First enantiospecific total synthesis of the important biogenetic intermediates, (+)-polyneuridine and (+)-polyneuridine aldehyde, as well as 16-epi-vellosimine and macusine A

The first enantiospecific total synthesis of the alkaloids 16-epi-vellosimine (1), (+)-polyneuridine (2), (+)-polyneuridine aldehyde (3), and macusine A (4) is reported. The key oxidation was accomplished with the Corey-Kim reagent to provide the important biogenetic intermediates, 16-epi-vellosimine (1) and polyneuridine aldehyde (3), the latter of which is required for the conversion of the sarpagan skeleton into the ajmalan system in the biosynthesis of quebrachidine. [reaction: see text].     

Evolution of a protecting-group-free total synthesis: studies en route to the neuroactive marine macrolide (-)-palmyrolide A

A full account of our synthetic work toward the first total synthesis of the neuroactive marine macrolide (-)-palmyrolide A is described. Our first-generation approach aimed to unlock the unknown C(5)-C(7) stereochemical relationship via the synthesis of four diastereomers of palmyrolide A aldehyde, a known degradation product. When these efforts provided inconclusive results, recourse to synthesizing all possible stereocombinations of the 15-membered macrolide was undertaken. These studies were critical in confirming the absolute stereochemistry, yielding the first total synthesis of (+)-ent-palmyrolide A. Subsequent to this work, the first protecting-group-free total synthesis of natural (-)-palmyrolide A is also reported.     

An approach towards the total synthesis of (+)-epiquinamide and (+)-α-conhydrine from Garner aldehyde

A short and stereoselective route for the synthesis of 1-hydroxyquinolizidine, an advanced synthetic intermediate for the total synthesis of (+)-epiquinamide is presented. The key synthetic steps involve diastereoselective nucleophilic addition on l-serine derived Garner aldehyde and acid mediated (PTSA) ring closing metathesis. The methodology is also elaborated successfully for the total synthesis of (+)-α-conhydrine, an important piperidine alkaloid.     

Total synthesis of (+)-spongistatin 1. An effective second-generation construction of an advanced EF Wittig salt,fragment union,and final elaboration

A stereocontrolled, total synthesis of (+)-spongistatin 1 (1) has been achieved. Union of a second-generation EF Wittig salt (+)-3 with the advanced ABCD aldehyde (-)-4, followed by regioselective macrolactonization and global deprotection afforded (+)-spongistatin 1 (1). The longest linear sequence, 29 steps, proceeded in 0.5% overall yield.     

A formal total synthesis of (+)-apicularen A: base-induced conversion of apicularen-derived intermediates into salicylihalamide-like products

A synthesis of apicularen precursor (-)-6 in 18 steps from D-glucal is reported. As (+)-6 has been converted into the potent, naturally occurring salicylate anti-cancer agent, (-)-apicularen A in 8 steps, this study constitutes a formal total synthesis of (+)-apicularen A. Key steps in the synthetic route include: (i) useful D-glucal elaboration processes, (ii) organometallic displacements at carbohydrate C-6 triflates using Knochel-type and related functionalised, aromatic Grignard reagents, (iii) stereoselective allyltrimethylsilane-acetal reactions generating C-allyl systems, (iv) stereocontrolled aldehyde allylation processes from both substrate and reagent, and (v) a novel Keck-type macrolactonisation. In addition, preliminary studies are reported in which a procedure has been devised to convert apicularen-derived intermediates into salicylihalamide-like products.     

Concise syntheses of coronarin A, coronarin E, austrochaparol and pacovatinin A

Total syntheses of (+)-coronarin A (1), (+)-coronarin E (2), (+)-austrochaparol (3) and (+)-pacovatinin A (4) were achieved from the synthetic (+)-albicanyl acetate (6). Dess-Martin oxidation of (+)-albicanol (5) derived from the chemoenzymatic product (6) gave an aldehyde (7), which was subjected to Julia one-pot olefination using beta-furylmethyl-heteroaromatic sulfones (8 or 9 ) gave (+)-trans coronarin E (2) and (+)-cis coronarin E (12) with high cis-selectivity. The synthesis of (+)-coronarin A (1) from (+)-trans coronarin E (2) was achiev-ed, while (+)-cis coronarin E (12) was converted to the natural products (+)-(5S,9S,10S)-15,16-epoxy-8(17),13(16),14-labdatriene (13) and (+)-austrochaparol (3). By the asymmetric synthesis of (+)-3, the absolute structure of (+)-3 was determined to be 5S, 7R, 9R, 10S configurations. Homologation of (+)-albicanol (5) followed by allylic oxidation gave (7 alpha)-hydroxy nitrile (17), which was finally converted to the natural (+)-pacovatinin A (4) in 8 steps from (+)-albicanol (5).     

Gram-scale synthesis of (+)-spongistatin 1: development of an improved, scalable synthesis of the F-ring subunit, fragment union, and final elaboration

In a quest to develop an effective, scalable synthesis of (+)-spongistatin 1 ( 1), we devised a concise, third-generation scalable synthesis of (+)- 7, the requisite F-ring tetrahydropyran aldehyde, employing a proline-catalyzed cross-aldol reaction. Subsequent elaboration to (+)-EF Wittig salt (+)- 3, followed by union with advanced ABCD aldehyde (-)- 4, macrolactonization and global deprotection permitted access to >1.0 g of totally synthetic (+)-spongistatin 1 ( 1).     

Total Synthesis of (+)-Halichlorine: An Inhibitor of VCAM-1 Expression

The diastereoselective addition of the highly functionalized organozinc compound 1 to the aldehyde 2 in the presence of the chiral amino alcohol 3 (-->4) is a key step in the first total synthesis of (+)-halichlorine. A series of protections/deprotections and a macrolaconization complete the synthesis. Halichlorine selectively inhibits the expression of the cell adhesion molecule VCAM-1. TBS=tert-butyldimethylsilyl.     

First total synthesis of (+)-crassalactone A

A simple and highly efficient first total synthesis of cytotoxic (+)-crassalactone A starting from (R)-mandelic acid is described. The strategy involves the osmium tetroxide-catalyzed cis-hydroxylation and the stereoselective addition of ethyl lithiopropiolate to a chiral aldehyde intermediate as key steps.     

Total synthesis of myxothiazols, novel bis-thiazole beta-methoxyacrylate-based anti-fungal compounds from myxobacteria

Convergent total syntheses of myxothiazols A and Z are described. The syntheses are based on elaboration of the (S)-E,E-diene thioamide 22, conversion of 22 into the bis-thiazole 27 and Wittig reactions between 27c and the aldehyde 30. The substituted beta-methoxyacrylate aldehyde 30 was produced via an Evans asymmetric aldol protocol or via the 2H-pyran-2-one 31. An E-selective Wittig reaction between the ylide derived from the phosphonium salt 27c and the (+)-aldehyde 30 led to (+)-myxothiazol Z (1b), and a corresponding reaction with the (+/-)-acrylamide aldehyde 44 gave (+/-)-myxothiazol A (1a). Complementary studies led to synthesis of the ester 47b, corresponding to myxothiazol R and myxothiazol S.     

Total synthesis of (+)-13-deoxytedanolide

In this communication we describe the first total synthesis of (+)-13-deoxytedanolide, an architecturally complex marine macrolide possessing significant antitumor activity. The cornerstone of the synthesis comprises a highly convergent dithiane coupling used to construct the carbon skeleton, followed by a novel use of the Evans-Tishchenko reduction to oxidize the C(1) aldehyde to an ester in the presence of the oxidatively labile dithiane.     

Total synthesis of (+)-macquarimicin A

The first total synthesis of (+)-macquarimicin A (1), a novel inhibitor of neutral sphingomyelinase (N-SMase) with antiinflammatory activity, has been accomplished. The present work determined the absolute configuration of (+)-1 and revised the C(2)-C(3) geometry to be Z. The synthesis features a transannular Diels-Alder reaction, which constructed the tetracyclic framework stereoselectively, and a convergent and efficient synthetic pathway, which afforded (+)-macquarimicin A (1) in 27 steps (longest linear sequence) with 9.9% overall yield.     

Convergent total synthesis of (+)-mycalamide A

The details of a convergent total synthesis of (+)-mycalamide A are described. Yb(OTf)3-TMSCl-catalyzed cross-aldol reaction conditions are used to synthesize the right segment of mycalamide A. In this reaction, an acid-sensitive aldehyde reacts with methyl trimethylsilyl dimethylketene acetal without epimerization to provide the desired aldol adduct. Additionally, a tetrahydropyran ring, which is the left segment of mycalamide A, is prepared using a novel one-pot delta-lactone formation methodology. Both segments are constructed from a common starting material, d-mannitol. These segments are then coupled in the presence of BuLi, and the functional groups are transformed to complete the synthesis of (+)-mycalamide A.     

Total synthesis of the Securinega alkaloid (-)-secu'amamine A

The first enantioselective total synthesis of the rearranged Securinega alkaloid (-)-secu'amamine A is reported starting from D-proline as the source of absolute chirality. The synthesis requires 15 steps starting from D-proline-derived N-trityl aldehyde 11 and proceeds in approximately 9% overall yield. Key steps include a stereoselective conjugate addition of pyrrolidino enedione 19 to afford indolizidine 24 as the major product and cyclization/lactonization of diketoester 25 to produce tetracycle 26. In addition, 1H NMR NOE studies and X-ray analysis on the synthetic alkaloid have established that the indolizidine moiety is trans-fused.     

Total synthesis and correct absolute configuration of malyngamide U

The enantioselective synthesis of the previously proposed structure of malyngamide U (1) was accomplished in 18 steps from (S)-(+)-carvone. The key steps involved a hydroxymethylation of (S)-(+)-carvone and an asymmetric Henry reaction of aldehyde (+)-5, as well as condensation with the acid 3. The 1H and 13C NMR data of the synthetic compound 1 were not consistent with the data of the reported malyngamide U. The C-2' epimer of compound 1 was therefore synthesized by a similar reaction sequence. While the NMR data of C-2' epimer 23 were in full agreement with those of the reported product, the discrepancy in the specific rotation data suggested the correct structure of malyngamide U should be structure 2, in which the absolute configuration of the amine part was enantiomeric with that in compound 23. Then the correct absolute configuration of revised malyngamide U (2) was confirmed by the similar synthesis from (R)-(-)-carvone.     

The first total synthesis of nakadomarin A

(-)-Nakadomarin A is a member of manzamine alkaloid isolated from a marine sponge and have a unique hexacyclic structure. The first total synthesis of (+)-nakadomarin A, an enantiomer of natural product, has been accomplished from stereochemically defined 4-oxopiperidin-3-carboxylic acid derivative. The synthesis established the structure of nakadomarin A including absolute configuration.     

Synthesis of cystothiazole E and formal syntheses of cystothiazoles A and C by Pd0-catalyzed cross-coupling reactions

The synthesis of the naturally occurring bithiazole (+)-cystothiazole E (1e) is described starting from oxazolidinone 2. It proceeded in 10 steps and an overall yield of 37%. The key reaction of the sequence was a Suzuki cross-coupling between bromobithiazole 4 and the (E)-alkenylboronic acid derived from alkyne 18 (94% yield). Prior to the synthesis, more general investigations related to the cross-coupling of bromobithiazole 4 were undertaken. Whereas Heck reactions failed Suzuki and Stille cross-coupling reactions were successfully conducted. By this means, the alkenylboronic acid derived from alkyne 11 and stannane 12 could be transformed into the corresponding alkenylbithiazoles 13 (92%) and 14 (52%). The Stille cross-coupling of compound 4 and stannane 5 allowed access to aldehyde 21 (97% yield) and paved the way for an alternative route to (+)-cystothiazole E (1e). In addition, aldehyde 21 was transformed into aldol product 22 (72%) which has been used in previous syntheses of cystothiazole A (1a) and C (1c). In this respect, the preparation of compound 21 represents a formal total synthesis of these cystothiazoles.     

A concise enantioselective synthesis of (+)-goniodiol and (+)-8-methoxygoniodiol via Co-catalyzed HKR of anti-(2SR, 3RS)-3-methoxy-3-phenyl-1, 2-epoxypropane

A short, enantioselective synthesis of (+)-goniodiol and (+)-8-methoxygoniodiol, cytotoxic styryllactones, has been achieved in high optical purities (99% ee). The strategy employs Co-catalyzed HKR of racemic anti-(2SR, 3RS)-3-methoxy-3-phenyl-1, 2-epoxypropane and Lewis acid-mediated diastereoselective allylation of aldehyde as chiral inducing key reactions.     

Total synthesis of (+)-thiazinotrienomycin E

[formula: see text] The first total synthesis of (+)-thiazinotrienomycin E (1), member of a novel class of cytotoxic ansamycin antibiotics, has been achieved. The synthesis features a highly efficient construction of the aromatic fragment 3 incorporating TBS protection of the aniline, a significantly improved synthesis of (-)-19, an intermediate employed in our trienomycins A and F total syntheses, application of the Kocienski modified Julia protocol to elaborate the E,E,E-triene subunit, an efficient union of 3 and (+)-4, and Mukaiyama macrolactamization to access the thiazinotrienomycin macrolide.     

Total synthesis and determination of the absolute configuration of coscinosulfate. A new selective inhibitor of Cdc25 protein phosphatase.

The first total synthesis of coscinosulfate 1, a metabolite isolated from a sea sponge, starting from (+)-sclareolide 3 is described. The convergent synthesis strategy relies on the coupling of sulfone 21 with the bromide 26. The sulfone fragment 21 was obtained by successive asymmetric aldol reaction with aldehyde 2 to introduce the stereocenters at C-12 and C-13, followed by one-carbon homologation via Horner-Wadsworth-Emmons olefination. The selective sulfatation at C-12 was accomplished through the quinone intermediate 31 obtained by selective oxidation of hydroquinone 30; this, when followed by reduction, furnished the desired coscinosulfate 1. X-ray analysis of the intermediate aldehyde 18 confirmed the proposed structure.