Total synthesis of Hirtellanine A

Article abstract of DOI:10.1016/j.tetlet.2010.03.092

The first total synthesis of hirtellanines A is described. The key transformations include (i) base-mediated regioselective pyran ring formation, (ii) one-pot sequential boronation and Suzuki-Miyaura cross-coupling, and (iii) a tandem acid-induced deprotection and subsequent tautomerizations.

Full text of DOI:10.1016/j.tetlet.2010.03.092

Tetrahedron Letters 51 (2010) 2883–2887
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Total synthesis of Hirtellanine A
Shu-Yan Zheng a, Zheng-Wu Shen a,b,
*
a School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, People’s Republic of China
b Basilea Pharmaceutica China Ltd., Haimen, Jiangsu 226100, People’s Republic of China
a r t i c l e i n f o
a b s t r a c t
Article history:
The first total synthesis of hirtellanines A is described. The key transformations include (i) base-mediated
regioselective pyran ring formation, (ii) one-pot sequential boronation and Suzuki–Miyaura cross-cou-
pling, and (iii) a tandem acid-induced deprotection and subsequent tautomerizations.
Ó 2010 Elsevier Ltd. All rights reserved.
Received 1 February 2010
Revised 16 March 2010
Accepted 23 March 2010
Available online 27 March 2010
Hirtellanine A is a coumaronochromone derivative isolated
from the roots of Campylotropis hirtella (Franch.) Schindl.1 In vitro
assay indicates that hirtellanine A has strong B lymphocyte sup-
Our retrosynthetic analysis of hirtellanine A was depicted in
Scheme 1. The ordinary approaches toward the synthesis of cou-
maronochromone derivatives involved oxidative cyclization of 20-
hydroxy isoflavones.2 Various oxidants were used such as
K3Fe(CN)6, Ag2CO3, Pb(OAc)4, SeO2, usually with relatively lower
yields.3 More recently, a mild oxidative cyclization method had
been developed for the synthesis of alkylpolyhydroxy- and alkoxy-
coumaronoc-hromones from 20-hydroxyisoflavones.4 The mecha-
nism of the reaction was assumed to be an oxy-michael addition
followed by dehydrogenation. However, it was still unclear
pression activity (IC50: 0.06
lM) and T lymphocyte suppression
activity (IC50: 0.92 M). Compared with cyclosporin A, hirtellanine
l
A displays stronger B lymphocyte suppression activity and lower
cytotoxicity, thus there is extreme interest in developing a concise
synthetic strategy for this compound. Herein, we describe the first
total synthesis of hirtellanine A, which could be useful for struc-
ture–activity relationship study.
O
O
O
O
O
OH
OH
O
A
B
C
D
E
O
O
O
OH
OH
OH
1
Hirtellanine A
OPMB
O
O
O
O
+
B
O
I
OPMB
O
OPMB
2
3
Scheme 1. Restrosynthetic analysis of hirtellanine A.
* Corresponding author. Tel.: +86 513 8219 8001; fax: +86 513 8219 8003.
E-mail address: jeff_shen_1999@yahoo.com (Z.-W. Shen).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.03.092

2884
S.-Y. Zheng, Z.-W. Shen / Tetrahedron Letters 51 (2010) 2883–2887
Cl
O
O
HO
HO
OH
O
O
O
O
DMF, CH3SO2Cl
K2CO3, KI
BF3.Et2O
rt~90ºC
OH
OH
CuI, acetone
refulx, 95%
OH
90%
6
4
5
Me2SO4
K2CO3
O
O
NaH, xylene
O
O
MeOH
A
B
C
A
B
C
130ºC
98%
acetone
reflux
96%
Piperidine
reflux
OH
O
O
O
7
8
OH
O
O
O
O
I2, py
N
CHCl3, rt
89%
I
O
O
O
9
2
Scheme 2. Construction of fragment 2.
whether this method could be applied to the synthesis of polyhy-
droxy coumaronochromones. In our current studies, the initial de-
sign (Scheme 1) was to synthesize the 20,40,50-trihydroxy isoflavone
derivative 1, and hoping to undergo an oxidative cyclization with
DDQ to deliver the desired compound hirtellanine A.
Thus, our first attempt was aimed at synthesizing the key inter-
mediate, 3-iodo-5-methoxy-dimethylchromene pyran-4-one 2,
which then underwent Suzuki–Miyaura reaction with 2,4,5-tri(p-
methoxyphenoxyl)phenylborane 3 to form compound 1.
Table 1
The regioselective cyclization of 6
Conditions
Temp (°C)
Times
Yielda
7:15
78
AcOH
DMF
DMA
Tol.
120
130
130
120
130
165
210
220
70
120
130
130
130
130
20 h
30 h
30 h
150 h
30 h
15 min
18 min
18 min
5 h
20 h
20 h
16 h
16 h
98
98
83
70b
98
98
90
88
98
98
98
98
95d
98
22
20
26
47
60
22
24
32
31
24
87
96
>99
>99
80
74
53
40
78
76
68
69
Xylene
DMF, MW
DMSO, MW
DEA, MW
Diox., PtCl4
Py
As shown in Scheme 2, the synthesis of the key intermediate 2
started from the commercially available acetylphlorog-lucinol 4,
which underwent Vilsmeier–Haack formylation and cyclization
catalyzed by BF3ꢀEt2O to afford 5 in 90% yield.5 Subsequently, the
regioselective Claisen rearrangement reaction was explored for
the construction of the A-ring of 7. A variety of reaction conditions6
were attempted, however, none of those reaction conditions gave
satisfactory results. Interestingly, as depicted in the Table 1, it
was found that the polarity of solvents significantly affected the
regioselectivity of this reaction. Further investigation unveiled that
the presence of a strong base could control the regioselectivity
effectively. NaH was among the best reagents which completely
controlled the direction of the reaction to yield 7 in 98% yield. As
shown in Scheme 3, the Claisen rearrangement process appeared
to be a kinetic controlled reaction (pathway A) and compound 15
was a main product of the reaction. However, compound 7 had
the linear structure and probably is more stable than 15. Thus, un-
der the strong alkaline conditions, the C-ring of compound 15 was
opened and reclosed to form 77 in a quantitative yield. The above-
mentioned assumption was further confirmed by the Claisen rear-
rangement of 108 which gave 11 in 98% yield (pathway C). Methyl-
ation of 7 under standard manipulations with Me2SO4 gave 8 in
96% yields. The C-ring of 8 was opened with piperidine in MeOH
76
13
4
c
Xylene, Ca(OH)2
c
Xylene, Cs2CO3
Xylene, KOHc
Xylene, NaHc
Tracee
Tracee
16 h
Calculated based on 1H NMR and HPLC signals.
About 30% of 6 was recovered.
6 equiv of base was used.
About 5% of 5 was obtained.
Observed by HPLC and TLC. DMA = N,N0-dimethyl aniline; DEA = N,N0-
a
b
c
d
e
diethylaniline.
and subsequently treated with I2 in the presence of 2 equiv of pyr-
idine to yield 2 in 89% overall yield.9
With the key intermediate 2 in hand, we focused on the synthe-
sis of 19 (Scheme 4). Protection of the phenol groups of 1,3,4-trihy-
droxybenzene (16) with PMBBr afforded 17,10 which was
subsequently brominated with NBS to form 1811 in 96% yield.
The boronation of 18 with pinacoborane according to modified
Yashima’s procedure12 went smoothly, which gave borate ester 3.
The crude product 3 could be used directly for the coupling with
2 without further purification and afforded 19 in an 89% overall

S.-Y. Zheng, Z.-W. Shen / Tetrahedron Letters 51 (2010) 2883–2887
2885
Pathway C
O
O
O
O
O
O
DMF
130ºC
98%
OMe
OMe
10
11
Me2SO4
K2CO3, acetone
refulx, 95%
120ºC, 98%
Xylene, NaH
Pathway B
A
O
O
Claisen rearran.
B
C
6
+
7
OH
O
15
H+
base
Pathway A
O
O
O
O
O-
OH
O
O-
O
O
O-
O
O-
14
12
13
Scheme 3. Proposed mechanism of the regioselectivity.
pinacoborane
Pd(PPh3)2Cl2
OH
PMBO
OPMB
HO
HO
PMBBr
PMBO
PMBO
OPMB
NBS
DMF
NaH, DMF
THF, TEA
under Ar
85ºC
PMBO
Br
0ºC~rt, 96%
0ºC~rt, 95%
17
18
16
PMBO
PMBO
OPMB
2
O
O
Pd(dppf)2Cl2
O
B
OPMB
OPMB
Na2CO3, H2O
under Ar
rt, 89%
O
O
O
PMBO
3
19
Scheme 4. One-pot boronation and Suzuki coupling.
yield. In fact, the boronation and subsequent coupling could be
performed conveniently in one flask.13 This one-pot protocol effec-
tively simplified the operation and avoided the stability issue of
borate ester 3.
Removing the PMB protection groups on the 3-substituted 5-
methoxy dimethylchromene pyran-4-one 19 in acidic condition
gave compound 1 in a reasonable yield.14 However, the oxidative
cyclization of 1 with various oxidative reagents was tried without
success and, in all cases, only a decomposed mixture was obtained.
It was reported that DDQ itself could be used as a reagent to re-
move PMB protection group.15 Thus, we adopted the reaction con-
dition, and hoped that the oxidative cyclization would happen
after the deprotection. Interestingly, DDQ only removed two PMB
groups at para positions and the quinone 20 was obtained in 92%
yield. The cyclization was blocked due to the third PMB-protecting
group being kept intact. Fortunately, treatment of 20 with various
acids (MeSO3H/CHCl3, AcOH, and HCl/EtOH) led to the formation of
desired hirtellanine A exclusively. This conversion might involve

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S.-Y. Zheng, Z.-W. Shen / Tetrahedron Letters 51 (2010) 2883–2887
O
O
TiCl4, DCM
50min, 0ºC
O
O
O
OPMB
OH
OH
H O, 0ºC
2
O
O
60%
O
PMBO
OPMB
HO
1
19
DDQ
DDQ
DCM
rt, 92%
O
O
O
OH
OH
O
O
AcOH
O
90ºC, 20h
54%
O
O
O
O
O
OPMB
20
Hirtellanine A
O
O
O
O
O
O
O
O
O
O
O
OH
O
OH
23
21
O
O
OH
O
O
O
O
22
Scheme 5. Proposed mechanism for the cascade tautomerization.
the following mechanistic steps (Scheme 5): removal of PMB pro-
tection group, tautomerization, intra-molecule oxy-Michael addi-
tion, and subsequent cascade tautomerizations which led to the
formation of hirtellanine A in 54% yield. The spectroscopic data
of hirtellanine A synthesized were identical with the authentic
sample obtained from plant material.
Supplementary data
Supplementary data (detailed experiment procedures, com-
pound characterization, and copies of spectra data.) associated with
this article can be found, in the online version, at doi:10.1016/
j.tetlet.2010.03.092.
In summary, we have developed the first synthetic route toward
hirtellanine A wherein regioselective pyran ring formation, one-
pot tandem boronation and Suzuki coupling as well as a cascade
tautomerization are used as key reactions. The overall yield start-
ing from acetylphloroglucinol 4 to hirtellanine A is 31.6% in eight
steps.
References and notes
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