Intramolecular Chiral Relay at Stereogenic Nitrogen. Synthesis and Application of A New Chiral Auxiliary Derived from (1R,2S)-Norephedrine and Acetone

Article abstract of DOI:10.1021/jo035325n

(1R,2S)-Norephedrine has been employed in the synthesis of a novel 3,4,5,6-tetrahydro-2H-1,3,4-oxadiazin-2-one via reductive alkylation with acetone, N-nitrosation, reduction, and cyclization. The oxadiazinone was treated with either propionyl chloride or

Full text of DOI:10.1021/jo035325n

In tr a m olecu la r Ch ir a l Rela y a t Ster eogen ic Nitr ogen . Syn th esis
a n d Ap p lica tion of a New Ch ir a l Au xilia r y Der ived fr om
(1R,2S)-Nor ep h ed r in e a n d Aceton e†
Shawn R. Hitchcock,* David M. Casper, J eremy F. Vaughn, J ennifer M. Finefield,
Gregory M. Ferrence, and J oel M. Esken
Department of Chemistry, Illinois State University, Normal, Illinois 61790-4160
hitchcock@xenon.che.ilstu.edu
Received September 8, 2003
(1R,2S)-Norephedrine has been employed in the synthesis of a novel 3,4,5,6-tetrahydro-2H-1,3,4-
oxadiazin-2-one via reductive alkylation with acetone, N-nitrosation, reduction, and cyclization.
The oxadiazinone was treated with either propionyl chloride or 3-thiophenylpropionyl chloride to
afford the corresponding N3-acylated oxadiazinones 9a and 9b, respectively. X-ray crystallographic
analysis of the N3-thiophenylpropionyl oxadiazinone 9b revealed that the C2-urethane carbonyl
and the N3-carbonyl are arranged in an anti-periplanar conformation. The oxadiazinones were
subsequently applied in the titanium-mediated asymmetric aldol addition reaction by treatment
with titanium tetrachloride, triethylamine, and a variety of aldehydes at 0 °C. The aldol adducts
10a -i and 11a ,b were found to have diastereoselectivities ranging from 8:1 to >99:1 favoring the
formation of the non-Evans syn configuration. The absolute stereochemistry of the adduct 10a was
determined by acid hydrolysis. This process afforded the N4-isopropyloxadiazinone 8 and (2S,3S)-
3-hydroxy-2-methyl-3-phenylpropanoic acid 14 in g95% enantiomeric excess.
In tr od u ction
The evolution of chiral auxiliaries over the last 30 years
has yielded an incredibly diverse array of asymmetric
templates for preparing enantiomerically enriched ma-
terials.1 Oxazolidinones2 have been central in the devel-
opment of chiral auxiliaries because of their successful
application in a wide variety of reactions, among which
the asymmetric aldol reaction has attracted the most
attention.3 We recently disclosed our efforts in developing
3,4,5,6-tetrahydro-2H-1,3,4-oxadiazin-2-ones (oxadiazi-
nones) as viable templates for asymmetric syntheses.4-6
We initiated our investigation of this ring system with
conformational studies of N3-acylated oxadiazinones
derived either from (1R,2S)-ephedrine or (1S,2S)-pseu-
doephedrine (Figure 1).4 These studies revealed that the
(1S,2S)-pseudoephedrine-based oxadiazinones were con-
formationally labile at the N4-nitrogen and might not be
suitable candidates for chiral auxiliary applications. In
contrast, the (1R,2S)-ephedrine-based oxadiazinones did
not exhibit any observable conformational mobility at the
F IGURE 1. Oxadiazinones.
N4-nitrogen. In fact, we were able to successfully con-
duct asymmetric aldol addition reactions with aro-
matic5 and aliphatic aldehydes6 using this oxadiazinone
(Figure 2).
(3) (a) Evans, D. A.; Downey, C. W.; Shaw, J . T.; Tedrow, J . S. Org.
Lett. 2002, 4, 1127-1130. (b) Evans, D. A.; Tedrow, J . S.; Shaw, J . T.;
Downey, C. W. J . Am. Chem. Soc. 2002, 124, 392-393. (c) Anaya de
Parrodi, C.; Clara-Sosa, A.; Perez, L.; Quintero, L.; Maranon, V.;
Toscano, R. A.; Avina, J . A.; Rojas-Lima, S.; J uaristi, E. Tetrahedron:
Asymmetry 2001, 12, 69-79. (d) Crimmins, M. T.; King, B. W.; Tabet,
E. A. Chaudhary, K. J . Org. Chem. 2001, 66, 894-902. (e) Crimmins,
M. T.; Chaudhary, K. Org. Lett. 2000, 2, 775-777. (f) Luetzen, A.; Koell,
P. Tetrahedron: Asymmetry 1997, 8, 1193-1206. (g) Sibi, M. P.;
Deshpande, P. K.; J i, J . Tetrahedron Lett. 1995, 36, 8965-8968. (h)
Yan, T. H.; Lee, H. C.; Tan, C. W. Tetrahedron Lett. 1993, 34, 559-
62. (i) Bonner, M. P.; Thornton, E. R. J . Am. Chem. Soc. 1991, 113,
1299-308. (j) Nerz-Stormes, M.; Thornton, E. R. J . Org. Chem. 1991,
56, 2489-98. (k) Evans, D. A.; Rieger, D. L.; Bilodeau, M. T.; Urpi, F.
J . Am. Chem. Soc. 1991, 113, 1047-1049. (l) Bermejo-Gonzalez, F.;
Perez-Baz, J .; Santinelli, F.; Mayer-Real, F. Bull. Chem. Soc. J pn. 1991,
64, 674-81. (m) Gage, J . R.; Evans, D. A. Org. Synth. 1990, 68, 83-
91. (n) Evans, D. A.; Sjogren, E. B.; Weber, A. E.; Conn, R. E.
Tetrahedron Lett. 1987, 28, 39-42. (o) Evans, D. A.; Bartroli, J .; Shih,
T. L. J . Am. Chem. Soc. 1981, 103, 2127-2129.
† Part of this work was presented at the 225th National Meeting of
the American Chemical Society, New Orleans, LA, March 23-27, 2003,
Abstract No. 390-CHED (J .M.F.).
(1) (a) J ones, S. J . Chem. Soc., Perkin. Trans. 1 2002, 1-21. (b) Lin,
G.-Q.; Li, YU.-M.; Chan, A. S. C. Principles and Applications of
Asymmetric Synthesis; J ohn Wiley & Sons: New York, 2001. (c)
Seyden-Penne, J . Chiral Auxiliaries and Ligands in Asymmetric
Synthesis; J ohn Wiley & Sons: New York, 1995.
(2) (a) Sibi, M. P. Aldrichim. Acta 1999, 32, 93-103. (b) Ager, D. J .;
Prakash, I.; Schaad, D. R. Aldrichim. Acta 1997, 30, 3-12. (c) Ager,
D. J .; Prakash, I.; Schaad, D. R. Chem. Rev. 1996, 96, 835-875. (d)
Evans, D. A. Aldrichim. Acta 1982, 15, 23-32.
10.1021/jo035325n CCC: $27.50 © 2004 American Chemical Society
Published on Web 01/10/2004
714
J . Org. Chem. 2004, 69, 714-718

Intramolecular Chiral Relay at Stereogenic Nitrogen
F IGURE 2. Intramolecular chiral relay with oxadiazinones.
SCHEME 1
In terms of the asymmetric aldol addition reaction of
N3-acyloxadiazinones, the asymmetry of the (1R,2S)-
ephedrine fragment of the oxadiazinone is not directly
responsible for the observed diastereoselectivity. It is
postulated that the stereochemical impact of the ephe-
drine fragment (C5-methyl and C6-phenyl of the oxadi-
azinone) is transmitted to the appendant N3-enolate by
way of intramolecular chiral relay via the stereogenic N4-
nitrogen (Scheme 1).7,8 This postulate is supported by the
X-ray crystallographic data of aldol adduct 3.5 The X-ray
crystal structure9 suggests that the proximity of the N4-
methyl group to the N3-substituent is the dominant
mechanism of asymmetric induction in the course of the
carbon-carbon bond-forming process during the aldol
addition reaction. Herein, we describe our efforts in
enhancing the observed diastereoselectivities of the aldol
addition reaction by modification of the N4-position.
Resu lts a n d Discu ssion
P r ep a r a tion of th e N3-Acyl-N4-isop r op yloxa d ia zi-
n on es. With a rationale for the observed diastereoselec-
tivity in hand, we sought to improve the asymmetric
induction of the oxadiazinone-directed aldol reaction by
modification of the N4-substituent. Thus, (1R,2S)-norephe-
(7) Sibi and co-workers have demonstrated intermolecular chiral
relay between a chiral, nonracemic Lewis acid and its interaction with
an achiral pyrazolidinone. The conformation preference of the stereo-
genic N1-nitrogen is determined by the structure of the chiral Lewis
acid. Please see: Sibi, M. P.; Venkatraman, L.; Liu, M.; J asperse, C.
P. J . Am. Chem. Soc. 2001, 123, 8444-8445.
(4) (a) Casper, D. M.; Blackburn, J . R.; Maroules, C. D.; Brady, T.;
Esken, J . M.; Ferrence, G. M.; Standard, J . M.; Hitchcock, S. R. J .
Org. Chem. 2002, 67, 8871-8876. (b) 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, 9789-9798.
(5) Casper, D. M.; Burgeson, J . R.; Esken, J . M.; Ferrence, G. M.;
Hitchcock, S. R. Org. Lett. 2002, 4, 3739-3742.
(6) Casper, D. M.; Hitchcock, S. R. Tetrahedron: Asymmetry 2003,
14, 517-521.
J . Org. Chem, Vol. 69, No. 3, 2004 715

Hitchcock et al.
TABLE 1. Asym m etr ic Ald ol Rea ction s Lea d in g to Ald ol Ad d u cts 11a -i a n d 12a ,b
entry
oxadiazinone
aldehyde R′CHO
C6H5CHO
p-ClC6H4CHO
(E)-C6H5CHdCHCHO
p-CH3OC6H4CHO
p-NO2 C6H4CHO
1-C10H7CHO
2-C10H7CHO
(CH3)3CCHO
(CH3)2CHCHO
C6H5CHO
C6H5CH2OCH2CHO
adduct
crude dra
purified dra
yieldb (%)
1
2
3
4
5
6
7
8
9
9a (R ) -CH3)
9a (R ) -CH3)
9a (R ) -CH3)
9a (R ) -CH3)
9a (R ) -CH3)
9a (R ) -CH3)
9a (R ) -CH3)
9a (R ) -CH3)
9a (R ) -CH3)
9b (R ) -CH2SPh)
9b (R ) -CH2SPh)
10a
10b
10c
10d
10e
10f
10g
10h
10i
>99:1c
>99:1c
>99:1c
>99:1c
38:1c
>99:1c
>99:1c
>99:1c
>99:1c
39:1c
78
73
85
31
74
59
98
96
97
82
45
8:1c
>99:1c
99:1c
99:1c
10:1c
29:1c
49:1c
>99:1c
>99:1c
g19:1d
10
11
11a
11b
99:1c
g19:1d
a
b
Diastereomer ratios reported as major isomer/Σ other isomers. Chemical yield of the purified product after chromatography or
recrystallization. c Diastereomer ratio determined by HPLC. Diastereomer ratio determined by 400 MHz 1H NMR where the detection
d
limit is taken to be no greater than 19:1.
drine (4) was reductively alkylated with acetone and
sodium borohydride10a to afford N-isopropylnorephe-
drine derivative 510b in 95% yield after recrystallization
(Scheme 1).11 This product was quantitatively converted
to the N-nitrosamine 612 by treatment with sodium nitrite
and HCl and, in turn, was reduced to afford â-hydroxy-
hydrazine 7 (78%) after recrystallization. Finally, the
hydrazine was cyclized with lithium hydride and diethyl
carbonate to afford the target heterocycle 8.13 To pursue
the asymmetric aldol reactions, oxadiazinone 8 was
acylated with either propionyl chloride or 3-thiophenyl-
propionyl chloride14 to afford N3-acylated oxadiazinones
9a and 9b, respectively.
X-r a y Cr ysta llogr a p h y. Single-crystal X-ray diffrac-
tion analysis of 9b revealed that the urethane C2-
(8) (a) Corminboeuf, O.; Quaranta, L.; Renaud, P.; Liu, P.; J asperse,
F IGURE 3. View of molecular structure of 9b showing the
C. P.; Sibi, M. P. Chem.sEur. J . 2003, 9, 28-35. (b) Quaranta, L.;
atom labeling scheme. Non-hydrogen atoms are represented
Corminboeuf, O., Renaud, P. Org. Lett. 2002, 4, 39-42.
by Gaussian ellipsoids at the 50% probability level. Hydrogen
(9) Solvation effects must also be taken into account when confor-
atoms have been drawn arbitrarily small and are not labeled.
mations of the oxadiazinones are being considered in the liquid state.
Yet, the X-ray crystallographic data of aldol adduct 3 would suggest
that the aldehyde must approach away from the N4-methyl substituent.
(10) (a) We have previously synthesized oxadiazinone derivatives
based on (1R,2S)-norephedrine. See: Hitchcock, S. R.; Casper, D. M.;
Nora, G. P.; Blackburn, J . R.; Bentley, J . T.; Taylor, D. C. J . Heterocycl.
Chem. 2002, 39, 823-828. (b) Other oxadiazinones prepared from
(1R,2S)-norephedrine via condensation with cyclohexanone or D-
camphor that have been recently synthesized in our laboratories. Work
is underway in applying these oxadiazinones to asymmetric syntheses.
(11) Baxter, E. W.; Reitz, A. B. Reductive Aminations of Carbonyl
Compounds with Borohydride and Borane Reducing Agents. In Org.
React. (Overman, L. E., Ed.) 2002, 59, pp 3-714.
(12) Saavedra, J . E.; Farnworth, D. W.; Pei, G.-K. Synth. Commun.
1988, 18, 313-322. It should be noted that many N-nitrosamines are
potentially dangerous carcinogens and should be handled with due
caution. See: Loeppky, R. N., Michejda, C. J ., Eds. Nitrosamines and
Related N-Nitroso Compounds: Chemistry and Biochemistry; ACS
Symposium Series 553; American Chemical Society: Washington, DC,
1994.
carbonyl and the N3-carbonyl groups are arranged in an
anti-periplanar conformation as evidenced by the 172.5-
(2)° [O(18)-C(17)-C(2)-O(28)] torsion angle (Figure 3).15
This was initially unexpected as the dominant conforma-
tion of the carbonyls for (1R,2S)-ephedrine- and (1S,2S)-
pseudoephedrine-based oxadiazinones is the syn-peripla-
nar arrangement based on X-ray crystallographic data4,5
and 13C NMR spectroscopy.4 It is believed that the syn-
periplanar conformation arises from lone pair repulsion
between the N4-nitrogen lone pair and the N3-carbonyl
lone pair. In contrast, the conformation of the carbonyls
in oxadiazinone 9b (and 9a ) probably originates from
repulsive interactions between the N4-isopropyl group
and the N3-substituent.
(13) The heterocycle is routinely prepared on multigram scale (5-
40 g).
Asym m etr ic Ald ol Rea ction s. The acylated auxil-
iaries 9a and 9b were complexed with titanium tetra-
(14) The 3-thiophenylpropionic acid was prepared by reaction of
thiophenol and 3-bromoproionic acid in the presence of an excess of
lithium hydride. The 400 MHz 1H NMR spectrum was identical with
the known literature examples. See: Anh, Y.; Cohen, T. J . Org. Chem.
1994, 59, 3142-3150.
(15) X-ray crystallographic data for 9b is collected in the Supporting
Information.
716 J . Org. Chem., Vol. 69, No. 3, 2004

Intramolecular Chiral Relay at Stereogenic Nitrogen
TABLE 2. Ster eoch em ica l Assign m en t
adducts (Table 2). The value of the coupling constants
for adducts 10a -i and 11a ,b were in the expected range
for syn-configured aldol adducts.19
The determination of the absolute stereochemistry was
conducted through hydrolysis of adduct 10a (eq 1).
entry product δ (ppm) J (Hz)
[R]25
configurationa
D
1
2
3
4
5
6
7
8
9
10a
10b
10c
10d
10e
10f
10g
10h
10i
4.18
4.12
4.08
4.14
4.19
4.45
4.29
4.27
4.11
4.41
4.31
2.8
3.4
3.3
3.8
1.6
4.8
3.2
1.6
1.8
2.6
4.0
-117.9 2′S,3′S,4R,5S,6R
-123.8 2′S,3′S,4R,5S,6R
-96.5 2′S,3′S,4R,5S,6R
-120.1 2′S,3′S,4R,5S,6R
-127.6 2′S,3′S,4R,5S,6R
-103.5 2′S,3′S,4R,5S,6R
-131.2 2′S,3′S,4R,5S,6R
-104.9 2′S,3′S,4R,5S,6R
-104.6 2′S,3′R,4R,5S,6R
-172.1 2′R,3′S,4R,5S,6R
-144.1 2′R,3′S,4R,5S,6R
10
11
11a
11b
a
Stereochemistry determined by analogy to the hydrolysis
product of 10a .
Treatment of 10a with 6 M sulfuric acid for 2 h at reflux
afforded the norephedrine-derived heterocycle 8 (46%)
and desired â-hydroxy acid 12 (56%). The remaining
mass balance consisted of the â-hydroxyhydrazine 7 and
byproducts. The generation of 7 is believed to come from
an endocyclic ring-opening process20 followed by hydroly-
sis of the amide bond to the N3-substituent. This alter-
nate pathway is most likely attributed to steric factors
associated with the N4-isopropyl group. Attempts to
conduct base hydrolysis21 were not successful and gave
rise to ring-opening processes, elimination of the aldol
side chain (R,â-unsaturation), or retro-aldol processes.
chloride (1 equiv) at 25 °C for a period of 25 min. The
reaction mixture was cooled to 0 °C, and triethylamine
was added to effect enolate formation. After 1 h, the
aldehyde (1 equiv) was added. This process successfully
yielded the aldol adducts 10a ,b,d -g and 11a in high
yield and diastereoselectivity (Table 1). However, in the
case of aliphatic aldehydes, 2 equiv of titanium tetra-
chloride as well as 2 equiv of triethylamine were em-
ployed to effect complete conversion. This process yielded
aldol adducts 10c,h ,i and 11b in good to excellent
chemical yield and good diastereoselectivity (Table 1).
Interestingly, the addition of 2 equiv of TiCl4 and
triethylamine did not change the stereochemical course
of the reactions.16,17 We were gratified to learn that the
diastereoselectivities observed in this work were superior
to those obtained from the aldol reactions with the
ephedrine based oxadiazinone 2. In fact, the reactions
involving the (1R,2S)-ephedrine-based oxadiazinone 2
were originally conducted at low temperature (enolate
formation and aldehyde addition at -78 °C).5 The reac-
tions of the (1R,2S)-norephedrine-based oxadiazinones 9a
and 9b (this work) were conducted at 0 °C due to low
conversion at lower temperatures. Nonetheless, these
reactions produced high diastereoselectivities despite
operating at higher temperatures. Unfortunately, alde-
hydes that had high steric requirements (entries 6 and
8) gave lower stereoselectivities.18
1
The crude H NMR spectrum of the isolated â-hydroxy
acid 12 suggested that there was no detectable sign of
epimerization.
The absolute stereochemistry of the â-hydroxyacid 12
was determined by comparison of the optical rotation to
literature values: an observed value of [R]24D -35 (c 0.8,
CHCl3) versus the literature value of [R]D -29.3 (c 0.8,
CHCl3)22 for the (2S,3S)-isomer.23 The enantiomeric
purity of (2S,3S)-12 was estimated to be greater than
95% enantiomeric excess based on the optical rotation.
(19) (a) Evans, D. A.; Nelson, J . V.; Taber, T. R. Top. Stereochem.
1982, 13, 1-115. (b) Heathcock, C. H.; Buse, C. T.; Kleschick, W. A.;
Pirrung, M. C.; J ohn, J . E.; Lampe, J . J . Org. Chem. 1980, 45, 1066-
1081.
(20) The undesired endocyclic ring opening process is postulated to
be a result of the steric environment of the N4-nitrogen proximal to
the N3-acyl moiety. See: (a) Prashad, M.; Kim, H.-Y.; Lu, Y.; Liu, Y.;
Har, D.; Repic, O.; Blacklock, T. J .; Giannousis, P. J . Org. Chem. 1999,
64, 1750-1753. (b) Ishizuka, T.; Kunieda, T. Tetrahedron Lett. 1987,
28, 4185-4187.
(21) Peroxide-assisted saponification (NaOH, H2O2) also failed to
give the desired â-hydroxyacid in significant yield. This may be due
to the susceptibility of the N4-nitrogen to oxidation. See: (a) Evans,
D. A.; Britton, T. C.; Ellman, J . A. Tetrahedron Lett. 1987, 28, 6141-
6144. (b) Vaughn, H. L.; Robbins, M. D. J . Org. Chem. 1975, 40, 1187-
1189.
(22) (a) Vicario, J . L.; Badia, D.; Dominguez, E.; Rodriguez, M.;
Carrillo, L. J . Org. Chem. 2000, 65, 3754-3760. (b) Fringuelli, F.;
Piermatti, O.; Pizzo, F. J . Org. Chem. 1995, 60, 7006-7009. (c) Davies,
S. G.; Doisneau, G. J .-M.; Prodger, J . C.; Sanganee, H. Tetrahedron
Lett. 1994, 35, 2373-2376. (d) Davies, S. G.; Edwards, A. J .; Evans,
G. B.; Mortlock, A. A.; Tetrahedron 1994, 50, 6621-6642. (e) van
Draanen, N. A.; Arsenyiadis, A.; Crimmins, M. T.; Heathcock, C. H.
J . Org. Chem. 1991, 56, 2499-2506. (f) Heathcock, C. H.; White, C.
T.; Morrison, J . H.; VanDerveer, D. J . Org. Chem. 1981, 46, 1296-
1309.
Deter m in a tion of Ster eoch em istr y. The relative
stereochemistry of the aldol adducts was determined to
be the syn configuration by evaluation of the vicinal
coupling constants [N3-COCHR(CH3)CHâ(OH)R)] of the
(16) With regard to the aldol adducts derived from the aliphatic
aldehydes, the characteristic signals for the 400 MHz 1H NMR spectra
(as well as the HPLC traces) remained unchanged after increasing the
amount of titanium chloride from 1 to 2 equiv.
(17) In contrast to the oxadiazinones, the stereochemical outcome
of asymmetric aldol reactions with oxazolidinones exhibits a strong
dependence on the stoichiometric amount of titanium tetrachloride
employed. See: Crimmins, M. T.; King, B. W.; Tabet, E. A. J . Am.
Chem. Soc. 1997, 119, 7883-7884.
(18) In some cases steric interactions may have given rise to poor
selectivity, possibly via alternate transition states, i.e., a boatlike
transition state vs a chair like transition state. See ref 3a.
J . Org. Chem, Vol. 69, No. 3, 2004 717

Hitchcock et al.
chemistry (see previous section). This suggests that the
diastereoselectivity of the aldol reaction of oxadiazinones
9a and 9b originates from a chairlike Zimmerman-
Traxler transition state in which the re-face of the
putative Z(O)-titanium enolate of the N3-substituent
reacts with the si-face of the aldehyde (Figure 4).26
Con clu sion
In summary, we have rationally designed, synthesized,
and applied a structurally novel chiral auxiliary derived
from (1R,2S)-norephedrine and acetone. The success of
the asymmetric induction in the transition state is due
to the chiral relay effect of the ephedrine core (C5-methyl
and C6-phenyl through the N4-isopropyl substituent.
When applied in the titanium mediated asymmetric aldol
reaction, the auxiliary affords aldol adducts 10a -i and
11a ,b in good to excellent chemical yield and, in general,
high diastereoselectivities. The reaction is believed to
occur via a Zimmerman-Traxler transition state involv-
ing a chelated Z(O)-titanium enolate. A significant
limitation to this oxadiazinone system is the resistance
to cleavage under mild conditions. Studies are underway
to address the cleavage of the chiral auxiliary and its
further application in asymmetric synthesis.
F IGURE 4. Proposed transition state.
Mech a n ist ic Im p lica t ion s of St er eoch em ist r y.
Previous efforts with the (1R,2S)-ephedrine-based N3-
propionyloxadiazinone5,6 suggest that enolization with
TiCl4 and triethylamine leads to the Z(O)-enolate.24 The
preference for the Z(O)-enolate is not unexpected as
related chiral imides such as the oxazolidinones are also
known to afford the same enolate geometry.25 When
oxadiazinones 9a and 9b undergo enolization with TiCl4
and triethylamine, their respective enolates are believed
to be engaged in a chelated chair conformation (Figure
4). The absolute stereochemistry of the products was
determined to possess the non-Evans syn-aldol stereo-
Ack n ow led gm en t. We thank Dr. Robert McDonald
and The University of Alberta Structure Determination
Laboratory for collecting the experimental data set for
the X-ray structure of 9b. We also thank Merck & Co.,
Inc., and Pfizer, Inc., for generous support. We thank
the donors of the Petroleum Research Fund, adminis-
tered by the American Chemical Society, for partial
support of this research.
(23) The â-hydroxy acid 12 had a specific rotation that was greater
than the expected -29.3. On the basis of 1H and 13C NMR spectroscopy
and melting point determination, the compound was identical to the
literature examples cited in ref 22. Mp (2S,3S)-12 ) 87.5-89 °C (lit.22f
Mp (2R,3R)-enantiomer ) 87-88 °C). 1H NMR (CDCl3, ppm): δ 1.16
(d, J ) 7.0 Hz, 3H), 2.86 (dq, J ) 7.3, 4.0 Hz, 1H), 5.18 (d, J ) 3.6 Hz,
1H), 7.28-7.37 (m, 5H). 13C NMR (CDCl3, ppm): δ 10.2, 46.2, 73.4,
125.9, 127.7, 128.3, 140.9, 181.1.
(24) The Z(O)-enolate geometry for the N3-acylated oxadiazinones
has not been rigorously established. The formation of the Z(O)-enolate
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and 12. This material is available free of charge via the
Internet at http://pubs.acs.org.
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