A synthesis of (+)-saxitoxin

An asymmetric synthesis of the bis-guanidinium poison, (+)-saxitoxin (STX), is described. Commencing from an N,O-acetal starting material made readily available through sulfamate ester C-H amination, the completed route to STX showcases the utility of oxathiazinane dioxide heterocycles for the assembly of polyfunctionalized amine derivatives. In the final preparative stages, an unusual nine-membered ring guanidine intermediate is oxidized selectively and made to undergo dehydrative cyclization to afford the tricyclic core of the natural product. Access to STX and related structures will provide unique pharmacological tools for the study of voltage-regulated Na+ ion channel proteins.     

Development of a stereoselective practical synthetic route to indolmycin, a candidate anti-H. pylori agent.

A stereoselective practical synthetic route to indolmycin is described. The route is composed of the regioselective coupling of indolyl magnesium halide with a trans-epoxy ester, diastereoselective oxazolone ring formation with guanidine and amine exchange reaction with methylamine. In the coupling step, use of dichloromethane as co-solvent and conversion of the resulting hydroxy ester to the hydroxy acid for purification, make this process efficient and practical. The oxazolone ring is formed in good yield without epimerization at the C5 position by treatment with guanidine and potassium tert-butoxide in tert-butanol at room temperature. In the final step, the amino group is efficiently converted to the methylamino group in aqueous methylamine solution at 5 degrees C. After examination of the route with racemates, indolmycin was synthesized stereoselectively in 22% total yield from optically active trans-epoxy ester. This route was applied to the preparation of the metabolites of indolmycin.     

An Expeditious Route for the Total Synthesis of Pondaplin Isolated from Annona glabra

A novel cyclic prenylated phenylpropanoid, pondaplin 1, was first synthesized in 26% overall yields through an expeditious route (7 steps) that employed highly regio- and stereoselective phenyltellurenylation to arylacetylene and palladium (Ⅱ) chloride-catalyzed carbonylation of hydroxy styryl phenyl telluride as key steps.     

Synthesis of the dysiherbaine tetrahydropyran core utilizing improved tethered aminohydroxylation conditions

A concise stereoselective route to the dysiherbaine tetrahydropyran core was achieved in nine steps and 39% overall yield. Donohoe’s improved tethered aminohydroxylation conditions were employed to concurrently install the amino and alcohol groups and construct the tetrahydropyran ring, which features four contiguous cis-stereocenters.     

New stereoselective route to the epoxyquinol core of manumycin-type natural products. Synthesis of enantiopure (+)-bromoxone, (-)-LL-C10037 alpha, and (+)-KT 8110

A practical route is decribed for the preparation of the C(7)N core of manumycin-type compounds. Starting from p-benzoquinone, optically pure compounds in both forms can be prepared via enzymatic resolution of a derived diacetoxy conduritol. A diepoxy aminoinositol is accessible which can function for formation of enantiopure epoxyquinones and quinols. Examples are given for acylation reactions of this amine with several acyl derivatives. With this approach (-)-LL-C10037alpha and quinones such as (+)-KT-8110 with 5R,6S-configuration can be synthesized through oxidation. In addition a short route to (+)-bromoxone is described. Most steps include simple epoxide formation and cleavage reactions which all can be carried out in a high stereoselective manner.     

Nitrone [2+3]-cycloadditions in stereocontrolled synthesis of a potent proteasome inhibitor: (-)-omuralide

A new stereocontrolled synthetic route to omuralide has been developed from methyl pyroglutamate. This route involves regio- and stereoselective N-methylnitrone 1,3-dipolar cycloadditions to appropriate pyrrolinones, beta-eliminations, and highly selective hydrogenations as the main steps.     

Stereoselective total synthesis of (+)-aspicilin

A stereoselective synthesis of (+)-aspicilin is described. Regio- and stereoselective functionalization by intramolecular participation of the sulfinyl group, ene reaction, and macrolactonization by Wadsworth-Emmons reaction employing Masamune-Roush protocol are the key steps of the route.     

Concise and stereoselective synthesis of the N7-C25 fragment of psymberin

[reaction: see text] The N7-C25 fragment of the potent and selective cytotoxic agent psymberin has been prepared through a short (12 linear steps, 15 total steps) and stereoselective sequence. Highlights of this route include a very rapid construction of the pentasubstituted arene, a substrate-controlled diastereoselective fragment coupling using a Mukaiyama aldol reaction, and an efficient entry into a key tetrahydropyranyl cyanide.     

Total synthesis of (+)-batzelladine A and (-)-batzelladine D, and identification of their target protein

Asymmetric total synthesis of batzelladine A (1) and batzelladine D (2) has been achieved. Our synthesis of batzelladines features 1) stereoselective construction of the cyclic guanidine system by means of successive 1,3-dipolar cycloaddition reaction and subsequent cyclization, 2) direct esterification of the bicyclic carboxylic acid 35 with the guanidine alcohol 8 or 59 to construct the whole carbon skeleton of batzelladines, and 3) one-step formation of the alpha,beta-unsaturated aldehyde 53 from the primary alcohol 47 with tetra-n-propylammoniumperruthenate (TPAP), providing an efficient route to the left-hand bicyclic guanidine alcohol of batzelladine A (1). With the synthetic compounds 1 and 2 in hand, their target protein was examined by using immobilized CD4 and gp120 affinity gels. The results indicated that batzelladines A (1) and D (2) bind specifically to CD4.     

Utility of the ammonia-free Birch reduction of electron-deficient pyrroles: total synthesis of the 20s proteasome inhibitor, clasto-lactacystin beta-lactone

A new synthesis of the 20S proteasome inhibitor clasto-lactacystin beta-lactone is described. Our route to this important natural product involves the partial reduction of an electron deficient pyrrole as a key step. By judicious choice of enolate counterion, we were able to exert complete control over the stereoselectivity of the reduction/aldol reaction. Early attempts to complete the synthesis by using a C-4 methyl substituted pyrrole are described in full, together with our attempts to promote regioselective elimination of a tertiary alcohol. The lessons learnt from this first approach led us to develop another, and ultimately successful, route that introduced the C-4 methyl group at a late stage in the synthesis. Our successful route is then described and this contains several highly stereoselective steps including a cis-dihydroxylation and an enolate methylation. The final synthesis proceeds in just 13 steps and in 15 % overall yield making it an extremely efficient route to this valuable compound.     

A stereoselective synthesis of (+/-)-C-secolimonoid BCDE model compounds related to the insect antifeedant ohchinolide.

A short and stereoselective synthesis of a (+/-)-BCDE C-secolimonid model insect antifeedant related to ohchinolide and nimbolidin was accomplished in 13 (30% overall yield) and 15 (30% overall yield) steps, respectively, from ethyl drimanate. The key steps are the torquoselective electrocyclization of the divinyl ketone 6, induced by perchloric acid, and the stereoselective rearrangement of the hydroxy lactone 12, inspired in a biosynthetic proposal. An alternative route, which provides access to (+/-)-BCDE ohchinolide and nimbolidin isomers, is also described.     

Synthesis of (-)-deoxypukalide, the enantiomer of a degradation product of the furanocembranolide pukalide.

A convergent stereoselective synthesis of (-)-deoxypukalide is described. This substance has not yet been found in Nature but is obtained through deoxygenation of pukalide, the first naturally occurring furanocembrane to be structurally elucidated. The route features a new intraannular furan synthesis that entails treatment of a 4-oxopropargylic beta-keto ester with silica gel. The product of this novel reaction, a 3-carboxy 2,5-bridged furan, is formed in 96% yield. The synthetic strategy was strongly directed by molecular mechanics calculations, which provided valuable insight into stereodefining steps including double bond stereochemistry and butenolide configuration.     

Enantioselective total synthesis of batzelladine F and definition of its structure

Batzelladine F (1) was synthesized in enantioselective and stereoselective fashion in 15 steps (longest linear sequence) and 1.7% overall yield from two readily available enantioenriched beta-hydroxy esters, methyl (R)-3-hydroxydecanoate and methyl (R)-3-hydroxybutyrate. Tethered Biginelli condensations are used to assemble both tricyclic guanidine fragments, with the second tethered Biginelli condensation (14 + 16 --> 17) also being employed to join the guanidine fragments. Three diastereomers of batzelladine F, 2-4, were prepared also. A combination of HPLC, optical rotation and CD spectroscopy was employed to distinguish stereoisomers 1-4, proving that 1 is the correct structure of the hexacyclic marine alkaloid batzelladine F.     

Efficient synthesis of IPL576,092: a novel anti-asthma agent

An enantioseletive synthesis of the novel anti-asthma agent IRL576,092 (2) is described. The synthetic route developed involves stereoselective 1,2-reduction of the enone carbonyl functionality of 6 and subsequent hydroboration as the key steps. Starting from the commercially available 5-androsten-3beta-ol-17-one 3, this approach affords IPL576,092 (2) in nine steps with overall yields of 25%, employing a limited number of chromatographic steps.     

A cross-metathesis route to the 5-F(2)-isoprostanes

A library of eight 5-F(2)-isoprostanes was prepared through a ring-opening metathesis/cross-metathesis protocol between functionalized bicyclo[3.2.0]heptenes, ethylene, and alpha,beta-unsaturated ketones. This sequence provided racemic enones in a regio- and stereoselective fashion that could be converted to enantiomerically enriched allylic alcohols through a catalyst-controlled asymmetric reduction. Completion of the sidechains, followed by global deprotection, resulted in a stereodivergent route to eight enantiomerically enriched 5-F(2)-isoprostanes. Overall, the synthesis of this library of known and anticipated lipid oxidation metabolites was achieved in 10 steps from commercially available 4-hydroxy-2-cyclopentenone.     

Stereoselective synthesis of Nuphar quinolizidine alkaloid, (−)-deoxynupharidine

A stereoselective synthetic route to Nuphar quinolizidine alkaloid, (−)-deoxynupharidine, was established by employing reductive carbon-nitrogen bond cleavage, followed by simultaneous recyclization of a proline derivative with samarium diiodide, and an intramolecular ring-closing metathesis, as the key steps.     

Synthesis of (R)‐3‐(tert‐Butoxycarbonylamino)‐4‐(2,4,5‐trifluorophenyl)butanoic Acid,a Key Intermediate,and the Formal Synthesis of Sitagliptin Phosphate

An alternate formal synthesis of Sitagliptin phosphate is disclosed from 2,4,5‐trifluorobenzadehyde in 8 linear steps with an overall yield of 31%. The chiral β‐amino acid moiety present in sitaglitpin is installed via an asymmetric hydrogenation followed by a stereoselective Hofmann rearrangement as the key steps. The key chiral intermediate Boc‐amino acid 1 prepared by this novel route was further converted to Sitagliptin phosphate following the known literature protocol.     

De novo asymmetric syntheses of muricatacin and its analogues via dihydroxylation of dienoates

A short and highly efficient route to both enantiomers of muricatacin as well as the C-5-epimer has been developed. The key to the overall transformation is the highly regio- and enantioselective Sharpless asymmetric dihydroxylation of an (E,Z)-dienoate. The highly efficient stereoselective synthesis prepares (-)-muricatacin in seven steps and 66% overall yield.     

Highly stereoselective and efficient total synthesis of (+)-laurencin

A highly stereoselective and efficient asymmetric total synthesis of (+)-laurencin (1) has been accomplished from the known oxazolidinone 5 in 15 steps. The route features an efficient internal alkylation to form oxocene 3 from 4 and a novel use of acetonitrile anion as a two-carbon acetaldehyde equivalent for direct synthesis of ketone 2 from alpha-alkoxy amide 3.     

A new and efficient strategy for the synthesis of podophyllotoxin and its analogues

[structure: see text]. An efficient and stereoselective strategy for the total synthesis of podophyllotoxin was developed. This route leads to podophyllotoxin 1 in only 12 steps with 29% overall yield. A notable feature of this synthetic strategy is the use of the cascade addition-alkylation to ensure the key C1-C2 stereochemistry that is pivotal for the synthesis of podophyllotoxin.