Synthesis of heterocyclic enamine-zinc complexes as precursors of stereocontrolled substitution of nitrogen α-position

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Synthesis of heterocyclic enamine-zinc complexes as

precursors of stereocontrolled substitution of nitrogen

α-position

H.-V. Tran, H.-D. Vu, J. Graton, D. Jacquemin, J. Renault, P. Uriac

To cite this version:

H.-V. Tran, H.-D. Vu, J. Graton, D. Jacquemin, J. Renault, et al.. Synthesis of heterocyclic

enamine-zinc complexes as precursors of stereocontrolled substitution of nitrogen α-position. Tetrahedron

Letters, Elsevier, 2020, 61 (44), pp.152405. �10.1016/j.tetlet.2020.152405�. �hal-03003339�

N O Boc n Z ZnCl21M (5 eq.) N Z x(ZnCl2)y * * N _Z X * * R R R n n n = 1; R = H, OCH3; Z H X = H, Allyl de : 50% n = 1, 2; R = H; Z = H X = Allyl de : 0% Z = Allyl, C C

alkaloids

1

Synthesis of heterocyclic enamine-zinc complexes as precursors of

stereocontrolled substitution of nitrogen α-position

Hoang-Van Tran

_{, Huy-Dinh Vu}

_{, Jérôme Graton}

_{, Denis Jacquemin}

_{, Jacques Renault}

_,

_{Philippe Uriac}

———

*_{Corresponding author. Fax: +33 2 23234425. E-mail: philippe.uriac@univ-rennes1.fr ORCID: 0000-0002-2526-5967}

a_{Université de Rennes I, Institut des Sciences Chimiques de Rennes - UMR CNRS 6226, F-35000 Rennes, France} b_{Department of Chemistry, Vietnam National University of Forestry, Hanoi, Vietnam}

c_{Laboratoire CEISAM - UMR CNRS 6230, Université de Nantes, 44322 Nantes, France}

Introduction

Stereocontrolled functionalization of the carbon in α-position of the nitrogen of heterocycles has been often a key-step in natural product synthesis.1 _{Efficient strategies have been}

proposed for the monosubstitution of various heterocycles2-4_but

the quaternization of the carbon in nitrogen α-position remains poorly explored.2a, 5 _{In some recent publications, we have shown}

that 1M ZnCl2 in solution in diethyl ether was a useful reactant to

prepare iminocomplexes I6 _{or enaminocomplexes II}7 _{which were}

very stable gums or solids (Fig. 1). The neutralization of the iminocomplexes I yielded to heterocyclic imines that revealed excellent ligands of Zn(II), Pd(II) and Au(III)8 _{whereas the}

reduction of the enaminocomplexes II using NaBH4 in EtOH

allowed obtaining of 2-substituted indolizidine with low diastereomeric excess (de = 20) (Fig. 1).7

N R N R (ZnCl2) x y _x(ZnCl2)_y (I) (II)

Figure 1. Structure of iminocomplexes (I) and

enaminocomplexes (II).

This latter result prompted us to design enamine-zinc complexes with α-methylbenzylamine acting as a chiral inductor

in order to obtain heterocycles mono- or disubstituted in α-position of the heterocyclic nitrogen atom.

Results and discussion

Access to the N-Boc protected aminoketones and

aminoaldehydes was realized as follows (Scheme 1). The

nucleophilic substitution of either the (R, S)

α-methylbenzylamine 1 or the (R) 4-methoxy-α-benzylamine 2 with the ethyl 5-bromopentanoate 3 (n=1)9 _{led to the aminoesters}

4 and 5 which were protected using (Boc)2O to give the

compounds 6-7. Then, the ester function was transformed into

Weinreb amide 8-910 _{in the presence of lithium phenylacetylide,}

lithium propylacetylide, allylmagnesium chloride or LiAlH4,6, 11

which allowed the formation of the desired N-Boc protected aminoketones 10-13 and aminoaldehyde 14. As indicated in the Scheme 2, yields were generally good. One can notice that the use of other bromoesters could allow introduction of diversity. Thus, with the ethyl 6-bromohexanoate 3’ (n=2), the N-Boc protected aminoaldehyde 14’ was obtained.

Then, we carried out the formation of the zinc complexes

(Scheme 2). The aminoketones 10-13 and the aminoaldehydes 14

and 14’ were allowed to react with 5 equivalents of a 1M ZnCl2

solution in diethyl ether, at room temperature for 12h. Six zinc-complexes 15-19 and 19’ were obtained as gums or solids after work-up.6, 7 _{The neutralization of the zinc-complex 15 with 1M}

NH4OH (aq.) allowed obtaining the corresponding enamine 35

A B S T R A C T

In the presence of ZnCl2,chiral protected amino-ketones and amino-aldehydes gave zinc enamino-complexes. Both enamine and iminium structures

of these complexes were observed in 1_{H and} 13_{C NMR spectra depending on the solvent. Introduction of either an allyl or a hydrogen substituent was}

performed using allylmagnesium chloride or NaBH4 in excess leading to various heterocycles. With the amino-ketones diastereoselectivity (de = 50)

methylbenzylamine and the imine carbon was observed near 160 ppm whereas; in the previously report of indolizidine, an

enamine intermediate was observed.7

NH2 _OEt O _(i) + Br _HN OEt O N O Boc N O Boc n = 1 3 n = 2 3' n = 1, R = H 4 (60%) n = 1, R = OCH35 (65%) n = 2, R = H 4' (65%) n=1 14 (94%) n=2 14' (80%) R R = H 1 (R,S) R = OCH32 (R) R N O Boc 12 (78%) N OEt O R Boc n = 1, R = H 6 (75%) n = 1, R = OCH37 (76%) n = 2, R = H 6' (79%) R R = H 10 (90%) R = OCH311 (91%) n n n N O N Boc n = 1, R = H 8 (87%) n = 1, R = OCH39 (89%) n = 2 ,R = H 8' (80%) n OCH3 CH3 8, 8' n 8, 9 8 N O Boc n-C3H7 13 (83%) (iv) (ii) (iii) (vii) (v) 8 (vi) R

Scheme 1. Synthesis of the starting aldehydes and ketones.

(i) K2CO3, KI/DMF, 100 oC, 4h (ii) Boc2O (1.02 eq.)/CH2Cl2,

RT, overnight; (iii) HN(OMe)Me.HCl (1.38 eq.), i-PrMgCl (2.78 eq.)/THF, –20 o_{C to 25} o_{C, 1h; (iv) C}

6H5‒C≡Cli (3.0 eq.)/THF, –

50 o_{C, 3h (v) CH}

2=CH‒CH2MgCl (2.6 eq.)/THF; (vi)

n-C3H7‒C≡Cli (3.0 eq.)/THF, –50 oC, 3h; (vii) LiAlH4 (50

mol%)/THF, 0 o_C

The strains resulting from the indolizidine bicyclic structure disappeared in the piperidine six-membered ring leading to an

iminium in CD3CN. When the more polar d6-DMSO is used, the

enamine is observed (Fig. 2 top). The presence of H2O in the

zinc-complex should allow the enamine-iminium tautomerism.12

In the case of 17, the iminium formation resulted in an allylic transposition giving an aza-dienic iminium (Fig. 3) probably due to the medium acidity. The structure of 17 was clearly attested in

1_{H NMR by the presence of an ABX system (J}

trans = 17 Hz). N _Z ZnCl2 10 - 14 5 eq. x(ZnCl2)y R R = H, Z = C C-C6H5 15 R = OCH3, Z = C C-C6H5 16 R = H, Z = CH2CH=CH217 R = H, Z = H 19 N 14' x H R = H, Z = C C-C3H7 18 (ZnCl₂)_y 19' Et2O, RT, 12h ZnCl2 5 eq. Et2O, RT, 12h

Scheme 2. Synthesis of enamine-zinc complexes.

15

(solution in CH2Cl2)

NH4OH(aq.)1M _N

H3CO

35 (46%)

Scheme 3. Synthesis of enamine 35

3

R = OCH3, 21a (RR), 21b (RS), 36% from 11

39% from 14'; a,b de = 0%

Re attack Si attack

Scheme 4. Reactivity of the zinc complexes with allyl

magnesium chloride. (i) CH2=CH‒CH2MgCl 1M (10 eq.)/THF, 20 oC, 2h -6 -4 -2 0 2 4 6 225 250 275 300 325 RR RS Delt a Eps ilon Wavelength (nm)

Figure 4. TD-DFT-simulated (left) and experimental (right)

electronic circular dichroism spectra of 19a-b.

All these piperidine derivatives were obtained as a mixture of

a (major) and b (minor) diastereomers. A diastereoselectivity (de

= 50) was only observed when the starting complex was substituted in position 2. The diastereomers were separated using column chromatography. The configurations of 21a and 21b (and then of 22) have been determined by electronic circular dichroism. Thus, comparing the calculated (see the ESI section

for details) and experimental ECD spectra of 21a and 21b (Fig. 4) led us to attribute the RR configuration to the major isomer

21a.

The configurations of 22a and 22b (and then of 23 and 24) were attributed using the literature data.4a _{These configurations}

were in accordance with a classical transition state postulated for nucleophilic attack involving piperidinium intermediates14 _and

conformational analysis of 21 (see the ESI). Optical purity was checked with 21a (RR) and 20 (RR + SS) by formation of salts

with the (R)-(-)-tert-butylphenylphosphanylthioic acid,15,4a

because use of various chiral columns in HPLC has failed (see

the ESI).

Some attempts of reduction/deprotection of 15 using H2 (5

bar) in the presence of Pearlman’s catalyst gave a mixture of

compounds corresponding to both debenzylation and N-C2

cleavage. Then, other strategies must be developed to obtain α, α- disubstituted heterocycles. The reactivity of 17 with NaBH4 in

EtOH16 _{(Scheme 5) has been tested and interestingly, 22 was}

obtained with a 60% yield and de = 50. This result can be probably explained by the basicity of the medium which did not allow allylic transposition. As the hydride attack occurred by the same face as the allyl one the major diastereomer 20a has the

R*S* absolute configuration. The same behaviour was observed

with 18 and 24a has also the R*S* absolute configuration.

N C3H7 N 17 NaBH4(excess) ₁₈ 22a (R*S*), 22b (R*R*) 24a (R*S*), 24b (R*R*) H H EtOH, RT, 3h NaBH4(excess) EtOH, RT, 3h

60% from 12; a,b de = 50% 31% from 13; a,b de = 50%

Scheme 5. Reactivity of 17, 18 with NaBH4

N N 26a N 25a N H.HCl rac- Homoconiine N 23a + 23b 22a rac-Coniine 22b 25b (85%) (i) (ii)* (ii)* (iii) (iii) (iii) N H (iv)* (90%) OH

Scheme 6. Alkaloids synthesis.

(i) 9-BBN (2.5 eq.)/THF, RT, overnight, then H2O2, NaOH, 3

min; (ii) H2 (3 bar)/Wilkinson’s catalyst (10%), EtOH, RT, 72h;

(iii)H2 (Pd/C); (iv)H2 (3 bar)/Pd(OH)2, EtOH, RT, 24h then HCl

(excess)/dioxane. *The quantitative reduction was checked by TLC.

We then carried out the synthesis to obtain natural alkaloids

(Scheme 6). The rac-homoconiine has been quantitatively

prepared from 23 in one step using H2 in the presence of

Pearlman’s catalyst at 3 bar.5a _{Addition of 1M HCl in dioxane}

furnished the hydrochloride. Starting from 22a (R*S*) and 22b

(R*R*) the coniine precursors 25a (R*R*) and 25b (R*S*)5a _were

prepared using H2 with Wilkinson’s catalyst at 3 bar whereas the

indolizidine precursor 26a (R*S*) was obtained with 9-BBN/H2O2.11 The NMR spectra of 25 and 26 are consistent with

the literature(see the ESI).5a

Conclusion

In conclusion, the proposed strategy for the 2-substituted heterocycles synthesis, involving formation and storage of iminium intermediates, is easy and can offer many possibilities. Then, diversity can be introduced by tuning the nature of the precursor (length, substitutions, cycle…) and/or changing the nature of the nucleophile. Finally, the use of enantiopure α-methylbenzylamine and the easy separation of the diastereomers by chromatography can allow obtaining enantiopure

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Supplementary Material

Supplementary data associated with this article can be found, in the online version, at http:

Declaration of interests

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Highlights

Enamine-zinc complexes

Stereoselective addition on cyclic iminiums

2-Substituted nitrogen heterocycles

(rac)-Homoconiine and coniine precursors

synthesis