Ryan Giggs, Wayne Rooney, Patrice Evra, Ji-sung Park and Darren Fletcher will all miss United's Champions League trip to CSKA Moscow.
The five players - many of them probable starters in Sir Alex Ferguson's strongest line-up - were absent from the squad flying out of Manchester on Monday afternoon.
There is an element of speculation over which position Manchester United manager Sir Alex Ferguson will bolster first this summer. With Owen Hargreaves' long-term injury jeopardising his career, the Scot could recruit in central midfield, but Darren Fletcher is hoping that his ball-winning and hard-running performances this season have convinced his boss that he is the man for a starring role.
Manchester United's second string could decide the Premier League's relegation battle when they face Hull City on the final day.
Manchester United midfielder Darren Fletcher will miss the Champions League final after Uefa rejected an appeal against his red card in the semi-final.
The 25-year-old was controversially sent off in the second leg of United's 4-1 aggregate win against Arsenal.
Italian referee Roberto Rosetti sent Fletcher off for what he saw as a foul on Cesc Fabregas and awarded a penalty.
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He may not be the new England captain but Rio Ferdinand will line up for his country tonight as Fabio Cappello’s side host Czech Republic at Wembley (20:00 BST).
John Terry was handed the armband yesterday, while Ferdinand was given the vice-captain role ahead of England’s 2012 World Cup qualifying campaign.
Barcelona defender Gerard Pique believes former Manchester United midfielder Darren Fletcher must seriously consider his future.
Manchester United midfielder Darren Fletcher admits he's had little chance to dwell on his Premiership and Champions League winners' medals achieved this season.