A new class of ammonium ylid for [2,3]-sigmatropic rearrangement reactions: ene-endo-spiro ylids

Article abstract of DOI:10.1021/ol050691+

(Chemical Equation Presented) The first examples of sigmatropic rearrangements of ene-endo-spirocyclic, tetrahydropyridine-derived ammonium ylids are reported. Thus, spiro[6.7]-ylids rearrange primarily by a [2,3]-pathway, whereas the analogous [6.6]-ylids rearrange by [1,2]- and [2,3]-mechanisms in roughly equal proportions. This method serves as a rapid entry to the core of a range of alkaloids bearing a pyrrolo[1,2-a]azepine or octahydroindolizidine nucleus.

Full text of DOI:10.1021/ol050691+

ORGANIC
LETTERS
2
005
Vol. 7, No. 10
075-2078
A New Class of Ammonium Ylid for
2,3]-Sigmatropic Rearrangement
Reactions: ene-endo-Spiro Ylids
2
[
†
‡
,‡
Edward Roberts, Julien P. Sanc
¸
on, and J. B. Sweeney*
School of Chemistry, UniVersity of Reading, Reading RG6 6AD, UK, and
The Scripps Research Institute, 10550 North Torrey Pines Road,
La Jolla, California 92037
j.b.sweeney@reading.ac.uk
Received April 1, 2005
ABSTRACT
The first examples of sigmatropic rearrangements of ene-endo-spirocyclic, tetrahydropyridine-derived ammonium ylids are reported. Thus,
spiro[6.7]-ylids rearrange primarily by a [2,3]-pathway, whereas the analogous [6.6]-ylids rearrange by [1,2]- and [2,3]-mechanisms in roughly
equal proportions. This method serves as a rapid entry to the core of a range of alkaloids bearing a pyrrolo[1,2-a]azepine or octahydroindolizidine
nucleus.
Due to their excellent potential for selective synthetic
transformations, much attention has been focused upon the
rearrangement reactions of ylids generated from diazo
Thus, West et al. reported that spiro[4.5]-ylid 1 rearranges
by stereoselective Stevens ([1,2]-) rearrangement, whereas
3
Clark et al. demonstrated that spiro[4.4]-ylid 2 rearranges
1
4
compounds. We have previously reported the use of metal
by a [2,3]-process onto its pendant exocyclic alkene (Figure
catalysis to mediate [2,3]-rearrangements of NMTP (“N-
methyltetrahydropyridine”) ylids (Scheme 1).2
1); in both cases, the reactions are highly diastereo- and
enantioselective, due to the influence of the adjacent (proline-
derived) chiral R-carbon. A reaction corresponding to
(
1) For reviews of the area, see: (a) Davies, H. M. L. (Ed.) Tetrahe-
Scheme 1. Functionalized Pyrrolidines via
dron: Asymmetry 2003, 14, 763-949. (b) Clark, J. S., Ed. Nitrogen, Oxygen
and Sulfur Ylide Chemistry; Oxford University Press: Oxford, 2002. (c)
Doyle, M. P.; McKervey, M. A.; Ye, T. Modern Catalytic Methods for
Organic Synthesis with Diazo Compounds; Wiley & Sons: New York, 1998.
[2,3]-Rearrangement of NMTP Ylids
(2) [2,3]-Sigmatropic rearrangements of NMTP ylids were first reported
by Ollis: (a) Mageswaran, S.; Ollis, W. D.; Sutherland, I. O. J. Chem.
Soc., Perkin Trans. 1 1981, 1953. (b) Mageswaran, S.; Ollis, W. D.;
Sutherland, I. O. J. Chem. Soc., Chem. Commun. 1973, 656.
(
3) (a) West, F. G.; Naidu, B. N. J. Am. Chem. Soc. 1994, 116, 8420-
8
(
421. (b) West, F. G.; Naidu, B. N. Tetrahedron 1997, 53, 16565-16574.
c) Beall, L. S.; Padwa, A. Tetrahedron Lett. 1998, 39, 4159-4162. (d)
Vanecko, J. A.; West, F. G. Org. Lett. 2002, 4, 2813-2816. (e) Saba, A.;
Tetrahedron Lett. 2003, 44, 2895-2898. (f) Muroni, D.; Saba, A.; Culeddu,
N. Tetrahedron: Asymmetry 2004, 15, 2609-2614.
Among the panoply of excellent research carried out by
others in this area, the rearrangement of spiro-ylids has been
shown to be an elegant synthetic tool, and the processes
reported by West and Clark particularly held our attention.
(4) (a) Clark, J. S.; Hodgson, P. B. J. Chem. Soc., Chem. Comun. 1994,
2
2
701-2702. Clark, J. S.; Hodgson, P. B. Tetrahedron Lett. 1995, 36, 2519-
522. (b) Wright, D. L.; Weekly, R. M.; Groff, R.; McMills, M. C.
Tetrahedron Lett. 1996, 37, 2165-2168. (c) Clark, J. S.; Hodgson, P. B.;
Goldsmith, M. D.; Blake, A. J.; Cooke, P. A.; Street, L. J. J. Chem. Soc.,
Perkin Trans. 1 2001, 3225-3337.
†
The Scripps Research Institute.
University of Reading
‡
1
0.1021/ol050691+ CCC: $30.25
© 2005 American Chemical Society
Published on Web 04/21/2005

given the relative rigidity of this class of ylid, when compared
to “normal” NMTP ylids, the reactive centers are constrained
by the geometry of the spiro-linkage to be more distant from
each other than is usual. One might logically conclude that
this structural feature would, therefore, disfavor the [2,3]-
rearrangement and enhance [1,2]-rearrangement (normally
not seen in the rearrangements of NMTP ylids). Thus, we
commenced our synthetic studies with the hope of resolving
this intriguing mechanistic condundrum, in addition to further
defining the scope of ammonium [2,3]-rearrangement chem-
istry and developing a useful synthetic tool.
Figure 1. New ammonium [2,3]-rearrangement: endo-spiro-ylids.
We initially chose to carry out a model study of the
proposed, “all-carbon”, rearrangement, using a more readily
prepared oxazepinone analogue (Scheme 3). The synthetic
Clark’s, in which the alkene component of the ylid is
endocyclic, has not been reported: we reasoned that such a
[2,3]-rearrangement (i.e., of a 6-aza-7-carboxyspiro[5.6]-
dodecan-8-one ylid, typified by 3) would, in addition to
providing an informative tool in understanding the mecha-
nism of such processes (vide infra), allow a rapid entry to
pyrroloazepines such as those at the core of the Stemona
alkaloids; we report here the realization of our proposal,
which represents a novel addition to the class of [2,3]-
rearrangement reactions of ammonium ylids.
Scheme 3. [2,3]-Rearrangement of Oxazepinone Spiro-ylid 5
The pyrrolo[1,2-a]azepine structural motif forms the core
of a range of alkaloids exhibiting potent biological activity:
more than 40 Stemona alkaloids (including croomine and
tuberostemonine) have been isolated, possessing a diverse
5
range of therapeutic properties. These properties, married
to the significant synthetic challenges presented by the
molecules, have led to a considerable interest in the design
6
of synthetic routes to enable their synthesis. As detailed in
Scheme 2, [2,3]-rearrangement of spiro-ylid 3 (prepared in
route to model ylid 5 began with hydroxypropylation of
pyridine, followed by reduction with NaBH ; subsequent
acylation with methylmalonyl chloride and diazo transfer
reaction gave key intermediate 6, in 42% yield over the four
steps of the sequence.
4
Scheme 2. Pyrroloazepines via [2,3]-Rearrangement of
endo-Spiro Ammonium Ylids
Thus, we were set to carry out the key rearrangement
reaction: we observed that treatment of 6 with a substo-
ichiometric amount of Cu(acac)
2
in refluxing toluene gave
[2,3]-rearrangement product 7 (dr ) 57:43, major isomer as
shown; we define this isomer as being cis-configured and
use this terminology throughout the manuscript) in 54% yield
(unoptimized), along with the product of [1,2]-rearrangement
8
(23% yield) (Scheme 3). This is, to our knowledge, the
first example of a [2,3]-sigmatropic rearrangement of spiro-
NMTP ylids. The mixture of diastereoisomers probably
(6) For recent reports, see: (a) Morimoto, Y.; Iwahashi, M.; Kinoshita,
T.; Nishida, K. Chem. Eur. J. 2001, 7, 4107-4116. (b) Ginn, J. D.; Padwa,
situ from diazoester 4) would give the pyrroloazepine core
directly, while also providing peripheral functionality to
enable subsequent preparation of the more densely func-
tionalized members of the class. The proposed reaction would
also act as a probe for the scope of the endo-alkene class of
A. Org. Lett. 2002, 4, 1515-1517. (c) Martin, S. F. Acc. Chem. Res. 2002,
3
5, 895-904. (d) Jacobi, P. A.; Lee, K. J. Am. Chem. Soc. 2000, 122, 4295-
4
303. (e) Gurjar, M. K.; Reddy, D. S. Tetrahedron Lett. 2002, 43, 295-
298. (f) Kende, A. S.; Hernando, J. I. M.; Milbank, J. B. J. Tetrahedron
2
002, 58, 61-74. (g) Williams, D. R.; Fromhold, M. G.; Earley, J. D. Org.
Lett. 2001, 3, 2721-2724. (h) Lindsay, K. B.; Pyne, S. G. Synlett 2004,
79-782. (i) Bruggemann, M.; McDonald, A. I.; Overman, L. E.; Rosen,
M. D.; Schwink, L.; Scott, J. P. J. Am. Chem. Soc. 2003, 125, 15284-
5285. (j) Williams, D. R.; Shamin, K.; Reddy, J. P.; Amato, G. S.; Shaw,
7
[2,3]-rearrangements to which the NMTP reactions belong:
1
S. M. Org. Lett. 2003, 5, 3361-3364. (k) Booker-Milburn, K. I.; Hirst, P.;
Charmant, J. P. H.; Taylor, L. H. J. Angew. Chem., Int. Ed. 2003, 42, 1642-
1644. (l) Wipf, P.; Rector, S. R.; Takahashi, H. J. Am. Chem. Soc. 2002,
124, 14848-14849.
(
5) For a review of the structures and properties of Stemona alkaloids,
see: Pilli, R. A.; Ferreira de Oliveira, M. C. Nat. Prod. Rep. 2000, 17,
17-127.
1
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Org. Lett., Vol. 7, No. 10, 2005

results from the possibility of two different secondary orbital
interactions (known to be important in these rearrangements)
with either of the two carbonyl groups present in the ylid.
Scheme 5. [2,3]-Rearrangement of Morpholinone [5.5]-Spiro
Ammonium Ylids
The preparation of the all-carbon ylid 3 was best executed
via the introduction of the NMTP subunit at a late stage of
the sequence (Scheme 4).7 Given the intimacy of the
Scheme 4. Efficient Preparation of Pyrrolo[1,2-a]azepines by
[2,3]-Rearrangement of endo-Spiro Ammonium Ylids
of the heterocyclic subunit (Scheme 6). As seen previously
in the higher homologue, the introduction of a methylene in
Scheme 6. [2,3]-Rearrangement of Piperidinone [5.5]-Spiro
Ammonium Ylids
proposed transition state in NMTP ammonium ylid rear-
rangements, we were encouraged to hope that the presence
of a more sterically demanding methylene group, rather than
the endocyclic oxygen atom of 5, would lead to a higher
selectivity in the [2,3]-rearrangement step: thus, we were
pleased to witness that the rearrangement of carbon ylid 3
(
Scheme 4) proceeded to give azepinones 9 and 10 but with
place of the lactonic oxygen atom improved the diastereo-
selectivity of the [2,3]-rearrangement, though the regiochem-
istry was unaltered: a 5:3:2 mixture of [1,2]- and cis- and
trans-[2,3]-products (15, cis-16, and trans-16, respectively)
was isolated in 86% combined yield. Though the reaction is
less selective in this case, the diastereomeric [2,3]-products
are easily purified and, given the resemblance of 16 to potent
natural products (such as castanospermine, inter alia), the
method nonetheless represents a very efficient entry into
structures with potential biological significance.
Some comment upon the differences in the ratios of [2,3]-
and [1,2]-rearrangement of these ylids is appropriate. In the
rearrangement of [5.5]-ylids 11 and 14, there are four
possible structures available: two endo-conformed (A and
B) and two exo-conformed (C and D) (Figure 2).
improved regioselectivity (9:10 ) 88:12) and with better
diastereocontrol in the [2,3]-process (cis-9:trans-9 ) 70:30;
this stereochemical assignment was confirmed by X-ray
crystallography). Compared to existing methods, this rep-
resents a highly efficient entry into the pyrrolazepine
architecture, and the method also allows a facile introduction
of a quaternary center to the ring junction of such structures.
To better define the scope of the reaction, we next
investigated this new rearrangement reaction in two lower
homologues. Thus, morpholinone spiro[5.5]-ylid 11 was
prepared in a manner analogous to that used for synthesis
of 5; 11 underwent rearrangement in 85% yield to give the
[2,3]- and [1,2]-rearrangement products (12 and 13, respec-
tively) as a separable 1:1 mixture (Scheme 5); the [2,3]-
product was itself obtained as a 1:1 mixture of diastereoi-
somers. Clearly, the extra rigidity of the [5.5]-system now
does place unfeasible geometric constraints upon the [2,3]-
reaction, resulting in an increased propensity for the Stevens
[1,2]-process.
Once again, the synthesis of the analogous all-carbon [5.5]-
ylid 14 was best accomplished using a late-stage introduction
Figure 2. Rigidity of conformation controls the rearrangement of
(
7) For an analogous strategy, see: Vanecko, J. A.; West, F. G. Org.
[6.6]-endo-spiro ylids.
Lett. 2002, 4, 2813.
Org. Lett., Vol. 7, No. 10, 2005
2077

In the case of spiro[5.6]-ylids 3 and 5 (Figure 3), we
rationalize the enhanced yield of the [2,3]-rearranged product
by assuming that its greater flexibility facilitates the [2,3]-
process, meaning that interconversion between the possible
conformers is rapid compared to the C-C bond-forming
events and that the [2,3]-process is faster than the [1,2]-
8
reaction. Thus, the yield of [2,3]-rearrangement product is
enhanced, at the expense of the [1,2]-byproduct. Once again,
greater diastereoselectivity is observed when X ) CH .
2
Figure 3. Flexibility in endo-spiro[6.7]-ylids favors [2,3]-rear-
rangement.
In summary, we have described the first [2,3]-sigmatropic
rearrangements of spirocyclic ammonium ylids in which the
alkene component is endocyclic. These ylids are efficiently
prepared from readily available starting materials, and the
method represents a novel and efficient route to the core
structures of two classes of bicyclic alkaloids. In particular,
the use of this reaction in the synthesis of a range of Stemona
alkaloids is a current objective within our laboratories.
Only the endo-transition state allows a [2,3]-rearrange-
ment: the alternative exo-TS has its anionic component
geometrically constrained to be distant from the alkene,
preventing [2,3]-rearrangement and favoring the (non-
concerted) [1,2]-process. If one assumes that ylid formation
is irreversible, the observation that there is no regiocontrol
in the reaction of the [5.5]-ylid implies two things: first,
that ring-flip (the process by which the endo- and exo-anions
are interconverted) is slow compared to C-C bond forma-
tion, and, second, that the endo- and exo-transition states
have similar energy (meaning that they are formed at
comparable rates). Under these constraints, a 1:1 ratio of
Acknowledgment. We thank the University of Reading
and F. Hoffman-LaRoche, Ltd., for financial support and
acknowledge the guidance provided by Mr. S. P. A.
Nishankolai.
[
1,2]:[2,3] products must inevitably result. With regard to
Supporting Information Available: Experimental and
spectroscopic data for new compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
the preference for formation of the cis isomer in the
rearrangement of the carbon ylid, we rationalize this as
arising from a repulsive interaction between the X group
OL050691+
2
(CH in ylid 14) and the methylene indicated (endo-anion
A, Figure 2). In the rearrangement of ylid 11, X ) O and
there is relatively little interaction between the smaller
oxygen atom and the same methylene, leading to a 1:1
mixture of diastereomers.
(8) Where both processes are possible, [2,3]-rearrangement is usually
more rapid than [1,2]-rearrangement. See, for instance: Workman, J. A.;
Garrido, N. P.; San c¸ on, J.; Roberts, E.; Wessel, H. P.; Sweeney, J. B. J.
Am. Chem. Soc. 2005, 126, 1066-1067.
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