Approach towards an EPC synthesis of nodusmicin. Part 5: Stereoselective introduction of a side chain at the cis-decalin part of nodusmicin

TETRAHEDRON

Pergamon

Tetrahedron 57 82001) 3045±3061

Approach towards an EPC synthesis of nodusmicin. Part 5:^q

Stereoselective introduction of a side chain at the

cis-decalin part of nodusmicin

p

Edda Gossinger, Alexander Schwartz and Natascha Sereinig

È

È È È

Institut fur Organische Chemie, Universitat Wien, Wahringerstr. 38, A-1090 Wien, Austria

Received 9 October 2000; revised 29 January 2001; accepted 31 January 2001

AbstractÐThe introduction of the side chain at C-4 of cis-decalin 2 and closure of the oxygen bridge are reported. Partial dehydrogenation

of 2 was followed by oxymercuration and halogen±mercury exchange. Intermolecular radical addition to acrylic ester occurred from the

convex face of the tricyclic compounds 7a and 7b. Consecutive epimerization failed. Therefore, two methods using intramolecular attach-

ment of the side chain were developed. Formation of the b-iodoacetal of the cyclic allylic alcohol 21 permitted intramolecular radical

addition generating the desired con®guration at C-4 of the decalin. Likewise formation of the b bromoacetal with the exo-cyclic hydroxy

group of tricycle 12 led via S_N2-reaction to tetrahydropyrans with the desired con®guration at C-4. The oxygen bridge was introduced by

dehydration of the exo-cyclic alcohol and consecutive oxymercuration. Mercury±oxygen exchange completed the reaction sequence.

The increasing resistance of bacterial pathogens to antibiotics

necessitates the development of new and effective antibiotic

species.²We therefore chose nodusmicin 81)^3,4as a target of a

convergent enantiomerically pure synthesis. This macrolide

antibiotic was isolated from cultures of Saccharopolyspora

hirsuta⁴and, like the structurally related nargenicins,⁵is

active against Gram positive bacteria. This activity extends

to drug resistant bacteria and is coupled with low toxicity

and substantial oral activity.⁶These facts and its unusual

structure initiated several approaches towards the synthesis

of nodusmicin⁷which have culminated in the total synthesis

of 18-deoxynodusmicin by Kallmerten et al.^7g

As we have shown earlier, the ether bridge can be success-

fully introduced in the octalin system by oxy-mercuration.^7k

This strategy can be used to attach the ester side chain by

intermolecular radical addition. Therefore, decalin 2 was

partially dehydrogenated to octalindione 4 under improved

conditions with ferric chloride, strong base and low

temperatures. Luche reduction led to the diastereomeric

octalintriols 5a and 5b 81⁰R^p/1⁰S^p1:2.5).^7kThis mixture

was transformed to the chromatographically separable

crystalline oxygen bridged mercury compounds 6a and

6b.⁸The separated compounds were treated with iodine in

methylene chloride.⁹As noted in the literature,^9,10halogen±

mercury exchange with rather unpolar solvents afforded

diastereomeric mixtures of the iodides in high yields.

NMR data especially NOESY experiments permitted the

So far we have completed the synthesis of the highly

substituted oxygen bridged decalin fragment^7i,kand have

developed methods to extend the exo-cyclic acetyl group

of bicyclic compound 2 to the unsaturated substituted side

chain by adding the enantiomerically pure fragment 3.¹

Herein we report our attempts to stereoselectively attach

the remaining subunit of our convergent synthesis to the

cis-decalin system. In anticipation of the dif®culties

associated with attaching this group to the already highly

substituted decalin fragment,^7fwe have designed several

pathways 8Scheme 1).

O

H

OBn

H

19

OH

2

18

20

O

OBn

H

O

1

16

OH

21

O

OTBDMS

14

HO

OCH₃

H

22

23

11

3

4

H

O

OBn

5

RO

8

H

^qFor Part 4 see ref. 1.

Y

1

R = H: Nodusmicin

Y

or

RO

C₂H₅O

Keywords: total synthesis; antibiotic; nodusmicin; radical addition; substi-

tuted cis-decalins.

Corresponding author. Tel.: 143-01-4277152142; fax: 143-01-

R = : Nargenicin A₁

X

N

X = H or OCH₃

Y = Br, I

p

H

O

427719521; e-mail: edda.goessinger@univie.ac.at;

edgo@felix.orc.univie.ac.at

Scheme 1.

PII: S0040-4020801)00155-7

È

E. Gossinger et al. / Tetrahedron 57 -2001) 3045±3061

3046

R¹

O

R²

OBn

OH

OBn

OH

1. Hg(OCOCF₃)₂

HgO, THF, 0 °C

H

KH, t-BuOK

CeCl₃, NaBH₄

MeOH, -78 °C

76%

FeCl₃, THF, DMF

-78 °C, 90%

2. NaCl

O

OBn

O

OBn

HO

72%

H

OH

2

4

5a R¹= OH, R²= H

5b R¹= H, R²= OH

5a : 5b = 1: 2.5

OBn

BnO

HO

H

OBn

O

OH

BnO

R²

I

OH

R¹

9

I₂, CH₂Cl₂, 0 °C

96%

7c

7d

I = exo

I = end

7c : 7d = 2:1

ethyl acrylate

NaCNBH₃, Bu₃SnCl

t-BuOH, AIBN, 85 °C

O

H

ClHg

+

6a R¹= OH, R²= H

6b R¹= H, R²= OH

6a : 6b = 1 : 2.5

OBn

BnO

HO

H

O

I

OH

EtO

7a

7b

I = exo

I = endo

50%

8

7a : 7b = 4.6:1

Scheme 2.

assignment of the relative con®guration of the exo-cyclic

stereocenter as well as the newly formed 8cyclic) stereo-

center containing the iodide substituent. The R^p-con®gu-

rated alcohol 6a led to a 4.6:1 mixture of easily separable

iodides, with the exo-positioned iodide 7a, derived by reten-

tion of con®guration, as the main compound. The byproduct

7b possesses a high inversion barrier leading to coalescence

near room temperature. However, high temperature NMR-

measurements revealed the vicinal cis-position of the iodide

and the cyclic hydroxy group and thus the endo-position of

the iodide. The S^p-con®gurated exo-cyclic alcohol 6b led

under identical conditions to an inseparable 2:1 mixture of

exo- and endo-iodides 7c and 7d, indicating stronger steric

hindrance on the convex face of this diastereoisomer.

bis8trialkyl)stannanes,¹²tris8trimethyl)silylsilane,¹³and tri-

alkylborane/oxygen¹⁴were examined as mediators.) Best

results were achieved with catalytic amounts of tributyl-

stannyl chloride and NaCNBH₃.¹⁵Even under these condi-

tions only the R^p-con®gurated exo-cyclic alcohols 7a and 7b

produced ester 8 in 50% yield, whereas the S^p-con®gurated

alcohols were completely reduced to 9^7kdue to stronger

steric interactions in the main conformation which has a

hydrogen bridge between the exo-cyclic alcohol and the

benzyl ether oxygen. No addition product was detected

even with the R^p-con®gurated alcohols when using

a-methoxyacrylic ester 8Scheme 2).

To improve the overall yields we looked for more selective

reductants of the exo-cyclic ketone of 4. We were able to

achieve exclusive formation of the S^p-con®gurated alcohol

10b with the reagent combination MAD/DIBAL/n-BuLi/

toluene/2908C.¹⁶However, the best results to gain the

Iodides 7 were treated under a variety of radical reaction

conditions with acrylic esters to achieve radical addition.¹¹

8With radical initiators, AIBN or hn, tributyl stannanes,

HO H

H OH

O

OBn

OH

+

OBn

OH

10a

0

10b

1

4

O

a: MAD/DIBAL/

n-BuLi/toluene/-90 °C

b: MAD/DIBAL/

CH₂Cl₂/-90 °C

1.9

1

Scheme 3.

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E. Gossinger et al. / Tetrahedron 57 -2001) 3045±3061

3047

OBn

O

OBn

OH

H

BnO

TBDMSOTf

DIBAL

THF, -78 °C

88% 2 steps

CH₂Cl₂, Et₃N

-50 °C

O

HO

12

OBn

O

OTBDMS

2

11

OBn

R¹R²

BnO

O

SOCl₂

pyridine

MCPBA, NaHCO₃

TBAF, THF, 0 °C

42% 3 steps

OBn

CH₂Cl₂, 0 °C

radical scavenger

OBn

OH

O

10a:10b = 10:1

OTBDMS

13

14

O

10a: R¹= OH, R²= H

10b: R¹= H, R²= OH

Scheme 4.

desired R^p-con®gurated alcohol 10a by hydride reduction

were a meagre 1.9:1 mixture of 10a/10b using MAD/

DIBAL/methylene chloride/2908C 8Scheme 3).¹⁷

ing enones proved inert toward intramolecular 1,4-addition.

Oxymercuration was examined as a further possibility to

obtain the desired endo positioned side chain by reducing

ketone 17 to triol 19.²¹However, the diol 17 and its deriva-

tive 18 as well as triol 19 were inert against mercuric

tri¯uoroacetate 8Scheme 5).

Thus a quite different approach was chosen to afford the

R^p-con®gurated alcohol in good yields.

Dione 2 could be converted to the cyclic ketal 11 by treat-

ment with tert-butyl dimethyl silyl tri¯ate.^7kTransformation

to the enones 10a and 10b was achieved via reduction of the

exo-cyclic ketone 11 to alcohol 12 with DIBAL, dehydra-

tion with SOCl₂to ole®n 13, and epoxidation with peracid¹⁸

to 14. Treatment of 14 with a basic ¯uoride ion source

removed the silyl group and concomittantly opened the

epoxide via an E1_cb-reaction to provide the a,b-unsaturated

ketone 10 8in a 10:1 mixture of 10a/10b) 8Scheme 4).

To prevent addition from the sterically less hindered convex

face of the molecule, we now turned to intramolecular

radical reactions. We hoped to force attack from the more

hindered concave side of the molecule by connecting the

side chain to the cyclic endo-hydroxy group and then

forming a fused perhydrofuran where cis-connection is

kinetically as well as thermodynamically favored. To

achieve this goal, enedione 4 was protected as MOM-

ether 20 prior to regioselective reduction to 21 by inverse

addition of Luche's reagent.^21cHowever, the use of a-halo-

acetate²²for radical cyclization purposes proved

unsuccessful. Since we suspected the sp²-center as the

main reason of this failure²³we replaced the haloester by

a haloacetal.²⁴

The relative con®guration of the newly formed cyclic

stereocenter had to be determined and if necessary

epimerized. Therefore, the cyclic hydroxy group of 8 had

to be oxidized. Due to steric reasons, the differentiation of

the two hydroxy functions could be achieved by using

exactly one equivalent of Dess±Martin¹⁹or Jones reagent²⁰

to provide the mono oxidized cyclic ketone 15 in good

yields. NOE experiments with 15 and the corresponding

methoxy methyl ether 16 revealed that irradiation at the

signal of the bridgehead proton H-8 increased the intensity

of two of the proton signals of the newly attached side chain.

This effect is only possible if the side chain was introduced

from the less hindered convex face of the molecule.

Thus allyl alcohol 21 was treated with ethyl vinyl ether and

N-iodosuccinimide²⁵to yield a diastereomeric mixture of

the acetals 22a and 22b 81:1). Radical cyclization of these

haloacetals afforded the desired heterocycles 23a and 23b,²⁶

which could be separated for analytical purposes, in good to

high yield with up to 10% of the over-reduced exo-cyclic

alcohol. The radical generated by the cyclization was

quenched by hydrogen addition from the convex face of

the molecule. Attempts to introduce a halogen instead of

hydrogen by halogen transfer using either Co8I)

complexes²⁷or SmI₂and iodine²⁸led to disappointingly

low yields in the halosubstituted cyclic products with reduc-

tion product 23 as the major compound.

Neither acidic nor basic conditions led to epimerization of

the stereogenic center of adduct 15 and 16, respectively. The

only reaction observed was E1_cb-elimination to octalinones

17 and 18, respectively, under basic conditions. The result-

OBn

1 eq Jones or

HO H

RO H

NaBH₄

CeCl₃

MeOH

BnO

RO

BnO

HO

OBn

EtONa, EtOH

50%

OBn

H

Dess-Martin

reagent

OBn

OH

OBn

OH

O

EtO

0 °C,76%

R = H

OH

90%

O

8

O

OH

17 R = H

15 R = H

EtO

O

EtO

O

18 R = MOM

19

16 R = MOM

Scheme 5.

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E. Gossinger et al. / Tetrahedron 57 -2001) 3045±3061

3048

O

MeOH, CeCl₃

NaBH₄, 81%

OBn

OR

O

NaCNBH₃, Bu₃SnCl

AIBN, t-BuOH, 85 °C

H

I

NIS, CH₂Cl₂, -20 °C

92%

82%

HO

OBn

O

OBn

OMOM

O

OBn

22

21

OMOM

MOMCl, CH₂Cl₂

i-Pr₂EtN, 83%

4 : R = H

20: R = MOM

O

OBn

H

1. H₃O⁺, H₂O, 40 °C

H

1. NaBH₄, MeOH

2. LAH, THF, 0 °C

84%, 2 steps

O

HO

2. SOCl₂, Py, 0 °C

77% 2 steps

HO

OBn

OMOM

OBn

OMOM

OBn

OMOM

H

23

25

26a = E

26b = Z

26a : 26b = 3:1

1. Hg(OCOCF₃)₂,

HgO, THF, rt or 0 °C;

NaCl

1. H₃O⁺, MeOH,

50 °C, 81%

OBn

H

RO

TBDMSO

O

2. TBDMSCl, Im,

DMF, DMAP, 81%

HO

2. NaBH₄,O₂,DMF

44% two steps

OBn

H

OH

27a R= H

29a

29b

28a R= TBDMS

Scheme 6.

To close the ether bridge the following pathway was

designed. The exo-cyclic keto group of 23 was converted

into the trisubstituted ole®ns 25 8E/Z3:1) via reduction

with sodium borohydride to the inseparable epimeric exo-

alcohols 24 and consecutive dehydration. The diols 26 were

obtained by hydrolysis of the acetal and immediate

reduction.

tions failed to react. Reaction of the organo-mercury

compound with sodium borohydride in methanol at 08C

led to starting material 28 by retro-oxymercuration.

Stronger basic conditions for the sodium borohydride

reduction diminished this side reaction²⁹but increased

oxygen sensitivity which led to several products, one of

them is the oxidation product 29. To improve this desirable

consecutive reaction we used Whitesides' reaction condi-

tionsÐoxygen, DMF, sodium borohydride³⁰Ðwhich led

mainly to the epimeric exo-cyclic alcohols 29. However,

retro-oxymercuration was not totally suppressed leading

to 16% of starting material 28 8Scheme 6).

After separation on silica gel the diastereoisomers were

treated individually. Hydrolysis of the methoxy methyl

ether 26 to secondary alcohol 27 and regioselective pro-

tection of the primary alcohol led to silyl ether 28. The

con®guration of the double bond in 28a was determined

by NOESY experiments to be in the E-con®guration. Intra-

molecular oxymercuration of 28a with mercury8II)tri¯uor-

acetate and mercury8II)oxide was very fast. Addition of

sodium chloride allowed the isolation of the oxygen bridged

organomercury chloride. Surprisingly 28b 8with the

Z-con®gurated double bond) treated under identical condi-

A further route with an intramolecular nucleophilic substi-

tution as the key step was developed. The exo-cyclic alcohol

of tricyclic compound 12 was converted to the mixed acetals

30 by 1,2-dibromo-1-ethoxyethane or ethyl vinyl ether and

N bromosuccinimide.³¹Desilylation of 30 to 31 was

followed by protection of the secondary alcohol because

H

OBn

1,2-dibromo-1-ethoxy

ethane, CH₂Cl₂,

dimethylaniline, 0 °C - rt

O

OBn

BnO

H

BnO

H

TBAF, THF

0 °C - rt

Br

O

or

O

OBn

HO

NBS, CH₂Cl₂,

-20 - 5 °C

OTBDMS

12

OTBDMS

O

30

31

OH

H

O

OBn

O

OBn

H

OBn

H

MOMCl

i-Pr₂EtN, CH₂Cl₂

t-BuOK, toluene

100 °C, 81%

+

Br

O

OBn

OMOM

O

OBn

OMOM

35 °C, 66%, 3 steps

O

OBn

OMOM

H

33c

33a endo OC₂H₅

33b exo OC₂H₅

32

Scheme 7.

È

E. Gossinger et al. / Tetrahedron 57 -2001) 3045±3061

3049

the desired alkylation under basic conditions in a-position

to the ketone³²was hampered by the free hydroxyl group.

The cyclization rates of the two diastereoisomers of 32

under basic conditions were quite different. Nonetheless

both could be transformed in high yields to the tricyclic

perhydropyrans 33 when treated with t-BuOK in toluene

at 1008C. Cyclization with the separated diastereoisomers

showed that one cyclized within 5 h at 808C whereas the

other one required 15 h at 1008C. The faster cyclizing

compound with the R^p-con®guration at the acetalic carbon,

gave a mixture of diastereomers 84:1) at 808C. NOESY

experiments revealed that the main component was the

trans fused tetrahydropyran derivative 33a with all three

rings in a chair conformation, the ethoxy substituent in an

equatorial position, and the heterocyclic methyl group in an

axial position. The byproduct was the cis-fused tetrahydro-

pyran derivative 33c. The higher temperature needed for the

alkylation of 32 with the S^p-con®guration at the anomeric

center led exclusively to the trans-fused pyran 33b with all

three rings in a chair conformation and both substituents of

the heterocycle in an axial position 8Scheme 7).

organic layers were washed with brine and dried over

Na₂SO₄. After ®ltration and evaporation the product was

puri®ed by column chromatography with petroleum ether/

ethyl acetate 82:1) to afford 2.59 g 890%) 4 as light sensitive

yellowish crystals mp 111±1128C.

1.1.2. *1R,3S,4R,5S,7R,8S,9R,10R,11R)-9,11-Dibenzyl-

oxy-5-hydroxy-3-*1⁰-hydroxyethyl)-10-methyl-2-oxatri-

cyclo [5.4.0.0^3,8] undec-4-yl mercury chloride *6). A

solution of 216 mg 80.49 mmol) 5a/5b 81:2.5)^7kin dry

THF 85 ml) was treated at 08C with 105 mg 80.245 mmol)

mercury8II)tri¯uoroacetate and 54 mg 80.245 mmol)

mercury8II)oxide under an argon atmosphere. After stirring

for 1 h brine was added and the two-layer system was vigor-

ously stirred for 15 min. The aq. layer was extracted four

times with ethyl acetate, the combined organic layers were

washed with brine and dried over Na₂SO₄. After ®ltration

and evaporation the products were puri®ed and separated by

column chromatography with petroleum ether/ethyl acetate

81:2) to afford 6a and 6b 8239 mg, 72%, diastereomeric

ratio1: 2.5).

Thus we have successfully attached the side chain to the cis

decalin 82) with the correct con®guration at the newly

formed stereocenter via two different pathways. In conse-

quence we demonstrated with tricyclic compound 23 that

closure of the ether bridge is possible. Several options for

the stereo- and enantioselective extension of the side chain

to the a-substituted propanoate exist.³³

6a. White crystals, mp 75±808C. [a]²⁰12.868 8c0.7 g/

D

100 ml in CH₂Cl₂); IR3468 8OH), 2931 8C±H); ¹H NMR:

d1.08 8d, J6.5 Hz, 3H, 10-CH₃), 1.10 8d, J6.5 Hz, 3H,

2⁰-H), 1.94 8m, J_gem14.6 Hz, J₅,J₇,4 Hz, 1H, 6exo-H),

1.99 8m, J_gem15 Hz, J₅,J₇,J₄,1.5 Hz, 1H, 6endo-H),

2.10 8d, J₉3 Hz, 1H, 8-H), 2.29 8ddq, J_CH3,J₁₁,6 Hz,

J₉11.4 Hz, 1H, 10-H), 2.44 8dd, J_6ex,J_6en,2.7 Hz, 1H,

7-H), 2.79 8m, w_1/24.6 Hz, 1H, 4-H), 3.27 8d, J₅10 Hz,

1H, 5-OH), 3.38 8dd, J₁₀11 Hz, J₈3 Hz, 1H, 9-H), 3.49

0

8dd, J₁,J₁₀,5 Hz, 1H, 11-H), 3.74 8d, J₁5 Hz, 1H, 1 -

1. Experimental

1.1. General

OH), 4.32 8dd br, J_OH9.2 Hz, J_6exo3 Hz, 1H, 5-H), 4.39

8d, J₁₁5 Hz, 1H, 1-H), 4.42 8m, 1H, 1⁰-H), 4.43 8s, 2H, Bn),

4.47 8d, J10.5 Hz, 1H, Bn), 4.61 8d, J10.5 Hz, 1H, Bn),

7.0±7.4 8m, 10H, Ph); ¹³C NMR: d13.52/16.15 810-CH₃,

C-2⁰), 37.66 8C-6), 36.06/37.96/52.65/55.20 8C-4,7,8,10),

66.96/69.70/79.53/81.35/84.79 8C-1⁰,1,5,9,11), 73.09/

75.16 8Bn), 91.68 8C-3), 127.7±129.2 8Ph), 136.78/138.14

8Ph); MS 8FI,190±2408): m/z 8%)420 8100) [M¹2HgCl, ±

OH], 91 810) [C₇H₇¹]; Anal. Calcd for C₂₇H₃₃ClHgO₅:

C74.29%, H7.39%, found: C74.02%, H7.39%.

¹H and ¹³C NMR spectra were recorded on a Bruker Spectro-

spin AM 400-WB 8400 MHz) with CDCl₃as solvent at 248C

unless stated otherwise. EI mass spectra were recorded on a

spectrometer 8230 8Finnigan) and FI mass spectra on a MAT

900S 8Finnigan). IR spectra were recorded on a Perkin±

Elmer 1600 FTIR spectrometer neat on silicon and given in

wave numbers 8cm²¹). Optical rotations were recorded on a

Perkin±Elmer 241 polarimeter with the sodium D line. Melt-

ing points were obtained using a Reichert 'Ko¯er` hot stage

microscope and are uncorrected. Silica gel 8230±400 mesh

ASTM, Merck) was used for ¯ash chromatography.

6b. White crystals, mp 93±968C. IR3460 8OH), 2930 8C±

H); ¹H NMR: 1.11 8d, J7 Hz, 3H, 10-CH₃), 1.44 8d,

J6.5 Hz, 3H, 2⁰-H), 2.05±2.13 8m, 2H, 6exo/6endo-H),

2.24 8d, J₉3 Hz, 1H, 8-H), 2.42 8ddq, J₉11 Hz,

J₁₁,J_CH3,6 Hz, 1H, 10-H), 2.62 8dd₀, J_6exo,J_6endo,3 Hz,

1.1.1. *1R,6R,7S,8R,9R,10R)-5-Acetyl-7,9-dibenzyloxy-8-

methyl-10-hydroxybicyclo [4.4.0] dec-4-en-3-one *4).^7k

Improved procedure. 2.27 g 35 wt% potassium hydride

820 mmol) dispersion in mineral oil 8mineral oil was

removed with dry petroleum ether) and 3.7 g 833 mmol)

potassium tert-butanolate were stirred in 70 ml dry THF at

room temperature under an argon atmosphere for 15 min.

After cooling to 08C 2.9 g 86.6 mmol) 2, dissolved in 60 ml

dry THF, were added with a syringe within 5 min. The

yellow to orange solution was stirred at room temperature

for further 25 min. After cooling to 2788C 3.2 g 820 mmol)

anhydrous ferric chloride, dissolved in 100 ml dry DMF,

was added with a syringe within 10 min. The dark solution

was stirred at 2788C for 20 min and then quenched with aq.

sat. NH₄Cl and 2% aq. HCl. The yellow aq. layer was

extracted four times with ethyl acetate, the combined

0

1H, 7-H), 2.64 8d, J₁3 Hz, 1H, 1 -OH), 3.29 8m, w_1/

4.3 Hz, 1H, 4-H), 3.37 8dd, J₁₀11 Hz, J₈3.5 Hz, 1H,

2

9-H), 3.53 8dd, J₁,J₁₀,4.5 Hz, 1H, 11-H), 3.59 8d,

J₅9.5 Hz, 1H, 5-OH), 4.47±4.53 8m, 3H, 1⁰/1/5-H), 4.52

8s, 2H, Bn), 4.54 8d, J11.5 Hz, 1H, Bn), 4.62 8d,

J11.5 Hz, 1H, Bn), 7.2±7.4 8m, 10H, Ph); ¹³C NMR:

13.38/20.91 810-CH₃, C-2⁰), 38.15 8C-6), 35.87/39.04/

51.50/58.40 8C-4,7,8,10), 69.19/69.70/79.08/80.94/83.68

8C-1⁰,1,5,9,11), 73.15/73.33 8Bn), 93.51 8C-3), 127.7±

128.7 8Ph), 137.52/138.19 8Ph); MS 8FI, to 3008): m/z

8%)420 8100) [M¹2HgCl, ± OH], 91 810) [C₇H₇¹].

1.1.3. *1R,3S,5S,7R,8S,9R,10R,11R)-9,11-Dibenzyloxy-3-

*1⁰-hydroxyethyl)-4-iodo-10-methyl-2-oxatricyclo [5.4.0.0^3,8]

undecan-5-ol *7). For this reaction the isolated diastereo-

È

E. Gossinger et al. / Tetrahedron 57 -2001) 3045±3061

3050

isomers 6a and 6b, respectively, were treated separately. A

solution of 0.43 mmol 6 in dry methylene chloride 825 ml)

was treated with 0.43 mmol iodine at 08C under an argon

atmosphere. After stirring for 30 min 10% aq. Na₂S₂O₃

solution was added and the two-phase system was vigor-

ously stirred for 5 min. The aq. layer was extracted four

times with methylene chloride, the combined organic layers

were washed with brine and dried over Na₂SO₄. After

®ltration and evaporation the products were puri®ed

chromatographically, yielding 85±96% of 7: 7a/b4.6:1,

derived from 6a, were separated with petroleum ether/

diethyl ether 81:1) as eluents. The inseparable mixture of

7c/d2:1, derived from 6b, was puri®ed with petroleum

ether/ethyl acetate 82:1). The iodides were used immedi-

ately after preparation.

±Bn], 314 814), 254 811) [M¹2HI, ±Bn, ±Bn], 218

8100), 127 84%) [I¹], 108 854), 91 865) [C₇H₇¹].

1.1.4. *1⁰⁰R,1⁰R,3⁰S,4⁰R,5⁰S,7⁰R,8⁰S,9⁰R,10⁰R,11⁰R)-Ethyl-

3-[9⁰,11⁰-dibenzyloxy-3⁰-*1⁰⁰-hydroxy₀ethyl)-5⁰-hydroxy-

0

10⁰-methyl-2⁰-oxatricyclo

[5.4.0.0^{3 ,8}

]

undec-4⁰-yl]

propanoate *8). To a solution of 400 mg 80.708 mmol)

7a/b and 7.08 mmol degassed ethyl acrylate 8770 ml) in

degassed tert-butanol 825 ml) 67 mg 81.06 mmol) sodium

cyanoborohydride and 35 mg 80.212 mmol) AIBN were

added. The mixture was heated to 858C under an argon

atmosphere. 0.142 mmol tri-n-butyltin chloride 838 ml)

was added in three portions over 30 min, afterwards the

solution was heated for 1 h. Then brine and water were

added, the aq. layer was extracted four times with diethyl

ether, the combined organic layers were washed with brine

and dried over Na₂SO₄. After ®ltration and evaporation the

products were puri®ed and separated by column chromato-

graphy with petroleum ether/diethyl ether 82:1, then 1:1,

then 1:2) to afford 8 as a colorless oil 8,191 mg, ,50%)

and 9^7k8,100 mg, ,32%). Polymeric impurities could not

be removed completely. 8: IR: 3480 8OH), 2929 8C±H),

7a 8main product). Yellowish oil; [a]²⁰138.78

D

8c1.01 g/100 ml in CH₂Cl₂); IR3460 8OH), 2936 8C±

H); ¹H NMR: d1.15 8d, J6.5 Hz, 3H, 10-CH₃), 1.28 8d,

J6.5 Hz, 3H, 2⁰-H), 1.95 8m, J_gem15 Hz, 1H, 6endo-H),

2.39 8ddq, J_CH3,J₁₁,5.5 Hz, J₉11.5 Hz, 1H, 10-H), 2.49

8ddd, J_gem15 Hz, J₇3 Hz, J₅4.5 Hz, 1H, 6exo-H), 2.55

8dd, J_6ex,J_6en,3 Hz, 1H, 7-H), 3.22 8d, J₉3 Hz,1H, 8-H),

3.47 8dd, J₁₀11.5 Hz, J₈3.5 Hz, 1H, 9-H), 3.52 8d br,

1

1732 8CO); H NMR: d1.12 8m, 1H, 3b-H), 1.14 8d,

J6.8 Hz, 3H, 10⁰-CH₃), 1.23 8d, J6.4 Hz, 3H, 2⁰⁰-H),

J₅8 Hz, 1H, 5-OH), 3.58 8dd, J₁,J₁₀,5 Hz, 1H, 11-H),

1.28 8t, J7.1 Hz, 3H, OCH₂CH₃), 1.93 8ddd, J_gem15 Hz,

0

4.14 8d, J₁3 Hz, 1H, 1 -OH), 4.26 8m, w_1/215.4 Hz,

J₇3.2 Hz, J₅4.5 Hz, J,1, 1H, 6 b-H), 2.0 8ddd,

0

J_6ax4.5 Hz, 1H, 5-H), 4.33 8dq, J₁6.5 Hz, J_OH4 Hz,

J_gem15 Hz, J₅,J₇,3.2 Hz, 1H, 6 a-H), 2.10 8d br,

1H, 1⁰-H), 4.39 8m, w_1/24.5 Hz, 1H, 4-H), 4.44 8d,

J₁₁4.5 Hz, 1H, 1-H), 4.53 8s, 2H, Bn), 4.63 8d, J11 Hz,

1H, Bn), 4.74 8d, J11 Hz, 1H, Bn), 7.2±7.4 8m, 10H, Ph);

¹³C NMR: d13.48/16.40 810-CH₃, C-2⁰), 25.82 8C-4),

32.03 8C-6), 36.19/39.52/45.51 8C-7,8,10), 68.65/76.78/

79.11/81.49/84.23 8C-1⁰,1,5,9,11), 73.28/74.48 8Bn), 89.31

8C-3), 127.69±128.81 8Ph), 136.60/138.13 8Ph); MS 8FI,

1108): m/z 8%): 564 84) [M¹], 436 814) [M¹2IH], 418

828) [M¹2IH, ±H₂O], 312 8100), 218 829), 127 84%) [I¹],

91 819) [C₇H₇¹].

J_3b10.8 Hz, 1H, 4⁰-H), 2.48±2.32 8m, 4H, 2b/3a/8⁰/10⁰-

H), 2.48 8dd, J_{6 a},J_{6 b},3.1 Hz, 1H, 7⁰-H), 2.55 8dddd,

0

J_gem14.1 Hz, J_3a10.5 Hz, J_3b7.3 Hz, J₄1.4 Hz, 1H,

0

2a-H), 3.45 8dd, J₁₀11.1 Hz, J₈3.1 Hz, 1H, 9 -H), 3.58

0

8dd, J₁,J₁₀,5 Hz, 1H, 11 -H), 3.65 8s, 1H, 5 -OH), 3.65 8d

0

br, J₆3.5 Hz, 1H, 5 -H), 4.15 8dq, J_CH37.1 Hz, J1 Hz,

00

2H, OCH₂CH₃), 4.25 8d, J₁3.9 Hz, 1H, 1 -OH), 4.33 8dq,

J_OH4.5 Hz, J_CH36.5 Hz, 1H, 1⁰⁰-H), 4.39 8d, J₁₁4.6 Hz,

0

1H, 1⁰-H), 4.50 8d, J11.7 Hz, 1H, Bn), 4.54 8d, J11.7 Hz,

1H, Bn), 4.61 8d, J10.8 Hz, 1H, Bn), 4.69 8d, J11.0 Hz,

1H, Bn), 7.2±7.4 8m, 10H, Ph); ¹³C NMR: d13.6/14.22/

17.35 810⁰-CH₃,C-2⁰⁰,OCH₂CH₃), 24.26/33.39/34.0 8C-2,3,6⁰),

36.4/39.0/43.0/46.92 8C-4⁰,7⁰,8⁰,10⁰), 60.39 8OCH₂CH₃),

69.64/69.69/79.38/79.55/84.62 8C-1⁰,5⁰,9⁰,11⁰,1⁰⁰), 73.05/

74.57 8Bn), 91.49 8C-3⁰), 127.7±128.8 8Ph), 136.80/138.29

8Ph), 173.40 8CO); MS 8FI, 1908): m/z 8%): 539 8100)

[M1H¹], 494 845) [M1H¹2CH₃CH₂O], 449 811)

[M¹2C₇H₇], 91 8100) [C₇H₇¹].

7b 8by-product). White crystals, mp 132±1388C,

[a]²⁰134.788 8c0.23 g/100 ml in CH₂Cl₂): IR: 3364

D

8OH), 3030 8vC±H), 2932/2874 8C±H) ¹H NMR

8250 MHz, C₆D₆, 478C): d1.15 8d, J6.85 Hz, 3H, 10-

CH₃), 1.57 8d, J6.6 Hz, 3H, 2⁰-H), 1.65 8ddd,

J_gem13.7 Hz, J₅7.5 Hz, J₇2.3 Hz, 1H, 6a-H), 1.81

8ddd, J_gem13.7 Hz, J₅,J₇,5.9 Hz, 1H, 6b-H), 2.31 8d br,

J₅6.9 Hz, 1H, 5-OH), 2.32±2.40 8m, 2H, 7/8-H), 2.83

8ddq, J_CH3,J₁₁,6.6 Hz, J₉11.4 Hz, 1H, 10-H), 3.10±

3.25 8m, 2H, 5-H/1⁰-OH), 3.26 8dd, J₁₀11 Hz,

J₈3.2 Hz, 1H, 9-H), 3.49 8dd, J₁,J₁₀,5 Hz, 1H, 11-H),

4.29 8s, 2H, Bn), 4.31 8d, J₁₁4.8 Hz, 1H, 1-H), 4.33 8d,

J11.2 Hz, 1H, Bn), 4.48 8d, J11.2 Hz, 1H, Bn), 4.62

8dq, J_CH3,J_OH,6.6 Hz, 1H, 1⁰-H), 4.92 8d br,

J₅4.6 Hz, 1H, 4-H), 7.1±7.35 8m, 10H, Ph); ¹³C

NMR 8250 MHz, C₆D₆, 478C): d13.87/19.88 810-

CH₃,C-2⁰), 35.47 8C-6), 36.62/36.73/43.25 8C-7,8,10),

55.61 8C-4), 67.49/70.48/80.46/83.27/85.12 8C-1⁰,

1,5,9,11), 73.28/73.99 8Bn), 88.21 8C-3), 128±129

8Ph), 138.09/139.28 8Ph); MS 8FI, 1408): m/z 8%): 565

833) [M¹], 456 818 ) [M¹2C₇H₇, ±H₂O], 437 8100)

[M¹2I]; 7c/d 8inseparable mixture of isomers), yellow-

ish oil, IR: 3422 8OH), 3030/3015 8vC±H), 2933/2899/

2874 8C±H); MS 8FI, 1908): m/z 8%): 564 84%) [M¹],

418 87) [M¹2HI, ±H₂O], 328 810) [M¹2HI, ±H₂O,

1.1.5. *^)-*1R^p,6R^p,7S^p,8R^p,9R^p,10R^p)-7,9-Dibenzyloxy-

5-*1⁰-hydroxyethyl)-8-methyl-10-hydroxybicyclo [4.4.0]

dec-4-en-3-one *10). 8^)-10a. A solution of 0.56 mmol

14 in dry THF 830 ml) was treated at 08C with 353 mg

81.12 mmol) tetra-n-butylammonium ¯uoride trihydrate

under an argon atmosphere. After stirring at 08C for 1 h

and at room temperature for 24 h sat. aq. NH₄Cl solution

was added. The aq. layer was extracted three times with

ethyl acetate, the combined organic layers were washed

with brine and dried over Na₂SO₄. After ®ltration and

evaporation the crude product was puri®ed by column chro-

matography with petroleum ether/ethyl acetate 81:1.5) to

afford 10a 8103.7 mg, 42% after three steps) as a colorless

oil. IR: 3422 8OH), 3031.8 8vC±H), 2974/2956/2929

8C±H), 1652 8CvO); ¹H NMR: d0.96 8d, J7.5 Hz,

3H, 8-CH₃), 1.20 8d, J6.5 Hz, 3H, 2⁰-H), 1.41 8br,

w_1/217.37 Hz, 1H, OH), 2.45±2.5 8br, 1H, OH), 2.48

È

E. Gossinger et al. / Tetrahedron 57 -2001) 3045±3061

3051

8dd, J_gem16.5 Hz, J₁5 Hz, 1H, 2eq-H), 2.54 8ddd,

solution of 1.13 g 82.1 mmol) 2 and 10.5 mmol dry tri-

ethylamine 81.5 ml) in dry methylene chloride 890 ml) was

cooled to 2508C under an argon atmosphere and 2.5 mmol

tert-butyldimethylsilyl tri¯uoromethanesulfonate 8584 ml)

were added. After stirring for 20 min at 2508C sat. aq.

NaHCO₃solution was added. The aq. layer was extracted

four times with methylene chloride the combined organic

layers were washed with brine and dried over Na₂SO₄. After

®ltration and evaporation the crude product 11 was

dissolved in dry THF 890 ml) and cooled to 2788C under

an argon atmosphere. 6.3 mmol of 1.5 M diisobutyl-

aluminum hydride solution in toluene 84.2 ml) was added

and the mixture stirred for 5 h. The reaction mixture was

quenched with water 83 ml) and stirred for 30 min. The

mixture was ®ltrated through celite and the organic layer

was treated with brine and dried over Na₂SO₄. After ®ltra-

tion and evaporation the product was puri®ed by column

chromatography with petroleum ether/ethyl acetate 810:1)

to afford 12 81 g, 87.9% over two steps) as a colorless oil.

J_2ax13, J_2eq,J₁₀,J₆,5 Hz, 1H, 1-H), 2.57 8ddq, J_CH3

7.5 Hz, J₉4.5 Hz, J₇3 Hz, 1H, 8-H), 2.69 8dd, J_gem

16.6 Hz, J₁13 Hz, 1H, 2ax-H), 2.83 8dd, J₇,J₁,3.7 Hz,

1H, 6-H), 3.68 8dd, J₆,J₈,2.5, 1H, 7-H), 3.76 8dd,

J₈5 Hz, J₁₀10 Hz, 1H, 9-H), 3.91 8dd, J₉10 Hz,

J₁5.5 Hz, 1H, 10-H), 4.06 8q, J_CH37 Hz, 1H, 1⁰-H),

4.17 8d, J12.5 Hz, 1H, Bn), 4.36 8d, J11.4 Hz, 1H,

Bn), 4.42 8d, J12 Hz, 1H, Bn), 4.54 8d, J11.5 Hz, 1H,

Bn), 5.95 8s, 1H, 4-H), 7.0±7.4 8m, 10H, Ph); ¹³C NMR:

d11.20/21.79 88-CH₃,C-2⁰), 33.01/34.77/38.98 8C-1,6,8),

35.31 8C-2), 68.53/69.37/76.50/ 80.86 8C-1⁰,7,9,10), 71.18/

71.59 8Bn), 127.96±128.53 8Ph and C-4), 137.98/138.03

8Ph), 163.40 8C-5), 201.11 8CvO); MS 8FI, 1508C): m/z

8%)437 8100) [M1H¹], 391 819) [M1H¹2CH₃CHOH],

267 814), 91 858) [C₇H₇¹], 57 834); Anal. Calcd for

C₂₇H₃₂O₅: C74.29%, H7.39%, found: C74.02%,

H7.42%

1

10b. MAD-solution: A 2 M solution of trimethylalane

8288 ml) in dry toluene 80.575 mmol) was added dropwise

to a solution of 253 mg 81.15 mmol) 2,6-di-t-butyl-4-

methylphenol in dry toluene 83 ml) under an argon

atmosphere at room temperature. The mixture was stirred

for 1 h. DIBAL solution: A 1 M solution of diisobutyl-

aluminum hydride 8460 ml) in hexane 80.46 mmol) was

diluted with dry toluene 81 ml) and a 1.6 M solution of

n-butyllithium in hexane 80.46 mmol290 ml) was added

at 08C. The mixture was stirred for 10 min.

IR: 3421 8OH), 3032 8vC±H), 2959 8C±H); H NMR:

d20.01 8s, 3H, Si±CH₃), 0.00 8s, 3H, Si±CH₃), 0.77 8s,

9H, t-Bu), 1.00 8d, J6 Hz, 3H, 2⁰-H), 1.02 8d, J7 Hz, 3H,

6-CH₃), 1.36 8dd, J₃6.5 Hz, J_gem12.6 Hz, 1H, 2exo-H),

1.60 8d, J_gem11.5 Hz, 1H, 10exo-H), 1.76 8ddd,

J_gem11.5 Hz, J₉,J_2endo,3 Hz, 1H, 10endo-H), 1.85 8m,

0

J₄,4 Hz, J_2ex,6.5 Hz, J₁,9 Hz, J_2en,13 Hz, 1H, 3-H),

1.90 8ddd, J_gem,J₃,12.6 Hz, J_10en2 Hz, 1H, 2endo-H),

2.11 8ddq, J_CH37 Hz, J₇3 Hz, J₅10.5 Hz, 1H, 6-H),

2.31 8ddd, J₉,J₃,J₅,4.7 Hz, 1H, 4-H), 2.37 8ddd,

J₄,J₈,J_10en,3 Hz, 1H, 9-H), 3.30 8ddq, J_CH36 Hz,

J₃8.5 Hz, J_OH5 Hz, 1H, 1⁰-H), 3.51 8dd, J₄4 Hz,

J₆11.04 Hz, 1H, 5-H), 3.51 8m, 1H, 7-H), 3.73 8d,

The MAD solution was cooled to 2908C and a solution of

50 mg 80.115 mmol) 4 in dry toluene 82 ml) was added. The

DIBAL solution was added 10 min later. After stirring at

2908C for 1 h sat. aq. NH₄Cl solution and water were

added. 2% aq. HCl was added and the aq. layer was

extracted four times with ethyl acetate, the combined

organic layers were washed with brine and dried over

Na₂SO₄. After ®ltration and evaporation the crude product

was puri®ed by column chromatography with petroleum

ether/ethyl acetate 81:2) then petroleum ether/acetone

81:1) to afford 10b 819 mg, 39%) as a colorless oil. IR:

3430 8OH), 3032 8vC±H), 2974/2882 8C±H), 1652

0

J₁5 Hz, 1H, OH), 3.90 8dd, J₇,J₉,2.5 Hz, 1H, 8-H),

4.41 8d, J11 Hz, 1H, Bn), 4.42 8d, J11.6 Hz, 1H, Bn),

4.49 8d, J11.5 Hz, 1H, Bn), 4.54 8d, J10.5 Hz, 1H, Bn),

7.15±7.3 8m, 10H, Ph); ¹³C NMR: d22.87/22.81

8Si±CH₃), 13.31/21.87 86-CH₃,C-2⁰), 17.77 8t-Bu), 25.86

8t-Bu), 32.52/38.67/38.84/40.18 8C-3,4,6,9), 41.98/43.08

8C-2,10), 73.80/76.70/79.93/ 80.74 8C-1⁰,5,7,8), 73.44/

73.92 8Bn), 106.58 8C-1), 127.66±128.47 8Ph), 137.20/

138.45 8Ph); MS 8FI, 1308C): m/z 8%): 552 848) [M¹], 494

8100) [M¹2t-Bu], 404 812) [M¹2t-Bu, ±C₇H₇], 182 87), 91

834) [C₇H₇¹], 57 88) [t-Bu]; Anal. Calcd for C₃₃H₄₈O₅Si:

C71.7%, H8.75%, found: C71.47%, H8.61%.

1

8CvO); H NMR: d0.95 8d, J7 Hz, 3H, 8-CH₃), 1.10

8d, J3.5 Hz, 1H, 1⁰-OH), 1.18 8d, J6.5 Hz, 3H, 2⁰-H),

2.42 8br, 1H, OH), 2.43 8dd, J₇,J₁,3.5 Hz, 1H, 6-H),

2.48 8dd, J_gem16 Hz, J₁4.5 Hz, 1H, 2eq-H), 2.52±2.62

8m, 2H, 1/8-H), 2.67 8dd, J_gem16 Hz, J₁13.55 Hz, 1H,

2ax-H), 3.54 8dd, J₆,J₈,2.5 Hz, 1H, 7-H), 3.78 8dd,

J₈5 Hz, J₁₀10 Hz, 1H, 9-H), 3.88 8dd, J₉10 Hz,

J₁5.5 Hz, 1H, 10-H), 4.94 8dq, J_CH36 Hz, J_OH3 Hz,

1H, 1⁰-H), 4.16 8d, J12 Hz, 1H, Bn), 4.38 8d, J11 Hz,

1H, Bn), 4.44 8d, J12.6 Hz, 1H, Bn), 4.55 8d, J11 Hz,

1H, Bn), 6.13 8s, 1H, 4-H), 7.0±7.4 8m, 10H, Ph); ¹³C NMR:

d11.32/22.45 88-CH₃,C-2⁰), 33.17/36.50/38.66 8C-1,6,8),

35.32 8C-2), 68.21/68.46/76.51/80.63 8C-1⁰,7,9,10), 71.30/

71.73 8Bn), 126.17 8C-4), 127.98±128.57 8Ph), 137.89/

137.94 8Ph), 165.20 8C-5), 200.52 8CvO); MS 8FI): m/z

8%)436 8100) [M¹]; %: Calcd for C₂₇H₃₂O₅: C74.29%,

H7.39%, found: C72.74%, H7.28%.

1.1.7. *^)-*1R^p,4R^p,5S^p,6R^p,7R^p,8R^p,9R^p)-5,7-Dibenzyloxy-

3-ethylidene-1-*t-butyldimethylsilyloxy)-6-methyl-11-

oxatricyclo [6.2.1.0^4,9] undecane *13). 2.8 mmol SOCl₂

8204 ml, freshly distilled) and dry pyridine 85 ml) were

combined. A solution of 311 mg 80.56 mmol) 12 in dry

pyridine 830 ml) was added slowly 8over 1 h) at room

temperature 8The color of the solution turns to orange.)

After the addition was completed the mixture was stirred

for 30 min at room temperature. The reaction mixture was

quenched with sat. aq. NaHCO₃solution. The aq. layer was

extracted four times with ethyl acetate the combined organic

layers were washed with brine and dried over Na₂SO₄. After

®ltration and evaporation toluene was added several times

and evaporated. For analytical purposes a small part of the

product 13 was puri®ed by column chromatography

with petroleum ether/ethyl acetate 810:1) the rest was used

without puri®cation for the following reaction; 9.3% of an

isomeric product has been formed which could not be

1.1.6. *^)-*1S^p,3R^p,4S^p,5S^p,6R^p,7R^p,8R^p,9R^p)-5,7-Diben-

zyloxy-3-*1⁰-hydroxyethyl)-1-*t-butyldi-methylsilyloxy)-

6-methyl-11-oxatricyclo [6.2.1.0^4,9] undecane *12). A

È

E. Gossinger et al. / Tetrahedron 57 -2001) 3045±3061

3052

separated. Colorless oil; IR: 3031 8vC±H), 2931/2910/

1.1.9. *1)-*1⁰⁰R,1⁰R,3⁰S,4⁰S,7⁰R,8⁰S,9⁰R,10⁰R,11⁰R)-Ethyl

1

2857 8C±H); H NMR: d0.00 8two s, 6H, 2Si±CH₃),

3-{3⁰-*1⁰⁰-hydroxyethyl)-9⁰,11⁰-dibenzyloxy-10⁰-methyl-

3⁰,8⁰

0.77 8s, 9H, t-Bu), 0.90 8d, J7 Hz, 3H, 6-CH₃), 1.46 8dd,

2⁰-oxatricyclo [5.4.0.0 ] undecan-5⁰-on-4⁰-yl} propano-

J₁7 Hz, J_2en2.5 Hz, 3H, 2⁰-H), 1.65 8ddd, J_gem11.0 Hz,

ate *15). Method a. A 0.02 M solution of 8 in dry methylene

chloride was treated with 1 equiv. of Dess±Martin reagent

under an argon atmosphere at room temperature. After stir-

ring for 30 min sat. aq. NaHCO₃solution and 10% aq.

Na₂S₂O₃solution were added and the two phase system

was vigorously stirred for 5 min. The aq. layer was extracted

four times with methylene chloride, the combined organic

layers were washed with brine and dried over Na₂SO₄.

Method b. A 0.02 M solution of 8 in acetone was treated

with Jones reagent under an argon atmosphere at 08C until

starting material was no longer detectable by TLC. Sat. aq.

NH₄OAc solution was added, the aq. layer was extracted

four times with ethyl acetate, the combined organic layers

were washed with brine and dried over Na₂SO₄. After ®ltra-

tion and evaporation the product was puri®ed by column

chromatography with petroleum ether/diethyl ether 82:1,

then 1:2). Both methods yielded 70±90% 15 as a colorless

0

J₉4 Hz, J_2en1.5 Hz, 1H, 10endo-H), 1.71 8d, J_gem

11 Hz, 1H, 10exo-H), 1.88 8ddq, J_CH37 Hz, J₇2.5 Hz,

J₅12 Hz, 1H, 6-H), 2.49 8m, J₄,J₈,J_10en,4.5 Hz, 1H,

9-H), 2.51 8d, J_gem15.6 Hz, 1H, 2exo-H), 2.76 8m,

J_gem15.6 Hz, 1H, 2endo-H), 3.2 8dd, J₉,J₅,6.5 Hz, 1H,

4-H), 3.49 8dd, J₈,J₆,2.5 Hz, 1H, 7-H), 3.63 8dd,

J₆11.55 Hz, J₄5.5 Hz, 1H, 5-H), 3.95 8dd,

J₇,J₉,3.5 Hz, 1H, 8-H), 4.38 8d, J11 Hz, 1H, Bn), 4.41

8d, J10.5 Hz, 1H, Bn), 4.52 8d, J11.6 Hz, 1H, Bn), 4.58

8d, J11 Hz, 1H, Bn), 5.45 8m, J_CH37 Hz, 1H, 1⁰-H), 7.1±

7.3 8m, 10H, Ph); ¹³C NMR: d22.92/22.78 8Si±CH₃),

14.06/15.10 86-CH₃,C-2⁰), 17.80 8t-Bu), 25.88 8t-Bu),

33.17/36.69/38.76 8C-4,6,9), 40.59/53.58 8C-2,10), 73.39/

74.11 8Bn), 74.24/79.17/ 80.91 8C-5,7,8), 106.61 8C-1),

127.47±128.62 8Ph and C-1⁰), 131.11 8C-3), 138.49/

138.74 8Ph); MS 8FI, 808C): m/z 8%): 535 8100) [M1H¹],

478 837) [M1H¹2t-Bu], 444 874) [M¹2C₇H₇], 387 839)

[M¹2t-Bu, ±C₇H₇], 298 832), 91 823) [C₇H₇¹], 84 858), 57

842) [t-Bu]; Anal. Calcd for C₃₃H₄₆O₄Si: C74.11%,

H8.67%, found: C73.81%, H8.52%.

oil. [a]²⁰129.878 8c2.3 g/100 ml in CH₂Cl₂); IR: 3468

D

8OH), 2928/2854 8C±H), 1732 8CO); ¹H NMR: d1.06 8d,

J6.5 Hz, 3H, 10⁰-CH₃), 1.11 8d, J6 Hz, 3H, 2⁰⁰-H), 1.17

8t, J7 Hz, 3H, OCH₂CH₃), 1.48 8m, J_gem15.6 Hz,

0

J₄13.6 Hz, J_2a,J_2b,6.5 Hz, 1H, 3b-H), 2.23±2.19 8m,

1.1.8. *^)-*1⁰R^p,4⁰S^p,5⁰R^p,6⁰R^p,7⁰R^p,8⁰R^p,9⁰R^p)-5⁰,7⁰-Di-

2H, 2a/2b-H), 2.20 8ddd, J_gem16.6 Hz, J₄,J₇,2 Hz,

0

benzyloxy-1⁰-*t-butyldimethylsilyloxy)-6⁰-methyl-3-

1H, 6⁰eq-H), 2.31 8ddq, J_CH3,6.5 Hz, J₉11.6 Hz,

0

methylspiro{oxiran-2,3⁰-11⁰-oxatricyclo

[6.2.1.0^{4 ,9}

]

J₁₁,4 Hz, 1H, 10 -H), 2.59±2.49 8m, 3H, 3a/4 /7 -H),

0

undecane} *14). To a solution of 0.56 mmol of the crude

material 13 in dry methylene chloride 850 ml) 1.5 g

NaHCO₃and 248 mg 81.12 mmol) 2,6-di-t-butyl-4-methyl-

phenol were added. The mixture was cooled to 08C under an

argon atmosphere and 388 mg 82.24 mmol) MCPA was

added. After stirring for 2 h 10% aq. Na₂S₂O₃solution

was added and the two-phase system vigorously stirred for

20 min. The aq. layer was extracted four times with

methylene chloride the combined organic layers were

washed with brine and dried over Na₂SO₄. After ®ltration

and evaporation a small part of product 14 was puri®ed by

column chromatography for analytical purposes. The rest

was used without puri®cation for the following reaction.

Colorless oil. IR2930/2910/2858 8C±H); ¹H NMR:

d0.00 8two s, 6H, 2Si±CH₃), 0.76 8s, 9H, t-Bu), 1.0 8d,

J6.5 Hz, 3H, 6⁰-CH₃), 1.2 8d, J5 Hz, 3H, 3-CH₃), 1.74

2.63 8dd, J_gem16.6 Hz, J₇4 Hz, 1H, 6 exo-H), 2.76 8d,

0

J₉3 Hz, 1H, 8 -H), 3.45 8dd, J₁₀,J₁,4.5 Hz, 1H, 11 -H),

0

3.52 8dd, J₁₀11.0 Hz, J₈3 Hz, 1H, 9 -H), 3.90 8d,

0

J₁₁4.5 Hz, 1H, 1 -H), 4.03 8q, J7 Hz, 2H, OCH₂CH₃),

00

4.09 8d, J₁4 Hz, 1H, OH), 4.24 8dq, J_CH36.5 Hz,

J_OH4.5 Hz, 1H, 1⁰⁰-H), 4.36 8d, J12 Hz, 1H, Bn), 4.43

8d, J11.55 Hz, 1H, Bn), 4.58 8d, J11 Hz, 1H, Bn), 4.65

8d, J11 Hz, 1H, Bn), 7.15±7.35 8m, 10H, Ph); ¹³C NMR:

d13.57/14.18/16.75 810⁰-CH₃,C-2⁰⁰OCH₂CH₃), 23.41/

31.89/42.86 8C-2,3,6⁰), 36.39/39.28/43.01 8C-8⁰,7⁰,10⁰),

56.93 8C-4⁰), 60.37 8OCH₂CH₃), 73.34/74.80 8Bn), 69.62/

79.49/80.80/84.19 8C-1⁰,9⁰,11⁰,1⁰⁰), 89.53 8C-3⁰), 127.71±

128.83 8Ph), 136.67/138.18 8Ph), 173.04 8ester CO),

210.70 85⁰-CO); MS 8EI, 1608C, 70 eV): m/z 8%): 536

83.4) [M¹], 492 88.7), 386 815.7), 91 8100) [C₇H₇¹];

HRMS 8EI, 2008C, 70 eV): Calcd for C₃₂H₄₀O₇

536.2774, found M¹536.2782; Anal. Calcd for

C₃₂H₄₀O₇: C71.62%, H7.51%, found: C 71.39%,

H7.62%.

0

8ddd, J_gem11.5 Hz, J₉4.5 Hz, J_{2 en}1.5 Hz, 1H,

10⁰endo-H), 1.81 8d, J_gem14.55 Hz, 1H, 2⁰exo-H), 1.85

8d, J_gem11.5 Hz, 1H, 10⁰exo-H), 2.29 8m, 1H, 4⁰-H), 2.29

0

8ddq, J_CH36.2 Hz, J₇2.5 Hz, 1H, 6 -H), 2.40 8d,

J_gem14.6 Hz, 1H, 2⁰endo-H), 2.48 8ddd, J₄8 Hz,

1.1.10. *^)-*1⁰⁰R^p,1⁰R^p,3⁰S^p,4⁰S^p, 7⁰R^p,8⁰S^p,9⁰R^p,10⁰R^p,11⁰

0

J₈,J_{10 en},4 Hz, 1H, 9⁰-H), 2.55 8q, J_CH35.5 Hz, 1H,

R^p)-Ethyl 3-{3⁰-*1⁰⁰-methoxymethyloxy-ethyl)-9⁰,11⁰-di-

0

3-H), 3.55 8m, 1H, 7 -H), 3.57 8dd, J₆12 Hz, J₄5 Hz,

benzyloxy-10⁰-methyl-2⁰-oxatricyclo [5.4.0.0^{3 ,8}] unde-

can-5⁰-on-4⁰-yl} propanoate *16). To a solution of 26 mg

80.045 mmol) of 8^)-15 in dry methylene chloride 81 ml)

were added 1.35 mmol N,N-diisopropylethylamine8233 ml)

and 0.9 mmol chloromethyl methyl ether 868 ml) and the

reaction mixture was stirred under an argon atmosphere at

408C for 24 h. Sat. aq. NaHCO₃solution was added and the

aq. layer was extracted four times with methylene chloride.

The combined organic layers were washed with brine and

dried over Na₂SO₄. After ®ltration and evaporation the

crude product was puri®ed by column chromatography

with petroleum ether/ethyl acetate 82:1) to afford 15.5 mg

859%) 16 as colorless oil. IR: 3063/30318arom C±H),

0

1H, 5 -H), 3.94 8dd, J₇,J₉,3 Hz, 1H, 8 -H), 4.20 8d,

J11.5 Hz, 1H, Bn), 4.44 8d, J11.5 Hz, 1H, Bn), 4.50

8d, J11.5 Hz, 1H, Bn), 4.51 8d, J11.5 Hz, 1H, Bn),

7.1±7.3 8m, 10H, Ph); ¹³C NMR: d22.94/22.86

8Si±CH₃), 13.96/14.16 83-CH₃,6⁰-CH₃), 17.78 8t-Bu),

25.85 8t-Bu), 33.33/34.60/37.04 8C-4⁰,6⁰,9⁰), 40.56/52.79

8C-2⁰,10⁰), 57.81 8spiro C), 61.69 8C-3), 72.26/73.46

8Bn), 75.21/78.44/80.63 8C-5⁰,7⁰,8⁰), 105.45 8C-1⁰),

127.29±128.28 8Ph), 138.69/138.78 8Ph); MS 8FI, 958C):

m/z 8%): 550 818) [M¹], 493 858) [M¹2t-Bu], 459 818)

[M¹2C₇H₇], 403 832), 267 843), 91 825) [C₇H₇¹], 57

8100%) [t-Bu].

È

E. Gossinger et al. / Tetrahedron 57 -2001) 3045±3061

3053

2981/2854 8C±H), 1733 8CO); ¹H NMR: d1.06 8d,

J6.5 Hz, 3H, 10⁰-CH₃), 1.18 8t, J7 Hz, 3H, OCH₂CH₃),

1.23 8d, J6.5 Hz, 3H, 2⁰⁰-H), 1.51 8m, 1H, 3b-H), 2.15±

ethanol 81 ml) was added under an argon atmosphere at

room temperature. After stirring for 3 h sat. aq. NH₄Cl solu-

tion was added. The aq. layer was extracted four times with

ethyl acetate, the combined organic layers were washed

with brine and dried over Na₂SO₄. After ®ltration and

evaporation the product was puri®ed by column chromato-

graphy with petroleum ether/ethyl acetate 83:1, then 2:1) to

afford 85.3 mg, 44%) 18 as a colorless oil. IR: 3568 8OH),

3028 8vC±H), 2926 8C±H), 1733.5 8ester CO), 1664 8CO,

0

2.30 8m, 4H, 2a/2bor4 /10 /6b-H), 2.53 8dd, J_6a,J_6b,2 Hz,

1H, 7⁰-H), 2.60±2.75 8m, 3H, 3a/4⁰or 2b/6⁰-H), 2.95 8d,

0

J₉2.5 Hz, 1H, 8 -H), 3.18 8s, 3H, OCH₃), 3.34 8dd,

0

J₁₀10 Hz, J₈3.5 Hz, 1H, 9 -H), 3.44 8dd, J₁₀

,

0

J₁,5 Hz, 1H, 11 -H), 3.86 8d, J₁₁5 Hz, 1H, 1 -H), 4.04

8q, J7 Hz, 2H, OCH₂CH₃), 4.23 8q, J_CH36.5 Hz, 1H, 1⁰⁰-

H), 4.27 8d, J7 Hz, 1H, OCH₂O), 4.36 8d, J11.55 Hz,

1H, Bn), 4.39 8d, J12.5 Hz, 1H, Bn), 4.43 8d,

J11.5 Hz, 1H, Bn), 4.50 8d, J7 Hz, 1H, OCH₂O), 4.71

8d, J12.05 Hz, 1H, Bn), 7.15±7.35 8m, 10H, Ph); ¹³C

NMR: d13.71/14.19/16.89 810⁰-CH₃, C-2⁰⁰, OCH₂CH₃),

24.0/32.30/42.96 8C-2,3,6⁰), 35.73/39.55/40.40 8C-

4⁰,7⁰,10⁰), 55.31 8OCH₃), 57.20 8C-8⁰), 60.35 8OCH₂CH₃),

71.54/73.24 8Bn), 78.55/79.33/80.14/83.13 8C-1⁰,9⁰,11⁰,1⁰⁰),

88.62 8C-3⁰), 98.07 8OCH₂O), 127.35±128.41 8Ph), 138.36/

138.48 8Ph), 173.18 8ester CO), 210.82 85⁰-CO).

1

CvC); H NMR: d0.95 8d, J7.5 Hz, 3H, 8⁰-CH₃), 1.15

8t, J7 Hz, 3H, OCH₂CH₃), 1.27 8d, J6.5 Hz, 3H, 2⁰⁰-H),

2.26 8t, J,8 Hz, 2H, 2-or 3-H), 2.36 8w_1/26.7 Hz, 1H, OH),

0

2.42 8dd, J₂17.6 Hz, J₁6.5 Hz, 1H, 2 -H), 2.45±2.55

8m, 2H, 1⁰-H,8⁰-H), 2.52 8dt, J_gem14 Hz, J7.5 Hz, 1H,

3- or 2-H), 2.62 8dt, J_gem13.55 Hz, J8 Hz, 1H, 3- or

0

2-H), 2.72 8dd, J₂17.6 Hz, J₁13 Hz, 1H, 2 -H),

0

2.818dd, J₁,J₇,3.5 Hz, 1H, 6 -H), 3.25 8s, 3H, OCH₃),

0

3.73 8dd, J₁₀10 Hz, J₈5.5 Hz, 1H, 9 -H), 3.73 8dd,

0

J₆,J₈,3 Hz, 1H, 7 -H), 3.90 8dd, J₁5.5 Hz, J₉

10 Hz, 1H, 10⁰-H), 3.99 8dq, J_CH37 Hz, J_gem11 Hz, 1H,

OCH₂CH₃), 4.02 8dq, J_CH37 Hz, J_gem11 Hz, 1H,

OCH₂CH₃), 4.18 8d, J12 Hz, 1H, Bn), 4.30 8d, J11 Hz,

2H, Bn), 4.35 8d, J6.5 Hz, 1H, OCH₂O), 4.41 8d,

J6.5 Hz, 1H, OCH₂O), 4.48 8d, J11.5 Hz, 1H, Bn),

4.80 8q, J_CH36.5 Hz, 1H, 1⁰⁰-H), 7.0±7.3 8m, 10H, Ph);

¹³C NMR: d11.67/14.59/20.83 88⁰-CH₃,C-2⁰⁰,OCH₂CH₃),

21.55/33.86/35.98 8C-2,3,2⁰), 33.48/34.81/38.99 8C-

1⁰,6⁰,8⁰), 55.86 8OCH₃), 60.7 8OCH₂CH₃), 71.49/72.72

8Bn), 69.24/72.44/76.88/83.25 8C-7⁰,9⁰,10⁰,1⁰⁰), 95.01

8OCH₂O), 127.56±128.95 8Ph), 138.43/138.72 8Ph),

137.01/155.13 8C-4⁰,5⁰), 173.40 8ester CO), 200.06 83⁰-

CO); MS 8FI, 908C): m/z 8%): 581 818) [M1H¹], 391

884), 256 846), 106 8100), 61851) [CH₃OCH₂O¹]; HMRS:

Calcd for C₃₂H₄₀O₇536.2774, found M¹536.2782.

1.1.11. *^)-*1⁰⁰R^p,1⁰R^p,6⁰R^p,7⁰S^p,8⁰R^p,9⁰R^p,10⁰R^p)-Ethyl 3-

{5⁰-*1⁰⁰-hydroxyethyl)-7⁰,9⁰-dibenzyloxy-10⁰-hydroxy-8⁰-

methylbicyclo [4.4.0] dec-4⁰-en-3⁰-on-4⁰-yl} propanoate

*17). 117 mg 85 mmol) sodium were treated with dry

ethanol 85 ml). A solution of 39 mg 80.073 mmol) 8^)-15

in ethanol 85 ml) was added under an argon atmosphere at

08C. After stirring for 30 min at 08C and 2 h at room

temperature sat. aq. NH₄Cl solution was added. The aq.

layer was extracted four times with ethyl acetate, the

combined organic layers were washed with brine and

dried over Na₂SO₄. After ®ltration and evaporation the

product was puri®ed by column chromatography with petro-

leum ether/ethyl acetate 82:1, then 1:1) to afford starting

material 810.5 mg, 27%) and 17 819.6 mg, 50%) as a color-

less oil. IR: 3448 8OH), 3028 8vC±H), 2970/2925 8C±H),

1

1734 8ester CO), 1654 8CO, CvC); H NMR: d0.88 8d,

1.1.13.

*^)-*1⁰⁰R^p,1⁰R^p,3⁰S^p,6⁰R^p,7⁰S^p,8⁰R^p,9⁰R^p,10⁰R^p)-

J7.5 Hz, 3H, 8⁰-CH₃), 0.99 8t, J7 Hz, 3H, OCH₂CH₃),

Ethyl 3-{5⁰-*1⁰⁰-hydroxyethyl)-7⁰,9⁰-dibenzyloxy-3⁰,10⁰-

dihydroxy-8⁰-methylbicyclo [4.4.0] dec-4⁰-en-4⁰-yl}

propanoate *19). To a solution of 20 mg 80.037 mmol) 17

in methanol 82 ml) 14 mg 80.037 mmol) ceric8III)chloride

heptahydrate was added at 08C under an argon atmosphere.

After 20 min 3 mg 80.074 mmol) sodium borohydride were

added. After stirring for 15 min sat. aq. NH₄Cl solution and

water were added. The aq. layer was extracted four times

with methylene chloride the combined organic layers were

washed with brine and dried over Na₂SO₄. After ®ltration

and evaporation the product was puri®ed by column chro-

matography with petroleum ether/ethyl acetate 81:1) to

afford 19 815 mg, 76%) as a colorless oil. IR: 3448 8OH),

3028 8vC±H), 2970/2924 8C±H), 1734 8ester CO), 1654

8CvC); ¹H NMR: d0.96 8d, J7.5 Hz, 3H, 8⁰-CH₃), 1.16

8d, J6.5 Hz, 3H, 2⁰⁰-H), 1.17 8t, J7 Hz, 3H, OCH₂CH₃),

1.15 8d, J6.5 Hz, 3H, 2⁰⁰-H), 1.89 8w_1/28.6 Hz, 1H, OH),

2.18±2.40 8m, 6H, 1⁰/2⁰b/OH/3a or 2a/3b or 2b-H), 2.42

0

8ddq, J_CH37.5 Hz, J₇3 Hz, J₉5 Hz, 1H, 8 -H), 2.53±

0

2.7 8m, 2H, 3a or 2a/2 a-H), 2.70 8dd, J₁,J₇,3.5 Hz, 1H,

6⁰-H), 3.67 8dd, J₁₀10.5 Hz, J₈5 Hz, 1H, 9 -H), 3.70

0

8dq, J_CH37 Hz, J_gem10.55 Hz, 1H, OCH₂CH₃), 3.77 8dd,

J₆,J₈,3±2.5 Hz, 1H, 7⁰-H), 3.80 8dd, J₁5 Hz,

0

J₉10.5 Hz, 1H, 10 -H), 3.86 8dq, J_CH37 Hz, J_gem

10.55 Hz, 1H, OCH₂CH₃), 4.12 8d, J12.55 Hz, 1H, Bn),

4.24 8d, J11.55 Hz, 1H, Bn), 4.28 8d, J12.05 Hz, 1H,

Bn), 4.43 8d, J11.55 Hz, 1H, Bn), 4.81 8q, J_CH36.5 Hz,

1H, 1⁰⁰-H), 7.15±7.3 8m, 10H, Ph); ¹³C NMR: d11.27/

14.06/21.78 88⁰-CH₃, C-2⁰⁰, OCH₂CH₃), 20.85/33.1/35.62

8C-2,3,2⁰), 33.18/33.94/ 38.49 8C-1⁰,6⁰,8⁰), 60.41

8OCH₂CH₃), 71.01/71.91 8Bn), 67.19/68.81/76.59/82.18

8C-7⁰,9⁰,10⁰,1⁰⁰), 127.55±128.54 8Ph), 138.03/138.53 8Ph),

135.99/156.59 8C-4⁰,5⁰), 173.88 8ester CO), 200.30 83⁰-

CO); MS 8FI, 1408C): m/z 8%): 537 8100) [M1H¹], 91

827) [C₇H₇¹]; HRMS: Calcd for C₃₂H₄₀O₇536.2774,

found M¹536.2782.

0

1.33 8w_1/211.5 Hz, 1H, OH), 1.57 8d br, J₃9.5 Hz, 1H,

3⁰OH), 1.82 8ddd, J_gem,J₁,13.55 Hz, J₃7.5 Hz, 1H,

0

2⁰ax, endo-H), ₀2.04 8dddd, J_{2 b}14 Hz, J₆,J_{2 a},

0

J₁₀,5 Hz, 1H, 1 -H), 2.27 8ddd, J_gem13 Hz, J₃8 Hz,

0

J₁5 Hz, 1H, 2 eq8exo)-H), 2.32±2.48 8m, 4H, 3a or 2a/

0

2b/3b-H,OH), 2.52 8dd, J₁,J₇,3.5±4 Hz, 1H, 6₀-H), 2.58

1.1.12. *^)-*1⁰⁰R^p,1⁰R^p,6⁰R^p,7⁰S^p,8⁰R^p,9⁰R^p,10⁰R^p)-Ethyl 3-

{5⁰-*1⁰⁰-hydroxy)ethyl-7⁰,9⁰-dibenzyloxy-10⁰-hydroxy-8⁰-

methylbicyclo [4.4.0] dec-4⁰-en-3⁰-on-4⁰-yl} propanoate

*18). 32 mg 81.4 mmol) sodium were treated with dry

ethanol 82 ml). A solution of 12 mg 80.02 mmol) 16 in

8ddq, J_CH37.5 Hz, J₇2.5 Hz, J₉5 Hz, 1H, 8 -H), 2.63

0

8m, 1H, 3a or 2a-H), 3.75 8dd, J₁₀10.5 Hz, J₈5 Hz, 1H,

0

9 -H), 3.81 8dd, J₆,J₈,3±2.5 Hz, 1H, 7 -H), 3.84 8dd,

0

J₁5.5 Hz, J₉10 Hz, 1H, 10 -H), 4.01 8dq, J_CH37 Hz,

J_gem11 Hz, 1H, OCH₂CH₃), 3.95±4.07 8m, 1H, 3⁰-H),

È

E. Gossinger et al. / Tetrahedron 57 -2001) 3045±3061

3054

4.04 8dq, J_CH37 Hz, J_gem11 Hz, 1H, OCH₂CH₃), 4.24 8d,

J12 Hz, 1H, Bn), 4.35 8d, J11 Hz, 1H, Bn), 4.51 8d,

J12 Hz, 1H, Bn), 4.54 8d, J11 Hz, 1H, Bn), 4.72 8q,

J_CH36.5 Hz, 1H, 1⁰⁰-H), 7.15±7.3 8m, 10H, Ph); ¹³C

NMR: d11.50/14.22/21.41 88⁰-CH₃,C-2⁰⁰, OCH₂CH₃),

24.33/29.63/33.73 8C-2,3,2⁰), 33.05/34.03/ 38.52 8C-

1⁰,6⁰,8⁰), 60.43 8OCH₂CH₃), 71.05/71.54 8Bn), 67.03/

69.19/69.38/76.75/82.31 8C-3⁰,7⁰,9⁰,10⁰, 1⁰⁰), 127.89±

128.54 8Ph), 136.29/137.84 8C-4⁰,5⁰), 138.20/138.58

8Ph), 173.68 8ester CO); MS 8FI, 1508C): m/z 8%): 539

8100) [M1H¹], 521 880) [M¹2H₂O], 494 844)

[M1H¹2CH₃CH₂O], 91 865) [C₇H₇¹]; Anal. Calcd for

C₃₂H₄₂O₇: C71.35%, H7.86%, found: C71.08%,

H7.83%.

at 08C under an argon atmosphere. After 15 min THF 85 ml)

were added to improve the solubility. After stirring further

30 min at 08C sat. aq. NH₄Cl solution and water were added

and the aq. layer was extracted four times with ethyl acetate,

the combined organic layers were washed with brine and

dried over Na₂SO₄. After ®ltration and evaporation the

crude product was puri®ed by column chromatography

with petroleum ether/ethyl acetate 82:1) to afford 544 mg

881%) 21 as colorless crystals mp 1448C. IR: 3456 8O±H),

1

3028 8H±Cv), 2886 8C±H), 1667 8CO±Cv); H NMR:

d1.10 8d, J7.5 Hz, 3H, 9-CH₃), 1.35 8d, J₄8.8 Hz,

1H, OH), 2.03 8ddd, J₆13.8 Hz, J₅12.1 Hz, J₄9.5 Hz,

1H, 5ax-H), 2.20 8dddd, J_5ax13.8 Hz, J₇5.7 Hz,

J₁3.5 Hz, J_5eq2.6 Hz, 1H, 6-H), 2.28 8s, 3H, COCH₃),

2.36 8ddd, J₅12.1 Hz, J₄7.3 Hz, J₆2.6 Hz, 1H, 5eq-

H), 2.56 8qdd, J_CH37,4 Hz, J₈4.8 Hz, J₁₀2.7 Hz, 1H,

9-H), 3.01 8m, w_1/210 Hz, 1H, 1-H), 3.38 8s, 3H, OCH₃),

3.64 8t, J₁,J₉,2.8 Hz, 1H, 10-H), 3.88 8dd, J₇10.35 Hz,

J₉4.8 Hz, 1H, 8-H), 3.93 8dd, J₈10.35 Hz, J₆5.7 Hz,

1H, 7-H), 4.09 8d, J11.6 Hz, 1H, Bn), 4.38 8m,

J_5ax9.5 Hz, J_OH8.8 Hz, J_5eq7.3 Hz, J₃,J_lr,2.6 Hz,

1H, 4-H), 4.41 8d, J12.1 Hz, 1H, Bn), 4.59 8d,

J11.9 Hz, 1H, Bn), 4.63 8d, J11.9 Hz, 1H, Bn), 4.71

8d, J6.6 Hz, 1H, OCH₂O), 4.87 8d, J6.6 Hz, 1H,

OCH₂O), 6.88 8d, J₄2.5 Hz, 1H, 3-H), 7.18±7.4 8m,

10H, Ph); ¹³C NMR: d11.95 8CH₃-9), 26.06 8CH₃CO),

29.23 8C-5), 33.37/35.82/38.65 8C-9/6/1), 55.80 8CH₃O),

68.90 8C-4), 72.43/72.49 8Bn), 75.91/76.03/81.62 8C-

7,8,10), 97.32 8OCH₂O), 127.73±128.79 8Ph), 139.13/

139.59 8Ph), 139.84 8C-3), 145.28 8C-2), 198.93

8CH₃CO); MS 8EI): m/z 8%)480 8,2) [M¹], 462 8,2)

[M¹2H₂O], 435 8,2) [M¹2 CH₂OCH₃], 372 85)

[M¹2C₆H₅CH₂OH], 91 8100) [C₇H₇¹]; Anal. Calcd for

C₂₉H₃₆O₆: C72.48%, H7.55%, found: C72.47%,

H7.43%.

1.1.16. *^)-*1R^p,4S^p,6R^p,7R^p,8R^p,9R^p,10S^p)-2-Acetyl-8,

10-benzyloxy-9-methyl-7-*methoxymethyloxy)-4-*1⁰,3⁰-

dioxa-2⁰-iodomethylpent-1-yl)-bicyclo [4.4.0] dec-2-ene

*22). To a solution of 754 mg 81.57 mmol) 21 in dry

methylene chloride 7.85 mmol ethyl vinyl ether 8752 ml)

and 706 mg 83.14 mmol) N-iodosuccinimide were added

at 2208C under an argon atmosphere. After stirring for

6 h at 2208C the solvent was evaporated and the residue

®ltered through silica gel 8petroleum ether/ethyl acetate 4:1

then 2:1) yielding 22 8979 mg, 92%) as a 1:1 diastereomeric

mixture. The yellow oil was used immediately after prepara-

tion.

1.1.14. *^)-*1R^p,6R^p,7R^p,8R^p,9R^p,10S^p)-2-Acetyl-8,10-di-

benzyloxy-9-methyl-7-methoxymethyloxybicyclo [4.4.0]

dec-2-en-4-one *20). To a solution of 1.98 g 84.6 mmol)

light sensitive 4 in dry methylene chloride 820 ml) in a

brown round bottom ¯ask were added 92 mmol N,N-diiso-

propylethylamine 815.9 ml) and ,65 mmol chloromethyl

methyl ether 85 ml) and the reaction mixture was stirred

under an argon atmosphere for 21.5 h. Sat. aq. NaHCO₃

solution was added and the aq. layer was extracted four

times with methylene chloride. The combined organic

layers were washed with brine and dried over Na₂SO₄.

After ®ltration and evaporation the crude product was puri-

®ed by column chromatography with petroleum ether/ethyl

acetate 84:1) to afford 1.8 g 883%) 20 as colorless crystals

mp 1058C; IR: 3028 8H±Cv), 2890 8C±H), 1676

COCvCCO); ¹H NMR: d1.17 8d, J7.3 Hz, 3H,

9-CH₃), 2.25 8s, 3H, COCH₃), 2.56 8qdd, J_CH37.4 Hz,

J₈5.1 Hz, J₁₀2.8 Hz, 1H, 9-H), 2.6±2.65 8m, 2H, 6-H/

5eq-H), 2.93 8dd, J₅19 Hz, J₆15.7 Hz, 1H, 5ax-H),

3.218dd, J₆,5 Hz, J₁₀,2.7 Hz, 1H, 1-H), 3.36 8s, 3H,

OCH₃), 3.55 8t, J₁,J₉,2.7 Hz, 1H, 10-H), 3.91 8dd,

J₇10.35 Hz, J₉5.1 Hz, 1H, 8-H), 3.99 8dd,

J₈10.35 Hz, J₆5.6 Hz, 1H, 7-H), 4.10 8d, J12.1 Hz,

1H, Bn), 4.38 8d, J12.1 Hz, 1H, Bn), 4.58 8d,

J11.8 Hz, 1H, Bn), 4.63 8d, J11.6 Hz, 1H, Bn), 4.68

8d, J6.8 Hz, 1H, OCH₂O), 4.86 8d, J6.8 Hz, 1H,

OCH₂O), 6.66 8s, 1H, 3-H), 7.05±7.4 8m, 10H, Ph); ¹³C

NMR: d11.79 8CH₃-9), 26.50 8CH₃CO), 33.68/35.29/

38.62 8C-9,6,1), 36.61 8C-5), 55.96 8CH₃O), 72.37/72.59

8Bn), 75.24/75.67/81.51 8C-7,8,10), 97.27 8OCH₂O),

127.85±128.78 8Ph), 136.06 8C-3) 138.22/139.32 8Ph),

152.55 8C-2), 199.74/202.82 8CH₃CO/C-4); MS 8EI): m/z

8%)478 8,2) [M¹], 446 8,2) [M¹2CH₃OH], 434 83.5)

[M¹2CH₂OCH₃], 433 811) [M¹2CH₃OCH₃], 228 810), 219

825), [M¹], 91 8100) [C₇H₇¹]; Anal. Calcd for C₂₉H₃₄O₆:

C72.78%, H7.16%, found: C72.44%, H7.14.

1.1.17. *^)-*1R^p,2S^p,3R^p,4S^p,5R^p,6R^p,7R^p,8R^p,10S^p,12R^p/

12S^p)-2-Acetyl-4,6-dibenzyloxy-12-ethoxy-7-*methoxy-

methyloxy)-5-methyl-11-oxatricyclo

[8.3.0.0^3,8] tri-

1.1.15. *^)-*1R^p,4S^p,6R^p,7R^p,8R^p,9R^p,10S^p)-2-Acetyl-8,

10-dibenzyloxy-9-methyl-7-methoxymethyloxybi-cyclo

[4.4.0] dec-2-en-4-ol *21). 103 mg 82.8 mmol) sodium

borohydride were dissolved in methanol 830 ml) and stirred

at 08C under an argon atmosphere for 10 min. 335 mg

81.4 mmol) ceric8III)chloride heptahydrate dissolved in

methanol 810 ml) were added and stirring continued at

08C for 15 min. This reaction mixture was added dropwise

within 45 min with a syringe to a solution of 650 mg

81.4 mmol) 20, 335 mg 81.4 mmol) ceric8III)chloride hepta-

hydrate, methylene chloride 810 ml), and methanol 840 ml)

decane *23). To a solution of 1.08 g 81.59 mmol) 22 in

degassed tert-butanol 847 ml) 150 mg 82.38 mmol) sodium

cyanoborohydride and 78 mg 80.48 mmol) AIBN were

added. The mixture was heated to 858C under an argon

atmosphere. 0.32 mmol tri-n-butyltin chloride 886 ml)

were added in three portions over 40 min. Heating was

continued for further 80 min. Then brine and water were

added, the aq. layer was extracted four times with ethyl

acetate, the combined organic layers were washed with

brine and dried over Na₂SO₄. After ®ltration and evapora-

tion the product was puri®ed by column chromatography

È

E. Gossinger et al. / Tetrahedron 57 -2001) 3045±3061

3055

with petroleum ether/ethyl acetate 85:1 then 1:1) to afford a

1:1 diastereomeric mixture of 23 as a colorless oil 8719 mg,

82%) and the reduced product 24 872 mg, 8%). To charac-

terize the tricyclic compound a small part of the product

mixture 23 was separated by column chromatography with

petroleum ether/ethyl acetate 83:1).

26.39/33.22 8C-9,13), 29.43 8COCH₃), 34.51/34.95/38.60/

40.26 8C-1,3,5,8), 53.04 8C-2), 55.40 8OCH₃), 63.15

8OCH₂CH₃), 71.47/72.04 8Bn), 75.62/75.97/79.93/81.09

8C-4,6,7,10), 96.92 8OCH₂O), 105.72 8C-12), 127±128

8Ph), 139.15/139.22 8Ph), 207.9 8CO); MS 8FI,1308C): m/z

8%)552 844) [M¹], 507 861) [M¹2CH₃CH₂O], 106 865),

91 8100) [C₇H₇¹], 57 816); HRMS 8EI, 1808C, 70 eV): Calcd

for C₃₃H₄₄O₇552.3087, found M¹ 552.3065.

23a 8diastereoisomer with the higher R_f-value). IR: 3028

1

8vC±H), 2893 8C±H), 1710 8CO); H NMR: d1.01 8d,

J7.5 Hz, 3H, 5-CH₃), 1.14 8t, J7.5 Hz, 3H, OCH₂CH₃),

1.69 8ddd, J_gem12 Hz, J₁₀10 Hz, J₈13 Hz, 1H, 9endo-

H), 1.72 8dd, J_gem13 Hz, J₁7 Hz, 1H, 13exo-H), 1.94 8m,

J_9en13 Hz, J₇,J_9en,5.5 Hz, J₃3.5 Hz, 1H, 8-H), 2.05

8m, J_gem12.04 Hz, J₈6 Hz, J₁₀7 Hz, 1H, 9exo-H),

2.20 8s, 3H, COCH₃), 2.32 8ddd, J₂7 Hz, J₄,J₈,4 Hz,

1H, 3-H), 2.47 8ddd, J_gem,J₁,13 Hz, J₁₂5.5 Hz, 1H,

13endo-H), 2.5 8ddq, J_CH37 Hz, J₆4.5 Hz, J₄2.5 Hz,

1H, 5-H), 2.86 8dq, J_13en13.5 Hz, J_13ex,J₂,J₁₀,6.5±

7 Hz, 1H, 1-H), 3.14 8dd, J₁,J₃,6.5 Hz, 1H, 2-H), 3.31

8dq, J_CH37 Hz, J_gem9.5 Hz, 1H, OCH₂CH₃), 3.39 8s,

3H, OCH₃), 3.64 8dq, J_CH37 Hz, J_gem9.5 Hz, 1H,

OCH₂CH₃), 3.79 8m, 1H, 4-H), 3.81 8dd, J₇10.5 Hz,

J₅5 Hz, 1H, 6-H), 3.88 8dd, J₆10.5 Hz, J₈5.5 Hz, 1H,

7-H), 4.12 8ddd, J_9en10 Hz, J_9ex7 Hz, J₁6 Hz, 1H, 10-

H), 4.32 8d, J11.0 Hz, 1H, Bn), 4.37 8d, J11.0 Hz, 1H,

Bn), 4.53 8d, J12.05 Hz, 1H, Bn), 4.59 8d, J12.05 Hz,

1H, Bn), 4.67 8d, J_13en5.5 Hz, 1H, 12-H), 4.71 8d,

J6.5 Hz, 1H, OCH₂O), 4.85 8d, J7 Hz, 1H, OCH₂O),

7.1±7.4 8m, 10H, Ph); ¹³C NMR: d12.09/15.21 85-CH₃,

OCH₂CH₃), 26.58/33.81 8C-9,13), 29.85 8COCH₃), 34.46/

34.47/35.64/39.47 8C-1,3,5,8), 52.03 8C-2), 55.39 8OCH3),

62.47 8OCH₂CH₃),71.52/71.98 8Bn), 75.40/75.97/79.19/

80.38 8C-4,6,7,10), 96.86 8OCH₂O), 103.43 8C-12), 127±

128 8Ph), 138.37/139.14 8Ph), 208.22 8CO); MS

8FI,1308C): m/z 8%)552 824) [M¹], 507 830)

[M¹2CH₃CH₂O], 461 810) [M¹2 C₇H₇], 445 816)

[M¹2C₇H₇O], 106 8100), 91 844) [C₇H₇¹]; HRMS 8EI,

1808C, 70 eV): Calcd for C₃₃H₄₄O₇552.3087, found

M¹552.3098.

Data of the diastereomeric mixture. Anal. Calcd for

C₃₃H₄₄O₇: C71.71%, H8.02%, found: C70.18%,

H7.76%.

1.1.18. *^)-*1R^p,2S^p,3R^p,4S^p,5R^p,6R^p,7R^p,8R^p,10S^p)-4,6-

Dibenzyloxy-12-ethoxy-2-*1⁰-hydroxyethyl)-5-methyl-7-

methoxymethyloxy-11-oxatricyclo [8.3.0.0^3,8] tridecane

*24). A solution of 464 mg 80.84 mmol) 23 in methanol

840 ml) was treated with 64 mg 81.68 mmol) sodium boro-

hydride under an argon atmosphere at 08C. After stirring at

room temperature for 1.5 h sat. aq. NH₄Cl solution was

added. The aq. layer was extracted three times with meth-

ylene chloride, the combined organic layers were washed

with brine and dried over Na₂SO₄. After ®ltration and

evaporation the crude product 24 8452 mg, 97%), a mixture

of four diastereoisomers, was used for the following reac-

tion. IR: 3456 8OH), 3028 8vC±H), 2969/2924 8C±H); MS

8FI, 1208C): m/z 8%)554 875) [M¹], 522 832)

[M¹2CH₃OH], 509 8100) [M¹2CH₃CH₂O], 91 832)

[C₇H₇]; HRMS: Calcd for C₃₃H₄₆O₇554.3244, found

M¹554.3228.

1.1.19. *^)-*1R^p,3R^p,4S^p,5R^p,6R^p,7R^p,8R^p,10S^p)-4,6-Di-

benzyloxy-12-ethoxy-2-ethyliden-5-methyl-7-methoxy-

methyloxy-11-oxatricyclo [8.3.0.0^3,8] tridecane *25).

4.72 mmol SOCl₂8345 ml, freshly distilled) and dry pyri-

dine 810 ml) were combined and cooled to 08C. A solution

of 524 mg 80.945 mmol) 24 in dry pyridine 850 ml) was

added slowly 8over 30 min). After the addition was

completed the mixture was stirred for 30 min at 08C. The

reaction mixture was quenched with sat. aq. NaHCO₃solu-

tion. The aq. layer was extracted four times with ethyl

acetate the combined organic layers were washed with

brine and dried over Na₂SO₄. After ®ltration and evapora-

tion toluene was added several times and evaporated. The

reaction mixture was ®ltered through silica gel 8petroleum

ether/ethyl acetate 6:1) yielding 25 8400 mg, 79%) as a

colorless oil. The unseparated mixture of four diastereo-

isomers was used for the following reaction. IR: 3028

8vC±H), 2970/2891 8C±H); MS 8FI, 908C): m/z 8%)536

8100) [M¹], 505 84) [M¹2CH₃O], 491 845) [M¹2C₂H₅O],

391 832), 91 840) [C₇H₇]; HRMS: Calcd for C₃₃H₄₄O₆

536.3138, found M¹536.3135.

23b 8diastereoisomer with the lower R_f-value). IR: 3028

8vC±H), 2970/2892 8C±H), 1709 8CO); ¹H NMR:

d0.96 8d, J7.5 Hz, 3H, 5-CH₃), 1.16 8t, J7 Hz, 3H,

OCH₂CH₃), 1.95 8m, J₃3.5 Hz, J₇,J_9ex,5.5±6 Hz,

J_9en13.55 Hz, 1H, 8-H), 2.05 8m, 1H, 9exo-H), 2.11

8ddd, J_gem,J₈,13 Hz, J₁₀11 Hz, 1H, 9endo-H), 2.18 8s,

3H, COCH₃), 2.30 8ddd, J_gem13.55 Hz, J₁7 Hz, J₁₂

5.5 Hz, 1H, 13exo-H), 2.44 8ddd, J₂6 Hz, J₄,J₈,4 Hz,

1H, 3-H), 2.47 8ddq, J_CH37.5 Hz, J₄2.5 Hz, J₆5 Hz,

1H, 5-H), 2.61 8dddd, J_13en12 Hz, J_13ex7.5 Hz,

J₂,J₁₀,6 Hz, 1H, 1-H), 2.75 8ddd, J_gem,13 Hz,

J₁,11.5 Hz, J₁₂5.5 Hz, 1H, 13endo-H), 3.09 8dd,

J₁,J₃,6 Hz, 1H, 2-H), 3.36 8dq, J_CH37 Hz, J_gem9 Hz,

1H, OCH₂CH₃), 3.38 8s, 3H, OCH₃), 3.65 8dd, J₃,J₅,3±

2.5 Hz, 1H, 4-H), 3.70 8dq, J_CH37 Hz, J_gem9 Hz, 1H,

OCH₂CH₃), 3.73 8dd, J₇10.55 Hz, J₅5 Hz, 1H, 6-H),

3.87 8dd, J₆10.5 Hz, J₈6 Hz, 1H, 7-H), 3.94 8ddd,

J_9en11.04 Hz, J_9exo,J₁,6 Hz, 1H, 10-H), 4.21 8d,

J11.54 Hz, 1H, Bn), 4.22 8d, J12.55 Hz, 1H, Bn), 4.28

8d, J12.05 Hz, 1H, Bn), 4.66 8d, J12.55 Hz, 1H, Bn),

4.69 8d, J6.5 Hz, 1H, OCH₂O), 4.85 8d, J7 Hz, 1H,

OCH₂O), 5.15 8t, J_13en,J_13ex,5.5 Hz, 1H, 12-H), 7.1±7.4

8m, 10H, Ph); ¹³C NMR: d12/15.44 85-CH₃, OCH₂CH₃),

1.1.20. *^)-*1R^p,3R^p,4S^p,6R^p,7R^p,8R^p,9R^p,10S^p)-8,10-Di-

benzyloxy-2-ethyliden-3-*2⁰-hydroxyethyl)-9-methyl-7-

*methoxymethyloxy)-bicyclo [4.4.0] decan-4-ol *26). To a

solution of 400 mg 80.746 mmol) 25 in THF 830 ml) 2% aq.

HCl 815 ml) was added. The mixture was stirred at 408C

under an argon atmosphere for 2 h. The reaction mixture

was quenched with sat. aq. NaHCO₃solution, the aq.

layer was extracted four times with ethyl acetate the

combined organic layers were washed with brine and

dried over Na₂SO₄. After ®ltration and evaporation the

È

E. Gossinger et al. / Tetrahedron 57 -2001) 3045±3061

3056

residue was dissolved in dry THF 850 ml). This solution

was added to a suspension of 85 mg 82.24 mmol) lithium

aluminum hydride in dry THF 820 ml) at 08C. After addition

was completed the mixture was stirred another 1.5 h and

quenched with water 81 ml). After stirring for several min

the mixture was ®ltered through celite and evaporated. The

product was puri®ed and separated by column chromato-

graphy with petroleum ether/ethyl acetate 81:1 then 1:2) to

afford 26a 8241.5 mg, 63%) and 26b 880.5 mg, 21%) as

colorless oils.

8Ph), 137.43 8C-2), 138.57/139.17 8Ph); MS 8FI, 1108C):

m/z 8%)511 8100) [M1H¹], 479 814) [M1H¹2

CH₃OH], 450 811) [M1H¹2CH₃OCH₂O], 391 818), 91

834) [C₇H₇]; HRMS: Calcd for C₃₁H₄₂O₆510.2981,

found M¹ 510.2996.

The following reactions were executed with the separated

diastereoisomers.

1.1.21. *^)-*1R^p,3R^p,4S^p,6R^p,7R^p,8R^p,9R^p,10S^p)-8,10-Di-

benzyloxy-2-ethyliden-3-*2⁰-hydroxyethyl)-9-methylbi-

cyclo [4.4.0] decan-4,7-diol *27). To a solution of 222 mg

80.435 mmol) 26 in dry methanol 848 ml) 5.5 M methanolic

HCl 82 ml) was added under an argon atmosphere. After

stirring the reaction mixture at 508C for 1 h sat. aq.

NaHCO₃solution was added. The aq. layer was extracted

four times with ethyl acetate the combined organic layers

were washed with brine and dried over Na₂SO₄. After ®ltra-

tion and evaporation the reaction mixture was ®ltered

through silica gel 8petroleum ether/ethyl acetate 1:2) yield-

ing 27 8165 mg, 81%) as a colorless oil. The substance was

used immediately after preparation. IR: 3384 8OH), 3028

8vC±H), 2880 8C±H); MS 8FI, 1208C): m/z 8%)467 8100)

[M1H¹], 449 88) [M1H¹2H₂O], 391 816), 91 842) [C₇H₇].

8E)-26a 8main product). IR: 3331 8OH), 3028 8vC±H),

1

2884 8C±H); H NMR: d0.92 8d, J7 Hz, 3H, 9-CH₃),

1.38 8dddd, J_{2 a},J_{2 b},J₃,4 Hz, J_gem15 Hz, 1H, 1⁰a-H),

1.58 8d, J6.5 Hz, 3H, 2⁰⁰-H), 1.90±1.77 8m, 2H, 1⁰b/

5exo-H), 1.92 8ddd, J₄10 Hz, J_gem11.4 Hz, J₆13 Hz,

1H, 5endo-H), 2.02 8m, J₇,J₁,5.5 Hz, J_5en13.55 Hz,

J_5ex3 Hz, 1H, 6-H), 2.38 8dd, J₆5.5 Hz, J₁₀3.5 Hz,

1H, 1-H), 2.43 8ddq, J_CH37.5 Hz, J₈4.5 Hz, J₁₀3 Hz,

1H, 9-H), 2.51 8w_1/216 Hz, 2H, OH), 2.96 8dt,

0

J₄,J_{1 b},6.5 Hz, J_{1 a}4 Hz, 1H, 3-H), 3.25 8dd,

J₁,J₉,3 Hz, 1H, 10-H), 3.29 8s, 3H, OCH₃), 3.52±3.42

8m, 2H. 2⁰-H), 3.59 8ddd, J_5ex4 Hz, J₃6 Hz,

J_5en10.5 Hz, 1H, 4-H), 3.76 8dd, J₇10.5 Hz, J₉4.5 Hz,

1H, 8-H), 3.80 8dd, J₈10.5 Hz, J₆5.5 Hz, 1H, 7-H), 4.18

8d, J11.5 Hz, 1H, Bn), 4.27 8d, J11.5 Hz, 1H, Bn), 4.36

8d, J12 Hz, 1H, Bn), 4.43 8d, J12 Hz, 1H, Bn), 4.62 8d,

J6.5 Hz, 1H, OCH₂O), 4.77 8d, J6.5 Hz, 1, OCH₂O),

5.36 8q, J_CH37 Hz, 1H, 1⁰⁰-H), 7.1±7.3 8m, 10H, Ph); ¹³C

NMR: d11.74/13.48 89-CH₃,C-2⁰⁰), 28.30/33.69 8C-5,1⁰),

34.35/39.98/40.55/43.05 8C-1,3,6,9), 55.42 8OCH₃), 63.51

1.1.22. *^)-*1R^p,3R^p,4S^p,6R^p,7R^p,8R^p,9R^p,10S^p)-8,10-Di-

benzyloxy-2-ethyliden-3-*2⁰-t-butyldimethylsilyloxy-

ethyl)-9-methylbicyclo [4.4.0] decan-4,7-diol *28). To a

solution of 139 mg 80.298 mmol) 27 in dry DMF 810 ml)

49 mg 83.28 mmol) t-butyldimethylsilyl chloride, 101 mg

81.49 mmol) imidazole and a catalytic amount of 4-N,N-

dimethylamino pyridine were added under an argon

atmosphere at room temperature. Stirring was continued

until starting material was no longer detectable by TLC.

The reaction mixture was quenched with sat. aq. NaHCO₃

solution. The aq. layer was extracted four times with ethyl

acetate the combined organic layers were washed with brine

and dried over Na₂SO₄. After ®ltration and evaporation the

product was puri®ed by column chromatography with petro-

leum ether/ethyl acetate 82.5:1) to afford 28 8140 mg, 81%)

as colorless oils.

8C-2⁰),

71.64/72.21

8Bn),

73.09/74.92/75.62/88.34

8C-4,7,8,10), 96.67 8OCH₂O), 123.39 8C-1⁰⁰), 127±128

8Ph) 138.69/139.21 8Ph), 143.51 8C-2); MS 8FI, 1108C):

m/z 8%)511 8100) [M¹], 479 817) [M¹2CH₃OH], 450

816) [M¹2CH₃OCH₂O], 386 820), 91 833) [C₇H₇];

HRMS: Calcd for C₃₁H₄₂O₆510.2981, found M¹

510.2997.

8Z)-26b 8byproduct). IR: 3385 8OH), 3028 8vC±H), 2924/

1

2882 8C±H); H NMR: d0.98 8d, J7.5 Hz, 3H, 9-CH₃),

1.41 8d, J6 Hz, J1 Hz, 3H, 2⁰⁰-H), 1.50 8br, 1H, OH),

1.68 8dddd, J_{2 a},J_{2 b},J₃,5.5 Hz, J_gem,14.6 Hz, 1H, 1⁰a-

8E)-28a. IR: 3448 8OH), 3028 8vC±H), 2927/2883/2857

0

1

0

H), 1.77 8dddd, J_gem14 Hz, J₂,J₂,7 Hz, J₃2 Hz, 1H,

1⁰b-H), 1.78 8m, J_gem,J₄,J₆,13 Hz, 1H, 5endo-H), 2.08

8ddd, J_gem12 Hz, J₆,J₄,6 Hz, 1H, 5exo-H), 2.15 8m,

J_5en13 Hz, J_5ex,J₇,J₁,5 Hz, 1H, 6-H), 2.43 8m, 1H,

3-H), 2.46 8ddq, J_CH37.5 Hz, J₈5 Hz, J₁₀2.5 Hz, 1H,

9-H), 2.86 8br, 1H, OH), 2.90 8dd, J₁₀,J₆,3.8 Hz, 1H,

1-H), 3.30 8s, 3H, OCH₃), 3.51 8ddd, J_gem11.5 Hz,

8C±H); H NMR: d0/0.1 8s/s, 6H, 2Si±CH₃), 0.85 8s,

9H, t-Butyl), 0.93 8d, J7 Hz, 3H, 9-CH₃), 1.32 8dddd,

J_gem15.56 Hz, J_{2 a},J_{2 b},J₃,3 Hz, 1H, 1⁰b-H), 1.58 8s,

1H, OH), 1.63 8d, J7 Hz, 3H, 2⁰⁰-H), 1.77 8ddd,

J₄11 Hz, J_gem12 Hz, J₆13.5 Hz, 1H, 5endo-H), 1.92

8ddd, J_gem12.05 Hz, J₆,J₄,3 Hz, 1H, 5exo-H), 2.0

0

8dddd, J_{2 a},J₃,7.5 Hz, J_{2 b}9 Hz, J_gem,15.56 Hz, 1H,

J_1a4.5 Hz, J_1b7.5 Hz, 1H, 2⁰b-H), 3.52 8dd,

1⁰a-H),

2.08

8dddd,

J_5ex3 Hz,

J₁,J₇,6 Hz,

0

J₁,J₉,2.5±3.5 Hz, 1H, 10-H), 3.59 8ddd, J_gem11 Hz,

J_5en13.55 Hz, 1H, 6-H), 2.42 8dd, J₁₀3 Hz, J₆5.5 Hz,

0

J_1a5 Hz, J_1b6 Hz, 1H, 2 a-H), 3.79 8m, 1H, 4-H), 3.80

8dd, J₇10.5 Hz, J₉5 Hz, 1H, 8-H), 3.86 8dd, J₈10 Hz,

J₆5.5 Hz, 1H, 7-H), 4.18 8d, J11.5 Hz, 1H, Bn), 4.35 8d,

J12 Hz, 1H, Bn), 4.43 8d, J12 Hz, 1H, Bn), 4.51 8d,

J11.5 Hz, 1H, Bn), 4.63 8d, J6.5 Hz, 1H, OCH₂O),

4.77 8d, J6.5 Hz, 1H, OCH₂O), 5.31 8qt, J_CH37 Hz,

J₁,J₃,1±1.5 Hz, 1H, 1⁰⁰-H), 7.1±7.3 8m, 10H, Ph); ¹³C

NMR: d11.62/13.54 89-CH₃, C-2⁰⁰), 29.56/32.59 8C-

5,1⁰), 34.25/35.27/37.11/44.78 8C-1,3,6,9), 55.46 8OCH₃),

61.47 8C-2⁰), 71.62/72.02 8Bn), 70.23/75.30/75.34/83.03

8C-4,7,8,10), 96.58 8OCH₂O), 122.25 8C-1⁰⁰), 127±128

1H, 1-H), 2.50 8ddq, J_CH37.5 Hz, J₈5 Hz, J₁₀2.5 Hz,

0

1H, 9-H), 2.99 8ddd, J_{1 a},J₄,7 Hz, J_{1 b}2.2 Hz, 1H,

3-H), 3.34 8dd, J₁,J₉,3 Hz, 1H, 10-H), 3.57±3.5 8m, 2H,

2⁰-H), 3.59 8m, J_5ex4.5 Hz, J_5en10.54 Hz, J₃7 Hz, 1H,

4-H), 3.73 8dd, J₇10.5 Hz, J₉5 Hz, 1H, 8-H), 3.88±3.8

8m, 1H, OH), 3.85 8dd, J₈10 Hz, J₆6 Hz, 1H, 7-H), 4.23

8d, J11.55 Hz, 1H, Bn), 4.33 8s, 2H, Bn), 4.39 8d,

J11.5 Hz, 1H, Bn), 5.39 8q, J_CH36.5 Hz, 1H, 1⁰⁰-H),

7.1±7.3 8m, 10H, Ph); ¹³C NMR: d25.56/25.52 8Si±

CH₃), 11.56/13.47 89-CH₃,C-2⁰⁰), 18.31 8t-Butyl), 25.95

8t-Butyl), 29.69/33.97 8C-5,1⁰), 32.91/39.61/40.51/42.85

È

E. Gossinger et al. / Tetrahedron 57 -2001) 3045±3061

3057

8C-1,3,6,9), 64.32 8C-2⁰), 70.65/72.48 8Bn), 68.55/72.17/

76.93/89 8C-4,7,8,10), 122.53 8C-1⁰⁰), 127.41±128.46 8Ph),

138.33/138.92 8Ph), 144.55 8C-2); MS 8FI, 808C): m/z

8%)581 8100) [M1H¹], 523 861) [M¹2t-Butyl], 91 830)

[C₇H₇¹]; HRMS: Calcd for C₃₅H₅₂O₅Si580.3584, found

M¹580.3601.

J7 Hz, 3H, 2⁰⁰-H), 1.86 8m, 1H, 6exo-H), 1.90 8m, 1H, 4-

H), 1.94 8m, 1H, 1⁰-H), 2.02 8m, 1H, 1⁰-H), 2.06 8d,

J₉3 Hz, 1H, 8-H), 2.07 8m, J₅2 Hz, J₇3 Hz, J_gem

14±15 Hz, 1H, 6endo-H), 2.40 8dd, J_6a,J_6b,3.25 Hz, 1H,

7-H), 2.56 8ddq, J₁₁5.5 Hz, J₉11 Hz, J_CH37 Hz, 1H, 10-

H), 3.31 8dd, J₁₀11.05 Hz, J₈2.5 Hz, 1H, 9-H), 3.52 8d,

J₅7.5 Hz, 1H, 5-OH), 3.57 8dd, J₁,J₁₀,5 Hz, 1H, 11-H),

0

8Z)-28b. IR: 3442 8OH), 3029 8vC±H), 2956/2927/2857

3.60 8ddd, J_gem10.6 Hz, J₁4 Hz, J₁5.5 Hz, 1H, 2 b-H),

1

0

8C±H); H NMR: d0.0 8s, 6H, 2Si±CH₃), 0.85 8s, 9H,

3.72 8ddd, J_gem10.5 Hz, J₁3.5 Hz, J₁7.5 Hz, 1H, 2 a-

H), 3.99 8m, J_OH7 Hz, J_6exo,J₄,3.5 Hz, J_6endo,1 Hz, 1H,

5-H), 4.38 8d, J11 Hz, 1H, Bn), 4.44 8d, J12 Hz, 1H,

Bn), 4.49 8d, J,13 Hz, 1H, Bn), 4.52 8d, J₁₁4.5 Hz, 1H,

1-H), 4.63 8d, J_gem11.5 Hz, 1H, Bn), 5.18 8q, J_CH37 Hz,

1H, 1⁰⁰-H), 7.2±7.4 8m, 10H, Ph), 10.05 8s, 1H, 1⁰⁰-OH); ¹³C

NMR 8C±H correlation): d25.53/25.52 8Si±CH₃), 13.55

810-CH₃), 16.32 8C-2⁰⁰), 18.21 8t-Butyl), 25.9 8t-Butyl),

28.66 8C-1⁰), 36.79 8C-6), 35.75 8C-10), 37.49 8C-7),

44.08 8C-4), 48.94 8C-8), 61.48 8C-2⁰), 66.34 8C-5), 72.61/

72.94 8Bn), 79.40 8C-11), 81.63 8C-1), 83.36 8C-1⁰⁰), 84.2

8C-9), 93.06 8C-3), 127.51±128.40 8Ph), 138.07/138.34

8Ph); MS 8FI, 1308C): m/z 8%)596 893) [M¹], 552 87)

[M¹2CH₃CHOH], 537 871), 505 834) [M¹2 C₇H₇], 464

840), 447 8100), 405 822), 106 812), 91 849) [C₇H₇¹], 57

818) [t-Butyl]; Anal. Calcd for C₃₅H₅₂O₆Si: C70.43%,

H8.78%, found: C70.65%, H8.63%.

t-Butyl), 0.99 8d, J7 Hz, 3H, 9-CH₃), 1.49 8d, J7 Hz,

3H, 2⁰⁰-H), 1.56 8br, 1H, OH), 1.60 8dddd, J_gem14.55 Hz,

J_{2 a},J_{2 b},J₃,4.5 Hz, 1H, 1⁰b-H), 1.70 8ddd, J₄8 Hz,

0

J_gem,J₆,13.05 Hz,

1H,

5endo-H),

1.80

8dddd,

J_{2 a},J_{2 b,}6.5 Hz, J₃7.5 Hz, J_gem,14.05 Hz, 1H, 1⁰a-H),

2.09 8ddd, J_gem13.05 Hz, J₆,J₄,5 Hz, 1H, 5exo-H),

2.17 8dddd, J_5ex,J₁,J₇,5.5 Hz, J_5en13 Hz, 1H, 6-H),

2.46 8w_1/26 Hz, 1H, OH), 2.50 8m, 1H, 3-H), 2.54 8ddq,

J_CH37.5 Hz, J₈5 Hz, J₁₀2.5 Hz, 1, 9-H), 2.92 8dd,

J₁₀2.5 Hz, J₆5.5 Hz, 1H, 1-H), 3.62±3.52 8m, 3H, 2⁰/

10-H), 3.74 8m, 1H, 4-H), 3.76 8dd, J₇10 Hz, J₉5 Hz,

1H, 8-H), 3.91 8dd, J₈10 Hz, J₆6 Hz, 1H, 7-H), 4.28

8d, J11.55 Hz, 1H, Bn), 4.34 8d, J12.05 Hz, 1H, Bn),

4.40 8d, J12 Hz, 1H, Bn), 4.44 8d, J11 Hz, 1H, Bn),

5.39 8q, J_CH36.5 Hz, 1H, 1⁰⁰-H), 7.1±7.3 8m, 10H, Ph);

¹³C NMR: d25.42 8Si±CH₃), 11.37/13.54 89-CH₃,C-2⁰⁰),

18.3 8t-Butyl), 25.95 8t-Butyl), 28.37/32.86 8C-5,1⁰), 32.71/

35.14/37.56/45.17 8C-1,3,6,9), 62.81 8C-2⁰), 70.87/72.04

8Bn), 68.97/69.99/76.77/83.80 8C-4,7,8,10), 121.69 8C-1⁰⁰),

127.8±128.5 8Ph), 137.98/138.25 8Ph), 140.38 8C-2);

HRMS: Calcd for C₃₅H₅₂O₅Si580.3584, found M¹

580.3602.

0

29b 8diastereoisomer with the lower R_f-value). IR: 3483

1

8OH), 3031 8vC±H), 2928/2857 8C±H); H NMR: d0.0

8s, 6H, Si±CH₃), 0.84 8s, 9H, t-Butyl), 1.01 8d, J6.5 Hz,

3H, 10-CH₃), 1.15 8d, J6.5 Hz, 3H, 2⁰⁰-H), 1.97±1.82 8m,

3H, 1⁰/6exo/4-H), 2.03 8d, J₉3 Hz, 1H, 8-H), 2.07 8m,

J₅2 Hz, J₇3.3 Hz, J_gem15.5 Hz, 1H, 6endo-H), 2.12

8w_1/27.8 Hz, 1H, 1⁰⁰-OH), 2.41±2.28 8m, 2H, 1⁰/10-H),

2.42 8dd, J_6a,J_6b,3.25 Hz, 1H, 7-H), 3.27 8dd,

J₁₀11.04 Hz, J₈3 Hz, 1H, 9-H), 3.52 8d, J₅7.5 Hz,

1.1.23. *^)-*1R^p,3S^p,4S^p,5S^p,7R^p,8S^p,9R^p,10R^p,11R^p)-9,

11-Dibenzyloxy-2-*2⁰-t-butyldimethylsilyloxyethyl)-3-

*1⁰⁰-hydroxyethyl)-10-methyl-2-oxatricyclo

[5.4.0.0^3,8]

undecan-5-ol *29). A solution of 67 mg 80.115 mmol) 28a

in dry THF 82 ml) was treated at 08C with 29 mg

80.07 mmol) mercury8II)tri¯uoroacetate and 15 mg

80.07 mmol) mercury8II)oxide under an argon atmosphere.

After stirring until starting material was no longer detect-

able by TLC brine was added and the two-phase system was

vigorously stirred for 15 min. The aq. layer was extracted

four times with ethyl acetate, the combined organic layers

were washed with brine and dried over Na₂SO₄. After ®ltra-

tion and evaporation the crude product was dissolved in

DMF 82.5 ml, saturated with oxygen) 8,0.05 M solution).

This solution was added to a suspension of 6 mg

80.16 mmol) sodium borohydride in DMF 81 ml, saturated

with oxygen) 8,0.2 M solution) over 5 min, afterwards the

mixture was stirred for another 30 min. Oxygen was

bubbled through the solution all the time. The mixture

was quenched with water, stirred for 45 min and extracted

four times with methylene chloride. The combined organic

layers were washed with brine and dried over Na₂SO₄. After

®ltration and evaporation the products were separated by

column chromatography with petroleum ether/ethyl acetate

84:1 then 3:1) to afford 29 830 mg, 44%, the diastereomeric

ratio differed from reaction to reaction) and starting material

811 mg, 16%).

1H, 5-OH), 3.53 8dd, J₁,J₁₀,4.5±5.5 Hz, 1H, 11-H),

0

3.61 8ddd, J_gem10 Hz, J₁4.5 Hz, J₁5.5 Hz, 1H, 2 b-

0

H), 3.70 8ddd, J_gem10.5 Hz, J₁3.5 Hz, J₁8 Hz, 1H,

2⁰a-H), 3.98 8m, w_1/215.06 Hz, 1H, 5-H), 4.35 8d,

J11.54 Hz, 1H, Bn), 4.42 8d, J11.55 Hz, 1H, Bn), 4.44

8d, J₁₁4.5 Hz, 1H, 1-H), 4.49 8d, J11.54 Hz, 1H, Bn),

4.64 8d, J11.55 Hz, 1H, Bn), 4.72 8q, J_CH36.5 Hz, 1H,

1⁰⁰-H), 7.2±7.4 8m, 10H, Ph); ¹³C NMR: d25.52 8Si±

CH₃), 13.47 810-CH₃), 16.64 8C-2⁰⁰), 18.2 8t-Butyl), 25.89

8t-Butyl), 29.19 8C-1⁰), 36.95 8C-6), 35.80 8C-10), 38.91

8C-7), 44.17 8C-4), 48.14 8C-8), 61.65 8C-2⁰), 66.63 8C-5),

69.50 8C-1⁰⁰), 72.36/72.79 8Bn), 79.57 8C-11), 80.67 8C-1),

84.42 8C-9), 90.88 8C-3), 127.6±128.3 8Ph), 138.19/138.47

8Ph); MS 8FI, 1508C): m/z 8%)597 8100) [M1H¹], 539

838), 91 810) [C₇H₇¹]; HRMS: Calcd for C₃₅H₅₂O₆Si

596.3533, found M¹596.3554.

1.1.24.

*^)-*1S^p,3R^p,4S^p,5S^p,6R^p,7R^p,8R^p,9R^p)-5,7-Di-

benzyloxy-3-*4⁰bromomethyl-3⁰,5⁰-dioxahept-2⁰-yl)-1-

*t-butyldimethylsilyloxy)-6-methyl-11-oxatricyclo [6.2.1.0^4,9]

undecane *30). Method a. 0.4 ml 87.76 mmol) bromine was

cooled to 2258C. 14 mmol ethyl vinyl ether 81.3 ml) was

added slowly over 30 min. The resulting yellow solution

was stirred for 30 min at 2258C and cooled to 2608C after-

wards. The residue was evacuated for 45 min and after

bringing to 08C was ready for use. 270 ml 8,2 mmol) of

this reagent was added to a stirred solution of 220 mg

80.399 mmol) 12 and 405 ml 83.19 mmol) of freshly distilled

29a 8diastereoisomer with higher R_f-value). IR: 3422 8OH),

1

2932/2856 8C±H); H NMR: d0.0 8s, 6H, Si±CH₃), 0.84

8s, 9H, t-Butyl), 1.03 8d, J6.5 Hz, 3H, 10-CH₃), 1.13 8d,

È

E. Gossinger et al. / Tetrahedron 57 -2001) 3045±3061

3058

N,N-dimethylaniline in dry methylene chloride 813 ml) at

08C under an argon atmosphere. After stirring for 15 min

at 08C and 2.5 h at room temperature sat. aq. NaHCO₃solu-

tion was added. The aq. layer was extracted three times with

methylene chloride, the combined organic layers were

washed with brine and dried over Na₂SO₄. After ®ltration

and evaporation the crude product was puri®ed by column

chromatography with petroleum ether/ethyl acetate 820:1).

The N,N-dimethylaniline could not be removed completely.

J_gem14.05 Hz, J_10en2 Hz, 1H, 2endo-H), 2.18 8ddq,

J_CH36.5 Hz, J₇4 Hz, J₅10.5 Hz, 1H, 6-H), 2.32 8m,

0

w_1/211.7 Hz, 1H, 9-H), 2.42 8ddd, J₂4 Hz, J_2ex

7.7 Hz, J_2en10.5 Hz, J₄6.3 Hz, 1H, 3-H), 3.07 8dq,

0

J_CH37 Hz, J_gem9 Hz, 1H, 6 -Ha), 3.10 8dd, J₄5.5 Hz,

0

J_gem10.5 Hz, 1H, CH₂Br), 3.14 8dd, J₄5 Hz, J_gem

10.5 Hz, 1H, CH₂Br), 3.30 8dq, J_CH37 Hz, J_gem9 Hz,

1H, 6⁰-Hb), 3.40 8dd, J₆11.5 Hz, J₄4.5 Hz, 1H, 5-H),

3.53 8dd, J₈,J₆,3±2.5 Hz, 1H, 7-H), 3.71 8dq, J_CH3

6.5 Hz, J₃4.5 Hz, 1H, 2⁰-H), 3.91 8dd, J₇,J₉,2.5 Hz,

1H, 8-H), 4.34 8d, J_gem11.55 Hz, 1H, Bn), 4.40 8t,

J_CH25±6 Hz, 1H, 4⁰-H), 4.41 8d, J11.55 Hz, 1H, Bn),

4.42 8d, J12 Hz, 1H, Bn), 4.49 8d, J11.5 Hz, 1H, Bn),

7.15±7.30 8m, 10, Ph); ¹³C NMR: d22.81/22.78 8Si±

CH₃), 13.46/14.76/15.14 8C-1⁰,6-CH₃,C-7⁰), 17.83 8t-Bu),

25.93 8t-Bu), 32.83 8CH₂Br), 38.14/42.08 8C-2,10), 31.88/

34.54/35.82/39.34 8C-3,4,6,9), 62.48 8C-6⁰), 72.38/73.53

8Bn), 76.98/77.27/79.84/81.07 8C-2⁰,5,7,8), 100.89 8C-4⁰),

107.26 8C-1), 127.54-128.32 8Ph), 138.56/138.58 8Ph).

Method b. To a stirred solution of 62 mg 80.112 mmol) 12 in

dry methylene chloride 83 ml) 336 mmol ethyl vinyl ether

832 ml) and 40 mg 80.224 mmol) N bromosuccinimide were

added under an argon atmosphere at 2208C. After stirring

for 2 h the mixture was warmed to 258C and stirred for

another 5 h. The reaction was quenched with brine. The

aq. layer was extracted four times with methylene chloride,

the combined organic layers were washed with brine and

dried over Na₂SO₄. After ®ltration and evaporation the

crude product 30 was used for the next reaction. Using

this method a part of the product lost the silylic acetal

providing 31.

Data of the diastereomeric mixture. MS 8FI, 1058C): m/z

8%)702/704 82/2) [M¹], 645/647 892/100) [M¹2t-Bu],

226.8 848), 151/153 852/39) [CH₃CH₂OCHCH₂Br¹], 91

88) [C₇H₇¹]; Anal. Calcd for C₃₇H₅₅O₆SiBr: C63.14%,

H7.88%, found: C62.91%, H7.68%.

For analytical purposes a small part of the product

mixture 30 was separated by column chromatography the

rest was used as a diasteromeric mixture for the following

reaction.

1.1.25. *^)-*1R^p,5R^p,6S^p,7S^p,8R^p,9R^p,10R^p)-7,9-Dibenzyl-

oxy-8-methyl-5-*4⁰-bromomethyl-3⁰,5⁰-dioxahept-2⁰-yl)-

10-hydroxybicyclo[4.4.0]decan-3-one *31). A solution of

345 mg 80.49 mmol) 30 8diastereomeric mixture) in THF

850 ml) was treated with 216 mg 80.686 mmol) tetra-n-

butylammonium ¯uoride trihydrate under an argon

atmosphere. After stirring at 08C for 2.5 h and at room

temperature for 2.5 h sat. aq. NH₄Cl solution was added.

The aq. layer was extracted three times with ethyl acetate,

the combined organic layers were washed with brine and

dried over Na₂SO₄. After ®ltration and evaporation the

crude product was puri®ed by column chromatography

with petroleum ether/ethyl acetate 83:1) to afford 31

8269 mg, 93%) as a colorless oil. For analytical purposes a

small part of the product mixture 31 was separated by

column chromatography the rest was used without puri®ca-

tion for the following reaction.

30a 8diastereoisomer with the higher R_f-value). IR: 3029

1

8vC±H), 2932/2858 8C±H); H NMR: d0 8two s, 6H,

2Si±CH₃), 0.8 8s, 9H, t-Bu), 1.01 8t, J7 Hz, 3H, 7⁰-H),

1.02 8d, J6.5 Hz, 3H, 1⁰-H), 1.03 8d, J6.5 Hz, 3H, 6-

CH₃), 1.63 8d, J_gem11.5 Hz, 1H, 10exo-H), 1.69 8dd,

J_gem14.05 Hz, J₃7.5 Hz, 1H, 2exo-H), 1.74 8ddd,

J_gem11.6 Hz, J₉4 Hz, J_2en3 Hz, 1H, 10endo-H), 1.92±

1.8 8m, 2H, 2endo/4-H), 2.14 8ddq, J_CH36.5 Hz,

J₇3.5 Hz, J₅11 Hz, 1H, 6-H), 2.32 8ddd, J_10en5.2 Hz,

0

J₄,J₈,2.5 Hz, 1H, 9-H), 2.42 8ddd, J₂4 Hz, J_2ex,J₄,

0

7 Hz, J_2en11 Hz, 1H, 3-H), 3.03 8dd, J₄5 Hz, J_gem

0

10.5 Hz, 1H, CH₂Br), 3.06 8dd, J₄5 Hz, J_gem10.5 Hz,

1H, CH₂Br), 3.25 8dq, J_CH37 Hz, J_gem9 Hz, 1H, 6⁰-Ha),

3.40 8dd, J₆11.05 Hz, J₄4.5 Hz, 1H, 5-H), 3.48 8dq,

J_CH37 Hz, J_gem9.5 Hz, 1H, 6⁰-Hb), 3.51 8dd,

J₈,J₆,3 Hz, 1H, 7-H), 3.69 8dq, J_CH36 Hz, J₃4.5 Hz,

1H, 2⁰-H), 3.90 8dd, J₇,J₉,2.5 Hz, 1H, 8-H), 4.32 8d,

J11 Hz, 1H, Bn), 4.38 8t, J_CH25±6 Hz, 1H, 4⁰-H), 4.40

8d, J11 Hz, 1H, Bn), 4.42 8d, J11.55 Hz, 1H, Bn), 4.49

8d, J12 Hz, 1H, Bn), 7.15±7.30 8m, 10H, Ph); ¹³C NMR

8258C): d22.84/22.82 8Si±CH₃), 13.39/14.69/15.04

81⁰,6-CH₃,7⁰), 17.81 8t-Bu), 25.91 8t-Bu), 32.73 8CH₂Br),

38.62/41.94 8C-2,10), 31.87/35.15/35.81/39.27 8C-3,4,6,9),

62.71 8OCH₂CH₃), 72.55/73.5 8Bn), 76.64/76.83/79.86/

80.91 8C-2⁰,5,7,8), 100.73 8C-4⁰), 107.25 8C-1), 127.62±

128.33 8Ph), 138.46/138.57 8Ph).

31a 8diastereoisomer with higher R_f-value). IR: 3456 8OH),

3028 8vC±H), 2973/2899 8C±H), 1708 8CO); H NMR:

1

d0.93 8d, J7 Hz, 3H, 8-CH₃), 1.02 8d, J6.5 Hz, 3H,

H-1⁰), 1.12 8t, J7 Hz, 3H, 7⁰-H), 1.90 8m, w_1/

26.05 Hz, 1H, 5-H), 2.27 8dd, J_gem14.6 Hz, J₅9 Hz,

2

1H, 4a-H), 2.38 8m, 1H, 6-H), 2.39 8dd, J_gem16.9 Hz,

J₁5.8 Hz, 1H, 2exo-H), 2.4 8m, 1H, OH), 2.5 8dd,

J_gem16.6 Hz, J₁13 Hz, 1H, 2endo-H), 2.48±2.58 8m,

1H, 8-H), 2.52 8dd, J₅6 Hz, J_gem14.05 Hz, 1H, 4b-H),

2.65 8dddd, J_2en12.55 Hz, J_2ex,J₆,J₁₀,6 Hz, 1H, 1-H),

0

3.20 8dd, J₄5.5 Hz, J_gem10.55 Hz, 1H, CH₂Br), 3.27 8dd,

0

30b 8diastereoisomer with the lower R_f-value). IR: 3029

J₄4 Hz, J_gem10.5 Hz, 1H, CH₂Br), 3.42 8m, w_1/2

1

8vC±H), 2932/2857 8C±H); H NMR: d0 8two s, 6H,

7.3 Hz, 1H, 7-H), 3.49 8q, J_CH37 Hz, 2H, 6⁰-H), 3.53 8br,

1H, 2⁰-H), 3.68 8dd, J₁₀10 Hz, J₈5 Hz, 1H, 9-H), 3.87

8dd, J₉10 Hz, J₁5.5 Hz, 1H, 10-H), 4.27 8d, J11.5 Hz,

1H, Bn), 4.31 8d, J12 Hz, 1H, Bn), 4.47 8d, J11.5 Hz,

1H, Bn), 4.48 8d, J12 Hz, 1H, Bn), 4.55 8dd, J_CH25.5 Hz,

J_CH24.5 Hz, 1H, 4⁰-H), 7.15±7.35 8m, 10, Ph); ¹³C

NMR 8250 MHz, C₆D₆, 478C): d11.47/15.48/17.27

2Si±CH₃), 0.78 8s, 9H, t-Bu), 0.92 8t, J7 Hz, 3H, 7⁰-H),

1.02 8d, J6.5 Hz, 3H, 1⁰-H), 1.03 8d, J6 Hz, 3H, 6-CH₃),

1.60 8d, J_gem11.55 Hz, 1H, 10exo8ax)-H), 1.67 8dd,

J_gem13.6 Hz, J₃7.5 Hz, 1H, 2exo-H), 1.75 8ddd, J_gem

11.5 Hz, J₉4 Hz, J_2en2.5 Hz, 1H, 10endo-H), 1.82 8m,

J₃,J₉,J₅,4.5±6 Hz, 1H, 4-H), 1.87 8ddd, J₃10.5 Hz,

È

E. Gossinger et al. / Tetrahedron 57 -2001) 3045±3061

3059

8C-1⁰,8-CH₃,C-7⁰), 32.80 8CH₂Br), 39.13/42.11 8C-2,4),

33.10/33.73/38.16/43.35 8C-1,5,6,8), 63.14 8C-6⁰), 71.73/

72.63 8Bn), 69.63/75.28/77.93/87.08 8C-2⁰,7,9,10), 100.1

8C-4⁰), 127.9±128.8 8Ph), 139.08/139.26 8Ph), 210.14

8CO); MS 8EI, 1608C, 70 eV): m/z 8%): 590/588 82.5/2.5)

[M¹], 544/542 8,1) [M¹2EtOH], 463 810) [M¹

2Br2EtOH], 437 812) [M¹2CH₃CH₂OCHCH₂Br], 421

820) [M¹2CH₃CH₂OCH8O)CH₂Br], 59 810), 329 825.7),

313 825), 269 815), 223 823), 205 825), 181 851), 151/153

860/56) [CH₃CH₂OCHCH₂Br¹], 123 831), 91 8100)

[C₇H₇¹].

m/z 8%)632/634 892/96) [M¹], 601/603 815/16)

[M¹2CH₃O], 587/589 865/70) [M¹2CH₃OCH₂], 481

820)

[M¹2CH₃CH₂OCHCH₂Br],

197/195

84/5)

[8CH₃CH₂O)₂CHCH₂Br], 151/153 88/8) [CH₃CH₂OCHCH₂Br],

91 833) [C₇H₇]; Anal. Calcd for C₃₃H₄₅BrO₇: C62.56%,

H7.16%, found: C62.40%, H6.96%.

1.1.27. *^)-*4R^p,5R^p,6R^p,7R^p,8S^p,9R^p,10S^p)-6,8-Dibenzyl-

oxy-5-*methoxymethyloxy)-13-ethoxy-7,11-dimethyl-12-

oxatricyclo [8.4.0.0^4,9] tetradecan-2-one *33). A solution

of 230 mg 80.36 mmol) 32 8diastereomeric mixture) in dry

toluene 850 ml) was treated with 89 mg 80.72 mmol)

potassium tert-butanolate under an argon atmosphere.

After stirring at 1008C for 15 h sat. aq. NH₄Cl solution

was added. The aq. layer was extracted three times with

diethyl ether, the combined organic layers were washed

with brine and dried over Na₂SO₄. After ®ltration and

evaporation the crude product was puri®ed by column chro-

matography with petroleum ether/ethyl acetate 84:1) to

afford 33 8161 mg, 81%). For analytical purposes the

diastereoisomers were separated.

31b 8diastereoisomer with lower R_f-value). IR: 3460 8OH),

3029 8vC±H), 2974/2883 8C±H), 1709 8CO); H NMR:

1

0

d0.94 8d, J7.5 Hz, 3H, 8-CH₃), 1.10 8d, J₂6.5 Hz,

3H, 1⁰-H), 1.14 8t, J7 Hz, 3H, 7⁰-H), 1.92 8m, w_1/2

27.2 Hz, 1H, 5-H), 2.3 8m, 1H, 6-H), 2.32 8dd,

J_gem14.1 Hz, J₅8.5 Hz, 1H, 4a-H), 2.4 8m, 1H, OH),

2.41 8dd, J_gem16.6 Hz, J₁6 Hz, 1H, 2exo-H), 2.48 8dd,

J_gem16.6 Hz, J₁12.5 Hz, 1H, 2endo-H), 2.55 8m, 1H,

8-H), 2.57 8dd, J₅6 Hz, J_gem14.1 Hz, 1H, 4b-H), 2.65

8dddd, J_2en12 Hz, J_2ex,J₆,J₁₀,6 Hz, 1H, 1-H), 3.22

8dd, J₄5.5 Hz, J_gem11.6 Hz, 1H, CH₂Br), 3.26 8dd,

33a 81R^p,11S^p,13R^p; main product). White crystals, mp:

108±1138C; IR: 3029 8vC±H), 2969/2932 8C±H), 1712

8CO); ¹H NMR 8400 MHz, C₆D₆, 508C): d1.04 8d,

J6.8 Hz, 3H, 7-CH₃), 1.08 8d, J6.7 Hz, 3H, 11-CH₃),

1.16 8t, J7.2 Hz, 3H, OCH₂CH₃), 1.77 8ddd, J₁₃9.8 Hz,

J₁,12.3 Hz, J_gem13.1 Hz, 1H, 14b-H), 1.87 8ddd, J₁₀

11.5 Hz, J₄,J₈,4 Hz, 1H, 9-H), 1.99 8ddd, J_14b,J₁₀,

11.9 Hz, J_14a,3.3 Hz, 1H, 1-H), 2.11 8m, J_gem14 Hz,

J,6.5 Hz, 1H, 3a-H), 2.16 8m, J_gem14 Hz, J,3 Hz, 1H,

3b-H), 2.26 8m, 1H, 4-H), 2.29 8ddq, J_CH37 Hz, J₈11 Hz,

J₆2.7 Hz, 1H, 7-H), 2.46 8ddd, J₁₃,J₁,2.9 Hz,

J_gem13.3 Hz, 1H, 14a-H), 2.93 8ddd, J₉,J₁,11.9 Hz,

J₁₁3.7 Hz, 1H, 10-H), 3.03 8s, 3H, O±CH₃), 3.44 8dq,

J_CH37.2 Hz, J_gem9.6 Hz, 1H, OCH₂CH₃), 3.48±3.54 8m,

3H, 5/6/8-H), 3.92 8dq, J_CH37 Hz, J_gem9.4 Hz, 1H,

OCH₂CH₃), 4.26 8d, J11.9 Hz, 2H, Bn), 4.34 8d,

J12.5 Hz, 1H, Bn), 4.35 8s, 2H, OCH₂O), 4.38 8d,

J11.7 Hz, 1H, Bn), 4.66 8dd, J_14a2.7 Hz, J_14b9.8 Hz,

1H, 13-H), 5.01 8br, w_1/221.2 Hz, 1H, 11-H), 7.0±7.3

8m, 10H, Ph), ¹³C NMR 8400 MHz, C₆D₆, 508C):

d12.45/13.73/15.68 87-CH₃,11-CH₃, OCH₂CH₃), 33.06

8C-3,14), 33.16/38.62/42.77/43.42 8C-1,4,7,9,10), 55.82

8OCH₃), 63.41 8OCH₂CH₃), 71.29/78.70/81.24/82.57

8C-5,6,8,11), 73.25/74.18 8Bn), 95.78 8C-13), 97.92

8OCH₂O), 127.58±128.56 8Ph), 138.95/139.07 8Ph),

207.19 8CO); MS 8FI,1208C): m/z 8%)552 8100) [M¹],

521 816) [M¹2CH₃O¹], 507 8100) [M¹2CH₃CH₂O¹], 91

824) [C₇H₇¹].

0

J₄5.5 Hz, J_gem11.6 Hz, 1H, CH₂Br), 3.4 8m, w_1/2

8 Hz, 1H, 7-H), 3.42±3.56 8m, 1H, 2⁰-H), 3.47 8dq,

J_CH37 Hz, J_gem9 Hz, 1H, 6⁰-Ha), 3.52 8dq, J_CH37 Hz,

J_gem9 Hz, 1H, 6⁰-Hb), 3.69 8dd, J₁₀10 Hz, J₈5 Hz, 1H,

9-H), 3.89 8dd, J₉10 Hz, J₁5.5 Hz, 1H, 10-H), 4.3 8d,

J11 Hz, 1H, Bn), 4.3 8d, J12.7 Hz, 1H, Bn), 4.48 8d,

J11.55 Hz, 1H, Bn), 4.49 8d, J12.55 Hz, 1H, Bn), 4.52

8t, J_CH25.5 Hz, 1H, 4⁰-H), 7.15±7.35 8m, 10H, Ph); ¹³C

NMR 8250 MHz, C₆D₆, 478C): d11.86/15.39/18.64

8C-1⁰,8-CH₃,C-7⁰), 32.55 8CH₂Br), 39.35/42.03 8C-2,4),

33.36/33.65/38.38/43.17 8C-1,5,6,8), 61.80 8OCH₂CH₃),

71.84/72.56 8Bn), 69.65/77.65/78.04/86.63 8C-2⁰,7,9,10),

102.36 8C-4⁰), 127±128 8Ph), 138.95/139.24 8Ph), 210.13

8CO); MS 8EI, 1608C, 70 eV): m/z 8%): 590/588 82.5/2)

[M¹], 463.2 82.2) [M¹2Br2EtOH], 437 812.4)

[M¹2CH₃CH₂OCHCH₂Br], 421 812.3) [M¹2CH₃CH₂O-

CH8O)CH₂Br], 393 83), 329 825.7), 313 815.1), 269 810.2),

223 815.2), 205 816.5), 181 836), 177 811.2), 161 812.9), 123

823.1), 151/153 845.8/45.1) [CH₃CH₂OCHCH₂Br¹], 91

8100) [C₇H₇¹].

Data of the diastereomeric mixture. HRMS: Calcd for

C₃₁H₄₁BrO₆588.2087, found M¹588.2097.

1.1.26. *^)-*1R^p,5R^p,6S^p,7S^p,8R^p,9R^p,10R^p)-7,9-Dibenzyl-

oxy-8-methyl-5-*4⁰bromomethyl-3⁰,5⁰-dioxa-hept-2⁰-yl)-

10-*methoxymethyloxy)bicyclo[4.4.0]decan-3-one *32).

A solution of 269 mg 80.456 mmol) 31 8diastereomeric

mixture) and 13.7 mmol N,N-diisopropylethyl amine

82.6 ml) in methylene chloride 813 ml) was treated with

9.11 mmol chloromethyl methyl ether 80.742 ml) unter an

argon atmosphere. After stirring at 358C for 14 h sat. aq.

NaHCO₃solution was added. The aq. layer was extracted

three times with methylene chloride, the combined organic

layers were washed with brine and dried over Na₂SO₄. After

®ltration and evaporation the crude product was puri®ed by

column chromatography with petroleum ether/ethyl acetate

84:1) to afford 32 8242 mg, 84%) as a colorless oil. The 1:1

diastereomeric mixture could not be separated. IR: 3028

8vC±H), 2971/2925 8C±H), 1713 8CO); MS 8FI, 1358C):

33b 81R^p,11S^p,13S^p; main product). Colorless oil; IR: 3028

8vC±H), 2967/2921/2850 8C±H), 1702 8CO); H NMR

1

8250 MHz, C₆D₆, 508C): d1.16 8d, J6.8 Hz, 3H,

7-CH₃), 1.21 8t, J7 Hz, 3H, OCH₂CH₃), 1.54 8d,

J6.6 Hz, 3H, 11-CH₃), 1.96 8ddd, J_gem13.7 Hz, J₁

11.9 Hz, J₁₃4 Hz, 1H, 14ax-H), 2.15 8ddd, J₁₀10.7 Hz,

J₄,J₈,4 Hz, 1H, 9-H), 2.33±2.24 8m, 2H, 3a/3b-H), 2.50±

2.35 8m, 2H, 7/4-H), 2.69 8dd, J_gem13.9 Hz, J₁2.5 Hz,

1H, 14eq-H), 2.78 8ddd, J_14ax,J₁₀,10.7 Hz, J_14eq3.2 Hz,

1H, 1-H), 3.06 8m, J₁,J₉,10.5 Hz, J₁₁3 Hz, 1H, 10-H),

3.21 8s, 3H, O±CH₃), 3.40 8dq, J_CH36.8 Hz, J_gem9.6 Hz,

1H, OCH₂CH₃), 3.7±3.57 8m, 3H, 5/6/8-H), 3.94 8dq,

È

E. Gossinger et al. / Tetrahedron 57 -2001) 3045±3061

3060

6. 8a) Magerlein, B. J.; Mizsak, S. A. J. Antibiot. 1982, 35, 111±

112. 8b) Magerlein, B. J.; Reid, R. J. J. Antibiot. 1982, 35,

254±255.

J_CH37 Hz, J_gem9.6 Hz, 1H, OCH₂CH₃), 4.37 8d,

J11.6 Hz, 1H, Bn), 4.39 8d, J11.9 Hz, 1H, Bn), 4.51

8d, J11.9 Hz, 2H, Bn), 4.52 8s, 2H, OCH₂O), 5.0 8br,

1H, 11-H), 5.06 8d, J_14ax4 Hz, 1H, 13-H), 7.0±7.2 8m,

10H, Ph); ¹³C NMR 8250 MHz, C₆D₆, 508C): d13.81/

30.27/32.48

8C-3,14), 33.29/38.32/ 38.72/39.24/43.82 8C-1,4,7,9,10),

55.89 8OCH₃), 62.89 8OCH₂CH₃), 71.22/78.76/81.39/

82.84 8C-5,6,8,11), 73.28/74.3 8Bn), 98.03 8C-13), 98.14

8OCH₂O), 139.12/139.24 8Ph); Anal. Calcd for C₃₃H₄₄O₇:

C71.71%, H8.02%, found: C71.42%, H7.80%.

7. 8a) Jones, R. C. F.; Tunnicliffe, J. H. Tetrahedron Lett. 1985,

26, 5845±5848. 8b) Coe, J. W.; Roush, W. R. Tetrahedron

Lett. 1987, 28, 931±934. 8c) Coe, J. W.; Roush, W. R.

J. Org. Chem. 1989, 54, 915±930. 8d) Roush, W. R.; Koyama,

K.; Curtin, M. L.; Moriarty, K. J. J. Am. Chem. Soc. 1996, 118,

7502±7512. 8e) Kallmerten, J. Tetrahedron Lett. 1984, 25,

2843±2846. 8f) Plata, D. J.; Kallmerten, J. Heterocycles

1987, 25, 145±149. 8g) Plata, D. J.; Kallmerten, J. J. Am.

Chem. Soc. 1988, 110, 4041±4042. 8h) Rossano, L. T.;

Plata, D. J.; Kallmerten, J. J. Org. Chem. 1988, 53, 5189±

15.36/16.10

87-CH₃,11-CH₃,OCH₂CH₃),

33c 81S^p,11S^p,13R^p; byproduct). Colorless oil; IR: 2921 8C±

1

È

5191. 8i) Gossinger, E.; Graupe, M.; Zimmermann, K.

Monatsh. Chem. 1993, 124, 965±979. 8j) Zimmermann, K.

H), 1702 8CO); H NMR 8250 MHz, C₆D₆, 508C): d1.02

8d, J7.3 Hz, 3H, 7-CH₃), 1.11 8d, J₁₁6.9 Hz, 3H, 11-

CH₃), 1.22 8t, J7 Hz, 3H, OCH₂CH₃), 1.82 8ddd,

J₁₃3.7 Hz, J₁,5.5 Hz, J_gem13.7 Hz, 1H, 14b-H), 2.18

8ddd, J₉,J₁₁,4 Hz, J₁6.8 Hz, 1H, 10-H), 2.28 8ddd,

J_gem14 Hz, J₁10 Hz, J₁₃5 Hz, 1H, 14a-H), 2.37 8m,

1H, 9-H), 2.53 8ddq, J_CH37.5 Hz, J₈2.9 Hz, J₆4.8 Hz,

1H, 7-H), 3.1±2.95 8m, 3H, 4/3a/3b-H), 3.20 8m, 1H, 1-H),

3.28 8m, 1H, 8-H), 3.31 8s, 3H, O±CH₃), 3.41 8dq,

J_CH37.08 Hz, J_gem9.8 Hz, 1H, OCH₂CH₃), 3.73 8dq,

J_CH37 Hz, J_gem9.6 Hz, 1H, OCH₂CH₃), 4.02 8dd,

J₅10.3 Hz, J₇5 Hz, 1H, 6-H), 4.1 8dd, J₄3.3 Hz,

J₆10.3 Hz, 1H, 5-H), 4.13 8m, 1H, 11-H), 4.11 8d,

J12 Hz, 1H, Bn), 4.34 8d, J12 Hz, 1H, Bn), 4.56 8d,

J12 Hz, 1H, Bn), 4.68 8d, J11 Hz, 1H, Bn), 4.69 8d,

J6.4 Hz, 1H, OCH₂O), 4.93 8d, J6.4 Hz, 1H, OCH₂O),

4.99 8dd, J_14a,J_14b,4 Hz, 1H, 13-H), 7.0±7.3 8m, 10, Ph);

¹³C NMR 8250 MHz, C₆D₆, 508C): d11.59/15.48/18.01

87-CH₃,11-CH₃,OCH₂CH₃), 30.19/38.57 8C-3,14), 31.15/

35.04/38.01/ 39.12/ 44.7 8C-1,4,7,9,10), 55.46 8OCH₃),

62.94 8OCH₂CH₃), 64.59/71.90/75.75/86.36 8C-5,6,8,11),

72.03/72.87 8Bn), 96.97 8C-13), 97.20 8OCH₂O); Anal.

Calcd for C₃₃H₄₄O₇: C71.71%, H8.02%, found:

C71.96%, H8.23%.

È

Monatsh. Chem. 1993, 124, 1157±1167. 8k) Gossinger, E.;

Graupe, M.; Zimmermann, K. Tetrahedron 1997, 53, 3083±

È

3100. 8l) Auer, E.; Gossinger, E.; Graupe, M. Tetrahedron

Lett. 1997, 38, 6577±6580.

8. 8a) Zeller, K.-P.; Straub, H.; Houben-Weyl Methoden der

organischen Chemie, Vol. 13/2b; Thieme: Stuttgart, 1977

8pp. 153±160). 8b) Giese, B.; Heuck, K. Chem. Ber. 1981,

114, 1572±1575. 8c) Larock, R. C. Angew. Chem. 1978, 90,

28±38 8Angew. Chem. Int. Ed. 1978, 17, 27±37). 8d) Larock,

R. C. Tetrahedron 1982, 38, 1713±1754.

9. Zeller, K.-P.; Straub, H.; Houben-Weyl Methoden der

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8pp. 332±338).

10. Jensen, F. R. Electrophilic Substitution of Organomercurials,

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Carbon±Carbon Bonds, Pergamon: New York, 1986.

8b) Curran, D. P.; Porter, N. A.; Giese, B. Stereochemistry

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Angew.Chem. 1985, 97, 555±567 8Angew. Chem. Int. Ed.

1985, 24, 553±565). 8d) Koert, U. Angew.Chem. 1996, 108,

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1985, 50, 4317±4325.

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Acknowledgements

This work was supported by the Austrian Science Founda-

tion 8Project Nr. 12 154 CHE); N. S. thanks for a scholarship

of the Austrian Academy of Science.

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Article Doi

Approach towards an EPC synthesis of nodusmicin. Part 5: Stereoselective introduction of a side chain at the cis-decalin part of nodusmicin

DOI: 10.1016/S0040-4020(01)00155-7

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