Regio- and stereocontrolled formation of chiral epoxy oxazolidines via bromocarbamation of N-Boc alkenyl oxazolidines. Application to asymmetric synthesis

Article abstract of DOI:10.1021/jo962277g

Treatment of α-alkenyl N-Boc oxazolidines with N-bromosuccinimide leads to epoxy oxazolidines via a bromocyclocarbamation reaction which is completely stereoselective. Action of sodium azide on these epoxides, followed by a few functional group manipulations, eventually affords chiral β-amino alcohols which are intermediates for the enantioselective synthesis of bioactive products: the anti side chain of taxol and a hydroxyethylamine isostere. Both the bromocarbamation cyclization and the nucleophilic cleavage of epoxides are totally regioselective. AM1 calculations suggest that this selectivity is controlled by the positive charge distribution at the electrophilic centers.

Full text of DOI:10.1021/jo962277g

2106
J . Org. Chem. 1997, 62, 2106-2112
Regio- a n d Ster eocon tr olled F or m a tion of Ch ir a l Ep oxy
Oxa zolid in es via Br om oca r ba m a tion of N-Boc Alk en yl
Oxa zolid in es. Ap p lica tion to Asym m etr ic Syn th esis
Claude Agami,* Franc¸ois Couty,* Louis Hamon, and Olivier Venier
Laboratoire de Synthe`se Asyme´trique (URA CNRS 408), Boˆıte 47, Universite´ P. et M. Curie,
4 place J ussieu, 75005 Paris, France
Received December 6, 1996X
Treatment of R-alkenyl N-Boc oxazolidines with N-bromosuccinimide leads to epoxy oxazolidines
via a bromocyclocarbamation reaction which is completely stereoselective. Action of sodium azide
on these epoxides, followed by a few functional group manipulations, eventually affords chiral
â-amino alcohols which are intermediates for the enantioselective synthesis of bioactive products:
the anti side chain of taxol and a hydroxyethylamine isostere. Both the bromocarbamation
cyclization and the nucleophilic cleavage of epoxides are totally regioselective. AM1 calculations
suggest that this selectivity is controlled by the positive charge distribution at the electrophilic
centers.
Sch em e 1
Oxazolidine moieties are easily synthesized from enan-
tiomerically pure â-amino alcohols and are widely rec-
ognized as very useful chiral auxiliaries for several
asymmetric reactions.1 On the other hand, chiral ep-
oxides have frequently been involved in the design of
strategies for the achievement of stereocontrol.2 In this
respect, it is surprising to note that only one example3 is
known reporting the combined influence in the same
substrate of both epoxide and oxazolidine moieties. This
fact can be ascribed to the instability4 of epoxy aldehydes
which would otherwise constitute obvious materials for
the direct formation of such oxazolidines.
azolidine N-Boc substituent. In this reaction (Scheme
1) a bridged halonium ion is attacked by the carbamate
moiety which acts as a nucleophile.6 This process fea-
tures 1,2-stereoinduction directed by the C-2 oxazolidine
center, in agreement with other examples of such stereo-
selective halocyclizations.7 Completion of the synthesis
of the modified aldehydes 3 only requires a few straight-
forward functional group manipulations.
As exemplified below, epoxy oxazolidines synthesized
in this way were used for the enantioselective synthesis
of compounds of biological interest that contain a â-amino
alcohol moiety. Moreover theoretical calculations were
performed in order to explain the complete regioselec-
tivity which was observed during nucleophilic attack on
both the bridged halonium ion and the epoxy oxa-
zolidines.
We wish to report a full account5 of new methodology
which allows the preparation of enantiopure epoxy oxa-
zolidines 2 from R,â-unsaturated aldehydes 1. Nucleo-
philic attack on these epoxides occurs in a totally regio-
and stereoselective manner and eventually leads to
aldehydes 3. This sequence of reactions creates two
contiguous stereocenters, thus offering a new method for
enantioselective synthesis.
Resu lts a n d Discu ssion
Syn th esis of r-Ep oxy Oxa zolid in es. Condensation
of R,â-ethylenic aldehydes 4a -f and 4g with (R)- and (S)-
The key step of this transformation is a fully regio- and
stereoselective halocyclization process involving the ox-
(6) For other examples related to nucleophilic reactivity of carbam-
ate moieties, see: (a) Agami, C.; Couty, F.; Hamon, L.; Venier, O.
Tetrahedron Lett. 1993, 34, 4509-4512. (b) Curran, T. P.; Pollastri,
M. P.; Abelleira, S. M.; Messier, R. J .; McCollum, T. A. Tetrahedron
Lett. 1994, 35, 5409-5412. (c) Campanini, L.; Dure´ault, A.; Depezay,
J . C. Tetrahedron Lett. 1995, 36, 8015-8018. (d) Vanucci, C.; Brusson,
X.; Verdel, V.; Zana, F.; Dhimane, H.; Lhommet, G. Tetrahedron Lett.
1995, 36, 2971-2974. (d) Haddad, M.; Larcheveque, M. Tetrahedron
Lett. 1996, 37, 4525-4528. (e) Lee, J . W.; Lee, J . H.; Son, H. J .; Choi,
Y. K.; Yoon, G. J .; Park, M. H. Synth. Commun. 1996, 26, 83-88. (f)
Sepulveda-Arques, J .; Armero-Alarte, T.; Acero-Alarcon, A.; Zaballos-
Garcia, E.; Solesio, B. Y.; Carrera, J . E. Tetrahedron 1996, 52, 2097-
2102. (g) Williams, L.; Zhang, Z.; Shao, F.; Caroll, F. J .; J oullie´, M. M.
Tetrahedron 1996, 52, 11673-11694.
(7) For examples of 1,2-stereoinduction in this field, see: (a) Parker,
K. A.; O’Fee, R. J . Am. Chem. Soc. 1983, 105, 654-655. (b) Kobayashi,
S.; Tashiyuki, I.; Ohno, M. Tetrahedron Lett. 1984, 25, 5079-5082. (c)
Kamiyama, K.; Urano, Y.; Kobayashi, S.; Ohno, M. Tetrahedron Lett.
1987, 28, 3123-3126. (d) Pauls, H. W.; Fraser-Reid, B. J . Am. Chem.
Soc. 1980, 102, 3956-3957. (e) Guindon, Y.; Siassi, A.; Ghiro, E.;
Bantle, G.; J ung, G. Tetrahedron Lett. 1992, 33, 4257-4260. (f)
Guindon, Y.; Slassi, A.; Rancourt, J .; Bantle, G.; Bencheqroun, M.;
Murtagh, L.; Ghiro, E.; J ung, G. J . Org. Chem. 1995, 60, 288-289.
X Abstract published in Advance ACS Abstracts, March 1, 1997.
(1) For some recent examples, see: (a) Meyers, A. I.; Seefeld, M. A.;
Lefker, B. A. J . Org. Chem. 1996, 61, 5712-5713. (b) Andrews, M. D.;
Brewster, A. G.; Moloney, M. G. Synlett 1996, 612-614. (c) Roth, G.
P.; Leonard, S. F.; Tong, L. J . Org. Chem. 1996, 61, 5710-5711. (d)
Amat, M.; Llor, N.; Hidalgo, J .; Bosch, J .; Molins, E.; Miravittles, C.
Tetrahedron: Asymmetry 1996, 7, 2501-2504. (e) Froelich, O.; Desos,
P.; Bonin, M.; Quirion, J . C.; Husson, H. P.; Zhu, J . J . Org. Chem.
1996, 61, 6700-6705. (f) Garcia-Valverde, M.; Pedrosa, R.; Vicente,
M.; Garcia-Granda, S.; Guttierez-Rodriguez, A. Tetrahedron 1996, 52,
10761-10770. (g) O’Brien, P.; Warren, S. Tetrahedron Lett. 1996, 37,
3051-3054. (h) Agami, C.; Mathieu, H.; Couty, F. Tetrahedron Lett.
1996, 37, 4001-4002.
(2) Nicolaou, K. C.; Sorensen, E. J . Classics in Total Synthesis;
VCH: New York, 1996.
(3) Cardani, S.; Gennari, C.; Scolastico, C.; Villa, R. Tetrahedron
1989, 45, 7397-7404.
(4) Behrens, C. H.; Sharpless, K. B. J . Org. Chem. 1985, 50, 5696-
5704.
(5) Preliminary communication: Agami, C.; Couty, F.; Venier, O.
Synlett 1995, 1027-1028.
S0022-3263(96)02277-3 CCC: $14.00 © 1997 American Chemical Society

Formation of Chiral Epoxy Oxazolidines
J . Org. Chem., Vol. 62, No. 7, 1997 2107
Sch em e 2a
tivity that is displayed by this bromocarbamation reac-
tion can be rationalized on a conformational basis. The
intermediate bridged bromonium ion can be depicted
either as structure 11 or 12, depending on which ethyl-
enic double bond diastereoface was concerned. Actually,
the stereoselectivity which was observed in the cyclized
products 6a -g corresponds to the involvement of struc-
ture 11. Diasteromeric intermediates 11 and 12 show a
trans geometry between the bulky N-Boc group and both
the phenyl and the side-chain substituents; compared
with its diastereomer 12, reactive species 11 fulfills an
important requirement: the arrangement of the reactive
centers in 11 leads to a chair cyclization transition state.
Moreover we have to consider the possibility that not
only is 11 the reactive species but that it might also have
been produced in preference to 12. In fact, Danishefsky
et al.10 suggested that, when reacting with an electro-
philic reagent, the ethylenic double bond of propenyl
groups linked to pyranosides adopts a coplanar s-cis
conformation with respect to a C-O heterocycle bond.
This geometry would favor the stabilization of the incipi-
ent positive charge by the C-O dipole. In the present
case, should conformation 10 of the alkenyl oxazolidine
be the reactive one, in agreement with the Danishefsky
hypothesis, formation of the bridged halonium ion would
have indeed occurred on the less hindered diastereoface
(i.e. anti to the N-Boc group) leading to stereoisomer 11.
It is worth mentioning that the stereoselectivity of
dihydroxylation of alkenyl oxazolidines was already
explained by Colombo et al.11 on the basis of an analogous
CdCsCdO s-cis arrangement.
a
Reaction conditions: (a) (R)-phenylglycinol, 4 Å molecular
sieves, then (Boc)2O; (b) NBS, DME-H2O; (c) NaOEt, EtOH.
b
Respectively for ent-5g, ent-6g, and ent-7g from (S)-phenyl-
d
glycinol). c Overall yield from 4. Overall yield from 5f.
Ta ble 1. Ha locycliza tion of Oxa zolid in e 5a
entry
conditions
8/9a
yield,%b
1
2
3
4
Br2, CH2Cl2, 0 °C
Br2, CH2Cl2, -70 °C
I2, CH2Cl2, 20 °C
66/34
80/20
100/0
100/0
77
80
35
80
NBS, DME-H2O, 20 °C
a
Ratio determined by 1H NMR on the crude reaction mixture.
b
Isolated yields.
phenylglycinol, respectively, in the presence of di-tert-
butyl dicarbonate (Boc2O), afforded alkenyl oxazolidines
5a -g (Scheme 2). In all cases, 2,4-cis-disubstituted
oxazolidines were produced in agreement with the well
known stereoselectivity exhibited by such condensations.8
In addition, this cyclization was totally regioselective,
the preferred pathway being a 6-endo and not a 5-exo
process. This selectivity is discussed since it can be
related to the regioselective nucleophilic opening of
epoxides 7 (vide infra).
As shown in Scheme 2, epoxy oxazolidines 7a -g were
produced from the action of sodium ethoxide on the
corresponding bromo oxazinones 6a -g. A base-induced
cleavage of the cyclic carbamate moiety gives rise to an
intramolecular substitution of bromine leading to the
sterospecific formation of the epoxide group.
Syn th esis of ch ir a l â-Am in o Alcoh ols. From ep-
oxides 7a and ent-7g two series of reactions were
achieved with the aim of synthesizing two compounds of
biological interest. On the other hand, these transforma-
tions provide chemical correlations in order to confirm
the configurations of the starting epoxides.
The action of N-bromosuccinimide on compounds 5a -g
effected the cyclization step9 affording products 6a -g.
Table 1 shows the variation of the ratio of products 8 and
9 obtained from 5a with various halogenating reagents.
N-Bromosuccinimide reacted very suitably with all al-
kenyl oxazolidines 5a -g as regards reactivity as well as
stereoselectivity. Bromine was reversibly added to the
ethylenic diastereoface that is opposite to the urethane
moiety in order for the transient bromonium ion to be
intercepted by this group. The complete diastereoselec-
(8) (a) Agami, C.; Rizk, T. Tetrahedron 1985, 41, 537-540. (b)
Arsenyadis, S.; Huang, P. Q.; Molleret, N.; Beloeil, J . C.; Husson, H.
P. Heterocycles 1990, 31, 1789-1799. (c) Prien, O.; Hoffmann, H.;
Conde-Frieboes, K.; Krettek, T.; Berger, B.; Wagner, K.; Bolte, M.;
Hoppe, D. Synthesis 1994, 1313-1321. (d) Higashiyama, K.; Naka-
gawa, K.; Takahashi, H. Heterocycles 1995, 41, 2007-2017.
(9) For an excellent review on halocyclocarbamation and related
cyclizations including halolactonization, see: Cardillo, G.; Orena, M.
Tetrahedron 1990, 46, 3321-3408.
(10) Danishefsky, S. J .; Larson, E.; Springer, J . P. J . Am. Chem.
Soc. 1985, 107, 1274-1280. See also: Stork, G.; Kahn, M. Tetrahedron
Lett. 1983, 24, 3951-3954.
(11) Colombo, L.; Gennari, C.; Poli, G.; Scolastico, C. Tetrahedron
Lett. 1985, 26, 5459-5462.

2108 J . Org. Chem., Vol. 62, No. 7, 1997
Agami et al.
Sch em e 3a
Sch em e 4a
a
Reaction conditions: (a) NaN3, NH4Cl, EtOH, reflux (97%);
(b) H2, (Boc)2O, Pd/C, AcOEt (70%); (c) t-BuMe2SiOTf, 2,6-lutidine,
CH2Cl2, -78 °C (90%); (d) DIBAL-H, CH2Cl2, -78 °C; (e) SiO2,
CH2Cl2, H2O, oxalic acid (55%).
they are incorporated in many HIV-protease inhibitors.17
In relation to such work, Dondoni et al.18 have recently
reported the synthesis of molecule 22 which is of special
interest since its desilylated hydroxy derivative is a key
intermediate in the preparation of Ro 31-8959, a potent
and selective inhibitor of HIV proteinase.19
a
Reaction conditions: (a) NaN3, NH4Cl, EtOH, reflux; (b) NaH,
PhCH2Br, DMF, rt (71% from 7a ); (c) HSCH2CH2SH, Et2O-BF3,
CH2Cl2, reflux (73%); (d) CaCO3, MeI, acetone:H2O (4:1), 60 °C;
(e) PDC, MeOH (54% from 15); (f) H2, Pd/C, EtOH; (g) PhCOCl,
(N,N-dimethylamino)pyridine, Et3N (63% from 17).
Compound 22 was very easily obtained from epoxy
oxazolidine ent-7g (Scheme 4) by using our methodology.
The (2S,3S) absolute configuration of the target molecule
22 necessitated that, in this case, (S)-phenyl glycinol was
used as the chiral starting material. Therefore, epoxy
oxazolidine ent-7g was treated with sodium azide and,
in this case as in the preceding one, a completely
regioselective nucleophilic attack was observed (vide
infra). Then, by a one-pot reaction,20 the azido group of
alcohol 19 was transformed into an N-Boc substituent
yielding compound 20. The hydroxy function of 20 was
protected21 as its tert-butyldimethylsilyloxy derivative.
Finally, the oxazolidine moiety was removed in order to
liberate the aldehyde function by using a modified
procedure11 which consists of reduction of the NCO2Et
group followed by mild acidic hydrolysis.22 This final step
afforded the protected â-amino alcohol 22.
An t i Isom er of t h e Ta xol Sid e Ch a in Met h yl
Ester . The intense development of many syntheses of
taxol accounts for the special interest which was focused
on the elaboration of its side chain showing both syn and
anti diastereomerism.12,13 In this connection, epoxy
oxazolidine 7a was transformed into the phenyl isoserine
derivative 18 (Scheme 3), that is an anti stereoisomer of
the taxol A-ring side chain.
The epoxide ring of compound 7a was opened under
the action of sodium azide, in the presence of ammonium
chloride.14 This stereospecific attack onto the oxirane
moiety occurred in a totally regioselective manner and
this special point will be addressed below. The masked
aldehyde function was recovered by following the general
procedure developed by Scolastico et al.,15 who made use
of thioacetal intermediates. To this end, the hydroxy
group of compound 13 was protected as its O-benzyl
analog; this reaction was followed by treatment of 14 by
ethanedithiol with Lewis acid catalysis, and finally a
methyl iodide-mediated hydrolysis of thioacetal 15 af-
forded aldehyde 16. Product 16 was oxidized and yielded
ester 17 which was hydrogenolyzed and treated with
benzoyl chloride in order to produce the target molecule
18. Its physical properties are the same as those reported
for ent-18.13c,16
Th eor et ica l Tr ea t m en t of t h e Ob ser ved R egio-
selectivities. The cyclization involving a transient
bromonium ion during the cyclocarbamation reaction
(Scheme 1) as well as the substitution of epoxides 7a and
ent-7g (Schemes 3 and 4) are highly regioselective.23 In
both cases, nucleophilic attack occurs at the electrophilic
(17) For some recent leading references, see: (a) Slee, D. H.; Laslo,
K. L.; Elder, J . H.; Ollmann, I. R.; Gustchina, A.; Kervinen, J .; Zdanov,
A.; Wlodawere, A.; Wong, C. H. J . Am. Chem. Soc. 1995, 117, 11867-
11878. (b) Green, B. E.; Chen, X.; Norbeck, D. W.; Kempf, D. J . Synlett
1995, 613-614. (c) Beaulieu, P. L.; Wernic, D.; Duceppe, J . S. ;
Guindon, Y. Tetrahedron Lett. 1995, 36, 3317-3320. (d) Keenan, R.
M.; Eppley, D. F.; Tomaszek, T. A., J r. Tetrahedron Lett. 1995, 36,
819-822.
Ch ir a l â-Am in o Alcoh ol Used in th e Con str u ction
of P ep tid e Isoster es. Several synthetic approaches to
hydroxyethylamine isosteres have been reported because
(12) Nicolaou, K. C.; Dai, W. M.; Guy, R. K. Angew. Chem., Int. Ed.
Engl. 1994, 33, 15-44.
(18) Dondoni, A.; Perrone, D.; Merino, P. J . Org. Chem. 1995, 60,
8074-8080.
(13) The isomerization of anti to syn side chain stereoisomer has
been described: (a) Gennari, C.; Vulpetti, A.; Donghi, M.; Mongelli,
N.; Vanotti, E. Angew. Chem., Int. Ed. Engl. 1996, 35, 1723-1725. (b)
Bunnage, M. E.; Davies, S. G.; Goodwin, C. J . J . Chem. Soc., Perkin
Trans. 1 1993, 1375-1376. (c) Gou, D. M.; Liu, Y. C.; Chen, C. S. J .
Org. Chem. 1993, 58, 1287-1289. (d) Gennari, C.; Vulpetti, A.; Donghi,
M.; Mongelli, N.; Vanotti, E. Angew. Chem., Int. Ed. Engl. 1996, 35,
1723-1725.
(19) Parkes, K. E. B.; Bushnell, D. J .; Crackett, P. H.; Dunsdon, S.
J .; Freeman, A. C.; Gunn, M. P.; Hopkins, R. A.; Lambert, R. W.;
Martin, J . A.; Merett, J . H.; Redshaw, S.; Spurden, W. C.; Thomas, G.
J . J . Org. Chem. 1994, 59, 3656-3664.
(20) Saito, S.; Nakajima, H.; Inaba, M.; Moriwake, T. Tetrahedron
Lett. 1989, 30, 837-838.
(21) Corey, E. J .; Cho, H.; Ru¨cker, C.; Hua, D. H. Tetrahedron Lett.
1981, 22, 3455-3458.
(22) Huet, F.; Lechevallier, A.; Pellet, M.; Conia, J . M. Synthesis
1978, 63-65.
(23) Nucleophilic attacks of oxazolidines 5c and 5f by organo
cuprates, eventually leading to pheromones, have been described. They
show the same regioselectivity pattern as in the cases reported here.
See: Agami, C.; Couty, F.; Venier, O. Synlett 1996, 511-512.
(14) Commerc¸on, A.; Bezard, D.; Bernard, F.; Bourzat, J . D. Tetra-
hedron Lett. 1992, 33, 5185-5188.
(15) Bernardi, A.; Cardani, S.; Poli, G.; Scolastico, C. J . Org. Chem.
1986, 51, 5041-5043.
(16) Davis, F. A.; Reddy, R. T.; Reddy, R. E. J . Org. Chem. 1992,
57, 6387-6389.

Formation of Chiral Epoxy Oxazolidines
J . Org. Chem., Vol. 62, No. 7, 1997 2109
Ta ble 2. AM1 Ca lcu la tion s
charges
bond indices
compound
CR
Câ
CR-X
Câ-X
23a
23b
24a
24b
-0.15
-0.25
+0.07
-0.02
+0.16
+0.10
+0.20
+0.09
0.815
0.922
0.828
1.015
0.481
0.006
0.607
0.006
F igu r e 1. Regioselectivity of nucleophilic attacks.
Sch em e 5
attracting effect. This second series of calculations
reveals that the positive charge on the Câ center is less
pronounced in such cases: +0.13 and +0.06, respectively.
It can therefore be concluded that the above reported
regioselectivities are, at least partially, directed by the
distribution of the positive charge at the electrophilic
centers.
In conclusion, the reported regio- and stereoselective
cleavage of the epoxide moiety eventually affords func-
tionalized aldehydes. The synthesis of enantiopure R-hy-
droxy â-amino aldehydes or esters has received consid-
erable attention,13 and this new methodology offers an
alternative access to these biologically interesting com-
pounds.
center which is the more distant one from the oxazolidine
ring (see Figure 1).
Exp er im en ta l Section
Gen er a l Meth od s. 1H NMR spectra (CDCl3 solutions
unless otherwise stated) were carried out at 250 or 400 MHz,
and 13C NMR spectra (CDCl3 solutions unless otherwise stated)
were carried out at 62.9 or 100 MHz. Melting points are
uncorrected. Column chromatography was performed on silica
gel 230-400 mesh with various mixture of diethyl ether (E)
and petroleum ether (PE). Tetrahydrofuran (THF) and dichlo-
romethane were freshly distilled before use, respectively, from
benzophenone ketyl and from CaH2.
Gen er a l P r oced u r e for t h e Syn t h esis of Alk en yl
Oxa zolid in e 5a -f. Unsaturated aldehydes 4a -f (15 mmol)
were reacted with (R)-phenylglycinol (2 g, 14.6 mmol) in dry
CH2Cl2 (30 mL) in the presence of 4 Å molecular sieves (10 g).
The mixture was kept at ambient temperature for 3 h, filtered,
and concentrated. The resulting residue was dissolved in
EtOAc (60 mL), treated with di-tert-butyl dicarbonate (3.3 g,
15 mmol), refluxed for 15 h, and concentrated in vacuo.
Purification of the residue by flash chromatography (E/PE 10/
90) gave pure oxazolidines 5a -f.
(2R,4R,2′E)-4-P h en yl-2-(2-p h en ylvin yl)oxa zolid in e-3-
ca r boxylic Acid ter t-Bu tyl Ester (5a ): yield 93%; yellow
solid, mp 72 °C. 1H NMR: 1.3-1.5 (bm, 9H), 4.02 (dd, J )
5.3 and 8.8 Hz, 1H), 4.3 (dd, J ) 7 and 8.8 Hz, 1H), 4.9 (bs,
1H), 5.75 (bs, 1H), 6.25 (dd, J ) 5 and 15.6 Hz, 1H), 6.75 (d,
J ) 15.6 Hz, 1H), 7.1-7.5 (m, 10H); 13C NMR: 28.7, 61, 73.8,
81, 90.5, 126.7, 126.9, 127.3, 127.9, 128.6, 129, 134.4, 136.6,
141, 154; IR (CHCl3): 1705, 1160 cm-1. [R]20D: +8 (c 1 CHCl3).
Anal. Calcd for C22H25NO3: C, 75.19; H, 7.17; N, 3.99.
Found: C, 75.03; H, 7.25; N, 4.07.
(2R ,4R ,2′E )-2-(1-Me t h y l-2-p h e n y lv in y l)-4-p h e n y l-
oxa zolid in e-3-ca r boxylic Acid ter t-Bu tyl Ester (5b): yield
62%; white solid, mp 101 °C. 1H NMR: 1.4 (bs, 9H), 1.94 (s,
3H), 4.12 (dd, J ) 5.2 and 8.7 Hz, 1H), 4.29 (dd, J ) 7.1 and
8.9 Hz, 1H), 4.96 (t, J ) 6.2 Hz, 1H), 5.6 (s, 1H), 6.67 (s, 1H),
7.2-7.4 (m, 10H); 13C NMR: 13.6, 28.3, 60.8, 72.6, 80.7, 94.2,
126.8, 127.3, 128.2, 129.1, 135, 137.2, 140.5, 154.4. [R]20D: +8
(c 1 CHCl3). Anal. Calcd for C23H27NO3: C, 75.59; H, 7.45;
N, 3.83. Found: C, 75.59; H, 7.49; N, 3.76.
Clearly the intramolecular nature of the bromocar-
bamation reaction should be considered. As mentioned
above, the 6-endo-tet ring closure appeared to be pre-
ferred over the corresponding 5-exo-tet process. Although
neither process can be favored on the sole basis of
Baldwin’s rules,24 it has been frequently observed that
intramolecular attack onto epoxides generally follows the
5-exo path unless there is some kind of positive charge
stabilization favoring the 6-endo process.25 On the other
hand, intermolecular nucleophilic attacks onto epoxides
linked to heterocycles (acetals,26,4 furanosides,4 imid-
azolidines,27 or oxazolidines28 ) were reported to occur,
as in the present cases, on the distal oxiranyl carbon
atom.
It was therefore appealing to assume that the above-
reported regioselectivities may proceed from the same
cause. Thus, we have undertaken an AM1 series of
calculations on bromonium ions 23a ,b and on protonated
epoxides29 24a ,b Table 2.
These calculations unambiguously indicate that in each
case (i) the fraction of positive charge is much larger in
the Câ position, that is on the carbon atom which is the
more distant one from the heterocycle, in agreement with
the experimental results; (ii) the bond indices are con-
sistent with the positive charge disposal since the Câ-O
bond of protonated epoxides or the Câ-Br bond in
bromonium ions show the smaller bond index. The larger
value of positive charge on the Câ center is obviously due
to the electroattracting effect of the C-O and C-N bonds
belonging to the oxazolidine moiety. Analogous calcula-
tions were performed on the N-unsubstituted compounds
23a and 24a (R′ ) R′′ ) H, R ) Pr), that is on molecules
in which the C-N oxazolidine bond has a less electro-
(2R,4R,2′E)-4-P h en yl-2-p r op en yloxa zolid in e-3-ca r box-
ylic Acid ter t-Bu tyl Ester (5c): yield 57%; oil. 1H NMR: 1.3
(bs, 9H), 1.73 (dd, J ) 1.5 and 6.6 Hz, 3H), 3.92 (dd, J ) 5 and
8.8 Hz, 1H), 4.18 (dd, J ) 6.7 and 8.8 Hz, 1H), 4.85 (bm, 1H),
5.5-5.63 (m, 2H), 5.89 (m, 1H), 7.1-7.35 (m, 5H); 13C NMR:
(24) Baldwin, J . E. J . Chem. Soc., Chem. Commun. 1976, 734-738.
(25) See ref 2, pp 732-733.
(26) Fourneau, J . P.; Chantalou, S. Bull. Soc. Chim. Fr. 1945, 845-
864.
(27) Behrens, C. H.; Sharpless, K. B. Aldrichim. Acta 1983, 16, 67-
79.
(28) Bernardi, A.; Cardani, S.; Scolastico, C.; Villa, R. Tetrahedron
1990, 46, 1987-1998.
(29) The substitution of epoxides 7a and ent-7g by azide ion was
performed in the presence of ammonium chloride.
17.6, 28.3, 60.5, 73, 80.3, 90.1, 126.5, 127.3, 128.4, 128.6, 130.8,
D
140.9, 153.4. [R]20
: -62 (c 0.5 CHCl3). Anal. Calcd for
C17H23NO3: C, 70.56; H, 8.01; N, 4.84. Found: C, 70.58; H,
8.08; N, 4.95.

2110 J . Org. Chem., Vol. 62, No. 7, 1997
Agami et al.
(2R ,4R ,2′E )-2-(1-Me t h ylb u t -1-e n yl)-4-p h e n yl-2-p r o-
p en yloxa zolid in e-3-ca r boxylic Acid ter t-Bu tyl Ester (5d ):
yield 80%; oil. 1H NMR: 0.93 (t, J ) 7.5 Hz, 3H), 1.3 (bs, 9H),
1.55 (s, 3H), 2.05 (q, J ) 7.4 Hz, 2H), 4.02 (dd, J ) 4.8 and
8.8, 1H), 4.18 (dd, J ) 7 and 8.8 Hz, 1H), 4.87 (bt J ) 5 Hz,
83.4, 92.6, 127.7, 127.73, 127.9, 128.4, 128.7, 129, 129.3, 132.2,
D
139, 148.6. [R]20
: +197 (c 1 CHCl3). Anal. Calcd for
C19H18NO3Br: C, 58.78; H, 4.67; N, 3.61. Found: C, 58.80;
H, 4.64; N, 3.54.
(3R ,7S ,8S ,9R )-8-B r o m o -7-m e t h y l-3-p h e n y lt e t r a -
h yd r ooxa zolo[3,2-c][1,3] oxa zin -5-on e (6c): crystallized
from absolute EtOH; 53% overall yield from aldehyde 4c;
colorless crystals: mp 169 °C. 1H NMR: 1.52 (d, J ) 6.2 Hz,
3H), 3.75 (dd, J ) 8.8 and 10.7 Hz, 1H), 4.06 (dd, J ) 1.3 and
9.2 Hz, 1H), 4.18 (dd, J ) 6.5 and 9.2 Hz, 1H), 4.39 (dq, J )
6.2 and 10.7 Hz, 1H), 4.85 (dd, J ) 1.3 and 6.5 Hz, 1H), 4.95
1H), 5.38 (bs, 1H), 5.6 (bt, J ) 7 Hz, 1H), 7.1-7.5 (m, 5H); 13
C
NMR: 11.4, 13.8, 21, 28.2, 60.7, 72.3, 80.3, 94.1, 127.2, 127.3,
D
128.3, 131.5, 140.8, 154.3; IR (CHCl3): 1690, 990 cm-1. [R]20
:
-47 (c 1 CHCl3). Anal. Calcd for C19H27NO3: C, 71.89; H,
8.57; N, 4.41. Found: C, 71.72; H, 8.69; N, 4.48.
(2R,4R,2′E,4′E)-2-P en ta-1,3-dien yl-4-ph en yloxazolidin e-
1
3-ca r boxylic Acid ter t-Bu tyl Ester (5e): yield 80%; oil. H
(d, J ) 8.8 Hz, 1H), 7.15-7.3 (m, 5H); 13C NMR: 28.6, 47,
D
NMR: 1.37 (bs, 9H), 1.8 (d, J ) 6.6 Hz, 3H), 4.0 (dd, J ) 5.3
and 8.8 Hz, 1H), 4.3 (dd, J ) 7.6 and 7.6 Hz, 1H), 4.95 (bs,
1H), 5.66 (bs, 2H), 5.83 (m, 2H), 6.14 (ddd, J ) 1.4, 10.7 and
13.6 Hz, 1H), 6.4 (bm, 1H), 7.2-7.4 (m, 5H); 13C NMR: 13.8,
60.6, 73.8, 75.6, 89, 126.5, 128.1, 128.7, 139.8, 148.6. [R]20
:
+112 (c 0.7 CHCl3). Anal. Calcd for C13H14NO3Br: C, 50.02;
H, 4.52; N, 4.49. Found: C, 50.00; H, 4.42; N, 4.45.
(3R ,7S ,8S ,9R )-8-Br om o-7-e t h yl-8-m e t h yl-3-p h e n yl-
tetr a h yd r ooxa zolo[3,2-c][1,3]oxa zin -5-on e (6d ): chromato-
graphed (E/PE: 50/50); yield 73%; colorless crystals: mp 141
°C. 1H NMR: 1.05 (t, J ) 7.3 Hz, 3H), 1.49 (d, J ) 0.8 Hz,
3H), 1.5-1.7 (m, 1H), 2.0-2.2 (m, 1H), 4.18 (d, J ) 10.2 Hz,
1H), 4.24 (m, 2H), 4.81 (t, J ) 4.4 Hz, 1H), 5.11 (d, J ) 0.6
Hz, 1H), 7.15-7.5 (m, 5H); 13C NMR: 10.9, 16.6, 22.1, 57.9,
59.9, 73.7, 83.6, 92.3, 127.6, 128.2, 128.5, 139.1, 148.9; IR
(CHCl3): 1715 cm-1. [R]20D: +24 (c 1 CHCl3). Anal. Calcd
for C15H18NO3Br: C, 52.96; H, 5.33; N, 4.12. Found: C, 53.30;
H, 5.26; N, 4.14.
(3R,7S,8S,9R,E)-8-Br om o-3-p h en yl-7-p r op en ylt et r a -
h ydr ooxazolo[3,2-c][1,3]oxazin -5-on e (6e): crystallized from
absolute EtOH; yield 80%; colorless crystals: mp 113 °C. 1H
NMR: 1.7 (dd, J ) 0.7 and 6.5 Hz, 3H), 3.79 (dd, J ) 8.9 and
10.7 Hz, 1H), 4.1 (d, J ) 9.1 Hz, 1H), 4.2 (dd, J ) 7.1 and 9.2
Hz, 1H), 4.64 (dd, J ) 7.7 and 10.7 Hz, 1H), 4.88 (d, J ) 6.3
Hz, 1H), 4.98 (d, J ) 8.8 Hz, 1H), 5.44 (ddd, J ) 1.5, 7.7 and
15 Hz, 1H), 5.9 (m, 1H), 7.1-7.4 (m, 5H); 13C NMR: 13.6, 45.8,
60.4, 73.3, 79.7, 90.6, 124.5, 126.4, 127.8, 128.4, 134.5, 139.8,
148.3; IR (CHCl3): 1720 cm-1. [R]20D: +68 (c 0.8 CHCl3). Anal.
Calcd for C15H16NO3Br: C, 53.27; H, 4.77; N, 4.14. Found:
C, 53.37; H, 4.84; N, 4.31.
28.7, 60.9, 73.6, 80.8, 90.4, 126.9, 127.2, 127.8, 128.9, 130.8,
D
132.1, 134.6, 141.2, 153.8; IR (CHCl3): 1690, 905 cm-1. [R]20
:
-57.3 (c 0.5 CHCl3). Anal. Calcd for C19H25NO3: C, 72.35;
H, 7.99; N, 4.44. Found: C, 72.34; H, 8.08; N, 4.46.
(2R,4R,2′E)-2-P en t -1-en yl-4-p h en yloxa zolid in e-3-ca r -
boxylic Acid ter t-Bu tyl Ester (5f): yield 81%; oil. 1H
NMR: 0.95 (t, J ) 7.4 Hz, 3H), 1.38 (s, 9H), 1.47 (sext, J )
7.4 Hz, 2H), 2.12 (q, J ) 7.1 Hz, 1H), 4.01 (dd, J ) 5 and 8.7
Hz, 1H), 4.28 (dd, J ) 7 and 8.6 Hz, 1H), 5.62 (bm, 2H), 5.96
(bdd, 7.1 and 14.8 Hz, 1H), 7.3-7.4 (m, 5H); 13C NMR: 13.6,
22, 28.2, 34.1, 60.5, 72.8, 80.3, 90.1, 126.5, 127.3, 128.4, 135.8,
D
140.9, 153.4; IR (CHCl3): 1700 cm-1
.
[R]20
:
-57.3 (c 0.5
CHCl3). Anal. Calcd for C19H27NO3: C, 71.89; H, 8.57; N, 4.41.
Found: C, 71.8; H, 8.75; N, 4.39.
(2S,4S,2′E)-4-P h en yl-2-(3-p h en ylp r op en yl)oxa zolid in e-
3-ca r boxylic Acid ter t-Bu tyl Ester (en t-5g). 4-Phenyl-2-
butenal30 (4g) (2 g, 15 mmol) was reacted with (S)-phenyl-
glycinol (2 g, 14.6 mmol) in dry CH2Cl2 (50 mL) in the presence
of 4 Å molecular sieves (15 g). The mixture was kept at
ambient temperature for 0.5 h, filtered, and concentrated. The
resulting residue was dissolved in EtOAc (60 mL), treated with
di-tert-butyl dicarbonate (6.5 g, 30 mmol), stirred at rt for 18
h, and concentrated in vacuo. Purification of the residue by
flash chromatography using E/PE (10/90) afforded ent-5g (3.2
g, 60%) as a white solid: mp 58 °C. 1H NMR: 1.27 (bs, 9H),
3.42 (d, J ) 6.8 Hz, 2H), 3.94 (d, J ) 5.2 and 8.7 Hz, 1H), 4.25
(dd, J ) 6.8 and 8.7 Hz, 1H), 4.9 (bs, 1H), 5.58 (bs, 1H), 5.64
(bm, 1H), 6.04 (bm, 1H), 7.1-7.3 (m, 10H); 13C NMR: 28.3,
(3R,7S,8S,9R)-8-Br om o-3-p h en yl-7-p r op yltetr a h yd r o-
oxa zolo[3,2-c][1,3] oxa zin -5-on e (6f): crystallized from
absolute EtOH; 77% overall yield from aldehyde 4f; colorless
crystals: mp 126 °C. 1H NMR: 0.97 (t, J ) 7.4 Hz, 3H), 1.4-
1.5 (m, 1H), 1.55-1.7 (m, 1H), 1.7-1.82 (m, 1H), 2.02-2.15
(m, 1H), 3.9 (dd, J ) 8.7 and 10.7 Hz, 1H), 4.19 (dd, J ) 1.1
and 9.4 Hz, 1H), 4.3 (dd, J ) 6.6 and 9.3 Hz, 1H), 4.38 (m,
1H), 4.98 (dd, J ) 1 and 6.5 Hz, 1H), 5.05 (d, J ) 8.7, 1H),
7.3-7.4 (m, 5H); 13C NMR: 13.5, 17.4, 34.1, 45.6, 60.7, 73.8,
38.5, 60.6, 73.3, 80.5, 89.8, 126.3, 126.6, 127.4, 128.5, 128.7,
D
134.1, 139.7, 140.8, 153.5; IR (CHCl3): 1685 cm-1
.
[R]20
:
-16.4 (c 1 CHCl3). Anal. Calcd for C23H27NO3: C, 75.59; H,
89.1, 126.5, 128.1, 128.7, 139.9, 149.1; IR (CHCl3): 1715 cm-1
.
7.45; N, 3.83. Found: C, 75.47; H, 7.52; N, 3.77.
[R]20D: +49 (c 0.5 CHCl3). Anal. Calcd for C15H18NO3Br: C,
52.96; H, 5.33; N, 4.12. Found: C, 52.95; H, 5.42; N, 4.11.
(3S,7R,8R,9S)-7-Ben zyl-8-br om o-3-p h en yltetr a h yd r o-
oxa zolo[3,2-c][1,3]oxa zin -5-on e (en t 6g): crystallized from
i-PrOH; yield 92%; colorless crystals: mp 196 °C. 1H NMR:
3.1 (dd, J ) 4.8 and 14.7 Hz, 1H), 3.37 (dd, J ) 3.1 and 14.7
Hz, 1H), 3.65 (dd, J ) 8.8 and 10.7 Hz, 1H), 3.97 (d, J ) 9.1
Hz, 1H), 4.18 (dd, J ) 6.6 and 9.1 Hz, 1H), 4.65 (ddd, J ) 3.1,
4.8 and 10.7 Hz, 1H), 4.85 (d, J ) 6.2 Hz, 1H), 5.01 (d, J ) 8.8
Hz, 1H), 6.87 (dd, J ) 1.6 and 7.2 Hz, 2H), 7.1-7.4 (m, 8H);
13C NMR: 37, 44.3, 60.5, 73.9, 74, 88.5, 126, 127.4, 128, 128.69,
Gen er a l P r oced u r e for th e Syn th esis of Bicyclic Com -
p ou n d s 6a -g. NBS (0.57 g, 3.5 mmol) was added to a
solution of oxazolidine 5 (3.2 mmol) in DME/H2O (10 mL/10
mL), and the mixture was stirred at rt for 3 h. Water was
then added, and the resulting mixture was extracted with
CH2Cl2. The combined organic layers were dried (MgSO4) and
concentrated in vacuo. Purification of the residue by flash
chromatography using a variable E/PE mixture or by crystal-
lization gave pure bicyclic compounds 6a -f and ent-6g.
(3R,7S,8S,9R)-8-Br om o-3,7-diph en yltetr ah ydr ooxazolo-
[3,2-c][1,3]oxa zin -5-on e 6a : crystallized from absolute EtOH;
yield 80%; colorless crystals: mp 178 °C. 1H NMR: 4.05 (dd,
J ) 8.8 and 10.8 Hz, 1H), 4.15 (dd, J ) 9 and 1.4 Hz, 1H),
4.25 (dd, J ) 6.5 and 9 Hz, 1H), 4.94 (dd, J ) 1.4 and 6.5 Hz,
1H), 5.13 (d, J ) 8.8 Hz, 1H), 5.2 (d, J ) 10.8 Hz, 1H), 7.15-
7.35 (m, 10H); 13C NMR: 47.1, 60.9, 74.0, 81.3, 89.3, 126.7,
127.8, 128.4, 128.7, 128.9, 129.8, 134.8, 139.8, 148.6; IR
(CHCl3): 1715 cm-1. [R]20D: +104 (c 1.3 CHCl3). Anal. Calcd
for C18H16NO3Br: C, 57.77; H, 4.31; N, 3.74. Found: C, 57.75;
H, 4.32; N, 3.74.
128.73, 130.2, 134.3, 139.5, 148.5; IR (CHCl3): 1710 cm-1
.
[R]20D: -13 (c 1 CHCl3). Anal. Calcd for C19H18NO3Br: C,
58.78; H, 4.67; N, 3.61. Found: C, 58.88; H, 4.78; N, 3.53.
Gen er a l P r oced u r e for th e Syn th esis of Ep oxid es 7a -f
a n d en t-7g. Bicyclic compounds 6a -f and ent-6g (1 mmol)
were added to a solution of NaOEt (5 mmol) in absolute EtOH
(8 mL), and the mixture was stirred at rt for 3 h. Saturated
aqueous ammonium chloride was then added, and the result-
ing mixture was extracted with CH2Cl2. The combined organic
layers were dried (MgSO4) and concentrated in vacuo. Puri-
fication of the residue by flash chromatography using an E/PE
eluent gave pure epoxides 7a -f and ent-7g.
(3R,7S,8S,9R)-8-Br om o-8-m eth yl-3,7-d ip h en yltetr a h y-
d r ooxa zolo[3,2-c] [1,3]oxa zin -5-on e (6b): chromatographed
(E/PE: 50/50); yield 90%; colorless crystals: mp 172 °C. 1H
NMR: 1.72 (s, 3H), 4.4 (m, 2H), 4.98 (m, 1H), 5.43 (s, 1H),
5.53 (s, 1H), 7.3-7.5 (m, 10H); 13C NMR: 16.7, 57.9, 60.1, 73.9,
(2R ,4R,2′R,3′S)-4-P h en yl-2-(3-p h en yloxir a n -2-yl)oxa -
zolid in e-3-ca r boxylic Acid Eth yl Ester (7a ): E/PE: 60/40;
72% overall yield from aldehyde 4a ; white solid, mp 83 °C. 1H
NMR: 1-1.35 (bm, 3H), 3.38 (bs, 1H), 3.85 (d, J ) 1.9 Hz,
1H), 4-4.2 (m, 2H), 4.14 (dd, J ) 6.9 and 8.3 Hz, 1H), 4.33
(30) Funk, R. L.; Bolton, G. L. J . Am. Chem. Soc. 1988, 110, 1290-
1292.

Formation of Chiral Epoxy Oxazolidines
J . Org. Chem., Vol. 62, No. 7, 1997 2111
(dd, J ) 6.7 and 8.8 Hz, 1H), 4.94 (t, J ) 6.6 Hz, 1H), 5.58 (bs,
1H), 7.1-7.45 (m, 10H); 13C NMR: 14.5, 55.1, 60.9, 62, 62.6,
74.2, 88, 125.8, 126.8, 127.8, 128.4, 128.6, 128.65, 136.4, 139.4,
155; IR (CHCl3): 1670, 1250 cm-1; [R]20D: +17 (c 0.5 CHCl3).
Anal. Calcd for C20H21NO4: C, 70.78; H, 6.24; N, 4.13.
Found: C, 70.79; H, 6.22; N, 4.26.
solid: mp 232 °C. 1H NMR: 3.87 (dd, J ) 7.6 and 9.1 Hz,
1H), 3.98 (dd, J ) 8 and 11.1 Hz, 1H), 4.54 (dd, J ) 7.7 and
9.1 Hz, 1H), 5.13 (d, J ) 11 Hz), 5.2-5.3 (m, 1H), 5.3 (d, J )
7.9 Hz, 1H), 7.2-7.4 (m, 10H); 13C NMR: 46.2, 61.3, 72.8, 79.5,
91.3, 126.3, 127.9, 128.3, 128.7, 129.0, 129.9, 134.3, 138.1,
151.3. [R]20D: -40 (c 0.15 CHCl3).
(2R ,4R ,2′R ,3′S )-2-(2-Me t h yl-3-p h e n yloxir a n -2-yl)-4-
p h en yloxa zolid in e-3-ca r boxylic Acid Eth yl Ester (7b):
E/PE: 40/60; yield 85%; white solid, mp 65 °C. 1H NMR:
1.05-1.2 (bs, 6H), 4-4.15 (bs, 3H), 4.19 (t, J ) 8.7 Hz, 1H),
4.30 (t, J ) 8.6 Hz, 1H), 4.88 (bt, J ) 8 Hz, 1H), 5.45 (bs, 1H),
7.17-7.3 (m, 8H), 7.4-7.5 (m, 2H); 13C NMR: 13.6, 14.6, 59.9,
62.1, 62.2, 64, 74.2, 92.1, 126.7, 127.5, 127.8, 127.9, 128.2,
128.6, 135.4, 138.9, 156. [R]20D: +24 (c 0.5 CHCl3).
(2R,4R,1′R,2′r )-2-(2-Azid o-1-h yd r oxy-2-p h en yleth yl)-4-
p h en yloxa zolid in e-3-ca r boxylic Acid Eth yl Ester (13).
Sodium azide (13.4 g, 206 mmol) and water (70 mL) were
successively added to a solution of epoxy oxazolidine 7a (7 g,
20.6 mmol) and ammonium chloride (10.9 g, 206 mmol) in
EtOH (380 mL). The mixture was refluxed for 24 h and
concentrated. Water was then added, and the resulting
mixture was extracted with ether. The combined organic
(2R,4R,2′R,3′S)-2-(3-Met h yloxir a n -2-yl)-4-p h en yloxa -
zolid in e-3-ca r boxylic Acid Eth yl Ester (7c): E/PE: 30/70;
yield 80%; oil. 1H NMR: 0.9-1.2 (bm, 3H), 1.27 (d, J ) 5.1
Hz, 3H), 2.98 (m, 2H), 4.01 (dd, J ) 6.8 and 8.6 Hz, 1H), 3.9-
4.15 (bm, 2H), 4.23 (dd, J ) 7 and 8.7 Hz, 1H), 4.86 (m, 1H),
layers were dried (MgSO4). After evaporation, azido alcohol
13 was isolated as an oil (7 g), and the crude product was used
as such in the next step. A sample was purified by flash
chromatography (E/PE: 60/40). 1H NMR: 1.0 (t, J ) 7.1 Hz,
3H), 3.96-4.08 (m, 3H), 4.11 (dd, J ) 6.7 and 8.9 Hz, 1H),
4.18 (dd, J ) 6.9 and 8.8 Hz, 1H), 4.72 (d, J ) 3.5 Hz, 1H),
4.85-4.9 (d, J ) 8.3 Hz, 1H), 4.95 (dd, J ) 6.7 and 6.9 Hz,
1H), 7.1-7.55 (m, 10H); 13C NMR: 14.2, 60.5, 62.4, 66.4, 73.6,
76.1, 90.2, 126.2, 127.8, 128.5, 128.7, 134.9, 139.4, 156.7.
[R]20D: -47 (c 0.7 CHCl3).
(2R,4R,1′R,2′r )-2-[2-Azido-1-(ben zyloxy)-2-ph en yleth yl]-
4-p h en yloxa zolid in e-3-ca r boxylic Acid Eth yl Ester (14).
Sodium hydride (0.625 g, 60% dispersion in mineral oil, 16.3
mmol) was added to a solution of compound 13 (7 g, 20.6 mmol)
in DMF (80 mL) at 0 °C. The mixture was stirred for 15 min,
and then benzyl bromide (1.93 mL, 16.3 mmol) was added. The
mixture was stirred for 15 min and then hydrolyzed with an
ammonium chloride saturated aqueous solution. The resulting
mixture was extracted with ether. The combined organic
layers were dried (MgSO4) and concentrated in vacuo. Puri-
fication of the residue by flash chromatography (E/PE: 20/
80) gave compound 14 (4.4 g, 71% overall yield from 7a ) as a
yellow solid: mp 70 °C. 1H NMR: 1.03 (t, J ) 7.1 Hz, 3H),
3.65 (dd, J ) 4.1 and 7.2 Hz, 1H), 3.96-4.1 (m, 4H), 4.2 (m,
1H), 4.7 (d, J ) 7.3 Hz, 1H), 4.95 (m, 1H), 5.5 (m, 1H), 6.7-
7.5 (m, 15H); 13C NMR: 14.4, 61.4, 62.1, 66.0, 73.2, 75.1, 83.6,
90.4, 126.9, 127.5, 127.6, 128.1, 128.4, 128.6, 128.9, 136.6,
139.5, 156.3. IR (CHCl3): 2100, 1670 cm-1. [R]20D: -59 (c 0.6
CHCl3).
(1R,2r )-2-(Ben zyloxy)-2-[1,3]d it h iola n -2-yl-1-p h en yl-
eth yl Azid e (15). Boron trifluoride etherate (0.52 mL, 4.2
mmol) was added to a solution of oxazolidine 14 (1 g, 2.1 mmol)
and ethanedithiol (1.23 mL, 14.7 mmol) in CH2Cl2 (20 mL).
The mixture was stirred for 3 days and then hydrolyzed by
an aqueous saturated solution with sodium hydrogen carbon-
ate. The resulting mixture was extracted with ether. The
combined organic layers were dried (MgSO4) and concentrated
in vacuo. Purification of the residue by flash chromatography
(E/PE: 5/95) gave compound 15 (0.53 g, 73%) as a solid: mp
57 °C. 1H NMR: 3-3.3 (m, 4H), 3.6 (t, J ) 6.1 Hz, 1H), 4.3-
4.65 (m, 2H), 4.51 (d, J ) 6.2 Hz, 1H), 4.72 (d, J ) 6.1 Hz,
1H),7.1-7.5 (m, 10H); 13C NMR: 38.2, 38.9, 54.6, 68.0, 76.3,
86.1, 127.6, 128.1, 128.5, 128.6, 128.7, 135.6, 137.5. IR
(CHCl3): 2110 cm-1. [R]20D: -66 (c 1.7 CHCl3).
(1R,2r )-3-Azid o-2-(b en zyloxy)-3-p h en ylp r op ion a ld e-
h yd e (16). Methyl iodide (3.6 mL, 58 mmol) and water (3.2
mL) were successively added to a solution of thioacetal 15 (1
g, 2.9 mmol) and calcium carbonate (0.87 g, 8.7 mmol) in
acetone (12.8 mL). The mixture was heated at 60 °C for 4
days and concentrated. Water was then added, and the
resulting mixture was extracted with CH2Cl2. The combined
organic layers were dried (MgSO4). After evaporation, alde-
hyde 16 was isolated as a colorless oil (0.75 g, 90%), and the
crude product was used as such in the next step. 1H NMR:
4.01 (dd, J ) 2 and 5.8 Hz, 1H), 4.56-4.7 (m, 2H), 4.6 (d, J )
5.8 Hz, 1H), 7.1-7.7 (m, 10H), 9.6 (d, J ) 2 Hz, 1H); 13C
NMR: 65.6, 73.6, 84.8, 128.1, 128.4, 128.7, 128.9, 134.8, 136.6,
200.4.
5.43 (m, 1H), 7.1-7.4 (m, 5H); 13C NMR: 14.4, 17.0, 51.2, 59.5,
D
60.8, 61.8, 74.0, 88.3, 126.7, 127.7, 128.5, 139.5, 155.0. [R]20
:
+16 (c 1.8 CHCl3). Anal. Calcd for C15H19NO4: C, 64.97; H,
6.91; N, 5.05. Found: C, 64.92; H, 6.96; N, 5.04.
(2R ,4R ,2′R ,3′S )-2-(2-Me t h y l-3-e t h y lo x ir a n -2-y l)-4-
p h en yloxa zolid in e-3-ca r boxylic Acid Eth yl Ester (7d ):
E/PE: 20/80; yield 71%; oil. 1H NMR: 1.03 (t, J ) 8.4 Hz,
3H), 1.16 (bs, 3H), 1.43 (s, 3H), 1.55 (m, 1H), 1.7 (m, 1H), 2.95
(t, J ) 6.5 Hz, 1H), 4.1 (m, 2H), 4.18 (t, J ) 8.6 Hz, 1H), 4.31
(dd, J ) 7.5 and 8.5 Hz, 1H), 4.87 (bt, J ) 7.8 Hz, 1H), 5.4 (bs,
1H), 7.2-7.6 (m, 5H); 13C NMR: 10.3, 14, 14.4, 21.25, 60.2,
61.3, 61.8, 61.9, 73.9, 92, 127.4, 127.7, 128.4, 139, 154.1; IR
(CHCl3): 1690 cm-1. [R]20D: +2.2 (c 0.5 CHCl3).
(2R,4R,2′R,3′S,4E)-4-P h en yl-2-(3-p r op en yl-3-oxir a n -2-
yl)oxa zolid in e-3-ca r boxylic Acid Eth yl Ester (7e): E/PE:
20/80; yield 80%; oil. 1H NMR: 1.11 (bs, 3H), 1.7 (dd, J ) 1.6
and 66Hz, 3H), 3.22 (bs, 1H), 3.33 (dd, J ) 2.1 and 8.3 Hz,
1H), 4.05 (m, 3H), 4.25 (dd, J ) 7 and 8.8 Hz, 1H), 4.86 (t, J
) 6.6 Hz 1H), 5.18 (ddd, J ) 1.6, 8.3 and 15.4 Hz, 1H), 5.46
(bs, 1H), 5.9 (m, 1H), 7.15-7.5 (m, 5H); 13C NMR: 14.4, 17.9,
50.8, 59.9, 60.8, 61.8, 74, 88.1, 126.7, 127.3, 127.7, 128.5, 132.7,
139.4, 154.9; IR (CHCl3): 1690 cm-1; [R]20D: +15 (c 0.5 CHCl3).
(2R ,4R ,2′R ,3′S )-4-P h e n yl-2-(3-p r op yl-3-oxir a n -2-yl)-
oxa zolid in e-3-ca r boxylic Acid Eth yl Ester (7f): E/PE: 30/
70; 68% overall yield from aldehyde 4f; oil. 1H NMR: 0.85 (t,
J ) 7.2 Hz, 3H), 0.9-1.2 (bm, 3H), 1.3-1.6 (m, 4H), 2.87 (m,
1H), 2.99 (m, 1H), 3.8-4.1 (m, 3H), 4.16 (dd, J ) 7.2 and 8.7
Hz, 1H), 4.8 (m, 1H), 5.38 (m, 1H), 7.1-7.4 (m, 5H); 13C NMR:
13.5, 14.1, 19.0, 33.0, 54.6, 58.1, 60.5, 61.3, 73.5, 88.1, 126.4,
D
127.3, 128.1, 139.3, 154.5; IR (CHCl3): 1690, 1250 cm-1. [R]20
:
-13 (c 0.3 CHCl3). Anal. Calcd for C17H23NO4: C, 66.86; H,
7.59; N, 4.59. Found: C, 66.86; H, 7.63; N, 4.66.
(2S,4s,2′s,3′r )-2-(3-Ben zyl-3-oxir a n -2-yl)-4-p h en yloxa -
zolid in e-3-ca r boxylic Acid Eth yl Ester (en t-7g): E/PE: 40/
60; yield 97%; oil. 1H NMR: 1.07 (t, J ) 7 Hz, 3H), 2.82 (dd,
J ) 5.1 and 14.4 Hz, 1H), 2.97 (dd, J ) 5.4 and 14.4 Hz, 1H),
3.17 (bs, 1H), 3.22 (dt, J ) 2 and 5.5 Hz, 1H), 4.00 (dd, J )
7.3 and 8 Hz, 1H), 4.02 (q, J ) 7 Hz, 1H), 4.24 (dd, J ) 6.9
and 8.8 Hz, 1H), 4.86 (bt, J ) 5.1 Hz, 1H), 5.45 (bs, 1H), 7.15-
7.3 (m, 10H); 13C NMR: 14.3, 37.7, 55.2, 58.3, 60.8, 61.8, 73.9,
88.2, 126.7, 127.7, 128.5, 128.6, 129, 136.8, 139.2, 154.9. IR
(CHCl3): 1715 cm-1; [R]20D: -4 (c 0.7 CHCl3). Anal. Calcd
for C21H23NO4: C, 71.37; H, 6.56; N, 3.96. Found: C, 71.23;
H, 6.57; N, 3.96.
Br om oca r ba m a tion of Com p ou n d 5a w ith Br om in e.
A 1 M solution of bromine in CH2Cl2 (3.1 mL) was added to a
solution of oxazolidine 5a (1 g, 2.8 mmol) in CH2Cl2 (30 mL),
and the mixture was stirred at 0 °C for 1 h. A saturated
aqueous solution of NaHCO3 was then added, and the resulting
mixture was decolorized with a few drops of 0.1 N solution of
Na2S2O3. After extraction with CH2Cl2, the combined organic
layers were dried (MgSO4) and concentrated in vacuo. The
8/9 (X ) Br) ratio was determined by comparing the corre-
sponding 1H NMR signals in the crude resulting mixture. A
sample of compound 9 (X ) Br) was isolated from compound
8 (which corresponds to the above-described compound 6a ) by
flash chromatography using a (40/60) E/PE mixture. White
(1R,2r )-3-Azid o-2-(ben zyloxy)-3-p h en ylp r op ion ic Acid
Meth yl Ester (17). PDC (4 g, 11.2 mmol) was added to a
solution of aldehyde 16 (0.63 g, 2.24 mmol) in DMF/MeOH (11
mL/1.1 mL), and the mixture was stirred at rt for 19 h. Water

2112 J . Org. Chem., Vol. 62, No. 7, 1997
Agami et al.
and ether were then added, and the resulting mixture was
filtered on Celite. The filtrate was extracted with ether. The
combined organic layers were dried (MgSO4) and concentrated
in vacuo. Purification of the residue by flash chromatography
(E/PE: 5/95) gave compound 17 (0.38 g, 60%) as an oil. 1H
NMR: 3.69 (s, 3H), 4.07 (d, J ) 7.3 Hz, 1H), 4.3-4.6 (m, 2H),
4.75 (d, J ) 7.3 Hz, 1H), 7.-7.4 (m, 10H); 13C NMR: 52.3; 66.0;
73.0; 80.6; 128.0; 128.1; 128.6; 128.9; 135.4; 136.5; 170.4. IR
(CHCl3): 2115, 1740 cm-1. [R]20D: -41 (c 1 CHCl3).
Hz 1H), 2.95 (dd, J ) 4.7 and 13.9 Hz, 1H), 3.85-3.95 (bm,
1H), 4.2-4.3 (m, 3H), 4.22 (dd, J ) 6.9 and 8.9 Hz, 1H), 4.2-
4.3 (bm, 1H), 4.6-5.2 (bm, 2H), 5.15 (d, J ) 7.5 Hz, 1H), 7.1-
7.4 (m, 11H); 13C NMR: 14.4, 28.4, 35.0, 53.0, 60.7, 62.6, 73.8,
76.4, 79.0, 91.1, 126.2, 126.7, 127.9, 128.3, 128.8, 129.6, 138.6,
D
139.9, 155.2, 156.7. IR (CHCl3): 3400, 1700, 1600 cm-1. [R]20
:
-67.6 (c 0.5 CHCl3). Anal. Calcd for C26H34N2O6: C, 66.36;
H, 7.28; N, 5.95. Found: C, 66.43; H, 7.26; N, 5.75.
(2S,4S,1′S,2′S)-2-[2-[N-(ter t-Bu toxyca r bon yl)a m in o]-1-
[(ter t-b u t yld im et h ylsilyl)oxy]-3-p h en ylp r op yl]-4-p h en -
yloxa zolid in e-3-ca r boxylic Acid Eth yl Ester (21). 2,6-
Lutidine (0.248 mL, 2.12 mmol) and tert-butyldimethylsilyl
triflate (0.4 mL 1.74 mmol) were successively added to a
solution of alcohol 20 (0.5 g, 1.06 mmol) in CH2Cl2 (5 mL) at
-80 °C. The mixture was stirred for 4 h at -40 °C and treated
by water. The resulting mixture was extracted with CH2Cl2.
The combined organic layers were dried (MgSO4) and concen-
trated in vacuo. Purification of the residue by flash chroma-
tography (E/PE: 10/90) gave compound 21 (0.554 g, 90%) as
a colorless oil. 1H NMR: -0.18 (s, 3H), -0.08 (s, 3H), 0.83 (s,
9H), 1.2 (t, J ) 7 Hz, 3H), 1.31 (s, 9H), 2.7 (dd, J ) 10.2 and
14.5 Hz, 1H), 3.02 (dd, J ) 4.5 and 14.5 Hz, 1H), 3.95-4.4 (m,
6H), 4.56 (bs, 1H), 5.14 (bt, J ) 6.1 Hz, 1H), 5.37 (bd, J ) 4.4
Hz, 1H), 7-7.3 (m, 8H), 7.4-7.5 (m, 2H); 13C NMR: -5.0, -4.5,
14.5, 18.2, 26.0, 28.3, 34.7, 53.1, 60.6, 62.0, 71.6, 75.2, 78.8,
90.6, 126.1, 127.3, 127.6, 128.3, 128.5, 129.1, 138.5, 139.2,
155.1, 156.5. IR (CHCl3): 3400, 1700 cm-1; [R]20D: -19 (c 0.3
CHCl3). Anal. Calcd for C32H48N2O6Si: C, 65.72; H, 8.27; N,
4.79. Found: C, 65.64; H, 8.26; N, 4.82.
(1R,2r )-3-(Ben zoyla m in o)-2-(ben zyloxy)-3-p h en ylp r o-
p ion ic Acid Meth yl Ester (18). A mixture of ester 17 (0.067
g, 0.24 mmol) and 5% Pd on carbon (0.04 g) in methanol (5
mL) was refluxed under hydrogen (1 atm) for 36 h. The
catalyst was filtred on Celite, and the filtrate was evaporated.
The resulting solid (0.04 g) and triethylamine (0.01 g, 0.1
mmol) were dissolved in CH2Cl2 (1 mL), and (dimethylamino)-
pyridine (0.002 g, 0.002 mmol) and benzoyl chloride (0.024 mL,
0.2 mmol) were successively added. The mixture was stirred
at rt for 1.5 h. Water was then added, and the resulting
mixture was extracted with ether. The combined organic
layers were dried (MgSO4) and concentrated in vacuo. Puri-
fication of the residue by flash chromatography (E/PE: 75/
25) gave compound 18 (0.044 g, 63%) as a solid: mp 156-157
°C. 1H NMR: 2.97 (d, J ) 6.6 Hz, 3H), 3.67 (s, 3H), 4.65 (dd,
J ) 3.5 and 6.6 Hz, 1H), 5.56 (dd, J ) 3.5 and 6.6 Hz, 1H),
7.09 (d, J ) 9 Hz, 1H), 7.2-7.5 (m, 8H), 7.7-7.8 (m, 2H); 13C
NMR: 52.8, 55.6, 73.1, 127.5, 128.5, 128.7, 131.8, 134.2, 136.6,
D
160.7, 172.3. IR (CHCl3): 3520, 3440, 1735, 1635 cm-1. [R]20
:
+19 [(c 0.2 CHCl3), lit.13c: -23 for ent-18].
(2S,4S,1′S,2′S)-2-(2-Azid o-1-h yd r oxy-3-p h en ylp r op yl)-
4-p h en yloxa zolid in e-3-ca r boxylic Acid Eth yl Ester 19.
Sodium azide (0.976 g, 15 mmol) and water (5 mL) were
successively added to a solution of epoxyoxazolidine ent-7g
(0.265 g, 0.75 mmol) and ammonium chloride (0.803 g, 15
mmol) in EtOH (20 mL). The mixture was refluxed for 15 days
and concentrated. Water was then added, and the resulting
mixture was extracted with ether. The combined organic
layers were dried (MgSO4). After evaporation, azido alcohol
19 was isolated as a yellow oil (0.288 g, 97%) and used crude
for the next step: 1H NMR: 1.11 (t, J ) 7.1 Hz, 3H), 2.99 (s,
1H), 3.02 (d, J ) 2.3 Hz, 1H), 3.78 (m, 1H), 3.98 (m, 1H), 4.06
(dd, J ) 4.1 and 8.9 Hz, 1H), 4.09 (q, J ) 7.1 Hz, 2H), 4.25
(dd, J ) 6.8 and 8.9 Hz, 1H), 4.9-5.3 (bs, 1H), 4.9 (dd, J ) 4.2
and 6.7 Hz, 1H), 5.27 (d, J ) 7.5 Hz, 1H), 7.15-7.3 (m, 10H);
13C NMR: 14.4, 34.9, 60.4, 62.8, 65.6, 73.8, 76.3, 90.9, 126.3,
126.7, 128.0, 128.6, 128.9, 129.4, 138.2, 139.7, 156.8. IR
(2S ,3S )-3-[N -(t er t -Bu t oxyca r b on yl)a m in o]-2-[(t er t -
bu tyld im eth ylsilyl)oxy]-4-p h en ylbu ta n a l 22. A solution
of 1.0 M diisobutyl aluminum hydride (2.5 mL, 2.5 mmol) in
toluene was added to a solution of oxazolidine 21 (0.256 g, 0.5
mmol) in CH2Cl2 (10 mL) at -78 °C. The mixture was stirred
for 3 h at -78 °C and then hydrolyzed by an ammonium
chloride saturated aqueous solution. The resulting mixture
was extracted with CH2Cl2. The combined organic layers were
dried (MgSO4) and concentrated in vacuo. The residue was
dissolved in CH2Cl2 (10 mL), and SiO2 (4.8 g), water (0.58 mL),
and oxalic acid (0.048 g) were successively added. The
heterogeneous mixture was stirred for 20 h at rt and then
filtered on Celite. The filtrate was evaporated, and the
aldehyde 22 (0.093 g, 55%) was obtained after flash chroma-
tography (cyclohexane/AcOEt: 10/90) as a solid: mp 95 °C.
1H NMR: 0.03 (s, 6H), 0.92 (s, 9H), 1.13 (s, 9H), 2.6-2.8 (m,
2H), 4-4.25 (bm, 2H), 4.4-4.5 (bm, 1H), 7.1-7.3 (m, 5H), 9.31
(d, J ) 1Hz, 2H); 13C NMR: -5, -4.5, 18.3, 25.9, 28.4, 35.8,
54.2, 79.5, 79.8, 126.9, 128.6, 137.0, 155.0, 201.4; IR (CHCl3):
3400, 1730, 1700 cm-1. [R]20D: -30 [(c 1.06 CHCl3), lit.18: -31].
AM1 Ca lcu la tion s. The calculations on species 23 and 24
were carried out using the AM1 hamiltonian31 as implemented
in the AMPAC program version 4.0 QCPE No 527. The
geometries were optimized by using the Davidson-Fletcher-
Powell algorithm (FLEPO procedure) that minimizes the
energy with respect to all internal coordinates.
(CHCl3): 3300, 2105, 1695 cm-1
.
[R]20D: -4 (c 0.7 CHCl3).
Anal. Calcd for C21H24N4O4: C, 63.62; H, 6.10; N, 14.13.
Found: C, 63.70; H, 6.13; N, 14.04.
(2S,4S,1′S,2′S)-2-[2-[N-(ter t-Bu toxyca r bon yl)a m in o]-1-
h yd r oxy-3-p h en ylp r op yl]-4-p h en yloxa zolid in e-3-ca r box-
ylic Acid Eth yl Ester (20). A solution of azido alcohol 19
(0.3 g, 0.76 mmol) and di-tert-butyl dicarbonate (0.319 g, 1.46
mmol) in AcOEt (4 mL) was injected into a hydrogenation flask
containing a prehydrogenated suspension of 5% Pd on carbon
(0.06 g) in AcOEt (4 mL). The hydrogenation was complete
in 17 h. The catalyst was filtered on Celite, and the filtrate
was evaporated. The compound 20 (0.25 g, 70%) was obtained
pure after crystallization in PE: mp 169 °C. 1H NMR: 1.07
(t, J ) 7.1 Hz, 3H), 1.24 (s, 9H), 2.80 (dd, J ) 10.1 and 13.8
J O962277G
(31) Dewar, M. J . S.; Zoebisch, E. G.; Healy, E. F.; Stewart, J . J . P.
J . Am. Chem. Soc. 1985, 107, 3902-3909.