Total synthesis isocyanates

In addition to its utility in the enantioselective formation of C-0 bonds (cf. Scheme 15), Trost s chiral ligand 102 has been used in the catalytic asymmetric synthesis of C-N bonds. An impressive application of this protocol is in the enantioselective total synthesis of pancrastatin by Trost (Scheme 17) H9i Thus, Pd-catalyzed desymmetrization of 112 leads to the formation of 113 efficiently and in > 95 % ee. The follow-up use of the N3 group to fabricate the requisite cyclic amide via isocyanate 117 demonstrates the impressive versatility of this asymmetric technology. 

Kozikowski s group has been particularly active in the application of the INOC reaction toward the construction of a variety of natural products. One of the many examples from his laboratory involves the synthesis of tetracyclic compounds possessing suitably functionalized C rings for elaboration to a diverse number of ergot alkaloids via the INOC reaction. A total synthesis of chanoclavine I (65) was accomplished by this chemistry (Scheme 15). The key step in the synthesis involved the conversion of the nitro group of indole (62) into the corresponding nitrile oxide using the phenyl isocyanate procedure developed by Mukaiyama.57 The major product corresponded to isoxazoline (64). The isoxazoline nucleus was converted into chanoclavine I (65) in a series of subsequent steps. The application of nitrile oxide cycloaddition chemistry to the construction of other natural products can be expected to be an active area in future years. 

An ab initio study of the 2 + 2-cycloadditions of allene to isocyanic acid and ketene to vinylimine found the reactions to be concerted and mostly asynchronous.28,29 The diastereoselective 2 + 2-cycloaddition of dichloroketene with a chiral enol ether (26) produced the cyclobutanone (27), which leads to a key intermediate (28) in (g) the total synthesis of the natural alkaloid (-)-Swainsonine (29) (Scheme 8).30 The... 

Several other synthetic sequences have been developed that lead to the production of potentially useful intermediates for the total synthesis of galanthamine-type alkaloids. For example, the 4-arylbutyric acid 348 has been converted to the tetrahydrobenzazepine 349 by a modified Curtius reaction followed by cycliza-tion of the intermediate isocyanate with polyphosphoric acid (168). N-Methyla-tion of 349 and photooxidation of the resulting tertiary lactam in the presence of NBS gave 350. 

The enantioselective total synthesis of the cytokine modulator (-)-cytoxazone using a syn-stereoselective aldol addition and a Curtius rearrangement as key steps was described by J.A. Marco et al. The key intermediate acid was treated with DPPA and triethylamine in toluene at reflux. This step furnished the oxazolidinone directly and in good yield through an in situ capture of the isocyanate group by the free secondary alcohol functionality. Removal of the protecting group led to the formation of the natural product. 

A key carbamate intermediate during the total synthesis of pancratistatin was prepared via the Curtius rearrangement of the corresponding carboxylic acid by S. Kim et a. The isocyanate intermediate was rather stable and was converted to the desired carbamate in 82% overall yield by treatment with NaOMe/MeOH. 

The unusual 6-azabicyclo[3.2.1]oct-3-ene core of the alkaloid (+)-peduncularine was assembled using the [3+2] annulation of an allylic silane with chlorosulfonyl isocyanate by K.A. Woerpel and co-workers. In the endgame of the total synthesis, the bicyclic aldehyde was masked as the acetal, and an efficient Fischer indole synthesis was performed using phenylhydrazine hydrochloride along with 4% H2SO4. Several subsequent steps led to the natural product. 

The first asymmetric total synthesis of the hasubanan alkaloid (+)-cepharamine was completed by A.G. Schultz et al. In order to construct the c/s-fused A/-methylpyrrolidine ring, the advanced tetracyclic lactone was first converted to the primary carboxamide by treatment with sodium amide in liquid ammonia. Next the Hofmann rearrangement was induced with sodium hypobromite in methanol initially affording the isocyanate, which upon reacting with the free secondary alcohol intramolecularly gave the corresponding cyclic carbamate in excellent yield. 

The first total synthesis of ( )-lycoridine margetine (33), a member of the non-basic alkaloids which possess antimitotic activity has been achieved (Scheme 3). The homoallylic alcohol (26) served as a latent diene in a Diels-Alder reaction with ethyl acrylate to give a diastereomeric mixture of adducts which upon base equilibration and hydrolysis provided the tmns-acid (27). Modified Curtius reaction on (27) afforded the corresponding isocyanate which was cyclized to the lactam (28) in 89% yield by a new method using boron trifluoride etherate. Compound (28) was converted into an N-acetyl derivative which upon basic hydrolysis gave the acid (29). Treatment of (29) with NBS followed by reflux in pyridine solution gave the lactone... 

Numerous theoretically interesting hydrocarbons, like iptycenes [137b], starphenylenes (see Scheme 41 [140]) and highly strained threefold bicycloan-nelated benzenes (see Scheme 40 [139 a, c]) were synthesized by this very versatile approach. In addition, when alkynes are brought into a cocyclization reaction with alkyl and aryl nitriles or co-alkynyl isocyanates validated routes to heterocycles become available as it was demonstrated e. g. for the total synthesis... 

Cyclization of isocyanates. In a total synthesis of the alkaloid ( )-lycoricidine... 

Cyclization of isocyanates. In a total synthesis of the alkaloid ( )-lycoricidine (3), Ohta and Kimoto effected cyclization of the isocyanate (1) to the lactam (2) with boron trifluoride etherate at room temperature. They state that this... 

A facile assembly of 2,4-orthogonally-functionalised oxazoles as useful bidirectional linchpins was achieved by treatment with diazomethane of acyl isocyanates, generated in situ from acyl halides 132 oxazolones 133 were converted to the oxazole triflates 134, useful intermediates for further synthetic elaborations as highlighted by the synthesis of 135 via Wittig and Stille reactions <01SL1739>. This linchpin tactic was used in the stereocontrol led total synthesis of the potent cytostatic agent (+)-phorboxazole A <01JA10942>. 

Jain and co-workers reported a concise total synthesis of cefuroxin (Ceftin) from readily accessible 7-amino-3-acetoxymethyl-3-cephem-4-carboxylic acid. Hydrolysis of 7-amino-3-acetoxymethyl-3-cephem-4-carboxylic acid in aqueous methanol followed by acidification with tetrabutylammonium hydroxide provided the corresponding alcohol in 88% yield. Condensation of this compound with the ammonium salt of 2-furanyl-(Z)-2-methoxyiminoacetyl chloride provided the core structure in 77% yield. Protection of the free alcohol as a carbamate with chlorosulfonyl isocyanate, followed by conversion to the sodium salt, gave the desired compound in 83% yield (56% overall yield). 

Rigby s studies on the synthesis of alkenylisocyanates fostered the preparation of a suitable substituted aryl enamide, which on photocyclization yielded the polysubstituted pentacyclic system. Key to the success of this process is the hydrogen bond between the phenolic OH and the carbonyl group, which restricts the rotation around the aryl-amide bond and directs the cyclization. Further functionalization allowed the total synthesis of pancratistatin (272) and narciclasine (68) (275) (Scheme 11). The [4-1-1] cycloaddition of bis(alkylthio)carbenes with vinyl isocyanates was the key process in a recent synthesis of (+)-mesembrine (92) 274). 

In 2003, Trost and Frandrick developed a novel type of DYKAT based on the asymmetric palladium-catalysed cycloaddition between isocyanates and vinylaziridines. Performed in the presence of a chiral diphosphine as the ligand, the reaction allowed the access to a broad array of imidazolidin-2-ones with high yields and enantioselectivities of up to 95% ee, as shown in Scheme 2.58. In 2005, the same authors applied this methodology to the total synthesis of (-I- )-pseudodistomin D. ... 

In contrast, cyanoynamines react with phenyl isocyanate via an initial [2+2] cycloaddition reaction across the CM3 bond of the isocyanate to give a quinoline derivative Intramolecular cobalt catalyzed cyclization of alkynes and isocyanates was employed in the total synthesis of camptothein, an antitumor alkaloid. The key step of the synthesis involves the reaction of the acetylene group-containing isocyanate 185 with the acetylene derivative 186 to give 187. ... 

When the protecting group on oxygen is replaced by an acetoxy group, mixtures of the [3+2] adducts resulting from addition across the C=N and the C=0 bonds of the isocyanate are obtained. The [3+2] cycloaddition of CSI across the C=0 bond is utilized in the total synthesis of (+)-blasto-mycinone . The more common annulation, involving the C=N bond in CSI, was used in the synthesis of (+)-peduncularin. ... 

Also, bis-alkylthiocarbene undergoes the [4+1] cycloaddition reaction with a suitably substituted indol isocyanate to give the [4+1] cycloadduct in 72 % yield. This approach was utilized in the total synthesis of (+) phenserin . Numerous examples of vinyl isocyanates, generated from the corresponding carbonyl azides, in the presence of bis-alkylthiocarbene precursors afford the [4+1] cycloadducts, often in high yields . ... 

Yu, R. T., Rovis, T. (2006). Enantioselective rhodium-catalyzed [2-I-2-I-2] cycloaddition of alkenyl isocyanates and terminal alkynes application to the total synthesis of (+)-lasubine II. Journal of the American Chemical Society, 128,12370-12371. 

While the replacement of an alkyne against an olefin unit in the transition-metal-mediated [2 -I- 2 -I- 2] cycloaddition widens the scope of its applicability to more complex carbo- and/or heterocyclic structures, the same accounts for the formal replacement of an alkyne against a heterocumulene moiety [60]. However, as such a strategy led to the development of new concepts for the construction of heterocyclic compounds (i.e., the formation of 2-pyridinones via the [2- -2-1-2] cycloaddition reaction of alkynes with isocyanates [61]), the application in the field of total synthesis is still at its infancy and so is limited to a few examples. 

The first one is Earl and VolUiardt s formal total synthesis of the antitumor agent camptothecin (196), which is based on the cobalt-catalyzed crossed cyclization of isocyanate 191 with the silylated alkyne 192 to give the 2-pyridinone 193 in 63% yield with high regioselectivity (dr >20 1) (Scheme 7.42) [62],... 

Use of the phosphoramidite ligand (-)-199 proved to be crucial for the enantioselective rhodium-catalyzed crossed [2 + 2 + 2] cycloaddition of alkenyl isocyanate 197 with phenylacetylene 198, which provided the vinylogous amide 200 in 62% yield (98% ee). Thereafter, cycloaddition product 200 underwent a diastereoselective hydrogenation followed by a Mitsunobu reaction to complete the total synthesis of (+)-lasubine II (201). 

Chiral auxiliaries feature in two amiiKxleoxysugar syntheses. The L-forosamine derivative 54 (Scheme 16) was prepared from the N-acylated oxazolidinone 53 derived from L-phenylalanine, and used in the total synthesis of the macrolide antibiotic lepicidin A. Key steps were asymmetric aldol condensation (step i) and Clurtius reaction (acid to isocyanate with capture by fluorenylmethanol stq) iv). The 5-amino-2,5-dideoxy-D-rhreo-pentoside 57 and 3,5-diamino-2,3,5-trideoxy-l>-e/yrhro-pentoside 58 were synthesized by conventional triflate displacenoent reactions from iodolactone 56,... 

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