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Synthesis 2024; 56(16): 2537-2548
DOI: 10.1055/a-2328-2947
paper

Ex-Chiral-Pool Synthesis of Optically Active 4-Alkylidene-Tetrahydro­isoquinolines – Key Intermediates for Crinane Alkaloid Total Syntheses

Stefan Bernhard
a   Organische Chemie, Johannes Gutenberg-Universität Mainz, Duesbergweg 10–14, 55128 Mainz, Germany
,
Nadine Kümmerer
a   Organische Chemie, Johannes Gutenberg-Universität Mainz, Duesbergweg 10–14, 55128 Mainz, Germany
,
Dagmar Urgast
b   Bodenkunde, Technische Hochschule Bingen, Berlinstr. 109, 55411 Bingen am Rhein, Germany
,
Frederik Hack
c   Backhaushohl 14a, 55128 Mainz, Germany
,
Julia Ungelenk
d   Chambolle-Musigny-Str. 13a, 55270 Schwabenheim, Germany
,
Andrea Frank
a   Organische Chemie, Johannes Gutenberg-Universität Mainz, Duesbergweg 10–14, 55128 Mainz, Germany
,
Dieter Schollmeyer
a   Organische Chemie, Johannes Gutenberg-Universität Mainz, Duesbergweg 10–14, 55128 Mainz, Germany
,
Udo Nubbemeyer∗
a   Organische Chemie, Johannes Gutenberg-Universität Mainz, Duesbergweg 10–14, 55128 Mainz, Germany
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Dedicated to Prof. Dr. Johann Mulzer on the occasion of his 80th birthday

Abstract

A seven-step ex-chiral-pool synthesis of optically active 4-alkylidenetetrahydroisoquinolines was developed. Starting from 6-bromopiperonal and (S)-serine esters, N-benzylation via reductive amination gave enantiopure N-piperonyl serine esters. Subsequent NH and OH protection delivered defined (S)-serine building blocks. The best results to achieve the conversion into the corresponding serinal were obtained via a two-step sequence of NaBH4/LiCl reduction and subsequent TEMPO oxidation. Then, chain elongation using the Masamune–Roush variant of the Horner olefination afforded ethyl (E)-4-(N-6-bromopiperonyl)-substituted pentenoates in high yields. Intramolecular Heck cyclization employing the Herrmann–Beller catalyst enabled generation of enantiopure 4-(2-ethoxycarbonylmethylidene)tetrahydroisoquinoline building blocks in high Z-selectivity. Subsequent selected functional group transformations gave carbinols and lactones, which can be used as key intermediates in crinane alkaloid total syntheses.

Key words

l-serine ester - 6-bromopiperonal - reductive amination - Horner olefination - intramolecular Heck reaction - 4-alkylidene-substituted tetrahydroisoquinolines - ex-chiral-pool synthesis

Supporting Information

    Supporting information for this article is available online at https://doi.org/10.1055/a-2328-2947.
  • Supporting Information


Publication History

Received: 20 March 2024

Accepted after revision: 15 May 2024

Accepted Manuscript online:
15 May 2024

Article published online:
06 June 2024

© 2024. Thieme. All rights reserved

Georg Thieme Verlag KG
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  • References

  • 1 Mabberly DJ. The Plant Book. Cambridge University Press; Cambridge: 1990
    Search in Google Scholar

      • For an N5–C12 ring closure incorporating C6 and C11 carbonyl groups, see:
    • 7a Hendrickson JB, Bogard TL, Fisch ME, Grossert S, Yoshimura N. J. Am. Chem. Soc. 1974; 96: 7781
      CrossrefSearch in Google Scholar

      • For an N5–C12 ring closure incorporating C6 and C11 CH2 groups, see:
    • 7b Ninomiya I, Naito T, Kiguchi T. J. Chem. Soc., Perkin Trans. 1 1973; 2261
      Crossref
    • 7c Grigg R, Santhakumar V, Sridharan V, Thorton-Pett M, Bridge AW. Tetrahedron 1993; 49: 5177
      CrossrefSearch in Google Scholar
    • 7d Du K, Yang H, Guo P, Feng L, Xu G, Zhou Q, Chung LW, Tang W. Chem. Sci. 2017; 8: 6247
      CrossrefPubMedSearch in Google Scholar
  • 8 Aldol reactions including the installation of the quaternary C10b center are unknown so far. For a C2–C3 bond formation via an aldol reaction (C11 CH2), see: Pandey G, Gupta NR, Gadre SR. Eur. J. Org. Chem. 2011; 740
    Crossref

      • For a Claisen rearrangement to generate an alkaloid quaternary center, see:
    • 13a Erhard T, Ehrlich G, Metz P. Angew. Chem. Int. Ed. 2011; 50: 3892 ; Angew. Chem. 2011, 123, 3979
      CrossrefPubMedSearch in Google Scholar
    • 13b Mulzer J, Bats JW, List B, Opatz T, Trauner D. Synlett 1997; 441
      Thieme Connect
    • 13c Trauner D, Porth S, Opatz T, Bats JW, Giester G, Mulzer J. Synlett 1998; 653
    • 13d Chandler M, Parsons PJ. J. Chem. Soc., Chem. Commun. 1984; 322
      Crossref

      For 6-bromopiperonal, see:
    • 16a Stanislawski PC, Willis AC, Banwell MG. Org. Lett. 2006; 8: 2143
      CrossrefPubMedSearch in Google Scholar

      • Alternatively, for 6-iodopiperonal (SI), see:
    • 16b Xu X, Kim H.-S, Chen W.-M, Ma X, Correy GJ, Banwell MG, Jackson CJ, Willis AC, Carr PD. Eur. J. Org. Chem. 2017; 4044
      Crossref

      For l-serine ethyl ester (hydrochloride), see:
    • 17a van Dijk M, Postma TM, Rijkers DT. S, Liskamp RM. J, van Nostrum CF, Hennink WF. Polymer 2010; 51: 2479
      CrossrefSearch in Google Scholar

      • For l-serine methyl ester (hydrochloride), see:
    • 17b Alqahtani N, Porwal SK, James ED, Bis DM, Karty JA, Lane AL, Viswanathan R. Org. Biomol. Chem. 2015; 13: 7177
      CrossrefPubMedSearch in Google Scholar

      Since both termini of l-serine have been used likewise as anchors for the OPG group and the aldehyde moiety as present in intermediate H, the enantiopure standard l-amino acid can be used to start the total synthesis series of both enantiomers of the target alkaloids. Synthesis of both R- and S- enantiomer starting materials from the (S)-serine: standard (S)-serine ester NH and C3 OH protection enables C1 chain elongation via the corresponding C1 aldehyde. In contrast, NH protection and C1 protection as an ortho ester allows C3 chain elongation via the corresponding C3 aldehyde, see:
    • 18a Blaskovich MA, Lajoie GA. J. Am. Chem. Soc. 1993; 115: 5021
      CrossrefSearch in Google Scholar
    • 18b Rose NG. W, Blaskovich MA, Wong A, Lajoie GA. Tetrahedron 2001; 57: 1497
      CrossrefSearch in Google Scholar
  • 20 For comparison and, especially, for running smooth and reliable Heck cyclizations to generate enantiopure 4-alkylidenene tetrahydroisoquinoline derivatives, an analogous sequence replacing the piperonyl bromide by an iodo function was developed. For brominated and iodinated compounds identical numbering was used. Always, the iodo derivatives were labeled with the supplement -(I), e.g., XX-(I). For procedures and data of the aryl iodide series, see the SI.
  • 21 Initial attempts to achieve N-serine ester monobenzylation via nucleophilic substitution with suitably activated piperonyl alcohols only gave disappointing results.

      • For deprotonation of the reactant ammonium salt, exactly one equivalent of each of NaOEt and NaOMe was used. Ethyl ester in analogy to:
    • 22a Ichitsuka T, Komatsuzaki S, Masuda K, Koumura N, Sato K, Kobayashi S. Chem. Eur. J. 2021; 27: 10844
      CrossrefPubMedSearch in Google Scholar
    • 22b Methyl ester in analogy to: Kawase Y, Yamagashi T, Kutsuma T, Kataoka T, Ueda K, Iwakuma T, Nakata T, Yokomatsu T. Synthesis 2010; 1673

      The condensation of serine ester 3, piperonal 2, and MgSO4 generated an intermediate azomethine ester 4, highly sensitive in respect to racemization in the presence of any excess of a base. Careful control of the specific rotation of the product was recommended. For Mannich bases and the equilibrium reaction forming intermediate oxazolidines 5, see:
    • 23a Graham TH. Org. Lett. 2010; 12: 3614
      CrossrefPubMedSearch in Google Scholar
    • 23b Beduerftig S, Weigl M, Wuensch B. Tetrahedron: Asymmetry 2001; 12: 1293
      CrossrefSearch in Google Scholar
    • 23c Fueloep F, Pihlaja K. Tetrahedron 1993; 49: 6701
      CrossrefSearch in Google Scholar
    • 23d Badr MZ. A, Aly MM, Fahmy AM, Mansour ME. Y. Bull. Chem. Soc. Jpn. 1981; 54: 1844
      CrossrefSearch in Google Scholar

      It should be pointed out that the condensation building up the imine function had to be completed prior to any reducing agent addition (avoiding the regeneration of 6-bromopiperonyl alcohol as side product). Reductive amination in analogy to:
    • 24a Cobb SL, Vederas JC. Org. Biomol. Chem. 2007; 5: 1031
      CrossrefPubMedSearch in Google Scholar
    • 24b Kim M, Gajulapati K, Kim C, Jung HY, Goo J, Lee K, Kaur N, Kang HJ, Chung SJ, Choi Y. Chem. Commun. 2012; 48: 11443
      CrossrefPubMedSearch in Google Scholar
  • 26 Below 50 °C, no reaction was observed. Heating to 60–80 °C increased the rate, but the formation of O-Boc-protected and carbamate side products was observed. For data, see SI.
  • 27 The introduction of a MOM ether succeeded in high yield, see: Berliner M., Belecki K.; Org. Synth.; 2007, 84: 102; however, several competing β-eliminations within subsequent steps led to this series being abondoned; for details, see SI.
    • 28a CCDC 2338530 contains the supplementary crystallographic data for serine ester 7a (R = Et) of this paper. The data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/structures.
    • 28b For all ethyl ester derivatives 6a–7a, [α]D values of –25 to –35 were found for almost enantiopure compounds, indicating the maintenance of the integrity of the stereogenic center; [α]D values of 0 to –15 pointed to partial racemization (especially after running the reductive amination to 6a).

      For DIBAL-H ester to aldehyde, see:
    • 29a Baldwin JE, Moloney MG, Parsons AF. Tetrahedron 1990; 46: 7263
      CrossrefSearch in Google Scholar
    • 29b See ref. 15b
    • 29c Note that workup conditions caused some racemization of the α-amino aldehyde leading to this strategy being abandoned.

      Additionally, the alternative Rapoport oxazolidine amide was tested (lower yield upon generation of the amide). However, the use of an excess of Grignard reagent increased the risk of competing racemization and β-elimination of the protected hydroxyl group, see:
    • 31a Campbell JA, Lee WK, Rapoport H. J. Org. Chem. 1995; 60: 4602
      CrossrefSearch in Google Scholar
    • 31b Cubbs TL, Boutin RH, Rapoport H. J. Org. Chem. 1985; 50: 3972
      CrossrefSearch in Google Scholar

      For DIBAL-H ester to carbinol, the use of DIBAL-H adjacent to a sterically congested nitrogen function might have been the major drawback. Furthermore, aqueous workup of the aluminum reagent residues caused competing cleavage of the silyl ether moiety, delivering the optically inactive 2-aminopropane-1,3-diol derivative. See:
    • 33a Loss of TBS group: de Vries EF. J, Brussee J, van der Gen A. J. Org. Chem. 1994; 59: 7133
      CrossrefSearch in Google Scholar
    • 33b For racemization via protecting group shift, see: Jones SS, Reese CB. J. Chem. Soc., Perkin Trans. 1 1979; 2762 ; for data, see SI; reductive removal of the aryl bromide had not been observed
      Crossref
    • 33c For an example of an Ar–Br to Ar–H transformation, see: Gevorgyan V, Lukevics E. J. Chem. Soc., Chem. Commun. 1985; 1234
      Crossref
    • 34a Jagadeesh Y, Rao BV. Tetrahedron Lett. 2011; 52: 6366
      CrossrefSearch in Google Scholar
    • 34b Krasinski A, Jurczak J. Tetrahedron Lett. 2001; 42: 2019
      CrossrefSearch in Google Scholar
    • 34c Gryko D, Jurczak J. Tetrahedron Lett. 1997; 38: 8275 ; the use of non-pestled reactants and LiBH4, longer reaction times, and higher temperatures delivered minor 1,3-diol, 2-aminopropan-1-ol, and carbamate side products, too; for data see SI
      CrossrefSearch in Google Scholar
    • 34d The [α]D value of –3 to –4 gave no information concerning any (complete) maintenance of the chiral information

      The Paterson Ba(OH)2 variant induced some β-elimination side products. The MOM-protected serinal derivative predominantly suffered from such competing processes, leading to this series being abandoned. For data of selected side products, see the SI. See also:
    • 38a Paterson I, Yeung K.-S, Smaill JB. Synlett 1993; 774
      Thieme Connect
    • 38b Rathke MW, Nowak M. J. Org. Chem. 1985; 50: 2624
      CrossrefSearch in Google Scholar
    • 38c Alvarez-Ibarra C, Arias S, Banón G, Fernández MJ, Rodriguez M, Sinisterra V. J. Chem. Soc., Chem. Commun. 1987; 19: 1509
      CrossrefSearch in Google Scholar
    • 39a Soeda H, Towada R, Ogura Y, Mohri T, Ponert G, Kuwahara S. Tetrahedron 2019; 75: 1555
      CrossrefSearch in Google Scholar
    • 39b Blanchette MA, Choy W, Davis JT, Essenfeld AP, Masamune S, Roush WR, Saka T. Tetrahedron Lett. 1984; 25: 2183 ; Caution: the specific rotation of the E/Z mixture obtained here resulted in a weakly positive value, indicating potential racemization!
      CrossrefSearch in Google Scholar

      Such a reaction was enforced upon treatment of ketone (E)-13 with TMSOTf/DIPEA; product oxazolidinone was isolated in 49% yield (not optimized). For reaction details and data, see SI. See also:
    • 41a Kawano T, Negoro K, Nitta H, Ueda I. Heterocycles 2000; 52: 1261
      CrossrefSearch in Google Scholar
    • 41b Kawano T, Negoro K, Ueda I. Tetrahedron Lett. 1997; 38: 8219
      CrossrefSearch in Google Scholar
  • 44 In contrast, the aryl iodide series required lower reaction temperatures and less intensive microwave support. Starting from iodoaryl alkenyl ester (E)-11-(I), the Z-configured 4-alkylidene tetrahydroisoquinoline (Z)-12 was generated stereoselectively in 66% yield. The analogous reaction involving the Z-starting material (Z)-11-(I) gave the corresponding (E)-alkylidene tetrahydroisoquinoline (E)-14 in 64% yield as a single isomer. For reaction details, see the SI.
  • 45 Because of difficult reaction control, the yield varied between about 50% and 80%. Prolonged reaction times partly induced thermal removal of the Boc protecting group. Furthermore, the very low optical rotation values of both isomers indicated a significant percentage of racemization. See also: Yokoyama Y, Kondo K, Mitsuhashi M, Murakami Y. Tetrahedron Lett. 1996; 37: 9309
    CrossrefSearch in Google Scholar
  • 47 The separation of the tetrahydroisoquinolines (Z)-12 and (E)-12 proved laborious and need to be run after a transformation (for examples, see Scheme 5). For data of a dihydroisoquinoline side product, see the SI (exo to endo double-bond isomerization).
  • 48 CCDC 2338529 contains the supplementary crystallographic data for ester rac-(Z)-12 of this paper. The data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/structures.
  • 49 In most runs, complete removal of residual (E)-12 and optically inactive 1,2-dihydroisoquinoline succeeded after the next step, resulting a reduced [α]D value (material including small amounts of remaining side products). For details, see the SI.

      • The 1,2-dihydroisoquinoline could be described as a side product involving two successive 1,5-H shifts: a C1→exo alkylidene H shift might have formed an o-quinodimethide intermediate, which immediately undergoes re-aromatization via a C3→C1 H shift delivering the product. Alternatively, C3→ester C=O 1,5-H shift for a dienol intermediate and a subsequent enol/C=O tautomerization (1,3-H shift). For data, see the SI. See also:
    • 50a Doering WE, Keliher EJ. J. Am. Chem. Soc. 2007; 129: 2488
      CrossrefPubMedSearch in Google Scholar
    • 50b Doering WE, Keliher EJ, Zhao X. J. Am. Chem. Soc. 2004; 126: 14206
      CrossrefPubMedSearch in Google Scholar

      • For catalyzed variants, see:
    • 50c Amador-Sánchez YA, López-Mendoza P, Mijangos MV, Miranda LD. Eur. J. Org. Chem. 2022; e202200080
      Crossref
    • 50d Amador-Sánchez YA, Aguila-Granada A, Flores-Cruz R, González-Calderón D, Orta C, Rodríguez-Molina B, Jiménez-Sánchez A, Miranda LD. J. Org. Chem. 2020; 85: 633
      CrossrefPubMedSearch in Google Scholar
    • 50e Beautement K, Clough JM. Tetrahedron Lett. 1984; 25: 3025
      CrossrefSearch in Google Scholar
  • 51 For HCl/MeOH use, see: Nudelman A, Bechor Y, Falb E, Fischer B, Wexler BA, Nudelman A. Synth. Commun. 1998; 28: 471
    CrossrefSearch in Google Scholar
  • 52 Since amine 16 was labile in the presence of oxidizing reagents/O2, the material should be stored as hydrochloride 16 (HCl).
  • 53 Still, removal of the dihydroquinoline lactone (double-bond-positional isomer) side product remained problematic (laborious HPLC). In contrast to the major isomer 16, dehydrogenation of the dihydroquinoline forming the isoquinoline enabled a more facile separation. If necessary, remaining dihydroquinoline side products (traces) definitely were removed upon generating the quaternary stereocenters. Here, the dihydroisoquinolines remained as reactants.

      • For O-Ac mandelic acid amides, see:
    • 54a Nishiguchi A, Ikemoto T, Tomimatsu K. Tetrahedron 2007; 63: 4048
      CrossrefSearch in Google Scholar
    • 54b Bolm C, Zani L, Rudolph J, Schiffes I. Synthesis 2004; 2173
      Thieme Connect
    • 54c Suna E. Synthesis 2003; 251
      Thieme Connect
    • 54d Weerawarna AA, Davis RD, Nelson WL. J. Med. Chem. 1994; 37: 2856
      CrossrefPubMedSearch in Google Scholar

      • For O-Me mandelic acid amides, see:
    • 54e Finlay MR. V, Anderton M, Bailey A, Boyd S, Brookfield J, Cairnduff C, Charles M, Cheasty A, Critchlow SE, Culshaw J, Ekwuru T, Hollingsworth I, Jones N, Leroux F, Littleson M, McCarron H, McKelvie J, Mooney L, Nissink JW. M, Perkins D, Powell S, Quesada MJ, Raubo P, Sabin V, Smith J, Smith PD, Stark A, Ting A, Wang P, Wilson Z, Winter-Holt JJ, Wood JM, Wrigley GL, Yu G, Zhang P. J. Med. Chem. 2019; 62: 6540
      CrossrefPubMedSearch in Google Scholar
    • 54f Jourdain F, Hirokawa T, Kogane T. Tetrahedron Lett. 1999; 40: 2509
      CrossrefSearch in Google Scholar
    • 54g Trost BM, Bunt RC, Pulley SR. J. Org. Chem. 1994; 59: 4202
      CrossrefSearch in Google Scholar
  • 55 For dihydropyranone in diol, see: Tomooka K, Miyasaka S, Motomura S, Igawa K. Chem. Eur. J. 2014; 20: 7598
    CrossrefPubMedSearch in Google Scholar
  • 57 Long reaction times and more acidic conditions (predominantly upon workup) gave some dihydropyran as a side product. For data, see SI.
  • 59 Soai K, Ookawa A. J. Org. Chem. 1986; 51: 4000
    CrossrefSearch in Google Scholar