Enantioselective synthesis of (-)-dihydrocodeinone: a short formal synthesis of (-)-morphine

[reaction: see text] The radical cyclization approach to the morphine alkaloids has been applied in an asymmetric synthesis of (-)-dihydrocodeinone. A chiral cyclohexenol (R-32), from the CBS reduction of the enone, is the source of chirality. The first key step, tandem closure in which stereochemistry is controlled by geometric constraints, (-)-15b --> (+)-16, was followed by an unprecedented reductive hydroamination, completing the synthesis of (-)-dihydroisocodeine ((-)-17) in 13 steps from commercially available materials.     

Straightforward synthesis of (R)-(-)-kjellmanianone

A direct route to enantiomerically pure (-)-kjellmanianone is reported. The synthesis involves a cerium-catalyzed alpha-hydroxylation and an enzyme-catalyzed procedure to resolve tertiary alcohols at key stages. The intermediate beta-oxo ester was alpha-hydroxylated to give good yields of racemic kjellmanianone. The resolution of the racemic material was achieved by enzymatic saponification, followed by a chemical decarboxylation sequence to give enantiopure (-)-kjellmanianone with 99 % ee. Bromination then afforded the (-)-bromo derivative, whose X-ray structure provided evidence for the R configuration of (-)-kjellmanianone.     

Total synthesis of (-)-bafilomycin A(1)

A highly stereoselective total synthesis of (-)-bafilomycin A(1), the naturally occurring enantiomer of this potent vacuolar ATPase inhibitor, is described. The synthesis features the highly stereoselective aldol reaction of methyl ketone 8b and aldehyde 60c and a Suzuki cross-coupling reaction of the highly functionalized advanced intermediates 12 and 39. Vinyl iodide 12 was synthesized by a 14-step sequence starting from the readily available beta-alkoxy aldehyde 14, while the vinylboronic acid component 39 was synthesized by a nine-step sequence from beta-hydroxy-alpha-methyl butyrate 44 via a sequence involving the alpha-methoxypropargylation of chiral aldehyde 49 with the alpha-methoxypropargylstannane reagent 54. Syntheses of fragments 12 and 39 also feature diastereoselective double asymmetric crotylboration reactions to set several of the critical stereocenters. The Suzuki cross-coupling of 12 and 39 provided seco ester 40, which following conversion to the seco acid underwent smooth macrolactonization to give 41. The success of the macrocyclization required that C(7)-OH be unprotected. The Mukaiyama aldol reaction between aldehyde 60c and the TMS enol ether generated from 8b provided aldol 65 with high diastereoselectivity. Finally, all silicon protecting groups were removed by treatment of the penultimate intermediate 65 with TAS-F (tris(dimethylamino)sulfonium difluorotrimethylsilicate), thereby completing the total synthesis of (-)-bafilomycin A(1).     

An expedient total synthesis of (-)-dactylolide and formal synthesis of (-)-zampanolide

[reaction: see text] A highly convergent and efficient total synthesis of (-)-dactylolide and formal synthesis of (-)-zampanolide is reported.     

Palladium(II)-catalyzed asymmetric synthesis of (Z)-alpha-alkylidene-gamma-butyrolactams from (Z)-N-allylic 2-Alkynamides. Total synthesis of (-)-isocynometrine

Pd(OAc)2 combined with nitrogen-containing ligands catalyzed the cyclization of (Z)-N-allylic 2-alkynamides in acetic acid to afford the alpha-(Z)-acetoxyalkylidene-gamma-butyrolactams in high yield and high stereoselectivity. When chiral nitrogen-containing ligands were used, the catalytic asymmetric protocol was achieved with moderate enantioselectivity (up to 80 degrees C). The utility of this new methodology was exemplified by the total synthesis of (-)-isocynometrine.     

Total synthesis of (-)-aplaminal

The total synthesis and assignment of absolute configuration of (-)-aplaminal ( 1), a cytotoxic metabolite from a sea hare possessing a triazobicyclo[3.2.1]octane skeleton, has been achieved. The synthesis entailed condensation of a monoprotected diamine ( 3) with dimethyl 2-oxomalonate ( 4) to generate the imidazolidine core ( 2). Introduction of the third nitrogen via Mitsunobu activation and azide displacement, followed by reduction and lactam formation (AlMe 3), furnished (-)-aplaminal ( 1). Overall, the synthesis entailed 9 steps and proceeded in 19% overall yield.     

Total synthesis of (-)-himgaline

The first total synthesis of (-)-himgaline and a highly enantioselective synthesis of its congener (-)-GB 13 are described. Decarboxylative aza-Michael reaction of the hexacyclic lactone precursor under acidic conditions, followed by basic workup, yielded (-)-GB 13 in 80% yield. Cyclization of (-)-GB 13 to oxohimgaline under acidic conditions, followed by internally coordinated sodium triacetoxyborohydride reduction, gave (-)-himgaline as the exclusive product.     

Total synthesis of (R)-telomestatin

We have achieved a total synthesis of telomestatin, and its absolute configuration was determined to be (R). Coupling of cysteine-containing trisoxazole amine and serine-containing trisoxazole carboxylic acid, followed by macrocyclization, provided a 24-membered diamide. The seventh oxazole ring was formed by a Shin's procedure via dehydroamide. Cyclodehydration of a modified (R)-cysteine-(S-(t)Bu) moiety using Kelly's method (PPh3(O)-Tf2O) with anisole furnished (R)-telomestatin, whose CD spectrum was in good agreement with that of the natural product.     

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.     

Enantioselective synthesis of (-)-pentalenene

A short, enantioselective synthesis of (-)-pentalenene is described. Catalytic enantioselective cyclopropenation with (R,R)-Rh2(OAc)(DPTI)3 was used to set the absolute stereochemistry, and an intramolecular Pauson-Khand reaction of the resulting cyclopropenyne was used to establish the quaternary center.     

Total synthesis of (-)-gambierol

The first total synthesis of (-)-gambierol (1), a marine polycyclic ether toxin, has been achieved. Key features of the successful synthesis include (1) a convergent union of the ABC and EFGH ring fragments (5 and 6, respectively) via our developed B-alkyl Suzuki-Miyaura cross-coupling strategy leading to the octacyclic polyether core 4 and (2) a late-stage introduction of the sensitive triene side chain by use of Pd(PPh(3))(4)/CuCl/LiCl-promoted Stille coupling. The ABC ring fragment 5 was synthesized in a linear manner (B --> AB --> ABC), wherein the A ring was formed by intramolecular hetero-Michael reaction and the C ring was constructed via 6-endo cyclization of hydroxy epoxide 7. An improved synthetic entry to the EFGH ring fragment 6 is also described, in which SmI(2)-induced reductive cyclization methodology was applied to the stereoselective construction of the F and H rings, leading to 6 with remarkable overall efficiency. Stereoselective hydroboration of 5 and subsequent Suzuki-Miyaura coupling with 6 provided endocyclic enol ether 45 in high yield, which was then converted to octacyclic polyether core 4. Careful choice of the global deprotection stage was a key element for the successful total synthesis. Functionalization of the H ring and global desilylation gave (Z)-vinyl bromide 2. Finally, cross-coupling of 2 with (Z)-vinyl stannane 3 under Corey's Pd(PPh(3))(4)/CuCl/LiCl-promoted Stille conditions completed the total synthesis of (-)-gambierol (1).     

Total synthesis of (±)-alliacolide

A total synthesis of the unique epoxy-lactone alliacolide (3), featuring a novel, stereoselective intramolecular radical cyclisation onto an enolic double-bond, $\text{viz}$ (13) → (14), as a key step, is described.     

Transition-metal-catalyzed synthesis of diboranes(4)

The diboranes(4) bis(catecholato)diborane (B(2)Cat(2)) and bis(pinacolato)diborane (B(2)Pin(2)) are important precursors for organoboronic esters, which are versatile reagents for the formation of carbon-carbon bonds. A new catalytic synthesis for these compounds starts from catecholborane or pinacolborane and gives the dehydrocoupling products B(2)Cat(2) and B(2)Pin(2) with turnover numbers of up to 11,600 (see scheme).     

Total synthesis of (-)-laulimalide

(-)-Laulimalide (1), a structurally novel macrolide isolated in trace amounts from marine sponges, promotes abnormal tubulin polymerization and apoptosis in vitro, with a similar mode of action to that of Taxol(R), but with potentially less susceptibility to multidrug resistance. Herein, a flexible and convergent asymmetric synthesis of (-)-laulimalide is described. This synthesis featured a highly diastereoselective Sakurai reaction of 2 with 3 and a regioselective macrolactonization of an unprotected vicinal diol. Laulimalide was synthesized in 25 steps (longest linear; 36 overall) in 3.5% overall yield, providing a uniquely short and efficient route to 1 and its analogues.     

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 (-)-strychnine

Total synthesis of (-)-strychnine is described. Notable features of our synthesis include (1) palladium-catalyzed coupling of the indole and vinyl epoxide moieties, (2) synthesis of the nine-membered cyclic amine derivative from the diol precursor in a one-pot procedure, and (3) transannular cyclization of the nine-membered cyclic amine.     

Total synthesis of (±)-surugatoxin

Total synthesis of surugatoxin 1, isolated from the toxic Japanese ivory shell ($\text{Babylonia japonica}$), was achieved from 6-bromoisatin by stepwise ring construction involving two key steps: the stereospecific cyclization (9→10) and hydration (17→1).     

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 (-)-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.     

(一)-莪术二酮的全合成

(+)-莪术二酮系从中药温莪术中分到的抗癌活性成份. 本文研究了由(-)-香芹酮经12步反应合成(-)-莪术二酮的过程, 并以此结果证实了天然(+)-莪术二酮的绝对构型.