Siloxycyclopropanes in Ugi Four-Component Reaction: A New Method for the Synthesis of Highly Substituted Pyrrolidinone Derivatives

Abstract

Reaction of methyl trimethylsiloxycyclopropanecarboxylates 3 with amino acids, tert-butylisonitrile and methanol furnished amino diacid derivatives 2 as the result of an Ugi 5-center 4-component reaction. This one-pot reaction involves b-formyl esters such as 1 as intermediate, which are liberated in situ. Adducts 2 could be thermally cyclized to provide g-lactams 4 in good yields.The multi component reaction was combined with this cyclization process to a fairly efficient one-pot procedure. Thus, cyclopropane derivative 3a was converted into g-lactam 4a in good yield. Two of the g-lactams 4 were reduced with lithium aluminum hydride to give pyrrolidine derivatives 5. Based on an X-ray analysis of the major diastereomer of compound 5d, the diastereoselectivity of the 4-component reaction is discussed.

Asymmetric Multicomponent Reactions (AMCRs): The New Frontier

“…[118] On the other hand, when the reaction was performed with functionalized aromatic aldehydes the newly formed stereogenic center proved to have the R configuration, [119] which contradicts the previous results. Moreover, when the reaction was performed with aliphatic alkoxycarbonyl aldehyde derivatives the absolute configuration of the new stereocenter was deduced as R (according to X-ray crystallography), and the stereochemical course of the reaction was explained simply by changing the above geometry of the imine from Z to E. [120] Therefore, a general mechanistic interpretation requires more experimental investigations.…”

Asymmetric Isocyanide‐Based MCRs

“…The U-5C-4CR with a-aminoacids typically leads to diastereoselectivities ranging from good to very good, as illustrated by the examples reported in Scheme 1.24, and has been exploited by different research groups [62][63][64][65][66][67][68][69][70][71]. Reactions are usually carried out at À30 C and the temperature is then left to rise to 0 C or room temperature; however, it is worth noting that, by performing the same reactions at room temperature, the diastereoselectivity seems not to be affected (see for example compound 66 [64]).…”

“…Reactions are usually carried out at À30 C and the temperature is then left to rise to 0 C or room temperature; however, it is worth noting that, by performing the same reactions at room temperature, the diastereoselectivity seems not to be affected (see for example compound 66 [64]). It is also interesting to note that diastereoselectivity usually increases when bulky aminoacids (see for example compound 62 [62] using valine) and aldehydes (see for example compound 63 [67] using isobutyraldehyde) are used; similar considerations apply when comparing, for example, compounds 64 and 65 [69] or compounds 66 and 67 [70] Sung et al [71] attempted to explain the reasons for the observed stereoselectivities on the basis of the mechanism outlined in Scheme 1.25: it is assumed that the cyclic intermediate 68 is formed under thermodynamic control and can equilibrate to the more stable isomer before being attacked by the external nucleophile. When the aminoacid has a bulky side chain (for example Y ¼ i-Pr), the cyclohexyl intermediate 68 will preferentially dispose this chain in the equatorial position.…”

Linear and Cyclic Hybrids of Alternating Thiophene–Amino Acid Units: Synthesis and Effects of Chirality on Conformation and Molecular Packing

“…In recent years, our group has explored the synthesis and reactivity of 5-aminothiophenecarboxylic acids [11] obtained by a three-component Gewald reaction [12][13][14][15] using methyl 2-siloxycyclopropanecarboxylates A as equivalents of functionalized aldehydes B (Scheme 1). [15,16] This process gives direct access to compounds C, which can be considered as unnatural amino acids with a thiophene backbone and as isosteres of dipeptides D. The ready accessibility of the unique amino acids C opens new prospects for the preparation of a variety of novel linear and cyclic peptidomimetics containing thiophene moieties.…”