Total synthesis of (+)-cocaine via desymmetrization of a meso-dialdehyde

[reaction: see text] The total synthesis of (+)-cocaine is described. An extension of the recently reported proline catalyzed intramolecular enol-exo-aldol reaction to a meso-dialdehyde provided the tropane ring skeleton directly with good enantiomeric excess. The meso-dialdehyde was prepared using a 2-azaallyllithium [3 + 2] cycloaddition to generate a cis-2,5-disubstituted pyrrolidine. Overall, the synthesis proceeded in 6.5% yield and 86% ee over 14 linear steps starting from commercially available 3-benzyloxy-1-propanol.     

Total synthesis of (-)-salicylihalamide

A concise total synthesis of the potent cytotoxic marine natural products salicylihalamide A and B (la, b) is reported. Key steps of our approach were the asymmetric hydrogenation reactions of beta-keto esters 18 and 32 catalyzed by [((S)-BINAP)Ru-Cl2]2. NEt3 and the cyclization of the macrolide core by ring closing olefin metathesis (RCM) using the "second-generation" ruthenium carbene complex 24 as the catalyst which bears an imidazol-2-ylidene ligand. The EIZ ratio obtained in this macrocyclization reaction was determined by the protecting groups at the remote phenolic OH group of the cyclization precursor. The elaboration of the resulting cycloalkene 37 into the final target involved a CrCl2-mediated synthesis of vinyliodide 49 which, after deprotection, did undergo a copper-catalyzed cross-coupling process with the (Z,Z)-configurated carboxamide 42 to form the labile enamide moiety of 1. Compound 42 was derived from a palladium-catalyzed Negishi coupling between butynylzinc chloride and 3-iodoacrylate 39 followed by a Lindlar reduction of enyne 40 thus obtained and a final aminolysis of the ester group.     

Total synthesis of (-)-borrelidin

The total synthesis of borrelidin has been achieved. The best feature of our synthetic route is SmI(2)-mediated intramolecular Reformatsky-type reaction for macrocyclization after esterification between two segments. The two key segments were synthesized through chelation-controlled carbotitanation, chelation-controlled hydrogenation, stereoselective Reformatsky reaction, and MgBr(2).Et(2)O-mediated chelation-controlled allylation. [reaction: see text]     

Total synthesis of (-)-pironetin

[structure: see text] The asymmetric total synthesis of pironetin, a compound that shows plant growth regulatory activity, immunosuppressive as well as a remarkable antitumoral activity, is described. The approach involves the use of three very efficient Evans oxazolidinone-mediated syn-aldol condensations, a high-yielding coupling between lithium acetylide ethylenediamine complex and a tosylate followed by methylation, and selective reduction to establish the C12-C13 (E) double bond.     

Total synthesis of (-)-kendomycin

An enantioselective synthesis of (-)-kendomycin is described and is based on the application of the organosilane-based [4 + 2]-annulation strategy for the assembly of the C1a-C10 fragment. An underutilized samarium(II) iodide-assisted cyclization (intramolecular Barbier-type reaction) is employed to afford the protected macrocycle.     

Total synthesis of (-)-histrionicotoxin

A total synthesis of (-)-histrionicotoxin was achieved. Our synthesis features preparation of a pseudosymmetrical dienyne through chirality transfer from an allenylsilane, a dienyne metathesis to produce the bicyclo [5.4.0] system in optically active form, selective functionalization of a diene via a 5-exo-trig iodoetherification, and an asymmetric propargylation.     

Total synthesis of (-)-lemonomycin

When life gives you lemons: An efficient and convergent enantioselective total synthesis of (-)-lemonomycin, which shows potent activity against methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococcus faecium (VREF), is presented. The key reaction steps are a Hosomi-Sakurai-type cyclization, a thermodynamically controlled Pictet-Spengler reaction, and a glycosidation reaction with lemonose.     

Total synthesis of (-)-ratjadone

[reaction in text] A convergent asymmetric synthesis of (-)-ratjadone (1) has been achieved, confirming the assignments of stereochemistry for the naturally occurring antifungal metabolite.     

Total synthesis of (-)-dysiherbaine

The enantioselective synthesis of (-)-dysiherbaine (1) has been established with efficiency via a unique synthetic strategy involving the desymmetrization of 2-substituted glycerol to install a quaternary chiral carbon, which induces further stereochemistry in the bicyclic perhydrofuropyran through mercuriocyclization and epoxidation.     

Total synthesis of (-)-dendrobine

Cascading to alkaloids: An 18-step total synthesis of (-)-dendrobine is based on a reaction cascade with a key amine group (see scheme, Bn=benzyl). The amine is the initiator of the cascade and provides an efficient method for installing the stereocenters at C11 and C3. The overall transformation occurs stereoselectively only when the conversion is carried out without the isolation of intermediates.     

Total synthesis of (-)-raumacline

The total synthesis of (-)-raumacline from L-tryptophan was achieved, featuring a cis-specific Pictet-Spengler reaction, a stereoselective Dieckmann cyclization, and an epimerization step that allowed complete stereocontrol of five chiral centres.     

Total synthesis of (-)-anisatin

A novel synthetic route to (-)-anisatin has been developed. Our synthesis features a rhodium-catalyzed 1,4-addition of an arylboronic acid, an intramolecular Diels-Alder reaction of an ortho-quinone monoketal, a stereoselective [2,3]-Wittig rearrangement, and construction of the oxabicyclo [3.3.1] skeleton via cleavage of an epoxide by a primary amide.     

Total synthesis of (-)-stemonine

[reaction: see text] An enantioselective total synthesis of (-)-stemonine (1) is reported via a convergent assembly of the acyclic precursor 2. Key transformations include a Staudinger-aza-Wittig reaction to form the central perhydroazepine ring system and an iodine-induced tandem cyclization to construct the pyrrolidino-butyrolactone framework.     

Total synthesis of (-)-stemospironine

[structure: see text]. A stereocontrolled total synthesis of the polycyclic Stemona alkaloid, (-)-stemospironine (1) has been achieved. Key transformations include the use of a Staudinger reaction leading to the aza-Wittig ring closure of the perhydroazepine system. Formation of the vicinal pyrrolidine butyrolactone is described via the stereoselective intramolecular capture of an intermediate aziridinium salt.     

Total synthesis of (-)-diversifolin

First total synthesis of biologically active germacrane-type sesquiterpene (−)-diversifolin has been achieved. The features of the synthesis involve (i) ring-closing metathesis to give a 10-membered carbocycle, (ii) regioselective Mukaiyama aldol reaction of silyl dienol ether with formaldehyde at the α-position, and (iii) lactone transposition of the fully functionalized 11-oxabicyclo[6.2.1]undecane system.