Spiroacetal, preparation

In TaHe and Kocienski s total synthesis of lacrimin A (272), methoxyallene 268 was easily prepared via consecutive alkylations and subjected to acidic conditions to afford the presumed enone intermediates 269 and 270 (Scheme 19.48) [57]. Enone 269 underwent spontaneous spiroacetal formation to give a single stereoisomer 271 in 78% yield from 268. This compound was taken on to complete a total synthesis of lacrimin A (272). 

The spiroacetal morpholine work of Scheme 38 subsequently inspired research on the preparation of a novel family of morpholino-glycosides from sucrose via lead tetraacetate cleavage and reductive amination (Scheme 40). Significantly, the latter work, which was done with the present author, unveiled a completely new structural class of sweeteners, more intense than sucrose but having a similar taste profile. 

Separation of these spiroacetal isomers was initially achieved using normal phase semi-preparative HPLC, which allowed re-equilibration of the undesired spiroacetal 35 and thereby a method to convert essentially all of the material to the desired isomer 36 after several cycles. The scale-up of this procedure was greatly facilitated by the determination of a simple method for separating the spiroacetal isomers by flash column... 

The preparation of carbohydrate-derived spiroacetals by RCM was reported by van Boom and co-workers <00EJO873> (Scheme 45). The Pauson-Khand cyclization of these enynes was reported in the same manuscript. 

A versatile approach to spiro-oxacycles is the use of cyclic a-methylene enol ethers employed by us in an efficient and short enantioselective total synthesis of the mycotoxin talaromycin B (see Sect. 7.1). Later Pale and Vogel [148] employed the same protocol for the preparation of spiroacetals 2-145 using e.g. acrolein 2-78, methyl vinyl ketone and 2-pentenal, respectively with the enol ether 2-143 (Fig. 2-39). In most cases the yields were only modest, however, reaction of 2-143 and 2-78 in benzene in the presence of the mild Lewis acid ZnCl2 gave 2-145 in 70% yield as a single adduct. 

For the synthesis of the a-lithiated 5-methoxy-3,4-dihydro-2H-pyran 642, the deprotonation must be carried out with n-BuLi or f-BuLi at 0 to 50 °C in ether, DME or hexane947,948. For the preparation of hemiacetals947 948 or spiroacetals948, bifunctional electrophiles were used. Scheme 168 illustrates the preparation of the spiroacetal 644 from the alkylated product 643948. 

Hydroxy groups of cyclodextrins can be regioselectively alkylated in positions 2 and 6 of the glucose residues due to the high reactivity of these hydroxy groups. The 3-positions are much less reactive and can be alkylated or acylated under more drastic conditions. The preparation of pure per-O-alkylated cyclodextrin derivatives, which are mainly used for the separation of unpolar compounds (alkanes, alkenes, spiroacetals, alkyl halides, etc.) as well as a method for characterization of these phases have been described in detail (29). 

Carboxylic Adds and Derivatives.—Esters may be reduced to ethers in low yield by lithium aluminium hydride-aluminium chloride.This reaction would not normally be used for preparative purposes, being more effectively carried out with sodium borohydride-boron trifluoride, but could complicate the use of LiAlH4-AICI3 for other purposes such as the reductive cleavage of the spiroacetal system in sapogenins. 

Using rapid acetal hydrolysis and mild acetal exchange, initial studies showed that the spiroacetal 4,8-dioxaspiro[2.5]oct-l-ene (20) is more stable than monocyclic 3,3-dimethoxycy-clopropene (19). Both can easily be prepared from 1,2-dichloroprop-2-ene (18). ... 

In preliminary studies we have found that this is also a powerful approach to the preparation of enantiomerically pure complex spiroacetals (Fig. 22 [23,24]). Intramolecular oxymercuration of 84 proceeds efficiently, although without any stereoselectivity. 

The synthesis of the northern spiroacetal segment 394 features the selective ringopening of a symmetric 1,4-bis-epoxide 389 by successive introduction of the Cl 1-C15 unit 388 and C21-C28 phenylsulfonylpyran 391 (Scheme 57). Addition of vinyl lithium of 388, prepared via Brown asymmetric crotylboration, to a symmetric... 

Other spiroacetal natural products have been prepared using malic acid-derived epoxides as the chiral source (Scheme 54). Chalcogran (407, R=CH3, = 1) is the principal component of the aggregation pheromone of the beetle Pityogenes chalcographus (L.), a pest of Norway spruce. Spiroacetal 407 (R—H, = 2) is a minor volatile component found in the common wasp, Paravespula vulgaris. 

The bromo epoxide 402 used in these syntheses is prepared from 371 by initial conversion to (iS)-l,4-dibromo-2-butanol (401) [16] followed by cyclization with potassium hydroxide [18]. Alkylation of 1,3-dithiane first with EE-protected co-chloroalcohols to give 403 and then with the ( S)-epoxide 402 affords 404. Opening the oxirane with either Super-Hydride or methyl cuprate creates the requisite carbon skeletons 405 with the appropriate fimctionality patterns. Removal of the EE protecting group and mercury-mediated hydrolysis of the thioacetal directly furnishes the spiroacetals 407 as a 3 2 mixture of diastereomers [16]. 

In the area of spironucleoside chemistry, a considerable effort has been devoted to the synthesis of 2-thiohydantocidin, its 5-epimer [154,155,166,167, 172] and other thiohydantoin spironucleosides [154,160,162,173,174], Thus, Puentes and co-workers have prepared recently [154,155] 2-thiohydantoin spironucleosides 164glycosyl isothiocyanates 162 via the transient thioureas 163, as depicted in Scheme 35. Aminoesters 161 and isothiocyanates 162 were obtained from psicofuranose spiroacetal 148 as well as from fruc-topyranose spiroacetal 156. 

The similar reaction of 2-alkyl-l,3-disilyloxypropanes with chiral ketones is highly selective and has been used to prepare spiroacetal starting materials for an asymmetric synthesis of a-tocopherol subunits (eq 12). ... 

Preparation of another fragment began with 182 [75]. The asymmetry of the secondary hydroxyl groups of 183 and that of the tertiary one of 184 was derived from Sharpless epoxidation and Sharpless dihydroxylation. Acidic treatment to remove the acetonide group afforded tricychc spiroacetal 185. The stereochemistry was confirmed by NOE observed in the dithiane 169. 

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. 

Preparation of rigid polymers containing spiroacetal units [130],... 

The compound (2-ethynylphenyl)methanol 88 (X = O) and the corresponding phenylmethanamine 89 (X = NTs) were also used by the group of Xu in 2013 [45] for the preparation of spiroacetals 90 (X = O) and spiroaminals 91 (X = NTs), respectively (Scheme 9.25). This bimetallic relay catalysis sequence includes a gold-mediated cyclization followed by a Lewis acid-catalyzed inverse-electron-... 

---