Synthesis of novel azaspiro[3.4]octanes as multifunctional modules in drug discovery

Article abstract of DOI:10.1021/ol2025313

Step-economic and scalable syntheses of novel thia-azaspiro[3.4]octanes are reported. These spirocycles and some related intermediates can serve as uncharted multifunctional modules for drug discovery chemistry.

Full text of DOI:10.1021/ol2025313

ORGANIC
LETTERS
2011
Vol. 13, No. 22
6134–6136
Synthesis of Novel Azaspiro[3.4]octanes
as Multifunctional Modules in Drug
Discovery
Dong Bo Li,† Mark Rogers-Evans,*,‡ and Erick M. Carreira*,†
Laboratorium fu€r Organische Chemie, ETH Zu€rich, CH-8093 Zu€rich, Switzerland, and
Discovery Research, Chemistry Technologies & Innovation, F. Hoffmann-La Roche AG,
CH-4070 Basel, Switzerland
mark.rogers-evans@roche.com; carreira@org.chem.ethz.ch
Received September 19, 2011
ABSTRACT
Step-economic and scalable syntheses of novel thia-azaspiro[3.4]octanes are reported. These spirocycles and some related intermediates can
serve as uncharted multifunctional modules for drug discovery chemistry.
The identification of novel building blocks through
design and synthesis constitutes a critical role for organic
chemistry in the drug discovery process. We have recently
described a collection of spirocylic building blocks,1À3
which provide entry into novel chemical, pharmacological,
and proprietary space. In line with these interests we con-
tinue to expand the collection of spirocycles by exploring
new structures. Characteristics of these “compact mod-
ules” are that they should have tunable polarities affecting
the phys-chem and safety parameters as well as that they
should be amenable to vectorization. The latter provides
ready shape diversity, a feature critical to contemporary
compound collections looking to access poorly or un-
charted 3D-macromolecular biological targets. In this
context, our recent pursuits have included thia-azaspiro-
[3.4]octanes (Figure 1). The concept driving our interest in
these structures initially was their similarity to the parent
diazaspiro[3.3]heptanes2b,c and newly developed azaspiro-
[3.3]heptane scaffolds2a in our group (Figure 1) and the
fact that these position functional groups and attendant
exit vectors in a cambered environment. Additionally, we
reasoned that the inclusion of a heteroatom, such as sulfur,
particularly in its oxidized state, at different positions of
the spirocycle would serve to generate uncharted spiro-
[3.4]octanes that intuitively resembled “drug-like” frag-
ments. Herein, we report convenient constructions of the
novel thia-azaspirocyclic systems.
† ETH Z€urich.
‡ F. Hoffmann-La Roche AG.
(1) For oxetanes and related spirocycles, see: (a) Wuitschik, G.;
€
Rogers-Evans, M.; Muller, K.; Fischer, H.; Wagner, B.; Schuler, F.;
Polonchuk, L.; Carreira, E. M. Angew. Chem., Int. Ed. 2006, 45, 7736–
7739. (b) Wuitschik, G.; Rogers-Evans, M.; Buckl, A.; Bernasconi, M.;
€
Marki, M.; Godel, T.; Fischer, H.; Wagner, B.; Parrilla, I.; Schuler, F.;
Schneider, J.; Alker, A.; Schweizer, W. B.; Muller, K.; Carreira, E. M.
€
Angew. Chem., Int. Ed. 2008, 47, 4512–4515. (c) Wuitschik, G.; Carreira,
€
E. M.; Rogers-Evans, M.; Muller, K. Oxetan-3-one: chemistry and
synthesis. In Process Chemistry in the Pharmaceutical Industry;
Gadamasetti, K., Braish, T., Eds.; CRC Press: Boca Raton, FL, 2008; pp
217À229. (d) Wuitschik, G.; Carreira, E. M.; Wagner, B.; Fischer, H.;
€
Parrilla, I.; Schuler, F.; Rogers-Evans, M.; Muller, K. J. Med. Chem. 2010,
(3) For other recent related work, see: (a) Xu, R.; Czarniecki, M.; de
Man, J.; Pan, J.; Qiang, L.; Root, Y.; Ying, S.; Su, J.; Sun, X.; Zhang, Y.;
Yu, T.; Zhang, Y.; Hu, T.; Chen, S.-H. Tetrahedron Lett. 2011, 52, 3266–
3270. (b) Meyers, M. J.; Muizebelt, I.; van Wiltenburg, J.; Brown, D. L.;
Thorarensen, A. Org. Lett. 2009, 11, 3523–3525. (c) Duncton, M. A. J.;
Estiarte, M. A.; Johnson, R. J.; Cox, M.; O’Mahony, D. J. R.; Edwards,
W. T.; Kelly, M. G. J. Org. Chem. 2009, 74, 6354–6357. (d) Duncton,
M. A. J.; Estiarte, M. A.; Tan, D.; Kaub, C.; O’Mahony, D. J. R.;
Johnson, R. J.; Cox, M.; Edwards, W. T.; Wan, M.; Kincaid, J.; Kelly,
M. G. Org. Lett. 2008, 10, 3259–3262.
53, 3227–3246. (e) Burkhard, J. A.; Wuitschik, G.; Rogers-Evans, M.;
€
Muller, K.; Carreira, E. M. Angew. Chem., Int. Ed. 2010, 49, 9052–9067.
ꢀ
(2) For azaspiro[3.3]heptanes, see: (a) Guerot, C.; Tchitchanov, B. H.;
Knust, H.; Carreira, E. M. Org. Lett. 2011, 13, 780–783. (b) Burkhard,
€
J. A.; Wagner, B.; Fischer, H.; Schuler, F.; Muller, K.; Carreira, E. M.
ꢀ
Angew. Chem., Int. Ed. 2010, 49, 3524–3527. (c) Burkhard, J. A.; Guerot,
C.; Knust, H.; Rogers-Evans, M.; Carreira, E. M. Org. Lett. 2010, 12,
1944–1947. (d) Burkhard, J.; Carreira, E. M. Org. Lett. 2008, 10, 3525–
3526.
r
10.1021/ol2025313
Published on Web 10/18/2011
2011 American Chemical Society

Scheme 1. Synthesis of Spirocyclic Modules 5 and 7
Figure 1. Azaspiro[3.4]octanes incorporating sulfones shown
with exit vectors.
The first targets for synthesis were 8-functionalized
5-thia-2-azaspiro[3.4]octanes 5 and 7 (Scheme 1) from
commercially available 1-N-Boc-3-azetidinone4 as a start-
ing point. Thus, aldol addition of 4-butyrothiolactone with
1-N-Boc-3-azetidinone produced adduct 1 on an 8-g scale in
85% yield. Subsequent dehydration provided conjugated
thiolactone 2 (82%). The key spirocyclization was then
realized upon exposure of 2 to alkaline methanol solution,
which produced 3b. We hypothesize the observed formation
of 3b from 2 proceeds by methanol-triggered opening of the
thiolactone5 followed by intramolecular conjugate addition
onto the unsaturated ester in 3a. After removal of volatiles, the
unpurified spirocyclic ester 3b was directly subjected to
oxidation with mCPBA to afford sulfone 4 in 70% yield
(two steps). Saponification furnished the corresponding acid 5
(86%). When 5 was subjected to the Curtius rearrangement
protocol, orthogonally protected bisamine 6 was isolated in
91% yield. Finally, after hydrogenolytic removal of the Cbz-
group, amine 7 was obtained in 82% yield.
In order to render the new spirocycles more versatile,
further manipulations were investigated that permitted
installation of carbonyl and alcohol groups. However,
attempts to implement Barton’s decarboxylative oxygena-
tion6 method on acid 5 were unsuccessful, despite the clean
formation of the intermediate thiopyridone adduct. Exam-
ination of ketone derivatives under conditions leading to
BayerÀVilliger rearrangement did not meet with success.
Our attention was then shifted to developing a de novo route
analogous to the approach to thiolanes reported by Warren.7
As shown in Table 1, the first step in the implementation
of Warren’s method was toaccess an efficient sulfenylation
to reach key intermediates 8a or 8b. Although access to 8a
was possible by conversion of commercially available 1-N-
Boc-3-azetidinone into the corresponding homologous
enol ether, which was then subjected to the sulfenylation
with BnSCl to provide the required aldehyde 8a, this two-
step protocol provided 8a in only 16% poor yield (entry 1,
Table 1). Formation of the corresponding enol ether under
the Peterson conditions8 did not lead to improvements
(entry 2, Table 1), and the attempted preparation of silyl
enol ether of the parent aldehyde9 was unsatisfactory as
well (entries 3 and 4,10 Table 1). Furthermore, the forma-
tion of silyl ketene acetal of the parent ester11 was not
detected (entry 5, Table 1); rather C-silylation was exclu-
sively observed. The direct sulfenylation of the enolate
derived from the parent ester with BnSSBn, by using
LiHMDS as a base, yielded an unknown product (entry
6, Table 1). However, ester enolization with LDA allowed
directsulfenylation togiveBnS-ester8bin40%yield (entry
7, Table 1). The yield could be improved to 53% with the
addition of HMPA as a cosolvent (entry 8, Table 1).12 It
should be emphasized that, unlike 1-N-Boc-3-azetidinone,
the chemistry of 1-N-Boc-3-azetidinecarboxaldehyde and
methyl 1-N-Boc-3-azetidinecarboxylate is not well-docu-
mented. Thus the enolization studies provide important
opportunities for this class of building blocks.
Ester 8b underwent Claisen condensation to provide
ketoester 9 in 84% yield (Scheme 2). Although the reduc-
tionto1,3-diol10proceededcleanly withDIBAL, the yield
was modest. Following the Warren conditions,7 treatment
of BnS-1,3-diol 10 with TsCl in pyridine smoothly produced
spirocyclic alcohol 13 at room temperature. We hypothe-
size that the reaction proceeds by [1,4]-SBn participation
(4) (a) From PharmaBlock, catalog no. PB00003. (b) For the chem-
istry of the ketone, see: Dejaegher, Y.; Kuz’menok, N. M.; Zvonok,
A. M.; De Kimpe, N. Chem. Rev. 2002, 102, 29–60.
(5) The mild, ring opening method has been reported for the synthesis
of methyl-4-thio-butanoate, see: De Gregori, A.; Jommi, G.; Sisti, M.;
Gariboldi, P.; Merati, F. Tetrahedron 1988, 44, 2549–2568.
(6) For recent review and references therein, see: Saraiva, M. F.;
Couri, M. R. C.; Hyaric, M. L.; de Almeida, M. V. Tetrahedron 2009, 65,
3563–3572.
(8) Magnus, P.; Roy, G. Organometallices 1982, 1, 553–559.
(9) From Apollo Scientific Ltd., catalog no. OR15687.
(10) Tanabe, Y.; Misaki, T.; Kurihara, M.; Iida, A.; Nishii, Y. Chem.
Commun. 2002, 1628–1629.
(11) From Apollo Scientific Ltd., catalog no. OR42009.
(12) For HMPA as cosolvent, see: Grieco, P. A.; Flynn, D. L.; Zelle,
R. E. J. Am. Chem. Soc. 1984, 106, 6414–6417.
(7) Eames, J.; Kuhnert, N.; Warren, S. J. Chem. Soc., Perkin Trans. 1
2001, 1504–1510.
Org. Lett., Vol. 13, No. 22, 2011
6135

Table 1. Screening for an Efficient Sulfenylation to Reach Key
Intermediate
Scheme 2. Synthesis of Spirocyclic Modules 14 and 15
Scheme 3. Synthesis of Spirocyclic Modules 20 and 21
a Not desired product. b The yield was not determined.
and debenzylation with the chloride generated in situ.7 Finally,
oxidation with mCPBA furnished sulfonyl alcohol 14 in 67%
yield, and subsequent oxidation with DMP proceeded very
well to provide the corresponding sulfonyl ketone 15.
We next examined the construction of 6-thia-2-azaspiro-
[3.4]octanes (20 and 21, Scheme 3). The aldol addition
reaction involving BnSCH2CHO13 and protectedazetidine
ester produced adduct 16 on gram scale in acceptable yield.
Azetidine 16 underwent stepwise reduction (DIBAL-
NaBH4) to afford 1,3-diol 17. Subsequent treatment of
1,3-diol 17 with TsCl in pyridine produced a mixture of
tosylate 18 along with desired spirocyclic thiolane 19. The
complete conversion of the intermediate tosylate into the
spirocyclic thiolane could be smoothly realized (50% for
19 overall from 16) by heating in DMF. Finally, oxidation
with mCPBA gave sulfone alcohol 20 in excellent yield.
ParikhÀDoering oxidation14 of 19 proceeded well to
provide the corresponding sulfenyl ketone 21 in 63% yield.
In summary, we have described the synthesis of six new
multifunctional modules through the use of highly step-
economic sequences. The syntheses of 5-thia-2-azaspiro-
[3.4]octanes 5 and 7 were accomplished in five and seven
steps, respectively. Sulfone alcohol 14 (five steps) and ketone
15 (six steps) are also conveniently accessed. Finally, alcohol
20 and ketone 21 were prepared in six steps each. We
anticipate these building blocks will be welcome additions as
novel scaffolds to the drug discovery tool box.
Acknowledgment. We are grateful to F. Hoffmann-La
Roche, the Swiss National Science Foundation, and ETH-
€
Zurich for generous support of the research program.
Supporting Information Available. Experimental pro-
cedures and compound characterization data. This ma-
terial is available free of charge via the Internet at http://
pubs.acs.org.
(13) For preparation, see: Bitan, G.; Muller, D.; Kasher, R.; Gluhov,
E. V.; Gilon, C. J. Chem. Soc., Perkin Trans. 1 1997, 1501–1510.
(14) Nicolaou, K. C.; Sun, Y.-P.; Peng, X.-S.; Polet, D.; Chen,
D. Y.-K. Angew. Chem., Int. Ed. 2008, 47, 7310–7313.
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Org. Lett., Vol. 13, No. 22, 2011