The use of pH to influence regio- and chemoselectivity in the asymmetric aminohydroxylation of styrenes

Article abstract of DOI:10.1021/ol027242j

(Matrix presented) The pH-controlled Sharpless asymmetric aminohydroxylation (AA) of styrenes provides 1-aryl-2-amino ethanols (regioisomer E enantio-, chemo-, and regioselectivity. As existing AA protocols typically give regioisomer A as the major reaction product when usin nitrogen sources, this method is a convenient alternative for the selective production of regioisomer B.

Full text of DOI:10.1021/ol027242j

ORGANIC
LETTERS
2003
Vol. 5, No. 3
281-284
The Use of pH to Influence Regio- and
Chemoselectivity in the Asymmetric
Aminohydroxylation of Styrenes
Vitaliy Nesterenko, Joshua T. Byers, and Paul J. Hergenrother*
Department of Chemistry, Roger Adams Laboratory, UniVersity of Illinois,
Urbana, Illinois 61801
hergenro@uiuc.edu
Received November 6, 2002
ABSTRACT
The pH-controlled Sharpless asymmetric aminohydroxylation (AA) of styrenes provides 1-aryl-2-amino ethanols (regioisomer B) with high
enantio-, chemo-, and regioselectivity. As existing AA protocols typically give regioisomer A as the major reaction product when using carbamate
nitrogen sources, this method is a convenient alternative for the selective production of regioisomer B.
The asymmetric aminohydroxylation (AA) is a useful reac-
tion for producing the ubiquitous â-amino alcohol moiety.
As developed by Sharpless and co-workers, this reaction
typically utilizes osmium, a chiral ligand, and a nitrogen
source in the generation of 1,2-N-protected amino alcohols
from alkenes.1 With R,â-unsaturated ester substrates the
regioselectivity of the reaction can be controlled with
appropriate experimental conditions, and the enantioselec-
tivites are typically excellent.2 Styrene derivatives have also
been investigated as AA substrates; however, the regio-
chemical outcome of the AA with these substrates has been
much less predictable. The ratio of regioisomeric products
in the AA of styrenes is known to be influenced markedly
by solvent, nitrogen source, substrate, and ligand.3 In
particular, the 2-aryl-2-amino ethanol regioisomer (A in
Scheme 1) is typically the major product in such reactions.
Scheme 1
(1) (a) Li, G.; Sharpless, K. B. Angew. Chem., Int. Ed. Engl. 1996, 35,
451-454. (b) O’Brien, P. Angew. Chem., Int. Ed. 1999, 38, 326-329.
(2) (a) Tao, B.; Schlingloff, G.; Sharpless, K. B. Tetrahedron Lett. 1998,
39, 2507-2510. (b) Morgan, A. J.; Masse, C. E.; Panek, J. S. Org. Lett.
1999, 1, 1949-1952. (c) Han, H.; Cho, C.-W.; Janda, K. D. Chem. Eur. J.
1999, 5, 1565-1569.
(3) (a) Reddy, K. L.; Sharpless, K. B. J. Am. Chem. Soc. 1998, 120,
1207-1217. (b) O’Brien, P.; Osborne, S. A.; Parker, D. D. J. Chem. Soc.,
Perkin Trans. 1 1998, 2519-2526. (c) Goossen, L. J.; Liu, H.; Dress, K.
R.; Sharpless, K. B. Angew. Chem., Int. Ed. 1999, 38, 1080-1083. (d)
Demko, Z. P.; Bartsch, M.; Sharpless, K. B. Org. Lett. 2000, 2, 2221-
2223. (e) Reddy, K. L.; Dress, K. R.; Sharpless, K. B. Tetrahedron Lett.
1998, 39, 3667-3670.
Although there is a report on the production of useful levels
of the 1-aryl-2-amino ethanol regioisomer (B in Scheme 1)
in the amide derived AA,4 it has not been possible to obtain
this B regioisomer with high regio- and enantioselectivities
with easily deprotected carbamate nitrogen sources. In fact,
it has been noted by Sharpless and co-workers that with
carbamate nitrogen sources regioselectivity of the B isomer
(4) Bruncko, M.; Schlingloff, G.; Sharpless, K. B. Angew. Chem., Int.
Ed. 1997, 36, 1483-1486.
10.1021/ol027242j CCC: $25.00 © 2003 American Chemical Society
Published on Web 01/07/2003

is inversely correlated with enantiselectivity.3a We now report
a method utilizing pH control to override other variables in
the AA reaction of styrenes to selectively provide the B
regioisomer with good enantiomeric ratios (ers).5
The regioselectivity of the AA is known to be influenced
by the nature of the alkaloid ligand used. With this in mind,
the common (DHQ)2AQN, (DHQ)2PHAL, and (DHQ)2PYR
ligands were examined, as well as some less common
alkaloid ligands. These reactions were performed in phos-
phate buffer (pH 7.5-7.7) with p-acetoxystyrene as the
substrate. As summarized in Table 1, the B regioisomer was
We required a convenient method to generate a variety of
1-aryl-2-amino ethanol derivatives for our program in the
synthesis of compounds that influence apoptosis. Investiga-
tion of styrene derivatives as substrates for the AA revealed
that the pH was changing during the course of the reaction.
As it is known that the asymmetric dihydroxylation is facile
at pH >10,6 we conducted our AA studies in the presence
of a phosphate buffer, allowing for precise control of pH.
When the reaction was buffered between pH 7.5 and 8.5,
we found that the B regioisomer was preferentially formed
irrespective of the nature of the styrene substrate, the solvent,
or the ligand.
Table 1. Ligand Effect on the Regiomeric Composition in the
Buffered Aminohydroxylation of p-Acetoxystyrene
solvent/buffer ratio yield er of
entry
ligand
(DHQ)2AQN
(DHQ)2AQN
(DHQ)2AQN
(DHQ)2PHAL
(DHQ)2PHAL
(DHQ)2PYR
(1:1)
A:Ba of Bb Bc (S:R)
1
2
3
4
5
6
7
CH3CN
n-propanol 1:4
THF
CH3CN
1:10 82
87:13
75:25
58:42
85:15
79:21
70:30
26:74
12:88
45:55
45:55
50:50
50:50
47:53
41:59
50:50
11:89
57
53
52
42
38
44
71
56
53
30
45
43
42
60
1:4
1:5
The dependence of chemo- and regioselectivity on pH is
depicted graphically in Figure 1 for styrene. The reactions
n-propanol 1:2
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
1:3
1:1
1:4
1:5
1:5
1:3
1:3
1:3
1:2
1:5
(DHQD)2BcPHAL
8. (DHQD)2PHALPh2
DHQD-MEQ
9
10 DHQD-CLB
11 (DHQD)2PYR(iPr)
12 (DHQD)2PYR
13 (DHQD)2PYR(Naph)
14 (DHQD)2PYR(OMe)3
15 (DHQD)2PYR(Morph) CH3CN
16 (DHQD)2AQN CH3CN
1:10 78
a Determined from 1H NMR of the crude reaction mixture. b Isolated
yield after chromatography on silica gel. c Ratios determined by chiral SFC.
Stereochemistry assigned from optical rotation and comparison to known
compounds.
preferentially formed for almost all ligand/solvent combina-
tions. Even under (DHQ)2PHAL/n-PrOH conditions (Table
1, entry 5), a combination known to give a strong preference
for regioisomer A,3a,b,e the buffered AA gave B as the
predominant product. In general, the AQN-based ligands with
acetonitrile gave the best yield, regioselectivity, and enan-
tioselectivity in this buffered asymmetric aminohydroxylation
(Table 1, entries 1 and 16).
A range of p-acetoxystyrene substrate concentrations was
evaluated under the buffered AA conditions. Substrate
concentrations greater than 80 mM led to significant diol
formation, up to 30% at 160 mM. Similar effects of
concentration on chemoselectivity have been previously
observed in the AA.7
The effect of temperature on the reaction outcome was
determined to be minimal, as the regio-, chemo-, and
enantioselectivities were essentially the same over a range
of temperatures. However, the reaction proceeded much more
rapidly at higher temperatures. Indeed, at 40 °C the reaction
was complete in 5 to 7 min (Figure 2).
Figure 1. Reaction mixture composition for the aminohydroxy-
lation of styrene in the pH range from 5.5 to 11.3. The ratio of
products was determined by integration of the 1H NMR of the crude
reaction mixture.
were performed in a 2:1 mixture of acetonitrile/0.5 M
phosphate buffer with a variety of pH values. As illustrated
in Figure 1, pH values in the range of 7.5-8.5 are optimal
for obtaining high yields of the B regioisomer; formation of
the A regioisomer and of the diol side product are maximally
suppressed at this pH.
Substitution of the carboxybenzylcarbamate (Cbz) nitrogen
source with tert-butylcarbamate (Boc) or n-butylcarbamate
(5) For recent studies on the pH dependence of the asymmetric
dihyroxylation see: (a) Krief, A.; Castillo-Colaux, C. Synlett 2001, 501-
504. (b) Dupau, P.; Epple, R.; Thomas, A. A.; Fokin, V. V.; Sharpless, K.
B. AdV. Synth. Catal. 2002, 344, 421-434.
(6) Dobler, C.; Mehltretter, G.; Beller, M. Angew. Chem., Int. Ed. 1999,
38, 3026-3028.
(7) Wuts, P. G. M.; Anderson, A. M.; Goble, M. P.; Mancini, S. E.;
VanderRoest, R. J. Org. Lett. 2000, 2, 2667-2669.
282
Org. Lett., Vol. 5, No. 3, 2003

Table 2. Results of the pH-Controlled Aminohydroxylation
entry
R
ratio A:Ba
yield Bb
er of B (S:R)c
1
2
3
4
5
6
7
8
9
H
p-OAc
1:8
1:10
1:8
1:10
1:10
1:21
1:12
1:5.4
1:8
72
85
64
70
70
76
81
58
58
54
47
88:12
85:15
85:15
85:15
87:13
88:12
74:26
85:15
86:14
61:39
85:15
p-OCH3
p-OtBu
p-OTBDMS
p-OTs
p-COOH
p-NO2
m-OCH3
o-OCH3
m-NO2
Figure 2. Effect of reaction temperature on the rate of amino-
hydroxylation of p-acetoxystyrene.
10
11
1:9
1:3.5
a Determined from 1H NMR of the crude reaction mixture. b Isolated
yield after chromatography on silica gel. c Ratios determined by chiral SFC.
Stereochemistry assigned from optical rotation and comparison to known
compounds.
had little effect on regio-, chemo-, or enantioselectivity,
although the reaction was faster with n-butyl carbamate as
the nitrogen source.8 In addition it was found that the ligand
and catalyst loading could be reduced 5-fold (to 1% and
0.8%, respectively) with no diminution in regio- or enantio-
selectivity, and with a slight improvement in chemoselec-
tivity. As the pKa of N-halogenated carbamate salts is known
to be dependent on the solvent-to-water ratio,9 all experiments
were performed with a constant ratio of solvent to buffer.
In addition, the formation of the dihydroxylated byproduct
can be diminished by careful loading of t-BuOCl, as the
presence of unreacted hypochlorite results in accelerated
dihydroxylation.
With optimized experimental conditions in place, the
regio-, chemo-, and enantioselectivity of the AA was
investigated for a variety of styrene substrates. The results
(Table 2) show that the desired B regioisomer is obtained in
good yields and modest-to-good enantioselectivity on dif-
ferently substituted styrenes. In general, enantiomeric ratios
in the 85:15 range are observed for all para- and meta-
substituted substrates; lower ers are observed for the ortho-
substituted styrene (Table 2, entry 10). In all cases the
regioisomers could be easily separated by chromatography
on silica gel. These buffered reaction conditions are a
complement to existing experimental protocols that selec-
tively generate the A regioisomer, and are a marked
improvement upon those that utilize carbamate nitrogen
sources to access the B regioisomer.
experimentation confirmed that the presence of regioisomer
A leads to the formation of even greater amounts of
regioisomer A. For instance, when purified regioisomer A
is added at the start of the aminohydroxylation, the regio-
meric composition of the products shifts from 1:10 (A:B) to
1:1.6 (A:B); initial addition of purified regioisomer B had
little effect on the reaction outcome (see Supporting Informa-
tion for details).
Described herein is a simple method to access the B
regioisomer in the aminohydroxylation of styrenes with high
yields and good enantioselectivites with carbamate nitrogen
A kinetic investigation revealed that under the reaction
conditions regioisomer B is the dominant product in the early
stages of the reaction (Figure 3). At a certain point (30 min
for the p-acetoxystyrene substrate) the rate of formation of
the A regioisomer starts to become significant. Further
(8) For use of less sterically challenged nitrogen sources in the asym-
metric aminohydroxylation see: Rudolph, J.; Sennhenn, P. C.; Vlaar, C.
P.; Sharpless, K. B. Angew. Chem., Int. Ed. Engl. 1996, 35, 2810-2813.
(9) (a) Menard, H.; Lessard, J. J. Chem. Eng. Data 1978, 23, 64-65.
(b) Bachand, C.; Driguez, H.; Paton, J. M.; Touchard, D.; Lessard, J. J.
Org. Chem. 1974, 39, 3136-3138.
Figure 3. Product formation as a function of time in the buffered
asymmetric aminohydroxylation of p-acetoxystyrene.
Org. Lett., Vol. 5, No. 3, 2003
283

sources. Further mechanistic investigations into the influence
of pH on regioselctivity in the AA are underway and will
be reported in due course.
Sharpless (Scripps) for the gift of the noncommercially
available chincona alkaloid ligands, and Professor Scott E.
Denmark (University of Illinois) for use of the chiral SFC.
Supporting Information Available: Experimental pro-
cedures and characterization data. This material is available
free of charge via the Internet at http://pubs.acs.org.
Acknowledgment. The authors gratefully acknowledge
the University of Illinois and the National Science Foundation
(NSF-CAREER award CHE-0134779 to P. J. H.) for support
of this research. The authors also thank Professor K. Barry
OL027242J
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Org. Lett., Vol. 5, No. 3, 2003