Central-to-axial chirality transfer in the benzannulation reaction of optically pure Fischer carbene complexes in the synthesis of allocolchicinoids

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Tetrahedron 64 (2008) 949e968

www.elsevier.com/locate/tet

Central-to-axial chirality transfer in the benzannulation reaction of optically

pure Fischer carbene complexes in the synthesis of allocolchicinoids

b

Andrei V. Vorogushin ^a, William D. Wulff ^a,, Hans-Jurgen Hansen

*

¨

^aDepartment of Chemistry, Michigan State University, East Lansing, MI 48824, United States

^bInstitute of Organic Chemistry, University of Zu¨rich, Winterhurerstrasse 190, CH-8057 Zu¨rich, Switzerland

Received 5 September 2007; received in revised form 25 October 2007; accepted 26 October 2007

Abstract

A method for the synthesis of allocolchicinoids is explored that involves the benzannulation reaction of Fischer chromium carbene complexes

with alkynes. The benzannulation reaction is employed to install the aromatic C-ring via the reaction of an a,b-unsaturated carbene complex in

which the carbene complex is attached to a seven-membered ring that is to become the B-ring of the allocolchicinoids. Two different regioiso-

meric series can be accessed depending on which position the carbene complex is on the seven-membered ring. A key issue that is addressed is

the stereochemistry of the newly formed axis of chirality that results from a stereo-relay from an existing chiral center on the seven-membered

ring at the position destined to be C(7) in the allocolchicinoids. The level of stereochemistry is dependent on the position of the carbene complex

on the seven-membered ring. A mechanism is proposed to account for this stereochemical dependence and to account for the observed effects of

temperature and solvent on the stereoselectivity. Finally, the benzannulation reactions of optically pure complexes are examined and quite

surprisingly one, but not both, of the diastereomeric products is racemized. The racemization can be prevented with the proper choice of solvent

and temperature. A mechanism is proposed to account for the racemization of only one of the diastereomers of the product that involves the

intermediacy of an o-quinone methide chromium tricarbonyl complex.

1. Introduction

total syntheses of (ꢀ)-allocolchichine have been reported⁶

allocolchicine derivatives have also been described.^5,7

and

a number of syntheses of allocolchicinoids and

Allocolchicine (ꢀ)-1 was isolated from Colchicum cornige-

rum and from the ﬂowers Colchicum autumnale.¹Like colchi-

cine, allocolchicine is tubulin-interactive agent that is capable

of blocking cell proliferation.²Other naturally occurring allo-

colchicinoids include androbiphenyline ((ꢀ)-4), colchibiphe-

nyline ((ꢀ)-5), salimine ((ꢀ)-2), jerusalemine ((ꢀ)-3) and

(ꢀ)-suhailamine (Scheme 1). Alkaloids 4 and 5 were isolated

from Colchicum ritchii;³(ꢀ)-2, (ꢀ)-3, and (ꢀ)-suhailamined

from Colchicum decaisnei Boiss.,⁴both being middle eastern

species. The structure (ꢀ)-1 has been assigned to (ꢀ)-suhail-

amine, but its spectroscopic and physical properties didn’t

match those of the authentic sample of (ꢀ)-1.⁵At this point

the true structure of (ꢀ)-suhailamine remains unclear. Two

Allocolchicinoids display molecular asymmetry resulting

from a noncoplanar arrangement of the rings A and C.^2,8

The rings are twisted with a torsion angle of about 53e55^ꢁ.

The major rotamer of natural (ꢀ)-(7S )-1 has its acetamido

group in pseudoequatorial position. This is consistent with

an aR axial conﬁguration. For (ꢀ)-allocolchicine 1 the

(aR,7S ) conformation is generally more preferred than the

(aS,7S ) conformation (Scheme 1). In solutions of allocolchici-

noids the equilibrium position also depends on the nature of

C(7) substituent and on the solvent polarity. It is not clear

whether the predominant (aR,7S ) conformation or a small

amount of the (aS,7S ) form, present in equilibrium, is active

in tubulin-binding processes. For this reason, we set out to pre-

pare allocolchicinoids in which the conformations were locked

in the (aR,7S ) and (aS,7S ) conformations. We have previously

reported that the benzannulation reaction of the carbene

* Corresponding author.

E-mail address: wulff@chemistry.msu.edu (W.D. Wulff).

doi:10.1016/j.tet.2007.10.115

950

A.V. Vorogushin et al. / Tetrahedron 64 (2008) 949e968

CO₂Me

NHAc

CO₂Me

NHAc

MeO

(aR,7S)-allocolchicine 1

(aS,7S)-allocolchicine 1

HO

MeO₂C

MeO

OMe

OH

MeO

OR²

NHAc

MeO

HO

NHAc

MeO

R¹O

NHAc

MeO

(–)-androbiphenyline 4 R¹= Me, R²= H

(–)-salimine 2

(–)-jerusalemine 3

(–)-colchibiphenyline 5 R¹= R²= H

Scheme 1.

1

determined by H NMR integration from the crude product

complexes 6 and 9 with 1-pentyne gives diastereomeric prod-

ucts (7,8 and 10,11, respectively, Scheme 2) as the result of the

formation of an axis of chirality when the new benzene ring is

being annulated.⁹The barrier to interconversion about the

chiral biaryl axis in these molecules is much higher than for

allocolchicine. The diastereomers 7 and 8 and 10 and 11 can

be separated and their interconversion can only be effected

when heated to greater than 150 ^ꢁC.¹⁰In the present work,

we present a more extensive examination of the benzannula-

tions of carbene complexes 6 and 9 with a 1-pentyne and

with a number of other alkynes and report on the synthesis

of optical pure carbene complexes 6 and 9 and their reactions

with 1-pentyne.

mixture and then conﬁrmed after chromatographic separation

of the diastereomers. Along with the phenols 7, 8, 10, 11,

a number of unidentiﬁed side-products were observed in this

1

reaction. Based on the crude H NMR spectrum, it could be

concluded that most of them were products of alkyne oligo-

merization. However, side-products incorporating rings A

and B of the carbene complexes were also formed, as judged

1

by the presence of OMe signals in the crude H NMR spec-

trum. The preparation of carbene complex 9 occurs with the

formation of w5e10% of the corresponding tetracarbonyl

complex where the alkoxy group at C(7) is coordinated to

the chromium.^11,12Since carbene complexes 6 and 9, and

especially the tetracarbonyl complex of 9 are not very soluble

in hexane, benzene was used as the solvent for these reactions.

Unless otherwise speciﬁed, the benzannulation was run at

55e58 ^ꢁC with 3-fold excess of alkyne (1 M in benzene).

The benzannulation reaction of carbene complexes 6aef

with 1-pentyne afforded phenols 7aef in moderate to good

yields (Table 1). We were pleased to observe high to complete

diastereoselectivities in every case with benzene as solvent.

Variations in the steric size of the R¹substituents had no effect

on the stereoselectivity of the reaction (entries 1e4): the only

phenolic products isolated from the reactions of 6aed were

2. Results and discussion

The reactions of carbene complexes 6 and 9 were examined

with various alkynes followed by oxidative demetalation

(Tables 1 and 2).⁹In most cases, phenolic allocolchicinoids

(7 and 8 or 10 and 11) were formed as major products. The

barrier to the rotation about the biaryl bond in 7, 8, 10, 11 is

higher than in the natural allocolchicinoids, which permits

the isolation of the conﬁgurationally stable (aR,7S; aS,7R)

and (aR,7R; aS,7S ) atropisomers. Diastereomeric excess was

Pr-n

OH

R²O

MeO

Cr(CO)₅

R²O

MeO

R²O

MeO

Pr-n

OH

OR¹

MeO

+

OR¹

benzene

55-58 °C

OR¹

MeO

6

7

8

7 : 8=12.5 to • 50

n-Pr

R²O

HO

MeO

Cr(CO)₅

OR¹

OR²

+

OR¹

OR²

OR¹

Pr-n

benzene

55-58 °C

MeO

11: 10=2.0 to 3.4

9

10

11

Scheme 2.

A.V. Vorogushin et al. / Tetrahedron 64 (2008) 949e968

951

Table 1

Atropselective benzannulation reaction of carbene complexes 6 with alkynes^a

R_S

R_L

OH

R_L

R²O

MeO

Cr(CO)₅

R²O

MeO

R²O

MeO

R_S

R_L

OH

OR¹

MeO

+

solvent

OR¹

MeO

6

7 (aR,7R; aS,7S)

8 (aR,7S; aS,7R)

Entry

Solvent

Carbene

complex

R¹

R²

R_S

R_L

Product

series

% Yield

7þ8^b

dr (7:8)^c

1

Benzene

(CH₂Cl)₂

THF

6a

6b

6c

6d

6e

6f

Me

Et

Me

Et

H

Et

H

n-Pr

TMS

Ph

a

b

c

d

e

f

40

43

47

50

73

72

45

39

43

58

nd^d

43

nd^d

7 Only

13.2:1

12.5:1

7 Only

4.2:1

2

3

i-Pr

t-Bu

Me

4

5

6

i-Pr

Et

7

6e

6a

g

h

i

8

Et

9

Et

t-Bu

Et

10

11

12

13

14

15

a

Et

j

Me

n-Pr

a

1.7:1

MeCN

Benzene^e

Benzene^f

1:5.4

5.3:1

>20:1

Unless otherwise speciﬁed, all reactions were carried out at 55e58 ^ꢁC for 36 h with 3 equiv of alkyne at 0.33 M in carbene complex.

Combined isolated yield of 7 and 8 after chromatography on silica gel. nd¼not determined.

Unless otherwise speciﬁed this is the ratio of isolated 7 and 8.

Ratio determined by ¹H NMR on crude reaction mixture.

Reaction at 40 ^ꢁC for 48 h.

Reaction at 70 ^ꢁC for 20 h.

b

c

d

e

f

identiﬁed as the (aR,7R; aS,7S ) diastereomers 7aed. Diaste-

benzene at different temperatures. A mixture of diastereomers

was observed at 40 ^ꢁC (entry 14), whereas only 7 was formed

at 70 ^ꢁC (entry 15). The preparative reaction in acetonitrile

gave a moderate 43% yield with the preferential formation

of diastereomer 8 (entry 13).

reomer 8 couldn’t be detected by NMR, HPLC, TLC even

in the mixture of side-products. However, an increase in the

size of the R²group on 6 led to a slight decrease in the stereo-

selectivity: from complete with 6a (R¼Me) to 12.5:1 with 6f

(R¼i-Pr), all still favoring diastereomer 7 (entries 1, 5, and 6).

After probing the effects of substituent changes in the

carbene complex 6 on the reaction with 1-pentyne, attention

was then concentrated on deﬁning the scope of the benzannu-

lation in terms of the alkyne. Thus, the reaction of carbene

complex 6e with terminal alkynes, such as trimethylsilylacety-

lene, 3,3-dimethylbut-1-yne and phenylacetylene furnished al-

locolchicinoids 7gei in moderate yields (entries 7e9). The

benzannulation with the internal alkyne 3-hexyne was also

successful, giving the product 7j (entry 10). Contrary to the

reaction of 6e with 1-pentyne, complete stereoselectivity for

the (aR,7R; aS,7S ) isomer 7 was observed in all four cases.

It was later noticed that a signiﬁcant amount of the diaste-

reomer 8 was formed in the reaction of 6a with 1-pentyne in

THF as a solvent. This prompted an undertaking of a solvent

screening. Each reaction was performed with 20 mg of 6a

and, upon completion, the diastereoselectivity was determined

The benzannulation reaction of carbene complexes 9aeh

with 1-pentyne followed by oxidative demetalation in air af-

forded the benzannulated phenol products, each as a mixture

of the (aR,7R; aS,7S ) and (aR,7S; aS,7R) atropisomers 10

and 11, respectively, with the diastereomer 11 as major in

all cases (Table 2). The stereochemical assignments will be

discussed below. In contrast to the reaction of complex 6,

the diastereoselectivity observed for complex 9 was only mod-

erate, decreasing gradually with an increase in the steric size

of both R¹(entries 1e4) and R²groups (entries 1, 5, and 6).

It recovers slightly only when both R²and R¹are sterically de-

manding substituents (entry 7). The reaction of 9h (R¼MOM)

(entry 8) showed the same diastereoselectivity as observed for

9a (R¼Me).

The benzannulation of carbene complexes 9a,c,d with other

terminal alkynes showed mixed results. The reaction of 9c

with trimethylsilylacetylene afforded the products 10i and

11i in moderate yield, but with lower selectivity for the

(aR,7S; aS,7R) diastereomer than in the case of 1-pentyne (en-

try 9). Utilization of phenylacetylene in the benzannulation re-

action with 9d met with no success, giving only trace amounts

of 10j and 11j, as judged from TLC and crude ¹H NMR

1

by H NMR as described above. Diastereomer 7 was favored

in benzene and dichloroethane (entries 1 and 11). However, in

THF both diastereomers formed in comparable amounts (entry

12) and in acetonitrile the opposite diastereomer 8 predomi-

nated (entry 13). Finally, the reaction was performed in

952

A.V. Vorogushin et al. / Tetrahedron 64 (2008) 949e968

Table 2

Atropselective benzannulation reaction of carbene complexes 9 with alkynes^a

R_L

R_S

OR²

R_S

R²O

HO

MeO

HO

MeO

R_L

benzene

Cr(CO)₅R_S

OR²

OR¹

MeO

+

OR¹

55-58 °C

MeO

9

10 (aR,7R; aS,7S)

11 (aR,7S; aS,7R)

Entry

Carbene complex

R¹

R²

R_S

R_L

Product series

% Yield 10þ11^b

53

dr (10:11)^c

1

9a

9b

9c

9d

9e

9f

Me

Et

Me

Et

H

Et

H

n-Pr

TMS

Ph

a

b

c

d

e

f

1:3.0

1:2.4

1:2.0

1:2.1

1:3.4

1:3.0

1:1.3

nd

2

45

51

3

i-Pr

t-Bu

Me

t-Bu

Me

i-Pr

t-Bu

Me

4

48

45

5

6

i-Pr

MOM

Me

45

48

7

9g

9h

9c

9d

9a

g

h

i

8

39

51

9

10

11

12

13

a

j

<10

32

t-Bu

Et

k

l

1:7.0^d

nd

1:2.9^e,f

<10

nd

n-Pr

a

Unless otherwise speciﬁed, all reactions were carried out at 55e58 ^ꢁC for 24 h with 3 equiv of alkyne at 0.33 M in carbene complex.

Combined isolated yield of 10 and 11 after chromatography on silica gel. nd¼not determined.

Unless otherwise speciﬁed this is the ratio of isolated 10 and 11.

b

c

d

e

f

This reaction also produced a 9% yield of 12 and a 20% yield of 13.

Ratio determined by ¹H NMR on crude reaction mixture.

Reaction in THF.

spectroscopy (entry 10). Extensive polymerization of the al-

kyne was observed in this case.

have been so far unsuccessful, only trace amounts of phenol

products were formed from this acetylene and carbene 9a, as

1

estimated from TLC and crude H NMR (Table 2, entry 12).

Carbene complex 9a reacted with 3,3-dimethylbut-1-yne to

furnish the expected phenols 10k and 11k, which were formed

in higher diastereoselectivity than was observed with 1-pen-

tyne (entry 11, Scheme 3). Signiﬁcant amounts of diastereo-

meric cyclopentenone products 12 and 13 were observed in

this reaction. These ﬁve-membered ring annulated products

result from cyclization without CO insertion, followed by hy-

drolysis of the cyclopentadiene product. This was surprising,

since the formation of the ﬁve-membered ring products is

rarely observed in the benzannulation reaction of vinyl car-

bene complexes of chromium.¹³It was reasoned that perform-

ing this transformation under an atmosphere of CO would

affect the phenol/cyclopentenone ratio in favor of the phenol

product. However, the product distribution was only slightly

affected by this modiﬁcation (Scheme 3). Attempts to use

the internal alkyne, 3-hexyne, in this benzannulation reaction

Contrary to carbene complex 6a, the benzannulation reac-

tion of 9a with 1-pentyne in THF showed almost the same

diastereoselectivity as observed in benzene (Table 2, entry 13).

Assignment of the relative stereochemistry of pairs of atro-

pisomers of 7 and 8 and 10 and 11 was made on the basis of

1

their H NMR spectra and conﬁrmed by X-ray diffraction for

11a.⁹In the (aR,7S; aS,7R) diastereomer where the C(7) func-

tionality is in a pseudoaxial position, the dihedral angle

between C(7)eH and C(6)eHa is about 90^ꢁresulting in the

absence of coupling between these protons (Fig. 1). The dihe-

dral angle between C(7)eH and C(6)eHb is about 30^ꢁand the

C(7)eH signal appears as a doublet in ¹H NMR spectrum. On

the other hand, the (aR,7R; aS,7S ) diastereomer has its C(7)

functionality in a pseudoequatorial position with the dihedral

angles between C(7)eH and C(6)eHa and C(6)eHb close

1)

Bu-t

t-Bu

benzene

MeO

t-Bu

MeO

HO

55-58 °C, 24 h

MeO

O

Cr(CO)₅

OMe

MeO

2) air, 25 °C, 12 h

3) Iodine

+

OMe

MeO

10k + 11k

12 + 13

9a

% Yield

10k + 11k 10k : 11k

dr

% Yield

12 + 13

dr

12 : 13

conditions

under Ar

under CO

32

39

1 : 7

29

21

1 : 2.0

1 : 2.3

Scheme 3.

A.V. Vorogushin et al. / Tetrahedron 64 (2008) 949e968

953

R⁴

R³

R¹

R⁵O

MeO

Ha

R⁵O

MeO

O

H

Ha

OR²

OR¹

OR²

OR¹

6

7

H

Hb

6

H

MeO

J (H, Ha) = 11 Hz

J (H, Hb) = 5.7 Hz

J (H, Ha) = 0 Hz

J (H, Hb) = 5.6 Hz

H

(aR,7R; aS,7S)

Couping constants for 11a and 10a.

(aR,7S; aS,7R)

Figure 1. Determination of relative conﬁguration of the diastereomers.

to 150 and 30^ꢁ, respectively. In this case, a doublet of doublets

Me₃SiCH₂analog 16b, prepared according to literature proce-

dure,¹⁷were examined in both catalytic and stoichiometric

amounts (Table 4, Section 4). The enantiomeric purity of the

resulting alcohols 14 and 18 was determined by HPLC.

Thus, reduction of ketone 15 by BH₃eSMe₂in CH₂Cl₂at

0 ^ꢁC in the presence of either catalytic or equimolar amounts

of the oxazaborolidines (S )-16a or (S )-16b readily afforded

the alcohol (R)-14 in high chemical and optical yields. Under

the optimized conditions (R)-14 was prepared in 99% chemi-

cal and 99% optical yields. In contrast to 15, the stereoselec-

tivity observed in the reduction of ketone 19 to give (R)-18

was low, even when stoichiometric amounts of (S )-16a were

used (Table 4, Section 4). The use of the bulkier BeCH₂TMS

oxazaborolidine (S )-16b was expected to improve the situa-

tion by the steric interaction of the CH₂TMS group with the

b-Br in 19, however, no enhancement in enantiomeric purity

of the resulting alcohol (R)-18 was observed.

The low enantioselectivity observed in the CBS reduction

of ketone 19 prompted the search for another approach to

the stereoselective preparation of alcohol (S )-18. Chiral Lewis

acid TarBeNO₂20, prepared from the corresponding arylbor-

onic and (þ)-tartaric acids, has been previously shown to

induce high enantioselectivity in the asymmetric reduction

of ketones by LiBH₄to the corresponding secondary alco-

hols.¹⁸Unfortunately, 20 cannot be used catalytically and for

the best results the reaction requires 2 equiv of TarBeNO₂.

However, after the reaction is complete, the relatively expen-

sive arylboronic acid can be recovered and reused. Reduction

of ketone 19 using the above described conditions afforded the

alcohol (S )-18 in excellent yield and 42% ee (Scheme 5). It is

worth noting that this reduction gives (S )-18 as the major

1

for C(7)eH is observed in the H NMR spectrum. The cou-

pling constants given in Figure 1 are for compounds 11a

and 10a and as predicted from the model, the C(7)eH signal

in the (aR,7S; aS,7R) diastereomer of 11a appears in ¹H NMR

spectrum as doublet with J¼5.6 Hz. The same proton of the

(aR,7R; aS,7S ) diastereomer 10a shows a doublet of doublets

with J¼5.7 and 11 Hz. The other derivatives of 10 and 11 and

of 7 and 8 also follow this trend.

To access the enantiomerically enriched conﬁgurationally

stable allocolchicinoids, it was necessary to develop efﬁcient

methodology for the asymmetric synthesis of carbene com-

plexes 9 and 6. The key enantiogenic step in each synthesis

is the asymmetric reduction of the ketones 15 and 19, respec-

tively (Schemes 4 and 5). The syntheses begin with the oxida-

tion of the previously reported alcohols 14¹⁴and 18⁹to the

ketones 15 and 19, which were performed under the standard

conditions¹⁵reported for oxidation with N-methylmorpholine-

N-oxide (NMO) catalyzed by 5% tetrapropylammonium

perruthenate (TPAP) (Schemes 4 and 5). Both reactions pro-

ceeded similarly, giving 15 and 19 in good yield. However,

we were unable to drive the reactions to completion, about

15% of the unreacted starting material was observed in each

case. Performing the reactions in CH₃CN instead of CH₂Cl₂

or the use of increased amounts of TPAP failed to improve

the conversion of the starting material. Fortunately, unreacted

alcohols 14 and 18 can be readily chromatographically sepa-

rated from 15 and 19 and recycled.

Asymmetric reduction of ketones 15 and 19 was initially

examined using the catalytic CBS protocol.¹⁶The commer-

cially available oxazaborolidine (S )-16a (R¼Me) and its

Ph

N

O

MeO

5 mol% TPAP,

1.5 eq NMO

B

R

Br

4 mol%

16a (R=Me)

MeO

O

OH

CH₂Cl₂,

4 Å MS

25 °C, 2h

BH₃•SMe₂

CH₂Cl₂, 0 to 25 °C

(R)-14

99% yield, 99% ee

15 76%

14

MeO

Br

MeO

NaH, MeI

THF, reflux

Cr(CO)₅

OMe

1) t-BuLi, ether, -78 °C

MeO

OMe

2) Cr(CO)₆, ether, 0 °C

3) MeOTf, CH₂Cl₂, 25 °C

(R)-9a

75% yield, >99% ee

(R)-17

87% yield, >99% ee

Scheme 4.

954

A.V. Vorogushin et al. / Tetrahedron 64 (2008) 949e968

O₂N

O

CO₂H

Br

MeO

5 mol% TPAP,

B

1.5 eq NMO

MeO

O

2 equiv 20

O

OH

CH₂Cl₂,

4 Å MS

25 °C, 2 h

1.05 eq LiBH₄

THF, 25 °C

19 75%

18

N

Br

MeO

Br

Fe

MeO

Ph

MeO

Ph

MeO

Ph

OH

+

OH

OAc

2 mol% 21

Et₃N, Ac₂O

t-AmOH, 0 °C

(S)-18

97% yield, 42% ee

(S)-18

51% yield, 99% ee

22

46% yield

Cr(CO)₅

MeO

Br

MeO

NaH, MeI

THF, reflux

MeO

1) t-BuLi, ether, -78 °C

OMe

2) Cr(CO)₆, ether, 0 °C

3) MeOTf, CH₂Cl₂, 25 °C

MeO

(S)-23

85% yield, 99% ee

(S)-6a

86% yield, 99% ee

Scheme 5.

enantiomer, whereas (R)-18 was the major isomer obtained by

CBS reduction with (S )-16a.

enriched carbene complexes were subsequently prepared

from (S )-23 and (R)-17 using the conditions previously devel-

oped for the synthesis of the corresponding racemic carbene

complexes. The preparation of (S )-6a and (R)-9a was accom-

plished without loss of enantiomeric purity (HPLC). These

carbene complexes did not racemize even when left overnight

on a silica gel column or when their solution in CH₂Cl₂was

treated with acetic acid. However, when (S )-6a was stirred

with NEt₃in CH₂Cl₂for 11 h, its enantiomeric purity de-

creased to 94% ee. Under the same conditions racemization

of carbene complex (R)-9a was not detected.

The absolute stereochemistry assignments of the alcohols

(R)-14 and (S )-18 were made by the chemical correlation

shown in Scheme 6. We have recently reported^6bthe conver-

sion of alcohol (R)-25 to natural (ꢀ)-(7S )-allocolchicine 1,

which relied on the following sequence: (ꢂ)-18 to (ꢂ)-25 to

(R)-25 to (ꢀ)-(7S )-1. Comparison of (S )-25, prepared from

(S )-18, with (R)-25 used in the synthesis of allocolchicine 1

revealed that these were opposite enantiomers, therefore con-

ﬁrming the stereochemical assignment in (S )-18. The follow-

ing steps were taken to secure the absolute conﬁguration in the

regioisomeric vinyl halide (R)-14. Bromine was removed from

both the methyl ethers (S )-23 and (R)-17 by treatment with

t-BuLi followed by protonation, giving alkene 24 in almost

quantitative yield. Although it was not possible to measure

the enantiomeric excess of 24 by HPLC, it was assumed that

the reaction occurred with full retention of C(7) stereochemis-

try, since no racemization was observed during the preparation

of the carbene complexes (S )-6a and (R)-9a. The products 24

obtained from (S )-23 and (R)-17 were compared and found to

be in an enantiomeric relationship with identical but opposite

optical rotations.

An alternative approach toward the enantiomerically en-

riched alcohol (S )-18 would be kinetic resolution of racemic

18. Apart from enzymatic methods, kinetic resolution of alco-

hols can be accomplished through acylation or oxidation.

Thus, recently developed conditions¹⁹for palladium-catalyzed

oxidative kinetic resolution of alcohols in the presence of

(ꢀ)-sparteine were applied to 18. Unfortunately, no reaction

was observed even after the prolonged (92 h) exposure of an

80 ^ꢁC solution of 18 in toluene to oxygen atmosphere.

Kinetic resolution of 18 through acetylation catalyzed by

planar chiral DMAP analog (ꢀ)-21²⁰was more successful

(Scheme 5). Promising selectivity²¹(s¼13.2) was observed in

the kinetic resolution of (S )-18 (42% ee) with a newly opened

bottle of catalyst (ꢀ)-21. The slower reacting enantiomer in

this kinetic resolution was (S )-18. To our disappointment, the

selectivity gradually decreased in consecutive runs with the

same batch of (ꢀ)-21 to a value of sw5.5. This same level of se-

lectivity (sw5.5) was also observed when recycled catalyst was

utilized. Such behavior of this catalyst is surprising, since it

should not be affected by oxygen and moisture present in the

air. Indeed, when the catalyst was stored and used under argon,

comparable results were obtained (sw5.5). Although the selec-

tivity observed in this kinetic resolution was not synthetically

useful for resolving the racemate of 18, it was useful for en-

hancement of the enantiomeric purity of (S )-18 that was ob-

tained from the asymmetric reduction of 19 in the presence of

the chiral Lewis acid 20 (Scheme 5). It was found that (S )-18

of 42% ee could be improved to 99% enantiomeric purity at

49% conversion, which corresponds to a selectivity s>13.²²

Methylation of the enantiomerically enriched alcohols

(S )-18 and (R)-14 was performed under the standard condi-

tions to give the corresponding methylated substrates (S )-23

and (R)-17, respectively, both in good yields and both of which

were found by HPLC to be of the same optical purity as the

starting alcohols (Schemes 4 and 5). Enantiomerically

Reaction of carbene complex (S )-6a with 1-pentyne was

carried out under the conditions developed for the benzannu-

lation reaction of racemic complex 6a (Table 1). As expected,

the reaction afforded the phenol (aS,7S )-7a. We were quite

surprised to ﬁnd out that the enantiomeric purity of this

A.V. Vorogushin et al. / Tetrahedron 64 (2008) 949e968

Br

955

Br

MeO

NaH, MeI

THF, reflux

MeO

1) t-BuLi

OH

OMe

2) MeOH

MeO

(S)-18

(S)-23

MeO

(S)-24 99%

MeO

CO₂Me

OH

Br

MeO

1) t-BuLi

OMe

MeO

2) MeOH

(R)-17

(R)-24 97%

(S)-25

Scheme 6.

material was only 72% ee, which indicated that partial racemi-

zation occurred in the course of the benzannulation reaction

(entry 1). A possible explanation for this racemization is pre-

sented below. Traces of the minor (aR,7S ) diastereomer 8a

were observed in the reaction mixture, which was contrary

to the results obtained in the benzannulation reaction of race-

mic 6a (Table 1). The following experiments were performed

with small amounts of enantiomerically enriched (S )-6a (99%

ee) to ﬁnd the best conditions for the benzannulation reaction

(Table 3, entries 2e13). Thus, the reaction was performed in

benzene with a 3-fold excess of 1-pentyne at 58 ^ꢁC (standard

conditions) to afford 7a and 8a with a diastereomeric ratio of

9.8:1 as determined by ¹H NMR integration (entry 2). The en-

antiomeric excess of diastereomers 7a and 8a was assessed by

HPLC and found to be 80 and 99% ee, respectively, showing

that only diastereomer 7a was formed with a decrease in opti-

cal purity. Increase in the reaction temperature clearly led to

a decrease in the enantiomeric excess of (aS,7S )-7a (entries

2, 3, and 4). The effect of concentration was not so pro-

nounced, since running the reaction 5-fold diluted gave the

product with similar ee (entries 2 and 5). The use of several

other solvents in this reaction was evaluated (entries 6e10).

Of the solvents examined, only in neat 1-pentyne was the

loss of optical purity completely prevented (entry 6). In THF

the enantiomeric excess of 7a was not eroded as much as it

was in benzene, but in this solvent the diastereomer (aR,7S )-

8a was also formed in signiﬁcant amounts (entry 10). Since

it is not practical to run the benzannulation reaction in neat

alkyne, THF was employed as the solvent in further optimiza-

tion experiments. The enantiomeric excess of the diastereomer

7a sharply decreased and that of 8a remained unchanged with

an increase in the reaction temperature (entries 10e12). Run-

ning the reaction at higher temperature helps improve the di-

astereomeric ratio in favor of isomer 7a. Dilution of the

Table 3

Benzannulation reaction of chiral nonracemic carbene complexes (S )-6a^a

Pr-n

OH

Cr(CO)₅

MeO

Pr-n

solvent

OH

OMe

+

MeO

OMe

MeO

(S)-6a

[6a] (M)

(aS,7S)-7a

(aR,7S)-8a

Entry

Solvent

Temp (^ꢁC)

Time (h)

% Yield

dr (7:8)^b

% ee 7^c

% ee 8^c

1

Benzene

1-Pentyne

n-Heptane

CH₂Cl₂

MeCN

THF

0.33

58

85

40

58

70

85

58

35

36

12

48

36

13

36

20

14

36

60

46^d

nd

85^e

nd

72

80

54

93

79

99

60

58

82

90

16

8

nd

99

nd

99

2

9.8:1

nd

3

4

nd

5

0.066

0.33

0.033

0.33

6

nd

7

8

nd

9

1:5.7

1.4:1

>20:1

1.1:1

2.7:1

10

11

12

13

14

a

THF

94

99

Unless otherwise speciﬁed, all reactions were carried out at 55e58 ^ꢁC for 36 h with 3 equiv of alkyne at 0.33 M in carbene complex. nd¼not determined.

Ratio determined by ¹H NMR on crude reaction mixture.

b

c

d

e

Determined after chromatographic separation of 7 and 8 by HPLC with a Chiralcel OD-H column.

Isolated yield of 7 after chromatography on silica gel.

Combined isolated yield of 7 and 8 after chromatography on silica gel.

956

A.V. Vorogushin et al. / Tetrahedron 64 (2008) 949e968

n-Pr

HO

MeO

HO

MeO

Cr(CO)₅

OMe

Pr-n

benzene

55-58 °C

OMe

MeO

+

MeO

(aR,7R)-11a

12% yield, 99% ee

(R)-9a 99% ee

(aS,7R)-10a

37% yield, 99% ee

Scheme 7.

Figure 2. CD spectra of 10a, 7a, and 11a.

reaction mixture was found to have only little effect on the

enantioselectivity, but led to the formation of almost equimo-

lar amounts of diastereomers 7a and 8a (entries 10 and 13).

Based on our ﬁndings, the reaction of (S )-6a with 1-pentyne

was carried out in THF at the lowest possible temperature

(35 ^ꢁC) to avoid the loss of optical purity. Indeed, diastereo-

mers (aR,7S )-8a and (aS,7S )-7a were formed under these con-

ditions in a 1:2.7 ratio, both in 99% ee (entry 14). It is worth

noting that the yield in this reaction was much higher than

using benzene as a solvent (entries 1 and 14).

Reaction of the carbene complex (R)-9a with 1-pentyne

was performed under the conditions developed for the benzan-

nulation reaction of the corresponding racemic carbene com-

plex (Scheme 7). This reaction gave the two diastereomeric

phenols (aS,7R)-10a and (aR,7R)-11a in a 3:1 ratio, which

was in line with the racemic complex. The enantiomeric ex-

cess of the products was determined by HPLC and found to

be more than 99% ee for both of the diastereomers.

The absolute conﬁguration in (aS,7S ) diastereomer 7a, the

(aS,7R) diastereomers 10a, and the (aR,7R) diastereomer 11a

has been tentatively assigned based on their CD spectra by

comparison with the CD spectra of similarly substituted biar-

yls²³(Fig. 2). Thus, phenols 7a and 10a exhibited negative

Cotton effect (CE) at 229 and 230 nm and positive CE at

205 and 200 nm, respectively, suggesting an aS axial conﬁgu-

ration for these compounds. On the contrary, phenol 10a

showed positive CE at 228 nm and negative CE at 201 nm,

as expected for an aR axial conﬁguration. Consequently, 7S

conﬁguration was assigned to the series of enantiomerically

enriched compounds 18, 6a, 7a, and 8a and the opposite 7R

conﬁgurationdto the series 14, 9a, 10a, and 11a.

2.1. Mechanism and discussion

The asymmetric induction observed in the formation of the

diastereomers 7 and 8 and 10 and 11 probably occurs via the

face-selective installation of a chromium tricarbonyl group in

one of the reaction intermediates, which leads to overall cen-

tral-to-planar-to-axial chirality transfer. To support this

hypothesis, the isolation and structural elucidation of an air-

stable protected phenol chromium tricarbonyl complex would

be highly desirable. Unfortunately, all our attempts to trap the

intermediate chromium tricarbonyl complexes of the phenols

produced in the reaction of carbene complex 6a with 1-pen-

tyne by triﬂation or methylation met with no success.

To account for the observed diastereoselectivity in the ben-

zannulation reactions of carbene complexes 6 the following

model is proposed (Scheme 8).^24,25Due to the high barrier to

the rotation about the biaryl bond,¹⁰the atropisomers 7 and 8

cannot equilibrate under the reaction conditions, nor would it

be expected for their corresponding chromium tricarbonyl com-

plexes. Thus, the stereochemistry must be determined prior to

the cyclization of either the vinyl ketene complex 28a or 28b.

It is also assumed that the ketene complexes 28a and 28b do

not interconvert since DFT calculations reveal that the vinyl ke-

tene generated from alkenyl carbene complexes does not have

a local minimum but rather that CO insertion and electrocyclic

ring closure are a single step.²⁵This is consistent with the fact

that the vinyl ketene complex cannot be intercepted even if

the benzannulation reaction is performed in methanol as sol-

vent.²⁶Thus the likely transition states are 27a and 27b that re-

sult when CO migration from chromium to carbon occurs in the

diastereomeric h¹,h³-vinyl carbene complexes 26a and 26b.

A.V. Vorogushin et al. / Tetrahedron 64 (2008) 949e968

957

OR¹

H

R¹O

O

R¹O

O

C

(CO)₄

Cr

O

Cr(CO)₃

R_L

[Cr]

O

8

R_L

O

R_L

R_S

O

R²O

R_S

O R²O

O

R_S

O

26a

27a

28a

R¹O

[Cr]

R¹O

H

O

C

(OC)₄Cr

R_L

(OC)₃Cr

R_L

O

7

R_L

R_S

O

R_S

²O

O

OR

OR²O

R_S

OR

O

26b

27b

28b

Scheme 8.

The key assumption is that the reaction of carbene complex

6 and an alkyne kinetically affords the h¹,h³-vinyl carbene in-

termediate 26a which results from the addition of the alkyne to

the carbene complex 6 where the chromium is above the plane

of the molecule and the alkoxy group is below. Support for this

assumption can be taken from the reaction of alkenyl carbene

complexes with propargyl ethers (Scheme 9). The reaction of

complex 29 with the TIPS ether of 3-butyn-1-ol gives a 95:5

mixture of the arene chromium tricarbonyl groups 30 shown

in Scheme 9 with the anti-isomer predominating.²⁷The size

and electronic nature of the protecting group on the oxygen

both contributed to the high selectivity. The origin of the ster-

eoselectivity was attributed to a stereoelectronic effect in

which the propargylic oxygen substituent has a conformational

preference to be anti to the chromium in the h¹,h³-vinyl car-

bene complexed intermediate. In a more closely related exam-

ple, the reaction of carbene complex 31 with 1-pentyne gives

rise to the arene chromium tricarbonyl complexes 32 in which

the anti-isomer predominates by a factor of 96:4 when R is

methoxyl and only 76:24 when R is methyl.²⁸The origin of

this selectivity may again be due to a stereoelectronic prefer-

ence for the methoxyl group to be anti to the chromium in the

h¹,h³-vinyl carbene complexed intermediate.

and 1-pentyne (Scheme 8). The major product is the diastereo-

mer 7 which would come from CO insertion in the h¹,h³-vinyl

carbene complexed intermediate 26b. The conversion of 26a

to 26b requires inversion of both the planar and axial conﬁg-

urations. The latter involves rotation about a single bond,

which is controlled by the steric interaction of OR²and

OMe substituents and is expected to proceed but with a signif-

icant barrier. In order to explain the results observed here, the

h¹,h³-vinyl carbene complexed intermediate 26a must be able

to isomerize to 26b and thus the h¹,h³-vinyl carbene com-

plexed intermediate 26b must be more stable than 26a (or per-

haps more reactive). Of the two, intermediate 26a is the

diastereomer with the OR¹functionality in a pseudoaxial po-

sition on ring B and the Cr(CO)₄fragment anti to the methoxy

substituents on ring A. Intermediate 26b has its OR¹group in

a pseudoequatorial position and on this basis may be expected

to be more thermodynamically favorable.

Both of the h¹,h³-vinyl carbene complexed intermediates

26a and 26b can undergo CO insertion to give ketene com-

plexes 28a and 28b via transition states 27a and 27b, respec-

tively. If the conversion of 26a to 26b is slow relative to the

CO insertion, then 26a will react via transition state 27a to

form 28a, which will undergo cyclization followed by deme-

talation to afford phenol 8. However, if conversion of 26a to

26b is complete before CO insertion can occur, then exclusive

formation of the diastereomer 7 would result via vinyl ketene

complex 28b. Thus the branchpoint for product formation

With the assumption that 26a is the kinetic h¹,h³-vinyl car-

bene complexed intermediate, it can be seen that CO insertion

and cyclization in 26a would lead to the diastereomer 8, which

is not the major product of the reaction of carbene complex 6

R

TBSO

R

TBSO

R

OMe

R

anti/syn

+

(CO)₅Cr

t-Bu

55:45 *

TBSCl, EtN(i-Pr)₂

OTIPS 95:5

Cr(CO)₃

* Not assigned

OMe

syn-30

OMe

anti-30

29

R

OTBS

Pr-n

R

OTBS

Pr-n

R

anti/syn

OMe

Pr-n

+

(CO)₅Cr

Me

76:24

94:6

TBSCl, EtN(i-Pr)₂

OMe

Cr(CO)₃

R

OMe

anti-32

syn-32

31

Scheme 9.

958

A.V. Vorogushin et al. / Tetrahedron 64 (2008) 949e968

OR¹

OR²

H

R¹O

O

OR²

R_S

R¹O

OR²

Cr(CO)₃

R_L

O

R_S

11

[Cr]

O

[Cr]

O

C

R_L

O

33a

34a

35a

R¹

R¹O

O

R²O

H

R²O

H

R²O

R_S

(OC)₃Cr

R_S

O

R_S

O

10

[Cr]

O

C

O

R_L

O

33b

34b

Scheme 10.

35b

would be the h¹,h³-vinyl carbene complexed intermediate 26a

and the ratio of 7 to 8 would be expected to be a function of

the relative rates of CO insertion to give 28a and of isomeri-

zation to the h¹,h³-vinyl ketene complexed intermediate

26b. This situation is probably realized in the reaction of 6a

with 1-pentyne in benzene. For 6e,f with a bulkier R²group,

the barrier to the rotation in 26a increases, thus slowing

down the conversion to 26b, which results in the formation

of some 28a, and, consequently, minor diastereomer 8 (Table

1, entries 6 and 7). Diastereomer 8 disappears if the reaction is

performed at higher temperature, suggesting a higher rate of

conversion of 26a to 26b (Table 1, entries 14 and 15). Polar

coordinating solvents would be expected to stabilize the tran-

sition states 27 by coordination to the chromium center during

CO insertion, hence accelerating the reaction, which will lead

to increased formation of ketene complex 28a and the product

ratio will be biased toward diastereomer 8. Indeed, if the reac-

tion of 6a with pent-1-yne is run in THF or CH₃CN, increased

amounts of diastereomer 8 are observed (Table 1, entries 12

and 13).

since the alkoxy group is cross-conjugated to the h¹,h³-vinyl

carbene complexed intermediate 33 just as it is in the starting

carbene complex 9a. Given the different position of the car-

bene complex on the seven-membered ring, close contacts of

interest in this case may involve the steric interaction between

OR²and OR¹groups, which may be expected to disfavor the

transition state 34b relative to 34a and thus to the preferential

formation of the phenol 11 as the major product as is in fact

seen to be the case (Table 2). Surprisingly, the diastereomeric

ratio only poorly correlates with the size of R²and R¹substit-

uents, but is found in all cases to be between 2.1:1 and 3.4:1.

The reason that the nature of the acetylene has such a pro-

nounced effect not only on the diastereomer distribution

(Table 2, entry 11) but also on the product distribution (Table

2, entries 10e12) is not completely clear at this time.

In the benzannulation reaction of optically pure carbene

complex (S )-6a with 1-pentyne, the phenolic product

(aS,7S )-7a, but not its diastereomer (aR,7S )-8a, showed de-

creased enantiomeric purity (Table 3). This was completely

unexpected, since this racemization would require an inversion

of both the central and axial chiral elements. It cannot be ex-

plained by racemization of the carbene complex since only

one of the diastereomers is racemized. Thus, the racemization

must occur after the stereochemistry of each diastereomer 7

and 8 is set and the inversion of the central chiral element at

C(7) would most likely involve a dissociation of the C(7)eO

A similar situation can be considered in the benzannulation

reaction of carbene complexes 9. In this case, however, the in-

terconversion of the diastereomeric vinyl carbene intermedi-

ates 33a and 33b is expected to be fast, due to the absence

of the OR²eOMe steric interaction (Scheme 10). The selective

kinetic formation of 33a would not be expected in this case

Pr

Cr(CO)₃

Pr

Cr(CO)₃

MeO

O

MeO

Cr(CO)₃

O

OH

O

8

O

X

H

7

O

H

OMe

O

x

Me

36

(aS,7S)-7a'

(aS,7R)-8a'

Pr

Cr(CO)₃

Pr

Cr(CO)₃

O

Pr

MeO

O

MeO

O

Cr(CO)₃

OH

8

O

H

8

O

x

H

7

O

H

OMe

Me

O

ent-36

Scheme 11.

(aR,7R)-7a'

(aR,7S)-8a'

A.V. Vorogushin et al. / Tetrahedron 64 (2008) 949e968

959

Figure 3. Minimized structures of diastereomers 7a and 8a.

bond. To provide an explanation for these observations, we

propose that intramolecular hydrogen bonding¹⁰between

C(8)eOH and pseudoequatorial C(7)eOMe occurs in chro-

mium tricarbonyl complex (aS,7S )-7a⁰, but not in (aR,7S )-

8a⁰, where the C(7)eOMe group is in pseudoaxial position

(Scheme 11). The compound (aS,7S )-7a⁰is the chromium tri-

carbonyl complex of phenol 7a where the stereochemistry of

the chromium tricarbonyl group is assigned based on the reac-

tion of complex 31 (R¼OMe) shown in Scheme 9. To support

the idea that intramolecular hydrogen bonding is more impor-

tant in 7a⁰than in 8a⁰, these compounds were energy mini-

mized (without the Cr(CO)₃group) with the molecular

mechanics routine in Spartan 04 and the two resulting struc-

tures are shown in Figure 3. The two oxygens on carbons 7

and 8 are nearly in the same plane containing the benzene

ring formed in the benzannulation for 7a but in 8a the oxygen

on carbon 7 is considerably below this plane. The OeO dis-

The formation of o-quinone methide intermediates related

to 36 has been previously postulated in the benzannulation

reaction of aryl and heteroaryl carbene complexes with al-

kynes.²⁹Following the benzannulation reaction, elimination

of the benzylic oxygen functionality generates o-quinone

methide and alkene intermediates, which subsequently partic-

ipated in a hetero-DielseAlder reaction to form the isolable

dimeric products.^29a,bIn our case, incorporation of C(7)e

OCD₃group in 7a would be expected if the benzannulation re-

action was carried out in the presence of CD₃OD, which

would support the proposed racemization pathway. Thus, per-

forming the reaction of (S )-6a, 10-fold excess of CD₃OD, and

1-pentyne under the conditions of entry 12, Table 3 resulted in

a signiﬁcantly different diastereomeric ratio (7a:8a¼1.6:1)

and enantiomeric excess of 7a (87% ee). The latter observa-

tion indicated that the additive inhibited the racemization path-

way, probably by the displacement of Cr(CO)₃from 7a⁰.

Incorporation of OCD₃group at C(7) of 7a was investigated

by mass spectrometry and found to be low (ꢃ10%). Similar

inhibition of racemization by CD₃OD (90% ee of 7a) was

also observed when the reaction was run in benzene according

to the conditions of entry 3 of Table 3. Further studies aimed to

support the proposed racemization mechanism are underway.

˚

tance is 2.52 A for 7a and 2.84 A for 8a. The hydrogen on

the oxygen at the C8 position in both structures is pointing di-

rectly at the oxygen at the C7 position and the resulting HeO

˚

distance is 2.00 A for 8a and 1.62 A for 7a.

The key to the proposal for the epimerization of 7a⁰out-

lined in Scheme 11 is that the presence of the Cr(CO)₃moiety

and the intramolecular hydrogen bond assist the reversible dis-

sociation of methanol in (aS,7S )-7a⁰to give the o-quinone

methide chromium tricarbonyl complex 36. Because the intra-

molecular H-bonding is only possible in diastereomer 7, the

opposite diastereomer 8 will not participate in this reaction

and its enantiomeric purity will remain unchanged. The re-ad-

dition of methanol to 36 will be assisted by H-bonding to the

carbonyl group and will follow the same pathway, giving the

starting material (aS,7S )-7a⁰. However, if axial inversion in

36 to afford ent-36 is relatively fast, addition of methanol to

ent-36 will furnish (aR,7R)-7a⁰, which is the enantiomer of

the starting material. Although the barrier to the rotation in

7a and, likely, in 7a⁰is high and will not allow the axial inver-

sion under the reaction conditions,¹⁰it may be lower in the

o-quinone methide complex 36 due to the loss of aromaticity

of ring C and the installation of a double bond in ring B. Pre-

sumably, both H-bonding and Cr(CO)₃coordination are

necessary elements for this reaction to occur, since less race-

mization is observed when polar coordinating solvents are

used in the benzannulation reaction, which can be best ex-

plained by early displacement of Cr(CO)₃from (aS,7S )-7a⁰,

hence stopping the racemization pathway.

3. Conclusion

The benzannulation of a,b-unsaturated carbene complexes

with alkynes provides moderate to good yields of allocolchici-

noids with moderate to high diastereoselectivities. The stereo-

selectivity results from the creation of an axial chiral element

of a biaryl bond when the new benzene ring is formed via a ste-

reo-relay from an alkoxy group at a chiral center that will be-

come the C(7) carbon in the product. The stereoselectivity is

high when the alkenyl carbene complex is in conjugation

with the alkoxy group and much lower when the alkoxy group

is cross-conjugated with the carbene complex. This is pro-

posed to result from the kinetic formation of an h¹,h³-vinyl

carbene complexed intermediate that is less stable than its di-

astereomer. With increased temperature, isomerization occurs

to give the more stable diastereomer of this intermediate and

the formation of a single diastereomer of the product. The re-

action of optically pure carbene complexes with alkynes can

occur to either give complete retention of the stereochemistry

of the alkoxy group in the carbene complex or racemization.

The racemization was found to occur after the product was

960

A.V. Vorogushin et al. / Tetrahedron 64 (2008) 949e968

formed and not in the starting carbene complex. One of the

diastereomers of the product can be racemized but not the

other. This was proposed to be a result of the generation of

an o-quinone methide chromium tricarbonyl intermediate

whose formation is made possible by an intramolecular hydro-

gen bond that is conformationally possible in one diastereomer

of the product but not in the other.

in hexane and ﬁltered through a layer of silica gel. The crude

products were puriﬁed by ﬂash chromatography on silica gel

(15e25% gradient of EtOAc in hexane) to give the individual

diastereomeric phenols 7 and/or 8 as yellowish crystals or yel-

lowish oils. Structural and stereochemical assignment of the

diastereomers as either (aR,7R; aS,7S ) or as (aR,7S; aS,7R)

1

was determined by analysis of H NMR spectra as discussed

in the text.

4. Experimental

4.2.1. Reaction with 1-pentyne

4.1. General information

This reaction was carried out in benzene with complex 6a

(R¹, R²¼Me) to give 7a in 40% yield. Only one diastereomer

was obtained which was identiﬁed as the (aR,7R; aS,7S ) dia-

stereomer 7 (R_L¼n-Pr, R_S¼H) and thus the diastereomeric

excess (de)¼100%. If the reaction was performed in CH₃CN

instead of benzene, a 5.7:1 mixture of diastereomers was

obtained (43% combined yield), with (aR,7S; aS,7R)-isomer

8a predominating. Diastereomeric ratio (dr) (8a:7a)¼5.7:1.

Diastereomeric excess (de)¼70%. The results from reactions

in other solvents and under other conditions are shown in Ta-

ble 1. Unless otherwise indicated in Table 1, the ratio of 7:8

was determined by the ratio of the weight of isolated products.

In other cases indicated in Table 1, the diastereomeric ratio

Routine NMR spectra were recorded on 300, 400, 500, and

600 MHz Bruker and Varian instruments in CDCl₃(internal

standard tetramethylsilane, d_H, d_C¼0.00 ppm), benzene-d₆

(d_H¼7.15 ppm, d_C¼128.0 ppm), acetone-d₆(d_H¼2.04 ppm,

d_C¼29.8 ppm), DMSO-d₆(d_H¼2.49 ppm, d_C¼39.5 ppm). Pro-

1

ton signal assignments in the H NMR spectra, which where

not obvious from the chemical shift and multiplicity data,

were determined using standard COSY and NOESY experi-

ments. Carbon signal multiplicities in the ¹³C NMR spectra

were determined from standard DEPT experiments. Mass

spectral analyses (low and high resolutions) were performed

1

at both Michigan State University and University of Zurich

¨

(dr) was determined from the H NMR spectrum of the crude

reaction mixture obtained after ﬁltration through silica gel.

Phenol 7a: pale yellow crystals; mp 148e148.5 ^ꢁC; ¹H

Mass Spectrometry Facilities. Elemental analyses were per-

formed by Galbraith Laboratories, Inc, Knoxville, TN. Anhy-

drous ether and THF were distilled under nitrogen from

sodium benzophenone ketyl. Anhydrous benzene and toluene

were distilled under nitrogen from sodium. Anhydrous methy-

lene chloride was distilled under nitrogen from CaH₂. Unless

otherwise mentioned, all reagents were purchased from com-

mercial sources and were used without further puriﬁcation.

Isolated yields are reported for compounds estimated to be

more than 95% pure as determined by ¹H NMR or combustion

analysis. In the cases where the product ratios were

determined from the crude mixture by integration of their

¹H NMR signals, the spectra were obtained from the solutions

containing at least 30 mg of the mixture in 0.6 mL of CDCl₃

with at least 16 scans.

NMR (300 MHz, CDCl₃)

d

1.03 (t, 3H, J¼7.4 Hz,

CH₂CH₂CH₃), 1.64e1.77 (m, 2H, CH₃CH₂CH₂), 2.01e2.13

(m, 1H, C6eHa), 2.25e2.48 (m, 3H, C5eH₂, C6eHb),

2.55e2.73 (m, 2H, CH₃CH₂CH₂), 3.42 (s, 3H, C7eOCH₃),

3.71 (s, 3H, OCH₃), 3.78 (s, 3H, OCH₃), 3.89 (s, 6H,

2OCH₃), 4.13 (dd, 1H, J¼11.3, 5.3 Hz, C7eH), 6.55 (s, 1H,

C4eH), 6.74 (s, 1H, C10eH), 8.86 (s, 1H, OH, exchange

with D₂O); ¹³C NMR (75 MHz, CDCl₃) d 14.2 (CH₃), 22.9

(CH₂), 30.2 (CH₂), 32.5 (CH₂), 36.9 (CH₂), 55.9 (CH₃), 56.4

(CH₃), 58.4 (CH₃), 60.7 (CH₃), 60.8 (CH₃), 83.5 (CH),

106.9 (CH), 112.5 (CH), 120.6 (C), 120.7 (C), 120.8 (C),

129.7 (C), 135.0 (C), 140.5 (C), 146.5 (C), 149.0 (C), 151.6

(C), 152.9 (C); IR (KBr) 3365 (s, OH), 2941 (m), 1599 (m),

1463 (s), 1069 (s) cm^ꢀ1. Mass spectrum (EI) m/z (% rel inten-

sity) 402 M^þ(100), 370 M^þꢀMeOH (60), 355 (8), 339 (12),

324 (6), 295 (6), 165 (3); HRMS (EI) calcd for C₂₃H₃₀O₆m/z

402.2042, found 402.2044. Anal. Calcd for C₂₃H₃₀O₆: C,

68.64; H, 7.51. Found C, 68.49; H, 7.56. Phenol 8a: colorless

4.2. General procedure for the benzannulation reaction

of carbene complexes 6 with alkynes

The following procedure is related to one reported for the

reaction of complexes 6 with 1-pentyne.⁹An approximately

0.33 M solution of the appropriate carbene complex 6 in the

requisite solvent was introduced into a single necked pear

shaped ﬂask in which the 14/20 joint was replaced with

a threaded high-vacuum Teﬂon stopcock. A 3-fold excess of

the desired alkyne was added and the resulting solution was

deoxygenated by the freezeepumpethaw method (ꢀ196 ^ꢁC/

25 ^ꢁC, three cycles). The ﬂask was back-ﬁlled with argon at

room temperature, sealed and then heated for 36 h at

55e58 ^ꢁC. The red clear solution gradually changed to

a dark mixture. The reaction mixture was opened to air and

stirred in the open ﬂask for 12 h. The solvent was removed

in vacuo and the crude product was diluted with 50% EtOAc

1

crystals, mp 158.5e159.5 ^ꢁC; H NMR (500 MHz, acetone-

d₆) d 0.99 (t, 3H, J¼7.3 Hz, CH₂CH₂CH₃), 1.64e1.73 (m,

2H, CH₃CH₂CH₂), 2.11e2.23 (m, 2H, C6eH₂), 2.29e2.35

(m, 2H, C5eH₂), 2.69 (dd, 2H, J¼9.1, 6.6 Hz, CH₃CH₂CH₂),

2.81 (s, 3H, C7eOCH₃), 3.67 (s, 3H, OCH₃), 3.70 (s, 3H,

OCH₃), 3.75 (s, 3H, OCH₃), 3.81 (s, 3H, OCH₃), 5.11 (dd,

1H, J¼6.0, 1.4 Hz, C7eH), 6.55 (s, 1H, C4eH), 6.77 (s,

1H, OH), 6.80 (s, 1H, C10eH); ¹H NMR (500 MHz,

CDCl₃) d 1.05 (t, 3H, J¼7.4 Hz, CH₂CH₂CH₃), 1.65e1.78

(m, 2H, CH₃CH₂CH₂), 2.18e2.40 (m, 3H, C5eHa, C6eH₂),

2.42e2.53 (m, 1H, C5eHb), 2.53e2.67 (m, 2H,

CH₃CH₂CH₂), 2.92 (s, 3H, C7eOCH₃), 3.72 (s, 3H, OCH₃),

3.78 (s, 3H, OCH₃), 3.85 (s, 3H, OCH₃), 3.86 (s, 3H,

A.V. Vorogushin et al. / Tetrahedron 64 (2008) 949e968

961

OCH₃), 4.42 (s, 1H, OH), 5.05e5.11 (br s, 1H, C7eH), 6.53

(s, 1H, C4eH), 6.71e6.77 (br s, 1H, C10eH); ¹³C NMR

(125 MHz, acetone-d₆) d 14.3 (CH₃), 24.0 (CH₂), 31.2

(CH₂), 33.5 (CH₂), 40.0 (CH₂), 55.6 (CH₃), 56.1 (CH₃), 56.3

(CH₃), 60.5 (CH₃), 60.7 (CH₃), 74.6 (CH), 107.4 (CH),

113.2 (CH), 123.9 (C), 124.8 (C), 128.0 (C), 129.7 (C),

136.5 (C), 141.3 (C), 146.6 (C), 151.8 (C), 152.7 (C), 153.1

(C); IR (KBr) 3458 (s, OH), 3215 (s, OH), 2934 (s), 1600

(m), 1477 (s), 1225 (s) cm^ꢀ1. Mass spectrum (EI) m/z (% rel

intensity) 402 M^þ(31), 370 M^þꢀMeOH (100), 355 (12),

339 (20), 324 (11), 295 (5), 185 (10); HRMS (EI) calcd for

C₂₃H₃₀O₆m/z 402.2042, found 402.2056. Anal. Calcd for

C₂₃H₃₀O₆: C, 68.64; H, 7.51. Found C, 68.49; H, 7.78.

121.3 (C), 124.1 (C), 126.7 (CH), 127.9 (CH), 128.7 (C),

129.4 (CH), 134.8 (C), 138.7 (C), 140.5 (C), 145.9 (C),

149.0 (C), 151.8 (C), 153.0 (C), based on integration, the

signal at 60.8 ppm may contain 2 (CH₃); IR (KBr) 3310 (s,

OH), 2933 (s), 1599 (m), 1458 (s), 1328 (m), 1233 (m),

1084 (s) cm^ꢀ1. Mass spectrum (EI) m/z (% rel intensity) 450

M^þ(45), 418 M^þꢀMeOH (100), 389 (9), 358 (22), 303

(10), 234 (24). Anal. Calcd for C₂₇H₃₀O₆: C, 71.98; H, 6.71.

Found C, 72.03; H, 6.52.

4.2.4. Reaction with tert-butylacetylene

This reaction was carried out in benzene with complex 6e

(R¹¼Me, R²¼Et) to give 7i in 43% yield. Only one diastereo-

mer was obtained which was identiﬁed as the (aR,7R; aS,7S )

diastereomer 7 (R_L¼t-Bu, R_S¼H). Diastereomeric excess

4.2.2. Reaction with trimethylsilylacetylene

This reaction was carried out in benzene with complex 6e

(R¹¼Me, R²¼Et) to give 7g in 45% yield. Only one diastereo-

mer was obtained which was identiﬁed as the (aR,7R; aS,7S )

diastereomer 7 (R_L¼TMS, R_S¼H). Diastereomeric excess

(de)¼100%. Phenol 7g: pale yellow crystals, mp

(de)¼100%.

Phenol

7i:

yellowish

crystals,

mp

1

149.5e151 ^ꢁC; H NMR (500 MHz, CDCl₃) d 1.16 (t, 3H,

J¼6.9 Hz, CH₂CH₃), 1.45 (s, 9H, C(CH₃)₃), 2.03e2.13 (m,

1H, C6eHa), 2.25e2.36 (m, 2H, C5eHa, C6eHb),

2.37e2.45 (m, 1H, C5eHb), 3.41 (s, 3H, OCH₃), 3.71 (s,

3H, OCH₃), 3.73e3.89 (m, 2H, CH₂CH₃), 3.891 (s, 3H,

OCH₃), 3.893 (s, 3H, OCH₃), 4.16 (dd, 1H, J¼11.7, 5.6 Hz,

C7eH), 6.53 (s, 1H, C4eH), 6.91 (s, 1H, C10eH), 9.04 (s,

1H, OH); ¹³C NMR (75 MHz, CDCl₃) d 15.1 (CH₃), 29.5

(CH₃), 30.3 (CH₂), 35.0 (C), 36.7 (CH₂), 55.8 (CH₃), 58.2

(CH₃), 60.77 (CH₃), 60.82 (CH₃), 65.9 (CH₂), 83.8 (CH),

106.6 (CH), 113.4 (CH), 120.4 (C), 120.9 (C), 122.3 (C),

134.8 (C), 136.5 (C), 140.3 (C), 148.15 (C), 148.19 (C),

151.7 (C), 152.6 (C); IR (CH₂Cl₂) 3303 (s, OH), 1597 (m),

1424 (s) cm^ꢀ1. Mass spectrum (EI) m/z (% rel intensity) 430

M^þ(100), 399 M^þꢀMeO (63), 383 M^þꢀMeOHꢀMe (40),

369 (32), 355 (17), 338 (47), 323 (27), 264 (30), 233 (52),

84 (48), 49 (46); HRMS (EI) calcd for C₂₅H₃₄O₆430.2355,

found 430.2356. Anal. Calcd for C₂₅H₃₄O₆: C, 69.74; H,

7.96. Found C, 69.74; H, 8.28.

1

129.8e131.3 ^ꢁC; H NMR (600 MHz, CDCl₃) d 0.33 (s, 9H,

Si(CH₃)₃), 1.18 (t, 3H, J¼7.0 Hz, CHaHbCH₃), 2.02e2.10

(m, 1H, C6eHa), 2.30e2.38 (m, 2H, C5eHa, C6eHb),

2.39e2.45 (m, 1H, C5eHb), 3.41 (s, 3H, C7eOCH₃), 3.72

(s, 3H, OCH₃), 3.79e3.85 (m, 1H, CHaHbCH₃), 3.85e3.91

(m, 1H, CHaHbCH₃), 3.89 (s, 3H, OCH₃), 3.90 (s, 3H,

OCH₃), 4.13 (dd, 1H, J¼11.8, 5.6 Hz, C7eH), 6.53 (s, 1H,

C4eH), 6.95 (s, 1H, C10eH), 8.80 (s, 1H, OH); ¹³C NMR

(125 MHz, CDCl₃) d ꢀ0.86 (CH₃), 15.2 (CH₃), 30.2 (CH₂),

36.8 (CH₂), 55.9 (CH₃), 58.3 (CH₃), 60.83 (CH₃), 60.85

(CH₃), 65.8 (CH₂), 83.4 (CH), 106.6 (CH), 119.8 (C), 120.2

(CH), 121.0 (C), 126.1 (C), 126.4 (C), 134.8 (C), 140.4 (C),

148.7 (C), 151.7 (C), 152.9 (C), 153.9 (C); IR (KBr) 3327

(s, OH), 2936 (s), 1595 (m), 1459 (s), 1400 (s), 1228 (m),

1119 (m) cm^ꢀ1. Mass spectrum (EI) m/z (% rel intensity)

446 M^þ(62), 414 M^þꢀMeOH (100), 399 (22), 354 (21),

338 (32); HRMS (EI) calcd for C₂₄H₃₄O₆Si 446.2125, found

446.2128. Anal. Calcd for C₂₄H₃₄O₆Si: C, 64.54; H, 7.67.

Found C, 64.50; H, 7.64.

4.2.5. Reaction with 3-hexyne

This reaction was carried out in benzene with complex 6e

(R¹¼Me, R²¼Et) to give 7j in 58% yield. Only one diastereo-

mer was obtained which was identiﬁed as the (aR,7R; aS,7S )

diastereomer 7 (R_L¼Et, R_S¼Et). Diastereomeric excess

4.2.3. Reaction with phenylacetylene

1

This reaction was carried out in benzene with complex 6e

(R¹¼Me, R²¼Et) to give 7h in 39% yield. Only one diastereo-

mer was obtained which was identiﬁed as the (aR,7R; aS,7S )

diastereomer 7 (R_L¼Ph, R_S¼H). Diastereomeric excess

(de)¼100%. Phenol 7j: yellowish oil; H NMR (500 MHz,

CDCl₃) d 0.99 (t, 3H, J¼7.1 Hz, CH₂CH₃), 1.206 (t, 3H,

J¼7.4 Hz, CH₂CH₃), 1.214 (t, 3H, J¼7.4 Hz, CH₂CH₃),

1.98e2.09 (m, 1H, C6eHa), 2.28e2.38 (m, 2H, C5eHa,

C6eHb), 2.39e2.48 (m, 1H, C5eHb), 2.63e2.78 (m, 4H,

2CH₂CH₃), 3.01e3.08 (m, 1H, CHaHbCH₃), 3.34e3.41 (m,

1H, CHaHbCH₃), 3.42 (s, 3H, OCH₃), 3.77 (s, 3H, OCH₃),

3.89 (s, 3H, OCH₃), 3.91 (s, 3H, OCH₃), 4.10 (dd, 1H,

J¼11.7, 5.8 Hz, C7eH), 6.53 (s, 1H, C4eH), 8.96 (s, 1H,

OH); ¹³C NMR (125 MHz, CDCl₃) d 14.4 (CH₃), 15.6

(CH₃), 15.8 (CH₃), 19.7 (CH₂), 20.0 (CH₂), 30.2 (CH₂), 36.7

(CH₂), 55.9 (CH₃), 58.4 (CH₃), 60.8 (CH₃), 68.6 (CH₂), 83.5

(CH), 106.4 (CH), 117.5 (C), 121.7 (C), 124.8 (C), 130.0

(C), 134.7 (C), 135.3 (C), 140.7 (C), 147.7 (C), 148.5 (C),

151.5 (C), 152.8 (C), one (CH₃) couldn’t be located: based

on integration, the signal at 60.8 ppm may contain 2 (CH₃);

(de)¼100%.

Phenol

7h:

yellowish

crystals,

mp

1

150.3e151.0 ^ꢁC; H NMR (600 MHz, CDCl₃) d 1.22 (t, 3H,

J¼7.0 Hz, CH₂CH₃), 2.08e2.17 (m, 1H, C6eHa),

2.33e2.42 (m, 2H, C5eHa, C6eHb), 2.42e2.51 (m, 1H,

C5eHb), 3.44 (s, 3H, C7eOCH₃), 3.76 (s, 3H, OCH₃),

3.86e3.97 (m, 2H, CH₂CH₃), 3.906 (s, 3H, OCH₃), 3.909 (s,

3H, OCH₃), 4.22 (dd, 1H, J¼11.7, 5.9 Hz, C7eH), 6.56 (s,

1H, C4eH), 6.95 (s, 1H, C10eH), 7.32 (t, 1H, J¼7.4 Hz,

Ph), 7.43 (t, 2H, J¼7.7 Hz, Ph), 7.67 (d, 2H, J¼7.6 Hz, Ph),

9.13 (s, 1H, OH); ¹³C NMR (75 MHz, CDCl₃) d 15.0 (CH₃),

30.2 (CH₂), 36.9 (CH₂), 55.9 (CH₃), 58.5 (CH₃), 60.8 (CH₃),

65.5 (CH₂), 83.7 (CH), 106.8 (CH), 115.8 (CH), 120.6 (C),

962

A.V. Vorogushin et al. / Tetrahedron 64 (2008) 949e968

IR (neat) 3326 (s, OH), 1597 (m), 1436 (s), 1262 (m) cm^ꢀ1

.

37.7 (CH₂), 56.0 (CH₃), 56.7 (CH₃), 57.4 (CH₃), 61.4 (CH₃),

61.8 (CH₃), 81.3 (CH), 109.0 (CH), 114.5 (CH), 121.4 (C),

123.7 (C), 124.1 (C), 131.1 (C), 137.1 (C), 140.5 (C), 144.8

(C), 149.1 (C), 150.6 (C), 153.0 (C); IR (mix. of diastereo-

mers) (CH₂Cl₂) 3378 (s, OH), 1597 (m) cm^ꢀ1. Mass spectrum

(EI) m/z (% rel intensity) 402 M^þ(100), 371 M^þꢀMeO (16),

339 (21), 323 (5), 295 (4), 221 (6), 181 (5); HRMS (EI) calcd

for C₂₃H₃₀O₆m/z 402.2042, found 402.2036. Anal. (mix. of

diastereomers) Calcd for C₂₃H₃₀O₆: C, 68.64; H, 7.51. Found

C, 68.66; H, 7.61.

Mass spectrum (EI) m/z (% rel intensity) 430 M^þ(94), 398

M^þꢀMeOH (92), 369 (72), 338 (100), 323 (23), 309 (12);

HRMS (EI) calcd for C₂₅H₃₄O₆m/z 430.2355, found

430.2358. Anal. Calcd for C₂₅H₃₄O₆: C, 69.74; H, 7.96. Found

C, 69.68; H, 8.31.

4.3. Benzannulation reaction of carbene complexes 9

with alkynes

The reactions were performed with the procedure described

above for the reactions of complexes 6 with the exception that

the reaction time was 24 h in all cases. The preparation of the

carbene complexes 9 has been previously described as well

as the reaction of several complexes with 1-pentyne.⁹Puriﬁca-

tion of the crude product by ﬂash chromatography on silica

gel (15% and then 25% EtOAc in hexane) led to the separation

and isolation of the diastereomeric phenols 10 and 11 as

yellowish crystals or yellowish oils. Structural and stereo-

chemical assignment of the diastereomers was performed by

4.3.2. Reaction of 1-pentyne with complex 9g

(R¹¼t-Bu, R²¼i-Pr)

This reaction was carried out in benzene to give the (aR,7R;

aS,7S ) diastereomer 10g in 11% yield and the (aR,7S; aS,7R)

diastereomer 11g in 37% yield. Diastereomeric excess

(de)¼55%. Phenol 11g (R¹¼t-Bu, R²¼i-Pr, R_L¼Pr, R_S¼H):

yellowish oil; ¹H NMR (300 MHz, CDCl₃) d 0.88 (s, 9H,

C(CH₃)₃), 0.97 (t, 3H, J¼7.2 Hz, CH₂CH₂CH₃), 1.34 (d, 3H,

J¼6.1 Hz, CH₃CHCH₃), 1.35 (d, 3H, J¼6.1 Hz, CH₃CHCH₃),

1.63e1.71 (m, 2H, CH₃CH₂CH₂), 2.04e2.15 (m, 1H,

C5eHa), 2.25e2.47 (m, 3H, C5eHb, C6eH₂), 2.66e2.71

(m, 2H, CH₃CH₂CH₂), 3.71 (s, 3H, OCH₃), 3.88 (s, 3H,

OCH₃), 3.89 (s, 3H, OCH₃), 4.46 (septet, 1H, J¼6.1 Hz,

CH₃CHCH₃), 5.27 (d, 1H, J¼5.3 Hz, C7eH), 6.62 (s, 1H,

C4eH), 6.67 (s, 1H, OH), 6.71 (s, 1H, C9eH); ¹³C NMR

(75 MHz, CDCl₃) d 13.8 (CH₃), 22.3 (CH₃), 22.4 (CH₃),

23.3 (CH₂), 27.9 (CH₃), 31.1 (CH₂), 33.1 (CH₂), 42.5 (CH₂),

56.0 (CH₃), 61.2 (CH₃), 61.3 (CH₃), 63.9 (CH), 70.8 (CH),

73.1 (C), 108.8 (CH), 115.4 (CH), 124.2 (C), 125.3 (C),

130.7 (C), 130.9 (C), 138.1 (C), 140.1 (C), 145.5 (C), 146.4

(C), 148.9 (C), 151.9 (C); IR (mix. of diastereomers)

(CH₂Cl₂) 3368 (s, OH), 1421 (m) cm^ꢀ1. Mass spectrum (EI)

m/z (% rel intensity) 472 M^þ(85), 356 M^þꢀt-

BuOHꢀCH₃CHCH₂(77), 313 (21), 181 (100), 57 (100);

HRMS (EI) calcd for C₂₈H₄₀O₆m/z 472.2825, found

472.2828. Phenol 10g (R¹¼t-Bu, R²¼i-Pr, R_L¼Pr, R_S¼H):

yellowish oil; ¹H NMR (300 MHz, CDCl₃) d 0.96 (t, 3H,

J¼7.3 Hz, CH₂CH₂CH₃), 1.01 (s, 9H, C(CH₃)₃), 1.31 (d,

3H, J¼6.1 Hz, CH₃CHCH₃), 1.37 (d, 3H, J¼6.1 Hz,

CH₃CHCH₃), 1.59e1.70 (m, 2H, CH₃CH₂CH₂), 2.00e2.26

(m, 3H, C5eHa, C6eH₂), 2.35e2.42 (m, 1H, C5eHb),

2.60e2.72 (m, 2H, CH₃CH₂CH₂), 3.70 (s, 3H, OCH₃), 3.91

(s, 6H, 2OCH₃), 4.19 (dd, 1H, J¼11.2, 6.8 Hz, C7eH), 4.50

(septet, 1H, J¼6.1 Hz, CH₃CHCH₃), 6.50 (s, 1H, OH), 6.65

(s, 1H, C4eH), 6.77 (s, 1H, C9eH); ¹³C NMR (75 MHz,

CDCl₃) d 13.9 (CH₃), 22.1 (CH₃), 22.7 (CH₃), 23.3 (CH₂),

27.8 (CH₃), 31.3 (CH₂), 32.8 (CH₂), 40.3 (CH₂), 56.1 (CH₃),

61.4 (CH₃), 62.0 (CH₃), 71.2 (CH), 71.4 (CH), 73.8 (C),

108.9 (CH), 120.4 (CH), 121.8 (C), 122.8 (C), 130.0 (C),

130.2 (C), 137.4 (C), 140.6 (C), 144.9 (C), 149.2 (C), 152.9

(C), one (C) could not be located; IR (mix. of diastereomers)

(CH₂Cl₂) 3368 (s, OH), 1421 (m) cm^ꢀ1. Mass spectrum (EI)

m/z (% rel intensity) 472 M^þ(29), 356 M^þꢀt-

BuOHꢀCH₃CHCH₂(34), 232 (24), 149 (100), 57 (54);

HRMS (EI) calcd for C₂₈H₄₀O₆m/z 472.2825, found

472.2827.

1

the analysis of H NMR spectra as described in the text and

conﬁrmed by X-ray crystallographic analysis of 11a.

4.3.1. Reaction of 1-pentyne with complex 9a (R¹, R²¼Me)

This reaction was carried out in benzene to give the (aR,7R;

aS,7S ) diastereomer 10a in 13% yield and the (aR,7S; aS,7R)

diastereomer 11a in 40% yield. Diastereomeric excess

(de)¼50%. Phenol 11a (R¹¼Me, R²¼Me, R_L¼Pr, R_S¼H):

1

yellowish crystals, mp 104.5e105 ^ꢁC; H NMR (400 MHz,

CDCl₃) d 1.00 (t, 3H, J¼7.4 Hz, CH₂CH₂CH₃), 1.63e1.75

(m, 2H, CH₃CH₂CH₂), 2.19e2.29 (m, 1H, C5eHa),

2.31e2.48 (m, 3H, C5eHb, C6eH₂), 2.65e2.79 (m, 2H,

CH₃CH₂CH₂), 2.90 (s, 3H, C7eOCH₃), 3.72 (s, 3H, OCH₃),

3.82 (s, 3H, OCH₃), 3.88 (s, 6H, 2OCH₃), 5.07 (d, 1H,

J¼5.5 Hz, C7eH), 6.63 (s, 1H, C4eH), 6.70 (s, 1H, OH,

exchange with D₂O), 6.78 (s, 1H, C9eH); ¹³C NMR

(100 MHz, CDCl₃) d 14.0 (CH₃), 23.4 (CH₂), 31.1 (CH₂),

33.3 (CH₂), 39.9 (CH₂), 55.8 (CH₃), 56.2 (CH₃), 56.7 (CH₃),

61.1 (CH₃), 61.9 (CH₃), 73.8 (CH), 108.6 (CH), 112.9 (CH),

123.0 (C), 124.9 (C), 125.5 (C), 132.1 (C), 137.5 (C), 140.3

(C), 145.8 (C), 149.2 (C), 151.1 (C), 152.3 (C); IR (mix. of

diastereomers) (CH₂Cl₂) 3378 (s, OH), 1597 (m) cm^ꢀ1

.

Mass spectrum (EI) m/z (% rel intensity) 402 M^þ(100),

371 M^þꢀMeO (20), 339 (34), 323 (9), 281 (7), 221 (9), 181

(6); HRMS (EI) calcd for C₂₃H₃₀O₆m/z 402.2042, found

402.2042. Anal. (mix. of diastereomers) Calcd for

C₂₃H₃₀O₆: C, 68.64; H, 7.51. Found C, 68.66; H, 7.61. Phenol

10a (R¹¼Me, R²¼Me, R_L¼Pr, R_S¼H): yellowish crystals,

1

107.5e108 ^ꢁC; H NMR (300 MHz, CDCl₃) d 0.98 (t, 3H,

J¼7.5 Hz, CH₂CH₂CH₃), 1.60e1.74 (m, 2H, CH₃CH₂CH₂),

2.10e2.34 (m, 3H, C5eHa, C6eH₂), 2.39e2.45 (m, 1H,

C5eHb), 2.64e2.74 (m, 2H, CH₃CH₂CH₂), 3.22 (s, 3H,

C7eOCH₃), 3.66 (s, 3H, OCH₃), 3.86 (s, 3H, OCH₃), 3.89

(s, 3H, OCH₃), 3.90 (s, 3H, OCH₃), 3.99 (dd, 1H, J¼11.4,

6.3 Hz, C7eH), 6.54 (s, 1H, OH, exchange with D₂O), 6.63

(s, 1H, C4eH), 6.81 (s, 1H, C9eH); ¹³C NMR (75 MHz,

CDCl₃) d 14.1 (CH₃), 23.4 (CH₂), 30.8 (CH₂), 33.0 (CH₂),

A.V. Vorogushin et al. / Tetrahedron 64 (2008) 949e968

963

4.3.3. Reaction of 1-pentyne with complex 9h

(dr)¼1.3:1. Diastereomeric excess (de)¼13%. Phenol 11i

(R¹¼i-Pr, R²¼Me, R_L¼TMS, R_S¼H): yellowish oil; ¹H

NMR (600 MHz, CDCl₃) d 0.34 (s, 9H, Si(CH₃)₃), 0.73 (d,

3H, J¼6.2 Hz, CH₃CHCH₃), 0.91 (d, 3H, J¼6.1 Hz,

CH₃CHCH₃), 2.21e2.30 (m, 2H, C6eH₂), 2.36e2.42 (m,

1H, C5eHa), 2.48 (td, 1H, J¼12.7, 7.9 Hz, C5eHb), 3.21

(septet, 1H, J¼6.1 Hz, CH₃CHCH₃), 3.77 (s, 3H, OMe),

3.84 (s, 3H, OMe), 3.88 (s, 3H, OMe), 3.89 (s, 3H, OMe),

5.37 (d, 1H, J¼4.9 Hz, C7eH), 6.65 (s, 1H, C4eH), 6.86 (s,

1H, OH), 6.97 (s, 1H, C9eH); ¹³C NMR (125 MHz, CDCl₃)

d ꢀ0.8 (CH₃), 20.7 (CH₃), 22.9 (CH₃), 30.9 (CH₂), 39.2

(CH₂), 55.9 (CH₃), 56.6 (CH₃), 61.1 (CH₃), 61.4 (CH₃), 66.6

(CH), 67.6 (CH), 108.7 (CH), 116.9 (CH), 122.8 (C), 124.8

(C), 128.3 (C), 130.2 (C), 137.9 (C), 140.1 (C), 148.7 (C),

150.6 (C), 152.3 (C), 152.5 (C); IR (mix. of diastereomers)

(KBr) 3397 (s, OH), 1601 (m), 1464 (s), 1376 (m), 1125

(m) cm^ꢀ1. Mass spectrum (EI) m/z (% rel intensity) 460 M^þ

(100), 385 (7), 370 (5), 369 (8), 181 (7), 149 (8). Anal.

(mix. of diastereomers) Calcd for C₂₅H₃₆O₆Si: C, 65.19; H,

7.88. Found C, 65.54; H, 7.55. Phenol 10i (R¹¼i-Pr,

R²¼Me, R_L¼TMS, R_S¼H): yellowish oil; ¹H NMR

(600 MHz, CDCl₃) d 0.34 (s, 9H, Si(CH₃)₃), 0.92 (d, 3H,

J¼6.1 Hz, CH₃CHCH₃), 1.15 (d, 3H, J¼6.1 Hz, CH₃CHCH₃),

2.17e2.29 (m, 3H, C5eHa, C6eH₂), 2.42e2.47 (m, 1H,

C5eHb), 3.52 (septet, 1H, J¼6.1 Hz, CH₃CHCH₃), 3.67 (s,

3H, OMe), 3.88 (s, 3H, OMe), 3.91 (s, 3H, OMe), 3.93

(s, 3H, OMe), 4.28 (dd, 1H, J¼9.8, 7.8 Hz, C7eH), 6.65 (s,

1H, C4eH), 6.72 (s, 1H, OH), 7.00 (s, 1H, C9eH); ¹³C

NMR (75 MHz, CDCl₃) d ꢀ0.9 (CH₃), 20.4 (CH₃), 23.1

(CH₃), 31.0 (CH₂), 38.2 (CH₂), 56.0 (CH₃), 56.6 (CH₃), 61.4

(CH₃), 61.8 (CH₃), 69.2 (CH), 75.5 (CH), 109.2 (CH), 119.0

(CH), 121.2 (C), 123.6 (C), 127.5 (C), 129.4 (C), 137.2 (C),

140.6 (C), 149.1 (C), 151.4 (C), 151.6 (C), 153.0 (C); IR

(mix. of diastereomers) (KBr) 3397 (s, OH), 1601 (m), 1464

(s), 1376 (m), 1125 (m) cm^ꢀ1. Mass spectrum (EI) m/z (%

rel intensity) 460 M^þ(100), 417 (5), 385 (9), 370 (7), 369

(11), 181 (10), 149 (5). Anal. (mix. of diastereomers) Calcd

for C₂₅H₃₆O₆Si: C, 65.19; H, 7.88. Found C, 65.54; H, 7.55.

(R¹¼Me, R²¼MOM)

This reaction was carried out in benzene to give the (aR,7R;

aS,7S ) diastereomer 10h in 9% yield and the (aR,7S; aS,7R)

diastereomer 11h in 30% yield. Diastereomeric ratio

(dr)¼3.0:1. Diastereomeric excess (de)¼50%. Phenol 11h

(R¹¼Me, R²¼MOM, R_L¼Pr, R_S¼H): yellowish oil; ¹H

NMR (500 MHz, CDCl₃)

d

0.99 (t, 3H, J¼7.4 Hz,

CH₃CH₂CH₂), 1.61e1.75 (m, 2H, CH₃CH₂CH₂), 2.26 (td,

1H, J¼13.6, 5.5 Hz, C5eHa), 2.32e2.40 (m, 2H, C6eH₂),

2.45 (td, 1H, J¼13.3, 6.5 Hz, C5eHb), 2.65e2.75 (m, 2H,

CH₃CH₂CH₂), 2.92 (s, 3H, C7eOMe), 3.52 (s, 3H, OMe),

3.73 (s, 3H, OMe), 3.88 (s, 3H, OMe), 3.89 (s, 3H, OMe),

5.07 (d, 1H, J¼6.2 Hz, C7eH), 5.13 (d, 1H, J¼6.5 Hz,

CH₃OCHaHb), 5.17 (d, 1H, J¼6.5 Hz, CH₃OCHaHb), 6.63

(s, 1H, C4eH), 6.73 (s, 1H, OH), 6.94 (s, 1H, C9eH); ¹³C

NMR (75 MHz, CDCl₃) d 14.0 (CH₃), 23.2 (CH₂), 30.9

(CH₂), 33.1 (CH₂), 39.9 (CH₂), 55.7 (CH₃), 56.1 (CH₃), 56.1

(CH₃), 61.1 (CH₃), 61.9 (CH₃), 74.1 (CH), 96.0 (CH₂),

108.5 (CH), 116.5 (CH), 122.7 (C), 124.5 (C), 126.4 (C),

132.4 (C), 137.4 (C), 140.2 (C), 146.8 (C), 148.7 (C), 149.1

(C), 152.3 (C); IR (mix. of diastereomers) (CH₂Cl₂) 3354 (s,

OH), 1608 (m), 1423 (m), 1261 (m) cm^ꢀ1. Mass spectrum

(EI) m/z (% rel intensity) 432 M^þ(97), 401 M^þꢀMeO (7),

400 M^þꢀMeOH (8), 356 M^þꢀMeOꢀMeOCH₂(100), 324

(26), 313 (16), 181 (17); HRMS (EI) calcd for C₂₄H₃₂O₇m/z

432.2148, found 432.2140. Anal. (mix. of diastereomers)

Calcd for C₂₄H₃₂O₇: C, 66.65; H, 7.46. Found C, 66.77; H,

7.61. Phenol 10h (R¹¼Me, R²¼MOM, R_L¼Pr, R_S¼H):

yellowish oil; ¹H NMR (500 MHz, CDCl₃) d 0.99 (t, 3H,

J¼7.4 Hz, CH₃CH₂CH₂), 1.62e1.73 (m, 2H, CH₃CH₂CH₂),

2.10e2.16 (m, 1H, C6eHa), 2.23e2.34 (m, 2H, C6eHb,

C5eHa), 2.41e2.46 (m, 1H, C5eHb), 2.68 (t, 2H,

J¼7.7 Hz, CH₃CH₂CH₂), 3.26 (s, 3H, C7eOMe), 3.58 (s,

3H, OMe), 3.67 (s, 3H, OMe), 3.91 (s, 3H, OMe), 3.92 (s,

3H, OMe), 4.01 (dd, 1H, J¼11.4, 6.0 Hz, C7eH), 5.16 (s,

2H, CH₃OCH₂), 6.54 (s, 1H, OH), 6.65 (s, 1H, C4eH), 7.02

(s, 1H, C9eH); ¹³C NMR (75 MHz, CDCl₃) d 14.0 (CH₃),

23.3 (CH₂), 30.7 (CH₂), 32.8 (CH₂), 38.0 (CH₂), 56.0 (CH₃),

56.1 (CH₃), 57.4 (CH₃), 61.3 (CH₃), 61.8 (CH₃), 81.2 (CH),

96.6 (CH₂), 108.9 (CH), 119.5 (CH), 121.1 (C), 123.7 (C),

125.1 (C), 131.4 (C), 136.9 (C), 140.5 (C), 146.1 (C), 148.1

(C), 149.2 (C), 153.0 (C); IR (mix. of diastereomers)

(CH₂Cl₂) 3354 (s, OH), 1608 (m), 1423 (m), 1261

(m) cm^ꢀ1. Mass spectrum (EI) m/z (% rel intensity) 432 M^þ

(83), 402 (16), 401 M^þꢀMeO (5), 400 M^þꢀMeOH (7), 387

M^þꢀMeOCH₂(6), 356 M^þꢀMeOꢀMeOCH₂(100), 324

(27), 313 (14), 181 (21); HRMS (EI) calcd for C₂₄H₃₂O₇

m/z 432.2148, found 432.2151. Anal. (mix. of diastereomers)

Calcd for C₂₄H₃₂O₇: C, 66.65; H, 7.46. Found C, 66.77;

H, 7.61.

4.4. Benzannulation reaction of carbene complex 9a with

tert-butylacetylene

To a solution of 9a (0.323 g, 0.649 mmol) in dry benzene

(1.95 mL) in a single necked pear shaped ﬂask in which the

14/20 joint was replaced with a threaded high-vacuum Teﬂon

stopcock was added a 3-fold excess of 3,3-dimethyl-but-1-yne

(0.160 g, 1.946 mmol) and the resulting solution was deoxy-

genated by the freezeepumpethaw method (ꢀ196 ^ꢁC/25 ^ꢁC,

three cycles). The ﬂask was back-ﬁlled with argon (conditions

1) or CO (conditions 2) at room temperature, closed, and then

heated for 24 h at 55e58 ^ꢁC. The clear red solution gradually

changed to dark opaque solution. The reaction mixture was

opened to air and stirred in the open ﬂask for 12 h. The solvent

was removed in vacuo and the crude product was diluted with

50% EtOAc in hexane and ﬁltered through a layer of silica gel.

The solvent was removed in vacuo, the residue was dissolved

in ether (2 mL), then I₂(0.033 g, 0.130 mmol) was added, and

4.3.4. Reaction of trimethylsilylacetylene with complex 9c

(R¹¼i-Pr, R²¼Me)

This reaction was carried out in benzene to give the (aR,7R;

aS,7S ) diastereomer 10i in 22% yield and the (aR,7S; aS,7R)

diastereomer 11i in 29% yield. Diastereomeric ratio

964

A.V. Vorogushin et al. / Tetrahedron 64 (2008) 949e968

the mixture was stirred at room temperature for 15 min. The

reaction was quenched with excess of saturated aqueous

Na₂S₂O₃solution. The organic layer was separated and the

aqueous layer was extracted with ether. The combined organic

layers were dried over MgSO₄, the solvent was removed, and

the residue was ﬁltered through a layer of silica gel (50%

EtOAc in hexane) giving, after solvent removal, a crude mix-

ture of products. The product ratio was then measured from

(C); IR (mix. of diastereomers) (KBr) 3396 (s, OH), 1599

(m), 1456 (s), 1123 (m) cm^ꢀ1. Mass spectrum (EI) m/z (%

rel intensity) 416 M^þ(100), 369 (12), 353 (15), 294 (5), 248

(9); HRMS (EI) calcd for C₂₄H₃₂O₆m/z 416.2199, found

416.2193. Anal. (mix. of diastereomers) Calcd for

C₂₄H₃₂O₆: C, 69.21; H, 7.74. Found C, 68.94; H, 7.95.

4.4.3. Cyclopentenone 13 (major)

1

the crude mixture by H NMR. Puriﬁcation by ﬂash chroma-

Colorless crystals, mp 102.3e103.7 ^ꢁC; ¹H NMR

(500 MHz, CDCl₃) d 0.81 (s, 9H, C(CH₃)₃), 2.25 (td, 1H,

J¼14.3, 5.3 Hz, C6eHa), 2.42e2.51 (m, 3H, C5eHa,

C6eHb, C9eHa), 2.57e2.69 (m, 2H, C5eHb, C9eHb),

2.94 (s, 3H, C7eOMe), 3.76 (dd, 1H, J¼6.9, 1.6 Hz,

C10eH), 3.80 (s, 3H, OMe), 3.84 (s, 3H, OMe), 3.88 (s,

3H, OMe), 4.40 (d, 1H, J¼7.0 Hz, C7eH), 6.57 (s, 1H,

C4eH); ¹³C NMR (75 MHz, CDCl₃) d 27.9 (CH₃), 31.9

(CH₂), 35.0 (C), 38.9 (CH₂), 40.0 (CH₂), 50.0 (CH), 55.7

(CH₃), 55.9 (CH₃), 60.9 (CH₃), 61.1 (CH₃), 70.4 (CH),

108.2 (CH), 124.0 (C), 135.9 (C), 140.6 (C), 142.2 (C),

151.6 (C), 153.8 (C), 175.3 (C), 207.6 (C); IR (mix. of diaste-

reomers) (KBr) 2939 (s), 1698 (s, CO), 1595 (m), 1467 (m),

1283 (m), 1109 (s) cm^ꢀ1. Mass spectrum (EI) m/z (% rel inten-

sity) 374 M^þ(100), 359 M^þꢀMe (10), 344 M^þꢀ2Me (22),

303 (14), 286 (72), 271 (19), 258 (10), 243 (14), 231 (8),

229 (9). Anal. (mix. of diastereomers) Calcd for C₂₂H₃₀O₅:

C, 70.56; H, 8.07. Found C, 70.48; H, 8.22.

tography on silica gel (20% EtOAc in hexane, followed by

25% and 50% mixtures) gave the individual diastereomeric

phenols 10k and 11k and the cyclopentenone derivatives 12

and 13.

Conditions 1. Under Ar: phenol 11k (aR,7S; aS,7R):phenol

10k (aR,7R; aS,7S ):cyclopentenone 13:cyclopentenone

12¼7.0:1.0:4.9:2.4. Combined yield of 10k and 11k:

0.085 g (32%). Combined yield of 12 and 13: 0.070 g

(29%).

Conditions 2. Under CO: phenol 11k (aR,7S; aS,7R):phenol

10k (aR,7R; aS,7S ):cyclopentenone 13:cyclopentenone

12¼7.0:1.0:4.0:1.7. Combined yield of 11k and 10k:

0.085 g (39%). Combined yield of 12 and 13: 0.070 g

(21%).

4.4.1. Phenol 11k (major)

Pale yellow oil; ¹H NMR (300 MHz, CDCl₃) d 1.48 (s, 9H,

C(CH₃)₃), 2.17e2.51 (m, 4H, C5eH₂, C6eH₂), 2.91 (s, 3H,

C7eOMe), 3.70 (s, 3H, OMe), 3.83 (s, 3H, OMe), 3.88 (s,

3H, OMe), 3.90 (s, 3H, OMe), 5.05 (d, 1H, J¼6.0 Hz,

C7eH), 6.63 (s, 1H, C4eH), 6.73 (s, 1H, OH), 6.95 (s, 1H,

C9eH); ¹³C NMR (75 MHz, CDCl₃) d 29.8 (CH₃), 31.1

(CH₂), 35.4 (C), 39.7 (CH₂), 55.8 (CH₃), 56.3 (CH₃), 57.0

(CH₃), 61.2 (CH₃), 61.8 (CH₃), 73.7 (CH), 108.7 (CH),

110.6 (CH), 123.0 (C), 125.7 (C), 125.9 (C), 137.6 (C),

139.3 (C), 140.4 (C), 146.8 (C), 149.3 (C), 150.9 (C), 152.4

(C); IR (mix. of diastereomers) (KBr) 3396 (s, OH), 1599

(m), 1456 (s), 1123 (m) cm^ꢀ1. Mass spectrum (EI) m/z (%

rel intensity) 416 M^þ(100), 369 (14), 353 (18), 286 (9), 249

(7), 233 (11), 149 (25); HRMS (EI) calcd for C₂₄H₃₂O₆m/z

416.2199, found 416.2195. Anal. (mix. of diastereomers)

Calcd for C₂₄H₃₂O₆: C, 69.21; H, 7.74. Found C, 68.94;

H, 7.95.

4.4.4. Cyclopentenone 12 (minor)

1

Yellowish oil; H NMR (500 MHz, CDCl₃) d 0.79 (s, 9H,

C(CH₃)₃), 2.14e2.22 (m, 1H, C6eHa), 2.36e2.45 (m, 1H,

C6eHb), 2.45 (dd, 1H, J¼18.5, 1.4 Hz, C9eHa), 2.48e2.59

(m, 2H, C5eH₂), 2.64 (dd, 1H, J¼18.5, 6.9 Hz, C9eHb),

3.31 (s, 3H, C7eOMe), 3.62 (d, 1H, J¼6.9 Hz, C10eH),

3.79 (ddd, 1H, J¼10.9, 3.8, 1.5 Hz, C7eH), 3.82 (s, 3H,

OMe), 3.86 (s, 3H, OMe), 3.91 (s, 3H, OMe), 6.59 (s, 1H,

C4eH); ¹³C NMR (75 MHz, CDCl₃) d 27.9 (CH₃), 30.5

(CH₂), 34.9 (C), 38.7 (CH₂), 40.7 (CH₂), 49.5 (CH), 55.9

(CH₃), 58.2 (CH₃), 60.9 (CH₃), 61.0 (CH₃), 77.8 (CH),

108.2 (CH), 123.1 (C), 135.9 (C), 140.9 (C), 141.0 (C),

151.3 (C), 153.9 (C), 170.9 (C), 205.7 (C); IR (mix. of diaste-

reomers) (KBr) 2939 (s), 1698 (s, CO), 1595 (m), 1467, 1283

(m), 1109 (s) cm^ꢀ1. Mass spectrum (EI) m/z (% rel intensity)

374 M^þ(35), 344 M^þꢀ2Me (100), 287 (80), 271 (17), 259

(12), 243 (14), 231 (9), 229 (9). Anal. (mix. of diastereomers)

Calcd for C₂₂H₃₀O₅: C, 70.56; H, 8.07. Found C, 70.48;

H, 8.22.

4.4.2. Phenol 10k (minor)

1

Yellowish oil; H NMR (600 MHz, CDCl₃) d 1.47 (s, 9H,

C(CH₃)₃), 2.10e2.17 (m, 1H, C6eHa), 2.23e2.31 (m, 2H,

C6eHb, C5eHa), 2.40e2.46 (m, 1H, C5eHb), 3.25 (s, 3H,

C7eOMe), 3.65 (s, 3H, OMe), 3.88 (s, 3H, OMe), 3.91 (s,

3H, OMe), 3.93 (s, 3H, OMe), 3.97 (dd, 1H, J¼11.7,

5.3 Hz, C7eH), 6.58 (s, 1H, OH), 6.65 (s, 1H, C4eH), 6.99

(s, 1H, C9eH); ¹³C NMR (125 MHz, CDCl₃) d 29.8 (CH₃),

30.8 (CH₂), 35.2 (C), 37.7 (CH₂), 56.1 (CH₃), 57.1 (CH₃),

57.5 (CH₃), 61.4 (CH₃), 61.7 (CH₃), 81.2 (CH), 109.1 (CH),

112.6 (CH), 121.4 (C), 124.2 (C), 125.1 (C), 137.1 (C),

138.3 (C), 140.6 (C), 145.8 (C), 149.2 (C), 150.3 (C), 153.0

4.5. 8-Bromo- and 9-bromo-1,2,3-trimethoxy-6,7-

dihydro-5H-benzocyclohepten-7-ones 15 and 19

The reactions were conducted employing the general

TPAP/NMO oxidation procedure.³⁰To a stirred solution of ei-

ther the alcohol 14¹⁴or 18⁹(1 equiv) and NMOeH₂O

(1.5 equiv) in dry CH₂Cl₂(w0.5 M) was added TPAP

(0.05 equiv) under argon, followed by powdered molecular

˚

sieves MS 4 A (0.25 g/mL). The reaction was monitored by

TLC. After stirring at room temperature for 1 h the ratio of

A.V. Vorogushin et al. / Tetrahedron 64 (2008) 949e968

965

ketone and alcohol had stabilized and didn’t change with ad-

ditional time. After 2 h of stirring, the mixture was ﬁltered

through a layer of silica gel (35% EtOAc in hexane), the sol-

vent was removed, and the residue was puriﬁed by column

chromatography on silica gel.

(R¼Me) (0.024 mL, 0.024 mmol), followed by 0.92 mL of

the BH₃$SMe₂solution (0.33 mmol). This mixture was stirred

at room temperature for 15 min, then cooled to 0 ^ꢁC. Ketone

15 (0.196 g, 0.599 mmol) was added quickly as a solid and

the stirring continued for 2 h at 0 ^ꢁC. The solution was then

warmed to room temperature and stirred for 1.5 h. The rest

of BH₃$SMe₂solution was then added and the progress of

the reaction was monitored by TLC (5% Et₂O in CH₂Cl₂)

for the disappearance of the starting ketone (w1 h). The reac-

tion was quenched with MeOH (1.2 mL), the volatiles were re-

moved in vacuo, and the residue ﬁltered through a short plug

of silica gel (1:1 Et₂O/CH₂Cl₂) to give, after solvent removal,

0.196 g of the alcohol (R)-14 (99% yield). The spectral data

for this product matched those previously reported for this

compound.¹⁴The enantiomeric purity of (R)-14 was deter-

mined to be 99% ee by HPLC (Chiralcel OD column, ﬂow

rate: 1 mL/min; hexane/i-PrOH 98:2 to 90:10 over 15 min;

t_Rof (R)-14: 11.3 min; t_Rof (S )-14: 12.4 min). Recrystalliza-

tion from methyl ethyl ketone (by diffusion of hexane) gave

enantiopure material (ﬁrst crop, 89% yield); [a]²_D⁰þ206 (c

1, CH₂Cl₂). The CBS reduction of ketone 15 and ketone 19

was also examined under a variety of conditions and the

results are indicated in Table 4. This method was not suitable

for the reduction of ketone 19.

4.5.1. Ketone 19

The crude product was puriﬁed by silica gel chromatogra-

phy with 20% EtOAc in hexane to give the target ketone 19

as a yellow oil (75%) along with a 15% recovery of the start-

ing alcohol 18. The ketone solidiﬁed upon storage. Ketone 19:

yellowish crystals, 76.6e77.8 ^ꢁC (ether/hexane); ¹H NMR

(300 MHz, CDCl₃)

d 2.45e2.77 (br s, 2H, C5eH₂),

2.77e3.25 (br s, 2H, C6eH₂), 3.84 (s, 3H, OMe), 3.90 (s,

3H, OMe), 4.00 (s, 3H, OMe), 6.52 (s, 1H, C4eH), 6.79 (s,

1H, C8eH); ¹³C NMR (75 MHz, CDCl₃) d 30.1 (CH₂)),

46.0 (CH₂), 55.9 (CH₃), 60.7 (CH₃), 61.2 (CH₃), 106.2

(CH), 121.9 (C), 132.9 (C), 134.4 (CH), 136.0 (C), 141.3

(CH), 153.3 (C), 154.9 (C), 200.6 (C); IR (KBr) 2943 (m),

1679 (s, CO), 1591 (s), 1348 (m), 1119 (s) cm^ꢀ1. Mass spec-

trum (EI) m/z (% rel intensity) 328 M^þ(97, ⁸¹Br), 326 M^þ

(100, ⁷⁹Br), 300 (28, ⁸¹Br), 298 (28, ⁷⁹Br), 285 (9, ⁸¹Br),

283 (9, ⁷⁹Br), 247 M^þꢀBr (58), 232 (12), 219 (96), 205

(51), 188 (39), 161 (19), 115 (21), 102 (15); HRMS (EI) calcd

79

for C₁₄H BrO₄m/z 326.0154, found 326.0159.

15

Table 4

Asymmetric CBS reductions of ketones 15 and 19^a

4.5.2. Ketone 15

The crude product was puriﬁed by silica gel chromatogra-

phy with 2% ether in CH₂Cl₂to give the target ketone 15 as

a yellow solid (76%) along with 18% recovery of the starting

alcohol 14. Ketone 15: yellow crystals, 129.9e130.3 ^ꢁC (i-Bu-

COMe/hexane) (reported³¹128e130 ^ꢁC); ¹H NMR

(300 MHz, CDCl₃) d 2.84e2.96 (m, 4H, C5eH₂, C6eH₂),

3.86 (s, 3H, OMe), 3.92 (s, 3H, OMe), 3.96 (s, 3H, OMe),

6.57 (s, 1H, C4eH), 8.29 (s, 1H, C9eH); ¹³C NMR

(75 MHz, CDCl₃) d 29.3 (CH₂)), 41.1 (CH₂), 56.0 (CH₃),

60.9 (CH₃), 61.8 (CH₃), 107.7 (CH), 120.4 (C), 123.8 (C),

138.4 (C), 138.8 (CH), 140.5 (C), 153.6 (C), 155.3 (C),

192.6 (C); IR (KBr) 2938 (m), 1666 (s, CO), 1599 (s), 1341

(s), 1125 (m) cm^ꢀ1. Mass spectrum (EI) m/z (% rel intensity)

328 M^þ(51, ⁸¹Br), 326 M^þ(51, ⁷⁹Br), 247 M^þꢀBr (100), 219

Ketone (S )-16

R

(S )-16 (equiv) Alcohol % Yield % ee

19

15

15^b

a

16a

16b

16a

16b

16a

Me 1.0

CH₂TMS 0.04

(R)-18

(R)-14

91

95

94

97

99

10

6

Me

0.04

1.0

6

98

95

96

99

CH₂TMS 0.04

Me

0.04

Ketone was added as a solid to a solution of (S )-16 and BH₃$SMe₂

(0.7 equiv) in CH₂Cl₂at 0 ^ꢁC. The reaction was stirred at 0 ^ꢁC for 0.5e3 h

and then warmed to 25 ^ꢁC.

b

The ketone was added as a solid to a solution of (S )-16 and BH₃$SMe₂

(0.5 equiv) in CH₂Cl₂at 0 ^ꢁC. The reaction was stirred at 0 ^ꢁC for 2 h and

then at 25 ^ꢁC for 1.5 h before additional BH₃$SMe₂(0.2 equiv) was added.

(23), 204 (17), 188 (46), 161 (20), 118 (16), 57 (15); HRMS

4.7. Asymmetric reduction¹⁹of ketone 19 using

TarBeNO₂eLiBH₄

79

(EI) calcd for C₁₄H BrO₄m/z 326.0154, found 326.0162.

15

Anal. Calcd for C₁₄H₁₅BrO₄: C, 51.40; H, 4.62. Found C,

51.16; H, 4.77.

The starting ketone 19 (0.467 g, 1.428 mmol) was dried in

vacuo (0.1 mmHg) with a heat gun for 0.5 h and then dis-

solved under argon in a 0.4 M solution of TarBeNO₂20

(2.856 mmol, 7.1 mL) in THF. The solution was stirred at

room temperature for 0.5 h and then a 2 M LiBH₄solution

(1.499 mmol, 0.75 mL) in THF was added over 20 min via

a syringe pump. The mixture was stirred for 10 min and

then it was quenched by the dropwise addition of water

(2 mL). A 10% aqueous HCl solution (2 mL) was added and

the THF was removed in vacuo. The product was extracted

into ether (10 mL), the organic layer separated, and then

extracted with 10% aqueous NaOH solution (2ꢄ15 mL). The

organic layer was separated and dried over MgSO₄. Solvent

4.6. CBS reduction¹⁶of ketone 15dpreparation

of (R)-8-bromo-1,2,3-trimethoxy-6,7-dihydro-5H-

benzocyclohepten-7-ol (R)-14

Glassware for the reaction was dried at 150 ^ꢁC for at least

12 h and then cooled under argon. Ketone 15 was dried in

vacuo (0.1 mmHg) with a heat gun for 0.5 h prior to the reac-

tion. A solution of BH₃$SMe₂was prepared by dissolving the

w10 M neat complex (0.044 mL, 0.44 mmol) in 1.22 mL of

dry CH₂Cl₂. To a 10 mL reaction ﬂask ﬁlled with argon was

added a 1 M toluene solution of oxazaborolidine (S )-16a

966

A.V. Vorogushin et al. / Tetrahedron 64 (2008) 949e968

removal gave 0.458 g of (S )-18 (97%). The spectral data for

alcohol 18 matched those previously reported for this com-

pound.⁹The enantiomeric purity of 18 was determined to be

42% ee by HPLC (Chiralpak AS column, ﬂow rate: 1 mL/

min; hexane/i-PrOH 90:10 to 80:20 over 10 min, 80:20 for

1 min, and then to 90:10 over 1 min; t_Rof (R)-18: 10.2 min;

t_Rof (S )-18: 11.1 min).

(3 equiv) and the mixture was reﬂuxed under argon for 3 h.

MeI (3 equiv) was added and the reﬂux was continued for

15 h. TLC analysis showed full conversion in both cases.

The solvent was removed in vacuo and water (7.14 mL/

mmol of alcohol) was added to the residue containing the

product, which was extracted twice with ether. The combined

organic layers were dried over MgSO₄, the solvent was

removed, and the crude product was puriﬁed by column chro-

matography (silica gel, 15% EtOAc in hexane) to give (S )-23

(85%, 99% ee, [a]²_D⁰ꢀ159 (c 1, CH₂Cl₂)) or (R)-17 (87%,

>99% ee, [a]²_D⁰þ183 (c 1, CH₂Cl₂)). Enantiomeric purity

of (S )-23 and (R)-17 was determined by HPLC (Chiralcel

OD-H column, ﬂow rate: 0.8 mL/min; hexane/i-PrOH 100:0

to 98:2 over 10 min, 98:2 for 5 min; t_Rof (R)-23: 14.6 min;

t_Rof (S )-23: 15.6 min; t_Rof (R)-17: 13.0 min; t_Rof (S )-17:

13.3 min).

4.8. Kinetic resolution²⁰of scalemic (S )-18 through

acetylation

Fu’s catalyst 21 (0.018 g, 0.028 mmol, 2 mol %) was pur-

chased from Strem Chemicals. It was dried in vacuo

(0.1 mmHg) with a heat gun for 15 min prior to use. Alcohol

(S )-18 (0.458 g, 1.392 mmol, 42% ee) was dissolved in

5.4 mL of t-AmOH (distilled over CaH₂). To this solution was

added NEt₃(0.084 g, 0.835 mmol), followed by the catalyst

and then the ﬂask was ﬂushed with Ar. The mixture was soni-

cated to dissolve the catalyst, cooled to 0 ^ꢁC, and then Ac₂O

(0.071 g, 0.696 mmol) was added dropwise. The solution was

stirred at 0 ^ꢁC under argon for 15 h, then it was ﬁltered through

the short plug of silica gel (40% EtOAc in hexane), from which

the catalyst can be recovered (17 mg, 94%) by washing with

a 1:1 mixture of EtOAc and Et₃N. The ﬁltrate was analyzed

by HPLC (see conditions above), which revealed that (S )-18

was 99% ee at 49% conversion. The solvent was removed and

the residue subjected to column chromatography (silica gel,

25% EtOAc in hexane) to give after the solvent removal, 22

(0.238 g, 46%) and (S )-18 (0.234 g, 51%, 99% ee). This level

of optical purity enhancement corresponds to an s value of the

catalyst of 13.2. With a second run with the recycled catalyst

the s value was 8.3. For runs 3e8 with the recycled catalyst

the s value was w5.5. The spectral data for alcohol 18 matched

those previously reported for this compound.⁹Optical rotation

of (S )-18: [a]²_D⁰ꢀ109 (c 1, CH₂Cl₂) on 99% ee material . Spec-

tral data for 22: ¹H NMR (500 MHz, CDCl₃) d 1.98e2.03 (br s,

3H, COMe), 2.00e2.07 (m, 1H, C6eHa), 2.44e2.56 (m, 2H,

C6eHb, C5eHa), 2.70e2.81 (m, 1H, C5eHb), 3.86 (s, 3H,

OCH₃), 3.88 (s, 3H, OCH₃), 3.97 (s, 3H, OCH₃), 4.97e5.03

(m, 1H, C7eH), 6.45e6.50 (br s, 1H, C8eH), 6.50 (s, 1H,

C4eH); ¹³C NMR (75 MHz, CDCl₃) d 20.9 (CH₃), 30.3

(CH₂), 38.5 (CH₂), 55.9 (CH₃), 60.8 (CH₃), 61.0 (CH₃), 71.6

(CH), 107.1 (CH), 113.6 (C), 122.9 (C), 134.2 (CH), 135.6

(C), 141.0 (C), 151.9 (C), 154.1 (C), 169.9 (C); IR (KBr) 2943

4.10. Preparation of carbene complex (S )-6a

To a stirred solution of (S )-23 (0.55 g, 1.603 mmol, 99%

ee) in 22 mL of absolute THF at ꢀ78 ^ꢁC was added

a 1.35 M t-BuLi solution in pentane (3.206 mmol, 2.4 mL)

dropwise under argon. The mixture was stirred at ꢀ78 ^ꢁC

for 15 min and then slowly (w5 min) transferred via cannula

into a stirred suspension of Cr(CO)₆(0.353 g, 1.603 mmol)

in 33 mL of absolute THF at 0 ^ꢁC. The mixture was stirred

0.5 h at 0 ^ꢁC and 1.5 h at room temperature. Then the solvent

was removed in vacuo, the residue dissolved in 25 mL of

CH₂Cl₂, and then Me₃O^þBF^ꢀ₄(0.712 g, 4.809 mmol) was

added. The reaction was started by the addition of 25 mL of

water. The resulting mixture was stirred for 20 min at room

temperature. The red reaction mixture was quenched with

25 mL of the saturated aqueous NaHCO₃solution, the organic

layer was separated, and the aqueous layer was extracted once

with ether. The organic layers were combined and dried over

MgSO₄. The solvent was removed in vacuo and the residue

was subjected to ﬂash chromatography (silica gel, 20% EtOAc

in hexane) giving, after removal of solvent, carbene complex

(S )-6a (0.687 g, 86%). The spectral data for 6a matched those

previously reported for the racemic compound.⁹Enantiomeric

purity of (S )-6a was determined to be 99% ee by HPLC (Chir-

alcel OD column, ﬂow rate: 1 mL/min; hexane/i-PrOH 98:2 to

95:5 over 8 min, 95:5 to 90:10 over 7 min; t_Rof (R)-6a:

6.9 min; t_Rof (S )-6a: 7.9 min).

(m), 1736 (s), 1593 (m), 1459 (m), 1238 (s), 1119 (s) cm^ꢀ1

.

Mass spectrum (FAB^þ) m/z (% rel intensity) 372 M^þ(74,

⁸¹Br), 370 M^þ(74, ⁷⁹Br), 313 M^þꢀOCOMe (92, ⁸¹Br),

311 M^þꢀOCOMe (100, ⁷⁹Br), 231 (43); HRMS (FAB^þ) calcd

for C₁₆H₁₉O₅Br m/z 370.0416, found 370.0403. Anal. Calcd

for C₁₆H₁₉BrO₅: C, 51.77; H, 5.16. Found C, 51.73; H, 5.23.

4.11. Preparation of carbene complex (R)-9a

To a stirred solution of (R)-17 (0.273 g, 0.796 mmol, >99%

ee) in 10 mL of absolute THF at ꢀ78 ^ꢁC was added a 1.5 M

t-BuLi solution in pentane (1.592 mmol, 1.06 mL) dropwise

under argon. The mixture was stirred at ꢀ78 ^ꢁC for 15 min

and then slowly (w5 min) transferred via cannula into a stirred

suspension of Cr(CO)₆(0.175 g, 0.796 mmol) in 15 mL of

absolute THF at 0 ^ꢁC. The mixture was stirred 0.5 h at 0 ^ꢁC

and 1.5 h at room temperature. Then the solvent was removed

in vacuo, the residue dissolved in 15 mL of CH₂Cl₂, and then

Me₃O^þBF^ꢀ₄(0.353 g, 2.388 mmol) was added. The reaction

4.9. (S )-9-Bromo-1,2,3,7-tetramethoxy-6,7-dihydro-5H-

benzocycloheptene and (R)-8-bromo-1,2,3,7-tetramethoxy-

6,7-dihydro-5H-benzocycloheptene (S )-23 and (R)-17

To a solution of (S )-18 or (R)-14 (1 equiv) in dry THF

(7.14 mL/mmol of alcohol) was added NaH (60% in oil)

A.V. Vorogushin et al. / Tetrahedron 64 (2008) 949e968

967

was started by the addition of 15 mL of water. The resulting

mixture was stirred for 20 min at room temperature. The red

reaction mixture was quenched with 15 mL of the saturated

aqueous NaHCO₃solution, the organic layer was separated,

and the aqueous layer was extracted once with ether. The

organic layers were combined and dried over MgSO₄. The sol-

vent was removed in vacuo and the residue was subjected to

ﬂash chromatography (silica gel, 20% EtOAc in hexane) giv-

ing, after removal of solvent, carbene complex (R)-9a together

with 5e10% of the tetracarbonyl chelate complex (0.309 g,

78%). The spectral data of 9a matched those previously re-

ported for the racemic compound.⁹The enantiomeric purity

of (R)-9a was determined to be >99% ee by HPLC (Chiralcel

OD column, ﬂow rate: 1 mL/min; hexane/i-PrOH 98:2 to 95:5

over 8 min, 95:5 to 90:10 over 7 min; t_Rof (R)-9a: 7.8 min; t_R

of (S )-9a: 9.1 min).

diastereomers was performed and the enantiomeric purity of

8a (aR,7S ) and 7a (aS,7S ) was determined by HPLC on a Chir-

alcel OD-H column. For 8a: ﬂow rate: 1 mL/min; hexane/i-

PrOH 90:10 to 80:20 over 10 min; t_Rof (aR,7S )-8a: 3.5 min;

t_Rof (aS,7R)-8a: 4.5 min. For 7a: ﬂow rate: 1 mL/min; hex-

ane/i-PrOH 99:1 to 98:2 over 8 min; t_Rof (aR,7R)-7a:

5.0 min; t_Rof (aS,7S )-7a: 8.1 min. The results for the different

solvents, temperatures, and concentrations are given in Table 3.

4.14. Benzannulation reaction of carbene complex (S )-6a

with pent-1-yne in benzene and THF

The reaction of (S )-6a with pent-1-yne in benzene was per-

formed according to the general procedure. Diastereomer

(aS,7S )-7a was isolated in 46% yield and 72% ee (determined

by HPLC (see conditions above)). Recrystallization from Et-

C(O)Me/hexane mixture (8 h at 25 ^ꢁC, 2 d at ꢀ20 ^ꢁC) gave

crystals of 7a (22.5%, 8% ee). Enantiopure (aS,7S )-7a was

isolated by evaporation of the mother liquor in vacuo

(77.5%, >99% ee). The reaction of (S )-6a with pent-1-yne

in THF was carried out at 35 ^ꢁC for 60 h. The products were

isolated according to the general procedure. The diastereo-

meric ratio (dr) 7a:8a was 2.7:1 and the combined yield was

85%. Both diastereomers were formed without racemization

(99% ee (HPLC)). For (aR,7S )-8a: [a]²_D⁰ꢀ83 (c 1, CH₂Cl₂)

on 99% ee material. For (aS,7S )-7a: [a]²_D⁰ꢀ67 (c 1,

CH₂Cl₂) on >99% ee material. CD ([q]ꢄ10^ꢀ4(nm), hexane)

ꢀ1.2 (308), ꢀ5.3 (257), ꢀ2.0 (229), þ10.9 (201).

4.12. Conﬁrmation of absolute stereochemistry.

Reduction of bromides (S )-23 and (R)-17 to give

(S )- and (R)-24

To a stirred 0.05 M solution of (S )-23 (99% ee) or (R)-17

(>99% ee) (1 equiv) in absolute THF at ꢀ78 ^ꢁC was added

a 1.29 M t-BuLi solution in pentane (1.2 equiv) dropwise

under argon. The mixture was stirred at ꢀ78 ^ꢁC for 15 min

and then quenched by the dropwise addition of MeOH

(2.4 mL/mmol of bromide). The mixture was allowed to reach

room temperature and then the solvent was removed in vacuo

and water was added to the residue. The product was extracted

twice with ether, the organic layers were combined, and then

dried over MgSO₄. The solvent was removed to give (S )-24

(99%) and (R)-24 (97%), respectively. We were unable to mea-

sure the ee of 24 by HPLC. However, metalehalogen exchange

in (S )-23 and in (R)-17 was expected to proceed without racemi-

zation, since carbene complexes (S )-6a and (R)-9a can be been

prepared without the loss of enantiomeric purity (see above). For

(S )-24: [a]²_D⁰ꢀ247 (c 1, CH₂Cl₂) on 99% ee material. For (R)-

24: [a]²_D⁰þ248 (c 1, CH₂Cl₂) on >99% ee material.

4.15. Benzannulation reaction of carbene complex (R)-9a

with 1-pentyne

The reaction of (R)-9a with pent-1-yne in benzene was per-

formed according to the general procedure. Diastereomeric ra-

tio (dr) 10a:11a was 3.0:1 and the diastereomers (aS,7R)-10a

and (aR,7R)-11a were isolated in 49% combined yield, both

in >99% ee as determined by HPLC (Chiralcel OD-H column,

ﬂow rate: 1 mL/min; hexane/i-PrOH 99:1 to 98:2 over 8 min,

then 98:2 to 95:5 over 7 min; t_Rof (aS,7R)-10a: 5.2 min; t_Rof

(aS,7S )-11a: 7.1 min; t_Rof (aR,7S )-10a: 7.5 min; t_Rof

(aR,7R)-11a: 10.2 min). For (aS,7R)-10a: [a]²_D⁰þ64 (c 1,

CH₂Cl₂); CD ([q]ꢄ10^ꢀ4(nm), hexane) ꢀ1.3 (307), ꢀ1.2

(257), ꢀ3.6 (230), þ14.1 (200). For (aR,7R)-11a: [a]_D²⁰

þ104 (c 1, CH₂Cl₂); CD ([q]ꢄ10^ꢀ4(nm), hexane) þ1.1

(306), þ1.9 (255), þ4.1 (228), ꢀ8.8 (201).

4.13. Benzannulation reaction of carbene complex (S )-6a

with pent-1-yne. Screening of reaction conditions

To a solution of (S )-6a (0.04 mmol, 20 mg) in dry solvent

was added

a 3-fold excess of pent-1-yne (8.16 mg,

0.12 mmol, 0.012 mL). The resulting solution was deoxygen-

ated by the freezeepumpethaw method (ꢀ196 ^ꢁC/25 ^ꢁC, three

cycles). The ﬂask was back-ﬁlled with argon at room tempera-

ture and sealed. The reaction was performed under the condi-

tions indicated in Table 3. The red clear solution gradually

changed to a dark mixture. The reaction mixture was opened

to air, diluted with 1.5 mL of 40% EtOAc in hexane and stirred

in the open ﬂask for 24 h. The solvent was removed invacuo and

the crude product was ﬁltered through a layer of silica gel (40%

EtOAc in hexane). After the removal of the solvent, the diaste-

reomeric ratio (dr) was determined from the crude product

Acknowledgements

This work was supported by a grant from the National

Institutes of Health (PHS-GM 33589).

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Article Doi

Central-to-axial chirality transfer in the benzannulation reaction of optically pure Fischer carbene complexes in the synthesis of allocolchicinoids

DOI: 10.1016/j.tet.2007.10.115

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