Study towards γ-lactâmic cores synthesis from α-nitroketones

Study towards γ-lactâmic cores synthesis from α-nitroketones

Daphne Cristina da Silva Ferreira (PG), Vera Lúcia Patrocinio Pereira (PQ)*
Instituto de Pesquisas de Produtos Naturais (IPPN), Centro de Ciência da Saúde (CCS) – Universidade Federal do Rio de Janeiro (UFRJ), Cidade Universitária, Rio de Janeiro, RJ, Brasil
*[email protected]

The World Health Organization (WHO) has expressed great concern about the increased bacterial resistance to currently available antibiotics.1 Among the various classes of antibiotics available on the market, β-lactam are of great interest for even after decades of its discovery, this class of medicine is still the most used for treating infectious diseases both in outpatient and in hospitals.2
Due to the increasing bacterial resistance to this class of antibiotics, it is necessary to search for new effective agents, so the interest arises for γ-lactams, which are viable alternatives present in many natural products and have extensive biological activities.3 The presence of activated amide binding has been related to biological activity, thus a great interest arises in the studies of this nucleus.3
This work aims to access new γ-lactam nuclei through an unexplored route, using as the key intermediate the chiral α-nitroketones.
We used as starting material the natural L-phenylalanine 1, which was subjected to tribenzylation generating the phenylalanine ester4 2, followed by a reduction reaction, resulting in the corresponding aminoalcohol4 3. Subsequent Swern oxidation led to aldehyde4 4. This was reacted with nitromethane leading to the formation of nitroalcohol4 5 (Scheme 1).

Scheme 1: Synthetic route to access α-nitroketone.

The nitroalcohol 5 was oxidized to α-nitroketone 6 using PCC or PV-PCC (Table 1).

Table 1: Synthesis of α-nitroketone.

Entry Oxidizing Agent Yields
1 PV-PCC 2 mol% / H5IO6 1.1 eq. 54%
2 PV-PCC 10 mol% / H5IO6 1.1 eq. 49%
3 PCC 10 mol% / H5IO6 1.1 eq. 52%
4 PCC 10 mol% / H5IO6 1.2 eq. 59%
All reactions were processed in 2 weeks and room temperature

To access the γ-lactam core 7, the α-nitroketone 6 will be submitted to carboetoxyolefination reaction, followed of reduction of the nitro group and lactamization in one pot (see table 1).

Bibliographic References

1 - WHO - https://www.who.int/en/news-room/fact-sheets/detail/antimicrobial-resist..., accessed in 08/09/2019 às 20:30.
2 - Suarez, C., Gudiol F. Enferm Infecc Microbiol Clin. 2009, 27, 116–129.
3 - Caruano, J. et al. Org. Biomol. Chem. 2016, 43, 10134.
4 - Pereira, V. et al. Beilstein J. Org. Chem. 2013, 9, 832–837.