(Rh), and allylation (Ni and Pd).4 While the carbohydrate
backbone provided the necessary stereochemical diversity,
substitution patterns around phosphorus were used to vary
the steric and electronic properties of the ligand. One salient
property of carbohydrates that has not been fully exploited
is their water solubility due to the polyhydroxylic nature.
Pioneering studies conducted by the Selke and Oehme5 have
amply demonstrated that even phosphinite ligands derived
from monosaccharides have some solubility in water. They
also showed impressive enhancement of enantioslectivity in
the presence of micelle-forming amphiphiles when sparingly
soluble substrates are used. The high ee of these reactions
notwithstanding, anecdotal evidence seems to suggest that
these monosaccharide-derived ligands have only limited
aqueous solubility. In connection with the asymmetric
hydrocyantion project, in 1992 we first reported a number
of bisphosphinite ligands from disaccharides including a few
from R,R′-trehalose.6 We wondered ever since how the
enantioselectivity of the Rh-catalyzed hydrogenation using
the corresponding fully deprotected ligands will be affected
by the incorporation of four more hydroxyl groups (vis-a´-
vis monosaccharide ligands) and the attendant greater
solubility in water.7 Here we record the details of the relevant
chemistry for the selective functionalization of R,R′-trehalose
for the synthesis of novel bisphosphinites. In addition, we
have studied the stability, solubility properties, and ap-
plicability of the Rh-complexes of these ligands for hydro-
genation of dehydroamino acids.
Scheme 1. Selective Functionalization of R,R′-Trehalose for
the Synthesis of Macrocyclic Bisphosphinite Ligands
Synthesis of a series of C2-symmetric phosphine and
phosphinite ligands from R,R′-trehalose is shown in Scheme
1.8 The 4,6:4′,6′-benzylidene acetal 2a (or 2b) is a key
intermediate, which can be readily prepared from trehalose
in two steps. Selective cleavage of the benzylidene acetal
using either Na(CN)BH3/HCl9 or LiAlH4/AlCl310 gives 4,4′-
and 6,6′-unprotected trehalose derivatives 3 or 6, respectively.
Treatment of these compounds with diarylchlorophosphines
in the presence of a base gives the corresponding bisphos-
phinites (e.g., 4a or 4b). The 6,6′-diol 6 is a useful precursor
for the synthesis of bisphosphine 7, a compound that has
been prepared by an alternate route before.8a All bisphos-
phinites were fully characterized by 1H, 13C and 31P
spectroscopy.11
The bisphosphinites are excellent ligands for Ni(0)-
catalyzed asymmetric hydrocyanation3b and Rh(I)-catalyzed
hydrogenation. The Rh complexes of the bisphosphinite (5a/
5b) are readily prepared by treating the ligands with Rh+-
(COD)2 SbF6- in CH2Cl2 or CDCl3 at room temperature. The
(5) See, for example: Kumar, A.; Oehme, G.; Roque, J. P.; Schwarze,
M.; Selke, R. Angew. Chem., Int. Ed. Engl. 1994, 33, 2197 and references
therein.
(6) (a) RajanBabu, T. V.; Casalnuovo, A. L. J. Am. Chem. Soc. 1992,
114, 6265, footnote 10. Also ref 3b and: Casalnuovo, A. L.; RajanBabu,
T. V. U.S. Patent 5 175 335, 1992.
(7) For other recent reports dealing with the use of carbohydrates for
solubilizing an organometallic catalyst, see: (a) Beller, M.; Krauter, J. G.
E.; Zapf, A. Angew. Chem., Int. Ed. Engl. 1997, 36, 772. (b) Sawamura,
M.; Kitayama, K.; Ito, Y. Tetrahedron: Asymmetry 1993, 4, 1829. (c)
Mitchell, T. N.; Heesche-Wagner, K. J. Organomet. Chem. 1992, 436, 43.
(8) For the synthesis of phosphine ligands from trehalose see: (a) Brown,
J. M.; Cook, S. J.; Kent, A. G. Tetrahedron 1986, 42, 5097.; Gilbertson, S.
R.; Chang, C. T. J. Org. Chem. 1995, 60, 6226. (b) Just prior to the
submission of this manuscript (7/30/1999) a report dealing with the syntheis
and applications of phosphinites related to 14 has appeared. Yonehara, K.;
Hashizume, T.; Mori, K.; Ohe, K.; Uemura, S. J. Org. Chem. 1999, 64,
5593. Our work was presented at the Central Regional ACS Meeting,
Columbus, OH, June 21-23, Abstract No. 129. (c) Wallace, P. A.; Minnikin,
D. E. J. Chem. Soc., Chem. Commun. 1993, 1292.
C2-symmetric nature of the complex is evident from the 31
P
NMR spectrum. The major 31P signal appears as a doublet
in 5a at δ ) 122.2 (JP-Rh ) 181 Hz). In addition, the 31P
NMR spectrum of 5a shows broad signals between δ 152
and 158. The intensity ratio of the major doublet to the broad
signal(s) is highly dependent on the temperature (<10% at
37 °C, and increasing as the temperature is decreased),
suggesting that the latter arises from a mixture of complexes
in which the benzyloxy group is probably coordinated to
Rh.12 Lack of coupling between the two phosphorus atoms
(11) See the Supporting Information for details.
(9) Garegg, P.; Hultberg, H. Carbohydr. Res. 1981, 93, C10.
(10) Lipta´k, A.; Joda´l, I.; Na´na´si, P. Carbohydr. Res. 1975, 44, 1.
(12) Borns, S.; Kadyrov, R.; Heller, D.; Baumann, W.; Spannenberg,
A.; Kempe, R.; Holz, J.; Bo¨rner, A. Eur. J. Inorg. Chem. 1998, 1291.
1230
Org. Lett., Vol. 1, No. 8, 1999