Stereocontrolled synthesis of a C1-C10 building block ("Southwestern Moiety") for the unnatural enantiomers of the polyene polyol antibiotics filipin III and pentamycin: A sultone-forming ring-closing metathesis for protection of hom

FULL PAPER

DOI: 10.1002/ejoc.201400145

Stereocontrolled Synthesis of a C¹–C¹⁰Building Block (“Southwestern

Moiety”) for the Unnatural Enantiomers of the Polyene Polyol Antibiotics

Filipin III and Pentamycin: A Sultone-Forming Ring-Closing Metathesis for

Protection of Homoallylic Alcohols

Patrick Walleser^[a][‡]and Reinhard Brückner*^[a]

Keywords: Synthetic methods / Metathesis / Oxidation / Diastereoselectivity / 1,4-Addition

In C₂-symmetric diol 10 one OH group was substituted by

crotonic acid and the other was incorporated in an ethene-

sulfonate. A twofold ring-closing metathesis under forcing

conditions provided unsaturated lactone/unsaturated sultone

24. Conjugate addition of Li₂(PhMe₂Si)₂Cu(CN) to both C=C

bonds was followed by opening of the sultone moiety with

Bu₄N⁺F^–. Resultant homoallylic alcohol 28 was carried on to

acetonide-containing lactone 31. Its CpTiCl₂enolate under-

went a completely diastereoselective aldol addition to hexa-

nal. Functional group interconversions rendered “southwest-

ern” C¹–C¹⁰building block 37. The steps (1) ethenesulfon-

ylation of a homoallylic alcohol, (2) sultone formation, (3)

Li₂(PhMe₂Si)₂Cu(CN) addition, and (4) alcohol release by

fluoride-induced fragmentation, from our main sequence

represent a new protection/deprotection stragegy for a sec-

ondary homoallylic alcohol, as demonstrated with a model

compound, too.

addition, the researchers stated that the configurations of

C-14 and C-15 might require concomitant reversal.^[9]This

original incertitude appears to have been clarified in favor

of complete configurational identity (2) in a subsequent

publication.^[10]Moreover, if one accepts “configurational

analogy for biosynthetic homology” as supporting evi-

dence, the 3D structure of the polyol polyene macrolide

Introduction

The family of polyene polyol macrolides comprises more

than 200 secondary metabolites from bacteria of the genus

Streptomyces^[1]and is growing continuously.^[2]Figure 1 il-

lustrates typical structural features of polyene polyol mac-

rolides through unnatural enantiomers ent-1 and ent-2 of

antifungals filipin III (1) and pentamycin (2), respectively.

Filipins were first isolated from Streptomyces filipensis in

1955.^[3]They are a mixture of four components, which were

separated chromatographically in 1968.^[4]Filipin III (1) was

isolated as the third eluted compounds from the filipin mix-

ture. The relative as well as absolute configuration of filipin

III (1) was elucidated by Rychnovsky et al. in 1995.^[5]The

first total synthesis of filipin III (1) was accomplished by

the same group in 1997.^[6]Kiyooka et al. synthesized the

polyol part of filipin III (1) again.^[7]The polyene polyol

macrolide pentamycin (2) was first isolated from Streptomy-

ces pentaticus in 1958.^[8]Pentamycin has the same consti-

tution as 14-hydroxyfilipin III according to a study by the

Oishi group.^[9]For almost all of its stereostructure, penta-

mycin is the same as 14-hydroxyfilipin III, too.^[9]In

[a] Institut für Organische Chemie, Albert-Ludwigs-Universität

Freiburg,

Albertstr. 21, 79104 Freiburg, Germany

E-mail: reinhard.brueckner@organik.chemie.uni-freiburg.de

http://ww w .chemie.uni-freiburg.de/orgbio/brueck/w3br/

[‡] New address: Dr. Patrick Walleser,

Figure 1. Top: unnatural enantiomers ent-1 and ent-2 of the natu-

rally occurring polyene polyol macrolides filipin III (1)^[3–5]and

pentamycin (2),^[8,9]respectively. A synthetic equivalent 4 of the all-

syn-configured 1,3,5,7,9-polyol/enoate building block 3, which they

share (“southwestern moiety”) was synthesized in the present study.

Department of Chemistry, University of Hawai’i at Mãnoa,

2545 The Mall, Honolulu, HI 96822, USA

Supporting information for this article is available on the

WWW under http://dx.doi.org/10.1002/ejoc.201400145.

3210

Eur. J. Org. Chem. 2014, 3210–3224

Sultone-Forming RCM for a Protection of Homoallylic Alcohols

antibiotic TPU-0043 from Streptomyces sp. TP-A0625 is three steps (bottom line of Scheme 1; 60% overall yield).

constitutionally close to both filipin III (1) and pentamycin To start a Noyori hydrogenation of 1,5-dichloropentane-

(2).^[11]In TPU-0043, C-15 is configured such as implied by 2,4-dione (11) delivered anti-configured dichlorinated diol

stereostructures ent-1 and ent-2 of Figure 1.^[11]We are un- 12 in 75% yield. Treatment with KOH yielded bisepoxide

aware of a 100% complete total synthesis of pentamycin 13 in 88% yield. Opening both epoxide rings at the less

(2), although the original effort by Oishi was close.^[9]

hindered carbon with vinyl cuprate afforded dienediol 10 in

Rychnovsky’s total synthesis of filipin III (1)^[6]as well as 91% yield.^[22]

Kyooka’s approach^[7]on the one hand, and Oishi’s effort

towards pentamycin (2)^[9]on the other used totally different

synthetic strategies. Of course the structural similarity of

filipin III (1) and pentamycin (2) suggests that a common

strategy might be used for accomplishing both targets. Such

a strategy would bifurcate at a very advanced stage to reach

both structures selectively. We have embarked on de-

veloping such a common approach. To date we have synthe-

sized the C¹–C¹⁰polyol building block (“southwest moi-

ety”), which the two antibiotics have in common. However,

we did not choose these antibiotics themselves as targets.

Instead we strive for their mirror images, i.e., for unnatural

enantiomer ent-1 of filipin III (1) and unnatural enantiomer

ent-2 of pentamycin (2). We made this choice because in

the polyol/polyene class of antibiotics little is known about

structure/activity relationships.^[12]Accordingly, it would be

valuable to synthesize materials like unnaturally configured

filipin III (ent-1) and unnaturally configured pentamycin

(ent-2): This would allow comparisons of their biological

activities – if there were any – and those of their counter-

parts filipin (1) and pentamycin (2), respectively.

Scheme 1. Lines 1–3: retrosynthetic simplification of synthetic

Retrosynthetic Analysis

equivalent 4 of the “southwestern moiety” 3 of the macrolides of

Figure 1 to anti-configured 1,3-diol 10. Line 4: three-step synthe-

sis^[18]of 1,3-diol 10 from dichlorodiketone 11. Reagents and condi-

Figure 1 defined the common “southwestern moiety” 4

of ent-filipin III (ent-1) and ent-pentamycin (ent-2) as the

synthetic target of the present study. Scheme 1 depicts our

retrosynthetic analysis of compound 4, which represents a

–

tions: (a) [Me₂NH₂]⁺[RuCl(R-BINAP)]₂(μ-Cl)₃(0.2 mol-%), H₂

(134 bar), MeOH, 110 °C, 60 min; Ǟroom temp.; 75% (ref.^[18a]

specified the yield only for enantiomeric diol ent-12; 64%), high ee

lactol “ether”. Accordingly, it was traced back to lactone (ref.^[18a]: Ն 97% ee). (b) Et₂O, 0 °C; KOH (6.6 equiv.), 1 h; Ǟroom

temp., 3 h; 88% (ref.^[18a]specified the yield only for enantiomeric

5. At C-3 (filipin- and pentamycin-numbering) lactone 5

contains an ArR₂Si substituent, which might be converted

bisepoxide ent-13; 89%). (c) CuI (40 mol-%), tetrahydrofuran

(THF), –10 °C; vinylMgBr (4.0 equiv.) in THF, Ǟ–78 °C, 2 h; 13,

into the C-3-bound oxygen substituent in lactol “ether” 4

by a Fleming or Tamao oxidation.^[13]We envisaged deriva-

tion of lactone 5 from lactone 7 by an aldol addition, which

would hopefully exhibit the desired induced and simple dia-

stereoselectivity.^[14,15]Lactone 7 would be obtained from

lactone 6 by an S_N2 reaction. Lactone 6, in turn, was ex-

THF, 30 min; 91% (ref.^[18b]: 89%). Note: The enantiopurity of our

dichlorodiol 12 was assessed by analyzing its specific rotation

{[α]²_D⁰= –22.2 (c = 0.98, CHCl₃)} relative to the published value

{[α]²_D⁴= –20.8 (c = 0.99, CHCl₃)^[18a]}. The specific rotation of

bisepoxide 13 {[α]²_D⁰= –56.2 (c = 0.29, CHCl₃)} was published in

ref.^[18a]{[α]²_D⁵= –55.5 (c = 0.92, CHCl₃), Ն 97% ee}. The specific

rotation of dienediol 10{[α]²_D⁰= –28.3 (c = 0.51, CHCl₃)} was re-

pected to result from the 1,4-addition of an ArR₂Si-con- ported in the Supporting information of ref.^[19b]{[α]²_D⁶= –23.5

(c = 1.00, CHCl₃), Ͼ 99% ee}. These ee values show that our ee

taining cuprate to α,β-unsaturated lactone 8 and iodo-

carbonate formation. Lactone 8 was expected to result from

values were in the upper 90 percentile.

a regioselective ring-closing metathesis (RCM) between two

of the three C=C bonds of acrylate 9.^[16,17]Acrylate 9 is the

Mono-esterification of dienediol 10 under standard Mit-

monoester of a syn-configured dienediol, which we planned

sunobu (inversion) conditions^[20]failed with acrylic acid^[23]

to access from anti-configured dienediol 10, a known com-

but succeeded with crotonic or cinnamic acid (Scheme 2).

pound.^[18,19]One OH group of 10 would have to be involved

We limited the amounts of DIAD, PPh₃, and the α,β-unsat-

in a stereoselective ester formation with inversion of config-

urated acid to 1.1 equiv. each to avoid diester formation.

uration, i.e. in a Mitsunobu esterification.^[20,21]

These conditions gave mono-crotonate 14b in 62% yield

and mono-cinnamate 14c in 60% yield. Employing

Results and Discussion

1.3 equiv. of each reagent in the Mitsunobu mixture gave

Following descriptions by Rychnosvky et al.^[18]we syn- no diesters but decreased the monoester yields somewhat

thesized dienediol 10 from dichlorinated diketone 11 in (54 and 45% for 14b and 14c, respectively).

Eur. J. Org. Chem. 2014, 3210–3224

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3211

P. Walleser, R. Brückner

FULL PAPER

Scheme 3. Synthesis of (vinylsilyl)ether 16 and its failed ring-

closure by olefin metathesis. Reagents and conditions: (a) NEt₃

(3.0 equiv.), CH₂Cl₂, 0 °C; vinylMe₂SiCl (1.2 equiv.), Ǟroom

temp., 3 h; 87%. (b) [(2,6-Diisopropylphenyl)imido]neophylidene-

molybdenum bis{[1,1-bis(trifluoromethyl)ethoxide]} (Schrock cata-

lyst; 5 mol-%), benzene, 80 °C, 24 h; 7% 18 (separated from 10%

reisolated 16).

Scheme 2. Syntheses of monoesters 14b and 14c by symmetry-

breaking Mitsunobu inversions of anti-configured 1,3-diol 10.

RCMs providing cycloheptenes 15b and 15c instead of lactone 8.

Reagents and conditions: (a) R-CH=CH-CO₂H (R = H, Me or Ph;

1.1 equiv.), PPh₃(1.1 equiv.), toluene, room temp., 10 min;

Ǟ–30 °C, diisopropyl azodicarboxylate (DIAD; 1.1 equiv.),

Ǟroom temp., overnight; for R = H partial decomposition (52%

10 reisolated). (b) {1,3-Bis[(2,4,6-trimethylphenyl)]-2-imidazolidi-

nylidene}dichloro(phenylmethylidene)(tricyclohexylphosphane)-

ruthenium (Grubbs II catalyst; 0.5 mol-%), toluene, room temp.,

2 h.

Ring-closures of monoesters 14b and 14c in the presence

of Grubbs II catalyst^[24]yielded only cycloheptenes, namely

compounds 15b (69%) and 15c (67%), respectively

(Scheme 2). They result from incorporating the least hin-

dered C=C bonds into the newly formed C=C bond. We

first hypothesized that this looked like the outcome of ki-

netically controlled ring-closures. However, we could not di-

rect (or redirect) either of these metatheses towards the de-

sired lactone 8, regardless of whether the amount of the

catalyst was increased (from 0.5 mol-% to 5 mol-%) or the

temperature (110 °C instead of room temp.). Accordingly,

the preference for cycloheptene formation appears to be

thermodynamic. The strain released upon ring-opening a

cycloheptene (E_strain= 3.6 kcal/mol)^[25]is small relative to

the energy expenditure for converting an acyclic α,β-unsatu-

rated ester into an α,β-unsaturated δ-lactone. This is be-

cause the acyclic ester (like in cycloheptenes 15b and 15c)

assumes an s-cis conformation of the C–O–C(=O) subunit

and the lactone (like 8) an s-trans conformation. The energy

difference associated therewith might be as large as

4.8^[26]–12.8^[27]kcal/mol.

Scheme 4. Synthesis of ethenesulfonate 21 and its double ring-

closure by olefin metathesis to give 24. Reagents and conditions:

(a) Et₂O, –40 °C; addition of 2,6-lutidine (1.2 equiv.) in Et₂O;

Ǟroom temp., 1 h; 70% (ref.^[33]: 72%). (b) NEt₃(2.0 equiv.), THF,

–15 °C; addition of 19 (1.05 equiv.), 30 min; 99%; used without

further purification owing to decomposition on silica gel.

(c) Grubbs II catalyst (3.0 mol-%), toluene, 100 °C, 3 h; 93%.

The synthesis of (vinylsilyl)ether 16 from hydroxy-

We wanted to make up for the suspected lack of driving crotonate 14b, vinylMe₂SiCl, and triethylamine succeeded

force for desired lactone formations (14b and 14cǞ8) ver- under standard conditions from the literature^[28]in 87%

sus undesired cycloheptene formations (14b and 14cǞ15b yield. RCM of (vinylsilyl)ether 16 was mainly studied em-

and 15c) of Scheme 2 by scavenging the “interfering” ploying Schrock catalyst.^[29]This choice was made because

CH=CH₂moiety of the substrate by a second ring-closure this catalyst has been employed routinely for RCM of sim-

under metathesis conditions. Scheme 3 shows an obvious ilar substrates.^[28,30]However, by using Schrock catalyst at

approach to turning this concept into reality: by forming 80 °C we obtained none of the desired bis(ring-closure)

(vinylsilyl)ether 16 from hydroxycrotonate 14b through sil- product 17 and only 7% of its precursor, mono(ring-clo-

ylation with vinylMe₂SiCl. In response to the failure of the sure) product 18. Disturbingly, the latter was an unsatu-

approach of Scheme 3 we devised the new approach, shown rated (vinylsilyl)ether and not an unsaturated lactone, i.e.

in Scheme 4, as an alternative. This alternative starts by totally devoid of the structural motif required to continue

forming ethenesulfonate 21 from hydroxycrotonate 14b the project. Grubbs II catalyst^[24]or Grubbs–Hoveyda cata-

through sulfonylation with vinylSO₂Cl and worked well.

lyst^[31]did not cyclize (vinylsilyl)ether 16 at all.

3212

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Eur. J. Org. Chem. 2014, 3210–3224

Sultone-Forming RCM for a Protection of Homoallylic Alcohols

We then turned to ethenesulfonate 21 (Scheme 4). We en- con nucleophile, presumably the higher-order cyanocuprate

visioned that 21 would ring-close in the presence of Li₂(PhMe₂Si)₂Cu(CN). At –78 °C, the latter added chemo-

Grubbs II catalyst^[24]to provide unsaturated lactone/unsat- selectively to the C=C bond of the lactone moiety of com-

urated sultone 24. This expectation was based on two litera- pound 24 when a stoichiometric amount of Me₃SiCl was

ture examples, in which an ethenesulfonate gave an α,β-un- present. Moreover, this addition was perfectly trans-selec-

saturated six-membered sultone.^[32]Ethenesulfonate 21 re- tive and in accordance with related observations from our

sulted from condensation of hydroxycrotonate 14b and eth- group.^[14,15]We isolated the resultant silyllactone/unsatu-

enesulfonyl chloride 19 in virtually quantitative yield. Sulf- rated sultone 26 in 70% yield. When the same presumed

onylating agent 19 was derived as described by Cossy et higher-order cyanocuprate was allowed to react with unsat-

al.^[32]from commercially available sulfonyl chloride 20.^[33]urated lactone/unsaturated sultone 24 at –50 °C, it added to

In toluene solution, ethenesulfonate 21 and 1 mol-% of both C=C bonds. The addition to the lactone moiety was

Grubbs II catalyst reacted to completion within 30 min at trans-selective when executed separately (Ǟ26, see above)

room temp. Work-up by means of flash chromatography on whereas the addition to the sultone moiety of 24 was hardly

silica gel^[34]yielded a mixture of three products but none of diastereoselective. Accordingly, silyllactone/silylsultone 27

desired bicycle 24. The three products were separated to resulted as a 68:32 mixture of unassigned epimers; under

give 22, 23, and 25. Compound 22 (18% yield) eluted first optimized reaction conditions its yield was 88%.^[37]

and was perceived as a cycloheptene. It was interpreted as

a mono-metathesis product, in which the two allyl groups

of substrate 21 had disappeared. Compound 23 (52% yield)

eluted next and appeared to be an α,β-unsaturated six-

membered sultone. It would therefore be a mono-metathesis

product, in which one allyl group of substrate 21 had disap-

peared. Compound 25 (9% yield) eluted last. It seemed to

originate from a cross-metathesis of sultone 23, in which

the allyl groups were consumed.

Compounds 23 and 25 would be unable to form a cyclo-

heptene if subjected to more forcing olefin metathesis con-

ditions assuming that the C=C bonds of their sultone moie-

ties proved inert. Accordingly, we re-united the two species

in toluene solution and added 2 mol-% (rather than 1 mol-

Scheme 5. Double 1,4-addition reaction of a silyl cuprate to the

%) of Grubbs II catalyst.^[24]Heating the resulting solution

unsaturated lactone and unsaturated sultone moieties of metathesis

at 100 °C (rather than at room temp.) for 3 h (rather than

for 30 min) provided desired bicycle 24 in 75% yield. Not

giving up prematurely on the third product of our initial

metathesis, cycloheptene 22, we subjected it to the more

forcing conditions of the metathesis reaction of the 23/25

product 24. Regeneration of the homoallylic alcohol motif, from

which the sultone had been obtained (cf. Scheme 4). Reagents and

conditions: (a) Li (30 equiv.), PhMe₂SiCl (4.0 equiv.), THF, –10 °C,

18 h; addition to CuCN (2.0 equiv.), THF, –10 °C, 2 h; Ǟ–78 °C,

Me₃SiCl (1.2 equiv.), 1 min; addition of 24, THF, 30 min; 70%, ds

= 100:0. (b) Li (60 equiv.), PhMe₂SiCl (8.0 equiv.), THF, –10 °C,

mixture. This also yielded the desired bicycle 24 (72% 18 h; addition to CuCN (4.0 equiv.), THF, –10 °C, 2 h; Ǟ–78 °C,

Me₃SiCl (1.2 equiv.), 1 min; addition of 24, THF, 1 h; Ǟ–50 °C,

yield). After optimization, which included diluting the reac-

1 h; 88%, ds_{lactone moiety}= 100:0, ds_{sultone moiety}= 68:32. (c) Li

tant 10 times,^[35]we advanced from ethenesulfonate 21 di-

(30 equiv.), PhMe₂SiCl (4.0 equiv.), THF, –10 °C, 18 h; addition to

rectly to the bicycle 24 in 93% yield without isolating any

CuCN (2.0 equiv.), THF, –10 °C, 2 h; Ǟ–78 °C, Me₃SiCl

of the intermediates 22, 23 or 25 (Scheme 4).

(1.2 equiv.), 1 min; addition of 26, THF, 30 min; Ǟ–50 °C, 30 min;

75%, ds_{lactone moiety}= 100:0, ds_{sultone moiety}= 68:32. The gray back-

grounds highlight the temperature effect on the outcome of the 1,4-

addition reaction: At –78 °C, only the unsaturated lactone reacted;

not earlier than after raising the temperature to –50 °C did the

unsaturated sultone react as well.

At that point we ran a risk of getting stuck with lactone/

sultone 24. The only literature report of “deprotecting” an

α,β-unsaturated six-membered sultone to yield the underly-

ing homoallylic alcohol was by Metz and Cramer.^[36]They

cleaved two sultones of this kind by solutions of lithium in

liquid ammonia/THF containing tert-butyl alcohol or not.

This rendered the respective homoallylic alcohols in 65 and

We realized that the β-silylated six-membered sultone

90% yield.^[36]Unfortunately, Birch conditions decomposed portion of compound 27 (Scheme 5) resembles a β-silylated

24. We blamed this sensitivity on the presence of the unsat- five-membered sultame, which the Metz group fragmented

urated lactone moiety. Accordingly, we decided to elaborate giving an allylic amine by treatment with nBu₄N⁺F^–.^[38]

the latter part of compound 24 towards the “southwestern Those workers had recognized that the mentioned sultame

moiety” 4 of ent-filipin III and ent-pentamycin, until reach- is an N-β-(trimethylsilyl)ethanesulfonamide of sorts, from

ing a compound that would allow a Birch reduction^[36]to which sulfonyl groups had been removed with nBu₄N⁺F^–

release a homoallylic alcohol from the sultone moiety.

before.^[39]We expected

a similar reaction between

To process unsaturated lactone/unsaturated sultone 24, nBu₄N⁺F^–and silylated sultone/silylated lactone 27. It

we combined PhMe₂SiLi (prepared from PhMe₂SiCl and should establish the C=C bond of the desired homoallylic

lithium) and CuCN in a 2:1 ratio (Scheme 5) to give a sili- alcohol 28 (Scheme 5). At first we employed 1.05 equiv. of

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3213

P. Walleser, R. Brückner

FULL PAPER

Table 1. Regeneration of the homoallylic alcohol motif in compound 28 from disilane 27 (Scheme 5, last step).

Entry

Reagent

[1.05 equiv.]

Additive

Conditions for

27Ǟ28

Reisolated

27 [%]

Yield

28 [%]

1

2

3

4

5

nBu₄N⁺F^–

nBu₃BnN⁺F^–[c]

3 Å mol. sieves

–

3 Å mol. sieves

–

3 Å mol. sieves

1.5 h, 0 °C Ǟ

4 h, room temp.

1.5 h, 0 °C Ǟ

1.5 h, room temp.

3 h, room temp.

–

28

32

40–52

39–50

–

34–49% (70–81^[b]

38–50% (75–82^[b]

50–57

)

[a] The diastereomeric mixture is separable by flash chromatography^[34]but was not separated. [b] These yields were calculated taking

into account the specified amount of reisolated 27. [c] Prior to use, the THF solution of nBu₃BnN⁺F^–was stirred over molecular sieves

(3 Å) for 16 h.

nBu₄N⁺F^–to conserve the PhMe₂Si group in the lactone

moiety. This made the transformation 27Ǟ28 feasible in

28% yield in the presence of 3 Å molecular sieves (Table 1,

Entry 1) and in 32% yield in its absence (Table 1, Entry 2).

The use of up to 2 equiv. of nBu₄N⁺F^–was preferable.

Moreover, it was advantageous to interrupt the fragmenta-

tion 27Ǟ28 before it reached completion and to re-isolate

residual 27 unchanged. By the combined measures we ob-

tained homoallylic alcohol 28 in 70–81% yield (taking into

account 40–52% reisolated 27; Table 1, Entry 3) in the pres-

ence of 3 Å molecular sieves and in 75–82% yield in its

absence (taking into account 39–50% reisolated 27; Table 1,

Scheme 6. 2-Step iodocarbonate formation from homoallylic

alcohol 28 and iodine/phenysulfanyl exchange in preparation for

the Pummerer rearrangement required for unmasking the formyl

Entry 4). Employing nBu₃BnN⁺F^–instead of nBu₄N⁺F^–re-

sulted in homoallylic alcohol 28 in 50–57% yield after com-

plete consumption of 27 (providing that before use the

nBu₃BnN⁺F^–solution was stirred over 3 Å molecular sieves

for 16 h; Table 1, Entry 5). From then onwards, we relied

on the conditions of Table 1, Entry 3 to synthesize com-

pound 28.

group of building block 3 (cf. Figure 1). Reagents and conditions:

(a) THF, –20 °C; nBuLi (1.1 equiv.), 1 h; CO₂, 90 min; I₂

(2.2 equiv.), 0 °C, 2 h; 0%; compound 28 was reisolated in about

32% yield and was not entirely pure. (b) tBuOCl (2.0 equiv.), NaI

(1.0 equiv.), CO₂, THF, –20 °C, overnight; 0%;^[b]compound 28 was

reisolated in ≈ 78% yield and was not entirely pure. (c) CH₂Cl₂,

0 °C; Boc₂O (4.0 equiv.), DMAP (20 mol-%), NEt₃(1.3 equiv.);

Ǟroom temp., overnight; 86%. (d) CH₃CN, –20 °C; I₂(3.0 equiv.),

16 h; 94%, ds = 100:0. (e) Acetone, room temp.; pTsOH·H₂O

(1.2 equiv.), 4 d; 92%. (f) NaH (2.4 equiv.), THF, 0 °C; PhSH

(2.5 equiv.), Ǟroom temp., 30 min; addition to 32, THF, Ǟ50 °C,

90 min; 99%.

Our next objective was to convert homoallylic alcohol 28

into cis-iodocarbonate 29 (Scheme 6). As a 1-pot transfor-

mation this failed to work by using nBuLi, CO₂gas, and

[40]

I₂or by using tBuOCl, CO₂gas, and NaI.^[41]However, a

two-step route to 29 worked. It began by making mixed

carbonate 30 (86% yield) from homoallylic alcohol 28, 4-

(dimethylamino)pyridine (DMAP), NEt₃, and di-tert-butyl

dicarbonate (Boc₂O). At –20 °C a solution of carbonate 30 34 was 63% if the reaction mixture was worked up immedi-

and solid I₂in acetonitrile furnished iodocarbonate 29 with ately after TLC monitoring revealed that lactol 35 had dis-

perfect cis-selectivity (94% yield). Treatment of 29 with appeared; any delay and the yield of 34 decreased.

pTsOH·H₂O in acetone replaced the carbonate by an acet-

An attempted Tamao–Fleming oxidation^[13]of the

onide group (Ǟ92% 32).^[40]An S_N2 reaction with NaSPh, PhMe₂Si–C bond of compound 34 was based on prece-

which was prepared in situ from NaH and PhSH, delivered dence in our group.^[14b]Nevertheless, it effected nothing ex-

mixed sulfide 31 in 99% yield.

cept oxidizing the phenylsulfanyl group to a sulfone (79%

Compound 31 was deprotonated with lithium diisoprop- yield; not shown in Scheme 7). We achieved the oxidative

ylamide to render a lactone enolate (Scheme 7). This was replacement of the PhMe₂Si group (in compound 34) by an

transmetallated to give a CpTi^IVCl₂enolate. Such an enol- OH group (in compound 36) for the first time (12% yield)

ate had been involved in aldol addition reactions, which under conditions that Smitrovich and Woerpel described for

proceeded with perfect simple and induced stereoselectivi- an analogous oxidation:^[42]by treatment of silane 34 with

ties, by Müller from our group.^[14b]Gratifyingly, the respec- KH, tBuOOH, and freshly prepared lyophilized nBu₄N⁺F^–.

tive titanium enolate derived from lactone 31 and hexanal When we replaced nBu₄N⁺F^–by K⁺F^–as a fluoride source,

reacted analogously. Aldol product 33 was formed in 82% oxidation product 36 was formed in 66% yield. The final

yield. Reduction with diisobutylaluminum hydride step was to silylate the hydroxy groups of the latter com-

(DIBAH) gave lactol 35 (90% yield) and acetalization with pound (TBS-OTf, imidazole). This furnished C¹–C¹⁰build-

MeOH gave corresponding lactol “ether” 34. The yield of ing block 37 in 93% yield.

3214

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Eur. J. Org. Chem. 2014, 3210–3224

Sultone-Forming RCM for a Protection of Homoallylic Alcohols

Scheme 7. Processing silylated lactone 31 by aldolization (Ǟ33),

lactone protection (Ǟ34), Tamao oxidation (Ǟ36), and O-sil-

ylation (ǞC¹-C¹⁰building block 37). Reagents and conditions:

(a) iPr₂NH (1.3 equiv.), nBuLi (1.25 equiv.), Et₂O, –78 °C, 60 min;

addition of 31, Et₂O, 2 h; addition of CpTiCl₃(1.4 equiv.), 24 h;

addition of n-hexanal (2.2 equiv.), 24 h; 82%. (b) Toluene/n-hexane,

1:1 (v:v), –78 °C, 1.5 h; DIBAH (4.5 equiv.), 1.5 h; 90%. (c) MeOH,

room temp.; pyridinium para-toluenesulfonate (PPTS; 20 mol-%),

2.5 h; 63%. (d) KH (6.1 equiv.), N-methylpyrrolidone, 0 °C;

tBuOOH (6.1 equiv.), Ǟroom temp.; 31, 10 min; KF (2.1 equiv.,);

Ǟ60 °C, 1.5 h; 66%. (e) Imidazole (2.2 equiv.), dimethylform-

amide, 0 °C; tBuMe₂OTf (2.2 equiv.), 30 min; Ǟroom temp.,

30 min; 93%.

Scheme 8. Top: This work’s protection/deprotection strategy for

homoallylic alcohol 14b by a metathesis/fragmentation sequence.

Bottom: The identical protection/deprotection scheme applied to

model homoallylic alcohol 39. Reagents and conditions: (a) NEt₃

(2.0 equiv.), THF, –15 °C; addition of ethenesulfonyl chloride (19;

1.05 equiv.), 30 min; 99%. Used without further purification owing

The step expenditure for reaching synthetic target 37

from diketone 11 totaled 17. The overall yield was 4.9%. A

key step was the stereoselective aldolization 31Ǟ33

(Scheme 7), which is remarkable and new. The exclusive for- to decomposition on silica gel. (b) Grubbs II catalyst (3.0 mol-%),

toluene, 100 °C, 3 h; 93%. (c) Li (60 equiv.), PhMe₂SiCl

(8.0 equiv.), THF, –10 °C, 18 h; addition to CuCN (4.0 equiv.),

mation of the undesired cycloheptenes 15b and 15c in pref-

erence to the desired dihydropyranone 8 by RCMs of the

THF, –10 °C, 2 h; Ǟ–78 °C, Me₃SiCl (1.2 equiv.), 1 min; addition

trienes 14b and 14c is noteworthy (Scheme 2). We circum-

of 24, THF, 1 h; Ǟ–50 °C, 1 h; 88%, ds_{lactone moiety}= 100:0,

vented this obstacle by the lactone- and sultone-forming

double RCM 21Ǟ24 (Scheme 4). The intermediacy of a

sultone might have implied a detour. This was avoided when

we found an innovative way to remove that moiety

(24Ǟ27Ǟ28, Scheme 5). During the latter operations, the

ds_{sultone moiety}= 68:32. The diastereomeric mixture is separable by

flash chromatography^[34]but was not separated. (d) nBu₄N⁺F^–

(1.05 equiv.), THF, 0 °C, 1.5 h; Ǟroom temp., 1.5 h; 38–50% (75–

82% based on recovered 27). (e) NEt₃(2.0 equiv.), THF, –15 °C;

addition of ethenesulfonyl chloride (19; 1.05 equiv.), 30 min; 96%.

Used without further purification owing to decomposition on silica

rest of the molecule was pushed ahead, structurally speak- gel. (f) nBu₄N⁺F^–(1.2 equiv.), THF, 0 °C, 1 h; Ǟroom temp., 2 h;

60%. (g) Grubbs II catalyst (1.0 mol-%), toluene, 100 °C, 7 h; 88%.

ing.

The way we formed and destroyed a sultone from homo-

allylic alcohol 14b warrants attention as a novel protection/

(1.2 equiv.), 1 min; addition of 42, THF, 30 min; Ǟ–50 °C, 30 min;

deprotection strategy for homoallylic alcohols more gen-

erally. This is underlined by the 4-step sequences shown in

Scheme 8. The upper sequence consists of the respective

steps from our synthetic endeavor. It comprises transforma-

tions 14bǞ21Ǟ24Ǟ27Ǟ28. The box in Scheme 8 ratio-

(h) Li (30 equiv.), PhMe₂SiCl (4.0 equiv.), THF, –10 °C, 18 h; ad-

dition to CuCN (2.0 equiv.), THF, –10 °C, 2 h; Ǟ–78 °C, Me₃SiCl

87%.

Summary

We have synthesized the C¹–C¹⁰“southwestern moiety”

nalizes the final step as fragmentation of the 27-based sili- 4 (PG¹= tBuMe₂Si and PG²= CMe₂) common to the un-

cate 38. For good measure the lower part of Scheme 8 dis- natural enantiomers ent-1 and ent-2 of macrolides filipin III

plays an unadulterated variant of the same set of transfor- (1) and pentamycin (2). Unsaturated lactone/unsaturated

mations. It led from homoallylic alcohol 39 through ethene- sultone 24 was established by a double RCM reaction of

sulfonate 40 (96% yield) through olefin metathesis to unsat- crotonate/ethenesulfonate 21, which itself was obtained

urated sultone 42 (88%). The Cu-promoted 1,4-addition re- from 1,5-dichloropentane-2,4-dione (11) in 6 steps. A

action of a SiMe₂Ph group gave the saturated sultone 41 double Cu-promoted 1,4-addition reaction of PhMe₂SiCl

(69%). It released homoallylic alcohol 39 in 60% yield by followed by regenerating the homoallylic alcohol motif gave

nBu₄N⁺F^–-mediated silicate formation and in-situ fragmen- lactone 28 as a single diastereomer. A diastereoselective

tation.

iodocarbonate formation and an iodine/phenylsulfanyl ex-

Eur. J. Org. Chem. 2014, 3210–3224

www.eurjoc.org

3215

P. Walleser, R. Brückner

FULL PAPER

30 min and the mixture was stirred for 30 min at –78 °C. The reac-

tion mixture was then quenched cautiously with satd. aq. NH₄Cl

(90 mL) and stirred for 1 h. The phases were separated and the aq.

phase was extracted with AcOEt (3ϫ 90 mL). The combined or-

ganic phases were washed with brine (90 mL), dried with MgSO₄,

and concentrated under reduced pressure. Flash chromatography^[34]

(4.5 cmϫ16.5 cm, 50 mL, cyclohexane/AcOEt, 2:1) provided the

title compound (fractions 9–29, 4.54 g, 91%) as a colorless oil.

change delivered lactone 31. Another 5 steps finished

“southwestern” C¹–C¹⁰building block 37, a perfectly dia-

stereoselective aldol addition of lactone 31 to hexanal

making the start.

A spin-off result of our study is a new protection/depro-

tection sequence for secondary homoallylic alcohols. It in-

volves protecting a homoallylic alcohol as ethenesulfone,

performing a RCM, adding a silylcuprate to the resulting

sultone, and fragmenting the silylsultone with nBu₄N⁺F^–.

20

[α] = –28.3, [α] = –28.3, [α] = –29.9, [α] = –52.0, [α] =

589

579

546

365

1

–80.2 (c = 0.51 in CHCl₃). H NMR (400.1 MHz, CDCl₃/CHCl₃):

δ = 1.65 [dd, J_1-H(A),2= 6.3, J_1-H(B),2= 5.2 Hz, 2 H, 1-H₂], AB

signal [δ_A= 2.25, δ_B= 2.30, J_AB= 13.8 Hz, A part additionally

Experimental Section

4

split by J_A,4= 7.5, J_A,2= 7.4, J_{A,5–H(trans)}= J_A,5–H(cis)= 1.2 Hz,

4

B part additionally split by J_B,4= 6.9, J_B,2= 5.9, J_{B,5–H(trans)}

=

General Information: Reactions were performed under N₂in glass-

ware dried with a heat gun under vacuum. THF was freshly dis-

tilled from K, Et₂O was freshly distilled from Na/K, toluene was

freshly distilled from Na, and CH₂Cl₂and N-methylpyrrolidone

(NMP) were freshly distilled from CaH₂. Products were purified by

flash chromatography^[34](column diameter, filling height, fraction

volume, and eluents are given in parentheses. The fractions that

contained the isolated product are indicated in each description as

“fractions xx–yy”) on Merck silica gel 60 (0.040–0.063 mm). Yields

⁴J_B,5–H(cis)= 1.3 Hz, 4 H, 3-H₄], 2.39 [br. d, J_4-OH,4= 3.8 Hz, 2 H,

4-(OH)₂], 4.00 [m_c, approximately interpretable as ddddd, J_2,3–H(A)

= 7.2, J_2,1–H(A)= 6.2, J_2,3–H(B)= 5.6, J_2,1–H(B)= 5.3, J_2,2–OH

=

2

4.0 Hz, 2 H, 2-H₂], 5.14 [dddd, J_5-H(cis),4= 9.5, J_{5-H(cis),5–H(trans)}

4

2.1, J_{5-H(cis),3–H(A)}= J_{5-H(cis),3–H(B)}= 1.3 Hz, 2 H, 5-H₂(cis)], 5.14

[dddd, J_5-H(trans),4= 17.7, ²J_{5-H(trans),5–H(cis)}= 2.1, ⁴J_{5-H(trans),3–H(A)}

=

⁴J_{5-H(trans),3–H(B)}= 1.3 Hz, 2 H, 1-H₂(trans)], 5.82 [dddd, J_{4,5–H(trans)}

= 17.7, J_4,5–H(cis)= 9.6, J_4,3–H(A)= 7.5, J_4,3–H(B)= 6.8 Hz, 2 H, 4-

H₂] ppm. ¹³C NMR (100.6 MHz, CDCl₃/CDCl₃): δ = 41.63 (C-

1), 42.11 (C₂-3), 68.19 (C₂-2), 118.29 (C₂-5), 134.72 (C₂-4) ppm. IR

1

refer to analytically pure samples. H NMR spectroscopy [CHCl₃

(δ = 7.26 ppm) as internal standard in CDCl₃, CD₅H (δ =

7.16 ppm) as internal standard in C₆D₆, and CD₃COCD₂H (δ =

2.05 ppm) as internal standard in (CD₃)₂CO]: Varian Mercury VX

300, Bruker Advance II 400, and Bruker DRX 500. Integrals agree

with the given assignments. ¹³C NMR spectroscopy [CDCl₃(δ =

77.10 ppm) as internal standard in CDCl₃, C₆D₆(δ = 128.06 ppm)

as internal standard in C₆D₆, and (CD₃)₂CO (δ = 29.80 ppm) as

internal standard in (CD₃)₂CO]: Bruker Advance II 400, and

Bruker DRX 500. Assignments of ¹H and ¹³C NMR spectroscopic

resonances refer to IUPAC nomenclature except within substitu-

ents (for cases in which primed numbers are used) or in cases ex-

plicitly indicated otherwise. NMR spectroscopic measurements:

Dr M. Keller, F. Reinbold, M. Schonhard, Institut für Organische

Chemie, Universität Freiburg. MS measurements: Dr J. Wörth,

C. Warth, Institut für Organische Chemie, Universität Freiburg.

Combustion analyses: F. Tönnies, A. Siegel, Institut für Organische

Chemie, Universität Freiburg. IR spectra: Perkin–Elmer FT-IR

Paragon 1000. Optical rotations α_expwere measured with a Perkin–

Elmer polarimeter 341 MC at 589, 578, 546, 436, and 365 nm/20 °C

(film): ν = 3370, 3070, 2980, 2935, 1715, 1640, 1435, 1375, 1265,

˜

1050, 995, 915, 870, 830 cm^–1. HRMS (CI, NH₃): calcd. for

C₉H₁₇O₂[M + H⁺] 157.1229; found 157.1227 (δ = –1.0 ppm).

(2S,4S)-1,5-Dichlorpentane-2,4-diol (12)

Freshly distilled 1,5-dichloropentane-2,4-dione (10.4 g, 61.4 mmol)

was dissolved in MeOH (40 mL), which was degassed for 20 min

with an argon stream prior to use. This solution was transferred

into an argon flushed 100 mL autoclave followed by the addition

of the commercially available [Me₂NH₂]⁺[RuCl(R-BINAP)]₂-

–

(μ-Cl)₃(205 mg, 123 μmol, 0.2 mol-%) in one portion. Then the

reaction vessel was sealed and placed in a steel autoclave. The latter

was inserted into an oven, which, to ensure good mixing, was ro-

tated during the hydrogenation reaction. The autoclave was pres-

surized at room temp. with hydrogen gas to 123 bar and rotation

of the reaction vessel and heating to 110 °C was started. After

5 min at this temp. absorption of the hydrogen began. When no

more hydrogen was absorbed (60 min), the reaction mixture was

cooled to room temp., concentrated under reduced pressure, and

filtered through a plug of silica gel and washed with tBuOMe

(20 mL). The solvent was removed under reduced pressure to ob-

tain the crude title compound, which crystallized in the refrigerator.

The crude product was recrystallized (n-hexane/CH₂Cl₂, 2:3) to

provide the title compound (7.97 g, 75%) as white crystalline need-

and calculated according to the Drude equation {[α]_D

=

(α_expϫ100)/(cϫd)}; rotational values are the average of five mea-

surements of α_expin a given solution of the respective sample. Melt-

ing points were measured with a Dr Tottoli apparatus (Büchi). The

concentration of vinylMgBr was determined by titration according

to Love,^[43]the concentration of nBuLi was determined by titration

according to Suffert,^[44]and the concentration of tBuOOH was de-

1

termined by H NMR spectroscopic analysis.^[45]

(4R,6R)-Nona-1,8-diene-4,6-diol (10):^[18b]

20

les. M. p. 80–82 °C. [α]

= –22.2, [α]

= –24.5, [α]

= –27.9,

589

578

546

20

[α]

436

= –45.1, [α]

= –66.6 (c = 0.98 in CHCl₃); the ee of this

365

compound was not measured because the literature precedence

1

supported the expectation that it would be “very high”. H NMR

A suspension of CuI (2.44 g, 12.8 mmol, 0.4 equiv.) in THF

(330 mL) was cooled to –10 °C and vinylmagnesium bromide (0.7 m

in THF, 183 mL, 128 mmol, 4.0 equiv.) was added over a period of

30 min. The reaction mixture was cooled to –78 °C and stirred for

2 h at this temperature. Afterwards, compound 13 (3.20 g,

32.0 mmol) dissolved in THF (35 mL) was added slowly over

[400.1 MHz, (CD₃)₂CO/CD₃COCD₂H]: δ = 1.69 [dd, J_1-H(A),2=

6.6, J_1-H(B),2= 5.7 Hz, 2 H, 1-H₂], AB signal (δ_A= 3.55, δ_B= 3.61,

J_AB= 11.0 Hz, A part additionally split by J_A,2= 5.9 Hz, B part

additionally split by J_B,2= 4.9 Hz, 4 H, 3-H₄), 4.07 [m_c, approxi-

mately interpretable as ddddd, J_2,1–H(A)= 6.3, J_2,3–H(A)= 6.1,

J_2,1–H(B)= 6.0, J_2,2–OH= 5.7, J_2,3–H(B)= 5.4 Hz, 2 H, 2-H₂], 4.23

3216

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Eur. J. Org. Chem. 2014, 3210–3224

Sultone-Forming RCM for a Protection of Homoallylic Alcohols

4

[br. d, J_2-OH,2= 5.6 Hz, 2 H, 2-(OH)₂] ppm. ¹³C NMR [100.6 MHz,

(CD₃)₂CO/(CD₃)₂CO]: δ = 39.58 (C-1), 50.82 (C₂-3), 69.81 (C₂-

1 H, 2-H], 5.76–5.84 (m, 1 H, 8-H), 5.83 (dq, J_2Ј,3Ј= 15.5, J_2Ј,4Ј=

1.7 Hz, 1 H, 2Ј-H), 6.97 (dq, J_3Ј,2Ј= 15.5, J_3Ј,4Ј= 6.9 Hz, 1 H, 3Ј-

2) ppm. IR (KBr): ν = 3365, 2960, 2890, 1740, 1435, 1400, 1380,

H) ppm. ¹³C NMR (100.6 MHz, CDCl₃/CDCl₃): δ = 18.06 (C-4Ј),

˜

1340, 1325, 1295, 1215, 1185, 1100, 1070, 1050, 950, 910, 870, 835, 39.02 (C-3), 40.61 (C-7), 41.97 (C-5), 68.47 (C-6), 71.44 (C-4),

710, 690, 600 cm^–1. C₅H₁₀Cl₂O₂(173.04): calcd. C 34.71, H 5.82;

found C 34.74, H 5.63.

118.12 (C-9), 118.48 (C-1), 122.90 (C-2Ј), 133.47 (C-2), 134.40 (C-

8), 145.02 (C-3Ј), 166.25 (C-1Ј) ppm. IR (film): ν = 3430, 3075,

˜

2980, 2915, 1720, 1655, 1445, 1375, 1310, 1295, 1185, 1105, 1050,

1000, 970, 915, 840, 745, 690 cm^–1. HRMS (CI, NH₃): calcd. for

C₁₃H₂₁O₃[M + H⁺] 225.1491; found 225.1493 (+1.0 ppm).

Di[(S)-oxiran-2-yl]methane (13)

(4S,6R)-6-[(Ethenesulfonyl)oxy]nona-1,8-dien-4-yl (E)-But-2-enoate

(21)

Compound 12 (5.80 g, 33.5 mmol) was dissolved in Et₂O (260 mL)

and cooled to 0 °C. Freshly powdered KOH (12.4 g, 221 mmol,

6.6 equiv.) was then added in one portion. After 1 h at 0 °C the

reaction mixture was warmed to room temp. and stirred for an

additional 3 h. The mixture was filtered through a plug of MgSO₄,

the solvent was removed under reduced pressure and the title com-

pound (2.95 g, 88%) was obtained without further purification as

Enoate 14b (1.49 g, 6.64 mmol) and NEt₃(1.85 mL, 1.34 g,

13.3 mmol, 2.0 equiv.) were dissolved in THF (70 mL). After cool-

ing to –15 °C ethenesulfonyl chloride (19; 882 mg, 6.98 mmol,

1.05 equiv.) was added dropwise. After complete addition the mix-

ture was stirred for 30 min at –15 °C. Then the reaction mixture

was quenched cautiously with cold H₂O (25 mL). The phases were

separated and the aq. phase was satd. with solid NaCl and ex-

tracted with tBuOMe (3ϫ 25 mL). The combined organic phases

were washed with aq. HCl (1 m, 15 mL) and satd. aq. NaHCO₃

(25 mL) and dried with MgSO₄. The solvent was removed under

20

a colorless liquid. [α]

= –56.2, [α]

= –59.0, [α]

= –67.3,

589

578

546

20

[α] = –106.9, [α] = –159.0 (c = 0.29 in CHCl₃); the ee of this

436

365

compound was not measured because the literature precedence

1

supported the expectation that it would be “very high”. H NMR

(400.1 MHz, CDCl₃/CHCl₃): δ = 1.65 [dd, J_1-H(A),2= J_1-H(B),2

=

5.7 Hz, 2 H, 1-H₂], AB signal (δ_A= 2.54, δ_B= 2.82, J_AB= 5.0 Hz,

A part additionally split by J_A,2= 2.7, B part additionally split by

J_B,2= 4.0 Hz, 4 H, 3-H₄), 3.10 [dddd, J_2,1–H(A)= J_2,1–H(B)= 5.7,

J_2,3–H(B)= 4.0, J_2,3–H(A)= 2.7 Hz, 2 H, 2-H₂] ppm. ¹³C NMR

(100.6 MHz, CDCl₃/CDCl₃): δ = 36.14 (C-1), 46.90 (C₂-3), 49.43

reduced pressure and the title compound (2.07 g, 99%) was ob-

20

tained without further purification as a pale yellow oil. [α]

=

436

20

1

+19.9, [α] = +30.9 (c = 0.35 in CHCl₃). H NMR (400.1 MHz,

CDCl₃/CHCl₃): δ = 1.89 (dd, J_4Ј,3Ј= 6.9, J_4Ј,2Ј= 1.8 Hz, 3 H, 4Ј-

365

4

(C -2) ppm. IR (film): ν = 3430, 3055, 3000, 2925, 1645, 1485, 1420,

˜

2

1315, 1260, 1090, 1065, 980, 915, 880, 845, 790, 745 cm^–1.

H₃) ppm, AB signal (δ_A= 1.96, δ_B= 2.09, J_AB= 14.5 Hz, A part

additionally split by J_A,4= 7.4, J_A,6= 4.5 Hz, B part additionally

split by J_B,6= 8.6, J_B,4= 5.8 Hz, 2 H, 5-H₂), 2.34–2.40 (m, 2 H, 3-

H₂), AB signal [δ_A= 2.42, δ_B= 2.55, J_AB= 14.7 Hz, A part ad-

(4S,6R)-6-Hydroxynona-1,8-dien-4-yl (E)-But-2-enoate (14b)

4

ditionally split by J_A,8= 7.6, J_A,6= 6.1, J_{A,9–H(trans)}= J_A,9–H(cis)

= 1.2 Hz, B part additionally split by J_B,6= 6.4, J_B,8= 5.2,

⁴J_{B,9–H(trans)}= ⁴J_B,9–H(cis)= 1.4 Hz, 2 H, 7-H₂], 4.66 [dddd, J_4,5–H(A)

= 7.5, J_4,3–H(A)= J_4,5–H(B)= 5.7, J_4,3–H(B)= 5.4 Hz, 1 H, 4-H], 5.04

[dddd, J_6,5–H(B)= 8.5, J_6,7–H(A)= J_6,7–H(B)= 6.2, J_6,5–H(B)= 4.5 Hz,

1 H, 6-H], 5.07–5.18 (m, 4 H, 1-H₂, 9-H₂), 5.67–5.79 (m, 2 H, 2-

Diol 10 (3.71 g, 23.7 mmol) was dissolved in toluene (250 mL).

Crotonic acid (2.24 g, 26.1 mmol, 1.1 equiv.) and PPh₃(6.83 g,

26.1 mmol, 1.1 equiv.) were added at room temp. After 10 min the

reaction mixture was cooled to –30 °C and DIAD (5.1 mL, 5.3 g,

26 mmol, 1.1 equiv.) was added over a period of 30 min. After com-

plete addition the reaction mixture was slowly warmed to room

temp. and stirred overnight. Silica gel (20 g) was added and the

solvent was removed under reduced pressure. The silica gel pad

thus obtained was added on the top of the column and Flash

chromatography^[34](4.5 cmϫ17.5 cm, 50 mL, cyclohexane/AcOEt,

20:1) provided the title compound (fractions 23–44, 3.29 g, 62%)

4

H, 8-H), 5.83 (dq, J_2Ј,3Ј= 15.5, J_2Ј,4Ј= 1.7 Hz, 1 H, 2Ј-H), 6.06

[d, J_{2Љ-H(cis),1Љ}= 9.9 Hz, 1 H, 2Љ-H(cis)], 6.37 [d, J_{2Љ-H(trans),1Љ}

=

16.7 Hz, 1 H, 2Љ-H(trans)], 6.55 [dd, J_{1Љ,2Љ–H(trans)}= 16.6, J_{1Љ,2Љ–H(cis)}

= 9.9 Hz, 1 H, 1Љ-H], 6.99 (dq, J_3Ј,2Ј= 15.5, J_3Ј,4Ј= 6.0 Hz, 1 H,

3Ј-H) ppm. ¹³C NMR (100.6 MHz, CDCl₃/CDCl₃): δ = 18.11 (C-

4Ј), 37.92 (C-5), 38.47 (C-7), 38.82 (C-3), 69.46 (C-6), 80.06 (C-4),

118.66 (C-9), 119.58 (C-1), 122.59 (C-2Ј), 129.28 (C-2Љ), 131.91 (C-

1Љ), 132.81 (C-8), 133.75 (C-2), 145.47 (C-3Ј), 165.95 (C-1Ј) ppm.

IR (film): ν = 3080, 2980, 2920, 1715, 1655, 1445, 1365, 1310, 1265,

˜

20

as a colorless oil. [α]

= +14.2, [α]

= +18.0, [α]

= +20.3,

1175, 1105, 995, 970, 910, 840, 790, 730, 690, 660 cm^–1. HRMS

(CI, NH₃): calcd. for C₁₅H₂₆NO₅S [M + NH₄⁺] 332.1532; found

332.1537 (+1.6 ppm).

589

578

546

20

[α]

436

= +36.8, [α]

= +61.9 (c = 0.47 in CHCl₃). ¹H NMR

365

(400.1 MHz, CDCl₃/CHCl₃): δ = AB signal (δ_A= 1.75, δ_B= 1.81,

J_AB= 14.5 Hz, A part additionally split by J_A,4= J_A,6= 5.1 Hz, B

part additionally split by J_B,6= J_B,4= 7.4 Hz, 2 H, 5-H₂), 1.87 (dd,

(S)-6-{[(R)-2,2-Dioxo-5,6-dihydro-1,2-oxathiin-6-yl]methyl}-5,6-di-

hydro-2H-pyran-2-one (24)

4

J_4Ј,3Ј= 6.9, J_4Ј,2Ј= 1.7 Hz, 3 H, 4Ј-H₃), 1.99 (d, J_6-OH,6= 4.0 Hz,

1 H, 4-OH) AB signal [δ_A= 2.16, δ_B= 2.31, J_AB= 14.0 Hz, A part

4

additionally split by J_A,6= J_A,8= 7.6, J_{A,9–H(trans)}= J_A,9–H(cis)

=

1.2 Hz, B part additionally split by J_B,8= 6.7, J_B,6= 4.6,

4

⁴J_{B,9–H(trans)}= J_B,9–H(cis)= 1.3 Hz, 2 H, 7-H₂], 2.34–2.45 (m, 2 H,

3-H₂), 3.76 [m_c, approximately interpretable as ddddd, J_6,5–H(B)

=

J_6,7–H(A)= 7.6, J_6,5–H(A)= 4.9, J_6,7–H(B)= 4.6, J_6,6–OH= 4.2 Hz, 1

A solution of 21 (1.02 g, 3.24 mmol) in toluene (325 mL) was

H, 6-H], 5.05–5.15 (m, 5 H, 1-H₂, 4-H, 9-H₂), 5.76 [dddd, treated with Grubbs II catalyst (83 mg, 97 μmol, 3.0 mol-%) and

J_{2,1–H(trans)}= 17.2, J_2,1–H(cis)= 10.1, J_2,3–H(A)= J_2,3–H(B)= 7.1 Hz, heated at 100 °C for 3 h. After evaporation of the solvent, the resi-

Eur. J. Org. Chem. 2014, 3210–3224

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3217

P. Walleser, R. Brückner

due was purified by flash chromatography^[34](2.5 cm ϫ14.5 cm, 2 H, 5Љ-H₂), AB signal (δ_A= 1.72, δ_B= 1.89, J_AB= 14.2 Hz, A

FULL PAPER

20 mL, cyclohexane/AcOEt, 1:3) to yield 24 (fractions 8–20,

part additionally split by J_A,6= 9.8, J_A,4= 9.2 Hz, B part addition-

737 mg, 93%) as a slightly brown oil, which crystallized in the re-

ally split by J_B,4= 7.0, J_B,6= 4.2 Hz, 2 H, 5-H₂), AB signal (δ_A

1.76, δ_B= 2.15, J_AB= 14.5 Hz, A part additionally split by J_A,6

6.7, J_A,6Љ= 4.4 Hz, B part additionally split by J_B,6Љ= 8.5, J_B,6

=

20

frigerator. M. p. 82–83 °C. [α]

= –9.9, [α]

= –14.9, [α]

=

589

578

546

–18.4, [α]₄²₃⁰₆= –50.1, [α] = –135.9 (c = 0.57 in CHCl₃). ¹H NMR

20

365

(400.1 MHz, CDCl₃/CHCl₃): δ = AB signal (δ_A= 2.13, δ_B= 2.39,

6.1 Hz, 2 H, 1Ј-H₂), 1.86 [dddd, J_{4Љ,3Љ–H(A)}= 13.9, J_{4Љ,5Љ–H(A)}= 13.5,

J_AB= 15.0 Hz, A part additionally split by J_A,6= 5.8, J_A,6Љ

=

J_{4Љ,5Љ–H(B)}= 3.1, J_{4Љ,3Љ–H(B)}= 3.0 Hz, 1 H, 4Љ-H], AB signal (δ_A

2.23, δ_B= 2.43, J_AB= 15.9 Hz, A part additionally split by J_A,4

13.1, B part additionally split by J_B,4= 5.4 Hz, 2 H, 3-H₂), AB

signal (δ_A= 2.79, δ_B= 3.07, J_AB= 13.8 Hz, A part additionally

split by J_A,4Љ= 13.8 Hz, B part additionally split by J_B,2Ј= 2.8 Hz,

2 H, 3Љ-H₂), 4.24 [dddd, J_6,5–H(A)= 10.0, J_6,1Ј–H(A)= 6.7, J_6,1Ј–H(B)

=

4.4 Hz, B part additionally split by J_B,6Љ= 7.5, J_B,6= 6.2 Hz, 2 H,

1Ј-H₂), AB signal (δ_A= 2.45, δ_B= 2.66, J_AB= 19.1 Hz, A part

4

additionally split by J_A,3Љ= 5.1, J_A,6Љ= 3.3 Hz,J_A,4Љ= 1.1 Hz, B

4

part additionally split by J_B,6Љ= 11.5, J_B,4Љ= J_B,3Љ= 2.3 Hz, 2 H,

5Љ-H₂), 2.43–2.52 (m, 2 H, 5-H₂), 4.72 [dddd, J_6,1Ј–H(A)= 10.1,

J_6,1Ј–H(A)= J_6,1Ј–H(B)= J_6,5–H(B)= 6.0 Hz, 2 H, 6-H₂], 5.24 [dddd, = 6.1, J_6,5–H(B)= 4.0 Hz, 1 H, 6-H], 4.78 [dddd, J_{6Љ,5Љ–H(A)}= 11.3,

J_{6Љ,5Љ–H(B)}= 11.6, J_{6Љ,1Ј–H(B)}= 7.5, J_{6Љ,1Ј–H(A)}= 4.3, J_{6Љ,5Љ–H(A)}J_{6Љ,1Ј–H(B)}= 8.4, J_{6Љ,1Ј–H(A)}= 4.3, J_{6Љ,5Љ–H(B)}= 2.0 Hz, 1 H, 6Љ-H],

3.3 Hz, 2 H, 6Љ-H₂], 6.05 [ddd, J_3,4= 9.8, J_3,5–H(A)= 2.3, J_3,5–H(B)7.34–7.50 (m, 10 H, 2ϫ ortho-H, 2ϫ meta-H, para-H, 2ϫ orthoЈ-

=

4

= 1.4 Hz, 1 H, 3-H], 6.52 [dddd, J_3Љ,4Љ= 10.9, J_{3Љ,5Љ–H(A)}= 5.3,

⁴J_{3Љ,5Љ–H(B)}= 2.1, ⁵J_3Љ,6Љ= 0.4 Hz, 1 H, 3Љ-H], 6.57 [ddd, J_4Љ,3Љ= 10.8,

J_{4Љ,5Љ–H(B)}= 2.5, J_{4Љ,5Љ–H(A)}= 1.2 Hz, 1 H, 4Љ-H], 6.93 [ddd, J_4,3= 9.9,

J_4,5–H(A)= 5.0, J_4,5–H(B)= 3.5 Hz, 1 H, 4-H] ppm. ¹³C NMR

H, 2 ϫ metaЈ-H, paraЈ-H) ppm. ¹³C NMR (100.6 MHz, CDCl₃/

CDCl₃): δ = –5.55 and –5.49 and –5.39 [4-Si(CH₃)₂, 4Ј-Si(CH₃)₂],

15.11 (C-4), 22.50 (C-4Љ), 27.50 (C-5), 29.96 (C-3), 30.23 (C-5Љ),

39.82 (C-1Ј), 48.57 (C-3Љ), 73.66 (C-6), 83.99 (C-6Љ), 128.27 and

(100.6 MHz, CDCl₃/CDCl₃): δ = 28.70 (C-5), 30.12 (C-5Љ), 38.84 128.44 (2 ϫ meta-C, 2 ϫ metaЈ-C), 129.82 and 130.21 (para-H,

(C-1Ј), 73.60 (C-6), 78.05 (C-6Љ), 121.37 (C-3), 126.22 (C-3Љ), 136.67 paraЈ-H), 133.86 and 133.91 (2ϫ ortho-C, 2ϫ orthoЈ-C), 134.16

(C-4Љ), 145.10 (C-4), 163.61 (C-2) ppm. IR (film): ν = 3065, 2925, and 135.47 (ipso-C, ipsoЈ-C), 173.09 (C-2) ppm. Diastereomer B:

˜

20

1720, 1625, 1440, 1405, 1420, 1390, 1350, 1255, 1180, 1150, 1100,

[α] = +13.6, [α] = +14.6, [α] = +17.1, [α] = +34.3, [α]

589 578 546 436 365

1155, 1035, 970, 930, 880, 860, 815, 775, 735, 715, 675 cm^–1

.

= +67.3 (c = 1.15 in CHCl₃, 10 cm). ¹H NMR (400.1 MHz, CDCl₃/

CHCl₃): δ = 0.34 and 0.34 and 0.39 and 0.40 [2ϫ s, 6 H, 4-Si-

(CH₃)₂, 2 ϫ s, 6 H, 4Љ-Si(CH₃)₂], 1.43 [dddd, J_4,3–H(A)= 13.2,

J_4,5–H(A)= 9.2, J_4,5–H(B)= 7.5, J_4,3–H(B)= 5.5 Hz, 1 H, 4-H], 1.62–

C₁₀H₁₂O₅S (244.26): calcd. C 49.17, H 4.95, S 13.13; found C 49.24,

H 5.02, S 12.95. HRMS (CI, NH₃): calcd. for C₁₀H₁₆NO₅S [M +

NH₄⁺] 262.0749; found 262.0743 (δ = –1.5 ppm).

1.72 (m, 1 H, 5Љ-H_A), AB signal (δ_A= 1.69, δ_B= 1.83, J_AB

14.2 Hz, A part additionally split by J_A,6= J_A,4= 9.3 Hz, B part

additionally split by J_B,4= 7.4, J_B,6= 4.4 Hz, 2 H, 5-H₂), 1.78–1.98

=

(4R,6R)-4-(Dimethylphenylsilyl)-6-{[(6S)-4-(dimethylphenylsilyl)-

2,2-dioxo-1,2-oxathian-6-yl]methyl}-3,4,5,6-tetrahydro-2H-pyran-

2-one (27)

(m, 2 H, 4Љ-H, 5Љ-H_B), AB signal (δ_A= 1.91, δ_B= 2.54, J_AB

=

14.7 Hz, A part additionally split by J_A,6= 6.3, J_A,6Љ= 6.2 Hz, B

part additionally split by J_B,6Љ= 8.1, J_B,6= 6.9 Hz, 2 H, 1Ј-H₂),

AB signal (δ_A= 2.21, δ_B= 2.42, J_AB= 16.0 Hz, A part additionally

split by J_A,4= 13.3 Hz, B part additionally split by J_B,4= 5.2 Hz,

2 H, 3-H₂), AB signal (δ_A= 2.96, δ_B= 3.14, J_AB= 14.1 Hz, A part

additionally split by J_A,4Љ= 10.9 Hz, B part additionally split by

A suspension of small pieces of Li (1.55 g, 223 mmol, 60.0 equiv.)

in THF (80 mL) was cooled to –10 °C. PhMe₂SiCl (4.90 mL,

5.06 g, 29.6 mmol, 8.0 equiv.) was added dropwise. After the reac-

tion mixture was stirred for 18 h the resulting deep-red solution

was transferred to a suspension of CuCN (1.33 g, 14.9 mmol,

4.0 equiv.) in THF (60 mL) at –10 °C. After 2 h the reaction mix-

ture was cooled to –78 °C and SiMe₃Cl (0.57 mL, 0.48 g,

4.46 mmol, 1.2 equiv.) and a solution of 24 (907 mg, 3.71 mmol) in

THF (24 mL) was added dropwise. The reaction mixture was

stirred at –78 °C for 1 h, warmed to –50 °C and stirred for an ad-

ditional hour. Afterwards the reaction mixture was quenched by

addition of satd. aq. NH₄Cl (100 mL), and was warmed to room

temp. under vigorous stirring. The phases were separated, and the

aq. phase was extracted with AcOEt (3ϫ 60 mL). The combined

organic extracts were washed with brine (75 mL), and dried with

MgSO₄. The solvent was removed under reduced pressure, and the

residue was purified by flash chromatography^[34](4.5 cmϫ19.5 cm,

50 mL, cyclohexane/AcOEt, 6:1) to yield 27 [fractions 31–39 (dia-

stereomer A), fractions 41–54 (diastereomer B), 1.69 g, 88%; dia-

stereoselectivity 32:68] as a colorless sticky oil. Diastereomer A:

J_B,4Љ= 3.9 Hz, 2 H, 3Љ-H₂), 4.15 [dddd, J_6,5–H(A)= 9.5, J_6,1Ј–H(A)

=

J_6,1Ј–H(B)= 6.7, J_6,5–H(B)= 4.3 Hz, 1 H, 6-H], 4.81 [dddd, J_{6Љ,1Ј–H(B)}

= 8.4, J_{6Љ,1Ј–H(B)}= 6.5, J_{6Љ,5Љ–H(A)}= 4.4, J_{6Љ,5Љ–H(B)}= 4.0 Hz, 1 H, 6Љ-

H], 7.34–7.50 (m, 6 H, 2ϫ meta-H, para-H, 2ϫ metaЈ-H, paraЈ-

H), 7.44–7.49 (m, 4 H, 2ϫ ortho-H, 2ϫ orthoЈ-H) ppm. ¹³C NMR

(100.6 MHz, CDCl₃/CDCl₃): δ = –5.44 and –5.35 and –5.10 and

–4.83 [4-Si(CH₃)₂, 4Ј-Si(CH₃)₂], 15.14 (C-4), 19.14 (C-4Љ), 27.53 (C-

5), 28.12 (C-5Љ), 29.99 (C-3), 37.41 (C-1Ј), 49.33 (C-3Љ), 74.42 (C-

6), 82.50 (C-6Љ), 128.28 and 128.40 (2 ϫ meta-C, 2 ϫ metaЈ-C),

129.87 and 130.17 (para-H, paraЈ-H), 133.87 and 133.89 (2ϫ ortho-

C, 2 ϫ orthoЈ-C), 134.63 and 135.47 (ipso-C, ipsoЈ-C), 172.92 (C-

2) ppm. IR (film): ν = 3070, 2955, 2930, 1745, 1430, 1360, 1310,

˜

1255, 1220, 1170, 1115, 1065, 1030, 1000, 885, 835, 815, 775,

740 cm^–1. IR (film): ν = 3070, 2955, 2930, 1745, 1430, 1360, 1310,

˜

1255, 1220, 1170, 1115, 1065, 1030, 1000, 885, 835, 815, 775,

740 cm^–1. HRMS (CI, NH₃): calcd. for C₂₆H₄₀NO₅SSi₂[M +

NH₄⁺] 534.2166; found 534.2175 (+1.7 ppm).

(4R,6R)-4-(Dimethylphenylsilyl)-6-[(R)-2-hydroxypent-4-en-1-yl]-

3,4,5,6-tetrahydro-2H-pyran-2-one (28)

20

[α]

= +25.7, [α]

= +27.0, [α]

= +31.3, = +60.0, [α]

=

589

578

546

v

365

+110.9 (c = 1.23 in CHCl₃). ¹H NMR (400.1 MHz, CDCl₃/CHCl₃):

δ = 0.35 and 0.35 and 0.36 and 0.36 [2ϫ s, 6 H, 4-Si(CH₃)₂, 2ϫ s,

6 H, 4Љ-Si(CH₃)₂], 1.43 [dddd, J_4,3–H(A)= 13.1, J_4,5–H(A)= 9.4,

J_4,5–H(B)= 7.1, J_4,3–H(B)= 5.7 Hz, 1 H, 4-H], AB signal (δ_A= 1.47,

δ_B= 1.70, J_AB= 14.4 Hz, A part additionally split by J_A,4Љ= 13.3,

J_A,6Љ= 11.3, B part additionally split by J_B,4Љ= 2.8, J_B,6Љ= 2.1 Hz,

Sultone 27 (1.58 g, 3.06 mmol) was dissolved in THF (100 mL) and

cooled to 0 °C. nBu₄N⁺F^–(1.0 m in THF, 3.20 mL, 3.21 mmol,

3218

www.eurjoc.org

Eur. J. Org. Chem. 2014, 3210–3224

Sultone-Forming RCM for a Protection of Homoallylic Alcohols

1.05 equiv.) was added slowly. The resulting mixture was stirred at [α] = +15.5, [α] = +30.0, [α] = +35.5, [α] = +66.4, [α]

20

589

20

578

20

546

20

436

20

365

this temperature for 1.5 h. The cooling bath was removed and the

reaction mixture was stirred for an additional 1.5 h at room temp.

silica gel (5 g) was added and the solvent was removed under re-

duced pressure. The obtained silica pad was added on the top of

the column and Flash chromatography^[34](4.5 cm ϫ 17.5 cm,

50 mL, cyclohexane/AcOEt, 3:1) provided the title compound [frac-

tions 17–34, 487 mg, 50% (616 mg of unchanged 27 was reisolated;

taking this into account the yield of the title compound was 82%)]

as a colorless oil together with reisolated 27 (fractions 8–15,

= +123.6 (c = 0.40 in CHCl₃). ¹H NMR (400.1 MHz, CDCl₃/

CHCl₃): δ = 0.24 [s, 6 H, Si(CH₃)₂], 1.34 [dddd, J_{4ЉЈ,3ЉЈ–H(A)}= 13.4,

J_{4ЉЈ,5ЉЈ–H(A)}= 8.7, J_{4ЉЈ,5ЉЈ–H(B)}= 7.9, J_{4ЉЈ,3ЉЈ–H(B)}= 5.3 Hz, 1 H, 4ЉЈ-

H], AB signal (δ_A= 1.66, δ_B= 2.28, J_AB= 14.1 Hz, A part ad-

ditionally split by J_A,6= J_A,4= 11.5 Hz, B part additionally split

by J_B,6= J_B,4= 3.1 Hz, 2 H, 5-H₂), 1.62–1.78 (m, 2 H, 5ЉЈ-H₂), AB

signal (δ_A= 1.77, δ_B= 2.12, J_AB= 14.6 Hz, A part additionally

split by J_A,6ЉЈ= 6.3, J_A,4= 4.5 Hz, B part additionally split by J_B,4

= 8.3, J_B,6ЉЈ= 5.8 Hz, 2 H, 1Љ-H₂), AB signal (δ_A= 2.21, δ_B= 2.41,

J_AB= 16.1 Hz, A part additionally split by J_A,4ЉЈ= 13.3 Hz, B part

20

616 mg, 39%). [α] = +31.4, [α] = +36.2, [α] = +39.3, [α]

589

578

546

436

20

= +65.8, [α]

= +107.3 (c = 0.64 in CHCl₃). ¹H NMR

additionally split by J_B,4ЉЈ= 5.0 Hz, 2 H, 3ЉЈ-H₂), AB signal (δ_A

=

365

(400.1 MHz, CDCl₃/CHCl₃): δ = 0.34 and 0.34 [2 ϫ s, 6 H, 3.20, δ_B= 3.31, J_AB= 10.7 Hz, A part additionally split by J_A,6

Si(CH₃)₂], 1.46 [dddd, J_4,3–H(A)= 13.3, J_4,5–H(A)= 8.8, J_4,5–H(B)

7.9, J_4,3–H(B)= 5.4 Hz, 1 H, 4-H], AB signal (δ_A= 1.66, δ_B= 1.89,

J_AB= 14.4 Hz, A part additionally split by J_A,6= 5.7, J_A,2Ј

=

7.2 Hz, B part additionally split by J_B,6= 4.4 Hz, 2 H, 1Ј-H₂), 4.18

(m_c, 1 H, 4-H), 4.35 [dddd, J_6,5–H(A)= 11.3, J_6,1Ј–H(A)= 7.4, J_6,1Ј–

=

= 4.3, J_6,5–H(B)= 3.3 Hz, 1 H, 6-H], 4.58 [dddd, J_{6ЉЈ,5ЉЈ–H(A)}=

H(B)

3.9 Hz, B part additionally split by J_B,2Ј= 8.5, J_B,6= 7.7 Hz, 2 H,

1Ј-H₂), AB signal (δ_A= 1.74, δ_B= 1.84, J_AB= 14.2 Hz, A part

additionally split by J_A,4= J_A,6= 8.9 Hz, B A part additionally

split J_B,4= 7.9, J_B,6= 4.6 Hz, 2 H, 5-H₂), 2.06 (br. s, 1 H, 2Ј-OH),

AB signal [δ_A= 2.18, δ_B= 2.27, J_AB= 13.9 Hz, A part additionally

12.0, J_{6ЉЈ,1Љ–H(A)}= J_{6ЉЈ,1Љ–H(B)}= 6.0, J_{6ЉЈ,5ЉЈ–H(B)}= 2.6 Hz, 1 H, 6ЉЈ-

H], 7.30–7.38 (m, 3 H, para-H, 2ϫ meta-H), 7.40–7.43 (m, 2 H,

2 ϫ ortho-H) ppm. ¹³C NMR (100.6 MHz, CDCl₃/CDCl₃): δ =

–5.45 and –5.30 [Si(CH₃)₂], 5.32 (C-1Ј), 15.24 (C-4ЉЈ), 28.27 (C-5ЉЈ),

30.06 (C-3ЉЈ), 32.76 (C-5), 39.76 (C-1Љ), 73.36 (C-4), 74.84 (C-6ЉЈ),

2

split by J_A,2Ј= J_A,4Ј= 7.5, J_{A,5Ј–H(trans)}= J_{A,5Ј–H(cis)}= 1.1 Hz, B 77.21 (C-6), 128.31 (2ϫ meta-C), 129.56 (para-C), 133.87 (2ϫ

2

part additionally split by J_B,4Ј= 6.5, J_B,2Ј= 5.1 Hz, J_{B,5Ј–H(trans)}

=

ortho-C), 135.38 (ipso-C), 147.90 (C-2), 172.76 (C-2ЉЈ) ppm. IR

²J_{B,5Ј–H(cis)}= 1.3 Hz, 2 H, 3Ј-H₂], AB signal (δ_A= 2.26, δ_B= 2.44, (film): ν = 2955, 2930, 1745, 1425, 1400, 1375, 1255, 1220, 1190,

˜

J_AB= 16.0 Hz, A part additionally split by J_A,4= 13.3 Hz, B part

additionally split by J_B,4= 5.4 Hz, 2 H, 3-H₂), 3.78 [dddd,

1115, 835, 815, 775, 740, 700 cm^–1. HRMS (CI, NH₃): calcd. for

C₁₉H₂₉NO₅SiI [M + NH₄⁺] 506.0860; found 506.0864 (+0.8 ppm).

J_{2Ј,1Ј–H(B)}= 8.5, J_{2Ј,3Ј–H(A)}= 7.4, J_{2Ј,3Ј–H(B)}= 4.9, J_{2Ј,1Ј–H(B)}

=

tert-Butyl {(R)-1-[(2R,4R)-4-(Dimethylphenylsilyl)-6-oxo-3,4,5,6-

tetra-hydro-2H-pyran-2-yl]pent-4-en-2-yl} Carbonate (30)

3.9 Hz, 1 H, 2Ј-H], 4.33 [dddd, J_6,5–H(A)= 9.0, J_6,1Ј–H(B)= 7.6,

J_6,1Ј–H(A)= 5.5, J_6,5–H(B)= 4.6 Hz, 1 H, 6-H], 5.12 [dddd,

2

4

J_{5Ј-H(trans),4Ј}= 16.9, J_{5Ј-H(trans),5Ј–H(cis)}= 1.9, J_{5Ј-H(trans),3Ј–H(A)}

=

⁴J_{5Ј-H(trans),3Ј–H(B)}= 1.3 Hz, 1 H, 5Ј-H(trans)], 5.14 [dddd, J_{5Ј-H(cis),4Ј}

2

4

= 10.5 Hz, J_{5Ј-H(cis),5Ј–H(trans)}= 2.0, J_{5Ј-H(cis),3Ј –H (A )}

=

⁴J_{5Ј-H(cis),3Ј–H(B)}= 1.1 Hz, 1 H, 5Ј-H(cis)], 5.78 [dddd, J_{4Ј,5Ј–H(trans)}

= 16.9, J_{4Ј,5Ј–H(cis)}= 10.4, J_{4Ј,3Ј–H(A)}= 7.7, J_{4Ј,3Ј–H(B)}= 6.6 Hz, 1 H,

4Ј-H], 7.35–7.43 (m, 3 H, para-H, 2ϫ meta-H), 7.46–7.50 (m, 2 H,

2 ϫ ortho-H) ppm. ¹³C NMR (100.6 MHz, CDCl₃/CDCl₃): δ =

–5.46 and –5.33 [Si(CH₃)₂], 15.10 (C-4), 28.22 (C-5), 30.13 (C-3),

41.48 (C-1Ј), 41.96 (C-3Ј), 68.09 (C-2Ј), 76.79 (C-6), 118.62 (C-5Ј),

128.20 (2ϫ meta-C), 129.78 (para-C), 133.89 (2ϫ ortho-C), 134.19

A solution of 28 (705 mg, 2.21 mmol) in CH₂Cl₂(70 mL) at 0 °C

was treated with NEt₃(370 μL, 291 mg, 2.88 mmol, 1.3 equiv.),

Boc₂O (1.90 mL, 1.93 g, 8.85 mmol, 4.0 equiv.) and DMAP (54 mg,

0.44 mmol, 20 mol-%) and was stirred at room temp. for 16 h. After

the addition of aq. KHSO₄(5%, 20 mL), the phases were separated

and the aq. phase was extracted with tBuOMe (3ϫ 20 mL). The

combined organic phases were washed with brine (20 mL) and

dried with MgSO₄. After evaporation of the solvent the residue

was purified by flash chromatography^[34](2.5 cmϫ20.5 cm, 20 mL,

cyclohexane/AcOEt, 6:1) to yield 30 (fractions 8–18, 797 mg, 86%)

(C-4Ј), 135.70 (ipso-C), 173.21 (C-2) ppm. IR (film): ν = 3425,

˜

3070, 2950, 1730, 1640, 1430, 1260, 1215, 1165, 1115, 1070, 915,

835, 815, 775, 735 cm^–1. C₁₈H₂₆O₃Si (318.48): calcd. C 67.88, H

8.23; found C 67.50, H 8.39. HRMS (CI, NH₃): calcd. for

C₁₈H₃₀NO₃Si [M + NH₄⁺] 336.1995; found 336.1988 (–2.1 ppm).

20

as a colorless oil. [α]

= +29.9, [α]

= +31.7, [α]

= +37.3,

(4S,6S)-4-{[(4R,4R)-4-(Dimethylphenylsilyl)-6-oxo-3,4,5,6-tetra-

hydro-2H-pyran-2-yl]methyl}-6-(iodomethyl)-1,3-dioxan-2-one (29)

589

578

546

[α]

= +68.9, [α]

= +126.3 (c = 0.48 in CHCl₃). ¹H NMR

20

436

365

(400.1 MHz, CDCl₃/CHCl₃): δ = 0.33 and 0.33 [2 ϫ s, 6 H,

Si(CH₃)₂], 1.33–1.50 (m, 1 H, 4Љ-H), 1.47 [s, 9 H, 2-(CH₃)₃], AB

signal (δ_A= 1.70, δ_B= 1.87, J_AB= 14.0 Hz, A part additionally

split by J_A,4Љ= J_A,6Љ= 9.1 Hz, B part additionally split by J_B,4Љ

=

7.6, J_B,6Љ= 4.4 Hz, 2 H, 5Љ-H₂), 1.77 [ddd, J_{1Ј-H(A),1Ј–H(B)}= 14.5,

J_1Ј-H(A),6Љ= 6.9, J_1Ј-H(A),2Ј= 4.3 Hz, 1 H, 1Ј-H_A], 2.07–2.18 (m, 1

H, 1Ј-H_B), AB signal (δ_A= 2.23, δ_B= 2.41, J_AB= 15.9 Hz, A part

additionally split by J_A,4Љ= 13.1 Hz, B part additionally split by

J_B,4Љ= 5.6 Hz, 2 H, 3Љ-H₂), 2.32–2.41 (m, 2 H, 3Ј-H₂), 4.26 [dddd,

J_{6Љ,5Љ–H(A)}= 9.2, J_{6Љ,1Ј–H(A)}= J_{6Љ,1Ј–H(B)}= 6.6, J_{6Љ,5Љ–H(B)}= 4.4 Hz, 1

H, 6Љ-H], 4.79 [dddd, J_{2Ј,1Ј–H(B)}= 8.2, J_{2Ј,3Ј–H(A)}= J_{2Ј,3Ј–H(B)}= 6.2,

A solution of 30 (600 mg, 1.43 mmol) in acetonitrile (35 mL) was

cooled to –20 °C and iodine (1.09 g, 4.30 mmol, 3.0 equiv.) was

added. The resulting mixture was stirred at –20 °C overnight. After

the completion of the reaction (monitored by TLC), the reaction

was quenched by the addition of aq. Na₂S₂O₃(20%, 10 mL) and

aq. NaHCO₃(5%, 10 mL). The phases were separated and the aq. J_{2Ј,1Ј–H(A)}= 4.5 Hz, 1 H, 2Ј-H], 5.04–5.15 (m, 2 H, 5Ј-H₂) 5.74

layer was extracted with AcOEt (3ϫ 15 mL). The combined or-

ganic layers were washed with brine (15 mL), dried with MgSO₄,

and concentrated under reduced pressure. Flash chromatography^[34]

(4.5 cmϫ16.0 cm, 50 mL, cyclohexane/AcOEt, 1:1) provided the ti-

tle compound (fractions 12–21, 658 g, 94%) as a pale yellow oil.

[dddd, J_{4Ј,5Ј–H(trans)}= 17.5, J_{4Ј,5Ј–H(cis)}= 9.8, J_{4Ј,3Ј–H(A)}= J_{4Ј,3Ј–H(B)}

= 7.2 Hz, 1 H, 4Ј-H], 7.34–7.42 (m, 3 H, para-H, 2ϫ meta-H),

7.43–7.50 (m, 2 H, 2 ϫ ortho-H) ppm. ¹³C NMR (100.6 MHz,

CDCl₃/CDCl₃): δ = –5.44 [Si(CH₃)₂], 15.05 (C-4Љ), 27.87 (C₃-2),

28.02 (C-5Љ), 30.07 (C-3Љ), 38.71 (C-1Ј), 38.85 (C-3Ј), 72.89 (C-2Ј),

Eur. J. Org. Chem. 2014, 3210–3224

www.eurjoc.org

3219

P. Walleser, R. Brückner

FULL PAPER

74.98 (C-6Љ), 82.33 (C-1), 118.66 (C-5Ј), 128.24 (2 ϫ meta-C), 1200, 1170, 1115, 1090, 1025, 975, 940, 835, 815, 775, 740 cm^–1.

129.80 (para-C), 132.91 (C-4Ј), 133.89 (2ϫ ortho-C), 135.72 (ipso- C₂₇H₃₆O₄SSi (484.72): calcd. C 66.90, H 7.49, S 6.62; found C

C), 153.09 [O(C=O)OtBu], 173.20 (C-2Љ) ppm. IR (film): ν = 3070,

67.06, H 7.64, S 6.34. HRMS (CI, NH₃): calcd. for C₂₇H₄₀NO₄SSi

[M + NH₄⁺] 502.2447; found 502.2449 (+0.3 ppm).

˜

2980, 1740, 1645, 1430, 1395, 1370, 1280, 1255, 1165, 1115, 1095,

920, 880, 835, 815, 775, 735, 700, 665 cm^–1. C₂₃H₃₄O₅Si (418.60):

calcd. C 65.99, H 8.19; found C 65.86, H 8.16. HRMS (CI, NH₃):

calcd. for C₂₃H₃₈NO₅Si [M + NH₄⁺] 436.2519; found 436.2524

(+1.1 ppm).

(4R,6R)-4-(Dimethylphenylsilyl)-6-{[(4S,6S)-6-(iodomethyl)-2,2-di-

methyl-1,3-dioxan-4-yl]methyl}-3,4,5,6-tetrahydro-2H-pyran-2-one

(32)

(4R,6R)-4-(Dimethylphenylsilyl)-6-{[(4S,6S)-2,2-dimethyl-6-(phenyl-

sulfanylmethyl)-1,3-dioxan-4-yl]methyl}-3,4,5,6-tetrahydro-2H-pyr-

an-2-one (31)

A solution of 6 (450 mg, 921 μmol) in acetone (35 mL) was treated

with pTsOH·H₂O (210 mg, 1.11 mmol, 1.2 equiv.) at room temp.

After 4 d at this temp. imidazole (82 mg, 1.2 mmol, 1.3 equiv.) was

added followed by the addition of silica gel (3 g) 5 min later. The

solvent was removed under reduced pressure and the obtained silica

pad was added on the top of the column. Flash chromatography^[34]

(4.0 cmϫ17.0 cm, 50 mL, cyclohexane/AcOEt, 4:1) provided the

title compound (fractions 7–20, 426 mg, 92%) as a colorless oil.

A suspension of washed NaH (48 mg, 2.0 mmol, 2.4 equiv.) in THF

(4 mL) was cooled to 0 °C. PhSH (0.22 mL, 0.23 g, 2.1 mmol,

2.5 equiv.) was added dropwise. After complete addition the cool-

ing bath was removed and the reaction mixture was stirred for

30 min at room temp. The resulting suspension was then transfer-

red to a solution of 32 (420 mg, 836 μmol) in THF (18 mL) at 50 °C

for 1.5 h. Thereafter the reaction mixture was cooled to room temp.

and quenched by addition of satd. aq. NH₄Cl (10 mL) and H₂O

(5 mL). The phases were separated, and the aq. phase was extracted

with tBuOMe (3ϫ 10 mL). The combined organic extracts were

washed with brine (10 mL), and dried with MgSO₄. The solvent

was removed under reduced pressure, and the residue was purified

by flash chromatography^[34](2.5 cm ϫ19.0 cm, 20 mL, cyclohex-

ane/AcOEt, 6:1) to yield 31 (fractions 7–18, 405 mg, 99%) as a

20

[α] = +38.6, [α] = +40.5, [α] = +46.6, [α] = +88.7, [α]

589

578

546

436

365

= +160.2 (c = 0.87 in CHCl₃). ¹H NMR (400.1 MHz, CDCl₃/

CHCl₃): δ = 0.34 and 0.34 [s, 6 H, Si(CH₃)₂], AB signal (δ_A= 1.09,

δ_B= 1.75, J_AB= 12.6 Hz, A part additionally split by J_A,4Љ= J_A,6Љ

= 11.4 Hz, B part additionally split by J_B,4Љ= J_B,6Љ= 2.5 Hz, 2 H,

5Љ-H₂), 1.38 [s, 6 H, 2Љ-(CH₃)₂], 1.46 [dddd, J_4,3–H(A)= 13.1,

J_4,5–H(A)= 8.7, J_4,5–H(B)= 7.8, J_4,3–H(B)= 5.5 Hz, 1 H, 4-H], AB

signal (δ_A= 1.58, δ_B= 2.03, J_AB= 14.1 Hz, A part additionally

split by J_A,6= J_A,4Љ= 6.1 Hz, B part additionally split by J_B,6

J_B,4Љ= 7.1 Hz, 2 H, 1Ј-H₂), AB signal (δ_A= 1.71, δ_B= 1.82, J_AB

=

14.2 Hz, A part additionally split by J_A,6= 8.8, J_A,4= 8.7 Hz, B

part additionally split by J_B,4= 7.6, J_B,6= 4.4 Hz, 2 H, 5-H₂), AB

signal (δ_A= 2.27, δ_B= 2.45, J_AB= 16.0 Hz, A part additionally

split by J_A,4= 13.1 Hz, B part additionally split by J_B,4= 5.4 Hz,

2 H, 3-H₂), AB signal (δ_A= 3.08, δ_B= 3.15, J_AB= 10.0 Hz, A part

additionally split by J_A,6Љ= 6.1 Hz, B part additionally split by J_B,6Љ

20

colorless oil. [α] = +28.5, [α] = +28.7, [α] = +33.0, [α] =

589

578

546

436

20

+64.1, [α] = +118.0 (c = 0.42 in CHCl₃). ¹H NMR (400.1 MHz,

365

CDCl₃/CHCl₃): δ = 0.33 and 0.33 [s, 6 H, Si(CH₃)₂], AB signal (δ_A

= 1.15, δ_B= 1.69, J_AB= 12.7 Hz, A part additionally split by J_A,4Љ

= J_A,6Љ= 11.5 Hz, B part additionally split by J_B,4Љ= J_B,6Љ= 2.5 Hz,

2 H, 5Љ-H₂), 1.34 and 1.35 [2 ϫ s, 6 H, 2Љ-(CH₃)₂], 1.45 [dddd,

J_4,3–H(A)= 13.2, J_4,5–H(A)= 8.7, J_4,5–H(B)= 7.7, J_4,3–H(B)= 5.5 Hz,

1 H, 4-H], AB signal (δ_A= 1.56, δ_B= 2.01, J_AB= 14.0 Hz, A part

additionally split by J_A,6= J_A,4Љ= 6.2 Hz, B part additionally split

= 5.7 Hz, 2 H, 1ЉЈ-H₂), 3.82 [dddd, J_{6Љ,5Љ–H(A)}= 11.5, J_{6Љ,1ЉЈ–H(A)}

J_{6Љ,1ЉЈ–H(B)}= 5.8, J_{6Љ,5Љ–H(B)}= 2.5 Hz, 1 H, 6Љ-H], 3.98 [dddd,

J_{4Љ,5Љ–H(A)}= 11.3, J_{4Љ,1Ј–H(B)}= 7.1, J_{4Љ,1Ј–H(A)}= 5.9, J_{4Љ,5Љ–H(B)}

=

2.4 Hz, 1 H, 4Љ-H], 4.29 [dddd, J_6,5–H(A)= 8.9, J_6,1Ј–H(B)= 7.1,

J_6,1Ј–H(A)= 6.3, J_6,5–H(B)= 4.4 Hz, 1 H, 6-H], 7.35–7.42 (m, 3 H,

para-H, 2ϫ meta-H), 7.45–7.49 (m, 2 H, 2ϫ ortho-H) ppm. ¹³C

NMR (100.6 MHz, CDCl₃/CDCl₃): δ = –5.47 and –5.27

[Si(CH₃)₂], 9.24 (C-1ЉЈ), 15.10 (C-4), 19.90 and 29.94 [2Љ-(CH₃)₂],

28.04 (C-5), 30.16 (C-3), 36.34 (C-5Љ), 41.15 (C-1Ј), 65.30 (C-4Љ),

69.09 (C-6Љ), 74.53 (C-6), 99.43 (C-2Љ), 128.26 (2ϫ meta-C), 129.86

(para-C), 133.88 (2ϫ ortho-C), 135.73 (ipso-C), 173.35 (C-2) ppm.

by J_B,6= J_B,4Љ= 7.1 Hz, 2 H, 1Ј-H₂), AB signal (δ_A= 1.70, δ_B

1.80, J_AB= 14.1 Hz, A part additionally split by J_A,6= 8.9, J_A,4

8.8 Hz, B part additionally split by J_B,4= 7.7, J_B,6= 4.4 Hz, 2 H,

5-H₂), AB signal (δ_A= 2.26, δ_B= 2.44, J_AB= 16.0 Hz, A part

additionally split by J_A,4= 13.1 Hz, B part additionally split by

=

J_B,4= 5.4 Hz, 2 H, 3-H₂), AB signal (δ_A= 2.86, δ_B= 3.09, J_AB

=

13.4 Hz, A part additionally split by J_A,6Љ= 6.7 Hz, B part ad-

ditionally split by J_B,6Љ= 5.8 Hz, 2 H, 1ЉЈ-H₂), 3.94 [m_c, approxi-

mately interpretable as dddd, J_{6Љ,5Љ–H(A)}= 11.3, J_{6Љ,1ЉЈ–H(A)}= 6.5,

J_{6Љ,1ЉЈ–H(B)}= 5.5, J_{6Љ,5Љ–H(B)}= 2.6 Hz, 1 H, 6Љ-H], 3.95 [m_c, approxi-

mately interpretable as dddd, J_{4Љ,5Љ–H(A)}= 11.4, J_{4Љ,1Ј–H(B)}= 7.5,

J_{4Љ,1Ј–H(A)}= 5.9, J_{4Љ,5Љ–H(B)}= 2.2 Hz, 1 H, 4Љ-H], 4.27 [dddd,

J_6,5–H(A)= 9.0, J_6,1Ј–H(B)= 6.9, J_6,1Ј–H(A)= 6.4, J_6,5–H(B)= 4.5 Hz,

1 H, 6-H], 7.18 (m_c, 1 H, paraЈ-H), 7.25–7.31 (m, 2 H, 2ϫ metaЈ-

H), 7.33–7.40 (m, 5 H, para-H, 2ϫ meta-H, 2ϫ orthoЈ-H), 7.45–

7.49 (m, 2 H, 2ϫ ortho-H) ppm. ¹³C NMR (100.6 MHz, CDCl₃/

CDCl₃): δ = –5.49 and –5.28 [Si(CH₃)₂], 15.08 (C-4), 19.81 and

30.06 [2Љ-(CH₃)₂], 27.99 (C-5), 30.15 (C-3), 35.87 (C-5Љ), 39.50 (C-

1ЉЈ), 41.27 (C-1Ј), 65.33 (C-4Љ), 68.27 (C-6Љ), 74.57 (C-6), 99.05 (C-

2Љ), 126.23 (paraЈ-H), 128.24 (2ϫ meta-C), 129.03 (2ϫ metaЈ-C),

129.38 (2ϫ orthoЈ-C), 129.82 (para-C), 133.87 (2ϫ ortho-C), 135.75

IR (film): ν = 2990, 2950, 1740, 1430, 1380, 1255, 1200, 1165, 1115,

˜

975, 940, 880, 835, 815, 775, 735, 700 cm^–1. HRMS (CI, NH₃):

calcd. for C₂₁H₃₂O₄SiI [M + H⁺] 503.1115; found 503.1109 (δ =

–1.1 ppm).

(3R,4R,6R)-4-(Dimethylphenylsilyl)-6-{[(4S,6S)-2,2-dimethyl-6-

(phenylsulfanylmethyl)-1,3-dioxan-4-yl]methyl}-3-[(S)-1-hydroxy-

hexyl]-3,4,5,6-tetrahydro-2H-pyran-2-one (33)

(ipso-C), 136.35 (ipsoЈ-C), 173.39 (C-2) ppm. IR (film): ν = 3070,

2990, 2950, 2350, 1745, 1585, 1480, 1440, 1430, 1380, 1305, 1260,

nBuLi (2.37 m in n-hexane, 0.14 mL, 0.34 mmol, 1.25 equiv.) was

added to a solution of iPr₂NH (0.05 mL, 35.3 mg, 0.35 mmol,

˜

3220

www.eurjoc.org

Eur. J. Org. Chem. 2014, 3210–3224

Sultone-Forming RCM for a Protection of Homoallylic Alcohols

1.3 equiv.) in Et₂O (4 mL) at –78 °C. The resulting mixture was

stirred for 60 min at this temp. and then cooled to –78 °C. A solu-

tion of 31 (130 mg, 268 mmol) in Et₂O (1.5 mL) was added drop-

wise. After 2 h, solid CpTiCl₃(88 mg, 0.4 mmol, 1.4 equiv.) was

added in one portion and the resulting dark red solution was stirred

for 24 h at –78 °C. Then n-hexanal (0.08 mL, 58.5 mg, 0.59 mmol,

2.2 equiv.) was added slowly and the resulting yellow suspension

was stirred for an additional 24 h at –78 °C. The reaction mixture

was quenched by addition of satd. aq. NH₄Cl (3 mL), and was

warmed to room temp. under vigorous stirring. Next brine (3 mL)

and AcOEt (5 mL) were added and the phases were separated. The

aq. phase was extracted with AcOEt (3ϫ 5 mL). The combined

organic extracts were washed with brine (3 mL), and dried with

MgSO₄. The solvent was removed under reduced pressure, and the

residue was purified by flash chromatography^[34](2.0 cmϫ18.0 cm,

20 mL, cyclohexane/AcOEt, 6:1) provided the title compound

0.56 mL, 0.56 mmol, 4.5 equiv.) was added slowly. After 1.5 h the

reaction mixture was quenched by addition of satd. aq. Na/K

tartrate (3.0 mL) and warmed to room temp. under vigorous stir-

ring. The phases were separated and the aq. phase was extracted

with AcOEt (3 ϫ 3 mL). The combined organic phases were

washed consecutively with satd. aq. Na/K tartrate (3.0 mL), H₂O

(3 mL) and brine (20 mL), and dried with MgSO₄. The solvent was

removed under reduced pressure and hemiacetal 35 (cf. Scheme 7;

66 mg, 90%) could be obtained without further purification as a

pale yellow oil.

Hemiacetal 35 (cf. Scheme 7; 66 mg, 0.11 mmol) was dissolved in

MeOH (3 mL). PPTS (5.6 mg, 22 μmol, 20 mol-%) was added at

room temp. The reaction mixture was stirred at this temp. until all

of the starting material was converted (monitored by TLC, approxi-

mately 1.5–3.5 h). Next, imidazole (82 mg, 1.2 mmol, 1.3 equiv.)

was added to the reaction mixture followed by the addition of silica

gel (500 mg) after 5 min. The solvent was removed under reduced

pressure and the obtained silica pad was added on the top of the

column. Flash chromatography^[34](1.5 cmϫ19.5 cm, 7 mL, cyclo-

hexane/AcOEt, 8:1) provided the title compound (fractions 8–17,

20

(fractions 10–20, 128 mg, 82%) as a colorless oil. [α] = [α]

=

589

578

20

[α]

546

= [α]

= Ϯ0 (c = 0.58 in CHCl₃). ¹H NMR

436

365

(400.1 MHz, CDCl₃/CHCl₃): δ = 0.38 and 0.40 [s, 6 H, Si(CH₃)₂],

1.13 (t, J_6Ј,5Ј= 7.1 Hz, 3 H, 6Ј-H₃), AB signal (δ_A= 1.13, δ_B= 1.63,

J_AB= 12.7 Hz, A part additionally split by J_A,4ЉЈ= J_A,6ЉЈ= 11.5 Hz,

B part additionally split by J_B,4ЉЈ= J_B,6ЉЈ= 2.4 Hz, 2 H, 5ЉЈ-H₂),

1.14–1.32 (m, 7 H, 4-H, 2Ј-H_A, 3Ј-H_A, 4Ј-H₂, 5Ј-H₂), 1.32 and 1.36

[2ϫ s, 6 H, 2ЉЈ-(CH₃)₂], 1.40–1.52 (m, 2 H, 2Ј-H_B, 3Ј-H_B), AB sig-

nal (δ_A= 1.52, δ_B= 1.97, J_AB= 14.3 Hz, A part additionally split

20

43 mg, 63%) as a colorless oil. [α] = +2.5, [α] = +3.3, [α] =

589

578

546

+19.3, [α] = +31.9, [α] = +47.1 (c = 0.37 in CHCl₃). ¹H NMR

20

436

365

(400.1 MHz, C₆D₆/C₆D₅H): δ = 0.46 and 0.48 [s, 6 H, Si(CH₃)₂],

0.88 (t, J_6,5= 7.0 Hz, 3 H, 6-H₃), 1.11 [ddd, J_{5ЉЈ-H(A),5ЉЈ–H(B)}= 12.7,

J_{5ЉЈ-H(A),4ЉЈ}= J_{5ЉЈ-H(A),6ЉЈ}= 11.4 Hz, 1 H, 5ЉЈ-H_A], 1.13–1.97 (m, 14

H, 2-H₂, 3-H₂, 4-H₂, 5-H₂, 4Ј-H, 5Ј-H₂, 1Љ-H₂, 5ЉЈ-H_B), 1.23 and

by J_A,4= J_A,6= 7.1 Hz, B part additionally split by J_B,4= J_B,6

=

6.0 Hz, 2 H, 5-H₂), AB signal (δ_A= 1.79, δ_B= 1.89, J_AB= 14.3 Hz,

A part additionally split by J_A,6= 9.3, J_A,4ЉЈ= 7.3 Hz, B part ad-

ditionally split by J_B,4ЉЈ= 5.2, J_B,6= 3.5 Hz, 2 H, 1Љ-H₂), 2.77 (dd,

1.49 [2ϫ s, 6 H, 2ЉЈ-(CH₃)₂], 1.67 (ddd, J_3Ј,1= 4.5, J_3Ј,2Ј= J_3Ј,4Ј

=

1.5 Hz, 3Ј-H), AB signal (δ_A= 2.73, δ_B= 3.08, J_AB= 13.2 Hz, A

part additionally split by J_A,6ЉЈ= 6.5 Hz, B part additionally split

by J_B,6ЉЈ= 5.8 Hz, 2 H, 1ЉЉ-H₂), 3.12 (s, 3 H, OCH₃), 3.69 [dddd,

J_3,4= 7.8, J_3,1Ј= 3.9 Hz, 1 H, 3-H), AB signal (δ_A= 2.86, δ_B

=

3.09, J_AB= 13.3 Hz, A part additionally split by J_A,6ЉЈ= 6.6 Hz, B

part additionally split by J_B,6ЉЈ= 5.8 Hz, 2 H, 1ЉЉ-H₂), 3.11 (br. d,

J_1Ј-OH,1Ј= 10.2 Hz, 1 H, 1Ј-OH), 3.54 [dddd, J_1Ј,1Ј–OH= J_{1Ј,2Ј–H(A)}

= 10.1, J_1Ј,3= 3.6, J_{1Ј,2Ј–H(B)}= 2.9 Hz, 1 H, 1Ј-H], 3.91 [m_c, approxi-

mately interpretable as dddd, J_{4ЉЈ,5ЉЈ–H(A)}= 11.3, J_{4ЉЈ,1Љ–H(A)}= 7.4,

J_{4ЉЈ,1Љ–H(B)}= 5.5, J_{4ЉЈ,5ЉЈ–H(B)}= 2.4 Hz, 1 H, 4ЉЈ-H], 3.94 [m_c, approx-

imately interpretable as dddd, J_{6ЉЈ,5ЉЈ–H(A)}= 11.3, J_{6ЉЈ,1ЉЉ–H(A)}= 6.6,

J_{6ЉЈ,1ЉЉ–H(B)}= 6.0, J_{6ЉЈ,5ЉЈ–H(B)}= 2.3 Hz, 1 H, 6ЉЈ-H], 4.31 [dddd,

J_6,1Љ–H(A)= 9.6, J_6,5–H(A)= 6.8, J_6,5–H(B)= 6.2, J_6,1Љ–H(B)= 3.3 Hz,

1 H, 6-H], 7.19 (m_c, 1 H, paraЈ-H), 7.26–7.31 (m, 2 H, 2ϫ metaЈ-

H), 7.34–7.40 (m, 5 H, para-H, 2ϫ meta-H, 2ϫ orthoЈ-H), 7.46–

7.51 (m, 2 H, 2ϫ ortho-H) ppm. ¹³C NMR (100.6 MHz, CDCl₃/

CDCl₃): δ = –4.11 and –3.91 [Si(CH₃)₂], 14.12 (C-6Ј), 18.35 and

19.81 [2ЉЈ-(CH₃)₂], 22.70 (C-4), 26.06 (C-5Ј), 28.77 (C-1Љ), 30.07 (C-

3Ј), 31.83 (C-4Ј), 32.35 (C-2Ј), 35.84 (C-5ЉЈ), 39.48 (C-1ЉЉ), 41.59

(C-5), 46.08 (C-3), 65.17 (C-4ЉЈ), 68.23 (C-6ЉЈ), 73.69 (C-1Ј), 75.03

(C-6), 99.06 (C-2ЉЈ), 126.24 (paraЈ-H), 128.41 (2ϫ meta-C), 129.05

(2ϫ metaЈ-C), 129.34 (2ϫ orthoЈ-C), 129.94 (para-C), 133.80 (2ϫ

ortho-C), 136.37 (ipsoЈ-C), 136.49 (ipso-C), 174.85 (C-2) ppm. IR

J_{4ЉЈ,5ЉЈ–H(A)}= 11.1, J_{4ЉЈ,1Љ–H(A)}= 8.5, J_{4ЉЈ,1Љ–H(B)}= 4.9, J_{4ЉЈ,5ЉЈ–H(B)}

2.5 Hz, 1 H, 4ЉЈ-H], 3.76 [m_c, approximately interpretable as ddd,

J_1,2–H(A)= 8.3, J_1,3Ј= 4.3, J_1,2–H(B)= 4.2 Hz, 1 H, 1-H], 3.84 [dddd,

=

J_{6ЉЈ,5ЉЈ–H(A)}= 11.4, J_{6ЉЈ,1ЉЉ–H(A)}= 6.3, J_{6ЉЈ,1ЉЉ–H(B)}= 6.0, J_{6ЉЈ,5ЉЈ–H(B)}

=

2.4 Hz, 1 H, 6ЉЈ-H], 4.00 [dddd, J_{6Ј,1Љ–H(A)}= 10.7, J_{6Ј,5Ј–H(A)}= 7.3,

J_{6Ј,5Ј–H(B)}= 6.8, J_{6Ј,1Љ–H(B)}= 3.1 Hz, 1 H, 6Ј-H], 4.54 (br. s, 2Ј-H),

6.91 (m_c, 1 H, paraЈ-H), 6.99–7.40 (m, 2 H, 2ϫ metaЈ-H), 7.18–

7.28 (m, 3 H, para-H, 2ϫ meta-H), 7.30–7.33 (m, 2 H, 2ϫ orthoЈ-

H), 7.60–7.64 (m, 2 H, 2ϫ ortho-H) ppm. ¹³C NMR (100.6 MHz,

C₆D₆/C₆D₅H): δ = –3.01 and –2.76 [Si(CH₃)₂], 14.12 (C-6), 17.29

and 19.67 [2ЉЈ-(CH₃)₂], 23.05 (C-4Ј), 26.02 (C-5), 28.05 (C-3), 30.38

(C-4), 32.33 (C-2), 35.10 (C-1Љ), 36.72 (C-5ЉЈ), 39.66 (C-1ЉЉ), 42.49

(C-5Ј), 42.75 (C-3Ј), 53.77 (2-OCH₃), 63.42 (C-2), 65.72 (C-4ЉЈ),

68.82 (C-6ЉЈ), 73.91 (C-6Ј), 98.93 (C-2ЉЈ), 102.17 (C-2Ј), 125.99

(paraЈ-H), 128.65 (2ϫ meta-C), 129.09 (2ϫ metaЈ-C), 129.16 (2ϫ

orthoЈ-C), 129.24 (para-C), 134.37 (2ϫ ortho-C), 137.58 (ipsoЈ-C),

139.97 (ipso-C) ppm. IR (film): ν = 3435, 3070, 2990, 2930, 2860,

˜

1585, 1480, 1440, 1425, 1380, 1260, 1110, 1045, 1025, 950, 835,

815, 775, 735, 700, 640, 610 cm^–1.

(film): ν = 3420, 3070, 3050, 2990, 2950, 2930, 2870, 1715, 1585,

˜

1480, 1440, 1430, 1380, 1305, 1260, 1200, 1165, 1115, 1090, 1025,

(3S,4R,6S)-6-{[(4S,6S)-2,2-Dimethyl-6-(phenylsulfanylmethyl)-1,3-

dioxan-4-yl]methyl}-3-[(S)-1-hydroxyhexyl]-2-methoxytetra-

hydro-2H-pyran-4-ol (36)

1000, 975, 940, 880, 835, 815, 775, 740, 700, 690 cm^–1.

(S)-1-{(3R,4R,6R)-4-(Dimethylphenylsilyl)-6-{[(4S,6S)-2,2-dimeth-

yl-6-(phenylsulfanylmethyl)-1,3-dioxan-4-yl]methyl}-2-methoxy-

3,4,5,6-tetrahydro-2H-pyran-3-yl}hexan-1-ol (34)

A suspension of KH (22 mg, 0.55 mmol, 6.1 equiv.) in NMP

(1.5 mL) at 0 °C was treated dropwise with tBuOOH (3.15 m in

toluene, 0.17 mL, 0.55 mmol, 6.1 equiv.). After warming to room

temp. a solution of 34 (54 mg, 90 μmol) in NMP (3.0 mL) was

added. After 10 min at room temp. KF (11 mg, 0.19 mmol,

A solution of lactone 33 (73 mg, 0.12 mmol) in toluene/n-hexane

[6 mL, 1:1 (v:v)] was cooled to –78 °C. DIBAH (1.0 m in n-hexane,

Eur. J. Org. Chem. 2014, 3210–3224

www.eurjoc.org

3221

P. Walleser, R. Brückner

FULL PAPER

2.1 equiv.) was added in one portion, the reaction mixture was

heated at 60 °C for 1.5 h, and then quenched by addition of satd.

aq. Na₂S₂O₃(1 mL). The phases were separated and the aq. phase

was extracted with AcOEt (3 ϫ 2 mL). The combined organic

phases were washed consecutively with H₂O (3.0 mL) and brine

(3.0 mL), and were dried with MgSO₄. The solvent was evaporated

under reduced pressure and the residue was purified by flash

chromatography^[34](1.5 cmϫ15 cm, 7.0 mL, cyclohexane/AcOEt,

2:1) to afford 36 (fractions 11–21, 29 mg, 66%) as a colorless oil.

and 1.40 [2ϫ s, 6 H, 2ЉЉ-(CH₃)₂], 1.41–1.66 (m, 6 H, 2Ј-H₂, 3Ј-H_B,

5Љ-H₂, 1ЉЈ-H_A), 1.77 (ddd, J_3Љ,1Ј= J_3Љ,4Љ= 5.5, J_3Љ,2Љ= 2.9 Hz, 1 H,

3Љ-H), 1.85 [dd, J_{1ЉЈ-H(B),1ЉЈ–H(A)}= 13.6, J_B,6Љ= 8.1, J_B,4ЉЉ= 6.3 Hz,

1 H, 1ЉЈ-H_B], 1.77 (ddd, J_3Љ,1Ј= J_3Љ,4Љ= 5.5, J_3Љ,2Љ= 2.9 Hz, 1 H, 3Љ-

H), AB signal (δ_A= 2.88, δ_B= 3.12, J_AB= 13.2 Hz, A part ad-

ditionally split by J_A,6ЉЉ= 6.8 Hz, B part additionally split by J_B,6ЉЉ

= 5.9 Hz, 2 H, 1ЉЉЉ-H₂), 3.29 (s, 3 H, OCH₃), 3.79 [m_c, approxi-

mately interpretable as ddd, J_{1Ј,2Ј–H(A)}= J_{1Ј,2Ј–H(B)}= J_1Ј,3Љ= 5.7 Hz,

1 H, 1Ј-H], 3.95–4.06 (m, 3 H, 4Љ-H, 4ЉЉ-H, 6ЉЉ-H), 4.16 [m_c, ap-

proximately interpretable as dddd, J_{6Љ,5Љ–H(A)}= J_{6Љ,1ЉЈ–H(A)}= 8.2,

20

[α] = [α] = [α] = [α] = [α] = Ϯ0 (c = 0.26 in CHCl₃).

589

578

546

436

365

¹H NMR (400.1 MHz, CDCl₃/CHCl₃): δ = 0.89 (t, J_6Ј,5Ј= 6.8 Hz,

3 H, 6Ј-H₃), 1.20–1.37 (m, 6 H, 3Ј-H_A, 4Ј-H₂, 5Ј-H₂, 5ЉЈ-H_A), 1.39 2.8 Hz, 1 H, 2Љ-H), 7.17 (m_c, 1 H, para-H), 7.24–7.30 (m, 2 H, 2ϫ

and 1.41 [2ϫ s, 6 H, 2ЉЈ-(CH₃)₂], 1.43–1.62 (m, 4 H, 5-H_A, 2Ј-H₂, meta-H), 7.33–7.37 (m,

H, 2ϫ ortho-H) ppm. ¹³C NMR

3Ј-H_B), 1.67–1.96 (m, 5 H, 3-H, 5-H_B, 1Љ-H₂, 5ЉЈ-H_B), AB signal (100.6 MHz, CDCl₃/CDCl₃): δ = –4.50 and –4.32 and –4.12 [2Ј-

J_{6Љ,5Љ–H(B)}= J_{6Љ,1ЉЈ–H(B)}= 4.8 Hz, 1 H, 6Љ-H], 4.54 (br. d, J_2Љ,3Љ=

2

(δ_A= 2.87, δ_B= 3.13, J_AB= 13.2 Hz, A part additionally split by

J_A,6ЉЈ= 7.0 Hz, B part additionally split by J_B,6ЉЈ= 5.6 Hz, 2 H,

1ЉЉ-H₂), 3.40 (s, 3 H, OCH₃), 3.72 [m_c, approximately interpretable

as dddd J_{1Ј,2Ј–H(A)}= 7.9, J_{1Ј,2Ј–H(B)}= 6.7, J_1Ј,3= 4.0 Hz, 1 H, 1Ј-

OSi(CH₃)₂and 4Љ-OSi(CH₃)₂], 14.15 (C-6Ј), 19.85 and 30.16 [2ЉЉ-

(CH₃)₂], 17.98 and 18.19 (C-2 und C-1ЉЉЈ), 22.75 (C-5Ј), 24.77 (C-

3Ј), 25.85 and 26.01 (C₃-2 und C₃–2ЉЉЈ), 32.18 (C-4Ј), 34.38 (C-2Ј),

36.13 (C-1ЉЈ), 36.99 (C-5ЉЉ), 39.57 (C-1ЉЉЉ), 42.16 (C-5Љ), 50.47 (C-

3Љ), 55.27 (2Љ-OCH₃), 61.70 (C-6Љ), 64.90 (C-4Љ), 66.05 (C-4ЉЉ),

68.56 (C-6ЉЉ), 71.40 (C-1Ј), 99.00 (C-2ЉЉ), 100.08 (C-2Љ), 126.10

(para-H), 129.97 (2ϫmeta-C), 129.25 (2ϫortho-C), 136.58 (ipso-

H], 3.98 [m_c, approximately interpretable as dddd, J_{6ЉЈ,5ЉЈ–H(A)}

11.3, J_{6ЉЈ,1ЉЉ–H(A)}= 7.2, J_{6ЉЈ,1ЉЉ–H(B)}= 5.7, J_{6ЉЈ,5ЉЈ–H(B)}= 2.3 Hz, 1 H,

6ЉЈ-H], 4.01 [m_c, approximately interpretable as dddd, J_{4ЉЈ,5ЉЈ–H(A)}

=

11.3, J_{4ЉЈ,1Љ–H(A)}= 6.7, J_{4ЉЈ,1Љ–H(B)}= 6.3, J_{4ЉЈ,5ЉЈ–H(B)}= 2.2 Hz, 1 H, C) ppm. IR (film): ν = 3060, 2950, 2930, 2855, 1740, 1645, 1585,

˜

4ЉЈ-H], 4.13–4.21 (m, 2 H, 4-H, 6-H), 4.69 (br. s, 1 H, 2-H), 7.17 1470, 1465, 1440, 1380, 1360, 1255, 1200, 1170, 1090, 1055, 975,

(m_c, 1 H, para-H), 7.25–7.30 (m, 2 H, 2ϫ meta-H), 7.32–7.37 (m, 950, 875, 835, 810, 775, 735, 690, 670 cm^–1.

2 H, 2ϫ ortho-H) ppm. ¹³C NMR (100.6 MHz, CDCl₃/CDCl₃): δ

1-Phenylpent-4-en-2-ol (39)

= 14.11 (C-6Ј), 19.83 and 30.13 [2ЉЈ-(CH₃)₂], 22.69 (C-5Ј), 25.43 (C-

3Ј), 31.88 (C-4Ј), 35.44 (C-2Ј), 35.71 (C-1Љ), 36.36 (C-5ЉЈ), 39.47 (C-

1ЉЉ), 42.11 (C-5), 47.81 (C-3), 55.54 (2-OCH₃), 60.35 (C-6), 64.66

(C-4), 65.88 (C-4ЉЈ), 68.51 (C-6ЉЈ), 71.33 (C-1Ј), 99.09 (C-2ЉЈ),

102.39 (C-2), 126.15 (para-H), 129.00 (2ϫ meta-C), 129.20 (2ϫ

ortho-C), 136.46 (ipso-C) ppm. IR (film): ν = 3370, 3055, 2990,

Sultone 41 (106 mg, 294 μmol) was dissolved in THF (10 mL) co-

oled to 0 °C. nBu₄N⁺F^–(1.0 m in THF, 350 μL, 353 μmol,

1.2 equiv.) was added slowly. The resulting mixture was stirred at

this temperature for 1 h. The cooling bath was removed and the

reaction mixture was stirred for an additional 2 h at room temp.

Silica gel was added and the solvent was removed under reduced

pressure. The obtained pad of silica was added on the top of a

˜

2925, 2855, 1645, 1585, 1480, 1440, 1380, 1265, 1200, 1170, 1110,

1045, 975, 945, 875, 800, 740, 690 cm^–1.

tert-Butyl [((S)-1-{(3S,4R,6R)-4-(tert-butyldimethylsilyloxy)-6-

[(4S,6S)-2,2-dimethyl-6-(phenylsulfanylmethyl)-1,3-dioxan-4-

yl]methyl}-2-methoxy-3,4,5,6-tetrahydro-2H-pyran-3-yl)hexyloxy]di-

methylsilane (37)

chromatography

column

and

flash

chromatography^[34]

(1.5 cmϫ17.0 cm, 7 mL, cyclohexane/AcOEt, 5:1) provided the

title compound (fractions 8–15, 29 mg, 60%) as a colorless liquid.

¹H NMR (300.1 MHz, CDCl₃/CHCl₃): δ = 1.71 (br. s, 1 H, 2-OH),

AB signal [δ_A= 2.24, δ_B= 2.34, J_AB= 13.8 Hz, A part additionally

4

split by J_A,2= J_A,4= 7.3, J_A,5–H(cis)

=

⁴J_{A,5–H(trans)}= 1.1 Hz, B

4

part additionally split by J_B,2= 6.3, J_B,4= 5.9, J_B,5–H(cis)

=

⁴J_{B,5–H(trans)}= 1.3 Hz, 2 H, 3-H₂], AB signal (δ_A= 2.74, δ_B= 2.83,

J_AB= 13.6 Hz, A part additionally split by J_A,2= 8.0 Hz, B part

additionally split by J_B,2= 4.9 Hz, 2 H, 1-H₂), 3.89 [dddd, J_2,1–H(A)

= J_2,3–H(A)= 7.8, J_2,1–H(B)= J_2,3–H(B)= 4.8 Hz, 1 H, 2-H], 5.15–

5.22 [m, 2 H, 5-H(trans), 5-H(cis)], 5.88 (m_c, 1 H, 4-H), 7.21–7.27

(m, 3 H, para-H, 2ϫ meta-H), 7.29–7.35 (m, 2 H, 2ϫ ortho-

H) ppm. ¹³C NMR (100.6 MHz, CDCl₃/CDCl₃): δ = 41.27 (C-3),

43.38 (C-1), 71.76 (C-2), 118.20 (C-5), 126.56 (para-C), 128.62 (2ϫ

meta-C), 129.50 (2ϫ ortho-C), 134.78 (4-C), 138.47 (ipso-C) ppm.

A solution of diol 36 (23 mg, 48 μmol) and imidazole (7.1 mg,

0.10 mmol, 2.2 equiv.) in DMF (2.0 mL) at 0 °C was treated slowly

with trimethylsilyl trifluoromethanesulfonate (TBSOTf; 24 μL,

28 mg, 0.10 mmol, 2.2 equiv.). After 30 min the reaction mixture

was warmed to room temp. and stirred for additional 30 min. H₂O

(1.5 mL) was added and the reaction mixture was extracted with

tBuOMe (3ϫ 2 mL). The combined organic extracts were washed

with brine (2 mL) and dried with MgSO₄. The solvent was evapo-

rated under reduced pressure and the residue was purified by flash

chromatography^[34](1.0 cmϫ18.5 cm, 7 mL, cyclohexane/AcOEt,

20:1) to afford 37 (fractions 7–11, 34 mg, 93%) as a pale yellow

IR (film): ν = 3400, 3065, 3030, 2980, 2920, 2360, 1640, 1605, 1495,

˜

1455, 1435, 1355, 1220, 1080, 1030, 1000, 915, 880, 850, 745 cm^–1.

1-Phenylpent-4-en-2-yl Ethenesulfonate (40)

20

oil. [α] = [α] = [α] = [α] = [α] = Ϯ0 (c = 0.22 in CHCl₃).

589

578

546

436

365

¹H NMR (400.1 MHz, CDCl₃/CHCl₃): δ = 0.018 and 0.041 and

0.046 and 0.048 [4ϫ s, 12 H, Si(CH₃)₂], 0.88 and 0.89 (2ϫ s, 18

H, 2-H₉, 2ЉЉЈ-H₉), 0.88 (t, J_6Ј,5Ј= 7.1 Hz, 3 H, 6Ј-H₃), 1.19–1.37

(m, 5 H, 3Ј-H_A, 4Ј-H₂, 5Ј-H₂), AB signal (δ_A= 1.20, δ_B= 1.82, J_AB

= 12.7 Hz, A part additionally split by J_A,4ЉЉ= J_A,6ЉЉ= 11.7 Hz, B

part additionally split by J_B,4ЉЉ= J_B,6ЉЉ= 2.6 Hz, 2 H, 5ЉЉ-H₂), 1.39

Alcohol 39 (1.99 g, 12.3 mmol) and NEt₃(3.40 mL, 2.48 g,

24.5 mmol, 2.0 equiv.) were dissolved in THF (120 mL). The re-

3222

www.eurjoc.org

Eur. J. Org. Chem. 2014, 3210–3224

Sultone-Forming RCM for a Protection of Homoallylic Alcohols

sulting solution was cooled to –15 °C. Ethenesulfonyl chloride (19;

1.63 g, 12.9 mmol, 1.05 equiv.) was added dropwise. After comple-

tion of the addition the mixture was stirred for 30 min at –15 °C.

The reaction was quenched cautiously with cold H₂O (50 mL). The

phases were separated. The aq. phase was satd. with solid NaCl

and extracted with tBuOMe (3ϫ 50 mL). The combined organic

phases were washed with aq. HCl (1 m, 30 mL) and satd. aq.

NaHCO₃(50 mL) and dried with MgSO₄. The solvent was re-

moved under reduced pressure and the title compound (2.97 g,

96%) was obtained without further purification as a pale yellow

oil. ¹H NMR (300.1 MHz, CDCl₃/CHCl₃): δ = 2.51 (m_c, 2 H, 3-

H₂), AB signal (δ_A= 2.94, δ_B= 2.98, J_AB= 14.1 Hz, A part ad-

(ipso-C, ipsoЈ-C) ppm. IR (film): ν = 2960, 1360, 1260, 1170, 1115,

˜

895, 810, 740, 700 cm^–1.

6-Benzyl-5,6-dihydro-1,2-oxathiine 2,2-Dioxide (42)

A solution of Grubbs II catalyst (15 mg, 1.8 μmol, 1.0 mol-%) and

40 (455 mg, 1.80 mmol) in toluene (18 mL) was heated at 100 °C

for 7 h. After evaporation of the solvent, the residue was purified

by flash chromatography^[34](1.5 cmϫ18.0 cm, 20 mL, cyclohex-

ane/AcOEt, 3:1) to yield 42 (fractions 19–31, 356 mg, 88%) as an

off-white solid. ¹H NMR (300.1 MHz, CDCl₃/CHCl₃): δ = AB sig-

nal (δ_A= 2.28, δ_B= 2.46, J_AB= 19.1 Hz, A part additionally split

ditionally split by J_A,2= 7.3 Hz, B part additionally split by J_B,2

=

5.9 Hz, 2 H, 1-H₂), 4.68 [dddd, J_2,1–H(A)= 7.3, J_2,1–H(B)= J_2,3–H(A)

= J_2,3–H(B)= 5.9, 1 H, 2-H], 5.17 [dddd, J_5-H(trans),4= 17.0,

²J_{5-H(trans),5–H(cis)}

= =

⁴J_{5-H(trans),3–H(A)}⁴J_{5-H(trans),3–H(B)}= 1.6 Hz, 1

H, 5-H(trans)], 5.20 [dddd, J_5-H(cis),4= 10.3, ²J_{5-H(cis),5–H(trans)}= 1.9,

4

by J_A,4= 5.5, J_A,6= 3.2, J_A,3= 1.5 Hz, B part additionally split

⁴J_{5-H(cis),3–H(A)}⁴J_{5-H(cis),3–H(B)}= 1.0 Hz, 1 H, 5-H(cis)], 5.75 [d,

=

4

by J_B,6= 11.4, J_B,4= J_B,3= 2.5 Hz, 2 H, 5-H₂), AB signal (δ_A

3.01, δ_B= 3.23, J_AB= 14.2 Hz, A part additionally split by J_A,6

=

J_{2Ј-H(cis),1Ј}= 10.0 Hz, 1 H, 2Ј-H(cis)], 5.83 [dddd, J_{4,5–H(trans)}= 17.1,

J_4,5–H(cis)= 10.2, J_4,3–H(A)= J_4,3–H(B)= 7.0 Hz, 1 H, 4-H], 5.91 [dd,

J_{1Ј,2Ј–H(trans)}= 16.6, J_{1Ј,2Ј–H(cis)}= 10.0 Hz, 1 H, 1Ј-H], 6.18 [d, J_2Ј-

_H(trans),1Ј= 16.4 Hz, 1 H, 2Ј-H(trans)], 7.17–7.26 (m, 3 H, 2ϫ ortho-

C, para-H), 7.26–7.34 (m, 2 H, 2ϫ meta-H) ppm. ¹³C NMR

(100.6 MHz, CDCl₃/CDCl₃): δ = 39.09 (C-3), 40.52 (C-1), 84.14

(C-2), 119.49 (C-5), 127.11 (para-C), 128.64 (2ϫ meta-C), 129.92

(2ϫ ortho-C), 132.26 (C-2Ј), 132.92 (C-1Ј), 136.58 (ipso-C) ppm.

6.8 Hz, B part additionally split by J_B,6= 6.3 Hz, 2 H, 1Ј-H₂), 5.19

[dddd, J_6,5–H(B)= 11.4, J_6,1Ј–H(A)= 6.7, J_6,1Ј–H(B)= 6.5, J_6,5–H(A)

=

3.1 Hz, 1 H, 6-H], 6.44 [ddd, J_4,3= 10.7, J_4,5–H(A)= 5.5, J_4,5–H(B)

4

= 2.2 Hz, 1 H, 4-H], 6.54 [ddd, J_3,4= 10.7, J_3,5–H(B)= 2.8,

⁴J_3,5–H(A)= 1.5 Hz, 1 H, 3-H], 7.20–7.38 (m, 5 H, 2ϫ ortho-H,

para-H, 2ϫ meta-H) ppm. ¹³C NMR (100.6 MHz, CDCl₃/CDCl₃):

δ = 29.73 (5-C), 41.07 (1Ј-C), 81.91 (6-C), 126.32 (para-C), 127.45

(3-C), 128.93 (2ϫ meta-C), 129.49 (2ϫ ortho-C), 134.57 (4-C),

IR (film): ν = 3065, 3030, 2925, 1955, 1605, 1495, 1455, 1435, 1360,

˜

1255, 1170, 1085, 975, 910, 790, 750, 730, 700 cm^–1.

136.50 (ipso-C) ppm. IR (film): ν = 2355, 1340, 1170, 1150, 1055,

˜

945, 900, 825, 780, 760, 715, 700 cm^–1.

6-Benzyl-4-(dimethylphenylsilyl)-1,2-oxathiane 2,2-Dioxide (41)

Supporting Information (see footnote on the first page of this arti-

cle): Rreproductions of the ¹H and ¹³C NMR spectroscopic data

of the compounds prepared during this study.

Acknowledgments

A suspension of small pieces of Li (93 mg, 13 mmol, 30.0 equiv.) in

THF (80 mL) was cooled to –10 °C. PhMe₂SiCl (300 μL, 304 mg,

1.78 mmol, 4.0 equiv.) was added dropwise. After the reaction mix-

ture was stirred for 18 h the resulting deep-red solution was trans-

ferred to a suspension of CuCN (80 mg, 0.89 mmol, 2.0 equiv.) in

THF (8 mL) at –10 °C. After 2 h the reaction mixture was cooled

to –78 °C. SiMe₃Cl (130 μL, 107 mg, 535 μmol, 1.2 equiv.) and a

solution of 42 (100 mg, 446 μmol) in THF (3 mL) were added drop-

wise. The reaction mixture was stirred at –78 °C for 30 min,

warmed to –50 °C, and stirred for another 30 min. The reaction

was quenched by the addition of satd. aq. NH₄Cl (15 mL). The

resulting mixture was warmed to room temp. under vigorous stir-

ring. The phases were separated and the aq. phase was extracted

with AcOEt (3ϫ 10 mL). The combined organic extracts were

washed with brine (15 mL) and dried with MgSO₄. The solvent was

removed under reduced pressure and the residue was purified by

flash chromatography^[34](1.5 cmϫ20.0 cm, 7 mL, cyclohexane/Ac-

OEt, 10:1) to yield 41 (fractions 14–20, 140 mg, 87%) as a pale

The authors are grateful to the Deutsche Forschungsgemeinschaft

(DFG) (IRTG 1038 Internationales Graduiertenkolleg “Catalysts

and Catalytic Reactions for Organic Synthesis”) for financial sup-

port.

[1] For reviews, see: a) J. M. T. Hamilton-Miller, Bacteriol. Rev.

1973, 37, 166–196; b) J.-M. Beau, G. Lukacs, in: Recent Pro-

gress in the Chemical Syntheses of Antibiotics (Ed.: M. Ohno),

Springer, Berlin, 1990, p. 137–179; c) S. Omura, H. Tanaka,

Macrolide Antibiotics: Chemistry, Biochemistry and Practice

(Ed.: S. Omura), Academic Press, New York, 1984, p. 351–404;

d) S. D. Rychnovsky, Chem. Rev. 1995, 95, 2021–2040; e) S. B.

Zotchev, Curr. Med. Chem. 2003, 10, 211–223.

[2] The most recent members of this class of compounds are bah-

amaolide A and B: D.-G. Kim, K. Moon, S.-H. Kim, S.-H.

Park, S. Park, S. K. Lee, K.-B. Oh, J. Shin, D.-C. Oh, J. Nat.

Prod. 2012, 75, 959–967.

[3] G. B. Whitfield, T. D. Brock, A. Ammann, D. Gottlieb, H. E.

Carter, J. Am. Chem. Soc. 1955, 77, 4799–4801.

1

yellow solid. H NMR (300.1 MHz, CDCl₃/CHCl₃): δ = 0.32 [s, 6

[4] M. E. Bergy, T. E. Eble, Biochemistry 1968, 7, 653–659.

[5] a) T. I. Richarson, S. D. Rychnovsky, Angew. Chem. Int. Ed.

Engl. 1995, 34, 1227–1230; Angew. Chem. 1995, 107, 1355–

1358; b) T. I. Richarson, S. D. Rychnovsky, J. Org. Chem. 1996,

61, 4219–4231.

[6] a) T. I. Richardson, S. D. Rychnovsky, J. Am. Chem. Soc. 1997,

119, 12360–12361; b) T. I. Richardson, S. D. Rychnovsky, Tet-

rahedron 1999, 55, 8977–8996.

H, 4-Si(CH₃)₂], 1.41 (m_c, 1 H, 4-H), 1.67–1.89 (m, 2 H, 5-H₂), 2.69–

3.08 (m, 4 H, 3-H₂, 1Ј-H₂), 4.85 [dddd, J_6,5–H(A)= 11.3, J_6,1Ј–H(A)

= 7.4, J_6,1Ј–H(B)= 5.9, J_6,5–H(B)= 2.0 Hz, 1 H, 6-H], 7.12–7.19 (m,

2 H, 2ϫ ortho-H), 7.21–7.30 (m, 3 H, para-H 2ϫ meta-H), 7.35–

7.45 (m, 5 H, 2ϫ ortho-H, para-H, 2ϫ meta-H) ppm. ¹³C NMR

(100.6 MHz, CDCl₃/CDCl₃): δ = –5.30 [4-Si(CH₃)₂], 22.31 (4-C),

29.90 (5-C), 41.67 (1Ј-C), 48.44 (3-C), 87.96 (6-C), 128.42 and

128.93 (2ϫ meta-C, 2ϫ metaЈ-C), 126.62 and 128.00 (paraЈ-H),

129.49 and 133.87 (2ϫ ortho-C, 2ϫ orthoЈ-C), 135.76 and 136.50

[7] a) S.-I. Kiyooka, M. A. Hena, F. Goto, Tetrahedron: Asym-

metry 1999, 10, 2871–2879; b) S.-I. Kiyooka, M. A. Hena, T.

Eur. J. Org. Chem. 2014, 3210–3224

www.eurjoc.org

3223

P. Walleser, R. Brückner

FULL PAPER

Yabukami, K. Murai, F. Goto, Tetrahedron Lett. 2000, 41,

7511–7516.

[8] S. Umezawa, Y. Tanaka, M. Ooka, S. Shiotsu, J. Antibiot., Ser.

A 1958, 11, 26–29.

[9] T. Oishi, Pure Appl. Chem. 1989, 61, 427–430.

[23]

We are aware of no more than four literature reports on Mitsu-

nobu inversions of secondary alcohols involving acrylic acid:

a) N. F. Langille, J. S. Panek, Org. Lett. 2004, 6, 3203–3206; b)

G. Sabitha, M. N. Prasad, K. Shankaraiah, J. S. Yadav, Synthe-

sis 2010, 1171–1175; c) S. Tang, X. Xie, X. Wang, L. He, K.

Xu, X. She, J. Org. Chem. 2010, 75, 8234–8240; d) A. Take-

mura, Y. Katagiri, K. Fujiwara, H. Kawai, T. Suzuki, Tetrahe-

dron Lett. 2011, 52, 1222–1224.

Grubbs II catalyst is [1,3-bis(2,4,6-trimethylphenyl)-2-imid-

azolidinylidene]dichloro(phenylmethylidene)tricyclohexylphos-

phaneruthenium.

K. B. Wiberg, Angew. Chem. Int. Ed. Engl. 1986, 25, 312–322;

Angew. Chem. 1986, 98, 312–322.

R. Huisgen, H. Ott, Tetrahedron 1959, 6, 253–267.

K. N. Houk, A. Jabbari, H. K. Hall Jr., C. Alemán, J. Org.

Chem. 2008, 73, 2674–2678.

J. M. Muhuhi, S. Denmark, J. Am. Chem. Soc. 2010, 132,

11768–11778.

[10] a) K. Matsumoto, M. Shimagaki, T. Nakata, T. Oishi, Tetrahe-

dron Lett. 1993, 34, 4935–4938; b) see reference 4c in ref.^[10a]

[11] Y. Igarashi, Y. In, T. Ishida, T. Fujita, T. Yamakawa, H. Ouka,

T. Furumai, J. Antibiot. 2005, 58, 523–525.

[12] For reviews, see: a) J. Bolard, Biochim. Biophys. Acta 1986, 864,

257–304; b) S. C. Hartsel, C. Hatch, W. Ayenew, J. Liposome

Res. 1993, 3, 377–408; c) ref.^[1e]

[13] For key references regarding the use of silyl groups as masked

hydroxy groups, see: a) I. Fleming, R. Henning, H. Plaut, J.

Chem. Soc., Chem. Commun. 1984, 29–31 (use of PhMe₂Si

groups); b) I. Fleming, R. Henning, D. C. Parker, H. E. Plaut,

P. E. J. Sanderson, J. Chem. Soc. Perkin Trans. 1 1995, 317–

337; c) G. R. Jones, Y. Landais, Tetrahedron 1996, 52, 7599–

7662; d) I. Fleming, A. Barbero, D. Walter, Chem. Rev. 1997,

97, 2063–2192 (see chapter IV).

[24]

[25]

[26]

[27]

[28]

[29]

[30]

Schrock catalyst is [(2,6-diisopropylphenyl)imido]neophylid-

enemolybdenum bis{[1,1-bis(trifluoromethyl)ethoxide]}.

[14] a) S. Anklam, Dissertation, Universität Freiburg, 2003; b) S.

Müller, Dissertation, Universität Freiburg, 2007.

For examples, see: a) S. Chang, R. H. Grubbs, Tetrahedron

Lett. 1997, 38, 4757–4760; b) M. Ahmed, A. G. M. Barrett,

J. C. Beall, D. C. Braddock, K. Flack, Tetrahedron 1999, 55,

3219–3232; c) S.-M. Yang, S. E. Denmark, Org. Lett. 2001, 3,

1749–1752; d) S.-M. Yang, S. E. Denmark, J. Am. Chem. Soc.

2002, 124, 2102–2103; e) S.-M. Yang, S. E. Denmark, J. Am.

Chem. Soc. 2002, 124, 15196–15197; f) S.-M. Yang, S. E. Den-

mark, J. Am. Chem. Soc. 2004, 126, 12432–12440; g) S.-M.

Yang, S. E. Denmark, Tetrahedron 2004, 60, 9695–9708.

[15] A related aldol addition reaction with the same induced dia-

stereoselectivity but the opposite simple diastereoselectivity

was communicated recently: S. B. Kamptmann, R. Brückner,

Eur. J. Org. Chem. 2013, 6584–6600.

[16] For reviews on syntheses of heterocycles by RCM reactions,

see: a) A. Deiters, S. F. Martin, Chem. Rev. 2004, 104, 2199–

2238; b) K. C. Majumdar, B. Chattopadhyay, K. Ray, Curr.

Org. Synth. 2010, 7, 153–176.

[17] For examples of the formation of α,β-unsaturated δ-lactones

by RCM reactions, see: a) A. K. Chatterjee, F. D. Toste, S. D.

Goldberg, R. H. Grubbs, Pure Appl. Chem. 2003, 75, 421–425;

b) A. B. Smith III, B. S. Freeze, M. J. LaMarche, T. Hirose, I.

Brouard, P. V. Rucker, M. Xian, K. F. Sundermann, S. J. Shaw,

M. A. Burlingame, S. B. Horwitz, D. C. Myles, Org. Lett. 2005,

7, 311–314; c) J. A. Marshall, J. J. Sabatini, Org. Lett. 2005, 7,

4819–4822; d) S. Reymond, J. Cossy, Eur. J. Org. Chem. 2006,

4800–4804; e) A. Dánnibale, L. Ciaralli, M. Bassetti, C. Pas-

quini, J. Org. Chem. 2007, 72, 6067–6074; f) E. Roulland, An-

gew. Chem. Int. Ed. 2008, 47, 3762–3765; Angew. Chem. 2008,

120, 3822–3825; g) G. W. O’Neil, M. J. Black, Synlett 2010,

107–110; h) I. N. C. Kiran, R. S. Reddy, G. Suryavanshi, A.

Sudalai, Tetrahedron Lett. 2011, 52, 438–440.

[18] a) S. D. Rychnovsky, G. Griesgraber, S. Zeller, D. Skalitzky, J.

Org. Chem. 1991, 56, 5161–5169; b) S. D. Rychnovsky, G. Yang,

Y. Hu, U. R. Khire, J. Org. Chem. 1997, 62, 3022–3023.

[19] a) Y. Lu, I. S. Kim, A. Hassan, D. J. Del Valle, M. J. Krische,

Angew. Chem. Int. Ed. 2009, 48, 5018–5021; Angew. Chem.

2009, 121, 5118–5121; b) S. B. Han, A. Hassan, I. S. Kim, M. J.

Krische, J. Am. Chem. Soc. 2010, 132, 15559–15561.

[31]

[32]

Grubbs–Hoveyda catalyst is [1,3-bis(2,4,6-trimethylphenyl)-

2-imidazolidinylidene]dichloro[(2-isopropoxyphenyl)methyl-

idene]ruthenium.

a) C. Meyer, J.-R. Desmurs, J.-C. Galland, A. Le Flohic, J.

Cossy, Synlett 2003, 667–670; b) C. Meyer, A. Le Flohic, J.

Cossy, Tetrahedron 2006, 62, 9017–9037.

C. S. Rondestvedt, J. Am. Chem. Soc. 1954, 76, 1926–1929.

W. C. Still, M. Kahn, A. Mitra, J. Org. Chem. 1978, 43, 2923–

2925.

[33]

[34]

[35] In certain RCM reactions high dilution appears to be required

for success, see: B. Schmidt, D. Geißler, ChemCatChem 2010,

2, 423–429.

[36] E. Cramer, P. Metz, Tetrahedron Lett. 1993, 34, 6371–6374.

[37] The same mixture was obtained when we added

Li₂(PhMe₂Si)₂Cu(CN) to the sultone moiety of silyllactone/

unsaturated sultone 26 at –50 °C (75% yield; Scheme 5).

[38] V. Rogachev, S. Merten, T. Seiser, O. Kataeva, P. Metz, Tetrahe-

dron Lett. 2008, 49, 133–136.

[39] S. M. Weinreb, D. M. Demko, T. A. Lessen, Tetrahedron Lett.

1986, 27, 2099–2102.

[20] For reviews, see: a) T. Y. S. But, P. H. Toy, Chem. Asian J. 2007,

2, 1340–1355; b) N. N. B. Kumar, E. Balaraman, K. V. P. P. Ku-

mar, K. C. K. Swamy, Chem. Rev. 2009; 109, 2551–2651.

[21] In a related esterification reaction under Mitsunobu conditions

we transformed an alcohol with a stereogenic C–OH bond into

a cinnamate with 80% inversion and 20% retention of configu-

ration: P. Walleser, R. Brückner, Org. Lett. 2013, 15, 1294–

1297. Accordingly, conducting the transformation 10Ǟ9

might have encountered problems with respect to stereoselec-

tivity (which, in truth, did not arise).

[22] Synthesizing dienediol enantiomer 10 in 3 steps as described

by Rychnovsky et al.^[18]we were well aware of the impressive

1-step synthesis of the same compound from propane-1,3-diol

(58% yield) by Krische et al.^[19]We reproduced their reaction

but abandoned it upon scale-up because of the high cost both

for the catalyst (5 mol-% of [Ir(cod)Cl]₂) and the ligand

[10 mol-% of (R)-2,2Ј-bis(diphenylphosphano)-5,5Ј-dichloro-

6,6Ј-dimethoxy-1,1Ј-biphenyl].

[40] For the procedure, see: K. S. K. Murthy, A. G. H. Wee, J. S.

Prasad, G. V. J. da Silva, M. Majewski, P. C. Anderson, C. F.

Evans, R. D. Haugen, L. D. Heerze, J. R. Barrie, D. L. J. Clive,

J. Am. Chem. Soc. 1990, 112, 3018–3028.

[41] For the procedure, see: I. Sasaki, T. Die, S. Minakata, Angew.

Chem. Int. Ed. 2010, 49, 1309–1311; Angew. Chem. 2010, 122,

1331–1333.

[42] J. H. Smitrovich, K. A. Woerpel, J. Org. Chem. 1996, 61, 6044–

6046.

[43] B. E. Love, E. G. Jones, J. Org. Chem. 1999, 64, 3755–3756.

[44] J. Suffert, J. Org. Chem. 1989, 54, 509–510.

[45] For the preparation of a solution of tBuOOH in toluene, see:

J. G. Hill, B. E. Rossiter, K. B. Sharpless, J. Org. Chem. 1983,

48, 3607–3608 (the concentration of the solution was deter-

mined by ¹H NMR spectroscopic analysis as described in foot-

note 12 of that communication).

Received: January 27, 2014

Published Online: April 14, 2014

3224

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Stereocontrolled synthesis of a C1-C10 building block ("Southwestern Moiety") for the unnatural enantiomers of the polyene polyol antibiotics filipin III and pentamycin: A sultone-forming ring-closing metathesis for protection of hom

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