Spiro-acetals synthesis

Talaromycin B is a spiro-acetal produced by the fungus Talaromyces stipitatus, the toxicity of which may be due to its ability to block outward potassium fluxes. In an elegant synthesis, the requisite open-chain polyol with hydroxy groups in the y-and y -positions was assembled from nitrile oxide and olefin building blocks 50 and 51, both of which carry a f>w(hydroxyethyl) moiety protected as a cyclohexanone acetal (284). Hydrogenolysis of the N O bond of isoxazoline 52 using Raney nickel, followed by treatment with aqueous acid, gave the spiroketal 53, which was further transformed into racemic talaromycin B (54) (Scheme 6.54) (284). 

As previously mentioned, certain methyl ketone aldol reactions enable the stereocontrolled introduction of hydroxyl groups in a, 5-anti relationship (Scheme 9-7) [9], and this was now utilized twice in the synthesis. Hence, methyl ketones 48 and 98 were converted to their respective Ipc boron enolates and reacted with aldehydes 97 and 99 to give almost exclusively the, 5-anti aldol adducts 100 and 101, respectively (Scheme 9-34). In the case of methyl ketone 48, the j -silyl ether leads to reduced stereoinduction however, this could be boosted to >97%ds with the use of chiral ligands. In both examples, the y9-stereocenter of the aldehyde had a moderate reinforcing effect (1,3-syn), thus leading to triply matched aldol reactions. Adducts 100 and 101 were then elaborated to the spiro-acetal containing aldehyde 102 and ketone 103, respectively. 

The volatile component of the mandibular secretion of Andrena haemorrhoa F. contains 2,7-dimethyl-l,6-dioxaspiro[4.6]undecane. All four thermodynamically stable stereoisomers of the Spiro acetal pheromone have been prepared using the two enantiomers of ethyl lactate (which supplies the 2-methyl substituent via butyrolactone 51) and the two enantiomers of 3-hydroxybutanoate (which supplies the 7-methyl via iodide 52). Scheme 8 shows the synthesis of the (2S, 5S, 7/ )-isomer 55. The overall yield in the sequence is 9%, and the purity of the final product is 97% [18]. 

In an alternative synthesis of ( + )-milbemycin B, Baker et al. have applied their previously described spiro-acetal intermediate... 

The alkoxycarbonylation reaction is also useful for the synthesis of spiroacetals (Scheme 24) [38] Thus, certain hydroxyenones react under the standard conditions in the presence of trimethyl orthoformate (TMOF) to afford the corresponding spiroacetals via hemiketal intermediates in high yield. It is also possible to prepare spiroacetals starting from dienones (Table 3). The stereochemistry of the products was not established however, this method is of potential value for the synthesis of bioactive compounds with spiro acetal substrucmre. 

In spite of their intrinsic synthetic potential, addition reactions of metal enolates of non-stabilized esters, amides, and ketones to epoxides are not widely used in the synthesis of complex molecules. Following the seminal work of Danishefsky [64], who introduced the use of Et2AlCl as an efficient catalyst for the reaction, Taylor obtained valuable spiro lactones through the addition reaction of the lithium eno-late of tert-butyl acetate to spiro-epoxides, upon treatment of the corresponding y-... 

Giomi s group developed a domino process for the synthesis of spiro tricyclic nitroso acetals using a, 3-unsaturated nitro compounds 4-163 and ethyl vinyl ether to give the nitrone 4-164, which underwent a second 1,3-dipolar cycloaddition with the enol ether (Scheme 4.35) [56]. The diastereomeric cycloadducts formed, 4-165 and 4-166 can be isolated in high yield. However, if R is hydrogen, an elimination process follows to give the acetals 4-167 in 56% yield. 

Aminopyrans 244, spiro-conjugated with an polycyclic N,0,S-system, have been synthesized using N,S-acetal derivatives of actylacetone and acetoacetic ester 245 (00PS(160)105). Diacetyl derivative 245 (Z = COMe) undergoes deacetylation in the course of pyran synthesis (Scheme 93). 

The 1,2,3-triazine ring was constructed from o-aminophenyl oximes in the conditions of nitrosation (NaN02/HCl) , while hydrazinooximes were used for the synthesis of the 1,2,4-triazine ring Thus, cyclization of a-hydrazinooxime 342 with Pb304 in the presence of acetic acid afforded 1,2,4-triazines 343 in 44-54% yields (equation 149) . Interaction of oxime 344 with hydrazine leads to the spiro compound product 345 in 73% yield (equation 150) °. 

These results prompted them to attempt the stereoselective synthesis of the IV-phenylsulfonyl substituted spiro- (3-lactams 150, 151 (Scheme 36) from the N-(phenylmethyIe ne )be n ze nesulfonamide and the ketene valence tautomer of the bicyclic mesoionic compounds such as (2 S,4/ )-4-acetyloxy or benzoyloxy-IV-acyl-prolines 149 in the presence of acetic anhydride [109]. The presence of the stereocenter in position 4 of the cyclic amino acid 149 was found to be sufficient to ensure complete stereoselectivity on the spiranic C-4. 

The deMayo-type photochemistry of 1,3-dioxin-4-ones has been beautifully applied by Winkler et al. to the synthesis of complex natural products. Substrate 133 gave under sensitized irradiation (with acetone as cosolvent) product 134 as single diastereoisomer (Scheme 6.47). The diastereoselectivity results from cyclic stereocontrol exerted by the two stereogenic centers in the spiro-bis-lactone part of the starting material. After installation of the furan, saponification and bond scission in a retro-aldol fashion generated a keto carboxylic add, which produced the natural product ( )-saudin (135) by simultaneous formation of two acetal groups [128]. 

An excellent review of the isolation, structural elucidation, total synthesis, and postulated biosynthesis of sesquiterpenoids based on the spiro[4,5]decane (vetis-pirane) skeleton has been published." Further studies on the development of alternative routes to the vetispirane sesquiterpenoids have been described. In one report100 the spirocyclic acetal (217), previously used as an intermediate in the synthesis of (—)-a-acorenol (218),101,102 has been converted into (—)-agarospirol (219) and (-)-/3-vetivone (220) by the reaction sequence outlined in Scheme 26. 

When benzo-l,3-dithiolium tetrachlorozincate is heated in acetic anhydride, a 30% yield of dibenzotetrathiafulvalene (286) is obtained. Compound 286 is also formed, together with benzoisodithione, during the pyrolysis of the spiro compound (287), and its structure has been confirmed by independent synthesis from 1,2-benzenedithiol and tetrachloroethylene. 

Alternatively, synthesis of compound 215 (4-epimer of 208) started by initial inversion of the OH group at C-l of 207 (Scheme 27).35,96,99 101 Acid hydrolysis of 207 gave the triol 209 (100%), which was identified as its tetraacetate 210, whose allylic hydroxyl group was selectively sulfonylated with mesyl chloride to afford 211, which was then converted into the acetate 212 (65%). On treatment with an excess of sodium acetate in DMF, 212 afforded 213 (60%). Oxidation of 213 with osmium tetraoxide gave, after acetylation, 214 and 216. Furthermore, epoxidation of 213 gave a single spiro epoxide 214 (64%), which was transformed exclusively into 216 (83%)... 

The reaction proceeds well in the presence of side chains with ether or acetal protecting groups, thus providing a convenient route to methylenecyclopropanes with hydroxy and oxo groups. The synthesis and subsequent hydrolysis of l,la,6,6a-tetrahydro-l-methylene-spiro[cyclopropa[c ]indene-6,2 -[l, 3]dioxolane] (10) provides an illustrative example. ... 

Further evidence for the specificity of the interaction of UROS with the spirolactam 48 came when its two enantiomers were separately prepared by including a resolution step halfway through the synthesis [70]. One of the two enantiomers inhibited UROS at least 20 times more strongly than the other. The unsubstituted parent spiro ring system of 48 does in fact have a plane of symmetry and the difference between the enantiomers lies only in the arrangement of the acetate and propionate side-chains on the three pyrrolic rings of the macrocycle. This makes the discrimination shown by the enzyme between the two enantiomers all the more impressive. 

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