The topics I came across during the period I spent as a Ph.D. student are mainly two. The first concerns
new organocatalytic protocols for Mannich-type reactions mediated by Cinchona alkaloids derivatives
(Scheme I, left); the second topic, instead, regards the study of a new approach towards the enantioselective
total synthesis of Aspirochlorine, a potent gliotoxin that recent studies indicate as a highly selective and
active agent against fungi (Scheme I, right).
At the beginning of 2005 I had the chance to join the group of Prof. Alfredo Ricci at the Department of
Organic Chemistry of the University of Bologna, starting my PhD studies. During the first period I started to
study a new homogeneous organocatalytic aza-Henry reaction by means of Cinchona alkaloid derivatives as
chiral base catalysts with good results. Soon after we introduced a new protocol which allowed the in situ
synthesis of N-carbamoyl imines, scarcely stable, moisture sensitive compounds. For this purpose we used
α-amido sulfones, bench stable white crystalline solids, as imine precursors (Scheme II).
In particular we were able to obtain the aza-Henry adducts, by using chiral phase transfer catalysis, with a
broad range of substituents as R-group and excellent results, unprecedented for Mannich-type
transformations (Scheme II).
With the optimised protocol in hand we have extended the methodology to the other Mannich-type
reactions. We applied the new method to the Mannich, Strecker and Pudovik (hydrophosphonylation of
imines) reactions with very good results in terms of enantioselections and yields, broadening the usefulness
of this novel protocol.
The Mannich reaction was certainly the most extensively studied work in this thesis (Scheme III).
Initially we developed the reaction with α-amido sulfones as imine precursors and non-commercially
available malonates with excellent results in terms of yields and enantioselections.3 In this particular case we
recorded 1 mol% of catalyst loading, very low for organocatalytic processes. Then we thought to develop a
new Mannich reaction by using simpler malonates, such as dimethyl malonate.4 With new optimised
condition the reaction provided slightly lower enantioselections than the previous protocol, but the Mannich
adducts were very versatile for the obtainment of β3-amino acids. Furthermore we performed the first
addition of cyclic β-ketoester to α-amido sulfones obtaining the corresponding products in good yield with
high level of diastereomeric and enantiomeric excess (Scheme III).
Further studies were done about the Strecker reaction mediated by Cinchona alkaloid phase-transfer
quaternary ammonium salt derivatives, using acetone cyanohydrin, a relatively harmless cyanide source
(Scheme IV). The reaction proceeded very well providing the corresponding α-amino nitriles in good yields
and enantiomeric excesses.
Finally, we developed two new complementary methodologies for the hydrophosphonylation of imines
(Scheme V). As a result of the low stability of the products derived from aromatic imines, we performed the
reactions in mild homogeneous basic condition by using quinine as a chiral base catalyst giving the α-aryl-α-amido phosphonic acid esters as products (Scheme V, top).6 On the other hand, we performed the addition of
dialkyl phosphite to aliphatic imines by using chiral Cinchona alkaloid phase transfer quaternary ammonium
salt derivatives using our methodology based on α-amido sulfones (Scheme V, bottom). The results were
good for both procedures covering a broad range of α-amino phosphonic acid ester.
During the second year Ph.D. studies, I spent six months in the group of Prof. Steven V. Ley, at the
Department of Chemistry of the University of Cambridge, in United Kingdom. During this fruitful period I
have been involved in a project concerning the enantioselective synthesis of Aspirochlorine. We provided a
new route for the synthesis of a key intermediate, reducing the number of steps and increasing the overall
yield. Then we introduced a new enantioselective spirocyclisation for the synthesis of a chiral building block
for the completion of the synthesis (Scheme VI).
| Identifer | oai:union.ndltd.org:unibo.it/oai:amsdottorato.cib.unibo.it:1047 |
| Date | 15 April 2008 |
| Creators | Fini, Francesco <1979> |
| Contributors | Ricci, Alfredo |
| Publisher | Alma Mater Studiorum - Università di Bologna |
| Source Sets | Università di Bologna |
| Language | English |
| Detected Language | English |
| Type | Doctoral Thesis, PeerReviewed |
| Format | application/pdf |
| Rights | info:eu-repo/semantics/openAccess |
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