Solvent-mediated tuning of the regioselectivity of intramolecular diaryl ether formation: Total synthesis of (+)-aspercyclide C

Article abstract of DOI:10.1246/cl.131045

A concise total synthesis of the 11-membered cyclic (+)-aspercyclide C is reported. Key to success was the fine-tuning of the reaction media to realize an oxidative, macrocyclic diaryl C-O bond formation in a regioselective and direct fashion.

Full text of DOI:10.1246/cl.131045

Received: November 8, 2013 | Accepted: November 16, 2013 | Web Released: November 21, 2013
CL-131045
Solvent-mediated Tuning of the Regioselectivity of Intramolecular Diaryl Ether Formation:
Total Synthesis of (+)-Aspercyclide C
1
1
1,2
1
1,2
Tatsuya Yoshino, Shuji Yamashita, Itaru Sato, Yujiro Hayashi, and Masahiro Hirama*
1
Department of Chemistry, Graduate School of Science, Tohoku University, Sendai, Miyagi 980-8578
2
Research and Analytical Center for Giant Molecules, Graduate School of Science,
Tohoku University, Sendai, Miyagi 980-8578
(
E-mail: hirama@m.tohoku.ac.jp)
7
a,9,10
A concise total synthesis of the 11-membered cyclic
+)-aspercyclide C is reported. Key to success was the fine-
tuning of the reaction media to realize an oxidative, macrocyclic
diaryl C­O bond formation in a regioselective and direct
fashion.
Heck conditions to afford 9 in 72% yield (Scheme 2).
11
(
Esterification of alcohol 9 with the salicylate 7, followed by
hydrolysis of the MOM group, furnished the diphenolic cy-
OH
regioselective
etherification
at C2
O
O
OH
In 2004, Singh and co-workers isolated three novel natural
products from the fermentation broth of Aspergillus sp., named
aspercyclides A (1), B (2), and C (3) (Figure 1). Each structure
O
less hindered
OBn
1
4
Aspercyclide C (3)
features an 11-membered unsaturated macrolactone flanked by
differently substituted diaryl ether backbones. Due to their
intriguing frameworks and potential use against allergy disor-
2
O
OH
HO
more hindered
O
2
,3
ders,
the aspercyclides have attracted keen interest from
Br
OBn
4
­8
synthetic organic chemists. The total synthesis of (+)-asper-
cyclide C (3) was first achieved by Fürstner et al. in 2005 using
ring-closing metathesis (RCM) to construct the 11-membered
macrolactone ring. In 2007, Ramana et al. reported a formal
total synthesis of 3, also via RCM. In 2009, Fürstner et al.
4
1. Mizoroki−Heck reaction
. esterification
OH
OMOM
2
5
O
O
6
4
,5
O
6
Me
disclosed the first synthesis of (+)-aspercyclides A (1) and B (2)
using an intramolecular Nozaki­Hiyama­Kishi (NHK) reac-
7
5
tion. In 2010, Spivey et al. synthesized («)- and (+)-aspercy-
Scheme 1. Retrosynthesis of aspercyclide C (3).
7
clide A (1) via an intramolecular Mizoroki­Heck reaction.
Recently, we reported the total synthesis of (+)-aspercyclides A
PMP
N
N PMP
(
1) and B (2) via a unique oxidative macrocyclization strategy
Br MOMCl, NaH
DMF, rt
Br
Pd(OAc) , Cs CO
OBn
2
2
3
1,4-dioxane, 120 °C
by adopting a chemo- and regioselective intramolecular diaryl
+
8
etherification step. The present report demonstrates that this
91%
72%
OH
OH
OMOM
new strategy is not only versatile but also applicable to the
efficient construction of aspercyclide C (3).
8
5
6
OBn
OH
NaH
THF, 40 °C
The most challenging step in the synthesis of 3 was assumed
to be the intramolecular oxidative cyclization of the substituted
diphenol 4 (Scheme 1). In particular, the regiochemical control
of C­O bond formation in 4 was anticipated to be more difficult
than that encountered in the synthesis of 1 and 2, because the C2
position of the electron-rich phenol unit of 4 would be more
sterically hindered than C4.
O
O
+
9
5%
O
Me
OMOM
7
9
OBn
O
OBn
4
HO
4
2
O
OH
O
Our synthesis began by reacting the MOM ether 5 of m-
See Table 1
OR
8
bromophenol (8) with the chiral alcohol 6 under Mizoroki­
O
O
R1
OH
4 M HCl aq
THF/MeOH
10 : R = MOM
12
R2
4
0 °C, 98%
+
4
: R = H
O
OH
OBn
O
BCl3
CH2Cl2
-78 °C
R3
O
2
O
O
O
O
8
7%
Aspercyclide A (1) : R1 = CHO, R2 = OH, R = H
3
OH
OH
O
O
Aspercyclide B (2) : R = CH2OH, R2 = OH, R3 = H
1
Aspercyclide C (3) : R = R2 = H, R3 = OH
1
Aspercyclide C (3)
11
Figure 1. Structures of aspercyclides A­C (1­3).
Scheme 2. Total synthesis of aspercyclide C (3).
Chem. Lett. 2014, 43, 349–351 | doi:10.1246/cl.131045
© 2014 The Chemical Society of Japan | 349

Table 1. Examination of regioselective diaryl ether formation
OBn
O
Entry Reagents
PhI(OAc)2 EtOH
1.0 equiv)
K2CO3
3.0 equiv)
PhI(OAc)2 CH2Cl2/EtOH (= 5/1)
2.0 equiv)
K2CO3
5.0 equiv)
PhI(OAc)2 CH3CN/EtOH (= 5/1)
2.0 equiv)
K2CO3
5.0 equiv)
PhI(OAc)2 ClCH2CH2Cl/EtOH (= 5/1) 11:12 = 3:2
2.0 equiv)
K2CO3
5.0 equiv)
PhI(OAc)2 PhCl/EtOH (= 5/1)
2.0 equiv)
K2CO3
5.0 equiv)
PhI(OAc)2 PhCl
2.0 equiv)
K2CO3
5.0 equiv)
Solvents
Resultsa
2
1
2
3
4
5
6
11:12 = 0:1
1
1
O
(
I
O
O
Ph
(
11:12 = 1:4
11:12 = 1:2
13a
(
PhI(OAc)2
K CO
aprotic
solvent
EtOH
2
3
4
(
Ph
OEt
I
OBn
O
(
O
12
4
O
(
O
(
13b
(
11:12 = 3:1
(11: 52%, 12: 18%)
Scheme 3. Alternative mechanistic modes of regioselective
etherification.
b
(
(
spectroscopic data of synthetic (+)-3 matched exactly those
of authentic natural aspercyclide C, thereby confirming its
identity. The optical rotation of our synthetic material was found
to be identical to Fürstner’s report.
decomposed
1
(
4
(
In summary, an efficient regioselective total synthesis of
+)-aspercyclide C (3) was accomplished by virtue of a
a
1
b
Determined by H NMR analysis. Isolated yield.
(
versatile, intramolecular, oxidative diaryl etherification tactic.
It should be noted that the direct chemo- and regioselective aryl
C­O bond formation was realized without the need to resort to
aryl C­halogens or aryl C­O­triflates. More interestingly, the
regiocontrol in the macrocyclization step was manifested by
appropriately tuning the polarity and nucleophilicity of the
reaction media. Collectively, our synthetic strategy described
herein represents a new and concise entry to the syntheses of
clization precursor 4 in 93% yield over two steps. The key
intramolecular, oxidative aryl C­O bond formation was then
examined using PhI(OAc)2 and K CO3 in ethanol at room
2
8
temperature. In practice, this step proceeded with high chemo-
selectivity but resulted in exclusive formation of the undesired
C4-bonded diaryl ether 12 (Table 1, Entry 1). We thus decided
to investigate solvent effects to alter the regioselectivity by
careful consideration of the potential mechanistic modes of
cyclization (Scheme 3). Thus, the putative aryloxy iodo-
nium(III) intermediate 13b, which would afford undesired 12,
was speculated to equilibrate with a cyclic intermediate (e.g.,
1
3,14
various bioactive natural and unnatural diaryl ethers.
This work was supported financially by a Grant-in-Aid for
Specially Promoted Research from the Ministry of Education,
Culture, Sports, Science and Technology (MEXT) in Japan.
1
3a) in less polar aprotic media, which would lead to the desired
12
cyclic diaryl ether 11. Under this speculation, various aprotic
cosolvents were added to the ethanolic reaction mixture
References and Notes
(
Table 1). Indeed, mixed solvent systems such as CH2Cl2/EtOH
1
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3
1
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1
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5
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2
Chem. Lett. 2014, 43, 349–351 | doi:10.1246/cl.131045
© 2014 The Chemical Society of Japan | 351