Stereocontrolled synthesis of gem-difluoromethylenated goniodiols and goniothalamin epoxides based on ring-closing metathesis

Article abstract of DOI:10.1055/s-2006-942467

An efficient and general method to stereoselectively synthesize gem-difluoromethylenated goniodiols and goniothalamin epoxides has been developed. The introduction of a gem-difluoromethyl-containing group was achieved by the reaction of aldehydes with 3-bromo-3,3-difluoropropene in the presence of indium. The gem-difluoromethylenated α,β-unsaturated- δ-lactone moiety was constructed through the ring-closing metathesis of highly electron-deficient gew-difluoromethylenated acryloyl esters by Grubbs' II catalyst in toluene at reflux. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2006-942467

PAPER
2535
Stereocontrolled Synthesis of gem-Difluoromethylenated Goniodiols and
Goniothalamin Epoxides Based on Ring-Closing Metathesis
S
ynthesis of gem
h
-Difluorom
e
e
thylenated
n
G
oniodiols
g
and
G
oniotha
-
lamin
E
W
poxides ei You,a Xingang Zhang,a Feng-Ling Qinga,b
a
Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Science, 354 Fenglin Lu,
Shanghai 200032, P. R. of China
b
Institute of Biological Sciences and Biotechnology, Donghua University, 2999 North Renmin Lu, Shanghai 201620, P. R. of China
Fax +86(21)64166128; E-mail: flq@mail.sioc.ac.cn
Received 27 February 2006; revised 28 March 2006
ciated with this class of natural products, as well as the in-
teresting heterocyclic structural features, much effort has
been focused on the chemical investigation of different
styryllactones.4 It was found that substitution at the 5-po-
Abstract: An efficient and general method to stereoselectively syn-
thesize gem-difluoromethylenated goniodiols and goniothalamin
epoxides has been developed. The introduction of a gem-difluoro-
methyl-containing group was achieved by the reaction of aldehydes
with 3-bromo-3,3-difluoropropene in the presence of indium. The sition of styryllactones can greatly change their biological
gem-difluoromethylenated a,b-unsaturated-d-lactone moiety was
constructed through the ring-closing metathesis of highly electron-
deficient gem-difluoromethylenated acryloyl esters by Grubbs’ II
catalyst in toluene at reflux.
activities and 5-acetoxyisogoniothalamin oxide (Figure 1)
was highly effective in blocking the mitochondrial respi-
ratory chain.5 The similarity in size but substantial differ-
ence in electrostatic properties between fluorine and
hydrogen makes fluorination an interesting strategy in the
design of biologically active compounds.6 The gem-di-
fluoromethylene group (CF2) has been proven to be a key
structural unit in many fluorinated compounds of biologi-
cal and pharmaceutical significance.6,7 In view of the
above fact, the introduction of a gem-difluoromethylene
group (CF2) to styryllactones at the 5-position may lead to
more active anti-tumor agents. Herein, we describe the
synthesis of 5,5-gem-difluoromethylenated goniodiols
(1a and its epimer) and goniothalamin epoxides (2a and
its epimer).
Key words: gem-difluoromethylenated compounds, styryllactone,
ring-closing metathesis, a,b-unsaturated-d-lactone
Recently, a series of styryllactones isolated from various
species of the genus Goniothalamus have been found to
possess remarkable immunosuppressive, anti-inflamma-
tory, and anti-tumor properties.1 Among them, 7-epi-
goniodiol2 and isogoniothalamin epoxide3 (Figure 1) are
two new and representative members of the styryllac-
tones. 7-epi-Goniodiol isolated from the ethanolic extract
of barks of Goniothalamus leiocarpus was demonstrated
to have strong and selective cytotoxicity against HL-60.2
Isogoniothalamin epoxide was found to possess moderate
cytotoxicity against the HUGC (human gastric cancer)
and HONE-1 (human nasopharyngeal carcinoma).3 Due
to the broad spectrum of pharmacological properties asso-
The ring-closing metathesis (RCM) reaction is an effi-
cient way to achieve different ring size lactones8 and it has
been demonstrated that RCM can be applied to olefins
bearing fluorine substituents.9 Recently we have reported
the synthesis of gem-difluoromethylenated massoialac-
O
O
O
2
1
1
3
4
3
2
OH
8
O
6
O
O
6
O
O
7
4
8
Ph
Ph
Ph
5
7
5
OH
OAc
5-acetoxyisogoniothalamin oxide
7-epi-goniodiol
isogoniothalamin
epoxide
O
O
O
OH
O
O
Ph
Ph
F
F
F
F
OH
1a
2a
Figure 1
SYNTHESIS 2006, No. 15, pp 2535–2542
x
x.
x
x
.
2
0
0
6
Advanced online publication: 04.07.2006
DOI: 10.1055/s-2006-942467; Art ID: F02706SS
© Georg Thieme Verlag Stuttgart · New York