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DOI: 10.1055/a-2328-2947
Ex-Chiral-Pool Synthesis of Optically Active 4-Alkylidene-Tetrahydroisoquinolines – Key Intermediates for Crinane Alkaloid Total Syntheses
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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 synthesisSupporting 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
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For comprehensive reviews, see:
For key reactions for the introduction of the quaternary center and the stereotriad C4a, C10b, C11, see:
For an N5–C12 ring closure incorporating C6 and C11 carbonyl groups, see:
For an N5–C12 ring closure incorporating C6 and C11 CH2 groups, see:
For a ring-closing metathesis upon crinane alkaloid C ring generation, see
For further examples, see:
For crinane alkaloid C-ring formations, see:
For an intramolecular radical Michael reaction, see:
For an intramolecular Stetter reaction, see:
For a Claisen rearrangement to generate an alkaloid quaternary center, see:
For reviews on the Heck reaction, see:
For Horner olefination, see:
For 6-bromopiperonal, see:
Alternatively, for 6-iodopiperonal (SI), see:
For l-serine ethyl ester (hydrochloride), see:
For l-serine methyl ester (hydrochloride), see:
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:
For bromination, see:
For deprotonation of the reactant ammonium salt, exactly one equivalent of each of NaOEt and NaOMe was used. Ethyl ester in analogy to:
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:
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:
For Boc protection, see:
For Boc and TBS protection, see:
For DIBAL-H ester to aldehyde, see:
For Weinreb amide, see:
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:
For DIBAL-H/nBuLi Weinreb amide to aldehyde, see:
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:
For Swern oxidation, see:
For use of TEMPO, see:
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:
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:
For microwave-supported Heck reactions, see:
For HBC, see:
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:
For catalyzed variants, see:
For O-Ac mandelic acid amides, see:
For O-Me mandelic acid amides, see:
For Luche reduction of lactone, see: