Enantioselective total synthesis of briarellins E and F: the first total syntheses of briarellin diterpenes

Enantioselective total syntheses of briarellin E (4) and briarellin F (5) have been achieved starting with (S)-(+)-carvone and (S)-(-)-glycidol. These total syntheses are the first of briarellin diterpenes. The central step in these syntheses is acid-promoted condensation of cyclohexadienyl diol 15 and (Z)-alpha,beta-unsaturated aldehyde 16 to form, with complete stereocontrol, the hexahydroisobenzofuran core and six stereocenters of these coral metabolites. These syntheses also feature stereospecific photolytic deformylation of beta,gamma-unsaturated aldehyde 17 to remove the extraneous carbon introduced in the Prins-pinacol step, chemo- and stereoselective hydroxyl-directed epoxidation of dienyl alcohol 18 to incorporate the C3 oxygen stereocenter, regio- and stereoselective rearrangement of epoxy ester 19 to install the C4 oxygen substituent, efficient dehydrative cyclization of a 1,6-diol intermediate to form the oxepane ring, and diastereoselective Nozaki-Hiyama-Kishi cyclization of vinyl iodide aldehyde 25 to forge the oxacyclononane ring and the C6 hydroxyl stereocenter. These total syntheses establish the absolute configurations of 4 and 5, define a concise strategy for the total synthesis of briarellin diterpenes, and provide additional illustrations of the uncommon utility of pinacol-terminated cationic cyclizations for stereocontrolled synthesis of complex oxacyclic natural products.     

Asymmetric first total syntheses and assignment of absolute configuration of oxazinin-5, oxazinin-6 and preoxazinin-7

Asymmetric first total syntheses of the unprecedented toxins oxazinin-5, oxazinin-6 and preoxazinin-7 have been achieved from a common key intermediate 18, derived from a regiocontrolled Sharpless asymmetric aminohydroxylation and oxa-Michael reaction, which in addition to confirming the structure also established the absolute configuration of the natural products. On the way an expeditious synthesis of a metabolite bursatellin was completed in 8 steps.     

The first asymmetric total syntheses of both enantiomers of cryptocaryone

The first asymmetric total syntheses of the (+)- and (−)-cryptocaryones are described. Removal of the acetal unit of the enone acetal 5, which was obtained in our previous study from the cyclohexadiene acetal 3, afforded the enone acetal 8 in a one-pot procedure. The acylation of 8 with cinnamoyl chloride and subsequent hydrolysis of the resulting acetal gave the lactol 11. Its oxidation with NIS and tetra-n-butylammonium iodide (TBAI) finally furnished the natural (+)-cryptocaryone 2. The same procedure from ent-3 afforded the unnatural one 1.     

First total syntheses of (+)-7-deoxynogarol and (+)-7-con-o-methylnogarol

The first total syntheses of (+)-7-deoxynogarol (2) and (+)-7-con-O-methylnogarol (3), the notable members of nogalamycin congeners, were achieved employing the Diels-Alder reaction of the highly functionalized dienes (11 and 20) with the (+)-naphthoquinone (6), the CDEF-ring system of nogalamycin congeners, as a key synthetic step.     

Enantioselective total syntheses of omuralide, 7-epi-omuralide, and (+)-lactacystin

An alkylidene carbene 1,5-CH insertion has been used as a key step in an enantioselective total syntheses of omuralide, its C7-epimer, and (+)-lactacystin. An additional noteworthy feature of the synthesis is the use of a novel oxidative deprotection procedure, utilizing DMDO, for the conversion of a late-stage benzylidene acetal into a primary alcohol and a secondary benzoate ester.     

The first asymmetric total syntheses and determination of absolute configurations of xestodecalactones B and C

The first efficient asymmetric total syntheses of xestodecalactones B and C have been accomplished in 10 steps with an overall yield of 22 and 20.2%, respectively. The key steps involve the utility of Evans oxazolidinone-mediated syn-aldol condensations to establish the C-9 configuration and the macrolide ring formation by intramolecular acylation. The absolute configurations of xestodecalactones B and C have been determined via these syntheses.     

Stereoselective total syntheses and reassignment of stereochemistry of the freshwater cyanobacterial hepatotoxins cylindrospermopsin and 7-epicylindrospermopsin

A stereoselective total synthesis of the structure 1 proposed for the freshwater cyanobacterial heptatotoxin cylindrospermopsin has been accomplished in approximately 30 operations starting from commercially available 4-methoxypyridine. Utilizing methodology developed by Comins, the tetrasubstituted piperidine A-ring unit of the hepatotoxin was efficiently constructed. The two remaining stereocenters in the natural product were then set by a stereospecific intramolecular N-sulfinylurea Diels-Alder cyclization/Grignard ring opening/allylic sulfoxide [2,3]-sigmatropic rearrangement sequence previously developed in these laboratories, leading to key intermediate 29. The stereochemical assignment of alcohol 29, which contains all six of the stereogenic centers of the natural product, was confirmed by an X-ray crystal structure determination of a derivative. Installation of the D-ring uracil moiety was effected by using our new methodology developed for this purpose, and construction of the C-ring guanidine completed the total synthesis of racemic structure 1. However, the (1)H NMR data for this compound do not match that of cylindrospermopsin, but instead agree with the data reported for 7-epicylindrospermopsin, a minor toxic metabolite that co-occurs with cylindrospermopsin. Therefore, we propose a revision of the stereochemical assignments of these natural products such that cylindrospermopsin is now represented as structure 2 and 7-epicylindrospermopsin is 1. This reassignment was further confirmed by Mitsunobu inversion of the C-7 alcohol 51 to epimer 52, and conversion of this compound to tetracyclic diol 57, which has previously been transformed to cylindrospermopsin (2).     

Practical total syntheses of epiquinamide enantiomers

Short and practical syntheses of epiquinamide and its enantiomer were accomplished with high overall yields and high stereoselectivity from readily available starting materials.     

The first asymmetric syntheses of l-homocysteine and l-homocystine

Asymmetric syntheses of l-homocysteine 1 and l-homocystine 2 are described. Alkylation of the carbanion derived from Schöllkopf reagent 3 and ensuing hydrolyses gave S-triphenylmethyl-l-homocysteine 6. Removal of the triphenylmethyl group gave l-homocysteine 1 and subsequent oxidation provided l-homocystine 2.     

Imidazole alkaloids of Macrorungia longistrobus: Revised structures and total syntheses

By total synthesis, it was shown that the imidazole alkaloids dehydroisolongistrobine and isolongistrobine possess structures 1 and 2, respectively, rather than the structures proposed by Arndt, Eggers and Jordaan in 1969. Reaction of methyl 1-methylimidazole-5-carboxylate with phenylsulfonylmethyl magnesium bromide provided a β-ketosulfone which was alkylated with o-nitrobenzyl bromide to provide 6. In the key step, amino alcohol 10 and tetrahydroquinoline 8 were obtained through aluminum amalgam reduction of 6. 8 was converted to isomacrorine 12. 10 could be converted to 1 by a three-step sequence; 2 was obtained from 10 by acylation with 4-pentenoyl chloride, oxidation, and osmium tetroxide catalyzed periodate cleavage of the vinyl group. Comparison of samples of synthetic alkaloids 1 and 2 with the corresponding alkaloids from natural sources showed that the natural and synthetic samples of each were identical.     

Efficient total syntheses of natural pterin glycosides: limipterin and tepidopterin

The key, versatile precursors N²-(N,N-dimethylaminomethylene)-1′-O-(4-methoxybenzyl)-3-[2-(4-nitrophenyl)ethyl]biopterin (29a) and its ciliapterin analog (29b) were prepared, respectively, from d-xylose (in 14 steps) and l-xylose (in 11 steps). Treatment of 29a and 29b with 3,4,6-tri-O-acetyl-2-deoxy-2-phthalimido-β-d-glucopyranosyl bromide in the presence of silver triflate and tetramethylurea, followed by removal of the protecting groups, led to the first selective syntheses of limipterin (3) and tepidopterin (5), respectively.     

Efficient total syntheses of louisianins C and D

An efficient synthetic route for the preparation of louisianins C and D was developed starting with the commercially available 4-cyanopyridine. Louisianins C and D were synthesized in seven steps and with overall yields 22% and 20%, respectively, following a novel cyclization-decarboxylation sequence involving 4-bromo-6,7-dihydrocyclopenta[c]pyridin-5-one as the key intermediate.     

Biomimetic total syntheses of flinderoles B and C

A simple and efficient biomimetic synthesis of pyrrolo[1,2-a]indoles using a highly stereo- and regioselective [3 + 2] reaction cascade was developed and then further applied in the first total synthesis of flinderoles B and C, which proceeded in 17.2% yield over the longest linear sequence of 11 steps.     

Concise total syntheses of heliannuols B and D

Concise and efficient enantioselective total syntheses of heliannuols B and D have been accomplished using chirality transfer through a Lewis acid-promoted Claisen rearrangement for the construction of the C7 tertiary stereogenic center and a relay ring-closing metathesis for assembling the dihydrobenzo[b]oxepine backbone of the natural products as the key steps.     

Biomimetic total syntheses of cassiarins A and B

Total syntheses of cassiarins A and B have been efficiently accomplished using a common strategy with biomimetic considerations. Key reactions involved in this synthesis include a Negishi-type coupling, a Ag(I)-promoted formation of the tricyclic 8H-pyrano[2,3,4-de]chromen-8-one core, and a sequential amine-condensation and cyclization. Three new analogues of cassiarin A bearing different substituents at the C-11 position were synthesized in parallel from the same intermediate. In addition, two other transformations to the key tricyclic cores and cassiarins A and B were achieved from corresponding chemically equivalent precursors.     

Catalytic asymmetric total syntheses of quinine and quinidine

The catalytic, asymmetric syntheses of quinine and quinidine were achieved in 16 steps. The recently developed salen(Al)-catalyzed enantioselective Michael addition of methyl cyanoacetate served to set the crucial C4 stereocenter in 92% ee, and a late-stage asymmetric dihydroxylation was used to differentiate the common intermediate and access the two desired diastereomeric products with high selectivity.