Spain coach Vicente del Bosque on Friday rang the changes as he announced his squad for next week's friendly away to Ecuador.
A host of senior players who featured in the side that reached the final of the recent Confederations Cup have been rested for the game across the Atlantic on Wednesday, which comes just three days before the start of the new season in La Liga.
In their place come several members of the team that won the European Under-21 Championship in Israel in June, including Real Sociedad defender Inigo Martinez, Atletico Madrid midfielder Koke, Barcelona winger Cristian Tello, Real Madrid new-boy Isco and Thiago Alcantara, who captained the under-21 team to glory before signing for Bayern Munich.
There are also recalls for Fernando Llorente and Alvaro Negredo, two strikers who have moved abroad in the close season, joining Juventus and Manchester City respectively.
Among those to be rested are the Barcelona quartet of Gerard Pique, Sergio Busquets, Xavi Hernandez and Pedro Rodriguez, and injured duo Xabi Alonso and Juan Mata.
The match in Guayaquil comes before Spain travel to Finland in a World Cup qualifier on September 6.
Goalkeepers: Iker Casillas (Real Madrid), Jose Manuel Reina (Napoli/ITA), Victor Valdes (Barcelona) Defenders: Alvaro Arbeloa, Sergio Ramos (both Real Madrid), Inigo Martinez (Real Sociedad), Raul Albiol (Napoli/ITA), Cesar Azpilicueta (Chelsea/ENG), Jordi Alba (Barcelona)
Midfielders: Javier Martinez, Thiago Alcantara (Bayern Munich/GER), Koke Resurreccion (Atletico Madrid), Cesc Fabregas, Andres Iniesta (Barcelona), Francisco Alarcon 'Isco' (Real Madrid), Santiago Cazorla (Arsenal/ENG), Jesus Navas (Sevilla), David Silva (Manchester City/ENG)
Forwards: Alvaro Negredo (Manchester City/ENG), Fernando Llorente (Juventus/ITA) Cristian Tello (Barcelona)