The synthesis commenced with the preparation of indole di-tert-butyl malonate 9 using a standard sequence (Scheme ).() Reaction of the magnesium enolate of di-tert-butyl malonate (7) with 2-nitrophenylacetyl chloride, generated in situ from the corresponding acid, gave keto diester 8 in 78% yield. Reduction of the nitro group and concomitant cyclization delivered indole-2-malonate 9 in 69% yield. After examining several alternate ways to append a 3-piperidone fragment to intermediate 9, we discovered that this junction was readily accomplished by simply allowing indole 9 to react at room temperature in N,N-dimethylformamide (DMF) with the crude bromopiperidone 10,() generated by bromination of 1-tert-butoxycarbonyl-3-piperidone.() In this way, indole 11 was prepared on multigram scale in 85% yield.
Our plan for preparing actinophyllic acid (1) is outlined in retrosynthetic format in Scheme . Initial disconnection of the C5 hemiketal and oxidation state adjustments reveals pentacyclic ketone 2, which we envisaged arising from allylic alcohol 5 by aza-Cope−Mannich rearrangement of formaldiminium ion derivative 4.() The hexahydro-1,5-methanoazocino[4,3-b]indole ring system of the ketone precursor of allylic alcohol 5 we saw deriving from intramolecular oxidative coupling of a dienolate() generated from indole-2-malonate precursor 6.
Short-chain dicarboxylic acids are of great importance in thegeneral metabolism and up to n=3 they cannot be considered as lipids since their watersolubility is important. The simplest of these intermediates is oxalic acid (n=0), theothers are malonic (n=1), succinic (n=2) and glutaric (n=3) acids.
The other lipid members of the group found in natural products or from synthesis have a"n" value from 4 up to 21.
– the process of writing one functional group for another to help synthetic planning and to help disconnection. Note, there must be a good reaction in the reverse (forward!) direction.
While investigating the chemistry of the newly available porphyrin system the group discovered another new phlorin – and a remarkable reaction. It was found that when the porphyrin was heated under nitrogen in acetic acid for just one hour then two hydrogen atoms from the meso-propionic acid sidechain migrated to give the phlorin acrylate ester shown (bottom left). Although this wasn’t planned, and certainly hadn’t featured in the group’s retrosynthesis (if such a term was in use at the outset of this project), it did open up possibilities for the synthetic route. Further investigation found that if the reaction was conducted under air or oxygen then oxidation of the phlorin took place to give the porphyrin acrylate ester in excellent yield. This compound, when isolated and heated for much longer, with acid but under nitrogen, underwent an unusual cyclisation. Finally, the acetamide was hydrolysed under acidic conditions and the rather unstable resulting amine was subjected to Hofmann elimination by treatment with dimethyl sulfate and aqueous sodium hydroxide.
In conclusion, the first total synthesis of (±)-actinophyllic acid (1) was accomplished from di-tert-butyl malonate in an overall yield of 8% by a concise sequence that proceeds by way of only seven isolated intermediates. Of the eight stages of the synthesis, all but one construct C−C or C−N bonds. Key bond formations include an intramolecular oxidative coupling of ketone and malonate enolates and an aza-Cope−Mannich rearrangement to construct the unprecedented actinophyllic acid ring system.
The first three steps to the D-ring were shared with those of the A-ring, comprising selective hydrolysis of the β-ester, decarboxylation of the acid obtained, and formylation of the free position. This aldehyde was then condensed with malonic acid in the presence of aniline to give the unsaturated diacid as the Knoevenagel-type product. Hydrogenation with Raney Nickel under a hydrogen atmosphere in aqueous sodium hydroxide solution reduced the double bond, and effected monodecarboxylation to give the β-propionic acid. The α-methyl group was oxidised to the carboxylic acid, employing slightly different conditions to those used in the synthesis of the C-ring. Treatment of this compound with sodium hydroxide solution then simultaneously caused decarboxylation of this acid, as well as hydrolysis and decarboxylation of the ethyl ester. The propionic acid sidechain was then esterified using diazomethane and a semi-regioselective Vilsmeier-Haack formylation then gave a mixture of regioisomeric aldehydes. These could be separated by hydrolysis of their methyl esters to give two regioisomeric acids with very different solubilities in water. Re-esterification with yet more diazomethane gave the D-ring pyrrole in 8 steps and around 16% overall yield.
The synthesis of the C-ring pyrrole began with the oxidation of the α-methyl group to the corresponding acid that was then removed decarboxylatively by heating neat with copper bronze. The α-ester was then selectively hydrolysed without affecting the β-ester, and removed in the same fashion to give the C-ring pyrrole in just four steps.
The synthesis of the B-ring began with the same two steps as for the previous ring to selectively remove the β-ester, and the free position was then filled by an acetyl group, introduced by a Friedel-Crafts reaction with acetyl chloride in the presence of aluminium trichloride. This was then reduced all the way to the ethyl group using a Wolff-Kischner reduction, and the harsh conditions required for this transformation also caused hydrolysis and decarboxylation of the α-ester. Formylation of the α-position under Vilsmeier-Haack conditions gave an aldehyde that was again protected by condensation with malononitrile in essentially quantitative yield. Finally, chlorination of the α-methyl group using sulfuryl chloride in acetic acid gave the B-ring pyrrole in an excellent overall yield of 39% over 7 steps.
The route to the A-ring pyrrole began with selective hydrolysis and decarboxylation of the β-ester group. The now free position opened up was then formylated under Vilsmeier-Haack conditions (on up to 2.5 kg at a time!), this sequence providing a neat and surprisingly high yielding solution to adjusting the oxidation level of the group at this position without affecting the α-ester. This aldehyde was then protected by condensation with malononitrile to allow oxidation of the α-methyl group to the corresponding methyl ester. A global hydrolysis of the methyl and ethyl esters, as well as the dicyanovinyl protecting group, with concentrated sodium hydroxide solution, gave the formyldiacid. The unmasked aldehyde was then condensed with nitromethane in a Henry reaction to give the nitroalkene, and this was then reduced to the nitroalkane using sodium borohydride in methanol. Both carboxylic acids were then removed by decarboxylation in sodium acetate – potassium acetate melt and final catalytic reduction of the nitroalkane to the primary amine using hydrogen and a platinum catalyst gave the required A-ring pyrrole. It was anticipated that Hofmann elimination later in the sequence could be used to convert this aminoethyl chain to the vinyl group present in the target. Although the preparation of this compound took 10 steps, the longest of any of the four pyrroles, the yields were generally good, and skilful optimisation allowed the required reactions to be performed on large scale to provide sufficient material.
The first total synthesis of (±)-actinophyllic acid (1) is reported. Key steps of this synthesis include an intramolecular oxidative coupling of ketone and malonic ester enolates and an aza-Cope−Mannich rearrangement that assembled the core structure of the natural product’s unique ring system. The synthesis was accomplished from di-tert-butyl malonate in 8% overall yield by a concise sequence that proceeds by way of only seven isolated intermediates.