Copper-catalyzed asymmetric conjugate addition of trialkylaluminium reagents to trisubstituted enones: Construction of chiral quaternary centers

DOI: 10.1002/chem.200701001

Source and publish data:

Chemistry - A European Journal p. 9647 - 9662 (2007)

Update date:2022-08-02

Topics: Chiral Asymmetric Conjugate addition Copper-Catalyzed Quaternary centers

Authors:

Vuagnoux-D'Augustin, Magali

Alexakis, Alexandre

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Article abstract of DOI:10.1002/chem.200701001

Me₃Al, Et₁Al, and vinylalane species undergo enantioselective conjugate addition to a wide range of 2- or 3-substituted enones (cyclopent-2enones, cyclohex-2-enones, 3-methyl cyclohept-2-enone) in the presence of catalytic amount of copper salt (copper thiophene carboxylate, [Cu(CH₃-CN)₄]BF₄ or [CuOTf]₂· C₆H₆) and tropos-phosphoramidite-based ligand. Thus, chiral quaternary centers can be built, with up to 98% ee after rigorous optimization of experimental conditions. It was shown that the main important parameter was the order of the introduction of the reagents. Then, the generated enantioenriched aluminium enolates and the chiral conjugate adducts were functionalized and used for subsequent reactions.

Full text of DOI:10.1002/chem.200701001

FULL PAPER

DOI: 10.1002/chem.200701001

Copper-Catalyzed Asymmetric Conjugate Addition of Trialkylaluminium

Reagents to Trisubstituted Enones: Construction of Chiral Quaternary

Centers

Magali Vuagnoux-dꢀAugustin and Alexandre Alexakis*^[a]

Dedicated to the memory of Professor Yoshihiko Ito

Abstract: Me₃Al, Et₃Al, and vinylalane

species undergo enantioselective conju-

gate addition to a wide range of 2- or

tropos-phosphoramidite-based ligand.

Thus, chiral quaternary centers can be

built, with up to 98% ee after rigorous

optimization of experimental condi-

tions. It was shown that the main im-

portant parameter was the order of the

introduction of the reagents. Then, the

generated enantioenriched aluminium

enolates and the chiral conjugate ad-

ducts were functionalized and used for

subsequent reactions.

3-substituted

enones (cyclopent-2-

enones, cyclohex-2-enones, 3-methyl

cyclohept-2-enone)in the presence of

catalytic amount of copper salt (copper

Keywords: aluminium · asymmetric

catalysis

· conjugate addition ·

thiophene

carboxylate,

[Cu(CH₃-

copper · phosphoramidite ligands

ACHTREUNG

Introduction

doubly activated enones^[5,6]are able to react with dialkylzinc

species. Recently, the use of chiral bidentate N-heterocyclic

carbenes was developed for the copper-catalyzed asymmet-

ric conjugate addition (A.C.A.)of zinc species to 3-substi-

tuted cyclohex-2-en-1-ones^[7]and g-keto esters,^[8]and for the

Cu-catalyzed A.C.A. of Grignard reagents to several 3-sub-

stituted cyclohex-2-en-1-ones.^[9]Finally, the asymmetric syn-

thesis of quaternary stereocenters was successfully achieved

through copper-catalyzed 1,6-asymmetric addition of dia-

lkylzinc reagents to Meldrumꢀs acid derivatives in the pres-

ence of phosphoramidite ligands with good enantioselectivi-

ties.^[10]We report here our focused efforts to find the right

chiral ligand to copper salt, and experimental conditions,

that could induce high levels of enantioselectivities in good

yields, for a large range of trisubstituted substrates. More-

over, the use of the enantioenriched aluminium enolates will

be detailed as the further use of the chiral conjugate ad-

ducts.

The creation of enantioenriched all-carbon quaternary cen-

ters is still a synthetic challenge.^[1]Solutions to this problem

through the asymmetric conjugate addition (A.C.A.)^[2]have

been recently disclosed. We have found that the enhanced

Lewis acidity of trialkylaluminium species allows the

copper-catalyzed conjugate addition to proceed on simple 2-

or 3-substituted cyclic enones (Scheme 1).^[3]On the other

hand, more reactive substrates, such as nitroalkenes,^[4]or

Scheme 1. Copper-catalyzed A.C.A. of Me₃Al to 3-substituted cyclohex-

2-enones.

Results and Discussion

Tri- and tetrasubstituted a,b-unsaturated ketones used for

this study are compiled in Figure 1. Some of them were

commercially available (1, 12, 13, 14, and 18)or were a gen-

erous gift from the industry (20). The remaining compounds

were prepared according to general procedures (see Experi-

mental Section).^[11–14]

[a] M. Vuagnoux-dꢀAugustin, Prof. Dr. A. Alexakis

DØpartement de Chimie Organique

UniversitØ de Genve

30, quai Ernest Ansermet, 1211 Geneve (Switzerland)

Fax : (+41)22-379-32-15

E-mail: Alexandre.Alexakis@chiorg.unige.ch

Supporting information for this article is available on the WWW

under http://www.chemeurj.org/ or from the author.

Chem. Eur. J. 2007, 13, 9647 – 9662

ꢁ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

9647

Table 1. Cu-catalyzed A.C.A. of Et₃Al to 1.

Entry CuX

Ligand Solvent Conv.^[a]

[%]

ee^[b]

[%]

Abs.

conf.

CuTC

L10

L11

Et₂O

THF

Et₂O

THF

Et₂O

THF

>95

nd^[e]

5^[c]

6^[d]

Figure 1. Tri- and tetrasubstituted a,b-unsaturated ketones studied.

Copper-catalyzed A.C.A. optimization of experimental con-

ditions: We first extensively optimized the experimental

conditions for the conjugate addition of triethylaluminium

species to 3-methylcyclohex-2-en-1-one (1)and found that

the reaction proceeded to completion after 18 h at À308C,

and more rapidly at higher temperatures. Two sets of condi-

tions were found, the choice of which depends on the

copper salt used (diethyl ether was best with copper thio-

phene carboxylate (CuTC), whereas tetrahydrofuran was

>95

[Cu

–

better with [Cu(CH₃CN)₄]BF₄). Although the addition of

[a] Conversion determined by GC-MS. [b] ee determined by chiral GC.

[c] Reaction performed at À258C. [d] Reaction performed at À158C. [e]

Not determined.

Me₃SiCl has been reported to increase the chemical yield,^[15]

we found that it was detrimental in the presence of phos-

phorous ligands. Some attempts to reduce selectively the

double bond, with a chiral induction, by adding DiBAl-H

(iBu₂AlH)to 1, as described by Saegusa in stoichiometric

version,^[16]were unfruitful since the corresponding a,b-unsa-

turated alcohol was mainly generated in a very complex

mixture. Similarly, use of triisobutylaluminium (iBu₃Al), as

organometallic species, led to a complex mixture whereas

the conjugate adduct was not formed.

97% ee). In general, the conversions were higher in diethyl

ether than in THF, although the enantioselectivity was unaf-

fected. Raising the reaction temperature increased the con-

version at the cost of a small drop in enantioselectivity

(Table 1, entries 4, 5 and 6)from 94% ee to 88% ee, at

À158C. The binaphthol ligands (L8–L11)were less efficient.

It should be noticed that there was a strong matched/mis-

matched effect (Table 1, entries 13 vs 14 and 20 vs 21), and

that the absolute configuration of the conjugate adduct was

dictated by the binaphthol part of the ligand.

To optimise reaction conditions for the copper-catalyzed

A.C.A. of trimethylaluminium reagents, the addition of

Me₃Al was done to 3-ethylcyclohex-2-enone (2; Table 2).

As expected, the absolute configuration of the adduct 28

is opposite to that given in Table 1, thus showing that the

face selectivity remains the same whatever the organoalumi-

nium species. As previously, biphenols L4 and L7 gave the

best results in terms of conversion and enantioselectivity

(Table 2, entries 3, 5 and 14). In general, the conversions

were better in diethyl ether than in THF, even if the asym-

metric induction was quite similar or slightly inferior. It

should be noticed, here also, that there is a major matched/

mismatched effect (Table 2, entries 15 vs 16 and 17 vs 18)in

THF, and that the absolute configuration of the conjugate

adduct is dictated by the amine moiety of the ligand in THF,

and by its binaphthol part in Et₂O.

In a second step, we screened several biphenol- and bi-

naphthol-based phosphoramidite ligands (Figure 2)for the

copper-catalyzed asymmetric conjugate addition of Et₃Al

species to 1 (Table 1).

The biphenol ligands L4 (Table 1, entries 4 and 17)and,

particularly, L7 (Table 1, entry 10)afforded the best results

in terms of enantioselectivity, whatever the solvent (up to

Figure 2. Ligands used in this study.

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Construction of Chiral Quaternary Centers

FULL PAPER

Table 2. Cu-catalyzed A.C.A. of Me₃Al to 2.

showed us that the steric hindrance was a non-negligible

factor to generate chiral quaternary centers with good con-

versions. However, these problems could be solved by differ-

ent experimental conditions (see later).

Scope and limitations: The optimized conditions determined

previously were used to screen various a,b-unsaturated ke-

tones. First, the copper-catalyzed asymmetric conjugate ad-

dition of trimethylaluminium species to several 3-trisubsti-

tuted cyclohex-2-en-1-ones was studied because of the syn-

thetic utility of the methyl group in organic chemistry

(Scheme 2, Table 4). Moreover, two equivalents of the alu-

minium reagents were added in order to overcome the low

reactivity of hindered substrates.

Entry CuX

Ligand Solvent Conv.^[a]

[%]

ee^[b]

[%]

Abs.

conf.

CuTC

Et₂O

THF

>95

L10

L11

>95

[Cu

ACHTREUNG

L10

L11

[a] Conversion determined by GC-MS. [b] ee determined by chiral GC.

Scheme 2. Copper-catalyzed asymmetric conjugate addition of Me₃Al to

various 3-substituted cyclohexenones.

The experimental conditions were further optimized by

copper-catalyzed A.C.A. of the two aluminium species to

the bulkier substrate 3 to determine the limits of our

system. As previously, biphenols L4 and L7 gave the best re-

sults in terms of conversion and enantioselectivity (Table 3,

entries 3 and 5)for the copper-catalyzed A.C.A. of trime-

thylaluminium species. The conversions were worse than for

the less hindered substrates (1 and 2)in diethyl ether and

very low in THF. However, the level of asymmetric induc-

tion remained high. The addition of triethylaluminium spe-

cies never succeeded even at higher temperature and with

more equivalents of organometallic species. These attempts

Table 4. Cu-catalyzed asymmetric conjugate addition of Me₃Al to vari-

ous 3-substituted enones.

Entry Substrate Ligand Adduct Conv.^[a][%] ee^[b][%] Abs.

conf.

>95 (78)94

84 (nd^[c])97

35 (nd^[c])93

42 (nd^[c])93

>95 (nd^[c])91

>95 (80)95

>95 (nd^[c])93

>95 (76)95

>95 (81)95

>95 (62)92

00 (À)nd

9^[d]

10^[d]

Table 3. Cu-catalyzed A.C.A. of R₃Al to 3.

[c]

[a] Conversion determined by GC-MS. [b] ee determined by chiral GC.

[c] Not determined. [d] Reaction performed with 5.0 mol% of CuTC and

10.0 mol% of L4.

Entry CuX

Ligand Solvent R₃Al

Conv.^[a][%] ee^[b][%] Abs.

The addition of trimethylaluminium to 3-ethyl cyclohex-2-

en-1-one (2)afforded excellent yields and enantioselectivi-

ties, which reached 97% ee with L7 (Table 4, entry 2). Al-

though the enantioselectivity remained high (93% ee;

Table 4, entries 3 and 4), the A.C.A. to 3-isobutylcyclohex-2-

en-1-one (3)proceeded with lower conversion owing to the

increased steric demand. In this respect 3-phenylcyclohex-2-

en-1-one (8)did not give any adduct (Table 4, entry 11,)

whereas substrates 4 and 5, both of which contain a remote

double bond, gave excellent yields and enantioselectivities

(91 and 93% ee, respectively with L4; 95% with L7;

Table 4, entries 5 to 8). Finally, an acetal functionality on 6

conf.

CuTC

Et₂O

Me₃Al

Et₃Al

L10

L11

[c]

–

[a] Conversion determined by GC-MS. [b] ee determined by chiral GC.

[c] Not determined.

Chem. Eur. J. 2007, 13, 9647 – 9662

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9649

A. Alexakis and M. Vuagnoux-dꢀAugustin

Table 6. Cu-catalyzed A.C.A. of R₃Al to 2-methylcyclohex-2-en-1-one

(13).

and 7 was tolerated, again with high yields and asymmetric

induction up to 95% ee (Table 4, entries 9 and 10).

Then, the copper-catalyzed asymmetric conjugate addition

of triethylaluminium species to several cyclic 3-methyl a,b-

unsaturated ketones was studied (Table 5).

Table 5. Cu-catalyzed asymmetric conjugate addition of Et₃Al to various

3-methyl-substituted enones.

Entry Ligand R₃Al

(equiv)

Adduct Conv.^[a]

[%]

ee^[b]

[%]

Abs.

conf.

Me₃Al (2.0)

Et₃Al (1.4)

>95

ACHTREUNG

Entry Substrate Ligand Adduct Conv.^[a][%] ee^[b][%] Abs.

ACHTREUNG

conf.

ACHTREUNG

>95 (50)^[c]93

ACHTREUNG

1^[c]

2^[d]

3^[d]

4^[d]

5^[c]

00 (À)

–

>95 (56)81

>95 (55)86

>95 (58)95

00 (À)

[a] Conversion determined by GC-MS. [b] ee determined by chiral GC.

[c] Isolated yield.

–

[a] Conversion determined by GC-MS. [b] ee determined by chiral GC.

[c] Reaction performed with 1.4 equiv of Et₃Al. [d] Enone added before

Et₃Al, see Section on improved experimental conditions.

Lastly, some attempts were done with the exocyclic a,b-

unsaturated ketone 14 to find out if a rigid substrate is nec-

essary to obtain high levels of enantioselectivity (Table 7). It

appeared that the major diastereomer obtained was the cis

one, the kinetic product of protonation from the least hin-

dered side of the enolate. However, the mixture of isomers

could be equilibrated to a trans/cis ratio of 95:5, in presence

of DBU at room temperature. The trans isomer could be

isolated in a pure form to determine its absolute configura-

tion by comparison of its optical rotation with previously re-

ported data.^[18]We assumed that the face selectivity re-

mained the same whatever the added group (Me or Et)

under an identical catalytic system.

As expected, isophorone 12 did not give any adduct be-

cause of its steric hindrance (Table 5, entry 1). On the other

hand, the five-membered cyclic substrate 18 did not give

any adduct either (Table 5, entry 5). The larger ring system

17 gave the desired adduct in good yield and excellent enan-

tioselectivities up to 95% ee when the “reverse addition”

procedure was applied (see Section on improved experimen-

tal conditions). In this case the binaphthol ligand L8

(Table 5, entry 4)was more efficient than biphenol-based

ones.

To increase the interest of our methodology, the 2-trisub-

stituted a,b unsaturated ketone 13 was submitted to the

copper-catalyzed A.C.A. of triorganoaluminium species

(Table 6). The reaction proceeded with complete conversion

with good to high levels of

Some attempts to generate selectively the kinetic cis

isomer by quenching the aluminium enolate with ethyl sali-

cylate, as described by Krause, did not increase the cis/trans

ratio.^[19]Substrate 14 is quite interesting since it did not give

asymmetric induction whatever

Table 7. Cu-catalyzed A.C.A. of R₃Al to 1-cyclohexenylethan-2-one (14).

the organoaluminium reagent

used. This substrate was quite

interesting since the copper-cat-

alyzed asymmetric conjugate

addition was never reported.

The crude hydrolyzed product

afforded a trans/cis ratio around

80:20 and was isomerized with

DBU and isolated as a pure

trans form to determine its ab-

solute configuration by correla-

tion with the literature.^[17]The

best results were obtained with

the binaphthol ligand L8 (93%

ee for Et₃Al; Table 6, entry 9

and 90% ee for Me₃Al; Table 6,

entry 6).

Entry

Ligand

R₃Al (equiv)

t [h]

Adduct

Conv.^[a][%]

ee^[b][%]

Abs.

conf.

Me₃Al (2.0)18

Et₃Al (1.4)48

>95 (72)^[c]

nd^[d]

ACHTREUNG

88 (51)^[c]

ACHTREUNG

–

[a] Conversion determined by GC-MS. [b] ee determined by chiral GC. [c] Isolated yield. [d] Not determined.

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Chem. Eur. J. 2007, 13, 9647 – 9662

Construction of Chiral Quaternary Centers

FULL PAPER

any conjugate adduct when zinc species were added^[20]while

the use of aluminium reagents was successful (Table 7).

However, the reaction rate was low, especially when Et₃Al

was added (Table 7, entries 8 to 10). The conjugate addition

of trimethylaluminium species proceeded with high levels of

enantioselectivity up to 86% in presence of L7 (Table 2,

entry 4). Surprisingly, the enantioselectivity decreased

during the A.C.A. of triethylaluminium reagents to 28% ee

with L4 as chiral ligand. These results showed that the more

flexible substrate 14 was tolerated in the copper-catalyzed

asymmetric conjugate addition of triorganoaluminium spe-

cies.

enone, the exact same experimental conditions were used. It

is noteworthy that the order of introduction of the reagents

was opposite to ours. We first added the aluminium species

and, then, the substrate at the desired temperature. Chan

first introduced the substrate, at room temperature, and

then, at the desired temperature, the organoaluminium spe-

cies. To check the influence of the order of introduction of

the reagents on conversion, the copper-catalyzed A.C.A. of

R₃Al was carried out in the presence of phosphoramidite

ligand L1.

Interestingly, the addition of organoaluminium species to

the catalyst and the substrate (“reverse” addition)had a

very important influence on the conversion of the reaction.

Whereas the “normal” addition led to only 14% conversion

(Table 8, entry 1), the “reverse” one led to a quasi-complete

conversion with 54% of enantioselectivity with the simple

biphenol-based phosphoramidite L1. Higher asymmetric in-

duction could not be obtained with an increase of the cata-

lyst loading (Table 8, entries 2 to 4). The enantioselectivity

dropped when the reaction was performed at higher temper-

ature (Table 8, entry 5). A similar effect was observed when

Me₃Al was added, although less important than with Et₃Al

(Table 8, entries 6 and 7). Thus, these experiments showed

that the lack of reactivity of our substrates was probably

due to the experimental procedure and not to a lack of effi-

ciency of the phosphoramidite ligands. Moreover, we have

demonstrated that the phosphoramidite ligands were stable

in presence of Me₃Al in coordinating solvent (Et₂O or THF)

whereas they were cleaved in presence of CH₂Cl₂into an

aminophosphine species.^[22]Thus, this higher reactivity could

be due to the formation of a more reactive Cu cluster using

the “reverse” order of introduction of the reagents.

Improved experimental conditions: Although we have dis-

covered a way to build chiral quaternary carbon centers that

allows the straightforward construction of chiral building

blocks for more elaborated natural products, some sub-

strates did not give any conjugate adduct (8, 12, and 18)and

it was necessary to find special reaction conditions to over-

come this lack of reactivity.

The first modifications of previously described experimen-

tal conditions were performed for five-membered ring sub-

strates (18 and 19). In fact, it has been reported by Chan

that copper-catalyzed A.C.A. of triorganoaluminium re-

agents was possible to simple cyclopent-2-en-1-one^[21]and

we have shown that the Lewis acidity of the aluminium spe-

cies overcame the steric hindrance of 3-substituted cyclo-

hex-2-en-1-ones.^[3]Compounds 18 and 19 were the substrates

of choice to develop new experimental conditions since they

did not have a too large steric bulk, which was the main

limit of the previously described catalytic system. In a first

step, we extensively changed the reaction temperature, the

copper salt, the solvent and the catalyst loading for the

copper-catalyzed A.C.A. of triethylaluminium compounds to

3-methylcyclopent-2-en-1-one (18)in presence of a phos-

phoramidite ligand L1 without any success. To compare our

results with those obtained by Chan^[21]on cyclopent-2-

To find good “reverse” experimental conditions for the

copper-catalyzed conjugate addition of organoaluminium

species, we extensively looked for the best phosphoramidite

ligand and, then, for the best copper salt. As for 3-substitut-

ed cyclohex-2-en-1-ones, the best results for triethylalumini-

Table 8. Cu-catalyzed A.C.A. to 3-substituted cyclopent-2-en-1-ones in presence of L1.

[b]

Entry

Substrate

Addition^[a]

R¹Al (equiv)

T [8C]

CuX (mol%)Ligand (mCooln%v.)

[%]

ee^[c][%]

Abs.

conf.

[d]

normal

reverse

normal

reverse

Et₃Al (2.0)

Me₃Al (2.0)

À30

À15

À30

CuTC (2.0)

CuTC (4.0)

CuTC (2.0)

L1 (4.0)14

–

L1 (4.0)95

L1 (8.0)47

L1 (16.0)95

L1 (8.0)70

L7 (4.0)

ent-L7 (8.0)

L1 (4.0)09

L1 (4.0)26

ent-L7 (8.0)50

>95

[d]

CuTC (2.0)

[CuOTf]₂·C₆H₆(2.0)

–

[a] Normal: first R₃Al, then enone; reverse: first enone, then R₃Al. [b] Conversion determined by GC-MS. [c] ee determined by chiral GC. [d] Not deter-

mined.

Chem. Eur. J. 2007, 13, 9647 – 9662

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9651

A. Alexakis and M. Vuagnoux-dꢀAugustin

um and 18 were obtained with the biphenol-based ligand L7

in terms of conversion (>95%)and enantioselectivity (93%

ee)(Table 8, entry 7.) The copper salts screening showed

dition of triethylaluminium to a mixture containing the cata-

lyst and the substrate had a positive effect since a small in-

crease of the asymmetric induction was observed (up to

67% ee with L1)with a complete conversion. To complete

our previous results we went back to the study of the Cu-

catalyzed asymmetric conjugate addition of R₃Al to six-

membered ring substrates that did not give any adduct or

with low conversion (Table 9).

that the use of Kubas salt ([Cu(CH₃CN)₄]BF₄), or other in-

organic salts did not give the conjugate adduct 38 in good

conversions, in contrast to the excellent results obtained in

terms of conversion and enantioselectivity for the copper-

catalyzed A.C.A. of diethylzinc species to disubstituted

enones.^[23]The addition of trimethylaluminium to 19 was

more problematic. Even the use of phosphoramidite ligand

L7 led to a dramatic decrease of the conversion and the

asymmetric induction (50% conv., 33% ee (S)) (entry 10).

However, these results could be improved to >95% conver-

sion and 72% ee with a chiral diphosphite ligand as depicted

in Scheme 3.^[24]As expected, the absolute configuration of

conjugate adduct 38 was opposite depending on the enone

and the aluminium species added, thus showing that the

face selectivity remained the same.

We first began with the most hindered substrate 12 that

presents 1,3-diaxial interactions, during the nucleophilic ap-

proach, due to the gem-dimethyl groups (Table 9, entries 1

to 6). The order of introduction of the reagents had a strong

influence since when the enone was added to the triethylalu-

minium species (“normal”)no conjugate adduct was ob-

tained, whereas when the triethylaluminium species was

added to the substrate (“reverse”)a conversion of 35% was

obtained with an enantioselectivity of 82% with the simple

biphenol based phosphoramidite L1 (Table 9, entries 1 and

2). A slight improvement of the conversion was achieved at

À108C, but a drop of enantioselectivity was observed with

standard conditions (Table 9, entry 3). Change of the copper

salt to [CuOTf]₂·C₆H₆combined with a higher temperature

considerably increased the conversion of the reaction to

61% with 75% ee (Table 9, entry 4). However, use of the

more hindered and efficient, in terms of enantioselectivity,

ligand ent-L7 led to a slowdown of the reaction rate

(Table 9, entry 5)which was overcome by adding 4.0 equiva-

lents of the organometallic species and doubling the catalyst

loading to give the desired chiral adduct 36 in 87% yield

(97% ee; Table 9, entry 6). To check if these new experi-

mental conditions developed for the highly hindered sub-

strate 12 were more general than the previous ones, the

copper-catalyzed A.C.A. of trimethylaluminium species was

As the order of introduction of the reagents seemed to in-

fluence the formation of chiral conjugate adduct, a new

series of experiments was done with 1. As expected, the ad-

Scheme 3. Synthesis of compound 38.

Table 9. Cu-catalyzed A.C.A. of R₃Al to six-membered ring substrates.

Entry

Substrate

Addition^[a]

R²Al (equiv)CuX (mol%)

Ligand (mol%)

T [8C]

Adduct

Conv.^[b][%]

ee^[c][%]

Abs.

conf.

normal

reverse

Et₃Al (1.4)CuTC (2.0)

Et₃Al (2.0)CuTC (2.0)

L1 (4.0)

ent-L7 (4.0)

ent-L7 (8.0)

L7 (8.0)

ent-L7 (8.0)

L7 (8.0)

À30

À10

35 (48 h)82

–

[d]

75^[d]

96^[d]

97^[d]

rac

Et₃Al (2.0)

Et₃Al (4.0)

Me₃Al (2.0)

>95 (87)^[e]

>95 (85)^[e]

70 (50)^[e]

–

>95

L7 (8.0)

[a] normal: first R₃Al, then enone; reverse: first enone, then R₃Al. [b] Conversion determined by GC-MS. [c] ee determined by chiral GC. [d] Constant

ee during the reaction time. [e] Isolated yield.

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Chem. Eur. J. 2007, 13, 9647 – 9662

Construction of Chiral Quaternary Centers

FULL PAPER

then performed to the 3-isobutylcyclohex-2-en-1-one (3),

which gave low results in terms of conversion (Table 3, en-

tries 3 and 4). The “reverse” addition of reagents led to sim-

ilar results as those obtained by the “normal” way with

CuTC and L4. However, the use of the conditions devel-

oped for isophorone 1 led to an impressive increase of the

conversion to more than 95%. The chiral adduct was gener-

ated in 85% isolated yield with an enantioselectivity reach-

ing 98% in presence of L7 and 2.0 equivalents of trimethyl-

aluminium (Table 9, entry 7). The 3-aromatic cyclohex-2-en-

1-ones (8–11)were quite difficult substrates since the steric

effects, and the electronic effects were combined. We have

seen that the simple 3-phenylcyclohex-2-en-1-one (8)did

not give any adduct using the standard conditions previously

reported (Table 4, entry 11). We found that these new im-

proved conditions (Table 9, entry 8)enlarged the scope of

our methodology, since it is not possible to obtain such

chiral quaternary adducts by another procedure than copper

catalysis.^[5]However, the conversion of the reaction was not

complete in 18 h and the enantioselectivity was lower than

for other non-aromatic substrates (70% conv., 50% isolated

yield, 72% ee; Table 9, entry 8). To check the influence of

electronic effects on the b-position of the enone, some ex-

periments of copper-catalyzed asymmetric conjugate addi-

tion of trimethylaluminium reagents were done on several

3-aryl cyclohex-2-en-1-ones (Table 9, entries 8 to 11)under

the best experimental conditions. As expected, the substrate

bearing an EWG (CF₃; Table 9, entry 9)on the aromatic

ring had a higher reactivity than that bearing an EDG

(OMe; Table 9, entry 10)in the same para position. The sub-

strate with no substituent on the aromatic ring 8 presented

an intermediate reactivity (Table 9, entry 8). That could be

easily explained since an EWG tends to decrease the elec-

tronic density of the b-position and made it more electro-

philic and reactive. The opposite was observed when the ar-

omatic ring bore an EDG. However, the substrate bearing

an OMe in ortho position gave the adduct with complete

conversion, but as a racemate (Table 9, entry 11). Probably,

due to the high oxophilicity of aluminium, a chelating phe-

nomenon took place overcoming the electronic effects.

Scheme 4. Tandem hydroalumination–Cu-catalyzed A.C.A.

The use of “standard” conditions (CuTC, Et₂O)only led

to the 1,2-addition–dehydration product. Increased catalyst

loading up to 15.0 mol% or temperature did not give the

conjugate adduct. Only, when 30.0 mol% of CuTC and

30.0 mol% of ligand were used, the formation of the conju-

gate adduct appeared, with 80% of asymmetric induction

(ent-L7). However, there was not a complete selection in

favor of the conjugate addition, and the 1,2-addition–dehy-

dration product was observed in variable amounts. To dis-

criminate against the 1,2-addition of vinylalane 47, the ex-

perimental conditions were changed to the other set devel-

oped: [Cu(CH₃CN)₄]BF₄and THF. Surprisingly, the 1,2-ad-

dition–dehydration product was never obtained even at

room temperature. However, it was necessary to work with

a high catalyst loading of 30.0 mol% to obtain good enan-

tioselectivity (73% ee, L4). As expected, the more efficient

but more hindered ligand L7 did not give any conversion in

this set of conditions. The (À)-stereoisomer was isolated

which was assigned to the same facial selectivity as the

other asymmetric conjugate additions as already observed

for addition of vinalalane to disubstituted enone.^[26]To the

best of our knowledge only racemic addition of such vinyla-

lane to trisubstituted enones have been reported before.^[27]

Reactivity and use of aluminium enolates: The asymmetric

conjugate addition is an essential method for the specific in-

troduction of a hydrocarbon unit to the b-position of a car-

bonyl function. Furthermore, the eminent nucleophilicity of

the metal enolate intermediate allows for reaction with vari-

ous electrophiles, affording the a,b-vicinal structural modifi-

cation of enones and providing a powerful tool for the syn-

thesis of complex molecules. In contrast to zinc enolates, the

reactivity of aluminium enolates is not well documented.

Mole first reported, in 1974, the use of isolated aluminium

enolates for an aldol reaction,^[28]whereas Tsuda and Saegusa

studied the alkylation and the silylation of aluminium eno-

lates generated by hydroalumination of a,b-unsaturated car-

bonyl compounds.^[16]Alkylation of the aluminium enolates

generated from the MeCu-catalyzed reaction of a,b-unsatu-

rated carbonyl compounds and DIBAl–H-HMPA with alkyl

halides did not proceed easily. It has been found that con-

version of the aluminium enolates into the “ate” complexes

by addition of an equimolar amount of methyllithium in-

To enlarge the scope of the procedure developed to gen-

erate chiral quaternary centers, we tried to add aluminium

species to tetrasubstituted a,b-unsaturated ketones. Unfortu-

nately, all attempts were unsuccessful with both, 2-methyl-3-

ethylcyclohexen-1-one (15), and 3,4,7,8-tetrahydronaphtha-

lene-1,5

[26]

tuted jasmone (20)did not give any adduct either.

Tandem hydroalumination-Cu-catalyzed A.C.A.: One main

attraction of organoaluminium reagents is the ease with

which novel reagents can be attained by hydro- and carboa-

lumination reactions.^[25]Hydroalumination of pent-1-yne

(46)was performed under Zweifel conditions, and quantita-

tively led to the vinylalane species 47 in complete conver-

sion. It was then added to the enone 1 in presence of copper

salt and chiral phosphoramidite ligand to lead the conjugate

adduct 48 in complete conversion and 73% ee (Scheme 4).

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9653

A. Alexakis and M. Vuagnoux-dꢀAugustin

creases their nucleophilic reactivity toward alkyl halides to

produce alkylated products in moderate to good yields.

We first checked the stability of the aluminium enolate

generated via the copper-catalyzed asymmetric conjugate

addition of trimethylaluminium species to 4 and 5, sub-

strates bearing a remote double bond. Indeed, it could be

envisaged that this intermediate species was not stable

enough and reacted intramolecularly to undergo a carbome-

tallation reaction and generated bicyclic systems, like zinc

species which promoted an easy cyclization reaction of spe-

cific substrates.^[29]However, the cyclization product was not

obtained because of the high stability of the aluminium eno-

late probably due to the “strong” bond between the alumini-

um and the oxygen atoms. It was in accordance with previ-

ous results since the product of the undesired side trapping

of the aluminium enolate to unreacted trisubstituted sub-

strates was never observed. This high stability allowed the

isolation of aluminium enolates by Mole.^[30]Moreover, this

very high stability prevented the reaction between various

aluminium enolates, generated by copper-catalyzed asym-

metric conjugate addition of triorganoaluminium reagents,

and diethylcarbonate, or several allylating reagents under

numerous experimental conditions. As the direct reaction

with these aluminium enolates, generated by Cu-catalyzed

A.C.A. of R₃Al, to form a,b-functionalized adducts was not

feasible, we envisaged then to functionalize their oxygen

atom in order to generate precursors of lithium enolates

(silyl enol ether or enol acetate)or precursors of a-allylated

adducts (enol acetates or allyl enol carbonate)via the Tsuji–

Trost rearrangement.^[31]

The formation of allyl enol carbonate was also envisaged

and surprisingly, the CuTC–phosphoramidite ligand system,

in diethyl ether, instead of CuBr, in THF, inhibited the reac-

tion. In view of the importance of THF on conversion, in

this tandem reaction, we used the other set of conditions

previously developed (THF and [Cu(CH₃CN)₄]BF₄). Best

results were obtained, since 50 was formed in good conver-

sion (68%)in 24 h00 (Scheme 6). It could be possible to im-

prove the conversion by an increase of the equivalents of al-

lylchloroformate added.

Scheme 6. Tandem Cu-catalyzed A.C.A. of Et₃Al–allyl enol carbonate

formation.

Finally, by analogy to disubstituted enones,^[32]the O-acyla-

tion reaction was realized to generate enol acetates

(Scheme 7), which are much more stable than silyl enol

The silylation of aluminium enolates has been already re-

ported by Tsuda^[16]in good yields with a small excess of tri-

methylsilyl chloride. However, when we tried to silylate the

aluminium enolate generated via the copper-catalyzed asym-

metric conjugate addition of triorganoaluminium reagents to

1 with TMSOTf, the silyl enol ether could not be isolated in

spite of its complete formation according to GC-MS. All at-

tempts to the generation of the silyl enol ether 49 failed

after purification. To confirm its formation, an optimization

of the work-up and the purification was done to avoid the

degradation of the compound and furnished it in 58% iso-

lated yield (Scheme 5, see Experimental Section).We envis-

aged then to quench the aluminium enolate with other sily-

lating reagents less sensitive to the slightly acidic conditions

of the work-up and to the purification. Unfortunately,

TBDMSCl and TBDPSCl did not give the silylated adducts,

even after seven days at room temperature, probably be-

cause of their steric hindrance.

Scheme 7. Tandem Cu-catalyzed A.C.A. of Et₃Al-O-acylation.

ethers and are precursors of lithium enolates^[33–35]or mono-

allylated adducts via intermolecular Tsuji reaction.^[31c]The

tandem copper-catalyzed A.C.A-O-acylation worked well

since whatever the ring-size, conversions were complete and

good yields were obtained. The C-acylation was never ob-

served. One-gram scale was tolerated since no loss of asym-

metric induction was observed for the copper-catlyzed

A.C.A. part of the reaction, and the enol acetate 51 was iso-

lated in 73% yield.

The lithium enolate could be quantitatively regenerated

with no loss of enantioselectivity following the procedures

described by House^[33]and Posner.^[34]The attempted a-ally-

lation resulted in fact in the gem-bisallylated 53 product.

With an excess of allyl bromide, 53 was generated in good

yield and was cyclized via a ring closure metathesis to form

the spirocyclic compound 54 in good yield (Scheme 8). The

gem-bismethallylated intermediate could be similarly gener-

ated among various allylated adducts, and an improvement

of the experimental conditions would be necessary.

Scheme 5. Tandem Cu-catalyzed A.C.A. of Et₃Al–silylation reaction.

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Chem. Eur. J. 2007, 13, 9647 – 9662

Construction of Chiral Quaternary Centers

FULL PAPER

the absolute configuration of all new conjugate adducts

bearing a chiral quaternary center by chemical correlation

with this known compound. The negative optical rotation

([a] = À74.8, c=1.53, CHCl₃)corresponds to the R config-

uration of 56, which is an intermediate in the synthesis of

Axanes derivatives family isolated from the marine sponge

Axinella cannabia (Scheme 11).^[36b]It is assumed that all ad-

ducts listed in Tables 4, 5 and 9 follow the same trend.

Scheme 8. Bis-allylation-RCM reaction.

Finally, a reductive ozonolysis was done to generate a

(1,6)-diol bearing a chiral quaternary carbon 55 (Scheme 9).

Scheme 11. Synthetic approach to axanes.

Scheme 9. Reductive ozonolysis.

The Baeyer–Villiger reaction was a way to generate acy-

clic adducts since a simple basic treatment could lead to acy-

clic adducts bearing a chiral quaternary center. However, it

was necessary that the carbon in b-position bearing quater-

nary center influenced the regioselectivity of such a reac-

tion. Thus, the Baeyer–Villiger reaction was also performed

with various peracids. A good selectivity of 85:15 was ob-

served when the adduct 28 was treated with m-CPBA

(Scheme 12)in favor of 58. The oxygen insertion took place

preferentially on the more hindered side. However, chang-

ing the oxidative reagent to CF₃CO₃H or CH₃CO₃H led to

worse selectivity and a decrease of the reaction rate.

To conclude on the reactivity of aluminium enolates, we

saw that it was difficult to use them directly with electro-

philes probably due to their high stability. However, the sily-

lation, carbonation and O-acylation were feasible in good

yields. These intermediates could eventually be used for

later applications such as Tsuji reaction, ozonolysis, to gen-

erate more elaborated adducts.

To enlarge the scope of our methodology to generate

chiral quaternary carbon centers, we explored the potential

use of the chiral adducts formed. Novel routes to carbobicy-

clic compounds in enantiomerically pure form continue to

offer a synthetic challenge since numerous products includ-

ing terpenes and steroids show this structural feature. In the

pursuit of novel catalytic asymmetric annulation strategies,

we focused on the construction of enantiomerically pure car-

bobicyclic products. We envisaged to make an intramolecu-

lar aldolization–crotonization reaction with substrates bear-

ing an acetal functionality, which could easily be deprotect-

ed in one-pot by acidic treatment (Scheme 10). This trans-

formation gave bicyclic a,b-unsaturated compounds bearing

a chiral quaternary center, and occurred without any loss of

enantioselectivity. These fused bicyclic systems are impor-

tant intermediates for asymmetric synthesis of sesquiter-

penes derivatives.^[36a]

Scheme 12. Ring expansion by Baeyer–Villiger oxidation.

Finally, the adduct arising from the tandem hydroalumina-

tion–A.C.A. was submitted to oxidative ozonolysis to gener-

ate the aldehyde 60 (Scheme 13).

This reaction worked well with six-membered ring com-

pounds (33 and 34)and bicyclic adducts were obtained in

good isolated yields. Compound 56 allowed us to determine

Scheme 13. Ozonolysis reaction.

The 1,4-ketoaldehyde 60 is described in the literature and

allowed us to compare its optical rotation^[37]and to confirm

that the face selectivity remained the same whatever the or-

ganoaluminium species for a given catalytic system. Such a

derivative bearing an aldehyde in the a-position to the

Scheme 10. Tandem aldolization–crotonization reaction.

Chem. Eur. J. 2007, 13, 9647 – 9662

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9655

A. Alexakis and M. Vuagnoux-dꢀAugustin

tained by EI (70 eV)and High Resolution Mass Spectra (HRMS)by

Electrospray Ionisation (ESI)or by Electronic Impact (EI). Optical rota-

tions were measured at 208C in a 10 cm cell in the stated solvent; [a]_D

values are given in 10^À1degcm²g^À1(concentration c given as g100 mL^À1).

chiral quaternary center, as 60, could be used for further

functionalizations such as Horner–Wadsworth–Emmons re-

action, 1,2-addition, cross metathesis, to generate more ela-

borated molecules. Thus, the scope of our methodology was

greatly enlarged.

Typical procedure for ligand (L1 to L11) synthesis: A solution of amine

(22.2 mmol)in THF (10 mL)was added to a stirred mixture of Et ₃N

(111.1 mmol, 15.5 mL)and PC L3 (22.2 mmol, 1.9 mL)at 0 8C, and the re-

action mixture was stirred for 3 h at room temperature. Biphenol or bi-

naphthol (22.2 mmol)in a solution of THF (5 mL)was slowly added to

the reaction mixture at 08C and then the suspension was stirred at RT

overnight. The suspension was diluted in toluene (8 mL)and filtered on

neutral alumina, the solution was concentrated and purified by flash

chromatography through neutral alumina using dry toluene as eluent, to

give the pure ligand as a white solid or a colorless oil.

Ligand L1:^{[38] 1}H NMR (400 MHz, CDCl₃): d=7.49–7.45 (m, 2H, Ar),

7.38–7.10 (m, 16H, Ar), 4.60 (q, J=7.0 Hz, 1H, CH), 4.58 (q, J=7.0 Hz,

1H, CH), 1.73 ppm (d, J=7.0 Hz, 6H, CH₃); ¹³C NMR (100 MHz,

CDCl₃): d=152.0, 151.9, 151.1, 151.0, 143.0, 131.2, 130.0, 129.8, 129.1,

129.0, 128.9, 128.2, 127.9, 127.7, 126.6, 125.3, 124.0, 122.5, 122.0, 52.7,

52.6, 22.2 ppm; ³¹P (162 MHz, CDCl₃): d=147.0 ppm; [a]²_D⁰=À236 (c=

3.0 in toluene).

Conclusion

To summarize, we took advantage of the Lewis acidity of tri-

organoaluminium species to overcome the steric hindrance

of b-trisubstituted Michael acceptors, and to generate chiral

quaternary centers via copper-catalyzed asymmetric conju-

gate addition. The biphenol-based ligands L4 and L7 afford-

ed the best results whatever the set of conditions used,

whereas the binaphthol L8 gave good results in some cases.

Several “simple” substrates gave excellent conversions

(yields)and enantioselectivities in similar experimental con-

ditions as to those used for disubstituted substrates, whereas

some Michael acceptors (five-membered ring system, highly

hindered substrates)needed the carefully optimized condi-

tions to give excellent results. The conditions developed

were applied to other trisubstituted substrates (a-substitu-

tion or exocyclic ketone)without any loss of asymmetric in-

duction. The first example of tandem hydroalumination–

A.C.A. catalyzed by copper was developed with an enantio-

selectivity reaching 73%. Finally, aluminium enolates, gener-

ated by copper-catalyzed-A.C.A., could be used to form

protected enols (silylation, carbonation, O-acylation). These

stable intermediate compounds could react to generate

more elaborated products. Similarly, conjugate adducts bear-

ing chiral quaternary center could be elaborated into the

more valuable intermediates in organic synthesis.

Ligand L3:^{[38] 1}H NMR (400 MHz, CDCl₃): d=7.51–7.54 (m, 2H, Ar),

7.42–7.36 (m, 2H, Ar), 7.32–7.19 (m, 4H, Ar), 7.07–7.00 (m, 10H, Ar),

4.28 (t, J=10.3 Hz, 1H, CH), 4.27 (t, J=10.3 Hz, 1H, CH), 2.32–2.24 (m,

2H, CH₂), 2.17–2.10 (m, 2H, CH₂), 0.83 ppm (t, J=7.3 Hz, 6H, CH₃);

¹³C NMR (100 MHz, CDCl₃): d=151.9, 151.8, 150.9, 141.0, 131.4, 129.9,

129.7, 129.1, 129.0, 128.3, 127.5, 126.2, 124.6, 123.7, 122.5, 121.7, 59.8,

59.7, 29.6, 28.3, 11.6 ppm; ³¹P (162 MHz, CDCl₃): d=144.4 ppm; [a]_D²⁰

+231 (c=3.5 in toluene).

Ligand L4:^{[38] 1}H NMR (400 MHz, CDCl₃): d=7.30–6.98 (m, 14H, Ar),

4.78–4.58 (m, 2H, CH), 2.47 (s, 3H, CH₃), 2.35 (s, 3H, CH₃), 2.33 (s, 3H,

CH₃), 2.09 (s, 3H, CH₃), 1.71ppm (d, J=7.0 Hz, 6H, CH₃); ¹³C NMR

(100 MHz, CDCl₃): d=148.0, 147.9, 147.1, 143.5, 137.5, 133.3, 132.6,

131.0, 130.9, 130.2, 129.3, 129.0, 128.2, 128.1, 127.9, 127.8, 127.6, 126.5,

125.3, 109.6, 52.5, 20.8, 17.3, 16.3 ppm; ³¹P (162 MHz, CDCl₃): d=

144.4 ppm; [a]²_D⁰=À221 (c=2.2 in toluene).

Ligand L5:^{[3] 1}H NMR (400 MHz, CDCl₃): d=7.10–7.03 (m, 14H, Ar),

4.32 (s, 2H, CH), 2.49 (s, 3H, CH₃), 2.36 (s, 6H, CH₃), 2.28 (m, 2H,

CH₂), 2.07 (s, 2H, CH₂), 1.99 (s, 3H, CH₃), 0.78 ppm (s, 6H, CH₃);

¹³C NMR (100 MHz, CDCl₃): d=147.9, 147.3, 133.2, 132.7, 131.2, 131.1,

130.9, 130.4, 130.3, 129.3, 128.7, 128.2, 127.6, 126.4, 60.2, 23.2, 20.9, 20.8,

17.2, 16.4, 11.9 ppm; ³¹P (162 MHz, CDCl₃): d=144.4 ppm; [a]²_D⁰=À215

(c=1.06 in CHCl₃).

Experimental Section

Ligand L6:^{[39] 1}H NMR (500 MHz, CDCl₃): d=7.53–7.17 (m, 22H, Ar),

4.82–4.78 (m, 2H, CH), 1.90 ppm (d, J=7.0 Hz, 6H, CH₃); ¹³C NMR

(125 MHz, CDCl₃): d=151.9, 151.8, 151.0, 140.4, 132.9, 132.4, 131.2,

130.0, 129.8, 129.2, 129.0, 128.2, 127.9, 127.3, 127.0, 126.1, 125.7, 125.6,

125.3, 124.7, 124.1, 122.5, 122.1, 52.8, 52.7, 22.1 ppm; ³¹P NMR (203 MHz;

CDCl₃): d=146.3 ppm; [a]²_D⁰=+405 (c=1.12 in CHCl₃).

General methods: All reactions were carried out under argon atmos-

phere with oven-dried glassware. Solvents were dried by filtration over

alumina previously activated at 3508C during 12 h under nitrogen before

use. All solvents were degassed by nitrogen bubbling before use to all ex-

periments. Triethylamine was distilled over CaH₂prior to use. PCL3 was

degassed and distilled prior to use. Trimethylaluminium 2.0m in heptane

(Aldrich or Fluka), triethylaluminium 1.0m in hexane (Aldrich or Fluka),

methyllithium 1.6m in diethyl ether (Acros), methyllithium·lithium bro-

mide 1.5m in Et₂O (Fluka)were used without any further purification.

Ligand L7:^{[39] 1}H NMR (400 MHz, CDCl₃): d=7.67 (d, J=6.8 Hz, 2H,

Ar), 7.52–7.02 (m, 16H, Ar), 4.89 (m, 2H, Ar), 2.55 (s, 3H, CH₃), 2.38 (s,

3H, CH₃), 2.36 (s, 3H, CH₃), 2.11 (s, 3H, CH₃), 1.85 ppm (d, J=4.0 Hz,

6H, CH₃); ¹³C NMR (100 MHz, CDCl₃): d=147.5, 141.2, 133.8, 133.3,

133.1, 132.7, 131.4, 130.6, 130.5, 129.7, 128.6, 128.2, 127.7, 127.6, 127.2,

126.6, 126.0, 125.8, 53.1, 53.0, 21.2, 17.8, 16.9 ppm; ³¹P NMR (162 MHz,

CDCl₃): d=142.0 ppm; [a]²_D⁰=À435 (c=1.0 in CHCl₃).

Copperthiophene carboxylate (FrontierScientific), [Cu(OTf)₂] (Aldrich),

and [CuOTf]₂·C₆H₆(Aldrich)were purchased and used without any fur-

ther purification. Evolution of reaction was followed by GC-MS Hewlett

Packard (EI mode)HP6890-5973 or by TLC (visualisation by UV and

anisaldehyde, KMnO₄or PMA staining). Flash chromatography was per-

formed using silica gel 32–63 mm, 60 . ¹H (300, 400 or 500 MHz)and

Ligand L8:^{[40] 1}H NMR (400 MHz, CDCl₃): d=8.08–8.98 (m, 4H, Ar),

7.74–7.17 (m, 18H, Ar), 4.63 (q, J=7.2 Hz, 2H, CH), 1.75 ppm (d, J=

7.2 Hz, 6H, CH₃); ¹³C NMR (100 MHz, CDCl₃): d=150.5–122.4, 52.3,

51.1, 21.8 ppm; ³¹P NMR (162 MHz, CDCl₃): d=146.1 ppm; [a]²_D⁰=À456

(c=0.79 in CHCl₃).

¹³C (75, 100 or 125 MHz)NMR spectra were recorded in CDCl on

Bruker AMX-300, À400 or À500 spectrometers. Chemical shift (d)are

given in ppm relative to residual deuterated solvent. Coupling constants

are reported in Hz. Enantiomeric excesses were determined by chiral-

GC (capillary column, 10 psi H₂), temperature programs are described as

follows: initial temperature [8C]–initial time [min]–temperature gradient

[8Cmin^À1]–final temperature [8C], or by chiral Supercritical Fluid Chro-

matography (SFC), with appropriated program using a gradient of meth-

anol. Retention times (t_R)are given in minutes. Mass spectra were ob-

Ligand L9:^{[40] 1}H NMR (400 MHz, CDCl₃): d=8.08–7.78 (m, 4H, Ar),

7.65–7.24 (m, 18H, Ar), 4.47 (q, J=7.2 Hz, 2H, CH), 1.75 ppm (d, J=

7.2 Hz, 6H, CH₃); ¹³C NMR (100 MHz, CDCl₃): d=150.5–122.5, 54.5,

54.3, 23.1, 21.8 ppm; ³¹P NMR (162 MHz, CDCl₃): d=151.3 ppm; [a]_D²⁰

+11 (c=0.79 in CHCl₃).

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Construction of Chiral Quaternary Centers

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Ligand L10:^{[41] 1}H NMR (400 MHz, CDCl₃): d=8.05–5.03 (m, 20H, Ar),

(100 MHz, CDCl₃): d=200.1, 161.4, 159.3, 130.9, 127.8, 123.81, 114.3,

55.5, 37.3, 28.0, 22 ppm.

5.07 (dq, J=7.1, J=1.0 Hz, 2H, CH), 3.52 (s, 6H, -OCH₃), 1.61 ppm (d,

J=7.1 Hz, 6H, CH₃); ¹³C NMR (100 MHz, CDCl₃): d=155.9, 150.7,

150.16, 133.0, 132.3, 131.4, 130.5, 129.5, 128.4, 128.2, 127.5, 127.4, 127.3,

127.2, 126.0, 125.8, 124.7, 124.4, 124.4, 124.3, 122.8, 122.5, 121.8, 119.4,

109.3, 65.9, 54.6, 48.3, 48.2, 22.2, 15.3 ppm; ³¹P NMR (162 MHz, CDCl₃):

d=152.15 ppm; [a]_D²⁰=À272.2 (c=1.0 in CHCl₃).

3-(2-Methoxyphenyl)cyclohex-2-en-1-one (11):^{[47] 1}H NMR (400 MHz,

CDCl₃): d=7.3 (ddd, ¹J=9.4, ²J=7.6, ³J=1.8 Hz, 1H, CH Ar), 7.20 (dd,

¹J=9.3, ²J=1.8 Hz, 1H, CH Ar), 6.98 (td, ¹J=7.6, ²J=1.0 Hz, 1H, CH

Ar), 6.93 (d, J=8.4 Hz, 1H, CH Ar), 6.21 (s, 1H, CH), 3.85 (s, 3H,

OCH₃), 2.75 (t, J=5.8 Hz, 2H, CH₂), 2.49 (t, J=6.3 Hz, 2H, CH₂),

2.11 ppm (q, J=5.8 Hz, 2H, CH₂); ¹³C NMR (100 MHz, CDCl₃): d=

200.2, 161.7, 156.6, 130.3, 128.7, 128.2, 120.7, 111.1, 55.4, 37.5, 30.0,

23.3 ppm.

Ligand L11:^{[41] 1}H NMR (400 MHz, CDCl₃): d=8.04–6.52 (m, 20H, Ar),

4.99 (dq, ¹J=7.1, ²J=1.2 Hz, 2H, CH), 3.58 (s, 6H, OCH₃), 1.55 ppm (d,

J=7.1 Hz, 6H, CH₃); ¹³C NMR (100 MHz, CDCl₃): d=156.1, 149.9,

132.8, 132.5, 131.4, 130.3, 129.2, 128.3, 128.0, 127.7, 127.6, 127.4, 127.3,

125.9, 125.6, 124.7, 124.5, 124.2, 122.7, 121.5, 119.6, 109.2, 54.6, 50.3, 50.2,

22.6, 22.5 ppm; ³¹P NMR (162 MHz, CDCl₃): d=155.25 ppm; [a]_D=

+144.3 (c=1.1 in CHCl₃).

3-Ethyl-2-methylcyclohex-2-en-1-one

(15):^[48]

¹H NMR

(400 MHz,

CDCl₃): d=2.38–2.31 (m, 4H, CH₂), 2.24 (q, J=7.6 Hz, 2H, CH₂), 1.91

(quint, J=6.3 Hz, 2H, CH₂), 1.75 (s, 3H, CH₃), 1.05 ppm (t, J=7.6 Hz,

3H, CH₃); ¹³C NMR (100 MHz, CDCl₃): d=199.6, 160.4, 130.2, 37.6,

30.2, 28.2, 22.5, 11.6, 10.2 ppm; IR (neat): n˜ =2965, 2935, 2868, 2825,

1664, 1628 cm^À1; EI-MSHR: m/z: calcd for C₉H₁₄O: 138.1045, found

138.1045 [M]⁺.

3-Ethylcyclopent-2-en-1-one (19):^{[49] 1}H NMR (400 MHz, CDCl₃): d=

5.93 (s, 1H, CH), 2.57 (q, J=7.1 Hz, 2H, CH₂), 2.44–2.37 (m, 4H),

1.17 ppm (t, J=7.3 Hz, 3H, CH₃); ¹³C NMR (100 MHz, CDCl₃): d=

210.1, 184.5, 128.6, 35.3, 31.3, 26.6, 11.4 ppm; IR (neat): n˜ =2966, 1710,

1617, 1180 cm^À1; EI-MSHR: m/z: calcd for C₇H₁₀O: 110.0732, found

110.0731 [M]⁺.

Typical procedure for 3-substituted enones synthesis: A flame-dried flask

was charged with Grignard reagent (2.0 equiv)and cooled to 0 8C. The

ethoxycyclohex-2-en-1-one or methoxycyclopent-2-enone (50 mmol)in

THF (40 mL)was added dropwise. Once the addition was complete the

reaction mixture was left at room temperature until complete disappear-

ance of the starting material. The reaction was hydrolyzed by addition of

aqueous sulfuric acid (5% w/w). Et₂O (50 mL)was added and the aque-

ous phase was separated and extracted further with Et₂O (320 mL).

The combined organic fractions were washed with NaHCO₃, brine and

water, dried over Na₂SO₄, filtered and concentrated in vacuo. The oily

residue was purified by Kugelrohr distillation under reduced pressure.

4-Chlorobutan-1-al

(24):

Pyridinium

chlorochromate

(30.10 g,

139.6 mmol, 2.0 equiv)in dry CH ₂Cl₂(200 mL)was suspended in a

250 mL round-bottomed flask equipped with a condenser. 4-chlorobuta-

nol (1.0 equiv)in dry dichloromethane (20 mL)was added in one portion

to the magnetically stirred solution. After 2 h, Et₂O (200 mL)was added

and the supernacant decanted from the black residue. The insoluble gum

was washed with Et₂O (350 mL)whereupon it became granular solid.

The organic layers were filtered through a short pad of florisil, and the

solvents were removed in vacuum in order to give a dark green oil. Dis-

tillation under reduced pressure (508C, 13 mmHg)furnished the desired

product in 49% yield as a colorless oil. ¹H NMR (400 MHz, CDCl₃): d=

9.78 (s, 1H, CHO), 3.57 (t, J=6.3 Hz, 2H, CH₂), 2.65 (dt, ¹J=7.0, ²J=

1.0 Hz, 2H, CH₂), 2.07 ppm (quint, J=6.6 Hz, 2H, CH₂); ¹³C NMR

(100 MHz, CDCl₃): d=220.9, 44.0, 40.8, 24.7 ppm.

3-Ethylcyclohex-2-en-1-one (2):^{[42] 1}H NMR (500 MHz, CDCl₃): d=5.89

(t, J=1.4 Hz, 1H, CH), 2.37 (t, J=3.3 Hz, 2H, CH₂), 2.29 (t, J=5.7 Hz,

2H, CH₂), 2.25 (qd, ¹J=7.4, ²J=0.6 Hz, 2H, CH₂), 2.0 (quint, J=7.0 Hz,

2H, CH₂), 1.1 ppm (t, J=7.4 Hz, 3H, CH₃); ¹³C NMR (125 MHz,

CDCl₃): d=200.0, 167.8, 124.6, 37.4, 30.8, 29.7, 22.7, 11.2 ppm.

3-Isobutylcyclohex-2-en-1-one (3):^{[43] 1}H NMR (400 MHz, CDCl₃): d=

5.84 (s, 1H, CH), 2.35 (t, J=6.7 Hz, 2H, CH₂), 2.25 (t, J=5.9 Hz, 2H,

CH₂), 2.07 (d, J=7.3 Hz, 2H, CH₂), 1.97 (quint, J=6.4 Hz, 2H, CH2),

1.87 (m, 1H, CH), 0.9 ppm (d, J=6.6 Hz, 6H, CH₃); ¹³C NMR

(100 MHz, CDCl₃): d=199.9, 165.7, 126.9, 47.7, 37.3, 29.7, 26.4, 22.8,

22.5 ppm.

3-(3-Butenyl)cyclohex-2-en-1-one (4):^{[44] 1}H NMR (500 MHz, CDCl₃): d=

5.80 (s, 1H, CH), 5.75–5.67 (m, 1H, CH), 4.98 (dd, ¹J=17.1, ²J=1.5 Hz,

1H, =CH), 4.92 (dd, ¹J=9.4, ²J=1.6 Hz, 1H, =CH), 2.29–2.19 (m, 8H),

1.94–1.89 ppm (m, 2H, CH₂); ¹³C NMR (125 MHz, CDCl₃): d=199.9,

165.6, 137.1, 126.1, 115.7, 37.5, 37.4, 31.1, 29.9, 22.8 ppm.

3-(4-Pentenyl)cyclohex-2-en-1-one (5):^{[45] 1}H NMR (400 MHz, CDCl₃):

d=5.82 (s, 1H, CH), 5.78–5.68 (m, 1H, CH), 4.99–4.91 (m, 2H, =CH₂),

2.31–1.90 (m, 10H), 1.59–1.51 ppm (m, 2H, CH₂); ¹³C NMR (100 MHz,

CDCl₃): d=200.0, 166.5, 138.0, 125.9, 115.5, 37.5, 37.5, 33.4, 29.9, 26.2,

2-(3-Chloropropyl)-1,3-dioxane

25:

4-Chlorobutan-1-al

(4.02 g,

37.7 mmol)and 1,3-propanediol (6.0 mL, 83.02 mmol)in dry toluene

(50 mL)were placed in a round-bottomed flask equipped with a Dean-

Stark under nitrogen. The reaction mixture was refluxed in presence of

catalytic amount of p-TsOH·H₂O (200 mg)for 3 h. The reaction was

quenched at room temperature by the addition of aqueous saturated so-

lution of NaHCO₃. The organic layer was washed with water, dried over

K₂CO₃and solvent was removed in vacuo to give the desired protected

aldehyde in quantitative yield. The crude mixture was used without any

further purification. ¹H NMR (400 MHz, CDCl₃): d=4.56 (t, J=5.0 Hz,

22.9 ppm.

[45]

3-[2-(1,3-Dioxan-2-yl)ethyl]cyclohex-2-en-1-one

(6):

¹H NMR

1H, CH), 4.10 (dd, J=10.6, J=5.0 Hz, 2H, CH₂), 3.76 (td, J=12.4, J=

2.3 Hz, 2H, CH₂), 2.13–2.01 (m, 1H, CH), 1.93–1.86 (m, 2H, CH₂), 1.77–

1.72 (m, 2H, CH₂), 1.34ppm (dd, ¹J=13.4, ²J=1.3 Hz, 1H, CH);

¹³C NMR (100 MHz, CDCl₃): d=101.4, 66.9, 44.9, 32.4, 27.1, 25.6 ppm.

(400 MHz, CDCl₃): d=5.70 (s, 1H, CH), 4.39 (t, J=5.0 Hz, 1H, CH),

3.93 (dd, ¹J=10.6, ²J=5.0 Hz 2H, CH₂), 3.60 (td, ¹J=12.4, ²J=2.3 Hz,

2H, CH₂), 2.21–2.14 (m, 6H), 1.86–1.80 (m, 2H, CH₂), 1.65–1.60 (m, 2H,

CH₂), 1.20 ppm (dt, ¹J=13.4, J=1.2 Hz, 2H, CH₂); ¹³C NMR (100 MHz,

3-(3-(1,3-Dioxan-2-yl)propyl)cyclohex-2-en-1-one (7):^[50]Lithium (540 mg,

CDCl₃): d=199.6, 165.8, 125.4, 101.0, 66.7, 37.2, 32.1, 32.0, 29.6, 25.6,

22.6 ppm.

77.81 mmol)was suspended in dry Et O (10 mL)in presence of a catalyt-

ic amount of naphthalene. Dibromoethane and TMSCl (0.1 mL)were

added at 08C in order to activate the lithium. 2-(3-chloropropyl)-1,3-di-

oxane (4.29 g, 26.08 mmol)in solution in dry Et ₂O (20 mL)was added

dropwise at 08C. A white precipitate was formed. At the end of the addi-

tion, the mixture was allowed to warm up to room temperature. At this

stage an aliquot of the reaction showed no formation of the lithiated spe-

cies. 3-Ethoxycyclohexenone (3.71 g, 26.5 mmol)in solution in dry THF

(40 mL)was slowly added to the mixture at room temperature, and the

reaction was stirred for 18 h. The reaction was quenched by the addition

of water and Et₂O. The aqueous layer was extracted with Et₂O (3), and

the combined organic layers were washed with brine, dried over K₂CO₃,

and concentrated in vacuo. The crude mixture was purified by flash chro-

matography (R_f=0.27, pentane/Et₂O 1:2)in order to furnish the not to-

tally clean product as a yellow oil (1.49 g, 25%). ¹H NMR (400 MHz,

3-Phenylcyclohex-2-en-1-one (8):^{[11a] 1}H NMR (400 MHz, CDCl₃): d=

7.55–7.38 (m, 5H, Ph), 6.41 (t, J=1.4 Hz, 1H, CH), 2.77 (td, J=6.1, J=

1.3 Hz, 2H, CH₂), 2.48 (t, J=6.7 Hz, 2H, CH₂), 2.15 ppm (quint, J=

6.4 Hz, 2H, CH₂); ¹³C NMR (100 MHz, CDCl₃): d=199.9, 159.8, 138.8,

130.0, 128.8, 126.1, 125.4, 37.2, 28.1, 22.8 ppm.

3-(4-(Trifluoromethyl)phenyl)cyclohex-2-en-1-one

(9):^[46]

¹H NMR

(400 MHz, CDCl₃): d=7.70–7.62 (m, 4H, Ar), 6.44 (s, 1H, CH), 2.80–

2.77 (t, J=5.8 Hz, 2H, CH₂), 2.53 (t, J=6.8 Hz, 2H, CH₂), 2.20 ppm

(quint, J=6.3 Hz, 2H, CH₂); ¹³C NMR (100 MHz, CDCl₃): d=199.6,

158.2, 127.1, 126.6, 125.9, 125.7, 37.3, 28.3, 22.9 ppm.

3-(4-Methoxyphenyl)cyclohex-2-en-1-one (10):^{[46] 1}H NMR (400 MHz,

CDCl₃): d=7.52 (d, J=8.0 Hz, 2H, CH Ar), 6.94 (d, J=8.0 Hz, 2H, CH

Ar), 6.41 (s, 1H, CH), 3.86 (s, 3H, OCH₃), 2.78–2.74 (m, 2H, CH₂), 2.47

(t, J=6.3 Hz, 2H, CH₂), 2.15 ppm (quint, J=6.3 Hz, 2H, CH₂); ¹³C NMR

CDCl₃): d=5.82 (s, 1H, CH), 4.48 (t, J=4.0 Hz, 2H, CH₂), 4.04 (dd, J=

Chem. Eur. J. 2007, 13, 9647 – 9662

ꢁ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

www.chemeurj.org

9657

A. Alexakis and M. Vuagnoux-dꢀAugustin

4.8, ²J=11.6 Hz, 2H, CH₂), 3.71 (t, J=11.9 Hz, 2H, CH₂), 2.30 (t, J=

6.6 Hz, 2H, CH₂), 2.24 (t, J=5.8 Hz, 2H, CH₂), 2.18 (t, J=6.6 Hz, 2H,

CH₂), 2.07–1.98 (m, 1H, CH), 1.93 (quint, J=6.3 Hz, 2H, CH₂), 1.56–1.53

(m, 4H), 1.33–1.30 ppm (m, 1H, CH); ¹³C NMR (100 MHz, CDCl₃): d=

199.7, 166.0, 125.6, 101.6, 66.7, 37.6, 37.2, 34.4, 29.4, 25.6, 22.5, 21.1 ppm;

IR (neat): n˜ =2955, 2847, 1669, 1144 cm^À1; EI-MSHR: m/z: calcd for

C₁₃H₂₀O₃: 224.1412, found 224.1407 [M]⁺.

addition of MeOH at À308C, followed by aqueous saturated NH₄Cl solu-

tion or 2n HCl (3 mL)at room temperature. Et ₂O (10 mL)was added

and the aqueous layer was separated and extracted further with Et₂O

(33 mL). The combined organic fractions were washed with brine

(5 mL), dried over anhydrous Na₂SO₄, filtered and concentrated in

vacuo. The oily residue was purified by flash column chromatography

(pentane/Et₂O)to yield the 1,4-adduct.

3-Ethyl-3-methylcyclohexan-1-one (28):^{[4] 1}H NMR (400 MHz, CDCl₃):

d=2.26 (t, J=6.6 Hz, 2H, CH₂), 2.16 (d of AB, J=13.6 Hz, 1H, CH₂),

2.08 (d of AB, J=13.6 Hz, 1H, CH₂), 1.88–1.81 (m, 2H, CH₂), 1.64–1.48

(2m, 2H, CH₂), 1.33 (q, J=7.3 Hz, 2H, CH₂), 0.88 (s, 3H, CH₃),

3,4,7,8-Tetrahydronaphthalene-1,5

(16):^[14]

¹H NMR

(400 MHz, CDCl₃): d=2.37 (t, J=6.3 Hz, 8H, CH₂), 1.88 ppm (quint, J=

6.3 Hz, 4H, CH₂); ¹³C NMR (100 MHz, CDCl₃): d=201.0, 145.4, 37.8,

21.9, 21.3 ppm.4

0.83 ppm (t, J=7.6 Hz, 3H, CH₃); ¹³C NMR (100 MHz, CDCl₃): d

1-Methylcyclohept-2-en-1-ol (27): An ethereal solution of methyllithium

(25.0 mL, 40.0 mmol)was added dropwise to a stirred solution of cyclo-

heptenone (3.58 g, 32.49 mmol)in dry Et ₂O (40 mL)at À308C. The re-

sulting solution was allowed to warm to room temperature, stirred for

3 h, and quenched by the dropwise addition of water (20 mL). The

phases were separated and the aqueous layer extracted with Et₂O (2

20 mL). The combined organic layers were washed with water and dried

over MgSO₄. The solvent was removed under reduced pressure to afford

the alcohol (3.71 g, 90%)as a pale yellow oil. The crude mixture was

used without any further purification. ¹³C NMR (100 MHz, CDCl₃): d=

139.6, 129.6, 74.1, 40.9, 28.9, 27.6, 27.4, 24.4 ppm.

212.5, 53.3, 41.0, 38.6, 35.3, 34.0, 24.4, 22.0, 7.7 ppm; [a]²_D⁰=+5.45 (c=

1.64 in CHCl₃, 92% ee R. Absolute configuration was assigned in analogy

with 43). Enantiomeric excess was measured by chiral GC (lipodex E,

isotherm 608C, t_R1=32.8 min (R), t_R2=43.3 min (S)).

3-Isobutyl-3-methylcyclohexan-1-one (29):^{[3] 1}H NMR (400 MHz, CDCl₃):

d=2.29–2.23 (m, 2H, CH₂), 2.19 (d of AB, J=13.4 Hz, 1H, CH₂), 2.09 (d

of AB, J=13.4 Hz, 1H, CH₂), 1.93–1.51 (3m, 5H), 1.19 (t, J=5.0 Hz,

2H, CH₂), 0.93 (s, 3H, CH₃), 0.91 ppm (dd, ¹J=6.6, ²J=1.0 Hz, 6H).

¹³C NMR (100 MHz, CDCl₃): d=212.7, 54.6, 51.2, 41.3, 39.7, 36.8, 25.8,

25.7, 25.6, 24.2, 22.5 ppm; IR (neat): n˜ =2956, 1716, 1467 cm^À1; ESI-

MSHR: m/z: calcd for C₁₁H₂₀ONa: 191.1406364, found 191.1408390

[M+Na]⁺; [a]_D²⁰=À5.25 (c=1.73 in CHCl₃, 93% ee R. Absolute configu-

ration was assigned in analogy with 43). Enantiomeric excess was mea-

3-Methylcyclohept-2-en-1-one (17): A solution of 1-methylcyclohept-2-

enol (3.71 g, 29.40 mmol)in dichloromethane (30 mL)was added in one

portion to a magnetically stirred slurry of PCC (13.44 g, 62.3 mmol)in

dry CH₂Cl₂(90 mL), at room temperature. The resulting dark-red black

mixture was allowed to stir for 2 h at room temperature and was diluted

with Et₂O (120 mL). The ethereal solution was decanted from the black

resinous polymer, which was washed with Et₂O (360 mL). The organic

layers were washed successively with 5% aqueous sodium hydroxide (2

300 mL), 5% aqueous HCl (300 mL), and saturated aqueous NaHCO₃

(2150 mL). The solvent was removed at reduced pressure and the resi-

due was purified by flash chromatography (R_f=0.33, pentane/Et₂O 3:1)

to afford the desired product as a colorless oil (755 mg, 21%). ¹H NMR

(400 MHz, CDCl₃): d=5.89 (s, 1H, CH), 2.54 (t, J=7.1 Hz, 2H, CH₂),

2.39 (t, J=5.1 Hz, 2H, CH₂), 1.93 (s, 3H, CH₃), 1.81–1.72 ppm (m, 4H);

¹³C NMR (100 MHz, CDCl₃): d=203.6, 158.3, 42.4, 34.4, 27.5, 25.0,

21.4 ppm; IR (neat): n˜ =2934, 2866, 1652, 1440, 1376, 1268 cm^À1; EI-

MSHR: m/z: calcd for C₈H₁₂O: 124.0888, found 124.0890 [M]⁺.

sured by chiral GC (lipodex E, isotherm 808C, t_R1=13.0 min (S), t_R2

15.6 min (R)).

3-(But-3-enyl)-3-methylcyclohexan-1-one (31):^[3,4^{4] 1}H NMR (500 MHz,

CDCl₃): d=5.83–5.75 (m, 1H, CH), 5.00 (dd, ¹J=17.0, ²J=1.7 Hz, 1H,

CH), 4.93 (dd, ¹J=10.3, ²J=1.3 Hz, 1H, CH), 2.32–2.24 (m, 2H, CH₂),

2.20 (d of AB, J=13.4 Hz, 1H, CH₂), 2.12 (d of AB, J=13.4 Hz, 1H,

CH₂), 2.05–1.98 (m, 2H, CH₂), 1.90–1.83 (m, 2H, CH₂), 1.66–1.53 (m,

2H, CH₂), 1.39–1.34 (m, 2H, CH₂), 0.93 ppm (s, 3H, CH₃); ¹³C NMR

(125 MHz, CDCl₃): d=212.5, 139.1, 114.7, 54.0, 41.3, 41.2, 38.9, 36.2, 28.2,

25.2, 22.4ppm; [a]²_D⁰=+0.90 (c=1.71 in CHCl₃, 93% ee R. Absolute con-

figuration was assigned in analogy with 43). Enantiomeric excess was

measured by chiral GC (Hydrodex B-3P, isotherm 1308C, t_R1=6.4 min

(S), t_R2=6.7 min (R)).

3-(Pent-4-enyl)-3-methylcyclohexan-1-one (32):^[3,5^{1] 1}H NMR (400 MHz,

CDCl₃): d=5.82–5.72 (m, 1H, CH), 5.00–4.91 (m, 2H, =CH₂), 2.25 (t, J=

6.8 Hz, 2H, CH₂), 2.18 (d of AB, J=13.4 Hz, 1H, CH₂), 2.09 (d of AB,

J=13.4 Hz, 1H, CH₂), 2.03–1.98 (m, 2H, CH₂), 1.87–1.81 (m, 2H, CH₂),

1.65–1.49 (2m, 2H, CH₂), 1.36–1.23 (m, 4H), 0.90 ppm (s, 3H, CH₃);

¹³C NMR (100 MHz, CDCl₃): d=212.6, 138.9, 115.0, 54.1, 41.3, 38.9, 36.1,

34.6, 25.4, 23.0, 22.4 ppm; [a]²_D⁰=À1.67 (c=1.70 in CHCl₃, 93% ee S. Ab-

solute configuration was assigned in analogy with 43). Enantiomeric

excess was measured by chiral GC (Hydrodex B-3P, isotherm 1308C,

Typical procedure for “normal” Cu-catalyzed asymmetric conjugate ad-

dition to trisubstituted enones: A flame-dried Schlenk tube was charged

with copper salt (2.0 mol%)and the chiral ligand (4.0 mol%.) Solvent

(2.5 mL)was added and the mixture was stirred at room temperature for

30 min before being cooled to À308C. The trialkylaluminium (2.0 equiv

for Me₃Al, 1.0 mL of a 2m solution in heptane, or 1.4 equiv for Et₃Al,

1.6 mL of a 0.9m in hexane)was introduced dropwise at such a rate that

the temperature did not rise above À308C, and the reaction mixture was

stirred at À308C for further 5 min. Then the Michael acceptor (1.0 equiv,

t_R1=10.1 min (R), t_R2=10.5 min (S)).

3-(2-(1,3-Dioxan-2-yl)ethyl)-3-methylcyclohexan-1-one (33):^[3,3^{6] 1}H NMR

(500 MHz, CDCl₃): d=4.46 (t, J=5.0 Hz, 1H, CH), 4.08 (dd, ¹J=10.6,

²J=4.9 Hz, 2H, CH₂), 3.73 (tt, ¹J=12.3, ²J=2.4 Hz, 2H, CH₂), 2.29–2.22

(m, 2H, CH₂), 2.17–2.00 (m, 3H, CH₂and CH), 1.89–1.78 (m, 2H, CH₂),

1.63–1.49 (m, 4H, CH₂), 1.38–1.30 (m, 3H, CH₂and CH), 0.89 ppm (s,

3H, CH₃); ¹³C NMR (125 MHz, CDCl₃): d=212.4, 102.9, 67.2, 54.1, 41.3,

38.4, 35.9, 35.8, 29.7, 26.1, 25.1, 22.4 ppm; [a]²_D⁰=+0.08 (c=1.25 in

CHCl₃, 94% ee R. Absolute configuration was assigned in analogy with

43). Enantiomeric excess was measured by chiral GC (Hydrodex B-3P,

isotherm 1308C, t_R1=36.7 min (S), t_R2=37.4 min (R)).

1.0 mmol)in Et O or THF (0.5 mL)was added dropwise. Once the addi-

tion completed the reaction mixture was left at À308C overnight. The re-

action was hydrolyzed by the addition of MeOH at À308C, followed by

aqueous saturated NH₄Cl solution or 2n HCl (3 mL)at room tempera-

ture. Et₂O (10 mL)was added and the aqueous layer was separated and

extracted further with Et₂O (33 mL). The combined organic fractions

were washed with brine (5 mL), dried over anhydrous Na₂SO₄, filtered

and concentrated in vacuo. The oily residue was purified by flash column

chromatography (pentane/Et₂O)to yield the 1,4-adduct.

Typical procedure for “reverse” Cu-catalyzed asymmetric conjugate ad-

dition to trisubstituted enones: A flame-dried Schlenk tube was charged

with copper salt (2.0 mol%)and the chiral ligand (4.0 mol%.) Solvent

(2.5 mL)was added and the mixture was stirred at room temperature for

3-(3-(1,3-Dioxan-2-yl)propyl)-3-methylcyclohexan-1-one (34):^{[50] 1}H NMR

(500 MHz, CDCl₃): d=4.48 (t, J=5.4 Hz, 1H, CH), 4.06 (ddd, ¹J=6.0,

²J=4.7, J=0.9 Hz, 2H, CH₂), 3.72 (dt, J=2.6 Hz, 2H, CH₂), 2.24 (t, J=

6.7 Hz, 2H, CH₂), 2.15 (d of AB, J=13.7 Hz, 1H, CH), 2.07 (d of AB,

J=13.3 Hz, 1H, CH₂), 2.07–1.99 (m, 1H, CH), 1.85–1.70 (m, 2H, CH₂),

1.64–1.58 (m, 1H, CH), 1.54–1.48 (m, 3H, CH₂an CH), 1.36–1.29 (m,

3H, CH₂and CH), 1.26–1.17 (m, 2H, CH₂), 0.88 ppm (s, 3H, CH₃);

¹³C NMR (125 MHz, CDCl₃): d=212.2, 102.0, 66.8, 53.7, 41.4, 40.9, 38.5,

35.7, 35.5, 25.7, 24.9, 22.0, 17.8 ppm; IR (neat): n˜ =2955, 2849, 2848, 1709,

1144 cm^À1; EI-MSHR: m/z: calcd for C₁₄H₂₃O₃: 239.1647, found 239.1647

30 min. Then the Michael acceptor (1.0 equiv, 1.0 mmol)in Et O or THF

(0.5 mL)was added dropwise at room temperature and the reaction mix-

ture was stirred for further 5 min before being cooled to À308C. Then,

the trialkylaluminium (2.0 equiv for Me₃Al, 1.0 mL of a 2m solution in

heptane, or 1.4 equiv for Et₃Al, 1.6 mL of a 0.9m in hexane)was intro-

duced dropwise over 2 min. Once the addition was complete the reaction

mixture was left at À308C overnight. The reaction was hydrolyzed by the

9658

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ꢁ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Chem. Eur. J. 2007, 13, 9647 – 9662

Construction of Chiral Quaternary Centers

FULL PAPER

[MÀH]^À; [a]_D²⁰=À1.84 (c=1.86 in CDCl₃, 97% ee S. Absolute configura-

tion was assigned in analogy with 43). Enantiomeric excess was measured

1.80–1.56 (m, 5H), 1.30–1.17 (m, 3H), 0.98–0.90 (m, 1H), 0.81 ppm (d,

J=6.5 Hz, 3H, CH₃); ¹³C NMR (125 MHz, CDCl₃): d=213.5, 59.5, 34.7,

by chiral GC (Hydrodex B-3P, 130–100–1–170, t_R1=141.1 min (R), t_R2

141.8 min (S)).

34.1, 29.8, 29.3, 26.2, 26.0, 20.9 ppm; IR (neat): n˜ = 2926, 2855,

1709 cm^À1; EI-MSHR: m/z: calcd for C₉H₁₆O: 140.1201, found 140.1198

[M]⁺; [a]²_D⁰=À9.4 (c=1.29 in EtOH, 84% ee (1R,2R), trans/cis 94:06);

enantiomeric excess was measured by chiral GC (chirasil DEX CB, 60–

0–1–170, trans adduct: t_R1=33.0 min (1S,2S), t_R2=34.1 min (1R,2R) ; cis

adduct: t_R1=37.1 min (1S,2R), t_R2=38.0 min (1R,2S)); absolute configu-

ration of trans adduct was assigned in analogy with references.

3-Methyl-3-phenylcyclohexan-1-one (35):^[7,9^{] 1}H NMR (500 MHz, CDCl₃):

d=7.33 (d, J=4.4 Hz, 4H, CH Ar), 7.22 (sext, J=4.4 Hz, 1H, CH Ar),

2.89 (d of AB, J=14.2 Hz, 1H, CH₂), 2.45 (d of AB, J=14.2 Hz, 1H,

CH₂), 2.32 (t, J=6.8 Hz, 2H, CH₂), 2.23–2.18 (m, 1H), 1.96–1.85 (2m,

2H, CH₂), 1.72–1.64 (m, 1H), 1.34 ppm (s, 3H, CH₃); ¹³C NMR

(125 MHz, CDCl₃): d=211.4, 147.4, 128.5, 126.2, 125.5, 53.1, 42.8, 40.8,

37.9, 29.7, 22.0ppm; [a]²_D⁰=À48.8 (c=1.15 in CHCl₃, 72% ee R. Absolute

configuration was assigned in analogy with 43). Enantiomeric excess was

measured by chiral GC (Hydrodex-B-3P, isotherm 1408C, t_R1=31.7 min

(R), t_R2=32.6 min (S)).

3-Ethyl-3,5,5-trimethylcyclohexan-1-one (36):^{[9] 1}H NMR (400 MHz,

CDCl₃): d=2.19–2.07 (m, 4H, CH₂), 1.59 (d of AB, J=14.1 Hz, 1H,

CH₂), 1.48 (d of AB, J=14.1 Hz, 1H, CH₂), 1.41–1.25 (2m, 2H, CH₂),

1.04 (s, 3H, CH₃), 1.03 (s, 3H, CH₃), 0.97 (s, 3H, CH₃), 0.84 ppm (t, J=

7.6 Hz, 3H, CH₃); ¹³C NMR (100 MHz, CDCl₃): d=212.7, 54.3, 52.7,

48.6, 38.8, 37.0, 36.0, 32.3, 30.6, 26.8, 8.2 ppm; IR (neat): n˜ =2961,

1713 cm^À1; EI-MSHR: m/z: calcd for C₁₁H₂₀O: 168.1514, found 168.1515

[M]⁺; [a]²_D⁰=À9.5 (c=3.1 in CHCl₃, 97% ee S. Absolute configuration

was assigned in analogy with 43). Enantiomeric excess was measured by

trans-1-(2-Ethylcyclohexyl)ethan-2-one (42):^{[18] 1}H NMR (500 MHz,

CDCl₃): d=2.15 (td, ¹J=3.0, ²J=11.0 Hz, 1H, CH), 1.85–1.82 (m, 1H,

CH), 1.78–1.69 (m, 3H), 1.53–1.45 (m, 1H), 1.31–1.18 (m, 5H), 1.05–0.99

(m, 1H), 0.81 ppm (t, J=7.5 Hz, 3H, CH₃); ¹³C NMR (125 MHz, CDCl₃):

d=213.6, 57.8, 40.2, 30.4, 30.0, 29.2, 27.6, 26.1, 26.0, 11.2 ppm; IR (neat):

n˜ = 2931, 1708, 891 cm^À1; EI-MSHR: m/z: calcd for C₁₀H₁₈O: 154.1358,

found 154.1358 [M]⁺; [a]_D²⁰=À18.5 (c=1.17 in CHCl₃, 75% ee (1R,2R),

trans/cis 92:08); enantiomeric excess was measured by chiral GC (chirasil

DEX CB, 60–0–1–110–20–170–5, trans adduct:

_R2=42.3 min (1R,2R); cis adduct: t_R1=43.8 min (1R,2S), t_R2=44.8 min

(1S,2R)).

t_R1=41.6 min (1S,2S),

3-Methyl-3-(4-(trifluoromethyl)phenyl)cyclohexan-1-one (43): ¹H NMR

(500 MHz, CDCl₃): d=7.58 (d, J=8.5 Hz, 2H, CH Ar), 7.44 (d, J=

8.5 Hz, 2H, CH Ar), 2.89 (d of AB, J=14.2 Hz, 1H, CH₂), 2.48 (d of AB,

J=14.5 Hz, 1H, CH₂), 2.28–2.30 (m, 2H, CH₂), 2.27–2.13 (m, 1H), 1.99–

1.87 (m, 2H, CH₂), 1.68–1.60 (m, 1H), 1.34 ppm (s, 3H, CH₃); ¹³C NMR

chiral GC (chirasil DEX-CB, 60–110–2–170, t_R1=134.9 min (R), t_R2

135.5 min (S)).

3-Ethyl-3-methylcycloheptan-1-one (37):^[7,9^{] 1}H NMR (400 MHz, CDCl₃):

d=2.52 (d of AB, J=12.1 Hz, 1H, CH₂), 2.43–2.39 (m, 1H), 2.36 (d of

AB, J=12.1 Hz, 1H, CH₂), 1.79–1.49 (m, 6H), 1.36–1.24 (m, 2H, CH₂),

0.87 (s, 3H, CH₃), 0.85 ppm (t, J=7.6 Hz 3H, CH₃); ¹³C NMR (100 MHz,

CDCl₃): d=214.4, 54.4, 43.9, 42.1, 35.2, 34.8, 25.3, 24.6, 24.2, 7.9 ppm; IR

(neat): n˜ =2966, 2932, 1736, 1797, 1457 cm^À1; EI-MSHR: m/z: calcd for

C₁₀H₁₉O: 155.1435, found 155.1439 [M+H]⁺; [a]_D²⁰=+12.57 (c=1.41 in

CHCl₃, 93% ee R. Absolute configuration was assigned in analogy with

43). Enantiomeric excess was measured by chiral GC (Lipodex E, 60–0–

1–170, t_R1=24.5 min (R), t_R2=25.7 min (S)).

3-Ethyl-3-methylcyclopentan-1-one (38):^{[9] 1}H NMR (400 MHz, CDCl₃):

d=2.34–2.20 (m, 2H, CH₂), 2.06 (d of AB, J=5.9 Hz, 1H, CH₂), 2.00 (d

of AB, J=5.9 Hz, 1H, CH₂), 1.83–1.69 (m, 2H, CH₂), 1.43 (q, J=7.6 Hz,

2H, CH₂), 1.02 (s, 3H, CH₃), 0.89 ppm (t, J=7.6 Hz, 3H, CH₃); ¹³C NMR

(100 MHz, CDCl₃): d=220.2, 51.8, 39.7, 36.8, 34.7, 33.9, 24.4, 9.0 ppm;

EI-MSHR: m/z: calcd for C₈H₁₄O: 126.1045, found 126.10420 [M]⁺; IR

(neat): n˜ =2960, 1743, 1456 cm^À1. [a]_D²⁰=+55.0 (c=1.41 in CHCl₃, 93%

ee R. Absolute configuration was assigned in analogy with 43). Enantio-

meric excess was measured by chiral GC (lipodex E, isotherm 708C,

(125 MHz, CDCl₃): d=210.7, 151.4, 128.5 (q, J_C,F=31.9 Hz), 126.1, 125.5

(q, ²J_C,F=3.4 Hz), 52.8, 43.1, 40.7, 37.8, 29.8, 21.9 ppm; IR (neat): n˜

2951, 1710, 1330, 1168, 1122, 909 cm^À1

; EI-MSHR: m/z: calcd for

C₁₄H₁₅OF₃: 256.1075, found 256.1075 [M]⁺; [a]_D²⁰=+30.3 (c=1.4 in

CDCl₃, 66% ee S; absolute configuration was assigned in analogy with

43). Enantiomeric excess was measured by chiral SFC (AD-2%-2–1–

15% MeOH, 200 bar, 2 mLmin^À1, 308C, t_R1=3.8 min (R), t_R2=4.4 min

(S)).

3-(4-Methoxyphenyl)-3-methylcyclohexan-1-one

(44):^[7]

¹H NMR

(500 MHz, CDCl₃): d=7.24 (d, J=15.6 Hz, 2H, CH Ar), 6.86 (d, J=

15.5 Hz, 2H, CH Ar), 3.79 (s, 3H, OCH₃), 2.86 (d of AB, J=14.2 Hz,

1H, CH₂), 2.43 (d of AB, J=13.6 Hz, 1H, CH₂), 2.31 (t, J=7.3 Hz, 2H,

CH₂), 2.19–2.13 (m, 2H, CH₂), 1.70–1.62 (m, 1H), 1.30 ppm (s, 3H,

CH₃); ¹³C NMR (125 MHz, CDCl₃): d=211.9, 157.8, 139.4, 126.6, 113.8,

55.2, 53.3, 42.3, 40.8, 38.0, 30.1, 22.0 ppm; [a]²_D⁰not determined; enantio-

meric excess was measured by chiral SFC (OD H-2%-2–1–15% MeOH,

200 bar, 2 mLmin^À1, 308C, t_R1=5.9 min (R), t_R2=6.4 min (S)).

3-(2-Methoxyphenyl)-3-methylcyclohexan-1-one

(45):

¹H NMR

(500 MHz, CDCl₃): d=7.24–7.21 (m, 2H, CH Ar), 6.93–6.89 (m, 2H, CH

Ar), 3.84 (s, 3H, OCH₃), 3.00 (d of AB, J=14.5 Hz, 1H, CH₂), 2.61–2.56

(m, 1H), 2.46 (d of AB, J=14.2 Hz, 1H, CH₂), 2.31 (t, J=6.6 Hz, 2H,

CH₂), 1.89–1.81 (m, 2H, CH₂), 1.70–1.62 (m, 1H), 1.41 ppm (s, 3H,

CH₃); ¹³C NMR (125 MHz, CDCl₃): d=212.4, 157.8, 134.8, 127.7, 127.4,

120.6, 111.8, 54.9, 53.4, 42.8, 40.9, 35.0, 26.3, 22.1 ppm; IR (neat): n˜ =

2951, 1711, 1242, 632 cm^À1; EI-MSHR: m/z: calcd for C₁₄H₁₈O₂: 218.1307,

found 218.1306; [a]²_D⁰not determined; enantiomeric excess was measured

by chiral SFC (OD H-1%-2–1–15% MeOH, 200 bar, 2 mLmin^À1, 308C,

t_R1=9.1 min (R), t_R2=10.2 min (S)).

2,3-Dimethylcyclohexan-1-one (39): ¹H NMR (500 MHz, CDCl₃)mixture

of diastereomers: d=2.61–2.00 (4m, 4H, CH), 1.90–1.43 (3m, 4H, CH₂),

1.06 (d, J=6.2 Hz, 3H, CH₃trans), 1.02 (d, J=6.6 Hz, 3H, CH₃trans),

0.98 (d, J=6.8 Hz, 3H, CH₃cis), 1.02 ppm (d, J=7.1 Hz, 3H, CH₃cis);

¹³C NMR (125 MHz, CDCl₃)mixture of diastereomers: d=213.3, 51.8,

49.3, 41.5, 41.1, 40.6, 37.3, 34.2, 31.1, 26.1, 23.3, 20.7, 14.5, 11.8, 11.7 ppm;

IR (neat): n˜ =2932, 1709, 1456, 908 cm^À1; EI-MSHR: m/z: calcd for

C₈H₁₄O: 126.1045, found 126.1044 [M]⁺; [a]_D²⁰=À19.5 (c=1.39 in CHCl₃,

94% ee (2S,3R), trans/cis 77:23). Enantiomeric excess was measured by

chiral GC (Lipodex E, isotherm 708C, trans adduct: t_R1=9.7 min (2S,3R),

t_R1=9.9 min (R), t_R2=10.4 min (S)).

(E)-3-Methyl-3-(pent-1-enyl)cyclohexan-1-one (48): 1n diisobutylalumi-

nium hydride (2.0 mL, 2.0 mmol)in n-heptane (2.0 mL)was added to 1-

pentyne (0.3 mL, 3.0 mmol)while maintaining the temperature below

408C. When the initial exothermic reaction has subsided, the reaction

mixture was heated for 2 h at 508C. The vinylalane formed was used in

solution in heptane. A flame-dried Schlenk tube was charged with [Cu-

t_R2=10.5 min (2R,3S); cis adduct t_R1=12.5 min, t_R2=13.2 min).

3-Ethyl-2-methylcyclohexan-1-one (40):^[3,5^{2] 1}H NMR (500 MHz, CDCl₃)

mixture of diastereomers: d=2.37 (m, 1H, CH), 2.26 (m, 1H, CH), 2.16

(m, 1H), 2.04 (m, 1H), 1.89 (m, 1H), 1.62 (m, 2H, CH₂), 1.36 (m, 3H),

1.02 (d, J=6.7 Hz, 3H, CH₃), 0.90 ppm (t, J=7.4 Hz, 3H, CH₃);

¹³C NMR (125 MHz, CDCl₃) trans diastereomer: d=213.8, 49.5, 46.7,

41.5, 29.7, 26.2, 25.9, 11.8, 10.2 ppm; ¹³C NMR (125 MHz, CDCl₃) cis dia-

30.0 mol%). Dry THF (2.5 mL) was added and the mixture was stirred

at room temperature for 30 min. Then, the 3-methylcyclohexen-1-one

(110.2 mg, 1.0 mmol)in THF (0.5 mL)was added dropwise at room tem-

perature and the reaction mixture was stirred for further 5 min before

being cooled to À308C. Then, the freshly prepared vinylalane in solution

in heptane was introduced dropwise over 2 min. Once the addition was

complete the reaction mixture was left at À308C overnight. The reaction

was hydrolyzed by the addition of MeOH at À308C, followed by 2n HCl

stereomer: d=214.8, 48.8, 43.9, 39.7, 26.5, 23.9, 21.9, 11.6, 11.3. [a]_D²⁰

À12.7 (c=1.29 in CHCl₃, 82% ee (2S,3R)). Enantiomeric excess was

measured by chiral GC (Hydrodex B-3P, isotherm 708C, t_R1=31.9 min

(2S,3R), t_R2=33.8 min (2R,3S)).

trans-1-(2-Methylcyclohexyl)ethan-2-one (41):^[53,5^{4] 1}H NMR (500 MHz,

CDCl₃): d=2.11 (s, 3H, CH₃), 2.05 (td, ¹J=3.0, ²J=11.0 Hz, 1H, CH),

Chem. Eur. J. 2007, 13, 9647 – 9662

ꢁ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

www.chemeurj.org

9659

A. Alexakis and M. Vuagnoux-dꢀAugustin

(3 mL)at room temperature. Et ₂O (10 mL)was added and the aqueous

layer was separated and extracted further with Et₂O (33 mL). The com-

bined organic fractions were washed with brine (5 mL), dried over anhy-

drous Na₂SO₄, filtered and concentrated in vacuo. The oily residue was

purified by flash column chromatography (R_f=0.33, pentane/Et₂O 9:1)

give the 1,4-adduct (122.5 mg, 68%). ¹H NMR (400 MHz, CDCl₃): d=

5.37–5.24 (m, 2H, CH), 2.40 (dd of AB, ¹J=13.9, ²J=1.3 Hz, 1H, CH₂),

2.30–2.17 (m, 2H, CH₂), 2.13 (d of AB, J=14.1 Hz, 1H, CH₂), 1.93 (q,

J=7.3 Hz, 2H, CH₂), 1.81 (quint, J=5.8 Hz, 2H, CH₂), 1.70–1.64 (m,

1H), 1.61–1.54 (m, 1H), 1.33 (sext, J=7.3 Hz, 2H, CH₂), 1.02 (d, J=

10.4 Hz, 1H, CH), 5.25 (s, 1H, CH), 4.63 (dd, ¹J=5.6, ²J=1.3 Hz, 2H,

CH₂), 2.22–2.08 (m, 2H, CH₂), 1.78–1.73 (m, 2H, CH₂), 1.50–1.31 (2m,

4H, CH₂), 0.98 (s, 3H, CH₃), 0.84 ppm (t, J=7.3 Hz, 3H, CH₃); ¹³C NMR

(100 MHz, CDCl₃): d=153.3, 147.6, 131.5, 123.0, 119.0, 68.6, 35.0, 34.9,

33.6, 26.6, 26.5, 19.4, 8.4 ppm; IR (neat): n˜ =2961, 1756, 1249, 891 cm^À1

;

EI-MSHR: m/z: calcd for C₁₃H₂₀O₃: 224.1412, found 224.1412 [M]⁺;

[a]²_D⁰=À6.9 (c=1.08 in CHCl₃, 67% ee R); enantiomeric excess was mea-

sured by chiral GC (Hydrodex-B6-TBDM, 60–0–1–170–5, t_R1=70.3 (R),

_R2=50.1 (S)).

Typical procedure for the Cu-catalyzed asymmetric conjugate addition of

trialkylalanes–enol acetates formation:^[32]The ligand (0.04 mmol)was

added to a solution of CuTC (0.02 mmol)in dry Et ₂O (2.5 mL)at room

temperature under argon. The solution was stirred at room temperature

for 30 min and the enone (1.0 mmol)in dry Et ₂O (0.5 mL)was then

added dropwise. The mixture was then cooled to À308C and the trialky-

lalane was added dropwise so that the temperature did not rise over

À308C. The reaction mixture was stirred at À308C until complete con-

sumption of the starting material. Ac₂O (0.4 mL, 4.2 mmol)was added

dropwise at À308C and the reaction mixture was allowed to warm up to

room temperature until complete conversion. The mixture was quenched

by adding NH₄Cl_sat/HCl and Et₂O. The aqueous layer was extracted with

Et₂O (3), and the organic layers were washed with a saturated solution

of NaHCO₃and water before dried over MgSO₄and filtered off. The sol-

vents were removed in vacuo to afford the crude mixture, which was pu-

rified by flash chromatography (pentane/Et₂O). Enantiomeric excesses

were determined on an aliquot before the addition of the acetic anhy-

dride by chiral GC.

1.9 Hz, 3H, CH₃), 0.83 ppm (td, ¹J=7.1, J=1.8 Hz, 3H, CH₃); ¹³C NMR

(100 MHz, CDCl₃): d=211.5, 137.6, 128.4, 52.3, 40.8, 40.7, 37.0, 34.7, 28.1,

22.5, 22.1, 13.5 ppm; IR (neat): n˜ =2957, 2930, 3871, 1713, 1455 cm^À1; EI-

MSHR: m/z: calcd for C₁₂H₂₀O: 180.1514, found 180.1514 [M]⁺; [a]_D²⁰

À30.7 (c=1.1 in CHCl₃, 73% ee R. Absolute configuration was assigned

in analogy with 60). Enantiomeric excess was measured by chiral GC

(hydrodex B-6-TBDM, 60–0–1–170–5, t_R1=53.7 min (R), t_R2=55.4 min

(S)).

(R)-(3-Ethyl-3-methylcyclohex-1-enyloxy)trimethylsilane (49): A flame-

dried Schlenk tube was charged with CuTC (3.9 mg, 2.0 mol%)and L1

(4.0 mol%). Dry Et₂O (2.5 mL)was added and the mixture was stirred at

room temperature for 30 min. 3-Methylcyclohex-2-en-1-one (110 mg,

1.0 equiv, 1.0 mmol)in Et ₂O (0.5 mL)was then added dropwise at room

temperature and the reaction mixture was stirred for further 5 min

before being cooled to À308C. Then, the triethylaluminium (2.0 equiv,

2.2 mL of a 0.9m in hexane)was introduced dropwise over 2min. Once

the addition was complete the reaction mixture was left at À308C over-

night. The complete disappearance of the starting material was controlled

by GC-MS, and the enantiomeric excess was measured by chiral GC

(same method as 3-ethyl-3-methylcyclohexan-1-one 28). The aluminium

enolate was quenched, at À308C, by the addition of 4 equiv TMSOTf

(0.78 mL)previously dried over 0.5 mL of Et ₃Al. The reaction mixture

was allowed to warm to room temperature for 3 h. Then, the reaction

was cooled to 08C before been poured in Et₃N (2.0 mL)at 0 8C. A satu-

rated aqueous solution of NaHCO₃(5.0 mL)was quickly dropwise

added, and the aqueous layer was extracted with Et₂O (3). The com-

bined organic fractions were quickly dried over K₂CO₃, filtered and con-

centrated in vacuo. The oily residue was purified by filtration over a mix-

ture of dry NaHCO₃(2.0 g)and silica gel (8.0 g, R_f=0.3, pentane)to give

the pure product as a colorless oil (123 mg, 58%). ¹H NMR (400 MHz,

CDCl₃): d=4.65 (s, 1H, CH), 1.96–1.93 (m, 2H, CH₂), 1.70–1.64 (m, 2H,

CH₂), 1.42–1.36 (m, 2H, CH₂), 1.42–1.36 (m, 1H), 1.32–1.25 (m, 3H),

0.93 (s, 3H, CH₃), 0.83 (t, J=7.3 Hz, 3H, CH₃), 0.18 ppm (s, 9H, Si-

(R)-3-Ethyl-3-methylcyclohex-1-enyl acetate (51): ¹H NMR (400 MHz,

CDCl₃): d=5.12 (s, 1H, CH), 2.17–2.03 (m, 5H), 1.76–1.70 (m, 2H, CH₂),

1.50–1.43 (m, 1H), 1.38–1.31 (m, 3H), 0.98 (s, 3H, CH₃), 0.84 ppm (t, J=

7.6 Hz, 3H, CH₃); ¹³C NMR (100 MHz, CDCl₃): d=169.3, 147.4, 122.9,

35.0, 34.8, 33.6, 26.9, 26.6, 21.1, 19.4, 8.3 ppm; IR (neat): n˜ =2963, 2938,

1755, 1688, 1214 cm^À1; EI-MSHR: m/z: calcd for C₁₁H₁₈O₂: 182.1307,

found 182.1309 [M]⁺; [a]_D²⁰= À11.4 (c=2.09 in CHCl₃, 67% ee R).

(R)-3-Ethyl-3-methylcyclohept-1-enyl acetate (52): ¹H NMR (400 MHz,

CDCl₃): d=5.17 (s, 1H, CH), 2.39–2.28 (m, 2H, CH₂), 2.11 (s, 3H,

COCH₃), 1.79–1.65 (m, 5H), 1.50–1.35 (m, 3H), 1.04 (s, 3H, CH₃),

0.89 ppm (t, J=7.3 Hz, 3H, CH₃); ¹³C NMR (100 MHz, CDCl₃): d=

169.7, 150.0, 127.1, 37.3, 36.1, 35.0, 32.0, 26.9, 25.9, 24.2, 21.0, 8.4 ppm; IR

(neat): n˜ =2962, 2923, 1748, 1679, 1457, 1366, 1224, 1202 cm^À1

; EI-

MSHR: m/z: calcd for C₁₂H₂₀O₂: 196.1463, found 196.1462 [M]⁺; [a]_D²⁰

+6.12 (c=1.24 in CHCl₃, 90% ee R).

(CH₃)₃); ¹³C NMR (100 MHz, CDCl₃): d=149.2, 114.6, 35.6, 36.4, 34.1,

29.9, 27.5, 19.7, 8.5, 0.3 ppm; IR (neat): n˜ =2961, 1664, 1363, 1252,

(R)-2,2-Diallyl-3-ethyl-3-methylcyclohexan-1-one (53): The enol acetate

51 (383.0 mg, 2.10 mmol)in THF (1.0 mL)was added dropwise to a 1.5

1200 cm^À1

; EI-MSHR: m/z: calcd for C₁₂H₂₄OSi: 212.1596; found

in Et₂O solution of MeLi·LiBr (4.0 mL, 6 mmol)in dry THF (5.0 mL)at

212.1597 [M]⁺; [a]_D²⁰=À10.6 (c=1.12 in EtOH, 67% ee R).

room temperature. The mixture was stirred for 2 h before being

quenched at room temperature by the addition of ally bromide (1.5 mL,

17.2 mmol). The reaction was exothermic and stirred at room tempera-

ture overnight before the addition of Et₂O and water. The aqueous layer

was extracted with Et₂O (3)and the combined organic layers were

dried over MgSO₄and concentrated in vacuo. The crude residue was pu-

rified by flash chromatography (R_f=0.48, pentane/Et₂O 95:5)to give the

title product (342 mg, 74%). ¹H NMR (400 MHz, CDCl₃): d=5.74–5.60

(m, 2H, 2CH), 5.07 (s, 2H, =CH₂), 5.03 (d, J=10.1 Hz, 2H, =CH₂), 2.39–

2.10 (m, 6H), 1.76–1.64 (m, 3H), 1.56–1.48 (m, 1H), 1.27 (q, J=7.6 Hz,

2H, CH₂), 0.86 (s, 3H, CH₃), 0.83 ppm (t, J=7.6 Hz, 3H, CH₃); ¹³C NMR

(100 MHz, CDCl₃): d=214.2, 133.9, 133.5, 118.1, 118.0, 50.6, 50.4, 39.3,

39.2, 38.7, 34.0, 31.4, 31.3, 24.4, 7.7 ppm; IR (neat): n˜ =2964, 1705,

910 cm^À1; EI-MSHR: m/z: calcd for C₁₅H₂₄O: 220.1827, found 220.1826

[M]⁺; [a]_D²⁰=+6.1 (c=1.25 in CHCl₃, 90% ee R).

(R)-Allyl-3-ethyl-3-methylcyclohex-1-enyl carbonate (50): A flame-dried

Schlenk tube was charged with [Cu(CH₃CN)₄]BF₄(2.0 mol%)and the

chiral ligand L8 (4.0 mol%). Dry THF (2.5 mL) was added and the mix-

ture was stirred at room temperature for 30 min. 3-Methylcyclohex-2-en-

1-one (1.0 equiv, 1.0 mmol)in THF (0.5 mL)was added dropwise at

room temperature and the reaction mixture was stirred for further 5 min

before being cooled to À308C. Triethylaluminium (2.0 equiv, 2.2 mL of a

0.9m in hexane)was then introduced dropwise over 2 min. Once the ad-

dition completed the reaction mixture was left at À308C overnight. The

complete disappearance of the starting material was controlled by GC-

MS, and the enantiomeric excess was measured by chiral GC (same

method as 3-ethyl-3-methylcyclohexan-1one 28). The aluminium enolate

was quenched, at À308C, by the addition of 4 equiv allyl chloroformate

(0.4 mL), and 2.0 mL of THF. The reaction mixture was allowed to warm

to room temperature for 48 h. The reaction was hydrolyzed by addition

of MeOH followed by 2n HCl (3 mL)at room temperature. Et ₂O

(10 mL)was added and the aqueous layer was separated and extracted

further with Et₂O (33 mL). The combined organic fractions were dried

over MgSO₄, filtered and concentrated in vacuo. The oily residue was pu-

rified by flash column chromatography (R_f=0.62, pentane/Et₂O 95:5)to

spiro[4.5]-((R)-10-Ethyl-10-methyl)-dec-2-en-6-one (54): A solution of

(R)-2,2-diallyl-3-ethyl-3-methylcyclohexanone (53)(322.2 mg, 1.46 mmol)

in Et₂O (2.0 mL)was introduced to a solution of Grubbꢀs first generation

catalyst (64.0 mg, 0.08 mmol)in dry CH ₂Cl₂(8.0 mL). The mixture was

stirred at room temperature until the complete disappearance of the

starting material (1 h). The reaction was quenched with aqueous 1m HCl.

The aqueous fraction was extracted with Et₂O (3)and the combined or-

ganic layers were dried over MgSO₄and concentrated in vacuo. The

give a colorless oil (121 mg, 54%). H NMR (400 MHz, CDCl₃): d=6.00–

5.90 (m, 1H, CH), 5.38 (dd, ¹J=15.6, ²J=1.5 Hz, 1H, CH), 5.28 (d, J=

9660

www.chemeurj.org

ꢁ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Chem. Eur. J. 2007, 13, 9647 – 9662

Construction of Chiral Quaternary Centers

FULL PAPER

crude residue was purified by flash chromatography (R_f=0.34, pentane/

Et₂O 95:5)to give the title product (185.2 mg, 66%. )

tion of NaHCO₃, water and brine, dried over MgSO₄, filtered and con-

centrated in vacuo. The crude residue was purified by flash chromatogra-

phy (R_f=0.24, pentane/Et₂O 2:1)to afford the mixture of the two iso-

mers (78 mg, 50%). ¹H NMR (400 MHz, CDCl₃): d=3.94 (d of AB, J=

13.1 Hz, 1H, CH₂), 3.90 (d of AB, J=12.6 Hz, 1H, CH₂), 2.59 (t, J=

3.3 Hz, 2H, CH₂), 1.77–1.71 (m, 2H, CH₂), 1.49–1.25 (m, 4H), 0.88 (s,

3H, CH₃), 0.83 ppm (t, J=7.6 Hz, 3H, CH₃); ¹³C NMR (100 MHz,

CDCl₃): d=175.8, 75.5, 40.1, 39.8, 36.3, 34.1, 18.9, 7.4 ppm; IR (neat):

¹H NMR

(500 MHz, CDCl₃): d=5.59–5.56 (m, 1H, CH), 5.54–5.51 (m, 1H, CH),

2.95 (dquint, ¹J=16.7, ²J=2.2 Hz, 1H, CH₂), 2.78 (dquint, ¹J=16.7, ²J=

2.6 Hz, 1H, CH₂), 2.30 (d of AB, J=13.3 Hz, 1H, CH₂), 2.25 (d, J=

16.7 Hz, 1H, CH₂), 2.19 (dd of AB, ¹J=13.6, ²J=1.3 Hz, 1H, CH₂), 2.14

(d, J=16.7 Hz, 1H, CH₂), 1.85–1.76 (m, 2H, CH₂), 1.70–1.65 (m, 1H),

1.56–1.50 (m, 1H), 1.31 (q, J=7.6 Hz, 2H, CH₂), 0.90 (s, 3H, CH₃),

0.85 ppm (t, J=7.6 Hz, 3H, CH₃); ¹³C NMR (125 MHz, CDCl₃): d=

213.2, 128.2, 127.4, 54.8, 50.8, 41.8, 41.5, 38.7, 35.7, 33.9, 32.7, 24.3,

7.8 ppm; IR (neat): n˜ =2926, 1708, 1366, 1217, 632 cm^À1; EI-MSHR: m/z:

calcd for C₁₃H₂₀O: 192.1514, found 192.1513 [M]⁺; [a]_D²⁰=À8.2 (c=1.09

in CDCl₃, 92% ee R).

n˜

2965, 1735 cm^À1; ESI-MSHR: m/z: calcd for C₉H₁₇O₂: 157.1223,

found 157.1219 [M+H]⁺.

(R)-1-Methyl-3-oxocyclohexanecarbaldehyde (60):^[37]

A solution of 3-

methyl-3-(pent-1-enyl)cyclohexan-1-one (49)(38.5 mg, 0.2 mmol)in

CH₂Cl₂(2.0 mL)was treated with O at À788C. After complete con-

sumption of the substrate, excess O₃was removed by O₂and N₂bubbling,

and the mixture was treated with an excess of Me₂S (0.1 mL). The mix-

ture was warmed up to room temperature and stirred overnight. The re-

action mixture was diluted with Et₂O and water. The aqueous layer was

extracted 4 times and combined organic fractions were dried over MgSO₄

and concentrated in vacuo. The residue was purified by flash chromatog-

raphy (R_f=0.12, pentane/Et₂O 3:2)to give the keto-aldehyde as a color-

less oil (11 mg, 39%). ¹H NMR (500 MHz, CDCl₃): d=9.45 (s, 1H,

CHO), 2.63 (d of AB, J=14.5 Hz, 1H, CH₂), 2.38–2.27 (m, 2H, CH₂),

2.13 (d of AB, J=14.5 Hz, 1H, CH₂), 2.02–1.90 (m, 2H, CH₂), 1.88–1.79

(m, 1H), 1.70–1.65 (m, 1H), 1.17 ppm (s, 3H, CH₃); ¹³C NMR (125 MHz,

(R)-2-Ethyl-2-methylhexane-1,6-diol (55): A solution of enol acetate 51

(368.3 mg, 2.02 mmol)in CH Cl₂/MeOH 3:1 (60 mL)was treated with O

at À788C. After complete consumption of the substrate, excess O₃was

removed by O₂and N₂bubbling, and the mixture was treated with

NaBH₄(904 mg, 23.9 mmol). After stirring at À788C for 30 min, the mix-

ture was warmed up to room temperature. The reaction mixture was di-

luted with Et₂O and sequentially washed with aqueous saturated citric

acid solution and saturated NaCl solution. The organic layer was concen-

trated in vacuo and the residue was purified by flash chromatography

(R_f=0.26, Et₂O)to give the diol as a colorless oil (90.6 mg, 28%.)

¹H NMR (500 MHz, CDCl₃): d=3.63 (t, J=6.3 Hz, 2H, CH₂), 3.34 (d of

AB, J=10.7 Hz, 1H, CH₂), 3.30 (d of AB, J=11.0 Hz, 1H, CH₂), 2.85

(brs, 2H, OH), 1.53 (quint, J=6.6 Hz, 2H, CH₂), 1.32–1.21 (m, 6H), 0.80

(t, J=7.6 Hz, 3H, CH₃), 0.79 ppm (s, 3H, CH₃); ¹³C NMR (125 MHz,

CDCl₃): d=68.9, 62.4, 37.3, 35.3, 33.2, 28.8, 21.3, 19.4, 7.8 ppm; IR (neat):

n˜ =3368, 2938 cm^À1; EI-MSHR: m/z: calcd for C₈H₁₇O: 129.1279, found

129.1275 [MÀCH₃O]⁺; [a]_D²⁰=À0.6 (c=2.9 in CHCl₃, 92% ee R).

CDCl₃): d=208.9, 203.1, 50.1, 46.7, 40.5, 30.7, 21.6, 20.6 ppm; [a]_D²⁰

+11.1 (c = 1.09 in CDCl₃, 73% ee R).

Acknowledgement

(R)-7a-Methyl-1,2,5,6,7,7a-hexahydroinden-4-one (56):^[36]According to

literature, the 1,4-adduct 33 (565.8 mg, 2.5 mmol)was dissolved in a 6 n

HCl solution in THF (10 mL)at room temperature. After being stirred

at room temperature for 18 h, the mixture was neutralized at 08C with a

sodium bicarbonate saturated solution, diluted with Et₂O, washed with

water (3), and one of brine, dried over anhydrous Na₂SO₄, filtered and

concentrated in vacuo. The crude mixture was purified by flash chroma-

tography (pentane/Et₂O)to afford pale yellow oil (255.2 mg, 68%.)

¹H NMR (400 MHz, CDCl₃): d=6.43 (t, J=3.0 Hz, 1H, CH), 2.54–2.18

(3m, 5H), 2.03–1.79 (m, 6H), 1.57 (td, ¹J=13.9, ²J=4.8 Hz, 1H),

1.07 ppm (s, 3H, CH₃); ¹³C NMR (100 MHz, CDCl₃): d=200.8, 149.7,

136.4, 47.7, 42.5, 40.0, 38.5, 30.1, 24.2, 21.5 ppm; [a]²_D⁰=À74.6 (c=1.53 in

CHCl₃, 90% ee R; absolute configuration was attributed in comparison

with literature data). Enantiomeric excess was measured by chiral GC

(Hydrodex B-3P, isotherm 1308C, t_R1=5.6 min (S), t_R2=5.8 min (R)).

The authors thank the Swiss National Research Foundation (no. 20–

068095.02), and COST action D24/0003/01 (OFES contract no. C02.0027)

for financial support, and BASF for a generous gift of chiral amines, Fir-

menich SA for a generous gift of enones.

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(ddt, ¹J=17.1, ²J=5.4, ³J=2.9 Hz, 1H), 2.26–2.19 (m, 1H), 2.15–2.09 (m,

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(m, 2H), 1.37 (td, ¹J=12.6, ²J=5.1 Hz, 1H), 0.99 ppm (s, 3H, CH₃);

¹³C NMR (125 MHz, CDCl₃): d=202.8, 144.4, 133.1, 40.2, 38.7, 37.6, 35.4,

25.7, 25.3, 19.1, 17.6 ppm; [a]²_D⁰=À92.5 (c = 1.7 in CHCl₃, 92% ee S); en-

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1.01 mmol)was introduced to

(58):

solution of

Ketone

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