The Use of Domino Reactions for the Synthesis of Chiral Rings

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The Use of Domino Reactions for the Synthesis of Chiral Rings

Helene Pellissier

To cite this version:

Helene Pellissier. The Use of Domino Reactions for the Synthesis of Chiral Rings. SYNTHESIS,

Georg Thieme Verlag, 2020, �10.1055/s-0040-1707905�. �hal-02988822�

The Use of Domino Reactions for the Synthesis of Chiral Rings

Hélène Pellissier*

0000-0003-0773-5117

Aix Marseille Univ, CNRS, Centrale Marseille, iSm2, Marseille, France

h.pellissier@univ-amu.fr

Published as part of the Special Topic Recent Advances in Metal-Catalyzed Ring Construction

A [B]

Chiral Rings

metal catalyst*

Y

X X

X = N, O, S, C Y = O, N, C

X ( )

m

X = N, O, C n = 1–2 m = 0–2

N

A + B [C]

Chiral Rings

metal catalyst*

Chiral Rings =

( )

n

Received: 22.04.2020

Accepted after revision: 28.05.2020 Published online: 22.07.2020

DOI: 10.1055/s-0040-1707905; Art ID: ss-2020-c0191-sr

Abstract This short review highlights the recent developments re- ported in the last four years on the asymmetric construction of chiral rings based on enantioselective domino reactions promoted by chiral metal catalysts.

1 Introduction

2 Formation of One Ring Containing One Nitrogen Atom 3 Formation of One Ring Containing One Oxygen/Sulfur Atom 4 Formation of One Ring Containing Several Heterocyclic Atoms 5 Formation of One Carbon Ring

6 Formation of Two Rings 7 Conclusion

Key words chiral rings, enantioselective domino reactions, enantiose- lectivity, asymmetric metal catalysis, chirality

1 Introduction

In the last decades, asymmetric metal catalysis

¹

has been intensively combined with various types of domino reactions

²

to give simple and economic access to many highly functionalized and complex chiral molecules.

³

The goal of this short review is to highlight the advances made on the use of domino reactions catalyzed by chiral metals to synthesize chiral rings published in the last four years. It is divided into five parts, outlining successively the formation of one ring containing one nitrogen atom, one ring contain- ing one oxygen/sulfur atom, one ring containing several heterocyclic atoms, one carbon ring, and two rings through enantioselective metal-catalyzed domino reactions.

2 Formation of One Ring Containing One Nitrogen Atom

2.1 Five-Membered Rings

Many densely functionalized chiral cyclic molecules have been easily synthesized through a variety of highly ef- ficient enantioselective metal-catalyzed domino reactions.

The frameworks of a wide range of natural products contain a five-membered ring.

⁴

Chiral silver complexes have been shown to efficiently catalyze various types of domino reac- tions.

⁵

For example, in 2016, Oh and co-workers described the synthesis of chiral pyrrolidines 3 based on the reaction of ,-unsaturated ketones 1 with imino esters 2 catalyzed by a catalyst system composed of AgF and chiral 1,2-diol li- gand 4.

⁶

The chiral five-membered products 3 were ob- tained from successive Michael and Mannich reactions with complete diastereoselectivity (>99% de), good to quantita- tive yields (50–99%) and variable enantioselectivities (22–

98% ee) (Scheme 1). In the possible transition state depicted in Scheme 1, the silver atom coordinates the two ligands through the N-19 tertiary amine.

Hélène Pellissier carried out her PhD under the supervision of Dr. G.

Gil in Marseille (France) in 1987. The work was focused on the reactivity

of isocyanides. In 1988, she entered The National Center for Scientific

Research (CNRS) as a researcher. After a postdoctoral period in Profes-

sor K. P. C. Vollhardt’s group at the University of California, Berkeley

(USA), she joined the group of Professor M. Santelli in Marseille in 1992,

where she focused on the chemistry of allylsilanes and their applica-

tions to the development of novel very short total syntheses of unnatu-

ral steroids starting from 1,3-butadiene and benzocyclobutenes. She is

currently researcher (CNRS) at Aix-Marseille Université.

In 2016, Fukuzawa et al. employed an alternative chiral silver complex derived from AgOAc and ferrocenyl chiral li- gand 5 to promote asymmetric domino reactions between imino esters 2/7 and nitroalkenes 6.

⁷

As illustrated in Scheme 2, chiral pyrrolidines 8 were obtained in good yields (47–86%), diastereoselectivities (76–92% de) and en- antioselectivities (86–97% ee) from sequential Michael and aza-Henry reactions.

Chiral bicyclic pyrrolidines 12 were synthesized in 2016 by Wang et al. through domino reactions of imino esters 9 with N-(2-t-butylphenyl)maleimide ( 10 ) using a combina- tion of AgOAc and chiral phosphine ligand 11 as the catalyst system (Scheme 3).

⁸

Products 12 , arising from a Michael ad- dition followed by a Mannich reaction, were obtained in ho- mogeneous high yields (86–99%), diastereoselectivities (>90% de) and enantioselectivities (90 to >99% ee).

Similar reactions were also investigated in 2016 by Xia and Xu in the presence of another catalyst system com- posed of AgF and Xing-Phos ligand.

⁹

In this case, the reac- tion of N-arylmaleimides 13 with aromatic imino esters 2

or 14 afforded the corresponding bicyclic pyrrolidines 15 as single diastereomers (>96% de) in high yields (83–99%) and enantioselectivities (65–98% ee) (Scheme 4).

Along with chiral silver catalysts, various chiral cobalt complexes have also been recently investigated as promot- ers in domino reactions. The use of cobalt catalysts is ad- vantageous because of their low toxicity, their low cost and their ability to adopt various reaction pathways.

¹⁰

For ex- ample, a chiral cobalt catalyst generated in situ from Co(acac)

₂

and chiral biphosphine ligand 16 was employed in 2017 by Ge et al. in the synthesis of enantiopure pyrroli- dine 18 through the domino reaction of nitrogen-tethered 1,6-enyne 17 with pinacolborane (Scheme 5).

¹¹

The process involved an anti-Markovnikov hydroboration followed by a cyclization.

Scheme 1 Synthesis of pyrrolidines through an Ag-catalyzed domino reaction

4 (10 mol%)

1

2

3 t-BuOH (10 mol%)

+

Ar

¹

= Ph, p-ClC

6

H

4

, p-Tol, p-FC

6

H

4

, m-BrC

6

H

4

, 2-thienyl Ar

²

= Ph, p-ClC

6

H

4

Ar

³

= Ph, p-Tol, p-ClC

₆

H

₄

, o-ClC

₆

H

₄

, m-ClC

₆

H

₄

AgF (10 mol%)

Ar

³

Ar

²

O

Ar

¹

N CO

2

Me

N H

CO

2

Me Ar

³

O Ar

²

Ar

¹

N

OH O

HO N H

OMe OMe

H O H

H

THF, –15 °C 50–99% yield >99% de 22–98% ee

N HO O

HO N H

OMe OMe

H O H

H

21 19 22

N

19

(4) N O Ag

Ar

¹

MeO

O Ar

²

Ar

³

proposed transition state:

Scheme 2 Synthesis of pyrrolidines through an Ag-catalyzed domino reaction

5 (5 mol%)

6 2, 7

8

1,4-dioxane, r.t.

+

R = Ph, o-Tol, m-Tol, p-Tol, p-MeOC

₆

H

₄

, p-FC

₆

H

₄

, p-ClC

₆

H

₄

, p-BrC

₆

H

₄

, 1-Naph, 2-thienyl, Cy

Ar = Ph, o-Tol, p-Tol, p-MeOC

6

H

4

, p-ClC

6

H

4

, p-BrC

6

H

4

, 2-furyl, ferrocenyl AgOAc (5 mol%)

R N MeO

2

C

Fe N

N N

Ph

t-BuS

Ph

₂

P

NO

2

Ar

N H

CO

2

Me Ar O

2

N R 47–86% yield

76–92% de 86–97% ee

Scheme 3 Synthesis of bicyclic pyrrolidines through an Ag-catalyzed domino reaction

11 (3 mol%)

10

9

12

+

R

¹

= Ph, p-ClC

6

H

4

, p-Tol, m-ClC

6

H

4

, p-BrC

6

H

4

, m-BrC

6

H

4

, o-FC

6

H

4

, 2-Naph, p-MeOC

₆

H

₄

, m-MeOC

₆

H

₄

, 2-thienyl, (E)-PhCH=CH, n-Bu R

²

= H, Me, Et, n-Bu, i-Bu, Bn

AgOAc (3 mol%)

R

¹

N

CO

2

Me

CH

2

Cl

2

, r.t.

N O

O

N HN

R

¹

MeO

2

C O

R

²

O

R

²

CF

3

CF

₃

Br NH

2

NHPPh

2

Br F

3

C

F

3

C

t-Bu

t-Bu

86–99% yield

>90% de

90 to >99% ee

While using chiral ligand 16 resulted in an anti- Markovnikov hydroboration of the alkyne moiety of sub- strate 17 (Scheme 5), the same authors showed that the in- volvement of chiral ligand 19 combined with the same pre- catalyst led to chiral pyrrolidine 20 with 92% ee and 66%

yield, arising from a Markovnikov hydroboration of the alkyne group of the nitrogen-tethered 1,6-enyne 17 with pinacolborane (Scheme 6).

¹¹

In 2018, Fan et al. developed an unprecedented synthe- sis of chiral 3,4-dimethylene-pyrrolidines possessing an oxa/azabenzonorbornadiene moiety based on the asym- metric domino reaction of oxa/azabenzonorbornadienes 21 with 1,6-enynes 22.

¹²

The process, employing a catalyst sys- tem composed of [Rh(cod)

₂

]BF

₄

and chiral diphosphine li- gand (R)-An-SDP, provided enantiopure (97–99% ee) 3,4-di- methylene-pyrrolidines 23 in good yields (44–89%). A pos- sible mechanism for the reaction is depicted in Scheme 7.

Complex 24 , arising from the coordination of the rhodium catalyst to 1,6-enyne 22 , underwent a cyclization to afford intermediate 25 . Next, a -hydride elimination led to inter- mediate 26 that coordinates to substrate 21 to give inter-

mediate 27 . Subsequent insertion of the alkene into the Rh–

C bond led to intermediate 28 , which finally delivered prod- uct 23.

Palladium has been previously applied to promote many enantioselective domino transformations.

¹³

In 2017, Jia et al. employed asymmetric palladium catalysis to devel- op a method for the synthesis of chiral 2,3-disubstituted in- dolines 32 .

¹⁴

The process involved the reaction between in- doles 29 and terminal alkynes 30 promoted by a chiral pal- ladium catalyst derived from Pd(dba)

₂

and chiral phosphoramidite ligand 31. Complex molecules 32 were obtained through consecutive Heck and Sonogashira reac- tions as almost single diastereomers (>90% de) with high enantioselectivities (79–94% ee) and good yields (50–93%) (Scheme 8).

Chiral nickel catalysts

¹⁵

have also been successfully ap- plied to promote enantioselective domino processes.

¹⁶

For example, the synthesis of chiral bis-heterocycles 35 was de- veloped by Kong et al. in 2018 through enantioselective nickel-catalyzed domino reactions of alkenes 33 with aryl bromides 34 .

¹⁷

As presented in Scheme 9, the reactions pro- ceeded with excellent enantioselectivities (94–98% ee), af- fording the products in good yields (40–81%). The process employed a combination of Ni(cod)

₂

and chiral ferrocenyl phosphine ligand 36 as the catalyst system leading to a cy- clization followed by a cross-coupling reaction.

In 2018, Feng and Liu reported an example of bimetallic relay catalysis applied to the synthesis of chiral 2,2,3-tri- substituted indolines.

¹⁸

As shown in Scheme 10, the cata- lyst system consisted of a combination of Sc(OTf)

₃

, chiral N,N-dioxide ligand 37 and Rh

2

(OAc)

₄

, which promoted the intramolecular trapping of ammonium ylides generated from -diazoketones 38 and 2-aminophenyl-substituted ,-unsaturated ketones 39 . This domino process yielded a range of chiral indolines 40 as single diastereomers (>90%

de) in good to excellent yields (66–99%) and enantioselec- tivities (73–99% ee).

Later, in 2019, the same authors employed related chiral N,N-dioxide ligand 41 combined with Mg(OTf)

2

to promote Scheme 4 Synthesis of other bicyclic pyrrolidines through an Ag-cata-

lyzed domino reaction

Xing-Phos (5.5 mol%)

toluene, –20 °C

Ar

¹

= Ph, o-MeOC

6

H

4

, m-MeOC

6

H

4

, m-BrC

6

H

4

, p-Tol, p-FC

6

H

4

, p-ClC

6

H

4

,

p-BrC6

H

4

, p-PhC

6

H

4

, p-MeSC

6

H

4

, 3,5-(F

3

C)

2

C

6

H

3

Ar

²

= Ph, m-ClC

6

H

4

, m-Tol, m-BrC

6

H

4

, p-EtOC

6

H

4

, p-MeOC

6

H

4

,

p-BrC6

H

4

, 3,5-Me

2

C

6

H

3

R = Me, Et

AgF (2.5 mol%) PPh

₂

N(i-Pr)

₂

O H N

Ph S O

t-Bu

13

2, 14

15

+

Ar

¹

N

CO

2

R N

O

O

N HN RO

2

C

Ar

¹

O

O Ar

²

Ar

²

83–99% yield

>96% de 65–98% ee

H

2

O

Scheme 5 Synthesis of pyrrolidine 18 through a Co-catalyzed domino reaction

51% yield 99% ee

16 (4 mol%)

toluene, r.t. or 60 °C Co(acac)

₂

(3 mol%)

N

N P

P

t-Bu t-Bu

Ph

NTs + HBPin

Ts N

Ph BPin

17 18

Scheme 6 Synthesis of pyrrolidine 20 through a Co-catalyzed domino reaction

66% yield 92% ee

19 (4 mol%)

THF, r.t.

Co(acac)

₂

(3 mol%) + HBPin

17 20

Ph

NTs

Ts N

H

Ph BPin

P

P

Fe

the asymmetric synthesis of spiroindolines 42 .

¹⁹

The latter were obtained in good to excellent yields (50–99%), diaste- reoselectivities (50 to >90% de) as well as enantioselectivi- ties (70–97% ee) via the ring-opening reaction of the corre- sponding meso-aziridines 43 with C2-substituted 2-isocya- noethylindoles 44 followed by intramolecular cyclization (Scheme 11).

2.2 Six-Membered Rings

In 2016, chiral tricyclic indolines 48 were synthesized by Reisman et al. through the one-step reaction of amidoac- rylate 45 with indoles 46 promoted by a combination of ZrCl

₄

with chiral BINOL-derived ligand 47.

²⁰

As illustrated in

Scheme 12, the process occurred with high enantioselectiv- ities (81–91% ee), moderate diastereoselectivities (50–66%

de) and good yields (66–93%). The domino reaction evolved through successive Michael addition, protonation and aza- Prins reaction.

Asymmetric domino reactions can also be promoted by chiral green copper catalysts.

²¹

For example, in 2016, chiral 5,6-dihydrocanthin-4-ones 51 were prepared in good yields (57–92%) and enantioselectivities (68 to >99% ee) from a domino reaction promoted by a chiral copper catalyst de- rived from CuI and chiral proline derivative 50 .

²²

The reac- tion occurred between terminal alkynes 30 and 1-formyl- 9H--carbolines 49 (Scheme 13). The mechanism involved Scheme 7 Synthesis of 3,4-dimethylene-pyrrolidines through a Rh-catalyzed domino reaction

+

(R)-An-SDP (6.5 mol%) [Rh(cod)

2

]BF

4

(5 mol%)

22 21

44–89% yield 97–99% ee R

¹

= H, Me, OMe, Br

23

R

¹

–R

¹

= OCH

₂

O, O(CH

₂

)

₂

O R

²

= H, OMe

Y = Ts, Boc, Ns, SO

₂

Ph X = NBoc, NTs

PAr

2

PAr

₂

Ar = p-MeOC

6

H

4

DCE, 40 °C N

X R

²

R

¹

R

¹

R

²

X R

²

R

¹

R

¹

R

²

N

proposed mechanism:

22

YN [Rh(cod)

2

]BF

4

+ (R)-An-SDP

[Rh]*

24

YN [Rh]*

[Rh]*

YN

25

[Rh]*H YN

26

21

X R

²

R

¹

R

¹

R

² 27

X R

²

R

¹

R

¹

R

²

[Rh]*H YN

28

X R

²

R

¹

R

¹

R

²

YN M

M = [Rh]*H

23

X R

²

R

¹

R

¹

R

²

YN

Y

Y

the formation of iminium species 52 from aldehyde 49 and amine catalyst 50 . Then, iminium ion 52 reacted with cop- per-coordinated alkyne 53 to give intermediate 54, which subsequently underwent an intramolecular aza-Michael addition to afford the final product.

Another green metal, magnesium,

²³

has been used by Lin et al. in a recent synthesis of chiral spirooxindole tetra- hydroquinolines 57 based on an intramolecular domino re- action of oxindoles 55.

²⁴

The process occurred through se- quential 1,5-hydride transfer and cyclization reactions car- ried out in the presence of a combination of MgCl

₂

and chiral phosphoric acid 56 (Scheme 14). The products were formed in high yields (80–95%) and diastereoselectivities (80 to >90% de) combined with good enantioselectivities (50–97% ee).

Scheme 8 Synthesis of 2,3-disubstituted indolines through a Pd-cata- lyzed domino reaction

Pd(dba)

2

(5 mol%) K

2

CO

3

(2 equiv) Ar = p-MeOC

6

H

4

MTBE/THF, 100 °C

29

32

50–93% yield

>90% de 79–94% ee

Ar O O Ar

P N

31 (10 mol%)

N

O Br

R

⁵

R

⁴

R

³

R

²

R

⁶

+

30

N O

R

³

R

²

R

⁶

R

¹

R

⁴

R

⁵

R

¹

R

¹

= H, Me R

²

= H, i-Pr, Me, Cl, F

R

³

= Me, Ph, p-F

3

CC

6

H

4

, 2-furyl, Et, CO

2

Me R

⁴

= H, OMe

R

⁵

= H, OMe, Me, F

R

⁶

= Ph, p-MeOC

₆

H

₄

, p-Tol, p-FC

₆

H

₄

, p-ClC

₆

H

₄

, p-(Pent)C

₆

H

₄

, p-PhC

₆

H

₄

,

p-F3

CC

6

H

4

, p-(PentO)C

6

H

4

, p-(t-Bu)C

6

H

4

, p-(MeO

2

C)C

6

H

4

, p-NCC

6

H

4

,

p-NCCH2

C

6

H

4

, p-(F

3

CO)C

6

H

4

, p-(OHC)C

6

H

4

, m-Tol, m-MeOC

6

H

4

,

m-FC6

H

4

, m-ClC

6

H

4

, o-Tol, o-F

3

CC

6

H

4

, o-ClC

6

H

4

, o-FC

6

H

4

,

2-Naph, 2-thienyl, 1-thienyl, 3-pyridyl, 2-ferrocenyl, CH(OEt)

2

, t-Bu, PhthNCH

2

, Cl(CH

₂

)

₄

, HO(CH

₂

)

₄

, HO(CH

₂

)

₂

, TMS, (Me)C=CH

₂

Scheme 9 Synthesis of bicyclic 2-pyrrolidinones through a Ni-cata- lyzed domino reaction

+

36 (20 mol%)

Ni(cod)

2

(10 mol%) B

2

Pin

2

(2 equiv)/Zn (2 equiv) K

3

PO

4

(2 equiv), KI (0.5 equiv)

35 34

33

40–81% yield 94–98% ee

Fe PPh

2

N O

i-Pr

NMP, 40 °C ArBr

X N

R

²

O

R

³

Br R

¹

R

⁴

X R

¹

R

⁴

N R

²

O Ar R

³

X = CH, C(Me), N R

¹

= H, Me, F R

²

= Me, Bn

R

³

= Me, Bn, n-Hex, i-Pr, MeOCH

₂

R

⁴

= H, Cl, Me, Cl, OMe Ar = Ph, p-Tol, 3,4,5-MeO

₃

C

₆

H

₂

Scheme 10 Synthesis of 2,2,3-trisubstituted indolines through a Rh- and Sc-catalyzed domino reaction

+

37 (12 mol%)

Sc(OTf)

3

(10 mol%) Rh

2

(OAc)

4

(1 mol%)

40 38

39

66–99% yield >90% de 73–99% ee THF, 25 °C NH

2

R

¹

= Ph, p-FC

6

H

4

, p-ClC

6

H

4

, p-BrC

6

H

4

, p-F

3

CC

6

H

4

, p-Tol, p-MeOC

6

H

4

,

p-PhC6

H

4

, 2-furyl, 3-thiophenyl, 1-Naph, 2-Naph, Me, n-Bu, Cy, R

²

= H, 5-F, 4-Cl, 4-Br, 4-F

3

C, 4-MeO

R

³

= Ph, o-FC

6

H

4

, m-FC

6

H

4

, m-F

3

CC

6

H

4

, p-FC

6

H

4

, p-ClC

6

H

4

, p-BrC

6

H

4

,

p-Tol

R

⁴

= Me, Et, n-Bu, i-Bu, c-Pr N N

O O

O

NHAr O

ArHN Ar = 2,4,6-i-Pr

3

C

6

H

2

5 Å MS R

¹

O R

²

R

³

R

⁴

O

N

₂

R

²

N H

R

³

R

⁴

O R

¹

O O

O

Scheme 11 Synthesis of spiroindolines through a Mg-catalyzed domi- no reaction

+

Mg(OTf)

2

(10 mol%)

41 (10 mol%)

Et

₂

O, 20 °C

43

44 42

N N

O O

ArHN O NHAr

O

Ar = 2,6-(i-Pr)

2

C

6

H

3

R

¹

= H, Cl R

²

= H, Cl R

³

= H, Br, Me, Cl R

²

,R

³

= (CH=CH)

2

R

⁴

= H, Me, F, Cl R

⁵

= Me, Ph

50–99% yield 50 to >90% de 70–97% ee

LiNTf

2

N O

N R

³

R

¹

R

²

O N

NH R

¹

R

²

R

³

N H R

⁴

R

⁵

NC

N

N

R

⁴

R

⁵

Another chiral magnesium catalyst derived from MgSO

₄

and a chiral phosphoric acid ligand 60 was applied by Schneider and Hodik in 2018 to develop a synthesis of chi- ral spirocyclic dihydroquinolones 61 through the reaction of ortho-quinone methide imines 58 with cyclic -oxo es- ters 59 (Scheme 15).

²⁵

This one-step process evolved through successive addition and lactamization reactions, affording spirocyclic dihydroquinolones 61 with good yields (39–98%) and both moderate to excellent diastereo- (50 to

>90% de) and enantioselectivities (66–98% ee).

3 Formation of One Ring Containing One Oxygen/Sulfur Atom

3.1 Five-Membered Rings

In 2017, Ge et al. disclosed a synthesis of chiral tetrahy- drofurans 63 on the basis of a domino reaction of oxygen- tethered 1,6-enynes 62 with pinacolborane (Scheme 16).

¹¹

The process employed a combination of Co(acac)

₂

with chi- ral biphosphine ligand 16 as the catalyst system, allowing

products 63 to be obtained with homogeneous excellent enantioselectivities (92–99% ee) and good yields (47–87%).

The process evolved through an anti-Markovnikov hydrobo- ration followed by a cyclization.

On the other hand, chiral alkyl boronate esters 65, in- stead of chiral vinyl-substituted boronate esters 63 (Scheme 16), were generated from the reaction of more sterically hindered oxygen-tethered 1,6-enynes 64 with pinacolbo- rane in the presence of the same catalyst system.

¹¹

Indeed, in this case, a Markovnikov hydroboration occurred, deliv- ering, after subsequent cyclization, tetrahydrofurans 65 in high yields (69–91%) and enantioselectivities (86–92% ee) (Scheme 17).

In 2018, Fan and co-workers reported the synthesis of chiral tetrahydrofuran 68 through a domino reaction be- tween oxygen-tethered 1,6-enyne 66 and azabenzonorbor- nadiene 67 performed in the presence of a combination of Scheme 12 Synthesis of tricyclic chiral indolines through a Zr-cata-

lyzed domino reaction +

47 (20 mol%)

ZrCl

4

(1.6 equiv) 2,6-dibromophenol (1 equiv)

TMSCl (1 equiv)

TFAHN CO

2

Me N

R

²

R

¹

CH

2

Cl

2

, r.t.

N MeO

2

C

NHTFA H

R

¹

Cl H R

²

45

48 46

OH OH Br

Br

66–93% yield 50–66% de 81–91% ee

mechanism:

TFAHN CO

2

Me

N R

²

R

¹

NHTFA OZrCl

3

MeO

Michael

protonation

Cl

N R

²

R

¹

NHTFA O MeO

Cl H

ZrCl

4

aza-Prins cyclization

46

48

ZrCl

₄

(47)

N MeO

2

C

NHTFA H

R

¹

Cl H R

²

N

R

²

R

¹

45

R

¹

= H, 1-Me, 2-Me, 3-Me, 4-Me, 2-OMe, 2-Br R

²

= Me, allyl, Bn

Scheme 13 Synthesis of 5,6-dihydrocanthin-4-ones through a Cu-cat- alyzed domino reaction

+

50 (20 mol%)

CuI (10 mol%) DIPEA (35 mol%) N

H

toluene, 85 °C

51 30

49

N

R

²

CHO

R

¹

N R

²

N

R

¹

O

N H Ph

Ph OTMS

N R

²

N H

R

¹

N

aza-Michael

Ph Ph OTMS

51

N

R

²

N

R

¹

O

proposed mechanism:

R

¹

Cu

N H

N R

²

N Ph

Ph OTMS

57–92% yield 68 to >99% ee

R

¹

= Ph, p-t-BuC

6

H

4

, p-FC

6

H

4

, p-ClC

6

H

4

, p-BrC

6

H

4

, p-Tol, p-MeOC

6

H

4

,

m-FC6

H

4

, m-Tol, 2-pyridyl, 2-cyclohexenyl, n-Bu, CO

2

Me, 2-thienyl,

p-n-BuC6

H

4

, p-PhOC

6

H

4

, p-MeO(2-Naph), 3,4-Cl

2

C

6

H

3

R

²

= CO

2

Me, H

+ N H

49 30

N

R

²

CHO R

¹

N H

Ph Ph OTMS

50

CuI

54 53

52

[Rh(cod)

₂

]BF

₄

and chiral diphosphine ligand (R)-An-SDP.

¹²

The enantiopure product (98% ee) was obtained in 38%

yield through cyclization followed by an addition reaction (Scheme 18).

A synthesis of chiral bicyclic furans 72 was disclosed in 2018 by Marinetti and Betzer through a silver-catalyzed domino reaction of 2-(1-alkynyl)-2-cyclohexenone 69 with 5-substituted indoles 70 (Scheme 19).

²⁶

The process was catalyzed by preformed chiral silver phosphate 71 and evolved through successive cycloisomerization and addi- Scheme 14 Synthesis of spirooxindole tetrahydroquinolines through a Mg-catalyzed domino reaction

toluene, 80 °C

56 (10 mol%)

80–95% yield 80 to >90% de 50–97% ee Ar = 9-phenanthryl

MgCl

2

(2.5 mol%) 4 Å MS

O O P O

OH Ar

Ar

N CO

2

Me

O N

R

³

R

⁴

R

¹

R

²

N

CO

₂

Me O R

¹

R

²

N R

³

R

⁴

R

¹

= H, NO

2

, F, Br, Me R

²

= H, Cl

R

³

,R

⁴

= (CH

2

)

3

, (CH

2

)

4

R

³

= Bn, R

⁴

= Ph

55 57

H

Scheme 15 Synthesis of spirocyclic dihydroquinolones through a Mg- catalyzed domino reaction

60 (10 mol%)

CPME, 0 °C

39–98% yield

61

50 to >90% de 66–98% ee

59

Ar O O Ar

P O OH

Ar = C

6

Me

5

MgSO

4

(0.025 mol%) NH

PG OH R

¹

R

²

+

X CO

₂

Et O

R

⁵ 58

N PG R

¹

R

²

O X O

R

⁵

R

¹

= p-MeOC

6

H

4

, TMS, t-Bu, decyl, c-Pr, Cy, cyclohexenyl, Ph,

p-(t-Bu)C₆

H

₄

, p-ClC

₆

H

₄

, m-MeOC

₆

H

₄

, 2-thienyl R

²

= H, Me, Cl

R

³

= H, OMe

R

⁴

= H, Me, OMe, NO

₂

, Br R

⁵

= H, Cl

X = O, S

PG = Me, Et, Bu, allyl

R

³

R

³

R

⁴

R

⁴

Scheme 16 Synthesis of tetrahydrofurans through a Co-catalyzed domino reaction

47–87% yield 92–99% ee

16 (4 mol%)

R = Ph, p-F

3

CC

6

H

4

, p-MeOC

6

H

4

, p-Tol, p-t-BuC

6

H

4

, p-TMSC

6

H

4

,

p-FC6

H

4

, p-ClC

6

H

4

, p-BrC

6

H

4

, m-Tol, p-AcC

6

H

4

, p-OHCC

6

H

4

,

p-MeO2

CC

6

H

4

, p-NCC

6

H

4

, p-TBSOC

6

H

4

, 2-thienyl, BnO(CH

2

)

3

, (2-Naph)(O)CO(CH

₂

)

₃

, 3-pyridyl,

toluene, r.t.

Co(acac)

2

(3 mol%) N

N P

P

t-Bu t-Bu

R

O

+ HBPin

O

R BPin

N N O

,

62

63

Scheme 17 Synthesis of other tetrahydrofurans through a Co-cata- lyzed domino reaction

69–91% yield 86–92% ee

16 (4 mol%)

THF, r.t.

Co(acac)

2

(3 mol%)

+ HBPin

R

¹

= o-Tol, 2-Naph, Ph, p-Tol, p-t-BuC

6

H

4

, p-F

3

CC

6

H

4

, m-Tol R

²

= H, Me, Ph

R

²

,R

²

= (CH

2

)

3

, (CH

2

)

4

, (CH

2

)

5

, (CH

2

)

6

, (CH

2

)

7

,

_O ^O

O

,

64

65

R

¹

O R

²

R

²

O

H

R

¹

Bpin

R

²

R

²

Scheme 18 Synthesis of a tetrahydrofuran through a Rh-catalyzed domino reaction

+

(R)-An-SDP (6.5 mol%) [Rh(cod)

2

]BF

4

(5 mol%)

66 67

38% yield

98% ee

68

PAr

2

PAr

2

Ar = p-MeOC

6

H

4

DCE, 40 °C

O Boc N

Boc N

O

tion reactions to deliver the final bicyclic furans 72 in vari- able yields (27–97%) and moderate to high enantioselectivi- ties (39–86% ee).

Chiral 3-substituted isobenzofuranones 76 were gener- ated by Gros et al. through a magnesium-catalyzed domino reaction occurring between ethyl 2-iodobenzoate ( 73 ) and aldehydes 74 .

²⁷

(S)-BIPHEN-BuMgLi was used as the cata-

lyst, which formed intermediate 75 on reaction with ethyl 2-iodobenzoate ( 73 ). Addition of the latter to aldehyde 74 followed by intramolecular cyclization then led to final product 76 in variable enantioselectivities (8–92% ee) and good to excellent yields (44–95%) (Scheme 20).

Chiral tetrahydrothiophenes 80 were produced by Pun- niyamurthy et al. through an iron-catalyzed domino reac- tion of aromatic ,-unsaturated ketones 1 and 77 with 1,4- dithiane-2,5-diol ( 78 ).

²⁸

A combination of FeCl

₃

with novel reusable chiral dendrimer ligand 79 was used as the cata- lyst system, which triggered successive sulfa-Michael addi- tion and aldol condensation to give chiral tetrahydrothio- phenes 80 as single diastereomers (>99% de) in low to high yields (21–84%) and enantioselectivities (16–70% ee) (Scheme 21).

In 2019, Wang et al. reported the synthesis of chiral 3,3- dihydrofuran spirooxindoles 81 on the basis of an enantio- selective zinc-catalyzed three-component reaction of isat- ins 82, -hydroxy ketones 83 and malononitrile 84.

²⁹

The process involved a bimetallic catalyst generated in situ from ZnEt

₂

and chiral triol ligand 85 . It evolved through a domino Knoevenagel/Michael/cyclization reaction, affording highly functionalized spirooxindoles 81 in uniformly high yields (82–99%), variable diastereoselectivities (4–98% de) and high enantioselectivities in most cases (6 to >99% ee) (Scheme 22).

Scheme 19 Synthesis of bicyclic furans through an Ag-catalyzed domi- no reaction

+

69 70

cis-HClC=CClH, r.t.

72 71 (10 mol%)

27–97% yield 39–86% ee

R

¹

= Ph, p-MeOC

6

H

4

, Bn R

²

= H, Me

R

³

= H, Me, F, OMe R

⁴

R

⁴

O

O P

O OAg

R

⁴

= m-terphenyl

O R

¹

N R

²

R

³

O R

¹

N R

³

R

²

*

Scheme 20 Synthesis of 3-substituted isobenzofuranones through a Mg-catalyzed domino reaction

THF, –60 °C

76

44–95% yield

8–92% ee

74

t-Bu

O O

t-Bu

(S)-BIPHEN-BuMgLi (1 equiv)

+

73

Mg Bu Li

O O

I

RCHO

O O

R

*

R = p-MeOC

6

H

4

, m-MeOC

6

H

4

, o-MeOC

6

H

4

, 2,4,6-(MeO)

3

C

6

H

2

, 3,4,5-(MeO)

3

C

6

H

2

,

p-ClC6

H

4

, m-ClC

6

H

4

, p-F

3

CC

6

H

4

, p-FC

6

H

4

, p-(t-Bu)C

6

H

4

, 2-Naph, 2-thienyl, 2-pyridyl, n-Pent, piperidinyl,

O O

O O

Mg Li

t-Bu

O O

t-Bu

O R

H

75

Scheme 21 Synthesis of tetrahydrothiophenes through an Fe-cata- lyzed domino reaction

21–84% yield

>99% de 16–70% ee

80 79 (5 mol%)

FeCl

3

(15 mol%) toluene/DCE (2:1), 0 °C

78

Ar = Ph, p-EtOC

6

H

4

, p-EtC

6

H

4

, p-FC

6

H

4

R = o-Tol, p-MeOC

6

H

4

, p-ClC

6

H

4

, p-FC

6

H

4

, p-Tol, p-NCC

6

H

4

, 2-furyl, 2-thienyl, Cy, i-Pr, 2-Naph

+

1, 77

OH

t-Bu

HO

t-Bu

HO

t-Bu

NH

t-Bu

OH NH

t-Bu

OH

NH

t-Bu

OH

S S

OH HO

O

Ar R

O Ar

S OH

R

3.2 Six-Membered Rings

In 2016, densely functionalized chiral chromans 89 were synthesized by Schneider et al. by using [Rh

₂

(OAc)

₄

] and chiral phosphoric acid 88 as the catalyst system.

³⁰

As shown in Scheme 23, the reaction of ortho-hydroxy ben- zhydryl alcohols 86 with diazoesters 87 evolved through the Michael addition of rhodium carbene 91 to intermedi- ate ortho-quinone methides 90 . This was followed by a he- miketalization reaction of intermediate 92 leading to chiral chromans 89 as single diastereomers in good yields (55–

87%) and high enantioselectivities (78–96% ee).

Tietze et al. disclosed the synthesis of another chiral chroman, constituting a key intermediate in a total synthe- sis of (–)-siccanin, by using a chiral palladium catalyst de- rived from Pd(TFA)

₂

and the (R,R)-Bn-BOXAX ligand.

³¹

Alke- nyl phenol 93 reacted through Wacker oxidation, carbon- ylation and then methoxylation to afford chiral chroman 94 in 93% ee and 71% yield (Scheme 24).

In 2018, Quintard and Rodriguez reported the synthesis of chiral bicyclic -lactones 98 through domino reactions of cyclic -keto esters 95 with allylic alcohols 96 , by employ- ing a combination of achiral iron tricarbonyl complex 97 , Cu(acac)

₂

and chiral proline derivative 50.

³²

The process evolved through successive oxidation, Michael addition, re- duction and lactonization to give bicyclic -lactones 98 in high enantioselectivities (90–93% ee) combined with low to moderate yields (21–51%) (Scheme 25).

Scheme 22 Synthesis of 3,3-dihydrofuran spirooxindoles through a Zn-catalyzed domino reaction

82–99% yield 4–98% de

6 to >99% ee

81

85 (2 mol%)

ZnEt

2

(4 mol%)

CH

₂

Cl

₂

, 25 °C

83

R

¹

= H, Me, OMe, F, Cl, Br R

²

= H, Br

R

³

= Ph, p-FC

₆

H

₄

, p-ClC

₆

H

₄

, p-BrC

₆

H

₄

, p-MeOC

₆

H

₄

, p-Tol, m-ClC

₆

H

₄

,

m-BrC6

H

4

, m-Tol, o-MeOC

6

H

4

, 2-Naph, 2-thienyl, 2,5-(MeO)

2

C

6

H

3

, Me

+

84

OH Ar OH Ar

Ar = 2-Naph

N N

HO Ar Ar

4 Å MS

82

+ N H O

O R

¹

R

²

CN CN

R

³

O

OH

N H O R

¹

R

²

O NC

H

2

N R

³

O

Scheme 23 Synthesis of chromans through a Rh-catalyzed domino re- action

+

88 (5 mol%)

[Rh

2

(OAc)

4

] (2 mol%)

CHCl

₃

, r.t.

87 86

55–87% yield 78–96% ee OH

OH R

³

R

²

R

⁴

R

¹

O Ar

N

2

CO

2

R

⁵

O O

P O OH Ar'

Ar' Ar' = 3,5-(CF

3

)

2

C

6

H

3

89

O R

³

R

²

R

⁴

R

¹

OH

Ar CO

2

R

⁵

OH

R

¹

= H, OMe, t-Bu R

²

= H, Et, Me R

³

= H, Me, Ph, t-Bu, Cl, F R

⁴

= H, OMe

R

⁵

= Et, Me

proposed mechanism:

86

OH

OH R

³

R

²

R

⁴

R

¹

88

90

O R

³

R

²

R

⁴

R

¹

O Ar

[RhL

_n

] CO

2

R

⁵

91

92

OH

R

³

R

²

R

⁴

R

¹

OH CO

2

R

⁵

Ar O

Michael

hemiketalization

89

O R

³

R

²

R

⁴

R

¹

OH

Ar CO

2

R

⁵

OH Ar = Ph, p-Tol, m-Tol, o-Tol, p-O

2

NC

6

H

4

, p-MeOC

6

H

4

, p-PhC

6

H

4

,

p-FC₆

H

₄

, p-ClC

₆

H

₄

, p-BrC

₆

H

₄

, 2-Naph

Scheme 24 Synthesis of a chroman through a Pd-catalyzed domino re- action

HO OMe

Pd(TFA)

₂

(5 mol%)

CO (1 atm), MeOH, r.t.

(R,R)-Bn-BOXAX (20 mol%) N O N Bn

O Bn

p-benzoquinone (4 equiv)

OMe

MeO O O

93 94

71% yield

93% ee

Scheme 25 Synthesis of bicyclic -lactones through a multicatalyzed domino reaction

4 Formation of One Ring Containing Several Heterocyclic Atoms

In 2016, Dixon et al. employed a combination of Ag

₂

O and chiral cinchona alkaloid 102 to develop a novel total synthesis of the antibiotic (–)-chloramphenicol.

³³

Actually, the latter was obtained from trans-oxazoline 99, itself pre- pared from a domino reaction occurring between p-nitro- benzaldehyde ( 100 ) and isocyanoacetate 101 with 93% ee, 84% de and 68% yield. The process evolved through sequen- tial aldol and cyclization reactions. It was found that other alkyl isocyanoacetates 101 were also compatible by using related chiral cinchona alkaloid ligands 103 and 104 , thus leading to chiral oxazolines ent- 99 in good yields (56–80%), diastereo- (76–82% de) and enantioselectivities (78–87%

ee) (Scheme 26).

In the same year, Feng et al. employed a catalyst system composed of Mg(OTf)

₂

and chiral N,N-dioxide ligand 105 in the synthesis of chiral 2-alkyl-5-aminooxazoles 108.

³⁴

The process involved the Michael addition of -isocyanoacet- amides 107 to alkylidene malonates 106 followed by an in- tramolecular cyclization reaction to provide chiral 2-alkyl- 5-aminooxazoles 108 in variable yields (28–99%) and good enantioselectivities (72–96% ee) (Scheme 27).

In 2019, the same authors employed related chiral N,N- dioxide ligand 41 combined with Mg(OTf)

₂

to promote the asymmetric synthesis of other 2-alkyl-5-aminooxazoles 109 .

¹⁹

The latter were obtained in good to excellent yields (40–99%) and enantioselectivities (50–95% ee) from the ring-opening reaction of the corresponding meso-aziridines 43 with -isocyanoacetamides 107 followed by intramolec- ular cyclization (Scheme 28).

98 50 (13 mol%)

96

R = Me, n-Pr, Ph, CH

₂

Bn X = CH

2

, C(Me)

2

+

95

xylenes, 10 °C O

OMe O

OH X

R

O

X O

TMS

Fe TMS OC

OC CO

97 (6.5 mol%)

Me

₃

NO•(2H

₂

O) (8 mol%) Ph

Ph N OTMS H Cu(acac)

2

(5 mol%)

then DBU/toluene, r.t.

O O

R 21–51% yield

90–93% ee

Scheme 26 Synthesis of oxazolines through Ag-catalyzed domino re- actions

+

100

101

EtOAc, 20 °C

ent-99

Ag

2

O (2.5 mol%)

4 Å MS

(5 mol%)

CN O

OR

N O

CO

2

R O

2

N

CHO

O

₂

N

103 (X = H)

or 104 (X = OMe) N NH

N O

PPh

2

OMe

102 (5 mol%)

(–)-chloramphenicol +

100

101

CN

O OR O

₂

N

CHO

Ag

₂

O (2.5 mol%) EtOAc, 20 °C

4 Å MS

99

N O

CO

2

R

2

O

2

N 68% yield

84% de 93% ee

O

₂

N

OH

HN OH

CHCl

2

O

N HN

N O Ph

2

P

X

R = CHPh

2

56–80% yield 76–82% de 78–87% ee

R = t-Bu, Me, Bn, p-MeOC

6

H

4

CH

2

, 3,5-(F

3

C)

2

C

6

H

3

CH

2

Scheme 27 Synthesis of 2-alkyl-5-aminooxazoles through a Mg-cata- lyzed domino reaction

R

¹

= Ph, o-FC

6

H

4

, m-FC

6

H

4

, m-ClC

6

H

4

, m-BrC

6

H

4

, m-Tol, m-MeOC

6

H

4

,

m-PhOC6

H

4

, p-FC

6

H

4

, p-ClC

6

H

4

, p-BrC

6

H

4

, p-F

3

CC

6

H

4

, p-NCC

6

H

4

,

p-O₂

NC

₆

H

₄

, p-Tol, p-PhC

₆

H

₄

, p-MeOC

₆

H

₄

, p-PhOC

₆

H

₄

, p-BnOC

₆

H

₄

, 3,4-Cl

2

C

6

H

3

, 2-Naph, 2-thienyl, 3-furyl, Cy, Me

R

²

= Me, Et, i-Pr

R

³

= t-Bu, Bn, Ph, Me, i-Pr, H X,Y = (CH

2

)

2

O(CH

2

)

2

, (CH

2

)

5

, (CH

2

)

4

Mg(OTf)

₂

(10 mol%)

105 (10 mol%)

N N

O O

O NHAr

O ArHN Ar = 2,6-i-Pr

2

C

6

H

3

R

¹

CO

2

R

²

CO

2

R

²

+

CH

2

Cl

2

, 0 °C R

³

CN O

N Y X

N Y O X N

R

³

R

¹

CO

2

R

²

R

²

O

2

C

108

28–99% yield

72–96% ee

107

106

Scheme 28 Synthesis of other 2-alkyl-5-aminooxazoles through a Mg- catalyzed domino reaction

A chiral scandium catalyst derived from Sc(OTf)

₃

and chiral diphosphine oxide ligand 111 was applied by Shi et al. to promote the synthesis of chiral aryl 5-bromo-1,3-ox- azinan-2-ones 112 (Scheme 29).

³⁵

The reaction occurred between (E)-cinnamyl tosylcarbamates 110 and 1,3-dibro- mo-5,5-dimethylhydantoin (DBDMH) through successive bromination and amination reactions, delivering the domi- no products in excellent enantioselectivities (87–99% ee) and good to excellent yields (65–96%).

Scheme 29 Synthesis of aryl 5-bromo-1,3-oxazinan-2-ones through a Sc-catalyzed domino reaction

A novel route to chiral 3,4-dihydro-2H-1,2,4-benzothia- diazine-1,1-dioxides 115 was disclosed in 2016 by Zhou et al. using a catalyst system based on Sc(OTf)

₃

and chiral Py- box (pyridine-bisoxazoline) ligand 114 .

³⁶

The process in- volved imine formation using aldehydes 74 and 2-amino- benzenesulfonamide ( 113 ), followed by an intramolecular

amination reaction to provide products 115 in good yields (60–88%) and enantioselectivities (36–93% ee) (Scheme 30).

Scheme 30 Synthesis of 3,4-dihydro-2H-1,2,4-benzothiadiazine-1,1- dioxides through a Sc-catalyzed domino reaction

In 2016, Liu and Feng described the first asymmetric synthesis of benzimidazoles based on a metal-catalyzed domino process.

³⁷

The catalyst system was generated from ScCl

₃

·(H

₂

O)

₆

and chiral N,N-dioxide ligand 121 (Scheme 31). The reaction occurred between cyclopropanes 116 and diamines 117, which firstly underwent a ring-opening ad- dition reaction to give 118 . The latter intermediate was then submitted to an intramolecular cyclization to provide 119 and a subsequent retro-Mannich reaction afforded the final products 120 in high enantioselectivities (80–97% ee) and good yields (56–99%).

5 Formation of One Carbon Ring 5.1 Five-Membered Rings

In 2016, Enders et al. reported the synthesis of chiral spiropyrazolones 125 on the basis of a relay multicatalysis with Ag

₂

O and chiral squaramide 124 as the organocata- lyst.

³⁸

The products were formed in variable yields (27–

99%) from 5-pyrazolones 122 and alkyne-tethered ni- troalkenes 123 through consecutive organocatalyzed Michael addition and Ag-catalyzed Conia-ene reaction. As presented in Scheme 32, high diastereoselectivities (78 to

+

Mg(OTf)

2

(10 mol%)

41 (10 mol%)

Et

2

O, 20 °C

43

107

109

N N

O O

ArHN O NHAr

O

Ar = 2,6-(i-Pr)

2

C

6

H

3

R

¹

= H, Cl R

²

= H, Cl R

¹

,R

²

= (CH=CH)

₂

R

³

= H, Me, Cl, Br R

⁴

= Bn, t-Bu, i-Pr, i-Bu, Ph X,Y = (CH

2

)

2

O(CH

2

)

2

, (CH

2

)

5

, (CH

2

)

4

40–99% yield 50–90% ee

Na

2

CO

3

N O

N R

³

R

¹

R

²

R

⁴

CN N

O

O N

NH R

¹

R

²

R

³

N O

R

⁴

X N

Y

X Y

CHCl

3

, –50 °C

Ar = Ph, p-MeOC

6

H

4

, m-MeOC

6

H

4

, o-MeOC

6

H

4

, p-BrC

6

H

4

, m-BrC

6

H

4

,

p-ClC6

H

4

, m-FC

6

H

4

, p-FC

6

H

4

, 2,4,6-F

3

C

6

H

2

, o-Tol, p-Tol, 3,5-Me

₂

C

₆

H

₃

, 2,4,6-Me

₃

C

₆

H

₂

, 1-Naph, 2-Naph, 2-thienyl

111 (2 mol%)

NaCl (1.2 equiv) Sc(OTf)

3

(2 mol%)

110

112

HN NH

O O P Ph

2

P Ph

2

O O

Ar O NHTs

O

O NTs

O

Ar

+ DBDMH 65–96% yield Br

87–99% ee

CH

2

Cl

2

, –40 °C +

R = i-Bu, i-Pr, t-BuCH

₂

, Cy, c-Pent, c-Pr, Bn, BnCH

₂

, Ph, p-MeOC

₆

H

₄

,

p-BrC₆

H

₄

, m-BrC

₆

H

₄

, o-BrC

₆

H

₄

, 3-Br-4-MeOC

₆

H

₃

, 1-furyl

NH

2

114 (20 mol%)

4 Å MS Sc(OTf)

₃

(10 mol%) O N

N N

O

NH

2

O O

S

113

O

H

R N

H

O O

S NH R

74 115

amination imine formation

O N N

N O Sc

N R

H S

O O

NH

2

H

H H 60–88% yield

36–93% ee

>90% de) combined with good enantioselectivities (42–99%

ee) were obtained.

In the same year, Ratovelomanana-Vidal, Michelet and Vitale described a novel diastereo- and enantioselective for-

mal [3+2] cycloaddition of vinyl cyclopropanes 126 with ,-unsaturated aldehydes 127 catalyzed by a combination of Pd

₂

(dba)

₃

(CHCl

₃

), dppe as the ligand and proline-derived chiral amine 50 as the organocatalyst.

³⁹

The process evolved through a domino Michael/cyclization reaction, af- fording the corresponding enantiopure trisubstituted cyclo- pentanes 128 (>99% ee) with good to high yields (54–88%) and diastereoselectivities (72–80% de) when starting from 1,1-dicyano-2-vinyl cyclopropane [Z = C(CN)

₂

] (Scheme 33).

The same synergistic catalytic system also promoted the re- action of other vinyl cyclopropanes, such as 1,3-indanedi- one-derived vinyl cyclopropane, Meldrum’s acid derived vi- nyl cyclopropane and 1,3-dimethylbarbituric vinyl cyclo- propane, which led to the corresponding enantiopure cyclopentanes 128 (>99% ee) with low to excellent yields (29–98%) and diastereoselectivities (24–82% de), as shown in Scheme 33.

Scheme 33 Synthesis of trisubstituted cyclopentanes through a multi- catalyzed domino reaction

This type of reaction was also investigated at the same time by Jørgensen et al. by using a related catalyst system, albeit employed at lower catalyst loadings.

⁴⁰

Indeed, per- formed in the presence of only 10 mol% of organocatalyst 50 and 3 mol% of Pd

₂

(dba)

₃

, the domino Michael/cyclization reaction of ,-unsaturated aldehydes 127 with vinylcyclo- propanes 129 led to the corresponding chiral pentasubsti- tuted cyclopentanes 130 bearing up to four stereogenic centers, including one quaternary, with both uniformly high yields (80–97%) and enantioselectivities (91 to >99%

ee), combined with moderate to high diastereoselectivities (42–82% de) (Scheme 34). In addition to the vinyl cyclopro- pane 129 bearing two nitrile groups (X = CN), vinyl cyclo- propanes possessing a methyl or a benzyl ester were also compatible as were various aromatic ,-unsaturated alde- hydes.

These reactions were also studied by Rios and Meazza almost at the same time.

⁴¹

In this case, a combination of 20 mol% of the same organocatalyst 50 with 5 mol% of Pd

₂

(dba)

₃

was used. For example, the domino Michael/cy- Scheme 31 Synthesis of benzimidazoles through a Sc-catalyzed domi-

no reaction

DCE, 35 °C

121 (10 mol%)

ScCl

3

·(H

2

O)

6

(10 mol%)

116

120

+

56–99% yield 80–97% ee

N N

O O

O NHAr O

ArHN Ar = 2,4,6-(i-Pr)

3

C

6

H

2

R

¹

COR

²

COR

²

NH

2

NH

2

R

³

R

⁴

117

N

N R

²

R

³

R

⁴

R

¹

O

R

²

NH

2

NH R

³

R

⁴

R

¹

COR

²

COR

²

ring-opening

reaction

cyclization retro-Mannich

reaction N

N R

²

R

³

R

⁴

R

¹

O

R

²

H

118

119

mechanism:

116

R

¹

COR

²

COR

²

NH

2

NH

₂

R

³

R

⁴ 117

120

N

N R

²

R

³

R

⁴

R

¹

O

R

²

+

R

¹

= Ph, p-MeOC

₆

H

₄

, p-Tol, p-FC

₆

H

₄

, p-ClC

₆

H

₄

, p-BrC

₆

H

₄

, m-Tol,

m-ClC6

H

4

, o-Tol, 3,4-Cl

2

C

6

H

3

, 1-Naph, 2-Naph, vinyl, Me R

²

= Ph, p-Tol, p-FC

₆

H

₄

R

³

= H, Me, OMe, F, Cl, Br, NO

2

R

⁴

= H, Me, OMe, F, Cl, Br, NO

2

Scheme 32 Synthesis of spiropyrazolones through a multicatalyzed domino reaction

124 (1 mol%)

122

123

125

Ag

₂

O (3 or 10 mol%)

CHCl

₃

, –40 °C to r.t.

+ N N

O R

²

R

³

N NH

N MeO

O O

N H

CF

3

CF

3

NO

2

R

⁴

O

2

N

N N O

R

³

R

²

R

⁴

R

¹

= H, OMe, F, Cl R

²

= Me, Et, i-Pr, CF

₃

, Ph

R

³

= Ph, o-ClC

6

H

4

, p-ClC

6

H

4

, p-Tol, Me R

⁴

= H, Cy, n-Bu

R

¹

R

¹

27–99% yield 78 to >90% de 42–99% ee

N H Ph

OTMS

50 (20 mol%)

Pd

2

(dba)

3

(CHCl

3

) (5 mol%)

dppe (10 mol%)

p-O₂

NC

₆

H

₄

CO

₂

H (20 mol%)

PhCF

₃

, r.t.

Ar CHO

Z

Z OHC

Ar +

Z = C(CN)

2

,

127 126

128

O

O O O O

O N N O

O O

, ,

29–98% yield 24–82% de >99% ee

Ph

Ar = Ph, p-Tol, m-Tol, o-Tol, p-(t-Bu)C

6

H

4

, p-FC

6

H

4

, p-F

3

CC

6

H

4

, p-ClC

6

H

4

,

m-MeOC6

H

4

, m-MeO

2

CC

6

H

4

, 2-Naph

clization reaction of spirocyclic vinyl cyclopropane 131 with a range of either aromatic or aliphatic ,-unsaturated aldehydes 127 afforded the corresponding chiral spirocyclic products 132 in high yields (76–96%) and both moderate to high diastereo- (42–84% de) and enantioselectivities (30–

99% ee) (Scheme 35). The scope of the reaction could be ex- tended to other vinyl cyclopropanes 133 , which through re- actions with aromatic ,-unsaturated aldehydes 127 led to the corresponding chiral cyclopentanes 134 in good to quantitative yields (50–99%) combined with low diastereo- selectivities (10–38% de) and good to excellent enantiose- lectivities (76 to >99% ee) (Scheme 35).

Scheme 35 Synthesis of spirocyclic cyclopentanes through multicata- lyzed domino reactions

In 2017, Feng et al. employed a chiral yttrium catalyst prepared from Y(OTf)

₃

and chiral N,N-dioxide ligand 135 for the synthesis of chiral tetrasubstituted diquinanes.

⁴²

In this process, electron-deficient enynes 136 reacted with ,-unsaturated ester 137 through two sequential Michael

additions to afford almost enantiopure (91–98% ee) diquinanes 138 in variable yields (35–73%) (Scheme 36).

In the same year, Ge et al. described the synthesis of chi- ral cyclopentanes on the basis of a domino reaction pro- moted by a combination of Co(acac)

₂

and chiral biphos- phine ligand 16 .

¹¹

As depicted in Scheme 37, 1,6-enynes 139 reacted with pinacolborane through an anti- Markovnikov hydroboration followed by a cyclization to yield the corresponding enantiopure (99% ee) vinyl-substi- tuted boronate esters 140 in good yields (49–54%).

Scheme 37 Synthesis of functionalized cyclopentanes through a Co- catalyzed domino reaction

When the same reaction was performed in the presence of related chiral biphosphine ligand 19 instead of ligand 16, a Markovnikov hydroboration occurred (Scheme 38), which was followed by cyclization to give enantiopure (96–98%

ee) alkyl boronate esters 141 in good yields (50–63%).

¹¹

In 2020, asymmetric nickel catalysis was applied by Ye and Peng to develop a novel synthesis of chiral indenes 142 bearing a quaternary stereocenter.

⁴³

Indeed, in the presence of Ni(cod)

₂

and ,,,-tetraphenyl-2,2-dimethyl-1,3-di- Scheme 34 Synthesis of pentasubstituted cyclopentanes through a

multicatalyzed domino reaction N

H Ph

OTMS

50 (10 mol%)

Pd(dba)

₂

(3 mol%) PhCO

₂

H (10 mol%)

MeCN, r.t.

Ar CHO

CHO +

Ar = Ph, p-MeOC

6

H

4

, p-ClC

6

H

4

, p-EtO

2

CC

6

H

4

X = CN, CO

₂

Me, CO

₂

Bn

127 129 130

NC X

Ar

NC X

Ph

80–97% yield 42–82% de 91 to >99% ee

N H Ph

OTMS

50 (20 mol%) Pd2(dba)3 (5 mol%)

EtOAc, r.t.

R CHO

R = Ph, p-NCC6H4, p-BrC6H4, p-O2NC6H4, p-FC6H4, o-BrC6H4, m-O2NC6H4, p-Tol, Me, Et, Hept, n-Pr

127 131 132

O

O

R CHO

Z Z

OHC

+

R

R = Me, Ph, p-BrC6H4

Z = C(CN)(CO2Me), C(CN)(CO2Et),

127 133 134

+

O

O R

76–96% yield

CHO

42–84% de 30–99% ee

same conditions

N Boc

O O

O O O

O

O

, ,

50–99% yield 10–38% de 76 to >99% ee

Ph

Scheme 36 Synthesis of diquinanes through a Y-catalyzed domino re- action

DIPEA (50 mol%) 135 (10 mol%)

137

R

138

N N

O O

O NHAr

ArHN O

Ar = 2,4,6-Me3C6H2

Y(OTf)3 (10 mol%)

CH2Cl2, 30 °C

O

MeO

2

C

CO

₂

Me CO

2

Me

136 +

O R MeO

2

C

MeO

2

C CO

2

Me

R = Ph, p-FC6H4, p-ClC6H4, p-BrC6H4, p-Tol, p-MeOC6H4, o-ClC6H4, p-AcC₆H₄, m-ClC₆H₄, m-FC₆H₄, m-Tol, 2-thienyl, 2-Naph, ferrocenyl, TMS

35–73% yield 91–98% ee

49–54% yield 99% ee

16 (4 mol%)

THF, 60 °C Co(acac)2 (3 mol%)

N

N P

P

t-Bu t-Bu

Ph

+ HBPin

Ph BPin

139 140

RO

2

C CO

2

R CO

2

R

CO

₂

R

R = i-Pr, Me