Enantioselective Conjugate Addition of Catalytically Generated Zinc Homoenolate

Yoshiya Sekiguchi and Naohiko Yoshikai*

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Enantioselective Conjugate Addition of Catalytically Generated Zinc

Homoenolate

Cite This: J. Am. Chem. Soc. 2021, 143, 4775 −4781

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ABSTRACT: We report herein an enantioselective conjugate addition

reaction of a zinc homoenolate, catalytically generated via ring opening

of a cyclopropanol, to an α,β-unsaturated ketone. The reaction is

promoted by a zinc aminoalkoxide catalyst generated from Et Zn and a

chiral β-amino alcohol to aﬀord 1,6-diketones, which undergo, upon

heating, intramolecular aldol condensation to furnish highly substituted

cyclopentene derivatives with good to high enantioselectivities. The

reaction has proved applicable to various 1-substituted cyclopropanols

as well as chalcones and related enones. The chiral amino alcohol has proved to enable ligand-accelerated catalysis of the

homoenolate generation and its conjugate addition. Positive nonlinear eﬀects and lower reactivity of a racemic catalyst have been

observed, which can be attributed to a stable and inactive heterochiral zinc aminoalkoxide dimer.

INTRODUCTION

Metal homoenolates represent useful organometallic nucleo-

philes that allow for umpolung functionalization of the β

position of a carbonyl group. Pioneering studies by Nakamura

and Kuwajima established 1-alkoxy-1-siloxycyclopropanes as

precursors to various main group and transition-metal ester

homoenolates, among which zinc homoenolate proved to be a

particularly versatile nucleophile for fundamental C−C bond-

forming reactions including 1,2/1,4-addition, allylic substitu-

from Et Zn and a chiral β-amino alcohol promotes ring-

■

opening addition of cyclopropanols to chalcone and related

enones, which displays the feature of ligand-accelerated

catalysis and represents a rare example of transition-metal-

free ECA of organozinc reagents. Upon heating, the 1,6-

diketone products undergo facile intramolecular aldol con-

densation to aﬀord multisubstituted cyclopentene derivatives

with high enantioselectivity.

tion, and cross-coupling (Scheme 1a). Nevertheless, an

RESULTS AND DISCUSSION

■

enantioselective variant of such transformations remains

elusive. This is in sharp contrast to the fact that the catalytic

enantioselective 1,2/1,4-addition and allylic substitution

reactions of simple dialkylzincs have been developed and

matured to the level that they now serve as benchmarks for the

evaluation of new chiral ligands and catalysts. For example,

more than 800 and 100 articles can be found for the

In light of Cha’s seminal work on the equilibrium generation of

zinc homoenolate from zinc cyclopropoxide, our ﬁrst question

was whether it is possible to exploit such a process for C−C

bond formation catalytic in zinc. Thus, we initially examined

the reaction between 1-phenylcyclopropanol (1a) and

chalcone (2a). Upon brief screening, a catalytic system

composed of Et Zn (10 mol %) and DABCO (10 mol %)

enantioselective addition of Et Zn to benzaldehyde and

was found to promote the desired ring-opening conjugate

addition in DMSO at 80 °C, aﬀording 1,6-diketone 3aa in 47%

yield along with a small amount of cyclopentene derivative 4aa

as a result of intramolecular aldol condensation of 3aa (eq 1).

By adding molecular sieves 4 Å, the reaction gave 4aa as the

dominant product.Given the feasibility of zinc-catalyzed

generation and conjugate addition of homoenolate from

cyclopropanol, we next attempted to render the reaction

cyclohexenone, respectively, while no analogous asymmetric

reaction involving a preformed zinc homoenolate has been

reported.

Recently, cyclopropanols have emerged as viable precursors

for the in situ generation of ketone homoenolates.

seminal studies in this context is Cha’s work on allylic and

propargylic substitutions mediated by stoichiometric Et Zn in

combination with Cu(I) salt, where equilibrium generation of

zinc homoenolate from the corresponding cyclopropoxide and

its transmetalation to Cu(I) are likely involved (Scheme 1b).

1c−f

One of

Received: January 23, 2021

Published: March 16, 2021

However, such in situ generated zinc homoenolate has also not

been exploited for an enantioselective C−C bond formation.

Herein, we report on an enantioselective conjugate addition

ECA) of a catalytically generated chiral zinc homoenolate to

(

α,β-unsaturated ketones (Scheme 1c). A catalyst generated

2021 American Chemical Society

J. Am. Chem. Soc. 2021, 143, 4775−4781

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Scheme 1. Generation and C−C Bond-Forming Reactions

of Zinc Homoenolate

Table 1. Zinc-Catalyzed Addition of 1-Phenylcyclopropanol

(1a) to Chalcone (2a)

entry

ligand

solvent

yield (%)

DMSO

DMPU

82:18

47:54

79:21

52:48

77:23

87:13

82:18

93:7

95:5

The reaction was performed using 0.15 mmol of 1a and 0.1 mmol of

a in 0.3 mL of solvent (0.33 M). Determined by GC using

c d

mesitylene as an internal standard. Determined by chiral HPLC. 15

mol % each of Et Zn and L6 was used. The reaction was performed at

°C for 48 h and then at 100 °C for 6 h.

yield (89%) and the enantioselectivity (95:5 er) was achieved

(

entry 9).

With the optimized catalytic system (Table 1, entry 9) in

hand, we explored the scope of the present homoenolate ECA.

First, a variety of cyclopropanols were subjected to the reaction

with chalcone (2a) (Scheme 2). Various 1-arylcyclopropanols

participated in the ring-opening conjugate addition/intra-

molecular aldol cascade, thus aﬀording cyclopentenes 4aa−

ha in moderate to high yields and enantioselectivities with

tolerance to methoxy, bromo, iodo, and triﬂuoromethyl

groups. A modest trend of decreasing enantioselectivity with

electron-withdrawing aryl group was observed, as manifested in

the case of the p-triﬂuoromethyl group (see 4ea). The absolute

conﬁguration of the Br-substituted product 4da was

determined to be R by X-ray crystallographic analysis. The

reaction of 1a could be performed on a 3 mmol scale without a

decrease in the enantioselectivity. Importantly, the reaction of

1a and 2a, when quenched before the aldol step, gave the 1,6-

diketone product 3aa in good yield with enantioselectivity

(95:5 er) identical to that of 4aa. This underlines that the

enantiomeric ratio of 4aa solely reﬂects the ECA step despite

the feasibility of kinetic resolution during the intramolecular

aldol condensation (see Table S1 ). 1-(2-Thienyl)-

cyclopropanol and 1-(1-cyclohexenyl)cyclopropanol also

smoothly took part in the reaction to furnish the desired

products 4ia and 4ja, respectively, with 96:4 er. The reactions

of 1-(sec-alkyl)cyclopropanols were somewhat sluggish and

required higher temperatures. Nonetheless, the corresponding

cyclopentene products (4ka and 4la) were obtained with

excellent enantioselectivity (97:3 er). In contrast, the reaction

of 1-pentylcyclopropanol produced a mixture of inseparable

products, as indicated by GC analysis prior to aldol

condensation. The formation of the desired ECA product

enantioselective. In this respect, we explored a host of chiral β-

amino alcohols as ligands, which have found extensive use in

the enantioselective addition of dialkylzincs as well as

preformed or in situ generated zinc acetylide. In view of

the relevance of ﬁve-membered ring scaﬀolds in bioactive

compounds, we focused on the formation of the cyclo-

pentene product rather than the 1,6-diketone. In doing so, the

e ﬀ ect of kinetic resolution in the aldol condensation step (see

Table S1 ) was eliminated by forcing it to complete under harsh

conditions (typically 100 °C, 6 h). Upon screening of ligands,

solvents, and other reaction conditions, a few amino alcohols

(

L1, L3, and L5−L7) emerged as promising ligands (Table 1,

entries 1−7; see also Tables S1 and S2). For example, the

reaction of 1a and 2a in the presence of Et Zn and the

norephedrine derivative L6 (10 mol % each) and 4 Å MS in

DMSO was performed at 30 °C for 24 h, followed by heating

at 100 °C for 6 h, to aﬀord the cyclopentene 4aa in 73% yield

with 87:13 er (entry 6). The use of DMPU as the solvent

improved the enantioselectivity to 93:7 er (entry 8). By

performing the ECA step at 0 °C for 48 h with an increased

catalyst loading (15 mol %), an additional improvement in the

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Scheme 2. Asymmetric Ring-Opening Addition of Various

Cyclopropanols to 2a

This outcome can be rationalized by highly selective kinetic

resolution in the ring-opening step and moderately enantio-

selective conjugate addition of each diastereomeric zinc

homoenolate (see Scheme S1).

We next explored the addition of 1a to various α,β-

unsaturated ketones (Scheme 4). Chalcone-type di(hetero)-

Scheme 4. Asymmetric Ring-Opening Addition of 1a to

Various Enones

The reaction was performed on a 0.3 mmol scale under the

conditions in Table 1, entry 9. 3 mmol scale reaction. The reaction

was quenched without aldol condensation step. The ECA step was

performed at 0 °C for 72 h. The ECA step was performed at 30 °C

for 12 h. The ECA step was performed at 30 °C for 48 h.

along with other bimolecular products (e.g., enolate Michael

adduct) was suggested but not unambiguously conﬁrmed.

A racemic bicyclic cyclopropanol 1m (2 equiv) underwent

selective cleavage of the less substituted C−C bond and

aﬀorded the desired conjugate adduct 3ma as a diastereomer

mixture (78:22 dr) in 96% yield, with 98:2 and 90:10 ers for

the major and minor diastereomers, respectively (Scheme 3).

Meanwhile, the unreacted 1m was isolated in the form of

benzoyl ester 1m′ in 24% yield (based on 1m) with 96:4 er.

The reaction was performed on a 0.3 mmol scale under the

^c^oⁿ^dⁱ^tⁱ^oⁿ^sⁱⁿ^T^a^b^l^e¹^,^eⁿ^t^r^y⁹^.c The aldol condensation step was

performed at 50 °C for 16 h. L3 was used instead of L6. The

reaction was performed in DMSO at 40 °C for 48 h and then at 100

C for 6 h. The ECA step was performed at 30 °C for 48 h. The

ECA step was performed at 30 °C for 24 h. The ECA and aldol steps

were performed at 60 °C for 12 h.

aryl-substituted enones proved to be excellent substrates,

aﬀording the corresponding cyclopentenes 4ab−4aj in

moderate to high yields with 92:8 to 96:4 er. A variety of

functionalized aryl and heteroaryl groups could be tolerated on

both ends of the enone skeleton. An α,β,γ,δ-unsaturated

ketone underwent selective 1,4-addition of the homoenolate to

give the alkenyl-substituted cyclopentene 4ak with 97:3 er.

Dibenzylideneacetone selectively aﬀorded the monoconjugate

addition product, which cyclized into the cyclopentene 4al

with equally high enantioselectivity (96:4 er). Unlike these

examples, enones bearing an alkyl substituent at either the β

position or the acyl position failed to participate in the reaction

under the standard conditions. Using L3 as the ligand, such

Scheme 3. Addition of Bicyclic Cyclopropanol 1m to 2a

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substrates aﬀorded the desired products 4am and 4an with

moderate enantioselectivities (ca. 80:20 er). β-Triﬂuoromethyl

enone also took part in the reaction, albeit in modest yield and

enantioselectivity (see 4ao). GC analysis of the reaction

mixture prior to aldol condensation indicated the formation of

other bimolecular products. Cinnamaldehyde was also found

to undergo the homoenolate conjugate addition, aﬀording the

disubstituted cyclopentene 4ap in diminished yield and

enantioselectivity.

The reaction of (E)-2-benzylidenecyclohexan-1-one fur-

nished, after 3 h of the aldol condensation step, a bicyclic

product 4aq as a mixture of diastereomers (80:20 dr) with ers

of 84:16 (major) and 70:30 (minor) (Scheme 5). The relative

Scheme 5. Addition of 1a to (E)-2-Benzylidenecyclohexan-

1-one

Figure 1. Mechanistic experiments. (a) Nonlinear eﬀects with

diﬀerent catalyst loadings of Et Zn/L6 (30 °C, 30 h and 100 °C, 6

h). (b) Initial reaction progress using L6 of diﬀerent ees (15 mol %

catalyst loading, 0 °C). (c) Ring-opening of 1a alone. (d) Ees and

yields of 3aa in THF/DMPU mixed solvents.

was also found to signiﬁcantly inﬂuence the reaction rate.

Thus, the initial rate of the reaction using enantiopure L6 was

found to be more than four times faster than that using racemic

L6 (Figure 1b). Note that the reaction mixtures appeared clear

and homogeneous regardless of using enantiopure or racemic

L6. Apart from these observations under the actual reaction

conditions in DMPU, we found that mixing racemic L6 and

Et Zn in Et O immediately generated a white precipitate,

stereochemistry of the major diastereomer of 4aq was

conﬁrmed by X-ray crystallographic analysis of its anilide

derivative 5aq. Notably, extension of the condensation step for

this product resulted in transposition of the CC bond to the

bicyclic juncture to give a tetrasubstituted oleﬁn isomer 4aq′

which was a signature of the formation of insoluble

(

66% yield, 50:50 dr and 80:20 er for both diastereomers),

heterochiral aggregates, while a mixture of enantiopure L6

presumably via a zinc dienolate intermediate (see Scheme S2).

Note that other types of Michael acceptors such as

cyclohexenone, methyl cinnamate, and β-nitrostyrene failed

to undergo homoenolate conjugate addition under the achiral

reaction conditions (see eq 1). As such, we did not explore the

feasibility of their homoenolate ECA at this time.

and Et Zn in Et O formed a homogeneous solution. These

observations may suggest that, in highly polar and Lewis basic

DMPU, both homochiral and heterochiral Zn aminoalkoxide

dimers form as soluble species and that the latter is reluctant to

dissociate into catalytically relevant monomeric Zn species

13b

(vide infra).

To gain insight into the ligand eﬀect and the zinc species

involved in the present homoenolate ECA, we performed a

series of mechanistic experiments. The model reaction of 1a

and 2a (performed at 30 °C to facilitate the reaction at low

catalyst loadings and/or with low-ee catalysts) was found to

display concentration-dependent nonlinear eﬀects (NLEs;

The ability of the amino alcohol to accelerate the whole

reaction process as well as the ring-opening step alone was

clearly demonstrated by control experiments. Thus, no

reaction took place between 1a and 2a by omitting L6 from

or replacing L6 with DABCO under the standard conditions.

The reaction of 1a alone under the standard conditions

quantitatively produced propiophenone 1a′ after 48 h, while

the ring opening was rather sluggish by omitting L6 or using

DABCO (Figure 1c). We also probed the solvent eﬀect

(DMPU, THF, and their mixed solvents) on the model

reaction (Figure 1d). The enantioselectivity proved rather

insensitive to the solvent composition. By contrast, the product

yield dropped signiﬁcantly in pure THF (15%) owing to

competitive Michael addition of propiophenone enolate to 2a,

while the yield, albeit with some ﬂuctuation, remained

substantial (≥50%) in the mixed solvents (%THF up to 75%).

Figure 1a). Thus, a clear positive NLE was observed with

0 mol % catalyst loading (67 mM [Zn]), while NLE became

rather weak upon reducing the catalyst loading down to 10 mol

(33 mM [Zn]). Furthermore, the reaction procedure was

found to have a slight but non-negligible inﬂuence on NLE.

Thus, while the above NLE experiments were set up according

to the general procedure, which involves sequential addition

(

without a break longer than 15s) of Et Zn, 2a, and 1a to a

mixture of L6 and 4 Å MS in DMPU, aging of a mixture of L6

and Et Zn for 10 min at room temperature prior to the

addition of 1a and 2a slightly enhanced the NLE (Figure S5).

On the other hand, the reaction temperature (30 vs 0 °C) and

the solvent composition (DMPU vs DMPU/THF) had only a

minor impact on NLE (see Figures S6 and S7). The ee of L6

It is well established that a 1:1 mixture of Et Zn and chiral β-

amino alcohol gives rise to homochiral and heterochiral

ethylzinc aminoalkoxide dimers, depending on the enantio-

13b

meric composition of the ligand. The heterochiral dimer is

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J. Am. Chem. Soc. 2021, 143, 4775−4781

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often much more stable and reluctant to dissociate into

undergo ring-opening to generate the corresponding homo-

enolate C. Association of the homoenolate C with the

aminoalkoxide A and the enone 2 would generate a bimetallic

monomers, which is responsible for NLE in Et Zn addition to

aldehyde. A question relevant to the present reaction system is

what happens to such ethylzinc aminoalkoxide dimers upon

exposure to cyclopropanol. In attempts to address this

question, we measured ¹H NMR spectra of zinc species

species D, followed by delivery of the homoenolate to give an

enolate species E. Proton transfer from the amino alcohol to

the enolate would furnish the conjugate adduct 3 while

formed by mixing L6 and Et Zn in a 1:1 ratio followed by

regenerating the aminoalkoxide dimer [A] . The heterochiral

dimer [A·ent-A], preferentially formed when using racemic

ligand, would be reluctant to dissociate into the monomer [A·

another alcohol (1 equiv; tBuOH, iPrOH, or MeOH) as a

model of the cyclopropanol substrate (see Figures S8 −S11).

]. When there is no enone or ECA is sluggish, the

Except for the case using MeOH, the H NMR spectra showed

homoenolate C could be protonated, possibly via internal

proton transfer from the amino alcohol, to give the

corresponding ketone 1′, which could further participate in

enolate Michael addition under zinc catalysis. On the basis of

the solvent eﬀect (Figure 1d), the ability of DMPU as a Lewis

base to Zn, rather than its bulk polarity as a solvent, appears to

be critical for the preferential CA of the homoenolate over its

protonation. Thus, we speculate that coordination of DMPU

to zinc would assist in dissociation of the dimeric species and/

or increasing the nucleophilicity of the homoenolate.

clearly resolved quartet (∼0.6 ppm) and triplet (∼1.6 ppm)

signals that could be assigned to an ethyl group on Zn. This

observation indicates that ethylzinc aminoalkoxide [(L6-

H)ZnEt] resists protonation of the remaining ethyl group by

a bulky alcohol such as tBuOH and iPrOH, which should also

be the case for the tertiary cyclopropanol substrates used in the

present reaction. Similar observations have been made for the

reluctance of [LZnEt] species toward protonation of the Zn−

Et bond by alcohol. Note also that, a sample prepared by

mixing Et Zn and tBuOH ﬁrst, followed by L6, gave rise to a

Selected transformations of the enantioenriched cyclo-

pentene product 4aa are shown in Scheme 7. Conversion of

H NMR spectrum close to that of the above-mentioned

experiment. This suggests that the initially formed (tBuO)-

ZnEt underwent deprotonation of L6 with tBuO rather than

Et, thus generating [(L6-H)ZnEt] and tBuOH.

Scheme 7. Product Transformations

Given the reluctance of bulky alcohols to protonate the Zn−

Et bond of [(L6-H)ZnEt], we speculate that the formation of a

mixed zinc bisalkoxide species such as [(L6-H)(1-H)Zn] in

the present reaction system is less likely and that a zinc

cyclopropoxide species would form as a transient rather than

resting species via reversible protonation of the aminoalkoxide

ligand. With this conjecture, and on the basis of the above

NLE and other experiments as well as the literature knowledge

3a,13b

on chiral amino alcohol-catalyzed organozinc addition,

suggest a tentative catalytic cycle as illustrated in Scheme 6.

Coordination of the cyclopropanol 1 would break down the

homochiral ethylzinc aminoalkoxide dimer [A]₂into a

monomeric species [A·1]. Deprotonation of the cyclopropyl

OH with the internal aminoalkoxide base would reversibly

generate a cyclopropoxide species B, which would further

the benzoyl group to an anilide moiety via Beckmann

rearrangement was achieved through oxime formation and

subsequent treatment with Tf O, aﬀording the product 5 in

good yield. Epoxidation with mCPBA provided the tetrasub-

stituted epoxide 6 in a diastereoselective manner, albeit in a

modest yield. Generation of a dienolate species from 4aa and

LiHMDS was followed by trapping with benzyl bromide,

which took place regioselectively at the α position to generate

a quaternary stereocenter in the product 7 in a diastereose-

lective manner.

Scheme 6. Possible Catalytic Cycle

CONCLUSION

■

In summary, we have developed an enantioselective ring-

opening conjugate addition of cyclopropanols to α,β-

unsaturated ketones via catalytic generation of zinc homo-

enolate. A chiral β-amino alkoxide ligand on zinc accelerates

the ring-opening of a cyclopropanol and aids in enantiose-

lective addition of the resulting homoenolate to chalcones and

related enones without assistance of a transition-metal catalyst.

The ensuing intramolecular aldol condensation of the 1,6-

diketone products allows for facile preparation of multi-

substituted cyclopentene derivatives with good to high

enantioselectivity. The reaction represents the ﬁrst example

of enantioselective transformation of zinc homoenolate and

also a rare example of asymmetric transformations of metal

homoenolates in general. Further development and mecha-

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(2) (a) Nakamura, E.; Kuwajima, I. Copper-Catalyzed Acylation and

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nistic study of synthetic transformations involving catalytically

generated metal homoenolates are ongoing in our laboratory.

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Aoki, S.; Sekiya, K.; Oshino, H.; Kuwajima, I. Carbon-Carbon Bond-

Forming Reactions of Zinc Homoenolate of Esters. A Novel Three-

Carbon Nucleophile with General Synthetic Utility. J. Am. Chem. Soc.

ASSOCIATED CONTENT

sı Supporting Information

The Supporting Information is available free of charge at

https://pubs.acs.org/doi/10.1021/jacs.1c00869.

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AUTHOR INFORMATION

Corresponding Author

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6) (a) Parida, B. B.; Das, P. P.; Niocel, M.; Cha, J. K. C-Acylation of

5) Das, P. P.; Belmore, K.; Cha, J. K. S 2 ’ Alkylation of

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517−9520.

Naohiko Yoshikai − Division of Chemistry and Biological

Chemistry, School of Physical and Mathematical Sciences,

Nanyang Technological University, Singapore 637371,

Singapore; orcid.org/0000-0002-8997-3268;

Email: nyoshikai@ntu.edu.sg

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from Cyclopropanols and Amines. J. Am. Chem. Soc. 2017, 139,

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Quaternary Carbon by Nucleophilic Cyclopropanation with Bis-

Yoshiya Sekiguchi − Division of Chemistry and Biological

Chemistry, School of Physical and Mathematical Sciences,

Nanyang Technological University, Singapore 637371,

Singapore

Complete contact information is available at:

https://pubs.acs.org/10.1021/jacs.1c00869

the following references and ref 9 : (a) Yang, J.; Shen, Y.; Lim, Y. J.;

Iodozincio)Methane. Chem. - Asian J. 2010, 5, 147−152.

Notes

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8) In fact, examples of enantioselective transformation of

The authors declare no competing ﬁnancial interest.

catalytically generated metal homoenolates remain very rare. See

Yoshikai, N. Divergent Ring-Opening Coupling between Cyclo-

propanols and Alkynes under Cobalt Catalysis. Chem. Sci. 2018 , 9 ,

ACKNOWLEDGMENTS

This work was supported by the Ministry of Education

Singapore) and Nanyang Technological University

MOE2016-T2-2-043 and RG101/19). We thank Dr. Yongxin

■

(

6928 −6934. (b) Yang, J.; Sekiguchi, Y.; Yoshikai, N. Cobalt-Catalyzed

Enantioselective and Chemodivergent Addition of Cyclopropanols to

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alkylation of Cyclopropenes with Cobalt Homoenolates. Angew.

Chem., Int. Ed. 2021, 60, 2694−2698.

Li (Nanyang Technological University) for his assistance with

the X-ray crystallographic analysis.

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This article is dedicated to Professor Eiichi Nakamura on the

occasion of his 70th birthday and in recognition of his seminal

contribution to the chemistry of metal homoenolates.

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(16) Alternatively, the aminoalkoxide oxygen of A may form a

hydrogen bond with the amino alcohol OH of the homoenolate C to

give a diﬀerent association complex. For such a complex, one may

conceive a mechanism involving concerted proton transfer from C to

A along with the nucleophile delivery. In any case, the bimetallic

mechanism for the conjugate addition remains speculative and

warrants further investigation.

(17) Note that the model reaction between 1a and 2a under the

standard conditions did not give any trace of a byproduct arising from

conjugate addition of the ethyl group to 2a.

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