Synthesis of azabicyclo[n.1.0]alkane-derived bifunctional building blocks via the Corey–Chaykovsky cyclopropanation

Article abstract of DOI:10.1016/j.tetlet.2018.11.047

An efficient approach towards the synthesis of monoprotected azabicyclo[5.1.0]octane-derived conformationally restricted γ-amino acids and diamines is reported. Optimization of the conditions for the key Corey–Chaykovsky reaction allowed the construction

Full text of DOI:10.1016/j.tetlet.2018.11.047

Accepted Manuscript
Synthesis of azabicyclo[n.1.0]alkane-derived bifunctional building blocks via
the Corey–Chaykovsky cyclopropanation
Dmytro V. Yarmoliuk, Dmytro Serhiichuk, Vladyslav Smyrnov, Andriy V.
Tymtsunik, Oleksandr V. Hryshchuk, Yuliya Kuchkovska, Oleksandr O.
Grygorenko
PII:
S0040-4039(18)31385-6
https://doi.org/10.1016/j.tetlet.2018.11.047
TETL 50432
DOI:
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
28 September 2018
7 November 2018
16 November 2018
Please cite this article as: Yarmoliuk, D.V., Serhiichuk, D., Smyrnov, V., Tymtsunik, A.V., Hryshchuk, O.V.,
Kuchkovska, Y., Grygorenko, O.O., Synthesis of azabicyclo[n.1.0]alkane-derived bifunctional building blocks
via the Corey–Chaykovsky cyclopropanation, Tetrahedron Letters (2018), doi: https://doi.org/10.1016/j.tetlet.
2018.11.047
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Tetrahedron Letters
Synthesis of azabicyclo[n.1.0]alkane-derived bifunctional building blocks via the
Corey–Chaykovsky cyclopropanation
Dmytro V. Yarmoliuk,a,b Dmytro Serhiichuk,a,c Vladyslav Smyrnov,a,b Andriy V. Tymtsunik,a,c Oleksandr
V. Hryshchuk,a,b Yuliya Kuchkovskaa,b and Dr. Oleksandr O. Grygorenko a,b
*
a
Enamine Ltd. (www.enamine.net) Chervonotkatska Street 78, Kyiv 02094, Ukraine
National Taras Shevchenko University of Kyiv, Volodymyrska Street 60, Kyiv 01601, Ukraine
b
c National Technical University of Ukraine "Igor Sikorsky Kyiv Polytechnic Institute", Prospect Peremogy 37, Kyiv 03056, Ukraine
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
An efficient approach towards the synthesis of monoprotected azabicyclo[5.1.0]octane-derived
conformationally restricted γ-amino acids and diamines is reported. Optimization of the
conditions for the key Corey–Chaykovsky reaction allowed the construction of two isomeric
methanoazepane frameworks on a multigram scale in 55–65% yield. Additionally, the developed
approach was used in the three-step synthesis of 3,4-methano-β-proline and its diamine
derivatives.
Available online
Keywords:
2018 Elsevier Ltd. All rights reserved.
Amino acids
Bicyclic compounds
Azepane
Cyclopropane
Pyrrolidine
Diamines
Extension of the natural amino acid repertoire by newly
designed synthetic analogues has made a significant contribution
to both small molecule drugs and peptide therapeutics
development.1–7 The success of tailor-made unnatural amino
acids in medicinal chemistry can be partially attributed to their
ability to modulate physical parameters, improve stability and
provide structural pre-organization of the designed ligands.8,9
This is often addressed by the introduction of conformational
restriction to the substrate backbone, thus enhancing its binding
affinity to the target biomolecule.10 This effect can be achieved
by the cyclization of initially linear fragments, construction of
bridged, spirocyclic or fused bi- and polycyclic frameworks, and
increasing the substituent steric bulk.
pharmacophoric groups in the case of the triple reuptake inhibitor
GSK1360707F.14
Proline is the most conformationally restricted among the 20
standard proteinogenic amino acids. Along with its closest
homologue, pipecolic acid, and their structural isomers bearing
the endocyclic amine functionality in the β- and γ-positions to the
carboxylic group, proline has attracted the attention of organic
chemists as the starting template for further structural
modifications. One of the most advantageous and atom-economic
tactics for such optimization is introduction of a methylene unit
as a part of a fused cyclopropane ring.11 This approach was
crucial to achieve improved in vivo stability of the anti-diabetic
drug Saxagliptin,12,13 as well as to enhance binding of the
Figure 1. Amino acids bearing azabicyclo[n.1.0]alkane moieties and their
derivatives known in the literature (only the parent structures are shown)
Synthetic approaches towards tailor-made conformationally
rigid amino acids have been comprehensively surveyed in several
reviews.15–19 In particular, a number of amino acids or their
derivatives bearing fused cyclopropane moieties (compounds 1–
6) were reported in the literature (Fig. 1).
__________________________
 Corresponding author. Tel.: +38-044-239-3315; fax: +38-044-573-2643; e-mail: gregor@univ.kiev.ua

2
Tetrahedron Letters
Scheme 1. Known approaches towards azabicyclo[5.1.0]octane core synthesis
Most efforts have been put into the synthesis of - and -
amino acids of this type;20–29 preparation of their γ counterparts is
studied to a lesser extent.30–32 Meanwhile, the synthetic analogues
of γ-aminobutyric acid (GABA), an important neurotransmitter in
the mammalian central nervous system, remains of great interest
for the treatment of neurological disorders.33,34 Being inspired by
previous successful syntheses of the amino acids shown in Figure
1, we aimed to develop an approach towards novel γ-amino acids
Although the Corey–Chaykovsky cyclopropanation is used
extensively in organic synthesis, this step required tedious
optimization of the reaction conditions when applied to
tetrahydro-1H-azepines 9 and 10. Synthesis of the bicyclic
compound 15 was carried out with an excess of the ylide
generated by deprotonation of trimethylsulfoxonium iodide.
Optimization of the cyclopropanation step included variation of
the base and the solvent, as well as reaction temperature and time
(Table 1). As a result, a procedure applying moderate heating (50
°C) of the substrate with the trimethylsulfoxonium ylide
generated from Me3SO+I– using NaH in DMSO for 18 h provided
the highest yield (55%).43 When the reaction was performed at
increased temperature (70 °C), the crude product contained
neither the target compound 15 nor the starting material 9
according to 1H NMR, indicating their instability at elevated
temperatures. In the case of the t-BuOK – DMSO system,
formation of product 15 was also observed, but its yield was
unsatisfactory. Finally, replacing DMSO as the solvent with
DMF was not effective.
based on
a
homologous methanoazepane ring system.
Specifically, N-protected 4-azabicyclo[5.1.0]octane-1-carboxylic
(7) and 3-azabicyclo[5.1.0]octane-7-carboxylic (8) acids derived
from the 3-azabicyclo[5.1.0]octane scaffold were chosen as the
synthetic targets.
Several approaches to the synthesis of 3-azabicyclo[5.1.0]-
octanes with the free C-8 position are described in the literature.
Apart
from
the
Beckmann
rearrangement
of
bicyclo[4.1.0]heptan-2-one derived oxime35 (Scheme 1, A), most
of these methods are based on intramolecular transition metal-
catalyzed cyclizations, including the Kulinkovich–Szymoniak
reaction (B),36 Pd- and Rh-catalyzed 5-exo-trig cyclopropanation
of 1,8-enynes (C),37,38 and Rh-catalyzed recyclization of N-
allylated
(triazolylalkyl)amine
bicyclo[1.1.0]butylalkylamine
(D)39
Whereas
or
the
(E)40
derivatives.
aforementioned methods showed good performance for 3-
azabicyclo[3.1.0]hexane and 3-azabicyclo[4.1.0]heptane
derivatives, they were less effective for the construction of the
azabicyclo[5.1.0]octane core. To the best of our knowledge,
synthesis of the isomeric 4-azabicyclo[5.1.0]octanes has not been
reported to date.
In this work, we envisaged the Corey-Chaykovsky
cyclopropanation of tetrahydro-1H-azepines 9 and 10 as the key
step for the formation of azabicyclo[5.1.0]octane bicyclic
frameworks (Scheme 1, F and G). In contrast to methods B–E,
this approach does not include intramolecular cyclization of
linear substrates, which is usually less favorable for larger than
six-membered rings. Instead, construction of the seven-
membered ring is achieved via the known reaction of
commercially available N-Boc protected piperidinones 11 and 12
with ethyl diazoacetate (Scheme 2).41,42 This method allowed for
the preparation of -ketoester 13 as a single product in 68%
yield, while 14 was obtained in 48% yield after chromatographic
separation of the regioisomeric mixture. The key α,β–unsaturated
esters 9 and 10 were obtained via a three-step reaction sequence
including reduction of ketones 13 and 14 with NaBH4, alcohol
mesylation, and elimination (64% and 55% yield, respectively).43
Scheme 2. Synthesis of tetrahydro-1H-azepines 9 and 10.
In the case of substrate 16, variation of the reaction conditions
followed similar trends (although alkene 10 was somewhat more
stable compared to 9 at elevated temperatures); again, the highest
yield of the product (65%) was obtained using NaH in DMSO at
50 C for 18 h. In addition, the utility of the trimethylsulfonium
iodide – NaH system as a source of the ylide was studied; this
modification of the reagent was not fruitful.

Alkaline hydrolysis of bicyclic esters 15 and 16 led to the
target amino acids 7 and 8 in 99% yield (Scheme 3). Subsequent
Curtius rearrangement of 7 and 8 using benzyl alcohol as the
isocyanate trapping reagent, followed by hydrogenolysis, resulted
in the formation of monoprotected diamines 17 and 18,
respectively (53% and 49% yield for two steps, respectively). It
should be noted that the synthesis of building blocks 7, 8, 17 and
18 was performed on a multigram scale (8–31 g).
latter step was required since the conditions described above for
15 and 16 did not led to the target product 21 (Table 2). It was
found that increasing the reaction temperature or time, as well as
variation of the solvent were not efficient. In this case, the
reagent ratio appeared to be critical: upon decreasing the amount
of NaH and Me3SO+I– to 1.1 and 1.0 equivalents, respectively,
and the reaction time to 1 h, the target product 21 could be
obtained in 29% yield. We believe that these results can be
explained by decomposition of the starting material 20 and the
product 21 under the basic reaction conditions.
Table 1. Corey – Chaykovsky cyclopropanation of 15 and 16.
Table 2. Corey – Chaykovsky cyclopropanation of 20.
Entry
NaH
(eq)
Me3SO+I–
(eq)
Temp.
(°C)
Time
(h)
Yield
21 (%)
Solvent
1
2
3
4
5
2.2
2.2
2.2
1.1
1.1
1.1
1.1
1.1
1.0
1.0
DMSO
DMSO
THF
80
25
25
25
25
3
14
14
3
0
0
Entry
Time
(h)
Yield
15 (%)
Yield
16 (%)
Base
Solvent
Temp.
0
1
2
NaH
NaH
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMF
rt
70 °C
50 °C
rt
3
3
15
0
0
DMSO
DMSO
10
29
15
40
0
1
3
NaH
3
40
15
0
4
NaH
18
18
18
3
The acidic hydrolysis of 21 quantitatively provided the
monoprotected amino acid 22 as the hydrochloride salt (Scheme
4). Subsequent modified Curtius rearrangement of 22 involving
the use of t-BuOH to trap the intermediate isocyanate gave
orthogonally protected diamine derivative 23 (81% yield). The
intermediate 23 was transformed into the corresponding
monoprotected diamine derivatives 24 and 25 by hydrogenolysis
(72% yield) or removal of the Boc protective group under acidic
conditions (90% yield, obtained as the dihydrochloride salt),
respectively.
5
NaH
70 °C
50 °C
rt
50
65
0
6
NaH
55
0
7
NaH
8
NaH
DMF
rt
18
3
0
0
9
t-BuOK
t-BuOK
DMSO
DMSO
rt
20
30
15
25
10
rt
48
Scheme 4. Synthesis of amino acid 22, monoprotected diamines 24 and 25.
Scheme 3. Synthesis of amino acids 7 and 8 and diamines 17 and 18.
In conclusion, the Corey–Chaykovsky reaction of tetrahydro-
1H-azepines containing an α,β-unsaturated ester moiety with the
trimethylsulfoxonium ylide is an efficient method for
construction of the azabicyclo[5.1.0]octane ring system. With
optimized reaction conditions for this step, the corresponding N-
protected bicyclic amino esters were obtained in 55–65% yield
on up to 25 g scale. As a result, two novel bicyclic amino acids 7
and 8 were obtained in 23% and 17% yield over 6 steps,
respectively. Moreover, conformationally restricted diamine
derivatives 17 and 18 were also prepared in 12% and 8% overall
yield over 8 steps. In addition, the developed method can also be
Being inspired by successful application of the Corey–
Chaykovsky cyclopropanation for the synthesis of
azabicyclo[5.1.0]octane derivatives, we anticipated its potential
utility for the preparation of other homologous bicyclic systems.
In particular, we have implemented this method for construction
of the 3-azabicyclo[3.1.0]hexane system in two steps starting
from readily available N-(methoxymethyl)-N-(trimethylsilyl)-
benzylamine (19) and ethyl prop-2-ynoate. The synthetic scheme
commenced with the known [3+2] cycloaddition reaction of these
starting materials, followed by the Corey–Chaykovsky
cyclopropanation. In this case, additional optimization of the
applied
for
the
synthesis
of
lower
homologous

4
Tetrahedron Letters
24.
Matsumura Y., Inoue M., Nakamura Y., Talib I. L., Maki T.,
azabicyclo[n.1.0]alkanes, in particular, 3-azabicyclo[3.1.0]-
Onomura O. Tetrahedron Lett. 2000; 41: 4619–4622.
Medda A., Lee H.-S. Synlett. 2009; 2009: 921–924.
Yang C., Shen H. Tetrahedron Lett. 1993; 34: 4051–4054.
Adamovskyi M. I., Artamonov O. S., Tymtsunik A. V., Grygorenko
O. O. Tetrahedron Lett. 2014; 55: 5970–5972.
hexanes, which was demonstrated by the preparation of the 3,4-
methano-β-proline derivative. It should be noted that this
synthetic sequence included only
commenced from readily available starting compounds.
Therefore, it might be preferable over the existing multistep
approaches to the derivatives of amino acid 22 despite the
moderate yield of the key step – the Corey–Chaykovsky
cyclopropanation (29%).
25.
26.
27.
3 steps; moreover, it
28.
29.
Napolitano C., Borriello M., Cardullo F., Donati D., Paio A.,
Manfredini S. Tetrahedron. 2010; 66: 5492–5497.
Tymtsunik A. V., Ivon Y. M., Komarov I. V., Grygorenko O. O.
Tetrahedron Asymmetry. 2015; 26.
30.
31.
32.
Mori M., Kubo Y., Ban Y. Tetrahedron Lett. 1985; 26: 1519–1522.
Mori M., Kubo Y., Ban Y. Tetrahedron. 1988; 44: 4321–4330.
Ordóñez M., Cativiela C., Romero-Estudillo I. Tetrahedron:
Asymmetry. 2016; 27: 999–1055.
Acknowledgments
33.
Gajcy K., Lochynski S., Librowski T. Curr Med Chem. 2010; 17:
2338–2347.
Ashton H., Young A. H. J Psychopharmacol. 2003; 17: 174–178.
Crowley P. J., Aspinall I. H., Gillen K., Godfrey C. R. A., Devillers
I. M., Munns G. R., Sageot O., Swanborough J., Worthington P. A.,
Williams J. Chim Int J Chem. 2003; 57: 685–691.
Laroche C., Bertus P., Szymoniak J. Tetrahedron Lett. 2003; 44:
2485–2487.
Zheng J., Li Z., Wu W., Jiang H. Org Lett. 2016; 18: 6232–6235.
Ma J., Chen K., Fu H., Zhang L., Wu W., Jiang H., Zhu S. Org
Lett. 2016; 18: 1322–1325.
Walczak M. A. A., Wipf P. J Am Chem Soc. 2008; 130: 6924–
6925.
Pan X.-H., Jiang P., Jia Z.-H., Xu K., Cao J., Chen C., Shen M.-H.,
Xu H.-D. Tetrahedron. 2015; 71: 5124–5129.
Yang H. Y., Tae J., Seo Y. W., Kim Y. J., Im H. Y., Choi G. D.,
Cho H., Park W.-K., Kwon O. S., Cho Y. S., Ko M., Jang H., Lee
J., Choi K., Kim C.-H., Lee J., Pae A. N. Eur J Med Chem. 2013;
63: 558–569.
Shireman B. T., Dvorak C. A., Rudolph D. A., Bonaventure P.,
Nepomuceno D., Dvorak L., Miller K. L., Lovenberg T. W.,
Carruthers N. I. Bioorg Med Chem Lett. 2008; 18: 2103–2108.
Song S., Zhu S.-F., Pu L.-Y., Zhou Q.-L. Angew Chem Int Ed.
2013; 52: 6072–6075.
The work was funded by Enamine Ltd. The authors thank
Prof. A. Tolmachev for his encouragement and support and Mr.
Andriy Kozytskyi for NMR measurements.
34.
35.
Supplementary data
36.
1
Experimental details, characterization data, and copies of H
37.
38.
and 13C NMR spectrum of products can be found, in the online
version, at http://dx.doi.org/
39.
40.
41.
References and notes
1.
2.
Blaskovich M. A. T. J Med Chem. 2016; 59: 10807–10836.
Stevenazzi A., Marchini M., Sandrone G., Vergani B., Lattanzio M.
Bioorg Med Chem Lett. 2014; 24: 5349–5356.
3.
4.
Sorochinsky A. E., Aceña J. L., Moriwaki H., Sato T., Soloshonok
V. A. Amino Acids. 2013; 45: 691–718.
Aceña J. L., Sorochinsky A. E., Soloshonok V. Amino Acids. 2014;
46: 2047–2073.
42.
5.
6.
Soloshonok V. A. Curr Org Chem. 2002; 6: 341–364.
Wang Y., Song X., Wang J., Moriwaki H., Soloshonok V. A., Liu
H. Amino Acids. 2017; 49: 1487–1520.
43.
44.
4-tert-Butyl 1-ethyl 4-azabicyclo[5.1.0]octane-1,4-dicarboxylate
(15). To a suspension of NaH (21.2 g, 0.318 mol, 60 % dispersion
in mineral oil) in DMSO (650 mL), S,S,S-trimethylsulfoxonium
iodide (72.9 g, 0.331 mol) was added in small portions and stirred
at rt for 1 h until gas evolution ceased. A solution of 1-tert-butyl
4-ethyl 2,3,6,7-tetrahydro-1H-azepine-1,4-dicarboxylate (9) (34.3
g, 0.127 mol) in DMSO (150 mL) was added dropwise and the
reaction mixture was stirred at 50 °C overnight. The resulting
solution was cooled to rt, poured into ice-cold H2O (1 L) and
extracted with t-BuOMe (3700 mL). The combined organic
extracts were washed with brine (3500 mL), dried over anhydrous
Na2SO4 and evaporated under reduced pressure. The product was
purified by column chromatography (gradient hexane to hexane – t-
7.
Sorochinsky A. E., Aceña J. L., Moriwaki H., Sato T., Soloshonok
V. Amino Acids. 2013; 45: 1017–1033.
8.
9.
Di L. AAPS J. 2015; 17: 134–143.
Vagner J., Qu H., Hruby V. J. Curr Opin Chem Biol. 2008; 12:
292–296.
10.
Fang Z., Song Y., Zhan P., Zhang Q., Liu X. Future Med Chem.
2014; 6: 885–901.
11.
12.
Talele T. T. J. Med. Chem., 2016, 59.
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. J Med Chem. 2005;
48: 5025–5037.
1
BuOMe (7:3) as eluent). Yield: 19.8 g (55 %); colourless oil. H
NMR(500 MHz, CDCl3): δ 4.14 – 4.06 (m, 2H), 3.98 – 3.78 (m,
2H), 3.10 (s, 1H), 2.96 (s, 1H), 2.77 (dd, J=15.3, 6.4 Hz, 1H), 2.36
(dt, J=14.1, 6.5 Hz, 1H), 1.75 – 1.65 (m, 1H), 1.49 (dd, J=9.2, 4.3
Hz, 1H), 1.43 (s, 9H), 1.37 – 1.26 (m, 2H), 1.23 (t, J=7.1 Hz, 3H),
0.77 (t, J=6.6, 4.3 Hz, 1H). 13C NMR(126 MHz, CDCl3): δ 175.4,
155.1, 79.3, 60.6, 47.6, 47.2, 32.7, 32.4, 28.4, 27.7, 26.9, 24.7, 14.2.
MS (APCI): m/z = 284 [M+H]+. Anal. Calcd. for C15H25NO4: C
63.58; H 8.89; N 4.94. Found: C 63.86; H 8.58; N 5.13.
13.
14.
Magnin D. R., Robl J. A., Sulsky R. B., Augeri D. J., Huang Y.,
Simpkins L. M., Taunk P. C., Betebenner D. A., Robertson J. G.,
Abboa-Offei B. E., Wang A., Cap M., Xin L., Tao L., Sitkoff D. F.,
Malley M. F., Gougoutas J. Z., Khanna A., Huang Q., Han S.-P.,
Parker R. A., Hamann L. G. J Med Chem. 2004; 47: 2587–2598.
Micheli F., Cavanni P., Andreotti D., Arban R., Benedetti R.,
Bertani B., Bettati M., Bettelini L., Bonanomi G., Braggio S.,
Carletti R., Checchia A., Corsi M., Fazzolari E., Fontana S.,
Marchioro C., Merlo-Pich E., Negri M., Oliosi B., Ratti E., Read K.
D., Roscic M., Sartori I., Spada S., Tedesco G., Tarsi L., Terreni S.,
Visentini F., Zocchi A., Zonzini L., Di Fabio R. J Med Chem. 2010;
53: 4989–5001.
15.
16.
17.
Grygorenko O. O. O. Tetrahedron. 2015; 71: 5169–5216.
Trabocchi A., Scarpi D., Guarna A. Amino Acids. 2008; 34: 1–24.
Tymtsunik A. V., Kokhan S. O., Ivon Y. M., Komarov I. V.,
Grygorenko O. O. RSC Adv. 2016; 6: 22737–22748.
Cativiela C., Ordóñez M. Tetrahedron Asymmetry. 2009; 20: 1–63.
Kiss L., Fülöp F. Chem Rev. 2014; 114: 1116–1169.
Barluenga J., Aznar F., Gutiérrez I., García-Granda S., Llorca-
Baragaño M. A. Org Lett. 2002; 4: 4273–4276.
18.
19.
20.
21.
22.
23.
Switzer F. L., Van Halbeek H., Holt E. M., Stammer C. H., Saltveit
M. E. Tetrahedron. 1989; 45: 6091–6100.
Hercouet A., Bessières B., Le Corre M. Tetrahedron: Asymmetry.
1996; 7: 1267–1268.
Hercouet A., Bessières B., Le Corre M., Toupet L. Tetrahedron
Lett. 1996; 37: 4529–4532.

Graphical Abstract.

6
Tetrahedron Letters
Highlights




Synthesis of azabicyclo[5.1.0]octane(methanoazepane)-
derived amino acids and diamines is reported.
The Corey–Chaikovsky cyclopropanation is a key step
of the synthetic strategy used.
Utility of the method is demonstrated by preparation of
3,4-methano-β-proline and its diamine derivatives.
The target building blocks can be obtained at multigram
scale.