Letter pubs.acs.org/OrgLett
Total Synthesis of Scholarisine K and Alstolactine A Dan Wang, Min Hou, Yue Ji, and Shuanhu Gao* Shanghai Key Laboratory of Green Chemistry and Chemical Processes, School of Chemistry and Molecular Engineering, East China Normal University, 3663 N Zhongshan Road, Shanghai 200062, China S Supporting Information *
ABSTRACT: The first asymmetric total syntheses of scholarisine K and alstolactine A have been accomplished. Our syntheses feature (1) ring closure metathesis and an intramolecular Heck reaction to construct the 1,3-bridged [3,3,1] bicycle (C−D ring), (2) intramolecular alkylation followed by Fischer indolization to form the basic skeleton of akuammilines, and (3) bioinspired, acid-promoted epoxide opening/lactonization to generate the second lactone ring of alstolactine A. These results provide evidence of a biogenetic relationship between scholarisine K and alstolactine A, which should facilitate the preparation of other akuammiline-type natural products and their derivatives for functional studies.
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kuammiline alkaloids are a family of biogenetically related indole monoterpenoids isolated mainly from Alstonia scholaris.1 The intriguing structures of these natural molecules and their broad spectrum of biological activities have made them the focus of many synthetic studies. Several strategies and methodologies have been developed to generate the challenging cage-like structures, starting with the first total synthesis of vincorine (3) by Qin and co-workers.2 Since then, the total syntheses of several members of this family of natural alkaloids have been reported by the groups of Ma,3 MacMillan,4 Smith,5 Snyder,6 Garg,7 Zhu,8 Li,9 Zu,10 Yang,11 Fujii and Ohno,12 Gaich,13 and Zhai.14 Most akuammiline alkaloids share indolecontaining polycyclic rings (A-B ring), a 1,3-bridged [3,3,1] bicycle (C−D ring), and an all-carbon quaternary stereocenter on C-7. Structural and functional diversity within this family of alkaloids is due to the oxidation state and connectivity at C-5. In rhazimal (1),15 C-5 in the core methanoquinolizine can be oxidized, disconnected from N-4, and reconnected with either C-2 or C-20, thereby generating vincorine (3) or scholarisine A (4).16 The resulting fused furanoindoline skeleton with altered oxidation state on C-5 also appears in the structures of aspidophylline A (5),17 scholarisine C (6),18 E (7),18 picrinine (8),19 scholarisine K (9),20 and alstolactine A (10).21 We also noticed that the C19−C20 double bond can be epoxidized, such as in compounds 7 and 9 (Figure 1). Since our research group is devoted to the synthesis of bioactive natural products, we initiated a research program to explore the chemical synthesis of this family of natural alkaloids as well as divergent preparation of its analogues and derivatives for medicinal studies. Here we report the total synthesis of scholarisine K (9) and biogenetic transformation of 9 into alstolactine A (10). Scholarisine K (9) and alstolactine A (10) were isolated by Liu, Luo and co-workers from Alstonia scholaris leaves that had been stored for 7 years.20,21 The remarkable, highly oxidized skeleton bearing a two-lactone framework in 10 can be biogenetically derived from 9 via acid-promoted lactonization.21 © XXXX American Chemical Society
Figure 1. Akuammiline alkaloids.
Based on the retrosynthetic analysis shown in Scheme 1, we planned to install the epoxide on C19−C20 via late-stage oxidation of intermediate 11, which already contains the basic skeleton of akuammiline alkaloids. When the fused lactone of 11 is reduced to a hemiacetal, subsequent acid-promoted C5− N4 bond formation transforms 11 to picrinine (8). Basepromoted ring opening of cyclic anhydride 13 followed by recyclization via 12 can generate the lactone fragment of 11. Received: March 10, 2017
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DOI: 10.1021/acs.orglett.7b00722 Org. Lett. XXXX, XXX, XXX−XXX
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Organic Letters Scheme 1. Retrosynthetic Analysis of the Scholarisine K and Alstolactine A
Scheme 2. Synthesis of the Chiral C−D Ring
We also planned to develop a reliable approach for synthesis of 13 from easily available building blocks such as 14−18. In these reactions, the chirality of the amino group on C-3 is generated through use of the chiral amino acid L-2-allylglycine (14). Our synthesis commenced with asymmetric construction of the C ring of the scholarisine family of alkaloids. This ring contains a chiral amino group at C-3. This source of chirality was the commercially available amino acid L-2-allylglycine (>98% ee), which was transformed into aldehyde 19 (see details in Supporting Information) without loss of ee via a modified three-step sequence on a large scale.22 In-mediated Barbier reaction between 19 and methyl 2-(bromomethyl) acrylate 17 gave rise to the desired amino alcohol 20 as a mixture of two diastereomers (dr 1.7:1) in 72% yield. The two isomers of 20 were carefully isolated with 98.9% and 96.7% ee. Ring-closing metathesis (RCM)23 of 20 using Grubbs II catalyst afforded the cyclized product 21 in 82% yield. Trifluoroacetic acid-mediated removal of Boc followed by 2nitrobenzenesulfonyl protection of the free amino group furnished 22 in a one-pot operation. Subsequently, alkylation of 22 with allyl bromide 1824 yielded 23, which served as the precursor for the formation of the D ring. Pd(0)-catalyzed intramolecular Heck reaction25 of 23 connected the C15−C20 bond, and the o-nitrobenzenesulfonyl protecting group was replaced with Cbz to provide α,β-unsaturated ester 24 in 77% yield. Since direct hydrogenation of the unsaturated ester of 24 turned out to be surprisingly difficult, 24 was oxidized to conjugated keto-ester 25 (>98.4% ee) with Dess−Martin reagent. The conjugated double bond was then reduced via SmI2-mediated reduction to afford 26 as a mixture of two diastereomers at C-16 (dr 5.7:1) in 83% yield (Scheme 2). With chiral ketone 26 in hand, we started to prepare heteroanhydride 28 for the formation of cyclic anhydride 13 based on the retrosynthetic analysis (Scheme 1). We anticipated that intramolecular alkylation of 28 would construct the C6−C7 bond of akuammilines. Fischer indolization of ketoester 26 with phenylhydrazine followed by hydrolysis with lithium hydroxide produced acid 27 (Scheme 3). We found that the carboxyl acid group at C-16 was completely epimerized to the α-configuration. We also tested classical conditions to prepare anhydride 28, in expectation that the ester could be isomerized again. However, mixing 27 with 2-bromoacetyl bromide resulted only in starting material with none of the desired heteroanhydride 28. We obtained similar results when we treated the acyl chloride of 27 with 2-bromoacetic acid under basic conditions (see details in Supporting Information).
Scheme 3. Attempts to Prepare Heteroanhydrides 28 and 30
We also attempted to construct the C6−C7 bond prior to indolization by using heteroanhydride 30 for the intramolecular alkylation. Therefore, we hydrolyzed ester 26 to produce acid 29 without isomerization, which unfortunately proved inert in the reaction with 2-bromoacetyl bromide. We hypothesized that inductive effects by the bromide group rendered substrates such as 28 and 30 extremely unstable under basic conditions, causing them to hydrolyze rapidly to form the corresponding acids. Therefore, we revised our strategy for generating a stable side chain, opting for formation of the C6−C7 carbon bond (Scheme 4). We discovered that SmI2 reduced the conjugated ketoester 25 to alcohol 32 in the presence of water (100 equiv) in 72% yield, together with the isomer 31 (11% yield). We readily protected 32 as the TES ether using TESCl/imidazole/ DMAP in dichloromethane. Then the ester group of 33 was reduced using lithium aluminum hydride (LiAlH4) in 98% yield. The resulting primary alcohol was treated with vinyl ethyl ether and NIS, and then the TES group was deprotected using concentrated HCl/MeOH to give iodide 34 in a one-pot operation. This two-carbon synthon has been used by Li and co-workers in their elegant syntheses of the aspidophylline alkaloids aspidodasycarpine and lonicerine.9 The compound 34 was oxidized to ketone 35 in 75% yield in a modified Swern reaction, in which reaction temperature and time were strictly controlled in order to prevent side reactions (see details in Supporting Information). With ketone 35 in hand, we screened a variety of bases, solvents, and additives to achieve the intramolecular SN2 reaction to form the C6−C7 bond. Under B
DOI: 10.1021/acs.orglett.7b00722 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters Scheme 4. Total Synthesis of Scholarisine K
harsh conditions involving heating at 105 °C in toluene for 27 min, cyclization occurred with KHMDS as the base, producing 36 in 57% yield (71% brsm). Hydrolysis of acetal 36 afforded the crude hemiacetal, which was oxidized to lactone 37 in the presence of Ac2O/DMSO.26 Lactone 37 was transformed via Fischer indolization to indolenine 38, which bears an all-carbon quaternary stereocenter on C-7. The structure and relative configuration of 38 was confirmed by X-ray crystallographic analysis. Subsequently, base-promoted (LiOH) lactone opening and recyclization generated hydro-indol 39 in 61% yield over two steps. Our approach echoes the interrupted Fischer indolization used in Garg’s original synthesis of akuammiline alkaloids.7 To construct the epoxide group of scholarisine K (9), we first attempted without success to directly epoxidate the double bond of 39 using m-CPBA, H2O2, and oxone. We hypothesized that the exposed amino group of the hydro-iodole might be participating in the oxidation, giving rise to side reactions. Therefore, we designed a two-step oxidation sequence in which we oxidized the primary alcohol of 39 to the corresponding carboxylic acid, and then we performed iodolactonization in the presence of KI/I2/NaHCO3 to produce iodide 40 in 54% yield over three steps.9,27 Transesterification and epoxide formation under basic conditions in MeOH generated epoxide 41 in 80% yield. Removal of N-Cbz under Pd(OH)2/C and reductive amination in 79% yield over two steps achieved scholarisine K (9), which gave 1H NMR, 13C NMR, high-resolution mass spectrometric, and optical rotation results identical to those of the natural compound. We envisioned that alstolactine A (10), which contains an additional lactone framework, could be biogenetically derived from 9 via acid-promoted lactonization. Unfortunately, exposing scholarisine K (9) to acidic conditions led to its decomposition. Further experiments showed that epoxide 41 could be used to construct the second lactone. Treatment of 41 with 3 M H2SO4 in acetone produced 42 in 31% yield and elimination product 43 in 42% yield (Scheme 5). We propose that the epoxide is first activated by protonic acid, followed by intermolecular SN2 addition by water to produce intermediate 45, which gives the cationic intermediate 46 under acidic
Scheme 5. Total Synthesis of Alstolactine A
conditions. Intramolecular lactonization generates 42 (path A, Scheme 5), and a second dehydration affords conjugated diene 43 (path B, Scheme 5). Based on the similar transformations, we generated alstolactine A (10) in 79% yield by replacing the Cbz with a methyl group. In summary, the first asymmetric total syntheses of two akuammiline natural products, scholarisine K and alstolactine A, have been accomplished. Schlorisine K was synthesized in 25 linear steps from commercial materials. In these syntheses, commercially available L-2-allylglycine was used to introduce the chiral amino group at C-3. Intramolecular alkylation followed by Fischer indolization was developed to construct the basic akuammiline skeleton. The bioinspired synthesis of alstolactine A was achieved through acid-promoted epoxide ring opening and lactonization. These results imply a biogenetic relationship between scholarisine K and alstolactine A. The syntheses described here may provide a new approach to other akuammilines and derivatives for medicinal studies. C
DOI: 10.1021/acs.orglett.7b00722 Org. Lett. XXXX, XXX, XXX−XXX
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Organic Letters
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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.7b00722. Experimental procedures, characterization data, and NMR spectra (PDF) X-ray data for compound 38 (CIF)
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AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. ORCID
Shuanhu Gao: 0000-0001-6919-4577 Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS We thank the National Natural Science Foundation of China (21422203), National Young Top-notch Talent Support Program, and Program for Changjiang Scholars and Innovative Research Team in University (PCSIRT) for generous financial support. We thank Kui Liao and Renyi Zhu (ECNU) for HPLC analysis.
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REFERENCES
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DOI: 10.1021/acs.orglett.7b00722 Org. Lett. XXXX, XXX, XXX−XXX
