SBM CDT Pharma Disconnections 2
SBM CDT Pharma Disconnections 2
SBM CDT Pharma Disconnections 2
N NH
N N MeO
N NH2 O O
O MeO O N NH2
H
OH
Pharma Disconnections
NC N
N
HN Prof Edward A. Anderson N
HO
O
N MeO
H
N N
N N O
N F
HN
O N
N O
Aims of the Course
• Recognize how multiple solutions are available for given target molecules, and how
to critically assess retrosynthetic options
2
Retrosynthesis: Course Outline
• Introduction to retrosynthesis: The origins of the subject, nomenclature, how we go about breaking up
molecules
• Synthons and Reagents: Acceptor and Donor synthons – how to recognise these disconnections and the
importance of (di)oxygenation relationships
• Focus on specific reaction types and methods to install functionality (e.g. amines, alkenes, cycloadditions,
cross-coupling)
3
Retrosynthesis: Supporting Material
4
Introduction: The history of retrosynthesis
• The birth of retrosynthesis can be traced to Sir Robert Robinson’s landmark synthesis of the alkaloid tropinone
in 1917.
Recognition of available
starting materials!
Me O
N
NHMe2 O
O O
Me
N O
NHMe2 O
O O
In the event, use of the calcium salt of acetone dicarboxylic acid at neutral pH facilitates the Mannich reactions:
O CO2Ca Me
N
pH 7, H2O
NHMe2 O
92%
O CO2Ca
O
R. Robinson, J. Chem. Soc., Trans., 1917, 111, 762; C. Schöpf, G. Lehmann, Leibigs Annalen, 1935, 518, 1.
6
Introduction: Getting started!
• Retrosynthesis arrows:
Forward reaction (Synthetic connection)
Retrosynthetic disconnection
O HO NaH,
THF or
Br DMF
a
O
d O
Br
O OH NaH,
THF or
DMF
d a Risk of E2; SN2 on 2° halide not great!
Key principle: Disconnect at a bond that is EASY TO MAKE; it may be a strong bond!
• A synthon is an imaginary (charged) species formed by the conceptual process of breaking a bond in a molecule
(retrosynthetically). Our job is to identify real-life reagents that correspond to these synthons.
• Synthons are assigned labels (a (acceptor), d (donor)) so we can talk about what type of disconnection we are using.
7
Introduction: Synthons
• A synthon is an imaginary (charged) species formed by the conceptual process of breaking a bond in a molecule (retrosynthetically). Synthons
are assigned labels (a (acceptor), d (donor)) so we can talk about what type of disconnection we are using. The subscript number refers to the
position of the charge relative to a heteroatom that forms part of the functional group.
OH OH
Acceptor Synthons:
a a1 a2
O O
Donor Synthons:
d d1 d2
Reagents (e.g.):
HO
Example 2: OH
+ / H+ (Fischer esterification)
Synthons: O
O O
or Cl / Et3N;
O O O or NaHCO3 aq. / Et2O
"Schotten-Baumann conditions"
a1
d
Bu O Bu N
or • Why use pyridine in this
reaction?
O O
8
Introductions: Functional group interconversions
• In addition to disconnections that break / make bonds, we can carry out functional group interconversions that change either the nature, or
number, of functional groups present in a molecule.
C–O
O ester O Problem:
(a / d) • We cannot directly introduce either of these
OEt OH EtOH
functionalities
H2N H2N • The acid group is meta-directing in SEAr
benzocaine
FGI
C–N
O nitration
FGI Me (a / d) Me
OH
O2N
O2N O2N
a d
Synthesis:
O
HNO3 / H2, H+ /
Me H SO Me KMnO4 CO2H cat. Pd/C CO2H EtOH
2 4 OEt
O deactivating, meta-directing
deactivating, o,-p- directing Cl
see Appendix for
aromatic chem recap
activating, o,-p- directing
The best electron donating group (activator) is the one that ‘wins’ –
stabilisation is more important than ‘lack of destabilisation’
AlCl3 rearrangement
Cl3Al H NOT
Cl Cl
t-Bu t-Bu
polyalkylation
t-Bu
product is more
reactive than sm
O deactivating, meta-directing
deactivating, o,-p- directing Cl
• Solution: Use Friedel-Crafts Acylation then remove carbonyl group. This again uses the important concept of FGI to reintroduce functionality into
the molecule to enable control.
C–C
O C–Cl O (a1 / d) O
Cl (a / d) F–C acylation
Cl
FGI or Clemmensen
Zn / HCl
C–C
(a1 / d) or H2, Pd/C
F–C acylation
O Cl O
AlCl3
11
Exercise
Plan a synthesis of the following molecule from m-cresol:
NO2
NO2
OMe OH
m-cresol
A synthetic musk (available)
Retrosynthesis:
NO2
2 x C–N C–C
nitration F-C alkylation Cl
=
NO2
OMe OMe OMe OMe
Synthesis:
NO2
K2CO3 / MeI
or (MeO)2SO2 AlCl3, t-BuCl HNO3
regioselectivity: ortho to
MeO, not Me (sterics)
12
Selectivity
Control / selectivity is paramount in planning a synthesis. There are three main considerations we need to think about:
O H O O
NH2 N NaBH4
Cl
? O
OMe ? OMe
HO py HO O OH
The amine is more nucleophilic than the alcohol... The ketone is more electrophilic than the ester...
(see Appendix for stereoelectronic discussion) (see Appendix for stereoelectronic discussion)
OH OH OH O
Contemporary, cat. , PhI(OAc)2
chemoselective: N
R R H
O
TEMPO / BAIB
Br
Br
The aniline nitrogen atom is such a powerful activating The acetamide nitrogen atom is now a weaker
group that it is difficult to prevent over-bromination, activating group due to conjugation. Mono-
despite the lower reactivity of the product. bromination can now be achieved.
Key principle: Modifying functional groups (by FGI) can help us to control / influence selectivity
Br Br Br
14
Selectivity
1b. Chemoselectivity: over-reaction.
O O
Br2 Br
OH– or H+ ??
The haloform reaction can be
quite a useful route to
• Under basic conditions: carboxylic acids!
O Br
O O O OH O
Br
H Br Br
OH
OH CBr3
Br Br
pKa = 25 pKa = 21
Key principle: Thinking about mechanism can also help us to control selectivity
15
Protecting groups
Protecting groups provide an obvious way to protect reactive functionality and achieve chemoselectivity. The cost is at
least one additional step in a synthesis, usually two.
• Sometimes the deprotection of protecting groups can be the most challenging step in a synthesis!
• Protecting group-free synthesis preferred – and may be achieved using a careful ordering of steps...
O Ph
SiR3 O Ph
O Me
O R O O O O O Ph
X
2. Protection for amines 3. Protection for carbonyls (and diols!) 4. Protection for carboxyls
O O O O
R S O O
HN O HN R O R
16
Introduction: Selectivity
2. Regioselectivity. WHERE will the molecule or functional group react?
X
• We have already looked at this. The best cation
stabilising group wins!
Y
b) Hard vs Soft
HO H HO Me
NaBH4, CeCl3,
MeOH, –78 °C MeLi or
O MeMgBr
(Luche)
O O
[Ph3PCuH]6 Me2CuLi or
(Stryker) MeMgBr, cat. CuI
H Me
• 1,2-Addition = ‘hard’: These reactions are charge controlled and depend on electrostatic attraction of nucleophile and
electrophile. Highly charged / charge dense reagents.
• 1,4-Addition = ‘soft’: These reactions are orbital controlled and depend on the overlap and energies of the HOMO and
LUMO. Neutral / polarisable reagents.
Many other examples such as: Enolisation (see d2): Control over the site of enolisation for non-symmetrical carbonyls; Elimination (e.g.
Hofmann vs Saytzeff elimination), etc.
17
Introduction: Selectivity
3. Stereoselectivity / Stereospecificity: We may need to control stereochemistry in a given step
Stereoselective: One stereochemical outcome is favoured over two (or more) possible outcomes
Stereospecific: A reaction where only one stereochemical outcome is possible due to the reaction mechanism.
6 4
SM 1 SM 1
13 1 4 1
Linear: SM 1 Target Convergent: Target Multicomponent: SM 2 Target
6 4
SM 2 SM 3
13 steps @ 90% = 0.913 = 25% yield
6 steps @ 90% + 1 step @ 90% 4 steps @ 90% + 1 step @ 90%
= 0.97 = 48% yield = 0.95 = 59% yield
2. Stereocontrol: Substrate stereocontrol, chiral auxiliaries, catalyst stereocontrol, chiral pool, enzymes
3. Atom economy: (B. M. Trost, Science 1991, 254, 1471) and Green chemistry – minimise waste! Compare Wittig / olefin metathesis –
Catalytic vs stoichiometric:
R'
PPh3 O R'
R O R + PPh3 vs. R R +
R' R'
Ru cat.
MW = 262 MW = 28
4. Step economy: Use of cascade strategies, multicomponent reactions, no protecting groups. Aim for e.g. 10 steps in total from cheap
starting materials (not possible for really complex molecules).
5. Redox economy: (N. Z. Burns, P. S. Baran, R. W. Hoffmann, Angew. Chem. Int. Ed. 2009, 48, 2854): Installing functional groups at the required
oxidation state avoids excessive manipulations and protecting groups strategies.
O
1. O3; PPh3 [OX]
2. Ph3P=CO2Me Grubbs II cat. Contemporary,
Classical: R R O R
redox economic:
3. LiAlH4 [RED] atoms introduced at
4. PCC [OX] ?? required oxidation level
19
Acceptor synthons
X
Synthon: R Reagents: R X = I, Br, Cl, OTs
SOCl2
or POCl3 TsCl, py, CH2Cl2
R R R
Cl OH OTs
or CCl4 / PPh3
a1 synthons
OH OH O O
RO
O O O O O O O
Reagents =
H X Cl OR N CO2 RO X
OMe
O O
=
H X H N
20
Acceptor synthons
Synthons Reagents
a2 synthons
OH OH
OH O OH Problem:
Ph Ph Regioselectivity
O Br
Ph d a
OH O O HO
Ph Ph
a2 d
OH
NaH, THF; then
Synthesis: HO O
Ph
O
Ph
O O
R Problem:
O OH Cl R Synthesis of
Ph Ph
hydroxyketone?
O a1 O
d O
O R
O O O
O R
HO R
Ph O Ph
a2 d
Br O
C–N
N OH N
N N F H
N N
F N N
Fluconazole N
F
F
N
N
N
N N a2
N N
a2 OH O O
O FGI C–N
N N N
N N N F F
F = F
N N
F F
F F N N
N N
Synthesis: N N
H O O H
O
O Cl N N 1. Ph3P=CH2 N N
F Cl F F 2. m-CPBA F
Cl N N
Fluconazole
AlCl3 or K2CO3, DMF,
O CTAB (R4NBr) heat
F F F NaOH, tol, F
S
100 °C
O O O
Corey-Chaykovsky
S epoxide
S
epoxide synthesis O
US Patent 4,404,216 22
Donor synthons
These are typically carbanions or anionic / neutral heteroatoms. Here we have two considerations: is the reagent hard or soft
d synthons: (i.e. does it match the electrophile); and, can multiple reactions occur?
Amine synthesis: As amines are such good nucleophiles, polyalkylation is a big risk!
C–N alkylation
Et or Et
Ph N Ph NH2 I Ph N Ph N I
H
Et Et Et
... different solutions are required for the synthesis of highly nucleophilic amines and sulfides!
a) Synthesis of sulfides:
i) Using thiourea: S
NaOH / H2O
NH work-up
Na2S H2N NH2
S Br S NH2 SH
Not isolated
NaN3
PPh3; H2O (Staudinger)
DMSO
R Br R N3
or H2, Pd/C
24
Donor synthons
b) Synthesis of 1° amines:
NH2OH•HCl
H base (e.g. NaOH) H LiAlH4
• From oximes:
OH R NH2
R O R N
There are two important methods for the synthesis of secondary amines, both of which feature reductive processes that again avoid revealing
the amine too early in the reaction.
R2 NH2 R2 NaBH3CN R2
O N HN chemoselective reduction
of imine over aldehyde
R R1 mild H+ e.g. NH4+ R R1 acid-stable mild R R1
or AcOH reducing agent
R2 R3
N R2 R3 R2 R3 R2 R3
O H N N NaBH3CN N
R mild H+ e.g. NH4+ R R R
R1 R1 R1 R1
or AcOH
O O
O
R2 Cl LiAlH4 R3 Cl R1
R1 R1 N R2
R1 NH2 N R2 N R2
H H
O R3
Selective mono-acylation
O
This trick is relevant for the R3 I O LiAlH4 R1
R1 N R2
alkylation of all amide derivatives N R2 R1
N R2
R3
R3
R1 O
OH R1 N
Branched amine R1 NH
N
synthesis: the Ritter H+ / H2O
reaction
Methylamine synthesis: R1 H H R1 R1
N R2 N R2 N R2
the Eschweiler-Clarke reaction H O Me
H
O H stable iminium ion
26
Exercise
Plan a synthesis of the sedative captodiamine from thiophenol, HSC6H5
NMe2
S
S
captodiamine
C–S
d/a
Na2CO3
2-chloroethyl
dimethylamine
SH NMe2
Cl
Bu
S
thiourea; FGI
OH–
C–C C–S
FGI d / a1 d/a
Cl O
Bu Bu
Bu S S HS
S
NaBH4; PhCOCl, Na2CO3,
SOCl2 AlCl3 BuCl
27
Exercise
Plan a synthesis of the following amine from any available starting materials!
N Ph
suggests epoxide?
C–N H C–N
N Ph O HN Ph O H2N Ph
NaBH3CN / H+ NaBH3CN
/ H+
Disconnect at centre
FGI (COCl)2, DMSO;
of molecule
Et3N
C–C
a2 / d
OH Br
Mg O
28
Donor synthons 2: Enolates
An extremely useful disconnection of carbonyls via the enolate. Enolates of almost all carbonyl derivatives are used for both
d2 synthons: alkylation, aldol, and Michael addition chemistry.
O O
O
I
d2 a
Reaction conditions:
LDA, THF, –78 °C;
O O then add iodide
I
d2
a CH3
This ketone is not – so the alkylation
disconnection will never work!
Note that alkylation doesn’t always work: the following two compounds are challenging for ‘normal’ enolate alkylation...
O
O
29
Donor synthons 2: Enolates
Specific enol equivalents: When the direct alkylation won’t give good selectivity, or in the absence of symmetry, we need to improve the
regioselectivity of alkylation. For this, we can use a ‘specific enol equivalent’ – a compound with the reactivity of an enol that affords control.
Li
O OTMS
Li
OTMS O O
MeLi EtI
Et3N,
DMF,
TMSCl
• Silyl enol ethers are also useful (required!) for (Mukaiyama) aldol chemistry...
30
Donor synthons 2: Enolates
b) 1,3-dicarbonyls (malonates and beta-ketoesters). These enable regioselective enolisation and are also ‘soft’ (i.e. good!) nucleophiles
d2 d2
O FGI O O O O O
OMe OMe
O OMe
Problem: two possible a
sites of enolisation... a
Br O O O
O O NaH O O NaH;
OMe
OMe OMe Br
alkylation 1 O OMe
alkylation 2
pKa ~ 12
Allyl bromide is the
better electrophile
O O O O
H H H+ / heat
O
O O O
Key principle: Introduce the better electrophile / nucleophile in the more difficult step
31
Donor synthons 2: Enolates
b) 1,3-dicarbonyls (malonates and beta-ketoesters)
Note: A trick for alkylation at the other position: form the dienolate:
Br
O O NaH O O BuLi O O O O
pKa ~ 12 pKa ~ 35
“Last in – First out”
c) enamines. These ‘soft’ enol equivalents can be isolated, and are useful to control site selectivity of alkylation. The resultant iminium ions
hydrolyse on work up. For aldehydes, they provide an attractive alternative to aldehyde enolates, which are prone to undergo self-aldol reaction.
O N N N O
H Et–I H+ / H2O
mild H+
1,3-allylic
strain N
This isomer is disfavoured by 1,3-allylic strain
...although enamines can be useful for alkylation, they are potentially more useful to control selectivity in aldol- or Michael-type processes...
32
Donor synthons 2: Enolates
The Aldol and Michael Reactions
This will be one of the main methods by which we assemble heterocycle precursors!
Example 1:
Reagents:
C–C
O FGI (aldol)
OH O OH O O O
Ph rehydration Ph Ph Ph H
a1 d2
O O O O O O C–N O O
C–C O
(aldol) d / a3
OEt OEt EtO OEt EtO OEt
= = OEt
N N N N
a3
O O O O O O
O EtONa
Synthesis: EtO OEt OEt OEt
MeNH2
OEt EtOH
N N N
O O O O
Example: Problem: The d2 reagent must be soft =
HO MeO
to avoid competing 1,2-addition
a3 d2 O OMe
O C–O O
(d / a2) O OH FGI O O Solution: Use a
O O =
HO HO 1,3-dicarbonyl
O O
NaOH H+ / heat
HO
O OH 34
Exercise
Plan a synthesis of the following diketone from any available starting materials!
O C–C C–C O
aldol O Michael
O NaOEt O O NaOEt O O
O
Note: Aldol is under TD control. Na
C–C O
Enolisation at other sites leads NaOEt aldol
to strained rings (i.e. reversible) Note: product
‘protected’ as
enolate
O
OEt
35
Donor synthons 3: Umpolung
Synthons such as d1 represent the reversal of natural polarity of the functional group. O O
d1 synthons These synthons are very useful as they increase the number of methods available for R' R'
bond formation! R R
d1 a
a) Dithiane: A classical umpolung reagent, which truly converts a carbonyl into the umpolung synthon, then back to C=O.
PIFA
R' Br (PhI(O2CCF3)2)
O SH SH S n-BuLi S S S O
R' R'
R H BF3•OEt2 R S R S R or R
H Hg2+ / H2O
pKa ~ 31 O
= acyl anion Raney Ni
R'
equivalent R
R
b) Nitroalkanes: A nitroalkane, although not prepared from the original carbonyl or amine, can serve as a versatile d1 equivalent.
TiCl3 / O O
Problem: polyalkylation possible =
H2O R'
R R
NO2
Br R' R'
R NH2 NH2
=
NO2 weak base NO2 H2, Pd/C R'
R R
R R
pKa ~ 10 R
O R' R' H2, Pd/C NH2
O2N R'
R
Note: The nitroalkane anion is ‘soft’
36
Donor synthons 3: Umpolung
Synthons such as d1 represent the reversal of natural polarity of the functional group. O O
d1 synthons These synthons are very useful as they increase the number of methods available for R' R'
bond formation! R R
d1 a
c) Cyanohydrin and related umpolung agents (Thiazolium salts, other heterocyclic carbenes)
This classical reaction has been superseded by soft carbene nucleophiles such as:
Cl
N-Heterocyclic carbenes
Mes N N Mes
Reviews: K Scheidt et al., Angew. Chem. Int. Ed. 2012, 51, 11686.
A. Grossmann and D. Enders, Angew. Chem. Int. Ed. 2012, 51, 314 37
Latent functionality
In the previous section, we saw the nitro group serving as an umpolung reagent which was later ‘revealed’ to be a ketone (or amine). Although on the
face of it this is just an FGI, the nitro group was serving as a ‘latent’ carbonyl. A more accurate definition of ‘latent’ functionality is the introduction of a
reactive functional group in unreactive form, that can be revealed at a chosen stage of a synthesis.
Example 1: Alkenes
Typical Reagents / Synthons
Br MgBr MgBr
O O O O
a2 d2 d1
O3; PPh3 R
BH3; R
R a3 d3 d2
H2O2, OH– OH OH OH OH
O O O O
a2 d2 d1
Pd(II) / Cu(II),
R
O2, H2O
The alkene serves as a latent carbonyl or alcohol, and as an acceptor or donor synthon; it is
unreactive towards conditions which the carbonyls and alcohols are reactive.
Example 2: Silanes
TBAF; then H2O2,
SiMe2Bn KHCO3, MeOH, THF OH
...note analogy to protecting groups...
R R' R R'
38
Exercise
Plan a synthesis of the following enone from any available starting materials!
Ph
O O
C–C O
Ph + EtO
or
Ph
Br N O O
Ph O
FGI C–C
O
O HO
O
Cl Ph
Ph Ph
O d1 S N Bn
NO2 a3
O
Ph
NO2
39
Alkene / Alkyne synthesis
Alkenes are not only useful as masked functionality, or as a source of diols, epoxides, etc., but are also found in many bioactive targets, particularly
natural products. An example of this is Novartis’ everolimus. Although not directly prepared by synthesis, its parent rapamycin has been synthesised
a number of times, and chemists need to address this alkene synthesis. Here we recap some important methods for doing just that.
O
HO
MeO
Everolimus
(immunosuppressant) O O OH
(Novartis) N
O O O
O MeO
HO
O OMe
Olefination methods:
• Aldol / dehydration
• Heteroatom mediated: Wittig, Horner-Wadsworth Emmons, Julia, Peterson
• Metathesis
• Cross-coupling (for dienes etc.), Heck reaction
• Alkyne semihydrogenation
• Metal-mediated olefinations: (Takai, etc.)
Key Principle: Aside from metathesis, aldehydes are key precursors to alkenes and alkynes
40
Alkene / Alkyne synthesis
Heteroatom Method 1: Wittig
Br 1. NaH, THF
Non-stabilized ylid:
R1 PPh3 R1 R2 (Z)-selective
2. R2
O
O O
EtO P R2 electron-rich
EtO O
R3 phosphonate:
R1 O R1 R2 (E)-selective
base (e.g. LDA,
NaH, MHMDS) R3
O O electron-poor
EWG–O P R2 phosphonate:
EWG–O R1 (Z)-selective
R1 O
base (e.g. KHMDS) R2 O
For mechanisms:
EWG = CH2CF3 Still-Gennari
See Appendix EWG = Ph Ando
41
Alkene / Alkyne synthesis
Heteroatom Method 3: Julia
Base (e.g. n- R1
BuLi, LDA); 1. Ac2O, py
Ph R2 Ph R2
R1 S S R1
H 2. Na/Hg
O O HO O O
R2 O
Highly (E)-selective
t-Bu
N N
N N R2 O R2 O N N R2 O
N Base (e.g. LDA); N N N N R2
R1 S N N R1
H R1 S N R1 S N N R1 S
O
O O t-Bu O2
O O t-Bu t-Bu O
R2 O
Grubbs II Hoveyda-Grubbs II
For classification of alkenes in cross-metathesis, see: Grubbs et al. JACS 2003, 125, 11360
For a review of cross-metathesis, see: Blechert and Connon, Angew. Chem. Int. Ed. 2003, 42, 1900 43
Alkene / Alkyne synthesis
Metal-Mediated reaction 2: Heck Reaction Ar–I, cat. Pd(PPh3)4,
NaHCO3, Bu4NCl,
O DMF Ar O
OR OR
cat. Pd(0)
Metal-Mediated reaction 3: Cross-coupling R1 R2 R2
X M R1
R O Conditions Conditions
Synthesis of Alkynes: R H R R'
H
Terbinafine (Lamisil)
(Antifungal)
(Novartis)
NHMe N Cl expensive
FGI PBr3
E/Z imperfect
K2CO3, KI,
DMF
NHMe Cl Cl
OH
C–C
toxic expensive
O
TL 1996, 37, 57.
EP1753770 45
Exercise
Process route:
Cl Cl TMSCl, Et3N
NH2 HN Cl N Cl
TMS
(excess)
cheap! Cl
2 eq. n-BuLi
cat. Ni(PPh3)2Cl2 cheap!
Cl Cl FeCl3 Cl Cl Li
TBAB N
Terbinafine TMS
Cl
Selectivity:
HOMO EDG
H
• Orbital energy considerations mean ideal DA setup is electron rich diene
(HOMO) + electron poor dienophile (LUMO) EWG H
LUMO (or π4s + π2s)
OMe OMe
EDG
H
• Regioselectivity reflects overlap of the largest coefficients of
EWG these orbitals
O O H
R R
(–) EDG
H
O H
O2N O2N
cross-coupling Wittig
• enal easy to make by aldol / dehydration
• stereoselectivity of Wittig is wrong! FGI
Wittig O OH
OMe
Example 2:
H
HO FGI D-A?? [2+2] O • We need a
‘ketene equivalent’
HO O H
O O
cat. OsO4,
NMO
TiCl3, H2O ‘ketene DA
Note: stereoselective exo-face
equivalent’
dihydroxylation O
e.g.
Cl CN , NO2 NO2 ‘enamine DA
H2, Pd/C equivalent’
NH2
48
Exercise
Plan a synthesis of the following molecules using Diels-Alder chemistry
HO
OH OH
CO2Me
CO2Me
Whilst we could probably
OMe OH
HO do FGIs to make this work,
there is an alternative....
Recognise potential dienophile
HO 6 HO
OH OH OH
CO2Me – C–O CO2Me ?
O
CO2Me CO2Me
OMe OMe 1 OH OH
HO HO
– H+
1,6-O
O3; NaBH4 ozonolysis
OH OH
H
CO2Me
CO2Me OH
CO2Me CO2Et
MeO CO2Me
OMe
LiAlH4 CO2Et
D-A OH
D-A
OMe CO2Me
Good electronics! Alkene ozonolysis CO2Et
(furan e-rich) O can reconnect
1,6-dioxygenation EtO2C
CO2Me
49
Saturated Heterocycles
The synthesis of saturated heterocycles can be achieved in many ways; the common theme to most of these is to use the nucleophilicity of the
heteroatom.
1. SN2 Cyclisation onto halides, epoxides, etc.
basic conditions • Works well for 3, 5, 6 and 7-membered rings, and azetidines
X Cl X • Irreversible – SN2 reactivity – stereochemistry of sm
converted into products
basic conditions • However this means stereochem of sm must be controlled
X X
O
OH
3. Palladium-mediated cyclisations
I2
I • Iodoetherification or iodolactonisation, and other good electrophiles,
R1 OH R1 O promote this reaction. Stereoselective for equatorial sidechain.
R2 R2
H+ / NaBH3CN R1
R1 R2 H N R2 N R1
R2 H H
R1 N R2
NH2 O H H
Nu
axial delivery of nucleophile Nu
n
cat. Ru=CHR n
• Particularly useful for medium-sized rings!
N N
R m
R m
OTES OTES R1 R1
cat. Cr(III)(salen)
N
O R1 O EWG N
R2 R2 O R1 R2 R2 O EWG
13 1 1
4
SM 1 Target Target SM 2 Target
6 4
13 steps @ 90% = 0.913 = 25% yield SM 2 SM 3
5. Disconnect near the middle of the molecule (e.g at branch points, or disconnect rings from chains)
6. Use symmetry
7. Use the ‘best’ disconnection / forward reaction as late as possible in the synthesis
52
Problem Session 1
Propose syntheses of the following compounds from starting materials of your choice
O O
OH O
a) b) CO2Et c) Ph OEt d)
OEt
OH O
Ph
O N Ph O
e) f) MeO g) h)
N
OAc O
O HO Ph
t-Bu
i) from t-Bu O j) k)
NH2
O
O
O
O O
OH Ot-Bu
l) O m) n) o) BocHN OH
NH
Ph
53
Problem Session 1
Propose syntheses of the following pharmaceutical agents from starting materials of your choice
Me
O N
H
O2N N
N
NH2
CN O
Cl HO
CO2H OH O
Baclofen Entacapone Tropisetron
(Novartis) (Parkinson's) (antiemetic)
(Novartis) (Novartis)
HO
HN
N OH
N
N NH2
H
Antazoline Maprotiline Fingolimod
(Antihistamine) (antidepressant) (Immunosuppressive)
(Novartis) (Novartis) (Novartis)
OBn
OH O
N HO
MeO O O
O
O
MeO
• Introduction to retrosynthesis: The origins of the subject, nomenclature, how we go about breaking up
molecules
• Synthons and Reagents: Acceptor and Donor synthons – how to recognise these disconnections and the
importance of (di)oxygenation relationships
• Focus on specific reaction types and methods to install functionality (e.g. amines, alkenes, cycloadditions,
cross-coupling)
55
Aromatic heterocycle synthesis 1: Furans, Pyrroles, Thiophenes
The general theme disconnecting aromatic heterocycles is to cleave C–X bonds within the ring, with a carbonyl precursor. Here we
recognise these C–X bonds as being enols, or imines / enamines (for O, N heterocycles).
2 x enol
FGI C–O O
OH R1 H+
R2
R1 O R2 R1 O R2 (–H2O) R1 O R2
O
1,4-dicarbonyl
(See earlier slides on carbonyl synthesis + next section)
O
FGI 2 x C–O O I O O
OH OEt
R1 R1
R2 EtO R2
R1 O R2 R1 O R2 O O
O OEt
56
Aromatic heterocycle synthesis 1: Furans, Pyrroles, Thiophenes
The general theme disconnecting aromatic heterocycles is to cleave C–X bonds within the ring, with a carbonyl precursor. Here we
recognise these C–X bonds as being enols, or imines / enamines (for O, N heterocycles).
C–N C–N
imine R2 enamine R2
+ NH3
R1 N R2
O O
H R1 NH2 R1 O
FGI (tautomerise)
C–C Br
R2 d2 / a2 R2
O O
R1 NH R1 NH2
C–Br: SOFT
Enamine: SOFT
H NH3
R1 N R2 R1 R2 R1 R2 R1 R2
N N N
H H H OH2 H2 OH
57
Aromatic heterocycle synthesis 1: Furans, Pyrroles, Thiophenes
The general theme disconnecting aromatic heterocycles is to cleave C–X bonds within the ring, with a carbonyl precursor. Here we
recognise these C–X bonds as being enols, or imines / enamines (for O, N heterocycles).
2 x C–S O
R1
R2
R1 S R2
O
1,4-dicarbonyl
P2S5 S
MeO P S
Lawesson’s reagent
S P OMe
S
O O O
R2 R2 R2
R1 R1 R1
a2 d2 O O a3 O d1
umpolung umpolung
58
1,4-dicarbonyl synthesis revisited
O
O
R2 α-halocarbonyl = soft
R1 H+/ H2O w up R2
Br R1 Enamine / 1,3-diCO= soft
N
O
Nef reaction
H+
O O HO O HO OH HO OH
N H+ N N +/- H+ O
HO N
H OH2
59
1,4-dicarbonyl synthesis revisited
SN2 O O + various
O
then H3O+ d1 reagents
R2 R1 Br
R1
a3 O d1 O
1. Base (e.g. Al2O3, R2
R1
OH–, etc.) Et3N, EtOH
O
O R2 O H R2
2. H3O+ or TiCl3 S
R1 NO2 N Bn R1 O
HO
Stetter reaction
Cl
Cl Bn Bn Bn
N Et3N, EtOH N N
H nucleophilic carbene
HO S HO S HO S
Breslow Intermediate
Bn Bn
R H N R +/– H+ N R
O O
R' S H R' S OH
R2
H O
O O R1 Bn O R1 Bn
R2 R2 N R2 N
R1
O O S O S
R' R'
Review of nitroalkane conjugate addition: Ballini et al., Chem. Rev. 2005, 105, 933. 60
For recent leading references on the Stetter reaction, see: Org. Biomol. Chem., 2011, 9, 8437; JACS 2005, 127, 14675.
Aromatic heterocycle synthesis 1: Furans, Pyrroles, Thiophenes
Further functionalization of the heterocycle nucleus can be be achieved under a variety of conditions; these heterocycles react readily with
electrophiles as they are electron rich.
N
H deprotonate at N with NaH (pKa = 16.5)
c) Diels-Alder reactions:
O O O
O Br
O
O 1. Br2 O Heat
O Br O
O 2. amine O
O base O
Note exo-selective
61
Case Study: Atorvastatin
The Pfizer synthesis of atorvastatin contains a classic example of Paal-Knorr pyrrole synthesis, combined with the highly efficient Stetter protocol
to prepare the 1,4-dicarbonyl.
O
O
NH2 O O C–N
HN
OMe
O
toluene
http://www2.chemistry.msu.edu/courses/cem958/FS06_SS07%5CAmand.pdf 62
Aromatic heterocycle synthesis 2: Azoles
For 5-membered rings with two heteroatoms, look for ring-opening C=O disconnections which form C–Heteroatom bonds
Oxazoles:
Use dehydrating conditions R2
Example 1:
R2 N
e.g. POCl3, SOCl2,etc.
R1 R1 R3
NH O
O
Cl R3
R2 R2 C–N R2
N C–O acylation
R1 R1
NH NH2 Cl
R1 O R3
O O
O R3 O R3
enol C=O
C
Ts N - H+
N C O O O
N N
Ph N K2CO3
O Ph H Ph Ph
Ts
'TosMIC'
H
O O O
C N N
N
Ph Ph Ph
Ts Ts Ts
63
Aromatic heterocycle synthesis 2: Azoles
e.g. POCl3 N
O O
R2 1,3-dipolar R2
cycloaddition Synthesis of the nitrile
N oxide is achieved by
R1 O N
R2 dehydration
R1 O
NCS
then N
HO
KHCO3
R2 C–N
C–O
R1 R2 • How can we control
R1 N H2N OH
O the regioselectivity?
O O
Regioselectivity: e.g. Hydroxylamine reacts with the most electrophilic of the two carbonyls:
MeO
O O O OH O
N
soft-soft NH4OAc
O O
Et3N
HS R2 S R2
R1 R1
X O O
O R3
Example 3: By exhaustive imine synthesis!
O O R3 H HN
N
R1 R2 XS NH4OAc R1
R3 R2
HN
N R3 R3 R3
R1 NH2 H2N
R2 HN NH N H2N HN
R1 N N
R3 H R1 R1
R1 R2 H2N R2 H2N H3N
R2 R2
65
Aromatic heterocycle synthesis 2: Azoles
Lithiation:
X n-BuLi X n-BuLi
X X Reaction fails for isoxazoles
Y Y Li Y Li Y
66
Exercise
Plan a synthesis of the non-steroidal anti-inflammatory drug tolmetin, from N-methylpyrrole.
CO2H
N
O
tolmetin
Retro:
C–C
FGI acylation
tolmetin CN CN CN
N N N
O O
Friedel-Crafts equivalent
or direct reaction with acid chloride
Synthesis:
NMe2
1. MeI
NMe2, CH2O 2. NaCN O
NMe2 CN CN
N Mannich N N POCl3 N
Villsmeier O
Reaction at C2
Reaction at C5
NaOH
via NMe3
N N
CO2H
N
O
67
Exercise
Br
N
O N
H
OH O
Broxaterol
OH
N
HO
H2N
Br2
C–N
Br Br Br
a2 / d FGI Br Br
N N N N
O N O O HO
H O O
OH O
Br2,
NaBH4; NaH Br cat. H+ K2CO3
Br
N
O
O Br N
O O
68
Exercise
Propose a synthesis of of the angina / hypertension drug amlopidine:
Amlopidine stepwise Cl
Cl Hantzsch
MeO2C CO2Et O H
Synthesis:
available
EtO2C HO CO2Et CO2Et
N3 NH4OAc
O O O
NaH O N3 H2N N3
Cl
Cl
available
MeO2C CO2Et
O
N N3
MeO2C Cl H
NaOMe
Cl MeO2C
O H2, Pd/CaCO3
O H O
Cl
Amlopidine MeO2C CO2Et
O
N NH2
H
69
Aromatic heterocycle synthesis 3: Pyridines
The classical pyridine disconnection is to recognise a 1,5-dicarbonyl precursor:
–H2O NH2OH
R1 N R2
OH
O O Here we can use our
vast array of 1,5-di-CO
or disconnections....!!
R1 N R2 R1 R2
[ox] R1 N R2
e.g. DDQ, Ce(IV) NH4OAc
H
2x O O O O R2 O O R2 O
NH3
EtO R2 EtO R2 EtO OEt EtO OEt
R1 O R1 O R1 R1 R1 N R1
OO H
O
may proceed
via EtO
R1 NH2
70
Aromatic heterocycle synthesis 3: Pyridines
Variants: To avoid the use of overly reactive Michael acceptors or aldehydes:
NMe2
O O
NH2OH•HCl EtO OEt
heat CO2Et
OEt
O Ph O Ph N Ph NH4OAc
O O N
OEt
PBr3
NaOMe
susceptible to
SEAr reactions...
Br R
NBS
R
N OMe N OMe
71
Aromatic heterocycle synthesis 4: Diazines
The synthesis of Diazines and derivatives simply involves putting the disconnections we have seen so far together! Also remember oxydiazines...
2 x C–N
R2 + ox. O
R2 H2N NH2
N R1
R1 N
Pyridazine: O Note: Oxydiazines are easy to
O convert to chlorides using POCl3.
2 x C–N
This provides a straightforward
O H2N NH2 way to perform SNAr reactions.
O
R2
N
R2
2 x C–N O O NH R1 N O
N H
R1 R2 H2N R3
Pyrimidine: R1 N R3 POCl3
Note: can also include R3 = O, N, S
R2
2 x C–N O X R2
N
R1 R2 H2N NH2 N
R1 N X
X = O, N, S R1 N Cl
Nu
2 x C–N
N R2 + ox. NH2
R2
x2
Pyrazine: R1 N R1 O N
2 x C–N R1 N Nu
R1 N R2 + ox. R1 O H2N R2
R1 N R3 R1 O H2N R3
72
Aromatic heterocycle synthesis 5: Benzannulated heterocycles
Obviously a very important class of compounds – we will again look briefly at some trends, which can equally be applied to bis-heterocyclic systems.
OMe N
Leimgruber-Batcho Nitro reduction
N MeO N
H NO2 NO2
1. heat
2. reduce NO2 DMFDMA
R2 R1 R2
I
Larock R1 R1 R2 Pd(II) Regioselectivity in
N carbopalladation
NH2 NH2
H
Pd(0)
b) Benzofurans [3,3]
O
C–O
O CO2H O
R R
73
Aromatic heterocycle synthesis 5: Benzannulated heterocycles
c) 1,3-Benzimidazoles,
C–X
Benzothiazoles, C–N X "O " R / H+ HN
X e.g.
Benzoxazoles R R reagent at acid H
oxidation level MeO OMe
N NH2 HO OMe , H2N
Ph
X C–X I
X X = S: K3Fe(CN)6 X OAc
R via
X = NH: PhI(OAc)2
N N R N R
H
LG
d) Indazoles, X N–X X Examples:
Benzisothiazoles, N OH
NH DEAD, PPh3 O
Benzisoxazoles
N
R N
R OH
R R
X N–X X
N
N
LG
R R
NMe2
R R
X C–C X N Cl Cl N
N NH2
N N
R
R N NMe2
via NH
Cl NMe2
X C–X F
X SNAr
N
N
R R
74
Aromatic heterocycle synthesis 5: Benzannulated heterocycles
2. Benzannulated 6-membered rings
a) Quinolines
R2 R2
C–C C–N O O
Combes O
R1 R2
N R1 N R1 NH2
H+ H+ or heat
R2 R2 R2
R3 C–C C–N O
Friedländer O O
R3
(acid or base) R1
N R1 NH NH2
H+ H+
R1
R3
b) Isoquinolines
FGI C–C
Bischler-Napieralski
/ POCl3
N N N HN O
R R R R
75
Aromatic heterocycle synthesis 6: Rings with ≥ 3 heteroatoms
To prepare triazoles, oxadiazoles, tetrazoles, etc. we simply modify our disconnections used so far with an emphasis on carbonyl recognition. The
strategies below are colour coded into cycloadditions, excision of a single atom, cyclisation (dehydration), and ‘stepwise cycloaddition’.
1,2,3-triazoles
N
N N R R N N N R
cat. Cu(I)
R
N O
N N R N N N R
R 1,2,4-triazoles
R PPh3 R'
N O O
R R R'
R R
HN NH NH2
R N N
N R
N O N N R'
N R H2N
N R N R R OR
R O R
PPh3 PPh3 N N H2N N O
H
R N R R N R
tetrazoles H2N NH
N N O O R
N R
HN N R N N N N SnBu3
N or TMSN3
R or LiCl, NaN3,
NH4Cl
R N N N R
NH
N NaN3, Tf2O
R R O
76
Aromatic heterocycle synthesis 6: Rings with ≥ 3 heteroatoms
To prepare triazoles, oxadiazoles, tetrazoles, etc. we simply modify our disconnections used so far with an emphasis on carbonyl recognition. The
strategies below are colour coded into cycloadditions, excision of a single atom, cyclisation (dehydration), and ‘stepwise cycloaddition’.
1,2,3-oxadiazoles
O
N N HO N N OH + dehydrating agent
(e.g. Ac2O)
R R R R
1,2,4-oxadiazoles and thiadiazoles
R O R O O
R R + dehydrating agent
N N (e.g. (EtO)3CH)
HN NH
O R OH
N N O
N
R NH2 Cl R
R
S
N N H2N NH2 + S2Cl2
(oxidative method)
purines R R R R
N N NH2
N O
R
N N Cl R
H N NH2
O
O
HN N Y
H2N N
R
X N N X Z
H2N N
H R
77
Exercise
Plan a synthesis of deferasirox from starting materials of your choice
HO2C
N N
N
OH HO
Deferasirox
HO2C
HO2C
HN NH2
N N O O O
2 x C–N
N N N OH
=
H
OH HO Et3N OH HO O
Symmetry suggests
hydrazine disconnection C–N
O O
O
NH2 Cl
N OH
H O
OH HO
OH
N
HN
Amodiaquine
Cl N (antimalarial)
OH OH C–N OH
N N N
HN C–N H2N H2N
Cl
Cl N Problem: Regio/chemoselectivity
Cl N
Et2NH, C–N
CH2O
OH OH
HN H2N
C–N
Cl O OEt
C–N
FGI C–C
Cl N O
Cl N Cl N Cl NH2 O CO2Et
H
POCl3 H+; then heat, OH–
79
Exercise
Plan a synthesis of valatinib from starting materials of your choice
Cl
Cl
H2N
HN Cl O O
C–N FGI FGI
N Valatinib N NH OH NH2
(cancer)
N (Novartis) N N O NH2
heat POCl3
N N N N
NaOMe N
O N
O
O O
OH
NH
O OMe OMe H2N NH2
N
N
N O N O
N
1. ortho-Functionalization. This is a very large topic. Some highlights are selected below.
a) Classical methods
O O OH
i) Claisen rearrangement – a very convenient ~200 °C
method to install an allyl group at the 2-position. H
O
R very versatile functionality
O OH O for further manipulation!
b) Directed ortho-Metallation.
DMG DMG DMG
n- or s-BuLi Li E+ E
Review of directed metallation: V. Snieckus et al., Chem. Rev. 1990, 90, 879. 81
Revisiting arenes – advanced disconnections
Regioselectivity:
TMS =
blocking
group
NEt2 NEt2 NEt2 NEt2
O O O O O O O O OH NEt2
s-BuLi, s-BuLi,
TMEDA Li TMSCl TMS TMEDA TMS Li warm to RT TMS
O
Cl Cl Cl Cl anionic Fries Cl
rearr. iterative DoM
E+ E+
inductive
effect controls NEt2 NEt2 NEt2
regioselectivity
O O O O O O Review of directed metallation:
E E H+ or TBAF TMS E V. Snieckus et al., Chem. Rev. 1990, 90, 879.
For a review of the uses of metallated
heterocycles in organic chemistry, see:
Cl Cl Cl Chem. Rev. 2004, 104, 2667.
• Heteroaromatics: DoM can be useful in heteroaromatic systems, but often the anion can be unstable.
Reviews of heteroaromatic lithiation: Tetrahedron 2001, 57, 4059; Tetrahedron 2001, 57, 4489 82
Revisiting arenes – advanced disconnections
2. Palladium / copper catalyzed cross-coupling: An obviously important strategy. The synthesis of boronic esters and acids is key to this chemistry;
common methods include:
R B(OH)2
H+
R Bpin PdCl2dppf R Br BuLi; R B(OMe)2
R Bpin
pinB–Bpin B(OMe)3
pinacol
[Ir(OMe)cod] / dtbpy
hexane, rt R
See Hartwig, Chem. Soc. Rev., 2011, 40, 1992
pinB–Bpin
Copper-catalyzed amination / amidation is a very attractive and cheap route into aryl amines etc.:
N NH
Cu2O, ligand,
Cs2CO3, MeCN, reflux N N
Br I N N 92% See Beletskaya, Organometallics 2012, 31, 7753
N
then add NH
Reviews:
2 x C–H activation: Chem. Rev. 2011, 111, 1215
Arene arylation by C–H activation: Angew. Chem.
Int. Ed. 2009, 48, 9792
Pd-cat C–H activation: Angew. Chem. Int. Ed.
2009, 48, 5094
Chem Soc Rev 2011 issue 4
83
Asymmetric Synthesis
Due to the breadth of this area, we will not cover in detail! General strategies to bear in mind:
1. Look for available chiral sms, such as amino acids, sugars, epoxides (epichlorohydrin)
O OH O OH O
H2N RO
OH OR Cl OMe
O
R O OH
2. Look for ‘high quality’ catalytic asymmetric processes such as Sharpless AD and AE, Jacobsen epoxidation and hydrolytic kinetic
resolution, Noyori hydrogenations, CBS reduction, organocatalysis (!)
Sharpless AD Sharpless AE
RS RS OH R1
SAD RS RM OH SAE OH
RM RM O
RL RL RL H OH
R1 R1
OH
84
Asymmetric Synthesis
2. Look for ‘high quality’ catalytic asymmetric processes such as Sharpless AD and AE, Jacobsen epoxidation and hydrolytic kinetic
resolution, Noyori hydrogenations, CBS reduction, organocatalysis (!)
Mn(III)(S,S)Salen Cr(III)(R,R)SalenOAc OH
OH
R1
N N
Mn O H2O
R O O R R1
Cl TMSN3
R1 RL OTMS
R1 RL R R
Cr(III)(R,R)SalenN3 1
N3
aq. NaOCl R
O
Ph Ts
N R-BINAP gives R-stereocentre
Ru (when ester has highest priority)
Ph N
O H , i-PrOH OH
R1 R1
>95% ee cat. RuCl2((R)-BINAP)(diamine),
R2 R2 O H2 (8 atm), MeOH OH
(R,R)-Tsdpen ligand gives R- R1 99% ee R1
Ar Ar
stereocentre (when alkyne has
highest priority)
R-BINAP gives S-stereocentre
(when arene has highest priority)
85
Asymmetric Synthesis
3. Look for ‘high quality’ chiral auxiliary / reagent approaches: Asymmetric allylation, Evans auxiliary, etc.
Evans auxiliary
M
O O O O
base, M+ R1
O N O N
R1
Bn Bn
Br
N
Si / cat. Sc(OTf)3,
N Cl CH2Cl2, –30 °C
Br
4. Look for high quality substrate stereocontrol, e.g. Felkin-Anh, Allylic strain, ring functionalisation (stereoelectronics), steric effects (less-
hindered face approach in bicyclics), stereospecific reactions (e.g. epoxide opening with amines or azides to prepare aminoalcohols)
5. Use enzymatic or chemical resolution, which can work really well at an early stage of a synthesis
86
Case Study: Indacaterol
The synthesis of this drug requires the installation of a chiral benzylic alcohol adjacent to an amine. This could well suggest an epoxide strategy, albeit
with regiocontrol issues in the ring-opening due to benzylic stabilisation of the SN2 reaction.
FGI
For Owen: $189/kg
H2N H2N
HN C–N
O
HO HO
Br
Indacaterol C–O
(Chronic Obstructive
Pulmonary Disease)
O N (Novartis) O N O N Identify p-directing group
H H H
OH OH OH
O
Br
C–C
N O N O N
H H
OH OBn OBn
O O O
1. AcCl / AlCl3 1. m-CBPA AcO
2. BnBr, K2CO3 2. Ac2O, 40 °C
N N O N N
H
OH OBn OBn O O OBn
Br2, BF3•OEt2
O
H Ph Ph
O
HO O O
Br N B / BH3•SMe2 Br AcO
K2CO3, H N
acetone Me
O O OBn
91% ee
O N O N O N
H H H
OBn OBn OBn – AcOH, AcO–
Ph 2-pyridone
1. Heat with amine salt O
2. H2, Pd, AcOH N Me
Ph B
H H
Indacaterol B
O
H RS
‘Small’ group positioned here to minimise 1,3-allylic strain
Interestingly RL is the CH2Br
Org. Proc. Res. Dev. 2006, 10, 135. RL
See also: Bioorg. Med. Chem. 2011, 19, 1136. 88
Case study: Gleevec
Gleevac (Novartis) – Tyrosine kinase inhibitor used against gastrointestinal tumours.
Process synthesis developed ca.1996.; several reports on improved syntheses including OPRD paper in 2008, and flow synthesis in 2010.
N N
H H
N N N N FGI OH
N C–N N C–N
N N
HN Cl HO
pyridine NH2
N O O O
N
(4-hydroxymethylbenzoic
Gleevec
Gleevac (Imatinib) acid is available)
FGI
N O NH2
Key steps:
1. Convergent late stage aniline acylation Me2N OEt O
2. Pyrimidine ring formation used as arene coupling step
OEt
N
H H
N N N N N
N C–N Cl
N N
N
H
HN heat HN
91%
N O N O
Gleevec
Gleevac (Imatinib)
C–N 1. NH2NH2 / FeCl3 83%
2. acid chloride, Et3N, 93%
H
Cl N N C–N N NH2 Br
N N
Cl
NO2 DMEDA, CuI, NO2
O K2CO3, dioxane,
N 100 °C, 82% N
guanidine nitrate,
2 x C–N NaOH, BuOH, 86%
Me2N
Key steps / features: HN NH2
• Yields and cost improved through simplifying key steps – e.g pyrimidine O
NH2
ring formation now with guanidine, not functionalised guanidine
• Copper-catalyzed pyrimidine–arene union
N
• Avoids use of H2NCN
C–N
+ FGI FGI 2 x C–N
HN HN HN HN HN
N NH N Cl N O H2N O H2N O
N Ph N NH EtO
H2N H
Novartis PKI 166 NH O
(anticancer) Ph
H2N
Reagent:
NH3
HCl, NH2 Cl
N
EtOH
OEt
CO2Et CO2Et
91
Case study: PKI 166
Synthesis:
HCl, NH2 Cl NH
N NH3
EtOH NaOEt
OEt NH2
CO2Et CO2Et CO2Et
MeO
NH
NH2
MeO
O CO2Et
Br
O
α-methylbenzylamine: available
HN 2. BBr3 HN HN HN
N NH N Cl N O H2N O
N Ph N NH EtO
Synthesis: http://www.chem24h.com/drug/synthesis/ykkjfgvlg.html
Traxler, P.; Bold, G.; Brill, W.K.-D.; Frei, J. (Novartis AG); Pyrrolopyrimidines and processes for the preparation thereof. EP 0836605; JP 1999508570; US 6140332; WO 9702266 . 92
Case Study: Linezolid
O
O
O N N H
N $1.3 billion
sales in 2013
F O
O Linezolid
Cl (antibiotic)
(Pharmacia/Upjohn)
O
O FGI C–C OH
O N N H O N NH OH
N O N NH2
NH
F O F NH F
CDI, imid
O
O
Actual process synthesis: key step: FGI
NH
O O
OBn C–N
O
O N N OBn O N N OLi
H LiOt-Bu
F F NAc O NH F NO2
O
F
O
O N N H
N
F O
OPRD 2003, 7, 533
J. Med. Chem. 1996, 39, 673 93
Case Study: Telcagepant
F3C
The azepane in this Merck migraine drug features two remote
O O stereocentres. These were installed using an organocatalytic
N asymmetric conjugate addition reaction:
F
N N
F H
N N
Telcageplant EtO2CN
NH OL 2006 3307
(migraine) O OL 2006 3311
(Merck) N
O H2N
Cl
1. NaBH3CN, TFA
C–N
C–N N
2 x C–N (CDI) 2. ClO2S then H2O
O
F3C
HN C–N HN
F N O NO2
F N
N N N O
NH2 Cl F
NH Pd(OAc)2 (1 mol%)
O H2N O F
dppb (2 mol%)
aq. i-PrOH, 83 °C
FGI 99% C–N
asymmetric
conjugate addn
CF3
F3C
NH NHAc NO2 NHAc NO2
F N O C–N FGI C=C
F O
CO2H CO2H
NHAc
NH2 F F F
F F F
Ph
N Ph
(5 mol%)
H OTMS NO2 NO2 NHAc
O NHAc
PivOH, B(OH)3,
, DMA CO2H
aq. THF HO2C CO2H
O F F
F 73%, 95% ee
F (35 mol%)
F N F
H
91%, Z:E = 94:6
steps
CF3
F3C
1. HCl, aq. i-PrOH NH NHAc
O 1. PivCl, Et3N,
2. CDI N DMAP
Telcageplant CO2H
3. KOt-Bu, NHAc 2. NaOH / F
>99.9% ee DMSO
HN
F F
F
N N
NH
O
96
Problem Session 2
NC N O
N H
N N NMe2
N O S
HN CF3
O O
N
H
Lestrozole Leflunomide
(Breast cancer) (Arthritis) Sumatriptan
(Novartis) CN (Sanofi-Aventis) (Migraine)
O OH N
N NH
N N
N N O N
N
O
Cl
F
N N
O
H
Valsartan Clozapine Risperidone N
(Blood pressure) (Bipolar disorder) (Antipsychotic)
(Novartis) (Novartis) (J&J) N
Pazopanib OH
(Anticancer) N N
(GSK) N
N N
N N N H2N N
H CN
O
N
Vildagliptin Famciclovir
H2NO2S N N (Anti-diabetic) (Herpes virus)
H (Novartis) (Novartis) OAc OAc
97
Problem Session 2
N
NH NH2
N NC Br
N NH N
O Cl N N N O
N S H
N
O
N N OH F
NH N
H
MeO N N N O N N N
H N
H2N N N HN O O
Fasiplon
(Anxiolytic) N
(Roussel Ucla) Abacavir O Raltegravir
(HIV) N (HIV)
(ViiV healthcare) HO (Merck)
OH O O
F
OH CN
Alvimopan
(Gastrointestinal) N N N N
N Ruxolitinib
Cl (Cancer)
Ph H2N (Novartis)
F
O NH N
Sitafloxacin
OH (Ulcer) N N
(Daiichi Sankyo) H
O
98
99
Appendix: Selectivity in Electrophilic aromatic substitution (SEAr)
Directing effects are crucial for arene functionalization:
π-donors: groups with lone pairs are o-, π-acceptors: groups with low-lying π*
E
p- directing E orbitals are m- directing
HO O
H e.g. OR, OC(O)R, NR2, NHAc, RS e.g. CO2R, NO2, COR, CONH2,
H SO2R, etc.
• Deactivating electron-donating groups: Cl, Br, I, F partial positive charge on EWG also
destabilizes these intermediates.
E weak π-donor so still o-, p- directing but
Cl strong I– deactivates
H
100
Appendix: Selectivity in Nucleophilic aromatic substitution (SNAr)
We can also effect nucleophilic substitution in specific arene systems:
i-Pr2HN – H+
Classical aromatic SN1 is particularly useful for the synthesis of aryl iodides, phenols, nitriles
N
NH2 HONO N Nu or Cu(I)X Nu Particularly useful for Nu:
H2O, ROH
Cu(I)X (Cl, Br, CN)
N
N F KI
NaNO2,
HBF4 BF4
101
Appendix: Arenes – other disconnections
4. Miscellaneous transformations
a) ipso-substitution R O R
O SiMe3
TMS / AlCl3 O TMS
Cl R2 – TMSCl
R1 R R COR
σC–Si → p
Regiospecific substitution
b) oxidative OH O
OH O
dearomatisation
[oxidant] [Oxidant] = DDQ, [oxidant]
R1 R1 Ce(IV)(NO3)6(NH4)2 (CAN), R1 R1
PhI(OAc)2, etc.
O
OMe O
HO
103
Recap: Chemoselectivity based on stereoelectronics
Nucleophile selectivity: In the absence of steric effects, nucleophile selectivity is based on the relative energies of the lone pairs – the higher the
HOMO energy, the better the nucleophile...
π*C=O
O
H
NH2 N S
Cl
HO py
? O Better energy match =
HO N earlier / stronger bond
in TS
O
Electrophile selectivity: Electrophile selectivity is based on sterics, electrostatics, and the relative energies of the acceptor orbitals – the lower the
LUMO energy, the better the electrophile. Another way of looking at this is to consider the degree of stabilisation of the carbonyl, which will be lost on
nucleophilic addition.
O O O O O O O
< N < < < < <
NR2 OR H O Cl
H
R Good overlap of Lower energy R Poor overlap of Cl
O N O donor orbital – O Cl
R high energy l.p. δ+ R l.p. (3p). Negative
stabilises the less stabilisation. inductive effect
amide and raises Positive inductive increases
nN π*C=O the π* energy σC–H π*C=O effect. nCl π*C=O electrophilicity
+I effect –I effect
104
Appendix: Protecting groups
Protecting groups provide an obvious way to protect reactive functionality and achieve chemoselectivity. The cost is at
least one additional step in a synthesis, usually two.
• Sometimes the deprotection of protecting groups can be the most challenging step in a synthesis!
• Protecting group-free synthesis preferred – and may be achieved using a careful ordering of steps...
Order of stability (towards acid): TMS < TES < TBS (TBDMS) < TPS (TBDPS) < TIPS
• The TBDPS group is somewhat more base labile than expected – Ar–Si is more electrophilic.
Selective deprotection of silyl ethers: R. D. Crouch, Tetrahedron 2013, 69, 2383. 105
Appendix: Protecting groups
• Esters / carbonates
Protection Deprotection
O Esters: RCOCl or (RCO)2O, py, DMAP, CH2Cl2 NaOH (aq.), DIBALH. Others are case specific...
O R Particular favourites: R = Me, Ph, CCl3 Halogenated: Use Zn
Carbonates: ROCOCl, py, DMAP, Allyl: Use Pd(0) (generates pi-allyl)
Particular favourites: R = Me, Allyl, Bn, CH2CCl3 Benzyl: Use H2, Pd/C
• Acetals
Protection Deprotection
O O
THP: Dihydropyran / PPTS Mild acid (aq. or methanolic) (e.g. PPTS or
AcOH)
• Other ethers
Protection Deprotection
Me
O O
MOMCl, Hunig’s base, CH2Cl2 HCl (aq.) (fairly concentrated!)
MOMCl, NaH, THF TFA, CH2Cl2
Boron-based Lewis acids
Ph
Ph Trityl chloride, DMAP, DMF (selective for 1° OH)
O Ph Ph3C BF4 very mild acid! (e.g. a column!)
106
Appendix: Protecting groups
2. Protection for amines
• Sulfonamides
Protection Deprotection
O O
RSO2Cl, py, CH2Cl2 Ts: Mg / MeOH, sonication.
S
HN R Particular favourites: or Na/Hg or other single electron reductants
R = p-toluene (Ts) (e.g. Na naphthalenide) or strong base
R = p-nitrophenyl (Ns) Ns: PhSH / K2CO3
Protection Deprotection
For carbonyl: MeOH, H2O, PPTS or HCl
O O HOCH2CH2OH, PPTS or TsOH
For alcohol:
ketone / aldehyde / dimethyl acetal, PPTS or
TsOH
107
Appendix: Alkene synthesis : Wittig Mechanisms
Mechanistic focus: Wittig reaction
Br 1. NaH, THF
Non-stabilized ylid:
R1 PPh3 R1 R2 (Z)-selective
2. R2
O
Sterically disfavoured
Approach of reagents Transition state but it’s TOO LATE!!
Ph Ph R'
Ph O R' Ph O R' R
[2+2] Ph retro [2+2]
Ph P
P P R Z
O H
Ph H Ph H Ph
H R H H
Sterically favoured
Puckered EARLY TS minimises
sterics between R and R’
Ph Ph O R' Ph Ph R'
O R' H retro [2+2]
Ph [2+2] Ph P
P P H E
O H
Ph H Ph H Ph
R H R R
Recent literature: Gilheany et al., JACS, 2012, 134, 9255. Aggarwal et al., JACS, 2006, 128, 2394. 108
Appendix: Alkene synthesis : Wittig Mechanisms
Mechanistic focus: Wittig reaction
• The initial [2+2] is irreversible, and the geometry of the transition state is believed to be controlled by sterics and favourable dipole alignment:
EtO EtO
O O
Ph Ph All structures benefit from
Planar Transition states Ph
Ph R H favourable opposed dipole
P P
H O H alignment
O
Ph H Ph
Sterically R
disfavoured
Rotate Rotate
O O O O
R1 O O
R–O P R–O P
R2 O R1 R2 O H R2 R2 R1
Z H H
E
H R1
110
Appendix: Methods for the synthesis of alkenyl halides and metals
R
cat. Cp2ZrCl2,
Me3Al; I2 R CrCl2, CHCl2Bpin
I R O R
dioxane Bpin
111
Case Study: Aliskiren
The aminoalcohol / diisopropyl core of this drug poses a significant chemical
MeO
challenge. Compare chiral auxiliary approaches (including those used by Novartis) NH2 O O
with a superior recent development that recognises symmetry.
MeO O N NH2
H
OH
• Approach 1: Novartis J. Med. Chem. 1997, 50, 4818 and 4832.
Aliskiren
(Hypertension)
O O (Novartis)
LiHMDS
N O
Li
Bn O O
N O O O Br
BnO BnO BnO
Br Bn N O steps
MeO
N
OH O
BrMg N
BocHN BocHN OMe
H
OBn HCl BnO
RO OBn RO
steps
MeO
MeO non-selective MeO
addition (~1:1)
112
Case Study: Aliskiren
The aminoalcohol / diisopropyl core of this drug poses a significant chemical
MeO
challenge. Compare chiral auxiliary approaches (including those used by Novartis) NH2 O O
with a superior recent development that recognises symmetry.
MeO O N NH2
H
OH
• Approach 2: S. Y. Ko Helv. Chim. Acta. 2012, 95, 1937
Aliskiren
(Hypertension)
(Novartis)
Attack less-hindered face
O O O
LiHMDS;
O acetone O PCl5 O H2 / Pd/C
HO OH
O O O O
(from SAD)
O O O O
Bn
O O LDA; allyl O O O O
bromide Grubbs II RO Li
N O
O N O N O N AD-mix α
O O MeO
Bn Bn Bn
desymmetrisation
O O
H2N NH2 1. H2, Pd/C O O
O
2. MsCl RO
1. O RO 3. LiBr (invert)
Aliskiren OH
2. H2, Pd/C N3 4. NaN3 (invert) MeO
MeO
113