Osmium-catalyzed olefin dihydroxylation and aminohydroxylation in the second catalytic cycle

Article abstract of DOI:10.1002/adsc.200505252

Two catalytic cycles operate in the osmium-catalyzed olefin dihydroxylation and aminohydroxylation. Slow hydrolysis of the Os(VI) monoglycolate (or monoazaglycolate in aminohydroxylation) intermediate often results in the addition of another molecule of o

Full text of DOI:10.1002/adsc.200505252

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DOI: 10.1002/adsc.200505252
Osmium-Catalyzed Olefin Dihydroxylation and Aminohydroxyla-
tion in the Second Catalytic Cycle
Peng Wu,a Robert Hilgraf,a, b and Valery V. Fokina,*
a
Department of Chemistry, The Scripps Research Institute, 10550 N. Torrey Pines Road, La Jolla, CA 92037, USA
Fax : (+1)-858-784-7562; e-mail: fokin@scripps.edu
Present address: Celgene Corporation, San Diego, CA 92121, USA
b
Received: June 21, 2005; Revised: April 28, 2006; Accepted: May 8, 2006
Supporting information for this article is available on the WWW under http://asc.wiley-vch.de/home/.
Abstract: Two catalytic cycles operate in the of new chelating ligands were devised, which force
osmium-catalyzed olefin dihydroxylation and amino- the catalysis into the second cycle while maintaining
hydroxylation. Slow hydrolysis of the Os(VI) mono- enantiocontrol in the olefin addition step. Excellent
glycolate (or monoazaglycolate in aminohydroxyla- catalytic turnover and moderate to good enantiose-
tion) intermediate often results in the addition of an- lectivity were achieved.
other molecule of olefin thereby shunting the cataly-
sis into the second catalytic cycle. As a result, both Keywords: alkenes; aminohydroxylations; asymmet-
enantio- and chemoselectivity are reduced. A series ric catalysis; dihydroxylations; osmium
Introduction
enantio-), (2) substrate scope, and (3) catalyst activity.
Of these, chemoselectivity is the most serious, for up
The cornerstone for catalytic aminohydroxylation was to 70% of corresponding vicinal diol can be produced
laid in 1975 with the discovery that the tert-alkylimido in unfavorable cases.[4]
complex of osmium
A
Insights into the mechanism of the AD process pro-
ductive cleavage of the resulting osmium(VI) azagly- vided a foundation for understanding the aminohy-
colate yields the corresponding mono-, di-, or trisub- droxylation reaction. Most important was the realization
stituted cis-amino alcohols.[1] The first catalytic ver- that the two processes share a potential for having
sion of this reaction was developed soon afterwards, multiple catalytic cycles, and that these cycles must in-
utilizing chloramine-T as both the nitrogen source and tersect since both dihydroxylation and aminohydroxy-
the oxidant.[2] It was not until 1996, however, that the lation are simultaneously observed in many cases.
crucial importance of a high water content for achiev-
ing optimal turnover rates without any additives was lation, in analogy to that of dihydroxylation,[5,6] is out-
recognized, enabling the first catalytic asymmetric lined in Scheme 1. Osmium(VIII) trioxoimido species
An overall mechanistic pathway for aminohydroxy-
AHCTREUNG
aminohydroxylation of an olefin using an excess of I can add to an olefin generating the Os(VI) azaglyco-
chloramine-T and catalytic amounts of K2OsO2(OH)4 late complex II. This step is presumably strongly ac-
in the presence of chiral Cinchona alkaloid ligands celerated by the chiral ligand L, accounting the for
(DHQ)2PHAL and (DHQD)2PHAL.[3] Given that asymmetric induction in the process. Complex II is
the vicinal amino alcohol moiety is found in a vast then reoxidized to the pivotal Os(VIII) azaglycolate
number of natural products and synthetic drugs, it III. This species completes the first cycle by hydroly-
was not surprising that a general method for stereose- sis, or enters the second cycle by oxidizing another
lective introduction of this functionality into the olefin to give bis(azaglycolate) complex IV. We pro-
olefin backbone quickly found many applications.
pose that the five-coordinate nature of III (in contrast
However, in spite of the great deal of effort that to the four-coordinate I) provides sufficient electron
has been devoted to make asymmetric aminohydroxy- density at the metal center to allow olefin oxidation
lation (AA) as reliable, versatile and convenient to to proceed without external ligand. (Indeed, chiral li-
use as its asymmetric dihydroxylation (AD) counter- gands such as those derived from DHQ and DHQD,
part, several problems have limited its utility. Chief even in five-fold excess relative to osmium, have no
among those are (1) selectivities (chemo-, regio-, and effect on the rate, yield, chemo-, regio- or stereo-
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Scheme 1. Two catalytic cycles in aminohydroxylation of olefins.
chemical outcome of the reaction.) Hydrolysis of IV
restores II, completing the second cycle.
When “special A” substrates are subjected to the
standard conditions for either the osmium-catalyzed
An important insight is that for aminohydroxylation dihydroxylation or aminohydroxylation process, only
reactions, hydrolysis steps, (h1 and h2), are the turn- racemic products are formed, even when an enormous
over-limiting events in either catalytic cycle. This has excess of the chiral ligand is added. This and other
been demonstrated in several ways, one example available evidence strongly suggest that these olefins
being the general observation that aminohydroxyla- turn over almost exclusively in the second catalytic
tion of a mixture of two olefins invariably proceeds at cycle, in which osmium(VI) bis(azaglycolate) is the
the same rate as the slower substrate alone.[4] In these most stable intermediate. According to our current
cases, the resting state of the osmium catalyst is the mechanistic hypothesis, the resident carboxylate
À
À
azaglycolate complex of the slowest substrate, with groups ( COO ) in this complex facilitate the rate-
the overall reaction rate determined by the rate of its determining step, hydrolysis, thereby accounting for
hydrolysis.
the dramatically increased reactivity of these sub-
The second cycle in the Upjohn dihydroxylation [in strates.
which the oxidant is an Os(VIII) trioxoglycolate spe-
In support of the hypothesis that the second cycle is
cies] was shown to result in low enantiomeric excess important in aminohydroxylation processes, the os-
of the product diols.[6] This does not mean that it will mium(VI) azaglycolate complex V (an example of
necessarily be deleterious to aminohydroxylation; general structure IV, Scheme 1) from the catalytic
indeed, it appears to be the dominant catalytic mech- aminohydroxylation of cyclohexene was isolated.[4]
anism for “special ” reactions which exhibit unprece- The X-ray crystal structure of V is shown in Scheme 2.
dented efficiency (vide infra), as well as for dihydrox- The complex has the expected square-pyramidal
ylation of olefins at low pH with added citric acid.[7] structure that is consistent with solution-phase NMR
In the last few years, we have discovered that cer- data. Note that, in comparison to the Os(VI) bis(gly-
tain classes of olefins undergo rapid and nearly quan- colate) species that occupies the same position in the
titative conversion to the expected products, vicinal AD second cycle, complex V has much greater steric
diols or amino alcohols, in the absence of the alkaloid hindrance along the path by which water must ap-
ligand, even with very low catalyst loadings.[7,8] This is proach the only open coordination site of osmium to
in sharp contrast to other olefins, whose turnover is initiate hydrolysis. The approach of water may also be
crucially dependent on the ligand-acceleration slowed by the hydrophobic pocket created by the two
effect.[9] We grouped these reactions under the gener- tosyl groups that point “down” and around the vacant
al terms “special D” and “special A”. Unsaturated coordination site. These features are consistent with
carboxylates constitute an extreme example,[10] with the observation that catalytic aminohydroxylation is
turnover rates among the highest observed for any di- generally slower than dihydroxylation, and with the
hydroxylation reported to date.
hypothesis that hydrolysis is turnover-limiting.
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Osmium-Catalyzed Olefin Dihydroxylation and Aminohydroxylation
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Scheme 2. X-ray crystal structure of osmium bis(azaglycolate) complex V.
Although every attempt has been made to avoid
the second cycle in the “traditional”, Cinchona alka-
loid-based dihydroxylation and aminohydroxylation,
deleterious as it is to enantioselectivity, the enticing
possibilities it offers for a new way to control
osmium(VIII) catalysis became clear immediately
G
after it was discovered. While the early attempts to
design a 2nd cycle ligand were not successful, the
recent jump in the effectiveness of the “special A”
systems sets the stage for the development of new cat-
alytic processes which take advantage of the unique
features of the 2nd catalytic cycle. The idea is simple:
the azaglycolate ligand resident on III can, in princi-
ple, contribute to selectivity in the oxidative addition
of the second olefin molecule. As long as the resulting
diol or amino alcohol can be hydrolytically released
in the next step, the catalysis can be confined to the
2nd cycle. Hence, a successful second cycle ligand
should a) be chiral and capable of controlling stereo-
chemistry in the olefin oxidation step r3; b) aid in the
hydrolytic release (h2) of the diol from the initial
Os(VI) product complex (IV); and c) not itself be hy-
drolytically removable from the osmium coordination
sphere.[11]
Scheme 3. Effect of racemic additives on enantioselectivity
of asymmetric dihydroxylation (AD) of styrene.
Herein, we offer our account of the development of
the first ligands that effect asymmetric osmium-cata- product (95% ee) was obtained. However, the inher-
lyzed dihydroxylation and aminohydroxylation pro- ent, substantial enantioselectivity was destroyed by
ceeding in the second catalytic cycle.
even small amounts of added racemic hydroxysucci-
nate salts. Thus, in the presence of 2.5 mol% of N-tol-
uenesulfonyl-2-amino-3-hydroxysuccinate, only race-
mic diols were formed. Even a tartrate salt, albeit to a
lesser extent, had an impact at the enantioselectivity
Results and Discussion
The dihydroxylation of styrene under the Upjohn of the process. This finding suggests that N-toluene-
conditions[12] has been chosen as a simple model for sulfonyl-2-amino-3-hydroxysuccinic acid has higher
screening carboxylate-containing molecules as poten- binding constants for osmium than its vicinal diol
tial osmium binding ligands. The following two ex- counterpart, the tartrate, and the Cinchona alkaloids,
periments confirmed the viability of our approach.
and it is capable of shunting the dihydroxylation pro-
First, we found that addition of racemic N-toluene- cess almost exclusively into a 2nd, non-enantioselec-
sulfonyl-2-amino-3-hydroxysuccinate had a marked tive catalytic cycle.
effect on the level of enantioselectivity achieved in
Second, aminohydroxylation of stilbene, which does
asymmetric dihydroxylations of styrene (Scheme 3). not proceed to any appreciable extent in tert-butyl al-
In the absence of any additives, the R-configured diol conol/water (1:1), proceeded to completion in less
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Peng Wu et al.
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Scheme 4. Aminohydroxylation of styrene: effect of a hy-
droxysulfonamide ligand. See Supporting Information for
details.
than 12 h when 5 mol% of N-toluenesulfonyl-2-
amino-3-hydroxysuccinate was added to the mixture
(Scheme 4). Neither its dimethyl ester, nor the N-
methyl-N-toluenesulfonyl analogue had an effect on
the reaction. This was the first example of a 1,2-hy-
droxysulfonamide derivative acting as a 2nd cycle ami-
nohydroxylation ligand.
We, therefore, focused our initial search for the 2nd
cycle ligand on the N-sulfonyl-a,b-hydroxyamino
acids. Readily available starting materials and simple
synthetic strategies for the introduction of vicinal hy-
droxysulfonamide moiety in enantiomerically en-
riched form allowed the preparation of a library of N-
(sulfonyl)-isophenylserine and N-sulfonylthreonine
derivatives (a representative subset is shown in
Figure 1).
Figure 1. 2nd cycle ligands used in this study.
The effects of these new ligands were first tested in cation of the substituents on the sulfonamide group
the dihydroxylation of styrene under the Upjohn con- (R-SO2NH-) had only a minor effect on the stereo-
ditions. Although ligand 1, derived from p-carboxy- chemical outcome of the reaction. Incorporation of
substituted N-(4-toluenesulfonyl)-isophenylserine, re- electron-withdrawing groups did not necessarily in-
sulted in low enantioselectivity (13% ee; Table 1, crease enantioselectivity (Table 1, entry 12 vs.
entry 1), introduction of a more electron-withdrawing entry 11; entry 18 vs. entry 17). Decreased ees in dihy-
trifluoromethyl substituent in the para-position droxylation of all cinnamate derivatives were ob-
(ligand 2) led to higher enantioselectivity (30% ee; served when an ortho-nitro substituent was intro-
Table 1, entry 2). Use of an analogous para-trifluoro- duced (ligand 7), which might be explained by a more
methylsulfonyl derivative 3 resulted in further im- crowded environment at the osmium coordination
provement of enantioselectivity (44% ee; Table 1, sphere created by an ortho substituent which sterical-
entry 3), as did replacement of the para-carboxylate ly hinders the approach of an olefin.
group with two nitro substituents in the 2- and 4-posi-
Next, the effects of these new second cycle ligands
tions (58% ee; Table 1, entry 4). A similar trend was on the osmium-catalyzed aminohydroxylation of sty-
observed with 2-vinylnaphthalene, methyl cinnamate rene and methyl cinnamate were tested. We were
and methyl (para-nitro)cinnamate as substrates pleased to find that both substrates were converted to
(Table 1). Only racemic diols were obtained when the corresponding hydroxysulfonamides in high
methyl esters of ligands 1–4 were employed, thus con- yields, albeit with modest ee values ranging from 14
firming that a free carboxylate was an essential com- to 84% (Table 2). Importantly, and in contrast to the
ponent of a 2nd cycle ligand.
AA with alkaloid ligands, significantly lower loading
Further investigations have shown that when apply- of osmium catalyst was required (1.0 mol% as op-
ing N-sulfonylthreonine derivatives as ligands, modifi- posed to 4–5 mol%), and no diol formation was ob-
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Osmium-Catalyzed Olefin Dihydroxylation and Aminohydroxylation
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Table 1. Osmium-catalyzed dihydroxylation of olefins with second cycle ligands.[a]
Entry
Olefin
Ligand
Yield [%]
ee [%] (absolute
configuration)[b]
1
2
3
4
1
2
3
4
74
87
90
89
13 (R)
30 (R)
44 (R)
58 (R)
5
6
7
8
1
2
3
4
92
88
98
93
8 (R)
55 (R)
70 (R)
69 (R)
9
2
3
5
6
7
8
96
98
93
91
94
95
54 (2S,3R)
70 (2S,3R)
51 (2R,3S)
59 (2R,3S)
37 (2R,3S)
55 (2S,3R)
10
11
12
13
14
15
16
17
18
19
20
2
3
5
6
7
8
93
89
92
90
89
90
49 (2S,3R)
61 (2S,3R)
70 (2R,3S)
65 (2R,3S)
35 (2R,3S)
52 (2S,3R)
21
4
92
74 (1R,2R)
22
4
90
42 (S)
[a]
All reactions were performed on a 1 mmol scale at 0.5M concentration in t-BuOH/H2O (1:1) with 1.1 equivs. NMO and
0.2 mol% of OsO4. The progress was monitored by GC, and ee values were determined by HPLC [diols from styrene,
Chiralcel OB, 10% i-PrOH/hexane, 13.4 min (R), 16.9 min (S); diols from 2-vinylnaphthalene, Chiralcel OJ, 8% i-PrOH/
hexane, 21.8 min (R), 25.6 min (S); diols from methyl cinnamate, Chiralcel OB, 10% i-PrOH/hexane, 20.2 min (2R,3S),
21.6 min (2S,3R); diols from methyl p-nitrocinnamate, Chiralcel OG, 20% iPrOH/hexane, 12.1 min (2S,3R), 18.3 min
(2R,3S); diols from 1-phenyl-1-cyclohexene, Chiralcel OJ, 2% i-PrOH/hexane, 26.7 min (S,S), 37.6 min (R,R); diols from
allyl phenyl ether, Chiralcel OD, 10% i-PrOH/hexane, 18.9 min (R), 37.6 min (S)].
[b]
The absolute configurations of diols were assigned by comparison with authentic samples.
served. The products were isolated as white solids, vis- nylserine derivatives (Table 2, entries 9 and 10 vs. 7
ually free of osmium contamination. In the aminohy- and 8).
droxylation of styrene, ligands bearing electron-with-
drawing substituents gave higher levels of enantiose-
lectivity (Table 2, entry 2, 3 vs. 1). Threonine deriva- Conclusions
tive 6 gave the highest ee of 70% for the major regio-
isomer (Table 2, entry 5). On the contrary, in the In summary, a series of N-sulfonyl-a,b-hydroxyamino
aminohydroxylation of methyl cinnamate, threonine- acid-based ligands has been synthesized and studied
derived ligands gave lower level of asymmetric induc- in osmium-catalyzed dihydroxylation and aminohy-
tion comparing to the N-(4-toluenesulfonyl)-isophe- droxylation of olefins. Although enantioselectivity
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Table 2. Osmium-catalyzed aminohydroxylation of olefins with second cycle ligands.
Entry
R
Ligand Yield [%] Ratio (12:13) ee of 12 (absolute configuration)[b] ee of 13 (absolute configuration)[b]
1
2
3
4
5
6
7
8
H
H
H
H
H
H
1
2
4
7
6
8
2
4
6
7
8
90
92
92
94
92
92
94
94
90
89
91
1:1.0
1:2.0
1:2.0
1:2.0
1:2.0
1.1.8
1:2.0
1:2.0
1:3.0
1:3.0
1:3.0
24 (S)
55 (S)
43 (S)
72 (S)
84 (S)
44 (R)
54 (2S,3R)
18 (R)
54 (R)
55 (R)
40 (R)
70 (R)
13 (S)
54 (2R,3S)
20 (2R,3S)
40 (2R,3S)
19 (2R,3S)
27 (2S,3R)
COOMe
COOMe
COOMe
COOMe
COOMe
49
14
ACHTREUNG
9
10
11
ACHTREUNG
15 (2S,3R)
37 (2R,3S)
[a]
The regioisomers were separated by reversed-phase preparative liquid chromatography and the ee values were de-
termined for each regioisomer separately [R=H, 12: Chiralcel OG (30% i-PrOH in hexane), 5.3 min (R), 7.2 min (S);
13: Chiralpak AS(15% i-PrOH in hexane), 17.7 min (R), 24.0 min (S); R=COOCH3, 12: Chiralcel OG (30% i-PrOH in
hexane), 11.2 min (2R,3S), 14.4 min (2S,3R); 13: Chiralpak AD (20% i-PrOH in hexane), 8.4 min (2S,3R), 14.6 min
(2R,3S)].
[b]
The absolute configuration of the products was assigned by comparison with authentic samples.
and evaporation of the solvents, methyl (2R,3S)-(+)-2,3-di-
hydroxy-3-(p-nitrophenyl)-propionate was obtained in 70%
ee (HPLC: Chiralcel OG, 20% i-PrOH/hexane). The reac-
tion time can be reduced to about 24 h by maintaining con-
stant pH using a pH-stat. A 10 mmol scale reaction, per-
formed under these conditions, afforded product as white
solid in 75% yield (1.8 g) and 70% ee. Recrystallization
from ethanol produced needle-shaped crystals in 57% yield
and 81% ee.
was good to moderate, excellent catalytic turnover,
resulting in high yields, was observed. Much lower
loading of osmium catalyst was required, and no diol
by-products were detected in the aminohydroxylation
reactions. Products were isolated free of osmium con-
tamination. Further studies on kinetics and mecha-
nism of olefin aminohydroxylation in the presence of
the second cycle ligands as well as combinatorial ap-
proaches for new ligand discovery are ongoing in our
laboratory.
Typical Aminohydroxylation Procedure as
Exemplified for Styrene
Experimental Section
A
Typical Dihydroxylation Procedure as Exemplified
for Methyl 4-Nitrocinnamate
(212 mg, 0.5 mmol) and sodium bicarbonate (42 mg,
0.5 mmol) were dissolved in t-BuOH/H2O (1:1, 20 mL). Sty-
rene (1.040 g, 10 mmol), chloramine-T trihydrate (2.870 g,
10 mmol), and K2OsO2(OH)4 (36 mg, 0.1 mmol) were then
added successively. The reaction mixture was stirred at
room temperature for 20 h, at which point LC-MSanalysis
indicated 90% conversion. Sodium sulfite (100 mg) was
added, and the mixture was stirred for an additional hour. It
was then extracted (ethyl acetate, 3”25 mL), dried over an-
hydrous sodium sulfate, and concentrated to yield an amor-
phous solid. Flash chromatography purification afforded a
mixture of regioisomers 12:13 (32:68, determined by
1H NMR) as a white crystalline product (2.5 g, 86%). Re-
gioisomers were separated by preparative HPLC [CH3CN/
H2O, 30:70, 0.1% trifluoroacetic acid (TFA), YMCC18
column, 100 mg scale]. Enantiomeric excess was determined
Methyl 4-nitrocinnamate (207 mg, 1 mmol) and N-(4-tolu-
enesulfonyl)-l-threonine (13.6 mg, 5 mol%) were dissolved
in a t-BuOH/H2O mixture (1:1, 2 mL). NMO (50 wt% in
water, 228 mL, 1.1 mmol) and OsO4 (0.1M in acetonitrile,
20 mL, 0.002 mmol) were added successively. The pH was
adjusted to 5 by addition of 2 N H2SO4 (150 mL), and the re-
action mixture was stirred vigorously for 24 h, at which time
the pH was adjusted to 5 again. After an additional 12 h
(>95% conversion by liquid chromatography), 1 mL satu-
rated solution of Na2SO3 was added. The reaction mixture
was stirred for another 5 min before t-BuOH was evaporat-
ed. The residue was diluted with 100 mL ethyl acetate and
washed with 15 mL HCl (2M) and 2”20 mL saturated
NaHCO3 solution sequentially. After drying with MgSO4
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Osmium-Catalyzed Olefin Dihydroxylation and Aminohydroxylation
FULL PAPERS
by chiral HPLC and the absolute configuration was estab-
lished by comparing optical rotation with authentic samples.
(S)-12, 43% ee (Chiralcel-OG, i-PrOH/hexane, 30:70,
1.5 mLminÀ1) and (R)-13, 55% ee (Chiralcel-AS, i-PrOH/
hexane, 30:70, 1.5 mLminÀ1).
[2] E. Herranz, K. B. Sharpless, J. Org. Chem. 1978, 43,
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X-Ray Crystallographic Study
The synthesis and X-ray crystallographic study of complex
V can be found in the Supporting Information. Crystallo-
graphic data (excluding structure factors) for the struc-
ture(s) reported in this paper have been deposited with the
Cambridge Crystallographic Data Centre as supplementary
publication no. CCDC-267259. Copies of the data can be ob-
tained free of charge on application to CCDC, 12 Union
Road, Cambridge CB2 1EZ, UK [Fax: int. code + 44-
(1223)336–033; E-mail: deposit@ccdc.cam.ac.uk].
Acknowledgements
The authors are grateful to Prof. K. B. Sharpless for encour-
agement and advice. Financial support from the National In-
stitute of General Medical Sciences, National Institutes of
Health (GM 28384), the Skaggs Institute for Chemical Biol-
ogy, and Pfizer, Inc is gratefully acknowledged. P.W. is a
Skaggs predoctoral fellow.
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Adv. Synth. Catal. 2006, 348, 1079 – 1085
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