Toward the development of a structurally novel class of chiral auxiliaries: Diastereoselective Aldol reactions of a (1R,2S)-ephedrine-based 3,4,5,6-tetrahydro-2H-1,3,4-oxadiazin-2-one

Article abstract of DOI:10.1021/ol026721f

(equation Presented) 8 examples Asymmetric aldol addition reactions have been conducted with (1R,2S)-ephedrine-derived 3,4,5,6-tetrahydro-2H-1,3,4-oxadiazin-2-one (2). Diastereoselectivities range from 75:25 to 99:1 for the formation of the crude non-Evan

Full text of DOI:10.1021/ol026721f

ORGANIC
LETTERS
2002
Vol. 4, No. 21
3739-3742
Toward the Development of a
Structurally Novel Class of Chiral
Auxiliaries: Diastereoselective Aldol
Reactions of a (1R,2S)-Ephedrine-Based
3,4,5,6-Tetrahydro-2H-1,3,4-oxadiazin-2-one
David M. Casper, James R. Burgeson, Joel M. Esken, Gregory M. Ferrence, and
Shawn R. Hitchcock*
Department of Chemistry, Illinois State UniVersity, Normal, Illinois 61790-4160
hitchcock@xenon.che.ilstu.edu
Received August 12, 2002
ABSTRACT
Asymmetric aldol addition reactions have been conducted with (1R,2S)-ephedrine-derived 3,4,5,6-tetrahydro-2H-1,3,4-oxadiazin-2-one (2).
Diastereoselectivities range from 75:25 to 99:1 for the formation of the crude non-Evans syn adducts 8a−h. The facial selectivity of the enolate
is directed by the stereogenic N -methyl substituent. Aldol adduct 8a is readily cleaved by acid hydrolysis to afford (2S,3S)-3-hydroxy-2-
4
methyl-3-phenylpropionic acid (9) in >95% ee.
The remarkable successes in diastereoselective carbon-
carbon bond formation that have been achieved with 1,3-
oxazolidin-2-ones (1)1 derived from R-amino acid-based Vic-
amino alcohols and norephedrine have spurred on much
research. A significant aspect to this research is based on
modifying the amino alcohol structure of the oxazolidinone
for the potential enhancement of reaction diastereoselectivi-
ties.2 Numerous other related chiral auxiliaries3 have been
developed for this purpose, but oxazolidinones have remained
among the most examined, especially with regard to the
asymmetric aldol reaction.1 We became interested in devel-
oping a chiral auxiliary that offered an altered template away
from the oxazolidinone model pioneered by Evans.1a-c In
this context, 3,4,5,6-tetrahydro-2H-1,3,4-oxadiazin-2-ones (2)
represent a class of heterocycles that have received little
(2) (a) Ghosh, A. K.; Duong, T. T.; McKee, S. P. J. Chem. Soc., Chem.
Commun. 1992, 1673. (b) Davies, S. G.; Edwards, A. J.; Evans, G. B.;
Mortlock, A. A. Tetrahedron 1994, 50, 6621. (c) Wang, Y.-C.; Hung, A.-
W.; Chang, C.-S.; Yan, T.-H. J. Org. Chem. 1996, 61, 2038. (d) Ghosh, A.
K.; Cho, H.; Onishi, M. Tetrahedron: Asymmetry 1997, 8, 821. (e)
Andersson, P. G.; Schink, H. E.; O¨ sterlund, K. J. Org. Chem. 1998, 63,
8067. (f) Anaya de Parrodi, C.; Clara-Sosa, A.; Pe´rez, L. Quintero, L.;
Maran˜o´n, V.; Toscano, R. A.; Avin˜a, J. A. Rojas-Lima, S. Juaristi, E.
Tetrahedron: Asymmetry 2001, 12, 69. (g) Guz, N. R.; Phillips, A. J. Org.
Lett. 2002, 4, 2253. (h) Cipiciani, A.; Fringuelli, F.; Piermatti, O.; Pizzo,
F.; Ruzziconi, R. J. Org. Chem. 2002, 67, 2665.
(3) (a) Meyers, A. I.; Knaus, G.; Kamata, K.; Ford, M. E. J. Am. Chem.
Soc. 1976, 98, 567. (b) Oppolzer, W.; Moretti, R.; Rhomi, S. Tetrahedron
Lett. 1989, 30, 5603. (c) Studer, A.; Hintermann, T.; Seebach, D. HelV.
Chim. Acta 1995, 78, 1185. (d) Boeckman, R. K., Jr.; Connell, B. T. J.
Am. Chem. Soc. 1995, 117, 12368. (e) Seyden-Penne, J. Chiral Auxiliaries
and Ligands in Asymmetric Synthesis; Wiley & Sons: New York, 1995.
(f) Mulzer, J.; Langer, O.; Hiersemann, M.; Bats, J. W.; Buschmann, J.;
Luger, P. J. Org. Chem. 2000, 65, 6540. (g) Boeckman, R. K., Jr.; Laci,
M. A.; Johnson, A. T. Tetrahedron: Asymmetry 2001, 12, 205. (h) Lakner,
F. J.; Negrete, G. R. Synlett 2002, 4, 643.
(1) (a) Evans, D. A.; Taber, T. R. Tetrahedron Lett. 1980, 21, 4675. (b)
Evans, D. A.; Bartroli, J.; Shih, T. L. J. Am. Chem. Soc. 1981, 103, 2127.
(c) Gage, J. R.; Evans, D. A. Org. Synth. 1990, 68, 83. (d) Ager, D. J.;
Prakash, I.; Schaad, D. R. Aldrichimica Acta 1997, 30, 3. (e) Crimmins,
M. T.; King, B. W.; Tabet, E. A.; Chaudhary, K. J. Org. Chem. 2001, 66,
894. (f) Evans, D. A.; Tedrow, J. S.; Shaw, J. T.; Downey, C. W. J. Am.
Chem. Soc. 2002, 124, 392. (g) Evans, D. A.; Downey, C. W.; Shaw, J. T.;
Tedrow, J. S. Org. Lett. 2002, 4, 1127.
10.1021/ol026721f CCC: $22.00 © 2002 American Chemical Society
Published on Web 09/17/2002

was 60-70%.6c The auxiliary was acylated with propionyl
chloride and lithium hydride to afford N3-propionyl-3,4,5,6-
tetrahydro-2H-1,3,4-oxadiazin-2-one (6) in 84% yield after
recrystallization. Once acylated, the heterocycle adopts a
twist boat conformation wherein the stereogenic N4-methyl
substituent is arranged in a pseudoaxial position.6d
Scheme 1. Preparation of the
N3-Propionyl-3,4,5,6-tetrahydro-2H-1,3,4-oxadiazin-2-one
With 6 in hand, we pursued the application of this
heterocycle in the asymmetric aldol reaction. Unfortunately,
our initial attempts were not successful. The central problem
was determined to be the formation of a stable enolate of 6.
Direct attempts to form the enolate with nonnucleophilic
bases [LDA, MHMDS (Li+, Na+, K+)] were not successful.9
Finally, inverse addition (chlorotrimethylsilane/KHMDS)
was employed to trap the enolate as the corresponding
enolsilane 7 (Scheme 2). We were gratified to learn that this
Scheme 2. Synthesis of
3,4,5,6-Tetrahydro-2H-1,3,4-oxadiazin-2-one Enol Ether 7
notice since their disclosure by Trepanier in 1968.4 After
nearly three decades of dormancy, Husson and co-workers
successfully employed these compounds as chiral auxiliaries
in diastereoselective alkylations5a and in dipolar cycloaddi-
tions.5b,c
At nearly the same time as Husson and co-workers, we
became interested in the chemistry of these heterocycles and
conducted synthetic and conformational studies with the
ephedrine-based heterocycle 2 and its related pseudoephedrine6a
and norephedrine derivatives.6b We have now extended our
studies into asymmetric applications and have initiated an
investigation into using 2 as a chiral auxiliary in the
asymmetric aldol addition reaction. Herein we report the
synthesis, acylation, and diastereoselectivity observed using
this auxiliary in the asymmetric aldol addition.
Synthesis of the enantiomerically enriched 2 was readily
achieved by N-nitrosation7,8 of (1R,2S)-ephedrine (5), fol-
lowed by the reduction to the corresponding â-hydrazino-
alcohol, and cyclization with lithium hydride and diethyl
carbonate (Scheme 1). The overall yield of the heterocycle
method afforded the desired enolsilane, tentatively assigned
as the Z(O)-geometry,10 although it was contaminated with
1
∼10% of 6 as determined by H NMR.
Even though it was possible to “trap” the enolate as
enolsilane 7 via inverse addition, it was not possible to use
this method to conduct aldol reactions. When these conditions
were employed in the presence of aldehydes, the major
product was deacylation of 6 to afford 2. We next explored
the use of chlorotitanium enolates as a more viable pathway
into the aldol reaction.1e,11 Unfortunately, the aldol addition
reaction of 6 via TiCl4 and an amine base followed by
addition of the aldehyde was not successful. The reaction
was modified so that the aldehyde was present as the
chlorotitanium enolate was formed. Thus, 2 was dissolved
in THF, and to this solution was added stoichiometric
benzaldehyde and an amine base. Titanium tetrachloride was
then added last to create the putative chlorotitanium enolate
in the presence of the aldehyde. We were gratified to learn
(4) (a) Trepanier, D. L.; Elbe, J. N.; Harris, G. H. J. Med. Chem. 1968,
11, 357. (b) Trepanier, D. L.; Harris, J. N. US Patent 3,377,345, 1968;
Chem. Abstr. 1969, 70, 78026c.
(5) (a) Roussi, F.; Bonin, M.; Chiaroni, A.; Micouin, L.; Riche, C.;
Husson, H.-P. Tetrahedron Lett. 1998, 39, 8081. (b) Roussi, F.; Bonin, M.;
Chiaroni, A.; Micouin, L.; Riche, C.; Husson, H.-P. Tetrahedron Lett. 1999,
40, 3727. (c) Roussi, F.; Chauveau, A.; Bonin, M.; Micouin, L.; Husson,
H.-P. Synthesis 2000, 1170.
(6) (a) Hitchcock, S. R.; Nora, G. P.; Casper, D. M.; Squire, M. D.;
Maroules, C. D.; Ferrence, G. M.; Szczepura, L. F.; Standard, J. M.
Tetrahedron 2001, 57, 9789. (b) Casper, D. M.; Nora, G. P.; Blackburn, J.
R.; Bentley, J. T.; Taylor, D. C.; Hitchcock, S. R. J. Heterocycl. Chem.
2002, 39, 823. (c) The heterocycle is synthesized on multigram scales (5-
25 g) in a period of 2 days with no chromatography. (d) This conformation
has been observed by X-ray crystallography (ref 6a) for the N3-phenylacetyl-
3,4,5,6-tetrahydro-2H-1,3,4-oxadiazin-2-one derived from (1R,2S)-ephedrine
and represents the most stable conformer in the solid state. The conformation
adopted in solution may be dependent on other factors, including solvation
effects.
(7) The N-nitrosamine of (1R,2S)-ephedrine was prepared previously:
Hitchcock, S. R.; Nora, G. P.; Hedberg, C.; Casper, D. M.; Buchanan, L.
S.; Squire, M. D.; West, D. X. Tetrahedron 2000, 56, 8799. Caution: It
should be noted that many N-nitrosamines are potentially carcinogenic and
should be handled with great care. For more information on N-nitrosamines,
see: Lawley, P. D. In Chemical Carcinogens; Searle, C. D., Ed.; ACS
Monograph Series 182; American Chemical Society; Washington, DC, 1984.
(8) A variety of methods were explored to circumvent the usage of the
N-nitrosamine. These methods included electrophilic amination pathways.
See: (a) Kim, M.; White, J. D. J. Am. Chem. Soc. 1977, 99, 1172. (b)
Greck, C.; Bischoff, L.; Ferreira, F.; Genet, J. P. J. Org. Chem. 1995, 60,
7010. (c) Greck, C.; Genet, J. P. Synlett 1997, 741. (d) Friestad, G. K.;
Qin, J. J. Am. Chem. Soc. 2000, 112, 8329. These methods proved to be
more cumbersome and expensive than the nitrosation procedure in
which the N-nitrosamine spontaneous crystallizes during the removal of
solvents after extraction. The transformation and yield are both nearly
quantitative.
(9) We have also had difficulties in forming the enolate of the
N3-propionyl pseudoephedrine-based heterocycle using the same nonnu-
cleophilic bases. The dominant product observed in these reactions is
deacylation.
3740
Org. Lett., Vol. 4, No. 21, 2002

Scheme 3. Asymmetric Aldol Reactions of 6
1
that aldol reaction occurred in high chemical yield and good
diastereoselectivity to provide aldol adducts 8a-h (Scheme
3). The diastereoselectivities are listed in Table 1. The
configuration via the H NMR coupling constants for the
vicinal protons of the aldol adduct (Table 2).2f,12
Table 2. 1H NMR Coupling Constants for 8a-h
Table 1. Stereoselective Aldol Additions of the Enolate
Derived from 6
diastereomeric ratiosa
syn:∑(all other diastereomers)
entry
RCHO
crude
purified
% yieldb
8a C6H5CHO
95:5
97:3
99:1
87:13
93:7
75:25
93:7
93:7
>99:1
96:4
99:1
88:12c
99:1
97:3
73
93
84
97
59
70
91
62
8b p-CH3OC6H4CHO
8c o-CH3OC6H4CHO
8d p-ClC6H4CHO
8e m-CH3C6H4CHO
8f (CH3)3CCHO
entry
R
δ Ha (ppm) J Ha-b (Hz) configuration
8a
8b
8c
8d
8e
8f
C6H5-
4.13
4.09
4.25
4.09
4.11
4.22
4.34
4.06
3.7
3.7
4.4
3.3
3.7
2.6
3.3
3.7
(2′S,3′S,5S,6R)a
(2′S,3′S,5S,6R)b
(2′S,3′S,5S,6R)b
(2′S,3′S,5S,6R)b
(2′S,3′S,5S,6R)b
(2′S,3′S,5S,6R)b
(2′S,3′S,5S,6R)b
(2′S,3′S,5S,6R)b
8g 1-C10H7CHO
8h (CH2O2)C6H3CHO
99:1
97:3
p-CH3OC6H4-
o-CH3OC6H4-
p-Cl C6H4-
m-CH3C6H4-
(CH3)3C-
a Diastereomer ratios determined by HPLC. b Chemical yield of the
purified product after chromatography and recrystallization. c Ratio of
diastereomers was increased to 97:3 after a second recrystallization.
8g
8h
1-C10H7-
(CH2O2)C6H3-
selectivity of this aldol reaction is believed to be due to the
presence of the stereogenic N4-methyl group. The optimal
position of this group is in the pseudoaxial position due to
allylic strain interactions with the N3-acyl substituent.6a It
must also be noted that the C5-methyl and C6-phenyl
substituents may also have an impact on the course of the
reaction with regard to the approach of the aldehyde.
However, on the basis of 1H NMR and X-ray crystallographic
analysis of 8a, the N4-methyl group is the primary substituent
that guides the stereochemical course of the reaction in terms
of facial selectivity of the enolate.
a Configuration determined by X-ray crystallography. b Absolute con-
figuration determined by analogy with 8a.
The absolute configuration of the aldol adduct was
determined by evaluation of the hydrolyzed product. Adduct
8a was subjected to acid hydrolysis13 to afford the parent
heterocycle 2 in nearly quantitative yield and the 3-hydroxy-
2-methyl-3-phenylpropionic acid (9) in 71% yield after a
single recrystallization (Scheme 4). The optical rotation value
of [R]D -29.5° (c 1.02, CH2Cl2) revealed that the recovered
carboxylic acid was obtained as the (2S,3S)-enantiomer in
>95% ee (lit.14 [R]D -29.3° (c 0.8, CHCl3). X-ray crystal-
The relative configuration of the major diastereomer of
the aldol addition reaction was determined to be the syn
Org. Lett., Vol. 4, No. 21, 2002
3741

Scheme 4. Acid Hydrolysis of 8a
Figure 1. Evolution of 3,4,5,6-tetrahydro-2H-1,3,4-oxadiazin-2-
ones.
lamine (TEA) proved to be superior to Hunig’s base
(ethyldiisopropylamine), as there were only trace amounts
of product when the more sterically hindered base was
employed. It was also determined that the use of the 2 equiv
of TiCl4 was less effective than the use of a single equivalent
with regard to overall yield and diastereoselectivity. It was
also determined that the order of addition of TiCl4 and the
amine base was not critical for success.11,17
lographic analysis of aldol adduct 8a confirmed the stereo-
chemical assignment (Figure 2).15 The collected results
We have demonstrated that asymmetric aldol addition reac-
tions are viable with an 3,4,5,6-tetrahydro-2H-1,3,4-oxadi-
azin-2-one serving as the chiral auxiliary, although further
research is necessary to refine the aldol reaction involving
aliphatic aldehydes. The crude diastereoselectivities ranged
from 75:25 to 95:5 for the formation of the non-Evans syn
adduct as determined by 1H NMR and X-ray crystallography.
Studies are underway to further investigate the reactivity of
the 3,4,5,6-tetrahydro-2H-1,3,4-oxadiazin-2-ones, especially
with regard to the directing, stereogenic N4-nitrogen.
Acknowledgment. We thank Dr. Marjorie Jones for
HPLC support. We also thank Paddi Ekhlassi of the
Analytical Research and Development Department of Pfizer
Global Research and Development in La Jolla, CA for optical
activity measurements. We also thank Dr. Robert McDonald
and the University of Alberta Structure Determination
Laboratory for the collection of low temperature CCD X-ray
data. We gratefully acknowledge financial support for D.
M. Casper and J. M. Esken from Abbott Laboratories for
summer research. We also acknowledge continued support
from Merck & Co., Inc. We also thank the donors of the
Petroleum Research Fund, administered by the American
Chemical Society, for partial support of this research.
Figure 2. ORTEP diagram of 8a with 50% probability ellipsoids
shown. Hydrogen atoms are drawn arbitrarily small for clarity.
suggested a Zimmerman-Traxler transition state in which
the re-face of the Z(O)-configured enolate of 6 and the si-
face of the aldehyde are combined (Scheme 3).16
With the exception of trimethylacetaldehyde, aliphatic
aldehydes did not undergo reaction cleanly.17 The reaction
was sluggish, and the dominant product was deacylation,
which suggested that chlorotitanium enolate of 6 was not
sufficiently nucleophilic to capture the aldehydes. Triethy-
Supporting Information Available: Experimentals for
1
compounds 7, 8a-h, and (2S,3S)-9, copies of H and 13C
(10) 1,3-Oxazolidin-2-ones are known to have a strong preference for
the formation of the Z(O)-configured enolate. The 3,4,5,6-tetrahydro-2H-
1,3,4-oxadiazin-2-ones most likely form Z(O)-enolates as well. See: Evans,
D. A.; Ennis, M. D.; Mathre, D. J. J. Am. Chem. Soc. 1982, 104, 1737 and
references contained therein.
(11) Evans, D. A.; Urpi, F.; Somers, T. C.; Clark, J. S.; Bilodeau, M. T.
J. Am. Chem. Soc. 1990, 112, 8215. See also ref 2f.
NMR spectra for compounds 7, 8a-h, and (2S,3S)-9, and
X-ray crystal data for 8a. This material is available free of
charge via the Internet at http://pubs.acs.org.
OL026721F
(12) Coupling constants for all of the derivatives were in the range of
2.6-4.4 Hz as would be expected for the syn configuration. See: (a) Evans,
D. A.; Nelson, J. V.; Taber, T. R. Top. Stereochem. 1982, 13, 1. (b) Roush,
W. R.; Bannister, T. D.; Wendt, M. D.; VanNieuwenhze, M. S.; Darin J.
G.; Dilley, G. J.; Lane, G. C.; Scheidt, K. A.; Smith, W. J., III. J. Org.
Chem. 2002, 67, 4284 and references therein. See also refs 1g (anti adducts)
and 2f (syn adducts).
(13) Vicario, J. L.; Bad´ıa, D.; Dom´ıngues, E.; Rodr´ıguez, M.; Carillo,
L. J. Org. Chem. 2000, 65, 3754.
(14) (a) van Draanen, N. A.; Arsenyiadis, A.; Crimmins, M. T.;
Heathcock, C. H. J. Org. Chem. 1991, 56, 2499-2506. (b) Davies, S. G.;
Doisneau, G. J.-M.; Prodger, J. C.; Sanganee, H. Tetrahedron Lett. 1994,
35, 2373-2376. (c) Fringuelli, F.; Piermatti, O.; Pizzo, F. J. Org. Chem.
1995, 60, 7006 and references therein.
(15) Akin to other 3,4,5,6-tetrahydro-2H-1,3,4-oxadiazin-2-ones that we
have reported, 8a adopts a half chair conformation.6 The X-ray crystal
structure also reveals that the N4-methyl group does indeed adopt an trans-
1,2-diaxial arrangement with the C5-methyl group. In effect, the N4-position
determines the facial selectivity of the enolate and the C5-methyl group
influences of the facial selectivity of the aldehyde. In addition, the urethane
carbonyl and the N3-carbonyl adopt a nearly parallel configuration as
evidenced by the 33.9° O(27)-C(2)-C(15)-O(16) torsion angle.
(16) Zimmerman, H. E.; Traxler, M. D. J. Am. Chem. Soc. 1957, 79,
1920.
(17) The reaction has been successful with nonenolizable aldehydes, but
the chlorotitanium enolate does not react well with enolizable aldehydes.
Research is underway to address this deficiency. See: Harrison, C. R.
Tetrahedron Lett. 1987, 28, 4135.
3742
Org. Lett., Vol. 4, No. 21, 2002