This is the third time I've tried this out, so here goes nothing. Thanks to Thande (and, ultimately, Shakespeare) for the name!
The outline of the POD is Joanna of Castile dying while in labour with her first child (not too unlikely, given the fate of sister Isabella) and the child dying of some infection a few months into its life. This becomes one of a series of incidents, mostly OTL, that end with the only heir to the thrones of Castile and Aragon being Catherine, Henry VIII's first wife. Salic law could allow the succession to pass through her to a son, if sufficiently mangled by a group of partisan Legal Eagles, and thus we see the kingdoms of Spain united with England under Tudor rule, for the time being at least.
The OTL events are in blue, whereas the TTL events are in black.
FROM 1st JANUARY 1498 TO THE FOUNDING OF NEW ENGLAND
1498
April: Charles VIII of France dies, and the throne passes to Louis XII.
May: John Cabot sets out on his second voyage to the Americas. He is not heard from for over a decade.
June: Machiavelli is elected Chancellor of Florence.
August: Miguel da Paz is born, and becomes the heir presumptive to the thrones of Portugal, Castile and Aragon.
November: Joanna of Castile gives birth to a girl named Eleanor. Complications during the childbirth result in her death, and Eleanor dies of an infection soon afterwards.
1499
July: The Turkish Navy defeat the Venetian fleet at Lepanto.
September: Vasco da Gama returns to Lisbon from his expedition to India. He is granted the title of Admiral of the Indian Ocean.
November: Edward of Warwick is executed, ending the male-line of the House of York.
1500
January: Duke Sforza of Milan recaptures the city temporarily.
April: Explorer Pedro Álvares Cabral discovers Brazil for Portugal.
July: Prince Miguel dies at the age of two.
August: The Second Battle of Lepanto - again, a Turkish victory.
October: Maria of Aragon marries Manuel I of Portugal, and becomes Queen.November: France and Aragon agree to split Naples between them.
1501
February: Arrangements are made between the Spanish and English courts for the wedding of Prince Arthur and Princess Catherine, in order for Henry to improve the Tudor claim to the throne (Catherine is descended from the House of Lancaster).
October: Austria and France sign the Treaty of Trente, which recognises the French conquests in Northern Italy.
November: Prince Arthur and Princess Catherine meet, and subsequently marry.
December: Queen Maria of Portugal suffers a miscarriage, and dies from the trauma. Manuel I is left childless.
1502
April: Prince Arthur dies of some unknown illness, possibly sweating sickness. Catherine testifies to the effect that their marriage was unconsummated. In order to salvage the union, Arthur's younger brother Henry is suggested as a possible husband for Catherine, but matters of scripture delay this possibility, with the matter being sent to the Holy See.
May: Columbus launches his fourth and last expedition to the Americas, where he will explore much of the Central American isthmus.
1503
January: The town of Seville is granted exclusive trading rights with the Spanish colonies in the New World.
May: James IV of Scotland and Margaret Tudor are married, according to Papal Bull.
July: Pope Alexander VI decrees that, given that Catherine and Arthur never consummated their marriage, Henry and Catherine may marry. Henry VII agrees, and it is decided that the wedding will take place once Henry is fifteen.
September: Pope Pius III achieves the mantle of Pontiff, upon Alexander VI's death.
November: Margaret of York dies, nearly five years to the day after her daughter-in-law (Joanna of Castile) died in childbirth.
December: Anne of Bohemia is born to Vladislaus II and Anna of Foix-Candale.
1504
January: France cedes Naples to Aragon, concluding the Italian War.
April: The guilds of England come under the control of the state.
November: Isabella of Castile dies aged 53, and Catherine accedes to the throne as Queen of Castile.
1505
April: Manuel I of Portugal marries Margaret of Austria, after the death of husband Philibert II the previous year.
May: King Alexander of Poland agrees to the Nihil novi act, transforming the political system of the country overnight.
October: Ivan III of Russia dies, and is succeeded by Basil III, who inherits a land more than four times the size of Ivan’s inheritance.
1506
January: The Swiss Guards become the Vatican’s armed forces, under Pope Pius III.
June: Prince Henry of England turns fifteen and marries Queen Catherine, becoming King Consort of Castile.
August: Anna of Foix-Candale gives birth to Vladislaus of Hungary.
1507
February: Queen Catherine gives birth to Prince Edward, heir apparent to the thrones of Spain.
July: Henry VII succumbs to a bout of smallpox. His son becomes Henry VIII of England, and Prince Edward becomes the Prince of Wales, standing to accede to the thrones of Castile, Aragon and England upon the death of their incumbents. The Duke of Buckingham reigns in Henry's stead until his eighteenth birthday.
October: The Short Rebellion: Alarmed by the number of private armies being amassed by English nobles, the Duke of Buckingham orders the arrest and prosecution of several nobles. The country seems doomed to break into civil war until Henry offers to mediate the dispute, ending the rebellion before it really started. This event does much to establish Henry's credentials as a diplomat.
1508
January: The Venetian War begins, as Maximilian I launches an invasion of the Republic while on his way to Rome to be formally crowned Emperor.
July: The Venetian War ends in an Austrian victory, and several territories - including Lombardy and Istria - are ceded to Maximilian. The territories on the Illyrian coast are seized by the Ottoman Empire, but claimed by Hungary and Venice, and will be a point of tension in the region for a long time.
1509
May: Spanish scouts in the Caribbean are astonished to discover John Cabot and the remnants of his expedition, which they set out on over ten years previously. They are granted passage on a ship heading to Europe, and a letter from the Spanish authorities urging all who can help to allow them to return to England as soon as possible.
June: Henry VIII reaches eighteen and assumes the throne, with the Duke of Buckingham stepping down to the position of Trusted Advisor (read: Grand Vizier without the benefits of an awesome pointy hat).
September: Cabot and his expedition are granted an audience with King Henry, who is intrigued by their tales of the Americas. He agrees to finance a new expedition, with the intent of establishing a trading colony. Since he is married to the Queen of Castile and his father-in-law is the King of Aragon, he does not need to worry much about the Treaty of Tordesillas.
1510
February: The Portuguese colonial empire in India expands, with the conquest of Goa.
April: The third Cabot expedition to the Americas is dispatched, with a significant number of colonists.
May: The Cabot expedition lands on the site of OTL South Carolina, and the colony of New England is founded.
Comments? Criticisms? Death threats? All will be welcomed.