Stereoselective construction of fused cyclopropane from ynamide and its application to synthesis of small drug candidate molecules

Article abstract of DOI:10.1016/j.tetlet.2021.152985

Herein, we report the development of an asymmetric intramolecular cyclopropanation reaction under silver catalysis. The strategy is based on diazo-free silver–carbene generation, providing γ-lactam fused cyclopropane in an enantioenriched form. The ring s

Full text of DOI:10.1016/j.tetlet.2021.152985

Tetrahedron Letters 70 (2021) 152985
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Stereoselective construction of fused cyclopropane from ynamide and its
application to synthesis of small drug candidate molecules
a,b,
Tsubasa Ito a, Hiroki Takenaka a, Haruka Homma a, Shingo Harada a, , Tetsuhiro Nemoto
⇑
⇑
a Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1, Inohana, Chuo-ku, Chiba 260-8675, Japan
b Molecular Chirality Research Center, Chiba University, 1-33, Yayoi-cho, Inage-ku, Chiba 263-8522, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Herein, we report the development of an asymmetric intramolecular cyclopropanation reaction under sil-
ver catalysis. The strategy is based on diazo-free silver–carbene generation, providing -lactam fused
Received 8 February 2021
Revised 3 March 2021
Accepted 7 March 2021
Available online 23 March 2021
c
cyclopropane in an enantioenriched form. The ring system of the product is frequently encountered in
bioactive molecules and pharmaceuticals. To highlight the utility of this method, the fused cyclopropane
was converted into drug candidate molecules in short steps. In addition, computational investigations
were performed to elucidate the reaction pathway. The computation based on density functional theory
rationalized the experimentally observed chemoselectivity between the desired cyclopropanation and
overoxidation process.
Keywords:
Asymmetric synthesis
Carbenes
Ó 2021 Elsevier Ltd. All rights reserved.
Cyclization
Density functional calculations
Enantioselectivity
R1
N
H
N
Introduction
R
N
O
O
Azabicyclo[3.1.0]hexane variants with an aryl group at the
1-position exhibit diverse biological activities, and thus have an
immense potential for pharmaceutical applications (Fig. 1). For
instance, cycloclavine [1] acts as a 5-HT2C receptor antagonist
and cyproximide exhibits activity as a central nervous system
depressant, and is used as a tranquilizing agent, hypnotic agent,
or muscle relaxant. Therefore, continuous endeavor has been direc-
ted toward constructing nitrogen-containing bicycles. Recently,
Cramer et al. reported an asymmetric synthesis protocol for the
pivotal scaffold via palladium(0)-catalyzed intramolecular CAH
functionalization of cyclopropane [2,3].
Metal–carbenes are reactive species that can cause unique reac-
tion manifolds, such as CAH insertion [4], cyclopropanation [6] of
olefins and arenes, or ylide formation. Thus far, ruthenium [7], cop-
per [8], and rhodium [9] catalysts have been used to construct
heterocyclic systems through intramolecular cyclopropanation
reactions using a diazo substrate as the carbene precursor (eq 1,
Scheme 1). These methods have also been applied to asymmetric
reactions using chiral complexes [10]. While these metal–carbene
reactions have proven to be a powerful strategy for efficient molec-
H
H
R2
H
Ar
Cl
Azabicyclo
[3.1.0]hexane
Antidepressant
Candidate
(Antidepressant)
H
N
H
N
3,4-dichlorophenyl
4-methylphenyl
NH
H
(Analgesic)
Ar =
(Antidepressant)
(ADHD treatment)
Ar
2-naphthyl
(5-HT2C
receptor antagonist)
Fig. 1. Biologically active molecules with the 3- azabicyclo[3.1.0]hexane scaffold.
ular synthesis, some diazo compounds are potentially explosive;
therefore, advantageous alternative methods are in demand.
Indeed, considerable attention has been paid to metal–carbene
generation under diazo-free conditions [11]. Among the possible
methods, a combination of ynamide compounds with mild oxi-
dants is easy to apply to generate metal–carbene species because
of the stability and accessibility of ynamides [12].
⇑
Corresponding authors at: Graduate School of Pharmaceutical Sciences, Chiba
University, 1-8-1, Inohana, Chuo-ku, Chiba 260-8675, Japan (T. Nemoto).
E-mail address: tnemoto@faculty.chiba-u.jp (T. Nemoto).
https://doi.org/10.1016/j.tetlet.2021.152985
0040-4039/Ó 2021 Elsevier Ltd. All rights reserved.

T. Ito, H. Takenaka, H. Homma et al.
Tetrahedron Letters 70 (2021) 152985
Table 1
Survey of chiral catalysts.a)
Entry
5–13
Yield (%)
er of 2
(mol%)
2 3
Scheme 1. Intramolecular olefin cyclopropanation for constructing
system.
a bicyclic
1
2
3
4
5 (10)
6 (10)
7 (10)
8 (10)
50
58
4
5
32
8
76:24
46:54
31:59
61:39
46:54
50:50
50:50
48:52
50:50
53:47
51:49
54:46
4
2
5b)
6b)
7b)
8b)
9b)
10b)
11b)
12b)
9 (20)
27
20
36
14
34
23
48
28
41
28
28
10
33
13
40
16
10 (20)
10 (10)
11 (20)
11 (10)
12 (20)
12 (10)
13 (20)
As part of our ongoing investigation to develop metal–carbene
chemistry [12,14], we previously reported asymmetric intramolec-
ular dearomatization [15] of nonactivated arenes with ynamides
(eq 3) [16]. The silver-catalyzed reaction proceeds via enantiose-
lective arene cyclopropanation [17] followed by electrocyclization.
Based on the precedents and our previous studies, we anticipated
that the synthesis of an azabicyclo[3.1.0]hexane derivative in an
asymmetric format would be feasible based on the silver–carbene
reaction. In fact, associated methods for synthesizing azabicyclo
[3.1.0]hexane variants have been reported using an ynamide. In
2013, Xu and Tang used a rhodium(I) complex and 3,5-dichloropy-
ridine N-oxide to generate Rh–carbene species (eq 2) [18]. A reac-
a)
b)
Reactions were performed at 0.1 mmol scale.
AgNTf2 (20 mol%) was used instead of Ag2CO3.
[20]. The reaction of 1 with 5 and N-oxide 4a in THF solvent
at room temperature provided the desired azabicyclo[3.1.0]hex-
ane 2 in 50% yield with an enantiomeric ratio (er) of 76:24, as
tion
pathway
through
carbene-mediated
concerted
cyclopropanation was proposed. Li et al. also reported a related
transformation using ynamide with a gold catalyst in the same
year [19]. Interestingly, a mechanism that does not involve carbene
species was proposed. The two similar but distinct approaches
afforded the azabicyclo[3.1.0]hexane ring system in a racemic for-
mat; since then, asymmetric synthesis from an ynamide has not
been established.
In this context, we describe the development of a cyclopropana-
tion reaction using an ynamide and a chiral silver catalyst to
assemble azabicyclo[3.1.0]hexane derivatives in an enantioen-
riched form. The product was converted into bioactive products
in short steps. Quantum computations for mechanistic studies
were also conducted to shed light on the reaction pathway.
well as
a-keto amide 3 through an overoxidation process (entry
1). A survey of several chiral phosphoric acids did not improve
the enantioselectivity of 2 (entries 2–4). With reference to the
previous literature regarding asymmetric reactions of silver–car-
benes [21], a catalyst system consisting of chiral phosphine/
AgNTf2 was also investigated. Unfortunately, reactions using
phosphine or phosphoramidite ligands gave unsatisfactory
results (entries 5–12).
The reaction conditions were further optimized using a pre-
formed [(S)-TRIPAg]2 catalyst (Table 2) [16]. The reaction using
[(S)-TRIPAg]2 produced 2 in an enhanced yield with a comparable
level of enantioselectivity (entry 1 in Table 2 vs. entry 1 in
Table 1). Less sterically hindered oxidants 4b and 4c decreased
the yield of 2 (32% and 36% yield, entries 2 and 3, respectively).
In light of the outcome in entries 4 and 5, two equivalents of
4a were deemed sufficient for this transformation. Subsequent
solvent screening revealed that chlorobenzene was the best reac-
tion medium (entries 6–9). The use of MS3A showed a slight pos-
itive impact on the enantioinduction, providing 2 in 85% yield
with 83:17 er (entry 10).
Results and discussion
First, we prepared an ynamide (1) with an allyl group as a
substrate to develop asymmetric cyclopropanation (Table 1).
The chiral catalyst system was examined by in-situ generation
of a chiral catalyst using silver carbonate and phosphoric acids
2

T. Ito, H. Takenaka, H. Homma et al.
Tetrahedron Letters 70 (2021) 152985
Table 2
The practicality of the developed strategy was demonstrated
through the following synthetic applications. Reaction under
the optimum conditions at 0.5 mmol scale showed the same
results as in entry 10 in Table 2 (Scheme 2). After recrystalliza-
tion of 2 from MeOH to enhance the optical purity (>99:1 er,
32% yield), the reductive cleavage of the Ts group using Na/-
naphthalene yielded the corresponding secondary amide 14.
The transformation of 14 into the pyrrolidine variant and N-
alkylation produced bioactive molecules 15 and 16 in good
yields [22]. The absolute configuration of 16 was confirmed by
comparing the value of optical rotation with that of the reported
compound [21c].
Optimization of reaction conditions.a)
The ring opening reaction of 14 by acid treatment provided con-
formationally restricted c-amino butyric acid (GABA) derivative 17
in a quantitative yield (Scheme 3).
The developed reaction process was analyzed on the basis of
computational quantum mechanical modeling (Fig. 2). In previ-
ous studies using ynamides and gold catalysts reported by Li
et al., interesting pathways were proposed; the 6-endo-dig
cyclization mode from ynamide or 6-endo-trig cyclization mode
from the vinyl metal intermediate (SM ? CPA, CP2 ? CP30,
respectively, in this case). However, these elemental reaction
pathways were not observed on the computed potential energy
surface when using a silver catalyst. Instead, the silver–carbene
species, CP3 (C = Ag, 2.09 Å), was generated through the nucle-
ophilic addition of 8-methylquinoline oxide followed by the
elimination of 8-methylquinoline with reasonable activation bar-
riers (+10.41, 8.65 kcal/mol, TS1, TS2, respectively). A concerted
intermolecular cyclopropanation (TS3) from CP3 occurred, pro-
ducing the desired bicyclic molecule PRO2 concomitant with
catalyst regeneration. The overoxidation process was also com-
puted to gain mechanistic insight into the chemoselectivity.
The second addition of 8-methylquinoline oxide into CP3 pro-
vided CPEO, which evolved into PRO3 via TSEO2. The slightly
favorable energy gap (DDGà = 0.87 kcal/mol) between TS4 and
TSEO1 could explain the experimentally observed product
selectivity.
Entry
N-oxide
solv.
Yield (%)
2 3
er of 2
1
2
3
4
THF
THF
THF
THF
THF
DCE
Et2O
Toluene
PhCl
PhCl
80
32
36
34
80
66
66
54
82
85
14
7
11
6
20
25
34
34
18
15
79:21
77:23
75:25
77:23
75:25
75:25
83:17
80:20
78:22
83:17
4b
4c
4a
4a
4a
4a
4a
4a
4a
4b)
5c)
6
7
8
9
10d)
a)
b)
c)
Reactions were performed at 0.1 mmol scale.
N-oxide (1.0 equiv).
N-oxide (4.0 equiv).
d)
MS3A (1 g/mmol) was used.
Scheme 2. Synthesis of drug candidates.
3

T. Ito, H. Takenaka, H. Homma et al.
Tetrahedron Letters 70 (2021) 152985
H2N
H
O
6N HCl aq. HCl H2N
(0.07 M)
H
O
NEt2
OH
quant.
(serotonin norepinephrine
reuptake inhibitor)
Scheme 3. Synthesis of a pharmaceutically relevant molecule.
Fig. 2. Computed reaction route for the cyclopropanation and side reaction based on the RMN15/SDD (Ag)/6–311++G**//RB3LYP/LANL2DZ(Ag)/6–31G* levels of theory. Bond
lengths are shown in Å.
DG: kcal/mol.
Conclusions
Declaration of Competing Interest
A stereoselective olefin cyclopropanation reaction was devel-
oped without using a diazo compound as an advantageous alterna-
tive method. After recrystallization to increase the optical purity,
the obtained bicyclic lactam was transformed into pharmaceuti-
cally relevant molecules in enantiopure forms via simple opera-
tions. Computational studies indicated that the reaction proceeds
through silver–carbene generation followed by concerted cyclo-
propanation. This process is distinct from the previously proposed
mechanism using a group 11 coinage metal complex [19]. Further
methodology development based on the diazo-free strategy is
underway by our group.
The authors declare that they have no known competing finan-
cial interests or personal relationships that could have appeared
to influence the work reported in this paper.
Acknowledgments
This work was supported by Futaba Electronics Memorial Foun-
dation, the Toray Science Foundation, Takeda Science Foundation,
and JSPS KAKENHI Grant Numbers JP18H02550, 18K05098 and
20J11421. Numerical calculations were carried out on SR24000 at
4

T. Ito, H. Takenaka, H. Homma et al.
Tetrahedron Letters 70 (2021) 152985
[11] (a) Shindoh, N.; Kitaura, K.; Takemoto, Y.; Takasu, K. J. Am. Chem. Soc. 2011,
133, 8470–8473; (b) Wang, Z.-S.; Chen, Y. -B.; Zhang, H.-W.; Sun, Z.; Zhu, C.;
Ye, L.-W. J. Am. Chem. Soc. 2020, 142, 3636–3644; (c) Ghosh, N.; Nayak, S.;
Sahoo, A. K. Chem. Eur. J. 2013, 19, 9428–9433.
the Institute of Management and Information Technologies, Chiba
University of Japan.
[12] (a) H. Nakayama, S. Harada, M. Kono, T. Nemoto, J. Am. Chem. Soc. 139 (2017)
10188–10191;
Appendix A. Supplementary data
(b) S. Harada, M. Yanagawa, T. Nemoto, ACS Catal. 10 (2020) 11971–11979.
[13] (a) J.E. Spangler, H.W.L. Davies, J. Am. Chem. Soc. 135 (2013) 6802–6805;
(b) X. Xu, P.Y. Zavalij, M.P. Doyle, J. Am. Chem. Soc. 135 (2013) 12439–12447;
(c) S. Jana, Y. Guo, R.M. Koenigs, Chem. Eur. J. 27 (2021) 1270–1281;
(d) H.D. Khanal, R.S. Thombal, S.M.B. Maezono, Y.R. Lee, Adv. Synth. Catal. 360
(2018) 3185–3212.
Supplementary data to this article can be found online at
https://doi.org/10.1016/j.tetlet.2021.152985.
References
[14] (a) T. Nemoto, Y. Ishige, M. Yoshida, Y. Kohno, M. Kanematsu, Y. Hamada, Org.
Lett. 12 (2010) 5020–5023;
[1] (a) S.R. McCabe, P. Wipf, Synthesis 51 (2019) 213–224;
(b) D. Jakubczyk, L. Caputi, A. Hatsch, C.A.F. Nielsen, M. Diefenbacher, J. Klein,
A. Molt, H. Schrçder, J.Z. Cheng, M. Nmaesby, S.E. O‘Connor, Angew. Chem. Int.
Ed. 54 (2015) 5117–5121;
(c) D. Stauffacher, P. Niklaus, H. Tscherter, H.P. Weber, A. Hofmann,
Tetrahedron 25 (1969) 5879–5887.
[2] J. Pedroni, N. Cramer, J. Am. Chem. Soc. 139 (2017) 12398–12401.
[3] J.W. Epstein, H.J. Brabander, W.J. Fanshawe, C.M. Hofmann, T.C. McKenzie, S.R.
Safir, A.C. Osterberg, D.B. Cosulich, F.M. Lovell, J. Med. Chem. 24 (1981) 481–
490.
(b) Q.-F. Wu, H. He, W.-B. Liu, S.-L. You, J. Am. Chem. Soc. 132 (2010) 11418–
11419;
(c) T. Nemoto, Z. Zhao, T. Yokosaka, Y. Suzuki, R. Wu, Y. Hamada, Angew.
Chem. Int. Ed. 52 (2013) 2217–2220.
[15] T. Ito, S. Harada, H. Homma, H. Takenaka, S. Hirose, T. Nemoto, J. Am. Chem.
Soc. 143 (2021) 604–611.
[16] K.L. Smith, C.L. Padgett, W.D. Mackay, J.S. Johnson, J. Am. Chem. Soc. 142
(2020) 6449–6455.
[17] R. Liu, G.N. Winston-McPherson, Z.-Y. Yang, X. Zhou, W. Song, I.A. Guzei, X. Xu,
W. Tang, J. Am. Chem. Soc. 135 (2013) 8201–8204.
[18] K.-B. Wang, R.-Q. Ran, S.-D. Xiu, C.-Y. Li, Org. Lett. 15 (2013) 2374–2377.
[19] (a) T. Akiyama, J. Itoh, K. Yokota, K. Fuchibe, Angew. Chem. Int. Ed. 43 (2004)
1566–1568;
[4] (a) C. Sambiagio, D. Schönbauer, R. Blieck, T. Dao-Huy, G. Pototschnig, P.
Schaaf, T. Wiesinger, M.F. Zia, J. Wencel-Delord, T. Besset, B.U.W. Maes, M.
Schnürch, Chem. Soc. Rev. 47 (2018) 6603–6743;
(b) Y.-J. Liu, H. Xu, W.-J. Kong, M. Shang, H.-X. Dai, J.-Q. Yu, Nature 515 (2014)
389–393;
(c) T. Newhouse, P.S. Baran, Angew. Chem. Int. Ed. 50 (2011) 3362–3374;
(d) X. Xu, Y. Deng, D.N. Yim, P.Y. Zavalij, M.P. Doyle, Chem. Sci. 6 (2015) 2196–
2201;
(b) D. Uraguchi, M. Terada, J. Am. Chem. Soc. 126 (2004) 5356–5357;
(c) D. Parmar, E. Sugiono, S. Raja, M. Rueping, Chem. Rev. 114 (2014) 9047–
9153;
(d) S. Hoffmann, A.M. Seayad, B. List, Angew. Chem. Int. Ed. 44 (2005) 7424–
7427;
(e) G.L. Hamilton, E.J. Kang, M. Mba, F.D. Toste, Science 317 (2007) 496–499;
(f) M.E. Muratore, C.A. Holloway, A.W. Pilling, R.I. Storer, G. Trevitt, D.J. Dixon,
J. Am. Chem. Soc. 131 (2009) 10796–10797.
(e) A. McNally, B. Haffemayer, B.S.L. Collins, M.J. Gaunt, Nature 510 (2014)
129–133;
(f) W.-J. Kong, L.H. Finger, A.M. Messinis, R. Kuniyil, J.C.A. Oliveira, L.
Ackermann, J. Am. Chem. Soc. 141 (2019) 17198–17206.
[5] Z. Yu, A. Mendoza, ACS Catal. 9 (2019) 7870–7875.
[6] H.S.A. Mandour, S. Chanthamath, K. Shibatomi, S. Iwasa, Adv. Synth. Catal. 359
(2017) 1742–1746.
[7] Y. Takekawa, K. Shishido, J. Org. Chem. 66 (2001) 8490–8503.
[8] M.P. Doyle, I.M. Phillips, Tetrahedron Lett. 42 (2001) 3155–3158.
[9] X. Ren, A.L. Chandgude, R. Fasan, ACS Catal. 10 (2020) 2308–2313.
[10] (a) L. Chen, K. Chen, S. Zhu, Chem 4 (2018) 1208–1262;
(b) D. Qian, J. Zhang, Chem. Soc. Rev. 44 (2015) 677–698;
(c) Y. Xia, J. Wang, Chem. Soc. Rev. 46 (2017) 2306–2362;
(d) M. Jia, S. Ma, Angew. Chem. Int. Ed. 55 (2016) 9134–9166.
[20] S. Harada, K. Tanikawa, H. Homma, C. Sakai, T. Ito, T. Nemoto, Chem. Eur. J. 25
(2019) 12058–12062.
[21] (a) M. Zhang, F. Jovic, T. Vickers, B. Dyck, J. Tamiya, J. Grey, J.A. Tran, B.A. Fleck,
R. Pick, A.C. Foster, C. Chen, Bioorg. Med. Chem. Lett. 18 (2008) 3682–3686;
(b) J.W. Epstein, H.J. Brabander, W.J. Fanshawe, C.M. Hofmann, T.C. McKenzie,
S.R. Safir, A.C. Osterberg, D.B. Cosulich, F.M. Lovell, J. Med. Chem. 24 (1981)
481–490;
(c) A. Marrazzo, A. Pappalardo, O. Prezzavento, F. Vittorio, G. Ronsisvalle,
ARKIVOC 5 (2004) 156–169.
5