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