The document discusses various organic reaction mechanisms and total syntheses of specific molecules, highlighting methods such as enantioselective synthesis and catalytic reactions. It details the synthesis of compounds like (−)-pavidolide b and eupalinilide e, using strategies that involve chiral templates and specific reagents. Additionally, it notes challenges in synthesis procedures and adaptations made to improve reaction yields and efficiency.

1. Learning organic reaction mechanisms
and new reactions from few total
syntheses of molecules.
Roshen Reji Idiculla
ID MS 14/11
IIRBS

2. Enantioselective Total Synthesis of (−)-Pavidolide B; J. Am. Chem. Soc. 2017,
139, 13989−13992 ; DOI: 10.1021/jacs.7b07388
1. Preparation of chiral alcohol from (+)-carvone
2. enantioselective synthesis of formyl cyclopropane

4. 3. Mitsunobu reaction of chiral alcohol from (+)-carvone and acid of formyl cyclopropane

9. Enantiospecific Total Synthesis of the Highly Strained
(−)-Presilphiperfolan-8-ol via a Pd-Catalyzed Tandem
Cyclization; DOI: 10.1021/jacs.7b01454 ;

14. Protecting Group-Free Total Synthesis of (−)-Lannotinidine B ;
dx.doi.org/10.1021/ja305261h | J. Am. Chem. Soc. 2012, 134, 12323−12325
coupling of the α-position of activated alkenes with carbon
electrophiles under the catalytic influence of a Lewis base (N-nBu3
or P-nBu3). BrØnsted acid assisted proton transfer step accelerate
the reaction, BrØnsted acid remain hydrogen bonded to the resulting
enolate in the enantioselectivity determining adol addition step.

17. https://newreactions.wordpress.com/2011/07/31/its-a-tpap/

19. Oxygen-containing proton donors sovent t-BuOH, coordinate to oxophilic SmI2 (but THF coordinates to SmI2, hence in
presence of THF, proton donor donot coordinate to SmI2) .

21. Total Synthesis of (𝛽)-Cyperolone; 10.1021/ol300058t ; Org. Lett.,
Vol. 14, No. 5, 2012

25. https://www.chem.wisc.edu/areas/reich/syntheses/syntheses.htm
1. Total synthesis of Sterpurenone New: Sahu, R.; Singh, V. J. Org. Chem. 2017, 82, 6268-6278. DOI
the HOMO of the diene interacts with LUMO of the dienophile ,so
the larger and smaller coefficients can lie side by side
respectively. secondary orbital interactions also prefer endo
isomer (kinetic product) than exo isomer (thermodynamic product)

26. Another analogue of this ketone molecule was created similarly.
Then the feasibility of following reactions were confirmed on this molecule.

27. So this pathway worked for
Next we consider case of
But it didn’t give ketal protection ,when keto-ester was treated with ethylene glycol in the presence of p- TsOH .
the keto-ester was treated with LiAlH4 to give the diol as result of reduction of both the ketone and ester groups

28. BUT THIS bromoketone does not follow cyclization pathway and leads to fragmentation.
SO hydroxy-tosylate was converted into the bromo alcohol and subjected to radical cyclization.

30. Eupatorium lindleyanum, commonly called is a herbaceous perennial plant in Asteraceae native from
China, Japan, Korea and Siberia , which is used as antibacterial or antihistamine agent. . eupalinilide E,
isolated from Eupatorium lindleyanum, showed selective cytotoxic activity against A549 cells (lung cancer
harboring KRAS mutation). J. Am. Chem. Soc. 2016, 138, 6068−6073
reports an enantioselective synthesis of eupalinilide E
accessing >400 mg in a single batch starting from (R)-
carvone.
-
http://www.organic-chemistry.org/namedreactions/yamaguchi-esterification.shtm
https://www.synarchive.com/named-reactions/yamaguchi-esterification

31. This proposal shows the scheme
Synthesis of bicyclic ketone
1st
step involves bromination of R-carvone, which acts as a chiral template.
Then Favorskii rearrangement of carvone tribromide occurs.

32. The cyclic iminolactone is hydrolyzed with aqueous acid to generate lactone.

33. use of CeCl3 offers the possibility of coordinates with the other O in ring, which results in a shielding of
the frontside of molecule.
4-Methoxybenzyl ether (PMB)

37. the addition of vinylmagnesium bromide into lactol formed the incorrect diastereomer which relayed subsequent
stereochemistry generated in the synthesis. The formation of the diastereomer, can be rationalized by the chelation
controlled addition of vinyl Grignard into the open form alkoxide of lactol .
Two changes to the general approach were implemented: delaying the C−H bond oxidation, previously using lactone
, until later in the synthesis and installing the 1,1-disubstituted olefin prior to the vinyl addition
New procedure

38. Previously, the poor yields using Burgess reagent to eliminate the tertiary alcohol prompted the development of a
different method for elimination to form olefin

39. Trimethylsilylmethylenelactones are Inert to protodesilylation with trifluoroacetic acid or
hydroiodic acid.

40. This four-step sequence proved cumbersome and made scale-up difficult; as a consequence silicon removal prior to
oxidation was achieved by protodesilylation of 42 using trifluoroacetic acid, cleanly yielding triene

41. KETONE
EPOXIDE