ates common to many P-P ligand syntheses. We have
recently demonstrated scalability by rapidly preparing >1
kg of BIPI 69 in a very facile campaign.
mization involved changing the “benzo core” from phenyl
to naphthyl (entries 5-6). This modification led to a dramatic
breakthrough in stereoselectivity, generating urea 2 with 98%
ee and >99% ee, respectively, for BIPI 166 and BIPI 153.
The reasons for this improvement are not immediately clear,
yet we speculate that the peri hydrogen of the naphthyl ring
restricts the number of conformations available to the two
cyclohexyl substituents. The remaining conformations may
be more inherently enantioselective, leading to the extreme
selectivity observed.
We next decided to screen our best ligand, BIPI 153,
against a variety of structurally diverse dehydrourea esters
to gain an understanding of the scope of this new asymmetric
hydrogenation. The results for six different substrates are
collected in Figure 2.
Figure 1. Ligands used.
The ligands used in this study are shown in Figure 1. The
BIPI ligands were designed to allow for ready electronic
tuning by varying the nitrogen substituent. We had expected
that alkyl substitution on nitrogen would be beneficial, since
most of the successful P-P ligands for asymmetric hydro-
genation of olefins, such as DuPhos, Tangphos, and others,9
are quite electron rich. To our surprise, alkyl substitution
led to catalysts that gave poor turnover and low selectivity
(0-10% ee). We then examined different types of acyl
substitution on nitrogen. As shown in Table 1, electron rich
Table 1. Asymmetric Hydrogenation of Substrate 1
entry
ligand no.
er
% ee
Figure 2. Asymmetric hydrogenation of additional substrates.
1
2
3
4
5
6
BIPI 41
BIPI 39
BIPI 164
BIPI 69
BIPI 166
BIPI 153
85.5:14.5
92.5:7.5
97.2:2.8
97.7:2.3
99.1:0.9
>200:1
71
85
94
95
98
The phenylalanine analogues 7b-9b were each generated
in >99% ee, and the isoleucine target 10b, in 99% ee.
Variation of the urea functionality (11b) was also completely
tolerated, as was introduction of a terminal olefin (12b), as
less than 5% hydrogenation of this moiety was observed,
and the product still formed in >99% ee.
We wanted to determine the absolute configuration of
these urea products. This was accomplished by converting
both (S)-phenylalanine methyl ester and (S)-isoleucine methyl
ester to their morpholine urea derivative using commercial
morpholine carbonyl chloride.
>99
p-isopropoxybenzoyl was more enantioselective (85% ee)
than the p-CF3 analogue (71% ee, entries 1-2). We therefore
reasoned that an alkyl amide might prove to be better still.
This was indeed the case, as N-acetyl and N-cyclohexan-
ecarbonyl gave the product with 94% ee and 95% ee,
respectively (entries 3-4). The final stage of ligand opti-
In both cases, these materials coeluted on chiral HPLC
with the major enantiomer formed through the use of the
(S,S)-BIPI ligands (7b, 10b). Although we did not rigorously
assign the absolute stereochemistry of the other products, it
seems quite likely that the (S,S) ligand series will furnish
ureas with the (S) absolute configuration in most cases.
In conclusion, we have applied the BIPI ligands to the
asymmetric hydrogenation of unsaturated urea esters and
have uncovered a catalyst, BIPI 153, that proceeds with near-
perfect enantioselection. The synthetic process to access this
ligand class is short, simple, and scalable, and leads to a
very practical asymmetric hydrogenation sequence. The high
(9) For examples, see: (a) Cobley, C. J.; Johnson, N. B.; Lennon, I. C.;
McCague, R.; Ramsden, J. A.; Zanotti-Gerosa, A. In Asymmetric Catalysis
on Industrial Scale; Blaser, H. U., Schmidt, E., Eds.; Wiley:Weinheim, 2004;
269-282. (b) Burk, M. J. Acc. Chem. Res. 2000, 33 (6), 363. (c) Tang,
W.; Zhang, X. Org. Lett. 2002, 4 (23), 4159. (d) Liu, D.; Zhang, X. Eur.
J. Org. Chem. 2005, 4, 646. (e) Almena, J.; Monsees, A.; Kadyrov, R.;
Riermeier, T. H.; Gotov, B.; Holz, J.; Boerner, A. AdV. Synth. Cat. 2004,
346 (11), 1263. (f) Hoge, G.; Wu, H.-P.; Kissel, W. S.; Pflum, D. A.; Greene,
D.; Bao, J. J. Am. Chem. Soc. 2004, 126 (19), 5966. (g) Lefort, L.; Boogers,
J. A. F.; de Vries, A. H. M.; de Vries, J. G. Top. Catal. 2006, 40 (1-4),
185. (h) Blaser, H.-U.; Brieden, W.; Pugin, B.; Spindler, F.; Studer, M.;
Togni, A. Top. Catal. 2002, 19 (1), 3. For P-N ligands, see: (i)
Bunlaksananusorn, T.; Polborn, K.; Knochel, P. Angew. Chem., Int. Ed.
2003, 42, 3941. (j) Liu, D.; Tang, W.; Zhang, X. Org. Lett. 2004, 6 (4),
513.
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