New synthesis of (−)- and (+)-actinobolin from d-glucose

The total synthesis of (−)-actinobolin 2, an antipode of the natural product starting from d-glucose is described. A three-component coupling reaction of a functionalized cyclohexenone (+)-6, derived from d-glucose by way of Ferrier's carbocyclization, with vinyl cuprate and an aldehyde (R)-5 effectively constructed the carbon framework of 2 in a highly stereoselective manner. The formal synthesis of the natural enantiomer 1 from d-glucose was also achieved.     

The combined use of stereoelectronic control and ring closing metathesis for the synthesis of (−)-8-epi-swainsonine

A novel and efficient synthesis of (−)-8-epi-swainsonine 2 is reported. Stereocontrolled diol formation from the bicyclic alkene 3 followed by a stereoselective vinylation of the aldehyde and ring closing metathesis gave the indolizidine ring system, which was converted into (−)-8-epi-swainsonine 2.     

Studies on the total synthesis of sanglifehrin A: stereoselective synthesis of the C(29)-C(39) fragment

A highly stereoselective synthesis of the C(29)-C(39) fragment of the potent immunosuppressant sanglifehrin A has been accomplished by a sequence involving 16 steps (18% overall yield) from N-propionyloxazolidinone 9. Key steps are a diastereoselective hydroboration, and a diastereoselective epoxidation of an allylic alcohol followed by a 1,5-anti boron-mediated aldol reaction of methyl ketone 4 with chiral aldehyde 5.     

Development of a Double Allylboration Reagent Targeting 1,5-syn-(E)-Diols: Application to the Synthesis of the C(23)-C(40) Fragment of Tetrafibricin

Interest in the synthesis of the C(23)-C(40) fragment 2 of tetrafibricin prompted us to develop a new method for the synthesis of 1,5-syn-(E)-diols. Toward this end, the kinetically controlled hydroboration of allenes 6, 33, ent-39, 42, and 45 with the Soderquist borane 25R were studied. Tetrabutylammonium allenyltrifluoroborate 45 gave superior results and was utilized in a double allylboration sequence with two different aldehydes to provide the targeted 1,5-syn-(E)-diols in generally high yields (72-98%), and with high enantioselectivity (>95% ee), diastereoselectivity (dr >20:1), and (E)/(Z) selectivity (>20:1). This new method was applied to the synthesis of the C(23)-C(40) fragment 2 of tetrafibricin.     

Synthesis of the C15-C23 fragment of dictyostatin using a highly stereoselective Carreira alkynylation

A straightforward synthesis of the C15-C23 fragment of dictyostatin has been achieved by a highly stereoselective Carreira alkynylation between alkyne 1 and aldehyde 2, followed by three chemoselective reductions.     

Synthesis of the C(1)-C(16) fragment of bryostatins using an ‘ene’ reaction between an allylsilane and an alkynone

The zinc(II) iodide mediated ‘ene’ reaction between (4R)-4,5-bis-(tert-butyldimethylsilyloxy)-2-(trimethylsilylmethyl)pent-1-ene (43) and (5S,7R,9S)-5,11-dibenzyloxy-4,4-dimethyl-7,9-dihydroxy-7,9-O-isopropylideneundec-1-yn-3-one (53) gave the (E)-vinylsilane 54 with excellent stereoselectivity. Simultaneous deprotection and cyclisation via a stereoselective oxy-Michael reaction gave the bicyclic acetal 57 after treatment with trimethyl orthoformate. A synthesis of the ester 60 corresponding to the C(1)-C(16) fragment of the bryostatins was then completed by O-silylation, oxidative cleavage of the methylene group and a stereoselective condensation of the resulting ketone 59 with the chiral phosphonate 61.     

Synthesis of 12-aza analogs of epothilones and (E)-9,10-dehydroepothilones

N-Boc-12-aza-epothilone analog (azathilone) 1 is a potent inhibitor of human cancer cell growth and represents a structurally new class of natural product-derived microtubule-stabilizing agents. Compound 1 has been prepared employing a convergent strategy that is based on the consecutive assembly of building blocks 3, 4, and 19 into diene 20 and subsequent RCM-mediated macrocycle formation. The aldol reaction between aldehyde 3 and ketone 4 delivered the required 6R,7S diastereoisomer 5 with good selectivity and provided a reliable entry into the stereoselective synthesis of carboxylic acid 12. RCM with diene 20 was highly E-selective, thus giving efficient access to (E)-9,10-dehydro-1 (2). The latter is a key analog in SAR studies with 1.     

Stereoselective synthesis of tubuvaline methyl ester and tubuphenylalanine, components of tubulysins, tubulin polymerization inhibitors

Synthetic studies of two components of tubulysins, tubulin polymerization inhibitors are described. The highly stereoselective synthesis of tubuvaline methyl ester (2) was accomplished by 1,3-dipolar cycloaddition of nitrone d-6 and acrylic acid derivatives 7 as a key step. The synthesis of tubuphenylalanine (3) was conducted by an aldol reaction of a boron enolate of (S)-4-isopropyl-3-propionyl-2-oxazolidinone (13) with aldehyde 14, readily prepared from phenylalanine, followed by Barton deoxygenation under radical conditions.     

Stereoselective synthesis of (2S,3S,7S)-3,7-dimethylpentadec-2-yl acetate and propionate, the sex pheromones of pine sawflies

The stereoselective synthesis of (2S,3S,7S)-3,7-dimethylpentadec-2-yl acetate (2) and propionate (3) was accomplished by utilizing the cheap and easily available chiron (R)-4-methyl-δ-valerolactone (4). The key steps were chelation-controlled addition of Gilmann reagent to chiral β-alkoxy aldehyde 12 and the Cu(I)-catalyzed coupling of Grignard reagent with bromoester 5 in the presence of NMP.     

Synthesis and structural determination of the C33-C42 fragment of symbiodinolide

Symbiodinolide (1) is a polyol macrolide with a molecular weight of 2859 mu. As one of the degradation reactions, cross-metathesis of 2, which is a methyl ester of 1, with ethylene was performed to give the C33-C42 degraded fragment 4. The absolute configuration of 4 was estimated to be (36S,40S) by Mosher method. Stereoselective synthesis of 4 was achieved in 14 steps from l-aspartic acid. Synthetic bis-(S)- and (R)-MTPA esters exhibited the spectroscopic data identical with those of bis-(S)- and (R)-MTPA esters derived from the degraded fragment 4. Thus, the absolute stereochemistry of 4 was elucidated to be (36S,40S).     

A concise synthesis of (±) and a total synthesis of (+)-epiquinamide

A total synthesis of the quinolizidine alkaloid (+)-epiquinamide 1 has been achieved starting from (−)-pipecolinic acid 3. The key step is the highly diastereoselective addition of a TBDMS-protected propargyl alcohol to a chiral aldehyde derived from 3 to give erythro alkynol 19, which is then easily transformed into the desired bicyclic skeleton.     

Gold catalysis in stereoselective natural product synthesis: (+)-linalool oxide, (−)-isocyclocapitelline, and (−)-isochrysotricine

A stereoselective synthesis of the tetrahydrofuran-containing natural products (2S,5R)-(+)-linalool oxide (1), (−)-isocyclocapitelline (2), and (−)-isochrysotricine (3) is reported. Key steps are the copper-mediated S_N2′-substitution of propargyl oxiranes 7 and the gold-catalyzed cycloisomerization of dihydroxyallenes 8/17, resulting in a highly efficient center-to-axis-to-center chirality transfer. The enantioselective total synthesis of (−)-isocyclocapitelline (2) and (−)-isochrysotricine (3) allowed the elucidation of the absolute configuration of these β-carboline natural products.     

Total synthesis of the mushroom metabolite (+)-calopin

A synthesis of (+)-calopin (1a) was achieved employing a highly stereoselective ene reaction between 8-phenylmenthyl glyoxylate (3) and the β,β-dimethylstyrene 4c. Transesterification of the resulting homoallylic alcohol 5c, followed by allylic oxidation and hydrogenation yielded the δ-lactone 13 which was deprotected to the natural product 1a.     

Total synthesis of (−)-amathaspiramide F

The stereoselective total synthesis of the marine alkaloid, (−)-amathaspiramide F (1), was achieved from the α-hydroxy-α-ethynylsilane 2. The key steps involved in the synthesis were (1) the enolate Claisen rearrangement of the α-acyloxy-α-alkenylsilane for the stereoselective construction of the consecutive C5 and C9 chiral centers of 1 (erythro configuration), (2) the construction of aza-spirohemiaminal 28, and (3) dibromination during the final stage of the total synthesis. The reaction of the (Z)-α-acyloxy-α-alkenylsilane 22 possessing the Boc-homoallylglycine ester as the acyloxy group underwent stereoselective enolate Claisen rearrangement to give the desired erythro product 23. On the other hand, the reaction of the α-acyloxy-α-alkenylsilane (Z)-5 having Boc-proline gave the unexpected threo product 6. Oxidative cleavage of the vinylsilane group of 23 followed by treatment with heptamethyldisilazane as the methylamine equivalent gave aza-spirohemiaminal 28. The problematic regioselective dibromination to 28 was achieved using n-Bu₄NBrCl₂.     

Synthesis of (±)-phthalascidin 650 analogue: new synthetic route to (±)-phthalascidin 622

A synthesis of functionalized phenolic α-amino-alcohol (±)-13 as synthetic precursor of the catechol tetrahydroisoquinoline structure of phthalascidin 650 is disclosed. Starting from 3-methylcatechol 5, eight steps of synthesis give rise to the synthesis of phenolic α-amino-alcohol (±)-13 in 27% overall yield. This synthetic strategy involves the elaboration of fully functionalized aromatic aldehyde 8 and its transformation into a phenolic α-amino-alcohol (±)-13, through a Knoevenagel condensation, simultaneous reduction of nitroketene and ester functions and hydrogenolysis of the benzyl protecting group. The pentacycle (±)-18 was obtained after four additional steps. The Pictet-Spengler cyclisation between the phenolic α-amino-alcohol (±)-13 and N-protected α-amino-aldehyde 4 allowed to obtain (1,3′)-bis-tetrahydroisoquinoline 14 with N-methylated and N-Fmoc removed. The last step was a Swern oxidation for allowing an intramolecular condensation.     

Synthesis of (2S,3R)- and (2S,3S)-[3-H1]-proline via highly stereoselective hydrolysis of a silyl enol ether

A straightforward synthesis of (2S)-[3,3-²H₂]-proline 1c and (2S,3R)- and (2S,3S)-[3-²H₁]-proline, 1b and 1a, respectively, has been devised. The key step of the route to the latter compounds involves highly stereoselective hydrolysis of the silyl enol ethers 3 and 3a, respectively, with protonation (deuteriation) from the re-face of the silyl enol ether.     

Synthesis of the common FGHI-ring part of ciguatoxins

The common FGHI-ring part (2) of ciguatoxins has been synthesized from the F- and I-ring parts (6 and 5, respectively). The Nozaki-Hiyama-Kishi coupling of 6 with 5 followed by regio- and stereoselective epoxidation at C29 and C30 afforded an epoxide (4), which was transformed into a tricyclic compound (3) corresponding to the F-HI-ring part by 6-exo-epoxide opening and the subsequent inversion of the C29 stereocenter. Reductive cyclization of 3 forming the C31-O26 bond of the G-ring successfully produced 2.     

Chemistry of renieramycins. Part 9: Stereocontrolled total synthesis of (±)-renieramycin G

A 25-step stereocontrolled total synthesis of (±)-renieramycin G (1g) from readily available 2-hydroxy-3-methyl-4,5-dimethoxybenzaldehyde (3) is described. This synthesis features the concise construction of the pentacyclic framework using the stereoselective Pictet-Spengler type cyclization reaction of lactam (14) with ethyl diethoxyacetate, followed by the base-catalyzed isomerization of the C-1 stereo center.     

Stereocontrolled total synthesis of (±)-pisiferol and (±)-pisiferal

The stereoselective total synthesis of (±)-pisiferol (1) and (±)-pisiferal (2) has been successfully accomplished using the trans-octahydrophenanthrene derivative 20 as a key intermediate. Intramolecular cyclisation of the diazoketone 15 followed by catalytic hydrogenation provided, stereoselectively, the keto-ester 17 which was converted into the acetate 20 through the intermediates 18 and 19.     

Total Synthesis of Amphidinolide E and Amphidinolide E Stereoisomers

Four amphidinolide E stereoisomers, amphidinolide E (1), 2-epi-amphidinolide E (2), 19-epi-amphidinolide E (3), and 2-epi-19-epi-amphidinolide E (4), have been synthesized via the judicious union of aldehyde 5, allylsilanes 7 or 8, acids 9 or 10, and vinylstannane 6. The C19 stereocenters of the C19 epimeric allylsilanes 7 and 8 were introduced via crotylboration reactions early in the synthesis. [3+2] Annulation reactions of aldehyde 5 with allylsilanes 7 and 8 were employed to set the core tetrahydrofuran units of 1-4. Finally, the C2 stereocenter was installed by esterification using acid 9, without incident, or with acid 10, in which case an unexpected and completely stereoselective inversion of C2 occurs.