COMMUNICATION
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NeoPHOX—an easily accessible P,N-ligand for iridium-catalyzed
asymmetric hydrogenation: preparation, scope and application in
the synthesis of demethyl methoxycalamenenew
Marcus G. Schrems and Andreas Pfaltz*
Received (in Cambridge, UK) 26th June 2009, Accepted 14th August 2009
First published as an Advance Article on the web 27th August 2009
DOI: 10.1039/b912680e
Using a new class of chiral iridium hydrogenation catalysts, the
antitumor natural product demethyl calamenene was synthesized
in four steps in 420% overall yield and high enantiomeric
purity.
(eqn (1)) and give excellent results in the iridium-catalyzed
enantioselective hydrogenation of unfunctionalized tetra-
6
substituted olefins. Encouraged by these findings, we hoped
that we could also access new phosphino-oxazolines (1) by
nucleophilic substitution on the corresponding chloro-alkyl-
oxazolines (2). Obviously, neopentyl systems such as 2 cannot
Enantioselective hydrogenation has become the method of
choice to convert prochiral olefins to optically active
1
compounds. Since our discovery that complexes of the
N N
undergo a simple S 1 or S 2 reaction, but it is known that
neopentyl halides undergo a radical nucleophilic substitution
7
(SNR1) with diphenylphosphide anions.
type [Ir(L*)(COD)][BAr ] (L*: chiral P,N ligand; COD:
F
cyclooctadiene; BArF: tetrakis[3,5-bis(trifluoromethyl)phenyl]-
borate) are exceptional catalysts for the enantioselective
2
hydrogenation of unfunctionalized olefins, we and others
3
ð1Þ
have invested considerable efforts in finding ligand structures
that are easily accessible and also give high catalytic activity
and enantioselectivity. Although many efficient P,N- and
C,N-ligands for the iridium-catalyzed enantioselective
hydrogenation are known today, most ligands do not fulfill
the requirements for preparation on manufacturing scale,
ð2Þ
4
i.e. high overall yield, facile purification, and scalability.
We have now found a class of P,N-ligands that fulfills these
requirements and employed them in the iridium-catalyzed
hydrogenation of unfunctionalized olefins.
Indeed, the thermally initiated reaction of neopentyl
2
chloride with a commercially available solution of KPPh in
THF gave considerable amounts of substitution product.
Surprisingly, the product was stable enough to be purified
by flash chromatography in air. Next we synthesized a series
of oxazolines (2) starting from commercially available
3
-chloropivaloyl chloride. Amides 3 were obtained in good to
quantitative yield and could be purified by crystallization or
distillation. Cyclization of the amides was achieved using
8
Burgess’ reagent, giving the corresponding oxazolines in high
yield after a simple Kugelrohr distillation (Scheme 1). The
2
reaction of the oxazolines with KPPh proved to be much
Some time ago, we introduced SimplePHOX as an efficient
5
ligand for iridium-catalyzed asymmetric hydrogenation.
faster than the analogous reaction with neopentyl chloride.
After 6 h at reflux, the starting material (KPPh ) was
2
Although this ligand class is accessible by simple reactions,
scale up was hampered by low overall yields and difficult
purification steps. We therefore sought a structurally similar
ligand motif that is as easy to prepare as SimplePHOX, but,
which could be obtained in higher overall yield and without
chromatographic purification steps.
consumed and only product could be observed in the
3
P-NMR-spectrum. We were pleased to see that ligands 1
1
could be obtained in analytically pure form by simple filtration
through silica gel in air. The steric bulk around the
phosphorus atom seems to make these ligands remarkably
air stable. The formation of ligands 1c and 1d with o-tolyl
(o-Tol) and 3,5-dimethylphenyl (Xyl) substituents on the
phosphorus atom turned out to be simple as well. These
ligands could be prepared by refluxing a mixture of the corres-
ponding secondary phosphines, potassium hydride, the
chloro-oxazoline, and THF in one pot. The iridium complexes
were either obtained from the crude products (Ir-1a, e) or
alternatively from the purified ligands (Ir-1b–d). They are
highly stable against air and moisture: a sample, which was
Phosphinomethyl-oxazolines can be easily prepared by
nucleophilic substitution from 2-chloromethyl-oxazolines
Department of Chemistry, University of Basel, St. Johanns-Ring 19,
CH-4056 Basel, Switzerland. E-mail: andreas.pfaltz@unibas.ch;
Fax: +41 61-267-1103
w Electronic supplementary information (ESI) available: Experimental
details for compounds 1–3, Ir-1, 13–16 and spectroscopic data. See
DOI: 10.1039/b912680e
6
210 | Chem. Commun., 2009, 6210–6212
This journal is ꢀc The Royal Society of Chemistry 2009