lecture six Aldol-like reactions and now, the end is my final curtain. OH NH 2 R 1 R 2 1,3-aminoalcohols

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1 lecture six near; and so. I face and now, the end is my final curtain. Aldol-like reactions H H R 2 1,3-aminoalcohols

2 the reaction C i. base ii. H reduce H H 2 pka of the alpha hydrogens of acetonitrile is about 25 (the same as alpha to an ester) The reductioon can be achieved with LiAlH4 or TM-catalysed hydrogenation H venlafaxine antidepressant Buena Vista 2005

3 Remember: retrosynthesis when we are performing the of this compound that alkylation of the amine with methyl iodide is probably not the best reaction. Instead we should do a reductive amination (in reality they used methanal and formic acid; see if you can work out the mechanism for this reaction). H C amine H H 2 FGI reduction C 1,3-, C (ish) H Aldol-like reactions R 3 R R 2 2 1,3-amino ketones

4 retrosynthesis C C R 3 2 R 2 Mannich R 2 H H R 3 H R 3 MMIII-MMVIII - William H. Baird H atropine deadly nightshade

5 retrosynthesis H C FGI H Ph ester reduction FGI decarbonylation CH C 2 H 2 x 1,3- C 2 H H 2 CH C 2 H 2 x Mannich C 2 H synthesis CH H 2 C 2 H amine condensation C 2 H H CH C 2 H H C 2 H Mannich reaction C 2 H C 2 H C 2 H H 2 C Mannich reaction C 2 H H H C 2 H

6 1,3-dicarbonyl compounds 1 3 R 2 2 aisen-type condensations the reaction X X R 2 R 2 R 2

7 Ph tazadolene antidepressant Buena Vista 2005 retrosynthesis Ph several steps Ph 1,3-diC Ph

8 synthesis Ph H enamine formation Ph The chemistry of enamines is quite fascinating. The last few years have seen an explosion in the use of proline derivatives for the temporary formation of chiral enamines. hydrolysis Ph 1,5-dicarbonyl compounds R 2 Michael addition

9 the reaction 1,5-diC H 2 C H 2 C the reaction 1,5-diC H 2 C H 2 C Why do malonates prefer 1,4 addition? Might be time to learn about Hard-Soft Acid-Base theory (or when reactions are controlled by electrostatics and when they are controlled by orbital overlap!!) Then again, perhaps not... Et 2 C Et 2 C Et 2 C i. KH ii. H +, heat C 2 Et C 2 H

10 Et rogletimide sedative H retrosynthesis H C imide C 2 Et C 2 Et The real synthesis uses acrylamide instead of ethyl acrylate; this allows a simple final cyclisation step. 1,5-diC Br C 2 Et C C C 2 Et C 2 Et

11 steroid skeleton retrosynthesis C=C 1,5-diC

12 The Robinson annelation base base base The Robinson annelation base base base H H

13 alkene disconnection R 3 C C R 2 R 4 H H Br valuable intermediate H H H Br H H H

14 Aldol condensation R 2 C=C R 2 reagents R 2 R 2 Wittig reaction R 2 C=C R 2 R 4 R 3 R 4 R 3 I guess it could be argued that the synthons should be a double +ve and a double ve but this looks confusing! R 4 PPh 3! R 2 R 3

15 Wittig reaction simplification! H Br R 4 base PPh 3 H PPh 3 R 4 PPh 3 R 4 PPh 3 R 2 R 3 R 4 R 2 PPh 3 R 3 R 4 R 2 R 3 PPh 3 R 4 H phenaglycol tranquilliser H

16 retrosynthesis I H H FGI dihydroxylation PPh 3 C=C C=C Ph 3 P retrosynthesis II H H FGI dihydroxylation H H 3 possible Grignards 3 possible Grignards

17 retrosynthesis III C C H H H Et FGI C C C H umpolung R!+ R! reverse polarity

18 example!+! Mg!!+ R Br R MgBr umpolung C Ph R C Ph H R This is not a true example of umpolung but is just meant to aid us understanding the concept of polarity reversal dithianes Curiously, the 5-membered dithioacetal ring (dithiolane) cannot be used in this reaction and fragments on treatment with strong base R H electrophile HS H SH S R H S BuLi S S R nucleophile Some interesting uses of this kind of chemistry have been reported by the group of Amos B Smith III

19 H H H H (+)-tedanolide anti-carcinogen retrosynthesis remove reactive functionality split molecule H H H umpolung H J. Am. Chem. Soc. 2007, 129, 10957

20 synthesis P P P P S S P the only way to improve is practice