Synlett 2020; 31(09): 907-910
DOI: 10.1055/s-0039-1690829
letter
© Georg Thieme Verlag Stuttgart · New York

Formal Synthesis of Pseudolaric Acid B

Naoki Mori
Research Foundation ITSUU Laboratory, C1232 Kanagawa Science Park R & D Building, 3-2-1 Sakado, Takatsu-ku, Kawasaki, Kanagawa 213-0012, Japan   Email: nmori@itsuu.or.jp
› Author Affiliations
This work was supported by Grant-in-Aid for Scientific Research (C) from the Japan Society for the Promotion of Science (Grant Number 16K07712).
Further Information

Publication History

Received: 28 December 2019

Accepted after revision: 02 February 2020

Publication Date:
18 February 2020 (online)

 


Abstract

A formal synthesis of pseudolaric acid B, a diterpene isolated from the root bark of Pseudolarix kaempferi Gordon (Pinaceae), to Trost’s synthetic intermediate was achieved in 17 steps from a known ketone. Key features of this synthesis include a Claisen rearrangement and iodoetherification to construct quaternary stereocenters and ring-closing metathesis to form the seven-membered ring.


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More than 20 natural pseudolaric acids, including pseudolaric acids A (1) and B (2), have been isolated from the root bark of Pseudolarix kaempferi Gordon (Pinaceae) (Figure [1]).[1] Among the members of this family, pseudolaric acid B (2) has significant medical potential, exhibiting potent antifungal, antifertility, and cytotoxic activities, even against multidrug-resistant cancer cell lines. These latter activities suggest that 2 might function as a potential lead for new anticancer agents. Structurally, pseudolaric acids A (1) and B (2) feature a distinctive tricyclic core with an unusual trans-fused [5–7] ring system. The complicated structures, as well as the important biological properties, of pseudolaric acids have fascinated both biochemists and synthetic chemists. In fact, Mafu et al.[2] recently identified an enzyme involved in the biosynthetic pathway of 2, and two total syntheses of 1 by Chiu and co-workers[3] [26 steps for (–)-1] and Yang and co-workers[4] [16 steps for (±)-1], and one total synthesis of 2 by Trost et al.[5] [28 steps for (–)-2] have been reported. We previously attempted to improve on the synthesis of 2 by using a Dieckmann condensation as the key step to construct its trans-fused core framework.[6] Here, we describe a formal synthesis of 2 by using a new synthetic strategy.

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Figure 1 Structures of pseudolaric acids A (1) and B (2)

We previously synthesized model compound 9, containing the trans-fused bicyclic core of 2, in 20 steps, starting from the known compound 3 [7] (Scheme [1a]).[6] However, the yield of the radical coupling reaction 45 was quite low due to undesirable side reactions; i.e., a 1,6-hydrogen shift to generate compound 6, and a direct reduction by Bu3SnH to generate compound 7. To overcome these disadvantages, we designed an alternative approach for the synthesis of 2 (Scheme [1b]). Pseudolaric acid B (2) can be accessed from Trost’s intermediate 10 in six steps; we therefore chose 10 as our synthetic goal. Based on our retrosynthetic analysis, the seven-membered ring of 10 might be constructed through a ring-closing metathesis (RCM) reaction of diene 11, obtained by a reductive opening of the tetrahydrofuran ring of the iodo ester 12. Installation of an unsaturated ester side chain onto 12 might be achieved through a radical coupling of iodo alcohol 14 with the allylstannane 13.[8] We expected that this Keck radical allylation, which proceeds in the absence of Bu3SnH, would be effective in increasing the yield of the desired product. Compound 14 might be prepared from the known starting material 15,[9] in which a TIPS protecting group replaces the previously employed Bn group to avoid the presence of troublesome benzylic hydrogens.

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Scheme 1 Our (a) previous work[6] and (b) current retrosynthetic analysis for pseudolaric acid B (2)

Our synthesis commenced with the preparation of aldehyde 22 (Scheme [2]). Methoxycarbonylation of 15 provided a diastereomeric mixture of esters 16 (dr = 2:1), which were converted into the enol triflate 17 in 78% yield. Because a Stille-type coupling[10] of 17 with Bu3SnCH2OPMB[11] was unsuccessful, we installed a hydroxymethyl group through palladium-catalyzed carboxylation[12] and subsequent reduction to afford the alcohol 20 in 65% yield over two steps. After the formation of a vinyl ether of alcohol 20, Claisen rearrangement of the resultant product 21 in refluxing DMF for one hour gave aldehyde 22 [50%; quantitative based on recovered starting material (brsm)] in a 3.3:1 diastereomeric ratio, which was consistent with our previous results.[6] Note that longer reaction times adversely affect the yield of 22, owing to its decomposition in refluxing DMF (14% after 6 h).

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Scheme 2 Preparation of aldehyde 22

We next sought to prepare diene 11, beginning with the introduction of a hydroxymethyl group onto aldehyde 22 (Scheme [3]). Unfortunately, the addition of LiCH2OPMB to 22 resulted in the formation of lactone 23. Therefore, 22 was first converted into the diene 25, which could be obtained as a single diastereomer about the quaternary center following separation by column chromatography on silica gel. Diene 25 was then dihydroxylated with OsO4 under neutral conditions to afford diol 26 as a 1:1 mixture of diastereomers in good yield (96%). The next step of the reaction, the iodoetherification of 26, required optimization with respect to the solvent. For example, treatment of 26 with NIS in MeCN afforded the desired product 14 (dr = 1:1) in 78% yield, whereas the use of CH2Cl2 resulted in the oxidative cleavage of the 1,2-diol to regenerate aldehyde 22 in 51% yield. For the installation of the unsaturated ester side chain, 14 was treated with the allylstannane 13 [8] and AIBN in refluxing benzene to afford alcohol 27 (dr = 1:1) in 59% yield. After iodination of alcohol 27 under Appel’s conditions, the tetrahydrofuran ring of iodide 12 was reductively opened by treatment with Zn in EtOH at 60 °C to afford diene 11 as a single diastereomer in 82% yield.

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Scheme 3 Preparation of diene 11
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Scheme 4 Formal synthesis of pseudolaric acid B (2)

The formal synthesis of 2 was accomplished by first subjecting 11 to RCM conditions, using the Grubbs second-generation catalyst, to construct the seven-membered ring of 28 [13] in 86% yield (Scheme [4]). The TIPS protecting group was then removed with TBAF/AcOH, giving alcohol 29 in 54% yield with 34% of unreacted 28 remaining. Note that in the absence of AcOH, the reaction was dominated by 1,4-addition of the tertiary alcohol to the unsaturated ester. After oxidation to the aldehyde 30, nucleophilic addition of a methyl group was attempted. Unfortunately, the standard conditions proved fruitless (MeLi, THF, –78 °C: decomposition; MeMgBr, THF, –78 °C: no reaction). Trost et al.[5] reported that an organocerium reagent served as an excellent nucleophile in a similar transformation. To our delight, treatment of 30 with MeCeCl2 [14] followed by Dess–Martin oxidation successfully afforded Trost’s intermediate 10, in racemic form, from which pseudolaric acid B (2) has been obtained in six steps, thus completing a formal synthesis of 2. The 1H NMR and 13C NMR spectra of compound 10 prepared in this work agreed with those reported by the Trost group.

In conclusion, we have accomplished a formal synthesis of pseudolaric acid B (2) from the known ketone 15 to Trost’s synthetic intermediate 10 in 17 steps (six more steps are required to obtain 2). The key elements in the present synthesis include: (1) construction of the vicinal quaternary stereocenters via a Claisen rearrangement (2122) and stereoselective iodoetherification (2614) and (2) formation of the seven-membered ring through an RCM reaction (1128). This current synthesis is more efficient than our previous preparation,[6] and could expand the opportunities for derivatization of pseudolaric acid B and related compounds as lead anticancer drugs by using (S)-2-(hydroxymethyl)cyclopentan-1-one[15] as a chiral substrate.


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Acknowledgment

I am grateful to Professor Masayuki Inoue (The University of Tokyo), Professor Hidenori Watanabe (The University of Tokyo), and Professor Hirosato Takikawa (The University of Tokyo) for their kind and helpful discussions. I thank Professor Shuji Akai (Osaka University), Professor Takeo Kawabata (Kyoto University), Professor Tomohiko Ohwada (The University of Tokyo), Dr. Mitsuaki Ohtani (ITSUU Laboratory), and Dr. Kin-ichi Tadano (ITSUU Laboratory) for their helpful discussions throughout this work. I also thank Mr. Yoshihisa Akamatsu (The University of Tokyo) for the preparation of the starting material 15.

Supporting Information

  • References and Notes

  • 1 Chiu P, Leung LT, Ko BC. B. Nat. Prod. Rep. 2010; 27: 1066
  • 2 Mafu S, Karunanithi PS, Palazzo TA, Harrod BL, Rodriguez SM, Mollhoff IN, O’Brien TE, Tong S, Fiehn O, Tantillo DJ, Bohlmann J, Zerbe P. Proc. Natl. Acad. Sci. U.S.A. 2017; 114: 974
  • 3 Geng Z, Chen B, Chiu P. Angew. Chem. Int. Ed. 2006; 45: 6197
  • 4 Xu T, Li C.-C, Yang Z. Org. Lett. 2011; 13: 2630
    • 5a Trost BM, Waser J, Meyer A. J. Am. Chem. Soc. 2007; 129: 14556
    • 5b Trost BM, Waser J, Meyer A. J. Am. Chem. Soc. 2008; 130: 16424
  • 6 Mori N, Mase C, Watanabe H, Takikawa H. Tetrahedron Lett. 2018; 59: 2600
  • 7 Mittendorf J, Kunisch F, Matzke M, Militzer H.-C, Schmidt A, Schönfeld W. Bioorg. Med. Chem. Lett. 2003; 13: 433
  • 8 Baldwin JE, Adlington RM, Birch DJ, Crawford JA, Sweeney JB. J. Chem. Soc., Chem. Commun. 1986; 1339
  • 9 Sano S, Matsumoto T, Nakao M. Tetrahedron Lett. 2014; 55: 4480
    • 10a Cook GK, Hornback WJ, Jordan CL, McDonald JH. III, Munroe JE. J. Org. Chem. 1989; 54: 5828
    • 10b Chen X.-T, Bhattacharya SK, Zhou B, Gutteridge CE, Pettus TR. R, Danishefsky SJ. J. Am. Chem. Soc. 1999; 121: 6563
  • 11 Semmelhack MF, Gu Y, Ho DM. Tetrahedron Lett. 1997; 38: 5583
  • 12 Yoshimitsu T, Arano Y, Kaji T, Ino T, Nagaoka H, Tanaka T. Heterocycles 2009; 77: 179
  • 13 Dimethyl 8a-Hydroxy-1-{[(triisopropylsilyl)oxy]methyl}-2,3,4,7,8,8a-hexahydroazulene-3a,6(1H)-dicarboxylate (28 ) A mixture of diene 11 (16.4 mg, 34.0 μmol) and the Grubbs second-generation catalyst (2.9 mg, 3.42 μmol) in benzene (1.5 mL) was refluxed for 5 h, then cooled to rt. The mixture was then concentrated under reduced pressure, and the residue was purified by preparative TLC (hexane–EtOAc, 5:1) to give a colorless oil; yield: 13.3 mg (86%). IR (film): 3515, 2945, 2866, 1716, 1463, 1238, 1194, 1055, 882, 755, 681 cm–1. 1H NMR (400 MHz, CDCl3): δ = 6.96 (m, 1 H), 4.00 (dd, J = 9.6, 6.4 Hz, 1 H), 3.70 (s, 3 H), 3.59 (m, 1 H), 3.58 (s, 3 H), 2.85 (m, 1 H), 2.76 (m, 1 H), 2.58–2.45 (m, 2 H), 2.37 (dt, J = 2.8, 14.0 Hz, 1 H), 2.20 (m, 1 H), 2.08–1.85 (m, 4 H), 1.23 (m, 1 H), 1.12–1.00 (m, 21 H). 13C NMR (100 MHz, CDCl3): δ = 174.64, 168.53, 140.74, 135.51, 82.74, 65.29, 58.91, 57.38, 51.88, 51.55, 34.71, 30.39, 29.82, 26.00, 20.35, 18.06, 11.97. HRMS (ESI): m/z [M + Na]+ calcd for C24H42NaO6Si: 477.2643; found: 477.2637.
  • 14 Imamoto T, Sugiura Y, Takiyama N. Tetrahedron Lett. 1984; 25: 4233
  • 15 Mase N, Inoue A, Nishio M, Takabe K. Bioorg. Med. Chem. Lett. 2009; 19: 3955

  • References and Notes

  • 1 Chiu P, Leung LT, Ko BC. B. Nat. Prod. Rep. 2010; 27: 1066
  • 2 Mafu S, Karunanithi PS, Palazzo TA, Harrod BL, Rodriguez SM, Mollhoff IN, O’Brien TE, Tong S, Fiehn O, Tantillo DJ, Bohlmann J, Zerbe P. Proc. Natl. Acad. Sci. U.S.A. 2017; 114: 974
  • 3 Geng Z, Chen B, Chiu P. Angew. Chem. Int. Ed. 2006; 45: 6197
  • 4 Xu T, Li C.-C, Yang Z. Org. Lett. 2011; 13: 2630
    • 5a Trost BM, Waser J, Meyer A. J. Am. Chem. Soc. 2007; 129: 14556
    • 5b Trost BM, Waser J, Meyer A. J. Am. Chem. Soc. 2008; 130: 16424
  • 6 Mori N, Mase C, Watanabe H, Takikawa H. Tetrahedron Lett. 2018; 59: 2600
  • 7 Mittendorf J, Kunisch F, Matzke M, Militzer H.-C, Schmidt A, Schönfeld W. Bioorg. Med. Chem. Lett. 2003; 13: 433
  • 8 Baldwin JE, Adlington RM, Birch DJ, Crawford JA, Sweeney JB. J. Chem. Soc., Chem. Commun. 1986; 1339
  • 9 Sano S, Matsumoto T, Nakao M. Tetrahedron Lett. 2014; 55: 4480
    • 10a Cook GK, Hornback WJ, Jordan CL, McDonald JH. III, Munroe JE. J. Org. Chem. 1989; 54: 5828
    • 10b Chen X.-T, Bhattacharya SK, Zhou B, Gutteridge CE, Pettus TR. R, Danishefsky SJ. J. Am. Chem. Soc. 1999; 121: 6563
  • 11 Semmelhack MF, Gu Y, Ho DM. Tetrahedron Lett. 1997; 38: 5583
  • 12 Yoshimitsu T, Arano Y, Kaji T, Ino T, Nagaoka H, Tanaka T. Heterocycles 2009; 77: 179
  • 13 Dimethyl 8a-Hydroxy-1-{[(triisopropylsilyl)oxy]methyl}-2,3,4,7,8,8a-hexahydroazulene-3a,6(1H)-dicarboxylate (28 ) A mixture of diene 11 (16.4 mg, 34.0 μmol) and the Grubbs second-generation catalyst (2.9 mg, 3.42 μmol) in benzene (1.5 mL) was refluxed for 5 h, then cooled to rt. The mixture was then concentrated under reduced pressure, and the residue was purified by preparative TLC (hexane–EtOAc, 5:1) to give a colorless oil; yield: 13.3 mg (86%). IR (film): 3515, 2945, 2866, 1716, 1463, 1238, 1194, 1055, 882, 755, 681 cm–1. 1H NMR (400 MHz, CDCl3): δ = 6.96 (m, 1 H), 4.00 (dd, J = 9.6, 6.4 Hz, 1 H), 3.70 (s, 3 H), 3.59 (m, 1 H), 3.58 (s, 3 H), 2.85 (m, 1 H), 2.76 (m, 1 H), 2.58–2.45 (m, 2 H), 2.37 (dt, J = 2.8, 14.0 Hz, 1 H), 2.20 (m, 1 H), 2.08–1.85 (m, 4 H), 1.23 (m, 1 H), 1.12–1.00 (m, 21 H). 13C NMR (100 MHz, CDCl3): δ = 174.64, 168.53, 140.74, 135.51, 82.74, 65.29, 58.91, 57.38, 51.88, 51.55, 34.71, 30.39, 29.82, 26.00, 20.35, 18.06, 11.97. HRMS (ESI): m/z [M + Na]+ calcd for C24H42NaO6Si: 477.2643; found: 477.2637.
  • 14 Imamoto T, Sugiura Y, Takiyama N. Tetrahedron Lett. 1984; 25: 4233
  • 15 Mase N, Inoue A, Nishio M, Takabe K. Bioorg. Med. Chem. Lett. 2009; 19: 3955

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Figure 1 Structures of pseudolaric acids A (1) and B (2)
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Scheme 1 Our (a) previous work[6] and (b) current retrosynthetic analysis for pseudolaric acid B (2)
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Scheme 2 Preparation of aldehyde 22
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Scheme 3 Preparation of diene 11
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Scheme 4 Formal synthesis of pseudolaric acid B (2)