Organic Synthesis A problem–solving guide for Organic Chemistry I/II

? Goal: propose a synthesis of a target molecule H OH N using given starting materials and any other N reagents you need. starting target materials molecule

These key strategies should guide your approach:1

Mapping

• Systematically label all the atoms in the ? 1 starting materials, then identify those atoms in H OH N 6 N the target molecule 2 4 5 7 6 1 3 5 7 2 3 4 • Use landmarks (heteroatoms, functional groups) to help you

Identifying bonds formed/broken

? and atoms added/removed H OH 1 N 6 N Having labeled atoms, it becomes easier to see: 2 4 5 7 6 1 3 5 7 2 3 4 bonds formed: C7–N2 σ, C6–O σ atoms added • where bonds have been formed/broken bonds broken: C6–C7 π atoms removed • where atoms (including protons) have been added/removed

? Regiochemical and stereochemical analysis H OH 1 N 6 N 2 4 5 7 6 • Look for regiochemical patterns that can 1 3 5 7 2 3 4 provide ideas for synthetic strategies target molecule is 1,2–difunctionalized at C6–C7

• Look for changes in configuration at C7–N2 bond formed at less substituted C of propylene stereocenters (not always applicable) reaction: base–catalyzed epoxide opening

1 OH OH 1 Synthon-based retrosynthetic analysis N + N 6 2 4 6 2 4 Construct hypothetical starting materials for 5 7 3 5 7 3 • synthons forming required bonds 1 This process is called constructing synthons, O δ- • + + HN 6 6 δ 2 4 and it is the basis of retrosynthetic analysis 5 7 5 7 3 possible reagents • Synthons are a tool for choosing reagents

1Based in part on strategies observed in successful students’ responses to synthetic Flynn Research Group 2017 – FlynnResearchGroup.com problems on exams; see: Bodé, N. E.; Flynn, A. B. J. Chem. Educ. 2016, 593–604. Created by Nicholas Bodé Organic Synthesis A problem–solving guide for Organic Chemistry I/II

Constructing synthons to identify intermediate reagents

Select a bond that was formed (as you identified in prior steps)

OH 1 N “hockey stick” represents a 6 5 7 2 3 4 retrosynthetic disconnection

Draw the products of the reverse mechanism for its formation

Electrons in the disconnected bond go to one of the bonding atoms, creating a negatively charged synthon (donor) and a positively charged synthon (acceptor) 1 OH OH 1 N + N 6 2 4 6 2 4 5 7 3 5 7 3 acceptor (a) donor (d)

Choose two reagents that have the same reactivity as your synthons

OH 1 1 O + δ- + N δ+ HN 6 2 4 6 2 4 5 7 3 5 7 3 acceptor (a) donor (d) electrophile nucleophile synthons possible reagents

Repeat this process, switching the donor and acceptor synthons

OH 1 OH 1 OH OBn - + + N + δ N δ N 6 6 6 2 4 5 7 2 4 5 7 2 3 4 5 7 3 1 3 donor (d) acceptor (a) nucleophile electrophile synthons possible reagents

Evaluate which reagents are more appropriate for forming the bond you need

1 OH OBn O + - - + + + HNδ δ N δ 6 δ 2 4 6 2 4 5 7 3 5 7 1 3 electrophile nucleophile nucleophile electrophile

strong nucleophile and electrophile weak nucleophile and electrophile nucleophile is given starting material nucleophile and electrophile not readily electrophile easily accessed from given accessible from given starting materials starting material (1 step)

Flynn Research Group 2017 – FlynnResearchGroup.com | Created by Nicholas Bodé