Total Synthesis and NMR Investigations of Cylindramide

Abstract

Cylindramide (1) was built up from three components: a hydroxyornithine derivative 7, a tetrazolylsulfone 8, and a substituted pentalene subunit 9. Derivative 7 was prepared in a six-step reaction sequence involving the Wittig reaction and a Sharpless asymmetric dihydroxylation starting from N-Boc-3-aminopropanal (12). Tetrazolylsulfone 8 was accessible in four steps from dioxinone 22. The synthesis of the pentalene fragment 9 started from cycloocta-1,5-diene 26, that was converted into enantiopure bicyclo[3.3.0]octanedione 29. The latter was functionalized to give derivative 9. The total synthesis was accomplished by inducing C-C bond formation by Sonogashira coupling of derivatives 9 and 7 followed by olefination with tetrazolylsulfone 8 under Julia-Kocienski conditions, macrocyclization, and subsequent Lacey-Dieckmann condensation to form the tetramic acid unit. As indicated by extensive 1H and 13C NMR spectroscopic investigations (DQF-COSY, ROESY spectra), the stereochemistry of synthetic cylindramide (1) corresponds with that of the naturally occurring product. ROE data were used for molecular modeling of the lowest-energy structures for cylindramide.

Stereoselective Synthesis of (2E,4Z)‐Dienamides Employing (Triphenylphosphoranylidene)ketene

“…Because of its structural relation-ship to the original hydroxyornithine subunit [16] we chose 5-aminopentanoic acid as the amine component, which was treated with SOCl 2 in EtOH to give ethyl 5-aminopentanoate hydrochloride 8a. [31] Scheme 4.…”

“…[12,13] Other known synthetic routes involved photoisomerization of the corresponding (2E,4E)-dienamides [11a] or proceeded via metal exchange starting from N-isobutyl-5-telluro-(2E,4Z)-pentadienamide, [14] or via solid-phase Wittig and Stille reactions of amino acid derivatives. [15] The E,Z-dienamide structure in cylindramide 6 was built up by Lindlar reduction of the coupling enyne fragment from the propynyl-substituted pentalene and a hydroxyorni-thine-derived subunit, [16,17] which is also present in related natural products such as 7. However, the Lindlar reduction suffered from overreduction of the (Z)-configured double bond.…”

An efficient synthesis of tetramic acid derivatives with extended conjugation from L-Ascorbic Acid

“…3-Acetyl tetramic acid derivatives are known to act as anti-HSV and anti-HIV agents with potent tyrosine phosphatase inhibitory activities. [10-12] The distinct structural features and pharmacological properties of tetramic acid antibiotics pose challenges to organic chemists [13,14] to develop simple, practical and efficient syntheses of these compounds. Many groups are engaged in the synthesis of such molecules in sufficient quantities in order to study their in vivo activities and detailed modes of action.…”

Development of Chiral Building Blocks Having a Bicyclo[3.3.0]Octane Framework Using a Diastereomeric Resolution‐Selective Deprotection

“…However, some methods to obtain enantiomerically pure bicyclo[3.3.0]octane‐2,8‐dione derivatives include complicated reactions yielding products with moderate regio‐ and stereoselectivity and involve the use of complex starting materials that require multistep synthesis . The use of C s ‐symmetric bicyclo[3.3.0]octane‐2,8‐dione for general applications is often associated with problems, especially in preparing enantiomerically pure synthons, since there are chemically equivalent sites of reaction, and the reaction needs to discriminate between two chemically equivalent functional groups including structures with internal mirror symmetry (Fig.…”