Diastereoselective and regioselective singlet-oxygen ene reaction of oxazolidine-substituted alkenes: Control through hydrogen bonding mediated by the urea functionality of chiral auxiliaries [10]

Full text of DOI:10.1021/ja001113l

7610
J. Am. Chem. Soc. 2000, 122, 7610-7611
The oxazolidines 1a-d were synthesized by condensing
S-phenylglycinol with 3-methyl-2-butenal in analogy with the
reported procedure,8 followed by acylation (Scheme 1). The
Diastereoselective and Regioselective Singlet-Oxygen
Ene Reaction of Oxazolidine-Substituted Alkenes:
Control through Hydrogen Bonding Mediated by the
Urea Functionality of Chiral Auxiliaries
Scheme 1a
Waldemar Adam,† Karl Peters,‡ Eva-Maria Peters,‡ and
Simon B. Schambony*,†
Institut fu¨r Organische Chemie, UniVersita¨t Wu¨rzburg
D-97074 Wu¨rzburg, Germany
Max-Planck-Institut fu¨r Festko¨rperforschung
Heisenbergstrasse 1, D-70569 Stuttgart, Germany.
a (i) molecular sieves (4 Å), CH2Cl2, 20 °C, 3 h. (ii) 1a (X ) OtBu):
Boc2O, EtOAc, 77 °C, 15 h; 1b (X ) Ph): PhCOCl, N-methylmorpholine,
CH2Cl2, 20 °C, 10 h; 1c/1d (X ) ArNH, see Table 1): ArNCO, Et2O/
CH2Cl2, 20 °C, 16 h. (iii) CH3I, KOH, DMSO, 20 °C, 16 h.
ReceiVed March 30, 2000
ReVised Manuscript ReceiVed May 15, 2000
The ene reaction between singlet oxygen (1O2) and alkenes with
allylic hydrogen atoms has attracted much attention in the last
years both from the synthetic1 and mechanistic2 points of view.
Most attention has been directed toward the stereochemical control
of the new stereogenic center that is formed in this process.3
Although much data has by now been accumulated to define the
prerequisites for high diastereoselectivity in this reaction, all
attempts hitherto to achieve chiral-auxiliary-induced diastereo-
meric control in the singlet-oxygen ene reaction led only to low
or at best moderate (dr e 82:18) selectivities.3,4 Nevertheless,
chiral auxiliaries have been successfully employed in directing
effectively the stereochemical course of a great variety of reaction
types,5 also that of singlet oxygen ([4 + 2] cycloaddition).6 The
facts at hand accentuate that singlet oxygen, the smallest possible
enophile, is not sensitive enough to the steric repulsion usually
exerted by the chiral auxiliaries and that such an approach
seems futile. Clearly, a completely different strategy must be
used for achieving efficient diastereoselectivity mediated by
chiral auxiliaries in the singlet-oxygen ene reaction.
N-methylated oxazolidine 1e was prepared by methylation of
N-phenyl derivative 1c. The like relative configuration of the
stereogenic centers in the oxazolidine ring was assessed by NOE
spectroscopy for all cases.
The oxazolidines 1 were photooxygenated at low temperature
(-5 °C or below) by using 5,10,15,20-tetrakis(pentafluorophenyl)-
porphine (TPFPP) as sensitizer, followed by in situ reduction of
the resulting hydroperoxides with triphenylphosphine. The allylic
alcohols 3 were obtained as main regioisomers, along with some
of the spiro-dioxolanes 4 (Table 1) that arise from hydrogen
Table 1. Regio- and Diastereoselectivities in the Photooxygenation
of the Optically Active Oxazolidines 1
The recently established hydroxy-group directiVity3b in the
photooxygenation of chiral allylic alcohols with 1,3-allylic strain
has focused on the efficacy of electronic interactions through
hydrogen bonding between the substrate and singlet oxygen.
Herein we report that, indeed, a high chiral-auxiliary-controlled
diastereoselectivity may be realized by providing beneficial
hydrogen bonding in the ene reaction between singlet oxygen and
an urea functionality. As chiral auxiliaries, we chose optically
active N-acetylated oxazolidines,7,8 which are readily removed
after the key diastereoselective step,8 and are structurally related
to those introduced by Kanemasa and Porter.11
conditions
selectivityb
T
td mbb,c regio diastereo
entry substrate
X
solvent [°C] [h] [%] (3:4) (lk-3:ul-3)
1
2
3
4
5
6
1a
1b
1c
1c
1d
1e
OtBu
Ph
CCl4
-5 20
-5 23
-5
92 75:25
86 86:14
>95 93: 7
72 96: 4
25:75
45:55
94: 6
85:15
CDCl3
NHPh CDCl3
4
NHPh d6-acetone -10 40
NHAre CDCl3
NMePhf CDCl3
-10 28
-10 48
85 96: 4 >95: 5
90 70:30 41:59
a Sensitizer was 5,10,15,20-tetrakis(pentafluorophenyl)porphine (TPF-
PP). b Determined by H NMR spectroscopy with 1,2-diphenylethane
1
as internal standard, error (5% of the stated value. c Mass balance.
d Time needed for full conversion (>95%). e p-Nitrophenyl. f Dimethyl
isophthalate as internal standard.
† Institut fu¨r Organische Chemie. Fax: +49(0)931/8884756. E-mail:
adam@chemie.uni-wuerzburg.de. Internet: http://www-organik.chemie.uni-
wuerzburg.de.
‡ Max-Planck-Institut fu¨r Festko¨rperforschung.
(1) (a) Adam, W.; Griesbeck, A. Angew. Chem., Int. Ed. Engl. 1985, 24,
1070-1071. (b) Adam, W.; Bru¨nker, H.-G. Synthesis 1995, 1066-1068. (c)
Adam, W.; Renze, J.; Wirth, T. J. Org. Chem. 1998, 63, 226-227.
(2) (a) Orfanopoulos, M.; Stratakis, M.; Elemes, Y. Tetrahedron Lett. 1989,
30, 4875-4878. (b) Clennan, E. L.; Chen, X.; Koola, J. J. J. Am. Chem. Soc.
1990, 112, 5193-5199.
(3) (a) Adam, W.; Prein, M. Angew. Chem., Int. Ed. Engl. 1996, 35, 477-
494. (b) Adam, W.; Wirth, T. Acc. Chem. Res. 1999, 32, 703-710.
(4) (a) Adam, W.; Griesbeck, A. Synthesis 1986, 1050-1052. (b) Adam,
W.; Bru¨nker, H.-G.; Nestler, B. Tetrahedron Lett. 1991, 32, 1957-1960. (c)
Dussault, P. H.; Woller, K. R.; Hillier, M. C. Tetrahedron 1994, 50, 8929-
8940. (d) Adam, W.; Wirth, T.; Pastor, A.; Peters, K. Eur. J. Org. Chem.
1998, 4, 501-506.
(5) (a) Atta-ur-Rahman; Shah, Z. StereoselectiVe Synthesis in Organic
Chemistry, Springer: New York, 1993. (b) Atkinson, R. S. StereoselectiVe
Synthesis, John Wiley & Sons: Chichester, 1997. (c) Regan, A. C. J. Chem.
Soc., Perkin Trans. 1 1999, 357-373. (d) Ru¨ck-Braun, K.; Kunz, H. Chiral
Auxiliaries in Cycloadditions; Wiley-VCH: Weinheim, 1999.
(6) Adam, W.; Gu¨thlein, M.; Peters, E.-M.; Peters, K.; Wirth, T. J. Am.
Chem. Soc. 1998, 120, 4091-4093.
(7) (a) Colombo, L.; Gennari, C.; Poli, G.; Scolastico, C. Tetrahedron
Lett. 1985, 26, 5459-5462. (b) Cardani, S.; Poli, G.; Scolastico, C.; Villa,
R. Tetrahedron 1988, 44, 5929-5938. (c) Hussain, A.; Wyatt, P. B.
Tetrahedron 1993, 49, 2123-2130. (d) Colombo, L.; DiGiacomo, M.;
Brusotti, G.; Milano, E. Tetrahedron Lett. 1995, 36, 2863-2866. (e) Agami,
C.; Couty, F.; Lam, H.; Mathieu, H. Tetrahedron 1998, 54, 8783-8796. (f)
Garc´ıa-Valverde, M.; Nieto, J.; Pedrosa, R.; Vicente, M. Tetrahedron 1999,
55, 2755-2762.
(8) Agami, C.; Couty, F.; Hamon, L.; Venier, O. J. Org. Chem. 1997, 62,
2106-2112.
(9) (a) Kanemasa, S.; Suenaga, H.; Onimura, K. J. Org. Chem. 1994, 59,
6949-6954. (b) Porter, N. A.; Rosenstein, I. J.; Breyer, R. A.; Bruhnke, J.
D.; Wu, W.-X.; McPhail, A. T. J. Am. Chem. Soc. 1992, 114, 7664-7676.
(10) Peters, K.; Peters, E.-M.; Adam, W.; Schambony, S. B. Z. Kristallo-
graph. NCS 2000, 215, 213-214.
(11) (a) Adam, W.; Bru¨nker, H.-G.; Kumar, A. S.; Peters, E.-M.; Peters,
K.; Schneider, U.; von Schnering, H. G. J. Am. Chem. Soc. 1996, 118, 1899-
1905. (b) Linker, T.; Fro¨hlich, L. Angew. Chem., Int. Ed. Engl. 1994, 33,
1971-1972.
10.1021/ja001113l CCC: $19.00 © 2000 American Chemical Society
Published on Web 07/21/2000

Communications to the Editor
J. Am. Chem. Soc., Vol. 122, No. 31, 2000 7611
abstraction at the aminal position in the substrates 1, followed
by cyclization of the resulting hydroperoxides. The relative
configuration of the predominantly formed allylic alcohol 3c was
determined by X-ray analysis.10 Comparison of the NMR data
did not allow a definitive assignment of the configurations for
the other derivatives; however, for the reported bromination of
similar oxazolidine-substituted olefins, the usually observed unlike
selectivity was established8 and by chemical correlation assessed
for 3a, 3b, and 3e.
reVersed! This impressive selectivity cannot be explained in terms
of steric or electrostatic interactions, as proposed for the urethane
(1a) and amide (1b) substrates. Instead, electronic attraction
through hydrogen bonding between the negatively charged
terminal oxygen atom and the favorably oriented NH donor of
the urea functionality in the like exciplex (Scheme 2) manifests
itself, which lowers the barrier of the exciplex formation. Since
such coordination is prohibited in the unlike exciplex, the like
product is formed predominately, in compliance with the observed
high diastereoselectivity. In addition, an excellent regioselectivity
accompanies the photooxygenation of the derivatives 1c and 1d;
presumably in the preferred like exciplex, the hydrogen bonding
of the singlet oxygen to the NH group impedes the abstraction
of the aminal hydrogen atom (see Scheme 2). The high regiose-
lectivity coupled with the excellent diastereoselectivity (cf. Table
1) is fortunate and speaks unequivocally for the efficacy of
hydrogen bonding in oxygen-transfer processes.3b That hydrogen
bonding operates as controlling factor is further emphasized by
the fact that in the more polar solvent acetone, the diastereo-
selectivity of the ene reaction drops significantly (cf. Table 1,
entry 4). The beneficial intra-exciplex hydrogen bonding is
disturbed through competing intermolecular associations of the
substrate to acetone molecules. Similar to the ene reaction of
allylic alcohols and derivatives with singlet oxygen,12 no ap-
preciable effect has been detected on the regioselectivity. The
dioxolanes 4c and 4d stem from the unlike exciplex (Scheme 2),
which constitutes a minor pathway and the expected change in
the regioselectivity in acetone versus chloroform is too small
to be sensed within experimental error. However, capping of
the NH functionality by methylation, as in the derivative 1e,
not only completely erases the control of diastereoselectivity,
it significantly reduces also the regioselectivity (cf. Table 1,
entry 6).
The ene reaction of the oxazolidines 1a and 1b with 1O2
(entries 1 and 2 in Table 1) displays the moderate or even low
diastereoselectivity that is usually found in attempted chiral-
auxiliary-controlled singlet-oxygen ene reactions.4 The observed
slight preference for the unlike attack of singlet oxygen, that is,
opposite to the urethane (1a, X ) OtBu) and amide (1b, X )
Ph) functionalities, may be understood in terms of the repulsive
(electrostatic, steric) interactions between the incoming singlet
oxygen and the carbonyl substituent on the nitrogen atom that
shields the like face of the double bond (Scheme 2). This
Scheme 2
In summary, the present results show convincingly that the
diastereoselectivity as well as the regioselectivity in the ene mode
of singlet oxygen may be effectively steered by chiral oxazolidine
auxiliaries through hydrogen bonding between the NH group of
the urea functionality and the attacking singlet oxygen. Although
the directing propensity of hydroxy12 and amino13 groups to act
as efficient hydrogen donors in the singlet-oxygen ene reaction
is well documented, it is unprecedented for the NH hydrogen-
bonding donor of an urea functionality, especially, since it is
attached to the chiral auxiliary. Subsequent removal of the chiral
auxiliary opens up promising prospects in the preparation of
optically active building blocks for asymmetric synthesis.
interaction may derive from a weak electrostatic repulsion between
the partially negatively charged carbonyl oxygen11 and the
negatively polarized singlet oxygen or a weak steric interaction
between singlet oxygen and the substituent of the carbonyl moiety
(tBuO or Ph in 1a or 1b). Furthermore, the appreciable (up to
25%) amounts of the 1,2-dioxolanes 4, formed by cyclization of
the minor regioisomer (path a in Scheme 3), reflect the moderate
regioselectivity of the reaction.
Acknowledgment. The generous financial support by the Deutsche
Forschungsgemeinschaft (Schwerpunktprogramm “Peroxidchemie: Mech-
anistische und pra¨parative Aspekte des Sauerstofftransfers”) and the Fonds
der Chemischen Industrie (doctoral fellowship 1998-2000 for S.B.S.) is
gratefully appreciated. We thank Professor Dr. K.-H. Drauz and Dr. M.
Schwarm (Degussa-Hu¨ls AG, Hanau) for generous gifts of optically active
phenylglycinol.
Scheme 3
Supporting Information Available: Experimental details (PDF). This
material is available via the Internet at http://pubs.acs.org.
In contrast to the low selectivities in the above ene reactions,
the photooxygenation of the ureas 1c and 1d in CDCl3 (Table 1,
entries 3 and 5) yielded, after in situ reduction, the corresponding
like allylic alcohols lk-3c and lk-3d nearly exclusively. Not only
does this oxyfunctionalization proceed highly diastereo- and
regioselectively, but also the sense of the preferred attack is
JA001113L
(12) (a) Adam, W.; Nestler, B. J. Am. Chem. Soc. 1992, 114, 6549-6550.
(b) Adam, W.; Nestler, B. J. Am. Chem. Soc. 1993, 115, 5041-5049.
(13) (a) Adam, W.; Bru¨nker, H.-G. J. Am. Chem. Soc. 1993, 115, 5, 3008-
3009. (b) Bru¨nker, H.-G.; Adam, W. J. Am. Chem. Soc. 1995, 117, 3976-
3982.