Convergent synthesis of fluorescence labeled solamin

Article abstract of DOI:10.3987/COM-08-S(D)45

The convergent synthesis of dansyl-labeled solamin, an antitumor Annonaceous acetogenin, has been achieved. The carbon skeleton was assembled from three fragments: the THF ring fragment, the fluorescent fragment, and the γ-lactone fragment, by asymmetric

Full text of DOI:10.3987/COM-08-S(D)45

HETEROCYCLES, Vol. 79, 2009
387
HETEROCYCLES, Vol. 79, 2009, pp. 387 - 393. © The Japan Institute of Heterocyclic Chemistry
Received, 29th September, 2008, Accepted, 28th November, 2008, Published online, 2nd December, 2008.
DOI: 10.3987/COM-08-S(D)45
CONVERGENT SYNTHESIS OF FLUORESCENCE LABELED
SOLAMIN†
Naoto Kojima,1 Takekuni Morioka,1 Masahiro Yano,1 Yuki Suga,1
Naoyoshi Maezaki,2 and Tetsuaki Tanaka1*
1 Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamadaoka,
Suita, Osaka 565-0871, Japan; E-mail: t-tanaka@phs.osaka-u.ac.jp
2
Faculty of Pharmacy, Osaka Ohtani University, 3-11-1 Nishikiori-Kita,
Tondabayashi, Osaka 584-8540, Japan.
Abstract – The convergent synthesis of dansyl-labeled solamin, an antitumor
Annonaceous acetogenin, has been achieved. The carbon skeleton was assembled
from three fragments: the THF ring fragment, the fluorescent fragment, and the
γ-lactone fragment, by asymmetric alkynylation.
Annonaceous acetogenins are waxy derivatives of long-chain fatty acids (C32 or C34) that are linked by a
2-propanol unit at C-2 position to form a γ-methyl-α,β-unsaturated-γ-lactone.1 Most acetogenins are
characterized by one to three 2,5-disubstituted tetrahydrofuran(s) (THFs) with one or two flanking
hydroxyl group(s) at the center of a long carbon chain. Many researchers are engaged in the synthesis of
acetogenins2 and their analogues3 due to their unique structures and potent antitumor activities. The
mechanism of action is considered to involve the inhibition of mitochondrial NADH ubiquinone
oxidoreductase (complex I). The inhibition suppresses ATP production, leading to apoptosis of cancer
cells.4 However, the structure–activity relationship for complex I inhibition is not completely related to its
cytotoxicity. McLaughlin and co-workers suggested that as the mitochondrial assay is cell-free, it does
not take into consideration factors such as membrane transport, intracellular transport, and metabolic
inactivation.5 In order to visualize cell distribution, Poupon and co-workers synthesized a γ-lactone-free
dansyl-labeled squamocin analogue.6 Moreover, Yao and co-workers reported the synthesis of a new
fluorescent acetogenin analogue whose THF rings were replaced with acyclic ethers for simplification.7
In living cells, it was suggested that the hydrophilic THF moiety in natural acetogenins is located at the
†
Dedicated to the late Professor John W. Daly for his outstanding contributions to natural products
chemistry.

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HETEROCYCLES, Vol. 79, 2009
surface of the mitochondrial inner membrane and that the γ-lactone moiety interacts with the active site of
the membrane.8 Therefore, we synthesized 7-nitrobenzo[c][1,2,5]oxadiazol-4-yl-amino (NBD-NH-)
solamin (2) that retains all functionalities.9 However, the total yield of our synthesis was low and the
preparation of other derivatives was inconvenient because the synthetic route was linear. Herein, we
report
a
novel
approach
to
labeled
solamins
and
its
application
to
5-dimethylaminonaphthalen-1-yl-sulfonamide (dansyl-NH-) solamin (3), a fluorescent mono-THF
annonaceous acetogenin, bearing all functionalities.
Me
O2
S
dansyl-NH-
=
NBD-NH-
O2N
=
H
N
N
R
O
H
O
8
11
HO
OH
O
N
solamin (1, R = n-C3H7)
N
O
Me2N
NBD-labeled solamin (2, R = NBD-NH-)
dansyl-labeled solamin (3, R = dansyl-NH-)
Figure 1. Structure of solamin and fluorescent derivatives
The retrosynthesis of fluorescent acetogenins is summarized in Scheme 1. Fluorescent acetogenins (4) are
divided into three fragments: fluorescent fragment (5), THF fragment (6), and γ-lactone fragment (7). The
fragments could be connected by reagent-controlled asymmetric alkynylation. This synthetic plan should
provide ready access to diverse fluorescent derivatives that have other fluorescent groups or long
hydrocarbon chains as linker.
Me
FG
O
O
n
11
HO
OH
O
fluorescent acetogenins (4)
(FG = fluorescent group)
Me
CHO
O
FG
+
+
O
O
n-1
O
9
PhS
O
fluorescent fragment (5)
THF fragment (6)
γ-lactone fragment (7)
Scheme 1. Retrosynthesis of fluorescent acetogenins
Synthesis of THF fragment (6) started from known aldehyde (8) and 3-butyne-1,2-diol derivative (9)10
prepared from 8 (Scheme 2). Asymmetric alkynylation of aldehyde (8) with alkyne (9) was carried out
under Carreira’s conditions11 with (1R,2S)-N-methylephedrine as chiral ligand to give syn-adduct12 (10) in
93% yield with high diastereoselectivity (>97:3 dr). Hydrogenation of the triple bond and deprotection of
the benzylidene acetal gave triol (11) in 84% yield. Selective sulfonylation of primary alcohol followed

HETEROCYCLES, Vol. 79, 2009
389
by base treatment of resulting 12 afforded trans/threo THF-ring (13). DMSO oxidation of 13 with
SO3·pyridine complex gave α-tetrahyrofuranyl aldehyde (6) in good yield.
Ph
Ph
O
OH
O
b
O
a
O
O
O
OH
+
O
O
O
O
CHO
OH
OH
8
9
11
10
OH
O
d
e
c
OTris
CHO
O
O
O
O
O
O
O
OH
OH
(Tris = 2,4,6-triisopropylbenzenesulfonyl)
12
6
13
Scheme 2. Reagents and Conditions: (a) Zn(OTf)2, Et3N, (1R,2S)-N-methylephedrine, toluene, rt, 93%
(>97:3 dr); (b) H2 (3 atm), 10% Pd–C, EtOAc, rt, 84%; (c) TrisCl, pyridine, CH2Cl2, 0 °C to rt, 79%; (d)
K2CO3, MeOH, 0 °C to rt, 98%; (e) SO3·pyridine, DMSO, i-Pr2NEt, CH2Cl2, 0 °C to rt, 89%.
Fluorescent fragment (16) was prepared from known iodoalkyne (14)13 (Scheme 3). Azidation of 14 was
carried out to give azide (15) in high yield. The reduction of 15 under Staudinger conditions followed by
coupling with dansyl chloride afforded fluorescent fragment (16).
H
b, c
a
I
N3
N
NMe2
S
O2
5
5
5
14
15
16
Scheme 3. Reagents and Conditions: (a) NaN3, DMSO, rt, 97%; (b) PPh3, Et2O–H2O (17:1), 0 °C; (c)
dansyl chloride, i-Pr2NEt, CH2Cl2, 0 °C to rt, 96% in two steps.
γ-Lactone fragment (7) was easily prepared by alkylation of known α-sulfenyl-γ-lactone (18)14 with
12-iodo-1-dodecyne (17) 15 under basic conditions in high yield (Scheme 4).
Me
Me
a
I
+
O
O
9
9
PhS
PhS
O
O
17
18
7
Scheme 4. Reagents and Conditions: (a) LDA, THF–HMPA (2:1), –78 °C to rt, 97%.
With all the fragments in hand, we examined the assembly of THF fragment (6) and γ-lactone fragment
(7) because we thought it best that the expensive fluorescent fragment (16) be introduced at the late stage

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HETEROCYCLES, Vol. 79, 2009
of the synthesis (Scheme 5). Coupling reaction of the two fragments (6 and 7) was accomplished by
asymmetric alkynylation with high stereoselectivity (95:5 dr).16 After the secondary alcohol of adduct
(19) was protected as a TBDPS ether, the hydrolysis of acetonide gave diol (21). Oxidative cleavage of
1,2-diol moiety gave α-tetrahydrofuranyl aldehyde (22) in 98% yield.
Me
Me
Me
O
9
O
O
7
b
PhS
O
9
9
6
PhS
PhS
a
O
O
O
O
O
O
OH
OTBDPS
O
O
19
20
Me
Me
c
d
O
O
9
9
PhS
PhS
O
HO
OHC
O
O
O
OH
OTBDPS
OTBDPS
21
22
Scheme 5. Reagents and Conditions: (a) 7, Zn(OTf)2, i-Pr2NEt, (1R,2S)-N-methylephedrine, toluene, rt,
74% (95:5 dr); (b) TBDPSCl, imidazole, DMF, 0 °C to rt, quant; (c) Dowex 50 W, THF–MeOH (1:1), rt
to 55 ˚C, 82%; (d) NaIO4, THF–H2O (4:1), rt, 98%.
The introduction of fluorescent fragment (16) into α-tetrahydrofuranyl aldehyde (22) proceeded
successfully, giving desired propargyl alcohol (23) in 66% yield with high stereoselectivity (91:9 dr).16
Resulting diyne (23) was hydrogenated on Wilkinson’s catalyst to give alcohol (24) in 73% yield.
Oxidation of the sulfide followed by thermal elimination of the resulting sulfoxide afforded
α,β-unsaturated-γ-lactone (25). Synthesis of dansyl-labeled solamin (3) was completed via deprotection
of TBDPS ether under acidic conditions.17
In conclusion, we have accomplished the convergent synthesis of fluorescent solamin bearing all
functionalities from 8 in 7.5% yield over 14 steps. Our synthesis should provide ready access to diverse
derivatives labeled by other fluorescent groups. Further synthesis of other fluorescence labeled
acetogenins and visualization of cell distribution are under way.

HETEROCYCLES, Vol. 79, 2009
391
Me
H
N
NMe2
H
O
S
N
Me2N
6
O2
S
O2
9
6
PhS
16
O
O
22
OTBDPS
HO
23
a
Me
O
b
H
N
Me2N
Me2N
Me2N
S
O
O
O
6
9
O2
OTBDPS
OTBDPS
OH
HO
PhS O
24
Me
O
c, d
H
N
S
O2
6
9
HO
O
25
Me
O
e
H
N
S
6
9
O2
HO
O
dansyl-labeled solamin (3)
Scheme 6. Reagents and Conditions: (a) 16, Zn(OTf)2, i-Pr2NEt, (1R,2S)-N-methylephedrine, toluene, rt,
66% (91:9 dr); (b) H2 (3 atm), (Ph3P)3RhCl, benzene, rt, 73%; (c) mCPBA, CH2Cl2, 0 °C; (d) toluene,
reflux, 68% in two steps; (e) 48% HF aq., MeCN, rt, 71%.
ACKNOWLEDGEMENT
We acknowledge financial support through a Grant-in-Aid for Scientific Research on Priority Area
‘Creation of Biologically Functional Molecules’ from The Ministry of Education, Culture, Sports,
Science, and Technology, Japan.
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1
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