A highly stereoselective aza-[3,3]-Claisen rearrangement of vinylaziridines as a novel entry to seven-membered lactams

Full text of DOI:10.1021/ja971572v

J. Am. Chem. Soc. 1997, 119, 8385-8386
A Highly Stereoselective Aza-[3,3]-Claisen
8385
Rearrangement of Vinylaziridines as a Novel Entry
to Seven-Membered Lactams
Ulf M. Lindstro¨m and Peter Somfai*
(1)
Organic Chemistry 2, Center for Chemistry and
Chemical Engineering, Lund Institute of Technology
Lund UniVersity, P.O. Box 124, S-221 00 Lund, Sweden
ReceiVed May 15, 1997
N-Alkyl and N-sulfonyl vinylaziridines have received con-
siderable interest as intermediates in the stereoselective synthesis
of alkaloids and peptidomimetics, and, as a consequence, several
efficient routes toward them have been developed.11,12 Some-
what surprisingly, the corresponding N-acyl and N-H vinylaziri-
dines, which might serve as a precursor for all types of
vinylaziridines, have received less attention, and, prior to this
investigation, no general and enantioselective synthesis of them
has been documented. The N-acyl vinylaziridines 4a-g
required for the present study were prepared from the corre-
sponding vinylepoxides 1a-d13 (ee >95%) as outlined in
Scheme 1. Acid-catalyzed aminolysis of 1 resulted in a
stereospecific and highly regioselective ring-opening to give
amino alcohols 2 (69-93%).14 The subsequent ring closure
was best effected using the standard Mitsunobu protocol,15
affording aziridines 3 (49-54%) and treatment of these materials
with acetic anhydride, propionic anhydride, benzyloxyacetic
anhydride, or N-Boc glycine anhydride16 gave the N-acyl
vinylaziridines 4a-g, the precursors for the projected rear-
rangement. The crude products from the acylation step were
Sigmatropic rearrangements provide a powerful tool for
stereocontrolled bond construction. Of these reactions, those
variants in which a carbon-heteroatom bond, which is normally
easily formed, is transformed into a carbon-carbon bond have
proven particularly useful, prominent examples being the [2,3]-
Wittig and [3,3]-Claisen rearrangements.1,2 The often excellent
stereoselectivities obtained in these reactions are usually
rationalized by assuming cyclic transition states in which the
stereochemical information embedded in the substrate is ef-
fectively communicated, for steric or stereoelectronic reasons,
to the product. The main thrust in this area has traditionally
been directed toward substrates in which the migrating bond is
a C-O σ-bond, while other heterologs have received consider-
ably less attention. In this respect we,3 and others,4 have
recently documented the use of variously N-substituted vinyl-
aziridines as substrates in the aza-[2,3]-Wittig rearrangement
to yield the corresponding di- or trisubstituted tetrahydropy-
ridines in high yield (a, eq 1), the driving force being the relief
of ring strain.5 It was also demonstrated that the stereochemical
outcome of the reaction is dependent on the substitution pattern
of the aziridine nuclei. In an effort to expand the synthetic
potential of vinylaziridines we became interested in the pos-
sibility of using them in an aza-[3,3]-Claisen rearrangement,2b,6
thus providing a novel entry to seven-membered lactams (b, eq
1),7,8 compounds that are of interest in natural product synthesis9
and as peptide turn mimetics.10 Herein we disclose our
preliminary findings in this area.
1
judged to be >95% pure according to H NMR spectroscopy.
However, attempts to purify 4b on silica gel resulted in a
quantitative rearrangement into the corresponding trans-4,5-
disubstituted oxazoline 5,17 and, consequently, the crude prod-
ucts from the acylation step were used directly in the subsequent
Claisen rearrangements, the yields of which thus refer to such
two-step sequences.
The results of the aza-[3,3]-Claisen rearrangements are
collected in Scheme 2. When N-acetyl vinylaziridine 4a was
added to LiHMDS in THF at -78 °C followed by slowly
warming the resultant mixture to room temperature, lactam 6a
* Corresponding author. Telephone: +46 46 2228220. FAX: +46 46
2228209. E-mail: peter.somfai@orgk2.lth.se.
(1) Nakai, T.; Mikami, K. Org. React. 1994, 46, 105-209. Marshall, J.
A. In ComprehensiVe Organic Synthesis; Trost, B. M., Fleming, I., Eds.;
Pergamon: Oxford, 1991; Vol. 3, Chapter 3.11. Mikami, K.; Nakai, T.
Synthesis 1991, 594-604.
(2) (a) Kazmaier, U. Liebigs Ann./Recueil 1997, 285-295. (b) Enders,
D.; Knopp, M.; Schiffers, R. Tetrahedron: Asymmetry 1996, 7, 1847-
1882. (c) Frauenrath, H. In Houben-Weyl E 21; Helmchen, G., Hoffmann,
R. W., Mulzer, J., Schaumann, E., Eds.; Thieme: Stuttgart, 1996; Vol. 6,
Chapter 1.6.3.1. (d) Pereira, S.; Srebnik, M. Aldrichim. Acta 1993, 26, 17-
29. (e) Wipf, P. In ComprehensiVe Organic Synthesis; Trost, B. M., Fleming,
I., Eds.; Pergamon: Oxford, 1991; Vol. 5, Chapter 7.2. (f) Hill, R. K. In
Asymmetric Synthesis; Morrison, J. D., Ed.; Academic: Orlando, 1984; Vol.
3, Chapter 8.
(3) (a) A° hman, J.; Jareva˚ng, T.; Somfai, P. J. Org. Chem. 1996, 61,
8148-8159. (b) A° hman, J.; Somfai, P. Tetrahedron Lett. 1996, 37, 2495-
2498. (c) A° hman, J.; Somfai, P. J. Am. Chem. Soc. 1994, 116, 9781-9782.
(4) Coldham, I.; Collis, A. J.; Mould, R. J.; Rathmell, R. E. J. Chem.
Soc., Perkin Trans. 1 1995, 2739-2745.
(5) For a general discussion, see: Strain-Assisted Syntheses; Ghosez, L.,
Ed.; Tetrahedron Symposia-in-Print 38; Tetrahedron 1989, 45, 2875-3231.
(6) For previous attempts in this area, see: Gilbert, J. C.; Cousins, K.
R. Tetrahedron 1994, 50, 10671-10684. Tsunoda, T.; Sasaki, O.; Itoˆ, S.
Tetrahedron Lett. 1990, 31, 727-730. Kurth, M. J.; Brown, E. G. Synthesis
1988, 362-366. Kurth, M. J.; Soares, C. J. Tetrahedron Lett. 1987, 28,
1031-1034. Kurth, M. J.; Decker, O. H. W.; Hope, H.; Yanuck, M. D. J.
Am. Chem. Soc. 1985, 107, 443-448. Hill, R. K.; Khatri, H. N. Tetrahedron
Lett. 1978, 4337-4340. Jolidon, S.; Hansen, H.-J. HelV. Chim. Acta 1977,
60, 978-1032.
(7) For the rearrangement of N-vinyl and N-aryl vinylaziridines into
azepines, see: Hudlicky, T.; Fan, R.; Reed, J. W.; Gadamasetti, K. G. Org.
React. 1992, 41, 1-133.
(8) For an aza-[2,3]-Wittig rearrangement of 1-benzyl-4-vinyl-2-azeti-
dinones into the corresponding seven-membered lactams, see: Durst, T.;
Elzen, R. V. D.; LeBelle, M. J. J. Am. Chem. Soc. 1972, 94, 9261-9263.
(9) Evans, P. A.; Holmes, A. B. Tetrahedron 1991, 47, 9131-9166.
(10) Robl, J. A.; Cimarusti, M. P.; Simpkins, L. M.; Weller, H. N.; Pan,
Y. Y.; Malley, M.; DiMarco, J. D. J. Am. Chem. Soc. 1994, 116, 2348-
2335. Brady, S. F.; Paleveda, W. J., Jr.; Arison, B. H.; Saperstein, R.; Brady,
E. J.; Raynor, K.; Reisine, T.; Veber, D. F.; Freidinger, R. M. Tetrahedron
1993, 49, 3449-3466. Yanagisawa, H.; Ishihara, S.; Ando, A.; Kanazaki,
T.; Miyamoto, S.; Koike, H.; Iijima, Y.; Oizumi, K.; Matsushita, Y.; Hata,
T. J. Med. Chem. 1988, 31, 422-428.
(11) For recent applications of vinylaziridines in organic synthesis, see:
Ibuka, T.; Mimura, N.; Aoyama, H.; Akaji, M.; Ohno, H.; Miwa, Y.; Taga,
T.; Nakai, K.; Tamamura, H.; Fujii, N.; Yamamoto, Y. J. Org. Chem. 1997,
62, 999-1015. Wipf, P.; Fritch, P. C. J. Org. Chem. 1994, 59, 4875-
4886. Hudlicky, T.; Tian, X.; Ko¨nigsberger, K.; Rouden, L. J. Org. Chem.
1994, 59, 4037-4039. Ibuka, T.; Nakai, K.; Habashita, H.; Hotta, Y.; Fujii,
N.; Mimura, N.; Miwa, Y.; Taga, T.; Yamamoto, Y. Angew. Chem., Int.
Ed. Engl. 1994, 33, 652-654. Tanner, D. Angew. Chem., Int. Ed. Engl.
1994, 33, 599-619. Hudlicky, T.; Reed, J. W. ComprehensiVe Organic
Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon: Oxford, 1991; Vol.
5, Chapter 8.1.
(12) For a recent listing of vinylaziridine syntheses, see ref. 3a.
(13) Vinyl epoxides 1a-c were obtained from the corresponding epoxy
alcohols: D´ıez-Martin, D.; Kotecha, N. R.; Ley, S. V.; Mantegani, S.;
Mene´ndez, J. C.; Organ, H. M.; White, A. Banks, B. J. Tetrahedron 1992,
48, 7899-7938. Compound 1d was prepared in racemic form by MCPBA
epoxidation of (E,E)-1-benzyloxy-2,4-hexadiene.
(14) Lindstro¨m, U. M.; Franckowiak, R.; Pinault, N.; Somfai, P.
Tetrahedron Lett. 1997, 38, 2027-2030.
(15) Hughes, D. L. Org. React. 1992, 42, 335-656. Pfister, J. R.
Synthesis 1984, 969-970. Carlock, J. T.; Mack, M. P. Tetrahedron Lett.
1978, 5153-5156.
(16) Chen, F. M. F.; Kuroda, K.; Benoiton, N. L. Synthesis 1978, 928-
929.
(17) Eastwood, F. W.; Perlmutter, P.; Yang, Q. J. Chem. Soc., Perkin
Trans. 1 1997, 35-42. Mente, P. G.; Heine, H. W.; Scharoubim, G. R. J.
Org. Chem. 1968, 33, 4547-4548.
S0002-7863(97)01572-2 CCC: $14.00 © 1997 American Chemical Society

8386 J. Am. Chem. Soc., Vol. 119, No. 35, 1997
Communications to the Editor
was formed in 83% yield. Repeating the procedure with 4b
gave 6b in equally good yield (83%). Having thus established
the feasibility of the rearrangement our next concern was the
stereochemical outcome when using more highly substituted
substrates. Deprotonation of 4c, the R-benzyloxy derivative 4d
and the glycine amide 4e, which are known to give preferentially
the corresponding (Z)-enolates,18 and rearrangement gave the
seven-membered lactams 6c (85%, R:â 22:1), 6d (81%), and
6e (76%), respectively. For the last two cases only single
diastereomers of the products could be detected. Similarly, (Z)-
and (E)-alkenyl derivatives 4f and 4g were rearranged into 6f
(73%) and 6g (73%), respectively, as the only detectable
diastereomers in each case,19 indicating that the stereochemistry
of the olefinic moiety is retained throughout the reaction. The
relative stereochemistry of 6c-g was secured by NOE analysis
in each case, showing an interaction between the C3 and C7
methine protons, while that of 6f and 6g also required an
Scheme 1a
1
inspection of the relevant coupling constants in their H NMR
spectra.20
The results from the rearrangements of vinylaziridines 4 can
be rationalized by assuming that the reaction proceeds through
the six-membered boat-like transition-state assembly 7 (eq 2).
It should be noted that boat transition states have been invoked
previously to explain the outcome in Claisen-type rearrange-
ments of certain cyclic substrates, while the acyclic cases are
generally believed to involve chair-like structures.2d,e The main
features of 7 are that the olefin and enolate moieties are cis in
order to facilitate bond formation and that both these groups
adopt an endo conformation, projecting over the three-membered
ring. Bond formation between the enolate and the alkene and
concomitant opening of the aziridine gives the observed
products. This model then correctly accounts for (i) the
formation of R-isomers 6c-e when deprotonating and rear-
ranging 4c-e, the sound assumption being that (Z)-enolates are
involved in each case,18,21 and (ii) the stereochemical outcome
when using the alkenyl derivatives 4f and 4g. It is also
presumed that the ease with which these transformations occur
is a consequence of the considerable relief of ring strain when
going from a three- to a seven-membered ring.
a Conditions: (a) NH3, TsOH‚H2O, 130 °C, 4 days, 69-93%. (b)
DEAD, Ph3P, THF, ∆, 49-54%. (c) (R2CH2CO)2O, Et3N, DMAP,
CH2Cl2.
Scheme 2
(2)
In conclusion, we have described a novel and highly
stereoselective aza-[3,3]-Claisen rearrangement of N-acyl vi-
nylaziridines into the corresponding tetrahydroazepin-2-ones.
Work is in progress to investigate the scope of this reaction
and to apply it in natural product synthesis and for the
preparation of peptidomimetics.
Some additional support for the above model was obtained
when trying to rearrange vinylaziridine 8, prepared from the
corresponding cis-vinylepoxide by the route shown in Scheme
1. Deprotonation of 8 (LiHMDS, -78 °C) followed by
warming to room temperature and quenching with D2O gave
only recovered starting material (10%), with complete incor-
poration of deuterium at the R-position, along with decomposed
material, indicating that for steric reasons the enolate derived
from 8 is not capable of attaining the required transition state
structure to participate in the [3,3]-rearrangement.
Acknowledgment. This work was supported financially by the
Swedish Natural Science Research Council. We are grateful to Ms. N.
Pinault for the initial preparation of aziridine 8 and to Dr. A.-L.
Gustavsson for the conformational analysis of 6a-g.
Supporting Information Available: A procedure for the rear-
rangement of vinylaziridine 4b and spectroscopic data for compounds
4a-g and 6a-g (5 pages). See any current masthead page for ordering
and Internet access instructions.
JA971572V
(20) Compounds 6a-g adopts a “boat-like” conformation in which H-3â
and H-7 are in close proximity, as judged from NOE experiments and
confirmed by conformational analysis using MacroModel 5.5 (MM2).
1
(18) Tanner, D.; Birgersson, C.; Gogoll, A.; Luthman, K. Tetrahedron
1994, 50, 9779-9824. Evans, D. A.; Nelson J. V.; Taber, T. R. In Topics
in Stereochemistry; Allinger, N. L., Eliel, E. L., Wilen, S. H., Eds.; Wiley:
New York, 1982; Vol. 13, Chapter 1.
(19) The isomeric ratio of 4f (E:Z 1:13) was retained in the rearrangement
to give 6f (R:â 1:13).
Selected H NMR data for 6f: δ 2.37 (ddd, J ) 12.1, 6.2, 1.7 Hz, H-3R),
2.73 (t, J ) 12.1 Hz, H-3â). 6g: δ 2.60 (ddt, J ) 13.3, 5.4, 1.5 Hz, H-3R),
3.00 (dd, J ) 13.3, 4.0 Hz, H-3â).
(21) This explains why the enolates derived from 4d,e, which have the
possibility of forming chelated (Z)-enolates, rearrange with higher selectivi-
ties than the enolate derived from 4c.