Received: December 18, 2014 | Accepted: December 29, 2014 | Web Released: January 8, 2015
CL-141168
Total Synthesis of a Monomeric Phloroglucinol Derivative Isolated from Myrtus communis
Eiji Nishimura, Yasufumi Ohfune, and Tetsuro Shinada*
Graduate School of Science, Osaka City University, 3-3-138 Sugimoto, Sumiyoshi-ku, Osaka 558-8585
(E-mail: shinada@sci.osaka-cu.ac.jp)
The first total synthesis of a monomeric phloroglucinol
O
O
[(1R*,2S*)-2-hydroxy-2-isobutyl-4,4,6,6-tetramethyl-3,5-dioxo-
cyclohexyl acetate] was achieved by stereoselective reduction
of a symmetrical α-ketol as a key step. The corresponding
cis-stereoisomer of the natural product was synthesized from
phloroglucinol via cis-dihydroxylation using OsO4. Comparison
of 1H NMR data for synthetic 1 and 2 confirmed the trans-
stereochemistry of the natural product.
M
HO
O
HO
O
H
O
O
AcO
O
O
7
1
OH
O
Me x 4
HO
OH
O
O
2-Hydroxy-2-isobutyl-4,4,6,6-tetramethyl-3,5-dioxocyclo-
hexyl acetate (1) was isolated from the essential oil of Myrtus
communis which has been widely utilized as a traditional
medicine.1 The relative stereochemistry of 1 was proposed as
1R* and 2S*. The absolute stereochemistry has not been
determined yet. Natural product 1 and related natural products
3,2 4,1 and 53 are monomeric phloroglucinols4 and characterized
by the highly oxygenated 2,2,4,4-tetramethylcyclohexane-1,3-
dione framework with the vicinal diol moiety (Figure 1).
Although syntheses and biological activities of monomeric
phloroglucinol 6 and its analogs have been extensively
studied,1,5 those of 1, 3, 4, and 5 have been less studied except
for the total synthesis of 3.6 We herein report the stereoselective
synthesis of rac-1 bearing the trans-diol moiety and its cis-
isomer 2. The relative stereochemistry of the natural product 1
was confirmed as trans by NMR analyses of 1 and 2.
9
8
Scheme 1. Retrosynthetic analysis of 1.
O
OH
O
Cl (1.01 equiv)
OH
MeI (7.0 equiv)
NaOMe (5.0 equiv)
.
BF3 OEt2 (3.0 equiv)
O
O
HO
MeOH
reflux, 18 h
71%
rt, 72 h
89%
HO
OH
O
O
OH
10
9
11
O
1) (COCl)2 (2.0 equiv)
DMF (cat.)
toluene, 90 °C, 0.5 h
OMe
NaBH3CN (2.5 equiv)
DMF. rt, 20 h
2) NaOMe (3.0 equiv)
MeOH, 45 °C, 15 h
75% (2 steps)
39%
O
O
O
O
8
12
O
Retrosynthetic analysis of rac-1 featuring the diastereo-
selecive desymmetrization of 7 is depicted in Scheme 1. We
employed a hydroxy group-directing reduction of 7 to the
construction of the trans-diol moiety of 1. Ketol 7 could be
derived by oxidation of 8. Triketone 8 could originate from
phloroglucinol (9) via sequential introduction of the isobutyl
side chain and tetramethyl groups.
1) m-CPBA (3.0 equiv)
CH2Cl2, rt, 16 h
HO
O
2) H2SO4 (cat.)
THF/H2O, reflux, 17 h
quant. (2 steps)
O
7
Scheme 2. Synthesis of symmetrical α-ketol 7.
α-Ketol 7 was prepared from phloroglucinol (9) in seven
steps (Scheme 2). Treatment of 9 with isobutyryl chloride in the
presence of BF3¢OEt2 gave 10 in 89% yield.6 Tetramethylation
of 10 with an excess of MeI gave 11 in 71% yield. Chemo-
selective reduction of 11 with NaBH3CN7 gave ketone 8 in 39%
yield. Triketone 8 was converted to 12 in 75% yield over two
steps. The hydroxylation of 12 was achieved by epoxidation
with m-CPBA followed by an acidic hydrolysis to give ketol 7
in quantitative yield.
O
O
O
O
HO
HO
HO
HO
HO
2
1
AcO
O
AcO
O
AcO
O
O
natural product 1
cis-isomer 2
triumphalone (3)
4
O
We next investigated the stereoselective reduction of 7.
Treatment of 7 with NaBH4 (1.0 equiv) in MeOH at 0 °C resulted
in a complex mixture of 13 and highly polar tri- and tetraols
(Scheme 3). To suppress the undesired over-reduction pathway,
NaBH(OAc)3 was employed as an alternative reagent. As
expected, the reduction smoothly took place without over-
reduction. However, a 4:1 mixture of the desired trans-diol 13
and unexpected cyclopentanone 14 which would arise from 13
by the ring constructive α-ketol rearrangement was obtained.8
HO
O
O
O
OH
R
O
O
HO
O
O
O
HO
OH
HO
OH
OH
6: R = alkyl, aryl, etc.
5
Figure 1. Structure of monomeric phloroglucinols.
© 2015 The Chemical Society of Japan | 445