Streamlined Symmetrical Total Synthesis of Disorazole B1and Design, Synthesis, and Biological Investigation of Disorazole Analogues

Article abstract of DOI:10.1021/jacs.0c07094

Taking advantage of the C2-symmetry of the antitumor naturally occurring disorazole B1 molecule, a symmetrical total synthesis was devised with a monomeric advanced intermediate as the key building block, whose three-step conversion to the natural product

Full text of DOI:10.1021/jacs.0c07094

pubs.acs.org/JACS
Article
Streamlined Symmetrical Total Synthesis of Disorazole B1 and
Design, Synthesis, and Biological Investigation of Disorazole
Analogues
K. C. Nicolaou,* Johannes Krieger, Ganesh M. Murhade, Parthasarathi Subramanian, Balu D. Dherange,
Dionisios Vourloumis, Stefan Munneke, Baiwei Lin, Christine Gu, Hetal Sarvaiaya, Joseph Sandoval,
Zhaomei Zhang, Monette Aujay, James W. Purcell, and Julia Gavrilyuk
Cite This: https://dx.doi.org/10.1021/jacs.0c07094
Read Online
sı
*
Metrics & More
Article Recommendations
Supporting Information
ACCESS
ABSTRACT: Taking advantage of the C2-symmetry of the
antitumor naturally occurring disorazole B1 molecule, a sym-
metrical total synthesis was devised with a monomeric advanced
intermediate as the key building block, whose three-step
conversion to the natural product allowed for an expeditious
entry to this family of compounds. Application of the developed
synthetic strategies and methods provided a series of designed
analogues of disorazole B1, whose biological evaluation led to the
identification of a number of potent antitumor agents and the first
structure−activity relationships (SARs) within this class of
compounds. Specifically, the substitutions of the epoxide units
and lactone moieties with cyclopropyl and lactam structural motifs,
respectively, were found to be tolerable for biological activities and
beneficial with regard to chemical stability.
Such an approach was expected to be considerably shorter than
our previous nonsymmetrical approach that required the
construction of two advanced intermediates reached through
multistep sequences, as opposed to our new strategy that would
require only one advanced intermediate, whose dimerization−
cyclization would lead directly to the required macrocyclic
precursor of the targeted molecules. Furthermore, our new
strategy avoids the facile isomerization of certain olefinic bonds
of the conjugated structural motifs of the precyclization
intermediates by replacing the vulnerable double bonds with
acetylenic units until after cyclization, when they can be safely
converted to their desired (Z)-olefinic bonds through Lindlar
hydrogenation.
1. INTRODUCTION
Comprising numerous synthetically challenging natural prod-
ucts, the disorazole family of compounds1 attracted the interest
of synthetic organic chemists and biologists alike due to their
novel molecular structures and potent antitumor properties.2
We recently reported the first total syntheses of disorazoles A1
(1, Figure 1) and B1 (2, Figure 1) and assigned the full
stereochemical structure of the latter,3 whose epoxide
configurations were previously unknown.1a We also subse-
quently disclosed the application of our developed modular
synthetic strategies toward these natural products to the
synthesis of the corresponding biscyclopropyl and bisthiazolyl
analogues of both disorazoles A1 (1) and B1 (2), including
biscyclopropyl disorazole B1 (3, Figure 1).4 In this article we
report a streamlined, symmetrical total synthesis of disorazole B1
(2) and its application to, in addition to the previously reported
biscyclopropyl disorazole B1 (3), several new analogues (i.e., 4−
12, Figure 2), and their biological evaluation and that of the
parent compound disorazole B1 (2), as antitumor agents.
Figure 2 depicts the designed disorazole B1 analogues (4−12)
synthesized in this study, applying the newly developed
symmetrical total synthesis of disorazole B1. The design of
these analogues was based on the following rationales: (a) the
synthetic strategy employed (e.g., involvement of bisacetylene
Received: July 1, 2020
2. RESULTS AND DISCUSSION
Our first objective was to develop a more efficient route to
disorazole B1 (2) than our first total synthesis now based on a
symmetrical and more convergent synthetic strategy, taking
advantage of the C2-symmetrical structure of the molecule.5
https://dx.doi.org/10.1021/jacs.0c07094
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX
© XXXX American Chemical Society
A

Journal of the American Chemical Society
pubs.acs.org/JACS
Article
opposed to the macrolactone of its parent natural product
epothilone B).
2.1. Streamlined Symmetrical Total Synthesis of
Disorazole B1 (2). Figure 3 summarizes, in retrosynthetic
format, our original nonsymmetrical approach to disorazole B1
(2, Figure 3A) through intermediate 13 and our proposed
symmetrical approach based on a Sonogashira coupling/
macrocyclization (Figure 3B).7 The construction of required
building blocks 14 and 15 (Figure 3A) required numerous steps
and then stepwise coupling (to afford 13) and macro-
lactonization. In contrast, the new symmetrical approach
(Figure 3B) required building blocks iodide 18,3,4 aldehyde
19, and acetylene carboxylic acid 20 to be assembled into key
advanced intermediate 17, whose palladium−copper-catalyzed
Sonogashira coupling/macrocyclization, followed by sequential
selective Lindlar hydrogenation and deprotection, was expected
to afford disorazole B1 (2), via bisacetylene precursor 16, in a
shorter and streamlined way, as outlined in Figure 3B.
Scheme 1 depicts the construction of the defined building
blocks 19 (Scheme 1A) and 20 (Scheme 1B) and their
sequential coupling with our previously synthesized iodide
building block 183,4 and elaboration to disorazole B1 (2)
(Scheme 1C). Thus, commercially available acetylene diethox-
yacetal 21 was treated with NaI in the presence of H2SO4 to
afford the corresponding vinyl iodide aldehyde, which was
reacted with the anion of the commercially available methyl ester
phosphonate 22 (KHMDS, 18-crown-6) to afford selectively
(Z,E)-methyl ester iodide 23 (78% overall yield). The latter was
reduced with DIBAL-H to the corresponding allylic alcohol,
whose Sharpless epoxidation [TBHP, Ti(OiPr)4, (−)-DET]
furnished the expected epoxide 25 as the major enantiomer as
Figure 1. Molecular structures of disorazole A1 (1), B1 (2), and
biscyclopropyl disorazole B1 (3).
advanced precursors); (b) the expected stability of the
biscyclopropyl structural motifs (as opposed to the more labile
epoxide structural motifs); (c) the opportunity to explore
substituents on the lipophilic side-chain residues and oxazole
moieties of disorazoles B1 (biological evaluation); and (d) the
inspiring success of the clinically used anticancer drug
Ixabepilone6 (containing the macrolactam structural motif as
Figure 2. Molecular structures of designed and synthesized disorazole B1 analogues 4−12. (A) Biscyclopropyl bislactone analogues. (B)
Biscyclopropyl bislactam analogues. PMB = para-methoxybenzyl.
B
https://dx.doi.org/10.1021/jacs.0c07094
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
pubs.acs.org/JACS
Article
Figure 3. Retrosynthetic analyses of disorazole B1 (2). (A) Previously developed3 stepwise macrolactonization approach. (B) Proposed streamlined
symmetrical Sonogashira dimerization/cyclization approach. TMS = trimethylsilyl; TBS = tert-butyldimethylsilyl.
theoretically predicted [(−)-DET-facilitated Si face attack of the
allyl alcohol double bond (61% overall yield from 23)], as shown
in Scheme 1A. The enantiomeric excess of the latter was
enriched through kinetic resolution by exposure to vinyl acetate
and Amano lipase PS, with the undesired enantiomer (24, see
Scheme 1A) being removed chromatographically as the acetate
derivative (76% yield for 25). DMP oxidation of intermediate
epoxy alcohol (25) then gave the desired aldehyde 19 (55%
yield). Due to the rather labile nature of this aldehyde and its
precursor allylic alcohol 25, these intermediates were rushed
through the sequence (i.e., epoxidation, Amano lipase PS kinetic
resolution, oxidation, and Wittig olefination). The absolute
configurations of 25 and 19 were confirmed at a later stage as we
shall discuss below.
The required acetylene carboxylic acid 20 was prepared from
commercially available oxazole ethyl ester 26 as shown in
Scheme 1B. Thus, oxazole 26 was lithiated (LHMDS), and the
resulting lithio derivative was quenched with 1,2-diiodoethane
to afford iodo oxazole 27 (51% yield), whose palladium/copper-
catalyzed coupling with TIPS-acetylene led to oxazole acetylene
28 (75% yield). Sequential deprotection of 28 (TBAF, 86%
yield; then LiOH, 99% yield) furnished the desired building
block acetylene carboxylic acid 20, as shown in Scheme 1B.
With both fragments 19 and 20 readily available, their
assembly with previously synthesized fragment 183,4 proceeded
as summarized in Scheme 1C. Thus, iodide 18 was converted to
its phosphonium salt (PPh3, i-Pr2NEt), which underwent Wittig
olefination with epoxy aldehyde 19 as facilitated with ylide
formation (LHMDS, DMPU) to afford epoxy vinyl iodide 29
(64% yield for the two steps). The latter (29, more stable as
opposed to the labile aldehyde 19 and its precursor alcohol 25)
was transformed to the key monomeric building block 17 by
sequential selective TMS removal (3HF·Et3N, 73% yield) and
esterification of the resulting hydroxy intermediate with
carboxylic acid acetylene 20 [2,4,6-trichlorobenzoyl chloride
(TCBC), Et3N, DMAP, 92% yield] as depicted in Scheme 1C.
Exposure of vinyl iodide terminal acetylene 17 to Pd(PPh3)4 cat.
in the presence of stochiometric CuI furnished macrocycle 16
(40% yield) through coupling and macrocyclization. The latter
was selectively reduced with H2 under Lindlar conditions in the
presence of quinoline to afford bis-TBS disorazole B1 (30, 70%
yield), whose desilylation (TASF, 78% yield) furnished the
coveted natural product disorazole B1 (2). Ultimate precursor
30 and synthetic disorazole B1 (2) exhibited identical physical
data to those previously observed in our first total synthesis,3
thereby confirming the absolute configurations of building block
19 and its precursor 25 (Scheme 1A). This symmetrical total
synthesis of disorazole B1 (2) proceeded in 17 total number of
steps and in 3% overall yield (12 steps longest linear sequence
from 21) from readily available building blocks 21, 26, and 18,3,4
as opposed to our first total synthesis, which required a total of
29 steps and gave the desired natural product in 1.8% overall
yield (15 steps longest linear sequence) starting from propargyl
alcohol.3
2.2. Synthesis of Disorazole B1 Analogues 3−9. The
synthetic strategy for the streamlined total synthesis of
disorazole B1 analogues 3 (biscyclopropyl disorazole B1) and
4 (biscyclopropyl bisacetylene disorazole B1) was derived from
the retrosynthetic analysis indicated in Scheme 2A. Requiring
key building blocks 18,3,4 20 (Scheme 1B), and 33 and
proceeding through advanced monomeric precursor iodo
acetylene 32, the total synthesis of these analogues proceeded
as summarized in Scheme 2. While intermediates 20 (Scheme
1B) and 183,4 were available to us from our earlier studies, the
C
https://dx.doi.org/10.1021/jacs.0c07094
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
pubs.acs.org/JACS
Article
a
Scheme 1. Streamlined Total Synthesis of Disorazole B1
a
Reagents and conditions: (a) 4 M aq. H2SO4:Et2O (1:1, v/v), NaI (1.5 equiv), 0 °C, 20 h; (b) 18-crown-6 (4.0 equiv), 22 (1.2 equiv), KHMDS
(1.1 equiv), −78 °C, 5 min; then (E)-3-iodo acrylaldehyde, −78 °C, 0.5 h, 78% over two steps; (c) DIBAL-H (2.2 equiv), Et2O, −78 to 0 °C, 2 h;
(d) TBHP (2.0 equiv), Ti(Oi-Pr)4 (0.10 equiv), (−)-DET (0.15 equiv), 3 Å molecular sieves, CH2Cl2, −78 to −20 °C, 16 h, 80% over two steps;
(e) Amano lipase PS, vinyl acetate, CH2Cl2, 0 °C, 16 h, 76%; (f) DMP (1.2 equiv), NaHCO3 (4.0 equiv), CH2Cl2, 0 °C, 2 h, 55%; (g) LHMDS
(1.5 equiv), THF, −78 °C, 1 h; then 1,2-diiodoethane (1.2 equiv), −78 to −20 °C, 5 h, 51%; (h) TIPS-acetylene (3.0 equiv), CuI (0.06 equiv),
Pd(PPh3)4 (0.03 equiv), DMF:Et3N (1:1, v/v), 60 °C, 16 h, 75%; (i) TBAF (1.3 equiv), AcOH (4.0 equiv), THF, 0 °C, 2 h, 86%; (j) LiOH·H2O
(2.0 equiv), dioxane:H2O (4:1, v/v), 23 °C, 16 h, 99%; (k) 18 (1.2 equiv), PPh3 (1.9 equiv), i-Pr2NEt, 90 °C, 20 h; (l) LHMDS (1.2 equiv), THF,
−78 °C, 0.5 h; then DMPU (0.7 equiv), −78 °C, 15 min; then 19 (1.0 equiv), −78 to 23 °C, 8 h, 64% two steps [(Z):(E) ca. 6:1]; (m) 3HF·Et3N
(1.7 equiv), THF, 23 °C, 3 h, 73%; (n) 20 (2.0 equiv), Et3N (4.0 equiv), DMAP (4.0 equiv), TCBC (2.0 equiv), toluene, 23 °C, 3 h, 92%; (o) CuI
(1.0 equiv), Pd(PPh3)4 (0.25 equiv), DMF:Et3N (2:1, v/v), 0 °C, 6 h, 40%; (p) Lindlar cat., quinoline, H2, ethyl acetate, 23 °C, 1 h, 70%; (q)
TASF, H2O, DMF, 45 °C, 48 h, 78%. KHMDS = potassium 1,1,1-trimethyl-N-(trimethylsilyl)silanaminide; LHMDS = lithium 1,1,1-trimethyl-N-
(trimethylsilyl)silanaminide; DMPU = 1,3-dimethyl-1,3-diazinan-2-one; DIBAL-H = diisobutylaluminum hydride; DET = diethyl 2,3-
dihydroxybutanedioate; TBHP = 2-methylpropane-2-peroxol; DMP = Dess−Martin periodinane; TIPS = triisopropylsilyl; TBAF = tetra-n-
butylammonium fluoride; TCBC = 2,4,6-trichlorobenzoyl chloride; DMAP = N,N-dimethylpyridin-4-amine; TASF = tris(dimethylamino)-
sulfonium difluorotrimethylsilicate.
requisite iodo aldehyde 33 was prepared from readily available
allylic alcohol 348 through the dual path shown in Scheme 2B.
Thus, 34 was subjected to cyclopropanation (CH2I2, ZnEt2) to
afford hydroxy cyclopropyl diastereoisomers 35 and 36 [72%
yield, 35 (path a):36 (path b) ca. 1:6.2 dr]. The desired
diastereoisomer 35, whose absolute configuration was estab-
lished by comparison of its spectroscopic and optical rotation
data to those of the previously synthesized material,8b was
converted to vinyl iodide 37 [(E):(Z) ca. 4.5:1 dr] by sequential
DMP oxidation (94% yield) to the corresponding aldehyde and
reaction of the latter with CH2I2 and CrCl2 (67% yield). The
targeted (E)-vinyl iodide 33 was then prepared from the (E/Z)-
mixture of 37 through sequential deprotection (p-TsOH, H2O,
99% yield) and cleavage of the so-formed 1,2-diol (NaIO4, 75%
yield) followed by chromatographic purification, as shown in
Scheme 2B (path a). The other, chromatographically separated
diastereoisomer 36 was transformed to the same desired
fragment 33 through path b, as summarized in Scheme 2B.
Thus, PMB protection of the hydroxyl group within 36 (38,
PPTS cat.), followed by acetonide cleavage (aq. HCl), afforded
dihydroxy PMB-ether 39 in 86% overall yield. The 1,2-diol
moiety of the latter was cleaved (NaIO4, 84% yield), and the
resulting aldehyde was subjected to Takai olefination (CHI3,
CrCl2, 63% yield) to yield iodo olefin 40 [(E):(Z) ca. 4.6:1], as
shown in Scheme 2B (path b). Removal of the PMB protecting
group (DDQ, 98% yield) from 40 and DMP oxidation (78%
yield) of the resulting primary alcohol gave, after chromato-
graphic separation, the same cyclopropyl iodo aldehyde
fragment 33 (78% yield) as the one obtained via path a
(Scheme 2B).
D
https://dx.doi.org/10.1021/jacs.0c07094
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
pubs.acs.org/JACS
Article
a
Scheme 2. Synthesis of Disorazole B1 Analogues 3 and 4
a
Reagents and conditions: (a) CH2I2 (4.0 equiv), Et2Zn (2.1 equiv), CH2Cl2, 0 °C, 1 h; then 34 (1.0 equiv), 0 to 23 °C, 12 h, 10% for 35; 62% for
36; (b) DMP (1.25 equiv), NaHCO3 (3.0 equiv), CH2Cl2, 23 °C, 2 h, 94%; (c) CrCl2 (7.0 equiv), CHI3 (2.0 equiv), THF, 0 °C, 3 h, 67% [(E)/
(Z) = 4.5:1)]; (d) p-TsOH·H2O (0.1 equiv), THF:H2O (4:1, v/v), 45 °C, 24 h, 99%; (e) NaIO4 (2.0 equiv), CH2Cl2:H2O:aq. NaHCO3 (2:1:1,
v/v/v), 23 °C, 3 h, 75%; (f) 38 (1.3 equiv), PPTS (0.05 equiv), CH2Cl2, 23 °C, 16 h; (g) THF:4 M aq. HCl (4:1, v/v), 23 °C, 3 h, 86% over two
steps; (h) NaIO4 (1.75 equiv), CH2Cl2:H2O:aq. NaHCO3 (2:1:1, v/v/v), 23 °C, 3 h, 84%; (i) CrCl2 (7.0 equiv), CHI3 (2.0 equiv), THF, 0 °C, 2
h, 63% [(E):(Z) = 4.6:1]; (j) DDQ (1.75 equiv), CH2Cl2:pH 7 buffer (20:1, v/v), 23 °C, 1 h, 98%; (k) DMP (1.2 equiv), NaHCO3 (3.0 equiv),
CH2Cl2, 23 °C, 2 h, 78%; (l) PPh3 (1.75 equiv), i-Pr2NEt, 90 °C, 20 h; (m) LHMDS (1.05 equiv), THF, −78 °C, 0.5 h; then DMPU (0.6 equiv),
−78 °C, 15 min; then 33 (1.0 equiv), −78 to 23 °C, 8 h, 83% over two steps; (n) HCO2H (3.0 equiv), MeOH, 0 °C, 2 h, 81%; (o) 20 (1.5 equiv),
Et3N (3.0 equiv), DMAP (4.0 equiv), TCBC (2.0 equiv), toluene, 23 °C, 3 h, 80%; (p) CuI (0.40 equiv), Pd(PPh3)4 (0.2 equiv), DMF:Et3N (2:1,
v/v), 23 °C, 16 h, 51%; (q) Lindlar cat., quinoline, H2, ethyl acetate, 23 °C, 3 h, 80%; (r) H2SiF6 (75 equiv), MeOH, 23 °C, 48 h, 77%; (s) H2SiF6
(75 equiv), MeOH, 23 °C, 48 h, 83%.
E
https://dx.doi.org/10.1021/jacs.0c07094
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
pubs.acs.org/JACS
Article
a
Scheme 3. Synthesis of Disorazole B1 Analogues 5−8
a
Reagents and conditions: (a) 44 (2.0 equiv), p-TsOH (0.05 equiv), 38 (1.1 equiv), 23 °C, 24 h, 67%; (b) DMP, CH2Cl2, 23 °C, 2 h, 90%; (c)
BH3·THF (1.05 equiv), 46 (1.1 equiv), CH2Cl2, 0 to 23 °C, 1.5 h; then cooled to −78 °C, 45 (1.0 equiv), 47 (1.15 equiv), 2 h, 95%; (d)
NaHMDS (1.1 equiv), THF, −78 to 23 °C, 89%; (e) TiCl4 (1.6 equiv), CH2Cl2, 0 °C, 10 min; then −78 °C, i-Pr2NEt (1.2 equiv), 0.5 h; then −50
°C; 2 h; then −78 °C, 49 (1.0 equiv), 1 h, 87%; (f) TMSOTf (1.05 equiv), 2,6-lutidine (2.5 equiv), CH2Cl2, 0 °C, 1 h, 95%; (g) DIBAL-H, Et2O,
−78 to 23 °C, 2 h; (h) imidazole (1.5 equiv), PPh3 (1.2 equiv), I2 (1.35 equiv), CH2Cl2, 0 °C, 1 h; 84% over two steps; (i) PPh3 (1.75 equiv), i-
Pr2NEt, 90 °C, 20 h; (j) LHMDS (1.05 equiv), THF, −78 °C, 0.5 h; then DMPU (0.6 equiv), −78 °C, 15 min; then 33 (1.0 equiv), −78 to 23 °C,
8 h, 65% over two steps; (k) HCO2H (3.0 equiv), MeOH, 0 °C, 2 h, 77%; (l) 20 (2.0 equiv), Et3N (4.0 equiv), DMAP (4.0 equiv), TCBC, (2.0
equiv), toluene, 0 to 23 °C, 5 h, 86%; (m) CuI (1.0 equiv), Pd(PPh3)4 (0.25 equiv), DMF:Et3N (2:1, v/v), 0 to 23 °C, 12 h, 48%; (n) Lindlar
catalyst, quinoline, H2, ethyl acetate, 23 °C, 8 h, 64%; (o) DDQ (4.0 equiv), CH2Cl2:pH 7 buffer (40:1, v/v), 23 °C, 3 h, 98%; (p) H2SiF6 (75
equiv), MeOH, 23 °C, 36 h, 70%; (q) H2SiF6 (75 equiv), MeOH, 23 °C, 48 h, 75%; (r) DDQ (4.0 equiv), CH2Cl2:pH 7 buffer (40:1, v/v), 23 °C,
3 h, 76%; (s) H2SiF6 (75 equiv), MeOH, 23 °C, 36 h, 87%; (t) H2SiF6 (75 equiv), MeOH, 23 °C, 48 h, 58%. p-TSA = 4-methylbenzene-1-sulfonic
acid; TMSOTf = trimethylsilyl trifluoromethanesulfonate; DDQ = 4,5-dichloro-3,6-dioxocyclohexa-1,4-diene-1,2-dicarbonitrile.
With all three building blocks (i.e., 18, 20, and 33) now
available, the synthesis of targeted analogues 3 and 4 was
completed through the short pathway shown in Scheme 2C.
Thus, iodide 183,4 was converted to its phosphonium salt (PPh3,
i-Pr2NEt), which was reacted with LHMDS in the presence of
DMPU and aldehyde 33 to afford (Z)-olefin 41 (83% overall
yield). The TMS protecting group was removed from the latter
(HCO2H, 81% yield), and the intermediate hydroxy compound
was esterified with acetylene carboxylic acid fragment 20
(TCBC, Et3N, DMAP, 80% yield) to yield the targeted
monomeric vinyl iodide acetylene 32. The latter underwent
dimerization/macrocyclization through a two-step sequential
reaction [Pd(PPh3)4 cat., CuI cat.] to give biscyclopropyl
bisacetylene macrocycle 42 in 51% yield. The latter served well
F
https://dx.doi.org/10.1021/jacs.0c07094
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
pubs.acs.org/JACS
Article
a
Scheme 4. Synthesis of Disorazole B1 Analogue 9
a
Reagents and conditions: (a) 5810 (1.05 equiv), CH2Cl2, 23 °C, 12 h, 83%; (b) LiHMDS (1.5 equiv), 1,2-diiodoethane (1.2 equiv), THF, −78 to
23 °C, 12 h, 86%; (c) triisopropylsilylacetylene (3.0 equiv), Pd(PPh3)4 (0.03 equiv), CuI (0.06 equiv), DMF:Et3N (1:1, v/v), 60 °C, 10 h, 79%;
(d) LiOH·H2O (3.0 equiv), THF:H2O (3:1, v/v), 23 °C, 4 h, 76%; (e) 62 (2.0 equiv), Et3N (4.0 equiv), DMAP (4.0 equiv), TCBC, (2.0 equiv),
toluene, 0 to 23 °C, 3 h, 45%; (f) CuI (1.0 equiv), Pd(PPh3)4 (0.25 equiv), DMF:Et3N (2:1, v/v), 0 to 23 °C, 12 h, 42%; (g) Lindlar catalyst,
quinoline, H2, ethyl acetate, 23 °C, 8 h, 64%; (h) H2SiF6 (75 equiv), MeOH, 23 °C, 48 h, 65%.
as a precursor to the coveted biscyclopropyl disorazole B1
analogue 3 as achieved through a two-step sequence, via
intermediate 43, involving Lindlar hydrogenation (H2, Lindlar
cat., quinoline, 80% yield), followed by desilylation (H2SiF6,
77% yield), as shown in Scheme 2C. Biscyclopropyl bisacetylene
analogue 4 was directly generated from precursor 42 upon
exposure to H2SiF6, in 83% yield, as summarized in Scheme 2C.
Scheme 3 summarizes the total synthesis of dehydroxylated
biscyclopropyl disorazole B1 analogues 5−8. The common
advanced precursor 55 was defined through retrosynthetic
analysis that involved a divergent approach to all four targeted
analogues and defined as key fragments 20 (see Scheme 1B for
preparation) and 53, whose construction and further elabo-
ration to the targeted compounds are shown in Scheme 3. Thus,
starting with readily available diol 44, PMB α,β-unsaturated
aldehyde 45 was prepared through reaction with benzylating
reagent 38 in the presence of p-TsOH cat. (67% yield of mono
PMB ether), followed by oxidation of the remaining hydroxyl
group (DMP, 90% yield). Reaction of aldehyde 45, first with the
chiral borane reagent [prepared in situ from BH3·THF and N-
tosyl-D-valine (46)] and subsequently with ketene silyl acetal 47,
followed by treatment of the resulting β-hydroxy hemisilylacetal
(see structure 48 in brackets in Scheme 3, 95% yield) with
NaHMDS (inducing migration of the TBS group and collapse of
the acetal) furnished, enantioselectively, extended fragment
aldehyde 49 in 89% yield. Addition of aldehyde 49 to the anion
generated from Nagao auxiliary 509 and i-Pr2NEt in the
presence of TiCl4 gave, stereoselectively, the corresponding
hydroxy compound (87% yield), which was silylated (TMSCl,
2,6-lutidine) leading to intermediate 51 (95% yield), as shown
in Scheme 3. Treatment of the latter with DIBAL-H, followed by
exposure of the so-formed alcohol to I2 and PPh3 in the presence
of imidazole, gave iodide 52 (84% overall yield from 51).
Conversion of iodide 52 to its phosphonium salt (PPh3, i-
Pr2NEt), followed by ylide formation (LHMDS) and sequential
addition of DMPU and iodo aldehyde 33, led to fragment 53
stereoselectively and in 65% overall yield, as depicted in Scheme
3. Selective removal of the TMS group from the latter
(HCOOH, 77% yield), followed by esterification (TCBC,
Et3N, DMAP) of the so-generated alcohol with carboxylic acid
20, afforded the coveted vinyl iodide acetylene fragment 54, in
86% yield as depicted in Scheme 3. This monomeric precursor
was then subjected to the palladium/copper dimerization/
macrocyclization [Pd(PPh3)4 cat., CuI, 48% yield] to give
bisacetylene diolide precursor 55, which was transformed
selectively to the next polyunsaturated precursor 56 through
hydrogenation with Lindlar catalyst in the presence of quinoline
in 64% yield, as shown in Scheme 3. Precursor 56 gave rise to
targeted tetrahydroxy analogue 5 after sequential exposure, first
to DDQ (98% yield) and then H2SiF6 (70% yield), and
bishydroxy bis-PMB analogue 6 upon treatment with H2SiF6
(75% yield), as summarized in Scheme 3. Similarly, bisacetylene
precursor 55 was converted to tetrahydroxy analogue 7 through
a two-step sequence involving removal of the PMB protecting
groups (DDQ, 76% yield) followed by cleavage of the TBS
groups (H2SiF6, 87% yield) and to bis-PMB dihydroxy analogue
8 by exposure to H2SiF6 (58% yield), as shown in Scheme 3.
G
https://dx.doi.org/10.1021/jacs.0c07094
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
pubs.acs.org/JACS
Article
a
Scheme 5. Synthesis of Bislactam Disorazole B1 Analogues 10−12
a
Reagents and conditions: (a) 70 (1.0 equiv), Ti(OEt)4 (2.0 equiv), CH2Cl2, 0 to 23 °C, 12 h, 86%; (b) 7112 (5.0 equiv), CH2Cl2, −78 to −30 °C,
3 h, 72%; (c) 6711 (1.0 equiv), Cs2CO3 (2.5 equiv), 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (0.06 equiv), PdCl2(CH3CN)2 (0.02
equiv), THF, 60 °C, 12 h, 80%; (d) Ni(OAc)2·4H2O (0.25 equiv), NaBH4(0.25 equiv), ethylene diamine (1.0 equiv), EtOH, H2, 23 °C, 12 h, 90%;
(e) DMP (2.0 equiv), NaHCO3 (4.0 equiv), CH2Cl2, 0 to 23 °C, 3 h, 80%; (f) CrCl2 (7.0 equiv), CHI3 (2.0 equiv), THF, −12 °C, 12 h, 55%; (g)
HCl (4.0 M in dioxane, 2.0 equiv), MeOH, 23 °C, 1 h; (h) 62 (1.2 equiv), EDCI (1.5 equiv), HOAt (1.1 equiv), i-Pr2NEt (3.0 equiv), CH2Cl2, 23
°C, 3 h, 61% over two steps; (i) TBAF (1.5 equiv), THF, 0 to 23 °C, 3 h, 83%; (j) Pd(PPh3)4 (0.25 equiv), CuI (1.0 equiv), DMF:Et3N (2:1, v/v),
0 to 23 °C, 12 h, 29%; (k) HCl (4.0 M in dioxane, 2.0 equiv), MeOH, 23 °C, 1 h; (l) 20 (1.2 equiv), EDCI (1.5 equiv), HOAt (1.1 equiv), i-
Pr2NEt (3.0 equiv), CH2Cl2, 23 °C, 3 h, 65% over two steps; (m) TBAF (1.5 equiv), THF, 0 to 23 °C, 3 h, 88%; (n) Pd(PPh3)4 (0.25 equiv), CuI
(1.0 equiv), DMF:Et3N (2:1, v/v), 0 to 23 °C, 12 h, 31%; (o) Lindlar catalyst, quinoline, ethyl acetate, 23 °C, 8 h, 71%.
Designed disorazole B1 analogue 9 with both of its two
oxazole rings functionalized with an oxygenated residue was
synthesized as shown in Scheme 4. Retrosynthetic analysis of
this molecule based on the same general strategy relying on the
symmetrical acetylene−vinyl iodide coupling/macrocyclization
tactic required the substituted oxazole fragment 62, whose
H
https://dx.doi.org/10.1021/jacs.0c07094
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
pubs.acs.org/JACS
Article
synthesis is summarized in Scheme 4A, and vinyl iodide
fragment 63 [see Scheme 4B and Scheme 2C, conditions (n)].
The construction of required fragment 62 proceeded
smoothly through a four-step sequence starting with readily
available carboxylic acid 57. Thus, 57 reacted with reagent 5810
to afford, in 83% yield, oxazole derivative 59 as shown in Scheme
4A. The latter was iodinated (LHMDS, 1,2-diodoethane, 86%
yield) to afford iodo oxazole 60, from which acetylene 61 was
obtained through a Sonogashira coupling with TIPS-acetylene
[Pd(PPh3)4 cat., CuI cat., 79% yield]. Cleavage of the TIPS
group from TIPS-acetylene 61 (LiOH·H2O, 78% yield) finally
led to the targeted fragment terminal acetylene 62. Scheme 4B
depicts the completion of the synthesis of targeted analogue 9,
starting with the coupling of vinyl iodide 63 (for preparation via
41, see Scheme 2C) and carboxylic acid terminal acetylene 62.
Thus, reaction of 62 with iodide 63 in the presence of TCBC,
Et3N, and DMAP furnished ester 64 (45% yield). Subjecting the
monomeric advanced intermediate 64 to the palladium/copper-
catalyzed coupling/macrocyclization [Pd(PPh3)4 cat., CuI cat.,
42% yield] led to macrocyclic bisacetylene precursor 65, whose
controlled hydrogenation with Lindlar catalyst/quinoline (64%
yield) afforded the ultimate precursor 66. Finally, exposure of
the latter to H2SiF6 led to the desired analogue 9 in 65% yield, as
shown in Scheme 4.
through pathway b and toward analogues 11 and 12 as depicted
in Scheme 5B. Thus, acid-induced cleavage (HCl in dioxane) of
the sulfonamide moiety of 75, followed by amide formation
between the so-generated amine and oxazole carboxylic acid 20
(EDCI, HOAt), led to amide 78 in 65% overall yield for the two
steps. Removal of the TBS group from 78 (TBAF, 88% yield),
followed by dimerization/macrocyclization of the so-formed
hydroxy vinyl iodide acetylene precursor under the influence of
Pd(PPh3)4 cat. and CuI, furnished coveted lactam analogue 11
(31% yield). Finally, biscyclopropyl bislactam disorazole B1
analogue 12 was generated from analogue 11 by Lindlar
hydrogenation in the presence of quinoline, in 71% yield, as
shown in Scheme 5 B.
2.4. Biological Evaluation of Disorazole B1 and
Analogues 3−12. Having secured synthetic disorazole B1 (2,
Figure 1) and its analogues 3−12 (Figure 2), their biological
activities against uterine sarcoma cells (MES-SA), MES-SA cells
with marked multidrug resistance due to overexpression of Pgp
(MES-SA/Dx), and immortalized human embryonic kidney
cells (HEK 293T) were evaluated with monomethyl auristatin E
(MMAE) as a standard. Table 1 summarizes the results of these
Table 1. Cytotoxicity Data Against Cell Lines MES-SA, MES-
SA/Dx, and HEK 293T for Disorazole B1 (2) and Disorazole
a
Analogues 3−12
2.3. Synthesis of Bislactam Disorazole B1 Analogues
10−12. Inspired by the clinically used anticancer drug
Ixabepilone6 (the lactam counterpart of epothilone B),
disorazole B1 analogues 10, 11, and 12 were designed and
synthesized as summarized in Scheme 5. Based on the
retrosynthetic analysis shown in Scheme 5A, the developed
synthetic strategies defined the bisacetylene disorazole B1
analogue 11 as the ultimate precursor from which disorazole
B1 analogue 12 could be generated through Lindlar hydro-
genation. Precursor 11 and its modified oxazole counterpart 10
carrying a methyl-oxygenated side chain were then traced back
to building blocks 20, 62, 67,11 and 68 as shown in Scheme 5A.
Scheme 5B summarizes the total synthesis of bislactam
disorazole B1 analogues 10, 11, and 12 starting with readily
available aldehyde 69.3 Thus, sequential reaction of 69 with
primary sulfonamide 70 in the presence of Ti(OEt)4, followed
by addition of Grignard reagent 7112 to the so-formed N-
sulfonyl imine, gave secondary sulfonamide 72 (86% yield,
single diastereoisomer). The configuration of the stereogenic
centers within 72 were confirmed by X-ray crystallographic
analysis of a downstream derivative (see below). Palladium-
catalyzed coupling of acetylenic intermediate 72 with cyclo-
propyl iodide 6711 furnished hydroxy acetylene 73, whose
selective reduction [H2, Ni(OAc)2·4H2O, NaBH4, 90% yield]
led to (Z)-olefin 74. Crystalline 74 [mp 96−98 °C, EtOAc:n-
pentane (1:3, v/v)] yielded to X-ray crystallographic analysis13
(see ORTEP representation of 74 in Scheme 5B). Oxidation of
alcohol 74 (DMP, 80% yield) afforded aldehyde 68, which was
converted to (E)-vinyl iodide 75 through the action of CHI3/
CrCl2 (55% yield). The latter was diverted along two different
pathways toward lactam analogues 10 (pathway a), 11, and 12
(pathway b), as depicted in Scheme 5B. Thus, exposure of 75 to
HCl in dioxane liberated the corresponding amine, whose
reaction with carboxylic acid fragment 62 in the presence of
EDCI and HOAt afforded amide 76 in 61% overall yield.
Desilylation of the latter (TBAF; 83% yield) gave ultimate
precursor 77, whose palladium/copper-catalyzed dimerization/
macrocyclization furnished bislactam analogue 10 (29% yield),
as shown in Scheme 5B. Intermediate 75 was then funneled
a
For details of the biological assays, see the Supporting Information.
b
c
Human uterine sarcoma cell line. MES-SA cell line with marked
d
multidrug resistance due to overexpression of Pgp. Immortalized
human embryonic kidney cell line. Monomethylauristatin E.
e
studies, and Figure 4 shows the structures of the most potent
compounds discussed below. Thus, synthetic disorazole B1 (2)
exhibited single digit picomolar IC50 values against MES-SA
(IC50 = 0.009 nM) and HEK 293T (IC50 = 0.003 nM) and
subnanomolar potencies against MES-SA DX (IC50 = 0.32 nM).
Interestingly, we could not find any previous cytotoxicity studies
for disorazole B1 (2) in the literature, making these findings, to
our knowledge, the first report of the potent antitumor activities
of disorazole B1 (2). The biscyclopropyl disorazole B1 analogue
3 also exhibited high potencies against MES-SA (IC50 = 0.059
nM) and HEK 293T (IC50 = 0.103 nM) but proved less potent
against the drug-resistant MES-SA/Dx cell line (IC50 = 630.9
nM). From the remaining tested compounds, the bislactam
analogues 11 and 12 proved to be the most potent, with 11
revealing the lowest IC50 values against all three cell lines (IC50 =
0.02 nM against MES-SA; IC50 = 0.01 nM against HEK 293T;
I
https://dx.doi.org/10.1021/jacs.0c07094
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
pubs.acs.org/JACS
Article
Figure 4. Potent disorazole B1 analogues.
and IC50 = 0.71 nM against MES-SA/Dx). Analogue 12 also
exhibited good potencies against all three cell lines tested (IC50 =
0.23 nM against MES-SA; IC50 = 0.27 nM against HEK 293T;
and IC50 = 3.18 nM against MES-SA/Dx). Analogue 6, equipped
with the two PMB ether residues on its lipophilic wings, showed
good activities against all three cell lines (IC50 = 6.29 nM against
MES-SA; IC50 = 9.44 nM against HEK 293T; and IC50 = 299.10
nM against MES-SA/Dx). Particularly noteworthy are the high
potencies of disorazole B1 (2, IC50 = 0.32 nM) and analogues 11
(IC50 = 0.71 nM) and 12 (IC50 = 3.18 nM) against the
multidrug-resistant cell line MES-SA/Dx. The described
biological studies (with the three cell lines, as reported in
Table 1) are the first step to a better understanding of the
structure−activity relationships (SARs) and cytotoxicity proper-
ties of this class of compounds. More diverse and in-depth
biological evaluations to decipher cytotoxicity against normal
cells are expected later. However, these interesting results
establish the first SARs within the disorazole B1 (2) family of
compounds (see summary in Figure 5), providing further
guidance for future studies in the field.
compounds. Particularly interesting are the observations that the
substitutions of the two epoxide moieties of disorazole B1 with
two cyclopropyl units lead to higher stability for the molecule
while maintaining significant cytotoxic potencies [cf. IC50 values
of compounds 2 and 3 (Figure 4), Table 1]. These investigations
also revealed that substituting the two lactone moieties of
disorazole B1 for two lactam units also ensures significant
cytotoxic properties of the molecule [cf. IC50 values of analogues
11 and 12 (Figure 4), Table 1], while they are expected to
feature higher plasma stabilities than their bislactone counter-
parts. Analogue 6 (Figure 4), carrying the two extended
oxygenated wings, maintains respectable potencies against the
tested cell lines, pointing to tolerance of the disorazole B1
scaffold to such modifications. Reported for the first time, the
impressive potencies of disorazole B1 (2) against the cell lines
tested, especially the multidrug-resistant MES-SA/Dx cell line,
elevate this molecule and its analogues to the front line as
potential payloads for ADCs and possibly other applications as
potential drugs alone or in combination with other drugs. These
findings set the stage for further promising investigations aiming
at novel payloads for antibody−drug conjugates14 and/or small-
molecule anticancer drugs, especially given the higher chemical
stabilities of the newly synthesized compounds and their potent
antitumor properties.
3. CONCLUSION
Providing short and streamlined total syntheses to disorazole B1
(2) and its analogues, the described chemistry opened new
synthetic avenues to a variety of novel analogues of this naturally
occurring molecule and resulted in the first structure−activity
relationships (SARs) within this subclass of the disorazole B1
ASSOCIATED CONTENT
■
sı
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/jacs.0c07094.
Experimental procedures and characterization data for all
new compounds (PDF)
Crystallographic information for intermediate 74 (CIF)
AUTHOR INFORMATION
■
Corresponding Author
K. C. Nicolaou − Department of Chemistry, BioScience Research
Collaborative, Rice University, Houston, Texas 77005, United
States; orcid.org/0000-0001-5332-2511; Email: kcn@
rice.edu
Figure 5. Structure−activity relationships of the synthesized disorazole
B1 analogues.
J
https://dx.doi.org/10.1021/jacs.0c07094
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
pubs.acs.org/JACS
Article
C. D.; Wipf, P. Isolation, Biology and Chemistry of the Disorazoles:
Authors
New Anti-Cancer Macrodiolides. Nat. Prod. Rep. 2009, 26, 585−601.
Johannes Krieger − Department of Chemistry, BioScience
Research Collaborative, Rice University, Houston, Texas 77005,
United States
Ganesh M. Murhade − Department of Chemistry, BioScience
Research Collaborative, Rice University, Houston, Texas 77005,
United States
Parthasarathi Subramanian − Department of Chemistry,
BioScience Research Collaborative, Rice University, Houston,
Texas 77005, United States
Balu D. Dherange − Department of Chemistry, BioScience
Research Collaborative, Rice University, Houston, Texas 77005,
United States; orcid.org/0000-0002-4123-5012
∥Dionisios Vourloumis − Department of Chemistry, BioScience
Research Collaborative, Rice University, Houston, Texas 77005,
United States; Laboratory of Chemical Biology of Natural
Products & Designed Molecules, Institute of Nanoscience and
Nanotechnology, National Centre for Scientific Research
“Demokritos”, 153 10 Agia Paraskevi, Greece
Stefan Munneke − AbbVie Inc., South San Francisco, California
94080, United States
Baiwei Lin − AbbVie Inc., South San Francisco, California 94080,
United States
Christine Gu − AbbVie Inc., South San Francisco, California
94080, United States
Hetal Sarvaiaya − AbbVie Inc., South San Francisco, California
94080, United States
Joseph Sandoval − AbbVie Inc., South San Francisco, California
94080, United States
̈
(2) (a) Irschik, H.; Jansen, R.; Gerth, K.; Hofle, G.; Reichenbach, H.
Disorazol A, an Efficient Inhibitor of Eukaryotic Organisms Isolated
from Myxobacteria. J. Antibiot. 1995, 48, 31−35. (b) Carvalho, R.; Reid,
R.; Viswanathan, N.; Gramajo, H.; Julien, B. The Biosynthetic Genes
for Disorazoles, Potent Cytotoxic Compounds that Disrupt Micro-
tubule Formation. Gene 2005, 359, 91−98. (c) Wipf, P.; Graham, T. H.;
Vogt, A.; Sikorski, R. P.; Ducruet, A. P.; Lazo, J. S. Cellular Analysis of
Disorazole C1 and Structure−Activity Relationship of Analogs of the
Natural Product. Chem. Biol. Drug Des. 2006, 67, 66−73. (d) Tierno, M.
B.; Kitchens, C. A.; Petrik, B.; Graham, T. H.; Wipf, P.; Xu, F. L.;
Saunders, W. S.; Raccor, B. S.; Balachandran, R.; Day, B. W.; Stout, J. R.;
Walczak, C. E.; Ducruet, A. P.; Reese, C. E.; Lazo, J. S. Microtubule
Binding and Disruption and Induction of Premature Senescence by
Disorazole C1. J. Pharmacol. Exp. Ther. 2009, 328, 715−722.
(e) Elnakady, Y. A.; Sasse, F.; Lunsdorf, H.; Reichenbach, H. Disorazol
̈
A1, a Highly Effective Antimitotic Agent Acting on Tubulin
Polymerization and Inducing Apoptosis in Mammalian Cells. Biochem.
Pharmacol. 2004, 67, 927−935.
(3) Nicolaou, K. C.; Bellavance, G.; Buchman, M.; Pulukuri, K. K.
Total Syntheses of Disorazoles A1 and B1 and Full Structural
Elucidation of Disorazole B1. J. Am. Chem. Soc. 2017, 139, 15636−
15639.
(4) Nicolaou, K. C.; Buchman, M.; Bellavance, G.; Krieger, J.;
Subramanian, P.; Pulukuri, K. K. Syntheses of Cyclopropyl Analogues
of Disorazoles A1 and B1 and Their Thiazole Counterparts. J. Org.
Chem. 2018, 83, 12374−12389.
(5) For a dimerization approach toward disorazole C1, see:
(a) Ralston, K. J.; Ramstadius, H. C.; Brewster, R. C.; Niblock, H. S.;
Hulme, A. N. Self-Assembly of Disorazole C1 through a One-Pot
Alkyne Metathesis Homodimerization Strategy. Angew. Chem., Int. Ed.
2015, 54, 7086−7090. For a review on biomimetic approaches toward
dimeric natural products, see: (b) Stanley, P. A.; Spiteri, C.; Moore, J.
C.; Barrow, A. S.; Sharma, P.; Moses, J. E. Biomimetic Approaches
Towards The Synthesis of Complex Dimeric Natural Products. Curr.
Pharm. Des. 2016, 22, 1628−1657.
(6) Lee, F. Y. F.; Borzilleri, R.; Fairchild, C. R.; Kim, S.-H.; Long, B. H.;
Reventos-Suarez, C.; Vite, G. D.; Rose, W. C.; Kramer, R. A. BMS-
247550: A Novel Epothilone Analog with a Mode of Action Similar to
Paclitaxel but Possessing Superior Antitumor Efficacy. Clin. Cancer Res.
2001, 7, 1429−1437.
(7) For another total synthesis of a disorazole utilizing the
Sonogashira reaction, see: Wipf, P.; Graham, T. H. Total Synthesis of
(−)-Disorazole C1. J. Am. Chem. Soc. 2004, 126, 15346−15347.
(8) (a) Schmid, C. R.; Bryant, J. D. D-(R)-Glyceraldehyde Acetonide.
Org. Synth. 1995, 72, 6−8. (b) Zhao, Y.; Yang, T.; Lee, M.; Lee, D.;
Newton, M. G.; Chu, C. K. Asymmetric Synthesis of (1′S,2′R)-
Cyclopropyl Carbocyclic Nucleosides. J. Org. Chem. 1995, 60, 5236−
5242.
(9) Nagao, Y.; Hagiwara, Y.; Kumagai, T.; Ochiai, M.; Inoue, T.;
Hashimoto, K.; Fujita, E. New C4-Chiral 1,3-Thiazolidine-2-thiones:
Excellent Chiral Auxiliaries for Highly Diastereocontrolled Aldol-Type
Reactions of Acetic Acid and α,β-Unsaturated Aldehydes. J. Org. Chem.
1986, 51, 2391−2393.
(10) Ren, Z.-L.; Guan, Z.-R.; Kong, H.-H.; Ding, M.-W. Multifunc-
tional Odorless Isocyano(triphenylphosphoranylidene)-Acetates: Syn-
thesis and Direct One-Pot Four-Component Ugi/Wittig Cyclization to
Multisubstituted Oxazoles. Org. Chem. Front. 2017, 4, 2044−2048.
(11) Inuki, S.; Ohta, I.; Ishibashi, S.; Takamatsu, M.; Fukase, K.;
Fujimoto, Y. Total Synthesis of Cardiolipins Containing Chiral
Cyclopropane Fatty Acids. J. Org. Chem. 2017, 82, 7832−7838.
(12) Reyes, J. R.; Winter, N.; Spessert, L.; Trauner, D. Biomimetic
Synthesis of (+)-Aspergillin PZ. Angew. Chem., Int. Ed. 2018, 57,
15587−15591.
Zhaomei Zhang − AbbVie Inc., South San Francisco, California
94080, United States
Monette Aujay − AbbVie Inc., South San Francisco, California
94080, United States
James W. Purcell − AbbVie Inc., South San Francisco, California
94080, United States
Julia Gavrilyuk − AbbVie Inc., South San Francisco, California
94080, United States
Complete contact information is available at:
https://pubs.acs.org/10.1021/jacs.0c07094
Notes
The authors declare no competing financial interest.
∥Dionisios Vourloumis unexpectedly passed away on March 21,
2020.
ACKNOWLEDGMENTS
■
We thank Drs. Lawrence B. Alemany and Quinn Kleerekoper
(Rice University) for NMR spectroscopic assistance, Drs.
Christopher L. Pennington (Rice University) and Ian
Riddington (University of Texas at Austin) for mass
spectrometric assistance, and Dr. Gary J. Balaich (University
of California, San Diego) for the X-ray crystallographic analysis
of compound 74. This work was supported by AbbVie
Stemcentrx, the Cancer Prevention & Research Institute of
Texas (CPRIT), and The Welch Foundation (grant C-1819).
K.C.N. is a CPRIT scholar in cancer research.
REFERENCES
■
̈
(1) (a) Jansen, R.; Irschik, H.; Reichenbach, H.; Wray, V.; Hofle, G.
(13) CCDC-2011802 contains the supplementary crystallographic
data for sulfinamide intermediate 74. These data can be obtained free of
charge from the Cambridge Crystallographic Data Centre, via www.
ccdc.cam.ac.uk/structures.
Antibiotics from Gliding Bacteria, LIX. Disorazoles, Highly Cytotoxic
Metabolites from the Sorangicin-Producing Bacterium Sorangium
Cellulosum Strain So ce12. Liebigs Ann. Chem. 1994, 1994, 759−773.
For a review on the disorazole family of compounds, see: (b) Hopkins,
K
https://dx.doi.org/10.1021/jacs.0c07094
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
pubs.acs.org/JACS
Article
(14) (a) Chari, R. V.; Miller, M. L.; Widdison, W. C. Antibody-Drug
Conjugates: An Emerging Concept in Cancer Therapy. Angew. Chem.,
Int. Ed. 2014, 53, 3796−3827. (b) Nicolaou, K. C.; Rigol, S. Total
Synthesis in Search of Potent Antibody−Drug Conjugate Payloads.
From the Fundamentals to the Translational. Acc. Chem. Res. 2019, 52,
127−139. (c) Nicolaou, K. C.; Rigol, S. The Role of Organic Synthesis
in the Emergence and Development of Antibody−Drug Conjugates as
Targeted Cancer Therapies. Angew. Chem., Int. Ed. 2019, 58, 11206−
11241.
L
https://dx.doi.org/10.1021/jacs.0c07094
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX