Toward the Development of A Structurally Novel Class of Chiral Auxiliaries. Conformational Properties of the Aldol Adducts of Oxadiazinones: Observation of Unusual Shielding Effects

Article abstract of DOI:10.1021/jo035481u

Asymmetric aldol reactions were conducted with the titanium enolate of N₃-hydrocinnamoyl-3,4,5,6-tetrahydro-2H-1,3,4-oxadiazin-2-one to afford aldol adducts 5a-j. The dominant product of the asymmetric aldol reaction was the non-Evans syn adduct as determined by ¹H NMR spectroscopy and X-ray crystallography. When evaluating the ¹H NMR spectra of adducts 5a-j, a highly shielded signal with an average chemical shift of 0.05 ppm was observed. This signal was readily determined to be the C₅-methyl group of the oxadiazinone. It is presumed that the overall conformation adopted by the aldol adducts in solution places an aromatic ring of the N₃-substituent in close proximity to the C₅-methyl group. An investigation of this conformational preference is conducted employing ¹H NMR spectroscopy, X-ray crystallography, and computational methods.

Full text of DOI:10.1021/jo035481u

Tow a r d th e Develop m en t of a Str u ctu r a lly Novel Cla ss of Ch ir a l
Au xilia r ies. Con for m a tion a l P r op er ties of th e Ald ol Ad d u cts of
Oxa d ia zin on es: Obser va tion of Un u su a l Sh ield in g Effects†
J ames R. Burgeson,‡ Matthew K. Renner,§ Ingo Hardt,§ Gregory M. Ferrence,‡
J ean M. Standard,*,‡ and Shawn R. Hitchcock*,‡
Department of Chemistry, Illinois State University, Normal, Illinois 61790-4160, and
Pfizer Global Research, 3565 General Atomics Court, San Diego, California 92121
hitchcock@xenon.che.ilstu.edu
Received October 9, 2003
Asymmetric aldol reactions were conducted with the titanium enolate of N3-hydrocinnamoyl-3,4,5,6-
tetrahydro-2H-1,3,4-oxadiazin-2-one to afford aldol adducts 5a -j. The dominant product of the
1
asymmetric aldol reaction was the non-Evans syn adduct as determined by H NMR spectroscopy
and X-ray crystallography. When evaluating the 1H NMR spectra of adducts 5a -j, a highly shielded
signal with an average chemical shift of 0.05 ppm was observed. This signal was readily determined
to be the C5-methyl group of the oxadiazinone. It is presumed that the overall conformation adopted
by the aldol adducts in solution places an aromatic ring of the N3-substituent in close proximity to
the C5-methyl group. An investigation of this conformational preference is conducted employing
1H NMR spectroscopy, X-ray crystallography, and computational methods.
In tr od u ction
The asymmetric aldol addition reaction continues to
be a synthetic process of great interest.1 This is primarily
due to the fact that the aldol reaction can be manipulated
to generate either syn or anti adducts,2,3 which are
valuable intermediates in the synthesis of many natural
products. A great variety of methods have emerged over
the last 25 years that are capable of achieving high
selectivities for one isomer or another. These methods
include the use of stoichiometric chiral auxiliaries and
substoichiometric asymmetric catalysts.4 Catalytic meth-
ods are proving to be very effective, but chiral auxiliaries
F IGURE 1. Oxadiazinones as chiral auxiliaries.
† 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. 450-ORGN (J .R.B.).
still remain as a viable means for obtaining chiral,
nonracemic aldol adducts. We have recently reported on
the application of a (1R,2S)-ephedrine-based 3,4,5,6-
tetrahydro-2H-1,3,4-oxadiazin-2-one (oxadiazinone) as a
chiral auxiliary in the titanium-mediated asymmetric
aldol addition reaction (Figure 1).5
‡ Illinois State University.
§ Pfizer Global Research.
(1) (a) Arya, P.; Qin, H. Tetrahedron 2000, 56, 917-947. (b) Lin,
G.-Q.; Li, Y.-M.; Chan, A. S. C. Principles and Applications of
Asymmetric Synthesis; J ohn Wiley & Sons: New York, 1995. (c)
Seyden-Penne, J . Chiral Auxiliaries and Ligands in Asymmetric
Synthesis; J ohn Wiley & Sons: New York, 1995.
As evidenced by X-ray crystallography,5c,6 the ephe-
drine-based oxadiazinone adopts a twist boat conforma-
(2) Syn adducts: (a) Anaya de Parrodi, C.; Clara-Sosa, A.; Perez,
L.; Quintero, L.; Maran˜o´n, V.; Toscano, R. A.; Avin˜a, J . A.; Rojas-Lima,
S.; J uaristi, E. Tetrahedron: Asymmetry 2001, 12, 69-79. (b) Crim-
mins, M. T.; King, B. W.; Tabet, E. A. Chaudhary, K. J . Org. Chem.
2001, 66, 894-902. (c) Crimmins, M. T.; Chaudhary, K. Org. Lett. 2000,
2, 775-777. (d) Luetzen, A.; Koell, P. Tetrahedron: Asymmetry 1997,
8, 1193-1206. (e) Sibi, M. P.; Deshpande, P. K.; J ianguo, J . Tetrahe-
dron Lett. 1995, 36, 8965-8968. (f) Yan, T. H.; Lee, H. C.; Tan, C. W.
Tetrahedron Lett. 1993, 34, 559-62. (g) Bonner, M. P.; Thornton, E.
R. J . Am. Chem. Soc. 1991, 113, 1299-308. (h) Nerz-Stormes, M.;
Thornton, E. R. J . Org. Chem. 1991, 56, 2489-98. (i) Gage, J . R.;
Evans, D. A. Org. Synth. 1990, 68, 83-91. (j) Evans, D. A.; Bartroli,
J .; Shih, T. L. J . Am. Chem. Soc. 1981, 103, 2127-2129.
(4) (a) Lang, F.; Zewge, D.; Song, Z. J .; Biba, M.; Dormer, P.;
Tschaen, D.; Volante, R. P.; Reider, P. J . Tetrahedron Lett. 2003, 44,
5285-5288. (b) Evans, D. A.; Downey, C. W.; Hubbs, J . L. J . Am. Chem.
Soc. 2003, 125, 8706-8707. (c) Tanaka, H.; Sawayama, A. M.;
Wandless, T. J . J . Am. Chem. Soc. 2003, 125, 6864-6865. (d)
Yoshikawa, N.; Shibasaki, M. Tetrahedron 2001, 57, 2569-2579. (e)
Kobayashi, S.; Uchiro, H.; Shiina, I.; Mukaiyama, T. Tetrahedron 1993,
49, 1761-72. (f) Kobayashi, S.; Mukaiyama, T. Chem. Lett. 1989, 2,
297-300.
(5) (a) Hoover, T. R.; Hitchcock, S. R. Tetrahedron: Asymmetry 2003,
14, 3233-3241. (b) Casper, D. M.; Hitchcock, S. R. Tetrahedron:
Asymmetry 2003, 14, 517-521. (c) Casper, D. M.; Burgeson, J . R.;
Esken, J . M.; Ferrence, G. M.; Hitchcock, S. R. Org. Lett. 2002, 4,
3739-3742.
(3) Anti adducts: (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-
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10.1021/jo035481u CCC: $27.50 © 2004 American Chemical Society
Published on Web 01/09/2004
J . Org. Chem. 2004, 69, 727-734
727

Burgeson et al.
SCHEME 1. Asym m etr ic Ald ol Rea ction s w ith
tion wherein the C5-methyl group and the stereogenic N4-
methyl group are arranged in a 1,2-trans-pseudodiaxial
relationship. These two positions work as a stereochem-
ical tandem (intramolecular chiral relay)7 that directs the
outcome of asymmetric induction. The major diastere-
omer of this asymmetric aldol reaction was determined
Oxa d ia zin on e 4
1
by H NMR spectroscopy and X-ray crystallography to
be the non-Evans syn adduct.5c
In connection with a program focused on the synthesis
of the HIV protease inhibitor saquinavir (3),8 we have
acylated the ephedrine-based oxadiazinone (1) with hy-
drocinnamoyl chloride to yield the corresponding N3-
hydrocinnamoyloxadiazinone (4) and have conducted a
series of test aldol reactions. The chemical yields were
fair to very good, and diastereoselectivities were, in
general, good for the aromatic aldehydes and poor for the
aliphatic aldehydes. More interesting, however, was the
fact that all of the aldol adducts exhibited a signal in their
TABLE 1. Asym m etr ic Ald ol Ad d u cts 5a -j
1
respective H NMR spectra that appeared near 0 ppm.
This was unusual, as we had not observed any chemical
shift values near this region in our previous applications
of the ephedrine-based oxadiazinone in the aldol reac-
tion.5 It is believed that this change in the position of
the signal in the 1H NMR spectra is due to conformational
effects that arise from the unusual conformation adopted
by oxadiazinones. Previous work in our labs suggested
that oxadiazinones derived from ephedrine and pseu-
doephedrine adopt a conformation in which the C2-
carbonyl group and the N3-acyl substituent are arranged
in a syn parallel orientation.9a In this paper, we examine
the conformational aspects of the syn-aldol adducts
generated from the aldol reaction with the N3-hydro-
cinnamoyloxadiazinone (4) that most likely give rise to
entry
aldehyde
-C6H5
-C6H3(CH2O2)
-p-C6H4Cl
-o-C6H4OCH3
-p- C6H4NO2
-1-C10H7
-2-C10H7
-C(CH3)3
-CH(CH3)2
-CH3
product
dra
% yieldb
1
2
3
4
5
6
7
8
9
5a
5b
5c
5d
5e
5f
5g
5h
5i
47:1
6:1c
21:1
5:1
22:1
13:1
13:1
1.4:1
3:1
84
68
60
46
69
78
86
38
47
42
10
5j
5:1
1
the unexpected chemical shift values by employing H
NMR spectroscopy, X-ray crystallography, and compu-
tational methods.
a
Diastereomeric ratio (dr) was determined either by HPLC or
400 MHz 1H NMR. bIsolated yield after column chromatography
or recrystallization.
Resu lts a n d Discu ssion
the corresponding N3-hydrocinnamoyl heterocycle in 90%
yield after column chromatography. The acylated oxadi-
azinone was then treated with 2 equiv of TiCl4 at room
temperature for 25 min. The reaction mixture was then
cooled to -78 °C, and triethylamine was added. The
temperature was allowed to slowly come to 25 °C over a
period of 60 min and was then again chilled to -78 °C
for the addition of the aldehyde (Scheme 1).
Syn th esis. (1R,2S)-Ephedrine-based oxadiazinone 1
was acylated by reaction with lithium hydride and
hydrocinnamoyl chloride in methylene chloride to afford
(6) 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.
(7) (a) Sibi, M. P.; Venkatraman, L.; Liu, M.; J asperse, C. P. J . Am.
Chem. Soc. 2001, 123, 8444-8445. (b) Corminboeuf, O.; Quaranta, L.;
Renaud, P.; Liu, M.; J asperse, C. P.; Sibi, M. P. Chem.sEur. J . 2003,
9, 29-35.
The chemical yield for the 10 aldehyde examples
ranged from 38 to 86% (Table 1). The diastereoselectivi-
ties of these reactions were, in general, varied (1.4:1.0 to
47:1), favoring the non-Evans syn isomer over the
remaining isomers. This stereochemistry was determined
by analogy with our previous efforts in the asymmetric
aldol reaction with oxadiazinones.5 In addition, single-
crystal X-ray crystallography of aldol adduct 5c con-
firmed this stereochemical orientation.
(8) (a) Edmonds, M. K.; Abell, A. D. J . Org. Chem. 2001, 66, 3747-
3752. (b) Ghosh, A. K.; Hussain, K. A.; Fidanze, S. J . Org. Chem. 1997,
62, 6080-6082. (c) Roberts, N. A.; Martin, J . A.; Kinchington, D.;
Broadhurst, A. V.; Craig, J . C.; Duncan, I. B.; Galpin, S. A.; Handa, B.
K.; Kay, J .; Krohn, A.; Lambert, R. W.; Merrett, J . H.; Mills, J . S.;
Parkes, K. E. B.; Redshaw, S.; Ritchie, A. J .; Taylor, D. L.; Thomas,
G. J .; Machin, P. J . Science 1990, 358.
(9) (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) Pseudoephedrine-based oxadi-
azinone 6 exhibits unique line broadening in its 13C NMR spectrum.
The line broadening is attributed to the proximity of the N4-methyl
group to the N3-hydrocinnamoyl side chain. The N4-methyl undergoes
observable pyramidal inversion and is slowed by the nearness of the
N3-hydrocinnamoyl side chain. These results suggest that the C2-
carbonyl group and the N3-carbonyl group are arranged in a syn
parallel orientation in solution and correlate favorably with the
observed solid-state X-ray structure of 5c. This spatial arrangement
is believed to be the result of the repulsion between the lone pair
electrons of the N4-nitrogen and the lone pair electrons of the carbonyl
of the N3-substituent.
X-r a y Cr ysta llogr a p h y.10 The asymmetric aldol ad-
duct 5c was recrystallized to afford crystals suitable for
X-ray diffraction studies (Figure 2). With 5c containing
(10) Please see Supporting Information for details pertaining to the
X-ray crystal structure. X-ray structural data has been deposited
at the Cambridge Crystallographic Data Center CCDC-221499.
Copies of this information may be obtained free of charge from The
Director, CCDC, 12 Union Road, Cambridge CB2 1EZ, UK (Fax: +44-
1223-336033; e-mail: deposit@ccdc.cam.ac.uk; Internet: http://
www.ccdc.cam.ac.uk).
728 J . Org. Chem., Vol. 69, No. 3, 2004

Aldol Adducts of Oxadiazinones
TABLE 2. Ch em ica l Sh ifts of th e C5-Meth yl Su bstitu en t
for Oxa d ia zin on e Ad d u cts 2 a n d 5a -j
δ, ppma
entry adduct R-substituent R′ â-substituent R” (C5-methyl)
1
2
3
4
5
6
7
8
9
2
-CH3
-C6H5
0.82
0.04
0.05
0.03
0.08
0.04
0.02
0.05
0.02
0.11
0.09
5a
5b
5c
5d
5e
5f
5g
5h
5i
-CH2C6H5
-CH2C6H5
-CH2C6H5
-CH2C6H5
-CH2C6H5
-CH2C6H5
-CH2C6H5
-CH2C6H5
-CH2C6H5
-CH2C6H5
-C6H5
-C6H3(CH2O2)
-p-C6H4Cl
-o-C6H4OCH3
-p- C6H4NO2
-1-C10H7
-2-C10H7
-C(CH3)3
-CH(CH3)2
-CH3
10
11
5j
F IGURE 2. RASTEP drawing (50% probability level) of 5c,
with hydrogen atoms drawn arbitrarily small for clarity.
a
All chemical shifts measurements were recorded in CDCl3
using a 400 MHz NMR spectrometer.
F IGURE 4. Proximity effects in a (1S,2S)-pseudoephedrine-
derived oxadiazinone.
appear to be the dominant hydrogen bonding interaction
in the solid state.
1
1H NMR Sp ectr oscop y. Interestingly, the H NMR
F IGURE 3. Intermolecular hydrogen bonding in the solid
state.
spectra of adducts 5a -j also revealed structural informa-
tion pertaining to the N3-substituent and its spatial
relationship to the oxadiazinone. All of the 1H NMR
spectra have a signal near an average value of 0.05 ppm,
and this signal was determined to be the C5-methyl group
of the oxadiazinone (Table 2). In contrast, the average
chemical shift for the C5-methyl group in a variety of
related oxadiazinone aldol adducts is 0.85 ppm (e.g.,
oxadiazinone 2).5 It is believed that the aromatic ring of
the N3-substituent is folded in toward the heterocycle and
has a shielding effect on the C5-methyl group. The X-ray
crystal structure (Figure 2) suggests that it is the
terminal aromatic ring of the N3-substituent. The origins
of this conformational preference are not well understood.
It is speculated that this is the result of the unique
conformational preference of (1R,2S)-ephedrine- and
(1S,2S)-pseudoephedrine-based N3-substituted oxadiazi-
nones.6,9 In fact, the conformational arrangement of the
related (1S,2S)-pseudoephedrine-based N3-hydrocin-
namoyloxadiazinone (6) shows a similar orientation of
the imide carbonyls as that of oxadiazinone 5c depicted
in Figure 4.9b However, the proximity effects in the
pseudoephedrine system are manifested by observable
line broadening rather than shielding effects.
a chlorine atom, absolute stereochemical assignment was
achieved by refinement of the Flack parameter. Analo-
gous to the related (1S,2S)-pseudoephedrine-based oxa-
diazinones,6,9 the crystallographic analysis revealed that
the structure adopted by 5c is a twist-boat conformation
in which the imide carbonyls are arranged with the
carbonyls oriented in a syn parallel conformation; how-
ever, the steric restraints of the C(15) substituent (i.e.,
the N3-acyl substituent) lead to a significant distortion
of the imide dicarbonyl from planarity as evidenced by
the 30.2(2)° torsion angle for [O(34)-C(2)-C(15)-O(16)].
The conformation adopted by 5c in the solid state has
the terminal para-chlorophenyl substituent proximal to
the C5-methyl group and the hydrocinnamoyl substituent
(C17-C27Ph) proximal to the N4-methyl group with re-
spective aryl centroid to C(13) and to C(14) distances
equal to 3.622(2) and 3.619(2) Å.
This conformation precludes any intramolecular hy-
drogen bonding involving the O19-hydrogen atom; how-
ever, intermolecular hydrogen bonding exists between the
O19-hydrogen atom and the imide dicarbonyl oxygen
atoms of the proximal molecule located at X + 1, Y, Z as
illustrated in Figure 3 and evidenced by the O(19)-O(16)′
2.851(12), O(16)′-H(19) 2.14(2), O(19)-O(34)′ 3.295(2),
and O(34)′-H(19) 2.54(2) Å separations. On the basis of
these separations, the O(16)′-H(19) interaction would
NOE Exp er im en ts. X-ray crystallography suggested
that the terminal aromatic ring was responsible for the
chemical shift change, but this work was limited to the
solid state and did not address issues of solvation that
J . Org. Chem, Vol. 69, No. 3, 2004 729

Burgeson et al.
F IGURE 5. NMR spectrum of oxadiazinone 5e. (a) 700 MHz 1H NMR spectrum of 5e in DMSO-d6. (b) 500 MHz 1H NMR NOEDIFF
spectrum of 5e in DMSO-d6.
would be relevant in solution. To more fully probe the
nature of the observed shielding effect in solution, a series
of NOE difference experiments were conducted to dem-
onstrate the proximity of the terminal aromatic ring of
the N3-substituent to the C5-methyl group. In this regard,
oxadiazinone aldol adduct 5e was subjected to the NOE
experiment (Figure 5). Interestingly, a strong, positive
NOE effect was observed between the protons of the C5-
methyl group and the protons of the aromatic moiety of
the N3-hydrocinnamoyl fragment. This was in stark
contrast to what was observed in the solid-state X-ray
crystal structure wherein the terminal aromatic ring was
proximal to the C5-methyl group.
Oxadiazinone 5h was also investigated by NOE. This
oxadiazinone was selected because it does not have a
terminal aromatic ring; rather, a tert-butyl group is at
this position. Again, a positive NOE effect was observed
for the C5-methyl group and the N3-hydrocinnamoyl
aromatic ring (Figure 6). This collected body of evidence,
along with the observed chemical shifts of adducts 5a -
d ,f,g,i,j (δavg ≈ 0.05 ppm) suggests that the substituents
in question (C5-methyl/N3-hydrocinnamoyl aromatic) are
proximal to one another. Interestingly, this conformation
requires that the arrangement of the N3-hydrocinnamoyl
and aryl substituent must be reversed in solution,
relative to the solid-state X-ray crystal structure (Figure
2). This is feasible given the generalized packing of the
known acylated ephedrine- and pseudoephedrine-based
oxadiazinones and the ability of H19 to hydrogen bond to
the imide dicarbonyls.5c,6,9a
To further support the NOE difference experiments, a
related oxadiazinone was prepared to demonstrate the
impact of the hydrocinnamoyl moiety on the C5-methyl
group (Scheme 2). Thus, ephedrine-based oxadiazinone
1 was acylated with cyclohexanepropanoyl chloride to
afford the acylated heterocycle 7 in 78% yield. This
product was then treated with titanium tetrachloride,
triethylamine, and benzaldehyde to afford the aldol
adduct 8 in 40% yield and a diastereomeric ratio of 4:1
favoring the syn diastereomer as determined by 1H NMR
spectroscopy. As predicted, the chemical shift of the C5-
methyl group returned to its characteristic value of 0.85
ppm. This further supported the fact that the aromatic
730 J . Org. Chem., Vol. 69, No. 3, 2004

Aldol Adducts of Oxadiazinones
F IGURE 6. NMR spectrum of oxadiazinone 5h . (a) 700 MHz 1H NMR spectrum of 5h in DMSO-d6. (b) 500 MHz 1H NMR NOEDIFF
spectrum of 5h DMSO-d6.
SCHEME 2. Oxa d ia zin on e Ald ol Ad d u ct 8
moiety of the hydrocinnamoyl group is responsible for the
observed change in chemical shift.
Spartan02 software packages.11 Because we were inter-
ested in the positioning of the aromatic rings of the N3-
substituent and their effect on the 1H NMR chemical shift
of the C5-methyl group, a systematic conformation search
was employed in which initial structures were generated
by variation of the dihedral angles responsible for
positioning of the aromatic ring of the N3-hydrocinnamoyl
unit and the aromatic ring at the terminus of the N3-
Com p u ta tion a l Stu d ies. The objectives of the com-
putational studies are to search for conformations of
1
oxadiazinone 5a that exhibit unusual H NMR chemical
shifts of the C5-methyl protons and to characterize the
structural origins of these unusual chemical shifts. A
conformation search employing the AM1 semiempirical
molecular orbital method was carried out to locate low-
energy conformations of oxadiazinone 5a . The conforma-
tion search was performed using the Spartan5.1 and
(11) Spartan 5.1 and Spartan 02; Wavefunction, Inc.: Irvine, CA,
2002.
J . Org. Chem, Vol. 69, No. 3, 2004 731

Burgeson et al.
F IGURE 7. Conformational analysis of oxadiazinone 5a .
substituent chain (Figure 7). The geometries of the initial
structures obtained in the systematic search were then
optimized in the gas phase using the AM1 method. The
AM1 semiempirical method was selected because it has
been previously shown to produce structures for similar
molecular systems in good agreement with X-ray struc-
tural data.9a
The NMR chemical shifts of the protons of the methyl
group attached to the C5 position were determined for
each conformation from single-point energy calculations
at the B3LYP/DZVP level of theory using the equilibrium
geometry obtained from the AM1 calculations. The NMR
shielding tensors were computed in the gas phase using
the Gauge Invariant Atomic Orbital technique as imple-
mented in the PQS ab initio software package.12
The conformation search resulted in the determination
of 25 conformations of oxadiazinone 5a with enthalpies
of formation within 7.5 kcal/mol (1.8 kJ /mol) of the lowest
energy conformation obtained. The two lowest energy
conformers are shown in Figure 8. The calculated en-
thalpies of formation of the 11 lowest conformers within
4 kcal/mol (0.96 kJ /mol) of the lowest energy conforma-
tion are listed in Table 3. Also listed in Table 3 are the
dihedral angles between the C2- and N3-carbonyl groups,
as well as the average calculated gas phase 1H NMR
chemical shifts of the protons of the C5-methyl group,
measured relative to tetramethylsilane.
Even though the two carbonyl groups (C2-carbonyl/N3-
carbonyl) were initially aligned to be close to syn parallel
in orientation in generating the initial structures for the
conformation search (with a dihedral angle of about 26°
between the carbonyls), sometimes this orientation
changed during the geometry optimization so that in
some conformers the carbonyl groups became nearly
perpendicular. Overall, dihedral angles between the two
carbonyl groups range from 21 to 86° in the 25 conformers
that were located. The calculated dihedral angle of 31.8°
between the C2- and N3-carbonyl groups of conformation
2 of oxadiazinone 5a is close to the orientation found in
the solid-state X-ray crystal structure of oxadiazinone 5c,
30.2(2)°. It is also interesting to note that conformer 2 of
oxadiazinone 5a is very similar overall to the X-ray
crystal structure of oxadiazinone 5c. For example, in
conformation 2 of oxadiazinone 5a , the terminal aromatic
ring of the N3-substituent is in close contact with the C5-
methyl group, with a distance from the aryl centroid to
C(13) (Figure 2) of 3.68 Å. The hydrocinnamoyl substitu-
ent of conformation 2 of oxadiazinone 5a is in close
contact with the N4-methyl group, with a distance from
the aryl centroid to C(14) of 3.60 Å. These calculated
structural results are quite comparable with respective
distances of 3.622(2) and 3.619(2) Å obtained from the
X-ray crystal structure of oxadiazinone 5c.
F IGURE 8. Isodensity surfaces of the optimized geometry of
(a) conformer 1 and (b) conformer 2 of oxadiazinone 5a
obtained using the AM1 semiempirical method. The isodensity
surface is plotted at a value of 0.002.
TABLE 3. Ca lcu la ted En th a lp ies of F or m a tion (k ca l/
m ol),a Dih ed r a l An gle betw een Ca r bon yl Gr ou p s, a n d
Aver a ge Ch em ica l Sh ifts (p p m )b of th e C5-Meth yl P r oton s
for th e 11 Low est Con for m a tion s
dihedral average C5 methyl
∆Hf kcal/mola
(kJ /mol)
angle
chemical shift
conformation
(degrees)
(ppm)b
1
2
3
4
5
6
7
8
9
-37.39 (-8.936)
-35.79 (-8.554)
-35.25 (-8.425)
-35.20 (-8.413)
-34.81 (-8.320)
-34.51 (-8.248)
-34.30 (-8.198)
-34.19 (-8.170)
-34.07 (-8.143)
-33.86 (-8.093)
-33.45 (-7.995)
32.0
31.8
26.3
29.8
37.5
65.6
71.0
48.2
85.7
21.2
82.3
0.95
-0.37
0.99
1.08
1.03
1.09
1.12
0.44
1.14
0.18
1.19
10
11
a
Enthalpies of formation were computed using the AM1
b
semiempirical method. Gas-phase chemical shifts in parts per
million relative to TMS are reported.
The lowest energy conformation of oxadiazinone 5a is
(12) PQS, version 2.5; Parallel Quantum Solutions: Fayetteville,
Arkansas, 2002.
stabilized by an intramolecular hydrogen bond between
732 J . Org. Chem., Vol. 69, No. 3, 2004

Aldol Adducts of Oxadiazinones
the OH group and the carbonyl group attached to N3-
substituent; the bond distance of this hydrogen bond is
2.19 Å. In fact, 8 of the 11 lowest energy conformations
found have an intramolecular hydrogen bond from the
OH group to either the carbonyl at the N3 position or
directly to the N3-nitrogen, and 16 of the total 25
conformers found have an intramolecular hydrogen bond
between the OH group and either one of the carbonyl
groups or the ring nitrogens. The large amount of
intramolecular hydrogen bonding found in the gas-phase
conformers of oxadiazinone 5a is in contrast to the solid-
state X-ray crystal structure of oxadiazinone 5c, which
exhibits intermolecular hydrogen bonding. In the solution
phase, both these systems would also have the capability
to form hydrogen bonds with polar solvent molecules.
The average proton NMR chemical shifts of the protons
of the methyl group attached to the C5 position for the
compounds exhibiting intramolecular hydrogen bonding
are in the expected range, with values from 0.9 to 1.23
ppm depending on the conformer. Of the 11 lowest energy
conformers found within 4 kcal/mol (0.96 kJ /mol) of the
lowest energy conformation, three (conformers 2, 8, and
10 in Table 3) do not exhibit intramolecular hydrogen
bonding. In all three of these conformers, the C5-methyl
group comes into relatively close contact with the termi-
nal aromatic ring of the N3-substituent. These three low-
energy conformers exhibit unusual chemical shifts for the
protons of the C5-methyl group. The chemical shifts of
the protons of the C5-methyl group for these conformers
range from -0.37 to 0.44 ppm. These chemical shifts are
much lower than those expected for a methyl group and
are in accord with the solution-phase NMR studies of the
C5-methyl groups of oxadiazinones 5a -j, which exhibit
chemical shifts of close to 0 ppm. The conclusion from
the computational studies is that the close contact
between the C5-methyl protons and the terminal aromatic
group of the N3-substituent is responsible for the unusual
chemical shifts of the C5-methyl protons in conformers
2, 8, and 10 of oxadiazinone 5a .
That the close contact of the terminal aromatic ring of
the N3-substituent is responsible for the unusual chemi-
cal shift of the methyl protons attached to C5-position of
oxadiazinone 5a has been tested by truncating the
structure of the molecule by removing the aromatic ring
and recalculating the chemical shifts. After truncation,
the average chemical shift of the protons of the C5-methyl
group in conformer 2 is 0.81 ppm (compared to -0.37 ppm
before truncation). The positioning of the protons of the
C5-methyl group between the aromatic residue at the
terminus of the N3-substituent chain and the benzene
ring attached to C6-position also plays a role in changing
the chemical shift. When the aromatic ring at the
terminus of the N3-substituent chain is left in place and
the aromatic ring attached to the C6-position is truncated,
the average chemical shift of the C5-methyl protons in
conformer 2 is 0.16 ppm (compared to -0.37 ppm before
truncation). This would suggest that both aromatic rings
must be present for the full shift to be observed, though
the close contact of the aromatic ring at the terminus of
the N3-substituent is most important in causing the
unusual chemical shift.
F IGURE 9. Conformer 25 of oxadiazinone 5a .
F IGURE 10.
aromatic ring of the N3-hydrocinnamoyl unit can lead to
unusual chemical shifts for the C5-methyl protons. The
three lowest energy gas-phase conformers of oxadiazinone
5a (conformers 2, 8, and 10) that exhibit unusual chemi-
cal shifts of the C5-methyl protons involve close contact
between the C5-methyl group and the terminal aromatic
group of the N3-substituent. However, the conformation
search also uncovered one conformation in the gas phase,
conformer 25, that exhibits an unusual chemical shift of
the C5-methyl protons due to close contact between the
C5-methyl group and the aromatic ring of the N3-
hydrocinnamoyl unit (Figure 9), with a calculated chemi-
cal shift of 0.16 ppm. This conformer is 7.4 kcal/mol (1.8
kJ /mol) above the lowest energy conformer in the gas
phase, exhibits intramolecular hydrogen bonding be-
tween the hydroxyl group and N4, and has a dihedral
angle between the C2- and N3-carbonyl positions of 63.4°.
Thus, the computational studies indicate that either
aromatic ring in proximity to the C5-methyl group can
lead to the unusual chemical shift.
Con for m a tion a l An a lysis Su m m a r y. The results of
the computational studies suggest that the chemical shift
change of the C5-methyl group is a result of the proximity
of either the terminal aromatic group of the N3-substitu-
ent or the aromatic ring of the N3-hydrocinnamoyl unit
in oxadiazinone 5a . The lowest energy conformers in the
gas phase that exhibit this effect correspond to those in
which the terminal aromatic group of the N3-substituent
is in close contact with the C5-methyl group. These results
are somewhat at odds with the results obtained from the
NOE experiments, which suggest that in solution it is
solely the aromatic ring of the N3-hydrocinnamoyl moiety
that is responsible for the change in chemical shift and
not the terminal aromatic ring (Figure 10).
In contrast, the results of the computational study are
in excellent agreement with the solid state X-ray crystal
structure. The reason for the differences among the NOE,
X-ray crystallographic, and computational studies is
attributed to the impact of solvation effects and hydrogen
The computational studies also reveal that close con-
tact between the C5-methyl protons and either the
terminal aromatic group of the N3-substituent or the
J . Org. Chem, Vol. 69, No. 3, 2004 733

Burgeson et al.
bonding on the oxadiazinone conformation. The confor-
mation observed in the solid-state structure is likely
attributable to the intermolecular hydrogen bonding
interactions (Figure 3). Were the conformation observed
in solution to prevail in the solid state, any conventional
type of intermolecular hydrogen bonding interactions
would be disrupted. While the impact such a conforma-
tional change would have on the crystal packing is
unclear, nominally it appears the dominant change would
be the elimination of conventional hydrogen bonding
interactions.
In the computational studies, the gas-phase conforma-
tions of oxadiazinone 5a are quite polar (for example, the
dipole moments of conformations 1 and 2 are 6.89 and
6.09 D, respectively) which could lead to strong interac-
tions with polar solvent molecules. In addition, the ability
of oxadiazinone 5a to form both intramolecular hydrogen
bonds and explicit hydrogen bonds with the solvent leads
to the conclusion that the gas-phase energy ordering of
the conformers is not necessarily the same in the solution
phase. This is especially likely because the conformers
are relatively closely spaced in energy. While calculations
employing continuum solvent methods would partially
address this issue, the inclusion of explicit solvent
molecules in the calculations also would probably be
necessary to obtain more reliable energy ordering of the
conformers of oxadiazinone 5a . The lengthy calculations
required for a complete solution-phase study of the
conformations of oxadiazinone 5a in the presence of a
continuum solvent model and/or explicit solvent mol-
ecules were deemed to be outside the scope of the present
work. Nevertheless, the present computational studies
do provide corroborating evidence that the origin of the
unusual chemical shift of the C5-methyl protons is the
close proximity of one of the aromatic groups of the N3-
substituent.
stated earlier. It is more likely that the carbonyls are
syn parallel and that the aromatic rings are switched in
position.
Con clu sion
In summary, we have conducted a series of asymmetric
aldol reactions with the titanium enolate of N3-hydro-
cinnamoyl-3,4,5,6-tetrahydro-2H-1,3,4-oxadiazin-2-one to
afford aldol adducts 5a -j. The dominant product of the
asymmetric aldol reaction was the non-Evans syn adduct
as determined by 1H NMR spectroscopy and X-ray
crystallography. The 1H NMR spectra of aldol adducts
5a -j suggested that the C5-methyl group of the oxadi-
azinone ring is highly shielded by an aromatic ring on
the N3-substituent chain. The solution-phase NOE ex-
periments suggest that the aromatic ring of the N3-
hydrocinnamoyl group is responsible for the unusual
shielding of the C5-methyl group. In contrast, X-ray
crystallography reveals that in the solid state, the
terminal aromatic ring of the N3-substituent is proximal
to the C5-methyl group. Computational studies reach this
same conclusion for the three lowest gas-phase conforma-
tions that have unusual chemical shifts of the C5-methyl
protons; however, among the 25 conformations located,
one other that has the unusual chemical shift involves
close contact between the C5-methyl group and the
aromatic ring of the N3-hydrocinnamoyl unit (as was
observed in the solution-phase NOE studies).
Ack n ow led gm en t. J . R. B. thanks Abbott Labora-
tories for support of summer research. We also acknowl-
edge continued support from Merck & Co., Inc. The
authors thank Dr. R. McDonald and the University of
Alberta X-ray Crystallography Laboratory for the col-
lection of low-temperature, CCD X-ray data. We also
thank Teresa Navio (Pfizer, Inc.) and Hasan Palandoken
(University of California-Davis) for their assistance in
measuring optical activities. Acknowledgment is made
to the Donors of the Petroleum Research Fund, admin-
istered by the American Chemical Society, for partial
support of this research.
Another explanation of the differences observed among
the NOE spectra, X-ray crystallographic data, and com-
putational results could be that while in solution, the C2-
and the N3-carbonyls are arranged in an antiperiplanar
conformation. In this orientation, the aromatic rings of
the N3-substituent effectively change places and would
yield the results of the NOE difference experiments.
However, this idea is countered by our prior observa-
tions that the dominant conformation is the synclinal
arrangement.5c,6,9 The synclinal arrangement of the car-
bonyls is believed to be the dominant conformation in
solution and in the solid state for reasons that were
Su p p or tin g In for m a tion Ava ila ble: Experimental de-
tails of X-ray crystallography, computational studies, charac-
terization data (400 MHz 1H NMR, 100 MHz 13C NMR) for all
1
new compounds, and 500 MHz H NMR spectra (NOE) of 5e
and 5h . This material is available free of charge via the
Internet at http://pubs.acs.org.
J O035481U
734 J . Org. Chem., Vol. 69, No. 3, 2004