As a graduate student in chemistry, you should be reading the current journals in your field on a regular basis. Below are problems concerning syntheses from recent reports in J. Am. Chem. Soc. and J. Org. Chem.; two journals that all organic graduate students should be reading. The first problem simply asks you to match the reagents to the reaction arrow. The second problem asks you to provide the structures along a synthetic sequence in which all the reagents have been provided. And the third problem asks you to use your knowledge of synthetic organic transformations to design a synthesis.

1) Recently Larry Overman and co-worker Arthur Brosius from UC-Irvine reported the stereocontrolled synthesis of diastereomers of the naturally ocurring alkaloid, aloperine. Aloperine, isolated from plant sources, has been used in traditional Chinese medicine to treat inflammatory disorders. Below is the sequence Overman reported for the synthesis of one stereoisomer. Match the reagent (from the list below) with the reaction arrow. Each reagent conditions may be used only once. There are more reagents listed than necessary.

Brosius, A. D.; Overman, L. E. J. Org. Chem. 1997, 62, 440.

Here are the correct reagents:

2) Tuckolide, recently isolated from the Canadian Tuckahoe fungi, is of interest due to its ability to inhibit cholesterol biosynthesis. Merrite Andrus and co-worker Tzenge-Lien Shih, from Purdue, reported the following synthesis of this medium sized lactone. All the reagents are provided for you as well as definitions for the various abbreviations we organic chemists use. Please fill in the products of the reactions in the appropriate box.

M. B. Andrus; T.-L. Shih J. Org. Chem. 1996, 61, 8780.

Here are the correct structures:

PMB = p-methoxybenzoate	PPTS = pyridinium p-toluenesulfonate
DIBAL = diisobutylaluminum hydride	TBAF = tetrabutylammonium fluoride
PNBA = p-nitrobenzoic acid	DEAD = diethylazodicarboxylate
MOM = methoxymethyl	AD-mix-a = OsO4 cat. with quinoline ligand and oxidant
IBX = o-iodoxybenzoic acid	DDQ = dichlorodicyanoquinone

3) Interest in antiviral compounds has been tremendous, especially since the onslaught of AIDS and the HIV virus. Recently, some analogs of carbocyclic sialic acid were synthesized and shown to inhibit the enzyme neuraminidase of the influenza virus. This anti-influenza activity increased dramatically when the free hydroxyl group was alkylated with varying carbon chains. One of these analogs is shown below. The authors used rather standard synthetic organic manipulations to make this compound starting from (-)-shikimic acid. Beginning from shikimic acid and progressing through the intermediates A and B, map out a synthesis to the inhibitor showing all reagents, conditions, and intermediates along the way. Keep in mind you must control the stereochemistry throughout the synthesis.

Kim, C. U.; Lew, W.; Williams, M. A.; Liu, H.; Zhang, L.; Swaminathan, S.; Bischofberger, N.; Chen, M. S.; Mendel, D. B.; Tai, C. Y.; Laver, W. G.; Stevens, R. C. J. Am. Chem. Soc. 1997, 119, 681.

Here is the sequence that the authors carried out:

The route to intermediate A was carried out according to a reported procedure (McGowan, D. A.; Berchtold, G. A. J. Org. Chem. 1981, 46, 2381.). First, shikimic acid was converted into a methyl ester - one way to do this is to use diazomethane. Then, the beta alcohol was activated under Mitsunobu conditions with triphenylphosphine and DEAD for displacement by the neighboring hydroxyl group.

The free hydroxyl of intermediate A was protected as the MOM-ether by reaction with methoxymethyl chloride in the pressence of the base, diisopropylethylamine (DIPEA). The epoxide was then opened by reaction with sodium azide. The alcohol was converted into the mesylate by reaction with methanesulfonyl chloride. This neighboring azide is reduced to the amine in the presence of triphenylphosphine and then water. This amine displaces the mesylate giving the aziridine in intermediate B.

The aziridine was opened with sodium azide in a similar fashion as the epoxide above. The primary amine generated in the ring opening was then acylated with acetyl chloride. Reduction of the azide was carried out under hydrogenation conditions with Lindlar's catalyst. Hydrolysis of the ester with potassium hydroxide and removal of the MOM protecting group under acidic conditions completed the synthesis.

Work by NDSU faculty in Total Synthesis

Construction of Hydroxylated Alkaloids (±)-Mannonolactam, (±)-Deoxymannojirimycin, and (±)-Prosopinine through Aza-Annulation. Cook, G. R.; Beholz, L. G.; Stille, J. R. J. Org. Chem. 1994, 59, 3575.

An Asymmetric Synthesis of (-)-Epibatidine. Trost, B. M.; Cook, G. R. Tetrahedron Lett. 1996, 37, 7485.

Other publications by Dr. Cook

Enantiospecific Synthesis of Trisubstituted Butyrolactone Natural Products and their Analogs. Sibi, M. P.; Lu, J.; Talbacka, C. L. J. Org. Chem. 1996, 61, 7848.

Regio-and Stereocontrolled Conjugate Radical Addition to a Desymmetrized Fumarate. An Efficient Synthesis of (-)-Nephrosteranic Acid and (-)-Roccellaric Acid. Sibi, M. P.; Ji, J. Angew. Chem. Int. Ed. Engl. 1997, 36, 0000.

A New Methodology for the Synthesis of b-Amino Acids. Sibi, M. P.; Deshpande, P. K. Synlett 1997, 0000.

Synthesis of Secolignans. A Concise Route to (+)-Peperomin A and (+)-Peperomin C. Sibi, M. P.; Punniyamurthy, T. Synlett submitted for publication.

Other publications by Dr. Sibi