Catalytic asymmetric carbon-carbon bond forming reactions: Preparation of optically enriched 2-aryl propionic acids by a catalytic asymmetric hydroboration-homologation sequence

Article abstract of DOI:10.1039/a809435g

A new catalytic asymmetric one-carbon homologation strategy has been developed which employs a rhodium catalyzed asymmetric hydroboration followed by homologation with LiCHCl₂ and oxidation to generate 2-arylpropionic acids of high enantiomeric purity.

Full text of DOI:10.1039/a809435g

Catalytic asymmetric carbon–carbon bond forming reactions: preparation of
optically enriched 2-aryl propionic acids by a catalytic asymmetric
hydroboration–homologation sequence†
Austin C. Chen, Li Ren and Cathleen M. Crudden*
Department of Chemistry, University of New Brunswick, Fredericton, New Brunswick, PO Box 45222, Canada
E3B 6E2
Received (in Corvallis, OR, USA) 2nd December 1998, Accepted 16th February 1999
A new catalytic asymmetric one-carbon homologation strat-
B(OR)2
CO2H
CH3
H–B(OR)2
Metal Cat.
egy has been developed which employs a rhodium catalyzed
asymmetric hydroboration followed by homologation with
LiCHCl2 and oxidation to generate 2-arylpropionic acids of
high enantiomeric purity.
"C-1" source
(1)
Ar
Ar
CH3
Ar
Several potential ‘C-1’ sources can be employed for the
stereospecific C–C bond forming reaction. We first examined
lithiated methylthiophenyl methyl ether,7 but found the reaction
to be low yielding with substrate 1 [eqn. (2)]. Transesterifica-
Asymmetric carbon–carbon bond forming reactions are among
the most important transformations in organic synthesis.1
Catalytic methods are the most efficient means to affect these
reactions, since the source of chirality is also used in catalytic
quantities. The asymmetric synthesis of 2-aryl substituted
carboxylic acids is of particular importance since non-steroidal
anti-inflammatory agents such as Ibuprofen™ and Naproxen™
are among this class of compounds. Furthermore, the positive
medicinal effects of these pharmaceuticals are ascribed to only
one of the enantiomeric forms.2 State-of-the-art catalytic
asymmetric C–C bond forming methods for the synthesis of
2-aryl substituted propionic acids include hydrocarbonylation
techniques employing carbon monoxide.3 The key step in these
methods is the enantioselective addition of a transition metal
hydride across an olefin, which is followed by C–C bond
formation (carbonylation). It occurred to us that an alternative
strategy would be to employ a catalytic asymmetric reaction to
install the required stereocentre followed by a second, stereo-
specific C–C bond forming reaction (Scheme 1). This basic
principle has been realized in our labs leading to a highly
enantioselective synthesis of 2-arylpropionic acids with the aid
of catalytic asymmetric hydroboration.4
The catalytic asymmetric hydroboration reaction occurs with
essentially complete regiochemical control and extremely high
enantiocontrol in the hydroboration of vinylarenes to give the
corresponding chiral 2-aryl boronate esters.4 Despite the
success of this transformation, it has thus far been relegated to
a method for the preparation of enantiomerically enriched aryl
methyl alcohols,4 and more recently extended to include the
preparation of amines.5
Although the application of chiral borane species prepared
using stoichiometric amounts of chiral materials in C–C bond
forming reactions has been reported in the elegant work of
Matteson6 and Brown,7 no such use of the catalytically
synthesized catecholate 1 has been described. We report herein
a new asymmetric hydroboration–homologation method in
which vinyl arenes are converted into 2-arylpropionic acids
using only catalytic quantities of chiral material [eqn. (1)].
O
H
(1) PhSCH2OMe / BusLi
B(OR)2
CH3
C
(2)
(2) HgCl2
(3) H2O2, pH 8
Ar
Ar
CH3
2
1 (OR)2 = catechol
3 (OR)2 = pinacol
pinacol
99% yield
25–75% yield
(as hydrazone)
(1) LiCHCl2, ZnCl2
(2) NaBO3
(3)
3
2
(3) reduction or oxidation
76% yield (alcohol)
70% yield (acid)
tion of catechol boronate 1 to the corresponding pinacol
boronate 3 prior to homologation gave 2 in higher yields, up to
75% isolated (as the hydrazone), but the highly capricious
procedure requiring large quantities of HgCl2 prompted us to
consider alternative homologating reagents. Matteson has
described the use of LiCHCl2 in his homologation–Grignard
addition strategy carried out on boronate esters prepared with
stoichiometric amounts of chiral borane reagents.6 Indeed
LiCHCl2 could be reliably prepared using Matteson’s detailed
procedure6 and reacted with boronate ester 3 to yield, after
oxidative workup, the homologation product 2 in good yield:
79% isolated as the alcohol after BH3·SMe2 reduction, or 70%
as the carboxylic acid after Lindgren oxidation [eqn. (3)].
Having established a reliable homologation method, we then
carried out the sequence under asymmetric conditions. Reaction
of styrene with catechol borane in the presence of catalytic
–
amounts of [Rh(COD)2]+BF4 and (S)-BINAP4 generated the
boronate ester 1 asymmetrically. Conversion of boronate ester 1
to pinacolate 3 allowed us to isolate and purify this species by
column chromatography. The enantioselectivity of the process
was high (91% ee).‡ The purified material was then homo-
logated with LiCHCl2. Oxidation of the intermediate chlorobor-
onate using Kabalka’s procedure8 yielded aldehyde 2, which
was further oxidized to the carboxylic acid under Pinnick-
modified Lindgren conditions.9 Analysis of this material by
optical rotation and chiral GC§ showed that the homologation–
oxidation had proceeded with some loss of enantiomeric purity,
yielding the desired product in only 77% ee. This decrease in ee
was determined by independent experiments to be occurring via
the aldehyde. Thus direct oxidation of the intermediate
chloroboronate to the acid under Lindgren conditions10 was
affected and yielded the desired product in a slightly reduced
yield, but with complete retention of enantioselectivity [eqns.
(4) and (5)].¶
"C"
ML*n
+
+ "C"
ML*n
H–X
Ar
catalytic
Ar
CH3
"C"
X
"C"
stereospecific
+
H–X
Ar
catalytic
Ar
CH3
Ar
CH3
Scheme 1
† Presented in part: 80th Canadian Society for Chemistry conference,
Whistler, B.C., June, 1998.
Chem. Commun., 1999, 611–612
611

0.088 mmol) were mixed. Dried, deoxygenated DME was added (4 ml) and
the suspension stirred for 30 min. Styrene, previously distilled, was filtered
through a plug of alumina and added to the mixture (0.46 ml, 4.0 mmol),
which was then cooled to 266 °C. Catechol borane (0.5 ml, 4.7 mmol,
distilled) was added as a solution in 2 ml DME dropwise over 45 min.
During the addition, the internal temp did not exceed 266 °C. The solution
was kept between 267 and 266 °C for 4 h. Pinacol (recrystallised and
dried, 1.0121 g, 8.56 mmol) was added and the solution warmed slowly to
room temperature overnight. Flash chromatography (silica gel, 24:1
hexane–EtOAc) yielded 761.4 mg (82%) of 3. Enantioselectivity was
determined to be 91% ee by oxidizing a small portion of this material under
the conditions described in ref. 4, and analyzing the resulting material by
chiral GC.
Homologation: this was carried out using LiCHCl2 (1.25 mmol)
generated by the slow addition of BunLi (0.8 ml of a 1.57 m solution in
hexane, 1.25 mmol) to a mixture of THF (6.5 ml) and CH2Cl2 (0.67 ml, 10
mmol) at 2100 °C in a 95% EtOH–liq. N2 bath. The clear colourless
solution was stirred at 2100 °C for 10 min before the rapid addition of
boronate ester 3 (246 mg, 1.06 mmol) as a solution in 2 ml THF. ZnCl2 (1.1
ml of a 1.0 m solution in Et2O, 1.1 mmol) was then added. The reaction was
left to warm to room temperature overnight. After this time, the volatiles
were removed under a vigorous flow of N2. The residue was quenched with
5 ml of sat. aq. NH4Cl, extracted with light petroleum (4 3 20 ml), dried
over MgSO4, filtered and concentrated in vacuo. NMR analysis of the
material thus obtained (283 mg, 95% crude yield) indicated no starting
material remained, and only the chloroboronate product was present. This
material was then oxidized to the acid directly following the procedure in
ref. 9, (48 h reaction time were necessary). Purification of acid 4 was
affected by an acid–base extraction, followed by methylation with CH2N2
and flash chromatography (7:1 hexane–EtOAc) giving the methyl ester of
4 in 52% yield (91% ee).
B(OR)2
(1) catechol borane / Rh+, (S)-BINAP (2%)
(2) pinacol
84% yield
Ph
(4)
91% ee
Ph
CH3
3
CO2H
CH3
(1) LiCHCl2, ZnCl2
(2) NaClO2 oxidation
52% yield
91% ee
3
(5)
Ph
4
(as Me ester)
The slow addition of catechol borane as a solution in DME
and maintenance of a low internal temperature were found to be
crucial for achieving good enantioselectivities in our hands. (R)-
BINAP gave slightly better enantioselectivities in the hydro-
boration, yielding 3 (ent.) in 95% ee (95% yield), which
translated into 95% ee (45% yield) in the homologated
carboxylic acid 4 (ent.).
The homologation method described herein is, to the best of
our knowledge, the first use of chiral boronate esters prepared
by catalytic hydroboration in a carbon–carbon bond forming
reaction. With our method, the high regioselectivity observed in
the catalytic asymmetric hydroboration is transferred to the
subsequent C–C bond forming process, and the enantioselectiv-
ity is completely retained, offering a useful alternative to
catalytic asymmetric hydrocarbonylation strategies. We are
currently examining the application of this carbon monoxide-
free hydrocarboxylation to more complex systems, and will
report these results in due course.
The Natural Sciences and Engineering Research Council of
Canada (NSERC) is gratefully acknowledged for support of this
research in terms of research grants to C. M. C. and a PGS-A
scholarship to A. C. C. We thank Professors David Magee,
Steven Westcott and Donald Matteson for helpful discus-
sions.
1 I. Ojima, Catalytic Asymmetric Synthesis, VCH, New York, 1993.
2 J. P. Rieu, A. Boucherle, H. Cousse and G. Mouzin, Tetrahedron, 1986,
42, 4095.
3 H. Alper and N. Hamel, J. Am. Chem. Soc., 1990, 112, 2803; N. Sakai,
S. Mano, K. Nozaki and H. Takaya, J. Am. Chem. Soc., 1993, 115,
7033.
4 T. Hayashi, Y. Matsumoto and Y. Ito, J. Am. Chem. Soc., 1989, 111,
3426; J. M. Brown, D. E. Hulmes and T. P. Layzell, J. Chem. Soc.,
Chem. Commun., 1993, 1673.
5 E. Fernandez, M. W. Hooper, F. I. Knight and J. M. Brown, Chem.
Commun., 1997, 173.
6 D. S. Matteson, K. M. Sadhu and M. L. Peterson, J. Am. Chem. Soc.,
1986, 108, 810.
7 H. C. Brown, I. Imai, M. C. Desai and B. Singaram, J. Am. Chem. Soc.,
1985, 107, 4980.
Notes and references
‡ Determined by oxidizing a small portion of the boronate ester, and
subjecting the resulting alcohol to chiral gas chromatography: Column =
2,3-di-O-acetyl-6-O-tert-butyldimethylsilyl-b-cyclodextrin,
(Suppelco,
BETA DEX-225) 30 m, 0.25 mm diameter, 0.25 mm thickness, He carrier,
12.5 psi head pressure, 1.15 ml min21 flow, FID detection. Retention time
(tR) = 44.6 (R) and 46.0 min (S) @ 70 °C for 5 min, then increase 1 °C per
min to 150 °C for 30 min.
§ Column and conditions as above, 4: (converted to Me ester by treatment
with CH2N2) 154.1 (S) and 155.0 (R) min @ 50 °C for 100 min, then ramp
at 1 °C per min to 160 °C.
¶ We thank a reviewer for pointing out this oxidation technique. The
following procedure (styrene) is representative.
8 G. W. Kabalka, T. M. Shoup and N. M. Goudgaon, J. Org. Chem., 1989,
54, 5930.
9 B. S. Bal, W. E. Childers and H. W. Pinnick, Tetrahedron, 1981, 37,
2091.
10 D. S. Matteson and E. C. Beedle, Tetrahedron Lett., 1987, 28, 4499.
Hydroboration: In
a
flame dried round-bottomed flask,
[Rh(COD)2]+BF4 (32.4 mg, 0.078 mmol) and (S)-(2)-BINAP (54.8 mg,
Communication 8/09435G
–
612
Chem. Commun., 1999, 611–612