Gold-catalyzed cycloisomerizations of ene-ynamides

Tetrahedron 65 (2009) 1809–1832

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Tetrahedron

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Gold-catalyzed cycloisomerizations of ene-ynamides

*

Sylvain Couty, Christophe Meyer , Janine Cossy

Laboratoire de Chimie Organique, ESPCI, CNRS (UMR 7084), 10 rue Vauquelin, 75231 Paris Cedex 05, France

a r t i c l e i n f o

a b s t r a c t

Article history:

Received 30 June 2008

Received in revised form 23 October 2008

Accepted 24 October 2008

Available online 24 December 2008

The gold-catalyzed cycloisomerizations of 1,6-ene-ynamides proceed under mild conditions and lead to

cyclobutanones from terminal or trimethylsilyl substituted ynamides, or to carbonyl compounds bearing

a 2,3-methanopyrrolidine subunit from substrates possessing a propargylic alcohol moiety. High dia-

stereoselectivities are observed with 1,6-ene-ynamides having a stereocenter at the

nitrogen atom.

a or b position of the

1. Introduction

ene-ynamide 1 catalyzed by Grubbs’ second generation catalyst.⁹

However, under the same conditions, the 1,7-ene-ynamide 3

exhibited a different behavior as the cyclobutenamide 4, having

a tetrasubstituted alkene, was formed. This rather unstable com-

pound could be isolated in modest yield (44%) but a hydrolytic

work-up under acidic conditions led to cyclobutanone 5 in a better

yield (65%) (Scheme 1).⁸

In the presence of transition metal catalysts, 1,n-enynes can

undergo an impressive number of chemical transformations lead-

ing to highly functionalized cyclic or polycyclic complex molecules

that could not be so easily and efﬁciently attained by other routes.^1–3

Due to their exceptional ability to selectively coordinate to alkynes

and activate the triple bond toward intramolecular nucleophilic

attack by alkenes, gold salts and complexes have been shown to be

highly active catalysts for enyne cycloisomerizations.^2–5In recent

years, remarkable achievements in this ﬁeld have been reported,^2–5

but the gold-catalyzed cycloisomerizations of the triisopropylsilyl

ethers derived from ene-ynols were the only examples of such

reactions involving enynes with a heterosubstituted carbon–carbon

triple bond.⁴ⁿDuring the last decade, ynamides, which possess an

electron-withdrawing group on the nitrogen atom and constitute

a stable class of acetylenic amines derivatives, have been successfully

used as partners in synthetically useful metal-catalyzed processes.⁶

Among them, Ru, Rh, Pd, Cu, and Pt have been employed,⁶however,

before 2006, there was no report concerning the reactivity of

ynamides in the presence of gold catalysts⁷and we were thus

interested in investigating the gold-catalyzed cycloisomerizations of

ene-ynamides.

Ts

N

Ts

N

Cl

N

Mes

N

Mes

PtCl₂or Grubbs II (5 mol %)

Ru

PCy₃

toluene, 80 °C

98% or 76%

Ph

2

1

Grubbs II

Ts

O

N

aq. HCl

PtCl₂(5 mol %)

H

N

toluene, 80 °C

EtOAc

65%

Ts

3

4

5

Scheme 1.

In the original mechanistic proposal, the authors suggested that

a platinum cyclopropylcarbene intermediate of type A (M¼PtCl₂),

generated by electrophilic activation of the ynamide and concom-

itant nucleophilic attack of the alkene, would undergo ring-ex-

pansion to form a cyclobutyl cation B.⁸The latter species should

beneﬁt from stabilization by the nitrogen atom compared to the

non-heterosubstituted series. After demetalation and regeneration

of the catalyst, a cyclobutenamide of type C would be formed and

its evolution would depend on the ring size. In the case of the 1,6-

ene-ynamide 1, the strained cyclobutenamide C (n¼1) would

preferentially undergo electrocyclic ring-opening to generate

dienamide 2. However, by analogy with mechanistic investigations

carried out in the non-heterosubstituted series, dienamide 2 could

also result from the skeletal rearrangement of the platinum

cyclopropylcarbene A (M¼PtCl₂), through intermediates D and/or

Previously, the cycloisomerization of ene-ynamides had been

investigated with PtCl₂as a catalyst.⁸It was reported that treatment

of the 1,6-ene-ynamide 1 with a catalytic amount of PtCl₂

[(5 mol %), toluene, 80 ^ꢀC] led to the ﬁve-membered ring nitrogen

heterocycle 2 (98%), possessing a dienamide moiety.⁸This com-

pound had also been synthesized by ring-closing metathesis of

* Corresponding authors. Tel.: þ33 1 40795845; fax: þ33 1 40794660 (C.M.); tel.:

þ33 1 40794429; fax: þ33 1 40794660 (J.C.).

E-mail addresses: christophe.meyer@espci.fr (C. Meyer), janine.cossy@espci.fr

(J. Cossy).

doi:10.1016/j.tet.2008.10.108

1810

S. Couty et al. / Tetrahedron 65 (2009) 1809–1832

E.^1–3,4a–gFor the 1,7-ene-ynamide 3, the less strained cyclo-

butenamide intermediate C (n¼2) could undergo alkene migration

to generate cyclobutenamide 4 bearing a tetrasubstituted double

bond (Scheme 2).⁸

compound 5 was obtained in a much better yield by the platinum-

catalyzed reaction,⁸our subsequent investigations exclusively

focused on the gold-catalyzed cycloisomerizations of 1,6-ene-

ynamides (Scheme 3).

M

O

Ts

AcOOH Ts

AcONa

O

Ts

NH

O

N

NH

AuCl (5 mol %)

CH₂Cl₂, rt

50%

cat. M

AcOH, rt

77%

n

1

6

7

Ts

N

n = 1

n = 2

1

M

Ts

3

O

N

AuCl (5 mol %)

CH₂Cl₂, rt

26%

Ts

N

and/or

M

H

N

D

Ts

N

Ts

M

3

5

n

− M

Scheme 3.

A

E

Ts

N

Interestingly, upon treatment with a catalytic amount of AuCl

(5–15 mol %), the silylated ene-ynamides 8 and 9, bearing a tosyl

group or a benzyloxycarbonyl group on the nitrogen atom, were

also cleanly converted to the cyclobutanones 6 (61%) and 10 (59%),

respectively. The opportunity to carry out those transformations

directly with trimethylsilyl-ynamides is particularly attractive since

these compounds are generally more stable than terminal

ynamides and, further more, no additional desilylation step was

required (Scheme 4).

n = 1

Ts

N

Ts

N

2

M

n

− M

Ts

N

B

C

n = 2

4

Scheme 2.

Ts

O

TMS

N

Assuming the intermediacy of cyclobutenamides of type C in the

cycloisomerization of ene-ynamides 1 and 3, we hypothesized that

the use of milder conditions may prevent their electrocyclic ring-

opening or their isomerization. Although platinum and gold

catalysts are known to trigger similar processes, gold-catalyzed

reactions generally proceed under milder conditions.^2–5Thus, we

decided to explore the reactivity of ene-ynamides in the presence

of gold catalysts to see whether there would be a difference com-

pared to the platinum-catalyzed reactions. Herein, we report a full

account of our investigations on gold-catalyzed cyclo-

isomerizations of 1,6-ene-ynamides and their application to the

AuCl (5 mol %)

CH₂Cl₂, rt

61%

Ts

N

H

8

6

Cbz

O

N

AuCl (15 mol %)

Cbz

CH₂Cl₂, rt

59%

N

H

9

10

Scheme 4.

diastereoselective synthesis of cyclobutanones,

g-lactones as well

as functionalized 2,3-methanopyrrolidines.¹⁰

The gold-catalyzed cycloisomerizations of the 1,6-ene-

ynamides 1 or 8 presumably involve gold cyclopropylcarbene

intermediates of type A (Scheme 2, M¼AuCl) that evolve by ring-

expansion and provide cyclobutenamides 11 and 12, respectively.^2–5

However, all attempts to isolate these latter compounds were un-

successful. Although the reactions were conducted under anhy-

drous conditions, the crude products were exposed to air upon

work-up and traces of water were probably sufﬁcient to promote the

hydrolysis of these strained species. An acidic aqueous work-up has

also been used occasionally and comparable results were obtained.

Thus, protonation of the enamide moiety in compound 11 would

2. Gold-catalyzed cycloisomerizations of 1,6-ene-ynamides

2.1. Preliminary investigations

In our initial experiments, the 1,6-ene-ynamide 1^8,9was

treated with a catalytic amount of AuCl [(5–10 mol %), CH₂Cl₂, rt,

12–24 h]. Under these conditions, we found that dienamide 2 was

formed as a minor product (<5–10%) whereas cyclobutanone 6

was isolated as the major compound in 50% yield. The use of AuCl₃

[(5 mol %), MeCN, rt] led to the same result and in fact an Au(III)

species may always be the actual catalyst as AuCl is known to

disproportionate to Au(III) and Au(0) in CH₂Cl₂.¹¹However, the use

of AuCl was preferred as it is less hygroscopic than AuCl₃and

hence easier to handle and weigh on a small scale. The formation

of cyclobutanone 6 was also conﬁrmed by its conversion to

generate an a-aza-cyclobutyl cation, which could be attacked by

hydroxide (or water) and give rise to hemiaminal 13, which is in

equilibrium with cyclobutanone 6. Protonation of the enamide

moiety of the trimethylsilyl-cyclobutenamide 12 would

generate a cation stabilized by the nitrogen atom and the b-effect of

silicon.¹³After Peterson type elimination, with formation of

trimethylsilanol, the intermediate cyclobutenamide 11 would be

generated and then ultimately converted to cyclobutanone 6

(Scheme 5).¹⁴

g-lactone 7 (77%) through a Baeyer–Villiger oxidation (AcOOH,

AcONa, AcOH, rt).¹²Thus, the gold-catalyzed reaction of the 1,6-

ene-ynamide 1 effectively proceeded under mild conditions and

provided a product different from the one generated by the

platinum-catalyzed process.⁸In a similar fashion, the 1,7-ene-

ynamide 3 was also treated with AuCl [(5 mol %), CH₂Cl₂, rt] but

a slow reaction was observed and cyclobutanone 5 was isolated in

low yield (26%), which was not improved by heating at reﬂux. As

We have indeed observed that the gold-catalyzed cyclo-

isomerization of ene-ynamide 8 could be carried out in CH₂Cl₂

containing D₂O [AuCl (10 mol %), D₂O (25 equiv), CH₂Cl₂, rt] and

led to the gem-dideuteriated cyclobutanone 6⁰(52%, >95% D₂)

(Scheme 6).

S. Couty et al. / Tetrahedron 65 (2009) 1809–1832

1811

Ts

O

Ts

³O

*

N

H

N

TMS

NH

*

NH

R

Bayer-Villiger

R⁴

R³R⁵

*

R²

R¹

*

R²

⁵R⁴

R

1

8

F

G

AuCl (cat.)

CH₂Cl₂, rt

AuCl (cat.)

CH₂Cl₂, rt

Ts

OR

NH

R³

OR

R¹

Au(I)-catalyzed

⁵R⁴

²R

1,3-aminoalcohol subunit

HO

Si

cycloisomerization

R

O

Ts

N

Ts

N

Ts

N

H⁺

TMS

Ts

− Me₃SiOH

NH

N

TMS

R³

*

11

*

Alkynylation

R¹

R³

R¹

*

12

*

H⁺

Ts

H₂O

R²

R⁴

R²

R⁴

R⁵

H

Ts

N

O

OH

Ts

OH

I

NH

N

Scheme 7.

*

13

6

of type K. The latter would be prepared from allylic alcohols L by

a Claisen rearrangement. Finally, sulfonamides I can also be syn-

thesized from homoallylic alcohols of type M by a Mitsunobu re-

action utilizing a nitrogen nucleophile (route c) (Scheme 8).

Scheme 5.

Ts

D

AuCl (10 mol %)

D₂O (25 equiv)

O

Ts

N

TMS

NH

D

CH₂Cl₂, rt

52%

Ts

N

8

6'

Allylation

(a)

R¹

H

J

Scheme 6.

Ts

CO₂H

R³

NH

R¹

R³

Claisen

R⁵

R⁴

Schmidt

(b)

Though the mechanism of the gold-catalyzed reaction of ene-

ynamides was not established unambiguously, the main difference

compared to the platinum-catalyzed process would be that cyclo-

butenamides 11 and 12 did not undergo electrocyclic ring-opening

due to the milder reaction conditions. An important consequence is

that the stereogenic center (depicted with an asterisk on Scheme

5), initially created during the cycloisomerization process in in-

termediates 11 and 12, is still present in the ﬁnal cyclobutanone 6.

Controlling the conﬁguration of this stereocenter would be in-

teresting as cyclobutanones can be involved in stereospeciﬁc re-

actions such as, for example, the Baeyer–Villiger rearrangement

R²

R⁴

R²

R⁴

HO

L

R⁵

K

I

OH

Mitsunobu

(c)

R¹

R³

R²

R⁴

R⁵

M

Scheme 8.

Two sulfonamides substituted at the

a position of the nitrogen

leading to

g-lactones.

atom were ﬁrst prepared. Treatment of N-tosylbenzaldimine 14

with allylmagnesium chloride or methallylmagnesium chloride

(THF, 0 ^ꢀC) provided the homoallylic sulfonamides 15 (80%) and 16

(42%), respectively (Scheme 9).

Thus, a variety of substituted

an interesting 1,3-aminoalcohol subunit, could be prepared by the

Baeyer–Villiger oxidation of the corresponding cyclobutanones of

g

-lactones of type F, which contain

type

G that would be synthesized by gold-catalyzed cyclo-

isomerizations of 1,6-ene-ynamides of type H. An important issue

in these studies was to examine the possibility of achieving 1,3- or

1,2-stereochemical induction in the case of substrates bearing

Ts

MgCl

THF, 0 °C

NH

Ph

a stereogenic center at the

a or b

position of the nitrogen atom (R¹

Ts

H

or R²sH), respectively. Additionally, the creation of a quaternary

80%

15

Ts

N

center (R³sH) or an additional stereocenter (R⁴or R⁵sH) on the

Ph

ring of

g-lactones F and cyclobutanones G would be feasible

NH

MgCl

14

starting from 1,6-ene-ynamides of type

H

possessing a di-

THF, 0 °C

42%

substituted alkene (R³or R⁴or R⁵sH). The 1,6-ene-ynamides of

type H should be easily prepared by alkynylation of the corre-

sponding sulfonamides I (Scheme 7).

16

Scheme 9.

A sulfonamide possessing a stereogenic center at the

b position

of the nitrogen atom was prepared from allylic alcohol 17. A John-

son–Claisen rearrangement [EtCO₂H (cat.), MeC(OEt)₃, reﬂux] led to

ethyl ester 18,¹⁵which was saponiﬁed to afford the crude carboxylic

acid 19 (81%, two steps from 17). The latter compound underwent

a Schmidt reaction [(PhO)₂P(]O)N₃(DPPA), Et₃N, toluene, rt to

reﬂux]¹⁶and the resulting isocyanate 20 was hydrolyzed in situ by

heating at reﬂux in the presence of 35% aq NaOH. After acidiﬁcation

(35% aq HCl), the crude hydrochloride 21 was isolated (93%). The

nitrogen atom was then tosylated [TsCl, DMAP (cat.), Et₃N, CH₂Cl₂,

2.2. Diastereoselective cycloisomerizations

of 1,6-ene-ynamides

2.2.1. Preparation of the substrates

Three routes have been used to prepare sulfonamides I. The ﬁrst

one (route a) relies on the addition of an allylic organometallic

reagent to a N-tosylaldimine J. The second route (route b) involves

the formation of sulfonamides I from the corresponding primary

amines generated by a Schmidt reaction applied to carboxylic acids

1812

S. Couty et al. / Tetrahedron 65 (2009) 1809–1832

rt] to provide sulfonamide 22 (86%) bearing a benzyloxymethyl

group substituent at the allylic position (Scheme 10).

OH

1) DIBAL-H

hexanes−Et₂O, rt

OTHP

2) TsOH (cat.)

MeOH, rt

SiMe₂Ph

PhMe₂Si

28

O

46%

27

OH

EtCO₂H (cat.)

KOH

OEt

HO

PPh₃, DIAD

Phthalimide 88%

THF, rt

MeC(OEt)₃

reflux

MeOH, reflux

BnO

81%

BnO

(two steps

from 17)

BnO

17

18

19

DPPA, Et₃N

toluene, rt to reflux

O

N

Ts

1) N₂H₄.H₂O

EtOH, reflux

NH

O

Ts

2) TsCl, Py, rt

74%

TsCl, Et₃N

DMAP (cat.)

1) 35% aq. NaOH

toluene, reflux

O

•

NH

NH₃,Cl

N

PhMe₂Si

30

PhMe₂Si

29

2) 35% aq. HCl

CH₂Cl₂

93%

86%

BnO

22

21

20

Scheme 12.

Scheme 10.

The synthesis of 1,6-ene-ynamides bearing an a,b-disubstituted

Ts

CO₂t-Bu

double bond of deﬁned conﬁguration was then examined. It was

envisaged to synthesize substrates bearing a dimethylphenylsilyl

group as this substituent could later be transformed to a hydroxyl

group by oxidation of the carbon–silicon bond.¹⁷The (E)-alkenyl

iodide 23¹⁸underwent lithium–iodine exchange (n-BuLi, THF,

ꢁ78 ^ꢀC) and the resulting alkenyllithium was silylated with

PhMe₂SiCl to afford, after cleavage of the THP ether [TsOH (cat.),

MeOH, rt], the homoallylic alcohol 24 bearing a (E)-alkenyl silane

(70%, two steps from 23).¹⁹A Mitsunobu reaction with phthalimide

[PPh₃, diisopropyl azodicarboxylate (DIAD), THF, rt] led to imide 25,

which underwent hydrazinolysis followed by tosylation of the

resulting amine [TsCl, pyridine (Py), rt] to provide sulfonamide 26

in 24% unoptimized yield (two steps from 25) (Scheme 11).

NH

Grubbs II (7.5 mol %)

CH₂Cl₂, reflux

84%

Ph

CO₂t-Bu

15

31

DIBAL-H, CH₂Cl₂

64%

−78 °C to rt

Ts

NH

TBSCl, imidazole

Ph

DMF, rt

99%

33

32

OH

OTBS

Scheme 13.

OTHP

OH

1) n-BuLi, THF, −78 °C

Having synthesized several homoallylic sulfonamides of type I,

their conversion to the corresponding 1,6-ene-ynamides H was

achieved by metalation with KHMDS (toluene, 0 ^ꢀC) followed by

alkynylation with (trimethylsilylethynyl)phenyliodonium triﬂate

(34)²³(toluene, 0 ^ꢀC to rt) to provide compounds 35–40 in mod-

erate to good yields (48–86%) (Table 1).²⁴

then PhMe₂SiCl

2) TsOH (cat.)

MeOH, rt

I

SiMe₂Ph

74%

23

24

70%

PPh₃, DIAD

Phthalimide

THF, rt

The gold-catalyzed cycloisomerizations of these 1,6-ene-yn-

amides could then be investigated and an important goal was to

determine whether efﬁcient levels of 1,3- or 1,2-stereochemical

induction could be observed for substrates bearing a stereogenic

O

N

Ts

1) N₂H₄.H₂O

NH

EtOH, reflux

O

center at the

a or b position of the nitrogen atom, respectively.

2) TsCl, Py, rt

24%

SiMe₂Ph

26

25

2.2.2. Gold-catalyzed cycloisomerizations of 1,6-ene-ynamides

bearing substituents at the or position of the nitrogen atom

Scheme 11.

a

b

2.2.2.1. Cycloisomerization reactions. At ﬁrst, the 1,3-stereochemi-

cal induction was examined. Thus, ene-ynamide 35 was treated

with a catalytic amount of AuCl [(5–10 mol %), CH₂Cl₂, rt]. A slow

reaction took place (24–48 h) and analysis of the ¹H NMR spectrum

of the crude material indicated the formation of cyclobutanone 41

with high diastereoselectivity (dr >95:5).²⁵However, a slight ero-

sion of the diastereomeric purity was observed after puriﬁcation by

ﬂash chromatography on silica gel since cyclobutanone 41 was

isolated as an 88:12 mixture of epimers (77%).²⁶To conﬁrm this

result, the crude cyclobutanone 41 was not puriﬁed but directly

subjected to a Baeyer–Villiger reaction.¹²Under these conditions,

The isomeric sulfonamide bearing a (Z)-alkenyl silane was

synthesized from alkynylsilane 27.²⁰After hydroalumination with

DIBAL-H (hexanes/Et₂O, 0 ^ꢀC to rt)²¹and subsequent cleavage of the

THP ether, the (Z)-homoallylic alcohol 28 was obtained (46%, two

steps from 27).²⁰The latter compound was converted to the

homoallylic sulfonamide 30 as described previously (65%, three

steps from 28) (Scheme 12).

Finally, a sulfonamide possessing an

a,b-disubstituted alkene

and a stereogenic center at the position of the nitrogen atom was

a

prepared from the homoallylic sulfonamide 15. A cross-metathesis

with tert-butyl acrylate [Grubbs II catalyst (7.5 mol %), CH₂Cl₂,

the

>95:5) and isolated in 65% yield (two steps from 1,6-ene-ynamide

35). The relative conﬁguration of -lactone 42, and hence the one of

g-lactone 42 was obtained with high diastereoselectivity (dr

reﬂux] led to the a,b-unsaturated ester 31 (84%) as a single (E)-

isomer.²²Reduction of ester 31 to alcohol 32 (DIBAL-H, CH₂Cl₂,

ꢁ78 ^ꢀC to rt, 64%) followed by protection of the hydroxyl group as

a tert-butyldimethylsilyl ether (TBSCl, imidazole, DMF, rt) provided

the homoallylic sulfonamide 33 (99%) (Scheme 13).

g

cyclobutanone 41 from which it has been obtained by a stereospe-

ciﬁc Baeyer–Villiger reaction (retention of conﬁguration at the

migrating center),¹²was ascertained by chemical correlation (see

S. Couty et al. / Tetrahedron 65 (2009) 1809–1832

1813

Table 1

Ts

N

1) AuCl (5 mol %)

CH₂Cl₂, rt

O

Preparation of substituted 1,6-ene-ynamides H

Ts

TMS

NH

Ph

Ts

2) Chromatography

(SiO₂)

NH

N

TMS

R⁴

Ph

R¹

R³

R¹

R³

R⁵

1) KHMDS, toluene, 0 °C

35

41 (dr = 88:12)

77%

Ph

R²

R⁴

R²

2)

I

TMS

Ts

O

R⁵

TfO

34

N

1) AuCl (10 mol %)

Ts

NH

O

0 °C to rt

Ph

2) AcOOH, AcONa

AcOH, rt

Ph

Sulfonamides I

Ynamides H

Yield (%)

65%

35

42 (dr > 95:5)

(two steps from 35)

Ts

NH

N

TMS

Ts

Ph

60

63

48

O

AcOOH

AcONa

AuCl

O

N

Ts

NH

(10 mol %)

NH

O

15

35

O

MeO

O

AcOH

67%

CH₂Cl₂

65%

Ts

43

44

OMe

(dr = 95:5)

45

NH

N

TMS

OMe

(dr = 95:5)

Scheme 14.

BnO

Ts

36

22

Ts

NH

N

TMS

reactive catalyst (Ph₃P)AuSbF₆[generated from (Ph₃P)AuCl

(5 mol %) and AgSbF₆(5 mol %)] enabled to improve the isolated

yields of cyclobutanone 46 (55% and 47%, respectively).²⁸The ob-

served diastereoselectivity was satisfactory (dr¼90:10) although

SiMe₂Ph

TMS

26

37

Ts

slightly lower than for substrates substituted at the a position of the

NH

N

nitrogen atom. Finally, a gold-catalyzed cycloisomerization and

Baeyer–Villiger oxidation two-step sequence, without puriﬁcation

of the intermediate cyclobutanone 46, afforded

86

g

-lactone 47 in 56%

PhMe₂Si

overall yield (Scheme 15).

30

38

Ts

N

O

Ts

TMS

NH

N

TMS

Gold catalyst

CH₂Cl₂, rt

Ph

50

67

BnO

33

39

BnO

36

46 (dr = 90:10)

OTBS

TMS

OTBS

AuCl (5 mol %)

AuCl (20 mol %)

(Ph₃P)AuSbF₆(5 mol %)

35%

55%

47%

Ts

NH

N

Ph

O

1) AuCl (15 mol %)

CH₂Cl₂, rt

N

TMS

Ts

16

40

NH

2) AcOOH, AcONa

AcOH, rt

BnO

36

47 (dr = 90:10)

56%

BnO

Section 4.6.3). The observed sense of 1,3-stereochemical induction

in the gold-catalyzed cycloisomerizations of 1,6-ene-ynamides

(two steps from 36)

Scheme 15.

substituted at the

a position of the nitrogen atom was also later

conﬁrmed with substrates bearing a propargylic alcohol (Section

2.3.2). To highlight the functional group tolerance of the gold-

catalyzed cycloisomerizations, the known terminal ene-ynamide

43 was also prepared²⁷and treated with a catalytic amount of AuCl

[(10 mol %), CH₂Cl₂, rt]. Cyclobutanone 44 was obtained with high

diastereoselectivity (dr¼95:5) and isolated in 65% yield. Subsequent

Baeyer–Villiger oxidation of cyclobutanone 44 provided the

Thus, the gold-catalyzed cycloisomerizations of substituted 1,6-

ene-ynamides occurred with synthetically useful levels of diastereo-

selectivity (dr¼90:10 to >95:5). The observed sense of 1,3- and

1,2-induction in the case of 1,6-ene-ynamides of type H1 and H2,

respectively, indicates that the three-membered ring in the gold

cyclopropylcarbene intermediates is predominantly formed anti to

the substituent on the chain, leading after ring-expansion, deme-

talation, and hydrolysis to cyclobutanone of type G1 and G2

(Scheme 16).

functionalized

high diastereoselectivity of the gold-catalyzed cycloisomerization of

ene-ynamides bearing a stereogenic center at the position of the-

g-lactone 45 (67%). This result conﬁrmed the

a

nitrogen atom whatever the substituent (Ph or CO₂Me) (Scheme 14).

In order to evaluate the 1,2-stereochemical induction, the gold-

catalyzed cycloisomerization of ene-ynamide 36, bearing a stereo-

2.2.2.2. Interpretation of the diastereoselectivity. The formation of

the different possible products in the noble metal-catalyzed

cycloisomerization of ene-ynes has been well rationalized on the

basis of mechanisms involving metal cyclopropylcarbene in-

termediates.^3,4Nevertheless, as pointed out in a recent article, the

reactive intermediates in the gold-catalyzed cycloisomerization of

enynes should rather be considered as gold-stabilized carboca-

tions.²⁹To explain the diastereoselectivity of the gold-catalyzed

reactions of substituted 1,6-ene-ynamides, we indeed considered

center at the

b position of the nitrogen, was investigated. A slow

reaction was observed under standard conditions [AuCl (5 mol %),

CH₂Cl₂, rt, 48 h] and cyclobutanone 46 was isolated in low yield

(35%). The steric hindrance around the oleﬁnic moiety may slow

down its attack on the ynamide activated by the gold catalyst. In-

creasing the loading of AuCl (20 mol %) or the use of the more

1814

S. Couty et al. / Tetrahedron 65 (2009) 1809–1832

Ts

The cycloisomerizations of 1,6-ene-ynamides bearing a di-

substituted alkene was next investigated.

Ts

H

Ts

N

AuCl

R

O

N

R

NH

R¹

AuCl

R¹

α

R¹

H

2.2.3. Cycloisomerizations of 1,6-ene-ynamides possessing

a disubstituted alkene

H

H1

G1

R = H or TMS

The gold-catalyzed cycloisomerization of ene-ynamides 37 and

38, bearing a (E)- or a (Z)-alkenyl silane, respectively, was then

studied. A high catalyst loading [AuCl (25–30 mol %), CH₂Cl₂, rt] was

required for those substrates due to the steric hindrance brought by

the phenyldimethylsilyl group. Side-products were also formed but

their structure could not be unambiguously determined. Under

those conditions, ynamide 37 led to a 75:25 inseparable mixture of

O

R

N

Ts

AuCl

R

Ts

NH

N

R

AuCl

β

R²

G2

R²

H2

H

Scheme 16.

the expected cyclobutanone 48 and the b

-silylenone 49 (46%).³¹

The cycloisomerization of ynamide 38, possessing a (Z)-alkenyl si-

lane, produced cyclobutanone 51 in 47% yield. Cyclobutanones 48

and 51 were obtained in each reaction with high diastereo-

selectivity (dr >95:5), indicating that the gold-catalyzed cyclo-

isomerization involves a stereospeciﬁc process. The Baeyer–Villiger

oxidation of cyclobutanones 48 and 51 led to the diastereomeric

lactones 50 (57%) and 52 (62%), respectively, whose relative con-

ﬁgurations were ascertained by a chemical correlation (see Section

4.6.3). Additionally, the possibility of carrying out a gold-catalyzed

cycloisomerization followed by one-pot Baeyer–Villiger and

Tamao–Fleming oxidation reactions¹⁷was examined with ene-

ynamide 38. This could be achieved by simply adding KBr in the

an analogy with cationic cyclizations involving N-acyliminium

ions.³⁰Thus, a cyclic chair-like transition state may be considered

wherein a

p-complex is formed between the alkene and the de-

veloping nitrogen-stabilized vinylic carbocation, generated upon

coordination of the gold catalyst to the alkyne. Thus, for 1,6-ene-

ynamides H2 bearing a substituent at the

b position of the nitrogen

atom, cyclization should occur faster through the reactive con-

former N compared to O, as the R²substituent should preferentially

occupy a pseudo-equatorial position. This hypothesis would effec-

tively explain the formation of cyclobutanones G2 as the major

diastereomers. For 1,6-ene-ynamides H1 bearing a substituent at

presence of AcOOH during the oxidation step¹⁷and the

-substituted lactone 53 was obtained (26%) but no attempt was

made to improve the overall yield of this sequence (Scheme 18).

b-hydroxy-

the

a position of the nitrogen atom, the diastereoselective forma-

g

tion of cyclobutanones of type G1 suggested that cyclization should

be faster through the reactive conformer P than through conformer

Q. This result is in agreement with the literature precedents on

cationic cyclization involving N-acyliminium cations.³⁰Indeed, the

R¹substituent should preferentially occupy an axial position in the

cyclic transition state to avoid a severe gauche interaction with

the substituent on the nitrogen atom (tosyl group). Stabilization of

the developing carbocation by the nitrogen should further enhance

this interaction, which becomes similar to A^1,2strain (Scheme 17).

Ts

O

SiMe₂Ph

NH

Ts

TMS

49

N

+

O

AuCl (25 mol %)

Ts

NH

CH₂Cl₂, rt

46%

SiMe₂Ph

37

(48/49 = 75:25)

48 (dr > 95:5)

AcOOH

57%

O

AcONa, AcOH, rt

ClAu

H

AuCl

Ts

H

Ts

H

Ts

H

R

H

R

H

NH

O

N

R

N

Ts

H

AuCl

β

R²

SiMe₂Ph

50 (dr > 95:5)

Ts

R²

H

TMS

N

H2

N

O

R = H or TMS

O

Favored

Ts

Disfavored

AuCl (30 mol %)

NH

CH₂Cl₂, rt

47%

1) AuCl (30 mol %), CH₂Cl₂

2) AcOOH, AcONa, KBr

PhMe₂Si

38

SiMe₂Ph

51 (dr > 95:5)

Ts

N

Ts

N

AuCl

R

AuCl

R

O

Ts

NH

AcOOH

26%

62%

O

AcONa, AcOH, rt

H

AcOH, rt

O

R²

H

G2

Ts

gauche

ClAu

NH

NH O

interaction

AuCl

H

Ts

H

R

N

R

N

R¹

R

H

Ts

OH

SiMe₂Ph

52 (dr > 95:5)

N

R¹

AuCl

H

53 (dr > 95:5)

H

α

R¹

Scheme 18.

H

H1

P

Q

H

The cycloisomerization of ene-ynamide 39 bearing both a ster-

eogenic center at the position of the nitrogen atom and an

-disubstituted alkene proceeded smoothly by treatment with

AuCl [(5–10 mol %), CH₂Cl₂, rt] and afforded cyclobutanone 54 as

a single diastereomer (55%). When this compound was not puriﬁed

but directly engaged in a Baeyer–Villiger oxidation, the corre-

Favored

Disfavored

a

a,b

Ts

H

O

Ts

N

Ts

N

AuCl

R

AuCl

R

NH

R¹

H

G1

H

sponding disubstituted g-lactone 55 was isolated (46%, two steps

from 39) (Scheme 19).

Scheme 17.

S. Couty et al. / Tetrahedron 65 (2009) 1809–1832

1815

Ts

AuCl

Ts

N

Ts

N

OH

R

OH

R

N

TMS

O

Ts

R¹

R²

AuCl (5-10 mol %)

NH

AuCl (cat.)

Ph

R¹

H

CH₂Cl₂, rt

55%

OTBS

Ph

R²

H

R

S

39

54 (dr > 95:5)

OTBS

TMS

1,2-hydride shift

O

Ts

1) AuCl (5 mol %)

CH₂Cl₂, rt

NH

O

AuCl

Ts

N

Ts

N

O

Ph

H

R¹

R²

R¹

AuCl

Ph

2) AcOOH, AcONa

AcOH, rt

R

OTBS

55 (dr > 95:5)

OTBS

R²

39

H

46%

H

T

Scheme 19.

Scheme 21.

The gold-catalyzed cycloisomerization of ene-ynamide 40,

possessing an -disubstituted alkene, was ﬁnally examined. The

a,a

a terminal ynamide. However, metalation of ynamide 1 with

LiHMDS (THF, 0 ^ꢀC) followed by addition of paraformaldehyde

(0–50 ^ꢀC) led to the disubstituted ynamide 59 in low yield (28%).

Indeed, direct metalation of terminal ynamides is not efﬁcient for

the generation of the corresponding lithium alkynylides³²

but generation of such species is best achieved by treatment of

reaction led to an 80:20 equilibrium mixture of the bicyclic hemi-

aminal 56 and the cyclobutanone 57 (single diastereomers, 52%). It

is worth noting that the formation of bicyclic hemiaminals was also

observed in some platinum-catalyzed cycloisomerizations of 1,7-

ene-ynamides bearing an

Baeyer–Villiger oxidation of the mixture of compounds 56 and 57

a,a

-disubstituted double bond.⁸The

N-(b,b

-dichlorovinyl)enamides with n-BuLi (2 equiv, THF, ꢁ78 ^ꢀC to

ꢁ40 ^ꢀC).^32,33These conditions were applied to

b,b-dichloro-

proceeded extremely slowly and afforded

yield (52%) (Scheme 20).

g-lactone 58 in modest

enamide 60 and after addition of acetaldehyde or iso-

butyraldehyde, the secondary propargylic alcohols 61 (67%) and 62

(90%) were obtained, respectively (Scheme 22).

Ts

N

OH

Ph

Ts

OH

Ts

O

N

TMS

AuCl

Ts

AcOOH

AcONa

N

1) LiHMDS, THF, 0 °C

NH

O

(15 mol %)

Ph

56

2) (HCHO)_n, 0 °C to 50 °C

CH₂Cl₂, rt

52%

AcOH, rt

52%

O

+

Ph

28%

58

40

Ts

1

59

NH

Cl

Ph

1) n-BuLi (2 equiv)

THF, 78 °C to 40 °C

OH

R

Cl

57

(56:57 = 80:20)

Scheme 20.

2) RCHO, 40 °C to 0 °C

Thus, the gold-catalyzed cycloisomerization of 1,6-ene-

ynamides bearing substituents on the alkene can lead to cyclo-

67%

90%

R = Me

R = i-Pr

61

62

60

butanones and g-lactones possessing a quaternary center.

Scheme 22.

2.3. Cycloisomerizations of 1,6-ene-ynamides possessing

a propargylic alcohol moiety

A straightforward access to ene-ynamides of type R was also

achieved by a copper-catalyzed cross-coupling between various

sulfonamides³⁴and bromoalkyne 63 derived from propargyl alco-

hol [CuSO₄$5H₂O (10 mol %), 1,10-phenanthroline (20 mol %),

K₂CO₃, toluene, 65–90 ^ꢀC].^35,36The corresponding disubstituted

ynamides underwent subsequent deprotection of the alcohol

(n-Bu₄NF, THF, 0 ^ꢀC) to afford the 1,6-ene-ynamides 59, 66–68,

bearing a propargylic alcohol moiety (28–87% overall yield) (Table 2).

In the preceding examples of gold-catalyzed cycloisomerization

of ene-ynamides, the putative intermediate cyclobutenamides, that

may have potentially been interesting building blocks for the for-

mation of nitrogen heterocycles, could not be isolated due to their

sensitivity toward moisture. The key reactive intermediate in the

gold-catalyzed cycloisomerization of ene-ynamides contains

a substituted 2,3-methanopyrrolidine subunit that would be in-

teresting to keep in the ﬁnal products. The reactivity of 1,6-ene-

ynamides of type R bearing a propargylic alcohol moiety was thus

examined. For those substrates, by analogy with the behavior of

2.3.2. Cycloisomerization reactions

The ene-ynamide 59, bearing a primary propargylic alcohol,

reacted rapidly in the presence of AuCl [(5 mol %), CH₂Cl₂, rt] and

afforded aldehyde 69 (40%), possessing a 2,3-methanopyrrolidine

subunit. The ene-ynamides 61 and 62, bearing a secondary prop-

argylic alcohol, also led to clean reactions and the corresponding

ketones 70 and 71 were isolated in 60% and 42% yield, respectively.

As expected, the gold-catalyzed cycloisomerization of 1,6-ene-

non-heterosubstituted enynes bearing

a propargylic alcohol

moiety,^4jthe corresponding gold cyclopropylcarbenes S should

undergo a rapid 1,2-hydride shift leading, after demetalation, to

carbonyl compounds of type T bearing a 2,3-methanopyrrolidine

subunit (Scheme 21).

ynamides 66 and 67, substituted at the

a position of the nitrogen

Thus, the preparation of ene-ynamides of type R was carried out

to examine their reactivity in the presence of gold catalysts.

atom, proceeded with high diastereoselectivity (dr >95:5) and

provided aldehydes 72 (61%) and 73 (51%). In agreement with the

results observed for the related trimethylsilyl ene-ynamides, ene-

2.3.1. Preparation of the substrates

The simplest route toward ene-ynamides of type R appeared to

involve the functionalization of a lithium alkynylide derived from

ynamide 68, which is substituted at the

atom, underwent gold-catalyzed cycloisomerization with

slightly lower but appreciable level of diastereoselection

b position of the nitrogen

a

1816

S. Couty et al. / Tetrahedron 65 (2009) 1809–1832

Table 2

Table 3

Preparation of ynamides of type R

Gold-catalyzed cycloisomerization of ene-ynamides of type R

OTBDPS

Ts

N

Ts

OH

R

O

1)

Br

N

R¹

R²

AuCl (5 mol %)

CH₂Cl₂, rt

R¹

63

Ts

OH

R

CuSO₄.5H₂O (10 mol %)

1,10-phenanthroline (20 mol %)

K₂CO₃(2 equiv), toluene, 65-90°C

2) n-Bu₄NF, THF, 0 °C

NH

N

R²

R¹

H

R²

Ene-ynamides R

Ts OH

Products

Yield (%)

Ts

N

O

Sulfonamides

Ene-ynamides R

Yield (%)

N

R

Ts

OH

NH

N

H

66

59 R¼H

69 R¼H

40

60

42

61 R¼Me

62 R¼i-Pr

70 R¼Me

71 R¼i-Pr

64

59

Ts

NH

Ts

OH

Ts

N

OH

R

Ts

N

O

55

28

Ph

61

51

H

66

Ts

15

H

Ts

OH

72

66

BnO

NH

BnO

N

Ts

N

Ts

OH

O

BnO

N

65

67

BnO

H

Ts

OH

Ts

67

73

NH

N

87

Ts

N

Ts

OH

BnO

N

BnO

22

68

60^a

BnO

H

BnO

a

68

74

(dr¼90:10). The resulting aldehyde, which partially decomposed

when puriﬁcation by chromatography on silica gel was attempted,

was immediately reduced (NaBH₄, MeOH, rt) to provide the pri-

mary alcohol 74 in 60% yield. The relative conﬁguration of com-

pounds 72 and 74 was unambiguously ascertained by NMR (NOESY

correlations, see Section 4.8) (Table 3).

a

The intermediate aldehyde was reduced (NaBH₄, MeOH, rt).

t¼CH₂, q¼CH₃). Mass spectra with electronic impact (MS-EI) were

recorded from a Hewlett–Packard tandem 5890A GC (12 m capil-

lary column)d5971 MS (70 eV). THF and diethyl ether were dis-

tilled from sodium/benzophenone. CH₂Cl₂, CH₃CN, toluene, Et₃N,

i-Pr₂NH were distilled from CaH₂. Other reagents were obtained

from commercial suppliers and used as received. TLC was per-

formed on silica gel plates and visualized either with a UV lamp

(254 nm), or by using solutions of p-anisaldehyde/H₂SO₄/AcOH in

EtOH or KMnO₄/K₂CO₃in water followed by heating. Flash chro-

matography was performed on silica gel (230–400 mesh).

3. Conclusion

The gold-catalyzed cycloisomerizations of 1,6-ene-ynamides

can provide access to cyclobutanones if the ynamide is terminal or

substituted by a trimethylsilyl group. Alternatively, from ynamides

possessing a propargylic alcohol moiety, aldehydes or ketones

bearing

a 2,3-methanopyrrolidine subunit can be efﬁciently

synthesized. Particularly noteworthy are the high 1,3- or 1,2-

diastereoselectivities observed with substrates bearing a stereo-

4.2. Preliminary investigations

center at the

a or b position of the nitrogen atom.

The terminal ene-ynamides 1 and 3 were synthesized as

described in the literature,^8,9whereas the trimethylsilyl ene-

ynamides 8 and 9 were prepared by alkynylation of the corre-

sponding sulfonamides.

4. Experimental section

4.1. General procedures

4.2.1. N-(But-3-enyl)-4-methyl-N-(trimethylsilylethynyl)-

Infrared (IR) spectra were recorded on a Bruker Tensor 27 (IR-

benzenesulfonamide (8)

FT), wavenumbers are indicated in cm^ꢁ1

.

¹H NMR spectra were

To a solution of N-(but-3-enyl)-4-methylbenzenesulfonamide^8,9

(3.08 g, 13.7 mmol) in toluene (150 mL) at 0 ^ꢀC was added KHMDS

(30.2 mL, 0.5 M in toluene, 15.1 mmol, 1.1 equiv). After 2 h at 0 ^ꢀC,

(trimethylsilylethynyl)phenyliodonium triﬂate (34) (7.40 g,

16.4 mmol, 1.2 equiv) was added portionwise. After 24 h at rt, the

reaction mixture was ﬁltered through Celite (toluene/Et₂O: 80:20).

The ﬁltrate was evaporated under reduced pressure and the crude

material was puriﬁed by ﬂash chromatography (petroleum ether/

EtOAc 95:5, 90:10) to afford 3.43 g (78%) of 8 as a pale yellow solid.

(C₁₆H₂₃NO₂SSi, MW¼321.51 g mol^ꢁ1). Mp 53–55 ^ꢀC; IR 2155, 1590,

recorded on a Bruker Avance 400 (400 MHz) and data are reported

as follows: chemical shift in parts per million from tetramethylsi-

lane as an internal standard, multiplicity (s¼singlet, d¼doublet,

t¼triplet, q¼quartet, m¼multiplet or overlap of non-equivalent

resonances), integration. ¹³C NMR spectra were recorded in CDCl₃

at 75 or 100 MHz and data are reported as follows: chemical shift in

parts per million from tetramethylsilane with the solvent as an

internal indicator (CDCl₃,

d 77.0 ppm), multiplicity with respect to

proton (deduced from DEPT experiments, s¼quaternary C, d¼CH,

S. Couty et al. / Tetrahedron 65 (2009) 1809–1832

1817

1365, 1245, 1165, 1085, 910, 840, 755, 730, 660 cm^ꢁ1

(CDCl₃)

;

¹H NMR

0.024 mmol, 0.1 equiv). After 3 h of vigorous stirring at rt, the re-

action mixture was diluted with EtOAc and H₂O, the layers were

separated, and the aqueous phase was extracted with EtOAc. The

combined extracts were dried over MgSO₄, ﬁltered, and concen-

trated under reduced pressure. The crude material was puriﬁed by

preparative TLC on a silica gel plate (pentane/EtOAc 60:40) to

d

7.79 (d, J¼8.3 Hz, 2H), 7.34 (d, J¼8.3 Hz, 2H), 5.70 (ddt,

J¼16.9, 10.3, 6.6 Hz, 1H), 5.08 (dq, J¼16.9, 1.5 Hz, 1H), 5.03 (dq,

J¼10.3, 1.5 Hz, 1H), 3.36 (t, J¼7.4 Hz, 2H), 2.45 (s, 3H), 2.41–2.33 (m,

2H), 0.16 (s, 9H); ¹³C NMR (CDCl₃)

d 144.5 (s), 134.5 (s), 133.6 (d),

129.5 (d, 2C), 128.1 (d, 2C), 117.5 (t), 94.8 (s), 73.5 (s), 50.5 (t), 32.0

(t), 21.5 (q), 0.0 (q, 3C); MS-EI m/z (relative intensity) 321 (M^þ, 1),

256 (29),166 (77),164 (23),155 (30),150 (22),149 (33),139 (25),110

(37), 91 (77), 84 (23), 73 (100), 59 (29), 55 (29). Anal. Calcd for

C₁₆H₂₃NO₂SSi: C, 59.77; H, 7.21; N, 4.36. Found: C, 59.81; H, 7.37; N,

4.28.

afford 34 mg (52%) of 6⁰as

a colorless oil (C₁₃H₁₅D₂NO₃S,

MW¼269.36 g mol^ꢁ1). ¹H NMR (CDCl₃)

7.74 (d, J¼8.3 Hz, 2H), 7.30

d

(d, J¼8.3 Hz, 2H), 5.17 (br t, J¼6.0 Hz, 1H, NH), 3.27 (dddd, apparent

dq, J¼10.7, 7.9 Hz, 1H), 3.14–3.06 (m, 1H), 2.98–2.89 (m, 1H), 2.43 (s,

3H), 2.19 (dd, apparent br t, J¼10.7 Hz, 1H), 1.83–1.67 (m, 2H), 1.62–

1.58 (m, 1H); ¹³C NMR (CDCl₃)

d 211.5 (s), 143.3 (s), 137.0 (s), 129.7

4.2.2. Benzyl N-(but-3-enyl)-N-(trimethylsilylethynyl)-

carbamate (9)

(d, 2C), 127.0 (d, 2C), 58.2 (d), 44.1 (CD₂, barely visible signal), 41.4

(t), 29.4 (t), 21.5 (q), 16.5 (t).

To a solution of benzyl N-(but-3-enyl)carbamate³⁷(731 mg,

3.61 mmol) in toluene (45 mL) at 0 ^ꢀC was added KHMDS (8.54 mL,

0.5 M in toluene, 4.27 mmol, 1.2 equiv). After 1 h at 0 ^ꢀC, (trimethyl

silylethynyl)phenyliodonium triﬂate (34) (2.11 g, 4.69 mmol,

1.3 equiv) was added. After 24 h at rt, the reaction mixture was

ﬁltered through Celite (toluene/Et₂O 80:20). The ﬁltrate was

evaporated under reduced pressure and the crude material

was puriﬁed by ﬂash chromatography (petroleum ether/EtOAc

gradient 98:2 to 90:10) to afford 120 mg (11%) of 9 as a yellow oil

(C₁₇H₂₃NO₂Si, MW¼301.46 g mol^ꢁ1). IR 2174, 1726, 1642, 1391,

4.2.5. 4-Methyl-N-[2-(5-oxotetrahydrofuran-2-yl)ethyl]-

benzenesulfonamide (7)

To a solution of cyclobutanone 6 (110 mg, 0.412 mmol) in AcOH

(3 mL) were added AcONa$3H₂O (67 mg, 0.49 mmol, 1.2 equiv) and

a solution of AcOOH (0.35 mL, 32% in AcOH, 1.6 mmol, 4 equiv).

After 2 h at rt, the reaction mixture was cooled in an ice-bath and

hydrolyzed with a 25% aqueous solution of Na₂S₂O₃. After addition

of water and extraction with CH₂Cl₂, the combined organic extracts

were dried over MgSO₄, ﬁltered, and concentrated under reduced

pressure. The crude material was puriﬁed by ﬂash chromatography

(petroleum ether/EtOAc gradient 50:50 to 30:70) to afford

1275, 1248, 1210, 1149, 916, 838, 757, 734, 695, 616 cm^ꢁ^{1 1}H NMR

;

(CDCl₃)

d

7.41–7.30 (m, 5H), 5.78 (ddt, J¼17.1, 10.2, 6.9 Hz, 1H), 5.22

(s, 2H), 5.13 (dd, J¼17.1,1.3 Hz,1H), 5.06 (br d, J¼10.2 Hz,1H), 3.78 (t,

89 mg (77%) of 7 as a viscous colorless oil (C₁₃H₁₇NO₄S,

J¼7.2 Hz, 2H), 2.44 (td, apparent q, J¼7.0 Hz, 2H), 0.19 (s, 9H); ¹³C

MW¼283.34 g mol^ꢁ1). IR 3265, 1760, 1597, 1324, 1189, 1152, 1091,

NMR (CDCl₃)

d

155.2 (s), 135.6 (s), 134.1 (d), 128.4 (d, 2C), 128.0 (d,

1069, 917, 814, 660 cm^ꢁ1; ¹H NMR (CDCl₃)

d

7.73 (d, J¼8.1 Hz, 2H),

2C),127.3 (d),117.4 (t), 95.3 (s), 72.8 (s), 68.2 (t), 48.9 (t), 31.9 (t), 0.15

(q, 3C); MS-EI m/z (relative intensity) 301 (M^þ, 1), 256 (6), 242 (5),

184 (4), 168 (4), 167 (14), 110 (6), 92 (9), 91 (100), 73 (8), 65 (6), 55

(4). Anal. Calcd for C₁₇H₂₃NO₂Si: C, 67.73; H, 7.69; N, 4.65. Found: C,

67.67; H, 7.51; N, 4.62.

7.30 (d, J¼8.1 Hz, 2H), 5.46 (t, J¼6.2 Hz, 1H, NH), 4.55 (m, 1H), 3.10–

3.02 (m, 2H), 2.52–2.48 (m, 2H), 2.42 (s, 3H), 2.36–2.30 (m, 1H),

1.90–1.78 (m, 3H); ¹³C NMR (CDCl₃)

d 177.0 (s), 143.4 (s), 136.4 (s),

129.7 (d, 2C),126.9 (d, 2C), 78.4 (d), 39.8 (t), 35.4 (t), 28.5 (t), 27.8 (t),

21.5 (q); MS-EI m/z (relative intensity) 283 (M^þ, 14), 219 (4), 184

(57), 155 (100), 128 (13), 92 (9), 91 (82), 85 (11), 65 (17).

4.2.3. 4-Methyl-N-[2-(2-oxocyclobutyl)ethyl]benzene-

sulfonamide (6)

4.2.6. Benzyl N-[2-(2-oxocyclobutyl)ethyl]carbamate (10)

To a solution of ynamide 1 (90 mg, 0.36 mmol) in CH₂Cl₂(3 mL)

was added AuCl (4 mg, 0.02 mmol, 0.05 equiv). After 1 h at rt, the

reaction mixture was ﬁltered through Celite (CH₂Cl₂) and the ﬁl-

trate was evaporated under reduced pressure. The crude material

was puriﬁed by ﬂash chromatography (petroleum ether/EtOAc

70:30þ0.5% Et₃N) to afford 48 mg (50%) of 6 as a pale yellow oil.

This compound can also be prepared from the trimethylsilyl-1,6-

ene-ynamide 8 (100 mg, 0.311 mmol) by treatment with AuCl

(3.8 mg, 0.016 mmol, 0.05 equiv) in CH₂Cl₂(3 mL) (16 h, rt). After

the same work-up as described above, puriﬁcation by ﬂash chro-

matography (petroleum ether/EtOAc 70:30þ0.5% Et₃N), 53 mg

(61%) of 6 was obtained as a yellow oil. Compound 6 was obtained

in similar yield if a hydrolytic work-up with a 1 M solution of

hydrochloric was used, followed by extraction (EtOAc) and drying

(MgSO₄) (C₁₃H₁₇NO₃S, MW¼267.34 g mol^ꢁ1). IR 3278, 1773, 1598,

This compound was prepared by treatment of ynamide 9

(62 mg, 0.20 mmol) with AuCl (7 mg, 0.03 mmol, 0.15 equiv) in

CH₂Cl₂(3 mL). After 48 h at rt, work-up and puriﬁcation by ﬂash

chromatography (petroleum ether/EtOAc gradient 80:20 to 70:30)

gave 29 mg (59%) of 10 as

a colorless oil (C₁₄H₁₇NO₃,

MW¼247.29 g mol^ꢁ1). IR 3337, 1773, 1698, 1525, 1454, 1242, 1135,

1088, 1026, 775, 735, 697 cm^ꢁ^{1 1}H NMR (CDCl₃)

; d 7.37–7.27 (m,

5H), 5.21 (m, apparent br s, 1H, NH), 5.09 (br s, 2H), 3.37–3.26 (m,

2H), 3.24–3.16 (m, 1H), 3.10–3.00 (m, 1H), 2.95–2.86 (m, 1H), 2.21

(apparent qd, J¼10.6, 5.0 Hz, 1H), 1.88–1.62 (m, 3H); ¹³C NMR

(CDCl₃)

d 211.5 (s), 156.4 (s), 136.6 (s), 128.4 (2d, 3C), 128.0 (d, 2C),

66.5 (t), 58.3 (d), 44.4 (t), 39.1 (t), 29.7 (t), 16.7 (t); MS-EI m/z

(relative intensity) 219 (MꢁC₂H^þ₄, 1), 128 (6), 111 (25), 108 (30), 107

(20), 92 (9), 91 (100), 79 (28), 77 (18), 69 (5), 65 (8), 56 (12), 55 (26),

51 (7). Anal. Calcd for C₁₄H₁₇NO₃: C, 68.00; H, 6.93; N, 5.66. Found:

C, 67.89; H, 7.02; N, 5.57.

1428, 1325, 1156, 1091, 816, 662 cm^ꢁ^{1 1}H NMR (CDCl₃)

; d 7.74 (d,

J¼8.3 Hz, 2H), 7.30 (d, J¼8.3 Hz, 2H), 5.17 (br t, J¼6.0 Hz, 1H, NH),

3.33–3.22 (m, 1H), 3.14–3.00 (m, 2H), 2.98–2.84 (m, 2H), 2.43 (s,

3H), 2.19 (dddd, apparent qd, J¼10.7, 4.8 Hz, 1H), 1.83–1.67 (m, 2H),

4.3. Preparation of sulfonamides of type I

1.66–1.57 (m, 1H); ¹³C NMR (CDCl₃)

d

211.5 (s), 143.3 (s), 137.0 (s),

4.3.1. 4-Methyl-N-(1-phenylbut-3-enyl)benzenesulfonamide (15)³⁷

To a solution of N-tosylbenzaldimine (14)³⁸(3.00 g, 11.6 mmol)

in THF (20 mL) at ꢁ10 ^ꢀC was added allylmagnesium chloride

(8.70 mL, 2 M in THF, 17.4 mmol, 1.5 equiv). After 2 h at 0 ^ꢀC, the

reaction mixture was poured into a saturated aqueous solution of

NH₄Cl and extracted with EtOAc. The combined organic extracts

were successively washed with H₂O and brine, dried over MgSO₄,

ﬁltered, and concentrated under reduced pressure. The residue was

puriﬁed by ﬂash chromatography on silica gel (petroleum ether/

EtOAc 70:30) to afford 2.78 g (80%) of 15 as white crystals

129.7 (d, 2C),127.0 (d, 2C), 58.2 (d), 44.3 (t), 41.4 (t), 29.4 (t), 21.5 (q),

16.5 (t); MS-EI m/z (relative intensity) 239 (MꢁC₂H^þ₄, 29), 184 (50),

157 (6), 156 (9), 155 (100), 132 (8), 112 (13), 92 (10), 91 (86), 77 (9),

65 (19), 55 (10).

4.2.4. 4-Methyl-N-[2-(3,3-dideuterio-2-oxocyclobutyl)-

ethyl]benzenesulfonamide (6⁰)

To a solution of ynamide 8 (78 mg, 0.24 mmol) in CH₂Cl₂(2 mL)

were added D₂O (110 mL, 6.0 mmol, 25 equiv) and AuCl (5.6 mg,

1818

S. Couty et al. / Tetrahedron 65 (2009) 1809–1832

(C₁₇H₁₉NO₂S, MW¼301.40 g mol^ꢁ1). Mp 77–78 ^ꢀC; IR 3260, 1595,

2-Benzyloxybut-3-enylamine (free amine derived from hydro-

chloride 21): A sample of 21 was treated with a 15% aqueous NaOH

solution. After extraction with Et₂O, the combined extracts were

dried over MgSO₄, ﬁltered, and concentrated under reduced pres-

sure to afford 2-benzyloxybut-3-enylamine as a colorless oil. ¹H

1420, 1320, 1155, 915, 810, 700, 665 cm^ꢁ^{1 1}H NMR

; d 7.57 (d,

J¼8.5 Hz, 2H), 7.19–7.06 (m, 7H), 5.60–5.46 (m, 1H), 5.30 (d,

J¼7.0 Hz, 1H, NH), 5.08–5.01 (m, 2H), 4.38 (apparent q, J¼7.0 Hz,

1H), 2.58–2.39 (m, 2H), 2.37 (s, 3H); ¹³C NMR

d 143.0 (s), 140.4 (s),

137.5 (s), 133.1 (d), 129.3 (d, 2C),128.3 (d, 2C), 127.3 (d), 127.1 (d, 2C),

126.6 (d, 2C), 119.0 (t), 57.3 (d), 41.8 (t), 21.4 (q); MS-EI m/z

(relative intensity) 301 (M^þ, 1), 261 (18), 260 (MꢁAllyl^þ, 100), 155

(56), 91 (71).

NMR (CDCl₃)

d

7.30–7.18 (m, 5H), 5.61 (ddd, J¼16.8, 11.0, 9.3 Hz, 1H),

5.09 (br d, J¼11.0 Hz, 1H), 5.08 (br d, J¼16.8 Hz, 1H), 4.44 (br s, 2H),

3.42 (dd, J¼9.2, 5.7 Hz, 1H), 3.47 (dd, J¼9.2, 6.9 Hz, 1H), 2.82 (dd,

J¼12.6, 4.8 Hz, 1H), 2.60 (dd, J¼12.6, 7.7 Hz, 1H), 2.39–2.30 (m, 1H),

1.48 (br s, 2H, NH₂); ¹³C NMR (CDCl₃)

d 138.4 (s), 128.4 (d, 2C), 137.8

4.3.2. 4-Methyl-N-(3-methyl-1-phenylbut-3-enyl)-

(d), 127.7 (2d, 3C), 117.3 (t), 73.1 (t), 71.8 (t), 47.5 (d), 43.4 (t).

To a solution of 21 (1.00 g, 4.39 mmol) in CH₂Cl₂(40 mL) at 0 ^ꢀC

were successively added Et₃N (1.1 mL, 8.8 mL, 2 equiv), DMAP

(54 mg, 0.44 mmol, 0.1 equiv), and TsCl (837 mg, 4.39 mmol,

1 equiv). After 1 h at rt, the reaction mixture was poured into a 1 M

solution of hydrochloric acid and extracted with CH₂Cl₂. The

combined organic extracts were washed with a saturated aqueous

solution of NaCl, dried over MgSO₄, ﬁltered, and concentrated un-

der reduced pressure. The residue was puriﬁed by ﬂash chroma-

tography on silica gel (petroleum ether/EtOAc 80:20 to 70:30) to

benzenesulfonamide (16)

To

a

solution of N-tosylbenzaldimine (14)³⁸(760 mg,

2.93 mmol) in THF (10 mL) at 0 ^ꢀC was slowly added meth-

allylmagnesium chloride (8.8 mL, 0.5 M in THF, 4.4 mmol,

1.5 equiv). After 1 h at 0 ^ꢀC, another quantity of methallyl-

magnesium chloride (8.8 mL,1.5 equiv) was added. After 1 h at 0 ^ꢀC,

the reaction mixture was poured into a saturated aqueous solution

of NH₄Cl and extracted with EtOAc. The combined organic extracts

were successively washed with H₂O and brine, dried over MgSO₄,

ﬁltered, and concentrated under reduced pressure. The residue was

puriﬁed by ﬂash chromatography on silica gel (toluene/i-PrOH

98:2) to afford 402 mg (43%) of 16 as white crystals (C₁₈H₂₁NO₂S,

MW¼315.43 g mol^ꢁ1). Mp 72 ^ꢀC; IR 3251, 1652, 1598, 1494, 1440,

provide 1.30 g (86%) of sulfonamide 22 as

a colorless oil

(C₁₉H₂₃NO₃S, MW¼345.46 g mol^ꢁ1). IR 3281, 1641, 1598, 1495,

1454, 1420, 1325, 1157, 1091, 995, 920, 813, 736, 698, 660 cm^ꢁ1; ¹H

NMR

d

7.73 (d, J¼8.3 Hz, 2H), 7.40–7.27 (m, 7H), 5.60 (ddd, J¼17.2,

1415,1320,1303,1289,1155,1085, 941, 891, 815, 757, 701, 667 cm^ꢁ1

;

10.5, 7.9 Hz, 1H), 5.13 (ddd, apparent dt, J¼10.4, 1.0 Hz, 1H), 5.09

(ddd, apparent dt, J¼17.4, 1.0 Hz, 1H), 5.01 (t, J¼6.2 Hz,1H, NH), 4.49

(d, AB syst, J¼12.0 Hz, 1H), 4.45 (d, AB syst, J¼12.0 Hz, 1H), 3.50 (dd,

J¼9.4, 4.8 Hz, 1H), 3.38 (dd, J¼9.4, 7.6 Hz, 1H), 3.15–3.09 (m, 1H),

¹H NMR

d

7.52 (d, J¼8.3 Hz, 2H), 7.20–7.09 (m, 7H), 4.87 (d,

J¼4.5 Hz, 1H, NH), 4.83 (apparent t, J¼1.5 Hz, 1H), 4.73 (apparent br

s, 1H), 4.37 (ddd, J¼8.0, 7.0, 4.5 Hz, 1H), 2.40–2.33 (m, 2H), 2.36 (s,

3H), 1.52 (s, 3H); ¹³C NMR

d

143.0 (s), 141.1 (s), 140.9 (s), 137.1 (s),

3.06–3.03 (m, 1H), 2.57–2.48 (m, 1H), 2.45 (s, 3H); ¹³C NMR

d 143.2

129.2 (d, 2C),128.3 (d, 2C),127.3 (d),127.2 (d, 2C),126.6 (d, 2C),115.2

(t), 55.5 (d), 46.7 (t), 21.5 (q), 21.4 (q); MS-EI m/z (relative intensity)

261 (17), 260 (MꢁMethallyl^þ,100),156 (5),155 (56),129 (6),104 (8),

92 (6), 91 (71), 77 (7), 65 (10).

(s), 137.7 (s), 136.9 (s), 135.5 (d), 129.6 (d, 2C), 128.4 (d, 2C),127.7 (d),

127.5 (d, 2C),127.0 (d, 2C),118.0 (t), 73.1 (t), 71.9 (t), 45.2 (t), 43.0 (d),

21.4 (q); MS-EI m/z (relative intensity) 254 (MꢁBn^þ, 1), 237

(MꢁBnOH^þ, 10), 190 (11), 184 (29), 155 (55), 108 (27), 107 (10), 92

(10), 91 (100), 82 (10), 65 (12), 54 (6).

4.3.3. N-(2-Benzyloxymethylbut-3-enyl)-4-methyl-

benzenesulfonamide (22)

To a solution of 17 (4.00 g, 22.4 mmol) in triethyl orthoacetate

(20.4 mL, 112 mmol, 5 equiv) was added propionic acid (170 mL,

4.3.4. (E)-4-(Dimethylphenylsilyl)but-3-en-1-ol (24)¹⁹

To a solution of (E)-alkenyl iodide 23¹⁸(812 mg, 2.88 mmol) in

THF (10 mL) at ꢁ78 ^ꢀC was added n-BuLi (1.27 mL, 2.5 M in hex-

anes, 3.17 mmol, 1.1 equiv). After 45 min at ꢁ78 ^ꢀC, chloro-

2.24 mmol, 0.1 equiv). The reaction mixture was slowly heated at

100 ^ꢀC while EtOH was distilled off. The temperature was increased

to 150 ^ꢀC and after 2 h, the reaction mixture was concentrated

under reduced pressure. The crude ester 18¹⁵was dissolved in

MeOH (25 mL) and KOH (2.52 g, 44.9 mmol, 2 equiv) was added.

After 4 h heating at reﬂux, the reaction mixture was cooled to rt,

diluted with H₂O, and extracted with Et₂O. The organic extracts

were discarded and the aqueous phase was acidiﬁed (pH <1) by

slow addition of 35% hydrochloric acid at 0 ^ꢀC. After extraction with

CH₂Cl₂, the combined organic extracts were dried over MgSO₄,

ﬁltered, and concentrated under reduced pressure to afford 4.00 g

(18.2 mmol) (81%) of the crude carboxylic acid 19 as a colorless oil,

which was dissolved in toluene (100 mL). To the resulting solution

at rt were added Et₃N (3.04 mL, 21.8 mmol, 1.2 equiv) and DPPA

(4.3 mL, 20 mmol, 1.1 equiv). After 1 h at rt, the reaction mixture

was heated at reﬂux for 2 h and cooled to rt. Half of the solvent was

evaporated under reduced pressure and the resulting solution of

isocyanate 20 was treated with a 30% aqueous solution of NaOH

(15 mL). After 2 h heating at reﬂux, the reaction mixture was cooled

to rt, diluted with water, and extracted with Et₂O. The combined

organic extracts were cooled to 0 ^ꢀC and acidiﬁed (pH <1) by ad-

dition of 35% hydrochloric acid. The organic layer was separated,

discarded, and the aqueous layer was evaporated under reduced

pressure. The residue was taken-up several times with absolute

EtOH and evaporated under reduced pressure to remove residual

water. The crude material was dried under reduced pressure to

afford 3.85 g (93%) of 2-benzyloxybut-3-enylamine hydrochloride

(21).

dimethylphenylsilane (580 mL, 3.45 mmol, 1.2 equiv) was added.

After 1 h at 0 ^ꢀC and 0.5 h at rt, the reaction mixture was hydrolyzed

with a saturated aqueous solution of NH₄Cl and diluted with Et₂O.

The layers were separated and the aqueous phase was extracted

with Et₂O. The combined organic extracts were washed with

a saturated aqueous solution of NaCl, dried over MgSO₄, ﬁltered,

and concentrated under reduced pressure. The residue was dis-

solved in MeOH (10 mL) and TsOH$H₂O (27 mg, 0.29 mmol,

0.05 equiv) was added. After 3 h at rt, the reaction mixture was

neutralized by addition of a few drops of a saturated aqueous so-

lution of NaHCO₃and evaporated under reduced pressure. The

residue was partitioned between H₂O and Et₂O, the layers were

separated, and the aqueous phase was extracted with Et₂O. The

combined organic extracts were washed with brine, dried over

MgSO₄, ﬁltered, and concentrated under reduced pressure. The

residue was puriﬁed by ﬂash chromatography on silica gel (petro-

leum ether/toluene/Et₂O 50:30:20) to afford 414 mg (70%,

two steps from 23) of 24 as

a colorless oil (C₁₂H₁₈OSi,

MW¼206.36 g mol^ꢁ1). IR 3322, 1617, 1427, 1247, 1114, 1045, 986,

818, 781, 728, 698 cm^ꢁ1; ¹H NMR

d 7.52–7.50 (m, 2H), 7.36–7.34 (m,

3H), 6.09 (dt, J¼18.6, 6.3 Hz,1H), 5.92 (dt, J¼18.6,1.4 Hz,1H), 3.70 (t,

J¼6.3 Hz, 2H), 2.43 (apparent qd, J¼6.3, 1.4 Hz, 2H), 1.40 (br s, 1H,

OH), 0.34 (s, 6H); ¹³C NMR

d 144.5 (d), 138.7 (s), 133.8 (d, 2C), 131.6

(d), 128.9 (d), 127.8 (d, 2C), 61.5 (t), 40.0 (t), ꢁ2.6 (q, 2C); MS-EI m/z

(relative intensity) 191 (MꢁMe^þ, 44), 178 (18), 164 (15), 163 (100),

151 (18), 145 (57), 137 (94), 130 (23), 121 (86), 119 (17), 105 (33), 104

(15), 91 (28), 78 (22), 75 (90), 61 (19), 59 (16), 53 (21).

S. Couty et al. / Tetrahedron 65 (2009) 1809–1832

1819

4.3.5. 2-[(E)-4-(Dimethylphenylsilyl)but-3-enyl]-isoindole-1,3-

dione (25)

(11.5 mL, 1 M in hexanes, 11.5 mmol, 1.1 equiv). After 20 h at rt,

another quantity of DIBAL-H (10.5 mL, 10.5 mmol, 1.01 equiv) was

added. After a further 2 h at rt, the reaction mixture was cau-

tiously poured into a saturated aqueous solution of sodium po-

tassium tartrate. The resulting mixture was diluted with EtOAc

and stirred for 2 h. The layers were separated and the aqueous

phase was extracted with EtOAc. The combined organic extracts

were washed with brine, dried over MgSO₄, ﬁltered, and con-

centrated under reduced pressure. The residue was puriﬁed by

ﬂash chromatography on silica gel (petroleum ether/Et₂O

97.5:2.5) to afford 1.55 g (51%) of 75 as a pale yellow oil

To a solution of 24 (405 mg, 1.96 mmol) in THF (10 mL) at 0 ^ꢀC

were successively added PPh₃(618 mg, 2.35 mmol, 1.2 equiv),

phthalimide (347 mg, 2.35 mmol, 1.2 equiv), and DIAD (467 mL,

2.35 mmol, 1.2 equiv). After 1 h at rt, the reaction mixture was

evaporated under reduced pressure. The residue was puriﬁed by

ﬂash chromatography on silica gel (petroleum ether/EtOAc gradient

100:0 to 95:5) to afford 491 mg (74%) of 25 as a viscous oil

(C₂₀H₂₁NO₂Si, MW¼335.47 g mol^ꢁ1). IR 1772, 1707, 1616, 1392,

1356, 1247, 1112, 996, 818, 785, 717, 698 cm^ꢁ1; ¹H NMR

d 7.85–7.80

(m, 2H), 7.72–7.68 (m, 2H), 7.41–7.38 (m, 2H), 7.32–7.23 (m, 3H),

6.07 (dt, J¼18.5, 6.6 Hz, 1H), 5.79 (br d, J¼18.5 Hz, 1H), 3.80 (t,

J¼7.0 Hz, 2H), 2.52 (apparent br q, J¼7.0 Hz, 2H), 0.24 (s, 6H); ¹³C

(C₁₇H₂₆O₂Si, MW¼290.47 g mol^ꢁ1). ¹H NMR (CDCl₃)

d 7.60–7.56

(m, 2H), 7.38–7.35 (m, 3H), 6.50 (dt, J¼14.3, 7.3 Hz, 1H), 5.79 (br d,

J¼14.3 Hz, 1H), 4.55 (apparent t, J¼3.4 Hz, 1H), 3.87–3.80 (m, 1H),

3.73 (dt, J¼9.6, 7.0 Hz, 1H), 3.52–3.46 (m, 1H), 3.38 (dt, J¼9.6,

6.8 Hz, 1H), 2.41 (apparent br q, J¼7.0 Hz, 2H), 1.87–1.49 (m, 6H),

NMR (CDCl₃)

d 168.2 (s, 2C), 144.2 (d), 138.5 (s), 133.8 (d, 2C), 133.7

(d, 2C), 132.0 (s, 2C), 131.6 (d), 128.8 (d), 127.6 (d, 2C), 123.1 (d, 2C),

37.0 (t), 35.4 (t), ꢁ2.8 (q, 2C); MS-EI m/z (relative intensity) 335

(M^þ, 35), 320 (MꢁMe^þ, 16), 261 (51), 204 (16), 185 (14), 184

(100), 182 (13), 160 (69), 145 (20), 135 (33), 130 (48), 121 (28), 105

(21), 77 (20).

0.43 (s, 6H); ¹³C NMR (CDCl₃)

d 146.7 (d), 139.4 (s), 133.6 (d, 2C),

129.2 (d), 128.9 (d), 127.7 (d, 2C), 98.5 (d), 66.6 (t), 62.0 (t), 34.0

(t), 30.5 (t), 25.4 (t), 19.4 (t), ꢁ0.9 (q, 2C).

4.3.7.2. (Z)-4-(Dimethylphenylsilyl)but-3-en-1-ol (28)^19,20. To a so-

lution of 75 (1.48 g, 5.08 mmol) in MeOH (10 mL) was added

TsOH$H₂O (10 mg, 0.052 mmol, 0.1 equiv). After 3 h at rt, the

reaction mixture was neutralized by addition of a few drops of

a saturated aqueous solution of NaHCO₃and evaporated under

reduced pressure. The residue was partitioned between H₂O and

Et₂O, the layers were separated, and the aqueous phase was

extracted with Et₂O. The combined organic extracts were washed

with brine, dried over MgSO₄, ﬁltered, and concentrated under

reduced pressure. The residue was puriﬁed by ﬂash chromatogra-

phy on silica gel (petroleum ether/EtOAc 90:10) to afford 950 mg

(91%, 46% for the two steps from alkynylsilane 27) of 28 as a pale

yellow oil (C₁₂H₁₈OSi, MW¼206.36 g mol^ꢁ1). IR 3318, 1606, 1427,

4.3.6. N-[(E)-4-(Dimethylphenylsilyl)but-3-enyl-4-methyl-

benzenesulfonamide (26)

To a solution of 25 (468 mg, 1.39 mmol) in EtOH (5 mL) was

added N₂H₄$H₂O (102 mL, 2.09 mmol,1.3 equiv). After 2 h heating at

reﬂux, the reaction mixture was diluted with H₂O and ﬁltered (H₂O/

EtOAc). The ﬁltrate was evaporated under reduced pressure and the

residue was partitioned between H₂O and EtOAc. The layers were

separated and the aqueous phase was extracted with EtOAc. The

combined organic extracts were washed with brine, dried over

MgSO₄, ﬁltered, and concentrated under reduced pressure. The

crude primary amine was dissolved in pyridine (4 mL) and TsCl

(320 mg,1.67 mmol,1.2 equiv) was added at 0 ^ꢀC. After 48 h at rt, the

reaction mixture was hydrolyzed with a saturated aqueous solution

of NH₄Cl and diluted with EtOAc, the layers were separated, and the

aqueous phase was extracted with EtOAc. The combined organic

extracts were washed with brine, dried over MgSO₄, ﬁltered, and

concentrated under reduced pressure. The residue was puriﬁed by

ﬂash chromatography on silica gel (petroleum ether/EtOAc 85:15) to

provide 122 mg (24%, two steps from 25) of sulfonamide 26 as

a yellow oil (C₁₉H₂₅NO₂SSi, MW¼359.56 g mol^ꢁ1). IR 3277, 1616,

1598, 1427, 1322, 1247, 1156, 1113, 1094, 988, 814, 784, 730, 699,

1248, 1111, 1045, 816, 776, 729, 698 cm^ꢁ^{1 1}H NMR (CDCl₃)

; d 7.56–

7.52 (m, 2H), 7.35–7.31 (m, 3H), 6.47 (dt, J¼14.3, 7.0 Hz,1H), 5.88 (dt,

J¼14.3, 1.2 Hz, 1H), 3.60 (t, J¼6.6 Hz, 2H), 2.35 (apparent qd, J¼6.6,

1.2 Hz, 2H), 1.66 (br s, 1H, OH), 0.45 (br s, 6H); ¹³C NMR (CDCl₃)

d

146.0 (d), 139.3 (s), 133.6 (d, 2C), 130.3 (d), 128.9 (d), 127.8 (d, 2C),

61.9 (t), 36.8 (t), ꢁ0.96 (q, 2C); MS-EI m/z (relative intensity) 191

(MꢁMe^þ, 26), 163 (40), 145 (54), 137 (69), 136 (14), 135 (100), 129

(43), 121 (37), 113 (83), 111 (34), 105 (27), 75 (64), 61 (16).

660 cm^ꢁ1; ¹H NMR

d

7.72 (d, J¼8.3 Hz, 2H), 7.48–7.45 (m, 2H), 7.38–

4.3.8. 2-[(Z)-4-(Dimethylphenylsilyl)but-3-enyl]isoindole-

1,3-dione (29)

To a solution of alcohol 28 (956 mg, 4.63 mmol) in THF (5 mL) at

0 ^ꢀC were successively added PPh₃(1.21 g, 6.02 mmol, 1.3 equiv),

7.33 (m, 3H), 7.28 (d, J¼8.3 Hz, 2H), 5.89 (dt, J¼18.6, 6.1 Hz, 1H), 5.76

(dt, J¼18.6, 1.2 Hz, 1H), 4.37 (t, J¼6.0 Hz, 1H, NH), 3.04 (apparent q,

J¼6.6 Hz, 2H), 2.42 (s, 3H), 2.29 (apparent qd, J¼6.6,1.2 Hz, 2H), 0.30

(s, 6H); ¹³C NMR (CDCl₃)

d

143.6 (d), 143.4 (s), 138.4 (s), 136.9 (s),

phthalimide (681 mg, 6.02 mmol, 1.3 equiv), and DIAD (920 mL,

133.7 (d, 2C), 132.1 (d), 129.7 (d, 2C), 129.0 (d), 127.8 (d, 2C), 127.1 (d,

2C), 41.8 (t), 36.3 (t), 21.5 (q), ꢁ2.6 (q, 2C); MS-EI m/z (relative in-

tensity) 344 (MꢁMe^þ, 14), 213 (15), 204 (MꢁTs^þ, 27), 185 (6), 184

(58), 155 (100), 145 (10), 135 (20), 121 (12), 91 (89), 78 (74), 77 (22),

65 (17), 52 (12), 51 (14).

6.02 mmol, 1.3 equiv). After 3 h at rt, the reaction mixture was

concentrated under reduced pressure. The residue was puriﬁed by

ﬂash chromatography on silica gel (petroleum ether/Et₂O gradient

100:0 to 92:8) to give 1.38 g (88%) of 29 as a colorless oil

(C₂₀H₂₁NO₂Si, MW¼335.47 g mol^ꢁ1). IR 1772, 1707, 1608, 1393,

1358, 1248, 1108, 1020, 816, 779, 715, 699 cm^ꢁ^{1 1}H NMR (CDCl₃)

;

4.3.7. Preparation of homoallylic alcohol 28

d 7.82–7.78 (m, 2H), 7.71–7.66 (m, 2H), 7.49–7.46 (m, 2H), 7.29–7.23

(m, 3H), 6.43 (dt, J¼14.4, 7.2 Hz, 1H), 5.79 (br d, J¼14.0 Hz, 1H), 3.71

(t, J¼7.0 Hz, 2H), 2.52 (apparent br q, J¼7.2 Hz, 2H), 0.36 (s, 6H); ¹³C

OTHP

OH

NMR (CDCl₃)

d 168.2 (s, 2C), 145.5 (d), 139.0 (s), 133.8 (d, 2C), 133.5

OTHP

DIBAL-H

hexanes/Et₂O, rt

51%

TsOH (cat.)

MeOH, rt

91%

(d, 2C), 132.0 (s, 2C), 130.3 (d), 128.8 (d), 127.7 (d, 2C), 123.1 (d, 2C),

37.3 (t), 32.7 (t), ꢁ1.0 (q, 2C); MS-EI m/z (relative intensity) 335 (M^þ,

36), 320 (16), 261 (49), 204 (15), 185 (14), 184 (100), 182 (15), 160

(58), 145 (160), 135 (29), 130 (40), 121 (16), 105 (16), 77 (13).

SiMe₂Ph

PhMe₂Si

75

PhMe₂Si

27

28

4.3.9. N-[(Z)-4-(Dimethylphenylsilyl)but-3-enyl]-4-methyl-

benzenesulfonamide (30)

To a solution of phthalimide 29 (650 mg, 1.94 mmol) in EtOH

(5 mL) was added hydrazine monohydrate (0.12 mL, 2.5 mmol,

4.3.7.1. Dimethylphenyl-[(Z)-4-(tetrahydropyran-2-yloxy)but-1-enyl]-

silane (75). To a solution of alkynylsilane 27²⁰(3.00 g, 10.4 mmol)

in Et₂O (15 mL) at 0 ^ꢀC was slowly added a solution of DIBAL-H

1820

S. Couty et al. / Tetrahedron 65 (2009) 1809–1832

1.3 equiv). After 2 h heating at reﬂux, the reaction mixture was

diluted with H₂O and ﬁltered (H₂O/EtOAc). The ﬁltrate was evap-

orated under reduced pressure and the residue was partitioned

between H₂O and EtOAc. The layers were separated and the

aqueous phase was extracted with EtOAc. The combined organic

extracts were washed with brine, dried over MgSO₄, ﬁltered, and

concentrated under reduced pressure. The crude primary amine

was dissolved in pyridine (5 mL) and TsCl (445 mg, 2.32 mmol,

1.2 equiv) was added at 0 ^ꢀC. After 16 h at rt, the reaction mixture

was hydrolyzed with a saturated aqueous solution of NH₄Cl and

diluted with EtOAc. The layers were separated and the aqueous

phase was extracted with EtOAc. The combined organic extracts

were washed with brine, dried over MgSO₄, ﬁltered, and concen-

trated under reduced pressure. The residue was puriﬁed by ﬂash

chromatography on silica gel (petroleum ether/EtOAc gradient 95:5

to 85:15) to afford 516 mg (74%, two steps from 29) of 30 as a yellow

oil (C₁₉H₂₅NO₂SSi, MW¼359.56 g mol^ꢁ1). IR 3277, 1600, 1427, 1323,

(CDCl₃)

d

7.55 (d, J¼8.2 Hz, 2H), 7.14–7.02 (m, 7H), 5.83 (d, J¼7.5 Hz,

1H, NH), 5.65 (dt, J¼15.4, 5.6 Hz, 1H), 5.42 (dt, J¼15.4, 7.0 Hz, 1H),

4.38 (apparent q, J¼7.0 Hz,1H), 3.98 (d, J¼5.6 Hz, 2H), 2.47–2.31 (m,

3H, 2HþOH), 2.35 (s, 3H); ¹³C NMR (CDCl₃)

d 143.1 (s), 140.6 (s),

137.6 (s), 133.8 (d),129.3 (d, 2C),128.3 (d, 2C),127.2 (d),127.1 (d, 2C),

126.6 (d), 126.5 (d, 2C), 63.1 (t), 57.5 (d), 40.3 (t), 21.5 (q).

4.3.12. N-[(E)-5-(tert-Butyldimethylsilyloxy)-1-phenylpent-3-

enyl]-4-methylbenzenesulfonamide (33)

To a solution of alcohol 32 (122 mg, 0.368 mmol) and imidazole

(58 mg, 0.85 mmol, 2.3 equiv) in DMF (5 mL) was added tert-

butylchlorodimethylsilane (91 mg, 0.60 mmol, 1.6 equiv). After 3 h

at rt, the reaction mixture was hydrolyzed with a saturated aqueous

solution of NH₄Cl, diluted with H₂O, and extracted with EtOAc. The

combined organic extracts were washed with brine, dried over

MgSO₄, ﬁltered, and concentrated under reduced pressure. The

crude material was puriﬁed by ﬂash chromatography on silica gel

(petroleum ether/EtOAc 90:10) to afford 164 mg (99%) of 33 as

a white solid (C₂₄H₃₅NO₃SSi, MW¼445.69 g mol^ꢁ1). Mp 81 ^ꢀC; IR

3251, 1600, 1458, 1322, 1251, 1159, 1096, 1054, 965, 834, 813, 776,

1248, 1156, 1110, 1093, 814, 778, 731, 700, 660 cm^ꢁ1

(CDCl₃)

;

¹H NMR

d

7.68 (d, J¼8.1 Hz, 2H), 7.54–7.50 (m, 2H), 7.38–7.34 (m,

3H), 7.29 (d, J¼8.1 Hz, 2H), 6.22 (dt, J¼14.3, 7.0 Hz, 1H), 5.80 (br d,

J¼14.3 Hz, 1H), 4.16 (t, J¼6.0 Hz, 1H, NH), 2.88 (apparent br q,

J¼6.6 Hz, 2H), 2.44 (s, 3H), 2.29 (apparent qd, J¼7.0,1.2 Hz, 2H), 0.37

705, 671 cm^ꢁ1

;

¹H NMR (CDCl₃)

d

7.55 (d, J¼8.3 Hz, 2H), 7.19–7.13

(m, 5H), 7.08–7.04 (m, 2H), 5.57 (dt, J¼15.4, 4.8 Hz, 1H), 5.33 (dt,

J¼15.4, 7.0 Hz, 1H), 4.84 (d, J¼6.4 Hz, 1H, NH), 4.35 (apparent q,

J¼6.6 Hz,1H), 4.08 (dd, J¼4.8, 1.1 Hz, 2H), 2.50–2.39 (m, 2H), 2.37 (s,

(s, 6H); ¹³C NMR (CDCl₃)

d 145.2 (d), 143.3 (s), 139.1 (s), 136.8 (s),

133.6 (d, 2C), 131.2 (d), 129.6 (d, 2C), 129.1 (d), 127.9 (d, 2C), 127.1 (d,

2C), 42.4 (t), 33.2 (t), 21.5 (q), ꢁ1.1 (q, 2C); MS-EI m/z (relative in-

tensity) 344 (MꢁMe^þ, 20), 282 (10), 266 (7), 213 (15), 204 (29), 184

(67), 156 (10), 155 (100), 149 (10), 145 (11), 135 (28), 121 (10), 105

(9), 91 (68), 78 (17), 65 (12).

3H), 0.87 (s, 9H), 0.03 (s, 3H), 0.02 (s, 3H); ¹³C NMR (CDCl₃)

d 143.1

(s), 140.3 (s), 137.5 (s), 134.2 (d), 129.3 (d, 2C),128.4 (d, 2C),127.4 (d),

127.1 (d, 2C), 126.6 (d, 2C), 124.6 (d), 63.3 (t), 57.2 (d), 40.3 (t), 25.9

(q, 3C), 21.5 (q), 18.4 (s), ꢁ5.2 (q, 2C); MS-EI m/z (relative intensity)

430 (MꢁMe^þ, 1), 388 (Mꢁt-Bu^þ, 24), 261 (17), 260 (100), 228 (33),

155 (37), 144 (8), 143 (66), 128 (9), 113 (10), 91 (57), 75 (23), 73 (15).

4.3.10. tert-Butyl (E)-5-phenyl-5-(toluene-4-sulfonylamino)-

pent-2-enoate (31)

To a solution of sulfonamide 15 (380 mg, 1.26 mmol) in CH₂Cl₂

(30 mL) were added tert-butyl acrylate (554 mL, 3.78 mmol, 3 equiv)

4.4. Preparation of trimethylsilyl-1,6-ene-ynamides of type H

from sulfonamides of type I

and Grubbs II catalyst (53 mg, 0.063 mmol, 0.05 equiv). After 12 h

at rt and 5 h heating at reﬂux, another quantity of Grubbs II catalyst

(26 mg, 0.031 mmol, 0.025 equiv) was added. After 3 h at reﬂux, the

reaction mixture was concentrated under reduced pressure. The

residue was puriﬁed by ﬂash chromatography on silica gel (petro-

leum ether/EtOAc 90:10, 85:15) to afford 425 mg (84%) of 31 as

a pale brown solid (C₂₂H₂₇NO₄S, MW¼401.52 g mol^ꢁ1). Mp 125 ^ꢀC;

IR 3268, 1706, 1687, 1654, 1322, 1147, 1092, 1070, 984, 808, 699,

4.4.1. 4-Methyl-N-(1-phenylbut-3-enyl)-N-(trimethyl-

silylethynyl)benzenesulfonamide (35) (representative procedure)

To a solution of sulfonamide 15 (1.00 g, 3.32 mmol) in toluene

(40 mL) at 0 ^ꢀC was added a solution of KHMDS (7.3 mL, 0.5 M in

toluene, 3.65 mmol, 1.1 equiv). After 1 h at 0 ^ꢀC, (trimethylsilyl-

ethynyl)phenyliodonium triﬂate (34) (1.79 g, 3.98 mmol, 1.2 equiv)

was added portionwise. After 24 h at rt, the reaction mixture

was ﬁltered through Celite (toluene/Et₂O 80:20). The ﬁltrate was

evaporated under reduced pressure and the crude material was

puriﬁed by ﬂash chromatography on silica gel (petroleum ether/

EtOAc 90:10) to afford 790 mg (60%) of ynamide 35 as a yellow oil

(C₂₂H₂₇NO₂SSi, MW¼397.61 g mol^ꢁ1). IR 2156, 1643, 1597, 1494,

665 cm^ꢁ1

;

¹H NMR (CDCl₃)

d

7.55 (d, J¼8.2 Hz, 2H), 7.17–7.12 (m,

5H), 7.05–7.02 (m, 2H), 6.53 (dt, J¼15.5, 7.3 Hz, 1H), 5.70 (d,

J¼15.5 Hz, 1H), 5.21 (d, J¼7.2 Hz, 1H, NH), 4.41 (apparent q,

J¼7.0 Hz, 1H), 2.67–2.51 (m, 2H), 2.35 (s, 3H), 1.43 (s, 9H); ¹³C NMR

(CDCl₃)

d 165.2 (s), 143.2 (s), 141.5 (d), 139.6 (s), 137.3 (s), 129.4 (d,

2C),128.6 (d, 2C),127.7 (d), 127.1 (d, 2C),126.6 (d),126.5 (d, 2C), 80.4

(s), 57.0 (d), 39.8 (t), 28.1 (q, 3C), 21.5 (q); MS-EI m/z (relative in-

tensity) 328 (Mꢁt-BuO^þ, 2), 262 (6), 261 (16), 260 (100), 155 (37),

104 (5), 91 (47), 65 (6), 57 (6), 56 (22), 55 (8).

1366, 1248, 1167, 1089, 972, 919, 838, 812, 758, 739, 698, 664 cm^ꢁ1

;

¹H NMR (CDCl₃)

d

7.79 (d, J¼8.4 Hz, 2H), 7.26–7.11 (m, 7H), 5.60

(ddt, J¼17.0, 9.9, 7.0 Hz, 1H), 5.09 (apparent dq, J¼17.0, 1.5 Hz, 1H),

4.97 (m, 1H), 4.92 (dd, J¼9.2, 6.2 Hz, 1H), 2.77 (m, 1H), 2.56 (m, 1H),

2.37 (s, 3H), 0.17 (s, 9H); ¹³C NMR (CDCl₃)

d 144.1 (s), 138.8 (s), 135.2

4.3.11. N-[(E)-5-Hydroxy-1-phenylpent-3-enyl]-4-

methylbenzenesulfonamide (32)

(s),133.5 (d), 129.1 (d, 2C),128.3 (d, 2C),128.1 (d), 127.9 (d, 2C),127.2

(d, 2C), 118.3 (t), 93.2 (s), 86.3 (s), 62.9 (d), 38.2 (t), 21.6 (q), 0.1 (q,

3C); MS-EI m/z (relative intensity) 397 (M^þ, 1), 356 (MꢁAllyl^þ, 13),

242 (MꢁTs^þ, 31), 155 (53), 132 (12), 131 (100), 130 (19), 129 (15), 91

(60), 73 (14).

To a solution of 31 (250 mg, 0.623 mmol) in CH₂Cl₂(10 mL) at

ꢁ78 ^ꢀC was added dropwise a solution of DIBAL-H (1.9 mL, 1 M in

hexanes, 1.9 mmol, 3 equiv). After 15 min at ꢁ78 ^ꢀC, the reaction

mixture was warmed to rt over 1.5 h and then cautiously poured

into a saturated aqueous solution of sodium potassium tartrate.

After 1 h stirring, the layers were separated and the aqueous phase

was extracted with CH₂Cl₂. The combined organic extracts were

washed with brine, dried over MgSO₄, ﬁltered, and concentrated

under reduced pressure. The crude product was puriﬁed by ﬂash

chromatography on silica gel (petroleum ether/EtOAc 60:40) to

4.4.2. N-[2-(Benzyloxymethyl)but-3-enyl]-4-methyl-

N-(trimethylsilylethynyl)benzenesulfonamide (36)

This compound was synthesized from sulfonamide 22 (638 mg,

1.85 mmol) in toluene (22 mL) with KHMDS (4.8 mL, 0.5 M in tol-

uene, 2.4 mmol, 1.3 equiv) and iodonium triﬂate 34 (1.17 g,

2.58 mmol, 1.4 equiv) according to the representative procedure

(14 h at rt). After puriﬁcation by ﬂash chromatography on silica gel

(petroleum ether/Et₂O 95:5 then petroleum ether/EtOAc 95:5),

515 mg (63%) of ynamide 36 was obtained as a colorless oil

give 130 mg (64%) of 32 as

a colorless oil (C₁₈H₂₁NO₃S,

MW¼331.43 g mol^ꢁ1). IR 3482, 3272, 1598, 1495, 1455, 1319, 1304,

1289, 1152, 1091, 1055, 970, 812, 758, 699, 665 cm^ꢁ^{1 1}H NMR

;

S. Couty et al. / Tetrahedron 65 (2009) 1809–1832

1821

(C₂₄H₃₁NO₃SSi, MW¼441.66 g mol^ꢁ1). IR 2160, 1597, 1495, 1454,

839, 813, 776, 699, 665 cm^ꢁ1

;

¹H NMR (CDCl₃)

d

7.52 (d, J¼8.3 Hz,

1366, 1248, 1169, 1090, 1000, 920, 840, 813, 735, 697, 659 cm^ꢁ1; ¹H

2H), 7.27–7.17 (m, 5H), 7.13 (d, J¼8.3 Hz, 2H), 5.62 (dt, J¼15.4, 5.1 Hz,

1H), 5.42 (dt, J¼15.4, 7.0 Hz,1H), 4.89 (dd, J¼9.0, 6.7 Hz,1H), 3.99 (dd,

J¼5.1, 0.8 Hz, 2H), 2.79–2.71 (m, 1H), 2.60–2.53 (m, 1H), 2.38 (s, 3H),

0.89 (s, 9H), 0.18 (s, 9H), 0.04 (s, 3H), 0.03 (s, 3H); ¹³C NMR (CDCl₃)

NMR (CDCl₃)

d

7.76 (d, J¼8.3 Hz, 2H), 7.34–7.20 (m, 7H), 5.72 (ddd,

J¼17.3, 10.4, 8.1 Hz, 1H), 5.13 (dt, J¼17.3, 1.3 Hz, 1H), 5.09 (dt, J¼10.4,

1.3 Hz, 1H), 4.49 (d, AB syst, J¼12.0 Hz, 1H), 4.45 (d, AB syst,

J¼12.0 Hz, 1H), 3.52–3.46 (m, 2H), 3.46 (dd, J¼12.9, 6.9 Hz, 1H), 3.31

(dd, J¼12.9, 7.8 Hz, 1H), 2.83–2.74 (m, 1H), 2.43 (s, 3H), 0.13 (s, 9H);

d

144.0 (s), 138.8 (s), 135.1 (s), 133.1 (d), 129.0 (d, 2C), 128.2 (d, 2C),

128.0 (d), 127.7 (d, 2C), 127.1 (d, 2C), 125.6 (d), 93.2 (s), 76.4 (s), 63.6

(t), 63.0 (d), 36.8 (t), 25.9 (q, 3C), 21.5 (q), 18.4 (s), 0.1 (q, 3C), ꢁ5.2

(q, 2C). Anal. Calcd for C₂₉H₄₃NO₃SSi₂: C, 64.28; H, 8.00; N, 2.58.

Found: C, 64.27; H, 8.15; N, 2.51.

¹³C NMR (CDCl₃)

d 144.5 (s), 138.1 (s), 135.8 (d), 134.3 (s), 129.5 (d,

2C), 128.2 (d, 2C), 127.7 (2d, 3C), 127.4 (d, 2C), 117.9 (t), 95.3 (s), 73.2

(s), 73.0 (t), 70.5 (t), 52.5 (t), 42.7 (d), 21.5 (q), 0.0 (q, 3C); MS-EI m/z

(relative intensity) 441 (M^þ, 1), 426 (MꢁMe^þ, 2), 286 (13), 203 (6),

180 (3), 155 (10), 131 (16), 110 (7), 92 (9), 91 (100), 73 (22), 65 (6).

4.4.6. 4-Methyl-N-(3-methyl-1-phenylbut-3-enyl)-N-

(trimethylsilylethynyl)benzenesulfonamide (40)

4.4.3. N-[(E)-4-(Dimethylphenylsilyl)but-3-enyl]-4-methyl-

N-(trimethylsilylethynyl)benzenesulfonamide (37)

This compound was synthesized from sulfonamide 16 (382 mg,

1.21 mmol) in toluene (22 mL) with KHMDS (3.64 mL, 0.5 M in

toluene, 1.82 mmol, 1.5 equiv) and iodonium triﬂate 34 (870 mg,

1.94 mmol, 1.6 equiv) according to the representative procedure

(48 h at rt). After puriﬁcation by chromatography on silica gel

(petroleum ether/Et₂O 95:5), 336 mg (67%) of 40 was obtained as

a pale yellow oil (C₂₃H₂₉NO₂SSi, MW¼411.63 g mol^ꢁ1). IR 2158,

1650, 1597, 1365, 1248, 1166, 1090, 962, 839, 812, 758, 738, 698,

This compound was synthesized from sulfonamide 26 (65 mg,

0.18 mmol) in toluene (5 mL) with KHMDS (0.55 mL, 0.5 M in tol-

uene, 0.28 mmol, 1.5 equiv) and iodonium triﬂate 34 (135 mg,

0.299 mmol, 1.7 equiv) according to the representative procedure

(14 h at rt). After puriﬁcation by chromatography on silica gel

(petroleum ether/Et₂O 97.5:2.5), 40 mg (48%) of ynamide 37 was

obtained as a yellow oil (C₂₄H₃₃NO₂SSi₂, MW¼455.76 g mol^ꢁ1). IR

2161, 1617, 1597, 1427, 1369, 1248, 1169, 1113, 1091, 985, 838, 729,

664 cm^ꢁ1

;

¹H NMR (CDCl₃)

d

7.49 (d, J¼8.2 Hz, 2H), 7.28–7.14 (m,

5H), 7.10 (d, J¼8.2 Hz, 2H), 5.09 (dd, J¼9.3, 6.1 Hz, 1H), 4.76 (br s,

1H), 4.74 (br s, 1H), 2.78 (dd, J¼14.4, 9.3 Hz, 1H), 2.45 (dd, J¼14.4,

6.1 Hz, 1H), 2.36 (s, 3H), 1.72 (s, 3H), 0.17 (s, 9H); ¹³C NMR (CDCl₃)

698, 659 cm^ꢁ1

;

¹H NMR (CDCl₃)

d

7.78 (d, J¼8.3 Hz, 2H), 7.51–7.48

(m, 2H), 7.37–7.30 (m, 5H), 6.0 (dt, J¼18.6, 6.1 Hz, 1H), 5.84 (dt,

J¼18.6, 1.3 Hz, 1H), 3.93 (t, J¼7.5 Hz, 2H), 2.50–2.42 (m, 2H), 2.44 (s,

d

144.0 (s), 140.3 (s), 139.0 (s), 135.1 (s), 128.9 (d, 2C), 128.2 (d, 2C),

3H), 0.31 (s, 6H), ꢁ0.15 (s, 9H); ¹³C NMR (CDCl₃)

d

144.5 (s), 143.2

127.9 (d), 127.8 (d, 2C), 127.1 (d, 2C), 114.5 (t), 93.2 (s), 77.2 (s), 61.2

(d), 42.1 (t), 22.1 (q), 21.5 (q), 0.0 (q, 3C); MS-EI m/z (relative in-

tensity) 411 (M^þ, 3), 396 (MꢁMe^þ, 3), 356 (8), 256 (22), 240 (6), 186

(10), 155 (36), 146 (12), 145 (100), 144 (28), 143 (14), 130 (14), 129

(67), 128 (40), 127 (12), 117 (17), 115 (13), 91 (56), 73 (23), 65 (9);

HRMS calcd for C₂₃H₃₀NO₂SSi (MþH^þ): 412.1767, found: 412.1764.

(d), 138.6 (s), 134.5 (s), 133.8 (d, 2C), 131.5 (d), 129.6 (d, 2C), 128.9

(d), 127.7 (2d, 2Cþ2C), 94.9 (s), 73.4 (s), 50.3 (t), 34.9 (t), 21.6 (q), 0.1

(q, 3C), ꢁ2.7 (q, 2C); MS-EI m/z (relative intensity) 455 (M^þ, 1), 440

(MꢁMe^þ, 4), 309 (19), 307 (12), 301 (24), 300 (MꢁTs^þ, 80), 280 (16),

216 (12), 155 (22), 150 (11), 149 (31), 136 (14), 135 (100), 121 (20),

110 (13), 91 (43), 73 (36), 59 (14).

4.5. Preparation of the terminal 1,6-ene-ynamide 43²⁷

4.4.4. N-[(Z)-4-(Dimethylphenylsilyl)but-3-enyl]-4-methyl-

N-(trimethylsilylethynylbenzene)sulfonamide (38)

Ph

This compound was synthesized from sulfonamide 30 (407 mg,

1.13 mmol) in toluene (15 mL) with KHMDS (3.2 mL, 0.5 M in tolu-

ene, 1.6 mmol, 1.4 equiv) and iodonium triﬂate 34 (765 mg,

1.70 mmol, 1.5 equiv) according to the representative procedure

(14 h at rt). After puriﬁcation by chromatography on silica

gel (petroleum ether/Et₂O 97.5:2.5), 445 mg (86%) of ynamide

38 was obtained as a pale yellow oil (C₂₄H₃₃NO₂SSi₂, MW¼

455.76 g mol^ꢁ1). IR 2160, 1599, 1369, 1248, 1169, 1111, 1091, 997, 837,

Ts

I

O

NH₂

O

NHTs

O

N

1) SOCl₂, MeOH

OTf

2) TsCl, DMAP

Et₃N, CH₂Cl₂

65%

Cs₂CO₃

DMF/CH₂Cl₂, rt

65%

HO

MeO

76

43

814, 778, 756, 730, 699, 659 cm^ꢁ1

;

¹H NMR (CDCl₃)

d

7.72 (d,

4.5.1. Methyl 2-(toluene-4-sulfonylamino)pent-4-enoate (76)

J¼8.3 Hz, 2H), 7.52–7.49 (m, 2H), 7.35–7.29 (m, 5H), 6.32 (dt, J¼14.0,

7.4 Hz,1H), 5.77 (dt, J¼14.0, 0.9 Hz, 1H), 3.26 (br t, J¼7.4 Hz, 2H), 2.44

(s, 3H), 2.39 (apparent qd, J¼7.4, 0.9 Hz, 2H), 0.36 (s, 6H), ꢁ0.14 (s,

To a solution of allylglycine (2.02 g, 17.5 mmol) in MeOH (35 mL)

at 0 ^ꢀC was added dropwise thionyl chloride (1.53 mL, 20.9 mmol,

1.2 equiv). After 12 h at rt, the reaction mixture was concentrated

under reduced pressure. The residue was crystallized in Et₂O/EtOAc

(95:5) and allylglycine methyl ester hydrochloride was dissolved in

CH₂Cl₂(70 mL). To the resulting solution at 0 ^ꢀC were successively

added Et₃N (7.3 mL, 53 mmol, 3 equiv), DMAP (214 mg, 1.75 mmol,

0.1 equiv), and TsCl (4.02 g, 21.05 mmol, 1.2 equiv). After 24 h at rt,

the reaction mixture was hydrolyzed with a saturated aqueous

solution of NH₄Cl and extracted with CH₂Cl₂. The combined organic

extracts were washed with brine, dried over MgSO₄, ﬁltered, and

concentrated under reduced pressure. The residue was puriﬁed by

ﬂash chromatography on silica gel (petroleum ether/EtOAc gradient

90:10 to 75:25) to afford 3.33 g (65%) of sulfonamide 76 as a viscous

yellow oil (C₁₃H₁₇NO₄S, MW¼283.34 g mol^ꢁ1). IR 3268, 1748, 1597,

9H); ¹³C NMR (CDCl₃)

d

144.5 (sþd, 2C), 139.0 (s), 134.5 (s), 133.6 (d,

2C), 130.8 (d), 129.6 (d, 2C), 129.0 (d), 127.9 (d, 2C), 127.8 (d, 2C), 94.9

(s), 73.4 (s), 50.7 (t), 32.0 (t), 21.6 (q), 0.0 (q, 3C), ꢁ1.0 (q, 2C); MS-EI

m/z (relative intensity) 440 (MꢁMe^þ, 2), 309 (19), 307 (11), 302 (8),

301 (23), 300 (MꢁTs^þ, 77), 270 (11), 155 (21), 149 (17), 136 (14), 135

(100),121 (14),110 (12), 91 (45), 75 (12), 73 (41), 59 (14); HRMS calcd

for C₂₄H₃₄NO₂SSi₂(MþH^þ): 456.1849, found: 456.1856.

4.4.5. N-[(E)-5-(tert-Butyldimethylsilyloxy)-1-phenylpent-3-enyl]-

4-methyl-N-(trimethylsilylethynyl)benzenesulfonamide (39)

This compound was synthesized from sulfonamide 33 (172 mg,

0.386 mmol) in toluene (5 mL) with KHMDS (1.1 mL, 0.5 M in tolu-

ene, 0.55 mmol, 1.4 equiv) and iodonium triﬂate 34 (261 mg,

0.578 mmol, 1.5 equiv) according to the representative procedure

(15 h at rt). After puriﬁcation by chromatography on silica gel

(petroleum ether/Et₂O 90:10), 105 mg (50%) of ynamide 39 was

obtained as a yellow solid (C₂₉H₄₃NO₃SSi₂, MW¼541.89 g mol^ꢁ1).

Mp 65 ^ꢀC; IR 2160,1598,1458,1371,1250,1169, 1122,1091,1054, 967,

1432, 1339, 1160, 1092, 922, 814, 750, 662 cm^ꢁ1; ¹H NMR

d 7.71 (d,

J¼8.5 Hz, 2H), 7.28 (d, J¼8.0 Hz, 2H), 5.61 (ddt, J¼17.6, 10.0, 7.0 Hz,

1H), 5.18 (d, J¼9.0 Hz, 1H, NH), 5.12–5.04 (m, 2H), 4.02 (dt, J¼9.0,

6.0 Hz, 1H), 3.51 (s, 3H), 2.45 (dd, apparent t, J¼6.5 Hz, 2H), 2.41 (s,

3H); ¹³C NMR

d 171.3 (s), 143.7 (s), 136.8 (s), 131.2 (d), 129.6 (d, 2C),

127.2 (d, 2C), 119.7 (t), 55.2 (d), 52.4 (q), 37.5 (t), 21.5 (q); MS-EI m/z

1822

S. Couty et al. / Tetrahedron 65 (2009) 1809–1832

(relative intensity) 283 (M^þ, 1), 243 (8), 242 (MꢁAllyl^þ, 63), 224

(MꢁCO₂Me^þ, 22), 156 (9), 155 (100), 92 (9), 91 (91), 65 (15).

a 25% aqueous solution of Na₂S₂O₃. After addition of H₂O and ex-

traction with CH₂Cl₂, the combined organic extracts were dried over

MgSO₄, ﬁltered, and concentrated under reduced pressure. The

crude material was puriﬁed by ﬂash chromatography on silica gel

(petroleum ether/EtOAc 60:40, 50:50) to afford 110 mg (65%) of

lactone42 asa paleyellowsolid(C₁₉H₂₁NO₄S, MW¼359.44 g mol^ꢁ1).

Mp 164 ^ꢀC; IR 3201,1755,1324,1183,1150,1093,1059, 923, 843, 815,

4.5.2. Methyl 2-[ethynyl(toluene-4-sulfonyl)amino]pent-4-

enoate (43)²⁷

To a solution of sulfonamide 76 (567 mg, 2.00 mmol) in DMF

(15 mL) was added Cs₂CO₃(850 mg, 2.60 mmol, 1.3 equiv). After 1 h

at rt, a stirred suspension of ethynylphenyliodonium triﬂate (1.0 g,

2.6 mmol, 1.3 equiv) in CH₂Cl₂(10 mLþ5 mL rinse) was added via

a cannula. After 2 h at rt, the reaction mixture was diluted with H₂O

(60 mL). The layers were separated and the aqueous phase was

extracted with EtOAc. The combined organic extracts were washed

with brine, dried over MgSO₄, ﬁltered, and concentrated under

reduced pressure. The residue was puriﬁed by ﬂash chromatogra-

phy on silica gel (petroleum ether/EtOAc 75:25) to afford 500 mg

(65%) of 43 as a colorless oil (C₁₅H₁₇NO₄S, MW¼307.36 g mol^ꢁ1). IR

3283, 2133, 1744, 1644, 1596, 1436, 1366, 1258, 1164, 1089, 1012,

765, 706, 668 cm^ꢁ1; ¹H NMR (CDCl₃)

d

7.55 (br d, J¼8.0 Hz, 2H), 7.17–

7.14 (m, 3H), 7.11 (d, J¼8.0 Hz, 2H), 7.03–6.99 (m, 2H), 5.59 (d,

J¼8.6 Hz, 1H, NH), 4.60 (ddd, apparent td, J¼8.6, 4.6 Hz, 1H), 4.52–

4.45 (m,1H), 2.47–2.42 (m, 2H), 2.34 (s, 3H), 2.30–2.22 (m,1H), 2.09–

1.96 (m, 2H),1.83–1.73 (m,1H); ¹³C NMR (CDCl₃)

d 176.5 (s),143.3 (s),

139.9 (s), 137.4 (s), 129.4 (d, 2C), 128.7 (d, 2C), 127.6 (d), 127.1 (d, 2C),

126.2 (d, 2C), 77.2 (d), 55.2 (d), 43.1 (t), 28.7 (t), 28.0 (t), 21.4 (q); MS-

EI m/z (relative intensity) 281 (MꢁPhH^þ, 3), 261 (16), 260 (100), 207

(8),155 (36),104 (9), 91 (40). Anal. Calcd for C₁₉H₂₁NO₄S: C, 63.49; H,

5.89; N, 3.90. Found: C, 63.11; H, 5.84; N, 3.74.

924, 813, 704, 660 cm^ꢁ1

;

¹H NMR (CDCl₃)

d

7.78 (d, J¼8.4 Hz, 2H),

7.33 (d, J¼8.4 Hz, 2H), 5.64 (ddt, J¼17.0, 10.1, 6.8 Hz, 1H), 5.16 (ap-

parent dq, J¼17.0, 1.3 Hz, 1H), 5.05 (apparent dq, J¼10.1, 1.3 Hz, 1H),

4.53 (dd, apparent t, J¼10.0, 5.1 Hz, 1H), 3.56 (s, 3H), 2.85 (s, 1H),

2.73–2.65 (m, 1H), 2.62–2.55 (m, 1H), 2.44 (s, 3H); ¹³C NMR (CDCl₃)

4.6.3. Chemical correlation for the attribution of the relative

conﬁguration of g-lactone 42 and cyclobutanone 41

OH

O

OH OH

d

169.1 (s), 144.9 (s), 134.7 (s), 131.9 (d), 129.5 (d, 2C), 128.0 (d, 2C),

a,b

c

Ph

H

Ph

119.3 (t), 72.8 (s), 61.7 (d), 60.4 (d), 52.4 (q), 33.9 (t), 21.6 (q); MS-EI

m/z (relative intensity) 307 (M^þ, 1), 306 (3), 292 (MꢁMe^þ, 2), 248

(MꢁCO₂Me^þ, 19), 200 (25), 184 (30), 155 (26), 139 (28), 120 (9), 110

(14), 92 (33), 91 (100), 81 (8), 71 (17), 67 (7), 65 (24), 59 (13), 52

(12). Anal. Calcd for C₁₅H₁₇NO₄S: C, 58.61; H, 5.57; N, 4.56. Found: C,

58.79; H, 5.35; N, 4.56.

64%

(dr = 70:30)

77

78

79

(three steps

from 77)

d

OH

e

O

CO₂H

O

f,g

65%

Ph

(two steps

82

81

80

4.6. Diastereoselective gold-catalyzed cycloisomerizations

of 1,6-ene-ynamides

from 79)

(three steps from 81)

h

96%

O

Ts

4.6.1. 4-Methyl-N-[(R

*

)-2-((2S )-2-oxocyclobutyl)-1-phenyl-

*

i

64%

j,k

NH

O

OH

O

N₃

O

ethyl]benzenesulfonamide (41) (representative procedure)

31%

Ph

To a solution of ynamide 35 (115 mg, 0.289 mmol) in CH₂Cl₂

(5 mL) was added AuCl (3.4 mg, 0.012 mmol, 0.05 equiv). After 24 h

at rt, the reaction mixture was ﬁltered through a short plug of Celite

(CH₂Cl₂) and the ﬁltrate was evaporated under reduced pressure.

The crude material was puriﬁed by ﬂash chromatography on silica

gel (petroleum ether/EtOAc 80:20) to afford 77 mg (77%) of cyclo-

butanone 41 as a colorless oil (88:12 inseparable mixture of dia-

stereomers) (C₁₉H₂₁NO₃S, MW¼343.44 g mol^ꢁ1). IR 3271, 1771,

83 (dr = 70:30)

84 (dr = 70:30)

42

Reagents and conditions: (a) OsO₄(1 mol %), NMO, acetone/H₂O

(4:1); (b) NaIO₄, THF/H₂O (1:1); (c) AllylSnCl₃, CH₂Cl₂, ꢁ78 ^ꢀC to

rt; (d) 2,2-dimethoxypropane, CSA (cat.), acetone, rt; (e) BH₃$THF,

THF, 0 ^ꢀC then NaOH, H₂O₂; (f) IBX, THF/DMSO (1:1), rt; (f) NaClO₂,

2-methylbut-2-ene, NaH₂PO₄, t-BuOH/H₂O (7:2); (h) 80% aq AcOH

then CSA (cat.), toluene, reﬂux; (i) (PhO)₂P(O)N₃, DBU, toluene, rt;

(j) PPh₃, THF/H₂O (9:1), 50 ^ꢀC; (k) TsCl, Py. CSA¼10-camphor-sul-

fonic acid, IBX¼2-iodoxybenzoic acid, DBU¼1,8-diaza-bicy-

clo[5.4.0]undec-7-ene.

An authentic sample of lactone 42 was synthesized by an in-

dependent route. Homoallylic alcohol 77 was dihydroxylated [OsO₄

(1 mol %), NMO (1.1 equiv), acetone/H₂O (4:1), rt, 18 h] and the

resulting triol (91%) underwent oxidative cleavage [NaIO₄, THF/H₂O

1599, 1495, 1456, 1324, 1155, 1089, 813, 701, 666 cm^ꢁ^{1 1}H NMR

;

(CDCl₃)

d

7.56 (br d, J¼8.1 Hz, 2H), 7.16–7.14 (m, 3H), 7.11 (d,

J¼8.1 Hz, 2H), 7.05–7.01 (m, 2H), 6.04 (br d, J¼8.5 Hz, 1H, NH), 4.53

(ddd, apparent dt, J¼8.5, 6.0 Hz, 1H), 3.14–3.05 (m, 1H), 2.99 (dddd,

J¼18.1, 11.0, 8.5, 2.5 Hz, 1H), 2.85 (dddd, J¼18.1, 9.5, 4.5, 2.5 Hz, 1H),

2.34 (s, 3H), 2.09 (m, 1H), 2.00–1.90 (m, 2H), 1.61 (m, 1H); ¹³C NMR

(CDCl₃)

d 212.0 (s), 142.9 (s), 139.8 (s), 137.9 (s), 129.3 (d, 2C), 128.5

(d, 2C), 127.4 (d), 127.0 (d, 2C), 126.3 (d, 2C), 56.2 (d), 55.9 (d), 44.1

(t), 36.8 (t), 21.4 (q), 14.2 (t); MS-EI m/z (relative intensity) 343 (M^þ,

1), 315 (4), 261 (17), 260 (100), 188 (MꢁTs^þ, 15), 155 (58), 130 (10),

106 (11), 104 (12), 91 (84), 77 (9), 65 (12), 55 (8).

(1:1), rt] to afford the

b-hydroxyaldehyde 78. The latter crude

compound was allylated with allyltrichlorostannane (generated

from allyltrimethylsilane and SnCl₄, CH₂Cl₂, rt) to obtain the 1,3-

diol 79 (64%, three steps from 77, syn/anti¼70:30).³⁹After forma-

tion of the acetonide 80, which conﬁrmed the syn relative conﬁg-

uration of the major diastereomer,⁴⁰the terminal alkene

underwent hydroboration followed by alkaline oxidative work-up

to afford the primary alcohol 81 (65%). Oxidation of alcohol 35 gave

the corresponding aldehyde [IBX, THF/DMSO (1:1), rt], which was

oxidized to the carboxylic acid 82 [NaClO₂, 2-methylbut-2-ene,

NaH₂PO₄, t-BuOH/H₂O (7:2), rt]. The carboxylic acid 82 underwent

acetonide hydrolysis (80% aq AcOH) and, after removal of water and

AcOH by azeotropic evaporation with toluene, lactonization [CSA

4.6.2. 4-Methyl-N-[(R

*

)-2-((2S )-5-oxotetrahydrofuran-2-yl)-1-

*

phenylethyl]benzenesulfonamide (42) (representative procedure for

gold-catalyzed cycloisomerization and Baeyer–Villiger oxidation)

To a solution of ynamide 35 (379 mg, 0.953 mmol) in CH₂Cl₂

(5 mL) was added AuCl (22 mg, 0.095 mmol, 0.1 equiv). After 24 h at

rt, the reaction mixture was ﬁltered through Celite (CH₂Cl₂) and the

ﬁltrate was evaporated under reduced pressure. The crude cyclo-

butanone 41 was dissolved in AcOH (5 mL) and AcONa$3H₂O

(154 mg, 1.14 mmol, 1.2 equiv) and AcOOH (0.74 mL, 35% solution in

AcOH, 3.8 mmol, 4 equiv)weresuccessivelyadded. After3 hatrt, the

reaction mixture was cooled in an ice-bath and hydrolyzed with

(cat.), toluene, reﬂux] afforded

81). Conversion of the benzylic alcohol in compound 83 to the

g-lactone 83 (96%, three steps from

S. Couty et al. / Tetrahedron 65 (2009) 1809–1832

1823

corresponding azide, with inversion of conﬁguration (DPPA, DBU,

toluene, rt),⁴¹provided compound 84 (64%, dr¼70:30). After re-

duction [PPh₃, THF/H₂O (9:1), rt] and tosylation of the resulting

primary amine (TsCl, Py, rt), a 70:30 mixture of diastereomers was

formed and the major one was found to be identical to lactone 42

(31% isolated yield, two steps from 84).

117.3 (t), 99.0 (s), 71.5 (d), 68.8 (d), 40.8 (t), 38.8 (t), 30.3 (q),19.8 (q);

MS-EI m/z (relative intensity) 217 (MꢁMe^þ, 49), 157 (67), 133 (54),

129 (43),115 (63),107(29),104 (41),103 (23), 91 (54), 79(21), 78 (21),

77 (35), 68 (43), 59 (34). trans diastereomer: ¹H NMR (CDCl₃)

d 7.37–

7.22 (m, 5H), 5.88–5.76 (m,1H), 5.14–5.03 (m, 2H), 4.86 (dd, apparent

t, J¼4.5 Hz, 1H), 4.06–3.98 (m, 1H), 2.42–2.31 (m, 2H), 2.27 (m, 1H),

1.45–1.39 (m, 1H), 1.45 (s, 3H), 1.44 (s, 3H); ¹³C NMR (CDCl₃)

d 142.5

4.6.3.1. 1-Phenylhex-5-en-1,3-diol (79). To a solution of alcohol 77

(3.58 g, 24.2 mmol) in acetone/H₂O (4:1, 50 mL) were added NMO

(3.06 g, 26.1 mmol, 1.1 equiv) and OsO₄(1.5 mL, 4% in H₂O,

0.245 mmol, 0.01 equiv). After 18 h at rt, Celite (5 g) and ﬁnely

ground Na₂S₂O₃$5H₂O (4 g) were added to the reaction mixture.

After 1 h, the resulting mixture was ﬁltered through Celite (EtOAc)

and the ﬁltrate was evaporated under reduced pressure. The resi-

due was adsorbed on silica gel and puriﬁed by ﬂash chromatogra-

phy on silica gel (petroleum ether/EtOAc 70:30, 0:100 then EtOAc/

EtOH 90:10) to afford 4.03 g (91%) of the corresponding triol as

a waxy solid.⁴²To a solution of the latter triol (2.0 g, 11 mmol) in

THF/H₂O (1:1, 80 mL) was added NaIO₄(9.4 g, 44 mmol, 4 equiv).

After 1 h at rt, the reaction mixture was diluted with a saturated

aqueous solution of NH₄Cl and EtOAc. The layers were separated

and the aqueous phase was extracted with EtOAc. The combined

organic extracts were dried over MgSO₄, ﬁltered, and concentrated

(s), 134.2 (d), 128.4 (d, 2C), 127.3 (d), 126.0 (d, 2C), 117.1 (t), 100.7 (s),

68.6 (d), 66.4 (d), 40.2 (t), 39.5 (t), 25.1 (q), 24.8 (q); MS-EI m/z

(relative intensity) 217 (MꢁMe^þ, 13), 174 (30), 162 (9), 157 (39), 133

(34), 129 (29), 115 (42), 107 (58), 106 (11), 105 (100), 104 (53), 103

(27), 91 (40), 79 (20), 78 (24), 77(37), 68 (62), 67(34), 59 (41), 51 (12).

4.6.3.3. 3-(2,2-Dimethyl-6-phenyl-[1,3]dioxan-4-yl)-propan-1-ol(81).

To a solution of 80 (107 mg, 0.46 mmol) in THF (2 mL) at 0 ^ꢀC was

added dropwise a solution of BH₃$THF (1.1 mL,1 M in THF, 1.1 mmol,

2.5 equiv). After 1 h at 0 ^ꢀC, a 3 M aqueous solution of NaOH (3 mL)

and a 30% aqueous solution of H₂O₂(3 mL) were successively added

dropwise at 0 ^ꢀC. After 2 h at rt, the resulting mixture was diluted

with Et₂O and H₂O. The layers were separated and the aqueous

phase was extracted with Et₂O. The combined organic extracts were

washed with brine, dried over MgSO₄, ﬁltered, and concentrated

under reduced pressure. The residue was puriﬁed by ﬂash chro-

matography on silica gel (petroleum ether/EtOAc gradient 80:20

to 70:30) to provide 68 mg (65%) of alcohol 81 as a colorless oil

and as a 70:30 mixture of cis/trans diastereomers (C₁₅H₂₂O₃,

MW¼250.33 g mol^ꢁ1). IR 3384, 1452, 1378, 1253, 1199, 1163, 1119,

1049, 954, 875, 753, 699 cm^ꢁ1. Major cis diastereomer: ¹H NMR

under reduced pressure. The resulting crude

was dissolved in CH₂Cl₂(25 mL) and

b

a

-hydroxyaldehyde 78

solution of allyltri-

chlorostannane [36 mL, 0.365 M stock solution in CH₂Cl₂(prepared

from allylSiMe₃(3.18 mL, 20 mmol) and SnCl₄(2.35 mL, 20 mmol)

in CH₂Cl₂(50 mL), rt, 14 h), 13.2 mmol, 1.2 equiv] was added

at ꢁ78 ^ꢀC. After 1 h at ꢁ78 ^ꢀC, the reaction mixture was allowed to

warm to rt and then successively treated with MeOH (5 mL) and

a saturated aqueous solution of NH₄Cl (10 mL). The resulting mix-

ture was diluted with H₂O and extracted with CH₂Cl₂. The com-

bined organic extracts were washed with brine, dried over MgSO₄,

ﬁltered, and concentrated under reduced pressure. The residue was

puriﬁed by ﬂash chromatography on silica gel (CH₂Cl₂/EtOAc gra-

dient 85:15 to 75:25) to afford 1.50 g (71%, 64% three steps from 77)

of the 1,3-diol 79⁴³as an oil and as a 70:30 inseparable mixture of

syn/anti diastereomers (C₁₂H₁₆O₂, MW¼192.25 g mol^ꢁ1). Major

(CDCl₃)

(m,1H), 3.69–3.59 (m, 2H), 2.58 (br s,1H, OH),1.74–1.49 (m, 6H),1.56

(s, 3H), 1.51 (s, 3H); ¹³C NMR (CDCl₃)

142.2 (s), 128.4 (d, 2C), 127.6

d

7.38–7.24 (m, 5H), 4.90 (dd, J¼11.6, 2.5 Hz, 1H), 4.07–3.94

d

(d), 125.9 (d, 2C), 99.1 (s), 71.5 (d), 69.3 (d), 62.6 (t), 39.2 (t), 33.1 (t),

30.1 (q), 28.7 (t), 19.7 (q); MS-EI m/z (relative intensity) 235

(MꢁMe^þ, 66), 175 (55), 158 (13), 157 (100), 133 (14), 131 (12), 130

(15), 129 (78), 115 (34), 107 (39), 105 (61), 104 (76), 103 (23), 91 (33),

79 (15), 78 (21), 77 (31), 71 (80), 68 (48), 67 (18), 59 (44). Minor trans

diastereomer: ¹H NMR (CDCl₃)

6.2 Hz, 1H), 4.07–3.94 (m, 1H), 3.69–3.59 (m, 2H), 2.58 (br s,1H, OH),

d

7.38–7.24 (m, 5H), 4.87 (dd, J¼9.6,

(1S

*

,3S

*

) syn-diastereomer: ¹H NMR (CDCl₃)

d

7.36–7.24 (m, 5H),

2.02 (ddd, J¼13.0, 9.6, 6.2 Hz, 1H), 1.91 (ddd, J¼13.0, 9.0, 6.2 Hz, 1H),

5.85–5.71 (m, 1H), 5.15–5.08 (m, 2H), 4.91 (dd, J¼9.0, 3.8 Hz, 1H),

1.74–1.49 (m, 4H), 1.45 (br s, 6H); ¹³C NMR (CDCl₃)

d 142.4 (s), 128.4

4.00–3.88 (m, 1H), 3.63 (br s, 1H, OH), 3.22 (br s, 1H, OH), 2.29–2.20

(d, 2C), 127.3 (d), 125.9 (d, 2C), 100.8 (s), 68.6 (d), 67.0 (d), 62.5 (t),

40.0 (t), 32.5 (t), 29.0 (t), 25.0 (q), 24.6 (q); MS-EI m/z (relative in-

tensity) 235 (MꢁMe^þ, 15), 192 (32), 175 (30), 158 (13), 157 (62), 129

(62), 115 (29), 107 (74), 105 (73), 104 (100), 103 (33), 91 (31), 78 (30),

77 (41), 71 (66), 68 (78), 59 (67).

(m, 2H), 1.94–1.76 (m, 2H); ¹³C NMR (CDCl₃)

d

144.3 (s), 134.1 (d),

128.4 (d, 2C), 127.5 (d), 125.6 (d, 2C), 118.3 (t), 75.1 (d), 71.5 (d), 44.8

(t), 42.4 (t). Minor (1S ,3R

) anti-diastereomer: ¹H NMR (CDCl₃)

7.35–7.24 (m, 5H), 5.85–5.71 (m, 1H), 5.14–5.08 (m, 2H), 5.03

*

d

(apparent br d, J¼7.0 Hz, 1H), 4.00–3.88 (m, 1H), 3.27 (br s, 1H, OH),

2.60 (br s, 1H, OH), 2.29–2.20 (m, 2H), 1.94–1.76 (m, 2H); ¹³C NMR

4.6.3.4. 5-(2-Hydroxy-2-phenylethyl)dihydrofuran-2-one (83). To a

solution of 81 (115 mg, 0.459 mmol) in THF/DMSO (1:1, 4 mL) was

added IBX (386 mg, 1.38 mmol, 3 equiv). After 3 h at rt, H₂O (4 mL)

and Et₂O (8 mL) were added and the resulting mixture was ﬁltered

through Celite (Et₂O). The layers of the ﬁltrate were separated and

the aqueous phase was extracted with Et₂O. The combined organic

extracts were washed with brine, dried over MgSO₄, ﬁltered, and

concentrated under reduced pressure. The crude aldehyde was

dissolved in t-BuOH/H₂O (7:2, 9 mL) and to the resulting solution at

(CDCl₃)

d 144.4 (s), 134.4 (d), 128.4 (d, 2C), 127.2 (d), 125.5 (d, 2C),

118.3 (t), 71.5 (d), 67.9 (d), 44.0 (t), 41.9 (t).

4.6.3.2. 6-Allyl-2,2-dimethyl-4-phenyl-[1,3]dioxane (80). To a solu-

tion of 79 (1.10 g, 5.72 mmol) in acetone/2,2-dimethoxypropane

(1:1, 20 mL) was added CSA (66 mg, 0.29 mmol, 0.05 equiv). After

14 h at rt, the reaction mixture was hydrolyzed with a saturated

aqueous solution of NaHCO₃and extracted with EtOAc. The com-

bined organic extracts were washed with brine, dried over MgSO₄,

ﬁltered, and concentrated under reduced pressure to give 1.32 g

(100%) of acetonide 80 as a colorless oil and as a 70:30 mixture of cis/

trans diastereomers. This compound was directly engaged in the

next step without puriﬁcation (C₁₅H₂₀O₂, MW¼232.32

g mol^ꢁ1). IR 1642, 1378, 1198, 1167, 1100, 1070, 961, 914, 752,

rt were successively added 2-methylbut-2-ene (490 mL, 4.59 mmol,

10 equiv), NaH₂PO₄$H₂O (790 mg, 5.05 mmol, 11 equiv), and

NaClO₂(250 mg, 2.76 mmol, 6 equiv). After 1.5 h at rt, the reaction

mixture was hydrolyzed with a saturated aqueous solution of

NaH₂PO₄and slightly acidiﬁed (pH <3) by dropwise addition of

a 1 M aqueous solution of KHSO₄. After extraction with Et₂O, the

combined organic extracts were dried over MgSO₄, ﬁltered, and

concentrated under reduced pressure. The crude carboxylic acid 82

was treated with 80% aqueous AcOH (2 mL). After 3 h at rt, the

reaction mixture was concentrated under reduced pressure and the

residue was taken-up several times with toluene and evaporated

697 cm^ꢁ1. cis diastereomer: ¹H NMR (CDCl₃)

d 7.37–7.22 (m, 5H),

5.88–5.76 (m, 1H), 5.14–5.03 (m, 2H), 4.88 (dd, J¼9.1, 2.6 Hz, 1H),

4.06–3.98 (m, 1H), 2.42–2.31 (m, 1H), 2.18 (m, 1H), 1.95 (m, 1H), 1.73

(apparent dt, J¼13.2, 2.5 Hz, 1H), 1.55 (s, 3H), 1.51 (s, 3H); ¹³C NMR

(CDCl₃)

d 142.4 (s), 133.9 (d), 128.4 (d, 2C), 127.5 (d), 125.9 (d, 2C),

1824

S. Couty et al. / Tetrahedron 65 (2009) 1809–1832

under reduced pressure. The crude material was dissolved in tol-

uene (10 mL) and a few crystals of CSA were added. The resulting

mixture was heated at reﬂux for 1 h and concentrated under re-

duced pressure. The crude material was puriﬁed by ﬂash chro-

matography on silica gel (petroleum ether/EtOAc 50:50) and

79 mg (96%, four steps from alcohol 81) of lactone 83 was

obtained as a colorless oil and as a 70:30 mixture of diastereomers

(C₁₂H₁₄O₃, MW¼206.24 g mol^ꢁ1). IR 3424, 1761, 1179, 1142, 1039,

915, 760, 701, 642 cm^ꢁ1. Major diastereomer: ¹H NMR (CDCl₃)

reaction mixture was hydrolyzed with a 1 M solution of hydro-

chloric acid and diluted with EtOAc. After 1 h stirring, the layers

were separated and the aqueous phase was extracted with EtOAc.

The combined organic extracts were successively washed with

a saturated aqueous solution of NaHCO₃, brine, dried over MgSO₄,

ﬁltered, and concentrated under reduced pressure. The residue was

puriﬁed by ﬂash chromatography on silica gel (petroleum ether/

EtOAc 70:30þ0.5% Et₃N) to afford 78 mg (65%) of cyclobutanone 44

as a colorless oil (dr¼95:5) (C₁₅H₁₉NO₅S, MW¼325.38 g mol^ꢁ1). IR

3266, 1775, 1740, 1597, 1495, 1435, 1339, 1206, 1158, 1090, 815,

d

7.38–7.32 (m, 5H), 4.87 (t, J¼7.0 Hz, 1H), 4.38 (m, 1H), 2.75 (br s,

1H, OH), 2.55–2.40 (m, 2H), 2.35–2.24 (m, 2H), 2.00–1.80 (m, 2H);

¹³C NMR (CDCl₃)

176.9 (s), 143.3 (s), 128.7 (d, 2C), 128.1 (d), 126.0

(d, 2C), 78.6 (d), 71.8 (d), 44.6 (t), 28.5 (t), 28.2 (t). Minor dia-

stereomer: ¹H NMR (CDCl₃)

7.38–7.32 (m, 5H), 4.94 (dd, J¼9.4,

3.4 Hz, 1H), 4.84–4.79 (m, 1H), 2.75 (br s, 1H, OH), 2.55–2.40 (m,

2H), 2.35–2.24 (m, 1H), 2.00–1.80 (m, 3H); ¹³C NMR (CDCl₃)

177.1

662 cm^ꢁ1

;

¹H NMR (CDCl₃)

d

7.72 (d, J¼8.2 Hz, 2H), 7.27 (d,

d

J¼8.2 Hz, 2H), 5.61 (d, J¼9.4 Hz, 1H, NH), 4.08 (ddd, J¼9.4, 7.5,

4.7 Hz, 1H), 3.49 (s, 3H), 3.48–3.37 (m, 1H), 3.08 (dddd, J¼18.0, 10.7,

8.4, 2.3 Hz, 1H), 2.88 (dddd, J¼18.0, 9.4, 4.6, 2.7 Hz, 1H), 2.40 (s, 3H),

2.23 (dddd, apparent qd, J¼10.7, 4.6 Hz, 1H), 2.07 (ddd, J¼14.2, 7.8,

4.7 Hz, 1H), 1.85 (ddd, apparent dt, J¼14.2, 7.5 Hz, 1H), 1.68–1.59 (m,

d

(s), 144.1 (s), 128.7 (d, 2C), 127.8 (d), 125.5 (d, 2C), 77.8 (d), 70.8 (d),

45.1 (t), 28.8 (t), 28.3 (t); MS-EI m/z (relative intensity) 206 (M^þ,

10), 188 (MꢁH₂O^þ, 5), 133 (7), 108 (10), 107 (79), 106 (9), 105 (50),

104 (9), 103 (7), 101 (7), 100 (100), 85 (10), 82 (9), 79 (67), 78 (13),

77 (44), 58 (7), 55 (14), 51 (11).

1H); ¹³C NMR (CDCl₃)

d 210.0 (s), 171.4 (s), 143.6 (s), 136.7 (s), 129.6

(d, 2C), 127.2 (d, 2C), 56.2 (d), 54.2 (d), 52.5 (q), 44.7 (t), 32.7 (t), 21.5

(q), 16.9 (t); MS-EI m/z (relative intensity) 325 (M^þ, 1), 297 (15), 266

(18), 242 (27), 238 (8), 224 (11), 174 (8), 170 (28), 155 (99), 142 (17),

94 (12), 92 (11), 91 (100), 88 (9), 65 (18), 55 (17). Anal. Calcd

for C₁₅H₁₉NO₅S: C, 55.37; H, 5.89; N, 4.30. Found: C, 55.46; H, 5.73;

N, 4.23.

4.6.3.5. 5-(2-Azido-2-phenylethyl)dihydrofuran-2-one (84). To a so-

lution of benzylic alcohol 83 (35 mg, 0.17 mmol) and DPPA (73

0.34 mmol, 2 equiv) in toluene (2 mL) at 0 ^ꢀC was added DBU

(51 L, 0.34 mmol, 2 equiv). After 14 h at rt the reaction mixture

mL,

4.6.5. Methyl (2R

*

,3S )-3-(5-oxotetrahydrofuran-2-yl)-2-(toluene-

*

m

4-sulfonylamino)propanoate (45)

was hydrolyzed with H₂O (1 mL) and a 1 M solution of hydrochloric

acid (1 mL). After extraction with EtOAc, the combined organic

extracts were dried over MgSO₄, ﬁltered, and concentrated under

reduced pressure. The residue was puriﬁed by ﬂash chromatogra-

phy on silica gel (petroleum ether/EtOAc 80:20) to afford 25 mg

(64%) of azide 84 as a colorless oil and a 70:30 mixture of dia-

stereomers (C₁₂H₁₃N₃O₂, MW¼231.25 g mol^ꢁ1). IR 2099, 1777, 1179,

1028, 958, 919, 763, 702 cm^ꢁ1. Major diastereomer: ¹H NMR (CDCl₃)

This compound was prepared by Baeyer–Villiger oxidation of

cyclobutanone 44 (10 mg, 0.030 mmol) with AcOOH (25 mL, 32% in

AcOH, 0.12 mmol, 4 equiv) in the presence of AcONa$3H₂O (5 mg,

0.04 mmol, 1.2 equiv) in AcOH (1 mL). After 12 h at rt, work-up and

puriﬁcation by ﬂash chromatography on silica gel (petroleum

ether/EtOAc 50:50 to 30:70) provided 7 mg (67%) of lactone 45 as

a white oil (C₁₅H₁₉NO₆S, MW¼341.38 g mol^ꢁ1). IR 3281, 1775, 1724,

1453, 1430, 1336, 1154, 1091, 1058, 812, 666 cm^ꢁ1; ¹H NMR (CDCl₃)

d

7.44–7.30 (m, 5H), 4.81–4.74 (m, 2H), 4.24–4.17 (m, 1H), 2.64–2.49

(m, 2H), 2.45–2.36 (m, 1H), 2.07–1.81 (m, 3H). Minor diastereomer:

¹H NMR (CDCl₃)

d

7.73 (d, J¼8.2 Hz, 2H), 7.30 (d, J¼8.2 Hz, 2H), 5.29 (d, J¼9.6 Hz, 1H,

NH), 4.72–4.64 (m, 1H), 4.13 (ddd, apparent td, J¼9.6, 3.5 Hz, 1H),

d

7.44–7.30 (m, 5H), 4.70 (dd, J¼9.6, 5.9 Hz, 1H),

3.51 (s, 3H), 2.57–2.50 (m, 2H), 2.42 (s, 3H), 2.41–2.33 (m, 1H), 2.10–

4.21 (m, 1H), 2.64–2.49 (m, 2H), 2.30–2.22 (m, 1H), 2.07–1.81 (m,

2.04 (m, 1H), 1.90–1.80 (m, 2H); ¹³C NMR (CDCl₃)

d 176.1 (s), 171.5

3H). ¹³C NMR (CDCl₃) only the signals corresponding to the major

(s), 144.0 (s), 136.2 (s), 129.7 (d, 2C), 127.4 (d, 2C), 76.6 (d), 53.3 (d),

52.8 (q), 39.6 (t), 28.7 (t), 28.1 (t), 21.6 (q); MS-EI m/z (relative in-

tensity) 341 (M^þ, 3), 283 (15), 282 (MꢁCO₂Me^þ, 100), 236 (8), 198

(23), 155 (58), 110 (21), 91 (79), 85 (38), 65 (14). Anal. Calcd for

C₁₉H₂₁NO₄S: C, 63.49; H, 5.89; N, 3.90. Found: C, 63.11; H, 5.84; N,

3.74.

diastereomer could all be assigned unambiguously

(s), 129.1 (d, 2C), 128.7 (d), 126.7 (d, 2C), 77.3 (d), 62.8 (d), 42.9 (t),

28.7 (t), 28.1 (t).

d 176.6 (s), 139.1

4.6.3.6. Synthesis of

g-lactone 42 from azide 84. To a solution of

azide 84 (25 mg, 0.11 mmol) in THF/H₂O (9:1, 2 mL) was added PPh₃

(31 mg, 0.12 mmol, 1.1 equiv). After 3 h at 50 ^ꢀC, the reaction mix-

ture was diluted with H₂O and Et₂O. The layers were separated and

the aqueous phase was extracted with Et₂O. The combined organic

extracts were dried over MgSO₄, ﬁltered, and concentrated under

reduced pressure. The residue was dissolved in pyridine (2 mL) and

TsCl (23 mg, 0.12 mmol, 1.1 equiv) was added. After 48 h at rt, the

reaction mixture was acidiﬁed by addition of a 4 M solution of

hydrochloric acid. After extraction with EtOAc, the combined or-

ganic extracts were dried over MgSO₄, ﬁltered, and concentrated

4.6.6. N-[(2S

*

)-3-Benzyloxy-2-((2S )-2-oxocyclobutyl)propyl]-4-

*

methylbenzenesulfonamide (46)

According to the representative procedure (see Section 4.6.1),

the gold-catalyzed cycloisomerization of ynamide 36 (136 mg,

0.310 mmol) with AuCl (14 mg, 0.062 mmol, 0.2 equiv) in CH₂Cl₂

(5 mL) (72 h at rt) led, after puriﬁcation by ﬂash chromatography on

silica gel (petroleum ether/EtOAc 75:25, 70:30), to 66 mg (55%) of

cyclobutanone 46 (55%) as a colorless oil and as a 90:10 inseparable

mixture of diastereomers (C₂₁H₂₅NO₄S, MW¼387.49 g mol^ꢁ1). IR

3277, 1771, 1597, 1327, 1156, 1089, 1027, 814, 737, 698, 661 cm^ꢁ1; ¹H

NMR (CDCl₃) only the signals corresponding to the major dia-

under reduced pressure. A 70:30 mixture of diastereomeric

tones was obtained and the major diastereomer was found to be

identical to -lactone 42 (prepared by the gold-catalyzed cyclo

g-lac-

g

stereomer could all be assigned unambiguously

d

7.52 (d, J¼8.3 Hz,

isomerization and Baeyer–Villiger oxidation sequence applied to

ynamide 35). The crude product was puriﬁed by ﬂash chromatog-

raphy on silica gel (petroleum ether/EtOAc 80:20) to afford 11.5 mg

(31%) of 42 as a white solid.

2H), 7.20–7.00 (m, 7H), 5.39 (t, J¼6.2 Hz, 1H, NH), 4.25 (d, AB syst,

J¼11.9 Hz, 1H), 4.21 (d, AB syst, J¼11.9 Hz, 1H), 3.25 (dd, J¼9.5,

4.0 Hz, 1H), 3.16 (dd, J¼9.5, 6.1 Hz, 1H), 3.13–3.04 (m, 1H), 2.97–2.86

(m, 2H), 2.86–2.74 (m, 1H), 2.62 (dddd, J¼17.8, 9.5, 4.6, 2.6 Hz, 1H),

2.21 (s, 3H), 1.92–1.80 (m, 2H), 1.56–1.43 (m, 1H); ¹³C NMR (CDCl₃)

only the signals corresponding to the major diastereomer could all be

4.6.4. Methyl (2R

*

,3S )-3-(2-oxocyclobutyl)-2-(toluene-4-

*

sulfonylamino)propanoate (44)

assigned unambiguously d 210.8 (s), 143.1 (s), 137.7 (s), 137.0 (s),

To a solution of 43 (114 mg, 0.371 mmol) in CH₂Cl₂(3 mL) was

added AuCl (8.0 mg, 0.037 mmol, 0.1 equiv). After 1 h at rt, the

129.6 (d, 2C), 128.4 (d, 2C), 127.8 (d), 127.6 (d, 2C), 127.0 (d, 2C), 73.1

(t), 69.6 (t), 60.0 (d), 44.1 (t), 44.0 (t), 39.5 (d), 21.4 (q), 15.0 (t); MS-

S. Couty et al. / Tetrahedron 65 (2009) 1809–1832

1825

EI m/z (relative intensity) 296 (MꢁBn^þ, 2), 281 (MꢁBnOH^þ, 3), 266

(MꢁCH₂OBn^þ, 2), 232 (18), 207 (5), 184 (11), 155 (32), 92 (11), 91

(100), 65 (8); HRMS calcd for C₂₁H₂₆NO₄S (MþH^þ): 388.1583,

found: 388.1579.

133.8 (d, 2C), 129.7 (d), 129.6 (d, 2C), 128.0 (d, 2C), 127.1 (d, 2C), 42.7

(t), 36.3 (t), 23.4 (t), 21.5 (q), ꢁ3.2 (q, 2C).

4.6.9. N-{2-[(2R

*

,3S )-3-(Dimethylphenylsilyl)-5-oxotetra-

*

hydrofuran-2-yl]ethyl}-4-methylbenzenesulfonamide (50)

4.6.7. N-[(2S

*

)-3-Benzyloxy-2-((2S

*

)-2-oxotetrahydrofuran-3-

This compound was prepared by treatment of a 75:25 mixture

of cyclobutanone 48 and enone 49 (21 mg, 0.052 mmol,

0.039 mmol of 48) with AcOOH (0.16 mL, 32% in AcOH, 0.80 mmol,

16 equiv) in the presence of AcONa$3H₂O (8.5 mg, 0.062 mmol,

1.2 equiv) in AcOH (1 mL). After 72 h at rt, work-up and puriﬁcation

by ﬂash chromatography on silica gel (petroleum ether/EtOAc

75:25, 70:30) afforded 12.5 mg (57%, 77% based on cyclobutanone

yl)propyl]-4-methylbenzenesulfonamide (47)

According to the representative procedure (see Section 4.6.2),

ynamide 36 (450 mg, 1.02 mmol) underwent a gold-catalyzed

cycloisomerization with AuCl (36 mg, 0.15 mmol, 0.15 equiv) in

CH₂Cl₂(5 mL). After 72 h at rt and work-up, the crude cyclo-

butanone 46 was subjected to a Baeyer–Villiger oxidation with

AcOOH (790

m

L, 32% in AcOH, 4.07 mmol, 4 equiv) in the presence

48) of lactone 50 as

a

colorless oil (C₂₁H₂₇NO₄SSi,

of AcONa$3H₂O (167 mg, 1.22 mmol, 1.2 equiv) in AcOH (5 mL).

After 16 h at rt, work-up and puriﬁcation by ﬂash chromatography

on silica gel (petroleum ether/EtOAc 50:50) afforded 229 mg (56%)

of lactone 47 as a yellow oil and as a 90:10 inseparable mixture of

diastereomers (C₂₁H₂₅NO₅S, MW¼403.49 g mol^ꢁ1). IR 3274, 1769,

1598, 1454, 1328, 1184, 1156, 1091, 1018, 913, 813, 738, 699,

MW¼417.59 g mol^ꢁ1). IR 3286, 1770, 1598, 1427, 1330, 1253, 1212,

1159,1094, 947, 817, 780, 737, 703, 663 cm^ꢁ1; ¹H NMR (CDCl₃)

d 7.71

(d, J¼8.2 Hz, 2H), 7.47–7.40 (m, 5H), 7.30 (d, J¼8.2 Hz, 2H), 4.54 (br t,

J¼5.9 Hz, 1H, NH), 4.33 (ddd, apparent td, J¼10.0, 2.2 Hz, 1H), 3.10–

2.94 (m, 2H), 2.50 (dd, J¼17.7, 9.1 Hz, 1H), 2.43 (s, 3H), 2.32 (dd,

J¼17.7, 12.8 Hz, 1H), 1.77–1.68 (m, 1H), 1.64–1.55 (m, 2H), 0.37 (s,

661 cm^ꢁ1

;

¹H NMR (CDCl₃) only the signals corresponding to the

7.71 (d,

6H); ¹³C NMR (CDCl₃)

d 176.5 (s), 143.6 (s), 136.6 (s), 134.9 (s), 133.8

major diastereomer could all be assigned unambiguously

d

(d, 2C), 130.1 (d), 129.8 (d, 2C), 128.4 (d, 2C), 127.1 (d, 2C), 81.2 (d),

40.4 (t), 36.2 (t), 31.7 (t), 29.6 (d), 21.5 (q), ꢁ4.3 (q), ꢁ4.9 (q); MS-EI

m/z (relative intensity) 402 (MꢁMe^þ, 9), 340 (MꢁPh^þ, 8), 318 (26),

213 (20), 211 (18), 184 (13), 156 (23), 155 (32), 149 (8), 137 (20), 136

(16), 135 (100), 112 (9), 105 (9), 91 (42), 65 (8); HRMS calcd for

C₂₁H₂₈NO₄SSi (MþH^þ): 418.1508, found: 418.1509.

J¼8.3 Hz, 2H), 7.38–7.24 (m, 7H), 4.99 (t, J¼6.5 Hz, 1H, NH), 4.48

(d, AB syst, J¼11.9 Hz, 1H), 4.46–4.42 (m, 1H), 4.42 (d, AB syst,

J¼11.9 Hz, 1H), 3.57 (dd, J¼9.7, 4.4 Hz, 1H), 3.51 (dd, J¼9.7, 5.3 Hz,

1H), 3.20 (ddd, J¼13.2, 6.5, 4.6 Hz, 1H), 3.13 (ddd, apparent dt,

J¼13.2, 6.5 Hz, 1H), 2.52–2.42 (m, 2H), 2.42 (s, 3H), 2.23 (dq ap-

parent, J¼12.6, 6.2 Hz, 1H), 2.02–1.86 (m, 2H); ¹³C NMR (CDCl₃)

only the signals corresponding to the major diastereomer could all be

4.6.10. N-{2-[(1S

*

,2R )-2-(Dimethylphenylsilyl)-4-oxocyclo-

*

assigned unambiguously

d

176.4 (s), 143.4 (s), 137.4 (s), 136.6 (s),

butyl]ethyl}-4-methylbenzenesulfonamide (51)

129.7 (d, 2C), 128.5 (d, 2C), 127.9 (d), 127.7 (d, 2C), 126.9 (d, 2C),

79.8 (d), 73.4 (t), 67.8 (t), 43.8 (d), 42.5 (t), 28.7 (t), 26.4 (t), 21.5

(q); MS-EI m/z (relative intensity) 312 (MꢁBn^þ, 1), 297

(MꢁBnOH^þ, 3), 281 (MꢁCH₂OBn^þ, 2), 248 (27), 231 (7), 184

(18), 171 (6), 155 (32), 142 (20), 127 (15), 92 (11), 91 (100), 65

(10); HRMS calcd for C₂₁H₂₆NO₅S (MþH^þ): 404.1532, found:

404.1537.

According to the representative procedure (see Section 4.6.1),

the gold-catalyzed cycloisomerization of ynamide 38 (100 mg,

0.22 mmol) with AuCl (15 mg, 0.066 mmol, 0.3 equiv) in CH₂Cl₂

(5 mL) (48 h at rt) led, after work-up and puriﬁcation by ﬂash

chromatography on silica gel (petroleum ether/EtOAc 85:15,

80:20), to 41 mg (47%) of cyclobutanone 51 as a yellow oil

(C₂₁H₂₇NO₃SSi, MW¼401.59 g mol^ꢁ1). IR 3274, 1763, 1597, 1427,

1327, 1251, 1156, 1111, 1091, 812, 772, 732, 701, 660 cm^ꢁ^{1 1}H NMR

;

4.6.8. Gold-catalyzed cycloisomerization of 1,6-ene-ynamide 37

According to the representative procedure (see Section 4.6.1),

the gold-catalyzed cycloisomerization of ynamide 37 (52 mg,

0.11 mmol) with AuCl (7 mg, 0.03 mmol, 0.25 equiv) in CH₂Cl₂

(5 mL) (48 h at rt) led, after work-up and puriﬁcation by ﬂash

chromatography on silica gel (petroleum ether/EtOAc 85:15,

80:20), to 21 mg (47%) of a 75:25 inseparable mixture of cyclo-

(CDCl₃)

d

7.69 (d, J¼8.3 Hz, 2H), 7.47–7.43 (m, 2H), 7.38–7.30 (m,

3H), 7.28 (d, J¼8.3 Hz, 2H), 5.34 (dd, J¼7.4, 4.3 Hz, 1H, NH), 3.52–

3.42 (m, 1H), 3.27 (ddd, J¼17.5, 12.2, 1.5 Hz, 1H), 3.03–2.95 (m, 1H),

2.80–2.71 (m, 2H), 2.41 (s, 3H), 2.02 (ddd, apparent td, J¼12.2,

6.0 Hz,1H),1.71–1.59 (m,1H),1.57–1.48 (m,1H), 0.29 (s, 3H), 0.25 (s,

3H); ¹³C NMR (CDCl₃)

d 210.5 (s), 143.1 (s), 137.3 (s), 137.1 (s), 133.5

(d, 2C), 129.6 (d, 2C), 129.4 (d), 128.0 (d, 2C), 127.0 (d, 2C), 60.1 (d),

45.8 (t), 42.0 (t), 28.0 (t), 21.4 (q), 14.4 (d), ꢁ3.2 (q), ꢁ3.8 (q); MS-EI

m/z (relative intensity) 386 (MꢁMe^þ, 4), 373 (8), 371 (5), 318 (15),

213 (34), 211 (28), 184 (11), 155 (22), 149 (10), 137 (12), 136 (14), 135

(100), 91 (36), 78 (22), 77 (10).

butanone 48 and enone 49 as

a yellow oil (C₂₁H₂₇NO₃SSi,

MW¼401.59 g mol^ꢁ1). IR 3274, 1766, 1673, 1597, 1427, 1326, 1250,

1156, 1114, 1092, 812, 773, 734, 700, 658 cm^ꢁ1

.

N-{2-[(1S

*

,2S

*

)-2-(Dimethylphenylsilyl)-4-oxo-cyclobutyl]ethyl}-

4-methylbenzenesulfonamide (48). ¹H NMR (CDCl₃)

d

7.69

(d, J¼8.1 Hz, 2H), 7.52–7.45 (m, 2H), 7.42–7.34 (m, 3H), 7.28 (d,

J¼8.1 Hz, 2H), 5.24 (br s, 1H, NH), 3.05–2.90 (m, 3H), 2.83–2.76

(m, 2H), 2.41 (s, 3H), 1.72–1.60 (m, 1H), 1.57–1.48 (m, 1H), 1.31 (ddd,

4.6.11. N-{2-[(2R

*

,3R )-3-(Dimethylphenylsilyl)-5-oxotetra-

*

hydrofuran-2-yl]ethyl}-4-methylbenzenesulfonamide (52)

This compound was prepared by Baeyer–Villiger oxidation of

cyclobutanone 51 (13 mg, 0.032 mmol) with AcOOH (50 mL, 32% in

apparent q, J¼9.8 Hz, 1H), 0.33 (s, 6H); ¹³C NMR (CDCl₃)

d

209.0 (s),

143.2 (s),137.0 (s),136.3 (s),133.6 (d, 2C),129.7 (d),129.6 (d, 2C),128.1

(d, 2C),127.0 (d, 2C), 60.2 (d), 45.8 (t), 41.4 (t), 30.0 (t), 21.5 (q),16.5 (d),

ꢁ4.7 (q), ꢁ5.1 (q); MS-EI m/z (relative intensity) 386 (MꢁMe^þ, 2), 373

(9), 318 (16), 213 (32), 211 (28), 184 (11), 155 (24), 149 (12), 137 (16),

136 (16), 135 (100), 91 (48), 65 (11).

AcOH, 1.6 mmol, 8 equiv) in the presence of AcONa$3H₂O (5 mg,

0.04 mmol, 1.2 equiv) in AcOH (1 mL). After 16 h at rt, work-up and

puriﬁcation by ﬁltration through a short plug of silica gel (petroleum

ether/EtOAc 70:30) afforded 8.3 mg (62%) of lactone 52 as a colorless

oil (C₂₁H₂₇NO₄SSi, MW¼417.59 g mol^ꢁ1). IR 3274, 1771, 1598, 1428,

N -[(E)-6-(Dimethylphenylsilyl)-4-oxohex-5-enyl]-4-methylben

zenesulfonamide (49). The spectral data of this compound were

deduced from the analysis of the spectra of the 75:25 inseparable

1330, 1256, 1160, 1111, 1094, 818, 738, 704, 663 cm^ꢁ^{1 1}H NMR

;

(CDCl₃)

d

7.69 (d, J¼8.3 Hz, 2H), 7.47–7.35 (m, 5H), 7.29 (d, J¼8.3 Hz,

2H), 4.72–4.65 (m, 2H, 1HþNH), 3.04–2.95 (m, 2H), 2.48 (dd, J¼17.4,

8.9 Hz, 1H), 2.42 (s, 3H), 2.37 (dd, J¼17.4, 12.2 Hz, 1H), 2.20–2.12 (m,

1H),1.75–1.67(m,1H),1.59–1.49 (m,1H), 0.36 (s, 3H), 0.34(s, 3H); ¹³C

mixture of compounds 48 and 49. ¹H NMR (CDCl₃)

d 7.70 (m, 2H),

7.52–7.27 (m, 7H), 7.15 (d, J¼19.2 Hz, 1H), 6.46 (d, J¼19.2 Hz, 1H),

4.75 (m, 1H, NH), 2.98–2.89 (m, 2H), 2.66 (t, J¼6.8 Hz, 2H), 2.40 (s,

3H), 1.77 (apparent quintet, J¼6.8 Hz, 2H), 0.42 (s, 6H); ¹³C NMR

NMR (CDCl₃)

d 176.9 (s), 143.6 (s), 136.7 (s), 135.8 (s), 133.6 (d, 2C),

129.9 (d), 129.8 (d, 2C), 128.3 (d, 2C), 127.1 (d, 2C), 81.4 (d), 40.5 (t),

33.6 (t), 29.9 (t), 28.3 (d), 21.5 (q), ꢁ3.4 (q), ꢁ3.7 (q).

(CDCl₃)

d

199.4 (s), 145.3 (d), 143.3 (s), 143.0 (d), 136.9 (s), 136.2 (s),

1826

S. Couty et al. / Tetrahedron 65 (2009) 1809–1832

4.6.12. N-{2-[(2R

*

,3R

*

)-3-Hydroxy-5-oxotetrahydrofuran-2-

(d, J¼8.2 Hz, 2H), 7.48 (dd, J¼5.6, 1.5 Hz, 1H), 7.31 (d, J¼8.2 Hz, 2H),

yl]ethyl}-4-methylbenzenesulfonamide (53)

6.10 (dd, J¼5.6, 2.0 Hz, 1H), 5.14 (m, 1H), 4.92 (br t, J¼6.2 Hz, 1H,

Ynamide 38 (81 mg, 0.18 mmol) was subjected to a gold-cata-

lyzed cycloisomerization with AuCl (10 mg, 0.044 mmol,

0.25 equiv) in CH₂Cl₂(2 mL). After 72 h at rt and work-up, the crude

cyclobutanone 51 was dissolved in AcOH (1 mL) and to the resulting

solution were successively added AcONa (44 mg, 0.55 mmol,

3.3 equiv), KBr (44 mg, 0.37 mmol, 2.1 equiv), and AcOOH (4.3 mL,

32% in AcOH, 22.2 mmol, 125 equiv). After 16 h at rt, the reaction

mixture was diluted with EtOAc, cooled to 0–5 ^ꢀC, and hydrolyzed

with a 25% aqueous solution of Na₂S₂O₃(20 mL). After addition of

H₂O, the layers were separated and the aqueous phase was

extracted with EtOAc. The combined organic extracts were suc-

cessively washed with a saturated aqueous solution of NaHCO₃,

brine, dried over MgSO₄, ﬁltered, and concentrated under reduced

pressure. The residue was puriﬁed by ﬂash chromatography on

silica gel (petroleum ether/EtOAc 30:70) to afford 15 mg (26%) of

lactone 53 as a yellow oil (C₁₃H₁₇NO₅S, MW¼299.34 g mol^ꢁ1). IR

NH), 3.22–3.05 (m, 2H), 2.43 (s, 3H), 2.14–2.06 (m, 1H), 1.76–1.68

(m, 1H); ¹³C NMR (CDCl₃)

d 172.6 (s), 156.0 (d), 143.8 (s), 136.4 (s),

129.9 (d, 2C), 127.1 (d, 2C), 121.7 (d), 80.9 (d), 39.6 (t), 33.5 (t), 21.5

(q); MS-EI m/z (relative intensity) 281 (M^þ, 22), 239 (6), 156 (11),

126 (53), 106 (6), 92 (23), 91 (100), 89 (6), 84 (27), 80 (10), 68 (6), 65

(20), 56 (6).

4.6.13.2. Synthesis of

g-lactone 50 by silylcupration of the a,b-un-

saturated -lactone 85. To a suspension of lithium pieces (21 mg,

g

3.0 mmol) in THF (2 mL) at 0 ^ꢀC was added chloro-

dimethylphenylsilane (0.17 mL, 1.0 mmol). The reaction ﬂask was

placed in an ultrasound bath for 15 min to initiate the reaction and

then stirred at 0 ^ꢀC. After 16 h, the resulting organosilyllithium

reagent (PhMe₂SiLi) was cannulated into a suspension of CuCN

(45 mg, 0.50 mmol) in THF (2.5 mL) at ꢁ50 ^ꢀC. After 30 min at

ꢁ50 ^ꢀC, the resulting silylcyanocuprate solution ((PhMe₂Si)₂

-

3480, 3275, 1759, 1597, 1421, 1322, 1154, 1091, 815, 704, 663 cm^ꢁ1

¹H NMR (CDCl₃)

;

Cu(CN)Li₂) was cannulated into a solution of the a,b-unsaturated

d

7.73 (d, J¼8.3 Hz, 2H), 7.32 (d, J¼8.3 Hz, 2H), 5.33

g

-lactone 85 (10 mg, 0.035 mmol) in THF (2 mL) at ꢁ50 ^ꢀC. After 2 h

(t, J¼6.2 Hz, 1H, NH), 4.54–4.47 (m, 2H), 3.18 (br s, 1H, OH), 3.09 (td,

apparent q, J¼6.5 Hz, 2H), 2.81 (dd, J¼17.8, 5.5 Hz, 1H), 2.54 (ap-

parent d, J¼17.8 Hz, 1H), 2.43 (s, 3H), 2.04 (td, apparent q, J¼6.5 Hz,

at ꢁ50 ^ꢀC, the reaction mixture was poured into a mixture of

a saturated aqueous solution of NH₄Cl and a 28% aqueous solution

of NH₄OH (pH¼8). The resulting mixture was stirred until it became

homogeneous and was then extracted with EtOAc. The combined

organic extracts were washed with brine, dried over MgSO₄, ﬁl-

tered, and concentrated under reduced pressure. The residue was

puriﬁed by ﬂash chromatography on silica gel (petroleum ether/

EtOAc 80:20, 70:30) to afford 13 mg (80%) of lactone 50.

2H); ¹³C NMR (CDCl₃)

d 176.1 (s), 143.8 (s), 136.1 (s), 129.9 (d, 2C),

127.1 (d, 2C), 82.8 (d), 68.7 (d), 40.0 (t), 39.1 (t), 28.6 (t), 21.5 (q);

MS-EI m/z (relative intensity) 281 (MꢁH₂O^þ, 22), 239 (7), 156 (11),

155 (43), 139 (4), 126 (52), 106 (6), 92 (23), 91 (100), 89 (7), 84 (27),

80 (11), 68 (6), 65 (22), 56 (6).

4.6.13. Chemical correlation for the attribution of the relative

4.6.14. N-{(R

*

)-2-[(1R

*

,2S )-2-(tert-Butyldimethylsilyl-

*

conﬁguration of lactones 50 and 52

oxymethyl)-4-oxocyclobutyl]-1-phenylethyl}-4-methylbenzene-

sulfonamide (54)

The

b

-hydroxylactone 53 was dehydrated (MsCl, Et₃N, CH₂Cl₂,

-substituted -unsaturated -lac-

0 ^ꢀC to rt) and the resulting

g

a

,

b

g

According to the representative procedure (see Section 4.6.1),

the gold-catalyzed cycloisomerization of ynamide 39 (15 mg,

0.028 mmol) with AuCl (1 mg, 0.002 mmol, 0.1 equiv) in CH₂Cl₂

(1 mL) (16 h at rt) led, after work-up and puriﬁcation by ﬂash

chromatography on silica gel (petroleum ether/EtOAc 85:15), to

7.5 mg (55%) of cyclobutanone 54 as a colorless oil (C₂₆H₃₇NO₄SSi,

MW¼487.73 g mol^ꢁ1). IR 3272, 1774, 1599, 1460, 1332, 1253, 1160,

tone 85 (71%) underwent a highly diastereoselective silylcupration

[(PhMe₂Si)₂Cu(CN)Li₂, THF, ꢁ50 ^ꢀC] leading to the trans-

b-silyllac-

tone 50 (80%, dr >95:5).⁴⁴The same compound was obtained from

ynamide 37, bearing a (E)-alkenyl silane, by a gold-catalyzed

cycloisomerization followed by a Baeyer–Villiger oxidation.

1092, 837, 814, 777, 701, 669 cm^ꢁ^{1 1}H NMR (CDCl₃)

; d 7.57 (d,

O

J¼8.5 Hz, 2H), 7.18–7.08 (m, 5H), 7.06–7.02 (m, 2H), 6.34 (d,

J¼8.4 Hz, 1H, NH), 4.62 (ddd, dt apparent, J¼8.4, 5.2 Hz, 1H), 3.64

(dd, J¼10.3, 4.2 Hz, 1H), 3.57 (dd, J¼10.3, 5.2 Hz, 1H), 2.97–2.90 (m,

1H), 2.85 (ddd, J¼17.2, 8.1, 2.4 Hz, 1H), 2.78 (ddd, J¼17.2, 8.3, 1.9 Hz,

1H), 2.34 (s, 3H), 2.16–2.06 (m, 1H), 1.96–1.90 (m, 2H), 0.77 (s, 9H),

Ts

NH

O

NH O

MsCl, Et₃N

CH₂Cl₂, 0 °C to rt

71%

OH

53

85

(PhMe₂Si)Cu(CN)Li₂

80%

O

ꢁ0.08 (s, 3H), ꢁ0.14 (s, 3H); ¹³C NMR (CDCl₃)

d 210.6 (s), 142.8 (s),

THF, −50 °C

Ts

O

139.7 (s),138.2 (s),129.3 (d, 2C),128.4 (d, 2C),127.2 (d),127.0 (d, 2C),

126.3 (d, 2C), 63.7 (t), 57.0 (d), 55.5 (d), 45.0 (t), 35.9 (t), 32.0 (d),

25.8 (q, 3C), 21.4 (q), 18.2 (s), ꢁ5.7 (q, 2C); MS-EI m/z (relative in-

tensity) 430 (Mꢁt-Bu^þ), 332 (MꢁTs^þ, 9), 261 (16), 260 (100), 259

(14), 229 (9), 228 (34), 227 (96),167 (11),155 (45),143 (17),129 (15),

117 (10), 115 (22), 91 (72), 75 (37), 73 (42).

Ts

N

TMS

NH

1) AuCl (cat.)

2) Baeyer-Villiger

SiMe₂Ph

37

50 (dr > 95:5)

4.6.15. N-{(R

*

)-2-[(2R

*

,3R )-3-(tert-Butyldimethylsilyloxymethyl)-

*

4.6.13.1. 4-Methyl-N-[2-(5-oxo-2,5-dihydrofuran-2-yl)ethyl]benzen-

esulfonamide (85). To a solution of -hydroxylactone 53 (15 mg,

0.050 mmol) and Et₃N (20 L, 0.15 mmol, 3 equiv) in CH₂Cl₂(2 mL)

at 0 ^ꢀC was added MsCl (62

L, 0.080 mmol, 1.6 equiv). After 2 h at

rt, the reaction mixture was hydrolyzed with a saturated aqueous

solution of NH₄Cl and extracted with EtOAc. The combined organic

extracts were washed with brine, dried over MgSO₄, ﬁltered, and

concentrated under reduced pressure. The residue was puriﬁed by

ﬂash chromatography on silica gel (petroleum ether/EtOAc 50:50,

5-oxotetrahydrofuran-2-yl]-1-phenylethyl}-4-methyl-

benzenesulfonamide (55)

g

m

According to the representative procedure (see Section 4.6.2),

ynamide 39 (70 mg, 0.13 mmol) was subjected to a gold-catalyzed

cycloisomerization with AuCl (2 mg, 0.006 mmol, 0.05 equiv) in

CH₂Cl₂(2 mL). After 18 h at rt and work-up, the resulting cyclo-

butanone 54 was subjected to a Baeyer–Villiger oxidation with

AcOOH (0.11 mL, 32% in AcOH, 0.55 mmol, 4 equiv) in the presence

of AcONa$3H₂O (23 mg, 0.17 mmol, 1.3 equiv) in AcOH (3 mL). After

4 h at rt, puriﬁcation by ﬂash chromatography on silica gel (pe-

troleum ether/EtOAc 80:20, 70:30) afforded 30 mg (46%) of lactone

55 as a pale yellow solid (C₂₆H₃₇NO₅SSi, MW¼503.73 g mol^ꢁ1). Mp

m

40:60) to afford 10 mg (71%) of

a,b-unsaturated g-lactone 85 as

a colorless oil (C₁₃H₁₅NO₄S, MW¼281.33 g mol^ꢁ1). IR 3270, 1751,

1598, 1420, 1328, 1159, 1093, 816, 668 cm^ꢁ1; ¹H NMR (CDCl₃)

d 7.73

S. Couty et al. / Tetrahedron 65 (2009) 1809–1832

1827

127 ^ꢀC; IR 3189, 1744, 1335, 1208, 1160, 1112, 1095, 992, 934, 833,

813, 776, 697, 665 cm^ꢁ^{1 1}H NMR (CDCl₃)

7.56 (d, J¼8.2 Hz, 2H),

2.05–1.99 (m, 1H), 1.40 (s, 3H); ¹³C NMR (CDCl₃)

d

176.3 (s), 143.1

;

d

(s), 140.6 (s), 137.1 (s), 129.2 (d, 2C), 128.6 (d, 2C), 127.5 (d), 127.1

(d, 2C), 126.2 (d, 2C), 85.6 (s), 55.2 (d), 47.5 (t), 32.7 (t), 28.9 (t),

26.5 (q), 21.4 (q); HRMS calcd for C₂₀H₂₄NO₄S (MþH^þ): 374.1426,

found: 374.1435.

7.18–7.08 (m, 5H), 7.04–7.00 (m, 2H), 5.43 (d, J¼8.5 Hz,1H, NH), 4.66

(ddd, apparent td, J¼8.5, 3.6 Hz, 1H), 4.28 (ddd, J¼9.8, 6.6, 2.6 Hz,

1H), 3.53 (dd, J¼10.3, 4.6 Hz, 1H), 3.49 (dd, J¼10.3, 5.6 Hz, 1H), 2.47

(dd, J¼17.5, 8.8 Hz, 1H), 2.39–2.20 (m, 1H), 2.34 (s, 3H), 2.29–2.21

(m, 1H), 2.13 (ddd, J¼14.8, 8.5, 2.6 Hz, 1H), 1.95 (ddd, J¼14.8, 9.8,

3.6 Hz, 1H), 0.81 (s, 9H), ꢁ0.03 (s, 3H), ꢁ0.06 (s, 3H); ¹³C NMR

4.7. Preparation of 1,6-ene-ynamides possessing a propargylic

alcohol moiety

(CDCl₃)

d 175.6 (s), 143.1 (s), 139.8 (s), 137.6 (s), 129.3 (d, 2C), 128.6

(d, 2C), 127.5 (d), 127.1 (d, 2C), 126.2 (d, 2C), 79.4 (d), 62.5 (t), 55.3

(d), 43.0 (d), 42.4 (t), 31.0 (t), 25.8 (q, 3C), 21.4 (q), 18.1 (s), ꢁ5.6 (q),

ꢁ5.7 (q); MS-EI m/z (relative intensity) 446 (Mꢁt-Bu^þ, 20), 275

(10), 261 (16), 260 (100), 246 (19), 245 (75), 228 (22), 207 (10), 183

(7), 155 (46), 117 (18), 91 (54), 75 (31), 73 (19). Anal. Calcd for

C₂₆H₃₇NO₅SSi: C, 61.99; H, 7.40; N, 2.78. Found: C, 61.72; H, 7.41; N,

2.76.

4.7.1. N-(But-3-enyl)-N-(3-hydroxybut-1-ynyl)-4-

methylbenzenesulfonamide (61)

To

a solution of b,b

-dichloroenamide 60^8,9(641 mg, 2.00

mmol) in THF (10 mL) at ꢁ78 ^ꢀC was added dropwise a solution

of n-BuLi (1.8 mL, 2.5 M in hexanes, 4.5 mmol, 2.25 equiv). After

0.5 h at ꢁ78 ^ꢀC and 1.5 h at ꢁ40 ^ꢀC, freshly distilled acetalde-

hyde (0.60 mL, 10 mmol, 5 equiv) was added. After 0.5 h at 0 ^ꢀC,

the reaction mixture was hydrolyzed with a saturated aqueous

solution of NH₄Cl and extracted with EtOAc. The combined or-

ganic extracts were washed with brine, dried over MgSO₄, ﬁl-

tered, and concentrated under reduced pressure. The residue

was puriﬁed by ﬂash chromatography on silica gel (petroleum

ether/EtOAc 90:10, 80:20) to afford 392 mg (67%) of ynamide 61

4.6.16. (1R

4-sulfonyl)-2-azabicyclo-[3.2.0]heptan-1-ol (56) and 4-methyl-

N-[(R )-2-((1S )-1-methyl-2-oxocyclobutyl)-1-phenylethyl]ben-

*

,3R

*

,5S

*

)-5-Methyl-3-phenyl-2-(toluene-

*

zenesulfonamide (57)

According to the representative procedure (see Section 4.6.1),

the gold-catalyzed cycloisomerization of ynamide 40 (99 mg,

0.24 mmol) with AuCl (8.4 mg, 0.036 mmol, 0.15 equiv) in CH₂Cl₂

(7 mL) (30 h at rt) led, after work-up and puriﬁcation by ﬂash

chromatography on silica gel (petroleum ether/EtOAc 85:15), to

45 mg (52%) of a 80:20 equilibrium mixture of the bicyclic hemi-

as

a

yellow oil (C₁₅H₁₉NO₃S, MW¼293.38 g mol^ꢁ1). IR 3377,

2242, 1642, 1597, 1358, 1166, 1089, 894, 813, 706, 678, 657 cm^ꢁ1

;

¹H NMR (CDCl₃)

d

7.76 (d, J¼8.3 Hz, 2H), 7.33 (d, J¼8.3 Hz, 2H),

5.68 (ddt, J¼17.0, 10.3, 6.8 Hz, 1H), 5.06 (dq, J¼17.0, 1.5 Hz, 1H),

5.02 (dq, J¼10.3, 1.5 Hz, 1H), 4.67–4.60 (m, 1H), 3.39–3.28 (m,

2H), 2.43 (s, 3H), 2.39–2.32 (m, 3H, 2HþOH), 1.44 (d, J¼6.6 Hz,

aminal 56 and cyclobutanone 57 as

a pale brown solid

(C₂₀H₂₃NO₃S, MW¼357.47 g mol^ꢁ1). IR 3439, 3283, 1770, 1598,

3H); ¹³C NMR (CDCl₃)

d 144.6 (s), 134.4 (s), 133.5 (d), 129.7 (d,

1455, 1317, 1162, 1139, 1086, 1026, 993, 810, 763, 699, 674 cm^ꢁ1

;

2C), 127.6 (d, 2C), 117.7 (t), 77.1 (s), 73.1 (s), 58.4 (d), 50.5 (t),

32.1 (t), 24.3 (q), 21.6 (q). Anal. Calcd for C₁₅H₁₉NO₃: C, 61.41; H,

6.53; N, 4.77. Found: C, 61.32; H, 6.71; N, 4.53.

MS-EI m/z (relative intensity) 339 (MꢁH₂O^þ, 2), 330 (12), 329

(58), 261 (15), 260 (89), 202 (13), 184 (12), 174 (26), 155 (65), 144

(18), 143 (18), 129 (15), 106 (23), 104 (19), 91 (100), 77 (17), 69

(30), 65 (17).

4.7.2. N-(But-3-enyl)-N-(3-hydroxy-4-methylpent-1-ynyl)-4-

methylbenzenesulfonamide (62)

Bicyclic hemiaminal (56): ¹H NMR (CDCl₃)

d

7.23 (d, J¼8.3 Hz,

2H), 7.08–6.88 (m, 7H), 4.82 (dd, J¼10.4, 6.5 Hz, 1H), 3.95 (s, 1H,

OH), 2.97 (ddd, J¼13.1, 9.6, 4.0 Hz, 1H), 2.53 (ddd, J¼13.1, 11.2,

9.1 Hz, 1H), 2.29 (s, 3H), 2.17 (dd, J¼13.0, 6.5 Hz, 1H), 1.88–1.62 (m,

This compound has been prepared by treatment of a solution of

b,b

-dichloroenamide 60^8,9(700 mg, 2.19 mmol) in THF (11 mL)

with n-BuLi (1.95 mL, 2.5 M in hexanes, 4.87 mmol, 2.22 equiv)

(0.5 h at ꢁ78 ^ꢀC, 1 h at ꢁ40 ^ꢀC) followed by addition of freshly

distilled isobutyraldehyde (0.75 mL, 11 mmol, 5 equiv) (ꢁ40 ^ꢀC to

0 ^ꢀC, 1 h at 0 ^ꢀC). After work-up and puriﬁcation by ﬂash chrom-

atography on silica gel (petroleum ether/EtOAc gradient 95:5 to

80:20), 633 mg (90%) of ynamide 62 was obtained as a colorless oil

(C₁₇H₂₃NO₃S, MW¼321.43 g mol^ꢁ1). IR 3506, 2241,1642, 1597,1359,

1167, 1090, 1018, 920, 865, 813, 708, 691, 657 cm^ꢁ1; ¹H NMR (CDCl₃)

3H), 1.28 (s, 3H); ¹³C NMR (CDCl₃)

d 142.5 (s), 138.2 (s), 138.0

(s), 128.6 (d, 2C), 128.2 (d, 2C), 127.7 (d, 2C), 127.5 (d, 2C), 127.3

(d), 87.3 (s), 63.5 (d), 47.9 (s), 47.4 (t), 33.8 (t), 24.5 (t), 21.4 (q),

20.5 (q).

Cyclobutanone (57): ¹H NMR (CDCl₃)

d

7.38 (d, J¼8.3 Hz, 2H),

7.08–6.88 (m, 7H), 4.95 (d, J¼9.5 Hz, 1H, NH), 4.58 (ddd, apparent

td, J¼10.0, 4.7 Hz, 1H), 3.20–3.04 (m, 2H), 2.39–2.32 (m, 1H), 2.28 (s,

3H), 2.08 (dd, J¼15.0,10.5 Hz,1H),1.88–1.62 (m, 2H),1.19 (s, 3H); ¹³C

d

7.77 (d, J¼8.3 Hz, 2H), 7.32 (d, J¼8.3 Hz, 2H), 5.69 (ddt, J¼17.0,10.3,

NMR (CDCl₃)

d

216.1 (s), 142.8 (s), 140.6 (s), 137.4 (s), 129.1 (d, 2C),

6.8 Hz,1H), 5.06 (dq, J¼17.0,1.5 Hz,1H), 5.02 (dq, J¼10.3,1.5 Hz,1H),

4.29 (dd, apparent t, J¼5.3 Hz, 1H), 3.35 (t, J¼7.4 Hz, 2H), 2.43 (s,

3H), 2.40–2.33 (m, 2H), 2.15 (d, J¼5.3 Hz, 1H, OH),1.92–1.84 (m, 1H),

0.97 (d, J¼6.8 Hz, 3H), 0.95 (d, J¼6.8 Hz, 3H); ¹³C NMR (CDCl₃)

128.4 (d, 2C), 127.3 (d), 127.0 (d, 2C), 126.1 (d, 2C), 62.2 (s), 56.0 (d),

43.2 (t), 43.0 (t), 22.8 (t), 22.7 (q), 21.4 (q).

4.6.17. 4-Methyl-N-[(R

*

)-2-((2S

*

)-2-methyl-5-oxotetrahydrofuran-

d 144.6 (s), 134.5 (s), 133.5 (d), 129.7 (d, 2C), 127.5 (d, 2C), 117.7 (t),

2-yl)-1-phenylethyl]benzenesulfonamide (58)

This compound was prepared by Baeyer–Villiger oxidation of

the 80:20 mixture of bicyclic hemiaminal 56 and cyclobutanone

78.4 (s), 70.9 (s), 68.0 (d), 50.6 (t), 34.7 (d), 32.1 (t), 21.6 (q), 18.1 (q),

17.4 (q). Anal. Calcd for C₁₇H₂₃NO₃S: C, 63.52; H, 7.21; N, 4.36.

Found: C, 63.49; H, 7.44; N, 4.36.

57 (20 mg, 0.056 mmol) with AcOOH (43 mL, 32% in AcOH,

0.22 mmol, 4 equiv) in the presence of AcONa$3H₂O (9 mg,

0.07 mmol, 1.2 equiv) in AcOH (1 mL). After 5 d at rt, work-up and

puriﬁcation by ﬂash chromatography on silica gel (petroleum

ether/EtOAc 60:40) afforded 11 mg (52%) of lactone 58 as a color-

less oil (C₂₀H₂₃NO₄S, MW¼373.47 g mol^ꢁ1). IR 3262, 1751, 1598,

4.7.3. Copper-catalyzed cross-coupling between sulfonamides 15,

22, 64, 65 and bromoalkyne 63 (see the following Table)

4.7.3.1. N-(But-3-enyl)-N-{3-[(tert-butyldiphenylsilyl)-oxy]prop-1-

ynyl}-4-methylbenzenesulfonamide (86) (representative proce-

dure). To a solution of sulfonamide 64 (1.40 g, 6.21 mmol) and

bromoalkyne 63 (2.55 g, 6.83 mmol, 1.1 equiv) in toluene (15 mL)

were successively added K₂CO₃(1.72 g, 12.4 mmol, 2 equiv),

CuSO₄$5H₂O (155 mg, 0.621 mmol, 0.1 equiv), and 1,10-phenan-

throline (224 mg, 1.24 mmol, 0.2 equiv). After 17 h at 65 ^ꢀC, the

reaction mixture was diluted with CHCl₃and ﬁltered through

1455, 1322, 1285, 1155, 1089, 930, 812, 756, 701, 666 cm^ꢁ^{1 1}H

;

NMR (CDCl₃)

d

7.46 (d, J¼8.2 Hz, 2H), 7.13–7.08 (m, 3H), 7.05 (d,

J¼8.2 Hz, 2H), 6.99–6.95 (m, 2H), 5.43 (d, J¼8.2 Hz, 1H, NH), 4.52

(ddd, apparent td, J¼8.2, 5.2 Hz, 1H), 2.60 (ddd, J¼18.2, 9.6, 8.8 Hz,

1H), 2.49 (ddd, J¼18.2, 9.6, 5.1 Hz, 1H), 2.32 (s, 3H), 2.28 (dd,

J¼14.9, 8.7 Hz, 1H), 2.24–2.15 (m, 1H), 2.05 (dd, J¼14.9, 5.2 Hz, 1H),

1828

S. Couty et al. / Tetrahedron 65 (2009) 1809–1832

OTBDPS

63

Ts

OTBDPS

Ts

OH

Br

NH

N

cat. CuSO₄.5H₂O

n-Bu₄NF

R¹

cat. 1,10-phenanthroline

K₂CO₃, toluene, 65-90 °C

THF, 0 °C

R²

Sulfonamides

Products

Ene-ynamides

Ts OH

Ts

OTBDPS

NH

N

86

Ts

59

Ts

64

Ts

NH

OTBDPS

OH

N

Ph

15

87

Ts

66

Ts

OTBDPS

OH

BnO

NH

BnO

N

BnO

N

65

88

67

Ts

OH

NH

N

BnO

89

68

22

Celite (CHCl₃). The ﬁltrate was evaporated under reduced pres-

sure and the crude material was puriﬁed by ﬂash chromatogra-

phy on silica gel (petroleum ether/Et₂O 97:3, 95:5) to afford 2.47 g

(77%) of disubstituted ynamide 86 as a yellow oil (C₃₀H₃₅NO₃SSi,

MW¼517.75 g mol^ꢁ1). IR 2242, 1596, 1428, 1362, 1170, 1109, 1066,

m/z (relative intensity) 238 (MꢁAllyl^þ, 5), 216 (12), 214 (13), 200

(10), 184 (11), 155 (36), 139 (13), 124 (16), 108 (10), 92 (18), 91 (100),

79 (14), 66 (19), 65 (28), 55 (77), 53 (11).

4.7.3.3. N-[3-(tert-Butyldiphenylsilyloxy)prop-1-ynyl]-4-methyl-N-(1-

phenylbut-3-enyl)benzenesulfonamide (87). The coupling between

sulfonamide 15 (411 mg, 1.36 mmol) and bromoalkyne 63 (610 mg,

1.63 mmol, 1.2 equiv) in the presence of CuSO₄$5H₂O (34 mg,

0.14 mmol, 0.1 equiv), 1,10-phenanthroline (49 mg, 0.27 mmol,

0.2 equiv), and K₂CO₃(377 mg, 2.72 mmol, 2 equiv) in toluene (5 mL)

(30 h at 90 ^ꢀC) led, after puriﬁcation by ﬂash chromatography on

silica gel (petroleum ether/EtOAc 98:2), to 157 mg (60%) of the di-

813, 739, 701, 679, 657, 611 cm^ꢁ^{1 1}H NMR (CDCl₃)

; d 7.78 (d,

J¼8.0 Hz, 2H), 7.72–7.68 (m, 4H), 7.45–7.35 (m, 6H), 7.29 (d,

J¼8.0 Hz, 2H), 5.68 (ddt, J¼17.1, 10.5, 6.8 Hz, 1H), 5.06 (dq, J¼17.1,

1.5 Hz, 1H), 5.03 (dq, J¼10.3, 1.5 Hz, 1H), 4.49 (s, 2H), 3.29 (t,

J¼7.5 Hz, 2H), 2.43 (s, 3H), 2.33–2.27 (m, 2H), 1.05 (s, 9H); ¹³C

NMR (CDCl₃)

d 144.4 (s), 135.6 (d, 4C), 134.7 (s), 133.6 (d), 133.2

(2s, 2C), 129.7 (2d, 2Cþ2C), 127.7 (2d, 4C), 127.6 (d, 2C), 117.6 (t),

78.2 (s), 70.0 (s), 52.9 (t), 50.6 (t), 32.1 (t), 26.6 (q, 3C), 21.6 (q),

19.2 (s).

substituted ynamide 87 as

a

colorless oil (C₃₆H₃₉NO₃SSi,

MW¼593.85 g mol^ꢁ1). IR 2240, 1643, 1597, 1428, 1363, 1169, 1111,

1072, 997, 823, 741, 702, 663, 609 cm^ꢁ1; ¹H NMR (CDCl₃)

d 7.71–7.68

4.7.3.2. N-But-3-enyl-N-(3-hydroxyprop-1-ynyl)-4-methylbenzene-

sulfonamide (59) (representative procedure). To a solution of the

disubstituted ynamide 86 (300 mg, 0.580 mmol) in THF (10 mL)

was added a solution of n-Bu₄NF (0.75 mL, 1 M in THF, 0.75 mmol,

1.3 equiv). After 10 min at 0 ^ꢀC, the reaction mixture was hydro-

lyzed with a saturated aqueous solution of NH₄Cl and extracted

with EtOAc. The combined organic extracts were dried over MgSO₄,

ﬁltered, and concentrated under reduced pressure. The crude ma-

terial was puriﬁed by ﬂash chromatography on silica gel (petroleum

ether/EtOAc gradient 90:10 to 60:40), to afford 140 mg (86%, 66%

for the two steps from sulfonamide 64) of ynamide 59 as a colorless

oil (C₁₄H₁₇NO₃S, MW¼279.35 g mol^ꢁ1). IR 3378, 2241, 1642, 1596,

(m, 4H), 7.51 (d, J¼8.3 Hz, 2H), 7.45–7.34 (m, 6H), 7.23–7.12 (m, 5H),

7.08 (d, J¼8.3 Hz, 2H), 5.57 (ddt, J¼17.0, 10.2, 6.9 Hz, 1H), 5.06

(dq, J¼17.0, 1.4 Hz, 1H), 4.97–4.91 (m, 2H), 4.51 (s, 2H), 2.72–2.63 (m,

1H), 2.55–2.48 (m, 1H), 2.34 (s, 3H), 1.04 (s, 9H); ¹³C NMR (CDCl₃)

d

144.0 (s), 137.7 (s), 135.5 (d, 4C), 135.3 (s), 133.5 (d), 133.3 (2s, 2C),

129.8 (2d, 2C), 129.2 (d, 2C), 128.3 (d, 2C), 127.9 (d), 127.8 (2d, 4C),

127.7 (d, 2C), 127.1 (d, 2C), 118.3 (t), 76.4 (s), 72.8 (s), 63.0 (d), 53.1 (t),

38.3 (t), 26.6 (q, 3C), 21.6 (q), 19.2 (s); MS-EI m/z (relative intensity)

337 (Mꢁt-BuPh₂SiOH^þ, 28), 275 (7), 274 (26), 273 (100),199 (28),197

(7), 181 (6), 139 (4), 91 (8), 77 (8).

4.7.3.4. N-(3-Hydroxyprop-1-ynyl)-4-methyl-N-(1-phenylbut-3-enyl)-

benzenesulfonamide (66). The disubstituted ynamide 87 (459 mg,

0.773 mmol) was desilylated [n-Bu₄NF (1.32 mL, 1 M in THF,

1.32 mmol, 1.7 equiv), THF (15 mL), 0 ^ꢀC, 0.5 h] and puriﬁcation by

ﬂash chromatography on silica gel (petroleum ether/EtOAc 75:25)

afforded 250 mg (91%, 55% for the two steps from sulfonamide 15)

of ynamide 66 as a colorless oil (C₂₀H₂₁NO₃S, MW¼355.45 g mol^ꢁ1).

IR 3394, 2239, 1642, 1597, 1359, 1166, 1089, 1017, 982, 923, 813, 701,

1357, 1166, 1089, 1017, 998, 915, 854, 813, 706, 678, 658 cm^ꢁ1

;

¹H

NMR (CDCl₃)

d

7.77 (d, J¼8.3 Hz, 2H), 7.34 (d, J¼8.3 Hz, 2H), 5.68

(ddt, J¼17.0, 10.2, 6.8 Hz, 1H), 5.07 (dq, J¼17.0, 1.5 Hz, 1H), 5.02 (dq,

J¼10.2, 1.5 Hz, 1H), 4.38 (d, J¼5.5 Hz, 2H), 3.36 (t, J¼7.3 Hz, 2H), 2.43

(s, 3H), 2.42–2.31 (m, 2H), 2.06 (br t, J¼5.5 Hz, 1H, OH); ¹³C NMR

(CDCl₃)

d 144.7 (s), 134.6 (s), 133.5 (d), 129.8 (d, 2C), 127.5 (d, 2C),

117.7 (t), 78.8 (s), 70.0 (s), 51.1 (t), 50.6 (t), 32.1 (t), 21.6 (q); MS-EI

S. Couty et al. / Tetrahedron 65 (2009) 1809–1832

1829

662, 605 cm^ꢁ1

;

¹H NMR (CDCl₃)

d

7.48 (d, J¼8.3 Hz, 2H), 7.20–7.12

1079, 970, 823, 741, 703, 674 cm^ꢁ1

;

¹H NMR (CDCl₃)

d

7.78 (d,

(m, 5H), 7.08 (d, J¼8.2 Hz, 2H), 5.52 (ddt, J¼17.0, 10.2, 6.9 Hz, 1H),

5.02 (dq, J¼17.0, 1.4 Hz, 1H), 4.93–4.87 (m, 2H), 4.36 (d, J¼5.6 Hz,

2H), 2.73–2.64 (m, 1H), 2.57–2.49 (m, 1H), 2.31 (s, 3H), 1.62 (br t,

J¼8.5 Hz, 2H), 7.75–7.70 (m, 4H), 7.46–7.36 (m, 6H), 7.32–7.25 (m, 3H),

7.20–7.15 (m, 4H), 5.62 (ddt, J¼17.0, 10.0, 7.0 Hz, 1H), 5.06 (dq, J¼17.0,

1.5 Hz, 1H), 4.97 (dm, apparent br d, J¼10.0 Hz, 1H), 4.51 (d, AB syst,

J¼16.0 Hz, 1H), 4.46 (d, AB syst, J¼16.0 Hz, 1H), 4.37 (d, AB syst,

J¼12.0 Hz, 1H), 4.30 (d, AB syst, J¼12.0 Hz, 1H), 4.22–4.16 (m, 1H), 3.43

(dd, J¼10.0, 8.0 Hz,1H), 3.38 (dd, J¼10.0, 5.2 Hz,1H), 2.37 (s, 3H), 2.33–

J¼5.6 Hz, 1H, OH); ¹³C NMR (CDCl₃)

d 144.3 (s), 138.6 (s), 135.2 (s),

133.4 (d), 129.3 (d, 2C), 128.4 (d, 2C), 128.1 (d), 127.7 (d, 2C), 127.1 (d,

2C), 118.4 (t), 76.7 (s, overlap with CDCl₃), 72.8 (s), 62.9 (d), 51.4 (t),

38.1 (t), 21.6 (q).

2.18 (m, 2H), 1.06 (s, 9H); ¹³C NMR (CDCl₃)

d 144.0 (s), 137.8 (s), 135.9

(d), 135.5 (d, 4C), 134.6 (s), 133.2 (s, 2C), 129.7 (d, 2C), 129.6 (d, 2C),

128.3 (d, 2C), 127.7 (d, 4C), 127.6 (2d, 3C), 127.5 (d, 2C), 118.2 (t), 75.3

(s), 72.9 (t), 72.2 (s), 69.9 (t), 59.5 (d), 52.9 (t), 34.4 (t), 26.6 (q, 3C), 21.6

(q), 19.2 (s).

4.7.3.5. N-[1-(Benzyloxymethyl)but-3-enyl]-4-methylbenzenesulfon-

amide (65). This sulfonamide was prepared from (benzyloxy)

acetaldehyde by formation of the (sulfonamido)sulfone 90 [TsNH₂,

TsNa, HCOOH/H₂O (1:1), rt].⁴⁵This adduct could not be converted

to the corresponding unstable N-tosylimine 91 under the reported

conditions.⁴⁵However, treatment of compound 90 with allylmag-

nesium chloride (2.2 equiv, THF, ꢁ10 ^ꢀC) resulted in the generation

of the N-tosylimine 91 in situ and condensation of the Grignard

reagent provided sulfonamide 65.

4.7.3.7. N-[1-(Benzyloxymethyl)but-3-enyl]-N-(3-hydroxyprop-1-ynyl)-

4-methylbenzenesulfonamide (67). The disubstituted ynamide 88

(267 mg, 0.419 mmol) was desilylated [n-Bu₄NF (0.63 mL, 1 M in

THF, 0.63 mmol, 1.5 equiv) in THF (5 mL), 0 ^ꢀC, 15 min] and puriﬁ-

cation by ﬂash chromatography on silica gel (petroleum ether/

EtOAc 70:30) afforded 146 mg (87%, 28% for the two steps from

sulfonamide 65) of ynamide 67 as a colorless oil (C₂₂H₂₅NO₄S,

MW¼399.50 g mol^ꢁ1). IR 3421, 2239, 1644, 1597, 1495, 1454, 1359,

1168,1091,1002, 922, 856, 814, 741, 702, 666 cm^ꢁ1; ¹H NMR (CDCl₃)

O

NHTs

TsNH₂, TsNa

BnO

HCO₂H/H₂O (1:1), rt

H

Ts

90

d

7.79 (d, J¼8.3 Hz, 2H), 7.33–7.12 (m, 7H), 5.63 (ddt, J¼17.0, 10.1,

AllylMgCl (2.2 equiv)

7.1 Hz, 1H), 5.06 (dq, J¼17.0, 1.3 Hz, 1H), 4.98 (apparent br d,

J¼10.1 Hz, 1H), 4.40 (d, AB syst, J¼12.0 Hz, 1H), 4.36 (d, AB syst,

J¼16.6 Hz, 1H), 4.31 (d, AB syst, J¼16.6 Hz, 1H), 4.29 (d, AB

syst, J¼12.0 Hz, 1H), 4.24–4.13 (m, 1H), 3.47 (dd, J¼10.2, 8.1 Hz, 1H),

3.40 (dd, J¼10.2, 5.0 Hz, 1H), 2.83 (s, 3H), 2.34–2.26 (m, 2H), 1.86 (br

THF, −10 °C

MgCl

NHTs

N

AllylMgCl

N

BnO

Ts

BnO

Ts

BnO

H

Ts

65

s, 1H, OH); ¹³C NMR (CDCl₃)

d 144.3 (s), 137.8 (s), 135.5 (s), 133.1 (d),

A solution of (benzyloxy)acetaldehyde (560

m

L, 4.00 mmol),

129.3 (d, 2C),128.3 (d, 2C),128.0 (d, 2C),127.7 (d, 2C),127.6 (d),118.4

(t), 76.1 (s), 72.9 (t), 72.3 (s), 69.7 (t), 59.6 (d), 51.3 (t), 34.5 (t), 21.6

(q); HRMS calcd for C₂₂H₂₆NO₄S (MþH^þ): 400.1583, found:

400.1578.

p-toluenesulfonamide (685 mg, 4.00 mmol, 1 equiv), and sodium

p-toluenesulﬁnate (713 mg, 4.00 mmol, 1 equiv) in a mixture of

HCOOH (6 mL) and H₂O (6 mL) was stirred at rt. After 16 h, the

white precipitate was collected by ﬁltration, washed with H₂O

(2ꢂ7 mL), pentane (7 mL), and dried under reduced pressure. The

crystalline sulfonamidosulfone adduct was dissolved in THF

(10 mL) and a solution of allylmagnesium chloride (4.4 mL, 2 M in

THF, 8.8 mmol, 2.2 equiv) was added at ꢁ10 ^ꢀC. After 1.5 h at

ꢁ10 ^ꢀC, the reaction mixture was poured into a saturated aqueous

solution of NH₄Cl and extracted with EtOAc. The combined organic

extracts were successively washed with H₂O, brine, dried over

MgSO₄, ﬁltered, and concentrated under reduced pressure. The

residue was puriﬁed by ﬂash chromatography on silica gel (petro-

leum ether/EtOAc 90:10) to afford 480 mg (ca. 35%) of sulfonamide

65 as a colorless oil. This compound showed slight contamination

by unidentiﬁed impurities (C₁₉H₂₃NO₃S, MW¼345.46 g mol^ꢁ1). IR

3277, 1641, 1598, 1328, 1158, 1091, 1027, 994, 914, 813, 735, 698,

4.7.3.8. N-[2-(Benzyloxymethyl)but-3-enyl]-N-[3-(tert-butyldiphen-

ylsilyloxy)prop-1-ynyl]-4-methylbenzenesulfonamide (89). The cou-

pling between sulfonamide 22 (609 mg, 1.76 mmol) and

bromoalkyne 63 (723 mg, 1.94 mmol, 1.1 equiv) in the presence of

CuSO₄$5H₂O (44 mg, 0.18 mmol, 0.1 equiv), 1,10-phenanthroline

(64 mg, 0.35 mmol, 0.2 equiv), and K₂CO₃(487 mg, 3.52 mmol,

2 equiv) in toluene (5 mL) (16 h at 65 ^ꢀC) led, after puriﬁcation by

ﬂash chromatography on silica gel (petroleum ether/EtOAc 95:5), to

1.08 g (96%) of disubstituted ynamide 89 as a viscous colorless oil

(C₃₈H₄₃NO₄SSi, MW¼637.90 g mol^ꢁ1). IR 2241, 1596, 1362, 1106,

1068, 921, 813, 738, 700, 653, 611 cm^ꢁ1; ¹H NMR (CDCl₃)

d 7.76 (d,

J¼8.2 Hz, 2H), 7.69–7.65 (m, 4H), 7.43–7.24 (m, 13H), 5.71 (ddd,

J¼17.4, 10.3, 8.1 Hz, 1H), 5.14–5.06 (m, 2H), 4.49 (d, AB syst,

J¼12.0 Hz, 1H), 4.44 (d, AB syst, J¼12.0 Hz, 1H), 4.43 (s, 2H), 3.47

(dd, J¼9.3, 5.4 Hz, 1H), 3.44 (dd, J¼9.3, 5.4 Hz, 1H), 3.42 (dd, J¼12.7,

7.1 Hz, 1H), 3.24 (dd, J¼12.7, 7.8 Hz, 1H), 2.78–2.68 (m, 1H), 2.41 (s,

663 cm^ꢁ1

;

¹H NMR (CDCl₃)

d

7.71 (d, J¼8.3 Hz, 2H), 7.36–7.20 (m,

7H), 5.56 (ddt, J¼17.0, 9.6, 7.1 Hz, 1H), 5.02–4.96 (m, 2H), 4.89 (d,

J¼7.3 Hz, 1H, NH), 4.36 (s, 2H), 3.42–3.35 (m, 2H), 3.25 (dd, J¼10.7,

6.4 Hz, 1H), 2.40 (s, 3H), 2.30–2.24 (m, 2H); ¹³C NMR (CDCl₃)

d

143.2

3H), 1.03 (s, 9H); ¹³C NMR (CDCl₃)

d 144.4 (s), 138.2 (s), 135.9 (d),

(s), 137.8 (s), 137.7 (s), 133.5 (d), 129.5 (d, 2C), 128.3 (d, 2C), 127.7 (d),

127.5 (d, 2C), 127.0 (d, 2C), 118.4 (t), 73.1 (t), 70.6 (t), 52.8 (d), 36.6

(t), 21.4 (q); MS-EI m/z (relative intensity) 304 (MꢁAllyl^þ, 24), 225

(5), 224 (41), 190 (7), 155 (26), 92 (9), 91 (100), 65 (8), 54 (6).

135.5 (d, 4C),134.6 (s),133.2 (s, 2C),129.7 (d, 2C),129.6 (d, 2C),128.3

(d, 2C), 127.7 (d, 4C), 127.6 (2d, 3C), 127.5 (d, 2C), 117.9 (t), 78.6 (s),

73.1 (t), 70.5 (t), 69.8 (s), 52.8 (t), 52.6 (t), 42.6 (d), 26.6 (q, 3C), 21.6

(q), 19.1 (s); MS-EI m/z (relative intensity) 337 (27), 275 (7), 274

(26), 273 (100), 199 (23), 197 (7), 181 (6), 91 (4), 77 (7).

4.7.3.6. N-[1-(Benzyloxymethylbut)3-enyl]-N-[3-(tert-butyldipheny-

lsilyloxy)prop-1-ynyl]-4-methylbenzenesulfonamide (88). The coupling

between sulfonamide 65 (319 mg, 0.923 mmol) and bromoalkyne 63

(413 mg, 1.11 mmol, 1.2 equiv) in the presence of CuSO₄$5H₂O (23 mg,

0.092 mmol, 0.1 equiv), 1,10-phenanthroline (33 mg, 0.18 mmol,

0.2 equiv), and K₂CO₃(255 mg, 1.85 mmol, 2 equiv) in toluene (5 mL)

(30 h at 90 ^ꢀC) led, after puriﬁcation by ﬂash chromatography on silica

gel (petroleum ether/Et₂O 95:5, petroleum ether/EtOAc 95:5), to

188 mg (32%) of the disubstituted ynamide 88 as a yellow oil

(C₃₈H₄₃NO₄SSi, MW¼637.90 g mol^ꢁ1). IR 2238, 1462, 1362, 1170, 1112,

4.7.3.9. N-[2-(Benzyloxymethyl)but-3-enyl]-N-(3-hydroxy-prop-1-

ynyl)-4-methylbenzenesulfonamide (68). The disubstituted yna-

mide 89 (1.01 g, 1.59 mmol) was desilylated [n-Bu₄NF (2.5 mL,

1 M in THF, 2.5 mmol, 1.6 equiv) in THF (10 mL), 0 ^ꢀC, 0.5 h] and

puriﬁcation by ﬂash chromatography on silica gel (petroleum

ether/EtOAc gradient 80:20 to 60:40) afforded 574 mg (91%, 87%

for the two steps from sulfonamide 22) of ynamide 68 as a color-

less oil (C₂₂H₂₅NO₄S, MW¼399.50 g mol^ꢁ1). IR 3406, 2241, 1596,

1454, 1360, 1167, 1090, 1005, 923, 814, 738, 700, 655 cm^ꢁ^{1 1}H

;

1830

S. Couty et al. / Tetrahedron 65 (2009) 1809–1832

NMR (CDCl₃)

d

7.78 (d, J¼8.3 Hz, 2H), 7.36–7.26 (m, 7H), 5.73 (ddd,

2.58 (ddd, apparent td, J¼10.0, 8.1 Hz, 1H), 2.45 (s, 3H), 2.32 (d, AB

syst, J¼16.7 Hz, 1H), 2.28–2.19 (m, 1H), 1.72 (dd, J¼12.4, 7.8 Hz, 1H),

1.46 (ddd, apparent dt, J¼8.6, 5.3 Hz, 1H), 1.12 (d, J¼7.0 Hz, 6H), 0.45

(dd, J¼8.6, 6.5 Hz, 1H), 0.03 (dd, apparent t, J¼6.0 Hz, 1H); ¹³C NMR

J¼17.4, 10.3, 8.1 Hz, 1H), 5.15 (d, J¼17.4 Hz, 1H), 5.12 (d, J¼10.3 Hz,

1H), 4.50 (d, AB syst, J¼12.0 Hz, 1H), 4.46 (d, AB syst, J¼12.0 Hz,

1H), 4.34 (d, J¼5.3 Hz, 2H), 3.54–3.44 (m, 3H), 3.33 (dd, J¼12.7,

7.9 Hz, 1H), 2.86–2.75 (m, 1H), 2.44 (s, 3H), 1.10 (br t, J¼5.3 Hz, 1H,

(CDCl₃)

d 211.8 (s), 143.7 (s), 133.0 (s), 129.4 (d, 2C), 128.5 (d, 2C),

OH); ¹³C NMR (CDCl₃)

d

144.7 (s), 138.2 (s), 135.8 (d), 134.5 (s),

48.1 (t), 43.9 (t), 43.7 (s), 41.1 (d), 24.4 (t), 23.6 (d), 21.5 (q), 18.0 (q),

17.7 (q), 12.5 (t); MS-EI m/z (relative intensity) 321 (M^þ, 1), 278

(Mꢁi-Pr^þ, 3), 186 (5), 167 (12),166 (100),155 (7), 96 (40), 96 (49), 91

(21), 71 (17), 65 (6), 55 (29).

129.8 (d, 2C), 128.4 (d, 2C), 127.7 (d), 127.6 (2d, 4C), 118.1 (t), 79.4

(s), 73.1 (t), 70.6 (t), 69.8 (s), 52.7 (t), 51.2 (t), 42.8 (d), 21.7 (q).

4.8. Gold-catalyzed cycloisomerizations of 1,6-ene-ynamides

possessing a propargylic alcohol moiety

4.8.4. [(1R

*

,3R

*

,5R )-3-Phenyl-2-(4-methylbenzenesulfonyl)-2-

*

azabicyclo-[3.1.0]hex-1-yl]ethanal (72)

4.8.1. (1R

*

,5R

*

)-[2-(4-Methylbenzenesulfonyl)-2-azabicyclo-

The gold-catalyzed cycloisomerization of ynamide 66 (127 mg,

0.357 mmol) with AuCl (4 mg, 0.02 mmol, 0.05 equiv) in CH₂Cl₂

(3 mL) (1 h at rt) afforded, after puriﬁcation by ﬂash chromatog-

raphy on silica gel (petroleum ether/EtOAc gradient 90:10 to

70:30), 78 mg (61%) of aldehyde 72 as a colorless oil (C₂₀H₂₁NO₃S,

MW¼355.45 g mol^ꢁ1). IR 1726, 1597, 1493, 1450, 1340, 1160, 1085,

[3.1.0]hex-1-yl]ethanal (69) (representative procedure)

To a solution of ynamide 59 (70 mg, 0.25 mmol) in CH₂Cl₂

(5 mL) was added AuCl (2.9 mg, 0.012 mmol, 0.05 equiv). After

20 min at rt, the reaction mixture was ﬁltered through a short plug

of Celite. The ﬁltrate was evaporated and the crude material was

puriﬁed by ﬂash chromatography on silica gel (petroleum ether/

EtOAc 70:30) to afford 28 mg (40%) of aldehyde 69 as a colorless oil

(C₁₄H₁₇NO₃S, MW¼279.35 g mol^ꢁ1). IR 1724, 1597, 1336, 1159, 1088,

1029, 961, 812, 760, 729, 699, 657 cm^ꢁ1; ¹H NMR (CDCl₃)

d 9.96 (t,

J¼1.6 Hz, 1H), 7.45 (br d, J¼8.1 Hz, 2H), 7.18–7.10 (m, 5H), 7.12 (br d,

J¼8.1 Hz, 2H), 4.12 (dd, apparent t, J¼8.8 Hz, 1H), 3.83 (apparent br

d, J¼17.4 Hz, 1H), 2.33 (dd, J¼17.4, 1.6 Hz, 1H), 2.31 (s, 3H), 2.27 (dd,

J¼13.1, 8.8 Hz, 1H), 2.16 (ddd, J¼13.1, 8.8, 5.5 Hz, 1H), 1.42 (apparent

dt, J¼8.8, 5.5 Hz, 1H), 0.61 (dd, J¼8.8, 6.6 Hz, 1H), 0.47 (dd, J¼6.6,

1037, 911, 815, 730, 709, 657 cm^ꢁ^{1 1}H NMR (CDCl₃)

; d 9.98 (appar-

ent t, J¼1.5 Hz, 1H), 7.71 (d, J¼8.0 Hz, 2H), 7.33 (d, J¼8.0 Hz, 2H),

3.68 (apparent dt, J¼17.0, 1.5 Hz, 1H), 3.60 (apparent td, J¼10.5,

1.5 Hz, 1H), 2.60 (ddd, apparent td, J¼10.5, 8.0 Hz, 1H), 2.44 (s, 3H),

2.34 (dd, J¼17.0, 1.5 Hz, 1H), 2.22–2.12 (m, 1H), 1.78 (dd, J¼12.5,

8.0 Hz, 1H), 1.46 (apparent dt, J¼8.5, 5.5 Hz, 1H), 0.49 (dd, J¼8.5,

5.5 Hz, 1H); ¹³C NMR (CDCl₃)

d 200.8 (d), 143.8 (s), 141.6 (s), 134.3

(s), 129.3 (d, 2C), 128.4 (d, 2C), 128.3 (d, 2C), 127.3 (d), 126.8 (d, 2C),

65.0 (d), 48.1 (t), 45.1 (s), 37.8 (t), 21.9 (d), 21.5 (q),14.9 (t); MS-EI m/z

(relative intensity) 355 (M^þ, 1), 327 (2), 263 (32), 262 (20), 200 (51),

172 (26), 155 (15), 132 (16), 131 (78), 129 (16), 117 (19), 116 (16), 105

(21), 104 (21), 103 (16), 91 (100), 77 (11), 65 (14); HRMS calcd for

C₂₀H₂₂NO₃S (MþH^þ): 356.1320, found: 356.1326.

6.5 Hz,1H), 0.47 (dd, J¼6.5, 5.5 Hz,1H); ¹³C NMR (CDCl₃)

d 200.9 (d),

144.0 (s), 132.5 (s), 129.5 (d, 2C), 128.5 (d, 2C), 47.6 (t), 46.9 (t), 43.2

(s), 24.2 (t), 23.2 (d), 21.6 (q), 12.1 (t); MS-EI m/z (relative intensity)

251 (MꢁCO^þor MꢁC₂H^þ₄, 15), 187 (29), 186 (48), 172 (7), 155 (Ts^þ,

12), 131 (7), 124 (MꢁTs^þ, 64), 105 (17), 96 (34), 95 (7), 94 (11), 92

(10), 91 (100), 89 (7), 82 (7), 65 (25), 56 (7), 55 (100), 54 (8), 53 (9).

Relevant NOESY correlations (500 MHz, CDCl₃)

H

Ts

N

CHO

H

Ph

H²

4.8.2. {(1R

*

,5R )-1-[2-(4-Methylbenzenesulfonyl)-2-

*

azabicyclo[3.1.0]hex-1-yl]}propan-2-one (70)

H

H³

The gold-catalyzed cycloisomerization of ynamide 61 (80 mg,

0.27 mmol) with AuCl (3.1 mg, 0.013 mmol, 0.05 equiv) in CH₂Cl₂

(3 mL) (0.5 h at rt) afforded, after puriﬁcation by ﬂash chromatog-

raphy on silica gel (petroleum ether/EtOAc 75:25), 48 mg (60%) of

ketone 70 as a colorless oil (C₁₅H₁₉NO₃S, MW¼293.38 g mol^ꢁ1). IR

H¹

72

4.8.5. [(1R

*

,3R

*

,5R )-3-Benzyloxymethyl-2-(4-methylbenzene-

*

1715, 1597, 1334, 1159, 1088, 1042, 816, 711, 659 cm^ꢁ1

;

¹H NMR

sulfonyl)-2-azabicyclo[3.1.0]hex-1-yl]acetaldehyde (73)

(CDCl₃)

d

7.70 (d, J¼8.2 Hz, 2H), 7.32 (d, J¼8.2 Hz, 2H), 3.78 (d, AB

The gold-catalyzed cycloisomerization of ynamide 67 (73 mg,

0.18 mmol) with AuCl (2 mg, 0.009 mmol, 0.05 equiv) in CH₂Cl₂

(3 mL) (0.5 h at rt) afforded, after puriﬁcation by ﬂash chromatog-

raphy on silica gel (petroleum ether/EtOAc: 80:20), 37 mg (51%) of

aldehyde 73 as a colorless oil (C₂₂H₂₅NO₄S, MW¼399.50 g mol^ꢁ1). IR

1723, 1597, 1494, 1453, 1342, 1159, 1089, 1042, 815, 737, 698, 665,

syst, J¼16.7 Hz, 1H), 3.58 (ddd, apparent td, J¼10.0, 1.3 Hz, 1H), 2.56

(ddd, apparent td, J¼10.0, 8.0 Hz, 1H), 2.43 (s, 3H), 2.28 (d, AB syst,

J¼16.7 Hz, 1H), 2.26 (s, 3H), 2.24–2.13 (m, 1H), 1.72 (dd, J¼12.3,

7.8 Hz, 1H), 1.46 (apparent dt, J¼8.8, 5.2 Hz, 1H), 0.45 (dd, J¼8.8,

6.5 Hz, 1H), 0.03 (dd, apparent t, J¼6.0 Hz, 1H); ¹³C NMR (CDCl₃)

d

206.5 (s), 143.8 (s), 132.7 (s), 129.4 (d, 2C), 128.5 (d, 2C), 47.8 (t),

594 cm^ꢁ1

;

¹H NMR (CDCl₃)

d

9.92 (dd, J¼2.3, 1.5 Hz, 1H), 7.71 (d,

46.6 (t), 43.9 (s), 31.1 (q), 24.2 (t), 23.4 (d), 21.5 (q), 12.3 (t); MS-EI

m/z (relative intensity) 293 (M^þ, 1), 155 (5), 139 (11), 138 (100), 97

(4), 96 (49), 95 (4), 94 (5), 91 (24), 65 (9), 55 (45). Anal. Calcd for

C₁₅H₁₉NO₃S: C, 61.41; H, 6.53; N, 4.77. Found: C, 61.12; H, 6.53; N,

4.45.

J¼8.4 Hz, 2H), 7.39–7.28 (m, 7H), 4.55 (d, AB syst, J¼11.9 Hz,1H), 4.50

(d, AB syst, J¼11.9 Hz,1H), 3.71 (dd, J¼8.6, 3.3 Hz,1H), 3.67–3.60 (m,

1H), 3.57 (dd, J¼8.6, 7.3 Hz, 1H), 3.53 (dd, J¼17.2, 1.5 Hz, 1H), 2.44 (s,

3H), 2.33 (dd, J¼17.2, 2.3 Hz, 1H), 2.30–2.23 (m, 1H), 1.91 (apparent

dd, J¼13.2, 8.5 Hz, 1H), 1.52–1.46 (m, 1H), 0.70 (ddd, J¼8.8, 6.0,

0.8 Hz, 1H), 0.17 (dd, apparent br t, J¼6.0 Hz, 1H); ¹³C NMR (CDCl₃)

4.8.3. {(1R

*

,5R

*

)-3-Methyl-1-[2-(4-methylbenzenesulfonyl)-2-

d 201.2 (d), 144.0 (s), 138.1 (s), 134.9 (s), 129.6 (d, 2C), 128.4 (d, 2C),

azabicyclo[3.1.0]hex-1-yl]}butan-2-one (71)

128.3 (d, 2C), 127.8 (d, 2C), 127.7 (d), 73.5 (2t, 2C), 63.3 (d), 48.2 (t),

46.0 (s), 31.5 (t), 22.8 (d), 21.6 (q), 19.6 (t). Anal. Calcd for

C₂₂H₂₅NO₄S: C, 66.14; H, 6.31; N, 3.51. Found: C, 65.71; H, 6.49; N,

3.52.

The gold-catalyzed cycloisomerization of ynamide 62 (152 mg,

0.473 mmol) with AuCl (5.5 mg, 0.024 mmol, 0.05 equiv) in CH₂Cl₂

(4 mL) (35 min at rt) afforded, after puriﬁcation by ﬂash chroma-

tography on silica gel (petroleum ether/EtOAc 98:2, 95:5),

64 mg (42%) of ketone 71 as

a

colorless oil (C₁₇H₂₃NO₃S,

4.8.6. [(1R

*

,4S

*

,5S )-3-Benzyloxymethyl-2-(4-methylbenzene-

*

MW¼321.43 g mol^ꢁ1). IR 1714, 1597, 1335, 1160, 1089, 1036, 945,

sulfonyl)-2-azabicyclo[3.1.0]hex-1-yl]ethanol (74)

814, 782, 710, 660 cm^ꢁ1

;

¹H NMR (CDCl₃)

d

7.70 (d, J¼8.2 Hz, 2H),

To a solution of ynamide 68 (488 mg, 1.22 mmol) in CH₂Cl₂

(10 mL) was added AuCl (14 mg, 0.060 mmol, 0.05 equiv). After

0.5 h, the reaction mixture was ﬁltered through Celite (CH₂Cl₂). The

7.31 (d, J¼8.2 Hz, 2H), 3.91 (d, AB syst, J¼16.7 Hz, 1H), 3.58 (ap-

parent td, J¼10.0, 1.7 Hz, 1H), 2.75 (apparent septet, J¼7.0 Hz, 1H),

S. Couty et al. / Tetrahedron 65 (2009) 1809–1832

1831

C.; Mun˜oz, M. P.; Jime´nez-Nu´ n˜ez, E.; Nevado, C.; Herrero-Go´mez, E.; Raducan,

M.; Echavarren, A. M. Chem.dEur. J. 2006, 12, 1677–1693; (f) Nieto-Oberhuber,

C.; Lo´ pez, S.; Mun˜oz, M. P.; Jime´nez-Nu´ n˜ez, E.; Bun˜uel, E.; Ca´rdenas, D. J.;

Echavarren, A. M. Chem.dEur. J. 2006, 12, 1694–1702; (g) Nieto-Oberhuber, C.;

Lo´ pez, S.; Jime´nez-Nu´ n˜ez, E.; Echavarren, A. M. Chem.dEur. J. 2006, 12, 5916–

5923; (h) Toullec, P. Y.; Genin, E.; Leseurre, L.; Geneˆt, J.-P.; Michelet, V. Angew.

Chem., Int. Ed. 2006, 45, 7427–7430; (i) Genin, E.; Leseurre, L.; Toullec, P. Y.;

Geneˆt, J.-P.; Michelet, V. Synlett 2007, 1780–1784; (j) Mamane, V.; Gress, T.;

Krause, H.; Fu¨rstner, A. J. Am. Chem. Soc. 2004, 126, 8654–8655; (k) Luzung, M.

R.; Markham, J. P.; Toste, F. D. J. Am. Chem. Soc. 2004, 126, 10858–10859; (l)

Sherry, B. D.; Toste, F. D. J. Am. Chem. Soc. 2004, 126, 15978–15979; (m) Zhang,

L.; Kozmin, S. A. J. Am. Chem. Soc. 2005, 127, 6962–6963; (n) Zhang, L.; Kozmin,

S. A. J. Am. Chem. Soc. 2004, 126, 11806–11807; (o) Gagosz, F. Org. Lett. 2005, 7,

ﬁltrate was evaporated under reduced pressure and the crude

material was dissolved in MeOH (5 mL). To the resulting solution at

0 ^ꢀC was added NaBH₄(92 mg, 2.4 mmol, 2 equiv). After 1 h at 0 ^ꢀC,

the reaction mixture was hydrolyzed with a saturated aqueous

solution of NH₄Cl and MeOH was evaporated under reduced pres-

sure. The residue was extracted with EtOAc, the combined organic

extracts were dried over MgSO₄, ﬁltered, and concentrated under

reduced pressure. The crude material was puriﬁed by ﬂash chro-

matography on silica gel (petroleum ether/EtOAc 50:50) to afford

297 mg (60%) of alcohol 74 as a yellow oil and as a 90:10 mixture of

diastereomers (C₂₂H₂₇NO₄S, MW¼401.52 g mol^ꢁ1). IR 3246, 1597,

´

4129–4132; (p) Mezailles, N.; Ricard, L.; Gagosz, F. Org. Lett. 2005, 7, 4133–4136;

(q) Marion, N.; De Fremont, P.; Lemie`re, G.; Stevens, E. D.; Fensterbank, L.;

Malacria, M.; Nolan, S. P. Chem. Commun. 2006, 2048–2050.

1494, 1453, 1336, 1160, 1088, 1038, 815, 736, 699, 672 cm^ꢁ^{1 1}H

;

NMR (CDCl₃) only the signals corresponding to the major dia-

stereomer could all be assigned unambiguously

7.82 (d, J¼8.4 Hz,

5. For reviews on gold-catalysis including not solely enyne cycloisomerizations,

see: (a) Dyker, G. Angew. Chem., Int. Ed. 2000, 39, 4237–4239; (b) Hashmi, A. S.

K. Gold Bull. 2003, 36, 3–9; (c) Hashmi, A. S. K. Gold Bull. 2004, 37, 51–65; (d)

Arcadi, A.; Di Giuseppe, S. Curr. Org. Chem. 2004, 8, 795–812; (e) Hoffmann-

Ro¨der, A.; Krause, N. Org. Biomol. Chem. 2005, 3, 387–391; (f) Hashmi, A. S. K.

Angew. Chem., Int. Ed. 2005, 44, 6990–6993; (g) Hashmi, A. S. K.; Hutchings, G. J.

Angew. Chem., Int. Ed. 2006, 45, 7896–7936; (h) Ma, S.; Yu, S.; Gu, Z. Angew.

d

2H), 7.50–7.40 (m, 7H), 4.75 (d, AB syst, J¼12.2 Hz, 1H), 4.65 (d, AB

syst, J¼12.2 Hz, 1H), 4.30–4.22 (m, 1H), 3.90 (apparent dt, J¼11.5,

4.5 Hz, 1H), 3.66 (dd, J¼9.3, 4.7 Hz, 1H), 3.60 (dd, apparent br d,

J¼10.5 Hz, 1H), 3.51 (dd, J¼9.3, 4.7 Hz, 1H), 3.03 (ddd, apparent dt,

J¼14.8, 3.7 Hz, 1H), 2.91 (dd, J¼10.5, 8.4 Hz, 1H), 2.57 (s, 3H), 2.38–

2.32 (m, 1H), 1.53 (dd, J¼8.9, 5.0 Hz, 1H), 1.42 (ddd, J¼14.8, 9.6,

5.0 Hz, 1H), 0.42 (dd, J¼8.9, 6.4 Hz, 1H), 0.00 (dd, J¼6.4, 5.0 Hz, 1H);

¹³C NMR (CDCl₃) only the signals corresponding to the major dia-

´

´ ˜

Chem., Int. Ed. 2006, 45, 200–203; (i) Jimenez-Nunez, E.; Echavarren, A. M.

Chem. Commun. 2007, 336–346; (j) Fu¨rstner, A.; Davies, P. W. Angew. Chem., Int.

Ed. 2007, 46, 3410–3449; (k) Hashmi, A. S. K. Chem. Rev. 2007, 107, 3180–3211;

(l) Gorin, D. J.; Toste, F. D. Nature 2007, 446, 395–403; (m) Skouta, R.; Li, C.-J.

Tetrahedron 2008, 64, 4917–4938; (n) Muzart, J. Tetrahedron 2008, 64, 5815–

5849; (o) Shen, H. C. Tetrahedron 2008, 64, 3885–3903.

6. (a) Ziﬁcsak, C. A.; Mulder, J. A.; Hsung, R. P.; Rameshkumar, C.; Wei, L.-L. Tet-

rahedron 2001, 57, 7575–7606; (b) For a special issue devoted to the chemistry

of ynamides, see: Tetrahedron 2006, 62.

7. For recent references concerning the gold-catalyzed synthesis of oxazolones

from N-alkynylcarbamates, see: (a) Hashmi, A. S. K.; Salathe´, R.; Frey, W. Synlett

2007, 1763–1766; (b) Istrate, F. M.; Buzas, A. K.; Jurberg, I. D.; Odabachian, Y.;

Gagosz, F. Org. Lett. 2008, 10, 925–928.

8. (a) Marion, F.; Coulomb, J.; Courillon, C.; Fensterbank, L.; Malacria, M. Org. Lett.

2004, 6, 1509–1511; (b) Marion, F.; Coulomb, J.; Servais, A.; Courillon, C.; Fen-

sterbank, L.; Malacria, M. Tetrahedron 2006, 62, 3856–3871.

9. (a) Saito, N.; Sato, Y.; Mori, M. Org. Lett. 2002, 4, 803–805; (b) Mori, M.; Wa-

kamatsu, H.; Saito, N.; Sato, Y.; Narita, R.; Sato, Y.; Fujita, R. Tetrahedron 2006,

62, 3872–3881.

stereomer could all be assigned unambiguously

d 143.9 (s), 137.2 (s),

132.5 (s),129.4 (d, 2C),128.5 (2d, 4C),127.6 (d, 2C),127.4 (d), 73.5 (t),

72.1 (t), 59.6 (t), 51.6 (t), 45.7 (s), 37.9 (d), 36.7 (t), 25.6 (d), 21.5 (q),

12.0 (t); MS-EI m/z (relative intensity) 356 (Mꢁ(CH₂)₂OH^þ, 1), 280

(MꢁBnOCH^þ₂, 8), 247 (10), 246 (56), 155 (7), 140 (7), 125 (10), 124

(9), 108 (7), 92 (10), 91 (100), 65 (7); HRMS calcd for C₂₂H₂₈NO₄S

(MþH^þ): 402.1739, found: 402.1745.

Relevant NOESY correlations (500 MHz, CDCl₃)

H

Ts

N

OH

H

10. For a preliminary communication, see: Couty, S.; Meyer, C.; Cossy, J. Angew.

Chem., Int. Ed. 2006, 45, 6726–6730.

H

11. (a) Wabnitz, T. C.; Yu, J.-Q.; Spencer, J. B. Chem.dEur. J. 2004, 10, 484–493; (b)

Lemie`re, G.; Gandon, V.; Agenet, N.; Goddard, J.-P.; De Kozak, A.; Aubert, C.;

Fensterbank, L.; Malacria, M. Angew. Chem., Int. Ed. 2006, 45, 7596–7599.

12. (a) Krow, G. R. Org. React. 1993, 43, 251–798; (b) Krow, G. R.; Johnson, C. A.;

Guare, J. P.; Kubrak, D.; Henz, K. J.; Shaw, D. A.; Szczepanski, S. W.; Carey, J. T.

J. Org. Chem. 1982, 47, 5239–5243.

13. (a) Lambert, J. B. Tetrahedron 1990, 8, 2677–2689; (b) Lambert, J. B.; Zhao, Y.;

Emblidge, R. W.; Salvador, L. A.; Liu, X.; So, J.-H.; Chelius, E. C. Acc. chem. Res.

1999, 32, 183–190.

H

H²H¹

BnO

68

The absence of scalar coupling between H¹and H²(J³(H¹–

H²)z0 Hz) conﬁrmed the stereochemical assignment.⁴⁶

14. The possibility that desilylation occurs prior to the cycloisomerization cannot

be completely excluded even if some N-(trimethylsilylalkynyl)amides seem to

be stable in the presence of AuCl.¹⁰

15. Marotta, E.; Righi, P.; Rosini, G. Org. Lett. 2000, 2, 4145–4148.

16. (a) Shioiri, T.; Ninomiya, K.; Yamada, S. J. Am. Chem. Soc. 1972, 94, 6203–

6205; (b) Ninomiya, K.; Shioiri, T.; Yamada, S. Tetrahedron 1974, 30, 2151–

2152.

Acknowledgements

We thank Johnson&Johnson for ﬁnancial support (Focus Giving

Award to J.C.) as well as Dr. William V. Murray and Dr. Luc Van Hijfte

for stimulating discussions.

17. (a) Fleming, I.; Henning, R.; Parker, D. C.; Plaut, H. E.; Sanderson, P. E. J. J. Chem.

Soc., Perkin Trans. 1 1995, 317–337; (b) Jones, G. R.; Landais, Y. Tetrahedron 1996,

52, 7599–7662.

References and notes

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1832

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the b-dimethylphenylsilyl enone 49 through an intermediate allenamide 93.

Ts

HO

Ts

N

SiMe₃

Ts

N

SiMe₃

SiMe₂Ph

SiMe₃

SiMe₂Ph

H₂O

AuCl (cat.)

PhMe₂Si

37

92

− Me₃SiOH

Ts

N

Ts

N

Ts

O

SiMe₂Ph

OH

H₂O

NH

•

SiMe₂Ph

49

93

Article Doi

Gold-catalyzed cycloisomerizations of ene-ynamides

DOI: 10.1016/j.tet.2008.10.108

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