Turkish President Recep Tayyip Erdogan will host Russian President Vladimir Putin, French President Emmanuel Macron and German Chancellor Angela Merkel for a summit on the conflict, in which more than 360,000 people have been killed since 2011.
Russia, which supports the government of Syrian President Bashar al-Assad, and Turkey, which backs the militants, have held previous talks with Iran on the issue, in efforts that have often been greeted with suspicion in the West.
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But Saturday's summit will be the first to bring together the Turkish and Russian leaders with the European Union's two most significant national leaders.
Turkish presidential spokesperson Ibrahim Kalin said on Friday that the primary goal would be to "clarify the steps to be taken for a political solution and to determine a roadmap".
Forming a commission to create Syria's post-war constitution, seen as a stepping stone to staging elections in the war-torn country, would be a particular point of emphasis, Kalin told the state-run news agency Anadolu.
The talks will also look to extend a ceasefire around the last major militant-held bastion of Idlib, where aid groups have warned that a military offensive could spark one of the worst humanitarian disasters of the seven-year war.
With an assault by government troops seeming imminent, last month Russia and Turkey agreed to create a demilitarised buffer zone ringing Idlib, home to three million people.
The September 17 deal for the 15-20 kilometre-wide zone came after a flurry of activity as Turkey sought to avoid an assault leading to a further influx of people across its border.
However shelling in the area has continued intermittently, and the Syrian Observatory for Human Rights said Syrian regime artillery fire killed seven civilians in Idlib on Friday - the highest death toll there since the ceasefire deal.
The participants have damped down hopes of a long-term solution ahead of the summit, with France's Elysee palace saying there were "modest expectations" and Putin's spokesman Dmitry Peskov urging everyone to be "realistic".
Peskov said that while all sides want a political settlement in Syria, "certain disagreements may exist regarding the instruments and tactics".
"The issue of the day is to reconcile different formats in order to synchronise our watches, to negotiate, and to attempt to identify common topics," he said.
While two key global players in the Syria conflict - Iran and the United States - will be absent, Macron said he briefed US President Donald Trump on strategy this week.
The push by Turkey and Russia has overshadowed a rival United Nations-backed political process, which has been hampered by the Syrian government's refusal of "any foreign interference" in writing the new constitution.
However France and Germany's inclusion in Saturday's summit could help Turkey's bargaining position, as all three share the same view of Assad's government, said Jana Jabbour, professor of political science at Sciences Po university in Paris.
The talks could even let Erdogan "try to normalise relations with Europe" and show he can be "a good partner with the West" after relations were badly affected by Ankara's crackdown over a failed coup in 2016.
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The summit will also take place in the aftermath of journalist Jamal Khashoggi's murder in the Saudi consulate in Istanbul on October 2.
Turkish media reported that Erdogan will discuss the crisis in one-on-one talks with some leaders on the summit's sidelines.
Anthony Skinner, director for Middle East and North Africa at the Verisk Maplecroft consultancy, said the summit fits with Ankara's broader strategy, "one plank of which is to further solidify its position as a vital working partner for Russia and the Europeans".
"This runs in tandem with Erdogan's attempt to cut MBS back in Saudi Arabia while bolstering Turkey's standing in the Middle East," he said referring to Saudi Arabia's powerful Crown Prince Mohammed bin Salman.
The summit is expected to start at around 4:00 pm and the four leaders are expected to issue a joint statement ahead of individual press conferences.
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