Opposite π-face selectivity for the DMD and m-CPBA epoxidations of chiral 2,2-dimethyloxazolidine derivatives of tiglic amides: Control by steric interactions versus hydrogen bonding

Article abstract of DOI:10.1021/ol990405s

A high extent but opposite sense in the diastereoselectivity has been observed for the DMD and m-CPBA epoxidations of the optically active tiglic amides (S)-1 with 2,2-dimethyloxazolidines as chiral auxiliaries. This unprecedented reversed π-facial differ

Full text of DOI:10.1021/ol990405s

ORGANIC
LETTERS
2000
Vol. 2, No. 8
1019-1022
Opposite π-Face Selectivity for the DMD
and m-CPBA Epoxidations of Chiral
2,2-Dimethyloxazolidine Derivatives of
Tiglic Amides: Control by Steric
Interactions versus Hydrogen Bonding
,†
Waldemar Adam,†,‡ Aurelia Pastor,* Karl Peters,§,| and Eva-Maria Peters§
Institut fu¨r Organische Chemie, UniVersita¨t Wu¨rzburg, Am Hubland, D-97074
Wu¨rzburg, Germany, and Max-Planck-Institut fu¨r Festko¨rperforschung,
Heisenbergstrasse 1, D-70506 Stuttgart, Germany
adam@chemie.uni-wuerzburg.de
Received December 20, 1999
ABSTRACT
A high extent but opposite sense in the diastereoselectivity has been observed for the DMD and m-CPBA epoxidations of the optically active
tiglic amides (S)-1 with 2,2-dimethyloxazolidines as chiral auxiliaries. This unprecedented reversed π-facial differentiation for these two peroxidic
oxidants is rationalized in terms of like (lk) and unlike (ul) transition structures: For DMD, steric interactions dominate, such that the unlike
transition structure is favored, while for m-CPBA, hydrogen-bonding effects overcome these steric repulsions and the like one is preferred.
Optically active epoxides are key building blocks in organic
synthesis.1 These versatile functionalities are readily and
stereoselectively introduced2 and then further transformed
by ring opening into a plethora of oxyfunctionalized deriva-
tives.3 Despite much progress in recent years, efficient
reagents for the regio- and diastereoselective epoxidations
are still in great demand. Popular oxidants for epoxidations
are dioxiranes4 and peracids,2a,5 which have received much
attention from both the preparative and mechanistic point
of view. These extensively used oxidants are mild (isolated
dioxiranes epoxidize under strictly neutral conditions) and
react selectively at the site of higher nucleophilicity.6
Attractive opportunities for preparative purposes offer the
† Universita¨t Wu¨rzburg.
‡ FAX: +49 931/888 4756. Internet: http://www-organik.chemie.uni-
wuerzburg.de.
(3) (a) Fukuyama, T.; Wang, C.-L. J.; Kishi, Y. J. Am. Chem. Soc. 1979,
101, 260-262. (b) Marino, J. P.; Ferna´ndez de la Pradilla, R.; Laborde, E.
J. Org. Chem. 1984, 49, 5279-5280.
(4) Adam, W.; Smerz, A. Bull. Soc. Chim. Belg. 1996, 105, 581-599.
(5) (a) Rebek, J., Jr.; Marshall, L.; McManis, J.; Wolak, R. J. Org. Chem.
1986, 51, 1649-1653. (b) Koerner, T.; Slebocka-Tilk, H.; Brown, R. S. J.
Org. Chem. 1999, 64, 196-201.
§ Max-Planck-Institut fu¨r Festko¨rperforschung.
| FAX: +49 711/689 1503. E-mail: karpet@vsibm1.mpi-stuttgart-
.mpg.de.
(1) (a) Harvey, R. G. Synthesis 1986, 605-619. (b) Jørgensen, K. A.
Chem. ReV. 1989, 89, 431-458.
(2) (a) Rao, A. S. In ComprehensiVe Organic Synthesis; Trost, B. M.,
Fleming, I., Eds.; Pergamon: Oxford, 1991; Vol. 7, Chapter 3.1, pp 357-
387. (b) Hoveyda, A. H.; Evans, D. A.; Fu, G. C. Chem. ReV. 1993, 93,
1307-1370.
(6) (a) Bovicelli, P.; Lupattelli, P. J. Org. Chem. 1994, 59, 4304-4307.
(b) Adam, W.; Smerz, A. K. J. Org. Chem. 1996, 61, 3506-3510. (c)
Camps, F.; Messeguer, A.; Sa´nchez, F.-J. Tetrahedron 1988, 44, 5161-
5167.
10.1021/ol990405s CCC: $19.00 © 2000 American Chemical Society
Published on Web 03/23/2000

Scheme 1
control of their diastereoselectivity by steric,7 electronic,7b-e
(S)-1a-c at 20 °C for 24 h (3-fold excess of DMD) led to
a diastereomeric mixture of epoxides ul-2a-c and lk-2a-c,
with the ul diastereomers as the major ones (Scheme 1).
hydrogen-bonding,7b-c,8 solvent,7b-e and torsional effects.9
Although the diastereoselective epoxidation of electron-
rich alkenes by these two oxidants is well documented,4,5
the use of electron-poor substrates has to date not been much
explored.10 For example, an attractive and synthetically
valuable application would be the diastereoselective DMD
or m-CPBA oxyfunctionalization of tiglic acid derivatives
with 2,2-dimethyloxazolidines as chiral auxiliaries, which
would afford optically active epoxides after removal of the
chiral auxiliary.11 Subsequent ring opening with the ap-
propriate nitrogen nucleophile would readily lead to optically
active R-amino acids with R-methyl and â-hydroxy groups.
Such conformationally constrained, oxyfunctionalized R-ami-
no acids have hitherto been synthesized from tiglic acid as
starting material.12 They possess important utility as an
effective probe to understand the local conformations
responsible for the bioactivity of peptides.13
High conversions (up to 95%) and diastereoselectivities
(up to 91:9) were obtained for the three tested auxiliaries
(Table 1; entries 1-3). For comparison, the m-CPBA (2-
fold excess) epoxidation of the tiglic amides (S)-1a-c was
performed at 20 °C for 24 h; the conversions and diastereo-
selectivities are given in Table 1 (entries 4-6). These high
conversions under such mild conditions are impressive,
especially since electron-poor olefins possess a rather low
reactivity toward electrophilic oxidants such as DMD and
m-CPBA.4 Also significant is the fact, as depicted in Table
1, that the substituents in the oxazolidine ring have only a
minor influence on the diastereoselectivity of the epoxidation
for DMD (entries 1-3) as well as m-CPBA (4-6). Still more
surprising is the reversed diastereoselectivity between m-
CPBA and DMD, since for m-CPBA the major diastereomer
is the lk one, but for DMD it is ul. The configurational
assignment is based on the X-ray structure of the lk-2c
derivative (cf. Supplementary Information). To test the
influence of the medium polarity and hydrogen bonding on
the diastereoselectivity, the m-CPBA epoxidation of the
substrate (S)-1c was conducted in several solvents. Although
only a small effect was found on the diastereoselectivity
(entries 6-9), a dramatic drop was observed for the
conversion in MeOH.
In view of these facts, we have examined the diastereo-
selectivity in the DMD and m-CPBA epoxidation of the
optically active tiglic amides (S)-1, in which the amide
functionality is connected to optically active 4-substituted
2,2-dimethyloxazolidines. Indeed, high (dr > 90:10) dia-
stereoselectivities have been achieved for both oxidants;
mechanistically more significant, the sense of the π-facial
selectivity is opposite, i.e., unlike for DMD and like for
m-CPBA.14 These unprecedented results and their mecha-
nistic rationalization are reported presently.
To rationalize the opposite sense in the diastereoselectivity
observed herein for the epoxidation of the tiglic amides (S)-1
by DMD and m-CPBA (no other examples appear to be
known for this pair of oxidants), it is necessary to know the
preferred conformation of the starting amides. Although the
The optically active amides (S)-1a-c were obtained in
good yields from the appropriate amino alcohols by following
standard published procedures (cf. Supplementary Informa-
tion). Subsequent epoxidation of the tiglic acid amides
Table 1. Diastereoselectivities for the Epoxidation of Amides (S)-1 by DMD and m-CPBA
entry
amide
R1
R2
oxidant
solvent
mb (%)a
convn (%)a,b
epoxides 2 ul:lka
1
2
3
4
5
6
7
8
9
(S)-1a
(S)-1b
(S)-1c
(S)-1a
(S)-1b
(S)-1c
(S)-1c
(S)-1c
(S)-1c
CH2Ph
CH2Ph
Ph
CH2Ph
CH2Ph
Ph
Ph
Ph
Ph
H
Me
H
H
Me
H
H
H
H
DMD
DMD
DMD
m-CPBA
m-CPBA
m-CPBA
m-CPBA
m-CPBA
m-CPBA
CH3COCH3
CH3COCH3
CH3COCH3
CH2Cl2
CH2Cl2
CH2Cl2
CH3CN
t-BuOH
MeOH
89
>95
91
86
89
87
82
88
83
88
95
91:09
90:10
83:17
15:85
07:93
15:85
24:76
22:78
34:66
>95
>95
>95
>95
>95
>95
7
a Determined by 1H NMR analysis of characteristic signals directly on the crude product (error ( 5 of the stated value); durene was used as internal
standard. The mass balances (mb) for entries 4-9 were determined gravimetrically. b All experiments were run for 24 h.
1020
Org. Lett., Vol. 2, No. 8, 2000

favored conformation of the N-tigloyl fragment is syn with
respect to the oxazolidine ring, analogous to the N-acryloyl-
oxazolidines described by Kanemasa and Porter,15 the double
bond is twisted with respect to the carbonyl group to avoid
steric interactions with the substituent at the 4 position in
the oxazolidine ring (Scheme 2). This conformational
s-cis cannot be accommodated with the auxiliary for steric
reasons.16 Semiempirical calculations (cf. Supplementary
Information) confirm this expectation for the tiglic amides
(S)-1 and give values of 56° (conformer A in Scheme 2)
and 249° (conformer B in Scheme 2) for the dihedral angle
between the double bond and the carbonyl group in their
lowest energy conformations. The energy difference amounts
to only ca. 1.4 kcal/mol in favor of conformer B due to the
destabilization of A with respect to B on account of the steric
interaction between the H-4 atom in the oxazolidine ring and
the R-methyl group of the tigloyl moiety. On the basis of
the Curtin-Hammett principle,17 from this relatively low
energy difference in the ground-state conformations, no
significant diastereoselective control would be expected.
Moreover, both π faces of the double bond are equally well
shielded by the chiral auxiliary torward the attack of the
oxidant in these two conformers; thus, the Si face is shielded
in conformer B and the Re face in conformer A.
Scheme 2
The opposite and high diastereoselectivities observed for
DMD and m-CPBA may be rationalized in terms of the
energy differences between the unlike and like transition
structures for these oxygen-transfer processes, i.e., Cqlk versus
Cqul for DMD and Dqlk versus Dqul for m-CPBA, as depicted
in Scheme 2. The Cq transition structure suggests that the
lk
DMD attack on the olefin is disfavored by the steric
interactions between the H-4 atom in the oxazolidine ring
and the R-methyl group of the tiglate moiety. These steric
repulsions are absent in the Cq transition structure, which
ul
would implicate a pronounced unlike diastereoselectivity, as
is observed experimantally (Table 1, entries 1-3). In fact,
these steric interactions should become more important in
the transition structure Cq compared to the ground-state
lk
conformer A of the amide (S)-1 due to the partial rehybrid-
ization of the olefinic carbon atoms during the epoxidation
trajectory. That the H-4/R-Me steric interaction appears to
be decisive is suggested by the experimental fact that the
(8) (a) Henbest, H. B.; Wilson, R. A. L. J. Chem. Soc. 1957, 1958-
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orientation of the double bond with respect to the carbonyl
group is general for methacrylate and tiglate derivatives of
imides and amides since the planar rotamers (s-trans and
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and Prelog (Seebach, D.; Prelog, V. Angew. Chem., Int. Ed. Engl. 1982,
21, 654-660) and have been applied to the transition structures.
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W.-X.; McPhail, A. T. J. Am. Chem. Soc. 1992, 114, 7664-7676.
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Org. Lett., Vol. 2, No. 8, 2000
1021

substitution pattern in the oxazolidine ring exerts only a small
acidity19 and hence less effective for hydrogen bonding (entry
8). This reduced reactivity, which has also been observed in
the m-CPBA epoxidation of the N,N-diethyltiglic amide 3
(cf. Supplementary Information), agrees well with the
previously reported epoxidation of ethyl crotonate20 and may
be explained in terms of competitive hydrogen bonding
between the solvent and the peracid. Therefore, for the less
reactive electron-poor olefins (S)-1 and the N,N-diethyltiglic
amide 3, assistance through hydrogen bonding is critical in
the peracid epoxidation process.
effect on the diastereomeric ratios (entries 1-3) and, thus,
on the energy difference of the two transition structures Cq
lk
and Cq .
ul
The opposite sense in the stereoselectivity for m-CPBA
implies that the like transition structure Dqlk is favored over
the unlike one Dq ; consequently, factors other than the steric
ul
ones for DMD appear to operate in the case of m-CPBA.
Indeed, sufficiently strong hydrogen-bonding interactions
have been previously postulated between the peracid hydro-
gen atom and the carbonyl group of cyclic allylic carbamates
and amides to rationalize the preferred syn diastereoselec-
tivity in the m-CPBA epoxidation of 3-cyclohexenyl deriva-
tives.18 We propose similar hydrogen bonding to be also
responsible in our acyclic tiglic substrates, which outweigh
the steric effects implicated for the DMD oxidant. Thus, the
Dqlk transition structure would be favored over the Dqul one
because hydrogen bonding between the amide carbonyl
oxygen and the m-CPBA hydrogen atom is presumably
sufficiently strong to override the H-4/R-Me steric repulsions
In conclusion, a highly diastereoselective epoxidation of
the (S)-1a-c tiglic acid amides by DMD and m-CPBA has
been discovered which displays the reversed sense in the
diastereoselectivity. For DMD, steric interactions dominate
to afford the unlike diastereoselectivity, while hydrogen-
bonding effects are responsible for the like diastereoselec-
tivity in the case of m-CPBA.
Acknowledgment. We are grateful to the Deutsche
Forschungsgemeinschaft (Schwerpunktprogramm: Sauerst-
offtransfer/Peroxidchemie), the European Comission (post-
doctoral fellowship for A.P.), and the Fonds der Chemischen
Industrie for financial support. Prof. Dr. K.-H. Drauz and
Dr. M. Schwarm (Degussa-Hu¨ls AG) are thanked for a
generous gift of the optically active amino alcohols.
in the Dq geometry. This stabilization is not expected in
lk
the unlike transition structure Dqul because the carbonyl group
and the peracid hydrogen atom are too far apart for effective
hydrogen bonding. For the first time such unique hydrogen-
bonding effects have been now uncovered for acyclic,
electron-poor olefins such as the tiglic substrates. Mecha-
nistically more significant, the opposite sense in the diaste-
reoselectivity observed for m-CPBA and DMD may be
rationalized by hydrogen bonding in the transition structure.
While state-of-the-art computational chemistry might cor-
roborate these unusual directing effects, the synthetic utility
of these novel findings should be imperative: The mere
choice of DMD versus m-CPBA permits us now to select
the desired epoxide diastereomer for such tiglic substrates.
A dramatic drop in the m-CPBA reactivity was found when
the epoxidation of the tiglic amide (S)-1c was conducted in
MeOH (entry 9). That this decreased reactivity for this
electron-poor olefin relates to the hydrogen-bonding ef-
ficiency of the solvent was confirmed when the reaction was
conducted in t-BuOH, also a protic solvent but of lower
Supporting Information Available: Experimental Sec-
tion with the synthetic details and characteristic spectral data
of the R,â-unsaturated ammides (S)-1a-c, the optically
active epoxides ul-2a-c and lk-2a-c, the N,N-diethyltiglic
amide 3, and the N,N-diethyldimethyloxiranecarboxamide 4,
the configurational assignment of ul-2a-c and lk-2a-c
amides, and the semiempirical calculations for the preferred
conformation of the amides (S)-1a-c. This material is
available free of charge on the Internet at http://pubs.acs.org.
OL990405S
(19) Taft, R. W.; Kamlet, M. J. J. Am. Chem. Soc. 1976, 98, 2886-
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1979.
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1022
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