Six-membered bis(azaphosphorinane), readily available ligand for highly enantioselective asymmetric hydrogenations

Article abstract of DOI:10.1016/j.tetlet.2006.01.003

A new six-membered bis(azaphosphorinane) ligand has been readily prepared starting from an inexpensive chiral epoxide; excellent enantioselectivities (up to over 99% ee) have been achieved in the Rh-catalyzed asymmetric hydrogenations of β-dehydroamino ac

Full text of DOI:10.1016/j.tetlet.2006.01.003

Tetrahedron
Letters
Tetrahedron Letters 47 (2006) 1567–1569
Six-membered bis(azaphosphorinane), readily available ligand
for highly enantioselective asymmetric hydrogenations
Yongjun Yan and Xumu Zhang*
104 Chemistry Building, Department of Chemistry, The Pennsylvania State University, University Park, PA 16802, USA
Received 21 October 2005; revised 19 December 2005; accepted 3 January 2006
Available online 23 January 2006
Abstract—A new six-membered bis(azaphosphorinane) ligand has been readily prepared starting from an inexpensive chiral
epoxide; excellent enantioselectivities (up to over 99% ee) have been achieved in the Rh-catalyzed asymmetric hydrogenations
of b-dehydroamino acid derivatives and a-arylenamides.
Ó 2006 Elsevier Ltd. All rights reserved.
Transition-metal catalyzed asymmetric hydrogenation is
one of the most efficient methods for preparing chiral
compounds. Most of the efforts in this area have been
focused on the search for new highly enantioselective
chiral ligands1 because enantioselectivities are often sub-
strate dependent. Subtle changes of ligand structure
either electronically or sterically often have dramatic
impacts on enantioselectivities. Among numerous
ligands reported, DuPhos and BPE developed by Burk
et al. in early 1990s have been shown highly efficient
for asymmetric hydrogenations of functionalized pro-
chiral olefins and ketones.2 During the past decade,
many bis(phospholane) ligands derived from DuPhos
and BPE have been reported.3 The typical phospholane
synthesis involves the use of a chiral 1,4-diol. The expen-
sive chiral 1,4-diols used for the preparation of DuPhos
and BPE were originally synthesized through electro-
chemical Kolbe coupling. Biocatalysis route was intro-
duced later.3 Other chiral 1,4-diols prepared from
inexpensive chiral pool such as D-mannitol were pre-
pared by multistep synthesis.4 Though many five-mem-
bered bis(phospholane) ligands have been developed,
there is only one known six-membered bis(oxaphos-
phorinane) ligand reported for asymmetric hydrogena-
tions.5 A seven-step synthetic route to this ligand has
been developed and up to 97.5% ee and 94.2% ee were
obtained in the Rh-catalyzed asymmetric hydrogenation
of a-dehydroamino acid derivatives and itaconic acid,
respectively.
Previously, we have successfully prepared several
DuPhos type ligands such as PennPhos,6 Binaphane7
and Ketalphos.4d,f Our goal is to develop new chiral
ligands which are highly efficient, yet easily obtainable
from inexpensive and readily available starting materi-
als. As the result of our continued efforts, herein we
would like to report the facile synthesis of a novel six-
membered bis(azaphosphorinane) ligand, 4,40-(1,2-etha-
nediyl)bis[(3R,5R)-1,3,5-trimethyl-1,4-azaphosphophor-
inane] 1 and its applications in highly enantioselective
Rh-catalyzed asymmetric hydrogenations of b-dehydro-
amino acid derivatives and a-arylenamides.
The ligand design was based on the following consider-
ations: (1) conformation rigidity is often required to
achieve high enantioselectivities in asymmetric hydro-
genation. We reason a six-membered phosphorinane is
conformationally more rigid than a five-membered
phospholane thus may provide a rigid chiral environ-
ment around the metal center; (2) a chiral 1,5-diol, the
precursor to the six-membered phosphorinane ring,
can be readily prepared by reacting a primary amine
with a chiral epoxide in a single step. The synthetic route
for ligand 1 is depicted in Scheme 1. Thus, aqueous
methyl amine reacted with 2.2 equiv of (S)-propylene
oxide 2 in methanol at 60 °C to afford the chiral 1,5-diol
3 in 95% yield. After removing the solvent, the ring-
opening product was pure enough and was directly used
for the next step without further purification. Cycliza-
tion with thionyl chloride in dry dichloromethane at
0 °C in the presence of triethylamine proceeded
smoothly. The initial attempts to oxidize the cyclic
sulfite intermediate using the RuCl3/NaIO4 catalytic
*
Corresponding author. Tel.: +1 814 865 4221; fax: +1 814 865
3292; e-mail: xumu@chem.psu.edu
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.01.003

1568
Y. Yan, X. Zhang / Tetrahedron Letters 47 (2006) 1567–1569
Table 1. Asymmetric hydrogenation of b-alkyl b-(acylamino) acrylates
with Rh–1 catalysta
OH
OH
O
S
O
a
b
O
N
N
2
2
COOR
NHAc
COOR
NHAc
[Rh(1)(NBD)]SbF6
O
O
CH2Cl2, H2 (15 psi), rt
1
1
R
R
7
6
4
3
2
Entry
Substrate
R1
R2
ee (%)
c
P
P
PH2
H2P
1
2
3
4
5
6
7
8
9
(E)-6a
(E)-6b
(E)-6c
(E)-6d
(E)-6e
(E)-6f
(E)-6g
(Z)-6h
(Z)-6i
Me
Et
Me
Me
Me
Me
Et
>99
>99
>99
99
99
99
99
96
96
N
N
5
i-Pr
i-Bu
Me
n-Pr
Me
Me
Me
1
Scheme 1. Synthesis of ligand 1. Reagents and conditions: (a)
methylamine, 60 °C, MeOH, 95%; (b) (i) SOCl2, NEt3, CH2Cl2, (ii)
RuCl3, NaIO4, CH3CN/H2O, pH < 1, 61%; (c) (i) n-BuLi (2 equiv),
THF; (ii) 4 (2 equiv), (iii) n-BuLi (2.2 equiv), THF, 36%.
Et
i-Pr
Me
Et
a Reactions were carried out under 15 psi of H2 in CH2Cl2 at
room temperature for 24 h with full conversion. Substrate/
[Rh(1)(NBD)]SbF6 = 100:1. For absolute configuration and ee (%)
value determinations, see Ref. 12 for detail.
system developed by Sharpless8 under the standard reac-
tion condition were unsuccessful. The oxidation reaction
did not occur because the cyclic sulfite intermediate con-
tains a tertiary amine moiety, which poisoned the ruthe-
nium catalyst in the oxidation process. To facilitate the
Ru-catalyzed reaction, the nitrogen atom of the tertiary
amine has to be masked. Although the standard oxida-
tion condition requires the removing of acidic species,
we found that adjusting the pH to <1 by simply adding
concd HCl to the reaction mixture can efficiently mask
the amine moiety and promote the oxidation reaction.
Since the acidified cyclic sulfite is a salt and soluble in
water, a 1:1 CH3CN/H2O mixture was used as a solvent
instead of CCl4/CH3CN/H2O. The overall yield of cyclic
sulfate 4 from the chiral 1,5-diol 3 was 61%. Metalation
of 1, 2-bis(phosphino)ethane 5 with 2 equiv of n-BuLi at
room temperature followed by addition of 2 equiv of
cyclic sulfate 4 and another 2.2 equiv of n-BuLi finally
provided the desired ligand 19 in 36% yield as a viscous
oil.
of (Z)-isomers of b-alkyl b-(acylamino) acrylates.11
These results are among the highest enantioselectivities
achieved to date for the hydrogenations of b-alkyl
b-(acylamino) acrylates.
With Rh–1 catalyst, a variety of a-arylenamides 8 were
also hydrogenated to afford chiral amides 9 with excel-
lent enantioselectivities (Table 2). For terminal a-aryl-
enamides 8a–f (Table 2, entries 1–6), para-substituted
phenylenamides 8c–e (Table 2, entries 3–5) generally
led to better enantioselectivities than nonsubstituted a-
phenylenamide 8a (Table 2, entry 1), while enantioselec-
tivity decreased for a meta-substituted phenylenamide
8b (Table 2, entry 2). It should be noted that for the
hydrogenations of b-substituted arylenamides 8g–8l
(Table 2, entries 7–12), E/Z isomeric mixtures were
employed and the hydrogenation reactions can tolerate
The ligand 1 has been employed in the asymmetric
hydrogenations of b-dehydroamino acid derivatives.
The hydrogenation reactions were carried out at room
temperature under 15 psi of H2 in the presence of
1 mol % [Rh(1)(NBD)]SbF6 prepared by mixing ligand
1 with 1.0 equiv of [Rh(NBD)2]SbF6. As shown in Table
1, a variety of b-alkyl b-(acylamino) acrylates 6 have
been hydrogenated with excellent enantioselectivities.
Both (E)- and (Z)-isomeric substrates gave the hydroge-
nation products 7 with the same configuration using Rh-
1 catalyst. For hydrogenations of (E)-isomers 6a–g, high
enantioselectivities (99 to >99% ee) have been obtained
(Table 1, entries 1–7). Changing the ester groups and
alkyl substituents showed no significant variations in
enantioselectivities. Ligand 1 also gave excellent enantio-
selectivities for the hydrogenations of (Z)-isomers 6h–i
(Table 1, entries 8 and 9) though the ee values were
slightly less than those of the corresponding (E)-isomers
6a and 6e (Table 1, entries 1 and 5). Compared with the
Rh–Me–DuPhos catalyst (which gave 98.2% ee and
87.8% ee for the asymmetric hydrogenations of (E)-6a
and (Z)-6h, respectively),10 Rh–1 catalyst provided
much higher ee value for the (Z)-isomer (Table 1, entries
1 and 8). There are only few catalytic systems which can
achieve over 95% ee for the asymmetric hydrogenations
Table 2. Asymmetric hydrogenation of a-arylenamides with Rh–1
catalysta
R
R
[Rh(1)(NBD)]SbF6
CH2Cl2, H2 (15 psi), rt
Ar
NHAc
Ar
NHAc
9
8
Entry
Substrate
Ar
R
ee (%)
1
2
3
4
5
6
7
8
9
8a
8b
8c
8d
8e
8f
Ph
H
H
H
H
H
H
Me
Me
Me
Me
i-Pr
Bn
96
95
98
>99
98
>99
99
98
97
>99
98
97
m-MePh
p-CF3Ph
p-CyPh
p-PhPh
2-Np
8g
8h
8i
Ph
p-CF3Ph
p-MeOPh
2-Np
Ph
Ph
10
11
12
8j
8k
8l
a Reactions were carried out under 15 psi of H2 in CH2Cl2 at
room temperature for 24 h with full conversion. Substrate/
[Rh(1)(NBD)]SbF6 = 100:1. For the E/Z ratio of 8g–l, absolute
configuration and ee (%) value determinations, see Ref. 13 for detail.

Y. Yan, X. Zhang / Tetrahedron Letters 47 (2006) 1567–1569
1569
3. For a recent review, see: Clark, T. P.; Landis, C. R.
Tetrahedron: Asymmetry 2004, 15, 2123.
4. (a) Burk, M. J.; Feaster, J. E.; Harlow, R. L. Organo-
metallics 1990, 10, 2653; (b) Burk, M. J.; Feaster, J. E.;
Harlow, R. L. Tetrahedron: Asymmetry 1991, 2, 569; (c)
Holz, J.; Quirmbach, M.; Schmidt, U.; Heller, D.;
the geometry of the substrates. A series of b-substituted
phenylenamides 8g,k and 8l (Table 2, entries 7, 11 and
12), as E/Z isomeric mixtures, were hydrogenated with
excellent enantioselectivities regardless of different
b-substituents. No significant electronic effect of the sub-
stitution at the aryl group of the enamides was observed
on the enantioselectivities (Table 2, entries 8 and 9).
Enantiomeric excesses of over 99% were obtained in
the hydrogenations of more bulky 2-naphthyl enamides
8f and 8j (Table 2, entries 6 and 10). The enantioselectiv-
ities achieved with ligand 1 for the hydrogenation of
E/Z isomeric mixtures of b-substituted a-arylenamides
are comparable to or better than those reported with
Me–DuPhos and BPE ligands.13
Sturmer, R.; Bo¨rner, A. J. Org. Chem. 1998, 63, 8031;
¨
(d) Li, W.; Zhang, Z.; Xiao, D.; Zhang, X. Tetrahedron
Lett. 1999, 40, 6701; (e) Holz, J.; Sturmer, R.; Schmidt, U.;
¨
Drexler, H. J.; Heller, D.; Krimmer, H. P.; Bo¨rner, A. Eur.
J. Org. Chem. 2000, 4615; (f) Li, W.; Zhang, Z.; Xiao, D.;
Zhang, X. J. Org. Chem. 2000, 65, 3489; (g) Yan, Y. Y.;
RajanBabu, T. V. J. Org. Chem. 2000, 65, 900; (h) Yan, Y.
Y.; RajanBabu, T. V. Org. Lett. 2000, 2, 199; (i)
RajanBabu, T. V.; Yan, Y. Y.; Shin, S. J. Am. Chem.
Soc. 2001, 123, 10207.
5. Ostermeier, M.; Priess, J.; Helmchen, G. Angew. Chem.,
Int. Ed. 2002, 41, 612.
In conclusion, new bis(azaphosphorinane) ligand 1 has
been easily prepared from inexpensive, readily available
starting materials. To the best of our knowledge, this
ligand provides the first example of six-membered
bis(phosphorinane) ligands for the highly enantioselec-
tive asymmetric hydrogenations of b-dehydroamino
acid derivatives and a-arylenamides. To make the ligand
useful for large-scale industrial applications, further
ligand modification is needed because the substrate-
to-catalyst ratio and the reaction rate are lower
compared with other bisphosphine ligand such as
DuPhos due to the presence of basic nitrogen in the
ligand itself.
6. (a) Jiang, Q.; Jiang, Y.; Xiao, D.; Cao, P.; Zhang, X.
Angew. Chem., Int. Ed. 1998, 37, 1100; (b) Zhang, Z.; Zhu,
G.; Jiang, Q.; Xiao, D.; Zhang, X. J. Org. Chem. 1999, 64,
1774; (c) Jiang, Q.; Xiao, D.; Zhang, Z.; Cao, P.; Zhang,
X. Angew. Chem., Int. Ed. 1999, 38, 516.
7. (a) Xiao, D.; Zhang, Z.; Zhang, X. Org. Lett. 1999, 1,
1679; (b) Chi, Y.; Zhang, X. Tetrahedron Lett. 2002, 43,
4849.
8. Gao, Y.; Sharpless, K. B. J. Am. Chem. Soc. 1988, 110,
7538.
9. Spectra data for 1: 1H NMR (360 MHz, CD2Cl2): d 2.53–
2.46 (m, 4H), 2.30–2.20 (m, 4H), 2.17 (s, 6H), 2.01–1.93
(m, 2H), 1.80–1.75 (m, 2H), 1.56–1.51 (m, 2H), 1.45–1.37
(m, 2H), 1.26–1.11 (dd, J = 7.3, 16.4 Hz, 6H), 1.09–0.98
(dd, J = 7.3, 10.2 Hz, 6H); 13C NMR (90 MHz, CD2Cl2):
d 60.6, 59.6, 47.6, 25.9, 25.8, 25.7, 24.5, 24.4, 24.3, 18.1,
18.0, 17.9, 16.6, 15.2; 31P NMR (146 MHz, CD2Cl2): d
ꢀ23.17. HRMS (APCI) calcd for C16H35N2P2 [MH+]
317.2264, found 317.2282.
Acknowledgements
This work was supported by National Institute of
Health Grants.
10. Heller, D.; Holz, J.; Drexler, H. J.; Lang, J.; Drauz, K.;
Krimmer, H. P.; Bo¨rner, A. J. Org. Chem. 2001, 66, 6816.
11. (a) Lee, S. G.; Zhang, Y. J. Org. Lett. 2002, 4, 2429; (b)
Tang, W.; Zhang, X. Org. Lett. 2002, 4, 4159; (c) Pena, D.;
Minnaard, A. J.; de Vries, J. G.; Feringa, B. L. J. Am.
Chem. Soc. 2002, 124, 14552; (d) Wu, H. P.; Hoge, G. Org.
Lett. 2004, 6, 3645.
12. Zhu, G.; Chen, Z.; Zhang, X. J. Org. Chem. 1999, 64,
6907.
13. (a) Burk, M. J.; Wang, Y. M.; Lee, J. R. J. Am. Chem.
Soc. 1996, 118, 5142; (b) Zhu, G.; Zhang, X. J. Org. Chem.
1998, 63, 9590.
References and notes
1. For recent reviews, see: (a) Tang, W.; Zhang, X. Chem.
Rev. 2003, 103, 3029; (b) Blaser, H. U.; Malan, C.; Pugin,
B.; Spindler, F.; Steiner, H.; Studer, M. Adv. Synth. Catal.
2003, 345, 103.
2. For reviews, see: (a) Burk, M. J. Acc. Chem. Res. 2000, 33,
363; (b) Burk, M. J. Chemtracts 1998, 11, 787; (c) Burk,
M. J.; Gross, M. F.; Harper, G. P.; Kalberg, C. S.; Lee,
J. R.; Martinez, J. P. Pure Appl. Chem. 1996, 68, 37.