a-Carbonyl radical cyclization approach toward spiro[4.4]nonene: total
synthesis of dimethyl gloiosiphone A
Chin-Kang Sha* and Wen-Yueh Ho
Department of Chemistry, National Tsing Hua University, Hsinchu 300, Taiwan, ROC.
E-mail: cksha@chem.nthu.edu.tw
Received (in Cambridge, UK) 2nd November 1998, Accepted 9th November 1998
The total synthesis of dimethyl gloiosiphone A 2 was
achieved via an a-carbonyl radical spirocyclization.
O
NNMe2
O
i
ii
Gloiosiphone A 1 and its dimethyl derivative 2 were isolated
1
from red marine algae Gloiosiphonia verticillaris. Crude lipid
7
6
5
4
collections of Gloiosiphonia verticillaris were found to exhibit
profound antimicrobial activity against several Staphylococcus,
iii
O
O
OMe
iv
O
OH
I
RO
O
8
n
Scheme 2 Reagents and conditions: i, H
5
2
NNMe
2
, 90%; ii, Bu Li, 0 °C,
Cl , then
, 1.5 h,
RO
-iodopent-1-yne, then 10% HCl, 1 h, 80%; iii, HMDS, TMSI, CH
2
2
1
2
R = H
R = Me
NaI, MCPBA, THF, 82%; iv, (Bu Sn) (0.1 equiv.), sun lamp, C H
3
2
6 6
then Bu SnH (1.05 equiv.), AIBN, C H , 87%.
3
6 6
3
Treatment of 4 with Bu SnH under standard conditions
furnished the required spirocyclic compound 8 in 50% yield. To
Bacillus and Salmonella species. Since the causative agent 1
was not stable enough for isolation, the crude collections were
treated with CH N to furnish the more stable dimethyl
2 2
derivative 2.
improve the yield, an atom transfer radical reaction was
6
adopted. Thus, irradiation of a benzene solution of ketone 4 at
reflux with a sun lamp in the presence of (Bu
followed by reduction of the resulting vinyl iodide with Bu
1.05 equiv.) using AIBN as initiator furnished spiro compound
in 87% overall yield.
We then focused our attention on the introduction of enol
3
Sn)
2
(0.1 equiv.)
Compounds 1 and 2 comprise a new structural class featuring
a highly oxygenated spiro[4.4]nonene system. Due to their
potential antimicrobial activity and novel molecular skeleton,
these compounds are challenging synthetic targets. The first
total synthesis of dimethyl gloiosiphone A 2 has been achieved
3
SnH
(
8
2
ether moieties into 8. First, iodo ketone 9 was generated from 8
by the same method used for the transformation of 5?4
recently by Paquette’s group. As an extension of our work on
3
the a-carbonyl radical cyclization reaction, we report herein
(
Scheme 3).3 The iodo ketone 9 was then converted into
the total synthesis of 2 using an a-carbonyl radical cyclization
as the key step. The retrosynthetic analysis is outlined in
Scheme 1. The spirononene structure in 2 could be produced by
an a-carbonyl radical cyclization followed by appropriate
oxidation (4?3). The radical precursor iodo ketone 4 would be
7
unsaturated ketone 10 via a modified version of Sato’s method.
Accordingly, 9 was oxidized with DMSO at 70 °C followed by
addition of I
2
(1 equiv.) to provide 10.
O
O
4
generated according to our method from 5, which in turn could
HO
I
ii
be prepared from cyclopentanone 6 according to Yamashita’s
i
8
procedure.5
Treatment of cyclopentanone 6 with N,N-dimethylhydrazine
I
9
10
in the presence of TFA as catalyst furnished hydrazone 7
n
(
Scheme 2). Deprotonation of 7 with Bu Li at 0 °C followed by
iii
alkylation with 5-iodopent-1-yne and hydrolysis yielded the
required ketone 5. Ketone 5 was sequentially treated with
HMDS/TMSI and NaI/MCPBA in THF to afford iodo ketone 4.
O
O
MeO
iv MeO
O
MeO
Scheme 3 Reagents and conditions: i, HMDS, TMSI, CH
I
3
11
MeO
2
Cl
2
, then NaI,
2
, 86%; iii, NaH, MeI, DMF, 95%; iv,
2
MCPBA, THF, 82%; ii, DMSO, I
MeO
NaOMe (10 equiv.), MeOH, 92%.
3
Compound 10 was subsequently methylated with NaH and
MeI to give methoxy iodo enone 11. Nucleophilic displacement
of iodide in 11 with NaOMe then furnished dimethoxy enone
O
O
3
.
Allylic oxidation of 3 with SeO
2
gave diketone 12 (60%)
I
(Scheme 4). Treatment of 12 with a catalytic amount of OsO
4
with NMO as the co-oxidant gave dihydroxy ketone 13. Finally,
selective methylation of the primary alcohol with dimethyl
5
4
Scheme 1
sulfate in presence of excess K
CO
2 3
(10 equiv.) afforded
Chem. Commun., 1998, 2709–2710
2709