Catalytic enantioselective synthesis of a-aryl a-hydrazino esters and amides

Article abstract of DOI:10.1039/d0cc02478c

Catalysts generated by combinations of Pd(TFA)₂and pyridine-hydrazone ligands have allowed the asymmetric 1,2-addition of aryl boronic acids toN-carbamoyl (Cbz and Fmoc) protected glyoxylate-derived hydrazones, yielding a-aryl a-hydrazino esters/amides in high enantioselectivities. Subsequent removal of the carbamoyl moiety affords key building blocks en route to hydrazinopeptides,N-aminopeptides and peptidomimetics thereof.

Full text of DOI:10.1039/d0cc02478c

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10.1039/D0CC02478C.
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DOI: 10.1039/D0CC02478C
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Catalytic enantioselective synthesis of α-aryl α-hydrazino esters
and amides
Received 00th January 20xx,
Marta Velázquez,a Saúl Alberca,a Javier Iglesias-Sigüenza,a Rosario Fernández,*a José M.
Accepted 00th January 20xx
Lassaletta*b and David Monge*a
DOI: 10.1039/x0xx00000x
Catalysts generated by combinations of Pd(TFA)2 and pyridine-
hydrazone ligands have allowed the asymmetric 1,2-addition of
aryl boronic acids to N-carbamoyl (Cbz and Fmoc) protected
glyoxylate-derived hydrazones, yielding α-aryl α-hydrazino
esters/amides in high enantioselectivities. Subsequent removal of
the carbamoyl moiety affords key building blocks en route to
hydrazinopeptides, N-aminopeptides and peptidomimetics
thereof.
H2N
OH
OH
NH
HO
'Hydrazino turn'
O
L-Carbidopa
H
N
NH2
O
H
R
H
N
R
O
N
N
H2N
N
O
H
O
R
H
N
O
HO
I
II
III
α-Hydrazino acids I are an important family of compounds in
bioorganic and medicinal chemistry (Scheme 1).1 For example,
L-Carbidopa, acting as inhibitor of the peripheral aromatic L-
amino acid decarboxylase (DDC), has been shown to improve
the efficiency of Parkinson’s treatment in combination with L-
Dopa.2 Additionally, α-hydrazino acids are essential building
blocks for the synthesis of artificial peptides, in which the
presence of a NH–NH–C–CO motif induces conformational
restrictions (hydrazino turns) through intramolecular H-
bonds,3 and hence modify their biological activities.
Hydrazinopeptides II,4 N-aminopeptides (NAP) III,5 hydrazone-
ligated bioconjugates6 and other non-proteogenic amino acid
derivatives have attracted increasing interest as protease-
resistant peptidomimetics at the forefront of pharmaceutical
research. Traditional routes to enantioenriched α-hydrazino
acid derivatives,1 basically α-alkyl substituted ones,7 rely on
some transformations of amino acids from the chiral pool,8
electrophilic amination of enolates with azodicarboxylates and
diverse reactions using hydrazones (hydrogenation,9
cyanation,10 or introduction of side-chains11).
Readily
removable
O
group
O
RO
NH
N
[Pd(II)/L*] Cat
NH
HN
RO
ArB(OH)2
+
Ar
O
Z
O
Mild
deprotections
Z = OR’, NR’R''
Z
R'
N
Ar
H2N
IV
R' = H, PG
Z = OH, OR', NR'R''
Z
O
Scheme 1. Synthetic design to α-aryl α-hydrazino acid derivatives IV.
However, direct methodologies for accesing α-aryl substituted
α-hydrazino acids are scarce.12
In this communication, we report on a straightforward
approach based on Pd(II)-catalyzed enantioselective 1,2-
addition of aryl boronic acids to N-carbamoyl protected
glyoxylate-derived hydrazones. Effective removal of the
carbamoyl moiety provides an appealing entry to ad hoc
deprotected α-aryl α-hydrazino acid derivatives IV which might
serve to expand the repertoire of the above-mentioned
pharmacophores (Scheme 1).
Preliminary experiments were performed with phthaloyl-
protected hydrazone 1a and phenylboronic acid (2a) as model
reagents. The behavior of catalysts prepared in situ from
bipyridine (bipy, 11 mol%) and different Pd(II) sources (10
mol%) in trifluoroethanol (TFE) at 60 C was analyzed (See S1
in the ESI‡). From this screening, Pd(TFA)2 was identified as the
best precatalyst, affording the desired product 3aa in 87%
yield after 24 h.
a. Departamento de Química Orgánica, Universidad de Sevilla and Centro de
Innovación en Química Avanzada (ORFEO−CINQA), C/ Prof. García González, 1,
41012 Sevilla, Spain. E-mail: dmonge@us.es, ffernan@us.es
b. Instituto de Investigaciones Químicas (CSIC-US) and Centro de Innovación en
Química Avanzada (ORFEO−CINQA), Avda. Américo Vespucio, 49, 41092 Sevilla,
Spain. E-mail: jmlassa@iiq.csic.es
‡
Electronic Supplementary Information (ESI) available: Experimental procedures,
optimization experiments, characterization data, NMR spectra for new compounds
and HPLC traces. CCDC 1990722. For ESI and crystallographic data in CIF or other
electronic format see: DOI: 10.1039/x0xx00000x
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Table 1. Optimization of reaction conditionsa
Methyl ester derivative 1c afforded 3acViewinArticleloOwnliener
enantioselectivity (74% ee), while the iDnOtrIo: 1d0u.1c0t3io9/nD0oCfCb0u24lk7i8eCr
NR1R2
+
L* (11 mol%)
Pd(TFA)2 (10 mol%)
NR1R2
Ph
i
t
N
ester moieties (1d, R = Bn; 1e, R = Pr; 1f, R = Bu) had a
detrimental effect in reactivity, leading to products 3ad-af in
lower yields than 3ab, although with similar levels of
enantioselectivity (83-94% ee). It was therefore decided to
retain the ethyl ester scaffold and explore other alternative
removable N-protecting groups. Fmoc-derived hydrazone 1g
provided competitive results (70% yield, 87% ee), while Boc-
derived hydrazone 1h gave 3ah in high enantioselectivity (92%
ee), albeit in low yield (26%). Finally, the introduction of an
additional N-benzyl group in Cbz-protected hydrazone 1i
totally inhibited the reactivity, while PMP-protected hydrazone
1j reacted sluggishly to afford oxidized hydrazone 3aj’ instead
of the expected hydrazine 3aj.
HN
PhB(OH)2
Solvent, 60 °C
24 h
EtO2C
2a
EtO2C
1a,1b
3aa, 3ab
O
O
N
NR1R2
Ph
O
NH
O
Compound
1a, 3aa
1b, 3ab
Ph
N
O
X
N
N
N
N
tBu
L1
L2: X = H
L3: X = CO2Me
Ph
NR1R2
L2 (11 mol%)
Pd(TFA)2 (10 mol%)
NR1R2
N
HN
Entry
1
Solvent
L*
Yield (%)b
3
ee (%)c
PhB(OH)2
+
DCE, 60 °C
24 h
RO2C
1b-j
1
2
3
4
5
6
7
8
1a
1a
1a
(E)-1b
(E)-1b
(E)-1b
(E)-1b
(Z)-1b
TFE
TFE
TFE
TFE
TFE
DCE
DCE
DCE
L1
L2
L3
L1
L2
L2
L3
L2
52
82
86 (80)d
21
(R)-3aa
(S)-3aa
(S)-3aa
(R)-3ab
(S)-3ab
(S)-3ab
(S)-3ab
(S)-3ab
55
58
62
60
75
93
93
86
2a
RO2C
Ph
3
NHFmoc
HN
NHBoc
Ph
HN
NHCbz
56
HN
83 (75)d
87 (79)d
82
EtO2C
Ph
EtO2C
RO2C
Ph
3ag: 70%, 87% ee
3ah: 26%, 92% ee
3ab: R = Et, 75%, 93% ee
3ac: R = Me, 74%, 74% ee
3ad: R = Bn, 67%, 83% ee
3ae: R = iPr, 44%, 94% ee
3af: R = tBu, 38%, 86% ee
NBnCbz
HN
NHPMP
N
a
b
Reactions were performed under air on a 0.2 mmol scale. Yields were
determined by 1H NMR analysis of the crude reaction mixture using 1,3,5-
EtO2C
Ph
EtO2C
Ph
c
trimethoxybenzene as an internal standard. Determined by HPLC on chiral
stationary phases. d In parenthesis, isolated yield after column chromatography.
3ai: 0%
3aj’: 33%
Scheme 2. Screening for optimal hydrazone structure. Reactions were
performed under air on a 0.2 mmol scale. Isolated yields after column
chromatography. Enantiomeric excess (ee) determined by HPLC on
chiral stationary phases.
Diverse N,N-ligands13 bearing chiral oxazolines13b,c or C2-
symmetric hydrazones14 were evaluated (See S2 in the ESI‡). As
representative examples, pyridine-oxazoline L1 furnished 3aa
in 52% yield and 55% ee (entry 1, Table 1) while pyridine-
hydrazone L2 provided 3aa in better yield (82%), albeit in yet
moderate enantioselectivity (58% ee, entry 2). Structural
variations of the pyridine-hydrazone ligand were also
investigated without any improvement (See S3 in the ESI‡).
Only the introduction of an electron-withdrawing group
(CO2Me) at C5 of the pyridine ring (L3) led to similar or slightly
better results than those provided by L2 (entry 3). Next,
benzyloxycarbonyl (Cbz)-protected hydrazone (E)-1b was
selected as a model mono-carbamoyl substituted substrate.
Lower yields but better enantioselectivities were observed
(entries 4 and 5): 3ab was obtained in 56% yield and 75% ee
with L2. To our delight, a significant improvement was
observed by using dichloroethane (DCE) as the solvent (entries
6 and 7), affording 3ab in high yields (83-87%) and excellent
enantioselectivities (93% ee with both L2 or L3). A similar level
of reactivity, slightly lower enantioselectivity and the same
stereochemical outcome was observed in an additional
experiment employing (Z)-1b (entry 8), suggesting the
intervention of a common intermediate.
During the scaling-up at 0.4 mmol, we observed that the
presence of water had a strong impact in both yield and
enantioselectivity and was also possibly the origin of some
erratic data. Therefore, the remaining optimization studies
were performed in dry DCE with controlled amounts of water
(See S5 in the ESI‡). 0.6 Equiv. was found to be the optimal
amount, affording 3ab in good yield and without erosion of the
enantioselectivity [61%, 93% ee (L2); 69%, 94% ee (L3)].
Successive studies were aimed at analyzing the scope of the
reaction (Scheme 3). Thus, under optimized conditions, either
using L2 or L3 as the best option, Cbz- 1b and Fmoc-protected
1g reacted with a variety of arylboronic acids 2, affording α-
aryl α-hydrazino esters 3ab-hg in good yields (47-92%) and
good to excellent enantioselectivities (82-96% ee).
Electron-rich aryl boronic acids (p-Me-C6H4 and p-MeO-C6H4)
were suitable reagents. More challenging ortho-substituted
boronic acids, exemplified by 2d (o-Me-C6H4), also provided
the corresponding products 3db and 3dg in excellent
enantioselectivities (93-96% ee) and good yields (69-77%).
Electron-poor p-chlorophenylboronic acid 2e reacted slower
(<30% conversion to 3eb in 24 h) and prolonged reaction times
were required to increase conversions (up to 72% in 96 h).§
The influence of the structure of the ester moiety in the
glyoxylate hydrazone 1 was also investigated (Scheme 2).
2 | J. Name., 2012, 00, 1-3
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DOI: 10.1039/D0CC02478C
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L2 or L3 (11 mol%)
Pd(TFA)2 (10 mol%)
ArB(OH)2
NHPG
Ar
NHPG
HN
N
+
Z
Z
DCE, 60 °C
H2O (0.6 equiv.)
2
O
O
24 h
1
3
NHCbz
3ab: R = H, 69%, 94% ee (L3)
3bb: R = p-MeO, 92%, 94% ee (L3)
3cb: R = p-Me, 87%, 94% ee (L2)
3db: R = o-Me, 69%, 93% ee (L2)
3eb: R = p-Cl, 48%, 82% ee (L2)
HN
Ar =
EtO
R
Ar
O
Me
3fb: 77%, 87% ee (L2)
Me
O
Me
O
3hb: 63%, 92% ee (L2)
3gb: 70%, 91% ee (L3)
3ag: R = H, 81%, 92% ee (L3)
3bg: R = p-MeO, 78%, 92% ee (L2)
3cg: R = p-Me, 91%, 94% ee (L3)
3dg: R = o-Me, 77%, 96% ee (L3)
3eg: R = p-Cl, 47%, 87% ee (L2)
NHFmoc
HN
Ar =
EtO
O
O
R
Me
Me
Ar
Me
3fg: 89%, 85% ee (L2)
O
3hg: 52%, 96% ee (L2)
3gg: 70%, 93% ee (L3)
NHCbz
NHCbz
NHCbz
HN
Me HN
N
HN
H
BnHN
MeO2C
N
Bn
O
O
O
Me
Me
Me
3ck: 52%, 95% ee (L3)
3cl: 86%, 93% ee (L3)
3cm: 73%, 84% ee (L3)
Scheme 3. Reactions were performed under air on a 0.4 mmol scale. Isolated yields after column chromatography. Enantiomeric excesses (ee’s)
were determined by HPLC on chiral stationary phases.
transformed into deprotected α-aryl α-hydrazino ester 4a
Therefore, stopping the reaction at half conversion afforded which was isolated as its hydrochloride salt in 71% yield and
3eb (48 h) and 3eg (36 h) in 82% and 87% ee, respectively; 93% ee. Alternatively, a 2-step protection/base-promoted
consequently, in moderate yields (47-48%). Electron-rich di- deprotection protocol allowed to convert 3ag into N-
substituted boron reagents 2f,g were well tolerated, leading to aminopeptide precursor 5a in good overall yield (78%) and
3fb,fg and 3gb,gg in good yields (70-89%) and without erosion of enantioselectivity (93% ee). 5a was also
enantioselectivities (85-93% ee). Remarkably, a challenging 1- fully deprotected to 4a employing acidic conditions.
naphthyl boronic acid derivative 2h afforded α-hydrazino Additionally, hydrolysis of the ester moiety of 3cb was
esters 3hb,hg in good yields and enantioselectivities (92-96% efficiently performed under basic conditions to get free acid 6a
ee). We next investigated the asymmetric arylation of some in 85% yield. This compound is another key building block for
Cbz-protected hydrazones bearing amides. Gratifying, the synthesis of hydrazinopeptides. For example, a direct
employing optimized conditions and L3 as the best ligand, coupling with glycine methyl ester hydrochloride afforded α-
simple α-hydrazino amides 3ck and 3cl were obtained in tolyl α-hydrazino amide 3cm in 81% yield and 93% ee.
moderate to good yields (52-86%) and excellent Importantly this transformation proceeds without significant
enantioselectivities (93-95% ee). Glycine derivative 3cm was erosion of the chiral integrity during amide bond formation.§§
also synthesized in 73% yield, albeit in slightly lower The absolute configuration of 3ab was determined to be (S) by
enantioselectivity (84% ee). In order to evaluate the practical X-ray diffraction analysis. The absolute S configuration of
applicabbility of the developed methodology, the syntheses of products 3ag, 5a and 3cm were assigned by chemical
3ab (82%, 92% ee) and 3ag (85%, 92% ee) were performed on correlation.§§§ Assuming a uniform reaction pathway, the
1 mmol scale under slightly optimized reaction conditions [H2O absolute configurations of all other hydrazino esters and
(0.27 Equiv.), iterative addition of 2a (0.5-0.75 mmol/12 h)].
amides 3 were assigned by analogy.
To demonstrate the suitability of the carbamoyl protecting In summary, catalysts generated by combinations of Pd(TFA)2
groups in the developed strategy, complementary and pyridine-hydrazone ligands L2/L3 have shown excellent
deprotection conditions were applied to Cbz- and Fmoc- activities and enantioselectivities in the 1,2-addition of aryl
protected hydrazino esters 3ab and 3ag (Scheme 4). Applying boronic acids to N-carbamoyl (Cbz and Fmoc) protected
standard hydrogenolysis [Pd(C) / H2 (1 atm), rt] 3ab was glyoxylate-derived hydrazones, yielding α-aryl α-hydrazino
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COMMUNICATION
Journal Name
see the ESI‡). (b) The absolute S configuration Voiefw A3rtcicmle Ownlianes
esters/amides, key hydrazino acid derivatives. Moreover. the
orthogonal reactivity of the different carbamoyl groups offers
a versatile tool for the synthesis of hydrazinopeptides and N-
aminopeptides.
assigned by comparing HPLC traces of 3cm obtained from acid
DOI: 10.1039/D0CC02478C
(S)-6a with HPLC of 3cm obtained from direct arylation of amide
1m.
1
2
J. Vidal, Synthesis and chemistry of α-hydrazino acids, in
Amino Acids, Peptides and Proteins in Organic Chemistry:
Modified Amino Acids, Organocatalysis and Enzyme, ed. A. B.
Hughes, Wiley- VCH Verlag GmbH & Co. KGaA, Weinheim,
Germany, 2009, vol. 2.
(a) P. Burkhard, P. Dominici, C. Borri-Voltattorni, J. N.
Jansonius and V. N. Malashkevich, Nature Structural Biology
2001, 8, 963; (b) T. E. Delea, S. K. Thomas and M. Hagiwara,
CNS Drugs, 2011, 25, 53.
R. Günther and H.-J. Hofmann, J. Am. Chem. Soc., 2001, 123,
247.
S. S. Panda, C. El-Nachef, K. Bajaj and A. R. Katritzky, Eur. J.
Org. Chem. 2013, 19, 4156.
C. W. Kang, M. P. Sarnowski, Y. M. Elbatrawi and J. R. Del
Valle, J. Org. Chem. 2017, 82, 1833.
L. Bourel-Bonnet, E.-I Pécheur, C. Grandjean, A. Blanpain, T.
Baust, O. Melnyk, B. Hoflack and H. Gras-Masse,
Bioconjugate Chem. 2005, 16, 450.
Selected example: J. E. Taylor, D. S. B. Daniels and A. D.
Smith, Org. Lett. 2013, 15, 6058.
For a review, see: I. Avan, C. D. Hall and A. R. Katritzky,
Chem. Soc. Rev., 2014, 43, 3575. For selected examples, see:
J.-C. Hannachi, J. Vidal, J.-C. Mulatier and A. Collet, J. Org.
Chem., 2004, 69, 2367 and ref. 5.
NHCbz
HN
EtO
i) Pd (C) / H2 (1 atm)
ii) HCl / Et2O
Ph
71%
HN
O
(S)-3ab, 94% ee
NH2
Ph
EtO
O
3
4
5
6
O
N
(S)-4a-HCl: 93% ee
O
N
O
HCl / Dioxane
95%
NH2
O
NHFmoc
Boc
HN
N
i) Boc2O, DMAP, 0 °C
ii) Et2NH
EtO
EtO
Ph
Ph
O
O
7
8
(S)-5a: 78%, 93% ee
(S)-3ag, 92% ee
NHCbz
NHCbz
HN
HN
EtO
HO
LiOH, THF/ H2O
0 °C
O
O
Me
Me
(S)-6a: 85%
9
M. J. Burk, J. P. Martínez, J. E. Feaster and N. Cosford,
Tetrahedron, 1994, 50, 4399.
(S)-3cb, 94% ee
HBTU, DIPEA
NH2·HCl
CH2Cl2
MeO2C
MeO2C
10 (a) J. M. Keith and E. N. Jacobsen, Org. Lett. 2004, 6, 153; (b)
A. Zamfir and S. B. Tsogoeva, Org. Lett. 2010, 12, 188; (c) A.
Martínez-Muñoz, D. Monge, E. Martín-Zamora, E. Marqués-
López, E. Álvarez, R. Fernández and J. M. Lassaletta, Org.
Biomol. Chem. 2013, 11, 8247.
11 Selected examples: (a) S. Kobayashi, T. Hamada and K.
Manabe, J. Am. Chem. Soc. 2002, 124, 5640; (b) M. Fujita, T.
Nagano, U. Schneider, T. Hamada, C. Ogawa and S.
Kobayashi, J. Am. Chem. Soc. 2008, 130, 2914; (c) S. J. T.
Jonker, C. Diner, G. Schulz, H. Iwamoto, L. Eriksson and K. J.
Szabo, Chem. Commun., 2018, 54, 12852.
12 An example of enantioselective arylation of benzoyl-
protected hydrazones by Friedel-Craft employing
stochiometric amounts of a chiral silane: (a) S. Shirakawa, R.
Berger and J. L. Leighton, J. Am. Chem. Soc. 2005, 127, 2858.
Sporadic catalytic enantioselective example: (b) L. C. Morrill,
T. Lebl, A. M. Z. Slawin and A. D. Smith, Chem. Sci. 2012, 3,
2088.
NHCbz
HN
H
N
O
Me
(S)-3cm: 81%, 93% ee
Scheme 4. ORTEP drawing of (S)-3ab and representative deprotections
and transformations
This work was supported by the Spanish MINECO (CTQ2016-
76908-C2-1-P, CTQ2016-76908-C2-2-P and predoctoral
fellowship to S. A.), European FEDER funds and the Junta de
Andalucía (Grants P18-FR-3531 and P18-FR-644). We also
thank general NMR/MS services of the University of Sevilla.
13 For a review, see: (a) X. Chen and Z. Lu, Org. Biomol. Chem.
2017, 15, 2280. Selected examples: Pd(II)-catalyzed
arylations: (b) J. Chen, X. Lu, W. Lou, Y. Ye, H. Jiang and W.
Zeng, J. Org. Chem. 2012, 77, 8541; (c) H. Dai, M. Yang and X.
Lu, Adv. Synth. Catal. 2008, 350, 249; (d) X.-H. Wei, G.-W.
Wang and S.-D. Yang, Chem. Commun., 2015, 51, 832. (e) T.
Beisel, A. M. Diehl and G. Manolikakes, Org. Lett. 2016, 18,
4116. (f) M. Quan, G. Yang, F. Xie, I. D. Gridnev and W.
Zhang, Org. Chem. Front., 2015, 2, 398.
14 (a) A. Bermejo, A. Ros, R. Fernández and J. M. Lassaletta, J.
Am. Chem. Soc. 2008, 130, 15798; (b) Y. Álvarez-Casao, D.
Monge, E. Álvarez, R. Fernández and J. M. Lassaletta, Org.
Lett. 2015, 17, 5104; (c) Y. Álvarez-Casao, B. Estepa, D.
Monge, A. Ros, J. Iglesias-Sigüenza, E. Álvarez, R. Fernández
and J. M. Lassaletta, Tetrahedron 2016, 72, 5184; (d) M. G.
Retamosa, Y. Álvarez-Casao, E. Matador, A. Gómez, D.
Monge, R. Fernández and J. M. Lassaletta, Adv. Synth. Catal.
2019, 361, 176.
Notes and references
§ A decrease of the enantiomeric purity over reaction time was
observed independently of the nature of the aryl boronic acid
employed. Control experiments suggests that this fact is not due
to a racemization process of the products under the reaction
conditions and might instead be
a consequence of the
hemilabile performance of the ligand (hydrazone fragment),
leading to conversion by less-selective catalytic species (see ref
14d).
§§ Carbamoyl-protected L-arylglycines are extremely prone to
epimerization/racemization during the activation of carboxylic
acid by standard coupling reagents in peptide synthesis. See: (a)
G. G. Smith and T. Sivakua, J. Org. Chem. 1983, 48, 627; (b) W.
Muramatsu, T. Hattori and H. Yamamoto, J. Am. Chem. Soc.
2019, 141, 12288, and references therein.
§§§ (a) The absolute S configurations of 3ag and 5a were
assigned by deprotection of 5a and subsequent transformation
of hydrochloride salt (S)-4a-HCl into (S)-3ab (for HPLC analysis,
4 | J. Name., 2012, 00, 1-3
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DOI: 10.1039/D0CC02478C
Asymmetric 1,2-addition of aryl boronic acids to N-carbamoyl (Cbz and Fmoc) protected glyoxylate-
derived hydrazones affords α-aryl α-hydrazino esters/amides, key building blocks en route to artificial
peptides.