ 8.30-8.20 (m, 2H), 7.71-7.67 (m, 2H),
5.30 (br, 4H), 4.40-4.33 (m, 4H), 3.26-3.11 (m, 2H), 2.96-
2.85 (m, 2H), 1.95-1.91 (m, 2H), 1.76-1.72 (m, 2H), 1.37-
1.27 (m, 4H), 0.93 (t, J ) 7.35 Hz, 6H), 0.87 (t, J ) 7.26 HZ,
6H); 13C NMR (90 MHz, CD3OD) δ 137.1 (t, J ) 3.4 Hz), 133.3,
133.2, 78.0, 77.4, 42.3 (d, J ) 15.7 Hz), 39.6, 21.2 (d, J ) 13.3
Hz), 19.7, 14.2 (d, J ) 10.8 Hz), 13.5 (d, J ) 10.8 Hz); 31P NMR
(145 MHz, CD3OD) δ 5.65 (br); HRMS calcd for C22H36O4P2
427.2167, found 427.2165.
Ack n ow led gm en t. This work was supported by
grants from National Institute of Health and National
Science Foundation as well as a DuPont Young Faculty
Award. We acknowledge a generous loan of precious
metals from J ohnson Matthey Inc and a gift of chiral
GC columns from Supelco.
Gen er a l P r oced u r e for Asym m etr ic Ba ylis-Hillm a n
Rea ction . The mixture of 4-pyridinecarbonaldehyde (110 mg,
J O000066C