Total Synthesis of the Chlorinated Marine Natural Product Dysamide B

Durow, AC; Long, GC; O'Connell, SJ; Willis, Chris

doi:10.1021/ol062279f

Cited by 50 publications

(34 citation statements)

References 32 publications

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“…To gain further evidence for this assignment, the 13 C-1 H coupling constants from a 1 H-coupled 13 C NMR experiment were examined. Typically a proton cis to a carbonyl group in an a,b-unsaturated ester will have a much smaller coupling (4)(5)(6)(7)(8)(9)(10) to the carbonyl carbon than a proton trans (10)(11)(12)(13)(14)(15)(16)(17)(18). 7 Despite this being a welldocumented coupling, measurements of this type have rarely been used to assign the geometry in acrylate derivatives.…”

Section: Papermentioning

confidence: 99%

“…(2S,4S)-Dichloroleucine 19 has been prepared previously and used for example by Jiménez, Rodríguez, and co-workers in the total synthesis of (-)-dysithiazolamide 9 and by our group in the preparation of dysamide B. 10 The NMR spectroscopic data of the synthetic material reported by both groups did not match exactly with that given for 5,5-dichloroleucine isolated following degradation of victorin C. It is well known that the chemical shifts of amino acids are affected by pH; 11 in order for us to reliably compare the data for both diastereomers of L-dichloroleucine with the sample obtained from victorin C, it was necessary to acquire the NMR spectra under similar conditions. Hence protected (2S,4S)-dichloroleucine 22 was prepared as reported previously 10 and converted into the trifluoroacetate salt 23 in quantitative yield (Scheme 3).…”

Section: Stereochemical Assignment Of 55-dichloroleucine In Victorin Cmentioning

confidence: 99%

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Stereochemical Assignments of the Chlorinated Residues in Victorin C

Durow¹,

Willis²

2009

Synthesis

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Victorins are cyclic pentapeptide natural products isolated from the fungus Cochliobus victoriae. Using a combination of synthesis and spectroscopic methods we have assigned the geometry of the vinyl chloride residue and determined the stereochemistry of the 5,5-dichloroleucine moiety.Victoria blight is a disease of oats caused by the fungus Cochliobolus victoriae (also known as Helminthosporium victoriae) which only affects oat crops that have been derived from the oat variety Victoria. Five fractions displaying host-selective activity were isolated from the culture filtrate of C. victoriae and collectively these are known as 'victorin', 'the victorins' or HV-toxins. 1 Approximately 1-2 mg of the major metabolite, victorin C 2, was isolated from 1 L of culture broth and the NMR spectrum was complicated by the presence of different conformers. 1a,bThe cyclic pentapeptide structures of the victorins 1-5 ( Figure 1) were elucidated by extensive spectroscopic studies combined with degradation of the natural products. 1,2 The L-configuration of each amino acid residue was determined from the ORD shifts of their 2,4-DNP derivatives. 2 In addition the stereochemistry of erythro-bhydroxyleucine and threo-b-hydroxylysine residues were assigned by correlation with synthetic materials. 1,2 However, the unequivocal assignment of the stereochemistry of the two chlorinated moieties, 5,5-dichloroleucine and the a-amino-b-chloroacrylic acid requires further investigation. Herein we describe our synthetic and spectroscopic studies leading to elucidation of the geometry of the vinyl chloride moiety and stereochemistry of 5,5-dichloroleucine. Assignment of the Geometry of the a-Amino-b-chloroacrylic Acid ResidueThe 1 H NMR spectrum of the major metabolite from cultures of C. victoriae, victorin C (2) displayed a signal at d = 7.52, which was attributed to the vinylic proton, but the geometry of the vinyl chloride (highlighted in Figure 1) was not assigned by Macko, Arigoni and coworkers. 1a-c Subsequently Kinoshita, Daly, and co-workers isolated a further metabolite, victorin M (or HV-toxin M) (5), which differs from the other victorins in that the glyoxylic acid portion (R 3 , Figure 1) is replaced by glycine. 2 Following acetylation of victorin M (5) and methylation with diazomethane, they isolated methyl ester 6 as the major product as well as traces of methyl enol ethers 7 and 8, formed by displacement of the vinyl chloride (Scheme 1).Kinoshita, Daly, and co-workers 2 suggested that the geometry of the vinyl chloride in victorin M (5) was Z by comparison of the chemical shift (d = 7.68) of the olefinic proton in derivative 6 to that of (E) and (Z)-chloroacrylic acids 9 and 10 ( Figure 2). In the E-isomer 9, the b-proton is cis to the carboxylic acid and resonates at d = 7.32, similar to that observed for the signal assigned to the vinyl chloride in 6, whereas in the Z-isomer 10 the signal is upfield at d = 6.85. However, this assignment does not take into account the effect of the nitrogen of the peptide bond on the chemical s...

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Section: Papermentioning

confidence: 99%

Section: Stereochemical Assignment Of 55-dichloroleucine In Victorin Cmentioning

confidence: 99%

Stereochemical Assignments of the Chlorinated Residues in Victorin C

Durow¹,

Willis²

2009

Synthesis

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“…An alternative approach to the key intermediate aldehyde 71 began with hydrolytic cleavage of protected pyroglutamate using lithium hydroxide and the resultant g-acid was temporarily protected as an allyl ester 73 [45]. An efficient stereoselective alkylation of 73 was followed by introduction of a second Boc protecting to give 74 in 85% yield over the two steps.…”

Section: Halogenated Leucinesmentioning

confidence: 99%

“…A one-carbon homologation of aldehyde 71 to 75 was achieved using a series of straightforward transformations [45]. Treatment of aldehyde 75 with tertbutylamine and N-chlorosuccinimide (NCS) in the presence of molecular sieves led to the required a,a-dichlorination and oxidation of the intermediate dichloroaldehyde gave acid 76.…”

Section: Halogenated Leucinesmentioning

confidence: 99%

“…(2S,4S)-5,5-Dichloroleucine 72 has proved to be a valuable intermediate in the total syntheses of the marine natural products dysamide B and (À)-dysithiazolamide [45,46]. Furthermore, access to chlorinated leucines 66 and 72 labeled with 13 C has been important in the elucidation of the biosynthesis of barbamide in the cyanobacterium L. majuscula by Gerwick et al [47].…”

Section: Halogenated Leucinesmentioning

confidence: 99%

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Synthesis of Halogenated α‐Amino Acids

Strickland

Willis

2009

Amino Acids, Peptides and Proteins in Organic Chemistry

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Stereoselective Synthesis of Halogenated Natural Products

Yoshimitsu

2013

Stereoselective Synthesis of Drugs and Natural Products

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Halogen functionalities often influence the physical, chemical, and biological properties of organic molecules, creating molecular diversity. Because of their significant biological properties, organohalogens have attracted considerable attention as invaluable medicinal resources. As a result, the synthesis of organohalogens is a topic of immense interest and it has motivated us to develop new halogenation methodologies. This chapter will highlight synthetic approaches to selected bioactive organohalogens to which unique methods of carbon–halogen bond formation have been applied. Furthermore, recent developments in methodology, particularly in catalysis, for enantioselective halogenation with great potential for future applications to natural organohalogen synthesis will be briefly overviewed.

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Total Synthesis of the Chlorinated Marine Natural Product Dysamide B

Cited by 50 publications

References 32 publications

Stereochemical Assignments of the Chlorinated Residues in Victorin C

Stereochemical Assignments of the Chlorinated Residues in Victorin C

Synthesis of Halogenated α‐Amino Acids

Stereoselective Synthesis of Halogenated Natural Products

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