Photochemical Approaches to the Bilobalide Core

European Journal of Organic Chemistry

10.1002/ejoc.201700461

New Photochemical Approaches to the Bilobalide Core

Jens Emsermann and Till Opatz*

Institute of Organic Chemistry, University of Mainz, Duesbergweg 10–14, D-55128 Mainz,

Germany

E-Mail: opatz@uni-mainz.de

Homepage: www.uni-mainz.de/OC/AK-Opatz/

Keywords

Total synthesis; photochemistry; cycloadition; natural products; lactones

Abstract

Bilobalide is a tetracyclic sesquiterpene containing three contiguous γ-lactone rings and an unusual

tert-butyl group which is found in the leaves of the ginkgo tree (Ginkgo biloba). Three different

photochemical approaches towards bilobalide’s unique skeleton are presented. A meta-

photocycloaddition, a [2 + 2]-photocycloaddition, and a Paternò-Büchi-reaction were chosen as the

respective key steps.

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Introduction

The ginkgo tree (Ginkgo biloba) exists for about 270 million years and represents the last remainder

of its order, the ginkgoales. Due to good regenerative properties and resistance against external

1

,2

factors such as insects and diseases, the ginkgo tree managed to survive among these. Partly

responsible for these properties of their producer are the secondary metabolite bilobalide (1) and the

3

structurally related ginkgolides (2–6, Figure 1).

Figure 1. Structures of bilobalide (1) and ginkgolides (2–6).

The extract of the leaves of G. biloba, with bilobalide and ginkgolide as the main components, has

been used in Chinese folk medicine for about 5000 years. Treatment of cerebrovascular and

4

peripheral circulatory problems in the elderly belong to its current applications. Due to the

insecticidal properties of bilobalide (1) and the ginkgolides (2–6), the ginkgo constituents are also

of interest in the area of crop science.

5

Bilobalide (1) was first isolated by Major in 1967. Later on, Major together with Weinges and

6

-8

Nakanishi, elucidated its polycyclic structure. A first synthetic access to racemic and enantiopure

European Journal of Organic Chemistry

10.1002/ejoc.201700461

9

,10

bilobalide (1) was developed by Corey et al. in 1987/1988. Crimmins et al. published a shorter

1

racemic total synthesis of bilobalide (1) in 1993.

Photochemical reactions provide access to complex structures, which cannot easily be obtained by

classical methods. Photochemical approaches may be well suited for the synthesis of various classes

of natural products as nicely illustrated by Crimmins’ successful approach to 1 which is based on a

1

2

[

2 + 2]-photocycloaddition. Here, the use of a meta-photocycloaddition, a [2 + 2]-

photocycloaddition, and a Paternò-Büchi reaction as alternative key steps for the construction of

bilodalide’s skeleton was investigated.

Results and Discussion

In the first approach, a meta-photocycloaddition was chosen to construct an angular triquinane-like

1

3,14

system.

The application of the meta-photocycloaddition in the total synthesis of natural products

1

5

was thoroughly investigated by Wender. Three new C–C bonds and up to six new stereocenters,

depending on the structure of the reactants can be generated in a single step through this

methodology. To investigate this route, a model photoprecursor (10) should be prepared by

condensation of the monoprotected diol 11 and the α-chloroether 12 (scheme 1). After

intramolecular meta-photocycloaddition of 10 to the triquinane system 9a, it would be necessary to

isomerize the double bond into the required position under opening of the cyclopropane ring.

Ozonolytic cleavage of the newly positioned olefinic bond would then lead to dialdehyde 7b. The

C -unit highlighted in green serves for the formation of the α-hydroxylactone ring D and the C -unit

2

3

highlighted in blue would later serve for the construction of the lactone ring A. The sp -oxygen of

this lactone ring would need to be introduced by a C–H functionalization of a methylene group at

some stage (compound 7a vs. 7b, scheme 1) or it would need to be introduced into the

European Journal of Organic Chemistry

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photoprecursor for the meta-photocycloaddition. Initial experiments in the latter direction were

unsuccessful (data not shown), so that precursors 10 and 11 devoid of an additional oxygen attached

to the exo-methylene group were chosen to evaluate the usefulness of the general synthetic scheme.

Moreover, the aldehyde function would then needed to be converted into a tert-butyl group and the

methoxy group was chosen as a surrogate for the tertiary alcohol and could eventually be replaced

by a suitably protected hydroxyl function if the concept proved feasible.

Scheme 1: Retrosynthetic analysis with a meta-photocycloaddition as the key step.

1

,4-Butanediol (13) was monoprotected with TBSCl, the remaining hydroxy group was oxidized in

a Parikh-Doering reaction and after methylenation with Eschenmoser`s salt and reduction of the

aldehyde with sodium borohydride the allylic alcohol 11 was obtained (scheme 2). Condensation

with α-chloroether 12, which could be easily prepared starting from o-anisaldehyde (14) in two

1

6,17

steps, afforded the desired photocyclization precursor 10.

European Journal of Organic Chemistry

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Scheme 2: Synthesis of the photoprecursor 10

a)

NaH, TBSCl, THF, 0 °C, 1 h, quant.; b) DMSO, NEt , SO ·py, r.t., 3 h, then Eschenmoser`s salt (chloride), r.t.,

3 3

1

8 h, 70%; c) NaBH , EtOH, 0 °C, 30 min, 84%; d) CH(OCH ) , MeOH, CSA, r.t., 60 h, quant.; e) AcCl, thionyl

4

3 3

chloride, r.t., 21 h, quant.; f) NEt , CH Cl , 0 °C, 1 h, 86%

3

2

Upon meta-photocycloaddition of 10, the angular product 9a was obtained predominantly (scheme

). Shorter reaction times also resulted in the formation of the linear system 9b. A separation of 9a

3

and 9b via column chromatography was unsuccessful. As the linear system 9b was less photostable,

compound 9a could be enriched after longer irradiation times. An efficient photochemical

interconversion of the linear and the angular system through a vinylcyclopentene-cyclopentane-

1

3

rearrangement as reported in the literature could however not be observed since the production of

9

a in sufficient purity was only possible at the expense of the overall yield. Extensive screening of

the conditions (wavelength, solvent, concentration, time), also involving a design of experiments

approach, did not result in an isolated yield of 9a in excess of 27% (for experimental details, see the

Supporting Information).

European Journal of Organic Chemistry

10.1002/ejoc.201700461

Scheme 3: meta-photocycloaddition of 10.

Radical addition of thiophenol to the vinylcyclopropane 9a resulted in ring opening under migration

1

8

of the double bond into the desired position (scheme 4). The thioether 15 could be oxidized by

mCPBA to sulfone 16 but further oxidation to enone 17 with Davis reagent, MoOPH or (TMSO)₂

1

9-21

failed.

An oxygen functionality at the position of the phenylthio group in 15 would however be

necessary for construction of the α-hydroxylactone ring D. Sulfide 15 could be reductively cleaved

by Raney-Ni in ethanol which would require the hydroxylation of ring D at a later stage. For the

preparation of bilobalide (1), the double bond in the desulfurized intermediate 8 needed to be

cleaved in an ozonolysis or a Lemieux-Johnson oxidation through diol 18 to dialdehyde 7b.

Surprisingly, none of the conditions applied to diol 18 afforded the desired product 7b (no defined

product could be isolated in the attempted oxidative glycol cleavages instead) and the meta-

photocycloaddition-approach was eventually abandoned.

Scheme 4: Further modifications of the angular photoproduct 9.

European Journal of Organic Chemistry

10.1002/ejoc.201700461

a)

PhSH, Et B, air, CH Cl , r.t., 18 h, 46%; b) mCPBA, CH Cl , r.t., 1 h, 85%; c), Raney-Ni, EtOH, r.t., 90 min,

3 2 2 2 2

t

9

1%; d) K OsO ·2H O, NMO, H O, BuOH, r.t., 18 h, 93%.

2 4 2 2

The key step of the second approach was the hitherto unknown intramolecular [2 + 2]-

2

photocycloaddition of an enone to an allenyl ether in compound 22 furnishing

methylenecyclobutane 21a (scheme 6). Reduction of the ketone and ozonolysis of the exo-

methylene group would lead to the cyclobutanone 20, Baeyer-Villiger oxidation would in turn

afford lactone ring C and allow the oxidation of the tetrahydrofuran-type D-ring precursor through a

ring opening/oxidation/ring closure sequence. The advantage of this approach would be the

presence of the oxygen handle on ring B (highlighted in blue in intermediate 19, scheme 5) required

to close lactone ring A. The approach was first investigated on model compound 19 devoid of the

tert-butylcarbinol moiety and lacking the C chain bound to one of the two adjacent quaternary

2

centers while carrying a methyl group instead, to test the feasibility of the individual

European Journal of Organic Chemistry

10.1002/ejoc.201700461

transformations involved. For a total synthesis of bilobalide, two modifications of the starting

material would thus be required.

Scheme 5: Retrosynthetic Analysis with [2 + 2]-photocycloaddition as key step.

The precursor 22 for the [2 + 2]-photocycloaddition was readily synthesized in six steps starting

from commercial 2-methyl-1,3-cyclopentanedione (23) which was reacted with dimethyl sulfate to

afford methyl enol ether 24. Reaction with dimethyl malonate led to enone 25 and reduction with

lithium aluminium hydride provided the diol 26. The selective propargylation of the primary

hydroxy group of diol 26 was however problematic. The maximum yield of 41% was achieved in a

biphasic solvent mixture (CH Cl and H O) with sodium hydroxide and tetrabutylammonium

2

hydrogen sulfate. Isomerization of alkyne 27 with potassium tert-butoxide produced allene 28 in

5% yield. Oxidation of allylic alcohol 28 to enone 22 was accomplished by reaction with freshly

9

prepared IBX while the use of PDC, DMP or Swern-oxidation were unsuccessful due to

concomitant hydrolysis of the allenyl ether moiety. Intramolecular [2 + 2]-photocycloaddition of 22

gave methylenecyclobutane 21a in a yield of 20%. The photoreaction was carried out in different

solvents, at different wavelengths and temperatures as well as in the presence of triplet sensitizers

but a higher yield could not be achieved. When the irradiation was conducted at –30 °C instead of

1

room temperature, H NMR spectroscopy gave evidence of the formation of the other possible

European Journal of Organic Chemistry

10.1002/ejoc.201700461

cycloadduct, enol ether 21b, but the compound could not be isolated due to rapid hydrolysis upon

chromatography. The presence of triplet sensitizers (acetone, benzophenone) during irradiation led

to a faster consumption of the starting material but compound 21a could not be isolated in this case.

The structure of the desired methylencyclobutanone could be verified by X-ray crystallography (see

the Supporting information for details on crystallography and the optimization of the

photocycloaddition). Due to the low yields of the selective propargylation of the primary hydroxy

group and the [2 + 2]-photocycloaddition this approach was not further pursued as well.

Scheme 6: Synthesis of methylencyclobutanone 21a via [2 + 2]-photcycloaddition.

a) (CH O) SO , K CO , acetone, reflux, 8 h, 99%; b) Dimethyl malonate, NaOMe, methanol, reflux, 48 h, 72%; c)

3

2

3

n

t

LiAlH , Et O, reflux, 1 h, 79%; d) propargyl bromide, Bu NHSO , NaOH, CH Cl /H O, r.t., 24 h, 41%; e) KO Bu,

4

2

4

2

THF, r.t., 4 h, 95%; f), IBX, DMSO/THF, r.t., 5 h, 96%; g) hv (350 nm), pentane, r.t., 20 h, 20%.

European Journal of Organic Chemistry

10.1002/ejoc.201700461

The photochemical key step in the third approach is an intramolecular Paternò-Büchi reaction of a

2

3-25

ketone and a furan in precursor 32 to produce the tetracyclic system 31 (scheme 7).

A

succinimide as a C building block would allow the sequential attachment of both the furan moiety

4

(

i.e. the second C -unit - required to construct ring D) and a 4,4-dimethylpentane-2-one chain (ring

4

B-precursor) to the same carbon atom in an arylation/Michael addition sequence. The

photoprecursor 32 was prepared starting from the maleimide 33. Epoxidation of dihydrofuran 31,

oxidative cleavage of the epoxide and subsequent cleavage of the succinimide would afford

dicarboxylic acid 30. Ring-opening of the oxetane and lactone formation with the C -carboxylic

1

acid moiety would then give the tricyclic system 29. For the construction of lactone ring A, the

introduction of an oxygen functionality in the cyclopentane ring would be required and ring closure

with the C -carboxylic acid moiety would form lactone ring A. The procedure holds, however, the

2

risk of a poor or unfavorable diastereocontrol in the photocycloaddition step.

Scheme 7: Retrosynthetical Analysis with Paternò-Büchi reaction as key step.

European Journal of Organic Chemistry

10.1002/ejoc.201700461

Duan et al. described an enantioselective rhodium-catalyzed 1,4-addition to maleimides with a

2

6

hindered CN axis through memory of chirality. The required maleimide could easily prepared by

reaction of maleic anhydride (34) and 2-tert-butylaniline (35) (scheme 8). The highest yield of the

(

so far achiral) 1,4-addition with 86% could be achieved by using [RhCl(COD)] as the catalyst

2

which gave a distereomerically pure product. The tert-butyl substituent on the arene used in the

literature protocol was also used here to allow an easier adaption of the conditions to an

enantioselective procedure using a chiral rhodium catalyst in case of a successful onward route. The

final step of the synthesis of the precursor 32 for the Paternò-Büchi reaction was a Michael reaction

with tert-butyl vinyl ketone which was prepared by a standard literature protocol to introduce the

2

7

rare and characteristic tert-butyl substituent of bilobalide at an early stage.

Scheme 8: Synthesis of the precursor 32 of the Paternò-Büchi reaction.

European Journal of Organic Chemistry

10.1002/ejoc.201700461

a)

neat, 120 °C, 16 h, 93%; b) 3-furanylboronic acid, [RhCl(COD)] , KOH, dioxane/H O, 50 °C, 5 h, 86%; c)

2 2

tert-butylvinylketone, K CO , DMF, r.t., 16 h, 63%

2

3

Alternatively, the photoprecursor could be prepared by a Suzuki coupling. To this end, the

bromomaleimide 38 was first prepared from 3-bromomaleic anhydride (37) and 2-tert-butylaniline

(35) (scheme 9). The best yield with 93% for the Suzuki coupling was achieved using Pd(dppf)Cl₂

as the catalyst and cesium fluoride as the base. After hydrogenation of the double bond, the

succinimide (36) was obtained as a diastereomeric mixture (d.r. 1:1) inconsequential for the racemic

synthesis. After deprotonation of the benzylic position, the nucleophilic attack at the Michael

system could only occur from the face opposite of the directing tert-butyl group of the succinimide

3

6 to furnish the precursor 32.

Scheme 9: Alternative approach to furan 36.

European Journal of Organic Chemistry

10.1002/ejoc.201700461

a)

neat, 120 °C, 16 h, 78%; b) 3-furanylboronic acid, Pd(dppf)Cl , CsF, dioxane, MW, 100 °C, 20 min, 93%; c)

2

Pd/C, H , EtOAc, r.t., 6 h, 78%, d.r. 1:1

2

The Paternò-Büchi reaction of furan 32 led to an equimolar diastereomeric mixture of syn-31 and

anti-31 (scheme 10). For the synthesis of bilobalide, a syn-configuration of the two C -units of the

2

maleimide and the dihydrofuran moiety was required. Therefore, anti-31 was not useful for this

purpose. A separation of both diastereomers via column chromatography could not be achieved, so

the mixture was used in the subsequent reaction.

Scheme 10: Paternò-Büchi reaction of 32 and further modifications.

European Journal of Organic Chemistry

10.1002/ejoc.201700461

a)

hv (300 nm), toluene, r.t., 43 h, 40%, d.r. 1:1; b) dimethyldioxirane, acetone, quant; c) Jones reagent, acetone,

6

4% of anti-41, 70% of syn-31

During the reaction with a freshly prepared solution of dimethyldioxirane in acetone, only one of

the diastereomers was converted into the corresponding epoxide (40). However, a separation via

column chromatography was again not possible at this point. Oxidative cleavage of the epoxide

with Jones reagent should have produced the corresponding α-hydroxylactone but only the acidic

hydrolysis of the epoxide to diol 41 could be observed. The steric hindrance of the double bond and

European Journal of Organic Chemistry

10.1002/ejoc.201700461

the epoxide is so high that the conversion of both Paternò-Büchi products or the oxidation of the

epoxide 40 to the α-hydroxylactone could not be achieved. Nevertheless, diol 41 could be separated

1

and purified via column chromatography at that stage and a H- H-NOESY experiment allowed to

determine its relative configuration through characteristic contacts between the acetalic proton (H-

3

) and the methylene protons next to the spiro-center (Figure 2). After hydrolysis of the epoxide 40,

the unchanged photoproduct syn-31 could be isolated as well. In syn-31, only the correlation

between the acetalic proton H-3a and the proton H-6 could be observed.

Figure 2: Characteristic NOESY correlations of diol anti-41.

Hydrolysis of the succinimide syn-31 to the dicarboxylic acid under basic conditions was

unsuccessful. Due to the exclusive epoxidation of the undesired isomer anti-41, a total synthesis of

bilobalide could not be achieved along the third route as well. Nevertheless, the quick assembly of

all key structural elements of bilobalide along these lines appears promising.

Conclusions

European Journal of Organic Chemistry

10.1002/ejoc.201700461

Unfortunately, none of the attempted approaches towards the bilobalide core were successful. The

third strategy involving the intramolecular Paternò-Büchi reaction of a tethered tert-butylketone to

furan represents the most promising route among these and could be taken forward when the

problem of steric shielding of the enol ether double bond can be solved.

Experimental section

All reactions involving air or moisture sensitive reagents or intermediates were performed under an

inert atmosphere of argon in oven dried glassware. All reagents and solvents were obtained from

commercial suppliers and used without further purification. Anhydrous toluene, THF, diethyl ether

and pentane were distilled from sodium/benzophenone under argon. N,N-Dimethylformamide

(99+%, extra dry) was purchased from a commercial supplier and used without further purification.

Melting points were determined in open capillary tubes using an electrothermal apparatus with

1

0

7

.1 °C resolution. NMR spectra were recorded with a 300 MHz spectrometer (300 MHz H and

13

1

13

5.5 MHz C) or with a 400 MHz spectrometer (400 MHz H and 100.6 MHz C) with digital

architecture equipped with 5 mm probes. The values are reported in parts per million (ppm)

28

downfield from TMS and were referenced to the residual solvent signal (CHCl , 7.26 ppm).

3

Coupling constants (J) were reported in Hz and the multiplicity abbreviations used were: s, singlet;

d, doublet; t, triplet; m, multiplet; br, broad. Standard pulse sequences were used for the 2D

experiments. CDCl was stored over alumina (Brockmann activity grade I). IR spectra were

3

–

1

recorded using a diamond ATR unit and are reported in terms of frequency of absorption ( 휈̃ , cm ).

ESI-HRMS spectra were recorded on a Q-TOF instrument with a dual source and a suitable external

calibrant. Thin-layer chromatography (TLC) was carried out on 0.25 mm silica gel plates with

fluorescence indicator. Substance bands were detected by illumination with UV light (254 and

European Journal of Organic Chemistry

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3

60 nm) or an ethanolic solution of diluted aqueous sulfuric acid, ammonium pentamolybdate and

cerium(IV) sulfate (Seebach’s reagent), and heat as developing agents. Flash chromatography was

performed on 35–70 μm silica gel using the solvent systems indicated. Solvents were degassed

using freeze−pump−thaw cycles or by nitrogen bubbling and an ultrasonic bath. The photoreactions

were performed under argon atmosphere in a Rayonet-type photoreactor equipped with a circular

array of 16 UV lamps (254 nm, 300 nm or 350 nm, each 8 W), a magnetic stirrer, and a cooling fan.

2

9

4

-{[tert-Butyl(dimethyl)silyl]oxy}butan-1-ol (13a)

To a solution of 1,4-butanediol (6.59 g, 73.1 mmol) in THF (70 mL) was added sodium hydride

60% dispersion in mineral oil, 2.05 g, 51.2 mmol) at 0 °C. After stirring for 30 minutes at 0 °C,

(

TBSCl (7.66 g, 50.8 mmol) was added. After stirring for 1 h, the mixture was quenched by addition

of saturated ammonium chloride solution (30 mL). The aqueous layer was extracted with ethyl

acetate (3 × 50 mL) and the combined organic layers were washed with brine (50 mL), dired over

Na SO and concentrated in vacuo. The residue was purified by flash chromatography

s

4

(

cyclohexane/EtOAc 3:1) to afford 13a (10.5 g, quant.) as a colorless oil: R = 0.15

f

1

(

cyclohexane/EtOAc 5:1); H NMR (400 MHz, CDCl )  = 3.67–3.61 (m, 4H), 2.65 (s , 1H, OH),

3

br

13

1

.66–1.60 (m, 4H), 0.89 (s, 9H, C(CH ) ), 0.06 (s, 6H, Si(CH ) ) ppm; C NMR (100.6 MHz,

3 3 3 2

CDCl )  = 63.5, 62.9, 30.4, 30.0, 26.0 (3C, C(CH ) ), 18.4 (C(CH ) ), –5.3 (2C, Si(CH ) ) ppm.

3

3 3

3 2

2

9

Analytical data in accordance with literature.

3

0

4

-{[tert-Butyl(dimethyl)silyl]oxy}-2-methylidenebutanal (13b)

To a solution of alcohol 13a (7.77 g, 38.0 mmol) in DMSO (150 mL) and triethylamine (33 mL,

28 mmol) was added SO ·pyridine (12.1 g, 76.0 mmol) within 30 minutes. After stirring for 3 h at

2

3

room temperature, Eschenmoser`s salt (chloride salt, 4.37 g, 46.7 mmol) was added. The reaction

mixture was stirred for 18 h and then partitioned between Et O (100 mL) and a saturated NaHCO

2

3

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10.1002/ejoc.201700461

solution (100 mL) and was stirred until the gas evolution ceased. The organic layer was separated

and washed with water (50 mL) and brine (50 mL). After drying over Na SO the solvent was

2

4

removed in vacuo. Purification by flash column chromatography (cyclohexane/EtOAc 20:1) yielded

the title compound 13b (5.63 g, 70%) as a colorless liquid: R = 0.24 (cyclohexane/EtOAc, 1:1);

f

1

H NMR (400 MHz, CDCl )  = 9.51 (s, 1H, CHO), 6.34 (s, 1H, C=CH ), 6.04 (s, 1H, C=CH ),

3

2

3

.70–3.67 (m, 2H, H-4), 2.47–2.44 (m, 2H, H-3), 0.85 (s, 9H, C(CH ) ), 0.00 (s, 6H,

3 3

13

Si(CH ) ) ppm; C NMR (100.6 MHz, CDCl )  = 194.6 (CHO), 147.2 (C=CH ), 136.0 (C=CH ),

3

2

3

2

6

1.1 (C-4), 31.5 (C-3), 26.0 (3C, C(CH ) ), 18.4 (C(CH ) ), –5.2 (2C, Si(CH ) ) ppm. Analytical

3 3 3 3 3 3

3

0

data in accordance with literature.

4

-{[tert-Butyl(dimethyl)silyl]oxy}-2-methylidenebutan-1-ol (11)

To a suspension of NaBH (105 mg, 2.78 mmol) in EtOH (15 mL) was added the aldehyde 13b

4

(1.13 g, 5.25 mmol) in EtOH (5 ml) slowly at 0 °C. After stirring for 30 min the reaction mixture

was quenched by addition of water (5 mL) and brine (10 mL). The mixture was extracted with

EtOAc (3 × 30 mL). The combined organic layers were washed with brine (2 × 20 mL) and dried

over Na SO . Evaporation afforded the alcohol 11 (1.01 g, 4.67 mmol, 89%) as a colorless liquid :

2

4

1

R = 0.22 (cyclohexane/EtOAc 5:1); H NMR (400 MHz, CDCl )  = 5.03 (s, 1H, C=CH ), 4.88 (s,

f

3

2

1

H, C=CH ), 4.06–4.04 (m, 2H, H-1), 3.74 (t, J = 6.0 Hz, 2H, H-4), 3.08 (s , 1H, OH), 2.32 (t,

2 br

1

3

J = 6.0 Hz, 2H, H-3), 0.88 (s, 9H, C(CH ) ), 0.06 (s, 6H, Si(CH ) ) ppm; C NMR (100.6 MHz,

3

3 2

CDCl )  = 147.2 (C=CH ), 112.6 (C=CH ), 66.5, 63.5, 37.2, 26.0 (3C, C(CH ) ), 18.4 (C(CH ) ),

3

2

3 3

3

1

–

5.3 (2C, Si(CH ) ) ppm. Analytical data in accordance with literature. The sample still contained

3 2

some impurities but was used directly for the subsequent transformation.

1

-(Dimethoxymethyl)-2-methoxybenzene (14a)

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To a solution of o-anisaldehyde (13.1 g, 96.5 mmol) in methanol (100 mL) were added trimethyl

orthoformate (12.3 g, 116 mmol) and camphorsulfonic acid (2.20 g, 9.65 mmol). After stirring for

6

0 h at room temperature, the solvent was removed in vacuo. The title compound 14a (19.1 g,

quant.) was obtained without further purification as a reddish liquid: R = 0.16 (cyclohexane/EtOAc

f

1

6

0:1); H NMR (400 MHz, CDCl )  = 7.53 (dd, J = 7.6 Hz, J = 1.8 Hz, 1H), 7.33–7.28 (m, 1H),

3

.99–6.95 (m, 1H), 6.91–6.88 (m, 1H), 5.68 (s, 1H, CH(OCH ) ), 3.85 (s, 3H, OCH ), 3.36 (s, 6H,

3

2

3

1

3

CH(OCH ) ) ppm; C NMR, HSQC, HMBC (100.6 MHz, CDCl )  = 157.1 (C-2), 129.8, 127.4,

3

2

3

1

26.1 (C-1), 120.3, 110.7, 99.1 (CH(OCH ) ), 55.7 (OCH ), 53.6 (2C, CH(OCH ) ) ppm. Analytical

3 2 3 3 2

1

6

data in accordance with literature.

3

1

-(2-Methoxyphenyl)-10,10,11,11-tetramethyl-6-methylidene-2,4,9-trioxa-10-siladodecane (10)

-[Chloro(methoxy)methyl]-2-methoxybenzene (12)

Acetal 14a (4.16 g, 22.8 mmol), acetyl chloride (3.59 g, 45.7 mmol) and thionyl chloride

2 mL/mol, 0.05 mL) were stirred 21 h at room temperature. The mixture was concentrated in vacuo

(

and the very unstable chloroether 12 (4.11 g, 97%, ≈16% o-anisaldehyde due to decomposition)

1

was obtained as a dark liquid: H NMR (400 MHz, CDCl )  = 7.68 (d, J = 7.6 Hz, 1H, H-6), 7.34–

3

7

3

.32 (m, 1H, H-4), 7.06–6.99 (m, 1H, H-5), 6.91–6.89 (m, 1H, H-3), 6.83 (s, 1H, CHCl(OCH )),

3

13

.88 (s, 3H, OCH ), 3.71 (s, 3H, CHCl(OCH )) ppm; C NMR, HSQC, HMBC (100.6 MHz,

3

CDCl )  = 154.9 (C-2), 130.6 (C-4), 128.7 (C-1), 126.7 (C-6), 121.0 (C-5), 110.9 (C-3), 95.1

3

(

CHCl(OCH )), 58.4 (CHCl(OCH )), 55.8 (OCH ) ppm. Further analytical data could not be

3 3 3

acquired due to rapid decomposition.

To a solution of alcohol 11 (537 mg, 2.48 mmol) in CH Cl (40 mL) and NEt (2 mL) was added 12

2

3

(

694 mg, 3.72 mmol) in CH Cl (5 mL) slowly at 0 °C. After stirring for 1 h at 0 °C, the mixture

2 2

was quenched with saturated NaHCO (30 mL). The organic layer was separated, dried over

3

European Journal of Organic Chemistry

10.1002/ejoc.201700461

Na SO and evaporated. The residue was purified by column chromatography (cyclohexane/EtOAc

2

4

1

5:1 + 2% NEt ) to afford the photoprecursor 10 (782 mg, 86%) as a colorless liquid: R = 0.30

3 f

(

cyclohexane/EtOAc 15:1 + 2% NEt ); IR (ATR) 휈̃ = 2929, 1604, 1463, 1285, 1245, 1092, 833,

3

–

1 1

7

1

74, 754 cm ; H NMR, COSY (400 MHz, CDCl )  = 7.59–7.57 (m, 1H, Ph-H6), 7.32–7.28 (m,

3

H, Ph-H4), 6.99–6.95 (m, 1H, Ph-H5), 6.90–6.87 (m, 1H, Ph-H3), 5.78 (s, 1H, H-3), 5.12 (s, 1H,

C=CH ), 4.93 (s, 1H, C=CH ), 4.06–4.03 (m, 2H, H-5), 3.84 (s, 3H, Ph-C2-OCH ), 3.71 (t,

2

3

J = 7.0 Hz, 2H, H-8), 3.33 (s, 3H, H-1), 2.31 (t, J = 7.0 Hz, 2H, H-7), 0.88 (s, 9H, C(CH ) ), 0.03 (s,

3

13

6

H, (CH ) ) ppm; C NMR, HSQC, HMBC (100.6 MHz, CDCl )  = 157.2 (Ph-C2), 143.4

3

2

3

(

C=CH ), 129.7 (Ph-C4), 127.6 (Ph-C6), 126.4 (Ph-C1), 120.3 (Ph-C5), 113.0 (C=CH ), 110.6 (Ph-

2

C3), 97.6 (C-3), 69.5 (C-5), 62.3 (C-8), 55.6 (Ph-C2-OCH ), 53.1 (C-1), 36.9 (C-7), 26.0 (3C,

3



C(CH ) ), 18.4 (C-11), –5.2 (2C, Si(CH ) ) ppm; ESI-HRMS calcd for [C H O Si + Na]

3

3 2

20 34

4

3

89.2124 , found 389.2137.

rac-tert-Butyl{2-[(1S,3aS,6aR,6bR)-1,6b-dimethoxy-4,4a,4b,6b-

tetrahydrocyclopropa[3,4]pentaleno[1,6a-c]furan-3a(3H)-yl]ethoxy}dimethylsilane (9a)

The photoprecursor 10 (175 mg, 0.478 mmol) in cyclohexane (210 mL) was degassed and irradiated

1

(

254 nm, 16 × 8 W). After H NMR spectroscopy indicated consumption of the starting material

and the linear photoproduct (8 h), the solvent was removed in vacuo. Purification of the residue via

column chromatography (cyclohexane/EtOAc 15:1 + 2% NEt ) afforded the angular photoproduct

3

9

a (46.8 mg, 27%) as a colorless oil: R = 0.27 (cyclohexane/EtOAc 15:1 + 2% NEt ); IR (ATR)

f 3

–

1 1

휈̃ = 2929, 2857, 1471, 1387, 1254, 1089, 1016, 941, 836, 775 cm ; H NMR, COSY (400 MHz,

CDCl )  = 5.75 (dd, J = 5.7 Hz, J = 2.5 Hz, 1H, H-5), 5.66 (d, J = 5.7 Hz, 1H, H-6), 5.04 (s, 1H,

3

H-1), 4.12 (d, J = 8.5 Hz, 1H, H-3 ), 3.82 (dd, J = 8.5 Hz, J = 1.9 Hz, 1H, H-3 ), 3.57–3.51 (m, 2H,

a

b

CH CH OTBS), 3.40 (s, 3H, C-1-OCH ), 3.36 (s, 3H, C-6b-OCH ), 2.16–2.10 (m, 1H, H-4b),

2

3

European Journal of Organic Chemistry

10.1002/ejoc.201700461

2

.10–2.07 (m, 1H, H-4a), 2.05–1.98 (m, 1H, CH CH OTBS), 1.89 (dd, J = 14.0 Hz, J = 6.2 Hz, 1H,

2 2

H-4 ), 1.43–1.37 (m, 1H, CH CH OTBS), 1.36–1.33 (m, 1H, H-4 ), 0.87 (s, 9H, C(CH ) ), 0.01 (s,

a

2

b

3 3

1

3

6

1

H, Si(CH ) ) ppm; C NMR, HSQC, HMBC (100.6 MHz, CDCl )  = 131.2 (C-6), 127.3 (C-5),

3

2

3

03.7 (C-1), 91.5 (C-6b), 73.8 (C-6a), 73.2 (C-3), 64.8 (C-3a), 61.4 (CH CH OTBS), 56.9 (C-6b-

2

OCH ), 55.6 (C-1-OCH ), 36.2 (CH CH OTBS), 36.2 (C-4a), 35.1 (C-4b), 30.9 (C-4), 26.1 (3C,

3

2



C(CH ) ), 18.4 (C(CH ) ), –5.3 (2C, Si(CH ) ) ppm; ESI-HRMS calcd for [C H O Si + Na]

3

3 3

3 2

20 34

4

3

89.2124 , found 389.2142.

rac-tert-Butyl{2-[(1S,3aS,5aR,8aR)-1,5a-dimethoxy-8-(phenylsulfanyl)-4,5,5a,8-

tetrahydropentaleno[1,6a-c]furan-3a(3H)-yl]ethoxy}dimethylsilane (15)

To a solution of the photoproduct 9a (113 mg, 0.309 mmol) in CH Cl (10 mL) were added

2

thiophenol (119 mg, 1.08 mmol) and triethylborane (1 M in hexane, 0.15 mL, 0.150 mmol) and the

mixture was stirred for 18 h at room temperature under air atmosphere. The reaction was quenched

with aqueous NaOH (4 M, 10 mL) and extracted with CH Cl (2 × 10 mL). The combined organic

2

layers were dried over Na SO and evaporated. After purification by column chromatography

2

4

(

cyclohexane + 2% NEt ) the title compound (66.7 mg, 46%) was obtained as a colorless oil:

3

R = 0.28 (cyclohexane/EtOAc 10:1); IR (ATR) 휈̃ = 2931, 1583, 1472, 1345, 1254, 1091, 965, 833,

f

–

1 1

7

75, 740, 691 cm ; H NMR, COSY (400 MHz, CDCl )  = 7.44–7.41 (m, 2H, Ph-H2,6), 7.28–

3

.24 (m, 2H, Ph-H3,5), 7.18–7.14 (m, 1H, Ph-H4), 6.08 (dd, J = 5.7 Hz, J = 3.0 Hz, 1H, H-7), 5.69

(

d, J = 5.7 Hz, 1H, H-6), 5.10 (s, 1H, H-1), 4.18 (d, J = 3.0 Hz, 1H, H-8), 4.06 (dd, J = 8.8 Hz,

J = 1.7 Hz, 1H, H-3 ), 3.69–3.64 (m, 2H, CH CH OTBS), 3.62–3.55 (m, 1H, H-3 ), 3.35 (s, 3H, C-

a

2

b

5

a-OCH ), 3.14 (s, 3H, C-1-OCH ), 1.96–1.81 (m, 3H, H-4 , H-5), 1.68 (dd, J = 12.6 Hz,

3 3 a

J = 5.7 Hz, 1H, CH CH OTBS), 1.42–1.37 (m, 1H, H-4 ), 1.21–1.12 (m, 1H, CH CH OTBS), 0.89

2

b

2

1

3

(

s, 9H, C(CH ) ), 0.04 (s, 6H, Si(CH ) ) ppm; C NMR, HSQC, HMBC (100.6 MHz, CDCl )

3 3 3 2 3

 = 138.2 (Ph-C1), 136.4 (C-7), 132.9 (C-6), 130.1 (2C, Ph-C2,6), 128.6 (2C, Ph-C3,5), 125.9 (Ph-

European Journal of Organic Chemistry

10.1002/ejoc.201700461

C4), 107.6 (C-1), 96.0 (C-5a), 79.9 (C-3), 69.0 (C-8a), 60.6 (CH CH OTBS), 55.0 (C-8), 54.3 (C-1-

2

OCH ), 52.9 (C-5a-OCH ), 52.0 (C-3a), 40.9 (C-4), 35.6 (CH CH OTBS), 32.2 (C-5), 26.1 (3C,

3

2



C(CH ) ), 18.4 (C(CH ) ), –5.2 (2C, Si(CH ) ) ppm; ESI-HRMS calcd for [C H O SSi + Na]

3

3 3

3 2

26 40

4

99.2314 , found 499.2323.

rac-tert-Butyl{2-[(1S,3aS,5aR,8aR)-1,5a-dimethoxy-8-(phenylsulfonyl)-4,5,5a,8-

tetrahydropentaleno[1,6a-c]furan-3a(3H)-yl]ethoxy}dimethylsilane (16)

To a solution of 15 (56.9 mg, 0.119 mmol) in CH Cl (5 mL) was added mCPBA (64.7 mg,

2

0

.375 mmol) in CH Cl (5 mL) at 0 °C. After stirring for 1 h, the mixture was quenched with

2 2

saturated NaHCO (5 mL). The organic layer was separated and the aqueous layer was extracted

3

with CH Cl (3 × 10 mL). The combined organic layers were dried over Na SO . The solvent was

2

4

removed and the title compound (51.0 mg, 85%) was obtained as a colorless oil: R = 0.13

f

(cyclohexane/EtOAc 5:1); IR (ATR) 휈̃ = 2930, 2857, 1471, 1447, 1306, 1254, 1142, 1094, 967,

–

1 1

8

7

35, 776, 691 cm ; H NMR, COSY (400 MHz, CDCl )  = 7.84–7.82 (m, 2H, Ph-H2,6), 7.59–

3

.49 (m, 3H, Ph-H3,4,5), 6.09 (dd, J = 5.9 Hz, J = 1.2 Hz 1H, H-6), 5.84 (dd, J = 5.9 Hz,

J = 3.1 Hz, 1H, H-7), 5.40 (s, 1H, H-1), 4.54 (br d, J ≈ 3 Hz, 1H, H-8), 3.87 (dd, J = 8.9 Hz,

J = 1.6 Hz, 1H, H-3 ), 3.64–3.52 (m, 3H, H-3 , CH CH OTBS), 3.39 (s, 3H, C-5a-OCH ), 2.99 (s,

a

b

2

3

H, C-1-OCH ), 1.92 (dd, J = 12.2 Hz, J = 6.1 Hz, 1H, H-5 ), 1.87–1.82 (m, 1H, H-5 ), 1.81–1.73

3 a b

(

m, 1H, CH CH OTBS), 1.68 (dd, J = 12.7 Hz, J = 6.0 Hz, 1H, H-4 ), 1.30–1.24 (m, 1H,

2

a

CH CH OTBS), 1.12–1.04 (m, 1H, H-4 ), 0.85 (s, 9H, C(CH ) ), 0.00 (s, 6H, Si(CH ) ) ppm;

2

b

3 3

3 2

1

3

C NMR, HSQC, HMBC (100.6 MHz, CDCl )  = 143.1 (Ph-C1), 140.1 (C-6), 132.6 (Ph-C4),

3

1

29.8 (C-7), 128.8 (2C, Ph-C3,5), 127.2 (2C, Ph-C2,6), 105.4 (C-1), 95.8 (C-5a), 77.9 (C-3), 74.0

(

C-8), 69.0 (C-8a), 60.3 (CH CH OTBS), 53.4 (C-1-OCH ), 53.2 (C-3a), 53.0 (C-5a-OCH ), 41.1

2 2 3 3

European Journal of Organic Chemistry

10.1002/ejoc.201700461

(

CH CH OTBS), 35.2 (C-4), 32.4 (C-5), 26.0 (3C, C(CH ) ), 18.3 (C(CH ) ), –5.3 (2C,

2 2 3 3 3 3



Si(CH ) ) ppm; ESI-HRMS calcd for [C H O SSi + Na] 531.2213 , found 531.2198.

3

2

26 40

6

rac-tert-butyl{2-[(1S,3aS,5aR,8aR)-1,5a-dimethoxy-4,5,5a,8-tetrahydropentaleno[1,6a-c]furan-

a(3H)-yl]ethoxy}dimethylsilane (8)

3

To a suspension of Raney-Ni in EtOH (40 mL), that was washed before with water (3 × 5 mL) and

ethanol (10 × 10 mL), was added 15 (256 mg, 0.537 mmol). After stirring for 90 min at room

temperature the suspension was filtered. The solvent was removed in vacuo and the residue was

purified by column chromatography (cyclohexane + 2% NEt ) to afford the product 8 (179 mg,

3

9

1

2

1%) as a colorless oil: R = 0.25 (cyclohexane/EtOAc 10:1); IR (ATR) 휈̃ = 2930, 2858, 1471,

f

–

1 1

254, 1093, 1047, 977, 895, 836, 775 cm ; H NMR, COSY (400 MHz, CDCl )  = 5.75–5.73 (m,

3

H, H-6), 5.62–5.60 (m, 1H, H-7), 5.05 (s, 1H, H-1), 3.96 (d, J = 8.9 Hz, 1H, H-3 ), 3.68–3.66 (m,

a

H, H-3 ), 3.66–3.53 (m, 2H, CH CH OTBS), 3.29 (s, 3H, C-1-OCH ), 3.27 (s, 3H, C-5a-OCH ),

b

2

3

.69 (dt, J = 17.4 Hz, J = 2.2 Hz, 1H, H-8 ), 2.20 (dt, J = 17.4 Hz, J = 2.2 Hz, 1H, H-8 ), 1.93–1.85

a

b

(

m, 1H, H-5 ), 1.79–1.72 (m, 3H, H-5 , H-4 , CH CH OTBS), 1.47–1.39 (m, 2H, H-4 ,

a b a 2 2 b

13

CH CH OTBS), 0.88 (s, 9H, C(CH ) ), 0.03 (s, 6H, Si(CH ) ) ppm; C NMR, HSQC, HMBC

2

3 3

3 2

(

100.6 MHz, CDCl )  = 131.0 (C-6), 129.8 (C-7), 106.2 (C-1), 93.8 (C-5a), 78.2 (C-3), 75.5 (C-

3

8

a), 61.0 (CH CH OTBS), 54.5 (C-1-OCH )), 54.1 (C-3a), 51.7 (C-5a-OCH ), 41.9 (C-8), 40.1

2 2 3 3

(

CH CH OTBS), 35.4 (C-4), 33.7 (C-5), 26.1 (3C, C(CH ) ), 18.4 (C(CH ) ), –5.2 (2C,

2 2 3 3 3 2



Si(CH ) ) ppm; ESI-HRMS calcd for [C H O Si + Na] 391.2281, found 391.2286.

3

2

20 36

4

rac-(1S,3aS,5aS,6S,7S,8aR)-3a-(2-{[tert-Butyl(dimethyl)silyl]oxy}ethyl)-1,5a-

dimethoxyoctahydropentaleno[1,6a-c]furan-6,7-diol (18)

To a solution of 8 (32.5 mg, 88.2 μmol) in H O (1 mL) and tert-butanol (1 mL) were added

2

potassium osmate dihydrate (0.3 mg, 0.8 µmol) and N-methylmorpholine N-oxide (12.4 mg,

European Journal of Organic Chemistry

10.1002/ejoc.201700461

1

06 μmol). After stirring for 18 h at room temperature EtOAc (10 mL) was added. The mixture was

washed with brine (10 mL) and the organic layer was separated and dried over Na SO . Evaporation

2

4

yielded the title compound 18 (32.8 mg, 93%) as a colorless oil: R = 0.13 (cyclohexane/EtOAc

f

–

1 1

1

:2); IR (ATR) 휈̃ = 3448, 2932, 1463, 1255, 1093, 1052, 969, 835, 776, 720 cm ; H NMR, COSY

(

400 MHz, CDCl )  = 5.26 (s, 1H, H-1), 4.08–3.99 (m, 3H, H-6, H-7, H-3 ), 3.69–3.55 (m, 3H, H-

3

a

3_b, CH CH OTBS), 3.33 (s, 3H, C-1-OCH ), 3.29 (s, 3H, C-5a-OCH ), 2.25–2.18 (m, 1H, H-8 ),

2

3

a

2

.12–2.04 (m, 1H, H-8 ), 1.92–1.85 (m, 2H, H-5 , CH CH OTBS), 1.81–1.68 (m, 3H, H-5 , H-4 ,

b a 2 2 b a

OH), 1.53–1.47 (m, 1H, CH CH OTBS), 1.34–1.24 (m, 2H, H-4 , OH), 0.88 (s, 9H, C(CH ) ), 0.04

2

b

3 3

13

(

s, 6H, Si(CH ) ) ppm; C NMR, HSQC, HMBC (100.6 MHz, CDCl )  = 107.1 (C-1), 92.0 (C-

3

2

3

5

a), 80.3 (C-3), 76.2 (C-6), 72.6 (C-8a), 70.3 (C-7), 60.6 (CH CH OTBS), 54.1 (C-1-OCH ), 52.1

2 2 3

(

C-5a-OCH ), 51.5 (C-3a), 44.5 (C-8), 39.5 (CH CH OTBS), 35.2 (C-5), 35.0 (C-4), 26.1 (3C,

3 2 2



C(CH ) ), 18.4 (C(CH ) ), –5.3 (2C, Si(CH ) ) ppm; ESI-HRMS calcd for [C H O Si + Na]

3

3 3

3 2

20 38

6

4

25.2335 , found 425.2329.

3

2

3

-Methoxy-2-methylcyclopent-2-en-1-one (24)

To a suspension of 2-methyl-1,3-cyclopentanedione (23, 12.5 g, 111 mmol) and K CO (15.6 g,

2

3

1

11 mmol) in acetone (800 ml) was added dimethyl sulfate (14.0 g, 111 mmol). The mixture was

heated under reflux for 8 h. After evaporation the residue was taken up in EtOAc (150 mL) and

aqueous NaOH (1 M, 150 mL). The organic phase was separated and the aqueous phase was

extracted with EtOAc (3 × 150 mL). The combined organic layers were dried over Na SO After

2

4.

evaporation, the title compound 24 (13.8 g, 99%) was obtained as a yellow solid: mp 58.2–58.8 °C;

1

R = 0.18 (EtOAc); H NMR (400 MHz, CDCl )  = 3.89 (s, 3H, OCH ), 2.60–2.57 (m, 2H), 2.37–

f

3

13

2

.35 (m, 2H), 1.54 (t, J = 1.7 Hz, 3H, CH ) ppm; C NMR (100.6 MHz, CDCl )  = 205.3 (C=O),

3

European Journal of Organic Chemistry

10.1002/ejoc.201700461

1

84.7 (C-3), 116.0 (C-2), 56.5 (OCH ), 33.4, 24.7, 5.9 (CH ) ppm. Analytical data in accordance

3 3

3

2

with literature.

3

Methyl (2-methyl-3-oxocyclopent-1-en-1-yl)acetate (25)

To a freshly prepared sodium methanolate solution (2.58 g sodium in 250 mL MeOH, 112 mmol

NaOMe) was added dimethyl malonate (13.6 g, 103 mmol). After stirring for 15 min the enol ether

2

4 (11.8 g, 93.4 mmol) in MeOH (50 mL) was added. The mixture was heated under reflux for

4

8 h. After cooling to 0 °C concentrated hydrochloric acid was added until pH 7. The solvent was

removed in vacuo and the residue was taken up in brine (150 mL). The solution was extracted with

Et O (2 × 200 mL) and the combined organic layers were dried over Na SO . Distillation yielded 25

2

4

(

11.1 g, 72%) as a yellow liquid: bp 110 °C (1.5 mbar); R = 0.47 (cyclohexane/EtOAc 2:1);

f

1

H NMR (400 MHz, CDCl )  = 3.69 (s, 3H, OCH ), 3.41 (s, 2H), 2.59–2.55 (m, 2H), 2.39–2.37

3

1

3

(

m, 2H), 1.69–1.68 (m, 3H) ppm; C NMR (100.6 MHz, CDCl )  = 209.4, 169.6, 163.5, 139.0,

3

5

2.4, 36.8, 34.2, 29.9, 8.2 ppm. Analytical data in accordance with literature.

3

-(2-Hydroxyethyl)-2-methylcyclopent-2-en-1-ol (26)

To a suspension of LiAlH (8.98 g, 237 mmol) in Et O (600 mL) was added slowly a solution of

4

2

ester 25 (19.7 g, 118 mmol) in Et O (30 mL) at 0 °C. The mixture was heated under reflux for 1 h.

2

After cooling to 0 °C the mixture was quenched carefully with Glauber`s salt. The suspension was

filtered and washed with Et O (150 mL). The solution was dried over Na SO and evaporation

2

4

afforded the title compound 26 (13.2 g, 79%) as a colorless oil: R = 0.17 (EtOAc); IR (ATR)

f

–

1 1

휈̃ = 3335, 2936, 2850, 1677, 1437, 1379, 1043, 921, 846, 730 cm ; H NMR, COSY (400 MHz,

CDCl )  = 4.62–4.59 (m, 1H, H-1), 3.71–3.67 (m, 2H, CH OH), 2.51–2.43 (m, 1H, H-4 ), 2.41–

3

2

a

2

.37 (m, 1H, CH CH OH), 2.34–2.29 (m, 1H, CH CH OH), 2.28–2.20 (m, 2H, H-4 , H-5 ), 1.99

2 2 2 2 b a

13

(

s , 2H, OH), 1.72–1.71 (m, 3H, CH ), 1.68–1.62 (m, 1H, H-5 ) ppm; C NMR, HSQC, HMBC

br

3

b

European Journal of Organic Chemistry

10.1002/ejoc.201700461

(

100.6 MHz, CDCl )  = 136.6 (C-2), 136.2 (C-3), 81.5 (C-1), 60.8 (CH CH OH), 33.1

3

2

(

CH CH OH), 32.6 (C-4), 32.3 (C-5), 11.4 (CH ) ppm; ESI-HRMS calcd for [2 × C H O –

2

3

8

14

2



H O + Na] 289.1780 , found 289.1786.

2

-Methyl-3-[2-(prop-2-yn-1-yloxy)ethyl]cyclopent-2-en-1-ol (27)

To a biphasic mixture of CH Cl (60 mL) and aq. NaOH (40%, 60 mL) were added diol 26 (13.1 g,

2

9

2.1 mmol), tetrabutylammonium hydrogen sulfate (400 mg, 1.18 mmol) and propargyl bromide

(80% in toluene, 10.9 mL, 102 mmol). After stirring for 24 h at room temperature, the mixture was

diluted with water (100 mL). The organic layer was separated and the aqueous layer was extracted

with CH Cl (3 × 50 mL). The combined organic layers were dried over Na SO and evaporated.

2

4

After purification via column chromatography (cyclohexane/EtOAc 3:1), the title compound 27

6.81 g, 41%) was obtained as a colorless liquid: R = 0.09 (cyclohexane/EtOAc 3:1); IR (ATR)

(

f

–1 1

휈̃ = 3293, 2852, 1441, 1357, 1259, 1170, 1091, 1048, 973, 663 cm ; H NMR, COSY (400 MHz,

CDCl )  = 4.59 (s , 1H, H-1), 4.14 (d, J = 2.4 Hz, 2H, CH C≡CH), 3.57 (t, J = 7.1 Hz, 2H,

3

br

2

OCH CH ), 2.45–2.38 (m, 4H, C≡CH, OCH CH , H-4 ), 2.28–2.20 (m, 1H, H-4 ), 1.71–1.69 (m,

2

a

b

1

3

H, CH ), 1.66–1.59 (m, 2H, H-5) ppm; C NMR, HSQC, HMBC (100.6 MHz, CDCl )  = 136.2

3

(

C-3), 135.6 (C-2), 81.5 (C-1), 79.9 (C≡CH), 74.4 (C≡CH), 68.3 (OCH CH ), 58.1 (CH C≡CH),

2 2 2



3

2

3.2 (C-4), 32.7 (C-5), 29.2 (OCH CH ), 11.3 (CH ) ppm; ESI-HRMS calcd for [C H O + Na]

2 2 3 11 16 2

03.1048 , found 203.1053.

2

-Methyl-3-[2-(propadienyloxy)ethyl]cyclopent-2-en-1-ol (28)

t

To a solution of alkyne 27 (999 mg, 5.54 mmol) in THF (100 mL) was added KO Bu (20% in THF,

3

.8 mL, 6.1 mmol). After stirring for 4 h at room temperature, the mixture was diluted with CH Cl

2

(

100 mL). The solution was washed with water (100 mL) and dried over Na SO . Evaporation of

2 4

the solvent under reduced pressure yielded the allenyl ether 28 (949 mg, 95%) as a colorless oil:

European Journal of Organic Chemistry

10.1002/ejoc.201700461

R = 0.28 (cyclohexane/EtOAc 2:1); IR (ATR) 휈̃ = 3339, 2937, 1952, 1444, 1351, 1193, 1041, 889,

f

–

1 1

8

54, 732 cm ; H NMR, COSY (400 MHz, CDCl )  = 6.70 (t, J = 5.9 Hz, 1H, CH=C=CH ), 5.43

3

2

(

d, J = 5.9 Hz, 2H, CH=C=CH ), 4.58 (s , 1H, H-1), 3.60 (t, J = 7.0 Hz, 2H, OCH CH ), 2.49–2.37

2 br 2 2

(

m, 3H, OCH CH , H-4 ), 2.28–2.15 (m, 2H, H-4 , H-5 ), 1.69–1.66 (m, 3H, CH ), 1.65–1.58 (m,

2 2 a b a 3

1

3

1

4

2

H, H-5 ) ppm; C NMR, HSQC, HMBC (100.6 MHz, CDCl )  = 201.3 (CH=C=CH ), 135.9,

b

3

2

35.9 (C-2, C-3), 121.6 (CH=C=CH ), 90.8 (CH=C=CH ), 81.4 (C-1), 66.9 (OCH CH ), 33.2 (C-

2



), 32.7 (C-5), 28.8 (OCH CH ), 11.3 (CH ) ppm; ESI-HRMS calcd for [C H O + Na]

2

3

11 16

2

03.1048, found 203.1046.

-Methyl-3-[2-(propadienyloxy)ethyl]cyclopent-2-en-1-one (22)

To a solution of 28 (88.5 mg, 0.491 mmol) in THF (20 mL) and DMSO (20 mL) was added freshly

3

4

prepared IBX (206 mg, 0.737 mmol) in one portion. After stirring for 5 h at room temperature the

mixture was diluted with Et O. The mixture was cooled to –10 °C and quenched with sat. NaHCO

2

3

(

30 mL). The organic layer was separated and the aqueous phase was extracted with Et O

2

(

3 × 20 mL). The combined organic layers were washed with water (4 × 20 mL), dried over Na SO

2

4

and evaporated. The unstable product 22 (83.7 mg, 96%) was obtained as a colorless oil which was

directly used in the subsequent transformation: R = 0.19 (cyclohexane/EtOAc 5:1); IR (ATR)

f

–1 1

휈̃ = 2921, 1952, 1646, 1444, 1351, 1303, 1192, 1045, 893 cm ; H NMR, COSY (400 MHz,

CD CN)  = 6.75 (t, J = 6.0 Hz, 1H, CH=C=CH ), 5.47 (d, J = 6.0 Hz, 2H, CH=C=CH ), 3.77 (t,

3

2

J = 6.4 Hz, 2H, OCH CH ), 2.76 (t, J = 6.4 Hz, 2H, OCH CH ), 2.54–2.51 (m, 2H, H-4), 2.29–2.26

2

13

(

m, 2H, H-5), 1.64–1.63 (m, 3H, CH ) ppm; C NMR, HSQC, HMBC (100.6 MHz, CDCl )

3



 = 210.0 (C-1), 202.0 (CH=C=CH ), 170.9 (C-3), 137.8 (C-2), 122.0 (CH=C=CH ), 91.4

2

(

CH=C=CH ), 66.8 (OCH CH ), 34.6 (C-5), 31.6 (OCH CH ), 29.9 (C-4), 8.2 (CH ) ppm.

2 2 2 2 2 3

European Journal of Organic Chemistry

10.1002/ejoc.201700461

rac-(3aS,4aS,7aR)-4a-Methyl-4-methylidenehexahydrocyclopenta[2,3]cyclobuta[1,2-b]furan-

(3aH)-one (21a)

5

The photoprecursor 22 (143 mg, 0.802 mmol) in pentane (200 mL) was degassed and irradiated

1

3

50 nm, 16 × 8 W). After H NMR spectroscopy indicated consumption of the starting material

(20 h), the solvent was removed in vacuo. Purification of the residue via column chromatography

(cyclohexane/EtOAc 10:1) afforded the photoproduct 21a (28.0 mg, 20%) as colorless crystals: mp

7

1

4.5–75.3 °C; R = 0.08 (cyclohexane/EtOAc 10:1); IR (ATR) 휈̃ = 2926, 1735, 1453, 1411, 1195,

f

–

1 1

114, 1064, 937, 885, 683 cm ; H NMR, COSY (400 MHz, CDCl )  = 5.18–5.17 (m, 1H,

3

C=CH₂_,_c_i_s), 5.13–5.12 (m, 1H, C=CH₂_,_t_r_a_n_s), 4.71 (t, J = 1.2 Hz, 1H, H-3a), 4.15–4.11 (m, 1H, H-2_a),

.81 (ddd, J = 11.8 Hz, J = 9.1 Hz, J = 5.3 Hz, 1H, H-2 ), 2.60 (ddd, J = 18.2 Hz, J = 12.8 Hz,

3

b

J = 8.9 Hz, 1H, H-6 ), 2.39 (ddd, J = 18.2 Hz, J = 8.4 Hz, J = 1.1 Hz, 1H, H-6 ), 2.10 (ddd,

a

b

J = 12.8 Hz, J = 8.8 Hz, J = 1.1 Hz, 1H, H-7 ), 2.01–1.92 (m, 2H, H-7 , H-1 ), 1.78 (ddd,

a

b

a

13

J = 13.0 Hz, J = 11.8 Hz, J = 8.0 Hz, 1H, H-1 ), 1.13 (s, 3H, CH ) ppm; C NMR, HSQC, HMBC

b

3

(

[

100.6 MHz, CDCl )  = 217.6 (C-5), 149.5 (C-4), 111.6 (C=CH ), 83.8 (C-3a), 68.5 (C-2), 57.1

3

2

C-7a), 56.2 (C-4a), 37.6 (C-6), 32.1 (C-1), 28.8 (C-7), 13.4 (CH ) ppm; ESI-HRMS calcd for

3



C H O + H] 179.1072 , found 179.1067; Crystals suitable for X-ray crystallography could be

1

14

2

obtained by evaporation of the solvent after column chromatography.

3

5

1

-(2-tert-Butylphenyl)-1H-pyrrole-2,5-dione (33)

2

-tert-Butylaniline (4.43 g, 29.7 mmol) and maleic anhydride (8.70 g, 88.7 mmol) were mixed in a

closed round bottom flask and heated to 120 °C for 16 h. After cooling to room temperature the

®

solid was taken up in EtOAc (100 mL) and filtered over Celite . After evaporation the residue was

purified via column chromatography (cyclohexane/EtOAc 5:1  2:1) and the title compound 33

1

(

6.33 g, 93%) was obtained as a colorless solid: R = 0.10 (cyclohexane/EtOAc 9:1); H NMR (400

f

European Journal of Organic Chemistry

10.1002/ejoc.201700461

MHz, CDCl )  = 7.59 (dd, J = 8.1 Hz, J = 1.5 Hz, 1H), 7.43–7.39 (m, 1H), 7.28 (dt, J = 7.7 Hz,

3

J = 1.5 Hz, 1H), 6.90 (dd, J = 7.7 Hz, J = 1.5 Hz, 1H), 6.89 (s, 2H, H-3,4), 1.30 (s, 9H,

1

3

C(CH ) ) ppm; C NMR (100.6 MHz, CDCl )  = 171.0 (2C, C=O), 149.7, 135.2 (2C, C-3,4),

3

1

31.5, 130.0, 129.2, 128.8, 127.5, 35.6 (C(CH ) ), 31.7 (3C, C(CH ) ) ppm. Analytical data in

3 3 3 3

3

5

accordance with literature.

rac-(3R,S )-1-(2-tert-Butylphenyl)-3-(furan-3-yl)pyrrolidine-2,5-dione (36)

a

2

6

The title compound was synthesized by a modification of the protocol of Duan et al. To a solution

of [RhCl(COD)] (6.45 mg, 13.1 µmol) in dioxane was added a solution of KOH (7.34 mg,

2

0

.131 mmol) in H O (0.5 ml). After stirring for 10 min at room temperature, 3-furanylboronic acid

2

(87.9 mg, 0.786 mmol) was added and stirred for 3 min. After addition of imide 33 (60.0 mg,

0

.262 mmol) the mixture was stirred for 5 h at 50 °C. The mixture was filtered over silica gel and

the solvent was removed under reduced pressure. Purification of the residue via column

chromatography (cyclohexane/EtOAc 5:1) afforded the title compound 36 (66.6 mg, 86%) as a

colorless oil: R = 0.29 (cyclohexane/EtOAc 5:1); IR (ATR) 휈̃ = 2966, 1705, 1491, 1442, 1376,

f

–

1 1

1

300, 1179, 1019, 941, 873 cm ; H NMR, COSY (400 MHz, CDCl )  = 7.60 (dd, J = 8.2 Hz,

3

J = 1.4 Hz, 1H, Ph-H3), 7.54–7.53 (m, 1H, furyl-H2), 7.47 (t, J = 1.7 Hz, 1H, furyl-H5), 7.42–7.38

(

m, 1H, Ph-H4), 7.30–7.26 (m, 1H, Ph-H5), 6.82 (dd, J = 7.8 Hz, J = 1.5 Hz, 1H, Ph-H6), 6.48–6.47

m, 1H, furyl-H4), 4.14 (ddd, J = 9.6 Hz, J = 5.1 Hz, J = 1.0 Hz, 1H, H-3), 3.35 (dd, J = 18.3 Hz,

(

J = 9.6 Hz, 1H, H-4 ), 2.93 (dd, J = 18.3 Hz, J = 5.1 Hz, 1H, H-4 ), 1.34 (s, 9H, C(CH ) ) ppm;

a

b

3 3

1

3

C NMR, HSQC, HMBC (100.6 MHz, CDCl )  = 177.4 (C-5), 175.9 (C-2), 148.1 (Ph-C2), 144.2

3

(furyl-C5), 140.0 (furyl-C2), 130.8 (Ph-C6), 130.3 (Ph-C1), 130.1 (Ph-C4), 129.1 (Ph-C3), 127.6

(

Ph-C5), 120.7 (furyl-C3), 109.5 (furyl-C4), 37.6 (C-4), 36.4 (C-3), 35.8 (C(CH ) ), 31.8 (3C,

3



C(CH ) ) ppm; ESI-HRMS calcd for [C H NO + H] 298.1443, found 298.1447.

3

18 19

3

Article Doi

Photochemical Approaches to the Bilobalide Core

DOI: 10.1002/ejoc.201700461

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