3-benzyl-3-azabicyclo[3.1.1]heptan-6-one: A promising building block for medicinal chemistry

Article abstract of DOI:10.1021/ol101866x

Figure Presented. An efficient two-step multigram synthesis of the previously unknown 3-benzyl-3-azabicyclo[3.1.1]heptan-6-one is described. The compound is shown to be a promising building block for further selective derivatization of the cyclobutane ring providing novel conformationally restricted piperidine derivatives.

Full text of DOI:10.1021/ol101866x

ORGANIC
LETTERS
2010
Vol. 12, No. 19
4372-4375
3-Benzyl-3-azabicyclo[3.1.1]heptan-6-one:
A Promising Building Block for
Medicinal Chemistry
Aleksandr V. Denisenko,† Andrey P. Mityuk,† Oleksandr O. Grygorenko,†
Dmytro M. Volochnyuk,† Oleg V. Shishkin,‡ Andrey A. Tolmachev,† and
Pavel K. Mykhailiuk*,†
Enamine Ltd., Vul. Oleksandra MatrosoVa 23, 01103 KyiV, Ukraine and Department of
Chemistry, KyiV National Taras SheVchenko UniVersity, Vul. Volodymyrska 64,
01033 KyiV, Ukraine, and STC, “Institute for Single Crystalls”, National Academy of
Science of Ukraine, 60 Lenina AVe., KharkiV 61001, Ukraine
paVel.mykhailiuk@gmail.com
Received August 9, 2010
ABSTRACT
An efficient two-step multigram synthesis of the previously unknown 3-benzyl-3-azabicyclo[3.1.1]heptan-6-one is described. The compound is
shown to be a promising building block for further selective derivatization of the cyclobutane ring providing novel conformationally restricted
piperidine derivatives.
Conformational restriction is an effective tool used in
medicinal chemistry to improve/modify pharmacological
characteristics of drug candidates.1 As the result of fixation
of the functional groups in a biologically active conformation,
the sterically restricted compounds are often more efficient
and selective ligands for various targets, thus displaying
pronounced biological activity. On the other hand, com-
pounds comprising conformationally restricted units usually
possess higher metabolic stability compared to that of the
nonrestricted analogues.2 However, the corresponding con-
formationally restricted building blocks are often obtained
through multistep and low-yield synthetic procedures,3 so
that their up-scaled production is limited. In this context,
the development of new synthetic strategies for facile large-
scale preparation of the conformationally restricted synthons
of cheap and commercially available starting materials is of
particular interest.
The piperidine motif is seldom-used in drug discovery.
For example, of the ∼1350 small molecule FDA-approved
drugs, 136 contain a piperidine moiety.4 Herein, we report
a highly effective two-step multigram preparation of novel
3-benzyl-3-azabicyclo[3.1.1]heptan-6-one (1) and its ap-
(2) (a) Giannis, A.; Kolter, T. Angew. Chem., Int. Ed. 2003, 32, 1244.
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A. S.; Rich, D. H. Curr. Opin. Chem. Biol. 1998, 2, 441. (e) Kessler, H.
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† Enamine Ltd. and Kyiv National Taras Shevchenko University.
‡ National Academy of Science of Ukraine.
(3) (a) Cativiela, C.; Diaz-de-Villegas, M. D. Tetrahedron: Asymmetry
2000, 11, 645. (b) Cativiela, C.; Diaz-de-Villegas, M. D. Tetrahedron:
Asymmetry 2009, 20, 1. (c) Brackmann, F.; de Meijere, A. Chem. ReV. 2007,
37, 4493. (d) Brackmann, F.; de Meijere, A. Chem. ReV. 2007, 37, 4538.
(e) Trabocchi, A.; Scarpi, D.; Guarna, A. Amino Acids 2008, 34, 1. (f)
Kubyshkin, V. S.; Mikhailiuk, P. K.; Komarov, I. V. Tetrahedron Lett. 2007,
48, 4061. (g) Kubyshkin, V.; Mykhailiuk, P.; Ulrich, A.; Komarov, I.
Synthesis 2009, 19, 3327. (h) Tkachenko, A. N.; Radchenko, D. S.;
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10.1021/ol101866x  2010 American Chemical Society
Published on Web 08/26/2010

plication in the synthesis of the conformationally restricted
piperidine derivatives.
Next, several representative transformations of ketone 1
were performed in order to show its feasibility as a starting
compound in the synthesis of various pharmacologically
relevant intermediates (Scheme 2).
The double Mannich reaction of cyclic ketones with N,N-
bis(alkoxymethyl)alkylamine5 reagents is a facile strategy
to prepare bicyclic piperidine analogues. Since the first report
in 2006, a number of publications on the double Mannich
annulation of cyclopentanone, cyclohexanone, cyclohep-
tanone, and cyclooctanone with N,N-bis(alkoxymethyl)alky-
lamine reagents has appeared.6 However, to the very best
of our knowledge, so far absolutely nothing is known about
the corresponding reaction of the simplest stable cyclic
ketone, cyclobutanone (2).7 Therefore, we have become
interested in performing this transformation.
Scheme 2. Representative Modifications of Ketone 1
Indeed, heating the mixture of cyclobutanone (2) and N,N-
bis(methoxymethyl)benzylamine (3) in acetonitrile in the
presence of Me3SiCl afforded the bicyclic compound 4 in
48% yield (Scheme 1). Acidic hydrolysis of the ketal moiety
in 4 smoothly provided ketone 1 in 89% yield.
Scheme 1. Synthesis of
3-Benzyl-3-azabicyclo[3.1.1]heptan-6-one (1)
The building blocks depicted in Scheme 2 can be
considered as conformationally restricted analogues of
4-substituted piperidines, frequently occurring in approved
drugs (Figure 2).
The structure of ketone 1 was proven by an X-ray
diffraction study (Figure 1). Importantly, the synthesis of
Figure 2. Some marketed pharmaceuticals possessing the 4-sub-
stituted piperidine moiety.
First, an applicability of the benzyl moiety in compounds 1
and 4 as an N-protecting group, which provides an access to
various N-substituted piperidines, was demonstrated. Thus, the
synthesis of the simplest N-alkyl ketone 5 was pursued.
Figure 1. X-ray crystal structure of ketone 1.
(6) (a) Halliday, J. I.; Chebib, M.; Turner, P.; McLeod, M. D. Org. Lett.
2006, 8, 3399. (b) McLeod, M. D.; Halliday, J. I.; Chebib, M. WO2007/
051255, 2007. (c) Nippon Soda Co. EP2058303, 2009. (d) Darout, E.; Basak,
A. Tetrahedron Lett. 2010, 51, 2998. (e) Mityuk, A. P.; Denisenko, A. V.;
Dacenko, O. P.; Grygorenko, O. O.; Mykhailiuk, P. K.; Volochnyuk, D. M.;
Shishkin, O. V.; Tolmachev, A. A. Synthesis 2010, 3, 493.
compound 1 was easily up-scaled, so that 50 g of the pure
product was prepared in a single batch.
(7) For the reactions of N,N-bis(alkoxymethyl)alkylamine reagents with
another ketones, see: (a) Brocke, C.; Brimble, M. A.; Lin, D. S.-H.; McLeod,
M. D. Synlett 2004, 13, 2359. (b) Brimble, M. A.; Brocke, C. Eur. J. Org.
Chem. 2005, 2385. (c) Buckley, B. R.; Bulman Page, P. C.; Heaney, H.;
Sampler, E. P.; Carley, S.; Brocke, C.; Brimble, M. A. Tetrahedron 2005,
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2008, 17, 2601.
(4) Wishart, D. S.; Knox, C.; Guo, A. C.; Cheng, D.; Shrivastaya, S.;
Tzur, D.; Gautam, B.; Hassanali, M. Nucleic Acids Res. 2008, 36 (Database
issue), D901.
(5) (a) Earle, M. J.; Fairhurst, R. A.; Heaney, H.; Papageorgiou, G.;
Wilkins, R. F. Tetrahedron Lett. 1990, 31, 4229. (b) Heaney, H.;
Papageorgiou, G. Tetrahedron 1996, 52, 3473.
Org. Lett., Vol. 12, No. 19, 2010
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Scheme 3. Synthesis of Conformationally Restricted Piperidine Analogues 5, 7, 8, 10, and 12
Alkylation of the tertiary amine 4 with MeI followed by a
cyclobutanone in 43% overall yield; 50 g of ketone 1 was
easily prepared in a single batch. Compound 1 is a promising
hydrogenation of the benzyl group in the corresponding
quaternary salt, using 10% palladium on charcoal as the catalyst,
gave ketal 6 in 69% yield. Acidic cleavage of the ketal moiety
in 6 smoothly provided N-methyl ketone 5 in 92% yield
(Scheme 3).
Next, several modifications of the carbonyl group in
compound 1 were performed. An addition of PhMgBr to
ketone 1 in THF at -50 °C gave alcohol 7 in 87% yield. As
expected, a nucleophilic attack of the Grignard reagent at
the carbonyl group in 1 occurred at the less sterically
hindered side to give the product 7 as a single isomer.
Similarly, reduction of the carbonyl group in 1 with NaBH4
in MeOH at -50 °C afforded alcohol 8 as the sole isomer
in 96% yield. An addition of CF3TMS to ketone 1 in the
presence of NBu4F in THF8 at room temperature quantita-
tively gave the corresponding trifluoroethanol derivative 9.
Again, the formation of only one isomer was observed.
Acidic cleavage of the TMS group in 9 smoothly provided
the CF3-substituted alcohol 10 in 97% yield.
Finally, the synthesis of diamine 12 from ketone 1 was
performed. The reaction of 1 with NH2OH in water gave
the corresponding oxime 11 in 99% yield. Reduction of the
oxime group in 11 using Raney nickel alloy afforded pure
amine 12 in 91% yield as a mixture of two stereoisomers. If
needed, the isomeric derivatives of 12 substituted at the
primary amino can be readily separated. For example,
representative amide coupling of amine 12 with PhCOCl
provided the corresponding orthogonally protected diamines
13a/13b, which were easily separated by flash column
chromatography.
The structures of the compounds 7, 10, and 13a were
determined by X-ray analysis (Figure 3). The stereoconfig-
uration of alcohol 8 was established by NOESY experiments
(Supporting Information).
In summary, we have developed a two-step synthesis of
novel 3-benzyl-3-azabicyclo[3.1.1]heptan-6-one (1) from
Figure 3
.
X-ray crystal structures of the compounds 7, 10, and 13a.
Org. Lett., Vol. 12, No. 19, 2010
(8) Krishnamurti, R.; Bellew, D. R.; Prakash, G. K. S. J. Org. Chem.
1991, 56, 984.
4374

building block suitable for the preparation of conformation-
ally restricted piperidine derivatives. The representative
4-substituted piperidines 5, 7, 8, 10, and 12 were conve-
niently prepared from 1 by routine transformations. With
rapid scalable synthesis, we expect compound 1 and its
related derivatives described herein to find wide applications
in the field of drug discovery as piperidine analogues.
Supporting Information Available: Experimental pro-
cedures, crystallographic data, structure description, and
full spectroscopic data for all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL101866X
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