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World number five Daniil Medvedev and defending champion Alexander Bublik were both knocked out in the second round of the Halle Open.
Russian Medvedev, the 2021 US Open winner, lost a final set tie-break in a 6-3 2-6 7-6 (7-5) defeat by China's Zhang Zhizhen.
Kazakh Bublik, who defeated Russia's Andrey Rublev in last year's final, was beaten 7-6 (7-5) 4-6 6-3 by American Christopher Eubanks.
Second seed Alexander Zverev will play French 20-year-old Arthur Fils in the quarter-finals following a 6-4 7-6 (7-5) win over Italy's Lorenzo Sonego.
Elsewhere, Victoria Azarenka reached the Berlin Open quarter-finals before play was postponed because of rain.
Contesting his first grass court tournament of the season, Medvedev, a Wimbledon semi-finalist last year, lost out to Zhang as the world number 42 recovered from a 5-3 deficit in the decisive tie-break.
Zhang will meet Eubanks next after the Wimbledon quarter-finalist ended Bublik's title defence.
Also in Halle, former Wimbledon runner-up Matteo Berrettini, of Italy, won 7-6 (7-5) 6-2 against American Alex Michelsen.
Two-time major winner Azarenka reached the last eight in Berlin with a 6-3 6-3 win over Turkey's Zeynep Sonmez.
The Belarusian former world number one could face former Wimbledon champion Elena Rybakina next, with the Kazakh third seed meeting Russian Veronika Kudermetova on Thursday.
Tunisian eighth seed Ons Jabeur returned to complete a 6-4 7-6 (7-4) victory over China's Wang Xinyu after rain suspended their match on Tuesday evening.
World number three Aryna Sabalenka and reigning Wimbledon champion Marketa Vondrousova had their matches postponed by further bad weather on Wednesday.
Australian Open champion Sabalenka will now play Russian Daria Kasatkina on Thursday, when Vondrousova is also due to continue her campaign against Anna Kalinskaya.
At the Birmingham Classic, Canadian sixth seed Leylah Fernandez came back from a set down to beat Switzerland's Viktorija Golubic 4-6 7-5 6-3 and set up a quarter-final against Australian Ajla Tomljanovic.