Organic Chemistry, Natural Products, Synthesis, Methodology

Stereoselective Monofluoromethylation of Primary and Secondary Alcohols by Using a Fluorocarbon Nucleophile in a Mitsunobu Reaction

Link: ACIEE EarlyView

G. K. Surya Prakash*, Sujith Chacko, Steevens Alconcel, Timothy Stewart, Thomas Mathew, George A. Olah*

Loker Hydrocarbon Research Institute and, Department of Chemistry, University of Southern California, University Park, Los Angeles, CA 90089-1661, USA

The following method is very similar to this one, that it demonstrates a strategy to synthesize monofluoromethyl derivative compounds, at least in the purpose of the research. The products are different type as the one cited in the link above are amino fluoro methyl derivatives, but this one here, the method seems to be applicable to primary and secondary alcohols (via Mitsunobu), giving a wider variety of products. The reagent used in both papers is the same one, however (1).

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The initial products after the Mitsunobu step show an agreeable inversion of configuration at the former carbinol centers as shown in the table below.

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Applicability is general as shown in the table below.

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The bis-sulfonyl products could be di-hydrodesulfonated to give the monoflouoromethyl products in good to execellent yields.

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This method could be successfully applied to natural compounds such as vitamin D3 and the tetraacetyl glucopyranose as shown in Schemes 2 and 3.

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In addition to 1, a different fluoromethylating agent such as 6, possessing appropriate pKa, also smoothly participated in the current Mitsunobu strategy.

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May 24, 2007 Posted by | Methodology | Leave a comment

CuI-Catalyzed Conjugate Addition of Ethyl Propiolate

Link: ACIEE EarlyView

Shinji Fujimori, Erick M. Carreira*

Laboratorium für Organische Chemie, ETH Zürich, 8093 Zürich, Switzerland

This is a methodology paper on copper (II)-assisted 1,4-alkyl propiolate addition to Meldrum’s acid-derived enonone. The method is general to many Meldrum’s acid derivatives, and the products obtained can certainly be used as valuable building blocks.

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The reaction seems to be mild, plus it is run in aqueous media! In achiral Meldrum’s acid derivatives, the results are excellent as seen in Table 1.

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The products from this reaction can be elaborated as illustrated below in a hydrogenation.

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And when the enone derivatives contained chiral elements in the R group, the reaction occurred stereoselectively in a substrate-controlled fashion.

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To demonstrate the usefulness of the products further, the folllowing scheme shows that the products could be subjected through a series of transformations to give valuable chiral building blocks (9a and 9b).

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May 24, 2007 Posted by | Methodology | 1 Comment

Total Synthesis and Stereochemistry of Uncialamycin

Link: ACIEE EarlyView

K. C. Nicolaou, Hongjun Zhang, Jason S. Chen, James Crawford, Laxman Dasunoori

1Department of Chemistry and, The Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA
2Department of Chemistry and Biochemistry, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA

A new tot synth of Uncialamycin by Nicolaou. This is a natural occurring enediyne. Because the stereochemistry of C26 was unknown, both diastereomers as shown were synthesized. The retrosyn led back to simpler fragments 2, 3, and 4.

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The following scheme illustrates the route to fragment 2. The key transformation was the two-step Friedlander quinoline synthesis (7 to 9).

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Then fragment 2 was used in the following sequence. The key steps in the sequence involved installation of enediyne fragment 3 to give 11, the closure of the macrocycle to give 15, and the Hauser annulation in the last step to give 1a from 16.

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In this case, it was found that the final product’s spectrum (1a) did not match the reported value. And therefore, the other isomer was synthesized. This was easily done using fragment 12 through oxidation-reduction sequence to give 18 with the opposite stereochemistry at C26. Sequence in Scheme 3 was then repeated on this fragment.

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And 1b was found to match spectrum of the natural isomer. This natural compound was found to be stable as a solid and as solutions in a variety of solvents. But in presence of dray HCl in CH2Cl2 solution at rt, it rapidly converts to hexacyclic 19 through a cascade of Bergman cycloaromatization reaction. This cascade of reactions is believed to be responsible mode of action in damaging DNA and killing cells.

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May 24, 2007 Posted by | Total Synthesis | Leave a comment

Asymmetric Synthesis of syn-alpha-Substituted beta-Amino Ketones by Using Sulfinimines and Prochiral Weinreb Amide Enolates

Link: Org Lett ASAP

Franklin A. Davis* and Minsoo Song

Department of Chemistry, Temple University, Philadelphia, Pennsylvania 19122

This paper detailed the use of Weinreb amide in stereoselective addition to sulfinimine. Stereoselectivity was controlled by stereochemistry of the sulfinyl group. The major stereochemistry of the product was found to be syn-isomer in excellent ratio.

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The most optimal base was found to be LiHMDS in THF, and Et2O in only few cases. Both isomers of the amide products are useful building blocks in a variety of subsequent transformations as seen in schemes below.

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As seen in Scheme 5, propyl amide 24 could effectively be used in place of the usual ethyl amide.

May 22, 2007 Posted by | Methodology | Leave a comment

Highly Enantioselective Synthesis of gamma-Hydroxy-alpha,beta-acetylenic Esters Catalyzed by a beta-Sulfonamide Alcohol

Link: Org Lett ASAP

Li Lin, Xianxing Jiang, Weixia Liu, Li Qiu, Zhaoqing Xu, Jiangke Xu, Albert S. C. Chan, and Rui Wang*

State Key Laboratory of Applied Organic Chemistry, Institute of Biochemistry and Molecular Biology, Lanzhou University, Lanzhou 730000, China, and State Key Laboratory of Chinese Medicine and Molecular Pharmacology, Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Kowloon, Hong Kong, China

This is a study of three different chiral ligands and their effect in reaction of Ti-cat addition of organozinc reagent to aldehydes. The final result was enantioselective addition of methyl propiolate to aldehyde providing propargylic alcohol.

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The ligands being looked at are:

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It was found that there were differences in these three lignads, structure-wise and reactivity-wise. The reactivity difference was in term of the group being transferred to aldehyde. The result is summarized in the table below.

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The difference was suspected to lie in the Lewis acidity of the chelating heteroatoms. In L*, the sulfonamide nitrogen and oxygen activated the titanium complex as a Lewis acid less than the oxygen atoms in TADDOL, which in term activated titanium less yet than oxygen atoms of BINOL. As a result, titanium complex is most Lewis acidic in BINOL and least in L*. This resulted in a more efficient transfer of ethyl grounp in the presence of BINOL than L*.

In addition both TADDOL and L* have blue oxygen atoms which were suspected to increase their Lewis basicity, which presumably offset the Lewis acidity of Ti-center when coordinated. In the most optimal conditions of acetylide addition to aldehydes using L*, the Lewis basicity was increase further by addition of DME as an additive. The most optimal conditions resulted in the following efficient transformation:

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In addition to the example above, this methodology could be applied to a large number of aldehydes as summarized in the table below.

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The proposed mechanism of this activation and transformation is summarized in the two-step sequence; first in the generation of alkynylzinc, and second in the addition of the alkynylzinc to aldehyde. All of these happened in one pot.

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May 22, 2007 Posted by | Methodology | Leave a comment

Catalytic Enantioselective Friedel-Crafts Alkylations of Indoles with alpha’-Phosphoric Enones

Link: Org Lett ASAP

Hyeyeon Yang, Young-Taek Hong, and Sunggak Kim*

Center for Molecular Design & Synthesis and Department of Chemistry, School of Molecular Science, Korea Advanced Institute of Science and Technology, Daejeon 305-701, Korea

Friedel-Crafts alkylation of indoles and pyrrole was accomplished. The catalyst for this reaction is the copper-py-box complex 1a and the alkyl counterparts were the alpha’-phosphate enones. Both indoles and pyrrole were alkylated at the 3-position on the ring.

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The reaction was best conducted in CH2Cl2 at low temperatures. The reaction was applicable to a wide variety of both indoles and enones as shown in Tables 2 and 3. As can be seen, the reaction afforded the products in excellent yields and ees.

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The reaction also worked well with N-methyl pyrrole.

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The products could be elaborated in subsequent reactions as shown in equations below.

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The mechanism of this reaction has been well-studied and it is represented in the figure below.

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May 21, 2007 Posted by | Methodology | 3 Comments

alpha-Amidation of Cyclic Ethers Catalyzed by Simple Copper Salt and a Mild and Efficient Preparation Method for alpha,omega-Amino Alcohols

Link: Org Lett ASAP

Ling He, Jing Yu, Ji Zhang, and Xiao-Qi Yu*

Department of Chemistry, Key Laboratory of Green Chemistry and Technology (Ministry of Education), Sichuan University, Chengdu, 610064, People’s Republic of China, and Key Laboratory of Drug-Targeting of Education Ministry of China, West China School of Pharmacy, Sichuan University, Chengdu, 610041, People’s Republic of China

Another cool method using copper (II) triflate salt and hypervalent iodide reagent in a direct amidation of alpha-carbon in cyclic ethers. The products of the reaction could serve as a precursor to amino alcohol in a subsequent reduction.

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For example, alpha-amidation of THF could be performed in excellent yield.

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The mechanism was proposed as followed: 

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The reaction was subsequently performed on various substrates as shown in the table.

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Subsequent reduction could be performed using NaBH4 and results are summarized in the table below, giving a ready access to various amino alcohols.

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May 21, 2007 Posted by | Methodology | Leave a comment

Palladium-Catalyzed Direct Arylation of Aryl(azaaryl)methanes with Aryl Halides Providing Triarylmethanes

Link: Org Lett ASAP

Takashi Niwa, Hideki Yorimitsu,* and Koichiro Oshima*

Department of Material Chemistry, Graduate School of Engineering, Kyoto University, Kyoto-daigaku Katsura, Nishikyo-ku, Kyoto 615-8510, Japan

Quite interesting reaction to give neat-looking products. The reaction also looked really simple to conduct.

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Several examples were provided in the paper and all products were obtained in great yields. Especially interesting are the uniquely-looking products 6a and 6b in Eqs 1 and 2.

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May 21, 2007 Posted by | Methodology | Leave a comment

Synthesis of Kaempferitrin

Link: JOC ASAP

Sameer Urgaonkar and Jared T. Shaw*

Chemical Biology Program, Broad Institute of Harvard and MIT, 7 Cambridge Center, Cambridge, Massachusetts 02142

This is a paper presenting a synthesis of this bisglycosilated molecule called Kaempferitrin:

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The thing that caught my attention was the clever use of internal hydrogen-bonding to regioselectively putting protecting group on and taking protecting group off. For example, in the synthesis of 7, one of the ortho-OH group to the carbonyl did not react with MOMCl. And again in the transformation of 8 to 9, only the OH group ortho to the carbonyl was deprotected indicating the probable participation of that carbonyl.

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And in the final step from 10 to 11, the Ts group was used strategically so that the di-deprotection of OMOM and OMe was possible without affecting the OTs group. I guess this last point is not as significant as the earlier protecting group manipulation steps.

May 20, 2007 Posted by | Total Synthesis | Leave a comment

Methylpentanediolborane: Easy Access to New Air- and Chromatography-Stable, Highly Functionalized Vinylboronates

Link: JOC ASAP

Nageswaran PraveenGanesh, Sylvain d’Hondt, and Pierre Yves Chavant*

Département de Chimie Moléculaire, CNRS, Université Joseph Fourier, BP-53, 38041 Grenoble Cedex 9, France  

As the title says, the paper detailed the synthesis of air and silica gel stable vinyl boronate. Several of these compounds were prepared as the scheme below suggests.

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I guess one aspect of this paper that caught my attention was their way of making MPBH or 1 which I like:

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And that is by using the diborane gas they made from NaBH4 and I2. In their experimental, they said the gas is pyrophoric and hydrogen was also generated, so extra care must be taken. For everything else, look up the paper.

May 20, 2007 Posted by | Methodology | Leave a comment

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