Martin's Sulfurane Research Articles

N-Oxide Route to the Marine Natural Product Cyanogramide D

AbstractThe first synthesis of the marine natural product cyano­gramide D is reported. The key step is the acetylation of a β-carboline N-oxide, followed by acetyl migration. Since in this particular case it was not possible to incorporate the styryl side chain by Buchwald coupling, a phenylethanolamine side chain was attached, which was dehydrated with Martin’s sulfurane after assembly of the tetracycle. Pentacyclic products were obtained under Appel conditions. The synthesis will facilitate the exploration of the biomimetic oxidative spirocyclization of cyanogramide D to the spirooxindole cyanogramide.

Enantiospecific sp2 -sp3 Coupling of ortho- and para-Phenols with Secondary and Tertiary Boronic Esters.

The coupling of ortho‐ and para‐phenols with secondary and tertiary boronic esters has been explored. In the case of para‐substituted phenols, after reaction of a dilithio phenolate species with a boronic ester, treatment with Ph3BiF2 or Martin's sulfurane gave the coupled product with complete enantiospecificity. The methodology was applied to the synthesis of the broad spectrum antibacterial natural product (−)‐4‐(1,5‐dimethylhex‐4‐enyl)‐2‐methyl phenol. For ortho‐substituted phenols, initial incorporation of a benzotriazole on the phenol oxygen atom was required. Subsequent ortho‐lithiation and borylation gave the coupled product, again with complete stereospecificity.

Enantiospecific sp2–sp3 Coupling of ortho‐ and para‐Phenols with Secondary and Tertiary Boronic Esters

AbstractThe coupling of ortho‐ and para‐phenols with secondary and tertiary boronic esters has been explored. In the case of para‐substituted phenols, after reaction of a dilithio phenolate species with a boronic ester, treatment with Ph3BiF2 or Martin's sulfurane gave the coupled product with complete enantiospecificity. The methodology was applied to the synthesis of the broad spectrum antibacterial natural product (−)‐4‐(1,5‐dimethylhex‐4‐enyl)‐2‐methyl phenol. For ortho‐substituted phenols, initial incorporation of a benzotriazole on the phenol oxygen atom was required. Subsequent ortho‐lithiation and borylation gave the coupled product, again with complete stereospecificity.

Mechanism of Ylide Transfer to ­Carbonyl Compounds: Density Functional Calculations

AbstractWe report a computational study on the mechanism of the reaction of ethyl acetoacetate (1) with two sulfur reagents: Martin's sulfurane (Ra) and a mixture of diphenyl sulfide and triflic anhydride (Rb). These reagents are able to provide a sulfonium ion [Ph2S‐OX]+ and an anionic nucleophile –OX as active species [X = C(CF3)2Ph for Ra and X = SO2CF3 for Rb] in the reaction. Experimentally, the reaction of Ra with carbonyl compounds provides an S‐ylide as the only product whereas a low yield of S‐ylide is obtained in the case of Rb. To elucidate the mechanism of these reactions with prototype substrate 1, different plausible pathways have been investigated using density functional theory (DFT), mostly at the B3LYP‐D/6‐31+G** level. According to DFT calculations, initial deprotonation of 1 may furnish either an enolate (with Ra) or an O‐sulfenylated enolate (with Rb). Subsequent nucleophilic addition of the enolate to the sulfonium ion provides the simplest route to S‐ylide product, which is favored when using reagent Ra. In the case of reagent Rb, the preferentially formed O‐sulfenylated enolate may undergo either a series of nucleophilic displacements or a [1,3] sigmatropic shift or a [3,3] sigmatropic rearrangement, all followed by a final deprotonation to yield the product. These conversions are highly exothermic and involve thermodynamically stable products. The [3,3] sigmatropic rearrangement that directly produces an arylated carbonyl compound is computed to be the kinetically most facile reaction with Rb. Overall, the computational results unveil detailed mechanistic scenarios detailing possible transformations and providing qualitative explanations for some of the experimental findings.

Selective access to E- and Z-ΔIle-containing peptides via a stereospecific E2 dehydration and an O → N acyl transfer.

A concise synthesis of peptides that contain E- or Z-dehydroisoleucine (ΔIle) residues is reported. The key reaction is an unusual anti dehydration of β-tert-hydroxy amino acid derivatives that is mediated by the Martin sulfurane. A subsequent tandem Staudinger reduction-O → N acyl transfer process forges an amide bond to the ΔIle residue with minimal E/Z alkene isomerization. Density functional calculations attribute the stereospecific dehydration to a highly asynchronous E2 anti process.

Stereo-controlled total syntheses of ieodomycins A and B using d-glucose based chiral pool approach

The first stereo-controlled total syntheses of ieodomycins A and B have been accomplished in 15 steps using the chiral pool approach starting from d-glucose. The key features of this synthetic strategy are Wittig olefination, indium catalyzed Barbier reaction, and Martin sulfurane catalyzed dehydration to achieve preferential formation of the desired E isomer.

Martin Sulfurane - A Versatile Reagent for Organic Synthesis

Martin Sulfurane, a diphenylsulfur compound, has been a versatile reagent in organic synthesis since the 1970s.

SmI2-Promoted Reformatsky-Type Coupling Reactions in Exceptionally Hindered Contexts

Highly substituted, very hindered enones were synthesized using a two-step procedure that utilizes a diiodosamarium-promoted Reformatsky-type coupling and dehydration using Martin sulfurane. Both alpha-chloro- and alpha-bromoketones were coupled with a variety of carbonyl nucleophiles to form the intermediate beta-hydroxyketones, occurring with excellent diastereoselectivity, favoring the syn isomer (R1=Me). This technique complements other methods and enables the preparation of enones outside of the scope of current olefination methodology.

Formal Total Synthesis of Neocarzinostatin Chromophore

[reaction: see text] An efficient route to the neocarzinostatin chromophore aglycon has been developed. The present strategy involves a stereoselective intramolecular acetylide-aldehyde cyclization to form the C5-C6 bond, followed by efficient installation of alpha-epoxide, naphthoate, and carbonate functionalities. The C8-C9-olefin was introduced by using the Martin sulfurane dehydration reaction to furnish the highly reactive aglycon.

Difluorinated analogues of shikimic acid

Investigations into the quinate to shikimate transformation have been carried out, the results of which have been exploited in the synthesis of a novel difluoromethylene homologue of shikimic acid from (−)-quinic acid. Martin's sulfurane {Ph 2S[OC(CF 3) 2Ph] 2} was the reagent of choice for the key dehydration step of this synthesis. The results of investigations into the synthesis of the important natural product analogue, 6,6-difluoroshikimic acid are also reported.

Total Synthesis of Somamide A, an Ahp (3‐Amino‐6‐hydroxy‐2‐piperidone)‐Containing Cyclic Depsipeptide.

The first total synthesis of somamide A (1), an Ahp (3-amino-6-hydroxy-2-piperidone)-containing cyclic depsipeptide, from the marine cyanobacterium Lyngbya majuscula is described. The efficient and stereospecific dehydration of the N-acyl threonine ester using Martin's sulfurane provided the (Z)-2-amino-2-butenoic acid residue. The macrolactamization using FDPP(Ph2P(O)OC6F5), the final installation of the Ahp moiety by oxidation with 1-hydroxy-1,2-benziodoxol-3(1H)-one 1-oxide, and cyclization of the norvaline derivative to the cyclic hemiaminal afforded somamide A (1).

Novel Stereospecific Dehydration of β‐Hydroxy‐α‐amino Acids Using Martin′s Sulfurane.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Novel stereospecific dehydration of β-hydroxy-α-amino acids using Martin's sulfurane

The stereospecific dehydration of threo- N-acyl-β-hydroxy-α-amino acid derivatives was performed using Martin's sulfurane to give ( Z)-α,β-dehydroamino acids, while erythro- N-acyl-β-hydroxy-α-amino acid amides were converted to 4,5- trans-oxazolines using analogous reaction conditions.

Total synthesis of somamide A, an Ahp (3-amino-6-hydroxy-2-piperidone)-containing cyclic depsipeptide

The first total synthesis of somamide A ( 1 ), an Ahp (3-amino-6-hydroxy-2-piperidone)-containing cyclic depsipeptide, from the marine cyanobacterium Lyngbya majuscula is described. The efficient and stereospecific dehydration of the N-acyl threonine ester using Martin's sulfurane provided the ( Z)-2-amino-2-butenoic acid residue. The macrolactamization using FDPP(Ph 2P(O)OC 6F 5), the final installation of the Ahp moiety by oxidation with 1-hydroxy-1,2-benziodoxol-3(1 H)-one 1-oxide, and cyclization of the norvaline derivative to the cyclic hemiaminal afforded somamide A ( 1 ).

Development of an enantioselective synthetic route to neocarzinostatin chromophore and its use for multiple radioisotopic incorporation.

A convergent, enantioselective synthetic route to the natural product neocarzinostatin chromophore (1) is described. Synthesis of the chromophore aglycon (2) was targeted initially. Chemistry previously developed for the synthesis of a neocarzinostatin core model (4) failed in the requisite 1,3-transposition of an allylic silyl ether when applied toward the preparation of 2 with use of the more highly oxygenated substrates 27 and 54. An alternative synthetic plan was therefore developed, based upon a proposed reduction of the epoxy alcohol 58 to form the aglycon 2, a transformation that was achieved in a novel manner, using a combination of the reagents triphenylphosphine, iodine, and imidazole. The successful route to 1 and 2 began with the convergent coupling of the epoxydiyne 15, obtained in 9 steps (43% overall yield) from D-glyceraldehyde acetonide, and the cyclopentenone (+)-14, prepared in one step (75-85% yield) from the prostaglandin intermediate (+)-16, affording the alcohol 22 in 80% yield and with > or =20:1 diastereoselectivity. The alcohol 22 was then converted into the epoxy alcohol 58 in 17 steps with an average yield of 92% and an overall yield of 22%. Key features of this sequence include the diastereoselective Sharpless asymmetric epoxidation of allylic alcohol 81 (98% yield); intramolecular acetylide addition within the epoxy aldehyde 82, using Masamune's lithium diphenyltetramethyldisilazide base (85% yield); selective esterification of the diol 84 with the naphthoic acid 13 followed by selective cleavage of the chloroacetate protective group in situ to furnish the naphthoic acid ester 85 in 80% yield; and elimination of the tertiary hydroxyl group within intermediate 88 using the Martin sulfurane reagent (79% yield). Reductive transposition of the product epoxy alcohol (58) then formed neocarzinostatin chromophore aglycon (2, 71% yield). Studies directed toward the glycosylation of 2 focused initially on the preparation of the N-methylamino --> hydroxyl replacement analogue 3, an alpha-D-fucose derivative of neocarzinostatin chromophore, formed in 42% yield by a two-step Schmidt glycosylation-deprotection sequence. For the synthesis of 1, an extensive search for a suitable 2'-N-methylfucosamine glycosyl donor led to the discovery that the reaction of 2 with the trichloroacetimidate 108, containing a free N-methylamino group, formed the alpha-glycoside 114 selectively in the presence of boron trifluoride diethyl etherate. Subsequent deprotection of 114 under mildly acidic conditions then furnished the labile chromophore (1). The synthetic route was readily modified for the preparation of singly and doubly (3)H- and (14)C-labeled 1, compounds unavailable by other means, for studies of the mechanism of action of neocarzinostatin in vivo.

New synthesis of Δ6-estrogens

An efficient approach to synthesize Δ 6-estrogens is described. The key steps in the synthesis are the introduction of a hydroxyl group at the C-6 position of a suitably protected estrogen using a superbase and subsequent dehydration with Martin sulfurane reagent or methyltriphenoxyphosphonium iodide. The two-step synthetic procedure readily gave the Δ 6-estrogens in high yield.

Total Synthesis of (−)-Galbonolide B and the Determination of Its Absolute Stereochemistry

Through a trans-lactonization reaction, galbonolide B (1) was converted to 3 with the chiral secondary alcohol at C13 exposed for derivatization. Two independent methods were employed to determine the absolute chirality at C13. Both of these methods established S chirality at C13. Since the relative stereochemistry of galbonolide B had been determined from the X-ray structure, the absolute stereochemistry of galbonolide B was therefore formally established to be structure 1, which contradicted earlier speculations in the literature. A total synthesis of galbonolide B has been completed. A highly selective method was developed for the assembly of the peculiar diene unit using Martin's sulfurane reagent for the dehydration of the preceding tertiary alcohol 20. The chiral center at C4 was installed by “contra-steric” enolate chemistry. A novel macro-Dieckmann cyclization was employed to generate the macrocycle. The desired configuration at C2 was obtained from the kinetic protonation of the corresponding eno...