LIST OF ABBREVIATIONS
1.5 PYRROLOINDOLINES IN TOTAL SYNTHESIS
Given the enormous body of research dedicated to the total synthesis of pyrroloindolines, only a small sampling of total syntheses will be presented in the section below. One of the first successful examples employing a diastereoselective pyrroloindoline synthesis comes from the Danishefsky lab (Scheme 1.14).24 Beginning with Boc protected tryptophan 54, they were able to effect a selenation/cyclization sequence to furnish exo-pyrroloindoline 55 as a 9:1 diastereomeric mixture. Activation of the phenyl selenide with MeOTf and exposure to prenyl stannane 56, provided the reverse prenyl adduct in 60% yield. Saponification of the methyl ester, peptide coupling with the free amine, and successive diketopiperazine formation provided amauromine in only four-steps from tryptophan 54.
Scheme 1.14. Danishefsky’s synthesis of amauromine
In 2008, Baran and co-workers demonstrated the diastereoselective cyclization of tryptamines with nitrogen-based electrophiles.29 Beginning with tryptamine, treatment with the unique combination of N-iodosuccinimide, 2-iodoaniline, and Et3N at –45°C results in an electrophilic, C3-amination of the tryptamine to afford pyrroloindoline 76.
Under palladium catalysis, iodoaniline 76 underwent a Larock indole synthesis with
N Boc
NHBoc CO2Me
N N
Boc Boc
CO2Me SePh
H 55 (78% yield) 54
N O
O Se
Ph
p-TsOH, Na2SO4
N
t-Bu t-Bu
N N
Boc Boc
CO2Me H
Me Me
Me Me Bu3Sn
Me(OTf)
57 (60% yield)
N N
Boc Boc
CO2H H
Me Me NaOH
THF/MeOH reflux
74 (98% yield) NH
NH
CO2Me H
Me Me
BOP-Cl, Et3N;
TMSI N
N O
O HN
NH H H Me
Me
Me Me H
H amauromine (75) (45% yield, 2-steps)
56
alkyne 77 in excellent yield. C–N bond formation, followed by treatment with Red-Al provided the natural product psychotrimine (79) in excellent overall yield.
Scheme 1.15. Baran’s synthesis of psychotrimine
In 2011, Movassaghi and Kim reported a general strategy for the synthesis of 3- arylpyrroloindolines via a two-step bromocyclization/Friedel-Crafts sequence of tryptophan-derived diketopiperazines (Scheme 1.16).14 Treatment of protected diketopiperazine 80 with PyHBr3 in 2,2,2-trifluoroethanol effected an oxidative cyclization to form C3-bromopyrrolodinoline 81 in moderate yield and as a single diastereomer. In a subsequent step, addition of superstoichiometric silver salts resulted in halide abstraction to form a benzylic cation, which is then readily trapped in a stereoretentive fashion with excess nucleophile (82). Using this strategy, a variety of C3- substituted pyrroloindolines are readily prepared, accomodating C3-allyl, aryl, and hetereoaryl substitution. Although a number of arenes react to form a mixture of positional isomers during the Friedel-Crafts step in this reaction, the corresponding potassium trifluoroborate salts can be used to adequately restore regioselectivity. Using this method, the authors advanced bromotetracycle 81 to 3-arylpyrroloindolines 84 and 86 in 50 and 56% yield, respectively, utilizing an excess of functionalized potassium trifluoroborate salt 83, derived from 6-bromotryptophan. Subsequent global deprotection provided (+)-naseseazines A and B in 80% yield and 9-steps longest linear sequence.
N NH Br
CO2Me NH
H I
Pd(OAc)2 (21 mol %) Na2CO3 (2.6 equiv), LiCl (0.9 equiv) DMF, 102 °C 30 min
TMS NHCO2Me
(2.7 equiv)
N NH Br
CO2Me N
H
(85% yield)
N NH N
Me N
H
NHMe
NHMe 2. Red-Al
(79% yield, 2-steps) NH
NHMe
1. CuI, K2CO3, 1,2-diamine MeO2CHN
psychotrimine (79)
76 78
77
Scheme 1.16. Movassaghi’s synthesis of (+)-naseseazines A and B
A similar approach was adopted by Stephenson and co-workers in their synthesis of gliocladin C using photoredox catalysis.30 Following an oxidative cyclization of protected tryptophan 87, the bromopyrroloindoline underwent amidation to furnish carboximide 89. Subsequent exposure to [Ru(bpy)3Cl2] and visible light generated a tertiary benzylic radical, which was trapped with five equivalents of indole 90 to form the desired C3–C3’ aryl linkage. Notably, C2 substitution of the indole nucleophile is imperative to achieve the desired regioselectivity in the transformation. Additional elaboration to the natural product was accomplished in six-steps.
Scheme 1.17. Stephenson’s synthesis of gliocladin C
N HN
N O
O H
H R
Cbz
2,2,2-trifluoroethanol
N Cbz
N N
O
O H
R Br
H H
AgSbF6 (2.0 equiv)
EtNO2 or DCM N
Cbz
N N
O
O H
R Nu
H H
N HN
N O
O H
H
Cbz
R1 R1
R1
KF3B
N N N
O
O H
H H N
AgSbF6 (2.0 equiv)
R R
R = Cbz (84)
R = H (+)-naseseazine B (85), 80%
H2/Pd AcOH
51 - 67% yield, 1 diastereomer
H2/Pd AcOH R = Cbz (86)
R = H (+)-naseseazine A (26), 80%
(50% yield) (56% yield)
Nucleophile (2.0 equiv)
(2.0 equiv) HN
N O
O
N N NH
O
O H
H H N
R R HN
N O
O
Me
80 81 82
83 PyHBr3
NH
NHBoc CO2Me
i. CbzCl, NaOH, Bu4NHSO4 ii. NBS, PPTS, DCM
88 91% (2-steps)
N N
Boc Cbz Br
CO2Me MeNH2 THF
89 (87% yield)
N N
Boc Cbz Br
CONHMe
NH CHO (5 equiv)
[Ru(bpy)3Cl2] (1 mol %) Bu3N (2 equiv)
DMF Blue LEDs
91 (82% yield)
H
N N
Boc Cbz
CONHMe
H NH
CHO
NH N H NH
N O
O O
Me
gliocladin C (92) 87
90 H
6-steps
An intermediate bromopyrroloindoline 94, formed via the oxidative bromocyclization of tryptophan, was also utilized in Li’s synthesis of drimentine G.31 Employing a photoredox strategy similar to Stephenson’s, generation of a tertiary benzylic radical followed by conjugate addition into enone 95 provided complex pyrroloindoine 96 in excellent yield. An additional five-steps is subsequently required to construct the diketopiperazine moiety and effect deoxygenation to provide the natural product.
Scheme 1.18. Li’s synthesis of drimentine G
In 2014, Reisman and co-workers reported a concise total synthesis of the complex macrocyclic bispyrroloindoline (+)-nocardioazine A (102) utilizing their previously reported SnCl4•BINOL catalyzed formal (3 + 2) cycloaddition.32 Importantly, this complex natural product contains two pyrroloindoline units, each of opposite stereochemical configuration at the 5/5-ring junction, making an excellent case for convergent asymmetric synthesis. To this end, 3-allyl-N-methylindole (98) was subjected to the previously optimized reaction conditions to afford pyrroloindoline 99 in 52% yield, 19:1 dr, and 90% ee. Simultaneously, treatment of 3-methyl-N-allylindole (100) under newly optimized conditions provided pyrroloindoline 101 in 57% yield, 5.8 : 1 dr, and 98% ee. Subsequent functionalization of each fragment followed by coupling and
N Boc
NHBoc CO2Me
NBS PPTS
N N
Boc Boc
CO2Me Br
H 94 (96% yield) 93
N N
Boc Boc
CO2Me H
Me Me Me
H
O Me
Me
Me H
O
[Ir(ppy)2(dtbbpy)]PF6 (cat) blue LED Et3N, DMF
95
96 (91% yield)
5-steps
N NH H
Me Me Me
H
NH O
O iPr
drimentine G (97)
cyclocondensation to prepare the diketopiperazine assembles the natural product in short order.
Scheme 1.19. Reisman’s synthesis of nocardioazine A