Chemoenzymatic synthesis of (+)-alpha-polypodatetraene and methyl (5R,10R,13R)-labda-8-en-15-oate

The reported enzymatic resolution products {acetate of (1S,4aS,8aS)-1,2,3,4,4a,5,6,7,8,8a-decahydro-5,5,8a-trimethyl-2-oxo-trans-naphthalene-1-methanol-2-ethylene acetal} (8aS)-5 (>99% ee)] and [(1R,4aR,8aR)-1,2,3,4,4a,5,6,7,8,8a-decahydro-5,5,8a-trimethyl-2-oxo-trans-naphthalene-1-methanol-2-ethylene acetal (8aR)-4 (98% ee) were converted to (+)-alpha-polypodatetraene (1) and methyl (5R,10R,13R)-labda-8-en-15-oate (2), respectively. For the synthesis of (5R,10R,13R)-2, chiral isoprene congener (3S)-26 corresponding to the right part of 2 was synthesized based on the lipase-assisted resolution of (+/-)-2-methyl-3- (p-methoxyphenyl)propanol (17).     

Preparation of perhydroisoquinolines via the intramolecular Diels-Alder reaction of N-3,5-hexadienoyl ethyl acrylimidates: a formal synthesis of (+/-)-reserpine

The intramolecular Diels-Alder reaction of N-3,5-hexadienoyl ethyl acrylimidates provides an efficient method for the synthesis of cis-fused hexahydroisoquinolones. As a demonstration of the stereochemical control offered by this cycloaddition, two approaches to the construction of the DE rings of reserpine are reported. In the second entry, N-((4-(trimethylsilyl)ethoxymethoxy)methyl-6-benzyloxy-3Z,5E-hexadienoyl)-1-aza-2-ethoxy-1,3-butadiene (40) undergoes cycloaddition to produce as the major product (4aS,7R,8aS)-7-benzyloxy-5-((2-trimethylsilyl)ethoxymethoxy)methyl-3,4,4a,7,8,8a-hexahydroisoquinol-3-one (41). Cycloadduct 41 is then stereospecifically elaborated to (4aS,5S,6R,7R,8aR)-6-methoxy-5-methoxycarbonyl-7-(3,4,5-trimethoxy)benzoyldecahydroisoquinoline-2-carboxylic acid methyl ester (3), a key intermediate previously transformed to reserpine.     

A general enantioselective approach to jasmonoid fragrances: synthesis of (+)-(1R,2S)-methyl dihydrojasmonate and (+)-(1R,2S)-magnolione

Methyl dihydrojasmonate 1 and magnolione 3 are of both academic and industrial interest. In this paper, we describe a flexible, high-yielding route to diastereomerically pure (+)-cis-(1R,2S)-methyl dihydrojasmonate 1 and the first synthesis of (+)-cis-(1R,2S)-magnolione 3, both with enantiomeric excesses up to 93%. The two syntheses diverged from the same advanced intermediate 5, readily available from the enantioenriched hydroxymethyl delta-lactone (-)-(3aS,4S,6aR)-6. The olfactory properties of (1R,2S)-1 and (1R,2S)-3 are reported.     

A convenient new route to piperidines, pyrrolizidines, indolizidines, and quinolizidines by cyclization of acetylenic sulfones with beta and gamma-chloroamines. Enantioselective total synthesis of indolizidines (-)-167B, (-)-209D, (-)-209B, and (-)-207A

The methyl esters of (L)-phenylalanine and (L)-methionine underwent conjugate additions via their free amino groups to 1-(p-toluenesulfonyl)hexyne, followed by intramolecular acylation of the corresponding enamide anions and tautomerization to afford 2-benzyl-5-n-butyl-3-hydroxy-4-(p-toluenesulfonyl)pyrrole and 5-n-butyl-3-hydroxy-2-(2-methylthioethyl)-4-(p-toluenesulfonyl)pyr role, respectively. The conjugate additions of a series of acyclic and cyclic secondary beta- and gamma-chloroamines to acetylenic sulfones proceeded similarly under mild conditions. The resulting adducts were deprotonated with LDA in THF at -78 degrees C, and the resulting sulfone-stabilized carbanions underwent intramolecular alkylation to afford cyclic enamine sulfones. Thus, acyclic gamma-chloroalkyl-benzylamines afforded the corresponding 2- or 2,6-disubstituted piperidines, while 2-(chloromethyl)pyrrolidines, 2-(2-chloroethyl)pyrrolidines, 2-(chloromethyl)piperidines, and 2-(2-chloroethyl)piperidines produced the corresponding 3-substituted pyrrolizidines, 5- or 3-substituted indolizidines, and 4-substituted quinolizidines, respectively. 8-Methyl-5-substituted indolizidines were also prepared from the appropriate methyl-substituted chloroamine precursor. Enantioselective syntheses were achieved by employing chiral chloroamines derived from amino acids or other enantiopure precursors. Further transformations of several of the products provided concise syntheses of four dendrobatid alkaloids. Thus, reduction of (8aS)-5-n-propyl-6-(p-toluenesulfonyl)-delta5,6-indolizidine with sodium cyanoborohydride in trifluoroacetic acid, followed by reductive desulfonylation, afforded (-)-indolizidine 167B. The corresponding 5-n-hexyl derivative similarly produced (-)-indolizidine 209D, while (-)-(8R, 8aS)-8-methyl-5-n-pentyl-6-(p-toluenesulfonyl)-delta5,6-indo lizidine furnished (-)-indolizidine 209B. Finally, the similar reduction and debenzylation of (-)-(8R,8aS)-5-(2-benzyloxyethyl)-8-methyl-6-(p-toluenesulfo nyl)-delta5,6-indolizidine produced the corresponding 5-hydroxyethyl indolizidine. This was subjected to chlorination of the alcohol group with thionyl chloride and substitution with a higher order allyl cuprate reagent to afford (-)-indolizidine 207A.     

Putative Diels-Alder-Catalyzed Cyclization during the Biosynthesis of Lovastatin

A Diels-Alder cyclization proposed to occur during polyketide synthase assembly of the bicyclic core of lovastatin (1) (mevinolin) by Aspergillus terreus MF 4845 was examined via the synthesis of the N-acetylcysteamine (NAC) thioester of [2,11-(13)C(2)]-(E,E,E)-(R)-6-methyldodecatri-2,8,10-enoate (5a). In vitro Diels-Alder cyclization of the corresponding unlabeled NAC ester 5b, ethyl ester 18b, and acid 20b yielded two analogous diastereomers in each case, under either thermal or Lewis acid-catalyzed conditions. The reaction of thioester 5 proceeds readily at 22 degrees C in aqueous media. For 18b, one product is trans-fused ethyl (1R,2R,4aS, 6R,8aR)-1,2,4a,5,6,7,8,8a-octahydro-2,6-dimethylnaphthalene-1-carboxylate (30) (endo product), and the other is cis-fused ethyl (1R,2S,4aR,6R,8aR)-1,2,4a,5,6,7,8,8a-octahydro-2,6-dimethylnaphthalene-1-carboxylate (31) (exo product). Isomer 21 with stereochemistry analogous to 4a,5-dihydromonacolin L (2), a precursor of 1, was made by transformation of a tricyclic lactone, (1S,2S,4aR,6S,8S,8aS)-1-(ethoxycarbonyl)-1,2,4a,5,6,7,8,8a-octahydro-2-methyl-6,8-naphthalenecarbolactone (22) using reduction and Barton deoxygenation. Comparison of 21 with 30 and 31 confirmed the structural assignments and showed that the nonenzymatic 4 + 2 cyclizations of 5, 18, and 20 proceed via chairlike exo and endo transition states with the methyl substituent pseudoequatorial. The proposed biosynthetic Diels-Alder leading to lovastatin (1) would require an endo conformation with the methyl substituent pseudoaxial. Intact incorporation of the labeled hexaketide triene 5a into 1 was not achieved because of rapid degradation by A. terreus cells.     

A convergent approach to the marine natural product eleutherobin: synthesis of key intermediates and attempts to produce the basic skeleton

Synthesis of (1R,5R,6R)-2-(6-hydroxymethyl-5-isopropyl-2-methylcyclohex-2-enyl)-N- methoxy-N-methylacetamide 8 from R-(-)-phellandrene in six steps, and (3aR*,4S*,6R*,6aS*)- (6-hydroxymethyl-4-methoxy-2,2,6-trimethyltetrahydrofuro[3,4-d][1,3]dioxol- 4-yl)acetic acid methyl ester 17 from tetrabromoacetone and 2-methoxy-5-methylfuran in six steps, provided two key fragments which have been combined to produce intermediates for attempted construction of the basic skeleton of eleutherobin.     

Crystal structure of trans(3R,2aS)-(-)-3-phenyl-hexahydro-oxazolo[3,2-a]pyridin-5-one.

Chiral, non-racemic hexahydro-oxazolo[3,2-a]pyridin-5-ones are strategic starting materials for the asymmetric synthesis of alkaloids, via the stereoselective C-C bond formation at the position a to the nitrogen atom. The stereoselectivity of this key step is mainly driven by the geometry of the fused rings of the oxazolopyridine moiety. In this work, the synthesis and X-ray structure of trans(3R,2aS)-(-)-3-phenyl-hexahydro-oxazolo[3,2-a]pyridin-5-one is reported.     

Stereoselective syntheses of 1,4-dideoxy-1,4-imino-octitols and novel tetrahydroxyindolizidines

A new route for the preparation of four new indolizidines, (1R,2S,6S,7S,8aS)- and (1R,2S,6R,7R,8aS)-1,2,6,7-tetrahydroxyindolizidine (30 and 32) and (1S,2R,7S,8S,8aR)- and (1S,2R,7R,8R,8aR)-1,2,7,8-tetrahydroxyindolizidine (44 and 46), is reported. The synthesis is based on Knoevenagel homologation of the readily available enantiomerically pure pyrrolidin-carbaldehydes 13 and 37followed by asymmetric dihydroxylation of the subsequent alkenyl pyrrolidines and cyclization of the corresponding imino-octitols. The new indolizidines and their precursors (imino-octitols 20, 25, 26) and indolizidinones 28a and 28b have been tested for inhibitory activities toward 26 glycosidases. The enzymatic inhibition of trans-7-hydroxy-d-(-)-swainsonine (44) toward alpha-mannosidases is similar to that described for trans-7-hydroxy-l-(+)-swainsonine (11b) toward naringinase (alpha-l-rhamnosidase from Penicillium decumbens).     

Diels-alder reactions with 2-(Arylsulfinyl)-1,4-benzoquinones: effect of aryl substitution on reactivity, chemoselectivity, and pi-facial diastereoselectivity

Diels-Alder reactions of (SS)-2-(2'-methoxynaphthylsulfinyl)-1, 4-benzoquinone (1b), 2-(p-methoxyphenylsulfinyl)-1,4-benzoquinone (1c), and 2-(p-nitrophenylsulfinyl)-1,4-benzoquinone (1d) with cyclopentadiene are reported. These cycloadditions allowed the highly chemo- and stereoselective formation of both diastereoisomeric endo-adducts resulting from reaction on the unsubstituted double bond C(5)-C(6) of quinones working under thermal and Eu(fod)(3)- or BF(3).OEt(2)-catalyzed conditions. The synthesis of endo-adduct [4aS,5S,8R,8aR,SS]-9d resulting from cycloaddition on the substituted C(2)-C(3) double bond was achieved in a chemo- and diastereoselective way from quinone 1d in the presence of ZnBr(2). The reactivity and selectivity of the process proved to be dependent on the electron density of the arylsulfinyl group.     

Studies on the constituents of Broussonetia species X. Six new alkaloids from Broussonetia kazinoki Sieb.

Six new alkaloids, broussonetines W, X, M1, U1, J3, and J2 (1-6) were isolated from the branches of Broussonetia kazinoki SIEB. (Moraceae) as minor constituents. They were formulated as (2R,3R,4R,5R)-2-hydroxy-methyl-3,4-dihydroxy-5-17-(cyclohexy-2-on-1(6)-enyl)heptyllpyrrolidine (1), (2R,3S,4R,5R)-2-hydroxymethyl-3,4-dihydroxy-5-17-(cyclohexy-2-on-1(6)-enyl)heptyl]pyrrolidine-4-O-beta-D-glucopyranoside (2), (2R,3R,4R,5R)-2-hydroxymethyl-3,4-dihydroxy-5-[(9R)-9,13-dihydroxytridecyl]- pyrrolidine (3), (2S,3S,4S)-2-hydroxymethyl-3,4-dihydroxy-5-(10-oxo-13-hydroxytridecyl)-5- pyrroline (4), (2R)-2-[(IS,2S)-1,2-dihydroxy-8-1(2R,3R,4R,5R)-5-(2-hydroxymethyl-3,4-dihydroxy-1-acetylpyrrolidinyl)loctyl]piperidine (5), (2R)-2-[(1S,2S)-1,2-dihydroxy-8-[(2R,3R, 4R,5R)-5-(2-hydroxymethy]-3,4-dihydroxypyrrolidinyl)]octyl]piperidine (6).     

Studies on the constituents of Broussonetia species VIII. Four new pyrrolidine alkaloids, broussonetines R, S, T, and V and a new pyrroline alkaloid, broussonetine U, from Broussonetia kazinoki Sieb

Four new pyrrolidine alkaloids, broussonetines R, S, T, and V and a new pyrroline alkaloid, broussonetine U were isolated from the branches of Broussonetia kazinoki SIEB. (Moraceae) in low yield. Broussonetines R, S and T were formulated as (2R,3R,4R,5R)-2-hydroxymethyl-3,4-dihydroxy-5-[(1R)-1-hydroxy-3-[6-(4-hydroxybutyl)-cyclohexy-2-on-1(6)-enyllpropyl] pyrrolidine (1), (2R,3R,4R,5R)-2-hydroxymethyl-3,4-dihydroxy-5-[(1R,10S)-1,10,13-trihydroxytridecyl] pyrrolidine (2), (2R,3R,4R,5R)-2-hydroxymethyl-3,4-dihydroxy-5-[(1R,5S)-1,5, 13-trihydroxy-10-oxo-tridecyl] pyrrolidine (3). And broussonetines U and V were proposed to be (2S,3S,4S)-2-hydroxymethyl-3, 4-dihydroxy-5-(9-oxo-13-hydroxytridecyl)-5-pyrroline (4), (2R,3S,4R,5R)-2-hydroxymethyl-3,4-dihydroxy-5-[(E)-9-oxo-13-hydroxy-3-tridecenyl] pyrrolidine (5), respectively, by spectroscopic and chemical methods.     

Facile transformation of 2-azetidinones to 2-piperidones: application to the synthesis of the indolizidine skeleton and (8S,8aS)-perhydro-8-indolizinol

The highly functionalized bicyclic lactam 7 was prepared from diolefinic-2-piperidone 18 by the use of ruthenium-catalyzed RCM, and in turn, 18 was derived via a two-carbon addition process from readily accessible 4-olefinic-2-azetidinone 13. Bicyclic lactams 7 and 20 could serve as potentially valuable intermediates for the chiral synthesis of various hydroxylated indolizidine alkaloids as exemplified by the synthesis of (8S,8aS)-perhydro-8-indolizinol 19.     

seco-limonoids and quinoline alkaloids from Raputia heptaphylla and their antileishmanial activity

A novel seco-limonoid, rel-(1S,5R,9S,7R,8S,9R,10S,11R,13S,14R,15R,17R)-11,19-dihydroxy-7-acetoxy-7-deoxoichangin (raputiolide) (1), and two novel quinolone alkaloids N-methyl-2-phenoxyquinolin-4(1H)-one (heptaphyllone A) (2) and 6-methylbenzofuro[2,3-b]quinolin-4(1H)-one (heptaphyllone B) (3), along with the known seco-limonoid ichangin (4), were isolated from Raputia heptaphylla PITTIER (Rutaceae) stem bark. Five known alkaloids, N-methyl-8-methoxyflindersine (5), skimmianine (6), kokusaginine (7), dictamnine (8) and flindersiamine (9), were also isolated from R. heptaphylla leaves. Their structures were established on the basis of full spectroscopic data interpretation supported by data from the pertinent literature. seco-Limonoid 1 configuration was determined by enhanced nuclear Overhauser effect spectroscopy (NOESY) experiments and density functional theory (DFT) molecular modeling. The antileishmanial effect of the isolated compounds was evaluated on Leishmania Viannia panamensis (promastigotes and amastigotes). Whereas alkaloids 2-3, 6-8 and limonoid 4 exhibited no significant parasitocide activity against internalized L. (V.) panamensis amastigotes, limonoid 1 and alkaloid 5 had leishmanicidal activity on intracellular amastigotes (EC??: 8.7 μg/ml) and promastigotes (EC(50): 14.3 μg/ml), respectively.     

Five new nortropane alkaloids and six new amino acids from the fruit of Morus alba LINNE growing in Turkey

Investigation of the constituents of the fruits of Morus alba LINNE (Moraceae) afforded five new nortropane alkaloids (1-5) along with nor-psi-tropine (6) and six new amino acids, morusimic acids A-F (7-12). The structures of the new compounds were determined to be 2alpha,3beta-dihydroxynortropane (1), 2beta,3beta-dihydroxynortropane (2), 2alpha,3beta,6exo-trihydroxynortropane (3), 2alpha,3beta,4alpha-rihydroxynortropane (4), 3beta,6exo-dihydroxynortropane (5), (3R)-3-hydroxy-12-[(1S,4S)-4-[(1S)-1-hydroxyethyl]-pyrrolidin-1-yll-dodecanoic acid-3-O-beta-D-glucopyranoside (7), (3R)-3-hydroxy-12-[(1S,4S)-4-[(1S)-1-hydroxyethyl]-pyrrolidin-1-yll-dodecanoic acid (8), (3R)-3-hydroxy-12-1(1R,4R,5S)-4-hydroxy-5-methyl-piperidin-1-yll-dodecanoic acid-3-O-beta-D-glucopyranoside (9), (3R)-3-hydroxy-12-[(1R,4R,5S)-4-hydroxy-5-methyl-piperidin-1-yll-dodecanoic acid (10), (3R)-3-hydroxy-12-[(1R,4R,5S)-4-hydroxy-5-hydroxymethyl-piperidin-1-yl]-dodecanoic acid-3-O-beta-D-glucopyranoside (11), and (3R)-3-hydroxy-12-[(1R,4S,5S)-4-hydroxy-5-methyl-piperidin-1-yl]-dodecanoic acid (12) on the basis of spectral and chemical data.     

Synthesis and pharmacological effects of the enantiomers of the N-phenethyl analogues of the ortho and para e- and f-oxide-bridged phenylmorphans

The N-phenethyl analogues of (1R*,4aR*,9aS*)-2-phenethyl-1,3,4,9a-tetrahydro-2H-1,4a-propanobenzofuro[2,3-c]pyridin-6-ol and 8-ol and (1R*,4aR*,9aR*)-2-phenethyl-1,3,4,9a-tetrahydro-2H-1,4a-propanobenzofuro[2.3-c]pyridin-6-ol and 8-ol, the ortho- (43) and para-hydroxy e- (20), and f-oxide-bridged 5-phenylmorphans (53 and 26) were prepared in racemic and enantiomerically pure forms from a common precursor, the quaternary salt 12. Optical resolutions were accomplished by salt formation with suitable enantiomerically pure chiral acids or by preparative HPLC on a chiral support. The N-phenethyl (-)- para-e enantiomer (1S,4aS,9aR-(-)-20) was found to be a mu-opioid agonist with morphine-like antinociceptive activity in a mouse assay. In contrast, the N-phenethyl (-)-ortho-f enantiomer (1R,4aR,9aR-(-)-53) had good affinity for the mu-opioid receptor (K(i) = 7 nM) and was found to be a mu-antagonist both in the [(35)S]GTP-gamma-S assay and in vivo. The molecular structures of these rigid enantiomers were energy minimized with density functional theory at the level B3LYP/6-31G* level, and then overlaid on a known potent mu-agonist. This superposition study suggests that the agonist activity of the oxide-bridged 5-phenylmorphans can be attributed to formation of a seven membered ring that is hypothesized to facilitate a proton transfer from the protonated nitrogen to a proton acceptor in the mu-opioid receptor.     

Total syntheses of (+)-chloropuupehenone and (+)-chloropuupehenol and their analogues and evaluation of their bioactivities

Tetracyclic pyrans (+)-chloropuupehenone (1) and (+)-chloropuupehenol (5) and its C8-R-isomer (+)-3 were synthesized via a one-pot condensation of 1-chloro-2-lithio-3,5,6-tris(tert-butyldimethylsilyloxy)benzene (8) with (4aS,8aS)-3,4,4a,5,6,7,8,8a-octahydro-2,5,5,8a-tetramethylnaphthalene-1-carboxaldehyde (7). The major condensation product, (4aS,6aR,12bS)-2H-9,10-bis(tert-butyldimethylsilyloxy)-11-chloro-1,3,4,4a,5,6,6a,12b-octahydro-4,4,6a,12b-tetramethyl-benzo[a]xanthene (4), after desilylation provided tetracyclic pyran (+)-(4aS,6aR,12bS)-2H-11-chloro-1,3,4,4a,5,6,6a,12b-octahydro-4,4,6a,12b-tetramethyl-benzo[a]xanthene-9,10-diol (3). At a dosage of 42 mg/rat over 8 h, pyran diol 3 inhibited the intestinal absorption of cholesterol by 71% in rats. Tetracyclic pyran 4 was also converted to o-quinone 28, which inhibited cholesteryl ester transfer protein (CETP) activity and L1210 leukemic cell viability with IC(50) values of 31 and 2.4 microM, respectively. Diol (+)-5 inhibited CETP activity with an IC(50) value of 16 microM. The minor condensation product, (4aS,6aS,12bS)-2H-9,10-bis(tert-butyldimethylsilyloxy)-11-chloro-1,3,4,4a,5,6,6a,12b-octahydro-4,4,6a,12b-tetramethyl-benzo[a]xanthene (6), was transformed into (+)-5 and (+)-1. A stepwise stereoselective synthesis of (+)-1 was also developed utilizing an oxyselenylation ring-closure reaction. The synthetic sequence also produced four biologically active naturally occurring drimanic sesquiterpenes, (+)-drimane-8alpha,11-diol (34), (-)-drimenol (38), (+)-albicanol (39), and (-)-albicanal (31) as intermediates.     

A concise formal stereoselective total synthesis of （-）-swainsonine

A short formal stereoselective synthesis of （-）-swainsonine （1） is described. Our synthesis started with the versatile building block （R）-3-benzyloxyglutarimide 5. Through controlled regioselective reduction, Ley＇s-sulfone chemistry （N-α-sulfonylation and ZnCl2-catalyzed N-α-amidovinylation）, an RCM reaction, and an amide reduction, the synthesis of unsaturated indolizidine （8R,8aS）-3 has been achieved in five steps. The indolizidine （8R,8aS）-3 is an advanced intermediate toward the synthesis of （-）-swainsonine （1）.     

Total synthesis of (+)-trans-195A

[reaction: see text] The first enantioselective synthesis of (+)-trans-195A is described. The structure has been constructed by ring-rearrangement metathesis (RRM) and zirconium-mediated Negishi-coupling, used for the first time to prepare 6,6-membered heterocycles, as key steps. By comparison of the synthesized material with the isolated natural product, the absolute configuration of natural trans-195A was determined to be (2R,4aS,5R,8aS)-(-).     

Stereoselective photochemical 1,3-dioxolane addition to 5-alkoxymethyl-2(5H)-furanone: synthesis of bis-tetrahydrofuranyl ligand for HIV protease inhibitor UIC-94017 (TMC-114)

A convenient synthesis of (3R,3aS,6aR)-3-hydroxyhexahydrofuro[2,3-b]furan, a high-affinity nonpeptidal ligand for HIV protease inhibitor UIC-94017, is described. This inhibitor is undergoing advanced clinical trials. The synthesis utilizes a novel stereoselective photochemical 1,3-dioxolane addition to 5(S)-benzyloxymethyl-2(5H)-furanone as the key step. The requisite furanone derivative was prepared in high enantiomeric excess by an immobilized lipase-catalyzed selective acylation of (+/-)-1-(benzyloxy)-3-buten-2-ol and a ring-closing olefin metathesis with Grubbs' catalyst. Optically active bis-THF was converted to protease inhibitor 2 (UIC-94017).     

Total synthesis of optically active lycopladine A by utilizing diastereoselective protection of carbonyl group in a 1,3-cyclohexanedione derivative

We successfully synthesized two enantiomers of bicyclic enones, (7R,7aR)- and (7S,7aS)-9, from the hemiacetal 2a, which we first synthesized from the symmetrical diketone 1a via diastereoselective carbon-oxygen bond formation between one of the carbonyl groups and the chiral alcohol on the C2 side chain in a 2,2-disubstituted 1,3-cycloalkanedione derivative. We also report the total synthesis of natural (+)-lycopladine A [(+)-6] from (7R,7aR)-9 and the formal synthesis of unnatural (-)-lycopladine A [(-)-6] from (7S,7aS)-9.