Letter pubs.acs.org/OrgLett
Total Synthesis of (±)-Sculponeatin N Zhiqiang Pan, Cunying Zheng, Hongyu Wang, Yanhe Chen, Yun Li, Bin Cheng, and Hongbin Zhai* The State Key Laboratory of Applied Organic Chemistry, College of Chemistry and Chemical Engineering, Lanzhou University, Lanzhou 730000, China S Supporting Information *
ABSTRACT: The first total synthesis of the (±)-sculponeatin N (a 6,7-seco-ent-kaurane diterpenoid discovered by Sun and coworkers) has been achieved. The features include a regio- and stereoselective aldol reaction to form a lactone, an intramolecular Diels−Alder reaction to install B and C rings simultaneously, and a radical cyclization to forge the D ring.
6,7-seco-ent-Kaurane diterpenoids are active natural products that were first isolated from the Japanese folk medicine ‘enmeiso’. Most of these diterpenoids are reported to have antitumor, antibacterial, and anti-inflammatory activities with low toxicity.1 Sculponeatin N (1),2,3 a 6,7-seco-ent-kaurane diterpenoid, was isolated from the aerial parts of a Chinese perennial herb named Isodon sculponeatus by Sun and coworkers in 2010 (Figure 1). As established by NMR
Scheme 1. Retrosynthetic Analysis of 1 (PG = Protecting Group)
Figure 1. Two diterpenoid natural products named as sculponeatin N.
or a reductive Heck cyclization8 followed by oxidation9,10 at C15 (3 → 1), while 3 may be accessible from 5 via a protodesilylation rearrangement11 and the subsequent allylation (5 → 3). Tricycle 5 may be established by forming B and C rings synchronously through an intramolecular Diels−Alder reaction (IMDA, 6 → 5).12 Semireduction of the methoxycarbonyl within 8, Horner−Wadsworth−Emmons (HWE) reaction13 of the resultant aldehyde with 7, reduction of the lactone moiety to a diol, and acylation of the hydroxyls may lead to the precursor for the IMDA (7 + 8 → 6). It would be interesting to explore the feasibility of an efficient conversion of diastereomeric mixture 914 into lactone 8 via a formal [3 + 2] annulation (9 → 8). Based on the above analysis, our synthesis commenced from 9,14 which was treated sequentially with LDA and paraformaldehyde to directly afford bicycle 8 (72%), presumably through a regio- and stereoselective aldol reaction15 at C-10 (forming a
spectroscopic analysis, the compact tetracyclic backbone of 1 comprises a spiro- and bridged-ring system and five stereogenic centers, two of which are all-carbon quaternary centers residing at the spirocyclic (C-10) and bridged-ring/fused-ring (C-8) junctions, respectively. More importantly, 1 showed significant cytotoxicities against K562 and HepG2 human tumor cell lines, with IC50 values of 0.21 and 0.29 μM, respectively.2 Surprisingly, a different ent-kaurane diterpenoid 2 that was isolated by the group led by Liu in 2009 was also named sculponeatin N.4 Although the structures and biological activities of 6,7-secoent-kaurane diterpenoids have been known for decades, only a few synthetic studies leading toward these natural products have been reported.5,6 Herein, we wish to report a 13-step total synthesis of (±)-sculponeatin N (1), the one discovered by Sun and co-workers.2 The retrosynthetic analysis of 1 is outlined in Scheme 1. We envisioned that the diterpenoid may be generated from 3 by D ring formation via a radical cyclization7 © 2013 American Chemical Society
Received: November 7, 2013 Published: December 2, 2013 216
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Letter
quarternary center) followed by epimerization at C-5 and lactonization (Scheme 2). The structure of 8 was confirmed by
Scheme 3. IMDA, Protodesilylation Rearrangement, and Methanolysis Conducted in a One-Pot Fashion
Scheme 2. Synthesis of 12
converted into a single cis fused-ring structure via isomerization at C-8 in acidic media. Based on the above considerations, the experiments were subsequently conducted in a one-pot fashion (Scheme 4). Compound 12 was treated with BHT in toluene in a sealed tube at 190 °C for 2 days (the stage for the IMDA),
NOESY experiments and X-ray crystallographic analysis. Treatment of 8 with NaBH4 led to reduction of the methoxycarbonyl group rather than that of the lactone moiety. We reasoned that the boron−oxygen complexation between the carbonyl of the ester at C-10 and the alkoxy of the lactone at C-20 might lead to the reduction of the ester to an alcohol product via a six-membered ring transition state. The resultant alcohol was transformed into aldehyde 10 through the DessMartin oxidation, which subsequently underwent a Horner− Wadsworth−Emmons reaction with known phosphate 716 to afford 11 as a single isomer.12e The resulting diene 11 was reduced via LiAlH4 followed by double acylation to afford the desired compound 12. Importantly, the acrylate of 12 at C-20 reacted with the diene moiety during the subsequent IMDA, and the one at C-6 acted just as a protecting group, which did not participate in the reaction. However, the acrylate protection of the primary alcohol at C-6 was a better choice than the corresponding benzyl or silyl ether for the subsequent protodesilylation rearrangement, since the latter two substrates only gave complex mixtures. Next, our attention was shifted to the key IMDA, establishing the C-9 stereocenter and constructing the B and C rings simultaneously (Scheme 3). Treatment of 12 with BHT in toluene in a sealed tube at 190 °C for 2 days produced the endo tricyclic product 13 as the major product along with other isomers in 80% combined yield (dr = 60:9:9:2).17 The structure of 13 was confirmed by NMR spectral and X-ray crystallographic analysis. The C-9 stereocenter in 13 and its isomers all possess an (S*)-configuration. Treatment of the above mixture containing 13 and its isomers with anhydrous TsOH afforded a single isomer, demonstrating that C-8 and C-13 stereocenters in 13 and its isomers did not interfere with the protodesilylation rearrangement at all and that all C-8 epimers were
Scheme 4. Completed Synthesis of (±)-1
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ACKNOWLEDGMENTS We thank the National Basic Research Program of China (9732010CB833200), NSFC (Nos. 21172100; 21272105; 21290180), Program for Changjiang Scholars and Innovative Research Team in University (PCSIRT: IRT1138), FRFCU (lzujbky-2013-ct02), and “111” Program of MOE for financial support.
followed by a reaction with anhydrous TsOH in toluene at 120 °C for 4.5 h11c (the stage for protodesilylation rearrangement and epimerization at C-8) and methanolysis in the presence of K2CO3 for 12 h to generate in 80% overall yield the primary alcohol 14, which was silylated to form 15 in excellent yield. With 15 in hand, both an aldol reaction and an alkylation were attempted to install the C-8 all-carbon quaternary stereocenter. Deprotonation of 15 with LDA followed by reaction with 2-bromoacrolein18 led to a sole aldol product but only in low yield. Compound 15 was subjected to alkylation with propargyl bromide after deprotonation of 15 with LDA, in which both low yield and poor stereoselectivity (dr = 1:1) were observed for the propargylation products. Delightfully, allylation of the corresponding lithium enolate of 15 with 2,3-dibromopropene (4) afforded a single isomer 16 in 88% yield.7h At this stage, a reductive Heck reaction or a radical cyclization could potentially be applied to constructing ring D in 1. The former type of reaction was attempted on 16 by applying a series of commonly adopted conditions,19 but an unsatisfactory yield and selectivity were observed. On the other hand, radical cyclization7h of 16 in the presence of AIBN and nBu3SnH in benzene at 100 °C provided bicyclo[3.2.1]octane 17 (the desired product) and bicyclo[2.2.2]octane 17a (the undesired product) as an inseparable mixture in 92% combined yield (17:17a = 1:3). Here, use of AIBN as a radical initiator furnished the thermodynamically more stable tetracycle 17a as the major product. In order to reverse the regioselectivity, Et3B and s-Bu3B were selected as alternative radical initiators. By conducting the radical cyclization of 16 with s-Bu3B and (TMS)3SiH at 25 °C, a 5:3 ratio for 17:17a (in favor of 17) was obtained while the combined yield reached 90%. Exposure of 16 to Et3B and (TMS)3SiH at 25 °C for 2 h resulted in even better performance (17:17a = 2.5:1, 17 + 17a = 95%).20 Finally, the (inseparable) mixture of 17 and 17a was subjected to allylic oxidation, Dess-Martin oxidation, and desilylation to form (±)-1 along with (±)-18.21 The structures of (±)-1 and (±)-18 were unambiguously confirmed by both X-ray crystallographic analysis and comparison to the reported NMR spectral data.2 In summary, we have accomplished the first total synthesis of (±)-sculponeatin N (1, a kaurane diterpenoid discovered by Sun and co-workers2) in 13 steps from the known compound 9 with a 13.9% overall yield. Key features of the current synthesis include (i) a sequential regio- and stereoselective aldol/ epimerization/lactonization to produce the C-10 quaternary carbon center, (ii) an IMDA to simultaneously construct the B and C rings, and (iii) a radical cyclization to assemble the D ring. On the basis of its efficiency and flexibility, the current strategy should be amenable to the assembly of other related kaurane diterpenoids.
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REFERENCES
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ASSOCIATED CONTENT
S Supporting Information *
Experimental procedures and characterization data for new compounds. This material is available free of charge via the Internet at http://pubs.acs.org.
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AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. Notes
The authors declare no competing financial interest. 218
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NOTE ADDED AFTER ASAP PUBLICATION Reference 6 was incomplete in the version published ASAP on December 2, 2013; the correct version reposted on December 3, 2013.
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