Protecting-group-free synthesis
Synthetic chemists would dearly like to be able to work
without protecting groups, but they are very glad that they
exist.
Koert, U. Angew.
Chem. Int. Ed. Engl. 1995, 34, p. 1370
Hoffman R. W.;Synthesis 2006, 21, p. 3531-41
Introduction
Precise control of the individual reactivity of functional groups within
a complex molecular architecture remains a largely unanswered
challenge
Protecting groups are a standard solution to this
challenge.
Protecting groups are easily appended : - allow
smooth individual transformation
-Are then easily removed
Protecting groups use has became a routine even on
molecules of low complexity.
Abusing of protecting group
OH
iPrO
O
MeO
NH
OMe
NMe2
N
Cl
O
O
O
O
HO
OH
O
OH
O
O
O
Kedarcidin
MOMO
MOMO
MOMO
I
HO
OH
Ac2O, Et3N, MOMO
OAc
DMAP, DCM
OAc
TBSO
TBSO
TBSCl, DMF
Imidazole OAc
HO
I
I
HO
Ethyl vinyl ether
OAc
PPTS, DCM
EEO
OAc
PPTS,
OAc
2-butanone
I
I
OAc
HO
HO
i) TBAF, THF
HO
EEO
OAc ii) K2CO3, MeOH
I
OH
Yoshimura F.; Kawata S.; Hirama M. Tetrahedron. Lett. 1999, 40, 8281
Abusing of protecting group
Abusing of protecting group
OH
OAc
Géraniol
3 steps
1 PG manip.
OAc 4 steps
2 PG manip.
O
BzO
OH
MeO2C
OTHP
HO
4 steps
1 PG manip.
HO
OH
HO
2 steps
1 PG manip.
2 steps
2 PG manip.
O
O
H
2 steps
HO
4 steps
1 PG manip.
H
O
O
BnO
O
O
O
O
H
O
H
Me
H
O
H
O
OH
O
O
H
O
OH
BnO
BnO
OTBDMS
OH 3 steps
2 PG manip.
O
H
O
O
H
OH
H
H
O
CHO
Hemibrevetoxin B
Tetrahedron Lett. 1996, 217
27 steps
11 protecting group manipulations
Introduction
Hendrickson1 : “An ideal synthesis should consist of only skeletonbuilding reaction”
Protecting group are absolutely contrary to the
principles of an ideal synthesis.
- Addition of at least two steps
- Can lower efficiency of a synthesis in case of unforeseen
difficulties encountered during their removal or side reaction due
to their presence.
Multi-step industrial syntheses of drugs candidates
avoided the use of protecting groups, 35% are
protection-free synthesis
Org. Biomol. Chem. 2006, 4, p. 2337
(1) Hendrickson J. B.; JACS 1975, 97, 5784
Introduction
Example of an industrial synthesis : Kessane
H
Constituent of Japanese Valarian root
Sedative and anxiolitic effects
O
H
Booker-Milburn K.I.; Jenkins H.; Charmant J. P. H.; Mohr Peter
Org. Lett. 2003, 5, 3309
Introduction
Example of an industrial synthesis : Kessane
O
OSiMe3
OSiMe3
H
O
OH
3-butenylmagnesium bromide
TMSCl, DMPU, THF
then Et3N
Et2Zn, CH2I2
Toluene
OH
H
OH
Fe(No3)3
1,4 cyclohexadiène
DMF
H
PPh3=CHCH3,
THF
H
OH
BH3, THF
then PCC, THF
H
H
O
H
OH
+
Tebbe reagent
(Cp2TiCl2, AlMe3, PhMe)
THF
H
OH
H
OH
H
OH
H
NIS, DCM
I
O
H
H
8 steps
No PG
+
O
H
Pd/C, H2, EtOAc
H
O I
Booker-Milburn K.I.; Jenkins H.; Charmant J. P. H.; Mohr Peter
Org. Lett. 2003, 5, 3309
H
Introduction
Why do we want to avoid protecting groups?
Advantages :
Mask competitive reactivity
Allows the increase of synthetic targets complexity
(increase of the molecular weight)
Disadvantages :
Increase of the number of steps
Loss of material and time
Atom economy? green chemistry ?
Loss of the generality of the method.
Early examples
Early PG free synthesis : Muscarine
Isolated from “Amanita muscaria” in 1869
Mimics the action of neurotransmitter acetylcholine
OH
OH
O
HO
Me3N+
OH
HO
H
Hardegger, 1957
L-Arabinose
9 steps
O
Me
OH
H
O
OH
HO
Muscarine
OH
H
O
OH
L-Rhamnose
O
Chan, 1992
Fleet, 1992
9 steps
5 steps
(S)-Ethyl 2-hydroxypropanoate
Early examples
Muscarine synthesis
Early examples
Muscarine synthesis
Early examples
Muscarine synthesis
O
O
O
O
O
Cl
O
O
O
O
O
O
O
Cl
O
Me
Cl
O
Cl
LDA
P(NMe2)3
CCl4
O
O
RaNi
O
OH
+
O
O
O
3 steps from D-ribose
O
Me
OH
HO
- OTs
HO
O
OBz
+
Me3N
HO
Me
O
i) NaIO4
ii)NaBH4
Me
OBz
O
i) NaOMe
ii) pTsOH, pyridine
iii) NMe3
i) PPh3, DEAD, PhCOOH
ii) AcOH
Me
OH
Bandzouzi A.; Chapleur Y. J. Carbohydr. Res. 1987, 171, 13
13 steps, 4 PG manip.
Early examples
Muscarine synthesis
How to avoid Protecting Groups ?
Use of protection-deprotection in situ schemes
Use of biogenesis-oriented syntheses
Use of Transition-metal-catalysed skeleton
formation
Changing the order of introduction of functional
groups
Use of in-situ processes
Welwitindolinone A synthesis
Isolated from “Blue Green Algae” in 1994
Activity for reversing multiple drug resistance
Blue Green Algae (BGA) production unit at Bhawanipatna,
Kalahandi (Under Construction)
Use of in-situ processes
Welwitindolinone A Baran’s synthesis : retrosynthetic analysis
Use of in-situ processes
Welwitindolinone A Baran’s synthesis : without PG
Lactone in-situ protection : conversion into an enolate
Use of in-situ processes
Welwitindolinone A Wood’s synthesis : retrosynthetic analysis
Use of in-situ processes
Welwitindolinone A Wood’s synthesis : with PG
Use of in-situ processes
Welwitindolinone A Wood’s synthesis : with PG
Use biogenesis-oriented syntheses
Elysiapyrone A synthesis
Isolated from sea slug “Elysia Diomedea”
Activity for reversing multiple drug resistance
O
Me
Me
Me
O
OMe
H
Me
O
Me
O
elysiapyrone A
Barbarow J. E.; Miller A. K.; Trauner D. Org. Lett. 2005, 7, 2901
Use biogenesis-oriented syntheses
Elysiapyrone A synthesis
8π electrocylcisation
6π electrocylcisation
O
O
OMe
Key intermediate in the biosynthesis
Use of transition-metal-catalysed
skeleton formation
Aureothin synthesis
Found in the mycelia of several actinomycetes
Antitumor, antifungal and pesticide activities
OMe
O
I
O
Aureothin
O
Use of transition-metal-catalysed
skeleton formation
Aureothin Baldwin’s synthesis : retrosynthetic scheme
Use of transition-metal-catalysed
skeleton formation
Aureothin Baldwin’s synthesis : without PG
7 steps
No PG
Use of transition-metal-catalysed
skeleton formation
Aureothin Trauner’s synthesis : with PG
I
I
I
OH
i) CuI
I2, NaHCO3,
MeCN
OH
BrMg
I
O
97%
NaI
OH
CsO2CCF3, DMF
then basic work-up
83%
O
TBDPSCl,
Imidazole, DMF
95%
I
OTBDPS
O
i) TMSA, Pd(PPh3P)2Cl2, CuI,
THF, Et3N, 96%
ii) K2CO3, MeOH, DCM, 99%
OH
I
O
OTBDPS
i) n-Bu3SnMgMe, CuCN, THF, I
then MeI, 78%
ii) I2, DCM, 95%
O
O
i) (COCl)2, DMSO, Et3N, DCM I
ii)AgNO3, NaOH, H2O, EtOH
OH
O
CDI, THF
O
OTBDPS TBAF, THF
65%
O
I
Im
O
95%
85%
OMe
O
COOMe
O
i) NaH, nBuLi
ii) DBU, Benzene
iii) MeOSO2F, DCM
I
O
11 steps
O
1 PG
65%
Liang G.; Seiple I. B.; Trauner D. Org. Lett. 2005, 7, 2837
Use of transition-metal-catalysed
skeleton formation
Bipinnatin J synthesis
Isolated from “Pseudopterogorgia bipinnata” in 1998
OH
O
O
Bipinnatin J
O
Use of transition-metal-catalysed
skeleton formation
Bipinnatin J first synthesis : without PG
Retrosynthetic scheme :
Use of transition-metal-catalysed
skeleton formation
Bipinnatin J first synthesis : without PG
Ruthenium-catalysed Alder-ene, Stille, Nozaki-Hiyama-Kishi reaction
9 steps
No PG
Use of transition-metal-catalysed
skeleton formation
Bipinnatin J second synthesis : with PG
Retrosynthetic scheme
Huang Q.; Rawal V. H.; Org. Lett. 2006, 8, 543
Use of transition-metal-catalysed
skeleton formation
Bipinnatin J second synthesis : with PG
OMOM
OH
Br
Br
Br
SeO2,
tBuOOH
97%
LiO
OMOM
I
MOMCl,
iPr2NEt
91%
O
THF, HMPA
72%
NaI, acetone
100%
I
O
OMOM
SePh
OMOM
OMOM
TBSO
OMOM
O
Br
O
O
LDA,
PhSeCl
66%
O
OMOM
O
O
H2O2, THF
82%
O
LDA, TBSCl
100%
O
AgO2CCF3
60%
I
ClZn
OH
O
O
O
O
O
O
cat PdCl2dppf
100%
O
O
O
O
i) PPTS, TBuOH
81%
ii) CBr4, PPh3
DCM
68%
OMOM
O
11 steps
CrCl2, THF
73%
2 PG
O
O
O
O
Br
Huang Q.; Rawal V. H.; Org. Lett. 2006, 8, 543
Order of functional groups
introduction
With protecting group : 11 steps, 4 PG manipulation steps
PG manip.
PG manip.
PG manip.
PG manip.
Order of functional groups
introduction
Without protecting group : 6 steps
Conclusion
The advent of PG and the logic underpinning their use
revolutionized and empowered chemical synthesis but now the
bar has to be raised on “economies” of complex molecules total
syntheses. and PG free syntheses constitute a promising area .
Major challenge of today’s syntheses :
Minimum number of steps, atom economy, minimize waste
production…
Avoidance of PG is a major aspect to streamline the
synthesis of complex target molecules.
Conclusion
Limitations:
- PG free synthesis involved a certain amount of risk and
speculation owing to the unpredictable reactivity that is inevitably
encountered at the late stages of a total synthesis.
- In some case, the use of PG may offer a more efficient or even
sole solution.
Ex : certain classes of molecules will perhaps always require
some level of protection for practical issues of purification and
characterization.
“With regards to the issue of protecting groups, we would submit that these
artificial agents, while often enabling in the certain classes of molecules, are
the direct offspring of chemists inability to control chemoselectivity”
P. S. Baran et al. Acc. Chem. Rev. 2009, 42, 530
Conclusion
some tips if you can’t avoid them…
Good protecting groups :
Are small compared to the mass of you are trying to make.
Can be applied and remove in great yield
Allow the functionality to survive the reaction conditions required.
Allow selective deprotection under mild conditions.
Do not introduce stereocenters. Uncontrolled stereocenters in protecting groups
complicate the manipulation and handling of the material by increasing the
number of diastereoisomers.
To avoid them :
Remember adjustment of oxidation state is often easy.
Ex: never carry an aldehyde through multiple steps (undergo facile aldol
condensation, is easily air-oxidised.
Thank you for your attention…