Development of bifunctional organocatalysts and application to asymmetric total synthesis of naucleofficine I and II

The proline-type organocatalysts has been efficiently employed to catalyze a wide range of asymmetric transformations; however, there are still many synthetically useful and challenging transformations that remain unachievable in an asymmetric fashion. Herein, a chiral bifunctional organocatalyst with a spirocyclic pyrrolidine backbone-derived containing fluoro-alkyl and aryl sulfonamide functionalities, are designed, prepared, and examined in the asymmetric Mannich/acylation/Wittig reaction sequence of 3,4-dihydro-β-carboline with acetaldehyde, acyl halides, and Wittig reagents. As a result, the spirocyclic pyrrolidine trifluoromethanesulfonamide catalyst can facilitate this versatile sequence as demonstrated by 18 examples displaying excellent enantioselectivity (up to 94% ee), as well as moderate to good yields (up to 54% over 3 steps). As a practical application, the asymmetric total synthesis of naucleofficine I (1a) and II (1b) in ten steps have been accomplished.

T he metal-free organocatalysis based on the dual activation of amino acids and their analogs has been displaying versatile utilities in the synthesis of natural products and pharmaceuticals [1][2][3][4][5] . The proline-type organocatalysts represent a large class of useful bifunctional catalytic systems, which have facilitated a wide range of asymmetric reactions of carbonyls, imines, and their variants, including aldol, Michael addition, Diels-Alder cycloaddition, Mannich reaction, and so on [6][7][8][9][10][11][12] . Despite these advances, there are still many inspiring transformations that remain unachievable in asymmetric synthesis. Therefore, development of more and reliable bifunctional organocatalysts is of high demand for effecting these transformations. Aimed at the asymmetric synthesis of biologically important natural products and drug molecules, our current efforts have been focused on developing novel and effective catalysis systems to enable synthetically challenging transformations so as to explore the concise synthetic approaches. As indicated in Fig. 1, at least four kinds of different natural products, the naucleofficine I (1a) and II (1b), yohimbine, and berbanes, contain the common complex N-fused bicyclic structures 6 with multi-substituents and stereocenters. Compounds 1a and 1b are isolated from Nauclea genus and exhibit antibacterial and antiviral biological activities 13,14 . They represent the characteristic structures of a number of monoterpenoid indole alkaloids and have not been synthesized so far, although some approaches to their analogs have been reported by employing free radical cyclization and the Pictet-Spengler reaction as key steps [15][16][17][18] .
In previous reports, the the spirocyclic pyrrolidine (SPD) backbone-derived organocatalysts have displayed high enantioselectivity in several reactions, possibly due to the rigid chiral environment of quaternary carbon stereocenter and spirocylic scaffold, and the flexibility of the lone electron pair of the pyrrolidine moiety [19][20][21] . In this regard, it is hypothesized that attachment of the strong acidic fluoroalkylsulphonamide motif to a sterically hindered SPD backbone would generate a new bifunctional catalyst, which would exhibit stronger acidity and superior enantio-induction ability compared with proline but still maintain the active pyrrolidine amine. Furthermore, the BINOLphosphonyl TfNH catalyst (Table 1, Cat 8) exhibits much stronger acidity than BINOL-phosphoric acid alone, due to its stability of counter anion and strong electron-accepting property of Tf group [22][23][24][25] . Herein, we present our research results on the asymmetric Mannich/acylation/Wittig sequence to efficiently assemble the tetrahydro-β-carboline 5, which allows us to accomplish the total synthesis of naucleofficine I (1a) and naucleofficine II (1b) in a concise way.

Results
Design plan. The synthesis of natural products in Fig. 1 could be simplified to establishment of the single C3 stereocenter and installation of two unsaturated chains in 5. In this work, we focus on the synthesis of the alkaloids 1a and 1b, our retro-synthesis involves alternatively a late-stage O-hetero-Diels-Alder cycloaddition to construct the D/E rings with multi-functional groups and stereogenic centers in one step from the key intermediate 5 (Fig. 1). Therefore, we envision a versatile Mannich/acylation/ Wittig sequence would enable the construction of 5 from commercially available 3,4-dihydro-β-carboline 2, acetaldehyde, acyl halides, and corresponding Wittig reagents. To achieve this catalytic asymmetric sequence, however, some challenges exist, including the following: (1) the starting N-aliphatic imine is relatively inactive compared with generally used active Boc- 26,27 , Ts- 28,29 , aryl-imine species 30,31 , and Cbz-32 , which requires a stronger acidity to activate the C=N bond via hydrogen bonding; (2) the active acetaldehyde 33-39 could easily form byproducts via aldol condensation; and (3) asymmetric Mannich reaction of 3,4-dihydro-β-carboline and aldehydes is a challenging work, which has not been reported up to now, maybe due to the instability of the resulting amino aldehyde. Reaction condition optimization. Initially, four catalysts Cat 1-4 with substituents possessing different electronic properties were prepared from (S,S)-SPD-amine (for details, see Supplementary Note 2). Imine 2a was selected as a model substrate to screen the optimal condition of the Mannich sequence with acetaldehyde, acetyl bromide, and methyl(triphenylphosphoranylidene)-acetate. Fortunately, the expected Mannich sequence could take place in the presence of Cat 1 in DCE/H 2 O at 0°C, affording mainly the desired product 5a albeit with the poor yield (21% over three steps) and moderate enantiomeric excesses (ee) (51%) ( Table 1, entry 1). Encouraged by this result, the effect of additives was then investigated (for details, see Supplementary Table 1). The presence of a basic additive was found to be crucial to improve the reaction outcome, with Et 3 N giving the best result (entry 4), the main byproducts were the decomposition of the amino aldehyde in the second step of acylation and the byproducts of aldol condensation have not been detected. In contrast, the acid additives gave poor results and reversed the chirality of the resulting products (entries 2-3 vs. [4][5][6]. Subsequently, decreasing the reaction temperature led to slightly lower yield and ee (entries 7-8). Further examination of the analogous Cat 2-4 revealed that the TfNH modified Cat 1 provided a much better result than Cat 2-4 with the weaker and stronger electron withdrawing property of tolylsulfonyl, p-(triflouromethyl)-benzenesulfonyl, and methylsulfonyl, respectively (entries 9-11 vs. 4). In addition, other types of catalysts with quite different levels of reactivity and/or stereo-effect from Cat 1 were subjected to the reaction and compared with Cat 1 under the same condition as entry 4. These include the following: (1) Cat 5, Cat 13, which does not have an acidic functional group; (2) Cat 6, which has a protecting group of pyrrolidine amine; (3) Cat 8, which has a single, stronger acidity and generally identified excellent enatio-induction of BINOL framework; and (4) Cat 9-12 5,40-44 , which have similar reactivity but quite different stereo-effect of a linear derivative. Unfortunately, all of these catalysts gave poor results (entries [12][13][14][15][16][17][18]. Particularly, Cat 7 failed to promote this sequence and only the starting material was recovered (entry 14). These results indicated that Cat 1 exhibited both excellent reactivity and high enantio-induction ability toward the studied transformation.
Asymmetric total synthesis of naucleofficine I and II. To demonstrate the utility of this sequence, the asymmetric total synthesis of 1a/1b were carried out efficiently from intermediates 5o. First, 5p underwent an O-hetero-Diels-Alder cycloaddition under reflux in mesitylene to produce the advanced pentacyclic intermediate 7 with mainly cis-configuration of C3 and C15 (Fig. 3) 50 . Next, we turned to the asymmetric total synthesis of the natural alkaloids 1a and 1b from intermediate 5o, which was readily prepared on the gram-scale from 2a using 10 mol % (R,R)-Cat 1 in 42% yield and 91% ee (Fig. 4). After extensive screening of the reaction conditions (for details, see Supplementary  Table 2), ZnBr 2 was found to enable the expected O-hetero-Diels-Alder cyclization of 5o, efficiently affording the pentacyclic intermediate 8 with four desired stereocenters in 51% yield and >20:1 dr (Fig. 5), and there were amount of natural products that owned trans-configuration of C3 and C15 had not been synthesized. One-recrystallization of 8 in MeOH/Et 2 O enhanced the enantio-purity to >99% ee (85% yield) and its absolute configuration was confirmed by X-ray crystallographic analysis (for details, see Supplementary Table 6). However, a thermal cyclization of 5o in mesitylene under refluxing temperature resulted mainly in the formation of undesired C15-epimer. Hydroformylation of 8 with POCl 3 /DMF afforded aldehyde 9 in 48% yield, which was treated with freshly prepared Me 2 CuLi to provide the separable products 10, 11, and 11′ (2.8: 2.5: 1) with 63% total yield. Fortunately, isomer 11′ could be readily converted to 11 with 85% yield when stirred in DBU (1,8-diazabicyclo[5.4.0]undec-7-ene)/DCM. Subsequent reduction of 10 with NaBH 4 furnished 12 with 86% yield. After extensive investigations 51,52 , protection of the hydroxyl group of 12 with hexamethyl disilylamine at refluxing temperature gave a silyl ether, which was subjected to elimination of methoxy group and removal of Boc with BF 3 ·Et 2 O and TMSOTf in CH 3 CN to obtain acetal 14, and then the double bond isomerization to give 1a with 81% yield, so we developed an efficient method to construct the double bond of these natural products. In the same way, 1b was also synthesized separately from 11. The spectra data of synthetic (+)-1a and (−)-1b are consistent with literature 13 , and the ee of (+)-1a and (−)-1b are >99% determined by chiral highperformance liquid chromatography (HPLC).

Discussion
In summary, a chiral bifunctional organocatalyst has been successfully developed, which is a good assembly of strong acid and sterically hindered SPD framework, and thus exhibits high reactivity as well as excellent stereo-induction ability toward the asymmetric Mannich reaction of 3,4-dihydro-β-carboline with a broad substrate toleration. Furthermore, synthetic utility of this Mannich sequence has been exemplified through the asymmetric total synthesis of naucleofficine I (1a) and II (1b) in a concise way. Further expanded studies on asymmetric catalysis with our bifunctional organocatalysts toward other transformations and synthesis of other natural products are underway.

Methods
General information. All reactions requiring anhydrous conditions were carried out under argon atmosphere using oven-dried glassware (130°C), which was cooled under argon. All solvents were purified and dried by standard techniques, and distilled prior to use. All reactions under standard conditions were monitored by thin-layer chromatography (TLC) on gel F 254 plates. The products were purified by flash column chromatography on silica gel (200~300 mesh) or neutral alumina (200~300 mesh). 1 H NMR, 13