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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.