Towards the synthesis of the 4,19-diol derivative of (-)-mycothiazole: Synthesis of a potential key intermediate

FULL PAPER

DOI: 10.1002/ejoc.201100669

Towards the Synthesis of the 4,19-Diol Derivative of (–)-Mycothiazole:

Synthesis of a Potential Key Intermediate

Frédéric Batt^[a]and Fabienne Fache*^[a]

Keywords: Synthesis design / Natural products / Metathesis / Olefination / Allylic compounds

The synthesis of a potential key intermediate for the synthe-

sis of the 4,19-diol derivative of (–)-mycothiazole using con-

vergent strategies is described in this paper. Several ap-

proaches have been tested, including cross metathesis and a

Julia–Kocienski olefination. Finally, the formation of the 1,1-

dialkyl-1,2-ethanediol motif through C4–C5 bond construc-

tion was realized by nucleophilic addition of a vinyl iodide

derivative to a keto ester after halogen/lithium exchange fol-

lowed by reduction of the resulting hydroxy ester.

Introduction

(–)-Mycothiazole (1; Figure 1) was first isolated from the

marine sponge Cacospongia mycofijiensis.^[1]It exhibits tox-

icity towards lung cancer cells^[2]and very recently was

proven to be a valuable novel prototype of mitochondrial

complex I inhibitor.^[3]Its unique structure as well as its po-

tential pharmacological activities make it a good target for

laboratories interested in the total synthesis of biologically

active natural compounds. There are only two total synthe-

Figure 1. (–)-Mycothiazole (1) and mycothiazole-4,19-diol (2).

ses of mycothiazole (1)^[2,4]and three partial syntheses pub- generated by ring-closing metathesis, as reported by Cossy

lished so far^[5]but these lead to the wrong stereochemistry and co-workers.^[4b]Neither of these approaches turned out

at the C14–C15 double bond, which was first claimed to be to be valuable for the synthesis of 4,19-diol 2. A nonexhaus-

E and finally revised to Z.^[6]Compound 2, which possesses tive survey of the literature showed that the 1,1-dialkyl-1,2-

the same skeleton as 1 but with a 4,19-diol group, was iso- ethanediol motif is present in relatively few natural prod-

lated along with 1 (Figure 1).^[6]Its structure was elucidated ucts, the total syntheses of which, in general, have not yet

by comparison of the NMR spectra of 1 and 2, but the been described.^[7]Nevertheless, some methods have been

configuration at C4 remains unknown. To the best of our published in the literature that give access to such a group,

knowledge, no synthesis of compound 2 has been reported for example, by addition of a phenylboronic acid to an α-

so far and considering the potential interest in (–)-mycothi- keto ester catalyzed by rhodium,^[8]by addition of an

azole (1) itself, access to its derivatives presents a valuable alcohol to a vinyl epoxide in the presence of a catalytic

challenge for organic chemists. The main difference between amount of trialkylborane and palladium,^[9]or by rearrange-

1 and 2 is the presence of a conjugated homoallylic Z dienol ment of 2-(1-hydroxyalkyl)-1-cyclopropanols using or-

in mycothiazole (1) and an allylic 1,1-dialkyl-1,2-ethanediol ganozinc catalysis.^[10]The classical dihydroxylation of

group in 2 (Figure 1).

double bonds^[11]or reduction of hydroxy esters^[12]can also

The two previously described strategies for the synthesis be used. Other 1,1-dialkyl-1,2-ethanediol intermediates

of mycothiazole (1) used a standard Stille coupling reaction have also been reported in the total syntheses of natural

to create the C6–C19 diene, as reported by Shioiri and co- products, but they are obtained by tedious, not straightfor-

workers,^[4a]or a chain extension of a homoallylic alcohol ward methods.^[13]Herein we report our efforts to synthesize

proceeding through an unsaturated sultone intermediate a key intermediate of mycothiazole-4,19-diol (2) and more

especially to build the allylic 1,1-dialkyl-1,2-ethanediol moi-

ety.

[a] Université de Lyon, Université Lyon 1, Institut de Chimie et

Biochimie Moléculaire et Supramoléculaire (ICBMS), UMR

5246 CNRS,

Bat. Raulin, 43, Bd. du 11 Novembre 1918, 69622 Villeurbanne

Cedex, France

Results and Discussion

E-mail: fache@univ-lyon1.fr

Supporting information for this article is available on the

WWW under http://dx.doi.org/10.1002/ejoc.201100669.

As the synthesis of the 1,4-diene lateral side-chain^[14]and

the introduction of the carbamate moiety^[4]have already

Eur. J. Org. Chem. 2011, 6039–6055

6039

F. Batt, F. Fache

FULL PAPER

been well described, we focused our efforts on the synthesis temperature under 1 atm of H₂,^[15,19]however, in our case,

of the allylic 1,1-dialkyl-1,2-ethanediol group, the two 20 atm of hydrogen and a temperature of 100 °C were nec-

aforementioned parts being introduced at the end of the essary to obtain 13. Poisoning of the catalyst by the nitro-

synthesis. In our synthetic strategy outlined in Figure 2, we gen atom could be an explanation for this low reactivity

envisaged a convergent, late-stage assembly of the two ad- even though good results were published by others with ni-

vanced fragments by a cross-metathesis reaction to build trogen containing substrates.^[19]Finally, a classical Wittig

the C5–C6 double bond, which seemed reasonable con- reaction delivered the first fragment 3 (50%). The entire

sidering the E configuration of this olefin. The first frag- sequence was realized in nine steps from commercially

ment 3 could be obtained by dihydroxylation of the benzo- available and inexpensive 5 in 4% overall yield.

dioxepine 4 followed by the substitution of the mesyl group

by potassium phthalimidate, 4 being easily obtained from

the commercially available dimethyl itaconate (5). The ad-

vantage of compound 4 is its possible selective cleavage by

hydrogenolysis and its ability to perform π-stacking with

aromatic chiral auxiliaries in the case of asymmetric dihy-

droxylation, as reported by Oi and Sharpless.^[15]The con-

struction of the second fragment 6 could be achieved by

condensation of 2,2-dimethylpropanediol (7) and cysteine

(8) followed by aromatization of the resulting thiazolidine

and a few straightforward functional group manipulations.

Scheme 1. Synthesis of intermediate 3 from dimethyl itaconate.

As for the thiazole ring, the different approaches to my-

cothiazole (1) reported in the literature used either 2,4-di-

bromothiazole,^[4b]commercially available but very expens-

ive, or a cyclodehydration reaction based on the Hantzsch

synthesis, for which numerous steps are necessary as well as

the use of the strongly odorous Lawesson reagent.^[5]There-

fore we decided to synthesize the thiazole ring by oxidation

of the corresponding thiazolidine as proposed by Shioiri

and co-workers (Scheme 2).^[4a]

We started the synthesis of subunit 6 by monoprotection

of the commercial diol 7 according to the method described

Figure 2. Retrosynthetic analysis of mycothiazole-4,19-diol (2).

by Mc Dougal et al.^[20]followed by PCC oxidation (two

As shown in Scheme 1, our initial approach to building steps, 84% isolated yield). Condensation of the resulting al-

subunit 3 started from commercially available dimethyl ita- dehyde 14^[4a]with l-cysteine methyl ester gave compound

conate (5). Reduction of 5 with DIBAL in THF led to diol 15^[4a]as a diastereomeric mixture (98%). Oxidation of thi-

9, which was selectively oxidized to 10 according to our azolidines to thiazoles is most conveniently performed with

recently reported method.^[16]Mesylation of 10 followed by chemical manganese dioxide (CMD), as reported by Shioiri

protection of the aldehyde group as the 1,2-benzenedi- and co-workers.^[21]Owing to the difficulties involved in ac-

methanol acetal^[17]delivered 4 in 44% yield over the four cessing this reagent, we tested several other methods by

steps. Substitution of the mesyl group by potassium phthal- using NBS and alkyl peroxides,^[22]NiO₂,^[23]and standard

imidate followed by dihydroxylation according to the classi- manganese dioxide. After some experimentation, we found

cal conditions described by Van Rheenen et al.^[18]and sub- that the procedure performed in benzene using MnO₂syn-

sequent protection of the resulting diol as the diacetal gave thesized in our laboratory following the method of Fati-

product 12 with an overall yield of 45% for the three steps. adi^[24]was the most promising. Thus, thiazole 16^[4a]was ob-

Literature precedent predicted selective removal of the tained in 52% yield by using 20 equiv. of MnO₂, which

benzodioxepine moiety using catalytic PdO in THF at room compares with the 62% yield obtained with 60 equiv. of

6040

www.eurjoc.org

Eur. J. Org. Chem. 2011, 6039–6055

Synthesis of the 4,19-Diol Derivative of (–)-Mycothiazole

Scheme 3. CM between olefin 6 and olefins 3 and 20.

It is clear to us that the main problem was the steric

bulkiness at the C4 center. We therefore explored two alter-

native syntheses using CM as the key reaction followed by

introduction of the diol group. We first planned to perform

CM between thiazole 6 and compound 22 bearing a ter-

minal double bond, an epoxide group as the diol precursor,

and a primary alcohol protected by a TBDPS group, which

could later be transformed into a methyl carbamate as de-

scribed by Shioiri and co-workers^[4a](Figure 3).

Scheme 2. Synthesis of intermediate 6 from 2,2-dimethylpropane-

diol (7).

CMD by Shioiri and co-workers.^[4a]Reduction of ester 16

with LiAlH₄furnished alcohol 17,^[4a]which upon exposure

to PPh₃and CBr₄in the presence of 2,6-lutidine provided

the corresponding bromide derivative 18.^[4a]Deprotection

of the TBDPS ether using the HF·pyridine complex (71%

yield) followed by oxidation to the corresponding aldehyde

with Dess–Martin periodinane (67%) afforded 19, whereas

deprotection with TBAF and oxidation with PCC led to

degradation products. Finally, alkylation with allylmagne-

sium bromide provided 6 in an overall yield of 12% over

the ten steps.

With these two fragments in hand we tried to apply our

initial strategy: The connection of fragments 3 and 6 by

cross metathesis (CM; Figure 2). According to Grubbs’

model,^[25]olefins can be divided into four types depending

upon their reactivity. Thus, compound 3, bearing a quater-

nary center next to the double bond can be considered as a

type III olefin, not being very reactive and not being able

to homodimerize, whereas compound 6 can be considered

a type I olefin, capable of fast homodimerization and thus

much more reactive. Such types of double bonds have al-

ready been subjected with success to CM using Grubbs’

second-generation catalyst.^[26]Nevertheless, whatever the

conditions used (% catalyst, solvent, temperature, micro-

waves,^[27]etc.), every attempt to obtain the coupling prod-

uct resulted in recovery of the starting material. The

Grubbs–Hoveyda catalyst was also tried without success.

The presence of the bulky dioxolane group might explain

this lack of reactivity, preventing [2+2] cycloaddition with

the carbenic species and thus inhibiting the reaction. There-

fore we tried CM with diol 20 obtained by acidic deprotec-

tion of 3 (98% yield). However, only dimerization products

of compound 6 and starting materials (3 or 20) were ob-

tained (Scheme 3).

Figure 3. Alternative retrosynthetic approach to 2.

Protection of 10 as the corresponding silyl ether followed

by 1,4-addition of hydrogen peroxide ions formed in situ

from a H₂O₂–urea complex gave epoxide 24 (50% yield, two

steps). A classical Wittig reaction ended this sequence with

the synthesis of 22 and a modest overall yield of 14% in

five steps starting from dimethyl itaconate 5 (Scheme 4).

Scheme 4. Access to epoxide 22.

Eur. J. Org. Chem. 2011, 6039–6055

www.eurjoc.org

6041

F. Batt, F. Fache

FULL PAPER

G_Iand G_IIcatalysts were both tested in CH₂Cl₂at reflux enone 28, which could lead to epoxide 29 by a Corey–Chay-

for the CM reaction between intermediates 6 and 22 with- kovsky^[29]reaction. Two alternative syntheses of intermedi-

out the formation of the desired product. Thiazole 6 was ate 26 were thus explored (Scheme 6).

recovered but epoxide 22 was transformed into aldehyde 25.

We proposed the mechanism depicted in Scheme 5 to ex-

plain this reaction.

Scheme 5. Rearrangement of epoxide 22 catalyzed by the G_IIcata-

lyst.

Ru might be considered as a Lewis acid, which, after

chelation with the oxygen of the epoxide, could open it by

a [1,2] hydride shift leading to a nonisolated conjugated di-

Scheme 6. Two alternative syntheses of enone 26.

enol. Two routes could be considered to lead to the alde-

hyde: Route a based on a [1,5] sigmatropic rearrangement

promoted by the heating of the reaction mixture or route

Starting from 1,3-propanediol, we proceeded with its

monoprotection with the 4-methoxybenzyl (PMB) group

b catalyzed again by Ru, which is known to allow olefin

and subsequent oxidation to aldehyde 30 by IBX (o-iodoxy-

benzoic acid; 50%, two steps). Treatment of the protected

aldehyde thus obtained with vinylmagnesium bromide fol-

lowed by another IBX oxidation gave vinyl ketone 26 in

29% yield over the four steps. Because of this low yield, we

tested another strategy based on the condensation of tert-

butyl acetate with acrolein to provide β-hydroxy ester 31,

which was reduced with LiAlH₄to diol 32 and selectively

monoprotected and oxidized to furnish enone 26 in 41%

overall yield.

isomerization to the α,β-unsaturated aldehyde.^[28]Whatever

the mechanism, the epoxide rearrangement proceeded

faster than CM. Therefore, we decided to follow the syn-

thetic strategy outlined in Figure 4.

Considering the strategy developed by Rodriguez and co-

workers^[14]for the introduction of the 2,5-hexadienic lateral

chain by a Wittig reaction, a one-carbon homologation of

the ester side-chain in compound 16 was necessary. Direct

homologation following the method of Kowalski et al.^[30]

provided degradation products. We chose to transform

alcohol 17 into a leaving group and to substitute it with

potassium cyanide (Scheme 7). Nitriles are known to be me-

tathesis catalyst poisons, therefore it was necessary to elabo-

rate this group before testing the CM. Exposure of com-

pound 33 to chlorotrimethylsilane in MeOH^[31]provided

the ester function with concomitant cleavage of the silyl

ether due to the acidic conditions and afforded compound

34 in a good yield of 85% over two steps. Oxidation with

Dess–Martin periodinane followed by a chemoselective all-

ylation using Barbier conditions gave the homoallylic

alcohol 27, which upon exposure to TBSOTf in the pres-

Figure 4. Access to 2 by enone metathesis.

As with the previous strategy, the diol group would be ence of 2,6-lutidine provided the corresponding TBS ether

formed after the coupling between the thiazole part and the in 81% yield over the last three steps.

diol precursor by CM. Metathesis using olefin 26 (type II

After some experimentation, we found that the cross-

according to the Grubbs model) and olefin 27 (type I) could metathesis reaction between compounds 26 and 35 led to

be performed stereoselectively to provide the E isomer of the desired coupled product 36 in 50% isolated yield under

6042

www.eurjoc.org

Eur. J. Org. Chem. 2011, 6039–6055

Synthesis of the 4,19-Diol Derivative of (–)-Mycothiazole

case only the starting material 29 was recovered. The use of

BF₃·Et₂O in acetone gave a mixture of degradation prod-

ucts.^[35]A final attempt was performed with chlorohydrin

37: Exposure of this compound to TBSOTf in the presence

of 2,6-lutidine provided the corresponding TBS ether 38 in

50% yield, which was then treated with sodium hydroxide

without success (Scheme 10).^[36]

Scheme 7. Access to thiazole 35.

optimized conditions (G_IIcatalyst and microwave irradia-

tion,^[27]which enables one to lower both the catalyst quan-

tity and the reaction time as compared with classical ther-

mal conditions). This moderate yield was due to the fact

that it is not possible to achieve more than 60% conversion.

Nevertheless, always unreacted starting material was reco-

vered (Scheme 8).

Scheme 10. Silylation of compound 37.

Considering the difficulties encountered during our me-

tathesis approach, we decided to test olefination reactions

to build the C5–C6 double bond. We chose two approaches

from the various methods available, the Horner–Wad-

sworth–Emmons reaction and the modified Julia ole-

fination, which presented the advantage of having a com-

mon intermediate, aldehyde 42, the methyl carbamate func-

tion and the lateral 2,5-hexadienic side-chain being intro-

duced at the end of the synthesis (Figure 5).

Scheme 8. Successful coupling of 26 and 35 by CM.

Note that CM with the unprotected alcohol 27 gave the

coupled product but that further protection of the hydroxy

group as a silyl ether was not possible in our hands.

In our synthetic strategy outlined in Figure 4, we envis-

aged building the diol part of the molecule by opening the

epoxide 29 obtained from enone 36. The Corey–Chaykov-

sky^[29]reaction first considered gave only degradation prod-

ucts. We thus decided to construct the epoxide in two steps.

Addition of chloroiodomethane and nBuLi to the enone

36 afforded chlorohydrin 37, which upon exposure to basic

conditions led to the desired epoxide 29 (Scheme 9). This

molecule could not be purified over silica and caution had

to be taken over its storage.

Scheme 9. Synthesis of epoxide 29.

Figure 5. Double-bond construction through olefination reactions.

With epoxide 29 now available, several conditions could

be tested for its opening. Despite extensive experimentation,

Aldehyde 42 was synthesized from dimethyl itaconate via

all of our attempts remained unsuccessful when using either aldehyde 10 (Scheme 11). Protection of the alcohol group

basic, acidic, or neutral conditions,^[32,33]leading only to de- as a silyl ether and protection of the aldehyde group under

gradation products. To circumvent this problem, we tried to mild conditions gave benzodioxepine 44 in moderate yield

directly obtain the dioxolane adduct. Cu(OTf)₂in acetone is (27%, two steps). Dihydroxylation led to diol 45, which was

known to selectively open vinylic epoxides,^[34]but in our subsequently protected as diacetal 46. Finally, hydro-

Eur. J. Org. Chem. 2011, 6039–6055

www.eurjoc.org

6043

F. Batt, F. Fache

FULL PAPER

genolysis using PdO under an atmospheric pressure of hy-

Two sets of experimental conditions were tested for this

drogen afforded aldehyde 42 in 16% overall yield (seven coupling reaction: The Barbier protocol or premetalation

steps).

depending on the steric bulk of the sulfone.^[38]In our case,

none of these conditions was efficient and only starting ma-

terials were recovered. The steric hindrance of aldehyde 42

was proposed to explain this result as the modified Julia

reaction was successfully performed in our group with sul-

fone 41 and p-nitrobenzaldehyde. We thus decided to put

the aldehyde group on the thiazole fragment (compound

47, Scheme 12) and the sulfone on the protected diol (com-

pound 48, Scheme 13). This last product turned out to be

particularly unstable after deprotonation with LiHMDS as

only unidentified degradation products were recovered at

the end of the reaction.

Considering the difficulties encountered in achieving the

C5–C6 connection, we turned our attention to an alterna-

tive convergent strategy and the subsequent formation of

the diol by the formation of the C4–C5 bond. By analogy

with the preceding retrosyntheses, the methyl carbamate

function and the lateral 2,5-hexadienic side-chain would be

introduced at the end of the synthesis. The key step in this

approach would be a nucleophilic addition of the vinyl io-

dide derivative 49 to the α-hydroxy ketone 51 (Figure 6).

Scheme 11. Synthesis of aldehyde 42.

Phosphonate 40 could be prepared starting from thiazole

35, the synthesis of which has been developed previously

for the cross-metathesis strategy. Oxidative cleavage of the

terminal double bond followed by chemoselective reduction

of the aldehyde group by NaBH₄furnished alcohol 39 in

80% isolated yield over the two steps (Scheme 12).

Scheme 12. Synthesis of alcohol 39.

We then planned to introduce the phosphonate group by

an Arbuzov reaction,^[37]which necessitated the presence of

a halogen in place of the alcohol. Unfortunately, every at-

tempt to obtain this intermediate was unsuccessful. Hence

the Arbuzov reaction could not be tested. Therefore we

turned our attention to the Julia–Kocienski-type reagent 41,

which was obtained in two steps and 82% isolated yield

from alcohol 39 (Scheme 13).

Figure 6. Alternative strategies through C4–C5 bond formation.

Thus, hydroxy aldehyde 10, upon exposure to the corre-

sponding trichloroacetamidate, provided the PMB ether 50,

which after Luche reduction and treatment with TBSCl fur-

nished compound 54 (65%, two steps). The carbonyl func-

tion was then generated by oxidative cleavage giving ketone

51 in four steps and a 21% overall yield (Scheme 14).

Concerning the synthesis of the second key fragment, the

vinyl iodide derivative 49 was synthesized in 15 steps and a

14.8% overall yield from 2,2-dimethylpropanediol via alde-

hyde 47 by a Takai reaction (product 55, 70% isolated

yield),^[39]quantitative reduction of the ester group with Li-

AlH₄(alcohol 56), and subsequent primary alcohol protec-

tion to the TBS ether (Scheme 15).

Scheme 13. Synthesis of the Julia–Kocienski intermediates.

6044

www.eurjoc.org

Eur. J. Org. Chem. 2011, 6039–6055

Synthesis of the 4,19-Diol Derivative of (–)-Mycothiazole

Scheme 16. Synthesis of keto ester 57.

Of all the conditions tested on the preceding α-hydroxy

ketone, we chose the simple iodide/lithium exchange in the

presence of nBuLi at –78 °C (Scheme 17). By using THF as

solvent, compound 61 was isolated due to the acidity of

the proton at the 2-position in the thiazole ring and the

concomitant formation of the supposed intermediate 63. In

Et₂O, a less coordinating solvent than THF, 62 displayed

less basic character and the addition could be performed

with the keto ester 57 more rapidly than deprotonation at

C2, leading to the desired coupling product 58 in a 42%

isolated yield and recovery of excess of keto ester 57. This

difference in selectivity in THF and Et₂O has already been

described by Cossy and co-workers during the formylation

Scheme 14. Synthesis of ketone 51.

1

of bromothiazole derivatives.^[4c]Analysis of the H NMR

spectrum (see the Supporting Information) showed two dif-

ferent signals in the aromatic area: One doublet at δ =

7.24 ppm, which integrated for two protons, and another

doublet at δ = 6.84 ppm, which integrated for three protons.

NOESY experiments allowed the different signals to be as-

signed: Thus, the doublet at δ = 7.24 ppm was assigned to

Scheme 15. Vinyl iodide subunit synthesis.

With these fragments in hand, we investigated the cou-

pling step. We first tested Grignard conditions as described

by Kogen and co-workers^[40]for the synthesis of (+)-benzast-

atine or by Eustache and co-workers^[13b]for the fumagilline

series, but only the starting materials were recovered, which

indicates that the magnesium insertion did not take place.

The method developed by Knochel and co-workers,

using isopropylmagnesium bromide^[41a]or an iPrMgCl·LiCl

complex^[41b]to carry out the iodide/magnesium exchange,

was not successful either, even though the exchange was

proven as the olefin was observed after loss of iodide. An

alternative approach based on an iodide/lithium exchange

followed by a transmetalation with MgBr₂gave the same

result.^[42]Use of tBuLi only gave degradation products as

well. Finally, the Nozaki–Hiyama–Kishi reaction^[43]gave

only ketone 51 and the olefin analogue of 49. All these re-

sults show that the exchange takes place but that the reac-

tivity of the ketone has to be increased. Addition of a Lewis

acid was first envisaged but abandoned due to the fragility

of the different substrates. Introduction of an electron-with-

drawing group at the α position of the ketone could be a

solution, leading to an α-hydroxy ester, which could be re-

duced to the desired diol (Figure 6).

Therefore we turned our attention to the synthesis of

keto ester 57 (Scheme 16). Oxidation of aldehyde 50 accord-

ing to the Pinnick reaction^[44]gave acid 59, which – after

esterification and dihydroxilation/oxidation – gave keto es-

ter 57 with a 12% overall yield.

Scheme 17. Access to the desired coupling product 58.

Eur. J. Org. Chem. 2011, 6039–6055

www.eurjoc.org

6045

F. Batt, F. Fache

FULL PAPER

the two aromatic protons H_Adue to the correlation with prove the absolute configuration of the two chiral centers.

the singlet signal of the methoxy group at δ = 3.81 ppm. One of our intermediates, alcohol 27, could be obtained in

Part of the signal at δ = 6.84 ppm was attributed to the two its chiral form by an asymmetric allylation under Barbier

H_Baromatic protons, which correlate with the CH₂group conditions with the addition of chiral auxiliaries such as

(C1) at δ = 4.37 ppm, and the other proton was unambigu- amino alcohols,^[45]camphor derivatives,^[46]or cinchon-

ously assigned to the aromatic proton on the thiazole ring. ine.^[47]Oxidation of the alcohol function and subsequent

This proton signal correlates with that of the C13 protons Corey–Bakshi–Shibata^[48]reduction may be another pos-

at 2.93–2.97 ppm. These NMR experiments confirmed the sibility for controlling the center at C8. As for the chiral

successful coupling that led to compound 58.

center at C4, there are several possibilities. The coupling

The hydroxy ester 58 was reduced with LiAlH₄and a could be performed diastereoselectively under the control

mixture of diol 65 and aldehyde 64 was thus obtained of the C8 center. If not, the two diastereoisomers could be

(Scheme 18). These two products were easily separated by separated at the hydroxy ester level or at the diol level.

flash chromatography. Aldehyde 64 was reduced to diol 65 Derivatization of the diol with a chiral auxiliary could also

by repeating the same procedure (35% isolated yield in the lead to separable isomers. Replacement in compound 57 of

two steps, unoptimized).

the tert-butyl group by a bulky chiral moiety like 8-phen-

ylmenthol could also be considered. Further studies are in

progress in our laboratory to test these different possibilities

and to propose a complete synthesis and a definitive reliable

assignment of the different stereogenic centers of the 4,19-

diol derivative of mycothiazole.

Experimental Section

1

General: H and ¹³C NMR spectra were recorded either in CDCl₃

or in C₆D₆solvent with a Bruker AM 300 MHz, 500 MHz, or

75 MHz spectrometer at ambient temperature, which provided all

the necessary data for the full assignment of each compound.

Chemical shifts δ are given in ppm, coupling constants J are in Hz.

The chemical shifts are reported in ppm upfield from TMS as an

internal standard and signal patterns are indicated as follows: s,

singlet; d, doublet; dd, doublet of doublets; dt, doublet of triplets;

t, triplet; m, multiplet, br., broad singlet. High-resolution mass

Scheme 18. Synthesis of the diol 65.

spectrometry (HRMS) analyses were conducted by using

a

With compound 65 in hand, we now have at our disposal

a valuable key intermediate for the 4,19-diol skeleton. The

two lateral side-chains can be introduced according to the

previously described methods: The 1,4-diene part by a Wit-

tig reaction, as proposed by Rodriguez and co-workers,^[14]

and the carbamate moiety by introduction of a tosylate

function in place of the PMB group, according to the syn-

ThermoFinigan-MAT 95 XL instrument. Optical rotations were

measured with a digital polarimeter using a 5 mL cell with a 1 dm

pathlength. IR spectra were measured with a Perkin–Elmer Spec-

trum One FT-IR spectrometer. TLC analyses were performed on

plates (layer thickness 0.25 mm) and were visualized with UV light,

phosphomolybdic acid, or p-anisaldehyde solution. Column

chromatography was performed on silica gel (40–63 μm) using tech-

thesis of Shioiri and co-workers.^[2]This leaving group could nical-grade ethyl acetate (EtOAc) and petroleum ether (EP). When

appropriate, solvents and reagents were dried by distillation over

an appropriate drying agent prior to use. Diethyl ether and tetra-

hydrofuran were distilled from Na/benzophenone and used fresh.

Dichloromethane was distilled from CaH₂. All the reactions were

performed under nitrogen in flame- or oven-dried glassware with

magnetic stirring.

then be substituted by NaN₃, the azide obtained reduced

with triphenylphosphane, and upon treatment with methyl

chlorocarbonate we could have access to the desired carb-

amate. To perform such reactions, there has to be a careful

choice of protecting groups that can be selectively cleaved.

Protection of the diol function as a ketal also has to be

considered.

2-[2-(2,2-Dimethyl-4-vinyl-1,3-dioxolan-4-yl)ethyl]isoindoline-1,3-di-

one (3): nBuLi (1 m in hexane, 2.49 mL, 2.49 mmol) was added to

a

solution of methyltriphenylphosphonium bromide (889 mg,

2.48 mmol) in THF (11 mL) at 0 °C. The mixture was stirred for

10 min at 0 °C and then for 45 min at room temperature then co-

oled again to 0 °C before a solution of compound 13 (520 mg,

1.66 mmol) in THF (5 mL) was added dropwise. The resulting solu-

tion was stirred at room temperature for an additional 2 h and then

quenched by an aqueous saturated NH₄Cl solution (10 mL). The

aqueous phase was extracted with EtOAc (3ϫ10 mL), the com-

bined organic phases washed with water (10 mL) and brine

(10 mL), and then dried (MgSO₄). After evaporation of the solvent,

Conclusions

We have reported herein the first approach to the skel-

eton of the 4,19-diol derivative of mycothiazole. To the best

of our knowledge, no synthesis, neither total nor partial,

has been reported so far. One has to bear in mind that the

structure of the 4,19-diol derivative of the mycothiazole has

not yet been fully established. The asymmetric version of

this synthesis would have to be considered if we were to compound 3 was obtained by flash chromatography (hexanes/

6046

www.eurjoc.org

Eur. J. Org. Chem. 2011, 6039–6055

Synthesis of the 4,19-Diol Derivative of (–)-Mycothiazole

EtOAc, 85:15) in 50% isolated yield (323 mg, 0.77 mmol). ¹H

quantitatively 11 as a pale-yellow oil. ¹H NMR (300 MHz, CDCl₃):

NMR (300 MHz, CDCl₃): δ = 1.36 (s, 3 H), 1.46 (s, 3 H), 1.99 δ = 2.68 (t, J = 6.4 Hz, 2 H), 2.95 (s, 3 H), 4.29 (t, J = 6.4 Hz, 2

(ddd, J = 23.9, 10.3, 5.4 Hz, 2 H), 3.62–3.89 (m, 2 H), 3.85 (d, J =

5.5 Hz, 2 H), 5.19 (dd, J = 10.9, 1.3 Hz, 1 H), 5.40 (dd, J = 17.3,

H), 6.16 (s, 1 H), 6.42 (s, 1 H), 9.52 (s, 1 H) ppm. ¹³C NMR

(75 MHz, CDCl₃): δ = 28.7, 37.7, 67.6, 137.5, 144.8, 194.2 ppm. IR

1.3 Hz, 1 H), 5.88 (dd, J = 17.3, 10.9 Hz, 1 H), 7.67–7.86 (m, 4 (film, NaCl): ν = 2947, 2847, 1770, 1712, 1449, 1402, 1371, 1330,

˜

H) ppm. ¹³C NMR (75 MHz, CDCl₃): δ = 26.3, 27.3, 33.9, 36.6,

74.0, 82.3, 110.4, 115.3, 123.3, 132.4, 134.0, 139.4, 168.4 ppm. In

agreement with reported data.^[49].

1191, 1103, 1044, 724 cm^–1.

2-{2-[4-(1,5-Dihydrobenzo[e][1,3]dioxepin-3-yl)-2,2-dimethyl-1,3-di-

oxolan-4-yl]ethyl}isoindoline-1,3-dione (12): A solution of com-

pound 4 (1.26 g, 4.23 mmol) and potassium phthalimide (2.34 g,

12.68 mmol) was stirred in DMF (40 mL) at 80 °C for 2 h. After

cooling, the reaction mixture was quenched by the addition of

water (20 mL). The aqueous phase was extracted with EtOAc

(3ϫ40 mL) and the combined organic phases were dried (MgSO₄),

filtered, and concentrated in vacuo. The residue was purified by

flash chromatography (hexanes/EtOAc, 85:15) to yield the phthali-

midate intermediate in 57% isolated yield (841 mg, 2.41 mmol). ¹H

NMR (300 MHz, CDCl₃): δ = 2.54 (t, J = 7.1 Hz, 2 H), 3.85 (t, J

3-(1,5-Dihydrobenzo[e][1,3]dioxepin-3-yl)but-3-en-1-yl Methanesulf-

onate (4): A solution of 11 (1.72 g, 9.66 mmol), benzenedimethanol

(2 g, 14.5 mmol), and p-toluenesulfonic acid (183 mg, 0.96 mmol)

in benzene (75 mL) was heated at reflux for 1 h using a Dean Stark

apparatus. The reaction mixture was quenched by the addition of

a saturated Na₂CO₃solution (10 mL) and washed with brine

(10 mL). After separation, the organic phase was dried (MgSO₄)

and concentrated in vacuo. The residue thus obtained was purified

by flash chromatography (hexanes/EtOAc, 7:3) to give 4 as a color-

1

less oil (44% isolated yield from 5). H NMR (300 MHz, CDCl₃): = 7.1 Hz, 2 H), 4.82 (br. s, 4 H), 5.08 (s, 1 H), 5.35 (s, 1 H), 5.36

δ = 2.61 (t, J = 6.4 Hz, 2 H), 2.98 (s, 3 H), 4.37 (t, J = 6.4 Hz, 2

(s, 1 H), 7.02–7.19 (m, 4 H), 7.58–7.80 (m, 4 H) ppm. ¹³C NMR

H), 4.89 (s, 4 H), 5.17 (s, 1 H), 5.29 (s, 1 H), 5.45 (s, 1 H), 7.12–

(75 MHz, CDCl₃): δ = 31.1, 37.0, 70.1, 104.8, 115.3, 123.2, 127.0,

7.28 (m, 4 H) ppm. ¹³C NMR (75 MHz, CDCl₃): δ = 32.2, 37.8, 127.2, 132.2, 133.9, 138.9, 142.4, 168.3 ppm. IR (film, NaCl): ν =

˜

68.9, 71.3, 106.8, 116.7, 127.6, 127.8, 139.1, 140.9 ppm. IR (film,

3063, 2924, 2853, 1771, 1713, 1457, 1444, 1396, 1357, 1266, 1189,

NaCl): ν = 2873, 1451, 1357, 1196, 1081, 1042, 754 cm^–1.

1125, 1027, 926, 869, 719 cm^–1.

˜

2-[4-(Bromomethyl)thiazol-2-yl]-2-methylhex-5-en-3-ol (6): A solu-

OsO₄(4% in water, 284 μL, 46.4 μmol) and NMO (627 mg,

tion of magnesium bromide (1 m in Et₂O, 0.23 mL, 0.23 mmol) was 4.64 mmol) were added to a solution of the preceding intermediate

added dropwise to a solution of aldehyde 19 (59 mg, 0.23 mmol) in

anhydrous THF (4 mL) at –78 °C under nitrogen. After 35 min of

stirring at this temperature, the solution was quenched by addition

of a saturated NH₄Cl solution (5 mL). The aqueous phase was ex-

tracted with EtOAc (3ϫ10 mL). The combined organic extracts

were dried (MgSO₄), filtered, and concentrated. Purification of the

residue by flash chromatography on silica gel (hexanes/EtOAc,

95:5) gave the homoallylic alcohol 6 as a colorless oil in 67% iso-

lated yield (borsm). ¹H NMR (300 MHz, CDCl₃): δ = 1.42 (s, 3

H), 1.45 (s, 3 H), 1.94–2.08 (m, 1 H), 2.12–2.35 (m, 1 H), 3.76 (dd,

J = 10.0, 2.7 Hz, 1 H), 4.53 (s, 2 H), 5.04–5.10 (m, 2 H), 5.87 (ddt,

J = 16.9, 10.1, 6.7 Hz, 1 H), 7.18 (s, 1 H) ppm. ¹³C NMR (75 MHz,

CDCl₃): δ = 24.6, 27.0, 27.4, 36.9, 45.3, 77.9, 116.8, 117.2, 136.3,

(811 mg, 2.32 mmol) in a mixture of water/acetone (1:1, 20 mL).

The reaction mixture was stirred at room temperature for 2 d and

then extracted with CH₂Cl₂(3ϫ40 mL). The combined organic

phases were dried (MgSO₄), filtered, and concentrated in vacuo to

give the corresponding diol in 96% isolated yield (854 mg,

2.22 mmol); m.p. 156.1 °C. ¹H NMR (300 MHz, CDCl₃): δ = 1.85–

2.11 (m, 2 H), 3.01 (br. s, 2 H), 3.57 (d, J_AB= 11.5 Hz, 1/2 AB),

3.78 (d, J_AB= 11.5 Hz, 1/2 AB), 3.84–3.95 (m, 2 H), 4.81–4.99 (m,

4 H), 5.01 (s, 1 H), 7.11–7.30 (m, 4 H), 7.63–7.85 (m, 4 H) ppm.

¹³C NMR (75 MHz, CDCl₃): δ = 31.5, 33.4, 65.4, 74.4, 74.9, 112.3,

123.4, 128.4, 132.5, 134.1, 139.4, 168.3 ppm. HRMS (ESI): calcd.

for C₂₁H₂₁NNaO₆[M + Na]⁺406.1261; found 406.1258.

A solution of the crude product (854 mg, 2.22 mmol), 2,2-dimeth-

oxypropane (593 μL, 4.83 mmol), and p-toluenesulfonic acid

(23 mg, 0.12 mmol) in CH₂Cl₂(25 mL) was stirred for 2 h at room

temperature. The reaction mixture was quenched by the addition

of a saturated NaHCO₃solution (5 mL) and the aqueous phase

was extracted with CH₂Cl₂(3ϫ10 mL). The combined organic

phases were dried (MgSO₄), filtered, and concentrated in vacuo.

The residue was purified by flash chromatography (hexanes/EtOAc,

80:20 then 50:50) to yield compound 12 in 83% isolated yield

151.7, 180.1 ppm. IR (film, NaCl): ν = 3412, 2969, 2925, 1640,

˜

1463, 1421, 1360, 1199, 1051, 910, 732 cm^–1. HRMS (ESI): calcd.

for C₁₁H₁₇BrNOS [M + H]⁺290.0209; found 290.0205.

2-Methylenebutane-1,4-diol (9): DIBAL (100 mL of a 1 m solution

in hexanes, 100 mmol) was added to a 0 °C solution of dimethyl

itaconate (5; 3.19 mL, 22.7 mmol) in THF (150 mL) . After stirring

for 5 h at room temperature, the reaction mixture was quenched by

the addition of a H₂SO₄solution (5 m) until pH 1. The precipitate

was then filtered off and the aqueous layer was extracted with

EtOAc (5ϫ20 mL). The combined organic phases were dried

1

(782 mg, 1.85 mmol). H NMR (300 MHz, CDCl₃): δ = 1.46 (s, 3

H), 1.50 (s, 3 H), 2.10 (ddd, J = 6.4, 3.9, 2.6 Hz, 2 H), 3.88 (ddd,

J = 6.4, 3.9, 2.1 Hz, 2 H), 3.93 (d, J_AB= 9 Hz, 1/2 AB), 4.18 (d,

(MgSO₄) and concentrated in vacuo to afford diol 9 (98% isolated

1

yield). H NMR (300 MHz, CDCl₃): δ = 2.37 (t, J = 5.9 Hz, 2 H), J_AB= 9 Hz, 1/2 AB), 4.86–5.02 (m, 5 H), 7.12–7.28 (m, 4 H), 7.62–

2.60 (br. s, 1 H, OH), 3.75 (t, J = 5.9 Hz, 2 H), 4.10 (s, 2 H), 4.97

7.88 (m, 4 H) ppm. ¹³C NMR (75 MHz, CDCl₃): δ = 26.7, 27.1,

32.4, 33.8, 70.3, 74.4, 83.1, 110.8, 110.9, 123.3, 128.2, 132.5, 134.0,

(s, 1 H), 5.13 (s, 1 H) ppm. ¹³C NMR (75 MHz, CDCl₃): δ = 37.0,

61.6, 66.0, 113.3, 146.2 ppm. IR (film, NaCl): ν = 3340, 2931, 1652,

139.5, 168.4 ppm. IR (film, NaCl): ν = 3412, 3052, 2987, 2847,

˜

1435, 1044, 909 cm^–1. In agreement with reported data.^[50]

1771, 1722, 1449, 1372, 1265, 1198, 1105, 1060, 736 cm^–1. HRMS

(ESI): calcd. for C₂₄H₂₅NNaO₆[M + Na]⁺446.1574; found

446.1569.

3-Formylbut-3-en-1-yl Methanesulfonate (11): Et₃N (426 μL,

3.3 mmol) and mesyl chloride (378 mg, 3.3 mmol) were added to a

solution of 10 (220 mg, 2.2 mmol) in CH₂Cl₂(20 mL) at 0 °C. After 4-[2-(1,3-Dioxoisoindolin-2-yl)ethyl]-2,2-dimethyl-1,3-dioxolane-4-

stirring for 1 h at room temperature, the reaction mixture was

quenched by the addition of ca. 20 mL of a saturated NH₄Cl solu-

tion. The organic phase was then evaporated and the aqueous

phase was extracted with Et₂O (3ϫ20 mL). The combined organic

phases were dried (MgSO₄) and concentrated in vacuo to afford

carbaldehyde (13): A solution of compound 12 (500 mg, 1.18 mmol)

and PdO (1.4 mg, 11.08 μmol) in THF (1.2 mL) was heated at

100 °C under 20 bar H₂in a stainless steel pressure apparatus for

20 h. After cooling, the residue was filtered and washed with Et₂O.

Evaporation of the solvent gave the pure aldehyde 13 in 40% iso-

Eur. J. Org. Chem. 2011, 6039–6055

www.eurjoc.org

6047

F. Batt, F. Fache

FULL PAPER

1

lated yield (144 mg, 0.472 mmol). H NMR (300 MHz, CDCl₃): δ

= 1.37 (s, 6 H), 2.11 (ddd, J = 14.0,7.9, 2.3 Hz, 2 H), 3.77 (ddd, J

= 14.0, 7.9, 1.3 Hz, 2 H), 3.85 (d, J_AB= 9.1 Hz, 1/2 AB), 4.13 (d,

J_AB= 9.0 Hz, 1/2 AB), 7.68–7.39 (m, 4 H), 9.67 (s, 1 H) ppm. ¹³C

NMR (75 MHz, CDCl₃): δ = 26.6, 32.0, 33.5, 70.5, 86.4, 112.2,

123.5, 132.5, 134.3, 168.4, 203.0 ppm.

2-{2-[(tert-Butyldimethylsilyl)oxy]ethyl}oxirane-2-carbaldehyde (24):

A solution of γ-hydroxy aldehyde 10 (4.20 g, 42 mmol), imidazole

(3.43 g, 50.4 mmol), and DMAP (154 mg, 1.3 mmol) in CH₂Cl₂

(150 mL) was treated with TBSCl (7.59 g, 50.4 mmol) for 30 min.

The reaction mixture was then quenched with water (100 mL). The

aqueous phase was extracted with CH₂Cl₂(3ϫ100 mL) and the

combined organic phases were washed with brine, dried (MgSO₄),

filtered, and concentrated. Purification of the residue by flash

chromatography on silica gel (hexanes/EtOAc, 95:5) gave the TBS

ether as a colorless oil in 54% isolated yield (4.85 g, 22.7 mmol).

¹H NMR (300 MHz, CDCl₃): δ = 0.02 (s, 6 H), 0.87 (s, 9 H), 2.47

(t, J = 6.4 Hz, 2 H), 3.69 (t, J = 6.4 Hz, 2 H), 6.06 (s, 1 H), 6.37

(s, 1 H), 9.53 (s, 1 H) ppm. ¹³C NMR (75 MHz, CDCl₃): δ = –5.4,

2-[4-(Bromomethyl)thiazol-2-yl]-2-methylpropanal (19): HF·pyridine

(8 μL, 0.11 mmol) was added to a solution of compound 18 (54 mg,

0.11 mmol) in CH₃CN (1 mL) at 0 °C. The reaction mixture was

stirred at room temperature for 20 h. The solvent was evaporated

and the crude product purified by flash chromatography on silica

gel (hexanes/EtOAc, 70:30) to afford the corresponding alcohol in

71% isolated yield (19 mg, 78 μmol). ¹H NMR (300 MHz, CDCl₃):

18.2, 25.9, 31.4, 61.0, 135.8, 147.1, 194.4 ppm. IR (film, NaCl): ν

˜

δ = 1.41 (s, 6 H), 3.72 (s, 2 H), 4.54 (s, 2 H), 7.19 (s, 1 H) ppm. ¹³

C

= 2956, 2930, 2858, 1693, 1472, 1462, 1256, 1101, 1055, 925, 835,

NMR (75 MHz, CDCl₃): δ = 26.1, 27.3, 40.9, 71.4, 116.6, 151.3,

776 cm^–1.

180.0 ppm. IR (film, NaCl): ν = 3401, 2919, 1198, 1055 cm^–1.

˜

The urea–H₂O₂complex (35wt.-%, 2.95 g, 10.64 mmol) was added

to the TBS ether (759 mg, 3.54 mmol) in MeOH (35 mL). After

complete dissolution, a 1 m solution of NaOH (1 mL, 1 mmol) was

added at 0 °C. After stirring for 3 h at room temperature, the reac-

tion mixture was treated with brine (10 mL). The aqueous phase

was extracted with EtOAc (3ϫ50 mL) and the combined organic

phases were dried (MgSO₄), filtered, and concentrated. Purification

of the residue by flash chromatography on silica gel (hexanes/

EtOAc, 95:5) gave the epoxy aldehyde 24 as a colorless oil in 50%

Dess–Martin periodinane (15wt.-%, 514 mL, 0.24 mmol) was

added at 0 °C under nitrogen to a solution of the alcohol (50 mg,

0.20 mmol) in CH₂Cl₂(2 mL). The resulting mixture was stirred at

room temperature for 3 h. A 1:1 saturated NaHCO₃/Na₂S₂O₃solu-

tion (2 mL) was then added. The aqueous phase was separated and

extracted with CH₂Cl₂(3ϫ5 mL). The combined organic extracts

were dried (MgSO₄), filtered and concentrated. Purification of the

residue by flash chromatography on silica gel (hexanes/EtOAc,

95:5) gave aldehyde 19 as a colorless oil in 67% isolated yield

(33 mg, 0.13 mmol). ¹H NMR (300 MHz, CDCl₃): δ = 1.59 (s, 6

H), 4.58 (s, 2 H), 7.29 (s, 1 H), 9.69 (s, 1 H) ppm. ¹³C NMR

(75 MHz, CDCl₃): δ = 23.3, 27.3, 52.3, 118.2, 152.9, 172.9,

1

isolated yield (407 mg, 1.77 mmol). H NMR (300 MHz, CDCl₃):

δ = 0.02 (s, 6 H), 0.84 (s, 9 H), 1.98–2.12 (m, 2 H), 3.01 (d, J_AB

=

4.9 Hz, 1/2 AB), 3.13 (d, J_AB= 9.7 Hz, 1/2 AB), 3.69–3.81 (m, 2

H), 8.93 (s, 1 H) ppm. ¹³C NMR (75 MHz, CDCl₃): δ = –5.4, 18.3,

25.9, 31.2, 50.3, 58.6, 59.4, 198.9 ppm.

200.0 ppm. IR (film, NaCl): ν = 2934, 2927, 2710, 1736, 1199 cm^–1.

˜

2-[2-(tert-Butyldimethylsilyloxy)ethyl]but-2-enal (25): A solution of

epoxide 22 (46 mg, 0.2 mmol) and alcohol 6 (58 mg, 0.2 mmol) in

CH₂Cl₂(2 mL) was heated at reflux for 6 h with the G_Icatalyst

(4.2 mg, 5.1 μmol). The reaction mixture was cooled, concentrated

in vacuo and the crude product purified by flash chromatography

(hexanes/EtOAc, 98:2). Compound 6 was recovered untouched and

aldehyde 25 was obtained in 95% isolated yield (43 mg,

2-[3-Hydroxy-3-(hydroxymethyl)pent-4-en-1-yl]isoindoline-1,3-dione

(20): A solution of 3 (15 mg, 43 μmol) in THF/HCl (1 m, 1:1, 1 mL)

was heated at reflux for 10 h. After cooling, the mixture was ex-

tracted with EtOAc (3ϫ5 mL) and the combined organic phases

dried (MgSO₄), filtered, and concentrated in vacuo to provide 20

in 98% isolated yield (11 mg; 42 μmol). ¹H NMR (300 MHz,

CDCl₃): δ = 1.88–2.05 (m, 2 H), 2.87 (br. s, 2 H, OH), 3.47 (s, 2

H), 3.81 (t, J = 7.0 Hz, 1 H), 5.15 (dd, J = 10.9, 0.7 Hz, 1 H), 5.35

(dd, J = 17.3, 0.7 Hz, 1 H), 5.75 (dd, J = 17.3, 10.9 Hz, 1 H), 7.68–

7.85 (m, 4 H) ppm. HRMS (ESI): calcd. for C₁₄H₁₅NNaO₄[M +

Na]⁺284.0893; found 284.0893.

1

0.19 mmol). H NMR (300 MHz, CDCl₃): δ = 0.00 (s, 6 H), 0.86

(s, 9 H), 2.01 (d, J = 7.0 Hz, 3 H), 2.50 (t, J = 6.6 Hz, 2 H), 3.61

(t, J = 6.6 Hz, 2 H), 6.67 (q, J = 7.0 Hz, 1 H), 9.37 (s, 1 H) ppm.

¹³C NMR (75 MHz, CDCl₃): δ = –5.2, 15.4, 18.4, 26.0, 27.6, 61.5,

141.7, 152.0, 195.1 ppm. IR (film, NaCl): ν = 2946, 2929, 2857,

˜

1685, 1472, 1256, 1131, 836 cm^–1. HRMS (CI): calcd. for

C₁₂H₂₅O₂Si 229.1624; found 229.1619.

tert-Butyldimethyl[2-(2-vinyloxiran-2-yl)ethoxy]silane (22): A solu-

tion of methylenetriphenylphosphonium bromide (959 mg,

2.68 mmol) in THF (20 mL) was treated with nBuli (1.3 m in hex-

ane, 1.79 mL, 2.32 mmol) at 0 °C. The mixture was stirred for

10 min at 0 °C and then at 45 min at room temperature and then

cooled again to 0 °C before a solution of aldehyde 24 (412 mg,

1.79 mmol) in THF (20 mL) was added dropwise. The resulting

solution was stirred at room temperature for an additional 30 min

and then quenched by the addition of a saturated NH₄Cl solution

(10 mL). The aqueous phase was extracted with EtOAc (3ϫ20 mL)

and the combined organic phases were washed with water (20 mL)

and brine and (20 mL) then dried (MgSO₄). After evaporation of

the solvent, compound 22 was obtained by flash chromatography

(hexanes/EtOAc, 98:2) as a colorless oil in 50% isolated yield

(204 mg, 0.89 mmol). ¹H NMR (300 MHz, CDCl₃): δ = –0.01 (s, 6

H), 0.83 (s, 9 H), 1.72–1.99 (m, 2 H), 2.60 (d, J_AB= 5.5 Hz, 1/2

AB), 2.83 (d, J_AB= 5.5 Hz, 1/2 AB), 3.67 (td, J = 6.7, 1.7 Hz, 2

H), 5.13 (dd, J = 10.7, 1.1 Hz, 1 H), 5.27 (dd, J = 17.1, 1.1 Hz, 1

5-[(4-Methoxybenzyl)oxy]pent-1-en-3-one (26). Route A: A solution

of vinylmagnesium bromide (0.7 m in THF, 43 mL, 30.3 mmol) was

added to a solution of aldehyde 30 (4.90 g, 25.2 mmol) in THF

(100 mL) at 0 °C. After stirring for 1 h at this temperature, the reac-

tion mixture was quenched by the addition of a saturated NH₄Cl

solution (50 mL). THF was evaporated in vacuo and the aqueous

phase was extracted with Et₂O (3ϫ50 mL). The combined organic

phases were washed with water (20 mL) and brine (20 mL), and

dried (MgSO₄). After filtration and concentration, the residue was

purified by flash chromatography (hexanes/EtOAc, 80:20) to give

the intermediate alcohol in 81% isolated yield (4.56 g, 20.5 mmol)

1

as a colorless oil. H NMR (300 MHz, CDCl₃): δ = 1.78–1.91 (m,

2 H), 3.15 (br. s, 1 H, OH), 3.53–3.68 (m, 2 H), 3.79 (s, 3 H), 4.33

(dt, J = 6.0, 5.7 Hz, 1 H), 4.45 (s, 2 H), 5.09 (dd, J = 10.4, 1.5 Hz,

1 H), 5.25 (dd, J = 17.1, 1.5 Hz, 1 H), 5.87 (ddd, J = 17.1, 10.4,

6.0 Hz, 1 H), 6.88 (d, J = 8.7 Hz, 2 H), 7.25 (d, J = 8.7 Hz, 2

H), 5.73 (dd, J = 17.1, 10.1 Hz, 1 H) ppm. ¹³C NMR (75 MHz, H) ppm. ¹³C NMR (75 MHz, CDCl₃): δ = 36.3, 55.2, 67.8, 71.5,

CDCl₃): δ = –5.3, 18.3, 26.0, 36.7, 55.2, 56.8, 59.5, 116.4,

137.7 ppm.

72.8, 113.7, 114.2, 129.3, 130.0, 140.6, 159.2 ppm. IR (film, NaCl):

˜

ν = 3349, 2944, 2873, 1423, 1129, 1054, 991, 924 cm^–1.

6048

www.eurjoc.org

Eur. J. Org. Chem. 2011, 6039–6055

Synthesis of the 4,19-Diol Derivative of (–)-Mycothiazole

Compound 26: To a solution of this intermediate in THF (100 mL)

was added a solution of IBX (7.97 g, 28.6 mmol) in DMSO

(15 mL). After stirring for 6 h, water (20 mL) was added. After

filtration, the residue was washed with CH₂Cl₂(50 mL). The aque-

ous phase was extracted with CH₂Cl₂(3ϫ20 mL), dried (MgSO₄),

filtered and concentrated in vacuo. The crude product was purified

by flash chromatography (hexanes/EtOAc, 90:10), and compound

26 was recovered in 80% isolated yield (3.53 g, 25.5 mmol). ¹H

NMR (300 MHz, CDCl₃): δ = 2.89 (t, J = 6.4 Hz, 2 H), 3.77 (t, J

= 6.4 Hz, 2 H), 3.80 (s, 3 H), 4.45 (s, 2 H), 5.86 (dd, J = 10.1,

1.3 Hz, 1 H), 6.22 (dd, J = 17.7, 1.3 Hz, 1 H), 6.33 (dd, J = 17.7,

10.1 Hz, 1 H), 6.87 (d, J = 8.7 Hz, 2 H), 7.24 (d, J = 8.7 Hz, 2

H) ppm. ¹³C NMR (75 MHz, CDCl₃): δ = 39.2, 54.7, 64.6, 72.4,

113.4, 128.1, 128.9, 129.9, 136.3, 158.8, 198.3 ppm. IR (film, NaCl):

3-[(4-Methoxybenzyl)oxy]propanal (30): Camphorsulfonic acid

(1.16 g, 5 mmol) and p-methoxybenzyl trichloroacetamidate

(29.06 g, 100 mmol) were added to a solution of 1,3-propanediol

(7.36 mL, 101 mmol) in a mixture of cyclohexane/CH₂Cl₂(2:1,

100 mL). After stirring for 10 h, the reaction mixture was quenched

with a saturated NaHCO₃solution (50 mL). The aqueous phase

was extracted with CH₂Cl₂(3ϫ50 mL) and the combined organic

layers were washed with brine (30 mL), dried (MgSO₄), filtered,

and concentrated in vacuo. The crude product was purified by flash

chromatography (hexanes/EtOAc, 80:20) and the desired monopro-

tected diol was recovered in 59% isolated yield (11.36 g, 58 mmol)

1

as a colorless oil. H NMR (300 MHz, CDCl₃): δ = 2.55 (quint., J

= 6.0 Hz, 2 H), 2.87 (br. s, 1 H, OH), 3.59 (t, J = 6.0 Hz, 2 H),

3.72 (t, J = 6.0 Hz, 2 H), 3.76 (s, 3 H), 4.42 (s, 2 H), 6.85 (d, J =

8.7 Hz, 2 H), 7.23 (d, J = 8.7 Hz, 2 H) ppm. ¹³C NMR (75 MHz,

CDCl₃): δ = 32.2, 55.2, 62.2, 68.6, 72.8, 113.8, 129.3, 130.2,

159.2 ppm.

ν = 2928, 2906, 2868, 1731, 1680, 1613, 1513, 1247, 1098,

˜

1034 cm^–1.

Route B: The conditions described for the synthesis of compound

30 from butanediol were applied to compound 32 to yield 26 (see

below).

The alcohol (5.88 g, 30 mmol) was treated with a solution of IBX

(10.04 g, 36 mmol) in DMSO (20 mL). After stirring for 4 h water

(50 mL) was added to the reaction mixture, which was then filtered

through Celite and the insoluble residue was washed with CH₂Cl₂

(3ϫ50 mL). The combined organic layers were washed with water

(3ϫ50 mL), dried (MgSO₄), and concentrated. The crude product

was purified by flash chromatography (hexanes/EtOAc, 85:15) and

aldehyde 30 was recovered in 85% isolated yield (4.94 g,

25.5 mmol) as a colorless oil. ¹H NMR (300 MHz, CDCl₃): δ =

2.55 (dt, J = 6.0, 1.9 Hz, 2 H), 3.65 (t, J = 6.0 Hz, 2 H), 3.67 (s, 3

H), 4.34 (s, 2 H), 6.77 (d, J = 8.7 Hz, 2 H), 7.14 (d, J = 8.7 Hz, 2

H), 9.65 (t, J = 1.9 Hz, 1 H) ppm. ¹³C NMR (75 MHz, CDCl₃): δ

= 43.8, 55.1, 63.4, 72.8, 113.8, 129.3, 129.9, 159.2, 201.2 ppm. In

agreement with reported data.^[51]

Methyl 2-[2-(3-Hydroxy-2-methylhex-5-en-2-yl)thiazol-4-yl]acetate

(27): Compound 34 was oxidized according to the procedure de-

scribed for compound 19 (94% isolated yield). Zinc (4.04 g,

62.2 mmol) and allyl bromide (5.40 mL, 62.2 mmol) were added to

a solution of the resulting aldehyde (3.53 g, 15.5 mol) in a 1:1 mix-

ture of THF/saturated NH₄Cl solution (50 mL) at 0 °C. After 48 h

stirring at room temperature, the solution was filtered, THF evapo-

rated in vacuo, and the aqueous phase extracted with EtOAc

(3ϫ50 mL). The combined organic phases were dried (MgSO₄),

filtered, and concentrated in vacuo. The crude product was purified

by flash chromatography (hexanes/EtOAc, 80:20) and alcohol 27

was recovered in 98% isolated yield (4.09 g, 15.2 mmol) as a color-

1

less oil. H NMR (300 MHz, CDCl₃): δ = 1.41 (s, 3 H), 1.45 (s, 3

tert-Butyl 3 Hydroxy-4-pentenoate (31): Freshly distilled diisopro-

pylamine (15.55 mL, 110 mmol) was diluted in dried THF

(500 mL) and to this solution was added dropwise at –78 °C nBuli

(1.6 m in hexane, 68.75 mL, 110 mmol). After stirring for 1.5 h at

this temperature, tert-butyl acetate (13.51 mL, 100 mmol) was

added dropwise. After another 1.5 h of stirring at –78 °C, acrolein

(8.91 mL, 120 mmol) was introduced dropwise. The mixture was

stirred at –78 °C for a further 10 min and the reaction was

quenched at this temperature by the addition of a 1 m solution of

HCl (50 mL). The resulting solution was allowed to warm to room

temperature and then concentrated. The organic layer was ex-

tracted with Et₂O (3ϫ100 mL) and the organic extracts were com-

bined, washed with water (50 mL) and brine (50 mL), and dried

(MgSO₄). After concentration, the crude product was purified by

flash chromatography (hexanes/EtOAc, 80:20). Compound 26 was

recovered in 87% isolated yield (14.98 g, 87 mmol). ¹H NMR

(300 MHz, CDCl₃): δ = 1.46 (s, 9 H), 2.42 (dd, J_AB= 16.2, 8.0 Hz,

1/2 AB), 2.51 (dd, J_AB= 16.2, 4.3 Hz, 1/2 AB), 4.45–4.51 (m, 1 H),

5.14 (dd, J = 10.5, 1.3 Hz, 1 H), 5.30 (dd, J = 15.6, 1.3 Hz, 1 H),

5.87 (ddd, J = 16.0, 10.5, 5.4 Hz, 1 H) ppm. ¹³C NMR (75 MHz,

CDCl₃): δ = 28.0, 42.2, 69.0, 81.3, 115.0, 139.0, 171.6 ppm. IR

H), 1.93–2.03 (m, 1 H), 2.24–2.36 (m, 1 H), 3.68–3.76 (m, 4 H),

3.81 (s, 2 H), 5.02–5.12 (m, 2 H), 5.90 (ddt, J = 17.0, 10.3, 7.1 Hz,

1 H), 7.07 (s, 1 H) ppm. ¹³C NMR (75 MHz, CDCl₃): δ = 24.4,

26.5, 36.6, 36.7, 44.7, 52.0, 77.8, 114.9, 116.5, 136.2, 147.9, 170.6,

178.7 ppm. IR (film, NaCl): ν = 3422, 2966, 1740, 1640, 1523, 1436,

˜

1161, 1052, 914 cm^–1. HRMS (ESI): calcd. for C₁₃H₂₀NO₃S [M +

H]⁺2709.1158; found 270.1158.

Methyl (E)-2-{2-[3-(tert-Butyldimethylsilyl)oxy]-6-(2-{2-[(4-meth-

oxybenzyl)oxy]ethyl}oxiran-2-yl)-2-methylhex-5-en-2-yl]thiazol-4-

yl}acetate (29): A solution of chlorohydrin 37 (141 mg, 0.23 mmol),

NaI (7 mg, 45 μmol), and NaH (60% in oil, 11 mg, 0.27 mmol) in

THF (1 mL) was stirred at 0 °C for 2 h and at room temperature for

an additional 30 min. The reaction was quenched with a saturated

NH₄Cl solution (1 mL), the aqueous phase extracted with EtOAc

(3ϫ5 mL), and the combined organic layers dried (MgSO₄). After

filtration and evaporation in vacuo, vinyl epoxide 29 was obtained

quantitatively (135 mg, 0.23 mmol) and used in the following step

without further purification as a colorless oil (mixture of two dia-

stereoisomers, 1:1). ¹H NMR (300 MHz, CDCl₃): δ = –0.11 (s, 3

H), 0.03 (s, 3 H), 0.87 (s, 9 H), 1.34 (s, 3 H), 1.39 (s, 3 H), 1.98–

2.15 (m, 3 H), 2.19–2.35 (m, 1 H), 2.60 (d, J = 5.2 Hz, 1 H), 2.82

(d, J = 5.2 Hz, 1 H), 3.49 (t, J = 6.6 Hz, 2 H), 3.71 (s, 3 H), 3.72–

3.82 (m, 5 H), 3.99 (t, J = 5.0 Hz, 1 H), 4.40 (s, 2 H), 5.24 (d, J =

15.6 Hz, 1 H), 5.74 (dt, J = 15.6, 7.2 Hz, 1 H), 6.87 (d, J = 8.5 Hz,

(film, NaCl): ν = 3442, 3014, 2980, 2933, 1732, 1646, 1457, 1394,

˜

1369, 1257, 1157, 1040, 993, 924, 880 cm^–1. In agreement with re-

ported data.^[52]

2 H), 7.02 (s, 1 H), 7.23 (d, J = 8.5 Hz) ppm. ¹³C NMR (75 MHz, 4-Pentene-1,3-diol (32): Ester 31 (1 g, 5.8 mmol) in Et₂O (10 mL)

CDCl₃): δ = –4.6, –3.6, 18.2, 21.1, 24.8, 25.9, 26.1, 33.7, 36.9, 37.3, was added dropwise to suspension of LiAlH₄(440 mg,

a

46.3, 52.0, 54.7, 55.3, 56.4, 66.1, 72.7, 78.8, 113.8, 115.1, 129.2,

130.4, 130.4, 130.9, 147.7, 159.2, 170.9, 178.1 ppm. IR (film, NaCl):

11.6 mmol) in Et₂O (20 mL) at 0 °C. After stirring at this tempera-

ture for 1 h, the mixture was quenched by the addition of water

(440 μL), 2 m NaOH (440 μL), and water again (880 μL). The reac-

tion mixture was stirred for 30 min at room temperature, dried

(MgSO₄), and concentrated in vacuo to give diol 32 nearly quanti-

ν = 2950, 2929, 2856, 1743, 1613, 1514, 1463, 1249, 1095, 1038,

˜

836 cm^–1. HRMS (ESI): calcd. for C₃₁H₄₇NO₆SSi [M + H]⁺

590.2972; found 590.2972.

Eur. J. Org. Chem. 2011, 6039–6055

www.eurjoc.org

6049

F. Batt, F. Fache

tatively (602 mg, 5.8 mmol). ¹H NMR (300 MHz, CDCl₃): δ = 1 H), 7.13 (s, 1 H) ppm. ¹³C NMR (75 MHz, CDCl₃): δ = –4.6,

FULL PAPER

1.62–1.88 (m, 2 H), 2.16 (br. s, 2 H, OH), 3.79–3.91 (m, 2 H), 4.40

(dddd, J = 12.0, 6.2, 5.9, 1.0 Hz, 1 H), 5.14 (d, J = 10.6 Hz, 1 H),

5.28 (d, J = 17.3 Hz, 1 H), 5.87 (ddd, J = 17.3, 10.6, 5.9 Hz, 1

H) ppm. ¹³C NMR (75 MHz, CDCl₃): δ = 38.3, 60.6, 72.2, 114.6,

–3.4, 18.3, 24.7, 25.9, 26.1, 37.1, 38.7, 46.3, 52.1, 79.0, 115.1, 116.1,

136.4, 147.8, 171.1, 178.4 ppm. IR (film, NaCl): ν = 2954, 2928,

˜

2857, 1746, 1472, 1255, 1093, 836, 775 cm^–1. HRMS (ESI): calcd.

for C₁₉H₃₄NO₃SSi [M + H]⁺384.2023; found 384.2028.

140.6 ppm. IR (film, NaCl): ν = 885, 924, 990, 1055, 1428, 2945,

˜

Methyl

(E)-2-(2-{3-[(tert-Butyldimethylsilyl)oxy]-9-[(4-methoxy-

3390 cm^–1. In agreement with reported data.^[53]

benzy)oxy]-2-methyl-7-oxonon-5-en-2-yl}thiazol-4-yl)acetate (36): A

solution of enone 26 (1.34 g, 6.11 mmol) and thiazole 35 (1.56 g,

4.07 mmol) in anhydrous CH₂Cl₂(20 mL) was purged by bubbling

with N₂for 10 min. Then Grubbs’ second-generation catalyst

(17 mg, 20 μmol, 0.5 mol-%) was added and the reaction mixture

was submitted to microwave irradiation at 50 °C for 15 min. This

procedure (catalyst addition, microwave irradiation) was repeated

five times (5ϫ0.5 mol-% G_II) to give 66% conversion. The solvent

was evaporated in vacuo and the residue purified by flash

chromatography (hexanes/EtOAc, 90:10) to give compound 36

[1.17 g, 2.03 mmol, 83% isolated yield (borsm)] as a colorless oil.

¹H NMR (300 MHz, CDCl₃): δ = –0.05 (s, 3 H), 0.02 (s, 3 H), 0.89

(s, 9 H), 1.36 (s, 3 H), 1.40 (s, 3 H), 2.20–2.45 (m, 2 H), 2.72 (t, J

= 6.6 Hz, 2 H), 3.70 (t, J = 6.6 Hz, 2 H), 3.70 (s, 3 H), 3.78 (s, 2

H), 3.79 (s, 3 H), 4.01 (t, J = 5.2 Hz, 1 H), 4.43 (s, 2 H), 5.90 (d,

J = 16.0 Hz, 1 H), 6.64 (dt, J = 16.0, 7.6 Hz, 1 H), 6.86 (d, J =

8.7 Hz, 2 H), 7.01 (s, 1 H), 7.23 (d, J = 8.7 Hz, 2 H) ppm. ¹³C

NMR (75 MHz, CDCl₃): δ = –4.7, –3.8, 18.2, 24.2, 25.9, 26.3, 36.8,

37.3, 39.7, 46.0, 51.9, 55.2, 65.1, 72.8, 78.1, 113.7, 115.4, 129.3,

130.3, 131.5, 144.7, 147.9, 159.2, 170.8, 177.2, 198.0 ppm. IR (film,

Oxidation Procedure: See the synthesis of compound 30.

2-(2-{1-[(tert-Butyldiphenylsilyl)oxy]-2-methylpropan-2-yl}thiazol-4-

yl)acetonitrile (33): Mesyl chloride (32 μL, 0.42 mmol) and Et₃N

(59 μL, 0.42 mmol) were added to a solution of alcohol 17 (136 mg,

0.32 mmol) in CH₂Cl₂(5 mL) at 0 °C. After stirring for 1 h at room

temperature, the solvent was removed in vacuo and the residue dis-

solved in Et₂O (10 mL) and a saturated NH₄Cl solution (5 mL).

The aqueous phase was then extracted with Et₂O (3ϫ10 mL) and

the combined organic phases were washed with brine (10 mL),

dried (MgSO₄), filtered, and evaporated to give the mesyl interme-

diate quantitatively (160 mg, 0.32 mmol). ¹H NMR (300 MHz,

CDCl₃): δ = 1.00 (s, 9 H), 1.45 (s, 6 H), 2.96 (s, 3 H), 3.73 (s, 2 H),

5.32 (s, 2 H), 7.32 (s, 1 H), 7.33–7.43 (m, 6 H), 7.52–7.73 (m, 4

H) ppm.

Potassium cyanide (59 mg, 0.91 mmol) was added to the crude

product in DMSO (3 mL) at 0 °C. After stirring for 1 h at room

temperature, H₂O (5 mL) and EtOAc (5 mL) were added. The

aqueous phase was then extracted with EtOAc (3ϫ10 mL) and the

combined organic phases were washed with brine (2ϫ5 mL), dried

(MgSO₄), filtered, and evaporated in vacuo. The residue was puri-

fied by flash chromatography (hexanes/EtOAc, 95:5) to give com-

pound 33 in 66% isolated yield over the two steps (86 mg,

0.19 mmol) as a colorless oil. ¹H NMR (300 MHz, CDCl₃): δ =

1.01 (s, 9 H), 1.44 (s, 6 H), 3.73 (s, 2 H), 3.84 (s, 2 H), 7.18 (s, 1 H),

7.35–7.46 (m, 6 H), 7.52–7.62 (m, 4 H_.) ppm. ¹³C NMR (75 MHz,

CDCl₃): δ = 19.4, 20.6, 25.4, 26.8, 43.3, 72.6, 115.5, 127.7, 129.7,

133.4, 135.7, 143.9, 179.5 ppm. HRMS (ESI): calcd. for

C₂₅H₃₁N₂OSSi [M + H]⁺435.1921; found 435.1915.

NaCl): ν = 2954, 2934, 2856, 1740, 1670, 1613, 1513, 1362, 1249,

˜

1095, 1038, 836, 776 cm^–1. HRMS (ESI): calcd. for C₃₀H₄₆NO₆SSi

[M + H]⁺576.2810; found 576.2796.

Methyl (E)-2-(2-{3-[(tert-Butyldimethylsilyl)oxy]-7-(chloromethyl)-

7-hydroxy-9-[(4-methoxybenzyl)oxy]-2-methylnon-5-en-2-yl}thiazol-

4-yl)acetate (37): nBuLi (0.6 m in hexane, 2.59 mL, 1.51 mmol) was

added dropwise to a solution of enone 36 (796 mg, 1.38 mmol) and

chloroiodomethane (151 μL, 2.07 mmol) in anhydrous THF (5 mL)

at –78 °C. The resulting mixture was stirred at this temperature for

2 h and quenched with a saturated NH₄Cl solution (5 mL). The

mixture was allowed to warm to room temperature and the aque-

ous phase was extracted with EtOAc (3ϫ10 mL). The combined

organic layers were dried (MgSO₄), filtered, and concentrated in

vacuo. The residue was purified by flash chromatography (hexanes/

EtOAc, 90:10) to give chlorohydrin 37 as a colorless oil (495 mg,

0.79 mmol) in 57% isolated yield (mixture of two diastereoisomers,

Methyl

2-[2-(1-Hydroxy-2-methylpropan-2-yl)thiazol-4-yl]acetate

(34): A solution of compound 33 (150 mg, 0.34 mmol) and TMSCl

(175 μL, 1.38 mmol) in MeOH (3 mL) was heated for 15 h at 50 °C.

After cooling, a saturated NaHCO₃solution (5 mL) was added

dropwise and the aqueous phase was extracted with CH₂Cl₂

(3ϫ20 mL). The combined organic phases were washed with brine,

dried (MgSO₄), filtered, and evaporated in vacuo to give compound

1

1:1). H NMR (300 MHz, CDCl₃): δ = –0.10–0.02 (m, 3 H), 0.02–

34 in 85% isolated yield (66 mg, 0.28 mmol) as a colorless oil. H

0.19 (m, 3 H), 0.89 (s, 4.5 H), 0.90 (s, 4.5 H), 1.37 (s, 3 H), 1.42 (s,

3 H), 1.68–1.88 (m, 1 H), 2.01–2.21 (m, 2 H), 2.25–2.44 (m, 1 H),

3.34–3.49 (m, 2 H), 3.54–3.66 (m, 2 H), 3.70 (s, 3 H), 3.76–3.82 (m,

5 H), 4.00 (t, J = 5.1 Hz, 1 H), 4.42 (s, 2 H), 5.37 (dm, J = 15.6 Hz,

1 H), 5.74 (dt, J = 15.6, 8.2 Hz, 1 H), 6.86 (d, J = 8.0 Hz, 2 H), 7.02

(s, 1 H), 7.21 (d, J = 8.0 Hz) ppm. ¹³C NMR (75 MHz, CDCl₃): δ

= –4.3, –3.3, 18.6, 25.1, 26.2, 26.2, 26.4, 36.8, 36.9, 37.2, 37.7, 37.8,

46.7, 52.4, 52.6, 55.6, 67.1, 73.4, 74.7, 74.8, 79.4, 114.2, 115.6,

129.4, 129.7, 130.1, 133.3, 133.5, 148.0, 148.1, 159.7, 171.4, 178.5,

NMR (300 MHz, CDCl₃): δ = 1.38 (s, 6 H), 3.68 (s, 2 H), 3.72 (s,

3 H), 3.79 (s, 2 H), 7.06 (s, 1 H) ppm. ¹³C NMR (75 MHz, CDCl₃):

δ = 26.1, 36.6, 42.1, 52.1, 71.4, 114.8, 147.6, 170.7, 178.8 ppm. IR

(film, NaCl): ν = 3412, 2956, 2252, 1738, 1437, 1253, 1051, 910,

˜

733 cm^–1. HRMS (ESI): calcd. for C₁₀H₁₆NO₃S [M

230.0845; found 230.0847.

+

H]⁺

Methyl 2-(2-{3-[(tert-Butyldimethylsilyl)oxy]-2-methylhex-5-en-2-

yl}thiazol-4-yl)acetate (35): A solution of alcohol 27 (1.62 g,

6.02 mmol) and 2,6-lutidine (841 μL, 7.22 mmol) in CH₂Cl₂

(30 mL) was treated with TBSOTf (1.66 mL, 7.22 mmol) for 1 h at

–78 °C. The reaction mixture was quenched with a saturated

NH₄Cl solution, the aqueous layer was extracted with CH₂Cl₂

(3ϫ20 mL), and the combined organic phases were dried (MgSO₄)

and concentrated. The residue was purified by flash chromatog-

178.6 ppm. IR (film, NaCl): ν = 3478, 2954, 2923, 2856, 1742, 1613,

˜

1514, 1463, 1250, 1093, 836 cm^–1. MS (ESI): m/z (%) = 648.2 (95)

[M + Na]⁺; calcd. for C₃₁H₄₈ClNNaO₆SSi [M + Na]⁺648.2555;

found 648.2555.

Methyl

(E)-2-(2-{3,7-Bis[(tert-butyldimethylsilyl)oxy]-7-(chloro-

raphy (hexanes/EtOAc, 95:5) to yield 2.07 g (5.42 mmol, 90%) of methyl)-9-[(4-methoxybenzyl)oxy]-2-methylnon-5-en-2-yl}thiazol-4-

1

the TBS ether 35 as a colorless oil. H NMR (300 MHz, CDCl₃):

δ = –0.01 (s, 3 H), 0.14 (s, 3 H), 0.98 (s, 9 H), 1.46 (s, 3 H), 1.52

yl)acetate (38): Thiazole 37 (100 mg, 0.16 mmol) in CH₂Cl₂(2 mL)

was treated as described for compound 35 with 2,6-lutidine (22 μL,

(s, 3 H), 2.11–2.42 (m, 2 H), 3.81 (s, 3 H), 3.92 (s, 2 H), 4.13 (t, J 0.19 mmol) and TBSOTf (44 μL, 0.19 mmol) to give after purifica-

= 4.7 Hz, 1 H), 4.92–5.04 (m, 2 H), 5.79 (ddt, J = 16.8, 10.5, 7.5 Hz, tion (hexanes/EtOAc, 95:5) compound 38 (59.2 mg, 0.08 mmol) as

6050

www.eurjoc.org

Eur. J. Org. Chem. 2011, 6039–6055

Synthesis of the 4,19-Diol Derivative of (–)-Mycothiazole

a colorless oil in 50% isolated yield (mixture of two diastereoiso-

mers, 1:1). H NMR (300 MHz, CDCl₃): δ = –0.11 (s, 3 H), 0.04

(s, 9 H), 0.84 (s, 9 H), 0.85 (s, 9 H), 1.34 (s, 3 H), 1.40 (s, 3 H),

1.88–2.02 (m, 2 H), 2.05–2.39 (m, 2 H), 3.41–3.48 (m, 2 H), 3.48–

3.59 (m, 2 H), 3.71 (s, 3 H), 3.75–3.85 (m, 5 H), 3.92–4.09 (m, 1

was purified by flash chromatography (hexanes/EtOAc, 85:15) to

give sulfone 41 (384 mg, 0.55 mmol) in 90% isolated yield as a

white solid; m.p. 78 °C. ¹H NMR (300 MHz, CDCl₃): δ = –0.07 (s,

3 H), 0.00 (s, 3 H), 0.86 (s, 9 H), 1.34 (s, 3 H), 1.40 (s, 3 H), 1.90–

2.10 (m, 2 H), 3.24 (td, J = 11.6, 5.0 Hz, 1 H), 3.38 (td, J = 11.7,

1

H), 4.40 (s, 2 H), 5.40 (d, J = 15.7 Hz, 0.5 H), 5.42 (d, J = 15.7 Hz, 5.0 Hz, 1 H), 3.68 (s, 3 H), 3.73 (s, 2 H), 4.07 (t, J = 5.1 Hz, 1 H),

0.5 H), 5.67 (dt, J = 15.7, 7.1 Hz, 1 H), 6.86 (d, J = 6.1 Hz, 2 H),

7.01 (s, 1 H), 7.55–7.69 (m, 2 H), 8.02 (d, J = 7.2 Hz, 1 H), 8.20

7.03 (s, 1 H), 7.23 (d, J = 6.1 Hz) ppm. ¹³C NMR (75 MHz, (d, J = 7.4 Hz, 1 H) ppm. ¹³C NMR (75 MHz, CDCl₃): δ = –4.8,

CDCl₃): δ = –4.8, –3.6, –2.0, –1.9, 18.3, 18.6, 25.3, 25.6, 26.0, 26.1, –4.18, 18.0, 24.7, 25.8, 26.0, 26.4, 36.7, 45.7, 51.6, 51.9, 76.8, 115.6,

37.0, 37.7, 37.8, 38.0, 46.5, 51.7, 51.9, 52.1, 55.4, 66.0, 72.8, 76.1,

76.3, 78.9, 79.0, 113.9, 115.2, 128.5, 128.7, 129.4, 130.6, 134.1,

122.2, 125.2, 127.5, 127.9, 136.6, 147.9, 152.5, 165.4, 170.5,

176.6 ppm.

134.2, 147.8, 159.3, 171.1, 178.4 ppm. IR (film, NaCl): ν = 2856,

˜

4-{2-[(tert-Butyldimethylsilyl)oxy]ethyl}-2,2-dimethyl-1,3-dioxolane-

4-carbaldehyde (42): PdO (6 mg, 50 μmol) was added to a degassed

solution of ketal 46 (1.03 g, 2.52 mmol) in THF (2.5 mL). The reac-

tion mixture was stirred at room temperature under 1 atm H₂for

30 min and then filtered through Celite. The residue was rinsed

with CH₂Cl₂(3ϫ10 mL). Evaporation of the solvent led to the

pure aldehyde 42 (671 mg, 2.33 mmol) as a colorless oil in 93%

isolated yield. ¹H NMR (300 MHz, CDCl₃): δ = 0.02 (s, 6 H), 0.86

(s, 9 H), 1.42 (s, 6 H), 1.79–2.18 (m, 2 H), 3.62–3.80 (m, 2 H), 3.83

(d, J = 8.9 Hz, 1 H), 4.22 (d, J = 8.9 Hz, 1 H), 9.65 (s, 1 H) ppm.

¹³C NMR (75 MHz, CDCl₃): δ = –5.5, –5.4, 18.3, 26.0, 26.6, 26.7,

2929, 2856, 1746, 1614, 1514, 1471, 1361, 1250, 1093, 836,

775 cm^–1.

Methyl 2-(2-{3-[(tert-Butyldimethylsilyl)oxy]-5-hydroxy-2-methyl-2-

pentyl}thiazol-4-yl)acetate (39): NaBH₄(339 mg, 8.96 mmol) was

added portionwise to a solution of aldehyde 47 (2.65 g, 6.85 mmol)

in MeOH (35 mL) at 0 °C. After stirring for 1 h at 0 °C, water

(30 mL) was added with caution. The aqueous phase was extracted

with EtOAc (3ϫ50 mL). The combined organic layers were washed

with brine (20 mL), dried (MgSO₄), filtered, and concentrated in

vacuo. The residue was purified by flash chromatography (hexanes/

EtOAc, 70:30) to give alcohol 39 (2.12 g, 5.48 mmol) in 80% iso-

lated yield.¹H NMR (300 MHz, CDCl₃): δ = 0.00 (s, 3 H), 0.11 (s,

3 H), 0.90 (s, 9 H), 1.38 (s, 3 H), 1.41 (s, 3 H), 1.55–1.70 (m, 2 H),

2.16 (br. s, 1 H, OH), 3.35–3.58 (m, 2 H), 3.72 (s, 3 H), 3.80 (s, 2

H), 4.17 (dd, J = 6.0, 4.2 Hz, 1 H), 7.03 (s, 1 H) ppm. ¹³C NMR

(75 MHz, CDCl₃): δ = –4.5, –4.00, 18.2, 24.1, 26.0, 36.7, 37.2, 45.9,

38.9, 58.3, 70.8, 86.4, 110.9, 203.1 ppm. IR (film, NaCl): ν = 2950,

˜

2931, 2858, 1732, 1472, 1372, 1256, 1217, 1091, 836, 777 cm^–1.

tert-Butyl{[3-(1,5-dihydroxbenzo[e][1,3]dioxepin-3-yl)but-3-en-1-

yl]oxy}dimethylsilane (44): A solution of γ-hydroxy aldehyde 10

(4.20 g, 42 mmol) in CH₂Cl₂(150 mL) was stirred with imidazole

(3.43 g, 50.4 mmol), DMAP (154 mg, 1.3 mmol), and TBSCl

(7.59 g, 50.4 mmol) at room temperature for 30 min. After the ad-

dition of water (100 mL), the aqueous phase was extracted with

CH₂Cl₂(3ϫ100 mL) and the combined organic layers were washed

with brine (50 mL), dried (MgSO₄), filtered, and concentrated in

vacuo. The residue was purified by flash chromatography (hexanes/

EtOAc, 95:5) to give the TBS ether as a colorless oil (4.85 g,

52.1, 59.6, 75.8, 115.2, 147.7, 171.1, 178.7 ppm. IR (film, NaCl): ν

˜

= 3411, 2955, 2930, 2886, 2856, 1742, 1472, 1256, 1098, 1051, 837,

775 cm^–1. HRMS (ESI): calcd. for C₁₈H₃₄NO₄SSi [M + H]⁺

388.1972; found 388.1973.

Methyl 2-(2-{5-(Benzo[d]thiazol-2-ylsulfonyl)-3-[(tert-butyldimethyl-

silyl)oxy]-2-methylpentan-2-yl}thiazol-4-yl)acetate (41): DEAD

(264 μL, 1.68 mmol) was added to a solution of alcohol 39 (500 mg,

1.29 mmol), 2-mercaptobenzothiazole (281 mg, 1.68 mmol), and

triphenylphosphane (440 mg, 1.68 mmol) in THF (15 mL) at 0 °C.

The solution was stirred at room temperature for 1 h before the

addition of a saturated NaHCO₃solution (10 mL). The aqueous

phase was extracted with EtOAc (3ϫ10 mL) and the resulting or-

ganic layers were washed with brine (10 mL), dried (MgSO₄), fil-

tered, and concentrated in vacuo. The residue was purified by flash

chromatography (hexanes/EtOAc, 95:5) to give the intermediate

thioether (623 mg, 1.16 mmol) in 90 % isolated yield. ¹H NMR

(300 MHz, CDCl₃): δ = –0.04 (s, 3 H), 0.13 (s, 3 H), 0.92 (s, 9 H),

1.38 (s, 3 H), 1.44 (s, 3 H), 1.88–2.11 (m, 2 H), 3.00–3.18 (m, 1 H),

3.21–3.39 (m, 1 H), 3.71 (s, 3 H), 3.80 (s, 2 H), 4.13 (dd, J = 6.3,

4.0 Hz, 1 H), 7.04 (s, 1 H), 7.28 (td, J = 7.0, 1.1 Hz, 1 H), 7.74 (td,

J = 7.0, 1.1 Hz, 1 H), 7.75 (d, J = 7.0 Hz, 1 H), 7.85 (d, J = 7.0 Hz,

1 H) ppm. ¹³C NMR (75 MHz, CDCl₃): δ = –4.4, –3.7, 18.3, 24.5,

26.1, 30.7, 33.6, 36.9, 46.0, 52.0, 78.2, 115.3, 120.9, 121.5, 124.1,

125.9, 135.2, 147.8, 153.3, 166.6, 170.8, 177.7 ppm. IR (film, NaCl):

1

22.7 mmol) in 54% isolated yield. H NMR (300 MHz, CDCl₃): δ

= 0.02 (s, 6 H), 0.87 (s, 9 H), 2.47 (t, J = 6.4 Hz, 2 H), 3.69 (t, J =

6.4 Hz, 2 H), 6.06 (s, 1 H), 6.37 (s, 1 H), 9.53 (s, 1 H) ppm. ¹³C

NMR (75 MHz, CDCl₃): δ = –5.4, 18.2, 25.9, 31.4, 61.0, 135.8,

147.1, 194.4 ppm. IR (film, NaCl): ν = 2956, 2930, 2858, 1693,

˜

1472, 1462, 1256, 1101, 1055, 925, 835, 776 cm^–1.

1,2-Benzenedimethanol (5.25 g, 38.0 mmol), trimethyl orthofor-

mate (4.57 mL, 41.8 mmol), and PTSA (361 mg, 1.9 mmol) in 1,2-

dimethoxyethane (13 mL) were stirred at room temperature for

30 min. The solution was then diluted with Et₂O (100 mL), washed

with a saturated NaHCO₃solution (50 mL), dried (MgSO₄), fil-

tered, and concentrated in vacuo to give the benzodioxepine

(6.71 g, 37.2 mmol), which was used in the next step without fur-

1

ther purification. H NMR (300 MHz, CDCl₃): δ = 3.47 (s, 3 H),

4.71 (d, J_AB= 14.1 Hz, 1/2 AB), 5.08 (d, J_AB= 14.1 Hz, 1/2 AB),

5.48 (s, 1 H), 7.06–7.21 (m, 4 H) ppm.

A solution of the TBS ether (3.63 g, 16.9 mmol) in 1,2-dimethoxy-

ethane (80 mL), PTSA (160 mg, 0.84 mmol) and the benzodioxep-

ine obtained as described above (6.10 g, 33.8 mmol) was stirred for

12 h until total conversion and then quenched with a saturated

NaHCO₃solution (20 mL). The aqueous phase was extracted with

ν = 2953, 2928, 2856, 1743, 1462, 1428, 1256, 1094, 1048, 997, 837,

˜

775, 756, 727 cm^–1.

The above-mentioned thioether (330 mg, 0.615 mmol) in MeOH

(6 mL) was treated at 0 °C with Na₂O₄W·2H₂O (101 mg, Et₂O (3ϫ20 mL) and the combined organic layers were washed

0.31 mmol) and H₂O₂(35% H₂O, 210 μL, 2.46 mmol) was added

dropwise. The resulting mixture was stirred for 14 h until total con-

version before the reaction was quenched by the addition of a satu-

rated Na₂S₂O₃solution (10 mL). The aqueous phase was extracted

with CH₂Cl₂(3ϫ10 mL) and the combined organic layers were

dried (MgSO₄), filtered, and concentrated in vacuo. The residue

with brine (20 mL), dried (MgSO₄), filtered, and concentrated in

vacuo. The residue was purified by flash chromatography (hexanes/

EtOAc, 99:1) to give compound 44 as a colorless oil (2.83 g,

8.45 mmol) in 50% isolated yield. H NMR (300 MHz, CDCl₃): δ

= 0.07 (s, 6 H), 0.91 (s, 9 H), 2.40 (t, J = 7.1 Hz, 2 H), 3.78 (t, J =

1

7.1 Hz, 1 H), 4.70–4.98 (m, 4 H), 5.10 (s, 1 H), 5.29 (s, 1 H), 5.40

Eur. J. Org. Chem. 2011, 6039–6055

www.eurjoc.org

6051

F. Batt, F. Fache

(s, 1 H), 7.10–7.27 (m, 4 H) ppm. ¹³C NMR (75 MHz, CDCl₃): δ 2,6-lutidine (13 μL, 112.2 μmol) was treated at –78 °C with

FULL PAPER

= –5.2, 18.4, 26.0, 35.8, 62.6, 70.0, 105.5, 114.4, 127.0, 127.2, 139.0,

142.8 ppm.

TBSOTf (26 μL, 112.2 μmol) and stirred at this temperature for

1 h. The reaction was quenched by the addition of a saturated

NH₄Cl solution (2 mL) and the aqueous phase was extracted with

CH₂Cl₂(3ϫ5 mL). The combined organic layers were washed with

water (5 mL) and brine (5 mL), dried (MgSO₄), filtered, and con-

centrated in vacuo. The residue was purified by flash chromatog-

raphy (hexanes/EtOAc, 99:1) to give compound 49 (41 mg,

69 μmol) as a colorless oil in 74 % isolated yield. ¹H NMR

(300 MHz, CDCl₃): δ = –0.07 (s, 3 H), 0.00 (s, 6 H), 0.07 (s, 3 H),

0.86 (s, 9 H), 0.90 (s, 9 H), 1.34 (s, 3 H), 1.39 (s, 3 H), 2.02–2.13

(m, 1 H), 2.16–2.23 (m, 1 H), 2.96 (t, J = 6.6 Hz, 2 H), 3.87–3.94

(m, 2 H), 4.03 (dd, J = 6.5, 4.3 Hz, 1 H), 5.85 (dd, J = 14.7, 1.2 Hz,

1 H), 6.28 (ddd, J = 14.7, 8.3, 6.8 Hz, 1 H), 6.83 (s, 1 H) ppm. ¹³C

NMR (75 MHz, CDCl₃): δ = –5.2, –4.3, –3.5, 18.4, 24.1, 26.1, 26.2,

35.4, 40.6, 46.2, 62.5, 76.2, 78.2, 113.7, 144.2, 153.8, 177.2 ppm. IR

4-[(tert-Butyldimethylsilyl)oxy]-2-(1,5-dihydrobenzo[e]dioxepin-3-

yl)butane-1,2-diol (45): A solution of olefin 44 (1.17 g, 3.50 mmol)

was treated as described for compound 12 to give after flash

chromatography (hexanes/EtOAc, 80:20) diol 45 (1.05 g,

2.87 mmol) as a colorless oil in 82 % isolated yield. ¹H NMR

(300 MHz, CDCl₃): δ = 0.08 (s, 6 H), 0.89 (s, 9 H), 1.78–1.99 (m,

2 H), 3.61 (d, J_AB= 11.5 Hz, 1/2 AB), 3.66 (d, J_AB= 11.5 Hz, 1/2

AB), 3.82–3.99 (m, 2 H), 4.88–5.03 (m, 5 H), 7.16–7.31 (m, 4

H) ppm. ¹³C NMR (75 MHz, CDCl₃): δ = –5.9, 18.1, 25.8, 34.5,

59.5, 65.5, 74.2, 74.9, 112.1, 127.8, 139.2 ppm. HRMS (ESI): calcd.

for C₁₉H₃₂NaO₅Si [M + Na]⁺391.1911; found 391.1905.

tert-Butyl{2-[4-(1,5-dihydroxbenzo[e][1,3]dioxepin-3-yl)-2,2-dimeth-

yl-1,3-dioxolan-4-yl]ethoxy}dimethylsilane (46): A solution of diol

45 (1.07 g, 2.90 mmol) was treated as described for compound 12

to give after flash chromatography (hexanes/EtOAc, 95:5) ketal 46

(1.03 g, 2.52 mmol) as a colorless oil in 87 % isolated yield. ¹H

NMR (300 MHz, CDCl₃): δ = 0.00 (s, 6 H), 0.86 (s, 9 H), 1.42 (s,

3 H), 1.46 (s, 3 H), 1.89 (dt, J = 14.0, 6.8 Hz, 1 H), 2.04 (dt, J =

14.0, 7.1 Hz, 1 H), 3.79 (t, J = 7.0 Hz, 2 H), 3.97 (d, J = 8.9 Hz, 1

H), 4.11 (d, J = 8.9 Hz, 1 H), 4.83–4.98 (m, 5 H), 7.15–7.27 (m, 4

H) ppm. ¹³C NMR (75 MHz, CDCl₃): δ = –5.2, 18.4, 26.1, 26.8,

27.0, 36.3, 59.2, 70.3, 74.2, 83.3, 110.0, 111.0, 128.0, 139.5 ppm. IR

(film, NaCl): ν = 2950, 2928, 2856, 1471, 1254, 1098, 836, 775 cm^–1.

˜

HRMS (ESI): calcd. for C₂₄H₄₇INO₂SSi [M + H]⁺596.1912; found

596.1911.

4-[(4-Methoxybenzyl)oxy]-2-methylenebutanal (50): Compound 50

was obtained from alcohol 10 according to the procedure described

for 30: To a solution of compound 10 (1.02 g, 10.2 mmol) in a

mixture of cyclohexane/CH₂Cl₂(2:1) (10 mL) were added cam-

phorsulfonic acid (118 mg, 0.51 mmol) and p-methoxybenzyl tri-

chloroacetamidate (3.16 g, 11.2 mmol). After stirring for 10 h, the

reaction mixture was quenched with a saturated NaHCO₃solution

(20 mL). The aqueous phase was extracted with CH₂Cl₂

(3ϫ20 mL). The combined organic layers were washed with brine

(20 mL), dried (MgSO₄), filtered and concentrated in vacuo. The

crude product was purified by flash chromatography (hexanes/

EtOAc, 95:5), and the desired product 50 was recovered with 45%

isolated yield (1.01 g, 4.58 mmol) as a colorless oil. ¹H NMR

(300 MHz, CDCl₃): δ = 2.54 (t, J = 6.4 Hz, 2 H), 3.55 (t, J =

6.4 Hz, 2 H), 3.79 (s, 3 H), 4.42 (s, 2 H), 6.06 (s, 1 H), 6.36 (s, 1

H), 6.86 (d, J = 8.7 Hz, 2 H), 7.22 (d, J = 8.7 Hz, 2 H), 9.52 (s, 1

H) ppm. ¹³C NMR (75 MHz, CDCl₃): δ = 28.1, 55.2, 67.6, 72.4,

113.7, 129.2, 130.2, 135.8, 146.9, 159.1, 194.5 ppm. IR (film, NaCl):

(film, NaCl): ν = 2955, 2928, 2856, 1471, 1462, 1370, 1255, 1216,

˜

1107, 1056, 836, 775 cm^–1. HRMS (ESI): calcd. for C₂₂H₃₆NaO₅Si

[M + Na]⁺431.2224; found 431.2219.

Methyl 2-(2-{3-[(tert-Butyldimethylsilyl)oxy]-2-methyl-5-oxopentan-

2-yl}thiazol-4-yl)acetate (47): A solution of olefin 35 (2.74 g,

7.15 mmol) in a mixture dioxane/water (3:1, 40 mL) was treated at

room temperature with 2,6-lutidine (1.66 mL, 14.3 mmol), NaIO₄

(6.12 g, 28.6 mmol), and OsO₄(4% in water, 437 μL, 71.5 μmol).

After stirring for 1 h, CH₂Cl₂(100 mL) and water (50 mL) were

added. After separation of the two layers, the aqueous layer was

extracted with CH₂Cl₂(3ϫ50 mL). The combined organic layers

were washed with brine (50 mL), dried (MgSO₄), filtered, and con-

centrated in vacuo. The residue was purified by flash chromatog-

raphy (hexanes/EtOAc, 90:10) to give aldehyde 47 as a colorless

ν = 2934, 2857, 2829, 1686, 1612, 1513, 1248, 1175, 1098, 1034,

˜

822 cm^–1. HRMS (ESI): calcd. for C₁₃H₁₆NaO₃[M + Na]⁺

243.0992; found 243.0998.

1

oil (2.73 g, 7.07 mmol) in 99% isolated yield. H NMR (300 MHz,

CDCl₃): δ = –0.01 (s, 3 H), 0.01 (s, 3 H), 0.86 (s, 9 H), 1.37 (s, 3

H), 1.41 (s, 3 H), 2.44 (ddd, J_AB= 17.1, J = 5.0, 2.3 Hz, 1/2 AB),

2.61 (dd, J_AB= 17.1, J = 5.0 Hz, 1/2 AB), 3.70 (s, 3 H), 3.79 (s, 2

H), 4.51 (t, J = 5.0 Hz, 1 H), 7.05 (s, 1 H), 9.54 (s, 1 H) ppm. ¹³C

NMR (75 MHz, CDCl₃): δ = –4.8, –4.1, 18.2, 24.4, 25.9, 37.0, 45.9,

48.7, 52.2, 73.9, 115.7, 148.1, 170.9, 176.8, 200.9 ppm. IR (film,

1-[(tert-Butyldimethylsilyl)oxy]-4-[(4-methoxybenzyl)oxy]butan-2-

one (51): A solution of olefin 54 (275 mg, 0.82 mmol) in dioxane/

water (3:1, 10 mL) was treated at room temperature with 2,6-luti-

dine (191 μL, 1.63 mmol), NaIO₄(700 mg, 3.27 mmol), and OsO₄

(4% in water, 50 μL, 8.2 μmol). After 12 h stirring at room tem-

perature, CH₂Cl₂(10 mL) and water (10 mL) were added. The

aqueous phase was extracted with CH₂Cl₂(3ϫ10 mL) and the re-

sulting organic layers were washed with brine (10 mL), dried

(MgSO₄), filtered, and concentrated in vacuo. The residue was

purified by flash chromatography (hexanes/EtOAc, 95:5) to give

alcohol 51 (202 mg, 0.60 mmol) in 73% isolated yield as a colorless

NaCl): ν = 2955, 2931, 2857, 1743, 1725, 1523, 1472, 1362, 1256,

˜

1159, 1098, 1006, 838, 777 cm^–1.

2-[(4-{2-[(tert-Butyldimethylsilyl)oxy]ethyl}-2,2-dimethyl-1,3-dioxo-

lan-4-yl)methylsulfonyl]benzo[d]thiazole (48): Compound 48 was ob-

tained from aldehyde 42 according to the procedure described for

sulfone 41 from aldehyde 47. ¹H NMR (300 MHz, CDCl₃): δ =

0.05 (s, 6 H), 0.86 (s, 9 H), 1.09 (s, 3 H), 1.25 (s, 3 H), 1.99–2.12

(m, 1 H), 2.50 (dt, J = 14.3, 4.5 Hz, 1 H), 3.78–4.12 (m, 6 H), 7.52–

7.68 (m, 2 H), 8.00 (dd, J = 8.0, 1.5 Hz), 8.19 (dd, J = 7.6, 1.6 Hz,

1 H) ppm. ¹³C NMR (75 MHz, CDCl₃): δ = –5.2, –5.1, 18.5, 26.2,

26.5, 26.8, 39.5, 59.4, 60.4, 74.6, 80.7, 110.2, 122.6, 125.7, 127.9,

1

oil. H NMR (300 MHz, CDCl₃): δ = 0.07 (s, 6 H), 0.91 (s, 9 H),

2.76 (t, J = 6.2 Hz, 2 H), 3.72 (t, J = 6.2 Hz, 2 H), 3.80 (s, 3 H),

4.19 (s, 2 H), 4.43 (s, 2 H), 6.87 (d, J = 8.6 Hz, 2 H), 7.24 (d, J =

8.6 Hz, 2 H) ppm. ¹³C NMR (75 MHz, CDCl₃): δ = –5.5, 18.3,

25.8, 38.9, 55.2, 64.7, 69.7, 72.9, 113.8, 129.3, 130.2, 159.3,

208.9 ppm. IR (film, NaCl): ν = 2956, 2930, 2857, 1722, 1613, 1514,

˜

1463, 1362, 1249, 1172, 1100, 838 cm^–1. In agreement with reported

data.^[54]

128.2, 137.2 ppm. IR (film, NaCl): ν = 2983, 2950, 2929, 2851,

˜

1472, 1372, 1333, 1256, 1155, 1091, 1058, 836 cm^–1.

(E)-2-{3-[(tert-Butyldimethylsilyl)oxy]-6-iodo-2-methylhex-5-en-2-

yl}-4-{2-[(tert-butyldimethylsilyl)oxy]ethyl}thiazole (49): A solution

of alcohol 56 (45 mg, 93.5 μmol) in anhydrous CH₂Cl₂(1 mL) and

4-[(4-Methoxybenzyl)oxy]-2-methylenebutan-1-ol (53): Sodium

borohydride (125 mg, 3.31 mmol) was added portionwise to a

stirred solution of 50 (663 mg, 3.01 mmol) and cerium chloride

6052

www.eurjoc.org

Eur. J. Org. Chem. 2011, 6039–6055

Synthesis of the 4,19-Diol Derivative of (–)-Mycothiazole

heptahydrate (1.23 g, 3.31 mmol) in MeOH (8 mL) at 0 °C. The

reaction mixture was stirred for 30 min at 0 °C, after which water

(10 mL) was added to destroy the residual sodium borohydride.

The aqueous phase was extracted with Et₂O (3ϫ10 mL) and the

resulting organic layers were washed with brine (20 mL), dried

(MgSO₄), filtered, and concentrated in vacuo. The residue was

purified by flash chromatography (hexanes/EtOAc, 80:20) to give

alcohol 53 (568 mg, 2.55 mmol) in 85% isolated yield. ¹H NMR

(300 MHz, CDCl₃): δ = 2.34 (br. s, 1 H, OH), 2.40 (t, J = 6.2 Hz,

2 H), 3.58 (t, J = 6.2 Hz, 2 H), 3.80 (s, 3 H), 4.06 (s, 2 H), 4.46 (s,

2 H), 4.92 (s, 1 H), 5.05 (s, 1 H), 6.87 (d, J = 8.7 Hz, 2 H), 7.24 (d,

J = 8.7 Hz, 2 H) ppm. ¹³C NMR (75 MHz, CDCl₃): δ = 33.6, 55.1,

65.9, 69.1, 72.6, 111.7, 113.7, 129.3, 129.9, 146.5, 159.2 ppm. IR

H), 1.34 (s, 3 H), 2.05–2.14 (m, 1 H), 2.17–2.34 (m, 1 H), 2.96 (t,

J = 5.2 Hz, 2 H), 3.87–3.98 (m, 3 H), 5.85 (dd, J = 14.6, 1.3 Hz, 1

H), 6.28 (ddd, J = 14.6, 8.2, 6.9 Hz, 1 H), 6.84 (s, 1 H) ppm. ¹³C

NMR (75 MHz, CDCl₃): δ = –4.5, –3.5, 18.3, 24.7, 26.1, 26.3, 33.6,

40.5, 46.1, 62.3, 76.3, 78.2, 113.6, 143.6, 154.1, 178.2 ppm. IR (film,

NaCl): ν = 3394, 2929, 1522, 1473, 1256, 1094, 957, 837, 775,

˜

739 cm^–1.

tert-Butyl 4-[(4-Methoxybenzyl)oxy]-2-oxobutanoate (57): A solu-

tion of olefin 60 (246 mg, 0.84 mmol) was treated as reported for

the synthesis of compound 51 from 54 to give keto ester 57 (93 mg,

0.31 mmol) in 37 % isolated yield as a colorless oil. ¹H NMR

(300 MHz, CDCl₃): δ = 1.50 (s, 9 H), 3.03 (t, J = 6.2 Hz, 2 H),

3.73 (t, J = 6.2 Hz, 2 H), 3.77 (s, 3 H), 4.42 (s, 2 H), 6.83 (d, J =

8.7 Hz, 2 H), 7.22 (d, J = 8.7 Hz, 2 H) ppm. ¹³C NMR (75 MHz,

CDCl₃): δ = 27.8, 39.6, 55.3, 64.2, 72.9, 83.9, 113.8, 129.3, 130.0,

(film, NaCl): ν = 3400, 2923, 2851, 1712, 1612, 1513, 1248, 1033,

˜

819 cm^–1. In agreement with reported data.^[55]

tert-Butyl{4-[(4-methoxybenzyl)oxy]-2-methylenebutoxy}dimeth- 159.3, 160.2, 193.6 ppm. IR (film, NaCl): ν = 2978, 2933, 2862,

˜

ylsilane (54): A solution of alcohol 53 (240 mg, 1.08 mmol) was

treated as described for compound 24 to give after flash

chromatography (hexanes/EtOAc, 99:1) TBS ether 54 (277 mg,

0.82 mmol) as a colorless oil in 77 % isolated yield. ¹H NMR

(300 MHz, CDCl₃): δ = 0.05 (s, 6 H), 0.90 (s, 9 H), 2.33 (t, J =

7.0 Hz, 2 H), 3.56 (t, J = 7.0 Hz, 2 H), 3.80 (s, 3 H), 4.07 (s, 2 H),

4.44 (s, 2 H), 4.86 (s, 1 H), 5.08 (s, 1 H), 6.87 (d, J = 8.6 Hz, 2 H),

7.26 (d, J = 8.6 Hz, 2 H) ppm. ¹³C NMR (75 MHz, CDCl₃): δ =

–5.3, 18.4, 26.0, 33.2, 55.2, 66.1, 68.9, 72.6, 110.1, 113.8, 129.3,

1742, 1723, 1614, 1515, 1463, 1370, 1248, 1173, 1098, 1033 cm^–1.

In agreement with reported data.^[57]

tert-Butyl (E)-6-[(tert-Butyldimethylsilyl)oxy]-7-{4-[2-(tert-butyldi-

methylsilyloxy)ethyl]thiazol-2-yl}-2-hydroxy-2-{2-[(4-methoxybenz-

yl)oxy]ethyl}-7-methyloct-3-enoate (58): A solution of 49 (91 mg,

0.152 mmol) in anhydrous Et₂O (1.5 mL) was treated at –78 °C

with nBuLi (1.2 m in heptanes, 180 μmol) and stirred at this tem-

perature for 1 h before the dropwise addition of keto ester 57

(90 mg, 0.3 mmol). After an additional 1.5 h of stirring at –78 °C,

the solution was quenched with a saturated NH₄Cl solution

(2 mL). The reaction mixture was allowed to warm to room tem-

perature and the aqueous phase was extracted with EtOAc

(3ϫ5 mL). The combined organic layers were washed with brine

(5 mL), dried (MgSO₄), filtered, and concentrated in vacuo. The

residue was purified by flash chromatography (hexanes/EtOAc,

95:5) to give compound 58 (39 mg, 64 μmol) as a colorless oil in

42 % isolated yield (two diastereoisomers, 1:1). ¹H NMR

(300 MHz, CDCl₃): δ = –0.11 (s, 3 H), 0.00 (s, 6 H), 0.04 (s, 3 H),

0.87 (s, 18 H), 1.34 (s, 3 H), 1.40 (s, 3 H), 1.43 (s, 9 H), 1.84–1.93

(m, 1 H), 2.05–2.17 (m, 2 H), 2.24–2.33 (m, 1 H), 2.97 (t, J =

6.5 Hz, 2 H), 3.50–3.58 (m, 3 H), 3.81 (s, 3 H), 3.92 (t, J = 6.5 Hz,

2 H), 4.04 (br. s, 1 H), 4.39 (s, 2 H), 5.46 (dd, J = 15.4, 3.9 Hz, 1

H), 5.86 (dt, J = 15.4, 6.9 Hz, 1 H), 6.83 (s, 1 H), 6.84 (d, J =

8.5 Hz, 2 H), 7.25 (d, J = 8.5 Hz, 2 H) ppm. ¹³C NMR (75 MHz,

130.6, 145.9, 159.2 ppm. IR (film, NaCl): ν = 2950, 2929, 2856,

˜

1613, 1514, 1463, 1361, 1249, 1172, 1098, 836 cm^–1. HRMS (ESI):

calcd. for C₁₈H₃₀NaO₄Si [M + Na]⁺361.1806; found 361.1807. In

agreement with reported data.^[56]

Methyl (E)-2-(2-{3-[(tert-Butyldimethylsilyl)oxy]-6-iodo-2-meth-

ylhex-5-en-2-yl}thiazol-4-yl)acetate (55): A solution of aldehyde 47

(1.39 g, 3.61 mmol) and CH₃I (2.84 g, 7.22 mmol) in anhydrous

THF (15 mL) was added at 0 °C to a solution of CrCl₂(2.66 g,

21.66 mmol) in anhydrous THF (20 mL) and the resulting mixture

was stirred for 18 h at room temperature before being hydrolyzed

with water (20 mL). The aqueous phase was then extracted with

EtOAc (3ϫ20 mL) and the resulting organic layers were washed

with a saturated Na₂S₂O₃solution (10 mL) and brine (10 mL),

dried (MgSO₄), filtered, and concentrated in vacuo. The residue

was purified by flash chromatography (hexanes/EtOAc, 90:10) to

give compound 55 (1.29 g, 2.53 mmol) as a colorless oil in 70% C6D₆): δ = –5.0, –4.4, –3.3, 18.5, 25.4, 25.9, 26.3, 28.2, 30.0, 35.3,

isolated yield. ¹H NMR (300 MHz, CDCl₃): δ = –0.07 (s, 3 H),

0.06 (s, 3 H), 0.89 (s, 9 H), 1.35 (s, 3 H), 1.40 (s, 3 H), 2.01–2.10

(m, 1 H), 2.12–2.33 (m, 1 H), 3.72 (s, 3 H), 3.82 (s, 2 H), 4.02 (dd,

J = 6.4, 4.4 Hz, 1 H), 5.85 (dt, J = 14.3, 1.4 Hz, 1 H), 6.25 (ddd,

37.4, 38.7, 38.9, 46.7, 55.6, 62.6, 66.0, 73.2, 79.2, 82.8, 114.1, 120.4,

128.6, 129.8, 130.6, 133.5, 159.5, 174.4 ppm. IR (film, NaCl): ν =

˜

3412, 2929, 2857, 1722, 1514, 1463, 1250, 1098, 836, 775 cm^–1

HRMS (ESI): calcd. for C₄₀H₇₀NO₇SSi₂[M + H]⁺764.4409; found

.

J = 14.3, 8.2, 6.9 Hz, 1 H), 7.04 (s, 1 H) ppm. ¹³C NMR (75 MHz, 764.4406.

CDCl₃): δ = –4.4, –3.5, 18.3, 24.2, 26.1, 26.5, 37.1, 40.6, 46.1, 52.2,

4-[(4-Methoxybenzyl)oxy]-2-methylenebutanoic Acid (59): A solu-

76.4, 78.1, 115.5, 144.0, 148.0, 171.1, 177.8 ppm. IR (film, NaCl):

tion of aldehyde 50 (865 mg, 3.93 mmol) in a mixture of THF/H₂O/

tBuOH (4:4:1, 90 mL) was treated at 0 °C with 2-methyl-2-butene

(10 mL, 94.1 mmol), NaH₂PO₄(3.77 g, 31.4 mmol), and NaClO₂

(1.77 g, 15.7 mmol) and stirred for 4 h at room temperature. A satu-

ν = 2953, 2929, 2856, 1744, 1522, 1471, 1435, 1361, 1255, 1093,

˜

1046, 837, 775 cm^–1. HRMS (ESI): calcd. for C₁₈H₃₃INO₂SSi [M

+ H]⁺482.1040; found 482.1031.

(E)-2-(2-{3-[(tert-Butyldimethylsilyl)oxy]-6-iodo-2-methylhex-5-en- rated NH₄Cl solution (50 mL) was added. The aqueous phase was

2-yl}thiazol-4-yl)ethanol (56): A solution of ester 55 (1.29 g, extracted with EtOAc (3ϫ50 mL) and the resulting organic layers

2.53 mmol) in anhydrous Et₂O (10 mL) was added to a solution of

LiAlH₄(192 mg, 5.06 mmol) in anhydrous Et₂O (15 mL) at 0 °C

under argon. After stirring for 1 h at room temperature, water

(192 μL), a 2 m NaOH solution (192 μL), and water (384 μL) were

added at 0 °C. After stirring for 1 h at room temperature, the alu-

minium salts were filtered off and the filtrate was concentrated in

vacuo to give thiazole 56 (1.20 g, 2.50 mmol), which was used with-

out further purification in the next step. ¹H NMR (300 MHz,

were washed with a saturated NaHCO₃solution (3ϫ50 mL). The

basic aqueous layers were washed with EtOAc (3ϫ 20 mL) and

then acidified with 1 m HCl (50 mL). The acidic aqueous phase

thus obtained was extracted with EtOAc (3ϫ50 mL). The organic

phases were dried (MgSO₄), filtered, and concentrated in vacuo to

1

give acid 59 (656 mg, 2.77 mmol) in 71% isolated yield. H NMR

(300 MHz, CDCl₃): δ = 2.61 (t, J = 6.5 Hz, 2 H), 3.61 (t, J =

6.5 Hz, 2 H), 3.79 (s, 3 H), 4.46 (s, 2 H), 5.75 (s, 1 H), 6.35 (s, 1

CDCl₃): δ = –0.06 (s, 3 H), 0.06 (s, 3 H), 0.90 (s, 9 H), 1.29 (s, 3 H), 6.86 (d, J = 8.6 Hz, 2 H), 7.25 (d, J = 8.6 Hz, 2 H) ppm. ¹³C

Eur. J. Org. Chem. 2011, 6039–6055

www.eurjoc.org

6053

F. Batt, F. Fache

FULL PAPER

NMR (75 MHz, CDCl₃): δ = 31.7, 55.2, 68.2, 72.4, 113.7, 128.8,

purified by flash chromatography (hexanes/EtOAc, 90:10) to give

compound 64 (10 mg, 14.5 μmol, 28% isolated yield) and com-

pound 65 (10 mg, 15 μmol, 28% isolated yield) as colorless oils,

each as a 1:1 mixture of diastereoisomers. The same procedure ap-

plied again to the mixture led to 35% isolated yield of the diol.

129.3, 130.1, 136.9, 159.1, 171.9 ppm. IR (film, NaCl): ν = 3050,

˜

2936, 1698, 1613, 1514, 1442, 1249, 1173, 1095, 1035 cm^–1. In

agreement with reported data^[58]

tert-Butyl 4-[(4-Methoxybenzyl)oxy]-2-methylenebutanoate (60): A

solution of acid 59 (522 mg, 2.21 mmol) in tBuOH (10 mL) was

treated at 0 °C with Boc₂O (1.01 g, 4.64 mmol) and DMAP (81 mg,

0.66 mmol) and stirred at room temperature for 8 h. After evapora-

tion of the solvent, the residue was diluted in Et₂O (10 mL) and

brine (10 mL). The aqueous phase was extracted with Et₂O

(3ϫ10 mL) and the resulting organic layers washed with brine

(10 mL), dried (MgSO₄), filtered, and concentrated in vacuo. The

residue was purified by flash chromatography (hexanes/EtOAc,

95:5) to give ester 60 (300 mg, 1.02 mmol) as a colorless oil in 46%

isolated yield. ¹H NMR (300 MHz, CDCl₃): δ = 1.51 (s, 9 H), 2.62

(t, J = 6.7 Hz, 2 H), 3.61 (t, J = 6.7 Hz, 2 H), 3.81 (s, 3 H), 4.47

(s, 2 H), 5.57 (s, 1 H), 6.15 (s, 1 H), 6.89 (d, J = 8.6 Hz, 2 H), 7.27

(d, J = 8.6 Hz, 2 H) ppm. ¹³C NMR (75 MHz, CDCl₃): δ = 28.0,

32.3, 55.1, 68.4, 72.4, 80.4, 113.7, 125.3, 129.1, 130.5, 139.0, 159.1,

1

Product 64: H NMR (500 MHz, CDCl₃): δ = –0.1 (s, 3 H), –0.09

(s, 3 H), –0.01 (s, 6 H), 0.02 (s, 3 H), 0.04 (s, 3 H), 0.86 (s, 18 H),

1.25 (s, 3 H), 1.35 (s, 3 H), 1.43 (s, 3 H), 1.62 (m, 3 H), 1.79–1.85

(m, 1 H), 2.14–2.19 (m, 2 H), 2.27–2.29 (m, 1 H), 2.98 (m, 2 H),

3.47–3.55 (m, 2 H), 3.79 (s, 3 H), 3.91 (t, J = 6.5 Hz, 3 H), 4.04

(br. s, 1 H), 4.30 (q, J = 11.3 Hz, 2 H), 5.24–5.28 (m, 1 H), 5.75–

5.82 (m, 1 H), 6.86 (d, J = 8.9 Hz, 2 H), 6.87 (s, 1 H), 7.18 (d, J =

8.9 Hz, 2 H), 9.32 (s, 1 H), 9.34 (s, 1 H) ppm. ¹³C NMR (125 MHz,

CDCl₃): δ = –5.4, –4.6, –3.6, 18.2, 18.3, 25.9, 26.0, 36.7, 37.4, 46.2,

55.3, 62.2, 65.2, 72.9, 78.6, 79.7, 113.8, 128.9, 129.5, 129.8, 131.4,

153.1, 159.3, 177.5, 199.6 ppm. HRMS (ESI): calcd. for

C₃₆H₆₂NO₆SSi₂[M + H]⁺692.3831; found 692.3828.

Product 65: ¹H NMR (300 MHz, CDCl₃): δ = –0.08 (s, 3 H), –0.01

(s, 6 H), 0.07 (s, 3 H), 0.85, 0.87, 0.88 (s, 18 H), 1.25 (s, 3 H), 1.38

(s, 3 H), 1.44 (s, 3 H), 1.55–1.63 (m, 3 H), 2.02–2.34 (m, 3 H), 2.99

(m, 2 H), 3.36 (s, 2 H), 3.49–3.67 (m, 2 H), 3.80 (s, 3 H), 3.91 (t, J

= 6.5 Hz, 2 H), 4.40 (s, 2 H), 5.28–5.38 (m, 1 H), 5.70–5.80 (m, 1

H), 6.86 (d, J = 8.9 Hz, 2 H), 6.88 (s, 1 H), 7.18 (d, J = 8.9 Hz, 2

H) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = –5.0, –4.4, –4.3, –3.4,

–3.3, 18.5, 18.6, 26.0, 26.2, 26.3, 30.1, 36.5, 36.6, 37.8, 38.0, 55.7,

67.0, 67.1, 69.4, 73.4, 75.4, 75.5, 78.1, 79.1, 114.3, 128.5, 129.8,

129.9, 130.1, 130.5, 134.8, 159.7 ppm. HRMS (ESI): calcd. for

C₃₆H₆₄NO₆SSi₂[M + H]⁺694.3973; found 694.3987.

166.1 ppm. IR (film, NaCl): ν = 2978, 2934, 2857, 1713, 1613, 1514,

˜

1367, 1249, 1151, 1098 cm^–1. In agreement with reported data.^[59]

tert-Butyl 2-(2-{3-[(tert-Butyldimethylsilyl)oxy]-2-methylhex-5-en-2-

yl}-4-{2-[(tert-butyldimethylsilyl)oxy]ethyl}thiazol-5-yl)-2-hydroxy-

4-[(4-methoxybenzyl)oxy]butanoate (61): A solution of 49 (33 mg,

55 μmol) in anhydrous THF (0.5 mL) was treated at –78 °C with

nBuLi (1.2 m in heptanes, 61 μmol) and the mixture was stirred at

this temperature for 1 h before the dropwise addition of keto ester

57 (32 mg, 110 μmol). After an additional 1.5 h of stirring at

–78 °C, the solution was quenched with a saturated NH₄Cl solution

(2 mL). The reaction mixture was allowed to warm to room tem-

perature and the aqueous phase was extracted with EtOAc

(3ϫ5 mL). The combined organic layers were washed with brine

(5 mL), dried (MgSO₄), filtered, and concentrated in vacuo. The

residue was purified by flash chromatography (hexanes/EtOAc,

95:5) to give compound 61 (26 mg, 34 μmol) as a colorless oil in

Supporting Information (see footnote on the first page of this arti-

cle): H and ¹³C NMR spectra for all new compounds.

1

Acknowledgments

We thank Professor O. Piva for scientific discussions and the Min-

istère Français de l’Education Supérieure et de la Recherche for

financial support. We thank Caroline Toppan for NMR structure

determinations.

1

61% isolated yield as a 1:1 mixture of diastereoisomers. H NMR

(300 MHz, CDCl₃): δ = –0.12–0.04 (m, 9 H), 0.82–0.89 (m, 15 H,

H), 1.38–1.43 (m, 21 H), 1.99–2.13 (m, 1 H), 2.20–2.39 (m, 2 H),

2.49–2.64 (m, 1 H), 2.99–3.16 (m, 2 H), 3.52 (t, J = 6.7 Hz, 1 H),

3.62 (t, J = 6.7 Hz, 1 H), 3.80 (s, 3 H), 3.89 (t, J = 6.5 Hz, 2 H),

3.96–4.04 (m, 1 H), 4.41 (s, 2 H), 4.85 (m, 2 H), 5.67 (m, 1 H), 6.86 [1] P. Crews, Y. Kakou, E. J. Quinoa, J. Am. Chem. Soc. 1988, 110,

4365–4368.

(d, J = 8.7 Hz, 2 H), 6.98 (s, OH), 7.24 (d, J = 8.7 Hz, 2 H) ppm.

¹³C NMR (75 MHz, CDCl₃): δ = –5.3, –5.2, –4.3, –4.2, –3.4, 18.4,

18.6, 21.3, 23.0, 24.4, 25.5, 26.1, 26.2, 27.9, 28.1, 30.5, 38.8, 38.9,

39.7, 41.0, 46.2, 46.3, 55.4, 63.1, 65.7, 65.9, 72.9, 74.6, 74.7, 76.0,

77.3, 78.9, 113.9, 116.1, 125.7, 128.4, 129.6, 130.4, 135.9, 151.7,

159.3, 172.4 ppm. MS: (ESI) m/z = 764.2 (100) [M + H]⁺, 786.2

(49) [M + Na]⁺, 1549.7 (6) [2M + Na]⁺. HRMS (ESI): calcd. for

C₄₀H₆₉NO₇SSi₂Na [M + Na]⁺786.4235; found 786.4235.

[2] H. Sugiyama, F. Yokokawa, T. Shioiri, Tetrahedron 2003, 59,

6579–6593.

[3] J. B. Morgan, F. Mahdi, Y. Liu, V. Coothankandaswamy, M. B.

Jekadson, T. A. Johnson, K. V. Sashidhara, P. Crews, D. G. Na-

gle, Y.-D. Zhou, Bioorg. Med. Chem. 2010, 18, 5988–5994.

[4] a) H. Sugiyama, F. Yokokawa, T. Shioiri, Org. Lett. 2000, 2,

2149–2152; b) A. Le Flohic, C. Meyer, J. Cossy, Org. Lett.

2005, 7, 339–342; c) A. Le Flohic, C. Meyer, J. Cossy, Tetrahe-

dron 2006, 62, 9017–9037.

(E)-6-[(tert-Butyldimethylsilyl)oxy]-7-(4-{2-[(tert-butyldimethylsil-

yl)oxy]ethyl}thiazol-2-yl)-2-hydroxy-2-{2-[(4-methoxybenzyl)-

oxy]ethyl}-7-methyloct-3-enal (64) and (E)-6-[(tert-Butyldimethyl-

silyl)oxy]-7-(4-{2-[(tert-butyldimethylsilyl)oxy]ethyl}thiazol-2-yl)-2-

hydroxy-2-{2-[(4-methoxybenzyl)oxy]ethyl}-7-methyloct-3-ene-1,2-

diol (65): A solution of hydroxy ester 58 (39 mg, 0.051 mmol) in

anhydrous Et₂O (1 mL) was added to LiAlH₄(5.8 mg, 0.15 mmol)

covered with a minimum of Et₂O (300 μL) at 0 °C. The reaction

mixture was allowed to warm to room temperature and stirred for

3 h. Then H₂O (6 μL), 2.5 m NaOH (6 μL), and again H₂O (12 μL)

were added and the solution stirred for an additional 20 min. A

precipitate was thus formed, filtered, washed with Et₂O, dried

(MgSO₄), filtered, and concentrated in vacuo. The residue was

[5] G. Serra, G. Mahler, E. Manta, Heterocycles 1998, 48, 2035–

2048; S. Rodriguez-Conesa, C. Paloma, C. Jiménez, J. Rodrig-

uez, Tetrahedron Lett. 2001, 42, 6699–6702; G. Serra, G. Mah-

ler, E. Manta, Synth. Commun. 2005, 35, 1481–1492.

[6] R. N. Sonnenschein, T. A. Johnson, K. Tenney, F. A. Valeriote,

P. Crews, J. Nat. Prod. 2006, 69, 145–147.

[7] a) K. Kito, R. Ookura, S. Yoshida, M. Namikoshi, T. Ooi, T.

Kusimi, J. Nat. Prod. 2007, 70, 2022–2025; b) T. H. Kim, H.

Ito, T. Hatano, T. Hasegawa, A. Akiba, T. Machiguchi, T.

Yoshida, J. Nat. Prod. 2005, 68, 1805–1808; c) S. C. Finch,

A. L. Wilkins, A. D. Hawkes, D. J. Jensen, A. L. MacKenzie,

V. Beuzenberg, M. A. Quilliam, C. D. Olseng, I. A. Samdal, J.

Aasen, A. I. Selwood, J. M. Cooney, M. Sandvik, C. O. Miles,

Toxicon 2005, 46, 160–170.

6054

www.eurjoc.org

Eur. J. Org. Chem. 2011, 6039–6055

Synthesis of the 4,19-Diol Derivative of (–)-Mycothiazole

[8]

[9]

[33] W.-D. Z. Li, Y. Peng, Org. Lett. 2005, 7, 3069–3072; K. Oumzil,

M. Ibrahim-Ouali, M. Santelli, Steroids 2006, 71, 886–894.

[34] P. Krasik, M. Bohemier-Bernard, Q. Yu, Synlett 2005, 854–

856.

[35] J. M. Concellon, J. R. Suarez, S. Garcia-Granda, M. R. Diaz,

Org. Lett. 2005, 7, 247–250.

[36] R. Chênevert, M. Simard, J. Bergeron, M. Dasser, Tetrahedron:

Asymmetry 2004, 15, 1889–1892.

[37] A. K. Bhattacharya, G. Thyagarajan, Chem. Rev. 1981, 81,

415–430.

[38] For reviews on the modified Julia olefination, see: P. R. Blake-

more, J. Chem. Soc. Perkin Trans. 1 2002, 2563–2585; C. Aïssa,

Eur. J. Org. Chem. 2009, 1831–1844.

[39] K. Takai, K. Nitta, K. Utimoto, J. Am. Chem. Soc. 1986, 108,

7408–7410.

[40] N. Toda, M. Ori, K. Takami, K. Tago, H. Kogen, Org. Lett.

2003, 5, 269–271.

[41] a) P. Knochel, W. Dohle, N. Gommermann, F. F. Kneisel, F.

Kopp, T. Korn, I. Sapountzis, V. A. Vu, Angew. Chem. Int. Ed.

2003, 42, 4302–4320; b) H. Ren, A. Krasovskiy, P. Knochel,

Org. Lett. 2004, 6, 4215–4217.

H. F. Duan, J.-H. Xie, X.-C. Qiao, L.-X. Wang, Q.-L. Zhou,

Angew. Chem. Int. Ed. 2008, 47, 4351–4353.

B. M. Trost, E. J. McEachern, F. D. Toste, J. Am. Chem. Soc.

1998, 120, 12702–12703.

K. Nomura, S. Matsubara, Chem. Commun. 2009, 2212–2213.

I. Hueso-Falcon, N. Giron, P. Velasco, J. M. Amaro-Luis, A. G.

Ravelo, B. de las Heras, S. Hortelano, A. Eslevez-Braun, Bio-

org. Med. Chem. 2010, 18, 1724–35.

Y. Schmidt, K. Lehr, U. Breuninger, G. Brand, T. Reiss, B.

Breit, J. Org. Chem. 2010, 75, 4424–4433.

a) E. M. Carreira, J. Du Bois, J. Am. Chem. Soc. 1995, 117,

8106–8125; b) V. Rodeschini, P. Van de Weghe, C. Tarnus, J.

Eustache, Tetrahedron Lett. 2005, 46, 6691–6695; c) S. Kowa-

shi, T. Ogamino, J. Kamei, Y. Ishikawa, S. Nishiyama, Tetrahe-

dron Lett. 2004, 45, 4393–4396.

M. Rega, P. Candal, C. Jimenez, J. Rodriguez, Eur. J. Org.

Chem. 2007, 934–942.

R. Oi, K. B. Sharpless, Tetrahedron Lett. 1992, 33, 2095–2098.

F. Batt, E. Bourcet, Y. Kassab, F. Fache, Synlett 2007, 1869–

1872.

[10]

[11]

[12]

[13]

[14]

[15]

[16]

[42] Y.-G. Wang, Y. Kobayashi, Org. Lett. 2002, 4, 4615–4618.

[43] a) H. Jin, J. Uenishi, W. J. Christ, Y. Kishi, J. Am. Chem. Soc.

1986, 108, 5644–5646; b) K. Takai, M. Tagashira, T. Kuroda,

K. Oshima, K. Utimoto, H. Nozaki, J. Am. Chem. Soc. 1986,

108, 6048–6050.

[17]

[18]

[19]

S. D. Burke, D. N. Deaton, Tetrahedron Lett. 1991, 32, 4651–

4654.

V. Van Rheenen, R. C. Kelly, D. Y. Cha, Tetrahedron Lett.

1976, 17, 1973–1976.

N. Machinaga, C. Kibayashi, Tetrahedron Lett. 1989, 30, 4165–

4168.

[44] B. S. Bal, W. E. Childers Jr., H. W. Pinnick, Tetrahedron 1981,

37, 2091–2096.

[45] L. C. Hirayama, S. Gamsey, D. Knueppel, D. Steiner, K. DeLa-

Torre, B. Singaram, Tetrahedron Lett. 2005, 46, 2315–2318;

T. D. Haddad, L. C. Hirayama, P. Taynton, B. Singaram, Tetra-

hedron Lett. 2008, 49, 508–511.

[46] B.-C. Hong, J.-H. Hong, Y.-C. Tsai, Angew. Chem. Int. Ed.

1998, 37, 468–470.

[47] T.-P. Loh, J.-R. Zhou, Z. Yin, Org. Lett. 1999, 1, 1855–1857.

[48] E. J. Corey, C. J. Helal, Angew. Chem. Int. Ed. 1998, 37, 1986–

2012.

[49] P. Ferraboschi, P. Grisenti, A. Manzocchi, E. Santaniello, Tet-

rahedron: Asymmetry 1994, 5, 691–698.

[50] J. Fuchs, G. Szeimies, Chem. Ber. 1992, 125, 2517–2522.

[51] A. Zampella, V. Sepe, R. D’Orsi, G. Bifulco, C. Bassarello,

M. V. D’Auria, Tetrahedron: Asymmetry 2003, 14, 1787–1798.

[52] R. Zibuck, J. M. Streiber, J. Org. Chem. 1989, 54, 4717–4719.

[53] J. R. Walker, S. C. Rothman, C. D. Poulter, J. Org. Chem. 2008,

73, 726–729.

[20] P. G. Mc Dougal, J. G. Rico, Y.-I. Oh, B. D. Condon, J. Org.

Chem. 1986, 51, 3388–3390.

[21] Y. Hamada, M. Shibata, T. Sugiura, S. Kato, T. Shioiri, J. Org.

Chem. 1987, 52, 1252–1255.

[22] M. Z. A. Badr, M. M. Aly, A. M. Fahmy, M. E. Y. Mansour,

Bull. Chem. Soc. Jpn. 1981, 54, 1844–1847.

[23] M. Groarke, M. A. McKervey, H. Moncrieff, M. Nieuwen-

huyzen, Tetrahedron Lett. 2000, 41, 1279–1282.

[24] A. J. Fatiadi, Synthesis 1976, 65–104.

[25] A. K. Chatterjee, T.-L. Choi, D. P. Sanders, R. H. Grubbs, J.

Am. Chem. Soc. 2003, 125, 11360–11370.

[26] a) J. D. Eckelbarger, J. Y. Wilmot, M. T. Epperson, C. S.

Thakur, D. Shum, C. Antczak, L. Tarassishin, H. Djaballah,

D. Y. Gin, Chem. Eur. J. 2008, 14, 4293–4306; b) S.-Y. Wang,

Y.-J. Chin, T.-P. Loh, Synthesis 2009, 3557–3564.

[27] Y. Coquerel, J. Rodriguez, Eur. J. Org. Chem. 2008, 1125–1132.

[28] C. Cadot, P. I. Dalko, J. Cossy, Tetrahedron Lett. 2002, 43,

1839–1841.

[54] S. C. Miller, J. R. McCarthy, J. S. Sabol, Nucleosides Nucleo-

tides 1998, 17, 1099–1113.

[29] E. J. Corey, M. Chaykovsky, J. Am. Chem. Soc. 1965, 87, 1353–

[55] J. Du, G. Wang, Nucleosides Nucleotides Nucleic Acids 2000,

1364.

19, 867–879.

[30] C. J. Kowalski, M. S. Haque, K. W. Fields, J. Am. Chem. Soc.

1985, 107, 1429–1430.

[31] F.-T. Luo, A. Jeevanandam, Tetrahedron Lett. 1998, 39, 9455–

9456.

[32] J. M. Concellon, J. R. Suarez, V. del Solar, R. Llavona, J. Org.

Chem. 2005, 70, 10348–10353; J. S. Yadav, B. V. Reddy, K.

Harikishan, C. Madan, A. V. Narsaiah, Synthesis 2005, 2897–

2900; G. Li, B. Wang, J. Wang, Y. Ding, L. Yan, J. Suo, J. Mol.

Catal. A 2005, 236, 72–76.

[56] J. S. Sabol, S. P. Sunkara, S. C. Miller, PCT Int. Appl., WO

9500515, 1995 [Chem. Abstr. 1995, 123, 199303].

[57] K. Hirai, H. Ooi, T. Esumi, Y. Iwabuchi, S. Hatakeyama, Org.

Lett. 2003, 5, 857–859.

[58] X. Li, J. Li, D. R. Mootoo, Org. Lett. 2007, 9, 4303–4306.

[59] E. Hickmann, Ger. Offen., DE 3925256, 1991 [Chem. Abstr.

1991, 115, 8095].

Received: May 12, 2011

Published Online: August 30, 2011

Eur. J. Org. Chem. 2011, 6039–6055

www.eurjoc.org

6055

Article Doi

Towards the synthesis of the 4,19-diol derivative of (-)-mycothiazole: Synthesis of a potential key intermediate

DOI: 10.1002/ejoc.201100669

Source and publish data:

Authors:

Article abstract of DOI:10.1002/ejoc.201100669

Full text of DOI:10.1002/ejoc.201100669

Products guided by the article

R&D Labs maybe for 167629-48-3

Relevant to this article

Hot Product