CH 3 CH=CHCH=CHCH 2 OH meta-Cl-ArCH=CHCH 2 OH
2.2 Derivatives of 3-allyl-tetronic acids
2.2.1 Cyclopropanation of 5-spiro-(3-α αα αα -phenylallyl)-tetronic acids
One of the initial objectives of this work was the synthesis of the 5-spiro-3-(α-cyclopropylbenzyl) tetronic acids 120. These cyclopropyl tetronic acids should be easily prepared from the allyl precursors 122. Surprisingly we could find no examples in the literature where an allyl group located in the 3-position of a tetronic acid was cyclopropanated. Most methods in the literature make use of the addition of a cyclopropyl moiety while introducing an alkyl chain into the 3-position. An initial reaction of 122a with diiodomethane and a zinc/copper couple, the classic Simmons Smith reagent[163], failed to give any of the corresponding cyclopropane. Following this failure the more reactive reagent prepared from diiodomethane and diethyl zinc was attempted with no cyclopropane product detected. This was a surprising result as allylic alcohols are well known (Section 1.5.2.1) to accelerate the cyclopropanation reaction by bonding
of the oxygen to the cyclopropanating species which results in the carbanion 114 being directed towards the alkene. We expected this to be the case for 122a, however repeated experiments using various solvents, temperatures and even a large excess of the cyclopropanating agent failed each time, with 122a recovered each time in stoichiometric amounts. Clearly there is something unusual about our system which prevents cyclopropanation; normally a fast, efficient, high yielding reaction. We postulate that the hydroxy group of the tetronic acid forms a strong hydrogen bond interaction with the allyl group 187, this hydrogen bond interaction would have to be quite strong to prevent reaction with such a reactive species as the Simmons-Smith reagent. However we have already observed from the NMR data that compounds 141b-e exhibit
an interaction (Figure 3) between the hydroxy group and the alkoxy oxygen atom. In order to counter this observed effect our initial plan was to protect the hydroxy group thus breaking any hydrogen bond interaction, then cyclopropanate the double bond, followed by hydrolysis of the protecting group. The silyl protection of 3-allyl tetronic acids with TBDMSCl using 2,6-lutidine as a base is already known[115] and was thought to be the most suitable starting point. The reaction was followed for several hours with no formation of the protected tetronic acid. Heating solutions of the silylating reagent and 122a in solutions of DCM, acetonitrile and DMF to 60oC and even sonication of the respective solutions[164] failed to give any of the expected product, with 122a being recovered in quantitative yields. TBDMSCl has been largely replaced with the more reactive MTBSTFA[165], the silylating potential of which can be increased by the addition of 1% of TBDMSCl[166-168]. Once again despite numerous experiments from the analytical scale to the gram scale no reaction was observed; MSTFA was also attempted without success. Clearly the presence of the phenyl group is somehow having an influence on the protection step; probably due to steric constraints. Therefore it was obvious that another method would have to be found in order to introduce the cyclopropane moiety. We therefore decided to investigate different methods using the simple 3-allyl tetronic acid 188, which has never been converted to a cyclopropane which was surprising due to the interest in tetronic acids of type 120. 188 was formed from the Claisen rearrangement of 121x.The rationale was to use 188 as a simple substrate while we investigated the use of more reactive cyclopropanating agents. Further attempts began with two procedures by Charette[169] which are reported to lead to high conversions
O O
O H
187
with alkenes containing hydroxy groups. Both procedures utilise diethyl zinc and diiodomethane, with one procedure using a catalytic amount of oxygen which supposedly is required for carbenoid formation. The other procedure involved the use of a Lewis acid catalyst and we made use of diethyl aluminium chloride which was reported to give good results. Once again however both methods failed to give any of the desired product despite numerous attempts. Recently Evans[170]has reported the cyclopropanation of a vinyl chloride which proved difficult to react under Furukawa[171] and Denmark[172] reaction conditions. The use of Shi[173] conditions involving the addition of trifluoroacetic acid to the diethyl zinc solution followed by additon of diiodomethane resulted in a highly reactive cyclopropanating species which lead to high yields. The use of this reagent proved successful with 188, however it was found that reaction temperatures from 0oC gave no product and the reaction was very sluggish at room temperature. Good yields were obtained only when the solution was heated to 40oC. The structure of 189 was confirmed by X-ray single crystal structure analysis (Figure 7).
O O
OH
O O
OH 1) CF3COOH, Et2Zn
2) CH2I2 66%,
DCM, -10oC to 40oC
188 189
Figure 7: X-Ray structure for compound 189. Hydrogen atoms are omitted.
Derivatives of 3-allyl-tetronic acids 6 0
We subsequently found that this method could be easily extended to the more complicated 5-spiro-3-phenylallyl-tetronic acids leading to 190 in good to excellent yields. These examples demonstrate a fast general method for the construction of our original target molecules 120. No cyclopropanation reaction has ever been observed with the electron-poor sterically hindered endocyclic double bond.
X O O
OH
1) CF3COOH, Et2Zn 2) CH2I2
DCM, -10oC - 40oC
X O O
OH
122a X = CH2 122h X = O
190a X = CH2, 84% yield 190b X = O, 65% yield
2.2.2 Hydrogenation of 5-spiro-3-phenylallyl tetronic acid
Having successfully synthesised our original target molecules 190, we returned our interest to the 3-(phenylpropane) tetronic acids 183, which are expected to act as HIV protease inhibitors.
Earlier we attempted the synthesis of 183 through an hydrogenation of 119a (Section 2.1.5.9).
Clearly tetronic acid 183 should be easily amenable by a simple hydrogenation of 122a. We are happy to report that 183 was obtained through the use of a palladium on charcoal catalyst in excellent yield, thus opening a route to a potentially useful subclass of molecule.
O O
OH
EtOAc, H2, 10% Pd on charcoal
99%
122a
O O
OH
183
2.2.3 Iodocyclisation of 3-allyl tetronic acids
Iodine is an excellent electrophile for effecting intramolecular nucleophilic addition reactions; an especially important reaction is the iodolactonisation reaction.[174] The reaction of iodine with carboxylic acids bearing a closely located alkene results in the formation of iodolactones.[175]
Recently Antonioletti[176,177] has reported the iodine induced cyclisation of 2-alkenyl-1,3-dicarbonyl compounds which are very similar to compound 122a. Application of this reaction to our systems should lead to the formation of the furan 193 from 191. 193 could in principle be reacted over a number of steps to form 194 a known molecule which has been converted[178-180] to the
metabolite Canadensolide 195 isolated from Penicillium canadense.
The reaction of 122a following conditions described by Antonioletti[177] led not to the expected five ring furan but to the six ring pyrone 196 and to 197. Although the yield of 196 was disappointedly low (17%) it is the first example of utilising the tetronic acid OH to close a second annulated ring. Coupled with the fact that the new pyrone ring contains the highly useful iodine functionality this represents an important new reaction. This substucture is present in many natural products[181,182] including Massarilactione B 198 which has antibacterial properties.[183]
The fact that 197, the product from a formal addition of HI, exists in the keto form and not the enol form is difficult to explain but could arise due to the reaction proceeding in a basic solution which may encourage rearrangement to the keto form. Although 196 and 197 account for only 45% of the yield, no products arising from the formation of a five ring furan were detectable.
Five ring furans are almost always formed from iodocyclisation reactions with an anti configuration. We suspect that 196 also has an anti configuration between 1’-H and 2’-H, since a syn configuration would require bulky iodine and phenyl groups to be close together in space.
1H-NMR spectra of 196 gave only multiplet signals for 1’-H and 2’-H and we were therefore unable to prove the anti configuration.
Bu
Derivatives of 3-allyl-tetronic acids 6 2
Knight[184] has reported the use of large silyl protecting groups in the iodocyclisation of allylic alcohols as it prevents iodine oxidation of the alcohol. The iodonium ion is still attacked by the oxygen functionality with expulsion of the silyl group. This method could not be used in conjunction with 122a due to the problems encountered previously with silyl protection (Section 2.2.1). Iodine monobromide was also used in replacement of iodine with no change in results.
A second iodocyclisation reaction was attempted using a 3-[(2’E)-1-methylpent-2’-enyl] tetronic acid 212d. Once again no five ring furan product was detected, however the six ring pyrone was isolated in an overall yield of 66% 199. The higher yield could perhaps be attributed to the absence of base. Unfortunately this reaction did not proceed in a stereoselective manner and four different isomers were recovered, with tentative structures proposed from NOESY, HMQC and COSY spectra (Section 3). The four isomers can be explained from the mixture of enantiomers present on the C-1’ of the substrate, and from which face the hydroxy group attacks the iodonium ion. Unfortunately the choice of substrate was perhaps unwise as it was in itself a mixture of diastereoisomers, however the purpose of the experiment was to demonstrate that the reaction was general. Iodocyclisation reactions are well known and proceed stereoselectively with a great deal of literature devoted to the mechanism of addition. The use of enantiomerically pure 3-(2E)-1-methylalkyl-2-enyl] tetronic acids should lead to a stereoselective reaction.
2.2.4 Reaction of tetronic acid with 3-chlorobutyne
Chenevert[185] has prepared a number of furocoumarins by the reaction of 4-hydroxycoumarin with 3-chloro-3-methyl-butyne. We wished to extend this reaction to the tetronic acids which would be expected to react in a similar manner. The resulting product would be a bislactone 201 thus opening another possible route to Canadensolide 195. Commercially available tetronic acid was used, however reaction according to the conditions used by Chenevert for the structurally similar coumarins led only to complete decomposition.
O