proposal of synthesis of dictyolactone

1.The target is quite an interesting molecular.
2. This proposal mainly aims at the application of C-H insertion in total synthesis.

Stereoelectronic Effect for the Selectivity in C−H Insertion of Alkylidene Carbenes

Stereoelectronic Effect for the Selectivity in C−H Insertion of Alkylidene Carbenes and Its Application to the Synthesis of Platensimycin

Sang Young Yun, Jun-Cheng Zheng and Daesung Lee* Department of Chemistry, University of Illinois at Chicago, 845 West Taylor Street, Chicago, Illinois 60607-7061J. Am. Chem. Soc., 2009, 131 (24), pp 8413–8415DOI: 10.1021/ja903526g


High selectivity in the insertion between two competing C-H bonds was observed and is believed to be the manifestation of a strong stereoelectronic effect of oxygen substituents.

an interesting paper from Eun Lee

A Carbonyl Ylide Cycloaddition Approach to Platensimycin
Lee, Kim, Jang, Choi and Chung. ACIEE, 2008,















why interesting?
"they knew that a terminal olefin would have the incorrect electronic configuration to lead to the desired product in the [3+2] before attempting the chemistry. However, they did the reaction anyway, and ended out with a cracking yield of the wrong isomer and only a trace of the desired. Playing with the HOMO coefficient by using a vinyl halide in place of the terminal olefin allowed the chemistry to proceed in a tasty 83% yield, with small amounts of the competing products."
from http://totallysynthetic.com/blog/?p=976

An approach to Sordaricin

This proposal is just another application of carbene chemistry in the total synthesis of natural products.

A synthetic proposal of calicheamicinone

This synthetic plan features a rhodium mediated cyclopropanation and a curtius rearrangement. the overall steps is about 16 which is almost half of the existing synthesis!
The biggest problem I can forsee is the stability of the enediyne before the cyclopropanation.

keyword: calicheamicin, calicheamicinone, retrosynthetic plan, proposal, synthesis

alkylidene carbene insertion

formation: vinyl halide (-70C, DME, KHMDS).
or ketone + (Li-TMSdiazomethane), aldehyde will give (alkyne?)
the above reactions are very sensitive to steric hinderance. In my experience, ketone with a alpha quartary center can't react.

C-H Insertion/cyclopropanation (Rh, Cu...)

1. C-H insertion -> cyclopentane/cyclohexane
the biggest side product is the dimer ( two diazo ketone lost one N2). usually unstable carbenoid gives less dimer, for example carbenoid with two electron withdrawing group or the rhodium dimer have electron-withdrawing ligand( for ex. Rh2(pttl)4).
stablized carbenoid reacts slowly so more dimmer, but better selectivity. for example,
In some situation, cyclohexane is formed instead of cyclopentane, rh2(piv)4 gives best 6/5 ratio.

2. double bond inerstion -> cyclopropane

The yield is usually higher than C-H inserstion. if the double bond is in a ring before the reaction, open the cyclopropane by hydrogenation will give CIS-ring fusion product.

3. O-H/N-H insertion.

Common catalysts:

hashimoto's cat.
rh2(pttl)4 , ptpa,....
very active toward intra. C-H insertion of ketones. higgest ee so far.

Davies' cat.
Rh2(DOSP)4, ...
intermolecular C-H or cyclopropanation.
intramolecular also ok.

Doyle's cat.
Rh2(MEOX)4 , mppim....
good for diazo esters. less reactive for diazoketones.

Taber's cat.
two ligands instead of four. ligand stability increased.
no good results so far.

DuBois's cat.
Rh2(ESP)2
very electron rich ligand. N-H insertion. derived from taber's cat.

diazo transfer reaction
ketone, beta-ketoester:
base: TEA, DBU
diazotransfer reagent: MsN3, AABSA, PNBSA, TIBSA
solvent: DCM, MeCN, Toluene
for a-aryl ketone, TIBSA/toluene/DBU works better.
for beta-ketoester, TEA/MeCN/MsN3 works OK. 1N NaOH can wash away excess MsN3.

ester:
Danheiser's method J. Org. Chem. 1990, 55, 1959.
introduced 2,2,2-trifluoroethyl trifluoroacetate and lithium bis(trimethylsilyl) amide as an efficient acylation method.

Taber's method
The TiCl4-mediated reaction of an ester with benzoyl chloride results in high yields of the R-benzoylated ester. Diazo transfer of the benzoylated ester utilizing p-acetoamidobenzenesulfonyl azide affords the R-diazo ester in good yield

acid->acid chloride then treated with diazomethane. TMSdiazomethane is a good substitution, but not in all cases. I did a reaction where TMSdiazomethane is not successful but diazomethane works.

ketone-> hydrazone->