Post on 31-Jan-2023
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
Claire Coleman @ Wipf Group 2 1/22/2006
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
Claire Coleman @ Wipf Group 3 1/22/2006
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.
Claire Coleman @ Wipf Group 4 1/22/2006
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)
Claire Coleman @ Wipf Group 5 1/22/2006
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
Claire Coleman @ Wipf Group 6 1/22/2006
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
Claire Coleman @ Wipf Group 7 1/22/2006
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.
Claire Coleman @ Wipf Group 8 1/22/2006
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.
Claire Coleman @ Wipf Group 9 1/22/2006
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.
Claire Coleman @ Wipf Group 10 1/22/2006
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
Claire Coleman @ Wipf Group 11 1/22/2006
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
Claire Coleman @ Wipf Group 12 1/22/2006
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
Claire Coleman @ Wipf Group 13 1/22/2006
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
pyridine, microwave,230 ˚C, 20 min
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
Claire Coleman @ Wipf Group 14 1/22/2006
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.
Claire Coleman @ Wipf Group 15 1/22/2006
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
Claire Coleman @ Wipf Group 16 1/22/2006
Three-Component One –Pot Syntheses of analogues of Circumdatin E
CO2H
NH2
then
NH2
OMe
O
N
NO
N
OP(OPh)3
pyridine, microwave,150 ˚C, 10 min
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
Claire Coleman @ Wipf Group 17 1/22/2006
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
Claire Coleman @ Wipf Group 18 1/22/2006