A regio- and stereodivergent route to all isomers of vic-amino alcohols.

Article abstract of DOI:10.1021/jo0262053

Vicinal amino alcohols are substructures in several important natural products. They are also frequently employed ligands in asymmetric synthesis. Many enantioselective syntheses of vic-amino alcohols have been reported, but each structure has required its own synthetic route. This study presents a synthetic strategy leading to all eight possible isomers of a given beta-amino alcohol, starting from vinyl epoxides. The developed strategy focuses on the propensity of vinyl epoxides and vinylaziridines to be selectively ring-opened at the allylic position by suitable hard nucleophiles. Within this strategy, a novel large-scale aminolysis reaction and the synthesis of a trisubstituted N-H vinylaziridine are detailed.

Full text of DOI:10.1021/jo0262053

A Regio- a n d Ster eod iver gen t Rou te to All Isom er s of vic-Am in o
Alcoh ols
Berit Olofsson and Peter Somfai*
Department of Chemistry, Organic Chemistry, Royal Institute of Technology, S-100 44 Stockholm, Sweden
somfai@kth.se
Received J uly 17, 2002
Vicinal amino alcohols are substructures in several important natural products. They are also
frequently employed ligands in asymmetric synthesis. Many enantioselective syntheses of vic-amino
alcohols have been reported, but each structure has required its own synthetic route. This study
presents a synthetic strategy leading to all eight possible isomers of a given â-amino alcohol, starting
from vinyl epoxides. The developed strategy focuses on the propensity of vinyl epoxides and
vinylaziridines to be selectively ring-opened at the allylic position by suitable hard nucleophiles.
Within this strategy, a novel large-scale aminolysis reaction and the synthesis of a trisubstituted
N-H vinylaziridine are detailed.
In tr od u ction
reaction, as the choice of enolate decides which isomer
(syn/anti) will be the major product.
The â-amino alcohol moiety is found in a wide variety
of biologically active alkaloids and peptides;1 it is conse-
quently a common building block in the synthesis of
natural products.2 The importance of vicinal amino
alcohols is also well-recognized in asymmetric synthesis,
as many chiral auxiliaries and ligands contain this
substructure.3 Existing synthetic routes to enantiopure
amino alcohols often rely on the derivatization of the
available pool of amino acids, which limits the number
of accessible derivatives.4 Large efforts to develop asym-
metric routes to 1,2-amino alcohols have been made and
can be divided into two strategically different categories.
In the first class, the amino alcohol moiety is formed
by concomitant creation of a new C-C bond. Reported
enantio- or diastereoselectivities can be high, but the
reactions are often limited to substrates containing
certain functional groups. When one of the two stereo-
centers is set, the other can be created with good
diastereoselectivity, as in the case of addition of organo-
metallic nucleophiles to R-aminocarbonyls.4 By concur-
rent creation of two stereocenters, amino alcohols can be
obtained with high enantioselectivity, i.e., by addition of
nucleophiles to nitroalkenes5 or imines.1,6 Similar selec-
tivities can be obtained by reaction of chiral amino-
allylboranes and aldehydes.7 In this category, the addi-
tion of R-alkoxyenolates to aldimines is the most flexible
Alternatively, the amino alcohol moiety may be con-
structed without alteration of the carbon skeleton. The
substrates are primarily alkenes or alkene derivatives,
and the reactions proceed stereospecifically. Regioselec-
tivity is often a problem that can be circumvented only
when the substrate is substituted with groups having
different electronic or steric influence. This dilemma can
be exemplified by Sharpless aminohydroxylation of alk-
enes, which proceeds with high enantioselectivity but
often with moderate yields due to poor regioselectivity.8
With the advancement of diastereo- and enantioselective
syntheses of epoxides, cleavage of oxiranes by nitrogen
nucleophiles has become one of the most investigated
routes to vicinal amino alcohols.9 Both syn- and anti-
amino alcohols are available by employing cis- or trans-
epoxides, respectively. Also aziridines,10,11 cyclic sul-
fates,12 and carbonates13 can be ring-opened to give amino
alcohols.
Despite the great interest in the field of 1,2-amino
alcohols, no divergent route from a common starting
(7) Barrett, A. G. M.; Seefeld, M. A.; White, A. J . P. J . Org. Chem.
1996, 61, 2677-2685.
(8) (a) Li, G.; Chang, H.-T.; Sharpless, B. K. Angew. Chem., Int. Ed.
Engl. 1996, 35, 451. (b) O’Brien, P. Angew. Chem., Int. Ed. Engl. 1999,
38, 326-329.
(9) (a) Hayakawa, H.; Okada, N. M. M.; Miyashita, M. Tetrahedron
Lett. 1999, 40, 4589-4592. (b) Larrow, J . F.; Schaus, S. E.; J acobsen,
E. N. J . Am. Chem. Soc. 1996, 118, 7420-7421. (c) Mitsunobu, O. In
Comprehensive Organic Synthesis; Trost, B. M., Fleming, I., Eds.;
Pergamon: Oxford, 1991; Vol. 6, p Chapter 1.3. (d) Zwanenburg, B.
Pure Appl. Chem. 1999, 71, 423-430.
* Corresponding author. Phone (+46)-8-790 6960. Fax: (+46)-8-791
2333.
(1) Kobayashi, S.; Ishitani, H.; Ueno, M. J . Am. Chem. Soc. 1998,
120, 431-432.
(2) Castejon, P.; Moyano, A.; Pericas, M. A.; Riera, A. Tetrahedron
1996, 52, 7063.
(10) Takeuchi, H.; Koyama, K. J . Chem. Soc., Perkin Trans. 2 1981,
121-126.
(11) (a) Ibuka, T.; Nakai, K.; Akaji, M.; Tamamura, H.; Fujii, N.;
Yamamoto, Y. Tetrahedron 1996, 52, 11739-11752. (b) Cantrill, A.
A.; Osborn, H. M. I.; Sweeney, J . Tetrahedron 1998, 54, 2181-2208.
(c) Hwang, G.-I.; Chung, J .-H.; Lee, W. K. J . Org. Chem. 1996, 61,
6183-6188.
(3) Ager, D. J .; Prakash, I.; Schaad, D. R. Chem. Rev. 1996, 96, 835-
875.
(4) Reetz, M. T. Angew. Chem., Int. Ed. Engl. 1991, 30, 1531-1546.
(5) (a) Enders, D.; Haertwig, A.; Raabe, G.; Runsink, J . Eur. J . Org.
Chem. 1998, 1771-1792. (b) Enders, D.; Haertwig, A.; Runsink, J . Eur.
J . Org. Chem. 1998, 1793-1802.
(12) (a) Lohray, B. B.; Gao, Y.; Sharpless, K. B. Tetrahedron Lett.
1989, 30, 2623-2626. (b) Lohray, B. B.; Ahuja, J . R. J . Chem. Soc.,
Chem. Commun. 1991, 95-97.
(6) Hattori, K.; Yamamoto, H. Tetrahedron 1994, 50, 2785-2792.
10.1021/jo0262053 CCC: $22.00 © 2002 American Chemical Society
Published on Web 11/08/2002
8574
J . Org. Chem. 2002, 67, 8574-8583

Divergent Synthesis of vic-Amino Alcohols
SCHEME 1. Syn th etic Str a tegy
F IGURE 1. Vinyl epoxides used in the present study.
SCHEME 2. Syn th esis of Vin yl Ep oxid es 1
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 separate synthetic route for each isomer.
A divergent route leading to all possible isomers would
be a great simplification for studies on structure-activity
relationships of pharmacologically active derivatives
incorporating this structural motif. Such a route would
also allow optimization of the performance of chiral
ligands and auxiliaries containing this substructure.
We recently reported our preliminary findings on the
development of a route leading to all eight possible
isomers of a given 1,2-amino alcohol starting from a
readily synthesized substrate.14 The present paper de-
scribes investigations on the scope and limitations of the
reaction scheme, including a simplified synthesis of vinyl
epoxides by application of the enantioselective epoxida-
tion of dienes developed by Shi and co-workers.15 Fur-
thermore, a novel, large-scale aminolysis reaction and the
synthesis of a trisubstituted N-H vinylaziridine are
detailed.
of enantiomeric amino alcohol isomers can simply be
obtained by starting from ent-1.
Resu lts a n d Discu ssion
Figure 1 depicts a set of vinyl epoxides used in the
present study. The substrates were chosen to represent
variations of electronic character (1a vs 1b), terminal vs
internal olefin (1b vs 1c), steric hindrance (1d vs 1e),
and position of vinyl group substituent (1c-e vs 1f).
Vinyl epoxides 1a ,b were obtained from the corre-
sponding allylic alcohols using Sharpless asymmetric
epoxidation (SAE) followed by the Swern/Wittig proce-
dure (Scheme 2a),17 whereas 1c was obtained with SAE
of the corresponding dienol followed by benzylation
(Scheme 2b).18 The synthesis of vinyl epoxides 1d ,e was
simplified by application of the recently published asym-
metric epoxidation of dienes.15 This reaction was reported
with TMS-protected dienols, but could be applied to Bn-
protected dienols giving slightly lower enantioselectivities
(Scheme 2c). Epoxidation of benzylated hexadienol yielded
1d in 66% together with 10% of the corresponding
regioisomer, whereas 1e was epoxidized with complete
regioselectivity in 100% yield. Vinyl epoxide 1f was
synthesized by p-methoxybenzyl (PMB) protection of
corresponding epoxy alcohol (Scheme 2d).19,20 Enantio-
meric excesses were analyzed on the corresponding epoxy
alcohols for 1a ,b,f to g95% and on vinyl epoxides 1c-e
to g90%.21
The requirements for a generally applicable synthetic
route were readily available starting materials, flex-
ibility, predictability, and high regio- and diastereose-
lectivity. These demands could be met by choosing vinyl
epoxides 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.16 As depicted in Scheme 1, the syn-
thesis strategy designed to fulfill the above specifications
starts by ring-opening of epoxides 1 with a nitrogen
nucleophile. The opening can be performed either with
inversion or retention of stereochemistry, giving anti- and
syn-amino alcohols 2 and 3, respectively. Ring closure of
2 to the corresponding vinylaziridines 4 and subsequent
ring-opening with an oxygen nucleophile, either with
inversion or retention, would then give anti- and syn-
amino alcohols 5 and 6, all reactions taking place
regioselectively at the allylic position. The remaining set
(13) (a) Chang, H.-T.; Sharpless, B. Tetrahedron Lett. 1996, 37,
3219-3222. (b) Cho, G. Y.; Ko, S. Y. J . Org. Chem. 1999, 64, 8745-
8747.
(14) Olofsson, B.; Khamrai, U.; Somfai, P. Org. Lett. 2000, 2, 4087-
(17) 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.
4089.
(15) Frohn, M.; Dalkiewicz, M.; Tu, Y.; Wang, Z.-X.; Shi, Y. J . Org.
Chem. 1998, 63, 2948-2953.
(16) J aime, C.; Ortuno, R., M.; Font, J . J . Org. Chem. 1988, 53, 139-
141.
(18) See Supporting Information.
(19) Weigand, S.; Bruckner, R. Synlett 1997, 225-228.
(20) Lindstro¨m, U. M.; Somfai, P. Chem. Eur. J . 2001, 7, 94-98.
J . Org. Chem, Vol. 67, No. 24, 2002 8575

Olofsson and Somfai
TABLE 1. Am in olysis of Vin yl Ep oxid es 1 to a n ti-Am in o
Alcoh ols 2
improved from 2:1 to 3.5:1, at the expense of decreased
yield, when decreasing the power from 40 W for 11 min
to 30 W for 15 min.
As large-scale microwave chemistry is difficult to
perform, the aminolysis reaction was further investigated
using vinyl epoxides 1a ,b. Our first strategy involved the
use of protic solvents and excess ammonium hydroxide,
as amines have participated in epoxide openings per-
formed in various organic solvents.28 Pleasingly, when
1a was subjected to 10 equiv of NH4OH in EtOH at 70
°C in a sealed flask, slow formation of 2a occurred. The
reaction rate could be improved by employing a large
excess of NH4OH, which yielded 2a in 73% after 48 h of
heating. Addition of a catalytic amount of TsOH‚H2O
caused formation of the corresponding diol without
increasing the rate of formation of 2a . The change of
solvent to 2-methoxyethanol, which allowed heating to
120 °C, did not improve the results. Compared to the
original procedure with neat ammonia, the use of excess
NH4OH in protic solvents simplifies the handling without
shortening the reaction time.
Not satisfied with these results, we investigated if
there was a microwave effect29 in the aminolysis reaction
or if it would proceed with conventional heating. Gratify-
ingly, by heating vinyl epoxide 1b in NH4OH in a sealed
metal cylinder to 170 °C,30 complete conversion was
achieved within 4.5 h and 2b could be isolated in 93%
yield (Table 1, entry 2). This procedure was applied to
vinyl epoxide 1d , giving 2d in 72% yield and 6:1 regi-
oselectivity after only 1 h heating (entry 4). The result
could easily be improved to 82% and 9:1 regioselectivity
by decreasing the temperature to 140 °C, which was
sufficient also for the ring-opening of 1e (entry 5). The
reaction temperature could be decreased even further,
and amino alcohol 2a was isolated in excellent yield after
1 h at only 125 °C, albeit in 11:1 regioselectivity (entry
1). These results clearly indicate the absence of a
microwave effect. The regioisomeric mixtures obtained
with some substrates can most likely be optimized by
fine-tuning of reaction temperature and time. This novel
aminolysis method is the first practical large-scale pro-
tocol described for ring-opening of vinyl epoxides with
ammonia. The reaction is fast, stereospecific, and highly
regioselective. Furthermore, no special equipment is
needed, as the pressure reached at 125 °C in NH4OH is
moderate.
yield of 2 (%)a
micro-
oil
entry substrate
R1
R2
R3
R4
waveb bathc
1
2
3
4
5
6
1a
1b
1c
1d
1e
1f
PhCH2
BnO
BnO
H
Me
PMBO
H
H
H
H
Me
H
H
H
H
H
H
H
H
93
87
91d
93
CH2OPMB
CH2OBn
CH2OBn
H
88
100d
89f
84
82e
78f
CH2OBn
Isolated yields. 20-30 W, 8-15 min. c 125-170 °C, 1-4.5 h.
a
b
Regioisomeric mixture 11:1. e Regioisomeric mixture 9:1. f Re-
d
gioisomeric mixture 2:1.
Syn th esis of a n ti-Am in o Alcoh ols 2. Epoxides are
commonly ring-opened by sodium azide to afford azido
alcohols, which can be reduced to the corresponding
amino alcohols.22 Unfortunately, when vinyl epoxides are
treated with sodium azide, a mixture of products is
obtained due to a thermal [3,3]-rearrangement of the
initially formed allylic azide.23 Instead, vinyl epoxides 1
could be regioselectively and stereospecifically ring-
opened with ammonia to afford anti-amino alcohols 2.
The aminolysis of vinyl epoxides was originally performed
by prolonged heating in neat ammonia with tosic acid
as catalyst.24 Although this method gives good yields with
sterically unhindered substrates, it suffers from imprac-
tical handling, long reaction times and modest yields of
sterically hindered amino alcohols. To circumvent these
drawbacks a microwave-assisted aminolysis procedure
was designed, using ammonium hydroxide as nucleo-
phile.25,26 With this protocol the synthesis of anti-amino
alcohols 2 could be greatly improved due to simplified
handling, short reaction times, and high yielding reac-
tions also with sterically hindered substrates (Table 1).
When vinyl epoxides 1a ,b,f were irradiated at 30 W for
8 min in NH4OH, amino alcohols 2a ,b,f were formed with
complete regioselectivity (>20:1) in high yields (entries
1-3 and 6).27 Microwave irradiation of 1c afforded 2c,
together with a byproduct, which could be minimized by
decreasing the power to 15 W for 20 min (entry 3). Vinyl
epoxide 1d afforded amino alcohol 2d as a regioisomeric
mixture (11:1), the reason for which is unclear (entry 4).
When 1d was irradiated for 5 min at 50 W, the selectivity
was 6:1, whereas 10 min at 30 W gave an 11:1 selectivity.
This selectivity optimization confirmed the earlier ob-
served trend that decreased power gives improved regi-
oselectivity.25 Amino alcohol 2e was, as expected, ob-
tained with poor regioselectivity due to steric hindrance
at the allylic position (entry 5). The selectivity could be
Syn th esis of syn -Am in o Alcoh ols 3. Pd(0)-catalyzed
ring-opening of vinyl epoxides 1 in the presence of tosyl
isocyanate gave oxazolidinones 7 in high yields with
retention of configuration (Scheme 3, Table 2).31 Conver-
sion of 1 to 7 took place with complete diastereoselectivity
(>95%) when 1 contained additional vinylic substituents
(1c-f, entries 3-6). Unfortunately, the terminal vinyl
epoxides 1a ,b afforded 7a ,b as unseparable diastereo-
meric mixtures, the ratio of which could only be slightly
improved by optimizing the reaction conditions. Gratify-
(21) Analyzed by HPLC using ChiralCel OJ or ChiralCel OD-H.
(22) Bergmeier, S. C. Tetrahedron 2000, 56, 2561-2576.
(23) Lindstro¨m, U. M.; Somfai, P. Synthesis 1998, 109-117.
(24) Lindstro¨m, U. M.; Franckowiak, R.; Pinault, N.; Somfai, P.
Tetrahedron Lett. 1997, 38, 2027-2030.
(28) (a) Sekar, G.; Singh, V. K. J . Org. Chem. 1999, 64, 287-289.
(b) Cristau, H.-J .; Pirat, J .-L.; Drag, M.; Kafarski, P. Tetrahedron Lett.
2000, 41, 9781-9785.
(29) Perreux, L.; Loupy, A. Tetrahedron 2001, 57, 9199-9223.
(30) 170 °C was the maximum temperature reached in microwave
reactions in NH4OH at 50 W for 8 min.
(25) Lindstro¨m, U. M.; Olofsson, B.; Somfai, P. Tetrahedron Lett.
1999, 40, 9273-9276.
(26) Lidstrom, P.; Tierney, J .; Wathey, B.; Westman, J . Tetrahedron
2001, 57, 9225-9283.
(31) (a) Trost, B. M.; Sudhakar, A. R. J . Am. Chem. Soc. 1988, 110,
7933-7935. (b) Trost, B. M.; Sudhakar, A. R. J . Am. Chem. Soc. 1987,
109, 3792-3794.
(27) Regio- and diastereoselectivities were determined by 1H NMR.
8576 J . Org. Chem., Vol. 67, No. 24, 2002

Divergent Synthesis of vic-Amino Alcohols
SCHEME 3. Syn th esis of syn -Am in o Alcoh ols 3
SCHEME 4. Syn th esis of Azir id in es 4 a n d
a n ti-Am in o Alcoh ols 5
TABLE 3. Syn th esis of Azir id in es 4 a n d a n ti-Am in o
Alcoh ols 5
TABLE 2. Syn th esis of syn -Am in o Alcoh ols 3
yield (%)a
yield (%)a
entry substrate
R1
R2
R3
R4
4
5
entry substrate
R1
R2
R3
R4
7
9
3
1
2
3
4
5
6
2a
2b
2c
2d
2e
2f
PhCH2
BnO
BnO
H
Me
PMBO
H
H
H
H
Me
H
H
H
H
H
H
H
H
80
72
80
84
1
2
3
4
5
6
1a
1b
1c
1d
1e
1f
PhCH2
BnO
BnO
H
Me
PMBO
H
H
H
H
Me
H
H
H
H
H
H
H
H
82b 93c 100
88d 75c 97
CH2OPMB 60b 82
CH2OPMB 87 72
91
62c 74d
80e 67f
63
CH2OBn
CH2OBn
H
e
61f 95
CH2OBn
CH2OBn
H
94 80
93 84
98
86
CH2OBn
71
CH2OBn
a
b
Isolated yields. 23% 2c was recovered. c Isolation problems;
a
b
Isolated yields. Before separation of diastereomers. c dr 6:1.
see the text. dr 10:1. 13% 2e was recovered. f dr 2.5:1.
d
b
dr 14:1. e Not isolated; see the text. f Yield from 1d .
d
hindrance; 8 h reflux was needed for completion com-
pared to 1 h for 9a -d ,f.
Syn th esis of N-H Vin yla zir id in es 4. The two re-
maining amino alcohols 5 and 6 are regioisomers of 2
and 3. We envisaged the synthesis of 5 and 6 by ring-
opening of N-H vinylaziridines 4, which could be obtained
from anti-amino alcohols 2 (Scheme 1). Cyclization of
amino alcohols into N-H aziridines is known to be
difficult, having neither a nitrogen activating group nor
a good leaving group.35 We recently investigated this
transformation, and the best results were obtained with
an optimized Mitsunobu protocol employing PPh3 and
diisopropylazodicarboxylate (DIAD).36 Using this proce-
dure, aziridines 4 could be obtained in good yields
without involving activating groups (Scheme 4, Table 3).
N-H Vinylaziridines 4 were found to be unstable on silica
gel, which made purification on deactivated silica im-
portant. With this technique, the yield of aziridine 4b
could be raised from 30% to 72% (entry 2). However,
aziridine 4c was too unstable to allow for the difficult
separation from the formed Ph3PdO. This problem could
be circumvented by employing polymer-bound triphenyl-
phosphine, although this decreased the reaction rate, and
4c was isolated in 78% (entry 3). Surprisingly, aziridine
4d coevaporated with EtOAc, which made purification
troublesome, but it could finally be isolated in 62% yield
(entry 4).37
F IGURE 2. (Z)-4,5-cis-Oxazolidinone 8.
ingly, by equilibration of the initial product mixtures, the
kinetically obtained, poor ratios could be significantly
enhanced (1a dr ) 2:1 f 6:1, 1b dr ) 2:1 f 14:1, entries
1 and 2).27 A similar palladium-assisted equilibration of
vinyloxazolines was recently reported.32
Oxazolidinone 7d was formed along with a byproduct
in a 3:1 ratio, the structure of which has been identified
as (Z)-4,5-cis-oxazolidinone 8 (Figure 2). To the best of
our knowledge, an E f Z isomerization has not previ-
ously been reported in this reaction. As opposed to the
equilibration results above, the byproduct ratio could be
improved to 9:1 by decreasing the temperature (entry
4).33
Amino alcohols 3 could in principle be obtained from
7 either by sequential detosylation and hydrolysis or by
hydrolysis prior to detosylation. The latter method proved
inferior, as the corresponding N-tosyl amino alcohols
could not be selectively deprotected. Oxazolidinones 7
were detosylated using sodium naphthalide in THF to
the corresponding N-H derivatives 9 (Scheme 3, Table
2).34 At this stage the diastereomers of 9a ,b could be
separated by flash chromatography. Due to troublesome
purification of N-tosyl oxazolidinone 7d , the best yield
from 1d to 9d was obtained when 7d was used in unpure
form (entry 4). Subsequent basic hydrolysis of 9 afforded
syn-amino alcohols 3 in excellent yields (Scheme 3, Table
2). The hydrolysis of 9e was retarded due to sterical
Syntheses of trisubstituted N-H aziridines are rare and
described yields are moderate.38 This might be due to
(35) (a) Pearson, W. H.; Lian, B. W.; Bergmeier, S. C. In Compre-
hensive Heterocyclic Chemistry II, A review of the literature 1982-1995;
Padwa, A., Ed.; Pergamon: Elmsford, NY, 1996; Vol. 1A, pp 1-96. (b)
Tanner, D. Angew. Chem., Int. Ed. Engl. 1994, 33, 599-619. (c)
Hughes, D. L. Org. Prep. Proc. Int. 1996, 28, 127-164. (d) Osborn, H.
M. I.; Sweeney, J . Tetrahedron: Asymmetry 1997, 8, 1693-1715.
(36) Olofsson, B.; Wijtmans, R.; Somfai, P. Tetrahedron 2002, 58,
5979-5982.
(37) Other solvent systems destroyed the silica deactivation and
gave unpure aziridine.
(38) (a) Viallon, L.; Reinaud, O.; Capdevielle, P.; Maumy, M.
Tetrahedron 1996, 52, 13505-13614. (b) Wipf, P.; Henninger, T. C.;
Geib, S. J . J . Org. Chem. 1998, 63, 6088-6089.
(32) Cook, G. R.; Shanker, S. Tetrahedron Lett. 1998, 39, 3405-
3408.
(33) The temperature was decreased from room temperature to 0
°C; further decrease caused formation of a new byproduct.
(34) Heathcock, C. H.; Blumenkopf, T. A.; Smith, K. M. J . Org.
Chem. 1989, 54, 1548-1562.
J . Org. Chem, Vol. 67, No. 24, 2002 8577

Olofsson and Somfai
SCHEME 5. Syn th esis of syn -Am in o Alcoh ols 6
difficulties both in forming precursors as 2e and ring-
closing to aziridines, the reactions being retarded because
of sterical hindrance. To our delight, ring closure of 2e
to trisubstituted aziridine 4e was successful, and the
relatively unpolar 4e was easily isolated from Ph3PdO.
Although the reaction stopped before full conversion,39
4e could be isolated in 80% and the remaining 2e was
readily recovered (entry 5). The yield based on recovered
2e was an excellent 92%. Regioisomeric mixtures of 2 and
5, obtained in the aminolysis, can be used without
separation as both ring closures give aziridines 4. Sur-
prisingly, also the mixture of 2e and 5e obtained by
aminolysis of 1e could be ring-closed to 4e in good yield,
despite the sterical hindrance in 5e.
SCHEME 6. Rea r r a n gem en t a n d in Situ
Hyd r olysis to Hyd r oxy Am id es 12 F ollow ed by
Hyd r olysis to 6
Syn th esis of a n ti-Am in o Alcoh ols 5. Acidic hy-
drolysis of activated aziridines40 has been reported to
proceed with rather poor regioselectivity.10,41 There are
no reports on hydrolysis of N-H aziridines, which might
be due to the low reactivity of unactivated aziridines.35
To our delight, N-H vinylaziridines 4 could be hydrolyzed
into anti-amino alcohols 5 (Scheme 4) under acidic
conditions. Initial hydrolysis attempts with 4a were
performed with tosic acid in THF/H2O, affording 5a in
moderate yield. This result could be improved with
HClO4, and 5a was formed with complete regioselectivity
(>20:1) in 80% yield (Table 3, entry 1). The method was
applied to aziridines 4b-f, affording anti-amino alcohols
5b-f in good yields. The reaction proceeded with clean
SN2 inversion for substrates 4a -c,f, whereas amino
alcohol 5d surprisingly was formed in 10:1 diastereomeric
ratio (entry 4). As expected, trisubstituted vinylaziridine
4e behaved differently than 4a -d ,f under acidic condi-
tions. Amino alcohol 5e was formed as a 1:1 diastereo-
meric mixture, and optimization attempts with perchloric
acid failed. Also, LiClO4 was ineffective for this trans-
formation.42 Turning to Lewis acids, InCl3 at pH 4 gave
a 2:1 mixture of 6e and 5e, i.e., the unwanted diastere-
omer was the major compound. This might be explained
by internal delivery of water from In(H2O)63+ coordinated
to nitrogen.43 Fortunately, employment of 2 equiv of BF3‚
OEt2 in THF/H2O 10:1 yielded 5e in a 2.5:1 ratio (entry
5).41,44 Treatment with BBr3 instead resulted in partial
epimerization of aziridine 4e. The poorer diastereoselec-
tivity obtained in the Brønsted acid mediated solvolysis
of 4e can be reationalized by invoking a carbocation-type
of intermediate, the formation of which is somewhat
retarded when using Lewis acids.
oxazolines 11, followed by hydrolysis to 6 (Scheme 5).
Acetylation of aziridines 4 proceeded in nearly quantita-
tive yields, and N-acetylaziridines 10 were used as crude
products in the subsequent reaction, as they were un-
stable to standard purification.45 Acetylation of trisub-
stituted aziridine 4e was troublesome; standard condi-
tions (Ac2O, Et3N, catalytic amount DMAP) afforded a
mixture of 10e and an unidentified byproduct. When 4e
was subjected to Ac2O and Et3N without DMAP, solely
byproduct was formed, as was the case with AcCl and
Et3N. A large excess of Et3N (20 eqviv) and a catalytic
amount of DMAP improved the ratio. Surprisingly, clean
acetylation could be obtained with Ac2O and a stoichio-
metric amount of DMAP. To circumvent the problematic
workup of acid labile 10e, polymer-bound DMAP was
employed.
Several methods reported to cause the SNi rearrange-
ment were scanned with N-acetylaziridines 10a ; reflux
in chloroform was unsuccessful46 and TsOH‚H2O instead
afforded hydroxy amide 12a in moderate yield (Scheme
6).47 Early attempts with sodium iodide gave oxazoline
11a as a diastereomeric mixture,48 but fine-tuning of the
reaction conditions caused a slow, but clean, rearrange-
ment to 11a . Turning to Lewis acids, treatment with BF3‚
OEt2 resulted in a smooth rearrangement into oxazoline
11a ,49 whereas reaction with copper triflate was slow.50
Despite the clean rearrangement, 11a could only be
isolated in 55% yield. Unexpectedly, 11a was partly
hydrolyzed during purification,51 furnishing a mixture of
11a and hydroxy amide 12a after flash chromatography.
The lability of oxazoline 11a caused us to focus on
formation of 12a instead. Returning to the TsOH‚H2O-
catalyzed reaction, the results indicated in situ hydrolysis
of 11a to 12a . This could be proved by treating oxazoline
11a with TsOH‚H2O, which afforded 12a in high yield.
Apparently, when present during the rearrangement,
water causes byproduct formation. Unfortunately, rear-
rangement was retarded both with anhydrous TsOH and
camphorsulfonic acid. As Brønstedt acids seemed inef-
fective, we speculated if in situ hydrolysis of 11a to 12a
would be possible also in the BF3‚OEt2 rearrangement.
Indeed, by addition of 10% water to the reaction mixture
after complete formation of 11a , hydroxy amide 12a was
slowly formed along with byproducts (Scheme 6). Chang-
ing the solvent from toluene to THF considerably in-
Syn th esis of syn -Am in o Alcoh ols 6. Ring-opening
of aziridines 4 with retention of configuration would yield
syn-amino alcohols 6. Our synthetic strategy focused on
an SNi rearrangement of N-acetylaziridines 10 into
(39) Optimization attempts failed; neither prolonged reaction time
nor a large excess of reagents improved the conversion; instead, a
byproduct was formed.
(40) Ibuka, T.; Nakai, K.; Habashita, H.; Hotta, Y.; Otaka, A.;
Tamamura, H.; Fujii, N. J . Org. Chem. 1995, 60, 2044-2058.
(41) Prasad, B. A. B.; Sekar, G.; Singh, V. K. Tetrahedron Lett. 2000,
41, 4677-4679.
(42) (a) Parrodi, C. A.; Vazquez, V.; Quintero, L.; J uraristi, E. Synth.
Commun. 2001, 31, 3295-3302. (b) Yadav, J . S.; Reddy, B. V. S.;
J yothirmai, B.; Murty, M. S. R. Synlett 2002, 53-56.
(43) (a) Yadav, J . S.; Reddy, B. V. S.; Abraham, S.; Sabitha, G.
Tetrahedron Lett. 2002, 43, 1565-1567. (b) Fringuelli, F.; Pizzo, F.;
Vaccaro, L. J . Org. Chem. 2001, 66, 3554-3558.
(44) Reduced temperature considerably decreased the reactivity, and
with a catalytic amount of acid, the reaction proceeded only at reflux
with poor selectivity (dr 1.3:1).
(45) Lindstro¨m, U. M.; Somfai, P. J . Am. Chem. Soc. 1997, 119,
8385-8386.
(46) Cardillo, G.; Gentilucci, L.; Tolomelli, A.; Tomasini, C. Tetra-
hedron Lett. 1997, 38, 6953-6956.
8578 J . Org. Chem., Vol. 67, No. 24, 2002

Divergent Synthesis of vic-Amino Alcohols
TABLE 4. Syn th esis of syn -Am in o Alcoh ols 6
SCHEME 7. Rea r r a n gem en t to Oxa zolid in on e 14e
F ollow ed by Hyd r olysis to 6e
yield (%)a
entry substrate
R1
R2
R3
R4
12
6
1
2
3
4
5
6
4a
4b
4c
4d
4e
4f
PhCH2
BnO
BnO
H
Me
PMBO
H
H
H
H
Me
H
H
H
H
H
H
H
H
71
73
95b
92b
91c
CH2OPMB 73
CH2OBn
CH2OBn
H
74d 93b
70
73
e
CH2OBn
84c
a
b
d
Isolated yields. Acidic hydrolysis. c Basic hydrolysis. dr 10:
1. e See the text.
were investigated. Oxazoline 11e could be isolated in
89%, but reduction of this species with NaBCNH3 in
acidic medium followed by hydrolysis gave a mixture of
compounds.54 Instead, 6e could be obtained via BOC-
protection of aziridine 4e to BOC-aziridine 13e and
subsequent rearrangement to oxazolidinone 14e (Scheme
7).55 The BF3‚OEt2-induced rearrangement was con-
ducted with crude 13e, and 14e was obtained as a
separable mixture of diastereomers (2.3:1) in 66% com-
bined yield. Oxazolidinone 14e was easily hydrolyzed
with 1 M KOH to syn-amino alcohol 6e in 98% yield
(Scheme 7).
creased the hydrolysis rate, and 12a could be isolated in
71% yield from 4a . (Table 4, entry 1).
The rearrangement proceeded, as expected, with com-
plete diastereoselectivity (dr > 20:1) and gratifyingly also
with complete regioselectivity (>20:1). The latter 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. The timing of the
water addition is crucial: when added too early, the
diastereoselectivity is diminished, as water opens the
N-acetylaziridine; when added too late, the formation of
byproducts increases.
Deter m in ation of Relative Ster eoch em istr y. Amino
alcohols 2, 5, and 6 were converted into the corresponding
oxazolidinones.18 The ring protons (H4, H5) of these
compounds have coupling constants (J H4,H5) that are
larger for the cis- than the trans-configuration.7 When
anti-amino alcohols 2a -d ,f and 5a -d ,f were converted
into oxazolidinones 15a -d ,f and 16a -d ,f, the coupling
constants of the ring protons were 7.8-8.3 and 7.2-8.3
Hz, respectively, which is consistent with the cis-config-
uration. Oxazolidinones 9a -f (Scheme 3) show the rela-
tive configuration of syn-amino alcohols 3a -f. Com-
pounds 9a -d ,f have coupling constants ranging from 5.0
to 7.2 Hz, confirming the trans-configuration. Finally,
syn-amino alcohols 6a -d ,f yielded oxazolidinones 14a -
d ,f with coupling constants between 5.5 and 6.6 Hz,
agreeing with the trans-configuration. The relative con-
figurations of 9e, 14e, 15e, and 16e were confirmed by
NOESY experiments. Interactions between the ring
proton (H4) and the methyl group at C5 were present for
oxazolidinones 15e and 16e, indicating the cis-configu-
ration.
Also hydroxy amides 12b-f were formed with complete
regioselectivity in >70% yield over two steps (Table 4,
entries 2-6). The diastereoselectivity was likewise high
(dr > 20:1) in all cases apart from 12d (dr 10:1), the
reason for which is unclear. When 10e was rearranged
with byproduct present, 12e was formed as a diastereo-
meric mixture, the ratio of which depended on the
amount of byproduct.
Hydroxy amides 12a ,b,e were hydrolyzed in 5% aque-
ous H2SO4, giving syn-amino alcohols 6a ,b,e in excellent
yields (Scheme 6, Table 4). Due to the acid lability of the
PMB group, hydroxy amides 12c,f were hydrolyzed in 1
M KOH, which gave a slower reaction (Table 4, entries
3 and 6). In all cases the reaction proceeded without
alterations of the stereochemistry. The hydrolysis of 12e
was severely retarded by sterical hindrance. Several
reaction conditions were screened without success; acidic
media caused decomposition, whereas basic media was
ineffective.52 Conversion of 12e to the corresponding
acyloxazolidinone followed by LiOOH treatment only
resulted in recovered amide 12e.53 Alternative strategies
toward syn-amino alcohol 6e avoiding hydroxy amide 12e
Con clu sion s
We have presented a synthetic strategy that provides
a straightforward route from vinyl epoxides 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 vinyl epoxides and vinyl-
aziridines 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. The synthesis of vinyl epoxides
has been simplified by application of an enantioselective
(47) Nishiguchi, T.; Tochio, H.; Nabeya, A.; Iwakura, Y. J . Am.
Chem. Soc. 1968, 91, 5835-5845.
(48) Foglia, T. A.; Gregory, L. M.; Maerker, G. J . Org. Chem. 1970,
35, 3779-3785.
(49) Hori, K.; Nishiguchi, T.; Nabeya, A. J . Org. Chem. 1997, 62,
3081-3088.
(50) Ferraris, D.; Drury, W. J ., III; Cox, C.; Lectka, T. J . Org. Chem.
1998, 63, 4568-4569.
(51) (a) Lee, K.-Y.; Kim, Y.-H.; Park, M.-S.; Oh, C.-Y.; Ham, W.-H.
J . Org. Chem. 1999, 64, 9450-9458. (b) Greene, T. W.; Wuts, P. G. M.
Protective Groups in Organic Synthesis, 3rd ed.; Wiley: New York,
1999.
(52) Acidic conditions gave no reaction/decomposition: 5% H2SO4,
rt to reflux; 5% H2SO4 in THF/H2O 1:1, rt to reflux; 5 equiv BF3‚OEt2
in THF/H2O 10:1, rt to reflux; 10 equiv TsOH‚H2O in THF, rt to reflux.
Basic conditions gave no reaction: 1 M KOH in EtOH/H2O 1:1, 150
°C; NH4OH in EtOH/H2O 1:1, 140 °C; NH4OH in H2O, 50 W 15 min;
LiOH, H2O2 in THF/H2O 3:1, reflux. NaOEt in EtOH, reflux. NH2-
NH2‚H2O afforded reduced alkene with intact amide group; Ca/NH3
cleaved both the amide and benzyl group.
(54) Gosmann, G.; Guillaume, D.; Husson, H.-P. Tetrahedron Lett.
1996, 37, 4369-4372.
(55) Sepulveda-Arques, J .; Armero-Alarte, T.; Acero-Alarcon, A.;
Zaballos-Garcia, E.; Solesio, B. Y.; Carrera, J . E. Tetrahedron 1996,
52, 2097-2102.
(53) Evans, D. A.; Ratz, A. M.; Huff, B. E.; Sheppard, G. S. J . Am.
Chem. Soc. 1995, 117, 3448-3467.
J . Org. Chem, Vol. 67, No. 24, 2002 8579

Olofsson and Somfai
(15.0 mg, 15 µmol) in THF (1 mL) was added distilled (iPrO)3P
(36 µL, 0.146 mmol). The mixture was stirred for 20 min before
addition of distilled TsNCO (44 µL, 0.292 mmol) and vinyl
epoxide 1a (25.0 mg, 0.146 mmol) in THF (1 mL), and the
resultant mixture was refluxed for 36 h. Water was added,
and the mixture was extracted with Et2O. The organic phase
was washed with water and brine, dried (Na2SO4), and
concentrated. Flash chromatography (pentane/EtOAc 5:1 f
2:1) afforded oxazolidinone 7a as a yellow oil in 82% yield (43.7
mg, 0.117 mmol). NMR analysis indicated a diastereomeric
ratio of 4.5:1. 1H NMR (300 MHz, CDCl3, major isomer): δ
7.92 (d, 2H, J ) 8.5 Hz), 7.38-7.12 (m, 7H), 5.77 (ddd, 1H, J
) 16.8, 9.9, 8.2 Hz), 5.42 (d, 1H, J ) 16.8 Hz), 5.36 (d, 1H, J
) 9.9 Hz), 4.46 (dd, 1H, J ) 8.2, 4.6 Hz), 4.12 (dt, 1H, J ) 8.0,
4.6 Hz), 2.85-2.63 (m, 2H), 2.45 (s, 3H), 2.08-1.87 (m, 2H).
13C NMR (75 MHz, CDCl3): δ 151.3, 145.4, 139.6, 134.9, 133.5,
129.6, 128.5, 128.4, 128.3, 126.3, 120.5, 79.1, 64.7, 35.4, 30.7,
21.8. IR (neat): 2926, 2864, 1782, 1369 cm-1. HRMS (EI+)
exact mass calcd for C20H21NO4S (M): 371.1191. Found:
371.1182.
diene epoxidation. Furthermore, a novel, practical, large-
scale aminolysis reaction and the successful synthesis of
a trisubstituted N-H vinylaziridine have been detailed.
Exp er im en ta l Section
This Experimental Section contains typical procedures for
formation of compounds 2-7, 9, 10, 12, and 13 and analytical
data of all amino alcohols. For general experimental details
and analytical data of the remaining compounds, see the
Supporting Information.
Typ ica l P r oced u r e for th e Am in olysis of Ep oxid es 1
to a n ti-Am in o Alcoh ols 2. (3S,4R)-4-Am in o-1-p h en ylh ex-
5-en -3-ol (2a ):23 Micr ow a ve Ir r a d ia tion . Vinyl epoxide 1a
(15.0 mg, 86 µmol) in NH4OH (25%, 2.5 mL) was subjected to
focused microwave irradiation at 30 W for 8 min. The solvent
was evaporated at reduced pressure and the crude product
chromatographed (EtOAc/MeOH 6:1 + 1% NH3) to give anti-
amino alcohol 2a as a yellow oil in 93% yield (15.3 mg, 80
µmol).
With ou t Equ ilibr a tion : (4S,5R)-5-Ben zyloxym eth yl-4-
[3-(4-m eth oxyben zyloxy)-1(E)-pr open yl]-3-(tolu en e-4-su l-
fon yl)oxa zolid in -2-on e (7c) was prepared from vinyl epoxide
1c as described for 7a , except that the reaction was run at
room temperature for 1 h. The product was isolated as a yellow
Con ven tion a l Hea tin g. Vinyl epoxide 1a (0.55 g, 3.1
mmol) in NH4OH (25%, 7 mL) in a sealed tube was heated to
125 °C, in a preheated oil bath, for 1 h. The mixture was
extracted with 4 × 10 mL of Et2O, then the organic phase was
dried (Na2SO4) and concentrated. Flash chromatography as
above afforded 2a in 91% combined yield (regioisomeric
mixture 11:1).
1
oil in 87% yield. H NMR (400 MHz, CDCl3): δ 7.87 (d, 2H, J
) 8.4 Hz), 7.37-7.22 (m, 7H), 7.19 (d, 2H, J ) 8.7 Hz), 6.89
(d, 2H, J ) 8.7 Hz), 5.98 (dt, 1H, J ) 15.4, 5.0 Hz), 5.77 (ddt,
1H, J ) 15.4, 8.3, 1.5 Hz), 4.83 (dd, 1H, J ) 8.3, 3.8 Hz), 4.47
(s, 2H), 4.46 (s, 2H), 4.24 (q, 1H, J ) 3.8 Hz), 4.03 (dd, 2H, J
) 5.0, 1.5 Hz), 3.81 (s, 3H), 3.56 (dd, 1H, J ) 11.1, 3.8 Hz),
3.52 (dd, 1H, J ) 11.1, 3.8 Hz). 13C NMR (100 MHz, CDCl3):
δ 159.7, 151.9, 145.7, 137.4, 135.5, 133.4, 130.4, 139.9, 129.8,
129.0, 128.5, 128.2, 128.1, 114.3, 79.1, 74.0, 72.7, 69.2, 69.0,
60.9, 55.7, 22.1. IR (neat): 3062, 2983, 1784, 1371 cm-1. [R]D:
-11.2 (c 1.80, CH2Cl2). HRMS (CI+) exact mass calcd for
(2R,3R)-3-Am in o-1-ben zyloxyp en t-4-en -2-ol (2b)23 was
prepared from vinyl epoxide 1b as described for 2a . Microwave
irradiation at 30 W for 8 min gave 87% yield. Conventional
heating at 170 °C for 4.5 h gave 93% yield.
(2R,3R)-3-Am in o-1-ben zyloxy-6-(4-m eth oxyben zyloxy)-
4(E)-h exen -2-ol (2c) was prepared from vinyl epoxide 1c as
described for 2a . Microwave irradiation at 15 W for 20 min
gave 2c as a low-melting solid in 88% yield. 1H NMR (400
MHz, CDCl3): δ 7.35-7.27 (m, 5H), 7.25 (d, 2H, J ) 8.7 Hz),
6.87 (d, 2H, J ) 8.7 Hz), 5.75 (m, 2H), 4.52 (s, 2H), 4.42 (s,
2H), 3.97 (d, 2H, J ) 4.2 Hz), 3.80 (s, 3H), 3.77 (m, 1H), 3.51
(m, 3H), 2.16 (br s, 3H). 13C NMR (100 MHz, CDCl3): 159.2,
138.0, 133.4, 130.3, 129.4, 128.4, 128.3, 127.8, 113.8, 73.5, 72.7,
71.9, 71.7, 70.0, 55.6, 55.3. IR (neat): 3583, 3377 (br), 3922,
2852 cm-1. [R]D: +2.5 (c 0.25, CH2Cl2). HRMS (CI+) exact
mass calcd for C21H28NO4 (M + H): 358.2018. Found: 358.2014.
(2R,3S)-3-Am in o-6-ben zyloxy-4(E)-h exen -2-ol (2d )23 was
prepared from vinyl epoxide 1d as described for 2a . Microwave
irradiation at 30 W for 10 min gave 2d in 100% combined yield
(regioisomeric ratio 11:1). Conventional heating at 140 °C for
1 h gave 82% combined yield (regioisomeric ratio 9:1). [R]D:
-6.8 (c 1.00, CH2Cl2).
C
29H31NO7S (M): 537.1821. Found: 537.1819.
Typ ica l P r oced u r e for th e Detosyla tion of 7 to Oxa zo-
lid in on es 9. (4S,5S)-5-P h en eth yl-4-vin yloxa zolid in -2-on e
(9a ). Sodium naphthalide was prepared by stirring naphtha-
lene (200 mg, 1.6 mmol) and small pieces of sodium (50 mg,
2.2 mmol) in freshly distilled DME (3 mL) overnight. To a
solution of oxazolidinone 7a (30.0 mg, 81 µmol) in THF (0.5
mL) at -78 °C was dropwise added sodium naphthalide until
the blackish color persisted. The mixture was stirred for 15
min, quenched with EtOH, and allowed to reach 0 °C before
addition of phosphate buffer (pH 7). The mixture was extracted
with Et2O, then the organic phase was washed with water and
brine, dried (Na2SO4), and concentrated. The diastereomers
could be separated by careful flash chromatography (pentane/
EtOAc 4:1 f 1:1), affording the N-H oxazolidinone 9a as a
colorless oil in 93% yield (16.3 mg, 75 µmol). 1H NMR (400
MHz, CDCl3): δ 7.32-7.17 (m, 5H), 5.76 (ddd, 1H, J ) 17.4,
10.2, 7.4 Hz), 5.40 (br s, 1H), 5.30-5.22 (m, 2H), 4.21 (ddd,
1H, J ) 11.3, 7.0, 4.3 Hz), 3.96 (br t, 1H, J ) 7.0 Hz), 2.87
(ddd, 1H, J ) 14.3, 9.8, 5.3 Hz), 2.73 (ddd, 1H, J ) 14.3, 9.4,
7.2 Hz), 2.12-1.93 (m, 2H). 13C NMR (100 MHz, CDCl3): δ
158.3, 140.3, 135.3, 128.4, 129.3, 126.1, 119.1, 81.4, 61.3, 35.7,
31.3. IR (neat): 3361 (br), 2933,2808, 1749 cm-1. [R]D: -45.7
(c 0.14, CH2Cl2). HRMS (EI+) exact mass calcd for C13H15NO2
(M): 217.1103. Found: 217.1103.
(3R,4S)-4-Am in o-7-ben zyloxy-4-m eth yl-5(E)-h ep ten -3-
ol (2e) was prepared from vinyl epoxide 1e as described for
2a . Microwave irradiation at 40 W for 11 min gave 2e as a
colorless oil in 89% combined yield (regioisomeric ratio 2:1).
Conventional heating at 140 °C for 1 h gave 78% combined
1
yield (regioisomeric ratio 2:1). H NMR (400 MHz, CDCl3): δ
7.37-7.26 (m, 5H), 5.81 (d, 1H, J ) 15.8 Hz), 5.72 (dt, 1H, J
) 15.8, 5.6 Hz), 4.52 (s, 2H), 4.04 (d, 2H, J ) 5.6 Hz), 3.17
(dd, 1H, J ) 10.5, 2.2 Hz), 1.88 (br s, 3H), 1.51 (ddq, 1H, J )
13.9, 7.3, 2.2 Hz), 1.21 (s, 3H), 1.18 (m, 1H), 1.00 (t, 3H, J )
7.3 Hz). 13C NMR (100 MHz, CDCl3): δ 138.3, 138.2, 128.3,
127.7, 127.6, 125.1, 79.4, 72.2, 70.6, 56.8, 26.1, 24.8, 11.3. IR
(neat): 3356, 2964, 2873 cm-1. [R]D: +21.6 (c 0.76, CH2Cl2).
HRMS (CI+) exact mass calcd for C15H24NO2 (M + H):
250.1807. Found: 250.1811.
Typ ica l P r oced u r e for th e Hyd r olysis of 9 to syn -
Am in o Alcoh ols 3. (3S,4S)-4-Am in o-1-p h en yl-5-h exen -3-
ol (3a ). A solution of oxazolidinone 9a (12.6 mg, 58 µmol) in 1
M KOH (EtOH/H2O 2:1) was refluxed for 1.5 h. Aqueous NaOH
(2 M) was added, and the mixture was extracted several times
with Et2O. The organic phase was washed with brine, dried
(Na2SO4), and concentrated. The crude product was pushed
through a short silica plug to afford syn-amino alcohol 3a as
a yellow oil in 100% yield (11.1 mg, 58 µmol). 1H NMR (400
(2R,3R)-3-Am in o-4-ben zyloxym eth yl-1-(4-m eth oxyben -
zyloxy)p en t-4-en -2-ol (2f)20 was prepared from vinyl epoxide
1f as described for 2a . Microwave irradiation at 30 W for 8
min gave 2e in 84% yield.
Typ ica l P r oced u r es for th e Rin g Op en in g of Vin yl
Ep oxid es 1 To Give Oxa zolid in on es 7. With Equ ilibr a -
tion : (4S,5S)-5-P h en eth yl-3-(tolu en e-4-su lfon yl)-4-vin y-
56
loxa zolid in -2-on e (7a ). To a solution of (dba)3Pd2‚CHCl3
(56) dba ) dibenzylideneacetone.
8580 J . Org. Chem., Vol. 67, No. 24, 2002

Divergent Synthesis of vic-Amino Alcohols
MHz, CDCl3): δ 7.30-7.16 (m, 5H), 5.78 (ddd, 1H, J ) 17.2,
10.5, 7.4 Hz), 5.19 (dt, 1H, J ) 17.2, 1.2 Hz), 5.13 (dt, 1H, J )
10.5, 1.2 Hz), 3.32 (ddd, 1H, J ) 10.2, 7.4, 3.1 Hz), 3.14 (t, 1H,
J ) 7.4 Hz), 2.88 (ddd, 1H, J ) 13.9, 10.2, 5.1 Hz), 2.69 (ddd,
1H, J ) 13.9, 10.2, 7.0 Hz), 2.17 (br s, 3H), 1.85 (m, 1H), 1.69
(m, 1H). 13C NMR (100 MHz, CDCl3): δ 142.1, 139.9, 128.3,
128.2, 125.6, 115.8, 73.2, 59.5, 35.7, 32.2. IR (neat): 3357 (br),
2920, 2860 cm-1. [R]D: -27.5 (c 0.63, CH2Cl2). HRMS (EI+)
exact mass calcd for C12H18NO (M + H): 192.1388. Found:
192.1377.
solution of PPh3 (0.19 mg, 0.73 mmol) in THF (2 mL) at 0 °C
was added DIAD (0.14 mL, 0.73 mmol). After 20 min amino
alcohol 2a (0.10 g, 0.52 mmol) in THF (1.5 mL) was added,
and the resultant mixture was refluxed for 17 h. The solvent
was evaporated at reduced pressure, Et2O was added to the
crude product, and the mixture was stored overnight in the
freezer. Precipitated Ph3PO was removed by filtration and
careful flash chromatography on deactivated silica (10% Et3N
during packing), (pentane f pentane/EtOH 10:1) afforded
vinylaziridine 4a in 80% yield.
(2R,3S)-3-Am in o-1-ben zyloxy4-p en ten -2-ol (3b) was pre-
pared from oxazolidinone 9b as described for 3a and isolated
as a low-melting solid in 97% yield. 1H NMR (300 MHz,
CDCl3): δ 7.38-7.24 (m, 5H), 5.82 (ddd, 1H, J ) 17.3, 10.4,
6.9 Hz), 5.20 (d, 1H, J ) 17.3 Hz), 5.11 (d, 1H, J ) 10.4 Hz),
4.56 (AB-q, 2H, J ) 11.9 Hz), 3.58 (m, 2H), 3.50 (m, 1H), 3.40
(br t, 1H, J ) 6.9 Hz), 2.00 (br s, 3H). 13C NMR (100 MHz,
CDCl2): δ 139.2, 137.8, 128.3, 127.6, 115.9, 73.5, 73.0, 71.7,
56.2. IR (neat): 3356 (br), 2904, 2864 cm-1. [R]D: -9.1 (c 0.65,
CH2Cl2). HRMS (EI+) exact mass calcd for C12H18NO2 (M +
H): 208.1338. Found: 208.1340.
(2R,3S)-3-Am in o-1-ben zyloxy-6-(4-m eth oxyben zyloxy)-
4(E)-h exen -2-ol (3c) was prepared from oxazolidinone 9c as
described for 3a and isolated as yellow crystals in 91% yield.
mp 70-71 °C. 1H NMR (400 MHz, CDCl3): δ 7.34-7.27 (m,
5H), 7.25 (d, 2H, J ) 8.7 Hz), 6.88 (d, 2H, J ) 8.7 Hz), 5.75
(dt, 1H, J ) 15.6, 4.8 Hz), 5.69 (dd, 1H, J ) 15.6, 6.0 Hz), 4.56
(AB-q, 2H, J ) 12.1 Hz), 4.42 (s, 2H), 3.95 (d, 2H, J ) 4.8 Hz),
3.80 (s, 3H), 3.59-3.40 (m, 4H), 1.96 (br s, 3H). 13C NMR (100
MHz, CDCl3): δ 159.2, 138.0, 130.2, 129.4, 128.4, 128.3, 127.8,
113.8, 73.5, 73.3, 72.0, 71.8, 69.9, 55.3, 55.3. IR (neat): 3583,
3357 (br), 2920, 2856 cm-1. [R]D: -20.3 (c 1.10, CH2Cl2). HRMS
(CI+) exact mass calcd for C21H28NO4 (M + H): 358.2018.
Found: 358.2021.
With P olym er -Bou n d Tr ip h en ylp h osp h in e: (2S,3R)-2-
Ben zyloxym eth yl-3-[3-(4-m eth oxyben zyloxy)-1(E)-p r op e-
n yl]a zir id in e (4c). To amino alcohol 2c (8.1 mg, 23 µmol) and
polymer-bound PPh3 (15.2 mg, 45 µmol (3 mmol/g)) in THF (1
mL) at 0 °C was added DIAD (8.7 µL, 45 µmol). The resultant
mixture was refluxed for 26 h, after which some 2c still
remained. The solvent was evaporated at reduced pressure,
then careful flash chromatography on deactivated silica (10%
Et3N during packing, pentane/EtOAc 8:1 f EtOAc/MeOH 10:1
+ 1% NH4OH) afforded vinylaziridine 4c as a colorless oil in
78% yield (4.6 mg, 13.6 µmol) based on recovered 2c (1.9 mg,
1
5.3 µmol). H NMR (400 MHz, CDCl3): δ 7.37-7.27 (m, 5H),
7.26 (d, 2H, J ) 8.7 Hz), 6.88 (d, 2H, J ) 8.7 Hz), 5.88 (dt, 1H,
J ) 15.4, 5.8 Hz), 5.32 (dd, 1H, J ) 15.4, 8,3 Hz), 4.55 (d, 2H,
J ) 2.5 Hz), 4.44 (s, 2H), 3.97 (d, 2H, J ) 5.8 Hz), 3.80 (s,
3H), 3.60 (dd, 1H, J ) 10.3, 4.0 Hz), 3.47 (dd, 1H, J ) 10.3,
5.5 Hz), 2.37 (br d, 1H, J ) 8.0 Hz), 2.19 (br s, 1H), 1.60 (br s,
1H). 13C NMR (100 MHz, CDCl3): δ 159.6, 132.6, 132.5, 130.7,
129.8, 128.8, 128.1, 114.2, 73.5, 72.4, 70.13, 55.7. IR (neat):
3377 (br), 2956, 2858 cm-1. [R]D: +11.9 (c 1.08, CH2Cl2). HRMS
(CI+) exact mass calcd for C21H26NO3 (M + H): 340.1913.
Found: 340.1912.
Typ ica l P r oced u r e for th e Solvolysis of Azir id in es 4
in to a n ti-Am in o Alcoh ols 5. HClO4 P r oced u r e: (3S,4R)-
4-Am in o-6-p h en yl-1-h exen -3-ol (5a ). To a solution of viny-
laziridine 4a (30.0 mg, 0.173 mmol) in THF (3 mL) and H2O
(2.4 mL) was added HClO4 (15 µL, 0.173 mmol), and the
solution was heated to 50 °C for 7 h. After addition of K2CO3,
the mixture was stirred for 20 min, filtered, and concentrated.
Flash chromatography (EtOAc/MeOH 10:1+ 1% NH4OH)
afforded amino alcohol 5a as a low-melting solid in 80% yield
(2R,3R)-3-Am in o-6-ben zyloxy-4(E)-h exen -2-ol (3d ) was
prepared from oxazolidinone 9d as described for 3a and
isolated as a colorless oil in 95% yield. 1H NMR (400 MHz,
CDCl3): δ 7.36-7.27 (m, 5H), 5.78 (dt, 1H, J ) 15.6, 5.2 Hz),
5.70 (dd, 1H, J ) 15.6, 6.8 Hz), 4.52 (s, 2H), 4.02 (d, 2H, J )
5.2 Hz), 3.45 (dq, 1H, J ) 7.0, 6.2 Hz), 3.06 (br t, 1H, J ) 6.9
Hz), 2.06 (br s, 3H), 1.18 (d, 3H, J ) 6.2 Hz). 13C NMR (125
MHz, CDCl3): δ 138.6, 135.3, 128.8, 128.4, 128.2, 128.1, 72.8,
70.7, 70.7, 60.4, 20.1. IR (neat): 3356, 2970, 2858 cm-1. [R]D:
+14.8 (c 0.60, CH2Cl2). HRMS (CI+) exact mass calcd for
1
(26.6 mg, 0.139 mmol). H NMR (300 MHz, CDCl3): δ 7.33-
7.16 (m, 5H), 5.86 (ddd, 1H, J ) 17.3, 10.7, 6.1 Hz), 5.34 (dt,
1H, J ) 17.3, 1.5 Hz), 5.25 (dt, 1H, J ) 10.7, 1.5 Hz), 4.07 (br
s, 1H), 2.94-2.76 (m, 3H), 2.62 (ddd, 1H, J ) 14.0, 9.9, 6.9
Hz), 1.94 (br s, 3H), 1.91-1.76 (m, 1H). 1.63-1.49 (m, 1H).
13CNMR (67.5 MHz, CDCl3): δ 141.8, 136.6, 128.5, 128.3,
125.9, 117.0, 75.0, 54.5, 35.4, 32.8. IR (neat): 3373 (br), 2922,
2864 cm-1. [R]D: -15.8 (c 5.23, CH2Cl2). HRMS (EI+) exact
mass calcd for C12H18NO (M + H): 192.1388. Found: 192.1390.
C
13H20NO2 (M + H): 222.1494. Found: 222.1492.
(3R,4R)-4-Am in o-7-ben zyloxy-4-m eth yl-5(E)-h ep ten -3-
ol (3e) was prepared from oxazolidinone 9e as described for
3a and isolated as a yellow oil in 98% yield. 1H NMR (400
MHz, CDCl3): δ 7.37-7.27 (m, 5H), 5.79 (d, 1H, J ) 15.8 Hz),
5.73 (dt, 1H, J ) 15.8, 4.8 Hz), 4.52 (s, 2H), 4.03 (d, 2H, J )
4.8 Hz), 3.15 (dd, 1H, J ) 10.3, 2.0 Hz), 1.97 (br s, 3H), 1.50
(m, 1H), 1.28 (m, 1H), 1.11 (s, 3H), 1.02 (t, 3H, J ) 7.3 Hz).
13C NMR (125 MHz, CDCl3): δ 140.1, 138.2, 128.4, 127.8,
127.7, 125.0, 78.6, 72.4, 70.6, 56.8, 24.0, 21.3, 11.6. IR (neat):
3356, 2970, 2873 cm-1. [R]D: +15.9 (c 2.02, CH2Cl2). HRMS
(CI+) exact mass calcd for C15H24NO2 (M + H): 250.1807.
Found: 250.1814.
(2S,3S)-2-Am in o-1-ben zyloxypen t-4-en -3-ol (5b) was pre-
pared from aziridine 4b as described for 5a and isolated as a
colorless oil in 84% yield. 1H NMR (300 MHz, CDCl3): δ 7.39-
7.24 (m, 5H), 5.84 (ddd, 1H, J ) 17.3, 10.4, 6.0 Hz), 5.31 (dt,
1H, J ) 17.3, 1.7 Hz), 5.20 (dt, 1H, J ) 10.4, 1.7 Hz), 4.50 (s,
2H), 4.11 (br t, 1H, J ) 5.8 Hz), 3.51 (m, 2H), 3.06 (br q, 1H,
J ) 6.0 Hz), 2.01 (br s, 3H). 13C NMR (100 MHz, CDCl3): δ
137.7, 137.3, 128.3, 127.7, 127.6, 116.5, 74.6, 73.5, 72.3, 54.6.
IR (neat): 3343 (br), 2908, 2860 cm-1. [R]D: -11.4 (c 0.69, CH2-
Cl2). HRMS (EI+) exact mass calcd for C12H18NO2 (M + H):
208.1338. Found: 208.1344.
(2R,3S)-3-Am in o-4-ben zyloxym eth yl-1-(4-m eth oxyben -
zyloxy)-4-p en ten -2-ol (3f) was prepared from oxazolidinone
9f as described for 3a and isolated as a low-melting solid in
1
86% yield. H NMR (400 MHz, CDCl3): δ 7.31-7.14 (m, 7H),
6.80 (d, 2H, J ) 8.8 Hz), 5.12 (m, 2H) 4.44 (m, 2H), 4.39 (br s,
2H), 3.98 (AB-q, 2H, J ) 12.1 Hz), 3.74-3.68 (m, 1H), 3.73 (s,
3H), 3.52-3.36 (m, 3H), 2.00 (br s, 3H). 13C NMR (125 MHz,
CDCl3): δ 159.2, 147.0, 137.8, 130.2, 129.3, 128.4, 127.7, 115.0,
113.8, 73.0, 72.5, 71.7, 71.7, 71.4, 56.2, 55.2. IR (neat) 3373
(br), 2910, 2860 cm-1. [R]D -6.9 (c 1.00, CH2Cl2). HRMS (CI+)
exact mass calcd for C21H28NO4 (M + H): 358.2018. Found:
358.2019.
(2S,3S)-2-Am in o-1-ben zyloxy-6-(4-m eth oxyben zyloxy)-
4(E)-h exen -3-ol (5c) was prepared from aziridine 4c as
described for 5a and isolated as a low-melting solid in 82%
1
yield. H NMR (400 MHz, CDCl3): δ 7.35-7.24 (m, 7H), 6.88
(d, 2H, J ) 8.6 Hz), 5.88 (dt, 1H, J ) 15.6, 5.5 Hz), 5.73 (dd,
1H, J ) 15.6, 6.0 Hz), 4.52 (s, 2H), 4.44 (s, 2H), 4.15 (br t, 1H,
J ) 5.7 Hz), 4.00 (d, 2H, J ) 5.5 Hz), 3.81 (s, 3H), 3.54 (dd,
1H, J ) 9.5, 5.0 Hz), 3.50 (dd, 1H, J ) 9.5, 6.0 Hz), 3.06 (br q,
1H, J ) 5.5 Hz), 2.75 (br s, 3H). 13C NMR (100 MHz, CDCl3):
δ 159.6, 138.3, 132.1, 130.7, 129.8, 129.6, 128.9, 128.3, 128.2.
114.2, 74.4, 73.9, 72.8, 72.4, 70.2, 55.7, 55.1. IR (neat): 3585,
Typ ica l P r oced u r e for th e Rin g Closu r e of Am in o
Alcoh ols 2 to Azir id in es 4. With Regu la r Tr ip h en ylp h os-
p h in e: (2R,3R)-2-P h en eth yl-3-vin yla zir id in e (4a ).23 To a
J . Org. Chem, Vol. 67, No. 24, 2002 8581

Olofsson and Somfai
3357 (br), 2913, 2858 cm-1. [R]D: +11.4 (c 0.07, CH2Cl2). HRMS
(CI+) exact mass calcd for C21H28NO4 (M + H): 358.2018.
Found: 358.2020.
Aqueous NaOH (2 M) was added, and the mixture was
extracted several times with Et2O. The organic phase was
washed with saturated NaHCO3, dried (Na2SO4), and concen-
trated. Flash chromatography (EtOAc) afforded syn-hydroxy
amide 12a as white crystals in 71% yield (7.6 mg. 33 µmol).
mp 73-74 °C. 1H NMR (400 MHz, CDCl3): δ 7.30-7.16 (m,
5H), 5.85 (ddd, 1H, J ) 17.2, 10.5, 5.9 Hz), 5.61 (br d, 1H, J )
8.9 Hz), 5.28 (dt, 1H, J ) 17.2, 1.6 Hz), 5.18 (dt, 1H, J ) 10.5,
1.6 Hz), 4.16 (br t, 1H, J ) 4.7 Hz), 3.97 (ddd, 1H, J ) 14.1,
9.0, 4.7 Hz), 2.68 (t, 2H, J ) 8.0 Hz), 2.40 (br s, 1H), 2.03-
1.80 (m, 2H), 1.95 (s, 3H). 13CNMR (100 MHz, CDCl3): δ 170.5,
141.5, 138.0, 128.4, 128.2, 125.9, 116.2, 74.4, 53.5, 33.5, 32.7,
23.4. IR (neat): 3296 (br), 2929, 2862, 1647 cm-1. [R]D: +22.2
(c 0.46, CH2Cl2). HRMS (EI+) exact mass calcd for C14H20NO2
(M + H): 234.1494. Found: 234.1490.
(2S,3R)-2-Am in o-6-ben zyloxy-4(E)-h exen -3-ol (5d ) was
prepared from aziridine 4d as described for 5a and isolated
as a colorless oil in 74% combined yield (ds 91%). 1H NMR
(400 MHz, CDCl3): δ 7.36-7.27 (m, 5H), 5.88 (dtd, 1H, J )
15.6, 5.6, 0.9 Hz), 5.75 (ddt, 1H, J ) 15.6, 6.1, 1.2 Hz), 4.52 (s,
2H), 4.04 (d, 2H, J ) 5.6 Hz), 4.00 (dt, 1H, J ) 5.1, 0.9 Hz),
3.00 (dq, 1H, J ) 6.6, 4.2 Hz), 2.06 (br s, 3H), 1.04 (d, 3H, J )
6.6 Hz). 13C NMR (100 MHz, CDCl3): δ 138.2, 131.7, 129.1,
128.4, 127.7, 127.6, 75.3, 72.2, 70.1, 50.7, 18.4. IR (neat): 3354,
2925, 2856 cm-1. [R]D: +16.7 (c 1.75, CH2Cl2). HRMS (CI+)
exact mass calcd for C13H20NO2 (M + H): 222.1494. Found:
222.1501.
Typ ica l P r oced u r es for th e Hyd r olysis of Am id es 12
to syn -Am in o Alcoh ols 6. Acid ic Hyd r olysis: (3R,4R)-4-
Am in o-6-p h en yl-1-h exen -3-ol (6a ). Hydroxy amide 12a
(21.0 mg, 90 µmol) in aqueous H2SO4 (5%) was refluxed for 1
h, then aqueous NaOH (2 M) was added, and the mixture was
extracted several times with Et2O. The organic phase was
washed with brine, dried (Na2SO4), and concentrated. The
crude product was pushed through a short silica plug to afford
syn-amino alcohol 6a as a low-melting solid in 95% yield (16.4
mg, 86 µmol). 1H NMR (300 MHz, CDCl3): δ 7.30-7.21 (m,
5H), 5.83 (ddd, 1H, J ) 17.3, 10.4, 6.0 Hz), 5.33 (dt, 1H, J )
17.3, 1.4 Hz), 5.21 (dt, 1H, J ) 10.4, 1.4 Hz), 3.85 (br t, 1H, J
) 6.0 Hz), 2.79 (ddd, 1H, J ) 15.4, 10.2, 5.8 Hz), 2.67 (m, 2H),
1.94 (m, 1H), 1.58 (m, 1H). 13CNMR (100 MHz, CDCl3): δ
141.6, 138.7, 128.3, 128.2, 125.8, 116.6, 75.4, 54.9, 35.8, 32.7.
IR (CDCl3): 3602, 3300 (br), 3155, 2924 cm-1. [R]D: +13.8 (c
0.86, CH2Cl2). HRMS (EI+) exact mass calcd for C12H18NO (M
+ H): 192.1388. Found: 192.1387.
(2S,3R)-2-Am in o-1-ben zyloxy-4-pen ten -3-ol (6b) was pre-
pared from hydroxy amide 12b as described for 6a and isolated
as a yellow oil in 92% yield. 1H NMR (300 MHz, CDCl3): δ
7.39-7.27 (m, 5H), 5.82 (ddd, 1H, J ) 17.3, 10.4, 5.3 Hz), 5.33
(dt, 1H, J ) 17.3, 1.4 Hz), 5.20 (dt, 1H, J ) 10.4, 1.4 Hz), 4.54
(AB-q, 2H, J ) 11.8 Hz), 4.08 (br t, 1H, J ) 5.3 Hz), 3.60 (dd,
1H, J ) 9.3, 4.4 Hz), 3.51 (m, 1H), 2.97 (br m, 1H), 2.34 (br s,
3H). 13C NMR (100 MHz, CDCl3): δ 138.0, 137.6, 128.3, 127.7,
127.6, 116.5, 73.4, 72.7, 72.3, 54.7. IR (neat): 3332 (br), 2912,
2864 cm-1. [R]D: +14.4 (c 0.55, CH2Cl2). HRMS (EI+) exact
mass calcd C12H18NO2 (M + H): 208.1338. Found: 208.1334.
(2S,3S)-4-Am in o-2-ben zyloxym eth yl-5-(4-m eth oxyben -
zyloxy)-1-p en ten -3-ol (5f) was prepared from aziridine 4f as
described for 5a and isolated as a yellow oil in 71% yield. H
1
NMR (400 MHz, CDCl3): δ 7.37-7.21 (m, 7H), 6.88 (d, 2H, J
) 8.6 Hz), 5.28 (s, 1H), 5.26 (s, 1H), 4.54 (m, 2H), 4.42 (m,
2H), 4.10 (d, 1H, J ) 6.3 Hz), 4.08 (m, 2H), 3.79 (s, 3H), 3.58
(dd, 1H, J ) 9.2, 4.3 Hz), 3.52 (dd, 1H, J ) 9.2, 6.3 Hz), 3.12
(td, 1H, J ) 6.3, 4.3 Hz), 1.80 (br s, 3H). 13C NMR (125 MHz,
CDCl3): δ 159.3, 144.7, 137.9, 130.0, 129.4, 128.5, 127.8, 127.7,
116.0, 113.9, 77.6, 73.2, 72.6, 71.1, 55.3, 53.0. IR (neat): 3369
(br), 2914, 2860, 2360 cm-1. [R]D: +7.0 (c 0.50, CH2Cl2). HRMS
(CI+): exact mass calcd for C21H28NO4 (M + H): 358.2018.
Found: 358.2019.
BF 3‚OEt2 P r oced u r e: (4R,5S)-5-Am in o-1-ben zyloxy-4-
m eth yl-2(E)-h ep ten -4-ol (5e). To a solution of vinylaziridine
4e (50 mg, 0.216 mmol) in THF (2 mL) and H2O (0.2 mL) at 0
°C was added BF3‚OEt2 (56 µL, 0.43 mmol), and the solution
was stirred at room temperature for 5 h. The reaction was
quenched with 2 M NaOH, and THF was removed in vacuo.
To the residue was added CH2Cl2 (2 mL), and the mixture was
filtered through an Extrelut NT3 tube, which was eluted with
CH2Cl2 (15 mL). The solution was concentrated, and flash
chromatography (EtOAc/MeOH 10:1+ 1% NH4OH) afforded
amino alcohol 5e as a diastereomeric mixture (2.5:1) in 67%
yield (36 mg, 0.145 mmol). The diastereomers could be
separated with careful flash chromatography, which gave 5e
1
as a yellow oil. H NMR (400 MHz, CDCl3): δ 7.37-7.27 (m,
5H), 5.90 (dt, 1H, J ) 15.6, 5.6 Hz), 5.73 (dd, 1H, J ) 15.6, 1.2
Hz), 4.52 (s, 2H), 4.06 (dd, 2H, J ) 5.6, 1.2 Hz), 2.44 (dd, 1H,
J ) 9.2, 2.1 Hz), 2.34 (br s, 3H), 1.71 (m, 1H), 1.29 (s, 3H),
1.06 (m, 1H), 0.98 (t, 3H, J ) 7.1 Hz). 13C NMR (100 MHz,
CDCl3): δ 138.3, 135.7, 128.3, 127.7, 127.6, 126.2, 73.4, 72.1,
(2S,3S)-2-Am in o-6-ben zyloxy-4(E)-h exen -3-ol (6d ) was
prepared from hydroxy amide 12d as described for 6a and
isolated as a colorless oil in 93% yield. 1H NMR (400 MHz,
CDCl3): δ 7.36-7.26 (m, 5H), 5.89 (dtd, 1H, J ) 15.5, 5.6, 0.9
Hz), 5.73 (ddt, 1H, J ) 15.5, 6.3, 1.3 Hz), 4.52 (s, 2H), 4.05 (d,
2H, J ) 5.6 Hz), 3.73 (dt, 1H, J ) 6.3, 0.9 Hz), 2.81 (qvi, 1H,
J ) 6.5 Hz), 2.05 (br s, 3H), 1.10 (d, 3H, J ) 6.5 Hz). 13C NMR
(100 MHz, CDCl3): δ 138.2, 133.4, 128.8, 128.4, 127.7, 127.6,
70.4, 62.1, 26.0, 25.3, 11.8. IR (neat): 3396, 2968, 2873 cm-1
.
[R]D: -5.2 (c 0.66, CH2Cl2). HRMS (CI+) exact mass calcd for
C
15H24NO2 (M + H): 250.1807. Found: 250.1809.
Typ ica l P r oced u r e for th e Acyla tion of Vin yla zir i-
d in es 4 to N-Acetyla zir id in es 10, F ollow ed by Rea r -
r a n gem en t to 11 a n d in Situ Hyd r olysis in to Hyd r oxy
Am id es 12: (2R,3R)-1-(2-P h en eth yl-3-vin yla zir id in -1-yl)-
eth a n on e (10a ). A solution of vinylaziridine 4a (100 mg, 0.58
mmol), Et3N (0.160 mL, 1.2 mmol), and DMAP (catalytic
amount) in CH2Cl2 (1.5 mL) was cooled to -78 °C before
addition of Ac2O (60 µL, 0.63 mmol). After 15 min the reaction
was quenched with H2O and the mixture was extracted with
Et2O. The organic phase was washed with water, saturated
NaHCO3, and brine, dried (Na2SO4), and concentrated to give
the crude N-acetyl vinylaziridine 10a (126.2 mg) that was
taken directly on to the next step. 1H NMR (400 MHz,
CDCl3): δ 7.31-7.18 (m, 5H), 5.40 (m, 1H), 5.25 (m, 2H), 2.87-
2.71 (m, 3H), 2.52 (dt, 1H, J ) 6.3, 2.7 Hz), 2.07 (s, 3H), 1.98
(m, 1H), 1.74 (m, 1H).
76.3, 72.2, 70.1, 51.1, 20.4. IR (neat): 3313, 2970, 2860 cm-1
.
[R]D: +3.4 (c 1.59, CH2Cl2). HRMS (CI+) exact mass calcd for
C
13H20NO2 (M + H): 222.1494. Found: 222.1505.
Ba sic Hyd r olysis: (2S,3R)-2-Am in o-1-ben zyloxy-6-(4-
m eth oxyben zyloxy)-4(E)-h exen -3-ol (6c). Hydroxy amide
12c (12.0 mg, 30 µmol) in 1 M KOH (EtOH/H2O 2:1) was
refluxed for 24 h. NaOH (2 M) was added, and the mixture
was extracted several times with Et2O. The organic phase was
washed with brine, dried (Na2SO4), and concentrated. The
crude product was pushed through a short silica plug to afford
syn-amino alcohol 6c as low-melting solid in 91% yield (9.8
mg, 27 µmol). 1H NMR (400 MHz, CDCl3): δ 7.35-7.25 (m,
7H), 6.88 (d, 2H, J ) 8.4 Hz), 5.88 (dt, 1H, J ) 15.6, 5.5 Hz),
5.73 (dd, 1H, J ) 15.6, 4.8 Hz), 4.53 (AB-q, 2H, J ) 11.8 Hz),
4.44 (s, 2H), 4.08 (br t, 1H, J ) 4.8 Hz), 4.01 (d, 2H, J ) 5.5
Hz), 3.81 (s, 3H), 3.57 (dd, 1H, J ) 9.0, 4.3 Hz), 3.48 (dd, 1H,
J ) 9.0, 6.3 Hz), 2.94 (br q, 1H, J ) 4.8 Hz), 1.86 (br s, 3H).
13C NMR (125 MHz, CDCl3): δ 159.0, 137.6, 132.6, 130.0,
129.5, 128.8, 128.5, 127.9, 127.8, 113.6, 73.5, 72.6, 72.1, 71.9,
69.7, 55.3, 54.5. IR (neat): 3394 (br), 2933, 2858 cm-1. [R]D:
(1R,2R)-N-(2-H yd r oxy-1-p h en et h yl-3-b u t en yl)a cet a -
m id e (12a ): To a solution of the crude 10a (10.0 mg, 46 µmol)
in THF (0.5 mL) at -25 °C was added BF3‚OEt2 (12 µL, 92
µmol). After 1.5 h full conversion into the corresponding
oxazoline was achieved, H2O (0.05 mL) was added, and the
resultant mixture was stirred at room temperature for 2 h.
8582 J . Org. Chem., Vol. 67, No. 24, 2002

Divergent Synthesis of vic-Amino Alcohols
+3.8 (c 0.29, CH2Cl2). HRMS (CI+) exact mass calcd for C21H28
NO4 (M + H): 358.2018. Found: 358.2022.
-
The solution was concentrated, and flash chromatography
(pentane:EtOAc 1:1 f 1:2) afforded trans-oxazolidinone 14e
as a diastereomeric mixture (2:1) in 66% yield (6.8 mg. 25
µmol). The diastereomers could be separated with careful flash
chromatography or by HPLC (Zorbax Rx-Sil semipreparative
column, 95% hexane, 5% i-PrOH, 5 mL/min) to give 14e as a
colorless oil. 1H NMR (500 MHz, CDCl3): δ 7.38-7.27 (m, 5H),
5.93 (dt, 1H, J ) 15.7, 4.9 Hz), 5.85 (dt, 1H, J ) 15.7, 1.2 Hz),
5.41 (br s, 1H), 4.53 (s, 2H), 4.06 (dd, 2H, J ) 4.9, 1.2 Hz),
3.49 (dd, 1H, J ) 9.3, 4.4 Hz), 1.61-1.45 (m, 2H), 1.42 (s, 3H),
0.97 (t, 3H, J ) 7.4 Hz). 13C NMR (125 MHz, CDCl3): δ 158.3,
138.0, 133.4, 128.4, 127.7, 127.7, 127.1, 84.2, 72.6, 69.6, 62.6,
23.3, 19.8, 11.1. IR (neat): 3265, 2937, 2856, 1747 cm-1. [R]D:
-11.4 (c 0.26, CH2Cl2). HRMS (CI+) exact mass calcd for
(2S,3R)-4-Am in o-2-ben zyloxym eth yl-5-(4-m eth oxyben -
zyloxy)-1-p en ten -3-ol (6f) was prepared from hydroxy amide
12f as described for 6c and isolated as a yellow oil in 84% yield.
1H NMR (500 MHz, CDCl3): δ 7.28-7.14 (m, 7H), 6.81 (m,
2H), 5.21 (br s, 1H), 5.19 (br s, 1H), 4.43 (m, 2H), 4.36 (m,
2H), 4.02 (m, 2H), 3.92 (m, 1H), 3.74 (s, 3H), 3.49 (m, 1H),
3.40 (m, 1H), 3.04 (m, 1H), 1.72 (br s, 3H). 13C NMR (125 MHz,
CDCl3): δ 159.3, 145.5, 138.0, 130.0, 129.4, 128.4, 127.7, 114.9,
113.9, 113.8, 73.2, 73.1, 72.8, 72.3, 70.9, 55.3, 52.9. IR (neat):
3361 (br), 2918, 2856 cm-1. [R]D: +7.8 (c 0.75, CH2Cl2). HRMS
(CI+) exact mass calcd for C21H28NO4 (M + H): 358.2018.
Found: 358.2022.
Typ ica l P r oced u r e for th e BOC-P r otection of Vin y-
la zir id in es 4 to N-BOC-Azir id in es 13, F ollow ed by Rea r -
r a n gem en t to tr a n s-Oxa zolid in on es 14: (2S,3R)-2-(3-
B e n z y lo x y p r o p e n y l)-3-e t h y l-2-m e t h y la z i r i d i n e -1-
car boxylic Acid ter t-Bu tyl Ester 13e.Aslurryofvinylaziridine
4e (17.0 mg, 73 µmol) and polymer-bound DMAP (5.5 mmol/
g, 27 mg, 0.15 mmol) in CH2Cl2 (1.0 mL) was cooled to 0 °C
before addition of BOC2O (32.0 mg, 0.15 mmol), stirred at room
temperature for 2 h, quenched with saturated NaHCO3, and
filtered through an Extrelut NT3 tube, which was eluted with
CH2Cl2 (15 mL). The solution was concentrated to give the
crude N-BOC-vinylaziridine 13e (24.4 mg), which was taken
directly on to the next step. 1H NMR (400 MHz, CDCl3): δ
7.36-7.26 (m, 5H), 5.89 (dt, 1H, J ) 15.6, 5.7 Hz), 5.30 (d,
1H, J ) 15.6 Hz), 4.51 (s, 2H), 4.03 (d, 2H, J ) 5.7 Hz), 2.39
(t, 1H, J ) 6.7 Hz), 1.50 (m, 2H), 1.41 (s, 9H 1.38 (s, 3H), 1.04
(t, 3H, J ) 7.5 Hz).
C
16H22NO3 (M + H): 276.1600. Found: 276.1601.
(4S,5S)-5-Am in o-1-ben zyloxy-4-m eth yl-2(E)-h ep ten -4-
ol (6e) was prepared by hydrolysis of trans-oxazolidinone 14e
as described for 3a and isolated as a colorless oil in 98% yield.
1H NMR (400 MHz, CDCl3): δ 7.36-7.25 (m, 5H), 5.89 (dt,
1H, J ) 15.6, 5.5 Hz), 5.77 (d, 1H, J ) 15.6 Hz), 4.52 (s, 2H),
4.06 (d, 2H, J ) 5.5 Hz), 2.60 (br s, 3H), 2.55 (app. d, 1H, J )
10.2 Hz), 1.67 (m, 1H), 1.19 (s, 3H), 1.17 (m, 1H), 0.98 (t, 3H,
J ) 7.4 Hz). 13C NMR (125 MHz, CDCl3): δ 138.4, 138.3, 128.4,
127.8, 127.6, 126.0, 73.4, 72.2, 70.4, 60.6, 24.1, 21.9, 11.7. IR
(neat): 3357, 2931, 2858 cm-1. [R]D: +22.0 (c 0.14, CH2Cl2).
HRMS (CI+) exact mass calcd for C15H23NO2 (M + H):
250.1807. Found: 250.1811.
Ack n ow led gm en t. This work was supported finan-
cially by the Swedish Research Council.
(4S,5S)-5-(3-Ben zyloxy-1(E)-p r op en yl)-4-eth yl-5-m eth -
yloxa zolid in -2-on e (14e). To a solution of the crude 13e (12.5
mg, 38 µmol) in THF (0.7 mL) at -78 °C was added BF3‚OEt2
(7.2 µL, 57 µmol), and the resulting mixture was stirred at
-78 °C for 2 h. The reaction was quenched with saturated
NaHCO3, and THF was removed in vacuo. To the residue was
added CH2Cl2 (2 mL), and the mixture was filtered through
an Extrelut NT3 tube, which was eluted with CH2Cl2 (15 mL).
Su p p or tin g In for m a tion Ava ila ble: Synthesis of vinyl
epoxides 1c-e and oxazolidinones 14a -d ,f, 15, and 16 and
analytical data of 4b,d -f, 7b,d -f, 8, 9b-f, 10b-f, 11a , and
12b-f. This material is available free of charge via the
Internet at http://pubs.acs.org.
J O0262053
J . Org. Chem, Vol. 67, No. 24, 2002 8583