Domino synthesis of bridged bicyclic tetrahydro-1,2-oxazines: Access to stereodefined 4-aminocyclohexanols

Article abstract of DOI:10.1021/ol901454y

Image Presented The intramolecular variant of the homo-[3 + 2]-dipolar cycloaddition of nitrones (generated in situ from an aldehyde and a hydroxylamine) with donor-acceptor cyclopropanes allows for the efficient synthesis of bridged tetrahydro-1,2-oxazines. This domino sequence produces adducts amenable to reductive N-O bond cleavage producing cis-1,4- aminocyclohexanols in excellent yields.

Full text of DOI:10.1021/ol901454y

ORGANIC
LETTERS
2009
Vol. 11, No. 16
3694-3697
Domino Synthesis of Bridged Bicyclic
Tetrahydro-1,2-oxazines: Access to
Stereodefined 4-Aminocyclohexanols
Dwayne A. Dias and Michael A. Kerr*
Department of Chemistry, The UniVersity of Western Ontario, London,
Ontario, Canada N6A 5B7
makerr@uwo.ca
Received July 3, 2009
ABSTRACT
The intramolecular variant of the homo-[3 + 2]-dipolar cycloaddition of nitrones (generated in situ from an aldehyde and a hydroxylamine)
with donor-acceptor cyclopropanes allows for the efficient synthesis of bridged tetrahydro-1,2-oxazines. This domino sequence produces
adducts amenable to reductive N-O bond cleavage producing cis-1,4-aminocyclohexanols in excellent yields.
Domino reaction sequences, aside from their aesthetic appeal,
are increasingly relied upon to generate complex structural
motifs in an efficient and reliable manner. Their use as a
practical synthetic tool is ever increasing, allowing ever more
elaborate structures to be assembled through sometimes awe-
inspiring cascades.1
Annulation reactions of donor-acceptor cyclopropanes
with dipolarphiles have received considerable interest in
recent years, allowing access to a variety of hetero- and
carbocycles. A wide array of dipolar reagents (e.g., alde-
hydes,2 imines,3,4 nitriles,5 azomethine imines,6 diazenes,7
and others) readily react with activated cyclopropanes8 to
form five- and six-membered heterocycles. Recently, we
reported that nitrones 3 react with 1,1-cyclopropanediesters
4 in a stepwise annulative process9 (via putative intermediate
5) resulting in high yields of functionalized tetrahydro-1,2-
oxazines 6 as single regioisomers with excellent diastereo-
selectivity (Scheme 1).10 This process was improved by
generating the nitrone in situ from hydroxylamines 1 and
aldehydes 2.11 We recently employed this reaction sequence
in the total synthesis of phyllantidine.12 Cleavage of the N-O
bond and subsequent ring closure results in the formation
of pyrrolidines 7,13 a central tactic in our synthesis of
nakadomarin A.14
(6) Perreault, C.; Goudreau, S. R.; Zimmer, L. E.; Charette, A. B. Org.
Lett. 2008, 10, 689.
(7) Korotkov, V. S.; Larionov, O. V.; Hofmeister, A.; Magull, J.; de
Meijere, A. J. Org. Chem. 2007, 72, 7504.
(1) (a) Enders, D.; Grondal, C.; Huettl, M. R. M. Angew. Chem., Int.
Ed. 2007, 46, 1570. (b) Padwa, A.; Bur, S. K. Tetrahedron 2007, 63, 5341.
(c) de Meijere, A.; von Zezschwitz, P.; Braese, S. Acc. Chem. Res. 2005,
38, 413. (d) Tietze, L. F.; Rackelmann, N. Pure Appl. Chem. 2004, 76,
1967. (e) Tietze, L. F. Chem. ReV. 1996, 96, 115.
(8) For reviews on the chemistry of donor-acceptor and electrophilic
cyclopropanes, see: (a) Yu, M.; Pagenkopf, B. L. Tetrahedron 2005, 61,
321. (b) Reissig, H.-U.; Zimmer, R. Chem. ReV. 2003, 103, 1151. (c) Wong,
H. N. C.; Hon, M.-Y.; Tse, C.-W.; Yip, Y.-C.; Tanko, J.; Hudlicky, T.
Chem. ReV. 1989, 89, 165. (d) Danishefsky, S. Acc. Chem. Res. 1979, 12,
66.
(2) (a) Pohlhaus, P. D.; Johnson, J. S. J. Org. Chem. 2005, 70, 1057.
(b) Pohlhaus, P. D.; Sanders, S. D.; Parsons, A. T.; Li, W.; Johnson, J. S.
J. Am. Chem. Soc. 2008, 130, 8642, and references therein.
(9) With inversion of stereochemistry in the initial cyclopropane ring-
opening event. See: Karadeolian, A.; Kerr, M. A. J. Org. Chem. 2007, 72,
10251.
(3) Alper, P. B.; Meyers, C.; Lerchner, A.; Siegel, D. R.; Carreira, E. M.
Angew. Chem., Int. Ed. 1999, 38, 3186
.
(4) (a) Carson, C. A.; Kerr, M. A. J. Org. Chem. 2005, 70, 8242. (b)
Kang, Y.-B.; Tang, Y.; Sun, X.-L. Org. Biomol. Chem. 2006, 4, 299, and
(10) (a) Young, I. S.; Kerr, M. A. Angew. Chem., Int. Ed. 2003, 42,
3023. (b) Wanapun, D.; Van Gorp, K. A.; Mosey, N. J.; Kerr, M. A.; Woo,
T. K. Can. J. Chem. 2005, 83, 1752.
references therein
.
(5) (a) Yu, M.; Pagenkopf, B. L. J. Am. Chem. Soc. 2003, 125, 8122.
(b) Yu, M. B. L.; Pagenkopf, B. L. Org. Lett. 2003, 5, 5099.
(11) Young, I. S.; Kerr, M. A. Org. Lett. 2004, 6, 139.
(12) Carson, C. A.; Kerr, M. A. Angew. Chem., Int. Ed. 2006, 45, 6560.
10.1021/ol901454y CCC: $40.75
Published on Web 07/24/2009
 2009 American Chemical Society

ring closure. The net result would be a bridged bicycle such
as 11.15 In an alternative sequence, the addition of a suitable
hydroxylamine to cyclopropane tethered aldehyde 12 should
be sufficient to trigger a domino sequence of events that starts
with the formation of nitrone 13. Cyclopropane ring opening
by this short-lived intermediate would lead to zwitterion 14,
which in turn would undergo Mannich cyclization16 to give
oxazine 15.
Scheme 1. Reaction of Nitrones with Cyclopropanediesters
Bicyclic oxazines such as 15, where n ) 1, when subjected
to reductive N-O bond scission, would lead to cis-1,4-
aminocyclohexanols. This motif and derivatives thereof are
ubiquitous in the natural product milieu with pancratistatin,17
tetrodotoxin,18 and 3-demethoxyerythratidinone19 being but
a few examples (Figure 1). In this Letter we disclose the
As rewarding as these pursuits have been, we realized the
potential to extend the utility of this reaction by designing
an intramolecular variant. Tethering the cyclopropane to the
nitrone should lead to a more facile reaction as well as
incorporate an additional ring into the product. This is shown
graphically in Scheme 2.
Scheme 2. Proposed Intramolecular Reactions
Figure 1. 1,4-Aminoalcohols present in natural products.
realization of the successful implementation of the type 2
(vide supra) intramolecular formal homo-[3 + 2]-dipolar
cycloaddition and its use in the synthesis of cis-1,4-
aminocyclohexanols.
At the outset of this study, we faced two major issues.
One was the necessity to generate the nitrone in the presence
of the electrophilic cyclopropane. In our intermolecular
studies involving the one-pot variant of this cycloaddition,
it was necessary to preform the nitrone prior to addition of
the cyclopropane. Failure to do so resulted in the competitive
addition of hydroxylamine to the cyclopropanediester. For
(15) This mode of reactivity is currently under investigation. However,
all attempts thus far have been unsuccessful.
(16) For previous examples of carbocycle construction by intramolecular
Mannich reaction, see: (a) Uchida, K.; Yokoshima, S.; Kan, T.; Fukuyama,
T. Org. Lett. 2006, 8, 5311. (b) Shibuguchi, T.; Mihara, H.; Kuramochi,
A.; Sakuraba, S.; Ohshima, T.; Shibasaki, M. Angew. Chem., Int. Ed. 2006,
45, 4635. (c) Taber, D. F.; Liang, J.-L.; Chen, B.; Cai, L. J. Org. Chem.
2005, 70, 8739. (d) Thomas, J. B.; Gigstad, K. M.; Fix, S. E.; Burgess,
J. P.; Cooper, J. B.; Mascarella, S. W.; Cantrell, B. E.; Zimmerman, D. M.;
Carroll, F. I. Tetrahedron Lett. 1999, 40, 403. (e) Winkler, J. D.; Axten,
J. M. J. Am. Chem. Soc. 1998, 120, 6425. (f) Winkler, J. D.; Haddad, N.;
Ogilvie, R. J. Tetrahedron Lett. 1989, 30, 5703.
(17) (a) Danishefsky, S. J.; Lee, J. Y. J. Am. Chem. Soc. 1989, 111,
4829. (b) Tian, X.; Hudlicky, T.; Koenigsberger, K. J. Am. Chem. Soc.
1995, 117, 3643, and references therein.
In one scenario, nitrone formation by condensation of a
hydroxylamino-tethered cyclopropane 8 with an aldehyde
would yield 9, which would undergo nucleophilic cyclopro-
pane ring opening to give 10, followed by a Mannich-style
(18) (a) Woodward, R. B.; Gougoutas, J. Z. J. Am. Chem. Soc. 1964,
86, 5030. (b) Kishi, Y.; Fukutama, T.; Aratani, M.; Nakatsubo, F.; Goto,
T.; Inoue, S.; Tanino, H.; Sugiura, S.; Kakoi, H. J. Am. Chem. Soc. 1972,
94, 9219.
(19) (a) Tsuda, Y.; Nakai, A.; Ito, K.; Suzuki, F.; Haruna, M.
Heterocycles 1984, 22, 1817. (b) Hosoi, S.; Ishida, K.; Tsuda, Y. Chem.
Pharm. Bull. 1992, 40, 3115.
(13) Young, I. S.; Williams, J. L.; Kerr, M. A. Org. Lett. 2005, 7, 953.
(14) Young, I. S.; Kerr, M. A. J. Am. Chem. Soc. 2007, 129, 1465.
Org. Lett., Vol. 11, No. 16, 2009
3695

the intramolecular variant to be successful, the nitrone
formation must be significantly faster than hydroxylamine
attack on the cyclopropane. A less worrisome issue was the
tether length necessary to allow successful reaction of the
nitrone moiety with the cyclopropane.
Scheme 5. Use of Alternative Tethers
Our research began with the employment of a substrate
with a one-carbon spacer between the aldehyde and the
cyclopropane functionalities (Scheme 3). This compound
Scheme 3. Decomposition of 18 via ꢀ-Elimination
proved labile under the reaction conditions and merely
decomposed via a ꢀ-eliminative ring opening of the cyclo-
propane.
The ꢀ-elimination pathway was obviated by preparing a
substrate with an additional methylene unit in the linker.20
We were delighted to observe that, upon addition of phenyl
hydroxylamine and a catalytic amount of Yb(OTf)3 to a
mixture of aldeyde 21 and molecular sieves in toluene, the
expected 2-oxa-3-azabicylo[2.2.2]octane was formed in 92%
yield. Other hydroxylamines were surveyed and performed
similarly, providing yields ranging from 82% to 92%
(Scheme 4). Interestingly other tether lengths did not fare
Scheme 4. Preparation of [2.2.2] Bridged Bicyclic Systems
63% yield. Incorporation of a benzene ring as part of the
linking moiety (29) was also well-behaved, and a variety of
hydroxylamines produced adducts 30-34 in yields of
80-91%. Interestingly, the presence of a nitro group in
conjugation with the electrophilic cyclopropane carbon (i.e.,
35) or the aldehyde (i.e., 37) did not seem to affect the
efficiency of the reaction, producing adducts 36 and 38 in
excellent yields. It was suspected a priori that compound 35
would be a sluggish substrate since the nitro group should
destabilize a developing positive charge on the electrophilic
cyclopropane carbon. An electron-donating group in the form
of a methylenedioxy moiety on the aromatic linker (39)
neither hindered nor helped the reaction course. Finally,
incorporation of a heteroaromatic group into the linker (41)
resulted in the formation of the indole product 42 in a useful
chemical yield.
as well, and so, at least for the time being, this process seems
restricted to the formation of the [2.2.2] system.21
Our attention now turned to an investigation of substrate
scope within this bicyclic framework (Scheme 5). Introduc-
tion of a cis-double bond in the tether (27) was well-tolerated
and resulted in the formation of the bicyclic alkene 28 in
(20) It is worth noting that geminal disubstitution a to the aldehyde in
18 would eliminate the ꢀ-elimination pathway and allow the desired reaction
to proceed. However, this was not investigated.
(21) The use of three-carbon and five-carbon tethers were also inves-
tigated but were unsuccessful.
With a variety of bicyclic tetrahydro-1,2-oxazines in hand,
we examined the reductive rupture of the N-O bond with
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Org. Lett., Vol. 11, No. 16, 2009

reduction was easily accomplished by stirring the substrate
with Zn dust in glacial acetic acid.22 The reduction products
are cis-4-aminocyclohexanols and cis-1-amino-4-hydrox-
ytetrahydronaphthalenes. The yields were usually excellent
ranging from 69-92%.
Scheme 6. Preparation of [2.2.2] Bridged Bicylic Systems
In summary, we have reported the first examples of an
intramolecular nitrone/cyclopropane formal cycloaddition.
The product bicyclic tetrahydro-1,2-oxazines are formed in
excellent yields and when subjected to mild reduction
conditions, produce cis-1,4-aminocyclohexanols in high
yield. Application to target oriented challenges is currently
underway in our laboratory.
Acknowledgment. We thank the Natural Sciences and
Engineering Research Council of Canada and Merck-Frosst
for funding. We thank Mr. Doug Hairsine of the University
of Western Ontario mass spectrometry facility for performing
MS analyses. We are also grateful to Ms. Cheryl A. Carson,
Terry P. Lebold, and Kasia Sapeta for their help in the
preparation of this manuscript.
Supporting Information Available: Full experimental
procedures and spectroscopic data for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
the goal of preparing cyclic 1,4-aminoalcohols. Scheme 6
illustrates the results. Two representative series, namely, the
oxazines 22-26 derived from a saturated tether and those
(30-34) derived from a phenyl tether, were subjected to
reductive conditions. In contrast to many monocyclic tet-
rahydro-1,2-oxazines, we have encountered, the N-O bond
OL901454Y
(22) Wuts, P. G. M.; Jung, Y.-W. J. Org. Chem. 1988, 53, 1957.
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