Total sythesis of phomoidride msc thesis D.pptx

Organometallics in materials science
7.1. Structural materials
7.2. Electronic and optoelectronic applications

1. BAHIR DAR UNIVERSITY COLLEGE OF SCIENCE DEPARTMENT OF CHEMISTRY Modern Methods of Organic Synthesis ( Chem 7463) Total Synthesis of Cp-molecules (±)- Phomoidride D By: Bekalu Lake Jan 2023 Bahirdar,Ethiopia Tuesday, February 7, 2023 1

2. Introduction Tuesday, February 7, 2023 2 Natural products with a bridgehead double bond, such as Taxol and CP molecules (Phomoidrides) have considerable attention from chemists because of their cholesterol-lowering , anticancer properties and structural complexity, with the high ring-strain energy and formidable synthetic challenge. In 1997, Phomoidrides A and B known by code numbers CP-225,917 and CP-263,114 , respectively were isolated by Pfizer researchers from an unidentified fungus (ATCC 74256) obtained from the twigs of a juniper tree in Dripping Springs, Texas. The first successful and elegant synthesis of Phomoidrides A and B was published by Nicolaou and co-workers in 1999. A numerous groups have devoted efforts toward developing new synthetic strategies to construct these natural products.

3. Cont… Tuesday, February 7, 2023 3 In 2000, Fukuyama and coworkers reported an elegant asymmetric total synthesis of (-)-Phomoidride B , In 2000 the asymmetric total synthesis of (+)-Phomoidride B was achieved by Shair and co-workers. Danishefsky and co-workers also reported total synthesis of (±)- Phomoidride B in 2000. In 2018, J . Wood and co-workers reported total synthesis of (±)-Phomoidride D after a long period of research effort .This elegant synthesis performed a tandem phenolic oxidation and intramolecular Diels–Alder c ycloaddition to assemble the carbocyclic core and a Wharton fragmentation reaction to construct the bicyclo [4.3.1] decene core. Hence, P homoidrides A and B differs from Phomoidrides C and D respectively in the relative stereochemistry at C7.

4. CP-Molecules (Phomoidride) Family Tuesday, February 7, 2023 4

5. Retrosynthetic Analysis of Phomoidride D Tuesday, February 7, 2023 5 Pinnick oxidation deprotection protection

6. Total Synthesis of (±)- Phomoidride D Tuesday, February 7, 2023 6 Starting from commercially available 1,5-dibromopentane ( 1 ) homologated to 2 by exposure to sodium acetylide followed by monomethylation of the intermediate diyne. 1 2

7. Total Synthesis of (±)- Phomoidride D Tuesday, February 7, 2023 7 Deprotonation of 2 at the terminal alkyne allowed for selective reduction to enyne 3 . 3 2

8. Cont… Tuesday, February 7, 2023 8 Successive hydroalumination by using diisobutylaluminium hydride followed by iodination of 3 delivered vinyl iodide ( 4 ) . 3 4 DIBAL-H

9. Cont… Tuesday, February 7, 2023 9 Then vinyl iodide conversion to the corresponding cuprate was advanced via conjugate addition to known α,β- unsaturated ketone ( 5 ). Under the illustrated TMSCl-accelerated conditions, this latter reaction furnishes an intermediate silyl enol ether which, upon in situ exposure to Nbromosuccinimide (NBS), delivers α- bromoketone ( 6 ). 4 5 6

10. Cont… Tuesday, February 7, 2023 10 Then commercially available 2,4-dihydroxybenzaldehyde ( 7 ) was sequentially nosylated, allylated, and exposed to Dakin oxidation conditions to furnish 8 . 7 8 nosyl mCPBA Dakin oxidation

11. Cont… Tuesday, February 7, 2023 11 O -alkylation of 8 with 6 furnished an intermediate ketone that was protected under modified Noyori conditions delivered 9 . 8 9 6

12. Cont… Tuesday, February 7, 2023 12 Then the derived acetal ( 9 ) was treated by Palladium-mediated catalyst allyl ether deprotection performed, which converted i n to phenolic compound ( 10 ). 9 10 Pd (PPh3)4,NaBH4 EtOH

13. Cont… Tuesday, February 7, 2023 13 A subsequent Pb(OAc) 4 -triggered tandem aryl oxidation cycloaddition sequence delivered α -hydroxy ketones ( 11 ) as an inseparable 1:3 mixture of diastereoisomers. 10 11

14. Cont… Tuesday, February 7, 2023 14 Interestingly, treatment of the mixture with TMSCl followed by the lithium enolate of methyl 3- (dimethylamino)propionate resulted in conversion of only the major β -diastereomer of 11 into the corresponding aldol product 12 . 11 12

15. Cont… Tuesday, February 7, 2023 15 Removal of the nosyl group from 12 followed by a Cope elimination of afforded 13 13 12 Cope elimination

16. Cont… Tuesday, February 7, 2023 16 Subsequent desilylation provides an intermediate containing an exo-methylene lactone 14 followed by condensing tertiary alcohol with di-bromide 15 led to Ueno–Stork bromoacetal 16 . 13 15 16 14 N,N- dimethylaniline

17. Cont… Tuesday, February 7, 2023 Then 16 was subjected to a cascade radical cyclization reaction initiated by SmI 2 to afford desired isotwistane 17 in an acceptable yield . 17 17 16 Hence, samarium ( II ) di-iodide (SmI 2 , Kagan’s reagent) is one of the most important reductant through transfer of Single-electron .

18. Cont… Tuesday, February 7, 2023 18 Subsequent tertiary alcohol 17 converted to corresponding acetate by Acetic anhydride, protection with 1,3-propanedithiol and Introduction of the requisite nucleofuge was accomplished via mesylation of the derived alcohol to provide fragmentation substrate 18 . 17 18

19. Cont… Tuesday, February 7, 2023 19 Treatment of 18 with KOH initiated the Wharton fragmentation reaction , furnishing ketone 19 which contained the bicyclic core with a bridgehead olefin. 18 19 Unwanted side-reaction that could be reversed by treating the reaction mixture with nosyl chloride and triethylamine.

20. Cont… Tuesday, February 7, 2023 20 Treatment of 19 with Mander’s reagent (methyl cyanoformate ) employed with under thermodynamic deprotonation conditions gave predominately the desired regioisomer 20 as a mixture of keto-enol tautomer's. Followed by triflation with Comins ’ reagent gave 21 . 21 19 20 Lithium bis ( trimethylsilyl )amide

21. Cont… Tuesday, February 7, 2023 21 Finally, the total synthesis of (±)- P homoidride D ( 23 ) was accomplished with a final three-step operation, involving palladium-catalyzed carbonylation, deprotection, and Pinnick oxidation. 21 22 ( 23 ) 1) MeI, CaCO3 80% MeCN aq . 2) NaClO2, NaH2PO4•H2O 2-Me-2-butene t-BuOH/THF/H2O (3:1:1)

22. Cont… Tuesday, February 7, 2023 22

23. The End ! Tuesday, February 7, 2023 23 THANK YOU!!!