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TpMo(CO)2(5-oxo-η3-pyranyl) scaffolds bearing an internal alkoxide undergo a novel intramolecular nucleophilic ketalization reaction. The anionic intermediate is easily demetalated, rapidly providing the 6,8-dioxabicyclo[3.2.1]oct-3-en-2-one framework in moderate to good yields with high enantiopurity. An enantiocontrolled total synthesis of (+)-(1R,2S,5S,7R)-2-hydroxy-exo-brevicomin was accomplished utilizing the reaction sequence.
High enantiopurity air and moisture-stable TpMo(CO)2(η3-pyranyl) and TpMo(CO)2(η3-pyridinyl) complexes have been utilized in the asymmetric construction of structurally diverse heterocyclic systems.1 Readily available in multigram quantities,1m these complexes function as versatile organometallic enantiomeric scaffolds. Synthetic bond construction strategies that have evolved from these novel scaffolds have relied almost solely on processes that proceed through molybdenum-stabilized cationic intermediates because, with very few exceptions,2 coordinatively saturated, charge-neutral η3-allylmolybdenum complexes are typically unreactive toward direct nucleophilic functionalization at the allyl moiety. Complementing these traditional cationic pathways, an unprecedented reactivity profile for coordinatively saturated, charge neutral TpMo(CO)2(η3-pyranyl) and TpMo(CO)2(η3-pyridinyl) complexes was recently disclosed:1j,1o the direct nucleophilic addition of an internal enolate to a terminal π-carbon of the η3-allyl moiety. This new mode of reactivity allows one to amplify the use of organometallic enantiomeric scaffolds for conceptually novel strategies of synthesis. Herein we report the direct nucleophilic functionalization of TpMo(CO)2(5-oxo-η3-pyranyl) complexes at the terminus of the η3-allyl moiety by an internal alkoxide. This strategically new C—O bond formation establishes a bicyclic ketal, stereospecifically, and, after in situ oxidative decomplexation of the anionic bicyclic intermediate produced upon alkoxide addition, allows the rapid, one-pot enantiocontrolled construction of the 6,8-dioxabicyclo[3.2.1]octane framework3 with complete regio- and stereocontrol (Scheme 1).
Synthetic studies of this new regio- and stereocontrolled intramolecular nucleophilic ketalization reaction started with the transformation of (±)-5-oxopyranyl complex 1 and (±)-2-methyl-5-oxopyranyl 2 to the corresponding anti and syn alcohols 3−7 by a Mukaiyama-aldol reaction4 for complex 1 or a traditional aldol reaction for complex 2.5 Four different aldehydes were studied in each case (Table 1). The aldol reactions took place in moderate to excellent yields with a slight preference for anti selectivity. The anti and syn relationships of these keto alcohols were determined by comparing the coupling constant between the hydrogen adjacent to the hydroxyl group and the vicinal hydrogen on the pyran ring. For the anti isomers, the vicinal coupling constants are approximately 5−6 Hz, while thevicinal coupling constants for the syn isomers are approximately 2−3 Hz. Using chiral, non-racemic (−)-1 (98.7% ee)1m (Table 1, entry 1), high enantiopurity (98.7% ee) aldol adducts syn and anti (−)-3 were prepared.
Treatment of syn- and anti-3−7 with NaH followed by in situ quenching with either NOPF6 or NOBF4 directly afforded the exo and endo 6,8-dioxabicyclo[3.2.1]oct-3-en-2-ones in moderate to good yields as depicted in Table 2.6
This one-pot transformation proceeds with complete facial diastereoselectivity. The exo and endo relationships of the C-7 substituent of 6,8-dioxabicyclo[3.2.1]oct-3-ene-2-one products are controlled by the stereochemistry of the hydroxyl groups: syn-alcohols afford the exo stereoisomers whereas the anti-alcohols afford the endo stereoisomers. The H-C6-C7-H vicinal coupling constants of the exo isomers are typically around 1−1.5 Hz, whereas the analogous coupling constants of endo isomers are relatively larger, around 6.0 Hz. It was also demonstrated that this sequence proceeded with no detectable loss of enantiopurity when carried out with chiral, non-racemic molybdenum complexes. Both the exo and endo demetalation products (8 and 12) can be prepared in 98.7% ee (Table 2, entries 1, 5) from (−)-syn-3 and (−)-anti-3, respectively.
Direct nucleophilic addition to the 5-oxo-η3-pyranyl complexes 1 and 2 is likely facilitated by the propensity of the TpMo(CO)2 moiety to favor 6-coordinate over 7-coordinate structures.7 This would generate the anionic TpMo(CO)2 intermediate A shown in brackets in Scheme 2, which possesses three good π-back-bonding ligands to delocalize the charge: 2 terminal CO's and the η2-enone ligand. In situ quenching of the bracketed anionic intermediate A with NOPF6 or NOBF4 generates in most cases an unstable complex, TpMo(CO)(NO)(η2-enone),8 that spontaneously demetalates upon workup to afford the observed 6,8-dioxabicyclo[3.2.1]oct-3-en-2-ones.
Infrared analysis of the anionic intermediate A derived from compound anti-7 (Scheme 2) displays two metal carbonyl stretches at 1890 cm−1 and 1723 cm−1; these are shifted to lower energy from those of the starting material (anti-7: 1927 and 1831 cm−1). The C-5 ketonic carbonyl stretch of the anionic intermediate also shifted from 1613 cm−1 for anti-7 to 1605 cm−1. These data support the presence of a reaction intermediate bearing an anionic TpMo(CO)2 moiety.
The synthetic potential of this new nucleophilic ketalization methodology was demonstrated by an enantiocontrolled synthesis of (+)-(1R,2S,5S,7R)-2-hydroxy-exo-brevicomin (Scheme 3).9 Aldol reaction of 98% ee (−)-2 (synthesis described in the Supporting Information) with acrolein10 furnished syn and anti-16 in 82% yield (syn : anti = 3:1, HPLC). Since syn and anti-16 are inseparable by column chromatography on silica gel, the mixture of syn and anti-16 was converted to the chromatographically separable syn and anti-7 in 91% yield and 98% ee by Pd catalyzed hydrogenation. Anti-7 be recycled to syn-7 by a Mitsunobu reaction as described in the Supporting Information. Upon treatment with NaH in DME followed by a decomplexative quench with NOPF6, (−)-syn-7 was transformed to bicyclic acetal (−)-exo-11 in 73% yield (98% ee). Hydrogenation then afforded ketone (+)-17 in 80% yield. Finally, reduction of the carbonyl with NaBH4 completed the synthesis of (+)-(1R,2S,5S,7R)-2-hydroxy-exo-brevicomin 18 in 82% yield: [α]D20 +40.3 (c 1.10, CHCl3), Lit.9d [α]D24 +33.3 (c 1.10, CHCl3). The spectroscopic properties of compound (+)-18 are in full accordance with those of the natural product.9d,11
In conclusion, this study discloses the use of a new organometallic enantiomeric scaffold-based aldol reaction-nucleophilic ketalization-demetalation sequence to rapidly generate the 6,8-dioxabicyclo[3.2.1]oct-3-en-2-one framework in moderate to good yields with high enantiopurity. The method was showcased with an effective enantioselective total synthesis of (+)-(1R,2S,5S,7R)-2-hydroxy-exo-brevicomin.
The National Institute of General Medical Sciences, DHHS, supported this work through Grant GM043107. The contributions of Drs. Ethel Garnier-Amblard (Emory) and Yongqiang Zhang (Displaytech) are gratefully acknowledged.