T - .T )

UNIVERSIDAD DE VALENCIA

S 3 3

FACULTAD DE CIENCIAS QUÍMICAS DEPARTAMENTO DE QUÍMICA ORGÁNICA

/^ \U N IV E R S r r A T DE VALENCIA y§

REGI STRE GENERAL

E N T R A D A

2 7 JUN. N.*

J S J I í L í C J J lIMS

HORA ______________________ ' OFICINA AUXILIAR NÚM. 15

SÍNTESIS DE TERPENOS CON ESQUELETO DE ESPONGIANO, ESCOPADULANO Y ESTRANO

TESIS DOCTORAL Presentada por

Miguel Angel González Cardenete Valencia, Junio 2001

UMI Number: U603145

All rights reserved INFORMATION TO ALL USERS The quality of this reproduction is dependent upon the quality of the copy submitted. In the unlikely event that the author did not send a complete manuscript and there are missing pages, these will be noted. Also, if material had to be removed, a note will indicate the deletion.

Disscrrlation Püblish3 and brine, dried, filtered and concentrated. The residue thus obtained was purified by column chromatography, using hexane-ethyl acétate (from 9:1 to

8

:2 ) as eluent, to afford at least three isomers of reduction and acetylation in

approximmately 70-80% overall yield. Mixture of epimers 33 (7 mg, 50%): For major epimer: ’H NMR (300 MHz) 5 5.94 (1H, br s, H-16), 4.42-4.17 (3H, m), 3.59 (1H, dd,J HO'

MeO'

MeO'

1

3a R= Me 3b R= H

2

M eO

4a R= Me 4b R= H

Schem e

2

p R

p R

PR

0 MeO

PiPhM e2

Schem e 3

142

PH

Estranos

Cascade radical macrocyclisation-transannulation approach...

C 0 2Et

C 0 2Et

MeO

MeO'

5

C 0 2Et

CHO

MeO

7 R=TBDS 8 R= H

6 C 0 2Et

-CHO v,v¡

MeO

Cl

► MeO' 10

S c h e m e 4 Reagents and conditions: i, H 2C C C H 2O H , P d (O A c )2l N a H C 0 3, Bu4N C I, D M F , 3 0 °C , 8 0 -8 5 % ; ii, B rP h 3P (C H 2) 3O T B D S , K H M D S , T H F , -7 8 °C , 92 % ; iii, T B A F , T H F , 0°C , 99% ; iv, N C S , Ph3P, K2C 0 3 , C H 2C I2, 0 °C , 9 5 % ; v, D IB A L , T H F , -7 8 °C , 1 0 0 % ; vi, M n 0 2, C H 2C I2, 0°C , 9 7 % .

Thus, the treatment o f the halide 5 with allylic alcohol at 30°C in the presence o f palladium acétate, sodium hydrogen carbonate as base, and tetrabutylammnonium chloride as a phase transfer agent in DMF led to the aldehyde 6 in 80-85% yield . 11 The wittig reaction between the corresponding phosphonium salt 1 2 and the aldehyde 6 at -78°C in THF, using sodium hexam ehtyldisilylazide as base, produced compound 7 in 92% yield, as the solé isomer isolated. On irradiation at the frequence due to the methylene groups, which are coupling with the olefinic protons, resulted in the collapse o f the multiplet o f the olefininc protons to a doublet o f J = 10.8 Hz, characteristic o f a cis double bond. The tbutyldimethylsilylether in 7 was hydrolysed under usual conditions with TBAF in THF at 0°C to give the corresponding alcohol 8 in 99% yield. Treatment of this alcohol with Nchlorosuccinamide, triphenylphosphine and potassium carbonate in CH 2 C12 at 0°C, led to the chloride 9 in 95% yield. Reduction o f compound 9 with a solution

o f D1BAL-H (1M; toluene) in THF at -78°C gave the corresponding cinnamyl alcohol in quantitative yield. Subsequent oxidation with activated manganese dioxide 1 3 ’ 1 4 in CH 2 C12 at 0°C afforded the intermediate aldehyde 10 in 97% yield. With the compound 10 in hand, the construction o f the top chain was undertaken using the Suffert’s m ethodology 1 5 (Scheme 5). Thus, the aldehyde 10 was treated at -78°C in dry THF with the acetylide generated from a mixture o f (Z/E)-l-bromopropene and n-BuLi to afford the carbinol 11 in 85% yield. Subsequent oxidation was achieved in only 56% yield using Dess-Martin periodinane/pyridine in DCM at 0°C . 1 6 At this stage, severa! repetitions were tried to improve this yield but, it seem s that during the working up the sensitive a,P-acetylenic ketone was affected decreasing the yield o f the conversión. This oxidation resulted later to be improved by using manganese oxide in DCM when using the carbinol 15.

S c h e m e 5 Reagents and conditions: i, (E /Z )-1 -B ro m o p ro p e n e , n-B uLi, T H F , -7 8 °C , 85% ; ii, D e s s -M a rtin p e rio d in a n e , py, C H 2C I2 , 0°C , 5 6 % ; iii, N a l, 2 -B u ta n o n e , reflux, 9 2 % .

143

Estranos

Cascade radical macrocyclisaíion-transannulation approach...

The ketone 12 was then subjected to chlorine-iodine exchange 1 7 to give in 92% yield the precursor 4a containing a 1 0 % o f an impurity, which I was not able to remove by chromatography and the precursor was used for the radical reaction without further purifi catión. Synthesis o f the radical precursor 4b. Initial studies were carried out for the preparation o f cinnamoyl a,P-acetylenic ketones. Therefore, addition o f ethynylmagnesium brom ide 1 8 to com m ercially available cinnamaldehyde at 0°C in THF foliow ed by oxidation o f the resulting alcohol 13 using manganese oxide 1 3 , 1 4 produced the ketone 14 as desired in 77% overall yield for the two steps. This m ethodology was then developed in the synthesis o f the precursor 4b (Scheme 6 ). The radical precursor 4b was readily synthesised using the above-mentioned procedure, from the aldehyde 10 in three steps as outlined in Schem e 7. Thus, addition o f ethynylmagnesium bromide in dry THF at 0°C yielded the ethynyl carbinol 15 in 90% yield. For synthetic purposes, the reduction o f 9, foliow ed by oxidation with M n 0 2 and addition o f the grignard reagent were carried out without the need o f purification o f any intermediate affording the carbinol 15 in 8 6 % overall yield for the three steps. Oxidation o f the carbinol 15 with manganese oxid e l j 1 4 led to the

ethynyl styryl ketone 16 in 72% yield (not optimised), which by Finkelstein halogen exchange 1 7 gave the required iodide 4b in essentially quantitative yield. Cascade reaction.

radical

macrocvclisation-transannulation

The iodide 4a was treated with tributyltin hydride (1.1 eq) and A IBN (0.8 eq) in dry degassed benzene (3mM ) under reflux, as reported in other radical cyclisations with a,P~ethynyl ketones 1 9 but changing the duration o f the addition time. The study o f the 'H NM R spectrum o f the crude residue revealed, a com plex mixture o f products since it could be seen several different m ethoxy and olefinic signáis. Purification o f the residue led to several impure fractions in very low yield and all containing tin, from which, no puré compound was isolated and clearly identifíed. N evertheless, when the iodide 4b was treated with tributyltin hydride (1.2 eq) and A IBN (0.8 eq) in dry degassed benzene (2m M ) under reflux over 12 h, and extending the time o f reaction after completing the addition to 6 h more, a 2 : 1 mixture o f 1 2 -ketosteroids 17 and 18 was obtained in approximmately 60% yield (Schem e 8 ). The structure o f the steroids 17-18 was deduced from a series o f ID N M R , COSY, HMQC and NOE difference experiments, and mass spectral data.

CHO

Ph

Ph'

cinnamaldehyde

Schem e

6

14

Reagents and conditions: i, HCCMgBr, THF, 0°C to rt, 95%; ii, Mn02, CH2 CI2, 0°C, 80%.

Cl

10 MeO

Cl

|ii

4b

MeO'

15

16

Schem e 7 Reagents and conditions: i, HCCMgBr, THF, 0°C to rt, 90%; ii, Mn02, CH2 CI2, 0°C, 72%; iii, Nal, 2-Butanone, reflux, quant.

144

Estranos

Cascade radical macrocyclisation-transannulation approach...

0

Jj

O ^

O U H

[ H ]

___ _ Bu3SnH/AIBN / I ------------------►PhH, reflux

I

h

MeO

|

/

f H T

Ti

h

h

i MeO

17

4b

18 ca 2:1

Schem e 8 It is interesting to note that the coupling constants predicted by molecular mechanincs calculations (MACROMODEL 5.5) were in good agreement with the observed experimental valúes. Compound 17 was obtained as a colourless oil with a molecular formula o f C | 8 H 2 0 O 2 as calculated from the El mass spectrum (m /i 268 [M]+). The 'Hand l3 C-NMR spectra displayed signáis assignable to a steroid with an a,/?-unsaturated ketone moiety (