Electrolytic macrocyclizations: Scalable synthesis of a diazonamide-based drug development candidate

Article abstract of DOI:10.1002/anie.201411663

An electrochemical method to synthesize the core macrolactam of diazonamides is described. Large ring-forming dehydrogenation is initiated by anodic oxidation at a graphite surface. The reaction requires no tailoring of the substrate and occurs at ambient temperature in aqueous DMF in an undivided cell open to air. This unique chemistry has enabled a concise, scalable preparation of DZ-2384; a refined analog of diazonamide A slated for clinical development as a cancer therapeutic.

Full text of DOI:10.1002/anie.201411663

Angewandte
Chemie
DOI: 10.1002/anie.201411663
Synthetic Methods
Electrolytic Macrocyclizations: Scalable Synthesis of a Diazonamide-
Based Drug Development Candidate**
Hui Ding, Patrick L. DeRoy, Christian Perreault, Alexandre Larivꢀe, Arshad Siddiqui,
Charles G. Caldwell, Susan Harran, and Patrick G. Harran*
Abstract: An electrochemical method to synthesize the core
macrolactam of diazonamides is described. Large ring-form-
ing dehydrogenation is initiated by anodic oxidation at
a graphite surface. The reaction requires no tailoring of the
substrate and occurs at ambient temperature in aqueous DMF
in an undivided cell open to air. This unique chemistry has
enabled a concise, scalable preparation of DZ-2384; a refined
analog of diazonamide A slated for clinical development as
a cancer therapeutic.
Figure 1. (À)-diazonamide A (1).
I
t is not uncommon to observe internal cross-links between
electron-rich aromatic side chains in peptide-derived natural
products. These bonds rigidify structure and often improve
pharmacological properties. Products of net dehydrogenation
product.[5–7] Assembling the core of the molecule was
a particular challenge.[7,8] Among solutions to the problem,
ours was an attempt to parallel biosynthesis. We found that
PhI(OAc)2 would mediate the conversion of peptidyl deriv-
ative 2 (Figure 2, R = o-NO2PhSO2) to isomeric aminals 3a
and 4a.[5c] The directness of the construction was valuable,
particularly as our interest in the pharmacology of diazon-
amides increased.[9] Numerous congeners of the natural
product were prepared and those molecules fueled early
in vivo experiments.[10] As rodent models made clear that
À
are frequently encountered, wherein C C bonding occurs at
À
the expense of two aryl C H bonds. Examples include
oxygenated biphenyls[1] derived from tyrosine oxidations and
bis-indoles resultant from tryptophan oxidations.[2] Some time
ago we began studying a structure that contains a linkage
hybrid of the above two; namely diazonamide A (1,
Figure 1),[3] wherein
a tyrosine residue has internally
bonded to an adjacent tryptophan. The 3-linked o-phenolic
3H-indole in that case exists as its aminal tautomer; giving
a core motif that was unknown at the time it was first
described in diazonamides.[4]
Structure 1 drew intense interest from the synthetic
community and methods were forged to prepare the natural
[*] Dr. H. Ding, Prof. Dr. P. G. Harran
Department of Chemistry and Biochemistry
University of California, Los Angeles
607 Charles E. Young Drive East
Los Angeles, California 90095-1569 (USA)
E-mail: harran@chem.ucla.edu
P. L. DeRoy, C. Perreault, Dr. A. Larivꢀe, Dr. A. Siddiqui
Paraza Pharma Inc.
7171, Frꢀdꢀrick-Banting, Montrꢀal, QC, H4S 1Z9 (Canada)
Dr. C. G. Caldwell, S. Harran
Joyant Pharmaceuticals
2600 North Stemmons Freeway, Dallas, TX 75207-2113 (USA)
[**] Experiments sponsored by Diazon Pharma with funds administered
by Therillia Corp. of Montreal, CA. UCLA NMR facilities supported
by an instrumentation grant from the NSF (CHE-1048804). We
thank Geeta Vadehra for assistance with cyclic voltammetry, and Dr.
Saeed Khan for crystallographic analyses. Paraza scientists wish to
thank Prof. Jean Lessard and Dr. Jean-Marc Chapuzet from
Universitꢀ de Sherbrooke and Pierre Bouchard from the Centre
National en ꢁlectrochimie et en Technologie Environnementales
Inc. for discussions on electrochemistry.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201411663.
Figure 2. Two mechanistically distinct syntheses of diazonamide core
structures.
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diazonamides may have utility as cancer therapy, additional
analogs with refined properties were sought, and material
consumption grew. In this regard, the original preparation of
3a became a bottleneck. Alongside 3a and 4a, PhI(OAc)2
oxidation of 2 invariably gave comparable amounts of
spirocyclohexadienones 6 (Figure 3A).[5c] These conventional
Kita oxidation[11] products limited the yield of 3a and
complicated its purification.
Figure 4. DZ-2384 (5).
over, due to improved pharmacokinetics, compound 5 was 10-
to 50-fold more efficacious than 1 as a cancer therapeutic
in vivo (rodents).
DZ-2384 was selected as a development candidate in
2012.[15] Attention turned to establishing a practical synthesis
of the molecule. The medicinal chemistry route was an
adaptation of our original synthesis of 1. Because 5 lacked the
right hand macrocycle (as drawn in Figure 1) of the natural
product, the main issue to be addressed was building the core
triarylacetaldehyde in proper diarylaminal form. Magnus,[6b]
Macmillan,[5a] and Sammakia[6a] had each described diaste-
reoselective chemistry for this purpose. However, when
evaluated in context of overarching goals for the project,
the electrochemical method above seemed especially prom-
ising. It operated on substrates derived from common amino
acids and formed the target motif at the requisite oxidation
state directly from a linear precursor.
The electrochemical step had been positioned in the
middle of the synthetic sequence. To further differentiate
oxidation potential of the indolic chromophore, we sought to
shift this reaction to a later stage. Here we describe a refined
Figure 3. Working mechanistic hypothesis.
An alternate method to prepare 3 was sought, wherein
oxidation of 2 could initiate at the indole rather than the
phenol. Presumably this would circumvent by-product for-
mations inherent to the Kita protocol. To date, only one
technique has achieved outcomes consistent with selective
internal oxidation. When substrate 2 (R = CO2Bn) was
electrolyzed at a controlled potential of + 1.6 V, anodic
oxidation occurred to give 3b and 4b in a 3:1 ratio.[12] Relative
to the PhI(OAc)2 procedure, the process was a major practical
advance. The reaction was run in wet DMF at 258C in an
undivided cell open to air. Substrate was stirred from the
center of a circular array of graphite rods. These served
alternately as cathode and anode. In line with the working
mechanistic hypothesis shown in Figure 3B,[13] products 3/4b
were obtained free of spirocyclohexadienone contaminants.
This simplified isolations of 3b and accelerated the medicinal
chemistry program. Hundreds of diazonamide analogs were
subsequently prepared—varying both in core structure and
peripheral substitutions. These efforts led to the identification
of DZ-2384 (5, Figure 4) as a simplified structure that fully
retained diazonamide anti-mitotic characteristics.[14] More-
Scheme 1. Assembling an oxidized tripeptide. Reagents and condi-
tions: a) 5-F-indole (2 equiv), Ac2O (2.2 equiv), AcOH, 60–658C.
b) l-Ser-OMe, EDC, HOBt, iPr2NEt, DMF, RT. c) DDQ (2 equiv), THF,
858C, 1.5 h. 73% from 9. EDC = 1-ethyl-3-(3-dimethylaminopropyl)-
carbodiimide, HOBt = 1-hydroxybenzotriazole, DMF = dimethylform-
amide, DDQ = 2,3-dichloro-5,6-dicyano-1,4-benzoquinone, THF =
tetrahydrofuran.
2
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Scheme 2. One-pot cyclodehydration/oxidation sequence. Reagents and conditions: a) Deoxo-Fluor (1.1 equiv), CH2Cl2 (0.37 m), À208C, 10 min.
b) add BrCCl3, (2.5 equiv), DBU (3.2 equiv) and additives (see Table 1) at RT, 3–4 h. Deoxo-Fluor = bis(2-methoxyethyl)aminosulfur trifluoride,
DBU = 1,8-diazabicyclo[5.4.0]undec-7-ene.
Table 1: Effects of protocol and additives on the synthesis of 12 from 10
(Scheme 2).
posing via retro-addition. It was unclear how this might occur,
although there was precedent for DBU reducing CCl4 via
single-electron transfers.[20] Along those lines, mixing equi-
molar amounts of BrCCl3 and DBU produced brominated
bicycle 13 and chloroform (1:1, 52% conversion after 1 h at
RT, see Scheme 3A). We discovered that Galvin Coppingerꢀs
radical[21] inhibited this reaction. In turn, 5 mol% of Galvin-
oxyl added together with BrCCl3 and DBU to crude solutions
of 11 improved the synthesis of 12 from 10 by eliminating the
+ 30 Da contaminant.[22] A second by-product accompanying
12 was a composite of 11 and DBU. Its structure was assigned
as spiroaminals 14 following X-ray crystallographic analysis
of congener 15 (see Scheme 3B and the Supporting Informa-
tion). Mechanistic details notwithstanding,[23] 14 was thought
to derive from DBU being oxidized with BrCCl3, not unlike
the + 30 Da contaminant discussed above. Galvinoxyl sup-
pressed formation of 14 and this benefit increased when
a portion of the DBU in the oxidation mixture was replaced
with Na2CO3. Combined, these two modifications more than
doubled the yield of 12 (Table 1, entry 5). For the synthesis of
Entry
Additive
Galvinoxyl (mol%)
Yield of 12 [%]
1
2
3
4
5
none
none
none
MgO[b]
0
0
5
5
5
31[a]
38
50
38
64
[b]
Na2CO3
[a] Stepwise yield (90 g scale). [b] 2.2 equiv (2.5 equiv DBU used).
route to DZ-2384 wherein electrolytic macrocyclization can,
in fact, be the final step in the process.
Our intent was to assemble DZ-2384 outwardly from
a
central dipeptide, namely tert-Leu-5-F-Trp-OH (9,
Scheme 1). Peptide 9 can be prepared in three steps from 5-
fluorotryptophan.[12] However, a four-step route proved more
cost effective. In that case, l-tert-leucine was acylated with
ClCO2Bn and the product was coupled to l-serine methyl
ester. After saponification with aq. LiOH, 7 was condensed
with 5-fluoroindole in the presence of Ac2O to afford
dipeptide 9. The overall yield of 9 from l-tert-leucine was
62% on kilogram scales. Compound 9 was isolated as an
inconsequential mixture of diastereomers; consistent with in
1
situ H NMR analyses by Yokoyama et al.[16] These authors
identified methylidene oxazolones (i.e. 8) as intermediates in
closely related reactions.
Coupling of 9 to l-serine methyl ester provided a tripep-
tide that was then incrementally oxidized, first with DDQ to
afford a single isomer of 3-(5-oxazolyl)indole 10.[17] Following
dessication of crude 10 with Deoxo-Fluor, the resultant
oxazoline (11) was further oxidized using a combination of
BrCCl3 and DBU.[18] This process proved interesting. The
dehydration step was uneventful. Oxazoline 11 could be
cleanly isolated. However, subsequent treatment with
BrCCl3/DBU gave bis-oxazole 12 in poor yield (25–35%
from 10, see Scheme 2 and Table 1, entry 1).
In an attempt to minimize handling, we implemented
Wipf and Williamsꢀ streamlined protocol.[19] Unmodified, this
one-pot procedure did little to improve yield (Table 1,
entry 2). Full conversion at a useful rate in the oxidation
step required 3 equiv of DBU. Significant by-products
accompanied formation of 12 under those conditions. One
of these was a compound 30 Da greater in mass than 12 that
degraded to 12 upon attempted isolation. It was as if 12 had
reacted with a formaldehyde synthon in situ, leading to
a hydroxymethylated adduct upon workup that was decom-
Scheme 3. Insights into the one-pot cyclodehydration/oxidation
sequence depicted in Scheme 2. Thermal ellipsoids drawn at 50%
probability.
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Scheme 4. Two concise syntheses of DZ-2384 employing electrolytic macrocyclization. Reagents and Conditions: a) Z-Tyr-OH, EDC, HOBt,
iPr2NEt, DMF, 08C to RT, 3 h. b) LiBH4 (5 equiv), TFE (5 equiv), THF, RT; for 17: t=12 h, 85% from 16; for 19: t=3 h, 63% from 16. c) 18:
+1.6 V, Et4NBF4, (NH4)2CO3, 1.8% aq. DMF, 5 d (35%, 43% based on recovered 17, d.r.=2.7:1; see the Supporting Information); 5: +1.6 V,
Et4NBF4, (NH4)2CO3, 2% aq. DMF, 56 h (35%, 48% based on recovered 19, d.r.=2.3:1; see the Supporting Information). d) H2 (1 atm), Pd/C
(10 mol%), tBuNH2 (1.5 equiv), MeOH, 4 h. e) (S)-(À)-hydroxyisovaleric acid, EDC, HOBT, iPr2NEt, DMF, 4 h, 91% from 18. f) Boc-Tyr-OH, EDC,
HOBt, N-methylmorpholine, DMF, 14 h. g) 4m HCl in dioxane, 20 min. h) (S)-(À)-hydroxyisovaleric acid, EDC, HOBt, N-methylmorpholine, DMF,
20 h. TFE = 2,2,2-trifluoroethanol. Thermal ellipsoids drawn at 50% probability.
DZ-2384, it was best to subject crude 10 directly to the
optimized, one-pot procedure. Following work-up, crude 12
(ca. 60% purity) was treated with HBr in AcOH to afford
amine salt 16 (Scheme 4) in 52% overall yield (95% purity,
> 98% ee) following precipitation with iPr2O and trituration
with cold EtOH.
With 16 in hand, two pathways to DZ-2384 were
developed. In the first, 16 was coupled to Z-Tyr-OH and the
product reduced with LiBH4 to afford 17. The reduction step
was complicated by limited solubility of the substrate in ether
solvents. It was found that adding trifluoroethanol (1 equiv
relative to LiBH4) formed a strongly reducing system[24] as
well as a homogenous solution. This allowed 17 to be isolated
in 85% yield (two steps from 16) on 70 gram scale.
Compound 17 was an electrolysis substrate. Cyclic vol-
tammetry indicated the molecule oxidized irreversibly at
+ 1.15 V (graphite anode vs. Ag/AgCl, DMF/H2O/Et4NBF4),
while oxidation of Z-Tyr-OMe under identical conditions
required a higher potential (+ 1.39 V). These data suggested
the mechanism invoked to explain anodic oxidation of 2
(Figure 3B) would remain plausible for 17. On preparative
scale, 17 was most efficiently converted to 18 by electrolysis at
a potential of + 1.6 V while adding solid (NH4)2CO3 portion-
wise.[25] Oxidizing 60 grams of 17 in this manner gave 21.0 g of
18 (d.r. 2.7:1) and 11.0 g of unreacted 17 after chromatog-
raphy on silica gel. Product yield peaked at about 80%
conversion. While HPLC analyses did not detect isolable by-
products, further electrolysis was detrimental. Based on
recovered 17, the yield of the macrocyclization was 43%.
Following hydrogenolysis of 18, the two isomeric amines
were separated (see the Supporting Information) and the
major isomer was acylated with (S)-2-hydroxyisovaleric acid
to give DZ-2384 (5). Twenty grams of 5 were prepared in this
manner and characterized as a free-flowing, white powder
(> 99% purity).[26]
A final series of experiments tested if electrolysis could
generate 5 directly. Because the batch reaction was run to
partial conversion and produced isomeric products, chroma-
tography was required. It was desirable to delay purification
until the last step. Hydrobromide 16 was condensed with Boc-
Tyr-OH and the product treated with 4n HCl. The resultant
C2 amine was coupled to (S)-2-hydroxyisovaleric acid and
treated with TFE modified LiBH4 to afford phenolic diol 19
(63% from 16, 87% purity, no chromatography). Anodic
4
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[8] a) M. Lachia, C. J. Moody, Nat. Prod. Rep. 2008, 25, 227 – 253;
oxidation of crude 19, under conditions identical to those used
for 17, afforded DZ-2384, its epi-C10,C11 diastereoisomer S7
(35%, > 98% purity, d.r. 2.3:1) and unreacted 19 (16%)
following chromatography on silica gel. Based on the purity of
starting material and the amount of 19 recovered in the
experiment, the yield of the macrocyclization was 48%.
The formation of a macrolactam-containing heptacyclic
diol directly from unprotected 19 was a milestone for the
project. It established a synthesis of DZ-2384 (5) that
proceeded in 13 total operations and 5.7% overall yield
from l-tert-leucine—wherein each kilogram of l-tert-leucine
would translate into 280 grams of DZ-2384.[27] The route
utilizes easily sourced raw materials and was completely free
of heavy metals. It also highlights the special potential of
electrochemical methods to elicit reactivity that is otherwise
elusive.[28] Further research along these lines is ongoing, as are
implementations of this chemistry according to good manu-
facturing practice.
b) K. C. Nicolaou, S. A. Snyder, Classics in Total Synthesis II,
Wiley-VCH, Weinheim, 2003, chap. 20.
[9] G. Wang, L. Zhang, A. W. G. Burgett, P. G. Harran, X. Wang,
Proc. Natl. Acad. Sci. USA 2007, 104, 2068 – 2073.
[10] N. Williams, A. W. G. Burgett, A. Atkins, X. Wang, P. G. Harran,
S. L. McKnight, Proc. Natl. Acad. Sci. USA 2007, 104, 2074 –
2079.
[11] Y. Kita, H. Tohma, K. Kikuchi, M. Inagaki, T. Yakura, J. Org.
Chem. 1991, 56, 435 – 438.
[12] C. Caldwell, G. Hanson, S. Harran, P. G. Harran, Q. Wei, M.
Zhou, US Patent #7,851,620 B2 Issued December 14, 2010.
[13] a) M. Malfoy, J. A. Reynaud, J. Electroanal. Chem. 1980, 114,
213 – 223; b) A. M. Oliveira-Brett, T. A. Enache, Electroanalysis
2011, 23, 1337 – 1344. Note: available data does not discern
whether electron transfers at the anode are ordered in the
manner proposed or, in fact, whether they need to be.
[14] Q. Wei, M. Zhou, X. Xu, C. Caldwell, S. Harran, L. Wang, US
Patent #8,592,469 B2 Issued November 26, 2013.
[15] See: http://www.therillia.com.
[16] Y. Yokoyama, M. Nakakoshi, H. Okuno, Y. Sakamoto, S.
Sakurai, Magn. Reson. Chem. 2010, 48, 811 – 817.
[17] Y. Oikawa, T. Yoshioka, K. Mohri, O. Yonemitsu, Heterocycles
1979, 12, 1457 – 1462.
Received: December 3, 2014
Published online: && &&, &&&&
[18] D. R. Williams, P. D. Lowder, Y. Gu, D. A. Brooks, Tetrahedron
Lett. 1997, 38, 331 – 334.
[19] A. J. Phillips, Y. Uto, P. Wipf, M. J. Reno, D. R. Williams, Org.
Lett. 2000, 2, 1165 – 1168.
[20] S. Lçfꢁs, P. Ahlberg, J. Chem. Soc. Chem. Commun. 1981, 998 –
999.
[21] a) G. M. Coppinger, J. Am. Chem. Soc. 1957, 79, 501 – 502;
b) P. D. Bartlett, C. Rꢂchardt, J. Am. Chem. Soc. 1960, 82, 1756 –
1502.
[22] The + 30 Da by-product (30–35%) was largely absent in BrCCl3-
mediated oxidations of isolated 11, implicating residual Deoxo-
Fluor or a product thereof acting in concert with a reduction
product of BrCCl3 in the one-pot procedure as its source. See the
Supporting Information.
[23] Spiroaminals 14 were not detected when 11, AIBN and 13 were
refluxed in (ClCH2)2. The same was true when 12, DBU and 13
were stirred at room temperature in CH2Cl2.
Keywords: anodic oxidation · electrosynthesis · macrocycles ·
natural products · oxazoles
.
[1] H. Aldemir, R. Richarz, T. A. M. Gulder, Angew. Chem. Int. Ed.
2014, 53, 8286 – 8293; Angew. Chem. 2014, 126, 8426 – 8433.
[2] T. R. Welch, R. M. Williams, Nat. Prod. Rep. 2014, 31, 1376 –
1404.
[3] N. Lindquist, W. Fenical, G. D. Van Duyne, J. Clardy, J. Am.
Chem. Soc. 1991, 113, 2303 – 2304.
[4] a) J. Li, S. Jeong, L. Esser, P. G. Harran, Angew. Chem. Int. Ed.
2001, 40, 4765 – 4769; Angew. Chem. 2001, 113, 4901 – 4906; b) J.
Li, A. W. G. Burgett, L. Esser, C. Amezcua, C. P. G. Harran,
Angew. Chem. Int. Ed. 2001, 40, 4770 – 4773; Angew. Chem.
2001, 113, 4906 – 4909.
[5] Total Syntheses: a) R. R. Knowles, J. Carpenter, S. B. Blakey, A.
Kayano, I. K. Mangion, C. J. Sinz, D. W. C. MacMillan, Chem.
Sci. 2011, 2, 308 – 311; b) K. C. Nicolaou, J. Hao, M. V. Reddy,
P. B. Rao, G. Rassias, S. A. Snyder, X. Huang, D. Y.-K. Chen,
W. E. Brenzovich, N. Giuseppone, A. OꢀBrate, P. Giannakakou,
J. Am. Chem. Soc. 2004, 126, 12897 – 12906; c) A. W. G. Burgett,
Q. Li, Q. Wei, P. G. Harran, Angew. Chem. Int. Ed. 2003, 42,
4961 – 4966; Angew. Chem. 2003, 115, 5111 – 5116; d) K. C.
Nicolaou, M. Bella, D. Y.-K. Chen, X. Huang, T. Ling, S. A.
Snyder, Angew. Chem. Int. Ed. 2002, 41, 3495 – 3499; Angew.
Chem. 2002, 114, 3645 – 3649.
[6] Formal syntheses: a) C. Mai, M. F. Sammons, T. Sammakia,
Angew. Chem. Int. Ed. 2010, 49, 2397 – 2400; Angew. Chem.
2010, 122, 2447 – 2450; b) C.-M. Cheung, F. W. Goldberg, P.
Magnus, C. J. Russell, R. Turnbull, V. Lynch, J. Am. Chem. Soc.
2007, 129, 12320 – 12327.
[24] K. Soai, A. Ookawa, J. Org. Chem. 1986, 51, 4000 – 4005.
[25] On scale, working potential was determined empirically using
a two-electrode system driven by a Protek 3003B power supply.
(NH4)2CO3 additions were made when current levels dropped to
about 50% of initial (ca. 12 h intervals on 60 g scale). See the
Supporting Information.
[26] DZ-2384 was handled according to guidelines established in:
M. I. Hensgen, B. Stump, Methods Mol. Biol. 2013, 1045, 133 –
143.
[27] Pre-clinical models project that clinical development of DZ-2384
through phase II (proof-of-concept) will require 50–100 g of
API.
[28] a) T. Siu, A. K. Yudin, J. Am. Chem. Soc. 2002, 124, 530 – 531;
b) T. Miura, S. Kim, Y. Kitano, M. Tada, K. Chiba, Angew. Chem.
Int. Ed. 2006, 45, 1461 – 1463; Angew. Chem. 2006, 118, 1489 –
1491; c) H.-C. Xu, J. D. Brandt, K. D. Moeller, Tetrahedron Lett.
2008, 49, 3868 – 3971; d) B. R. Rosen, E. W. Werner, A. G.
OꢀBrien, P. S. Baran, J. Am. Chem. Soc. 2014, 136, 5571 – 5574.
[7] Recent contributions: a) J. Zhang, M. A. Ciufolini, Org. Lett.
2011, 13, 390 – 393; b) J. Sperry, C. J. Moody, Tetrahedron 2010,
66, 6483 – 6495, and references therein.
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Communications
Synthetic Methods
H. Ding, P. L. DeRoy, C. Perreault,
A. Larivꢁe, A. Siddiqui, C. G. Caldwell,
S. Harran, P. G. Harran*
&&& — &&&
Electrolytic Macrocyclizations: Scalable
Synthesis of a Diazonamide-Based Drug
Development Candidate
Electrifying chemistry! The core macro-
lactam of diazonamides can be synthe-
sized electrochemically. This large ring
forming dehydrogenation has enabled
a concise preparation of DZ-2384,
a refined analog of diazonamide A slated
for clinical development as a cancer
therapeutic.
6
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