X-ray crystallographic study of substituted perhydropyrimidinones. Extreme changes in ring conformation

Article abstract of DOI:10.1021/jo991297q

X-ray crystal structures of 20 differently substituted perhydropyrimidin-4-ones are presented. Analysis of these data reveal a remarkable conformational sensitivity of a six-membered ring to substitution. Thus half-chair, envelope, boat, twist-boat, and intermediate conformations are found for the six-membered heterocycle, providing evidence for a relatively fiat conformational energy surface in this ring. Interpretation of the preferred conformations is advanced in terms of steric interactions among substituents and, in some cases, as the result of particular conformational (A¹.³ strain, anomeric) effects.

Full text of DOI:10.1021/jo991297q

8668
J . Org. Chem. 1999, 64, 8668-8680
X-r a y Cr ysta llogr a p h ic Stu d y of Su bstitu ted
P er h yd r op yr im id in on es. Extr em e Ch a n ges in Rin g Con for m a tion
Yara Ram´ırez-Quiro´s,1 Margarita Balderas,1 J aime Escalante,1 Delia Quintana,1
Itzell Gallardo,1 Domingo Madrigal,1 Elies Molins,2 and Eusebio J uaristi*,1,3
Departamento de Quı´mica, Centro de Investigacio´n y de Estudios Avanzados del Instituto Polite´cnico
Nacional, Apartado Postal 14-740, 07000 Me´xico, DF, Mexico, and Institut de Cie`ncia de Materials de
Barcelona (CSIC), Campus Universitat Auto`noma de Barcelona, 08193 Cerdanyola, Spain
Received August 16, 1999
X-ray crystal structures of 20 differently substituted perhydropyrimidin-4-ones are presented.
Analysis of these data reveal a remarkable conformational sensitivity of a six-membered ring to
substitution. Thus half-chair, envelope, boat, twist-boat, and intermediate conformations are found
for the six-membered heterocycle, providing evidence for a relatively flat conformational energy
surface in this ring. Interpretation of the preferred conformations is advanced in terms of steric
interactions among substituents and, in some cases, as the result of particular conformational (A1,3
strain, anomeric) effects.
Sch em e 1
In tr od u ction
One of the basic tenets of conformational analysis
establishes that substituents in six-membered rings are
most stable in equatorial rather than axial orientations.4
Nevertheless, a well-recognized exception pertains to the
anomeric effect, which has attracted considerable experi-
mental and theoretical attention.5 A second tenet in
conformational analysis is that staggered conformers are
significantly more stable than eclipsed ones, to the extent
that the latter are usually disregarded.4 However, struc-
tural data accumulated in the past decade have provided
experimental confirmation of the existence of nonstag-
gered, stable eclipsed conformation in several saturated
compounds.6,7
electrophilic addition toward the enolate face opposite to
this group.
Subsequent X-ray crystallographic structure determi-
nations of differently substituted perhydropyrimidinones,
to be described in the present paper, disclosed yet another
“anomaly” to general tendencies in the conformational
behavior of six-membered rings:11 it is usually observed
that conformational energy surfaces for a particular ring
system exhibit pronounced energy minima at specific
conformational coordinates.11b However, we have gath-
ered structural data indicating that relatively subtle
changes in substitution patterns for perhydropyrimidin-
Some years ago, 1-benzoyl-2-tert-butyl-3-methylperhy-
dropyrimidin-4-one (rac-1) was alkylated with high di-
astereoselectivity via the corresponding enolate.8 (Scheme
1). X-ray crystal-structure determinations used to eluci-
date the stereochemical outcome of this reaction revealed9
an axial disposition of the tert-butyl group at C(2)
(consequence of a powerful A1,3 effect10), which directs
(8) (a) J uaristi, E.; Quintana, D.; Lamatsch, B.; Seebach, D. J . Org.
Chem. 1991, 56, 2553-2557. For applications in enantioselective
synthesis, with enantiopure analogues: (b) J uaristi, E.; Quintana, D.;
Balderas, M.; Garc´ıa-Pe´rez, E. Tetrahedron: Asymmetry 1996, 7,
2233-2246. (c) J uaristi, E.; Balderas, M.; Ram´ırez-Quiro´s, Y. Tetra-
hedron: Asymmetry 1998, 9, 3881-3888. (d) J uaristi, E.; Seebach, D.
Enantioselective Synthesis of R-Substituted and R,â-Disubstituted
â-Amino Acids via Chiral Derivatives of 3-Aminopropionic Acid. In
Enantioselective Synthesis of â-Amino Acids; J uaristi, E., Ed.; Wiley-
VCH: New York, 1997; Chapter 13, pp 261-277.
(9) (a) Seebach, D.; Lamatsch, B.; Amstutz, R.; Beck, A. K.; Dobler,
M.; Egli, M.; Fitzi, R.; Gautschi, M.; Herrado´n, B.; Hidber, P. C.; Irwin,
J . J .; Locher, R.; Maestro, M.; Maetzke, T.; Mourin˜o, A.; Pfammatter,
E.; Plattner, D. A.; Schickli, C.; Schweizer, W. B.; Seiler, P.; Stucky,
G.; Petter, W.; Escalante, J .; J uaristi, E.; Quintana, D.; Miravitlles,
C.; Molins, E. Helv. Chim. Acta 1992, 75, 913-934. (b) Murer, P.;
Rheiner, B.; J uaristi, E.; Seebach, D. Heterocycles 1994, 39, 319-344.
(c) See, also: Seebach, D.; Boog, A.; Schweizer, W. B. Eur. J . Org.
Chem. 1999, 335-360.
(10) Reviews: (a) J ohnson, F. Chem. Rev. 1968, 68, 375-413. (b)
Hoffmann, R. W. Chem. Rev. 1989, 89, 1841-1860. For a computational
study, see: (c) Broeker, J . L.; Hoffmann, R. W., Houk, K. N. J . Am.
Chem. Soc. 1991, 113, 5006-5017.
(11) (a) J uaristi, E., Ed. Conformational Behavior of Six-Membered
Rings. Analysis, Dynamics, and Stereoelectronic Effects; VCH Publish-
ers: New York, 1995. (b) Cremer, D.; Szabo, K. J . Ab Initio Studies of
Six-Membered Rings: Present Status and Future Developments. In
ref 11a, Chapter 3, pp 59-135.
* Corresponding author.
(1) Instituto Polite´cnico Nacional.
(2) Institut de Cie`ncia de Materials.
(3) E-mail: juaristi@relaq.mx.
(4) See, for example: (a) J uaristi, E. Introduction to Stereochemistry
and Conformational Analysis; Wiley: New York, 1991. (b) Eliel, E. L.;
Wilen, S. H.; Mander, L. N. Stereochemistry of Organic Compounds;
Wiley: New York, 1994.
(5) Recent monographs: (a) Thatcher, G. R. J ., Ed. The Anomeric
Effect and Associated Stereoelectronic Effects; ACS Symposium Series
No. 539; American Chemical Society: Washington, DC, 1993. (b)
J uaristi, E.; Cuevas, G. The Anomeric Effect; CRC Press: Boca Raton,
FL, 1995.
(6) Review: J uaristi, E. Stable Eclipsed Conformations. In The
Encyclopedia of Computational Chemistry; Schleyer, P. v. R., Allinger,
N. L., Clark, T., Gasteiger, J ., Kollman, P. A., Schaefer, H. F., III,
Schreiner, P. R., Eds.; Wiley: New York, 1998; Vol. 4, pp 2688-2692.
(7) Leading original references: (a) J uaristi, E.; Mart´ınez, R.;
Me´ndez, R. A.; Toscano, R. A.; Soriano-Garc´ıa, M.; Eliel, E. L.; Petsom,
A.; Glass, R. S. J . Org. Chem. 1987, 52, 3806-3811. (b) Anderson, J .
E.; Watson, D. G. J . Am. Chem. Soc. 1992, 114, 1517-1518. (c) Gordillo,
B.; J uaristi, E.; Mart´ınez, R.; Toscano, R. A.; White, P. S.; Eliel, E. L.
J . Am. Chem. Soc. 1992, 114, 2157-2162. (d) Anderson, J . E.; Ijeh, A.
I.; Storch, C.; Casarini, D.; Lunazzi, L. J . Org. Chem. 1998, 63, 3310-
3317.
10.1021/jo991297q CCC: $18.00 © 1999 American Chemical Society
Published on Web 11/12/1999

Substituted Perhydropyrimidinones
J . Org. Chem., Vol. 64, No. 23, 1999 8669
4-ones produce drastic variations in the preferred con-
formation of the ring.
Resu lts a n d Discu ssion
Although qualitative description of ring shapes is based
on more or less intuitive comparison with some reference
conformations such as chair, boat, or half-boat,4 methods
are available for the description of the conformations of
cyclic molecules in quantitative terms.12-14 The most
successful procedure was worked out in 1975 by Cremer
and Pople (CP),11b,13 who made possible a general defini-
tion of ring puckering coordinates for the proper descrip-
tion of ring shape. According to the CP method, for a six-
membered ring, the set of 3 puckering coordinates
(amplitudes and phase angles deduced from the devia-
tions zj of the ring atoms from the “mean” plane) leads
to the description of all possible conformations, in terms
of total puckering Q, polar angle θ and phase angle φ.
This method generally works very well, although it has
been argued14 that it sometimes fails in the description
of ring conformations due to the dependence of the CP
puckering parameters on the geometrical characteristics
of the ring.
More recently, Zefirov, Palyulin, and Dashevskaya
(ZPD) have proposed some modifications to the CP
method, with the use of the endocyclic torsional angles
ψj as a basic parameter for the calculation procedure.
That is, instead of the normal deviations zj from the mean
plane, the values of sin(ψj/2) were used for determination
of the puckering amplitudes and phase angles. There is
some concern that the formulas advanced to compute
relationships between puckering parameters (defined by
the z-coordinates) and the endocyclic torsional angles
(depending on both x-, y-, and z-coordinates) may not
work well for large puckering and larger rings. Neverthe-
less, examination of this point can be made by compari-
son of the torsional angles that are recomputed from the
calculated puckering parameters with the original tor-
sional angles. If differences between the original and the
recomputed values (σ) do not exceed 3-5°, then it is
generally concluded that the ZPD method properly
describes the conformation of the cyclic molecule under
study. For the systems described in this paper, σ values
were found not to exceed 1.5°.
F igu r e 1. ZPD puckering parameters for the six-membered
ring in the conformational sphere.14 (Reproduced with permis-
sion of the Editor.)
computer programs, respectively, using the atomic coor-
dinates derived from X-ray crystallographic analysis. For
the purposes of this work, it was assumed that the crystal
conformations of racemic pyrimidinones 3, 7, 8, 15, and
18-20 do not differ significantly from the structures of
the same enantiopure compounds.17
Table 1 collects the conformational parameters for
pyrimidinones 1-20 obtained by the ZPD method, and
Table 2 collects the conformational parameters for the
same compounds obtained by the CP method. Figures 2
and 3 present the distributions of these heterocycles in
three-component triangle diagrams, which have been
proposed as an alternative presentation of the spherical
conformational map.15 The most interesting feature
revealed from these analyses is the extensive spread of
ring structures over the different conformational ex-
tremes; this is, the pyrimidinone ring exhibits a remark-
able sensitivity to the nature and position of the various
alkyl or aryl substituents. This conclusion is reached both
with the CP and ZPD methods. Comparison of data
presented in Figures 2 and 3 reveals good agreement
between the conformational distribution of the hetero-
cyclic structures 1-20, which is confirmed in the analysis
summarized in Tables 1 and 2.
A fundamental characteristic of the perhydropyrimi-
dinone ring is the presence of the endocyclic and exocyclic
amide functions. Thus, most of the C(2)-N(1)-C(6) bond
angles are between 115 and 120°, and the C(2)-N(3)-
C(4) angles vary between 120 and 125°. As a conse-
quence, the perhydropyrimidinones are rather flat mol-
ecules, which reduces the energy difference between
extreme conformations (or, for that matter, any of the
intermediate conformations).18 Therefore, the perhydro-
pyrimidinone ring is rather flexible, adjusting itself easily
to the steric (and/or stereoelectronic; see below) require-
ments of the substituents.
Both in the CP and ZPD methods the calculated
structural parameters allow schematic representation of
the ring forms on the surface of a sphere where values
of polar and phase angles dictate the distance between
the point corresponding to the ring under study and the
points of the extreme (canonical) conformations, such as
chair, boat, or twist-boat, on the surface of the confor-
mational sphere. (Figure 1).
The conformational analysis of 20 differently substi-
tuted 1-benzoylperhydropyrimidin-4-ones, 1-20 (Chart
1), was undertaken by means of the ZPD method and the
CP method as implemented in the RICON15 and RING9616
(12) For pioneering developments, especially with six-membered
rings: (a) Kilpatrick, J . E.; Pitzer, K. S.; Spitzer, R. J . Am. Chem. Soc.
1947, 69, 2483-2488. (b) Dunitz, J . D. Tetrahedron 1972, 28, 5459-
5467. (c) Buys, H. R.; Geise, H. J . Tetrahedron Lett. 1968, 5619-5624.
(d) Cano, F. H.; Foces-Foces, C.; Garc´ıa Blanco, S. Tetrahedron 1977,
33, 797-802. (e) Hendrickson, J . B. J . Am. Chem. Soc. 1967, 89, 7047-
7061.
In this context, the conformation of the perhydropyri-
midinone ring is somewhat related to the conformation
of the 4-cyclohexenone ring. Thus, it was of interest to
compare the conformational behavior of heterocycles
(13) Cremer, D.; Pople, J . A. J . Am. Chem. Soc. 1975, 97, 1354-
1358.
(14) Zefirov, N. S.; Palyulin, V. A.; Dashevskaya, E. E. J . Phys. Org.
Chem. 1990, 3, 147-158.
(15) Zotov, A. Y.; Palyulin, V. A.; Zefirov, N. S. J . Chem. Inf. Comput.
Sci. 1997, 37, 766-773.

8670 J . Org. Chem., Vol. 64, No. 23, 1999
Ram´ırez-Quiro´s et al.
Ch a r t 1a
a
1-Benzoylperhydropyrimidin-4-ones whose X-ray crystallographic structure and conformation are discussed in this paper.
Ta ble 1. Con for m a tion a l P a r a m eter s for Heter ocycles 1-20, Ca lcu la ted w ith th e ZP D Meth od a
compd
(2S)-1
S
S2
S3
θ
ψ
σ
conformation
0.773
0.823
0.806
0.702
0.816
0.654
0.730
0.766
0.734
0.578
0.646
0.744
0.771
0.786
0.687
0.758
0.807
0.679
0.640
0.828
0.371
0.398
0.395
0.595
0.371
0.649
0.727
0.764
0.722
0.569
0.610
0.714
0.759
0.392
0.470
0.449
0.374
0.679
0.615
0.821
-0.678
-0.720
-0.703
-0.371
-0.727
-0.074
0.065
-0.054
-0.130
-0.102
0.213
-0.208
-0.140
-0.682
0.501
-0.611
-0.715
0.031
28.7
29.0
29.3
58.1
27.1
83.5
84.9
86.0
79.8
79.8
70.7
73.8
79.6
29.9
43.1
36.3
27.6
87.4
74.2
82.6
8.6
27.4
11.4
26.5
22.0
11.2
16.8
6.3
0.60
0.44
0.32
0.68
0.61
0.93
1.31
1.21
1.09
0.89
1.03
1.46
0.50
0.62
0.56
0.69
0.99
0.51
0.87
1.06
between envelope and half-chair
distorted half-chair
between envelope and half-chair
distorted screw-boat
between half-chair and envelope
between boat and screw-boat
between twist and boat
between boat and screw-boat
between boat and screw-boat
between boat and screw-boat
between envelope and twist
between twist and envelope
between twist and envelope
between envelope and half-chair
between envelope and screw-boat
between envelope and half-chair
between half-chair and envelope
between boat and twist
2
rac-3
(2S)-4
(2S)-5
(2S,6R)-6
rac-7
rac-8
(2S,6S)-9
(2S,6S)-10
(2S,6S)-11
(2R,6R)-12
(2S,5R)-13
(2S,5R)-14
rac-15
(2S,5R)-16
(2S,5R)-17
rac-18
6.8
6.2
19.2
24.2
19.3
7.2
14.1
7.8
17.3
10.5
18.4
6.3
rac-19
rac-20
-0.175
0.107
between envelope and twist
between boat and screw-boat
a
S ) total puckering amplitude, S2 ) S sin θ, S3 ) S cos θ, θ ) polar angle, ψ ) phase angle, σ ) deviation of the calculated torsional
angles from the initial values.
1-20 with that exhibited by substituted 4-cyclohex-
enones. A search through the Cambridge Structural
Database (CSD) afforded 72 crystallographic structures
(R factor < 6%) of differently substituted 4-cyclohex-
enones, all of them distributed in a rather limited
conformational range, between envelope and half-chair/
screw-boat conformations (Figure 4, Supporting Informa-
tion). This is, of course, in contrast with perhydropyri-
midinones 1-20, encompassing essentially all regions of
the conformational space (Tables 1 and 2; Figures 2 and
3).
1-Ben zoyl-3-m eth ylp er h yd r op yr im id in -4-on e, 2.
This unsubstituted, “parent” pyrimidinone adopts a
distorted half-chair conformation, where the C(2)-N(3)-
C(4)-C(5) segment is quite planar owing to conjugation
in the amide segment, while N(1) and C(6) are displaced
away from the plane (Figure 5).
1-Ben zoyl-(2S)-ter t-bu tyl-3-m eth ylp er h yd r op yr i-
m id in -4-on e, (2S)-1. The crystal structure of a racemic
sample was previously discussed.8a,9a The most salient
observation is the quasi-axial orientation of the tert-butyl
group, as a consequence of A1,3 strain. The conformation
of the ring is intermediate between a half-chair and an
envelope, being closer to the latter (Figure 6a). Compari-
son with the crystal structure of 2 (see above) suggest
that steric repulsion between one of the methyl groups
of the axial tert-butyl and the methylene group at C(6)
is responsible for the flattening of the heterocyclic ring,
that is, the change from half-chair to envelope conforma-
tions upon incorporation of the tert-butyl group [2 f (S)-
1].
Replacement of the tert-butyl group by phenyl (1 f 3)
does not produce significant changes in the ring confor-
mation, intermediate between half-chair and envelope

Substituted Perhydropyrimidinones
J . Org. Chem., Vol. 64, No. 23, 1999 8671
Ta ble 2. Con for m a tion a l P a r a m eter s for Heter ocycles 1-20, Ca lcu la ted w ith th e CP Meth od b
compd
(2S)-1
Q
Q2
Q3
θ
φ
conformation
0.430(3)
0.473(2)
0.459(2)
0.493(4)
0.457(4)
0.507(4)
0.593(2)
0.612(2)
0.584(5)
0.456(2)
0.503(3)
0.591(3)
0.607(4)
0.447(3)
0.425(2)
0.452(3)
0.441(5)
0.550(3)
0.494(3)
0.690(2)
0.301(3)
0.331(2)
0.323(2)
0.465(5)
0.307(4)
0.506(4)
0.591(2)
0.612(2)
0.582(5)
0.454(2)
0.490(3)
0.579(2)
0.604(4)
0.316(3)
0.361(2)
0.352(3)
0.295(5)
0.549(3)
0.489(3)
0.685(2)
-0.307(3)
-0.338(2)
-0.326(3)
-0.166(4)
-0.339(4)
-0.027(4)
0.051(2)
-0.007(2)
-0.046(4)
-0.035(2)
0.111(3)
-0.119(2)
-0.057(4)
-0.316(3)
0.225(2)
-0.283(3)
-0.327(5)
0.026(3)
44.4(5)
44.4(3)
44.8(3)
70.4(5)
42.2(5)
86.9(5)
85.1(2)
89.3(2)
85.5(4)
85.6(3)
77.2(3)
78.4(2)
84.6(4)
45.0(4)
58.1(3)
51.1(4)
42.0(6)
87.3(3)
81.8(4)
83.5(2)
7.9(6)
29.9(5)
13.1(4)
27.0(5)
23.3(8)
9.8(5)
15.5(2)
6.2(2)
6.6(4)
between envelope and half-chair
distorted half-chair
between envelope and half-chair
distorted screw-boat
between half-chair and envelope
between boat and twist
between twist and boat
2
rac-3
(2S)-4
(2S)-5
(2S,6R)-6
rac-7
rac-8
between boat and twist
(2S,6S)-9
(2S,6S)-10
(2S,6S)-11
(2R,6R)-12
(2S,5R)-13
(2S,5R)-14
rac-15
(2S,5R)-16
(2S,5R)-17
rac-18
between boat and screw-boat
between boat and screw-boat
between screw-boat and boat
between twist and envelope
between twist and boat
between envelope and half-chair
between envelope and screw-boat
between envelope and half-chair
between half-chair and envelope
between boat and twist
5.9(3)
17.2(3)
22.3(3)
18.6(4)
9.5(6)
15.1(4)
8.3(4)
19.5(9)
8.7(3)
16.4(4)
6.5(2)
rac-19
rac-20
-0.070(3)
0.078(2)
between screw-boat and boat
between boat and screw-boat
b
Q ) total puckering amplitude, Q2 ) Q sin θ, Q3 ) Q cos θ, θ ) polar angle, φ ) phase angle.
F igu r e 2. Distribution of pyrimidinones 1-20 in a three-component triangle diagram of the conformational space, obtained by
the ZPD method. The triangle corresponds to a segment of the conformational sphere, where the canonical chair (θ ) 0°, ψ ) 0°),
boat (θ ) 90°, ψ ) 0°), and twist-boat (θ ) 90°, ψ ) 30°) are located at the triangle’s corners.
but closer to the latter. If any, steric repulsion between
the axial phenyl ring and the C(6) methylene decreases
in 3 relative to 1, as evidenced by a less pronounced
flattening of the ring [C(4)-C(5)-C(6)-N(1) torsional
angle ) 38.3° in 3 versus 27.7° in 1]. Also of interest is
the orientation of the phenyl ring, almost eclipsed to the
C(2)-N(3) bond [N(3)-C(2)-Cipso-Cortho ) 16.8°] (Figure
6b).
5,5-Disubstituted (2S,5R)-16 and (2S,5R)-17 pyrimi-
dinones suffer necessarily from steric repulsion between
the axial tert-butyl group at C(2) and the syn substituent
at C(5). Steric repulsion is minimized when the ring
adopts an envelope conformation, as found in rac-3.
(Figure 6c,d).
in 1 and phenyl group in 3). Furthermore, the isopropyl
group adopts an staggered conformation toward C(2)-
N(1) and C(2)-N(3) bonds, with the C-H bond pointing
inside the ring [H-C(15)-C(2)-N(1) torsional angle )
56.1° and H-C(15)-C(2)-N(3) ) 68.8°]. Apparently, in
the absence of any significant steric repulsion between
the axial substituent at C(2) and the C(6) methylene
group, the conformation of lowest energy is the twist-
boat.
1-Ben zoyl-(2S)-isop r op ylp er h yd r op yr im id in -4-
on e, (2S)-5. The axial orientation of the isopropyl group
at C(2) indicates that, as expected,19 A1,3 strain with the
N(1)-benzoyl moiety is still sufficiently strong to overcome
steric repulsion arising from the axial substituent. Nev-
ertheless, removal of the N(3)-methyl group in going from
(2S)-4 to (2S)-5 allows the C(2)-N(3)-C(4)-C(5) segment
1-Ben zoyl-(2S)-isop r op yl-3-m eth ylp er h yd r op yr i-
m id in -4-on e, (2S)-4. This derivative exhibited the struc-
ture closest to a twist-boat (Figure 7). The isopropyl group
is again in a pseudoaxial orientation (cf. tert-butyl group
(16) This program was supplied by D. Cremer in
communication.
a personal

8672 J . Org. Chem., Vol. 64, No. 23, 1999
Ram´ırez-Quiro´s et al.
F igu r e 3. Distribution of pyrimidinones 1-20 in a three-component triangle diagram of the conformational space, obtained by
the CP method. The triangle corresponds to a segment of the conformational sphere, where the canonical chair (θ ) 0°, ψ ) 0°),
boat (θ ) 90°, ψ ) 0°), and twist-boat (θ ) 90°, ψ ) 30°) are located at the triangle’s corners.
F igu r e 5. Structure and solid-state conformation of 1-benzoyl-
3-methylperhydropyrimidin-4-one, 2 (schematic view).
F igu r e 7. Structure and solid-state conformation of 1-benzoyl-
(2S)-isopropyl-3-methylperhydropyrimidin-4-one, (2S)-4.
oriented toward the inside of the ring [cf. (2S)-4] (Figure
7).
1-Benzoyl-(2S)-tert-butyl-3-methyl-(5R)-benzylperhy-
dropyrimidin-4-one, (2S,5R)-14, adopts a conformation
very similar to that exhibited by (2S)-5, intermediate
between a half-chair and an envelope. Apparently, no
significant steric interaction arises between the trans
benzyl group at C(5) and the tert-butyl group at C(2)
(Figure 8b).
trans-15 also exhibits a half-chair conformation, with
a fairly flat C(2)-N(3)-C(4)-C(5) segment (torsional
angle ) 14.9°) because of the conjugation in the amide
group (Figure 8c).
F igu r e 6. (a) Structure and solid-state conformation of
1-benzoyl-(2S)-tert-butyl-3-methylperhydropyrimidin-4-one, (2S)-
1. (b) Structure and solid-state conformation of 1-benzoyl-2-
(17) The assumption that the situation in individual enantiomers
and racemates is the same should be warranted for conglomerates.
Racemic 3 and 20 fall in this category, so that their crystallographic
phenyl-3-methylperhydropyrimidin-4-one, rac-3. (c) Structure
and solid-state conformation of 1-benzoyl-(2S)-tert-butyl-3,(5R)-
dimethyl-5-benzylperhydropyrimidin-4-one, (2S,5R)-16. (d)
Structure and solid-state conformation of 1-benzoyl-(2S)-tert-
butyl-3,(5R)-dimethyl-5-n-butylperhydropyrimidin-4-one,
(2S,5R)-17.
structural data clearly correspond to those of enantiopure compounds.
Nevertheless, we were able to confirm that structural data for racemic
compounds rac-1 and rac-14 (CSD: J OPYUI and J OPZAP,9a respec-
tively) are quite similar to those for enantiopure (2S)-1 and (2S,5R)-
14, as can be seen in Figure 21 and Table 6 (Supporting Information).
(18) This situation brings to mind the cyclohexane/cyclopentane
contrastable behavior: In the six-membered ring one deals with a ring
of essentially well-defined conformation, namely the chair form. By
contrast, in the five-membered ring there are no pronounced energy
minima. See: Willy, W. E.; Binsch, G.; Eliel, E. L. J . Am. Chem. Soc.
1970, 92, 5394-5402.
to be flat, just like in the case of the parent, unsubstituted
compound 2; thus, (2S)-5 adopts a half-chair ring con-
formation (Figure 8a). On the other hand, the isopropyl
group adopts again an orientation with the C-H bond
(19) Breaking conjugation at the N-CO segment requires over 15
kcal/mol, whereas a bulky substituent axially disposed in the pyrimi-
dinone ring requires less than 3-5 kcal/mol.

Substituted Perhydropyrimidinones
J . Org. Chem., Vol. 64, No. 23, 1999 8673
F igu r e 11. Structure and solid-state conformation of rac-cis-
1-benzoyl-2,6-diphenyl-3-methylperhydropyrimidin-4-one, cis-
8.
F igu r e 8. (a) Structure and solid-state conformation of
1-benzoyl-(2S)-isopropylperhydropyrimidin-4-one, (2S)-5. (b)
Structure and solid-state conformation of 1-benzoyl-(2S)-tert-
butyl-3-methyl-(5R)-benzylperhydropyrimidin-4-one, (2S,5R)-
14. (c) Structure and solid-state conformation of rac-trans-1-
benzoyl-2-tert-butyl-5-hydroxybenzyl-3-methylperhydropyrimi-
din-4-one, trans-15.
F igu r e 12. (a) Structure and solid-state conformation of
1-benzoyl-(2S)-isopropyl-(6S)-carbomethoxyperhydropyrimidin-
4-one, (2S,6S)-9. (b) Structure and solid-state conformation of
1-benzoyl-(2S)-tert-butyl-(6S)-carboxyperhydropyrimidin-4-
one, (2S,6S)-10.
is apparently achieved, since the ring conformation is
again [cf. (2S,6R)-6] closer to an ideal boat form (Figure
11).
1-Ben zoyl-(2S)-isop r op yl-(6S)-ca r bom eth oxyp er -
h yd r op yr im id in -4-on e, (2S,6S)-9. The lack of signifi-
cant steric repulsion between the axial isopropyl group
at C(2) and the syn carbomethoxy group at C(6) allows
for the ring conformation to exist again [cf. (2S,6R)-6 and
cis-8] in a boat shape (Figure 12a).
F igu r e 9. Structure and solid-state conformation of 1-benzoyl-
(2S)-tert-butyl-3,(6R)-dimethylperhydropyrimidin-4-one, (2S,6R)-
6.
By the same token, steric repulsion between the tert-
butyl and carboxylic groups is minimized in the boat
conformation of (2S,6S)-10 (Figure 12b).
1-Ben zoyl-(2S)-ter t-bu tyl-(6S)-m eth oxyp er h yd r o-
p yr im id in -4-on e, (2S,6S)-11. Since the axial tert-butyl
group at C(2) and the methoxy substituent at C(6) are
trans to each other, no steric repulsion between these
groups can be anticipated. Nevertheless, the ring adopts
a conformation intermediate between boat and twist-
boat, probably to benefit from an nN f σ*C-O hypercon-
jugative interaction5 that would not be feasible in the
envelope or half-chair conformations (Figure 13a). An
alternative or complementary rationalization for the axial
orientation of the methoxy group is that a ring conforma-
tion with equatorial methoxy would cause increased
gauche repulsion (A1,3 strain) with the adjacent N(1)-
benzoyl group.
The ring conformation in (2R,6R)-12 is quite similar
to that observed in (2S,6S)-11, between twist and enve-
lope (Figure 13b). The methyl group at C(6) adopts an
axial orientation as a consequence of A1,3 strain with the
N-benzoyl group.
1-Ben zoyl-(2S)-isop r op yl-3,(5R)-d im et h ylp er h y-
dr opyr im idin -4-on e, (2S,5R)-13. The twist form adopted
by this heterocycle permits the methyl substituent at C(5)
F igu r e 10. Structure and solid-state conformation of rac-cis-
1-benzoyl-2-tert-butyl-3-methyl-6-phenylperhydropyrimidin-4-
one, cis-7.
1-Ben zoyl-(2S)-ter t-b u t yl-3,(6R)-d im et h ylp er h y-
d r op yr im id in -4-on e, (2S,6R)-6. Derivatives of (2S)-1
containing a syn substituent at C(6) avoid the large steric
repulsion with the tert-butyl group by adopting boat or
twist-boat ring conformations, where the C(6) substituent
is pseudoequatorial (Figure 9).
r a c-cis-1-Ben zoyl-2-ter t-bu tyl-3-m eth yl-6-p h en yl-
p er h yd r op yr im id in -4-on e, cis-7. Upon substitution of
the C(6)-methyl group by a bulkier phenyl group, the ring
conformation changes from boat to twist-boat (cf. 6 f 7),
apparently to further minimize steric repulsion between
the tert-butyl and phenyl substituents (Figure 10).
r a c-cis-1-Ben zoyl-2,6-d ip h en yl-3-m eth ylper h yd r o-
p yr im id in -4-on e, cis-8. The axial phenyl group at C(2)
eclipses the C(2)-N(3) bond in order to reduce steric
repulsion with the phenyl group at C(6). This objective

8674 J . Org. Chem., Vol. 64, No. 23, 1999
Ram´ırez-Quiro´s et al.
F igu r e 17. Schematic view of the crystal packing in (2S)-5
(see text).
F igu r e 13. (a) Structure and solid-state conformation of
1-benzoyl-(2S)-tert-butyl-(6S)-methoxyperhydropyrimidin-4-
one, (2S,6S)-11. (b) Structure and solid-state conformation of
1-benzoyl-(2R)-tert-butyl-3,(6R)-dimethylperhydropyrimidin-4-
one, (2R,6R)-12. (This figure corresponds to the enantiomeric
structure, to facilitate the analysis).
assignment of ring conformation from the determination
of coupling constants between vicinal hydrogens. In the
case of compounds 1-20, measurement of J H(5)H(6) is
complicated by the manifestation of dynamic phenomena
that give rise to broad spectra. Nevertheless, good
agreement was found between the experimentally mea-
1
sured (solution H NMR spectroscopy) and calculated (by
means of Altona’s algorithm,20 using the solid-state
structural data) J ’s for rac-3 (Table 3, Supporting Infor-
mation). By contrast, in the case of (2S)-4, comparison
between the computed coupling constants and those
extracted from the 1H NMR spectra is obliterated by
conformational averaging owing to small energy differ-
ences among two or more ring conformers.
In this regard, a stochastic conformational search21
with Allinger’s MM3(94) program22 afforded three con-
formations of minimum energy for compound 2. (Figure
16, Supporting Information). Energy differences between
these conformations are very small (∆E ) 0.3-0.6 kcal/
mol), supporting the X-ray crystallographic evidence for
a highly flexible perhydropyrimidinone ring that adjusts
itself easily to the requirements of the substituents.
Finally, there is the question of potential hydrogen
bonding in (2S)-5, (2S,6S)-9, (2S,6S)-10, and (2S,6S)-11.
In particular, one wonders what role might intermolecu-
lar hydrogen bonding/crystal packing play in the confor-
mation of these compounds.
F igu r e 14. Structure and solid-state conformation (schematic
view) of 1-benzoyl-(2S)-isopropyl-3,(5R)-dimethylperhydro-
pyrimidin-4-one, (2S,5R)-13.
Analysis of the unit cell composition in the crystal
structure of (2S)-5 reveals the existence of an intermo-
lecular hydrogen bonding between N(3)-H and the
benzoyl carbonyl of an adjacent molecule (r ) 2.14 Å).
Two additional intermolecular interactions were ob-
served, between the para-hydrogen on the benzoyl ring
and the endocyclic carbonyl of an adjacent molecule (r )
2.48 Å) and between C(6)-Hax and the endocyclic carbo-
nyl of a vicinal molecule (r ) 2.37 Å). As a consequence
of these interactions, each pyrimidinone molecule is
hydrogen bonded to six adjacent molecules (Figure 17).
The X-ray crystallographic structure of (2S,6S)-9 also
provides evidence for strong hydrogen bonding between
N(3)-H and the benzoyl carbonyl of an adjacent molecule
(r ) 2.20 Å). Surprisingly, the methoxy oxygen seems to
interact with an isopropyl hydrogen of a vicinal molecule,
as the H- - -O distance is only 2.53 Å (Figure 18, Sup-
porting Information).
F igu r e 15. (a) Structure and solid-state conformation of rac-
1-benzoyl-r-2-tert-butyl-3,trans-5,cis-6-trimethylperhydropyri-
midin-4-one, (r2-t5,c6)-18. (b) Structure and solid-state con-
formation of rac-1-benzoyl-r-2-tert-butyl-3,cis-6-dimethyl-trans-
5-benzylperhydropyrimidin-4-one, (r2-t5,c6)-19. (c) Structure
and solid-state conformation of rac-1-benzoyl-r-2-phenyl-
3,trans-5-dimethyl-cis-6-phenylperhydropyrimidin-4-one, (r2-
t5,c6)-20.
to occupy an equatorial orientation. The isopropyl group
at C(2) is axial and staggered with all three remaining
bonds at C(2). The C-H bond at the isopropyl group
points inside the six-membered ring. (Figure 14).
r a c-r -2-ter t-Bu tyl-tr a n s-5,cis-6-tr isu bstitu ted De-
r iva tives, 18-20. Intermediate conformations between
boat and twist-boat were encountered in these hetero-
cycles, which seem plausible since now both the substit-
uents at C(5) and C(6) are equatorially oriented (Figure
15).
(2S,6S)-10 presents two types of intermolecular hy-
drogen bonding, (1) between N(3)-H and the carboxy
carbonyl (r ) 2.06 Å) and (2) between the carboxylic
(20) (a) Cerda-Garc´ıa-Rojas, C. M.; Zepeda, L. G.; J oseph-Nathan,
P. Tetrahedron Comput. Methodol. 1990, 3, 113-118. (b) Haasnoot,
C. A. G.; M. de Leeuw, F. A. A.; Altona, C. Tetrahedron 1980, 36, 2783-
2792.
(21) Saunders, M. J . Am. Chem. Soc. 1987, 109, 3150-3152.
(22) Allinger, N. L.; Yuh, Y. H.; Lii, J .-H. J . Am. Chem. Soc. 1989,
111, 8551-8566.
One wonders, of course, what happens in solution. In
1
principle, H NMR spectroscopic analysis should allow

Substituted Perhydropyrimidinones
J . Org. Chem., Vol. 64, No. 23, 1999 8675
TLC: F254 silica gel plates; detection by UV light or iodine
vapor. Flash column chromatography:25 silica gel (230-400
mesh). Melting points: not corrected. 1H NMR spectra: 60,
270, and 400 MHz spectrometers. 13C NMR: 22.5, 67.8, and
100 MHz spectrometers. Chemical shifts (δ) in ppm downfield
from internal TMS reference; the coupling constants (J ) are
given in Hz. Optical rotations were measured in a polarimeter,
using the sodium D-line (589 nm). Mass spectra: 70 eV.
Elemental analyses were performed by Galbraith Laboratories,
Inc., Knoxville, TN.
Syn th eses. The syntheses of 1-benzoyl-(2S)-tert-butyl-3-
methyl-perhydropyrimidin-4-one, (2S)-1,8b 1-benzoyl-(2S)-tert-
butyl-(6S)-carboxyperhydropyrimidin-4-one, (2S,6S)-10,8b 1-ben-
zoyl-(2S)-tert-butyl-3-methyl-(5R)-benzylperhydropyrimidin-4-
one, (2S,5R)-14,8b 1-benzoyl-(2S)-tert-butyl-3,(6R)-dimeth-
ylperhydropyrimidin-4-one, (2S,6R)-6,26 1-benzoyl-(2R)-tert-
butyl-3,(6R)-dimethylperhydropyrimidin-4-one, (2R,6R)-12,26
rac-1-benzoyl-r-2-tert-butyl-3,trans-5,cis-6-trimethylperhydro-
pyrimidin-4-one, (r2-t5,c6)-18,26 rac-1-benzoyl-r-2-tert-butyl-
3,cis-6-dimethyl-trans-5-benzylperhydropyrimidin-4-one, (r2-
t5,c6)-19,26 1-benzoyl-(2S)-isopropyl-(6S)-carbomethoxyperhydro-
pyrimidin-4-one, (2S,6S)-9,26 1-benzoyl-(2S)-tert-butyl-3,(5R)-
dimethyl-5-benzylperhydropyrimidin-4-one, (2S,5R)-16,8c and
1-benzoyl-(2S)-tert-butyl-3,(5R)-dimethyl-5-n-butylperhydro-
pyrimidin-4-one, (2S,5R)-17,8c have been described in the
literature.
F igu r e 19. Schematic view of the crystal packing in (2S,6S)-
10 (see text).
group OH and the endocyclic carbonyl of an adjacent
molecule (r ) 1.77 Å). Thus, each molecule binds to two
additional molecules in the unit cell, giving rise to chains
that are bonded themselves through H(6) and C(4)-O
(Figure 19).
Analysis of the crystal packing in (2S,6S)-11 reveals
intermolecular hydrogen bonding between N(3)-H and
the endocyclic carbonyl of an adjacent molecule (r ) 2.07
Å), giving rise to an infinite chain. A weaker inter-
molecular interaction exists between the same endocyclic
carbonyl and C(5)-Heq of a vicinal molecule (r ) 2.55 Å)
(Figure 20, Supporting Information).
3-(Meth ylid en ea m in o)-N-m eth ylp r op ion a m id e, 22:
Con clu sion s
Methyl 3-aminopropionamide hydrochloride8a (21, 9.5 g, 69
mmol) and 19.0 mL (137 mmol) of triethylamine in 50 mL of
CH2Cl2 were placed in a round-bottom flask provided with a
magnetic stirrer and treated dropwise with 6.12 g (204 mmol)
of paraformaldehyde. The reaction mixture was heated to
reflux for 4 h, with an inverse Dean-Stark trap being used to
collect the water that was generated. The triethylamine
hydrochloride was removed by filtration, and the filtrate was
concentrated to afford 5.56 g (71.7% yield) of the desired imine
as a pale-yellow oil: 1H NMR (60 MHz, CDCl3) δ 2.40 (t, J )
5.8 Hz, 2H), 2.90 (s, 3H), 2.75-3.25 (m, 2H), 4.10 (br s, 2H).
1-Ben zoyl-3-m eth ylp er h yd r op yr im id in -4-on e, 2:
Precise conformational analysis of 20 substituted per-
hydropyrimidinones was carried out by X-ray crystal
structure determination and quantitative examination of
the atomic coordinates by means of the CP and ZPD
computer programs. Both methods provide convincing
evidence that the perhydropyrimidin-4-one ring confor-
mation proved extremely sensitive to substitution. The
parent, unsubstituted system 2 adopts a half-chair
conformation, which is maintained in strain-free deriva-
tives 5 and 14, where A1,3 strain forces the C(2) substitu-
ent to occupy the axial orientation. Nevertheless, intro-
duction of a syn group at C(5) as in 16 and 17 causes
sufficient steric repulsion to compel the ring to choose
an envelope conformation. On the other hand, the steric
strain provoked upon incorporation of syn substituents
at C(6) is relieved in the boat conformations exhibited
by 6-10. In this regard, derivative 11 presents a methoxy
group anti (rather than syn) to the C(2) tert-butyl. The
boat ring conformation here allows for nN f σ*C-O
stabilizing hyperconjugation and minimizes A1,3 allylic-
type strain between the methoxy and N(1)-benzoyl
groups. Twist-boat conformations are preferred by 4,
where removal of the N(3) methyl eliminates strain with
the axial isopropyl group at C(2), and by 18-20, where
the twist-boat form allows for the diequatorial disposition
of both C(5) and C(6) substituents.
3-(Methylideneamino)-N-methylpropionamide (22, 5.0 g, 43
mmol) in 150 mL of dry benzene was treated with 4.72 g (38
mmol) of DMAP and 5.5 mL (47 mmol) of benzoyl chloride
(dropwise addition) and heated to reflux for 4 h. The precipi-
tate that formed at this stage was removed by filtration, and
the filtrate was concentrated on a rotary evaporator. The
residue was separated by flash chromatography (hexanes-
ethyl acetate, 70:30 f 10:90) to afford 7.4 g (81.5% yield) of 2
as a viscous colorless oil, which was slowly crystallized from
hexanes-ethyl acetate (9:1), mp 72.5-73.5 °C: 1H NMR (400
MHz, DMSO-d6, 100 °C) δ 2.43 (t, J ) 6.6 Hz, 2H), 2.81 (s,
Exp er im en ta l Section
(23) Brown, H. C.; Kramer, G. W.; Levy A. B.; Midland, M. M.
Organic Synthesis via Boranes; Wiley: New York, 1975; p 256.
(24) J uaristi, E.; Mart´ınez-Richa, A.; Garc´ıa-Rivera, A.; Cruz-
Sa´nchez, J . S. J . Org. Chem. 1983, 48, 2603-2606.
(25) Still, W. C.; Kahn, M.; Mitra, A. J . Org. Chem. 1978, 43, 2923-
2925.
Gen er a l Meth od s. Flasks, stirring bars, and hypodermic
needles used for the generation and reactions of organolithi-
ums were dried for about 12 h at 120 °C. Anhydrous THF was
obtained by distillation from benzophenone ketyl.23 The n-
butyllithium employed was titrated according to the method
of J uaristi et al.24 (4-biphenylmethanol indicator).
(26) J uaristi, E.; Escalante, J .; Lamatsch, B.; Seebach, D. J . Org.
Chem. 1992, 57, 2396-2398.

8676 J . Org. Chem., Vol. 64, No. 23, 1999
Ram´ırez-Quiro´s et al.
3H), 3.71 (t, J ) 6.6 Hz, 2H), 4.83 (s, 2H), 7.47 (m, 5H); 13C
NMR (100 MHz, DMSO-d6, 100 °C) δ 31.9, 32.2, 42.0, 61.1,
127.4, 128.9, 130.6, 135.6, 167.9, 169.9; MS, m/z 218 (M+), 161,
105, 98, 77, 51, 42.
Anal. Calcd for C14H16N2O2: C, 68.82; H, 6.60. Found: C,
68.59; H, 6.73.
1-Ben zoyl-(2S)-isop r op y1-3-m eth yl-2,3-d ih yd r o-4(1H)-
1,3-p yr im id in -4-on e, (2S)-26:
Anal. Calcd for C12H14N2O2: C, 66.03; H, 6.47. Found: C,
65.83; H, 6.67.
r a c-1-Ben zoyl-2-p h en yl-3-m eth ylp er h yd r op yr im id in -
4-on e, r a c-3:
In a round-bottom flask, provided with a magnetic stirrer, 3.2
g (13.1 mmol) of (S)-25 and 37 mL of dimethoxyethane (DME)
were placed. The flask was submerged in an ice-water bath
before the dropwise addition of 10 g of alumina-KF. The
resulting mixture was stirred for 1 h and then treated with
2.12 mL (34.1 mmol) of methyl iodide. The reaction mixture
was stirred at 0 °C for 2 h and 48 h more at ambient
temperature before the slow addition of 20 mL of chloroform.
The alumina was removed by filtration, and the filtrate was
concentrated on a rotary evaporator. The desired product was
purified by flash chromatography (ethyl acetate-hexane, 7:3)
and crystallized from ethyl ether-hexane to afford 2.46 g (72%
yield) of (2S)-26, mp 103-104 °C: [R]D ) +509.9 (c ) 1,
CHCl3); 1H NMR (CDCl3; 270 MHz) δ 0.98 (d, J ) 6.6 Hz, 3H),
1.08 (d, J ) 6.6 Hz, 3H), 2.48 (double of septets, J 1 ) 6.6 Hz,
J 2 ) 7.9 Hz, 1H), 3.17 (s, 3H), 5.37 (d, J ) 7.9 Hz, 1H), 5.66
Methyl 3-aminopropionamide hydrochloride8a (21, 0.5 g, 3.6
mmol) and 0.75 mL (5.4 mmol) of triethylamine in 35 mL of
CH2Cl2 were treated dropwise with 0.4 mL (3.9 mmol) of
benzaldehyde. The reaction mixture was heated to reflux for
5 h, with azeotropic removal of water. The triethylamine
hydrochloride was removed by filtration, and the filtrate was
concentrated to afford 0.7 g (100% yield) of the imine 23, which
was immediately dissolved in dry benzene and treated drop-
wise with 0.39 g (3.2 mmol) of DMAP and 0.51 g (3.6 mmol) of
benzoyl chloride. The reaction mixture was heated to reflux
for 4 h. The precipitate that formed at this stage was removed
by filtration, and the filtrate was concentrated on a rotary
evaporator. The residue was separated by flash chromatogra-
phy (hexanes-ethyl acetate, 90:10 f 10:90) to afford 0.34 g
(31.8% two step yield) of rac-3 as a white solid which was
recrystallized from CH2Cl2-hexane, mp 138-139 °C: 1H NMR
(d, J ) 7.9 Hz, 1H), 6.96 (d, J ) 7.9 Hz, 1H), 7.50 (m, 5H); 13
C
NMR (CDCl3; 22.49 MHz) δ 18.7, 19.1, 32.3, 35.9, 74.8, 106.3,
128.1, 128.6, 131.4, 132.8, 135.9, 162.3, 168.4.
Anal. Calcd for C15H18N2O2: C, 69.74; H, 7.02. Found: C,
70.04; H, 7.33.
1-Ben zoyl-(2S)-isop r op yl-3-m eth ylp er h yd r op yr im id in -
4-on e, (2S)-4:
(270 MHz, 60 °C, CDCl3) δ 2.39 (ddd, J gem ) 17.6 Hz, J gauche
5.4 Hz, J gauche ) 2.2 Hz, 1H), 2.59 (ddd, J gem ) 17.6 Hz, J anti
11.1 Hz, J gauche ) 7. 7 Hz, 1H), 2.96 (s, 3H), 3.21 (ddd, J gem
)
)
)
13.9 Hz, J anti ) 11.1 Hz, J gauche ) 5.4 Hz, 1H), 3.75 (br s, 1H),
6.82 (br s, 1H), 7.36-7.42 (m, 10H); 13C NMR (270 MHz, 60
°C, CDCl3) δ 31.8, 33.4, 38.6, 70.0, 126.6, 126.8, 128.7, 129.0,
129.1, 130.4, 134.8, 137.2, 167.7, 170.0.
1-Ben zoyl-(2S)-isop r op y1-2,3-d ih yd r o-4(1H )-1,3-p yr i-
m id in -4-on e, (2S)-25:
Heterocycle (2S)-26 (1.0 g, 3.9 mmol), 10 mL of methanol, and
0.1 g of 5% Pd(C) were placed in a hydrogenation flask. The
reaction mixture was pressurized to 56 atm of hydrogen,
heated to 70 °C, and stirred for 4.5 h. The catalyst was then
removed by filtration over Celite, and the filtrate was evapo-
rated at reduced pressure. The residue was crystallized from
ethyl acetate-hexane (1:9) to give 1.0 g (100% yield) of (2S)-4
as a white solid, mp 101-102 °C. [R]D ) +21.0 (c ) 1.02;
CHCl3); 1H NMR (DMSO-d6; 130 °C; 270 MHz) δ 0.92 (d, J )
7.0 Hz, 3H), 0.99 (d, J ) 7.0 Hz, 3H), 2.32 (double of septets,
J ) 9.8 Hz, J ) 7.0 Hz, 1H), 2.48 (ddd, J ) 7.7 Hz, J ) 8.8
Hz, J gem ) 17.6 Hz, 1H), 2.70 (ddd, J ) 7.7 Hz, J ) 5.1 Hz,
J gem ) 17.6 Hz, 1H), 2.92 (s, 3H), 3.56 (ddd, J ) 7.7 Hz, J )
7.7 Hz, J gem ) 13.6 Hz, 1H), 3.84 (dddd, J ) 8.8 Hz, J ) 5.1
Hz, J ) 0.7 Hz, J gem ) 13.6 Hz, 1H), 5.12 (dc, J ) 9.8 Hz, J )
0.7 Hz, 1H), 7.35-7.49 (m, 5H); 13C NMR (DMSO-d6; 100 °C;
67.8 MHz) δ 18.2, 18.2, 29.3, 32.1, 64.5, 38.9, 73.6, 126.1, 127.9,
129.2, 135.1, 166.4, 169.1.
In a round-bottom flask provided with magnetic stirrer, 10.0
g (34.5 mmol) of 1-benzoyl-(2S)-isopropyl-(6S)-carboxyperhy-
dropyrimidin-4-one,27 (2S,6S)-24, was dissolved in 100 mL of
benzene and 60 mL of THF containing 5 mL of pyridine. The
resulting solution was treated with 0.25 g (1.2 mmol) of copper
diacetate monohydrate, and the mixture was stirred at ambi-
ent temperature for 2 h. The reaction flask was then sub-
merged in an ice-water bath before the addition of 27 g (60.9
mmol) of lead tetraacetate. The cooling bath was removed, and
the reaction mixture was heated to reflux for 12 h. The
precipitate was removed by filtration, and the filtrate was
percolated over silica gel, using ethyl acetate as solvent. The
desired product was purified by crystallization from ethyl
acetate-hexane (7:3) to afford 5.46 g (75.9% yield) of (S)-25
as a white solid, mp 155-156 °C: [R]D ) +522.5 (c ) 1, CHCl3);
1H NMR (DMSO-d6; 80 °C; 270 MHz) δ 0.88 (d, J ) 7.3 Hz,
3H), 0.96 (d, J ) 6.6 Hz, 3H), 2.21 (m, 1H), 5.13 (dd, J 1 ) 7.9
Anal. Calcd for C15H20N2O2: C, 69.20; H, 7.74. Found: C,
69.06; H, 7.49.
1-Ben zoyl-(2S)-isopr opylper h ydr opyr im idin -4-on e, (2S)-
5:
Hz, J 2 ) 1.2 Hz, 1H), 5.41 (m, 1H), 7.10 (dd, J 1 ) 7.9 Hz, J 2
)
1.3 Hz, 1H), 7.47-7.60 (m, 5H), 8.00 (br s, 1H); 13C NMR
(DMSO-d6; 80 °C; 67.8 MHz) δ 17.7, 18.3, 32.7, 68.4, 105.2,
127.8, 128.7, 131.0, 133.5, 137.1, 162.3, 168.2.
(27) J uaristi, E.; Lo´pez-Ruiz, H.; Madrigal, D.; Ram´ırez-Quiro´s, Y.;
Escalante, J . J . Org. Chem. 1998, 63, 4706-4710.
Heterocycle (2S)-25 (1.0 g, 4.2 mmol), 10 mL of methanol, and

Substituted Perhydropyrimidinones
J . Org. Chem., Vol. 64, No. 23, 1999 8677
0.1 g of 5% Pd(C) was placed in a hydrogenation flask. The
reaction mixture was pressurized to 56 atm of hydrogen,
heated to 70 °C, and stirred for 4.5 h. The catalyst was then
removed by filtration over Celite, and the filtrate was evapo-
rated at reduced pressure. The residue was crystallized from
ethyl acetate-hexane (2:8) to give 1.0 g (100% yield) of (2S)-5
as a white solid, mp 142-144 °C. [R]D ) +71.45 (c ) 1.03;
CHCl3); 1H NMR (DMSO-d6; 130 °C; 270 MHz) δ 0.88 (d, J )
6.6 Hz, 3H), 0.95 (d, J ) 6.6 Hz, 3H), 2.10 (double of septets,
J ) 6.6 Hz, J ) 8.8 Hz, 1H), 2.25 (ddd, J ) 3.6 Hz, J ) 6.6
Hz, J gem ) 16.7 Hz, 1H), 2.34 (ddd, J ) 7.3 Hz, J ) 9.4 Hz,
J gem ) 16.7 Hz, 1H), 3.43 (ddd, J ) 10.4 Hz, J ) 7.0 Hz, J gem
) 14.0 Hz, 1H), 3.86 (ddd, J ) 3.5 Hz, J ) 7.0 Hz, J gem ) 14.0
Hz, 1H), 5.06 (d, J ) 8.8 Hz, 1H), 7.35-7.47 (m, 5H), 7.78 (br
s, 1H); 13C NMR (DMSO-d6; 130 °C; 67.8 MHz) δ 18.2, 18.6,
30.8, 33.4, 37.9, 67.7, 126.5, 128.5, 129.7, 135.9, 167.8, 169.7.
Meth yl 3-Am in o-3-p h en ylp r op ion a te, r a c-27:
for 5 h, with azeotropic removal of water. Concentration of the
mixture on a rotary evaporator afforded 5.52 g (89.7% yield)
of rac-29: 1H NMR (60 MHz, CDCl3) δ 1.08 (s, 9H), 2.4-2.9
(m, 2H), 2.68 (s, 3H), 4.52 (t, J ) 7 Hz, 1H), 6.4 (br s, 1H),
7.21 (m, 5H), 7.5 (s, 1H); 13C NMR (22.49 MHz, CDCl3) δ 25.7,
26.7, 36.1, 45.3, 69.9, 126.3, 126.8, 128.3, 142.7, 171.2, 172.9.
r a c-cis- a n d r a c-tr a n s-1-Ben zoyl-2-ter t-bu tyl-3-m eth yl-
6-p h en ylp er h yd r op yr im id in -4-on e, r a c-cis-7 a n d r a c-
tr a n s-7:
3-Phenyl-3-N-(2′,2′-dimethylpropilidene)amino-N-methylpro-
pionamide (rac-29, 4.69 g, 19 mmol) and 100 mL of dry benzene
was treated with 2.08 g (17 mmol) of DMAP and 2.4 mL (20
mmol) of benzoyl chloride (dropwise addition). The reaction
mixture was heated to reflux for 4 h. The precipitate that
formed at this stage was removed by filtration, and the filtrate
was concentrated on a rotary evaporator to afford 7.5 g of the
crude product, consisting of a 95:5 mixture of cis and trans
diastereomeric heterocycles. The mixture was separated by
flash chromatography (hexanes-ethyl acetate, 90:10 f 10:90)
to afford 569 mg of rac-cis-7 and 30 mg of rac-trans-7 (a
combined yield of 9%).
3-Amino-3-phenylpropionic acid28 (5 g, 30 mmol) in 100 mL of
methanol was placed in a round-bottom flask provided with
an addition funnel and a magnetic stirrer. The solution was
cooled to 0 °C and treated dropwise with 10 mL (83 mmol) of
trimethylsilyl chloride. The reaction mixture was stirred at
ambient temperature for 12 h and concentrated in a rotary
evaporator. For the liberation of the hydrochloride the residue
was dissolved in 10 mL of distilled water and then treated
with NaHCO3 until pH 8. The aqueous phase was extracted
with five portions of 5 mL of ethyl acetate, and the combined
extracts were dried (NaCl), filtered, and evaporated to give
5.32 g (100% yield) of rac-27, mp 148-149 °C (as the
hydrochloride): 1H NMR (60 MHz, CDCl3) δ 1.75 (s, 2H), 2.62
(d, J ) 7 Hz, 2H), 3.55 (s, 3H), 4.32 (t, J ) 7 Hz, 1H), 7.25 (s,
5H).
1
rac-cis-7: mp 174-175 °C; H NMR (270 MHz, CDCl3, 60
°C) δ 1.10 (s, 9H), 2.87 (dd, J 1 ) 16.5 Hz, J 2 ) 7.3 Hz, 1H),
3.03 (dd, J 1 ) 16.5 Hz, J 2 ) 11.9 Hz, 1H), 3.16 (s, 3H), 5.31
(dd, J 1 ) 11.9 Hz, J 2 ) 7.3 Hz, 1H), 5.68 (s, 1H), 7.02-7.19
(m, 10H); 13C NMR (22.49 MHz, CDCl3) δ 28.1, 38.3, 38.8, 40.5,
56.7, 80.1, 125.6, 127.0, 128.1, 128.5, 128.7, 136.8, 141.9, 169.0,
173.7.
rac-trans-7: mp 70-71 °C; 1H NMR (60 MHz, CDCl3) δ 1.20
(s, 9H), 2.42 (dd, J 1 ) 16.5 Hz, J 2 ) 1.3 Hz, 1H), 3.25 (s, 3H),
3.41 (dd, J 1 ) 16.5 Hz, J 2 ) 7.3 Hz, 1H), 5.26 (dd, J 1 ) 7.3 Hz,
J 2 ) 1.3 Hz, 1H), 6.16 (s, 1H), 6.63-6.65 (m, 2H), 6.96-7.32
(m, 8H); 13C NMR (22.49 MHz, CDCl3) δ 28.2, 38.4, 39.7, 42.1,
59.1, 77.0, 125.0, 126.4, 127.3, 128.1, 128.8, 129.7, 136.8, 143.6,
168.2, 173.9.
N-Meth yl-3-a m in o-3-p h en ylp r op ion a m id e, r a c-28:
r a c-cis- a n d r a c-tr a n s-1-Ben zoyl-2,6-d ip h en yl-3-m eth -
ylp er h yd r op yr im id in -4-on e, r a c-cis-8 a n d r a c-tr a n s-8:
A 5 g (27 mmol) amount of methyl 3-amino-3-phenylpropi-
onate, rac-27, in 15 mL of methanol was placed in a round-
bottom flask provided with a magnetic stirrer and an addition
funnel. The solution was cooled to 0 °C and treated dropwise
with 8.4 mL (108 mmol) of aqueous 40% methylamine. The
resulting mixture was stirred at ambient temperature for 40
h and concentrated in a rotary evaporator to give 4.8 g (100%
yield) of the desired product, rac-28, as a pale-yellow oil: 1H
NMR (60 MHz, CDCl3) δ 2.20 (br s, 2H), 2.43 (d, J ) 7 Hz,
2H), 2.65 (d, J ) 5 Hz, 3H), 4.28 (t, J ) 7 Hz, 1H), 7.22 (m,
5H).
3-P h en yl-3-N-(2′,2′-d im eth ylp r op ylid en e)a m in o-N-m e-
th ylp r op ion a m id e, r a c-29:
N-Methyl-3-amino-3-phenylpropionamide (rac-28, 2.2 g, 12
mmol) and 100 mL of CH2Cl2 were placed in round-bottom
flask provided with a magnetic stirrer and treated dropwise
with 1.48 g (14 mmol) of benzaldehyde. The reaction mixture
was heated to reflux for 5 h and then treated with 1.46 g (12
mmol) of DMAP and 1.84 g (13 mmol) of benzoyl chloride. The
reaction mixture was heated to reflux for 4 h additional hours.
The precipitate that formed at this stage was removed by
filtration, and the filtrate was concentrated on a rotary
evaporator to afford 5.2 g of the crude product, consisting of a
95:5 mixture of cis and trans diastereomeric heterocycles. The
mixture was separated by flash chromatography (hexanes-
ethyl acetate, 90:10 f 10:90) to afford 1.71 g of rac-cis-8 and
N-Methyl-3-amino-3-phenylpropionamide (rac-28, 4.5 g, 25
mmol) in 50 mL of CH2Cl2 was placed in a round-bottom flask
provided with an addition funnel and a magnetic stirrer. The
resulting solution was treated dropwise with 5.4 mL (50 mmol)
of pivalaldehyde, and the reaction mixture was heated to reflux
(28) Rault, S.; Dallemagne, P.; Robba, M. Bull Soc. Chim. Fr. 1987,
6, 1079.

8678 J . Org. Chem., Vol. 64, No. 23, 1999
Ram´ırez-Quiro´s et al.
0.09 g of rac-trans-8. (A combined yield of 41.3%.) Both
heterocycles were recrystallized from CH2Cl2-hexane.
rac-cis-8: mp 165-166 °C; 1H NMR (400 MHz, CDCl3) δ
2.12 (dd, J gem ) 15.7 Hz, J gauche ) 5.9 Hz, 1H), 2.75 (dd, J gem
) 15.7 Hz, J anti ) 11.0 Hz, 1H), 3.21 (s, 3H), 5.20 (br s, 1H),
6.53 (br s, 1H), 6.95-7.39 (m, 15H); 13C NMR (400 MHz,
CDCl3) δ 34.22, 39.13, 58.19, 71.26, 125.92, 126.36, 126.53,
127.26, 128.30, 128.47, 128.67, 129.16, 129.47, 135.94, 138.15,
140.52, 169.30, 172.48.
rac-trans-8: mp 166-167 °C; 1H NMR (270 MHz, CDCl3) δ
2.42 (dd, J gem ) 15.6 Hz, J gauche ) 1.9 Hz, 1H), 2.93 (dd, J gem
) 15.6 Hz, J anti ) 6.9 Hz, 1H), 3.34 (s, 3H), 5.24 (d, J anti ) 6.7
Hz, 1H), 6.86 (br s, 1H), 7.13-7.41 (m, 15H); 13C NMR (270
MHz, CDCl3) δ 34.90, 39.37, 57.67, 71.38, 125.37, 126.19,
127.65, 128.35, 128.66, 128.89, 129.42, 135.97, 139.47, 142.25,
168.68, 171.94.
A solution of diisopropylamine (0.31 mL, 2.2 mmol) in 20 mL
of anhydrous THF was cooled to -78 °C before the slow
addition of 1.2 mL (2.25 mmol) of n-BuLi in hexane (1.88 M).
The resulting solution was stirred at -78 °C for 30 min and
then treated with 0.55 g (2 mmol) of pyrimidinone rac-1 in 20
mL of THF. The solution formed was stirred at -78 °C for 1
h before the addition of 0.31 mL (3 mmol) of benzaldehyde.
The reaction mixture was stirred at this temperature for 4 h.
The mixture was then treated with 2 mL of saturated am-
monium chloride solution. The aqueous phase was extracted
with two 50 mL portions of CH2Cl2. The combined extracts
were washed with a saturated solution of NaHCO3 and then
with water, dried (Na2SO4), filtered, and evaporated to give
the crude product, which was purified by flash chromatography
(hexanes-ethyl acetate, 6:4) to afford 0.572 g (75% combined
yield) of three stereoisomeric products, in a 58.7:33.9:7.4 ratio.
These compounds were separated by flash chromatography
and crystallized from hexanes-ethyl acetate.
1-Ben zoyl-(2S)-ter t-bu tyl-(6S)-m eth oxyp er h yd r op yr i-
m id in -4-on e, (2S,6S)-11. In a glass cell for electrolysis were
placed 82 mL of a solution 0.1 M of (2S,6S)-10 (2.5 g, 8.2 mmol)
in methanol. The anode was placed in a rotor with a disk of
platinum (area 4.25 cm2) and the cathode in a grill of platinum,
separated by 5 mm. The electrode was rotated at 2000 rpm
while the temperature of the reaction mixture was maintained
between 15 and 20 °C, and a voltage of 7 V was applied while
0.5 mL of triethylamine was added dropwise, producing a
current of 350 mA, equivalent to a current density of 82 mA/
cm2. The reaction was followed by TLC until complete con-
sumption of the starting material (5 h) and then concentrated
in a rotary evaporator. The residue was dissolved in 50 mL of
CH2Cl2, and washed with a solution of Na2CO3 and finally with
water. The organic phase was dried (Na2SO4) and evaporated
to afford the crude product, consisting of a mixture of ethers
trans:cis, 3.5:1. The ether (2S,6S)-11 was isolated by flash
chromatography (hexanes-ethyl acetate, 90:10 f 10:90) and
crystallized from hexanes-ethyl acetate, mp 233-234 °C: [R]D
) -96.0° (c ) 1, CHCl3); 1H NMR (CDCl3; 270 MHz) δ 1.03 (s,
9H), 2.56 (dt, J 1 ) 16.5 Hz, J 2 ) 2.3 Hz, 1H), 2.74 (s, 3H),
2.90 (dd, J 1 ) 16.5 Hz, J 2 ) 3.3 Hz, 1H), 5.10 (dd, J 1 ) 3.3 Hz,
J 2 ) 2.3 Hz, 1H), 5.78 (d, J ) 4.6 Hz, 1H), 7.41-7.56 (m, 5H),
7.66 (br s, 1H); 13C NMR (CDCl3, 67.8 MHz) δ 26.3, 34.1, 41.1,
54.9, 69.1, 86.0, 127.1, 128.5, 130.2, 136.1, 168.9, 174.9.
1
15a : mp 180-181 °C; H NMR (CDCl3; 270 MHz, 50 °C) δ
1.09 (s, 9H), 2.87 (m, 1H), 3.18 (s, 3H), 3.34 (m, 1H), 3.53 (br
s, 1H), 4.61 (br s, 1H), 5.80 (br s, 1H), 5.86 (m, 1H), 6.9-7.5
(m, 10H); 13C NMR (CDCl3, 67.8 MHz) δ 27.9, 37.7, 37.9, 39.3,
44.5, 74.2, 74.8, 126.9, 127.1, 127.9, 128.2, 128.5, 130.3, 134.6,
140.2, 170.5, 171.3.
Anal. Calcd for C23H28N2O3: C, 72.60; H, 7.42; N, 7.36.
Found: C, 72.54; H, 7.45; N, 7.35.
15b: mp 190-191 °C; 1H NMR (CDCl3, 270 MHz) δ 1.09 (s,
9H), 2.60 (m, 1H), 3.12 (s, 3H), 3.36 (m, J 1 ) 13.9 Hz, J 2 ) 8.6
Hz, 1H), 3.87 (m, J 1 ) 13.9 Hz, 1H), 4.31 (br s, 1H), 5.54 (m,
1H), 5.85 (br s, 1H), 6.81 (m, 2H), 7.10 (m, 3H), 7.39 (m, 5H);
13C NMR (CDCl3, 67.8 MHz) δ 27.9, 38.1, 38.9, 42.0, 46.3, 73.3,
73.6, 125.4, 126.6, 127.6, 127.9, 128.1, 129.7, 135.5, 141.8,
169.9, 171.1.
Anal. Calcd for C16H22N2O3: C, 66.18; H, 7.64. Found: C,
66.08, H, 7.58.
1-Be n zoyl-(2S)-isop r op yl-3,(5R)-d im e t h ylp e r h yd r o-
p yr im id in -4-on e, (2S,5R)-13. A solution of diisopropylamine
(0.4 mL, 2.9 mmol) in 10 mL of anhydrous THF was cooled to
-78 °C before the slow addition of 1.26 mL (2.9 mmol) of
n-BuLi in hexane (2.3 M). The resulting solution was stirred
at -78 °C for 20 min and then treated with 0.759 g (2.9 mmol)
of pyrimidinone (S)-4 in 50 mL of THF. The solution formed
was stirred at -78 °C for 30 min before the addition of 0.18
mL (2.9 mmol) of methyl iodide. The reaction mixture was
stirred at this temperature for 4 h and then treated with 3
mL of saturated ammonium chloride solution. The solvent was
evaporated before the addition of 5 mL of water, and the
aqueous phase was extracted with three 20-mL portions of
CH2Cl2. The combined extracts were dried (Na2SO4), filtered,
and evaporated to give the crude product. Purification of the
crude product by flash chromatography (ethyl acetate-hexane,
7:3) afforded 0.601 g (82% yield) of (2S,5R)-13, mp 152-153
Anal. Calcd for C23H28N2O3: C, 72.60; H, 7.42; N, 7.36.
Found: C, 72.75; H, 7.43; N, 7.39.
15c: mp 214-215 °C; 1H NMR (CDCl3, 270 MHz) δ 1.00 (s,
9H), 2.84 (m, 1H), 3.13 (s, 3H), 3.41 (m, 1H), 3.45 (m, 1H),
4.37 (br s, 1H), 5.28 (m, 1H), 5.77 (br s, 1H), 7.1-7.5 (m, 10H);
13C NMR (CDCl3, 67.8 MHz) δ 28.3, 37.1, 37.5, 41.4, 47.6, 71.2,
73.7, 125.7, 126.1, 127.4, 128.3, 128.6, 130.0, 134.5, 140.6,
169.8, 170.3.
r a c-1-Be n zoyl-r -2-p h e n yl-3,t r a n s-5-d im e t h yl-cis-6-
p h en ylp er h yd r op yr im id in -4-on e, (r 2-t5,c6)-20. A solution
of diisopropylamine (0.08 mL, 0.59 mmol) in 20 mL of
anhydrous THF was cooled to -78 °C before the slow addition
of 0.29 mL (0.59 mmol) of n-BuLi in hexane (2.3 M). The
resulting solution was stirred at -78 °C for 30 min and then
treated with 0.2 g (0.54 mmol) of pyrimidinone cis-8 in 15 mL
of THF. The resulting solution was stirred at -78 °C for 50
min before the addition of 0.05 mL (0.8 mmol) of methyl iodide.
The reaction mixture was stirred at this temperature for 1 h
and at ambient temperature for 5 min. The mixture was
treated with 3 mL of saturated ammonium chloride solution
and then with 7 mL of water. The aqueous phase was extracted
with five 5-mL portions of CH2Cl2. The combined extracts were
dried (Na2SO4), filtered, and evaporated to give the crude
product. Purification of the crude product by flash chroma-
tography (hexanes-ethyl acetate, 90:10 f 10:90) and crystal-
lization from CH2Cl2-hexane afforded 0.17 g (82% yield) of
(r2-t5,c6)-20, mp 195-198 °C: 1H NMR (270 MHz, CDCl3) δ
1
°C: [R] ) +10.0 (c ) 1, CHCl3); H NMR (DMSO-d6; 100 °C;
270 MHz) δ 0.94 (d, J ) 6.6 Hz, 3H), 0.98 (d, J ) 6.6 Hz, 3H),
1.01 (d, J ) 7.3 Hz, 3H), 2.38 (m, 1H) 2.74 (ddc, J ) 7.3 Hz,
1H), 2.94 (s, 3H, CH3N), 3.34 (br s, 1H), 3.79 (dd, J 1 ) 12.9
Hz, J 2 ) 7.6 Hz, 1H), 5.2 (br s, 1H), 7.42 (m, 5H); 13C NMR
(DMSO-d6; 100 °C; 67.97 MHz) δ 15.1, 18.3, 18.4, 32.4, 33.2,
34.8, 46.7 (br s), 74.2 (br s), 126.3, 128.0, 129.2, 135.3, 169.3,
169.9.
Anal. Calcd for C16H22N2O2: C, 70.03; H, 8.08. Found: C,
70.27; H, 8.05.
r a c-tr a n s-1-Ben zoyl-2-ter t-b u t yl-5-h yd r oxyb en zyl-3-
m eth ylp er h yd r op yr im id in -4-on e, tr a n s-15:

Substituted Perhydropyrimidinones
J . Org. Chem., Vol. 64, No. 23, 1999 8679
Ta ble 4. Cr ysta l Da ta for All th e Str u ctu r es
(2S)-1
2
rac-3
(2S)-4
(2S)-5
formula
MW
cryst system
space group
a (Å)
b (Å)
c (Å)
C
16H22N2O2
C12H14N2O2
218.25
monoclinic
P21/c
13.866(3)
6.493(1)
12.323(2)
90
98.19(3)
90
1098.1(3)
4
C18H18N2O2
294.34
tetragonal
P41212
9.210(1)
9.210(1)
37.021(7)
90
C15H20N2O2
260.33
orthorhombic
P212121
8.977(2)
10.907(2)
14.479(3)
90
C14H18N2O2
246.3
274.36
orthorhombic
P212121
8.267(2)
8.332(2)
22.452(4)
90
orthorhombic
P212121
6.473(1)
11.458(2)
18.147(4)
90
R (deg)
â (deg)
γ (deg)
V (Å3)
Z
90
90
90
90
90
90
90
90
1546.5(6)
4
1.18
3140.3(8)
8
1.25
1417.7(5)
4
1.22
1345.9(4)
4
1.22
Dx (g cm-3
F(000)
)
1.32
464
592
1248
560
528
unique reflcns
of which I > 4σ
final R value
1906
1647
0.044
1025
868
0.034
1936
1658
0.034
1423
726
0.038
762
677
0.032
(2S,6R)-6
rac-7
rac-8
(2S,6S)-9
(2S,6S)-10
formula
MW
cryst system
space group
a (Å)
b (Å)
c (Å)
C
17H24N2O2
C22H26N2O2
350.45
triclinic
P1h
9.250(2)
10.491(2)
11.053(2)
63.92(3)
83.50(3)
87.49(3)
957.2(3)
2
C24H22N2O2
370.44
monoclinic
P21/c
10.725(2)
18.053(4)
10.219(2)
90
93.28(3)
90
1975.3(7)
4
C16H20N2O4
304.34
orthorhombic
P212121
7.722(2)
11.332(2)
17.745(4)
90
C16H20N2O4
304.35
orthorhombic
P212121
7.548(2)
10.197(2)
20.573(5)
90
288.38
monoclinic
P21
7.375(1)
8.663(2)
12.807(3)
90
90.36(3)
90
818.3(3)
2
R (deg)
â (deg)
γ (deg)
V (Å3)
Z
90
90
90
90
1552.8(6)
4
1.30
1583.6(6)
4
1.28
Dx (g cm-3
F(000)
)
1.17
312
1.22
376
1.25
784
648
648
unique reflecns
of which I > 4σ
final R value
1551
929
0.048
3351
1740
0.043
2800
2108
0.035
1585
860
0.035
1886
1586 (>1σ)
0.037
(2S,6S)-11
(2S,6S)-12
(2S,5R)-13
(2S,5R)-14
rac-15
formula
MW
cryst system
space group
a (Å)
b (Å)
c (Å)
C16H22N2O3
290.37
orthorhombic
P212121
6.582(1)
7.796(1)
30.965(5)
90
C17H24N2O2
288.38
monoclinic
P21
11.458(1)
5.965(1)
12.161(2)
90
104.60(1)
90
804.3(2)
2
C16H22N2O2
274.36
orthorhombic
P212121
8.755(2)
10.799(2)
15.699(3)
90
C23H28N2O2
364.47
orthorhombic
P212121
10.531(2)
11.700(2)
17.020(3)
90
C22H28N2O3
380.49
monoclinic
P21/c
10.278(2)
18.381(2)
11.526(2)
90
100.86(1)
90
2138.5(6)
4
R (deg)
â (deg)
γ (deg)
V (Å3)
Z
90
90
90
90
90
90
1589.0(3)
4
1.21
1484.3(5)
4
1.23
2097.1(7)
4
1.15
Dx (g cm-3
F(000)
)
1.19
312
1.18
816
624
592
784
unique reflecns
of which I > 4σ
final R value
2786
2095 (>1σ)
0.047
3511
2188
0.048
1520
772
0.039
2847
1891
0.045
3749
2766 (>1σ)
0.052
(2S,5R)-16
(2S,5R)-17
rac-18a
rac-19a
rac-20
formula
MW
cryst system
space group
a (Å)
b (Å)
c (Å)
C
24H30N2O2
C21H32N2O2
344.49
monoclinic
P21
8.873(2)
10.616(2)
11.269(2)
90
108.39(2)
90
1007.3(3)
2
C16H26N2O2
302.42
orthorhombic
Pbca
20.712
15.076
10.807
90
90
90
3374.53
8
1.19
C24H30N2O2
378.51
monoclinic
P21/c
8.311(2)
22.648(2)
11.782(3)
90
105.48(1)
90
2137.2(8)
4
C25H24N2O2
384.46
tetragonal
P43
13.497(2)
13.497(2)
11.423(2)
90
378.5
monoclinic
P21
6.084(1)
11.535(2)
15.297(3)
90
91.92(3)
90
1072.9(3)
2
R (deg)
â (deg)
γ (deg)
V (Å3)
Z
90
90
2080.9(6)
4
1.23
Dx (g cm-3
F(000)
)
1.17
408
1.14
376
1.18
816
1312
816
unique reflecns
of which I > 4σ
final R value
1987
1623
0.040
2475
1337
0.043
4894
1814 (>3σ)
0.049
3146
1978
0.052
1981
1802
0.027
a
The crystallographic data for compounds 18 and 19 were obtained from the Cambridge Structural Database34 (compounds J OPZET
and J OPZIX, respectively9a).

8680 J . Org. Chem., Vol. 64, No. 23, 1999
Ram´ırez-Quiro´s et al.
0.82 (d, J ) 6.18 Hz, 3H), 2.68 (m, 1H), 3.24 (s, 3H), 4.65 (br
s, 1H), 6.36 (br s, 1H), 6.90-7.89 (m, 15H); 13C NMR (270 MHz,
CDCl3) δ 12.61, 34.80, 40.51, 65.25, 70.86, 125.91, 126.48,
127.29, 127.78, 128.13, 128.32, 128.49, 128.81, 129.74, 136.32,
138.49, 140.20, 171.82, 172.54.
X-r a y An a lysis. The crystallographic data for compounds
1-17 and 20 were collected on Enraf-Nonius-CAD4 diffrac-
tometers (in all cases Mo KR radiation, λ ) 0.710 69 Å,
graphite monochromator). Data reduction for compounds 1-9,
12-14, 16, 17, and 20 was achieved with J ANA98.29 The
structures were solved by direct methods using the programs
SHELXS-9730 for compounds 1-9, 12-14, 16, 17, and 20,
MULTAN8031 for compound 15, and MULTAN 11/8232 for
compounds 10 and 11 and refined using SHELXL-9730 and
MoLEN.33 Space groups, cell constants, number of reflections
measured, and final R values are collected in Table 4. If not
mentioned otherwise, refinement was achieved using reflec-
tions with intensity I > 4 σ(I), where the non-H-atoms were
refined anisotropically and H-atoms isotropically.
Ack n ow led gm en t. We are most grateful to Profes-
sors E. L. Eliel (UNCsChapel Hill), D. Seebach (ETH-
Zurich), and D. Cremer (Goeteborg University) for
useful comments. We are indebted to the CONACYT
(Grant L-0006E) and to the Commission of the Euro-
pean Communities (Contract No. CI1*.0558 ME-J R) for
financial support.
Su p p or tin g In for m a tion Ava ila ble: Distribution of crys-
tallographic structures containing the 4-cyclohexenone ring in
three component diagrams of the conformational space, com-
parison of experimental and calculated coupling constants of
3 and 4, conformations of minimum energy for compound 2
found by a stochastic search, crystal packing figures for 9 and
11, comparison between racemic and enantiopure structures
for 1 and 14, tables of crystal data, structure solution and
refinement, atomic coordinates, bond lengths, bond and torsion
angles, and anisotropic thermal parameters, and ORTEP
figures for 1-17 and 20 (108 pages). This material is available
free of charge via the Internet at http://pubs.acs.org.
(29) Vaclav, P. J ANA98, A Program for Solved Structures, Praha,
1998.
(30) Sheldrick, G. M. SHELX97, Programs for Crystal Structure
Analysis, release 97-2; Institute for Inorganic Chemistry der Univer-
sita¨t: Tommanstrasse 4, D-3400 Go¨ttingen, Germany, 1998.
(31) Main, P.; Fiske, S. J .; Hull, S. E.; Lessinger, L.; Germain, G.;
DeClerq, J . P.; Woolfson, M. M. MULTAN80, A System of Computer
Programs for the Automatic Solution of Crystal Structures from X-ray
Diffraction Data; University of York: York, England, 1980.
(32) Main, P.; Fiske, S. J .; Hull, S. E.; Lessinger, L.; Germain, G.;
DeClerq, J . P.; Woolfson, M. M. MULTAN 11/ 82, A System of
Computer Programs for the Automatic Solution of Crystal Structures
from X-ray Diffraction Data; University of York: York, England, 1982.
(33) MoLEN, An Interactive Structure Solution Procedure; Enraf-
Nonius: Delft, The Netherlands, 1990.
J O991297Q
(34) Cambridge Crystallographic Data Centre, Cambridge Struc-
tural Database System (CSD), 12 Union Road, Cambridge CB2 1EZ,
England, April 1997.