Expanding the azaspiro[3.3]heptane family: Synthesis of novel highly functionalized building blocks

Article abstract of DOI:10.1021/ol2028459

The preparation of versatile azaspiro[3.3]heptanes carrying multiple exit vectors is disclosed. Expedient synthetic routes enable the straightforward access to these novel modules that are expected to have significance in drug discovery and design.

Full text of DOI:10.1021/ol2028459

ORGANIC
LETTERS
2012
Vol. 14, No. 1
66–69
Expanding the Azaspiro[3.3]heptane
Family: Synthesis of Novel Highly
Functionalized Building Blocks
†
Johannes A. Burkhard, Carine Guerot,†,‡ 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 October 21, 2011
ABSTRACT
The preparation of versatile azaspiro[3.3]heptanes carrying multiple exit vectors is disclosed. Expedient synthetic routes enable the
straightforward access to these novel modules that are expected to have significance in drug discovery and design.
In previous work we have shown that oxetanes and
spirocyclic azetidines are versatile elements for the modu-
lation and fine-tuning of pharmacokinetic properties.1
In particular, linear azaspiro[3.3]heptanes were found to
possess high aqueous solubilities and low metabolic clear-
ance rates.1c These encouraging results prompted us to
continue exploring the chemical space of spirocyclic sys-
tems (Figure 1). Accordingly, angular azaspirocycles
have been prepared and structurally characterized.2 While
many of these spiro[3.3]heptanes can be considered struc-
tural surrogates for commonly employed saturated hetero-
cycles, such as piperidines, piperazines, and morpholines,
their inherent structural features and accompanying bene-
ficial physicochemical properties can render these building
blocks distinctive. Herein we describe a new generation of
angular spirocycles that provide unique applications as
novel scaffolds for medicinal chemistry.
Figure 1. From linear to advanced angular azaspiro[3.3]-
heptanes. Red arrows denote vectors.
† ETH Zurich.
‡ F. Hoffmann-La Roche AG.
Most of the spirocycles we have previously documented
(1) Oxetanes, key references: (a) Wuitschik, G.; Carreira, E. M.;
can only be used as terminal fragments linked to the
Wagner, B.; Fischer, H.; Parrilla, I.; Schuler, F.; Rogers-Evans, M.;
remaining pharmacophore through the azetidine nitrogen
atom in analogy to morpholine and piperidine. The use of
these novel spiro[3.3]heptanes as scaffolds requires at least
two attachment points for the incorporation of a variety of
substituents that define exit vectors from the central core.3
We have thus embarked on the preparation of spirocyclic
€
Muller, K. J. Med. Chem. 2010, 53, 3227–3246. (b) Burkhard, J. A.;
€
Wuitschik, G.; Rogers-Evans, M.; Muller, K.; Carreira, E. M. Angew.
Chem., Int. Ed. 2010, 49, 9052–9067. Azetidines: (c) Burkhard, J. A.;
€
Wagner, B.; Fischer, H.; Schuler, F.; Muller, K.; Carreira, E. M. Angew.
Chem., Int. Ed. 2010, 49, 3524–3527.
ꢀ
(2) (a) Burkhard, J. A.; Guerot, C.; Knust, H.; Rogers-Evans, M.;
ꢀ
Carreira, E. M. Org. Lett. 2010, 12, 1944–1947. (b) Guerot, C.; Tchitchanov,
B. H.; Knust, H.; Carreira, E. M. Org. Lett. 2011, 13, 780–783.
r
10.1021/ol2028459
Published on Web 11/23/2011
2011 American Chemical Society

Scheme 1. Synthesis of C1-Functionalized Linear Spirocycles
structures that incorporate two heteroatoms within the
framework and include versatile functionality as a branch-
ing substituent.
Thus, tert-butylsulfinyl imine 5(prepared from aldehyde 1)1c
was reacted with lithiated furan to afford the adduct
6 in excellent yield as an inconsequential 1:1 mixture of
diastereomers. Subsequently, the unpurified mixture was
subjected to KOt-Bu in THF to afford azetidines 7 in 61%
yield over the two steps. In analogy to the final step in the
synthesis sequence to 4, RuO4-mediated oxidative fission
of the furan unveiled the targeted amino acid 8 in 83%
yield.8 Under the reaction conditions, the tert-butylsulfinyl
group was concomitantly oxidized to a tert-butylsulfonyl
(Bus) group.9
Next we turned our attention to substituted members of
angular azaspiro[3.3]heptanes. The first set of targets were
1-oxa-6-azaspiro[3.3]heptanes bearing a C3 substituent,
and their preparation was envisaged to commence from a
protected azetidin-3-one.10 Accordingly, N-Boc and N-Ts
protected azetidinones 10 and 11 were converted to the
corresponding propargylic alcohols 12 and 13 following
standard protocols (TMSCtCLi and then desilylation
with Bu4NF in THF, Scheme 3). We have found that
Zhang’s method for the preparation of azetidin-3-ones
from propargylic amines11 can be implemented for the
cyclization of 12 and 13. The use of 5 mol % [BrettPhos-
AuNTf2], 8-ethylquinoline-N-oxide (2 equiv), and metha-
nesulfonic acid (1.5 equiv) with 12 in dichloroethane
at room temperature afforded key oxetanone 14 in 53%
yield. However, somewhat more pressing conditions (8 mol %
[Au], 40 °C) were necessary to generate 15. The ketones
The first targets were based on linear spirocycles con-
taining a carboxylic acid at C1 (Scheme 1). Aldehyde 14
was identified as the starting material, and addition of
2-furyllithium at À78 °C afforded carbinol 2 in 89% yield.
Upon treatment with potassium carbonate (5 equiv) in hot
MeOH,5 this material cleanly converted to oxetane 3,
which was isolated in 61% yield. It is worth noting that
the choice of base and solvent is crucial to the successful
execution of ring closure. Thus, for example, treatment of2
with KOt-Bu in THF at 0 °C did not afford oxetane 2,
instead furnishing 3-methylene azetidine 9 (53% yield)
(Scheme 2). This Grob-type fragmentation is a known side
reaction in oxetane syntheses from 3-bromopropanols.6
Finally, the desired carboxylic acid (4) was obtained
in 68% yield following oxidation of furan 3 using
RuCl3•H2O/NaIO4.
Scheme 2. Fragmentation vs Oxetane Formation
(8) For similar protocols, see: (a) Borg, G.; Chino, M.; Ellman, J. A.
Tetrahedron Lett. 2001, 42, 1433–1435. (b) Luo, Y.-C.; Zhang, H.-H.;
Xu, P.-F. Synlett 2009, 833–837. (c) Luo, Y.-C.; Zhang, H.-H.; Liu,
Y.-Z.; Cheng, R.-L.; Xu, P.-F. Tetrahedron: Asymmetry 2009, 20, 1174–
1180.
The same strategy was then employed for the synthesis
of a homospiropiperazine7 having a carboxylic acid at C1.
(9) The Bus protecting group is commonly removed using TfOH in
CH2Cl2: Sun, P.; Weinreb, S. M.; Shang, M. J. Org. Chem. 1997, 62,
8604–8608.
(10) For the chemistry of azetidin-3-ones, see: (a) Dejaegher, Y.;
Kuz’menok, N. M.; Zvonok, A. M.; De Kimpe, N. Chem. Rev. 2002,
102, 29–60. (b) Brandi, A.; Cicchi, S.; Cordero, F. M. Chem. Rev. 2008,
108, 3988–4035.
(11) (a) Ye, L.; He, W.; Zhang, L. Angew. Chem., Int. Ed. 2011, 50,
3236–3239. The conditions described for the preparation of substituted
oxetan-3-ones gave the desired products in marginal yields only. For the
conditions, see:(b) Ye, L.; He, W.; Zhang, L. J. Am. Chem. Soc. 2010,
132, 8550–8551.
(3) For an insightful account on unusual molecular scaffolds in drug
design, see: Marson, C. M. Chem. Soc. Rev. 2011, 40, 5514–5533.
(4) Prepared in three steps from tribromopentaerythritol. For details,
see ref 1c and Burkhard, J.; Carreira, E. M. Org. Lett. 2008, 10, 3525–
3526.
(5) Couladouros, E. A.; Vidali, V. P. Chem.;Eur. J. 2004, 10, 3822–
3835.
(6) Searles, S.; Nickerson, R. G.; Witsiepe, W. K. J. Org. Chem. 1960,
24, 1839–1844.
(7) Due to their resemblance to piperazines, we refer to 2,6-
diazaspiro[3.3]heptanes as homospiropiperazines.
Org. Lett., Vol. 14, No. 1, 2012
67

were elaborated to the corresponding alcohols 16 and 17
(NaBH4; 99% yield), as well as to amine 18 (NH2OH•HCl,
then Raney-Ni/H2; 58% yield).
Scheme 4. Synthesis of Angular Spirocyclic Aryl Oxetane
Scheme 3. Synthesis of C3-Functionalized Angular Spirocyclic
Oxetanes
This and other similar bromoarenes serve as novel building
blocks for further derivatization using transition-metal-
mediated coupling reactions.
To complete the series, we were interested in the pre-
paration of azetidine-azetidine spirocycles that would
have an additional exit vector at C3. These novel modules
containing three vectors intotal willrender the highlyfunc-
tionalized, but slim, scaffold exceedingly attractive. Since
Au-catalyzed azetidin-3-one formation delivered the de-
sired product in a trace amount only, we focused on an
alternative strategy (Scheme 5). Previously reported
β-lactam 2313 was subjected to enolization using KHMDS
in THF, and subsequent treatment of the enolate with
the Davis oxaziridine 24 led to the isolation of R-hydroxy
lactam 25 in 63% yield. The β-lactam was successfully
reduced using chlorohydroalane,14 and azetidin-3-ol 26
was subsequently obtained in 67% yield. Its conversion
to the corresponding ketone 27 was effected under Swern
oxidation conditions (82% yield). This differentially pro-
tected trifunctional scaffold crystallized to give suitable
single crystals for X-ray analysis. Similar to the situation
noted in 17, the tosyl group is positioned on the same side as
the nitrogen of the adjacent ring. This leads to a situation,
where both aromatic rings point in the same surrounding
We were fortunate toobtain suitable crystals of oxetanol
17 for an X-ray diffraction analysis. The resulting solid-
state structure is visualized in Scheme 3 (ORTEP format
with ellipsoids at 50% probability). Two characteristics
are worth noting: (1) the azetidine ring is puckered, and (2)
the arene and oxetane oxygen are both found on the same
side of the plane roughly defined by the azetidine, while the
hydroxyl group is pointing outward on the opposite side of
this plane. This structural information should be valuable
when considering the use of this building block as a scaffold.
An alternative approach to C3-substituted 1-oxa-
6-azaspiro[3.3]heptanes is delineated in Scheme 4. N-Benz-
hydryl-protected azetidin-3-one (19) was treated with the
lithium enolate of methyl 2-(5-bromo-2-fluorophenyl)-
acetate to afford β-hydroxy ester 20 in 73% yield.12
Reduction of the ester group using LiAlH4 at 0 °C afforded
diol 21 (60% yield), which was cyclized to the corresponding
oxetane 22 using TsCl and KOt-Bu in THF (65% yield).
˚
hemisphere, with arene ring centroids separated by 5.7 A.
A two-step procedure, starting from β-lactam 23, was
developed for the synthesis of a protected triamine spiro
compound. As outlined in Scheme 6, 23 was subjected
to enolization, and the enolate was treated with isoamyl
nitrite.15 The intermediate nitroso compound smoothly
isomerized to oxime 28, which was isolated in 70% yield
1
(12:1 ratio of oxime isomers according to H NMR of
(13) Prepared in three steps from N-Ts-azetidin-3-one; see ref 2b.
(14) (a) Ojima, I.; Zhao, M.; Yamato, T.; Nakahashi, K.; Yamashita,
M.; Abe, R. J. Org. Chem. 1991, 56, 5263–5277. Seminal work on the
reduction of β-lactams: (b) Jackson, M.; Mander, L.; Spotswood, T.
Aust. J. Chem. 1983, 36, 779–788.
(15) Related work on β-lactams: (a) Takahashi, Y.; Yamashita, H.;
Kobayashi, S.; Ohno, M. Chem. Pharm. Bull. 1986, 34, 2732–2742.
(b) Yamashita, H.; Minami, N.; Sakakibara, K.; Kobayashi, S.; Ohno,
M. Chem. Pharm. Bull. 1988, 36, 469–480. (c) Folmer, J. J.; Acero, C.;
Thai, D. L.; Rapoport, H. J. Org. Chem. 1998, 63, 8170–8182.
(12) Baker, R. K.; Bao, J.; Miao, S.; Rupprecht, K. M. (Merck & Co.,
Inc.), WO 2005/000809, 2005.
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Org. Lett., Vol. 14, No. 1, 2012

Scheme 5. Synthesis of C3 Functionalized Angular Spirocyclic
Azetidines
Scheme 6. Synthesis of Angular Spirocyclic Triamine
In conclusion, we have developed efficient access to a
series of advanced angular azaspiro[3.3]heptanes. Azeti-
dines substituted at C3 served as starting materials for the
synthesis of these novel building blocks, which were pre-
pared in two to five steps from commercially available or
previously reported compounds. The ability to attach vec-
tors at multiple positions in an array of orientations makes
these compound scaffolds attractive in drug discovery
programs, and they should be considered in the context
of scaffold hopping.16,17 Owing to their remarkable che-
mical stability, their unique structural characteristics, and
their possibility to populate uncharted chemical space, we
expect these modules to find wide applications in drug
discovery and design.
Acknowledgment. Dr. W. B. Schweizer (ETH) is ac-
knowledged for the determination of X-ray structures. We
thank the ETH for support of this research in the form of
a grant (0-20449-07). J.A.B. thanks Novartis and the
Roche Research Foundation for graduate fellowships. We
are also grateful to F. Hoffmann-La Roche for generous
support of our research program (postdoctoral research
grant to C.G.).
unpurified reaction product). Its treatment with AlH2Cl
concomitantly led to reduction of the lactam unit and
the oxime to give 1,6-diazaspiro[3.3]heptan-3-amine 29 in
65% yield.
(16) For a seminal publication, see: (a) Schneider, G.; Neidhart, W.;
Giller, T.; Schmid, G. Angew. Chem., Int. Ed. 1999, 38, 2894–2896.
Reviews on the topic:(b) Schneider, G.; Schneider, P.; Renner, S. QSAR
Comb. Sci. 2006, 25, 1162–1171. (c) Schneider, G.; Fechner, U. Nat. Rev.
Drug Discov. 2005, 4, 649–663.
(17) The compounds that are the subject of this communication are
produced as racemates. This is a desirable situation as it maximizes the
potential for their use in drug discovery. Typically in the process, when
an optically active compound is necessary it is easiest and most practical
to effect resolution by chiral chromatography. In our experience, the
identification of a promising structure in the context of a specific project
then provides incentive for the development of an enantioselective route.
Supporting Information Available. Experimental pro-
cedures and characterization for all new compounds.
Crystallographic information files (CIF) for 17 and 27.
This material is available free of charge via the Internet at
http://pubs.acs.org.
Org. Lett., Vol. 14, No. 1, 2012
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