Total Synthesis of Shishijimicin A

Article abstract of DOI:10.1021/jacs.5b05575

The total synthesis of the rare but extremely potent antitumor agent shishijimicin A has been achieved via a convergent strategy involving carboline disaccharide 3 and hydroxy enediyne thioacetate 4.

Full text of DOI:10.1021/jacs.5b05575

Communication
pubs.acs.org/JACS
Total Synthesis of Shishijimicin A
K. C. Nicolaou,* Zhaoyong Lu,† Ruofan Li,† James R. Woods, and Te-ik Sohn
Department of Chemistry, Rice University, 6100 Main Street, Houston, Texas 77005, United States
S
* Supporting Information
a
Scheme 1. Structure and Retrosynthetic Analysis of 1
ABSTRACT: The total synthesis of the rare but
extremely potent antitumor agent shishijimicin A has
been achieved via a convergent strategy involving carboline
disaccharide 3 and hydroxy enediyne thioacetate 4.
aturally occurring substances provided the first medi-
N
cations to treat disease and continue to be a rich source and
inspiration for drug discovery and development.1,2 Among them
are cytotoxic compounds, some of which are used to treat
cancer.1 Unfortunately, most cytotoxic compounds, including
those with the highest potencies, fail to make it to the clinic
because of severe side effects. The advent of antibody−drug
conjugates (ADCs) ushered in by Mylotarg, the first ADC to be
approved by the FDA and equipped with the highly potent
3,4
I
natural product calicheamicin γ1 , led to a new paradigm
whereby previously failed potent cytotoxic agents became highly
desirable as payloads for conjugation to antibodies as potential
targeted drugs against cancer.5,6 Shishijimicin A (1) (Scheme 1)7
is a rare marine natural product endowed with extremely potent
antitumor properties (IC50 = 0.48 pM against P388 leukemia
cells).7 In view of its phenomenal biological activity and the new
paradigm for targeted cancer chemotherapy, shishijimicin A
constitutes a highly desirable payload for ADCs, an attractive
possibility thus far hindered by its scarcity. In this Communi-
cation, we report the first total synthesis of shishijimicin A,
rendering the molecule readily available for further biological
investigations and opening the way for the construction of
designed analogues of this valuable but rare molecule.
a
Abbreviations: TBS = tert-butyldimethylsilyl; TES = triethylsilyl; Ac =
acetyl; Alloc = allyloxycarbonyl; Bz = benzoyl; MEM = (2-
methoxyethoxy)methyl; Nap =2-naphthylmethyl; NB = o-nitrobenzyl.
7
3,4
I
The similarities between 1 and calicheamicin γ1
extend
from their common enediyne moiety to their Bergman
cycloaromatization-based mechanism of action involving
double-stranded DNA cleavage.8 Their structures, however,
differ substantially with regard to the constitution of their
pentacyclic DNA binding domains, which include a carboline
system for shishijimicin A and a fully substituted iodophenyl ring
employed in the total synthesis11−14 of calicheamicin γ1 .15 The
I
pentacyclic advanced intermediate 3 was further disconnected at
the indicated carbon−carbon bond bridging the carboline
structural motif to the disaccharide domain, furnishing
iodocarboline 6 and disaccharide aldehyde 7 [upon modification
of the trichloroacetimidate group to the photolabile o-nitro-
benzyl (NB) ether protecting group] as potential precursors.
Finally, 6 was traced back to tryptamine derivative 8, while 7 was
disconnected into its obvious monosaccharide units 9 (acceptor)
and 10 (donor) as key building blocks.16
The synthesis of the required enediyne thioacetate precursor 4
from key building block 513 proceeded as shown in Scheme 2.
This route represents a streamlined and significantly improved
version of the original synthesis of the benzoate counterpart of 4
I
for calicheamicin γ1 , both of which are known DNA-binding
structural motifs.9,10 The synthetic roadmap toward 1 was
designed on the basis of the retrosynthetic analysis shown in
Scheme 1. Thus, protection of the phenolic (TBS), amino
(Alloc), and tertiary hydroxyl (TES) groups and transformation
of the methyl trisulfide of the target molecule to a thioacetate
moiety in the retrosynthetic sense led to its protected enediyne
thioacetate 2 as a potential precursor. Disconnection of the
glycoside bond linking the enediyne domain of 2 with its
pentacyclic appendage revealed enediyne fragment 4 and
trichloroacetimidate 3 as potential advanced intermediates for
coupling in the synthetic direction. Enediyne 4 was traced back to
the readily available key building block 5, which was previously
I
employed in the total synthesis of calicheamicin γ1 (19 steps,
Received: May 29, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/jacs.5b05575
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
previous route).13 Conversion of the latter compound to ketone
12 (deprotection/oxidation) proceeded smoothly as previously
reported (two steps, 92% overall yield).13 The subsequent
coupling of 12 with enediyne fragment 13,17 however, was
significantly improved by using LiHMDS in the presence of
LaCl3·2LiCl,18 affording, after in situ acetylation, the desired
enediyne 14 in 90% overall yield (compared with 69% yield
under the originally employed conditions).13 Removal of the
MEM group from 14 followed by Swern oxidation of the
resulting secondary alcohol and concomitant oxidation of the
isoxazoline to the isoxazole moiety furnished keto−isoxazole 15
(85% overall yield for the two steps). The latter intermediate
served admirably as a substrate for the exclusively E-selective
Horner−Wadsworth−Emmons olefination that followed
[(MeO)2P(O)CH2CO2Me (15a), LiHMDS], leading to E-α,β-
unsaturated methyl ester 16 in 96% yield. Acetate 16 was then
transformed to terminal acetylene TES ether 17 in 94% overall
yield through a sequence involving removal of the acetate group
(K2CO3), cleavage of the TIPS moiety (TBAF), and silylation
(TESOTf). Rupture of the isoxazole moiety in 17 was then
achieved more conveniently and efficiently than before13
through the use of Fe in EtOH/H2O (83%), and the resulting
amino aldehyde was captured by phthaloyl chloride (PhthCl) in
the presence of pyridine to afford N-phthalide aldehyde 18
(81%). The direct and stereoselective cyclization of 18 to give
cyclic enediyne 19 (via intermediate 18a; see Scheme 2) using
LiHMDS−LaCl3·2LiCl18 in THF in 85% yield represents a
major improvement over the previously used three-step
sequence requiring inversion of the opposite configuration at
C8 obtained from the same substrate (i.e., 18) through the use of
KHMDS in toluene.13 The observed stereoselectivity is
presumed to be due to complexation of La3+ to the aldehyde
and ester oxygens, which fixes the conformation of the aldehyde
moiety in the proper orientation. The N-phthalide moiety of 19
was then converted to the desired methyl carbamate group by
reaction with MeNHNH2 followed by exposure of the resulting
amine to triphosgene in the presence of pyridine and MeOH as
previously reported,13 affording enediyne lactone 20 in 81%
overall yield. Reduction of the lactone moiety in 20 was achieved
in one step and 92% yield using NaBH4−CeCl3·7H2O (as
opposed to two steps and 84% overall yield in the original
route),13 providing a further improvement in the overall
sequence to enediyne diol 21. Finally, conversion of 21 to the
targeted enediyne thioacetate fragment 4 was accomplished
efficiently by sequential treatment with excess TMSCN (bis-
silylation), AcOH (selective primary TMS cleavage), Ph3P-
DEAD-AcSH (Mitsunobu reaction, thioacetate formation), and
HF·py (secondary TMS cleavage) in 95% overall yield.
a
Scheme 2. Synthesis of 4
a
Reagents and conditions: (a) t-BuOCl (3.0 equiv), benzene, 25 °C,
30 min, 81%; (b) 13 (3.0 equiv), LiHMDS (2.8 equiv), LaCl3·2LiCl
(5.0 equiv), THF, −78 °C, 30 min, then 12, −78 °C, 30 min, then
Ac2O (10.0 equiv), −78 to 25 °C, 2 h, 90%; (c) TMSCl (4.0 equiv),
NaI (2.0 equiv), MeCN, 0 to 25 °C, 30 min; (d) (COCl)2 (4.0 equiv),
DMSO (8.0 equiv), CH2Cl2, −78 °C, 30 min, then Et3N (10.0 equiv),
−78 to 25 °C, 1.5 h, 85% for the two steps; (e) 15a (2.0 equiv),
LiHMDS (1.5 equiv), THF, −78 to 25 °C, 1.5 h, 96%; (f) K2CO3 (1.0
equiv), MeOH/THF (1:1), 0 to 25 °C, 3 h; (g) TBAF (1.0 equiv),
THF, 0 °C, 10 min; (h) TESOTf (1.5 equiv), 2,6-lutidine (2.0 equiv),
CH2Cl2, 0 to 25 °C, 2 h, 94% for the three steps; (i) Fe (25 equiv),
NH4Cl (50 equiv), EtOH/H2O (1:1), 60 °C, 8 h, 83%; (j) PhthCl
(1.5 equiv), py (4.0 equiv), MeNO2, 0 °C, 30 min, 81%; (k) LiHMDS
(2.0 equiv), LaCl3·2LiCl (3.0 equiv), THF, −78 °C, 1 h, 85%; (l)
NaBH4 (2.0 equiv), CeCl3·7H2O (3.0 equiv), MeOH, 25 °C, 2 h, 92%;
(m) TMSCN (neat), 25 °C, 30 min, then remove excess TMSCN,
then dissolve in THF/H2O (5:1), AcOH (5.0 equiv), 0 °C, 30 min;
(n) PPh3 (5.0 equiv), DEAD (5.0 equiv), AcSH (5.0 equiv), THF, 0
°C, 5 min, 96% for the two steps; (o) HF·py/THF (1:20), 0 °C, 30
min, 99%. LiHMDS = lithium bis(trimethylsilyl)amide; TMS =
trimethylsilyl; DMSO = dimethyl sulfoxide; TBAF = tetra-n-butyl
ammonium fluoride; Phth = phthaloyl; py = pyridine; DEAD = diethyl
azodicarboxylate.
To construct iodocarboline 6 (Scheme 3a), carboline 22
[prepared in 52% overall yield from commercially available 5-
methoxytryptamine (8) through a known three-step sequence19]
was silylated (TBSOTf, Et3N, 97% yield) to afford 23, which was
converted to carbamate 24 (KHMDS, ClCO2Me, 98% yield).
The latter compound was reacted with 2,2,6,6-tetramethylpiper-
idinylmagnesium chloride·lithium chloride complex
(TMPMgCl·LiCl)20 and I2, furnishing the desired iodocarboline
6 in 83% yield.
21% overall yield from 5 vs 21 steps, 1.7% overall yield from
5).11−14 It should also be noted that thioacetate 4 is a more
advanced precursor for the methyl trisulfide unit required for
I
both shishijimicin A and calicheamicin γ1 , thereby saving steps in
The required disaccharide 7 was synthesized from the readily
available glucal 2521 and glycosyl fluoride 1016,22 as depicted in
Scheme 3b. Benzoylation of the free hydroxyl group of 25 (BzCl,
Et3N, 97% yield) followed by sequential treatment of the
resulting benzoate glucal 26 with in situ-generated DMDO and
o-nitrobenzyl alcohol (o-NBOH) furnished hydroxy-o-nitro-
the postcoupling sequence to the final target. Thus, as shown in
Scheme 2, oxidation of oxime 5 to the corresponding nitrile oxide
(5a) with the improved conditions involving t-BuOCl followed
by spontaneous [3 + 2] dipolar cycloaddition of the latter
intermediate (see 5a in Scheme 2) led to 11 in 81% overall yield
with ≥10:1 dr (compared with 51% yield and ca. 4:1 dr in the
B
DOI: 10.1021/jacs.5b05575
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Journal of the American Chemical Society
Communication
a
inconsequential), as shown in Scheme 4. Treatment of carboline
carbamate 33 with NaOH in EtOH led to the corresponding free
amine, whose oxidation with DMP gave ketone 34 in 68% yield
over the two steps. Photolytic cleavage14 of the o-nitrobenzyl
ether moiety from the latter compound followed by sequential
treatment with DDQ (removal of naphthyl group) and
Cl3CCN−NaH (trichloroacetimidate formation) resulted in
the stereoselective formation of the coveted trichloroacetimidate
3 (53% overall yield, β-anomer exclusively).
Scheme 3. Syntheses of 6 and 7
a
Scheme 4. Coupling of 6 and 7 and Elaboration To Give 3
a
Reagents and conditions: (a) TBSOTf (1.05 equiv), Et3N (3.0
a
equiv), DMF, 0 °C, 30 min, 97%; (b) ClCO2Me (1.1 equiv), KHMDS
(1.05 equiv), THF, 0 °C, 30 min, 98%; (c) TMPMgCl·LiCl (4.0
equiv), THF, −78 to 25 °C, 4 h, then I2 (5.0 equiv), THF, −78 to 0
°C, 30 min, 83%; (d) BzCl (1.05 equiv), Et3N (1.1 equiv), CH2Cl2, 0
°C, 30 min, 97%; (e) Oxone (5.0 equiv), NaHCO3 (25 equiv),
acetone/H2O/CH2Cl2 (1:3:4), 25 °C, 4 h, then o-NBOH (3.0 equiv),
ZnCl2 (1.5 equiv), 4 Å MS, THF, −78 to 25 °C, 4 h, 54%; (f)
TBSOTf (1.05 equiv), Et3N (1.1 equiv), CH2Cl2, 0 °C, 30 min; (g)
NaOMe (10.0 equiv), MeOH, 40 °C, 24 h; (h) DMP (1.2 equiv),
CH2Cl2, 0 to 25 °C, 1 h, 89% for the three steps; (i) TMSSMe (2.5
equiv), TMSOTf (1.5 equiv), toluene, −20 to 0 °C, 30 min, 61%; (j)
TMSCN (3.5 equiv), SnCl4 (1.5 equiv), CH2Cl2, 0 °C, 3 h, 87% (ca.
9:1 dr); (k) TBAF (5.0 equiv), NH4F (10.0 equiv), THF, 0 °C, 1 h,
95%; (l) 10 (2.2 equiv), AgClO4 (2.5 equiv), SnCl2 (2.5 equiv), 4 Å
MS, THF, −78 to 25 °C, 12 h, 85%; (m) DIBAL-H (3.0 equiv),
CH2Cl2, −78 °C, 45 min, 87%. KHMDS = potassium bis-
(trimethylsilyl)amide; TMP = 2,2,6,6-tetramethylpiperidinyl; DMDO
= dimethyldioxirane; o-NBOH = o-nitrobenzyl alcohol; DMP = Dess−
Martin periodinane; DIBAL-H = diisobutylaluminum hydride.
Reagents and conditions: (a) 6 (3.0 equiv), t-BuLi (6.0 equiv), THF,
−78 °C, 30 min, then 7 (1.0 equiv), −78 to −35 °C, 40 min, 86% (ca.
1:1 dr) based on 7; (b) NaOH (3.0 equiv), EtOH, 0 to 25 °C, 2.5 h;
(c) DMP (1.1 equiv), CHCl3, 0 to 35 °C, 10 min, 68% for the two
steps; (d) hν, THF/H2O (10:1), 4.5 h; (e) DDQ (2.5 equiv),
CH2Cl2/H2O (10:1), 30 °C, 1.5 h; (f) NaH (2.0 equiv), Cl3CCN/
CH2Cl2 (1:2), 25 °C, 5 min, 53% for the three steps. DDQ = 2,3-
dichloro-5,6-dicyano-1,4-benzoquinone.
Having assembled the two advanced intermediates, trichlor-
oacetimidate 3 and hydroxy enediyne 4, the next objective
became their coupling and elaboration of the resulting product to
give shishijimicin A (1). Scheme 5 depicts how this challenging
task was accomplished. Indeed, it was after considerable
experimentation that the two fragments (i.e., 3 and 4) were
joined through the action of BF3·Et2O to afford β-glycoside 2
selectively in 26% yield. It should be noted that the
corresponding naphthyl ether trichloroacetimidate proved
resistant to glycosidation, presumably because of severe steric
hindrance, an effect also assumed to be responsible for the rather
low yield observed for the reaction between 3 and 4.
Improvement of this coupling reaction ought to be possible,
and studies toward this goal are currently in progress. Enediyne
thioacetate 2 was transformed to the protected form of
shishijimicin A, precursor 36, through sequential treatment
with KOH in MeOH (acetate cleavage) and N-methyldithioph-
thalimide (PhthNSSMe)27 in 50% overall yield via thiol
derivative 35. Desilylation of 36 with HF·py furnished advanced
intermediate 37 (80% yield), from which the Alloc protecting
group was removed by exposure to catalytic Pd(PPh3)4, leading
to the shishijimicin A penultimate precursor ketal 38 (91%
yield). Finally, cleavage of the ketal moiety from precursor 38
gave the targeted natural product, shishijimicin A (1), in 73%
yield. The physical data for synthetic 1 matched those reported
for the natural substance.7
benzyl ether 27 in 54% overall yield via the corresponding
epoxide intermediate.23 The newly generated hydroxyl group of
27 was converted to its TBS ether (TBSOTf, Et3N) to afford 28,
from which the benzoate moiety was cleaved (NaOMe) to give
alcohol 29. DMP oxidation of 29 led to ketone 30 in 89% overall
yield for the three steps from 27. Reaction of 30 with TMSSMe
in the presence of TMSOTf furnished the corresponding
methylthioketal,16,24 which underwent stereoselective cyana-
tion25 upon exposure to TMSCN and SnCl4 to afford nitriles 31
and 4-epi-31 (ca. 9:1 dr, 53% yield for the two steps). Removal of
the TBS group from 31 (TBAF, NH4F)26 gave carbohydrate
acceptor 9 (95% yield), whose coupling with carbohydrate donor
1016,22 proceeded smoothly in the presence of AgClO4 and
SnCl2 to afford the desired α-glycoside 32 stereoselectively in
85% yield. Finally, DIBAL-H reduction of the nitrile group in 32
led to the targeted aldehyde 7 in 87% yield.
The coupling of iodocarboline 6 and disaccharide aldehyde 7
proceeded through the lithio derivative of the former (generated
with t-BuLi at −78 °C) to give alcohol 33 (86% yield, ca. 1:1 dr,
In conclusion, we have developed a convergent and modular
strategy for the total synthesis of the rare and precious marine
natural product shishijimicin A (1). The reported synthesis
C
DOI: 10.1021/jacs.5b05575
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
a
Scheme 5. Coupling of 3 and 4 and Total Synthesis of 1
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a
Reagents and conditions: (a) 3 (1.0 equiv), 4 (1.6 equiv), BF3·OEt2
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ASSOCIATED CONTENT
■
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* Supporting Information
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AUTHOR INFORMATION
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The authors declare no competing financial interest.
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ACKNOWLEDGMENTS
We thank Drs. L. B. Alemany and Q. Kleerekoper for NMR
spectroscopic assistance, Dr. C. Pennington for mass spectro-
■
59.
(28) McDonald, L. A.; Capson, T. L.; Krishnamurthy, G.; Ding, W.-D.;
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1
metric assistance, and Drs. N. Fusetani and N. Oku for the H
and 13C NMR spectra of natural shishijimicin A. This work was
supported by the Cancer Prevention & Research Institute of
Texas (CPRIT) and The Welch Foundation.
D
DOI: 10.1021/jacs.5b05575
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX