Trianion synthon approach to spirocyclic heterocycles

Article abstract of DOI:10.1021/ol400788q

A variety of spirocyclic heterocycles have been constructed by a double-alkylation and reductive cyclization approach utilizing α-heteroatom nitriles as trianion synthons. The method provides access to heteroatom-substituted spirocycles in a variety of ring sizes that are found in natural products and are important in pharmaceutical lead development and optimization.

Full text of DOI:10.1021/ol400788q

ORGANIC
LETTERS
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Vol. XX, No. XX
000–000
Trianion Synthon Approach to Spirocyclic
Heterocycles
Matthew A. Perry, Richard R. Hill, and Scott D. Rychnovsky*
Department of Chemistry, 1102 Natural Sciences II, University of California, Irvine,
Irvine, California 92697, United States
srychnov@uci.edu
Received March 22, 2013
ABSTRACT
A variety of spirocyclic heterocycles have been constructed by a double-alkylation and reductive cyclization approach utilizing R-heteroatom
nitriles as trianion synthons. The method provides access to heteroatom-substituted spirocycles in a variety of ring sizes that are found in natural
products and are important in pharmaceutical lead development and optimization.
Spirocyclic frameworks are important motifs found in
natural products and in medicinal lead compounds. These
complex structures have a well-defined three-dimensional
spatial arrangement that exhibit specificity of action with
biological receptors and enzymes.1 Spirocycic frameworks
have been the target of several synthetic methods2 aimed at
the construction of structurally diverse natural and non-
natural molecules. Described herein is a general strategy
for the construction of spiro-heterocycles based on a
reductive cyclization process.3
pharmaceutical targets (Figure 1).5 The assembly of carbo-
cyclic6,7 and, especially, heterocyclic8 frameworks by dou-
ble alkylation of R-heteronitriles is an underdeveloped
transformation. Nitrile anions are competent nucleophiles
that have been applied to the formation of complex mole-
cules using nitrile anion alkylation methodology.9 Based
on the double alkylation/reductive cyclization strategy
we developed for the lepadiformine alkaloids,7 we set out
to extend this method to the synthesis of diverse spirocyclic
heterocycles.
Efficient construction of spirocyclic heterocycles is
important in the synthesis of natural products4 and
Synthesis of a variety of spirocyclic frameworks begins
with double alkylation of a bis-electrophile (6) with the
appropriate nitrile partner (e.g., 5). Subsequent deprotec-
tion with TBAF and phosphorylation with diethyl chloro-
phosphate and N-methylimidazole10 generated the cyano
(1) (a) Rajesh, S. M.; Perumal, S.; Menendez, J. C.; Yogeeswari, P.;
Sriram, D. Med. Chem. Commun. 2011, 2, 626–630.
(2) Kotha, S.; Deb, A. C.; Lahiri, K.; Manivannan, E. Synthesis 2009,
2, 165–193.
(3) (a) Takaoka, L. R.; Buckmelter, A. J.; La Cruz, T. E.; Rychnovsky,
S. D. J. Am. Chem. Soc. 2005, 127, 528–529. (b) La Cruz, T. E.;
Rychnovsky, S. D. J. Org. Chem. 2006, 71, 1068–1073. (c) La Cruz,
T. E.; Rychnovsky, S. D. J. Org. Chem. 2007, 72, 2602–2611. (d) Riberio,
C. M. R.; Demelo, S. J.; Bonin, M.; Quirion, J. C.; Husson, H. P.
Tetrahedron Lett. 1994, 35, 7227–7230.
(4) (a) Biard, J. ꢀF.; Guyot, S.; Roussakis, C.; Verbist, J.-F. Tetra-
hedron Lett. 1994, 35, 2691–2694. (b) Issa, H.; Tanaka, J.; Rachmat, R.;
Setiawan, A.; Trainto, A.; Higa, T. Mar. Drugs 2005, 3, 78–83.
(c) Hirasawa, Y.; Morita, H.; Kobayashi, J. Org. Lett. 2004, 6, 3389–
3391. (d) Daly, J. W.; Karle, I.; Myers, C. W.; Tokuyama, T.; Waters,
J. A.; Witkop, B. Proc. Natl. Acad. Sci. U.S.A. 1971, 68, 1870.
(e) Burnell, R. H.; Mootoo, B. S. Can. J. Chem. 1961, 39, 1090.
(f) Blackman, A. J.; Li, C.; Hockless, D. C. R.; Skelton, B. H. Tetra-
hedron 1993, 49, 8645–8656. (g) Blackman, A. J.; Li, C. Aust. J. Chem.
1994, 47, 1355–1361. (h) Blackman, A. J.; Li, C. Aust. J. Chem. 1995, 48,
955–965. (i) Sakamoto, K.; Tsujii, E.; Abe, F.; Nakanishi, T.;
Yamashita, M.; Shigematsu, N.; Izumi, S.; Okuhara, M. J. Antibiot.
1996, 49, 37–44. (j) Shirafuji, H.; Tsubotani, S.; Ishimaru, T.; Harada, S.
PCT Int. Appl. WO 91 13,887, 1991; Chem Abstr. 1992, 116, 39780t.
(5) (1) Sanofi-Aventis, Fr, WO2009EP04393, 2009 June 18. (2)
GlaxoSmithKline LLC, USA, WO2010US46782, 2010 August 26. (3)
Ghosh, A. K.; Krishnan, K.; Walters, D. E.; Cho, W.; Cho, H.; Koo, Y.;
Trevino, J.; Holland, L.; Buthod, J. Bioorg. Med. Chem. Lett. 1998, 8, 979–
982. (4) Glaxo Group Limited, UK, WO2008EP53595, 2008 March 27.
(a) The Boots Company PLC, USA, US5610161, 1997 March 11.
(b) Targacept, Inc., USA, WO2006034089, 2006 March 30. (c) Takeda
Chemical Industries, Ltd., USA, US5591849, 1997 January 7.
(6) Guillaume, D.; Brum-Bousquet, M.; Aitken, D. J.; Husson, H.-P.
Bull. Soc. Chim. de Fran 1994, 131, 391–396.
(7) (a) Perry, M. A.; Morin, M. D.; Slafer, B. W.; Wolckenhauer,
S. A.; Rychnovsky, S. D. J. Am. Chem. Soc. 2010, 132, 9591–9593.
(b) Perry, M. A.; Morin, M. D.; Slafer, B. W.; Rychnovsky, S. D. J. Org.
Chem. 2012, 77, 3390–3400.
(8) Gharpure, S. J.; Reddy, S. R. B. Org. Lett. 2009, 11, 2519–2522.
(9) (a) Fleming, F. F.; Zhang, Z. Tetrahedron 2005, 61, 747–789.
(b) Fleming, F. F.; Shook, B. C. Tetrahedron 2002, 58, 1–23 and
references cited therein.
(10) Soorukram, D.; Knochel, P. Org. Lett. 2004, 6, 2409–2411.
r
10.1021/ol400788q
XXXX American Chemical Society

Table 1. R-Oxonitrile Double Alkylation and Spirocyclization
Figure 1. Spirocyclic rings in pharmaceutical targets.
phosphate intermediate (8). Reductive decyanation with
cyclization afforded spirotetrahydrofurans 9aꢀe (Table 1).
The double alkylation led to good yields of cyclobutaneni-
trile 7a, cyclopentanenitrile 7b, and cyclohexanenitrile 7c
(entries 1ꢀ3). The tetrahydropyranyl adduct 7d was readily
accessed from the double alkylation with 2,20-dibromodiethyl
ether (entry 4). Synthesis of the ketal cyclohexanenitrile
7e was achieved in moderate yield using protected 1,5-
dibromopentan-3-one 6e (entry 5). The deprotection and
phosphorylation steps were efficient in all cases. The reduc-
tive decyanation generates an intermediate tertiary alkyl-
lithium reagent that cyclizes with displacement of the
phosphate. The reductive cyclization in all cases proceeded
with very good yield. For the volatile products 9a and 9b,
the yields were estimated by GCMS analysis with an internal
standard. Attempts to isolate 9a from residual THF were
unsuccessful as the boiling point and polarity are too similar.
In a similar fashion, the use of aminonitrile 10 provided
spiropyrrolidines 13aꢀg (Table 2). The cyclobutane nitrile
11a was obtained in a modest yield from the double-
alkylation step. The double alkylation reactions to produce
unsubstituted cyclopentane 11b and cyclohexanenitrile 11c
were more efficient (entries 2 and 3). Double alkylation
with 1,6-dibromohexane gave a mixture of the desired
cycloheptanenitrile 11g, and an alkylationꢀelimination
product in an overall 18% yield and was not investigated
further. As above, the THPꢀaminonitrile product 11d
was isolated in good yield using dielectrophile 6d. Use of
protected 1,5-dibromopentan-2-one 6f (entry 7) resulted in
a moderate yield due to concomitant formation of a bis-
alkylated aminonitrile byproduct (19% yield). The reduc-
tive lithiation and cyclization of the N-Boc aminonitriles
were all effective, but yields were more varied than in the
spirotetrahydrofuran examples in Table 1. Construction
of the aliphatic spiropyrrolidines proceeded in moderate to
good yield irrespective of the carbocyclic ring size. Cycliza-
tion to provide unsymmetrically substituted spirocycle 13f
also proceeded in moderate yield. In the case of 12e, the
reductive cyclization proceeded in an unexpectedly low
a Yield estimated by GCMS analysis using decane as an internal
standard. Isolated yield of 9b was 56%.
37% yield to afford13e. In mostinstances, no side products
were observed or isolated in these reductive cyclization
reactions. In a few cases, reduced starting material contain-
ing a terminal olefin was observed as a byproduct (e10%),
which was inseparable from the desired product by
chromatography.11
The reductive cyclizations developed to date all use 2.2
equiv of the lithium di-tert-butyl biphenylide (LiDBB),
which limits the practical scale of the reaction. We have
investigated the cyclization using catalytic di-tert-butylbi-
phenyl (DBB) and lithium metal.12 The source of lithium
metal was important with lithium powder proving more
efficient than lithium wire, sheet, or granules. Equation 1
shows an example on 1.23 g scale using 10 mol % of DBB
run at 0 °C, which proceeds in good yield. Using catalytic
(11) Removal of the elimination byproduct can be accomplished by
dihydroxylation using OsO4 and NMO in acteone/water followed by
column chromatography.
(12) (a) Guijarro, D.; Yus, M. Tetrahedron 1994, 50, 3447–3452.
(b) Ramon, D.; Yus, M. Tetrahedron 1992, 48, 3585–3588. (c) Gomez,
C.; Lillo, V. J.; Yus, M. Tetrahedron 2007, 93, 4655–4662.
B
Org. Lett., Vol. XX, No. XX, XXXX

contains one more methylene unit than nitrile 10, with
dibromide 6e resulted in alcohol 15 after double alkylation
and deprotection (Scheme 1). Formation of the phosphate
16a, followed by reductive cyclization generated the spir-
opiperidine 17 in moderate yield. The chloride 16b was
prepared from 15 to test the effect of the leaving group on
the spirocyclization. Reductive lithation of 16b led to the
formation of both the expected spiropiperidine 17 (29%)
and the unexpected spiroazepinone 18 in 43% yield.
Compound 18 arose by competitive lithiation of the alkyl
chloride and cyclization onto the nitrile. We have pre-
viously observed competitive lithation of alkyl chlorides
with N-benzyl aminonitriles,13 but not with the more easily
reduced N-Boc aminonitriles. Formation of azepinone 18
would be enhanced by using a more easily reduced halide
such as bromide. Spiropiperidines are available in moder-
ate yield using the reductive decyanation and cyclization
strategy.
Table 2. R-Aminonitrile Double Alkylation and Spirocyclizationa
Scheme 1. Cyclizations to Piperidines and Azipinones
Spiroacetals 13f and 17 both incorporate protected
secondary amines and ketones. Selective deprotection
by treatment of 13f with acetic acid in THF/H2O led to
removal of the 1,3-dioxolane protecting group to provide
the hydrated ketone 19 in 65% yield (Scheme 2). Acid-
mediated removal of the nitrogen Boc group of 18 with
TFA led to a 2:1 mixture of deprotected aminoacetal and
amine 20. Dilution of the crude mixture in THF and 1 M
HCl provided the ketoamine 20 in 56% yield. In simple
cases, acidic removal of the N-Boc group proceeded with-
out issue (i.e., 13d to 21). Further transformations of these
types of spirocycles to give valuable medicinally relevant
compounds have been reported.14,5b
a Cycloheptane 11g was isolated as a 1:1 mixture with an elimination
byproduct.
DBB and noncryogenic temperatures makes the cycliza-
tion step amenable to scale-up.
(13) Bahde, R. J.; Rychnovsky, S. D. Org. Lett. 2008, 10, 4017–4020.
ꢀ
ꢀ
ꢀ
(14) (a) Bonjoch, J.; Diaba, F.; Puigbo, G.; Peidro, E.; Sole, D.
Tetrahedron Lett. 2003, 44, 8387–8390. (b) Nagumo, S.; Matoba, A.;
Ishii, Y.; Yamaguchi, S.; Akutsu, N.; Nishijima, H.; Nishida, A.;
Kawahara, N. Tetrahedron 2002, 58, 9871–9877. (c) Sanofi-Aventis,
Fr, WO2009156092, 2009 December 30. (d) Sunovion Pharmaceuticals,
Inc., USA, WO2011075699, 2011 June 23. (e) Rotta Research Laboratorium
S.p.A., Italy, US6075033, 2000 June 13.
Spiropiperidine and azepinone frameworks are also
accessible by this method. Reaction of nitrile 14, which
Org. Lett., Vol. XX, No. XX, XXXX
C

and cyclization of a nitrile phosphate to form the spiro-
cyclic pyrrolidine, piperidine, or tetrahydrofuran ring.
The reactions were successful with different heteroatoms
and a number of ring sizes. This method will be useful
in natural products synthesis and in medicinal chemistry.
We are continuing to explore the selectivity and scope of this
strategy.
Scheme 2. Deprotection of Spirocycles
Acknowledgment. We thank NIGMS (GM43854) for
their support of this program and Vertex for a Vertex
Fellowship (MAP).
Supporting Information Available. Experimental pro-
1
cedures and H and 13C NMR spectra of all new com-
pounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
We have presented a general strategy to construct spiro-
cyclic heterocycles. The key step is a reductive lithiation
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX