A Carbodiimide-Mediated P-C Bond-Forming Reaction: Mild Amidoalkylation of P-Nucleophiles by Boc-Aminals

Amidoalkylation of P ‑Nucleophiles by Boc-Aminals

Letter

A Carbodiimide-Mediated P−C Bond-Forming Reaction: Mild

Paraskevi Kokkala, Thayalan Rajeshkumar, Anastasia Mpakali, Efstratios Stratikos,

Konstantinos D. Vogiatzis,* and Dimitris Georgiadis*

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sı Supporting Information

ABSTRACT: The ﬁrst example of a carbodiimide-mediated P−C bond-

forming reaction is described. The reaction involves activation of β-

carboxyethylphosphinic acids and subsequent reaction with Boc-aminals

using acid-catalysis. Mechanistic experiments using P NMR spectroscopy

and DFT calculations support the contribution of unusually reactive cyclic

phosphinic/carboxylic mixed anhydrides in a reaction pathway involving ion-

pair “swapping”. The utility of this protocol is highlighted by the direct

synthesis of Boc-protected phosphinic dipeptides, as precursors to potent Zn-

aminopeptidase inhibitors.

hosphinic peptides constitute a class of bioactive

condensation between H-phosphinic acids, aldehydes, and

carbamates. The main drawback of these protocols is the

compounds that exhibit remarkable inhibitory properties

harsh conditions employed that are incompatible with acid-

against Zn-metallopeptidases. Proper tuning of their structural

features has successfully led to highly potent and selective

sensitive substrates. Aiming to address this issue, in this

report we present a general, mild methodology which is based

on the first use of carbodiimides for the formation of a P−C bond.

During the course of our studies on aminopeptidase

inhibitors of medicinally relevant carboxypeptidases, amino-

peptidases, and endopeptidases. Synthetic approaches toward

these structures fall into two main categories: the NP + C

approach which allows diversiﬁcation of the C-terminus (P₁

position) and the less common N + PC approach which oﬀers

3a,c

inhibitors,

we became interested in a synthetic protocol

that would oﬀer possibilities for the late-stage P -diversiﬁcation

of Boc-protected building blocks. Our initial eﬀorts were

focused on the amidoalkylation of phosphinic acid 2a (Table

the possibility to assemble the N-terminus (P position) at a

1c,5

late stage of the synthesis. For the latter case, the main tool

) by using Boc-NH₂and various aldehydes. However,

to achieve such a transformation is the Birum−Οleksyszyn

application of existing protocols using diﬀerent combinations

reaction, as it was modiﬁed by the research groups of Yuan,

of AcCl, Ac O, and acidic catalysts led consistently to low

Coward, Yiotakis, and Ragulin (Scheme 1), which involves a

yields and byproducts related to Boc-cleavage and subsequent

N-acetylation. In 2012, Ragulin et al. reported that milder

conditions can be achieved by replacing the carbamate/

Scheme 1. Amidoalkylation of Phosphinic Acids

aldehyde dyad with the respective aminals (Scheme 1).

Inspired by the work of Maruoka who introduced Boc-aminals

,10

as imine equivalents in acid-catalyzed Mannich reactions,

we envisioned that Boc-aminals could tolerate Ragulin’s

conditions. Indeed, by using TFAA the yields were signiﬁcantly

improved, however side-acylation was not completely sup-

pressed (Table 1, entries 1,2). These observations prompted us

to explore nonacylating conditions for the reaction, based on

the absence of any acylated P(III)-species in the P NMR

Received: January 14, 2021

Published: February 22, 2021

2021 American Chemical Society

726

Org. Lett. 2021, 23, 1726−1730

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Letter

Table 1. Optimization Experiments

entry

DA (equiv)

LA (equiv)

time (h)

NMR yield (%)

TFAA (1)

TFAA (2)

DCC (1)

DIC (1)

32 (24)

48 (35)

3.5

1.3

Cu(OTf) (0.1)

TMSOTf (0.5)

BF ·OEt (0.8)

BF ·OEt (0.1)

BF ·OEt (0.2)

Substrates 1 and 2 (0.2−0.4 mmol, 0.3 M), CDCl , inert atmosphere. Conversion to side-acylation byproducts in parentheses. Determined by

P NMR of the reaction mixture. Solvent: CH Cl . Determined by P NMR after aqueous workup. 13% Boc-cleavage, 33% silylation

byproducts.

spectra of reaction mixtures with 1 or 2 equiv of TFAA. We

assumed that TFAA may act as a dehydrating agent, rather

than an acylating one, and therefore, we reasoned that N,N-

carbodiimides may be suitable to mediate such trans-

formations. To our delight, with 1a and 1 equiv of DCC,

phosphinic acid 2a furnished 41% of 3a after 24 h (Table 1,

entry 3). Moreover, aminal 1b furnished 10% of product 3b in

Scheme 2. Formation of Reactive Intermediates 4a and 4a′

Monitored by ³¹P-NMR

.5 h, reaching an 87% conversion after 3 days (Table 1,

entries 4,5). This unique reactivity was further enhanced by the

addition of an acid catalyst, with BF ·OEt rendering the most

eﬃcient choice (Table 1, entries 6−8). In addition, an

impressive improvement was observed when DCC was

replaced by DIC, leading to 92% conversion of 1b in only

.3 h (Table 1, entry 11). Interestingly, when phosphinic acid

a′ was subjected at the same reaction conditions, only a 10%

P NMR signals are shifted downﬁeld when TFAA is used due to

released TFA that interacts with PO. All P NMR spectra are

formation of product 3b′ was observed after 24 h (Table 1,

entry 12), implying that the C-terminal of phosphinic

substrates contributes to the reactivity of P-nucleophiles.

In 1993, Campagne and co-workers proposed that

phosphinic diacids may cyclize by a coupling reagent (BOP)

proton decoupled.

DFT calculations to estimate the Gibbs free energies (ΔG) of

the prototropic P(V)/P(III) tautomerism for model com-

pounds 5a−c (Scheme 3). Strikingly, the tautomerism of cyclic

2,13

toward mixed anhydride species.

By monitoring the

reaction of diacid 2a with 1.0 equiv DCC by P NMR

spectroscopy, we observed rapid formation of two signals,

which was attributed to the two diastereoisomeric forms of

proposed intermediate 4a (Scheme 2). Interestingly, in a

separate experiment the same intermediate was observed when

Scheme 3. Gibbs Free Energies (ΔG) for the Tautomerism

of Model Compounds 5a−c Computed at the B3LYP-

D3(BJ)/def2-TZVPP Level of Theory

equiv of TFAA were employed. This was unambiguously

conﬁrmed by the formation of only one set of two signals when

a mixture of DCC (0.5 equiv) and TFAA (1.0 equiv) was used,

leading to the conclusion that the activated intermediate of the

reaction is irrelevant of the condensating agent. With

phosphinic acid 2a′, TFAA (1.0 equiv) and DIC (1.0 equiv)

generated a very similar ³¹P NMR proﬁle; only this time a

multiplet was observed rather than two signals. We suggest that

this multiplet corresponds to symmetric anhydride 4a′, also a

anhydride 5a is 5.8 and 6.3 kcal/mol less endothermic than the

tautomerism of its symmetric (5b) and asymmetric (5c)

acyclic anhydride counterparts, respectively. This observation

justiﬁes the experimentally observed increased reactivity of 4a,

dehydration product, albeit much less reactive.

Aiming to rationalize the diﬀerence in observed reactivity

between proposed intermediate anhydrides, we performed

as compared to 4a′. Interestingly, apart from the ability of 4a

to react even in the absence of an acid catalyst, additional

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Org. Lett. 2021, 23, 1726−1730

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Letter

evidence of its high reactivity is its tendency to rapidly oxidize

upon contact with air.

Scheme 5. Ion Pair “Swapping” Mechanistic Hypothesis

In order to explore the scope of this new P−C bond-forming

reaction, we synthesized a series of derivatives (3b−3k) by

using the corresponding Boc-aminals (1b−1k) that incorpo-

rate diverse aryl, alkenyl, alkynyl, as well as cyclic or acyclic

alkyl substituents (Scheme 4). In all cases, the reaction

Scheme 4. Substrate Scope for the DIC-Mediated

a,c

Amidoalkylation Reaction

anionic parts of ion pairs A and B. By performing DFT

calculations, we computed the Gibbs free energy of this

exchange, and we found that the process was highly exothermic

(

ΔG = −29.2 kcal/mol). This stabilization may be partially

attributed to the lower acidity of Boc-NH as compared to

phosphinic intermediate 5a′. Upon removal of Boc-NH from

the equilibrium, the P-nucleophile is positioned in close

proximity to the iminium ion, an arrangement that can be

further stabilized by a bridging eﬀect of BF (see Supporting

Information ). Ion pair B is expected to collapse rapidly to

intermediate 6, allowing the formation of a stable P−C bond

which cannot further dissociate. Further theoretical and

experimental conﬁrmation of proposed mechanistic hypothesis

is currently underway.

Apart from its simplicity and eﬃciency, the proposed

protocol may provide facile access to P -diversiﬁed Zn-

aminopeptidase inhibitors after standard TFA-deprotection.

To this regard, samples of 3b,c, and i were deprotected and

tested for their inhibitory potency against M1 aminopeptidase

IRAP, leading to IC ₅ ₀ values of 0.16, 4.17, and >10 μΜ,

respectively (see Supporting Information). By this technique,

SAR data can be rapidly collected: for example, by comparing

inhibitors derived from 3b and 3i it is concluded that IRAP

may easily accommodate aromatic rings (phenylglycine

surrogates) but not aliphatic rings in its P position. Taken

together, the expansion of structural variety that can be

achieved by the proposed protocol and the direct access to P₁-

diversiﬁed candidate inhibitors, this approach is expected to

facilitate drug discovery eﬀorts involving medicinally important

Zn-peptidases.

DIC was added at 0 °C in a mixture of 1 and 2a in CH Cl , followed

by the addition of the catalyst, and then the mixture was stirred at rt.

All reactions were performed under Ar atmosphere. Isolated yields are

shown. 0.5 equiv of BF ·Et O was used. In all cases, except 3l, the

ﬁnal products were obtained as a ∼1:1 mixture of diastereoisomers.

In summary, we have developed a carbodiimide-mediated

P−C bond-forming reaction between Boc-aminals and

phosphinic diacids of type 2, based on the observation that

amidoalkylation is driven by condensing rather than acylating

conditions. Moreover, to the best of our knowledge this is the

ﬁrst example of a carbodiimide-mediated reaction where the

reagent activates the nucleophile and not the electrophile, as it

is usually the case. Based on our mechanistic experiments, the

unique reactivity of cyclic mixed anhydride intermediates of

type 2a is attributed to their highest propensity to tautomerize,

as compared to symmetric anhydrides that are proposed to

mediate amidoalkylation of esters of type 2a′. The reaction is

operationally simple, compatible with acid-labile groups and

applicable to a wide range of substrates, facilitating the late-

performed well aﬀording compounds of type 3 in good to high

yields after chromatographic puriﬁcation. A noteworthy

observation is that alkynyl derivative 1h was found to be the

least reactive among tested aminals, contrary to reactivity

patterns reported by Maruoka et al. in Mannich-type reactions

involving Boc-aminals. Presumably, mechanistic diﬀerences

between these reactions may underlie the observed deviations.

Finally, Gly (3l), Leu (3m), Asp (3n), and Orn (3o) amino

acid surrogates were eﬃciently prepared, emphasizing the

compatibility of the reaction with diﬀerent side-chains and

acid-sensitive protecting groups.

Concerning the reaction mechanism and in accordance with

previous observations by Maruoka et al., we were also unable

to identify accumulation of imine or iminium ions by

monitoring the reaction by NMR spectroscopy. We envisioned

stage P -diversiﬁcation of phosphinic peptides. Finally, a

mechanistic hypothesis is formulated which involves a

thermodynamically favorable ion pair “swapping” process.

Further mechanistic studies and application of the proposed

protocol to the discovery of Zn-aminopeptidase inhibitors are

currently in progress.

that the unfavorable BF -catalyzed dissociation of Boc-aminal

b would form ion pair A that could participate in a second

equilibrium with ion pair B (Scheme 5). The latter would

involve the release of Boc-NH through a hydrogen transfer

process which allows an overall “swapping” between the

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Org. Lett. 2021, 23, 1726−1730

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The Supporting Information is available free of charge at

Letter

ASSOCIATED CONTENT

sı Supporting Information

Charitable Trust. T.R. and K.D.V. would like to acknowledge

the University of Tennessee for ﬁnancial support of this work

■

(

start-up grant) and the Advanced Computing Facility (ACF)

https://pubs.acs.org/doi/10.1021/acs.orglett.1c00155.

of the University of Tennessee for computational resources.

D.G. would also like to thank Prof. Alexandros Zografos

(Aristotle University of Thessaloniki) for helpful discussions.

Detailed experimental procedures and characterization

data for all new compounds, enzymatic data, computa-

tional details for the DFT calculations; Cartesian

coordinates for all optimized structures (PDF)

DEDICATION

■

This work is dedicated to Prof. Athanasios Yiotakis, on the

occasion of his 79th birthday.

AUTHOR INFORMATION

Corresponding Authors

■

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Dimitris Georgiadis − Department of Chemistry, Laboratory

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Efstratios Stratikos − National Centre for Scientiﬁc Research

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Kapodistrian University of Athens, 15784 Athens, Greece;

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D.G. conceived and supervised the project. P. K. performed the

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experiments. T.R. and K.D.V. designed and performed

computational analysis. D.G. wrote the manuscript with the

contributions of all authors. All authors have given approval to

the ﬁnal version of the manuscript.

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The authors declare no competing ﬁnancial interest.

ACKNOWLEDGMENTS

■

D.G. and P.K. would like to acknowledge support by the State

Scholarships Foundation (IKY) for P.K. under the “Granting

Scholarships for Postgraduate Studies of the second-cycle

(

PhD)” Action of the operational programme “Development

d) Grembecka, J.; Mucha, A.; Cierpicki, T.; Kafarski, P. The Most

of Human Resources, Education and Lifelong Learning”

cofunded by the European Social Fund (ESF) and National

Resources (NSRF 2014-2020). D.G. would like to acknowl-

edge support by funds from the Special Account for Research

Grants of NKUA (Account Nos: 10504 and 16672). E.S.

acknowledges ﬁnancial support from the Harry J. Lloyd

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