A divergent asymmetric approach to aza-spiropyran derivative and (1S,8aR)-1-hydroxyindolizidine

Abstract

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).

Results

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 afforded N,O-acetal 5a as an epimeric mixture in a combined yield of 89%. Subjection of the diastereomeric mixture of N,O-acetal 5a to acidic conditions for 0.5 h resulted in the formation of the desired functionalized aza-spiropyran 7 as a single diastereomer in quantitative yield. The stereochemistry of the aza-spiropyran 7 was determined by NOESY experiment. For the synthesis of ent-3, aza-spiropyran 7, or more conveniently, N,O-acetal 5a, was converted to lactam 6a under standard reductive dehydroxylation conditions in 78% or 77% yield. Reduction of lactam 6a with borane-dimethylsulfide provided pyrrolidine 8 in 95% yield. Compound 8 was then converted to 1-hydroxyindolizidine ent-3 via a four-step procedure, namely, N-debenzylation/O-mesylation/Boc-cleavage/cyclization, and O-debenzylation. Alternatively, amino alcohol 8 was mesylated and the resultant mesylate 12 was subjected to hydrogenolytic conditions, which gave (1S,8aR)-1-hydroxyindolizidine (ent-3) in 60% overall yield from 8.

Conclusion

By the reaction of functionalized Grignard reagent with protected (S)-malimide, either aza-spiropyran or (1S,8aR)-1-hydroxyindolizidine skeleton could be constructed in a concise and selective manner. The results presented herein constitute an important extension of our malimide-based synthetic methodology.

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. [1-3] 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, aza-spiropyrans 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]

On the other hand, hydroxylated indolizidines [13-20] such as castanospermine, (−)-swainsonine, (+)-lentiginosine (1) [21-23] and (−)-2-epilentiginosine (2) [21-26] constitute a class of azasugars showing potent and selective glycosidase inhibitory activities. [13-20] (1R,8aS)-1-Hydroxyindolizidine 3 has been postulated as a biosynthetic precursor [21-26] of (+)-lentiginosine (1), (−)-2-epilentiginosine (2) and (−)-swainsonine, a potentially useful antimetastasis drug for the treatment of cancer.[15] In addition, these molecules serve as platforms for testing synthetic strategies, and several asymmetric syntheses of both enantiomers of 1-hydroxyindolizidine (3) have been reported. [27-34]In continuation of our efforts in the development of enantiomeric malimide-based synthetic methodologies, [35-38] we now report concise and highly diastereoselective syntheses of an aza-spiropyran derivative 7 and (1S,8aR)-1-hydroxyindolizidine (ent-3).

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. [36-38] It was envisioned that if a C₄-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.

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.)/CH₂Cl₂, 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 cleavage-intramolecular nucleophilic addition occurred. When the stirring was prolonged to 2 h, about 5% of another epimer (no shown) was also formed according to the ¹H NMR analysis.

The stereochemistry of the aza-spiropyran 7 was determined on the basis of the NMR analysis. This was done firstly by a ¹H-¹H COSY experiment to confirm the proton assignments, and then by NOESY experiment. As shown in Figure 1, the strong NOE correlation of H-9a (δ_H 3.59) and H-4 (δ_H 4.22) indicates clearly O₄/O₅-trans relationship in compound 7.

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 2), and the two diastereomers of 5 shows different reactivities towards the acid-promoted dehydration. [36-38] The trans-diastereomer reacts much more slower than the cis-diastereomer, and some un-reacted trans-epimer was always recovered even starting with a pure cis-diastereomer. In the present study, not only both two diastereomers 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,O-acetal, was converted to lactam 6a under standard reductive dehydroxylation conditions (Et₃SiH, BF₃·OEt₂, −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 Et₃SiH and BF₃·OEt₂, and stirring for 1 hour.

Reduction of lactam 6a with borane-dimethylsulfide provided pyrrolidine derivative 8 in 95% yield. Compound 8 was then converted to (1S,8aR)-1-hydroxyindolizidine (ent-3) {[α]_D ²⁷ +50 (c 0.90, EtOH); lit.[29] [α]_D +51.0 (c 0.54, EtOH); lit.[32] −49.7 (c 0.95, EtOH) for the antipode} via a four-step procedure, namely, one-pot N-debenzylation-N-Boc formation/O-mesylation/Boc-cleavage/cyclication, and O-debenzylation.

In searching for a more concise method, amino alcohol 8 was mesylated (MsCl, NEt₃, 0 °C) and the resultant labile mesylate 12 was subjected to catalytic hydrogenolysis (H₂, 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 N-debenzylation 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]

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.

See Supporting Information File 1 for full experimental procedures and characterization data of the synthesized compounds.