Novel and stereocontrolled asymmetric synthesis of a new naturally occurring styryllactone, (+)-cardiobutanolide

Article abstract of DOI:10.1016/j.tetlet.2005.12.113

An efficient and stereodefined strategy is described for the asymmetric synthesis of a new styryllactone from the stem bark of Goniothalamus cardiopetalus, cardiobutanolide. The synthetic process is based on requisite manipulation of the functionalized bicyclic lactol-lactone intermediate incorporating the glucuronolactone-derived skeleton in a complete stereoselective manner.

Full text of DOI:10.1016/j.tetlet.2005.12.113

Tetrahedron
Letters
Tetrahedron Letters 47 (2006) 1371–1374
Novel and stereocontrolled asymmetric synthesis of a new
naturally occurring styryllactone, (+)-cardiobutanolide
Daisuke Matsuura, Kunihiko Takabe and Hidemi Yoda*
Department of Molecular Science, Faculty of Engineering, Shizuoka University, Johoku 3-5-1, Hamamatsu 432-8561, Japan
Received 24 November 2005; revised 12 December 2005; accepted 22 December 2005
Abstract—An efficient and stereodefined strategy is described for the asymmetric synthesis of a new styryllactone from the stem bark
of Goniothalamus cardiopetalus, cardiobutanolide. The synthetic process is based on requisite manipulation of the functionalized
bicyclic lactol–lactone intermediate incorporating the glucuronolactone-derived skeleton in a complete stereoselective manner.
Ó 2006 Elsevier Ltd. All rights reserved.
H
H
Trees of genus Goniothalamus of the plant family Anno-
naceae have for a long time aroused considerable
interest as a source of potent biologically active styryl-
lactones1 from a pharmacological point of view.2 These
styryl-types of natural products have been used as a tra-
ditional medicine in Asia to treat rheumatism, edema, as
an abortifacient, and as a mosquito repellent.3 Espe-
cially, lactones isolated can be mainly classified into
two groups related to the size of the lactone ring. The
first group consists of the five-membered lactones such
as cardiobutanolide (1) and goniofufurone (2) as shown
in Figure 1 and the second group consists of the six-
membered lactone moiety, for example, goniotriol (3),
etharvendiol (4), altholactone (5), and goniopyrone
(6). Their unique and intriguing structures coupled with
diverse and useful characteristics as well as their broad
spectrum of activity have made them inviting targets
for synthesis.4 In addition, one of the most useful repre-
sentatives of the plant family Annonaceae, the Indoma-
layan genus Goniothalamus cardiopetalus, has in 2003
given rise to the isolation of a new styryllactone, cardio-
butanolide (1) described above, possessing potentially
biological properties.5 Herein, we wish to communicate
a novel and stereocontrolled asymmetric synthesis of 1
based on nucleophilic Grignard addition to the bicyclic
lactol–lactone elaborated from commercially available
D-glucuronolactone followed by complete stereoselec-
tive reduction of the crucial hemiketal intermediate
OH
OH OH
OH
HO
Ph
H
O
O
O
O
HO
O
cardiobutanolide (1)
goniofufurone (2)
O
O
OH
O
OH
O
Ph
Ph
OH
OEt
OH OH
goniotriol (3)
etharvendiol (4)
H
H
O
O
Ph
Ph HO
O
O
O
O
H
HO
HO
H
altholactone (5)
goniopyrone (6)
Figure 1. Styryllactones.
obtained in this sequence. To the best of our knowledge,
only one approach to the synthesis of 1 has been
reported6 recently during the course of our synthetic
studies.
In formulating the synthetic plan for 1, we recognized
that the absolute configurations at C(3), C(4), and
C(5) are the same as the configurations at the corre-
sponding centers C(3), C(4), and C(5) of readily avail-
able and inexpensive D-glucuronolactone (7) as shown
in Figure 2. Further we envisioned that the stereo-
genic center of C(6) in 1 would be constructed through
nucleophilic addition of organometallic reagent to a
Keywords: Styryllactone; Cardiobutanolide; Grignard addition; Ster-
eoselective reduction; Glucuronolactone.
*
Corresponding author. Tel./fax: +81 53 478 1150; e-mail: tchyoda@
ipc.shizuoka.ac.jp
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.12.113

1372
D. Matsuura et al. / Tetrahedron Letters 47 (2006) 1371–1374
OH
HO
H
HO
OH OH
H
H
OR
OR OH
H
5
O
O
H
a
b
3
OH
6
OH
O
O
4
O
O
O
O
O
OR
H
O
OH
O
RO
cardiobutanolide (1)
(II)
8
glucuronolactone (7)
H
H
H
HO
H
O
H
O
O
c
O
d
OTBS
O
O
3
O
OH
HO
O
O
4
O
O
O
5
O
O
H
O
OTBS
H
H
9
10
OR
OH
(I)
glucuronolactone (7)
H
H
O
O
e
Figure 2. Retrosynthetic pathways.
OH
O
BnO
BnO
*
O
H
H
OR
OH
11
12a: R=Bn
12b: R=TBS
bicyclic lactol–lactone (I) followed by stereoselective
reduction of its hemiketal intermediate, allowing the
synthesis of the lactol derivative (II). Meanwhile, the
construction of (I) would have to be independently set
in chemo- and regioselective manipulation of the start-
ing material 7.
Scheme 1. Reagents and conditions: (a) acetone, H2SO4; 95%; (b) 1,
PhOC(S)Cl, DMPA, pyridine, CH3CN; 2, Bu3SnH, AIBN, toluene,
110 °C; 94% (two steps); (c) 1, TFA–H2O (20:1), THF; 89%; 2, TBSCl,
imidazole, DMF; 98%; (d) 1, DIBAL-H, THF, ꢀ78 °C; 98%; 2, BnBr,
Ag2O, AcOEt; 3, Bu4NF, THF; 55% (two steps); (e) 1, Ag2CO3,
toluene, Celite, reflux; 88%; 2, BnBr, Ag2O, AcOEt; 96% (12a); TBSCl,
imidazole, DMF; 92% (12b).
To begin with, an attempt to synthesize the important
intermediate such as the type of lactol–lactone (I) was
designed. The results are summarized in Scheme 1. a-
Hydroxyl function of D-glucuronolactone (7) was effec-
tively eliminated through successive acetonide7 and
phenylthiocarbonate formations, followed by deoxygen-
ation under radical conditions8 to give the lactone 9 in
89% yield (three steps).4r After exchange of the protect-
ing groups of 9 to the bis-TBS ethers,9 the lactonic
segment of 10 thus obtained was protected as the
lactol–benzyl ether through DIBAL-H reduction, which
was, in turn, submitted to desilylation, leading to the
diol–lactol derivative 11 as a mixture of four anomers.
Then, 11 was effected by chemoselective Fetizon’s oxida-
tion with Ag2CO3 of the lactol function only and the
following hydroxyl protection with two different groups
to provide the desired bicyclic lactol–lactone intermedi-
ates 12 in high yield. Interestingly both 12a and 12b are
obtained as a single anomer product, respectively.10
With the compounds 12 in hand, we next focused our
research on the total synthesis of 1 as shown in Scheme
2. Thus, 12a was initially effected with vinylmagnesium
11
chloride in the presence of CeCl3 at low temperature
to afford the labile hemiketal intermediate, which was
readily treated with NaBH4 also in the presence of CeCl3
at ꢀ40 °C, providing the corresponding allyl alcohol
mixture of 13a and 14a with moderately diastereofacial
differentiation (13a:14a = 76:24, determined by 1H
NMR). On the contrary, we were delighted to find that
27
the use of TBS-protected 12b, ½aꢁD +130.8 (c 0.96,
CHCl3), dramatically changed the results and fortu-
27:6
nately brought about the desired isomer 13b, ½aꢁD
+60.65 (c 1.17, CHCl3), as the single product (deter-
1
13
mined by H and C NMR)12 in 68% isolated yield
(two steps) under the same reaction conditions.13 For
H
OH
OH
OR
OR
H
H
O
a
O
BnO
*
+
O
*
*
O
O
OH
OH
H
OR
BnO
BnO
12a: R=Bn
12b: R=TBS
14a: R=Bn
14b: R=TBS
13a: R=Bn
13b: R=TBS
(76 : 24)
(>99 : 1<)
BnO
OBn
BnO
OBn
BnO
OBn OH
OBn
H
H
H
CHO
OBn
16
b
d
c
13b
*
*
*
O
O
OBn
15
O
BnO
BnO
BnO
17
BnO
OBn OH
OH
OH OH
OH
H
H
e
f
O
OBn
O
HO
O
cardiobutanolide (1)
18
Scheme 2. Reagents and conditions: (a) 1, vinylmagnesium chloride, CeCl3, THF, ꢀ78 °C; 2, NaBH4, CeCl3, MeOH, ꢀ40 °C; 55% (two steps)
(13a+14a); 68% (two steps) (13b); (b) 1, Bu4NF, THF; 95%; 2, NaH, BnBr, Bu4NI, THF; 90%; (c) 1, cat. OsO4, NMO, acetone–H2O (1:1); 2, NaIO4,
THF–H2O (1:1); (d) PhMgBr, CeCl3, THF, ꢀ78 °C; 56% (three steps); (e) 70%-AcOH; 91%; (f) 1, Ag2CO3, Celite, toluene, reflux; 97%; 2, H2, Pd/C,
AcOEt; 80%.

D. Matsuura et al. / Tetrahedron Letters 47 (2006) 1371–1374
1373
Tetrahedron 1999, 55, 13011; (h) Mereyala, H. B.; Gadi-
kota, R. R.; Joe, M.; Arora, S. K.; Datidar, S. G.;
Agarwal, S. Bioorg. Med. Chem. 1999, 7, 2095; (i) Bruns,
R.; Wenicke, A.; Ko¨ll, P. Tetrahedron 1999, 55, 9793; (j)
Tsubuki, M.; Kanai, K.; Nagase, H.; Honda, T. Tetrahe-
dron 1999, 55, 2493; (k) Chen, W.-P.; Roberts, S. M. J.
Chem. Soc., Perkin Trans. 1 1999, 103; (l) Yi, X.-H.;
Meng, Y.; Hua, X.-G.; Li, C.-J. J. Org. Chem. 1998, 63,
7472; (m) Cagnolini, C.; Ferri, M.; Jones, P. R.; Murphy,
P. J.; Ayres, B.; Cox, B. Tetrahedron 1997, 53, 4815; (n)
Mukai, C.; Hirai, S.; Km, I. J.; Kido, M.; Hanaoka, M.
Tetrahedron 1996, 52, 6547; (o) Shing, T. K. M.; Tsui, H.
C.; Zhou, Z. H. J. Org. Chem. 1995, 60, 3121; (p) Yang,
Z.-C.; Zhou, W.-S. Tetrahedron 1995, 51, 1429; (q)
Gracza, T.; Ja¨ger, V. Synthesis 1994, 1359; (r) Ye, J.;
Bhatt, R. K.; Falck, R. J. R. Tetrahedron Lett. 1993, 34,
8007; (s) Murphy, P. J.; Dennison, S. T. Tetrahedron 1993,
49, 6695; Prakash, K. R. C.; Rao, S. P. Tetrahedron 1993,
49, 1505; (t) Shine, T. K. M.; Tsui, H. C.; Zhou, Z. H.
Tetrahedron 1992, 48, 8659.
the purpose of reducing the formation of by-products,
the sily group in 13b was next replaced with the benzyl
function together with the same benzyl-protection of
the resulting two hydroxyl moieties. The olefinic part
25
in 15, ½aꢁD +4.57 (c 1.05, CHCl3), thus obtained was
then cleaved via dihydroxylation to afford the aldehyde
intermediate 16, which was successively subjected to
phenyl-Grignard addition at low temperature in the
presence of CeCl3 in expectation of higher stereoselec-
tive results. This effect resulted in the preparation of
25
the fully functionalized alcohol 17, ½aꢁD +4.18 (c 1.16,
CHCl3), as a sole product in 56% yield (three steps) with
the desired configuration14 as well as fortunately com-
plete stereoselectivity.15 Then, the use of 70% acetic acid
underwent chemoselective reaction for hydrolysis to
afford the corresponding lactol 18. Finally, this com-
pound was submitted to Fetizon’s Ag2CO3-oxidation
followed by deprotection of the tribenzyl groups with
H2 on Pd/C to complete the total synthesis of the natu-
Absolute configurations of these styryl groups are in
accord with those of all suggested biogenetic precursors
and allowed to propose the absolute configurations of
related cytotoxic styryllactones and strucutures of poten-
tial biosynthetic intermediates not identified so far, see:
Ref. 4q.
26
24
ral type of 1, ½aꢁD +9.72 (c 1.00, MeOH) {natural 1; ½aꢁD
+6.4 (c 0.28, MeOH)5 and synthetic 1, [a]D +5.5 (c 0.3,
MeOH)6} in 80% yield. The spectral data of synthetic
1 were identical to those of the reported natural and
synthetic product.
5. Hisham, A.; Toubi, M.; Shuaily, W.; Ajitha Bai, M. D.;
Fujimoto, Y. Phytochemistry 2003, 62, 597.
6. Ruiz, P.; Murga, J.; Carda, M.; Marco, J. A. J. Org.
Chem. 2005, 70, 713.
7. (a) Yoda, H.; Nakaseko, Y.; Takabe, K. Tetrahedron Lett.
2004, 45, 4217; (b) Yoda, H.; Nakaseko, Y.; Takabe, K.
Synlett 2002, 1532.
8. Robins, M. J.; Wilson, J. S. J. Am. Chem. Soc. 1981, 103,
932.
In summary, this process involves no separation of ste-
reoisomers and was substantially performed under mild
conditions through the entire sequence. Further it con-
stitutes a new synthetic strategy and, in addition, repre-
sents an easily accessible pathway to styryllactone
natural products.
9. Similar carbohydrate-derived starting materials were also
applied to the total synthesis of related styryllactones. For
example, see: Ref. 4o.
Acknowledgments
Direct treatment of 9 according to the following reaction
sequence cited in Scheme 1 yielded only intractable
materials at the final step of acetonide-deprotection.
10. It is not necessarily to determine the absolute configura-
tion at this anomer center, since the lactol function should
be oxidized to the corresponding lactone at the final stage
for the synthesis of 1.
This work was supported in part by a Grant-in-Aid (No.
15550031) for Scientific Research from the Japan Soci-
ety for the Promotion of Science.
References and notes
11. (a) Yoda, H.; Mizutani, M.; Takabe, K. Heterocycles
1998, 48, 479; (b) Yoda, H.; Mizutani, M.; Takabe, K.
Synlett 1998, 855.
1. For a review on styryllactones from Goniothalamus
`
species, see: Blazquez, M. A.; Bermejo, A.; Zafra-Polo,
12. The absolute configuration of the newly created stereo-
genic center of 13b was easily characterized to be R after
derivatization via the mesylate 19 to the corresponding cis-
epoxide 20 as shown below.
M. C.; Cortes, D. Phytochem. Anal. 1999, 10, 161.
2. (a) Alali, F. Q.; Liu, X. X.; McLaughlin, J. L. J. Nat.
`
Prod. 1999, 62, 504; (b) Zafra-Polo, M. C.; Figadere, B.;
´
Gallardo, T.; Tormo, J. R.; Cortes, D. Phytochemistry
´
`
1998, 48, 1087; (c) Cave, A.; Figadere, B.; Laurens, A.;
OH
MsO
OTBS
OTBS
´
Cortes, D. Prog. Chem. Org. Nat. Prod. 1997, 70, 81.
H
H
MsCl
3. On the cytotoxic activity and other bioactivity of styryl-
lactones, see: Mereyala, H. B.; Joe, M. Curr. Med. Chem.:
Anti-Cancer Agents 2001, 1, 293.
4. For some recent examples; (a) Prasad, K. R.; Gholap, S.
L. Synlett 2005, 2260; (b) Popsavin, V.; Grabezˇ, S.;
*
*
O
OMs
O
OH
13b
BnO
BnO
19
OH
Ha
O
H
Bu NF
4
Hb
´
´
´
Popsavin, M.; Krstic, I.; Kojic, V.; Bogdanovic, G.;
´
Divjakovic, V. Tetrahedron Lett. 2004, 45, 9409; (c) Peris,
*
O
79% (two steps)
Ja,b = 4.38 Hz
´
`
E.; Cave, A.; Estornell, E.; Zafra-Polo, M. C.; Figadere,
B.; Cortes, D.; Bermejo, A. Tetrahedron 2002, 58, 1335; (d)
Srikanth, G. S. C.; Krishna, U. M.; Trivedi, G. K.
Tetrahedron Lett. 2002, 43, 5471; (e) Harris, J. M.;
O’Doherty, G. A. Tetrahedron 2001, 57, 5161; (e) Harris,
J. M.; O’Doherty, G. A. Tetrahedron 2001, 57, 5161; (f)
Su, Y.-L.; Yang, C.-S.; Teng, S.-J.; Zhao, G.; Ding, Y.
Tetrahedron 2001, 57, 2147; (g) Surivet, J.-P.; Vatele, J.-M.
BnO
20
The observed vicinal coupling constant (Ja,b) of protons
(Ha,Hb) was 4.38 Hz, which indicates the epoxide in 20
occupy the cis-relation; see: Tanaka, K.; Horiuchi, H.;
Yoda, H. J. Org. Chem. 1989, 54, 63; Shimagaki, M.;
Maeda, T.; Matsuzaki, Y.; Mori, I.; Nakata, T.; Oishi, T.

1374
D. Matsuura et al. / Tetrahedron Letters 47 (2006) 1371–1374
Tetrahedron Lett. 1984, 25, 4775. Compound 13a was also
estimated to have the same configuration based on the
similarity of its spectral data to those of 13b.
performance would be attributed to the steric demand of
the CeCl3-mediated six-membered metal–chelate structure
due to the bottom-face shielding effect of the three large
functional groups described below.
13. When reduction of the labile hemiketal intermediate
derived from 12b was carried out under slightly different
conditions (change of the reduction temperature from ꢀ40
to ꢀ20 °C), the reaction occurred with unsatisfactory
stereoselectivity to give the mixture of the two diastereo-
mers (13b:14b = 86:14). It is consequently apparent that
stereochemical outcome in these reactions strongly
depends on the two factors; (a) steric bulkiness of the
protecting groups in 12 and (b) reduction temperature of
the hemiketal intermediates. These results can be
explained that the reaction would proceed simply in terms
of the thermodynamically more stable Cram’s non-chela-
tion transition structure.
PhMgBr
O
O
H
H
Bn
Ce
OBn
lactol
part
14. The absolute R-configuration of the generated stereogenic
center was determined unambiguously based on its spec-
tral data of synthetic (+)-1.
15. We also tried the same reaction in the absence of CeCl3,
leading, as we expected, to the mixture of stereoisomers of
1. At present we postulate that this high stereoselective
The same type of transition metal halide-promoted six-
membered chelating reactions have already been demon-
strated in this laboratory with high stereoselectivity; see:
Yoda, H.; Nakajima, T.; Takabe, K. Tetrahedron Lett.
1996, 37, 5531.