A regio-and stereodivergent synthesis of vic-amino alcohols

Article abstract of DOI:10.1021/ol006736i

(Matrix presented) A regio-and stereodivergent synthesis of vic-amino alcohols starting from vinylepoxides is described. The developed strategy focuses on the propensity of vinylepoxides and vinylaziridines to be ring-opened at the allylic position by sui

Full text of DOI:10.1021/ol006736i

ORGANIC
LETTERS
2000
Vol. 2, No. 25
4087-4089
A Regio- and Stereodivergent Synthesis
of vic-Amino Alcohols
Berit Olofsson, Uttam Khamrai, and Peter Somfai*
Department of Chemistry, Organic Chemistry, Royal Institute of Technology,
S-100 44 Stockholm, Sweden
somfai@kth.se
Received October 16, 2000
ABSTRACT
A regio- and stereodivergent synthesis of vic-amino alcohols starting from vinylepoxides is described. The developed strategy focuses on the
propensity of vinylepoxides and vinylaziridines to be ring-opened at the allylic position by suitable nucleophiles and makes use of reactions
that perform such tasks selectively with either retention or inversion of configuration.
The â-amino alcohol moiety is found in a wide variety of
biologically active alkaloids and peptides.1 The importance
of vicinal amino alcohols is also well recognized in asym-
metric synthesis, where the need for chiral auxiliaries and
ligands is continually increasing.2 Existing synthetic routes
to enantiopure amino alcohols rely heavily on the derivati-
zation of the available pool of amino acids, inherently
limiting the number of accessible derivatives.3 Large efforts
to develop asymmetric routes circumventing these drawbacks
have been made4 and can be divided into two strategically
different categories. First, the amino alcohol moiety can be
formed by concomitant creation of a new C-C bond; this
can be accomplished by stereoselective addition of nucleo-
philes to R-aminocarbonyls,3 nitroalkenes,5 or imines1,6 or
by reaction of chiral aminoallylboranes with aldehydes.7
Alternatively, the segment may be constructed without
alteration of the carbon skeleton, which can be done by
Sharpless aminohydroxylation8 or by ring opening of ep-
oxides,9 aziridines,10 or cyclic sulfates11 with appropriate
nucleophiles. Despite the great interest in this field, no
divergent route from a common starting material toward all
possible regio- and stereoisomers of a vicinal amino alcohol
has been documented, thus complicating the synthetic
planning substantially by the requirement of a conceptually
different synthesis route for each isomer. A divergent route
would be a great simplification for studies on structure-
activity relationships for pharmacologically active derivatives
(8) O’Brien, P. Angew. Chem., Int. Ed. 1999, 38, 326-329. Li, G.; Chang,
H.-T.; Sharpless, B. K. Angew. Chem., Int. Ed. Engl. 1996, 35, 451.
(9) Larrow, J. F.; Schaus, S. E.; Jacobsen, E. N. J. Am. Chem. Soc. 1996,
118, 7420-7421. Mitsunobu, O. Synthesis of Amines and Ammonium Salts;
Trost, B. M., Fleming, I., Eds.; Pergamon: Oxford, 1991; Vol. 6, pp Chapter
1.3. Trost, B. M.; Sudhakar, A. R. J. Am. Chem. Soc. 1987, 109, 3792-
3794. Zwanenburg, B. Pure Appl. Chem. 1999, 71, 423-430. Hayakawa,
H.; Okada, N. M., M.; Miyashita, M. Tetrahedron Lett. 1999, 40, 4589-
4592. Sekar, G.; Singh, V. K. J. Org. Chem. 1999, 64, 287-289.
(10) Takeuchi, H.; Koyama, K. J. Chem. Soc., Perkin Trans. 2 1981,
121-126. Ibuka, T.; Nakai, K.; Akaji, M.; Tamamura, H.; Fujii, N.;
Yamamoto, Y. Tetrahedron 1996, 52, 11739-11752. Hwang, G.-I.; Chung,
J.-H.; Lee, W. K. J. Org. Chem. 1996, 61, 6183-6188.
(1) Kobayashi, S.; Ishitani, H.; Ueno, M. J. Am. Chem. Soc. 1998, 120,
431-432 and references therein.
(2) Ager, D. J.; Prakash, I.; Schaad, D. R. Chem. ReV. 1996, 96, 835-
875. Seyden-Penne, J. Chiral Auxiliaries and Ligands in Asymmetric
Synthesis; Wiley: New York, 1995.
(3) Reetz, M. T. Angew. Chem., Int. Ed. Engl. 1991, 30, 1531-1546.
(4) Bergmeier, S. C. Tetrahedron 2000, 56, 2561-2576.
(5) Enders, D.; Haertwig, A.; Raabe, G.; Runsink, J. Eur. J. Org. Chem.
1998, 1771-1792. Enders, D.; Haertwig, A.; Runsink, J. Eur. J. Org. Chem.
1998, 1793-1802.
(6) Hattori, K.; Yamamoto, H. Tetrahedron 1994, 50, 2785-2792.
(7) Barrett, A. G. M.; Seefeld, M. A.; White, A. J. P. J. Org. Chem.
1996, 61, 2677-2685.
(11) Lohray, B. B.; Gao, Y.; Sharpless, K. B. Tetrahedron Lett. 1989,
30, 2623-2626. Lohray, B. B.; Ahuja, J. R. J. Chem. Soc., Chem. Commun.
1991, 95-97. Chang, H.-T.; Sharpless, B. Tetrahedron Lett. 1996, 37,
3219-3222. Cho, G. Y.; Ko, S. Y. J. Org. Chem. 1999, 64, 8745-8747.
10.1021/ol006736i CCC: $19.00 © 2000 American Chemical Society
Published on Web 11/03/2000

incorporating this structural motif and for optimizing the
performance of chiral ligands containing this substructure.
We therefore set out to develop a route leading to all eight
possible isomers of a given 1,2-amino alcohol starting from
a common substrate, and herein we present our preliminary
results.
The requirements for a generally applicable synthetic route
were readily available starting materials, flexibility, predict-
ability, and high regio- and stereoselectivity. These demands
could be met by choosing vinylepoxides as substrates, both
enantiomers being readily available in high enantiomeric
excess, as they are known to be ring opened selectively at
the allylic position by hard nucleophiles.12 As depicted in
Scheme 1, the synthesis strategy designed to fulfill these
Table 1. Data for the Opening of Vinylepoxides 1a
yield (%)b
substrate
R
R1
R2
3
7
2
a
b
c
d
BnO
PhCH2
BnO
H
H
H
H
H
87
93
88
86
88c 73
82c 93
87
93
CH2OPMB
H
66
73
PMBO
CH2OBn
a For experimental details, see Supporting Information. b Isolated yields.
c Diasteromeric mixture; see text.
opening of 1 in the presence of tosyl isocyanate, according
to the Trost procedure,16 gave oxazolidinones 7 with retention
of configuration.
Conversion of 1 to 7 took place with complete stereose-
lectivity (>20:1) when 1 contained additional vinylic sub-
stituents (1c,d), whereas the unsubstituted vinylepoxides 1a,b
gave a diastereomeric mixture. In these cases the kinetically
obtained, poor selectivity could be improved by equilibration
of the initial product mixture (1a ds 2:1 f 14:1, 1b ds 2:1
f 6:1).17 Oxazolidinones 7 were detosylated to the corre-
sponding N-H derivatives,18 the relative stereochemistry of
Scheme 1. Synthetic Strategy
1
which could be determined from the H NMR coupling
constants.7 At this stage the diastereomers could be separated
by flash chromatography, and subsequent basic hydrolysis
yielded syn-amino alcohols 2 (Scheme 2, Table 1).
To obtain regioisomers 5 and 6, amino alcohols 3 were
ring closed to give N-H aziridines 4 (Scheme 3, Table 2).19
specifications starts by ring opening of epoxide 1 with a
nitrogen nucleophile. The opening can be performed either
with retention or inversion of stereochemistry, giving syn-
and anti-amino alcohols 2 and 3, respectively. Ring closure
of 3 to the corresponding vinylaziridines 4 and subsequent
ring opening with an oxygen nucleophile, either with
retention or inversion, would then give syn- and anti-amino
alcohols 5 and 6, all reactions taking place regioselectively
at the allylic position. The remaining set of enantiomeric
amino alcohol isomers can simply be obtained by starting
from ent-1.
Scheme 3. Formation and Opening of Vinylaziridines 4
Aminolysis of vinylepoxides 113 was accomplished with
NH4OH under microwave irradiation14 to afford anti-amino
alcohols 3 regioselectivity (>20:1) and in high yields
(Scheme 2, Table 1).15 Alternatively, Pd(0)-catalyzed ring
Cyclization of primary amines into aziridines is known to
be difficult,20 but good yields of 4 were obtained under
optimized Mitsunobu conditions followed by careful puri-
Scheme 2. Opening of Vinylepoxides 1
(12) Jaime, C.; Ortuno, R. M.; Font, J. J. Org. Chem. 1988, 53, 139-
141.
(13) Vinylepoxides 1a,b were obtained from the allylic alcohols using
Sharpless asymmetric epoxidation followed by the Swern/Wittig procedure,
see: D´ıez-Martin, D.; Kotecha, N. R.; Ley, S. L.; Mantegani, S.; Mene´ndez,
J. C.; Organ, H. M.; White, A. D.; Banks, J. B. Tetrahedron 1992, 48,
7899-7938; 1c was obtained from the corresponding dienol; for 1d, see:
Weigand, S.; Bru¨ckner, R. Synlett 1997, 225-228. All vinylepoxides had
ee > 95%.
(14) Lindstro¨m, U. M.; Olofsson, B.; Somfai, P. Tetrahedron Lett. 1999,
40, 9273-9276.
(15) The stereochemistry was confirmed by converting amino alcohols
3, 5, and 6 into the corresponding oxazolidinones; see ref 18.
(16) Trost, B. M.; Sudhakar, A. R. J. Am. Chem. Soc. 1987, 109, 3792-
3794.
4088
Org. Lett., Vol. 2, No. 25, 2000

73% yield from 4. The timing of the water addition is crucial
for the successful outcome of the reaction; when added too
early the diastereoselectivity is diminished as water opens
the acylaziridine, and when added too late the formation of
byproducts increases. Interestingly, attempts to effect the
rearrangement of 4a using Brønsted acids proved inferior
because of increased byproduct formation. The stereoselec-
tivity of this rearrangement (>20:1) is gratifying and has
been explained by invoking an SNi mechanism.22 The
complete regioselectivity, which is of equal importance, can
be rationalized by the stabilizing effect of the vinyl group
on the transition state, thus favoring attack of the carbonyl
oxygen at the allylic position. Finally, mild acidic or basic
hydrolysis of 9, depending on the stability of the protective
groups, gave the remaining syn-amino alcohols 5.15,24
In conclusion, we have presented a synthetic strategy that
provides a straightforward route from vinylepoxides 1 to the
four isomeric Vic-amino alcohols 2, 3, 5 and 6. Since ent-1
is available from the same starting material as 1, this protocol
has the potential of delivering all eight possible isomers of
a given amino alcohol. The presented strategy focuses on
the propensity of vinylepoxides and vinylaziridines to be
ring-opened at the allylic position by suitable nucleophiles,
using reactions that perform such transformations selectively
with either inversion or retention of configuration. Further
investigations to define the scope and limitations of this
protocol are underway, as is the application to natural product
synthesis.
Table 2. Formation and Opening of Vinylaziridines 4a
yield (%)b
substrate
R
R1
R2
4
6
9
5
a
b
c
d
BnO
PhCH2
BnO
H
H
H
H
H
72
80
84 73 92c
80 71 95c
CH2OPMB 78d 82 73 91e
63
71 73 84e
PMBO CH2OBn
H
a For experimental details, see Supporting Information. b Isolated yields.
c Acidic hydrolysis. d Based on recovered starting material. e Basic hydroly-
sis.
fication on deactivated silica. Vinylaziridines 4 could then
be regioselectively hydrolyzed into anti-amino alcohols 6
under acidic conditions. Initial attempts to hydrolyze 4 using
TsOH gave 6 in modest yields and regioselectivity (9:1),
whereas complete regioselectivity (>20:1) was obtained with
HClO4 (1 equiv) in THF/H2O.15 Finally, syn-isomer 5 was
obtained via acetylation of 4 into the corresponding acy-
laziridines, which was unstable to standard purification and
therefore used as crude product in the subsequent step.21
When the acylaziridines were treated with BF3‚OEt2 in THF,
a clean rearrangement into oxazolines 8 (ds > 20:1) ensued,22
which surprisingly proved to be unstable toward workup and
purification (Figure 1).23
Acknowledgment. This work was supported financially
by the Swedish Natural Science Research Council, the Royal
Institute of Technology, and Stockholm University.
Supporting Information Available: Representative pro-
cedures for the preparation of compounds 2-7 and 9 and
characterization of 2, 3, 5, and 6. This material is available
free of charge via the Internet at http://pubs.acs.org.
Figure 1. Structure of oxazoline 8.
OL006736I
This could be circumvented by in situ hydrolysis of 8 into
hydroxyamide derivatives 9, which could be isolated in 70-
(21) Lindstro¨m, U. M.; Somfai, P. J. Am. Chem. Soc. 1997, 119, 8385-
8386.
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1998, 63, 4568-4569.
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Org. Chem. 1999, 64, 9450-9458. Greene, T. W.; Wuts, P. G. M. ProtectiVe
Groups in Organic Synthesis, 3rd ed.; Wiley: New York, 1999.
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F. T.; Berchtold, G. A. J. Org. Chem. 1982, 47, 2364-2369. Koft, E. R.;
Dorff, P.; Kulling, R. J. Org. Chem. 1989, 54, 2936-2940.
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D. Angew. Chem., Int. Ed. Engl. 1994, 33, 599-619. Osborn, H. M. I.;
Sweeney, J. Tetrahedron: Asymmetry 1997, 8, 1693-1715. Pearson, W.
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Org. Lett., Vol. 2, No. 25, 2000
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