Angewandte
Chemie
DOI: 10.1002/anie.201000955
Asymmetric Hydroformylation
Rhodium-Catalyzed Asymmetric Hydroformylation of N-Allylamides:
Highly Enantioselective Approach to b2-Amino Aldehydes**
Xiaowei Zhang, Bonan Cao, Shichao Yu, and Xumu Zhang*
Asymmetric hydroformylation (AHF) has attracted great
interest because it can provide enantiomerically pure alde-
hydes, which are important intermediates for pharmaceuticals
and fine chemicals, in an atom efficient manner.[1] Although a
number of chiral phosphorus ligands have been developed for
the rhodium-catalyzed AHF reaction,[2] the substrates are still
limited to simple functionalized terminal olefins without a-
hydrogen atoms, such as styrene derivatives and vinyl
carboxylates. Expansion of the substrate scope and widening
of the application of this methodology is highly desirable.
Chiral b2-amino aldehydes are important structural ele-
ments in natural products.[3] For instance, a Boc (tert-
butoxycarbonyl)-protected amino aldehyde is a key building
block in the synthesis of cyclamenolA (Scheme 1).[4] How-
efficiency of this synthesis prompted us to seek an alternative
approach for synthesizing chiral b2-amino aldehydes by the
direct hydroformylation of N-allylamides in a regio- and
enantioselective manner.
Allylic compounds are particularly challenging substrates
for the hydroformylation reaction because of the migration of
double bonds.[1] In most cases, the hydroformylation of allylic
substrates affords predominantly linear aldehydes, for exam-
ple, allylbenzene[6] derivatives and allylamines.[7] The hydro-
formylation reaction of allylic alcohol derivatives to form
branched aldehydes has been reported using catalyst-direct-
ing phosphine groups that are bound to the substrate,[8]
although optically pure aldehydes can only be obtained
from chiral substrates.[9] Ojima and co-workers found that the
amide group can enhance selectivity for the isoaldehyde
product in the hydroformylation of N-allylamides through
chelation of the carbonyl group to the rhodium center.[10] This
preference for branched products encouraged us to use amide
moieties as directing groups in the asymmetric hydroformy-
lation reaction, instead of expensive and environmentally
unfriendly phosphine groups. Herein, we report a rhodium-
catalyzed asymmetric hydroformylation reaction of N-allyla-
mides, N-allylsulfonamides, as well as other allylic substrates,
with excellent enantioselectivity (92–99% ee) and a turnover
number (TON) of up to 9700; this method provides an
alternative, concise, and environmentally friendly route to b2-
amino aldehydes, acids, and alcohols.
We started our investigation using commercially available
Boc-protected allyl amine 1a as a model substrate, as facile
removal of the Boc group affords the free b2-amino aldehyde.
We have previously reported that a class of hybrid phosphine–
phosphoramidite ligands (yanphos A–C; Scheme 2), are
highly efficient in the asymmetric hydroformylation of
styrene, vinyl acetate, and allyl cyanide.[11] The high regio-
and enantioselectivity afforded with these catalysts prompted
us to consider them in the hydroformylation of 1a. Two other
phosphoramidite ligands and several commercially available
chiral ligands (Scheme 2), which were highly efficient in the
asymmetric hydroformylation of a variety of functionalized
olefins, were also screened. The AHF reactions were carried
out with 0.1 mol% catalyst loading and 20 bar CO/H2 (1:1)
gas at 608C. The catalyst was prepared in situ by mixing
[Rh(acac)(CO)2] with the ligand in toluene. Under these
reaction conditions, all of the linear aldehyde 3a was trans-
formed into 2-hydroxy pyrrolidine 4a in quantitative yield, by
intramolecular attack of the primary amide on the carbonyl
group.[12]
Scheme 1. Synthesis of chiral b2-amino aldehydes. a) NH3, MeOH,
NaCN, 508C; b) BH3·Me2S, THF, reflux; c) (Boc)2O, Et3N, MeOH;
d) (COCl)2, DMSO, Et3N. DMSO=dimethyl sulfoxide.
ever, the synthesis of the enantiomerically pure amino
aldehyde requires at least four steps, starting from an
expensive chiral source, with moderate yields.[4,5] The low
[*] X. Zhang, B. Cao, Dr. S. Yu, Prof. Dr. X. Zhang
Department of Chemistry and Chemical Biology and Department of
Pharmaceutical Chemistry, Rutgers
The State University of New Jersey, Piscataway, NJ 08854 (USA)
Fax: (+1)732-445-6312
E-mail: xumu@rci.rutgers.edu
X. Zhang
Department of Chemistry, The Pennsylvania State University
University Park, PA 16802 (USA)
[**] This work was supported by the National Institutes of Health
(GM58832). The Bruker 400 MHz NMR spectrometer used in these
studies was purchased with grant No. 1S10RR023698-01A1 from
the National Center for Research Resources (NCRR), a component
of the NIH.
Some representative results are shown in Table 1. With
yanphos derivatives as ligands, up to 93% ee, full conversion,
and good regioselectivity were achieved (Table 1, entries 1–
Supporting information for this article is available on the WWW
Angew. Chem. Int. Ed. 2010, 49, 4047 –4050
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