Transannular deprotonation

C. Deprotonation of Bicyclo[3.2.1]alkadiene, Some Other Cycloalkadienes and Cyclooctatetraene Bishomoaromaticity and Transannular Cyclization... 

The ionisation-induced cyclization sequence could be followed by a proton-induced cyclization (Scheme 3). Protonation of the double bond of 13 generates a dolabellyl cation (15) that is transformed into a dolastyl cation (16) by a transannular cyclization between and (dolabellane numbering). Subsequent deprotonation at (dolastane numbering) leads to the dolasta-1 (15),8-diene which is further functionalized by enzymatic oxidation. 

The reaction became particularly interesting for synthetic purposes when enantiose-lective variants were elaborated. Thus, the deprotonation of meio-epoxides like 89 converts an achiral compound into a chiral one, the carbenoid 90. If the lithiation has been carried out with a differentiation of the enantiotopic protons, the subsequent transannular... 

As seen above, /3-deprotonation implies a six-center transition state. Recent computational studies show an important variation of the H —C—C—O dihedral angle from reactant to transition state . Thus, the ground state geometry of the oxirane cannot be used to predict its reactivity. However, for structural reasons, some oxiranes cannot adopt a suitable conformation for -deprotonation and furnish exclusively a-deprotonation products. This concept is well illustrated by the norbornene oxide 17, which gives exclusively the transannular 1,3 insertion product 18 in the presence of lithium amide (Scheme 5) . 

The deprotonation step, either by the sensitizer radical anion or by some adventitious base, is essential for the formation of any amine derived products. This step can be prevented if the a-hydrogens are arranged in a plane orthogonal to the singly occupied nitrogen n-orbital a requirement which is met for the radical cation of l,4-diazabicyclo[2.2.2]octane (DABCO). The low oxidation potential, due to the interaction of the pair of transannular nitrogens, makes this an excellent electron transfer quencher. Yet, no product formation is observed as a result of these interactions, with the possible exception of the zwitterionic adducts formed with highly electrophilic ketones [193]. 

Asami and coworkers also investigated the deprotonation of cyclooctene oxide 97, which is known to undergo both a-deprotonation to yield transannular products and / -deprotonation to yield allylic alcohols 98 upon reaction with lithium amides. Using his catalytic system Asami and coworkers obtained the allylic alcohol in 27% yield and 54% ee of (,S )-98 (Scheme 68c). (Z)-4-Octene oxide 99 was deprotonated yielding the allylic alcohol 100 in 54% yield and 60% ee of the (5)-enantiomer (Scheme 68d)110. 

Pt(II), bonded to two PhsP ligands, exhibits a profound difference in its bis-enolate complexes with the doubly deprotonated triones RC(0)CH2C(0)CH2C(0)R, R = Me and Ph. For R = Me, a highly puckered 2,4-diacetylated 3-platinacyclobutanone, 57, is formed with a weak transannular Pt-C bond. For R = Ph, the more usual 1 1 0,0 -chelate is formed and the product is isolated as the dienediolate complex 58. What would be the product if the two substituent groups were different, R = Me and R = Ph Would a 2-acetyl-4-benzoyl-3-platinacyclobutanone be formed would a 6-membered-ring fi-diketonate be formed with one Me and a PhCOCH substituent apiece or such a species with one Ph and an MeCOCH, or would an unprecedented l,3-dioxa-2-platinacyclooctadienone (59) result ... 

The first asymmetric total synthesis of (+)-maritimol, a diterpenoid natural product that possesses a unique tetracyclic stemodane framework was accomplished by P. Deslongchamps. To introduce the C12 stereocenter, the Enders SAMP/RAMP hydrazone alkylation was used. This stereocenter played a crucial role in controlling the diastereoselectivity of the key transannular Diels-Alder reaction later in the synthesis. The required SAMP hydrazone was formed under standard conditions using catalytic p-toluenesulfonic acid. Subsequent protection of the free alcohol as a f-butyidiphenylsilyl ether, deprotonation of the hydrazone with LDA and alkylation provided the product in high yield and excellent diastereoselectivity. The hydrazone was converted to the corresponding nitrile by oxidation with magnesium monoperoxyphthalate. 

Indolizidines The t-Boc derivative of azacyclononene oxide is deprotonated at an cK-position of the epoxide ring by. r-RLi-TMEDA. A transannular reaction follows. 

Note added in proof. ktotA synthesis of (-)-xialenon A using bicyclic alcohol 77 [Eq. (26)] represents the first application of enantioselective a-hthiation transannular C-H insertion of epoxides in natural product synthesis [78]. The first enantioselective generation - intermo-lecular nucleophile trapping of a lithium carbenoid has been described, via enantioselective a-deprotonation of the epoxides of oxa- and aza-bicyclic alkenes [e.g. 93 Eq. (30)] using alkyl-lithiums in the presence of (-)-sparteine or bisoxazoline 5 [Eq. (3)] [79]. Insertion of a second... 

Enantioselective desymetrization by a-deprotonation/tran-sannular C—H insertion of cyclooctene oxide (i.e., 173) was reported by Hodgson and co-workers for synthesis of bicycle[3.3.0] octanes, intermediates that are useful for pol-yquinane synthesis. The best yields and enantioselec-tivities of 175 were obtained when 173 was treated with j-PrLi and (—)-a-isosparteine (Scheme 20.42). Application of this reaction in natural product synthesis is yet to be reported. The same research group also reported expanding the scope of the reaction to synthesis of indolizidine 177 by a similar transannular reaction of 176. ... 

Hodgson DM, Robinson LA. A new and enantioselective indolizidine synthesis by meso-epoxide a-deprotonation-transannular N-C insertion. Cfem. Commun. 1999 309-310. 

In addition to asymmetric deprotonation. Cope observed that cyclic epoxides in the presence of base give rise to products derived from transannular reactions [110], Boeckman carried out a study of oxiranes fused to medium-size rings and noted that the more commonly observed deprotonation of oxiranes can be suppressed at low temperature, permitting the formation of bi-cyclic structures [118]. In such cases, a-lithiation of an epoxide followed by 1,1-elimination generates a carbene that participates in a subsequent CH-insertion process (cf. 131). An enantioselective version of this reaction was investigated by Hodgson (Scheme 9.15) [119]. Thus, in the presence of sparteine (130), treatment of cyclooctene oxide 129 with i-PrLi affords bicyclic alcohol 132 in 84% ee. 

---