Efficient π-facial control in the ene reaction of nitrosoarene, triazolinedione, and singlet oxygen with tiglic amides of the bornane-derived sultam as chiral auxiliary: An economical synthesis of enantiomerically pure nitrogen- and oxygen-functionalized

Article abstract of DOI:10.1021/ja026640e

The ene reaction of 4-nitronitrosobenzene (ArNO), N-phenyl-1,2,4-triazoline-3,5-dione (PTAD), and singlet oxygen (¹O₂) with the optically active tiglic-acid derivatives of Oppolzer's bornane-derived sultam affords the respective ene

Full text of DOI:10.1021/ja026640e

Published on Web 10/10/2002
Efficient π-Facial Control in the Ene Reaction of Nitrosoarene,
Triazolinedione, and Singlet Oxygen with Tiglic Amides of the
Bornane-Derived Sultam as Chiral Auxiliary: An Economical Synthesis of
Enantiomerically Pure Nitrogen- and Oxygen-Functionalized Acrylic Acid
Derivatives
Waldemar Adam,*,† Hans-Georg Degen, Oliver Krebs,* and Chantu R. Saha-Mo¨ller
Institut fu¨r Organische Chemie, UniVersita¨t Wu¨rzburg, Am Hubland, D-97074 Wu¨rzburg, Germany
Received April 23, 2002
The ene reaction of singlet oxygen (1O2) and N-phenyl-1,2,4-
Table 1. Product Studies for the Ene Reaction of ArNO, PTAD
and 1O2 with the Optically Active Tiglic Amides 1a,b
triazoline-3,5-dione (PTAD) has been extensively used for the
allylic functionalization of double bonds in a variety of olefins.1
Recently, also the nitrosoarene (ArNO) enophile has been success-
fully utilized for the regioselective2 and stereoselective3 synthesis
of nitrogen-functionalized compounds.1b,4 Generally, for stereose-
lective control, chiral auxiliaries may be employed, a powerful tool
in asymmetric synthesis.5 Unquestionably, the economical prepara-
ene product
tion of optically active heteroatom-functionalized acids derivatives,
dra,b
lk:ul
in particular â-amino acids, has become an attractive goal, since
these substances, and especially the therefrom derived peptides,
are of biological and pharmaceutical interest.6 For example, whereas
a variety of methods is available to prepare optically active â-amino
acids,6,7 the synthesis of highly functionalized R-methylene â-amino
acids is still demanding. Herein we demonstrate that the chiral-
auxiliary-mediated regioselective and stereoselective ene reaction
enophile
X ) Y
time
[d]
convn
[%]a,c
mb
yield
[%]d
Alk
[%]a,c
1
2
3
4
5
1a Me ArNOe
1b iPr
ArNO
2
1
1
1
3
85
77
>95
>95
90
80 2a
61f
55f
80f
90g
78g
>95:5
>95:5
>95: 5
83:17
79 2b
>95 3a
>95 4a
87 4b
1a Me PTAD
1a Me 1O2
1b iPr
1O2
>95: 5
1
a The reactions were run in CDCl3 and analyzed by H NMR spectros-
1
of ArNO, PTAD, and O2 with tigloyl sultams affords enantio-
merically pure acrylic-acid derivatives.
copy; error (5% of the stated values. b The configurations were assigned
by chemical correlation. c Based on olefin, versus tetrachlorethane or
pentafluorobenzene as internal standards. d Isolated material. e Ar ) p-NO2-
C6H4, 2.5 equiv. f From preparative runs in CH2Cl2. g From semipreparative
runs in CDCl3; yield of alcohol obtained by Ph3P reduction of the
hydroperoxide.
After extensive screening for a suitable chiral auxiliary, we found
that the optically active tiglic-acid derivatives of the bornane-derived
sultam8 afforded the desired ene products in high yield and excellent
regioselectivity and diastereoselectivity (Table 1). Only one dias-
tereomer was obtained for the ene reaction of ArNO and PTAD
with the tiglic amide 1a, while 1O2 afforded a 83:17 mixture of the
like and unlike diastereomers. To raise the diastereoselectivity for
1O2, the steric demand of the lone substituent2a in the substrate was
Scheme 1. Configurational Assignment for the Ene Products 3a
of PTAD and 4a,b of 1O2 by Chemical Correlationa
i
increased by employing the amide 1b (Alk ) Pr). Indeed, even
for 1O2, the smallest possible enophile, absolute diastereoselectivity
was achieved with this isopropyl derivative. As expected, the ene
reaction of ArNO with 1b also yielded the diastereomerically pure
ene product 2b in good yield.
a For 1O2, the ene products 4a,b are the corresponding alcohols after
Ph3P reduction (see Table 1, footnote g).
The configurational assignment of all four ene products 2-4 was
achieved by chemical correlation. The sultam auxiliary was removed
in the ene products by hydrolysis (PTAD), methanolysis (1O2), and
silica gel treatment (ArNO) for all three enophiles in one step. The
PTAD adduct 3a was converted with LiOH to the corresponding
amino acid derivative 6a (Scheme 1), its absolute configuration
was determined by comparison of the [R]D value (-57.2°) with
that of the known enantiomer (S)-6a (+61.7°),9 which establishes
also the R configuration of the newly formed stereocenter in the
1O2 ene products 4a,b. The authentic racemic samples rac-7a,b,
which were required for HPLC analysis as references, were prepared
according to the literature procedures11 (cf. Supporting Information).
Remarkable is the case of the nitroso enophile: The primary
ene products 2a,b were converted by silica gel treatment quanti-
tatively to the highly functionalized R-methylene isoxazolidinones
5a,b (Scheme 2). Reduction of their N-O bond with Na2S2O4
provided the â-amino acids 8a (8b) in 75% (84%) yield. An
independent synthesis of (R)-8a was carried out to assign the
configuration of the newly formed stereogenic center in the ene
product 2a. As described in the literature,12 the free ammonium
salt (R)-9a was prepared in seven steps starting from the racemic
1
the like configuration for urazole 3a. The O2 ene products 4a,b
were converted with sodium methoxide to the corresponding methyl
esters 7a,b. Comparison of the HPLC retention times and signs of
their optical rotations with those reported in the literature,10 revealed
* Corresponding authors.
† E-mail: adam@chemie.uni-wuerzburg.de. http://www-organik.chemie.uni-
wuerzburg.de/ak_adam/.
9
12938
J. AM. CHEM. SOC. 2002, 124, 12938-12939
10.1021/ja026640e CCC: $22.00 © 2002 American Chemical Society

C O M M U N I C A T I O N S
Scheme 2. Silica-Gel-Mediated Cyclization of the Nitroso Ene
Products 2 to the Isoxazolidinones 5, Reduction to the
Corresponding â-Amino Acids 8, and Determination of the
Configurations by Chemical Correlation
the sulfonyl groups with the double bond substituents. For this well-
locked conformation, the C(â)-re attack15 of the enophile is favored,
whereas the C(â)-si attack is efficiently shielded by the sulfonyl
oxygen atoms.16 By employing the sterically more demanding
isopropyl derivative 1b, the diastereoselectivity is increased, and
1
even for O2 exclusively one diastereomer was obtained. This is
the first example of absolute diastereoselectivity in 1O2 ene reaction
controlled by steric effects. Moreover, the high ene reactivity of
the “electron-poor” double bond in the tiglic sulfonamides toward
the enophiles, particularly ArNO, may be reconciled by the twisted
conformation of the double bond and the carbonyl functionality,
which reduces conjugation between the carbonyl group and the CC
double bond17 sufficiently such that the ene reactions proceed in
high yield.
In conclusion, this asymmetric allylic heteroatom functionaliza-
tion of the readily available tiglic sultams 1a,b provides an efficient
and economical route to valuable optically active building blocks.
Moreover, since both enantiomers of the bornane auxiliary are easily
accessible from (+)- and (-)-camphor, both stereoisomers of the
ene product are available.8 The cumbersome conventional synthesis
of the â-amino acid 9a in seven steps in only 5% overall yield and
93% enantiomeric purity (Scheme 2) emphasizes the convenience
and advantage of the present synthetic concept.
Scheme 3. Preferred Conformation of the Olefin in the π-Facially
Diastereoselective Enophilic Attack of ArNO, PTAD, and 1O2
Acknowledgment. The generous financial support by the
Deutsche Forschungsgemeinschaft (DFG Schwerpunkt) and the
Fonds der Chemischen Industrie is gratefully appreciated.
Supporting Information Available: Structure matrix and experi-
mental section (PDF). This material is available free of charge via the
Internet at http://pubs.acs.org.
â-hydroxy ester rac-7a, which included lipase-catalyzed kinetic
resolution of the hydroxy ester in an enantiomeric excess of 93%.
Arylation of the ammonium salt (R)-9a afforded the â-amino acid
(R)-8a.13 The optical rotations ([R]D ) +2.4°) of the â-amino acid
8a, derived from the ene product 2a, and the authentic material
(R)-8a matched perfectly in sign and extent. To confirm the
authenticity and the enantiomeric purity of the isoxazolidinone 5a,
obtained from the ene product 2a, the racemic sample rac-5a was
required for chiral HPLC analysis. The latter was prepared by
cyclization of the racemic ene product of ArNO with methyl tiglate
(cf. Supporting Information). The isopropyl derivatives 5b and 8b
are also R-configured, since their optical rotations (5b -381.7°;
8b +4.9°) match those of the methyl derivatives 5a (-421.7°) and
8a (+2.4°). Thus, in the ene reaction of ArNO with the tiglic amides
1a,b, the like diastereomers lk-2a,b were exclusively formed.
The mechanistic rationalization of the very high diastereoselec-
tivity in the ene reaction for all three enophiles ArNO, PTAD, and
1O2 requires knowledge of the preferred conformation of the
bornane-derived tiglic-acid sultamides. Informative in this regard
is the known X-ray structure of tigloyl sultam 1a,14 and we assume
that the preferred ground-state conformation in the crystalline state
also applies in solution, to account for the observed selectivity in
the π-facial attack (Scheme 3). The carbonyl group points away
from the sulfonyl functionality, due to mutual electrostatic repulsion
and the steric interaction between the CC double bond substituents
and the bornane skeleton (C-N rotation). Furthermore, the carbonyl
group and the double-bond possess the s-trans conformation (C-C
rotation) about the clockwise-twisted C(R)-CO bond (the dihedral
angle is 46° in the X-ray structure). This conformation results from
the balance between the steric interactions of the carbonyl and of
References
(1) (a) Clennan, E. L. Tetrahedron 2000, 56, 9151-9179. (b) Johannsen, M.;
Jørgensen, K. A. Chem. ReV. 1998, 98, 1689-1708.
(2) (a) Adam, W.; Bottke, N.; Krebs, O. J. Am. Chem. Soc. 2000, 122, 6791-
6792. (b) Adam, W.; Bottke, N.; Krebs, O.; Engels, B. J. Am. Chem. Soc.
2001, 123, 5542-5548.
(3) Adam, W.; Bottke, N. J. Am. Chem. Soc. 2000, 122, 9846-9847.
(4) Adam, W.; Bottke, N.; Krebs, O.; Saha-Mo¨ller, C. R. Eur. J. Org. Chem.
1999, 1963-1965.
(5) (a) Jones, S. J. Chem. Soc., Perkin Trans. 1 2002, 1-21. (b) Adam, W.;
Peters, K.; Schambony, S. B. J. Am. Chem. Soc. 2000, 122, 7610-7611.
(c) Kim, B. H.; Curran, D. P. Tetrahedron 1993, 49, 293-318.
(6) (a) Seebach, D.; Overhand, M.; Ku¨hnle, F. N. M.; Martinoni, B.; Oberer,
L.; Hommel, U.; Widmer, H. HelV. Chim. Acta 1996, 79, 913-945. (b)
Cole, D. C. Tetrahedron 1994, 50, 9517-9582. (c) Gademann, K.;
Seebach, D. HelV. Chim. Acta 2001, 84, 2924-2937.
(7) (a) Smith, M. B. Methods of Non-R-Amino Acid Synthesis; Marcel
Dekker: New York, 1995. (b) Juaristi, E. EnantioselectiVe Synthesis of
â-Amino Acids; Wiley-VCH: New York, 1997.
(8) (a) Oppolzer, W.; Poli, G.; Kingma, A. J.; Starkemann, C.; Bernardinelli,
G. HelV. Chim. Acta 1987, 70, 2201-2214. (b) Oppolzer, W. Angew.
Chem., Int. Ed. Engl. 1984, 23, 876-890.
(9) (a) Adam, W.; Wirth, T.; Pastor, A.; Peters, K. Eur. J. Org. Chem. 1998,
501-506. (b) Wirth, T. Dissertation, University of Wu¨rzburg, 1998.
(10) (a) Adam, W.; Hoch, U.; Saha-Mo¨ller, C. R.; Schreier, P. Angew. Chem.,
Int. Ed. Engl. 1993, 32, 1737-1739. (b) Adam, W.; Fell, R. T.; Hoch,
U.; Saha-Mo¨ller, C. R.; Schreier, P. Tetrahedron: Asymmetry 1995, 6,
1047-1050. (c) Hoch, U. Dissertation, University of Wu¨rzburg, 1996.
(11) Drewes, S. E.; Hoole, R. F. A. Synth. Commun. 1985, 15, 1067-1074.
(12) (a) Adam, W.; Groer, P.; Saha-Mo¨ller, C. R. J. Org. Chem. 2000, 65,
4919-4922. (b) Groer, P. Dissertation, University of Wu¨rzburg, 2000.
(13) Zyss, J.; Nicoud, J. F. J. Chem. Phys. 1984, 81, 4160-4167.
(14) Oppolzer, W.; Poli, G.; Starkemann, C.; Bernardinelli, G. Tetrahedron
Lett. 1988, 29, 3559-3562.
(15) Since only one stereogenic center is formed in these ene reactions, namely
at the â position of the CC double bond, the descriptor for the π-face
attack refers to the â-carbon atom.
(16) Curran, D. P.; Kim, B. H.; Daugherty, J.; Heffner, T. A. Tetrahedron
Lett. 1988, 29, 3555-3558.
(17) Curran, D. P.; Heffner, T. A. J. Org. Chem. 1990, 55, 4585-4595.
JA026640E
9
J. AM. CHEM. SOC. VOL. 124, NO. 44, 2002 12939