Tarek Sammakia

New chiral ligands for the asymmetric copper catalyzed conjugate addition of Grignard reagents to enones

Abstract The copper catalyzed conjugate addition of n-butyl Grignard to enones in the presence of chiral ferrocenyl phosphine oxazoline ligands has been studied and found to provide useful levels of asymmetric induction. A comparison of the ferrocene derived ligands 3 and 6 with the corresponding phenyl derived ligands 8 and 9 reveals that the ferrocene template plays an essential role in the reaction.

A Concise Formal Synthesis of Diazonamide A by the Stereoselective Construction of the C10 Quaternary Center

Diazonamide A (1, Figure 1) is a marine-derived natural product with potent antimitotic activity and an unusual architecture.[1] Its mechanism of action has been studied, and though it displays differential cytotoxicity in the NCI COMPARE[2] screen consistent with a tubulin-active agent,[3] recent studies by Harran, Wang and McKnight suggest a unique mechanism of action involving the mitochondrial matrix enzyme, ornithinine δ-amino transferase (OAT).[4] Prior to these studies, OAT had no known mitotic function, and diazonamide A does not inhibit the amino transferase activity of this enzyme, yet it disrupts its interaction with mitotic spindle promoting proteins. These same workers showed that a close synthetic analogue of diazonamide A lacking the two chlorine atoms retains the cytotoxicity of the natural product, but does not display overt toxicity nor does it cause weight loss, change in overall physical appearance, or evidence of neutropenia in mice.[4a] The combination of limited supply, unique biological activity, and structural complexity, renders this molecule and analogues thereof important targets for chemical synthesis.

α-Arylation of 3-Aryloxindoles

A versatile method for the synthesis of 3,3-diaryloxindoles via Pd-catalyzed alpha-arylations or an S(N)Ar reaction is described. The reaction proceeds using mild base, is tolerant of a variety of functional groups, and is capable of preparing hindered all-carbon quaternary centers.

Synthesis of Methyl-1-(tert-butoxycarbonylamino)-2-vinylcyclopropanecarboxylate via a Hofmann Rearrangement Utilizing Trichloroisocyanuric Acid as an Oxidant

A trichloroisocyanuric acid (TCCA) mediated Hofmann rearrangement was utilized to synthesize methyl-1-(tert-butoxycarbonylamino)-2-vinylcyclopropanecarboxylate. A variety of functional groups are tolerated in this reaction including vinyl, cyclopropyl, pyridyl, aryl, benzyl, and nitro groups.

Total Synthesis of Dermostatin A

The concise total synthesis of dermostatin A is described. Highlights include a two-directional application of the asymmetric acetate aldol method developed in our lab, a novel diastereotopic-group-selective acetal isomerization for terminus differentiation, and a selective cross-metathesis reaction between a terminal olefin and a trienal. A study of the scope and viability of similar cross-metathesis reactions is also described. The synthesis is convergent and utilizes fragments of roughly equal complexity.

Toward the synthesis of (+)-peloruside A via an intramolecular vinylogous aldol reaction.

The use of the intramolecular vinylogous aldol reaction for the preparation of an advanced intermediate for the synthesis of peloruside A is described. The reaction was applied to compound 19 and proceeds in high yield and good levels of diastereoselectivity. Application of the Achmatowicz reaction to this intermediate provided the corresponding pyranone, a late stage intermediate well positioned for conversion to the natural product.

Stereochemical studies of the skipped-polyol polyene macrolide class: NMR studies of a tetraformylal derivative of mycoticin A and B

Abstract The tetraformylal derivative of mycoticin A and B 2 has been prepared in high yield from the natural products 1 . 2D COSY NMR and NOEDS experiments allow assignment of all nonequivalent hydrogens in 2 . NOE difference experiments shed light on the relative stereochemistry and conformation of the skipped-polyol portion of the macrolide ring. Importantly, an anti-configuration of the diol subunit at C 21 -C 23 has been revealed.

Picolinic acid as a partner in the Mitsunobu reaction: Subsequent hydrolysis of picolinate esters under essentially neutral conditions with copper acetate in methanol

The use of picolinic acid and 6-methyl picolinic acid in the Mitsunobu reaction has been studied. These substrates are excellent partners in the Mitsunobu reaction, and offer the added advantage that the resulting esters can be cleaved under essentially neutral conditions using Cu(OAc)2 and methanol.

A mild synthesis of substituted furans from γ-hydroxy-α,β-unsaturated ketones

The acid-catalyzed cyclodehydration of (Z)- and (E)-γ-hydroxy-α,β-unsaturated ketones to furans is described. In the case of E olefins, photochemical trans- to cis- olefin isomerization was found to accelerate the reaction.

Dihydroxylation and oxidative cleavage of olefins in the presence of sulfur

Abstract The dihydroxylation of olefins using AD-mix or OsO 4 K 3 Fe(CN) 6 in the presence of sulfides has been examined as has the rate of oxidation of various classes of sulfides. The selectivity of olefin oxidation in preference to sulfur oxidation depends on the nature of the sulfur moiety, and can be problematic for certain classes of substrates.