Total synthesis of trioxacarcin DC-45-A2

Article abstract of DOI:10.1002/anie.201410369

An enantioselective total synthesis of trioxacarcin DC-45-A2 (1) featuring a novel Lewis acid-induced cascade rearrangement of epoxyketone 6 to forge the polyoxygenated 2,7-dioxabicyclo[2.2.1]heptane core of the molecule is described.

Full text of DOI:10.1002/anie.201410369

Angewandte
Chemie
DOI: 10.1002/anie.201410369
Natural Product Synthesis
Total Synthesis of Trioxacarcin DC-45-A2**
K. C. Nicolaou,* Quan Cai, Bo Qin, Mette T. Petersen, Remi J. T. Mikkelsen, and
Philipp Heretsch
Dedicated to Professor Stephen Hanessian on the occasion of his 80th birthday
Abstract: An enantioselective total synthesis of trioxacarcin
DC-45-A2 (1) featuring a novel Lewis acid-induced cascade
rearrangement of epoxyketone 6 to forge the polyoxygenated
2,7-dioxabicyclo[2.2.1]heptane core of the molecule is de-
scribed.
T
rioxacarcin DC-45-A2 (1, Figure 1)[1] is a naturally occur-
ring antitumor antibiotic that serves as a biosynthetic pre-
cursor to a variety of other biologically active members of the
family, including the highly potent DC-45-A1 (2), trioxacar-
cin A (3), and LL-D49194a1 (4) (Figure 1).[1] Possessing
a highly oxygenated and complex architecture, trioxacarcin
DC-45-A2 (1) presents an appealing synthetic challenge and
provides opportunities for method and strategy development,
chemical biology, and drug discovery efforts.[2] Recent
synthetic studies have culminated in a total synthesis of this
target molecule and a number of its congeners.[3] In this
Communication, we report an enantioselective and distinc-
tively different approach to the total synthesis of the parent
trioxacarcin DC-45-A2 (1) that could be applied to the
synthesis of all other members of the class and their designed
analogues.
Figure 1. Molecular structures of trioxacarcins DC-45-A2 (1), DC-45-A1
(2), A (3), and LL-D49194a1 (4).
The
polyoxygenated
2,7-dioxabicyclo[2.2.1]heptane
system of the trioxacarcins is a most intriguing structural
motif requiring special attention with regard to strategy and
experimentation for its construction. Figure 2 presents our
designed strategy toward DC-45-A2 (1) in retrosynthetic
format. Thus, disconnection of the hemiacetal moiety of
molecule could be envisioned through sequential and selec-
tive deprotection/oxidations. Dismantling of the bicyclo-
[2.2.1]heptane system within 5 through an epoxyketone
rearrangement[4] revealed epoxyketone 6 as a precursor,
whose origin could be traced back to key building blocks 7–10
through the disconnections indicated in Figure 2 [that is,
a) Hauser–Kraus annulation; b) Stille reaction; c) asymmet-
ric Jørgensen epoxidation; and d) Baylis–Hillman reaction].
The key epoxyketone rearrangement (6!5, Figure 2) was
presumed to be inducible in a stereo- and regioselective
manner through the action of a suitable monodentate Lewis
acid that would involve inversion of configuration at C6, as
indicated in Figure 2 (see arrows on structure 6).
The required cyclohexenone 10 was prepared enantiose-
lectively from cyclohexadiene 11, as summarized in Scheme 1.
Thus, 11 was subjected to Upjohn dihydroxylation (OsO4 cat.,
NMO, 50% yield) and the resulting diol 12 was silylated to
afford bis-TBS ether 13 (TBSCl, 92% yield). Epoxidation of
the latter (mCPBA, 89% yield) led selectively to epoxide 14,
whose regioselective opening with (ꢀ)-norephedrine-derived
amine 15 in the presence of nBuLi furnished allylic alcohol 16
in 94% yield and 89% ee.[5] Protection of this alcohol with 4-
methoxybenzyl-2,2,2-trichloroacetimidate (PMBTCA) fol-
lowed by TBAF-induced desilylation led to PMB-ether diol
17 in 84% yield. Selective oxidation of the allylic alcohol of
1
followed by functional group transformations led to
advanced precursor 5, whose conversion to the target
[*] Prof. Dr. K. C. Nicolaou, Dr. Q. Cai, Dr. B. Qin, M. T. Petersen,
R. J. T. Mikkelsen, Dr. P. Heretsch
Department of Chemistry, BioScience Research Collaborative
Rice University
6100 Main Street, Houston, TX 77005 (USA)
E-mail: kcn@rice.edu
[**] K.C.N. acknowledges financial support from the Cancer Prevention
& Research Institute of Texas (CPRIT), the Welch Foundation,
fellowships to Q.C. and B.Q. from Chongqing University, to M.T.P.
and R.J.T.M. from the Danish Agency for Science, Technology and
Innovation (The Frants Alling Scholarship), and to P.H. from
Deutsche Akademie der Naturforscher Leopoldina. Part of the initial
work of this project was carried out at The Scripps Research
Institute (TSRI). M.T.P. participated at TSRI only; K.C.N., Q.C., and
P.H. participated at both TSRI and Rice University; B.Q. and
R.J.T.M. participated at Rice University only.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201410369.
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the latter (TEMPO, pTSA, 74% yield)[6] furnished hydroxy-
enone 18, whose silylation (TBSCl, 99% yield) led to the
targeted key building block enone 10.
Enone 10 was coupled with the easily accessible iodocya-
nophthalide derivative 9 through a Hauser–Kraus annula-
tion,[7] and the product was elaborated to intermediate 21 as
shown in Scheme 2. Thus, iodocyanophthalide 9 [prepared
Scheme 2. Synthesis of key building block 21. Reagents and condi-
tions: a) NIS (1.4 equiv), DCE, ꢀ108C, 6 h; b) MOMCl (1.3 equiv),
DIPEA (3.0 equiv), CH2Cl2, 258C, 6 h, 50% over two steps; c) 9
(1.0 equiv), 10 (1.0 equiv), tBuOLi (3.0 equiv), THF, ꢀ788C, 0.5 h;
then Me2SO4 (10 equiv), 08C, 5 h, 69%; d) MgBr2·OEt2 (3.0 equiv),
THF, 08C, 15 min; e) tBu2Si(OTf)2 (1.2 equiv), 2,6-lutidine (2.5 equiv),
DMF, 08C, 0.5 h, 85% over two steps. DCE=1,2-dichloroethane,
DIPEA=N,N-diisopropylethylamine, DMF=N,N-dimethylformamide,
NIS=N-iodosuccinimide.
Figure 2. Retrosynthetic analysis of trioxacarcin DC-45-A2 (1). MOM=
methoxymethyl, PMB=para-methoxybenzyl, TBS=tert-butyldimethyl-
silyl, TMS=trimethylsilyl.
from the known cyanophthalide 19[8] by sequential iodination
(NIS) and MOM protection (MOMCl, DIPEA, 50% overall
yield)] was reacted with enone 10 in the presence of tBuOLi
(ꢀ788C)[3,8] and the resulting p-dihydroquinone derivative
was selectively methylated with Me2SO4 to afford tricyclic
system 20 in 69% overall yield. Removal of the MOM group
from the latter intermediate with MgBr2·OEt2,[9] followed by
treatment with tBu2Si(OTf)2 and 2,6-lutidine then gave
silylated product 21 in 85% overall yield.
Intermediate 21 was advanced to the key cyclization
precursor 6, as summarized in Scheme 3. Thus, Stille coupling
of aryl iodide 21 with stannane 8[10] proceeded in the presence
[11]
of CuTC and catalytic amounts of Pd(PPh3)4
to afford
allylic alcohol 22 (74% yield), whose oxidation with TEMPO
and PIDA gave aldehyde 23 (89% yield). Jørgensen asym-
metric epoxidation of a,b-unsaturated aldehyde 23 (24 cat.,
urea·H2O2)[12] led to epoxyaldehyde 25, which was subjected
without purification to Baylis–Hillman reaction with enone
7[13] (DABCO, 4-nitrophenol) to give labile hydroxyepoxide
26. The latter was immediately protected with N-trimethylsi-
lylimidazole (TMS-imid) to furnish the targeted precursor 6
(+C4-epi-6, d.r. ca. 3:1) in 36% yield over the three steps.
With the penultimate bis-cyclization precursor 6 in hand,
the stage was now set for the coveted cascade ring closures to
forge the targeted 2,7-dioxabicyclo[2.2.1]heptane system of
the growing molecule. To this end, and as shown in Scheme 4,
Scheme 1. Synthesis of key building block 10. Reagents and condi-
tions: a) OsO4 (4% w/v aq. solution, 0.02 equiv), NMO (1.0 equiv),
acetone, 258C, 72 h, 50%; b) TBSCl (2.4 equiv), imidazole (5.0 equiv),
CH2Cl2, 258C, 48 h, 92%; c) mCPBA (1.4 equiv), NaHCO3 (2.0 equiv),
cyclohexane, 258C, 17 h, 89%; d) 15 (2.0 equiv), nBuLi (2.0 equiv),
THF, 0!258C, 18 h, 94%, 89% ee; e) PMBTCA (2.5 equiv), TrBF4
(0.05 equiv), THF, 258C, 1 h; then TBAF (7.0 equiv), THF, 668C, 4 h,
84%; f) TEMPO (3.0 equiv), pTSA (3.0 equiv), CH2Cl2, 08C, 45 min,
74%; g) TBSCl (1.8 equiv), imidazole (3.0 equiv), CH2Cl2, 258C, 1.5 h,
99%. mCPBA=meta-chloroperoxybenzoic acid, NMO=N-methylmor-
pholine-N-oxide, PMBTCA=para-methoxybenzyl-2,2,2-trichloroacetimi-
date, pTSA=para-toluenesulfonic acid, TBAF=tetra-n-butylammonium
fluoride, TEMPO=2,2,6,6-tetramethyl-1-piperidinyloxy, THF=tetrahy-
drofuran, TrBF4 =trityltetrafluoroborate.
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Scheme 3. Synthesis of bis-cyclization precursor epoxyketone 6.
Reagents and conditions: a) Pd(PPh3)4 (0.2 equiv), 8 (3.0 equiv), CuTC
(1.2 equiv), DMF/THF 1:1, 858C, 12 h, 74%; b) TEMPO (0.1 equiv),
PIDA (1.3 equiv), CH2Cl2, 258C, 4 h, 89%; c) 24 (0.2 equiv), urea·H2O2
(7.0 equiv), CHCl3/H2O 20:1, 258C, 7 h; d) 7 (10 equiv), DABCO
(0.5 equiv), 4-nitrophenol (0.5 equiv), THF, 258C, 12 h; e) TMS-imid
(1.0 equiv), CH2Cl2, 258C, 0.5 h, 36% over three steps, d.r. ca. 3:1 at
C4. CuTC=copper(I)-thiophene-2-carboxylate, DABCO=1,4-
diazabicyclo[2.2.2]octane, PIDA=iodobenzene diacetate, TMS-
imid=N-trimethylsilylimidazole.
Scheme 4. Bis-cyclization of precursor epoxyketone 6. Reagents and
conditions: a) SnCl4 (0.05 equiv), CH2Cl2, ꢀ788C, 1 h, d.r. ca. 13:1 at
C4, 37%; b) BF3·OEt2 (0.3 equiv), CH2Cl2, ꢀ788C, 3 h, 54% (5a), 18%
(5b).
support our originally proposed monodentate Lewis acid-
catalyzed epoxyketone rearrangement upon which the strat-
egy for the construction of the dioxabicyclo[2.2.1]heptane
structural motif possessing the desired configurations was
based.
epoxyketone 6 (ca. 3:1 mixture of C4-diastereoisomers) was
reacted with catalytic amounts of BF3·OEt2 (monodentate
Lewis acid) in CH2Cl2 at ꢀ788C, furnishing the desired
product as a mixture of C4-diastereoisomers (d.r. ca. 3:1) (5a,
C4-a-diastereoisomer, 54% yield; 5b, C4-b-diastereoisomer,
18% yield). The assignments of the C4 and C6 configurations
of diastereoisomers 5a and 5b were based on their H4, H5,
Having succeeded in building the most challenging
structural domain of the targeted molecule, we proceeded
to complete the remaining tasks of the synthesis that included
installation of the epoxide moiety, oxidation at C4, and
deprotection. Thus, advanced intermediate 5a (major diaste-
reoisomer) was converted to the targeted natural product (1)
as shown in Scheme 5. Selective cleavage of the TMS-ether of
5a gave allylic alcohol 28 (TFA, 65% yield) and recovered 5a
(24% yield). Due to difficulties in obtaining the desired
epoxide 29 from 28 through mCPBA or tBuOOH/VO(acac)2
epoxidations, we resorted to a three-step process involving
diastereoselective Upjohn dihydroxylation of the olefinic
bond within 28 (OsO4 cat., NMO) followed by selective
monotosylation of the resulting triol (TsCl, Et3N, DMAP cat.)
and epoxide formation (K2CO3, MeOH, 82% overall yield).
TPAP-catalyzed oxidation of hydroxyepoxide 29 led to
ketoepoxide 30 (93% yield), which could be sequentially
and selectively deprotected to afford trioxacarcin derivatives
31 (Et3N·3HF, 3.0 equiv, 15 min, 88% yield) and 32 (DDQ,
93% yield). Finally, trioxacarcin DC-45-A2 (1) was liberated
H6 coupling constants (5a:[14]
5b:[14] 4,5 = 0 Hz, J5,6 = 3.6 Hz).[15] Both compounds were
J4,5 = 4.8 Hz, J5,6 = 3.0 Hz;
J
obtained as single diastereoisomers at C6 (inverted config-
uration). The reaction is presumed to proceed through
transition states TS-6·B and TS’-6·B as shown in Scheme 4.
In contrast, reaction of substrate 6 with catalytic amounts of
bidentate Lewis acid SnCl4 in CH2Cl2 at ꢀ788C led to the
opposite diastereoisomers at C6 (J5,6 = 0 Hz), 27 (+ C4-epi-
27) (37% yield, d.r. ca. 13:1). This reaction is presumed to
proceed through transition states TS-6·Sn and TS’-6·Sn, the
latter being favored over its more sterically congested
alternative conformer TS’’-6·Sn that would have led to
inversion of configuration at C6 (see Scheme 4). These results
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Keywords: antitumor agents · cascade reactions ·
.
natural products · total synthesis · trioxacarcins
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Scheme 5. Completion of the total synthesis of trioxacarcin DC-45-A2
(1). Reagents and conditions: a) TFA (0.1m, 10 equiv), THF/H2O 5:1,
258C, 6 h, 65% and recovered 5a, 24%; b) OsO4 (4% w/v, aq.
solution, 0.2 equiv), NMO (0.48m aq. solution, 4.0 equiv), acetone,
258C, 12 h; c) TsCl (5.0 equiv), Et3N (10 equiv), DMAP (0.2 equiv),
CH2Cl2, 0!258C, 5 h; d) K2CO3 (2.0 equiv), MeOH, 08C, 3 h, 82%
over three steps; e) TPAP (0.2 equiv), NMO·H2O (3.0 equiv), CH2Cl2,
08C, 2 h, 93%; f) Et3N·3HF (3.0 equiv), CH3CN, 258C, 15 min, 88%;
g) DDQ (2.0 equiv), CH2Cl2/H2O 10:1, 258C, 1 h, 93%; h) Et3N·3HF
(20 equiv), CH3CN, 258C, 13 h, 86%. DDQ=2,3-dichloro-5,6-dicyano-
1,4-benzoquinone, DMAP=N,N-dimethyl-4-aminopyridine, TFA=tri-
fluoroacetic acid, TPAP=tetra-n-propylammonium perruthenate,
Ts =4-toluenesulfonyl.
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The total synthesis described herein provides rapid access
to the parent trioxacarcin DC-45-A2 (1) and could be
deployed to reach all other members of the trioxacarcin
family of compounds. Furthermore, the developed synthetic
strategy and technologies could be applied to the construction
of designed analogues for structure activity relationship
studies and drug discovery efforts. Of particular interest is
the design and synthesis of potent trioxacarcins equipped with
handles that could be employed to attach them onto specific
antibodies to construct antibody drug conjugates (ADCs) for
targeted chemotherapy purposes. These objectives are cur-
rently being pursued.
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Received: October 22, 2014
Published online: && &&, &&&&
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Communications
Natural Product Synthesis
K. C. Nicolaou,* Q. Cai, B. Qin,
M. T. Petersen, R. J. T. Mikkelsen,
P. Heretsch
&&& — &&&
Total Synthesis of Trioxacarcin DC-45-A2
Zipping it all together: A monodentate
Lewis acid was used to induce the
stereoselective formation of the bicyclo-
[2.2.1]heptane structural motif of DC-45-
A2 (1), the parent naturally occurring
compound of the trioxacarcin class of
antitumor agents.
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