Microwave-Assisted Concise Total Syntheses of Quinazolinobenzodiazepine Alkaloids

Microwave-Assisted Concise Total Syntheses of Quinazolinobenzodiazepine Alkaloids

Ji-Feng Liu, Mira Kaselj, Yuko Isome, Jennifer Chapnick, Bailin Zhang, Grace Bi, Daniel Yohannes,

Libing Yu, and Carmen M. Baldino, Arqule, Inc., J. Org. Chem. 2005, 10488-1-493

N

N

N

N

O

N

O

HH H

Sclerotigenin

Circumdatin F

Asperlicin C

N

N

O

N

O

MeH H

N

N

O

N

O

H H

NH

N

N

O

N

O

H Me

Benzomalvin A Claire Coleman, Current Literature Jan 21 2006

Claire Coleman @ Wipf Group 1 1/22/2006

First Quinazoline Synthesised in late 1860’s

Griess, P. Berichte 1869, 2, 415. Kackler, I. K.; Zaheer, S. H. J. Indian Chem. Soc. 1951, 28, 344. Griess, P. Berichte 1878, 11, 1985. Quinazoline alkaloids (ca. 150)* have been isolated from several families in the plant kingdom, bacteria, animal species and biogenentically derived from anthranilic acid. *Current Organic Chemistry, 2003, 7, 659-677. Nat. Prod. Rep., 2004, 21, 650-668.

N

N

O

Methaqualone

sedative-hypnotic effects

N

NH

O

CN

First synthetic quinazoline


Quinazolinobenzodiazepine Alkaloids

N

N

O

N

O

HH H

Sclerotigenin Circumdatin F Asperlicin C

N

N

O

N

O

MeH H

N

N

O

N

O

H H

NH

N

N

O

N

O

H Me

Benzomalvin A anti-insectant CCK antagonist Snider 1998 Snider Snider Okamoto Thomas 2003 Bergman Bock Review: Natural Product Reports, 2004, 21, 650-668. All of these methodologies required multiple steps and gave low to moderate yields


Sniders’ Synthesis of Sclerotigenin

NH

NH

O O

R

N3

O

Cl

Et3N, DMAP

CH2Cl2/DMSO (2:1)

NH

N

O O

R

ON3

Bu3P, C6H6, 60 C

NH

N

O N

R

O

Sclerotigenin R = H

46 % 2 steps

Circumdatin F R = Me

69 %

(Eguchi-aza Wittig protocol)

(antiinsectant from organic extracts of sclerotia of Penicillium sclerotigenum)

Tetrahedron, 57, 2001, 3301-3307.


Synthesis of (-)Asperlicin C

HN

N

O

H

O

NH

ii)Bu3P, benzene, 60 ˚C

i) o-N3C6H4COCl, Et3N, DMAPHN

N

O

NH

N

O

2 step procedure by Posner, J. Org. Chem, 1987, 52, 1644-1646 64% 2 steps Snider et al J. Am. Chem. Soc. 1998, 120, 6417-6418. Also Bock et al, J. Org. Chem. 1987, 52, 1646-4647. (first total synthesis using regioselective annulation of benzodazepinedione with anthranilic acid)


Diverse Multi-Arrayed Library of the Circumdatin family of Natural products

ONH

N

O

MeO

OMe

N3

O

Cl

Hunigs base,CH2Cl2, rt, 2h, 88%

ON

N

O

MeO

OMe

O

N3

PPh2 (2.5 eqv), 5h

60 ˚C, CH2Cl2, toluene, 75 %

N

N

O

MeO

OMe

O

TFA (10 eqv). TfOH (0.1 eqv), CH2Cl2rt, 4h, 85%

N

N

NH

O

O

NSclerotigenin

Sclerotigenin prepared as model before library Polymer supported phosphine in key step intramolecular aza-wittig

Synthesis, 2003,1707-1711. Hoffmann-LaRoche


Diverse Natural Product like Library of Circumdatins

N

N

O

O

N

R

R

R

283 isolated products from 382 individual reactions

R

Buchi Syncore 24


Benzomalvin A

H2N CO2Me NH

MeCO2MeHCl

2 steps

N3

Cl

O

Et3N, THF, 0 ˚C to rt

NMe

CO2Me

O

N394 %

42 %

i)n-Bu3P, toluene,rt ,2.5h, thenreflux 5h

ii)TFA:H2O:THF1:1:12.5, rt 7 h, 87%

NH

N

O

O

Me

99.7 %ee

i)KHMDS, THF, - 78 ˚C, 1h,

ii) N3

Cl

O

- 78 ˚C to rt 82%

iii) Ph3P, toleune, rt, o/nthen reflux, 98%

N

NO N

Me

O

(-)-Benzomalvin A Okamoto et al, Tetrahedron, 1998, 7997-8008.


Circumdatin F (Bergman-2001)

NH2

O

O

Me

N

Cl

O

S O

toluene, rt, 48h NH2

NH

O

OO

Me

46%

i) Cbz-L-Ala, DCC, CH2Cl2, rt

NH

NH

O

OO

Me

O

MeNHCbzH

PPh3, I2, EtN(i-Pr)2, CH2Cl2, rt, 6h

N

O

N

O

OMe

Me

NHCbzH

57%

20% piperidine in EtOAc, rt, 5h, 67%

N

NH

O

OMe

O

N

Me

NHCbz

H

i)45% HBr in HOAc, 60 ˚C

ii) SiO2, Et3N, EtOAc, rtN

NH

O

H

NO

Circumdatin F

5.5% from 3

3

Bergman et al, J. Org. Chem. 2001, 66, 2784-2788.


One Pot Syntheses of 2,3-Disubstituted Quinazolin-4-ones and Pyrazino[2,1-b]quinazoline-3,6-diones

CO2H

NH2

R3

R4CO2H, then R5NH2

N

N

O

R5

R4

microwave, 3-component one-pot sequential reactions

N

N

O

NH

R2

O

R1

R3

2,3-disubstituted quinazolin-4-ones

pyrazino[2,1-b]quinazoline-3,6-dione core

HO2C NH

Boc

R1

then

R2 CO2Me

NH2HCl

Liu et al, Tetrahedron Lett. 2005, 46, 1241-1244. Liu et al , J. Org. Chem. 2005, 70, 6339-6345.


Total Syntheses of Quinazolinobenzodiazepine Alkaloids Liu et al

Developed a novel domino process for the synthesis of Quinazolinobenzodiazepine Alkaloids including

Sclerotigenin

(±) - Circumdatin F (±)-Aspercilin C

(±)-Benzomalvin A Circumdatin E analogues

Using one reagent, one protecting group and readily available anthranilic acids and Boc-amino acids


Synthesis of Sclerotigenin

CO2H

NH2

HO2C NH

Boc

then

NH2

OMe

ONH

N

O N

O

60 %

P(OPh)3

pyridine, microwave,150 ˚C, 10 min

microwave,250 ˚C, 15 min

Path A

Path B

N

O

O

NH2

N

N

O

H2N

HO2C

trace detected undetectable

three-component one pot reaction


Retrosynthetic Strategy for the “Symmetric” Quinazolinobenzodiazepine Alkaloids via Domino Reactions

N

N

N

O

OR3

R3

R2R1

I

III

II

R2=H

NH2

O

OHH2N

R3O

HOR3

HO2C

R1

N

R2

Boc

II

IIII

reaction sequence would be I, II then III to give products not II, I then III to give by-products


One Step total Syntheses of Sclerotigenin (±) - Circumdatin F (±)-Aspercilin C and the precursor of (±)-Benzomalvin A

CO2H

NH2

HO2C NH

Boc

NH

N

O N

O

P(OPh)3


R1

2 eqv

1 eqv

R1= H, Sclerotigenin, 55%R1 = Me, Circumdatin F, 32%R1 = CH2Indole, Asperlicin C, 20%R1 = Bn, Benzomalvin A precursor, 23%

R1


Formal Total Synthesis of (±)-Aspercilin E

NH

NO

N

O

HN

(rac)-Asperlicin C

N

NO

N

O

NH

HO

H

32%

1O2, rose bengal, CH3OH

pyridine (5%), 0 ˚C, 5h

(rac)-Asperlicin E

conditions- Bock et al, J. Org. Chem. 1987, 52, 1646-4647.


Synthesis of (±)-Benzomalvin A

NH

NO

N

Oi)LiHMDS (2.5 eqv), THF, - 78 ˚C

ii) MeI, rt, 30 min N

NO

N

O

(rac)-Benzomalvin A


Three-Component One –Pot Syntheses of analogues of Circumdatin E

CO2H

NH2

then

NH2

OMe

O

N

NO

N

OP(OPh)3


microwave,250 ˚C, 15 min

R3

N Boc

CO2H

R3 = 4-FR3 = 5- Me

R3

R3 = 4-F, 34%R3 = 5- Me, 29%

•non-symmetric Quinazolinobenzodiazepine Alkaloids


Summary

•Microwave assisted one pot total synthesis of the Quinazolinobenzodiazepine Alkaloids of Sclerotigenin (±) - Circumdatin F (±)-Aspercilin C via novel domino reactions •Two step total synthesis of (±)-Benzomalvin A and formal total synthesis of (±)-Asperlicin E •Access to symmetric and non-symmetric Quinazolinobenzodiazepine Alkaloids using 1 reagent, 1 protecting group and 1 solvent Future directions • Microwave assisted high-throughput natural product combinatorial libraries •Other scaffolds


Microwave-Assisted Concise Total Syntheses of Quinazolinobenzodiazepine Alkaloids

Documents

Transcript of Microwave-Assisted Concise Total Syntheses of Quinazolinobenzodiazepine Alkaloids