Synthesis of novel angular spirocyclic azetidines

Article abstract of DOI:10.1021/ol103050c

The syntheses of a variety of novel angular azaspiro[3.3]heptanes are reported. gem-Difluoro and gem-dimethyl variants of the angular 1,6-diazaspiro[3.3]heptane module were prepared in high yields using efficient sequences. Additionally, a practical one-p

Full text of DOI:10.1021/ol103050c

ORGANIC
LETTERS
2011
Vol. 13, No. 4
780–783
Synthesis of Novel Angular Spirocyclic
Azetidines
Carine Guerot,†,‡ Boris H. Tchitchanov,‡ Henner Knust,‡ and Erick M. Carreira*†
ꢀ
Laboratorium fu€r Organische Chemie, ETH Zu€rich, CH-8093 Zu€rich, Switzerland, and
F. Hoffmann-La Roche AG, pRED, Discovery Chemistry, CH-4070 Basel, Switzerland
carreira@org.chem.ethz.ch
Received December 16, 2010
ABSTRACT
The syntheses of a variety of novel angular azaspiro[3.3]heptanes are reported. gem-Difluoro and gem-dimethyl variants of the angular 1,6-
diazaspiro[3.3]heptane module were prepared in high yields using efficient sequences. Additionally, a practical one-pot synthesis of 5-oxo-2-
azaspiro[3.3]heptanes and subsequent conversions into functionalized derivatives are described. The methods reported are amenable to the
synthesis of these building blocks for drug discovery as members of a library or individually on a preparative scale.
The design and synthesis of novel, readily manipulated
building blocks is of fundamental importance in modern
drug discovery. In an effort to explore uncharted chemical
and pharmacological space,1 the preparation of novel spiro-
cyclic scaffolds has recently been the subject of significant
interest.2 Functionalized azaspiro[3.3]heptanes are especially
attractive scaffolds because they offer the potential of wide
variability in relative spatial disposition of functional groups
and attendant vectors. As shown in Figure 1, the linear
2-azaspiro[3.3]heptane modules (1-3) possess exit vec-
tors in geometrically opposing directions; by contrast
angular modules, such as 1,6-diazaspiro[3.3]heptane 4 and
5-8, position two exit vectors in a tilted arrangement. Of the
possible variants of azaspiro[3.3]heptanes, linear scaffolds
such as 2,6-azaspiro[3.3]heptanes 1,3 6-oxo-2-azaspiro-
[3.3]heptanes 2, and other spirocyclic derivatives 34 have
been covered in the literature. In contrast, angular frame-
works have only been described by our group.5 Because we
anticipate wide potential for the use of scaffold 4in medicinal
chemistry, we envisaged extending the profile of 4 by in-
corporation of a variety of substituents on the underlying
(3) (a) Govaert, F. J. Proc. Acad. Sci. Amsterdam 1934, 37, 156. (b)
Litherland, A.; Mann, F. G. J. Chem. Soc. 1938, 1588. (c) Hillier, M. C.;
Chen, C. Y. J. Org. Chem. 2006, 71, 7885. (d) Hamza, D.; Stocks, M. J.;
Decor, A.; Pairaudeau, G.; Stonehouse, J. P. Synlett 2007, 2584. (e)
Stocks, M. J.; Hamza, D.; Pairaudeau, G.; Stonehouse, J. P.; Thorne,
P. V. Synlett 2007, 2587. (f) Burkhard, J.; Carreira, E. M. Org. Lett.
2008, 10, 3525. (g) Burkhard, J. A.; Wagner, B.; Fischer, H.; Schuler, F.;
† ETH Z€urich.
‡ F. Hoffmann-La Roche AG.
(1) Lipkus, A. H.; Yuan, Q.; Lucas, K. A.; Funk, S. A.; Bartelt, W. F.;
Schenck, R. J.; Trippe, A. J. J. Org. Chem. 2008, 73, 4443.
(2) (a) Burkhard, J. A.; Wuitschik, G.; Rogers-Evans, M.; Muller,
K.; Carreira, E. M. Angew. Chem., Int. Ed. 2010, 49, 9052. (b) Wuitschik,
G.; Carreira, E. M.; Wagner, B.; Fischer, H.; Parrilla, I.; Schuler, F.;
Rogers-Evans, M.; Muller, K. J. Med. Chem. 2010, 53, 3227. (c)
Wuitschik, G.; Rogers-Evans, M.; Buckl, A.; Bernasconi, M.; Marki,
M.; Godel, T.; Fischer, H.; Wagner, B.; Parrilla, I.; Schuler, F.;
€
€
Muller, K.; Carreira, E. M. Angew. Chem., Int. Ed. 2010, 49, 3524.
(4) (a) Meyers, M. J.; Muizebelt, I.; van Wiltenburg, J.; Brown, D. L.;
Thorarensen, A. Org. Lett. 2009, 11, 3523. (b) Radchenko, D. S.;
Grygorenko, O. O.; Komarov, I. V. Amino Acids 2010, 39, 515. (c)
Radchenko, D. S.; Pavlenko, S. O.; Grygorenko, O. O.; Volochnyuk,
D. M.; Shishkina, S. V.; Shishkin, O. V.; Komarov, I. V. J. Org. Chem.
2010, 75, 5941.
€
€
Schneider, J.; Alker, A.; Schweizer, W. B.; Muller, K.; Carreira, E. M.
Angew. Chem., Int. Ed. 2008, 47, 4512. (d) Wuitschik, G.; Rogers-Evans,
€
ꢀ
M.; Muller, K.; Fischer, H.; Wagner, B.; Schuler, F.; Polonchuk, L.;
(5) Burkhard, J. A.; Guerot, C.; Knust, H.; Rogers-Evans, M.;
Carreira, E. M. Angew. Chem., Int. Ed. 2006, 45, 7736.
Carreira, E. M. Org. Lett. 2010, 12, 1944.
r
10.1021/ol103050c
Published on Web 01/14/2011
2011 American Chemical Society

sulfinyl aldimines;11 however, to the best of our knowledge,
no such reactivity has been observed with ketimines. The
only case where an N-tert-butylsulfinyl ketimine was used
in a Reformatsky reaction involved unsubstituted acetate
enolates.12
Scheme 1. Synthesis of 3,3-gem-difluoro- and 3,3-gem-
Dimethyl-1,6-diazaspiro[3.3]heptanes
Figure 1. Representation of linear and angular azaspiro-
[3.3]heptanes.
scaffold, such as gem-difluoro and -dimethyl groups by
virtue of their frequency of use in medicinal chemistry.6,7
We wish to report the syntheses of novel angular 3,3- and 2,2-
gem-disubstituted 1,6-diazaspiro[3.3]heptanes 5 and 6, as
well as 5-oxo-2-azaspiro[3.3]heptane 7 and derivatives 8 of
the underlying scaffold. These are derived from a common
precursor azetidin-3-one.
N-tert-Butylsulfinyl imines are known for their high sta-
bility and electrophilicity compared to other imine deriva-
tives; consequently they enable the facile addition of a wide
range of nucleophiles across CdN.8 We decided to take
advantage of these properties to prepare 3,3-disubstituted
1,6-diazaspiro[3.3]heptanes 11 and 12. Ti(OEt)4 mediated
condensation of commercially available N-benzhydryl azeti-
din-3-one 9and racemic tert-butylsulfinamide gave N-sulfinyl
imine 10 in good yield (Scheme 1).9 The Reformatsky
addition has been frequently employed for the preparation
of R,R-difluoro-β-amino acids, R,R-difluoro-β-lactams, and
3,3-difluoroazetidines.10 For example, their synthesis was
recently reported via reaction of the Reformatsky reagent
derived from ethyl bromodifluoroacetate and N-tert-butyl-
Ketimine 10 underwent addition of ethyl bromodifluoro-
acetate in the presence of activated Zn and CuCl at 60 °C to
quantitatively afford the corresponding ester. Subsequent
ester reduction and ring closure through the implementation
of Mitsunobu cyclization afforded 3,3-gem-difluoroazetidine
11 in excellent yield. In a similar fashion, 3,3-dimethyl-1,6-
diazaspiro[3.3]heptane 12 was prepared. Indium-mediated
Reformatsky reaction of ketimine 10 and ethyl 2-bromo-
2-methylpropanoate yielded a separable mixture of ester
(56%) and β-lactam (28%) products. Both were converted
individually to the targeted 3,3-dimethylazetidine 12, using
similar conditions as described above. To the best of our
knowledge, the enolate additions described above constitute
the first additions involving a N-tert-butylsulfinyl ketimine
and a Reformatsky reagent derived from ethyl bromodi-
fluoroacetate and ethyl 2-bromo-2-methylpropanoate.
(6) For gem-difluoromethylene compounds, see: (a) Yamazaki, T.;
Taguchi, T.; Ojima, I. In Fluorine in Medicinal Chemistry and Chemical
Biology; Wiley-Blackwell: 2009; Chapter 1, pp 3-46. (b) Reddy, V. P.;
Perambuduru, M.; Alleti, R. In Advances in Organic Synthesis; Bentham
Science: 2006; Vol. 2, pp 327-351.
(7) For gem-dimethyl substituted compounds, see: (a) Duffy, J. L.;
Rano, T. A.; Kevin, N. J.; Chapman, K. T.; Schleif, W. A.; Olsen, D. B.;
Stahlhut, M.; Rutkowski, C. A.; Kuo, L. C.; Jin, L. X.; Lin, J. H.; Emini,
E. A.; Tata, J. R. Bioorg. Med. Chem. Lett. 2003, 13, 2569. (b) Ahmad,
S.; Doweyko, L. M.; Dugar, S.; Grazier, N.; Ngu, K.; Wu, S. C.; Yost,
K. J.; Chen, B. C.; Gougoutas, J. Z.; DiMarco, J. D.; Lan, S. J.; Gavin,
B. J.; Chen, A. Y.; Dorso, C. R.; Serafino, R.; Kirby, M.; Atwal, K. S.
J. Med. Chem. 2001, 44, 3302.
Scheme 2. Synthesis of 2,2-gem-dimethyl-1,6-diazaspiro-
[3.3]heptane
(8) Robak, M. T.; Herbage, M. A.; Ellman, J. A. Chem. Rev. 2010,
110, 3600.
(9) Ketimine 10 proved to be stable enough to be purified by column
chromatography on silica and could be stored in the freezer for months
with no evidence of decomposition.
(10) Boyer, N.; Gloanec, P.; De Nanteuil, G.; Jubault, P.; Quirion,
J. C. Eur. J. Org. Chem. 2008, 4277 and references cited therein.
(11) (a) Staas, D. D.; Savage, K. L.; Homnick, C. F.; Tsou, N. N.;
Ball, R. G. J. Org. Chem. 2002, 67, 8276. (b) Sorochinsky, A.; Voloshin,
N.; Markovsky, A.; Belik, M.; Yasuda, N.; Uekusa, H.; Ono, T.;
Berbasov, D. O.; Soloshonok, V. A. J. Org. Chem. 2003, 68, 7448.
(c) Montavon, T. J.; Christianson, C. V.; Festin, G. M.; Shen, B.;
Bruner, S. D. Bioorg. Med. Chem. Lett. 2008, 18, 3099.
In order to access 2-substituted 1,6-diazaspiro[3.3]heptane,
such as 5, a modified approach was required (Scheme 2).
Base-mediated cyclization of previously reported β-amino
(12) Brinner, K.; Doughan, B.; Poon, D. J. Synlett 2009, 991.
Org. Lett., Vol. 13, No. 4, 2011
781

Scheme 3. Synthesis of 5-oxo-2-azaspiro[3.3]heptane 16
ester 135 into the corresponding β-lactam (28, see Supporting
Information (SI)) by treatment with MeMgBr proceeded in
good yield. Attempts to effect additions to the intermediate
β-lactam so as to generate 14, using modified Bouveault
reaction, with ZrCl4 and MeMgBr were unsuccessful.13
However, application of conditions recently reported for the
conversion of β-lactams to tert-alkylamines14 proved fruitful.
Thus, one-pot reductive bisalkylation of the β-lactam (28, see
SI) with MeMgBr afforded 2,2-gem-dimethylazetidine 14 in
48% yield (63% based on recovered starting material).
Syntheses of potential isosteres of the parent diazaspiro-
heptanesfor medicinalchemistry, suchasthe novel angular
modules 5-oxo-2-azaspiro[3.3]heptane 7 and its deriva-
tives 8, were then targeted. Application of the Trost method
for the synthesis of cyclobutanones was envisaged to furnish
1615 with N-benzhydryl azetidin-3-one as the starting mate-
rial (Scheme 3).16 Initially, when 9 was allowed to react with
cyclopropyldiphenylsulfonium tetrafluoroborate under
standard conditions (KOH in DMSO) no product was
isolated and we only observed decomposition. Similar re-
sults were obtained with KOtBu in toluene. Interestingly, the
use of KHMDS in THF at -40 °C led to complete conver-
sion of the azetidin-3-one to intermediate oxaspiropentane
15.17 The unpurified product was then submitted to rear-
rangement upon exposure to LiBF4 to afford the required
cyclobutanone 16 in modest yield (26%). The reaction was
also carried out with azetidin-3-ones incorporating a variety
of protecting groups (i.e., N-Boc and N-Ts), giving the corre-
sponding cyclobutanones within the same range of yield. In
order to improve the yield of this transformation, the reac-
tion conditions for each step were scrutinized. Addition of
cyclopropyl sulfonium tetrafluoroborate to the N-benzhy-
dryl azetidin-3-one 9 delivered the highly strained 6-aza-8-
oxa-dispiro[2.0.3.1]octane 15, which was, surprisingly, suffi-
ciently stable for isolation (57% yield) and characterization
(see X-ray structure). The second step was then carried out
with purified material to determine if it could be further
optimized. The rearrangement reaction utilizing lithium
tetrafluoroborate gave the desired cyclobutanone 16 in
52% yield. The use of substoichiometric quantities of lithium
iodide resulted in a dramatic improvement, as the reaction
was complete within 2 h and gave the 5-oxo-2-azaspiro-
[3.3]heptane 16 in 85% yield. Finally, for practical reasons, a
sequential one-pot synthesis was attempted, and it proved
successful as no yield loss was observed in the overall
formation of 16 (44% yield). The reaction can be easily
conducted on large scale up to 20 g, making this transforma-
tion a highly efficient process.
In subsequent investigations, manipulations of the carbon-
yl were performed so as to access useful building modules
for medicinal chemistry as shown in Scheme 4. Alcohol 17
Scheme 4. Derivatization of 5-oxo-2-azaspiro[3.3]heptane
(13) Denton, S. M.; Wood, A. Synlett 1999, 55.
(14) Xiao, K. J.; Luo, J. M.; Ye, K. Y.; Wang, Y.; Huang, P. Q.
Angew. Chem., Int. Ed. 2010, 49, 3037.
(15) While the manuscript was in preparation, tert-butyl 5-oxo-2-
azaspiro[3.3]heptane-2-carboxylate was reported to be commercially
available (from WuXi AppTec, publication date on SciFinder: 10/27/
2010), showcasing the importance of this new scaffold. No experimental
details are available.
(16) (a) Trost, B. M.; Bogdanowicz, M. J. J. Am. Chem. Soc. 1973, 95,
5298. (b) Trost, B. M.; Bogdanowicz, M. J. J. Am. Chem. Soc. 1973, 95,
5321. (c) Trost, B. M.; Bogdanowicz, M. J.; Kern, J. J. Am. Chem. Soc.
1975, 97, 2218.
(17) Jenkins, I. D.; Lacrampe, F.; Ripper, J.; Alcaraz, L.; Van Le, P.;
Nikolakopoulos, G.; Leone, P. D.; White, R. H.; Quinn, R. J. J. Org.
Chem. 2009, 74, 1304.
782
Org. Lett., Vol. 13, No. 4, 2011

was easily obtained in quantitative yield by reduction of 16
with sodium borohydride. Additionally, the corresponding
amine 18 was also prepared by sequential reductive amina-
tion via the intermediate oxime. The synthesis of carboxylic
acid 20 was then undertaken by conversion of cyclobuta-
none 16 into the corresponding homologous aldehyde 19.
At this stage, aldehyde 19 was subjected to the Pinnick
oxidation conditions; however, instead of the expected acid
20, lactone 21 was the isolated product (76% yield). We
hypothesized that acidic conditions had led to protonation
of the azetidine, which subsequently triggered lactone for-
mation. Therefore, oxidation reaction conditions under
neutral conditions were examined. Treatment of aldehyde
19 with AgO18 or air in the presence of Pt/C19 produced
amino acid. Consequently, the corresponding methyl ester
22 was successfully prepared by an alkaline iodine oxida-
tion20 in 98% yield.
In summary, we showcase the utility of the azetidin-
3-ones to access a wide range of new synthetically useful
azaspiro[3.3]heptanes. We have thus expanded the diver-
sity of 1,6-diazaspiro[3.3]heptane modules and have de-
scribed the synthesis of gem-difluoro and gem-dimethyl
substituted azetidines. We also report a one-pot synthesis
of 5-oxo-2-azaspiro[3.3]heptane and its transformation
into several useful derivatives. With rapid scalable synthe-
ses of these novel functionalized angular modules de-
scribed herein, we expect these building blocks to find a
wide range of applications in drug discovery.
1
lactone 21 in 50% and 95% yield, respectively. H NMR
ꢀ
Acknowledgment. Andre Alker (F. Hoffmann-La Roche
studies of the reaction revealed the intermediate formation
of carboxylic acid 20 which undergoes rearrangement to
lactone 21 within 24 h, due to the zwitterionic nature of the
AG, Basel) is acknowledged for the determination of the
X-ray structure.
Supporting Information Available. Experimental pro-
cedures and characterization for all new compounds.
Crystallographic information file (CIF) for 15. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(18) Corey, E. J.; Gilman, N. W.; Ganem, B. E. J. Am. Chem. Soc.
1968, 90, 5616.
(19) Abad, A.; Arno, M.; Cunat, A. C.; Marin, M. L.; Zaragoza, R. J.
J. Org. Chem. 1992, 57, 6861.
(20) Yamada, S.; Morizono, D.; Yamamoto, K. Tetrahedron Lett.
1992, 33, 4329.
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