Asymmetric synthesis of densely functionalized medium-ring carbocycles and lactones through modular assembly and ring-closing metathesis of sulfoximine-substituted trienes and dienynes

FULL PAPER

DOI: 10.1002/chem.201103060

Asymmetric Synthesis of Densely Functionalized Medium-Ring Carbocycles

and Lactones through Modular Assembly and Ring-Closing Metathesis of

Sulfoximine-Substituted Trienes and Dienynes

Michal Lejkowski,^{[a, b]}Prabal Banerjee,^{[a, c]}Sabine Schꢀller,^[a]Alexander Mꢀnch,^[a]

Jan Runsink,^[a]Cornelia Vermeeren,^[a]and Hans-Joachim Gais*^[a]

Abstract: An asymmetric synthesis of

densely functionalized 7–11-membered

carbocycles and 9–11-membered lac-

tones has been developed. Its key steps

are a modular assembly of sulfoximine-

substituted C- and O-tethered trienes

and C-tethered dienynes and their Ru-

catalyzed ring-closing diene and enyne

metathesis (RCDEM and RCEYM).

The synthesis of the C-tethered trienes

and dienynes includes the following

steps: 1) hydroxyalkylation of enantio-

merically pure titanated allylic sulfoxi-

mines with unsaturated aldehydes, 2)

a-lithiation of alkenylsulfoximines, 3)

alkylation, hydroxy-alkylation, formyla-

tion, and acylation of a-lithioalkenyl-

sulfoximines, and 4) addition of

metric induction in steps 1) and 4).

RCDEM of the sulfoximine-substituted

trienes with the second-generation Ru

catalyst stereoselectively afforded the

corresponding functionalized 7–11-

membered carbocyles. RCDEM of dia-

stereomeric silyloxy-substituted 1,6,12-

trienes revealed an interesting differ-

ence in reactivity. While the (R)-diaste-

reomer gave the 11-membered carbo-

cyle, the (S)-diastereomer delivered in

ACHTUNGTRENUN[NG 9.4.0]pentadecane skeleton. Selective

transformations of the sulfoximine- and

bissilyloxy-substituted carbocycles were

performed including deprotection,

cross-coupling reaction and reduction

of the sulfoximine moiety. Esterifica-

tion of a sulfoximine-substituted homo-

allylic alcohol with unsaturated carbox-

ylic acids gave the O-tethered trienes,

RCDEM of which yielded the sulfoxi-

mine-substituted 9–11-membered lac-

tones. RCEYM of a sulfoximine-substi-

tuted 1,7-dien-10-yne showed an unpre-

cedented dichotomy in ring formation

depending on the Ru catalyst. While

the second-generation Ru catalyst gave

the 9-membered exo 1,3-dienyl carbo-

cycle, the first-generation Ru catalyst

furnished a truncated 9-membered 1,3-

dieny carbocycle having one CH₂unit

less than the dienyne.

a

cascade of cross metathesis and

RCDEM 22-membered macrocycles.

RCDEM of cyclic trienes furnished bi-

cyclic carbocycles with

AHCTUNGTREG[NNUN 7.4.0]tridecane and

a

bicyclo-

Keywords: carbocycles · lactones ·

medium-sized rings · ring-closing

metathesis · sulfoximines

Grignard

reagents

to

a-formyl-

ACHTUNGTRENNUNG

mine group provided for high asym-

Introduction

as natural products with important biological activities,

poses considerable challenges including the construction of

the medium ring and creation of the stereogenic elements.^[1]

Although a number of imaginative methods have been de-

scribed, they are generally confined to the synthesis of rings

of a particular size.^[1,2]In recent years a new and perhaps

general method has emerged featuring the synthesis of ap-

propriate chiral dienes and enynes and their ring-closure

through transition-metal-catalyzed metathesis (RCDEM^[3]

and RCEYM^[4]).^[5–8]However, most asymmetric syntheses of

MRCs and MRLs based on this concept were either target

orientated or did not aim at the whole range of medium-

sized rings. We recognized the sulfoximine-substituted

MRCs and MRLs I–IV as advanced templates for the attain-

ment of structurally diversified MRCs and MRLs (see

below) and envisioned their synthesis through ruthenium-

catalyzed RCM of the corresponding chiral sulfoximine-sub-

stiuted C- and O-tethered trienes and dienynes (Figure 1).^[9]

Because of the planned modular asymmetric synthesis of

the trienes and dienynes (see below), the whole range of

MRCs and MRLs commencing with 9-membered rings

The asymmetric synthesis of medium-ring carbocycles

(MRCs) and lactones (MRLs), which are frequently found

[a] Dr. M. Lejkowski, Prof. Dr. P. Banerjee, Dipl.-Chem. S. Schꢀller,

Dipl.-Chem. A. Mꢀnch, Dr. J. Runsink, C. Vermeeren,

Prof. Dr. H.-J. Gais

Institute of Organic Chemistry

RWTH Aachen University, Landoltweg 1

52074 Aachen (Germany)

E-mail: gais@rwth-aachen.de

[b] Dr. M. Lejkowski

Present address:

Catalysis Research Laboratory

Im Neuenheimer Feld 584, 69120 Heidelberg (Germany)

[c] Prof. Dr. P. Banerjee

Present address:

Department of Chemistry, IIT Ropar, Nangal Road

Rupnagar, 140001 Punjab (India)

Supporting information for this article is available on the WWW

under http://dx.doi.org/10.1002/chem.201103060.

Chem. Eur. J. 2012, 18, 3529 – 3548

ꢁ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

3529

nucleophiles followed by a substitution of the alkylsulfoxi-

mine group by a I atom upon reaction with iodoformate

should afford iodides VII.^[11,14]The activation of the sulfoxi-

mine group of I through acyclation at the N atom with

chloroformate followed by a migratory chloride substitution

of the aminosulfoxonium group could give the allylic chlor-

ides VIII.^[15]An isomerization of the alkenylsulfoximines I

to the corresponding allylic sulfoximines followed by an al-

lylic substitution of the latter with cuprates should yield

dienes IX (R⁵=alkyl, aryl).^[16]Finally, oxidative deamination

of I could afford the corresponding sulfones X^[17a]carrying

the synthetically versatile alkenylsulfonyl group.^[17b]

The envisioned syntheses of MRCs and MRLs I–IV cru-

cially depend on the following factors. 1) Can an efficient

asymmetric synthesis of the trienes and dienynes XI–XIV

(Figure 3) be developed? 2) Are sterically demanding tri-

enes and dienynes of type XI–XIV substrates for the Ru-

catalyzed RCM? 3) Is the sulfoximine-substituted double

bond of XI–XIV an inert bystander in RCM? and 4) Will a

principally possible coordination of the sulfoximine group of

XI–XIV to the Ru atom of the catalyst or intermediates of

the catalytic cycle impair RCM?^[3]Prior to the beginning of

our work evidence has been obtained suggesting that the N-

methylsulfoximine-substituted double bond does not partici-

pate in RCM^[18]with the first- and second-generation Ru

catalysts.^[19]However, a detrimental effect of the N-alkylsul-

foximine group upon the first-generation Ru catalyst was

noted during the synthesis of cyclic sulfoximines from N,S-

sulfoximine-tethered dienes.^[20]

Figure 1. Mono- and bicyclic MRCs and MRLs I–IV through RCM of

sulfoximine-substituted trienes and dienynes (PG=protecting group).

should be accessible. Of particular interest would be the

possibility to also gain access to bicyclic MRCs of type II

having bicyclo

for

example

G

bicyclo-

A

are contained in a large number of terpenoids,^{[1a,b,d,h,5,10]}and

bicyclic MRLs of type IV, which are frequently found in na-

ture.^[2e–g]

Although MRCs and MRLs I–IV have a particular substi-

tution pattern, the arrangement and number of functional

groups should allow the synthesis of a wide range of substi-

tuted MRCs and MRLs. Because of the alkenylsulfoximine

moiety,^[11]the MRCs and MRLs I–IV should be amendable

to a number of additional specific transformations, some of

which are exemplified for MRCs I in Figure 2. Thus, a Ni-

catalyzed and Cu-mediated cross-coupling reaction of alke-

nylsulfoximines I with organometallics could allow the syn-

thesis of alkyl- and aryl-substituted dienes V (R⁵=alkyl,

aryl),^[12]and a reduction of I should give dienes VI.^[13]A Mi-

chael reaction of alkenylsulfoximines I with C- and hetero-

We planned a modular asymmetric synthesis of trienes

and dienynes XI–XIV based on the diastereoselective hy-

droxyalkylation of enantiomerically pure titanated cyclic

and acyclic allylic sulfoximines with aldehydes giving sulfox-

imine-substituted homoallylic alcohols (step 1) (Figure 3).^[21]

Further key steps would be the E-stereoselective alkylation,

formylation and acylation of a-lithioalkenylsulfoximines

(step

2), stereoselective

alkylation of

a-formyl-

AHCTUNGTRENNUNG

reagents (step 3), and esterification of homoallylic alcohols

with unsaturated carboxylic acids (step 4). Steps 2 and 3

could perhaps be combined in one step by hydroxyalkyla-

tion of the a-lithioalkenylsulfoximines with unsaturated al-

dehydes or ketones. It was hoped that the sulfoximine group

would provide asymmetric induction in both steps, the addi-

tion of organometallics to a-formyl-(acyl)alkenylsulfoxi-

mines (step 3) and hydroxyalkylation of a-lithioalkenylsul-

foximines with aldehydes and ketones (steps 1+2). The

modular synthesis of trienes and dienynes XI–XIV should

grant a high degree of flexibility in regard to the introduc-

tion of various substituents R², R³, R⁴and R⁵, the size and

substituent of the ring of XII and XIV,^[21]and length of the

chains bearing the terminal double and triple bonds.

In this article, we provide a detailed account^[22]of the

modular asymmetric synthesis and RCDEM of C- and O-

tethered trienes of type XI–XIV (X=CH=CHR), which re-

sulted in the synthesis of 7–11-membered carbocycles I (X=

H), bicyclic carbocycles II (X=H), and 9–11-membered lac-

Figure 2. Envisioned synthesis of MRCs V–X from sulfoximine-substitut-

ed MRCs I.

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Chem. Eur. J. 2012, 18, 3529 – 3548

Functionalized Medium-Ring Carbocycles and Lactones

FULL PAPER

ynes and RCM for the attainment of densely functionalized

medium-sized rings.

Results and Discussion

Synthesis of sulfoximine-substituted dienes: The successive

treatment of the enantiomerically pure acyclic allylic sulfoxi-

mine 1^[21]with nBuLi and ClTi

ACTHNUTRGEN(UNG OiPr)₃gave the correspond-

ing bisallyl titanium complex, the reactions of which with

but-2-enal and pent-4-enal according to the standard proce-

dure,^[21]afforded the corresponding enantio- and diastereo-

merically pure dienes 2 and 4 in 70 and 75% yield, respec-

tively (Scheme 1).^[24]The isopropyl group of 1 was selected

because of its frequent occurrence in natural products. Fur-

thermore, the choice of this sterically demanding group was

meant to probe the limits of RCM of the corresponding iso-

propyl-substituted trienes and dienynes (cf. Figure 3). Fol-

lowing the same route but starting from ent-1, the enantio-

meric dienes ent-2 and ent-4 were prepared.^[24]

Scheme 1. Stereoselective synthesis of sulfoximine-substituted acyclic

dienes.

Figure 3. Modular asymmetric synthesis of sulfoximine-substituted C- and

O-tethered trienes and dienynes.

Similarly, the successive treatment of the enantiomerically

pure 5-membered cyclic allylic sulfoximine 7^[21]with nBuLi,

tones III (X=H). A similar modular asymmetric synthesis

ClTiACTHNGUETRN(UNG OiPr)₃and pent-4-enal furnished the enantio- and dia-

ꢀ

gave dienynes of type XI (X=C CR). RCEYM of a 1,7-

stereomerically pure cyclic homoallylic alcohol 8 in 73%

yield (Scheme 2). Finally, the successive treatment of the

enantiomerically pure 6-membered cyclic allylic sulfoximine

ꢀ

dien-10-yne of type XI (X=C CR) with first- and second-

generation Ru catalysts revealed an unprecedented dichoto-

my depending on the catalyst and afforded normal and trun-

cated 9-membered 1,3-dienyl carbocycles. Examples are pro-

vided for the transformation of sulfoximine-substituted car-

bocyles I to MRCs of type V and VI. The syntheses of the

MRCs and MRLs described herein together with those of

medium-ring spirocycles^[13b]and N-heterocycles^[23]demon-

strate the general applicability of the combination of the sul-

foximine-route to C-, O-, and N-tethered trienes and dien-

10^[21]with nBuLi, ClTi

ACTHNUTRGNEU(GN OiPr)₃, but-2-enal and pent-4-enal,

respectively, furnished the corresponding enantio- and dia-

stereomerically pure cyclic homoallylic alcohols 11 and 13 in

60 and 78% yield, respectively. The protection of the hy-

droxyl groups of the homoallylic alcohols depicted in

Schemes 1 and 2 as silyl ethers concluded the synthesis of

the dienes, which were required for the attainment of the

trienes (cf. Figure 3). Thus, treatment of the acyclic alcohols

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H.-J. Gais et al.

Scheme 3. Z/E Isomerization of sulfoximine-substituted acyclic dienes.

ing the same procedure but starting from ent-3, the enantio-

meric alkenylsulfoximine ent-16 was synthesized.

The cyclic alkenylsulfoximine 12 showed a similar reactiv-

ity (Scheme 4). Lithiation of the Z-configured alkenylsulfox-

imine 12 with nBuLi gave the a-lithioalkenylsulfoximine 21,

the protonation of which after a metalation/isomerization

time of 30 min exclusively furnished the E-configured alke-

Scheme 2. Stereoselective synthesis of sulfoximine- and hydroxy-substi-

tuted cyclic dienes.

2 and 4 with ClSiEt₃gave the corresponding silyl ethers 3

and 5 in high yields. Following the same procedure but start-

ing from ent-2 and ent-4, the corresponding enantiomeric

silyl ethers ent-3 and ent-5 were synthesized. Silylation of

ent-2 with ClSitBuMe₂furnished the silyl ether ent-6. The

similar treatment of the cyclic alcohols 8, 11, and 13 with

ClSiEt₃afforded the corresponding silyl ethers 9, 12, and 14

in high yields. Finally, alcohol 13 was protected as the tert-

butyldimethylsilyl ether 15 (83%) in order to also have less

reactive silyl ether for synthetic purposes at hand.

Synthesis of sulfoximine-substituted C-tethered trienes: The

synthesis of E-configured trienes starting from the Z-config-

ured sulfoximine-substituted dienes required a lithiation at

the a-position and quantitative isomerization of the Z-con-

figured a-lithioalkenylsulfoximine to the E-configured deriv-

ative followed by reaction with a suitable electrophile at the

a-position (cf. Figure 3).

We have previously shown that Z- and E-configured alke-

nylsulfoximines are lithiated with nBuLi at the a-position at

low temperatures with the exclusive formation of the corre-

sponding E-configured a-lithioalkenylsulfoximines.^[14a,25]Iso-

merization of the Z-configured a-lithioalkenylsulfoximine to

the corresponding E-configured isomer generally was rapid

and quantitative at elevated temperatures. The successive

treatment of the Z-configured acyclic alkenylsulfoximines 3,

ent-6, and ent-5 with nBuLi and water exclusively afforded

the corresponding E-configured alkenylsulfoximines 16

(95%), ent-17 (91%), and ent-18 (98%) (Scheme 3). Follow-

Scheme 4. E/Z- and vinyl/allyl isomerization of sulfoximine-substituted

cyclic dienes.

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Functionalized Medium-Ring Carbocycles and Lactones

FULL PAPER

nylsulfoximine 19 in 98% yield. Similarly, lithiation of the

Z-configured alkenylsulfoximine 14 with nBuLi gave the a-

lithioalkenylsulfoximine 22, the protonation of which after a

metalation/isomerization time of 30 min exclusively afforded

the E-configured alkenylsulfoximine 20 in 89% yield. Inter-

estingly, application of the same lithiation sequence to 14

but extending the time for metalation/isomerization to 3 h

gave after treatment with NaHCO₃/H₂O the allylic sulfoxi-

mine 24 in 87% yield. Submitting the cyclopentanoid alke-

nylsulfoximine 9 to a successive treatment with nBuLi and

NaHCO₃/H₂O under similar conditions gave the allylic sul-

foximine 23 in 85% yield. Apparently, a remarkable and

highly regioselective isomerization of the a-lithioalkenylsul-

foximines 25 and 22 to the corresponding isomeric a-lith-

ioallylsulfoximines 26 and 27, the protonation of which se-

lectivity afforded 23 and 24, respectively, has occurred

under these conditions.^[26]

Scheme 6. Synthesis of the sulfoximine- and hydroxy-substituted acyclic

1,4,8-trienes.

Having secured with these experiments a ready access to

the E-configured a-lithioalkenylsulfoximines, their reaction

with suitable electrophiles en route to trienes (cf. Figure 3)

was investigated. Lithiation of the alkenylsulfoximines 3 and

5 with nBuLi furnished the corresponding a-lithioalkenylsul-

foximines 28 and 30, the alkylation of which with allyl bro-

mide afforded the corresponding E-configured 1,4,8-trienes

29 and 31 in 90 and 75% yield, respectively (Scheme 5).

Scheme 7. Synthesis of the sulfoximine- and hydroxy-substituted acyclic

1,6,10- and 1,8,12-trienes.

(36%), 38 (45%), and 39 (39%). Attempts to achieve a dia-

stereoselective hydroxyalkylation of the a-lithioalkenylsul-

foximines through for example a Li/Zn or Li/Ti exchange

were not successful.^[27]

The assembly of the acyclic 1,4,8-, 1,6,10-, and 1,8,12-tri-

enes was complemented by that of the hydroxy-substituted

1,6,12-trienes. Thus, the reaction of the a-lithioalkenylsul-

foximine 30 with pent-4-enal at À788C followed by a proto-

nation of the corresponding lithium alcoholates at À788C

afforded after chromatographic separation the hydroxy-sub-

stituted 1,6,12-trienes 40 and 41 in 32 and 40% yield, re-

spectively (Scheme 8).

The silylation of the acyclic alcohols 34, 35, 40, and 41

with ClSitBuMe₂gave the corresponding tert-butyldimethyl-

silyl-protected hydroxytrienes 36, 37, 42, and 43 in high

yields. The triethylsilyl and tert-butyldimethylsilyl protecting

groups of the trienes were chosen in anticipation of a selec-

tive deprotection of the corresponding MRCs at the triethyl-

silyloxy group for synthetic applications (cf. Figure 1).

Finally, the acyclic a-lithioalkenylsulfoximine 28 was con-

verted upon reaction with propanal to the diastereomeric al-

Scheme 5. Synthesis of sulfoximine-substituted acyclic trienes.

Next, the stereoselective synthesis of acyclic 1,4,8-, 1,6,10-

and 1,8,12-trienes carrying an additional hydroxyl group was

probed. Gratifyingly, the treatment of the a-lithioalkenylsul-

foximine 28 with but-2-enal, pent-4-enal, and hept-6-enal,

respectively, at À788C followed by a protonation of the in-

termediate lithium alcoholates at À788C afforded the corre-

sponding hydroxy-substituted 1,4,8-, 1,6,10-, and 1,8,12-tri-

enes 32/33, 34/35, and 38/39 (Schemes 6 and 7). However,

the hydroxyalkylations of the a-lithioalkenylsulfoximines

were not stereoselective and gave in all cases nearly 1:1 mix-

tures of the diastereomeric alcohols. Chromatography yield-

ed the pure alcohols 32 (40%), 33 (44%), 34 (38%), 35

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H.-J. Gais et al.

Scheme 10. Synthesis of sulfoximine- and hydroxy-substituted cyclic

1,6,10-trienes.

Scheme 8. Synthesis of the sulfoximine- and hydroxy-substituted acyclic

1,6,12-trienes.

cohols 44 and 45, which were isolated in 33 and 30% yield,

respectively (Scheme 9). The alcohols were required as

starting material for the stereoselective synthesis of trienes

carrying a hydroxy-substituted tertiary C atom (see below).

Scheme 11. Synthesis of sulfoximine- and hydroxy-substituted cyclic

1,4,10-trienes.

Scheme 9. Synthesis of sulfoximine-substituted acyclic dienes.

Cyclic hydroxy-substituted 1,6,10-, 1,4,10-, and 1,6,12-tri-

enes were also accessed by this route. Lithiation of the

cyclic alkenylsulfoximines 12, 14, and 15 with nBuLi in THF

at À78 to 08C afforded the corresponding E-configured a-

lithioalkenylsulfoximines 21, 22, and 52 (Schemes 10–12).

Their reactions with pent-4-enal and but-2-enal at À788C

followed by a protonation of the intermediate lithium alco-

holates at À788C gave the corresponding 1,6,10-trienes 46/

47, 1,4,10-trienes 48/49, and 1,6,12-hydroxytrienes 53/54 and

55/56 as nearly 1:1 mixtures of diastereomers. Chromato-

graphic separation of the diastereomeric alcohols yielded

the alcohols 47 (65%), 48 (30%), 49 (31%), 53 (45%), 54

(34%), 55 (22%), and 56 (25%). Silylation of the diastereo-

meric alcohols 48 and 49 afforded the corresponding tert-bu-

tyldimethylsilyl ethers 50 and 51 in 74 and 68% yield, re-

spectively.

Scheme 12. Synthesis of sulfoximine- and hydroxy-substituted cyclic

1,6,12-trienes.

with the aldehydes depicted in Schemes 6–12 varied, de-

pending on the reaction time, temperature and the time

which elapsed between the addition of the unsaturated alde-

hyde and the protonation of the intermediate lithium alco-

It was observed that the diastereoselectivities of the reac-

tions of the cyclic and acyclic a-lithioalkenylsulfoximines

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Functionalized Medium-Ring Carbocycles and Lactones

FULL PAPER

holates. Furthermore, an attempted protonation of the lithi-

um alcoholates at elevated temperatures gave mainly the

corresponding E-configured alkenylsulfoximines instead of

the hydroxytrienes. These observations point to a reversibili-

ty of the reaction of the a-lithioalkenylsulfoximines with the

aldehydes. Thus, the ratios of the isolated diastereomeric al-

cohols most likely do not reflect the selectivities of the hy-

droxyalkylation reactions.

of prop-1-enylmagnesium bromide, but-3-enylmagnesium

bromide, and pent-4-enylmagnesium bromide proceeded

with high diastereoselectivities (ꢁ96% d.e.) and gave the

corresponding hydroxytrienes 33, ent-35, ent-62, and 64 in

90, 82, 82 and 94% yield, respectively (Scheme 14). Only

Diastereoselective synthesis of secondary hydroxytrienes: A

diastereoselective synthesis of the hydroxytrienes through

the one-step hydroxyalkylation of the a-lithioalkenylsulfoxi-

mines with aldehydes turned out not to be feasible. The dia-

stereomeric alcohols served, however, as welcomed starting

materials for the synthesis of the corresponding ketotrienes

(see below). Furthermore, the diastereomeric hydroxy-

trienes were helpful in probing the influence of the configu-

ration of the hydroxyl group bearing C atom upon the RCM

(see below). Despite these advantages a stereoselective syn-

thesis of the hydroxytrienes was highly desirable. Therefore,

the stepwise attachment of an unsaturated hydroxyalkyl

group to the sulfoximine-substituted dienes at the a-position

was investigated.

Formylation of the a-lithioalkenylsulfoximines 28 and ent-

58, the latter of which was obtained through lithiation of

ent-17 with nBuLi, with N-formylmorpholine^[28]readily gave

the corresponding aldehydes 57 and ent-59 in 86 and 75%

yield, respectively (Scheme 13). Following the same proce-

Scheme 14. Diastereoselective synthesis of sulfoximine- and hydroxy-sub-

stituted trienes.

Scheme 13. Stereoselective synthesis of the sulfoximine-substituted for-

myldienes 57 and ent-59.

the reaction of 57 with 1 equiv of allylmagnesium bromide

occurred with a lower diastereoselectivity and gave the hy-

droxytrienes 60 and 61 in a ratio of 90:10. The diastereo-

merically pure alcohol 60 was isolated, however, by chroma-

tography in 84% yield. A comparison of the reactions of the

aldehydes ent-57 and ent-59, which differ in the silyl protect-

ing groups, with the Grignard reagent shows that the in-

creased bulkiness of the remote silyloxy group has no influ-

ence upon the degree of asymmetric induction. The configu-

rations of the newly generated stereogenic centers of the hy-

droxytrienes were indirectly determined by NOE experi-

ments of the corresponding MRCs derived thereof (see

below). Silylation of the alcohols ent-35, ent-62 and 64 with

ClSitBuMe₂gave the corresponding silyl ethers ent-37, ent-

63 and 65 in high yields.

dure but starting from ent-28, the enantiomeric aldehyde

ent-57 was prepared. The reaction of 28 with N-methoxy-N-

methylformamide^[29a]also afforded the aldehyde 57, which

was obtained in some experiments in yields up to 84%.

However, the reproducibility of the yield of the formylation

with this reagent was low because of the difficulties we en-

countered in the preparation of the pure formamide accord-

ing to the literature.^[29a]It was found that the thus prepared

formamide was contaminated by various amounts of metha-

nol and sodium methanolate, which caused a partial or even

complete cleavage of the formamide upon its attempted pu-

rification by distillation.^[27b,29b]

As hoped for the reactions of the sulfoximine-substituted

unsaturated aldehydes 57, ent-57, and ent-59 with 2–3 equiv

The high diastereoselectivities of the additions of the

Grignard reagents to the aldehydes can be rationalized by

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3535

H.-J. Gais et al.

action of the acyclic hydroxytrienes 32/33, 34/35, 38/39, 40/

41, and 44/45 (cf. Scheme 6–9), as mixtures of diastereomers,

with Dess–Martin periodinane (DMP)^[31]proceeded effi-

ciently and afforded the corresponding 1,4,8-ketotriene 67,

1,6,10-ketotriene 68, 1,8,12-ketotriene 69, and 1,6,12-keto-

triene 70 and the ketodiene 71 (Scheme 16) in yields of 91–

96%. Similarly, the oxidation of the cyclic hydroxytrienes

48/49 and 46/47 (cf. Schemes 11 and 10), as mixtures of dia-

stereomers, with DMP gave the corresponding cyclic 1,4,10-

ketotriene 72 and 1,6,10-ketotriene 73 in 91 and 89% yield,

respectively.

Figure 4. Chelate model for the stereoselective addition of Grignard re-

agents to sulfoximine-substituted unsaturated aldehydes as exemplified

for 57.

assuming the formation of a N,O-chelate of type XV be-

tween the aldehydes and the Grignard reagents (Figure 4).

In the chelate the Mg atom should be coordinated to the N

atom of the sulfoximine group, which is normally the pre-

ferred coordination site for Lewis acids.^[11]Addition of

RMgBr to the Si side of the carbonyl group of XV should

be preferred because of a shielding of the Re side by the

phenyl group.

It should be noted, however, that a chelate model of type

XV fails for a rationalization of the reactions of the structur-

ally related aldehyde XVI with Grignard reagents.^[23]

Diastereoselective synthesis of tertiary hydroxytrienes: Be-

cause of the envisioned synthesis of the MRCs and MRLs

carrying a carbonyl group (cf. Figure 1), an access to the ke-

totrienes (cf. Figure 3) were required. In a model reaction

the feasibility of an acylation of a-lithioalkenylsulfoximines

was probed. The treatment of the a-lithioalkenylsulfoximine

28 with 2 equiv of N-methoxy-N-methylacetamide^[30]at

À788C gave the ketodiene 66 in 40% yield together with

the E-configured alkenylsulfoximine 16 in 55% yield

(Scheme 15). Attempts to increase the yield of 66 by run-

Scheme 16. Sulfoximine-substituted acyclic ketotrienes and ketodienes

derived from the corresponding hydroxytrienes.

It was now of particular interest to see whether the addi-

tion of Grignard reagents to ketotrienes of this type would

also proceed with similar high diastereoselectivities as in the

case of the formyldienes. The treatment of ketone 68 with

2 equiv of PhMgCl gave the tertiary alcohol 74 with ꢁ96%

d.e. in 86% yield (Scheme 17). The reaction of ketone 68

Scheme 15. Synthesis of the sulfoximine-substituted ketodiene 66.

ning the acyclation at À45 or at 08C were not successful.

The relatively low yield of the ketone and formation of 16

are perhaps due to a competing transmetalation between

the alkenyllithium derivative 28 and the methylketone 66 or

the acetamide derivative. Further experiments with other

acylation reagents have not been undertaken.

The reaction of the a-lithioalkenylsulfoximine 28 with the

acylation reagent turned out to be less efficient than with

the formylation reagent. In order to obtain ketotrienes, the

oxidation of the diastereomeric hydroxytrienes was investi-

gated. After some experimentation it was found that the re-

Scheme 17. Diastereoselective synthesis of sulfoximine-substituted terti-

ary hydroxytrienes.

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Functionalized Medium-Ring Carbocycles and Lactones

FULL PAPER

with 2 equiv of MeMgBr was less selective and afforded the

tertiary alcohols 75 and 76 in 60 and 15% yield, respectively.

In contrast, the reaction of ketone 71 with 2 equiv of allyl-

magnesium chloride was highly diastereoselective and gave

the tertiary alcohol 77 with ꢁ96% d.e. in 90% yield. The

configuration of the newly formed stereogenic center of the

alcohol 77 was indirectly determined by NOE experiments

of the corresponding MRC derived thereof (see below). The

configurations of alcohols 74, 75 and 76 were assigned on

the basis of the configuration of alcohol 77. The highly dia-

stereoselective addition of the Grignard reagents to the ke-

tones 68 and 71 can also be rationalized by proposing the

formation of a chelate similar to XV but carrying an acyl in-

stead of the formyl group.

Scheme 18. Synthesis of the 7-membered carbocycle 79.

The formylation of the cyclic dienes and the reaction of

the corresponding formyldienes with organometallics were

not investigated. It is to be expected, however, that 1) the

cyclic a-lithiosulfoximines 21, 22, and 52 can be successfully

formylated with N-formylmorpholine and 2) the correspond-

ing cyclic unsaturated aldehydes will diastereoselectively

react with organometallics.

Scheme 19. Synthesis of the 9-membered carbocycle 80.

RCDEM of sulfoximine-substituted acyclic trienes: Having

achieved a modular asymmetric synthesis of a number of

functionalized acyclic and cyclic trienes, their RCM was

studied. The following trienes were investigated: the 1,4,8-

triene 29, 1,4,10-triene 31, diastereomeric 1,6,10-hydroxy-

trienes 34 and 35, diastereomeric 1,6,12-hydroxytrienes 40

and 41, diastereomeric 1,6,10-silyloxytrienes 36 and 37, dia-

stereomeric 1,6,12-silyoxytrienes 42 and 43, 1,5,9-hydroxy-

triene 77, 1,6,10-silyloxytriene ent-37, 1,6,10-silyloxytriene

ent-63, 1,7,11-silyloxytriene 64, and 1,6,10-ketotriene 68.

These trienes were selected in order to see whether the

whole range of medium-sized MRCs can be accessed. In ad-

dition, information was sought about the influence of the

structure of the terminal double bonds, functional groups,

and configuration of the trienes upon their RCM. RCM was

carried out by treatment of the respective triene at 5 mm

with 5 mol% of the second-generation Ru-catalyst 78^[19b,c]in

toluene, CH₂Cl₂and ClCH₂CH₂Cl at reflux in flasks open to

nitrogen or argon atmosphere and to full conversion, except

otherwise stated.

tion of the sulfoximine-substituted double bond nor a Ru-

catalyzed double bond isomerization of the triene followed

by RCM^[32]had occurred.

Next RCM of the acyclic trienes 34, 35, 40, and 41 was

studied, which all carry a secondary allylic hydroxyl group

(Scheme 20). The treatment of the hydroxytrienes 34, 35, 40,

and 41 with catalyst 78 in CH₂Cl₂at room temperature for

16 h led to no conversion of the trienes. Heating the mix-

tures of the trienes and the catalyst at reflux resulted in a

complete conversion of the trienes with the formation of

The reaction of the 1,4,8-triene 29 in CH₂Cl₂at reflux

with 78 gave the 7-membered carbocycle 79 only in 40%

yield together with the triene 29 in 50% yield (Scheme 18).

However, running RCM in toluene under otherwise identi-

cal conditions led to a full conversion of the triene and gave

the MRC in 96% yield.

RCM of the higher homologue of 29, the 1,4,10-triene 31

with catalyst 78 in toluene at reflux also occurred readily

and furnished the 9-membered carbocycle 80 in 90% yield

(Scheme 19). According to NMR spectroscopy the Z-config-

ured MRC was exclusively formed. Furthermore, NMR

spectroscopy of the crude reaction mixture gave no indica-

tion for the formation of the 6-membered carbocycle 81 and

8-membered carbocycle 82 or its 1,3-dienyl isomer (not

shown). Thus, neither RCM of the triene 31 under participa-

Scheme 20. Reactivity of trienes carrying an allylic hydroxyl group to-

wards catalyst 78.

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3537

H.-J. Gais et al.

several unidentified compounds. Formation of the corre-

sponding MRCs could not be detected by NMR spectrosco-

py. It has been reported that allylic alcohols can be cleaved

by Ru–alkylidene complexes with formation of the corre-

sponding alkyl ketones and alkenes.^[33a–c]Whether transfor-

mations of this type are responsible for the decomposition

of the trienes is not known.

In stark contrast to 34, 35, 40, and 41 the 1,5,9-triene 77,

which carries a tertiary allylic hydroxyl group, gave with 78

in CH₂Cl₂at reflux the 8-membered carbocycle 84 in 90%

yield (Scheme 21). The facile formation of 84 is noteworthy

because of the difficulties which are frequently encountered

in the synthesis of 8-membered carbocycles through

RCM.^[1,5,10]

Scheme 23. Synthesis of the 9-membered bissilyloxy-substituted carbocy-

cles ent-85, ent-86, ent-87, and ent-88.

Scheme 21. Synthesis of the hydroxy-substituted 8-membered carbocycle

83.

Because of the decomposition of the hydroxy-substituted

trienes 34, 35, 40, and 41 in the presence of 78, RCM of the

corresponding bissilyl-protected trienes was studied. The re-

actions of the diastereomeric 1,6,10-trienes 36 and 37 with

catalyst 78 in CH₂Cl₂for 16 h at reflux led to a complete

conversion of both trienes and gave the corresponding Z-

configured 9-membered carbocycles 84 and 85 in 90 and

80% yield, respectively (Scheme 22).

the isomers by HPLC gave ent-85 in 78% yield and ent-86

in 15% yield. Similarly, the 1,6,10-triene ent-63, which car-

ries two tert-butyldimethylsilyl groups, delivered with 78

after a reaction time of 18 h a mixture of the Z-configured

9-membered carbocyle ent-87 and its E-configured isomer

ent-88. Separation of the isomers by chromatography fur-

nished MRC ent-87 in 79% yield and MRC ent-88 in 12%.

The configurations of the disubstituted double bonds of the

MRCs were deduced by NMR spectroscopy. The formation

of the E-configured 9-membered carbocycles ent-83 and ent-

85 was perhaps caused by an isomerization of the Z-config-

ured MRCs via a ring-opening/ring-closure sequence cata-

lyzed by the intermediate Ru–methylidene complex.^[3]How-

ever, an investigation of the reactivity of the pure Z- and E-

configured MRCs towards 78, eventually in the presence of

ethylene or propylene,^[3]which may have proven this hy-

pothesis, was not undertaken.

In contrast to the Z-stereoselective RCM of the 1,6,10-tri-

enes 36, 37, ent-37, and ent-63 that of the higher homologue,

the 1,7,11-triene 65 proceeded E-stereoselectively. Thus, the

treatment of 65 with catalyst 78 in ClCH₂CH₂Cl for 16 h at

reflux furnished the E-configured 10-membered carbocycle

89 in 90% yield (Scheme 24).

Scheme 22. Synthesis of the 9-membered bissilyloxy-substituted carbocy-

cles 84 and 85.

Both the R- and S-configured 1,6,10-trienes 36 and 37, re-

spectively, were converted by the catalyst 78 to the corre-

sponding MRCs. RCM was not noticeably effected by the

configuration of the trienes at the C atom bearing the bulky

silyloxy group. This led to the question of whether the simi-

lar diastereomeric 1,6,12-trienes 42 and 43, the terminal

double bonds of which are in contrast to those of 36 and 37

structurally undifferentiated, would also undergo equally

facile RCM. The reaction of the R-configured 1,6,12-triene

42 with catalyst 78 in CH₂Cl₂for 16 h gave a mixture of the

The configurations of the tert-butyldimethylsilyloxy group

bearing C atoms of 84 and 85 were determined by NOE ex-

periments. Formation of the corresponding E-configured iso-

mers of 84 and 85 was not observed under these conditions.

However, treatment of the triene ent-37 with a different

batch of catalyst 78 under the same conditions but with an

extention of the reaction time from 16 to 18 h furnished the

Z-configured MRC ent-85 together with its E-configured

isomer ent-86 in a ratio of 80:20 (Scheme 23). Separation of

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Functionalized Medium-Ring Carbocycles and Lactones

FULL PAPER

Scheme 24. Synthesis of the 10-membered bissilyloxy-substituted carbocy-

cle 89.

Z- and E-configured 11-membered carbocycles 90 and 91,

respectively, in a ratio of 85:15 (Scheme 25). Separation of

the isomers by HPLC afforded the Z-configured MRC 90 in

70% yield and the E-configured MRC 91 in 4% yield. Thus,

in contrast to the 1,7,11-triene 65 and in analogy to the

1,6,10-trienes 36 and 37 RCM of the 1,6,12-triene had deliv-

ered with high selectivity the Z-configured MRC. The con-

figuration of the tert-butyldimethylsilyloxy group bearing C

atom of 90 was determined by NOE experiments.

Scheme 26. Synthesis of the densly functionalized 22-membered macrocy-

cles 92 and 93.

Scheme 25. Synthesis of the 11-membered bissilyloxy-substituted carbocy-

cles 90 and 91.

Surprisingly, the treatment of the diastereomeric S-config-

ured 1,6,12-triene 43 with catalyst 78 in CH₂Cl₂for 16 h

under similar conditions gave a mixture of the 22-membered

macrocycles 92 and 93 (Scheme 26). The 11-membered

MRC 94 with the Z-configuration was isolated only in 4%

yield. Separation of the isomeric macrocycles by chromatog-

raphy afforded the C₂-symmetric macrocycle 92 in 32%

yield and the C₁-symmetric macrocycle 93 in 38% yield.

The structural assignment of the macrocycles was made by

NMR spectroscopy based on the symmetry considerations

of the macrocycles including the C₂symmetry of the C1–C8

and C12–C19 units of 93.

Formation of the 22-membered macrocycles 92 and 93

can be ascribed to a cascade of cross-metathesis (CM) and

RCM.^[3,34]A tail-to-head CM reaction of the 1,6,12-triene 43

involving the 1,2- and 12,13-double bonds gave the

1,6,12,17,23-pentaene 95 (Scheme 27), while a head-to-head

CM of 43 entailing the 12,13-double bonds yielded the

1,6,12,18,23-pentaene 96 (Scheme 28). Subsequently, the

1,6,12,17,23-pentaene 95 and 1,6,12,18,23-pentaene 96 expe-

rienced RCM with formation of the corresponding macrocy-

cles 92 and 93. Alternatively, the synthesis of 93 could pro-

Scheme 27. Tail-to-head CM of triene 43 and RCM of pentaene 95.

ceed through RCM of a 1,7,12,17,23-pentaene formed in a

tail-to-tail CM of 43 involving the 1,2-double bonds (not

shown).

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H.-J. Gais et al.

Scheme 29. Synthesis of the bissulfoximine-substituted 1,5,10,15,19-pen-

taene 97.

The reactivity of the triene 68 is notable since RCM was

not observed. For the reaction of the 1,6,10-ketotriene 68

with catalyst 78 similar reaction conditions were applied as

for the reactions of the analogous 1,6,10-trienes 36 and 37,

which carry a H atom and a silyloxy group at C5 instead of

an O atom. The reason for the different reactivity of 1,6,10-

ketotriene 68 and the 1,6,10-silyloxytrienes 36 and 37, that

is, CM versus RCM, is not apparent. For example, principle

Scheme 28. Head-to-head CM of triene 43 and RCM of pentaene 96.

RCM of the trienes 36, 37 and 42 stands in a notable con-

trast to the cascade CM–RCM of the triene 43. At a first

glance the apparent failure of the Ru–alkylidene complex

derived from triene 43 (not shown in Scheme 28) to undergo

RCM may be attributed to a steric hindrance around the

À

differences in the conformations around the C5 C6 bonds

cannot be held responsible. All three trienes preferentially

À

adopt, according to MM2 calculations, C5 C6 conforma-

tions in which the unsaturated C1,C4 moieties are approxi-

À

C5 C6 bond, which could be missing in the diastereomeric

mately orthogonal to the C6 C7 bonds. Furthermore, steric

À

Ru–alkylidene complex derived from triene 42. While this

could be a contributing factor, the facile RCM of the diaste-

reomeric trienes 36 and 37 speaks against this hypothesis. A

rationalization has to consider, besides the important ther-

modynamic aspects, the various intramolecular cycloaddi-

tion steps of the Ru–alkylidene complexes derived from the

trienes together with the cycloreversion steps of the corre-

sponding ruthenacyclobutanes.^[3,35]RCM of the trienes is

complex because of the many conformations the substrates

and conformations and configurations the intermediates can

adopt.

hindrance around C5 C6 in 68 should be less than in 36 and

37.

RCDEM of sulfoximine-substituted cyclic trienes: Because

of the frequent occurrence of bicyclic rings as key structural

elements of terpenoids,^[10]RCM of the cyclic trienes 48 and

53 was studied (Scheme 30). The 1,4,10-triene 48 and 1,6,12-

triene 53, which both carry a secondary allylic hydroxyl

group, cleanly afforded upon treatment with 10 mol% of

catalyst 78 in CH₂Cl₂(5 mm) the corresponding Z-config-

The cascade of CM and RCM of the sulfoximine-substi-

tuted trienes and pentaenes depicted in Schemes 27 and 28

is of potential interest for the synthesis of densely substitut-

ed macrocycles.^[5f,34,36]However, the unselective formation

of the two macrocycles represents an obstacle to their syn-

thetic application. Formation of both pentaenes 95 and 96 is

most likely due to the similar reactivity of the terminal

double bonds of the triene 43. However, a selective CM re-

action of a triene of type 43 can perhaps be achieved if the

terminal double bonds were made structurally different^[3]as

in triene 68. Indeed, the reaction of the 1,6,10-ketotriene 68

with catalyst 78 in CH₂Cl₂gave in a tail-to-tail CM the

1,5,10,15,19-pentaene 97, to which the E-configuration was

tentatively assigned, as a single diastereomer in 84% yield

(Scheme 29). Interestingly, RCM of 97 with formation of the

corresponding 18-membered macrocycle was not observed.

Scheme 30. Synthesis of the bicyclic hydroxy-substituted carbocycles 98

and 99 having a bicycloACTHUNTGRENNUG[7.4.0]tridecane and bicycloACHTUNGTNER[NUGN 9.4.0]pentadecane

skeleton, respectively.

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Functionalized Medium-Ring Carbocycles and Lactones

FULL PAPER

ured bicyclic carbocycles 98 and 99. The bicycles, having a

Deprotection, reduction and cross-coupling reaction of bis-

silyl- and sulfoximine-substituted MRCs: The different silyl

protecting groups of the dihydroxy-substituted MRCs were

selected in the anticipation of a selective deprotection for

further synthetic transformations. The feasibility of a selec-

tive deprotection was probed with the 9- and 11-membered

MRCs ent-85 and 90, respectively (Scheme 32). It should be

noted that ent-85 and 90 do not only differ in ring size but

also in their relative configuration. While ent-85 has the

S_S,1R,4S,5R-configuration, 90 possesses the R_S,1R,4R,5S-con-

figuration.

bicycloACHTUNGTRENNUNG ACHTUGNTREN[NUGN 9.4.0] pentadecane

[7.4.0]tridecane^[37]and bicyclo

skeleton, respectively, were isolated in 75 and 70% yield, re-

spectively. Remarkably, in stark contrast to the acyclic hy-

droxy-substituted acyclic trienes 34, 35, 40, and 41 (see

above) no protection of the allylic and bisallylic hydroxyl

groups of the cyclic trienes were required for their RCM.

We have no explanation for the different behavior of the

acyclic and cyclic secondary hydroxytrienes towards 78.

Generally, the factors governing the competition between

RCM and degradation of dienes carrying a secondary allylic

hydroxyl group in the reactions with Ru–alkylidene com-

plexes are not known.^[33]

The introduction of substituents into the 6-membered

rings of bicycles 98 and 99 would still enhance their synthet-

ic potential. This should easily be accomplishable by using

instead of the allylic sulfoximine 10 its derivative having a

ketal group at the 4-position.^[38]Since a similar ketal-substi-

tuted derivative of the 5-membered cyclic allylic sulfoximine

9 is not readily available, another route was followed to

open a potential access to bicycles of type 98 and 99 but

having a substituted 5-membered ring. Therefore, the g-hy-

droxyalkylation of the 5-membered cyclic lithioallylsulfoxi-

mine 26 (cf. Scheme 4) was investigated en route to ana-

logues of 98 and 99, which carry a substituted 5-membered

ring. The alkenylsulfoximine 9 was used as starting material

in order to take advantage of the in situ isomerization of 25

to 26. Thus, alkenylsulfoximine 9 was successively treated

with nBuLi, ClTiACHTUNGTRENNUNG(OiPr)₃and pent-4-enal, which gave, as

hoped for, the a,a’-bishomoallylic alcohol 100 with ꢁ96%

d.e. in 67% yield (Scheme 31). In addition, the allylic sulfox-

Scheme 32. Selective deprotection of the bissilyloxy-substituted MRCs

ent-85 and 90.

The treatment of the bissilyl ether ent-85 with AcOH,

water and THF (0.5:2:2) led to a selective cleavage of the

triethylsilyloxy group and gave the allylic alcohol ent-103,

which was converted to the acetate ent-104 (80% yield

based on ent-85). Surprisingly, the similar treatment of the

bissilyl ether 90 with AcOH, water and THF resulted in a

selective cleavage of the tert-butyldimethylsilyloxy group

and afforded the allylic alcohol 105 in 96% yield. The oxi-

dation of 105 with DMP furnished the ketone 106 in 96%

yield. The allylic acetate and ketone were synthesized as po-

tential substrates for copper-mediated alkylation and Mi-

chael reactions, respectively.

Scheme 31. Envisioned synthesis of a bicyclo

both rings of which are substituted.

ACHTUNGTRNE[NUNG 9.3.0]tetradecane derivative,

While the selective hydrolysis of the triethylsilyloxy group

of ent-85 in the presence of the tert-butyldimethylsilyloxy

group was expected, that of the tert-butyldimethylsilyloxy

group of 90 in the presence of the triethylsilyloxy group

came as a surprise.^[39]The selective hydrolysis of the tert-bu-

tyldimethylsilyloxy group of 90 may be rationalized as fol-

lows. Because of the basicity of the sulfoximine group,^[11]

AcOH is expected to cause an equilibrium protonation of

the sulfoximines ent-85 and 90 at the N atom. The thus gen-

imine 23 was isolated in 20% yield. Because of the C₂sym-

metry of the parent methylene cyclopentanediol derivative

of 100, the successive silylation, lithiation, and hydroxyalky-

lation of the alcohol should afford the tetraene 101, RCM of

which might deliver the substituted bicycloACTHNUTRGNE[NUG 9.3.0]tetradecane

derivative 102.

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H.-J. Gais et al.

erated aminosulfoxonium group could serve to selectively

activate the neighboring tert-butyldimethylsilyloxy group by

the formation of a hydrogen bond with the O atom. Accord-

ing to MM2 calculations the 9-membered carbocycle ent-85

preferentially adopts a conformation in which both the sul-

foximine and tert-butyldimethylsilyloxy group are in pseudo-

axial position. This renders the formation of an activating

hydrogen bond between the aminosulfoxonium and the tert-

butyldimethylsilyloxy group in ent-85·H⁺, however, less

likely. In contrast, the 11-membered carbocycle 90 prefers a

conformation, in which the sulfoximine group is in pseudo-

axial and the tert-butyldimethylsilyloxy group in pseudo-

equatorial position, an arrange-

in 60% yield. The alkenylsulfoximine 79 was recovered in

35% yield. Interestingly, formation of the alkene 109 was

not observed in the absence of the chlorosilane.^[40]Although

the synthesis of 109 from 79 still requires optimization, the

feasibility of a cross-coupling reaction has been demonstrat-

ed.

Aluminum amalgam is an excellent reducing reagent for

S-alkyl and S-alkenyl-S-phenylsulfoximines. The sulfoxi-

mines are converted to the corresponding alkanesACTHNUTGRENUNG(alkenes)

and phenylsulfinamide with retention of configuration at the

S atom.^[11,13,41]Thus, the sulfoximine 80 was treated with

freshly prepared Al/Hg in wet THF at room temperature

(Scheme 35). Chromatographic work-up after a reaction

ment being more suitable for

the formation of an activating

hydrogen bond in 90·H⁺.

For

a functionalization of

MRCs I (cf. Figure 1) through,

for example, allylic alkylation it

would be desirable to have not

only access to the allylic acetate

ent-104 but also isomer ent-108

(Scheme 33). The allylic alcohol

ent-62 (cf. Scheme 14) served as

the starting material for the

synthesis of ent-104 via ent-85.

Scheme 35. Reduction of the sulfoximine-substituted MRC 80.

In order to develop a potential

route to ent-108 the acyclic al-

lylic acetate ent-107 was pre-

pared in 98% yield from alco-

hol ent-62. Preliminary evi-

Scheme 33. Envisioned synthe- dence suggests that triene ent-

time of 4 h gave the MRC 110 in 50% yield besides the dia-

stereomerically pure (NMR) cyclic alkenylsulfinamide 111

in 30% yield and phenylsulfinamide 112. The R-configura-

tion was tentatively assigned to sulfinamide 111. The exten-

sion of the reaction time to 12 h also led to a complete con-

sumption of alkenylsulfinamide 111. The MRC 110 and phe-

nylsulfinamide 112 were isolated in 76 and 42% yield, re-

spectively. These results show that two different reduction

pathways of the sulfoximine 80 were followed, a direct and

indirect one. The direct pathway involved a cleavage of the

S-alkenyl bond with formation of MRC 110 and phenylsulfi-

namide 112. The indirect pathway entailed a cleavage of the

S-phenyl bond to yield the alkenylsulfinamide 111, which

was further reduced to 110. Interestingly, the reduction of

alkenylsulfinamide 111 was faster than that of phenylsulfina-

mide 112.

sis of the isomeric allylic ace-

tate ent-108.

107 should also undergo RCM

with 78 under formation of ent-

108.

The sulfoximine group served in the synthesis of the C-

and O-tethered trienes a dual purpose, as chiral auxiliary

and carbanion stabilizing group (cf. Figure 3). It was further-

more planned to utilize the sulfoximine group of the MRCs

and MRLs as a nucleofuge in cross-coupling reactions, mi-

gratory substitution, and metal-mediated reduction (cf.

Figure 2). Thus, in model experiments a cross-coupling reac-

tion of the 7-membered carbocycle 79 and reduction of the

9-membered carbocycle 80 were studied.

Because of the facile cross-coupling reaction of acyclic al-

kenylsulfoximines with cuprates,^[12f]the cycloalkenylsulfoxi-

mine 79 was submitted to a treatment with 3 equiv of lithi-

um dimethylcuprate in the presence of 5 equiv of ClSiMe₃

(Scheme 34). This afforded the methyl-substituted MRC 109

Synthesis of sulfoximine-substituted O-tethered trienes: Be-

cause of the successful modular synthesis of sulfoximine-

substituted C-tethered trienes and their RCM with forma-

tion of the corresponding MRCs, the modular synthesis of

O-tethered trienes and their RCM were studied. Lithiation

of the alkenylsulfoximine 113^[21]with nBuLi followed by the

allylation of the thus generated a-lithioalkenylsulfoximine

with allyl bromide gave the sulfoximine-substituted diene

114 in 92% yield (Scheme 36). Cleavage of the silyl ether

114 afforded the homoallylic alcohol 115 in 95% yield. The

synthesis of the O-tethered trienes 116, 117, and 118 was

Scheme 34. Copper-mediated cross-coupling reaction of the sulfoximine-

substituted MRC 79.

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Chem. Eur. J. 2012, 18, 3529 – 3548

Functionalized Medium-Ring Carbocycles and Lactones

FULL PAPER

Synthesis and RCEYM of sulfoximine-substituted dienynes:

Having assembled MRCs and MRLs through RCDEM of

sulfoximine-substituted trienes, it was of interest to synthe-

ꢀ

size sulfoximine-substituted dienynes of type XI (X=C

CR) (cf. Figure 3) and to see whether they are amendable to

RCEYM. The successive treatment of the E-configured al-

kenylsulfoximines ent-17, ent-18, ent-123 and ent-124 (for the

later two see, Supporting Information) with 1-bromopent-2-

yne gave the corresponding E-configured 1,5-dien-8-yne ent-

122, 1,7-dien-10-yne ent-125,^[42]1,8-dien-11-yne ent-126 and

1,9-dien-12-yne ent-127 in 65, 75, 84, and 77% yield, respec-

tively (Scheme 38).

Scheme 36. Synthesis of O-tethered sulfoximine-substituted trienes.

performed through treatment of alcohol 115 with acrylic

acid, vinyl acetic acid and pent-4-enoic acid, respectively, by

using dicyclohexylcarbodiimide (DCC) and 4-N,N-dimethy-

laminopyridine (DMAP) as coupling reagents in CH₂Cl₂.

However, a complete conversion of the alcohol was not ac-

complished under these conditions, and the esters 116, 117,

and 118 were only isolated in 47, 50, and 67% yield, respec-

tively. The remaining alcohol was recovered, however, in 40,

40, and 15% yield, respectively.

RCDEM of sulfoximine-substituted O-tethered trienes: The

reaction of the O-tethered 1,4,10-triene 116, 1,4,11-triene

117, and 1,4,12-triene 118 with 8 mol% of catalyst 78 in tol-

uene (5 mm) at reflux gave the 9-membered lactone 119 in

87% yield, 10-membered lactone 120 in approximately 75%

yield, and 11-membered lactone 121 in 81% yield, respec-

tively (Scheme 37). The Z-configuration of the lactones was

deduced by NMR spectroscopy. According to NMR spec-

troscopy of the reaction mixtures the corresponding E-con-

figured lactones were not formed.

Scheme 38. Synthesis of sulfoximine-substituted 1,5,8-, 1,7,10-, 1,8,11- and

1,9,12-dienynes.

Gratifyingly, the reaction of the 1,7-dien-10-yne ent-125

with 10 mol% of the second-generation Ru-catalyst 78 in

toluene at room temperature cleanly afforded the 9-mem-

bered carbocycle ent-128 in an exo-mode cycloisomerization

as a single diastereomer in 92% yield (Scheme 39). The con-

figuration of the endocyclic double bond of the dienyl

moiety was determined by NOE experiments. Interestingly,

no conversion of ent-125 to ent-128 was observed in CH₂Cl₂

at reflux. Synthesis of the 9-membered carbocycle from the

1,10-enyne ent-125 is noteworthy since RCEYM of enynes

Scheme 39. RCEYM of the sulfoximine-substituted 1,7-dien-10-yne ent-

Scheme 37. Synthesis of the 9–11-membered sulfoximine-substituted lac-

125 with second- and first-generation Ru-catalysts 78 and 129, respective-

tones 119–121.

ly.

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3543

H.-J. Gais et al.

has thus far been confined to the formation of MRCs having

a 7- and 8-membered ring.^[5f,8]

Surprisingly, the reaction of the 1,7-dien-10-yne ent-125

with 10 mol% of the first-generation Ru-catalyst 129^[19a]in

toluene at room temperature and in CH₂Cl₂at reflux did

not give ent-128 but afforded the 9-membered carbocycle

ent-130 having a 1,3-diene moiety in 30% yield. The remain-

ing dienyne was recovered in high yield. An increase of the

amount of the catalyst 129 to 40 mol% resulted in a com-

plete conversion of ent-125 and furnished ent-130 as a single

diastereomer in 95% yield.^[43]According to the analytical

and spectroscopic data ent-130 has one CH₂unit less than

the starting dienyne ent-125. Nothing can be said about the

fate of the CH₂unit. The configuration of the exocyclic

double bond of ent-130 could not be assigned, and it is arbi-

trary depicted as E.

Because of the unprecedented dichotomy in RCEYM of

ent-125 with the Ru-catalysts 129 and 78, a rationalization of

the formation of both MRCs is put forward despite the lack

of experimental information about the fate of the CH₂unit.

According to the ene-then-yne pathway^[44]the 1,7-dien-10-

yne ent-125 gives with catalysts 129 and 78 the correspond-

ing Ru–alkylidene complexes ent-131a and ent-131b

(Scheme 40). Both alkylidene complexes ent-131a and ent-

131b undergo an intramolecular cycloaddition to furnish the

corresponding ruthenacyclobutenes^[4,45]ent-132a and ent-

132b. While the ruthenacyclobutene ent-132b suffers a ring-

opening with formation of the vinylalkylidene complex ent-

134b (path B), the ruthenacyclobutene ent-132a experiences

b-hydride elimination,^[46]because of the different ligands at

the Ru atom and affords the hydrido 1,3-dienyl Ru-complex

ent-133a (path A). Finally, a reductive elimination^[33a–c,47]of

ent-133a generates the MRC ent-130 and the complex

Scheme 40. Rationalization of the formation of the MRCs ent-130 and

ent-128 in the reactions of the 1,7-dien-10-yne ent-125 with the Ru-cata-

lysts 129 and 78, respectively, invoking ruthenacyclobutenes as intermedi-

ates (reversibility of steps and dissociation of ligands are not considered).

Cl₂RuACHTUNGTRENNUNG

(PCy₃)₂.^[48]The vinylalkylidene complex ent-134b

reacts with the dienyne ent-125 and gives the MRC ent-128

together with the alkylidene complex ent-131b.

In context with the mechanistic proposal of Scheme 40

the results of a study of RCEYM of the N,N-tethered 1-en-

10-yne 135 (Scheme 41) are of interest. The reaction of 135

with 129 gave the 9-membered 1,3-dienyl heterocycle 136

and the 9-membered 1,3-dienyl heterocycle 138 carrying one

CH₂unit less than the starting enyne. The formation of 138

was summarily attributed to a b-hydride elimination of the

ruthenacyclobutene 137. The heterocycles were obtained,

however, each only in 5% yield besides the corresponding

cross-metathesis product (22%) and recovered starting ma-

terial (62%).^[49]

Scheme 41. Formation of the 1,3-dienyl heterocycles 136 and 138 in the

reaction of the 1,10-enyne 135 with the Ru-catalyst 129 (Ts=

SO₂C₆H₄Me).^[49]

Although ruthenacyclobutenes have been frequently in-

voked as intermediates in RCEYM^[4]and other reactions,^[45]

proof for their existence is still missing.^[50]In addition, com-

putational studies are at odds whether ruthenacyclobutenes

are intermediates or transition states.^[51]Thus, a rationaliza-

tion of the formation of MRCs ent-128 and ent-130 is ad-

vanced in Scheme 42, which is not based on ruthenacyclobu-

tenes as intermediates.

ent-134a and ent-134b, respectively. The complex ent-134b

enters the catalytic cycle with ent-125 leading to ent-128 and

ent-131b. In contrast, the alkylidene complex ent-134a, be-

cause of the different ligands at the Ru atom, suffers HCl

elimination by the sulfoximine group^[11]to give the 1,3-

dienyl Ru-complex^[52]ent-139. Then the complex ent-139 ex-

periences HCl addition under protonation either at the d-

Cycloisomerizations of the alkylidene complexes ent-131a

and ent-131b directly afford the vinylalkylidene complexes

3544

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Chem. Eur. J. 2012, 18, 3529 – 3548

Functionalized Medium-Ring Carbocycles and Lactones

FULL PAPER

enyne RCM with formation of the corresponding cyclic exo

1,3-dienes.^[53]Finally, the reasons for the assumed divergence

in reactivity between the alleged ruthenacyclobutenes ent-

132a and ent-132b and vinylalkylidenes ent-134a and ent-

134b are not apparent. However, dissociation of PCy₃may

be an important factor determining the reactivity of the

complexes, which is perhaps easier in ent-132a and ent-134a,

which carry two phosphines, than in ent-132b and ent-134b,

which have the phosphine and heterocyclic carbene as li-

gands.^[3,54]

Conclusion

The sulfoximine route outlined in Figure 3 allowed the mod-

ular asymmetric synthesis of functionalized trienes and dien-

ynes. Its key steps are 1) the hydroxyalkylation of titanated

allylic sulfoximines with unsaturated aldehydes, 2) alkyla-

tion, formylation and acylation of a-lithioalkenylsulfoxi-

mines, and 3) alkylation of a-formyl- and a-acylalkenylsul-

foximines with Grignard reagents. The alkylation of the a-

formyl- and a-acylalkenylsulfoximines proceeded with high

diastereoselectivity. Because of the availability of the 6-

membered cyclic allylsulfoximine (cf. Scheme 2) carrying a

ketal group at the 4-position,^[38]cyclic trienes of type XII

and XIV (Y=OR,OR, o=2) (cf. Figure 3) will be accessi-

ble, the 6-membered rings of which are also functionalized.

RCDEM of the sulfoximine-substituted trienes with the

second-generation Ru catalyst generally gave the densely

functionalized MRCs with high stereoselectivity. Exemp-

tions were the acyclic trienes carrying an unprotected secon-

dary allylic hydroxyl group, which suffered decomposition.

A notable feature of the sulfoximine–RCDEM route is the

accessibility of the whole range of medium-sized rings (7–

11-membered). While the formation of the 7-, 8-, 9- and 11-

membered carbocycles was Z-stereoselective, that of the 10-

membered carbocycle was E-stereoselective. The 9–11-mem-

bered lactones were all formed with Z-stereoselectivity. Be-

cause of the experimental conditions used in RCM of the

trienes, a thermodynamically controlled Z- and E-selective

formation of the MRCs and MRLs seems likely.^[3]Most im-

portantly, a coordination of the N-methylsulfoximine group

of the substrates and products to the Ru atom, which may

have occurred, did neither deactivate the catalysts nor

impede the catalytic cycles. RCEYM of the sulfoximine-sub-

stituted 1,7-dien-10-yne with the first- and second-genera-

tion Ru catalyst showed an unprecedented dichotomy.

While the second-generation catalyst gave the correspond-

ing 9-membered exo 1,3-dienyl carbocycle, the first-genera-

tion Ru-catalyst afforded a 9-membered 1,3-dienyl MRC

carrying one CH₂unit less than the starting dienyne. The

fate of the CH₂unit, the mechanism of the formation of the

1,3-dienyl MRC ring and the underlying cause for the di-

chotomy are not clear at present and must await further in-

vestigation. It seems interesting to note that formally one

could think of the 1,3-dienyl carbocycle ent-130 being also

formed through an electrophilic 9-exo cyclization of the

Scheme 42. Rationalization of the formation of the MRCs ent-130 and

ent-128 from the alkylidene complexes ent-131a and ent-131b, respective-

ly, invoking vinylalkylidene complexes as intermediates (reversibility of

steps and dissociation of ligands are not considered).

position^[52]of the diene moiety to give back complex ent-

134a or at the b-position to yield the allyl alkylidene com-

plex ent-140. Complex ent-140 undergoes a b-hydride shift

from the allylic position to the Ru atom^{[33a–c,47b]}to afford

complex ent-133a, which suffers reductive elimination with

formation of the MRC ent-130 and complex [Cl₂Ru

ACHTUNGTRNE(NUNG PCy₃)₂]

(cf. Scheme 40).

Although single steps of Schemes 40 and 42 are in princi-

ple well-precedented, there are problems associated with

both schemes. While in the sequences leading to MRC ent-

128 the alkylidene complex ent-131b is generated in the last

step, which sustains the catalytic cycle, the pathways giving

MRC ent-130 are devoid of such an event. Thus, the conver-

sion of the dienyne ent-125 to the MRC ent-130 would ne-

cessitate the use of stochiometric amounts of the complex

129, a requirement which contradicts the experimental ob-

servation that only 40 mol% of 129, but not 10 mol%, were

sufficient for a complete conversion of the dienyne. Howev-

er, the complex [Cl₂Ru

ways leading to ent-130. Perhaps not only 129 but also com-

plex [Cl₂Ru(PCy₃)₂] or a species derived from this complex

ACHTUGNRTEN(NUGN PCy₃)₂] is generated in both path-

ACHTUNGTRENNUNG

and the 1,7-dien-10-yne ent-125 causes a turn-over of the

later. It has been described that the treatment of enynes car-

rying an internal triple bond with [Cl₂RuACHTUNGTRENUN(NG p-cymene)]₂, 1,3-

bis(mesityl)imidazolinium chloride and Cs₂CO₃led to an

ACHTUNGTRENNUNG

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3545

H.-J. Gais et al.

71.0 (d), 128.3 (d), 128.9 (d), 129.2 (d), 131.2 (d), 134.5 (d), 145.2 (d),

144.8 ppm (u); IR (capillary): n=3367 (w), 3066 (w), 2960 (s), 2808 (w),

1738 (w), 1450 (s), 1246 (s), 1150 (s), 1073 (m), 917 (w), 852 (s) cm^À1; MS

(EI, 70 eV): m/z (%): 592 [M⁺+H] (3), 534 (13), 437 (24), 436 (61), 394

(10), 393 (33), 379 (11), 305 (23), 304 (16), 298 (15), 292 (24), 291 (100),

275 (11), 270 (11), 261 (37), 240 (16), 211 (22), 197 (20), 125 (13), 115

(33), 87 (37); HMRS: calcd for C₃₂H₅₇NO₃SSi₂[M⁺]: 591.359775; found

591.358374.

lower 1,6-dien-9-yne homologue of ent-125. The facile syn-

thesis of the 9-membered 1,3-dienyl carbocycles from the

1,10-dienyne is noteworthy. Some of the synthetic transfor-

mations of the sulfoximine-substituted MRCs, alluded to in

the introduction, have been realized including reduction,

cross-coupling reaction, and selective desilylation.

((1R,2S,3E,6E)-6-(But-1-en-2-yl)-2-isopropyl-4-[(R)-N-methyl-S-phenyl-

sulfonimidoyl]-cyclonona-3,6-dienyloxy)triethylsilane (ent-128): To a so-

lution of complex 78 (20 mg, 24 mmol) was added a solution of the dien-

yne ent-125 (126 mg, 0.25 mmol) in toluene (40 mL). After the mixture

was stirred at room temperature for 18 h, it was filtered through silica gel

(1.5 g) and the filtrate was concentrated in vacuo. Purification by chro-

matography (cyclohexane/EtOAc 9:1) gave the MRC ent-128 (115 mg,

92%) as colorless solid. The use of refluxing CH₂Cl₂under otherwise

identical conditions saw no conversion of ent-125 to ent-128 and the dien-

yne was recovered in 90% yield (113 mg). [a]_D=À17.4 (c=1.00 in

Experimental Section

General methods and other experimental details are given in the Sup-

porting Information.

(1S,2E,4R,5S,6Z)-1-Ethyl-4-isopropyl-2-[(R)-N-methyl-S-phenylsulfoni-

midoyl]-5-(triethylsilyloxy)cycloocta-2,6-dienol (83): To a solution of the

complex 78 (6 mg, 7 mmol) in CH₂Cl₂(25 mL) was added a solution of

triene 77 (73 mg, 0.14 mmol) in CH₂Cl₂(3 mL). The mixture was stirred

at reflux for 16 h, after which time all of the starting material was con-

sumed as indicated by TLC. Then the mixture was cooled and filtered

through a short pad of silica gel, and the solvent was removed in vacuo.

Purification by chromatography (cyclohexane/EtOAc 5:1) gave MRC 83

(60 mg, 90%) as colorless liquid. [a]_D=À60.2 (c=1.00 in CH₂Cl₂); R_f=

0.46 (cyclohexane/EtOAc 5:1); ¹H NMR (400 MHz, C₆D₆): d=0.42 (q,

J=7.9 Hz, 6H, Si-CH₂-CH₃), 0.82 (d, J=6.6 Hz, 3H, CH₃), 0.83 (t, J=

7.9 Hz, 9H, Si-CH₂-CH₃), 0.89 (d, J=6.6 Hz, 3H, CH₃), 1.08 (t, J=

7.5 Hz, 3H, COH-CH₂-CH₃), 1.93–2.03 (m, 1H, CH-(CH₃)₂), 2.09–2.19

(dq, J=13.8, 7.5 Hz, 1H, COH-CHH-CH₃), 2.26–2.32 (dq, J=13.8,

7.5 Hz, 1H, COH-CHH-CH₃), 2.33–2.40 (m, 1H, CHOH-CHH-CH=

CH), 2.40–2.47 (m, 1H, CH-CH=CS), 2.57–2.65 (ddd, J=15.4, 9.1 Hz,

1H, COH-CHH-CH=CH), 2.70 (s, 3H, N-CH₃), 4.51 (dd, J=2.3, 1.7 Hz,

1H, CH-OSi), 5.23–5.28 (ddd, J=11.6, 1.7 Hz, 1H, CH₂-CH=CH), 5.64–

5.73 (ddd, J=11.6, 8.8, 2.3 Hz, 1H, CH₂-CH=CH), 6.93 (d, J=10.2 Hz,

1H, CH=CS), 6.97–7.08 (m, 3H, Ph), 7.49 (m, 1H, COH-CH₂), 8.07–

8.11 ppm (m, 2H, Ph); ¹³C NMR (100 MHz, C₆D₆): d=5.5 (u), 7.1 (d),

8.8 (d), 20.3 (d), 22.3 (d), 29.3 (d), 29.7 (d), 37.8 (u), 39.3 (u), 52.8 (u),

72.8 (d), 80.5 (u), 124.9 (d), 128.5 (d), 128.9 (d), 131.3 (d), 135.3 (d), 142.2

(u), 146.1 (d), 147.6 ppm (d); IR (capillary): n=3317 (w), 2950 (s), 2359

(w), 1642 (w), 1459 (s), 1378 (w), 1245 (s), 1148 (m), 1081 (s), 1014 (m),

850 (s) cm^À1; MS (EI, 70 eV): m/z (%): 477 [M⁺] (3), 449 (16), 448 (47),

322 (20), 307 (28), 304 (16), 294 (21), 293 (93), 279 (15), 278 (8), 270 (19),

265 (17), 264 (14), 263 (12), 261 (13), 251 (20), 250 (100), 247 (15), 223

(9), 219 (15), 185 (14), 161 (17), 156 (34), 147 (11), 139 (16), 124 (50), 122

(10), 119 (11), 115 (19), 107 (16), 104 (10), 103 (15), 87 (22); HRMS:

calcd for C₂₆H₄₃NO₃SSi [M⁺]: 477.273296; found 477.273389.

1

CH₂Cl₂); R_f=0.25 (cyclohexane/EtOAc, 9:1); H NMR (300 MHz, C₆D₆):

d=0.54 (q, J=7.9 Hz, 6H, Si-CH₂CH₃), 0.86 (d, J=6.9 Hz, 3H, CH-

A

ACHTNUGRTEN(NNUG CH₃)₂), 0.90–1.05 (m, 12H, Si-CH₂-

ACHTUNGTRENNUNG

2.12–2.27 (m, 2H, CHH-CH₂-CHOSi, CH₃-CH₂-C=CH₂), 2.88 (dt, J=

9.4 Hz, 1.9 Hz, 1H, CH-CH=CS), 3.01 (s, 3H, N-CH₃), 3.46 (d, J=

16.8 Hz, 1H, SCCHH), 3.71 (d, J=16.8 Hz, 1H, SCCHH), 3.91–3.98 (m,

1H, CHOSi), 4.92 (d, J=0.7 Hz, 1H, CHH=C-CH₂), 5.32 (brs, 1H,

CHH=C-CH₂), 5.69 (t, J=7.4 Hz, 1H, CH=C-CH₂), 6.99–7.10 (m, 3H,

Ph), 7.19 (dd, J=1.9, 7.7 Hz, 1H, CH=CS), 8.04–8.08 (m, 2H, Ph);

¹³C NMR (100 MHz, CDCl₃): d=5.6 (u), 7.3 (d), 13.8 (d), 20.7 (d), 21.6

(d), 22.4 (u), 27.2 (u), 29.5 (u), 29.8 (d), 30.3 (d), 35.7 (u), 47.8 (d), 73.5

(d), 110.9 (u), 128.8 (d), 129.4 (d), 129.9 (d), 131.8 (d), 136.1 (u), 139.1

(u), 141.2 (u), 144.7 (d), 150.7 ppm (u); IR (CHCl₃): n=3016 (w), 2959

(s), 2918 (s), 2878 (m), 2851 (m), 1578 (w), 1541 (w), 1445 (m), 1384 (m),

1260 (m), 1216 (m), 1083 (m), 1016 (m), 757 (s) cm^À1; MS (ESI): m/z

(%): 502 [M⁺+H] (52), 392 (49), 308 (38); HRMS (ESI): calcd for

C₂₉H₄₈NO₂SSi [M⁺+H]: 502.31695; found 502.31650.

Triethyl((1R,2S,3E,6E,7Z)-2-isopropyl-4-[(R)-N-methyl-S-phenylsulfoni-

midoyl]-6-propylidenecyclonona-3,7-dienyloxy)silane (ent-130): To a solu-

tion of the dienyne ent-125 (62 mg, 0.12 mmol) in CH₂Cl₂(20 mL) was

added complex 129 (40 mg, 48 mmol, 40 mol%). After the mixture was

heated at reflux for 18 h, it was filtered through silica gel (1.5 g) and the

filtrate was concentrated in vacuo. Purification by chromatography (cy-

clohexane/EtOAc 9:1) gave the MRC ent-130 (57 mg, 95%) as colorless

oil. The similar reaction of ent-125 with 10 mol% of complex 129 in tolu-

ene at room temperature or in CH₂Cl₂at reflux led only to a partial con-

version of the dienyne and isolation of the MRC in 30% yield (18 mg).

[a]_D=À24.0 (c=1.00 in CH₂Cl₂); R_f=0.30 (cyclohexane/EtOAc 9:1);

¹H NMR (400 MHz, CDCl₃): d=0.58 (q, J=7.9 Hz, 6H, Si-CH₂-CH₃),

0.76 (t, J=7.5 Hz, 3H, CH₃-CH₂-CH), 0.81 (d, J=6.6 Hz, 3H, CH-

tert-Butyl((1S,2E,4R,5S,6E)-4-isopropyl-2-[(R)-N-methyl-S-phenylsulfo-

nimidoyl]-5-(triethylsilyloxy)cyclodeca-2,6-dienyloxy)dimethylsilane (89):

To a solution of complex 78 (6 mg, 7 mmol) in ClCH₂CH₂Cl (25 mL) was

added a solution of triene 65 (73 mg, 0.14 mmol) in ClCH₂CH₂Cl (3 mL).

The mixture was stirred at reflux for 16 h, after which time all of the

starting material was consumed as indicated by TLC. Then the mixture

was cooled and filtered through a short pad of silica gel, and the solvent

was removed in vacuo. Purification by chromatography (cyclohexane/

EtOAc 19:1) gave MRC 89 (60 mg, 90%) as colorless liquid. [a]_D=

A

ACHTUGNTERN(NUNG CH₃)₂), 0.96 (t, J=7.9 Hz, 9H, Si-

AHCTUNGTRENNUNG

1

À15.6 (c=1.00 in CH₂Cl₂); R_f=0.28 (cyclohexane/EtOAc 19:1); H NMR

1H, CHH-CHOSi), 2.35–2.48 (m, 2H, CHH-CHOSi, CH-CH=CS), 2.89

(s, 3H, N-CH₃), 2.95 (d, J=17.6 Hz, SCCHH), 3.51 (d, J=17.6 Hz,

SCCHH), 3.90–3.94 (m, 1H, CHOSi), 5.21 (dt, J=8.8, 12.0 Hz, 1H, CH=

CH-CH₂), 5.42 (t, J=7.4 Hz, C=CH-CH₂-CH₃), 5.98 (brd, J ꢂ 12 Hz,

CH=CH-CH₂), 6.77 (dd, J=9.6, 1.6 Hz, 1H, CH=CS), 7.47–7.57 (m, 3H,

Ph), 7.90–7.93 ppm (m, 2H, Ph); ¹³C NMR (100 MHz, CDCl₃): d=5.2

(u), 6.9 (d), 13.6 (d), 20.4 (d), 20.8 (d,), 22.4 (d), 29.1 (d), 29.6 (d), 30.2

(u), 34.5 (u), 46.7 (d), 74.2 (d), 123.2 (d), 128.1 (d), 128.7 (d), 132.0 (d),

132.3 (u), 136.9 (d), 137.8 (u), 139.5 (u), 145.1 ppm (d); IR (CHCl₃): n=

3442 (w), 2922 (s), 2878 (m), 1680 (m), 1579 (w), 1542 (w), 1460 (m),

(400 MHz, 708C, C₆D₆): d=À0.3 (s, 3H, Si-CH₃), 0.0 (s, 3H, Si-CH₃),

0.65 (q, J=7.1 Hz, 6H, Si-CH₂-CH₃), 0.89 (s, 9H, Si-CACHTNUGTRENUNG(CH₃)₃), 0.95 (d,

J=6.9 Hz, 3H, CH₃), 1.04 (t, J=7.1 Hz, 9H, Si-CH₂-CH₃), 1.05 (d, J=

6.9 Hz, 3H, CH₃), 1.60–1.64 (m, 1H, CHOH-CHH’-CH₂-CHH’), 1.70–

1.80 (m, 1H, CHOH-CH₂-CHH), 1.80–1.85 (m, 1H, CHOH-CH₂-CHH),

1.98–2.15 (m, 2H, CHOH-CHH, CH-(CH₃)₂), 2.11–2.20 (m, 1H, CHOH-

CH₂-CH₂-CHH), 2.67 (t, J=10.3, 1H, CH-CH=CHS), 3.00 (s, 3H, N-

CH₃), 4.55 (dd, J=3.7 Hz, 1H, CH-OSi), 5.06 (dd, J=10.5, 6.4 Hz, 1H,

CH-OH), 5.31 (dd, J=15.5, 3.7 Hz, 1H, CH₂-CH=CH), 5.65 (ddd, J=

15.5, 9.6, 5.6 Hz, 1H, CH₂-CH=CH), 7.02–7.10 (m, 3H, Ph), 7.12 (d, J=

11.2 Hz, 1H, CH-CH=C), 7.96–7.99 ppm (m, 2H, Ph); ¹³C NMR

(400 MHz, 708C, C₆D₆): d=À5.7 (d), À4.7 (d), 5.2 (u), 6.7 (d), 20.8 (u),

21.1 (d), 21.9 (u), 26.0 (d), 29.5 (u), 32.5 (u), 34.6 (d), 53.7 (d), 68.8 (d),

1382 (m), 1241 (s), 1140 (m), 1086 (s), 1012 (m), 971 (w), 755 (s) cm^À1

;

MS (ESI): m/z (%): 488 [M⁺+H] (100); HRMS (ESI): calcd for

C₂₈H₄₆NO₂SSi [M⁺+H]: 488.30130; f:und 488.30262.

3546

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ꢁ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Chem. Eur. J. 2012, 18, 3529 – 3548

Functionalized Medium-Ring Carbocycles and Lactones

FULL PAPER

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Acknowledgements

This work was supported by the Deutsche Forschungsgemeinschaft (SFB

380 and GK 440). We thank Dr. Wolfgang Bettray for the MS measure-

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Received: September 29, 2011

Published online: February 16, 2012

3548

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Chem. Eur. J. 2012, 18, 3529 – 3548

Article Doi

Asymmetric synthesis of densely functionalized medium-ring carbocycles and lactones through modular assembly and ring-closing metathesis of sulfoximine-substituted trienes and dienynes

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