Crystal structures - A manifesto for the superiority of the valine-derived 5,5-diphenyloxazolidinone as an auxiliary in enantioselective organic synthesis

Article abstract of DOI:10.1002/1522-2675(200206)85:6<1546::AID-HLCA1546>3.0.CO;2-2

The crystal structures of 32 derivatives of 4-isopropyl-5,5-diphenyl-1,3-oxazolidin-2-one (A and 1-31) are presented (Fig. 2 and Tables 1-3). In all but four structures, the Me₂CH group is in a disposition that mimick a Me3C group (Figs. 3-5).

Full text of DOI:10.1002/1522-2675(200206)85:6<1546::AID-HLCA1546>3.0.CO;2-2

1546
Helvetica Chimica Acta Vol. 85 (2002)
Crystal Structures A Manifesto for the Superiority of the Valine-Derived
5,5-Diphenyloxazolidinone as an Auxiliary in Enantioselective Organic
Synthesis
by Christoph Gaul1), Bernd W. Schweizer, Paul Seiler, and Dieter Seebach*
Laboratorium f¸r Organische Chemie der Eidgenˆssischen Technischen Hochschule, Departement Chemie,
ETH-Hˆnggerberg, Wolfgang-Pauli-Strasse 10, CH-8093 Z¸rich
Dedicated to Professor David Evans on the occasion of his 60th birthday
The crystal structures of 32 derivatives of 4-isopropyl-5,5-diphenyl-1,3-oxazolidin-2-one (A and 1 31) are
presented (Fig. 2 and Tables 1 3). In all but four structures, the Me2CH group is in a disposition that mimick a
Me3C group (Figs. 3 5). The five-membered ring shows conformations from an envelope form with the Ph2C
group out of the plane containing the other four atoms to the twist form with the twofold axis through the CˆO
group (Fig. 6, and Table 2). In the entire series, the Me2CH and the neighboring trans Ph group are
approximately antiperiplanar (average torsion angle 1558). The structural features are used to interpret the
previously observed reactivity behavior of the diphenyl-oxazolidinone derivatives. The practical advantages of
the title compound over classical Evans auxiliaries are outlined (Figs. 1 and 7, and Scheme 2): high crystallinity
of all derivatives, steric protection of the CˆO group in the ring, excellent stereoselectivities in reactions of its
derivatives, and safe preparation and easy recovery of the auxiliary.
The use of covalently attached chiral auxiliaries for overall enantioselective and,
less frequently, diastereoselective2) transformations is of enormous importance in
organic synthesis, as demonstrated by a recent compendium consisting of three volumes
and containing 2700 references and 13000 entries [1]. In the era of catalytic
enantioselective reactions [2] cf. the 2001 Nobel prize in chemistry such a statement
seems questionable, but every practitioner in a research laboratory or in a
pharmaceutical early-development division will agree that it is more convenient to
take an auxiliary approach than to use a sometimes capricious catalytic reaction3) to
quickly prepare a sample of an enantiomerically pure compound. The principle of
auxiliary-based enantioselective transformations is simple (Scheme 1), and the proper-
ties of an ideal chiral auxiliary have been defined many times: inexpensive, of low
molecular weight, available in both enantiomeric forms, easy to introduce, efficient in
generating diastereotopic-face or -group bias, and easy to remove and to recover4).
1
)
)
Part of the Ph.D. Thesis of C. G., Dissertation No. 14516, ETH-Z¸rich, 2002.
If the auxiliary group is −dictating× the stereochemical course of reaction with a chiral enantiomerically pure
reactant, either one of two diastereoisomeric products may be obtained after removal of the corresponding
auxiliary.
Many of the most attractive catalytic methods require carefully controlled reaction conditions (e.g., inert
atmospheres, high pressures) and skilled and experienced experimentalists; catalytic methods are usually
much more effective on large scale, after sometimes laborious optimization.
Some of us would add that the ideal auxiliary should also be C2-symmetrical [3].
2
3
4
)
)

Helvetica Chimica Acta Vol. 85 (2002)
1547
Scheme 1. The Principle of Overall Enantioselective Transformations with the Help of Chiral Auxiliaries
Temporarily Attached through Covalent Bonds. In so-called −reagent-controlled× reactions, the chiral auxiliary
may also be used for overall diastereoselective processes involving chiral starting materials.
Achiral
Starting
Material
– XY
attachment by
covalent bond
Chiral
Chiral
*
X
Y
*
Auxiliary
Auxiliary
diastereoselective
reaction with generation
of new chirality element(s)
purification and
cleavage with
recovery of auxiliary
Enantiomeri-
cally Pure
Chiral Product
Chiral
*
R
Z
R
*
*
Auxiliary
Among the most important auxiliary groups are the chiral oxazolidinones (Evans
auxiliaries; Fig. 1, top)5), N-acyl and N-enoyl derivatives of which are widely used for
overall enantioselective enolate alkylations, aldol additions, Michael additions, and
Diels-Alder reactions, considering the synthetic equivalence of the carboxylic acid-
functional group with the aldehyde-, the primary-alcohol-, and thus the XÀCH2-
alkylating-functional group, the central role of this methodology in organic synthesis
can hardly be overestimated.
Guided by our experience with the TADDOL system [7], where we had learned
that the diarylmethanol moiety with its two geminal aryl groups greatly favors ring
formation6)7) and also increases ring stability, we have prepared [9][10]8) 4-isopropyl-
5,5-diphenyl-1,3-oxazolidin-2-one A (Fig. 1, bottom), and tested it as a chiral auxiliary
[10 18]. The compound had been described before [19 21] (both enantiomeric forms
are offered commercially as DIOZ by a Japanese company)9)10), but its virtues have
5
)
For review articles, see [4], and for early recognition of the advantages of S-containing analogs of the N-
acyl-oxazolidinones, see the discussion in [5]. For references to the seminal contributions by Meyers in the
use of chiral heterocycles for synthetic transformations, see [1][6].
6
)
See the discussions in Sect. 11 of a review article on TADDOLs [7b] and references 103 and 104 to the
Thorpe-Ingold or geminal-dimethyl effect in Sect. 4 (structures of TADDOLs) and 11 (auxiliaries and
catalyst ligands containing (Arl)2CÀO moieties), therein.
7
8
)
)
The use of geminal-dimethyl-substituted oxazolidinones (dubbed −SuperQuats×) has been investigated by
Davies and co-workers [8].
The preparation of A by reaction of ROÀCOÀNHÀCH(CHMe2)ÀCO2R (protected valine esters) with
phenyl Grignard reagent is practically more convenient than the preparation of the parent oxazolidinone
(with CH2 instead of CPh2), requiring hydride reagents, which can be hazardous on a large scale. An
Organic Syntheses procedure has been submitted (by M. Brenner, L. La Vecchia, T. Leutert, D. Seebach) for
checking by one of the editors. A copy of the manuscript can be obtained by request from the
correspondence author of the present paper.
9
)
)
(‡)-DIOZ and (À)-DIOZ, Shiratori Pharmaceutical Co., Ltd. Japan. DIOZ is also offered by Onyx
Scientific, Ltd., UK.
10
For other diphenyl-oxazolidinones of this type, derived from phenylalanine, phenylglycine, and tert-leucine,
see, e.g., [9][10][13][17][22][23].

1548
Helvetica Chimica Acta Vol. 85 (2002)
O
O
O
NH
R
O
NH
Me
chiral oxazolidinones
(Evans auxiliaries)
*
H
Ph
H
from amino acids
by hydride reduction
from norephedrine
4
H
5
O
O
3
O
O
3
3
4
H
R
O
N
O
N
R
O
NH
H
Me
Me
H
Me
Me
Me
Me
4
H
H
2
H
1
2
2
A (DIOZ)
B
C
1
Ph groups introduced by reaction of (S)- or (R)-valine ester with commercial phenyl
Grignard reagent
geminal diphenyl substitution leads to high crystallinity of all derivatives – DIOZ itself
(m.p. 251°) precipitates from reaction mixtures, is filtered, washed, dried, and
reused
2
Ph group in cis position to the i-Pr group has a buttressing effect, fixing the
conformation around the CH–CHMe2 bond to mimic a t-Bu group's effect upon
substituents on the N-atom
3
4
nucleophile attack on the C=O group (Bürgi-Dunitz trajectory) is sterically blocked
by a Ph group on one face and by an i-Pr group on the other face of the ring plane
deprotonation on the N-atom or on groups attached to it can be achieved directly
with BuLi, due to steric protection of the C=O group, to give amine- and salt-free
solutions of Li derivatives; low temperatures are not always required
the exocyclic C=O group is much more reactive than the endocyclic one, which
5
allows for simple cleavage of N-acyl groups
Fig. 1. Chiral oxazolidinone auxiliaries and derivatives. The classical Evans auxiliaries (top) and the valine-
derived 5,5-diphenyl-substituted analog A with N-acyl (B) and N-alkyl (C) groups; (1 5) are important issues
justifying the use of the diphenyl-oxazolidinone auxiliary (sold under the name DIOZ, cf. Footnote 9), in spite
of its higher molecular weight, as compared to the parent compound (281 vs. 129). For references, see the
accompanying paragraphs.

Helvetica Chimica Acta Vol. 85 (2002)
1549
become evident only recently, as we [9 18]11) and others [24 28] have employed it in
an ever increasing number of different types of reactions12). Some of the most prominent
features of the oxazolidinone A and its derivatives B and C are listed in Fig. 1.
It is the aim of this paper i) to demonstrate the high crystallinity of products
obtained from oxazolidinone A, and ii) to show what conclusions can be drawn about
the reactivity of its derivatives from crystal structures. The great tendency of these
compounds to crystallize is useful for their purification by recrystallization, so that the
minor diastereoisomeric products and other impurities can be removed without having
to resort to chromatographic methods. The auxiliary itself is essentially insoluble in all
common solvents (see crystal-packing pattern of A in Fig. 2); it precipitates upon
removal from the desired enantiomerically pure products.
Fig. 2. Crystal-packing pattern in the X-ray structure of the auxiliary A. The H-bonded chains of molecules cause
the high melting point (2518) and low solubility of A. The derivatives of A (Table 1) are soluble in common
organic solvents. On a laboratory scale, substituents on the N-atom of A are best introduced by addition of BuLi
at 08 to a slurry of A in THF, producing a colorless solution, which is combined with an acid chloride or
alkylating reagent. Alternatively, a mixed anhydride RÀCOÀOÀCOCMe3 is generated in situ, A is added, and
acylation with dissolution of A is mediated by LiCl at room temperature [29][30].
The crystallinity of the well-soluble products derived from A has rendered
structure determination by single-crystal X-ray diffraction, and thus configurational
11
)
)
For a short review article containing a section on the use of A, see [18].
These do not only include the transformations, in which Evans auxiliaries are usually employed [1][4], but,
e.g., also metallations with BuLi, which would not be possible without the geminal-diphenyl substitution on
the oxazolidinone ring [13 17].
12

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Helvetica Chimica Acta Vol. 85 (2002)
Table 1. Crystal Structures, Formulae, and Melting Points of A and Its Derivatives 1 31, with References to
Publications in Which the Preparation of the Compounds Has Been Described. The presentation of the structures
was produced with the program MOLMOL [31]. Color code: N: blue, O: red, S: yellow, Si: magenta, Br: green,
C and bonds: gray. Most of the structures were obtained in the course of the Ph.D. Thesis of Gaul [17]. The
ordering was chosen after the types of reactions by which the compounds have been prepared. All structures are
derived from (S)-valine. Crystal structures of 5,5-diphenyloxazolidinones with substituents other than i-Pr at
C(4) have also been published [9][10][17].

Helvetica Chimica Acta Vol. 85 (2002)
1551
Table 1 (cont.)

1552
Helvetica Chimica Acta Vol. 85 (2002)
Table 1 (cont.)

Helvetica Chimica Acta Vol. 85 (2002)
1553
Table 1 (cont.)

1554
Helvetica Chimica Acta Vol. 85 (2002)
Table 2. Geometric Deformation of the Amide Group and Puckering Coordinates of 37 Oxazolidinone
Fragments from A and Its Derivatives 1 31. Ring puckering for five-membered rings can be described with two
coordinates [36]: amplitude q shows total derivation of the ring atoms relative to its mean plane, phase f
describes kind of puckering (envelope, twist, see Fig. 6), and t is the torsion angle RÀNÀCˆO. The last two
columns show the out-of-plane distance of N- and of the carbonyl-C-atoms from their substituents
(pyramidalization).
Fragment
Compound
q [ä]
f [8]
23.64
6.85
9.32
13.32
12.05
0.58
8.31
7.37
15.98
11.11
7.14
7.69
5.94
6.53
5.01
4.51
6.89
15.65
8.29
15.45
19.47
4.43
17.46
À 1.15
0.72
17.55
16.85
8.10
17.90
21.35
16.14
17.48
20.26
15.51
13.46
17.95
18.29
t [8]
N ¥¥¥ P1 [ä]
C ¥¥¥ P2 [ä]
1
2
3
4
5
6
7
8
9
A
1
2
3
4
4
5
6
7
0.32
0.31
À 12.428
À 8.522
À 4.399
À 15.96
À 11.234
À 18.387
À 11.604
À 14.879
À 4.148
À 12.652
À 25.631
À 19.272
À 21.747
À 22.854
À 20.568
À 25.515
À 17.477
À 12.493
À 16.734
À 23.83
À 19.959
À 3.854
À 17.226
À 20.672
2.461
0.054
0.014
À 0.007
À 0.01
0.006
0.281
0.328
0.324
0.295
0.325
0.315
0.333
0.296
0.355
0.316
0.344
0.32
0.334
0.312
0.33
0.349
0.36
0.351
0.362
0.262
0.322
0.293
0.319
0.351
0.342
0.321
0.368
0.314
0.326
0.368
0.345
0.347
0.326
0.335
0.304
À 0.026
0.045
À 0.015
0.071
0.08
0.013
0.015
0.007
À 0.046
0.026
À 0.008
À 0.002
0.008
À 0.003
À 0.008
À 0.005
0.014
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
8
9
À 0.021
À 0.049
0.16
10
11
12
13
14
14
15
15
15
15
16
17
18
19
20
20
21
23
24
25
26
27
28
29
31
31
0.106
À 0.145
À 0.13
0.12
À 0.009
À 0.16
0.002
0.042
À 0.01
À 0.007
À 0.005
À 0.007
0.01
0.013
0.008
0.012
0.004
À 0.062
À 0.055
0.071
À 0.12
À 0.04
À 0.126
À 0.14
0.12
2.325
0.11
0.034
0.087
0.002
À 12.421
À 25.92
À 18.227
À 15.733
À 24.956
À 33.252
À 25.33
À 17.814
À 21.326
À 16.145
À 0.015
À 0.016
0.011
À 0.005
À 0.018
0.019
0.01
0.001
0.024
À 0.017
À 0.026
0.035
0.07
À 0.122
À 0.096
0.069
À 0.043
0.019

Helvetica Chimica Acta Vol. 85 (2002)
1555
Table 3. Crystallographic Data of the Oxazolidinones A and of 1 23. For the methods used in the structure
determination, see Exper. Part. The crystallographic data of oxazolidinones 24 31 have been published
previously [9][10][11][24].
Data
A
1
2
3
4
Formula
C18H19NO2
281.34
C20H23NO2S
341.45
C25H25NO2S
403.16
C23H29NO2S
383.53
C28H28N2O3S
472.58
Formula weight
[g molÀ1
]
T [K]
Wavelength [ä]
Source
293(2)
1.54184
CuKa
293(2)
0.71069
MoKa
0.35 Â 0.30
 0.20
monoclinic
P21
2.0 < q < 28.0
10.356(5)
8.802(4)
10.824(3)
90
109.57(3)
90
929.7(7)
2
1.220
0.185
293(2)
1.54184
CuKa
213(2)
1.54184
CuKa
0.15 Â 0.10
 0.10
monoclinic
C2
2.7 < q < 55.0
20.616(5)
6.411(1)
18.301(4)
90
114.56(2)
90
2200.0(8)
4
1.158
1.425
103(2)
1.54184
CuKa
0.30 Â 0.25
 0.25
triclinic
P1
3.7 < q < 55.0
8.885(2)
12.413(2)
13.302(2)
63.94(1)
80.41(2)
69.03(2)
1230.6(4)
2a)
Crystal
0.35 Â 0.25
 0.005
orthorhombic
P212121
4.1 < q < 64.8
6.277(2)
15.020(1)
15.677(1)
90
0.50 Â 0.10
 0.10
orthorhombic
P212121
1.6 < q < 24.9
6.787(1)
15.858(4)
20.218(8)
90
Dimensions [mm]
Crystal system
Space group
q Range [8]
a [ä]
b [ä]
c [ä]
a [8]
b [8]
90
90
90
90
g [8]
V [ä3]
1478.0(5)
4
1.264
2176.0(11)
4
1.232
Z
1calc. [g cmÀ3
]
1.275
1.424
m [mmÀ1
]
0.653
0.169
Refl. measured
Independent refl.
Refl. observed
Restraints
No. of variables
Criterion
2777
1511
366
2492
2375
1848
1
217
I > 3s(I)
4.09
2214
2189
1124
0
262
I > 3s(I)
4.40
1787
1551
1536
1
274
I > 2s(I)
4.02
3331
3331
3086
3
670
I > 2s(I)
3.28
0
85b)
I > 3s(I)
8.40
Final R [%]
wR2 [%]
14.29
12.47
10.87
11.08
8.72
Goodness-of-fit
D1 (max, min) [e äÀ3
0.789
0.139, À0.175
1.129
0.329, À0.323
0.960
0.156, À0.229
1.167
0.194, À0.251
1.039
0.426, À0.203
]
a) The structure contains two symmetrically independent molecules in the unit cell (Z' ˆ 2). b) The small size
and the poor quality of the crystal did not allow normal refinement. The Ph groups were refined as rigid bodies
with assumed ideal geometry and the other non-H-atoms were refined isotropically with SHELXL-97.
Data
5
6
7a)
8
9
Formula
C25H27NO4S ‡ CH3OH C24 H31NO3S
C28H31NO3S C33H42N2O4S2 C28H31NO3S
Formula weight
469.58
413.56
461.60
594.81
461.60
[g molÀ1
]
T [K]
Wavelength [ä]
Source
173(2)
1.54184
CuKa
173(2)
1.54184
CuKa
200(2)
1.54184
Cu
293(2)
0.71069
MoKa
173(2)
1.54184
CuKa
Crystal
0.25 Â 0.25
0.20 Â 0.20
0.30 Â 0.20
0.40 Â 0.15
0.20 Â 0.15
Dimensions [mm] Â 0.25
 0.15
 0.15
 0.10
 0.15
Crystal system
Space group
orthorhombic
P212121
orthorhombic monoclinic
P212121
orthorhombic orthorhombic
P212121
P21
P212121

1556
Helvetica Chimica Acta Vol. 85 (2002)
Table 3 (cont.)
Data
5
6
7a)
8
9
q Range [8]
a [ä]
b [ä]
c [ä]
a [8]
4.4 < q < 64.9
10.551(1)
11.978(2)
19.048(2)
90
3.4 < q < 64.9
6.492(1)
16.019(1)
21.564(2)
90
4.4 < q < 66.9
8.404(2)
14.063(4)
9.969(2)
90
1.3 < q < 25.0
6.448(6)
15.465(4)
32.102(9)
90
3.2 < q < 64.9
6.214(1)
18.515(3)
20.802(4)
90
b [8]
90
90
90
90
91.27(2)
90
1177.9(5)
2
1.301
1.459
90
90
3201(3)
4
1.234
90
90
g [8]
V [ä3]
Z
2407.3(5)
4
1.296
2242.6(4)
4
1.225
2393.3(7)
4
1.281
1calc. [g cmÀ3
]
m [mmÀ1
]
1.499
1.468
0.205
1.436
Refl. measured
Independent refl.
Refl. observed
Restraints
2363
2337
2281
0
2240
2214
2007
0
2270
2178
2133
2
3239
3239
1883
0
2380
2354
2079
0
No. of variables
Criterion
Final R [%]
340
I > 2s(I)
3.10
294
I > 2s(I)
3.11
307
I > 3s(I)
3.37
374
I > 3s(I)
4.57
330
I > 2s(I)
3.32
wR2 [%]
8.56
8.04
9.19
13.31
8.85
Goodness-of-fit
D1 (max, min) [e äÀ3
1.089
0.401, À0.195
1.048
0.258, À0.151
0.942
0.608, À0.300
1.233
0.407, À0.233
0.985
0.213, À0.223
]
a) The position of the H(O) atom was found from a difference Fourier map and was refined with fixed isotropic
displacement parameters.
Data
10a)
11
12b)
13
14
Formula
C30H33NO4S ‡
CH3OH
C24H29NO3S
C26H31NO3S
C25H31NO3S
C39H37NO3S
Formula weight
535.68
411.54
437.58
425.57
599.25
[g molÀ1
]
T [K]
Wavelength [ä]
Source
220(2)
1.54184
CuKa
113(2)
1.54184
CuKa
293(2)
1.54184
CuKa
173(2)
1.54184
CuKa
180(2)
1.54184
CuKa
Crystal
0.35 Â 0.30
0.20 Â 0.15
0.30 Â 0.30
0.40 Â 0.40
0.15 Â 0.10
Dimensions [mm]
Crystal system
Space group
q Range [8]
a [ä]
b [ä]
c [ä]
a [8]
b [8]
 0.25
 0.15
 0.15
 0.20
 0.08
triclinic
P1
monoclinic
P21
triclinic
P1
monoclinic
P21
triclinic
P1
3.6 < q < 66.9
6.308(2)
9.124(2)
12.388(3)
87.480(15)
86.538(15)
77.906(15)
695.5(3)
1
3.8 < q < 59.9
6.103(1)
15.021(5)
11.969(5)
90
100.47(29
90
1079.0(6)
2
5.3 < q < 54.9
6.416(7)
9.010(8)
11.535(6)
105.46(6)
97.75(7)
103.69(8)
610.3(9)
1
3.6 < q < 59.9
6.114(1)
14.923(1)
12.327(1)
90
91.68(1)
90
1124.2(2)
2
3.0 < q < 66.9
9.332(3)
12.117(4)
15.698(4)
68.04(2)
87.95(3)
78.48(3)
1611.7(8)
2c)
g [8]
V [ä3]
Z
1calc. [g cmÀ3
]
1.279
1.362
1.267
1.526
1.191
1.378
1.257
1.481
1.236
1.189
m [mmÀ1
]

Helvetica Chimica Acta Vol. 85 (2002)
1557
Table 3 (cont.)
Data
10a)
11
12b)
13
14
Refl. measured
Independent refl.
Refl. observed
Restraints
2401
2401
2393
3
1855
1671
1370
1
1520
1520
1405
3
1813
1725
1704
1
5576
5576
2709
3
No. of variables
Criterion
Final R [%]
354
I > 3s(I)
4.29
292
I > 2s(I)
3.39
280
I > 3s(I)
7.35
302
I > 2s(I)
3.04
799
I > 2s(I)
3.83
wR2 [%]
Goodness-of-fit
D1 (max, min) [e äÀ3
12.36
1.324
0.477, À0.467
8.40
18.04
1.777
0.423, À0.505
8.47
9.90
0.882
0.140, À0.184
1.232
0.250, À0.217
1.111
0.145, À0.350
]
a) The position of the H(O) atom was found from a difference Fourier map and was refined with fixed isotropic
displacement parameters. b) The structure contains an unresolved, disordered MeOH molecule. c) The
structure contains two symmetrically independent molecules in the unit cell (Z' ˆ 2).
Data
15
16
17
18
19
Formula
C19H19NO2S
325.41
C43H43NO3S
653.84
C35H35NO4
533.64
C35H37NO3S
551.72
C43H45NO4S
671.86
Formula weight
[g molÀ1
]
T [K]
Wavelength [ä]
Source
100(2)
1.54184
CuKa
0.20 Â 0.18
 0.16
monoclinic
P21
2.6 < q < 64.9
15.282(2)
12.881(2)
17.324(2)
90
293(2)
1.54184
CuKa
0.25 Â 0.25
 0.20
triclinic
P1
3.7 < q < 68.9
8.643(2)
8.875(3)
12.594(3)
71.51(2)
87.90(2)
80.10(2)
902.4(4)
1
293(2)
0.71069
MoKa
0.30 Â 0.10
 0.10
orthorhombic
P212121
1.8 < q < 23.0
12.286(15)
14.276(4)
17.559(5)
90
90
90
3080(4)
4
1.151
293(2)
1.54184
CuKa
0.30 Â 0.30
 0.10
monoclinic
P21
2.5 < q < 66.0
10.352(5)
8.271(4)
17.789(8)
90
98.29(4)
90
1507.2(12)
2
1.216
1.224
293(2)
1.54184
CuKa
Crystal
0.35 Â 0.30
 0.25
orthorhombic
P212121
3.3 < q < 69.9
10.813(3)
12.848(2)
26.757(8)
90
Dimensions [mm]
Crystal system
Space group
q Range [8]
a [ä]
b [ä]
c [ä]
a [8]
b [8]
89.99(1)
90
90
90
g [8]
V [ä3]
3410.2(8)
3717.2(16)
4
1.201
Z
8a)
1calc. [g cmÀ3
]
1.268
1.753
1.203
1.103
m [mmÀ1
]
0.075
1.103
Refl. measured
Independent refl.
Refl. observed
Restraints
No. of variables
Criterion
6340
6072
5488
1
831
I > 2s(I)
3.79
3266
3266
3146
3
438
I > 3s(I)
2.99
2434
2434
966
2976
2826
2518
1
364
I > 3s(I)
4.13
7936
7035
6003
0
446
I > 2s(I)
3.86
0
341b)
I > 3s(I)
5.36
Final R [%]
wR2 [%]
10.20
9.99
13.22
12.76
10.74
Goodness-of-fit
D1 (max, min) [e äÀ3
1.058
0.789, À0.304
0.994
0.152, À0.198
1.205
0.159, À0.182
1.208
0.409, À0.248
0.948
0.294, À0.202
]
a) The structure contains four symmetrically independent molecules in the unit cell (Z' ˆ 4). b) The poor quality
of the crystal did not allow normal refinement. Some of the non-H-atoms were refined isotropically with
SHELXL-97.

1558
Helvetica Chimica Acta Vol. 85 (2002)
Table 3 (cont.)
Data
20
21a)
22
23
Formula
Formula weight [g molÀ1
T [K]
Wavelength [ä]
Source
C25H31NO3
393.51
170(2)
1.54184
CuKa
C31H35NO3Si
497.69
200(2)
1.54184
CuKa
C28H29NO5
459.52
293(2)
1.54184
CuKa
C30H31NO4
469.56
293(2)
1.54184
CuKa
]
Crystal
0.45 Â 0.35
0.45 Â 0.08
 0.08
monoclinic
P21
2.5 < q < 70.4
11.932(5)
6.571(2)
18.590(6)
90
107.54(3)
90
1389.8(8)
2
0.35 Â 0.05
 0.05
orthorhombic
P212121
3.3 < q < 59.2
6.620(3)
17.368(3)
21.936(8)
90
0.50 Â 0.05
 0.05
monoclinic
P21
2.6 < q < 62.0
11.642(2)
6.660(7)
17.423(5)
90
102.80(2)
90
1317.3(14)
2
Dimensions [mm]
Crystal system
Space group
q Range [8]
a [ä]
b [ä]
c [ä]
a [8]
b [8]
 0.30
triclinic
P1
3.4 < q < 65.9
13.242(10)
8.767(5)
9.825(5)
88.88(3)
83.71(4)
78.40(5)
1110.6(12)
2b)
90
90
g [8]
V [ä3]
2522.1(15)
4
1.210
Z
1calc. [g cmÀ3
]
1.177
0.604
1.189
0.988
1.184
0.623
m [mmÀ1
]
0.671
Refl. measured
Independent refl.
Refl. observed
Restraints
No. of variables
Criterion
3407
3407
3390
3
537
I > 2s(I)
4.91
2431
2306
1669
1
327
I > 2s(I)
8.14
2296
2296
585
3127
3013
1053
1
316
I > 3s(I)
5.69
0
101c)
I > 3s(I)
16.30
Final R [%]
wR2 [%]
13.78
21.73
36.53
12.93
Goodness-of-fit
D1 (max, min) [e äÀ3
1.465
0.204, À0.441
1.961
0.543, À0.461
3.005
0.528, À0.569
1.121
0.191, À0.280
]
a) The determination of the structure was difficult, since, despite cooling, more than 50% of the crystal
decomposed during the measurement. b) The structure contains two symmetrically independent molecules in
the unit cell (Z' ˆ 2). c) The poor quality of the crystal did not allow normal refinement. The Ph groups were
refined as rigid bodies with assumed ideal geometry and the other non-H-atoms were refined isotropically with
SHELXL-97.
assignments, easy, so that we have a collection of more than 30 structures, only a few of
which have previously been published, with data deposition in the Cambridge
Crystallographic Data File; this statistically relevant number of structures is now
enabling us to interpret the reactivity observed experimentally with the derivatives of
oxazolidinone A.
In Table 1, we have listed the crystal structures of A and of all known13) derivatives
1 31, together with the corresponding formulae, melting points, and references.
Tables 2 and 3 contain the hitherto unpublished crystallographic and structural data of
13
)
Literature and Cambridge Crystallographic Data File search as of February 6, 2002. Only one conformer is
shown in Table 1 of structures with several symmetrically independent molecules (up to four, cf. 15).

Helvetica Chimica Acta Vol. 85 (2002)
1559
24 of the 32 compounds shown in Table 1. Clearly, most melting points are well above
1008, the average of the 32 values in Table 1 is actually 1578!
Inspection of the structures in Table 1 reveals immediately that the conformation
around the CHÀCHMe2 bond is such that the methine H-atom of the i-Pr group points
towards the Ph group in cis position (a in Fig. 3), with only four exceptions, where the i-
Pr H-atom is in a (À)-synclinal (sc) position with respect to the N-atom of the
heterocycle (b in Fig. 3); the third possible conformer c, with this H-atom above the
ring, is not observed.
Thus, geminal diphenyl substitution causes the i-Pr group to present itself to the
substituent on the N-atom of the oxazolidinone ring, where steric hindrance is desired
for face-selective reactions, as if it were a t-Bu group (buttressing effect [32]; for a
reaction in which this effect is borne out, see Scheme 2); the small coupling constant
(J ꢀ 2 Hz) between HÀC(4) and HCMe2 in the NMR spectra of most of the 32
Fig. 3. Prominent conformations a g in the structures of A and its derivatives (cf. Table 1 and Figs. 4 and 5; for
comments, see accompanying paragraph). Conformation a is present in ca. 90%, and b in ca. 10% of the
structures shown in Table 1, and c is not found at all; in a and e, it is demonstrated that both faces of the ring are
sterically blocked (by Me and Ph groups); in d, we illustrate the small dihedral angle between the Me2CH and
the cis Ph group; f shows the anti arrangement of the two CˆO dipoles in N-acyl derivatives, and, in g, the H-
bond between the oxazolidinone CˆO and the OH group in hydroxy compounds is depicted (these are formed
by addition of the lithiated NÀCHLiÀSMe derivative to aldehydes and ketones [13]).

1560
Helvetica Chimica Acta Vol. 85 (2002)
Scheme 2. Stereoselectivities of the Diels-Alder Additions of (E)-3-Butenoyl-oxazolidinones to Isoprene. A
second diastereoisomer is not present within routine NMR-spectroscopic detection limits, when the tert-leucine-
derived and the diphenyl-substituted valine-derived oxazolidinones are used as auxiliaries (hitherto
unpublished results, described in the dissertation of Gaul [17]).
O
O
Me
Me
H
isoprene, Me2AlCl
CH2Cl2, –20 °
+
Ox
Me
Ox
Me
O
O
O
O
N
O
N
O
N
Ox
Ph
Me
Me Me
Me
Me
Ph
Me
Me
ratios of
diastereoisomeric
85:15
> 99:1
> 98:2
Diels-Alder adducts
compounds (with the conformation a or b (Fig. 3) in the crystalline state) is proof that
the preferred conformation around the CHÀCHMe2 bond is the same in solution.
In all structures, a conformation is observed in which the Me2CH and the trans-Ph
group are as close to an antiperiplanar arrangement as possible. Average dihedral
angles of ca. À258 and À1558 between the i-Pr group and the neighboring Ph groups (d
in Fig. 3) are probably a maximum that can be achieved in a five-membered ring
containing two trigonal centers and a carbamate O-atom. Steric protection14) from
nucleophilic attack on the oxazolidinone CˆC group is evident from the Newman
projections a (Si face of the CˆO plane) and e (Re face of the CˆO plane) in Fig. 3. As
in all other known N-acyl-oxazolidinones, the two CˆO groups of the OˆCÀNÀCˆO
moiety are arranged in an anti orientation (f in Fig. 3; minimalization of A1,3 strain [34]
and dipole dipole repulsion).
Especially informative are the overlays of 27 structures with the preferred
conformation around the CHÀCHMe2 bond in Fig. 4 and of the four unusual structures
in Fig. 5. The conformation of the five-membered ring ranges from an envelope form
with the Ph2C atom out of the plane to the twist form with the two fold axis through the
CˆO group (Fig. 6 and Table 2). There is a slight-to-moderate torsion around the
amide bond in the ring (OˆCÀNÀR torsion angle, 0 to À338), with varying
pyramidalization of the two trigonal centers (Table 2). The structure of the ethane
moiety Ph2CÀC(4)H in the heterocycle appears to be extremely rigid, like a solid
scaffold, to which the substituents on the N-atom are attached in seemingly chaotic
arrangement, except that the exocyclic CˆO bond15) is always anti to the endocyclic
14
)
)
For examples of previous preparative exploitations of −sterically protected but electronically effective
functional groups×, see [33].
¥¥¥ and also the CˆS bond in compound 15!
15

Helvetica Chimica Acta Vol. 85 (2002)
1561
Fig. 4. Two views of the overlay of 27 structures of A and its derivatives with the preferred conformation of the
CHÀCHMe2 bond. Top : view along the main ring plane and the oxazolidinone CˆO bond axis; bottom: view
along the approximate planes containing the atoms CÀNÀCÀO and the atoms OÀCÀC of the heterocycle,
with best fits of the five ring atoms. Color coding as in Table 1. The programs INSIGHT [35] and MOLMOL
[31] were used to produce the overlay.

1562
Helvetica Chimica Acta Vol. 85 (2002)
Fig. 5. Overlay of four −runaway× structures of 4-isopropyl-5,5-diphenyloxazolidinone derivatives 7 9 and 31
with an unusual conformation of the i-Pr group. For details, see caption of Fig. 4.
one (cf. f in Fig. 3), and that, in the NÀCHÀSR derivatives, the CÀS bond is in an anti
arrangement with respect to the CHÀCHMe2 bond, in most cases. In the less common
structures of Fig. 5, it looks as if there are large groups in the exocyclic position on the
same side of the ring on which the i-Pr group resides. Note that, in two of these unusual
structures, there is a H-bond between an OH group in the N-substituent and the
oxazolidinone carbonyl O-atom (as in many other structures shown in Table 1, cf. g in
Fig. 3). In structures 7 and 9, a Ph group on the resulting seven-membered H-bonded
ring is forced into a position in which the i-Pr group winds up sandwiched between two
Ph groups. Such sandwiching may (7 and 9) or may not (10, 14, 18, and 19), lead to a
conformational switch.
The atoms of the 4-isopropyl-5,5-diphenyloxazolidinon-3-yl group, as seen in so
many crystal structures, are held like a template in a vise. There is no doubt in our minds
that this arrangement is also present in solution16). The template provides the proper
environment for diastereoselective reactions on substituents attached to the oxazoli-
dinone N-atom. Approach to one of the diastereotopic faces of trigonal centers on the
N-atom of the heterocycle is sterically hindered by the i-Pr group, as depicted in a and b
of Fig. 7 for metal-chelated derivatives17). Similarly, the results of reactions of lithiated
(methylthiomethyl)-and allyl-oxazolidinones can be interpreted [13 16] as occurring
on this template (see c and d in Fig. 7).
16
)
)
Cf. the CHÀCHMe2 NMR conformation alluded to above.
17
For the crystal structure of a Ti derivative of an N-acyl-oxazolidinone, see, e.g., [10].

Helvetica Chimica Acta Vol. 85 (2002)
1563
Fig. 6. Ring puckering of oxazolidinone fragments and examples of ideal envelope and twist forms. a) Polar
scattergram of Cremer-Pople ring puckering coordinates [36] of the 37 oxazolidinone fragments (Table 2). The
inner half-circle shows the phase f vs. the amplitude q, envelope f ˆ 08, twist f ˆ 188. The outer part of the
circle shows a histogram of the phase distribution. b) On the left, a typical envelope conformation (4); on the
right, a twist conformation (23).
The crystal structures of compounds 24 and 26 31 were determined in the course of the Ph.D. Thesis of T.
Hintermann [9] and M. Brenner (ETH-Dissertation No. 14409, 2001). The compounds 11 13 and 17 were
investigated in the course of the Master Thesis work (Diplomarbeit) of K. Sch‰rer, ETH-Z¸rich, 2000. Financial
support of our group by Novartis Pharma AG, Basel, is gratefully acknowledged.

1564
Helvetica Chimica Acta Vol. 85 (2002)
Fig. 7. Structures, facial selectivities of derivatives of A, and stereochemical course of reactions. In a and b, the
face differentiation of metal-chelated derivatives is illustrated. The structure of the Li compound c has been
derived from NMR measurements [14], and, in d, a model compatible with the observed outcome of additions
of metallated N-allyl-A to carbonyl compounds is pictured [16].
Experimental Part
The reflections were collected on an Enraf-Nonius CAD-4 diffractometer. If not indicated otherwise, the
following procedure was used in X-ray crystal-structure determinations: the structures were determined by
direct methods with SHELXS-96 [37], SIR92, or SIR97 [38]. In the case of compounds A, 2, 12, and 20 22,
parts of the structures were determined by direct methods with SIR97, and the remaining non-H-atoms were
found from a difference Fourier map. The non-H-atoms were refined anisotropically with SHELXL-97 [37]. The
H-atoms were calculated at idealized positions and included in the structure-factor calculations with fixed
isotropic displacement parameters in SHELXL-97.
The crystallographic data of all new structures presented in Table 1 have been deposited with the Cambridge
Crystallographic Data Centre (CCDC). Copies of the data can be obtained free of charge on application to the
CCDC, 12 Union Road, Cambridge, CB21EZ, UK (fax: ‡44-1223-336033; e-mail: deposit@ccdc.cam.ac.uk).

Helvetica Chimica Acta Vol. 85 (2002)
1565
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Received March 19, 2002