Francisco Sarabia

Chemistry and biology of cyclic depsipeptides of medicinal and biological interest

Cyclodepsipeptides comprise a wide variety of cyclic peptides of natural origin and are characterized by the occurrence of at least one ester linkage. The great interest that this class of natural products has elicited in scientific community is explained by their wide range of biological activities, intriguing mechanisms of action and attractive molecular architecture. For example, they display a variety of biological effects, such as immunosuppressant, antibiotic, antifungi, antiinflammatory or antitumoral activities. In addition, many of these cyclic depsipeptides represent useful tools for the research of biological processes involved in cellular regulation. The present review deals with the most interesting aspects of the biology and the chemistry of some of these compounds.

A Highly Stereoselective Synthesis of Glycidic Amides Based on a New Class of Chiral Sulfonium Salts: Applications in Asymmetric Synthesis

A new type of chiral sulfonium salts that are characterized by a bicyclic system has been designed and synthesized from α-amino acids. Their corresponding ylides, which were prepared by basic treatment of the sulfonium salts, reacted smoothly with a broad array of simple and chiral aldehydes to provide trans-epoxy amides in reasonable to very good yields and excellent stereoselectivities (>98%). The obtained epoxy amides were found to be useful as synthetic building blocks. Thus, they were reduced into their corresponding epoxy alcohols and subjected to oxirane-ring-opening reactions with different types of nucleophiles.

A macrolactonization approach to the stevastelins

A synthesis of the stevastelins, a novel class of immunosuppressant agents, is reported based on a macrolactonization approach. This synthesis commenced with the stereoselective preparation of the stearic acid segment from tetradecanal using Evans asymmetric synthesis methodology and an aldol reaction with a thioester. After a high yielding coupling reaction between the fatty acid residue and the corresponding tripeptide, we proceeded with the macrolactonization key step. Thus, macrolactonizations of hydroxy acid 27 and dihydroxy acid 30, according to Yamaguchi conditions, afforded the corresponding 13-membered ring stevastelin derivatives 28 and 31 in 90 and 82% yields, respectively. In this latter case, the corresponding 15-membered lactone was not formed. Finally, depsipeptide derivative 31 was converted into stevastelin C3 (5).

β-Oxy-α-diazo-carbonyl compounds. Part 5: An improved synthesis of β-hydroxy-α-diazo esters derived from monosaccharides and synthetic applications in the chemistry of 3-deoxy-2-ulosonic acids

Abstract Reactions of ethyl 2-diazoacetate with aldehydo sugars and monosaccharide derivatives in their hemiacetal form are reported. The use of diethyl zinc led to an improvement of yields and shorter reaction times compared with neutral conditions as previously described. The resulting products represent potentially useful substrates for the synthesis of 3-deoxy-2-keto-ulosonic acid derivatives. Thus, diazo derivatives from d -mannose were transformed into Ko and 3-epimer Ko derivatives in a straightforward process by reaction with mCPBA.

Synthetic studies towards the tunicamycins and analogues based on diazo chemistry. Total synthesis of tunicaminyl uracil.

A synthetic approach to the tunicamycins, a complex family of nucleosides with potent antibiotic and antiviral activities is reported based on diazo chemistry. The corresponding precursors for the synthesis of tunicaminyl uracil derivatives, the non-stabilized diazo derived from 13 and the aldehyde derivative of uridine, compound 4, were prepared efficiently from commercially available D-galactal and uridine, respectively. After a high yielding coupling reaction to obtain the ketone 14, a stereoselective reduction provided the corresponding tunicaminyl uracil derivative 17a and its C-7 epimer 17b. The interconversion of the diazo and aldehyde functional groups in the requisite building blocks was similarly achieved to obtain the ketone 32, which after reduction yielded the corresponding 7-deoxy-6-hydroxy tunicaminyl uracil analogs 33a and 33b.

Synthesis of 2-deoxy-α-DAH based on diazo chemistry by insertion reactions of 2-diazo-3-deoxy-d-arabino-heptulosonate derivatives mediated by rhodium(II)

The synthesis of 2-deoxy-α-DAH (2) is described based on the use of diazo chemistry as previously reported by us during the synthesis of the corresponding 2-deoxy-KDO. Initially, the d-arabino-aldehydo sugar derivative 3 was reacted with ethyl diazoacetate, using diethyl zinc as promoter. The corresponding β-hydroxy-α-diazo ester 4, obtained in very good yield, was transformed into the corresponding 2-diazo-3-deoxy-heptulosonate derivative 10, which was subjected to the action of rhodium(II). However, the major compound obtained in this reaction was the C-glycofuranoside 12 by the interaction of the benzyl protecting group employed at the OH of C-4 with the carbenoid generated at C-2. To avoid this undesired insertion reaction, aldehyde 13 was selected as a suitable starting material and, following the same chemistry than for 3, diazo 19 was efficiently synthesized. Finally, the intramolecular OH insertion mediated by rhodium(II) of 19 provided the targeted 2-deoxy-DAH derivative 21 in a reasonable good yield, which was finally transformed into the potassium salt of 2-deoxy-α-DAH 2.

An array of bengamide E analogues modified at the terminal olefinic position: synthesis and antitumor properties.

Based on our previously described synthetic strategy for bengamide E, a natural product of marine origin with antitumor activity, a small library of analogues modified at the terminal olefinic position was generated with the objective of investigating the effect of structural modifications on antitumor properties. Biological evaluation of these analogues, consisting of IC50 determinations against various tumor cell lines, revealed important aspects with respect to the structural requirements of this olefinic position for activity. Interestingly, the analogue possessing a cyclopentyl group displayed greater potency than the parent bengamide E, representing a key finding upon which to base further investigations into the design of new analogues with promising biological activities.

β-Oxy-α-diazo-carbonyl compounds. Part 6: Synthesis and reactivity of 3-deoxy-2-diazo-esters derived from monosaccharides. Applications in the synthesis of 2-C-alkyl-KDO analogues and related compounds

Abstract Reactions of 6- O -protected diazo derivatives 8 , 9 and 10 with transition metals Rh(II) and Cu(II) under a variety of different conditions of solvents and temperatures, were studied in order to obtain 2- C -alkyl analogues of KDO. In fact, these types of products ( 11 , 12 ) were obtained in good yields when Rh(II) was used as a catalyst in benzene. The interesting seven-membered ring products ( 13 ) were obtained only for 8 and 9 , as single diastereoisomers and their formations were favored when Cu(II) catalysts were used.

The Chiron Approach to Pironetins: Synthesis of the δ‐Lactonic Fragment and Modified Building Blocks from D‐Glucal

Abstract The synthesis of the δ‐lactonic fragment of pironetin (1), a natural product with outstanding antimitotic properties, is reported. The synthesis was achieved from commercially available tri‐O‐acetyl‐D‐glucal (6) that was employed as starting material for the preparation of ethyl ketone 4, through a synthetic sequence that included a Ferrier rearrangement of 6 and suitable functional group manipulations of the resulting O‐glycoside 7 to obtain the 4‐ethyl glycoside 11, together with a series of 4‐C‐alkyl modified derivatives. The completion of the synthesis of 4 was performed via chain elongation at C‐6 by the introduction of a nitrile group and subsequent reduction, nucleophilic attack with ethyl magnesium bromide, and, finally, oxidation of the resulting alcohol 20.

Silencing of Essential Genes within a Highly Coordinated Operon in Escherichia coli

ABSTRACT Essential bacterial genes located within operons are particularly challenging to study independently because of coordinated gene expression and the nonviability of knockout mutants. Essentiality scores for many operon genes remain uncertain. Antisense RNA (asRNA) silencing or in-frame gene disruption of genes may help establish essentiality but can lead to polar effects on genes downstream or upstream of the target gene. Here, the Escherichia coli ribF-ileS-lspA-fkpB-ispH operon was used to evaluate the possibility of independently studying an essential gene using expressed asRNA and target gene overexpression to deregulate coupled expression. The gene requirement for growth in conditional silencing strains was determined by the relationship of target mRNA reduction with growth inhibition as the minimum transcript level required for 50% growth (MTL50). Mupirocin and globomycin, the protein inhibitors of IleS and LspA, respectively, were used in sensitization assays of strains containing both asRNA-expressing and open reading frame-expressing plasmids to examine deregulation of the overlapping ileS-lspA genes. We found upstream and downstream polar silencing effects when either ileS or lspA was silenced, indicating coupled expression. Weighted MTL50 values (means and standard deviations) of ribF, ileS, and lspA were 0.65 ± 0.18, 0.64 ± 0.06, and 0.76 ± 0.10, respectively. However, they were not significantly different (P = 0.71 by weighted one-way analysis of variance). The gene requirement for ispH could not be determined due to insufficient growth reduction. Mupirocin and globomycin sensitization experiments indicated that ileS-lspA expression could not be decoupled. The results highlight the inherent challenges associated with genetic analyses of operons; however, coupling of essential genes may provide opportunities to improve RNA-silencing antimicrobials.