A.4.3. Carbonyl-Ene Reaction: Attempts towards synthesis of AB ring building block of anthracyclines

As discussed in chapter A.3, carbonyl-ene could be a powerful tool for the construction of

naphthalene derivatives. To begin with, the conversion of 186 to trihydronaphthacenol 187 was

examined. For the synthesis of AB ring building block, we thought to study few examples. Carbonyl ene

reaction was first examined with compound 186 which was prepared from isovanillin (183). Isovanillin

(183) was O-allylated by methylallyl bromide in acetone using potassium carbonate as the boibase.

Claisen rearrangement of allylated product 18425a in boiling DMF gave compound 185. This compound

did not give clear reaction under carbonyl ene reaction condition. So for better reaction, compound 185

was methylated with methyl iodide and potassium carbonate in acetone to obtain compound 186. But

when carbonyl ene reaction was performed with compound 186 with tintetrachloride pentahydrate

(100 mol %) in dry DCM, it gave ene reaction followed by rapid aromatization to give completely

aromatized product 188. Although it is somewhat obvious that the reaction proceded through 187, it

could not be isolated. Presence of 4 aromatic protons at 7.88, 7.67, 7.55 and 7.17-7.24 and 3 methyl

protons at 2.52 clearly indicated the formation of aromatized product.

CHO

OMe

OH

CHO

O

OMe

CHO

OMe

OH

CHO

OMe

OMeOMe

MeO

37'

184 185

186 188

Br

K2CO3acetone

86%

DMFreflux

39%

Me2SO4,

K2CO3

acetone

84%

DCM

SnCl4. 5H2O

85%

OH

MeO

OMe

187

183

Scheme 35. Preparation and carbonyl ene reaction of aldehyde 186

Next the reactivity of compound 195 towards ene was examined. It was prepared from 2,5-

dihydroxybenzoic acid (188). Methylation of acid 188 by DBU-MeI gave methyl derivative 190 which was

allylated by methylallyl bromide in acetone in the presence of potassium carbonate as base to obtain

compound 44’. Claisen rearrangement of 191 in boiling DMF gave two products 192a and 192b in 1:1

ratio. Presence of 2 –CH2 protons at 2.98 and 6 methyl protons at 1.50 indicated the formation of

192b. DEPT-135 spectrum was also matched. Formation of compound 192b was further confirmed by

acetylation to compound 192c. Now 192a was methylated to 193 by potassium carbonate and dimethyl

sulfate in acetone. Compound 193 was then reduced to alcohol 19425b by lithium aluminium hydride.

PCC oxidation of alcohol 194 gave the aldehyde 195 (Scheme 36). Carbonyl ene reaction of 195 again

gave the fully aromatized product 198.25c Presence of 3 aromatic protons at 8.09, 7.98 and 7.34 and 3

methyl protons at 2.52 indicated the formation of aromatized product 198.

OH

OH

CO2H

OH

OH

CO2Me

OH

CO2Me

O

OH

CO2Me

OH

+O

OH

OH

O

O

OH

OAc

O

OMe

OMe

CO2Me

OMe

OMe

OH

OMe

OMe

CHO

189 190 191

192a(38%)

192b(40%)

192c

193 194 195

DBU,MeI,

acetone

92%

Br

K2CO3

acetone

87%

DMF

reflux

Et3N

Acetyl chloride

dry DCM

83%

Me2SO4,

K2CO3,

acetone,

reflux

96%LiAlH4

dry ether

79%

PCC,dry DCM

77%

Scheme 36. Preparation of aldehyde 195

Attempted isolation of the 196 and 197 (Scheme 10) by varying reation time and amount of catalyst was

not possible.

OMe

OMe

198

SnCl4. 5H2O

DCM

83%

OMe

OMe

CHO

195

or

196 197

-H2O

Scheme 37. Carbonyl-ene reaction of 195

Now we planned to extend the study to examination of the reactivity of naphthalaldehyde 202

towards carbonyl ene reaction. This was prepared from naphthalylalcohol 199, which was

trimethylsilylated by TMEDA, n-BuLi and TMSCl in dry hexane to get product 200. Presence of 9 methyl

protons at 0.46 clearly indicated the formation of silylated product. Compound 20025d was then

converted to allyl naphthalyl alcohol 20125d in two steps. In the first step it was treated with methylallyl

chloride, CuI, lithium-tert-butoxide in DMF to obtain O-silyl allyl compound which was in next step

desilylated by tetrabutylammonium fluoride trihydrate in THF to give compound 201.

HO

SiMe3

OH OH CHO

199 200 201 202

TMEDA,n-BuLi,TMSCl

dry hexane84%

-30 0C - r. t.

1. LiOtBu,

CuI,

THF

2. TBAF.3 H2O

2 h76%

ClPCC,

dry DCM

65%

Scheme 38.

Preparation aldehyde 202

PCC oxidation of 201 gave aldehyde 202 which on treatment with tin tetrachloride pentahydrate gave

carbonyl ene reaction followed by rapid aromatization to give phenanthrene compound 203.25e

203

SnCl4. 5 H2O

dry DCM

83%

CHO

202

Scheme 39. Carbonyl ene reaction of aldehyde 202

Lastly, we looked into the possibility of utilizing carbonyl ene reaction on an anthraquinone

system. To this end we started from 194. CAN (Cerric ammonium nitrate) oxidation of 194 gave quinone

204. Hauser annulation reaction of 204 did not give good yield of annulation product 205. So we thought

to protect the terminal OH group. For this purpose we converted 204 to 206 by DHP protection in dry

DCM in presence of catalytic amount of PPTS. Annulation reaction of 206 gave product 207 in good

yield. Deprotection of 207 with PPTS-MeOH gave the alcohol 205 in good yield. PCC oxidation of it gave

aldehyde 208. This was treated with Lewis acid (SnCl4.5H2O) as before. Now we obtained only carbonyl

ene reaction product 209 which was not aromatized and it represented the core structure of

idarubicinone (56). Presence of protons at 5.30 (brs, 1H), 5.16 (s, 1H), 5.12 (s, 1H), 3.63 (ABd, 2H, J =),

3.52 (ABd, 2H, J =), 2.91 (brs, 1H), 2.71 (d, 2H, J = 4.4 Hz) indicated clearly the formation of exocyclic

double bond.

OMe

OMe

OH

O

O

OH

OH

OHO

O

OH

194 204 205

O

O

OTHP

206

206

OH

OHO

O

OTHP

OH

OHO

O

OH

207

OH

OHO

O

CHO

208

CAN,

acetonitrile-

H2O

66%

LiOtBu,

THF

O

O

SPh

– 60 0Cvry poor yield

DHP, cat. PPTS dry DCM

96%

LiOtBu,

THF

O

O

SPh

– 60 0C

68%

cat. PPTSmethanol

76%

PCC,dry DCM

69%

205

Scheme 40. Preparation and carbonyl ene reaction of aldehyde 208

OH

OHO

O OH

209

SnCl4.5H2O

dry DCM

89%

OH

OHO

O

CHO

208

Scheme 41. Carbonyl ene reaction of aldehyde 208

To establish the background for the total synthesis of idarubicin on the basis of appreciation of

an ene reaction, we accomplished four cases as tabulated as shown in Table 1. The results clearly point

to the possible and firm extension to the anthracyclines. Comparison of the results shows that in case of

tetracycline aromatization could not occur but bi and tricyclic system could not stop the aromatization.

Table 4. Summary of examples of carbonyl ene reaction

Sl No. Substrate Product Yield

1

CHO

OMe

OMe

186

OMe

MeO

188

85%

2

OMe

OMe

CHO

195

OMe

OMe

198

83%

3

CHO

202 203

83%

4

OH

OHO

O

CHO

208

OH

OHO

O OH

209

89%

After successful preparation of 209, core structure of idarubicinone (56), we tried to complete

the total synthesis of idarubicinone. So for this purpose, we should prepare quinone 148 was required.

For this purpose we tried to prepare ethylallyl chloride from n-butyraldehyde by dimethylamine

hydrochloride and formalin. But unfortunately we could not prepare it and for the time being we have

postponed our total synthesis.

O

O

CH2OH

148

A.4.4. Conclusions

In summary,

i) We have discovered the reaction conditions of the Hauser annulation reaction, which

have been elusive for many years and thus eased the synthesis of quinizarin.

ii) We have also applied the conditions to naturally occurring 1,4-

dihydroxyanthraquinones ventinone A (43) and ventinone B (174a or 174b) by

application of the Hauser annulation.

iii) We have founded a route to anthracyclinone based upon the combination of the

Hauser annulation and the carbonyl ene reaction.