Construction of Spiro[3-azabicyclo[31.0]hexanes] via 1,3-Dipolar Cycloaddition of 1,2-Diphenylcyclopropenes to Ninhydrin-Derived Azomethine Ylides

SYNTHESIS

0

3

9

-

7

8

1

4

3

7

-

2

1

0

X

Georg Thieme Verlag KG Rüdigerstraße 14, 70469 Stuttgart

2021, 53, A–S

paper

A

en

S. Wang et al.

Paper

Synthesis

Construction of Spiro[3-azabicyclo[3.1.0]hexanes] via 1,3-Dipolar

Cycloaddition of 1,2-Diphenylcyclopropenes to Ninhydrin-Derived

Azomethine Ylides

Siqi Wang^a

O

H

O

OH

n

Alexander S. Filatov^a

Stanislav V. Lozovskiy^a

Stanislav V. Shmakov^b

Olesya V. Khoroshilova^a

Anna G. Larina^a

Stanislav I. Selivanov^a

Vitali M. Boitsov*^b,c

Alexander V. Stepakov*^a,d

N

R¹= R²= H

N

O

H

O

X = NHCH₂CO[NHCH₂CO]_nOH

MeOH–H₂O, AcOH, reflux

R³

OH

O

Ph

R³

Me

N

Ph

O

+

R¹= Me, R²= H

X = OH

R²

H

O

Ph

R²

Ph

N

R¹

X

MeOH, reflux

O

R¹= H, X = OH

Ph

N

H

Ph

O

R³

MeOH–H₂O, reflux

O

Ph

R³

R

¹= Me, R²= H, X = OH

MeOH, rt

Me

N

O

Me

O

Ph

O

N

+

N

MeOH, reflux

^aSaint Petersburg State University, Universitetskaya nab.

7/9, 199034 St. Petersburg, Russian Federation

alstepakov@yandex.ru

O

Me

MeOH, reflux

^bSaint Petersburg Academic University Nanotechnology

Research and Education Centre RAS,

ul. Khlopina 8/3, 194021 St. Petersburg,

Russian Federation

bovitali@yandex.ru

^cPavlov First Saint Petersburg State Medical University,

ul. L’va Tolstogo 6/8, 197022 St. Petersburg,

Russian Federation

^dSaint Petersburg State Institute of Technology,

Moskovskii pr. 26, 190013 St. Petersburg,

Russian Federation

Dedicated to the memory of Dr. Yuri B. Koptelov

VitalCi Mor.reBsopitosnodving Authors

Saint Petersburg Academic University

–

Received: 06.11.2020

Accepted after revision: 18.01.2021

Published online: 18.01.2021

DOI: 10.1055/a-1360-9716; Art ID: ss-2020-t0574-op

The 3-azabicyclo[3.1.0]hexane is an important bicyclic

framework, which is a part of many natural products and

pharmaceuticals with a wide range of biological activity.^1–3

The most remarkable among these compounds are sero-

Abstract The multi-component 1,3-dipolar cycloaddition of ninhy-

drin, -amino acids (or peptides), and cyclopropenes for the synthesis

of spirocyclic heterocycles containing both 3-azabicyclo[3.1.0]hexane

and 2H-indene-1,3-dione motifs has been developed. This method pro-

vides easy access to 3-azabicyclo[3.1.0]hexane-2,2′-indenes with com-

plete stereoselectivity and a high degree of atom economy under mild

reaction conditions. A broad range of cyclopropenes and -amino acids

have been found to be compatible with the present protocol, which of-

fers an opportunity to create a new library of biologically significant

scaffold (3-azabicyclo[3.1.0]hexane). In addition, the сomprehensive

study of mechanism of azomethine ylide formation from ninhydrin and

sarcosine was performed by means of M11 density functional theory

(DFT) calculations. It has been revealed that experimentally observed 1-

methylspiro[aziridine-2,2′-indene]-1′,3′-dione is a kinetically controlled

product of this reaction and appears to act as a 1,3-dipole precursor.

This theoretical study also shed light on the main transformations of

the azomethine ylide derived from ninhydrin and sarcosine such as a

1,3-dipolar cycloaddition to cyclopropene dipolarophiles, a dimeriza-

tion reaction and a (1+5) electrocyclization reaction. The antitumor ac-

tivity of some synthesized compounds against cervical carcinoma

(HeLa) cell line was evaluated in vitro by MTS-assay.

tonin-norepinephrine-dopamine

reuptake

inhibitors

(SNDRI),⁴dopamine D₃receptor antagonists,^5–7inhibitors of

dual leucine zipper kinase (DLK, MAP3K12),^8,9histone

deacetylase inhibitors,^2amonoacylglycerol lipase (MAGL)

inhibitors,¹⁰hepatitis C virus NS3/4A (HCV NS3/4A) prote-

ase inhibitors,¹¹allosteric inhibitors of mutant isocitrate

dehydrogenase type 1 (R132H IDH1),¹²5-HT4 receptor par-

tial agonists,¹³oxytocin receptor (OTR) antagonist,¹⁴inhibi-

tors of 11-hydroxysteroid dehydrogenase type 1 (11-

HSD1),¹⁵and ghrelin receptor antagonists¹⁶(I–VI, Figure 1).

In this context, considerable efforts have been made to de-

velop general and straightforward methods for the prepara-

tion of the 3-azabicyclo[3.1.0]hexane derivatives. Nowa-

days, there is a number of effective synthetic procedures

that provide access to the class of compounds: (a) decompo-

sition of pyrazolines,¹⁷(b) Pd-catalyzed cyclopropanation of

maleimides with N-tosylhydrazones,¹⁸(c) metal-catalyzed

oxidative cyclization of 1,6-enynes,¹⁹(d) Pd-catalyzed stere-

oselective cyclopropanation of allenenes,²⁰(e) Pd-catalyzed

C–H cyclization of trifluoroacetimidoyl chlorides,²¹(f)

Ag₂O-catalyzed oxidative cyclization of an amidinoester,²²

Key words cyclopropenes, -amino acids, peptides, stereoselectivity,

reaction mechanism, DFT calculations, antitumor activity, cervical car-

cinoma (HeLa) cell line

Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany

B

S. Wang et al.

Paper

Synthesis

and (g) Au-catalyzed oxidative cyclopropanation of N-allyl-

ynamide.²³In the past few years, the [3+2] cycloaddition

process involving cyclopropenes and azomethine ylides has

also been a popular method for the synthesis of 3-azabicyclo-

[3.1.0]hexanes.²⁴It is essential to note that azomethine

ylides generated in situ from glycine aldiminoesters can re-

act with cyclopropenes in a highly enantioselecive manner

in the presence of Cu(MeCN)₄BF₄and chiral ligands.^24a,b

However, there is still a continued interest in creating sim-

ple and green methods that give rise to this rigid cyclopro-

pane system.

containing cyclopropane fragment was recently reported by

our research group.^24c–e,26In view of the relevance of use of

3-azabicyclo[3.1.0]hexane derivatives in medicinal chemis-

try, herein we report the study concerning the construction

of new biologically significant 3-azabicyclo[3.1.0]hexane

scaffold (VII, Figure 1) via a three-component approach us-

ing ninhydrin, -amino acids (or simplest peptides), and cy-

clopropenes as substrates. It should be added that we have

been able to isolate and characterize a new intermediate in

the reaction of azomethine ylide formation from ninhydrin

and sarcosine. Accordingly, based on Density Functional

Theory (DFT) calculation data, considerable refinements

have been made to the mechanism of the known reaction.

To probe the feasibility of the strategy, ninhydrin (1),

sarcosine (2), and 1,2,3-triphenylcycloprop-1-ene (3a)

were utilized as starting materials. Preliminary experi-

ments have shown that methanol is the best solvent for the

three-component 1,3-dipolar cycloaddition reaction. Upon

treatment of 3a with 1 and 2a in methanol at reflux for 5

hours, cycloadduct 4a was obtained in 71% yield (Scheme

1). The dimerization product 5 of the initially formed

azomethine ylide was also isolated from the reaction mix-

ture (10% yield). Regrettably, it was impossible to find reac-

tion conditions under which the formation of by-product 5

would be completely suppressed. Next, we turned our at-

tention to the scope and limitations of this reaction. A

broad variety of cyclopropene substrates 3 were examined

under the optimal conditions. The results are summarized

in Scheme 1. The reactions smoothly proceeded with 1,2-

diphenylcyclopropenes bearing different types of R substit-

uents such as aryl, alkyl, alkenyl, alkynyl, alkoxycarbonyl,

alkylamido, and nitrile groups. According to the experi-

mental data, it can be seen that the electronic properties of

the R substituents in cyclopropenes do not significantly af-

fect reactivity. Cyclopropenes 3a–e with electron-neutral

or electron-donating R substituents gave the cycloadducts

4a–e in moderate to good yields while cycloadducts 4f–i

containing electron-withdrawing groups were isolated in

similar yields (Scheme 1). In all cases, the dimer 5 can be

detected and isolated as a by-product in 10−17% yields (the

reaction of ninhydrin with sarcosine has been reported to

yield dispiropiperazine 5 after heating in methanol for 5

h).²⁷All cycloadducts 4 аnd the azomethine ylide dimer 5

were fully characterized by IR, ¹H and ¹³C NMR, and HRMS.

Unfortunately, this reaction is limited to cyclopropenes

containing only phenyl substituents at the double bond,

whereas tetrasubstituted cyclopropenes, trisubstituted cy-

clopropenes bearing alkyl groups at the double bond, and

unsubstituted at the double bond cyclopropenes, have

proved to be nonreactive. For example, when using 3-meth-

NH₂

N

OCF₃

N

H

N

Me

S

N

Me

i-Pr

H

O

F₃C

II, dual leucine zipper kinase inhibitor (ref. 8)

I, treatment of drug addiction (ref. 5)

H

N

O

HN

N

HN OH

H

F

N

H

O

III, antitumor activity (ref. 2a)

N

CF₃

OH

N

O

H

F

IV, treatment of neuroinflammation (ref. 10)

O

N

OH

N

OMe

F

N

H

N

O

N

O

Cl

H

HO

H

N

Me

OMe

V, mutant isocitrate dehydrogenase

VI, treatment of premature ejaculation (ref. 14)

inhibitor (ref. 12)

R¹

O

N

R²

O

Ph

R³

VII

Figure 1 Selected bioactive 3-azabicyclo[3.1.0]hexane derivatives I–VI

and spirocyclic scaffold VII from this study

In recent years, multi-component 1,3-dipolar cycloaddi-

tions involving azomethine ylides derived from -amino ac-

ids and 1,2-dicarbonyl compounds have received a great

deal of attention since this method is a powerful and reli-

able tool that enables to form several bonds in one step as

well as to avoid the isolation аnd purification of intermedi-

ate compounds.²⁵Besides, the main benefit of azomethine

ylide 1,3-dipolar cycloadditions is its concerted nature, re-

sulting in diastereoselective formation of a wide range of

heterocyclic frameworks. The realization of this three-com-

ponent strategy for the synthesis of spirocyclic systems

yl-1,2,3-triphenylcycloprop-1-ene,

2-phenyl-3-methyl-,

and 2,3-dimethylcycloprop-2-enecarboxylates, as well as 3-

methyl-3-phenylcyclopropene and methyl 1-methylcyclo-

prop-2-enecarboxylate, cycloaddition reactions did not

proceed.

C

S. Wang et al.

Paper

Synthesis

C₁₁H₉NO₂, was established by HRMS (ESI). An [M + H]⁺ion

peak at m/z 188.0703 (calcd for C₁₁H₁₀NO₂: 188.0706) was

observed. In the ¹³C NMR spectrum (CDCl₃) of the mixture,

compound 6 has signals at 71.9, 49.1 and 40.6 ppm, which

are readily assigned to С_spiro, СН₂, and СН₃, respectively. For

comparison, the signals of C_spiro, CH₂, and CH₃for azome-

thine ylide dimer 5 are observed at 69.7, 54.2, and 40.2

ppm. The signals of aromatic protons are represented in the

¹H NMR spectra of compounds 5 and 6 by strongly coupled

spin systems AA′BB′-type; however, for the former com-

pound, they are located in a lower field range (7.86–8.02

ppm) compared to the signals of the second compound

(7.68–7.80 ppm), which fully corresponds to their structur-

al differences [Figure S23 in the Supporting Information

(SI)]. In addition, the spectral differences of compounds 5

Me

N

O

Ph

OH

Me

OH

Ph

N

H

R

4a–i

O

+

O

MeOH

reflux

1

2

+

R

Me

O

N

O

Ph

3a–i

N

O

Me

5 (10–17%)

Me

O

N

Ph

O

Ph

O

1

Ph

Et

Ph

and 6 are manifested in the values of scalar constants J_C,H

1

4b (62%)

4c (59%)

4a (71%)

for CH₂groups. The registration of J_C,Hvalues was carried

out using HSQC method without ¹³C-decoupling, which al-

lowed us to separate the satellite pairs of C¹³H₂proton sig-

nals according to the chemical shifts of carbon atoms for

Me

O

N

Ph

O

Ph

O

Ph

1

Ph

compounds 5 and 6. In the usual H NMR spectrum of a

CO₂Me

4f (51%)

4d (67%)

4e (68%)

mixture of compounds 5 and 6, the proton signals of all CH₂

groups are at 3.42 ppm and form a common broadened sig-

nal, the analysis of the structure and multiplicity of which

is impossible. In contrast, the HSQCnd (nd–no ¹³C-decou-

pling) spectrum shows that all CH₂signals of the compound

5 have the same chemical shifts and the same values of con-

stants ¹J_C,H, which are equal to 142 Hz (Figure S24 in the SI).

The chemical and magnetic equivalence of these protons

indicates a high degree of symmetry of compound 5. At the

same time, it is clearly seen that for compound 6 the pro-

tons of the CH₂group are chemically and magnetically non-

equivalent, which manifests itself as AB-type doublet-dou-

blet structures of the C¹³H₂satellite pair in the HSQCnd

spectrum and two different values of heteronuclear scalar

Ph

Me

O

N

Ph

O

Ph

O

Ph

CONMe₂

4h (63%)

CN

CONHi-Pr

4i (61%)

4g (61%)

Scheme 1 One-pot three-component reactions of ninhydrin (1),

sarcosine (2), and cyclopropenes 3a–i. Reagents and conditions: Unless

otherwise indicated, the reactions were carried out with 1 (0.4 mmol),

2 (0.6 mmol), and 3 (0.4 mmol) in MeOH at reflux for 5 h. All products

are racemic and isolated yields are shown.

Previously, we described the cycloaddition reaction of

the stable azomethine ylide from ninhydrin and L-proline

with cyclopropenes.²⁶In this study, we attempted to obtain

a stable azomethine ylide from ninhydrin and sarcosine. For

that purpose, equimolar quantities of ninhydrin (1) and sar-

cosine (2) were stirred in methanol at room temperature

for 72 hours. The initially formed dark purple solution

changed color to brown over time, and a light brown solid

was precipitated. The solid was filtered and washed with

cold methanol. The isolated product was investigated by

NMR spectroscopy (¹H and ¹³C). It was found that it is a

mixture of two compounds in 4:1 ratio. In this case, the mi-

nor component is dispiropiperazine 5 (Scheme 2). There

was no way to separate the components of the mixture

chromatographically on SiO₂, since decomposition of the

main component occurred. When neutral or basic alumina

and Florisil were used as a stationary phase only adduct 5

was isolated, though it was contaminated with some un-

identified decomposition by-products. Attempts to sepa-

rate the mixture by crystallization were also unsuccessful.

Consequently, the major component was characterized in

the mixture with compound 5. Its molecular formula,

1

constants protons H′ and H′′: J_C,H′= 142 Hz, ¹J_C,H′′= 137 Hz.

Thus, based on the analysis of spectral data, the structure of

1-methylspiro[aziridine-2,2′-indene]-1′,3′-dione (6) was

assigned to the major component. The aziridine structure is

in good accordance with NMR spectral data since the chem-

ical and magnetic inequivalence of the protons of the CH₂

group result from the high energy barrier for nitrogen in-

version. Kuznetsov and co-workers previously described

spirocyclic compounds with a similar skeleton.²⁸

O

Me

+

O

OH

MeOH

72 h, rt

Me

OH

N

+

5

N

H

O

6

1

2

Scheme 2 The reaction of ninhydrin (1) and sarcosine (2) under mild

conditions

As noted above, aziridine 6 could not be isolated in pure

form, therefore it was used in subsequent transformations

as a mixture (4:1) with dispiropiperazine 5. The presence of

D

S. Wang et al.

Paper

Synthesis

compound 5 in the starting mixture does not influence the

reactions involving aziridine 6. In order to evaluate the abil-

ity of aziridine 6 to undergo ring-opening reaction resulting

in the formation of 1,3-dipole, cyclopropene dipolarophile

3a was selected as an azomethine ylide trap. Substrates 6

and 3a did not react at room temperature in methanol,

however, heating of the reaction mixture to the boiling

point temperature of the reaction solvent led to the forma-

tion of 4a in 74% yield. The progress of the reaction was

monitored by ¹H NMR and TLC. Analysis of the reaction

mixture showed the gradual disappearance of aziridine 6

signals and the appearance of cycloadduct 4a signals. Next,

we explored the scope of the reaction with a range of cyclo-

propenes 3c,f,h,i as cycloaddition partners. A series of func-

tional groups at the C3-position of cyclopropenes such as

phenyl, vinyl, methoxycarbonyl, dimethylamido, and nitrile,

were tolerated under the optimal reaction conditions, and

the desired spiro[3-azabicyclo[3.1.0]hexanes] 4c,f,h,i were

ther corroborated by single-crystal X-ray diffraction (Figure

2). In a similar way, the azomethine ylides [generated from

ninhydrin (1) and L-phenylalanine (7e), L-tyrosine (7f), 3,5-

diiodo-L-tyrosine (7g), L-methionine (7h), or DL-phenylgly-

cine (7i)] reacted with 3a to afford the racemic spiro[3-aza-

bicyclo[3.1.0]hexanes] 8e–i as single diastereomers in 57–

79% yields. Additionally, L-glutamic acid (7j) has proved to

be a suitable reactant, which in combination with ninhy-

drin (1) gave a 1,3-dipole. The latter was successfully

trapped by 1,2,3-triphenylcycloprop-1-ene (3a) to furnish

cycloadduct 8j in 62% yield. Also, we examined the scope

with respect to the cyclopropenes 3 in the reaction with

azomethine ylide derived from ninhydrin (1) and L-leucine

(7a) (Scheme 4). Three cyclopropene derivatives 3d,e,g pro-

vided the corresponding products 8k–m in good yields

with excellent diastereoselectivities. Additionally, the ¹H

NMR spectrum of the cycloadduct 8l was recorded in the

presence of a chiral shift reagent – praseodymium(III)

tris[3-(heptafluoropropylhydroxymethylene)-D-camphor-

ate] (Figure S50 in the SI). In accordance with the NMR

spectrum, peak shape of the H-C4 methine proton at 3.9

ppm indicates that compound 8l is a racemate. Unfortu-

nately, all attempts to carry out three-component reactions

involving glycine, L-alanine, L-serine, L-cysteine, L-histidine,

or L-tryptophan failed.

1

obtained in good yields (Scheme 3). The H NMR conver-

sions for the starting aziridine 6 varied between 90 and

96%. We also found that when heating 6 in boiling metha-

nol for 3 hours, it almost completely turned into dispiropip-

erazine 5 (Scheme 3). The reaction mechanism including

the stage of aziridine 6 transformation was studied by a

DFT computational method (vide infra).

O

R

R¹

OH

Me

R¹

Ph

H

O

Me

N

O

OH

Ph

3a,c,f,h,i

Ph

N

OH

H₂N

N

MeOH–H₂O (3:1)

reflux

O

+

MeOH, reflux

1

O

7a–j

Ph

O

Ph

6

Ph

R²

R

MeOH

reflux

8

4a, R = Ph (74%)

4c, R = vinyl (70%)

4f, R = CO₂Me (63%)

4h, R = CONMe₂(66%)

4i, R = CN (68%)

Ph

3a,d,e,g

Ph

Me

O

N

O

R³

R⁴

H

R¹

H

O

N

Me

Ph

N

5 (91%)

O

Me

Ph

O

Scheme 3 The ring opening reactions of aziridine 6 in the presence of

cyclopropenes 3a,c,f,h,i. All products are racemic and isolated yields

are shown.

R³

Ph

8e, R³= R⁴= H (79%)

8b, R¹= n-Pr (71%)

8c, R¹= n-Bu (81%)

8d, R¹= n-Hex (72%)

8a (74%)

8f, R³= H, R⁴= OH (62%)

8g, R³= I, R⁴= OH (57%)

O

H

O

Next, we focused on exploring the substrate scope with

respect to amino acids. We investigated three-component

reactions involving some primary -amino acids 7a–j, cy-

clopropenes 3a,d,e,g, and ninhydrin (1). The reactions

smoothly proceeded in methanol–water on heating, giving

spiro[3-azabicyclo[3.1.0]hexane-2,2′-indene]-1′,3′-diones 8

in acceptable yields with excellent diastereoselectivity

(Scheme 4). Initially, the reaction of azomethine ylide in

situ generated from ninhydrin (1) and alkyl-substituted -

amino acids 7a–d with cyclopropene 3a in methanol–water

(3:1) at reflux led to the formation of racemic spirocyclic

derivatives 8a–d in 71–81% yields. In all cases, cyclopro-

penes were not completely consumed during the reactions.

The structures of products 8a–d were identified by means

of ¹H and ¹³C NMR, and HRMS. The structure of 8a was fur-

H

O

S

Ph

H

O

N

Me

N

OH

Me

Ph

O

Ph

O

Ph

O

Ph

8h (73%)

8i (70%)

8j (62%)

H

O

H

Me

H

O

Me

Ph

N

Me

Ph

O

Ph

CONHiPr

8k (69%)

8l (76%)

8m (64%)

Scheme 4 One-pot three-component synthesis of 3-azabicyclo[3.1.0]-

hexane derivatives 8a–m. Reagents and conditions: Unless otherwise in-

dicated, reactions were carried out with 1 (0.4 mmol), 3 (0.4 mmol),

and 7 (0.8 mmol) in MeOH–H₂O (3:1) at reflux for 10 h. All products are

racemic and isolated yields are shown.

E

S. Wang et al.

Paper

Synthesis

with a peptide fragment were conducted using Gly-Gly

(10a) or Gly-Gly-Gly (10b) and cyclopropenes 3a,j (Scheme

6). Reactions of the azomethine ylides generated from nin-

hydrin (1) and peptides 10a,b with dipolarophiles 3a,j gave

products 11a–d in 42–63% yields (in all reactions incom-

plete conversion of cyclopropene substrate was observed).

All 1,3-dipolar cycloadditions involving nitrogen ylides de-

rived from peptides 10 were found to be highly diasteo-

selective. The compounds 11 were isolated as a single dia-

stereomer.

As discussed above, the reaction between sarcosine (2)

and ninhydrin (1) in MeOH at room temperature results in

the formation of a previously unknown spiroaziridine 6

(Scheme 7). Currently, spiroaziridine 6 is not mentioned in

any studies on 1,3-dipolar cycloaddition reactions involving

the azomethine ylide 12 generated from ninhydrin (1) and

sarcosine (2). There are only a few hypotheses regarding the

mechanism of azomethine ylide 12 formation from ninhy-

drin (1) and sarcosine (2). It is believed that the condensa-

tion reaction of 1 with 2 (MeOH, reflux) initially leads to

the formation of spirolactone 14, which subsequently loses

carbon dioxide as a result of retro-1,3-dipolar cycloaddition

to generate the 1,3-dipole 12.²⁹

In turn, the resulting azomethine ylide 12 can be not

isolated since it immediately undergoes either the 1,5-elec-

trocyclization or dimerization reaction.^27,29,30Several stud-

ies have been published concerning subsequent transfor-

mations of azomethine ylide 12. More than 30 years ago,

Grigg and co-workers have reported that the in situ gener-

ated 1,3-dipole 12 is prone to the 1,5-electrocyclization re-

Figure 2 ORTEP representation of the molecular structure of 8a

Since new derivatives of 3-azabicyclo[3.1.0]hexane-6-

carboxylic acid may be of interest for biomedical research,¹²

we tried to synthesize compounds containing this structur-

al fragment by carrying out one-pot three-component 1,3-

dipolar cycloaddition reactions of 2,3-diphenylcycloprop-

2-enecarboxylic acid (3j) with azomethine ylides generated

from ninhydrin (1) and several primary -amino acids 7. As

depicted in Scheme 5, when amino acids 7a,c,d were ap-

plied as reactants under standard conditions, racemic 4-al-

kyl-3-azabicyclo[3.1.0]hexane-6-carboxylic acids 9a–c

were obtained in 42–68% yields. In the same way, DL-

phenylglycine (7i) worked well, thus leading to 9d in 61%

yield. The 1,3-dipolar cycloaddition of azomethine ylide

generated from ninhydrin (1) and L-phenylalanine (7e) to

cyclopropene 3j afforded the corresponding compound 9e

in moderate yield (39%). When the reaction of azomethine

ylide derived from ninhydrin (1) and L-valine (7k) with cy-

clopropene 3j was carried out under standard conditions,

product 9f was obtained in modest yield (22%). This can be

caused by a diminished reactivity of such azomethine ylide

toward 1,3-dipolar cycloaddition due to the presence of a

bulky isopropyl group located near the reaction center of

the 1,3-dipole. The structures of the resultant cycloadducts

were established by considering their ¹H and ¹³C NMR spec-

tra. To the best of our knowledge, these reactions are the

first examples of a one-stage preparation of 3-azabicyclo-

[3.1.0]hexane-6-carboxylic acids via the 1,3-dipolar cyclo-

addition reaction.

O

R¹

OH

R¹

H

O

OH

N

OH

H₂N

MeOH–H₂O (3:1)

reflux

O

+

Ph

O

7a,c,d,e,i,k

1

Ph

CO₂H

9

Ph

3j

H

O

H

O

Me

Ph

CO₂H

N

Me

N

Ph

O

Ph

CO₂H

9c (42%)

O

Ph

Me

CO₂H

9a (68%)

9b (51%)

Me

H

O

H

O

H

O

Ph

N

Ph

Me

Ph

CO₂H

O

Ph

O

Ph

CO₂H

In previous studies, we reported the 1,3-dipolar cyclo-

addition of azomethine ylides derived from isatins, 11H-in-

deno[1,2-b]quinoxalin-11-one or tryptanthrins, and sim-

plest peptides with cyclopropene dipolarophiles.^24c–eIn that

work, under the optimized conditions for [3+2] cycloaddi-

tion reactions [AcOH (10 equiv), MeOH–H₂O (3:1), reflux],

the synthesis of four 3-azabicyclo[3.1.0]hexane derivatives

CO₂H

9d (61%)

9f (22%)

9e (39%)

Scheme 5 One-pot three-component synthesis of 3-azabicyclo[3.1.0]-

hexane-6-carboxylic acids 9a–f. Reagents and conditions: Unless other-

wise noted, all reactions were carried out with 1 (0.4 mmol), 3j (0.4

mmol), and 7 (0.8 mmol) in 15 mL MeOH–H₂O (3:1) at reflux for 10 h.

All products are racemic and isolated yields are shown.

F

S. Wang et al.

Paper

Synthesis

O

OH

O

H₂N

OH

N

O H

OH

n

AcOH

MeOH–H₂O (3:1)

H

N

O

n

H

O

+

O

1

10a,b

reflux

O

Ph

R

11

Ph

3a,j

O

H

N

H

OH

O

H

O

OH

N

H

O

Ph

O

Ph

11a (42%)

11b (54%)

O

H

N

H

OH

H

O

OH

N

H

O

Ph

CO₂H

11c (63%)

Ph

CO₂H

11d (50%)

O

Ph

Scheme 6 One-pot three-component synthesis of 3-azabicyclo[3.1.0]hexanes 11a–d with peptide fragments. Reagents and conditions: 1 (0.4 mmol),

3 (0.4 mmol), 10 (0.6 mmol), AcOH (50 L) in 20 mL MeOH–H₂O (3:1) at reflux for 8 h. All products are racemic and isolated yields are shown.

X-ray crystal structure analysis, and a comprehensive de-

O

MeOH

reflux

scription of the crystal structure was presented in that

study. To date, however, no theoretical studies concerning

the condensation reaction of ninhydrin (1) and sarcosine

(2) and subsequent transformations of the resulting 1,3-di-

pole 12 have been presented. Accordingly, there are no data,

which make it possible for researchers to rationalize the ex-

perimental results in this field of organic chemistry.

N

CO₂

2 H₂O

Me

O

Me

O

OH

12

N

H

OH

Me

2

1

N

MeOH

RT

CO₂

2 H₂O

O

6

In this paper, we have experimentally established that

spiroaziridine 6 is a stable compound at room temperature

and acts as a precursor of azomethine ylide 12. As shown

above, heating of the aziridine 6 in methanol in the pres-

ence of cyclopropenes 3 results in the formation of classic

[3+2] cycloadducts – spiro-3-azabicyclo[3.1.0]hexanes 4,

while thermal aziridine transformation in the absence of

dipolarophiles leads to azomethine ylide dimer 5. This sug-

gests that aziridine 6 undergoes a thermal ring-opening re-

action to give the in situ generated nitrogen ylide 12 which,

in turn, could be involved in intermolecular [3+2] and [3+3]

cycloadditions. In this way, we thought it necessary to per-

form a theoretical study regarding the mechanism of the

ninhydrin-derived azomethine ylide 12 formation as well

as to shed light on azomethine ylide 12 transformations

such as the 1,5-electrocyclization reaction, the [3+2] cyclo-

addition to cyclopropenes, and the [3+3] cycloaddition (the

dimerization reaction). It is also important to determine

whether spiroaziridine 6 is a kinetically controlled product

of the condensation reaction between ninhydrin (1) and

sarcosine (2).

Scheme 7 The condensation reaction between ninhydrin (1) and sar-

cosine (2) resulting in the formation of azomethine ylide 12 and aziri-

dine 6

action to give 3-methyl-2,3-dihydro-4H-indeno[2,1-d]ox-

azol-4-one (15) (vide infra) in the absence of dipolaro-

philes.²⁹In 2008, during the study of 1,3-dipolar

cycloaddition reactions involving this ninhydrin-derived

azomethine ylide 12, Bandyopadhyay’s research group pro-

vided results, which were contrary to Grigg’s findings.²⁷In

this study, the ylide 12 generated from 1 and 2 (MeOH, re-

flux, 5 h) was also found to be unstable. Its subsequent con-

version is accompanied by the formation of dispiro[indene-

2,2′-piperazine-5′,2′′-indene] derivative 5 resulting from

the dimerization reaction. The structure of dimerization

product was identified on the basis NMR spectroscopy and

mass spectral analysis. Additionally, the condensation reac-

tion of ninhydrin (1) and sacrosine (2) was considered by

Sudha’s research team.³⁰Dispiropiperazine 5 was obtained

as a result of the solvent-free microwave-assisted BiCl₃-cat-

alyzed condensation reaction between 1 and 2. Eventually,

the structure of dimer 5 was unequivocally corroborated by

Calculations at DFT/HF level of theory using M11 hybrid

exchange-correlation functional and cc-pVDZ basis set were

carried out to optimize the geometry of reactants,

G

S. Wang et al.

Paper

Synthesis

products, and transition state structures (TSs). At the begin-

ning of the theoretical study, the calculation of the Gibbs

free energy change for the reaction of azomethine ylide 12

formation from sarcosine (2) and ninhydrin (1) was per-

formed (Scheme 7, Table 1). Products of this reaction along

with azomethine ylide 12 are two molecules of water and

carbon dioxide. This transformation has proved to be an ex-

ergonic process occurring with a decrease in the Gibbs free

energy (ΔG = –16.1 kcal/mol) (Table 1, entry 1).

(PES). The mechanism of aziridine 6 formation from zwitte-

rion compound 13 could be suggested as an alternative. In

this case, there should also be the transition state structure

in which the C–C=O bond is broken and the C–C bond is

formed, that is, 3-endo-trig cyclization occurs. However,

such transformation is prohibited by Baldwin's rules. Thus,

aziridine 6 is more likely to be formed from spirolactone 14.

O

OH

Me

N

O

OH

Me

TS-lactone

Table 1 The Reaction Mechanism of Azomethine Ylide 12 Formation

from Ninhydrin (1) and Sarcosine (2)^a

N

O

1

O

– 2 H₂O

O

14

13

Me

O

ΔG^‡, kcal/mol

ΔG, kcal/mol

N

Entry

Reaction

Transition

– CO₂

H

OH

2

O

1

2

3

4

5

6

7

1 + 2 → 12

1 + 2 → 6

13 → 14

14 → 6

1 + 2 → 12

1 + 2 → 6

13 → TS-lactone

13 → 14

–

–16.1

–11.3

–

Me

TS-ylide

N

Me

1.6

–

O

12

6

–16.2

–9.9

–

Scheme 8 The proposed mechanism for azomethine ylide 12 genera-

tion from sarcosine (2) and ninhydrin (1)

14 → 6

–

6 → 12

6 → TS-ylide

6 → 12

29.6

–

6 → 12

–4.8

Then, we examined the experimentally observed trans-

formation of 6 into 12 (Scheme 8, Table 1). Having found

the transition state TS-ylide corresponding to the ring-

opening reaction of an aziridine cycle, we calculated the

Gibbs energy of activation (ΔG^‡) for this transformation and

obtained a value equal to 29.6 kcal/mol (Table 1, entry 6).

Generally, the thermodynamically favorable reactions with

the value of Gibbs energy of activation ca. 30 kcal/mol or

higher are kinetically inhibited at room temperature. Aziri-

dine 6 is a stable compound at room temperature and does

not convert to azomethine ylide 12. In this context, the val-

ue of Gibbs energy of activation for the transformation is

completely compatible with the experimental data and ex-

plains why aziridine 6 does not transform into ylide 12 at

room temperature. However, it is possible to overcome the

energy barrier at elevated temperatures, and the conversion

of aziridine 6 into a more stable azomethine ylide 12 is get-

ting kinetically favorable (entries 6, 7; Figure S74 in the SI).

Next, we concentrated on studying the main transfor-

mations of azomethine ylide 12 (Scheme 9, Table 2). The

1,5-electrocyclization reaction leading to oxazole 15, di-

merization of azomethine ylide 12, and [3+2] cycloaddition

reaction to 1,2,3-triphenylcycloprop-1-ene (3a) were thor-

oughly examined. Based on the calculated data, there is evi-

dence that the 1,5-electrocyclization of azomethine ylide

12 to oxazole derivative 15 is an endergonic reaction be-

cause the free energy change for this transformation is ca.

16.7 kcal/mol (ΔG >0) (Table 2, entries 1, 2; Figure S74 in

the SI). Then, we studied the experimentally confirmed

[3+3] cycloaddition reaction involving two azomethine

ylide molecules. When analyzing the potential energy sur-

face (PES), the dimerization reaction of azomethine ylide 12

is found to proceed by a two-step mechanism (Scheme 9,

^aRelative free energy change between reactants and transition states (free

energies of activation ΔG^‡) and relative free energy change between reac-

tants and products (ΔG) are given in kcal/mol.

We also calculated the change in the Gibbs free energy

for the reaction in which the final product is aziridine 6

rather than azomethine ylide 12. This reaction is also a

thermodynamically favorable process (ΔG = –11.3 kcal/mol)

(Table 1, entry 2). However, azomethine ylide 12 is ca. 4.8

kcal/mol more thermodynamically stable than aziridine 6

(entries 1, 2). This means that the transformation of aziri-

dine 6 into azomethine ylide 12 should be a spontaneous

reaction. Next, we focused on studying the mechanism of

azomethine ylide 12 formation.

The first intermediate formed by the reaction of 1 with

2 is a zwitterion compound 13 (Scheme 8). The latter

smoothly converts into spirolactone 14 as a result of the

1,5-electrocyclization reaction via TS-lactone. The Gibbs

energy of activation (ΔG^‡) for this transformation is ca. 1.6

kcal/mol (Table 1, entries 3, 4; Figure S74 in the SI). Then

the direct transformation of spirolactone 14 into aziridine 6

appears to οccur (Scheme 8). This reaction is thermody-

namically favorable, since the Gibbs free energy change for

this transformation is –10 kcal/mol (entry 5). Unfortunate-

ly, we have been unable to find the transition state corre-

sponding to the direct conversion of spirolactone 14 into

spiroaziridine 6. It is expected that the aziridine cycle is

formed through the transition state in which the cyclorev-

ersion of carbon dioxide and 1,3-electrocyclization take

place simultaneously. This transition state is consistent

with the general principles of organic chemistry and can

probably be found in analyzing the potential energy surface

H

S. Wang et al.

Paper

Synthesis

O

TS-oxazole

(12 15)

N

Me

O

15

12

Path I: 1,5-Electrocyclization

Me

O

Me

N

O

N

TS-2-[3+3]

(16 5)

TS-1-[3+3]

(12

16)

12

N

O

Me

16

O

Me

5

Path II: Unconcerted [3+3] cycloaddition (dimerization)

O

Me

O

Me

N

TS-4'-endo or TS-4'-exo

(16 4a')

N

TS-4-endo or TS-4-exo

(16 4a)

12 + 3a

Ph

O

Ph

4a

4a' (not formed)

Path III: Concerted [3+2] cycloaddition to cyclopropenes

Scheme 9 The main transformations of azomethine ylide 12 derived from sarcosine (2) and ninhydrin (1)

Table 2 Theoretical Investigation of the Main Azomethine Ylide 16

Transformations: 1,5-Electrocyclization, Dimerization reaction, and

[3+2] Cycloaddition^a

entries 3–7). The first step of [3+3]-cycloaddition reaction

is rate-determining (ΔG^‡= 15.1 kcal/mol) (entry 3). The

Gibbs energy of activation (ΔG^‡) for first step is satisfactory

in order to allow reaction to be kinetically favorable at 60

°C. The value of Gibbs free energy of activation for the sec-

ond stage is 7 kcal/mol (entry 5). Betaine 16 is energetically

less stable than starting two azomethine ylide molecules

(entry 4). So that means that intermediate 16 cannot be iso-

lated in pure form due to its spontaneous conversion into

the corresponding dispiropiperazine 5 (entry 6; Figure S74

in the SI).

Finally, the [3+2] cycloaddition reaction of azomethine

ylide 12 to cyclopropenes 3 was investigated. To study ki-

netics and thermodynamics of this process, we considered

the reaction with one of the most active cyclopropenes –

1,2,3-triphenylcyclopropene (3a) (Table 2; Figure S75in the

SI). Theoretically, in case of a concerted mechanism, the

[3+2] cycloaddition reaction may proceed through four

transition states. Full geometry optimization of the four

possible transition states TS-4a-endo, TS-4a-exo, TS-4a′-

endo and TS-4a′-exo for the reaction between 1,2,3-triph-

enylcycloprop-1-ene (3a) and azomethine ylide 12 was

successfully carried out using M11/cc-pVDZ (Table 2, en-

tries 8–13; Figure S75 in the SI). Two of these transition

states TS-4a-endo and TS-4a-exo give rise to the diastereo-

mer 4a with three cis-located phenyl groups, while TS-4a′-

endo and TS-4a′-exo correspond to the diastereomer 4a′,

which has the opposite configuration of the asymmetric C3

carbon atom. Each of the diastereomers 4a and 4a′ is a mix-

ture of two invertomers.

Entry Reaction

Transition

ΔG^‡, kcal/mol ΔG, kcal/mol

1,5-Electrocyclization

1

2

12 → 15

12 → TS-oxazole

12 → 15

22.4

–

16.7

Dimerization reaction ([3+3] cycloaddition)

3

4

5

6

7

12 → 16

16 → 5

12 → 5

12 → TS-1-[3+3]

12 → 16

15.1

–

10.0

–

16 → TS-2-[3+3]

16 → 5

7.0

–

–28.5

–18.5

12 → 5

–

[3+2] Cycloaddition reaction

8

9

12 + 3a → 4a

12 → TS-4a-endo

12 → TS-4a-exo

14.0

15.5

19.9

25.7

–

10

11

12

13

12 + 3a → 4a′ 12 → TS-4a′-endo

12 + 3a → 4a′ 12 → TS-4a′-exo

–

12 + 3a → 4a

12 → 4a

–31.8^b

–30.3^b

12 + 3a → 4a′ 12 → 4a′

–

^aRelative free energy change between reactants and transition states (free

energies of activation ΔG^‡) and relative free energy change between reac-

tants and products (ΔG) are given in kcal/mol.

^bTo calculate the change in Gibbs energy for the transformation 12 + 3a →

4a and 12 + 3a → 4a′, the energies of more stable invertomers are used.

However, there is no point to consider them separately

because pyramidal inversion for 3-azabicyclo[3.1.0]hexane

derivatives is very rapid at room temperature. According to

values of Gibbs energy of activation (ΔG^‡), the endo and exo

approaches leading to diastereomer 4a are more favorable

than the endo and exo ones corresponding to opposite dias-

tereomer 4a′ (Table 2, entries 8–11; Figure S75 in the SI).

TS-4a-endo and TS-4a-exo are more energetically stable

than their corresponding TS-4a′-endo and TS-4a′-exo (ca.

5.9 kcal/mol and 10.2 kcal/mol, respectively). This explains

I

S. Wang et al.

Paper

Synthesis

complete diastereofacial stereoselectivity of 1,3-dipolar

cycloaddition reaction between azomethine ylide 12 and

1,2,3-triphenylcycloprop-1-ene (3a). Additionally, [3+2]

cycloaddition of ylide 12 to 3a (ΔG^‡= 14.0 kcal/mol) is more

characterized by a high free energy of activation (ΔG^‡= 29.6

kcal/mol). This fact accounts for aziridine stability at low

temperatures. In turn, the values of free energy of activa-

tion for reactions involving azomethine ylide 12 – [3+2] cy-

cloaddition (~14 kcal/mol) and [3+3] cycloaddition (~15.1

kcal/mol) indicate that 1,3-dipolar cycloaddition to cyclo-

propenes 3 has priority over the dimerization reaction.

We also theoretically investigated the reaction involving

azomethine ylide 19 [generated from L-leucine (7a) and

ninhydrin (1)] and 1,2-diphenylcyclopropene (3e) to eluci-

date stereoselectivity of this 1,3-dipolar cycloaddition reac-

tion (Scheme 10). The azomethine ylide 19 generation is

believed to proceed through intermediate formation of

imine 17 and spirolactone 18. To evaluate the Gibbs energy

of activation (ΔG^‡) of endo and exo approaches, the full ge-

ometry optimization of the two possible transition states

TS-8l-endo and TS-8l-exo was carried out. Having obtained

both optimized geometries, it has been revealed that endo

cycloaddition is kinetically more favorable than exo one.

This calculation data is in full agreement with experimental

results. Simultaneously, the endo cycloadduct 8l is also a

thermodynamically controlled product of this reaction (Ta-

ble S2 in the SI). Apparently, TS-8l-endo prevailed over TS-

8l-exo due to favorable N_ylide–H_cyclopropenesecondary orbital

interactions [the distance in TS-8l-endo between ylide ni-

trogen atom and endo cyclopropene hydrogen atom is ca.

2.40 Å that is considerably shorter than the N–H van der

Waals radius (rw = 2.65 Å)].²⁶

kinetically preferable than dimerization reaction (ΔG^‡

=

15.5 kcal/mol) that is in good accordance with experimen-

tal results. Azomethine ylide 12 is actually more prone to

react with cyclopropene dipolarophiles than to undergo a

dimerization reaction.

Thus, we have revised the mechanism of azomethine

ylide 12 formation. Moreover, the main transformations of

azomethine ylide 12 have been discussed. The azomethine

ylide 12 formation appears to proceed via intermediate for-

mation of spirolactone 14 and spiroaziridine 6. There are

only two main transformations that are characteristic for

azomethine ylide 12 – [3+2] cycloaddition reaction and the

dimerization reaction. If the 1,2-diphenylcyclopropene de-

rivative 3 acts as a dipolarophile, [3+2] cycloaddition is

more kinetically favorable than dimerization reaction.

During our theoretical study, the mechanism of azome-

thine ylide formation from sarcosine (2) and ninhydrin (1)

was studied in detail. It was disclosed that one of the inter-

mediates that is formed during azomethine ylide 12 forma-

tion is spiro[aziridine-2,2′-indene]-1′,3′-dione (spiroaziri-

dine) 6, which was characterized by spectral methods for

the first time. The resulting aziridine 6 is a stable precursor

of azomethine ylide 12. On heating 6 undergoes a ring-

opening reaction to give 1,3-dipole 12, which can be readily

trapped with cyclopropene dipolarophiles 3 to form the

corresponding [3+2] cycloadducts 4. Conversely, aziridine 6

transformation in heating methanol in the absence of dipo-

larophiles results in the formation of dispiropiperazine 5,

which is a dimerization product of azomethine ylide 12.

Spiroaziridine 6 is less thermodynamically stable than 1,3-

dipole 12, and the conversion of 6 to azomethine ylide 12 is

In the same way, azomethine ylides derived from ninhy-

drin (1) and peptides 10a,b cycloadd to cyclopropenes 3a,j

with complete endo selectivity with the approach of 1,3-di-

pole from a less-hindered face of cyclopropenes to give cyc-

loadducts 11. It is worth mentioning that azomethine ylide

21 appears to be formed from intermediate imine 20 as a

result of thermal 1,2-prototropy (Scheme 11).

R¹

O

H

O

H₂N

CO₂H

N

R¹

O

OH 7a, R¹= i-Bu

O

OH

O

– H₂O

HO

18

– CO₂

R¹

O

1

17

H

N

R¹

H

N

R¹

Ph

H

N

O

3a

ΔG^‡= 17.3 kcal/mol

3a

O

ΔG^‡= 12.2 kcal/mol

H

O

Ph

H

19

Ph

TS-8l-endo

H

TS-8l-exo

Me

H

O

Me

H

O

N

Ph

O

Ph

rac-8l' (not formed)

rac-8l (experimentally observed)

Scheme 10 The proposed reaction mechanism for the reaction of ninhydrin (1), L-leuicne (7a), and 1,2-diphenylcyclopropene (3e)

J

S. Wang et al.

Paper

Synthesis

O

H

N

H₂N

N

O

CO₂H

O

H

N

1,2-prototropy

N

O

10a

H

HN

OH

1

O

– H₂O

20

21

OH

3a

O

H

NH

OH

O

N

O

H

O

N

H

O

OH

Ph

O

Ph

TS-11a-endo

Ph

rac-11a

Scheme 11 The proposed reaction mechanism for the reaction of ninhydrin (1), Gly-Gly (10a), and 1,2,3-triphenylcycloprop-1-ene (3a)

The cytotoxic activity of some of the newly synthesized

compounds against human cervical carcinoma (HeLa) cell

line was evaluated in vitro by the standard MTS assay for 24

and 72 hours. The results of these investigations are pre-

sented in Figures 3 and 4. It was found that among these

compounds with spiro-fused 3-azabicyclo[3.1.0]hexane

and 2H-indene-1,3-dione moieties only 8f, which has 4-hy-

droxybenzyl substituent at pyrrolidine ring, demonstrates

significant activity: IC₅₀24.5 ± 2.4 g/mL (44.7 ± 4.6 M) for

24 hours (Figure 3) and 9.6 ± 1.4 g/mL (17.5 ± 2.7 M) for

72 hours (Figure 4). The observed decrease in cell viability

under the action of substances 8a and 8h is explained by a

decrease in the cell number after the treatment for 72 hours

Figure 4 Cytotoxicity of compounds 8a, 8e–i and 11a,b against the

compared to the control (cells slowed down their division

compared to the control, but remain alive). It was found

that compound 8f demonstrates less cytotoxic activity

against benign cell line (Vero): IC₅₀56.9 ± 1.7 g/mL for 24

hours and 23.6 ± 1.6 g/mL for 72 hours. These results indi-

cated that spiro[3-azabicyclo[3.1.0]hexanes] with 2H-in-

dene-1,3-dione motif may be useful leads for further bio-

logical screenings. Evaluation of their biological activities

against other cell lines is in progress currently.

cervical carcinoma (HeLa) cell line (72 h)

In summary, we have developed an efficient method for

the synthesis of spirocyclic systems containing both 3-aza-

bicyclo[3.1.0]hexane and 2H-indene-1,3-dione moieties via

multi-component reaction of ninhydrin, -amino acids (or

peptides), and cyclopropenes. The present method provides

an effective approach to spirocyclic 3-azabicyclo[3.1.0]hex-

ane-2,2′-indenes with exclusive stereoselectivity in an effi-

cient and atom-economical manner under mild reaction

conditions. In this study, we postulate the formation of 1-

methylspiro[aziridine-2,2′-indene]-1′,3′-dione – a kineti-

cally controlled product of reaction between ninhydrin and

sarcosine, which seems to act as a source of reactive azome-

thine ylide. The reaction mechanisms of condensation reac-

tion between sarcosine and ninhydrin, including the stage

of aziridine transformation, and 1,3-dipolar cycloaddition

reactions of cyclopropenes to azomethine ylides from nin-

hydrin were studied by means of DFT calculations. Addi-

tionally, the antitumor activity of some synthesized com-

pounds against cervical carcinoma (HeLa) cell line was eval-

uated by MTS-assay in vitro.

Figure 3 Cytotoxicity of compounds 8a, 8e–i and 11a,b against the

cervical carcinoma (HeLa) cell line (24 h)

K

S. Wang et al.

Paper

Synthesis

¹H NMR (400 MHz, CDCl₃):  = 7.80 (d, J = 7.0 Hz, 1 H), 7.66–7.56 (m, 3

H), 7.49–7.42 (m, 2 H), 7.30–7.16 (m, 3 H), 6.99–6.91 (m, 2 H), 6.90–

6.81 (m, 3 H), 6.78–6.72 (m, 3 H), 6.48–6.42 (m, 2 H), 4.04 (s, 1 H),

3.92 (d, J = 9.1 Hz, 1 H), 3.62 (d, J = 9.1 Hz, 1 H), 2.42 (s, 3 H).

¹³C NMR (101 MHz, CDCl₃):  = 204.9, 201.5, 142.3, 140.9, 136.6,

135.7, 135.6, 134.4, 132.7 (2 C), 132.6 (2 C), 131.5, 131.3 (2 C), 127.8

(2 C), 127.5 (2 C), 127.1, 126.9, 126.4 (2 C), 125.2, 122.4, 122.0, 80.4,

67.5, 53.1, 43.8, 35.3, 32.2.

NMR spectra were recorded with Bruker Avance 400 spectrometer

(400.13 MHz for ¹H and 100.61 MHz for ¹³C). Chemical shifts are re-

ported in ppm relative to residual CHCl₃(¹H,  = 7.26), CDCl₃(¹³C,  =

77.17) and residual DMSO-d₅(¹H, 2.50 ppm), DMSO-d₆¹³C, 39.52

(

ppm) as internal standards. All ¹³C NMR spectra were proton-decou-

1

pled. Spectra H and H-¹³C HSQCnd (Heteronuclear Single Quantum

Coherence without ¹³C-decoupling during ¹H-acquisition time) of

mixture compounds 5 and 6 (Figures S23 and S24 in the SI, respec-

tively) were recorded on Bruker DPX-300 spectrometer (300.13 MHz

for ¹H and 75.468 MHz for ¹³C), which was equipped a normal for-

ward dual probe-head. In 2D HSQC experiment, relaxation delay d1

was equal to 3 s and delay for coherence transfer during evolution pe-

riod d2 = 1/[4¹J_C,H)] was equal to 1.72 ms. This value corresponds to

HRMS (ESI): m/z [M + H]⁺calcd for C₃₂H₂₆NO₂⁺: 456.1958; found:

456.1958.

(±)-(1R,5S,6R)-6-Ethyl-3-methyl-1,5-diphenyl-3-azaspiro[bicyclo-

[3.1.0]hexane-2,2′-indene]-1′,3′-dione (4b)

1

scalar constant J_C,H= 145 Hz. IR spectra were obtained in KBr and

wavelengths are reported in cm^–1. Mass spectra were recorded on a

HRMS-ESI-QTOF mass-analyzer, electrospray ionization, positive

mode. A single-crystal X-ray diffraction experiments for compound

8a was carried out using Agilent Technologies Xcalibur diffractometer

with monochromated MoK radiation. Melting points were deter-

mined on a melting point apparatus and are uncorrected. Cyclopro-

penes 3a–j were synthesized according to known procedures^31–36

while -amino acids 2 and ninhydrin (1) were obtained from com-

mercial sources.

Product 4b was obtained as a single diastereomer by following GP-A

from ninhydrin (1; 71 mg, 0.4 mmol), sarcosine (2; 53 mg, 0.6 mmol),

and cyclopropene 3b (88 mg, 0.4 mmol); yield: 101 mg (62%); yellow

solid; mp 142–143 °C; R_f= 0.53 (SiO₂; hexane–EtOAc 3:1).

IR (KBr): 3077, 3060, 2971, 2932, 2885, 1736, 1703, 1595, 1522, 1330,

1261, 1235, 774, 703 cm^–1

.

¹H NMR (400 MHz, CDCl₃):  = 7.83 (d, J = 7.4 Hz, 1 H), 7.64 (t, J = 7.4

Hz, 1 H), 7.57 (t, J = 7.4 Hz, 1 H), 7.47 (d, J = 7.4 Hz, 1 H), 7.25–7.15 (m,

5 H), 6.95 (d, J = 7.4 Hz, 2 H), 6.90–6.86 (m, 3 H), 3.94 (d, J = 8.6 Hz, 1

H), 3.69 (d, J = 8.6 Hz, 1 H), 2.70 (dd, J = 7.9, 6.1 Hz, 1 H), 2.36 (s, 3 H),

1.49 (m, 1 H), 1.20 (m, 1 H), 0.91 (t, J = 7.3 Hz, 3 H).

¹³C NMR (101 MHz, CDCl₃):  = 204.3, 202.0, 142.1, 140.9, 137.6,

135.6, 135.3, 132.3 (2 C), 132.2, 129.3 (2 C), 127.6 (2 C), 127.5 (2 C),

127.0, 125.8, 122.3, 121.9, 80.3, 63.5, 50.2, 38.6, 35.3, 30.9, 19.2, 13.8.

One-Pot Three-Component Reaction of Ninhydrin, Sarcosine, and

Cyclopropenes; General Procedure A (GP-A)

A mixture of ninhydrin (1; 71 mg, 0.4 mmol), sarcosine (2; 53 mg, 0.6

mmol) and the respective cyclopropene derivative 3a–i (0.4 mmol)

was stirred at reflux in MeOH (10 mL) for 5 h (the progress of the re-

action was monitored by TLC). Upon completion, the reaction mixture

was cooled to RT and the solvent was removed under reduced pres-

sure. After evaporation of the solvent, the resulting crude material

was purified by PTLC on silica gel (hexane–EtOAc 3:1), subsequent

trituration with a mixture of MeOH–H₂O (2:1) afforded the corre-

sponding pure products 4a–i. In all cases by-product 5 was also isolat-

ed in 10–17% yields.

HRMS (ESI): m/z [M + Na]⁺calcd for C₂₈H₂₅NO₂Na⁺: 430.1778; found:

430.1777.

(±)-(1R,5S,6R)-3-Methyl-1,5-diphenyl-6-vinyl-3-azaspiro[bicyclo-

[3.1.0]hexane-2,2′-indene]-1′,3′-dione (4c)

Product 4c was obtained as a single diastereomer by following GP-A

from ninhydrin (1; 71 mg, 0.4 mmol), sarcosine (2; 53 mg, 0.6 mmol),

and cyclopropene 3c (87 mg, 0.4 mmol).

Two-Component Reaction of Spiroaziridine and Cyclopropenes;

General Procedure B (GP-B)

Product 4c was obtained as a single diastereomer by following GP-B

from aziridine 6 (110 mg, 0.4 mmol, 67% purity) and cyclopropene 3c

(87 mg, 0.4 mmol).

A mixture of cyclopropene 3a,c,f,h,i (0.4 mmol) and aziridine 6 as a

mixture with 5 (110 mg, 0.4 mmol, the mass fraction of aziridine

67%) was stirred at reflux in MeOH (5 mL) for 3 h (progress of the re-

action was monitored by TLC). The solvent was evaporated under re-

duced pressure. The residue was purified by PTLC on a silica gel elut-

ing with a mixture of hexane–EtOAc (3:1 or 2:1) to afford pure prod-

ucts 4.

Yield: GP-A – 96 mg (59%), GP-B – 114 mg (70%); yellow solid; mp

156–157 °C; R_f= 0.48 (SiO₂; hexane–EtOAc 3:1).

IR (KBr): 3070, 3030, 3020, 2935, 2875, 2844, 2800, 1735, 1703, 1596,

1262, 1235, 1181, 909, 772, 732, 706 cm^–1

.

¹H NMR (400 MHz, CDCl₃):  = 7.81 (d, J = 7.5 Hz, 1 H), 7.67–7.54 (m, 5

H), 7.33–7.27 (m, 2 H), 7.23–7.17 (m, 1 H), 7.06–7.00 (m, 2 H), 6.86–

6.79 (m, 3 H), 5.50 (dd, J = 16.0, 4.0 Hz, 1 H), 5.09–4.96 (m, 2 H), 3.87

(d, J = 8.9 Hz, 1 H), 3.58–3.51 (m, 2 H), 2.35 (s, 3 H).

¹³C NMR (101 MHz, CDCl₃):  = 204.9, 201.5, 142.4, 141.1, 136.8,

136.4, 135.9, 135.7, 132.5 (2 C), 131.6 (2 C), 128.1 (3 C), 127.8 (2 C),

127.2, 127.0, 122.6, 122.1, 115.1, 80.2, 66.0, 51.0, 42.1, 35.4, 32.1.

(±)-(1R,5S,6R)-3-Methyl-1,5,6-triphenyl-3-azaspiro[bicyclo-

[3.1.0]hexane-2,2′-indene]-1′,3′-dione (4a)

Product 4a was obtained as a single diastereomer by following GP-A

from ninhydrin (1; 71 mg, 0.4 mmol), sarcosine (2; 53 mg, 0.6 mmol),

and cyclopropene 3a (107 mg, 0.4 mmol).

HRMS (ESI): m/z [M + H]⁺calcd for C₂₈H₂₄NO₂⁺: 406.1802; found:

406.1807.

Product 4a was obtained as a single diastereomer by following GP-B

from aziridine 6 (110 mg, 0.4 mmol, 67% purity) and cyclopropene 3a

(107 mg, 0.4 mmol).

(±)-(1R,5S,6R)-3-Methyl-1,5-diphenyl-6-(phenylethynyl)-3-

azaspiro[bicyclo[3.1.0]hexane-2,2′-indene]-1′,3′-dione (4d)

Yield: GP-A – 129 mg (71%), GP-B – 135 mg (74%); yellow solid; mp

192–193 °C; R_f= 0.43 (SiO₂; hexane–EtOAc 3:1).

Product 4d was obtained as a single diastereomer by following GP-A

from ninhydrin (1; 71 mg, 0.4 mmol), sarcosine (2; 53 mg, 0.6 mmol),

and cyclopropene 3d (117 mg, 0.4 mmol); yield: 129 mg (67%); yel-

low solid; mp 182–183 °C; R_f= 0.42 (SiO₂; hexane–EtOAc 3:1).

IR (KBr): 3303, 3093, 3070, 3034, 2941, 2892, 1746, 1731, 1707, 1599,

1495, 1270, 1170, 1115, 722, 700 cm^–1

.

L

S. Wang et al.

Paper

Synthesis

IR (KBr): 3081, 3057, 3048, 2974, 2946, 2929, 2890, 2843, 2225, 1740,

1705, 1592, 1490, 1445, 1346, 1268, 1231, 894, 772, 759, 701 cm^–1

(±)-(1R,5S,6R)-N-Isopropyl-3-methyl-1′,3′-dioxo-1,5-diphenyl-

1′,3′-dihydro-3-azaspiro[bicyclo[3.1.0]hexane-2,2′-indene]-6-car-

.

boxamide (4g)

¹H NMR (400 MHz, CDCl₃):  = 7.86 (d, J = 7.4 Hz, 1 H), 7.68 (t, J = 7.4

Hz, 1 H), 7.62 (t, J = 7.4 Hz, 1 H), 7.56 (d, J = 7.4 Hz, 1 H), 7.53 (d, J = 7.6

Hz, 2 H), 7.30–7.20 (m, 3 H), 7.20–7.05 (m, 7 H), 6.95–6.90 (m, 3 H),

4.14 (d, J = 8.6 Hz, 1 H), 3.84 (s, 1 H), 3.89 (d, J = 8.6 Hz, 1 H), 2.41 (s, 3

H).

Product 4g was obtained as a single diastereomer by following GP-A

from ninhydrin (1; 71 mg, 0.4 mmol), sarcosine (2; 53 mg, 0.6 mmol),

and cyclopropene 3g (111 mg, 0.4 mmol); yield: 113 mg (61%); yel-

low solid; mp 195–197 °C; R_f= 0.55 (SiO₂; hexane–EtOAc 1:1).

¹³C NMR (101 MHz, CDCl₃):  = 203.7, 200.4, 142.0, 140.9, 135.9,

135.6, 135.2, 132.6 (2 C), 131.2 (2 C), 130.7, 129.9 (2 C), 128.0 (2 C),

127.5 (3 C), 127.4 (3 C), 126.6, 123.8, 122.5, 122.1, 87.3, 87.0, 79.3,

62.3, 51.7, 41.6, 35.1, 20.3.

HRMS (ESI): m/z [M + H]⁺calcd for C₃₄H₂₆NO₂⁺: 480.1958; found:

480.1968.

IR (KBr): 3327, 3059, 3030, 2969, 2934, 2866, 2844, 2793, 1741, 1707,

1643, 1539, 1230, 768, 702 cm^–1

.

¹H NMR (400 MHz, CDCl₃):  = 7.84 (d, J = 7.4 Hz, 1 H), 7.67 (t, J = 7.4

Hz, 1 H), 7.61 (t, J = 7.4 Hz, 1 H), 7.58 (d, J = 7.7 Hz, 2 H), 7.55 (d, J = 7.4

Hz, 1 H), 7.30 (t, J = 7.7 Hz, 2 H), 7.22 (t, J = 7.7 Hz, 1 H), 7.09–7.04 (m,

2 H), 6.86–6.81 (m, 3 H), 4.90 (d, J = 7.6 Hz, 1 H), 3.84 (d, J = 9.2 Hz, 1

H), 3.81–3.77 (m, 1 H), 3.52 (d, J = 9.2 Hz, 1 H), 3.48 (s, 1 H), 2.29 (s, 3

H), 0.84 (d, J = 6.5 Hz, 3 H), 0.78 (d, J = 6.5 Hz, 3 H).

¹³C NMR (101 MHz, CDCl₃):  = 204.1, 201.0, 166.9, 142.2, 140.8,

135.9, 135.7, 134.2, 131.5 (2 C), 131.4, 131.2 (2 C), 127.7 (2 C), 127.6

(2 C), 127.5, 127.1, 122.5, 122.0, 79.5, 65.9, 51.4, 42.9, 41.1, 34.9, 31.3,

22.2, 22.1

(±)-(1R,5S)-3-Methyl-1,5-diphenyl-3-azaspiro[bicyclo[3.1.0]hex-

ane-2,2′-indene]-1′,3′-dione (4e)

Product 4e was obtained by following GP-A from ninhydrin (1; 71 mg,

0.4 mmol), sarcosine (2; 53 mg, 0.6 mmol), and cyclopropene 3e (77

mg, 0.4 mmol); yield: 103 mg (68%); yellow solid; mp 187–189 °C;

R_f= 0.44 (SiO₂; hexane–EtOAc 3:1).

HRMS (ESI): m/z [M + Na]⁺calcd for C₃₀H₂₈N₂O₃Na⁺: 487.1992; found:

487.1990.

IR (KBr): 3018, 2934, 2835, 2799, 1739, 1704, 1594, 1503, 1446, 1348,

1272, 1231, 1176, 1074, 1018, 895, 769, 705, 610, 522 cm^–1

.

(±)-(1R,5S,6R)-N,N,3-Trimethyl-1′,3′-dioxo-1,5-diphenyl-1′,3′-dihy-

dro-3-azaspiro[bicyclo[3.1.0]hexane-2,2′-indene]-6-carboxamide

(4h)

¹H NMR (400 MHz, CDCl₃):  = 7.81 (d, J = 7.4 Hz, 1 H), 7.63 (t, J = 7.4

Hz, 1 H), 7.58 (t, J = 7.4 Hz, 1 H), 7.55 (d, J = 7.4 Hz, 1 H), 7.28 (d, J = 7.7

Hz, 2 H), 7.21 (t, J = 7.7 Hz, 2 H), 7.12 (t, J = 7.7 Hz, 1 H), 6.89 (d, J = 7.7

Hz, 2 H), 6.83–6.78 (m, 3 H), 4.14 (d, J = 8.7 Hz, 1 H), 3.49 (d, J = 8.7 Hz,

1 H), 2.63 (d, J = 4.8 Hz, 1 H), 2.38 (s, 3 H), 1.50 (d, J = 4.8 Hz, 1 H).

¹³C NMR (101 MHz, CDCl₃):  = 204.7, 200.9, 141.8, 140.9, 137.7,

135.7, 135.5, 134.5, 131.7 (2 C), 128.4 (2 C), 128.0 (2 C), 127.5 (2 C),

127.1, 126.4, 122.5, 121.9, 79.5, 61.4, 48.5, 36.5, 35.4, 19.0.

Product 4h was obtained as a single diastereomer by following GP-A

from ninhydrin (1; 71 mg, 0.4 mmol), sarcosine (2; 53 mg, 0.6 mmol),

and cyclopropene 3h (105 mg, 0.4 mmol).

Product 4h was obtained as a single diastereomer by following GP-B

from aziridine 6 (110 mg, 0.4 mmol, 67% purity) and cyclopropene 3h

(105 mg, 0.4 mmol).

HRMS (ESI): m/z [M + Na]⁺calcd for C₂₆H₂₁NO₂Na⁺: 402.1465; found:

Yield: GP-A – 114 mg (63%), GP-B – 119 mg (66%); yellow solid; mp

402.1463.

218–219 °C; R_f= 0.33 (SiO₂; hexane–EtOAc 2:1).

Methyl (±)-(1R,5S,6R)-3-Methyl-1′,3′-dioxo-1,5-diphenyl-1′,3′-di-

hydro-3-azaspiro[bicyclo[3.1.0]hexane-2,2′-indene]-6-carboxyl-

ate (4f)

IR (KBr): 3048, 3020, 2935, 2880, 2845, 2805, 1742, 1707, 1647, 1598,

1448, 1261, 1241, 1151, 1072, 768, 703 cm^–1

.

¹H NMR (400 MHz, CDCl₃):  = 7.88–7.80 (m, 1 H), 7.71–7.66 (m, 1 H),

7.62–7.56 (m, 1 H), 7.44–7.36 (m, 1 H), 7.23–7.10 (m, 5 H), 7.00–6.90

(m, 2 H), 6.87–6.75 (m, 3 H), 4.13 (d, J = 8.9 Hz, 1 H), 3.80 (s, 1 H), 3.68

(d, J = 8.9 Hz, 1 H), 2.97 (s, 3 H), 2.69 (s, 3 H), 2.38 (s, 3 H).

Product 4f was obtained as a single diastereomer by following GP-A

from ninhydrin (1; 71 mg, 0.4 mmol), sarcosine (2; 53 mg, 0.6 mmol),

and cyclopropene 3f (100 mg, 0.4 mmol).

¹³C NMR (101 MHz, CDCl₃):  = 203.2, 200.6, 167.9, 142.2, 141.0,

135.8, 135.5, 135.4, 133.0 (2 C), 130.0, 128.8 (2 C), 127.5 (2 C), 127.1,

126.7 (2 C), 126.4, 122.4, 122.0, 80.4, 61.8, 51.8, 40.0, 37.1, 35.2 (2 C),

30.6.

Product 4f was obtained as a single diastereomer by following GP-B

from aziridine 6 (110 mg, 0.4 mmol, 67% purity) and cyclopropene 3f

(100 mg, 0.4 mmol).

Yield: GP-A – 89 mg (51%), GP-B – 110 mg (63%); yellow solid; mp

185–186 °C; R_f= 0.42 (SiO₂; hexane–EtOAc 2:1).

HRMS (ESI): m/z [M + H]⁺calcd for C₂₉H₂₇N₂O₃⁺: 451.2016; found:

451.2025.

IR (KBr): 3049, 2964, 2940, 2894, 2845, 2801, 1736, 1705, 1591, 1445,

1356, 1235, 1200, 1178, 901, 769, 707 cm^–1

.

(±)-(1R,5S,6R)-3-Methyl-1′,3′-dioxo-1,5-diphenyl-1′,3′-dihydro-3-

azaspiro[bicyclo[3.1.0]hexane-2,2′-indene]-6-carbonitrile (4i)

¹H NMR (400 MHz, CDCl₃):  = 7.83 (d, J = 7.4 Hz, 1 H), 7.70–7.55 (m, 3

H), 7.53–7.47 (m, 2 H), 7.35–7.27 (m, 2 H), 7.27–7.19 (m, 1 H), 7.06–

6.97 (m, 2 H), 6.90–6.79 (m, 3 H), 3.87 (d, J = 9.3 Hz, 1 H), 3.79 (s, 1 H),

3.58 (d, J = 9.3 Hz, 1 H), 3.49 (s, 3 H), 2.32 (s, 3 H).

¹³C NMR (101 MHz, CDCl₃):  = 203.8, 200.3, 169.7, 142.4, 141.0,

136.2, 136.0, 134.1, 131.5, 131.3 (2 C), 130.9 (2 C), 128.1 (2 C), 127.7

(2 C), 127.5, 127.4, 122.8, 122.3, 79.6, 65.9, 52.8, 51.6, 44.6, 35.2, 29.5.

Product 4i was obtained as a single diastereomer by following GP-A

from ninhydrin (1; 71 mg, 0.4 mmol), sarcosine (2; 53 mg, 0.6 mmol),

and cyclopropene 3i (87 mg, 0.4 mmol).

Product 4i was obtained as a single diastereomer by following GP-B

from aziridine 6 (110 mg, 0.4 mmol, 67% purity) and cyclopropene 3i

(87 mg, 0.4 mmol).

HRMS (ESI): m/z [M + H]⁺calcd for C₂₈H₂₄NO₄⁺: 438.1700; found:

Yield: GP-A – 99 mg (61%), GP-B – 110 mg (68%); yellow solid; mp

438.1686.

189–190 °C; R_f= 0.37 (SiO₂; hexane–EtOAc 2:1).

IR (KBr): 3070, 3048, 2948, 2886, 2839, 2800, 2238, 1741, 1704, 1597,

1265, 1242, 770, 760, 704 cm^–1

.

M

S. Wang et al.

Paper

Synthesis

¹H NMR (400 MHz, CDCl₃):  = 7.85 (d, J = 7.4 Hz, 1 H), 7.73–7.61 (m, 2

H), 7.60–7.56 (m, 1 H), 7.55–7.49 (m, 2 H), 7.37–7.30 (m, 2 H), 7.30–

7.24 (m, 1 H), 7.12–7.04 (m, 2 H), 7.01–6.91 (m, 3 H), 4.04 (d, J = 9.4

Hz, 1 H), 3.73 (s, 1 H), 3.58 (d, J = 9.4 Hz, 1 H), 2.33 (s, 3 H).

¹³C NMR (101 MHz, CDCl₃):  = 202.8, 199.0, 141.9, 140.7, 136.4,

136.2, 132.8, 131.8 (2 C), 129.6 (2 C), 128.9, 128.6, 128.4 (2 C), 128.3

(2 C), 127.9, 122.9, 122.4, 118.0, 77.9, 62.3, 50.7, 41.7, 34.9, 15.9.

HRMS (ESI): m/z [M + H]⁺calcd for C₃₅H₃₂NO₂⁺: 498.2428; found:

498.2438.

(±)-(1R,4R,5S,6R)-1,5,6-Triphenyl-4-propyl-3-azaspiro[bicyclo-

[3.1.0]hexane-2,2′-indene]-1′,3′-dione (8b)

The reaction was performed according to GP-C employing ninhydrin

(1; 71 mg, 0.4 mmol), cyclopropene 3a (107 mg, 0.4 mmol), and DL-

norvaline (7b; 94 mg, 0.8 mmol). Purification by PTLC on silica gel

(hexane−EtOAc 3:1) followed by trituration with a mixture of

MeOH−H₂O (2:1) afforded 8b as a single diastereomer; yield: 137 mg

(71%); yellow solid; mp 104–105 °C; R_f= 0.36 (SiO₂, hexane–EtOAc

3:1).

HRMS (ESI): m/z [M + Na]⁺calcd for C₂₇H₂₁N₂O₂Na⁺: 427.1417; found:

427.1399.

Mixture of 1-Methylspiro[aziridine-2,2′-indene]-1′,3′-dione (6)

and 1′,4′-Dimethyldispiro[indene-2,2′-piperazine-5′,2′′-indene]-

1,1′′,3,3′′-tetrone (5)

IR (KBr): 3056, 3027, 2957, 2930, 1745, 1600, 1496, 1267, 765, 702

cm^–1

.

A mixture of ninhydrin (1; 500 mg, 2.8 mmol) and sarcosine (2; 250

mg, 2.8 mmol) was stirred at RT in MeOH (5 mL) for 72 h. The result-

ing light brown solid was collected by filtration and washed with cold

MeOH to afford 6 and 5 as an inseparable mixture in 4:1 ratio, respec-

tively (the ratio was established by means of ¹H NMR spectroscopy);

yield: 240 mg (46%); light brown solid.

¹H NMR (400 МHz, CDCl₃):  (for 6) = 7.70–7.80 (m, 4 H), 3.45 (s, 2 H),

2.24 (s, 3 H).

¹³C NMR (101 МHz, CDCl₃):  (for 6) = 198.5 (2 C), 140.9 (2 C), 136.4 (2

C), 122.9 (2 C), 71.9, 49.1, 40.6.

¹H NMR (400 МHz, CDCl₃):  = 7.84–7.76 (m, 1 H), 7.69–7.52 (m, 3 H),

7.43–7.20 (m, 5 H), 7.05–6.60 (m, 8 H), 6.49–6.35 (m, 2 H), 4.41–4.35

(m, 1 H), 3.33 (s, 1 H), 2.19 (br s, 1 H), 1.69–1.17 (m, 4 H), 0.91–0.85

(m, 3 H).

¹³C NMR (101 МHz, CDCl₃):  = 202.1, 199.7, 141.7 (2 C), 136.0, 135.9,

135.4, 134.0, 132.8 (3 C), 132.6 (2 C) 131.3, 131.2 (2 C), 127.8 (2 C),

127.6, 126.9 (2 C), 126.5 (2 C), 125.4, 123.0, 122.7, 77.4, 71.3, 53.0,

49.2, 32.9, 28.3, 20.3, 14.3.

HRMS (ESI): m/z [M + H]⁺calcd for C₃₄H₃₀NO₂⁺: 484.2271; found:

484.2268.

On heating the mixture of 5 and 6 in MeOH, aziridine 6 completely

converted into dispiropiperazine 5. The spectral data for 5 are in good

accordance with previously published data (Figures S19 and S20 in

the SI).²⁷

(±)-(1R,4R,5S,6R)-4-Butyl-1,5,6-triphenyl-3-azaspiro[bicyclo-

[3.1.0]hexane-2,2′-indene]-1′,3′-dione (8c)

The reaction was performed according to GP-C employing ninhydrin

(1; 71 mg, 0.4 mmol), cyclopropene 3a (107 mg, 0.4 mmol), and DL-

norleucine (7c; 105 mg, 0.8 mmol). Purification by PTLC on silica gel

(hexane–EtOAc 3:1) followed by trituration with a mixture of MeOH–

H₂O (2:1) afforded 8c as a single diastereomer; yield: 163 mg (81%);

yellow solid; mp 95–96 °C; R_f= 0.38 (SiO₂, hexane–EtOAc, 3:1).

One-Pot Three-Component Reaction of Ninhydrin, Primary -

Amino Acids, and Cyclopropenes; General Procedure C (GP-C)

A mixture of ninhydrin (1; 71 mg, 0.4 mmol), cyclopropene 3 (0.4

mmol), and -amino acid 7 (0.8 mmol) in a 3:1 mixture of MeOH–

H₂O (12 mL) was refluxed for 10 h. The reaction progress was moni-

tored by TLC and by the change in the color of the reaction mixture

from blue to yellow. The solvent was evaporated under reduced pres-

sure. The residue was subjected by silica gel PTLC using a mixture of

hexane–EtOAc as an eluent. Subsequent trituration with a mixture of

MeOH–H₂O (2:1) gave desired products 8 and 9.

IR (KBr): 3305, 3027, 2954, 2929, 1745, 1601, 1497, 1445, 1267, 764,

701 cm^–1

.

¹H NMR (400 МHz, CDCl₃):  = 7.79 (d, J = 7.2 Hz, 1 H), 7.71–7.53 (m, 3

H), 7.44–7.34 (m, 2 H), 7.33–7.17 (m, 3 H), 7.00 (t, J = 7.1 Hz, 1 H), 6.90

(t, J = 7.2 Hz, 2 H), 6.84–6.61 (m, 5 H), 6.52–6.37 (m, 2 H), 4.45–4.29

(m, 1 H), 3.34 (s, 1 H), 2.19 (br s, 1 H), 1.68–1.17 (m, 6 H), 0.92–0.71

(m, 3 H).

¹³C NMR (101 МHz, CDCl₃):  = 202.3, 200.0, 141.7 (2 C), 136.1, 135.8,

135.3, 134.1, 132.8 (3 C), 132.6 (2 C), 131.5, 131.2 (2 C), 127.8 (2 C),

127.5, 126.9, 126.8, 126.5 (2 C), 125.3, 122.9, 122.7, 77.2, 71.5, 53.2,

49.4, 30.6, 29.3, 28.2, 22.9, 13.9.

(±)-(1R,4R,5S,6R)-4-Isobutyl-1,5,6-triphenyl-3-azaspiro[bicyclo-

[3.1.0]hexane-2,2′-indene]-1′,3′-dione (8a)³⁷

The reaction was performed according to GP-C employing ninhydrin

(1; 71 mg, 0.4 mmol), cyclopropene 3a (107 mg, 0.4 mmol), and L-leu-

cine (7a; 105 mg, 0.8 mmol). Purification by PTLC on silica gel (hex-

ane−EtOAc, 3:1) followed by trituration with a mixture of MeOH–H₂O

(2:1) afforded 8a as a single diastereomer; yield: 147 mg (74%); yel-

low solid; mp 171–172 °C; R_f= 0.37 (SiO₂, hexane–EtOAc 3:1).

HRMS (ESI): m/z [M + H]⁺calcd for C₃₅H₃₂NO₂⁺: 498.2428; found:

498.2427.

IR (KBr): 3300, 2998, 2960, 2887, 1743, 1710, 1598, 1495, 1267, 937,

(±)-(1R,4R,5S,6R)-4-Hexyl-1,5,6-triphenyl-3-azaspiro[bicyclo-

[3.1.0]hexane-2,2'-indene]-1',3'-dione (8d)

762, 719, 700 cm^–1

.

¹H NMR (400 MHz, CDCl₃):  = 7.85–7.73 (m, 1 H), 7.70–7.55 (m, 3 H),

7.39 (d, J = 7.2 Hz, 2 H), 7.33–7.18 (m, 3 H), 7.00 (t, J = 7.2 Hz, 1 H),

6.91 (t, J = 7.5 Hz, 2 H), 6.85–6.68 (m, 5 H), 6.45 (d, J = 7.5 Hz, 2 H),

4.39 (d, J = 8.1 Hz, 1 H), 3.27 (s, 1 H), 2.48 (br s, 1 H), 1.78–1.63 (m, 1

H), 1.56–1.44 (m, 1 H), 1.40–1.27 (m, 1 H), 0.90 (s, 3 H), 0.80 (s, 3 H).

¹³C NMR (101 MHz, CDCl₃):  = 202.3, 200.2, 141.7, 136.2, 135.8,

135.3, 134.0, 132.8 (3 С), 132.6 (2 C), 131.6, 131.2 (2 С), 127.8 (2 С),

127.5, 126.8 (3 C), 126.5 (2 С), 125.3, 122.9, 122.7, 77.4, 69.6, 53.2,

49.6, 39.9, 28.1, 25.7, 23.8, 21.7.

The reaction was performed according to GP-C employing ninhydrin

(1; 71 mg, 0.4 mmol), cyclopropene 3a (107 mg, 0.4 mmol), and DL-2-

aminocaprylic acid (7d; 127 mg, 0.8 mmol). Purification by PTLC on

silica gel (hexane–EtOAc, 3:1) followed by trituration with a mixture

of MeOH–H₂O (2:1) afforded 8d as a single diastereomer; yield: 151

mg (72%); yellow solid; mp 149–150 °C; R_f= 0.43 (SiO₂, hexane–EtOAc

3:1).

IR (KBr): 3297, 2940, 2889, 2855, 1745, 1596, 1495, 1354, 1268, 938,

723, 698 cm^–1

.

N

S. Wang et al.

Paper

Synthesis

¹H NMR (400 МHz, CDCl₃):  = 7.80 (d, J = 7.3 Hz, 1 H), 7.68–7.56 (m, 3

H), 7.39 (d, J = 6.7 Hz, 2 H), 7.33–7.19 (m, 3 H), 7.00 (t, J = 7.2 Hz, 1 H),

6.95–6.87 (m, 2 H), 6.84–6.64 (m, 5 H), 6.45 (d, J = 7.5 Hz, 2 H), 4.41–

4.27 (m, 1 H), 3.31 (s, 1 H), 2.19 (br s, 1 H), 1.65–1.05 (m, 10 H), 0.85

(t, J = 7.0 Hz, 3 H).

¹³C NMR (101 МHz, CDCl₃):  = 202.2, 199.9, 141.7 (2 C), 136.1, 135.8,

135.4, 134.0, 133.9, 132.8 (2 C), 132.6, 131.5, 131.4, 131.2 (2 C), 127.8

(2 C), 127.6, 126.9 (2 C), 126.5 (2 C), 125.4, 123.0, 122.7, 77.3, 71.6,

53.1, 49.4, 31.7, 30.9, 29.5, 28.2, 27.1, 22.5, 14.0.

(±)-(1R,4R,5S,6R)-4-(4-Hydroxy-3,5-diiodobenzyl)-1,5,6-triphenyl-

3-azaspiro[bicyclo[3.1.0]hexane-2,2′-indene]-1′,3′'-dione (8g)

The reaction was performed according to GP-C employing ninhydrin

(1; 71 mg, 0.4 mmol), cyclopropene 3a (107 mg, 0.4 mmol), and 3,5-

diiodo-L-tyrosine (8g; 346 mg, 0.8 mmol). Purification by PTLC on sil-

ica gel (hexane–EtOAc 2:1) followed by trituration with a mixture of

MeOH–H₂O (2:1) afforded 8g as a single diastereomer; yield: 182 mg

(57%); yellow solid; mp 205–206 °C; R_f= 0.43 (SiO₂, hexane–EtOAc,

2:1).

HRMS (ESI): m/z [M + H]⁺calcd for C₃₇H₃₆NO₂⁺: 526.2741; found:

526.2744.

IR (KBr): 3481, 3308, 3027, 2886, 1742, 1702, 1599, 1465, 1268, 1155,

701 cm^–1

.

¹H NMR (400 МHz, CDCl₃):  = 7.81–7.76 (m, 1 H), 7.68–7.55 (m, 3 H),

7.48 (s, 2 H), 7.40–7.36 (m, 2 H), 7.34–7.21 (m, 3 H), 7.05–7.00 (m, 1

H), 6.95–6.90 (m, 2 H), 6.87–6.64 (m, 5 H), 6.44 (d, J = 7.3 Hz, 2 H),

5.67 (br s, 1 H), 4.58 (dd, J = 9.0, 4.2 Hz, 1 H), 3.89 (s, 1 H), 2.81 (dd, J =

14.4, 4.2 Hz, 1 H), 2.65 (dd, J = 14.4, 9.0 Hz, 1 H). 2.18 (br s, 1 H).

¹³C NMR (101 МHz, CDCl₃):  = 202.8, 199.9, 152.5, 142.0, 141.8, 139.8

(2 C), 136.3, 136.0, 135.9, 134.9, 133.8, 133.2 (2 C), 132.9 (2 C), 131.6

(2 C), 131.4, 128.4 (2 C), 128.0 (2 C), 127.6, 127.4, 127.0 (2 C), 125.9,

123.3, 123.2, 82.7 (2 C), 76.9, 71.8, 53.1, 48.8, 35.5, 28.7.

(±)-(1R,4R,5S,6R)-4-Benzyl-1,5,6-triphenyl-3-azaspiro[bicyclo-

[3.1.0]hexane-2,2′-indene]-1′,3′-dione (8e)

The reaction was performed according to GP-C employing ninhydrin

(1; 71 mg, 0.4 mmol), cyclopropene 3a (107 mg, 0.4 mmol), and L-

phenylalanine (7e; 132 mg, 0.8 mmol). Purification by PTLC on silica

gel (hexane–EtOAc 2:1) followed by trituration with a mixture of

MeOH–H₂O (2:1) afforded 8e as a single diastereomer; yield: 168 mg

(79%); off-white solid; mp 192–193 °C; R_f= 0.59 (SiO₂, hexane–EtOAc,

2:1).

HRMS (ESI): m/z [M + H]⁺calcd for C₃₈H₂₈I₂NO₃⁺: 800.0153; found:

IR (KBr): 3426, 3059, 3026, 2921, 1740, 1600, 1493, 1445, 1276, 753,

800.0161.

699 cm^–1

.

¹H NMR (400 МHz, CDCl₃):  = 7.79–7.73 (m, 1 H), 7.65–7.56 (m, 3 H),

7.47 (d, J = 7.5 Hz, 2 H), 7.35–7.19 (m, 8 H), 7.02 (t, J = 7.2 Hz, 1 H),

6.95–6.86 (m, 2 H), 6.85–6.65 (m, 5 H), 6.41 (d, J = 7.5 Hz, 2 H), 4.72

(dd, J = 8.8, 3.7 Hz, 1 H), 3.32 (s, 1 H), 2.99 (dd, J = 14.3, 3.7 Hz, 1 H),

2.80 (dd, J = 14.5, 8.9 Hz, 1 H), 2.61 (br s, 1 H).

¹³C NMR (101 МHz, CDCl₃):  = 202.1, 199.5, 141.5 (2 C), 138.0 (2 C),

135.7 (2 C), 133.6, 132.8 (2 C), 132.4, 131.2 (2 C), 131.1, 129.0 (2 C),

128.4 (2 C), 127.8 (3 C), 127.4 (2 C), 126.9, 126.8, 126.4 (2 C), 126.3,

125.3, 122.8, 122.5, 77.4, 71.2, 52.3, 48.3, 36.3, 28.2.

(±)-(1R,4R,5S,6R)-4-[2-(Methylthio)ethyl]-1,5,6-triphenyl-3-

azaspiro[bicyclo[3.1.0]hexane-2,2′-indene]-1′,3′-dione (8h)

The reaction was performed according to GP-C employing ninhydrin

(1; 71 mg, 0.4 mmol), cyclopropene 3a (107 mg, 0.4 mmol), and L-

methionine (7h; 119 mg, 0.8 mmol). Purification by PTLC on silica gel

(hexane–EtOAc 3:1) followed by trituration with a mixture of MeOH–

H₂O (2:1) afforded 8h as a single diastereomer; yield: 151 mg (73%);

light yellow solid; mp 175–177 °C; R_f= 0.32 (SiO₂, hexane–EtOAc 5:2).

IR (KBr): 3304, 3025, 2913, 1745, 1705, 1599, 1496, 1443, 1352, 1269,

1183, 1153, 1099, 1028, 942, 910, 837, 754, 704, 623 cm^–1

.

HRMS (ESI): m/z [M + H]⁺calcd for C₃₈H₃₀NO₂⁺: 532.2271; found:

¹H NMR (400 МHz, CDCl₃):  = 7.85–7.75 (m, 1 H), 7.71–7.56 (m, 3 H),

7.44–7.36 (m, 2 H), 7.33–7.19 (m, 3 H), 7.08–6.95 (m, 1 H), 6.94–6.86

(m, 2 H), 6.84–6.65 (m, 5 H), 6.52–6.38 (m, 2 H), 4.52–4.43 (m, 1 H),

3.35 (s, 1 H), 2.72–2.40 (m, 2 H), 2.25 (br s, 1 H), 2.07 (s, 3 H), 1.96–

1.74 (m, 2 H).

¹³C NMR (101 МHz, CDCl₃):  = 202.0, 199.6, 141.7, 141.6, 135.9,

135.7, 135.5, 133.6, 132.7 (2 C), 132.5 (2 C), 131.2 (2 C), 131.1 (2 C),

128.0 (2 C), 127.6, 127.1, 127.0, 126.6 (2 C), 125.5, 123.0, 122.8, 76.7,

70.6, 52.9, 48.9, 31.6, 30.5, 28.2, 15.5.

532.2296.

(±)-(1R,4R,5S,6R)-4-(4-Hydroxybenzyl)-1,5,6-triphenyl-3-

azaspiro[bicyclo[3.1.0]hexane-2,2′-indene]-1′,3′-dione (8f)

The reaction was performed according to GP-C employing ninhydrin

(1; 71 mg, 0.4 mmol), cyclopropene 3a (107 mg, 0.4 mmol), and L-ty-

rosine (7f; 145 mg, 0.8 mmol). Purification by PTLC on silica gel (hex-

ane–EtOAc 3:2) followed by trituration with a mixture of MeOH–H₂O

(2:1) afforded 8f as a single diastereomer; yield: 136 mg (62%); off-

white solid; mp 234–235 °C; R_f= 0.38 (SiO₂, hexane–EtOAc 3:2).

HRMS (ESI): m/z [M + H]⁺calcd for C₃₄H₃₀NO₂S⁺: 516.1992; found:

IR (KBr): 3526, 3202, 3065, 3011, 2902, 1740, 1702, 1590, 1514, 1492,

516.1997.

1446, 1362, 1330, 1246, 1085, 1031, 755, 690 cm^–1

.

¹H NMR (400 МHz, CDCl₃):  = 9.11 (s, 1 H), 7.81–7.70 (m, 3 H), 7.60

(d, J = 6.7 Hz, 1 H), 7.38–7.24 (m, 5 H), 7.02–6.75 (m, 10 H), 6.61 (d, J =

8.1 Hz, 2 H), 6.35 (d, J = 8.1 Hz, 2 H), 4.58 (dd, J = 8.7, 3.6 Hz, 1 H), 3.38

(s, 1 H), 2.80 (dd, J = 14.1, 3.6 Hz, 1 H), 2.65 (dd, J = 14.3, 9.1 Hz, 1 H),

2.47 (br s, 1 H).

¹³C NMR (101 МHz, CDCl₃):  = 203.9, 200.6, 156.0, 141.6, 141.1,

137.0, 136.8, 136.5, 134.7, 132.8 (2 C), 132.4 (2 C), 132.1, 131.2 (2 C),

130.2 (2 C), 129.7, 128.4 (2 C), 128.0 (2 C ), 127.4 (2 C), 126.9 (2 C),

125.7, 122.9, 122.8, 115.4 (2 C), 75.8, 71.5, 51.3, 48.1, 35.5, 28.2.

(±)-(1R,4R,5S,6R)-1,4,5,6-Tetraphenylspiro[3-azabicyclo[3.1.0]hex-

ane-2,2′-indene]-1′,3′-dione (8i)

The reaction was performed according to GP-C employing ninhydrin

(1; 71 mg, 0.4 mmol), cyclopropene 3a (107 mg, 0.4 mmol), and DL-

phenylglycine (7i; 121 mg, 0.8 mmol). Purification by PTLC on silica

gel (hexane–EtOAc 2:1) followed by trituration with a mixture of

MeOH–H₂O (2:1) afforded 8i as a single diastereomer; yield: 145 mg

(70%); yellow solid; mp 128–130 °C; R_f= 0.55 (SiO₂, hexane–EtOAc

2:1).

HRMS (ESI): m/z [M + H]⁺calcd for C₃₈H₃₀NO₃⁺: 548.2220; found:

548.2229.

IR (KBr): 3342, 3028, 2886, 1741, 1708, 1598, 1494, 1285, 1262, 757,

701 cm^–1

.

O

S. Wang et al.

Paper

Synthesis

¹H NMR (400 МHz, CDCl₃):  = 7.85–7.80 (m, 1 H), 7.73–7.61 (m, 3 H),

7.42–7.36 (m, 2 H), 7.34–7.17 (m, 8 H), 7.04–6.97 (m, 1 H), 6.95–6.86

(m, 2 H), 8.84–6.74 (m, 5 H), 6.47 (d, J = 7.3 Hz, 2 H), 5.66 (s, 1 H), 3.84

(s, 1 H), 3.49 (br s, 1 H).

¹³C NMR (101 МHz, CDCl₃):  = 203.2, 199.7, 141.8, 141.4, 137.9,

135.9, 135.8, 135.6, 133.4, 133.1 (2 C), 132.7 (2 C), 131.3 (2 C), 131.2,

128.2 (2 C), 127.8, 127.6 (4 C), 127.5 (2 C), 127.1, 126.9, 126.5 (2 C),

125.5, 122.9, 122.8, 76.7, 73.6, 52.2, 49.1, 29.1.

(±)-(1R,4R,5S)-4-Isobutyl-1,5-diphenyl-3-azaspiro[bicyclo-

[3.1.0]hexane-2,2′-indene]-1′,3′-dione (8l)

The reaction was performed according to GP-C employing ninhydrin

(1; 71 mg, 0.4 mmol), cyclopropene 3e (77 mg, 0.4 mmol), and L-leu-

cine (7a; 105 mg, 0.8 mmol). Purification by PTLC on silica gel (hex-

ane–EtOAc 3:1) followed by trituration with a mixture of MeOH–H₂O

(2:1) afforded 8l as a single diastereomer; yield: 128 mg (76%); light

yellow solid; mp 130–132 °C; R_f= 0.54 (SiO₂, hexane–EtOAc 5:2).

HRMS (ESI): m/z [M + H]⁺calcd for C₃₇H₂₈NO₂⁺: 518.2115; found:

518.2121.

IR (KBr): 3316, 3027, 2956, 2912, 1744, 1709, 1598, 1497, 1447, 1348,

1274, 1194, 1151, 1078, 771, 707 cm^–1

.

¹H NMR (400 MHz, CDCl₃):  = 7.81 (d, J = 7.4 Hz, 1 H), 7.64–7.56 (m, 3

H), 7.42 (d, J = 7.6 Hz, 2 H), 7.25 (t, J = 7.6 Hz, 2 H), 7.14 (t, 1 H), 6.90

(d, J = 7.4 Hz, 2 H), 6.80–6.76 (m, 3 H), 4.61 (t, J = 6.5 Hz, 1 H), 2.10 (br

s, 1 H), 2.00 (d, J = 6.1 Hz, 1 H), 1.68 (m, 1 H), 1.44 (d, J = 6.1 Hz, 1 H),

1.42–1.57 (m, 2 H), 0.90 (d, J = 6.6 Hz, 3 H), 0.86 (d, J = 6.6 Hz, 3 H).

¹³C NMR (101 MHz, CDCl₃):  = 202.5, 199.8, 141.6, 137.3, 135.8,

135.3, 134.9, 131.5 (3 C), 129.2 (2 C), 128.2 (2 C), 127.5 (2 C), 126.9,

126.6, 122.9, 122.8, 76.6, 64.3, 48.8, 43.8, 41.1, 25.6, 23.5, 22.1, 13.2.

(±)-(1R,4R,5S,6R)-3-(1′,3′-Dioxo-1,5,6-triphenyl-1′,3′-dihydro-3-

azaspiro[bicyclo[3.1.0]hexane-2,2′-indene]-4-yl)propanoic Acid

(8j)

The reaction was performed according to GP-C employing ninhydrin

(1; 71 mg, 0.4 mmol), cyclopropene 3a (107 mg, 0.4 mmol), and L-glu-

tamic acid (7j; 118 mg, 0.8 mmol). Purification by PTLC on silica gel

(hexane–EtOAc 1:1) followed by trituration with a mixture of MeOH–

H₂O (2:1) afforded 8j as a single diastereomer; yield: 127 mg (62%);

yellow solid; mp 204–205 °C; R_f= 0.37 (SiO₂, hexane–EtOAc 1:1).

HRMS (ESI): m/z [M + Na]⁺calcd for C₂₉H₂₇NO₂Na⁺: 444.1934; found:

444.1932.

IR (KBr): 3306, 3015, 2950, 1745, 1708, 1600, 1496, 1443, 1351, 1270,

1187, 756, 720, 701 cm^–1

.

(±)-(1R,4R,5S,6R)-4-Isobutyl-N-isopropyl-1′,3′-dioxo-1,5-diphenyl-

1′,3′-dihydro-3-azaspiro[bicyclo[3.1.0]hexane-2,2'-indene]-6-car-

boxamide (8m)

¹H NMR (400 МHz, DMSO-d₆):  = 11.96 (br s, 1 H), 7.87–7.34 (m, 3

H), 7.73–7.63 (m, 1 H), 7.38–7.18 (m, 5 H), 7.03–6.94 (m, 1 H), 6.94–

6.86 (m, 2 H), 6.83–6.73 (m, 5 H), 6.35 (d, J = 7.3 Hz, 2 H), 4.20–4.05

(m, 1 H), 3.76–3.68 (m, 1 H), 3.61 (s, 1 H), 2.37–2.20 (m, 1 H), 2.20–

2.01 (m, 1 H), 1.84–1.66 (m, 1 H), 1.65–1.47 (m, 1 H).

¹³C NMR (101 МHz, DMSO-d₆):  = 203.6, 200.5, 174.8, 141.6, 141.0,

137.0, 136.9, 136.7, 134.6, 132.7 (2 C), 132.4 (2 C), 132.1, 131.1 (2 C),

130.2, 128.3 (2 C), 128.0 (2 C), 127.5, 127.4, 126.9 (2 C), 125.7, 123.0,

76.0, 69.4, 51.7, 48.3, 31.6, 28.2, 26.0.

The reaction was performed according to GP-C employing ninhydrin

(1; 71 mg, 0.4 mmol), cyclopropene 3g (111 mg, 0.4 mmol), and L-leu-

cine (7a; 105 mg, 0.8 mmol). Purification by PTLC on silica gel (hex-

ane–EtOAc 2:1) followed by trituration with a mixture of MeOH–H₂O

(2:1) afforded 8m as a single diastereomer; yield: 130 mg (64%); light

yellow solid; mp 240–242 °C; R_f= 0.31 (SiO₂, hexane–EtOAc 3:2).

IR (KBr): 3409, 3294, 3090, 3080, 3062, 3026, 2953, 2866, 1739, 1691,

1587, 1514, 1447, 1358, 1270, 1213, 1156, 1094, 760, 718, 701 cm^–1

.

HRMS (ESI): m/z [M + H]⁺calcd for C₃₄H₂₈NO₄⁺: 514.2013; found:

¹H NMR (400 MHz, CDCl₃):  = 7.86 (d, J = 7.4 Hz, 1 H), 7.71–7.60 (m, 5

H), 7.36 (t, J = 7.4 Hz, 2 H), 7.27 (t, J = 7.4 Hz, 1 H), 7.12–7.07 (m, 2 H),

6.90–6.85 (m, 3 H), 4.23 (dd, J = 10.0, 3.5 Hz, 1 H), 4.04 (d, J = 7.6 Hz, 1

H), 3.82–3.68 (m, 1 H), 2.83 (s, 1 H), 2.24 (br s, 1H), 1.65–1.54 (m, 1

H), 1.43 (ddd, J = 14.0, 10.0, 4.8 Hz, 1 H), 1.30 (ddd, , J = 14.0, 9.6, 3.5

Hz, 1 H), 0.83 (d, J = 6.5 Hz, 3 H), 0.75 (d, J = 6.5 Hz, 3 H), 0.66 (d, J = 6.5

Hz, 3 H), 0.51 (d, J = 6.5 Hz, 3 H).

¹³C NMR (101 MHz, CDCl₃):  = 201.3, 199.4, 167.1, 141.7, 141.5,

136.0, 135.6, 133.4, 132.0 (2 C), 131.5, 131.4 (2 C), 128.1 (2 C), 128.0

(2 C), 127.6, 127.5, 123.0, 122.9, 76.3, 69.1, 51.0, 49.4, 41.0, 39.6, 27.6,

25.6, 23.6, 21.9, 21.8, 21.6.

514.2027.

(±)-(1R,4R,5S,6R)-4-Isobutyl-1,5-diphenyl-6-(phenylethynyl)-3-

azaspiro[bicyclo[3.1.0]hexane-2,2′-indene]-1′,3′-dione (8k)

The reaction was performed according to GP-C employing ninhydrin

(1; 71 mg, 0.4 mmol), cyclopropene 3d (117 mg, 0.4 mmol), and L-

leucine (7a; 105 mg, 0.8 mmol). Purification by PTLC on silica gel

(hexane–EtOAc 3:1) followed by trituration with a mixture of

MeOH−H₂O (2:1) afforded 8k as a single diastereomer; yield: 144 mg

(69%); light yellow solid; mp 157–158 °C; R_f= 0.51 (SiO₂, hexane–

EtOAc 5:2).

HRMS (ESI): m/z [M + H]⁺calcd for C₃₃H₃₅N₂O₃⁺: 507.2642; found:

507.2638.

IR (KBr): 3298, 3087, 3078, 3056, 3027, 2956, 2927, 2905, 2869, 2223,

1745, 1712, 1599, 1491, 1447, 1418, 1346, 1328, 1270, 1192, 1157,

1077, 1020, 945, 755, 694 cm^–1

.

¹H NMR (400 MHz, CDCl₃):  = 7.90–7.83 (m, 3 H), 7.68–7.58 (m, 3 H),

7.33 (t, J = 7.4 Hz, 2 H), 7.22 (t, J = 7.4 Hz, 1 H), 7.17–7.10 (m, 5 H), 7.03

(d, J = 7.4 Hz, 2 H), 6.88–6.80 (m, 3 H), 4.44 (t, J = 6.3 Hz, 1 H), 3.03 (s,

1 H), 2.23 (br s, 1 H), 1.68 (m, 1 H), 1.48–1.42 (m, 2 H), 0.87 (d, J = 6.6

Hz, 3 H), 0.85 (d, J = 6.6 Hz, 3 H).

¹³C NMR (101 MHz, CDCl₃):  = 201.6, 199.5, 141.5 (2 C), 136.0, 135.5,

135.0, 132.1 (2 C), 131.5, 131.2 (2 C), 131.1 (2 C), 127.9 (2 C), 127.8 (2

C), 127.5, 127.4 (2 C), 127.1, 126.9, 123.7, 123.0, 122.9, 87.7, 87.1,

76.3, 67.2, 52.3, 49.0, 40.4, 25.7, 23.6, 21.8, 14.6.

(±)-(1R,4R,5S,6R)-4-Isobutyl-1′,3′-dioxo-1,5-diphenyl-1′,3′-dihy-

dro-3-azaspiro[bicyclo[3.1.0]hexane-2,2′-indene]-6-carboxylic

Acid (9a)

The reaction was performed according to GP-C employing ninhydrin

(1; 71 mg, 0.4 mmol), cyclopropene 3j (94 mg, 0.4 mmol), and L-leu-

cine (7a; 105 mg, 0.8 mmol). Purification by PTLC on silica gel (hex-

ane–EtOAc 1:1) followed by trituration with a mixture of MeOH–H₂O

(2:1) afforded 9a as a single diastereomer; yield: 127 mg (68%); white

solid; mp >260 °C; R_f= 0.56 (SiO₂, hexane–EtOAc 1:1).

HRMS (ESI): m/z [M + H]⁺calcd for C₃₇H₃₂NO₂⁺: 522.2428; found:

522.2438.

IR (KBr): 3270, 3090, 3081, 2990, 2984, 2535, 1749, 1678, 1602, 1402,

1345, 1328, 1288, 1265, 1192, 1009, 755, 719, 696 cm^–1

.

P

S. Wang et al.

Paper

Synthesis

¹H NMR (400 МHz, DMSO-d₆):  = 12.08 (br s, 1 H), 7.89–7.77 (m, 3

H), 7.68 (d, J = 6.9 Hz, 1 H), 7.47 (d, J = 7.6 Hz, 2 H), 7.37 (t, J = 7.5 Hz, 2

H), 7.27 (t, J = 7.3 Hz, 1 H), 7.00–6.92 (m, 2 H), 6.92–6.80 (m, 3 H),

4.22–4.11 (m, 1 H), 3.55 (br s, 1 H), 3.17 (s, 1 H), 1.60–1.37 (m, 2 H),

1.08–0.96 (m, 1 H), 0.80 (d, J = 6.4 Hz, 3 H), 0.66 (d, J = 6.4 Hz, 3 H).

¹³C NMR (101 МHz, DMSO-d₆):  = 203.3, 200.0, 141.6, 141.0, 137.0,

136.7, 134.9, 132.9, 131.6 (2 С), 131.1 (2 С), 128.2 (2 С), 127.7 (2 С),

127.3, 127.2, 123.1, 123.0, 75.5, 67.1, 40.6, 39.5, 39.4, 25.2 (2 С), 24.1,

21.7.

(±)-(1R,4R,5S,6R)-1′,3′-Dioxo-1,4,5-triphenyl-1′,3′-dihydro-3-

azaspiro[bicyclo[3.1.0]hexane-2,2′-inden]-6-carboxylic Acid (9d)

The reaction was performed according to GP-C employing ninhydrin

(1; 71 mg, 0.4 mmol), cyclopropene 3j (94 mg, 0.4 mmol), and DL-

phenylglycine (7i; 121 mg, 0.8 mmol). Purification by PTLC on silica

gel (hexane–EtOAc 1:1) followed by trituration with a mixture of

MeOH–H₂O (2:1) afforded 9d as a single diastereomer; yield: 118 mg

(61%); white solid; mp 250–251 °C; R_f= 0.53 (SiO₂, hexane–EtOAc

1:1).

HRMS (ESI): m/z [M + H]⁺calcd for C₃₀H₂₈NO₄⁺: 466.2013; found:

466.2020.

IR (KBr): 3263, 3000, 2723, 2500, 1727, 1706, 1590, 1498, 1447, 1354,

1196, 1000, 752, 695 cm^–1

.

¹H NMR (400 МHz, DMSO-d₆):  = 10.58 (br s, 1 H), 7.90–7.76 (m, 3

H), 7.67 (d, J = 7.5 Hz, 1 H), 7.41–7.22 (m, 8 H), 7.08–6.98 (m, 4 H),

6.94–6.82 (m, 3 H), 5.37 (d, J = 4.9 Hz, 1 H), 4.14 (d, J = 4.9 Hz, 1 H),

3.58 (s, 1 H).

(±)-(1R,4R,5S,6R)-4-Butyl-1′,3′-dioxo-1,5-diphenyl-1′,3′-dihydro-

3-azaspiro[bicyclo[3.1.0]hexane-2,2′-indene]-6-carboxylic Acid

(9b)

¹³C NMR (101 МHz, DMSO-d₆):  = 205.0, 200.2, 170.7, 141.7, 140.9,

139.3, 136.8, 137.6, 134.4, 132.7, 132.0 (2 C), 131.2 (2 C), 128.3 (2 C),

128.1, 128.0 (2 C), 127.8 (2 C), 127.5 (3 C), 127.4, 123.0, 122.8, 74.7,

70.7, 51.2, 50.4, 25.7.

HRMS (ESI): m/z [M + H]⁺calcd for C₃₂H₂₄NO₄⁺: 486.1700; found:

486.1706.

The reaction was performed according to GP-C employing ninhydrin

(1; 71 mg, 0.4 mmol), cyclopropene 3j (94 mg, 0.4 mmol), and DL-nor-

leucine (7c; 105 mg, 0.8 mmol). Purification by PTLC on silica gel

(hexane–EtOAc 1:1) followed by trituration with a mixture of MeOH–

H₂O (2:1) afforded 9b as a single diastereomer; yield: 95 mg (51%);

beige solid; mp >260 °C; R_f= 0.60 (SiO₂, hexane–EtOAc 1:1).

IR (KBr): 3262, 3090, 3065, 3028, 2955, 2931, 2871, 2693, 2526, 1746,

1721, 1588, 1496, 1449, 1208, 1186, 870, 754, 710 cm^–1

.

(±)-(1R,4R,5S,6R)-4-Benzyl-1′,3′-dioxo-1,5-diphenyl-1′,3′-dihydro-

3-azaspiro[bicyclo[3.1.0]hexane-2,2′-indene]-6-carboxylic Acid

(9e)

¹H NMR (400 МHz, DMSO-d₆):  = 12.03 (br s, 1 H), 7.90–7.75 (m, 3

H), 7.67 (d, J = 6.9 Hz, 1 H), 7.47 (d, J = 7.3 Hz, 2 H), 7.37 (t, J = 7.5 Hz, 2

H), 7.26 (t, J = 7.5 Hz, 1 H), 7.02–6.93 (m, 2 H), 6.92–6.80 (m, 3 H),

4.13–4.00 (m, 1 H), 3.60 (br s, 1 H), 3.19 (s, 1 H), 1.48–0.97 (m, 6 H),

0.75 (t, J = 7.0 Hz, 3H).

¹³C NMR (101 МHz, CDCl₃):  = 203.4, 200.1, 170.9, 141.6, 141.0,

137.0, 136.7, 135.1, 132.9, 131.6 (2 C), 131.1 (2 C), 128.2 (2 C), 127.7

(2 C), 127.3, 127.2, 123.1, 123.0, 75.4, 69.0, 51.8, 49.9, 30.2, 29.0, 25.3,

22.6, 14.3.

The reaction was performed according to GP-C employing ninhydrin

(1; 71 mg, 0.4 mmol), cyclopropene 3j (94 mg, 0.4 mmol, and L-phe-

nylalanine (7e; 132 mg, 0.8 mmol). Purification by PTLC on silica gel

(hexane–EtOAc 1:1) followed by trituration with a mixture of MeOH–

H₂O (2:1) afforded 9e as a single diastereomer; yield: 78 mg (39%);

off-white solid; mp 238–239 °C; R_f= 0.52 (SiO₂, hexane–EtOAc 1:1).

IR (KBr): 3432, 3262, 3055, 2929, 2684, 2510, 1732, 1706, 1497, 1448,

1415, 1379, 1269, 1198, 1017, 855, 729, 698 cm^–1

.

HRMS (ESI): m/z [M + H]⁺calcd for C₃₀H₂₈NO₄⁺: 466.2013; found:

¹H NMR (400 MHz, DMSO-d₆):  = 12.15 (br s, 1 H), 7.82 (d, J = 7.2 Hz,

1 H), 7.78 (t, J = 7.2 Hz, 1 H), 7.74 (t, J = 7.2 Hz, 1 H), 7.59 (d, J = 7.2 Hz,

1 H), 7.54 (d, J = 7.4 Hz, 2 H), 7.41 (t, J = 7.4 Hz, 2 H), 7.29 (t, J = 7.4 Hz,

1 H), 7.19 (t, J = 7.7 Hz, 2 H), 7.11 (t, J = 7.7 Hz, 1 H), 7.05 (d, J = 7.7 Hz,

2 H), 6.96 (d, J = 7.4 Hz, 2 H), 6.88 (t, J = 7.4 Hz, 2 H), 6.83 (t, J = 7.4 Hz,

1 H), 4.33 (ddd, J = 9.8, 7.2, 2.6 Hz, 1 H), 3.54 (d, J = 7.2 Hz, 1 H), 3.36

(s, 1 H), 2.69 (dd, J = 13.7, 9.8 Hz, 1 H), 2.60 (dd, J = 13.7, 2.6 Hz, 1 H).

¹³C NMR (101 MHz, DMSO-d₆):  = 203.6, 199.9, 170.9, 141.6, 141.0,

139.7, 136.8, 136.6, 134.7, 132.7, 131.7 (2 C), 131.1 (2 C), 129.2 (2 C),

128.7 (2 C), 128.4 (2 C), 127.8 (2 C), 127.5, 127.3, 126.4, 123.0, 122.9,

75.3, 70.7, 51.6, 49.6, 36.6, 25.3.

466.2023.

(±)-(1R,4R,5S,6R)-4-Hexyl-1′,3′-dioxo-1,5-diphenyl-1′,3′-dihydro-

3-azaspiro[bicyclo[3.1.0]hexane-2,2′-indene]-6-carboxylic Acid

(9c)

The reaction was performed according to GP-C employing ninhydrin

(1; 71 mg, 0.4 mmol), cyclopropene 3j (94 mg, 0.4 mmol), and DL-2-

aminocaprylic acid (7d; 127 mg, 0.8 mmol). Purification by PTLC on

silica gel (hexane–EtOAc 1:1) followed by trituration with a mixture

of MeOH–H₂O (2:1) afforded 9c as a single diastereomer; yield: 83 mg

(42%); beige solid; mp 205–207 °C; R_f= 0.66 (SiO₂, hexane–EtOAc 1:1).

HRMS (ESI): m/z [M + H]⁺calcd for C₃₃H₂₆NO₄⁺: 500.1856; found:

500.1872.

IR (KBr): 3262, 3059, 3025, 2955, 2929, 2859, 2515, 1750, 1713, 1679,

1264, 723, 705 cm^–1

.

¹H NMR (400 МHz, DMSO-d₆):  = 12.06 (br s, 1 H), 7.90–7.75 (m, 3

H), 7.66 (d, J = 7.2 Hz, 1 H), 7.46 (d, J = 7.5 Hz, 2 H), 7.37 (t, J = 7.6 Hz, 2

H), 7.26 (t, J = 7.2 Hz, 1 H), 6.97–6.92 (m, 2 H), 6.91–6.80 (m, 3 H),

4.08–4.03 (m, 1 H), 3.76 (br s, 1 H), 3.18 (s, 1 H), 1.31–1.08 (m, 10 H),

0.80 (t, J = 6.7 Hz, 3 H).

¹³C NMR (101 МHz, CDCl₃):  = 203.4, 200.1, 170.9, 141.6, 141.0,

137.0, 136.8, 135.0, 132.9, 131.6 (2 C), 131.1 (2 C), 128.2 (2 C), 127.7

(2 C), 127.3, 127.2, 123.1, 123.0, 75.4, 69.0, 51.8, 49.9, 31.6, 30.6, 29.2,

26.7, 25.3, 24.6, 22.4.

(±)-(1R,4R,5S,6R)-4-Isopropyl-1′,3′-dioxo-1,5-diphenyl-1′,3′-dihy-

dro-3-azaspiro[bicyclo[3.1.0]hexane-2,2′-indene]-6-carboxylic

Acid (9f)

The reaction was performed according to GP-C employing ninhydrin

(1; 71 mg, 0.4 mmol), cyclopropene 3j (94 mg, 0.4 mmol), and L-va-

line (7k; 94 mg, 0.8 mmol). Purification by PTLC on silica gel (hex-

ane–EtOAc 1:1) followed by trituration with a mixture of MeOH–H₂O

(2:1) afforded 9f as a single diastereomer; yield: 40 mg (22%); off-

white solid; mp >260 °C; R_f= 0.54 (SiO₂, hexane–EtOAc 1:1).

HRMS (ESI): m/z [M + Na]⁺calcd for C₃₂H₃₁NO₄⁺Na: 516.2145; found:

IR (KBr): 3445, 3260, 2905, 1725, 1595, 1494, 1430, 1339, 1281, 1202,

516.2148.

1155, 996, 956, 876, 823, 753, 729, 698 cm^–1

.

Q

S. Wang et al.

Paper

Synthesis

¹H NMR (400 MHz, DMSO-d₆):  = 12.13 (br s, 1 H), 7.90–7.75 (m, 3

H), 7.61 (d, J = 7.2 Hz, 1 H), 7.55–7.48 (d, J = 7.4 Hz, 2 H), 7.41–7.29 (m,

2 H), 7.26–7.20 (m, 1 H), 6.86–6.79 (m, 5 H), 4.18 (d, J = 5.0 Hz, 1 H),

3.58 (br s, 1 H), 3.41 (s, 1 H), 1.61 (m, 1 H), 0.95 (d, J = 6.6 Hz, 3 H),

0.70 (d, J = 6.6 Hz, 3 H).

¹³C NMR (101 MHz, DMSO-d₆):  = 203.1, 199.8, 169.8 (2 C), 169.1,

141.6, 141.0, 137.1, 136.9, 136.1, 133.1, 133.0 (3 C), 132.5 (2 C), 131.2

(3 C), 128.1 (2 C), 128.0 (2 C), 127.5, 126.9 (2 C), 125.9, 123.2, 123.1,

76.4, 71.2, 51.7, 47.5, 42.3, 41.2, 28.1.

HRMS (ESI): m/z [M + H]⁺calcd for C₃₆H₃₀N₃O₆⁺: 600.2129; found:

¹³C NMR (101 MHz, DMSO-d₆):  = 204.2, 200.5, 171.1, 141.7, 141.0,

136.8, 136.6, 135.5, 132.7, 131.6 (2 C), 131.3 (2 C), 128.2 (2 C), 127.6

(2 C), 127.2 (2 C), 122.9, 122.8, 74.3, 72.9, 50.4, 47.8, 29.7, 26.1, 21.3,

18.2.

600.2150.

(±)-(1R,4S,5S,6R)-4-[(Carboxymethyl)carbamoyl]-1′,3′-dioxo-1,5-

diphenyl-1′,3′-dihydro-3-azaspiro[bicyclo[3.1.0]hexane-2,2′-in-

dene]-6-carboxylic Acid (11c)

HRMS (ESI): m/z [M + H]⁺calcd for C₂₉H₂₆NO₄⁺: 452.1856; found:

452.1862.

Product 11c was obtained as a single diastereomer by following GP-D

from ninhydrin (1; 71 mg, 0.4 mmol), cyclopropene 3j (94 mg, 0.4

mmol), and Gly-Gly (10a; 106 mg, 0.8 mmol); yield: 129 mg (63%);

off-white solid; mp 207–208 °C; R_f= 0.54 (SiO₂, CH₂Cl₂–MeOH 10:1).

One-Pot Three-Component Reaction of Ninhydrin, Glycine Pep-

tides, and Cyclopropenes; General Procedure D (GP-D)

A mixture of ninhydrin (1; 71 mg, 0.4 mmol) cyclopropene 3 (0.4

mmol) and peptide 10 (0.8 mmol) was refluxed in a mixture of

MeOH–H₂O (3:1, 20 mL) in the presence of AcOH (50 L) for 12 h (TLC

control). After cooling, all volatiles were removed in vacuo and the

residue was subjected to silica gel PTLC using CH₂Cl₂–MeOH as an elu-

ent. Subsequent trituration with a mixture of MeOH–water (2:1) gave

pure cycloadduct 11.

IR (KBr): 3378, 3064, 1743, 1707, 1622, 1533, 1432, 1287, 1265, 1228,

1190, 953, 701 cm^–1

.

¹H NMR (400 MHz, DMSO-d₆):  = 12.20 (br s, 1 H), 7.90 (d, J = 7.3 Hz,

1 H), 7.88–7.76 (m, 3 H), 7.65 (s, J = 7.3 Hz, 1 H), 7.44 (d, J = 7.3 Hz, 2

H), 7.32 (t, J = 7.3 Hz, 2 H), 7.23 (t, J = 7.2 Hz, 1 H), 7.02–6.80 (m, 5 H),

4.58 (d, J = 8.0 Hz, 1 H), 3.72–3.57 (m, 2 H), 3.37 (s, 1 H).

¹³C NMR (101 MHz, DMSO-d₆):  = 202.4, 199.2, 170.2, 169.4 (2 C),

141.5, 141.0, 137.3, 137.0, 133.2, 132.1 (2 С), 132.0, 131.2 (2 С), 127.9

(4 C), 127.5, 127.4, 123.3, 123.2, 76.0, 70.6, 52.2, 48.8, 41.4, 25.1.

(±)-{(1R,4S,5S,6R)-1′,3′-Dioxo-1,5,6-triphenyl-1′,3′-dihydro-3-

azaspiro[bicyclo[3.1.0]hexane-2,2′-indene]-4-carbonyl}glycine

(11a)

HRMS (ESI): m/z [M + H]⁺calcd for C₂₉H₂₃N₂O₇⁺: 511.1500; found:

511.1512.

Product 11a was obtained as a single diastereomer by following GP-D

from ninhydrin (1; 71 mg, 0.4 mmol), cyclopropene 3a (107 mg, 0.4

mmol), and Gly-Gly (10a; 106 mg, 0.8 mmol); yield: 91 mg (42%); off-

white solid; mp 189–190 °C; R_f= 0.49 (SiO₂, CH₂Cl₂–MeOH, 10:1).

(±)-4-({2-[(Carboxymethyl)amino]-2-oxoethyl}carbamoyl)-1′,3′-

dioxo-1,5-diphenyl-1′,3′-dihydro-3-azaspiro[bicyclo[3.1.0]hexane-

2,2′-indene]-6-carboxylic Acid (11d)

IR (KBr): 3381, 3376, 3053, 2501, 1743, 1707, 1625, 1601, 1532, 1266,

Product 11d was obtained as a single diastereomer by following GP-D

from ninhydrin (1; 71 mg, 0.4 mmol), cyclopropene 3j (94 mg, 0.4

mmol), and Gly-Gly-Gly (10b; 151 mg, 0.8 mmol); yield: 114 mg

(50%); off-white solid; mp 194–195 °C; R_f= 0.42 (SiO₂, CH₂Cl₂–MeOH

10:1).

701 cm^–1

.

¹H NMR (400 MHz, DMSO-d₆):  = 12.55 (br s, 1 H), 7.96–7.72 (m, 4

H), 7.65 (d, J = 6.9 Hz, 1 H), 7.31–7.15 (m, 5 H), 7.01–6.91 (m, 1 H),

6.92–6.62 (m, 7 H), 6.28 (d, J = 7.4 Hz, 2 H), 4.66 (d, J = 7.5 Hz, 1 H),

3.89 (d, J = 8.0 Hz, 1 H), 3.84 (s, 1 H), 3.83–3.71 (m, 1 H), 3.71–3.56 (m,

1 H).

¹³C NMR (101 MHz, DMSO-d₆):  = 203.1, 199.9, 169.9 (2 C), 141.6,

141.0, 137.1, 136.9, 136.2, 133.2 (2 С), 133.1 (2 C), 132.5, 131.3 (3 С),

128.0 (4 С), 127.6, 127.5, 126.8 (2 С), 125.8, 123.2, 123.1, 76.4, 71.1,

51.7, 47.6, 41.3, 28.1.

IR (KBr): 3326, 3059, 2960, 1741, 1669, 1533, 1413, 1266, 1196, 700

cm^–1

.

¹H NMR (400 MHz, DMSO-d₆):  = 12.20 (br s, 2 H), 7.95 (br s, 1 H),

7.93–7.73 (m, 4 H), 7.65 (d, J = 7.4 Hz, 1 H), 7.48–7.40 (m, 2 H), 7.38–

7.30 (m, 2 H), 7.26–7.20 (m, 1 H), 7.01–6.80 (m, 5 H), 4.61 (d, J = 8.0

Hz, 1 H), 3.91–3.54 (m, 5 H), 3.36 (s, 1 H).

¹³C NMR (101 MHz, DMSO-d₆):  = 202.5, 199.2, 170.1, 169.3 (2 C),

169.0, 141.5, 140.9, 137.3, 137.0, 133.4, 132.0 (3 С), 131.2 (2 С), 128.0

(2 С), 127.9 (2 С), 127.5 (2 С), 123.3, 123.2, 76.0, 70.7, 52.2, 48.7, 42.4,

41.2, 25.2.

HRMS (ESI): m/z [M + H]⁺calcd for C₃₄H₂₇N₂O₅⁺: 543.1914; found:

543.1930.

(±)-{(1R,4S,5S,6R)-1′,3′-Dioxo-1,5,6-triphenyl-1′,3′-dihydro-3-

azaspiro[bicyclo[3.1.0]hexane-2,2′-indene]-4-carbonyl}glycylgly-

cine (11b)

HRMS (ESI): m/z [M + H]⁺calcd for C₃₁H₂₆N₃O₈⁺: 568.1714; found:

568.1727.

Product 11b was obtained as a single diastereomer by following GP-D

from ninhydrin (1; 71 mg, 0.4 mmol), cyclopropene 3a (107 mg, 0.4

mmol), and Gly-Gly-Gly (10b; 151 mg, 0.8 mmol); yield: 130 mg

(54%); white solid; mp 167–168 °C; R_f= 0.54 (SiO₂, CH₂Cl₂–MeOH

10:1).

Computational Methodology

The full geometry optimization of reactants, products, and transition

states structures (TSs) were carried out at DFT/HF level of theory us-

ing M11 hybrid exchange-correlation functional³⁸and cc-pVDZ basis

set.³⁹The polarizable continuum model (PCM) was used to calculate

solvent effects of MeOH.⁴⁰The optimizations were performed using

the Berny analytical gradient optimization method.⁴¹All stationary

points were described by harmonic vibrational frequency calcula-

tions to prove the location of correct minima (only real frequencies)

and transition states (only one imaginary frequency). For the transi-

tion states, the normal modes corresponding to the imaginary fre-

quencies were related to the vibrations of new developing bonds. IRC

IR (KBr): 3327, 3040, 2935, 2500, 1741, 1709, 1665, 1529, 1498, 1266,

1220, 1045, 702 cm^–1

.

¹H NMR (400 MHz, DMSO-d₆):  = 12.59 (br s, 1H), 7.97 (br s, 1 H),

7.92–7.72 (m, 4 H), 7.65 (d, J = 6.7 Hz, 1 H), 7.38–7.11 (m, 5 H), 7.07–

6.56 (m, 8 H), 6.27 (d, J = 7.3 Hz, 2 H), 4.69 (d, J = 7.5 Hz, 1 H), 3.94–

3.85 (m, 2 H), 3.82 (s, 1 H), 3.74 (br s, 1 H), 3.66–3.53 (m, 2 H).

R

S. Wang et al.

Paper

Synthesis

calculations were conducted to check the energy profiles connecting

each TS to the two associated minima of the proposed mechanism.⁴²

Thermal corrections to enthalpy and entropy values were evaluated

at 298.15 K and 1.0 atm. All calculations were performed using Gauss-

ian 09 computational program package.⁴³

Supporting Information

Supporting information for this article is available online at

https://doi.org/10.1055/a-1360-9716. Su

p

ortingInformationS

u

p

ortingI

n

formati

o

n

References

Bioassay Details

Tumor Cell Line

(1) (a) Liu, H.-W.; Walsh, C. T. In The Chemistry of the Cyclopropyl

Group; Rappoport, Z., Ed.; Wiley: New York, 1987, 959–1025.

(b) Netz, N.; Opatz, T. J. Org. Chem. 2016, 81, 1723.

The cervical carcinoma (HeLa) cell line was obtained from the Bank of

Cell Cultures of the Institute of Cytology of the Russian Academy of

Sciences. HeLa cells were cultured in the DMEM medium (Thermo

scientific, USA) with the addition of 10% fetal calf serum (FCS) (Ther-

mo scientific, USA) and 40 g/mL gentamicin (Sigma, USA).

(2) (a) Moffat, D.; Patel, S.; Day, F.; Belfield, A.; Donald, A.;

Rowlands, M.; Wibawa, J.; Brotherton, D.; Stimson, L.; Clark, V.;

Owen, J.; Bawden, L.; Box, G.; Bone, E.; Mortenson, P.;

Hardcastle, A.; Meurs, S.; Eccles, S.; Raynaud, F.; Aherne, W.

J. Med. Chem. 2010, 53, 8663. (b) Lunn, G.; Banks, B. J.; Crook, R.;

Feeder, N.; Pettman, A.; Sabnis, Y. Bioorg. Med. Chem. Lett. 2011,

21, 4608. (c) McHardy, S. F.; Heck, S. D.; Guediche, S.; Kalman,

M.; Allen, M. P.; Tu, M.; Bryce, D. K.; Schmidt, A. W.; Vanase-

Frawley, M.; Callegari, E.; Doran, S.; Grahame, N. J.; Mclean, S.;

Liras, S. Med. Chem. Commun. 2011, 2, 1001. (d) Orri, M.;

Abraham, L.; Giraldi, A. J. Sex. Med. 2013, 10, 2484.

(3) (a) Li, T.; Liang, J.; Ambrogelly, A.; Brennan, T.; Gloor, G.;

Huisman, G.; Lalonde, J.; Lekhal, A.; Mijts, B.; Muley, S.;

Newman, L.; Tobin, M.; Wong, G.; Zaks, A.; Zhang, X. J. Am.Chem.

Soc. 2012, 134, 6467. (b) Topczewski, J. J.; Cabrera, P. J.; Saper, N.

I.; Sanford, M. S. Nature 2016, 531, 220.

(4) Micheli, F.; Cavanni, P.; Arban, R.; Benedetti, R.; Bertani, B.;

Bettati, M.; Bettelini, L.; Bonanomi, G.; Braggio, S.; Checchia, A.;

Davalli, S.; Di-Fabio, R.; Fazzolari, E.; Fontana, S.; Marchioro, C.;

Minick, D.; Negri, M.; Oliosi, B.; Read, K. D.; Sartori, I.; Tedesco,

G.; Tarsi, L.; Terreni, S.; Visentini, F.; Zocchi, A.; Zonzini, L. J. Med.

Chem. 2010, 53, 2534.

(5) Micheli, F.; Arista, L.; Bonanomi, G.; Blaney, F. E.; Braggio, S.;

Capelli, A. M.; Checchia, A.; Damiani, F.; Di-Fabio, R.; Fontana, S.;

Gentile, G.; Griffante, C.; Hamprecht, D.; Marchioro, C.;

Mugnaini, M.; Piner, J.; Ratti, E.; Tedesco, G.; Tarsi, L.; Terreni, S.;

Worby, A.; Ashby, C. R. Jr.; Heidbreder, C. J. Med. Chem. 2010, 53,

374.

MTS Assay

A colorimetric MTS assay was used for assessing cell metabolic activi-

ty. This method in based on the reduction of 3-(4,5-dimethylthiazol-

2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazoli-

um (MTS) to colored and soluble in cell culture media formazan prod-

uct by NAD(P)H-dependent dehydrogenase enzymes. Since this con-

version and such decrease of MTS can only occur in metabolically ac-

tive cells, the level of activity is the measure of the viability of the

cells. Shortly, cells were seeded in a 96-well microtiter plates at a den-

sity of 100 × 10³cells per well in 100 L of complete medium and al-

lowed to grow and adhere onto the wells during 24 h at 37 °C. After

that the cells were treated with various concentrations of the com-

pounds for a period of 24 or 72 h. After the treatment, 20 L of MTS

reagent was added into each well and incubated at 37 °C for 2 h. Final-

ly, the absorbance was recorded at 490 nm using 96-well plate reader

‘Multiskan GO’ (Thermo Fisher Scientific, USA). For colored solutions

the protocol was modified as followed: the absorbance was recorded

directly before the addition of MTS reagent and measured values

were further subtracted from final absorbance.

Statistical Analysis

Significance of results was performed using Student’s t-test. Statisti-

cal processing of results was performed using Origin Pro software.

IC₅₀was calculated using Prism 6 for Windows. Differences between

groups were considered significant at р ≤0.05.

(6) Micheli, F.; Arista, L.; Bertani, B.; Braggio, S.; Capelli, A. M.;

Cremonesi, S.; Di Fabio, R.; Gelardi, G.; Gentile, G.; Marchioro, C.;

Pasquarello, A.; Provera, S.; Tedesco, G.; Tarsi, L.; Terreni, S.;

Worby, A. Heidbreder C. 2010, 53, 7129.

(7) Bonanomi, G.; Braggio, S.; Capelli, A. M.; Checchia, A.; Di Fabio,

R.; Marchioro, C.; Tarsi, L.; Tedesco, G.; Terreni, S.; Worby, A.;

Heibreder, C.; Micheli, F. ChemMedChem 2010, 5, 705.

(8) Patel, S.; Meilandt, W. J.; Erickson, R. I.; Chen, J.; Deshmukh, G.;

Estrada, A. A.; Fuji, R. N.; Gibbons, P.; Gustafson, A.; Harris, S. F.;

Imperio, J.; Liu, W.; Liu, X.; Liu, Y.; Lyssikatos, J. P.; Ma, C.; Yin, J.;

Lewcock, J. W.; Siu, M. J. Med. Chem. 2017, 60, 8083.

(9) Siu, M.; Ghosh, A. S.; Lewcock, J. W. J. Med. Chem. 2018, 61, 8078.

(10) McAllister, L. A.; Butler, C. R.; Mente, S.; O’Neil, S. V.; Fonseca, K.

R.; Piro, J. R.; Cianfrogna, J. A.; Foley, T. L.; Gilbert, A. M.; Harris,

A. R.; Helal, C. J.; Johnson, D. S.; Montgomery, J. I.; Nason, D. M.;

Noell, S.; Pandit, J.; Rogers, B. N.; Samad, T. A.; Shaffer, C. L.; da

Silva, R. G.; Uccello, D. P.; Webb, D.; Brodney, M. A. J. Med. Chem.

2018, 61, 3008.

(11) Velázquez, F.; Sannigrahi, M.; Bennett, B.; Lovey, R. G.;

Arasappan, A.; Bogen, S.; Nair, L.; Venkatraman, S.; Blackman,

M.; Hendrata, S.; Huang, Y.; Huelgas, R.; Pinto, P.; Cheng, K.-C.;

Tong, X.; McPhail, A. T.; Njoroge, F. G. J. Med. Chem. 2010, 53,

3075.

Funding Information

We gratefully acknowledge the financial support from the Russian

Foundation for Basic Research (Projects nos. 18-015-00443 and 18-

33-00464) and the Ministry of Education and Science of the Russian

Federation (Project No 0791-2020-0006). S.W. is grateful for the sup-

port and funding received from China Scholarship Council.

R

usia

n

F

o

u

n

datio

n

forBasi

c

R

esearch(18-0

1

5-0

0

4

3)Rusia

n

F

o

u

n

datio

n

forBasic

R

esearch(18-33-0

0

4

6

4)Ministry

o

f

E

d

u

catio

n

a

n

d

Science

o

f

th

e

R

usian

F

ederati

o

n

(0

7

9

1-2

0

2

0-0

0

6)C

h

inaSch

o

larship

C

o

u

n

cil

(

)

Acknowledgment

This research made use of resources from the X-ray Diffraction Cen-

tre, Computer Center, Centre for Magnetic Resonance, Educational Re-

source Center of Chemistry, and Centre for Chemical Analysis and

Materials of Saint-Petersburg State University.

S

S. Wang et al.

Paper

Synthesis

(12) Jones, S.; Ahmet, J.; Ayton, K.; Ball, M.; Cockerill, M.;

Fairweather, E.; Hamilton, N.; Harper, P.; Hitchin, J.; Jordan, A.;

Levy, C.; Lopez, R.; McKenzie, E.; Packer, M.; Plant, D.; Simpson,

L.; Simpson, P.; Sinclair, L.; Somervaille, T. C. P.; Small, H.;

Spencer, G. J.; Thomson, G.; Tonge, M.; Waddell, L.; Walsh, J.;

Waszkowycz, B.; Wigglesworth, M.; Wiseman, D. H.; Ogilvie, D.

J. Med. Chem. 2016, 59, 11120.

(d) Kumaran, S.; Saritha, R.; Gurumurthy, P.; Parthasarathy, K.

Eur. J. Org. Chem. 2020, 2725. (e) Prabhakaran, P.; Rajakumar, P.

RSC Adv. 2020, 10, 10263. (f) Gupta, S.; Khurana, J. M. Chemistry-

Select 2019, 4, 7200.

(26) Filatov, A. S.; Wang, S.; Khoroshilova, O. V.; Lozovskiy, S. V.;

Larina, A. G.; Boitsov, V. M.; Stepakov, A. V. J. Org. Chem. 2019,

84, 7017.

(13) Nirogi, R.; Mohammed, A. R.; Shinde, A. K.; Gagginapally, S. R.;

Kancharla, D. M.; Middekadi, V. R.; Bogaraju, N.; Ravella, S. R.;

Singh, P.; Birangal, S. R.; Subramanian, R.; Palacharla, R. C.;

Benade, V.; Muddana, N.; Jayarajan, P. J. Med. Chem. 2018, 61,

4993.

(27) Panja, S. K.; Karmakar, P.; Chakraborty, J.; Ghosh, T.;

Bandyopadhyay, C. Tetrahedron Lett. 2008, 49, 4397.

(28) (a) Beletskii, E. V.; Kuznetsov, M. A. Russ. J. Org. Chem. 2009, 45,

1229. (b) Pankova, A. S.; Kuznetsov, M. A. Tetrahedron Lett. 2014,

55, 2499.

(14) Li, X.; Zhang, Z.; Chen, Y.; Wan, H.; Sun, J.; Wang, B.; Feng, B.;

Hu, B.; Shi, X.; Feng, J.; Zhang, L.; He, F.; Bai, C.; Zhang, L.; Tao,

W. ACS Med. Chem. Lett. 2019, 10, 996.

(15) Scott, J. S.; Barton, P.; Bennett, S. N. L.; deSchoolmeester, J.;

Godfrey, L.; Kilgour, E.; Mayers, R. M.; Packer, M. J.; Rees, A.;

Schofield, P.; Selmi, N.; Swales, J. G.; Whittamore, P. R. O. Med.

Chem. Commun. 2012, 3, 1264.

(29) Aly, M. F.; Ardill, H.; Grigg, R.; Leong-Ling, S.; Rajviroongit, S.;

Surendrakumar, S. Tetrahedron Lett. 1987, 28, 6077.

(30) Nirmala, S.; Kamala, E. T. S.; Sudha, L.; Ramesh, E.; Raghunathan,

R. Anal. Sci.: X-Ray Struct. Anal. Online 2008, 24, x101.

(31) Breslow, R.; Chang, H. W. J. Am. Chem. Soc. 1961, 83, 2367.

(32) Padwa, A.; Blacklock, T. J.; Getman, D.; Hatanaka, N.; Loza, R.

J. Org. Chem. 1978, 43, 1481.

(16) Sabbatini, F. M.; Melotto, S.; Bernasconi, G.; Bromidge, S. M.;

D’Adamo, L.; Rinaldi, M.; Savoia, C.; Mundi, C.; Di Francesco, C.;

Zonzini, L.; Costantini, V. J. A.; Perini, B.; Valerio, E.; Pozzan, A.;

Perdonà, E.; Visentini, F.; Corsi, M.; Di Fabio, R. ChemMedChem

2011, 6, 1981.

(33) Gilbertson, R. D.; Weakley, T. J. R.; Haley, M. M. J. Org. Chem.

2000, 65, 1422.

(34) D’yakonov, I. A.; Komendantov, M. I.; Gokhmanova, I.; Kostikov,

R. R. Russ. J. Gen. Chem. 1958, 29, 3848.

(35) White, E. H.; Winter, R. E. K.; Graeve, R.; Zirngibl, U.; Friend, E.

W.; Maskill, H.; Mende, U.; Kreiling, G.; Reisenauer, H. P.; Maier,

G. Chem. Ber. 1981, 114, 3906.

(17) Zheng, Y.; Yu, X.; Lv, S.; Mykhailiuk, P. K.; Ma, Q.; Hai, L.; Wu, Y.

RSC Adv. 2018, 8, 5114.

(18) Chen, P.; Zhu, C.; Zhu, R.; Lin, Z.; Wu, W.; Jiang, H. Org. Biomol.

Chem. 2017, 15, 1228.

(36) Li, H.; Praveen Rao, P. N.; Habeeb, A. G.; Knaus, E. E. Drug Dev.

Res. 2002, 57, 6.

(19) Böhmer, J.; Grigg, R.; Marchbank, J. D. Chem. Commun. 2002,

768.

(37) Crystallographic data for compound 8a have been deposited at

the Cambridge Crystallographic Data Centre (Deposition No.

CCDC-1840079) and can be obtained free of charge via

www.ccdc.cam.ac.uk/structures

(38) Peveratti, R.; Truhlar, D. G. J. Phys. Chem. Lett. 2011, 2, 2810.

(39) Dunning, T. H. J. Chem. Phys. 1989, 90, 1007.

(20) (a) Ohno, H.; Takeoka, Y.; Miyamura, K.; Kadoh, Y.; Tanaka, T.

Org. Lett. 2003, 5, 4763. (b) Ohno, H.; Takeoka, Y.; Kadoh, Y.;

Miyamura, K.; Tanaka, T. J. Org. Chem. 2004, 69, 4541.

(21) Pedroni, J.; Cramer, N. J. Am. Chem. Soc. 2017, 139, 12398.

(22) Veeranna, K. D.; Das, K. K.; Baskaran, S. Chem. Commun. 2019,

55, 7647.

(40) Cossi, M.; Rega, N.; Scalmani, G.; Barone, V. J. Comput. Chem.

2003, 24, 669.

(23) Wang, K.-B.; Ran, R.-Q.; Xiu, S.-D.; Li, C.-Y. Org. Lett. 2013, 15,

2374.

(41) Schlegel, H. B. J. Comput. Chem. 1982, 3, 214.

(42) Fukui, K. J. J. Phys. Chem. 1970, 74, 4161.

(24) (a) Yuan, Y.; Zheng, Z.-J.; Ye, F.; Ma, J.-H.; Xu, Z.; Bai, X.-F.; Li, L.;

Xu, L.-W. Org. Chem. Front. 2018, 5, 2759. (b) Deng, H.; Yang, W.-

L.; Tian, F.; Tang, W.; Deng, W.-P. Org. Lett. 2018, 20, 4121.

(c) Filatov, A. S.; Knyazev, N. A.; Molchanov, A. P.; Panikorovsky,

T. L.; Kostikov, R. R.; Larina, A. G.; Boitsov, V. M.; Stepakov, A. V.

J. Org. Chem. 2017, 82, 959. (d) Filatov, A. S.; Knyazev, N. A.;

Ryazantsev, M. N.; Suslonov, V. V.; Larina, A. G.; Molchanov, A.

P.; Kostikov, R. R.; Boitsov, V. M.; Stepakov, A. V. Org. Chem.

Front. 2018, 5, 595. (e) Filatov, A. S.; Knyazev, N. A.; Shmakov, S.

V.; Bogdanov, A. A.; Ryazantsev, M. N.; Shtyrov, A. A.; Starova, G.

L.; Molchanov, A. P.; Larina, A. G.; Boitsov, V. M.; Stepakov, A. V.

Synthesis 2019, 51, 713.

(25) (a) Zimnitskiy, N. S.; Denikaev, A. D.; Barkov, A. Y.; Kutyashev, I.

B.; Korotaev, V. Y.; Sosnovskikh, V. Y. J. Org. Chem. 2020, 85,

8683. (b) Kutyashev, I. B.; Barkov, A. Y.; Zimnitskiy, N. S.;

Korotaev, V. Y.; Sosnovskikh, V. Y. Chem. Heterocycl. Comp.

2019, 55, 861. (c) Angyal, A.; Demjén, A.; Harmat, V.; Wölfling,

J.; Puskás, L. G.; Kanizsai, I. J. Org. Chem. 2019, 84, 4273.

(43) Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb,

M. A.; Cheeseman, J. R.; Scalmani, G.; Barone, V.; Mennucci, B.;

Petersson, G. A.; Nakatsuji, H.; Caricato, M.; Li, X.; Hratchian, H.

P.; Izmaylov, A. F.; Bloino, J.; Zheng, G.; Sonnenberg, J. L.; Hada,

M.; Ehara, M.; Toyota, K.; Fukuda, R.; Hasegawa, J.; Ishida, M.;

Nakajima, T.; Honda, Y.; Kitao, O.; Nakai, H.; Vreven, T.;

Montgomery, J. A.; Peralta, J. E.; Ogliaro, F.; Bearpark, M.; Heyd,

J. J.; Brothers, E.; Kudin, K. N.; Staroverov, V. N.; Kobayashi, R.;

Normand, J.; Raghavachari, K.; Rendell, A.; Burant, J. C.; Iyengar,

S. S.; Tomasi, J.; Cossi, M.; Rega, N.; Millam, N. J.; Klene, M.;

Knox, J. E.; Cross, J. B.; Bakken, V.; Adamo, C.; Jaramillo, J.;

Gomperts, R.; Stratmann, R. E.; Yazyev, O.; Austin, A. J.; Cammi,

R.; Pomelli, C.; Ochterski, J. W.; Martin, R. L.; Morokuma, K.;

Zakrzewski, V. G.; Voth, G. A.; Salvador, P.; Dannenberg, J. J.;

Dapprich, S.; Daniels, A. D.; Farkas, Ő.; Foresman, J. B.; Ortiz, J.

V.; Cioslowski, J.; Fox, D. J. Gaussian 09, Revision C.01; Gaussian:

Wallingford CT, 2013.

Article Doi

Construction of Spiro[3-azabicyclo[31.0]hexanes] via 1,3-Dipolar Cycloaddition of 1,2-Diphenylcyclopropenes to Ninhydrin-Derived Azomethine Ylides

DOI: 10.1055/a-1360-9716

Source and publish data:

Authors:

Article abstract of DOI:10.1055/a-1360-9716

Full text of DOI:10.1055/a-1360-9716

Products guided by the article

R&D Labs maybe for 1043422-75-8

Relevant to this article

Hot Product