Stereoselective cyclization and pyramidal inversion strategies for P-chirogenic phospholane synthesis

Article abstract of DOI:10.1021/ja048079l

Preparation of P-chirogenic mono- and bisphospholanes is reported. The demonstrated method employs a stereoselective cyclization of cyclic sulfates with primary phosphines in the presence of base to generate "cis" or "cis/cis" P-chirogenic phospholanes followed by heat-induced pyramidal inversion to provide "trans" or "trans/trans" P-chirogenic phospholanes. A rhodium complex of one "trans/trans" phospholane is applied to the highly enantioselective asymmetric hydrogenation of a substrate precursor to the pharmaceutical candidate pregabalin. Copyright

Full text of DOI:10.1021/ja048079l

Published on Web 07/23/2004
Stereoselective Cyclization and Pyramidal Inversion Strategies for
P-Chirogenic Phospholane Synthesis
Garrett Hoge*
Pfizer Global Research and DeVelopment, 2800 Plymouth Road, Ann Arbor, Michigan 48105
Received April 2, 2004; E-mail: garrett.hoge@pfizer.com
Scheme 1. Stereoselective Cyclization and Epimerizationa
Many contemporary bisphosphine ligands for asymmetric hy-
drogenation applications are P-chirogenic.1 However, despite the
current popularity of this motif, direct methodologies for producing
single enantiomer P-chirogenic compounds remain scarce. Our
recent efforts in this area were dedicated to the synthesis of
P-chirogenic ligand 1 (Figure 1) and its application to the highly
enantioselective rhodium-catalyzed asymmetric hydrogenation of
a substrate precursor to the pharmaceutical candidate, pregabalin.2
Desiring to diversify our ligand library, ligands such as 1,2-
bisphospholanobenzene 2 were enticing targets. However, ligand
1 was synthesized via CuCl2-promoted oxidative coupling of the
s-BuLi generated methyllithium anion of 3. It was apparent that a
nonparallel synthetic approach would be required for the synthesis
of P-chirogenic bisphospholanobenzenes.
Figure 1. Retrosynthetic analysis of 1,2-bisphospholanoethane, 1, and
structure of 1,2-bisphospholanobenzene, 2.
A classic approach to the synthesis of phospholane ring systems
employs the reaction of lithium phosphide anions (derived from
deprotonation of primary phosphines) with symmetrical cyclic
sulfates (derived from chiral 1,4-diols).3 Vedejs has reported the
utilization of this approach to synthesize P-chirogenic monophos-
pholanes from unsymmetrical cyclic sulfates.4 Desiring to apply
this methodology to a broader range of mono- and bisphospholanes,
unsymmetrical cyclic sulfates 5a-5c were synthesized from chiral
1,4-diols 4a-4c. The diols 4a,4b were accessible on 50-g scale
from L-glutamic acid via literature methods,5 while 4c was
synthesized as previously described from (S)-2,3-epoxypropylben-
zene (Scheme 1).2 Under similar conditions to those reported by
Vedejs,4 we found that reaction of the lithium phosphide anions of
6-8 with cyclic sulfates 5a-5c produced phospholanes 9-11
(Scheme 1). Interestingly, the cyclizations provided good selectivity
for cis monophospholanes and cis/cis bisphospholanes in all cases
(Scheme 1).6,7 No trans/trans isomer was observed from cyclization
in any of the bisphospholane cases. Despite the opposite configu-
ration of 10c (cis/cis) with respect to that of target ligand 2 (trans/
trans) this cyclization method offers a unique foray into a
synthetically challenging P-chirogenic compound class.
a Reagents and conditions: (a) (1) SOCl2, CH2Cl2, 0 °C; (2) RuCl3,
NaIO4, CH2Cl2/CH3CN/H2O, 0 °C f 25 °C. (b) (1) 1 equiv n-BuLi, THF,
0 °C; (2) 5; (3) 1 equiv n-BuLi. (c) (1) 2 equiv n-BuLi, THF, 0 °C, (2) 5
(3) 2 equiv n-BuLi; (d) 190 °C, 8 h; (e) 205 °C, 20 h. b One-pot sequential
cyclization and epimerization. Epimerization yields were essentially equal
to cyclization yields. c 4% of the cis/cis isomer remained unepimerized.
atoms.9 However, this subtle transformation has been under-utilized
in practical synthesis of P-chirogenic phosphines. Epimerization
via pyramidal inversion is an ideal reaction in terms of atom
efficiency and workup. Reagents and solvent are not necessary to
promote the transformation. Heating is the only requirement.10
Provided that decomposition of the epimerization substrate or
product does not occur at reaction temperature (or, in the case of
phosphorus epimerization, that oxygen is not present to promote
phosphine oxide formation), epimerization yields can easily ap-
proach 100%.
Having uncovered an acceptable method for producing the
P-chirogenic five-membered ring phospholane scaffold, it was
speculated that thermodynamically driven pyramidal inversion
might promote the conversion of predominantly cis or cis/cis
adducts to trans or trans/trans products. Pyramidal inversion is a
well-known phenomenon for phosphines8 as well as for other
When epimerized products were desired, it was convenient to
cyclize and then epimerize via a one-pot procedure (Scheme 1).
Solvent from cyclization reactions was merely removed in vacuo,
and then the resulting residue (a mixture of predominantly cis or
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C O M M U N I C A T I O N S
cis/cis phospholanes and sulfate salts) was heated to the appropriate
temperature without solvent in an oil bath under a nitrogen
atmosphere. While 2c and 13c were isolated as completely
epimerized products, the methyl- and methoxymethyl-substituted
compounds, 2a and 13a,13b showed incomplete epimerization
under the same conditions.11 Phospholane 1c was even more
difficult to epimerize despite a higher applied temperature (205 vs
190 °C).
The mechanism for pyramidal inversion-induced epimerization
likely involves a transition state featuring an sp2 phosphorus atom
that is in equilibrium with each form of the phospholane, 9 (cis)
and 13 (trans), as shown in Figure 2. The reaction is driven toward
the more thermodynamically stable trans phospholane, 13. That 9a
and 10a provide relatively lower conversions to cis and cis/cis
phospholanes 13a and 2a may be a function of similar energies of
cis vs trans isomers as a result of lessened steric effects from the
small methyl substituents of each compound.
generality of the two approaches we speculate that these method-
ologies may find applicability to the synthesis of as yet undiscovered
P-chirogenic ligands as well as new synthetic routes to those that
are known already. Furthermore, the use of 2c in the highly
enantioselective rhodium-catalyzed asymmetric hydrogenation of
17 bodes well for broader application of the ligands presented in
this communication.
Acknowledgment. I thank Brian Samas for assistance with
X-ray crystallography of phospholanes. Pfizer, Inc. is acknowledged
for continuing support of this research.
Supporting Information Available: Synthetic procedures, proof
of relative and absolute phospholane stereochemistry, spectral data,
representative determinations of the ratio of phospholane diastereomers,
and methods for converting to and purifying their borane and sulfide
adducts. This material is available free of charge via the Internet at
http://pubs.acs.org.
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(6) The terms “cis” and “trans” refer to the arrangement of substituents around
the monophospholane rings to prevent confusion with the arrangement
of the lone pair. The terms “cis/cis”, “cis/trans”, and “trans/trans” refer
to the arrangement of each phospholane ring within one molecule of a
bisphospholane.
Figure 2. Pyramidal inversion mechanism.
To highlight the potential utility of the trans/trans bisphos-
pholanes reported in this communication, ligand 2c was converted
to cationic rhodium complex 16 (Scheme 2). Rhodium complex
16 was then used as a catalyst for the asymmetric hydrogenation
of 17 to form 18. Product 18 was the sole hydrogenation product
with 96% enantiomeric excess. The (S) isomer of 18 is a precursor
to pharmaceutical candidate pregabalin.2,12
Scheme 2. Asymmetric Hydrogenation of a Pregabalin Precursora
(7) In most cases cis and cis/cis diastereomers could be isolated from cis:
trans and cis/cis:cis/trans mixtures via either crystallization or column
chromatography of borane or sulfide adducts of the phosphines as
described in the Supporting Information.
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(10) While heating is a requirement for the epimerizations involved in the
current discussion, it is not a requirement for all pyramidal inversions to
occur.
(11) In the cases of incomplete epimerization, most trans and trans/trans
diastereomers could be isolated from cis:trans and cis/trans:trans/trans
mixtures via either recrystallization or column chromatography of borane
or sulfide adducts of the phosphines as described in the Supporting
Information.
a Reagents and conditions: (a) 1. [Rh(COD)2]+ OTf-, MeOH; 2.
recrystallization from THF. (b) 1 mol % 16, MeOH, 30 psi H2, 25 °C, 2 h.
(12) Burk, M. J.; de Konig, P. D.; Grote, T. M.; Hoekstra, M. S.; Hoge, G.;
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In conclusion, stereoselective cyclization and epimerization via
pyramidal inversion have been demonstrated as viable routes for
the synthesis of a variety of P-chirogenic phospholanes. Given the
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