First asymmetric aminohydroxylation of acrylamides

Article abstract of DOI:10.1016/j.tetasy.2005.08.052

The first examples of the asymmetric aminohydroxylation of acryl amides are reported. This was accomplished with chiral acrylamides as substrates, which undergo diastereoselective oxidative transformation within the so-called 'second catalytic cycle' with diastereomeric excesses reaching 100:0. The reaction relies solely on the stereochemical information provided by the enantiomerically pure starting materials. A stereochemical model for the observed asymmetric induction is provided.

Full text of DOI:10.1016/j.tetasy.2005.08.052

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 16 (2005) 3492–3496
First asymmetric aminohydroxylation of acrylamides
Jan Streuff,a Brigitte Osterath,a Martin Niegerb and Kilian Muniza,*
˜
aKekule´-Institut fu¨r Organische Chemie und Biochemie, Rheinische Friedrich-Wilhelms-Universita¨t,
Gerhard-Domagk-Straße 1, D-53121 Bonn, Germany
bInstitut fu¨r Anorganische Chemie, Rheinische Friedrich-Wilhelms-Universita¨t, Gerhard-Domagk-Straße 1, D-53121 Bonn, Germany
Received 1 August 2005; accepted 23 August 2005
Available online 2 November 2005
Abstract—The first examples of the asymmetric aminohydroxylation of acryl amides are reported. This was accomplished with chi-
ral acrylamides as substrates, which undergo diastereoselective oxidative transformation within the so-called Ôsecond catalytic cycleÕ
with diastereomeric excesses reaching 100:0. The reaction relies solely on the stereochemical information provided by the enantio-
merically pure starting materials. A stereochemical model for the observed asymmetric induction is provided.
Ó 2005 Elsevier Ltd. All rights reserved.
1. Introduction
O
O
Os
O
R
Asymmetric oxidation represents a powerful tool for the
defined introduction of heteroatoms into carbon skele-
tons.1 With traditional investigation focussing on oxy-
gen-transfer, recent advances in the area of oxidative
nitrogen incorporation has put these transformations
at the centre of current research.2
R''HN
R'
R''N
N
R'
OH
up to 99% ee
*
R
R
R'
R'
R''NX-
Osmium(VIII) catalysis represents a particularly suc-
cessful approach to oxidative alkene functionalisation.
In particular, asymmetric dihydroxylation represents a
highly developed synthetic tool for the conversion of
an alkene into a vicinal diol entity.3 The simultaneous
introduction of an amino and hydroxy group through
the related aminohydroxylation process follows the gen-
eral pathways of dihydroxylation and employs an imi-
doosmium catalyst.4,5 The enantioselective variant of
this process requires the use of a chiral cinchona alka-
loid based ligand.4–6 Recent synthetic applications of
this protocol include the synthesis of various serine
and iso-serine derivatives from acrylates, among which
figures the synthesis of the side chain of the powerful
anticancer drug Paclitaxel (TaxolÒ) from cinnamate as
the most prominent example (Scheme 1).7 In 1997,
Sharpless reported that a,b-unsaturated amides and
acrylic acids do not undergo enantioselective amin-
ohydroxylation, but are oxidised in the so-called second
catalytic cycle. For this particular class of substrates,
PhC(O)HN
C6H5
O
OR
OH
Paclitaxel side chain
Scheme 1. Sharpless aminohydroxylation of olefins.4,5 R3N* repre-
sents a chiral cinchona alkaloid ligand.
chiral catalyst control cannot provide optically active
amino alcohols.8,9 Therefore, all products from the oxi-
dative conversion of this type of substrate under amin-
ohydroxylation conditions are racemic. We herein
report the first examples of an asymmetric aminohydr-
oxylation of chiral acrylamides.
2. Results and discussion
To achieve an asymmetric course during the aminohydr-
oxylation of acrylamides, attention was turned towards
chiral substrates. To this end, the condensation of
*
Corresponding author. Tel.: +49 228 73 6553; fax: +49 228 73
5813; e-mail: kilian.muniz@uni-bonn.de
0957-4166/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2005.08.052

J. Streuff et al. / Tetrahedron: Asymmetry 16 (2005) 3492–3496
3493
various unsaturated acid chlorides with commercially
available a-aryl ethylamines led to the synthesis of
amides 1, 2 and 4–7. Likewise, compound 3 was
obtained from alanine methyl ester. Oxidative conver-
sion of these compounds in the presence of only 2 mol %
of potassium osmate and 1.1 equiv of chloramine-T as
Table 1. Aminohydroxylation of chiral, non-racemic acryl amides
O
R''
R'
O
K2[OsO2(OH)4] (2 mol%)
R''
N
R
N
R
chloramine-T (1.1 eq.)
tBuOH/H2O, r.t.
TosHN
H
H
OH
R'
Entry
1
Substrate
Product(s)
Yield (%)a
Regioisomeric ratiob
Drb
O
O
84
81
88
96
79
100:0
100:0
N
H
Ph
N
Ph
Ph
TosHN
H
OH
(S)-1
(S,R)-8
O
O
2
3
4
5
100:0
100:0
100:0
100:0
100:0
12:1
7:1
N
H
Ph
N
H
(R)-1
TosHN
TosHN
TosHN
OH
(R,S)-8
O
O
N
H
2-Naph
N
2-Naph
H
OH
2
9
O
O
N
CO2Me
N
H
CO2Me
H
OH
3
10
O
O
N
H
Ph
1:3:1
N
H
Ph
TosHN
HO
11
4
O
N
H
Ph
TosHN
Ph
OH
OH
12
Ph
O
O
O
H
N
HN
NH
6
92
—
1:1
N
Ph
H
O
O
NHTos
Ph
13
5
OH
O
H
N
Ph
N
Ph
H
NHTos
14
O
7
8
All four stereoisomers
All four stereoisomers
77
86
50:50
50:50
1.1:1.1:1:1
1.1:1:1:1
N
Ph
H
6
O
Ph
N
Ph
H
7
Products from entries 7 and 8 were not separated.
a Isolated yield at 100% conversion.
b Determined from the crude 1H NMR spectrum.

3494
J. Streuff et al. / Tetrahedron: Asymmetry 16 (2005) 3492–3496
reoxidant and nitrogen source in a solvent mixture of
tert-butanol and water led to the expected aminohydr-
oxylation reaction. Complete conversion was observed
for all substrates and the desired amino alcohol prod-
ucts were obtained after reductive work-up (Table 1).
criminations in the related reactions of 2 and 3 are
noteworthy.
A definite mechanistic background for this surprising
reaction outcome remains to be established. Within this
context, we have recently investigated the stereochemi-
cal course of self-replication of chiral iso-serine deriva-
tives and concluded that for acrylic substrates. the
stereochemical course cannot be governed efficiently
by the stereochemical information of the azaglycolate
entity itself.13 In view of the high inductions observed
in the aminohydroxylation of 1, 2 and 3, the chiral
amine auxilary from the amide group must therefore
exercise a decisive influence on the overall stereochemi-
cal course of this catalysis.
As expected, the addition of a standard cinchona alka-
loid based ligands such as (DHQ)2PHAL or
(DHQ)2AQN did not alter the reaction course indicat-
ing that observation by Sharpless on the ligands unsuit-
ability for acrylamide substrates is valid for chiral
acrylamides as well.8 In the absence of any ligand,
unsubstituted acrylamides, such as compounds 1, 2
and 3 gave complete regioselective aminohydroxylation
with the amino group positioned at the terminal carbon
(Table 1, entries 1–4). In addition, acryl amide 1 from a-
phenyl ethylamine led to complete diastereoselectivity
regarding the newly established stereogenic centre.10
Moreover, the product from the aminohydroxylation
of 3 offers the synthesis of the iso-serine-alanine dipep-
tide analogue 10. The complete regioselectivity in these
reactions is restricted to acryl and methacryl amides,
respectively. Aminohydroxylation reactions of 3-substi-
tuted a,b-unsaturated amides, such as crotoyl derivative
5 or cinnamoyl derivative 6 lacked any selectivity
(entries 7 and 8), while the acryl amides give diastereose-
lectivities ranging from 100:0 to 7:1. This stereochemical
preference of an acrylic derivative over higher substi-
tuted derivatives matches the experimental outcome
for related diamination reactions observed by us in reac-
tions with preformed trisimidoosmium reagents.11
We propose that the reaction presented herein may pro-
ceed through the catalytic cycle as depicted in Figure 2.
It is initiated by the aminohydroxylation of 1 with
O3OsNTos, as obtained in situ from the osmate and
chloramine-T, to give osma(VI)azaglyolate A. Reoxida-
tion with chloramine-T forms the imidoosmium catalyst
as the osma(VIII)azaglycolate B. This oxidises 1 in a
completely stereoselective manner to arrive at the diaste-
O
N
H
Ph
(S)-1
The results obtained from the aminohydroxylation of
fumaryl amide 4 revealed the formation of two stereo-
isomers. Due to the absence of regioselectivity issues
for this substrate, these two isomers must represent dia-
stereomers with regards to the facial selection in the oxi-
dation step. Again, the substitution pattern of the alkene
prevents the formation of a product with diastereomeric
excess. In view of the complete regio and diastereoselec-
tivity in the aminohydroxylation of 1, product 8 was
submitted to X-ray analysis and a (2R)-configuration
was established (Fig. 1). The complete stereoselectivity
in the aminohydroxylation of 1 and the high stereodis-
K2[OsO2(OH)4]
chloramine-T
O
chloramine-T
O
N
H
Ph
TosN
O
Os
O
A
(S,R)-8
O
N
H
Ph
TosN
Os
H2O
Ph
O
O
B
NTos
O
O
Tos
N
O
O
N
Ph
NH
N
H
Os
(S)-1
O
Tos
C
O
H
O
H
O
O
N
TosN
O
N
H
(S)-1
Ph
TosN
O
Os
Ph
Os
O
NTos
NTos
H
O
O
O
N H
B
D
Ph
Figure 2. Catalytic cycle and proposed transition state for
aminohydroxylation.
Figure 1. Solid state structure of (S,R)-8.12

J. Streuff et al. / Tetrahedron: Asymmetry 16 (2005) 3492–3496
3495
J.; Du Bois, J. Angew. Chem., Int. Ed. 2004, 43, 4349; (f)
Espino, C. G.; Fiori, K. W.; Kim, M.; Du Bois, J. J. Am.
Chem. Soc. 2004, 126, 15378; (g) Timokhin, V. I.;
Anastasi, N. R.; Stahl, S. S. J. Am. Chem. Soc. 2003,
125, 12996; (h) Brice, J. L.; Harang, J. E.; Timokhin, V. I.;
Anastasi, N. R.; Stahl, S. S. J. Am. Chem. Soc. 2005, 127,
2868.
reomerically pure bisazaglycolate C. Subsequent hydro-
lysis of this intermediate releases the free amino alcohol
product 8 and regenerates A to close the catalytic cycle.
Since 8 is produced as a single stereoisomer, intermedi-
ate C must be homochiral, that is, it must contain two
azaglycolate ligands of identical absolute configuration.
Therefore, the catalytic aminohydroxylation of acryl-
amide 1 with catalyst B represents the rare case of a
truly stereoselective self-replication of a chiral ligand.13
As mentioned before, we deduced a pronounced role
of the amide on the overall stereochemical course of
the reaction. This should be influential at two stages.
First, the conformation of the square-planar intermedi-
ate B might be organised from intramolecular hydrogen
bonding between the non-transferable oxo-ligand and
the amide-NH group.14
3. Kolb, H. C.; VanNieuwenhze, M. S.; Sharpless, K. B.
Chem. Rev. 1994, 94, 2483.
4. Review on imidoosmium compounds: Muniz, K. Chem.
˜
Soc. Rev. 2004, 33, 166.
5. Reviews on aminohydroxylation: (a) Bodkin, J. K.;
McLeod, M. D. J. Chem. Soc., Perkin Trans. 1 2002,
2733; (b) Bolm, C.; Hildebrand, J. P.; Muniz, K. In
˜
Catalytic Asymmetric Synthesis; Ojima, I., Ed.; Wiley-
VCH: Weinheim, 2000; p 299; (c) Schlingloff, G.; Sharp-
less, K. B. In Asymmetric Oxidation Reactions: A Practical
Approach; Katsuki, T., Ed.; Oxford University Press:
London, 2001; p 104; (d) Nilov, D.; Reiser, O. Adv. Synth.
Catal. 2002, 344, 1169; (e) OÕBrien, P. Angew. Chem., Int.
Ed. 1999, 38, 326.
While this does not necessarily need to be the only con-
formation in solution, the kinetic preference of B is suf-
ficient to dominate the catalysis. Within the subsequent
step of olefin aminohydroxylation, the observed com-
plete face selectivity might again arise from a preorgani-
sation through hydrogen bonding. Obviously, such a
preorganisation seems to be strongly influenced by addi-
tional substituents as in the cases of substrates 6 and 7.
It agrees well with a substrate, such as 5, which due to its
symmetrical amide substitution pattern cannot distin-
guish the prochiral olefin faces through hydrogen bond-
ing. In addition, N-phenyl-N-(a-phenylethyl)-acryl-
amide as substrate only showed low conversion and no
stereoselectivity (1:1-mixture and 14% yield after 36 h),
which strengthens the importance of an amide NH on
the overall catalytic course.
6. For leading references: (a) Li, G.; Chang, H.-T.; Sharpless,
K. B. Angew. Chem., Int. Ed. Engl. 1996, 35, 451; (b)
Bruncko, M.; Schlingloff, G.; Sharpless, K. B. Angew.
Chem., Int. Ed. 1997, 36, 1483; (c) Reddy, K. L.; Sharpless,
K. B. J. Am. Chem. Soc. 1998, 120, 1207; (d) Gooßen, L.
J.; Liu, H.; Dress, K. R.; Sharpless, K. B. Angew. Chem.,
Int. Ed. 1999, 38, 1080.
7. Li, G.; Sharpless, K. B. Acta Chem. Scand. 1996, 50, 649.
8. (a) Rubin, A. E.; Sharpless, K. B. Angew. Chem., Int. Ed.
1997, 36, 2637; (b) Pringle, W.; Sharpless, K. B. Tetra-
hedron Lett. 1999, 40, 5150; See also: (c) Kolb, H. C.; Finn,
M. G.; Sharpless, K. B. Angew. Chem., Int. Ed. 2001, 40,
2004.
9. Fokin, V. V.; Sharpless, K. B. Angew. Chem Int. Ed. 2001,
40, 3455.
10. Selected analytical data: (À)-8: [a]D = À50 (c 0.3, acetone).
1H NMR (300 MHz, DMSO-d6): d = 1.36 (d, J = 7.0 Hz,
3H), 2.36 (s, 3H), 2.67–2.76 (m, 1H), 2.94–2.99 (m, 1H),
3.91–4.00 (m, 1H), 4.89 (quin, J = 4.7 Hz, 1H), 5.73 (d,
J = 6.0 Hz, 1H), 7.19–7.48 (m, 8H), 7.65 (s, 1H), 7.68 (s,
1H), 8.05 (d, J = 8.1 Hz, 2H). 13C NMR (75 MHz,
DMSO-d6): d = 21.4, 22.5, 47.2, 48.0, 71.0, 126.4, 127.0,
128.6, 130.0, 137.9, 143.0, 144.7, 171.0. IR (KBr): 3471,
3325, 3304, 3032, 2985, 2929, 2870, 1653, 1527, 1456, 1408,
1315, 1213, 1161, 1109, 1090, 1018, 937, 872, 815, 769, 706,
671 cmÀ1. MS (EI, eV): m/z (%): 362.2 (12) [M]+, 347.2
(3), 251.2 (1), 214.2 (17), 207.2 (20), 179.2 (52), 155.1 (44),
139.1 (3), 120.2 (55), 105.2 (100), 91.2 (45), 75.1 (13), 60.2
(7). HRMS: calcd for C19H22N2O4S: 362.1300. Found:
362.1297. Compound 13: [a]D = À141 (c 0.23, MeOH). 1H
NMR (300 MHz, DMSO-d6): d = 1.22 (d, J = 6.97 Hz,
3H), 1.28 (d, J = 6.97 Hz, 3H), 2.36 (s, 3H), 4.19 (m, 2H),
4.72 (m, 2H), 7.14–7.30 (m, 12H), 7.61 (d, J = 8.28 Hz,
2H), 7.68 (d, = 8.10 Hz, 1H), 7.96 (d, J = 7.73 Hz, 1H).
13C NMR (75 MHz, DMSO-d6): d = 21.1, 22.1, 22.5, 48.0,
48.3, 59.1, 72.3, 125.9, 126.1, 126.7, 126.8, 128.25, 128.31,
129.4, 142.6, 143.9, 144.2, 168.1, 169.7. IR (KBr): 3417,
3290, 3062, 3028, 2974, 2960, 2927, 1659, 1539, 1508, 1448,
1427, 1336, 1161, 1078, 1022, 941, 761, 698, 557 cmÀ1. MS
(EI, eV): m/z (%): 509.3 [M]+, 362.2 (8), 361.2 (25), 355.2
(5), 332.2 (10), 318.2 (2), 257.1 (15), 240.1 (1), 215.2 (5),
214.1 (15), 191.2 (4), 177.2 (20), 161.1 (1), 155.1 (10), 139.1
(4), 132.1 (0), 120.2 (25), 105.1 (100), 91.1 (10), 79.1 (5),
73.1 (1), 60.1 (8), 57.2 (1). HRMS: calcd for C27H31N3O5S:
509.1984. Found: 509.1989. Compound 14: [a]D = À78 (c
0.1, DMSO). 1H NMR (300 MHz, DMSO-d6): d = 1.04
(d, J = 6.97 Hz, 3H), 1.37 (d, J = 6.97 Hz, 3H), 2.32 (s,
3H), 4.24 (m, 2H), 4.64 (m, 1H), 4.90 (quin, J = 6.97, 1H),
3. Conclusion
In summary, we have described the first asymmetric
aminohydroxylations of chiral, non-racemic acryl
amides, which proceed exclusively in the second cycle.
The assumed stereoselectivity model of hydrogen bond-
ing should lead to a potential design of new ligands for
this type of oxidation catalysis.15 Mechanistic investiga-
tion along these lines is currently under investigation.
Acknowledgements
We are grateful to the Fonds der Chemischen Industrie
for generous ongoing support. J. S. thanks Bonn Uni-
versity for a Diploma fellowship.
References
1. Ba¨ckvall, J.-E. Modern Oxidation Methods; Wiley-VCH:
Weinheim, 2004.
2. Selected recent examples: (a) Modern Amination Reactions;
Ricci, A., Ed.; Wiley-VCH: Weinheim, 2000; (b) Dono-
hoe, T. J.; Johnson, P. D.; Cowley, A.; Keenan, M. J. Am.
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3496
J. Streuff et al. / Tetrahedron: Asymmetry 16 (2005) 3492–3496
7.15–7.37 (m, 12H), 7.57 (d, J = 8.28 Hz, 2H), 7.73 (d,
tary publication no. CCDC-279068. Copies of the data
can be obtained free of charge at www.ccdc.cam.ac.uk/
conts/retrieving.html [or from the Cambridge Crystallo-
graphic Data Centre, 12, Union Road, Cambrigde CB2
1EZ, UK; Fax: int. code +44 1223 336033; e-mail:
deposit@ccdc.cam.ac.uk].
J = 7.73 Hz, 1H), 7.93 (d, J = 8.29 Hz, 1H). 13C NMR
(75 MHz, DMSO-d6): d = 20.9, 21.8, 31.2, 47.6, 48.1, 59.6,
72.01, 125.87, 125.97, 126.06, 126.49, 126.56, 128.05,128.1,
129.2, 142.4, 143.6, 167.6, 169.4. IR (KBr): 3400, 3301,
3055, 3030, 2976, 2960, 2922, 1659, 1544, 1500, 1443, 1336,
1161, 1079, 1021, 936, 771 cmÀ1. MS (EI, eV): m/z (%):
509.3 [M]+, 362 (3), 361 (26), 332 (10), 257 (15), 215.2 (11),
214.1 (15), 191.2 (4), 177.2 (20), 161.1 (1), 155.1 (10), 120.2
(25), 105.1 (100), 91.1 (10), 79.1 (5), 60.1 (8). HRMS: calcd
for C27H31N3O5S: 509.1984. Found: 509.1991.
13. Muniz, K. Adv. Synth. Catal. 2005, 367, 275.
˜
14. For the effect of hydrogen bonding in dihydroxylation
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(c) Donohoe, T. Synlett 2002, 1223.
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Sharpless, K. B. Angew. Chem., Int. Ed. 2002, 41, 490.
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Int. Ed. 2003, 42, 5958.
12. Details concerning the X-ray analysis of 8: Crystallo-
graphic data (excluding structure factors) for the structure
reported in this paper have been deposited with the
Cambridge Crystallographic Data Centre as supplemen-