unlocking the elusive generation of carbyne equivalents
TRANSCRIPT
Carbon-based Reactive Speciesn New disconnection approach for chiral center construction with monovalent carbon species
Assembly-point functionalization of carbyne species
Development of an arene C–H bond diazomethylation5
n Carbon has the unique ability to bind four atoms and form stable tetravalent structures prevalent in nature. The lack of one or two valences leads to a set of species, which are fundamental to understand chemical reactivity1
References: [1] Trost, B. M. & Fleming, I. Comprehensive Organic Synthesis (Pergamon, Oxford, 1991). [2]Thap, D. M., Gunning, H. E. & Strausz, O. P. J. Am. Chem. Soc. 89, 6785–6787 (1967). [3] (a) Weiss, R., et alAngew. Chem. Int. Ed. 33, 1952–1953 (1994); (b) Bonge-Hansen, T. et al. J. Org. Chem. 78, 7488-7497 (2013).[4]. Prier, C. K., Rankic, D. A. & MacMillan, D. W. C. Chem. Rev. 113, 5322–5363 (2013). [5] (a) Ford, A. et al.Chem. Rev. 115, 9981–10080 (2015). (b) Davies, H. M. L. et al. Nature 451, 417–424 (2008). [6] Cernak, T., etal Chem. Soc. Rev. 45, 546–576 (2016). [7] Lovering F., et all J. Med. Chem. 52, 6752–6756 (2009).Acknowledgements: This work was funded by the ICIQ Foundation, the CERCA Programme (Generalitat deCatalunya), MINECO (CTQ2016-75311-P, AEI/FEDER-EU; Severo Ochoa Excellence Accreditation 2014–2018,SEV-2013- 0319), the CELLEX Foundation through the CELLEX-ICIQ high-throughput experimentationplatform. We thank the European Union for a Marie Curie-COFUND post-doctoral fellowship (to Z.W.) and theCELLEX Foundation for pre-doctoral (to A.G.H.) and post-doctoral fellowships (to A.M.d.H.). M.G.S. is a JuniorGroup Leader of the ICIQ Starting Career Programme 2014−2019.
Ana García Herraiz, Zhaofeng Wang, Ana M. del Hoyo, Marcos García Suero*Institute of Chemical Research of Catalonia (ICIQ), The Barcelona Institute of Science and Technology
Av Països Catalans 16, 43007 Tarragona − Spain *[email protected]
n In contrast, the monovalent carbon species — carbynes — have remained unexplored for over fifty years.2
n Sequencing control strategy by orthogonal catalytic activation modes:
carbocations carbanions radicalsmajority of carbon reactivity
is undestood withdi- and trivalent species carbynes
Late-stage assembly-point diversification of medically relevant agents
Stage b D
iazo diversification
diazo compound
N2
Ar
pivotal prochiral intermediate
carbene
Carbynes might reveal previously elusive disconnection approaches !
Challenges : (i) carbyne generation (ii) sequencing control
unexploredmonovalent carbon
carbynes
LG (−)
e± MN2
LG
designed carbyne source
LG is redox active
N2 is metal active
e±
M
ArH
aromatic feedstocks
n Selected scope
H
1 mol% Ru(bpy)3(PF6)2
NaHCO3, CH3CN white LED, rt, 2 hours
Ar Ar
N2
CO2EtO I
CO2Et
N2O
OTf
EtO2C
(hetero)arenes(2 equiv)
diazo compoundshypervalent iodine reagent(1 equiv)
diazomethyl radical
doublet carbyne equivalent
N2
monovalent carbon with three non-bonded electrons
doublet/quartet spin states
:C−H (methylidyne, 146 Kcal/mol) one of the first molecules detected
in interstellar space
distinct radical/carbene reactivity on the same carbon atom
innate ability to form three sigma bonds
.
This work has been published: Z. Wang, A. G. Herraiz, A. M. del Hoyo, M. G. Suero* Nature (2018,554, 86); and highlighted in Nature News & Views, Chemical & Engineering News Chemistry World.
H
Late StageFunctionalization
Can we introduce a tailored chiral center to drug molecules6,7
42% (1.25:1)(45%rsm) from ibuprofen
Me
Me CO2Et
Me
CO2EtN2
*
58% (1:1)(61%rsm)from fingolimod
OO
NHBoc
Me
Me
CO2EtN2
Me
NNF3C
Me
SO
O NH2
N2
CO2Et
35% (2:1*)(61%rsm) from celecoxib
*
OMe
MeO O
Cl
O
O
Me
OMe
EtO2C
N2
36% (71%rsm) from griseofulvin
NBoc
F
O
CO2EtN2
35% (10%rsm)from paroxetine
OO
H
Me
HOO
OOOH
OO
O
O
OHHN
O
Me
Me
O
Ph
OO
EtO2C
N2
10% (80%rsm) from placlitaxel
OMe
HH
H
HO
47% (41%rsm) from estrone
CO2EtN2
45% (23%rsm) from duloxetine
ONBoc
Me
SCO2Et
N2
72% (1:1 dr)
ONBoc
Me
SCO2Et
NBoc H
87% (1:1 dr)
ONBoc
Me
SCO2Et
OH
82% (3:1 dr)
ONBoc
Me
SCO2Et
NMe 78% (1:1 dr)
ONBoc
Me
SCO2Et
FFF
72% (1:1 dr)
ONBoc
Me
SCO2Et
HN
O75% (1:1 dr)
ONBoc
Me
SCO2Et
BuO
OMe
HH
H
HO
CO2EtHN
56% (1.6:1 dr)HO
ONBoc
Me
SCO2Et
Me
51% (1:1 dr)
Mechanistic hypothesis4
O
O
I R
R = OAc or OMe
Me3SiOTf, CH2Cl2, rt
CO2Et
N2H
43-96% yield
then
(1 equiv and Pyor 2 equiv )
New hypervalent iodine reagents as carbyne sources3
n Stoichiometric generation of a diazomethyl radical.
1 equiv Ru(bpy)3(PF6)2
CH3CN, 25 ºC, 2 h white LED
CO2EtEtO2C78-80%
N2 CO2Et CO2Et
diazomethyl radical
doublet carbyne equivalent
diethylacetylenedicarboxylate
2 x N2
DBX20 mol% Zn(NTf2)2
orpseudocyclic-DBX
single-electron/energy transfer catalyst
commercial available
long-lived excited state (1100 ns)
O ICO2Et
N2O
OTf
EtO2C
O
O
ICO2Et
N2
Diazomethylbenziodoxone-DBX pseudocyclic-DBX
Ered = -0.29 VEred = -0.91 V
(II)RuN
N
NN
NN
Ru(bpy)32+CO2Et
N2H
visible lightCO2Et
N2
CO2Et
N2N2 CO2Et
I(III)
HI (I)
diazo compound
Ar
Ar
hypervalent iodine reagents
Ru(bpy)32+
*Ru(bpy)32+
Ru(bpy)33+
electrophilic radical addition
photoredoxcatalytic
cycle
E1⁄2 (III)/(II) = +1.29 V
E1⁄2 (II)*/(III) = -0.81 V
N2
CO2Et
Me
62% (30:1:1)
N2
CO2Et
45% (10:2†:3*)
Me
Me
*†
N2
CO2Et
I
52% (18:1:1)
N2
CO2Et
NHBoc
51%
N2
CO2Et
Me
Me
73%; 96%§
N2
CO2Et
Me
71% (10:1)
Me
MeMe N2
CO2Et
Me
B
58% (9:1)
O
O
MeMeMeMe
N2
CO2Et
Me
F
61% (7:1)§
N2
CO2Et
Me
MeO2C
69% (10:1)§
N2
CO2Et
Me
99%
Me
Me
N2
CO2Et
52%§
N2
CO2EtS
75%‡
O
Me N2
CO2EtNBoc
N
59%‡
Nt-Bu t-Bu
N2
CO2Et
56 %
§10 eq of arene were used. ‡ 5 eq of heteroarene were used. ¶2,6-di-tertbutylpyridine was used as based. ß Na2CO3 was used as base.
N
O N2
CO2Et
70%‡ß
Me
Catalytic assembly-point functionalization with feedstock chemicalsn Carbyne pentannulation by double site-selective C–H functionalization
HAr
represents
Me
Me
n Catalytic assembly-point functionalization enables direct access to chiral centres.
1 mol% Ru(bpy)3(PF6)2
NaHCO3, CH3CN blue LED, rt, 20 hours
32% yieldisobutylbenzene carbyne source
MeMe
HH
MeMeCO2Et
H
O ICO2Et
N2O
OTf
EtO2C
indaneN2
CO2Et
MeMe
blue LED
MeCN, rt, 20h52% yield
Ar
N2
CF3Ar
N2
S Ar
N2
PO
O OEt OOMe
OMe
24%75% 73%Ar is mesityl
Stage a C−H
diazomethylation
CO2Et
N2I(III)Ar
e±
CO2Et
OHH
53%
Ar MsNH2
Ph
CO2Et
NHMsH
Ar
CO2EtAr
Ph
H2O
CO2Et
BH
Ar
NR3H H
H3B NR3
66%
35%47% H
“presence of chiral centres in drug candidates is linked with the success of transition from the
discovery stage to clinical testing”
chiral centres
chiral centres
prevalent motif in natural products and drugs
Unlocking the elusive generation of carbyne equivalents