Total Syntheses of Pleiocarpamine, Normavacurine, and C-Mavacurine

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Letter Cite This: Org. Lett. XXXX, XXX, XXX−XXX

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Total Syntheses of Pleiocarpamine, Normavacurine, and C‑Mavacurine Keigo Sato, Noriyuki Kogure, Mariko Kitajima, and Hiromitsu Takayama* Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8675, Japan

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ABSTRACT: The total syntheses of C-mavacurine-type indole alkaloids, (±)-pleiocarpamine, (±)-normavacurine, and (±)-Cmavacurine, were accomplished. The key step in the syntheses was the cyclization between the metal carbenoid at C16 and the N1 position in a Corynanthe-type compound that was equipped with a diazo function. For this cyclization, the N4 modification of the substrate using an amine−borane complex was indispensable to fix the molecular conformation. Herley-Mason5b required a strategy involving the C/D ring cleavage and the reclosure of the C3−N4 bond in the last synthetic step to construct a highly strained pentacyclic skeleton. Later, Bosch’s group achieved the total synthesis of (±)-2,7dihydropleiocarpamine,5c which features a C ring construction in the final stage of the total synthesis. However, there is no report on the total synthesis of C-mavacurine-type natural products by the direct coupling between the C16 and N1 positions in the Corynanthe skeleton, probably because its highly strained property owing to its pentacyclic framework has made synthesis difficult. Herein, we report the biomimetic total syntheses of pleiocarpamine (2), normavacurine (3), and Cmavacurine (4) via the cyclization between the C16 and N1 positions of Corynanthe compound (6) equipped with a diazo function at C16. Our initial synthetic plan is shown in Scheme 2. We considered that the ring closure between C16 and C7 and/or C16 and N1 would occur if an electrophilic carbon species is generated at C16 in a Corynanthe-type substrate. For this purpose, we designed diazo compound 6, which was prepared from geissoschizine (1) through the Regitz diazo transfer reaction.6 Our synthesis commenced with the preparation of diazo compound 6 via (±)-1, as shown in Scheme 3. According to Vincent’s report,7 α,β-unsaturated ester 8 was prepared from tryptamine (7). The Ni(cod)2-mediated reductive cyclization of 8 afforded trans-9 as the major product in 55% yield together with desired cis-9 in 31% yield.8 Then, we examined the conversion of trans-9 into cis-9, as shown in Scheme 3 and Table 1. The reduction of iminium intermediate 11 with conventional hydride reagents, such as borane-THF complex (entry 1), NaBH49 (entry 2), or LS-selectride (entry 3), completely or mainly afforded trans-9. Serendipitously, we observed that the Noyori transfer hydrogenation10 gave a different result, i.e., cis-9

C-Mavacurine-type alkaloids, such as pleiocarpamine (2), are considered to be biogenetically derived from geissoschizine (1) by the ring closure between the C16 and N1 positions.1 Geissoschizine (1) is also supposed to be a biogenetic common intermediate to provide akuammiline-type alkaloids, such as strictamine (5) (Scheme 1).1,2 Recently, studies of the total Scheme 1. Hypothetical Biosynthetic Route of Indole Alkaloids 2−5 Derived from Geissoschizine (1)

synthesis of akuammiline-type alkaloids have been enthusiastically carried out, which have resulted in the development of a number of total syntheses of this class of alkaloids.3,4 However, synthetic studies of C-mavacurine-type alkaloids are quite limited.5 Boekelheide and co-workers accomplished the total synthesis of (±)-19,20-dihydronormavacurine5a via the rearrangement of an intermediate with a pseudoindoxyl skeleton. The first total synthesis of (±)-C-mavacurine (4) achieved by © XXXX American Chemical Society

Received: March 27, 2019

A

DOI: 10.1021/acs.orglett.9b01084 Org. Lett. XXXX, XXX, XXX−XXX

Letter

Organic Letters Table 1. Conversion of trans-9 into cis-9

isolated yield (%) entry 1 2 3 4 5 6 7

reductant and additive BH3-THF (2.1 equiv) NaBH4 (1.5 equiv) LS-selectride (1.1 equiv) RuCl[(R,R)-Tsdpen](p-cymene) (10 mol %) HCO2H/Et3N (5:2) RuCl[(S,S)-Tsdpen](p-cymene) (10 mol %) HCO2H/Et3N (5:2) RuCl[(R,R)-Tsdpen](p-cymene) (10 mol %) HCO2H/Et3N (5:2) RuCl[(R,R)-Tsdpen](p-cymene) (10 mol %) HCO2H/Et3N (5:2), Ti(Oi-Pr)4 (2.0 equiv)

solvent

temp (°C)

time (h)

ratio of trans-9 /cis-9a

THF MeOH THF DMF DMF DMF DMF

0 0 0 0 0 30 30

14 0.5 0.5 14 14 15 18

1:0 30:1 3:1 1:2 1:2 1:4 1:5.3

trans-9

cis-9

76

2.5

12

65

a

The ratio was determined by 1H NMR.

Scheme 2. Synthetic Plan for Indole Alkaloids 2−5

Scheme 3. Synthesis of Cyclization Precursor 6

was obtained as the major product (entries 4 and 5). Then, we performed a screening for the reaction conditions using this reagent and found that treatment of iminium 11 with Noyori catalyst and formic acid/Et3N in DMF in the presence of titanium tetraisopropoxide at 30 °C (entry 7) gave cis-9 predominantly (cis/trans = 5.3:1).11 Thus, obtained cis-9 was treated with excess LDA and then with methyl formate to provide (±)-geissoschizine (1) in 80% yield. All the spectroscopic data except for the optical property of synthetic 1 are identical with those of the natural product.12 Next, (±)-1

was converted into diazo compound 6 in 60% yield by employing tosyl azide in the presence of Et3N. With diazo compound 6 in hand, we next investigated the cyclization under carbene-generating conditions (Table 2). Among the binuclear rhodium complex catalysts used, a separable product was obtained in 54% yield only when Rh2(OAc)4 was employed as the catalyst (entry 1). However, the product was the unexpected structure 12 given by D-ring expansion. The use of mononuclear rhodium complex (PPh3)3RhCl (entry 4) or copper catalyst Cu(MeCN)·BF4 (entry 5) did not promote the reaction at room temperature. When JohnPhosAu-(MeCN)SbF6 was used as the catalyst, ringexpanded product 12 was again obtained together with βhydride elimination product 13. The ring expansion giving 12 would proceed by the 1,2-alkyl migration of the C20 ethylidene B

DOI: 10.1021/acs.orglett.9b01084 Org. Lett. XXXX, XXX, XXX−XXX

Letter

Organic Letters Table 2. Trial for Metal Carbenoid Cyclization

Figure 1. Conformations of geissoschizine (1) and 14.

Scheme 5. Syntheses of (±)-2−4 yield (%) entry

metal cat. (mol %)

12

1 2a 3a 4b 5b 6

Rh2(OAc)4 (10) Rh2(cap)4 (10) Rh2(esp)2 (10) (PPh3)3RhCl (10) Cu(MeCN)·BF4 (10) JohnPhosAu(MeCN)SbF6 (15)

54

36

13

36

a

The substrate was decomposed. bNo reaction.

side chain onto the metal carbenoid at C16, as illustrated in Scheme 4. Scheme 4. Proposed Mechanism for the Ring Expansion of 6

With cyclization precursor 14 in hand, we examined again various metal catalysts for the cyclization. The Rh2(cap)4 catalyst gave cyclized product 15 in 55% yield as an inseparable mixture of diastereomers at C16 (ca. 7:1) through a carbene N− H insertion reaction. The amine−borane bond in product 15 was easily cleaved by heating 15 in the presence of trimethylamine oxide to give (±)-pleiocarpamine (2) and compound 16 (16-epi-pleiocarpamine) in 12% and 84% yields, respectively. All the spectroscopic data of synthetic 2 were completely identical with reported data.14,15 Reduction of methyl ester 16 with LiAlH414 afforded (±)-normavacurine (3) in 84% yield, and 3 was further converted into (±)-C-mavacurine (4) in 75% yield by treatment with excess methyl iodide.14 The spectral and physical properties of synthetic 316 and 414,17 were in good agreement with the reported data of the natural products. In conclusion, we have achieved the biomimetic total syntheses of (±)-pleiocarpamine (2), (±)-normavacurine (3), and (±)-C-mavacurine (4) via a direct cyclization by a carbene N−H insertion reaction between the C16 and N1 positions in Corynanthe compound 14. For this key cyclization, the N4 modification of the substrate using an amine−borane complex

Given the above results, we carefully reformulated our synthetic plan by taking the molecular conformation of Corynanthe-type alkaloids into consideration. Normal-type Corynanthe alkaloids, such as geissoschizine (1), are known to take the trans-quinolizidine form (1a),12 but can likewise adopt the cis-quinolizidine conformer (1b) through the inversion of the lone electron pair of nitrogen atom (N4) (Figure 1). We anticipated that when compound 6 took the cis-quinolizidine form, the distance of the reaction sites (between C16 and C7 and/ or C16 and N1) was reduced, affecting the desired cyclization. As it was previously proposed that geissoschizine (1) would take the cis-quinolizidine conformation,13 we attempted to modify the lone electron pair of N4 in compound 6 so that 6 would take the cis-quinolizidine form. We chose N4-borane complex (14) and prepared it by treatment of 6 with the BH3-THF complex (Scheme 5). NOE experiments of compound 14 (observation of signal between H-6β and H-21β) revealed that the complex had the cis-quinolizidine form, as expected (Figure 1). C

DOI: 10.1021/acs.orglett.9b01084 Org. Lett. XXXX, XXX, XXX−XXX

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Organic Letters was indispensable to fix the molecular conformation to a robust cis-quinolizidine structure.



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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.9b01084. Experimental procedures including spectroscopic data for all new compounds (UV, IR, 1H NMR, 13C NMR, HRMS) (PDF)



AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Hiromitsu Takayama: 0000-0003-3155-2214 Notes

The authors declare no competing financial interest.



ACKNOWLEDGMENTS This work was supported by JSPS (Japan Society for the Promotion of Science) KAKENHI Grant Numbers 16H05094, 17H03993, and 16K08155.



REFERENCES

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DOI: 10.1021/acs.orglett.9b01084 Org. Lett. XXXX, XXX, XXX−XXX