Johannes Gutenberg University of Mainz, Institute of Organic … · 2020-04-02 · Johannes...

1
α-Aminonitriles as Versatile Building Blocks for the Synthesis of the Bisbenzylisoquinoline Skeleton of Tubocurarine Johannes Gutenberg University of Mainz, Institute of Organic Chemistry, Duesbergweg 1014, 55128 Mainz, Germany Nicola Otto and Till Opatz* Acknowledgments: We thank Dr. J. C. Liermann (Mainz) for NMR spectroscopy and Dr. N. Hanold (Mainz) for mass spectrometry. The expert technical assistance by D. Kowalczyk (Mainz) is gratefully acknowledged. N. Otto is grateful for a PhD scholarship of the Studienstiftung des deutschen Volkes. References: [1] Schiff, P. L. J. Nat. Prod. 1991, 54, 645. [2] Blank, N.; Opatz, T. J. Org. Chem. 2011, 76, 97779784. [3] Kucukdisli, M.; Opatz, T. J. Org. Chem. 2013, 78, 6670.[4] Kison, C.; Meyer, N.; Opatz, T. Angew. Chem. Int. Ed. 2005, 44, 5662. [5] Bergner, I.; Opatz, T. J. Org. Chem. 2007, 72, 7083. [6] Werner, J.; Blank, N.; Opatz, T. Eur. J. Org. Chem. 2007, 23, 39113915. Bisbenzylisoquinoline alkaloids constitute a family of more than 400 phenylalanine-derived metabolites sharing the structural motif of at least one diaryl ether linkage. Many of them were found to exhibit diverse biological activities such as antiinflammatory, antibacterial, fungicidal and anticancer activities as well as antiarrhythmic effects which makes these compounds attractive for pharmaceutical and agrochemical purposes. The most prominent example is tubocurarine (1), known as the arrow poison curare, which acts as a skeletal muscle relaxant by inhibiting the nicotinic acetylcholine receptor. [1] The Chemistry of Deprotonated α-Aminonitriles Synthesis of Benzylisoquinoline Building Blocks Conclusions & Outlook Retrosynthetic Approach Synthesis of Benzylbromides Ullmann Coupling Studies Synthesis of α-Aminonitriles Starting from two benzyl tetrahydroisoquinoline units 8a and 34, the seco-heterodimer 35 can be prepared by head-to-tail Ullmann coupling. Currently, different reaction conditions based on variation of metal salt and ligand as well as choice of base and solvent are investigated to optimize the 1 st Ullmann coupling. Starting from Bn-protected vanilline 15, phenethyl- amine 17 has been synthesized by Henry- reaction and following reduction with LiAlH 4 . Bischler-Napieralski reaction of the formamide of 17 or Pictet-Spengler cyclization gives the imine 18 or the isoquinoline 19 respectively, which can be converted to the desired aminonitrile 10 in two steps. The 3-bromo- substituted phenethyl- amine 26 is obtained from the nitrile 25 which can be synthesized from vanilline 14 in five steps. Recently, we have shown α- aminonitriles to be useful building blocks for the modular enantioselective synthesis of dimeric benzyl tetrahydro- isoquinolines. [2] Here, we report on current studies towards the synthesis of the bisbenzyl- isoquinoline skeleton of tubocurarine from deprotonated α-aminonitriles. The α-aminonitriles 10 and 11 have been successfully synthesized in 51% and 20% yield over seven and nine linear steps, respectively. Starting from the aminonitriles, the benzylisoquinoline building blocks 34 and 8a have been synthesized in 40% yield over nine linear steps and in 7% yield over ten linear steps. Currently, different reaction conditions for the 1 st Ullmann coupling of the benzylisoquinolines 8a and 34 are investigated of which entry 4 (Table 1) shows potential for optimization. Furthermore, a stereoselective synthesis of the benzylisoquinolines 8 and 9 is in preparation. The deprotonation of α-aminonitriles 10 and 11 with KHMDS furnishes stabilized α-amino carbanions which can be C- alkylated with the corresponding benzylbromides 12 and 13. Subsequent reduction with NaCNBH 3 yields the 1- benzyl 3,4-dihydro-isoquinolines 9 and 8. [6] The Bn-protective group of 9 is cleaved by hydrogenation to yield the corresponding benzylisoquinoline 34. Introduction TIPS-protection of 4-hydroxy- benzaldehyde 29 and subsequent reduction gives benzylalcohol 30 which is converted to benzylbromide 12. The 3-iodobenzylbromide 31 can be obtained in five steps starting from p-anisaldehyde 33. Iodination of 33 and subsequent ether cleavage gives aldehyde 31b. Iodination of 4-hydroxy- benzaldehyde can not be performed selectively and furnishes the dihalogenated products, which are not separable by chromatography or crystallization. α-Aminonitriles bearing a hydrogen atom at the α-centre can be deprotonated resulting in the reversed polarity of an α-amino carbanion as compared to the electrophilic reactivity of the former iminium carbon. The resulting ketene iminate salts can undergo nucleophilic reactions such as 1,4-additions to α,β- unsaturated carbonyl compounds, alkylations, 1,2-additions to aldehydes, additions to alkynes and epoxide ring openings. In our group it was found, that the use of strong bases devoid of Lewis-acidic cations such as KHMDS allows the quantitative deprotonation of N-monosubstituted α-aminonitriles without risking the undesired retro-Strecker reaction. We used this methodology for the synthesis of a wide range of N-heterocycles as well as 1,2-aminoalcohols and 1,2 diamines. [3-5] Tab.1 Reaction Conditions for 1 st Ullmann Coupling. Entry Metal/Ligand (mol%) Alcohol/Halide (eq.) Solvent Base Temperature Time Result [a] 1 CuI (20 mol%) DMG (40 mol%) 1.2:1.0 MeCN K 3 PO 4 (2.0 eq.) MW, 80°C, 300 Watt 30 min [b] 2 CuI (20 mol%) DMG (40 mol%) 1.2:1 MeCN K 3 PO 4 (2.0 eq.) MW, 110 °C, 300 Watt 5 h <10% [c], [e] 3 CuI (10 mol%) DMG (30 mol%) 1:1 DMF K 3 PO 4 (2.0 eq.) MW, 140 °C 150 Watt 60 min [c] 4 CuBr*SMe 2 (2.0 eq.) 1:1 pyridine Cs 2 CO 3 (2.0 eq.) heating reflux 20% [e] [a] HPLC-MS analysis, [b] no conversion [c] stagnating conversion, deiodination, [d] decomposition, [e] not isolated XRD structure of aminonitrile 10b at 173 K (ORTEP- ellipsoids at 30 % probability)

Transcript of Johannes Gutenberg University of Mainz, Institute of Organic … · 2020-04-02 · Johannes...

Page 1: Johannes Gutenberg University of Mainz, Institute of Organic … · 2020-04-02 · Johannes Gutenberg University of Mainz, Institute of Organic Chemistry, Duesbergweg 10–14, 55128

α-Aminonitriles as Versatile Building Blocks

for the Synthesis of the

Bisbenzylisoquinoline Skeleton of Tubocurarine

Johannes Gutenberg University of Mainz, Institute of Organic Chemistry, Duesbergweg 10–14, 55128 Mainz, Germany

Nicola Otto and Till Opatz*

Acknowledgments:

We thank Dr. J. C. Liermann (Mainz) for NMR spectroscopy and Dr. N. Hanold (Mainz) for mass spectrometry. The expert technical assistance by D. Kowalczyk (Mainz) is gratefully acknowledged.

N. Otto is grateful for a PhD scholarship of the “Studienstiftung des deutschen Volkes”.

References:

[1] Schiff, P. L. J. Nat. Prod. 1991, 54, 645. [2] Blank, N.; Opatz, T. J. Org. Chem. 2011, 76, 9777–9784. [3] Kucukdisli, M.; Opatz, T. J. Org. Chem. 2013, 78, 6670.[4] Kison, C.; Meyer, N.; Opatz, T. Angew. Chem. Int. Ed. 2005, 44,

5662. [5] Bergner, I.; Opatz, T. J. Org. Chem. 2007, 72, 7083. [6] Werner, J.; Blank, N.; Opatz, T. Eur. J. Org. Chem. 2007, 23, 3911–3915.

Bisbenzylisoquinoline alkaloids constitute a family of more than 400 phenylalanine-derived metabolites

sharing the structural motif of at least one diaryl ether linkage. Many of them were found to exhibit

diverse biological activities such as antiinflammatory, antibacterial, fungicidal and anticancer activities as

well as antiarrhythmic effects which makes these compounds attractive for pharmaceutical and

agrochemical purposes. The most prominent example is tubocurarine (1), known as the arrow poison

curare, which acts as a skeletal muscle relaxant by inhibiting the nicotinic acetylcholine receptor.[1]

The Chemistry of Deprotonated α-Aminonitriles

Synthesis of Benzylisoquinoline Building Blocks

Conclusions & Outlook

Retrosynthetic Approach

Synthesis of Benzylbromides

Ullmann Coupling Studies

Synthesis of α-Aminonitriles

Starting from two benzyl tetrahydroisoquinoline units 8a and 34, the seco-heterodimer 35 can be prepared

by head-to-tail Ullmann coupling. Currently, different reaction conditions based on variation of metal salt

and ligand as well as choice of base and solvent are investigated to optimize the 1st Ullmann coupling.

Starting from Bn-protected

vanilline 15, phenethyl-

amine 17 has been

synthesized by Henry-

reaction and following

reduction with LiAlH4.

Bischler-Napieralski

reaction of the formamide

of 17 or Pictet-Spengler

cyclization gives the imine

18 or the isoquinoline 19

respectively, which can be

converted to the desired

aminonitrile 10 in two

steps. The 3-bromo-

substituted phenethyl-

amine 26 is obtained from

the nitrile 25 which can be

synthesized from vanilline

14 in five steps.

Recently, we have shown α-

aminonitriles to be useful

building blocks for the modular

enantioselective synthesis of

dimeric benzyl tetrahydro-

isoquinolines.[2] Here, we report

on current studies towards the

synthesis of the bisbenzyl-

isoquinoline skeleton of

tubocurarine from deprotonated

α-aminonitriles.

The α-aminonitriles 10 and 11 have been successfully synthesized in 51% and 20% yield over seven and

nine linear steps, respectively. Starting from the aminonitriles, the benzylisoquinoline building blocks 34 and

8a have been synthesized in 40% yield over nine linear steps and in 7% yield over ten linear steps.

Currently, different reaction conditions for the 1st Ullmann coupling of the benzylisoquinolines 8a and 34 are

investigated of which entry 4 (Table 1) shows potential for optimization. Furthermore, a stereoselective

synthesis of the benzylisoquinolines 8 and 9 is in preparation.

The deprotonation of α-aminonitriles 10

and 11 with KHMDS furnishes stabilized

α-amino carbanions which can be C-

alkylated with the corresponding

benzylbromides 12 and 13. Subsequent

reduction with NaCNBH3 yields the 1-

benzyl 3,4-dihydro-isoquinolines 9 and

8.[6] The Bn-protective group of 9 is

cleaved by hydrogenation to yield the

corresponding benzylisoquinoline 34.

Introduction

TIPS-protection of 4-hydroxy-

benzaldehyde 29 and

subsequent reduction gives

benzylalcohol 30 which is

converted to benzylbromide 12.

The 3-iodobenzylbromide 31

can be obtained in five steps

starting from p-anisaldehyde 33.

Iodination of 33 and subsequent

ether cleavage gives aldehyde

31b. Iodination of 4-hydroxy-

benzaldehyde can not be

performed selectively and

furnishes the dihalogenated

products, which are not

separable by chromatography or

crystallization.

α-Aminonitriles bearing a hydrogen atom at

the α-centre can be deprotonated resulting in

the reversed polarity of an α-amino carbanion

as compared to the electrophilic reactivity of

the former iminium carbon. The resulting

ketene iminate salts can undergo nucleophilic

reactions such as 1,4-additions to α,β-

unsaturated carbonyl compounds, alkylations,

1,2-additions to aldehydes, additions to

alkynes and epoxide ring openings.

In our group it was found, that the use of strong bases devoid of Lewis-acidic cations such as KHMDS

allows the quantitative deprotonation of N-monosubstituted α-aminonitriles without risking the undesired

retro-Strecker reaction. We used this methodology for the synthesis of a wide range of N-heterocycles as

well as 1,2-aminoalcohols and 1,2 diamines.[3-5]

Tab.1 Reaction Conditions for 1st Ullmann Coupling.

Entry Metal/Ligand

(mol%)

Alcohol/Halide

(eq.)

Solvent Base Temperature Time Result[a]

1 CuI (20 mol%)

DMG (40 mol%) 1.2:1.0 MeCN

K3PO4

(2.0 eq.) MW, 80°C, 300 Watt 30 min —[b]

2 CuI (20 mol%)

DMG (40 mol%) 1.2:1 MeCN

K3PO4

(2.0 eq.) MW, 110 °C, 300 Watt 5 h <10%[c], [e]

3 CuI (10 mol%)

DMG (30 mol%) 1:1 DMF

K3PO4

(2.0 eq.)

MW, 140 °C

150 Watt 60 min —[c]

4

CuBr*SMe2

(2.0 eq.)

1:1 pyridine Cs2CO3

(2.0 eq.) heating reflux 20%[e]

[a] HPLC-MS analysis, [b] no conversion [c] stagnating conversion, deiodination, [d]decomposition, [e] not isolated

XRD structure

of aminonitrile

10b at 173 K

(ORTEP-

ellipsoids at

30 %

probability)