Asymmetric synthesis of (+)-1-epiaustraline and attempted synthesis of australine

A diastereoselective synthesis of the pyrrolizidine alkaloid, (+)-1-epiaustraline has been achieved via a diastereoselective syn-dihydroxylation of a pyrrolo[1,2-c]oxazol-3-one precursor that was readily prepared by a RCM reaction. Attempts to extend this methodology to the synthesis of australine were not successful since the final pyrrolidine ring closure to produce the desired pyrrolizidine of the target molecule was not productive.     

Toward the total synthesis of elisapterosin B: A Hg(OTf)(2)-promoted diastereoselective intramolecular Friedel-Crafts alkylation reaction

As part of an approach to the synthesis of the antitubercular agent elisapterosin B, we prepared two different chiral, non-racemic olefinic substrates and examined their diastereoselective ring closure using mercury salts. The effort yielded potential precursors to elisapterosin B in good yield with good to excellent diastereocontrol.     

Stereoselective synthesis by double reductive amination ring closure of novel aza-heteroannulated sugars

We present here the stereoselective synthesis of a series of 2/3-N-pyrrolidine derivatives of glycosides produced by diastereoselective double reductive amination ring closure of 1,4-dicarbonyl compounds. These precursors were produced by tandem ozonolysis-reduction or Wacker oxidation of known alkenes. The potential of these new compounds as glycosidase inhibitors is illustrated for compound 16, showing selective inhibition of β-d-galactosidase.     

Asymmetric synthesis of (-)-swainsonine, (+)-1,2-di-epi-swainsonine,and (+)-1,2,8-tri-epi-swainsonine

The asymmetric synthesis of (-)-swainsonine via a nonchiral pool route that involves the Sharpless epoxidation to induce chirality is reported. The key steps involve vinyl epoxide aminolysis, ring-closing metathesis, and intramolecular N-alkylation to prepare the indolizidine ring and a highly diastereoselective cis-dihydroxylation using AD-mix-alpha. This synthetic strategy also allowed for the diastereoselective synthesis of (+)-1,2-di-epi-swainsonine and (+)-1,2,8-tri-epi-swainsonine.     

Enantioselective synthesis of (+)-crocacin C. An example of a highly challenging mismatched double asymmetric δ-stannylcrotylboration reaction

A concise, enantioselective synthesis of (+)-crocacin C is described, featuring a highly diastereoselective mismatched double asymmetric δ-stannylcrotylboration of the stereochemically demanding chiral aldehyde 9 with the bifunctional crotylborane reagent (S)-E-10. The total synthesis of (+)-crocacin C was accomplished in seven steps (longest linear sequence) starting from commercially available precursors.     

Asymmetric synthesis of (+)-allo-quercitol and (+)-talo-quercitol via free radical cycloisomerization of an enantiomerically pure alkyne-tethered aldehyde derived from a carbohydrate.

We describe for the first time the free radical cyclization of enantiomerically pure alkyne-tethered aldehydes obtained from a carbohydrate (6, 7). The synthesis of compounds 6 and 7 obtained from a derivative of D-ribose is reported. These radical precursors have been submitted to cyclization with tributyltin hydride plus azobisisobutyronitrile to yield, after ring closure, two carbocycles, respectively. These carbocycles have been obtained as mixtures of E and Z vinyltin isomers, but with excellent diastereoselection at the new stereocenter formed during the ring closure. After protodestannylation, only one diastereomer was detected and isolated. The absolute configuration at the new stereocenter formed during the carbocyclization has been established by detailed (1)H NMR analysis. The specific transformation of 7-methoxymethoxy-2,2-dimethyl-4-methylene-5-tert-butyldimethylsilyloxy-(3aR,5S,7S,7aS)-perhydrobenzo[d][1,3]dioxole into optically pure (+)-allo-quercitol and (+)-talo-quercitol is described. From these results, we conclude that under an appropriate choice of radical precursors and conditions, the synthesis of highly functionalized cyclohexane derivatives of biological interest is now available.     

Total synthesis of (+)-allocyathin B2

The first enantioselective synthesis of (+)-allocyathin was achieved. The synthesis features a Pd-catalyzed asymmetric allylic alkylation to install the first quaternary center, a Ru-catalyzed diastereoselective cycloisomerization to construct the six-membered ring, and a diastereoselective hydroxylative Knoevenagel reaction to introduce the final hydroxyl group. The unusual olefin isomerization of the Ru-catalyzed cycloisomerization was discussed and exploited for the synthesis.     

Total synthesis of (+)-pinnatoxin A

A convergent enantioselective total synthesis of (+)-pinnatoxin A is described. The synthesis capitalizes on the highly diastereoselective Ireland-Claisen rearrangement of an acyclic alpha-branched allylic ester to set the quaternary stereogenic center at the core of the spiroimine ring system along with the adjacent tertiary stereocenter. The all-carbon macrocyclic ring system was formed by ring-closing metathesis.     

A highly diastereoselective oxa-Pictet-Spengler approach to (+)-astropaquinone B and (+)-astropaquinone C and the formation of astropaquinone B dimer

A concise and highly diastereoselective synthesis of (+)-astropaquinone B and (+)-astropaquinone C is reported. The synthetic strategy is based on an efficient combination of Dötz benzannulation using a chiral alkyne to construct the naphthalene unit and a highly diastereoselective oxa-Pictet-Spengler reaction to install the trans-configured pyran ring as the key steps.     

Flexible strategy for the synthesis of pyrrolizidine alkaloids

A general strategy for the production of pyrrolizidine alkaloids is described, starting from intermediate (+)-9. The key features are diastereoselective dihydroxylation, inversion at the ring junction by hydroboration of an enamine, and ring closure to form the bicyclo ring system. This route is attractive because of its brevity and versatility; four natural products were prepared with differing stereochemistry and substitution patterns. Finally, this work allowed assignment of the absolute stereochemistry of 2,3,7-triepiaustraline and hyacinthacine A 7.     

A Divergent Synthetic Route to the Vallesamidine and Schizozygine Alkaloids: Total Synthesis of (+)‐Vallesamidine and (+)‐14,15‐Dehydrostrempeliopine

The total synthesis of representative members of the schizozygine alkaloids, (+)‐vallesamidine and (+)‐14,15‐dehydrostrempeliopine, were completed from a late‐stage divergent intermediate. The synthesis took advantage of efficient nitro‐group reactions with the A/B/C ring skeleton constructed concisely on a gram scale through an asymmetric Michael addition, nitro‐Mannich/lactamisation, Tsuji–Trost allylation, and intramolecular C?N coupling reaction. Other key features of the synthesis are a novel [1,4] hydride transfer/Mannich‐type cyclisation to build ring E and a diastereoselective ring‐closing metathesis reaction to construct ring D. This approach gave access to a late‐stage C14,C15 alkene divergent intermediate that could be simply transformed into (+)‐vallesamidine, (+)‐14,15‐dehydrostrempeliopine, and potentially other schizozygine alkaloids and unnatural derivatives.     

An asymmetric route to total synthesis of the furano lignan (+)-veraguensin

Total synthesis of the furano lignan (+)-veraguensin is described. The key steps involve a diastereoselective aldol-type condensation of an ester enolate having an α-chiral center with an aromatic aldehyde and a novel isomerization of the syn vicinal substituents on the furan ring via a ring opening-ring closing protocol.     

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.     

Enantioselective total synthesis of (-)- and (+)-petrosin

The enantioselective total synthesis of (-)- and (+)-petrosin is described. The union of two key segments was executed by Suzuki-Miyaura coupling. The quinolizidine rings were stereoselectively constructed via a diastereoselective Mannich reaction and an aza-Michael reaction. The 16-membered ring was constructed by ring-closing metathesis with the second-generation Grubbs catalyst.     

An asymmetric synthesis of (+)-monomorine I

The synthesis of (+)-monomorine I, an indolizidine alkaloid isolated from Monomorium pharaonis, has been achieved. The 2,6-cis-piperidine ring moiety of (+)-monomorine I was constructed using diastereoselective aminopalladation. Chain elongation via cross-metathesis using Hoveyda-Grubbs 2nd catalyst followed by deprotection of the Cbz group and cyclic reductive hydroamination afforded (+)-monomorine I.     

Synthetic studies on (+)-manzamine A: stereoselective synthesis of the tetracyclic core framework

The stereoselective synthesis of the tetracyclic intermediate 3 for (+)-manzamine A (1) has been achieved. The key features of this stereoselective synthesis of 3 are the Rh-catalyzed asymmetric hydrogenation and a diastereoselective intermolecular Diels-Alder reaction. The 8-membered ring is efficiently constructed utilizing our Ns-strategy.     

Enantiodivergent synthesis of (+)- and (−)-isolaurepan

The enantiodivergent synthesis of (+)-and (?)-isolaurepan was achieved from a common chiral template easily available from tri-O-acetyl-d-glucal, using as key step a diastereoselective thermal Claisen rearrangement, combined with a ring expansion reaction using trimethylsilyldiazomethane.     

Stereocontrolled total synthesis and biological evaluation of (−)- and (+)-petrosin and its derivatives

Total synthesis of (−)- and (+)-petrosin was accomplished. Stereocontrolled construction of the quinolizidine ring was achieved through a diastereoselective Mannich reaction and an aza-Michael reaction. Head-to-tail dimerization was performed by assembly of the two monomers using Suzuki–Miyaura cross coupling and subsequent ring-closing metathesis to construct the 16-membered ring. Biological evaluation of synthetic (−)- and (+)-petrosin and its derivatives indicated that the bispiperidine structure was necessary for the inhibition of syncytium formation.     

Total synthesis of the ristocetin aglycon

The first total synthesis of the ristocetin aglycon is described employing a modular and highly convergent strategy. An effective 12-step (12% overall) synthesis of the ABCD ring system 3 from its amino acid subunits sequentially features an intramolecular aromatic nucleophilic substitution reaction for formation of the diaryl ether and closure of the 16-membered CD ring system (65%), a respectively diastereoselective (3:1, 86%) Suzuki coupling for installation of the AB biaryl linkage on which the atropisomer stereochemistry can be further thermally adjusted, and an effective macrolactamization (51%) for closure of the 12-membered AB ring system. A similarly effective 13-step (14% overall) synthesis of the 14-membered EFG ring system 4 was implemented employing a room-temperature intermolecular S(N)Ar reaction of an o-fluoronitroaromatic for formation of the FG diaryl ether (69%) and a key macrolactamization (92%) with formation of the amide linking residues 1 and 2. The two key fragments 3 and 4 were coupled, and the remaining 16-membered DE ring system was closed via diaryl ether formation to provide the ristocetin tetracyclic ring system (15 steps, 8% overall) enlisting an unusually facile (25 degrees C, 8 h, DMF, >/=95%) and diastereoselective (>/=15:1) aromatic nucleophilic substitution reaction that benefits from substrate preorganization.     

Total synthesis of (+)-asperazine

The first total synthesis of the structurally novel cyclotryptophan alkaloid asperazine is reported. The central step in the synthetic sequence is a diastereoselective intramolecular Heck reaction in which the substituent controlling stereoselection is external to the ring being formed. This synthesis confirmed the structure of (+)-asperazine (1) proposed by Crews and co-workers and provided material for additional biological studies. The in vitro cytotoxicity originally reported for the marine isolate was not confirmed with synthetic (+)-asperazine.