The Hajos-Parrish-Eder-Sauer-Wiechert reaction can be considered as the origin of asymmetric organocatalysis, giving rise to the Wieland-Miescher ketone 1 (WMK), a versatile building block. Although 40 years have passed since its discovery, a highly enantioselective and scalable synthesis of the WMK has remained elusive. This account details a solution to that problem that came about in the development of methodology towards C-8a WMK analogues as part of the total synthesis of complex diterpene natural products. The work has been placed in the context of the historical background and reactivity of this important building block, highlighting the challenges faced by organocatalysis in large-scale reactions. 1 Introduction 2 The Wieland-Miescher Ketone 2.1 The Hajos-Parrish-Eder-Sauer-Wiechert Reaction: A Historical Perspective 2.2 Practicalities of the Wieland-Miescher Ketone Synthesis Using Proline 2.3 Alternative Catalysts for the Synthesis of the Wieland-­Miescher Ketone 3 Background to Developing a New Wieland-Miescher ­Ketone Synthesis 4 Optimization of Method and Conditions 5 Key Reactions of the Wieland-Miescher Ketone 5.1 Reduction, Oxidation, Protection, and Non-C-C-Bond-Forming Reactions 5.2 C-C-Bond-Forming Reactions 5.3 Ring-Expansion and -Contraction Reactions 6 Conclusions and Future Considerations

This review highlights advances in the synthesis of morphan compounds from 1980 to the present day. 1 Introduction 2 Synthetic Approaches from Carbocyclic Compounds 2.1 Aminocyclization Processes Forming the C(1)-N Bond 2.1.1 From Amino Alkenes 2.1.2 From Amino Ketones 2.1.3 By Amine Alkylation 2.1.4 By Amino Conjugate Addition upon Enones 2.2 Aminocyclization Processes Forming the N-C(3) Bond 2.3 Cyclization Processes Forming the C(3)-C(4) Bond 2.4 Cyclization Processes Forming the C(4)-C(5) Bond 2.4.1 Aldol Reactions 2.4.2 Piperidine Ring Closure by a Heck Reaction 2.4.3 Alkenylation of Enolates 2.4.4 Radical Cyclizations 2.4.5 Miscellaneous Approaches 3 Synthetic Approaches from Piperidine Derivatives 3.1 Cyclization upon Iminium Ions Forming the C(1)-C(8) Bond 3.2 Cyclization Processes Forming the C(5)-C(6) Bond 3.3 Cyclization Processes Forming the C(6)-C(7) Bond 4 Cascade Processes 5 Rearrangements 6 Synthesis of 5-Phenylmorphans 7 Conclusions