Beilstein Journal of Organic Chemistry Beilstein Journal of Organic Chemistry Beilstein Journal of Organic Chemistry a Divergent Asymmetric Approach to Aza-spiropyran Derivative and (1s,8ar)-1-hydroxyindolizidine

Background: Spiroketals and the corresponding aza-spiroketals are the structural features found in a number of bioactive natural products, and in compounds possessing photochromic properties for use in the area of photochemical erasable memory, self-development photography, actinometry, displays, filters, lenses of variable optical density, and photomechanical biomaterials etc. And (1R,8aS)-1-hydroxyindolizidine (3) has been postulated to be a biosynthetic precursor of hydroxylated indolizidines such as (+)-lentiginosine 1, (-)-2-epilentiginosine 2 and (-)-swainsonine, which are potentially useful antimetastasis drugs for the treatment of cancer. In continuation of a project aimed at the development of enantiomeric malimide-based synthetic methodology, we now report a divergent, concise and highly diastereoselective approach for the asymmetric syntheses of an aza-spiropyran derivative 7 and (1S,8aR)-1-hydroxyindolizidine (ent-3).


Background
Spiroketals of general structure A (Scheme 1) constitute key structural features of a number of bioactive natural products isolated from insects, microbes, fungi, plants or marine organisms. [1][2][3] The corresponding aza-spiroketal (cf: general structure B) containing natural products, while less common, are also found in plants, shellfish and microbes. [4,5] For example, pandamarilactone-1 and pandamarine were isolated from the leaves of Pandanus amaryllifolius; [6] solasodine and its derivatives were isolated from Solanum umbelliferum, which exhibited significant activity toward DNA repair-deficient yeast mutants; [7] azaspiracids are marine phycotoxins isolated from cultivated mussels in Killary harbor, Ireland; [8] and chlorofusin A is a novel fungal metabolite showing the potential as a lead in cancer therapy. [9] In addition, azaspiropyrans C, being able to equilibrate with the corresponding non-spiro analogue D, is a well known class of compounds possessing photochromic properties for use in the area of photochemical erasable memory, [10] and also found applications as self-development photography, actinometry, displays, filters, lenses of variable optical density, [11] and photomechanical biomaterials etc. [12] Scheme 1: The skeletons of useful aza-spiroketals and some naturally occurring hydroxylated indolizidines.

Results and discussion
Previously, we have shown that the addition of Grignard reagents to N,O-dibenzyl malimide 4 leads to N,O-acetals 5 in high regioselectivity (Scheme 2), and the subsequent reductive dehydroxylation gives 6 in high trans-diastereoselectivity. [35] On the other hand, treatment of N,O-acteals 5 with an acid furnished enamides E, which can be transformed stereoselectively to either hydroxylactams F or G under appropriate conditions. [36][37][38] It was envisioned that if a C 4 -bifunctional Grignard reagent was used, both aza-spiroketal H (such as aza-spiropyran, n = 1, path a) and indolizidine ring systems I (path b) could be obtained.

Scheme 2: Synthetic strategy based on N,O-dibenzylmalimide (4).
The synthesis of aza-spiropyran 7 started from the Grignard addition of malimide 4. Treatment of the THP-protected 4-hydroxybutyl magnesium bromide with malimide 4 at -20°C for 2.5 h afforded N,O-acetal 5a as an epimeric mixture in 7:1 ratio and with a combined yield of 89% (Scheme 3). If the reaction was allowed to stir at room temperature overnight, the diastereomeric ratio was inversed to 1: 1.8. Subjection of the diastereomeric mixture of the N,O-acetal 5a to acidic conditions [TsOH (cat.)/CH 2 Cl 2 , r.t.] for 0.5 h resulted in the formation of the desired functionalized aza-spiropyran derivative 7 as a single diastereomer in quantitative yield. The result means that a tandem dehydration-THP cleavageintramolecular nucleophilic addition occurred. When the stirring was prolonged to 2 h, about 5% of another epimer (no shown) was also formed according to the 1 H NMR analysis. The stereochemistry of the aza-spiropyran 7 was determined on the basis of the NMR analysis. This was done firstly by a 1 H-1 H COSY experiment to confirm the proton assignments, and then by NOESY experiment. As shown in Figure 1 These findings are surprising comparing with our recent observations. In our previous investigations, it was observed that the treatment of N,O-acetals 5 with an acid leads to the dehydration products E (Scheme 1), and the two diastereomers of 5 shows different reactivities towards the acid-promoted dehydration. [36][37][38] The trans-diastereomer reacts much more slower than the cisdiastereomer, and some un-reacted trans-epimer was always recovered even starting with a pure cis-diastereomer. In the present study, not only both two diastereom-ers have been completely converted to the aza-spiropyran 7, what is equally surprising is that no dehydration product was observed under acidic conditions! For the synthesis of ent-3, aza-spiropyran 7, a cyclic N,Oacetal, was converted to lactam 6a under standard reductive dehydroxylation conditions (Et 3 SiH, BF 3 ·OEt 2 , -78°C, 6 h; warm-up, yield: 78%) (Scheme 4). Under the same conditions, N,O-acetal 5a was converted to lactam 6a in 77% yield. It was observed that during the reaction of 5a, 7 was first formed as an intermediate after the addition of Et 3 SiH and BF 3 ·OEt 2 , and stirring for 1 hour.

Scheme 4: Stereoselective synthesis of (1S,8aR)-1-hydroxyindolizidine (ent-3).
Reduction of lactam 6a with borane-dimethylsulfide provided pyrrolidine derivative 8 in 95% yield. Compound 8 was then converted to (1S,8aR)-1-hydroxyindolizidine The observed NOE correlations (in part) and the region expanded NOESY spectrum of compound 7  In searching for a more concise method, amino alcohol 8 was mesylated (MsCl, NEt 3 , 0°C) and the resultant labile mesylate 12 was subjected to catalytic hydrogenolysis (H 2 , l atm, 10% Pd/C, r.t.), which gave (1S,8aR)-1-hydroxyindolizidine (ent-3) in 60% overall yield from 8 (Scheme 5). [39,40] The one-pot N,O-bis-debenzylation and cyclization of mesylate 12 deserves comment. Because the Ndebenzylation generally required longer reaction time, [41] or using of Pearlman's catalyst (cf. Scheme 4). The easy debenzylation of 12 allows assuming that an intramolecular substitution occurred firstly, and the formation of the quaternary ammonium salt K [40] then favors the reductive debenzylation. This mechanism is supported by the following observations. First, in a similar case, Thompson et al observed that the formation of a mesylate resulted in spontaneous quarternization leading to the bicyclic indolizidine. [40] Second, we have also observed that the tosylate of 8 is too labile to be isolated, and mesylate 12 decomposed upon flash column chromatography on silica gel, which are due to the spontaneous formation of a polar quaternary ammonium salt. In addition, the presence of the O-benzyl group in K is an assumption based on our previous observation on a similar case. [42] Scheme 5: One-pot synthesis of ent-3 from amino alcohol 8.

Conclusion
In summary, we have demonstrated that by the reaction of functionalized Grignard reagent with the protected (S)malimide 4, either aza-spiropyran derivative 7 or (1S,8aR)-1-hydroxyindolizidine skeleton (ent-3) can be constructed in a concise and selective manner. It is worthy of mention that in addition to the reductive dehydroxylation leading to 2-pyrrolidinones 6, and the acid-promoted dehydration leading to (E)-enamides E (and then F, G), acid treatment of the N,O-acetal 5a could provide, chemoselectively and quantitatively, the aza-spiropyran ring system 7. The results presented herein constitute a valuable extension of our malimides-based synthetic methodology.