Asymmetric synthesis of cryptofolione and determination of its absolute configuration

Article abstract of DOI:10.3987/COM-05-S(K)73

Two possible stereoisomers of cryptofolione, isolated from the Cryptocarya species in South Africa and Brazil, were synthesized in an enantioselective manner by using asymmetric hetero Diels-Alder reaction as the key steps. Comparative evaluation of the <

Full text of DOI:10.3987/COM-05-S(K)73

HETEROCYCLES, Vol. 66, 2005
187
HETEROCYCLES, Vol. 66, 2005, pp. 187 – 194. © The Japan Institute of Heterocyclic Chemistry
Received, 17th October, 2005, Accepted, 24th November, 2005, Published online, 29th November, 2005. COM-05-S(K)73
ASYMMETRIC
SYNTHESIS
OF
CRYPTOFOLIONE
AND
DETERMINATION OF ITS ABSOLUTE CONFIGURATION†
Yuko Matsuoka, Kohsuke Aikawa, Ryo Irie, and Tsutomu Katsuki*
Department of Chemistry, Faculty of Science, Graduate School, Kyushu
University 33, Hakozaki, Higashi-ku, Fukuoka 812-8581, Japan
Abstract – Two possible stereoisomers of cryptofolione, isolated from the
Cryptocarya species in South Africa and Brazil, were synthesized in an
enantioselective manner by using asymmetric hetero Diels-Alder reaction as the
1
13
key steps. Comparative evaluation of the H NMR, C NMR, CD spectra, and
specific rotation of the synthetic compounds with those reported in the literature
was performed to establish the absolute configuration of cryptofolione to be
[6R,10S,12R].
Naturally occurring 6-substituted 5,6-dihydro-α-pyrones have been observed in several botanical families
and fungi species.1 Among them, 6-(ω-arylalkenyl)-5,6-dihydro-α-pyrones bearing no substituent at C4
are characteristics of Cryptocarya species (Lauraceae).2 These α-pyrones are biosynthesized as
secondary metabolites via a mixed acetate-shikimate pathway3 and structurally characterized by
5,6-dihydro-α-pyrone, 1,3-diol or 1,3,5-triol, and trans-styryl skeletons. cryptofolione (1), a class of
6-(ω-arylalkenyl)-5,6-dihydro-α-pyrones, has been recently isolated from branch and stem bark of the
Cryptocarya species such as C. myrtifolia by Drewes et al.2a and C. moschata by Cavalheiro et al. 4,5
The bioactivities of this compound have been evaluated to show moderate tripanocidal and leishmancidal
effects in vitro.6 The configuration of their pyrone unit has been reported to be R based on their CD
spectra4 and the relative configurations of diol or triol units on the C6-side chain have been determined by
13C NMR spectral analysis for some compounds.7 However, their whole stereochemistries still remain
unestablished. Thus, in order to determinethe stereochemistry of this class of compounds in a synthetic
way, 8 we examined the synthesis of cryptofolione (1) by using asymmetric hetero Diels-Alder reaction
and diastereoselective reduction, the stereochemistries of which have been established unequivocally, as
13
key steps. Based on C NMR spectral analysis, the relative configuration of the 1,3-diol unit has been
†This paper is dedicated to the memory of the late Professor Emeritus Kenji Koga.

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HETEROCYCLES, Vol. 66, 2005
proposed to be anti.2a,4,7 Since the configuration of the α-pyrone unit is R, the stereochemistry of 1 is
either 6R,10S,12R or 6R,10R,12S (Figure 1).
OH OH
12
14
6'
10
O
O
6
2
*
*
1'
4'
anti
Cryptofolione (1)
OH OH
OH OH
O
O
O
O
(6R,10R,12S)-1
(6R,10S,12R)-1
Figure 1. Two possible stereoisomers, (6R,10R,12S)-1 and (6R,10S,12S)-1, for cryptofolione.
We have recently reported that second-generation (salen)chromium complex (2)9 is an efficient catalyst
for asymmetric hetero Diels-Alder (AHDA) reactions of Danishefsky diene (3) and aldehydes.10 The
reactions proceed with high enantioselectivity greater than 90% ee and their stereochemistry is
predictable from the catalyst used. The quenching the AHDA reactions with methanol and
triethylamine11 gives 2-methoxy-γ-pyrones (A) that can be stereoselectively reduced to give
4,6-cis-4-hydroxy-2-methoxytetrahydropyrans (B) according to Nakata's procedure.12 Ring-opening of
compounds (B) gives 3,5-anti-diols (C). On the other hand, the treatment of the AHDA reaction
O
1) 2 (2.5 mol %)
OTMS
0 °C, 24 h
RCHO
R= Ph, c-C H , n-C H
+
2) TFA
R
O
D
OMe
6
11
6
13
3
1) 2 (2.5 mol %)
91-97% ee
0 °C, 24 h
2) MeOH
Et N
O
3
(R)
N
N
+
Cr
R
O
OMe
R
O
O
O
O
A
Ph Ph
E
(R)
Nakata's procedure
-
4
OH
BF
(R,R)-2
R
CHO
OH OH
R
O
OMe
B
C
Scheme 1

HETEROCYCLES, Vol. 66, 2005
189
mixture with trifluoroacetic acid (TFA) gives 6-substituted 2,3-dehydro-γ-pyrones (D) that are readily
converted to the corresponding α-pyrones (E) according to the reported procedure13 (Scheme 1). Thus,
we expected that two possible stereoisomers of 1 could be synthesized by using AHDA reaction as the
key step. To use the 1,3-diol unit as the common intermediate for the synthesis of the two isomers, we
planned to synthesize 6R,10S,12R-1 (1R) and the enantiomer of 6R,10R,12S-1 (1S).
The synthesis started with AHDA reaction of cinnamyl aldehyde with diene (3) using complex (2) as the
catalyst (Scheme 2). The reaction gave 2-methoxy-γ-pyrone (4) of 95% ee, when the reaction was
quenched with methanol in the presence of triethylamine. The product was reduced with LiAlH412 to
give the corresponding cis-alcohol (5), the recrystallization of which from toluene gave optically pure 5 in
74% yield. Compound (5) was hydrolyzed under acidic conditions to lactol (6) which was subjected to
Wittig reaction using PPh3=CHCHO. However, the reaction was slow and the yield of the
corresponding α,β-unsaturated aldehyde was low (<30%) even after a prolonged reaction time.
Consequently, 6 was treated with the anion of triethyl phosphonoacetate, and α,β-unsaturated ester (7)
corresponding to the C6-C6’ fragment of 1 (or its enantiomer) was obtained in a quantitative yield. We
next attempted to protect the 1,3-diol as acetonide,13 but the reaction gave a 1:1 mixture of the
corresponding acetonide and 7, even if an excess amount of 2,2’-dimethoxypropane in the presence of a
strong acid like p-toluenesulfonic acid was used. This result probably supports that the configuration of
the 1,3-diol is anti, because the acetonization of anti-1,3-diol causes the undesired 1,3-diaxial repulsion
OH
OH
O
OTMS
b,c
d
a
CHO
+
Ph
Ph
O
OH
Ph
O
OMe
Ph
O
OMe
OMe
5
6
3
4
f, g, h
OH OH
TBSO
OTBS
e
COOEt
CHO
Ph
Ph
7
8
Cl
N
O
N
O
Ru
NO
Ru-salen complex
Scheme 2. Reaction conditions: a) (R,R)-2 (2.5 mol %), CH2Cl2, 0 °C, 24 h, then MeOH, Et3N (quant.,
95% ee); b) LiAlH4, -78 °C, THF (quant.); c) recrystallization from toluene (74%,100% ee); d) 0.025 M
HCl (H2O : MeCN = 1 : 2), 50 °C (80 %); e) (EtO)2P(O)CH2COOEt (3 eq.), NaH, -30 ° C, THF (quant.);
f) TBSCl, imidazole; g) DIBAL, -78 °C; h) Ru-salen (2 mol%), air (O2), visible light (58 % for 3 steps)

190
HETEROCYCLES, Vol. 66, 2005
(Figure 2). Therefore, compound (7) was protected as t-butyldimethylsilyl (TBS) ethers and transformed
to aldehyde (8) by DIBAL reduction and subsequent aerobic oxidation catalyzed by Ru-salen complex.14
AHDA reactions of 8 with 3 using 2 or ent-2 as the catalyst gave γ-pyrones (9R) and (9S) together with a
small amounts (<5 %) of their diastereomers (9S and 9R), respectively, after the reaction mixture was
treated with TFA (Scheme 3).10 γ-Pyrones (9R) and (9S) were converted into the corresponding
α-pyrones (10R and 10S), respectively, by the following sequence:15 i) reduction by Luche's method,16 ii)
acidic transformation of enol ether to methyl acetal associated with double bond migration,17 and c) Jones
oxidation. Treatment of α-pyrones (10R and 10S) with acetic acid-water gave 1R and 1S, respectively.18
Isomerically pure 1R and 1S were obtained by HPLC separation (DAICEL CHIRALCEL AS-H x 2,
hexane/2-propanol = 7/3, 0.7 mL/min) and subjected to the following experiments for characterization.
1H and C NMR spectra of 1R and 1S were recorded at 200 and 270 MHz (1H NMR) and at 68 or 100
13
MHz (13C NMR) and compared with those of cryptofolione (1). Both the 13C NMR spectral data of 1R
and 1S were found to be almost identical and to agree with the reported one2a,4 for cryptofolione (1) (Table
1). 1H NMR spectra of 1R and 1S are also very similar to one another (Figure 3). CD measurements of
1R and 1S showed positive and negative cotton effects, indicating that their C6-configurations are R and S,
COOEt
Ph
O
O
COOEt
O
O
Ph
Figure 2
O
O
i
R
OH OH
R
R
R
O
O
O
R
Ph
O
O
9
R
10
j, k, l
R
m
1
R
8
O
i
S
OH OH
S
R
O
O
Ph
O
O
9
S
10
S
1
S
TBSO
OTBS
R=
Ph
Scheme 3. Reaction conditions: iR) 2 (2.5 mol %), CH2Cl2, 0 °C, 24 h, then TFA (79%); iS) ent-2 (2.5
mol %), CH2Cl2, 0 °C, 24 h, then TFA (63%); j) NaBH4, CeCl3•7H2O, MeOH, -78 °C; k) MeOH, PPTS,
rt; l) Jones oxidation, 0 °C (10R : 30 % from 9R, 10S : 38 % from 9S); m) AcOH : H2O : THF= 3 : 1 : 1, rt
(1R : 81 %, 1S : 83 %)

HETEROCYCLES, Vol. 66, 2005
191
Table 1. Chemical shifts (13C NMR) for 1, 1R, and 1S
a)
1 (ppm)
b)
1R (ppm)
c)
1S (ppm)
a)
1 (ppm)
b)
1R (ppm) 1S (ppm)
c)
C
2
C
11
12
13
14
1'
164.3
121.3
145.1
29.6
164.0
121.5
144.7
29.7
164.1
121.5
144.8
29.7
42.3
70.1
42.1
70.5
42.2
70.3
3
4
129.7
131.9
136.7
126.4
128.6
127.6
130.0
131.6
136.5
126.5
128.6
127.7
130.0
131.7
136.6
126.4
128.6
127.7
5
6
78.0
77.8
77.9
7
129.6
131.3
40.4
130.0
131.0
40.4
130.0
131.1
40.4
2'/6'
3'/5'
4'
8
9
10
68.0
68.2
68.1
a) Data (50 MHz, CDCl3) extracted from reference 2a.
b) 68 MHz, CDCl3.
c) 100 MHz, CDCl3.
respectively, as expected from the sense of asymmetric induction of AHDA reactions (CD curves of 1R
and 1S were observed at 278 and 276 nm, respectively).4 Furthermore, the molecular structure of 1S was
determined by X-Ray crystallography, establishing the stereochemistry of 1S to be the supposed
6S,10S,12R in conjunction with the above CD spectral analysis (Figure 4).19 Thus, the structures of 1R
and 1S were confirmed to be 6R,10S,12R and 6S,10S,12R, respectively. Finally, comparative evaluation
["]23
["]24
+48° (c 0.011, CH2Cl2), and 1S
D
2a
+57° (c 0.52, CH2Cl2) , 1R (
for the specific rotations of 1 (
["]24
D
(
–14° (c 0.034, CH2Cl2) was performed to strongly suggest the absolute configuration of
D
cryptofolione to be 6R,10S,12R. 20
In conclusion, we have synthesized two possible stereoisomers of cryptofolione by using
Cr(salen)-catalyzed AHDA reaction as the key steps. Their absolute configurations were rationally
determined based on the sense of asymmetric induction of AHDA reactions and were also deduced from a
combination of CD measurement and X-Ray crystallographic analysis. Comparison of the specific
rotations of the synthetic samples with the one of natural product led to the establishment of the absolute
configuration of cryptofolione for the first time.
ACKNOWLEDGEMENTS
We are grateful to Professor Alberto Jose Cavalheiro, Instituto de la Quimica, Universidade Estadual
1
Paulista, Brazil for his kind donation of H NMR chart of cryptofolione (1). Financial supports from
Banyu Pharmaceutical Co. and Nissan Chemical Industries are gratefully acknowledged.

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HETEROCYCLES, Vol. 66, 2005
1R
(270 MHz)
natural 1
(200 MHz)
1S
(270 MHz)
Figure 3. 1H NMR spectral data of natural 1, 1R, and 1S
Figure 4. A Chem3D diagram for the X-Ray structure of 1S.

HETEROCYCLES, Vol. 66, 2005
193
REFERENCES AND NOTES
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19. Crystallographic data for 1S: Recrystallized from tetrahydrofuran-hexane, C19H22O4, M = 314.37,

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HETEROCYCLES, Vol. 66, 2005
monoclinic, space group P21, a = 10.653(2) Å, b = 6.0862(9) Å, c = 13.182(2) Å, V = 850.0(2) Å3, Z
= 2, Dc = 1.228, µ(Mo-Ka) = 0.85, R = 0.054, Rw = 0.046 for 1541 reflections and 207 variables,
GOF = 0.99. Data were collected on a Rigaku RAXIS RAPID imaging plate area detector with
graphite monochromated Mo-Ka at –90 °C. Structural analysis was performed using the teXsan
crystallographic software package. The structure was solved by heavy atom Patterson methods and
expanded using Fourier techniques. Hydrogen and all non-hydrogen atoms were refined
isotropically and anisotropically, respectively.
20. Although this result indicates that the specific rotations of both (6R,10R,12S)-1 and (6R,10S,12R)-1
have the same plus sign as the natural product, the absolute value for the former stereoisomer is
more comparable with that reported for cryptofolione.