The synthesis of a 2-azabicyclo[3.1.0]hexane by rearrangement of a spirocyclic epoxide

Article abstract of DOI:10.1016/j.tetlet.2014.09.020

An unusual rearrangement of a 1-oxa-6-azaspiro[2.5]octane derivative giving access to novel 5-substituted 2-azabicyclo[3.1.0]hexanes is described. The synthetic application of the reaction is demonstrated by the synthesis of N-Boc-2,3-methano-β-proline. The amino acid was prepared through a three-step synthesis from easily available reagents in an overall yield of 15%.

Full text of DOI:10.1016/j.tetlet.2014.09.020

Accepted Manuscript
The synthesis of a 2-azabicyclo[3.1.0]hexane by rearrangement of a spirocyclic
epoxide
Mykhailo I. Adamovskyi, Oleksiy S. Artamonov, Andriy V. Tymtsunik,
Oleksandr O. Grygorenko
PII:
S0040-4039(14)01509-3
DOI:
http://dx.doi.org/10.1016/j.tetlet.2014.09.020
TETL 45114
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
4 July 2014
27 August 2014
4 September 2014
Please cite this article as: Adamovskyi, M.I., Artamonov, O.S., Tymtsunik, A.V., Grygorenko, O.O., The synthesis
of a 2-azabicyclo[3.1.0]hexane by rearrangement of a spirocyclic epoxide, Tetrahedron Letters (2014), doi: http://
dx.doi.org/10.1016/j.tetlet.2014.09.020
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The synthesis of a 2-azabicyclo[3.1.0]hexane
by rearrangement of a spirocyclic epoxide
Mykhailo I. Adamovskyi, Oleksiy S. Artamonov, AndriyV. Tymtsunik, Oleksandr O. Grygorenko

1
Tetrahedron Letters
journal homepage: www.elsevier.com
The synthesis of a 2-azabicyclo[3.1.0]hexane by rearrangement of a spirocyclic
epoxide
Mykhailo I. Adamovskyi,a,b Oleksiy S. Artamonov,a AndriyV. Tymtsunik,b Oleksandr O. Grygorenkob
aInstitute of Organic Chemistry, National Academy of Sciences of Ukraine, Murmanska Street 5, Kyiv 02660, Ukraine
bNational Taras Shevchenko University of Kyiv, Volodymyrska Street, 64, Kyiv 01601, Ukraine
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
An unusual rearrangement of a 1-oxa-6-azaspiro[2.5]octane derivative giving access to novel 5-
substituted 2-azabicyclo[3.1.0]hexanes is described. The synthetic application of the reaction is
demonstrated by the synthesis of N-Boc-2,3-methano--proline. The amino acid was prepared
through a three-step synthesis from easily available reagents in an overall yield of 15%.
Available online
2014 Elsevier Ltd. All rights reserved.
Keywords:
Conformational restriction
β-Amino acids
Bicyclic compounds
Cyclopropanes
Epoxides
Bicyclic, saturated, conformationally restricted cores have
attracted significant attention in various areas of chemistry in
recent times.1 These compact scaffolds provide defined spatial
arrangement of the attached groups. Therefore, intramolecular
interactions involving such molecules become easily controlled
and more pronounced, which is of importance, e.g., in drug
discovery, supramolecular chemistry, coordination chemistry,
and asymmetric catalysis. 2-Azabicyclo[3.1.0]hexane belongs to
the family of the above described scaffolds. Derivatives of 2-
azabicyclo[3.1.0]hexane have been widely used in the design of
organocatalysts2 and biologically relevant molecules (Figure 1),
such as amino acids,3 dipeptidyl peptidase IV inhibitors
(including the antidiabetic drug Saxagliptin approved by the FDA
in 2009),4 captopril analogs,5 TNF-α converting enzyme (TACE)
inhibitors,6 and inhibitors of apoptosis protein (IAP) antagonists.7
Considering the 2-azabicyclo[3.1.0]hexane as the core with two
diversity points (one of them being located at the nitrogen atom)
leads to the five possible variations shown in Figure 2. Although
all of these variations have been reported in the literature, the 1,2-
and 2,3-disubstitued patterns were most heavily studied.8
Recently, we reported an approach to a 1,3-disubstituted 2-
azabicyclo[3.1.0]hexane derivative (namely, Boc-protected 4,5-
methano--proline 1) using a Simmons–Smith cyclopropanation
as the key step.9 In the present work, we describe a novel
approach to the construction of the 2-azabicyclo[3.1.0]hexane
core, thereby opening access to 1,5-disubstituted 2-azabicyclo-
[3.1.0]hexane derivatives, as well as the application of this
method to the synthesis of N-Boc-2,3-methano--proline (2).
Figure 1. Selected biologically relevant 2-azabicyclo[3.1.0]hexane
derivatives described in the literature
Figure 2. Literature data on the 2-azabicyclo[3.1.0]hexane scaffold
with two diversity points (one of them being placed at the nitrogen
atom) retrieved from Reaxys®
———
 Corresponding author. Tel.: +38-044-239-3315; fax: +38-044-573-2643; e-mail: gregor@univ.kiev.ua

2
Tetrahedron Letters
Scheme 4. Lithiation of compound 5
The only reported approach to the synthesis of 1,5-
disubstituted 2-azabicyclo[3.1.0]hexanes relied on Simmons–
Smith cyclopropanation of azaindole derivative 3 (Scheme 1).10
In our approach, we were inspired by the work of Beak and co-
workers,11 who reported the intramolecular cyclization of 1-Boc-
4-chloropiperidine (4) in the presence of sec-BuLi to obtain
1,2-disubstituted 2-azabicyclo[3.1.0]hexanes (Scheme 2). Our
initial idea relied on applying a similar transformation to the
analogue of 4 bearing the substituent at C-4. To retain a
possibility for further functionalization of the corresponding
product, piperidine 5 was selected as the substrate for the
lithiation. A tert-butyl protecting group was used to avoid the
possible attack of the organolithium species on the ester moiety.
Compound 5 was not described in the literature previously; it was
prepared from isonipecotic acid (6) in three steps using published
methods (Scheme 3).12–14
This result showed that an alternative leaving group should be
considered for the sec-BuLi-induced cyclization. We turned our
attention to the epoxide group as a possible electrophilic moiety
for trapping the 2-lithiated piperidine intermediate. The
corresponding spirocyclic epoxide 9 was prepared in 92% yield
through a Corey–Chaikowsky reaction of 4-piperidone derivative
10 (Scheme 5).15 The idea of a base-induced rearrangement of 9
giving the corresponding 2-azabicyclo[3.1.0]hexane derivative 11
appeared rather adventurous since it required intramolecular
nucleophilic attack at the quaternary carbon center via highly
strained transition state 12. To our satisfaction, compound 11 was
indeed formed in 21% yield via sec-BuLi–TMEDA treatment of
9 and subsequent work-up.16, 17 The reaction was accompanied by
a direct nucleophilic attack of the organometallic species on the
epoxide moiety of 9 leading to the formation of alkene 13 in 55%
yield.18 Variation of the amount of the base did not improve the
ratio of the products 11 and 13, but affected the reaction time.
Using a five-fold excess of sec-BuLi enabled completion of the
conversion of 9 at −78 C in only 3.5 hours. Notably, the
synthesis was reproducible on gram scale, so that nearly 1.5 g of
11 was prepared in a single run.
Scheme 1. Literature method for the preparation of 1,5-disubstituted
2-azabicyclo[3.1.0]hexanes
Scheme 2. Synthesis of 1,2-disubstituted 2-azabicyclo[3.1.0]hexanes
as reported by Beak and co-workers
Scheme 5. Synthesis of epoxide 9 and its reaction with organo-
lithium reagents
We considered increasing the strength of the base for the
lithiation of epoxide 9 as a factor which might improve the
outcome of the rearrangement. Uneventfully, reaction of 9 with
t-BuLi–TMEDA was slow, such that 40% of the starting material
was recovered after 3.5 hours; moreover, the only isolated
product of any transformations was alkene 14 (18%) (Scheme
5).19 No traces of 11 were detected in the crude product obtained
after aqueous work-up of the reaction mixture. Apparently, the C-
5 atom of spirocyclic compound 9 is less sterically accessible
towards attack of the organometallic species as compared to C-2,
so that increasing the size of the base is unfavorable.
Scheme 3. Synthesis of compound 5
However, no cyclopropane-containing products were formed
from 5 upon treatment with sec-BuLi–TMEDA under conditions
described for the reaction of 4. Instead, the precursor of 5,
compound 7 was isolated in 94% yield (Scheme 4). The
formation of 7 can be explained by a lithium–halogen exchange
in 5, leading to enolate 8, which, in turn, gives 7 upon aqueous
work-up.
To demonstrate the synthetic application of the approach
described above, alcohol 11 was oxidized to previously unknown
2,3-methano--proline derivative 2 by KMnO4 in 78% yield
(Scheme 6).20,21 This novel Boc-protected amino acid was

3
prepared in three steps and in 15% overall yield from easily
available materials.
10. Valeur, E.; Christmann-Franck, S.; Lepifre, F.; Carniato, D.;
Cravo, D.; Charon, C.; Bozec, S.; Musil, D.; Hillertz, P.; Doare,
L.; Schmidlin, F.; Lecomte, M.; Schultz, M.; Roche, D. Bioorg.
Med. Chem. Lett. 2012, 22, 5909–5914.
11. (a) Beak, P.; Wu, S.; Yum, E. K.; Jun, Y. M. J. Org. Chem. 1994,
59, 276–277. See also: (b) Bailey, W. F.; Beak, P.; Kerrick, S. T.;
Ma, S.; Wiberg, K. B. J. Am. Chem. Soc. 2002, 124, 1889–1896.
(c) O'Brien, P.; Rayner, P. J.; Horan, R. A. J. J. Am. Chem. Soc.
2013, 135, 8071–8077.
12. (a) Schmidt, M.; Barbayianni, E.; Fotakopoulou, I.; Hohne, M.;
Constantinou-Kokotou, V.; Bornscheuer, U. T.; Kokotos, G. J.
Org. Chem. 2005, 70, 3737–3740. (b) Arnold, R. T.; Kulenovic, S.
T. J. Org. Chem. 1978, 43, 3687–3689.
Scheme 6. Synthesis of N-Boc-2,3-methano--proline (2)
In conclusion, an unusual rearrangement of a spirocyclic
13. Di-tert-butyl piperidine-1,4-dicarboxylate (7): pale brownish
crystals. Mp = 65−67 С. GCMS (EI, m/z): 228 (M+−tBu),
172(M+−t-Bu–C4H8), 156 (M+−t-Bu–Ot-Bu), 128, 112, 82, 57
epoxide to give
a
5-substituted 2-azabicyclo[3.1.0]hexane
derivative is described. The synthetic utility of the approach was
demonstrated by the synthesis of a new -amino acid, i. e., 2,3-
methano--proline (as the N-Boc derivative).
+
(C4H9 ), 41. Anal. Calcd for C15H27NO4 C 63.13, H 9.54, N 4.91.
1
Found 63.38, H 9.35, N 5.02. H NMR (400 MHz, CDCl3) δ 3.93
(br s, 2H), 2.83 – 2.70 (m, 2H), 2.33 – 2.22 (m, 1H), 1.82 – 1.71
(m, 2H), 1.58 – 1.44 (m, 2H), 1.39 (s, 9H), 1.38 (s, 9H). 13C NMR
(100 MHz, CDCl3):  173.7, 154.5, 80.1, 79.3, 43.2, 42.7, 41.9,
28.3, 27.9.
Acknowledgments
The authors thank Dr. Sergey V. Ryabukhin and Dr. Sci.
Dmitry M. Volochnyuk for helpful discussions, and Dr. Oleg
Lukin for his help with the preparation of the manuscript.
14. Di-tert-butyl 4-chloropiperidine-1,4-dicarboxylate (5): white
crystals. Mp = 71−73 С. GCMS (EI, m/z): 262/264 (M+−t-Bu),
+
246/248 (M+−Ot-Bu), 206/208, 190, 170, 146, 126, 57 (C4H9 ),
41. Anal. Calcd for C15H26ClNO4 C 56.33, H 8.19, Cl 11.09, N
4.38. Found C 56.05, H 7.94, Cl 11.30, N 4.06. 1H NMR (400
MHz, CDCl3) δ 3.77 – 3.64 (m, 2H), 3.39 – 3.28 (m, 2H), 2.09 –
1.95 (m, 4H), 1.47 (s, 9H), 1.43 (s, 9H). 13C NMR (101 MHz,
CDCl3):  168.8, 154.3, 82.5, 79.8, 67.6, 39.9, 35.7, 28.4, 27.7.
15. Cui, J. J.; Tran-Dubé, M.; Shen, H.; Nambu, M.; Kung, P. P.;
Pairish, M.; Jia, L.; Meng, J.; Funk, L.; Botrous, I.; McTigue, M.;
Grodsky, N.; Ryan, K.; Padrique, E.; Alton, G.; Timofeevski, S.;
Yamazaki, S.; Li, Q.; Zou, H.; Christensen, J.; Mroczkowski, B.;
Bender, S.; Kania, R. S.; Edwards, M. P. J. Med. Chem. 2011, 54,
6342−6346.
16. A solution of 9 (7.00 g, 32.8 mmol) and TMEDA (19.06 g, 0.164
mol) in absolute THF (150 mL) was cooled to −78 C under an
argon atmosphere. sec-BuLi (118 mL, 0.164 mol, 1.4 M in
cyclohexane) was added dropwise at −78 C, and the mixture was
stirred at −78 C for 3.5 h. Saturated aq NH4Cl (150 mL) was
added dropwise with stirring at the same temperature, and the
mixture was allowed to reach rt slowly. The phases were
separated, and the aqueous phase was washed with CH2Cl2
(3×70 mL). The combined organic extracts were washed with 10%
aq citric acid (2×70 mL) and brine (50 mL), dried over Na2SO4
and evaporated in vacuo. The residue was purified by column
chromatography [hexanes – EtOAc (2 : 3) as eluent] to give 11
(1.47 g, 21%, Rf = 0.30) and 13 (4.57 g, 55%, Rf = 0.95).
References and notes
1. For selected reviews, see: (a) Hanessian, S.; Auzzas, L. Acc.
Chem. Res. 2008, 41, 1241–1251. (b) Komarov, I. V.;
Grygorenko, O. O.; Turov, A. V.; Khilya, V. P. Russ. Chem. Rev.
2004, 73, 785–810. (c) Trabocchi, A.; Scarpi, D.; Guarna, A.
Amino Acids 2008, 34, 1–24. (d) Grygorenko, O. O.; Radchenko,
D. S.; Volochnyuk, D. M.; Tolmachev, A. A.; Komarov, I. V.
Chem. Rev. 2011, 111, 5506–5568.
2. (a) Hanessian, S.; Shao, Z.; Warrier, J. S. Org. Lett. 2006, 8,
4787–4790. (b) Cheong, P. H.-Y.; Houk, K. N.; Hanessian, S.;
Warrier, J. S. Adv. Synth. Catal. 2004, 346, 1111–1115.
3. (a) Switzer, F. L.; Halbeek, H. Van; Holt, E. M.; Stammer, C. H.;
Saltveit, M. E. Tetrahedron 1989, 45, 6091–6100. (b) Aznar, F.;
Barluenga, J.; Garcia-Granda, S.; Gutierrez, I.; Llorca-Baragano,
M. A.; Aznar, F.; Barluenga, J.; Garcia-Granda, S.; Gutierrez, I.;
Llorca-Baragano, M. A. Org. Lett. 2002, 24, 4273–4276. (c)
Gentile, G.; Hanessian, S.; Reinhold, U. Angew. Chem. Int. Ed.
1997, 36, 1881–1884. (d) Belema, M.; Hamann, L. G.; James, C.
A.; Meanwell, N. A.; Wang, G. Tetrahedron Lett. 2013, 54, 6722–
6724.
4. (a) Savage, S. A.; Jones, G. S.; Kolotuchin, S.; Ramrattan, S. A.;
Vu, T.; Waltermire, R. E. Org. Proc. Res. Dev. 2009, 13, 1169–
1176. (b) Augeri, D. J.; Robl, J. A.; Betebenner, D. A.; Magnin, D.
R.; Khanna, A.; Robertson, J. G.; Wang, A.; Simpkins, L. M.;
Taunk, P.; Huang, Q.; Han, S. P.; Abboa-Offei, B.; Cap, M.; Xin,
L.; Tao, L.; Tozzo, E.; Welzel, G. E.; Egan, D. M.;
Marcinkeviciene, J.; Chang, S. Y.; Biller, S. A.; Kirby, M. S.;
Parker, R. A.; Hamann, L. G. A. J. Med. Chem. 2005, 48, 5025–
5037.
5. (a) Oliveira, D. F.; Miranda, P. C. M. L.; Correia, C. R. D. J. Org.
Chem. 1999, 64, 6646–6652. (b) Hanessian, S.; Reinhold, U.;
Saulnier, M.; Claridge, S. Bioorg. Med. Chem. Lett. 1998, 8,
2123–2128.
17. tert-Butyl 5-(hydroxymethyl)-2-azabicyclo[3.1.0]hexane-2-carbo-
xylate (11): pale yellow oil. GCMS (EI, m/z): 213 (M+), 195
(M+−H2O), 157 (M+−C4H8), 126, 82, 57 (C4H9+), 41. Anal. Calcd
for C11H19NO3 C 61.95, H 8.98, N 6.57. Found C 62.21, H 8.73, N
1
6.28. H NMR (400 MHz, CDCl3):  3.64 (br s, 1H), 3.61 (d, J =
11.5 Hz, 1H), 3.56 (d, J = 11.5 Hz, 1H), 3.35 – 3.18 (m, 1H), 3.05
– 2.87 (m, 2H), 2.12 (br s, 1H), 1.99 – 1.92 (m, 1H), 1.71 (s, 9H),
0.78 (s, 1H), 0.77 (s, 1H). 13C NMR (101 MHz, CDCl3):  154.9,
79.5, 65.6, 44.3, 39.3, 28.4, 28.3, 27.6, 15.4.
18. tert-Butyl 4-(2-methylbutylidene)piperidine-1-carboxylate (13):
colorless oil. GCMS (EI, m/z): 253 (M+), 238 (M+−CH3), 197
+
(M+−C4H8), 180, 168, 126, 97, 96, 57 (C4H9 ), 41. Anal. Calcd for
C15H27NO2 C 71.10, H 10.74, N 5.53. Found C 71.02, H 10.49, N
5.78. 1H NMR (400 MHz, CDCl3) δ 4.92 (d, J = 9.5 Hz, 1H), 3.45
– 3.26 (m, 4H), 2.28 – 2.12 (m, 3H), 2.08 (t, J = 5.6 Hz, 2H), 1.43
(s, 9H), 1.35 – 1.23 (m, 1H), 1.21 – 1.09 (m, 1H), 0.89 (d, J = 6.7
Hz, 3H), 0.79 (t, J = 7.4 Hz, 3H). 13C NMR (101 MHz, CDCl3): 
154.6, 133.5, 130.5, 79.2, 45.4, 44.5, 36.0, 33.2, 30.4, 28.7, 28.4,
21.3, 12.0.
6. Dai, C.; Li, D.; Piwinski, J. J.; Popovici-Muller, J.; Rosner, K. E.;
Shih, N.-Y.; Siddiqui, M. A.; Zhao, L.; Girijavallabhan, V. M.;
Guo, Z.; Kozlowski, J. A.; Lavey, B. J.; Orth, P.; Rizvi, R.;
Shankar, B. B.; Strickland, C. O.; Wong, M. K.C.; Lundell, D. J.;
Niu, X.; Sun, J.; Chen, S. Bioorg. Med. Chem. Lett. 2011, 21,
3172–3176.
19. tert-Butyl
4-(2,2-dimethylpropylidene)piperidine-1-carboxylate
7.
Aoyama, K.; Asano, M.; Hamada, T.; Hashimoto, K.; Ishikawa,
T.; Morishita, N.; Saito, B.; Shiokawa, Z.; Sumi, H.; Yabuki, M.;
Yoshida, S.; Yoshimatsu, M.; Dougan, D. R.; Mol, C. D. Bioorg.
Med. Chem. 2013, 21, 5725–5737.
(14): pale yellow crystals. Mp = 61−62 С. GCMS (EI, m/z): 253
+
(M+), 197 (M+-C4H8), 141, 97, 96, 57 (C4H9 ), 41. Anal. Calcd for
C15H27NO2 C 71.10, H 10.74, N 5.53. Found C 71.41, H 10.99, N
5.64. 1H NMR (400 MHz, CDCl3) δ 5.20 (s, 1H), 3.33 (dd, J =
10.9, 5.0 Hz, 4H), 2.28 (t, J = 5.5 Hz, 2H), 2.99 (t, J = 5.5 Hz,
2H), 1.40 (s, 9H), 1.04 (s, 9H). 13C NMR (101 MHz, CDCl3): 
8. Reaxys®, version 1.9.2; Reed Elsevier Properties SA; 2013
(accessed Feb 07, 2014)
9. Tymtsunik, A. V.; Ivon, Ye. M.; Komarov, I. V.; Grygorenko,
O. O. Tetrahedron Lett. 2014, 55, 3312–3315.

4
Tetrahedron Letters
13C NMR (101 MHz, CDCl3) δ 154.4, 134.5, 134.0, 79.0, 45.5,
43.9, 36.9, 31.6, 31.2, 29.1, 28.2.
20. To a solution of 11 (350 mg, 1.64 mmol) in t-BuOH (16.5 mL),
solutions of NaOH (256 mg, 6.15 mmol) in H2O (13 mL) and
KMnO4 (1.01 g, 6.40 mmol) in H2O (21.5 mL) were added
consecutively at rt. The resulting mixture was stirred at rt for 24 h,
and then quenched with a solution of Na2S2O35H2O (2.04 g) in
H2O (24 mL). The MnO2 precipitate was filtered off and washed
with H2O (7×25 mL). The resulting solution was washed with
Et2O (2×50 mL) and acidified with 15% aq citric acid (80 mL).
The resulting solution was extracted with EtOAc (5×50 mL). The
combined organic phases were washed with brine (50 mL), dried
over Na2SO4 and evaporated in vacuo to give 2 (290 mg, 78%).
An analytical sample was obtained by recrystallization from
MeCN.
21. 2-(tert-Butoxycarbonyl)-2-azabicyclo[3.1.0]hexane-5-carboxylic
acid (2): white solid. Mp = 118−120 С. GCMS (EI, m/z): 171
(M+−C4H8), 154 (M+−Ot-Bu), 127 (M+−C4H8−CO2), 126
(M+−Boc), 82, 57 (C4H9+), 41. Anal. Calcd for C11H17NO4
C
1
58.14, H 7.54, N 6.16. Found C 57.86, H 7.78, N 6.40. H NMR
(400 MHz, CDCl3) δ 10.16 (br s, 1H), 4.06 – 3.69 (m, 2H), 3.09 –
2.92 (m, 1H), 2.62 – 2.49 (m, 1H), 2.10 – 1.96 (m, 1H), 1.69 (s,
1H), 1.47 (s, 9H), 1.26 – 1.22 (m, 1H). 13C NMR (101 MHz,
CDCl3):  178.5, 154.3, 80.3, 45.4, 44.1, 28.5, 28.4, 25.2, 19.7.