An approach to the carbon backbone of bielschowskysin, part 1: Photocyclization strategy

FULL PAPER

DOI: 10.1002/ejoc.201300869

An Approach to the Carbon Backbone of Bielschowskysin, Part 1:

Photocyclization Strategy

Martin Himmelbauer,^[a]Jean-Baptiste Farcet,^[a]Julien Gagnepain,^[a]and Johann Mulzer*^[a]

Keywords: Natural products / Total synthesis / Asymmetric synthesis / Cycloaddition / Terpenoids

Several macrocyclization reaction attempts of highly ad-

vanced precursors toward a total synthesis of marine di-

terpene bielschowskysin are disclosed. Biomimetic [2+2]-

photocyclization reactions were applied to construct the

cyclobutane core in these intermediates, which could be

accessed along scalable high-yielding reaction sequences

from cheap enantiopure starting-materials.

pler macrocyclic precursor 3 (Scheme 1). We report two en-

tirely different approaches to the full carbon backbone of

bielschowskysin. The present article deals with the biomi-

metic [2+2]-photocyclization reaction, whereas the follow-

ing paper presents a non-photochemical route.^[5]

Introduction

In 2003 Rodríguez et al. reported the isolation of biel-

schowskysin (1) along with other congeners from the Carib-

bean Sea plume Pseudopterogorgia kallos,^[1]among which

1 and providencin (2)^[2]are the only ones bearing unusual

cyclobutane moieties (Figure 1). Owing to its densely func-

tionalized furanocembranoid structure featuring an unprec-

edented tricyclo[9.3.0.0^2,10]tetradecane ring system and

eleven stereogenic centers, bielschowskysin has attracted

considerable interest from the scientific community.^[3]

Furthermore, the compound shows significant biological

activity against the malaria-causing protozoan parasite

Plasmodium falciparum and two human cancer cell lines.

Scheme 1. Biosynthetic [2+2]-cycloaddition reaction forming biel-

schowskysin.

Results and Discussion

Our retrosynthetic considerations were centered on the

photochemical ring contraction^[6]of 14-membered carbocy-

cle 4 (Scheme 2). A gold-mediated cyclization reaction^[7]of

macrocyclic enyne 5 was expected to generate the required

exo-methylene dihydrofuran ring. Palladium-mediated in-

tramolecular Sonogashira reaction^[8]of vinyl iodide 6

should close the 14-membered carbon macrocycle. As out-

lined in Scheme 2, precursor 6 could be assembled from

Figure 1. Structures of bielschowskysin and providencin.

The members of the furanocembranoid family display a three rather simple building blocks. Thus, aldol reaction of

wide degree of functionalization. Nonetheless, they appear seleno lactone 9 and aldehyde 8 was planned to form the

to be biogenetically interconnected.^[4]Thus, the cyclobutane southern part and the enone functionality in 6, which is

moiety of bielschowskysin has been postulated to arise from essential for the [2+2]-cycloaddition reaction, which could

a transannular [2+2]-cycloaddition reaction of much sim- be established by regioselective oxidative elimination of the

selenide. After that, vinyl magnesium species 7 could intro-

duce the vinyl moiety for the later macrocyclization reac-

tion.

[a] Department of Organic Chemistry, University of Vienna,

Währinger Straße 38, 1090 Vienna, Austria

E-mail: johann.mulzer@univie.ac.at

The synthesis of aldehyde 8 commenced with d-mann-

http://mulzer.univie.ac.at/

Supporting information for this article is available on the

WWW under http://dx.doi.org/10.1002/ejoc.201300869.

itol, which was converted into enantiomerically pure buten-

olide 12 in five steps (Scheme 3).^[9]We noticed that the

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An Approach to the Carbon Backbone of Bielschowskysin, Part 1

Scheme 2. Initial retrosynthesis based on a transannular [2+2]-cycloaddition reaction.

Scheme 3. Synthesis of the eastern section of the backbone, fragment 8.

bulky tert-butyldiphenylsilyl (TBDPS) protecting group in Finally, p-methoxybenzyl ether (PMB) protection, re-

12 was essential for the stereochemical outcome of the cop- duction of the lactone, acetalization of the anomeric center

per-mediated Michael addition reaction of vinyl magnesium and a hydroboration/oxidation reaction sequence provided

bromide. Unexpectedly, the introduction of the α-hydroxy- desired aldehyde 8.

methylene group met with problems. Neither in situ genera-

For the synthesis of the western section of the backbone,

tion of formaldehyde,^[10]nor introduction of gaseous form- alkyne building block 9 (Scheme 4), known acetonide

aldehyde gave satisfying results. However, deprotonation of 16^[3a,3b]was converted into epoxide 17 in 68% yield over

the γ-butyrolactone followed by addition of a freshly pre- four steps. Various attempts to form α-phenylselenyl lactone

pared solution of formaldehyde in tetrahydrofuran (THF; 9 in a single step by opening the epoxide with the dianion

see 14 in Experimental Section) resulted in a 4:1 mixture of of phenylselenyl acetic acid failed.^[11]Thus, epoxide 17 was

diastereoisomers 13 and 14. As expected, 2,3-cis lactone 13 converted into γ-butyrolactone 19 by opening the epoxide

could be epimerized to all-trans 14 with 1,8-diazabi- with diethylmalonate followed by Krapcho decarboxyl-

cyclo[5.4.0]undec-7-ene (DBU) at elevated temperatures. ation^[12]and protection of the terminal alkyne. Unfortu-

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Scheme 4. Synthesis of the western section of the backbone, alkyne 19.

nately, 19 could not be α-selenylated by any means. Thus,

To our delight, the aldol reaction smoothly furnished the

we coupled intermediates 19 and 8 (Scheme 5) and tried to desired coupling product as a mixture of all four possible

introduce the selenide in the next step. Unfortunately, the diastereoisomers (Scheme 7). Oxidative elimination of the

yield of the aldol reaction was unacceptably low.

phenylselenyl group gave butenolide 22 as a mixture of two

diastereoisomers, which was used directly in the next reac-

tion. After protection of the free secondary alcohol a SAD

reaction was performed. Interestingly but unproductively,

the primary product 26 underwent a S_N2Ј reaction under

OMOM elimination to generate compound 27.

At this juncture we decided to abandon the transannular

[2+2]-approach and to modify our strategy as shown in

Scheme 8. Thus, aldol addition of 32 and 8 should provide

precursor 31, which in an allene–olefin [2+2]-photocycliza-

tion reaction should lead to polycycle 30. Further transfor-

mations should be directed toward 29 as the substrate of a

ring-closing metathesis (RCM) reaction to give dihy-

drofuran 28.

Scheme 5. Building block coupling.

In view of these failures we decided to add fragment 8 to

seleno lactone 23 (Scheme 6), which is readily available

from (R)-glycidol in three steps^[11](Scheme 7). If the cou-

pling indeed gave 22, elaboration of the isopropenyl moiety

(Scheme 6) might still lead to envisaged intermediate 6.

To start with, epoxide 36 was synthesized from 33 in two

steps (Scheme 9). Regioselective addition of diethylmalon-

Scheme 6. Altered retrosynthesis.

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An Approach to the Carbon Backbone of Bielschowskysin, Part 1

Scheme 7. Fragment coupling and formation of pyran 27.

Scheme 8. Retrosynthesis based on an allene–olefin [2+2]-photocyclization reaction.

ate, cyclization to the corresponding lactone and Krapcho terial in a few minutes. On narrowing the spectrum we

decarboxylation gave γ-butyrolactone 37 in fair yield. Cop- either isolated starting material or detected traces of pre-

per-mediated formation of the allene through the Searles- sumptive product in the mass-spectrum of the reaction mix-

Crabbé protocol^[13]proceeded with high yield and was ex- ture. Eventually, irradiation of 39 with UV-B light in cyclo-

ceptionally easy to carry out. Protection of the tertiary hexane for 2.5 h allowed the isolation of 10% (Table 1, En-

alcohol and α-selenylation delivered lactone 32 in scalable try 13), of desired [3.2.0]-carbocycle 40 as a diastereoiso-

seven steps with an overall yield of 35%. Interestingly, in meric mixture. Purification by column chromatography al-

situ formation of a trimethylsilyl enol ether and the use of lowed partial separation of the C13-epimers. Thus, for the

phenylselenyl chloride instead of the more reactive bromide first time the crucial all-carbon quaternary center at C-12

were essential to stop the reaction after mono-selenylation. of 1 was established.

Aldol coupling of building block 32 with 8 and regiose-

We reasoned that the formation of complex mixtures in

lective oxidative elimination of the selenide uneventfully the photoreaction might be a result of the presence of the

gave 39 as a mixture of diastereoisomers (Scheme 10). With- aryl chromophores in our substrate and decided to remove

out separation, a plethora of irradiation conditions was the PMB and the TBDPS-protecting groups in the [2+2]-

tested, some of which are outlined in Table 1. In many cases cycloaddition reaction precursor. The synthesis of the east-

complex product mixtures were formed, and we found that ern section of the backbone containing a tetrahydrofuran

irradiation of 39 with a sunlamp destroyed the starting ma- ring was redesigned accordingly (Scheme 11).

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Scheme 9. Synthesis of the western section of the backbone, allene building block 32.

Scheme 10. Fragment coupling and [2+2]-photocyclization reaction.

Table 1. [2+2]-photocyclization reaction conditions of 39 to 40.

Entry^[a]

Solvent

Conditions^[b]

Yield

1

2

3

4

EtOH

acetone

hexane/CH₂Cl₂

750 W, Ͼ 100 nm, 30 °C, 0.5 h

6 W, Ͼ 350 nm, r.t., 3 h

decomp.

SM

5

6

7

8

EtOH

hexane

MeOH

acetone

cy

6 W, Ͼ 350 nm, r.t., 3 h

6 W, Ͼ 350 nm, r.t., 9 h

2ϫ6 W, Ͼ 350 nm, r.t., 9 h

750 W, Ͼ 100 nm, 30 °C, 0.5 h

750 W, Ͼ 350 nm, 30 °C, 0.5 h

2ϫ6 W, Ͼ 350 nm, r.t., 7 h

8ϫ6 W, 320–400 nm, r.t., 7 h

8ϫ6 W, 280–320 nm, r.t., 1.5 h

SM

40, traces

decomp.

40, traces

SM

9

10

11

12

13

cy

40, 10%

[a] All solutions were 0.001 m and freshly degassed prior to use. [b] In all entries quartz tubes were used as reaction vessels.

To circumvent the experimentally tedious 1,4-addition α- workup, prolonged reaction-times or high pressure for ac-

alkylation procedure of 12 (Scheme 3) we started from di- quiring acceptable yields, we were able to hydrogenate the

acetone d-glucofuranose (41; Scheme 11), from which double bond with Raney-nickel in ethanol in an ultrasound

known α-d-ribofuranose 42^[14]was prepared in five steps bath at 1 atm of hydrogen pressure over 2 h. Removal of

along an optimized scalable sequence. Thus, 2-iodoxybenz- the acetonide, glycol cleavage and reductive workup yielded

oic acid (IBX) oxidation of 41 was followed by Horner– primary alcohol 42. Acid catalyzed acetalization of the an-

Wittig reaction giving an α,β-unsaturated ester. In contrast omeric center and protection of the primary alcohol gave

to the literature procedures, which either required aqueous lactone 43. After reduction to the diol, silyl protection and

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An Approach to the Carbon Backbone of Bielschowskysin, Part 1

Scheme 11. Synthesis of the new building block towards to new eastern section of the backbone.

subsequent Swern oxidation reaction afforded desired alde- group was necessary to obtain reasonable diastereoselectiv-

hyde 45.

ity (6:1) (Scheme 13). In presence of a 13-OAc (13-OTMS)

Deprotonation of 32, addition of 45 and oxidative elimi- the dr dropped to 2:1 (1:1). With mCPBA the reaction was

nation of the phenylselenide furnished [2+2]-photocycliza- much faster and gave higher yields with a dr of 4:1. To

tion precursor 46 (Scheme 12) with a dr of about 1:1. Capi- assign the relative configuration, crystalline acetate 52 was

talizing on our earlier results a solution of 46 in freshly prepared and subjected to single crystal diffraction.^[15]

degassed cyclohexane was irradiated with UV-B light for

For the opening of the epoxide, a number of nucleophiles

18 h to give 57% of diastereoisomeric cyclobutanes 49 and were tested both with the free alcohol and the acetate, to

50. As the UV-spectrum of 46 revealed an absorption maxi- no avail (Table 2). Interestingly, on 52 the lithium acetylide

mum at 235 nm, UV-light of 200–280 nm was applied. ethylenediamine complex acted as base and furnished

Gratifyingly the reaction time was reduced to 2 h and the pentacycle 53 in quantitative yield over 15 min at 0 °C,

yield of cyclization products 49/50 was increased to 67%. whereas 51 led to complex product mixtures. The exo-meth-

Additionally 15% of undesired regioisomers 47/48 were ylene group of 47 was subjected to a variety of alternative

formed. After separation of the isomers, “wrong” dia- functionalizations (dihydroxylation, ozonolysis, hydrobor-

stereoisomer 50 was recycled to 49 by an oxidation–re- ation, 1,3-dipolar cycloaddition reactions) with disappoint-

duction sequence, and all ensuing reactions were carried out ing results.

with enantiomerically pure 49 and 50.

Being aware of the rich potential of transition metal cata-

Next we epoxidized the exo-methylene group of 49 with lyzed C–C connections between olefins and alkynes,^[7]we

dimethyldioxirane (DMDO) and found that a free 13-OH envisage propargylic alcohol 56 as a suitable substrate for

Scheme 12. Fragment coupling and improved [2+2]-photocyclization. (a) TPAP, NMO, 4 Å MS, CH₂Cl₂, 0 °C; (b) (S)-2-(–)-methyl-CBS

oxazaborolidine, BH₃·THF, THF, –78 to –40 °C, 33% + 66% of 50.

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Scheme 13. Synthesis and X-ray structure of 52 and formation of pentacycle 53.

Table 2. Conditions for the epoxide opening.

Entry

Conditions

Yield

1

2

3

4

5

6

7

8

9

10

52, Me₃SI, nBuLi, THF, –78 °C, 8 h

SM

52, Me₃SI, nBuLi, THF, –21 °C, 8 h

52, Me₃SI, nBuLi, THF, 0 °C to room temp., 10 h

52, isopropenylMgBr, CuI, THF; –78 °C to 0 °C, 24 h

52, Me₃SBF₄, nBuLi, THF, –21 °C, 24 h

52, Me₃SBF₄, nBuLi, THF, –21 °C to r.t., 24 h

52, CH₂CHMgBr, nBuLi, CuCN, THF; –78 °C to r.t., 12 h

52, CH₂CHMgBr, nBuLi, CuCN, BF₃·OEt₂THF, –78 °C to r.t., 12 h

52, PhSH, 0.5 m NaOH, dioxane, reflux, 16 h

decomp.

53, quant.

52, Lithium acetylide ethylenediamine complex THF, DMSO, 0 °C, 15 min

closing both nine-membered carbocycle 55 and the furan

At the end, propargylic alcohol 61 was formed in good

moiety in 54 in a single step (Scheme 14). The introduction overall yield as a single diastereoisomer, and subjected to

of the alkyne into 49/50 through aldehydes 59 and 60^[3h]is macrocyclization (Table 3, Scheme 15). Although mass

outlined in Scheme 15.

analysis indicated the formation of the desired product in

some cases, we were not able to obtain a suitable NMR

spectra.

Trying to close a macrocyclic ether 66 by treating enyne

61 with NBS^[16](Scheme 16) only led to formation of 65

(connectivity and relative configuration of the bromides

were determined by 2D-NMR spectroscopic analysis). In

another attempt, aldehyde 59 was oxidized to carboxylic

acid 67 that was subjected to several halo-lactonization and

Wacker cyclization reaction conditions (Scheme 16,

Table 4),^[17]but the substrate either was unreactive or de-

composed without revealing any trace of products 68–71.

To get more flexibility in the eastern section building

block and to obtain a suitable protecting group pattern we

decided to modify the synthesis of 46 and prepared deriva-

tives 75, 76 and 77 along scalable and reliable routes

(Scheme 17).

Scheme 14. Retrosynthesis based on transition-metal-mediated cy-

clization reaction of the carbon core of bielschowskysin.

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An Approach to the Carbon Backbone of Bielschowskysin, Part 1

Scheme 15. Introduction of the alkyne and transition-metal-mediated cyclization reaction attempts.

Table 3. Conditions for the transition-metal-mediated cyclization reaction.

Entry

SM

Conditions

Yield

1

2

3

4

5

6

61

[(PPh₃)Au]NTf₂, CH₂Cl₂, –78 to 0 °C, 24 h

PtCl₂, toluene, 75 °C, 2 d

[(PPh₃)Au]Cl, AgSbF₆, CH₂Cl₂, 0 °C, 1 h

[(PPh₃)Au]Cl, AgSbF₆, MeOH, 0 °C, 6 h

[(CH₃CN)₄Cu]PF₆, toluene, 80 °C, 5 h

[(PPh₃)Au]NTf₂, CH₂Cl₂, 0 °C to r.t., 1 h

63, traces

61

64, traces

61

61 - global TES

63, traces

61

61 - global TES

decomp.

Scheme 16. Additional macrocyclization reaction attempts.

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Table 4. Conditions for alternative macrocyclization reactions.

Entry

SM

Conditions

Yield

1

2

3

4

5

6

7

8

61

67

NBS, CH₂Cl₂, 50 °C, 5 h

NIS, CDCl₃, 40 °C, 2 h

65, 66%

SM

decomp.

SM

I₂, NaHCO₃, CH₂Cl₂, 40 °C, 6 h

NBS. CH₃CN, 82 °C, 3 h

PdCl₂, CuCl, O₂, DMF, r.t., 16 h

PdCl₂, CuCl, O₂,NaHCO₃DMF, r.t., 16 h

PdCl₂, CuCl, CO, CH₃CN, MeOH, 140 °C, 4 h

Pd(OAc)₂, CuCl, CO, CH₃CN, MeOH, 140 °C, 6 h

SM

Scheme 17. New flexible route to the eastern section tetrahydrofuran moiety.

Metal halogen exchange of iodide 76 and addition of the the diastereoisomeric mixture gave pure 82 in 51% yield

lithium derivative to aldehyde 81, which was derived from after separation (Scheme 19).

our earlier intermediate 80^[3f,3g]in three steps, delivered 82

with a dr of 4:1 at C-13 but low yield (Scheme 18).

With a straightforward synthesis of 82 in hand we at-

tempted to close the macrocycle. On one hand we envisaged

In parallel, we repeated the aldol coupling by using part- an endo-selective Heck reaction^[18]of 86 to form a suitable

ners 83 and 77 and now adduct 84 was formed in high yield nine-membered carbon macrocycle (Scheme 20). Alterna-

and a dr of 3:1. The [2+2]-photocycloaddition reaction of tively a RCM reaction^[19]of 87 was tried to construct the

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An Approach to the Carbon Backbone of Bielschowskysin, Part 1

Scheme 18. Alternative synthesis of the southern section hemi-

sphere of Bielschowskysin.

tricyclo[9.3.0.0^2,10]tetradecane framework of bielschowsky-

sin.

The results of the Heck reaction have already been de-

scribed in detail.^[3h]Instead of desired diene 91, acetate 92

was obtained (Scheme 21), presumably along an unprece- Scheme 20. Heck- and RCM-macrocyclization reaction strategies.

dented mechanistic pathway as outlined in Scheme 22.

An interesting detail is the formation of vinyl cyanide 93. followed by Wagner–Meerwein rearrangement forming the

Though we have no plausible explanation yet, in all experi- Δ^6,5Јbond should deliver the desired nine-membered

ments leading to 93, Pd(OAc)₂has been used as catalyst, macrocycle and the ketone at C-4 in V. Elimination of the

and dimethylformamide as solvent and plausible “CN” formate and an olefination should give diene 91, which can

source.

The formation of macrocycle 92 with the wrong ring size consisting of protecting group operations and oxidations.

does not necessarily put an end to our synthesis because In parallel to the Heck-type cyclization reaction we tried

be processed to the natural product over a few steps mainly

there are a number of options available to achieve a suitable to set the stage for the RCM approach and various attempts

ring expansion, one of which is tentatively suggested in to introduce an allyl appendage at aldehyde 59/60 were initi-

Scheme 23.

ated (Scheme 24). Conventional treatment with allylmagne-

Thus, saponification of the acetate group at C-5 in 92 sium halides, allyl-zinc species, Brown-allylation^[20]and Du-

followed by oxidation to the aldehyde and Baeyer–Villiger thaler–Hafner allyl complex^[21]all failed. Finally, reaction

oxidation should provide III. Dihydroxylation of the exo- of 59/60 with allyltrimethylsilane or (Z)-crotyltrimethylsil-

methylene bond, mesylation of the primary alcohol at C-5Ј ane (94) and tin tetrachloride afforded 95 to 98 as insepa-

Scheme 19. Improved [2+2]-photocyclization reaction to 82.

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Scheme 21. Results from the palladium-catalyzed macrocyclization reaction attempts.

Scheme 22. Mechanistic explanation for the carbo-oxygenation.

rable mixtures of diastereoisomers along with some unre-

acted aldehyde. These mixtures were used in the RCM ex-

periments (Scheme 24, Table 5).

A broad spectrum of catalysts and solvents were em-

ployed (Table 5). Specifically, conventional Grubbs 2^ndgen-

Scheme 23. Tentative conversion of 92 to desired macrocycle 91.

eration catalyst 99,^[22]Grubbs–Hoveyda II catalyst 102,

100, Stevens catalyst 101,^[23]fast initiating Nitro-Grela cata-

lyst 103,^[24]and the doping-effect of poly-fluorinated sol-

vents on the RCM reaction were tested.^[25]In most cases

From the dimerization products we reasoned that replac-

complex product mixtures were obtained and indeed, in ing the terminal vinyl group by an isobutene appendage

some cases traces of desired macrocycles 104 to 107 were would facilitate the RCM reaction with the exo-methylene

identified in the mass spectrum. Predominantly however, group in the neo-pentyl position.^[26]Therefore, cross me-

homodimers 108 and 109 were obtained.

tathesis of 97 to 110 with isobutene was initiated (Table 5,

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An Approach to the Carbon Backbone of Bielschowskysin, Part 1

Scheme 24. Ring closing metathesis reaction attempts.

Table 5. Metathesis reaction conditions.

Entry

SM

Conditions

Yield

1^[a]

96

95

97

111

99 (0.4 equiv.), benzene (0.001 m), reflux, 24 h

102 (0.4 equiv.), benzene (0.001 m), reflux, 24 h

102 (0.4 equiv.), toluene (0.001 m), reflux, 24 h

102 (0.3 equiv.), toluene (0.001 m), reflux, 30 h

102 (0.3 equiv.), toluene (0.0005 m), reflux, 18 h

101 (0.2 equiv.), toluene (0.0005 m), reflux, 36 h

103 (0.2 equiv.), toluene (0.0005 m), reflux, 36 h

103 (0.2 equiv.), toluene (0.0005 m), reflux, 16 h

103 (0.2 equiv.), toluene (0.0005 m), reflux, 20 h

105, traces

108, traces

105, traces.

104, traces

109, 15%

SM

109, 25%

2^[a]

3^[a]

4^[a]

5^[a]

6^[a]

7^[a]

8^[b]

9^[a]

10^[a]

11^[b]

12^[b]

13^[b]

14^[a]

99 (0.2 equiv.), hexafluorobenzene (0.001 m), reflux, 38 h 109, 24%

99 (0.1 equiv.), isobutene (0.01 m), reflux, 16 h

99 (0.1 equiv.), isobutene (0.01 m), 45 °C, 24 h

102 (0.3 equiv.), isobutene (0.01 m), 45 °C, 24 h

102 (0.4 equiv.), toluene (0.001 m), reflux, 48 h

SM

112, traces

[a] Catalyst constantly added as 0.005 m solution through a syringe pump over 8 h. [b] Catalyst added in one portion as a solid.

Entries 11–12; Scheme 25), but no reaction occurred under outcome of the RCM reaction (Table 5, Entry 14;

these conditions. Finally, the free 3-OH in 96 was protected Scheme 25), leading only to traces of desired macrocycle

as silyl ether 111. Disappointingly, this did not improve the 112.

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Scheme 25. Additional metathesis reaction experiments.

Having sizeable quantities of iodide 76 in hand, we in excellent yield. This remarkable cascade generated three

thought of accessing the western section [3.2.0]-carbocyclic cycles and four stereogenic centers, including an all carbon

structure of bielschowskysin through a totally different quaternary center, in a single step. After conducting the re-

strategy (Scheme 26). This approach was centered on a Pau- action at lower temperatures and at higher dilution interme-

son–Khand reaction^[27]of 115 to form cyclopentenone 114, diate 118 could be identified in an inseparable mixture with

which after 1,4-addition reaction and contraction of the an uncharacterized side product. As pentacycle 119 features

five-membered ring by either Favorskii^[28]or Wolff re- a cis,trans,cis-triquinane terpene-type core, this serendipit-

arrangement^[29]should lead to cyclobutane 113.

ous result may be useful in other synthetic ventures.

Conclusions

In conclusion, in this part of our bielschowskysin project

we were able to synthesize several advanced macrocycliza-

tion precursors. Stereoselective high-yielding syntheses of

building blocks representing the eastern section hemisphere

of the target compound have led to optically active tetra-

hydrofuran building blocks 8, 45, and 75–77, which may be

also useful in other syntheses. Our initial synthetic plan was

modified and optimized, so that the biomimetic [2+2]-pho-

tocyclization reaction could be carried out on a large scale

and provided the [3.2.0]-carbocyclic core of bielschowskysin

in a stereoselective manner. Except for an epoxidation, the

exo-methylene group proved exceptionally unreactive to nu-

merous transformations. Various RCM reactions, instead of

closing the desired nine-membered macrocycle, exclusively

led to dimers 108 and 109. However, macrocyclization un-

der Jeffery–Heck conditions was successful, and, through

an unprecedented carbo-oxygenation, led to highly func-

tionalized macrocycle 92, which had the wrong ring size,

but eight correctly substituted stereocenters in place. At

present, synthetic efforts to enlarge the eight-membered

ring to the desired nine-membered one are well underway

in our laboratory.

Scheme 26. Pauson–Khand strategy to construct the cyclobutane

moiety.

Thus, prostaglandin precursor 116^[30]was readily con-

verted into 115 (Scheme 27). After formation of the stable

hexacarbonyldicobalt complex a trimethylamine N-oxide

(TMANO) induced Pauson–Khand reaction (PKR) was

performed. Interestingly, the intramolecular PKR to 118

was followed by an intermolecular PKR with a second mo-

lecule of 115 to furnish highly functionalized poly-cycle 119

Experimental Section

General Remarks: All moisture and oxygen sensitive reactions were

carried out in flame-dried glassware under a slight argon overpres-

sure. All solvents (except dichloromethane and methanol) were pur-

chased as the highest available grade from Sigma–Aldrich, Acros

Organics or Fischer Chemicals. Anhydrous dichloromethane was

purified by filtration through alumina under argon immediately be-

Scheme 27. Pauson–Khand reaction cascade.

8226

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Eur. J. Org. Chem. 2013, 8214–8244

An Approach to the Carbon Backbone of Bielschowskysin, Part 1

fore use. Methanol was heated at reflux for several hours over so-

dium before being distilled. NEt₃, iPr₂NEt and 2,6-lutidine were

distilled from CaH₂before use. All other reagents were used as

received from Sigma–Aldrich, Acros Organics, Fischer Chemicals,

TCI or ABCR unless otherwise stated. Preparative column

chromatography was performed with silica gel 60 from Merck

(0.040–0.063 μm, 240–400 mesh). All NMR spectra were measured

with a Bruker AV400, DRX400 or DRX600 instrument. Chemical

shifts are referenced to the solvent residual peaks (CDCl₃¹H, δ =

7.26 ppm, ¹³C, δ = 77.16 ppm). Infrared spectra were recorded as

thin films of pure products with an ATR-unit attached to a Bruker

Vertex 70 instrument. High-resolution mass spectra were measured

with a Bruker MaXis (ESI-TOF) instrument with a resolution of

10,000. A P341 Perkin–Elmer polarimeter equipped with in a 10 cm

cell and a Na-lamp (589 nm) was used for optical rotation measure-

ments.

11.7 mmol) at –21 °C. After 5 min the resulting solution was

warmed to 0 °C for 30 min. At –40 °C a solution of the 1,4 adduct

(3.9 g, 10.2 mmol) in THF (12 mL) was added dropwise over

15 min and the resulting solution was left for 1 h. The freshly pre-

pared cold solution of formaldehyde was added through a Teflon

cannula over 2 min and the resulting turbid reaction mixture was

allowed to stir for an additional 30 min. The reaction was quenched

with satd. aq. NH₄Cl (30 mL). The aqueous phase was separated

and extracted with diethyl ether (2ϫ 40 mL). The combined or-

ganic phases were washed with satd. aq. NaCl (40 mL), dried with

MgSO₄, filtered, and concentrated in vacuo resulting in a 2:1 mix-

ture of diastereoisomers. Purification by flash column chromatog-

raphy (SiO₂, hexane/EtOAc, 6:1) yielded 14 (2.21 g, 5.40 mmol) and

13 (1.11 g, 2.69 mmol) as single diastereoisomers in combined 79%

yield. Analytic data for 13: ¹H NMR (CDCl₃, 400 MHz): δ = 7.67–

7.65 (m, 4 H), 7.47–7.38 (m, 6 H), 5.88 (dt, J = 17.0, 9.9 Hz, 1 H),

5.22–5.20 (m, 1 H), 5.19–5.15 (m, 1 H), 4.36 (dt, J = 5.3, 3.1 Hz,

1 H), 3.94–3.84 (m, 2 H), 3.92 (dd, J = 11.7, 3.0 Hz, 1 H), 3.72

(dd, J = 11.7, 3.3 Hz, 1 H), 3.29 (td, J = 14.5, 5.2 Hz, 1 H), 3.04

(dt, J = 10.2, 5.1 Hz, 1 H), 2.18 (dd, J = 7.0, 4.8 Hz, 1 H), 1.55 (1

H), 1.06 (s, 9 H) ppm. ¹³C NMR (CDCl₃, 100 MHz): δ = 176.8,

135.8 (2 C), 135.7 (2 C), 134.7, 133.1 (2 C), 132.9, 130.0, 128.0 (4

C), 119.9, 83.2, 62.4, 59.8, 48.8, 43.2, 26.9 (3 C), 19.4 ppm. HRMS

(ESI): calcd. for C₂₄H₃₀O₄SiNa [M + Na]⁺433.1811; found

433.1815.

(3R,4S,5S)-5-{[(tert-Butyldiphenylsilyl)oxy]methyl}-3-(hydroxy-

methyl)-4-vinyldihydrofuran-2(3H)-one (14): In a round-bottomed

flask copper chloride (35 mg, 0.35 mmol) and lithium chloride

(37 mg, 0.87 mmol) were gently dried with a heat gun in vacuo.

The flask was carefully purged with argon and equipped with a

rubber septum. The solids were digested in THF (20 mL) at room

temperature and cooled to –78 °C. Vinyl magnesium bromide

(5.7 mL, 5.70 mmol) was added to the vigorously stirred mixture

by syringe over 10 min. After 30 min, to the resulting beige milky

suspension, a solution of butenolide 12 (1.54 g, 4.37 mmol) was

added dropwise in THF (20 mL) through a cannula over 30 min at

–78 °C. After 1 h the resulting yellow solution was warmed to

–40 °C and stirred for an additional hour. The resulting dark red

reaction mixture was quenched with satd. aq. NH₄Cl (40 mL) and

warmed to room temperature. The aqueous phase was separated

and extracted with diethyl ether (3ϫ 20 mL). The combined or-

ganic phases were washed with water (40 mL), satd. aq. NaCl

(40 mL) dried with MgSO₄, filtered and concentrated under re-

duced pressure. Column chromatography (SiO₂, hexane/EtOAc,

6:1) afforded the desired 1,4 adduct as a pale yellow gum (1.38 g,

3.62 mmol) in 83%. ¹H NMR (CDCl₃, 400 MHz): δ = 7.78–7.65

(m, 4 H), 7.47–7.38 (m, 6 H), 5.76 (ddd, J = 17.6, 9.6, 8.0 Hz, 1

H), 5.13 (d, J = 17.6 Hz, 1 H), 5.11 (d, J = 9.6 Hz, 1 H), 4.25 (ddd,

J = 6.8, 3.5, 2.7 Hz, 1 H), 3.93 (dd, J = 11.6, 2.7 Hz, 1 H), 3.73

(dd, J = 11.6, 3.5 Hz, 1 H), 3.20 (dddd, J = 8.9, 8.4, 8.0, 6.8 Hz, 1

H), 2.82 (dd, J = 17.6, 8.9 Hz, 1 H), 2.44 (dd, J = 17.6, 8.4 Hz, 1

H) ppm. ¹³C NMR (CDCl₃, 100 MHz): δ = 175.9, 136.4, 136.0,

135.5, 132.9, 132.5, 129.9, 127.8, 117.3, 104.5, 84.6, 63.3, 40.7, 35.0,

26.7, 19.2 ppm.

Epimerization of 13: Alcohol 13 (611 mg, 1.15 mmol) was dissolved

in toluene (5 mL) and DBU (170 μL, 1.13 mmol). The resulting

solution was heated to 60 °C for 3 h. The organic phase was washed

with 1 n HCl (2ϫ 5 mL) and water (5 mL), dried with MgSO₄,

filtered, concentrated under reduced pressure and subjected to col-

umn chromatography (SiO₂, hexane/EtOAc, 6:1). Desired alcohol

14 (529 mg, 1.0 mmol) was isolated as a colorless oil in 86% yield.

¹H NMR (CDCl₃, 400 MHz): δ = 7.68–7.65 (m, 4 H), 7.46–7.37

(m, 6 H), 5.68 (ddd, J = 16.9, 10.3, 8.3 Hz, 1 H), 5.21–5.16 (m, 2

H), 4.22 (ddd, J = 9.5, 4.0, 2.6 Hz, 1 H), 4.00–3.95 (m, 1 H), 3.96

(dd, J = 11.7, 2.7 Hz, 1 H), 3.78–3.72 (m, 1 H), 3.74 (dd, J = 11.9,

3.8 Hz, 1 H), 3.18 (dt, J = 11.4, 9.1 Hz, 1 H), 2.67 (ddd, J = 11.6,

5.8, 4.0 Hz, 1 H), 2.35 (dd, J = 7.5, 5.6 Hz, 1 H), 1.06 (s, 9 H) ppm.

¹³C NMR (CDCl₃, 100 MHz): δ = 178.3, 135.8 (2 C), 135.7 (2 C),

133.9, 133.0 (2 C), 132.6, 130.1, 128.0 (4 C), 119.4, 84.2, 63.8, 60.3,

46.3, 43.9, 26.9 (3 C), 19.4 ppm. HRMS (ESI): calcd. for

C₂₄H₃₀O₄SiNa [M + Na]⁺433.1811; found 433.1816. IR: ν = 3481,

˜

2932, 1859, 1770, 1472, 1428, 1113, 1047, 929, 703 cm^–1. [α]²_D³

+12.7, (CHCl₃, c = 1.2). R_f(hexane/EtOAc, 3:1) = 0.28.

=

2-((2S,3S,4R,5S)-2-{[(tert-Butyldiphenylsilyl)oxy]methyl}-5-meth-

oxy-4-{[(4-methoxybenzyl)oxy]methyl}tetrahydrofuran-3-yl)acet-

aldehyde (8): To a solution of alcohol 14 (5.0 g, 12.2 mmol) and

freshly prepared 4-methoxybenzyl-2,2,2-trichloroacetimidate (7.0 g,

24.9 mmol) in CH₂Cl₂(80 mL) was added camphor sulfonic acid

(CSA; 140 mg, 0.6 mmol) at 0 °C. The resulting pale yellow solu-

tion was warmed to room temperature overnight. After 18 h, water

(50 mL) was added and stirring was continued for an additional

hour. The organic phase was separated, dried with MgSO₄, filtered

and concentrated under reduced pressure. Flash column

chromatography (SiO₂, hexane/EtOAc, 12:1) yielded the desired

PMB protected alcohol (5.94 g, 11.2 mmol, 92%) as pale yellow

oil. ¹H NMR (CDCl₃, 400 MHz): δ = 7.68–7.66 (m, 4 H), 7.45–

7.36 (m, 4 H), 7.21 (d, J = 8.5 Hz, 2 H), 6.84 (d, J = 8.7 Hz, 2 H),

5.66 (ddd, J = 17.0, 10.3, 8.4 Hz, 1 H), 5.14–5.08 (m, 2 H), 4.51

(d, J = 11.8 Hz, 1 H), 4.43 (d, J = 11.9 Hz, 1 H), 4.18 (ddd, J =

9.5, 4.2, 2.7 Hz, 1 H), 3.93 (dd, J = 11.8, 2.7 Hz, 1 H), 3.81–3.78

(m, 1 H), 3.79 (s, 3 H), 3.75 (dd, J = 11.8, 4.3 Hz, 1 H), 3.61 (dd,

Preparation of the Formaldehyde Solution: Paraformaldehyde (3.8 g,

126 mmol) was placed in a two-necked round-bottomed flask

equipped with a rubber septum and an argon inlet on one side, and

a glass bridge filled with fresh calcium chloride on the other. The

glass bridge was connected to a second two-necked round-bot-

tomed flask that acted as a water trap, which was cooled to 0 °C.

The second neck was equipped with a rubber septum and a thick

Teflon cannula that reached into dry THF (28 mL) at –40 °C that

was stored in a third two-necked round-bottomed flask equipped

with a bubbler on the remaining neck. The flask containing formal-

dehyde was heated in an oil bath to 150 °C under a constant stream

of argon (one bubble per second through THF). Heating was con-

tinued for 15 min after all the formaldehyde was gone (overall 2 h).

The resulting clear solution was kept at –40 °C and used immedi-

ately without purification in the alkylation reaction.

A solution of diisopropylamine (1.75 mL, 12.3 mmol) in THF

(16 mL) was dropwise treated with nBuLi (1.6 m in hexane, 7.4 mL, J = 9.7, 3.5 Hz, 1 H), 3.37–3.30 (m, 1 H), 2.62 (dt, J = 11.2, 3.7 Hz,

Eur. J. Org. Chem. 2013, 8214–8244

www.eurjoc.org

8227

M. Himmelbauer, J.-B. Farcet, J. Gagnepain, J. Mulzer

FULL PAPER

1 H), 1.04 (s, 9 H) ppm. ¹³C NMR (CDCl₃, 100 MHz): δ = 175.8,

3.31 (s, 3 H), 3.24 (t, J = 9.0 Hz, 1 H), 2.34–2.29 (m, 1 H), 1.96–

159.3, 135.8 (2 C), 135.7 (2 C), 135.4, 133.3, 133.0, 130.2, 129.93, 1.90 (m, 1 H), 1.69–1.59 (m, 1 H), 1.58–1.51 (m, 1 H), 1.07 (s, 9

129.92, 129.3 (2 C), 127.9 (4 C), 119.1, 113.9 (2 C), 82.7, 73.1, 65.6, H) ppm. ¹³C NMR (CDCl₃, 100 MHz): δ = 159.5, 135.9 (2 C),

62.8, 55.4, 47.7, 43.3, 26.8 (3 C), 19.4 ppm. HRMS (ESI): calcd.

135.8 (2 C), 133.6, 133.5, 129.84 (2 C), 129.83 (2 C), 129.7, 127.83

(2 C), 127.81 (2 C), 114.0 (2 C), 107.3, 84.3, 73.2, 71.7, 65.2, 61.2,

55.4, 54.6, 51.4, 40.0, 36.1, 27.0 (3 C), 19.4 ppm. HRMS (ESI):

calcd. for C₃₃H₄₄O₆SiNa [M + Na]⁺587.2805; found 587.2814. IR:

for C₃₂H₃₈O₅SiNa [M + Na]⁺553.2386; found 553.2388. IR: ν =

˜

3000, 2858, 1777, 1513, 1247, 1113, 1008, 823, 702, 504 cm^–1

.

[α]²_D⁰= +0.63, (CHCl₃, c = 0.64). R_f(hexane/EtOAc, 3:1) = 0.37.

ν = 3470, 2932, 2859, 1613, 1472, 1249, 1112, 1080, 823, 703 cm^–1.

˜

To a solution of the PMB ether (4.34 g, 8.2 mmol) in CH₂Cl₂

(100 mL) was added diisobutylaluminium hydride (DIBALH; 25

wt.-% in toluene, 9.3 mL, 16.3 mmol) through a syringe at –78 °C

over 10 min. The resulting reaction mixture was allowed to stir at

this temperature for 1 h before the reaction was carefully quenched

with satd. aq. Na/K tartrate (100 mL). The resulting biphasic mix-

ture was vigorously stirred for 2 h. The aqueous phase was sepa-

rated and extracted with diethyl ether (3ϫ 50 mL). The combined

[α]²_D¹= +20.1, (CHCl₃, c = 0.30). R_f(hexane/EtOAc, 3:1) = 0.21.

A suspension of the alcohol (244 mg, 0.43 mmol) and IBX (242 mg,

0.86 mmol) in EtOAc (4.3 mL) was heated to reflux for 16 h. The

fine suspension was cooled to room temperature and hexane

(5 mL) was added. The mixture was filtered through a pad of Ce-

lite, which was rinsed with hexane (5 mL). The remaining colorless

filtrate was concentrated under reduced pressure. The residue was

organic phases were washed with water (100 mL) and satd. aq. subjected to column chromatography (SiO₂, hexane/EtOAc, 8:1),

NaCl (100 mL), dried with MgSO₄and filtered. Evaporation of all

volatiles provided the desired lactol at a dr of 2:1 as a pale yellow

oil, which was used without further purification in the next reac-

tion.

which gave desired aldehyde 8 (239 mg, 0.42 mmol, 98%) as a col-

orless oil. H NMR (CDCl₃, 400 MHz): δ = 9.65 (t, J = 1.3 Hz, 1

1

H), 7.69–7.65 (m, 4 H), 7.45–7.35 (m, 6 H), 7.21 (d, J = 8.7 Hz, 2

H), 6.85 (d, J = 8.7 Hz, 2 H), 4.86 (d, J = 1.0 Hz, 1 H), 4.41 (d, J

= 11.6 Hz, 1 H), 4.36 (d, J = 11.6 Hz, 1 H), 3.80 (s, 3 H), 3.79–

3.77 (m, 1 H), 3.77–3.75 (m, 2 H), 3.44–3.34 (m, 2 H), 3.31 (s, 3

H), 2.65 (ddd, J = 17.6, 8.4, 1.6 Hz, 1 H), 2.54 (ddd, J = 17.6, 5.4,

1.2 Hz, 1 H), 2.23–2.16 (m, 1 H), 2.15–2.10 (m, 1 H), 1.06 (s, 9

H) ppm. ¹³C NMR (CDCl₃, 100 MHz): δ = 201.3, 159.1, 135.7 (2

C), 135.6 (2 C), 133.3, 133.3, 130.3, 129.73, 129.71, 129.2 (2 C),

127.69 (2 C), 127.78 (2 C), 113.8 (2 C), 107.2, 82.9, 72.7, 70.4, 64.9,

55.2, 54.6, 52.4, 48.1, 36.4, 26.9 (3 C), 19.3 ppm. HRMS (ESI):

calcd. for C₃₃H₄₂O₆SiNa [M + Na]⁺585.2648; found 585.2665. IR:

The residue was dissolved in trimethyl orthoformate (40 mL) and

pyridinium p-toluenesulfonate (PPTS; 18 mg, 0.1 mmol) was

added. The reaction was stirred at room temperature for 24 h after

which satd. aq. NaHCO₃(20 mL) was added. The aqueous phase

was separated and extracted with diethyl ether (3ϫ 20 mL). The

combined organic phases were washed with water (40 mL) and

satd. aq. NaCl (40 mL), dried with MgSO₄, filtered and concen-

trated under reduced pressure. Purification by flash column

chromatography (SiO₂, hexane/EtOAc, 6:1) yielded the desired

acetal (3.6 g, 6.6 mmol, 80%). Major diastereoisomer: ¹H NMR

(CDCl₃, 400 MHz): δ = 7.70–7.67 (m, 4 H), 7.43–7.34 (m, 6 H),

7.23 (d, J = 8.7 Hz, 2 H), 6.86 (d, J = 8.7 Hz, 2 H), 5.71 (ddd, J =

16.9, 10.1, 8.8 Hz, 1 H), 4.95 (dd, J = 10.1, 1.6 Hz, 1 H), 4.94–4.90

(m, 1 H), 4.91 (d, J = 2.4 Hz, 1 H), 4.46 (d, J = 11.8 Hz, 1 H), 4.41

(d, J = 11.8 Hz, 1 H), 3.90 (ddd, J = 8.7, 7.9, 3.0 Hz, 1 H), 3.82

(dd, J = 9.4, 2.9 Hz, 1 H), 3.80 (s, 3 H), 3.70 (dd, J = 11.2, 4.7 Hz,

1 H), 3.43 (dd, J = 9.5, 5.2 Hz, 1 H), 3.38 (s, 3 H), 3.38–3.35 (m,

1 H), 2.40 (dd, J = 16.6, 8.6 Hz, 1 H), 2.26–2.20 (m, 1 H), 1.05 (s,

9 H) ppm. ¹³C NMR (CDCl₃, 100 MHz): δ = 159.3, 138.1, 135.9

ν = 2932.5, 1759.8, 1613.7, 1514.5, 1428.5, 1249.3, 1180.5, 1112.2,

˜

823.9, 704.0 cm^–1. [α]²_D²= +0.5, (CHCl₃, c = 1.1). R_f(hexane/

EtOAc, 3:1) = 0.44.

tert-Butyldimethyl({(S)-2-methyl-1-[(S)-oxiran-2-yl]but-3-yn-2-

yl}oxy)silane (17): Tertiary alcohol 16 (5.96 g, 32.3 mmol) and 2,6-

lutidine (7.6 mL, 65.3 mmol) were dissolved in CH₂Cl₂(130 mL)

and cooled to 0 °C. Trifluoromethanesulfonic acid tert-butyldime-

thylsilyl ester (TBSOTf ; 8.2 mL, 35.7 mmol) was added dropwise

through a syringe over 10 min. The resulting pale yellow solution

was stirred at that temperature for 16 h followed by addition of

(2 C), 135.8 (2 C), 133.8 (2 C), 130.6, 129.7 (2 C), 129.3 (2 C), satd. aq. NH₄Cl (50 mL). The organic phase was separated, dried

127.75 (2 C), 127.73 (2), 116.7, 113.9 (2 C), 107.6, 82.8, 72.7, 69.4,

64.2, 55.4, 55.2, 52.8, 47.4, 27.0 (3 C), 19.5 ppm. HRMS (ESI):

calcd. for C₃₃H₄₂O₅SiNa [M + Na]⁺569.2699; found 569.2697. IR:

with MgSO₄and concentrated under reduced pressure providing

the crude TBS ether (9.0 g, 30 mmol, 93%), which was exception-

ally clean and used in the next step without further purification.

¹H NMR (CDCl₃, 400 MHz): δ = 4.37–4.31 (m, 1 H), 4.14 (dd, J

= 8.1, 5.8 Hz, 1 H), 3.63 (t, J = 8.0 Hz, 1 H), 2.45 (s, 1 H), 2.12

(dd, J = 13.8, 4.3 Hz, 1 H), 1.90 (dd, J = 13.8, 7.6 Hz, 1 H), 1.50

(s, 3 H), 1.38 (s, 3 H), 1.35 (s, 3 H), 0.87 (s, 9 H), 0.18 (s, 3 H),

0.17 (s, 3 H) ppm. ¹³C NMR (CDCl₃, 100 MHz): δ = 107.9, 88.1,

72.8, 72.7, 70.4, 67.3, 48.8, 31.4, 27.0, 26.0, 25.9 (3 C), 18.2, –2.7,

–3.06 ppm. HRMS (EI): calcd. for C₁₅H₂₇NaO₃SiNa [M – CH₃]⁺

283.1729; found 183.1722.

ν = 2999, 2931, 2858, 1613, 1513, 1248, 1112, 1007, 823, 703 cm^–1.

˜

[α]²_D³= +15.7, (CHCl₃, c = 0.42). R_f(hexane/EtOAc, 3:1) = 0.48.

To a solution of the acetal (1.3 g, 2.38 mmol) in THF (24 mL) was

added BH₃·THF (1.0 m in THF, 7.2 mL, 7.2 mmol) at 0 °C over

10 min. After 5 h of stirring at 0 °C, 1 m NaOH (6 mL) and hydro-

gen peroxide (30 wt.-%, 3 mL) were added sequentially and the

resulting biphasic mixture was stirred for an additional hour at that

temperature. Sat. aq. Na₂S₂O₃(15 mL) was added and the aqueous

phase was separated and extracted with diethyl ether (3ϫ 20 mL).

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

satd. aq. NaCl (20 mL), dried with MgSO₄and concentrated under

reduced pressure. After column chromatography (SiO₂, hexane/

EtOAc, 6:1) the desired alcohol (1.0 g, 1.7 mmol, 75%) was ob-

The alkyne (50 mg, 0.17 mmol) was dissolved in CH₂Cl₂(2 mL)

and cooled to 0 °C. Trifluoroacetic acid (TFA; 85 μL, 1.1 mmol)

was added. After 3 h satd. aq. KHCO₃(10 mL) and CH₂Cl₂

(10 mL) were added. The aqueous phase was separated and ex-

tracted with CH₂Cl₂(3ϫ 10 mL). The combined organic phases

were dried with MgSO₄, filtered and concentrated under reduced

1

tained as pale yellow oil. H NMR (CDCl₃, 400 MHz): δ = 7.71–

7.67 (m, 4 H), 7.45–7.35 (m, 6 H), 7.20 (d, J = 8.7 Hz, 2 H), 6.85 pressure giving the desired vicinal diol (39 mg, 15 mmol, 90%) as

(d, J = 8.7 Hz, 2 H), 4.72 (s br., 1 H), 4.43 (d, J = 11.5 Hz, 1 H),

4.40 (d, J = 11.5 Hz, 1 H), 3.82 (ddd, J = 8.2, 4.8, 3.8 Hz, 1 H),

3.79 (s, 3 H), 3.77 (dd, J = 11.2, 3.6 Hz, 1 H), 3.72 (dd, J = 11.2,

colorless oil, which was clean enough to carry on to the next reac-

tion without further purification. H NMR (CDCl₃, 400 MHz): δ

= 4.31–4.25 (m, 1 H), 3.81 (s, 1 H), 3.66–3.61 (m, 1 H), 3.51–3.46

1

4.9 Hz, 1 H), 3.65–3.56 (m, 2 H), 3.52 (dd, J = 8.7, 6.8 Hz, 1 H), (m, 1 H), 2.53 (s, 1 H), 2.19–2.16 (m, 1 H), 1.92 (dd, J = 14.2,

8228

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Eur. J. Org. Chem. 2013, 8214–8244

An Approach to the Carbon Backbone of Bielschowskysin, Part 1

9.7 Hz, 1 H), 1.69 (dd, J = 14.3, 1.6 Hz, 1 H), 1.56 (s, 3 H), 0.89 5 h. The resulting brown mixture was cooled to room temperature

(s, 9 H), 0.26 (s, 3 H), 0.25 (s, 3 H) ppm. ¹³C NMR (CDCl₃,

100 MHz): δ = 86.6, 73.7, 70.9, 70.3, 66.9, 47.3, 32.0, 25.7 (3 C),

18.0, –2.6, –3.1 ppm. HRMS (ESI): calcd. for C₁₃H₂₆O₃SiNa [M +

and quenched with satd. aq. NH₄Cl (10 mL) and H₂O (10 mL).

The aqueous phase was extracted with diethyl ether (3ϫ 20 mL)

and the combined organic phases were dried with MgSO₄, filtered

and evaporated to give a viscous brown oil. Purification by flash

column chromatography (SiO₂, hexane/EtOAc, 3:1) afforded the

desired lactone (1.43 g, 5.1 mmol, 91%) as a colorless oil. ¹H NMR

(CDCl₃, 400 MHz): δ = 4.79 (ddd, J = 12.1, 8.8, 6.0 Hz, 1 H), 2.53

(dd, J = 9.9, 1.1 Hz, 1 H), 2.51 (d, J = 9.5 Hz, 1 H), 2.48 (s, 1 H),

2.45–2.39 (m, 1 H), 2.20 (dd, J = 14.3, 6.0 Hz, 1 H), 2.09–1.99 (m,

1 H), 1.98 (dd, J = 14.2, 5.6 Hz, 1 H), 1.5 (s, 3 H), 0.88 (s, 9 H),

0.194 (s, 3 H), 0.191 (s, 3 H) ppm. ¹³C NMR (CDCl₃, 100 MHz):

δ = 177.2, 87.9, 77.7, 73.0, 67.1, 50.4, 31.3, 29.5, 29.0, 25.8 (3 C),

18.2, –2.7, –3.0 ppm. HRMS (ESI): calcd. for C₁₅H₂₆O₃SiNa [M +

Na]⁺281.1549; found 281.1555. IR: ν = 3311, 2929, 2858, 1670,

˜

1463, 1254, 1120, 983, 838, 778 cm^–1. [α]²_D⁰= –1.6, (CHCl₃, c =

0.25). R_f(hexane/EtOAc, 1:1) = 0.50.

To a solution of the vicinal diol (1.2 g, 4.6 mmol) and tributyltin

oxide (25 mg, 0.02 mmol) in CH₂Cl₂(50 mL) was added tosyl

chloride (970 μL, 5.1 mmol) followed by triethylamine (711 μL,

5.1 mmol) at 0 °C. The resulting mixture was warmed to room tem-

perature after 15 min and stirred for a further 4 h. Water (30 mL)

was added, the aqueous phase was separated and extracted with

CH₂Cl₂(30 mL). The combined organic phases were dried with

MgSO₄, filtered and the volatiles were removed under reduced pres-

sure. The remaining residue was subjected to column chromatog-

raphy (SiO₂, hexane/EtOAc, 8:1) yielding the desired terminal tos-

ylate (1.68 g, 4.1 mmol) as a colorless oil in 87 %. ¹H NMR

(CDCl₃, 400 MHz): δ = 7.80 (d, J = 8.3 Hz, 2 H), 7.33 (d, J =

8.5 Hz, 2 H), 4.39–4.34 (m, 1 H), 3.98 (s, 1 H), 3.97 (s, 1 H), 3.65

(s, 1 H), 2.51 (s, 1 H), 2.43 (s, 3 H), 1.83 (dd, J = 14.3, 9.0 Hz, 1

H), 1.77 (dd, J = 14.3, 2.5 Hz, 1 H), 1.52 (s, 3 H), 0.84 (s, 9 H, s),

0.22 (s,3 H), 0.21 (s,3 H) ppm. ¹³C NMR (CDCl₃, 100 MHz): δ =

144.9, 133.0, 129.9 (3 C), 128.2 (3 C), 86.1, 74.0, 73.2, 70.6, 67.7,

47.1, 31.9, 25.7 (3 C), 21.7, 18.0, 17.6, –2.62, –3.16 ppm. HRMS

(ESI): calcd. for C₂₀H₃₂O₅SSiNa [M + Na]⁺435.1637; found

Na]⁺305.1549; found 305.1546. IR: ν = 2929, 2856, 1780, 1463,

˜

1253, 1166, 1113, 1002, 838, 778 cm^–1. [α]²_D⁰= –27.8, (CHCl₃, c =

0.54). R_f(hexane/EtOAc, 3:1) = 0.31.

To a solution of alkyne (50 mg, 0.18 mmol) in THF (2 mL), lithium

bis(trimethylsilyl)amide (LiHMDS; 390 μL, 0.39 mmol) was added

dropwise at –78 °C. Trimethylsilyl chloride (TMSCl; 52 μL,

0.41 mmol) was added dropwise through a syringe. The resulting

mixture was gradually warmed to –21 °C over 3 h. The reaction

was quenched with satd. aq. NH₄Cl (5 mL) and diethyl ether

(5 mL) was added to the biphasic mixture. The aqueous phase was

separated and extracted with diethyl ether (3ϫ 5 mL). The com-

bined organic phases were washed with satd. aq. NaCl (10 mL),

dried with MgSO₄, filtered and concentrated under reduced pres-

sure. Column chromatography (SiO₂, hexane/EtOAc, 3:1) of the

remaining residue gave 19 (31 mg, 0.08 mmol, 49%) as a colorless

435.1644. IR: ν = 3286 2984, 2921, 2887, 1463, 1409, 1298, 1164,

˜

1126, 999 cm^–1. [α]²_D⁰= –21.4, (CHCl₃, c = 1.0). R_f(hexane/EtOAc,

4:1) = 0.48.

1

oil. H NMR (CDCl₃, 400 MHz): δ = 4.78 (dq, J = 8.4, 6.0 Hz, 1

At 0 °C, K₂CO₃(1.4 g, 10.3 mmol) was added to a solution of the

tosylate (1.64 g, 3.97 mmol) in methanol (40 mL). After 30 min,

Et₂O/Hex (1:1, 30 mL) was added and the resulting solids were

removed by filtration. The organic phase was washed with water

(20 mL), dried with MgSO₄, filtered and concentrated under re-

duced pressure. Crude epoxide 17 (877 mg, 3.65 mmol, 92%) was

used in the next step without further purification. ¹H NMR

(CDCl₃, 400 MHz): δ = 3.21–3.16 (m, 1 H), 2.79 (t, J = 4.5 Hz, 1

H), 2.54 (dd, J = 5.0, 2.7 Hz, 1 H), 2.47 (s, 1 H), 1.97 (dd, J =

13.8, 5.7 Hz, 1 H), 1.80 (dd, J = 13.8, 5.6 Hz, 1 H), 1.54 (s, 3 H),

0.88 (s, 9 H), 0.20 (s, 6 H) ppm. ¹³C NMR (CDCl₃, 100 MHz): δ

= 87.9, 72.7, 67.9, 49.1, 48.0, 46.9, 31.1, 25.8 (3 C), 18.2, –2.7,

–3.1 ppm. HRMS (EI): calcd. for C₁₂H₂₁O₂Si [M – CH₃]⁺

H), 2.52 (d, J = 9.8 Hz, 1 H), 2.51 (d, J = 9.4 Hz, 1 H), 2.41 (sext,

1 H), 2.19 (dd, J = 14.1, 5.5 Hz, 1 H), 2.04 (dq, J = 12.5, 9.1 Hz,

1 H), 1.94 (dd, J = 14.1, 6.3 Hz, 1 H), 1.50 (s, 3 H), 0.87 (s, 9 H),

0.19 (s, 3 H), 0.18 (s, 3 H), 0.16 (s, 9 H) ppm. ¹³C NMR (CDCl₃,

100 MHz): δ = 177.3, 109.7, 89.2, 77.9, 77.2, 67.3, 50.2, 31.5, 29.4,

29.0, 25.9 (3 C), 18.2, 0.2 (3 C), –2.7, –3.0 ppm. HRMS (ESI):

calcd. for C₁₈H₃₄O₃Si₂Na [M + Na]⁺377.1944; found 377.1949.

IR: ν = 2956, 2857, 1780, 1462, 1360, 1251, 1165, 1110, 1000,

˜

838 cm^–1. [α]²_D³= –16.4, (CHCl₃, c = 0.7). R_f(hexane/EtOAc, 3:1)

= 0.45.

Secondary Alcohol 21: To a solution of 19 (30 mg, 0.08 mmol) in

THF (1 mL) was added LiHMDS (93 μL, 0.09 mmol) at –78 °C.

The resulting pale yellow solution was cooled to –40 °C for 30 min,

then to –78 °C and a solution of 8 (52 mg, 0.09 mmol) in THF

(1 mL) was added. The reaction was warmed to –40 °C over 1 h

and stirred for 2 h. The reaction was quenched with satd. aq.

NH₄Cl (5 mL) and diethyl ether (5 mL) was added to the biphasic

mixture. The aqueous phase was separated and extracted with di-

ethyl ether (3ϫ 5 mL). The combined organic phases were washed

with satd. aq. NaCl (10 mL), dried with MgSO₄, filtered and con-

centrated under reduced pressure. Purification of the residue by

column chromatography (SiO₂, hexane/EtOAc, 10:1) provided 21

as inseparable mixture of all four possible diastereoisomers (7 mg,

0.01 mmol). ¹H NMR (CDCl₃, 400 MHz): δ = 7.71–7.66 (m, 4 H),

7.44–7.35 (m, 6 H), 7.22–7.17 (m, 2 H), 6.88–6.84 (m, 2 H), 4.86–

4.81 (m, 1 H), 4.69–4.63 (m, 1 H), 4.47–4.36 (m, 1 H), 4.23–4.10

(m, 1 H), 3.84–3.68 (m, 5 H), 3.54–3.39 (m, 2 H), 3.34–3.28 (m, 3

H), 3.23–3.17 (m, 1 H), 2.63–2.39 (m, 2 H), 2.33–2.15 (m, 3 H),

2.11–2.02 (m, 2 H), 1.99–1.84 (m, 2 H), 1.49 (s, 3 H), 1.07 (s, 9 H),

0.86 (s, 9 H), 0.18 (s, 6 H), 0.16 (s, 6 H), 0.13 (s, 3 H) ppm. ¹³C

NMR (CDCl₃, 100 MHz): δ = 172.6, 159.5, 150.3, 135.9 (2 C),

135.7 (2 C), 133.3, 133.3, 130.3, 129.9, 129.8, 129.2 (2 C), 127.9 (2

C), 127.8 (2 C), 114.2 (2 C), 107.3, 107.4, 84.6, 84.2, 78.2, 73.4,

225.1311; found 225.1306. IR: ν = 2992, 2956, 2987, 1473, 1427,

˜

1304, 1165, 1135, 1047, 996 cm^–1. [α]²_D⁰= –9.7, (CHCl₃, c = 1.0). R_f

(hexane/EtOAc, 4:1) = 0.81.

(R)-5-{(S)-2-[(tert-Butyldimethylsilyl)oxy]-2-methyl-4-(trimethyl-

silyl)but-3-yn-1-yl}dihydrofuran-2(3H)-one (19): Sodium (0.93 g,

40.5 mmol) was added to ethanol (42 mL) at room temp. After the

evolution of gas ceased, diethylmalonate (3.8 mL, 25.2 mmol) was

added dropwise. The resulting solution was stirred for 1 h at room

temperature. A solution of epoxide 17 (1.22 g, 5.1 mmol) in EtOH

(12 mL) was added over 10 min and the resulting mixture was

stirred for 16 h. Diethyl ether (100 mL), satd. aq. NH₄Cl (50 mL)

and water (100 mL) were added. The aqueous phase was separated

and extracted with diethyl ether (3ϫ 50 mL). The combined or-

ganic phases were washed with water (50 mL), dried with MgSO₄,

filtered and concentrated under reduced pressure providing the de-

sired malonate as a mixture of diastereoisomers that was used in

the next reaction without further purification.

A solution of the malonate (2.0 g, 5.6 mmol) and LiCl (480 mg,

11.3 mmol) in dimethyl sulfoxide (DMSO; 12 mL) and water

(0.1 mL) was heated to 140 °C and stirred at this temperature for

Eur. J. Org. Chem. 2013, 8214–8244

www.eurjoc.org

8229

M. Himmelbauer, J.-B. Farcet, J. Gagnepain, J. Mulzer

FULL PAPER

72.8, 71.7, 66.9, 64.8, 55.4, 54.6, 52.4, 47.1, 41.0. 40.1, 38.7, 29.8,

27.9 (3 C), 26.9 (3 C), 19.3, 19.5. 2.4 (3 C), –2.7, –3.0 ppm. HRMS

(ESI): calcd. for C₅₁H₇₆O₉Si₃Na [M + Na]⁺939.4695; found

723.3334. IR: ν = 3407, 2975, 2936, 2904, 1779, 1746, 1467, 1392,

˜

1292, 1015 cm^–1. [α]²_D⁰= –11.2, (CHCl₃, c = 0.65). R_f(hexane/

EtOAc, 3:1) = 0.28.

939.4685. IR: ν = 3479, 2988, 2878, 1721, 1501, 1453, 1393, 1267,

˜

Pyran 27: To a solution of 22 (1.27 g, 1.8 mmol) as a mixture of

diastereoisomers in diisopropylethylamine (3.0 mL) was added

dropwise chloromethyl methyl ether (MOMCl; 410 μL, 5.4 mmol).

The resulting solution was stirred at room temperature for 16 h.

Sat. aq. NH₄Cl (10 mL) and diethyl ether (20 mL) were added. The

aqueous phase was separated and extracted with diethyl ether (3ϫ

10 mL). The combined organic layers were washed with satd. aq.

NaCl (20 mL), dried with MgSO₄, filtered and concentrated under

reduced pressure. Purification of the crude oil gave the desired

MOM-protected secondary alcohol (1.05 g, 1.4 mmol, 78%) as a

1101, 992 cm^–1. [α]²_D⁰= –11.3, (CHCl₃, c = 0.3). R_f(hexane/EtOAc,

3:1) = 0.38.

Butyrolactone 22: To a solution of diisopropylamine (150 μL,

1.06 mmol) in THF (2.8 mL) was added dropwise nBuLi (1.6 m in

hexane, 633 μL, 1.0 mmol) at –21 °C. 10 min after the addition the

resulting solution was put to 0 °C for 30 min and thereafter cooled

to –78 °C. A solution of seleno lactone 22 (274 mg, 0.93 mmol) in

THF (3.6 mL) was added dropwise over 10 min. The mixture was

warmed to –60 °C before aldehyde 8 (475 mg, 0.84 mmol) in THF

(3.6 mL) was added over 10 min. The mixture was further warmed

to –45 °C over 1 h. Sat. aq. NH₄Cl (15 mL) was added, the layers

were separated and the aqueous phase was extracted with diethyl

ether (3ϫ 10 mL). The combined organic phases were washed with

water (20 mL) and satd. aq. NaCl (20 mL), dried with MgSO₄and

concentrated under reduced pressure. The obtained yellow oil was

used without purification in the next step.

1

pale yellow oil. Diastereoisomer A: H NMR (CDCl₃, 400 MHz):

δ = 7.72–7.66 (s, 4 H), 7.42–7.35 (s, 6 H), 7.23 (d, J = 8.6 Hz, 2

H), 7.13 (s, 1 H), 6.86 (d, J = 8.6 Hz, 2 H), 4.97 (t, J = 6.8 Hz, 1

H), 4.91 (br. s, 1 H), 4.89 (s, 1 H), 4.79 (br. s, 1 H), 4.51 (s, 2 H),

4.42–4.40 (m, 3 H), 3.79 (s, 3 H), 3.76 (s, 1 H), 3.70 (dd, J = 11.9,

5.5 Hz, 1 H), 3.36–3.34 (m, 2 H), 3.32 (s, 3 H), 3.24 (s, 3 H), 2.40

(dd, J = 14.4, 7.3 Hz, 1 H), 2.34–2.26 (m, 2 H), 1.99–1.93 (m, 1

H), 1.86 (t, J = 6.4 Hz, 2 H), 1.78 (s, 3 H), 1.73 (d, J = 15.3 Hz, 1

H), 1.05 (s, 9 H) ppm. ¹³C NMR (CDCl₃, 100 MHz): δ = 171.6,

159.3, 149.7, 139.9, 135.9 (2 C), 135.8 (2 C), 135.6, 133.69, 133.66,

130.5, 129.8 (2 C), 129.5 (2 C), 127.80 (2 C), 127.78 (2 C), 114.5,

113.9 (2 C), 107.7, 96.0, 83.8, 79.9, 72.7, 71.1, 70.8, 64.8, 56.1, 55.4,

54.6, 52.2, 41.6, 38.7, 38.2, 27.0 (3 C), 23.1, 19.43 ppm. HRMS

(ESI): calcd. for C₄₃H₅₆O₉SiNa [M + Na]⁺767.3591; found

The mixture of diastereoisomers was dissolved in CH₂Cl₂(7.8 mL),

cooled to 0 °C and satd. aq. NH₄Cl (0.8 mL) and H₂O₂(30 wt.-%,

1.6 mL, 14 mmol) were added. After 1 h satd. aq. Na₂S₂O₃(10 mL)

was added and stirring was continued for an additional 30 min.

The separated aqueous layer was extracted with diethyl ether (3ϫ

15 mL). The combined organic phases were washed with water

(15 mL), satd. aq. NaCl (15 mL), dried with MgSO₄, filtered and

concentrated under reduced pressure. Purification of the crude resi-

due by column chromatography (SiO₂, hexane/EtOAc, 3:1) gave 22

(512 mg, 0.73 mmol, 86%) as a mixture of diastereoisomers. Dia-

767.3582. IR: ν = 2954, 2928, 2888, 1756, 1749, 1421, 1383, 1227,

˜

1117, 987 cm^–1. [α]²_D⁰= –26.1, (CHCl₃, c = 0.5). R_f(hexane/EtOAc,

1

3:1) = 0.48. Diastereoisomer B: H NMR (CDCl₃, 400 MHz): δ =

7.72–7.67 (m, 4 H), 7.44–7.36 (m, 6 H), 7.22 (d, J = 8.6 Hz, 2 H),

7.02 (s, 1 H), 6.85 (d, J = 8.6 Hz, 2 H), 4.95–4.91 (m, 1 H), 4.88

(s, 1 H), 4.87 (br. s, 1 H), 4.76 (br. s, 1 H), 4.47 (d, J = 6.8 Hz, 1

H), 4.45 (d, J = 6.7 Hz, 1 H), 4.40 (d, J = 11.8 Hz, 1 H), 4.37 (d,

J = 11.6 Hz, 1 H), 4.31 (t, J = 6.5 Hz, 1 H), 3.91–3.87 (m, 1 H),

3.82 (dd, J = 11.3, 3.0 Hz, 1 H), 3.79 (s, 3 H), 3.69 (dd, J = 11.2,

5.2 Hz, 1 H), 3.34 (s, 3 H), 3.34–3.30 (m, 2 H), 3.23 (s, 3 H), 2.33–

2.20 (m, 3 H), 1.99–1.94 (m, 2 H), 1.74 (s, 3 H), 1.31–1.27 (m, 1

H), 1.06 (s, 9 H) ppm. ¹³C NMR (CDCl₃, 400 MHz): δ = 171.4,

159.3, 150.4, 139.8, 135.9 (2 C), 135.8 (2 C), 134.8, 133.8, 133.6,

130.5, 129.8, 129.7, 129.4 (2 C), 127.81 (2 C), 127.78 (2 C), 114.4,

113.9 (2 C), 107.4, 95.6, 84.3, 79.8, 72.8, 71.0, 70.8, 65.3, 55.9, 55.4,

54.6, 52.6, 41.4, 38.6, 38.5, 27.01 (3 C), 23.1, 19.4 ppm. HRMS

(ESI): calcd. for C₄₃H₅₆O₉SiNa [M + Na]⁺767.3591; found

1

stereoisomer A: H NMR (CDCl₃, 400 MHz): δ = 7.71–7.66 (m, 4

H), 7.44–7.35 (m, 6 H), 7.22 (d, J = 8.8 Hz, 2 H), 7.04 (t, J =

1.5 Hz, 1 H), 6.86 (d, J = 8.6 Hz, 2 H), 4.96 (ddt, J = 7.7, 6.3,

1.4 Hz, 1 H), 4.91 (br. s, 1 H), 4.81 (br. s, 1 H), 4.69 (s, 1 H), 4.55–

4.51 (m, 1 H), 4.44 (br. s, 2 H), 3.90 (d, J = 5.7 Hz, 1 H), 3.88–

3.84 (m, 1 H), 3.80 (s, 3 H), 3.77 (dd, J = 11.1, 3.5 Hz, 1 H), 3.71

(dd, J = 11.2, 4.6 Hz, 1 H), 3.58 (dd, J = 8.6, 6.3 Hz, 1 H), 3.30 (s,

3 H), 3.28 (dd, J = 9.0, 1.1 Hz, 1 H), 3.22 (dd, J = 12.5, 6.3 Hz, 1

H), 2.42–2.34 (m, 2 H), 2.29 (dd, J = 14.4, 6.1 Hz, 1 H), 2.15–2.08

(m, 1 H), 1.90 (ddd, J = 13.8, 10.7, 3.1 Hz, 1 H), 1.78 (br. s, 3 H),

1.66 (ddd, J = 13.7, 9.7, 4.0 Hz, 1 H), 1.06 (br. s, 9 H) ppm. ¹³C

NMR (CDCl₃, 100 MHz): δ = 172.1, 159.6, 148.6, 140.0, 137.1,

135.9 (4 C), 135.8 (2 C), 133.54, 133.49, 129.8 (4 C), 129.5, 127.9

(2 C), 127.8 (2 C), 114.3, 114.1 (2 C), 107.1, 84.2, 80.1, 73.4, 71.7,

65.6, 64.7, 55.4, 54.5, 51.5, 41.5, 38.82, 38.77, 27.0 (3 C), 23.1,

19.4 ppm. HRMS (ESI): calcd. for C₄₁H₅₂O₈SiNa [M + Na]⁺

767.3596. IR: ν = 2954, 2928, 2888, 1756, 1749, 1421, 1383, 1227,

˜

1117, 987 cm^–1. [α]²_D⁰= –23.4, (CHCl₃, c = 0.6). R_f(hexane/EtOAc,

3:1) = 0.41.

723.3329; found 723.3325. IR: ν = 3386, 2967, 2930, 2889, 1773,

˜

1752, 1467, 1365, 1277, 1034 cm^–1. [α]²_D⁰= –16.6, (CHCl₃, c = 0.8).

The MOM-protected mixture of diastereoisomers (100 mg,

R_f(hexane/EtOAc, 3:1) = 0.29. Diastereoisomer B: ¹H NMR 0.13 mmol) was dissolved in tBuOH/H₂O (1:1, 1.4 mL), methyl-

(CDCl₃, 400 MHz): δ = δ = 7.71–7.67 (m, 4 H), 7.44–7.35 (m, 6

H), 7.22–7.17 (m, 3 H), 6.87–6.84 (m, 2 H), 5.03–4.99 (m, 1 H),

4.91 (br. s, 1 H), 4.81 (br. s, 1 H), 4.70 (s, 1 H), 4.46 (d, J = 11.9 Hz,

sulfonamide (12 mg, 0.28 mmol) and AD-mix-α (190 mg,

0.27 mmol) were added. The resulting mixture was stirred for 16 h,

diethyl ether (10 mL) and satd. aq. NaHS₂O₃(5 mL) were added.

1 H), 4.42–4.39 (m, 1 H), 4.40 (d, J = 11.6 Hz, 1 H), 3.85–3.81 (m, The aqueous phase was extracted with diethyl ether (3ϫ 10 mL).

2 H), 3.79 (s, 3 H), 3.79–3.75 (m, 2 H), 3.57 (dd, J = 8.5, 6.3 Hz,

1 H), 3.31 (s, 3 H), 3.27 (t, J = 9.1 Hz, 1 H), 2.49–2.44 (m, 1 H),

2.39 (dd, J = 14.5, 7.1 Hz, 1 H), 2.28 (dd, J = 14.5, 6.5 Hz, 1 H),

The combined organic extracts were washed with satd. aq. NaCl

(10 mL), dried with MgSO₄, filtered and concentrated under re-

duced pressure. Purification of the oil by column chromatography

2.06–2.00 (m, 1 H), 1.95–1.88 (m, 1 H), 1.79 (br. s, 3 H), 1.65–1.60 (SiO₂, hexane/EtOAc, 3:1) gave pyran 27 (80 mg, 0.11 mmol) in

1

(m, 1 H) 1.07 (br. s, 9 H) ppm. ¹³C NMR (CDCl₃, 100 MHz): δ =

171.6, 159.1, 148.6, 139.9, 137.0, 135.9 (2 C), 135.8 (2 C), 133.6, 7.44–7.36 (m, 6 H), 7.20 (d, J = 8.0 Hz, 2 H), 6.87–6.85 (m, 3 H),

133.5, 129.9, 129.8, 129.7 (2 C), 129.4, 127.91 (2 C), 127.85 (2 C), 5.15 (d, J = 5.5 Hz, 1 H), 5.04 (t, J = 6.1 Hz, 1 H), 4.84 (br. s, 1

83% yield. H NMR (CDCl₃, 400 MHz): δ = 7.69–7.66 (m, 4 H),

114.4, 114.1 (2 C), 107.3, 84.5, 80.1, 73.3, 71.6, 67.1, 64.8, 55.4, H), 4.38 (br. s, 2 H), 3.90–3.86 (m, 1 H), 3.80 (br. s, 3 H), 3.76 (dd,

54.6, 52.4, 41.6, 40.9, 39.9, 27.1 (3 C), 23.1, 19.5 ppm. HRMS J = 11.2, 3.9 Hz, 1 H), 3.72 (dd, J = 11.3, 3.7 Hz, 1 H), 3.47 (d, J

(ESI): calcd. for C₄₁H₅₂O₈SiNa [M + Na]⁺723.3329; found

= 11.3 Hz, 1 H), 3.36–3.22 (m, 3 H), 3.33 (s, 3 H), 2.63–2.48 (m, 2

8230

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Eur. J. Org. Chem. 2013, 8214–8244

An Approach to the Carbon Backbone of Bielschowskysin, Part 1

H), 2.42 (dd, J = 14.4, 6.6 Hz, 1 H), 2.10–2.03 (m, 2 H), 1.98–1.91

400 MHz): δ = 4.98–4.91 (m, 1 H), 4.28 (dd, J = 7.12, 1.3 Hz, 1

(m, 1 H), 1.88 (br. s, 1 H), 1.12 (s, 3 H), 1.06 (s, 9 H) ppm. ¹³C H), 4.24 (dd, J = 7.1, 1.2 Hz, 1 H), 3.61 (dd, J = 11.2, 9.1 Hz, 1

NMR (CDCl₃, 100 MHz): δ = 169.6, 159.4, 145.1, 135.82 (2 C),

135.77 (2 C), 133.51, 133.46, 130.4, 130.2, 129.90, 129.87, 129.4 (2

C), 127.9 (2 C), 127.8 (2 C), 114.0 (2 C), 107.4, 85.9, 83.4, 83.2,

77.4, 72.9, 70.5, 68.2, 64.9, 55.4, 54.8, 51.9, 41.3, 39.3, 34.0, 27.0

(3 C), 24.4, 19.4 ppm. HRMS (ESI): calcd. for C₄₁H₅₂O₉SiNa [M

H), 2.68 (dd, J = 9.1, 6.1 Hz, 1 H), 2.65 (dd, J = 9.1, 6.1 Hz, 1 H),

2.52 (s, 1 H), 2.43 (dd, J = 11.2, 9.8 Hz, 1 H), 2.18 (dd, J = 14.8,

8.7 Hz, 1 H), 2.07–2.03 (m, 1 H), 1.56 (s, 3 H), 1.31 (t, J = 1.4 Hz,

3 H) ppm. ¹³C NMR (CDCl₃, 100 MHz): δ = 171.2, 167.7, 86.5,

76.9, 72.8, 66.6, 62.4, 48.0, 46.8, 32.9, 30.5, 14.2 ppm. Minor dia-

stereoisomer: ¹H NMR (CDCl₃, 400 MHz): δ = 5.19–5.12 (m, 1

H), 4.27 (d, J = 7.1 Hz, 1 H), 4.23 (d, J = 7.1 Hz, 1 H), 3.57 (dd,

J = 9.6, 4.1 Hz, 1 H), 2.80 (dd, J = 6.7, 4.1 Hz, 1 H), 2.77 (dd, J

= 6.7, 4.1 Hz, 1 H), 2.54 (s, 1 H), 2.39 (dd, J = 11.2, 9.8 Hz, 1 H),

2.20 (m, 1 H), 2.05–2.02 (m, 1 H), 1.55 (s, 3 H), 1.31 (t, J = 7.1 Hz,

3 H) ppm. ¹³C NMR (CDCl₃, 100 MHz): δ = 171.2, 167.7, 86.4,

77.9, 72.9, 66.6, 62.5, 48.1, 46.5, 32.9, 30.5, 14.2 ppm. HRMS (EI):

+ Na]⁺739.3278; found 739.3287. IR: ν = 3461, 2943, 2917, 2875,

˜

1763, 1741, 1453, 1399, 1202, 1016 cm^–1. [α]²_D²= –41.1, (CHCl₃, c

= 1.0). R_f(hexane/EtOAc, 1:1) = 0.63.

(S)-2-Methyl-1-[(S)-oxiran-2-yl]but-3-yn-2-ol (36): Alkyne 33

(2.40 g, 13.0 mmol) was dissolved in a mixture of acetic acid

(27 mL) and H₂O (1.4 mL) at room temperature. The clear color-

less solution was stirred for 24 h and concentrated under reduced

pressure. The remaining pale yellow residue was evaporated with

toluene (3ϫ 10 mL) until the smell of AcOH was gone. Purification

by flash column chromatography (SiO₂, hexane/EtOAc, 2:1) af-

forded the corresponding triol as a colorless gum (1.67 g, 89%). ¹H

NMR (CDCl₃, 400 MHz): δ = 4.42–4.38 (m, 1 H), 4.05 (br. s, 1

H), 3.68 (dd, J = 11.1, 2.9 Hz, 1 H), 3.51 (dd, J = 10.7, 6.9 Hz, 1

H), 3.33 (br. s, 1 H), 2.51 (s, 1 H), 2.11 (br. s, 1 H), 1.85 (dd, J =

calcd. for C₁₁H₁₃O₅[M – CH₃]⁺225.0763; found 225.0765. IR: ν

˜

= 3473, 2984, 1767, 1450, 1371, 1260, 1156, 1095, 1035, 1008 cm^–1.

[α]²_D⁰= –33.5, (CHCl₃, c = 1.0). R_f(hexane/EtOAc, 1:1) = 0.51.

Aforementioned malonate (3.8 g, 15.83 mmol) was heated to

140 °C in the presence of LiCl (1.33 g, 31.66 mmol) in a mixture of

DMSO (32 mL) and water (1 mL) and stirred for 5 h. The resulting

brown mixture was cooled to room temperature and quenched with

14.4, 10.6 Hz, 1 H), 1.70 (dd, J = 14.4, 2.1 Hz, 1 H) 1.55 (s, 3 satd. aq. NH₄Cl (10 mL) and H₂O (30 mL). The aqueous phase

H) ppm. ¹³C NMR (CDCl₃, 100 MHz): δ = 87.0, 72.3, 71.3, 68.3,

was extracted with CH₂Cl₂(7ϫ 10 mL) and the combined organic

phases were dried with MgSO₄, filtered and evaporated to give a

viscous brown oil. Purification by flash column chromatography

(SiO₂, hexane/EtOAc, 3:1) afforded alcohol 37 as a colorless oil

(2.5 g, 94%). ¹H NMR (CDCl₃, 400 MHz): δ = 5.03–4.97 (m, 1 H),

2.72 (br. s, 1 H), 2.54 (dd, J = 9.9, 1.7 Hz, 1 H), 2.53 (d, J = 9.6 Hz,

1 H) 2.52 (s, 1 H), 2.47–2.39 (m, 1 H), 2.09–1.89 (m, 3 H), 1.55 (s,

3 H) ppm. ¹³C NMR (CDCl₃, 100 MHz): δ = 176.3, 86.6, 78.5,

72.7, 66.9, 48.2, 30.5, 28.9, 28.3 ppm. HRMS (ESI): calcd. for

66.8, 43.9, 31.2 ppm. HRMS (ESI): calcd. for C₇H₁₂O₃[M]⁺

144.0786; found 144.0791. IR: ν = 3298, 2983, 2359, 1418, 1133,

˜

1109, 1058, 1036, 1016, 908 cm^–1. [α]²_D⁰= –7.9, (CHCl₃, c = 1.0). R_f

(hexane/EtOAc, 1:2) = 0.19.

A solution of aforementioned triol (3.8 g, 26.4 mmol) in THF

(40 mL) was added to a suspension of NaH (5.2 g, 132 mmol) in

THF (100 mL) at 0 °C. The resulting heterogeneous mixture was

stirred at 0 °C for 30 min, warmed to room temperature and left

for 30 min before being cooled to 0 °C again. Solid trisylimidazole

34 (11.5 g, 34.3 mmol) was added in three portions under a con-

stant stream of argon. The resulting reaction mixture was vigor-

ously stirred at 0 °C for 1 h before it was quenched with H₂O

(50 mL) and brine (20 mL). The aqueous phase was extracted with

CH₂Cl₂(4ϫ 20 mL), the combined organic phases were dried with

MgSO₄, filtered and evaporated to give a brown oil. Purification by

flash column chromatography (SiO₂, hexane/EtOAc, 1:1) afforded

epoxide 36 as a colorless oil (2.36 g, 78 %). ¹H NMR (CDCl₃,

C₈H₉O₃[M – CH₃]⁺153.0552; found 153.0557. IR: ν = 3430, 3280,

˜

2985, 2934, 1760, 1357, 1173, 1124, 1035, 1008 cm^–1. [α]²_D⁰= –67.2,

(CHCl₃, c = 1.0). R_f(hexane/EtOAc, 1:2) = 0.41.

(R)-5-[(S)-2-Methyl-2-(trimethylsilyloxy)penta-3,4-dienyl]dihydro-

furan-2(3H)-one (38): A heterogeneous mixture of alcohol 37 (2.5 g,

14.9 mmol), paraformaldehyde (1.29 g, 44.6 mmol), iPr₂NH

(3.2 mL, 22.32 mmol) and CuBr (1.07 g, 7.45 mmol) in 1,4-dioxane

(30 mL) was stirred at 125 °C for 6 h. The resulting greenish reac-

tion mixture was cooled to room temperature, filtered through a

400 MHz): δ = 3.34–3.29 (m, 1 H), 3.07 (s, 1 H), 2.81 (dd, J = 4.8, pad of Celite followed by the addition of satd. aq. NH₄Cl (10 mL)

4.2 Hz, 1 H), 2.53 (dd, J = 4.9, 2.8 Hz, 1 H), 2.50 (s, 1 H), 2.02 and H₂O (30 mL). The aqueous phase was extracted with CH₂Cl₂

(dd, J = 4.2, 14.2 Hz, 1 H), 1.71 (dd, J = 14.2, 7.6 Hz, 1 H), 1.52

(5ϫ 10 mL) and the combined organic phases were washed with

satd. aq. NaCl (10 mL), dried with MgSO₄, filtered and evaporated

(s, 3 H) ppm. ¹³C NMR (CDCl₃, 100 MHz): δ = 87.0, 72.1, 67.2,

49.5, 46.7, 45.5, 30.2 ppm. HRMS (EI): calcd. for C₆H₇O₂[M – to give a brown oil. Purification by flash column chromatography

CH₃]⁺111.0446; found 111.0441. IR: ν = 3408, 3283, 2985, 2926,

(SiO₂, hexane/EtOAc, 2:1) afforded the desired allene as a colorless

oil (1.9 g, 86%). ¹H NMR (CDCl₃, 400 MHz): δ = 5.31 (t, J =

6.6 Hz, 1 H), 4.90 (d, J = 6.6 Hz, 2 H), 4.83–4.76 (m, 1 H), 2.51

(d, J = 9.7 Hz, 1 H), 2.49 (d, J = 9.7 Hz, 1 H), 2.40–2.32 (m, 1 H),

2.24 (br. s, 1 H), 2.02 (dd, J = 14.7, 8.5 Hz, 1 H), 1.94–1.82 (m, 2

H), 1.38 (s, 3 H) ppm. ¹³C NMR (CDCl₃, 100 MHz): δ = 205.5,

176.9, 99.4, 79.1, 78.1, 70.4, 47.7, 29.4, 28.9, 28.7 ppm. HRMS

˜

1450, 1410, 1304, 1165, 1135, 1047 cm^–1. [α]²_D⁰= –20.5, (CHCl₃, c

= 1.0). R_f(hexane/EtOAc, 1:2) = 0.58.

(R)-5-[(S)-2-Hydroxy-2-methylbut-3-ynyl]dihydrofuran-2(3H)-one

(37): Sodium (1.08 g, 46.8 mmol) was added as small pieces under

a constant stream of argon to EtOH (100 mL). After all solids were

dissolved, diethylmalonate (14.2 mL, 94 mmol) was added drop-

wise. A solution of epoxide 36 (2.36 g, 18.7 mmol) in EtOH

(100 mL) was added after stirring at room temperature for 15 min.

The reaction mixture was left at this temperature for 16 h and

quenched with satd. aq. NH₄Cl (50 mL) and H₂O (50 mL). The

aqueous phase was extracted with CH₂Cl₂(4ϫ 10 mL) and the

combined organic phases were dried with MgSO₄, filtered and

evaporated to give a pale yellow oil. Purification by flash column

chromatography (SiO₂, hexane/EtOAc, 4:1) afforded a (1:1.45) dia-

stereoisomeric mixture of the desired malonate as a colorless oil

(3.86 g, 86 %). Major diastereoisomer: ¹H NMR (CDCl₃,

(EI): calcd. for C₁₀H₁₂O₂[M]⁺164.0839; found 164.0837. IR: ν =

˜

3423, 2978, 2934, 1956, 1760, 1727, 1457, 1419, 1357, 1289, 1223,

1179, 1114, 1075, 1012, 986, 917, 850 cm^–1. [α]²_D⁰= –49.3, (CHCl₃,

c = 1.0). R_f(hexane/EtOAc, 1:1) = 0.18.

2,6-Lutidine (8.0 mL, 69.1 mmol) and TMSOTf (6.3 mL,

34.6 mmol) were sequentially added to a solution of the tertiary

allenic alcohol (4.2 g, 23.0 mmol) in THF (50 mL) at 0 °C. After

removal of the cooling bath and additional 30 min, the reaction

was quenched with satd. aq. NH₄Cl (50 mL). The aqueous phase

was extracted with hexanes (10 mL) and the combined organic

Eur. J. Org. Chem. 2013, 8214–8244

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8231

M. Himmelbauer, J.-B. Farcet, J. Gagnepain, J. Mulzer

FULL PAPER

phases were washed with satd. aq. NaCl (20 mL), dried with

MgSO₄, filtered and evaporated to give a crude colorless oil. Purifi-

cation by flash column chromatography (SiO₂, hexane/EtOAc, 4:1)

afforded lactone 38 as a colorless oil (5.1 g, 87 %). ¹H NMR

(CDCl₃, 400 MHz): δ = 5.25 (t, J = 6.6 Hz, 1 H), 4.82 (d, J =

rification by column chromatography (SiO₂, hexane/EtOAc, 6:1)

afforded desired butyrolactone 39 (224 mg, 0.28 mmol) as an in-

separable mixture of diastereoisomers. ¹H NMR (CDCl₃,

400 MHz): δ = 7.74–7.67 (m, 4 H), 7.44–7.37 (m, 6 H), 7.25–7.20

(m, 3 H), 7.07–7.02 (m, 0.4 H), 6.89–6.85 (m, 2 H), 5.27 (t, J =

6.6 Hz, 2 H), 4.76–4.70 (m, 1 H), 2.50 (dd, J = 8.4, 2.5 Hz, 1 H), 6.6 Hz, 1 H), 5.21–5.15 (m, 1 H), 4.86–4.84 (m, 1 H), 4.72 (d, J =

2.48 (d, J = 9.7 Hz, 1 H), 2.36 (sext, J = 6.5 Hz, 1 H), 1.99–1.84

(m, 3 H), 1.39 (s, 3 H), 0.10 (s, 9 H) ppm. ¹³C NMR (CDCl₃,

100 MHz): δ = 206.3, 177.4, 99.8, 78.1, 77.9, 72.8, 49.4, 29.8, 29.0,

27.7, 2.4 (3 C) ppm. HRMS (ESI): calcd. for C₁₃H₂₂O₃SiNa [M +

8.0 Hz, 1 H), 4.57–4.51 (m, 0.5 H), 4.48–4.40 (m, 2.5 H), 4.06 (d,

J = 4.2 Hz, 0.5 H), 3.90–3.84 (m, 1.5 H), 3.80–3.68 (m, 4 H), 3.62–

3.56 (m, 1 H), 3.31–3.27 (m, 4 H), 3.24–3.21 (m, 0.5 H), 2.49–2.40

(m, 1 H), 2.19–2.14 (m, 0.5 H), 2.07–2.01 (m, 0.5 H), 1.95–1.88 (m,

2 H), 1.82–1.61 (m, 2 H), 1.47 (s, 3 H), 1.09 (s, 4 H), 1.08 (s, 5 H),

0.15 (s, 5 H), 0.14 (s, 4 H) ppm. ¹³C NMR (CDCl₃, 100 MHz): δ

= 206.3, 172.5, 172.4, 159.6, 159.5, 150.4, 150.2, 136.0, 135.9, 135.8,

135.8, 135.7, 133.6, 133.5, 133.42, 133.38, 133.3, 129.82, 129.80,

129.78, 129.6, 127.9, 127.83, 127.80, 127.77, 114.1, 114.0, 107.3,

107.1, 99, 84.5, 84.2, 78.8, 78.7, 78.2, 78.1, 73.3, 73.2, 72.82, 72.77,

71.7, 71.5, 66.9, 65.7, 64.7, 64.5, 55.3, 54.5, 54.4, 52.4, 51.5, 47.1,

47.0, 40.7, 40.0, 38.8, 38.6, 27.78, 27.76, 27.02, 26.98, 19.41, 19.39,

2.39 ppm. HRMS (ESI): calcd. for C₄₆H₆₂O₉Si₂Na [M + Na]⁺

Na]⁺277.1233; found 277.1236. IR: ν = 2955, 1956, 1773, 1249,

˜

1154, 1110, 1078, 1001, 982, 916, 836 cm^–1. [α]²_D⁰= –42.3, (CHCl₃,

c = 1.0). R_f(hexane/EtOAc, 1:1) = 0.64.

2-Phenylselenyl-γ-butyrolactone 32: LiHMDS (1.0 m in toluene,

6.5 mL, 64.9 mmol) and TMSCl (0.83 mL, 64.9 mmol) were se-

quentially added to a solution of lactone 39 (1.50 g, 5.9 mmol) in

THF (30 mL) at –78 °C. After 2 h at –78 °C a solution of PhSeCl

(1.24 g, 64.9 mmol) in THF (30 mL) was added over 10 min. After

30 min at –78 °C, the reaction was quenched with satd. aq. NH₄Cl

(40 mL). The aqueous phase was extracted with diethyl ether (3ϫ

20 mL) and the combined organic phases were washed with satd.

aq. NaCl (40 mL), dried with MgSO₄, filtered and evaporated to

give a colorless oil. Purification by flash column chromatography

(SiO₂, hexane/EtOAc, 20:1) afforded a 1:1.5 diastereoisomeric mix-

ture of lactone 32 as a colorless oil (2.0 g, 83%). ¹H NMR (CDCl₃,

837.3830; found 837.3823. IR: ν = 3433, 2971, 2921, 2879, 1776,

˜

1429, 1227, 1164, 1023, 973 cm^–1. [α]²_D⁰= –13.7, (CHCl₃, c = 1.0).

R_f(hexane/EtOAc, 2:1) = 0.51.

Cage-Shaped Cyclobutane 40: A 1:1 diastereoisomeric mixture of

39 (25 mg, 0.03 mmol) was dissolved in freshly degassed cyclohex-

ane (13 mL) and placed 1 cm in front of UV-B lamps. The resulting

400 MHz): δ = 7.71–7.63 (m, 3 H), 7.41–7.29 (m, 4.6 H), 5.20 (t, J colorless solution was irradiated for 1.5 h. The volatiles were re-

= 6.6 Hz, 1 H), 5.19 (t, J = 6.6 Hz, 0.5 H), 4.81 (d, J = 6.6 Hz, 3 moved under reduced pressure and the resulting yellow oil was sub-

H), 4.70–4.62 (m, 0.5 H), 4.57–4.48 (m, 1 H), 4.02 (dd, J = 10.1, jected to column chromatography (SiO₂, hexane/EtOAc, 8:1) lead-

9.1 Hz, 0.5 H), 3.91 (dd, J = 6.4, 4.0 Hz, 1 H), 2.79–2.69 (m, 0.5

H), 2.41–2.35 (m, 2 H), 2.01 (dt, J = 13.3, 10.0 Hz, 0.5 H), 1.92

(dd, J = 14.3, 6.3 Hz, 1 H), 1.86–1.76 (m, 1.5 H), 1.70 (dd, J =

14.4, 5.1 Hz, 1 H), 1.35 (s, 1.5 H), 1.32 (s, 3 H), 0.09 (s, 9 H), 0.08

ing to the isolation of a diastereoisomeric mixture of 40 (3 mg,

0.003 mmol, 10%). ¹H NMR (CDCl₃, 400 MHz): δ = 7.71–7.66

(m, 4 H), 7.44–7.35 (m, 6 H), 7.21 (d, J = 8.8 Hz, 2 H), 6.85 (d, J

= 8.6 Hz, 2 H), 5.31 (dd, J = 2.6, 1.2 Hz, 1 H), 5.17–5.11 (m, 2 H),

(s, 4.5 H) ppm. ¹³C NMR (CDCl₃, 100 MHz): δ = 206.1, 175.8, 4.75 (br. s, 1 H), 4.45 (d, J = 11.7 Hz, 1 H), 4.40 (d, J = 11.8 Hz,

136.0, 135.9, 135.6, 128.7, 127.1, 126.8, 99.6, 99.6, 77.8, 76.6, 76.4,

72.6, 49.2, 48.9, 38.3, 37.0, 27.5, 2.2 (3 C) ppm. HRMS (ESI):

calcd. for C₁₉H₂₆O₃SeSiNa [M + Na]⁺433.0709; found 433.0715.

1 H), 4.01–3.99 (m, 1 H), 3.90–3.83 (m, 1 H), 3.80 (s, 3 H), 3.76–

3.74 (m, 2 H), 3.49 (d, J = 2.9 Hz, 1 H), 3.46–3.41 (m, 1 H), 3.30

(s, 3 H), 3.30–3.25 (m, 2 H), 3.09–3.06 (m, 1 H), 2.45 (qd, J = 12.4,

1.8 Hz, 1 H), 2.26–2.20 (m, 1 H), 2.06–1.99 (m, 1 H), 1.92 (dd, J

= 14.7, 5.3 Hz, 1 H), 1.65 (td, J = 19.0, 4.2 Hz, 1 H), 1.42–1.38 (m,

4 H), 1.06 (s, 9 H), 0.12 (s, 9 H) ppm. ¹³C NMR (CDCl₃,

100 MHz): δ = 177.2, 159.5, 144.8, 135.91 (2 C), 135.86 (2 C),

133.7, 133.5, 130.0, 129.80, 129.78, 129.5 (2 C), 127.82 (2 C), 127.79

(2 C), 114.5, 114.0 (2 C), 107.4, 84.9, 83.9, 83.7, 73.0, 71.5, 69.7,

65.5, 57.90, 57.88, 55.4, 54.6, 51.7, 49.5, 44.4, 39.6, 35.2, 27.0 (3

C), 23.5, 19.4, 2.44 (3 C) ppm. HRMS (ESI): calcd. for C₄₆H₆₂O₉S-

IR: ν = 2956, 1956, 1769, 1483, 1251, 1112, 1022, 840, 740 cm^–1.

˜

[α]²_D⁰= –53.5, (CHCl₃, c = 1.0). R_f(hexane/EtOAc, 8:1) = 0.27

(major), 0.32 (minor).

Butenolide 39: A freshly prepared solution of lithium diisoprop-

ylamide (LDA; 810 μL, 0.5 m THF, 0.40 mmol; see 22) was added

dropwise to a solution of 32 (153 mg, 0.37 mmol) in THF (1.5 mL)

at –78 °C. The resulting pale yellow solution was stirred for 30 min

before 8 (190 mg, 0.34 mmol) in THF (2 mL) was added over

10 min. The reaction mixture was gradually warmed to –40 °C over

2 h. Sat. aq. NH₄Cl (10 mL) and diethyl ether (10 mL) were added.

The aqueous phase was separated and extracted with diethyl ether

(3ϫ 10 mL). The combined organic layers were washed with water

(15 mL) and satd. aq. NaCl (15 mL), dried with MgSO₄, filtered

and concentrated under reduced pressure. NMR spectroscopic

analysis of the crude mixture of four diastereoisomers indicated

full consumption of 32. The crude mixture was used in the next

step without further purification.

i₂Na [M + Na]⁺837.3830; found 837.3809. IR: ν = 3433, 2971,

˜

2921, 2879, 1776, 1429, 1227, 1164, 1023, 973cm^–1. [α]²_D⁰= –33.9,

(CHCl₃, c = 0.08). R_f(hexane/EtOAc, 2:1) = 0.60.

Ethyl 2-[(3aR,5S,6R,6aR)-5-(Hydroxymethyl)-2,2-dimethyltetra-

hydrofuro[2,3-d][1,3]dioxol-6-yl]acetate (42): A mixture of diacet-

one-d-glucofuranose (34.4 g, 127.3 mmol) and IBX (82 g,

292.8 mmol) in EtOAc (1 L) was heated to reflux for 26 h. After

the thick suspension reached room temperature, hexane (500 mL)

was added and the resulting suspension was filtered through a pad

of Celite. The volatiles were removed under reduced pressure and

the crude ketone (35.4 g) was used in the olefination reaction with-

out further purification. R_f(hexane/EtOAc, 1:1) = 0.25.

The crude oil was dissolved in a mixture of CH₂Cl₂(3.5 mL) and

pyridine (350 μL) and cooled to 0 °C. Hydrogen peroxide (230 μL,

2.0 mmol) was added and the resulting biphasic mixture was stirred

at that temperature for 1 h. Sat. aq. Na₂S₂O₃(10 mL) and diethyl

ether (20 mL) were added and the resulting biphasic mixture was

stirred for another hour. The aqueous phase was extracted with

diethyl ether (2 ϫ 10 mL). The combined organic layers were

washed with satd. aq. CuSO₄(2ϫ 15 mL) and water (15 mL), dried

with MgSO₄, filtered and concentrated under reduced pressure. Pu-

To a solution of PPh₃(55 g, 209.6 mmol) in EtOAc (360 mL) was

added a solution of methyl bromoacetate (32.3 g, 211 mmol) in

EtOAc (90 mL) through a dropping funnel over 45 min at 0 °C.

The resulting thick white suspension was warmed to room tempera-

ture and stirred for 20 h. The solids were collected by filtration,

dissolved in CH₂Cl₂(400 mL) in a separatory funnel and vigor-

8232

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Eur. J. Org. Chem. 2013, 8214–8244

An Approach to the Carbon Backbone of Bielschowskysin, Part 1

ously shaken with 1 m NaOH (300 mL) for 30 min. The aqueous

layer was extracted with CH₂Cl₂(3ϫ 100 mL). The organic phases

were washed with satd. aq. NaCl (200 mL), dried with MgSO₄,

filtered and concentrated under reduced pressure yielding the Wit-

tig ylide (70 g, 209.3 mmol) as a white solid after extensive drying

under high vacuum for 2 h.

to the thick suspension. After 15 min the solids were removed by

filtration through a pad of Celite. The residue was washed with

MeOH (50 mL). The combined liquids were cooled to 0 °C fol-

lowed by the careful addition of NaBH₄(3.50 g, 92.5 mmol) in

three portions. After 1 h, acetic acid was added carefully until a

pH 6 for the solution was reached. The volatiles were removed and

the residue was subjected to column chromatography (SiO₂, hex-

ane/EtOAc, 1:1) yielding desired α-d-ribofuranose 42 (13.5 g,

A solution of the ylide (50.4 g, 150.7 mmol) in CHCl₃(500 mL)

was added through cannula to a solution of the ketone (35.4 g,

137.1 mmol) in CHCl₃(500 mL) at 0 °C over 30 min. After the ad-

dition, the reaction mixture was warmed to room temperature and

stirred for 16 h resulting in a dark red solution. The volatiles were

evaporated and the dark gum was filtered through a short pad of

silica (hexane/EtOAc, 2:1). After evaporation the orange gum (40 g,

127.3 mmol, 93%) was used in the next step without further purifi-

cation. R_f(hexane/EtOAc, 1:1) = 0.70.

1

51.8 mmol, 82%). H NMR (CDCl₃, 400 MHz): δ = 5.82 (d, J =

3.6 Hz, 1 H), 4.78 (dd, J = 4.3, 3.8 Hz, 1 H), 4.22–4.11 (m, 2 H),

3.90–3.85 (m, 2 H), 3.59–3.54 (m, 1 H), 2.70 (dd, J = 16.5, 8.1 Hz,

1 H), 2.48–2.41 (m, 1 H), 2.38 (dd, J = 16.5, 5.4 Hz, 1 H), 2.04 (br.

s, OH), 1.50 (s, 3 H), 1.32 (s, 3 H), 1.27 (t, J = 7.1 Hz, 3 H) ppm.

¹³C NMR (CDCl₃, 100 MHz): δ = 172.4, 111.9, 104.9, 81.8, 81.5,

61.6, 61.0, 39.8, 30.0, 26.8, 26.5, 14.3 ppm. HRMS (ESI): calcd. for

C₁₂H₂₀O₆Na [M + Na]⁺283.1158; found 283.1153. IR: ν = 3474,

˜

2985, 2937, 1731, 1374, 1214, 1167, 1112, 1013, 874 cm^–1. [α]²_D⁰

+62.9, (CHCl₃, c = 1.0). R_f(hexane/EtOAc, 1:1) = 0.33.

=

To a solution of the α,β-unsaturated ester (20 g, 63.6 mmol) in

EtOH (250 mL) was added Raney nickel 2400 (10 g). The round-

bottomed flask was sealed with a rubber septum. A rubber balloon

charged with H₂was connected to a needle that reached into the

solution. A gas outlet was installed and the flow of the gas was

regulated with a hose clamp to about 4 bubbles per second. The

round-bottomed flask was placed in an ultra sound bath and

treated for 2 h in a fume hood. The balloon was replaced by a

balloon filled with argon and the reaction mixture was purged in

the ultra sound bath for 30 min. The nickel catalyst was filtered off

through a pad of Celite, which was washed with EtOH (2 ϫ

100 mL). Removal of the solvent under reduced pressure gave the

desired product as a clean single diastereoisomer (20.0 g,

63.2 mmol, 99%) as a colorless gum, which was used in the next

reaction without further purification. ¹H NMR (CDCl₃,

400 MHz): δ = 5.77 (d, J = 3.8 Hz, 1 H), 4.81 (t, J = 4.2 Hz, 1 H),

4.19–4.13 (m, 2 H), 4.12–4.09 (m, 1 H), 4.00–3.97 (m, 1 H), 3.96–

3.92 (m, 1 H), 3.69 (dd, J = 9.9, 7.5 Hz, 1 H), 2.81 (dd, J = 17.4,

4.2 Hz, 1 H), 2.65 (dd, J = 17.4, 10.4 Hz, 1 H), 2.36–2.29 (m, 1 H),

1.50 (s, 3 H), 1.41 (s, 3 H), 1.33 (s, 3 H), 1.31 (s, 3 H), 1.26 (t, J =

7.15 Hz, 3 H) ppm. ¹³C NMR (CDCl₃, 100 MHz): δ = 172.5, 112.0,

109.8, 105.2, 81.7 81.1, 78.0, 68.0, 60.7, 44.7, 30.2, 26.9, 26.8, 26.5,

25.4, 14.4 ppm. HRMS (ESI): calcd. for C₁₆H₂₆O₇Na [M + Na]⁺

(3aR,4S,6R,6aR)-4-{[(tert-Butyldimethylsilyl)oxy]methyl}-6-meth-

oxytetrahydrofuro[3,4-b]furan-2(3H)-one (43): A mixture of tri-

fluoroacetic acid (60 mL) and α-d-ribofuranose 42 (9.8 g,

37.7 mmol) in MeOH (370 mL) was heated to reflux for 16 h. The

resulting pale yellow solution was concentrated in vacuo and the

remaining oil was co-evaporated with toluene (3ϫ 50 mL). Purifi-

cation by flash column chromatography (SiO₂, hexane/EtOAc,

1:1Ǟ1:2) afforded the desired lactone as a pale yellow oil (5.7 g,

81%). ¹H NMR (CDCl₃, 400 MHz): δ = 5.08 (s, 1 H), 4.89 (d, J =

6.8 Hz, 1 H), 4.23 (dd, J = 3.8 Hz, 1 H), 3.73 (dd, J = 12.2, 2.9 Hz,

1 H), 3.57 (dd, J = 12.2, 4.2 Hz, 1 H), 3.46 (s, 3 H), 3.25–3.19 (m,

1 H), 2.86 (dd, J = 18.4, 9.9 Hz, 1 H), 2.52 (dd, J = 18.4, 3.9 Hz,

1 H), 1.25 (br. s, 1 H) ppm. ¹³C NMR (CDCl₃, 100 MHz): δ =

175.5, 107.8, 89.6, 87.7, 64.7, 55.9, 38.1, 34.1 ppm. HRMS (ESI):

calcd. for C₈H₁₂O₅Na [M + Na]⁺211.0582; found 211.0582. IR: ν

˜

= 3412, 2923, 1776, 1454, 1377, 1161, 1106, 1049, 959, 813 cm^–1.

[α]²_D⁵= –40.3, (CHCl₃, c = 1.0). R_f(hexane/EtOAc, 1:4) = 0.29.

To a solution of the primary alcohol (4.1 g, 21.8 mmol) and imid-

azole (3.6 g, 52.3 mmol) in CH₂Cl₂(200 mL) was added tert-butyl-

dimethylsilyl chloride (3.9 g, 26.1 mmol) as a solid in three portions

under an argon stream at room temperature. After stirring for 2 h,

the resulting pale yellow reaction mixture was quenched by the

addition of water (100 mL). The aqueous layer was separated and

extracted with CH₂Cl₂(3ϫ 50 mL). The combined organic phases

were washed with water (100 mL) and aq. satd. NaCl (100 mL),

dried with MgSO₄and filtered. After evaporation of all volatiles

flash column chromatography (SiO₂, hexane/EtOAc, 3:1) of the res-

idue gave lactone 43 (6.0 g, 91 %) as a colorless oil. ¹H NMR

(CDCl₃, 400 MHz): δ = 5.06 (s, 1 H), 4.81 (d, J = 6.4 Hz, 1 H),

4.00 (ddd, J = 8.3, 5.1, 4.7 Hz, 1 H), 3.74 (dd, J = 9.8, 5.3 Hz, 1

H), 3.52 (dd, J = 9.8, 8.3 Hz, 1 H), 3.34 (s, 3 H), 3.05–3.00 (m, 1

H), 2.82 (dd, J = 18.1, 9.3 Hz, 1 H), 2.48 (dd, J = 18.1, 2.0 Hz, 1

H), 0.88 (s, 9 H), 0.59 (s, 6 H) ppm. ¹³C NMR (CDCl₃, 100 MHz):

δ = 175.8, 107.4, 88.1, 87.3, 65.8, 55.0, 40.3, 34.5, 25.9 (3 C), 18.3,

–5.2, –5.3 ppm. HRMS (ESI): calcd. for C₁₄H₂₆O₅SiNa [M +

353.1576; found 353.1586. IR: ν = 2986, 2938, 1734, 1381, 1333,

˜

1241, 1213, 1065, 1016, 847 cm^–1. [α]²_D²= +69.0, (CHCl₃, c = 1.0).

R_f(hexane/EtOAc, 1:1) = 0.70.

The crude diacetonide (20.0 g, 63.2 mmol) was dissolved in AcOH/

H₂O (2:1, 60 mL). After all of the crude gum was dissolved the

solution was stirred at room temperature for 18 h. The volatiles

were removed under reduced pressure and the resulting slightly yel-

low residue was co-evaporated with toluene (5ϫ 50 mL) until the

smell of acetic acid was gone. The desired vicinal diol (17.7 g,

63.2 mmol, 100%) was used in the next reaction without further

purification. ¹H NMR (CDCl₃, 400 MHz): δ = 5.78 (d, J = 3.7 Hz,

1 H), 4.78 (dd, J = 4.6, 4.1 Hz, 1 H), 4.20–4.12 (m, 2 H), 3.84 (dd,

J = 10.0, 5.7 Hz, 1 H), 3.80–3.76 (m, 1 H), 3.73–3.68 (m, 2 H), 2.78

(br. s, 1 H), 2.72 (d, J = 6.9 Hz, 2 H), 2.42–2.35 (m, 1 H), 2.25 (br.

s, 1 H), 1.49 (s, 3 H), 1.31 (s, 3 H), 1.27 (t, J = 7.2 Hz, 3 H) ppm.

¹³C NMR (CDCl₃, 100 MHz): δ = 173.1, 112.1, 104.9, 81.9, 81.6,

73.6, 64.1, 61.0, 43.3, 30.6, 26.9, 26.6, 14.4 ppm. HRMS (ESI):

calcd. for C₁₃H₂₂O₇Na [M + Na]⁺313.1263; found 313.1256. IR:

Na]⁺325.1447; found 325.1448. IR: ν = 2953.6, 2930.1, 2857.2,

˜

1787.9, 1471.8, 1254.4, 1154.0, 1106.7, 1004.4, 837.7 cm^–1. [α]²_D⁰

–88.3, (CHCl₃, c = 0.6). R_f(hexane/EtOAc, 1:2) = 0.73.

=

ν = 3438, 2924, 2854, 1732, 1460, 1377, 1218, 1168, 1016, 772 cm^–1.

˜

tert-Butyl[((2S,3R,4R,5R)-5-methoxy-4-[(triethylsilyl)oxy]-3-{2-[(tri-

ethylsilyl)oxy]ethyl}tetrahydrofuran-2-yl)methoxy]dimethylsilane

(44): A solution of lactone 43 (11.7 g, 38.8 mmol) in diethyl ether

(200 mL) was added to a suspension of freshly powdered lithium

aluminium hydride pellets (2.5 g, 66.1 mmol) in anhydrous diethyl

[α]²_D⁰= +10.0, (CHCl₃, c = 0.35). R_f(hexane/EtOAc, 1:1) = 0.18.

The gum (17.7 g, 63.2 mmol, 100 %) was dissolved in MeOH

(160 mL) and H₂O (20 mL). The solution was cooled to 0 °C and

NaIO₄(13.6 g, 63.6 mmol) was added under vigorous stirring. Af-

ter 1 h at that temperature, glucose (0.5 g, 2.77 mmol) was added ether (100 mL) at 0 °C over 30 min under vigorous stirring in a 1 L

Eur. J. Org. Chem. 2013, 8214–8244

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8233

M. Himmelbauer, J.-B. Farcet, J. Gagnepain, J. Mulzer

FULL PAPER

round-bottomed flask. After 1 h, satd. aq. NH₄Cl (200 mL) was

carefully added at 0 °C followed by the addition of satd. aq. Na/K

tartrate (200 mL). The resulting turbid biphasic system was stirred

for 2 h and warmed to room temperature. The aqueous phase was

separated and extracted with diethyl ether (5ϫ 100 mL). The com-

bined organic phases were washed with satd. aq. NaCl (200 mL)

and dried with MgSO₄. After evaporation of all volatiles under

reduced pressure the desired diol was isolated as colorless sticky oil

(11.9 g, quant.) that was used without further purification in the

next reaction. ¹H NMR (CDCl₃, 400 MHz): δ = 4.83 (s, 1 H), 4.18

(d, J = 4.6 Hz, 1 H), 3.95 (dt, J = 8.6, 5.5 Hz, 1 H), 3.86–3.81 (m,

1 H), 3.74 (dd, J = 10.3, 5.2 Hz, 1 H), 3.73–3.67 (m, 1 H), 3.62

(dd, J = 10.3, 5.8 Hz, 1 H), 3.33 (s, 3 H), 3.00 (br. s, 1 H), 2.29 (br.

s, 1 H), 2.23–2.17 (m, 1 H), 1.92–1.74 (m, 2 H), 0.90 (s, 9 H), 0.07

(s, 6 H) ppm. ¹³C NMR (CDCl₃, 100 MHz): δ = 109.0, 84.3, 77.2,

66.8, 62.0, 54.6, 43.9, 28.9, 26.1 (3 C), 18.5, –5.24, –5.26 ppm.

HRMS (ESI): calcd. for C₁₄H₃₀O₅SiNa [M + Na]⁺329.1760; found

δ = 9.79 (s, 1 H), 4.69 (s, 1 H), 4.22 (d, J = 4.4 Hz, 1 H), 3.94 (ddd,

J = 8.4, 5.5, 0.7 Hz, 1 H), 3.74 (dd, J = 10.3, 4.9 Hz, 1 H), 3.59

(dd, J = 10.3, 6.1 Hz, 1 H), 3.32 (s, 3 H), 2.79 (ddd, J = 17.3, 8.6,

1.0 Hz, 1 H), 2.64–2.76 (m, 1 H), 2.58–2.53 (m, 1 H), 0.94 (t, J =

8.0 Hz, 9 H), 0.89 (s, 9 H), 0.58 (ddd, J = 17.3, 7.5, 0.9 Hz, 6 H),

0.06 (s, 3 H), 0.06 (s, 3 H) ppm. ¹³C NMR (CDCl₃, 100 MHz): δ

= 201.2, 109.5, 83.3, 77.1, 66.4, 54.7, 41.0, 39.4, 26.1 (3 C), 18.5,

6.9 (3 C), 4.9 (3 C), –5.3 (2 C) ppm. HRMS (ESI): calcd. for

C

₂₀H₄₂O₅Si₂Na [M + Na]⁺441.2468; found 441.2476. IR: ν =

˜

2955, 2929, 2879, 1728, 1462, 1254, 1127, 1108, 1039, 837 cm^–1.

[α]²_D⁰= +1.4, (CHCl₃, c = 1.2). R_f(hexane/EtOAc, 8:1) = 0.68.

Butenolide 46: LiHMDS (720 μL, 1.0 m in toluene, 5.6 mmol) was

added to a solution of butyrolactone 32 (2.0 g, 4.9 mmol) in THF

(22 mL) at –40 °C over 10 min. After 30 min a solution of aldehyde

45 (2.05 mg, 4.9 mmol) in THF (25 mL) was added dropwise over

20 min. After 2 h at –40 °C the reaction mixture was quenched by

the addition of satd. aq. NH₄Cl (30 mL) and CH₂Cl₂(30 mL). The

aqueous phase was separated and extracted with CH₂Cl₂(3 ϫ

40 mL). The combined organic phases were washed with water

(40 mL) and satd. aq. NaCl (40 mL), dried with MgSO₄, filtered

and concentrated under reduced pressure. NMR spectroscopic

analysis of the crude pale yellow oil indicated consumption of

butyrolactone 32 and showed a complex mixture of four diastereo-

isomers (4.5 g, 4.9 mmol) and traces of aldehyde 45.

329.1749. IR: ν = 3394, 2929, 2857, 1471, 1254, 1103, 1061, 1036,

˜

951, 837 cm^–1. [α]²_D⁰= –28.2, (CHCl₃, c = 1.1). R_f(hexane/EtOAc,

1:1) = 0.19.

To a solution of the crude diol (10.9 g, 35.6 mmol) in CH₂Cl₂

(150 mL) and imidazole (9.7 g, 142.5 mmol) was added triethylsilyl

chloride (13.1 mL, 78.2 mmol) through a syringe over 15 min. The

resulting pale yellow solution was left at room temperature for 2 h,

during which a white precipitate formed. Sat. aq. NH₄Cl (100 mL)

was added and stirring was continued for another 30 min. The

aqueous layer was separated and extracted with diethyl ether (3ϫ

50 mL). The combined organic phases were washed with water

(100 mL), satd. aq. NaCl (100 mL) and dried with MgSO₄. After

removal of all volatiles a pale yellow oil was obtained that yielded

tetrahydrofuran 44 (17.3 g, 91%) as a colorless oil after flash col-

umn chromatography (SiO₂, hexane/EtOAc, 20:1). ¹H NMR

(CDCl₃, 400 MHz): δ = 4.67 (s, 1 H), 4.04 (d, J = 4.4 Hz, 1 H),

3.93 (ddd, J = 9.3, 5.4, 3.9 Hz, 1 H), 3.71 (dd, J = 10.8, 3.8 Hz, 1

H), 3.67–3.55 (m, 3 H), 3.32 (s, 3 H), 2.16–2.09 (m, 1 H), 1.89–1.80

(m, 1 H), 1.61–1.53 (m, 1 H), 0.96 (dt, J = 8.1, 4.3 Hz, 18 H), 0.91

(s, 9 H), 0.65–0.58 (m, 12 H), 0.07 (s, 6 H) ppm. ¹³C NMR (CDCl₃,

100 MHz): δ = 109.3, 84.8, 77.3, 66.3, 61.8, 54.5, 40.2, 28.9, 26.1

(3 C), 18.6, 6.9 (6 C), 5.1 (3 C), 4.6 (3 C), –5.2 (2 C) ppm. HRMS

(ESI): calcd. for C₂₆H₅₈O₅Si₃Na [M + Na]⁺557.3490; found

H₂O₂(3.7 mL, 32.6 mmol) was added under vigorous stirring to

the aforementioned complex mixture in CH₂Cl₂(50 mL) and pyr-

idine (5 mL) at 0 °C. The resulting biphasic mixture was left at this

temperature for 1 h, quenched by the addition of satd. aq. NaS₂O₃

(30 mL) and stirred for an additional 30 min. The aqueous phase

was separated and extracted with CH₂Cl₂(3ϫ 30 mL). After the

combined organic phases were washed with water (50 mL) and

satd. aq. NaCl (50 mL), MgSO₄was added followed by filtration.

Evaporation of the volatiles and flash column chromatography

(SiO₂, hexane/EtOAc, 12:1) of the remaining oil yielded desired

butenolide 46 as an inseparable 1:1 mixture as a pale yellow oil

(3.01 g, 4.5 mmol, 92%). Diastereoisomer A: ¹H NMR (CDCl₃,

400 MHz): δ = 7.30 (t, J = 1.5 Hz, 1 H), 5.26 (t, J = 6.7 Hz, 1 H),

5.24–5.20 (m, 1 H), 4.84 (d, J = 6.5 Hz, 1 H), 4.69 (s, 1 H), 4.51–

4.47 (m, 1 H), 4.16 (d, J = 4.6 Hz, 1 H), 4.12 (d, J = 7.1 Hz, 1 H),

4.06 (dt, J = 8.7, 5.3 Hz, 1 H), 3.77 (t, J = 4.7 Hz, 1 H), 3.72–3.69

(m, 1 H), 3.69–3.65 (m, 1 H), 3.31 (s, 3 H), 2.42–2.35 (m, 1 H),

1.98–1.90 (m, 2 H), 1.81 (dd, J = 14.3, 7.3 Hz, 1 H), 1.69–1.61 (m,

1 H), 1.47 (s, 3 H), 0.95 (t, J = 7.9 Hz, 9 H), 0.91 (s, 9 H), 0.73 (q,

J = 7.7 Hz, 6 H), 0.14 (s, 9 H), 0.1 (br. s, 6 H) ppm. ¹³C NMR

(CDCl₃, 100 MHz): δ = 172.7, 150.1, 136.0, 109.0, 99.7, 83.9, 79.0,

78.6, 78.2, 78.0, 72.8, 66.7, 66.2, 54.7, 47.1, 41.7, 32.1, 27.8, 26.1

(3 C), 18.6, 6.9 (3 C), 5.0 (3 C), 2.4 (3 C), –5.3 (2 C) ppm. Dia-

stereoisomer B: ¹H NMR (CDCl₃, 400 MHz): δ = 7.31 (t, J =

1.4 Hz, 1 H), 5.26 (t, J = 6.7 Hz, 1 H), 5.24–5.20 (m, 1 H), 4.85 (d,

J = 6.7 Hz, 1 H), 4.67 (s, 1 H), 4.51–4.46 (m, 1 H), 4.13 (d, J =

12.6 Hz, 1 H), 4.10 (d, J = 4.4 Hz, 1 H), 4.00 (dt, J = 9.0, 4.8 Hz,

1 H), 3.79 (t, J = 4.8 Hz, 1 H), 3.72–3.68 (m, 1 H), 3.40 (d, J =

5.2 Hz, 1 H), 3.31 (s, 3 H), 2.35–2.29 (m, 1 H), 2.20 (dd, J = 7.9,

2.6 Hz, 1 H), 2.17 (dd, J = 7.9, 2.5 Hz, 1 H), 1.96–1.90 (m, 1 H),

1.79 (dd, J = 14.3, 7.2 Hz, 1 H), 1.47 (s, 3 H), 0.96 (t, J = 7.9 Hz,

9 H), 0.90 (s, 9 H), 0.63 (q, J = 7.8 Hz, 6 H), 0.14 (s, 9 H), 0.1 (br.

s, 6 H) ppm. ¹³C NMR (CDCl₃, 100 MHz): δ = 172.8, 150.2, 135.9,

109.2, 99.7, 83.9, 78.9, 78.6, 78.2, 78.0, 72.8, 66.5, 66.1, 54.8, 47.2,

41.1, 32.3, 27.8, 26.1 (3 C), 18.6, 6.9 (3 C), 5.0 (3 C), 2.4 (3 C),

–5.3 (2 C) ppm. HRMS (ESI): calcd. for C₃₃H₆₂O₈Si₃Na

[M + Na]⁺693.3650; found 693.3650. R_f(hexane/EtOAc, 3:1) = 0.57.

557.3477. IR: ν = 2953, 2877, 1461, 1251, 1102, 1041, 1003, 958,

˜

834, 775 cm^–1. [α]²_D⁰= +6.9, (CHCl₃, c = 1.2). R_f(hexane/EtOAc,

10:1) 0.36.

2-((2S,3R,4R,5R)-2-{[(tert-Butyldimethylsilyl)oxy]methyl}-5-meth-

oxy-4-[(triethylsilyl)oxy]tetrahydrofuran-3-yl)acetaldehyde (45): To

a solution of oxalyl chloride (2.0 mL, 23.4 mmol) in CH₂Cl₂

(20 mL) in a flame-dried 50 mL round-bottomed flask equipped

with a bubbler, dimethyl sulfoxide (3.4 mL, 48.1 mmol) was added

dropwise over 5 min at –78 °C. After the evolution of gas had ce-

ased the bubbler was removed and stirring was continued for a

further 10 min at –78 °C. Tetrahydrofuran 44 (2.5 g, 4.7 mmol) dis-

solved in CH₂Cl₂(20 mL) was added to the resulting reaction mix-

ture through a syringe over 10 min. After 3 h at –78 °C an interme-

diate formed [TLC, hexane/EtOAc (3:1), R_f= 0.18]. The reaction

mixture was dropwise treated with Et₃N (6.5 mL, 46.7 mmol). The

turbid solution was quenched by the addition of satd. aq. NaHCO₃

(20 mL) after 4 h and warmed to room temperature. The aqueous

layer was separated and extracted with diethyl ether (3ϫ 20 mL).

The combined organic phases were washed with water (30 mL) and

satd. aq. NaCl (30 mL) and dried with MgSO₄. Removal of the

volatiles under reduced pressure and flash column chromatography

(SiO₂, hexane/EtOAc, 20:1) of the remaining residue gave aldehyde

45 (1.9 g, 97%) as a pale yellow oil. H NMR (CDCl₃, 400 MHz): diastereoisomeric mixture of 46 (dr = 1:1, 490 mg, 0.7 mmol) in

Cage-Shaped Lactones 49 and 50 (and 47 and 48): A solution of a

1

8234

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Eur. J. Org. Chem. 2013, 8214–8244

An Approach to the Carbon Backbone of Bielschowskysin, Part 1

freshly degassed cyclohexane (four pump-freeze-thaw cycles,

80 mL) was split in 8 equal parts and transferred to quartz tubes

of a diameter of 1 cm and a total height of 16 cm, which were

equipped with magnetic stirring bars. These charged quartz vials

52 mg, 0.45 mmol) and tetrapropylammonium perruthenate (5 mg,

0.05 mmol) were added sequentially to a solution of 50 (100 mg,

0.15 mmol) in CH₂Cl₂(2 mL). The reaction mixture was warmed

to room temperature and stirred for 18 h. Diethyl ether (10 mL)

were placed 0.5 cm in front of a UV-C lamp (SYLVANIA G8W was added and the resulting mixture was filtered through a pad of

T5, 8 W) in a custom-made reactor and irradiated and stirred for

2 h. The contents of all vials were combined and the volatiles were

removed under reduced pressure. The remaining slightly yellow oil

was subjected to flash column chromatography (SiO₂, hexane/

Celite. Removal of the volatiles and column chromatography (SiO₂,

hexane/EtOAc, 6:1) gave the desired ketone (74 mg, 0.11 mmol,

74%) as a colorless oil. H NMR (CDCl₃, 400 MHz): δ = 5.52 (t,

1

J = 2.4 Hz, 1 H), 5.30 (t, J = 2.2 Hz, 1 H), 5.22 (dt, J = 8.0, 5.3 Hz,

EtOAc, 20:1) yielding undesired [4.2.0]ring systems 47 and 48 1 H), 4.69 (s, 1 H), 4.32 (d, J = 4.5 Hz, 1 H), 3.93 (dt, J = 10.1,

(76 mg, 15% combined yield) as well as the desired cleft [2+2]-

photocyclization products 49 (170 mg, 35%) and 50 (169 mg, 34%)

as colorless oils. Analytic data for 49: ¹H NMR (CDCl₃, 400 MHz):

5.2 Hz, 1 H), 3.87 (dd, J = 8.2, 6.5 Hz, 1 H), 3.69 (dd, J = 10.6,

5.4 Hz, 1 H), 3.64 (dd, J = 10.5, 5.1 Hz, 1 H), 3.33 (s, 3 H), 3.22

(dd, J = 19.4, 3.4 Hz, 1 H), 3.17–3.13 (m, 1 H), 3.04 (dd, J = 19.4,

δ = 5.40 (dd, J = 2.7, 1.2 Hz, 1 H), 5.20 (dd, J = 2.1, 1.1 Hz, 1 H), 9.9 Hz, 1 H), 2.54–2.46 (m, 2 H), 1.94 (dd, J = 14.8, 5.3 Hz, 1 H),

5.16 (td, J = 7.9, 5.2 Hz, 1 H), 4.69 (s, 1 H), 4.14 (d, J = 4.5 Hz, 1

H), 4.02 (dt, J = 9.0, 5.5 Hz, 1 H), 3.98 (dt, J = 9.7, 2.9 Hz,1 H),

3.75 (dd, J = 10.4, 5.3 Hz, 1 H), 3.71 (d, J = 2.2 Hz, 1 H), 3.66

(dd, J = 10.4, 5.7 Hz, 1 H), 3.33–3.29 (m, 4 H), 3.14–3.11 (m, 1

H), 2.45 (qd, J = 12.4, 1.7 Hz, 1 H), 2.43–2.46 (m, 1 H), 1.94 (dd,

1.44 (s, 3 H), 0.92 (t, J = 8.0 Hz, 9 H), 0.90 (s, 9 H), 0.58 (dd, J =

8.0, 2.4 Hz, 3 H), 0.54 (dd, J = 8.0, 3.2 Hz, 3 H), 0.11 (s, 9 H), 0.06

(s, 6 H) ppm. ¹³C NMR (CDCl₃, 100 MHz): δ = 200.0, 171.7,

144.0, 115.7, 109.5, 84.8, 83.7, 83.4, 76.9, 66.5, 65.1, 57.5, 54.6,

49.5, 44.6, 39.5, 34.9, 26.1 (3 C), 23.5, 18.6, 6.9 (3 C), 5.0 (3 C),

J = 14.7, 5.3 Hz, 1 H), 1.79–1.67 (m, 2 H), 1.43 (s, 3 H), 0.96 (t, J 2.4 (3 C), –5.2, –5.3 ppm. HRMS (ESI): calcd. for C₃₃H₆₀O₈Si₃Na

= 7.9 Hz, 9 H), 0.91 (s, 9 H), 0.62 (q, J = 8.2 Hz, 6 H), 0.11 (s, 9 [M + Na]⁺691.3494; found 691.3495. IR: ν = 2955, 2929, 1769,

˜

H), 0.09 (s, 3 H), 0.08 (s, 3 H) ppm. ¹³C NMR (CDCl₃, 100 MHz): 1714, 1464, 1252, 1149, 1108, 1039, 840 cm^–1. [α]²_D⁰= –77.3,

δ = 177.7, 144.0, 115.1, 109.0, 84.9, 84.1, 83.7, 77.5, 70.4, 67.0,

57.8, 57.7, 54.6, 49.6, 44.8, 41.4, 27.9, 26.2 (3 C), 23.4, 18.6, 7.0 (3

C), 5.1 (3 C), 2.4 (3 C), –5.2, –5.3 ppm. HRMS (ESI): calcd. for

(CHCl₃, c = 0.3). R_f(hexane/EtOAc, 6:1) = 0.66.

To a solution of the ketone (15 mg, 0.02 mmol) and (S)-2-methyl-

CBS-oxazaborolidine (45 μL, 0.05 mmol, 1.0 m in toluene) in THF

(500 μL) was added BH₃·THF (45 μL, 0.05 mmol, 1.0 m in THF)

at –78 °C. No reaction was observed by TLC (hexane/EtOAc, 4:1)

until 0 °C. The reaction mixture was stirred at 0 °C for 6 h. Sat.

aq. NH₄Cl (5 mL) and diethyl ether (5 mL) were added. The aque-

ous layer was separated and washed with diethyl ether (2ϫ 5 mL).

The combined organic phases were washed with satd. aq. NaCl

(5 mL), dried with MgSO₄, filtered, and concentrated in vacuo to

give a 1:2 mixture of 49 and 50 (15 mg) in quantitative yield. For

analytic data see above.

C

₃₃H₆₂O₈Si₃Na [M + Na]⁺693.3650; found 693.3629. IR: ν =

˜

3500, 2954, 1767, 1462, 1375, 1301, 1251, 1186, 1104, 988 cm^–1.

[α]²_D⁰= –38.7, (CHCl₃, c = 1.1). R_f(hexane/EtOAc, 4:1) = 0.45.

Analytical data for 50: ¹H NMR (CDCl₃, 400 MHz): δ = 5.27 (dd,

J = 2.7, 1.4 Hz, 1 H), 5.19 (td, J = 8.0, 5.3 Hz, 1 H), 5.15 (dd, J =

2.0, 1.5 Hz, 1 H), 4.66 (s, 1 H), 4.17 (d, J = 4.8 Hz, 1 H), 4.12 (ddd,

J = 11.7, 5.7, 2.2 Hz, 1 H), 3.96 (ddd, J = 8.1, 5.9, 4.7 Hz, 1 H),

3.79 (dd, J = 10.5, 4.6 Hz, 1 H), 3.66 (dd, J = 10.6, 6.1 Hz, 1 H),

3.43 (dd, J = 8.2, 6.3 Hz, 1 H), 3.31 (s, 3 H), 3.13–3.09 (m, 1 H),

3.05 (d, J = 5.7 Hz, 1 H), 2.45 (qd, J = 12.4, 1.6 Hz, 1 H), 2.44–

2.38 (m, 1 H), 1.93 (dd, J = 14.8, 5.3 Hz, 1 H), 1.87 (ddd, J = 14.1,

8.7, 2.3 Hz, 1 H), 1.67 (ddd, J = 14.0, 11.7, 5.7 Hz, 1 H), 1.42 (s,

3 H), 0.97 (t, J = 7.9 Hz, 9 H), 0.91 (s, 9 H), 0.63 (q, J = 8.2 Hz,

6 H), 0.12 (s, 9 H), 0.11 (s, 3 H), 0.10 (s, 3 H) ppm. ¹³C NMR

(CDCl₃, 100 MHz): δ = 176.8, 145.4, 114.5, 109.2, 85.0, 84.0, 83.6,

79.1, 70.2, 67.1, 59.6, 57.7, 54.7, 49.8, 43.5, 41.6, 28.9, 26.2 (3 C),

23.6, 18.7, 6.9 (3 C), 5.1 (3 C), 2.4 (3 C), –5.3 (2 C) ppm. HRMS

(ESI): calcd. for C₃₃H₆₂O₈Si₃Na [M + Na]⁺693.3650; found

Cage Shaped Epoxide 52: At 0 °C, alcohol 49 (10 mg, 0.07 mmol)

was dissolved in a freshly prepared solution of DMDO (0.4 mL,

0.08 m, 0.03 mmol) in acetone. The resulting colorless reaction mix-

ture was warmed to room temperature overnight. Additional

DMDO (0.4 mL, 0.08 m, 0.03 mmol) was added and the reaction

was stirred for an additional 24 h. Because TLC analysis (hexane/

EtOAc, 4:1) still indicated remaining starting material, a further

portion of DMDO (0.4 mL, 0.08 m, 0.03 mmol) was added and the

reaction was stirred for another 24 h. The volatiles were removed

under reduced pressure in a cold-water bath (15 °C). The resulting

colorless residue was purified by flash column chromatography

(SiO₂, hexane/EtOAc, 12:1) yielding desired epoxide 51 (9 mg,

85%) as a colorless oil.

693.3647. IR: ν = 3484, 2954, 1768, 1462, 1348, 1251, 1187, 1106,

˜

1040, 991 cm^–1. [α]²_D⁰= –26.7, (CHCl₃, C = 0.6). R_f(hexane/EtOAc,

4:1) = 0.39.

1

Analytic Data for 47: H NMR (CDCl₃, 400 MHz): δ = 5.76–5.74

(m, 1 H), 4.75 (dt, J = 8.7, 1.8 Hz, 1 H), 4.66 (s, 1 H), 4.13 (m, 1

H), 4.09 (d, J = 4.9 Hz, 1 H), 3.93–3.90 (m, 2 H), 3.84 (dd, J =

10.1, 4.5 Hz, 1 H), 3.61 (dd, J = 10.1, 7.2 Hz, 1 H), 3.51–3.49 (m,

1 H), 3.29 (s, 3 H), 3.28–3.24 (m, 1 H), 2.74 (dd, J = 13.4, 1.1 Hz,

1 H), 2.35–2.27 (m, 1 H), 2.53 (dd, J = 15.4, 5.9 Hz, 1 H), 1.95

(dd, J = 15.4, 1.8 Hz, 1 H), 1.77 (dd, J = 6.0, 4.1 Hz, 2 H), 1.36 (s,

3 H), 0.96 (t, J = 7.9 Hz, 9 H), 0.91 (s, 9 H), 0.62 (q, J = 7.7 Hz,

6 H), 0.10 (s, 6 H), 0.06 (s, 9 H) ppm. ¹³C NMR (CDCl₃,

100 MHz): δ = 179.1, 137.9, 127.9, 108.8, 83.1, 78.3, 76.6, 71.1,

70.1, 67.0, 55.6, 54.5, 47.9, 44.8, 42.8, 38.8, 31.2, 29.2, 25.9 (3 C),

18.4, 6.7 (3 C), 4.8 (3 C), 2.2 (3 C), –5.5 (2 C) ppm. HRMS (ESI):

calcd. for C₃₃H₆₂O₈Si₃Na [M + Na]⁺693.3650; found 693.3650. IR:

Alternatively: To a solution of 49 (32 mg, 0.05 mmol) in CH₂Cl₂

(1 mL) was added NaHCO₃(12 mg, 0.14 mmol) and mCPBA

(25 mg, 0.14 mmol) at 0 °C. Prior to use, commercially available

mCPBA was purified by extraction of a solution in diethyl ether

(mL/g) with pH 7.5 buffer (3ϫ mL/g) and evaporation of the or-

ganic solvent in a water bath at 20 °C. After 4 h at 0 °C, satd. aq.

NaHCO₃(5 mL) and diethyl ether (5 mL) were added, the aqueous

phase was separated and extracted with diethyl ether (2ϫ 5 mL).

The combined organic phases were washed with satd. aq. NaCl

(5 mL), dried with MgSO₄, filtered and concentrated under re-

duced pressure. The residue was subjected to column chromatog-

raphy (SiO₂, hexane/EtOAc, 8:1) yielding desired epoxide 51

(30 mg, 94%) as a 4:1 diastereoisomeric mixture. ¹H NMR (CDCl₃,

400 MHz): δ = 5.21–5.15 (m, 1 H), 4.68 (s, 1 H), 4.11 (d, J = 4.5 Hz,

ν = 3476, 2955, 2930, 1768, 1462, 1251, 1111, 1042, 1005, 839 cm^–1.

˜

[α]_D²⁰= –44.1, (CHCl₃, c = 2.0). R_f(hexane/EtOAc, 4:1) = 0.28.

Oxidation/Reduction Sequence of 50 to 49: At 0 °C crushed molecu-

lar sieves (4 Å 100 mg), N-methylmorpholine N-oxide (NMO; 1 H), 4.03 (dt, J = 8.6, 5.4 Hz, 1 H), 3.95 (t, J = 6.6 Hz, 1 H), 3.76

Eur. J. Org. Chem. 2013, 8214–8244

www.eurjoc.org

8235

M. Himmelbauer, J.-B. Farcet, J. Gagnepain, J. Mulzer

FULL PAPER

(dd, J = 10.3, 5.2 Hz, 1 H), 3.67 (dd, J = 10.3, 5.7 Hz, 1 H), 3.56

(t, J = 7.7 Hz, 1 H), 3.31 (s, 3 H), 3.25 (s br., OH), 3.07 (dd, J =

5.2 (3 C), 2.4 (3 C), –5.2 (2 C) ppm. HRMS (ESI): calcd. for

C₃₅H₆₄O₁₀Si₃Na [M + Na]⁺751.3705; found 751.3694. IR: ν =

˜

7.3, 1.8 Hz, 1 H), 2.97 (d, J = 4.4 Hz, 1 H), 2.78 (d, J = 4.4 Hz, 1 2955, 2929, 1760, 1413, 1375, 1252, 1146, 1121, 1021, 838 cm^–1.

H), 2.57 (ddd, J = 14.7, 7.5, 1.9 Hz, 1 H), 2.40–2.33 (m, 1 H), 1.93 [α]²_D⁰= +28.4, (CHCl₃, c = 0.25). R_f(hexane/EtOAc, 3:1) = 0.31.

(dd, J = 14.7, 5.1 Hz, 1 H),1.66 (t, J = 6.7 Hz, 2 H), 1.32 (s, 3 H),

Acetate 57: To a solution of alcohol 49 (250 mg, 0.37 mmol) in

0.95 (t, J = 8.0 Hz, 9 H), 0.92 (s, 9 H), 0.63 (q, J = 7.8 Hz, 6 H),

CH₂Cl₂(4.0 mL), pyridine (90 μL, 1.12 mmol), acetic anhydride

0.11–0.09 (m, 15 H) ppm. ¹³C NMR (CDCl₃, 100 MHz): δ = 176.2,

(70 μL, 0.70 mmol) and DMAP (5 mg, 0.04 mmol) were sequen-

109.1, 83.9, 83.5, 82.9, 77.6, 67.5, 67.0, 62.9, 58.0, 56.9, 54.6, 50.7,

tially added at 0 °C. The reaction mixture was warmed to room

47.7, 42.1, 41.7, 27.9, 26.2 (3 C), 23.4, 18.9, 6.9 (3 C), 5.0 (3 C),

temperature overnight. Diethyl ether (20 mL) and satd. aq. NH₄Cl

2.4 (3 C), –5.2, –5.3 ppm. HRMS (ESI): calcd. for C₃₃H₆₂O₉Si₃Na

(20 mL) were added. The aqueous phase was separated and ex-

tracted with diethyl ether (3 ϫ 20 mL). The combined organic

phases were washed with satd. aq. CuSO₄(20 mL), water (20 mL)

and satd. aq. NaCl (20 mL), dried with MgSO₄, filtered and con-

[M + Na]⁺709.3555; found 709.3598. IR: ν = 2955, 2930, 1768,

˜

1462, 1376, 1252, 1143, 1040, 991, 840 cm^–1. [α]²_D⁰= –32.0, (CHCl₃,

c = 1.0). R_f(hexane/EtOAc, 4:1) = 0.53.

centrated under reduced pressure. The desired acetylated product

(266 mg, quant.) was isolated as a colorless amorphous solid, that

was used without further purification in the next reaction. ¹H

NMR (CDCl₃, 400 MHz): δ = 5.48 (dd, J = 11.0, 3.1 Hz, 1 H),

5.34 (dd, J = 2.6, 1.6 Hz, 1 H), 5.20 (dd, J = 2.2, 1.6 Hz, 1 H), 5.13

(dt, J = 8.0, 5.3 Hz, 1 H), 4.66 (s, 1 H), 4.14 (d, J = 4.1 Hz, 1 H),

3.87 (dt, J = 9.1, 5.1 Hz, 1 H), 3.69 (dd, J = 10.4, 4.8 Hz, 1 H),

3.60 (dd, J = 10.4, 5.4 Hz, 1 H), 3.40 (dd, J = 8.2, 6.5 Hz, 1 H),

3.27 (s, 3 H), 3.14–3.11 (m, 1 H), 2.47 (ddd, J = 14.8, 7.7, 1.7 Hz,

1 H), 2.08 (s, 3 H), 2.01–1.88 (m, 4 H), 1.41 (s, 3 H), 0.99 (t, J =

7.9 Hz, 9 H), 0.92 (s, 9 H), 0.69 (q, J = 7.8 Hz, 6 H), 0.12 (s, 9 H),

0.08 (s, 6 H) ppm. ¹³C NMR (CDCl₃, 100 MHz): δ = 174.2, 170.7,

144.1, 115.8, 109.4, 84.8, 83.7, 82.9, 76.5, 71.0, 66.1, 57.6, 57.2,

54.6, 49.6, 44.7, 40.5, 26.1 (3 C), 25.5, 23.6, 21.0, 18.5, 7.0 (3 C),

5.0 (3 C), 2.4 (3 C), –5.3 (2 C) ppm. HRMS (ESI): calcd. for

A solution of epoxide (21 mg, 0.03 mmol) in CH₂Cl₂(0.5 mL) was

cooled to 0 °C and pyridine (7 μL, 0.09 mmol), acetic anhydride

(6 μL, 0.06 mmol) and 4-(dimethylamino)pyridine (DMAP; 1 mg,

0.01 mmol) were sequentially added. The round-bottomed flask

was sealed with a stopper and the reaction mixture was warmed to

room temperature overnight. Diethyl ether (5 mL) and satd. aq.

NH₄Cl (5 mL) were added. The aqueous phase was separated and

extracted with diethyl ether (3 ϫ 5 mL). The combined organic

phases were washed with satd. aq. CuSO₄(10 mL), water (10 mL)

and satd. aq. NaCl (10 mL), dried with MgSO₄, filtered and con-

centrated under reduced pressure. Flash column chromatography

(SiO₂, hexane/EtOAc, 12:1) of the residue gave desired acylated

epoxide 52 (22 mg, quant.) as needle-shaped crystals that were sub-

jected to X-ray analysis. ¹H NMR (CDCl₃, 600 MHz): δ = 5.31

(dd, J = 11.1, 3.2 Hz, 1 H), 5.19 (dt, J = 7.9, 5.3 Hz, 1 H), 4.65 (s,

1 H), 4.23 (d, J = 4.2 Hz, 1 H), 3.83 (dt, J = 9.4, 5.1 Hz, 1 H), 3.71

(dd, J = 10.3, 4.9 Hz, 1 H), 3.57 (dd, J = 10.3, 5.8 Hz, 1 H), 3.54

(dd, J = 8.7, 7.4 Hz, 1 H), 3.27 (s, 3 H), 3.02 (dd, J = 7.1, 1.8 Hz,

1 H), 2.88 (d, J = 4.6 Hz, 1 H), 2.70 (d, J = 4.6 Hz, 1 H), 2.58 (dq,

J = 2.5, 2.0 Hz, 1 H), 2.14 (s, 3 H), 2.03–1.94 (m, 1 H), 1.91 (dd,

J = 14.7, 5.3 Hz, 1 H), 1.84–1.75 (m, 2 H), 1.31 (s, 3 H), 0.97 (t, J

= 8.0 Hz, 9 H), 0.92 (s, 9 H), 0.69 (q, J = 8 Hz, 6 H), 0.12 (s, 9 H),

0.08 (s, 6 H) ppm. ¹³C NMR (CDCl₃, 150 MHz): δ = 174.9, 170.3,

109.5, 83.5, 83.4, 82.6, 76.4, 68.2, 66.3, 62.2, 57.9, 55.8, 54.6, 50.2,

47.0, 42.4, 40.7, 26.1 (3 C), 25.7, 23.1, 21.3, 18.5, 7.0 (3 C), 4.9 (3

C), 2.4 (3 C), –5.3 (2 C) ppm. HRMS (ESI): calcd. for C₃₅H₆₄O₁₀S-

C

₃₅H₆₄O₉Si₃Na [M + Na]⁺735.3756; found 735.3769. IR: ν =

˜

2954, 1772, 1747, 1462, 1372, 1251, 1150, 1040, 991, 840 cm^–1

.

[α]²_D⁰= –15.8, (CHCl₃, c = 0.7). R_f(hexane/EtOAc, 5:1) = 0.52.

The acylated substrate was taken up in an AcOH/THF/H₂O (2:1:1)

mixture (2.8 mL) and left at room temperature for 24 h. All vola-

tiles were removed under reduced pressure and the remaining pale

yellow residue was subsequently co-evaporated with toluene (3ϫ

20 mL) until the smell of acetic acid was gone.

To a solution of the resulting crude colorless amorphous solid

(144 mg) and imidazole (600 mg, 8.75 mmol) in CH₂Cl₂(4.0 mL)

was added chlorotriethylsilane (650 μL, 3.85 mmol) through a sy-

ringe under vigorous stirring over 5 min. After 16 h, diethyl ether

(20 mL) and satd. aq. NH₄Cl (20 mL) were added to the resulting

suspension. The aqueous layer was separated and extracted with

diethyl ether (3 ϫ 20 mL). The combined organic phases were

washed with water (20 mL) and satd. aq. NaCl (20 mL) before be-

ing dried with MgSO₄. The solids were removed by filtration and

the filtrate was concentrated under reduced pressure. Flash column

chromatography (SiO₂, hexane/EtOAc, 10:1) gave desired globally

i₃Na [M + Na]⁺751.3705; found 751.3704, m.p. 93–95 °C. IR: ν =

˜

2955, 2928, 1768, 1744, 1231, 1124, 1041, 991, 843, 776 cm^–1

.

[α]²_D⁰= –23.1, (CHCl₃, c = 0.4). R_f(hexane/EtOAc, 4:1) = 0.53.

Hemiacetal 53: To a solution of 51b (5 mg, 0.01 mmol) in THF/

DMSO (2:1, 450 μL) was added lithium acetylide ethylenediamine

complex (50 mg, 0.54 mmol) at 0 °C. After 15 min diethyl ether

(5 mL) and satd. aq. NH₄Cl (5 mL) were added. The aqueous

phase was extracted with diethyl ether (2ϫ 5 mL). The combined

organic layers were washed with water (10 mL) and satd. aq. NaCl triethylsilyl (TES)-protected acetate 57 (265 mg, 94%) as a colorless

(5 mL), dried with MgSO₄, filtered and concentrated under re-

duced pressure. Purification by column chromatography (SiO₂, hex-

ane/EtOAc, 6:1) gave hemiacetal 53 (5 mg, 0.01 mmol) in quantita-

tive yield. ¹H NMR (CDCl₃, 400 MHz): δ = 4.96 (dd, J = 14.9,

oil. ¹H NMR (CDCl₃, 400 MHz): δ = 5.48 (dd, J = 10.2, 3.6 Hz, 1

H), 5.34 (dd, J = 2.6, 1.6 Hz, 1 H), 5.19 (dd, J = 2.1, 1.6 Hz, 1 H),

5.14 (dt, J = 8.0, 5.3 Hz, 1 H), 4.64 (s, 1 H), 4.14 (d, J = 3.8 Hz, 1

H), 3.89 (dt, J = 8.6, 5.2 Hz, 1 H), 3.69 (dd, J = 10.3, 5.2 Hz, 1

7.5 Hz, 1 H), 4.71 (s, 1 H), 4.53 (dd, J = 10.7, 3.7 Hz, 1 H), 4.19 H), 3.60 (dd, J = 10.3, 5.4 Hz, 1 H), 3.39 (dd, J = 8.2, 6.5 Hz, 1

(d, J = 4.3 Hz, 1 H), 3.93 (dt, J = 8.86, 5.13 Hz, 1 H), 3.72 (dd, J

= 10.5, 5.4 Hz, 1 H), 3.62 (dd, J = 10.5, 5.4 Hz, 1 H), 3.40 (t, J =

7.5 Hz, 1 H), 3.29 (s, 3 H), 3.02 (d, J = 4.8 Hz, 1 H), 3.00 (d, J =

4.8 Hz, 1 H), 2.87 (d, J = 15.3 Hz, 1 H), 2.77 (d, J = 15.3 Hz, 1

H), 3.28 (s, 3 H), 3.11–3.08 (m, 1 H), 2.44 (ddd, J = 14.7, 7.8,

1.6 Hz, 1 H), 2.08 (s, 3 H), 1.97–1.87 (m, 4 H), 1.41 (s, 3 H), 1.01–

0.90 (m, 27 H), 0.69 (q, J = 8.0 Hz, 6 H), 0.65–0.55 (m, 12 H) ppm.

¹³C NMR (CDCl₃, 100 MHz): δ = 174.3, 170.6, 144.3, 115.7, 109.4,

H), 2.73 (s, OH), 2.70 (dd, J = 7.2, 1.9 Hz, 1 H), 2.36 (dd, J = 13.9, 84.4, 83.7, 83.0, 76.5, 71.0, 66.1, 57.8, 57.2, 54.6, 49.7, 44.8, 40.8,

7.0 Hz, 1 H), 2.32–2.07 (m, 4 H), 1.34 (s, 3 H), 1.00 (t, J = 7.9 Hz, 25.5, 23.4, 21.0, 7.1 (3 C), 7.0 (3 C), 6.9 (3 C), 6.6 (3 C), 5.1 (3 C),

9 H), 0.89 (s, 9 H), 0.68 (q, J = 7.9 Hz, 6 H), 0.08 (s, 9 H), 0.07 (s,

4.5 (3 C) ppm. HRMS (ESI): calcd. for C₃₈H₇₀O₉Si₃Na [M +

3 H), 0.06 (s, 3 H) ppm. ¹³C NMR (CDCl₃, 100 MHz): δ = 169.1,

Na]⁺777.4225; found 777.4195. IR: ν = 2954, 2877, 1772, 1371,

˜

109.1, 108.0, 86.1, 85.7, 84.1, 79.6, 76.9, 66.5, 60.6, 57.7, 54.6, 54.2, 1230, 1150, 1040, 991, 807, 743 cm^–1. [α]²_D²= –17.8, (CHCl₃, c =

50.6, 49.5, 48.0, 45.4, 41.2, 26.2, 26.1 (3 C), 24.0, 18.4, 7.0 (3 C),

0.7). R_f(hexane/EtOAc, 3:1) = 0.59.

8236

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Eur. J. Org. Chem. 2013, 8214–8244

An Approach to the Carbon Backbone of Bielschowskysin, Part 1

Acetate 58: Alcohol 50 (284 mg, 0.42 mmol) was subjected to the

procedure as for alcohol 49 (see above, 57) giving corresponding

globally TES-protected acetate 58 (278 mg, 87%) as a colorless oil.

2.13 (m, 1 H), 2.07 (s, 3 H), 1.98–1.79 (m, 3 H), 1.41 (s, 3 H), 1.00

(t, J = 7.9 Hz, 9 H), 0.94 (t, J = 7.9 Hz, 9 H), 0.71 (q, J = 7.8 Hz,

6 H), 0.58 (q, J = 7.9 Hz, 6 H) ppm. ¹³C NMR (CDCl₃, 100 MHz):

δ = 202.4, 174.2, 170.7, 144.3, 115.6, 110.6, 86.5, 84.4, 83.2, 75.7,

70.6, 58.0, 57.4, 55.2, 49.7, 44.5, 40.4, 25.2, 23.5, 21.0, 7.1 (3 C),

6.9 (3 C), 6.6 (3 C), 5.0 (3 C) ppm. HRMS (ESI): calcd. for

C₃₃H₅₃O₁₀Si₂Na [M + MeOH + Na]⁺693.3466; found 693.3467.

1

Analytic Data for the Intermediate: H NMR (CDCl₃, 400 MHz):

δ = 5.48 (dd, J = 11.1, 2.4 Hz, 1 H), 5.32 (dd, J = 2.7, 1.6 Hz, 1

H), 5.22 (dd, J = 2.1, 1.7 Hz, 1 H), 5.18 (dt, J = 8.1, 5.4 Hz, 1 H),

4.67 (s, 1 H), 3.96 (d, J = 4.5 Hz, 1 H), 3.93–3.89 (m, 1 H), 3.73

(dd, J = 10.9, 3.7 Hz, 1 H), 3.62 (dd, J = 10.9, 6.0 Hz, 1 H), 3.42

(dd, J = 8.3, 6.4 Hz, 1 H), 3.30 (s, 3 H), 3.16–3.13 (m, 1 H), 2.47

(ddd, J = 14.7, 7.8, 1.7 Hz, 1 H), 2.11 (dd, J = 14.2, 6.0 Hz, 1 H),

2.07 (m, 1 H), 2.03 (s, 3 H), 1.92 (dd, J = 14.7, 5.4 Hz, 1 H), 1.84

IR: ν = 2955, 2877, 1770, 1745, 1459, 1373, 1231, 1151, 1038,

˜

808 cm^–1. [α]²_D⁰= –39.3, (CHCl₃, c = 0.6). R_f(hexane/EtOAc, 2:1)

= 0.50.

Aldehyde 60: Aldehyde 60 (310 mg, 87%, 97% brsm) was prepared

1

(m, 1 H), 1.42 (s, 3 H), 0.98 (t, J = 7.9 Hz, 9 H), 0.91 (s, 9 H), 0.63 according to the procedure for 59. H NMR (CDCl₃, 400 MHz): δ

(q, J = 8.13 Hz, 6 H), 0.11 (s, 9 H), 0.08 (s, 6 H) ppm. ¹³C NMR = 9.57 (d, J = 3.1 Hz, 1 H), 5.38 (t, J = 6.4 Hz, 1 H), 5.36 (dd, J

(CDCl₃, 100 MHz): δ = 174.7, 170.1, 144.4, 115.6, 109.2, 85.1, 84.9,

83.1, 77.9, 71.9, 66.8, 58.1, 58.0, 54.8, 49.4, 44.2, 40.9, 26.2 (3 C),

26.1, 23.4, 21.2, 18.6, 6.9 (3 C), 5.1 (3 C), 2.4 (3 C), –5.1, –5.2 ppm.

HRMS (ESI): calcd. for C₃₅H₆₄O₉Si₃Na [M + Na]⁺735.3756;

= 2.7, 1.7 Hz, 1 H), 5.26 (t, J = 2.0 Hz, 1 H), 5.20 (td, J = 8.1,

5.4 Hz, 1 H), 4.80 (s, 1 H), 4.11 (dd, J = 8.7, 3.0 Hz, 1 H), 4.00 (d,

J = 4.6 Hz, 1 H), 3.42 (dd, J = 8.3, 6.3 Hz, 1 H), 3.39 (s, 3 H),

3.15–3.11 (m, 1 H), 2.50–2.42 (m, 2 H), 2.04 (s, 3 H), 2.03 (t, J =

6.6 Hz, 2 H), 1.92 (dd, J = 14.7, 5.4 Hz, 1 H), 1.42 (s, 3 H), 0.98

(t, J = 8.0 Hz, 9 H), 0.94 (t, J = 8.2 Hz, 9 H), 0.64 (q, J = 8.2 Hz,

6 H), 0.58 (q, J = 8.3 Hz, 6 H) ppm. ¹³C NMR (CDCl₃, 100 MHz):

δ = 201.4, 174.6, 170.3, 144.1, 116.0, 110.3, 87.2, 84.7, 83.3, 77.6,

71.4, 58.2 58.1, 55.2, 49.5, 44.1, 40.6, 26.5, 23.3, 21.1, 7.1 (3 C), 6.9

(3 C), 6.6 (3 C), 5.02 (3 C) ppm. HRMS (ESI): calcd. for

C₃₃H₅₃O₁₀Si₂Na [M + MeOH + Na]⁺693.3466; found 693.3458.

found 735.3759. IR: ν = 2954, 2878, 1774, 1748, 1461, 1372, 1250,

˜

1149, 1040, 991 cm^–1. [α]²_D⁰= –46.6, (CHCl₃, c = 1.5). R_f(hexane/

EtOAc, 5:1) = 0.48.

Analytic Data for Acetate 58: ¹H NMR (CDCl₃, 400 MHz): δ =

5.49 (dd, J = 11.2, 2.2 Hz, 1 H), 5.32 (dd, J = 2.6, 1.6 Hz, 1 H),

5.22 (dd, J = 2.1, 1.6 Hz, 1 H), 5.19 (dt, J = 8.1, 5.4 Hz, 1 H), 4.67

(s, 1 H), 3.95 (d, J = 4.4 Hz, 1 H), 3.93–3.89 (m, 1 H), 3.73 (dd, J

= 10.8, 3.7 Hz, 1 H), 3.60 (dd, J = 10.8, 6.4 Hz, 1 H), 3.42 (dd, J

= 8.2, 6.4 Hz, 1 H), 3.30 (s, 3 H), 3.12 (m, 1 H), 2.45 (ddd, J =

14.7, 7.9, 1.6 Hz, 1 H), 2.12–2.05 (m, 1 H), 2.03 (s, 3 H), 2.05–2.01

IR: ν = 2955, 2912, 2877, 1773, 1748, 1231, 1150, 1106, 1040,

˜

1017 cm^–1. [α]²_D³= –50.0, (CHCl₃, c = 0.6). R_f(hexane/EtOAc, 3:1)

= 0.43.

(m, 1 H), 1.92 (dd, J = 14.7, 5.4 Hz, 1 H), 1.85 (ddd, J = 14.4, 5.4, Alkyne 61: A solution of 59 (72 mg, 0.11 mmol) in THF (1 mL)

2.4 Hz, 1 H), 1.42 (s, 3 H), 0.98 (t, J = 7.9 Hz, 9 H), 0.97 (t, J =

7.8 Hz, 9 H), 0.94 (t, J = 7.9 Hz, 9 H), 0.63 (q, J = 7.9 Hz, 12 H),

was treated with a 0.5 m solution of ethynylmagnesium bromide

(340 μL, 0.17 mmol) in THF at –78 °C. The resulting solution was

0.58 (q, J = 7.9 Hz, 6 H) ppm. ¹³C NMR (CDCl₃, 100 MHz): δ = warmed to –20 °C over 4 h and left at this temperature for 16 h.

174.7, 170.1, 144.5, 115.5, 109.2, 85.2, 84.6, 83.2, 76.9, 72.0, 66.6,

58.19, 58.16, 54.7, 49.5, 44.2, 41.1, 26.1, 23.3, 21.2, 7.1 (3 C), 6.9

Sat. aq. NH₄Cl (5 mL) and diethyl ether (5 mL) were added. The

aqueous phase was separated and extracted with diethyl ether (2ϫ

(3 C), 6.9 (3 C), 6.6 (3 C), 5.1 (3 C), 4.5 (3 C) ppm. HRMS (ESI): 5 mL). The combined organic phases were washed with satd. aq.

calcd. for C₃₈H₇₀O₉Si₃Na [M + Na]⁺777.4225; found 777.4232.

NaCl (10 mL), dried with MgSO₄, filtered and concentrated under

reduced pressure. Purification of the residue by column chromatog-

raphy (SiO₂, hexane/EtOAc, 8:1) gave desired propargylic alcohol

IR: ν = 2955, 2877, 1775, 1749, 1229, 1150, 1108, 1077, 1042,

˜

1001 cm^–1. [α]²_D³= –45.9, (CHCl₃, c = 0.7). R_f(hexane/EtOAc, 3:1)

1

= 0.52.

61 (45 mg, 0.07 mmol, 93% brsm) as a single diastereoisomer. H

NMR (CDCl₃, 400 MHz): δ = 5.47 (dd, J = 11.7, 2.4 Hz, 1 H),

5.34 (dd, J = 2.7, 1.7 Hz, 1 H), 5.20 (dd, J = 2.2, 1.7 Hz, 1 H), 5.16

(dt, J = 8.0, 5.3 Hz, 1 H), 4.68 (s, 1 H), 4.51 (dt, J = 3.7, 2.3 Hz,

1 H), 4.20 (d, J = 4.4 Hz, 1 H), 4.07 (dd, J = 9.0, 3.4 Hz, 1 H),

3.39 (dd, J = 6.3, 2.0 Hz, 1 H), 3.36 (s, 3 H), 3.12–3.09 (m, 1 H),

2.69 (d, J = 4.1 Hz, 1 H, 1 H), 2.50–2.42 (m, 1 H), 2.48 (d, J =

2.2 Hz, 1 H, 1 H), 2.34–2.27 (m, 1 H), 2.17–2.13 (m, 1 H), 2.11 (s,

3 H), 2.03–1.97 (m, 1 H), 1.90 (dd, J = 14.7, 5.3 Hz, 1 H), 1.41 (s,

3 H), 1.00 (t, J = 7.9 Hz, 9 H), 0.94 (t, J = 7.9 Hz, 9 H), 0.70 (q,

J = 8.0 Hz, 6 H), 0.58 (q, J = 7.9 Hz, 6 H) ppm. ¹³C NMR (CDCl₃,

100 MHz): δ = 174.2, 170.9, 144.3, 115.6, 109.7, 85.9, 84.5, 83.1,

81.4, 76.5, 74.8, 71.0, 63.4, 57.7, 57.2, 55.5, 49.7, 44.8, 38.1, 26.1,

23.5, 21.1, 7.1 (3 C), 7.0 (3 C), 6.6 (3 C), 5.0 (3 C) ppm. HRMS

(ESI): calcd. for C₃₄H₅₆O₉Si₂Na [M + Na]⁺687.3361; found

Aldehyde 59: To a solution of oxalyl chloride (660 μL, 7.7 mmol)

in CH₂Cl₂(8 mL) in a flame-dried 50 mL round-bottomed flask

equipped with a bubbler, dimethyl sulfoxide (1.1 mL, 15.5 mmol)

was added dropwise over 5 min at –78 °C. After the evolution of

gas had ceased the bubbler was removed and stirring was continued

for a further 10 min at –78 °C. Acetate 57 (1.16 g, 1.5 mmol) dis-

solved in CH₂Cl₂(8 mL) was added to the resulting reaction mix-

ture through a syringe over 10 min. After 3 h at –78 °C an interme-

diate formed [TLC, hexane/EtOAc (2:1), R_f= 0.23]. The reaction

mixture was dropwise treated with Et₃N (2.2 mL, 15.5 mmol). The

turbid solution was quenched by the addition of satd. aq. NaHCO₃

(15 mL) after 4 h and warmed to room temperature. The aqueous

layer was separated and extracted with diethyl ether (3ϫ 15 mL).

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

satd. aq. NaCl (20 mL) and dried with MgSO₄. Removal of the

volatiles under reduced pressure and flash column chromatography

(SiO₂, hexane/EtOAc, 8:1) of the remaining residue gave aldehyde

59 [666 mg, 67%, 89% based on recovered starting material (brsm)]

as a pale yellow oil. ¹H NMR (CDCl₃, 400 MHz): δ = 9.57 (d, J =

3.1 Hz, 1 H), 5.50 (dd, J = 11.6, 2.4 Hz, 1 H), 5.31 (dd, J = 2.7,

687.3366. IR: ν = 3484, 2955, 2877, 1770, 1745, 1459, 1231, 1151,

˜

1039, 991 cm^–1. [α]²_D⁰= –9.04, (CHCl₃, c = 0.37). R_f(hexane/EtOAc,

3:1) = 0.28.

Dibromide 65: N-Bromosuccinimide (NBS; 4 mg, 0.02) was added

as a solid to a solution of 61 (11 mg, 0.02 mmol) in CH₂Cl₂

(0.5 mL). The round-bottomed flask was sealed with a stopper and

1.7 Hz, 1 H), 5.19 (dd, J = 3.8, 2.0 Hz, 1 H), 5.17 (dt, J = 7.9, heated to 50 °C for 5 h. The volatiles were removed under reduced

5.4 Hz, 1 H), 4.81 (s, 1 H), 4.21 (d, J = 4.2 Hz, 1 H), 4.05 (dd, J =

9.7, 3.0 Hz, 1 H), 3.43 (dd, J = 8.2, 6.4 Hz, 1 H), 3.39 (s, 3 H),

pressure and the remaining residue was subjected to column

chromatography (SiO₂, hexane/EtOAc, 12:1). trans-Dibromo com-

3.10–3.07 (m, 1 H), 2.45 (ddd, J = 14.7, 7.8, 1.7 Hz, 1 H), 2.20– pound 65 (4 mg, 0.01 mmol, 30%, 66% brsm) was obtained as a

Eur. J. Org. Chem. 2013, 8214–8244

www.eurjoc.org

8237

M. Himmelbauer, J.-B. Farcet, J. Gagnepain, J. Mulzer

FULL PAPER

colorless oil. H NMR (CDCl₃, 400 MHz): δ = 8.66 (s, 1 H), 5.50

(dd, J = 11.4, 2.4 Hz, 1 H), 5.31 (dd, J = 2.5, 1.8 Hz, 1 H), 5.19 (t,

J = 1.8 Hz, 1 H), 5.16 (dt, J = 8.0, 5.3 Hz, 1 H), 4.75 (s, 1 H), 4.61

1

reduced pressure. Filtration (hexane/EtOAc, 3:1) through a short

pad of silica gave the desired iodide (8.5 g, 21.3 mmol, 97%) as a

pale yellow oil, which was used without further purification in the

1

(d, J = 8.9 Hz, 1 H), 4.21 (d, J = 4.32 Hz, 1 H), 3.45 (dd, J = 8.1, next step. H NMR (CDCl₃, 400 MHz): δ = 5.77 (d, J = 3.7 Hz, 1

6.5 Hz, 1 H), 3.25 (s, 3 H), 3.11–3.08 (m, 1 H), 2.61–2.54 (m, 1 H),

H), 4.66 (t, J = 3.9 Hz, 1 H), 4.09 (dd, J = 8.2, 6.3 Hz, 1 H), 4.02

2.45 (ddd, J = 14.7, 7.8, 1.6 Hz, 1 H), 2.09 (s, 3 H), 1.96–1.87 (m, (dd, J = 6.7, 5.3 Hz, 1 H), 3.91 (dd, J = 8.2, 5.3 Hz, 1 H), 3.79 (dd,

2 H), 1.83–1.76 (m, 1 H), 1.40 (s, 3 H), 1.00 (t, J = 7.9 Hz, 9 H),

0.95 (t, J = 7.9 Hz, 9 H), 0.72 (q, J = 7.9 Hz, 6 H), 0.58 (q, J =

7.9 Hz, 6 H) ppm. ¹³C NMR (CDCl₃, 100 MHz): δ = 189.9, 174.3,

170.8, 144.4, 131.6, 130.8, 115.5, 110.6, 84.6, 84.4, 83.3, 75.9, 70.6,

J = 9.1, 7.0 Hz, 1 H), 3.43–3.38 (m, 1 H), 3.25 (dt, J = 9.4, 6.3 Hz,

1 H), 2.31 (dt, J = 9.5, 7.3 Hz, 1 H), 2.15–2.04 (m, 2 H), 1.50 (s, 3

H), 1.42 (s, 3 H), 1.34 (s, 3 H), 1.31 (s, 3 H) ppm. ¹³C NMR

(CDCl₃, 100 MHz): δ = 112.1, 109.8, 105.1, 81.5, 80.8, 77.7, 67.6,

57.9, 57.5, 55.5, 49.7, 44.5, 40.9, 25.9, 23.5, 21.0, 7.2 (3 C), 49.0, 29.2, 26.9, 26.8, 26.6, 25.4, 4.9 ppm. HRMS (ESI): calcd. for

7.0 (3 C), 6.6 (3 C), 4.9 (3 C) ppm. HRMS (ESI): calcd. for C₁₄H₂₃IO₅Na [M + Na]⁺421.0488; found 421.0485. IR: ν = 2986,

˜

C₃₄H₅₄Br₂O₉Si₂Na [M + Na]⁺845.1550; found 845.1547. IR: ν =

2934, 1454, 1380, 1256, 1214, 1171, 1065, 1017, 847 cm^–1. [α]²_D⁰

+76.5, (CHCl₃, c = 0.9). R_f(hexane/EtOAc, 1:1) = 0.67.

=

˜

2955, 2877, 2349, 1770, 1702, 1460, 1373, 1232, 1151, 1042 cm^–1.

[α]²_D⁰= –11.1, (CHCl₃, c = 0.02). R_f(hexane/EtOAc, 4:1) = 0.48.

To a solution of the iodide (11.7 g, 29 mmol) in THF (300 mL) was

Carboxylic Acid 67: A solution of NaClO₂(34 mg, 0.37 mmol) and added tBuOK (9.9 g, 88 mmol) in three portions at 0 °C over

NaH₂PO₄(62 mg, 0.45 mmol) in water (450 μL) were added 30 min. The resulting mixture was stirred at that temperature for

through a Pasteur pipette to a solution of aldehyde 59 (24 mg,

0.04 mmol) in 2-methyl-2-butene (300 μL) and tBuOH (800 μL) at

0 °C. The resulting solution was warmed to room temperature and

stirred for 16 h. Sat. aq. NH₄Cl (5 mL) and diethyl ether (10 mL)

were added. The aqueous phase was separated and extracted with

diethyl ether (2 ϫ 10 mL). The combined organic layers were

washed with water (10 mL) and satd. aq. NaCl (10 mL), dried with

MgSO₄, filtered and concentrated under reduced pressure. Column

chromatography (SiO₂, hexane/EtOAc, 1:1) afforded desired acid

2 h. Sat. aq. NH₄Cl (100 mL) was added and the layers were sepa-

rated. The aqueous phase was extracted with diethyl ether (3 ϫ

50 mL). The combined organic layers were washed with water

(100 mL) and satd. aq. NaCl (100 mL), dried with MgSO₄, filtered

and concentrated under reduced pressure. Purification of the crude

residue by column chromatography (SiO₂, hexane/EtOAc, 6:1) gave

desired diacetonide 73 (7.7 g, 28.5 mmol, 97%) as a colorless oil.

¹H NMR (CDCl₃, 400 MHz): δ = 5.87 (dd, J = 10.3, 8.8 Hz, 1 H),

5.82 (d, J = 3.6 Hz, 1 H), 5.28 (ddd, J = 17.3, 1.6, 0.7 Hz, 1 H),

5.22 (dd, J = 10.3, 1.6 Hz, 1 H), 4.62 (dd, J = 4.5, 3.8 Hz, 1 H),

4.26 (dt, J = 4.0, 6.7 Hz, 1 H), 4.10 (dd, J = 10.1, 3.9 Hz, 1 H),

3.99 (dd, J = 8.2, 6.8 Hz, 1 H), 3.89 (dd, J = 8.2, 6.6 Hz, 1 H), 2.62

(dt, J = 4.8, 9.5 Hz, 1 H), 1.54 (s, 3 H), 1.43 (s, 3 H), 1.35 (s, 3 H),

1.32 (s, 3 H) ppm. ¹³C NMR (CDCl₃, 100 MHz): δ = 132.5, 119.2,

112.0, 109.7, 104.9, 83.9, 80.0, 76.3, 65.5, 50.7, 26.9, 26.6, 26.4,

1

67 (24 mg, 0.37 mmol, 98%) as a colorless oil. H NMR (CDCl₃,

400 MHz): δ = 9.6 (br. s, 1 H), 5.50 (dd, J = 11.6, 2.5 Hz, 1 H),

5.30 (dd, J = 2.6, 1.8 Hz, 1 H), 5.22–5.17 (m, 2 H), 4.82 (s, 1 H),

4.30 (d, J = 10.1 Hz, 1 H), 4.27 (d, J = 4.0 Hz, 1 H), 3.49 (dd, J =

8.2, 6.5 Hz, 1 H), 3.44 (s, 3 H), 3.40–3.30 (m, 1 H), 3.10–3.08 (m,

1 H), 2.44 (qd, J = 12.4, 1.7 Hz, 1 H), 2.28–2.20 (m, 1 H), 2.10–

1.88 (m, 4 H), 2.08 (s, 1 H), 1.41 (s, 3 H), 1.00 (t, J = 7.9 Hz, 9 H), 25.4 ppm. HRMS (ESI): calcd. for C₁₄H₂₂O₅Na [M + Na]⁺

0.95 (t, J = 7.9 Hz, 9 H), 0.73 (q, J = 8.2 Hz, 6 H), 0.58 (q, J =

7.9 Hz, 6 H) ppm. ¹³C NMR (CDCl₃, 100 MHz): δ = 174.3, 173.4,

170.9, 144.5, 115.4, 111.0, 84.4, 83.3, 80.7, 75.6, 70.4, 58.1, 57.5,

49.7, 44.4, 42.9, 29.9, 25.6, 23.5, 21.0, 7.15 (3 C), 6.89 (3 C), 6.62

(3 C), 4.95 (3 C) ppm. HRMS (ESI): calcd. for C₃₂H₅₄NaO₁₀Si₂

293.1365; found 293.1362. IR: ν = 2986, 2935, 1372, 1251, 1214,

˜

1167, 1102, 1065, 1015, 848 cm^–1. [α]²_D²= +94.5, (CHCl₃, c = 1.0).

R_f(hexane/EtOAc, 2:1) = 0.38.

Triethyl({(2S,3R,4R,5R)-5-methoxy-4-[(triethylsilyl)oxy]-3-vinyl-

tetrahydrofuran-2-yl}methoxy)silane (74): To a solution of diaceton-

ide 73 (330 mg, 1.22 mmol) in MeOH (13 mL) was added acetyl

chloride (260 μL, 3.66 mmol) at 0 °C. The resulting solution was

warmed to room temperature and stirred for 3 h. Et₃N (1 mL) was

[M + Na]⁺677.3153; found 677.3135. IR: ν = 3218, 2922, 2853,

˜

1769, 1743, 1460, 1374, 1231, 1137, 990 cm^–1. [α]²_D⁰= –14.7,

(CHCl₃, c = 0.5). R_f(hexane/EtOAc, 1:1) = 0.14.

(3aR,5S,6R,6aR)-5-[(S)-2,2-Dimethyl-1,3-dioxolan-4-yl]-2,2-di- added and the volatiles were removed under reduced pressure. The

methyl-6-vinyltetrahydrofuro[2,3-d][1,3]dioxole (73): To a suspension

of freshly powdered lithium aluminium hydride (LAH; 911 mg,

24 mmol) in diethyl ether (150 mL) was added a solution of ester

72 (7.6 g, 24 mmol) in diethyl ether (100 mL) at 0 °C over 15 min.

After 1 h at that temperature, satd. aq. NH₄Cl (100 mL) was care-

fully added followed by satd. aq. Na/K tartrate (100 mL). The re-

sulting biphasic mixture was stirred at room temperature for 1 h.

The aqueous phase was extracted with diethyl ether (3ϫ 50 mL).

The combined organic layers were washed with satd. aq. NaCl

(100 mL), dried with MgSO₄, filtered and concentrated under re-

duced pressure. The alcohol was isolated as a colorless gum (6.31 g,

21.9 mmol, 91%) and used without purification in the next reac-

tion.

remaining white residue was subjected to column chromatography

(SiO₂, EtOAc) giving the desired triol (170 mg, 0.83 mmol, 68%)

as a colorless gum. H NMR (CDCl₃, 400 MHz): δ = 5.91 (ddd, J

= 17.9, 9.9, 8.1 Hz, 1 H), 5.35–5.32 (m, 1 H), 5.30 (d, J = 0.8 Hz,

1 H), 4.83 (s, 1 H), 4.24 (dd, J = 9.0, 4.5 Hz, 1 H), 4.10 (t, J =

4.3 Hz, 1 H), 3.87–3.83 (m, 1 H), 3.67 (t, J = 4.8 Hz, 1 H), 3.40 (s,

3 H), 3.08 (td, J = 8.6, 4.5 Hz, 1 H), 2.71 (d, J = 3.7 Hz, 1 H), 2.28

(t, J = 5.6 Hz, 1 H), 2.09 (d, J = 4.3 Hz, 1 H) ppm. ¹³C NMR

(CDCl₃, 100 MHz): δ = 133.2, 120.2, 109.2, 83.0, 78.4, 73.8, 63.6,

55.5, 47.0 ppm. HRMS (ESI): calcd. for C₉H₁₆O₅Na [M + Na]⁺

1

227.0895; found 227.0891. IR: ν = 3363, 2926, 1438, 1420, 1306,

˜

1195, 1154, 1103, 1033, 943 cm^–1. [α]²_D²= +10.5, (CHCl₃, c = 0.6).

R_f(EtOAc) 0.29.

To a solution of the alcohol (6.3 g, 21.9 mmol), triphenylphosphine

(17.2 g, 65.7 mmol) and imidazole (4.5 g, 65.7 mmol) in CH₃CN/

Glycol cleavage of the vicinal diol (11.0 g, 53 mmol) was achieved

according to the procedure for 42 giving the desired diol (8.1 g,

benzene (1:2, 210 mL) was added iodine (16.7 g, 65.6 mmol) in 6 46.5 mmol, 86%) as a colorless gum. ¹H NMR (CDCl₃, 400 MHz):

portions over 30 min at 0 °C. The resulting mixture was stirred for

1 h before satd. aq. Na₂S₂O₃(50 mL) was added. The organic

phase was separated, washed with water (50 mL) and satd. aq.

NaCl (50 mL), dried with MgSO₄, filtered and concentrated under

δ = 5.89 (ddd, J = 17.2, 10.5, 8.1 Hz, 1 H), 5.30–5.28 (m, 1 H),

5.27–5.24 (m, 1 H), 4.84 (s, 1 H), 4.24 (ddd, J = 9.3, 4.2, 2.7 Hz, 1

H), 4.11 (t, J = 4.4 Hz, 1 H), 3.79 (ddd, J = 11.9, 4.3, 2.7 Hz, 1

H), 3.53–3.46 (m, 1 H), 3.41 (s, 3 H), 2.97 (td, J = 8.8, 4.4 Hz, 1

8238

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Eur. J. Org. Chem. 2013, 8214–8244

An Approach to the Carbon Backbone of Bielschowskysin, Part 1

H), 2.10 (dd, J = 7.8, 4.6 Hz, 1 H), 2.03 (d, J = 4.6 Hz, 1 H) ppm.

48.9, 6.8 (3), 6.7 (3 C), 4.8 (3 C), 4.3 (3 C) ppm. HRMS (ESI):

¹³C NMR (CDCl₃, 100 MHz): δ = 132.3, 120.1, 109.2, 83.1, 78.2, calcd. for C₁₉H₄₂O₅Si₂Na [M + Na]⁺465.3180; found 465.3172.

63.2, 55.8, 46.3 ppm. HRMS (ESI): calcd. for C₈H₁₄O₄Na [M +

IR: ν = 3471, 2954, 2912, 2877, 1460, 1240, 1113, 1006, 957,

˜

Na]⁺197.0790; found 197.0783. IR: ν = 3397, 2924, 1640, 1451,

810 cm^–1. [α]²_D⁰= –27.9, (CHCl₃, c = 1.0). R_f(hexane/EtOAc, 6:1)

˜

1352, 1305, 1248, 1092, 1035, 970 cm^–1. [α]²_D²= +14.6, (CHCl₃, c =

0.7). R_f(EtOAc) = 0.5.

= 0.43.

At 0 °C, to a solution of the alcohol (112 mg, 0.28 mmol), polymer-

bound triphenylphosphine (1.6 mmol/g, 344 mg, 0.55 mmol) and

imidazole (56 mg, 0.83 mmol) in CH₂Cl₂(5.5 mL) was added a

solution of freshly sublimated and crushed iodine (140 mg,

0.55 mmol) in CH₂Cl₂(2 mL). The reaction mixture was warmed

to room temp. and stirred for 6 h. Sat. aq. NH₄Cl solution (10 mL)

and satd. aq. Na₂S₂O₃solution (5 mL) were added and the aqueous

layer was extracted with diethyl ether (3ϫ 50 mL). The combined

organic layers were washed with brine (20 mL) and dried with

MgSO₄. After removal of the solvent the crude product was puri-

To a solution of the crude diol (8.1 g, 46.5 mmol) in CH₂Cl₂

(500 mL) was added imidazole (19.0 g, 279.0 mmol). Triethylsilyl

chloride (19.5 mL, 117.5 mmol) was added through a syringe over

10 min. The resulting suspension was stirred for 6 h. Water

(100 mL) was added and the separated aqueous phase was ex-

tracted with diethyl ether (3ϫ 50 mL). The combined organic lay-

ers were washed with satd. aq. NaCl (100 mL), dried with MgSO₄,

filtered and concentrated under reduced pressure. Column

chromatography (SiO₂, hexane/EtOAc, 30:1) afforded 74 (17.8 g,

1

44.2 mmol, 96%) as a colorless oil. H NMR (CDCl₃, 400 MHz): fied by flash chromatography (SiO₂, hexane/EtOAc, 20:1) de-

1

δ = 5.86 (dt, 1 H, J = 18.0, 9.3 Hz), 5.15 (dd, J = 5.1, 2.0 Hz, 1

H), 5.12–5.11 (m, 1 H), 4.70 (br. s, 1 H), 4.11 (ddd, J = 9.7, 6.0,

2.8 Hz, 1 H), 4.04 (d, J = 4.2 Hz, 1 H), 3.73 (dd, J = 10.9, 2.9 Hz,

1 H), 3.55 (dd, J = 10.9, 6.1 Hz, 1 H), 3.34 (s, 3 H), 2.67 (td, J =

livering iodide 76 (115 mg, 0.20 mmol, 81%) as a colorless oil. H

NMR (CDCl₃, 400 MHz): δ = 4.68 (s, 1 H), 4.17 (d, J = 4.0 Hz, 1

H), 3.84 (dt, J = 9.0, 5.7 Hz, 1 H), 3.74 (dd, J = 10.1, 5.3 Hz, 1

H), 3.59 (dd, J = 10.1, 6.2 Hz, 1 H), 3.31 (s, 3 H), 3.32–3.23 (m, 2

9.4, 4.2 Hz, 1 H), 0.96 (t, J = 7.9 Hz, 9 H), 0.95 (t, J = 7.9 Hz, 9 H), 2.57–2.50 (m, 1 H), 0.99 (t, J = 8.0 Hz, 9 H), 0.97 (t, J =

H), 0.61 (q, J = 8.0 Hz, 6 H), 0.60 (q, J = 7.8 Hz, 6 H) ppm. ¹³C

NMR (CDCl₃, 100 MHz): δ = 134.3, 118.4, 109.5, 83.8, 79.4, 65.0,

54.5, 48.6, 6.89 (3 C), 6.87 (3 C), 4.9 (3 C), 4.5 (3 C) ppm. HRMS

(ESI): calcd. for C₂₀H₄₂O₄Si₂Na [M + Na]⁺425.2519; found

8.0 Hz, 9 H), 0.69 (q, J = 8.1 Hz, 6 H), 0.62 (q, J = 7.9 Hz, 6

H) ppm. ¹³C NMR (CDCl₃, 100 MHz): δ = 108.5, 82.6, 77.8, 66.3,

54.6, 49.8, 7.0 (3 C), 6.9 (3 C), 5.2 (3 C), 4.50 (3 C), 0.64 ppm.

HRMS (ESI): calcd. for C₁₉H₄₁O₄Si₂Na [M + Na]⁺539.1486;

425.2518. IR: ν = 2954, 2912, 2877, 1459, 1415, 1239, 1120, 1042, found 539.1487. IR: ν = 2954, 2876, 1459, 1415, 1237, 1186, 1119,

˜

1004, 917 cm^–1. [α]²_D⁰= +12.1, (CHCl₃, c = 1.2). R_f(hexane/EtOAc,

2:1) = 0.89.

1071, 1005, 888 cm^–1. [α]²_D⁰= +21.9, (CHCl₃, c = 0.75). R_f(hexane/

EtOAc, 5:1) = 0.84.

(2S,3R,4R,5R)-5-Methoxy-4-[(triethylsilyl)oxy]-3-vinyltetrahydro-

furan-2-carbaldehyde (75): Compound 74 (5.0 g, 12.4 mmol) was

subjected to the same Swern-oxidation procedure as 57 (to 59) giv-

ing desired aldehyde 75 (3.3 g, 11.4 mmol, 92%) as a colorless oil.

¹H NMR (CDCl₃, 400 MHz): δ = 9.56 (d, J = 2.9 Hz, 1 H), 5.88

2-((2S,3R,4R,5R)-5-Methoxy-4-[(triethylsilyl)oxy]-2-{[(triethyl-

silyl)oxy]methyl}tetrahydrofuran-3-yl)acetaldehyde (77): To a solu-

tion of 74 (250 mg, 0.62 mmol) in THF (6 mL) was added

BH₃·THF (1.9 mL, 1.9 mmol) over 10 min at 0 °C. After 4 h satd.

aq. NaHCO₃(6 mL) and H₂O₂(170 μL, 1.49 mmol) were added.

(ddd, J = 17.1, 10.3, 8.8 Hz, 1 H), 5.23–5.21 (m, 1 H), 5.20–5.17 The resulting biphasic mixture was vigorously stirred for 1 h at 0 °C

(m, 1 H), 4.82 (s, 1 H), 4.30 (dd, J = 9.7, 2.8 Hz, 1 H), 4.10 (d, J before satd. aq. NaS₂O₃(10 mL) was added. The aqueous phase

= 4.2 Hz, 1 H), 3.43 (s, 3 H), 2.93 (dt, J = 9.2, 4.2 Hz, 1 H), 0.96 was separated and extracted with diethyl ether (3ϫ 10 mL). The

(t, J = 7.9 Hz, 9 H), 0.61 (q, J = 7.9 Hz, 6 H) ppm. ¹³C NMR

combined organic phases were washed with water (10 mL) and

(CDCl₃, 100 MHz): δ = 201.0, 131.9, 119.9, 110.6, 85.9, 78.6, satd. aq. NaCl (10 mL), dried with MgSO₄, filtered and concen-

55.1, 48.8, 6.8 (3 C), 4.9 (3 C) ppm. HRMS (ESI): calcd. for

trated under reduced pressure. Column chromatography (SiO₂, hex-

ane/EtOAc, 12:1) yielded the desired alcohol (200 mg, 0.48 mmol,

76%). ¹H NMR (CDCl₃, 400 MHz): δ = 4.66 (s, 1 H), 4.08 (d, J =

4.6 Hz, 1 H), 4.03–3.99 (m, 1 H), 3.72 (ddd, J = 10.4, 5.2, 1.1 Hz,

1 H), 3.68–3.60 (m, 3 H), 3.30 (s, 3 H), 2.30–2.17 (m, 2 H), 1.90–

1.81 (m, 1 H), 1.70–1.61 (m, 1 H), 0.96 (t, J = 7.9 Hz, 9 H), 0.96

(t, J = 8.0 Hz, 9 H), 0.66–0.58 (m, 12 H) ppm. ¹³C NMR (CDCl₃,

100 MHz): δ = 109.2, 84.0, 78.1, 66.6, 61.6, 54.5, 41.6, 29.5, 6.9 (3

C), 6.8 (3 C), 5.0 (3 C), 4.4 (3 C) ppm. HRMS (ESI): calcd. for

C₁₄H₂₆O₄SiNa [M + Na]⁺309.1498; found 309.1479. IR: ν = 2955,

˜

2832, 1737, 1460, 1415, 1314, 1239, 1120, 1002, 836 cm^–1. [α]²_D⁰

+10.8, (CHCl₃, c = 0.65). R_f(hexane/EtOAc, 3:1) = 0.45.

=

Triethyl[((2R,3R,4R,5S)-4-(iodomethyl)-2-methoxy-5-

{[(triethylsilyl)oxy]methyl}tetrahydrofuran-3-yl)oxy]silane (76):

Through a solution of 74 (1.3 g, 3.2 mmol) in CH₂Cl₂/MeOH (3:1,

40 mL) was bubbled an ozone/air mixture at –78 °C until the color

of the solution turned blue (10 min). The resulting solution was

degassed with a stream of air until colorless and NaBH₄(490 mg,

12.9 mmol) was added. The reaction mixture was warmed to 0 °C

and stirred for 1 h. Water (30 mL) and diethyl ether (30 mL) were

added and the aqueous phase was extracted with diethyl ether (3ϫ

20 mL). The combined organic layers were washed with satd. aq.

NaCl (30 mL), dried with MgSO₄, filtered and concentrated under

reduced pressure. Purification of the residue by column chromatog-

raphy (SiO₂, hexane/EtOAc, 10:1) gave the desired alcohol (1.0 g,

C₂₀H₄₄O₅Si₂Na [M + Na]⁺443.2625; found 443.2622. IR: ν =

˜

3458, 2954, 2912, 2877, 1459, 1415, 1239, 1128, 1041, 1005 cm^–1.

[α]²_D⁰= –9.7, (CHCl₃, c = 1.50). R_f(hexane/EtOAc, 6:1) = 0.33.

At 0 °C, SO₃·py (170 mg, 1.07 mmol) was added in one portion to

a solution of the alcohol (150 mg, 0.36 mmol) and Et₃N (250 μL,

1.78 mmol) in CH₂Cl₂/DMSO (4:1, 4.0 mL) at 0 °C. The resulting

mixture was warmed to room temperature and stirred for further

16 h. Sat. aq. NaS₂O₃(5 mL) and diethyl ether (5 mL) were added.

The aqueous phase was separated and extracted with diethyl ether

(3ϫ 5 mL). The combined organic phases were washed with water

(5 mL) and satd. aq. NaCl (5 mL), dried with MgSO₄, filtered and

concentrated under reduced pressure. Column chromatography

1

2.5 mmol, 76%) as a colorless oil. H NMR (CDCl₃, 400 MHz): δ

= 4.64 (s, 1 H), 4.21 (d, J = 4.8 Hz, 1 H), 4.20 (dt, J = 8.3, 4.7 Hz,

1 H), 3.86 (dd, J = 9.6, 4.8 Hz, 1 H), 3.78 (t, J = 5.7 Hz, 2 H), 3.46

(dd, J = 9.3, 8.5 Hz, 1 H), 3.30 (s, 3 H), 3.23 (t, J = 5.72 Hz, 1 H),

2.30–2.24 (m, 1 H), 0.96 (t, J = 7.9 Hz, 9 H), 0.95 (t, J = 7.9 Hz, (SiO₂, hexane/EtOAc, 6:1) gave desired aldehyde 77 (139 mg,

1

9 H), 0.63 (q, J = 7.9 Hz, 6 H), 0.61 (q, J = 7.9 Hz, 6 H) ppm. ¹³C

NMR (CDCl₃, 100 MHz): δ = 109.3, 82.8, 79.0, 66.2, 61.0, 54.6,

0.33 mmol, 93%) as a colorless oil. H NMR (CDCl₃, 400 MHz):

δ = 9.78 (br. s, 1 H), 4.68 (s, 1 H), 4.21 (d, J = 4.2 Hz, 1 H), 3.94

Eur. J. Org. Chem. 2013, 8214–8244

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8239

M. Himmelbauer, J.-B. Farcet, J. Gagnepain, J. Mulzer

FULL PAPER

(t, J = 8.7, 5.7 Hz, 1 H), 3.74 (dd, J = 10.2, 5.3 Hz, 1 H), 3.57 (dd,

J = 10.2, 6.1 Hz, 1 H), 3.32 (s, 3 H), 2.82–2.74 (m, 1 H), 2.61–2.53

(m, 2 H), 0.95 (t, J = 8.0 Hz, 9 H), 0.93 (t, J = 7.9 Hz, 9 H), 0.63–

0.54 (m, 12 H) ppm. ¹³C NMR (CDCl₃, 100 MHz): δ = 201.2,

109.5, 83.3, 77.1, 66.3, 54.6, 41.1, 39.6, 6.84 (6 C), 4.9 (3 C), 4.5 (3

1.7 m in THF, 0.20 mmol) at –78 °C. After 30 min a solution of

crude aldehyde 81 (30 mg, 0.09 mmol) in THF (700 μL) was added

over 5 min. The resulting mixture was warmed to 0 °C over 3 h.

Sat. aq. NH₄Cl (5 mL) and diethyl ether (5 mL) were added. The

aqueous phase was separated and extracted with diethyl ether (3ϫ

C) ppm. HRMS (ESI): calcd. for C₂₀H₄₂O₅Si₂Na [M + Na]⁺5 mL). The combined organic phases were washed with water

441.2468; found 441.2469. IR: ν = 2955, 2912, 2877, 1728, 1458,

(5 mL) and satd. aq. NaCl (5 mL), dried with MgSO₄, filtered and

concentrated under reduced pressure. Purification by column

chromatography (SiO₂, hexane/EtOAc, 6:1) provided 82 with a dr

of 4:1 (8 mg, 0.01 mmol, 12%) as a colorless oil. ¹H NMR (CDCl₃,

400 MHz): δ = 5.39 (dd, J = 2.7, 1.2 Hz, 1 H), 5.20 (dd, J = 1.9,

1.4 Hz, 1 H), 5.17 (td, J = 8.1, 5.6 Hz, 1 H), 4.69 (s, 1 H), 4.13 (d,

J = 4.5 Hz, 1 H), 4.05 (dt, J = 8.8, 5.7 Hz, 1 H), 3.98 (dt, J = 9.8,

2.9 Hz, 1 H), 3.83 (d, J = 2.4 Hz, 1 H), 3.74 (dd, J = 10.3, 5.7 Hz,

1 H), 3.64 (dd, J = 10.3, 5.8 Hz, 1 H), 3.32 (dd, J = 8.2, 6.2 Hz, 1

H), 3.31 (s, 3 H), 3.12–3.09 (m, 1 H), 2.45 (ddd, J = 14.6, 7.9,

1.7 Hz, 1 H), 2.39–2.32 (m, 1 H), 1.94 (dd, J = 14.6, 5.4 Hz, 1 H),

1.79–1.67 (m, 2 H), 1.42 (s, 3 H), 0.97 (t, J = 7.8 Hz, 9 H), 0.96 (t,

J = 8.0 Hz, 9 H), 0.93 (t, J = 7.7 Hz, 9 H), 0.63 (q, J = 8.0 Hz, 12

H), 0.57 (q, J = 8.8 Hz, 6 H) ppm. ¹³C NMR (CDCl₃, 100 MHz):

δ = 177.6, 144.3, 114.9, 109.1, 84.6, 84.1, 83.8, 77.6, 70.5, 67.0,

58.0, 57.8, 54.6, 49.6, 44.8, 41.7, 28.2, 23.3, 7.1 (3 C), 6.93 (3 C),

6.88 (3 C), 6.6 (3 C), 5.1 (3 C), 4.4 (3 C) ppm. HRMS (ESI): calcd.

˜

1386, 1239, 1107, 1007, 958 cm^–1. [α]²_D⁰= +7.0, (CHCl₃, c = 1.45).

R_f(hexane/EtOAc, 6:1) = 0.67.

Aldehyde 81: To a solution of alcohol 80 (40 mg, 0.12 mmol) in

MeOH (4.1 mL) was added AcCl (35 μL, 0.49 mmol) at 0 °C. The

mixture was warmed to room temperature and stirred for further

4 h, the volatiles were removed under reduced pressure and the resi-

due was dried under high vacuum for 2 h to yield 23 mg (89%) of

the diol as a pale pink solid. ¹H NMR (CDCl₃, 400 MHz): δ =

5.36 (br. s, 1 H), 5.32–5.25 (m, 1 H), 5.22 (br. s, 1 H), 4.01 (d, J =

11.6 Hz, 1 H), 3.87 (d, J = 11.6 Hz, 1 H), 3.53 (t, J = 6.2 Hz, 1 H),

3.21 (br. s, 1 H), 2.48 (dd, J = 7.7, 15.1 Hz, 1 H), 2.04 (dd, J = 4.7,

15.0 Hz, 1 H), 1.73 (br. s, 2 H), 1.45 (s, 3 H) ppm. ¹³C NMR

(CDCl₃, 100 MHz): δ = 176.8, 144.4, 115.0, 83.7, 82.7, 63.3, 56.8,

55.9, 48.6, 44.8, 24.1 ppm. HRMS (ESI): calcd. for C₁₁H₁₄O₄Na

[M + Na]⁺: 233.0790; found 233.0781. IR: ν = 3370, 2925, 1743,

˜

1352, 1158, 1056, 995, 906, 729, 647 cm^–1. [α]²_D¹= –26.7 (CHCl₃, c

= 1.1). R_f(hexane/EtOAc, 1:1) = 0.15, m.p. 110–112 °C.

for C₃₆H₆₈O₈Si₃Na [M + Na]⁺735.4120; found 735.4125. IR: ν =

˜

2954, 2876, 1767, 1460, 1376, 1300, 1240, 1104, 990, 906 cm^–1

.

The crude diol (15 mg, 0.07 mmol) was dissolved in CH₂Cl₂

(1.4 mL) and cooled to 0 °C. 2,6-Lutidine (50 μL, 0.43 mmol), fol-

lowed by TESOTf (64 μL, 0.29 mmol) were rapidly added to the

reaction vessel and the mixture was stirred at 0 °C for 45 min. The

reaction was quenched by addition of NaHCO₃(10 mL), diluted

with water (10 mL) and diethyl ether (30 mL). The phases were

separated and the aqueous phase was extracted with diethyl ether

(2ϫ 15 mL). The organic layers were washed with satd. aq. NaCl

(15 mL), dried with Na₂SO₄, filtered, and concentrated under vac-

uum. The residue was purified by column chromatography (SiO₂,

hexane/EtOAc, 15:1) furnishing 30 mg (96%) of the desired TES

[α]²_D⁰= –38.7, (CHCl₃, c = 0.55). R_f(hexane/EtOAc, 4:1) = 0.42.

(5S)-5-{(S)-2-Methyl-2-[(triethylsilyl)oxy]penta-3,4-dien-1-yl}-3-

(phenylselanyl)dihydrofuran-2(3H)-one (83): Alcohol 37 was sub-

jected to the same procedure as for 32 with TESOTf for protection

instead of TMSOTf. The use of Allenic alcohol (5.4 g, 29.6 mmol),

2,6-lutidine (10 mL, 88.9 mmol), TESOTf (10 mL, 44.5 mmol),

CH₂Cl₂(150 mL) gave TES-protected allenic alcohol (8.2 g,

27.6 mmol, 93%). ¹H NMR (CDCl₃, 400 MHz): δ = 5.26 (t, J =

6.6 Hz, 1 H), 4.83 (d, J = 0.6 Hz, 1 H), 4.82 (br. s, 1 H), 4.80–4.74

(m, 1 H), 2.51 (br. d, J = 10.1 Hz, 1 H), 2.49 (d, J = 9.8 Hz, 1 H),

2.39–2.31 (m, 1 H), 2.00–1.85 (m, 3 H), 1.40 (s, 3 H), 0.94 (t, J =

7.9 Hz, 9 H), 0.59 (q, J = 8.0 Hz, 6 H) ppm. ¹³C NMR (CDCl₃,

100 MHz): δ = 206.4, 177.4, 99.9, 78.1, 77.9, 72.4, 49.7, 29.9,

29.1, 27.7, 7.1 (3 C), 6.6 (3 C) ppm. HRMS (ESI): calcd. for

1

protected diol as a colorless oil. H NMR (CDCl₃, 400 MHz): δ =

5.22–5.16 (m, 2 H), 5.12 (dd, J = 1.5, 2.2 Hz, 1 H), 4.01 (d, J =

10.6 Hz, 1 H), 3.77 (d, J = 10.5 Hz, 1 H), 3.47 (dd, J = 6.2, 8.3 Hz,

1 H), 3.18–3.14 (m, 1 H), 2.45 (ddd, J = 1.8, 7.8, 14.7 Hz, 1 H),

1.92 (dd, J = 5.5, 14.6 Hz, 1 H), 1.41 (s, 3 H), 0.95 (t, J = 8.0 Hz,

9 H), 0.94 (t, J = 7.9 Hz, 9 H), 0.63–0.54 (m, 12 H) ppm. ¹³C NMR

(CDCl₃, 100 MHz): δ = 176.3, 145.7, 113.6, 84.7, 83.5, 62.9, 57.4,

56.4, 49.9, 44.8, 23.6, 7.1 (3 C), 6.8 (3 C), 6.6 (3 C), 4.5 (3 C) ppm.

HRMS (ESI): calcd. for C₂₃H₄₂O₄Si₂Na [M + Na]⁺461.2519;

C₁₆H₂₈O₃SiNa [M + Na]⁺319.1705; found 319.1708. IR: ν = 2953,

˜

2876, 1957, 1777, 1459, 1379, 1155, 1110, 1003, 917 cm^–1. [α]²_D⁰

–36.1, (CHCl₃, c = 1.0). R_f(hexane/EtOAc, 2:1) = 0.21.

=

The phenylselenyl group was introduced according to the pro-

cedure for 32. TES-protected allenic alcohol (2.5 g, 8.4 mmol),

LiHMDS (8.9 mL, 1.0 m in toluene, 8.9 mmol), TMSCl (1.2 mL,

9.3 mmol), PhSeCl (1.9 g, 9.7 mmol). Phenylseleno lactone 83

(3.31 g, 7.3 mmol, 87%) with a dr of 1:1 as a pale yellow oil. ¹H

NMR (CDCl₃, 400 MHz): δ = 7.69–7.65 (m, 4 H), 7.40–7.29 (m, 6

H), 5.21 (dt, J = 8.8, 6.7 Hz, 2 H), 4.82–4.80 (m, 4 H), 4.72–4.62

(m, 2 H), 4.02 (dd, J = 10.2, 9.1 Hz, 1 H), 3.93 (dd, J = 6.3, 4.0 Hz,

1 H), 2.75 (ddd, J = 13.6, 9.1, 6.4 Hz, 1 H), 2.39–2.36 (m, 2 H),

2.06–1.93 (m, 2 H), 1.87–1.79 (m, 2 H), 1.74–1.69 (m, 1 H), 1.35

(s, 3 H), 1.34 (s, 3 H), 0.93 (t, J = 7.9 Hz, 9 H), 0.91 (t, J = 7.9 Hz,

9 H), 0.57 (q, J = 7.5 Hz, 6 H), 0.55 (q, J = 7.6 Hz, 6 H) ppm. ¹³C

NMR (CDCl₃, 100 MHz): δ = 206.3, 136.0, 135.8, 129.5, 129.5,

129.2, 128.9, 127.3, 127.1, 99.8, 78.0, 77.2, 76.8, 76.5, 72.4, 72.3,

49.6, 49.3, 38.5, 37.9, 37.9, 37.3, 27.6, 7.18 (3 C), 7.15 (3 C), 6.62

(3CH), 6.59 (3CH) ppm. HRMS (ESI): calcd. for C₂₂H₃₂O₃SeSiNa

found 461.2517. IR: ν = 2954, 2876, 1773, 1458, 1239, 1146, 1107,

˜

991, 805, 742 cm^–1. [α]²_D⁴= –12.7 (CHCl₃, c = 1.5). R_f(hexane/

EtOAc, 10:1) 0.54.

The TES-protected diol (18 mg, 0.04 mmol) was subjected to the

same Swern-oxidation procedure as for 59. Purification by flash

chromatography (SiO₂, hexane/EtOAc, 3:1) furnished 11 mg (83%)

of aldehyde 81 as an amorphous white solid. ¹H NMR (CDCl₃,

400 MHz): δ = 9.83 (s, 1 H), 5.44 (t, J = 2.5 Hz, 1 H), 5.30 (t, J =

2.3 Hz, 1 H), 5.26 (dd, J = 5.7, 8.0 Hz, 1 H), 3.80 (dd, J = 6.2,

8.1 Hz, 1 H), 3.25–3.21 (m, 1 H), 2.52 (ddd, J = 1.8, 7.8, 14.8 Hz,

1 H), 1.96 (dd, J = 5.6, 14.8 Hz, 1 H), 1.43 (s, 3 H), 0.93 (t, J =

7.9 Hz, 9 H), 0.61 (q, J = 7.9 Hz, 6 H) ppm. ¹³C NMR (CDCl₃,

100 MHz): δ = 192.5, 171.8, 142.7, 116.2, 84.8, 84.2, 63.6, 57.8,

49.3, 42.7, 7.1 (3 C), 23.1, 6.6 (3 C) ppm. HRMS (ESI): calcd. for

[M + Na]⁺475.1184; found 475.1190. IR: ν = 2954, 2875, 1956,

C H O SiNa [M + Na]⁺: 345.1498; found 345.1490. IR: ν = 2931,

˜

17 26

4

1770, 1458, 1414, 1354, 1180, 1112, 1003 cm^–1. [α]²_D⁰= –23.7,

(CHCl₃, c = 1.0). R_f(hexane/EtOAc, 6:1) = 0.36.

2856, 1768, 1721, 1253, 1145, 1047, 987, 836, 775 cm^{– 1}

.

[α]²_D²= –87.6 (CHCl₃, c = 0.7). R_f(hexane/EtOAc, 3:1) = 0.28.

Cage-Shaped Cyclobutane 82: To a solution of 76 (48 mg,

0.09 mmol) in THF (700 μL) was added dropwise tBuLi (120 μL,

Butenolide 84: Phenylseleno lactone 83 (842 mg, 1.86 mmol) was

coupled with aldehyde 77 (820 mg, 1.96 mmol) according to the

8240

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Eur. J. Org. Chem. 2013, 8214–8244

An Approach to the Carbon Backbone of Bielschowskysin, Part 1

procedure for 46. A mixture of four diastereoisomers (1.63 g) was

obtained as a colorless oil that was used without further purifica-

tion in the next reaction. The oxidative elimination of the phenyl-

selenide was carried out according to the procedure for 22. A mix-

ture of four diastereoisomers (1.63 g) gave desired butenolide 84

(1.1 g, 1.54 mmol, 83% over 2 steps) with a dr of 3:1 as a colorless

gum that was used directly in the next reaction. ¹H NMR (CDCl₃,

400 MHz): δ = 7.30 (t, J = 1.5 Hz, 1 H), 7.29 (t, J = 1.5 Hz, 3 H),

5.28–5.23 (m, 8 H), 4.84–4.83 (m, 8 H), 4.68–4.66 (m, 4 H), 4.52–

J = 5.0, 0.3 Hz, 1 H), 3.40 (dd, J = 8.2, 6.4 Hz, 1 H), 3.35 (s, 3 H),

3.11–3.09 (m, 1 H), 2.45 (ddd, J = 14.7, 7.8, 1.7 Hz, 1 H), 2.39–

2.33 (m, 1 H), 2.08 (s, 3 H), 2.04–1.94 (m, 2 H), 1.90 (dd, J = 14.6,

5.3 Hz, 1 H), 1.41 (s, 3 H), 0.98 (t, J = 7.9 Hz, 9 H), 0.94 (t, J =

7.9 Hz, 9 H), 0.67 (q, J = 7.9 Hz, 6 H), 0.58 (q, J = 7.9 Hz, 1

H) ppm. ¹³C NMR (CDCl₃, 100 MHz): δ = 174.3, 170.7, 160.7,

144.1, 115.9, 110.9, 102.4, 84.5, 83.2, 76.2, 71.2, 57.8, 57.4, 55.6,

49.6, 44.9, 44.7, 25.0, 23.4, 21.1, 7.1 (3 C), 6.9 (3 C), 6.6 (3 C), 4.9

(3 C) ppm. HRMS (ESI): calcd. for C₃₂H₅₄O₁₀Si₂Na [M + Na]⁺

4.46 (m, 4 H), 4.16 (d, J = 4.6 Hz, 3 H), 4.12–4.07 (m, 4 H), 3.90 677.3153; found 677.3136. IR: ν = 2955, 2877, 1769, 1740, 1227,

˜

(d, J = 4.3 Hz, 3 H), 3.81–3.76 (m, 4 H), 3.66–3.61 (m, 4 H), 3.53 1152, 1111, 1039, 1017, 990 cm^–1. [α]²_D⁵= –9.3, (CHCl₃, c = 0.8). R_f

(d, J = 5.1 Hz, 1 H), 3.31 (s, 9 H), 3.30 (s, 3 H), 2.39–2.28 (m, 4

H), 2.23–2.17 (m, 3 H), 1.99–1.85 (m, 6 H), 1.83–1.75 (m, 4 H),

1.67–1.60 (m, 4 H), 1.46 (br. s, 12 H), 0.99–0.93 (m, 108 H), 0.67–

0.58 (m, 72 H) ppm. ¹³C NMR (CDCl₃, 100 MHz): δ = 206.42,

206.41, 172.7, 172.6, 150.1, 150.0, 136.2, 136.1, 109.2, 109.0, 99.7,

83.8, 83.7, 78.94, 78.87, 78.7, 78.17, 78.15, 77.2, 72.39, 72.37, 66.8,

66.5, 66.4, 66.0, 54.7, 54.6, 47.4, 47.2, 42.5, 41.5, 32.5, 32.5, 27.9,

27.8, 7.1, 6.9, 6.8, 6.6, 5.0, 4.4, 4.3 ppm. HRMS (ESI): calcd. for

C₃₆H₆₈O₈Si₃Na [M + Na]⁺735.4120; found 735.4128. R_f(hexane/

EtOAc, 6:1) = 0.30.

(hexane/EtOAc, 3:1) = 0.55.

Aldehyde 60: Secondary alcohol 85 (284 mg, 0.42 mmol) was sub-

jected to the identical acylation procedure as 57 (see above) giving

acetate 58 (300 mg, quant.) as a colorless oil (for analytical data

see there). For the preparation of aldehyde 60 and for analytical

data see above.

Vinyl Bromide 86: To a slightly turbid mixture of formate 89

(186 mg, 0.28 mmol) and bromoallylsilane 90 (112 μL, 0.65 mmol)

in CH₂Cl₂(5.6 mL) was added dropwise SnCl₄(454 μL, 0.45 mmol)

through a syringe at –78 °C. The reaction was stirred until TLC

analysis (hexane/EtOAc, 6:1) indicated full consumption of the

starting aldehyde. Thereafter, a mixture of MeOH and satd. aq.

NaHCO₃2:1 (6 mL) and diethyl ether (6 mL) were sequentially

added. The resulting heterogenic mixture was warmed to room

temperature and water was added until all solids were dissolved.

The resulting clear aqueous phase was extracted with diethyl ether

(3ϫ 10 mL). The combined organic extracts were washed with Na/

K tartrate (15 mL), water (15 mL) and satd. aq. NaCl (15 mL).

After drying with MgSO₄the solids were removed by filtration and

the filtrate was concentrated under reduced pressure giving a color-

less oil. The residue was taken up in a minimum amount of hexane/

EtOAc (6:1) and purified by filtration through a short pad of silica

(hexane/EtOAc, 6:1) yielding desired vinyl bromide 86 (194 mg,

94%) after removal of the volatiles as a colorless oil. ¹H NMR

(CDCl₃, 400 MHz): δ = 5.64 (s, 1 H), 5.52 (dd, J = 11.5, 2.7 Hz, 1

H), 5.50 (s, 1 H), 5.33 (dd, J = 2.5, 1.8 Hz, 1 H), 5.21 (dd, J = 1.9,

1.8 Hz, 1 H), 5.17 (dt, J = 8.0, 5.4 Hz, 1 H), 4.72 (s, 1 H), 4.40

(ddd, J = 10.3, 8.5, 2.6 Hz, 1 H), 4.07 (d, J = 4.2 Hz, 1 H), 3.39

(dd, J = 8.2, 6.5 Hz, 1 H), 3.31 (s, 3 H), 3.12–3.09 (m, 1 H), 2.79

Cage-Shaped Cyclobutanes 82 and 85: A diastereoisomeric mixture

of 84 (153 mg, 0.21 mmol) was treated with UV-C light according

to the procedure for 47/48 giving 82 (78 mg, 0.11 mmol) and 85

(38 mg, 0.05 mmol) as colorless gums. For analytic data of 82 see

above. Analytic data for 85: ¹H NMR (CDCl₃, 400 MHz): δ = 5.26

(dd, J = 2.7, 1.3 Hz, 1 H), 5.20 (td, J = 8.0, 5.3 Hz, 1 H), 5.14 (dd,

J = 2.0, 1.5 Hz, 1 H), 4.66 (s, 1 H), 4.18–4.12 (m, 2 H), 4.02–3.96

(m, 1 H), 3.78 (dd, J = 10.3, 4.8 Hz, 1 H), 3.59 (dd, J = 10.3,

6.8 Hz, 1 H), 3.54–3.49 (m, 1 H), 3.45 (dd, J = 8.2, 6.3 Hz, 1 H),

3.31 (s, 3 H), 3.22 (d, J = 5.6 Hz, 1 H), 3.09–3.06 (m, 1 H), 2.48–

2.38 (m, 2 H), 1.95–1.87 (m, 1 H), 1.71–1.61 (m, 1 H), 1.54 (s, 3 H),

0.99–0.91 (m, 27 H), 0.68–0.53 (m, 18 H) ppm. ¹³C NMR (CDCl₃,

100 MHz): δ = 176.8, 145.5, 114.4, 109.3, 84.7, 83.9, 83.7, 79.1,

69.9, 66.9, 59.6, 58.0, 54.6, 49.8, 43.4, 41.9, 29.2, 23.5, 7.1 (3 C),

6.92 (3 C), 6.86 (3 C), 6.6 (3 C), 5.0 (3 C), 4.3 (3 C) ppm. HRMS

(ESI): calcd. for C₃₆H₆₈O₈Si₃Na [M + Na]⁺735.4120; found

735.4123. IR: ν = 2955, 2912, 2877, 1769, 1459, 1414, 1240, 1107,

˜

1042, 1006 cm^–1. [α]²_D⁰= –107.1, (CHCl₃, c = 0.2). R_f(hexane/

EtOAc, 4:1) = 0.35.

Formate 89: The acylation of 82 (246 mg, 0.34 mmol) was per- (dd, J = 14.6, 10.5 Hz, 1 H), 2.48–2.36 (m, 3 H), 2.11 (s, 3 H), 1.90

formed according to the procedure for 57 giving the desired acetate

(260 mg, quant.) as a colorless oil. For the preparation of aldehyde

59 and for the analytic data see above.

(dd, J = 14.8, 5.3 Hz, 1 H), 1.89–1.77 (m, 2 H), 1.41 (s, 3 H), 0.98

(t, J = 7.9 Hz, 9 H), 0.94 (t, J = 7.8 Hz, 9 H), 0.66 (q, J = 7.9 Hz,

6 H), 0.58 (q, J = 7.9 Hz, 6 H) ppm. ¹³C NMR (CDCl₃, 100 MHz):

δ = 174.4, 170.7, 144.2, 131.8, 118.7, 115.8, 108.5, 84.4, 83.2, 77.9,

77.1, 71.5, 57.7, 57.3, 55.0, 49.6, 45.5, 44.8, 40.0, 23.8, 23.4, 21.1,

7.1 (3 C), 6.9 (3 C), 6.6 (3 C), 4.9 (3 C) ppm. HRMS (ESI): calcd.

for C₃₆H₆₄BrN₂O₈Si₂[M + H₃CCN+NH₄]⁺789.3364; found

To a suspension of aldehyde 59 (207 mg, 0.3 mmol) and NaHCO₃

(82 mg, 0.1 mmol) in CH₂Cl₂(3.5 mL) was added mCPBA

(111 mg, 0.7 mmol), which was purified by extraction of a solution

in diethyl ether with pH 7.5 buffer prior to use, in one portion

under vigorous stirring at 0 °C. After 2 h the reaction was

quenched by the addition of dimethyl sulfide (300 μL, 4 mmol).

After an additional 30 min diethyl ether (10 mL) and satd. aq.

NH₄Cl (10 mL) were added at 0 °C. The aqueous phase was sepa-

rated and extracted with diethyl ether (3ϫ 10 mL). The combined

organic extracts were washed with satd. aq. NaHCO₃(15 mL),

water (15 mL) and satd. aq. NaCl (15 mL). After drying with

MgSO₄and filtration, the volatiles were removed under reduced

pressure. Purification of the remaining residue by flash column

789.3349. IR: ν = 2954, 2877, 1770, 1747, 1459, 1372, 1226, 1151,

˜

1049, 990 cm^–1. [α]²_D⁵= –50.1, (CHCl₃, c = 1.5). R_f(hexane/EtOAc,

3:1) = 0.55.

Macrocycle 91: To a solution of vinyl bromide 86 (14 mg,

0.02 mmol) in freshly degassed toluene (0.8 mL) were added

Pd(OAc)₂(0.5 mg, 0.002 mmol), triphenylphosphine (1 mg,

0.004 mmol), Ag₂CO₃(16 mg, 0.058 mmol) and crushed molecular

sieves (4 Å 100 mg). After stirring at 80 °C for 3 d the reaction

mixture was cooled to room temperature at which diethyl ether

(5 mL) and water (5 mL) were added. The resulting heterogeneous

chromatography (SiO₂, hexane/EtOAc, 8:1) gave desired formate

1

89 (169 mg, 79%) as a colorless oil. H NMR (CDCl₃, 400 MHz): mixture was filtered through a short pad of Celite. The aqueous

δ = 8.11 (s, 1 H), 6.14 (d, J = 4.6 Hz, 1 H), 5.49 (dd, J = 10.5, phase was separated and extracted with diethyl ether (3ϫ 5 mL).

3.1 Hz, 1 H), 5.33 (dd, J = 2.6, 1.8 Hz, 1 H), 5.21 (dd, J = 2.1,

1.8 Hz, 1 H), 5.17 (dt, J = 8.0, 5.4 Hz, 1 H), 4.79 (s, 1 H), 4.26 (dd,

The combined organic phases were washed with water (5 mL) and

satd. aq. NaCl (5 mL) followed by drying with MgSO₄. Filtration

Eur. J. Org. Chem. 2013, 8214–8244

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8241

M. Himmelbauer, J.-B. Farcet, J. Gagnepain, J. Mulzer

FULL PAPER

of the solids, removal of the volatiles under reduced pressure and

flash column chromatography (SiO₂, hexane/EtOAc, 8:1) of the res-

idue and mass analysis of the collected fractions indicated the for-

mation of desired macrocycle 91. HRMS (ESI): calcd. for

C₃₆H₆₃N₂O₈Si₂[M+CH₃CN+NH₄]⁺707.4117; found 707.4108.

6 H), 0.58 (q, J = 7.8 Hz, 6 H) ppm. ¹³C NMR (CDCl₃, 100 MHz):

δ = 174.4, 170.7, 144.2, 132.4, 120.8, 118.9, 115.8, 108.6, 84.5, 83.2,

78.1, 77.0, 71.4, 57.7, 57.3, 55.0, 49.6, 44.8, 40.2, 39.1, 23.7, 23.4,

21.1, 7.1 (3 C), 6.9 (3 C), 6.6 (3 C), 4.9 (3 C) ppm. HRMS (ESI):

calcd. for C₃₇H₆₄N₃O₈Si₂[M + H₃CCN+NH₄]⁺734.4226; found

734.4215. IR: ν = 2955, 2914, 2877, 2259, 1769, 1747, 1373, 1227,

˜

Macrocycle 92: A suspension of vinyl bromide 86 (20 mg,

0.027 mmol), NaOAc (11 mg, 0.13 mmol), Bu₄NCl (15 mg,

0.053 mmol) and crushed molecular sieves (4 Å, 150 mg) in freshly

degassed dimethylformamide (DMF; 2.7 mL) was added Pd-

(OAc)₂(0.6 mg, 0.003 mmol) as a solid at room temperature. The

flask was sealed and immediately heated to 85 °C in an oil bath

under vigorous stirring. After 1.5 h the starting material was con-

sumed. The reaction mixture was cooled to room temperature fol-

lowed by the addition of diethyl ether (5 mL) and water (5 mL).

The resulting heterogeneous mixture was filtered through a short

pad of Celite. The aqueous phase was separated and extracted with

diethyl ether (3 ϫ 5 mL). The combined organic phases were

washed with water (5 mL) and satd. aq. NaCl (5 mL) followed by

drying with MgSO₄. Filtration of the solids, removal of the volatiles

under reduced pressure and flash column chromatography (SiO₂,

hexane/EtOAc, 8:1) of the residue resulted in isolation of carbo-

oxygenation product 92 (10 mg, 55%) and vinyl nitrile 93 (4 mg,

1152, 1050 cm^–1. [α]¹_D⁸= –69.4, (CHCl₃, c = 0.35). R_f(hexane/

EtOAc, 4:1) = 0.58.

General Procedure for the Tin Mediated Allylation; Homoallylic

Alcohol 97: To a solution of aldehyde 59 (25 mg, 0.04 mmol) and

(Z)-crotylsilane (94; 41 μL, 0.23 mmol) in CH₂Cl₂(800 μL) was

added dropwise SnCl₄(120 μL, 1.0 m in CH₂Cl₂, 0.12 mmol) at

–78 °C. The reaction mixture was stirred at his temperature for 4 h.

A suspension of satd. aq. NaHCO₃/MeOH (1:2, 3 mL) was rapidly

added at –78 °C. The cooling bath was removed and diethyl ether

(5 mL) and water (2 mL) were added. The separated aqueous phase

was extracted with diethyl ether (3ϫ 5 mL). The combined organic

phases were washed with satd. aq. Na/K tartrate (5 mL) and satd.

aq. NaCl (5 mL), dried with MgSO₄, filtered and concentrated un-

der reduced pressure. Column chromatography (SiO₂, hexane/

EtOAc, 8:1) gave homoallylic alcohol 97 (27 mg, 0.039 mmol, 98%)

as a mixture of diastereoisomers, which was used directly in the

next reaction. Major diastereoisomer: ¹H NMR (CDCl₃,

400 MHz): δ = 5.75 (ddd, J = 17.2, 10.3, 8.3 Hz, 1 H), 5.47 (dt, J

= 11.7, 2.1 Hz, 1 H), 5.34 (dd, J = 4.3, 2.3 Hz, 1 H), 5.20 (dd, J =

3.5, 1.7 Hz, 1 H), 5.17 (td, J = 8.0, 5.4 Hz, 1 H), 5.11 (ddd, J =

17.3, 1.8, 1.0 Hz, 1 H), 5.04 (dd, J = 10.3, 1.8 Hz, 1 H), 4.67 (d, J

= 1.4 Hz, 1 H), 4.14 (d, J = 4.2 Hz, 1 H), 4.02 (t, J = 10.2 Hz, 1

H), 3.40–3.32 (m, 2 H), 3.36 (s, 3 H), 3.18–3.09 (m, 2 H), 2.48–2.42

(m, 1 H), 2.25–2.13 (m, 2 H) 2.09 (s, 3 H), 1.92–1.87 (m, 2 H),

1.75–1.65 (m, 1 H), 1.41 (s, 3 H), 1.14 (d, J = 6.8 Hz, 3 H), 1.01–

0.92 (m, 18 H), 0.73–0.67 (m, 6 H), 0.61–0.55 (m, 6 H) ppm. ¹³C

NMR (CDCl₃, 100 MHz): δ = 174.3, 170.9, 144.3, 141.2, 116.0,

109.9, 84.4, 84.3, 83.1, 76.1, 73.5, 73.1, 70.9, 57.7, 57.2, 55.6, 49.7,

44.8, 43.1, 38.4, 24.9, 23.4, 21.9, 17.0, 7.2 (3 C), 6.9 (3 C), 6.6 (3

C), 5.0 (3 C) ppm. HRMS (ESI): calcd. for C₃₆H₆₂O₉Si₂Na [M +

1

22%). Analytic data for 92: H NMR (CDCl₃, 600 MHz): δ = 5.50

(dd, J = 11.3, 2.6 Hz, 1 H), 5.33 (dd, J = 2.7, 1.8 Hz, 1 H), 5.21 (t,

J = 1.92 Hz, 1 H), 5.18 (dt, J = 5.4, 8.0 Hz, 1 H), 4.83 (s, 2 H),

4.73 (s, 1 H), 4.25 (ddd, J = 10.8, 8.3, 2.7 Hz, 1 H), 4.09 (d, J =

4.3 Hz, 1 H), 3.40 (dd, J = 8.2, 6.5 Hz, 1 H), 3.31 (s, 3 H), 3.11–

3.09 (m, 1 H), 2.55 (dd, J = 15.1, 10.8 Hz, 1 H), 2.45 (ddd, J =

14.7, 7.8, 1.7 Hz, 1 H), 2.36–2.34 (m, 1 H), 2.34–2.32 (m, 1 H),

2.15 (s, 3 H), 2.08 (s, 3 H), 1.90 (dd, J = 14.6, 5.4 Hz, 1 H), 1.88–

1.79 (m, 2 H), 1.41 (s, 3 H), 0.99 (t, J = 8.0 Hz, 9 H), 0.94 (t, J =

7.9 Hz, 9 H), 0.67 (q, J = 8.0 Hz, 6 H), 0.58 (q, J = 7.9 Hz, 6

H) ppm. ¹³C NMR (CDCl₃, 150 MHz): δ = 174.4, 170.6, 169.3,

154.0, 144.2, 115.8, 108.8, 103.4, 84.4, 83.2, 77.6, 76.8, 71.4, 57.7,

57.3, 55.1, 49.6, 44.8, 40.1, 37.7, 23.7, 23.4, 21.3, 21.0, 7.2 (3 C),

6.9 (3 C), 6.6 (3 C), 6.4 (3 C) ppm. HRMS (ESI): calcd. for

C₃₆H₆₀NaO₁₀Si₂[M + H₃CCN+NH₄]⁺731.3623; found 731.3628.

Na]⁺717.3830; found 717.3833. IR: ν = 2958, 2933, 2909, 1775,

˜

1752, 1238, 1147, 1101, 1015, 988 cm^–1. [α]²_D⁰= –43.3, (CHCl₃, c =

0.4). R_f(hexane/EtOAc, 2:1) = 0.48.

IR: ν = 2955, 2915, 1769, 1371, 1226, 1207, 1101, 1051, 1018,

˜

990 cm^–1. [α]¹_D⁵= –50.8, (CHCl₃, c = 0.4). R_f(hexane/EtOAc, 4:1)

= 0.27.

Homoallylic Alcohol 95: Aldehyde 59 (26 mg, 0.04 mmol) and allyl-

trimethylsilane (26 μL, 0.16 mmol) were treated with SnCl₄(81 μL,

0.08 mmol) according to the general procedure for the tin mediated

allylation giving 95 (25 mg, 0.04 mmol, 93%) as a mixture of dia-

stereoisomers. Major diastereoisomer: ¹H NMR (CDCl₃,

400 MHz): δ = 5.96–5.82 (m, 1 H), 5.50–5.44 (m, 1 H), 5.35–5.29

(m, 1 H), 5.21,–5.20 (m, 1 H), 5.19–5.08 (m, 3 H), 4.68–4.66 (m, 1

H), 4.21–4.15 (m, 1 H), 3.89–3.85 (m, 1 H), 3.50–3.43 (m, 1 H),

3.41–3.27 (m, 4 H), 3.10 (br. d, J = 5.4 Hz, 1 H), 2.47–2.29 (m, 3

H), 2.27–2.14 (m, 1 H), 2.10–1.96 (m, 5 H), 1.94–1.87 (m, 2 H),

1.41 (br. s, 3 H), 1.01–0.92 (m, 18 H), 0.73–0.67 (m, 6 H), 0.61–

0.55 (m, 6 H) ppm. ¹³C NMR (CDCl₃, 100 MHz): δ = 175.2, 171.0,

144.8, 135.2, 117.2, 115.7, 110.3, 87.1, 84.8, 83.6, 78.2, 71.6 (2 C),

58.3, 58.2, 55.9, 49.6, 44.0, 39.6, 39.5, 27.7, 22.9, 20.8, 7.2 (3 C),

6.9 (3 C), 6.5 (3 C), 5.0 (3 C) ppm. HRMS (ESI): calcd. for

C₃₇H₆₇N₂O₉Si₂[M+CH₃CN+NH₄Cl]⁺739.4385; found 739.4388.

Vinyl Nitrile 93: A round-bottomed flask was charged with vinyl

bromide 86 (15 mg, 0.021 mmol) in freshly degassed DMF

(5.3 mL). Pd(OAc)₂(2.0 mg, 0.009 mmol), triphenylphosphine

(5 mg, 0.021 mmol), K₂CO₃(28 mg, 0.21 mmol) and crushed mo-

lecular sieves (4 Å 100 mg) were added. The reaction was stirred at

125 °C for 3 h and cooled to room temperature at which diethyl

ether (10 mL) and water (10 mL) were added. The resulting hetero-

geneous mixture was filtered through a short pad of Celite. The

aqueous phase was separated and extracted with diethyl ether (3ϫ

10 mL). The combined organic phases were washed with water

(10 mL) and satd. aq. NaCl (10 mL) followed by drying with

MgSO₄. Filtration of the solids, removal of the volatiles under re-

duced pressure and flash column chromatography (SiO₂, hexane/

EtOAc, 8:1) of the residue gave vinyl nitrile 93 (7 mg, 50%) as a

1

colorless oil. H NMR (CDCl₃, 400 MHz): δ = 5.92 (s, 1 H), 5.76

(s, 1 H), 5.52 (dd, J = 11.4, 2.6 Hz, 1 H), 5.33 (br. s, 1 H), 5.22 (s

br., 1 H), 5.18 (dt, J = 5.5, 7.9 Hz, 1 H), 4.72 (s, 1 H), 4.29 (ddd,

J = 10.8, 8.6, 2.2 Hz, 1 H), 4.08 (d, J = 4.1 Hz, 1 H), 3.40 (dd, J

= 7.9, 6.7 Hz, 1 H), 3.30 (s, 3 H), 3.13–3.10 (m, 1 H), 2.58 (dd, J

= 14.1, 11.2 Hz, 1 H), 2.46 (ddd, J = 14.8, 7.9, 0.8 Hz, 1 H), 2.41–

2.37 (m, 1 H), 2.34 (br. d, J = 14.8 Hz, 1 H), 2.12 (s, 3 H), 1.91

(dd, J = 14.3, 5.3 Hz, 1 H), 1.88–1.79 (m, 2 H), 1.42 (s, 3 H), 0.98

(t, J = 7.9 Hz, 9 H), 0.95 (t, J = 7.8 Hz, 9 H), 0.67 (q, J = 7.9 Hz,

IR: ν = 2962, 2946, 2928, 1781, 1741, 1243, 1178, 1119, 1024,

˜

998 cm^–1. [α]²_D⁰= –11.7, (CHCl₃, c = 0.2). R_f(hexane/EtOAc, 2:1)

= 0.50.

Homoallylic Alcohol 96: Aldehyde 60 (30 mg, 0.05 mmol) and allyl-

trimethylsilane (26 μL, 0.16 mmol) were treated with SnCl₄(71 μL,

0.07 mmol) according to the general procedure for the tin mediated

allylation giving 96 (30 mg, 0.04 mmol, 94%) as a mixture of dia-

8242

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Eur. J. Org. Chem. 2013, 8214–8244

An Approach to the Carbon Backbone of Bielschowskysin, Part 1

stereoisomers. Major diastereoisomer: ¹H NMR (CDCl₃,

400 MHz): δ = 5.91 (ddt, J = 17.2, 10.1, 7.0 Hz, 1 H), 5.45 (dd, J

= 11.1, 2.1 Hz, 1 H), 5.32 (dd, J = 2.7, 1.7 Hz, 1 H), 5.24 (t, J =

1.9 Hz, 1 H), 5.21 (td, J = 8.0, 5.4 Hz, 1 H), 5.14 (ddd, J = 17.1,

3.4, 1.4 Hz, 1 H), 5.09 (br. d, J = 10.2 Hz, 1 H), 4.69 (s, 1 H), 4.13

(d, J = 5.5 Hz, 1 H), 3.98 (dd, J = 6.6, 2.1 Hz, 1 H), 3.62–3.56 (m,

1 H), 3.43 (dd, J = 8.3, 6.3 Hz, 1 H), 3.39 (s, 3 H), 3.15–3.11 (m,

1 H), 2.50 (d, J = 8.8 Hz, 1 H), 2.45 (ddd, J = 14.7, 7.9, 1.7 Hz, 1

H), 2.38–2.28 (m, 3 H), 2.04 (s, 3 H), 2.09–2.01 (m, 1 H), 1.92 (dd,

J = 14.7, 5.4 Hz, 1 H), 1.85 (ddd, J = 14.8, 8.6, 2.2 Hz, 1 H), 1.42

(s, 3 H), 0.98 (t, J = 7.8 Hz, 9 H), 0.94 (t, J = 7.8 Hz, 9 H), 0.64

(q, J = 7.7 Hz, 6 H), 0.58 (q, J = 7.8 Hz, 6 H) ppm. ¹³C NMR

(CDCl₃, 100 MHz): δ = 174.8, 170.4, 144.5, 135.4, 117.2, 115.6,

110.1, 87.3, 84.7, 83.4, 78.5, 71.3 (2 C), 58.23, 58.17, 55.7, 49.5,

44.2, 39.6, 39.5, 27.1, 23.3, 21.1, 7.1 (3 C), 6.9 (3 C), 6.6 (3 C), 5.0

( 3 C ) p p m . H R M S ( E S I ) : c a l c d . fo r C _{3 7}H _{6 7}N ₂O ₉S i ₂

1151, 1043 cm^–1. [α]²_D⁰= –5.0, (CHCl₃, c = 0.2). R_f(hexane/EtOAc,

3:1) = 0.29.

Diene 111: A solution of 96 (32 mg, 0.05 mmol) and 2,6-lutidine

(27 μL, 0.23 mmol) in CH₂Cl₂(700 μL) was treated with TMSOTf

(27 μL, 0.15 mmol) at 0 °C. The resulting mixture was stirred for

3 h, satd. aq. NH₄Cl (5 mL) and diethyl ether (5 mL) were added.

The separated aqueous layer was extracted with diethyl ether (2ϫ

5 mL). The combined organic layers were washed with satd. aq.

NaCl (5 mL), dried with MgSO₄, filtered and concentrated under

reduced pressure. Purification of the residue by column chromatog-

raphy (SiO₂, hexane/EtOAc, 6:1) gave TMS-protected allylic

1

alcohol 111 (27 mg, 0.04 mmol, 76%) as a colorless oil. H NMR

(CDCl₃, 400 MHz): δ = 5.87–5.77 (m, 1 H), 5.56 (dd, J = 11.3,

2.7 Hz, 1 H), 5.33 (dd, J = 2.6, 1.6 Hz, 1 H), 5.22–517 (m, 1 H),

5.10 (dd, J = 17.1, 2.0 Hz, 1 H), 5.06–5.03 (m, 1 H), 4.64 (s, 1 H),

3.94 (d, J = 4.0 Hz, 1 H), 3.82 (dd, J = 8.1, 3.1 Hz, 1 H), 3.76–3.72

(m, 1 H), 3.43 (dd, J = 8.3, 6.3 Hz, 1 H), 3.31 (s, 3 H), 3.15–3.12

(m, 1 H), 2.45 (ddd, J = 14.7, 7.9, 1.7 Hz, 1 H), 2.40–2.33 (m, 1

H), 2.25–2.15 (m, 2 H), 2.14–2.07 (m, 1 H), 2.04 (s, 3 H), 1.92 (dd,

J = 14.7, 5.5 Hz, 1 H), 1.84 (dt, J = 14.3, 3.1 Hz, 1 H), 1.58 (br. d,

J = 3.1 Hz, 1 H), 1.42 (s, 3 H), 0.98 (t, J = 8.0 Hz, 9 H), 0.94 (t, J

= 8.0 Hz, 9 H), 0.64 (q, J = 8.0 Hz, 6 H), 0.58 (q, J = 7.9 Hz, 6

H), 0.11 (s, 9 H) ppm. ¹³C NMR (CDCl₃, 100 MHz): δ = 174.8,

170.1, 144.5, 135.9, 117.1, 115.5, 108.7, 85.5, 84.7, 83.3, 77.4, 73.2,

72.2, 58.23, 58.1, 54.7, 49.4, 44.2, 39.7, 38.1, 24.9, 23.3, 21.2, 7.10

(3 C), 6.91 (3 C), 6.61 (3 C), 5.16 (3 C), 0.62 (3 C) ppm. HRMS

(ESI): calcd. for C₃₈H₆₈O₉Si₃[M + Na]⁺775.4069; found 775.4050.

[M+CH₃CN+NH₄Cl]⁺739.4385; found 739.4388. IR: ν = 2955,

˜

2935, 2912, 1773, 1748, 1231, 1153, 1105, 1040, 1017 cm^–1. [α]²_D⁰

–44.0, (CHCl₃, c = 0.2). R_f(hexane/EtOAc, 2:1) = 0.37.

=

Homoallylic Alcohol 98: Aldehyde 60 (30 mg, 0.05 mmol) and (Z)-

crotylsilane (94) (26 μL, 0.16 mmol) were treated with SnCl₄

(71 μL, 0.07 mmol) according to the general procedure for the tin-

mediated allylation giving 98 (30 mg, 0.04 mmol, 94%) as a mixture

of diastereoisomers. Major diastereoisomer: ¹H NMR (CDCl₃,

400 MHz): δ = 5.94–5.88 (s, 1 H), 5.67 (d, J = 11.0 Hz, 1 H), 5.35

(br. d, J = 1.4 Hz, 1 H), 5.25–5.19 (m, 2 H), 5.15 (br. d, J = 3.3 Hz,

1 H), 5.12 (br. s, 1 H), 4.67 (br. s, 1 H), 4.08 (d, J = 5.6 Hz, 1 H),

3.82 (dd, J = 8.6, 5.5 Hz, 1 H), 3.43 (t, J = 7.3 Hz, 1 H), 3.39–3.35

(m, 1 H), 3.32 (s, 3 H), 3.12 (br. d, J = 4.1 Hz, 1 H), 2.71 (d, J =

6.4 Hz, 1 H), 2.63 (td, J = 10.7, 3.1 Hz, 1 H), 2.45 (dd, J = 14.7,

7.9 Hz, 1 H), 2.28–2.24 (m, 1 H), 2.07–2.02 (m, 4 H), 1.92 (dd, J

IR: ν = 2955, 2877, 1775, 1747, 1372, 1229, 1150, 1107, 1041,

˜

993 cm^–1. [α]²_D⁰= –51–8, (CHCl₃, c = 0.8). R_f(hexane/EtOAc, 3:1)

= 0.56.

(3S,5S)-3-(Methoxymethoxy)-3-methyl-5-(prop-2-yn-1-yloxy)cyclo-

= 14.7, 5.4 Hz, 1 H), 1.87 (dd, J = 14.9, 8.6 Hz, 1 H), 1.41 (s, 3 pent-1-ene (115): A solution of alcohol 117 (150 mg, 0.95 mmol) in

H), 1.13 (d, J = 7.0 Hz, 3 H), 0.97 (t, J = 7.9 Hz, 9 H), 0.94 (t, J THF (6 mL) was added dropwise to a suspension of NaH (164 mg,

= 7.9 Hz, 9 H), 0.63 (q, J = 7.8 Hz, 6 H), 0.57 (q, J = 7.9 Hz, 6 3.80 mmol) in THF (9 mL) at 0 °C. After 1 h propargyl bromide

H) ppm. ¹³C NMR (CDCl₃, 100 MHz): δ = 175.0, 171.6, 144.2,

139.2, 116.3, 115.8, 109.7, 85.6, 84.6, 83.4, 78.8, 77.7, 72.1, 58.3,

58.2, 55.2, 49.5, 44.0, 41.7, 40.0, 27.8, 23.3, 21.3, 17.5, 7.1 (3 C),

(310 μL, 2.80 mmol) was added through a syringe and the resulting

mixture was warmed to room temperature. After 16 h satd. aq.

NH₄Cl (10 mL) was added and the aqueous phase was separated

6.9 (3 C), 6.6 (3 C), 4.9 (3 C) ppm. HRMS (ESI): calcd. for and extracted with diethyl ether (3ϫ 10 mL). The combined or-

C

₃₆H₆₂O₉Si₂Na [M + Na]⁺717.3830; found 717.3836. IR: ν =

ganic phases were washed with satd. aq. NaCl (10 mL), dried with

MgSO₄, filtered and concentrated under reduced pressure. Column

chromatography (SiO₂, hexane/EtOAc, 3:1) of the residue afforded

desired propargyl ether 115 (184 mg, 0.94 mmol, 99%) as a color-

less oil. ¹H NMR ([D₆]DMSO, 400 MHz): δ = 6.05 (dd, J = 5.6,

2.0 Hz, 1 H), 5.89 (J = 5.6, 1.2 Hz, 1 H), 4.72–4.69 (m, 1 H), 4.54

(d, J = 7.2 Hz, 1 H), 4.49 (d, J = 7.2 Hz, 1 H), 4.15 (dd, J = 16.0,

2.4 Hz, 1 H), 4.11 (dd, J = 13.7, 2.4 Hz, 1 H), 3.39 (t, J = 2.4 Hz,

1 H), 3.21 (s, 3 H), 2.33 (dd, J = 14.1, 7.0 Hz, 1 H), 1.66 (dd, J =

1 4 . 1 , 3 . 7 H z , 1 H ) , 1 . 3 6 ( s , 3 H ) p p m . ^{1 3}C N M R

([D₆]DMSO, 100 MHz): δ = 139.3, 133.7, 91.2, 86.6, 82.1, 80.8,

76.8, 55.8, 54.4, 43.9, 27.1 ppm. HRMS (EI): calcd. for C₁₀H₁₃O₃

˜

3490, 2956, 2877, 1774, 1459, 1373, 1236, 1150, 1106, 997 cm^–1.

[α]²_D⁴= –35.6, (CHCl₃, c = 0.25). R_f(hexane/EtOAc, 3:1) = 0.57.

Dimer 109: To a degassed solution of 97 (42 mg, 0.06 mmol) in

toluene (120 mL) at reflux temperatures was added catalyst 103

(8 mg, 0.01 mmol) as a solid in one portion. After 20 h, air was

bubbled through the solution for 15 min to destroy the active cata-

lyst. The volatiles were removed and the residue was subjected to

column chromatography, and dimer 109 (10 mg, 0.02 mmol, 25%)

was isolated as a colorless oil. ¹H NMR (CDCl₃, 400 MHz): δ =

5.58–5.54 (m, 1 H), 5.43 (dd, J = 11.7, 2.1 Hz, 1 H), 5.33 (dd, J =

2.5, 1.6 Hz, 1 H), 5.20 (t, J = 1.8 Hz, 1 H), 5.16 (td, J = 8.0, 5.4 Hz,

1 H), 4.69 (s, 1 H), 4.16 (d, J = 4.2 Hz, 1 H), 3.89 (dd, J = 8.8,

5.0 Hz, 1 H), 3.77 (t, J = 4.7 Hz, 1 H), 3.39–3.32 (m, 4 H), 3.11–

3.08 (m, 1 H), 2.57 (d, J = 5.1 Hz, 1 H), 2.45 (ddd, J = 14.7, 7.8,

1.6 Hz, 1 H), 2.09 (s, 3 H), 2.04–1.98 (m, 1 H), 1.94–1.87 (m, 2 H),

1.76–1.70 (m, 1 H), 1.66 (br. s, 4 H), 1.41 (s, 3 H), 0.99 (t, J =

7.9 Hz, 9 H), 0.94 (t, J = 8.0 Hz, 9 H), 0.69 (q, J = 7.8 Hz, 6 H),

0.58 (q, J = 7.9 Hz, 6 H) ppm. ¹³C NMR (CDCl₃, 100 MHz): δ =

174.2, 170.8, 144.2, 135.2, 122.1, 115.8, 109.7, 85.4, 84.5, 83.0, 78.6,

76.2, 70.9, 57.7, 57.0, 55.3, 49.7, 44.8, 39.6, 25.0, 23.4, 21.0, 13.2,

7.12 (3 C), 6.98 (3 C), 6.60 (3 C), 5.01 (3 C) ppm. HRMS (ESI):

calcd. for C₇₀H₁₂₀O₁₈Si₄Na [M + Na]⁺1383.7449; found

[M – CH₃]⁺181.0865; found 181.0862. IR: ν = 3290, 2930, 1632,

˜

1444, 1361, 1270, 1142, 1095, 1031, 916 cm^–1. [α]²_D⁰= –88.7,

(CHCl₃, c = 0.54). R_f(hexane/EtOAc, 3:1) = 0.42.

Poly-cycle 119: To a solution of propargyl ether 115 (66 mg,

0.34 mmol) in CH₂Cl₂(3.5 mL) was added Co₂(CO)₈(133 mg,

0.37 mmol) at 0 °C. The resulting mixture was warmed to room

temperature and stirring was continued for 16 h. The volatiles were

removed under reduced pressure and the crude residue was used

without purification in the next reaction.

To a solution of the crude cobalt complex (12 mg, 0.03 mmol) in

THF (0.5 mL) was added trimethylamine N-oxide (TMANO; 6 mg,

1383.7454. IR: ν = 2956, 2914, 2877, 2369, 1771, 1746, 1373, 1222, 0.08 mmol) at –21 °C. The resulting mixture was warmed to room

˜

Eur. J. Org. Chem. 2013, 8214–8244

www.eurjoc.org

8243

Article Doi

An approach to the carbon backbone of bielschowskysin, part 1: Photocyclization strategy

DOI: 10.1002/ejoc.201300869

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Full text of DOI:10.1002/ejoc.201300869

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