Oxazaborolidines as functional monomers: Ketone reduction using polymer-supported Corey, Bakshi, and Shibata catalysts

Article abstract of DOI:10.1021/jo026132n

The first two polymer-supported versions of the Corey, Bakshi, and Shibata (CBS) catalyst have been prepared. Functional monomers based structurally upon the original B-methylated catalyst have been used to prepare catalytic polymers containing the CBS moiety bound both in a pendant fashion and in the form of a cross-link. Enantioselective reductions of two prochiral ketones have been carried out using the original catalyst in the solution phase as well as the two solid-state systems. While the pendant-bound system shows reduced stereoselectivity, the cross-linked version affords enantioselectivities almost identical to those of the solution-phase model.

Full text of DOI:10.1021/jo026132n

Oxa za bor olid in es a s F u n ction a l Mon om er s: Keton e Red u ction
Usin g P olym er -Su p p or ted Cor ey, Ba k sh i, a n d Sh iba ta Ca ta lysts
Michael D. Price, J ennifer K. Sui, Mark J . Kurth, and Neil E. Schore*
Department of Chemistry, University of California, One Shields Avenue, Davis, California 95616
neschore@ucdavis.edu
Received J uly 2, 2002
The first two polymer-supported versions of the Corey, Bakshi, and Shibata (CBS) catalyst have
been prepared. Functional monomers based structurally upon the original B-methylated catalyst
have been used to prepare catalytic polymers containing the CBS moiety bound both in a pendant
fashion and in the form of a cross-link. Enantioselective reductions of two prochiral ketones have
been carried out using the original catalyst in the solution phase as well as the two solid-state
systems. While the pendant-bound system shows reduced stereoselectivity, the cross-linked version
affords enantioselectivities almost identical to those of the solution-phase model.
In tr od u ction
study comparing the two environments4 and were inter-
ested to see how this would play out in the enantiose-
lectivity of ketone reduction.
The system devised by Corey, Bakshi, and Shibata,
known as the CBS catalyst (1), represented a major
breakthrough in catalytic enantioselective chemistry.1
Used in conjunction with BH3‚THF, it permits the
reduction of prochiral ketones to the corresponding
alcohols very rapidly, in high chemical yield, and with
excellent enantioselectivity (eq 1).2,3
Resu lts a n d Discu ssion
Ca ta lyst Syn th esis. We built upon both Corey’s
procedures and the sequence described by Kanth and
Periasamy2 to synthesize 2 and applied parallel meth-
odology as much as possible in the preparation of 3 and
4. We converted N-(t-BOC)-L-proline (5) into its methyl
ester (6), followed by addition of excess phenylmagnesium
bromide. Conventional procedures for liberation of less
hindered carbamate-protected amines gave ring closure
to the bicyclic oxazolidinone 9. We found instead that
hydrolysis with KOH in methanolic DMSO gave 8a in
50% overall yield for the three steps on a large scale. Once
this route was established, it was repeated using (p-
vinylphenyl)magnesium bromide, providing 8b, the mono-
mer precursor to the cross-link-bound polymeric catalyst
4, in similar overall yield (Scheme 1). Premature polym-
erization of 8b was observed (TLC) during the workup
after deprotection. This appeared to be the result of
concentration of the product in the presence of adventi-
tious initiators. To circumvent this problem, we devised
the simple solution of diluting the reaction mixture while
still hot with several volumes of water, which caused
precipitation of 8b upon cooling.
The B-methylated version of this catalyst, 2, adds the
practical advantages of air and moisture insensitivity.
As part of our ongoing program to critically compare the
reactivity of systems of synthetic significance in a variety
of physical environments, we decided to prepare two
polymer-supported versions, 3 and 4, of the CBS catalyst.
To access the single-site polymer-bound catalyst 3, we
made use of Weinreb amide 10, obtained from reaction
of 5 with N,O-dimethylhydroxylamine hydrochloride.
Subsequent addition of p-isopropylphenyl Grignard and
hydrolysis furnished ketone 11, which upon addition of
p-styryl Grignard yielded alcohol 12 (Scheme 2). Choice
of R ) p-isopropylphenyl as the nonpolymerizable group
in this system was based on its steric and electronic
similarity to the polystyrene moiety. Monomer 12 and,
ultimately, polymer 3 are of course mixtures of diaster-
Polymer-supported species 3 and 4 also offer the
opportunity to compare and contrast pendant vs cross-
link bonding as the site of polymer-supported functional-
ity. We noted stereoselectivity differences in a previous
(1) For reviews see Corey, E. J .; Helal, C. J . Angew. Chem., Int. Ed.
1998, 37, 1986-2012 and Srebnik, M.; Deloux, L. Chem. Rev. 1993,
93, 763-784. A portion of this work has been the subject of a
presentation: Sui, J . K.; Price, M. D.; Kurth, M. J .; Schore, N. E. Abstr.
Pap.sAm. Chem. Soc. 2001, 221st, CHED-249.
(2) Periasamy, M.; Kanth, J. V. B. Tetrahedron 1993, 49, 5127-5132.
(3) Corey, E. J .; Bakshi, R. K.; Shibata, S. J . Am. Chem. Soc. 1987,
109, 5551-5553.
(4) Price, M. D.; Kurth, M. J .; Schore, N. E. J . Org. Chem., in press.
10.1021/jo026132n CCC: $22.00 © 2002 American Chemical Society
Published on Web 10/24/2002
8086
J . Org. Chem. 2002, 67, 8086-8089

Polymer-Supported CBS Catalysts
SCHEME 1. Syn th esis of Au xilia r y P r ecu r sor s 8a
a n d 8b
SCHEME 4. P r ep a r a tion of DVB-Cr oss-Lin k ed
P en d a n t-F u n ction a lized P olym er 15
TABLE 1. Red u ction of Keton es by Solu tion -P h a se a n d
P olym er -Su p p or ted CBS Ca ta lysts
yielda
(%)
SCHEME 2. Syn th esis of 12
catalyst
substrate
R:S ratiob
ee
2
3
4
2
3
4
acetophenone
acetophenone
acetophenone
pinacolone
100
100
100
100
100
100
92.9:7.1
81.4:18.6
92.4:7.6
94.4:5.6
86.1:13.9
94.2:5.8
85.8
62.8
84.8
88.8
72.2
88.4
pinacolone
pinacolone
a
b
No ketone detected by GC. Determined by GC using a chiral
capillary column.
P r ep a r a tion of Oxa za bor olid in e Ca ta lysts. Fol-
lowing literature procedures,5 addition of trimethylborox-
ine to a solution of 8a in toluene resulted in the formation
of 2. The only purification of 2 we carried out was
submission of the crude material to two azeotropic
toluene distillations. It is well-established that even
slight amounts of moisture or other impurities can have
significant deleterious effects on the enantioselectivity
of reactions catalyzed by oxazaborolidines. Nevertheless,
for the purposes of this study we felt that it was
important to preserve comparability between the behav-
ior of 2 and its polymer-supported analogues, for which
little else in the way of purification is practical. In the
event, the performance of 2 isolated in this way was
somewhat poorer than that described in the literature,
but more than acceptable for our purposes (vide infra).
Indeed, when making comparisons between solution-
phase and polymer-supported conditions, it is generally
preferable for the former to give less than optimal results,
so that deviations in either direction may be quantified
on the polymer.
Treatment of polymeric amino alcohols 14 and 15 with
trimethylboroxine under conditions similar to those used
for the preparation of 2 resulted in the formation of
polymer-supported oxazaborolidines 4 and 3, respectively.
Ca ta lyzed Red u ction s. We chose reductions of ac-
etophenone and 3,3-dimethyl-2-butanone (pinacolone) to
comparatively evaluate our catalysts. The solution-phase
experiments and the solid-phase experiments were al-
lowed to proceed for 30 min and 24 h, respectively. The
latter was done to ensure complete consumption of
starting materials, which could be compromised by slow
diffusion of compounds into the beads. In each case BH3‚
THF was initially added to a THF suspension of the
catalyst, followed immediately by the ketone. Table 1
gives our results.
SCHEME 3. P r ep a r a tion of
Cr oss-Lin k -F u n ction a lized P olym er 14
eomers; our hope was to locally minimize any effect of
the additional side-chain stereocenter by making the two
substituents at this position as indistinguishable from
one another as possible.
P olym er Syn th esis. Suspension copolymerization of
8b with styrene yielded resin 14 in rather low (29%)
yield. As an alternative we submitted the Boc-protected
monomer 7b to the same procedure, followed by N-
deprotection (Scheme 3). The latter procedure proved to
be superior, affording beads of 14 which contained ca.
0.40 mequiv of diarylprolinol functional units/g of poly-
mer by elemental analysis, corresponding to incorpora-
tion of approximately 4.5% of the distyrylprolinol cross-
linker. That insoluble beads were formed is de facto
evidence that the prolinol-derived moieties were indeed
incorporated as cross-linkers.
Because monomer 12 is incapable of cross-linking, its
suspension polymerization was carried out in the pres-
ence of styrene plus 2% divinylbenzene. Given our
experiences with the preparation of polymer 14, polym-
erization of only the Boc-protected 12 was attempted;
deprotection was carried out postpolymerization to fur-
nish 15, containing ca. 0.32 mequiv of diarylprolinol
functional units/g of polymer by elemental analysis
(Scheme 4).
(5) Mathre, D. J .; J ones, T. K.; Xavier, L. C.; Blacklock, T. J .;
Reamer, R. A.; Mohan, J . J .; J ones, T. T.; Hoogsteen, K.; Baum, M.
W.; Grabowski, E. J . J . J . Org. Chem. 1991, 56, 751-762.
J . Org. Chem, Vol. 67, No. 23, 2002 8087

Price et al.
KOH (0.283 mol) in 128 mL of MeOH was heated to reflux
for 6 h. After addition of 128 mL of water, the product
precipitated out within 1 h. It was filtered, washed with cold
hexane, and recrystallized from Et2O and hexane to afford 6.80
g (86%) of 9 as a white solid: mp 148-150 °C. IR 3059, 2972,
No attempt was made to optimize reaction enantiose-
lectivities. Several groups have explored polymer-sup-
ported ketone reduction using amino alcohol-borane
catalysts.6-9 In general, enantioselectivities using solu-
tion-phase catalysts are better than those obtained using
(pendant) polymer-supported analogues. In a number of
cases, the solid-state results vary considerably from those
found in solution, but optimization has brought about
comparable results. Slow diffusion of the reagents into
the catalyst-bearing beads is typically cited as permitting
nonselective uncatalyzed reduction to compete, thus
reducing overall enantioselectivity. Our results indicate
that cross-linked catalyst 4 is superior to pendant system
3 and quite close to the solution model 2. Tellingly, the
lightly cross-linked beads of catalyst 4 swelled consider-
ably more in THF than did those of divinylbenzene-cross-
linked resin 3. Comparisons between N-benzylprolinol
and two (pendant) polymer-supported analogues with
different spacers showed that increasing the spacer
length improved enantioselectivity.7 These results are
consistent with improved accessibility of the auxiliary
toward solution-phase species being an important factor
for high enantioselectivity in these systems. Whether
other issues, such as differences between 3 and 4 in local
structural symmetry or in effective kinetic site isolation
(that would inhibit catalyst-catalyst interaction), con-
tribute in any significant way must await the results of
our continuing, more extensive studies of these systems.
1
1756, 1449 cm-1; H NMR δ 7.6 (m, 10H), 4.5 (dd, J ) 10.4,
5.5 Hz, 1H), 3.8-3.6 (m, 1H), 3.4-3.2 (m, 1H), 2.2-1.9 (m,
2H), 1.9-1.8 (m, 1H), 1.2-1.0 (m, 1H); 13C NMR δ 160.7, 143.1,
140.1, 128.5, 128.21, 128.18, 127.6, 125.8, 125.4, 85.8, 69.2,
46.1, 29.1, 25.0; [R]23
) -242.1 (c ) 0.025, MeOH). Lit.11
589
[R]589 -241.6 (c ) 0.002, MeOH).
P olym er -Su p p or t ed Boc-P r ot ect ed Cr oss-Lin k in g
Am in o Alcoh ol 13. Into a 500 mL two-necked indented flask
with a 45/50 joint equipped with a propeller-shaped mechan-
ical stirrer were added 184.9 mL of water and 12.9 g of Gum
Arabic, and a stir rate of 475 rpm was maintained. A mixture
of 9.44 g (90.59 mmol) of styrene, 0.107 g (0.442 mmol) of
benzoyl peroxide, 13.4 mL of chlorobenzene, and 0.75 g (1.85
mmol) of monomer 7b was prepared and added to the stirred
aqueous mixture. The reaction vessel was heated to 85 °C
while the 475 rpm stir rate was maintained. After 2 h the stir
rate was lowered to 215 rpm, and 0.178 g of Al2O3 (1.75 mmol)
was added to inhibit droplet coalescence. The temperature and
stir rate were maintained at 85 °C and 215 rpm, respectively,
for an additional 24 h. The newly formed resin was collected
by filtration and washed in turn with water, THF, CH2Cl2,
MeOH, CH2Cl2, MeOH, CH2Cl2, and MeOH. The beads were
dried under vacuum overnight to yield 7.03 g (69% yield) of
resin 13.
P olym er -Su p p or ted Cr oss-Lin k in g Am in o Alcoh ol 14.
A mixture of 5.00 g of resin 13, 1.07 g of KOH (19.0 mmol), 28
mL of DMSO, and 6.3 mL of MeOH was heated to 65 °C for 4
d. The resin was filtered and washed with water, THF, CH2-
Cl2, MeOH, CH2Cl2, MeOH, CH2Cl2, and MeOH. The beads
were dried under vacuum overnight to yield 4.52 g of resin
14: IR 3312 cm-1 (br), no absorption in the vicinity of 1670
cm-1. Elemental analysis (calcd, N, 0.56; found, N, 0.56)
indicated the presence of 0.40 mequiv of auxiliary/g of resin,
and a cross-link density of 4.53 mol %.
Con clu sion s
We have prepared and critically examined the perfor-
mance of what we believe are the first two polymer-
supported CBS catalysts. The readily accessible cross-
link-based resin 4 is clearly superior to pendant-linked
3 and is comparable to the conventional solution-phase
catalyst 2 in its ability to direct stereoselective ketone
reduction. While several factors may contribute to these
differences, the superior swelling characteristics of 4
relative to 3 are an obvious point in its favor. We plan to
expand on this work by preparing systems similar to 3
and 4 with different degrees of cross-linking and, if
feasible, defined stereochemistry at the side-chain ste-
reocenter in analogues of 12. Results of these experi-
ments will be reported in due course.
P olym er -Su p p or ted Cr oss-Lin k in g Am in o Alcoh ol 14
(Dir ect P r ep a r a tion fr om 8b). In the manner described for
the polymerization of monomer 7b, 0.56 g of monomer 8b was
copolymerized with styrene to afford 2.9 g (29% yield) of resin
14.
2-(Hyd r oxy[4-vin ylp h en yl][4-{1-m eth yleth yl}p h en yl]-
m eth yl)p yr r olid in e-1- ca r boxylic Acid ter t-Bu tyl Ester
(12). Freshly cut Mg ribbon (1.46 g, 60.3 mmol) was placed
under vacuum, flame dried, and stirred under vacuum for 24
h. A solution of 10.0 g of 4-isopropyl-1-bromobenzene (50.2
mmol) in 90 mL was added, the mixture was refluxed for 30
min, and 1.52 g of 1,2-dibromoethane (8.09 mmol) was added,
followed by 30 min of additional refluxing. The Grignard
solution was cooled to 0 °C, and a solution of 11.3 g of N-(t-
BOC)-L-proline N′-methoxy-N′-methylamide (10)12 (43.7 mmol)
in 20 mL of THF was added. The solution was slowly warmed
to rt and then heated at 45 °C for 24 h. The solution was cooled
to -78 °C, and 10 mL of water was slowly added. After the
mixture was allowed to warm to rt, the solution was decanted
and the precipitated salts were washed with Et2O. The
combined solution was washed with brine, dried (MgSO4), and
evaporated under reduced pressure. The crude ketone product
11 was not characterized but added directly at 0 °C to a
solution of 4-vinylphenylmagnesium bromide, which had been
Exp er im en ta l Section
Gen er a l Meth od s. All reactions were performed in oven-
dried glassware under an atmosphere of dry nitrogen or argon.
NMR spectra were recorded at 300 MHz in CDCl3. FTIR
spectra of liquids were recorded neat and those of solids either
as KBr pellets or using ATR. Optical purities were determined
by capillary GC using a 25 m Chirasil column (â-cyclodextrin
on OV-1701). (S)-Oxazaborolidine 2 was prepared from 8a and
trimethylboroxine according to the method of Mathre et al.5
Detailed preparations of 6,10 7a ,3,5 7b, 8a ,5 and 8b are
described elsewhere.4
(5S )-1-Aza -3-oxa -4,4-d ip h e n ylb icyclo[3.3.0]oct a n -2-
on e (9).11 A solution of 10.0 g of 7a (0.028 mol) and 15.9 g of
(10) Yuste, F.; Ortiz, B.; Carrasco, A.; Peralta, M.; Quintero, L.;
Sa´nchez-Obrego´n, R.; Walls, F.; Garc´ıa Ruano, J . L. Tetrahedron:
Asymmetry 2000, 11, 3079-3090.
(11) Delaunay, D.; Le Corre, M. J . Chem. Soc., Perkin Trans. 1 1994,
3041-3042.
(6) Caze, C.; Moualij, N. E.; Hodge, P.; Lock, C. J .; Ma, J . J . Chem.
Soc., Perkin Trans. 1 1995, 346-349.
(7) Itsuno, S.; Ito, K. J .; Hirao, A.; Nakahama, S. J . Chem. Soc.,
Perkin Trans. 1 1984, 2887-2893.
(8) Itsuno, S.; Ito, K.; Maruyama, T.; Kanda, N.; Hirao, A.; Naka-
hama, S. Bull. Chem. Soc. J pn. 1986, 59, 3329-3331.
(9) Itsuno, S.; Nakano, M.; Ito, K.; Hirao, A.; Owa, M.; Kanda, N.;
Nakahama, S. J . Chem. Soc., Perkin Trans. 1 1985, 2615-2619.
(12) (a) Sibi, M. P.; Stessman, C. C.; Schultz, J . A.; Christensen, J .
W.; Lu, J .; Marvin, M. Synth. Commun. 1995, 25, 1255-1264. (b) De
Luca, L.; Giacomelli, G.; Taddei, M. J . Org. Chem. 2001, 66, 2534-
2537.
8088 J . Org. Chem., Vol. 67, No. 23, 2002

Polymer-Supported CBS Catalysts
prepared as described above from 13.6 g of 4-bromostyrene
(74.3 mmol) and 2.17 g of Mg (89.1 mmol) in 250 mL of THF.
The solution was allowed to stir for 4 h and then cooled to
-78 °C. Workup as above (except for drying over anhydrous
K2CO3) gave the crude product, which was subjected to flash
chromatography (silica, EtOAc-hexane) to yield 8.98 g of 12
(49% overall yield): mp 83-84 °C; IR 3317(br), 1662, 1169
cm-1; 1H NMR δ 7.4 (m, 4H), 7.3 (d, J ) 8.2 Hz, 2H) 7.1 (d, J
) 8.2 Hz, 2H), 6.7 (dd, J ) 17.7, 10.9 Hz, 1H), 5.7 (dd, J )
17.6, 0.8 Hz, 1H), 5.2 (dd, J ) 10.9 Hz, 1.0 Hz, 1H), 4.9 (dd, J
) 8.9, 3.7 Hz, 1H), 3.4-3.2 (m, 1H), 3.0-2.8 (m, 2H), 2.2-2.0
(m, 1H), 2.0-1.8 (m, 1H), 1.5-1.3 (m, 10H), 1.2 (d, J ) 6.9
Hz, 6H), 0.8 (s, 1H); 13C NMR δ 147.7, 146.3, 140.9, 136.6,
136.3, 128.0, 127.9, 125.7, 125.4, 113.8, 81.5, 80.6, 65.8, 48.1,
Rep r esen ta tive P r oced u r e for Red u ction s Usin g Solu -
tion -P h a se Ca ta lyst 2. 1-P h en yleth a n ol fr om Acetop h e-
n on e Usin g Ca ta lyst 2. To 20 mL of a 0.074 M solution of 2
in THF at 0 °C was added 1.77 mL of 1 M BH3‚THF. This was
followed quickly by the addition of 0.35 g of acetophenone (2.94
mmol) in 0.5 mL of THF. The solution was stirred for 30 min
at rt, treated with 5 mL of 0.5 M HCl, and stirred for an
additional 10 min. The solution was extracted twice with Et2O.
The extracts were washed with brine, dried (Na2SO4), and
concentrated. A GC of the crude product was compared to those
of acetophenone and a racemic sample of 1-phenylethanol.
These data indicated an ee of 85.8% and a yield of 100%.
Repr esen tative P r ocedu r e for Redu ction s Usin g Solid-
Sta te Ca ta lysts 3 a n d 4. 1-P h en yleth a n ol fr om Ac-
etop h en on e Usin g Ca ta lyst 4. To a suspension of 1.84 g of
catalyst 4 (0.40 meq/gram) in 15 mL of THF at 0 °C was added
0.88 mL of 1M BH3‚THF, followed quickly by 0.18 g of
acetophenone (1.46 mmol). The flask was shaken for 24 h, the
mixture filtered, and the resin washed with THF, MeOH, THF,
MeOH, and THF. The combined filtrates were evaporated
under reduced pressure, treated with 5.0 mL of 0.5 M HCl,
and partitioned with Et2O. The organic extracts were dried
(Na2SO4) and concentrated. GC analysis indicated an ee of
84.8% and a 100% yield.
33.9, 30.0, 28.6, 24.3, 23.1; [R]23 -130.6 (c ) 0.027, MeOH).
589
Anal. Calcd for C27H35NO3: C, 76.92; H, 8.37. Found: C, 76.65;
H, 8.35.
P olym er -Su p p or ted P en d a n t Am in o Alcoh ol 15. In the
manner described for the polymerization of monomer 7b, 8.77
g (84.2 mmol) of styrene, 0.43 g of 55% p-divinylbenzene, and
0.80 g (1.90 mmol) of monomer 12 were copolymerized in the
presence of 180 mL of water, 12.5 g of Gum Arabic, 0.103 g
(0.426 mmol) of benzoyl peroxide, and 13 mL of chlorobenzene.
Similar workup gave 7.32 g (73.2% yield) of resin, 5.00 g of
which was deprotected directly as follows. A mixture of the
resin, 1.07 g of KOH (19.0 mmol), 28 mL of DMSO, and 6.3
mL of MeOH was heated to 65 °C for 4 d. Workup as described
above and drying gave 4.59 g of resin 15: IR 3313 cm-1 (br),
no absorption in the vicinity of 1670 cm-1. Elemental analysis
(calcd, N, 0.45; found, N, 0.39, 0.52) indicated the presence of
ca. 0.32 ((0.04) mequiv of auxiliary/g of resin.
P olym er -Su p p or ted Oxa za bor olid in e Ca ta lyst 3. A
solution of 0.074 g of trimethylboroxine (0.59 mmol) in 25 mL
of THF was added to 2.74 g of 15 (ca. 0.32 mequiv/g). The
mixture was gently agitated on an orbital shaker for 48 h,
followed by addition of 56 mL of toluene and slow short-path
distillation to remove most of the toluene. The toluene “flush-
ing” was repeated twice to ensure removal of water and
methylboronic acid, and finally the beads of 3 were dried under
vacuum.
Ack n ow led gm en t. We thank the National Science
Foundation (Grant CHE-0078191) for research support.
Funding sources for the NMR instrumentation at the
University of California, Davis (UC Davis), include the
NSF CRIF program (Grant CHE-9808183), the UC
Davis Office of Research, and Office of the Dean,
Division of Mathematics and Physical Sciences.
Note a d d ed in p r oof: In a paper that appeared
subsequent to the acceptance of this manuscript, Hodge,
et. al., report a comparison of solution-phase, pendant,
and cross-link polymer-bound diarylprolinol derivatives
in the enantioselective addition of dialkylzinc reagents
to aldehydes: Kell, R. J .; Hodge, P.: Nisar, M.; Watson,
D. Bioorg. Med. Chem. Lett. 2002, 12, 1803-1807.
P olym er -Su p p or ted Cr oss-Lin k -Bou n d Oxa za bor oli-
d in e Ca t a lyst 4. A solution of 0.10 g of trimethylboroxine
(0.80 mmol) in 25 mL of THF was added to 3.00 g of 14 (0.40
mequiv/g). Treatment as described for 3 above afforded beads
of 4.
J O026132N
J . Org. Chem, Vol. 67, No. 23, 2002 8089