Allylic 3+2 -annulation

Several 1,4-dicarbonyl compounds are prepared based on this oxidation. Typically, the 1,4-diketone 10 or the 1,4-keto aldehyde 12 can be prepared by the allylation of a ketone[24] or aldehyde[61,62], followed by oxidation. The reaction is a good annulation method for cyclopentenones (11 and 13). Syntheses of pentalenene[78], laurenene[67], descarboxyquadrone[79], muscone (14 R = Me)[80]) and the coriolin intermediate 15[71] have been carried out by using allyl group as the masked methyl ketone (facing page). 

Allyllic ether 53 is oxidized regioselectively to the /3-alkoxy ketone 54, which is converted into the a,/i-unsaturated ketone 55 and used for annulation[99]. The ester of homoallylic alcohol 56 is oxidized mainlv to the 7-acetoxy ketone 57[99]. 

The 1.3-allylic diacetate 135 can be used for the formation of the methy-lenecyclopentane 137 with the dianionic compound 136(86]. The cyclohexa-none-2-carboxylate 138 itself undergoes a similar annulation with the 1,3-allylic diacetate 135 to form the methylenecyclohexane derivative 139(90]. The reaction was applied as a key step in the synthesis of huperzin A[91]. On the other hand. C- and 0-allylations of simple J-dikctones or. 1-keto esters take place, yielding a dihydropyran 140(92]. 

The coupling product is converted to the allyl mesylate 6. This is reductively cyclized to yield bis(cyclopentano)annulated methylenecyclooctanol 7a, which furnishes the hydrocarbon 7b on reductive deoxygenation. 

An example for synthesis of the chiral [l-keto ester 69 is illustrated in equation 64. It involves conjugate addition of the dipotassium / -keto ester 68 to vinyl sulfone 67 followed by in situ quenching with allyl bromide54. The method provides a new procedure to sevenring annulation product 70 that is a potential precursor for (l)-(-)-cytochalasin C. 

Thiourea was used as stabilising agent for zerovalent Pd species [117]. The Pd-thiourea (H2NCSNH2) catalysed carbonylation of terminal alkynes and allylic alcohols has been described by Chiusoh [118]. More recently, Pd-thiourea-catalysed carbonylative annulation was studied. The reaction proceeds between alkynes, iodophenol acetates and carbon monoxide, in the presence of dppp, thiourea (H2NCSNH2) and base at 40 °C. Flavones have been obtained in good yields (Scheme 30) [119]. 

With regard to the mechanism of the cycloisomerization, Fiirstner et al. found strong evidence of a metallacyclic intermediate. By labeling the allylic position of enynes 46 and 48, they showed that reactions yielding traws-annulated rings 47 transferred the deuterium atom to the exocychc double bond (eq. 1 in Scheme 10), whereas c -annulated rings 49 formed with complete preservation of the position of the deuterium atom (eq. 2 in Scheme 10). This corresponds well to a metallacycUc... 

A first example of a combination of a Rh-catalyzed allylic substitution and a Pau-son-Khand annulation reaction has also been developed by the same group [222]. Thus, [RhCl(CO)dppp]2 is able to catalyze both transformations at different reaction temperatures. Treatment of the allylic carbonate 6-106 with the alkyne derivative 6-107 led to a diastereomeric mixture of 6-108 and 6-109 in 63-84% yield, with 6-108 as the main product (Scheme 6/2.23). 

Substituted (5R,6A,)-6-(dimethyl(phenyl)silyl)-2-phenyldihydropyrazolo[l,2- ][l,2,4]triazole-l,3(2//,5//)-dione 716, synthesized via the [3+2] annulation of a-substituted allylic silanes 715 with PTAD, were oxidized to the corresponding hydroxy substituted urazoles 717. This work shows that allylsilanes with a single substituent at the allylic carbon undergo exclusive stereoselective [3+2] annulation (Scheme 114) <2007TL6671>. 

Gold(I)-catalyzed synthesis of dihydrobenzo[ >]furans from aryl allyl ethers was reported as depicted below <06SL1278>. Highly efficient AuCl3/AgOTf-catalyzed atom-economical annulation of phenols with dienes was developed. This annulation generated various dihydrobenzo[ >]furans under mild conditions <06OL2397>. 

The above examples represent Jl-heteroaromatic annulation involving the reaction of allyl anions whose double bond is a part of the heterocyclic ring system (Scheme 1). The corresponding a-oxoketene dithioacetals (1,3-electrophilic component) were generally derived from nonheterocyclic carbonyl precursors. Alternatively the Jl-heteroaromatic annulation can also be employed to a-oxoketene dithioacetals derived from heterocyclic ketones (1,3-bielectrophile) and hetero/nonheteroallyl anions (1,3-binucleophile). These reactions are described below. 

The a-oxoketene dithioacetal 6.40 is derived from indoxyl (l,2-dihydroindol-3-one), a heterocyclic carbonyl precursor, and its reaction with simple allyl anions will also yield the corresponding Jl-annulation product. Thus when 6.40 was reacted with allyl anions 65 the corresponding carbinol acetals 66 formed insitu underwent smooth BF3.Et20 assisted cyclization to afford the corresponding carbazoles 67 in high yields <99T11563>. 

Reactions with participation of the C=C bond are the most studied of INOCs. Normal products of such reactions are annulated isoxazolines. A synthesis of bicyclic isoxazolines via sequential Michael and intramolecular 1,3-dipolar additions (403) are mentioned as an example. Michael addition of 1-nitroalkadiene, R1R2C=CH(CH2) CH=CHN02 to allylic stannane R3R4C=C(R5)CH2SnR63... 

The acyclic version of Larock s heteroannulation was successfully applied to the synthesis of highly substituted pyridines [166]. The annulation of rert-butylimine 210 with phenyl propargyl alcohol produced pyridine 211 regioselectively in excellent yield. The regiochemistry obtained was governed by steric effects. Furthermore, the choice of imines was crucial to the success of the heteroannulations. terr-Butylimine was the substrate of choice, since all other imines including methyl, isopropyl, allyl and benzyl imines failed completely to produce the desired heterocyclic products. 

One of the earliest and most important discoveries in metal-catalyzed asymmetric synthesis is Sharpless s Ti-catalyzed epoxidation of allylic alcohols. A mere mention of all the total syntheses that have used this technology would require a separate review article Here, we select Trost s masterful total synthesis of solamin (100, Scheme 14), for its beautiful and multiple use of Sharpless s asymmetric epoxidation.1161 Optically pure epoxy alcohol 95 is converted to both epoxy iodide 96 and diol 97 The latter two intermediates are then united to give 98, which is oxidized and converted to dihydrofuran 99 by a Ramberg-Backlund transformation. The Re catalyzed butenolide annulation that is used to afford the requisite unsaturated lactone only adds to the efficiency of this beautiful total synthesis. 

Unlike with sodium borohydride (see Section 11.01.5.2), pyrrolizin-3-one 2 reacts with lithium aluminohydride mainly as an amide. No conjugate addition occurs, and only the reductive lactam cleavage takes place to give stereoselectively the (Z)-allylie alcohol 77. Similarly, benzo-annulated pyrrolizin-3-one 17 gives the corresponding benzylic alcohol 78. The same reactivity was observed with organometallics such as methyllithium which gives exclusively the tertiary (Z)-allylic alcohol 79 (Scheme 7). 

Radical [3 + 2] annulation involving N-allyl-N-chlorotosylamidc provides a route to pyrrolidine derivatives (Scheme 21) [56]. 

Pyrimidine annulated heterocycles fused at positions 5 and 6 to uracil were synthesized via a three-step sequence starting from uracil 63 [20]. Firstly, the reaction with 3-bromocyclohexene gave the AT-allyl-vinyl core system 64 in 80% yield. Upon heating 64 in EtOH in the presence of HCl, aza-Claisen rearrangement gave rise to the C-cyclohexenyl uracil 65 in 38% yield. Final bromination ( 66) and dehydrogenation steps ( 67) allowed synthesis of the desired tricyclic fused uracil systems (Scheme 15). 

Reaction of linear conjugated dienes with la at —10 °C in hydrocarbon solvent in the presence of McsSiCl/AlCls affords stereospecific tra i-l-silyl-3-vinyl-cyclopentanes, indicating a [3 + 2] cycloaddition of the allyl group of la with a carbon arbon double bond of the diene [Eq. (9)]. In the [3 + 2] annulation reaction, of greater significance is the tram conformation of the trimethylsilyl group and vinyl groups. 

The reaction of 1,3-cyclohexadiene with la at a temperature of — 50°C gives a 97 3 mixture of 1,4-allylsilylated product, trara-3-allyl-6-(trimethylsilyl)cyclohexene and 1,2-allylsilylated product, tra 5-3-allyl-4-(trimethylsilyl)cyclohexene, in quantitative yield. At the same temperature, the [3 -I- 2] cycloaddition product is detected only in trace amounts after 1 h. As the reaction mixture is warmed to — 10°C, the allylsilylated compounds are converted to the [3-1-2] cycloaddition product (72%). When purified tra 5-3-allyl-6-(trimethylsilyl)cyclohexene and tra i-3-allyl-4-(tri-methylsilyl)cyclohexene are treated separately under the same reaction conditions, the former compound is converted to the [3 -I- 2] cycloaddition product (major) and 3-(trimethylsilyl)propylbenzene [Eq. (11)], while the latter compound is converted to polymeric materials without giving any [3-1-2] cycloaddition product. The reaction rates of allylsilylation and [3-1-2] annulation are also accelerated by the addition of trimethylchlorosilane to aluminum chloride, as observed in other allylsilylation reactions. 

The 1,3-diene moiety in 227 which included the carbon atoms and CVC was oxidized to the l,4-dihydroxy-2-ene moiety in 238 that was further exploited to functionalise the A-ring as well as for the annulation of the C-ring (Scheme 37). The transformation of 227 into 238 was realized by a diastereoselective epoxidation of 227 to afford a vinyl epoxide (241) that was subjected to the conditions for a Palladium(O)-catalysed allylic substitution with the acetate ion [126]. The mechanism and the stereochemical course of the allylic substitution may be explained as depicted in Scheme 37. Sn2 ring opening of the protonated vinyl epoxide 241 by an anionic Pd complex proceeded with a (3Si) topicity to the r-allyl Pd com-... 

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