Asymmetric aminohydroxylation of heteroaromatic acrylates

Article abstract of DOI:10.1055/s-1999-2973

N-, S- and O-heteroaromatic acrylates were aminohydroxylated with generally high regio- and enantioselectivity. While pyridylacrylates are not amenable towards this process, the corresponding N-oxides proved to be a useful substitute, allowing the access

Full text of DOI:10.1055/s-1999-2973

LETTER
1907
Asymmetric Aminohydroxylation of Heteroaromatic Acrylates
Dirk Raatz, Clara Innertsberger, Oliver Reiser*
Institut für Organische Chemie der Universität Regensburg, Universitätsstr. 31, D-93040 Regensburg, Germany
Received 24 September 1999
Abstract: N-, S- and O-heteroaromatic acrylates were aminohy-
droxylated with generally high regio- and enantioselectivity. While
pyridylacrylates are not amenable towards this process, the corres-
ponding N-oxides proved to be a useful substitute, allowing the ac-
cess to biologically important pyridine substituted taxol™ side
chain analogs.
Key words: aminohydroxylations, amino acids, asymmetric catal-
ysis, taxol™ (paclitaxel), pyridines
The osmium catalyzed asymmetric dihydroxylation (AD)
of alkenes according to Sharpless has proved to be one of
the most reliable tools for the asymmetric functionaliza-
tion of alkenes.1 More recently, the asymmetric aminohy-
droxylation (AA) of alkenes has also been successfully
developed,2 although this process is not yet as broadly ap-
plicable compared to the asymmetric dihydroxylation.
Based on the original protocol for the AA, which allowed
simultaneously the introduction of a N-tosyl and a hydrox-
yl group into an alkene,3 the process has been rapidly
advanced4 most notably in the discovery of different us-
able nitrogen sources.5 Especially useful seems to be the
Scheme 1
possibility to introduce nitrogen functionalities being sub-
stituted with easily removable protecting groups such as
benzyloxycarbonyl6 (Z) or tert-butyloxycarbonyl7 (Boc).
However, so far the substrate variability for the AA is still
limited to cinnamic esters, styrenes and unfunctionalized
alkenes.
The furanoyl acrylates 1a could be aminohydroxylated
both with high regioselectivity and enantioselectivity with
(DHQ)2PHAL. We obtained a lower yield in this reaction
compared to a recent report11 (28% instead of 44%) due to
incomplete conversion (entries 1-2), however, the regio-
isomeric ratio was considerably higher (>15:1 instead of
7:1). Likewise, the regioisomeric furanoyl acrylate 1c was
aminohydroxylated with high selectivity in both enantio-
meric series (entries 5-6). However, increasing the elec-
tron density in the furan moiety by donor substituents
(entries 3-4) led to decomposition of the starting material
1b, most likely due to oxidation of the aromatic ring.
The currently most valuable application8 of the AA is the
synthesis of the taxol™ (paclitaxel) side chain from readi-
ly available cinnamic esters.5c,9 Analogs of the taxol™
side chain should become also accessible from acrylic es-
ters via the AA, and especially derivatives containing
heteroaromatic moieties are attractive targets, since it has
been demonstrated that such derivatives display a consid-
erably increased biological activity when combined with
baccatin III to taxol™ analogs.10 A recent paper describes
the AA of 2-vinylfuran and 2-furanoyl ethylacrylate,11
which prompts us to report our results on the successful
application of the AA to N-, S-, and O-heteroaromatic
acrylates as well as address certain limitations.
The thiophene derivatives 1d–1f proved to be excellent
substrates for the AA, both in terms of reactivity and se-
lectivity (entries 7-12). Moreover, a single recrystalliza-
tion of the AA products of 1d was sufficient to remove the
minor regioisomer and to raise the enantiopurity of 2d to
>99% ee (entries 7-8). Interestingly, a bromo substituent
at the 5-position led to an even more superior substrate for
the AA (entries 9-10). Pyrrole derivatives 1g - 1j proved
to be problematic substrates (entries 13-20). Only the ben-
zyl protected derivative 1j gave rise to the desired AA
products, albeit with low regioselectivity. Moreover, 2j
and 3j turned out to be unstable, so that we were unable to
determine the enantiomeric excess of the products. In con-
trast, both indole derivatives 1k and 1l smoothly under-
The acrylates 1a - 1l were readily synthesized by Horner-
Wadsworth-Emmons reactions from the corresponding
aldehydes. Keeping in mind the desired transformation of
the AA product to taxol™ side chain analogs at a later
stage of the synthesis, aminohydroxylations using the pro-
tocol of transferring the easily deprotectable N-benzyl-
oxycarbonyl group6 were carried out (Scheme 1, Table 1).
Synlett 1999, No. 12, 1907–1910 ISSN 0936-5214 © Thieme Stuttgart · New York

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D. Raatz et al.
LETTER
Table 1 Asymmetric Aminohydroxylation of 5-membered Heteroaromatic Acrylates 1
went the aminohydroxylation. The products crystallized
directly from the reaction mixture with excellent regio-
and enantioselectivity.
Aminohydroxylated pyridylacrylates 5 are especially in-
teresting for the synthesis of highly biologically active
taxol™ analogs. Such side chains have been synthesized
before by a strategy using the Oppolzer sultam as the
chiral source.10 The 4-pyridyl derivative was obtained
with excellent enantioselectivity (95% ee), but the selec-
tivity for the 3-pyridyl derivative (31% ee) and especially
for the important 2-pyridyl derivative (44% ee), which
was found to be a superior taxol™ side chain analog, both,
in the microtubule assembly as well as in B16 melanoma,
was significantly lower. An obvious approach towards 5
would be the direct aminohydroxylation of pyridylacry-
lates 4, however, all our attempts in this direction were un-
successful: no conversion was observed and the starting
materials 4 were recovered quantitatively. Previously, it
was already reported that the aminohydroxylation of 2-vi-
nylpyridine proceeds sluggishly and in low yields, never-
theless, the catalytic cycle was not inhibited completely.8b
A plausible explanation for the observed failure of the AA
of 4, as was also suggested already for 2-vinylpyridine,8b
is that the pyridine nitrogen interferes with the catalytic
cycle by coordinating to osmium, however, the electronic
nature of the double bond also could have been responsi-
ble. The latter reasoning was readily excluded by carrying
out the aminohydroxylation of methyl cinnamate in the
presence of pyridine, which also resulted in a complete in-
hibition of the AA.
5a/6a: Raney-Ni, 1 bar H2, Ac2O/AcOH 9:1, rt, 46%, R = Ac; 5b-c/
6b-c: TiCl3 in 10% HCl, MeOH, 0 °C, 66-70%, R = H.
Scheme 2
Consequently, we turned our attention to a pyridine deriv-
ative in which the nitrogen functionality is blocked in or-
der not to interfere with the AA. We chose the N-oxides 7,
which can be readily obtained from 4 by oxidation with
hydrogen peroxide12 or mCPBA.13 Indeed, these deriva-
tives readily underwent aminohydroxylation, giving rise
to the regioisomers 8 and 9 (Scheme 2 and Table 2).14 A
control experiment, in which the aminohydroxylation of
Synlett 1999, No. 12, 1907–1910 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Asymmetric Aminohydroxylation of Heteroaromatic Acrylates
1909
Table 2 Asymmetric Aminohydroxylation of Pyridylacrylates N-oxides 7
methyl cinnamate was carried out in the presence of pyri-
dine-N-oxide, revealed that the latter apparently does not
interfere with the process neither with respect to rate nor
to selectivity.
Amino alcohol 8 was formed as the major regioisomer in
all cases, but all attempts to suppress the undesired 9 by
varying the reaction conditions or using other nitrogen
sources for the AA failed. However, the minor isomer 9
could be readily removed by recrystallization or after re-
duction of the N-oxides (vide infra) by chromatography.
Fortunately, 8 was formed with good enantioselectivity
(63-79% ee) which could be improved to enantiopurity by
recrystallization. Interestingly, 9 was obtained virtually
racemic (up to 22%ee) in all cases. The relative stereo-
chemistry of 8a was unambiguously assigned by X-ray
crystallography while the absolute configuration was as-
signed in analogy to the products obtained in the AA of
cinnamate esters.6
a) one recrystallization from hexanes/chloroform 3:1 b) 5% Pd/C, 1
bar H2, MeOH, rt, 24 h, 97% c) i:2 N HCl, ∆, 4 h; ii: BzCl, NaOH,
H2O, 0 °C, 6 h --> rt, 24 h, 69%
The reduction of the N-oxides14 to the pyridines 5 and 6
was accomplished either by Raney-Ni15 in acetic acid (8a/
9a) resulting in a simultaneous acylation of the hydroxyl
group or by TiCl3 in water/ ethanol16 (8b/9b and 8c/9c).
The enantioselectivity of these products could be deter-
mined most effectively by capillary electrophoresis on a
cyclodextrin column.
Scheme 3
Acknowledgement
The synthesis towards the pyridyl substituted taxol™ side
chains was demonstrated starting from the mixture of 5a/
6a (Scheme 3). Compound 6a was removed by column
chromatography, and the remaining 5a was obtained
enantiomerically pure after one recrystallization from
hexanes/chloroform 3:1. Removal of the Z group by
hydrogenolysis accompanied by an acetyl shift from oxy-
gen to nitrogen proceeded quantitatively to give rise to 10.
We are grateful to the Deutsche Forschungsgemeinschaft (Re 948/
3-1) and the Fonds der Chemischen Industrie for financial support
and Degussa-Hüls-AG for generous chemical gifts. C. I. thanks the
Fonds der Chemischen Industrie for a Ph. D. fellowship. We thank
Prof. Dr. A. Buschauer and his group, University of Regensburg, for
carrying out analyses by capillary electrophoresis, and Dr. W. Frey,
University of Stuttgart for the X-ray analysis of 5a.
Saponification of the ethyl ester 10 was achieved with
concurrent deprotection of the N-acetyl group by treat-
ment with HCl followed by N-benzoylation under
Schotten-Baumann conditions17 to yield the desired β-
amino acid 11.
References and Notes
(1) Reviews: (a) Kolb, H. C.; VanNiewenhze, M. S.; Sharpless, K.
B. Chem Rev. 1994, 94, 2483. (b) Kolb, H. C.; Sharpless, K.
B. in Transition Metals for Organic Synthesis; Beller, M.,
Bolm, C., Eds.; Wiley-VCH: New York, 1998; Vol. 2, p 219-
242.
(2) Reviews: (a) Kolb, H. C.; Sharpless, K. B. in Transition
Metals for Organic Synthesis; Beller, M., Bolm, C., Eds.;
Wiley-VCH: New York, 1998; Vol. 2, p 243-260. (b) O'Brien,
P. Angew. Chem. Int. Ed. 1999, 38, 326-329. (c) Reiser, O.
Angew. Chem. Int. Ed. 1996, 35, 1308-11.
In conclusion, various heteroaromatic acrylates could be
aminohydroxylated with high selectivity, giving access to
biologically interesting taxol™ side chain analogs.18
Synlett 1999, No. 12, 1907–1910 ISSN 0936-5214 © Thieme Stuttgart · New York

1910
D. Raatz et al.
LETTER
(3) Li, G.; Chang, H.-T.; Sharpless, K. B. Angew. Chem. Int. Ed.
1996, 35, 451-54.
(4) (a) Tao, B.; Schlinghoff, G.; Sharpless, K. B. Tetrahedron
Lett. 1998, 39, 2507-10. (b) Song, C. E.; Oh, C. R.; Lee, S. W.;
Lee, S.-G.; Canali, L.; Sherrington, D. C. Chem. Commun.
1998, 2435-36.
(5) (a) Bruncko, M.; Khuong, T.-A. V.; Sharpless, K. B. Angew.
Chem. Int. Ed. 1996, 35, 454-56. (b) Gooßen, L. J.; Liu, H.;
Dress, K. R.; Sharpless, K. B. Angew. Chem. Int. Ed. 1999, 38,
1080-83. (c) Song, C. E.; Oh, C. R.; Roh, E. J.; Lee, S.; Choi,
J. H. Tetrahedron: Asymmetry 1999, 10, 671-674.
(6) Li, G.; Angert, H. H.; Sharpless, K. B. Angew. Chem. Int. Ed.
1996, 35, 2837-48.
(2R,3S)-2-Acetoxy-3-benzyloxycarbonylamino-3-(pyridin-2-
yl)propionic acid ethyl ester (5a): According to the general
procedure, 7a (191 mg, 1.0 mmol, 1.0 equiv.) was reacted for
24 h to yield a mixture of 8a and 9a (288 mg, 0.80 mmol;
80%) after purification by column chromatography (CHCl3/
MeOH 19:1), Rf = 0.35 (CHCl3/MeOH 9:1). The same
reaction was carried out on a 15 mmol scale in a yield of 72%,
and on a 100 mmol scale in a yield of 62%.
300 mg Raney-Nickel were suspended in 10 mL AcOH/Ac2O
(1:1). To this solution was added a mixture of 8a/9a (360 mg,
1.0 mmol, 1.0 equiv.) which was placed under hydrogen and
stirred for 24 h at room temp. The mixture was hydrolyzed
with 20 mL of H2O and the aqueous layer was extracted with
3 x 10 mL of EtOAc. The combined organic layers were dried
over MgSO4, filtered and concentrated in vaccuo. The
obtained mixture was purified by flash chromatography
(hexanes/EtOAc 1:1) to yield 5a (116 mg, 0.30 mmol; 30%),
white solid (mp = 68 °C) and 6a (62 mg, 0.16 mmol; 16%),
white solid (mp = 82 °C). The enantiomeric excess of 5a was
determined by analysis with capillary electrophoresis to 79%
ee, which could be raised by a single recrystallization from
hexanes/chloroform 3:1 to ·99% ee. 5a: Rf = 0.48 (hexane/
EtOAc 1:1). – [a]20D = –12.9 (c = 1.00, CHCl3). –1H
NMR(300 MHz, CDCl3): d = 1.14 (t, 3 H, J = 7.1 Hz), 2.00 (s,
3 H), 4.17 (q, J = 7.1 Hz, 2 H), 5.09 - 5.17 (m, 2 H), 5.49 (dd,
J = 3.0 Hz, J = 9.2 Hz, 1 H), 5.60 (d, J = 3.6 Hz, 1 H), 6.17 (d,
J = 9.2 Hz 1 H), 7.09-7.26 (m, 7 H) 7.58 (dt, J = 1.7 Hz,
J = 7.7 Hz, 1 H), 8.45 (d, J = 4.3 Hz). –13C NMR(75.5 MHz,
CDCl3,+ = positive signal in DEPT 135, – = negative signal in
DEPT 135): d = 168.6 (quat), 166.7 (quat), 154.9 (quat), 154.8
(quat), 148.2 (+), 135.7 (+), 135.2 (quat), 127.5 (+), 127.1 (+),
127.0 (+), 121.9 (+), 120.5 (+), 72.8 (+), 66.0 (-), 60.8 (-), 55.1
(+), 19.3 (+), 12.9 (+). – IR (KBr): n = 3330, 3040, 2940,
1755, 1740, 1715, 1580, 1560, 1515, 1210, 1030, 740, 705,
680 cm-1. – Anal. Calcd for C20H22N2O6: C, 62.17; H, 5.74; N,
7.25. Found: C, 62.17; H, 5.91; N, 7.08.
(7) O'Brien, P.; Osborne, S. A.; Parker, D. D. Tetrahedron Lett.
1998, 39, 4099-4102.
(8) (a) Reddy, K. L.; Sharpless, K. B. J. Am. Chem. Soc. 1998,
120, 1207-17. (b) O'Brien, P.; Osborne, S. A.; Parker, D. D. J.
Chem. Soc., Perkin Trans. 1 1998, 2519-26. (c) Han, H; Yoon,
J.; Janda, D. J. Org. Chem. 1998, 63, 2045-48. (d) Phukan, P.;
Sudalai, A. Tetrahedron: Asymmetry 1998, 9, 1001-05. (e)
Cravotto, G.; Giovenzana, G. B.; Pagliarin, R.; Palmisano, G.;
Sisti, M. Tetrahedron: Asymmetry 1998, 9, 745-8. (f)
Upadhya, T. T.; Sudalai, A. Tetrahedron: Asymmetry 1997, 8,
3685-89. (g) Angelaud, R.; Landais, Y.; Schenk, K.
Tetrahedron Lett. 1997, 38, 1407-10.
(9) Li, G.; Sharpless, K. B. Acta Chem. Scand. 1996, 50, 649-51.
(10) Georg, G. I.; Harriman, G. C. B.; Hepperle, M.; Clowers, J. S.;
Velde, D. G. V.; Himes, R. H. J. Org. Chem. 1996, 61, 2664-
76.
(11) Bushey, M. L.; Haukaas, M. H.; O'Doherty, G. A. J. Org.
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(12) Katritzky, A. R.; Monro, A. M.; Beard, J. A. T. J. Chem. Soc.
1958, 3721.
(13) Agarwal, K. C.; Knaus, E. E. J. Heterocycl. Chem. 1985, 22,
65-69.
(14) General procedure for the asymmetric aminohydroxylation:
To a solution of benzylcarbamate (469 mg, 3.1 mmol, 3.1
equiv.) and NaOH (122 mg, 3.05 mmol, 3.05 equiv.) in 4 mL
of n-PrOH and 7.5 mL of H2O was added tert-
(15) Jerchel, D.; Melloh, W. Liebigs Ann. Chem. 1958, 613, 144-
153.
(16) McCall, J. M.; Brin, R. E. T. Synth. Commun. 1975, 5, 335.
(17) Wang, Z.-M.; Kolb, H. C.; Sharpless, K. B. J. Org. Chem.
1994, 59, 5104-05.
butylhypochlorite (328 mg, 0.35 mL, 3.05 mmol, 3.05 equiv.)
at room temp. To the clear solution was added (DHQ)2PHAL
(39 mg, 0.05 mmol, 0.05 equiv.) in 3.5 mL of n-PrOH, the
olefin (1.0 equiv.) and K2OsO2(OH)4 (14.7 mg, 0.04 mmol,
0.04 equiv.). After completion the reaction was quenched with
15 mL of EtOAc. The aqueous layer was extracted with
EtOAc (3 x 10 mL) and the combined organic layers were
washed with 15 mL of brine, dried with MgSO4 and
concentrated in vacuo. The crude product was purified by
flash chromatography and/or recrystallisation.
(18) All new compounds were fully characterized by spectroscopic
methods and gave satisfactory combustion analyses.
Article Identifier:
1437-2096,E;1999,0,12,1907,1910,ftx,en;G23799ST.pdf
Synlett 1999, No. 12, 1907–1910 ISSN 0936-5214 © Thieme Stuttgart · New York