Use of 5,5-(dimethyl)-i-Pr-PHOX as a practical equivalent to t-Bu-PHOX in asymmetric catalysis

Article abstract of DOI:10.1021/ol9005618

The use of 5,5-(dimethyl)-i-Pr-PHOX as a practical equivalent of t-Bu-PHOX in asymmetric catalysis is reported. This new member of the phosphinooxazoline (PHOX) ligand family behaves similarly in terms of stereoinduction to t-Bu-PHOX with the key advantage of being readily accessible as both enantiomers starting from either(S)- or (R)-valine.

Full text of DOI:10.1021/ol9005618

ORGANIC
LETTERS
2009
Vol. 11, No. 10
2201-2204
Use of 5,5-(Dimethyl)-i-Pr-PHOX as a
Practical Equivalent to t-Bu-PHOX in
Asymmetric Catalysis
´
Etienne Be´langer, Marie-France Pouliot, and Jean-Franc¸ois Paquin*
Canada Research Chair in Organic and Medicinal Chemistry, De´partement de chimie,
1045 aVenue de la Me´decine, UniVersite´ LaVal, Que´bec, QC, Canada G1V 0A6
jean-francois.paquin@chm.ulaVal.ca
Received March 17, 2009
ABSTRACT
The use of 5,5-(dimethyl)-i-Pr-PHOX as a practical equivalent of t-Bu-PHOX in asymmetric catalysis is reported. This new member of the
phosphinooxazoline (PHOX) ligand family behaves similarly in terms of stereoinduction to t-Bu-PHOX with the key advantage of being readily
accessible as both enantiomers starting from either (S)- or (R)-valine.
The phosphinooxazoline ligands (PHOX ligands) developed
by Pfaltz, Helmchen, and Williams are a versatile class of
P,N-chiral ligands (Figure 1).1 The only difference between
the well-known members of this class of ligands is the
substituent at C-4 (i.e., 1-4, Figure 1). Within this group,
the one bearing a t-butyl group at C-4 (i.e., 1) is often the
one affording the highest enantioselectivities, and therefore
it is extensively used in asymmetric catalysis1-3 and in
natural product synthesis.4 The (S)-enantiomer of this ligand
(1) (a) Williams, J. M. J. Synlett 1996, 705–710. (b) Helmchen, G.;
Pfaltz, A. Acc. Chem. Res. 2000, 33, 336–345.
(2) For selected examples of the use of (S)-t-Bu-PHOX in asymmetric
catalysis, see: (a) Loiseleur, O.; Meier, P.; Pfaltz, A. Angew. Chem., Int.
Ed. Engl. 1996, 35, 200–202. (b) Langer, T.; Helmchen, G. Tetrahedron
Lett. 1996, 37, 1381–1384. (c) Hiroi, K.; Watanabe, K. Tetrahedron:
Asymmetry 2002, 13, 1841–1843. (d) Hayashi, T.; Suzuka, T.; Okada, A.;
Kawatsura, M. Tetrahedron: Asymmetry 2004, 15, 545–548. (e) Cook, M. J.;
Rovis, T. J. Am. Chem. Soc. 2007, 129, 9302–9303. (f) Schulz, S. R.;
Blechert, S. Angew. Chem., Int. Ed. 2007, 46, 3966–3970. (g) Marinescu,
S. C.; Nishimata, T.; Mohr, J. T.; Stoltz, B. M. Org. Lett. 2008, 10, 1039–
1042. (h) Seto, M.; Roizen, J. L.; Stoltz, B. M. Angew. Chem., Int. Ed.
2008, 47, 6873–6876. (i) Linton, E. C.; Kozlowski, M. C. J. Am. Chem.
Figure 1. Some members of the PHOX ligand family and synthetic
precursor for the preparation of t-Bu-PHOX (1).
is now commercially available.5 Alternatively, it can be
synthesized in four steps from (S)-tert-leucine ((S)-6),6 a
rather expensive non-natural amino acid (Figure 1).7,8
However, the other enantiomer of tert-leucine, (R)-tert-
leucine ((R)-6), is prohibitively expensive, thus (R)-t-Bu-
Soc. 2008, 130, 16162–16163
(3) For our own work using (S)-t-Bu-PHOX, see: (a) Be´langer, E.;
Cantin, K.; Messe, O.; Tremblay, M.; Paquin, J.-F. J. Am. Chem. Soc. 2007,
129, 1034–1035. (b) Be´langer, E.; Houze´, C.; Guimond, N.; Cantin, K.;
Paquin, J.-F. Chem. Commun. 2008, 3251–3253
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10.1021/ol9005618 CCC: $40.75
Published on Web 04/23/2009
 2009 American Chemical Society

PHOX is virtually not accessible.9 This drawback has serious
consequence in asymmetric catalysis since it limits access
to one enantiomeric series for any given reaction using the
t-Bu-PHOX ligand. In this context, a readily accessible
substitute for t-Bu-PHOX that would be available in both
enantiomeric series at reasonable cost would be highly
valuable.10
the i-Pr where the two methyl groups pointed toward the
reaction center (i.e., enolate fragment) such that the i-Pr
mimicked a tert-butyl group.11a
On the basis of these results, we envisioned that the
incorporation of a gem-dimethyl group at C-4 of i-Pr-PHOX
(2) could result in a practical replacement for t-Bu-PHOX
(1). These new ligands would not only have a major
economic advantage over t-Bu-PHOX since the cost of the
starting amino acids, (S)- or (R)-valine (8), is much lower
than the corresponding tert-leucines (6) but also allow easy
access to both enantiomers.
It has been shown by Davies11 that the incorporation
of a gem-dimethyl group at C-5 of a 4-iso-propyloxazo-
lidinone (Evans’ auxiliary) resulted in a chiral auxiliary
that behaved similarly to a 4-tert-butyl-propyloxazolidi-
none in terms of stereoinduction in a wide range of
transformations. It was also demonstrated that steric
interaction between the gem-dimethyl group at C-5 and
the iso-propyl group at C-4 resulted in a conformation of
Herein, we describe a new and readily available member
of the PHOX family,12 5,5-(dimethyl)-i-Pr-PHOX (7) (Figure
2), which has a parallel reactivity to (S)-t-Bu-PHOX with
(4) For recent examples of the use of (S)-t-Bu-PHOX in total synthesis,
see: (a) Coe, J. W. Org. Lett. 2000, 2, 4205–4208. (b) Bian, J.; Van
Wingarden, M.; Ready, J. M. J. Am. Chem. Soc. 2006, 128, 7428–7429.
(c) Behenna, D. C.; Stockdill, J. L.; Stoltz, B. N. Angew. Chem., Int. Ed.
2007, 46, 4077–4080. (d) Enquist, J. A., Jr.; Stoltz, B. M. Nature 2008,
453, 1228–1231. (e) Dounay, A. M.; Humphreys, P. G.; Overman, L. E.;
Wrobleski, A. D. J. Am. Chem. Soc. 2008, 130, 5368–5377.
(5) Available from Sigma-Aldrich Co.
(6) Peer, M.; de Jong, J. C.; Jiefer, M.; Langer, T.; Rieck, H.; Schell,
H.; Sennhenn, P.; Sprinz, J.; Steinhagen, H.; Wiese, B.; Helmchen, G.
Tetrahedron 1996, 52, 7547–7583.
(7) The price per gram (in American dollars) was calculated using the
largest amount available from Sigma-Aldrich Co. (March 2009).
(8) Bommarius, A. S.; Schwarm, M.; Stingl, K.; Kottenhahn, M.;
Huthmacher, K.; Drauz, K. Tetrahedron: Asymmetry 1995, 6, 2851–2888.
(9) According to a recent SciFinder Scholar search (March 2009), only
5 examples of the use of (R)-t-Bu-PHOX had been reported. See: (a) Juhl,
K.; Hazell, R. G.; Jørgensen, K. A. J. Chem. Soc., Perkin Trans. 1 1999,
2293–2297. (b) Fang, X.; Johannsen, M.; Yao, S.; Gathergood, N.; Hazell,
R. G.; Jørgensen, K. A. J. Org. Chem. 1999, 64, 4844–4849. (c) Marinescu,
S. C.; Nishimata, T.; Mohr, J. T.; Stoltz, B. M. Org. Lett. 2008, 10, 1039–
1042. (d) Levine, S. R.; Krout, M. R.; Stoltz, B. M. Org. Lett. 2009, 11,
289–292. (e) Petrova, K. V.; Mohr, J. T.; Stoltz, B. M. Org. Lett. 2009, 11,
293–295.
Figure 2. New ligands 5,5-(dimethyl)-i-Pr-PHOX and their syn-
thetic precursor.
(10) These issues have been partly addressed before and resulted in the
design of (S)-5 (Figure 1).6 However, to date, the use of this ligand in
asymmetric catalysis remains scarce. See: (a) Langer, T.; Joerg, J.;
Helmchen, G. Tetrahedron: Asymmetry 1996, 7, 1599–1602. (b) Wiese,
B.; Helmchen, G. Tetrahedron Lett. 1998, 39, 5727–5730.
(11) (a) Bull, S. D.; Davies, S. G.; Key, M.-S.; Nicholson, R. L.; Savory,
E. D. Chem. Commun. 2000, 1721–1722. (b) Bull, S. D.; Davies, S. G.;
Garner, A. C.; Kruchinin, D.; Key, M.-S.; Roberts, P. M.; Savory, E. D.;
Smith, A. D.; Thomson, J. E. Org. Biomol. Chem. 2006, 4, 2945–2964.
(12) Pfaltz has recently reported a few related 5,5-(disubstituted)-i-Pr-
PHOX (not including (S)- or (R)-7) that were used in a different context,
i.e., [3 + 2] cycloadditions of azomethine ylides with moderate to excellent
results). See: Stohler, R.; Wahl, F.; Pfatlz, A. Synthesis 2005, 1431–1436.
(13) Gibson, S. E.; Mainolfi, N.; Kalindjian, S. B.; Wright, P. T.; White,
A. J. P. Chem.sEur. J. 2005, 69–80.
the key advantage of being easily accessible as both
enantiomers. The synthesis of these ligands and their
application in two enantioselective Pd-catalyzed transforma-
tions will also be demonstrated.
The desired ligand can be accessed by two different routes
from a common intermediate (S)-913 (Scheme 1). The
synthesis of the latter starts from (S)-valine ((S)-8) that was
first transformed into (S)-valine methyl ester hydrochloride
salt using a known procedure.14,15 The ester was then
converted into the previously reported amino alcohol (S)-9
in a three-step process involving protection of the amine,
methyl Grignard addition followed by deprotection of the
Boc group under acidic conditions.13 From (S)-9, the route
parallels the original sequence to access (S)-t-Bu-PHOX.6
In this case, amide formation with 2-fluorobenzoyl chloride
followed by cyclization under acidic conditions16 gave (S)-
10. The latter was converted to the desired ligand (S)-7 via
a SNAr reaction using KPPh2. Although this sequence
provided easy access to (S)-7, the intrinsic limitation of the
last step, the anionic displacement, where either electron-
rich phosphine anions or electron-rich aryl fluorides cannot
be used, puts unwanted boundaries on the eventual fine-
tuning of the electronic properties of the ligand for specific
reactions. To circumvent this potential limitation, a second
route was investigated taking profit of a recently published
(14) Bowman, N. J.; Hay, M. P.; Love, S. G.; Easton, C. J. J. Chem.
Soc., Perkin Trans. 1 1998, 259–264.
(15) (S)- and (R)-valine methyl ester hydrochloride are also commercially
available.
(16) (a) Denmark, S. E.; Stavenger, R. A.; Faucher, A.-M.; Edwards,
J. P. J. Org. Chem. 1997, 62, 3375–3389. (b) Ginotra, S. K.; Singh, V. K.
Tetrahedron 2006, 62, 3573–3581.
(17) (a) Tani, K.; Behenna, D. C.; McFadden, R. M.; Stoltz, B. M. Org.
Lett. 2007, 9, 2529–2531. (b) Krout, M. R.; Mohr, J. T.; Stoltz, B. M. Org.
Synth. 2009, 86, 181–193.
(18) Gelman, D.; Jiang, L.; Buchwald, S. L. Org. Lett. 2003, 5, 2315–
2318.
(19) For reviews on the asymmetric allylic alkylation reaction, see: (a)
Paquin, J.-F.; Lautens, M. In ComprehensiVe Asymmetric Catalysis,
supplement #2; Jacobsen, E. N., Pfaltz, A., Yamamoto, H., Eds.; Springer-
Verlag: Berlin, 2004; pp 73-95, and references therein. (b) Pfaltz, A.;
Lautens, M. In ComprehensiVe Asymmetric Catalysis; Jacobsen, E. N.,
Pfaltz, A., Yamamoto, H., Eds.; Springer: New York, 1999; Vol. 2, pp
833-884, and references therein.
(20) Ligand (R)-7 was prepared using “Stoltz’s approach” in Scheme
1. See the Supporting Information for details.
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Org. Lett., Vol. 11, No. 10, 2009

Scheme 1. Synthetic Approaches to (S)-7
approach to PHOX ligands by Stoltz.17 In this case, the key
C-P bond is made through an Ullmann-type coupling
developed by Buchwald18 allowing synthesis of ligand (S)-7
from (S)-11 in good yield.
The new ligands were first examined in the enantioselec-
tive allylation reaction19 using fluorinated silyl enol ether
precursors (12), a transformation developed recently by our
research group (Table 1).3a This reaction provides an efficient
The ligands were then tested in the enantioselective Heck
reaction21 between 2,3-dihydrofuran (14) and phenyl triflate (15)
where the use of the PHOX ligand, in particular (S)-t-Bu-PHOX,
was first reported by Pfaltz.2a The reactions were conducted
under microwave irradiation which has been shown to greatly
reduce the reaction time (18 h @ 100 °C vs 4 days @ 70 °C).22
Using (S)-t-Bu-PHOX, the desired 2,5-dihydrofuran (R)-16 was
isolated in good yield and 96% ee (Table 2, entry 1). Using
Table 2. Microwave-Assisted Enantioselective Heck Reaction of
Table 1. Enantioselective Pd-Catalyzed Allylation Reaction of
2,3-Dihydrofurana
Fluorinated Silyl Enol Ethera
yield (%)b
ee (%)c
entry
ligand
yield (%)b
ee (%)c
entry
ligand
1
2
3
4
(S)-t-Bu-PHOX
(S)-7
(R)-7
91
93
93
93
92
90
-90
80
1
2
3
4
(S)-t-Bu-PHOX
(S)-7
(R)-7
81
73
76
45
96
91
-92
86
(S)-i-Pr-PHOX
(S)-i-Pr-PHOX
a See the Supporting Information and ref 3a for details concerning the
a See the Supporting Information and ref 22 for details concerning the
reaction conditions. b Isolated yield. c Determined by chiral HPLC.
reaction conditions. b Isolated yield. c Determined by chiral HPLC.
access to allylated tertiary R-fluoroketones (13) and was
developed initially with (S)-t-Bu-PHOX as the chiral ligand
which gave (R)-13 in excellent yield and 92% ee (entry 1).
Using our new ligand (S)-7, the R-fluoroketone was obtained
in nearly identical results (93% yield, 90% ee). The use of
the enantiomer of the ligand, (R)-7,20 provided the other
enantiomer of the ketone, (S)-13, with identical results (entry
3). Finally, it is interesting to note that (S)-i-Pr-PHOX, which
lacks the gem-dimethyl at C-5 compared to (S)-7, provided
(R)-13 with excellent yield but with lower ee (80% ee), thus
demonstrating the beneficial effect of the substituents at C-5.
(S)-7, the product was obtained in good yield with slightly
reduced enantioselectivity (73% yield, 91% ee). The use of (R)-7
provided (S)-16 with nearly identical results (76% yield, 92%
ee). Here again, the use of (S)-i-Pr-PHOX provided the desired
product with lower ee (86% ee).
(21) Shibasaki, M.; Vogl, E. M.; Ohshima, T. AdV. Synth. Catal. 2004,
346, 1533–1552, and references therein.
(22) Nilsson, P.; Gold, H.; Larhed, M.; Hallberg, A. Synthesis 2002,
1611–1614.
(23) See the Supporting Information for more details.
(24) Hydrogen atoms and solvent molecules have been omitted for
clarity.
Org. Lett., Vol. 11, No. 10, 2009
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Palladium complexes of ligand (S)-7 and (S)-t-Bu-PHOX
were prepared by the reaction of PdCl2 in CH2Cl2 at 40 °C
for 48 h.23 The resulting crystals were analyzed by X-ray
diffraction, and the crystal structures are shown in Figure
3.23,24 In PdCl2[(S)-7], the distances from the palladium to
same distances are 3.298 and 3.4357 Å suggesting a similar
environment around the Pd atom from the stereoinducting
groups. Thus, the i-Pr flanked by a gem-dimethyl group
mimics a tert-butyl group. However, in PdCl2[(S)-7], the
presence of the gem-dimethyl group causes a slight distortion
as indicated by a torsion angle between Cl2-Pd1-N1-C4
of 38.7° as opposed to 47.3° in PdCl2[(S)-t-Bu-PHOX]. This
subtle difference as well as the presence of the gem-dimethyl
group at C-5 may explain why in certain reactions (e.g., Heck
reaction) slight differences in the enantioselectivities are
observed, whereas in others (e.g., allylic alkylation reaction)
both ligands behave equally well.
In conclusion, we have described a new and readily
available member of the PHOX family, 5,5-(dimethyl)-i-Pr-
PHOX (7), which in terms of stereoinduction behaves
similarly to (S)-t-Bu-PHOX but is easily accessible as both
enantiomers. The simple access of this family of ligands from
readily available starting materials opens the way to the fine-
tuning of the electronic/steric nature of the ligand for specific
reactions. We believe that this practical equivalent to t-Bu-
PHOX will find a wide use in asymmetric catalysis.
Acknowledgment. This work was supported by the
Canada Research Chair Program, the Natural Sciences and
Engineering Research Council of Canada, the Canada
Foundation for Innovation, Merck Frosst Centre for Thera-
peutic Research, the Fonds de recherche sur la nature et les
technologies, and the Universite´ Laval. Fre´de´ric G. Fontaine,
Christian N. Garon, and Christian Tessier (De´partement de
chimie, Universite´ Laval) are thanked for the crystallographic
analysis.
Supporting Information Available: General experimental
procedures, specific details for representative reactions, and
isolation and spectroscopic information for the new com-
pounds prepared. This material is available free of charge
via the Internet at http://pubs.acs.org.
Figure 3. Crystal structure of PdCl2[(S)-7] and PdCl2[(S)-t-Bu-
PHOX].
the methyl groups of the i-Pr group are 3.615 and 4.376 Å,
respectively. Correspondingly, in PdCl2[(S)-t-Bu-PHOX], the
OL9005618
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Org. Lett., Vol. 11, No. 10, 2009