O-(hydroxyalkyl)phenyl P-chirogenic phosphines as functional chiral lewis bases

Article abstract of DOI:10.1021/ol400515e

The stereoselective synthesis of P-chirogenic phosphines bearing an o-hydroxyalkyl chelating arm is described. The synthesis is based either on the hydroxyalkylation of P-chirogenic o-bromophenylphosphines (borane) or on their carbonatation and then reduction. The hydroxyalkylation with benzaldehyde or pivalaldehyde affords a mixture of epimers which are isolated by chromatography and characterized by their X-ray structures. Preliminary assays of free P-chirogenic o-(hydroxyalkyl)phenyl phosphines, as new functional Lewis bases in catalyzed asymmetric aza-MBH reaction, lead to β-aminoester derivatives with ee values up to 74%.

Full text of DOI:10.1021/ol400515e

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
o‑(Hydroxyalkyl)phenyl P‑Chirogenic
Phosphines as Functional Chiral
Lewis Bases
†
Emmanuelle Remond, Jerome Bayardon, Shinobu Takizawa, Yoann Rousselin,
†
‡
†
ꢀ
ꢀ ^
Hiroaki Sasai,* and Sylvain Juge*
,‡
,†
ꢀ
ꢀ
ꢀ
ꢀ ꢀ
Institut de Chimie Moleculaire de l’Universite de Bourgogne (ICMUB-StereochIM),
UMR CNRS 6302, 9 Avenue Alain Savary, BP 47870, 21078 Dijon cedex, France, and
The Institute of Scientific and Industrial Research (ISIR), Osaka University,
Mihogaoka, Ibaraki, Osaka 567-0047, Japan
sasai@sanken.osaka-u.ac.jp; sylvain.juge@u-bourgogne.fr
Received February 24, 2013
ABSTRACT
The stereoselective synthesis of P-chirogenic phosphines bearing an o-hydroxyalkyl chelating arm is described. The synthesis is based either on
the hydroxyalkylation of P-chirogenic o-bromophenylphosphines (borane) or on their carbonatation and then reduction. The hydroxyalkylation
with benzaldehyde or pivalaldehyde affords a mixture of epimers which are isolated by chromatography and characterized by their X-ray
structures. Preliminary assays of free P-chirogenic o-(hydroxyalkyl)phenyl phosphines, as new functional Lewis bases in catalyzed asymmetric
aza-MBH reaction, lead to β-aminoester derivatives with ee values up to 74%.
A chiral organophosphorus bearing a heteroatom or a
functionalgroup inthe ortho position ofanarylsubstituent
is a useful ligand or Lewis base for the development of
catalyzed or organocatalyzed asymmetric reactions.1ꢀ4
Among the chiral functional organophosphorus deriva-
tives, those bearing a phenol substituent have gained
attentionbecausetheycould be usedinvariousasymmetric
reactions using either transition-metal catalysts3 or bifunc-
tional organocatalysts.4 Despite the importance of the
functional chiral organophosphorus compounds, few effi-
cient stereoselective syntheses have been described to
date.1 The synthesis of a P-chirogenic organophosphorus
bearing a hydroxyalkyl (or aryl) substituent could be
achieved by demethylation of a methoxy substituent,2c,3a
by carbonatation then reduction,5 or by trapping a C,O-
phenol dilithium reagent with a chlorophosphine.6 A more
convenient method has been developed on the basis of
the ortho Fries-like rearrangement of the corresponding
2-bromoaryl phosphinite borane, with retention of config-
uration at the phosphorus atom.7
†
ꢀ
ꢀ
Institut de Chimie Moleculaire de l'Universite de Bourgogne.
‡ Osaka University.
(1) (a) Tang, W.; Zhang, X. Chem. Rev. 2003, 103, 3029. (b) Guiry,
P. J.; Saunders, C. P. Adv. Synth. Catal. 2004, 346, 497. (c) Grabulosa,
A.; Granell, J.; Muller, G. Coord. Chem. Rev. 2007, 251, 25. (d)
€
Phosphorus Ligands in Asymmetric Catalysis; Borner, A., Ed.; Wiley-
VCH: Weinheim, Germany, 2008; Vols. 1ꢀ3. (e) Phosphorus (III) Ligands
in Homogeneous Catalysis: Design and Synthesis; Kamer, P. C. J., van
Leeuwen, P. W. N. M., Eds.; Wiley: Chichester, U.K., 2012.
(2) (a) Quirmbach, M.; Kless, A.; Holz, J.; Tararov, V.; Borner, A.
Tetrahedron: Asymmetry 1999, 10, 1803. (b) Brunel, J. M.; Legrand, O.;
Buono, G. Tetrahedron: Asymmetry 1999, 10, 1979. (c) Takahashi, Y.;
Yamamoto, Y.; Katagiri, K.; Danjo, H.; Yamaguchi, K.; Imamoto, T.
J. Org. Chem. 2005, 70, 9009.
(3) (a) Brunel, J. M.; Buono, G. Tetrahedron Lett. 1998, 39, 2961.
(b) Legrand, O.; Brunel, J. M.; Buono, G. Tetrahedron Lett. 1998, 39,
9419. (c) Buono, G.; Chiodo, O.; Wills, M. Synlett 1999, 4, 377.
(d) Legrand, O.; Buono, G. Tetrahedron Lett. 2000, 41, 2105.
(4) (a) Shi, M.; Chen, L.-H.; Gao, J. J. Am. Chem. Soc. 2005, 127,
3790. (b) Liu, Y.; Chen, L.-H.; Shi, M. Adv. Synth. Catal. 2006, 348, 973.
(b) Ito, K.; Nishida, K.; Gotanda, T. Tetrahedron Lett. 2007, 48, 6147.
(c) Shi, M.; Ma, G.-N.; Gao, J. J. Org. Chem. 2007, 72, 9779. (d) Wei, Y.;
Shi, M. Acc. Chem. Res. 2010, 43, 1005.
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127, 11934. (b) Imamoto, T. J. Synth. Org. Chem. Jpn. 2007, 66, 18.
(c) Imamoto, T.; Tamura, K.; Ogura, T.; Ikematsu, Y.; Mayama, D.;
Sugiya, M. Tetrahedron: Asymmetry 2010, 21, 1522.
(6) Stephan, M.; Modec, B.; Mohar, B. Tetrahedron Lett. 2011, 52,
1086.
r
10.1021/ol400515e
XXXX American Chemical Society

Table 1. Synthesis of P-Chirogenic o-(Hydroxyalkyl)phenyl
Phosphines (Borane) 7aꢀda
Scheme 1. Stereoselective Synthesis of P-Chirogenic
o-Bromophenyl Phosphines Using Aryne Chemistry
ratioe yields
productsd 7:70 (%)f
entry reagentsa R1 R2 R3
Y
We have recently described an efficient stereoselective
synthesis of o-bromophenyl P-chirogenic phosphines 5,
based on the reaction between the secondary phosphine
borane 1 and benzyne 2, generated in situ from 1,2-
dibromobenzene 3 by metalꢀhalide exchange (Scheme 1).8
In continuity of this research, we were interested in the
synthesis of P-chirogenic phosphines bearing a hydroxyalkyl
chelating arm, for the development of a new class of chiral
o-functional Lewis bases.
1
2
3
4
5
6
7
(Rp)-5aa,g 6a Fc Ph Ph BH3 (Sp)-7a, 7a0 45:55 71
(Sp)-5aa,h 6a Ph Fc Ph BH3 (Rp)-7a, 7a0 64:36 72
(Sp)-5aa,h 6b Ph Fc t-Bu BH3 (Rp)-7b, 7b0 60:40 66
(Sp)-5ba,h 6a Ph o-An Ph ..
(Sp)-5bb,h 6a Ph o-An Ph ..
(Sp)-5bc,h 6a Ph o-An Ph ..
(Sp)-5ba,h 6b Ph o-An t-Bu ..
(Rp)-7c, 7c0 80:20i 45
(Rp)-7c, 7c0 70:30i 48
(Rp)-7c, 7c0 70:30i 42
(Rp)-7d, 7d0 60:40i 50
a Reaction conditions: 5 (0.4 mmol), n-BuLi (0.44 mmol) in THF
(2 mL) at ꢀ78 °C for 1 h. Aldehyde (0.8 mmol for benzaldehyde 6a or
1.6 mmol for pivalaldehyde 6b) in dry THF (0.5 mL) was added at
ꢀ78 °C, and the mixture was warmed to rt and stirred again for 1 h
30 min. b Benzaldehyde 6a was added at 0 °C. c Toluene solution of
benzaldehyde 6a was added. d ee >99% determined by HPLC on chiral
column. e Determined after isolation by chromatography. f Isolated yields
after purification by column chromatography. g Prepared from (ꢀ)-ephedrine.
h Prepared from (þ)-ephedrine. i The relative configuration was attributed
by comparison with the major epimers (RpS)-7a and (RpS)-7b.
Herein, we report an efficient stereoselective synthesis
of P-chirogenic o-(hydroxyalkyl)phenyl phosphines, either
by hydroxyalkylation of the corresponding o-bromophenyl
phosphine precursors 5 or by Fries-like rearrangement of a
phosphinite borane derived from 2-bromobenzyl alcohol.
In the first case, the hydroxyalkylation was achieved
by the reaction of the anion derived from the o-bromo
phenylphosphine borane 5a, or the free phosphine 5b,
with the benzaldehyde 6a or the pivalaldehyde 6b. The
corresponding P-chirogenic o-(hydroxyalkyl)phenyl phos-
phines (borane) were obtained as a mixture of two epimers
7 and 70 with respect to the absolute configuration at the
P-center, with yields ranging from 42% to 72% (Table 1).
Thus, the reaction of the phosphine borane (Rp)-5a with
the benzaldehyde 6a affords the epimeric mixture (Sp)-7a
and (Sp)-7a0 in the ratio 45:55 (entry 1). The epimers were
separated by chromatography, and their enantiomeric
purities were checked by HPLC on a chiral column.
Crystals of (Sp)-7a0 were grown from methylene chloride/
hexane as solvent, and its drawing is shown in Figure 1.
The structure of (Sp)-7a0 shows a distorted tetrahedral
geometry at the P-atom which is typical of phosphine
borane adducts, which proves the (Sp)-and(R)-configuration
at the P- and C-atom, respectively. These absolute configura-
tions are supported by refinement of the Flack parameter
(Table S1).
(Rp)-7a0 were obtained in a 64:36 ratio, 72% yield and with
99% enantiomeric excess (entry 2). The structure of the
major isomer has also been determined by single crystal
X-ray diffraction, as the enantiomer (Rp,S)-7a of the
o-(hydroxyalkyl)phenyl phosphine borane (Sp,R)-7a0
shows in Figure 1.
In the case of the reaction of the o-bromo ferrocenyl-
phenylphosphine borane (Sp)-5a with benzaldehyde 6a,
the o-(hydroxyalkyl)phenylphosphine borane (Rp)-7a and
Figure 1. OLEX2 view of the o-(hydroxymethyl)phenyl
phosphine (Sp,R)-7a0, showing thermal ellipsoids at the 50%
probability level. Selected bond lengths [A], angles [deg]: C1ꢀP
1.818(4); C7ꢀP 1.831(4); C13ꢀO 1.429(4); C27ꢀP 1.792(4);
PꢀB 1.913(4); C2ꢀC1ꢀP 120.1(3); OꢀC13ꢀC14 112.8(3);
OꢀC13ꢀC12 110.6(3); C27ꢀPꢀC1 105.26(16); C27ꢀPꢀC7
105.91(17); C1ꢀPꢀC7 104.03(16); C27ꢀPꢀB 110.35(18);
C7ꢀPꢀB 113.95(18). BꢀPꢀC27ꢀC28 30.90(4); BꢀPꢀC1ꢀC2
3.5(4); BꢀPꢀC7ꢀC12 63.5(3); C7ꢀC12ꢀC13ꢀO ꢀ101.4(4).
(7) (a) Tollefson, M. B.; Li, J. J.; Beak, P. J. Am. Chem. Soc. 1996,
118, 9052. (b) Legrand, O.; Brunel, J. M.; Constantieux, T.; Buono, G.
Chem.;Eur. J. 1998, 4, 1061. (c) Legrand, O.; Brunel, J. M.; Buono, G.
Eur. J. Org. Chem. 1999, 4, 1099. (d) Legrand, O.; Brunel, J. M.; Buono,
G. Tetrahedron 2000, 56, 595. Moulin, D.; Bago, S.; Bauduin, C.; Darcel,
ꢀ
C.; Juge, S. Tetrahedron: Asymmetry 2000, 11, 3939.
ꢀ
ꢀ
(8) (a) Bayardon, J.; Laureano, H.; Henry, J. C.; Remond, E.;
ꢀ
Colobert, F.; Leroux, F.; Juge. S. Intern. Patent pending 2011, US 61/
506,291; Fr 11 56686. (b) Bayardon, J.; Laureano, H.; Diemer, V.; Dutartre,
ꢀ
M.; Das, U.; Rousselin, Y.; Henry, J.-C.; Colobert, F.; Leroux, F. R.; Juge, S.
J. Org. Chem. 2012, 77, 5759.
B
Org. Lett., Vol. XX, No. XX, XXXX

When the reaction was achieved with the ferrocenyl-
(o-bromophenyl)phosphine borane (Sp)-5a and the piva-
laldehyde 6b, the corresponding o-(hydroxyalkyl) phenyl
phosphine borane (Rp)-7b (and 7b0) was obtained in 66%
yield and with a 60:40 ratio (entry 3). The structure of the
major isomer (Rp)-7b has also been determined by single
crystal X-ray diffraction (Figure 2).
Figure 3. OLEX2 view of o-(hydroxymethyl)phenylphosphine
borane (RpR)-7b0 showing thermal ellipsoids at the 50% prob-
ability level. Selected bond lengths [A], angles [deg]: C1ꢀP
1.816(4); C7ꢀP 1.844(4); C13ꢀO 1.440(5); C18ꢀP 1.791(4);
PꢀB 1.923(5); C2ꢀC1ꢀP 121.5(3); OꢀC13ꢀC14 106.9(4);
OꢀC13ꢀC12 110.7(4); C18ꢀPꢀC1 104.4(2); C18ꢀPꢀC7
103.5(2); C1ꢀPꢀC7 103.8(2); C18ꢀPꢀB 111.4(2); C7ꢀPꢀB
118.3(2); BꢀPꢀC18ꢀC22 157.4(4); BꢀPꢀC1ꢀC2 166.4(4);
BꢀPꢀC7ꢀC12 ꢀ77.5(4) ; C7ꢀC12ꢀC13ꢀO ꢀ124.7(4).
Figure 2. OLEX2 view of the o-(hydroxyalkyl)phenylphosphine
(Rp,S)-7b, showing thermal ellipsoids at the 50% probability
level. Selected bond lengths [A], angles [deg]: C1ꢀP 1.818(4);
C7ꢀP 1.842(4); C13ꢀO 1.436(5); C18ꢀP 1.792(4); PꢀB
1.934(5); C2ꢀC1ꢀP 121.2(3); OꢀC13ꢀC14 108.5(3); OꢀC13ꢀ
C12 109.7(3); C18ꢀPꢀC1 106.5(2); C18ꢀPꢀC7 104.9(2);
C1ꢀPꢀC7 106.3(2); C18ꢀPꢀB 110.2(2); C7ꢀPꢀB 112.9(2);
BꢀPꢀC18ꢀC22 163.4(4); BꢀPꢀC1ꢀC2 173.0(4); BꢀPꢀC7ꢀ
C12 ꢀ56.3(4); C7ꢀC12ꢀC13ꢀO 108.0(4).
On the other hand, as the reaction of paraformaldehyde
was sluggish, the stereoselective synthesis of P-chirogenic
ferrocenyl-o-(hydroxymethyl) phenyl phosphine borane
(Sp)-7e was achieved in 40% overall yield, by trapping
the anion derived from the o-bromophenyl phosphine
borane (Rp)-5a with CO2, followed by the reduction of
the carboxylic acid derivative (Sp)-8 with BH3 DMS
3
(Scheme 2a). The enantiomeric purity of the compound
(Sp)-7e was checked on a chiral column in regards to a
racemic sample, and no racemization was found to occur
during this process.
This structure shows again a distorted tetrahedral geometry
at the P-atom which is typical of phosphine borane adducts,
proving the (R)- and (S)-configuration at the P- and C-atom,
respectively. These absolute configurations are supported by
refinement of the Flack parameter (Table S1).
Interestingly, the stereoselective synthesis of the ferro-
cenyl-o-(hydroxymethyl)phenylphosphine (Sp)-7e could
also be achieved by the intramolecular ortho Fries-like
rearrangement of the 2-bromobenzylphosphinite borane
(Rp)-11, mediated by basic conditions (Scheme 2b).
The phosphinite borane 11was preparedin 51% yield by
reaction of the o-bromobenzyl alcohol 10 with the P-chiro-
genic chlorophosphine (Sp)-9, previously obtained using
the (þ)-ephedrine methodology.9 Finally, the phosphine
borane derivative (Sp)-7e was obtained in 58% yield by
rearrangement mediated by tert-butyllithium (Scheme 2b).
The stereochemistry with retention of the configuration at
the P-atom in the Fries-like rearrangement which was
previously described in literature7 allows the (S)-config-
uration to be attributed to 7e.
The structure of the minor isomer (Rp)-7b0 was also
determined by single crystal X-ray diffraction, and its
drawing is shown in Figure 3. In this case, the X-ray
structure proves the (R)-configuration at the P- and
C-atom, which is supported by refinement of the Flack
parameter (Figure 3, Table S1). After decomplexation of
the borane complex using DABCO at room temperature,
the anion obtained after metalꢀhalide exchange of the
o-anisyl-o-bromophenyl phenyl phosphine (Sp)-5b reacts
with the benzaldehyde 6a to afford the corresponding
o-(hydroxylalkyl)phenyl derivatives 7c, 7c0 in 45% yield
(entry 4). When the reaction was performed at rt, or in a
4:1 toluene/THF mixture, 7c and 7c0 were obtained in a
70:30 ratio, showing the poor influence of the temperature
or solvent on the diastereoselectivity (entries 5, 6). In the
case of the reaction of (Sp)-5b, with the pivalaldehyde 6b,
the corresponding o-(hydroxylalkyl)phenyl derivatives 7d
and 7d0 were obtained in 50% yield and with a 60:40 ratio
(entry 7).
During the past decade, chiral phosphines bearing protic
moieties have emerged as powerful catalysts for various
asymmetric reactions with CꢀC bonds formation [Michael,
BaylisꢀHillmann, aza-MoritaꢀBaylisꢀHillmann (aza-M-
B-H)].10 To the best of our knowledge, the use of
ꢀ
(9) Bauduin, C.; Moulin, D.; Kaloun, E. B.; Darcel, C.; Juge, S.
J. Org. Chem. 2003, 68, 4293.
Org. Lett., Vol. XX, No. XX, XXXX
C

Scheme 2. Stereoselective Synthesis of the P-Chirogenic
Ferrocenyl-o-(hydroxymethyl)phenylphosphine (Sp)-7e
Scheme 3. Asymmetric aza-MBH Reaction Catalyzed by the
P-Chirogenic o-(Hydroxyalkyl)phenyl Phosphine (Sp,S)-14
exchange from the P-chirogenic o-bromophenyl phos-
phines (free or as borane complexes). Under these condi-
tions, a mixture of epimers was obtained in a 45:55 to 80:20
ratio, and they were separated by chromatography. The
absolute configurations were determined by the X-ray
structure of the P-chirogenic phosphine borane complexes.
The stereoselective synthesis of P-chirogenic ferrocenyl-
o-(hydroxymethyl) phenyl phosphine borane could be
achieved either from o-bromophenyl phosphine borane
by reaction with CO2 and then reduction with borane or
from 2-bromobenzyl phosphinite borane, by an intra-
molecular Fries-like rearrangement. The use of the
P-chirogenic o-(hydroxyalkyl)phenyl phosphines as new
P-chirogenic functional Lewis bases for an asymmetric
aza-MBH reaction leads to the unsaturated β-aminoester
15 with ee values up to 74% in preliminary assays,
prompting further development in this area soon.
P-chirogenic phosphines as an organocatalyst has been
minimally considered to date in this area.11 In this context,
the P-chirogenic o-(hydroxyalkyl)phenylphosphines (Sp,S)-
14 and (Rp,R)-7c0 were preliminarily evaluated as a func-
tional Lewis base in the asymmetric aza-MBH reaction
(Scheme 3).12
The free phosphine (Sp,S)-14 was prepared in 98% yield
by decomplexation of (Sp,S)-7a with DABCO. When the
acrylate 12 reacts with the N-tosyl aldimine 13 in TBME
at 5 °C, in the presence of 5 mol % of (Sp,S)-14, the
unsaturated β-aminoester (S)-15 was obtained in 90%
yield and with 74% ee (Scheme 3). In the case of the use
of (Rp,R)-7c0 as an organocatalyst, the β-aminoester (S)-15
was obtained in 82% yield and with 68% ee.
In conclusion, we have developed an efficient stereose-
lective synthesis of P-chirogenic o-(hydroxyalkyl) phenyl
phosphine boranes. This synthesis is based on the hydro-
xyalkylation of the anion formed by metalꢀhalide
Acknowledgment. The authors gratefully acknowledge
financial support provided by CNRS (Centre National de
ꢁ
la Recherche Scientifique), the “Ministere de l’Education
Nationale et de la Recherche”, the Agence Nationale pour
la Recherche (Grant 07BLAN292-01 MetChirPhos), and
the Synthelor SAS (Nancy). WeacknowledgeM. J. Eymin,
(10) (a) Declerck, V.; Martinez, J.; Lamaty, F. Chem. Rev. 2007, 109,
1. (b) Denmark, S. E.; Beutner, G. L. Angew. Chem., Int. Ed. 2008, 47,
1560. (c) Palomo, C.; Oiarbide, M.; Lopez, R.; Palomo, C. Chem. Soc.
Rev. 2009, 38, 632. (d) Basavaiah, D.; Veeraraghavaiah, G. Chem. Soc.
Rev. 2012, 41, 68. (e) Giacalone, F.; Gruttadauria, M.; Agrigento, P.;
Noto, R. Chem. Soc. Rev. 2012, 41, 2406. (f) Liu, T.-Y.; Xie, M.; Chen,
Y.-C. Chem. Soc. Rev. 2012, 41, 4101.
ꢀ
F. Picquet, and M. J. Penouilh (Universite de Bourgogne,
ICMUB-StereochIM and Welience) for providing techni-
ꢀ ꢀ
cal assistance.
(11) For the use of P-chirogenic organophosphorus compounds in
asymmetric organocatalyzed reactions, see: (a) Denmark, S. E.; Fu, J.
Chem. Rev. 2003, 103, 2763. (b) Iseki, K.; Kuroki, Y.; Takahashi, M.;
Kobayashi, Y. Tetrahedron Lett. 1996, 29, 5149. (c) Chiodi, O.; Fotiadu,
F.; Sylvestre, M.; Buono, G. Tetrahedron Lett. 1996, 37, 39. (d) Vedejs,
E.; Daugulis, O. J. Am. Chem. Soc. 2003, 125, 4166. (e) Sampath, M.;
Loh, T.-P. Chem. Sci. 2010, 1, 739.
Supporting Information Available. Experimental pro-
cedures and spectral data for all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(12) Matsui, K.; Takizawa, S.; Sasaı, H. Synlett 2006, 5, 761.
The authors declare no competing financial interest.
¨
D
Org. Lett., Vol. XX, No. XX, XXXX