Synthesis of functionalised 3,5-dispirodihydrofuran-4,12-diones

Initial biological screening of 119a showed an intriguing herbicidal activity. Namely 119a caused a form of chlorosis, the discolouration of foliage due to a reduction in the number of chloroplasts or from the lack of nutrients such as iron or manganese, with the effect more pronunced in grasses and weeds.^[120] Theoretically available from two simple steps, coupled with herbicidal activity, 119a shows great potential to the chemical industry as a future commercial lead compound acting either as a photosynthetic inhibitor, with the vital process of photosynthesis disrupted, or as a pigment inhibitor with disruption of chlorophyll production. It therefore became necessary to investigate if a library of functionalised derivatives, hopefully possessing a greater biological effect could be synthesised by our sequence. It was envisaged that a library could be quickly constructed and tested from functionalised cinnamyl alcohols, and to this end strongly electron withdrawing and electron donating substituents were selected.

2.1.4.1 Synthesis of functionalised cinnamyl alcohols

Functionalised cinnamyl alcohols are not available for purchase from any of the major chemical suppliers (except for 4-nitrocinnamyl alcohol^[121]) however the corresponding chloro/nitro cinnamic acids are readily available. The reduction of carboxylic acids to alcohols is a well known and operationally simple chemical reaction, however problems were immediately encountered with the reduction of cinnamic acids.

OH

O LiAlH₄,

THF, reflux R

OH R

OH R

LiAlH₄,

124 125 126

126 R yield,

[%]

a b c d

meta-Cl para-Cl ortho-Cl

meta-NO₂

78 81 67 29 Table 3: LiAlH₄ reduction of functionalised cinnamic acids

In each attempt an over-reduction was encountered leading to the saturated alcohols (Table 3).

To overcome this problem the reaction was repeated several times using lower temperatures and by changing the solvent to ether, however in each case the saturated alcohol was always obtained Synthesis of 3,5-dispirodihydrofuran-4,12-diones

albeit with lower yields, and in many cases as complicated mixtures of acid, unsaturated alcohol and saturated alcohol.

Kanth^[122] recently published a new method for the reduction of cinnamic acid to cinnamyl alcohol by use of NaBH₄ and iodine in THF. The initially formed organoborane 127 is thought to react with iodine with expulsion of hydrogen and sodium iodide to give 128 which undergoes hydrolysis to give 125.

O₂N COOH NaBH₄ ^{O2N COOBH3Na}

I₂ -NaI, -H₂ -H₂

O₂N CH₂OBO 124d

O₂N

OH HCl

125d

127d

128d

Despite repeated attempts with 124d and 124b using different stoichiometries of NaBH₄ and iodine, alteration of reaction temperature and reaction times, the corresponding cinnamyl alcohol was never obtained. In each case the starting acid could be completely recovered. Reduction of the carboxylic acids was also attempted with the excellent reducing agent DIBAL-H. While the unsaturated alcohols were recovered, the yields of the products never exceeded 30% with numerous side products making workup difficult. Attempts were made to convert the acid to the acyl chloride followed by reduction of the acyl chloride with sodium borohydride, again this method of reduction repeatedly failed.To overcome this problem the functionalised cinnamic acids were converted to the corresponding methyl esters. This was accomplished by refluxing the acids in a mixture of chloroform and methanol in a Dean-Stark apparatus using p-toluenesulphonic acid as an acid catalyst. Yields ranged from 90 - 98%. Again the literature contains many examples of ester to alcohol reduction with LiAlH₄ being the preferred reagent.

[123 - 128] Once again LiAlH₄ failed as a suitable choice for ester reduction with the saturated alcohol being the main product recovered even with careful control of the stoichiometry and reaction temperature. 3,4-(Methoxyenedioxy)-cinnamyl acid methyl ester for example was reduced to the corresponding saturated alcohol in 77% yield. Other reagents which were attempted include NaBH₄, BF₃-THF and sodium bis(2-methoxyethoxy)-aluminium hydride, in each case the starting material was completely recovered. The esters were finally converted to the corresponding α,β-unsaturated alcohols by the action of DIBAL-H in a solution of dichloromethane.

Excellent yields (Table 4) were obtained in all cases except when a nitro group was present in the molecule probably due to partial reduction of the nitro functionality. It should be noted that in the recent literature DIBAL-H is replacing lithium aluminium hydride as the reducing agent for many cinnamic acid esters, probably due to the problem of over-reduction.

O

O DIBAL-H,

DCM, rt

OH

129 130

R R

Synthesis of 3,5-dispirodihydrofuran-4,12-diones 3 2

2.1.4.2 Synthesis of α α α α α-hydroxycarboxylic acids

α-Hydroxycarboxylic acids can be easily prepared by a procedure developed by Carr^[129,130]. Starting from the corresponding ketone, attack by potassium cyanide in the presence of sodium pyrosulfite leads directly to the cyanohydrins which are then simply hydrolysed by glacial acetic acid and hydrochloric acid mixtures.

Substituents located in the C-5 position of tetronic acids play an important role in the chemistry of tetronic acids. For this reason it was decided to synthesise 3,5-Dispirodihydrofuran-4,12-diones with variable substituents in the C-5 position; this also enables us to prove that our synthesis is versatile not only at C-3 but also at C-5. To this end when X = O the product was obtained in reasonable yield, the product was unamenable to recrystallisation but the crude product was of sufficient purity for characterisation and for follow-up chemistry. Replacement with sulphur unfortunately lead only to unspecified decomposition during the hydrolysis step, even when milder hydrolysis conditions were employed. The initial cyanohydrin step was also sluggish and gave poor yields.

Table 4: Formation of functionalised cinnamyl alcohols 130 by DIBAL-H reduction of methyl cinnamyl esters 129

2.1.4.3 Attempted synthesis of ααααα-aminocyclohexane carboxylic acid

With the knowledge that tetronates containing a cyclohexane moiety at C-5 lead to 3,5-Dispirodihydrofuran-4,12-diones an attempt was made to synthesise the 1,11-dimethyl-2-phenyl-11-azadispiro[2.1.5.2]dodecane-4,12-dione 136 starting from 135. 135 was considered a suitable candidate due to the presence of the cyclohexane ring which is known to facilitate Claisen rearrangents more readily than mono-substituted homologues. The use of a primary amine would after reaction with 1 have given a secondary amine which are difficult to separate from phosphine oxide, the byproduct from intramolecular Wittig olefination.^[131] Starting from a secondary amine would give a tertiary amine which should circumvent this potential problem. A slightly modified procedure by Kurtz^[132] was used, however formation of 134 was not observed. Other commericially available amino acids have not to date been examined due to the potential problems already mentioned.

HO CN

CH₃NH₂

HN CN H

N OH

O

N O H⁺ O

132a 134 135 136

2.1.4.4 Esterification of α α α α-hydroxycarboxylic acids using isoureas α

Isoureas represent a powerful class of compound for esterification reactions in organic synthesis.

This operationally simple, relatively non-toxic route is under-utilised in modern chemistry. Simple addition of an alcohol 138 in the presence of a copper catalyst to DCC 137 leads to the isourea 139 in excellent yields with the added advantage that solvents are not required, making this method extremely attractive from an environmental point of view.^[137] Isoureas can be purified by filtration over a small plug of neutral alumina. It should be noted that normal column chromatography leads to severe decomposition. Distillation can be employed when R is small, however distillation of isoureas with bulky/long chain residues once again leads to decomposition.

Table 5 shows new examples of α,β-unsaturated isoureas.

C N N C₆H₁₁

C₆H₁₁ O

N H

N C₆H₁₁ C₆H₁₁

R OH Cu(I)Cl or Cu(II)Cl

137 138 139

4 - 24h, rt R

Synthesis of 3,5-dispirodihydrofuran-4,12-diones 3 4

139 Alcohol yield,

[%]

a b c d

CH₃CH=CHCH=CHCH₂OH