Divergent Asymmetric Total Synthesis of (+)-Vincadifformine

There is no corresponding record for this reference. 2. (a) Malawista , S. E.; Sato , H.; Bensch , K. G. Science 1968, 160, 770 DOI: 10.1126/science.1...
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Divergent Asymmetric Total Synthesis of (+)-Vincadifformine, (−)-Quebrachamine, (+)-Aspidospermidine, (−)-Aspidospermine, (−)-Pyrifolidine, and Related Natural Products Nengzhong Wang,† Shuo Du,† Dong Li,† and Xuefeng Jiang*,†,‡ †

Shanghai Key Laboratory of Green Chemistry and Chemical Process, School of Chemistry and Molecular Engineering, East China Normal University, 3663 North Zhongshan Road, Shanghai 200062, P. R. China ‡ State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Road, Shanghai 200032, P. R. China S Supporting Information *

ABSTRACT: A uniformly strategic total synthesis of Aspidosperma alkaloids (+)-vincadifformine, (−)-quebrachamine, (+)-aspidospermidine, (−)-aspidospermine, (−)-pyrifolidine, and nine others from efficiently constructed tricyclic ketone 13 is reported. Highlights of these divergent and practical syntheses include (i) stereoselective intermolecular [4 + 2] cycloaddition to establish a C−E ring with one all-carbon quaternary stereocenter (C-5) and two bridged contiguous cis-stereocenters (C-12 and C-19), (ii) a Pd/C-catalyzed hydrogenation/deprotection/amidation cascade process to assemble the D ring, and (iii) Fischer indolization to forge the A−B ring.

A

spidosperma alkaloids are a class of structurally intricate and biologically active natural products that have been attracting significant attention from synthetic chemists.1 Recently, much more attention has been paid to this family due to the distinctly important pharmacological activities exhibited by its members.2 In particular, outstanding anticancer activities are displayed among the bisindole alkaloids, such as vinblastine and vincristine, which have been widely used as wellknown anticancer drugs for chemotherapy.2a−c Thus, the core members from Aspidosperma alkaloids, such as vincadifformine (1),3 aspidospermidine (2),4 aspidospermine (3),5 quebrachamine (5),6 cylindrocarpidine (6),7 cimicidine (7),8 and limaspermidine (8),9 have logically served as hotspots in alkaloids syntheses (Figure 1). All of these vital structures are derived from a pentacyclic (ABCDE [6.5.6.6.5] ring system) skeleton (9) bearing three contiguous cis-stereocenters (C-5, C12, and C-19) with two all-carbon quaternary chiral centers (C-5 and C-12). The structural and steric complexity of Aspidosperma alkaloids has inspired splendid and elegant synthetic efforts. Therefore, over 100 total syntheses of Aspidosperma alkaloids have been reported since Stork and Dolfini’s pioneering work in this family in 1963.5a The core construction can be basically divided into four primary strategies: (a) Stork’s Fischer indolization of a tricyclic ketone with phenylhydrazine,5a (b) Harley-Mason’s rearrangement of an indoloquinolizidine,4c (c) Huffman’s construction of the E ring after ABCD core establishment,4g and (d) Kuehne’s intramolecular Diels−Alder reaction of indole derivatives.3b Despite a large number of reported synthetic approaches, a unified and divergent stereospecific strategy with practicality on a gram scale still represents an attractive goal for comprehensive © 2017 American Chemical Society

Figure 1. Representative structures of Aspidosperma alkaloids.

establishment of this family. Six splendid syntheses have been achieved recently by the groups of MacMillan,3n Oguri,3g Zhu,3h Movassaghi,4ad Dixon,3i and Boger.10 From our point of view, it is the three contiguous cis-stereocenters (C-5, C-19, and C-12) with two all-carbon quarternary chiral centers (C-5 and C-12) of the core hydroindole (C−E ring) of Aspidosperma alkaloids that presents the key challenge. Continuous with our divergent synthesis concept,11 an asymmetric strategy for the total syntheses of this family based on efficient and scalable synthesis Received: April 28, 2017 Published: June 1, 2017 3167

DOI: 10.1021/acs.orglett.7b01292 Org. Lett. 2017, 19, 3167−3170

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Organic Letters was comprehensively targeted with a stereoselective intermolecular inverse-electron-demand [4 + 2] cycloaddition as the key step for the core hydroindole (C−E ring) construction (Scheme 1). From this central C−E ring, the A−B and D rings are subsequently established stereospecifically.

Scheme 2. Retrosynthetic Analysis for Aspidosperma Alkaloids

Scheme 1. Key Rule of [4 + 2] Cycloadditiona,b

through highly stereoselective intermolecular inverse-electrondemand [4 + 2] cycloaddition of 3-ethyl-5-bromo-2-pyrone 10c and enecarbamate (S)-11b, 10c could be facilely obtained in three steps from naturally abundant DL-malic acid,12b and (S)11b was also obtained in 100 g amount in three steps from commercially available L-pyroglutamic acid.13 It is noteworthy that both the sterically hindered tert-butoxycarbonyl group at C-2 of (S)-11b and the bulky bromine atom at C-5 of 10c effectively provided stereocontrol in the [4 + 2] cycloaddition (Scheme 2). The stereoselectivity can be unambiguously explained via an electronically and sterically preferred exo-approach of diene 10c from the less hindered side of (S)-11b with a bulky bromine atom substituent pointing in the opposite direction from the dienophile ring. Furthermore, the failure of [4 + 2] cycloaddition without the bromine atom substituent demonstrated that the key point of the electron-withdrawing group effect is lowering the LUMO energy of 10c. Using this concept, we achieved the total synthesis of (+)-dehydroaspidospermidine (18a), (+)-dehydrodeacetylaspidospermine (18b), and (+)-dehydrodeacetylpyrifolidine (18c) as shown in Scheme 3. The [4 + 2] cycloaddition between 10c and (S)-11b in toluene afforded the desired exo-bridgedtricycliclactone 12d (10.40 g, 54% yield, 77% brsm) with an exo/endo selectivity of 7:1. Subsequently, deprotection of 12d with neat trifluoroacetic acid gave free a amino acid, which was converted to carboxylic acid 14 (6.48 g) through benzyloxycarbonylation in 66% yield over two steps. The absolute configuration of 14 was further confirmed through X-ray analysis. The carboxylic acid functional group of 14 was easily removed by triethylsilane with the help of an iodobenzene diacetate, iodine, and visible light through an iminium ion intermediate, as developed by Suarez’s group.14 Reduction of bridged lactone 14 with Dibal-H provided the hemiacetal, which was subjected to the methyl 2-(triphenylphosphoranylidene) acetate Wittig reagent, affording an α,β-unsaturated ester 16 (4.12 g). A Pd/ C-catalyzed hydrogenation/deprotection/amidation cascade process was investigated. To our delight, the enoate was smoothly transformed to lactam 17 (1.43 g) in 53% yield over these three steps. Reduction of the amide group with lithium aluminum hydride (LiAlH4) and subsequent oxidation with Dess−Martin periodinane resulted in the formation of tricyclic ketone 13 (1.08 g) in 77% yield over two steps. This eight-step stereoselective synthesis of tricyclic ketone 13 was efficiently

a

Reaction conditions: 10 (1.0 mmol), 11 (1.5 mmol), and toluene (5.0 mL) under N2 (balloon) at 110 °C for 60 h. bIsolated yields.

Stimulated by our previous work,11a our synthesis commenced with [4 + 2] cycloaddition of 3,5-dibromo-2-pyrone 10a12a and chiral enamine (S)-11a, affording bridged cyclolactone 12a in 48% yield with a 3:1 exo/endo ratio (Scheme 1, 12a and 12a′). Noteworthy, four diastereomers are possible, but the other two were almost not observed. To increase the exo/endo ratio, installation of a bulky tert-butoxycarbonyl group at C-2 of 11 afforded the desired product 12b in 51% yield with a better diastereoselectivity of 5:1 exo/endo (Scheme 1, 12b and 12b′). Unfortunately, the yield and diastereoselectivity were reduced to 45% and 2:1, respectively, when a trimethylsilanylethynyl was present instead of a bromine atom at C-3 of 10 (Scheme 1, 12c and 12c′). To our satisfaction, when an ethyl substituent was introduced at C-3 of 10, the diastereoselectivity was raised to a 7:1 exo,endo ratio (Scheme 1, 12d and 12d′). Then chiral enamine (R)-11b was reacted with 10c to afford ent-12d in 53% yield with a 7:1 exo/endo ratio (Scheme 1, ent-12d and ent-12d′). Finally, [4 + 2] cycloaddition was not observed in reflux toluene even with toluene induced by microwave irradiation when there was no bromine atom present at C-5 of 10 (Scheme 1, 12e and 12e′). On the basis of the results of [4 + 2] cycloaddition, our retrosynthetic analysis of Aspidosperma alkaloids is outlined in Scheme 2. We conceived that a Pd/C-catalyzed hydrogenation/ deprotection/amidation cascade process from lactone 12d would afford tricyclic ketone 13, which could then be converted to Aspidosperma alkaloids via Fischer indolization. For construction of 13, we envisaged photoinduced radical decarboxylation and Wittig reaction. In addition, the Aspidosperma alkaloids’ core hydroindole 12d could be achieved 3168

DOI: 10.1021/acs.orglett.7b01292 Org. Lett. 2017, 19, 3167−3170

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Organic Letters

Scheme 3. Concise Total Syntheses of (+)-Dehydroaspidospermidine (18a), (+)-Dehydrodeacetylaspidospermine (18b), and (+)-Dehydrodeacetylpyrfolidine (18c)

(LiAlH4), which then underwent N-acetylation to furnish (−)-pyrifolidine (4) in 85% yield. (−)-N-acetylaspidospermidine (21a),16 (+)-N-methylaspidospermidine (21b),17 and (−)-demethoxypalosine (21c) were obtained via N-acetylation, methylation, and propionylation of arylamine from intermediate 2 in high yield (88%, 94%, and 87%). In summary, we developed a concise and divergent strategy for the collective total syntheses of 14 natural products in Aspidosperma alkaloids, namely (+)-vincadifformine (10 steps, 4.4% over yield), (−)-quebrachamine (10 steps, 4.3% over yield), (+)-aspidospermidine (11 steps, 7.1% over yield), (−)-aspidospermine (12 steps, 3.8% over yield), (−)-pyrifolidine (12 steps, 3.7% over yield), and nine others. This also represents the first asymmetric total synthesis of (−)-N-acetylaspidospermidine, (−)-demethoxypalosine, (+)-dehydrodeacetylpyrifolidine, (+)-deacetylpyrifolidine, and (−)-pyrifolidine. Our synthetic approach features (i) a key [4 + 2] cycloaddition to establish the core hydroindole (C−E ring) of Aspidosperma alkaloids, (ii) an efficient Pd/C-catalyzed cascade process to assemble the D ring, and (iii) a Fischer indolization to forge the A−B ring. Further synthetic and biological study of Aspidosperma alkaloids are currently ongoing in our group.

achieved in 13.4% overall yield on a gram scale. Treatment of 13 with phenylhydrazine, 2-methoxylphenyldrazine, or 2,3-dimethoxyphenylhydrazine to effect Fischer indole cyclization successfully afforded the natural products (+)-dehydroaspidospermidine (18a, 71% yield),5a (+)-dehydrodeacetylaspidospermine (18b, 66% yield),4j and (+)-dehydrodeacetylpyrifolidine (18c, 46% yield), respectively. The final stage for divergent synthesis of the Aspidosperma alkaloids was achieved as shown in Scheme 4. According to Scheme 4. Divergent Synthesis of Eleven Aspidosperma Alkaloids

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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.7b01292. Experimental procedures, NMR spectral, X-ray, and analytical data for all new compounds (PDF) X-ray data for compound 2 (CIF) X-ray data for compound 14 (CIF)

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

previous known work, a series of Aspidosperma alkaloids was subsequently achieved: (+)-vincadifformine (1),3n (−)-quebrachamine (5),5a (+)-aspidospermidine (2),4j (+)-deacetylaspidospermine (20a),5a and (−)-aspidospermine (3).5a In addition, (−)-N-methylquebrachamine (19)15 was obtained via methylation of 5 through treatment with iodomethane (MeI) in 78% yield. (+)-Deacetylpyrifolidine (20b) was easily produced through reduction of 18c with lithium aluminum hydride

Xuefeng Jiang: 0000-0002-1849-6572 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We are grateful for financial support provided by the NSFC (21672069, 21472050), DFMEC (20130076110023), Fok Ying 3169

DOI: 10.1021/acs.orglett.7b01292 Org. Lett. 2017, 19, 3167−3170

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Tung Education Foundation (141011), Program for Shanghai Rising Star (15QA1401800), Professor of Special Appointment (Eastern Scholar) at Shanghai Institutions of Higher Learning, and National Program for Support of Top-notch Young Professionals.

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DOI: 10.1021/acs.orglett.7b01292 Org. Lett. 2017, 19, 3167−3170