A Novel Class of P-O Monophosphite Ligands Derived from D-Mannitol: Broad Applications in High Enantioselective Rh-Catalyzed Hydrogenations

Article abstract of DOI:10.1021/jo035627p

We report on a new class of P-O monophosphite ligands (designated 3a-k) with a double six-membered-ring backbone onto which are attached additional groups and on applications of their Rh complexes in the hydrogenation of enamides, α-dehydroamino acid esters, dimethyl itaconate, and β-(acylamino)acrylates. Our results demonstrate that the Rh complexes with ligands 3a-k exhibit high enantioselectivity and reactivity in asymmetric hydrogenation reactions. An ee value of up to 98.0% was obtained for the hydrogenation of α-dehydroamino acid esters, and the ee values were all over 99% for the other three types of substrate, with a turnover number of up to 5000.

Full text of DOI:10.1021/jo035627p

A Novel Cla ss of P -O Mon op h osp h ite Liga n d s Der ived fr om
D-Ma n n itol: Br oa d Ap p lica tion s in High ly En a n tioselective
Rh -Ca ta lyzed Hyd r ogen a tion s
Hanmin Huang, Zhuo Zheng,* Huili Luo, Changmin Bai, Xinquan Hu, and Huilin Chen
Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian 116023, P. R. China
zhengz@dicp.ac.cn
Received November 5, 2003
We report on a new class of P-O monophosphite ligands (designated 3a -k ) with a double six-
membered-ring backbone onto which are attached additional groups and on applications of their
Rh complexes in the hydrogenation of enamides, R-dehydroamino acid esters, dimethyl itaconate,
and â-(acylamino)acrylates. Our results demonstrate that the Rh complexes with ligands 3a -k
exhibit high enantioselectivity and reactivity in asymmetric hydrogenation reactions. An ee value
of up to 98.0% was obtained for the hydrogenation of R-dehydroamino acid esters, and the ee values
were all over 99% for the other three types of substrate, with a turnover number of up to 5000.
In tr od u ction
work has opened a new frontier in the design and syn-
thesis, through a simple route, of efficient monophospho-
rus ligands with high commercial value.5 However, the
enantioselectivities obtained with the monophosphite
ligands developed thus far are not always sufficiently
high, which is probably attributable to rotation of the
Rh-P bond.
Transition-metal-catalyzed asymmetric hydrogenation
is one of the most powerful methods for the synthesis of
optically active compounds, and the design of new
phosphorus chiral ligands plays a central role in this
area.1 Although excellent enantioselectivities have been
obtained by using chiral bisphosphane ligands, only a few
ligands have found broad applications in various types
of asymmetric hydrogenation reaction.2
Recently, some new classes of easily prepared mono-
phosphorus ligands developed by Pringle,3a Reetz,3b,c and
Feringa3d have proven to be highly effective for Rh-
catalyzed asymmetric hydrogenation.4 This pioneering
More recently, Reetz4a and ourselves6 have indepen-
dently reported carbohydrate-derived7 monophosphite
ligands 1 and 2, which contain additional groups in the
proper spatial configuration to effectively restrain the
rotation of the Rh-P bond by secondary interactions.8
Those ligands exhibited excellent enantioselectivities in
Rh-catalyzed asymmetric hydrogenation of enamides and
dimethyl itaconate. The excellent enantioselectivities and
the pronounced effect of carbohydrate backbones in those
ligands indicated that the additional groups orientated
in a spatial configuration in monophosphites that im-
proved the enantioselectivity. To establish the general
utility of the design concept and to enhance the versatility
(1) For recent reviews, see: (a) Ohkuma, T.; Noyori, R. In Catalytic
Asymmetric Synthesis; Ojima, I., Ed.; Wiley-VCH: Weinheim, Ger-
many, 2000; p 1. (b) Brown, J . M. In Comprehensive Asymmetric
Catalysis; J acobsen, E. N., Pfaltz, A., Yamamoto, H., Eds.; Springer:
Berlin, Germany, 1999; p 121.
(2) Tang, W.; Zhang, X. Chem. Rev. 2003, 103, 3526.
(3) (a) Claver, C.; Fernandez, E.; Gillon, A.; Heslop, K.; Hyett, D.
J .; Martorell, A.; Orpen, A. G. P.; Pringle, G. Chem. Commun. 2000,
961. (b) Reetz, M. T.; Sell, T. Tetrahedron Lett. 2000, 41, 6333. (c) Reetz,
M. T.; Mehler, G. Angew. Chem., Int. Ed. 2000, 39, 3889. (d) van den
Berg, M.; Minnaard, A. J .; Schudde, E. P.; van Esch, J .; de Vries, J .
G.; Feringa, B. L. J . Am. Chem. Soc. 2000, 122, 11539.
(5) For review of monophosphorus ligands, see: (a) Komarov, I. V.;
Bo¨rner, A. Angew. Chem., Int. Ed. 2001, 40, 1197. (b) Lagasse, F.;
Kagan, H. B. Chem. Pharm. Bull. 2000, 48, 315.
(6) Huang, H.; Zheng, Z.; Luo, H.; Bai, C.; Hu, X.; Chen, H. Org.
Lett. 2003, 5, 4137.
(4) For other recent examples, see: (a) Reetz, M. T.; Goossen, L. J .;
Meiswinkel, A.; Paetzold, J .; J ensen, J . F. Org. Lett. 2003, 5, 3099. (b)
Hannen, P.; Militzer, H.-C.; Vogl, E. M.; Rampf, F. A. Chem. Commun.
2003, 2210. (c) Reetz, M. T.; Sell, T.; Meiswinkel, A.; Mehler, G. Angew.
Chem., Int. Ed. 2003, 42, 790. (d) J ia, X.; Li, X.; Xu, L.; Shi, Q.; Yao,
X.; Chan, A. S. C. J . Org. Chem. 2003, 68, 4539. (e) Fu, Y.; Xie, J .-H.;
Hu, A.-G.; Zhou, H.; Wang, L.-X.; Zhou, Q.-L. Chem. Commun. 2002,
480. (f) Hu, A.-G.; Fu, Y.; Xie, J .-H.; Zhou, H.; Wang, L.-X.; Zhou, Q.-
L. Angew. Chem., Int. Ed. 2002, 41, 2348. (g) Reetz, M. T.; Mehler, G.;
Meiswinkel, A.; Sell, T. Tetrahedron Lett. 2002, 43, 7941. (h) Pena, D.
M.; Minnaard, A. J .; de Vries, J . G.; Feringa, B. L. J . Am. Chem. Soc.
2002, 124, 14552. (i) J unge, K.; Oehme, G.; Monsees, A.; Riermeier,
T.; Dingerdissen, U.; Beller, M. Tetrahedron Lett. 2002, 43, 4977. (j)
Zeng, Q.; Liu, H.; Cui, X.; Mi, A.; J iang, Y.; Li, X.; Choi, M. C. K.; Chan,
A. S. C. Tetrahedron: Asymmetry 2002, 13, 115. (k) J ia, X.; Guo, R.;
Li, X.; Yao, X.; Chan, A. S. C. Tetrahedron Lett. 2002, 43, 5541. (l) van
den Berg, M.; Haak, R. M.; Minnaard, A. J .; de Vries, A. H. M.; de
Vries, J . G.; Feringa, B. L. Adv. Synth. Catal. 2002, 344, 1003. (m)
Hua, Z.; Vassar, V. C.; Ojima, I. Org. Lett. 2003, 5, 3831.
(7) For some selected chiral phosphine ligands made from carbohy-
drate, see: (a) Steiborn, D.; J unicke, H. Chem. Rev. 2000, 100, 4283.
(b) RajanBabu, T. V.; Casalnuovo, A. L.; Ayers, T. A. In Advances in
Catalytic Process; Doyle, M. P., Ed.; J AI Press: Greenwhich, CT, 1998;
Vol. 2, p 1. (c) Hale, K. J . In Rodd’s Chemistry of Carbon Compounds,
2nd ed.; Sainsbury, M., Ed.; Elsevier Science: New York, 1993; Suppl.
2, Vol. IE/F/G, Chapter 23b, p 273. (d) Yonehara, K.; Hashizume, T.;
Mori, K.; Ohe, K.; Uemura, S. J . Org. Chem. 1999, 64, 5593. (e)
Yonehara, K.; Ohe, K.; Uemura, S. J . Org. Chem. 1999, 64, 9381. (f)
Hashizume, T.; Yonehara, K.; Ohe, K.; Uemura, S. J . Org. Chem. 2000,
65, 5197. (g) Ohe, K.; Morioka, K.; Yonehara, K.; Uemura, S. Tetra-
hedron: Asymmetry 2002, 13, 2155. (h) Dieguez, M.; Ruiz, A.; Claver,
C. J . Org. Chem. 2002, 67, 3796. (i) Dieguez, M.; Ruiz, A.; Claver, C.
Chem Commun. 2001, 2702. (j) Park, H.; RajanBabu, T. V.; Yan, Y.-
Y.; Shin, S. J . Am. Chem. Soc. 2001, 123, 10207. (k) Shin, S.;
RajanBabu, T. V. Org. Lett. 1999, 1, 1229.
(8) For a review of the secondary interaction, see: Sawamura, M.;
Ito, Y. Chem. Rev. 1992, 92, 857.
10.1021/jo035627p CCC: $27.50 © 2004 American Chemical Society
Published on Web 02/27/2004
J . Org. Chem. 2004, 69, 2355-2361
2355

Huang et al.
F IGURE 1. Monophosphites 1-3.
SCHEME 1. Syn th esis of Mon op h osp h ites 3
of this type of ligand and the selectivity in asymmetric
reactions, the present paper reports on the development
of a new class of chiral monophosphite ligands (desig-
nated 3; abbreviated Ma n n iP h os, Figure 1) based on
D-mannitol, containing an extra chiral scaffold with an
fair degree of rigidity and flexibility in attaching ad-
ditional groups in a proper spatial configuration such that
the ligands may not only offer the effect of additional
groups but also act like hemilabile ligands9 to enhance
the enantioselectivity. Their applications to Rh-catalyzed
asymmetric hydrogenations of functionalized olefins are
also described. They were found to exhibit excellent cata-
lytic properties and enantioselectivities in Rh-catalyzed
enantioselective hydrogenations of four types of func-
tionalized olefins: enamides, R-dehydroamino acid esters,
dimethyl itaconate, and â-(acylamino)acrylates.
thesized from commercially available D-mannitol10 in
three steps, as illustrated in Scheme 1. Commercially
available D-mannitol was converted into 1,3:4,6-di-O-
benzylidene-D-mannitol 411 followed by selective monoal-
klyation of one of the remaining alcoholic groups afford-
ing compound 5. Reaction of compound 5 with PCl3 in
the absence of Et3N afforded RO-PCl2, which was then
directly reacted with BINOL or biphenol derivatives in
the presence of Et3N to afford the desired product.
Ligands 3a -k were easily purified through a short silica
gel plug and were stable in the solid state.
2. Asym m etr ic Hyd r ogen a tion of En a m id es. The
catalytic performance of ligands 3a -k was thoroughly
explored in Rh-catalyzed asymmetric hydrogenation re-
actions. In a first set of experiments, we used these
ligands in the Rh-catalyzed asymmetric hydrogenation
Resu lts a n d Discu ssion
(10) For some selected chiral phosphine ligands made from D-
mannitol, see: (a) Holz, J .; Quirmbach, M.; Schmidt, U.; Heller, D.;
Sturmer, R.; Bo¨rner, A. J . Org. Chem. 1998, 63, 8031. (b) Carmichael,
D.; Doueet, H.; Brown, J . M. Chem. Commun. 1999, 261. (c) Li, W.;
Zhang, Z.; Xiao, D.; Zhang, X. Tetrahedron Lett. 1999, 40, 6701. (d)
Reetz, M. T.; Neugebauer, T. Angew. Chem., Int. Ed. 1999, 38, 179.
(e) Yan, Y.-Y.; RajanBabu, T. V. Org. Lett. 2000, 2, 199. (f) Yan, Y.-Y.;
RajanBabu, T. V. J . Org. Chem. 2000, 65, 900. (g) Li, W.; Zhang, Z.;
Xiao, D.; Zhang, X. J . Org. Chem. 2000, 65, 3489. (h) Li, W.; Zhang, X.
J . Org. Chem. 2000, 65, 5871.
1. Syn th esis of New Ch ir a l Mon op h osp h ite Lig-
a n d s. The chiral ligands 3a -k were conveniently syn-
(9) For hemilabile ligands in asymmetric catalysis, see: (a) Nomura,
N.; J in, J .; Park, H.; RajanBabu, T. V. J . Am. Chem. Soc. 1998, 120,
459. (b) Nandi, M.; J in, J .; RajanBabu, T. V. J . Am. Chem. Soc. 1999,
121, 9899. (c) Park, H.; RajanBabu, T. V. J . Am. Chem. Soc. 2002,
124, 734. (d) For review of hemilabile ligands, see: Bader, A.; Lindner,
E. Coord. Chem. Rev. 1991, 108, 27.
(11) Baggett, N.; Stribblehill, P. J . Chem. Soc., Perkin Trans. 1 1977,
1123.
2356 J . Org. Chem., Vol. 69, No. 7, 2004

A Novel Class of P-O Monophosphite Ligands
TABLE 1. Th e Effect of Solven t a n d H2 P r essu r e on th e
En a n tioselective Hyd r ogen a tion of
TABLE 2. Asym m etr ic Hyd r ogen a tion of
N-Acetylp h en yleth en a m in e Ca ta lyzed by Rh -3a
N-Acetylp h en yleth en a m in e 6a a
ee, %
ee, %
(config)b
entry
ligand
(config)b
entry
solvent
P(H2), atm
conv, %
ee, % (config)b
entry
ligand
1
2
3
4
5
6
3a
3b
3c
3d
3e
3f
99.8 (S)
99.8 (S)
99.4 (S)
97.7 (S)
98.1 (S)
99.6 (S)
7
8
9
10
11
3g
3h
3i
3j
3k
99.5 (S)
91.3 (R)
92.1 (R)
49.7 (R)
9.7 (R)
1
2
3
4
5
6
CH2Cl2
CH2Cl2
EtOAc
toluene
CH3OH
THF
10
1.2
10
10
10
10
100
100
100
100
78
99.8 (S)
99.7 (S)
99.5 (S)
99.6 (S)
95.5 (S)
99.5 (S)
98
a
a
Solvent ) CH2Cl2; p(H2) ) 10 atm; T ) 20 °C; reaction time
) 12 h; substrate:[Rh(COD)2]BF4:3 ) 1:0.01:0.022; 100% conver-
T ) 20 °C; reaction time: 12 h; substrate:[Rh(COD)2]BF4:3a
b
) 1:0.01:0.022. Determined by chiral capillary GC on a Varian
b
sion was obtained in all cases. Determined by chiral capillary
Chirasil-L-Val column and a Supelco Chiral select 1000 column.
The absolute configuration was assigned by comparison of the
optical rotation with reported data.
GC on a Varian Chirasil-L-Val column and a Supelco Chiral select
1000 column. The absolute configuration was assigned by com-
parison of the optical rotation with reported data.
of enamides (6).12 The reactions proceeded smoothly at
room temperature. In general, the catalysts were pre-
pared in situ by mixing [Rh(COD)2]BF4 and the corre-
sponding monophosphite ligands in CH2Cl2.
Table 2). Values of ee up to 99.8% have been achieved
with Rh-3a and Rh-3b as catalysts, which demonstrates
that R-BINOL is matched cooperatively to the corre-
sponding D-mannitol-derived backbone. In marked con-
trast, ligands 3j and 3k derived from conformationally
flexible biphenols gave ee values of only 9.7-49.7%. In
contrast, the enantioselectivities produced by these ligands
are somewhat affected by the -OR groups contained in
the ligands, which can be attributed to their effects on
the degree of rigidity and flexibility of the D-mannitol-
derived double-ring backbone. As can be seen from Table
2, less bulky substituents generally induce a higher ee
value, and the simplest and more easily prepared ligand
3a is the most efficient.
To broaden the scope of this reaction, we subsequently
applied the most efficient monophosphite 3a in the Rh-
catalyzed hydrogenation of a variety of enamides under
the above optimal reaction conditions. The results in
Table 3 indicate that most of the reactions gave extremely
high ee values with full conversions (96-99.9%, entries
1-5 and 7-10, Table 3), except in the case of hydrogena-
tion of highly hindered substrates (entrie 6, Table 3).13
The results also revealed that there is no major electronic
effect on the substitution pattern of the R-phenylen-
amides. Hydrogenation of the 2-naphthyl derivative also
gave an excellent ee value (entry 8, Table 3). A high ee
value (99.2%) was also obtained for â-substituted ena-
mide mixtures (Z/E) (entry 9, Table 3). Asymmetric
hydrogenation of the cyclic enamide 1-(N-acetylamido)-
indene also proceeded smoothly to give (S)-(+)-N-(indan-
1-yl)acetamide in a quantitative yield and with an ee
value of 96.0% (entry 10, Table 3), which provides a first
example of using chiral monophosphorus ligands in the
asymmetric hydrogenation of cyclic enamide with a high
ee value. A high turnover number (ca. 5000) with a slight
drop in ee was also observed in the hydrogenation of
N-acetylphenylethenamine (entry 12, Table 3). The enan-
tioselectivities of the hydrogenation of R-arylenamides
with ligand 3a are higher than or comparable to other
reported families of efficient mono- and bidentate chiral
phosphorus ligands.12
To study the effect of H2 pressure and solvents on the
reaction, the reaction with [Rh(COD)2]BF4/3a as a cata-
lyst precursor and enamide 6a as a model substrate was
studied in more detail. The results, summarized in Table
1, show that the nature of the solvent had little effect on
the enantioselectivity, but had a significant effect on the
conversion. Reaction in a more polar solvent such as
CH3OH or THF resulted in a lower conversion rate (en-
tries 5 and 6, Table 1). The catalyst performance was best
when CH2Cl2 was used (entries 1 and 2, Table 1).
Changes in H2 pressure had little effect on the enantio-
selectivity and conversion (entries 1 and 2, Table 1); due
to the high activity of the catalyst, the reaction can
proceed smoothly under a lower H2 pressure without
deterioration (entry 2, Table 1).
To identify the most efficient ligands, the remaining
ligands were tested under “standard” conditions (a
ligand-to-Rh ratio of 2.2, an H2 pressure of 10 atm, and
CH2Cl2 as a solvent); the results are given in Table 2.
The screening of our ligands shows that the mono-
phosphites we prepared are efficient ligands for an
asymmetric hydrogenation reaction. However, the enan-
tioselectivities proved to be influenced dramatically by
the structure of the ligands. The results in Table 2 show
that the enantiomeric excess depends strongly on the
moiety of the P/O heterocycle in the chiral ligands. The
ee values of over 90% were achieved with ligands 3a -i,
which contain (S)- or (R)-BINOL in the P/O heterocycle.
Moreover, the ee values increased significantly when
R-BINOL was introduced in these ligands (entries 1-7,
(12) For some selected papers on Rh-catalyzed asymmetric hydro-
genation of enamides see the following. For monophosphorus ligands,
see: (a) refs 4b,d,e,4h,i. For diphosphorus ligands, see ref 10h. (b) Burk,
M. J .; Wang, Y. M.; Lee, J . R. J . Am. Chem. Soc. 1996, 118, 5142. (c)
Zhang, F.-Y.; Pai, C.-C.; Chan, A. S. C. J . Am. Chem. Soc. 1998, 120,
5808. (d) Zhu, G.; Zhang, X. J . Org. Chem. 1998, 63, 9590. (e) Xiao,
D.; Zhang, Z.; Zhang, X. Org. Lett. 1999, 1, 1679. (f) Gridnev, I, D.;
Yasutake, M.; Higashi, N.; Imamoto, T. J . Am. Chem. Soc. 2001, 123,
5268. (g) Lee, S.-G.; Zhang, Y.-J .; Song, C.-E.; Lee, J .-K.; Choi, J .-H.
Angew. Chem., Int. Ed. 2002, 41, 847. (h) Tang, W.; Zhang, X. Angew.
Chem., Int. Ed. 2002, 41, 1612. (i) Lotz, M.; Polborn, K.; Knochel, P.
Angew. Chem., Int. Ed. 2002, 41, 4708.
(13) The ee values given hy Reetz’s monophosphites were typically
76-97%, see ref 4g.
J . Org. Chem, Vol. 69, No. 7, 2004 2357

Huang et al.
TABLE 3. Asym m etr ic Hyd r ogen a tion of En a m id es
Ca ta lyzed by Rh -3a a
TABLE 4. Rh -Ca ta lyzed Asym m etr ic Hyd r ogen a tion of
r-Deh yd r oa m in o Acid Ester s 8a
entry
ligand
substrate
R
ee, % (config)b
1
2
3
4
5
6
7
8
9
3a
3b
3c
3d
3e
3f
3g
3a
3a
3a
3a
3a
8a
8a
8a
8a
8a
8a
8a
8b
8c
8d
8e
8f
H
H
H
H
H
H
H
Ph
97.7 (S)
96.3 (S)
95.9 (S)
95.5 (S)
94.4 (S)
96.9 (S)
93.9 (S)
96.8 (S)
98.0 (S)
97.4 (S)
97.1 (S)
96.6 (S)
p-MeOPh
o-MeOPh
p-ClPh
10
11
12
o-ClPh
a
Solvent ) CH2Cl2; p(H2) ) 1.2 atm; T ) 20 °C; reaction time
) 12 h; substrate:[Rh(COD)2]BF4:3 ) 1:0.01: 0.022; 100% conver-
b
sion was obtained in all cases. Determined by chiral capillary
GC on a Varian Chirasil-L-Val column and a Supelco Chiral select
1000 column. The absolute configuration was assigned by com-
parison of the optical rotation with reported data.
TABLE 5. Rh -Ca ta lyzed Asym m etr ic Hyd r ogen a tion of
Dim eth yl Ita con a te 10a
a
Solvent ) CH2Cl2; p(H2) ) 10 atm; T ) 20 °C; reaction time
entry
ligand
P(H2), atm
ee, % (config)b
) 12 h; substrate:[Rh(COD)2]BF4:3a ) 1:0.01:0.022; 100% conver-
sion was obtained in all cases otherwise mentioned. Determined
b
1
2
3
4
5
6
7
8
3a
3b
3c
3d
3e
3e
3e
3f
10
10
10
10
10
5
1.2
10
10
10
98.8 (R)
98.3 (R)
98.5 (R)
98.5 (R)
98.5 (R)
98.5 (R)
98.6 (R)
98.8 (R)
99.0 (R)
99.1 (R)
by chiral capillary GC on a Varian Chirasil-L-Val column and a
Supelco Chiral select 1000 column. The absolute configuration was
assigned by comparison of the optical rotation with reported data.
d
c Substrate-to-catalyst ratio (S/C) ) 1000. S/C ) 5000, 88%
conversion.
3. Asym m etr ic Hyd r ogen a tion of R-Deh yd r oa m -
in o Acid Der iva tives. Encouraged by these findings,
we investigated expanding the substrate scope of asym-
metric hydrogenations by using ligands 3a -g. The
results, summarized in Table 4, follow the same trend
as observed for substrate 6, but with somewhat lower ee
values. The catalyst precursor with ligand 3a produced
the highest ee value for 9a (97.7%, entry 1, Table 4). With
the best ligand 3a , a variety of R-dehydroamino acid
derivatives (8a -f) with different electronic properties
were employed as substrates for the Rh-catalyzed hy-
drogenation reaction under atmospheric pressure. An ee
value of over 96% was obtained for all substrates, indic-
ating their minimal electronic effect. The highest ee value
(up to 98.0%, entry 9, Table 4) was obtained for 9c.
4. Asym m etr ic Hyd r ogen a tion of Dim eth yl Ita -
con a te. The Rh-catalyzed asymmetric hydrogenation of
dimethyl itaconate (10) was also investigated. Similarly,
ligands 3a -g turned out to be very active in this reaction.
The high activity of these ligands means that the reaction
can also be carried out at an H2 pressure of 1.2 atm (entry
7, Table 5). An ee value of more than 98.0% can be
produced by employing any of these ligands; the catalyst
precursor containing ligand 3g induced the highest ee
value (99%, entry 9, Table 5). To evaluate further the
catalytic efficiency of the Rh-3 system in this asymmetric
hydrogenation, we increased the ratio of substrate to
9
3g
3g
10c
a
Solvent ) CH2Cl2; T ) 20 °C; reaction time ) 12 h; substrate:
[Rh(COD)2]BF4:3 ) 1:0.01:0.022; 100% conversion was obtained
b
in all cases. Determined by chiral capillary GC on a γ-DEX 225
column. The absolute configuration was assigned by comparison
of the optical rotation with reported data. c S/C) 5000.
catalyst. Hydrogenation of dimethyl itaconate 10 in the
presence of Rh-3g (with a turnover number of 5000)
within 3 h afforded the product 11 in 100% yield and with
an ee value of 99.1% (entry 10, Table 5).
5. Asym m etr ic Hyd r ogen a tion of â-Alk yl-Su bsti-
tu ted (E)-â-(Acyla m in o)a cr yla tes. Unlike the above-
mentioned three types of functionalized olefins, only a
few Rh-catalyst and Ru-catalyst systems can fulfill the
highly enantioselective hydrogenation of â-(acylamino)-
acrylates.14 The exciting results obtained in the Rh-3
catalyzed hydrogenation of the above three types of
substrates led us to attempt to use these ligands in this
challenging asymmetric reaction. The catalysts were also
prepared in situ by reacting the appropriate ligand with
[Rh(COD)2]BF4 in the corresponding solvent at room
temperature. The effects of solvent and H2 pressure were
investigated for the catalytic precursor containing ligand
3a ; the results are summarized in Table 6.
2358 J . Org. Chem., Vol. 69, No. 7, 2004

A Novel Class of P-O Monophosphite Ligands
TABLE 6. Th e Effect of Solven t a n d H2 P r essu r e on th e
En a n tioselective Hyd r ogen a tion of (E)-Meth yl
3-Aceta m id o-2-bu ten oa te Ca ta lyzed by Rh -3a a
substituted (E)-â-(acylamino)acrylates (12a -d ) catalyzed
by Rh-3g was studied, and consistently high enantiose-
lectivities were obtained in all cases (entries 7-10, Table
7). Substrate 12d with a bulky alkyl substituent gave
the best ee value (up to 99.9%, entry 10, Table 7). We
know of no reports of monophosphite ligands employed
in the asymmetric hydrogenation of â-(acylamino)acry-
lates that exhibit such high enantioselectivities.15
In contrast to other chiral monophosphites, the ligands
reported here can be used in a wide range of hydrogena-
tion reactions under ambient temperature and atmo-
spheric pressure. We assume that one of the critical
factors underlying the efficient catalytic properties of
these ligands is their double six-membered-ring backbone
structure derived from D-mannitol and the additional
groups attached to it. One of the ether moieties present
in the backbone may behave as a hemilabile ligand, and
thus reduce the conformational freedom. Although a
rational explanation of the observed enantioselectivities
is difficult at present, the short and convenient synthesis
of the new ligands and the superb enantioselectivities
obtained in asymmetric catalysis, combined with our
previous observations,6 provide new insights into the
design of efficient monophosphorus ligands.
entry
solvent
P(H2), atm
conv, %
ee, % (config)b
1
2
3
4
5
6
7
8
CH2Cl2
EtOAc
toluene
THF
CH3OH
CH2Cl2
CH2Cl2
CH2Cl2
10
10
10
10
10
35
40
50
72
2
0
99.6 (S)
89.0 (S)
N/A
91.3 (S)
1.1 (S)
99.4 (S)
96.7 (S)
92.5 (S)
9
93
82
98
94
a
T ) 20 °C; reaction time ) 12 h; substrate:[Rh(COD)2]BF4:3a
b
) 0.5:0.01:0.022. Determined by chiral capillary GC on a Supelco
Chiral select 1000 column. The absolute configuration was as-
signed by comparison of the optical rotation with reported data.
TABLE 7. Rh -Ca ta lyzed Asym m etr ic Hyd r ogen a tion of
(E)-â-(Acyla m in o)a cr yla tes 12a -d a
Con clu sion
In summary, we have developed novel and easily
prepared chiral ligands that provide the first examples
of highly efficient monophosphite ligands for the asym-
metric hydrogenation of all four types of functionalized
olefins: enamides, R-dehydroamino acid esters, dimethyl
itaconate, and â-(acylamino)acrylates. Furthermore, the
air-stable ligands can be readily prepared in three steps
from commercially available D-mannitol and BINOL,
which offers the benefits of simple processes and low cost.
Further studies to demonstrate the function of the
additional groups attached in these ligands and extension
of the scope of these ligands to other transition-metal-
catalyzed reactions are in progress.
entry ligand substrate
R1
R2 conv, % ee, % (config)b
1
2
3
4
5
6
7
8
9
3a
3b
3c
3d
3e
3f
3g
3g
3g
3g
12a
12a
12a
12a
12a
12a
12a
12b
12c
12d
Me
Me
Me
Me
Me
Me
Me
Me
Et
Me
Me
Me
Me
Me
Me
Me
Et
98
97
94
94
94
92
97
93
96.7 (S)
97.3 (S)
96.1 (S)
98.9 (S)
96.9 (S)
99.2 (S)
99.1 (S)
98.7 (S)
99.8 (S)
99.9 (S)
Me
99
10
i-Pr Me
100
a
Solvent ) CH2Cl2; p(H2) ) 40 atm; T ) 20 °C; reaction time
) 12 h; substrate:[Rh(COD)2]BF4:3 ) 0.5:0.01:0.022. b Determined
by chiral capillary GC on a Supelco Chiral select 1000 column and
a γ-DEX 225 column. The absolute configuration was assigned by
comparison of the optical rotation with reported data.
Exp er im en ta l Section
Gen er a l. All reactions and manipulations were performed
in a nitrogen-filled glovebox or with standard Schlenk-type
techniques. All solvents were dried and degassed by standard
methods and stored under nitrogen. Commercially available
methyl 2-acetamidoacrylate and dimethyl itaconate were used.
All other R-dehydroamino acid esters, enamides, and â-(acyl-
amino)acrylates are known compounds which were synthesized
by using procedures described elsewhere.16 All other chemicals
were obtained commercially.
Syn th esis of 1,3:4,6-Di-O-ben zylid en e-D-m a n n itol (4).
This compound was prepared by using procedures described
elsewhere.11
Gen er a l P r oced u r e for th e Syn th esis of th e Ch ir a l
Alcoh ols 5a -f. Sodium hydride (80% oil suspension, 330 mg,
10 mmol) was washed with hexane, and then 1,3:4,6-di-O-
benzylidene-D-mannitol 4 (3.58 g, 10 mmol) was added. To the
mixture was added DMF (30 mL), the resulting mixture was
The results show that the efficiency of the process
depended strongly on the nature of the solvent and the
H2 pressure: the catalyst performance was best when
CH2Cl2 was used under higher H2 pressure (entry 7,
Table 6). The ligands were screened under these optimal
conditions with 12a as the model substrate. Table 7
shows that these are excellent ligands for hydrogenation,
giving nearly full conversion and ee values of up to 99%.
Ligand 3g is superior to the other ligands in terms of
the activity and enantioselectivity (entries 1-7, Table 7).
The asymmetric hydrogenation of a variety of â-alkyl-
(14) For recent example see: (a) Heller, D.; Holz, J .; Drexler, H. J .;
Lang, J .; Drauz, K.; Krimmer, H. P.; Bo¨rner, A. J . Org. Chem. 2001,
66, 6816. (b) Lee, S.; Zhang, Y. J . Org. Lett. 2002, 4, 2429. (c) Holz, J .;
Monsees, A.; J iao, H.; You, J .; Komarov, I. V.; Fischer, C.; Drauz, K.;
Bo¨rner, A. J . Org. Chem. 2003, 68, 1701. (d) Tang, W.; Zhang, X. Org.
Lett. 2002, 4, 4159. (e) Zhou, Y.-G.; Tang, W.; Wang, W.-B.; Li, W.;
Zhang, X. J . Am. Chem. Soc. 2002, 124, 4952. (f) You, J .; Drexler, H.
J .; Zhang, S.; Fischer, C.; Heller, D. Angew. Chem., Int. Ed. 2003, 42,
913. (g) Yasutake, M.; Gridnev, I. D.; Higashi, N.; Imamoto, T. Org.
Lett. 2001, 3, 1701. (h) Ohashi, A.; Kikuchi, S.; Yasutake, M.; Imamoto,
T. Eur. J . Org. Chem. 2002, 8, 5196. (i) Tang, W.; Wang, W.; Chi, Y.;
Zhang, X. Angew. Chem., Int. Ed. 2003, 42, 3509.
(15) Reetz’s monophosphites only gave 12% ee for â-(acylamino)-
acrylates, see: Pena, D.; Minnaard, A. J .; Vries, A. H. M.; de Vries, J .
G.; Feringa, B. L. Org. Lett. 2003, 5, 475.
(16) (a) Herbst, R. M.; Shemin, D. Organic Syntheses; Wiley: New
York, 1943; Collect. Vol. II, p 1. (b) Burk, M. J .; Casy, G.; J ohnson, N.
B. J . Org. Chem. 1998, 63, 6084. (c) Zhang, Z.; Zhu, G.; J iang, Q.; Xiao,
D.; Zhang, X. J . Org. Chem. 1999, 64, 1774. (d) Zhu, G.; Chen, Z.;
Zhang, X. J . Org. Chem. 1999, 64, 6907.
J . Org. Chem, Vol. 69, No. 7, 2004 2359

Huang et al.
stirred at room temperature for 0.5 h, and then RX (10 mmol)
was added. The reaction mixture was stirred for 1-12 h at
room temperature, diluted with water, and then extracted with
ethyl acetate. The combined extracts were washed with water
and brine, dried over Na2SO4, and concentrated under reduced
pressure. The residue was purified by flash chromatography
on silica gel with EtOAc/hexane (at ratios of 1/20-1/5) to give
the corresponding product at yields of 30-95%.
1,3:4,6-Di-O-ben zylid en e-2-O-m eth yl-D-m a n n itol (5a ).
The above procedure was followed with use of 4 and iodo-
methane. After workup, 5a was obtained as a white solid. Mp
154-155 °C, [R]22D -23.11 (c 0.77, THF); 1H NMR (DMSO-d6)
δ 3.40 (m, 3H), 3.56-3.60 (m, 3H), 3.78-3.87 (m, 2H), 3.99 (d,
J ) 7.6 Hz, 1H), 4.16-4.19 (m, 1H), 4.39-4.46 (m, 1H), 5.58
(s, 1H), 5.61 (s, 1H), 7.35-7.44 (m, 10H); 13C NMR (DMSO-
d6) δ 58.1, 58.7, 58.8, 68.5, 68.6, 70.9, 76.6, 78.4, 100.0, 100.2,
126.0, 126.1, 128.0, 128.1, 128.6, 138.0, 138.2; HRMS (APCI)
calcd for C21H24O6 (M+ + 1) 373.1645, found 373.1641.
127.9, 128.3, 128.5, 128.6, 137.9, 141.8, 142.7; HRMS (APCI)
calcd for C33H32O6 (M+ - 1) 523.2115, found 523.2144.
1,3:4,6-Di-O-ben zylid en e-2-O-1-n a p h th ylm eth yl-D-m a n -
n itol (5g). The above procedure was followed with 4 and
1-chloromethyl-naphthalene. After workup, 5g was obtained
as a white solid. Mp 148-149 °C, [R]22 -37.46 (c 0.58, THF);
D
1H NMR (DMSO-d6) δ 3.40 (m, 1H), 3.67-3.76 (m, 3H), 3.85
(m, 1H), 4.07-4.13 (m, 2H), 4.58-4.61 (m, 1H), 4.93-4.98 (m,
2H), 5.14 (d, J ) 12.0 Hz, 1H), 5.58 (s, 1H), 7.12-7.13 (m,
2H), 7.30-7.42 (m, 9H), 7.48-7.56 (m, 3H), 7.79 (d, J ) 8.0
Hz, 1H), 7.86 (d, J ) 8.0 Hz, 1H), 8.14 (d, J ) 8.0 Hz, 1H); 13
C
NMR (DMSO-d6) δ 58.7, 65.2, 68.7, 69.2, 70.9, 76.3, 78.1, 99.7,
100.3, 124.2, 125.2, 125.9, 126.1, 127.5, 127.8, 127.9, 128.4,
128.5, 128.6, 128.8, 131.5, 133.3, 133.4, 137.8, 138.0; HRMS
(APCI) calcd for C31H30O6 (M+ + 1) 499.2115, found 499.2123.
Gen er a l P r oced u r e for th e Syn th esis of th e Mon o-
p h osp h ite Liga n d s (3a -k ). PCl3 (132 µL, 1.5 mmol) as a
solution in THF (4 mL) was slowly added to a stirred solution
of 5 (1.5 mmol) in THF (5 mL), and the resulting mixture was
stirred for 1 h at room temperature. The reaction mixture was
then cooled to -10 °C, and Et3N (1.07 mL, 4.5 mmol) was
slowly added. The reaction mixture was allowed to warm to
room temperature, maintained under these conditions for 0.25
h, and then cooled to 0 °C, solid BINOL or biphenol was added,
and the resulting mixture was allowed to warm to room
temperature and stirred overnight prior to dilution with
diethyl ether. The solids were removed by filtration through
a pad of Celite, the solvent was removed in vacuo, and the
residue was purified by flash chromatography (EtOAc/hexane
1/20-1/10), which furnished the title ligand as a white foam
at a yield of 75-87%.
1,3:4,6-Di-O-ben zylid en e-2-O-p r op yl-D-m a n n itol (5b).
The above procedure was followed with use of 4 and 1-bro-
mopropane. After workup, 5b was obtained as a white solid.
1
Mp 94-95 °C, [R]22 -29.97 (c 0.69, THF); H NMR (DMSO-
D
d6) δ 0.81-0.90 (m, 3H), 1.47-1.56 (m, 2H), 3.43-3.46 (m, 1H),
3.55-3.66 (m, 4H), 3.82-3.85 (m, 2H), 3.98 (d, J ) 9.2 Hz,
1H), 4.16-4.20 (m, 1H), 4.37-4.40 (m, 1H), 5.52 (s, 1H), 5.54
(s, 1H), 7.35-7.42 (m, 10H); 13C NMR (DMSO-d6) δ 10.5, 22.7,
58.7, 58.8, 66.9, 68.8, 70.9, 71.6, 76.7, 78.4, 100.1, 100.2, 125.9,
126.1, 127.9, 128.1, 128.6, 138.1, 138.2; HRMS (APCI) calcd
for C23H28O6 (M+ + 1) 401.1958, found 401.1971.
1,3:4,6-Di-O-ben zyliden e-2-O-isopr opyl-D-m an n itol (5c).
The above procedure was followed with use of 4 and 2-bro-
mopropane. After workup, 5c was obtained as a white solid.
Mp 106-107 °C, [R]22D -33.33 (c 0.62, THF); 1H NMR (DMSO-
d6) δ 1.11 (s, 6H), 3.56-3.58 (m, 2H), 3.71 (m, 2H), 3.83 (m,
2H), 3.95-3.97 (d, J ) 8.8 Hz, 1H), 4.16-4.18 (m, 1H), 4.31-
4.33 (m, 1H), 5.52 (d, J ) 9.6 Hz, 2H), 7.35-7.42 (m, 10H);
13C NMR (DMSO-d6) δ 22.1, 22.2, 58.7, 64.7, 69.4, 70.8, 76.7,
78.1, 100.2, 125.9, 126.1, 127.9, 128.1, 128.6, 138.1; HRMS
(APCI) calcd for C23H28O6 (M+ + 1) 401.1958, found 401.1965.
1,3:4,6-Di-O-ben zylid en e-2-O-m eth yl-3-O-((R)-2,2′-O,O-
(1,1′-bin a p h th yl)d ioxop h osp h ite)-D-m a n n itol (3a ). The
above procedure was followed with use of 5a and R-BINOL.
After workup, 3a was obtained. Mp 152-153 °C, [R]22D -289.21
1
(c 0.65, THF); H NMR (DMSO-d6) δ 3.39 (s, 3H), 3.47-3.49
(m, 1H), 3.59 (m, 1H), 3.79 (d, J ) 9.2 Hz, 1H), 3.91 (m, 1H),
4.10 (d, J ) 9.6 Hz, 1H), 4.42-4.43 (m, 1H), 4.58 (m, 1H), 4.61
(m, 1H), 5.48 (s, 1H), 5.76 (s, 1H), 7.22-7.36 (m, 2H), 7.38-
7.62 (m, 16H), 8.09-8.18 (m, 4H); 13C NMR (DMSO-d6) δ 58.1,
62.9, 63.1, 68.2, 68.8, 76.2, 76.5, 99.9, 100.1, 121.6, 121.9, 123.4,
125.3, 125.5, 125.9, 126.7, 126.8, 128.1, 128.2, 128.7, 130.3,
130.9, 131.3, 131.7, 132.0, 137.4, 137.7, 146.7, 147.0; 31P NMR
(DMSO-d6) δ 154.81; HRMS (APCI) calcd for C41H35O8P (M+
+ 1) 687.2142, found 687.2110.
1,3:4,6-Di-O-ben zylid en e-2-O-isobu tyl-D-m a n n itol (5d ).
The above procedure was followed with use of 4 and 1-bromo-
2-methylpropane. After workup, 5d was obtained as a white
1
solid. Mp 107-108 °C, [R]22 -24.49 (c 0.59, THF); H NMR
D
(DMSO-d6) δ 0.85-0.88 (m, 6H), 1.17-1.80 (m, 1H), 3.21 (t, J
) 8.0 Hz, 1H), 3.40-3.42 (m, 1H), 3.58-3.67 (m, 3H), 3.88-
3.90 (m, 2H), 4.02 (d, J ) 8.8 Hz, 1H), 4.18-4.21 (m, 1H), 4.40
(d, J ) 5.6 Hz, 1H), 5.51 (s, 1H), 5.55 (s, 1H), 7.35-7.43 (m,
10H); 13C NMR (DMSO-d6) δ 19.1, 19.1, 28.2, 58.6, 67.3, 68.8,
70.9, 76.7, 78.5, 100.2, 125.9, 126.1, 127.9, 128.1, 128.6, 138.1,
138.1; HRMS (APCI) calcd for C24H30O6 (M+ + 1) 415.2115,
found 415.2128.
1,3:4,6-Di-O-ben zylid en e-2-O-p r op yl-3-O-((R)-2,2′-O,O-
(1,1′-bin a p h th yl)d ioxop h osp h ite)-D-m a n n itol (3b). The
above procedure was followed with use of 5b and R-BINOL.
After workup, 3b was obtained. Mp 127-128 °C, [R]22
D
1
-229.40 (c 0.57, THF); H NMR (DMSO-d6) δ 0.80-0.83 (m,
3H), 1.43-1.48 (m, 2H), 3.41 (m, 1H), 3.48-3.52 (m, 2H), 3.64-
3.66 (m, 1H), 3.81-3.83 (m, 1H), 3.91 (m, 1H), 4.07-4.09 (m,
1H), 4.37-4.38 (m, 1H), 4.57-4.60 (m, 1H), 4.70 (m, 1H), 5.51
(s, 1H), 5.68 (s, 1H), 7.21-7.23 (m, 2H), 7.34-7.61 (m, 16H),
8.06-8.14 (m, 4H); 13C NMR (DMSO-d6) δ 10.5, 22.7, 62.8,
63.1, 66.5, 68.6, 68.8, 71.6, 76.2, 76.6, 100.1, 100.2, 121.6, 121.9,
123.4, 125.3, 125.4, 125.9, 125.9, 126.7, 126.8, 128.1, 128.2,
128.7, 128.8, 130.3, 130.9, 131.3, 131.7, 132.1, 137.4, 137.7,
146.7, 147.0; 31P NMR (DMSO-d6) δ 155.01; HRMS (APCI)
calcd for C43H39O8P (M+ + 1) 715.2455, found 715.2445.
1,3:4,6-Di-O-ben zylid en e-2-O-ben zyl-D-m a n n itol (5e).
The above procedure was followed with use of 4 and benzyl
bromide. After workup, 5e was obtained as a white solid. Mp
155-156 °C, [R]22D -38.17 (c 0.81, THF); 1H NMR (DMSO-d6)
δ 3.56-3.68 (m, 2H), 3.79-3.84 (m, 2H), 3.90 (d, J ) 9.6 Hz,
1H), 4.08 (d, J ) 9.2 Hz, 1H), 4.18 (t, J ) 5.2 Hz, 1H), 4.42-
4.43 (d, J ) 5.6 Hz, 1H), 4.57-4.66 (m, 2H), 5.49 (s, 1H), 5.57
(s, 1H), 7.22-7.44 (m, 15H); 13C NMR (DMSO-d6) δ 58.7, 66.1,
68.7, 70. 9, 71.3, 76.5, 78.2, 99.9, 100.2, 126.1, 126.1, 127.7,
127.9, 128.3, 128.5, 128.6, 138.0, 138.1, 138.2; HRMS (APCI)
calcd for C27H28O6 (M+ + 1) 449.1958, found 449.1972.
1,3:4,6-Di-O-b en zylid en e-2-O-isop r op yl-3-O-((R)-2,2′-
O,O-(1,1′-b in a p h t h yl)d ioxop h osp h it e)-D-m a n n it ol (3c).
The above procedure was followed with use of 5c and R-
BINOL. After workup, 3c was obtained. mp 135-136 °C, [R]22
1,3:4,6-Di-O-b en zylid en e-2-O-d ip h en ylm et h yl-D-m a n -
n itol (5f). The above procedure was followed with use of 4
and bromodiphenylmethane. After workup, 5f was obtained
D
-278.62 (c 0.62, THF); 1H NMR (DMSO-d6) δ 1.05-1.06 (s,
6H), 3.45-3.50 (m, 1H), 3.69-3.81 (m, 3H), 3.92 (t, J ) 10.0
Hz, 1H), 4.06-4.09 (m, 1H), 4.32-4.33 (m, 1H), 4.58 (m, 1H),
4.68-4.70 (m, 1H), 5.54 (s, 1H), 5.68 (s, 1H), 7.20-7.63 (m,
18H), 8.07-8.17 (m, 4H); 13C NMR (DMSO-d6) δ 22.0, 22.5,
23.2, 62.9, 63.1, 64.2, 68.8, 69.2, 70.8, 76.1, 76.3, 100.0, 100.2,
121.6, 121.9, 123.4, 125.3, 125.4, 125.9, 126.7, 126.8, 128.1,
128.2, 128.7, 128.9, 130.3, 130.9, 131.3, 131.8, 132.0, 137.4,
as a white solid. Mp 107-108 °C, [R]22 -16.44 (c 0.69, THF);
D
1H NMR (DMSO-d6) δ 3.59-3.62 (m, 1H), 3.73-3.86 (m, 3H),
3.95 (d, J ) 9.2 Hz, 1H), 4.16-4.21 (m, 2H), 4.31-4.45 (m,
1H), 5.46 (s, 1H), 5.70 (s, 1H), 5.75 (s, 1H), 7.12-7.43 (m, 20H);
13C NMR (DMSO-d6) δ 58.8, 58.9, 64.6, 68.8, 70.9, 76.5, 78.2,
80.9, 100.1, 100.3, 126.1, 126.5, 126.9, 127.4, 127.5, 127.8,
2360 J . Org. Chem., Vol. 69, No. 7, 2004

A Novel Class of P-O Monophosphite Ligands
137.7, 146.7, 146.9; 31P NMR (DMSO-d6) δ 155.22; HRMS
(APCI) calcd for C43H39O8P (M+ + 1) 715.2455, found 715.2433.
76.3, 99.9, 100.2, 121.2, 121.7, 123.3, 125.3, 125.5, 125.7, 125.9,
126.0, 126.1, 126.8, 127.9, 128.1, 128.5, 128.6, 128.7, 130.5,
130.7, 131.1, 131.3, 131.8, 131.9, 137.3, 137.6, 146.6, 147.2;
31P NMR (DMSO-d6) δ 144.50; HRMS (APCI) calcd for
1,3:4,6-Di-O-ben zylid en e-2-O-isobu tyl-3-O-((R)-2,2′-O,O-
(1,1′-bin a p h th yl)d ioxop h osp h ite)-D-m a n n itol (3d ). The
above procedure was followed with use of 5d and R-BINOL.
C
41H35O8P (M+ + 1) 687.2142, found 687.2112.
After workup, 3d was obtained. Mp 142-143 °C, [R]22
1,3:4,6-Di-O-ben zylid en e-2-O-ben zyl-3-O-((S)-2,2′-O,O-
D
1
(1,1′-b in a p h t h yl)d ioxop h osp h it e)-D-m a n n it ol (3i). The
above procedure was followed with use of 5e and S-BINOL.
-270.19 (c 0.62, THF); H NMR (DMSO-d6) δ 0.80-0.82 (m,
6H), 1.69-1.75 (m, 1H), 3.19-3.21 (m, 1H), 3.33-3.39 (m, 1H),
3.48-3.51 (m, 1H), 3.64-3.65 (m, 1H), 3.81-3.84 (m, 1H), 3.89
(t, J ) 10.0 Hz, 1H), 4.07 (d, J ) 9.2 Hz, 1H), 4.37-4.39 (m,
1H), 4.58-4.60 (m, 1H), 4.68-4.71 (m, 1H), 5.52 (s, 1H), 5.66
(s, 1H), 7.19-7.61 (m, 18H), 8.06-8.16 (m, 4H); 13C NMR
(DMSO-d6) δ 19.0, 19.1, 28.1, 31.4, 62.8, 63.0, 66.9, 68.5, 68.8,
76.2, 76.6, 100.1, 100.2, 121.6, 121.9, 122.1, 123.4, 125.3, 125.4,
125.8, 125.9, 126.4, 126.7, 126.8, 128.1, 128.2, 128.7, 128.8,
130.3, 130.9, 131.2, 131.8, 132.0, 137.4, 137.7, 146.7, 147.0;
31P NMR (DMSO-d6) δ 154.98; HRMS (APCI) calcd for
After workup, 3i was obtained. Mp 123-124 °C, [R]22 184.97
D
1
(c 0.76, THF); H NMR (DMSO-d6) δ 3.81-3.86 (m, 3H), 4.17
(d, J ) 9.6 Hz, 1H), 4.27-4.34 (m, 2H), 4.49-4.55 (m, 2H),
4.64 (d, J ) 12.0 Hz, 1H), 4.72 (d, J ) 11.6 Hz, 1H), 5.60 (s,
1H), 5.68 (s, 1H), 7.16-7.42 (m, 19H), 7.48-7.50 (m, 2H), 7.62
(d, J ) 8.8 Hz, 1H), 7.72 (d, J ) 8.8 Hz, 1H), 8.06-8.16 (m,
4H); 13C NMR (DMSO-d6) δ 63.0, 65.8, 68.7, 68.8, 71.3, 76.2,
99.9, 100.2, 121.2, 121.7, 125.3, 125.4, 125.7, 125.9, 126.8,
127.9, 127.9, 128.4, 128.6, 128.7, 130.4, 130.7, 131.1, 131.3,
131.9, 137.2, 137.5, 138.1, 146.6, 147.2; 31P NMR (DMSO-d6)
δ 144.79; HRMS (APCI) calcd for C47H39O8P (M+ + 1) 763.2455,
found 763.2496.
C
44H41O8P (M+ + 1) 729.2611, found 729.2640.
1,3:4,6-Di-O-ben zylid en e-2-O-ben zyl-3-O-((R)-2,2′-O,O-
(1,1′-bin a p h th yl)d ioxop h osp h ite)-D-m a n n itol (3e). The
above procedure was followed with use of 5e and R-BINOL.
After workup, 3e was obtained. Mp 122-123 °C, [R]22D -251.81
(c 0.69, THF); 1H NMR (DMSO-d6) δ 3.51 (m, 1H), 3.75 (m,
1H), 3.85-3.90 (m, 2H), 4.12 (d, J ) 9.2 Hz, 1H), 4.37-4.39
(m, 1H), 4.52-4.55 (m, 3H), 4.57-4.60 (m, 1H), 5.55 (s, 1H),
5.64 (s, 1H), 7.20-7.55 (m, 23H), 8.08-8.14 (m, 4H); 13C NMR
(DMSO-d6) δ 62.9, 63.1, 65.6, 68.5, 68.7, 71.2, 76.1, 76.4, 99.9,
100.0, 121.6, 121.9, 125.3, 125.5, 125.9, 126.7, 126.8, 127.7,
127.8, 128.1, 128.3, 128.7, 130.3, 130.9, 131.2, 137.3, 137.6,
138.0, 146.7, 147.0; 31P NMR (DMSO-d6) δ 154.86; HRMS
(APCI) calcd for C47H39O8P (M+ + 1) 763.2455, found 763.2490.
1,3:4,6-Di-O-ben zylid en e-2-O-ben zyl-3-O-(2,2′-O,O-(1,1′-
bip h en yl)d ioxop h osp h ite)-D-m a n n itol (3j). The above pro-
cedure was followed with use of 5e and 2,2′-biphenol. After
workup, 3j was obtained. Mp:75-76 °C, [R]22 -35.81 (c 0.81,
D
THF); 1H NMR (DMSO-d6) δ 3.68-3.79 (m, 2H), 3.89-3.92
(m, 1H), 4.07 (d, J ) 8.8 Hz, 1H), 4.15 (d, J ) 9.2 Hz, 1H),
4.41-4.47 (m, 2H), 4.56-4.67 (m, 3H), 5.52 (s, 1H), 5.62 (s,
1H), 7.22-7.53 (m, 19H), 7.53-7.56 (m, 2H); 13C NMR (DMSO-
d6) δ 62.7, 62.8, 65.7, 68.6, 68.8, 71.3, 76.2, 76.3, 99.9, 100.1,
121.5, 122.1, 125.8, 125.9, 127.8, 127.9, 128.1, 128.3, 128.6,
128.8, 129.7, 130.0, 130.2, 130.4, 137.3, 137.5, 138.0, 148.2,
148.8; 31P NMR (DMSO-d6) δ 145.39; HRMS (APCI) calcd for
1,3:4,6-Di-O-ben zylid en e-2-O-d ip h en ylm eth yl-3-O-((R)-
2,2′-O,O-(1,1′-bin aph th yl)dioxoph osph ite)-D-m an n itol (3f).
The above procedure was followed with use of 5f and R-
C
39H35O8P (M+ + 1) 663.2142, found 663.2102.
1,3:4,6-Di-O-b e n zylid e n e -2-O-b e n zyl-3-O-(2,2′-O,O-
(3,3′,5,5′-tetr a -ter t-bu tyl-1,1′-bip h en yl)d ioxop h osp h ite)-
D-m a n n itol (3k ). The above procedure was followed with use
of 5e and 3,3′,5,5′-tetra-tert-butyl-1,1′-biphenyl-2,2′-diol. After
workup, 3k was obtained. Mp 120-121 °C, [R]22D 19.36 (c 0.83,
THF); 1H NMR (DMSO-d6) δ 1.25 (s, 9H), 1.31 (s, 9H), 1.41 (s,
9H), 1.42 (s, 9H), 3.42 (m, 1H), 3.76-3.83 (m, 3H), 4.11-4.20
(m, 2H), 4.41-4.43 (m, 1H), 4.56-4.67 (m, 3H), 5.10 (s, 1H),
5.59 (s, 1H), 7.06 (m, 1H), 7.14-7.33 (m, 15H), 7.45 (m, 2H);
13C NMR (DMSO-d6) δ 31.0, 31.2, 34.2, 34.3, 35.0, 62.6, 65.6,
68.7, 68.9, 71.2, 76.1, 76.3, 99.9, 100.2, 124.1, 124.3, 125.8,
125.9, 126.3, 126.5, 127.6, 127.6, 127.9, 128.2, 128.5, 128.7,
132.1, 132.4, 137.2, 137.3, 138.2, 139.7, 139.9, 144.4, 144.7,
146.6; 31P NMR (DMSO-d6) δ 146.24; HRMS (APCI) calcd for
BINOL. After workup, 3f was obtained. Mp 125-126 °C, [R]22
D
-232.59 (c 0.58, THF); 1H NMR (DMSO-d6) δ 3.44 (t, J ) 10.4
Hz, 1H), 3.73-3.79 (m, 1H), 3.87-3.95 (m, 2H), 4.17 (d, J )
9.6 Hz, 1H), 4.37 (d, J ) 6.0 Hz, 1H), 4.54-4.57 (m, 1H), 4.65-
4.68 (m, 1H), 5.45 (s, 1H), 5.55 (s, 1H), 5.64 (s, 1H), 7.06 (m,
1H), 7.14-7.27 (m, 7H), 7.28-7.39 (m, 17H), 7.48-7.56 (m,
4H), 8.05-8.20 (m, 4H); 13C NMR (DMSO-d6) δ 62.8, 62.9, 64.2,
68.4, 68.7, 75.9, 76.3, 99.7, 121.7, 122.0, 125.3, 125.4, 125.9,
126.1, 126.4, 126.7, 127.4, 127.5, 127.8, 128.1, 128.3, 128.7,
130.3, 130.8, 131.3, 131.8, 137.6, 141.6, 142.6, 146.7, 147.0;
31P NMR (DMSO-d6) δ 154.69; HRMS (APCI) calcd for
C
53H43O8P (M+ + 1) 839.2768, found 839.2803.
1,3:4,6-Di-O-ben zylid en e-2-O-(1-n a p h th ylm eth yl)-3-O-
((R)-2,2′-O,O-(1,1′-bin a p h th yl)d ioxop h osp h ite)-D-m a n n i-
tol (3g). The above procedure was followed with use of 5g and
C
55H68O8P (M+ + 1) 887.4646, found 887.4604.
Gen er a l P r oced u r e for Asym m etr ic Hyd r ogen a tion .
Ligand 3 (0.011 mmol) was added to a solution of [Rh(COD)2]-
BF4 (2.0 mg, 0.005 mmol) in anhydrous and degassed CH2Cl2
(1 mL) in a nitrogen-filled glovebox. After the mixture was
stirred for 30 min, a substrate (0.5 mmol) dissolved in CH2Cl2
(1 mL) was added. The reaction mixture was transferred to a
stainless autoclave. The autoclave was purged three times with
H2 and the pressure was set to the desired value, and
hydrogenation was performed at room temperature for 12 h.
After carefully releasing the H2, the reaction mixture was
passed through a short silica gel plug to remove the catalyst.
The resulting solution was used directly for chiral GC to
measure enantiomeric excesses.
R-BINOL. After workup, 3g was obtained. Mp 141-142 °C,
1
[R]22 -239.12 (c 0.76, THF); H NMR (DMSO-d6) δ 3.51 (m,
D
1H), 3.68 (m, 1H), 3.82 (m, 2H), 3.89 (d, J ) 9.2 Hz, 1H), 4.47-
4.51 (m, 3H), 4.91 (d, J ) 12.4 Hz, 1H), 5.03 (s, 1H), 5.08 (d,
J ) 12.4 Hz, 1H), 5.47 (s, 1H), 7.06 (m, 2H), 7.19 (m, 2H),
7.21-7.41 (m, 11H), 7.48-7.53 (m, 6H), 7.60 (d, J ) 8.8 Hz,
1H), 7.80 (d, J ) 8.8 Hz, 1H), 7.82 (m, 1H), 8.06-8.14 (m, 5H);
13C NMR (DMSO-d6) δ 62.7, 62.9, 64.7, 68.4, 68.8, 69.1, 75.8,
76.3, 99.7, 100.1, 121.6, 121.9, 123.4, 124.1, 125.2, 125.3, 125.5,
125.8, 125.9, 126.3, 126.7, 126.9, 127.3, 127.9, 128.1, 128.5,
128.7, 130.3, 130.9, 131.3, 131.8, 132.0, 133.2, 133.4, 137.0,
137.6, 146.6, 147.0; 31P NMR (DMSO-d6) δ 154.36; HRMS
(APCI) calcd for C51H41O8P (M+ + 1) 813.2612, found 813.2641.
Ack n ow led gm en t. Financial support from the Na-
tional Natural Science Foundation of China (29933050)
is gratefully acknowledged. We also thank Prof. Y-G.
Zhou for helpful discussions.
1,3:4,6-Di-O-ben zylid en e-2-O-m eth yl-3-O-((S)-2,2′-O,O-
(1,1′-bin a p h th yl)d ioxop h osp h ite)-D-m a n n itol (3h ). The
above procedure was followed with use of 5a and S-BINOL.
After workup, 3h was obtained. Mp 117-118 °C, [R]22D 215.29
1
(c 0.74, THF); H NMR (DMSO-d6) δ 3.49 (s, 3H), 3.65-3.67
Su p p or tin g In for m a tion Ava ila ble: NMR spectra of new
ligands 3a -k and ee value determination conditions of GC.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(m, 1H), 3.77-3.89 (m, 2H), 4.17-4.21 (m, 2H), 4.32-4.36 (m,
1H), 4.53-4.57 (m, 2H), 5.68 (s, 1H), 5.75 (s, 1H), 7.18-7.28
(m, 7H), 7.38-7.41 (m, 7H), 7.52-7.54 (m, 2H), 7.63 (d, J )
8.8 Hz, 1H), 7.76 (d, J ) 8.8 Hz, 1H), 8.10-8.19 (m, 2H), 8.21-
8.24 (m, 2H); 13C NMR (DMSO-d6) δ 58.2, 63.0, 63.1, 68.4, 68.8,
J O035627P
J . Org. Chem, Vol. 69, No. 7, 2004 2361