Synthesis and Analysis of 1-Azafenestranes
A R T I C L E S
in the literature,8,9 unsubstituted fenestranes are low-molecular-
weight hydrocarbons, and they are not crystalline solids at room
temperature; therefore, no X-ray crystal structures for these
compounds have been reported. By substituting a nitrogen atom
for one of the external bridgehead carbons of a fenestrane,
opportunities for X-ray analysis of an unsubstituted azafenes-
trane exist. For example, c,c,c,c-[5.5.5.5]-1-azafenestrane 4
(Scheme 1)10 could be derivatized through salt (5) or adduct
(6) formation to give a crystalline solid that is amenable to solid-
state analysis. In addition, through synthesis of a series of
azafenestranes with varying ring sizes and stereochemical
relationships, the factors that lead to increased planarization
could be confirmed experimentally in a system where no carbon
ring substituents are present.
Scheme 2
Results and Discussion
1. c,c,c,c-[5.5.5.5]-1-Azafenestrane. 1.1. Retrosynthetic
Analysis. Azafenestrane 4 (Scheme 3) should be available from
azafenestranone 12 through two-stage deoxygenation (hydroxyl
removal and lactam reduction). Lactam 12 is derived from
hydrogenolytic unmasking of nitroso acetal 13, which involves
two N-O bond cleavage reactions, a reductive amination, and
a lactam formation, all predicted to take place under one set of
hydrogenation conditions. Nitroso acetal 13 is the direct product
of tandem [4+2]/[3+2] cycloaddition of nitrocyclopentene 14
and n-butyl vinyl ether. With regard to the configuration at the
ring fusions of nitroso acetal 13 (which in turn will lead to the
c,c,c,c-1-azafenestrane 3), only one stereogenic center was ex-
pected to be variable. The [3+2] cycloaddition is formally in
the spiro mode family13 and thus is expected to proceed via an
exo-tether mode pathway, which should provide cis relationships
at the o-p and p-m ring fusions. However, in the [4+2] cyclo-
addition, the dienophile can approach from either the same face
or the opposite face relative to the tethered dipolarophile, which
would result in a trans or cis relationship at the n-o ring fusion,
respectively (Scheme 3). Because the least hindered approach
should be opposite the tethered dipolarophile, we expected that
the favored pathway would lead to a nitroso acetal with
configurations at the ring fusions of an all-cis-azafenestrane.
Scheme 1
Because azafenestrane 4 is simply a pyrrolizidine fused to a
bicyclo[3.3.0]octane ring system, we planned to apply the
tandem [4+2]/[3+2] nitroalkene cycloaddition strategy to the
synthesis of 4 and other more strained variants (Scheme 2). A
number of pyrrolizidine-based alkaloids have been synthesized
in these laboratories utilizing the tandem cycloaddition of
nitroalkenes.11 To construct the azafenestrane ring system, cyclic
nitroalkenes with tethered dipolarophiles 7 would be required.
Intermolecular [4+2] cycloaddition with a vinyl ether 8,
followed by intramolecular [3+2] cycloaddition, would provide
tetracyclic nitroso acetals of type 9 which could be converted
to the corresponding pyrrolizidinones 10 through hydrogenoly-
sis. Further synthetic manipulation would complete the unsub-
stituted azafenestranes 11. This report describes the synthesis
of a number of strained 1-azafenestranes, their analysis through
X-ray crystallography, and calculations on relative strain energy
for this family of compounds.12
Scheme 3
(9) (a) Han, W. C.; Takahashi, K.; Cook, J. M.; Weiss, U.; Silverton, J. V. J.
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H. J. Am. Chem. Soc. 1986, 108, 8107-8109. (i) Bredenkotter, B.; Florke,
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(10) The nomenclature of Keese (ref 7a) has to be modified to specify the
location of the nitrogen atom. We propose to designate its location by listing
the two rings containing the nitrogen first, then proceeding to the smaller
of the remaining two rings. If the two nitrogen-containing rings are of
different size, the smaller will be specified first, following Keese.
(11) (a) Denmark, S. E.; Thorarensen, A.; Middleton, D. S. J. Am. Chem. Soc.
1996, 118, 8266-8277. (b) Denmark, S. E.; Martinborough, E. A. J. Am.
Chem. Soc. 1999, 121, 3046-3056. (c) Denmark, S. E.; Hurd, A. R. J.
Org. Chem. 2000, 65, 2875-2886. (d) Denmark, S. E.; Herbert, B. J. Org.
Chem. 2000, 65, 2887-2896. (e) Denmark, S. E.; Cottell, J. J. J. Org.
Chem. 2001, 66, 4276-4284.
1.2. Synthesis of Nitrocyclopentene 14. The synthesis of
nitroalkene 14 required the extension of Seebach’s14,15 nitroal-
lylation process to nitrocyclopentenes. Although its nitrocyclo-
hexene analogue was synthesized in good yield,14 a similar route
(12) For preliminary communications, see: (a) Denmark, S. E.; Kramps, L. A.;
Montgomery, J. I. Angew. Chem., Int. Ed. 2002, 41, 4122-4125. (b)
Denmark, S. E.; Montgomery, J. I. Angew. Chem., Int. Ed. 2005, 44, 3732-
3736.
(13) Denmark, S. E.; Middleton, D. S. J. Org. Chem. 1998, 63, 1604-1618.
(14) Seebach, D.; Calderari, G.; Knochel, P. Tetrahedron 1985, 41, 4861-4872.
(15) Knochel, P.; Seebach, D. Tetrahedron Lett. 1982, 23, 3897-3900.
9
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