Spiroaminals – Crystal Structure and Computational Investigation of Conformational Preferences and Tautomerization Reactions

Abstract

We report the first X‐ray structure of a spiroaminal hydrochloride. The chiral spiroaminal crystallizes as a racemic hydrochloride in the monoclinic space group P21/n and adopts the thermodynamically most stable conformation. Density functional calculations on several spiroaminals were used to establish correlations between trends in conformational energies, steric repulsions, and anomeric effects and to reveal the mechanism of the ring‐opening tautomerization reaction. In the unsubstituted and backbone‐substituted spiroaminals, the aminal tautomer is thermodynamically preferred. N‐Substituted spiroaminals favor the amine/imine form for steric reasons, except for those with bridging N,N′ groups. The tautomerization from the aminal to the amine/imine is endergonic and kinetically hindered in the neutral species but quite facile after protonation. Anomeric effects lower the barriers but are less important than steric factors for relative energies.

Bidirectional Synthesis of Di-tert-butyl (2S,6S,8S)- and (2R,6R,8R)-1,7-Diazaspiro[5.5]undecane-2,8-dicarboxylate and Related Spirodiamines

“…It is noteworthy that the stereochemistry of the resultant spirane center is controlled by the absolute stereochemistry of the ring substituents together with the double anomeric effect as observed with derivatives of 1,7-dioxaspiro[5.5]undecane (1). 11 In our work, spirodiamine 39 was only observed as a single diastereoisomer and showed no spirane center epimerization on even on storage in chloroform solution over 48 hours or over 6 months as a solid sample (Figure 3). The double Horner-Wadsworth-Emmons homologation process was also applied for the conversion of the enantiomeric (R)aldehyde 37 19 into the enantiomeric (R,R,R)-spirodiamine 39 (48%) {[]D = -5.5} (Scheme 6).…”

“…Within our group we have reported the synthesis of both aliphatic and benzannulated spirodiamines alongside studies of their reactivity with organic and inorganic electrophiles. [9][10][11] Herein we report alternative methods for the synthesis of more complex examples of spirodiamines utilizing bidirectional homologation strategies, which are concise but also ensure high enantiomeric purities with chiral derivatives as a result of the operation of the Horeau effect 12 (Scheme 1). In an improvement of the early work of Büchel 13 and Kaupp, 14 our original approach to spiroaminal 3, consisted of the self-Claisen condensation reaction of N-Boc-valerolactam (8) to produce lactam 14, followed by two-step decarboxylative spirocyclization via intermediate 15.…”

“…This lack of study is presumably due to the scarcity of the spirodiamine functionality in natural products, and the limited methods available for their synthesis. A selection of spirodiamine containing natural products are illustrated in Figure ,. − Within our group we have reported the synthesis of both aliphatic and benzannulated spirodiamines alongside studies of their reactivity with organic and inorganic electrophiles. − Herein we report alternative methods for the synthesis of more complex examples of spirodiamines utilizing bidirectional homologation strategies, which are concise but also ensure high enantiomeric purities with chiral derivatives as a result of the operation of the Horeau effect (Scheme ).…”

“…It is noteworthy that the stereochemistry of the resultant spirane center is controlled by the absolute stereochemistry of the ring substituents together with the double anomeric effect as observed with derivatives of 1,7-dioxa­spiro­[5.5]­undecane ( 1 ) . In our work, spirodiamine 39 was only observed as a single diastereoisomer and showed no spirane center epimerization even on storage in chloroform solution over 48 h or over 6 months as a solid sample (Figure ).…”

Synthesis and Reactions of Benzannulated Spiroaminals: Tetrahydrospirobiquinolines

“…There is a need to expand the structural classes of amines, especially to those that are C-(sp 3 )-rich, to enhance the structural complexity and for better interaction with biological targets . Whereas spiroketals, including benzannulated systems, − are common scaffolds in biologically active heterocyclic compounds and spirocyclic compounds with a single oxygen and single aminonitrogen attached to the spirane center are known, , spirodiamines, which contain two amino-groups at that center, are far less well studied. − The spirodiamine core is known in several natural products, including (−)-isochizogamine ( 1 ), − isoschizogaline ( 2 ), (+)-melodinine-E ( 3 ), − and the immunosuppressant (±)-spiroreticulatine ( 4 ) (Figure ) …”