Photochemical and thermal [2 + 2] cycloaddition to generate the bicyclo[3.2.0]heptane core of bielschowskysin

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FULL PAPER

The Bielschowskysin Core

J.-B. Farcet, M. Himmelbauer,

J. Mulzer* ....................................... 1–21

Photochemical and Thermal [2 + 2] Cyclo-

addition to Generate the Bicyclo[3.2.0]-

heptane Core of Bielschowskysin

Various photocycloaddition precursors

have been designed to study both biomi-

metic and non-biomimetic [2 + 2] cycload-

ditions to form the bicyclo[3.2.0]heptane

core of the marine diterpenoid bielschows-

kysin. Additionally, an optimized thermal

approach to aldehyde (–)-55 is described.

Keywords: Total synthesis / Natural prod-

ucts / Terpenoids / Photochemistry / Oxi-

dation

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FULL PAPER

DOI: 10.1002/ejoc.201300382

Photochemical and Thermal [2 + 2] Cycloaddition to Generate the

Bicyclo[3.2.0]heptane Core of Bielschowskysin

[a]

Jean-Baptiste Farcet, Martin Himmelbauer, and Johann Mulzer*

Keywords: Total synthesis / Natural products / Terpenoids / Photochemistry / Oxidation

A bicyclic core fragment of the marine diterpenoid biel-

schowskysin has been synthesized. First, a large library of

precursors for a photochemical [2 + 2] cycloaddition was pre-

pared and tested, but with limited success. In the end, a ther-

mal [2 + 2] cycloaddition followed by appropriate regio- and

stereocontrolled functionalization efficiently gave access to

the desired bicyclo[3.2.0]heptane core. An optimized route to

this remarkable molecular structure is presented.

Introduction

intramolecular [2 + 2] cycloaddition of an “ordinary” di-

terpenoid precursor.

[

3]

Furanocembranoids are diterpenoids that have, to date,

been isolated exclusively from marine sources, in particular

from gorgonian corals. The combination of significant bio-

activity and interesting architectural structures has aroused

the interest of the scientific community over the last decade.

Notwithstanding their wide structural diversity, all mem-

bers seem to be related and have biogenetic intercon-

It has been suggested that exo enol ethers or known cem-

branoids such as sethukarailide (3) or unnamed compound

4

are stable key intermediates in the biosynthesis of more

[1]

complex polycyclic diterpenes. These metabolites could

undergo transannular additions to form a furan-2(5H)-one

moiety en route to more complex furanocembranoids such

as bielschowskysin (1) and verrillin (2; Figure 1).

[

1]

nections. Although bielschowskysin (1) has an uncommon

To design a biomimetic route to bielschowskysin (1), we

investigated the suitability of a nucleophilic insertion into

the furan ring of 5 as a potential precursor in the biosynthe-

sis of bielschowskysin (Scheme 1). However, before starting

with the construction of the complex and fully substituted

furanocembranoid macrocycle, it seemed reasonable to test

[2]

bicyclo[3.2.0]heptane core, it probably originates from an

Figure 1. Furanocembranoid family members.

[

a] University of Vienna, Institute of Organic Chemistry,

Währinger Straße 38, 1090 Vienna, Austria

Fax: +43-1-4277-9521

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

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

Supporting information for this article is available on the

WWW under http://dx.doi.org/10.1002/ejoc.201300382.

Scheme 1. Biosynthesis of bielschowskysin.

2

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The Bicyclo[3.2.0]heptane Core of Bielschowskysin

Scheme 2. Synthesis of a test system. CAN = ceric ammonium nitrate.

the cycloaddition in a model system. Epoxide 10 was cho- precursor (–)-15, readily available from furfuryl alcohol^[⁶^]

sen as a model for the reactivity of 5 (Scheme 2).

(Figure 2).

Results and Discussion

To prepare alcohol 9, Wittig olefination of known alde-

[

4]

hyde 8 was used to generate a trisubstituted double bond.

This was followed by regioselective halogen–metal exchange

with isopropylmagnesium chloride (iPrMgCl) and addition

of the resulting intermediate to isobutyraldehyde to form

secondary alcohol 9. The hydroxy group was protected as

a methoxymethyl (MOM) ether to mimic the acetal group

in the target molecule. When a solution of dimethyldi-

Figure 2. Retrosynthesis based on photo-[2 + 2] cycloaddition.

A protection–deprotection sequence was used to convert

oxirane (DMDO) was added, oxirane 10 was the only prod- (–)-15 into (+)-16, whose esterification with known carbox-

[

7]

[8]

uct formed. By stirring 10 in methanol in presence of pyrid- ylic acid 17 under Mitsunobu conditions delivered ester

inium para-toluenesulfonate (PPTS), compound 12 was iso- (–)-18. However, the desired photo-cyclization to cyclobut-

lated as single product after work-up and chromatographic ane 19 was not observed under various photochemical acti-

purification (Scheme 2). This was not surprising, as Pat- vation conditions (Table 1, entry 3). Instead, malonate (–)-

tenden and co-workers have already reported the formation 20 was isolated in moderate yield (Scheme 3).

[

5]

of intermediate 13 and its rapid isomerization into 12.

Next, we envisaged that compound (–)-27, containing a

The lability of intermediate 13 discouraged us from pur- push–pull system, could be a suitable precursor for the

suing this approach further. Instead, we considered the photo-[2 + 2] reaction. Hence, mixed ester 22 was formed

[

9]

photo-[2 + 2] cycloaddition of enoate 14, which could be quantitatively from potassium malonate 21 and methyl 2-

accessed from known enantiomerically pure prostaglandin bromoacetate. Tetronic acid derivative 23 was obtained as

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FULL PAPER

crystalline tetrabutyl ammonium salt from 22 upon treat- (Scheme 4). As the Mitsunobu protocol failed to deliver es-

ment with TBAF in THF. Methylation followed by debenz- ter (–)-27 directly from alcohol (+)-16 and carboxylic acid

ylation gave carboxylic acid 25 in an excellent overall yield 25, the desired inversion was effected in a two-step pro-

Table 1. Screening of [2 + 2] cyclization substrates and conditions.

4

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The Bicyclo[3.2.0]heptane Core of Bielschowskysin

Table 1. (continued).

[

a] Irradiation conditions: A: UV-A lamps 8 ϫ 16 W, acetone, B: UV-B lamps 8 ϫ 16 W, acetone/CH

filter, pentane/CH Cl , 1:1, D: Sun lamp 750 W, duran filter, acetone, E: Sun lamp 750 W, quartz filter, pentane/CH

50 W, quartz filter, acetone, G: UV-B lamp 2 ϫ 16 W, quartz filter, Et O, H: UV-B lamp 2 ϫ 16 W, quartz filter, Et

I: Sun lamp 750 W, quartz filter, Et O + cat. Cu(OTf) , J: THF, 0 °C 90 min, then room temp. 6 h, K: DCE, room temp. 6 h, then reflux

h. [b] For preparation and characterization, see Supporting Information. [c] Formed in situ, not isolated.

2

Cl

2

, 1:1, C: Sun lamp 750 W, duran

Cl , 1:1, F: Sun lamp

O + cat. Cu(OTf)

2

7

2

,

2

Scheme 3. Synthesis of [2 + 2] precursor (–)-18. TBAF = tetra-n-butylammonium fluoride; TBS = tert-butyldimethylsilyl; b.r.s.m. = based

on recovered starting material.

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Scheme 4. Synthesis of [2 + 2] precursor (–)-27. DIAD = diisopropyl azodicarboxylate; DIC = N,NЈ-diisopropylcarbodiimide; DMAP =

-dimethyl aminopyridine.

4

cedure to give (–)-26 in good yield. Carbodiimide-mediated tected when ketene 43 or ketene iminium salts 46 and 48

esterification eventually gave [2 + 2] precursor (–)-27. Un- (Table 1, entries 12–14) were stirred at room temperature or

fortunately, this substrate only underwent decomposition even heated to reflux.

under photo-cyclization conditions, and polycycle 28 was

On reviewing these results, we suspected that cycload-

not formed (Scheme 4 and Table 1, entry 1). Nevertheless, a dition could have been prevented not only by electronic ef-

broad screening of potential photo-[2 + 2] substrates under fects, but also by conformational issues. Hence, an intermo-

various irradiation conditions was initiated (Table 1).

lecular cycloaddition was performed between alkene (–)-49

When enone (–)-30 (Table 1, entry 2) was used to pro- and an excess of maleic anhydride (Table 1, entry 15) in ace-

mote a stepwise ionic mechanism via zwitterionic interme- tone under UV-A irradiation (conditions A). Tricycle (–)-50

diates, decomposition occurred after a few minutes of UV was formed as a single isomer in satisfactory yield. Next,

irradiation (conditions A and B). Similarly, irradiation of the carbonyl group was exchanged for a methylene group

buta-2,3-dienoic esters (–)-32, (–)-33, (–)-35, (–)-36, and to give more flexibility to the allenic side-chain. Thus,

[

6]

(

–)-38 led to the formation of complex product mixtures, alcohol (+)-44 was alkylated with propargyl bromide in

[

10]

none of which contained the desired tricycle (Table 1, en- quantitative yield. A Searles–Crabbé reaction

gave de-

tries 4–8). Furylacrylic esters (–)-40 and (–)-41 (Table 1, en- sired allene (+)-51, which was unreactive to photoirradia-

tries 9 and 10) were more stable to irradiation, but under tion (conditions A, B, D, F, H, Table 1, entry 16, Scheme 5).

various conditions (conditions A, B, and F) only the start- However, when (+)-51 was converted into enone (+)-52 by

ing material was recovered. Substituted phenyl ester (–)-42 TBAF deprotection and oxidation of the allylic alcohol, ir-

(Table 1, entry 11) did not lead to cycloaddition, even after radiation of (+)-52 with UV-B light led to tricycle (+)-53

a prolonged irradiation time. Our attention turned to ther- as a volatile liquid in good overall yield (Table 1, entry 17,

mally driven [2 + 2] cycloadditions, but no product was de- Scheme 5).

6

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The Bicyclo[3.2.0]heptane Core of Bielschowskysin

rial,^[¹¹^]to give (–)-57. To functionalize the five-membered

[

12]

ring, photooxygenation

with molecular oxygen in the

presence of acetic anhydride and base was chosen. This oxi-

dation was exceptionally easy to carry out, even on a molar

scale, and produced α,β-unsaturated ketone (–)-58 with

high regioselectivity (isomeric ratio: 20:1). Conjugate ad-

dition of dimethyl cuprate and trapping of the enolate with

trimethylsilyl chloride (TMSCl) gave enol ether (–)-59,

[

13]

which was used in a Saegusa–Ito oxidation

to provide

enone (–)-60. The success of this oxidation crucially de-

pended on the use of dimethyl sulfoxide (DMSO) as solvent

and molecular oxygen as co-oxidant. Otherwise, the reac-

tion was difficult to scale up and suffered from inconsistent

yields. Moreover, TMS enol ether (–)-59 was prone to desil-

ylation to form undesired ketone (–)-61. It was shown that

this side-reaction was highly dependent on the batch of pal-

ladium(II) acetate used and, on a larger scale, the ratio of

products (–)-60 and (–)-61 was not reproducible. However,

it was possible to recover (–)-61 by chromatography, and to

reconvert it into (–)-59 in quantitative yield. This procedure

led to a 10% increase in the overall yield (Scheme 6).

Scheme 5. Synthesis of polycycle (+)-53.

From this screening, we concluded that precursors with

a carbonyl group in the position α to the reacting double

bond were unsuitable for intramolecular [2 + 2] photocycli-

zation under various conditions. Nevertheless, an intermo-

lecular cycloaddition seemed possible. More interestingly,

we showed that an intramolecular cycloaddition between

homoallenic ether and enone indeed gave tricyclic core (+)-

53. While further investigations to elaborate this intermedi-

ate were underway, we capitalized on the abundant non-

photochemical availability of functionalized bicyclo[3.2.0]

systems such as (+)-56.^[This compound was used in a

stereocontrolled synthesis of a fully substituted western

11]

[

2d]

fragment (–)-55

of bielschowskysin (1), including its all-

carbon quaternary center (Figure 3). Here, we disclose the

full details of this route, as well as optimized procedures for

nine steps of the sequence.

Scheme 6. Synthesis of enone (–)-60. TMSOTf = trimethylsilyl tri-

fluoromethanesulfonate.

Taking advantage of the “open-book” geometry of bicy-

cle (–)-60, the enone was epoxidized diastereoselectively un-

[

14]

der Scheffer–Weitz conditions.

No conditions could be

found for the opening of epoxide (–)-62 to install the re-

quired tertiary alcohol. For instance, a Wharton transposi-

[

15]

tion

to be highly unstable and impractical for the synthesis. Al-

Figure 3. Retrosynthesis based on a non-photochemical approach. ternatively, the carbonyl group was reduced diastereoselec-

did provide allylic alcohol (–)-63, but it turned out

[

16]

tively under Luche conditions, and the product was pro-

Our synthesis started with TBS protection of enantio- ected with a MOM group to give compound (–)-64. This

merically enriched (+)-56, which was obtained in a four- sequence could be carried out in 85% overall yield from

step sequence from commercially available racemic mate- (–)-57 (Scheme 7).

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

FULL PAPER

To assign the relative configuration by single crystal dif-

fraction, racemic crystalline acetoxy diol rac-71 was pre-

[

18]

pared by an analogous sequence (Scheme 9).

Scheme 7. Synthesis of enone (–)-63 and (–)-64.

Molecular oxygen, a catalytic amount of a cobalt com-

plex, and phenylsilane promoted the Mukaiyama–Isayama

oxidation–reduction–hydration sequence^[¹⁷^]in a regio- and

stereoselective manner, leading to tertiary alcohol (–)-65.

The yield could be increased from 64 to 87% by using a

24 h aqueous workup, a time that presumably allowed the

peroxide intermediate to rearrange and hydrolyse com-

pletely. After an optimized protection–deprotection se-

quence, the five-membered ring in bicycle (–)-66 was appro-

priately substituted, and the installation of the quaternary

center could be envisaged (Scheme 8). Oxidation with 2-

iodoxybenzoic acid (IBX) smoothly formed the ketone,

which underwent a double aldol reaction with formalin to

deliver key intermediate (–)-67. Triethylsilyl (TES) protec-

tion of the two primary alcohols and Petasis’ olefination

gave (–)-68 (Scheme 8). The four-step sequence from (–)-66

Scheme 9. Synthesis and X-ray structure of rac-71.

To form lactone rac-77, the two TES protecting groups

to (–)-68 was performed with a single final purification step, were removed to give diol rac-72. Subsequent Swern oxi-

and allowed a quick and high-yielding substitution of the dation led to dialdehyde rac-73 in excellent yield. However,

bicycle.

during evaporation of the volatiles at bath temperatures

Ͼ30 °C, a decarbonylation with concomitant double-bond

shift was observed, which led exclusively to compound rac-

74. Similarly, Pinnick oxidation of crude dialdehyde rac-73

and subsequent esterification of the product with trimethyl-

silyl diazomethane (TMSCHN ) gave dimethyl ester rac-75

2

and decarboxylated methyl ester rac-76 as a nearly 1:1 mix-

ture. Gratifyingly, dimethyl ester rac-75 could be trans-

formed into lactone rac-77 in good yield (Scheme 10).

After some experimentation, an optimized cascade reac-

tion was developed to create the tricyclic core of bielschow-

skysin directly from (–)-68. Thus, under the acidic condi-

tions of the Jones’ reagent, deprotection of the two TES

protecting groups was followed by oxidation of the resulting

diol to the dicarboxylic acid. Concomitantly, the MOM

protecting group was removed, and lactonization of the re-

sulting alcohol with the cis carboxy group occurred sponta-

neously. Without purification, the free carboxylic acid was

transformed into a mixed carbonate with ethyl chloro-

formate, and this product was reduced with NaBH to give

4

alcohol (–)-78 in 54% overall yield over eight transforma-

tions (Ͼ92% each) starting from (–)-68. Swern oxidation

gave desired aldehyde (–)-55 (Scheme 11).

Scheme 8. Synthesis of olefin (–)-68. acac = acetylacetonate; DBU

=

1,8-diazabicyclo[5.4.0]undec-7-ene; Cp = cyclopentadiene.

8

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The Bicyclo[3.2.0]heptane Core of Bielschowskysin

Scheme 10. Synthesis of bicyclo[3.2.0]heptane lactone rac-77.

Scheme 11. Synthesis of aldehyde (–)-55. Jones’ reagent = CrO

3

, H

2

SO

4

in water; IPA = isopropyl alcohol.

Conclusions

scalable non-photochemical route to aldehyde (–)-55

[Ͼ30% overall yield from known alcohol (+)-56]. This tri-

After screening various substrates to obtain the bicy- cyclic building block bears promising functional groups for

clo[3.2.0]heptane core of bielschowskysin by [2 + 2] photo- connection with an eastern fragment and completion of the

cycloaddition, we developed a stereoselective and optimized total synthesis of bielschowskysin.

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

72.0412; found 272.0413. IR: ν˜ = 3370, 2963, 2872, 1468, 1384,

FULL PAPER

2

1

Experimental Section

–

1

f

142, 1013, 844, 633, 537 cm . R (hexane/EtOAc, 10:1): 0.21.

General Remarks: All moisture- and oxygen-sensitive reactions

were carried out in flame-dried glassware under a slight argon over-

pressure. All solvents (except dichloromethane and methanol) were

purchased as the highest available grade from Sigma–Aldrich,

Acros Organics, or Fischer Chemicals. Anhydrous dichloromethane

was purified by filtration through alumina under argon immedi-

ately before use. Methanol was heated at reflux for several hours

3

-Bromo-5-(3,3-dimethyloxiran-2-yl)-2-[1-(methoxymethoxy)-2-meth-

ylpropyl]furan (10): MOMCl (3.77 mL, 41.7 mmol) was added

dropwise to a solution of alcohol 9 (3.8 g, 13.9 mmol) in DIPEA

2 2

(10 mL) and CH Cl (20 mL) at 0 °C. A few crystals of NaI were

added, and the solution was stirred for 1 h at 0 °C, and then for a

further 20 h at room temp. Water (100 mL) and EtOAc (100 mL)

were added, and the phases were separated. The aqueous phase

was extracted with EtOAc (3ϫ 50 mL), and the combined organic

extracts were washed with brine (30 mL), dried with MgSO

tered, and concentrated under reduced pressure. The residue was

purified by flash chromatography (SiO , hexane/EtOAc, 20:1) to

give the MOM-protected alkene (3.47 g, 79%) as a pale yellow oil.

over sodium and then distilled. NEt

3 2

, iPr NEt, and 2,6-lutidine

were distilled from CaH before use. All other reagents were used

2

4

, fil-

as received from Sigma–Aldrich, Acros Organics, Fischer Chemi-

cals, TCI, or ABCR, unless otherwise stated. Preparative column

chromatography was performed with silica gel 60 from Merck

2

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

1

H NMR (400 MHz, CDCl

H), 4.55 (d, J = 6.8 Hz, 1 H), 4.50 (d, J = 6.9 Hz, 1 H), 4.34 (d, J

8.9 Hz, 1 H), 3.36 (s, 3 H), 2.31–2.17 (m, 1 H), 1.95 (s, 3 H), 1.90

s, 3 H), 1.11 (d, J = 6.6 Hz, 3 H), 0.79 (d, J = 6.8 Hz, 3 H) ppm.

3

): δ = 6.15 (s, 1 H), 6.02–5.98 (m, 1

with Bruker AV400, DRX400, or DRX600 spectrometers. Chemi-

cal shifts are given in ppm and are referenced to the solvent residual

=

(

1

13

3

peaks (CDCl : H, δ = 7.26 ppm; C, δ = 77.16 ppm). Infrared

spectra were recorded as thin films of pure products on an ATR-

unit with a Bruker Vertex 70 instrument. High-resolution mass

spectra were measured with a Bruker MaXis (ESI-TOF) instrument

at a resolution of 10000. A P341 Perkin–Elmer polarimeter

equipped with in a 10 cm cell and a Na lamp (589 nm) was used

for the measurement of optical rotation.

1

3

C NMR (400 MHz, CDCl

01.7, 94.5, 74.8, 55.8, 32.3, 27.2, 20.4, 19.7, 18.7 ppm. HRMS

ESI): calcd. for C14

Br [M]⁺316.0674; found 316.0665. IR:

ν˜ = 2959, 1471, 1386, 1154, 1098, 1032, 971, 923, 784, 561 cm . R

hexane/EtOAc, 10:1): 0.43.

3

): δ = 153.5, 147.8, 137.6, 114.0, 110.3,

1

(

21 3

H O

–

1

f

(

A solution of dimethyldioxirane (2.8 mL, 0.13 mmol) was added to

a magnetically stirred solution of the MOM-protected alkene

1

-[3-Bromo-5-(2-methylprop-1-en-1-yl)furan-2-yl]-2-methylpropan-1-

ol (9): Potassium tert-butoxide (5.7 g, 51.0 mmol) was added in one

portion to a solution of isopropyl(triphenyl)phosphonium iodide

(

0

40 mg, 0.13 mmol) in acetone (1.3 mL) at 0 °C. After 30 min at

°C, the solvent was removed to give pure oxide 10 (42 mg, 99%)

(2.5 g, 56.7 mmol) in THF (200 mL) at 0 °C. 4,5-Dibromofuran-2-

1

as a 1:1 mixture of diastereoisomers. H NMR (400 MHz, CDCl

δ = 6.25 and 6.24 (2 d, J = 0.5 Hz, 1 H), 4.56–4.50 (m, 2 H), 4.33

d, J = 9.0 Hz, 1 H), 3.71 and 3.70 (2 s, 1 H), 3.36 and 3.34 (2 s, 3

H), 2.28–2.17 (m, 1 H), 1.44 and 1.43 (2 s, 3 H), 1.30 (s, 3 H), 1.10

2 d, J = 6.5 Hz, 3 H), 0.79 and 0.76 (2 d, J = 6.8 Hz, 3 H) ppm.

3

):

carbaldehyde (8; 7.20 g, 28.4 mmol) in THF (50 mL) was added

rapidly to the prepared solution. The mixture was stirred at 0 °C

for 60 min, after which TLC indicated complete consumption of

the starting material. Water (300 mL) was then added. The dark

solution was filtered through a pad of Celite, and the phases were

separated. The aqueous phase was extracted with EtOAc (2ϫ

(

13

3

C NMR (400 MHz, CDCl ): δ = 151.3, 150.3, 111.8 and 111.7,

1

5

00.8, 94.7 and 94.6, 74.9, 61.7 and 61.7, 58.7 and 58.6, 55.9 and

1

50 mL). The combined organic extracts were washed with brine

50 mL) and dried with MgSO . SiO (25 g) was added to the solu-

tion before it was concentrated under reduced pressure. The mate-

rial was purified by column chromatography (SiO , hexane) to give

a light yellow oil (6.03 g, 76%) that darkened within a few hours.

5.8, 32.3, 24.2, 19.7 and 19.6, 18.7, 18.6 ppm. HRMS (ESI): calcd.

(

4

2

+

for C15

H

25

O

5

BrNa [M + MeOH + Na] 387.0783; found 387.0796.

IR: ν˜ = 2977, 2871, 1676, 1461, 1370, 1099, 1010, 979, 840,

2

–1

6

f

53 cm . R (hexane/EtOAc, 5:1): 0.34.

1

1-{4-Bromo-5-[1-(methoxymethoxy)-2-methylpropyl]furan-2-yl}-1-

methoxy-2-methylpropan-2-ol (12)

H NMR (400 MHz, CDCl

H), 1.94 (s, 3 H), 1.90 (s, 3 H) ppm. ¹³C NMR (400 MHz,

CDCl ): δ = 155.6, 138.3, 120.2, 113.1, 111.9, 102.8, 27.0, 20.2 ppm.

HRMS (EI): calcd. for C

3

): δ = 6.20 (s, 1 H), 5.95 (m, J = 1.1 Hz,

1

3

Procedure A: PPTS (1 mg) was added to a solution of epoxide 10

(26 mg, 0.08 mmol) in MeOH (0.8 mL), and the solution was

IR: ν˜ = 1780, 1553, 1440, 1267, 1205, 951, 935, 925, 788, 586 cm . stirred at room temp. for 15 min. The reaction mixture was

+

8

H

8

OBr

2

[M] 277.8942; found 277.8940.

–

1

R

f

(hexane/EtOAc, 20:1): 0.93.

quenched with water (1.5 mL) and extracted with EtOAc (3ϫ

mL). The combined organic extracts were washed with brine

5 mL), dried with MgSO , filtered, and concentrated. The residue

was purified over a short column (SiO , hexane/EtOAc, 4:1) to give

5

A solution of dibromoalkene (5.3 g, 19.1 mmol) in THF (200 mL)

was cooled to –35 °C. A solution of isopropylmagnesium chloride

(

4

2

(2 m in ether; 11.5 mL, 23.0 mmol) was added slowly, and the re-

undesired tertiary alcohol 12 (26 mg, 91%) as a 1:1 mixture of dia-

stereoisomers.

sulting solution was stirred at the same temperature for 60 min.

Freshly distilled isobutanal (2.28 mL, 24.8 mmol) was added, and

the reaction mixture was stirred for 4 h at –35 °C, and then it was

Procedure B: Ceric ammonium nitrate (90 mg, 0.16 mmol) was

added to a solution of epoxide 10 (13.6 mg, 0.04 mmol) in MeOH

(2.7 mL). The reaction mixture was stirred for 4 min before being

cautiously quenched with sodium hydrogen carbonate (saturated

aq.; 2 mL). The mixture was diluted with water (5 mL) and EtOAc

(10 mL), and the phases were separated. The aqueous phase was

extracted with EtOAc (2ϫ 20 mL). The combined organic extracts

allowed to warm to room temp. over 3 h. NH

0 mL) was added, and the aqueous phase was extracted with

EtOAc (3ϫ 45 mL). The combined organic extracts were washed

with brine (20 mL) and dried with MgSO . After removal of the

solvent, the crude product was purified by flash chromatography

SiO , hexane/EtOAc, 20:1) to give 9 (4.07 g, 78%) as a colorless

4

Cl (saturated aq.;

4

(

2

1

oil. H NMR (400 MHz, CDCl

H), 4.41 (dd, J = 5.5, J = 8.3 Hz, 1 H), 2.21–2.09 (m, 1 H), 1.95 was purified by column chromatography (SiO

s, 3 H), 1.91 (d, J = 4.6 Hz, 1 H), 1.90 (s, 3 H), 1.09 (d, J = 6.6 Hz, to give undesired tertiary alcohol 12 (13.5 mg, 91%) as a 1:1 mix-

H), 0.82 (d, J = 6.8 Hz, 3 H) ppm. ¹³C NMR (400 MHz, CDCl

): ture of diastereoisomers. H NMR (400 MHz, CDCl

δ = 153.1, 149.7, 137.6, 113.9, 110.6, 99.3, 71.7, 33.8, 27.2, 20.4,

3

): δ = 6.15 (s, 1 H), 6.00–5.97 (m,

were dried with Na

2

SO

4

, filtered, and concentrated. The residue

1

(

3

2

, hexane/EtOAc, 4:1)

1

3

): δ = 6.36

and 6.34 (2 s, 1 H), 4.55 (d, J = 3.8 Hz, 1 H), 4.52 (s, 1 H), 4.34

and 4.32 (2 d, J = 4.0 Hz, 1 H), 3.99 and 3.96 (2 s, 1 H), 3.35 and

12 17 2

9.1, 18.6 ppm. HRMS (ESI): calcd. for C H O

Br [M]⁺

1

10

www.eurjoc.org

Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O30382

/KAP1

Date: 06-06-13 17:14:23

Pages: 21

The Bicyclo[3.2.0]heptane Core of Bielschowskysin

3

(

.34 (2 s, 3 H), 3.32 and 3.30 (2 s, 3 H), 2.45 (br. s, 1 H), 2.29–2.18

m, 1 H), 1.19 and 1.18 (2 s, 3 H), 1.17 and 1.14 (2 s, 3 H), 1.11

and 1.09 (2 d, J = 3.8 Hz, 3 H), 0.78 and 0.76 (2 d, J = 2.6 Hz, 3

H) ppm. ¹³C NMR (400 MHz, CDCl

): δ = 152.8 and 152.4, 150.2

2

was purified by chromatography (SiO , hexane/EtOAc, 5:1 to 0:1)

to give recovered starting material (+)-16 (18 mg, 19%) and ester

1

3

(–)-18 (160 mg, 81%). H NMR (400 MHz, CDCl ): δ = 6.00 (s, 2

3

H), 5.83 (dd, J = 2.9, J = 7.2 Hz, 1 H), 4.67 (d, J = 7.3 Hz, 1 H),

4.60 (s, 4 H), 4.59 (d, J = 7.3 Hz, 1 H), 3.73 (s, 3 H), 3.35 (s, 3 H),

2.54 (dd, J = 7.2, J = 14.6 Hz, 1 H), 1.88 (dd, J = 2.9, J = 14.6 Hz,

and 150.1, 112.9 and 112.2, 100.9 and 100.7, 94.8 and 94.7, 84.6

and 84.4, 75.2 and 75.0, 72.7, 57.9 and 57.7, 55.8, 32.3 and 32.2,

1

3

26.1 and 26.0, 24.6 and 24.4, 19.6, 18.6 ppm. HRMS (ESI): calcd.

1 H), 1.47 (s, 3 H) ppm. C NMR (400 MHz, CDCl

165.5, 165.0, 141.6, 132.4, 92.0, 87.5, 80.9, 78.8, 67.8, 67.7, 55.2,

51.8, 44.1, 27.1 ppm. HRMS (ESI): calcd. for C15 Na [M +

Na] 351.1056; found 351.1048. IR: ν˜ = 2926, 1724, 1686, 1471,

3

): δ = 170.5,

+

for C15

3

25 5

H O BrNa [M + Na] 387.0783; found 387.0797. IR: ν˜ =

–

1

466, 2981, 2877, 2401, 1370, 1137, 1098, 1035, 779, 597 cm . R

f

20 8

H O

+

(hexane/EtOAc, 1:1): 0.42.

–

1

20

1

304, 1270, 1084, 1031, 983, 954 cm . [α]

D

= – 131.8 (c = 1.11,

(1R,4S)-4-(Methoxymethoxy)-4-methylcyclopent-2-enol

[(+)-16]:

CHCl ). R (EtOAc): 0.23.

3

f

iPr

were added to a stirred solution of tertiary alcohol (–)-15 (450 mg,

.97 mmol) in CH Cl (4 mL) at 0 °C. The reaction mixture was

2

NEt (757 μL, 4.33 mmol) and MOMCl (225 μL, 2.96 mmol)

(1R,4R)-4-(Methoxymethoxy)-4-methylcyclopent-2-en-1-yl Methyl

Malonate [(–)-20]: Ester (–)-18 (13 mg, 0.04 mmol) was dissolved in

1

2

2 2

stirred at room temp. until the reaction was complete (after 24 h, degassed Et O (4 mL) in a quartz vial. One crystal of Cu(OTf)

only traces of starting material remained). After slow addition of

NH Cl (saturated aq.; 0.5 mL), the mixture was diluted with water

25 mL) and EtOAc (35 mL), and the phases were separated. The

aqueous phase was extracted with EtOAc (2ϫ 60 mL). The com-

bined organic extracts were dried with MgSO , filtered, and con-

centrated in vacuo. The crude product was purified by flash column

chromatography (SiO , hexane/EtOAc, 20:1) to give methoxy

methyl ether (434 mg, 81%) as a pale yellow oil. H NMR

was added, and the mixture was irradiated with two 16 W UV-B

lamps (Irradiation conditions H) at room temp. for 50 min. The

4

(

solution was diluted with ice (15 g) and NH

extracted with EtOAc. The organic phase was washed with brine

(5 mL), dried with MgSO , filtered, and concentrated. The residue

was purified by chromatography (SiO , hexane/EtOAc, 1:1 to 1:2)

4

OH (0.5 mL), and

4

2

1

2

3

to give undesired (–)-20 (6 mg, 46%). H NMR (400 MHz, CDCl ):

1

δ = 6.03 (dd, J = 5.7, J = 1.0 Hz, 1 H), 5.96 (dd, J = 5.7, J =

2.1 Hz, 1 H), 5.83–5.77 (m, 1 H), 4.66 (d, J = 7.4 Hz, 1 H), 4.57

3

(400 MHz, CDCl ): δ = 5.82 (dd, J = 1.0, J = 5.6 Hz, 1 H), 5.78

(dd, J = 1.9, J = 5.6 Hz, 1 H), 4.75 (d, J = 7.0 Hz, 1 H), 4.71–4.66 (d, J = 7.4 Hz, 1 H), 3.74 (s, 3 H), 3.36 (s, 2 H), 3.34 (s, 3 H), 2.56

(

m, 1 H), 4.65 (d, J = 7.0 Hz, 1 H), 3.35 (s, 3 H), 2.28 (dd, J = 7.1, (dd, J = 7.3, J = 14.7 Hz, 1 H), 1.85 (dd, J = 3.1, J = 14.7 Hz, 1

1

3

J = 13.8 Hz, 1 H), 2.92 (dd, J = 4.5, J = 13.8 Hz, 1 H), 1.33 (s, 3 H),

0

=

–

2

1

H), 1.47 (s, 3 H) ppm. C NMR (400 MHz, CDCl

166.5, 142.3, 131.7, 92.1, 87.3, 80.1, 55.3, 52.6, 44.1, 41.6,

3

): δ = 167.1,

.89 (s, 9 H), 0.07 (2 s, 6 H) ppm. ¹³C NMR (400 MHz, CDCl

138.2, 135.8, 91.9, 86.1, 75.0, 55.2, 47.9, 27.4, 26.0 (3 C), 18.3,

): δ

3

+

27.2 ppm. HRMS (ESI): calcd. for C12

18 6

H O Na [M + Na]

+

4.5 (2 C) ppm. HRMS (ESI): calcd. for C13

H

25

O

3

Si [M – CH ]

281.1001; found 281.1003. IR: ν˜ = 2920, 2852, 1736, 1439, 1349,

–

1

20

57.1573; found 257.1572. IR: ν˜ = 2930, 2858, 1365, 1255, 1100,

1275, 1144, 1029, 641, 597 cm . [α]

D 3

= –95.6 (c = 0.09, CHCl ).

–1

20

039, 836, 632, 534, 504 cm . [α]

D

= + 7.2 (c = 1.00, CHCl

3

). R

f

R (EtOAc): 0.61.

(

hexane/EtOAc, 1:1): 0.57.

Benzyl (2-Methoxy-2-oxoethyl) Malonate (22): Methyl bromoacet-

ate (2.61 mL, 28.4 mmol) was added dropwise to a suspension of

monopotassium carboxylate 21 (6.00 g, 25.8 mmol) in DMF

(51 mL) at 35 °C. The mixture was stirred for 1 h. The solvent was

removed (water bath at 55 °C), and the residue was partitioned

between water (100 mL) and toluene (100 mL). The phases were

separated, and the aqueous phase was extracted with toluene

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

Methoxy methyl ether (381 mg, 1.40 mmol) was dissolved in THF

(9 mL), and TBAF (1 m in THF; 1.82 mL, 1.82 mmol) was added

at 0 °C. The resulting solution was stirred at room temp. for 1 h.

The solvent was evaporated under reduced pressure, and the resi-

due was purified by column chromatography (SiO

2

, hexane/EtOAc,

5

:1) to give free alcohol (+)-16 (205 mg, 93%) as a colorless oil.

Alternatively, the crude methoxy methyl ether could be used di-

rectly to give the product in 90% yield over two steps. H NMR

1

(50 mL), dried with MgSO

pure malonate 22 (6.87 g, 99%). H NMR (400 MHz, CDCl

7.30–7.38 (m, 5 H), 5.20 (s, 2 H), 4.67 (s, 2 H), 3.76 (s, 3 H), 3.54

4

, and concentrated to give analytically

1

(400 MHz, CDCl

3

): δ = 6.10 (dd, J = 2.4, J = 5.5 Hz, 1 H), 5.74

3

): δ =

(d, J = 5.6 Hz, 1 H), 4.91 (d, J = 7.6 Hz, 1 H), 4.64–4.58 (m, 1 H),

1

3

4

2

1

C

2

.59 (d, J = 7.7 Hz, 1 H), 3.39 (s, 3 H), 3.11 (d, J = 9.6 Hz, 1 H),

(s, 2 H) ppm. C NMR (400 MHz, CDCl

3

): δ = 167.6, 165.8,

.24 (dd, J = 7.4, J = 15.0 Hz, 1 H), 2.00 (dd, J = 2.3, J = 14.9 Hz,

165.7, 135.2, 128.6, 128.5, 128.3, 67.4, 61.3, 52.3, 41.0 ppm. HRMS

H), 1.36 (s, 3 H) ppm. ¹³C NMR (400 MHz, CDCl

): δ = 138.1,

37.3, 92.0, 86.5, 75.6, 55.0, 46.9, 27.6 ppm. HRMS (EI): calcd. for

+

3

14 6

(EI): calcd. for C13H O [M] 266.0790; found 266.0784. IR: ν˜ =

–

1

1755, 1737, 1383, 1337, 1274, 1214, 1145, 633, 535, 498 cm . R

f

+

7

H

11

O

3

[M – CH

972, 2891, 1444, 1354, 1220, 1144, 1091, 1035, 773 cm . [α]

115.7 (c = 1.00, CHCl ). R (hexane/EtOAc, 1:1): 0.11.

3

]

143.0708; found 143.0712. IR: ν˜ = 3402,

(hexane/EtOAc, 1:1): 0.40.

–

1

20

D

=

Tetrabutylammonium

4-[(Benzyloxy)carbonyl]-5-oxo-2,5-dihy-

+

3

f

drofuran-3-olate (23): TBAF (1 m in THF; 19.3 mL, 19.3 mmol)

1

-[(1S,4S)-4-(Methoxymethoxy)-4-methylcyclopent-2-en-1-yl]

3- was slowly added to a solution of malonate 22 (3.43 g, 12.9 mmol)

in THF (26 mL) at 0 °C. The resulting solution was stirred at room

temp. for 15 h. The reaction mixture was concentrated, and the

residue was heated to reflux in EtOAc (50 mL). The suspension

was cooled to room temp. The precipitate was filtered off and

Methyl 2-(1,3-Dioxolan-2-ylidene)malonate [(–)-18]: Triphenylphos-

phane (318 mg, 1.2 mmol) was dissolved in THF (3 mL), and the

solution was cooled to 0 °C. DIAD (236 μL, 1.2 mmol) was added

very slowly, and the mixture was stirred for 30 min. At this stage,

a milky precipitate formed. Acid 17 (226 mg, 1.2 mmol) was added

in one portion, and then a solution of alcohol (+)-16 (95 mg,

washed with cold EtOAc (20 mL). After drying under high vac-

1

uum, 23 (4.89 g, 80%) was obtained as pure white crystals.

NMR (400 MHz, CDCl

H

0.60 mmol) in THF (0.5 mL) was added dropwise at 0 °C. The mix-

3

): δ = 7.45 (d, J = 7.3 Hz, 2 H), 7.29–7.23

ture was stirred at the same temperature for 20 h. Water (15 mL)

(m, 2 H), 7.21–7.15 (m, 1 H), 5.24 (s, 2 H), 4.19 (s, 2 H), 3.18–3.10

was added, and the aqueous phase was extracted with EtOAc (3ϫ

(m, 8 H), 1.59–1.48 (m, 8 H), 1.40–1.19 (m, 8 H), 0.95 (t, J =

1

3

20 mL). The combined organic extracts were washed with brine

7.4 Hz, 12 H) ppm. C NMR (400 MHz, CDCl

3

): δ = 193.6, 176.5,

(

15 mL), dried with MgSO , filtered, and concentrated. The residue

4

164.8, 138.9, 128.2 (2 C), 127.2 (2 C), 126.9, 85.0, 70.4, 63.4, 58.8

Eur. J. Org. Chem. 0000, 0–0

www.eurjoc.org

11

Job/Unit: O30382

/KAP1

Date: 06-06-13 17:14:23

Pages: 21

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

FULL PAPER

(

4 C), 24.0 (4 C), 19.8 (4 C), 13.7 (4 C) ppm. HRMS (ESI): calcd.

raphy (SiO

2

, hexane/EtOAc, 2:1) to give alcohol (–)-26 (86 mg,

–

for C12

2

1

H

9

O

5

[M – NBu

4

] 233.0450; found 233.0452. IR: ν˜ = 2959,

82%) as a colorless oil. Alternatively the crude product from the

–1

873, 1742, 1684, 1634, 1432, 1056, 736, 698, 609 cm , m.p. 151– Mitsunobu reaction could be used, which gave the product in 78%

1

53 °C. R

f

(hexane/EtOAc, 1:1): 0.00.

yield over two steps. H NMR (400 MHz, CDCl

3

): δ = 5.96 (dd, J

=

5.6, J = 1.9 Hz, 1 H), 5.86 (dd, J = 5.6, J = 1.2 Hz, 1 H), 5.03–

Benzyl 4-Methoxy-2-oxo-2,5-dihydrofuran-3-carboxylate (24): Am-

monium salt 23 (2.0 g, 4.20 mmol) was dissolved in THF (21 mL).

Dimethyl sulfate (0.42 mL, 4.41 mmol) was added at room temp.,

and the mixture was stirred for 2 h before further dimethyl sulfate

4

2

1

.96 (m, 1 H), 4.59 (dd, J = 31.7, J = 7.3 Hz, 2 H), 3.33 (s, 3 H),

.53 (dd, J = 14.4, J = 7.0 Hz, 1 H), 1.68 (dd, J = 14.3, J = 3.9 Hz,

1

3

H), 1.67 (br. s, 1 H), 1.48 (s, 3 H) ppm. C NMR (400 MHz,

): δ = 138.9, 137.0, 92.0, 87.8, 76.4, 55.2, 47.8, 27.8 ppm.

CDCl

HRMS (ESI): calcd. for C

3

(

1 equiv.) was added. Stirring was continued for a further 3 h, and

then the mixture was concentrated under reduced pressure. The

residue was filtered through a chromatography column (SiO , hex-

ane/EtOAc, 1:1 to 0:1) to give methylated product 24 (928 mg,

+

7

H

11

O

3

[M – CH

3

]

143.0708; found

1

6

1

43.0712. IR: ν˜ = 3371, 2932, 1449, 1356, 1143, 1091, 1030, 918,

34, 537 cm . [α]

:1): 0.45.

2

–

1

20

D 3 f

= –99.4 (c = 1.05, CHCl ). R (hexane/EtOAc,

1

8

9%) as a white solid. H NMR (400 MHz, CDCl

3

): δ = 7.47–7.40

(

m, 2 H), 7.40–7.27 (m, 3 H), 5.30 (s, 2 H), 4.75 (s, 2 H), 4.06 (s, 3

(

1S,4S)-4-(Methoxymethoxy)-4-methylcyclopent-2-en-1-yl 4-Meth-

oxy-2-oxo-2,5-dihydrofuran-3-carboxylate [(–)-27]: Secondary

alcohol (–)-26 (40 mg, 0.25 mmol) and carboxylic acid 25 (96 mg,

.61 mmol) were dissolved in CH Cl (5.1 mL), and the mixture

13

H) ppm. C NMR (400 MHz, CDCl

1

HRMS (ESI): calcd. for C13H O Na [M + Na] 271.0582; found

12 5

2

3

): δ = 182.5, 168.6, 160.8,

35.8, 128.7 (2 C), 128.3, 128.2 (2 C), 97.2, 66.7, 65.1, 59.9 ppm.

+

0

2

71.0583. IR: ν˜ = 1768, 1709, 1623, 1478, 1411, 1338, 1262, 1066,

was cooled to 0 °C. DIC (47 μL, 0.30 mmol) was added, followed

by DMAP (6 mg, 0.05 mmol). The mixture was stirred at 0 °C for

–1

1

025, 606 cm , m.p. 172–173 °C. R

f

(EtOAc): 0.28.

2

h, then it was allowed to warm to room temp., and stirring was

continued overnight. The volatiles were removed, and the residue

was purified by column chromatography (SiO , hexane/EtOAc, 1:1

to 1:2) to give starting material (–)-26 (22 mg, 55%) and ester (–)-

7 (30 mg, 40%, 88% based on recovered starting material) as a

4

-Methoxy-2-oxo-2,5-dihydrofuran-3-carboxylic Acid (25): Benzyl

ester 24 (928 mg, 3.74 mmol) was dissolved in MeOH (75 mL), and

Pd (5% on C; 50 mg) was added under Ar. Then a gentle flow of

H (1 atm) was bubbled through the solution for 60 min at room

2

temp. The heterogeneous mixture was filtered through a Celite pad

2

1

3

colorless oil. H NMR (400 MHz, CDCl ): δ = 6.08–6.00 (m, 2 H),

5.89 (dt, J = 7.2, J = 2.2 Hz, 1 H), 4.74 (s, 2 H), 4.64 (dd, J = 34.3,

J = 7.3 Hz, 2 H), 4.11 (s, 3 H), 3.35 (s, 3 H), 2.58 (dd, J = 14.6, J

and concentrated to give carboxylic acid 25 (587 mg, 99%) as a

_w_h_i_t_e_s_o_l_i_d_t_h_a_t_t_u_r_n_e_d_p_a_l_e_y_e_l_l_o_w_a_f_t_e_r_a_f_e_w_d_a_y_s_.1H NMR

1

3

(

400 MHz, [D

NMR (400 MHz, [D

0.4 ppm. HRMS (EI): calcd. for C

found 140.0108. IR: ν˜ = 2921, 1748, 1615, 1464, 1285, 1145, 1087,

4

]methanol): δ = 5.06 (s, 2 H), 4.15 (s, 3 H) ppm.

C

=

7.2 Hz, 1 H), 1.96 (dd, J = 14.7, J = 3.0 Hz, 1 H), 1.51 (s, 3 H)

4

]methanol): δ = 187.7, 172.9, 163.7, 96.3, 66.7,

1

3

+

ppm. C NMR (400 MHz, CDCl

31.8, 97.6, 92.1, 87.4, 79.7, 65.0, 59.9, 55.3, 44.1, 27.0 ppm.

HRMS (ESI): calcd. for C14

Na [M + Na]⁺321.0950; found

21.0951. IR: ν˜ = 2931, 1771, 1709, 1626, 1413, 1264, 1143, 1028,

3

): δ = 181.7, 168.5, 160.9, 142.4,

6

6 4 4 2

H O [M – H O] 140.0110;

1

–1

18 7

H O

1

059, 903, 701 cm , m.p. 157–159 °C. R

f

(EtOAc): 0.05.

3

6

(1S,4S)-4-(Methoxymethoxy)-4-methylcyclopent-2-enol

[(–)-26]:

–1

20

32, 538 cm . [α]

D 3 f

= –140.6 (c = 0.55, CHCl ). R (EtOAc): 0.22.

Secondary alcohol (+)-16 (133 mg, 0.84 mmol), triphenylphos-

phane (662 mg, 2.52 mmol), and p-nitrobenzoic acid (821 mg,

(

S)-4-Oxocyclopent-2-en-1-yl 4-Methoxy-2-oxo-2,5-dihydrofuran-3-

carboxylate [(–)-30]: Secondary alcohol (–)-29 (40 mg, 0.41 mmol)

and carboxylic acid 25 (77 mg, 0.49 mmol) were dissolved in

2

.52 mmol) were dissolved in THF (4 mL), and the solution was

cooled to 0 °C under Ar. DIAD (480 μL, 2.44 mmol) was added

slowly, and the mixture was stirred for 40 min. The mixture was

diluted with EtOAc (50 mL) and water (30 mL), and the aqueous

phase was extracted with EtOAc (30 mL). The combined organic

CH

DIC (76 μL, 0.49 mmol) was added, followed by DMAP (10 mg,

.08 mmol). The mixture was stirred at 0 °C for 2 h, then it was

2 2

Cl /MeCN (3:1; 4 mL), and the mixture was cooled to 0 °C.

0

allowed to warm to room temp., and stirring was continued over-

night. The volatiles were removed, and the residue was purified by

column chromatography (SiO , hexane/EtOAc, 2:1 to 0:1) to give

2

extracts were washed with NaHCO

0 mL), dried with MgSO , filtered, and concentrated. The residue

was then purified by flash chromatography (SiO , hexane/EtOAc,

:1) to give the para-nitrobenzoic ester (218 mg, 84%) as a clear

3

(15 mL) and brine (2ϫ

2

4

2

starting material (–)-29 (4 mg, 10%) ester (–)-30 (88 mg, 78%) as a

7

1

white solid that turned yellow on contact with air. H NMR

semi-solid. H NMR (400 MHz, CDCl

3

): δ = 8.31–8.22 (m, 2 H),

(400 MHz, CDCl

3

): δ = 7.64 (dd, J = 2.4, J = 5.7 Hz, 1 H), 6.36

8.22–8.14 (m, 2 H), 6.11 (dd, J = 0.7, J = 5.6 Hz, 1 H), 6.09 (dd,

(dd, J = 1.3, J = 5.7 Hz, 1 H), 5.99 (m, 1 H), 4.81 (s, 2 H), 4.12 (s,

J = 2.0, J = 5.6 Hz, 1 H), 6.05–6.00 (m, 1 H), 4.66 (dd, J = 35.9,

J = 7.4, 2 Hz), 3.37 (s, 3 H), 2.69 (dd, J = 14.7, J = 7.2 Hz, 1 H),

3

H), 2.87 (dd, J = 6.3, J = 18.8 Hz, 1 H), 2.44 (dd, J = 2.2, J =

1

3

1

.99 (dd, J = 14.8, J = 3.2 Hz, 1 H), 1.54 (s, 3 H) ppm. ¹³C NMR

18.8 Hz, 1 H) ppm.

3

C NMR (400 MHz, CDCl ): δ = 204.7, 183.5,

1

68.1, 160.3, 158.7, 137.5, 96.6, 72.7, 64.9, 59.8, 41.1 ppm. HRMS

(400 MHz, CDCl

3

): δ = 164.6, 150.7, 142.6, 135.9, 131.7, 130.8 (2

+

(

ESI): calcd. for C11

10 6

H O Na [M + Na] 261.0375; found 261.0377.

C), 123.7 (2 C), 92.1, 87.3, 80.5, 55.3, 44.3, 27.3 ppm. HRMS (ESI):

+

IR: ν = 1766, 1711, 1619, 1479, 1409, 1341, 1261, 1066, 1026,

calcd. for C15

H

17

O

6

NNa [M + Na] 330.0954; found 330.0961. IR:

˜

–

1

20

–

1

794 cm . [α] = 106.8 (c = 0.50, CHCl ), m.p. 148–149 °C. R

ν˜ = 1721, 1608, 1528, 1340, 1271, 1143, 1102, 1031, 842, 720 cm .

D

3

f

20

(EtOAc): 0.25.

α]

The p-nitrobenzoic ester (205 mg, 0.67 mmol) was dissolved in

MeOH (13 mL), and the solution was cooled to 0 °C. K CO

92 mg, 0.67 mmol) was added in one portion, and the mixture was

D 3 f

[ = +158.4 (c = 1.00, CHCl ). R (hexane/EtOAc, 5:1): 0.14.

(1S,4S)-4-(Methoxymethoxy)-4-methylcyclopent-2-en-1-yl Buta-2,3-

dienoate [(–)-32]: Triphenylphosphane (935 mg, 3.57 mmol) was

dissolved in THF (30 mL), and the solution was cooled to 0 °C.

DIAD (702 μL, 3.57 mmol) was added very slowly, and the mixture

was stirred for 30 min. At this stage, a milky precipitate formed.

Allenic acid 31 (300 mg, 3.57 mmol) was added in one portion, and

a solution of alcohol (+)-16 (470 mg, 2.97 mmol) in THF (5 mL)

was then added dropwise at 0 °C. The mixture was stirred at the

same temperature for 2 h. Water (45 mL) was added, and the re-

2

3

(

4

stirred for 35 min before being quenched with NH Cl. Almost all

of the organic solvent was removed under reduced pressure, and

EtOAc (20 mL) was added. The aqueous phase was removed and

extracted with EtOAc (20 mL). The combined organic extracts

were washed with brine (2ϫ 10 mL), dried with MgSO

4

, filtered,

and concentrated. The residue was purified by flash chromatog-

12

www.eurjoc.org

Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O30382

/KAP1

Date: 06-06-13 17:14:23

Pages: 21

The Bicyclo[3.2.0]heptane Core of Bielschowskysin

sulting mixture was extracted with EtOAc (3ϫ 80 mL). The com-

bined organic extracts were washed with brine (50 mL), dried with

0.22 mmol) in THF (0.5 mL) was added to the mixture. The reac-

tion mixture was allowed to warm to room temp. and stirred for

MgSO

4

, filtered, and concentrated. The residue was subjected to

, hexane/EtOAc, 6:1) to give ester

–)-32 (580 mg, 87%). H NMR (400 MHz, CDCl ): δ = 6.00 (dd,

J = 0.8, J = 5.7 Hz, 1 H), 5.96 (dd, J = 2.1, J = 5.7 Hz, 1 H), 5.82–

4

7 h. The reaction was quenched by the addition of NH Cl (satu-

rated aq.; 3 mL). The phases were separated, and the aqueous

phase was extracted with EtOAc (3ϫ 5 mL). The combined organic

column chromatography (SiO

(

2

1

3

extracts were washed with brine (5 mL), dried with MgSO

4

, filtered

5

4

7

.76 (m, 1 H), 5.60 (t, J = 6.5 Hz, 1 H), 5.20 (d, J = 6.6 Hz, 2 H), and concentrated in vacuo. Purification by column chromatog-

.61 (dd, J = 7.3, J = 33.4 Hz, 2 H), 3.33 (s, 3 H), 2.55 (dd, J =

.3, J = 14.6 Hz, 1 H), 1.84 (dd, J = 3.3, J = 14.7 Hz, 1 H), 1.46

2

raphy (SiO , hexane/EtOAc, 3:1) gave product (–)-36 (35 mg, 62%)

as an oil. H NMR (400 MHz, CDCl ): δ = 6.03 (dd, J = 0.7, J =

3

1

(

s, 3 H) ppm. ¹³C NMR (400 MHz, CDCl

3

): δ = 216.0, 165.7, 5.6 Hz, 1 H), 5.97 (dd, J = 2.1, J = 5.7 Hz, 1 H), 5.84–5.80 (m, 1

1

41.7, 132.2, 92.0, 88.14, 87.3, 79.4, 79.3, 55.2, 44.2, 27.2 ppm.

H), 5.21 (t, J = 2.1 Hz, 1 H), 4.62 (dd, J = 7.2, J = 33.8 Hz, 2 H),

4.31 (t, J = 1.8 Hz, 2 H), 3.34 (s, 3 H), 2.55 (dd, J = 7.2, J =

+

HRMS (ESI): calcd. for C11

H

13

O

4

[M – CH

3

]

209.0814; found

2

6

4

09.0808. IR: ν˜ = 2929, 1714, 1450, 1350, 1256, 1163, 1144, 1032,

14.6 Hz, 1 H), 2.48 (br. s, 1 H), 1.85 (dd, J = 3.1, J = 14.7 Hz, 1

H), 1.46 (s, 3 H) ppm. C NMR (400 MHz, CDCl ): δ = 213.3,

3

–1

20

13

32, 535 cm . [α]

D

= –187.3 (c = 1.04, CHCl

3

). R

f

(hexane/EtOAc,

:1): 0.22.

166.7, 142.1, 132.0, 100.0, 92.1, 87.3, 80.5, 79.6, 61.1, 55.3, 44.2,

+

2

1

7.1 ppm. HRMS (ESI): calcd. for C12

15 5

H O [M] 239.0919; found

(S)-4-Oxocyclopent-2-en-1-yl Buta-2,3-dienoate [(–)-33]: Alcohol

39.0906. IR: ν˜ = 3220, 2930, 1713, 1449, 1361, 1214, 1142, 1091,

(–)-29 (100 mg, 1.02 mmol) and carboxylic acid 31 (103 mg,

–1

20

030, 631 cm . [α]

D

= –172.0 (c = 0.27, CHCl

3

). R

f

(hexane/

2 2

1.22 mmol) were dissolved in CH Cl (5.1 mL), and the mixture

EtOAc, 1:1): 0.29.

was cooled to 0 °C. DIC (189 μL, 1.22 mmol) was added, followed

by DMAP (41 mg, 0.20 mmol). The mixture was stirred at 0 °C for

(

1

1S,4S)-4-(Methoxymethoxy)-4-methylcyclopent-2-en-1-yl

Ethoxy Methyl)buta-2,3-dienoate [(–)-38]: Secondary alcohol (+)-

6 (100 mg, 0.63 mmol), triphenylphosphane (232 mg, 0.88 mmol),

2-

2

h, then it was allowed to warm to room temp. and stirring was

continued overnight. The volatiles were removed, and the residue

was purified by chromatography column (SiO , hexane/EtOAc, 1:1

to 1:2) to give ester (–)-33 (100 mg, 60%) as a colorless oil.

NMR (400 MHz, CDCl ): δ = 7.58 (dd, J = 2.5, J = 5.8 Hz, 1 H),

.33 (dd, J = 1.2, J = 5.7 Hz, 1 H), 5.92–5.89 (m, 1 H), 5.64 (t, J

6.5 Hz, 1 H), 5.24 (d, J = 6.5 Hz, 2 H), 2.83 (dd, J = 6.3, J =

and carboxylic acid 37 (180 mg, 1.26 mmol) were dissolved in THF

(6.3 mL), and the solution was cooled to 0 °C under Ar. DIAD

2

1

H

(

174 μL, 0.88 mmol) was slowly added, and the mixture was stirred

for 30 min. The mixture was diluted with EtOAc (30 mL) and water

15 mL), and the aqueous phase was extracted with EtOAc

(30 mL). The combined organic extracts were washed with

NaHCO (15 mL) and brine (2ϫ 15 mL), dried with MgSO , fil-

tered, and concentrated. The residue was then purified by flash

column chromatography (SiO , hexane/EtOAc, 8:1) to give ester

(–)-38 (104 mg, 58%) as a viscous oil. H NMR (400 MHz,

CDCl ): δ = 6.01 (dd, J = 0.7, J = 5.6 Hz, 1 H), 5.98 (dd, J = 2.0,

J = 5.6 Hz, 1 H), 5.82–5.78 (m, 1 H), 5.21 (t, J = 2.2 Hz, 2 H),

.62 (dd, J = 7.4, J = 32.4 Hz, 2 H), 4.18 (t, J = 2.1 Hz, 2 H), 3.53

q, J = 7.0 Hz, 2 H), 3.34 (s, 3 H), 2.53 (dd, J = 7.2, J = 14.6 Hz,

3

6

=

1

(

₈_.₆_H_z_,₁_H₎_,₂_.₃₆₍_d_d_,_J₌₂_.₃_,_J₌₁₈_.₇_H_z_,₁_H₎_p_p_m_.1 C NMR

3

(400 MHz, CDCl ): δ = 216.4, 204.8, 165.2, 158.9, 137.2, 87.5, 79.8,

3

4

+

9 8 3

72.5, 41.1 ppm. HRMS (ESI): calcd. for C H O [M] 164.0473;

found 164.0475. IR: ν˜ = 3451, 2927, 2856, 1713, 1659, 1442, 1362,

2

1

–1

20

1231, 1184, 1102 cm . [α]

D 3 f

= –132.54 (c = 1.00, CHCl ). R (hex-

ane/EtOAc, 1:1): 0.48.

3

(

1S,4S)-4-Hydroxy-4-methylcyclopent-2-en-1-yl Buta-2,3-dienoate

(–)-35]: Triphenylphosphane (172 mg, 0.66 mmol) was dissolved in

THF (6.6 mL), and the solution was cooled to 0 °C. DIAD

129 μL, 0.66 mmol) was added very slowly, and the mixture was

4

(

[

1

=

H), 1.85 (dd, J = 3.1, J = 14.6 Hz, 1 H), 1.46 (s, 3 H), 1.20 (t, J

7.0 Hz, 3 H) ppm. C NMR (400 MHz, CDCl ): δ = 214.6,

3

(

13

stirred for 30 min. At this stage a milky precipitate formed. Allenic

acid 31 (55 mg, 0.66 mmol) was added in one portion, and a solu-

tion of alcohol (–)-34 (75 mg, 0.66 mmol) in THF (1 mL) was then

added dropwise at 0 °C. The mixture was stirred at the same tem-

perature for 2 h. Water (25 mL) was added, and the resulting mix-

ture was extracted with EtOAc (3ϫ 30 mL). The combined organic

1

4

65.8, 141.7, 132.0, 98.3, 91.9, 87.2, 79.5, 79.2, 67.2, 66.0, 55.1,

4.1, 27.0, 15.1 ppm. HRMS (ESI): calcd. for C15 Na [M +

22 5

H O

+

Na] 305.1365; found 305.1359. IR: ν˜ = 2975, 2873, 1967, 1710,

1

CHCl ). R (hexane/EtOAc, 3:1): 0.29.

–1

20

371, 1259, 1143, 1091, 1031, 535 cm . [α]

D

= –115.9 (c = 1.00,

3

f

(

0

E)-(1S,4S)-4-(Methoxymethoxy)-4-methylcyclopent-2-en-1-yl

Furan-2-yl)acrylate [(–)-(40)]: Secondary alcohol (+)-16 (100 mg,

.63 mmol), triphenylphosphane (249 mg, 0.95 mmol), and carbox-

3-

extracts were washed with brine (20 mL), dried with MgSO

tered, and concentrated. The residue was subjected to column

chromatography (SiO , hexane/EtOAc, 2:1) to give ester (–)-35

41 mg, 35%). H NMR (400 MHz, CDCl ): δ = 6.00 (dd, J = 0.9,

J = 5.5 Hz, 1 H), 5.90 (dd, J = 2.3, J = 5.5 Hz, 1 H), 5.85–5.80 (m,

H), 5.60 (t, J = 6.6 Hz, 1 H), 5.21 (d, J = 6.6 Hz, 2 H), 2.38 (dd,

J = 7.1, J = 14.6 Hz, 1 H), 1.98 (dd, J = 3.1, J = 14.6 Hz, 1 H),

4

, fil-

2

1

ylic acid 39 (131 mg, 0.95 mmol) were dissolved in THF (4.2 mL),

and the solution was cooled to 0 °C under Ar. DIAD (187 μL,

(

3

0

2

.95 mmol) was slowly added, and the mixture was stirred for

0 min. The mixture was diluted with EtOAc (20 mL) and water

1

_.₉₁₍_b_r_._s_,₁_H₎_,₁_.₄₈₍_s_,₃_H₎_p_p_m_.1 C NMR (400 MHz, CDCl

3

(15 mL), and the aqueous phase was extracted with EtOAc

40 mL). The combined organic extracts were washed with

NaHCO (10 mL) and brine (2ϫ 20 mL), dried with MgSO , fil-

tered, and concentrated. The residue was purified by flash column

chromatography (SiO , hexane/EtOAc, 6:1) to give ester (–)-40

175 mg, 99%) as a crystalline product. ¹H NMR (400 MHz,

1

3

):

(

δ = 215.9, 165.6, 143.6, 130.8, 88.0, 82.1, 79.3 (2 C), 46.6, 28.6 ppm.

+

3

4

HRMS (ESI): calcd. for C10

12 3

H O [M] 180.0786; found 180.0783.

IR: ν˜ = 3407, 1970, 1942, 1707, 1348, 1256, 1164, 1086, 854,

–1

20

2

6

0

D 3 f

31 cm . [α] = –130.3 (c = 0.95, CHCl ). R (hexane/EtOAc, 1:1):

.26.

(

3

CDCl ): δ = 7.47 (d, J = 1.6 Hz, 1 H), 7.40 (d, J = 15.7 Hz, 1 H),

(1S,4S)-4-(Methoxymethoxy)-4-methylcyclopent-2-en-1-yl

2-(Hy- 6.60 (d, J = 3.5 Hz, 1 H), 6.46 (dd, J = 1.8, J = 3.4 Hz, 1 H), 6.28

droxymethyl)buta-2,3-dienoate [(–)-36]: A solution of DABCO (pre-

dried under vacuum for 30 min; 5 mg, 0.04 mmol) in THF (0.5 mL)

was added dropwise to a suspension of paraformaldehyde (pre-

dried under vacuum at 50 °C for 30 min; 33 mg, 1.12 mmol) in

THF (1 mL) at –10 °C, and then a solution of ester (–)-32 (50 mg,

(d, J = 15.7 Hz, 1 H), 6.03–5.99 (m, 2 H), 5.89–5.84 (m, 1 H), 4.63

(dd, J = 7.3, J = 32.9 Hz, 2 H), 3.35 (s, 3 H), 2.60 (dd, J = 7.3, J

= 14.7 Hz, 1 H), 1.88 (dd, J = 3.3, J = 14.6 Hz, 1 H), 1.50 (s, 3 H)

1

3

ppm. C NMR (400 MHz, CDCl

3

): δ = 166.9, 151.1, 144.9, 141.6,

132.5, 131.3, 116.0, 114.9, 112.4, 92.1, 87.4, 78.8, 55.3, 44.3,

Eur. J. Org. Chem. 0000, 0–0

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13

Job/Unit: O30382

/KAP1

Date: 06-06-13 17:14:23

Pages: 21

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

FULL PAPER

2

1

7.3 ppm. HRMS (EI): calcd. for C15

H

18

O

5

[M]⁺278.1154; found

tracted with EtOAc (3ϫ 5 mL). The combined organic extracts

78.1097. IR: ν˜ = 2930, 1706, 1638, 1448, 1302, 1259, 1209, 1163, were washed with water (10 mL) and brine (10 mL), and then dried

–1

21

110, 1032 cm . [α]

D

= –242.9 (c = 1.50, CHCl

3

), m.p. 74–75 °C,

with MgSO

4

. After filtration, the solvents were removed under re-

, EtOAc) of the re-

R

f

(hexane/EtOAc, 3:1): 0.31.

duced pressure. Column chromatography (SiO

2

sulting yellow oil led neither to the recovery of starting material

nor to the isolation of the desired cyclization product or ketene 43.

(

S,E)-4-Oxocyclopent-2-en-1-yl 3-(Furan-2-yl)acrylate [(–)-(41)]:

Secondary alcohol (–)-29 (500 mg, 5.10 mmol) and carboxylic acid

9 (845 mg, 6.12 mmol) were dissolved in CH Cl (25.5 mL), and

Ketene Iminium Ion 46: A solution of amide (–)-45 (48 mg,

3

2

0

.14 mmol) and collidine (19 μL, 0.14 mmol) in DCE (2.0 mL) was

treated with a solution of triflic anhydride (25 μL, 0.15 mmol) in

CH Cl (0.5 mL) at room temp. The reaction mixture was stirred

the solution was cooled to 0 °C. DIC (947 μL, 6.12 mmol) was

added, followed by DMAP (201 mg, 1.02 mmol). The mixture was

stirred at 0 °C for 2 h, then it was allowed to warm to room temp.,

and stirring was continued overnight. The volatiles were removed

under reduced pressure, and the residue was purified by column

chromatography (SiO , hexane/EtOAc, 6:1 to 4:1) to give ester (–)-

2

4

3

CDCl ): δ = 7.61 (dd, J = 2.5, J = 5.8 Hz, 1 H), 7.48 (d, J = 1.4 Hz,

1

2

at this temperature for 6 h. As no reaction was indicated by TLC,

the reaction vessel was sealed with a stopper and heated to reflux

2 2

for an additional 2 h. Water (5 mL) and then CH Cl (5 mL) were

1

added. The resulting mixture was extracted with CH Cl (3ϫ

1 (788 mg, 71%) as a white crystalline solid. H NMR (400 MHz,

2

5

(

mL). The combined organic extracts were washed with water

10 mL) and brine (10 mL), and then dried over MgSO . After

evaporation of the volatiles, flash column chromatography (SiO

H), 7.44 (d, J = 15.7 Hz, 1 H), 6.64 (d, J = 3.5 Hz, 1 H), 6.47

dd, J = 1.8, J = 3.4 Hz, 1 H), 6.64 (dd, J = 1.3, J = 5.8 Hz, 1 H),

4

,

(

6

2

EtOAc) did not result in isolation of the desired cylization product

or 46.

.29 (d, J = 15.7 Hz, 1 H), 5.98–5.94 (m, 1 H), 2.86 (dd, J = 6.5,

1

3

J = 18.8 Hz, 1 H), 2.39 (dd, J = 2.2, J = 18.8 Hz, 1 H) ppm.

C

NMR (400 MHz, CDCl

3

): δ = 204.9, 166.3, 159.1, 150.6, 15.1,

Ketene Iminium Ion 48: A solution of alcohol (–)-26 (30 mg,

1

37.0, 132.1, 115.5, 114.5, 112.4, 71.9, 41.1 ppm. HRMS (EI):

0

.19 mmol), acid 47 (33 mg, 0.21 mmol), and DMAP (3 mg,

.02 mmol) in CH Cl (1.9 mL) was treated with DIC (35 μL,

.23 mmol) dropwise at 0 °C under an Ar atmosphere. The re-

+

10 4

calcd. for C12H O [M] 218.0579; found 218.0562. IR: ν˜ = 2933,

2

–1

21

1

–

0

D

708, 1635, 1479, 1353, 1282, 1207, 1156, 1016, 753 cm . [α] =

243.1 (c = 4.00, CHCl ), m.p. 80–81 °C, R (hexane/EtOAc, 3:1):

3 f

.21.

sulting pale beige suspension was allowed to warm to room temp.

and stirred for 24 h. As TLC indicated full consumption of the

starting material, ammonium chloride (saturated aq.; 5 mL) was

(

1S,4S)-4-(Methoxymethoxy)-4-methylcyclopent-2-en-1-yl 2-Acet-

oxybenzoate [(–)-42]: Secondary alcohol (+)-16 (100 mg,

.63 mmol), triphenylphosphane (199 mg, 0.76 mmol), and 2-acet-

oxybenzoic acid (137 mg, 0.76 mmol) were dissolved in THF

added to the reaction mixture. After extraction with CH

0 mL), MgSO was added to the combined organic extracts. Fil-

tration followed by removal of the volatiles resulted in a pale yellow

oil, which was purified by column chromatography (SiO , EtOAc)

to give the desired amide (56 mg, quant. yield) as a colorless oil.

2 2

Cl (3ϫ

1

4

0

2

(

6.3 mL), and the solution was cooled to 0 °C under Ar. DIAD

149 μL, 0.76 mmol) was added slowly, and the mixture was stirred

1

H NMR (400 MHz, CDCl

3

): δ = 6.01 (dd, J = 5.6, J = 0.9 Hz, 1

for 40 min. The mixture was diluted with EtOAc (30 mL) and water

H), 5.97 (dd, J = 5.6, J = 2.0 Hz, 1 H), 5.80 (m, 1 H), 4.65 (d, J =

(

15 mL), and the aqueous phase was extracted with EtOAc

50 mL). The combined organic extracts were washed with

7

3

1

3

1

.3 Hz, 1 H), 4.57 (d, J = 7.3 Hz, 1 H), 3.49 (t, J = 6.8 Hz, 2 H),

.43 (t, J = 6.8 Hz, 2 H), 3.36 (s, 2 H), 3.33 (s, 3 H), 2.55 (dd, J =

4.7, J = 7.2 Hz, 1 H), 1.96 (m, 2 H), 1.91–1.84 (m, 3 H), 1.46 (s,

NaHCO

tered, and concentrated. The residue was then purified by flash

column chromatography (SiO , hexane/EtOAc, 6:1) to give ester

–)-42 (106 mg, 52%) and recovered starting material (45 mg, 45%).

3 4

(25 mL) and brine (2ϫ 40 mL), dried with MgSO , fil-

1

3

H) ppm. C NMR (400 MHz, CDCl

3

): δ = 167.6, 164.4, 142.0,

2

32.0, 92.1, 87.3, 79.8, 55.3, 47.3, 46.1, 44.1, 42.7, 27.2, 26.2,

(

+

1

24.6 ppm. HRMS (EI): calcd. for C15

H23NNaO

5

[M + Na]

H NMR (400 MHz, CDCl

3

): δ = 7.97 (dd, J = 1.8, J = 7.9 Hz, 1

3

1

20.1474; found 320.1473. IR: ν˜ = 2973, 2881, 1736, 1646, 1442,

H), 7.54 (dt, J = 1.7, J = 7.8 Hz, 1 H), 7.29 (dt, J = 1.2, J = 7.7 Hz,

–

1

20

D 3

344, 1259, 1144, 1032, 750 cm . [α] = –97.7 (c = 0.60, CHCl ).

1 H), 7.08 (dd, J = 1.2, J = 8.1 Hz, 1 H), 6.07–6.02 (m, 2 H), 5.98–

5.93 (m, 1 H), 4.63 (dd, J = 7.4, J = 34.5 Hz, 2 H), 3.35 (s, 3 H),

2.64 (dd, J = 7.3, J = 14.9 Hz, 1 H), 2.32 (s, 3 H), 1.92 (dd, J =

3

.4, J = 14.8 Hz, 1 H), 1.51 (s, 3 H) ppm. ¹³C NMR (400 MHz,

R

f

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

A solution of amide (56 mg, 0.19 mmol) and collidine (26 μL,

.19 mmol) in DCE (2.0 mL) was treated with a solution of triflic

anhydride (34 μL, 0.21 mmol) in CH Cl (0.5 mL) at room temp.

0

CDCl

3

): δ = 169.7, 164.4, 150.7, 142.0, 133.9, 132.3, 131.9, 126.1,

2

123.9, 123.6, 92.1, 87.3, 79.5, 55.3, 44.3, 27.3, 21.2 ppm. HRMS

The reaction mixture was stirred at this temperature for 6 h. As no

reaction was indicated by TLC, the reaction vessel was sealed with

a stopper and heated to reflux for an additional 2 h. Water (5 mL)

+

(EI): calcd. for C17

20 6

H O Na [M + Na] 343.1158; found 343.1184.

IR: ν˜ = 2932, 1770, 1717, 1607, 1368, 1289, 1191, 1029, 961,

–1

20

9

0

D 3 f

15 cm . [α] = –147.5 (c = 1.00, CHCl ). R (hexane/EtOAc, 3:1):

.32.

and then CH

extracted with CH

were washed with water (10 mL) and brine (10 mL), and then dried

over MgSO . After evaporation of the volatiles, flash column

chromatography (SiO , EtOAc) did not result in isolation of the

2

Cl

2

(5 mL) were added. The resulting mixture was

2

Cl (3ϫ 5 mL). The combined organic extracts

Ketene 43: Et

alcohol (–)-26 (15 mg, 0.09 mmol) in THF (0.5 mL) at 0 °C. After

5 min at this temperature, the resulting clear reaction mixture was

3

N (14 μL, 0.10 mmol) was added to a solution of

4

2

1

desired cyclization product or 48.

slowly added to a pre-formed solution of suboxide at 0 °C [Ketene

preparation: A solution of malonyl dichloride (18 μL, 0.19 mmol)

in THF (0.5 mL) was treated with iPrEt N (35 μL, 0.21 mmol)

2

Anhydride (–)-50: A quartz vial of 1 cm diameter was charged with

cyclopentene (–)-49 (20 mg, 0.06 mmol), maleic anhydride (29 mg,

0.29 mmol), a magnetic stirrer bar and acetone (6.0 mL). The vial

was sealed with a rubber septum and equipped with an argon bal-

loon. The reaction vessel was placed in an ultrasound bath, and

the reaction mixture was degassed by passing a gentle stream of

argon through the solution. After 30 min, the quartz vial was

placed 1 cm in front of 8 ϫ 16 W UV-A lamps, and irradiated for

dropwise at 0 °C. The reaction mixture was kept at this temperature

for 30 min, resulting in an orange suspension]. The resulting sus-

pension was stirred at the same temperature for 90 min, and then

it was allowed to warm to room temp. After 6 h, no starting mate-

rial was left, as indicated by TLC. Water (5 mL) and then EtOAc

(5 mL) were added to the reaction mixture. The mixture was ex-

14

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The Bicyclo[3.2.0]heptane Core of Bielschowskysin

a period of 8 h. After full consumption of the cyclopentene, as

judged by TLC, the solvent was removed under reduced pressure.

The colorless semi-solid was purified by column chromatography

(S)-4-(Buta-2,3-dien-1-yloxy)cyclopent-2-enone [(+)-52]: Compound

(+)-51 (500 mg, 1.88 mmol) was dissolved in THF (2 mL), and

TBAF (1 m in THF; 2.40 mL, 2.40 mmol) was added at room temp.

(

5

SiO

8%) as a colorless oil, which partially crystallized upon storage in

the fridge. During purification by chromatography, as well as upon

dissolving and storing in CDCl , partial hydrolysis of the anhydride

functionality was observed, resulting in a small amount of impurity

2

, hexane/EtOAc, 10:1) to give desired tricycle (–)-50 (15 mg,

After TLC had indicated an almost complete conversion, CH

2 2

Cl

(12 mL) was added. Then MnO (4.89 g, 56.25 mmol) was added,

2

and stirring was continued overnight at room temp. The mixture

was filtered through Celite, and, after gentle evaporation of the

solvent in vacuo, the residue was purified by column chromatog-

3

1

in the NMR spectra. H NMR (400 MHz, CDCl

10.7, J = 7.0 Hz, 1 H), 3.56 (dd, J = 6.5, J = 2.6 Hz, 1 H), 3.51

dd, J = 6.5, J = 3.0 Hz, 1 H), 2.87 (dt, J = 6.7, J = 2.7 Hz, 1 H), 7.61 (dd, J = 2.3,. J = 5.7 Hz, 1 H), 6.26 (dd, J = 1.4, J = 5. 7 Hz,

3

): δ = 4.26 (dt, J

raphy (SiO

2 2

, pentane/Et O, 2:1) to give (+)-52 (164 mg, 58%) as a

1

=

(

volatile greenish-yellow liquid. H NMR (400 MHz, CDCl

3

): δ =

2.62 (dd, J = 6.1, J = 3.0 Hz, 1 H), 2.00 (dd, J = 12.7, J = 6.6 Hz,

1 H), 5.26 (t, J = 6.8 Hz, 1 H), 4.83 (td, J = 2.4, J = 6.6 Hz, 2 H),

1

H), 1.86 (m, 1 H), 1.52 (s, 3 H), 0.89 (s, 9 H), 0.88 (s, 9 H), 0.11

4.78 (m, 1 H), 4.16–4.09 (m, 2 H), 2.69 (dd, J = 5.9, J = 18.3 Hz,

13

(

3

–

s, 3 H), 0.10 (s, 3 H), 0.06 (s, 3 H), 0.05 (s, 3 H) ppm. C NMR 1 H), 2.33 (dd, J = 2.3, J = 18.3 Hz, 1 H) ppm. C NMR

400 MHz, CDCl

3

): δ = 173.9, 173.4, 76.7, 70.2, 51.6, 45.7, 44.5,

8.9, 35.9, 29.8, 29.4, 26.0 (3 C), 25.9 (3 C), 18.2, –2.2, –2.3, –4.7,

4.8 ppm. HRMS (EI): calcd. for C23 44NaO Si [M + MeOH +

= –127.8 (c = 0.75, CHCl ).

IR: ν˜ = 2973, 2879, 1875, 1834, 1642, 1601, 1332, 1269, 1144,

(400 MHz, CDCl

67.7, 41.8 ppm. HRMS (ESI): calcd. for C

150.0681; found 150.0699. IR: ν˜ = 2926, 2856, 1719, 1351, 1184,

3

): δ = 209.5, 205.8, 161.0, 135.8, 87.5, 76.5, 76.1,

+

9 10 2

H O Na [M + Na]

H

6

2

+

20

–1

20

Na] 495.2574; found 495.2592. [α]

D

3

1105, 1074, 996, 849, 792 cm . [α]

D 3 f

= +5.14 (c = 1.23, CHCl ). R

(Pentane/Et O, 2:1) : 0.20.

2

–1

f

834 cm . R (hexane/EtOAc, 6:1): 0.58.

(

3aS)-1-Methylenehexahydro-3-oxacyclobuta[cd]pentalen-5(1a1H)-

one [(+)-53]: Enone (+)-52 (30 mg, 0.21 mmol) was dissolved in di-

ethyl ether (6 mL). The solution was irradiated with UV-B light

under 2 ϫ 16 W lamps (Irradiation conditions G) in a quartz vial

for 6 h. After TLC indicated partial conversion, the solvent was

removed under reduced pressure. The residue was purified by flash

tert-Butyldimethyl{[(1R,4S)-4-(prop-2-yn-1-yloxy)cyclopent-2-en-

-yl]oxy}silane [(+)-54]: A solution of (+)-44 (1.00 g, 4.66 mmol) in

THF (3.5 mL) was added to a suspension of NaH (450 mg,

8.66 mmol) in THF (3.5 mL) at 0 °C. The mixture was allowed to

warm to room temp., and after the evolution of H had subsided,

the mixture was cooled again to 0 °C. Propargyl bromide (80 wt.-

in toluene; 1.51 mL, 13.99 mmol) was then slowly added, and

the reaction mixture was stirred overnight while it warmed to room

temp. The reaction was quenched with water (10 mL) and extracted

with EtOAc (3ϫ 20 mL). The combined organic extracts were

washed with brine (15 mL) and water (15 mL), and dried with

1

2

chromatography (pentane/Et

as a volatile liquid. H NMR (400 MHz, CDCl ): δ = 5.16 (m, 1

2

O, 2:1) to give (+)-53 (18 mg, 60%)

1

3

%

H), 5.00 (m, 1 H), 4.66 (t, J = 5.7 Hz, 1 H), 4.00 (d, J = 9.1 Hz, 1

H), 3.70 (dd, J = 4.2, J = 9.1 Hz, 1 H), 3.61–3.56 (m, 1 H), 3.49–

3

.44 (m, 1 H), 3.38–3.34 (m, 1 H), 2.70 (d, J = 18.2 Hz, 1 H), 2.54

1

3

(

ddd, J = 0.6, J = 5.0, J = 18.2 Hz, 1 H) ppm. C NMR (400 MHz,

CDCl ): δ = 214.1, 145.2, 111.7, 79.3, 73.9, 51.8, 48.7, 48.3,

2.7 ppm. HRMS (EI): calcd. for C

150.0692. IR: ν˜ = 2965, 2831, 1747, 1291, 1114, 1056, 1001, 943,

3

MgSO

4

, and the solvent was removed in vacuo. Purification by

, hexane/EtOAc, 15:1) gave (+)-54

+

4

9 10 2

H O [M] 150.0681; found

chromatography column (SiO

2

1

(1.38 g, 99%) as a slightly viscous liquid. H NMR (400 MHz,

–

1

21

8

2

D 3 f 2

19, 732 cm . [α] = +12.1 (c = 0.90, CHCl ). R (pentane/Et O,

3

CDCl ): δ = 5.97–5.90 (m, 2 H), 4.67 (m, 1 H), 4.56 (m, 1 H), 4.17

:1): 0.14.

(dd, J = 2.4, J = 4.1 Hz, 2 H), 2.69 (td, J = 7.2, J = 13.4 Hz, 1 H),

2

.41 (t, J = 2.4 Hz, 1 H), 1.60 (td, J = 5.3, J = 13.4 Hz, 1 H), 0.98

[

(1S,5R,6S)-Bicyclo[3.2.0]hept-2-en-6-yloxy](tert-butyl)dimethyl-

silane [(–)-57]: TBSCl (9.36 g, 59.0 mmol) was added to a solution

of alcohol (+)-56 (5.00 g, 45.4 mmol) in anhydrous CH Cl (91 mL)

at 0 °C under Ar, and then Et N (10.1 mL, 72.6 mmol) and DMAP

277 mg, 2.30 mmol) were added. The reaction mixture was allowed

to warm to room temp. overnight. NH Cl (saturated aq.; 50 mL)

was added. The mixture was diluted with CH Cl (50 mL), washed

in sequence with HCl (0.5 m; 40 mL), water (40 mL), and brine (2ϫ

0 mL), and dried with MgSO . The volatile materials were re-

moved under reduced pressure to give a crude product. Purification

by column chromatography (SiO , hexane) gave protected alcohol

13

(

s, 9 H), 0.83 (s, 3 H), 0.79 (s, 3 H) ppm. C NMR (400 MHz,

CDCl ): δ = 138.0, 132.2, 81.2, 80.4, 74.8, 74.0, 55.6, 41.2, 25.9 (3

C), 18.1, –4.6 (2 C) ppm. HRMS (EI): calcd. for C10 Si [M –

tBu] 195.0841; found 195.0841. IR: ν˜ = 2955, 2931, 2857, 1372,

3

2

15 2

H O

3

+

(

–1

20

1253, 1081, 1059, 905, 837, 777 cm . [α]

D

= +32.7 (c = 1.05,

4

CHCl ). R (hexane/EtOAc, 3:1): 0.48.

3

f

2

{

[(1R,4S)-4-(Buta-2,3-dien-1-yloxy)cyclopent-2-en-1-yl]oxy}(tert-

5

4

butyl)dimethylsilane [(+)-51]: Paraformaldehyde (416 mg,

1

2

3.85 mmol), DIPA (1.0 mL, 7.13 mmol), and CuBr (331 mg,

2

.31 mmol) were sequentially added to a solution of alkyne (+)-54

1

(

–)-57 (9.52 g, 94 %) as a colorless oil. H NMR (400 MHz,

(1.17 g, 4.38 mmol) in dioxane (30 mL). The reaction mixture was

3

CDCl ): δ = 5.85–5.75 (m, 2 H), 4.51–4.44 (m, 1 H), 3.14–3.04 (m,

heated at reflux overnight. After the reaction was complete (TLC

monitoring), the solvent was removed in vacuo. The residue was

1

H), 2.92–2.80 (m, 2 H), 2.64–2.54 (m, 1 H), 2.36–2.26 (m, 1 H),

.64–1.56 (m, 1 H), 0.88 (s, 9 H), 0.02 (s, 3 H), 0.00 (s, 3 H) ppm.

purified by column chromatography (SiO

0:1) to give (+)-51 (1.04 g, 84%) as a slightly yellow oil. H NMR

400 MHz, CDCl ): δ = 5.94–5.87 (m, 2 H), 5.25 (d, J = 6.8 Hz, 1

2

, hexane/EtOAc, 1:0 to

13

C NMR (400 MHz, CDCl

9.1, 31.5, 26.0 (3 C), 18.3, –4.7 (2 C) ppm. HRMS (EI): calcd. for

15_O_S_i_[_M_–_t_B_u_]+ 167.0892; found 167.0890. IR: ν˜ = 2930,

3

): δ = 134.6, 133.0, 65.6, 44.1, 40.8,

1

2

(

3

C H

9

2

(

3

H), 4.78 (td, J = 2.5, J = 6.6 Hz, 1 H), 4.66 (m, 1 H), 4.42 (m, 1

H), 4.05 (m, 1 H), 2.67 (td, J = 7.2, J = 13.2 Hz, 1 H), 1.58 (td, J

=

–1

22

857, 1709, 1471, 1254, 1125, 1004, 879, 837, 777 cm . [α]

D

= –0.2

c = 1.0, CHCl ). R (hexane): 0.49.

3

f

5.6, J = 13.2 Hz, 1 H), 0.89 (s, 9 H), 0.08 (s, 1 H), 0.08 (s, 1 H)

13

ppm. C NMR (400 MHz, CDCl

3

): δ = 209.2, 137.5, 132.7, 88.2,

(1R,5R,6S)-6-[(tert-butyldimethylsilyl)oxy]bicyclo[3.2.0]hept-3-en-2-

one [(–)-58]: A solution of alkyne (–)-57 (9.36 g, 41.7 mmol), acetic

anhydride (4.34 mL, 45.9 mmol), pyridine (1.69 mL, 20.9 mmol),

81.1, 75.6, 74.9, 66.3, 41.5, 25.9 (3 C), 18.2, –4.6 (2 C) ppm. HRMS

+

(

26 2

ESI): calcd. for C15H O SiNa [M + Na] 289.1600; found

2

8

1

89.1592. IR: ν˜ = 2955, 2931, 2857, 1368, 1253, 1079, 940, 905, DMAP (305 mg, 2.50 mmol), and tetraphenylporphyrin (25.6 mg,

–1

20

37, 777 cm . [α]

D

= +10.4 (c = 0.85, CHCl

3

). R

f

(hexane/EtOAc,

41.7 μmol) in CH

2

Cl

2

(52 mL) was irradiated with a halogen lamp

was bubbled con-

5:1): 0.49.

(500 W) for 7 d under vigorous stirring while O

2

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

FULL PAPER

tinuously through the solution. The mixture was diluted with

CH Cl (100 mL), washed in sequence with NaHCO (saturated

aq.; 50 mL), water (50 mL), CuSO (saturated aq.; 50 mL), and

brine (50 mL), and dried with MgSO . The volatile materials were

removed under reduced pressure to give crude enone (–)-58 (10.0 g,

00%) as a dark red oil containing Ͻ5% of starting material. An

aliquot was purified by column chromatography (SiO , hexane/

EtOAc, 5:1) for analytical purposes. H NMR (400 MHz, CDCl ):

δ = 7.66 (dd, J = 2.8, J = 5.6 Hz, 1 H), 6.39 (dd, J = 1.1, J =

H), 0.00 (s, 3 H) ppm. ¹³C NMR (400 MHz, CDCl

177.4, 132.3, 65.2, 51.9, 38.2, 34.9, 25.7 (3 C), 19.9, 17.9, –4.77,

–5.05 ppm. HRMS (ESI): calcd. for C14

Si [M]⁺252.1546;

3

): δ = 211.9,

2

3

4

24 2

H O

4

found 252.1548. IR: ν˜ = 2929, 2857, 1698, 1613, 1253, 1183, 1117,

–

1

20

D

955, 838, 778 cm . [α]

3 f

= –238.0 (c = 1.0, CHCl ). R (hexane/

1

EtOAc, 3:1): 0.32.

2

1

Data for ketone (–)-61: H NMR (400 MHz, CDCl

3

): δ = 4.43 (q,

1

3

J = 7.2 Hz, 1 H), 2.85–2.73 (m, 2 H), 2.73–2.55 (m, 2 H), 2.55–

.45 (m, 1 H), 2.00–1.90 (m, 2 H), 1.06 (d, J = 6.6 Hz, 3 H), 0.88

2

5.6 Hz, 1 H), 4.58 (q, J = 7.7 Hz, 1 H), 3.68–3.62 (m, 1 H), 2.84–

1

3

(

s, 9 H), 0.04 (s, 3 H), 0.02 (s, 3 H) ppm. C NMR (400 MHz,

CDCl ): δ = 220.9, 64.6, 50.9, 47.2, 39.6, 36.3, 27.3, 25.9 (3 C),

1.6, 18.1, –4.6, –4.9 ppm. HRMS (EI): calcd. for C13 Si [M –

239.1467; found 239.1465. IR: ν˜ = 2954, 2857, 1735, 1252,

2

.74 (m, 1 H), 2.60–2.52 (m, 1 H), 1.84–1.76 (m, 1 H), 0.86 (s, 9

13

3

H), 0.05 (s, 3 H), 0.01 (s, 3 H) ppm. C NMR (400 MHz, CDCl

3

):

2

23 2

H O

δ = 212.3, 162.7, 136.8, 65.3, 49.4, 36.9, 35.4, 25.8 (3 C), 18.1, –4.7,

+

3

CH ]

1

–

2

8

5

4.9 ppm. HRMS (ESI): calcd. for C13

22 2

H O Si 238.1389; found

–

1

25

187, 1118, 949, 887, 837, 777 cm . [α]

D 3

= –96.4 (c = 1.0, CHCl ).

38.1389. IR: ν˜ = 2953, 2857, 1706, 1252, 1183, 1122, 949, 870,

R

f

(hexane/EtOAc, 4:1): 0.24.

–1

25

37, 777 cm . [α]

D 3 f

= –179.5 (c = 1.0, CHCl ). R (hexane/EtOAc,

:1): 0.25.

(1R,2R,4R,6R,8S)-8-[(tert-Butyldimethylsilyl)oxy]-2-methyl-3-

oxatricyclo[4.2.0.02,4]octan-5-one [(–)-62]: Enone (–)-60 (150 mg,

Optimized Procedure for TMS Enol Ether (–)-59

Procedure A, From Enone (–)-58: MeLi (1.6 m in Et

0.59 mmol) was dissolved in MeOH (6.1 mL), and the solution was

2

O; 336 mL,

03 mmol) was slowly added to a suspension of CuI (47.9 g,

52 mmol) in anhydrous Et O (840 mL) at 0 °C. The resulting solu-

cooled to –20 °C. NaOH (1 m aq.; 179 μL, 0.179 mmol) was added,

followed by the dropwise addition of hydrogen peroxide (30 wt.-%;

750 μL). The reaction mixture was allowed to warm to 0 °C. After

1 h at this temperature, the reaction was quenched with HCl (0.5 m

5

2

tion was stirred at 0 °C for 30 min and then cooled to –78 °C. A

solution of enone (–)-58 (60.0 g, 252 mmol) in Et O (100 mL) was

2

2 2 3

aq.; 2 mL) and Na S O (saturated aq.; 5 mL). The solution was

slowly added to the solution over 25 min. The mixture was stirred

for 1 h at –78 °C and then warmed quickly to 0 °C. TMSCl

diluted with water (40 mL) and EtOAc (60 mL), the phases were

separated, and the aqueous phase extracted with EtOAc (60 mL).

(

39.9 mL, 315 mmol) was rapidly added, followed immediately by The combined organic extracts were washed with brine (40 mL),

Et N (43.8 mL, 315 mmol). The mixture was stirred for 16 h at 0 °C dried with MgSO , filtered and concentrated. The crude product

and then ether (300 mL) and water (300 mL) were slowly added. (160 mg, 99%) was used without further purification. H NMR

The organic phase was extracted with NH OH (10 % aq.; 3 ϫ (400 MHz, CDCl ): δ = 4.49–4.40 (m, 1 H), 3.35 (s, 1 H), 3.17 (t,

00 mL), water (3 ϫ 150 mL), and brine (200 mL), dried with

3

4

1

4

3

1

J = 6.8 Hz, 1 H), 2.75–2.64 (m, 1 H), 2.60–2.53 (m, 1 H), 1.77 (ddt,

J = 1.1, J = 4.1, J = 12.8 Hz, 1 H), 1.63 (s, 3 H), 0.86 (s, 9 H), 0.04

4

MgSO , and filtered. The volatiles were removed to give pure TMS

enol ether (–)-59 (82.2 g, quantitative).

1

3

(s, 3 H), 0.01 (s, 3 H) ppm. C NMR (400 MHz, CDCl

3

): δ =

2

–

2

1

11.0, 65.9, 64.2, 63.8, 47.4, 38.8, 35.2, 25.8 (3 C), 18.0, 16.8, –4.6,

Procedure B, From Ketone (–)-61: TMSOTf (17.2 mL, 95.1 mmol)

+

5.0 ppm. HRMS (ESI): calcd. for C14

H

24

O

3

SiNa [M + Na]

and Et

of ketone (–)-61 (12.1 g, 47.6 mmol) in anhydrous Et

at 0 °C. The mixture was stirred for 16 h at 0 °C and then NaHCO

3

N (23.2 mL, 166 mmol) were slowly added to a suspension

91.1392; found 291.1383. IR: ν˜ = 2931, 2587, 1743, 1399, 1254,

2

O (237 mL)

–

1

22

124, 1070, 922, 834, 776 cm . [α]

D 3 f

= –32.8 (c = 1.00, CHCl ). R

3

(

hexane/EtOAc, 5:1): 0.45.

(1R,2S,5S,7S)-7-[(tert-Butyldimethylsilyl)oxy]-2-methylbicyclo-

[3.2.0]hept-3-en-2-ol [(–)-63]: N ·H O (27 μL, 0.56 mmol) and

(saturated aq.; 500 mL) was added. The aqueous phase was ex-

2

tracted with Et O (2ϫ 250 mL), and the combined organic extracts

were washed with water (2ϫ 150 mL) and brine (200 mL), dried

with MgSO , and filtered. The volatiles were removed to give pure

2

H

4

2

4

AcOH (80 μL, 1.40 mmol) were added to a solution of epoxide

(–)-62 (75 mg, 0.28 mmol) in MeOH (3 mL) at 0 °C. After 5 min at

this temperature, TLC showed no remaining starting materials, and

the hydrazine intermediate and a new product spot had appeared.

The mixture was stirred for a further 15 min. The mixture was then

heated to reflux for 2 h. Then water (5 mL) was added. The solu-

TMS enol ether (–)-59 (15.4 g, 99%).

Optimized Procedure for Enone (–)-60: Crude TMS enol ether (–)-

5

9 (82.2 g, 252 mmol) was dissolved in DMSO (840 mL), and the

solution was warmed to 32 °C and saturated with oxygen by bub-

bling gas through the solution for 10 min. Under an O atmo-

sphere, Pd(OAc) (28.2 g, 126 mmol) was added in one portion.

2

tion was neutralized with NaHCO

5 mL). The combined organic extracts were washed with brine

15 mL) and dried with MgSO . Removal of the solvent by rotary

evaporation and purification by flash column chromatography

hexane/EtOAc, 6:1) gave tertiary alcohol (–)-63 (29 mg, 40%) as

3

and extracted with EtOAc (3ϫ

2

1

(

After 3 h, the reaction mixture was filtered through Celite (10 cm

thick). The filtrate was diluted with EtOAc (400 mL), and the fil-

tration through Celite (10 cm thick) was repeated. A mixture of

water (200 mL) and crushed ice (200 g) was added with vigorous

agitation. After separation of the phases, the organic phase was

washed with water (2ϫ 100 mL). The combined aqueous phases

were extracted with EtOAc (3ϫ 200 mL). The organic extracts were

combined, washed with water (3ϫ 100 mL) and brine (100 mL),

4

(

1

an unstable colorless oil. H NMR (400 MHz, CDCl

3

): δ = 5.93

dd, J = 2.4, J = 5.3 Hz, 1 H), 5.80 (d, J = 5.3 Hz, 1 H), 4.58–4.48

m, 1 H), 3.09–3.00 (m, 1 H), 2.91–2.83 (m, 1 H), 2.59–2.49 (m, 1

(

H), 1.62 (s, 3 H), 1.56–1.44 (m, 2 H), 0.86 (s, 9 H), 0.02 (s, 3 H),

1

3

0.00 (s, 3 H) ppm. C NMR (400 MHz, CDCl

3

): δ = 140.0, 136.7,

dried with MgSO

NMR analysis showed a 4:1 mixture of enone (–)-60 and ketone

–)-61. Compounds (–)-60 and (–)-61 were separated by column

chromatography (hexane/EtOAc, 20:1 then 5:1) to give ketone (–)-

1 (12.1 g, 19%) and enone (–)-60 (51.4 g, 81%). Data for enone

4

, and concentrated under reduced pressure.

85.4, 65.8, 54.7, 39.2, 38.6, 29.7, 25.8 (3 C), 24.1, –3.6, –4.8 ppm.

+

HRMS (ESI): calcd. for C14

H

26

O

2

SiNa [M + Na] 277.1600; found

(

2

8

5

77.1583. IR: ν˜ = 2998, 2787, 1319, 1124, 1099, 1021, 977, 902,

–

1

20

74, 736 cm . [α]

D 3 f

= –5.9 (c = 1.2, CHCl ). R (hexane/EtOAc,

6

:1): 0.17.

1

3

(–)-60: H NMR (400 MHz, CDCl ): δ = 6.09 (s, 1 H), 4.61 (q, J

=

7.7 Hz, 1 H), 3.50–3.44 (m, 1 H), 2.79–2.69 (m, 1 H), 2.59–2.52 Alkene (–)-64: Cerium chloride heptahydrate (5.79 g, 15.6 mmol)

was added to a stirred solution of enone (–)-60 (3.27 g, 13.0 mmol)

(m, 1 H), 2.19 (s, 3 H), 1.81–1.73 (m, 1 H), 0.85 (s, 9 H), 0.04 (s, 3

16

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The Bicyclo[3.2.0]heptane Core of Bielschowskysin

in MeOH (65 mL) at room temp. After 5 min, the mixture was

cooled to 0 °C, and NaBH (539 mg, 14.3 mmol) was added por-

4

tionwise. The reaction mixture was stirred at 0 °C until the starting

material had been completely consumed (30 min). The reaction was

quenched by the addition of acetic acid (1:1 in water; 5 mL). Water

ture was diluted with water (100 mL) and diethyl ether (200 mL).

The phases were separated, and the aqueous phase was extracted

with diethyl ether (2ϫ 150 mL). The organic phases were dried

with Na

2

SO

4

, filtered, and concentrated under vacuum. The resi-

, hexane/EtOAc,

due was purified by column chromatography (SiO

2

(

100 mL) and EtOAc (150 mL) were added, and the heterogeneous

15:1) to give the di-TBS-protected alcohol (25.5 g, quantitative)

contaminated with TBS-OH and 2,6-lutidine. H NMR (400 MHz,

CDCl ): δ = 4.61 (d, J = 6.6 Hz, 1 H), 4.57 (d, J = 6.6 Hz, 1 H),

3

1

mixture was extracted with EtOAc (4ϫ 80 mL). The organic phase

was washed with water (2ϫ 75 mL) and brine (2ϫ 50 mL). The

combined organic extracts were dried with MgSO

was removed under reduced pressure to give crude allylic alcohol

3.30 g, quantitative) as a viscous oil.

4

, and the solvent

4.45–4.32 (m, 2 H), 3.34 (s, 3 H), 2.70–2.63 (m, 1 H), 2.70–2.54 (m,

1 H), 2.28–2.17 (m, 1 H), 2.07–1.97 (m, 3 H), 1.48 (s, 3 H), 0.88 (s,

9 H), 0.83 (s, 9 H), 0.07 (s, 3 H), 0.05 (s, 3 H), 0.02 (s, 3 H), 0.01

(

1

3

(

6

1

s, 3 H) ppm. C NMR (400 MHz, CDCl

3

): δ = 96.3, 82.2, 79.7,

5.0, 55.9, 55.5, 45.6, 33.7, 30.3, 26.0 (3 C), 25.9 (3 C), 24.9, 18.2,

8.1, –2.0, –2.2, –4.6, –5.0 ppm. HRMS (ESI): calcd. for C22

The crude alcohol (3.30 g, 12.9 mmol) was dissolved in CH

2

Cl

NEt (6.78 mL, 38.9 mmol) and MOMCl

2.45 mL, 32.3 mmol) were added at 0 °C. The reaction mixture

2

(

43 mL), and iPr

2

46 4-

H O

+

SiNa [M + Na] 453.2832; found 453.2813. IR: ν˜ = 2929, 2856,

1

was stirred at room temp. for 15 h. After the addition of water

100 mL) and CH Cl (150 mL), the organic phase was washed

with NaHCO (5% aq.; 75 mL) and brine (3ϫ 60 mL), then dried

with MgSO , filtered, and concentrated in vacuo. The crude prod-

uct was purified by column chromatography (SiO , hexane/EtOAc,

–1

24

253, 1108, 1076, 1043, 1001, 939, 832, 772 cm . [α]

D

= –9.3 (c =

(

2

1

.0, CHCl ). R (hexane/EtOAc, 5:1): 0.61.

3

f

3

4

The crude residue was dissolved in THF (116 mL), and the solution

was cooled to 0 °C. Then, TBAF (1 m in THF; 69.6 mL,

69.6 mmol) was added over 15 min. The reaction mixture was al-

lowed to warm slowly to room temp. overnight, and then the vola-

2

1

2

0:1) to give alkene (–)-64 (3.29 mg, 85%) as a colorless oil. H

3

NMR (400 MHz, CDCl ): δ = 5.41 (br. s, 1 H), 4.80 (dq, J = 1.7,

J = 7.1 Hz, 1 H), 4.62 (d, J = 6.7 Hz, 1 H), 4.57 (d, J = 6.7 Hz, 1 tiles were removed under reduced pressure at 30 °C. The residue

H), 4.27 (q, J = 7.7 Hz, 1 H), 3.36 (s, 3 H), 3.19 (br. s, 1 H), 2.55– was purified by column chromatography (SiO , hexane/EtOAc, 3:1)

to give alcohol (–)-66 (17.1 g, 93%). H NMR (400 MHz, CDCl ):

2

1

2

3

.45 (m, 1 H), 2.32–2.22 (m, 1 H), 2.20–2.11 (m, 1 H), 1.83 (br. s,

H), 0.87 (s, 9 H), 0.03 (s, 3 H), 0.02 ppm. ¹C NMR (400 MHz,

3

δ = 4.60 (d, J = 6.6 Hz, 1 H), 4.57 (d, J = 6.6 Hz, 1 H), 4.53–4.42

CDCl

3

): δ = 144.0, 127.4, 96.3, 85.0, 65.4, 55.6, 55.3, 32.3, 31.7,

(m, 1 H), 4.40–4.31 (m, 1 H), 3.33 (s, 3 H), 2.69–2.57 (m, 2 H),

2

C

2

8

6.0 (3 C), 18.2, 17.1, –4.5, –4.8 ppm. HRMS (ESI): calcd. for 2.35–2.25 (m, 1 H), 2.11–1.97 (m, 3 H), 1.68 (d, J = 3.7 Hz, 1 H),

+

13

16

H

30

O

3

Si Na [M + Na] 321.1862; found 321.1866. IR: ν˜ = 2929,

1.50 (s, 3 H), 0.82 (s, 9 H), 0.07 (s, 3 H), 0.05 (s, 3 H) ppm.

NMR (400 MHz, CDCl ): δ = 96.3, 81.9, 79.6, 65.0, 55.5, 55.4,

45.9, 33.7, 28.9, 25.8 (3 C), 24.9, 18.1, –2.0, –2.2 ppm. HRMS

ESI): calcd. for C16

SiNa [M + Na]⁺339.1968; found

C

–

1

24

857, 2361, 2342, 1375, 1254, 1122, 1042, 835, 776 cm . [α]

1.4 (c = 1.1, CHCl ). R (hexane/EtOAc, 5:1): 0.55.

D

=

3

f

(

32 4

H O

Optimized Procedure for Alcohol (–)-65: Co(acac)

2

(741 mg,

.88 mmol) was added to a solution of alkene (–)-64 (8.60 g,

8.8 mmol) in THF (300 mL) in a 2 L flask at room temp. The

(40 min), and then

(14.2 mL, 115 mmol) was added over 45 min using a sy-

ringe pump, while a gentle flow of O was blown 5 cm above the

well-stirred solution. The O flow was reduced, and stirring was

3

8

3

39.1961. IR: ν˜ = 3444, 2930, 2856, 1461, 1252, 1107, 1036, 995,

2

–1

20

D 3 f

32, 772 cm . [α] = –34.8 (c = 1.0, CHCl ). R (hexane/EtOAc,

:1): 0.30.

reaction mixture was then saturated with O

PhSiH

2

3

Optimized Procedure for Diol (–)-67: Alcohol (–)-66 (8 g,

25.3 mmol) was dissolved in EtOAc (168 mL), and IBX (14.1 g,

50.6 mmol) was added to the solution. The heterogeneous mixture

was heated to reflux for 3 h and then cooled to room temp. Hexane

(150 mL) was added, and stirring was continued for 15 min. The

suspension was filtered through a Celite pad (3 cm), and the filtrate

was concentrated to give the ketone (7.90 g, 99 %). ¹H NMR

2

maintained for 15 h at room temp. The reaction mixture was di-

luted with EtOAc (250 mL), water (100 mL), and saturated

NaHCO (100 mL), and stirred for a further 24 h. The organic

3

phase was separated, and the aqueous phase was extracted with

EtOAc (3ϫ 200 mL). The aqueous phase was saturated with solid

NaCl and further extracted with EtOAc (2ϫ 200 mL). The com-

bined organic extracts were dried with MgSO

under reduced pressure. The residue was purified by flash column

chromatography (SiO , hexane/EtOAc, 3:1) to give tertiary alcohol

3

(400 MHz, CDCl ): δ = 4.65 (s, 2 H), 4.63–4.55 (m, 1 H), 4.43–

4.37 (m, 1 H), 3.35 (s, 3 H), 3.19–3.11 (m, 1 H), 3.10–3.00 (m, 1

H), 2.95–2.86 (m, 1 H), 2.15 (ddd, J = 1.9, J = 6.4, J = 13.0 Hz, 1

H), 1.63 (dd, J = 11.1, J = 13.0 Hz, 1 H), 1.38 (s, 3 H), 0.84 (s, 9

4

and concentrated

1

3

2

1

H), 0.10 (s, 36 H), 0.08 (s, 3 H) ppm. C NMR (400 MHz, CDCl

): δ = 4.60 (d, J δ = 209.1, 96.5, 79.5, 78.9, 76.0, 55.7, 45.3, 45.2, 31.4, 25.8 (3 C),

6.4 Hz, 1 H), 4.57 (d, J = 6.4 Hz, 1 H), 4.48–4.36 (m, 2 H), 3.34 24.5, 18.0, –2.2, –2.5 ppm. HRMS (ESI): calcd. for C16 SiNa

3

):

(–)-65 (7.93 g, 87%). H NMR (400 MHz, CDCl

3

=

(

30 4

H O

s, 3 H), 2.69–2.55 (m, 2 H), 2.29–2.20 (m, 1 H), 2.18–2.09 (m, 1 [M + Na]⁺337.1811; found 337.1804. IR: ν˜ = 2929, 2856, 1777,

–

1

20

H), 2.08–1.96 (m, 2 H), 1.49 (s, 3 H), 1.24 (br. s, 1 H), 0.88 (s, 9 1253, 1147, 1109, 1042, 833, 773, 696 cm . [α]

D

= –151.6 (c = 1.4,

13

H), 0.02 (s, 3 H), 0.01 (s, 3 H) ppm. C NMR (400 MHz, CDCl

δ = 96.1, 79.7, 78.9, 64.7, 55.5, 55.4, 44.5, 33.5, 30.3, 26.0 (3 C),

5.5, 18.2, –4.6, –5.0 ppm. HRMS (EI): calcd. for C16 SiNa

_M₊_N_a_]+ 339.3968; found 339.3964. IR: ν˜ = 3405, 2955, 2884,

3 3 f

): CHCl ). R (hexane/EtOAc, 2:1): 0.55.

DBU (11.2 mL, 75.4 mmol) was slowly added to a solution of crude

ketone (7.90 g, 25.1 mmol) in formalin (65 mL). A cold water bath

was used to avoid a slight increase of temperature. The water bath

was then warmed to 30 °C, and the solution was stirred vigorously

for a further 30 min. The reaction mixture was diluted with water

2

[

2

32 4

H O

–1

24

362, 1254, 1132, 1044, 869, 867, 777 cm . [α]

D

= –1.73 (c = 1.1,

CHCl

3

). R (hexane/EtOAc, 2:1): 0.25.

f

Optimized Procedure for Alcohol (–)-66: Alcohol (–)-65 (18.3 g, (120 mL) and EtOAc (200 mL), and the aqueous phase was ex-

7.8 mmol) was dissolved in THF (290 mL), and the solution was tracted with EtOAc (6ϫ 80 mL). The combined organic extracts

were washed with brine (40 mL), dried with MgSO , and concen-

5

cooled to 0 °C. 2,6-Lutidine (26.9 mL, 231 mmol) and then

TBSOTf (26.6 mL, 116 mmol) were rapidly added to the reaction

vessel, and the mixture was stirred at 0 °C for 15 min. The reaction

4

trated under reduced pressure to give diol (–)-67 (10.1 g, quantita-

tive) contaminated with polymethylene ether derivatives. H NMR

1

was quenched by the addition of NaHCO

3

(150 mL), and the mix-

(400 MHz, CDCl

3

): δ = 4.79–4.70 (m, 3 H), 4.11 (d, J = 12.9 Hz,

Eur. J. Org. Chem. 0000, 0–0

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17

Job/Unit: O30382

/KAP1

Date: 06-06-13 17:14:23

Pages: 21

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

FULL PAPER

1

9

H), 3.92 (d, J = 11.2 Hz, 1 H), 3.87–3.78 (m, 2 H), 3.49 (d, J = the starting material had been completely consumed (30 min). The

.6 Hz, 1 H), 3.42 (dd, J = 2.0, J = 7.5 Hz, 1 H), 3.39 (s, 3 H), 3.20 reaction was quenched by the addition of a few drops of acetic acid

(t, J = 7.7 Hz, 1 H), 2.83 (br. s, 1 H), 2.28 (ddd, J = 2.0, J = 6.5, (50% aq.) to reach neutral pH. Water (30 mL) and EtOAc (50 mL)

J = 12.6 Hz, 1 H), 1.71 (t, J = 12.3 Hz, 1 H), 1.42 (s, 3 H), 0.85 (s,

were added, and the heterogeneous mixture was extracted with

EtOAc (4ϫ 20 mL). The combined organic extracts were washed

1

3

9

H), 0.11 (s, 3 H), 0.10 (s, 3 H) ppm. C NMR (400 MHz,

CDCl

3

): δ = 210.0, 97.3, 80.6, 80.0, 71.5, 71.4, 67.3, 61.9, 55.9, 46.9, with water (2 ϫ 15 mL) and brine (2 ϫ 15 mL), and dried with

MgSO . The solvent was removed under reduced pressure to give

39.8, 25.8 (3 C), 24.5, 18.1, 0.0, –0.2 ppm. HRMS (ESI): calcd. for

4

+

C

18

H

34

O

6

SiNa [M + Na] 397.2022; found 397.2022. IR: ν˜ = 3416,

the crude allylic alcohol as a viscous oil.

–1

25

2929, 2856, 1766, 1254, 1153, 1109, 1001, 835, 774 cm . [α]

D

=

Acetic anhydride (394 μL, 4.15 mmol), pyridine (448 μL,

5

–91.6 (c = 1.05, CHCl ). R (hexane/EtOAc, 1:1): 0.25.

3

f

.54 mmol), and 4-(dimethylamino)pyridine (34 mg, 0.28 mmol)

were added to a solution of the crude alcohol (705 mg, 2.77 mmol)

in CH Cl (28 mL) at 0 °C. The solution was allowed to warm to

room temp. overnight. The mixture was diluted with CH Cl

(12 mL), washed in sequence with NaHCO (saturated aq.; 15 mL),

water (15 mL), and brine (10 mL), and dried with MgSO . The

volatile materials were removed by evaporation to give the crude

product. Purification over a short column (SiO , hexane/EtOAc,

20:1) gave acetate rac-69 (673 mg, 82%) as a colorless oil. H NMR

(400 MHz, CDCl ): δ = 5.66–5.61 (m, 1 H), 5.41 (br. s, 1 H), 4.29

(q, J = 7.7 Hz, 1 H), 3.22 (t, J = 6.6 Hz, 1 H), 2.77–2.65 (m, 1 H),

3

): δ = 4.80–4.72 (m, 1 2.17–2.09 (m, 2 H), 2.03 (s, 3 H), 1.88–1.84 (m, 3 H), 0.87 (s, 9 H),

Optimized Procedure for Alkene (–)-68: Imidazole (8.55 g,

1

2

26 mmol) was added to a solution of crude diol (–)-67 (10.1 g,

5.1 mmol) in CH Cl (251 mL) at 0 °C, and then neat TESCl

2

(

9.28 mL, 55.3 mmol) was added. The resulting mixture was al-

lowed to warm slowly to room temp. overnight before it was

quenched with NaHCO (saturated aq.; 120 mL). The aqueous

phase was extracted with CH Cl (2ϫ 80 mL). The combined or-

ganic extracts were washed with water (3 ϫ 90 mL) and brine

50 mL), dried with MgSO , and concentrated under reduced pres-

sure to give the desired ketone (17.2 g, quantitative) contaminated

3

4

3

2

1

(

4

3

1

with TES-OH. H NMR (400 MHz, CDCl

H), 4.71 (d, J = 6.6 Hz, 1 H), 4.56 (d, J = 6.6 Hz, 1 H), 3.98 (d, J

1

3

0.03 (s, 3 H), 0.02 (s, 3 H) ppm. C NMR (400 MHz, CDCl

3

): δ

=

10.5 Hz, 1 H), 3.91 (d, J = 10.5 Hz, 1 H), 3.86 (d, J = 9.3 Hz, 1 = 171.3, 146.2, 125.4, 82.65, 65.14, 55.18, 31.99, 31.49, 26.00 (3

H), 3.81 (d, J = 9.3 Hz, 1 H), 3.36 (s, 3 H), 3.27 (dd, J = 2.0, J =

C), 21.11, 18.21, 17.16, –4.61, –4.81 ppm. HRMS (EI): calcd. for

+

7

.6 Hz, 1 H), 3.12 (t, J = 7.6 Hz, 1 H), 2.11 (ddd, J = 2.2, J = 6.4,

J = 12.6 Hz, 1 H), 1.76 (t, J = 12.3 Hz, 1 H), 1.41 (s, 3 H), 0.95 (t,

J = 8.0 Hz, 9 H), 0.94 (t, J = 8.0 Hz, 9 H), 0.84 (s, 9 H), 0.62–0.53 EtOAc, 5:1): 0.54.

16 28 3

C H O Si Na [M + Na] 319.1705; found 319.1678. IR: ν˜ = 2929,

–

1

f

2858, 1735, 1372, 1242, 1123, 1021, 872, 836, 777 cm . R (hexane/

13

(m, 12 H), 0.09 (s, 3 H), 0.08 (s, 3 H) ppm. C NMR (400 MHz,

Alcohol rac-70: Co(acac)

of acetate rac-69 (100 mg, 0.34 mmol) in THF (6 mL). The reaction

mixture was then saturated with O (20 min), and then PhSiH

166 μL, 1.35 mmol) was added over 15 min. Stirring was continued

2

(18 mg, 67 μmol) was added to a solution

CDCl ): δ = 212.3, 96.0, 79.4, 78.4, 73.0, 71.3, 65.0, 60.2, 55.3,

3

4

–

6

1

7.7, 39.0, 25.8 (6 C), 24.7, 18.1, 6.9 (3 C), 4.5 (6 C), –2.3,

_N_a_[_M₊_N_a_]+

2

3

2.6 ppm. HRMS (ESI): calcd. for C30

62 6 3

H O Si

(

25.3752; found 625.3740. IR: ν˜ = 2954, 2877, 1772, 1461, 1085,

–1

25

2

under a static O atmosphere for 15 h at room temp. The reaction

046, 1003, 834, 805, 740 cm . [α]

D 3 f

= –113.6 (c = 1.0, CHCl ). R

mixture was then diluted with EtOAc (15 mL), washed with

NaHCO (10 mL), water (10 mL), and brine (10 mL), dried with

MgSO , and concentrated under reduced pressure. The residue was

purified by flash column chromatography (SiO , hexane/EtOAc,

5:1) to give tertiary alcohol rac-70 (71 mg, 67%) as a colorless oil.

(hexane/EtOAc, 1:1): 0.75.

3

Cp TiMe (19 wt.-% in toluene; 54.7 mL, 42.7 mmol) was mixed

2

4

with the carbonyl compound (17.2 g, 25.1 mmol) and the mixture

was stirred under argon at 65 °C for 3 d. The mixture was diluted

with hexane (150 mL), stirred for 30 min, and then cooled in the

fridge overnight. The resulting yellow-orange precipitate was re-

moved by filtration (two or three filtrations were required), and the

filtrate was concentrated. The residue was purified by flash column

2

1

3

H NMR (400 MHz, CDCl ): δ = 5.34–5.26 (m, 1 H), 4.48–4.40

(m, 1 H), 2.85–2.77 (m, 1 H), 2.66–2.59 (m, 1 H), 2.30–2.15 (m, 2

H), 2.13–2.06 (m, 1 H), 2.03 (s, 3 H), 1.94–1.86 (m, 1 H), 1.50 (s,

3 H), 1.18 (br. s, 1 H), 0.89 (s, 9 H), 0.03 (s, 3 H), 0.02 (s, 3 H)

1

3

chromatography (SiO

2

, hexane/EtOAc, 20:1) to give alkene (–)-68

ppm. C NMR (400 MHz, CDCl

3

): δ = 171.0, 79.6, 76.3, 64.7,

1

(

14.2 g, 94 %, 93 % over 4 steps) as a colorless oil. H NMR 55.1, 43.6, 33.4, 30.2, 26.0 (3 C), 25.2, 21.2, 18.2, –4.7, –4.9 ppm.

+

400 MHz, CDCl

.1 Hz, 1 H), 4.69 (d, J = 6.4 Hz, 1 H), 4.60–4.52 (m, 1 H), 4.49

d, J = 6.4 Hz, 1 H), 3.96 (d, J = 10.1 Hz, 1 H), 3.87 (d, J = 9.3 Hz,

3

): δ = 5.15 (d, J = 2.7 Hz, 1 H), 4.82 (d, J =

HRMS (ESI): calcd. for C16

30 4

H O SiNa [M + Na] 337.1811; found

2

(

337.1821. IR: ν˜ = 3420, 2930, 2857, 1737, 1374, 1250, 1131, 1041,

–

1

f

837, 778 cm . R (hexane/EtOAc, 1:1): 0.48.

1

3

2

H), 3.84 (d, J = 10.2 Hz, 1 H), 3.40 (d, J = 9.3 Hz, 1 H), 3.33 (s,

H), 3.01–2.96 (m, 1 H), 2.86 (t, J = 7.2 Hz, 1 H), 2.00–1.86 (m,

H), 1.38 (s, 3 H), 0.96 (t, J = 7.9 Hz, 9 H), 0.95 (t, J = 7.9 Hz, 9

Diol rac-71: TBAF (1 m in THF; 159 μL, 0.16 mmol) was added to

a stirred solution of alcohol rac-70 (50 mg, 0.16 mmol) in THF

(

2 mL) at 0 °C. The solution was allowed to warm to room temp.,

and after stirring for 1 h, the reaction was quenched by the addition

of NaHCO (saturated aq.; 10 mL). The mixture was diluted with

water (30 mL) and Et O (50 mL). The phases were separated, and

the aqueous phase was extracted with Et O (2ϫ 20 mL). The or-

ganic phases were combined, dried with Na SO , filtered, and con-

centrated to give a colorless oil. This residue was purified by flash

column chromatography (SiO , hexane/EtOAc, 1:1) to give diol

rac-71 (27 mg, 85%), which crystallized from CHCl as a colorless

): δ = 5.31 (dt, J = 7.1, J =

H), 0.84 (s, 9 H), 0.54 (q, J = 7.9 Hz, 6 H), 0.54 (q, J = 7.9 Hz, 6

_H₎_,₀_.₀₉₍_s_,₃_H₎_,₀_.₀₇₍_s_,₃_H₎_p_p_m_.1 C NMR (400 MHz, CDCl

δ = 155.2, 112.1, 97.6, 83.5, 80.2, 68.5, 64.3, 57.9, 57.5, 54.9, 48.4,

5.1, 28.5 (3 C), 26.4, 20.3, 9.2 (3 C), 9.2 (3 C), 6.9 (3 C), 6.9 (3

C), 0.0, –0.1 ppm. HRMS (ESI): calcd. for C31 Si Na [M +

Na] 623.3959; found 623.3952. IR: ν˜ = 2954, 2878, 1461, 1253,

3

):

3

2

4

2

H

64

O

5

3

+

2

4

–1

25

1072, 1046, 1004, 836, 773, 742 cm . [α]

D 3

= –60.5 (c = 1.0, CHCl ).

2

R

f

(hexane/EtOAc, 40:1): 0.26.

3

1

Acetate rac-69: Cerium chloride heptahydrate (1.24 g, 3.33 mmol)

was added to a stirred solution of crude enone rac-60 (700 mg,

plates. H NMR (400 MHz, CDCl

3

10.4 Hz, 1 H), 4.53 (q, J = 8.1 Hz, 1 H), 2.90–2.80 (m, 1 H), 2.66–

2.77 mmol) in MeOH (14 mL) at room temp. After 5 min, the mix-

2.58 (m, 1 H), 2.38–2.27 (m, 1 H), 2.24–2.10 (m, 2 H), 2.03 (s, 3

4

ture was cooled to 0 °C, and NaBH (115 mg, 3.05 mmol) was H), 1.99–1.90 (m, 1 H), 1.64 (br. s, 1 H), 1.53 (s, 3 H), 1.33 (br. s,

1

3

added portionwise. The reaction mixture was stirred at 0 °C until

3

1 H) ppm. C NMR (400 MHz, CDCl ): δ = 171.0, 79.4, 76.2,

18

www.eurjoc.org

Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O30382

/KAP1

Date: 06-06-13 17:14:23

Pages: 21

The Bicyclo[3.2.0]heptane Core of Bielschowskysin

4.7, 54.6, 43.7, 33.2, 28.7, 25.6, 21.2 ppm. HRMS (EI): calcd. for

6

140.4, 95.8, 78.0, 74.0, 59.0, 55.4, 44.5, 43.9, 25.8 (3 C), 25.6, 18.2,

+

C

10

H

16

O

4

Na [M + Na] 223.0946; found 223.0937. IR: ν˜ = 3367,

15.4, –2.1, –2.1 ppm. HRMS (EI): calcd. for C18

H

32

O

4

SiNa [M +

–1

+

2

1

925, 1714, 1377, 1264, 1173, 1107, 1039, 853, 612 cm , m.p. 117– Na] 363.1968; found 363.1962. IR: ν˜ = 2928, 2855, 1678, 1254,

20 °C. R

–

1

f

(EtOAc): 0.40.

1150, 1101, 1040, 918, 860, 772 cm . R

Dimethyl Ester rac-75: A solution of dialdehyde rac-73 (40 mg,

.11 mmol) and 2-methylbutene (300 μL) in tBuOH (1.4 mL) was

cooled to 0 °C, then a solution of NaClO (122 mg, 1.09 mmol)

and NaH PO (180 mg, 1.30 mmol) in water (1 mL) was added.

The mixture was stirred for 30 min. The solution was diluted with

NH Cl (aq.; 15 mL) and extracted with Et O (2ϫ 30 mL). The

combined organic extracts were washed with brine (15 mL), dried

with MgSO , and concentrated. The crude dicarboxylic acid was

dissolved in benzene/MeOH (3:2; 2 mL), and then TMSCHN (2 m

in Et O; 200 μL, 0.40 mmol) was added slowly at 0 °C. The solu-

f

(hexane/EtOAc, 2:1): 0.49.

{

(1R,2S,4S,5S)-2-[(tert-Butyldimethylsilyl)oxy]-4-(methoxymeth-

oxy)-2-methyl-7-methylenebicyclo[3.2.0]heptane-6,6-diyl}dimethanol

(–)-72]: HF (70 % in pyridine; 269 μL, 9.22 mmol) was slowly

0

[

2

added to a solution of (–)-68 (277 mg, 0.46 mmol) in THF (3 mL)

in a teflon vial at 0 °C. The mixture was stirred for 30 min at the

same temperature, after which time TLC analysis indicated a clean

2

4

2

conversion. The reaction was carefully quenched with NaHCO

3

(

saturated aq.; 10 mL) and the mixture was extracted with EtOAc

3 ϫ 30 mL). The combined organic extracts were washed with

, concentrated

under reduced pressure, and purified by column chromatography

SiO , hexane/EtOAc, 2:1) to give diol (–)-72 (170 mg, 99%) as a

viscous colorless oil. H NMR (400 MHz, CDCl

1.9 Hz, 1 H), 4.83 (d, J = 2.5 Hz, 1 H), 4.71 (d, J = 6.6 Hz, 1

H), 4.69 (d, J = 6.6 Hz, 1 H), 4.64–4.55 (m, 1 H), 4.05 (d, J =

4

(

2

water (30 mL) and brine (50 mL), dried with MgSO

4

2

tion was stirred at this temperature for 2 h, and then it was allowed

to warm to room temp. overnight. After concentration, the residue

(

2

1

was purified by column chromatography (SiO , hexane/EtOAc,

): δ = 4.88 (d, J

2

3

15:1) to give an inseparable mixture (39 mg) containing dimethyl

=

ester rac-75 (23 mg, 50%) and methyl ester rac-76 (16 mg, 40%).

1

Data for rac-75: H NMR (400 MHz, CDCl

3

): δ = 5.37 (dd, J =

1

3

1.9 Hz, 1 H), 3.80 (dd, J = 3.1, J = 11.1 Hz, 1 H), 3.77–3.63 (m,

H), 3.37 (s, 3 H), 3.20 (br. d, J = 7.0 Hz, 1 H), 3.07–2.98 (m, 2

0

4

3

.8, J = 2.7 Hz, 1 H), 5.21 (dd, J = 0.9, J = 2.1 Hz, 1 H), 4.68–

.60 (m, 1 H), 4.58 (d, J = 6.6 Hz, 1 H), 4.46 (d, J = 6.6 Hz, 1 H),

.83 (t, J = 7.4 Hz, 1 H), 3.74 (s, 3 H), 3.67 (s, 3 H), 3.32 (s, 3 H),

H), 2.12 (ddd, J = 1.4, J = 6.4, J = 13.4 Hz, 1 H), 1.86 (t, J =

2.0 Hz, 1 H), 1.37 (s, 3 H), 0.84 (s, 9 H), 0.10 (s, 3 H), 0.08 (s, 3

1

13

3.10–3.04 (m, 1 H), 2.12 (t, J = 12.0 Hz, 1 H), 1.99–1.91 (m, 1 H),

H) ppm. C NMR (400 MHz, CDCl

3

): δ = 151.0, 108.8, 97.1, 81.6,

0.8, 71.7, 65.7, 55.9, 55.1, 52.2, 45.6, 43.9, 25.8 (3 C), 24.0, 18.1,

2.2, –2.3 ppm. HRMS (ESI): calcd. for C19 SiNa [M +

1

3

1.42 (s, 3 H), 0.84 (s, 9 H), 0.09 (s, 3 H), 0.08 (s, 3 H) ppm.

C

8

–

3

NMR (400 MHz, CDCl ): δ = 170.1, 169.3, 143.6, 115.4, 95.8, 81.3,

36 5

H O

+

77.1, 59.2, 58.1, 56.4, 53.2, 52.3, 44.9, 44.2, 25.8 (3 C), 23.7, 18.1,

Na] 395.2230; found 395.2219. IR: ν˜ = 3435, 2929, 1462, 1372,

+

–1

20

–2.2, –2.3 ppm. HRMS (EI): calcd. for C H O SiNa [M + Na]

1253, 1151, 1106, 1034, 835, 772 cm . [α]

D

= –64.4 (c = 1.0,

21 36

7

4

51.2128; found 451.2143. R

f

(hexane/EtOAc, 5:1): 0.28.

): δ = 4.83 (d, J =

.9 Hz, 1 H), 4.53 (d, J = 6.9 Hz, 1 H), 4.34 (dt, J = 6.7, J =

CHCl ). R (hexane/EtOAc, 2:1): 0.12.

3

f

Data for rac-76: ¹H NMR (400 MHz, CDCl

6

1

2

3

Dialdehyde rac-73: DMSO (118 μL, 0.1.66 mmol) was added to a

solution of oxalyl chloride (70 μL, 0.83 mmol) in CH Cl (0.8 mL)

at –78 °C. The solution was stirred at –78 °C for 20 min. Com-

pound rac-72 (50 mg, 0.08 mmol) in CH Cl (0.5 mL) was then

added slowly to the reaction mixture. The solution was stirred at

78 °C for 1 h. Et N (290 μL, 2.08 mmol) was added to the mix-

ture, and stirring was continued at –78 °C for 15 min and then at

°C for 1 h. The reaction was quenched with NH Cl (5 mL), and

2

0.4 Hz, 1 H), 3.71 (s, 3 H), 3.51–3.46 (m, 1 H), 3.34 (s, 3 H), 2.76–

.73 (m, 1 H), 2.04 (t, J = 1.3 Hz, 3 H), 2.00–1.91 (m, 1 H), 1.86

2

(

dd, J = 10.5, J = 12.8 Hz, 1 H), 1.34 (s, 3 H), 0.85 (s, 9 H), 0.10

1

3

(

s, 3 H), 0.10 (s, 3 H) ppm. C NMR (400 MHz, CDCl

3

): δ =

69.3, 159.8, 131.5, 95.5, 73.6, 59.1, 55.5, 55.2, 51.0, 44.4, 43.7,

5.8 (3 C), 23.7, 18.2, 16.1, –2.0, –2.1 ppm. HRMS (EI): calcd. for

SiNa [M + Na]⁺391.2073; found 391.2083. R

(hexane/

–

3

1

2

C

0

4

19

H

34

O

5

f

the aqueous phase was extracted with EtOAc (2ϫ 25 mL). The

combined organic extracts were washed with brine (15 mL), dried

EtOAc, 5:1): 0.28.

with MgSO

4

, and concentrated under reduced pressure (water bath

Lactone rac-77: AcCl (10 drops) was added to an ice-cold solution

of dimethyl ester rac-75 (54 mg, 0.12 mmol) in MeOH (6.3 mL).

The resulting solution was stirred at the same temperature for 5 h,

and then allowed to warm to room temp. to be stirred for a further

temperature: 30 °C) to give pure dialdehyde rac-73 (29 mg, 95%).

1

H NMR (400 MHz, CDCl

dd, J = 1.6, J = 2.0 Hz, 1 H), 5.21 (dd, J = 1.5, J = 2.7 Hz, 1 H),

.63 (dt, J = 6.8, J = 11.3 Hz, 1 H), 4.57 (d, J = 6.5 Hz, 1 H), 4.54

d, J = 6.5 Hz, 1 H), 3.75 (t, J = 7.3 Hz, 1 H), 3.29 (s, 3 H), 3.07–

.03 (m, 1 H), 2.15 (ddd, J = 1.4, J = 6.7, J = 12.7 Hz, 1 H), 1.82

dd, J = 11.6, J = 12.5 Hz, 1 H), 1.42 (s, 3 H), 0.83 (s, 9 H), 0.10

s, 3 H), 0.08 (s, 3 H) ppm. ¹³C NMR (400 MHz, CDCl

): δ =

96.4, 194.6, 141.4, 115.8, 96.6, 82.0, 79.0, 71.3, 56.4, 46.2, 44.3,

5.8 (3 C), 23.6, 18.1, 8.8, –2.2, 2.3 ppm. HRMS (EI): calcd. for

3

): δ = 9.88 (s, 1 H), 9.61 (s, 1 H), 5.30

(

4

0 h. The mixture was concentrated and purified by column

(

chromatography (SiO , hexane/EtOAc, 2:1) to give the tricycle

2

3

1

(

30 mg, 99%) as a colorless oil. H NMR (400 MHz, CDCl

3

): δ =

(

5.63 (dd, J = 1.9, J = 2.8 Hz, 1 H), 5.36–5.29 (m, 2 H), 3.89 (dd,

3

J = 6.5, J = 8.3 Hz, 1 H), 3.83 (s, 3 H), 3.31–3.26 (m, 1 H), 2.48

ddd, J = 1.7, J = 7.8, J = 15.2 Hz, 1 H), 2.05 (dd, J = 5.0, J =

1

2

(

13

1

(

5

5.1 Hz, 1 H), 1.45 (s, 3 H), 1.30 (br. s, 1 H) ppm. C NMR

400 MHz, CDCl ): δ = 171.1, 167.1, 141.3, 117.3, 83.3, 82.4, 57.5,

3.4, 48.5, 46.9, 29.9, 24.3 ppm. HRMS (ESI): calcd. for

_N_a_[_M₊_N_a_]+ 261.0739; found 261.0738. IR: ν˜ = 3498,

+

19 32 5

C H O SiNa [M + Na] 391.1917; found 391.1903. IR: ν˜ = 2929,

3

–1

2855, 1728, 1700, 1254, 1153, 1109, 1042, 835, 774 cm . R

f

(hex-

ane/EtOAc, 2:1): 0.38.

12 14 5

C H O

–

1

2

928, 1771, 1734, 1437, 1302, 1227, 1156, 1030, 906 cm . R

f

Aldehyde rac-74: While trying to synthesize rac-73, undesired prod-

uct rac-74 was formed almost quantitatively if the concentration of

(

EtOAc): 0.42.

the organic phases was done in a water bath warmer than 30 °C.

H NMR (400 MHz, CDCl ): δ = 9.69 (s, 1 H), 4.80 (d, J = 6.8 Hz,

3

The tricycle (30 mg, 0.13 mmol) was dissolved in THF (1.2 mL),

and the solution was cooled to 0 °C. Lutidine (59 μL, 0.50 mmol)

and then TBSOTf (58 μL, 0.25 mmol) were added to the reaction

vessel, and the mixture was stirred for a further 45 min at 0 °C.

The reaction was quenched by the addition of water (5 mL), and

diluted with additional sodium hydrogen carbonate (aq.; 3 mL) and

1

1 H), 4.55 (d, J = 6.8 Hz, 1 H), 4.36–4.28 (m, 1 H), 3.58–3.52 (m,

1 H), 3.34 (s, 3 H), 2.86–2.81 (m, 1 H), 2.12 (t, J = 1.4 Hz, 3 H),

2.02 (ddd, J = 1.7, J = 3.4, J = 12.9 Hz, 1 H), 1.83 (dd, J = 10.6,

J = 12.8 Hz, 1 H), 1.37 (s, 3 H), 0.86 (s, 9 H), 0.11 (s, 3 H), 0.10

s, 3 H) ppm. ¹³C NMR (400 MHz, CDCl

): δ = 186.2, 162.6, diethyl ether (30 mL). The phases were separated, and the aqueous

3

(

Eur. J. Org. Chem. 0000, 0–0

www.eurjoc.org

19

Job/Unit: O30382

/KAP1

Date: 06-06-13 17:14:23

Pages: 21

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

FULL PAPER

phase was extracted with diethyl ether (2ϫ 20 mL). The organic

phases were dried with Na SO , filtered, and concentrated under

vacuum. The residue was purified by column chromatography

SiO , hexane/EtOAc, 10:1) to give lactone rac-77 (36 mg, 81%) as

a colorless oil. H NMR (400 MHz, CDCl

J = 2.8 Hz, 1 H), 5.31–5.24 (m, 2 H), 3.82 (s, 3 H), 3.79 (dd, J =

sure. Purification by flash chromatography (SiO

2

, hexane/EtOAc,

2

4

3:1) gave aldehyde (–)-55 (17 mg, 94%) as an amorphous white

1

3

solid. H NMR (400 MHz, CDCl ): δ = 9.83 (s, 1 H), 5.44 (t, J =

(

2

2.5 Hz, 1 H), 5.30 (t, J = 2.3 Hz, 1 H), 5.26 (dd, J = 5.7, J = 8.0 Hz,

1 H), 3.80 (dd, J = 6.2, J = 8.1 Hz, 1 H), 3.25–3.21 (m, 1 H), 2.52

(ddd, J = 1.8, J = 7.8, J = 14.8 Hz, 1 H), 1.96 (dd, J = 5.6, J =

1

3

): δ = 5.58 (dd, J = 1.8,

6

7

.6, J = 8.5 Hz, 1 H), 3.31–3.26 (m, 1 H), 2.48 (ddd, J = 1.7, J = 14.8 Hz, 1 H), 1.43 (s, 3 H), 0.83 (s, 9 H), 0.11 (s, 3 H), 0.10 (s, 3

1

3

.8, J = 14.7 Hz, 1 H), 1.94 (dd, J = 5.5, J = 14.7 Hz, 1 H), 1.42

3

H) ppm. C NMR (400 MHz, CDCl ): δ = 192.5, 171.8, 142.7,

13

(

s, 3 H), 0.83 (s, 9 H), 0.10 (s, 3 H), 0.09 (s, 3 H) ppm. C NMR 116.2, 84.8, 84.2, 63.6, 57.8, 49.3, 42.7, 25.7 (3 C), 23.1, 18.0, –2.3

400 MHz, CDCl

+

3

): δ = 171.3, 167.3, 141.7, 117.0, 84.6, 83.6, 58.3,

(2 C) ppm. HRMS (ESI): calcd. for C17

26 4

H O SiNa [M + Na]

5

7.9, 53.4, 49.3, 47.1, 25.7 (3 C), 23.3, 18.0, –2.3 (2 C) ppm. HRMS

345.1498; found 345.1490. IR: ν˜ = 2931, 2856, 1768, 1721, 1253,

1145, 1047, 987, 836, 775 cm . [α] = –87.6 (c = 0.7, CHCl ). R

D 3 f

+

–1

22

(

EI): calcd. for C18

H

28

O

5

SiNa [M + Na] 375.1604; found

3

8

75.1613. IR: ν˜ = 2954, 2857, 1779, 1734, 1254, 1151, 1038, 990, (hexane/EtOAc, 3:1): 0.28.

–1

f

36, 775 cm . R (hexane/EtOAc, 5:1): 0.34.

Supporting Information (see footnote on the first page of this arti-

cle): Preparation/characterization of (–)-29, 31, (–)-34, 37, 39, (+)-

Alcohol (–)-78: Cold Jones reagent (2.5 m in water; 665 μL,

.66 mmol) was added to a stirred cooled (water/ice bath, 0 °C)

1

13

44, (–)-45, 47, and (–)-49. Copies of H and C NMR spectra for

1

compounds: 9, 10, 12, (+)-16, (–)-18, (–)-20, 22, 23, 24, 25, (–)-26,

solution of alkene (–)-68 (100 mg, 0.17 mmol) in acetone (3.3 mL).

Stirring was continued for 40 min. The excess of the Jones reagent

was quenched by the addition of IPA (1.5 mL). The suspension was

stirred for 5 min at 0 °C and for 10 min at room temp. The clear

greenish supernatant was decanted, and the remaining green solid

residue was extracted with EtOAc (5ϫ 15 mL). The combined or-

ganic extracts were washed with brine (2ϫ 5 mL) and dried with

(–)-27, (–)-30, (–)-32, (–)-33, (–)-35, (–)-36, (–)-38, (–)-40, (–)-41,

(–)-42, (–)-50, (+)-54, (+)-51, (+)-52, (+)-53, (–)-57, (–)-58, (–)-60,

(–)-61, (–)-62, (–)-63, (–)-64, (–)-65, (–)-66, (–)-67, (–)-68, rac-69,

rac-70, rac-71, (–)-72, rac-73, rac-74, rac-75, rac-76, rac-77, (–)-78,

–)-55.

(

Na

acid.

2

SO

4

. The volatiles were removed to give the crude carboxylic

Acknowledgments

Financial support from the University of Vienna (doctoral pro-

gram, Initiativkolleg Functional Molecules IK I041-N) and from

the Austrian Science Fund (FWF) (project number P22180) is

gratefully acknowledged. The authors thank H. P. Kählig, L.

Brecker, and S. Felsinger for assistance with NMR spectroscopy,

M. Drescher for experimental work, and A. Roller and V. Arion

A solution of the crude carboxylic acid in THF (3.7 mL) was

stirred at 0 °C under Ar while Et N (43 μL, 0.31 mL) was added.

The solution was stirred for 30 min, and then ethyl chloroformate

40 μL, 0.40 mmol) was added. The reaction mixture became

cloudy as it was stirred at 0 °C for 1.5 h. At this point, IPA (1 mL)

was added, followed by NaBH (30 mg, 0.79 mmol) 5 min later.

The mixture was stirred at 0 °C for 5 h, then it was diluted with

Et O (20 mL), treated dropwise with HCl (5% aq.; 2 mL), and

poured into a mixture of Et O (30 mL) and HCl (1% aq.; 20 mL).

The aqueous phase was extracted with Et O (2ϫ 20 mL), and the

combined organic extracts were washed with NaHCO

aq.; 2ϫ 20 mL) and brine (20 mL), dried with Na SO

3

(

4

(

all of the University of Vienna) for X-ray analysis.

2

[

1] a) P. A. Roethle, D. Trauner, Nat. Prod. Rep. 2008, 25, 298–

17.

2

3

2

2] Isolation article: J. Marrero, A. D. Rodriguez, P. Baran, R. G.

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see: a) B. Doroh, G. A. Sulikowski, Org. Lett. 2006, 8, 903–

3

(saturated

4

, and con-

2

centrated. The residue was purified by flash column chromatog-

raphy (SiO , hexane/EtOAc, 4:1) to give primary alcohol (–)-78

2

906; b) R. Miao, S. G. Gramani, M. J. Lear, Tetrahedron Lett.

1

(

29 mg, 54%) as a colorless oil. H NMR (400 MHz, CDCl

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5.31 (dd, J = 1.4, J = 2.8 Hz, 1 H), 5.23 (dt, J = 5.5, J = 8.2 Hz,

1 H), 5.18 (dd, J = 1.6, J = 2.1 Hz, 1 H), 4.00 (dd, J = 7.1, J =

11.9 Hz, 1 H), 3.84 (dd, J = 5.6, J = 11.7 Hz, 1 H), 3.45 (dd, J =

6.0, J = 8.2 Hz, 1 H), 3.22–3.17 (m, 1 H), 2.47 (ddd, J = 1.9, J =

7.9, J = 14.6 Hz, 1 H), 2.23 (t, J = 6.4 Hz, 1 H), 1.94 (dd, J = 5.5,

6

833.

[

3] Y. Li, G. Pattenden, Nat. Prod. Rep. 2011, 28, 1269–1310.

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5] Y. Li, G. Pattenden, J. Rogers, Tetrahedron Lett. 2010, 51,

J = 14.6 Hz, 1 H), 1.42 (s, 3 H), 0.83 (s, 9 H), 0.10 (s, 3 H), 0.09

s, 3 H) ppm. ¹³C NMR (400 MHz, CDCl

): δ = 177.0, 144.9,

14.5, 84.9, 84.0, 63.4, 57.1, 55.6, 49.3, 44.8, 25.7 (3 C), 23.2, 18.0,

2.3, –2.3 ppm. HRMS (ESI): calcd. for C17 SiNa [M +

(

3

1

–

1280–1283.

H

28

O

4

[6] a) T. T. Curran, D. A. Hay, Tetrahedron: Asymmetry 1996, 7,

2791–2792; b) A. Roy, S. W. Schneller, J. Org. Chem. 2003, 68,

9269–9273; c) M. W. Gilbert, A. Galkina, J. Mulzer, Synlett

+

Na] 347.1655; found 347.1648. IR: ν˜ = 3446, 2930, 2856, 1764,

1

–1

20

252, 1153, 1047, 988, 835, 774 cm . [α]

D 3

= –52.3 (c = 1.0, CHCl ).

2

004, 14, 2558–2562.

R

f

(hexane/EtOAc, 3:1): 0.20.

[

7] A. Rutar, F. Tratar, D. Kikelj, Synthesis 1995, 512–514.

Aldehyde (–)-55: DMSO (16 μL, 0.22 mmol) was added to a solu-

tion of oxalyl chloride (9 μL, 0.11 mmol) in CH Cl (0.6 mL) at

78 °C. The solution was stirred for 20 min at –78 °C, then alcohol

–)-78 (18 mg, 0.06 mmol) in CH Cl (0.5 mL) was slowly added to

the reaction mixture. The solution was stirred for 1 h at –78 °C.

Et N (46 μL, 0.33 mmol) was added, and stirring was continued

for 15 min at –78 °C and then for 1 h at 0 °C. The reaction was

quenched with NH Cl (5 mL) and extracted with EtOAc (2 ϫ

0 mL). The combined organic extracts were washed with brine

15 mL), dried with MgSO , and concentrated under reduced pres-

[8] O. Mitsunobu, Y. Yamada, Bull. Chem. Soc. Jpn. 1967, 40,

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2

[

9] P. C. B. Page, D. C. Leach, C. M. Hayman, A. S. Hamzah,

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S. M. Allin, V. McKee, Synlett 2003, 7, 1025–1027.

(

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1366; b) PhD Thesis Harald Weinstabl, University of Vienna,

4

2011.

2

[12] E. D. Mihelich, D. J. Eickhoff, J. Org. Chem. 1983, 48, 4135–

(

4

4137.

20

www.eurjoc.org

Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O30382

/KAP1

Date: 06-06-13 17:14:23

Pages: 21

The Bicyclo[3.2.0]heptane Core of Bielschowskysin

[

13] Y. Ito, T. Hirao, T. Saegusa, J. Org. Chem. 1978, 43, 1011–1013.

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[17] S. Isayama, T. Mukaiyama, Chem. Lett. 1989, 18, 1071–1074.

[18] CCDC-884126 contains the supplementary crystallographic

data for this paper. These data can be obtained free of charge

from The Cambridge Crystallographic Data Centre via

www.ccdc.cam.ac.uk/data_request/cif.

2344.

[

15] a) P. S. Wharton, D. H. Bohlen, J. Org. Chem. 1961, 26, 3615–

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616; b) C. Dupuy, J.-L. Luche, Tetrahedron 1989, 45, 3437–

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Received: March 13, 2013

[16] J.-L. Luche, J. Am. Chem. Soc. 1978, 100, 2226–2227.

Published Online: ᭿

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21

Article Doi

Photochemical and thermal [2 + 2] cycloaddition to generate the bicyclo[3.2.0]heptane core of bielschowskysin

DOI: 10.1002/ejoc.201300382

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