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Published in final edited form as: J Am Chem Soc. 2017 Sep 21;139(39):13668–13671. doi: 10.1021/jacs.7b08683

Total Synthesis of (−)-Nahuoic Acid Ci (Bii)

Qi Liu 1, Yifan Deng 1, Amos B Smith III 1,*
PMCID: PMC5655813  NIHMSID: NIHMS913785  PMID: 28933833

Abstract

A convergent total synthesis of (−)-nahuoic acid Ci(Bii) (3), a novel cis-decalin polyketide has been achieved. Key synthetic transformations include Type II Anion Relay Chemistry (ARC) to construct the polyol chain, a Ti-catalyzed asymmetric Diels-Alder reaction to generate the cis-decalin skeleton, and a latestage large fragment union exploiting a Micalizio alkoxide-directed alkyne-alkene coupling tactic.

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Nahuoic acid A (1; Figure 1), isolated by Anderson and coworkers in 2013 from a culture of a Stremptomyces sp. obtained from a tropical marine sediment, displays selective (S)-adenosylmethionine (SAM)-competitive inhibitor activity against the histone lysine methyltransferase1 SETD8 enzyme.2 In 2016, the same group reported the isolation of nahuoic acids Bi-Ei (2, 3, 5, and 6), which exhibit similar inhibitory effects on SETD8.3 In the same year, the Qi group independently reported the isolation of four related congeners, the nahuoic acids Bii-Eii (3, 4, 5, 7),4 leading to a total of seven members of this architecturally intriguing family of polyketide acids. Herein, we reported the first total synthesis of a member of the nahuoic acid family, namely Ci(Bii) (3).

Figure 1.

Figure 1

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Structures of Nahuoic Acids

The nahuoic acids (1–7) feature highly functionalized cis-decalin motifs in conjunction with polyol side chains. From the retrosynthetic perspective, we envisioned that a disconnection between C(13) and C(14), exploiting a Micalizio alkyne-alkene union protocol,5 would permit a unified convergent approach to the nahuoic acids and their potential analogues (Scheme 1). Such a disconnection would lead to two major fragments cis-decalin 8 and acetylene 9. We also note that the nahuoic acids differ specifically in the hydroxylation patterns at C(7) and C(8) of the cis-decalin motif. To permit facile adjustment at these stereogenic centers, we targeted enone 10 as a common intermediate, which would hold the promise of access to the various decalin skeletons, via dihydroxylation leading to nahuoic acid 3, epoxidation-ring opening to furnish nahuoic acids 1,2,5 and 6, and via hydrogenation for nahuoic acids 4 and 7. Importantly, for nahuoic Ci(Bii) (3), as illustrated in Scheme 1, dihydroxylation of 10 can be envisioned to occur from the convex face, leading to the most functionalized nahuoic decalin structural fragment (8) possessing eight contiguous stereogenic centers. Enone 10 in turn would derive from 11, which would be constructed via an asymmetric Diels-Alder reaction between quinone 12 and diene 13. Also of note, the nahuoic acids differ in the length and functionality of their polyol side chains, featuring either 1,3,5-triols or 1,3,5,7-tetrols. Such advanced intermediates in turn would appear readily accessible via Anion Relay Chemistry (ARC),6 an efficient, multicomponent union protocol developed in our Laboratory. For example, side chain 9 possessing the 1,3,5-triol functionality could be constructed via a Type II ARC tactic employing bifunctional linchpin 16 recently introduced by our group.6e

Scheme 1.

Scheme 1

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Retrosynthetic Analysis of Nahuoic Acids

We chose to initiate the synthesis of nahuoic acid Ci(Bii) (3) with construction of the 1,3,5-triol side chain 9 employing the ARC tactic outlined in Scheme 2. In one-flask, employing isopropyl lithium (15), linchpin (+)-16 and (R)-(−)-epichlorohydrin [(−)-17], the three-component adduct (+)-14 was constructed in 76% yield on five-gram scale with excellent diastereoselectivity (>20:1). This ARC process was initiated by nucleophilic attack of isopropyl lithium (15) to linchpin (+)-16. A [1,4]-Brook rearrangement7 was in turn triggered by the addition of HMPA to relay the negative charge via silyl group migration from carbon C(1) in 18 to oxygen in 19. Carbanion 19 was then trapped with (R)-(−)-epichlorohydrin [(−)-17] to complete the one-flask construction process. Adduct (+)-14 was then subjected to dithiane removal with simultaneous hydrolysis of the TMS ether to provide ketone (+)-21.8 Chelation controlled reduction of (+)-21 furnished syndiol (+)-22,9 which was protected as an acetonide to provide (+)-23.10 Epoxide ring opening of (+)-23 at the terminal position with propynyl-lithium in the presence of BF3•THF11 and final protection as the methoxymethyl (MOM) ether12 completed construction of the alkyne side chain (+)-9 in a total of six flasks in 30% overall yield.

Scheme 2.

Scheme 2

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Synthesis of Side Chain (+)-9 via Type II ARC

We turned next to construction of the requisite cis-decalin 8, exploring a Lewis acid catalyzed asymmetric Diels-Alder reaction (Scheme 3). Thermal cycloaddition between 1213,14 and 1315 led to the desired chemo- and regio-selective isomer (±)-11. Encouraged by this initial Diels-Alder success, we turned to a series of Lewis acids16 to achieve enantioselectivity. Titanium-complex (−)-25,17,18 possessing the 1-naphthyl substituted TADDOL ligand, was identified to furnish the optimal enatioselectivity (ca. 73% ee), when employing 1 eq. Interestingly, we discovered that addition of 4 Å molecular sieves reduced the required loading of Lewis acid to 20 mol%. Further optimization including temperatures and solvents afforded the desired enantiomer (−)-11 in 95% yield with 86% ee. The enantiomeric excess of 11 could then be further enriched equal to or higher than 98% (determined by chiral SFC) by crystallization. The absolute configuration (−)-11 was established via single crystal X-ray analysis.

Scheme 3.

Scheme 3

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Ti-Catalyzed Asymmetric Diels-Alder Reaction

With highly enantio-enriched intermediate (−)-11 in hand, we proceeded to complete construction of cis-decalin 8 for the proposed Micalizio union (Scheme 4 and 5). Intermediate (−)-11 was first subjected to exhaustive reduction with LiAlH4, followed by acid-mediated hydrolysis with concomitant elimination to provide enone (−)-26.19 The secondary hydroxyl in (−)-26 was then protected as a TBS ether to furnish (−)-10. Although we encountered difficulties to dihydroxylate selectively the desired C(2,3) double bond in (−)-10, the enone olefin C(6,7) could first be reduced by selective hydrogenation to yield (+)-27, which was then dihydroxylated20 from the convex face to furnish the requisite diol (+)-28. Upon protection of the diol as acetonide (+)-29,21 the enone functionality in (−)-30 was then efficiently regenerated via a Pd(OAc)2 catalyzed Saegusa–Ito oxidation.22

Scheme 4.

Scheme 4

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Synthesis of Intermediate (−)-30

Scheme 5.

Scheme 5

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Synthesis of Cis-Decalin (+)-8

We next employed a CuBr•DMS-mediated vinyl conjugate addition23 to (−)-30 from the convex face to provide ketone (+)-31, which was subjected to the formation of vinyl triflate (+)-32 and subsequently to cross coupling24,25 with methylmagnesium bromide to furnish diene (+)-33 in a combined yield of 53% (Scheme 5). Upon careful hydrolysis of the TBS ether with TBAF at 60 °C, cis-decalin fragment (+)-8, the second union partner was now available in a total of 11 steps in 15% overall yield from (−)-11. The relative and absolute stereostructures of (−)-30 and (+)-8 were confirmed by X-ray analysis (Scheme 4 and 5).

Having arrived at the requisite decalin (+)-8 and alkyne (+)-9, we initiated studies on their union employing the alkoxide directed alkyne-alkene coupling tactic developed by Micalizio and coworkers (Scheme 6).26–28 This tactic begins with the generation of Tialkyne complex29,30 34 by treatment of (+)-9 with TiCl(Oi-Pr)3 and Grignard reagent c-C5H9MgCl. In a separate flask, the allylic hydroxyl in decalin (+)-8 is deprotonated with n-BuLi in toluene. The resulting lithium alkoxide 35 is then introduced to the flask containing Ti-alkyne complex 34 to direct approach from the concave face, leading to the desired stereochemistry at C(13) in (−)-36. Importantly, the desired regioselectivity is also achieved to furnish the trisubstituted E-alkene between C(14) and C(15), presumably due to minimization of the steric hindrance between the methyl group with the decalin vis-a-vis the methylene group. Pleasingly, this alkoxide directed union between the two fragments [(+)-8 and (+)-9] furnished adduct (−)-36 in 61% yield.

Scheme 6.

Scheme 6

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Hydroxyl-Directed Alkyne-Alkene Coupling

The endgame to complete the total synthesis of nahuoic acid Ci(Bii) (3) now only required selective installation of the unsaturated carboxylic acid moiety to the terminal olefin, and then global deprotection (Scheme 7). Olefin metathesis between (−)-36 and methyl methacrylate in the presence of Hoveyda-Grubbs II catalyst produced the a,b-unsaturated methyl ester (−)-37 with correct geometry.31,32 The fully protected intermediate (−)-37 was then subjected to mild LiBF4 mediated hydrolysis to reveal the six hydroxyl groups,33,34 and in turn saponification with LiOH to complete the total synthesis of (−)-nahuoic acid Ci(Bii) [(−)-3].

Scheme 7.

Scheme 7

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Endgame Strategy towards the Completion of (−)-Nahuoic Acid Ci(Bii).

The spectral data for (−)-nahuoic acid Ci(Bii) was independently reported by both the Anderson and Qi groups, with the major difference observed in 1H NMR between 4.0–4.5 ppm, corresponding to the six hydroxyl proton resonances. Pleasingly, initial 500 MHz 1H NMR spectra of totally synthetic material displayed excellent agreement with that derived from the natural product as reported by Qi and coworker.4 Upon addition of a trace amount of deuterated TFA to the NMR sample, the six exchangeable proton resonances could no longer be distinguished in 1H NMR,2 resulting in NMR spectral properties (500 MHz 1H and 125 MHz 13C) identical with that published by Anderson and coworkers.3 Other spectral properties (i.e., HRMS parent ion identification and chiroptical properties) of synthetic nahuoic Ci(Bii) [(−)-3] were also in total agreement with that published by both the Qi and Anderson groups.

In summary, we have achieved the first total synthesis of a member of the nahuoic acid family of cis-decalin-containing polyketides, namely Ci(Bii) [(−)-3], in a longest linear sequence of 16 steps. Highlights of the synthesis include Type II Anion Relay Chemistry (ARC) to construct the polyol chain, a Ti-catalyzed asymmetric Diels-Alder reaction to generate the cis-decalin skeleton in a highly enantiomerically enriched form, and a late-stage strategic large fragment union via the Micalizio alkoxide-directed alkyne-alkene tactic. Studies toward the synthesis of other members of the nahuoic acid family, as well as the development of analogues for biological evaluations continue in our laboratory.

Supplementary Material

Supporting Information

Acknowledgments

Financial support was provided by the NIH through Grants CA-19033 and GM-29028. We thank Professor Raymond J. Anderson at University of British Columbia for providing the 1H and 13C NMR spectrum FIDs of the isolated nahuoic acid Ci(Bii). We thank Drs. George Furst and Jun Gu at the University of Pennsylvania for help in obtaining the NMR spectral data. We also thank Drs. Patrick J. Carroll and Brian C. Manor for obtaining X-ray crystallographic data. We thank Dr. Charles W. Ross III, Director: Automated Synthesis and laboratory research associates, Sung-Eun Suh and Joo Myung Jun for providing chromatographic and mass spectral method development, analyses, and data interpretation.

Footnotes

ASSOCIATED CONTENT

Supporting Information

The supporting information is available free of charge on the ACS Publications website at DOI:

Experimental procedures, as well as spectroscopic and analytical data for all new compounds (PDF)

X-ray data for compound (+)-8 (CIF)

X-ray data for compound (−)-11 (CIF)

X-ray data for compound (−)-30 (CIF)

The authors declare no competing financial interests.

References

  • 1.For review: Kaniskan HÜ, Martini ML, Jin J. [10.1021/acs.chemrev.6b00801];Chem. Rev. ArticleASAP, and references therein.
  • 2.Williams DE, Dalisay DS, Li F, Amphlett J, Maneerat W, Chavez MAG, Wang YA, Matainaho T, Yu W, Brown PJ, Arrowsmith CH, Vedadi M, Andersen RJ. Org. Lett. 2013;15:414. doi: 10.1021/ol303416k. [DOI] [PubMed] [Google Scholar]
  • 3.Williams DE, Izard F, Arnould S, Dalisay DS, Tantapakul C, Maneerat W, Matainaho T, Julien E, Andersen RJ. J. Org. Chem. 2016;81:1324. doi: 10.1021/acs.joc.5b02569. [DOI] [PubMed] [Google Scholar]
  • 4.Nong X-H, Zhang X-Y, Xu X-Y, Wang J, Qi S-H. J. Nat. Prod. 2016;79:141. doi: 10.1021/acs.jnatprod.5b00805. [DOI] [PubMed] [Google Scholar]
  • 5.For reviews: O’Rourke NF, Kier MJ, Micalizio GC. Tetrahedron. 2016;72:7093. doi: 10.1016/j.tet.2016.08.053.Micalizio GC, Hale SB. Acc. Chem. Res. 2015;48:663. doi: 10.1021/ar500408e. and references therein.
  • 6.For reviews: Smith AB, III, Wuest WM. Chem Commun (Camb) 2008;7:5883. doi: 10.1039/b810394a.Smith AB, III, Adams CM. Acc. Chem. Res. 2004;37:365. doi: 10.1021/ar030245r. and references therein.For recent examples of ARC linchpins: Liu Q, Chen Y, Zhang X, Houk KN, Liang Y, Smith AB., III J. Am. Chem. Soc. 2017;139:8710. doi: 10.1021/jacs.7b04149.Farrell M, Melillo B, Smith AB., III Angew. Chem. Int. Ed. 2016;55:232. doi: 10.1002/anie.201509342.Melillo B, Chen MZ, Forestieri R, Smith AB., III Org. Lett. 2015;17:6242. doi: 10.1021/acs.orglett.5b03235.Chen MZ, Gutierrez O, Smith AB., III Angew. Chem. Int. Ed. 2014;53:1279. doi: 10.1002/anie.201309270.
  • 7.Brook AG. Acc. Chem. Res. 1974;7:77. [Google Scholar]
  • 8.Dong L, Gordon VA, Grange RL, Johns J, Parsons PG, Porzelle A, Reddell P, Schill H, Williams CM. J. Am. Chem. Soc. 2008;130:15262. doi: 10.1021/ja807133p. [DOI] [PubMed] [Google Scholar]
  • 9.Chen K-M, Hardtmann GE, Prasad K, Repič O, Shapiro MJ. Tetrahedron Lett. 1987;28:155. [Google Scholar]
  • 10.Clive DLJ, Zhang C. J. Org. Chem. 1995;60:1413. [Google Scholar]
  • 11.Robles O, McDonald FE. Org. Lett. 2008;10:1811. doi: 10.1021/ol800659z. [DOI] [PubMed] [Google Scholar]
  • 12.Kocienski P, Narquizian R, Raubo P, Smith C, Farrugia LJ, Muir K, Boyle FT. J. Chem. Soc. Perkin Trans. 2000;1:2357. [Google Scholar]
  • 13.Stevens RV, Angle SR, Kloc K, Mak KF, Liu YX, Trueblood KN. J. Org. Chem. 1986;51:4347. [Google Scholar]
  • 14.Kats-kagan R, Herzon SB. Org. Lett. 2015;17:2030. doi: 10.1021/acs.orglett.5b00841. [DOI] [PubMed] [Google Scholar]
  • 15.McDougal PG, Rico JG. J. Org. Chem. 1987;52:4817. [Google Scholar]
  • 16.For examples: Ryu DH, Corey EJ. J. Am. Chem. Soc. 2003;125:6388. doi: 10.1021/ja035393r.Breuning M, Corey EJ. Org. Lett. 2001;3:1559.Moharram SM, Hirai G, Koyama K, Oguri H, Hirama M. Tetrahedron Lett. 2000;41:6669.Engler TA, Letavic MA, Lynch KO, Jr, Takusagawa F. J. Org. Chem. 1994;59:1179.Narasaka K, Iwasawa N, Inoue M, Yamada T, Nakashima M, Sugimori J. J. Am. Chem. Soc. 1989;111:5340.
  • 17.Bernardi A, Karamfilova K, Sanguinetti S, Scolastico C. Tetrahedron. 1997;53:13009. [Google Scholar]
  • 18.Bussche-Hünnefeld CVD, Beck AK, Lengweiler U, Seebach D. Helv. Chim. Acta. 1992;75:438. [Google Scholar]
  • 19.Ohkubo M, Hirai G, Sodeoka M. Angew. Chem. Int. Ed. 2009;48:3862. doi: 10.1002/anie.200900634. [DOI] [PubMed] [Google Scholar]
  • 20.VanRheenen V, Kelly RC, Cha DY. Tetrahedron Lett. 1976;23:1973. [Google Scholar]
  • 21.Liu Q, An C, TenDyke K, Cheng H, Shen YY, Hoye AT, Smith AB., III J. Org. Chem. 2016;81:1930. doi: 10.1021/acs.joc.5b02771. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 22.Nicolaou KC, Li H, Nold AL, Pappo D, Lenzen A. J. Am. Chem. Soc. 2007;129:10356. doi: 10.1021/ja074297d. [DOI] [PubMed] [Google Scholar]
  • 23.Normant JF, Bourgain M. Tetrahedron Lett. 1971;12:2583. [Google Scholar]
  • 24.Scheiper B, Bonnekessel M, Krause H, Fürstner A. J. Org. Chem. 2004;69:3943. doi: 10.1021/jo0498866. [DOI] [PubMed] [Google Scholar]
  • 25.Alonso P, Pardo P, Galván A, Fañanás FJ, Rodríguez F. Angew. Chem. Int. Ed. 2015;54:15506. doi: 10.1002/anie.201508077. [DOI] [PubMed] [Google Scholar]
  • 26.Reichard HA, Micalizio GC. Angew. Chem. Int. Ed. 2007;46:1440. doi: 10.1002/anie.200603515. [DOI] [PubMed] [Google Scholar]
  • 27.Kolundzic F, Micalizio GC. J. Am. Chem. Soc. 2007;129:15112. doi: 10.1021/ja075678u. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 28.Diez PS, Micalizio GC. Angew. Chem. Int. Ed. 2012;51:5152. doi: 10.1002/anie.201200035. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 29.Kulinkovich OG, Savchenko AI, Sviridov SV, Vasilevski DA. Mendeleev Commun. 1993;3:230. [Google Scholar]
  • 30.Harada K, Urabe H, Sato F. Tetrahedron Lett. 1995;36:3203. [Google Scholar]
  • 31.(a) Yet L. Olefin Ring-Closing Metathesis. In: Denmark SE, editor. Organic Reactions. Vol. 89. John Wiley & Sons; Hoboken, NJ: 2016. pp. 1–1342. [Google Scholar]; (b) Chatterjee AK, Choi T-L, Sanders DP, Grubbs RH. J. Am. Chem. Soc. 2003;125:11360. doi: 10.1021/ja0214882. [DOI] [PubMed] [Google Scholar]
  • 32.Xu S, Arimoto H, Uemura D. Angew. Chem. Int. Ed. 2007;46:5746. doi: 10.1002/anie.200701581. [DOI] [PubMed] [Google Scholar]
  • 33.Lipshutz BH, Harvey DF. Synth. Commun. 1982;12:267. [Google Scholar]
  • 34.Ireland RE, Varney MD. J. Org. Chem. 1986;51:635. [Google Scholar]

Associated Data

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Supplementary Materials

Supporting Information
NIHMS913785-supplement-Supporting_Information.pdf (5.2MB, pdf)

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