Synthesis of the C-1027 chromophore framework through atropselective macrolactonization

Article abstract of DOI:10.1002/anie.200461428

Long-range steric interactions of the protecting groups of the 1,5-diol were harnessed for the successful atropselective macrolactonization (A) in the synthesis of the C-1027 chromophore framework (see scheme). Subsequent LiN(SiMe₃)₂

Full text of DOI:10.1002/anie.200461428

Communications
(Figure 1) has extremely limited stability in solution and has
been shown to undergo spontaneous Masamune–Bergman
rearrangement without any external activator.[6] Through this
rearrangement, 1 generates p-benzyne biradical 2, which
Figure 1. Structure of the C-1027 chromophore 1 and its Masamune–
Bergman rearrangement to 3.
Natural Products Synthesis
exerts its potent toxicity by abstracting hydrogen atoms (2!
3) from the backbone of DNA to cleave the double strand.[7]
This chemical instability and its complex structure distinguish
1 as a challenging target for total synthesis.[8–11]
Synthesis of the C-1027 Chromophore Framework
through Atropselective Macrolactonization**
The structure of 1 is highly unusual, characterized by a
Masayuki Inoue,* Takeo Sasaki, Suguru Hatano, and
Masahiro Hirama*
chlorocatechol-containing
ansa-bridge,
a
strained
bicyclo[7.3.0]dodecatrienediyne, an appended benzooxa-
zine,[12] and an aminosugar.[13] The synthetic challenge pre-
sented by 1 is heightened by the presence of nonbiaryl
atropisomerism arising from hindered rotation of the chloro-
catechol ring in the ansa-bridge.[14,15] Herein we present the
synthesis of the C-1027 chromophore framework through a
newly designed atropselective macrocyclization.
Our synthetic strategy is outlined in Scheme 1. The total
synthesis of 1 would be attained from its framework 4 by
attaching the amino sugar[16] and the benzoxazine, followed by
introducing two olefins (C4–C5 and C11–C12).[17] As the nine-
membered diyne of 4 could be chemically unstable, as
suggested by experiments on a model compound,[18] the
macrolactone system would have to be constructed prior to
the nine-membered ring.[19] We planned to form this strained
nine-membered diyne 4 by LiN(TMS)2/CeCl3-promoted cyc-
lization of 5.[16,17,19b,20] The highly unsaturated macrocycle 5
was to be synthesized through the coupling of the three
fragments 6, 7, and 8 in a convergent manner.
C-1027 is a chromoprotein enediyne natural product with
potent in vitro and in vivo cytotoxicity against a variety of
cancer cell lines.[1] It is a member of the subset of enediyne
antibiotics that includes neocarzinostatin,[2] kedarcidin,[3] and
maduropeptin.[4,5] Each of these agents is composed of
protein and small-molecule (chromophore) components,
which form a 1:1 complex. The C-1027 chromophore 1
[*] Prof. Dr. M. Inoue, Dr. T. Sasaki, S. Hatano, Prof. Dr. M. Hirama
Department of Chemistry
Graduate School of Science, Tohoku University
Sendai 980-8578 (Japan)
Fax: (+81)22-217-6566
E-mail: inoue@ykbsc.chem.tohoku.ac.jp
hirama@ykbsc.chem.tohoku.ac.jp
Prof. Dr. M. Inoue
Research and Analytical Center for Giant Molecules
Graduate School of Science, Tohoku University
Sendai 980-8578 (Japan)
The synthesis of the five-membered ring 14 bearing the b-
tyrosine moiety was improved from a previously published
procedure,[21] and started with the known intermediate 9
(Scheme 2).[22] Nucleophilic addition of vinylmagnesium bro-
mide to enone 9 occurred from the opposite side of the bulky
TBS ether to afford tertiary alcohol 10 as the sole isomer.
[**] This work was supported by CREST, Japan Science and Technology
Agency (JST). A fellowship to T.S. from the Japanese Society for the
Promotion of Science (JSPS) is gratefully acknowledged.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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DOI: 10.1002/anie.200461428
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less hindered side of the five-membered chelate 15. The
secondary alcohol of 12 was selectively mesylated with MsCl
and Et3N, and the monomesylate was converted into epoxide
13 by the addition of DBU (one-pot reaction). Next, the TBS
group of 13 was replaced by a MOM group to give 6 in a two-
step sequence. Finally, the b-tyrosine moiety 7[21] was coupled
to 6 by the action of CsF in DMF,[23] leading to adduct 14.
To evaluate potential strategies for the desired atropse-
lective macrolactonization, substrate 19 was first synthesized
(Scheme 3). The tertiary alcohol of 14 was converted into the
TMS ether, and the TMS group was also introduced to the
terminal acetylene to afford 16. Sonogashira coupling[24] of 16
with acetylene moiety 8[19a] in the presence of catalytic
[Pd(PPh)4] and CuI led to 17. Treatment of 17 with K2CO3
in methanol resulted in simultaneous removal of the acetyl
and two TMS groups to produce 18, and subsequent
saponification of the methyl ester of 18 with KOH gave rise
to seco-acid 19.
Macrolactonization of 19 was successfully realized by two
methods, but with a non-atropselective outcome. Carboxylic
acid 19 was treated with 2,2’-dipyridyl disulfide and PPh3 to
give the corresponding thioester, which was heated at reflux
in toluene,[25] resulting in the formation of macrolactone 20
and 21 in 50% yield (1:1).[19a] A higher yield of 20 was
achieved by the powerful method recently developed by
Shiina and co-workers:[26] Treatment of 19 with MNBA and
DMAP at 408C produced macrolactones 20 and 21 (1:1.1
ratio in 65% combined yield). Importantly, the ratio of the
atropisomers was unaffected under the two different con-
ditions, and thus the structure of the substrate was likely to be
the decisive factor in the selectivity of the reaction. Further-
more, isomerization to enrich the desired atropisomer 20 was
unsuccessful. Separate heating of atopisomers 20 and 21 at
1608C in deuterated 1,2-dichlorobenzene for 12 h did not
result in isomerization, which suggests that these macrocycles
are highly rigid.[27,28] Consequently, selective formation of the
desired atropisomer would be possible only by controlling the
transition state of the macrolactonization by using an
appropriately functionalized substrate.
Scheme 1. Retrosynthesis of the C-1027 chromophore.
MOM=methoxymethyl, MPM=p-methoxyphenylmethyl, TES=triethyl-
silyl, Boc=tert-butoxycarbonyl.
To examine the effect of substituents of the aromatic ring
on selectivity, the OMOM group at C23 of 19 was replaced
with OH in the alternative substrate 27 (Scheme 3). First, bis-
MOM ether 14 was successfully transformed into mono-
MOM ether 22 by treatment with TFA and subsequent
reattachment of Boc to the C18 amine. After conversion of
phenol 22 into pivaloate ester 23, TMS groups were intro-
duced at 9-OH and at the C6-methyne to produce Sonoga-
shira coupling substrate 24. Adduct 25 was then obtained by
coupling 24 with 8 in the presence of catalytic Pd0 and CuI.
Deprotection of four protecting groups (two TMS, Ac, and
Piv) from 25 with K2CO3 in methanol and subsequent
treatment with KOH resulted in seco-acid 27 with the free
23-OH group. Surprisingly, macrolactonization of 27 by using
the Corey–Nicolaou thioester method generated solely the
undesired atropisomer 28 in modest yield.
=
Scheme 2. Reagents and conditions: a) CH2 CHMgBr, Et2O, ꢀ70!
08C, 83%; b) O3, CH2Cl2/MeOH/pyridine (4:4:1), ꢀ808C; then Me2S,
ꢁ
ꢀ608C!RT; c) HC CMgBr, toluene, ꢀ858C!RT, 62% (over two
steps); d) MsCl, CH2Cl2, ꢀ708C; then DBU, ꢀ708C!RT, 69%;
e) TBAF, THF, 08C, 95%; f) MOMCl, iPr2NEt, (CH2Cl)2, 408C, 86%;
g) 7 (1.1 equiv), CsF, DMF, 758C, 77%. TBS=tert-butyldimethylsilyl;
Ms=methanesulfonyl; DBU=1,8-diazabicyclo[5.4.0]undec-7-ene;
TBAF=tetrabutylammonium fluoride; MOM=methoxymethyl;
DMF=N,N-dimethylformamide.
Selective ozonolysis of the terminal olefin of 10 and
subsequent reductive workup generated aldehyde 11. Treat-
ment of 11 with ethynylmagnesium bromide in toluene
exclusively produced diol 12 bearing the b-hydroxy group at
C8. The stereochemical outcome of the reaction was presum-
ably governed by magnesium chelation and the presence of
the bulky iodine, forcing the nucleophile to attack from the
From NOESY data and molecular modeling (Macro-
Model Ver 8.0),[29] all the macrolactones (20, 21, and 28) were
found to have similar conformations. The structure of 28 is
shown as a representative example (Figure 2), in which it can
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Scheme 3. Reagents and conditions: a) TMSCl, imidazole, DMF, room temperature, 89%; b) TMSCl, LiN(TMS)2, THF, ꢀ788C, 94%; c) 8
(1.1 equiv), [Pd(PPh3)4] (10 mol%), CuI (20 mol%), iPr2NEt, DMF, room temperature, 97%; d) K2CO3, MeOH, room temperature, 74%; e) KOH,
THF/H2O/MeOH (6:4:3), room temperature, 95%; f) 2,2’-dipyridyl disulfide, PPh3, THF, room temperature, 96%; g) toluene (1 mm), 1208C, slow
addition of thioester over 15 h, 25% (20), 25% (21), 28% (dimer); h) MNBA, DMAP, CH2Cl2 (1 mm), 408C, slow addition of 19 over 12 h, 31%
(20), 34% (21), 14% (dimer); i) TFA, CH2Cl2, 08C; j) (Boc)2O, NaHCO3, 1,4-dioxane/H2O (1:1), room temperature, 84% (over two steps);
k) PivCl, DMAP, pyridine, 83%; l) TMSCl, imidazole, DMF, room temperature, 94%; m) TMSCl, LiN(TMS)2, THF, ꢀ788C, 87%; n) 8 (1.1 equiv),
[Pd(PPh3)4] (25 mol%), CuI (40 mol%), iPr2NEt, DMF, room temperature, 59%; o) K2CO3, MeOH, room temperature, 84%; p) KOH, THF/H2O
(1:1), room temperature, 90%; q) 2,2’-dipyridyl disulfide, PPh3, THF, room temperature, 66%; r) toluene (1 mm), 1208C, slow addition of thioester
over 15 h, 31%. TMS=trimethylsilyl; MNBA=2-methyl-6-nitrobenzoic anhydride; TFA=trifluoroacetic acid; Piv=pivaloyl.
be seen that the terminal acetylene and the chlorocatechol are
perpendicular to the macrocycle plane. It is evident that the
1,5 hydroxy groups (9-OH and 23-OH) are in spatial
proximity, suggesting hydrogen bonding. This hydrogen
bonding could also fix the conformation of the transition
state (Figure 3), which explains the sole formation of 28 from
27. In the cyclization of 19, the larger unfavorable steric
Figure 2. Three-dimensional structure of 28 based on NOESY data
Figure 3. Potential hydrogen bonding in the transition state of the
(C6D6) and molecular modeling.
macrolactonization reaction.
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interaction between the 23-OMOM group and the tertiary 9-
OH group could counteract the attractive hydrogen bond,
which could be the reason for the nonstereoselective outcome
observed. Hence, the atropselectivity of the macrolactoniza-
tion appears to be controlled by the balance between steric
interaction and hydrogen bonding of the substituents at C9
and C23.
From these considerations, placement of a bulky protect-
ing group on the tertiary 9-OH group could force an
atropselective macrolactonization to the desired isomer,
because both increased steric interaction with the 23-
OMOM group and elimination of the hydrogen bond would
impose an energetic penalty on the transition state of the
unwanted atropisomer. For undertaking an experimental
verification of this hypothesis, we designed a new macro-
lactonization substrate 31, which bears 23-OMOM and 9-
OTES groups (Scheme 4).
As shown in Scheme 4, seco-acid 31 was synthesized from
14 in a route similar to that used for 19. The TES group was
introduced at the tertiary alcohol function of 14, and the
acetylene moiety was transformed to its TMS-protected form
29. Condensation of 8 and 29 under Sonogashira conditions
led to diyne 30, whose acetate, methyl esters, and TMS group
were hydrolyzed with KOH in THF/MeOH/H2O, without
affecting the TES ether, giving 31.
Atropselective macrolactonizaton of seco-acid 31 was
effected by using the MNBA method. Upon treatment of 31
with MNBA and DMAP in refluxing CH2Cl2, the desired
isomer 32 was formed with 4:1 atropselectivity and isolated in
61% yield.[31] Remarkably, the yield of the desired atrop-
isomer (32 versus 20) was doubled by strategic protection of
the 9-OH group.
With the desired ansa macrolide 32 in hand, our next focus
was to construct the nine-membered diyne ring. Before doing
so, the reaction conditions of protecting- and functional-
group manipulations were carefully tuned. First, the cyclo-
pentylidene ketal of 32 was selectively removed with TfOH in
CF3CH2OH/THF[30] without affecting other acid-labile pro-
tecting groups (MOM, TES, MPM, and Boc) to afford 1,2-diol
34. After conversion of 34 into tris-TES ether 35, another Boc
group was introduced by using (Boc)2O and DMAP to mask
the acidic 18-NH proton of 35, leading to biscarbamate 36.[32]
The primary alcohol at C5 was selectively deprotected by
using HF·py to produce 37, which was oxidized to aldehyde 5
with (COCl)2 and DMSO.
Cyclization of 5 was promoted by a 1:1 mixture of
LiN(TMS)2 and CeCl3 in THF from ꢀ508C to room temper-
ature, giving rise to the strained nine-membered diyne 4 as the
sole isomer in 30% yield. Thus, this LiN(TMS)2/CeCl3
reagent combination proved to be applicable to the highly
complex and conformationally rigid system 5. The stereo-
chemical structure of 4, including the newly formed b
secondary alcohol, was unambiguously determined by
ROESY experiments in [D6]DMSO. The correct atropisom-
erism of 4 was again confirmed at this stage, indicating the
high energy barrier to rotation of the chlorocatechol in all the
synthetic intermediates. Diyne 4 slowly decomposed at room
temperature, presumably through Cope rearrangement, as
Scheme 4. Reagents and conditions: a) TESCl, imidazole, DMF, room temperature, 98%; b) TMSCl, LiN(TMS)2, THF, ꢀ788C, 87%; c) 8
(1.2 equiv), [Pd(PPh3)4] (20 mol%), CuI (40 mol%), iPr2NEt, DMF, room temperature, 80%; d) KOH, THF/H2O/MeOH (5:1:1), 90%; e) MNBA
(2.4 equiv), DMAP (4.8 equiv), CH2Cl2 (1 mm), 408C, slow addition of 31 over 12 h, 61% (32), 15% (33), 5% (dimer); f) TfOH, CF3CH2OH/THF
(5:1), 65%; g) TESCl, imidazole, DMF, 408C, 93%; h) (Boc)2O, DMAP, MeCN, 408C, 100%; i) HF·py, THF, 08C, 78%; j) (COCl)2, DMSO, Et3N,
CH2Cl2, ꢀ788C, 100%; k) LiN(TMS)2 (58 equiv), CeCl3 (61 equiv), THF (1 mm), ꢀ50!08C, 30%. Tf=trifluoromethanesulfonyl, DMSO=dimethyl
sulfoxide.
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Goldberg, Angew. Chem. 2002, 114, 1104 – 1109; Angew. Chem.
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demonstrated with previously synthesized model com-
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In conclusion, we achieved the stereoselective synthesis of
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the C-1027 chromophore framework through atropselective
macrolactonization. The key features in this synthesis were
1) strategic protection of a 1,5-diol to attain atropselective
macrocyclization, and 2) LiN(TMS)2/CeCl3-promoted acety-
lide–aldehyde condensation to build the nine-membered
diyne ring in a highly unsaturated and heavily substituted
macrocycle. Further studies on the total synthesis of the C-
1027 chromophore from 4 are currently underway in this
laboratory.
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[15] Only a few examples have been reported on the stereoselective
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Received: July 26, 2004
Keywords: alkynes · antitumor agents · atropisomerism ·
.
lactones · macrocycles
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[32] Bis-Boc protection of the amine was found to have a dramatic
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[33] Cope rearrangement of the nine-membered cyclic 1,5-diyne to
the bisallene is considered to be the major decomposition
pathway.[18]
Angew. Chem. Int. Ed. 2004, 43, 6500 –6505
www.angewandte.org
ꢀ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
6505