Anna Giarratana, Katherine Redford, Sarah Burke, and Stephanie Vrakas.
-
Upload
joana-wynn -
Category
Documents
-
view
221 -
download
3
Transcript of Anna Giarratana, Katherine Redford, Sarah Burke, and Stephanie Vrakas.
A COMPARISON OF TWO
ENANTIOSELECTIVE MINFIENSINE
SYNTHESES
Anna Giarratana, Katherine Redford, Sarah Burke, and
Stephanie Vrakas
Strychnos Alkaloids Alkaloid: a chemical compound that
contains a basic nitrogen. Used traditionally in Chinese medicine. Show anticancer, cytoxicity, antimalarial
properties.
Minfiensine Minfiensine is a pentacyclic indole
strychnos alkaloid. It can be extracted from the African
plantstrychnos minfiensis.
Discovered in 1989 by Massiot and coworkers.
Related Compounds with Tetracyclic Core
Synthetic interest: Challenging to synthesize which gives organic chemists a chance to showcase cascade ring formation reactions.
Tetracyclic Core
What Makes the Synthesis of Minfiensine so Complex?
Minfiensine has a pentacyclic ring system. Integrated into this ring system is an aminal
functionality. Two amines bonded to same carbon atom (similar to acetal).
Several chiral carbons.
NH
N
OH
Sequential Catalytic Asymmetric Heck-Iminium Ion Cyclization:
Enantioselective Total Synthesis of the Strychnos Alkaloid Minfiensine
Overman et al.
SCHEME 1
Click icon to add pictureNH2
OTIPS
+ HN
O
OTIPS
O
NO
NMeO2C O
OTIPS
N
MeO2C TfO
OTIPS
N
CO2Me
NHBoc
NMeO2C
NBoc
p-TsOH, PhH
50 C(95 %)
ClCO2Me, NaHMDS,
THF, -78 C(52-60 %)
Comins' Rgnt,NaHMDS
THF, -78 C(89 %)
N
MeO2C
OTIPS
BocHN
1)9-BBN, NHBoc, 0 C - rt2)NaOH, rt
3) PdCl2(dppf), THF, rt4) H2O2, 0 C(72 %)
N
MeO2C
OTf
BocHN
Comins' Rgnt, CsF, Cs2CO3
DMF, rt(85-95 %)
Pd(OAc)2, Pfaltz ligand, PMP, tolulene, 100 C, 70 h
Pd(OAc)2, Pfaltz ligand, PMP, tolulene, 170 C, 30 min in microwave reactor
or
75-87 %, 99 % ee
TFA
CH2Cl2 N
CO2Me
NHBoc
Overman Scheme 1
NH2
OTIPS
+ HN
O
OTIPS
O
NO
NMeO2C O
OTIPS
N
MeO2C TfO
OTIPS
N
CO2Me
NHBoc
NMeO2C
NBoc
p-TsOH, PhH
50 C(95 %)
ClCO2Me, NaHMDS,
THF, -78 C(52-60 %)
Comins' Rgnt,NaHMDS
THF, -78 C(89 %)
N
MeO2C
OTIPS
BocHN
1)9-BBN, NHBoc, 0 C - rt2)NaOH, rt
3) PdCl2(dppf), THF, rt4) H2O2, 0 C(72 %)
N
MeO2C
OTf
BocHN
Comins' Rgnt, CsF, Cs2CO3
DMF, rt(85-95 %)
Pd(OAc)2, Pfaltz ligand, PMP, tolulene, 100 C, 70 h
Pd(OAc)2, Pfaltz ligand, PMP, tolulene, 170 C, 30 min in microwave reactor
75-87 %, 99 % ee
TFA
CH2Cl2 N
CO2Me
NHBoc
8
1112
Scheme 1- 2 important intermediate steps
Preparation of the cyclohexadienyl aryl triflate precursor
This molecule undergoes Heck Asymmetric Cyclization to produce the tetracyclic core.
5 Steps
NH2
OTIPS
+ HN
O
OTIPS
O
NO
NMeO2C O
OTIPS
N
MeO2C TfO
OTIPS
p-TsOH, PhH
50 C(95 %)
ClCO2Me, NaHMDS,
THF, -78 C(52-60 %)
Comins' Rgnt,NaHMDS
THF, -78 C(89 %)
N
MeO2C
OTIPS
BocHN
1)9-BBN, NHBoc, 0 C - rt2)NaOH, rt
3) PdCl2(dppf), THF, rt4) H2O2, 0 C(72 %)
N
MeO2C
OTf
BocHN
Comins' Rgnt, CsF, Cs2CO3
DMF, rt(85-95 %)
8
NH2
OTIPS
+ HN
O
OTIPS
O
NO p-TsOH, PhH
50 C(95 %)
ClCO2Me, NaHMDS,
THF, -78 C(52-60 %)
NMeO2C O
OTIPS
8
Synthesis of 8- 2 Steps
O
NOO
HO
Step 1: Transamination Step 2: Nitrogen Protection
vs.
NH2
OTIPS
+ HN
O
OTIPS
O
NO
NMeO2C O
OTIPS
N
MeO2C TfO
OTIPS
p-TsOH, PhH
50 C(95 %)
ClCO2Me, NaHMDS,
THF, -78 C(52-60 %)
Comins' Rgnt,NaHMDS
THF, -78 C(89 %)
N
MeO2C
OTIPS
BocHN
1)9-BBN, NHBoc, 0 C - rt2)NaOH, rt
3) PdCl2(dppf), THF, rt4) H2O2, 0 C(72 %)
N
MeO2C
OTf
BocHN
Comins' Rgnt, CsF, Cs2CO3
DMF, rt(85-95 %)
8
Mechanism of Transamination
NH2
OTIPS
+ N
H O
OTIPS
O
NO 1)p-TsO-H, PhH
O
NO
NH2
OTIPS
O
NO
HN
OTIPS
H-0Ts-pN
H O
OTIPS
Nitrogen Protection
Cl OMe
ON
Si
SiHN
O
OTIPS
Na
HN
O
OTIPS
NaN
O
OTIPS
Cl OMe
ON
Si
SiHN
O
OTIPS
Na
Tried: LHMDS, KHMDS, NaHMDS, NaH
Yielded a mixture of 8 and carbamate
N
O
OTIPS
THF, -78 C(52-60 %)
NMeO2C O
OTIPS
Cl OMe
ON
Si
SiHN
O
OTIPS
Cl OMe
O
Na
Nitrogen Protection Mechanism
Optimization of Nitrogen Protection
HN
O
OTIPS
CNCO2Me, LHMDS,
THF, -78 C(89%)
Mandar’s Reagent
NMeO2C O
OTIPS
8
60% to 89% yield
Why? L.G.?
NH2
OTIPS
+ HN
O
OTIPS
O
NO
NMeO2C O
OTIPS
N
MeO2C TfO
OTIPS
p-TsOH, PhH
50 C(95 %)
ClCO2Me, NaHMDS,
THF, -78 C(52-60 %)
Comins' Rgnt,NaHMDS
THF, -78 C(89 %)
N
MeO2C
OTIPS
BocHN
1)9-BBN, NHBoc, 0 C - rt2)NaOH, rt
3) PdCl2(dppf), THF, rt4) H2O2, 0 C(72 %)
N
MeO2C
OTf
BocHN
Comins' Rgnt, CsF, Cs2CO3
DMF, rt(85-95 %)
8
NMeO2C O
OTIPS
N
MeO2C TfO
OTIPS
Comins' Rgnt,NaHMDS
THF, -78 C(82 %)
Triflation
Triflation Mechanism
NMeO2C O
OTIPS
N
MeO2C TfO
OTIPSTHF, -78 C(89 %)
8
N
Si
Si Na
SN
SO
O
OF3C
OCF3
NMeO2C O
OTIPS
Na
N
Cl
Suzuki Cross Coupling
N
MeO2C TfO
OTIPS
N
MeO2C
OTIPS
BocHN
1)9-BBN, NHBoc, 0 C - rt2)NaOH, rt
3) PdCl2(dppf), THF, rt4) H2O2, 0 C(72 %)
NH2
OTIPS
+ HN
O
OTIPS
O
NO
NMeO2C O
OTIPS
N
MeO2C TfO
OTIPS
p-TsOH, PhH
50 C(95 %)
ClCO2Me, NaHMDS,
THF, -78 C(52-60 %)
Comins' Rgnt,NaHMDS
THF, -78 C(89 %)
N
MeO2C
OTIPS
BocHN
1)9-BBN, NHBoc, 0 C - rt2)NaOH, rt
3) PdCl2(dppf), THF, rt4) H2O2, 0 C(72 %)
N
MeO2C
OTf
BocHN
Comins' Rgnt, CsF, Cs2CO3
DMF, rt(85-95 %)
8
- add beta-aminoethyl
Suzuki RXN
N
MeO2C TfO
OTIPS
PdCl2(dppf)
Pd(dppf)
N
MeO2C Pd
OTIPS
LL
OTf
N
MeO2C Pd
OTIPS
LL
NHBoc
N
MeO2C
OTIPS
BocHN
oxidative addition
transmetallation
reductive elimination
Triflation
N
MeO2C
OTIPS
BocHN
N
MeO2C
OTf
BocHN
Comins' Rgnt, CsF, Cs2CO3
DMF, rt(85-95 %)
NH2
OTIPS
+ HN
O
OTIPS
O
NO
NMeO2C O
OTIPS
N
MeO2C TfO
OTIPS
p-TsOH, PhH
50 C(95 %)
ClCO2Me, NaHMDS,
THF, -78 C(52-60 %)
Comins' Rgnt,NaHMDS
THF, -78 C(89 %)
N
MeO2C
OTIPS
BocHN
1)9-BBN, NHBoc, 0 C - rt2)NaOH, rt
3) PdCl2(dppf), THF, rt4) H2O2, 0 C(72 %)
N
MeO2C
OTf
BocHN
Comins' Rgnt, CsF, Cs2CO3
DMF, rt(85-95 %)
8
cyclohexadienyl aryl triflate precursor
Triflation Mechanism
N
MeO2C
OTf
BocHN
DMF, rt(85-95 %)
N
MeO2C
OTIPS
BocHN
CsF, Cs2CO3
SN
SO
O
OF3C
OCF3
N
Cl
Formation of the tetracyclic core
Pd(OAc)2, Pfaltz ligand, PMP, tolulene, 100 C, 70 h
N
CO2Me
NHBoc
75-87 %, 99 % ee
N
MeO2C
OTf
BocHN
N
CO2Me
NHBoc
NMeO2C
NBoc
N
MeO2C
OTf
BocHN
Pd(OAc)2, Pfaltz ligand, PMP, tolulene, 100 C, 70 h
Pd(OAc)2, Pfaltz ligand, PMP, tolulene, 170 C, 30 min in microwave reactor
75-87 %, 99 % ee
TFA
CH2Cl2 N
CO2Me
NHBoc
1112
Asymmetric Heck Cyclization
A little bit about the rxn... The Heck rxn was discovered in 1970 In 1977 Mori and Ban reported the first
INTRAmolecuar Heck Shibasaka and Overman discovered the
Asymmetric Heck Cyclization in 1989- still being studied to this day
Makes tertiary and quaternary stereocenters
Needs precatalyst, a chiral ligand, a base, a polar aprotic solvent, heat
Example Ligands
Attempt 1:
N
MeO2C
OTf
BocHN
Pd(OAc)2, BINAP, PMP, toulene, 80 C
N
CO2Me
NHBoc
60 % yield
N
CO2Me
NHBoc
N
CO2Me
NHBoc
vs.
BINAP PMP
Problem:
N
CO2Me
NHBoc
Pd
Mix it up!
N
MeO2C
OTf
BocHN
Pd(OAc)2, PHOX, PMP, toulene, 100C, 70h
N
CO2Me
NHBoc
79 % yield88% e.e.
Use chiral (phosphinoaryl) oxazolines ligands!
However, to improve enantioselectivity to 96 % e.e. ACN was used at 80 C
Problem: 10% alkene isomerization
N
CO2Me
NHBoc
N
O
PPH3
iPr
i-Pr PHOX
So then...
N
MeO2C
OTf
BocHN
Pd(OAc)2, Faltz, PMP, toulene, 100C, 70 h
N
CO2Me
NHBoc
75-85 % yield99% e.e.
N
O
PPH3
tBu
With the replacement of the PHOX ligand and a consideration of time:
N
MeO2C
OTf
BocHN
Pd(OAc)2, PHOX, PMP, toulene, 170 C, 30 mins in a microwave
N
CO2Me
NHBoc
75-85 % yield99% e.e.
Asymmetric HeckCyclization
Mechanism of Asymmetric Heck Cyclization
Pd(OAC)2
oxidative addition
PdL2
N
MeO2C
Pd
BocHN
L
LTfO
N
MeO2C
Pd
BocHN
LL
ligandsubstitution
1, 2 insertion
N
CO2Me
NHBoc
PdOTf
HL
L
PMP
1,2 deinsertion
N
MeO2C
BocHN
OTfReductiveElimination
N
MeO2C
BocHN
L2Pd
N
CO2Me
BocHN
PdL2
Synthesis of 12, the tetracyclic core
N
CO2Me
NHBoc
NMeO2C
NBoc
TFA
CH2Cl2 N
CO2Me
NHBoc
1112
N
CO2Me
NHBoc
NMeO2C
NBoc
N
MeO2C
OTf
BocHN
Pd(OAc)2, Pfaltz ligand, PMP, tolulene, 100 C, 70 h
Pd(OAc)2, Pfaltz ligand, PMP, tolulene, 170 C, 30 min in microwave reactor
75-87 %, 99 % ee
TFA
CH2Cl2 N
CO2Me
NHBoc
1112
Note: It is important to recognize that
although the core is formed the absolute configuration was not established
SCHEME 2
Click icon to add pictureN N
BocMeO2CN N
BocMeO2C
OmCPBA
CH2Cl2, 0 oC -> rt (87%)
N NAllocMeO2C
O
rt (92%)
O Cl
O(alloc), K2CO3 (PhSe)2 , NaBH4
MeOH/THF, 70oCN N
AllocMeO2C
HO SePhH2O2
0oC -> 70oC (83%)
N NAllocMeO2C
HO
15
TES-Cl, imidazole
CH2Cl2, rt (90%)N N
AllocMeO2C
OTES
16
N NMeO2C
O
TES
17
Pd(PPh3)4 ,
TfO I
pyrrolidine, THF, rt
70oC (96%) IN N
MeO2C
OTES
Pd(OAc)2, K2CO3, NaO2CH
Bu4NCl, DMF, 80oC (80%)
18
K2CO3, MeCN
N NHMeO2C
OTES
N NHMeO2C
OTFA
0oC -> rt (98%)
Step A: Epoxide Synthesis The authors were initially concerned about the facial
selectively of epoxidation. Using mCPBA the epoxide adds to the back face with
10:1 stereoselectivity.
CH2Cl2, 0 oC -> rt (87%)N NBocMeO2C
12
O
O
OH
Cl
N NBocMeO2C
O
Epoxide Stereoselectivity
Favored Conformation of Cyclohexene Ring
Computational studies showed that the cyclohexene ring prefers to exist in a half chair conformation.
Therefore mCPBA will approach anti to the indole bridge.
Steps B, C, and D:Initial Plan
N NBocMeO2C
O
N NBocMeO2C
HO
N NBocMeO2C
BnOTFA
N NHMeO2C
BnO
Ring FragmentationUnder Acid Conditions
However, the acid conditions used to remove Boc promoted fragmentation of the molecule.
N NBocMeO2C
BnOCH3COOH
NCO2Me
BnOBocHN
NCO2Me
NHBoc
OBn
CF3COO-
NCO2Me
NHBoc
OBn
OCOCF3
NCO2Me
NHBoc
CHOH2O
38
Boc Deprotection Take 2 Because the fragmentation only
occurred under acid conditions, other methods were attempted to remove the Boc protecting group.
Heating in DMSO Heating in a microwave reactor
None of these methods worked!
Boc Can Be RemovedEarlier in the Scheme
However, the Boc protecting group can be removed immediately following epoxidation.
Why here and not later? The same protonation and initial ring opening
will occur in the presence of acid, but the epoxide ensures that further fragmentation will not.
NCO2Me
BnOBocHN
vs.
NCO2Me
BocHN O
Steps B and C Protection Problems?
So following epoxidation, the Boc protecting group is removed with TFA.
N NBocMeO2C
O
N NHMeO2C
OTFA
0oC -> rt (98%)
N NMeO2C
O
OO
CF3COOH
N NMeO2C
O
OO+ H
H
:Base
N NHMeO2C
O
+ CO2 +
Steps B and C Protection Problems?
Then the amine is REPROTECTED with alloc (allyloxy carbonyl)!
Alloc can be removed using catalytic reduction conditions later in the scheme which will not cause a ring opening like acid did.
N NHMeO2C
O
N NAllocMeO2C
O
rt (92%)
O Cl
O
(alloc-Cl), K2CO3
15
Step D: Epoxide Opening/Elimination Using Sharpless-Lauer Conditions
N NAllocMeO2C
O1) (PhSe)2 , NaBH4, MeOH/THF, 70oC
15
N NAllocMeO2C
O
15
(PhSe)2 + NaBH4 NaSePh
N NAllocMeO2C
HO
2) H2O2, 0oC -> 70oC (83%)
-SePh
N NAllocMeO2C
HO SePhHO - OH
N NAllocMeO2C
HO Se+Ph
:Base
N NAllocMeO2C
HO Se+Ph
OH
H
O-
N NAllocMeO2C
HO
Step D: Initial Epoxide Opening/Elimination Attempts Before using the organoselenide
method, the authors attempted using lithium amide bases.
They tried lithium diisopropylamide and lithium diethylamide and even heated the reaction to 45 degrees C!
N NAllocMeO2C
LiNR2H
N NAllocMeO2C
HOO
Rapid Loss of Methyl Carbamate This did not work because there was a
rapid loss of the methyl carbamate group.
N NAlloc
O
LiNR2
OMeO
NH
NAlloc
O
Steps E and F: Hydroxyl Protection and Amine Alkylation
Note that the hydroxyl group is protected with TES and not Bn as in the initial scheme.
Bn will be removed by the catalytic reduction conditions used to remove Alloc.
N NAllocMeO2C
HOTES-Cl, imidazole
CH2Cl2, rt (90%)N N
AllocMeO2C
OTES
N NAllocMeO2C
OTES
16
16
N NMeO2C
OTES
17
Pd(PPh3)4 ,
TfO I
pyrrolidine, THF, rt
70oC (96%) I
K2CO3, MeCN
N NHMeO2C
OTES
Step G: Synthesis of 18 To form the final ring of minfiensine
Heck cyclization-carbonylation sequence First Attempt:
Step G: Synthesis of 18 Inability to create desired product
Led to attempt using reductive conditions Second Attempt:
Scheme 2 Step G: Synthesis of 18
Fail. Why?
Thoughts:
Scheme 2 Step GSynthesis of 18
Rational behind undesired product formation:Double bond migrationPd (II) functions as a Lewis acidActivates aminal functionality towards ring
cleavageFacilitates double bond migration
Scheme 2 Step GSynthesis of 18
Heck reaction under Jeffrey Conditions Inorganic bases and
tetraalkylammonium halides Hope that Heck cyclization
faster than double bond isomerization
After optimization: DMF, 30 min, 80 C 1 mol % Pd(OAc)2, K2CO3 (5
eq), (n-Bu)4-NCl (2.5 eq), NaO2CH (1.2 eq)
No pentacyclic isomer (57) Limited deallylation
product (46)
Synthesis of 18 (Step G): Heck Reaction with a Reductive Trap
K2CO3, Bu4NCl, NaO2CH, DMF
80oC (80%)
Pd(OAc)2
Ligand Substitution
L-Pd0-L
Oxidative Addition
Ligand Associatioin
Reductive Elimination
N NMeO2C
OTES
17
I
Pd(OAc)2
N NMeO2C
OTES
18
N NMeO2C
OTES
17
I
N NMeO2C
OTES
Pd
L
L
I
N NMeO2C
OTES
Pd
L
L
N NMeO2C
OTES
Oxidative Additoin
N NMeO2C
OTES
Pd
L
L
1, 2 Insertion
N NMeO2C
OTES
Pd
H
O-
OI
H
Phosphine-Free Heck: A Heck Reaction Using Jeffrey Conditions
These conditions do not contain a phosphine ligand!!! But Pd(II) cannot do a Heck and Pd(0) cannot exist without any ligands…
We think that water might act as a ligand in this reaction.
Note that the salt Bu4NCl is believed to speed up the reaction.
K2CO3, Bu4NCl-H2O, NaO2CH, DMF
80oC (80%)
N NMeO2C
OTES
17
I
Pd(OAc)2
N NMeO2C
OTES
18
SCHEME 3
Click icon to add pictureN N
MeO2C
OTES
N NMeO2C
HO
TBAF
THF, rt (100%)
DMP
CH2Cl2, rt (99%) N NMeO2C
O
18
CNCO2Me, LiHMDS
THF, -78 C (71%)
N NMeO2C
OOMeHO
N NMeO2C
OOMeBzO
BzOTf, pyridine
CH2Cl2, 60 C (100%)
KHMDS
THF, -78 C (83%)
N NMeO2C
O
OOMe
N NMeO2C
OOMeHO
tautomerization
19
NaBH4
MeOH/THF, 0 C (60%)
N NMeO2C
OOMe
20
N NMeO2C
OH
LiAlH4
THF, -20 C (89%) NH
N
OH
NaOH, MeOH
H2O, 100 C, 95%
4
Scheme 3 Made tetracyclic core! Last Step:
A double bond and a one carbon side chain installed in the cyclohexane ring
Steps A and B Deprotection and Oxidation
N NMeO2C
OTES
N NMeO2C
HOTBAF
THF, rt (100%)
DMP
CH2Cl2, rt (99%)
N NMeO2C
O
18
NH
N
HO
DMP
CH2Cl2, rt (99%) N NMeO2C
O
O
I
O
OAcAcO
N
N
CO2MeO
H
O
I
O
OAcAcO
OAc
Steps C and DMandar’s Reagent and Reduction
N NMeO2C
O
CNCO2Me, LiHMDS
THF, -78 C (71%)N N
MeO2C
O
OOMe
N NMeO2C
O
OOMe
N NMeO2C
OOMeHO
tautomerization
19
NaBH4
MeOH/THF, 0 C (60%) N NMeO2C
OOMeHO
Beta-keto ester exists nearly exclusively as enol tautomer
Mechanism of Step D Reduction
N NMeO2C
O
OOMe
NaBH4
MeOH/THF, 0 C (60%)N N
MeO2C
OOMeHO
N NMeO2C
O
OOMe
MeOH
Na BH2
H
Synthesis of 20 First:
Tried traditional methods to dehydrate beta-hydroxy ester
Tried reaction with: Methanesulfonyl chloride Triflic anhydride and triethylamine
Next: Tried two step dehydration
Steps E and F, Synthesis of 20
N NMeO2C
OOMeHO
N NMeO2C
OOMeTfO
BzOTf, pyridine
CH2Cl2, 60 C (100%)
N NMeO2C
OOMeTfO
N NMeO2C
OOMe
20
KHMDS
THF, -78 C (83%)
H
N NMeO2C
OOMeTfO
Scheme 3: Finally…
N NMeO2C
OOMe
20
N NMeO2C
OHLiAlH4
THF, -20 C (89%)
NaOH, MeOH
H2O, 100 C, 95%
NH
N
OH
4Minfiensine!!!
Nine-Step Enantioselective Total
Synthesis of (+)-Minfiensine
MacMillan et al
STEP A: AMINE PMB PROTECTION
NH
NHBoc
NPMB
NHBocNaH, PMBCl
DMF, 0oC
12
N
NHBoc
NaHH
N
NHBoc
O
Cl
PMBN
NHBoc
Steps B and C: Aldehyde Formation + HWE Reaction
NPMB
NHBoc
H
n-Bu Li
NPMB
NHBoc
Li
NPMB
NHBoc
Li
O
NMe2
NPMB
NHBoc
H
O
NPMB
NHBoc
H
O
S P
O
OEtOEt
NPMB
NHBoc
OP(OEt)2
S
NHBoc
OP(OEt)2
S
NPMB
NHBoc
S
O
O
SYNTHESIS OF 15:STEP D
Click icon to add picture
N SMe
NR
R
BocHN
PMB
NPMB
NBoc
SMe
cyclization
N
NHBoc
SMeN SMe
NR
R
BocHN
PMB
PMB
N SMe
NR
R
BocHN
PMB N SMe
NR
R
BocHN
PMB
O
NH
N
Bn
O
N
N
Bn
O
N
NHBoc
SMePMB
89
H-A
H-A
NPMB
NBocS
Me
O
11
NR
R
NPMB
NBoc
SMe
NR
RNaBH4, CeCl3, MeOH
NPMB
NBocS
Me
OH
15
Enantioselective Diels-Alder
N
NHBoc
SMeN SMe
NR
R
BocHN
PMB
PMB
O
NH
N
Bn
O
N
N
Bn
O
N
NHBoc
SMePMB
89
Cyclization Cascade
N SMe
NR
R
BocHN
PMB
NPMB
NBoc
SMe
cyclization
N SMe
NR
R
BocHN
PMB N SMe
NR
R
BocHN
PMB
H-A
H-A
NR
R
Aldehyde Formation and Reduction
NPMB
NBocS
Me
O
11
NPMB
NBoc
SMe
NR
RNaBH4, CeCl3, MeOH
NPMB
NBocS
Me
OH
15
Enantiocontrol
Step E: Protection of the Alcohol
NPMB
NBocS
Me
OH
15
NPMB
NH
SMe
O
16
TESTESOTf
MeCN, 0 C
Mechanism:
NPMB
NBocS
Me
OH
15
NPMB
NH
SMe
O
16
TES
Si
OS O
OF3C
NPMB
NH
SMe
OHTES
Si
O
Steps F: N-Alkylation
NPMB
NH
OTES
SMe O
sBuN
PMB
N
OTES
SMe
H
O SBu
A H
NPMB
N
OTES
SMeOH SBu
A H
NPMB
N
OTES
SMeOH2 SBu
A
NPMB
N
OTES
SMe SBuA H
NPMB
N
OTES
SMe SBu
Step G: In Situ Reagent Formation
NN
NN
AIBN = Azobisisobutyronitrile
N N +
N
N
N
+SnH tBu
Sn
tBu
H
Step G: Alkyne Radical Cyclization
Using AIBN and Bu3SnH, the reaction was unsuccessful. Therefore the authors used the more hindered tBu3SnH.
NPMB
N
OTES
19
AIBN (0.3 eq) , t-BuSnH (3 eq)
Toluene, 110 C
NPMB
N
OTES
18
StBuSMe
H
NPMB
N
OTES
StBu
NPMB
N
OTES
StBu
Recall: 6-exo-dig
A six-membered ring is formed (6)The bond broken to form the ring lies
outside of the ring (exo)The electrophilic carbon is sp hybridized
(dig)
Steps H and I: Reduction and Deprotection
Pd selectively reduces the less hindered double bond.
NPMB
N
OTES
19
NPMB
N
OTESPd/C, H2
THF, -15 C
Me
PhSh, TFA, rt NH
N
OH
Me1
Overman vs. MacMillan
Retrosynthesis Comparison
Comparison of the Two Methods
Overman et al. MacMillan et al.
Linear Progression 2005:
22 Steps 4.1 % overall yield
2008: 15 steps 6.5% overall yield
Original Synthesis Noteworthy
reactions Asymmetric Heck
Retrosynthetic Approach
9 Steps 21% overall yield New Synthesis Noteworthy
reactions Diels-Alder Alkyne Radical
Coupling