Concise total syntheses of bis(cyclotryptamine) alkaloids via thio-urea catalyzed one-pot sequential Michael addition

Abstract

Naturally occurring bis(cyclotryptamine) alkaloids feature vicinal all-carbon quaternary stereocenters with an elongated labile C-3a–C-3a′ Sigma bond with impressive biological activities. In this report, we have developed a thio-urea catalyzed one-pot sequential Michael addition of bis-oxindole onto selenone to access enantioenriched dimeric 2-oxindoles with vicinal quaternary stereogenic centers at the pseudobenzylic position (up to 96% ee and >20 : 1 dr). This strategy has been successfully applied for the total syntheses of either enantiomers of chimonanthine, folicanthine, and calycanthine.

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Bis(cyclotryptamine) alkaloids comprise a large family of secondary metabolites that are biosynthetically derived from the oxidative cyclization of L-tryptophan.¹ The complex bridged bicyclic structure of this family, i.e. (+)-calycanthine 1 (Fig. 1), was the first isolated Calycanthaceae alkaloid way back in 1888.² However, after more than seven decades the correct structure of 1 was established by Woodward^3a and Hamor,^3b independently. In 1954, based on a hypothetical bio-synthon, dialdehyde 6, Robinson and Teuber proposed five plausible structural isomers 1–5 (Fig. 1).^4–6 Structurally, bis(cyclotryptamine) alkaloids are characterized by the presence of vicinal quaternary all-carbon stereocenters⁷ at C-3a and C-3a′ (sp³–sp³) with six interlocked rings (Fig. 1). Because of their intriguing architecture along with important biological activities, these alkaloids drew the attention of scientists worldwide. Towards this, most of the literature reports feature the synthesis of pyrroloindoline ring systems.

Fig. 1 Naturally occurring bis(cyclotryptamine) alkaloids (1–5) and hypothetical biosynthetic dialdehyde precursor 6.

The initial contributions in this area have established a biosynthetically inspired oxidative dimerization of tryptamine and oxindole derivatives in a stereo-random manner.⁸ Overman and co-workers have reported elegant approaches via double Heck cyclization^9a or dialkylation^9b to address the formation of congested all-carbon quaternary stereocenters. Subsequent pioneering Co(I)-mediated reductive dimerization was developed by Movassaghi^10a,b and others.^10c,11 Later a number of oxidative dimerizations of 2-oxindoles were established by Liang,^12a Ishikawa,^12b Li,^12c Xia,^12d Zhang^12e and our group.¹³ Very recently, Jiang et al.¹⁴ reported an Fe-catalyzed stereoselective oxidative dimerization approach to access isocalycanthine structural motifs. Furthermore, a number of impressive catalytic enantioselective approaches have been reported by various research groups.¹⁵ These include Gong's enecarbamate addition onto 3-hydroxy 2-oxindole,^15a Kanai and Matsunaga's Michael addition onto nitroethylene,^15b Zhang's indole addition onto α,β-unsaturated aldehyde,^15c asymmetric allylations independently by Trost^15d and our group,^16a,b dialkylations by Tu and co-workers,^15e and malonate addition by our group.^16c,d Despite multifarious ventures,⁹ efforts towards a catalytic asymmetric one-pot sequential construction of a congested vicinal all-carbon quaternary stereocenter still hold a substantial challenge. We argued that a C₂-symmetric enantioenriched dimeric 2-oxindole 8 could be a common intermediate for asymmetric total syntheses of bis(cyclotryptamine) alkaloids having pyrrolidinoindolines 2a–b.

Retrosynthetically, we imagined that a unified approach to (+)-chimonanthine (2a) and (−)-calycanthine (1) [via2a] could be possible from Kanai/Matsunaga's intermediate^15b9via a reductive cyclization (Scheme 1), which in turn could be accessed from bis-selenone 12 following azide displacement and synthetic manipulations (see compounds 9–11).

Scheme 1 Retrosynthetic analysis.

Towards this, we thought of exploring a thio-urea catalyzed^17,18 stereo-mutative¹⁹ asymmetric sequential Michael addition of dimeric 2-oxindole such as 13 onto vinyl selenone²⁰ for the installation of a vicinal all-carbon quaternary stereogenic center in a highly enantioselective manner with excellent diastereocontrol.²¹ In this regard, Liu and Chen's TU-catalyzed Michael addition of 2-oxindole onto vinyl selenone at room temperature ionic liquids (RTILs) afforded the product in up to 95% ee.^20a We hypothesized that compound 13 having a mixture of active [(±)-13] and meso-isomer (13), of any ratio, could be efficiently transformed onto dienol (14) in the presence of a quinuclidine moiety of thio-urea, thereby affecting the stereomutation required for an enantioconvergent catalysis. However, the major difficulties with such a transformation include the presence of pre-existing stereocentres in 13, that would be responsible for developing mismatched catalyst–substrate interactions, and thus, negatively impact the chemical yield (Fig. 2).^15b Therefore, catalytic asymmetric transformation of such a complex mixture of 13 would be challenging and needs special attention.

Fig. 2 Rationale of stereomutative enantioconvergent catalysis.

The rationale of our stereomutative enantioconvergent catalysis is depicted in Fig. 2. Under the optimized conditions, the mixture of diastereomers of 13 must undergo stereomutative¹⁹ enolization to produce racemic enols 13A, which upon subsequent Michael addition on vinyl selenone may form intermediate 13B (Fig. 2). If the enantiopure TU-catalyst controls the formation of the new stereocentre, a pair of diastereomers 13Bi.e., (R,S)-13B and (S,S)-13B will predominantly form over the other pair, i.e., (R,R)-13B and (S,R)-13B. The influence of the remaining substrate stereocentre may either reinforce or conflict with catalyst control during this process. A second stereomutative enolization from diastereomeric pairs (R,S)-13B and (S,S)-13B would then generate a mixture of enols (S)-13C and (R)-13C. Finally, a second facially selective Michael addition onto vinyl selenone would afford the bis-Michael product as a diastereomeric mixture of enantioenriched (S,S)-12 and optically inactive meso-12 (Fig. 2). We also thought that if the enantiopure thio-urea catalyst imposes a high degree of facial selectivity at both steps of C–C bond formation, the simultaneous Michael addition of the complex mixture of 13 may be smoothly converged into a single product with excellent levels of diastereo and enantioselectivity.^22,23

Based on our hypothesis, initially we choose dimeric 2-oxindoles 15a–c and reacted them with 2.2 equivalents of phenylvinylselenone in the presence of 10 mol% of thio-urea (TU) C1. However, to our displeasure, there were no reactions observed and 15a–c were isolated almost quantitatively (entries 1–3). This probably indicates that the choice of an electron-withdrawing group such as Boc-group on the nitrogen might be necessary in order to tune the electronics. This could essentially decrease the pK_a of hydrogen situated at the pseudobenzylic position.¹⁷ To our delight, bis-Boc protected dimeric 2-oxindole 13 afforded bis-Michael addition product (S,S)-12 in 84% ee (79% yield) in the presence of 10 mol% C1. Gratifyingly, this reaction afforded 12 in >20 : 1 dr (entry 4). With this encouraging result, we then checked the efficiencies of other TU-based catalysts (Table 1). A quick optimization showed that acetonitrile is a better choice as compared to other solvents. Following exhaustive optimization, it was observed that 10 mol% catalyst C2 furnished (S,S)-12 in 93% ee (86% yield) with >20 : 1 dr (entry 7). Noteworthy to observe was that 10 mol% of a pseudoenantiomeric catalyst C3 afforded (R,R)-12 in 96% ee (90% yield) with >20 : 1 dr (entry 9). It was observed that the ee's were compromised a bit when the reaction was carried out at 0 °C (entries 8, 10 and 11). Further optimization revealed that TU catalysts C5–C6 and urea C7 were inferior as compared to C2 and C3 (entries 13–15). In order to have an efficient reaction both NH of the TU catalyst must be free, as N-Me thio-urea C8 failed to provide the product (entry 16). TU catalysts C9 and C10 furnished product (R,R)-12 only in 72-76% ee, however maintaining >20 : 1 dr (entries 17–18). Furthermore, TU catalysts C11 and C12 afforded (R,R)-12 in 83–91% ee with >20 : 1 dr (entries 19–20). Gratifyingly, the reaction can be scaled up to 1.5 g scale of 13, which afforded (R,R)-12 in 93% ee (85% yield) with >20 : 1 dr (96 h).

Table 1 Sequential Michael addition of dimeric 2-oxindoles onto phenylvinylselenone

S. n.	Substrate/Cat.^a	solvent	Temp. (°C)	dr^b	Time/product	Yield (%)	ee^c (%)
a Reactions were carried out with 0.25 mmol of 15a–c and 13 with 0.60 mmol of phenylvinylselenone in 5 mL of solvent in the presence of 10 mol% of TU catalysts under N2-atm. b dr's were calculated from crude ^1H-NMR. c ee's were determined by IA column by converting the product to bis-carbamate 8 (see, Scheme 2).
1	15a/C1	CH2Cl2	25 °C	—	5d/16a	—	—
2	15b/C1	CH2Cl2	25 °C	—	5d/16b	—	—
3	15c/C1	CH2Cl2	25 °C	—	5d/16c	—	—
4	13/C1	CH2Cl2	25 °C	∼20 : 1	72 h/12	79	−84
5	13/C1	PhMe	25 °C	∼12 : 1	72 h/12	62	−87
6	13/C1	MeCN	25 °C	∼20 : 1	72 h/12	88	−89
7	13/C2	MeCN	25 °C	∼20:1	72 h/12	86	−93
8	13/C2	MeCN	0 °C	∼20 : 1	96 h/12	64	−90
9	13/C3	MeCN	25 °C	∼20 : 1	72 h/12	90	96
10	13/C3	MeCN	0 °C	∼20 : 1	96 h/12	72	93
11	13/C3	CHCl3	0 °C	∼20 : 1	96 h/12	72	91
12	13/C4	MeCN	25 °C	∼20 : 1	72 h/12	84	87
13	13/C5	MeCN	25 °C	∼9 : 1	96 h/12	72	70
14	13/C6	MeCN	25 °C	∼12 : 1	96 h/12	81	67
15	13/C7	MeCN	25 °C	∼20 : 1	96 h/12	80	78
16	13/C8	MeCN	25 °C	∼9 : 1	96 h/12	41	ND
17	13/C9	MeCN	25 °C	∼20 : 1	72 h/12	82	76
18	13/C10	MeCN	25 °C	∼20 : 1	72 h/12	76	72
19	13/C11	MeCN	25 °C	∼20 : 1	72 h/12	82	91
20	13/C12	MeCN	25 °C	∼20 : 1	72 h/12	79	83

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We next turned our attention to the utilization of (R,R)-12 for the total syntheses of (+)-chimonanthine (2a) and (−)-calycanthine (1) as planned. Towards this end, nucleophilic displacement of selenone with sodium azide furnished (R,R)-10 in 96% yield (Scheme 2), and subsequent Staudinger reaction followed by protection with ClCOOMe afforded (R,R)-9 in 86% yield over 2 steps. The latter on treatment with TFA furnished our proposed intermediate (R,R)-8 in 97% yield.

Scheme 2 Total syntheses of (+)-chimonanthine (2a), (+)-folicanthine (2b) and (−)-calycanthine (1).

However, lithium aluminum hydride reduction of (R,R)-8 led to a complex mixture of products, which we were unable to characterize. To our delight, reduction of (R,R)-8 using sodium bis(2-methoxyethoxy)aluminum hydride (Red-Al) afforded (+)-chimonanthine 2a in 85% isolated yield. Next, N-methylation using formaldehyde and NaBH(OAc)₃ completed the synthesis of (+)-folicanthine (2b) following Overman's^9c and Movassaghi's protocol.^10a Furthermore, a biomimetic route to (−)-calycanthine (1) from (+)-chimonanthine (2a) was carried out under refluxing AcOH^9c (61% yield). Since both the antipodes of 1 and 2a–b are naturally occurring,⁷ we undertook the total synthesis of (−)-chimonanthine (ent-2a), (−)-folicanthine (ent-2b), and (+)-calycanthine (ent-1) starting from (S,S)-12 (see SI for the details). Of note, we have carried out C2 catalyzed sequential Michael reaction of 13 at 1.5 g scale to access (S,S)-12 in 93% ee (87% yield) with >20 : 1 dr (96 h).

In conclusion, we developed a catalytic asymmetric approach to a general strategy to bis(cyclotryptamine) alkaloids. Our approach features a catalytic enantioselective synthesis of dimeric 2-oxindoles bearing vicinal quaternary stereocenters with an overwhelming control of the absolute and relative stereochemistry. The approach demonstrated that the designed chiral precursor 8 was an excellent complement for cyclotryptamine alkaloid synthesis. Furthermore, total syntheses of both antipodes to naturally occurring alkaloids have been shown.

Support from the SERB [CRG/2019/000113] is gratefully acknowledged. AK, PS and AM gratefully thank the INSPIRE, UGC and CSIR, respectively, for research fellowships. AB is a SERB-STAR Fellow and sincerely acknowledges the SERB [STR/2020/000061] for the generous support.

Conflicts of interest

There are no conflicts to declare.

Notes and references

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22. We sincerely thank one of the reviewers for valuable comments and suggestions on the rationale of a sequential process.
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Footnote

† Electronic supplementary information (ESI) available: Experimental procedures, characterization data, and NMR spectra. See DOI: 10.1039/d2cc01008a

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