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.

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

NMeO2C O

MeO2C TfO

NMeO2C

p-TsOH, PhH

50 C(95 %)

ClCO2Me, NaHMDS,

THF, -78 C(52-60 %)

Comins' Rgnt,NaHMDS

THF, -78 C(89 %)

1)9-BBN, NHBoc, 0 C - rt2)NaOH, rt

3) PdCl2(dppf), THF, rt4) H2O2, 0 C(72 %)

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

CH2Cl2 N

Overman Scheme 1

NMeO2C O

MeO2C TfO

NMeO2C

p-TsOH, PhH

50 C(95 %)

ClCO2Me, NaHMDS,

THF, -78 C(52-60 %)

Comins' Rgnt,NaHMDS

THF, -78 C(89 %)

DMF, rt(85-95 %)

75-87 %, 99 % ee

CH2Cl2 N

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

NMeO2C O

MeO2C TfO

p-TsOH, PhH

50 C(95 %)

ClCO2Me, NaHMDS,

THF, -78 C(52-60 %)

Comins' Rgnt,NaHMDS

THF, -78 C(89 %)

DMF, rt(85-95 %)

NO p-TsOH, PhH

50 C(95 %)

ClCO2Me, NaHMDS,

THF, -78 C(52-60 %)

NMeO2C O

Synthesis of 8- 2 Steps

Step 1: Transamination Step 2: Nitrogen Protection

NMeO2C O

MeO2C TfO

p-TsOH, PhH

50 C(95 %)

ClCO2Me, NaHMDS,

THF, -78 C(52-60 %)

Comins' Rgnt,NaHMDS

THF, -78 C(89 %)

DMF, rt(85-95 %)

Mechanism of Transamination

NO 1)p-TsO-H, PhH

H-0Ts-pN

Nitrogen Protection

Cl OMe

Tried: LHMDS, KHMDS, NaHMDS, NaH

Yielded a mixture of 8 and carbamate

THF, -78 C(52-60 %)

NMeO2C O

Cl OMe

Nitrogen Protection Mechanism

Optimization of Nitrogen Protection

CNCO2Me, LHMDS,

THF, -78 C(89%)

Mandar’s Reagent

NMeO2C O

60% to 89% yield

Why? L.G.?

NMeO2C O

MeO2C TfO

p-TsOH, PhH

50 C(95 %)

ClCO2Me, NaHMDS,

THF, -78 C(52-60 %)

Comins' Rgnt,NaHMDS

THF, -78 C(89 %)

DMF, rt(85-95 %)

NMeO2C O

MeO2C TfO

Comins' Rgnt,NaHMDS

THF, -78 C(82 %)

Triflation

Triflation Mechanism

NMeO2C O

MeO2C TfO

OTIPSTHF, -78 C(89 %)

NMeO2C O

Suzuki Cross Coupling

MeO2C TfO

NMeO2C O

MeO2C TfO

p-TsOH, PhH

50 C(95 %)

ClCO2Me, NaHMDS,

THF, -78 C(52-60 %)

Comins' Rgnt,NaHMDS

THF, -78 C(89 %)

DMF, rt(85-95 %)

- add beta-aminoethyl

Suzuki RXN

MeO2C TfO

PdCl2(dppf)

Pd(dppf)

MeO2C Pd

oxidative addition

transmetallation

reductive elimination

Triflation

DMF, rt(85-95 %)

NMeO2C O

MeO2C TfO

p-TsOH, PhH

50 C(95 %)

ClCO2Me, NaHMDS,

THF, -78 C(52-60 %)

Comins' Rgnt,NaHMDS

THF, -78 C(89 %)

DMF, rt(85-95 %)

cyclohexadienyl aryl triflate precursor

Triflation Mechanism

DMF, rt(85-95 %)

CsF, Cs2CO3

Formation of the tetracyclic core

75-87 %, 99 % ee

NMeO2C

75-87 %, 99 % ee

CH2Cl2 N

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:

Pd(OAc)2, BINAP, PMP, toulene, 80 C

60 % yield

BINAP PMP

Problem:

Mix it up!

Pd(OAc)2, PHOX, PMP, toulene, 100C, 70h

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

i-Pr PHOX

So then...

Pd(OAc)2, Faltz, PMP, toulene, 100C, 70 h

75-85 % yield99% e.e.

With the replacement of the PHOX ligand and a consideration of time:

Pd(OAc)2, PHOX, PMP, toulene, 170 C, 30 mins in a microwave

75-85 % yield99% e.e.

Asymmetric HeckCyclization

Mechanism of Asymmetric Heck Cyclization

Pd(OAC)2

oxidative addition

ligandsubstitution

1, 2 insertion

1,2 deinsertion

OTfReductiveElimination

Synthesis of 12, the tetracyclic core

NMeO2C

CH2Cl2 N

NMeO2C

75-87 %, 99 % ee

CH2Cl2 N

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

rt (92%)

O(alloc), K2CO3 (PhSe)2 , NaBH4

MeOH/THF, 70oCN N

AllocMeO2C

HO SePhH2O2

0oC -> 70oC (83%)

N NAllocMeO2C

TES-Cl, imidazole

CH2Cl2, rt (90%)N N

AllocMeO2C

N NMeO2C

Pd(PPh3)4 ,

pyrrolidine, THF, rt

70oC (96%) IN N

Pd(OAc)2, K2CO3, NaO2CH

Bu4NCl, DMF, 80oC (80%)

K2CO3, MeCN

N NHMeO2C

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

N NBocMeO2C

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

BnOTFA

N NHMeO2C

Ring FragmentationUnder Acid Conditions

However, the acid conditions used to remove Boc promoted fragmentation of the molecule.

N NBocMeO2C

BnOCH3COOH

NCO2Me

BnOBocHN

NCO2Me

CF3COO-

NCO2Me

OCOCF3

NCO2Me

CHOH2O

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

NCO2Me

BocHN O

Steps B and C Protection Problems?

So following epoxidation, the Boc protecting group is removed with TFA.

N NBocMeO2C

N NHMeO2C

0oC -> rt (98%)

N NMeO2C

CF3COOH

N NMeO2C

N NHMeO2C

+ 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

N NAllocMeO2C

rt (92%)

(alloc-Cl), K2CO3

Step D: Epoxide Opening/Elimination Using Sharpless-Lauer Conditions

N NAllocMeO2C

O1) (PhSe)2 , NaBH4, MeOH/THF, 70oC

N NAllocMeO2C

(PhSe)2 + NaBH4 NaSePh

N NAllocMeO2C

2) H2O2, 0oC -> 70oC (83%)

N NAllocMeO2C

HO SePhHO - OH

N NAllocMeO2C

HO Se+Ph

N NAllocMeO2C

HO Se+Ph

N NAllocMeO2C

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

Rapid Loss of Methyl Carbamate This did not work because there was a

rapid loss of the methyl carbamate group.

N NAlloc

NAlloc

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

N NAllocMeO2C

N NMeO2C

Pd(PPh3)4 ,

pyrrolidine, THF, rt

70oC (96%) I

K2CO3, MeCN

N NHMeO2C

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

Pd(OAc)2

N NMeO2C

Oxidative Additoin

N NMeO2C

1, 2 Insertion

N NMeO2C

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

Pd(OAc)2

N NMeO2C

SCHEME 3

Click icon to add pictureN N

N NMeO2C

THF, rt (100%)

CH2Cl2, rt (99%) N NMeO2C

CNCO2Me, LiHMDS

THF, -78 C (71%)

N NMeO2C

OOMeHO

N NMeO2C

OOMeBzO

BzOTf, pyridine

CH2Cl2, 60 C (100%)

THF, -78 C (83%)

N NMeO2C

OOMeHO

tautomerization

MeOH/THF, 0 C (60%)

N NMeO2C

LiAlH4

THF, -20 C (89%) NH

NaOH, MeOH

H2O, 100 C, 95%

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

HOTBAF

THF, rt (100%)

CH2Cl2, rt (99%)

N NMeO2C

CH2Cl2, rt (99%) N NMeO2C

OAcAcO

CO2MeO

OAcAcO

Steps C and DMandar’s Reagent and Reduction

N NMeO2C

CNCO2Me, LiHMDS

THF, -78 C (71%)N N

N NMeO2C

OOMeHO

tautomerization

MeOH/THF, 0 C (60%) N NMeO2C

OOMeHO

Beta-keto ester exists nearly exclusively as enol tautomer

Mechanism of Step D Reduction

N NMeO2C

MeOH/THF, 0 C (60%)N N

OOMeHO

N NMeO2C

Na BH2

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

THF, -78 C (83%)

N NMeO2C

OOMeTfO

Scheme 3: Finally…

N NMeO2C

OHLiAlH4

THF, -20 C (89%)

NaOH, MeOH

H2O, 100 C, 95%

4Minfiensine!!!

Nine-Step Enantioselective Total

Synthesis of (+)-Minfiensine

MacMillan et al

STEP A: AMINE PMB PROTECTION

NHBocNaH, PMBCl

DMF, 0oC

Steps B and C: Aldehyde Formation + HWE Reaction

n-Bu Li

OEtOEt

OP(OEt)2

SYNTHESIS OF 15:STEP D

Click icon to add picture

cyclization

SMeN SMe

PMB N SMe

SMePMB

RNaBH4, CeCl3, MeOH

Enantioselective Diels-Alder

SMeN SMe

SMePMB

Cyclization Cascade

cyclization

PMB N SMe

Aldehyde Formation and Reduction

RNaBH4, CeCl3, MeOH

Enantiocontrol

Step E: Protection of the Alcohol

TESTESOTf

MeCN, 0 C

Mechanism:

Steps F: N-Alkylation

SMeOH SBu

SMeOH2 SBu

SMe SBuA H

SMe SBu

Step G: In Situ Reagent Formation

AIBN = Azobisisobutyronitrile

+SnH tBu

Step G: Alkyne Radical Cyclization

Using AIBN and Bu3SnH, the reaction was unsuccessful. Therefore the authors used the more hindered tBu3SnH.

AIBN (0.3 eq) , t-BuSnH (3 eq)

Toluene, 110 C

StBuSMe

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

Steps H and I: Reduction and Deprotection

Pd selectively reduces the less hindered double bond.

OTESPd/C, H2

THF, -15 C

PhSh, TFA, rt NH

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

anna giarratana, katherine redford, sarah burke, and stephanie vrakas

heat slide

carbamate slide

triflation slide

tetracyclic core slide

suzuki rxn slide

stephanie vrakas slide

betaaminoethyl slide

heck asymmetric cyclization

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