Stereoselective Yang cyclizations of α-amido ketones

Article abstract of DOI:10.1039/a901723b

The photocyclization of methyl-substituted α-acetamido butyrophenone derivatives is highly stereoselective and leads to 2-aminocyclobutanols with complete control of three new stereogenic centers.

Full text of DOI:10.1039/a901723b

Stereoselective Yang cyclizations of a-amido ketones
Axel G. Griesbeck,* Heike Heckroth and Johann Lex
Institute of Organic Chemistry, University of Cologne, Greinstr. 4, D-50939 Köln, Germany.
E-mail: griesbeck@uni-koeln.de
Received (in Liverpool, UK) 4th March 1999, Accepted 29th April 1999
The photocyclization of methyl-substituted a-acetamido
butyrophenone derivatives is highly stereoselective and
leads to 2-aminocyclobutanols with complete control of
three new stereogenic centers.
diastereoisomer. The tert-leucine 1a and the leucine derivative
1b, respectively, were transformed into cyclobutanols with only
one additional stereogenic center and thus solely show the
influence of a given stereogenic center on a proximate radical
center. In both cases, the cis-diastereoisomers were formed with
ds > 96%.
The term Yang cyclization describes the formation of cyclobu-
tanols from 1-hydroxytetramethylene biradicals which are
produced via photochemical g-hydrogen abstraction.1 In the
course of this reaction up to eight diastereoisomers could be
formed from one chiral substrate molecule. Three subsequent
steps influence the chemo- and stereoselectivity of this reaction:
(i) g-H abstraction, (ii) biradical dynamics and (iii) biradical
combination vs. cleavage reaction. Triplet excited carbonyls
give rise to triplet 1,4-biradicals and, consequently, the lifetime
of these intermediates (100–1000 ns)2 rises due to slow spin
inversion processes (ISC). The g-H abstraction proceeds most
likely through a six-membered chair-like transition state.3
Detailed mechanistic investigations have been performed by
Wagner and co-workers which also included stereochemical
probing.4 During our studies on photochemical transformations
of enantiomerically pure a-amino acids (N-activation mode)5
we became interested in using Yang cyclizations as a simple
tool for the synthesis of 2-aminocyclobutanols (C-activation
mode). As substrates a-acetamido butyrophenone derivatives
1a–f were synthesized from the corresponding amino acids by a
three-step reaction protocol.6 The photochemical behaviour of
these compounds was investigated by irradiation with light l >
320 nm in benzene solutions (Scheme 1). The tert-leucine
derivative 1a gave the cyclobutanol 2a (FC = 0.11 ± 0.02) and
the Norrish II fragmentation product 3 (FF = 0.08 ± 0.02).7 The
Yang cyclization product was isolated in 45% yield as a single
Characteristic NMR shifts were observed for H-2 (d 4.2–4.8)
and the methyl groups in 2b which showed strong anisotropic
effects (Dd = 0.45 ppm).8 Additional proof came from the X-
ray structure analysis for 2b (Fig. 1).† A reasonable explanation
for the high 1,2-asymmetric induction might be an intra-
molecular hydrogen bond at the stage of the triplet 1,4-biradical
which has already been described for Yang cyclizations of a-
ester-substituted ketones.9 The valine derivative 1c cyclized
more efficiently (FC = 0.19 ± 0.02) and gave the cyclobutanol
2c in 74% yield with ds > 96%. The relative configuration was
established via X-ray structure analysis.† Two explanations for
the high 1,3-asymmetric induction are possible: selective g-H
abstraction from one of the diastereotopic methyl groups or
non-selective g-H abstraction followed by selection at the
biradical stage (radical combination vs. cleavage and/or hydro-
gen back transfer). Biradical dynamics most likely were
responsible for the results obtained with the isoleucine and
alloisoleucine derivatives (2S,3S)-1d and (2R,3S)-1d. Whereas
the (2S,3S)-isomer gave exclusively the Norrish II cleavage
product 3, (2R,3S)-1d cyclized efficiently to give the cyclobuta-
nol 2d. The latter compound again was formed diastereoisomer-
ically pure (i.e. ds > 96%) with complete control of the three
newly formed stereogenic centers. X-Ray structure analysis
completed the configuration analysis.†
R2
NHAc
R3
R2
R1
R4
NHAc
O
hν
Tol
R4
benzene
OH
Tol
R1
R3
1
2
R1
R2
R3 R4
C/F
Fig. 1 Crystal structures of the cyclobutanols 2b, 2c and 2d.
a
Me Me
H
H
50:50
49:51
74:26
33:67
48:52
b
c
e
f
H
H
H
H
H
Me Me
Finally, the unbranched substrates 2e and 2f (from norvaline
and norleucine, respectively) were investigated. Both substrates
preferentially showed fragmentation and, as a minor reaction
path, formation of the cyclobutanols 2e,f with excellent
diastereoselectivity. Thus, the radical coupling step also
proceeds with high inherent stereoselectivity in addition to the
1,2-induced stereoselectivity.
In the mechanistic scenario (vide supra) for the Yang
cyclization process induced and inherent diastereoselectivity
are related to two different steps: biradical dynamics and spin
inversion coupled with radical-radical combination. This rela-
tion is depicted in Scheme 2 for substrate (2R,3S)-2d. After
hydrogen abstraction from the more reactive methylene group,
equilibration of the triplet 1,4-biradical leads to three possible
conformers, anti, syn and synA. The energies of these species
were calculated using the PM3 method. The cyclization path is
not available from the anti-isomer, however, this structure is
less favourable compared with the syn-isomer. Hydrogen
Me
H
H
Me
Et
H
H
H
H
NHAc
H3C
H3C
NHAc
hν
Et
Tol
benzene
95%
OH
Tol
Me
O
(2R,3S)-1d
2d
NHAc
NHAc
hν
Et
Tol
Tol
benzene
95%
Me
O
O
(2S,3S)-1d
3
Scheme 1 C/F = cyclization/fragmentation ratio.
Chem. Commun., 1999, 1109–1110
1109

NHAc
Notes and references
Tol
(1) hν
† Crystal data for 2b: C15H21NO2·1/2H2O (from MeOH), M = 256.3,
monoclinic, a = 12.840(1), b = 18.077(1), c = 12.920(1) Å, b = 90.62(1)°,
space group C2/c, Mo-Ka, 11448 reflections measured, 1748 reflections
with I > 2s(I), R1 = 0.058, wR2 = 0.117. For 2c: C14H19NO2 (from
MeOH), M = 233.3, monoclinic, a = 7.459(1), b = 11.63(2), c = 15.652(3)
Å, b = 102.67(2)°, space group P21/c, Mo-Ka, 2478 reflections measured,
1202 reflections with I > 2s(I), R1 = 0.064 , wR2 = 0.119. For 2d:
C15H21NO2 (from MeOH), M = 247.33, orthorhombic, a = 7.546(1), b =
11.848(1), c = 15.712(1) Å, space group P212121, Mo-Ka, 3096 reflections
measured, 1942 reflections with I > 2s(I), R1 = 0.050, wR2 = 0.099.
CCDC 182/1248. See http://www.rsc.org/suppdata/cc/1999/1109/ for crys-
tallographic files in .cif format.
(2) ISC
O
(2R,3S)-1d
Tol
Tol
NHAc
NHAc
•
C-1
H
C-4
H
O
O
•
O
CH3
O
H
O
H
H
H
•
O
O
•
O
•
CHCH3
NH
•
NH
•
NH
CH3
–1
Tol
Tol
Tol
CHCH3
H
H
(–53.9 kcal mol–1
H
H3CHC
H3C
•
H
H
(–55.1 kcal mol–1
)
)
syn
(–57.0 kcal mol
)
syn´
anti
fragmentation (F)
1 N. C. Yang and D.-D. H. Yang, J. Am. Chem. Soc., 1958, 80, 2913.
2 J. C. Scaiano, Acc. Chem. Res., 1982, 15, 252; L. J. Johnston and J. C.
Scaiano, Chem. Rev., 1989, 89, 521.
cyclization (C)
cyclization (C)
3 A. E. Dorigo, M. A. McCarrick, R. J. Loncharich and K. N. Houk, J. Am.
Chem. Soc., 1990, 112, 7508; R. R. Sauers and L. A. Edberg, J. Org.
Chem., 1994, 59, 7061.
4 P. J. Wagner and B.-S. Park, Org. Photochem., 1991, 11, 227; P. J.
Wagner, in Handbook of Photochemistry and Photobiology, ed. W. M.
Horspool and P.-S. Song, CRC Press, Boca Raton, 1995, p. 449.
5 A. G. Griesbeck, Chimia, 1998, 52, 272; A. G. Griesbeck, EPA Newsl.,
1998, 3; A. G. Griesbeck, Liebigs Ann. Chem., 1996, 1951.
6 O. Itoh, T. Honnami, A. Amano, K. Murata, Y. Koichi and T. Sugita,
J. Org. Chem., 1992, 57, 7334.
Scheme 2 Mechanistic scenario for the photocyclization of (2R,3S)-1d.
bonding stabilizes all three possible conformers and is the major
contribution to the high 1,2-asymmetric induction.
The reverse is the case for (2S,3S)-2d and fragmentation
dominates the reaction due to the more stable triplet anti
1,4-biradical. This theory however, does not take into account
the fact that the calculated biradical minima structures are not
necessarily identical with the actual ISC-reactive structures.
Spin–orbit coupling, the major contribution to triplet/singlet
ISC, is higher for syn-biradicals10 and depends on the
orientation of the p-orbitals localized at the spin-bearing carbon
atoms.11 An orthogonal orientation of these orbitals prior to C–
C bond formation leads to a trans arrangement of the methyl at
C-4 and the tolyl group at C-1 (inherent diastereoselectivity).
Thus, the induced and inherent stereoselectivity of the Yang
cyclization can be correlated with different selection stages of
the reaction.
7 Quantum yields by actinometry (GC product analyses) using valer-
ophenone as standard with FF
= 0.33: P. J. Wagner and A. E.
Kemppainen, J. Am. Chem. Soc., 1972, 94, 7495.
8 F. D. Lewis and T. A. Hilliard, J. Am. Chem. Soc., 1972, 94, 3852.
9 T. Hasegawa, Y. Arata, M. Endoh and M. Yoshioka, Tetrahedron, 1985,
41, 1667; T. Hasegawa, Y. Arata and A. Kageyama, Tetrahedron Lett.,
1983, 24, 1995.
10 M. Klessinger, Pure Appl. Chem., 1997, 69, 773.
11 A. G. Griesbeck, S. Stadtmüller and H. Mauder, Acc. Chem. Res., 1994,
27, 70.
This work was supported by the Deutsche Forschungsge-
meinschaft, the Fonds der Chemischen Industrie and the
Universität zu Köln (postgraduate grant for H. H.)
Communication 9/01723B
1110
Chem. Commun., 1999, 1109–1110