Novel approach to 1,5-benzodiazepine-2-ones containing peptoid backbone via one-pot diketene-based Ugi-4CR

Article abstract of DOI:10.1021/cc100037v

An efficient and simple route for preparation of substituted 1,5-benzodiazepine-2-one containing peptoid backbone is presented. The classical Ugi reaction is considerably extended by application of o-phenylenediamine and diketene as amine and oxo componen

Full text of DOI:10.1021/cc100037v

J. Comb. Chem. 2010, 12, 497–502
497
Novel Approach to 1,5-Benzodiazepine-2-ones Containing Peptoid
Backbone via One-Pot Diketene-Based Ugi-4CR
Nasrin Zohreh,† Abdolali Alizadeh,*,† Hamid Reza Bijanzadeh,† and Log-Guan Zhu‡
Department of Chemistry, Tarbiat Modares UniVersity, P.O. Box 14115-175, Tehran, Iran, and
Department of Chemistry, Zhejiang UniVersity, Hangzhou 310027, PR China
ReceiVed March 7, 2010
An efficient and simple route for preparation of substituted 1,5-benzodiazepine-2-one containing peptoid
backbone is presented. The classical Ugi reaction is considerably extended by application of o-phen-
ylenediamine and diketene as amine and oxo component. 1,3-Dihydro-1,5-benzodiazepine-2-one is generated
in situ from these two building blocks combined with isocyanide and aromatic or aliphatic carboxylic acid
to assemble the multifunctionalized titled scaffold in high yields. The reaction is performed in the mixture
of toluene/CH2Cl2 under reflux condition without catalyst. Conformational isomerism is seen in the solution
phase because of restricted free rotation around amide and C-CO bands due to steric bulk of substitutions.
In single crystal state, the product is found to possess dimeric structure arising from intermolecular hydrogen
bonding.
peptoid-peptide backbones. Peptoids17 are a class of oli-
gomeric N-alkyl-glycines that mimic the primary natural
structure of peptides. Since the pioneering work of Ugi, many
acyclic adducts, from the classical versions of this reaction,
and interesting heterocyclic structures, using intramolecular
variants or MCR coupling with subsequent secondary trans-
formation, have been accessed, taking advantage of additional
functionalities suitably placed on its components.18
Some of the most important diazepines are prepared using
U-4CR.19 To the best of our knowledge, there is no report
for synthesis of 1,5-benzodiazepine-2-ones, which contain
an R-amino-amide moiety and are peptoid products of
U-4CR. In the context of our ongoing studies, we have
devoted our investigations to synthesis of important acyclic
and heterocyclic scaffolds via a diketene-based multicom-
ponent reaction. These compounds have unique synthetic and
pharmacological applications.20 In this paper, we would like
to report and describe a novel effort toward the synthesis of
1-aryl (or alkyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine-
2-carboxamide 15 in high yield.
Introduction
The medicinal value of benzodiazepines is well docu-
mented. Benzodiazepines1 have been important pharmacoph-
ores in pharmaceutical industry. Some of the therapeutic
applications of benzodiazepines include vasopressin antag-
onists,2a HIV reverse transcriptase inhibitors,2b and chole-
cystokinin antagonists.2c In this class of compound, the 1,5-
benzodiazepin-2-one is a privileged scaffold and compounds
containing such substructures exhibit a range of biological
activities. For instance, some of them have been clinically
used as anxiolytic or antisecretory agents, such as lofendazam
11,3 and telenzepine 24 (Figure 1), respectively. In addition,
they exhibit activities including interleukin-1b converting
enzyme inhibition, delayed rectifier potassium current block-
ing,5 and antiarrhythmic properties.6 They are also known
as active compounds against a variety of target types such
as protease inhibitors and 7-TM receptors. For example,
compound 3 is a CCK receptor antagonist (Figure 1).7-9
Actually, less research has been undertaken on the 1,5-
benzodiazepin-2-ones, compared to the 1,4-benzodiazepin-
2-ones.
Results and Discussion
Multicomponent reactions (MCRs)10 are, for their intimate
nature, extremely convergent, producing a remarkably high
increase of molecular complexity in just one step. The
multicomponent reaction story began as far back as in 1850
by the publication of the Strecker reaction.11 During this one
and a half century period, some notable achievements include
the discovery of Biginelli,12 Mannich,13 and Passerini14
reactions culminating in 1959 when Ugi published15 probably
the most famous and versatile 4-CR based on the reactivity
of isocyanides.16 U-4CR is known to be one of the most
versatile tools for construction of peptoid and mixed
Recently, our research group reported synthesis of a novel
series of 1,5-benzodiazepin-2-one with phosphite ylide 8 or
phosphonate 9 substitutions (depending on the reaction
conditions) from the reaction of o-phenylenediamine 4,
diketene 5, dialkyl acetylenedicarboxylate 6, and trialkyl
phosphite 7 (Scheme 1).20g
We also have investigated synthesis of arylsulfonamide-
substituted 1,5-benzodiazepine-2-one 11 by treatment of
o-phenylenediamine 4 and diketene 5 with arylsulfonyl
isocyanates 10 (Scheme 2). However, both of the mentioned
reactions were performed under one-pot MCR. We purified
and characterized the key intermediate of the two reactions
as 1,3-dihydro-1,5-benzodiazepine-2-one 12.21
* To whom correspondence should be addressed.
† Tarbiat Modares University.
‡ Zhejiang University.
10.1021/cc100037v  2010 American Chemical Society
Published on Web 06/07/2010

498 Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 4
Zohreh et al.
Figure 1. Examples of medicinal 1,5-benzodiazepine-2-one.
Scheme 1. Synthesis of 1,5-Benzodiazepin-2-ones with Phosphite Ylide 8 or Phosphonate 9 Substitutions
Scheme 2. Synthesis of Arylsulfonamide-Substituted 1,5-Benzodiazepine-2-ones
As shown in Figure 2, intermediate 12 is found to possess
three different reactive sites. The first is the acidic hydrogen
of an amide functional group used to trap the trialkyl
phosphite-dialkyl acetylenedicarboxylate zwitterion (Scheme
1). The second is CH2 nucleophilic carbon which gave rise
to arylsulfonamide-substituted 1,5-benzodiazepine-2-one 11.
The other, and maybe the most important reactive site, is
the imine functional group. This fact intrigued us to perform
a Ugi reaction for preparation of substituted 1,5-benzodiaz-
epine-2-one containing peptoid backbone 15. As outlined in
Scheme 3, the reaction of o-phenylenediamine 4 and diketene
5, as amine and oxo components, with carboxylic acid 13
and cyclohexyl isocyanide 14 proceeds smoothly in the
mixture of CH2Cl2/toluene at 25-120 °C to afford desired
compound 15 in 70-80% yields after 8 h.
To investigate the scope of limitations of the reaction, we
first decided to study the effect of the acid component using
different types of aliphatic and aromatic carboxylic acid
(Table 1, entries 1-5). It was found that the reaction was
quite general toward the acid component. In view of the
success of the above reactions, we then employed 4-methyl-
o-phenylenediamine under a similar circumstance to evaluate
the substrate scope and especially regioselectivity of this
reaction. However, the reaction of 4-methyl-o-phenylenedi-
amine, diketene, carboxylic acid, and cyclohexyl isocyanide
led to the corresponding 1,5-benzodiazepine-2-one, but the
reaction was not regioselective and the mixture of desired
Figure 2. 1,3-Dihydro-1,5-benzodiazepine-2-one 12 as the key
intermediate.
Scheme 3. Synthesis of 1-Aryl (or Alkyl)-2,3,4,5-Tetrahydro-1H-1,5-benzodiazepine-2-carboxamide 15 from the Reaction of
o-Phenylenediamine 4, Diketene 5, and Carboxylic Acid 13 in the Presence of Cyclohexyl Isocyanide 14

1,5-Benzodiazepine-2-ones Containing Peptoid Backbone
Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 4 499
Table 1. 1,5-Benzodiazepin-2-one Derivatives Prepared by the
Mentioned Reaction
pairs. Unfortunately, attempts to perform the reaction with
tertiarybutyl isocyanide failed to give the desired 1,5-
benzodiazepin-2-one, probably because of its lower reactivity
compared to cyclohexyl isocyanide.
entry
R
R1
product
15a
15b
15c
ratio of regioisomers yield %
1
2
3
4
5
6
7
8
H
PhCH2
PhCHdCH
80
75
78
75
77
The steric bulk of CO-R1 and CO-NHCy substitutions on
the 1 and 2 positions of the seven-membered ring of the
products is enough to restrict the free rotation around N-CO
amide and C-CO single bonds, resulting in conformational
isomerism (Figure 3).
H
H
H
H
Ph
p-NO2-C6H4 15d
2-Furyl
15e
15f and 15g
15h and 15i
Me PhCH2
Me PhCHdCH
Me p-NO2-C6H4 15j and 15k
67:33
62:38
60:40
72
70
75
The mass spectrum of 15a displayed a M+ + 1 peak at
m/z 420. Almost, for all of the products, initial fragmenta-
tion involved loss of the NH-Cy moiety that for 15a was
shown at 321. In the IR spectrum of 15a, two absorption
bands at 3395 and 3170, a broad band at 1667, and two
absorption bands at 1584 and 1490 cm-1, which are related
to two NH, three NC)O, and aromatic stretching frequen-
cies, clearly indicated the most significant functional
groups of the product. However, the interconversion
between these two rotamers is stopped at room temper-
ature, and we were not able to isolate them. The presence
of these two rotational isomers in CDCl3 solvent (solution
1-alkyl (or aryl)-N2-cyclohexyl-2,7 and 2,8-dimethyl-4-oxo-
2,3,4,5-tetrahydro-1H-1,5-benzodiazepine-2-carboxamide were
produced (Table 1, entries 6-8). Sorrowfully, we were not
able to isolate two regioisomers using usual column chro-
matography and crystallization by different solvent or solvent
1
phase) is precisely confirmed by the H and 13C NMR
spectra of 15a-k where a set of peaks were detected for
1
each of them. The H NMR spectrum of 15a exhibited
two sharp singlet signals at 1.59 and 2.01 ppm, readily
recognized as two methyl groups for two rotamers. Two
Figure 3. Structure of the two conformational isomerism in solution
phase.
Figure 4. Structure of products in single crystal state and the ORTEP diagram of 15a.
Scheme 4. Plausible Mechanism for the Formation of Substituted 1,5-Benzodiazepine-2-ones

500 Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 4
Zohreh et al.
Figure 5. Structure of products 15a-k.
sets of multiplets from 0.66-1.57 ppm and 1.60-1.90
ppm were attributed to the 10 methylenes (CH2) of the
two cyclohexyl groups. The CH2 group of the seven-
membered ring in one of the two rotamers appears as ABq
at 2.42 ppm (2JHH ) 17.9 Hz), and the other CH2 appears
as two separated doublet peaks at 2.48 and 3.04 ppm (2JHH
) 14.2 and 13.7 Hz). The spectrum also contains another
ABq at 3.32 (2JHH ) 15.1 Hz) and two doublets at 3.41
and 3.58 ppm (2JHH ) 14.1 Hz for both of them), which
are attributed to diastereotopic hydrogens of the two
CH2Ph groups. There are two multiplet signals between
6.63 and 3.78 ppm which are related to two CHNH groups
of cyclohexyls. For both of the rotamers, the signal
corresponding to the NH group attached to cyclohexyl
appears as two doublets at 5.50 (3JHH ) 8.0 Hz) and 7.55
ppm (3JHH ) 7.9 Hz). We believe that the last value fits
rotamer I, regarding its interamolecular hydrogen bonding.
The other two amidic hydrogens resonance at 8.39 and
8.53 ppm as sharp singlet signals. Eighteen aromatic
hydrogens of the two rotamers gave rise to characteristic
1
signals in the aromatic region of the spectrum. The H
decoupled 13C NMR spectrum of 15a is in agreement with
the product structure. In the aliphatic region, there are 18
signals related to two methyls, 12 CH2 of two cyclohexyls,
two CH2 of the two seven-membered rings, and two
CHNH moieties. The quaternary carbon of the two
rotamers, which are attached to a methyl group, resonance
at 69.80 and 70.99 ppm. The most important region of
the spectrum is related to carbonyl groups which produce
1
six CdO signals for the two rotamers. The H and 13C

1,5-Benzodiazepine-2-ones Containing Peptoid Backbone
Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 4 501
Ru, X.; Mazandarani, H.; Bailey, T. J. Med. Chem. 1998, 41,
2442. (b) Breslin, H. J.; Kukla, M. J.; Ludovici, D. W.;
Mohrbacher, R.; Ho, W.; Miranda, M.; Rodgers, J. D.;
Hitchens, T. K.; Leo, G.; Gauthier, D. A.; Ho, C. Y.; Scott,
M. K.; De Clercq, E.; Pauwels, R.; Andries, K.; Janssen,
M. A. C.; Janssen, P. A. J. Med. Chem. 1995, 38, 771. (c)
Castro, J. L.; Broughton, H. B.; Russell, M. G. N.; Rathbone,
D.; Watt, A. P.; Ball, R. G.; Chapman, K. L.; Patel, S.; Smith,
A. J.; Marshall, G. R.; Matassa, V. G. J. Med. Chem. 1997,
40, 2491.
NMR spectra of 15b-k compounds are similar to those
of 15a, except for the group bonded to NC)O which
exhibits characteristic signals with appropriate chemical
shifts.
It is noteworthy that, in the single crystal state, the product
is a dimer due to intermolecular hydrogen bonding of
NHC)O in the benzodiazepine rings (Figure 4).
The 1H and 13C NMR of entries 6-8 (Table 1) confirmed
the presence of four compounds: two regioisomers, each with
a conformational isomerism. For more details of spectro-
scopic data of entries 1-8 (Table 1), see Supporting
Information. The structures of all products are shown in
Figure 5.
(3) Muller, W. E.; Groh, B.; Bub, O. Pharmacopsychiatry 1986,
10, 314.
(4) Eltze, M.; Gonne, S.; Riedel, R.; Schlotke, B.; Schudt, C.;
Simon, W. A. Eur. J. Pharmacol. 1985, 112, 211.
(5) Herpin, T. F.; Van Kirk, K. G.; Salvino, J. M.; Yu, S. T.;
Labaudiniere, R. F. J. Comb. Chem. 2000, 2, 513.
Regarding the well-documented general mechanism of the
Ugi reaction,18,19 we proposed a five key step plausible
mechanism for the mentioned reaction (Scheme 4). Since
diketene is a strained ꢀ-lacton ring, it is reasonable to propose
that the first step begins through a nucleophilic addition of
NH2 to diketene followed by ring-opening and proton transfer
to produce N-(2-aminophenyl)-3-oxobutanamide 16.20g Then,
the other NH2 condenses with a ketone moiety via an
intramolecular process to form 4-methyl-1,3-dihydro-2H-1,5-
benzodiazepin-2-one 12 that could be converted to iminium
salt 17 in the presence of carboxylic acid 13, a Brønsted
acid in the third step. Cyclohexyl isocyanide is subsequently
added to the iminium salt 17 to produce the reactive nitrilium
intermediate 18. The reactive O-acyl iminolate 19 is formed
via the R-addition of carboxylate anion to the nitrilium ion
18. The final step involves O- to N-acyl transfer (Mumm
rearrangement) to afford the corresponding substituted 1,5-
benzodiazepine-2-one 15.
(6) Claremon, D. A.; Frieidinger, R. M.; Liverton, N.; Selnick,
H. G.; Smith, G. R. PCT Int. Appl. WO 9640656, 1996.
(7) (a) Tranquillini, M. E.; Cassara, P. G.; Corsi, M.; Curotto,
G.; Donati, D.; Finizia, G.; Pentassuglia, G.; Polinelli, S.;
Tarzia, G.; Ursini, A.; Van Amsterdam, F. T. M. Arch. Pharm.
(Weinheim, Ger.) 1997, 330, 353. (b) Trist, D.; Pentassuglia,
G.; Tranquillini, M. E.; Ursini, A. PCT Int. Appl. WO
9314075, 1993.
(8) (a) Batchelor, M. J.; Bebbington, D.; Bemis, G. W.; Fridman,
W. H.; Gillespie, R. J.; Golec, J. M. C.; Gu, Y.; Lauffer, D. J.;
Livingston, D. J.; Matharu, S. S.; Mullican, M. D.; Murcko,
M. A.; Murdoch, R.; Nyce, P. L.; Robidoux, A. L. C. PCT
Int. Appl. WO 9722619 A2 19970626, 1977. (b) Bemis,
G. W.; Golec, J. M. C.; Lauffer, D. J.; Mullican, M. D.;
Murcko, M. A.; Livingston, D. J. PCT Int. Appl. WO
9535308, 1995.
(9) Selnick, H. G.; Liverton, N. J.; Baldwin, J. J.; Butcher, J. W.;
Claremon, D. A.; Elliott, J. M.; Freidinger, R. M.; King, S. A.;
Libby, B. E.; McIntyre, C. J.; Pribush, D. A.; Remy, D. C.;
Smith, G. R.; Tebben, A. J.; Jurkiewicz, N. K.; Lynch, J. J.;
Salata, J. J.; Sanguinetti, M. C.; Siegl, P. K. S.; Slaughter,
D. E.; Vyas, K. J. Med. Chem. 1997, 40, 3865.
Conclusion
(10) Zhu, J., Bienayme, H., Eds. Multicomponent Reactions; Wiley-
VCH: Weinheim, 2005.
A concise and efficient one-pot synthesis of substituted
1,5-benzodiazepine-2-ones with a peptoid backbone has
been developed based on Ugi-4CR, using o-phenylendi-
amine and diketene instead of amine and aldehyde in a
reaction with carboxylic acid and cyclohexyl isocyanide.
The product is of potential synthetic and pharmacological
interest. This study brings forward a new concept of
conformational isomerism in solution phase. In addition,
the dimeric structure of the product in the single crystal
state may be of theoretical and experimental interest. Easy
reaction performance in neutral conditions with no bases
or catalysts, high yield, and simple purification of products
are the advantages of our work. The simplicity of the
present procedure makes it an interesting alternative to
the complex multistep approaches.
(11) Strecker, A. Justus Liebigs Ann. Chem. 1850, 75, 27.
(12) (a) Biginelli, P. Gazz. Chim. Ital. 1891, 24, 1317. (b) Kappe,
O. Acc. Chem. Res. 2000, 33, 879.
(13) (a) Mannich, C.; Kro¨schl, W. Arch. Pharm. 1912, 250, 647.
(b) Mannich, C. Arch. Pharm. 1917, 255, 261. (c) Tramontini,
M.; Angiolini, L. Tetrahedron 1990, 46, 1791.
(14) (a) Passerini, M. Gazz. Chim. Ital. 1921, 51, 126. (b) Passerini,
M. Gazz. Chim. Ital. 1921, 51, 181.
(15) (a) Ugi, I.; Meyr, R.; Fetzer, U. Angew. Chem. 1959, 71, 386.
(b) Ugi, I.; Steinbru¨ckner, C. Chem. Ber. 1961, 94, 734.
(16) (a) Do¨mling, A.; Ugi, I. Angew. Chem., Int. Ed. 2000, 39,
3168. (b) Ugi, I.; Werner, B.; Do¨mling, A. Targets Heterocycl.
Syst. 2000, 4, 1. (c) Do¨mling, A. Curr. Opin. Chem. Biol.
2002, 6, 306.
(17) (a) Zuckermann, R. N.; Matin, E. J.; Spellmeyer, D. C.;
Stauber, G. B.; Shoemaker, K. R.; Kerr, J. M.; Figliozzi,
G. M.; Goff, D. A.; Siani, M. A.; Simon, R. J.; Banville, S. C.;
Brown, E. G.; Wang, L.; Richter, L. S.; Moss, W. H. J. Med.
Chem. 1994, 37, 2678. (b) Shin, S. B. Y.; Yoo, B.; Todaro,
L. J.; Kirshenbaum, K. J. Am. Chem. Soc. 2007, 129, 3218.
Wessjohann, L. A.; Andrade, C. K. Z.; Vercillo, O. E.; Rivera,
D. G. Targets Heterocycl. Syst. 2006, 10, 24.
(18) (a) Do¨mling, A. Chem. ReV 2006, 106, 17. (b) Li, X.;
Danishefsky, S. J. J. Chem. Soc. 2008, 130, 5446. (c)
Gulevich, A. V.; Balenkova, E. S.; Nenajdenko, V. G. J. Org.
Chem. 2007, 72, 7878. (d) Lu, K.; Luo, T.; Xiang, Z.; You,
Z.; Fathi, R.; Chen, J.; Yang, Z. J. Comb. Chem. 2005, 7,
958. (e) El Kaim, L.; Grimaud, L.; Oble, J. J. Org. Chem.
2007, 72, 5835. (f) Wang, W.; Do¨mling, A. J. Comb. Chem.
2009, 11, 403. (g) Kusebauch, U.; Beck, B.; Messer, K.;
Herdtweck, E.; Do¨mling, A. Org. Lett. 2003, 5, 4021. (h) El
Supporting Information Available. Experimental pro-
1
cedures, IR, mass, H and 13C NMR for all compounds,
crystallographic data, and ORTEP/X-ray structure for 15a.
This material is available free of charge via the Internet at
http://pubs.acs.org.
References and Notes
(1) (a) Archer, G. A.; Sternbach, L. H. Chem. ReV 1968, 68, 747.
(b) Sternbach, L. H. Prog. Drug Res. 1978, 22, 229.
(2) (a) Albright, J. D.; Feich, M. F.; Santos, E. G. D.; Dusza,
J. P.; Sum, F. W.; Venkatesan, A. M.; Coupet, J.; Chan, P. S.;

502 Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 4
Zohreh et al.
Kaim, L.; Grimaud, L.; Vieu, E. Org. Lett. 2007, 9, 4171. (i)
Akritopoulou-Zanze, I.; Whitehead, A.; Waters, J. E.; Henry,
R. F.; Djuric, S. W. Org. Lett. 2007, 9, 1299. (j) De Silva,
R. A.; Santra, S.; Andreana, P. R. Org. Lett. 2008, 10, 4541.
(k) Vercillo, O. E.; Kleber, C.; Andrade, Z.; Wessjohann, L. A.
Org. Lett. 2008, 10, 205.
Chem. Soc. 2004, 126, 14475. (h) Kennedy, A. L.; Fryer,
A. M.; Josey, J. A. Org. Lett. 2002, 4, 1167.
(20) (a) Alizadeh, A.; Zohreh, N.; Rostamnia, S. Tetrahedron
2007, 63, 8083. (b) Alizadeh, A.; Zohreh, N. Synthesis 2008,
3, 429. (c) Alizadeh, A.; Zohreh, N. HelV. Chim. Acta 2008,
91, 844. (d) Alizadeh, A.; Zohreh, N.; Zhu, L. G. Synthesis
2008, 13, 2076. (e) Zohreh, N. Synlett 2008, 1913. (f)
Alizadeh, A.; Zohreh, N.; Zhu, L. G. Synthesis 2009, 3, 464.
(g) Alizadeh, A.; Zohreh, N.; Zhu, L. G. Tetrahedron 2009,
65, 268.
(21) 4-Methyl-1,3-dihydro-2H-1,5-benzodiazepin-2-one: 1H NMR
(500.13 MHz, CDCl3) 2.38 (s, 3 H), 2.13 (s, 2 H), 7.06-7.10
(m, 1 H), 7.16-7.18 (m, 2 H), 7.31-7.34 (m, 1 H), 9.59
(s, 1 H).
(19) (a) Banfi, L.; Basso, A.; Guanti, G.; Kielland, N.; Repetto,
C.; Riva, R. J. Org. Chem. 2007, 72, 2151. (b) Hulme, C.;
Ma, L.; Kumar, N. V.; Krolikowski, P. H.; Allen, A. C.;
Labaudiniere, R. Tetrahedron Lett. 2000, 41, 1509. (c)
Hulme, C.; Peng, J.; Morton, G.; Salvin, J. M.; Herpin,
G. T.; Labaudiniere, R. Tetrahedron Lett. 1998, 39, 7227.
(d) Tempest, P.; Ma, V.; Kelly, M. G.; Jones, W.; Hulme,
C. Tetrahedron Lett. 2001, 42, 4963. (e) Keating, T. A.;
Armstrong, R. W. J. Org. Chem. 1996, 61, 8935. (f) Faggi,
C.; Marcaccini, S.; Pepino, R.; Pozo, M. C. Synthesis 2002,
18, 2756. (g) Cuny, G.; Bois-Choussy, M.; Zhu, J. J. Am.
CC100037V