A stereoselective synthesis of agelastatin A, a potent cytotoxin and inhibitor of osteopontin (OPN)–mediated neoplastic transformations, has been accomplished in 14 steps (12 operations) with an approximate overall yield of 8%. Notable features of this route include the direct manner in which the pyrroloketopiperazine A-ring of the target is generated and the efficient employment of a trichloroacetamide, introduced through Overman rearrangement, as a protecting group, pendant nucleophile and latent urea.
The Shibasaki synthesis ((-) chiral, 2002) was a second published method in strychnine total synthesis using an . 1 was reacted with 2 in an using to form chiral diester 3. It's group was protected as an (2-ethyl-2-methyl-1,3-dioxolane, ) and a carboxyl group was removed (, 140 °C) in monoester 4. A C2 fragment was added as 5 to form 6 using . The ketone was then reduced to the alcohol (, ) and then water was (, ) to form 7. After reduction () to the alcohol and its protection (TIPSOTf, ), the acetal group was removed (catalytic ) in ketone 8. 9 was then formed by . The conversion to alcohol 10 was accomplished via a using , to 11 (, ) was followed by a (, , ) incorporating unit 12. Alcohol 13 was formed after protection (SEMCl,i-Pr2NEt) and TIPS removal ().
In summary, the total synthesis of (±)-agelastatin A (1) has been accomplished from a readily available starting material in 14 steps (12 operations) with an overall yield of ~8%. Modification of this synthetic route so as to encompass the antibiotic nagelamide J (5) is curently underway and will be reported in due course.
Proceeding to now unmask the urea functionality latent within compound 13, a solution of this substrate in DMF was heated at 100 °C in the presence of N-methylbenzylamine and NaHCO3 to provide compound 14 (R = Bn) in good yield. Although it had not been our original intention to incorporate an N-benzyl protecting group at this stage, the corresponding N-methylurea 14 (R = H) proved to be too polar to be convieniently carried forward in the synthetic sequence.
AB - A chiral base route from a meso cyclohexene oxide to an allylic alcohol provides key intermediates for the synthesis of cyclic polyols. A Mitsunobu approach and an Overman rearrangement approach transform allylic alcohols into some aminodeoxyconduritols (95% ee). Elaboration of a chiral enone (89% ee) via (i) alpha -hydroxylation and (ii) stereoselective reduction completes a high yielding synthesis of the tetraacetate of conduritol F. (C) 2001 Elsevier Science Ltd. All rights reserved.
Indoline 9 was to N-acetyl compound 10 (, ) and then the veratryl group was then with in aquaeous to 11 (made possible by the two electron-donating methoxide groups). This is an example of bioinspired synthesis already proposed by Woodward in 1948 . Cleavage of the acetyl group and ester hydrolysis with in methanol resulted in formation of ester 12 with additional of the double bond to an endocyclic double bond (destroying one asymmetric center). Subsequent treatment with and removed the tosyl group and hydrolysed both remaining ester groups to form 13. Acetylation and () produced acetyl diester 14 which was then subjected to a with in methanol to 15.
The synthesis of ring II was accomplished with an using 1 and derivative acetoveratrone 2 (catalyst ) to give the 2-veratrylindole 3. The veratryl group not only blocks the 2-position for further but will also become part of the strychnine skeleton. A with and ) produced 4. with gave an intermediate which reacted with in a to 5 and then in a with to 6. with give the 7. The reaction of this imine with in to the ring-closed N-tosyl compound 8 was described by Woodward as a concerted nucleophilic attack and formally a . This compound should form as a but only one compound was found although which one was not investigated. Finally the newly formed double bond was reduced by to 9 with the C8 hydrogen atom approaching from the least hindered side (this proton is destroyed later on in the sequence and of no importance).
In the Rawal synthesis (1994, racemic) 1 and 2 were combined in a followed by quench to triene 3 which was then reacted in a (benzene 185° C) to hexene 4. The three ester groups were hydrolyzed using iodotrimethylsilane forming pentacyclic 5 after a methanol quench in a combination of 7 reaction steps (one of them a ). The C4 segment 6 was added in an and of 7 formed isostrychnine 8 after TBS deprotection.
In the Bosch synthesis of (1999, chiral) the olefin group in dione 1 was converted to an by and chiral amine 2 was formed in a double with (S)-1-. The phenylethyl was removed using ClCO2CHClCH3 and the group was introduced in a using TMSI, then PhSeCl then and then forming 3. The amino group was deprotected by refluxing in methanol and then using (Z)-BrCH2CICH=CH2OTBDMS, to tertiary amine 4. A reductive took place next followed by methoxycarbonylation (LiHMDS , NCCO2Me) to tricycle 5. Reaction with dust in 10% removed the , reduced the and brought about a reductive amino-carbonyl cyclization in a single step to tetracyclic 6 (epimeric mixture). In the final step to the 7 reaction with in MeOH afforded the correct epimer was followed by reduction of the methyl ester.
Strychnine total synthesis in describes the of the complex . The first reported method by the group of in 1954 is considered a classic in this research field.
The key reaction in the Vollhardt synthesis (2000, racemic) was an of derivative 1 with and CpCo(C2H4)2 (THF, 0 °C) to tricycle 2 after of the amine group (KOH, MeOH/H2O reflux). Subsequent reaction with brought about a [1,8]- to tetracycle 3, with (Z)-1-bromo-4-[(tert-butyldimethylsilyl)oxy]-2-iodobut-2-ene (see Rawal synthesis) and , and of the system (NaOiPr, iPrOH) formed enone 4. A as in the Rawal synthesis ( / ), accompanied by formed 5 and reduction and TBS group deprotection formed isostrychnine 6.