The Synthesis of (+)-Allopumiliotoxin 323B′

Tan, Choon‐Hong; Holmes, Andrew B.

doi:10.1002/1521-3765(20010504)7:9<1845::aid-chem1845>3.0.co;2-2

Cited by 56 publications

(18 citation statements)

References 41 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…β -Hydroxy ester 10 (readily available by enzymatic resolution of the corresponding racemic aldol adduct9) served as the departure point for the valine-containing fragment and completion of the synthesis (Scheme 2). EDCI-mediated coupling with FmocValOH and subsequent Fmoc removal with diethylamine gave 4 in 62% yield for the two steps.…”

mentioning

confidence: 99%

A Concise Total Synthesis of Largazole, Solution Structure, and Some Preliminary Structure Activity Relationships

et al. 2008

View full text Add to dashboard Cite

A total synthesis of largazole that proceeds in 8 steps from commercial materials is reported, along with some structure-activity relationships. A combination of NMR studies and molecular modeling have also provided a preliminary picture of the conformation of largazole.As part of an investigation into the natural products chemistry of the marine cyanobacterium Symploca sp. collected in the Florida Keys, Leusch and co-workers recently described the isolation and structure elucidation of the depsipeptide largazole (1, Figure 1). 1 Largazole's structure is defined by the presence of an α-methylcysteine-derived thiazoline coupled to a thiazole embedded within a 16-membered macrocycle and the presence of a caprylic acidderived thioester. Largazole's structural simplicity belies its potent antiproliferative activity against a number of cancer cell-lines including MDA-MB-231 mammary cells (GI 50 7.7 nM), U2OS fibroblastic osteosarcoma cells (GI 50 55 nM), HT29 colon cells (GI 50 12 nM), and IMR-32 neuroblastoma cells (GI 50 16 nM).In broad connection with our interest in the synthesis of marine natural products, 2,3 we were attracted to largazole on the basis of biological activity and potential as a small-molecule natural product lead for the development of new therapeutics or cellular probes. Given these considerations, our overall synthesis plan was predicated on considerations of brevity and in andrew.phillips@colorado.edu. Supporting Information Available: Experimental procedures, characterization data, and copies of spectra for compounds 2→8, 10→14, and largazole. This material is available free of charge via the Internet at http://pubs.acs.org. (Figure 1). In accord with this, introduction of the potentially delicate thioester by cross-metathesis as the final step of the synthesis and this analysis led ultimately to three fragments of comparable size: olefin 2, ester 4, and thiazoline-thiazole 5. As well as providing plans for a very direct approach to largazole, this strategy is also amenable to the systematic variation of structure in search of improved activity. It should be noted that contemporaneous with our studies, Luesch and Hong also developed a total synthesis that shares strategic similarities, although notably the macrocyclization occurs at different positions. 4 NIH Public AccessThe synthesis commenced with commercially available Boc-protected gylcine thioamide 6, which was converted to thiazolyl amide 7 in 53% yield by a two-step, one-pot protocol consisting of a Hantzsch thiazole synthesis 5 with ethyl α-bromopyruvate followed by aminolysis of the ester with aqueous ethanolic ammonia (Scheme 1). 6 Dehydration of the amide with trifluoroacetic anhydride produced nitrile 8 in essentially quantitative yield, 7 and it proved possible to engage this nitrile directly with commercially available α-methylcysteine 9 to give thiazolylthiazoline 5 in 77% yield for these two steps. 8β-Hydroxy ester 10 (readily available by enzymatic resolution of the corresponding racemic aldol adduct 9 ) served as ...

show abstract

mentioning

confidence: 99%

A Concise Total Synthesis of Largazole, Solution Structure, and Some Preliminary Structure Activity Relationships

et al. 2008

View full text Add to dashboard Cite

show abstract

“…Indeed, Holmes and co-workers have reported that methylmagnesium bromide addition to N -Cbz-protected piperidin-3-one 8 produced exclusively the trans -methylation product 9 [44] (Scheme 3). In that case, the N -benzyloxycarbonyl group imposed A 1,3 -strain on piperidine derivatives founded the basis for the observed stereocontrol.…”

Section: Resultsmentioning

confidence: 99%

Towards stereochemical control: A short formal enantioselective total synthesis of pumiliotoxins 251D and 237A

Zhang¹,

Zhang²,

Huang³

2013

Beilstein J. Org. Chem.

View full text Add to dashboard Cite

SummaryA concise enantioselective synthesis of the advanced intermediate 5 for the synthesis of pumiliotoxins (Gallagher’s intermediate) is described. The synthesis started from the regio- and trans-diastereoselective (dr = 98:2) reductive 3-butenylation of (R)-3-(tert-butyldimethylsilyloxy)glutarimide 14. After O-desilylation and Dess–Martin oxidation, the resulting keto-lactam 10 was subjected to a highly trans-stereoselective addition of the methylmagnesium iodide to give carbinol 11 as sole diastereomer. An efficient ring closure procedure consisting of ozonolysis and reductive dehydroxylation provided the indolizidine derivative 5, which completed the formal enantioselective total synthesis of pumiliotoxins 251D and 237A.

show abstract

“…[20][21][22][23][24][25][26][27][28][29][30][31] We found PS-C lipase (Pseudomonas cepacia immobilized on ceramic particles) to be as efficient as PS-Amano lipase in this operation giving the known tert-butyl (R)-3-hydroxy-4-pentenoate (+)-1 in >95% ee and 45% yield. 32 The secondary hydroxyl group was protected under standard conditions as its tert-butyldimethylsilyl ether (+)-2.…”

Section: Methodsmentioning

confidence: 99%

Enantioselective Approach to Tropane Skeleton: Synthesis of (1S,5S,6R)-6-Hydroxy-8-methyl-8-azabicyclo[3.2.1]octan-3-one

Pollini¹,

Risi²,

Lumento³

et al. 2004

Synlett

View full text Add to dashboard Cite

The original and classical Mannich-type construct for the tropane skeleton, developed over half a century ago by Willstätter, Robinson and Schöpf as the first biomimetic synthesis, has been employed for the enantioselective construction of 6b-hydroxytropinone. The component compounds of this novel one-step Mannichtype condensation sequence are acetonedicarboxylic acid, methylamine hydrochloride and (2R)-hydroxy-1,4-butanedial, in turn prepared from tert-butyl (R)-3-hydroxy-4-pentenoate as the starting chiral synthon.Tropane alkaloids constitute a group of some 200 natural products, mostly occurring in plants of Solanaceae family, featuring the 8-azabicyclo[3.2.1]octane skeleton as the key structural element. The remarkable biological activity associated to many tropane alkaloids has attracted much attention, achieving a significant folklore and influence in medicine for hundred of years, while their structure elucidation and synthesis has contributed in no small part to the development of organic chemistry since the middle of the 19 th century. [1][2][3][4] A prodigious number of tropane analogues have been synthesized, major efforts being expended in the search for cocaine antagonists or partial agonists. Beside the original and still widely used Mannich-type 5-8 construct for the tropane skeleton a number of synthetic methodologies have since been developed. 9-11 However, few asymmetric versions of cycloadditions for the stereospecific synthesis of tropane analogues are known and still suffer from low yield and poor stereoselectivity. Therefore, most of the non-racemic tropane derivatives were synthesized by the derivatization of natural cocaine or through enantioselective deprotonation of tropinone, 12-14 while others were obtained by resolution or separation of racemic or diastereomeric reaction mixtures. 15Despite a pertinent accumulation of tropane chemistry, no enantioselective variant of the Mannich-type condensation between acetonedicarboxylic acid and methylamine hydrochloride using optically active 2-hydroxysuccinaldehyde or its equivalents as a chiral control element has been described in the literature. It seems likely that concerns about the preservation of the integrity of the stereocenter of the a-hydroxyaldehyde during the reaction, coupled with the commercial availability of 2,5-dimethoxy-2,5-dihydrofuran (a convenient precursor of racemic 2-hydroxysuccinaldehyde), have made the preparation of racemic tropane derivatives through the Mannich-type condensation followed by resolution more attractive. [16][17][18][19][20][21][22][23] Interestingly, the enzymatic resolution of tropinone derivatives, including racemic 6-hydroxytropinone, has been successfully achieved but the absolute configuration of the chiral derivatives could not be determined. 24 In this paper, we describe a direct, enantioselective approach to 6-hydroxytropinone through a suitable adaptation of the classical Robinson-Willstätter route employing an optically active 2-hydroxysuccinaldehyde derivative in the classical one-pot, mult...

show abstract

The Synthesis of (+)-Allopumiliotoxin 323B′

Cited by 56 publications

References 41 publications

A Concise Total Synthesis of Largazole, Solution Structure, and Some Preliminary Structure Activity Relationships

A Concise Total Synthesis of Largazole, Solution Structure, and Some Preliminary Structure Activity Relationships

Towards stereochemical control: A short formal enantioselective total synthesis of pumiliotoxins 251D and 237A

Enantioselective Approach to Tropane Skeleton: Synthesis of (1S,5S,6R)-6-Hydroxy-8-methyl-8-azabicyclo[3.2.1]octan-3-one

Contact Info

Product

Resources

About