(18)O]-oxygen incorporation reveals novel pathways in spiroacetal biosynthesis by Bactrocera cacuminata and B. cucumis

The origins of the oxygen atoms in 1,7-dioxaspiro[5.5]undecane (1) and hydroxyspiroacetal (2) from Bactrocera cacuminata, and in 2,8-dimethyl-1,7-dioxaspiro[5.5]undecane (3) and hydroxyspiroacetal (4) from B. cucumis, have been investigated by incorporation studies from both [(18)O(2)]-dioxygen and [(18)O]-water. Combined GC-MS examination and high-field NMR analysis have demonstrated that all oxygen atoms in 1 and 2 from B. cacuminata are dioxygen derived, but in contrast, the spiroacetals 3 and 4 from B. cucumis incorporate one ring oxygen from water and one ring oxygen (and the hydroxyl oxygen in 4) from [(18)O(2)]-dioxygen. These results reveal not only the generality of monoxygenase mediation of spiroacetal formation in Bactrocera sp., but also an unexpected complexity in their biosynthesis. A general paradigm accommodating these and other observations is presented.     

Synthesis of aromatic spiroacetals related to γ-rubromycin based on a 3H-spiro[1-benzofuran-2,2′-chromane] skeleton

The synthesis of a series of aromatic 5,6-benzannelated and naphthyl-benzannelated spiroacetals related to the spiroacetal unit present in the quinonoid antibiotic γ-rubromycin is reported. The key steps include the use of Sonogashira coupling to construct an aryl acetylene that is coupled to an aryl aldehyde forming a propargyl alcohol intermediate. Hydrogenation of the resultant alkynol followed by oxidation produces a masked dihydroxyketone that upon treatment with silica-supported sodium hydrogen sulfate undergoes concomitant deprotection and cyclisation to afford the desired fused aromatic spiroacetal.     

Synthesis of the spirofungin B core by a reductive cyclization strategy

[reaction: see text] A reductive decyanation approach to the synthesis of the core of spirofungin B has been developed. Spirofungin B has only one anomeric stabilization in the spiroacetal and was isolated along with its spiroacetal epimer, spirofungin A. The cyclization precursor was constructed from readily available starting materials. The reductive cyclization reaction was both efficient and stereoselective. The reductive cyclization strategy to spiroacetals is convergent and effective.     

Short diastereoselective synthesis of the C1-C13 (AB spiroacetal) and C17-C28 fragments (CD spiroacetal) of spongistatin 1 and 2 through double chain-elongation reactions

A unique and practical synthetic sequence for rapid access to polyketides and to further the spiroacetals derived from them, which utilizes a bidirectional Hosomi-Sakurai allylation approach around key allylsilanes in the synthesis of the AB and CD ring systems of spongistatin 1 and 2, is reported. The synthesis of the AB spiroacetal 9 requires 13 steps, with a longest linear sequence of seven steps in an overall yield of 27%. The synthesis of the CD spiroacetal 13 requires 15 steps, with a longest linear sequence of 11 steps in an overall yield of 30%. Both syntheses start from but-3-enol.     

Synthesis of Chiral Spiroacetals from Carbohydrates

Chiral spiroacetals of the 1,7-dioxaspiro[5.5]undecane, 1,6-dioxaspiro[4.5]decane, and 1,6-dioxaspiro[4.4]nonane types have been prepared from carbohydrates in pyranose or furanose forms. The spirocyclization reaction has been accomplished from a conveniently homologated carbohydrate by an intramolecular hydrogen abstraction reaction promoted by alkoxy radicals. Thus, 2,3,4,6-tetra-O-benzyl-1-deoxy-1-(3'-hydroxypropyl)-alpha-D-glucopyranose (2) was photolyzed with visible light in the presence of (diacetoxyiodo)benzene and iodine to give a mixture of (1R)-(3) and (1S)-2,3,4,6-tetra-O-benzyl-1-deoxy-D-glucopyranose-1-spiro-2'-tetrahydrofuran (4). The photolysis of methyl 6-deoxy-6-(2'-hydroxyethyl)-2,3,4-tri-O-methyl-alpha-D-glucopyranoside (8) gave the isomeric spiroacetals methyl (5S)- (9) and (5R)-6-deoxy-5,2'-epoxy-6-ethyl-2,3,4-tri-O-methyl-alpha-D-glucopyranoside (10) in which the spirocenter is now located at C-5. The spiroacetals of the [5.5]undecane series: methyl (5R)- (19) and (5S)-6-deoxy-5,3'-epoxy-2,3,4-tri-O-methyl-6-propyl-beta-D-glucopyranoside (20) have been prepared starting from methyl 6-deoxy-6-(3'-hydroxypropyl)-2,3,4-tri-O-methyl-beta-D-glucopyranoside (18). The reaction has also been applied to hexofuranoses and 1-deoxy-1-(3'-hydroxypropyl)-2,3:5,6-di-O-isopropylidene-alpha-D-mannofuranose (21) gave rise to (1S)- (22) and (1R)-1-deoxy-2,3:5,6-di-O-isopropylidene-D-mannofuranose-1-spiro-2'-tetrahydrofuran (23); and 1-deoxy-1-(4'-hydroxybutyl)-2,3:5,6-di-O-isopropylidene-alpha-D-mannofuranose (28) to (1R)- (30) and (1S)-1-deoxy-2,3:5,6-di-O-isopropylidene-D-mannofuranose-1-spiro-2'-tetrahydropyran (32). Both spiroacetal enantiomers are formally available from the same carbohydrate.     

A New Two-Step Stereospecific Synthesis of Glycidic Spiroacetals

ABSTRACT

The spiroacetal moiety has received much attention in recent years owing to its occurence in several biologically important natural products.¹ In that field, the antibiotics avermectins,² milbemycins³ and papulacandins⁴ are of particular interest to us because a carbohydrate precursor could be employed for their syntheses.^5-7 other glycidic spiroacetals were obtained by photocarbocyclization of 2-carbophenyl-β-D-glucopyranosides.⁸     

Spiroacetal biosynthesis: (+/-)-1,7-dioxaspiro[5.5]undecane in Bactrocera cacuminata and Bactrocera oleae (Olive Fruit Fly)

[reaction: see text] A biosynthetic scheme rationalizing the formation of (+/-)-1,7-dioxaspiro[5.5]undecane (5) in the fruit fly species Bactrocera cacuminata and Bactrocera oleae (olive fruit fly) is presented. Incorporation studies with deuterium-labeled keto aldehyde (10), 1,5-nonanediol (11), and 1,5,9-nonanetriol (12), and our previous finding that both oxygen atoms of 5 originate from dioxygen, are strongly evidentiary. The racemic condition of the natural spiroacetal 5 is accounted for, and inter alia, it is demonstrated that dihydropyran (18) is not an important intermediate en route to 5.     

Synthesis of the ABC tricyclic fragment of the pectenotoxins via stereocontrolled cyclization of a gamma-hydroxyepoxide appended to the AB spiroacetal unit

The stereocontrolled synthesis of the C1-C16 ABC spiroacetal-containing tricyclic fragment of pectenotoxin-7 6 has been accomplished. The key AB spiroacetal aldehyde 9 was successfully synthesized via acid catalyzed cyclization of protected ketone precursor 28 that was readily prepared from aldehyde 12 and sulfone 13. The syn stereochemistry in aldehyde 12 was installed using an asymmetric aldol reaction proceeding via a titanium enolate. The stereogenic centre in sulfone 13 was derived from (R)-(+)-glycidol. The absolute stereochemistry of the final spiroacetal aldehyde 9 was confirmed by NOE studies establishing the (S)-stereochemistry of the spiroacetal centre. Construction of the tetrahydrofuran C ring system began with Wittig olefination of the AB spiroacetal aldehyde 9 with (carbethoxyethylidene)triphenylphosphorane 10 affording the desired (E)-olefin 32. Appendage of a three carbon chain to the AB spiroacetal fragment was achieved via addition of acetylene 11 to the unstable allylic iodide 39. Epoxidation of (E)-enyne 8 via in situ formation of L-fructose derived dioxirane generated the desired syn-epoxide 36. Semi-hydrogenation of the resulting epoxide 36 followed by dihydroxylation of the alkene effected concomitant cyclization, thus completing the synthesis of the ABC spiroacetal ring fragment 6.     

The stereocontrolled total synthesis of altohyrtin A/spongistatin 1: the CD-spiroacetal segment

Stereocontrolled syntheses of the C16-C28 CD-spiroacetal subunit of altohyrtin A/spongistatin 1 , relying on kinetic and thermodynamic control of the spiroacetal formation, are described. The kinetic control approach resulted in a slight preference (60 : 40) for the desired spiroacetal isomer. The thermodynamic approach allowed ready access to the desired spiroacetal by acid-promoted equilibration, chromatographic separation of the C23 epimers and resubjection of the undesired isomer to the equilibration conditions. This scalable synthetic sequence provided multi-gram quantities of , thus enabling the successful completion of the total synthesis of altohyrtin A/spongistatin 1, as reported in Part 4 of this series.     

Conformational preferences of oxy-substituents in butenolide-tetrahydropyran spiroacetals and butenolide-piperidine spiro-N,O-acetals

We describe the synthesis of a series of oxy-substituted butenolide spiroacetals and spiro-N,O-acetals by oxidative spirocyclisation of 2-[(4-hydroxy or 4-sulfonamido)butyl]furans. The axial-equatorial preference of each oxy-substituent is investigated (NMR) by an acid-catalysed thermodynamic relay of configuration between the spiro- and oxy-centres. The axial site is preferred for most oxy-substituents at synthetically useful levels. The potential origins of this preference are discussed in terms of a stabilising gauche effect combined with the influence of solvation. These results have relevance to the synthesis of bis(acetylenic)enol ether spiroacetals including AL-1 and related compounds.     

Flexible synthesis of enantiomerically pure 2,8-dialkyl-1,7-dioxaspiro[5.5]undecanes and 2,7-dialkyl-1,6-dioxaspiro[4.5]decanes from propargylic and homopropargylic alcohols

A new approach to enantiomerically pure 2,8-dialkyl-1,7-dioxaspiro[5.5]undecanes and 2,7-dialkyl-1,6-dioxaspiro[4.5]decanes is described and utilizes enantiomerically pure homopropargylic alcohols obtained from lithium acetylide opening of enantiomerically pure epoxides, which are, in turn, acquired by hydrolytic kinetic resolution of the corresponding racemic epoxides. Alkyne carboxylation and conversion to the Weinreb amide may be followed by triple-bond manipulation prior to reaction with a second alkynyllithium derived from a homo- or propargylic alcohol. In this way, the two ring components of the spiroacetal are individually constructed, with deprotection and cyclization affording the spiroacetal. The procedure is illustrated by acquisition of (2S,5R,7S) and (2R,5R,7S)-2-n-butyl-7-methyl-1,6-dioxaspiro[4.5]-decanes (1), (2S,6R,8S)-2-methyl-8-n-pentyl-1,7-dioxaspiro[5.5]undecane (2), and (2S,6R,8S)-2-methyl-8-n-propyl-1,7-dioxaspiro[5.5]undecane (3). The widely distributed insect component, (2S,6R,8S)-2,8-dimethyl-1,7-dioxaspiro[5.5]undecane (4), was acquired by linking two identical alkyne precursors via ethyl formate. In addition, [(2)H(4)]-regioisomers, 10,10,11,11-[(2)H(4)] and 4,4,5,5-[(2)H(4)] of 3 and 4,4,5,5-[(2)H(4)]-4, were acquired by triple-bond deuteration, using deuterium gas and Wilkinson's catalyst. This alkyne-based approach is, in principle, applicable to more complex spiroacetal systems not only by use of more elaborate alkynes but also by triple-bond functionalization during the general sequence.     

A Palladium(II)‐Catalyzed Synthesis of Spiroacetals through a One‐Pot Multicomponent Cascade Reaction

Functionalized spiroacetals have been easily prepared in a one‐pot three‐component coupling process that involves the reaction of pentynol derivatives, salicylaldehydes, and amines in the presence of catalytic amounts of a palladium(II) complex (see scheme). Alternatively, oxygen‐substituted spiroacetals can be obtained by using orthoesters as the third component.

     

Total synthesis of paecilospirone

Neutrality is the best policy: Key features of the first total synthesis of paecilospirone include an anti-selective, lactate-derived aldol reaction, and a double deallylation/spirocyclization conducted at neutral pH to construct the sensitive hydroxy-substituted benzannulated spiroacetal (see scheme; Bn=benzyl, TBS=tert-butyldimethylsilyl, TES=triethylsilyl).     

Diastereoselective synthesis of the pectenotoxin 2 non-anomeric AB spiroacetal

The reductive cyclization reaction of a cyanoacetal has been used to prepare the pectenotoxin 2 (PTX-2) AB spiroacetal with high diastereoselectively for the first time. The strategy is convergent and makes use of the axial-selective reductive lithiation of 2-cyano tetrahydropyran rings to introduce the spiroacetal center with the desired non-anomeric selectivity. [reaction: see text].     

Total Synthesis of Pectenotoxin‐2

Pectenotoxin‐2 (PTX2) is a shellfish toxin and has a non‐anomeric spiroacetal, which is not stabilized by an anomeric effect. The selective construction of the non‐anomeric spiroacetal has been a major problem in the synthesis of PTX2. Described herein is the stereoselective total synthesis of PTX2 via the isomerization of anomeric spiroacetal pectenotoxin‐2b (PTX2b). The synthesis of PTX2b was achieved by a simple process including sulfone‐mediated assembly of spirocyclic and bicyclic acetals and subsequent macrocyclization by ring‐closing olefin metathesis. Finally, the selective construction of PTX2 was accomplished by the early termination of a dynamic transition process to equilibrium in the acid‐catalyzed isomerization of anomeric PTX2b. [6,6]‐Spiroacetal pectenotoxin‐2c (PTX2c) was also synthesized from PTX2b. The cytotoxicity assay of the synthetic compounds against HepG2 and Caco2 cancer cells showed a potency of the order: PTX2?PTX2b>PTX2c.     

Enantioselective synthesis of C-linked spiroacetal-triazoles as privileged natural product-like scaffolds

The enantioselective synthesis of novel C-linked spiroacetal-triazoles 10 is reported. The key step involves reaction of acetylenic spiroacetal 11 with several azides by the Copper-Catalysed Azide-Alkyne Cycloaddition (CuAAC). The biologically privileged spiroacetal scaffold 11 was prepared from silyl-protected Weinreb amide 19 using several reliable Grignard additions and a highly diastereoselective enzymatic kinetic resolution.     

Synthesis and assignment of the absolute configuration of the anti-Helicobacter pylori agents CJ-12,954 and CJ-13,014

The synthesis of the spiroacetal-containing anti-Helicobacter pylori agents (3S,2'S,5'S,7'S)- (ent-CJ-12,954) and (3S,2'S,5'R,7'S)- (ent-CJ-13,014) has been carried out based on the convergent union of a 1:1 mixture of heterocycle-activated spiroacetal sulfones and with (3S)-phthalide aldehyde . The synthesis of the (3R)-diastereomers (3R,2'S,5'S,7'S)- and (3R,2'S,5'R,7'S)- was also undertaken in a similar manner by union of (3R)-phthalide aldehyde with a 1:1 mixture of spiroacetal sulfones and . Comparison of the (1)H and (13)C NMR data, optical rotations and HPLC retention times of the synthetic compounds (3S,2'S,5'S,7'S)- and (3S,2'S,5'R,7'S)- and the (3R)-diastereomers (3R,2'S,5'S,7'S)- and (3R,2'S,5'R,7'S)-, with the naturally occurring compounds, established that the synthetic isomers and were in fact enantiomeric to the natural products CJ-12,954 and CJ-13,014. The (2S,8S)-stereochemistry in protected dihydroxyketone , the precursor to the mixture of spiroacetal sulfones and was established via union of readily available (S)-acetylene with aldehyde in which the (4S)-stereochemistry was established via asymmetric allylation. Deprotection and cyclization of protected dihydroxyketone afforded an inseparable 1:1 mixture of spiroacetal alcohols and that were converted into a 1:1 inseparable mixture of spiroacetal sulfones and . Phthalide-aldehyde was prepared via intramolecular acylation of bromocarbamate in which the (3S)-stereochemistry was established via asymmetric CBS reduction of ketone .     

Formation of the Δ18,19 Double Bond and Bis(spiroacetal) in Salinomycin Is Atypically Catalyzed by SlnM,a Methyltransferase‐like Enzyme

Salinomycin is a widely used polyether coccidiostat and was recently found to have antitumor activities. However, the mechanism of its biosynthesis remained largely speculative until now. Reported herein is the identification of an unprecedented function of SlnM, homologous to O‐methyltransferases, by correlating its activity with the formation of the Δ^18,19 double bond and bis(spiroacetal). Detailed in vivo and in vitro investigations revealed that SlnM, using positively charged S‐adenosylmethionine (SAM) or sinefungin as the cofactor, catalyzed the spirocyclization‐coupled dehydration of C19 in a highly atypical fashion to yield salinomycin.     

Rational synthesis of contra-thermodynamic spiroacetals by reductive cyclizations

A synthesis of spiroacetals was developed using a reductive cyclization strategy that leads stereoselectively to spiroacetals with a single anomeric stabilization. The method begins with the synthesis of spiro ortho esters. The ortho ester is converted to a cyano acetal. Reductive lithiation of the cyano acetal generates an axial dialkoxylithium reagent, and intramolecular cyclization produces a new ring with retention of configuration. The strategy is convergent and produces complex spiro acetals in only a few steps. The method will be useful in the synthesis of natural products and will facilitate the synthesis of previously inaccessible contra-thermodynamic acetals.     

Total synthesis of aculeatins A and B from (S)-malic acid

A simple convergent approach towards the total synthesis of bioactive spiroacetals aculeatins A and B is described. The key features of the synthetic strategy include a syn-stereoselective 1,3-asymmetric reduction, epoxide ring opening and oxidative spirocyclization reaction by employing (S)-malic acid as the starting material.