Three-Component Homo 3 + 2 Dipolar Cycloaddition. A Diversity-Oriented Synthesis of Tetrahydro-1,2-oxazines and FR900482 Skeletal Congeners

Article abstract of DOI:10.1021/ol0362919

(Equation presented) The reaction of nitrones, formed in situ by reaction of hydroxylamines with aldehydes, with 1,1-cyclopropanediesters results in the formation of tetrahydro-1,2-oxazines via a homo 3 + 2 dipolar cycloaddition. This three-component coupling allows for the formation of a diverse array of cycloadducts with excellent diastereoselectivity (>95%) and yields (66-96%). The procedure has been used in the two-step preparation of congeners of the FR900482 skeleton.

Full text of DOI:10.1021/ol0362919

ORGANIC
LETTERS
2
004
Vol. 6, No. 1
39-141
Three-Component Homo 3 + 2 Dipolar
Cycloaddition. A Diversity-Oriented
Synthesis of Tetrahydro-1,2-oxazines
and FR900482 Skeletal Congeners
1
Ian S. Young and Michael A. Kerr*
Department of Chemistry, The UniVersity of Western Ontario, London,
Ontario, Canada N6A 5B7
makerr@uwo.ca
Received November 24, 2003
ABSTRACT
The reaction of nitrones, formed in situ by reaction of hydroxylamines with aldehydes, with 1,1-cyclopropanediesters results in the formation
of tetrahydro-1,2-oxazines via a homo 3 + 2 dipolar cycloaddition. This three-component coupling allows for the formation of a diverse array
of cycloadducts with excellent diastereoselectivity (>95%) and yields (66−96%). The procedure has been used in the two-step preparation of
congeners of the FR900482 skeleton.
1
5
The antitumor, antibiotic natural products FR900482 and
tions of which are not abundant. A flexible synthesis of this
2
FR66979, structurally related to the anticancer drug mito-
mycin C, have emerged as promising therapeutic candidates.
As with the synthetic derivatives FK317 and FK973, they
heterocycle would aid in the synthesis of these natural targets
and their evaluation as a drug scaffolds.
3
are thought to act as minor groove-binding cross-linkers.
Not surprisingly there has been significant activity toward
4
the synthesis of these molecules in pursuit of preparing
analogues with improved biological profiles. An equally
compelling motivation for their synthesis lies in their unique
and formidable structure, its central feature being the
relatively uncommon tetrahydro-1,2-oxazine ring, prepara-
Recently, we reported the first cycloaddition reaction
between a nitrone 5 and a 1,1-cyclopropane diester 6 to yield
a tetrahydro-1,2-oxazine 7, always as the cis isomer exclu-
(1) Uchida, I.; Shigehiro, T.; Hiroshi, K.; Sumio, K.; Hashimoto, M.;
Tada, T.; Shigetaka, K.; Morimoto, Y. J. Am. Chem. Soc. 1987, 109, 4108-
4
109.
6
sively (Scheme 1). The exact nature of this fundamentally
(2) Terano, H.; Takase, S.; Hosoda, J.; Kohsaka, M. J. Antibiot. 1989,
4
2, 145-148.
unique reaction is under investigation (stepwise annulative
vs concerted cycloaddition); however, the synthetic utility
is clearly evident, with tetrahydro-1,2-oxazines being pre-
pared in excellent yields with virtually complete diastereo-
selectivity.
(
3) Judd, T. C.; Williams, R. M. Org. Lett. 2002, 4, 3711-3714 and
references therein.
4) Racemic total syntheses: (a) Fukuyama, T.; Xu, L.; Goto, S. J. Am.
Chem. Soc. 1992, 114, 383-385. (b) Schkeryantz, J. M.; Danishefsky, S.
J. J. Am. Chem. Soc. 1995, 117, 4722-4723. Enantioselective total
syntheses: (c) Kato, T.; Itoh, E.; Yoshino, T.; Terashima, S. Tetrahedron
(
1
997, 53, 10253-10270. (d) Judd, T. C.; Williams, R. M. Angew. Chem.,
Int. Ed. 2002, 41, 4683-4685. (e) Suzuki, M.; Kambe, J.; Tokuyama, H.;
Fukuyama, T. Angew. Chem., Int. Ed. 2002, 41, 4686-4688. (f) Paleo, M.
R.; Aurrecoechea, N.; Jung, K.-Y.; Rapoport, H. J. Org. Chem. 2003, 68,
(5) (a) Tsoungas, P. G. Heterocycles 2002, 57, 1149-1178. (b) Gilchrist,
T. L.; Wood, J. E. In ComprehensiVe Heterocyclic Chemistry II; Elsevier:
Oxford, UK, 1996; Vol. 6, pp 279-299, 1177-1307.
(6) Young, I. S.; Kerr, M. A. Angew. Chem., Int. Ed. 2003, 26, 3023-
3026.
1
30-138. For a synthesis of related racemic FR66979, see: (g) Ducray,
R.; Ciufolini, M. A. Angew. Chem., Int. Ed. 2002, 41, 4688-4691.
1
0.1021/ol0362919 CCC: $27.50 © 2004 American Chemical Society
Published on Web 12/13/2003

Scheme 1. Reaction of Nitrones with Cyclopropanes
While many nitrones are readily available and stable, some
are difficult to prepare or are unstable due to oligomerization
under the required Lewis acidic conditions. During efforts
to address this, it occurred to us that the nitrone could be
prepared in situ from the reaction of a hydroxylamine 8 and
an aldehyde 9 in the presence of the Lewis acid, avoiding
the isolation or handling of the nitrone at all. In this com-
munication, we report our efforts and success in developing
an effective three-component, one-pot protocol, and we
showcase it with the efficient synthesis of a diverse selection
of tetrahydro-1,2-oxazines. In addition, we report the syn-
thesis of a short array of FR900482 skeletal congeners.
Our study commenced with the selection and preparation
of suitable substrates for the development of the cycload-
7
8
dition (Figure 1). Hydroxylamines and cyclopropanediesters
Figure 1. Substrates for three-component coupling reactions.
Figure 2. Tetrahydro-1,2-oxazines prepared by three-component
coupling.
were prepared via literature methods, while the aldehydes
were commercially available. The array of aldehydes include
benzaldehydes (electron rich and poor), an alkenal, an
alkanal, and heterocyclic aldehydes. The cyclopropanes bear
alkyl, alkenyl, phenyl, and heteroaromatic substituents.
Typically, the hydroxylamine 8 (1.3 equiv) and the
aldehyde 9 (1.4 equiv) were combined in toluene in the
(
7) 8a and 8b: Corminboeuf, O.; Renaud, P. Org. Lett. 2002, 4, 1735-
1
2
738. 8c: Maskill, H.; Jencks, W. J. Am. Chem. Soc. 1987, 109, 2062-
070. 8d: Crautheson-Chapoulaud, V.; Pandya, S. U.; Cividino, P.; Masson,
G.; Py, S.; Vallee, Y. Synlett 2001, 1281-1283.
40
1
Org. Lett., Vol. 6, No. 1, 2004

min prior to the addition of the cyclopropane, to ensure
complete formation of the nitrone. Failure to do so resulted
in the ring-opening of the cyclopropane by the hydroxy-
lamine in many cases. As a case in point, in the preparation
of compound 28, only a 6% yield was realized if the three
components were mixed at once with the catalyst in contrast
to the 90% yield obtained upon premixing the hydroxylamine
and the aldehyde prior to addition of the cyclopropane. In
the case of the unsubstituted cyclopropane, 20 mol % catalyst
was required to effect satisfactory conversion to the product.
It should be noted that the times in Figure 2 are not
necessarily an accurate description of the time required for
complete reaction; the cyclopropane and product coelute in
many cases, and the reaction was left to stir for a longer
time to ensure complete consumption of the cyclopropane.
As an illustration of the utility and versatility of this
process, a series of compounds all possessing the bridged
tricyclic skeleton of FR900482 and related molecules (vide
supra), was prepared via the sequence of reactions in Scheme
Scheme 2. Synthesis of FR900482 Congenersa
2. 2-Iodophenylhydroxylamine 8d was treated with a variety
of aldehydes (9a-c,g,h) followed by the addition of cyclo-
propane 6b. The initially formed adducts were treated under
Heck conditions to effect cyclization to the desired com-
pounds 31-35, much in the manner of Danishefsky in his
a
Conditions: (a) 9 (a-c,g, or h), 10 mol % Yb(OTf)
toluene, 25 °C 30 min, then 6b 18 h; (b) 20 mol % Pd(PPh
Et N, CH CN, 80 °C, 18 h.
3
, 4 Å MS,
3 4
) ,
3
3
4
b
synthesis of FR900482.
In summary, we have reported a convenient preparation
of highly substituted tetrahydro-1,2-oxazines. This method
should be useful for the preparation of interesting new
molecular scaffolds as well as have potential application to
the synthesis of FR900482 and related structures. Our efforts
toward these goals as well as our studies of the mechanistic
aspects will be reported in due course.
presence of 4 Å molecular sieves and catalytic (10 mol %)
Yb(OTf) (as the hydrate). After 30 min, the cyclopropane
(1.0 equiv) was added and the mixture stirred until thin-
3
6
layer chromatography indicated that the cyclopropane had
been consumed. Purification by flash chromatography yielded
the heterocycles 10-30 (Figure 2). In most cases, the
reactions produced only the cis diastereomers shown;
however, for 20, 22, 23, 25, and 26, a small amount (<5%)
of what appears to be the trans isomer was evident in the
NMR spectra of chromatographically purified material.
Crystallization yielded the pure cis adducts.
Acknowledgment. We gratefully acknowledge the fi-
nancial support of the Natural Sciences and Engineering
Research Council (NSERC), The Ontario Ministry of Science
and Technology, and MedMira Laboratories. I.S.Y. is an
NSERC PGSA awardee.
It was found to be vital that the hydroxylamine and the
aldehyde be mixed together with the catalyst for about 30
Supporting Information Available: Experimental pro-
cedures and compound characterization data. This material
is available free of charge via the Internet at http://pubs.acs.org.
(8) 6a: commercially available (Aldrich). 6b: Kierstead, R. W.; Linstead,
R. P.; Weedon, B. C. L. J. Chem. Soc. 1952, 3610-3616. 6c-g: Corey,
E. J.; Chaykovsky, M. J. Am. Chem. Soc. 1965, 87, 1353-1364.
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