Synthesis of amphidinolide E C10-C26 fragment

The key C10-C26 fragment in a total synthesis of (-)-amphidinolide E has been prepared from an oxolane-containing C10-C17 segment (9, derived from L-glutamic acid) via a Julia-Kocienski reaction with aldehyde 3, followed by a Sharpless AD to obtain the desired diol. The C22-C26 fragment was installed by means of an efficient Suzuki-Molander coupling, with an organotrifluoroborate reagent (4, arising from a cross-metathesis reaction between a vinylboronate and 2-methyl-1,4-pentadiene).     

Total synthesis and structure confirmation of leptofuranin D

A convergent total synthesis of leptofuranin D is described. The linear polyketide C12-C24 segment was assembled through addition of a chiral allenylzinc reagent, derived from mesylate 12, to the chiral aldehyde 11. Directed hydrostannation of the adduct 13 followed by iodinolysis and Sonogashira coupling yielded the enyne 16, which was converted to the methyl-substituted enye 20, through hydrogenolysis of the derived bromide 19. Hydrostannation of the terminal alkyne converted 21 to 22, which was then treated with iodine to afford the vinyl iodide 23. The dihydropyranone precursor 40 was prepared by addition of allenystannane 29 to aldehyde 27. Partial hydrogenation of the derived propargylic alcohol then protection as the TBS ether afforded the (Z)-olefin 34. Further homologation was effected through Witttig condensation of aldehyde 36 with the ylide derived from phosphonium bromide 37. Selective deprotection of the primary TES ether of 38, followed by conversion of alcohol 39 to iodide 40, completed the synthesis of the C1-C11 segment. Suzuki coupling of boronate 41, prepared from iodide 40, with vinyl iodide 23 led to diene 42, with the complete carbon skeleton of leptofuranin D. The synthesis was completed by oxidation of the unprotected alcohol of 42, followed by global desilylation and exposure of the resulting tetrol to MnO(2).     

A convergent total synthesis of ouabagenin

A convergent total synthesis of ouabagenin, an aglycon of cardenolide glycoside ouabain, was achieved by assembly of the AB-ring, D-ring and butenolide moieties. The multiply oxygenated cis-decalin structure of the AB-ring was constructed from (R)-perillaldehyde through the Diels–Alder reaction and sequential oxidations. The intermolecular acetal formation of the AB-ring and D-ring fragments, and combination of the intramolecular radical and aldol reactions, assembled the requisite steroidal skeleton in a stereoselective fashion. Finally, stereoselective installation of the C17-butenolide via the Stille coupling and hydrogenation led to ouabagenin.     

Construction of the DEF-ring system of nogalamycin and menogaril via an efficient Suzuki-Miyaura reaction

A new approach to the total synthesis of anthracycline natural products, nogalamycin and menogaril, was explored. The goal was to enable late-stage introduction of the EF-ring segment. The new synthetic route has been developed through strategic application of a Suzuki-Miyaura reaction as the key step, which coupled the EF-ring segment with the D-ring to give a 1,1′-disubsitituted alkene in good yield under biphasic conditions. Further manipulation of the coupling product completed the construction of the DEF-ring system.     

Total syntheses of the Securinega alkaloids (+)-14,15-dihydronorsecurinine, (-)-norsecurinine, and phyllanthine

A new strategy for enantiospecific construction of the Securinega alkaloids has been developed and applied in total syntheses of (+)-14,15-dihydronorsecurinine (8), (-)-norsecurinine (6), and phyllanthine (2). The B-ring and C7 absolute stereochemistry of these biologically active alkaloids originated from trans-4-hydroxy-L-proline (10), which was converted to ketonitrile 13 via a high-yielding eight-step sequence. Treatment of this ketonitrile with SmI2 afforded the 6-azabicyclo[3.2.1]octane B/C-ring system 14, which is a key advanced intermediate for all three synthetic targets. Annulation of the A-ring of (-)-norsecurinine (6) with the required C2 configuration via an N-acyliminium ion alkylation was accomplished using radical-based amide oxidation methodology developed in these laboratories as a key step, providing tricycle 33. Annulation of the D-ring onto alpha-hydroxyketone 33 with the Bestmann ylide 45 at 12 kbar gave (+)-14,15-dihydronorsecurinine (8). In the securinine series, the D-ring was incorporated using an intramolecular Wadsworth-Horner-Emmons olefination of phenylselenylated alpha-hydroxyketone 47. The C14,15 unsaturation was installed late in the synthesis by an oxidative elimination of the selenoxide derived from tetracyclic butenolide 50 to give (-)-norsecurinine (6). The A-ring of phyllanthine (2) was formed from hydroxyketone 14 using a stereoselective Yb(OTf)3-promoted hetero Diels-Alder reaction of the derived imine 34 with Danishefsky's diene, affording adduct 35. Conjugate reduction and stereoselective equatorial ketone reduction of vinylogous amide 35 provided tricyclic intermediate 36, which could then be elaborated in a few steps to stable hydroxyenone 53 via alpha-selenophenylenone intermediate 52. The D-ring was then constructed, again using an intramolecular Wadsworth-Horner-Emmons olefination reaction to give phyllanthine (2).     

Total Synthesis,Stereochemical Assignment,and Biological Activity of Chamuvarinin and Structural Analogues

A highly stereocontrolled synthesis of (+)‐chamuvarinin has been completed in 1.5 % overall yield over 20 steps. The key fragment coupling reactions were the addition of alkyne 8 to aldehyde 7 (under Felkin–Anh control), followed by the two step activation/cyclization to close the C20–C23 2,5‐cis‐substituted tetrahydrofuran ring and a Julia–Kocienski olefination at C8–C9 to introduce the terminal butenolide. The inherent flexibility of our coupling strategy led to a streamlined synthesis with 17 steps in the longest sequence (2.2 % overall yield), in which the key bond couplings are reversed. In addition, a series of structural analogues of chamuvarinin have been prepared and screened for activity against HeLa cancer cell lines and both the bloodstream and insect forms of Trypanosoma brucei, the parasitic agent responsible for African sleeping sickness.     

Synthesis of the CD-ring of the anticancer agent streptonigrin: studies of aryl-aryl coupling methodologies

A series of functionalized 4-bromopyridines, representing the C-ring of the anticancer agent streptonigrin have been prepared and their abilities to undergo Pd-catalyzed cross-coupling with streptonigrin D-ring siloxanes were evaluated. The coupling reaction was generally tolerant to the preparation of hindered CD biaryls; however, the electronic effects of both partners play a pivotal role in the success of the coupling process. Analogs of the CD biaryl were prepared by coupling of aryl siloxane derivatives (D-ring component) with highly functionalized 4-bromopyridines (C-ring); however, the CD biaryl of the natural product could not be prepared in high yield by siloxane coupling due to the facile formation of reduced pyridine under the coupling conditions. Alternatively, the fully functionalized CD biaryl of streptonigrin was prepared using a Suzuki coupling of appropriately functionalized C-ring bromide and D-ring aryl boronic acid. The described approach is highly convergent and readily amenable to the synthesis of analogs.     

Total Synthesis of Siomycin A: Construction of Synthetic Segments

The five practical segments for the total synthesis of siomycin A, that is, the dehydropiperidine segment A ( 5 ), the pentapeptide segment B ( 3 ), the dihydroquinoline segment C ( 6 ), and the β‐phenylselenoalanine dipeptide segments D ( 7 ) and E ( 4 ), were synthesized. Segment A ( 5 ) was constructed by the coupling of the azomethine ylide and the chiral sulfinimine, followed by the stereoselective reduction of the six‐membered imine function. Segment B ( 3 ) was synthesized by the phenylselenylation of the β‐lactone, stereoselective vinylzinc addition to the chiral sulfinimine, and oxazoline–thioamide conversion. Segment C ( 6 ) was prepared by the one‐pot olefination of the tetrahydroquinoline N‐oxide using triflic anhydride and triethylamine, stereoselective reduction of the methyl ketone function, and regioselective Yb(OTf)₃‐catalyzed epoxide opening by the amino group. Segments D ( 7 ) and E ( 4 ) were synthesized by coupling of the properly protected β‐phenylselenoalanines.     

Enantiospecific total synthesis of (-)-(E)16-epiaffinisine, (+)-(E)16-epinormacusine B,and (+)-dehydro-16-epiaffinisine as well as the stereocontrolled total synthesis of alkaloid G

An efficient strategy is described for the total synthesis of the sarpagine-related indole alkaloids (-)-(E)16-epiaffinisine (1), (+)-(E)16-epinormacusine B (2), and (+)-dehydro-16-epiaffinisine (4). A key step employed the chemospecific and regiospecific hydroboration/oxidation at C(16)-C(17); this method has also resulted in the synthesis of (+)-dehydro-16-epinormacusine B (5). The oxy-anion Cope rearrangement followed by protonation of the enolate that resulted under conditions of kinetic control has been employed to generate the key asymmetric centers at C(15), C(16), and C(20) in alkaloid G (7) in a highly stereocontrolled fashion (>43:1). Conditions that favor control of the sarpagine stereochemistry at C(16) vs the epimeric ajmaline configuration at the same stereocenter have been determined. The formation of the required cyclic ether in 4, 5, and 7 was realized with complete control from the top face on treatment of the corresponding alcohols with DDQ/THF or DDQ/aq THF in excellent yields.     

Multigram synthesis of the C29-C51 subunit and completion of the total synthesis of altohyrtin C (spongistatin 2)

A multigram synthesis of the C29-C51 subunit of altohyrtin C (spongistatin 2) has been accomplished. Union of this intermediate with the C1-C28 fragment and further elaboration furnished the natural product. Completion of the C29-C51 subunit began with the aldol coupling of the boron enolate derived from methyl ketone 8 and aldehyde 9. Acid-catalyzed deprotection/cyclization of the resulting diastereomeric mixture of addition products was conducted in a single operation to afford the E-ring of altohyrtin C. The diastereomer obtained through cyclization of the unwanted aldol product was subjected to an oxidation/reduction sequence to rectify the C35 stereocenter. The C45-C48 segment of the eventual triene side chain was introduced by addition of a functionalized Grignard reagent derived from (R)-glycidol to a C44 aldehyde. Palladium-mediated deoxygenation of the resulting allylic alcohol was followed by adjustment of protecting groups to provide reactivity suitable for the later stages of the synthesis. The diene functionality comprising the remainder of the C44-C51 side chain was constructed by addition of an allylzinc reagent to the unmasked C48 aldehyde and subsequent dehydration of the resulting alcohol. Completion of the synthesis of the C29-C51 subunit was achieved through conversion of the protected C29 alcohol into a primary iodide. The synthesis of the C29-C51 iodide required 44 steps with a longest linear sequence of 33 steps. From commercially available tri-O-acetyl-d-glucal, the overall yield was 6.8%, and 2 g of the iodide was prepared. The C29-C51 primary iodide was amenable to phosphonium salt formation, and the ensuing Wittig coupling with a C1-C28 intermediate provided a fully functionalized, protected seco-acid. Selective deprotection of the required silicon groups afforded an intermediate appropriate for macrolactonization, and, finally, global deprotection furnished altohyrtin C (spongistatin 2). This synthetic approach required 113 steps with a longest linear sequence of 37 steps starting from either tri-O-acetyl-d-glucal or (S)-malic acid.     

A biomimetically inspired, efficient synthesis of the South 7 hemisphere of cephalostatin 7

Synthesis of the South 7 hemisphere of cephalostatin 7 is described applying a second-generation synthetic strategy, which retains all the existing carbons in hecogenin acetate 1. TFAT (trifluoroacetyl trifluoromethanesulfonate)-assisted E-ring opening yields the key D-ring cyclopentadiene. A facially selective [4 + 2] cycloaddition between a series of steroidal D-ring dienes and singlet oxygen was conformationally directed by the C21-Me stereochemistry of the side chain. Sharpless asymmetric dihydroxylation of the terminal olefin provides (S)-C25-OH. An acid-catalyzed SN2' intramolecular alkylation of an acetal oxygen was followed by a one-pot sequence of beta-elimination and spiroketalization. The new route provides a practical 16-operation synthesis of the South 7 hemisphere (20% overall), as well as a model for construction of the crucial North 1 hemisphere.     

Stereocontrolled and convergent total synthesis of amphidinolide T3

Stereocontrolled and convergent total synthesis of amphidinolide T3 has been described. A retrosynthetic scheme was constructed that led to the recognition of readily available and enantiomerically related compounds as starting materials for the total synthesis of amphidinolide T3. Thus, the two key building blocks 6 and 7 were defined as subtargets and synthesized in optically active forms. The C1-C12 fragment 6 was derived from commercially available D-glutamic acid or its synthetically equivalent (R)-5-hydroxymethyltetrahydrofuran-2-one 16 as starting material involving highly diastereoselective asymmetric allylation as a key step. The C13-C21 fragment 7 was efficiently synthesized in high yield through the dithiane coupling of the segment 10 and iodide 11, followed by subsequent deprotection and Petasis olefination. Eventually, assembly of the fragment aldehyde 6 and dithiane 7 along with C-C bond formation, a two-step oxidation-reduction sequence, selective macrolactonization, and functional transformation furnished the convergent total and formal synthesis of amphidinolide T3 and T4, and this approach also provides a flexible and practical synthesis of amphidinolide T macrolides.     

Insights into long-range structural effects on the stereochemistry of aldol condensations: a practical total synthesis of desoxyepothilone F.

A processable total synthesis of a potent antitumor agent, desoxyepothilone F (dEpoF, 21-hydroxy-12,13-desoxyepothilone B, 21-hydroxyepothilone D), has been accomplished. The route is highly convergent. The new technology has also been applied to a total synthesis of 12,13-desoxyepothilone (dEpoB). The crucial point of departure from previous syntheses of dEpoB and dEpoF involves presentation of the C1-C11 sector for Suzuki coupling with C3 in reduced form. Hitherto, the required S stereochemistry at C3 had been implemented via reduction of a keto function after Suzuki coupling. Whereas that chemistry worked quite well in a synthesis of dEpoB, it was not transferable to a high-yielding synthesis of dEpoF. The reduction of the keto group at C3 via a Noyori protocol after Suzuki coupling had proved to be very difficult. In our current approach, two consecutive aldol reactions are used to fashion the acyl sector. In the first aldol condensation, C6 becomes attached to C7. Following protection at C7, a two-carbon acetate equivalent is used to join C2 and C3 with very high asymmetric induction at C3. Only after this center has been implemented is the Suzuki reaction conducted. This major advance allowed us to synthesize dEpoF in a straightforward fashion. These findings found ready application in the total synthesis of dEpoB. Another part of the study involved analysis of the factors associated with aldol condensations joining C6 to C7. In the work described herein, the consequences of the status of C3 in promoting the C6-C7 aldol coupling are probed in detail. Dramatic stereochemical long-range effects uncovered during the study are described, and a working model to explain these effects has emerged.     

Total Synthesis of Siomycin A: Completion of the Total Synthesis

The total synthesis of siomycin A ( 1 ), a representative compound of the thiostrepton family of peptide antibiotics, was achieved by incorporating the five synthetic segments A ( 2 ), B ( 3 ), C ( 4 ), D ( 5 ), and E ( 6 ). The dehydropiperidine segment A ( 2 ) was esterified with the dihydroquinoline segment C ( 4 ), and the subsequent coupling with the β‐phenylselenoalanine dipeptide segment D ( 5 ) at the segment C portion followed by lactamization between the segments A and D gave segment A‐C‐D ( 27 ). This was amidated with the pentapeptide segment B ( 3 ) at the segment A portion followed by one‐pot cyclization (between segments A and B) and elongation (with the β‐phenylselenoalanine dipeptide segment E ( 6 ) at the segment A portion), thus furnishing siomycin A ( 1 ).     

Toward the total synthesis of phorboxazole B: an efficient synthesis of the C20-C46 segment

An efficient synthesis of the C20-C46 segment of phorboxazole B is described. The key steps involved Hg(OAc)(2)/I(2)-induced cyclization to construct the cis-tetrahydropyran moiety, the coupling of the metalated 2-methyloxazole 7 with lactone 6, and Julia olefination to furnish the conjugated diene moiety.     

A chemoenzymatic total synthesis of (+)-clividine

The title compound, ent-1, the non-natural enantiomeric form of the lycorenine-type alkaloid (-)-clividine (1), has been prepared using the enantiomerically pure (ee >99.8%) cis-1,2-dihydrocatechol 3 as starting material. A key feature associated with the closing stages of the synthesis involved the diastereoselective addition of a nitrogen-centered radical onto a pendant cyclohexene to establish the cis-fused D-ring and the required stereochemistry at C11b in the final product ent-1.     

Synthetic anthracyclines: regiospecific total synthesis of D-ring thiophene analogues of daunomycin

The key anhydride 2-acetoxy-[2-carboxy-5-(trimethylsilyl)thiophen-3-yl]acetic acid anhydride (8), prepared from (2-carboxythiophen-3-yl)acetic acid (5), underwent a strong base-induced cycloaddition reaction with the chloroquinone acetal (11) to give the 7,7-ethylenedioxy-2-trimethylsilyl-6,7,8,9- tetrahydroanthra[2,3-b]thiophene-5,10-dione (12) regioselectively. Similarly, the regioisomeric 8,8-ethylenedioxy-2-trimethylsilyl-6,7,8,9-tetrahydroanthra[2,3-b] thiophene- 5,10-dione (30) was obtained by the strong base-induced cycloaddition reaction of 8 with the chloroquinone acetal (29). These cycloadducts (12 and 30) were converted to D-ring thiophene analogues (28 and 38) of daunomycin (1a). Another D-ring thiophene analogue (42) which has a trimethylsilyl substituent in the D-ring was also prepared.     

Efficient convergent synthesis of 1alpha,25-dihydroxyvitamin D3 and its analogues by Suzuki-Miyaura coupling

[reaction: see text] 1alpha,25-Dihydroxyvitamin D(3) was synthesized by the Suzuki-Miyaura coupling of the A-ring intermediate 1, which was efficiently prepared from readily available 1,7-enyne 2, with the corresponding boronate compound of the C,D-ring portion. The method was applied to prepare des-C,D analogues of 1alpha,25-dihydroxyvitamin D(3).     

Total synthesis of (+/-)-deoxypenostatin A. Approaches to the syntheses of penostatins A and B

A short synthesis of (+/-)-deoxypenostatin A (28) has been carried out using the convergent coupling of dienal 11, epoxide 13, and methylenetriphenylphosphorane (17) to prepare trienol 19 in only two steps. The key step is the Yb(OTf)(3)-catalyzed intramolecular Diels-Alder reaction of hydrated trienyl glyoxylate 23, which gives lactone 24 stereoselectively. Elaboration of lactone 24 to enone 27 by an intramolecular Horner-Emmons Wittig reaction and epimerization completes the synthesis of 28. Modest yields of Diels-Alder adducts 45a and 46a could be prepared analogously from MEM ether 44c, but the sensitivity of several of the intermediates precluded the elaboration of 45a to penostatin A (1).     

Stereoselective preparation of (e)-configured 1,2-disubstituted propenes from two aldehydes by a two-carbon stitching strategy: convergent synthesis of 18,21-diisopropyl-geldanamycin hydroquinone and its c7 epimer

The title compounds were synthesized in a longest sequence of 27 linear steps and with an overall yield of 2.9 and 3.9?%. In the course of the synthesis, two aldehydes representing carbon fragments C1?C7 (Eastern fragment) and C9?C21 (Western fragment) were prepared from D-mannitol, each of which incorporated a key stereogenic center at the respective secondary methyl ether group (C6, C12) from the chiral pool material. The assembly of the two aldehydes was achieved employing α-chloroethyl magnesium chloride as a two-carbon building block. The carbenoid reagent was generated from α-chloroethyl para-tolylsulfoxide by sulfoxide-magnesium exchange and it added smoothly to the highly sensitive aldehyde of the Eastern fragment (C1?C7). Upon oxidation, an α-chloroethyl ketone was generated, which underwent a clean and high-yielding reductive SmI(2) -promoted addition to the other aldehyde fragment. Dehydration delivered the key double bond between C8 and C9 in an overall yield of 72?% over four steps. The method was shown to be generally applicable to the racemization-free conversion of several aldehydes into the respective α-chloroethyl ketone (11 examples, 64-95?%) and to the coupling protocol (5 examples, 66-90?%). The further course of the geldanamycin hydroquinone synthesis included a diastereoselective reduction at C7 and the implementation of the amino group at C20. Since deprotection of the two isopropyl protecting groups could not be achieved in significant yields, the structure of 18,21-diisopropyl-geldanamycin hydroquinone was proven by its independent synthesis from the natural product.