Namenamicin is a enediyne.
the construction of the sulfur-containing quartery center is the critical part of the synthesis. This proposal uses a thionium ion to directly form the quartery center which can lead to the desired structure in an efficient way.
1.The target is quite an interesting molecular.
2. This proposal mainly aims at the application of C-H insertion in total synthesis.
1. POCl3-DMF to make the indole aldehyde,
2.nitromethane to make unsaturated nitro indole.
3. LAH reduction to give you tryptamine.
to save one step, step 1 and 2 can be made into one step:
TFA, (CH3)2N-CH=CH-NO2, DCM to make the unsaturated nitro indole.
to increase the functional group compatibility of this sequence,
the LAH reduction step can be replaced by a 2 step sequence:
1. NaBH4/SiO2 reduction to take off the double bond.
2. Fe/AcOH reduction to convert the nitro group to amine.
1. BH3. 0C.
slow reaction, low yielding, but can tolerate many functional groups, like ester.
can over reduced to indoline.
2. LAH
of course, amide can be reduced.
3. triflation first, then Pd/Et3SiH remove triflate.
4. lawesson’s reagent to convert oxygen to sulfur, then reduce it by
Raney Ni.
5. some reducing reagent (red-al, super hydride…) under the help of acid (TFA, BF3-OEt2…)
N-Cbz is sensitive to H2/pd/c even in basic condition (TEA).
Known methods to prevent N-Cbz from falling off when doing hydrogenation reactions are not many.
1. Pd/c (en), H2, THF by Kosaku Hirota
pd/c (en) is pd/c deactivated by ethylenediamine. It is developed for chemoselective hydrogenation of reducible functionalities such as olefin, acetylene, nitro, azide, aromatic bromine or benzyl ester moieties, in the presence of O-Bn or N-Z protective
groups.
alkyl N-cbz is stable while double bonds are saturated.
aryl-N-cbz is unstable under this catalyst.
H. Sajiki, K. Hattori and K. Hirota, J. Org. Chem., 1998, 63, 7990.
2. Pd(OAc)2, DPPF,TEA, dmf,formic acid
Can do deoxygenation of phenol by OTf in the presences of N-Zbz.
3. squaric acid derivative/pd/c/H2
works ok, can saturate double bond without touch n-cbz.
4. pd/c/ph2s/H2
also can saturate double bond without touching n-cbz.
5. Pd(OAc)2, DPPF, TEA, dmf,formic acid, Et3SiH
works for deoxygenation of phenol triflate in the presense of N-Cbz.
Note:
1. pd/c(en) was tried. but n-cbz falled off quickly.
2. dppe/pd/formic acid method is OK.
3. ph2s/pd/c/h2 didn’t touch N-cbz in my hand. but can’t do deoxygenation of a phenol.
United States Patent: 4946840
Preparation of 1-methyl tryptamine
This step began with a solution of:
(1) 1.6 g (10 mmol) of tryptamine; and (2) 20 ml of dimethylformamide. This solution was added dropwise to a suspension of: (1) 440 mg (11 mmol) of sodium hydride oil in (2) 30 ml of dimethylformamide. A dark brown solution resulted.
The dark brown solution was then stirred for 30 minutes at room temperature, cooled to 0.degree. C., and mixed with methyl iodide. (The methyl iodide was purified before use by passing it through a column of basic alumina.) After stirring for an hour at room temperature, the reaction mixture was partitioned between ethyl acetate and water. The ethyl acetate layer was washed with saturated brine and then dried by sodium sulfate filtration. The filtrate was concentrated, the filtration residue loaded onto a 5.times.25 cm silicon dioxide column, and the column eluted with dichloromethane:methanol:triethylamine, 95:4:1. Pure fractions were concentrated to afford 970 mg (a 56% yield) of the first intermediate as a yellow oil.
note:
1. usual procedure requires protection of NH2 then alkylation on the indole Nitrogen which is unnecessary if you follow the above procedure.
the reaction works fine although the yield is not high and product separation is difficult.
he reaction was first reported by Kenkichi Sonogashira and Nobue Hagihara in 1975.
The coupling of terminal alkynes with aryl or vinyl halides is performed with a palladium catalyst, a copper(I) cocatalyst, and an amine base. Typically, the reaction requires anhydrous and anaerobic conditions, but newer procedures have been developed where these restrictions are not important.
solvent/base : tea or other amine, DMF, MeCN
Pd (0) is needed, pd(pph3)4, also pd (II) can be used which will be reduced to pd (0) by alkyne. pdcl2(pph3)2.
CuI.
some additive can increase the rate and yields: ex. Bu4NI,
temp: rt or heat.
note:
1. electron deficient aromatic halides gave better yields. electron rich aromatics don’t react well.
The title compound seems easy to make, but actually costs a lot of steps, especially in enantiomeric form.
In the following paper, the auther had a new preparaion method.
Syntheses of (-)-Oleocanthal
by AB Smith III
J. Org. Chem. 2007, 72, 6891-6900
We began by adopting a protocol developed by Borchardt14 et al. (Scheme 6). Exhaustive
oxidation of 16 employing pyridinium chlorochromate (PCC) (4 equiv) provided lactone 17 in 62% yield. This transformation involves both oxidation of the primary alcohol and cleavage of
a C-C bond. Treatment of the resultant lactone (17) with the lithium anion derived from dimethyl methylphosphate produced enone (-)-18, which upon hydrogenolysis furnished ketone (-)- 11. The overall yield of (-)-11 from D-lyxose was reproducibly 50% on a 10 gram scale. Although D-lyxose is more expensive (ca. 3 times) than D-ribose, the starting material utilized in the first-generation synthesis, this sequence eliminates three steps, reduces the use of several expensive reagents, and is scalable. Equally important, only a single chromatographic separation is required after hydrogenolysis. Alkylation as achieved in the firstgeneration synthesis then afforded (-)-12 in 55-60% yield.
Is the new way really good?
I don’t know. But at least there is a big drawback they didn’t say it here.
In the experimental, they described the pcc reaction which needs a lot of benzene (cause cancer) as solvent.
a very interesting paper.
in jacs asap.
Solving maze problems is not only relevant to the everyday issues
of urban transportation1 and to experimental psychology2 but is
also one of the model problems of network and graph theory3 as
well as robotics.4 With the advent of computers, algorithms for
maze solving have become automated, but the solution times still
scale unfavorably with maze size/complexity.5 Several groups have
thus explored the possibility of maze solving by physical, chemical,
or even biological systems: microfluidic networks,6 chemical waves7
or plasmas,8 or microorganisms growing in response to food
gradients within the maze.9 Inspired by the latter example, we
wished to create a system in which an inanimate/chemical construct
would be self-propelled and solve mazes in response to chemical
stimuli. Here we describe one such system comprising small
droplets powered by the combination of acid/base chemistry and
surface tension effects. When subject to a pH gradient within a
maze, these droplets move toward regions of low pH and find the
shortest of multiple possible paths. Taxis in our system is over
distances of several centimeters and derives from the convection
flows developed outside of the droplets.1
the following procedure seems to be the easiest.
from a chinese patent. application number:99124902
1. liquifiy pure diphenol by warming. no solvent needed.
2. add 1-5% TsOH-H2O.
3. keep temp at 135C, add 1 eq. MTBE dropwise in 2-3 hr (a cold condenser needed).
4. 1 hr later, you get the title compound with a yield >75%
note:
I tried the reaction, everything worked out as described.
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