The motivation of this thesis arose from preliminary investigations of the total synthesis of (−)-combretastatin D-1 (9) by the Schobert´s group (see section 3.1). The cyclisation of 111 remains the key step for synthesis of 9. Diarylether 111 should be cyclized to macrolactone 112 by an intramolecular addition-Wittig-cascade with ketenylidentriphenylphosphorane (101) (scheme 62). Unfortunately, numerous attempts only furnished the unwanted dimer 113 and no trace of the desired compound 112 was observed. This result has been proved by NMR-spectroscopy and high resolution mass spectrometry.
Scheme 62: Synthesis of the unsaturated dimer 113.
So another cyclization approach relying on triol 118 was considered. This compound was prepared by Ullmann-coupling of the building blocks 110 and 106 followed by a subsequent asymmetric Sharpless-dihydroxylation with AD-mix-β over two steps in 32% yield. During the reaction of 118 with 101 an acylshift of the intermediate formed ylide 121 took place accompanied by an intramolecular formation of a carbonate functionality by elimination of methylene-triphenylphosphorane. The released ylide reacted with the aldehyde moiety to finally led to the isomeric styrenes 119 and 120 in a ratio of 4:1 (scheme 63).
Scheme 63: Attempt to cyclize the unprotected triol 118.
At this point of the thesis the synthesis of the simplest congener of the combretastatins D, combretastatin D-4 (79), was focused. As neither the intramolecular Wittig-reaction nor a RCM approach was successful, a completely new synthetic strategy was considered. This new strategy relies on obtaining 132 by ring contraction of a larger cycle. Therefore the Ramberg-Bäcklund reaction (RBR) was performed by sulfone 136, which was derived from diarylether 127 (scheme 64).
Initially the diarylether 127 was reacted with acetylmercaptoacetic acid (138) in a Steglich-esterification to furnish thioacetate 144. Selective reduction of the aldehyde moiety of 144 with NaBH4 released 145, which was treated with N2H4 to obtain the thiol 137. Intramolecular acid catalyzed nucleophilic substitution of the benzyl alcohol with the sulfide moiety in 137 provided the desired macrocyclic sulfide 147. Oxidation of sulfide 147 with mCPBA delivered the sulfone 136 over 5 steps in 39% yield starting from 127.
The RBR of 136 was tried under various reaction conditions. Neither the classic two-step process nor the in situ variation of this key transformation provided the ring-contracted compound 132 after numerous efforts. So another approach for the ring contraction of the sulfone 136 was necessary. The preparation of 11-O-methyl corniculatolide A (80) was
successfully realized by sulfone pyrolysis which was performed by Alan Aitken at the University of St. Andrews. The procedure for the final demethylation step was optimized to reveal combretasatin D-4 (79) in 97% yield. Combretastatin D-4 (79) could be synthesized in a straightforward fashion from 127 over seven steps in 20% overall yield.
Scheme 64: Total synthesis of 11-O-Methylcorniculatolid A (80) and Combretastatin D-4 (79) via sulfone pyrolysis.
In the course of this thesis it has appeared that the sulfone pyrolysis approach has a great capability in the straightforward synthesis of other natural products of the combretastatin D family. In addition to the total synthesis of 11-O-methyl corniculatolide A (80) and combretastatin D-4 (79), an enantioselective formal synthesis for (−)-combretastatin D-1 (9) as well as the total synthesis for combretastatin D-2 (10) was accomplished using this approach.
The synthesis of (−)-combretastatin D-1 (9) starts with pivaloyl protection of the diarylether 126 to furnish 168 (scheme 66). Subsequent asymmetric Sharpless-dihydroxylation with AD-mix-β provided the syn-(R,R)-diol 169 with an ee >99% and 43% yield based on 126. The so obtained glycol 169 was protected as bissilyl ether and for certainty purposes the TBS- as well as the TIPS-protecting group were examined. Starting from the TIPS-protected diol 170 thioacetate 173 was obtained over four steps in 71% yield. In case of TBS protection the
benzaldehyde moiety was also protected as N,O-TBS-acetal to provide compound 174. As the TBS-protected semiaminal keeps the masked benzaldehyde from reduction to the corresponding benzyl alcohol during the reductive cleavage of the pivaloyl moiety the reoxidation step to the required benzaldehyde can be omitted. The aldehyde was in situ regenerated during the work up of the esterification (175). So the thioacetate 176 could be prepared from diol (R,R)-169 over three steps in 20% yield (scheme 65).
Scheme 65: Synthesis of TIPS-protected thioacetate 173 and TBS-protected thioacetate 176.
The two thiols 179 and 180 were easily prepared form benzaldehydes 173 and 176 employing the previously established procedures. Attempts to cyclize the thiols with H2SO4 were unsuccessful due to the relatively acid-labile silyl protecting groups. So after various failed endeavors a mild and novel macrocyclization protocol employing SO3∙py was developed, which is described for the first time in this work.
Thioethers 181 and 182 were oxidized to the corresponding sulfones 183 and 184 by means of mCPBA and subsequently subjected to FVP by Dr. Aitken. After some problems with the desilylation of 185 and 186, the diol 187 could be revealed by treatment with HF(aq) in MeCN.
So the advanced diol 187 could be obtained over twelve steps in 1.3% yield based on 126 via the TIPS route, respectively over eleven steps in 0.4% yield applying the TBS approach (scheme 66). The formation of the epoxide 188 should work analog to the synthesis of
Couladouros et al. However this transformation as well as the final demethylation step couldn´t carried out within this work.
Scheme 66 Formal Synthesis of (−)-Combretastatin D-1 (9) up to Diol 187.
The final part of this thesis describes the total synthesis of combretastatin D-2 (10). The decisive structural motif of 10 is the cis double bound, which should be implemented at the beginning of the synthesis. The required Z-cinnamate 205 was prepared by Ando-HWE-reaction of p-bromobenzaldehyde (89) and phosphonate 204 in an isomeric ratio of E/Z = 3:17. Subsequent reduction of the ester 205 furnished the Z-cinnamyl alcohol 195 over two steps in 79% yield.
The following steps up to sulfone 194 were accomplished according to the already established synthetic strategy. Sulfone pyrolysis of 194 yielded methylcombretastatin D-2 (21), which could be converted to combretastatin D-2 (10) by a final demethylation (scheme 67). So this interesting natural product could be synthesized form 89 over ten steps in 0.6% overall yield.
Scheme 67: Total synthesis of Combretastatin D-2 (10).
Beside the desired O-methyl-combretastatin D-2 (21) the sulfone pyrolysis also led to the interesting byproduct 212 via further CO2 extrusion. The structure of this novel compound was doubtlessly confirmed by x-ray crystallographic analysis. No comparable cyclic diarylethers of this type consisting of five carbons in the alicyclic chain are known to date, while analogous diarylethers with seven carbons in the alicyclic fragment are well known and referred as diarylheptanoide (DAEH). So the new compound 212 is very interesting as it represents the first diarylpentanoide (DAEP) with an oxa[1.5]metaparacyclophane scaffold.