Diversity-oriented synthesis of azaspirocycles

Article abstract of DOI:10.1021/ol0487783

(Equation Presented) Multicomponent condensation of N- diphenylphosphinoylimines, alkynes, zirconocene hydrochloride, and diiodomethane provides a rapid access to ω-unsaturated dicyclopropylmethylamines. These novel building blocks are converted into hete

Full text of DOI:10.1021/ol0487783

ORGANIC
LETTERS
2004
Vol. 6, No. 17
3009-3012
Diversity-Oriented Synthesis of
Azaspirocycles
Peter Wipf,* Corey R. J. Stephenson, and Maciej A. A. Walczak
Department of Chemistry and Center for Chemical Methodologies & Library
DeVelopment, UniVersity of Pittsburgh, Pittsburgh, PennsylVania 15260
pwipf@pitt.edu
Received June 26, 2004
ABSTRACT
Multicomponent condensation of N-diphenylphosphinoylimines, alkynes, zirconocene hydrochloride, and diiodomethane provides a rapid access
to ω-unsaturated dicyclopropylmethylamines. These novel building blocks are converted into heterocyclic 5-azaspiro[2.4]heptanes, 5-azaspiro-
[2.5]octanes, and 5-azaspiro[2.6]nonanes by means of selective ring-closing metathesis, epoxide opening, or reductive amination. The resulting
functionalized pyrrolidines, piperidines, and azepines are scaffolds of considerable relevance for chemistry-driven drug discovery.
Multicomponent reactions allow rapid access to structurally
varied and increasingly complex intermediates or scaffolds.
These reactions present an opportunity to explore combina-
torial chemistry approaches for the synthesis of a diverse
set of target molecules from simple, readily available building
blocks.1
alkyne 1 initiated a sequenced reaction cascade leading to
C,C-dicyclopropylmethyl amide 3 with the concomitant
formation of 10 new C,C-bonds (Figure 1). The conversion
We have reported a number of new multicomponent
condensations and cascade reactions involving vinyl zir-
conocenes,2 dihaloalkanes, and N-diphenylphosphinoyl imi-
nes leading to allylic,3 homoallylic,4 C-cyclopropyl-,3,5 and
C,C-dicyclopropylmethyl amides6 in a highly regio- and
stereoselective fashion. For example, hydrozirconation7 of
Figure 1. One-pot preparation of C,C-dicyclopropylmethylamines.
(1) Orru, R. V. A.; de Greef, M. Synthesis 2003, 1471.
(2) Wipf, P.; Nunes, R. L. Tetrahedron 2004, 60, 1269.
(3) (a) Wipf, P.; Kendall, C.; Stephenson, C. R. J. J. Am. Chem. Soc.
2003, 125, 761. (b) Wipf, P.; Stephenson, C. R. J. Org. Lett. 2003, 5, 2449.
(c) Wipf, P.; Kendall, C. Chem. Eur. J. 2002, 8, 1778.
(4) Wipf, P.; Kendall, C. Org. Lett. 2001, 3, 2773.
(5) Wipf, P.; Kendall, C.; Stephenson, C. R. J. J. Am. Chem. Soc. 2001,
123, 5122.
(6) Wipf, P.; Stephenson, C. R. J.; Okumura, K. J. Am. Chem. Soc. 2003,
125, 14694
of 1 and 2 to 3 proceeds under mild conditions by repeated
methylene group transfers to intermediate bicyclo[1.1.0]-
butanes and 1,4-dienes.6
As demonstrated herein, this methodology has now been
extended to include the transformation of alkynyl phosphin-
amides where alkenylzinc addition is no longer the initiating
step in the cascade. After addition of Me2Zn, the phosphin-
amides 4 and 5 are treated with Zn(CH2I)2‚DME complex
and afford the C-cyclopropylalkylamides 6 and 7 in good
(7) (a) Wipf, P.; Jahn, H. Tetrahedron 1996, 52, 12853. (b) Lipshutz, B.
H.; Pfeiffer, S. S.; Tomioka, T.; Noson, K. In Titanium and Zirconium in
Organic Synthesis; Marek, I., Ed.; Wiley-VCH: Weinheim, 2002; p 110.
10.1021/ol0487783 CCC: $27.50 © 2004 American Chemical Society
Published on Web 07/28/2004

yield (Scheme 1).8 This extension further generalizes our
strategy for the preparation of C-cyclopropylalkylamides and
allows direct access to these interesting functional groups
independent of the availability of imines 2 or alkynes 1.
Table 1. Conversions of C,C-dicyclopropylmethylamines 3
into Azepines 9 According to Scheme 2
Scheme 1. Preparation of C-Cyclopropylalkylamides from
Propargyl Phosphinamides
Recently, it has been demonstrated that molecular flex-
ibility in biological screening samples is often associated with
increased metabolism and decreased bioavailability.9 In
addition to minimizing this risk by cyclizing cyclopropyla-
lkylamides 3, 6, and 7, we were interested in expanding the
structural diversity of these novel building blocks by
selectively converting them into common 5-, 6-, and 7-
membered heterocyclic scaffolds used for biological screens.10
Indeed, we were able to take advantage of the functional
groups in 3, 6, and 7 for the straightforward preparation of
spirocyclic azepines, piperidines, and pyrrolidines. Although
N-heterocycles are often present in natural products and
pharmaceutically useful compounds, these azaspirocyclic
scaffolds represent novel structures for biological evaluation.
Ring-closing metathesis precursors 8a-g11,12 were readily
available in 65 to 96% yield via N-alkylation (NaH, HMPA,
allyl iodide) of phosphinamides 3a-g. While the ring-closing
event using 10 mol % of Grubbs’ second generation catalyst13
was rapid in dichloroethane,12a alkene isomerization to the
enamide was competitive (azepine/enamide ∼1:1).12b,14 How-
ever, this undesired isomerization pathway could be mini-
mized by lowering the reaction temperature (CH2Cl2, reflux)
leading to the desired 1H-azepines 9a-g in 63-84% yield
(Scheme 2). Functionalization was tolerated on both the arene
segment as well as the alkyne side chain, and no ring opening
of cyclopropanes was observed (Table 1).15
a Yield of isolated products.
We also envisioned the preparation of smaller nitrogen-
containing heterocycles using a reductive amination strategy.
The ω-disubstituted alkene moiety in 3 and 6 was easily
converted to an aryl ketone under Johnson-Lemieux16
conditions (Scheme 3). We were unable to affect reductive
amination under Lewis acidic conditions (BF3‚OEt2/Ph3SiH17
or TiCl4/Et3SiH), but a simple three-step, one-pot protocol
involving N-deprotection (HCl/MeOH) followed by reductive
amination (NaBH3CN, MeOH) and acylation (AcCl, DIPEA)
(8) Zn(CH2I)2‚DME was used for mmole-scale preparations of C,C-
dicyclopropylmethylamides 3, 6, and 7 as a safer alternative to Zn(CH2I)2
without noticeable attenuation of reactivity. Cf. Charette, A. B.; Prescott,
S.; Brochu, C. J. Org. Chem. 1995, 60, 1081.
Scheme 2. Azepine Formation by Sequential N-Allylation/
Ring-Closing Metathesis
(9) Veber, D. F.; Johnson, S. R.; Cheng, H.-Y.; Smith, B. R.; Ward, K.
W.; Kopple, K. D. J. Med. Chem. 2002, 45, 2615.
(10) Lee, M.-L.; Schneider, G. J. Comb. Chem. 2001, 3, 284.
(11) (a) Schuster, M.; Blechert, S. Angew. Chem., Int. Ed. Engl. 1997,
36, 2037. (b) Grubbs, R. H.; Chang, S. Tetrahedron 1998, 54, 4413. (c)
Fu¨rstner, A. Angew. Chem., Int. Ed. 2000, 39, 3012.
(12) For the preparation of azepines by ring-closing metathesis, cf. (a)
Hoffmann, T.; Waibel, R.; Gmeiner, P. J. Org. Chem. 2003, 68, 62. (b)
Wipf, P.; Rector, S. R.; Takahashi, H. J. Am. Chem. Soc. 2002, 124, 14848.
(c) Furstner, A.; Guth, O.; Duffels, A.; Seidel, G.; Liebl, M.; Gabor, B.;
Mynott, R. Chem. Eur. J. 2001, 7, 4811. (d) Fu, G. C.; Grubbs, R. H. J.
Am. Chem. Soc. 1992, 114, 7324.
(13) Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett. 1999, 1,
953.
(14) (a) Sutton, A. E.; Seigal, B. A.; Finnegan, D. F.; Snapper, M. L. J.
Am. Chem. Soc. 2002, 124, 13390. (b) Lehman, S. E., Jr.; Schwendeman,
J. E.; O′Donnell, P. M.; Wagener, K. B. Inorg. Chim. Acta 2003, 345, 190.
(c) Hong, S. H.; Day, M. W.; Grubbs, R. H. J. Am. Chem. Soc. 2004, 126,
7414.
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Org. Lett., Vol. 6, No. 17, 2004

Scheme 3. Reductive Amination Approach to Pyrrolidines
Scheme 4. Piperidine Synthesis via 6-Endo Epoxide Opening
21 derived from C,C-dicyclopropylmethylamine 3a cyclized
stereospecifically to yield piperidine 22 and pyrrolidine 23,
respectively (Scheme 5). Individual reactions of the chro-
Scheme 5. Stereospecific Formation of Pyrrolidines and
Piperidines by Intramolecular Epoxide Aminolysis
afforded the desired pyrrolidines in good yield. While the
diastereoselectivity of the reductive amination step was
poor,18 the diastereomers were readily separated by column
chromatography.
In addition to the formation of 5- and 7-membered
azaspirocycles, piperidines could be obtained via the 6-endo
opening of epoxides 16 and 17 (Scheme 4).19 After epoxi-
dation of 6 and 7, cyclization under basic conditions afforded
the desired piperidines 18 and 19, respectively. The latter
compound was formed as a mixture of diastereomers
originating from a lack of selectivity in the epoxidation step.
Interestingly, the more highly substituted epoxides 20 and
(15) Exposure of A to the allylation conditions led to carbamate cleavage
product B, which upon ring-closing metathesis provided the 11-membered
C rather than the azepine product. Interestingly, this reaction was much
faster (<1 h) than the formation of azepines 9.
matographically separated, pure epoxides confirmed that
6-endo cyclization of 20 led to 22 as a single reaction
product, as expected based on steric hindrance and the
precedence of 16 and 17, while diastereomer 21 afforded
exclusively the 5-exo cyclization product pyrrolidine 23.
At this time, we can only speculate about the origin of
the stereospecificity of the intramolecular aminolysis of 20
and 21, but the steric influence of the substituent R to the
nitrogen atom clearly plays a role since it reverses the
inherent 6-endo selectivity in the case of the 1,4-syn
diastereomer 21.20
(16) (a) Pappo, R.; Allen, D. S.; Lemieux, R. U.; Johnson, W. S. J. Org.
Chem. 1956, 21, 478. (b) Wipf, P.; Kim, Y.; Goldstein, D. M. J. Am. Chem.
Soc. 1995, 117, 11106.
(17) Rudolph, A. C.; Machauer, R.; Martin, S. F. Tetrahedron Lett. 2004,
45, 4895.
(18) These observations are in agreement with the results of Rudolph et
al. (ref 17); however, Lewis acidic conditions appear to promote N-
dephosphinoylation and do not furnish the desired pyrrolidines in acceptable
yields.
(19) (a) LaLonde, R. T.; Muhammad, N.; Wong, C. F.; Sturiale, E. R. J.
Org. Chem. 1980, 45, 3664. (b) Nuhrich, A.; Moulines, J. Tetrahedron 1991,
47, 3075. (c) Breternitz, H.-J.; Schaumann, E. J. Chem. Soc., Perkin Trans.
1 1999, 1927. (d) Abe, H.; Aoyagi, S.; Kibayashi, C. J. Am. Chem. Soc.
2000, 122, 4583.
Org. Lett., Vol. 6, No. 17, 2004
3011

In summary, we have extended the multicomponent
condensation of alkenylzirconocenes with N-diphenylphos-
phinoyl imines and diiodomethane to the direct cyclopro-
panation-rearrangement of readily available alkynyl phos-
phinamides. The resulting C-[1-(2-arylallyl)cyclopropyl]-
alkylamines 3, 6, and 7 provide valuable starting points for
the diversity-oriented synthesis of heterocycles. Functional-
ized pyrrolidines, piperidines, and azepines are easily ac-
cessible in 2-3 steps in good overall yields. Further
applications of the Zr f Zn transmetalation/multicomponent
condensation methodology as well as the biological evalu-
ation21 of new azaspirocycles will be reported in due course.
Acknowledgment. This work has been supported by NIH
P50-GM067082.
Supporting Information Available: Experimental pro-
cedures and spectral data for all new compounds, including
copies of 1H and 13C NMR spectra. This material is available
free of charge via the Internet at http://pubs.acs.org.
(20) The relative stereochemistry of 23 was assigned by NOESY and
the product was assumed to arise from an inversion of configuration at the
quaternary carbon atom.
OL0487783
(21) Preliminary screening of compounds 3 revealed interesting nuclear
receptor binding and antiproliferative effects.
3012
Org. Lett., Vol. 6, No. 17, 2004