1. Chapter 23 The Synthesis of Organic Compounds
Contents
Protecting Groups in Organic Synthesis
Retrosynthetic Analysis to Design
Syntheses of More Complex Organic Compound

2. Protecting Groups
Needed for sugar/oligo(DNA, RNA)/peptide and other bioactive molecules synthesis
Protecting groups: temporary modification of FG
should be introduced under mild cond
must be stable under desired rxn cond
should be removed readily
Example:
 1012

3. 23.1 Protecting Groups For Alcohols
Classification:
Ether Type (Methyl, THP, Bzl, TMS, Trityl,....)
Ester Type
Acetal Type
Removing Condition:
Acid, Lewice acid
Base
Hydrogen
Fluoride ion
 1012

4. Tetrahydropypanyl (THP) Ether - an acetal
strong to base; removed by acid
reversible rxn, needed condition for equil shift
Ex: as an acid lable linker in SPOS : CMPS  DHP-PS
 1012

5. - via stablized cabocation
Mechnism for THP Ether
- via stablized cabocation
 1013

6. Methoxymethyl Ether - an acetal
introduced by SN2 rxn; removed by acid
strong to base
 1013

7. - benzylic position: good for hyrogenolysis introduced by SN2
Benzyl Ether
- benzylic position: good for hyrogenolysis
introduced by SN2
removed by H2/Pd, acid, Na/NH3
 1014

8. Example
 1014

9. Silyl Ether (TMS, TBDMS)
stable to heat, base, Ox (TBDMS, quite stable to hydrolysis)
removed by acid, F-
 1014

10. Triphenylmethyl Ether (Trityl, Tr-)
stable to base, Ox
can act on 1o OH only vs 2o OH
- very sens. to mild acid
Dimethoxytriphenylmethyl Ether (DMT)
ultra sens. to mild acid
cleavage detected by UV
 1014

11. Ester Type
introduced by acylation (w/ acyl halide, anhydride, ketene, ..)
stable to mild acid, Ox
removed by H3O+, LAH, H2(benzyl ester),..
Acetal Type (1,2 diol)
cis 1,2 diol w/ aceton; 1,3-diol w/ benzaldehyde
eg) selective protection of glycerol
sens. to acid
 1014

12. 23.2 Protecting Groups For Aldehydes and Ketones
As an acetal (ketal) type :
- Acid catalyzed reversible rxn, stable to Ox
- also good for 1,2-diols
 1015

13. 23.2 Protecting Groups For Carboxylic Acids
As Esters
simple alkyl ester (-OMe, -OEt)
- introduce by acid catalyst (dry HCl, SOCl2)
- removed by acid or saponification (OH-)
 1015

14. - introduced by isobutene(gas), ester exchange (t-butyl acetate),..
t-Butyl ester (-OtBu)
- introduced by isobutene(gas),
ester exchange (t-butyl acetate),..
- stable to base, Nu
- removed by mild acid (simlar to Boc)
- acyl cleavage or C-O cleavage? how to?
 1016, 1017

15. - introduced by SN2 w/ carboxylate, ester exchage, esterification
Benzyl ester (-OBzl)
- introduced by SN2 w/ carboxylate, ester exchage,
esterification
- used in SPPS (from CMPS)
- removed by H2, OH-, NH2HN2, HBr/HOAc, HF(SPPS)
AA loading in SPPS
- As benzyl ester: AA Cs salt + CM PS resin
(why Cs salt?)
 1016, 1017

16. Example
 1017

17. 23.4 Protecting Groups for Amines
No More basic !
1. Amide Type
simple amide : sometimes difficult to cleavage
urethane type: acid/base/hydrogen for cleavage
 1018

18. 2. Urethane Type t-Boc group - introduced by BOC2O, Not by t-Boc-Cl
t-Butyloxycarbonyl (t-Boc) : acid cleavage
Fluorenyloxycarbonyl (Fmoc) : base cleavage
Benzyloxycarbonyl (Cbz, Z) : hydrogen for cleavage
t-Boc group
- introduced by BOC2O, Not by t-Boc-Cl
- stable to H2, OH, Nu,
- removed by TFA, HCl/Dioxane, formic aicd, HF,..
 1018

19. Mechanism : SN1-like, SN2
 1018

20. Carbobenzoxy (Cbz, Z) group - Introduced by CBZ-Cl (biphasic, Schatum Baum cond) - Removed by H2/Pd-C, HBr/HOAc
Mechanism : SN1-like, SN2, Push Pull w/thioanisol, substituent effect
 1019

21. Fmoc group (9-Fluorenylmethoxycarbonyl)
- Introduced by Fmoc-Cl or -OSu (SB condition) - Removed by pip (20%) or DBU (1%)
Mechanism : E1cb
TS : E1cb, E1, E2
Photo-cleavable Protecting Group
NVOC (N-Veratoryloxycarbonyl)
MeNPOC (5’-(a-methyl-2-nitropiperonyl)oxycarbonyl)
Mech for cleavage ?
Alloc Protecting Group
Cleaved by Pd[0]
 1019

22. MeNPOC (5’-(a-methyl-2-nitropiperonyl)oxycarbonyl)
NVOC (N-Veratoryloxycarbonyl)

23. 3. Others Trityl group - How it works. 4
3. Others Trityl group - How it works? 4. Examples of Protecting Group Application - DNA, RNA monomer - Amino acid monomer
 1019

24. 23.5 Retrosynthetic Analysis
Route A
Reagents
 1020

25. Route B
Reagents
Route C
Reagents
 1021

26. Retrosynthetic Analysis
Failed scheme (poor yield)
Pheromone of bark beetle
 1022

27.  1022

28.  1023

29. 23.6 Examples of Syntheses Retrosynthetic Analysis  1026
Pheromone of gypsy moth
 1026

30. Synthesis of Dispalure
 1027

31. Retrosynthetic Analysis
Aggregation Pheromone of Western pine beetle △
 1027

32. Synthesis of Brevicomin
 1028

33. Retrosynthetic Analysis (Oxanamide)
Tranquilizer
 1028

34. The Synthesis of Oxanamide
 1029

35. 23.7 Carbon-Carbon Bond Formation
Disconnection Approach
Table 23.1
- 1,3-Di CO
1,5-Di CO
- b-hydroxy CO
 1030

36. 23.8 Prepartion of Functional Groups
Table 23.2
C-C Bond-Forming Rxn
W/ Various Nu
- Org-Metals
- Class I
Class II
Class III
Double bonds
 1031

37. Cont’d Table 23.2
 1032

38. Prepartion of Functional Groups (1) Table 23.3
Practice & Report : Problems 11, 12dfpqr, 15aceh
 1033, 1034

39. Prepartion of Functional Groups (2) Table 23.3
 1035, 1036

40. Prepartion of Functional Groups (3) Table 23.3
1037, 1038

41. Prepartion of Functional Groups (4) Table 23.3
1039, 1040

42. Prepartion of Functional Groups (5) Table 23.3
1041, 1042

43. Prepartion of Functional Groups (6) Table 23.3
 1043