First total synthesis and determination of the absolute configuration of strictifolione, a new 6-(ω-phenylalkenyl)-5,6-dihydro-α-pyrone, isolated from Cryptocarya strictifolia

Article abstract of DOI:10.1016/S0040-4039(02)02181-0

Starting from (S)-malic acid and (S)-glycidol, the first total synthesis of strictifolione, a new 6-(ω-phenylalkenyl)-5,6-dihydro-α-pyrone isolated from Cryptocarya strictifolia, was accomplished, which confirmed its structure including the absolute confi

Full text of DOI:10.1016/S0040-4039(02)02181-0

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 8657–8660
First total synthesis and determination of the absolute
configuration of strictifolione, a new
6-(v-phenylalkenyl)-5,6-dihydro-a-pyrone, isolated from
Cryptocarya strictifolia
Lia Dewi Juliawaty,a,b Yoshimi Watanabe,a Mariko Kitajima,a Sjamsul Arifin Achmad,b
Hiromitsu Takayamaa,* and Norio Aimia
aGraduate School of Pharmaceutical Sciences, Chiba University, 1-33 Yayoi-cho, Inage-ku, Chiba 263-8522, Japan
bChemistry Department, Institut Teknologi Bandung, Jl. Ganeca 10, Bandung 40132, Indonesia
Received 4 September 2002; revised 26 September 2002; accepted 27 September 2002
Abstract—Starting from (S)-malic acid and (S)-glycidol, the first total synthesis of strictifolione, a new 6-(v-phenylalkenyl)-5,6-
dihydro-a-pyrone isolated from Cryptocarya strictifolia, was accomplished, which confirmed its structure including the absolute
configuration of the asymmetric centers. © 2002 Elsevier Science Ltd. All rights reserved.
Recently, a number of 5,6-dihydro-a-pyrone derivatives
possessing an v-arylalkyl side chain at the C6 position
have been isolated from the genus Cryptocarya (Lau-
raceae).1 The biological activities of these compounds
have not been well studied, but, some have been found
to exhibit significant antifungal1g or cytotoxic1a activi-
ties. Their structures were elucidated mainly based on
spectroscopic methods, and among them, the syntheses
of cryptocaryalactone2 and kurizilactone3 have been
reported so far. In the course of study on the chemical
constituents of the Cryptocarya plants in Indonesia,4 we
have recently isolated a new 6-substituted 5,6-dihydro-
a-pyrone (1),5 named strictifolione, from Cryptocarya
strictifolia, and proposed its structure based on spectro-
scopic analysis, as follows. The relative stereochemistry
of the 1,3-diol function at C4% and C6% was elucidated
Our basic approach to strictifolione synthesis, which
features the condensation of two fragments in the last
stage of the synthesis, both of which can be prepared
from chiral synthons (2 and 3) with known absolute
stereochemistry, is outlined in Fig. 1.
Before starting the total synthesis, we prepared frag-
ment 5 by degrading the natural product (Scheme 1) to
confirm the absolute configuration of the 1,3-diol part
in 1 by means of direct comparison with the synthetic
intermediate described below. Thus, acetonide (4) pre-
pared from natural 1 was treated with NaIO4 in the
presence of a catalytic amount of OsO4 in aqueous
1
from the H NMR spectrum of the acetonide derivative
(4), and the absolute configurations of their stereogenic
centers were deduced by the Mosher method. The
absolute configuration at C6 was assumed based on the
Cotton effect in the CD spectrum. To confirm the
structure inferred by spectroscopic analysis, we
attempted the chiral total synthesis of 1.
Keywords: Cryptocarya; a-pyrone; chiral total synthesis; absolute
configuration.
* Corresponding author. Tel./fax: +81-43-2902902; e-mail: htakayam
@p.chiba-u.ac.jp
Figure 1.
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)02181-0

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L. D. Juliawaty et al. / Tetrahedron Letters 43 (2002) 8657–8660
ondary alcohol (14) in 98% yield. Deprotection of the
dithioacetal group with I2–NaHCO3 in aqueous acetone
yielded b-hydroxy ketone (15) in 77% yield. Stereoselec-
tive reduction was accomplished using Me4NHB-
(OAc)37 in acetonitrile–acetic acid (1:1) at −20°C, giving
anti-diol (16) with excellent anti-selectivity (anti:syn=
99.2:0.8 by HPLC analysis). In order to confirm the
relative configuration of 1,3-diol as well as to protect
the diol function required for the following reactions,
both anti and syn diols were transformed into the
corresponding acetonide derivatives. The 13C chemical
shift of the two methyl groups in the acetonide part in
17 had almost the same values, namely, at l 24.88 and
24.85 ppm, indicating that the two alcohol groups are
in a 1,3-anti orientation.8 In contrast, in the acetonide
derivative prepared from a minor reduction product,
signals were found at l 19.93 and 30.44 ppm, which
were characteristic for the methyl groups in the ace-
tonide part of 1,3-syn diol.8 The silyl protective group
in 17 was removed by using TBAF in THF in the
Scheme 1. Reagents and conditions: (a) OsO4, NaIO4, 1,4-
dioxane–H2O (3:1), rt, 45 min, 26%; (b) NaBH4, EtOH, rt, 75
min, 66%.
dioxane, and then the resultant aldehyde was reduced
with NaBH4 in EtOH to give primary alcohol (5), that
exhibited [h]2D2 +26.8 (c 0.43, CHCl3).
,
presence of 4 A molecular sieves to afford primary
alcohol (5) in 100% yield. The synthetic 5, as well the
ent-5 derived from (R)-malic acid, were completely
identical with
5 prepared from natural product
The synthesis of the two enantiomers of primary alco-
hol (5), which corresponded to the left-hand part of 1,
began with (S)- and (R)-malic acid, respectively, as
illustrated in Scheme 2 (for simplicity, only the synthe-
sis starting from the (S) form will be described here).
Initially, a known chiral epoxide (12)6 was prepared
from malic acid in good yield by a newly developed
process. In this synthetic route, the protection of the
secondary alcohol with a trityl group enabled the
regioselective silylation of one of two primary alcohols
in 8. The thus-obtained epoxide (12) was coupled with
the anion generated from dithiane (13) to give sec-
described above, respectively, by comparison of their
chromatographic behavior, as well as their spectral data
1
(MS, H and 13C NMR data). Compound 5 and its
antipode showed [h]2D5 +24.9 (c 1.7, CHCl3) and [h]2D2
−21.9 (c 1.5, CHCl3), respectively, demonstrating that
the absolute configurations at C4% and C6% in 1 are S.
The right-hand part of 1, i.e. the masked pyranone
aldehyde (21), was synthesized from (S)-glycidol (3)
according to the procedure of Crimmins et al.9 with
slight modification, as shown in Scheme 3. Two
Scheme 2. Reagents and conditions: (a) conc. H2SO4, EtOH, reflux, 4 h, 93%; (b) Ph3CCl, DBU, CH2Cl2, rt, 25 h, 71%; (c)
LiAlH4, Et2O, reflux, 1.5 h, 88%; (d) TBDPSCl, Et3N, DMAP, CH2Cl2, −10°C, 72%; (e) MsCl, CH2Cl2, rt, 12 h, quant.; (f) BCl3,
CH2Cl2, −10°C, quant.; (g) K2CO3, MeOH, 0°C, 88%; (h) 13, n-BuLi, THF, rt, 98%; (i) NaHCO3, I2, aq. acetone, 0°C, 77%; (j)
Me4NHB(OAc)3, MeCN–AcOH (1:1), −20°C, 25 h, 95%; (k) 2,2-dimethoxypropane, p-TsOH, CH2Cl2, rt, 3 h, 82%; (l) TBAF, 4
,
A MS, THF, rt, 2 h, 100%.

L. D. Juliawaty et al. / Tetrahedron Letters 43 (2002) 8657–8660
8659
by column chromatography, was subjected to further
reactions to complete the synthesis. Hydrolysis of the
acetals at C2 and of the diol function with PPTS in
aqueous acetone, followed by MnO2 oxidation of the
resulting allylic alcohol moiety gave the 5,6-dihydro-a-
pyrone, which was recrystallized from n-hexane/CHCl3
to afford the pure E-isomer in 30% overall yield. Synthetic
1 was completely identical in all respects (chromato-
graphic behavior; mp (110–113°C); mass; IR; UV; CD;
1H and 13C NMR; [h]D) with natural strictifolione.
Therefore, the structure including the absolute configura-
tion of the three chiral centers in 1 was established.
Scheme 3. Reagents and conditions: (a) TBDPSCl, imidazole,
CH2Cl2, rt, 3 h, 67%; (b) vinylmagnesium bromide, CuI, THF,
−25°C, 1 h, 88%; (c) acrolein diisopropylacetal, PPTS, 40“
60°C, 32 h, 74% (diastereomeric mixture 1:1); (d)
RuCl2(ꢀCHPh)(PCy3)2, CH2Cl2, reflux, 2 h, quant. (trans:cis
1:1, isolated trans-isomer 44%); (e) TBAF, THF, rt, 1 h, 87%;
(f) (COCl)2, DMSO, Et3N, CH2Cl, −78°C, 10 min, 90%.
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To achieve the total synthesis, Wittig olefination of
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a mixture (4:1) of isomeric E- and Z-alkenes in 34% yield
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chemistries should be inverted. The synthetic
MTPA-esters in compounds 3, 4, 5 and 6 in this reference
had actually R, R, S, and S forms, respectively, resulting
in the opposite conclusions based on calculations using
Mosher’s method.)
Figure 2.
Scheme 4. Reagents and conditions: (a) MsCl, 2,6-lutidine,
CH2Cl2, rt, 10 h, quant.; (b) LiBr, DMF, rt, 5 days, 86%; (c)
1-phenyl-5-mercaptotetrazole, NaH, DMF, rt“70°C, 96%; (d)
m-CPBA, CH2Cl2, rt, 24h, 96%;(e)21, NaHMDS, THF, −60°C,
1.5 h, 34% (E-, Z-isomer 4:1); (f) PPTS, acetone–H2O (6:1), rt,
1.5 h, 80%; (g) MnO2, pyridine, CH2Cl2, 24 h, 50%.
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