Sulfoxide-directed enantioselective synthesis of functionalized dihydropyrans

[reaction: see text] The highly selective base-promoted cyclization of enantiopure sulfinyl dienols affords allylic sulfinyl dihydropyrans.     

2,3]-Sigmatropic rearrangements of 3-sulfinyl dihydropyrans: application to the syntheses of the cores of ent-dysiherbaine and deoxymalayamicin A

The [2,3]-sigmatropic rearrangement of a variety of configurationally stable diastereomeric allylic sulfinyl dihydropyrans, produced by base-promoted cyclization of sulfinyl dienols, has been studied. In some cases, the efficient transformation of these substrates into dihydropyranols required an in-depth study of reaction conditions, with the preferred protocol relying on the use of DABCO in warm toluene. This methodology has been applied to the syntheses of the cores of ent-dysiherbaine and deoxymalayamicin A by means of efficient tethered aminohydroxylations.     

Palladium-catalyzed intramolecular allylic alkylation of α-sulfinyl carbanions: a new asymmetric route to enantiopure γ-lactams

Asymmetric intramolecular palladium-catalyzed allylic alkylation allowing access to disubstituted sulfinyl γ-lactams is described. The use of unsaturated amides bearing a sulfinyl group of defined absolute configuration together with enantiopure BINAP as the ligand in a biphasic medium provided good diastereoselectivities with clear solvent effect.     

Synthesis of Polycyclic Tertiary Carbinamines by Samarium Diiodide Mediated Cyclizations of Indolyl Sulfinyl Imines

Samarium diiodide mediated cyclizations of N‐acylated indole derivatives bearing sulfinyl imine moieties afforded polycyclic tertiary carbinamines with moderate to excellent diastereoselectivities. Lithium bromide and water turned out to be the best additives to achieve these transformations in good yields. Using enantiopure sulfinyl imines the outcome strongly depends on the reactivity of the indole moiety. Whereas with unactivated indole derivatives desulfinylation and formation of racemic products was observed, indoles bearing electron‐withdrawing substituents at C‐3 afforded the polycyclic products with intact N‐sulfinyl groups and with excellent diastereoselectivity, finally allowing the preparation of enantiopure tertiary carbinamines. The mechanisms of these processes are discussed.     

Base-Induced Enantioselective Synthesis of Sulfinyl Dihydropyrans

2-Sulfinyl dienols undergo an efficient base-promoted cyclization to produce sulfinyl dihydropyrans with creation of two asymmetric centers. The configurational stability of the allylic sulfoxide in most cases is noteworthy. Simple manipulations lead to a variety of functionalized tetrahydropyrans.     

Synthesis of enantiopure ethyl deoxymonate B from allylic sulfinyl dihydropyrans

A completely stereoselective dihydroxylation of a dihydropyranol and a cross-metathesis in the presence of a free homoallylic hydroxyl group are the key steps of a synthesis of enantiopure ethyl deoxymonate B from a sulfinyl dienol.     

A modular approach to aryl-C-ribonucleosides via the allylic substitution and ring-closing metathesis sequence. a stereocontrolled synthesis of all four α-/β- and D-/L-C-nucleoside stereoisomers

Iridium(I)-catalyzed allylation of the enantiopure monoprotected copper(I) alkoxide, generated from (S)-5a, with the enantiopure allylic carbonates (R)-9a,b has been developed as the key step in a new approach to C-nucleoside analogues. The anomeric center was thus constructed via a stereocontrolled formation of the C-O rather than C-C bond with retention of configuration. The resulting bisallyl ethers 15a,b (≥90% de and >99% ee) were converted into C-ribosides 29a,b via the Ru-catalyzed ring-closing metathesis, followed by a diastereoselective dihydroxylation catalyzed by OsO(4) or RuO(4) and deprotection. Variation of the absolute configuration of the starting segments 5a and 9a,b allowed a stereocontrolled synthesis of all four α/β-D/L-combinations.     

Highly regio- and stereoselective palladium-catalyzed allylic carbonate amination. A practical route to dehydro-β-amino esters

A pratical, highly enantioselective method for the synthesis of dehydro-β-amino acids was developed starting from easily accessible enantiopure allylic carbonates. The substitution with amines for C–N bond formation on these substrates bearing substituents on the Cα, Cβ, and Cγ position of the allylic system has received, until now, little attention. The reactions, carried out under palladium-catalyzed conditions, resulted in good yields and complete regioselectivity. Moreover, starting from enantiopure carbonates, complete retention of the configuration could be observed, affording enantiopure allylic amines.     

Catalytic asymmetric synthesis of a 1-deoxy-1,1-difluoro-D-xylulose

[reaction: see text] A new route, of potential strategic importance, to a difluorosugar analogue has been developed. Key steps included a Stille coupling and a highly regio- and enantioselective dihydroxylation of a highly substituted diene. Protecting groups were chosen to enhance the reactivity of the disubstituted allylic fragment in the AD reaction and allow deprotection under orthogonal conditions.     

Dihydroxylation-based approach for the asymmetric syntheses of hydroxy-γ-butyrolactones

A method of preparing enantiopure hydroxy-γ-butyrolactones containing multiple contiguous stereocenters in high yield with good diastereoselectivity has been developed. Osmium tetroxide mediated dihydroxylation of a range of β-alkenyl-β-hydroxy-N-acyloxazolidin-2-ones results in formation of triols that undergo spontaneous intramolecular 5-exo-trig cyclization reactions to provide hydroxy-γ-butyrolactones. The stereochemistry of these hydroxy-γ-butyrolactones has been established using NOE spectroscopy, which revealed that 1-substituted, 1,1-disubstituted, (E)-1,2-disubstituted, (Z)-1,2-disubstituted, and 1,1,2-trisubstituted alkenes undergo dihydroxylation with anti-diastereoselectivity, while 1,2,2-trisubstituted systems afford syn-diastereoisomers. The synthetic utility of this methodology has been demonstrated for the asymmetric synthesis of the natural product 2-deoxy-D-ribonolactone.     

Enantiopure sulfinyl azobenzenes as chiroptical switches

[reaction: see text] Photoswitchable enantiopure sulfinyl azo compounds have been synthesized. A remarkable perturbation of the azo system by the stereogenic sulfinyl moiety has been observed by CD in both the trans and the cis azobenzenes resulting by photoisomerization. After five irradiation cycles, the configurational integrity of these chiral switches remains unchanged.     

Asymmetric synthesis of aziridine 2-phosphonates from enantiopure sulfinimines (N-sulfinyl imines). Synthesis of alpha-amino phosphonates

An aza-Darzens reaction, involving the addition of chloromethylphosphonate anions to enantiopure sulfinimines, has been developed for the asymmetric synthesis of aziridine 2-phosphonates. Best results involve cyclization of the syn and anti diastereomerically pure alpha-chloro-beta-amino phosphonates to cis- and trans-N-sulfinyl aziridine 2-phosphonates, respectively, with n-BuLi. A transition-state hypothesis is proposed wherein the chloromethylphosphonate anion adds to the C-N bond on the side that is opposite the bulky p-tolyl sulfinyl group. The N-sulfinyl group is easily removed by treatment with MeMgBr or TFA/MeOH, which affords the NH-aziridines in good yield. Using transfer hydrogenation conditions, the NH-aziridines were regioselectively opened to the corresponding enantiopure alpha-amino phosphonates without N-activation and in excellent yield.     

Access to the Enantiopure Axially Chiral Cyclophane Isoplagiochin D through Atropo‐diastereoselective Heck Coupling

Macrocyclization is typically the key step in the syntheses of cyclophane‐type natural products. Considering cyclophanes with axially chiral biaryl moieties, the control of atroposelectivity is essential with biological activity and is synthetically challenging. We report an atroposelective approach involving Heck cyclization, which for the first time enables the total synthesis of an enantiopure macrocyclic bis(bibenzyl), namely isoplagiochin D. An enantiopure sulfinyl auxiliary in the ortho position of a biaryl axis (still flexible) was used to induce an atropo‐diastereoselective Heck coupling (up to 98 % de). The traceless character of the sulfinyl auxiliary enables the introduction of a hydroxy group to give the target molecule with 98 % ee as well.     

Total synthesis of (+)-4,5-deoxyneodolabelline

The first total synthesis of the marine dolabellane diterpene (+)-4,5-deoxyneodolabelline (1) has been accomplished. The highly efficient approach is characterized by the convergent assembly of dihydropyrans 2ab and cyclopentylsilanes 3ab. Allylic silane 3a was prepared from 2-methyl-2-cyclopentenone via a copper-catalyzed 1,4-addition followed by diastereoselective alkylation of the resulting enolate. A chemical resolution of racemic cyclopentanone 8 was effected by (S)-CBS-catalyzed borohydride reduction. Direct hydroxymethylation of the enantioenriched ketone 8 to form allylic alcohol 14 was achieved by a Stille palladium-catalyzed cross-coupling from the cyclopentenyl triflate 13. Treatment of the corresponding allylic phosphate 15 with trimethylsilylcopper reagent provided for displacement with allylic transposition yielding the exocyclic allylsilane 3a with excellent diastereoselectivity. Dihydropyrans 2a and 2b were prepared from optically pure acyclic acetals via ring-closing metathesis. Coupling of 3a and 2a or 2b via the carbon-Ferrier protocol gave trans-2,6-disubstituted dihydropyrans 30 and 35 with complete stereoselectivity. Vanadium-based pinacol coupling reactions were explored for closure of the medium-sized carbocycle to yield syn-diol 33. X-ray diffraction studies of the monobenzoate 34 have provided unambiguous stereochemical assignments. Substantial ring strain accounted for the lack of alkene products typical of reductive elimination using TiCl(3) and zinc-copper couple (McMurry) conditions leading to 37. Finally, the natural product 1 was obtained via Swern oxidation of the diol 37.     

Metal‐Catalyzed Cyclization of β‐ and γ‐Allenols Derived from D‐Glyceraldehyde—Synthesis of Enantiopure Dihydropyrans and Tetrahydrooxepines: An Experimental and Theoretical Study

Regiocontrolled metal‐catalyzed preparations of enantiopure dihydropyrans and tetrahydrooxepines have been synthesized starting from β‐ and γ‐allenols derived from D ‐glyceraldehyde. The Pd^II‐catalyzed cyclizative coupling reactions of β‐allenols 1 a and 1 b with allyl bromide effectively afforded enantiopure tetrafunctionalized dihydropyrans through a 6‐endo oxycyclization protocol, whereas the gold‐, platinum‐, and palladium‐mediated heterocyclization of γ‐allenol 2 furnished tetrahydrooxepines 13 – 16 through regioselective 7‐endo‐trig oxycyclization reactions. Moreover, density functional calculations were performed to predict the regioselectivity of the γ‐allenol cycloetherification to tetrahydrooxepines on the basis of both the tether nature and characteristics of the metals, and to gain an insight into the mechanism of the oxycyclization reactions.     

Nucleophilic epoxidation of alpha'-hydroxy dienyl sulfoxides

A novel route to enantiopure densely functionalized epoxy sulfinyl tetrahydrofurans, based on the unexpected and highly stereoselective remote nucleophilic epoxidation of hydroxy 1-sulfinyl butadienes with t-BuOOK, followed by ring closure and subsequent epoxidation of the resulting sulfinyl dihydrofurans, is described. Alternatively, the treatment of these dienes with m-CPBA followed by acid-catalyzed cyclization gives rise to related sulfonyl dihydrofurans in high yields but with low selectivity. The stereochemical outcome of the nucleophilic epoxidation of these substrates has also been studied.     

The RuO4-catalysed dihydroxylation, ketohydroxylation and mono oxidation--novel oxidation reactions for the synthesis of diols and alpha-hydroxy ketones

Alpha-hydroxy ketones are versatile intermediates for the synthesis of complex molecular architectures and subunits of a variety of natural products. Different approaches towards the synthesis of this important functional group combination have been elaborated. The present article summarises our research on the field of RuO4-catalysed oxidations of alkenes that resulted in the development of the first RuO4-catalysed ketohydroxylation of olefins. Mechanistic investigations of both dihydroxylation and ketohydroxylation led to the discovery of the first regioselective catalytic mono oxidation of vic-diols, which was applied in a two-step sequence of asymmetric dihydroxylation and regioselective mono oxidation to furnish enantiopure alpha-hydroxy ketones with both predictable regioselectivity and absolute configuration.     

Stereoselective cis-dihydroxylation of azulene and related non-aromatic polyenes

Dioxygenase-catalysed dihydroxylation of azulene and related non-aromatic polyenes has been found to yield enantiopure chiral cis-diols of synthetic potential.     

Palladium-catalyzed allylic nucleophilic substitution reactions of (E)-γ-acetoxy-α,β-unsaturated p-tolylsulfoxides

Regio- and diastereoselective nucleophilic allylic substitutions of optically pure (E)-γ-acetoxy-α,β-unsaturated p-tolylsulfoxides 2 and 3 with sodium dimethyl malonate have been carried out. The reactivity of these substrates is controlled by both the chiral sulfinyl group and the size of the alkyl group attached at the γ-terminus of the allylic system. This process constitutes an example of palladium-mediated resolution of a 1:1 mixture of acetates 2 and 3.     

Asymmetric synthesis of pyrrolo[2,1-a]isoquinoline derivatives by 1,3-dipolar cycloadditions of stabilized isoquinolinium N-ylides with sulfinyl dipolarophiles

Enantiomerically pure pyrrolo[2,1-a]isoquinoline derivatives are obtained by 1,3-dipolar reactions of isoquinolinium azomethine ylides with enantiopure 3-p-tolylsulfinylacrylonitriles, tert-butyl (2E)-4,4-diethoxy-2-p-tolylsulfinylbut-2-enoate, and 5-ethoxy-3-p-tolylsulfinylfuran-2(5H)-ones. Reactions evolve through the anti conformation of the ylide with complete regioselectivity. The facial selectivity is completely controlled by the configuration of the sulfinyl sulfur for acyclic dipolarophiles, whereas it is high (dr 83/17 or 89/11) but controlled by the C-5 configuration for sulfinylfuranones. Complete endo selectivity is observed with cyclic dipolarophiles and substituted acrylonitriles, but it is low with butenoate. The sulfinyl group also exerts a positive influence on the dipolarophilic reactivity toward these ylides.