Stereoselective total synthesis of (-)-9-deoxygoniopypyrone

Article abstract of DOI:10.1055/s-2007-973873

Stereoselective synthesis of (-)-9-deoxygoniopypyrone was achieved from the naturally occurring L-(+)-tartaric acid. Key step involves the elaboration of a γ-hydroxybutyramide to the title compound involving high-yielding stereoselective transformations.

Full text of DOI:10.1055/s-2007-973873

1112
LETTER
Stereoselective Total Synthesis of (–)-9-Deoxygoniopypyrone
Stereoselective
To
a
tal Synthesi
v
s
of (–)-9-D
e
oxygo
r
niopypy
a
rone yani R. Prasad,* Madhuri G. Dhaware
Department of Organic Chemistry, Indian Institute of Science, Bangalore 560012, India
E-mail: prasad@orgchem.iisc.ernet.in
Received 24 November 2006
tinuation of our efforts, herein we report a facile and high-
yielding total synthesis of ent-9-deoxygoniopypyrone.
Abstract: Stereoselective synthesis of (–)-9-deoxygoniopypyrone
was achieved from the naturally occurring L-(+)-tartaric acid. Key
step involves the elaboration of a g-hydroxybutyramide to the title
compound involving high-yielding stereoselective transformations.
Our approach for the synthesis of (–)-9-deoxygoniopy-
pyrone is based on the cyclization of diol 4, which can be
Key words: styryllactone, (–)-9-deoxygoniopypyrone, stereoselec- obtained from the acryloyl ester 13 by a ring-closing
tive reduction, tartaric acid
metathesis reaction. Synthesis of the ester 13 was antici-
pated from the elaboration of the a-hydroxy ester 8. Bis-
dimethylamide 5 derived from L-(+)-tartaric acid was
envisaged as the starting point for the synthesis of 8
(Scheme 1).
Trees of genus Goniothalamus of the plant family Annon-
aceae have been known for a long time as a source of
potent biologically active styryllactones.1 The extracts
and leaves from these plants have traditionally been used
in folk medicine to treat various ailments. The research
group of McLaughlin isolated a series of styryllactones,
possessing marginal to significant cytotoxic, antitumour,
pesticidal, ratogenic and embryotoxic activities. These
styryllactones can be mainly classified into two groups,
on the basis of the size of the lactone ring. Amongst the
group comprising the six-membered lactones, 9-deoxygo-
niopypyrone (1), goniopypyrone (2), and goniodiol (3)
(Figure 1), isolated from the ethanol extract of the stem
bark of Goniothalamus giganteus showed considerable
antitumor activity.2 The unique structural feature and the
associated bioactivity made lactone 1 an interesting syn-
thetic target.
H
OH
O
O
Ph
O
Ph
O
O
O
Ph
O
O
O
OH
HO
(–)-1
H
O
4
13
O
O
OH
NMe2
Me2N
OMe
Ph
O
O
O
O
5
8
Scheme 1 Retrosynthesis for (–)-9-deoxygoniopypyrone
The synthetic sequence commenced with the known g-hy-
droxybutyramide 6, readily obtained from the bisdi-
methylamide 5, derived from tartaric acid employing a
combination of selective Grignard addition and a stereo-
selective reduction.4a
O
H
H
O
O
OH
O
Ph
HO
O
Ph
O
O
Ph
O
HO
HO
H
OH
goniodiol (3)
H
Deprotection of acetonide with concomitant hydrolysis of
the amide to the methyl ester within 6 was achieved in
refluxing MeOH–benzene with p-toluenesulfonic acid to
afford the trihydroxy ester 7 in 88% yield.5 Treatment of
the trihydroxy ester 7 with 2,2-dimethoxypropane result-
ed in the a-hydroxy ester 8 in 96% yield (Scheme 2).
9-deoxygoniopypyrone (1)
goniopypyrone (2)
Figure 1 Cytotoxic styryllactones isolated from Goniothalamus
giganteus
Asymmetric hetero-Diels–Alder reaction,3a asymmetric
allylation3b and asymmetric dihydroxylation3c were em-
ployed as key reactions in the recent syntheses of 9-de-
oxygoniopypyrone. Syntheses starting from abundant
chiral compounds such as, glyceraldehyde and mandelic
acid have also been reported.3d,e As part of our program
involving the asymmetric synthesis of styryllactones, we
recently accomplished the total synthesis of 7-epi-gonio-
fufurone and goniothalesdiol from tartaric acid.4 In con-
The free hydroxyl group in 8 was protected as the corre-
sponding tert-butyldimethylsilyl ether 9 using the stan-
dard conditions. Reduction of the ester 9 with DIBAL-H
furnished the alcohol 10 in almost quantitative yield. Con-
version of the alcohol 10 to the corresponding tosylate,
followed by deprotection of the silyl group with TBAF
produced the epoxide 11 in 95% yield. Reaction of the ep-
oxide 11 with vinylmagnesium bromide in the presence of
CuI afforded the homoallylic alcohol 12, which on reac-
tion with acryloyl chloride resulted in the ester 13 in 75%
yield. Ring-closing metathesis (RCM) of 13 with Grubbs’
first-generation catalyst yielded the lactone 14 in 52%
SYNLETT 2007, No. 7, pp 1112–1114
Advanced online publication: 13.04.2007
DOI: 10.1055/s-2007-973873; Art ID: D35606ST
© Georg Thieme Verlag Stuttgart · New York
2
4.
0
4.
2
0
0
7

LETTER
Stereoselective Total Synthesis of (–)-9-Deoxygoniopypyrone
1113
HO
O
O
O
PTSA (1.5 equiv)
ref. 4a
NMe2
NMe2
Ph
Me2N
MeOH–benzene (1:1)
reflux, 5 h, 88%
O
O
O
O
5
6
MeO
MeO
PTSA (10 mol%)
O
OH
OH OH
OMe
OMe
Ph
Ph
O
O
CH2Cl2, r.t., 1 h, 96%
OH
O
8
7
Scheme 2 Synthesis of methyl-a,b,g-trihydroxy-g-phenylbutyrate
yield, while employing Grubbs’ second-generation cata- In summary, (–)-9-deoxygoniopypyrone was prepared in
lyst afforded the lactone in 76% yield.6 Deprotection of 30% overall yield from g-hydroxybutyramide 6, readily
25
the acetonide group in 14 afforded the diol 4, {[a]D
obtained from tartaric acid dimethylamide. Further
+12.9 (c = 0.7, CHCl3); lit.2 [a]D –13.7 (c = 0.7, application of this strategy in the synthesis of other styryl-
CHCl3)}, which on treatment with DBU furnished ent-9- lactones is underway.
25
25
deoxygoniopypyrone (1), {[a]D –12 (c = 0.5, EtOH);
lit3d [a]D25 +12 (c = 0.1, EtOH for the enantiomer)} in 91%
Acknowledgment
yield (Scheme 3).7
We thank CSIR, New Delhi for funding of this project.
O
OH
References and Notes
TBDMSCl, imidazole
O
OTBDMS
OMe
OMe
DMAP, DMF, r.t.
12 h, 95%
(1) For a review on the cytotoxic activity and other bioactivity
of styryllactones, see: (a) Mereyala, H. B.; Joe, M. Curr.
Med. Chem. Anti-Cancer Agents 2001, 1, 293.
(b) Blàzquez, M. A.; Bermejo, A.; Zafra-Polo, M. C.; Cortes,
D. Phytochem. Anal. 1999, 10, 161.
(2) Fang, X.-P.; Anderson, J. E.; Chang, C.-J.; McLaughlin, J.
L.; Fanwick, P. E. J. Nat. Prod. 1991, 54, 1034.
Ph
Ph
O
O
O
O
8
9
i) TsCl (2 equiv), pyridine
r.t., 12 h, 98%
O
OTBDMS
OH
DIBAL-H, toluene
–78 °C to r.t., 1 h, 94% Ph
ii) TBAF( 2 equiv), THF
0 °C to r.t., 11 h, 96%
(3) For recent synthesis of 9-deoxygoniopypyrone, see:
(a) Yamashita, Y.; Saito, S.; Ishitani, H.; Kobayashi, S. J.
Am. Chem. Soc. 2003, 125, 3793. (b) Ramachandran, P. V.;
Chandra, J. S.; Reddy, M. V. R. J. Org. Chem. 2002, 67,
7547. (c) Chen, J.; Lin, G.-Q.; Wang, Z.-M.; Liu, H.-Q.
Synlett 2002, 1265. (d) Tsubaki, M.; Kanai, K.; Nagase, H.;
Honda, T. Tetrahedron 1999, 55, 2493. (e) Survivet, J.-P.;
Vatèle, J.-M. Tetrahedron 1999, 55, 13011. (f) Mukai, C.;
Hirai, S.; Hanaoka, M. J. Org. Chem. 1997, 62, 6619.
(4) (a) Prasad, K. R.; Gholap, S. L. Synlett 2005, 2260.
(b) Prasad, K. R.; Gholap, S. L. J. Org. Chem. 2006, 71,
3643.
(5) For the synthesis of a,b-dihydroxy-g-alkyl(aryl)-g-
butyrolactones from g-hydroxybutyramides, see: Prasad, K.
R.; Chandrakumar, A. Tetrahedron 2007, 63, 1798.
(6) To circumvent the use of expensive Grubbs’ second-
generation catalyst in the synthesis of lactone 14, an
alternate route for 14 from alcohol 12 was examined. As
shown below (Scheme 4), homoallylic alcohol 12 was
protected as its allyl ether, which underwent smooth RCM
reaction with Grubbs’ first generation catalyst to yield the
dihydropyran 15 in 90% yield. PCC oxidation of the
dihydropyran 15 resulted in the lactone 14 in 44% yield
(72% based on recovered starting material).
O
10
MgBr
3 equiv
Ph
H2C=CHCOCl
O
O
CuI (10 mol%)
O
OH
NEt3, DMAP
Ph
THF, –30 °C
1 h, 93%
CH2Cl2, 0 °C
2 h, 75%
O
O
11
12
O
O
Grubbs' II catalyst
(3 mol%)
O
O
O
O
toluene, reflux
8 h, 76%
Ph
Ph
O
O
13
14
O
H
TFA ( 2 equiv)
CH2Cl2, 0 °C
O
OH
O
DBU (cat.), THF
r.t., 1 d, 91%
Ph
O
30 min, 87%
Ph
O
HO
OH
H
4
(–)-1
Scheme 3 Synthesis of (–)-9-deoxygoniopypyrone
Synlett 2007, No. 7, 1112–1114 © Thieme Stuttgart · New York

1114
K. R. Prasad, M. G. Dhaware
LETTER
exchangeable with D2O), 1.55 (s, 3 H), 1.50 (s, 3 H). 13
NMR (75 MHz): d = 172.7, 136.9, 128.6, 128.4, 126.6,
C
i) NaH, allyl bromide
THF, 0 °C, 5 h, 92%
O
OH
109.8, 83.6, 78.4, 67.6, 52.6, 27.1, 26.5. HRMS: m/z [M +
Na] calcd for C14H18O5: 289.1054; found: 289.1052.
Compound 12: [a]D25 –18.9 (c = 0.9, CHCl3). 1H NMR (300
MHz, CDCl3): d = 7.27–7.44 (m, 5 H), 5.68–5.84 (m, 1 H),
4.94–5.07 (m, 3 H), 3.76 (ddd, J = 1.2, 2.4, 8.4 Hz, 1 H),
3.58–3.68 (m, 1 H), 2.13–2.35 (m, 3 H), 1.58 (s, 3 H), 1.53
(s, 3 H). 13C NMR (75 MHz): d = 137.6, 134.2, 128.6, 128.3,
126.9, 117.8, 109.2, 84.9, 79.3, 68.0, 39.6, 27.2, 27.0.
HRMS: m/z [M + Na] calcd for C15H20O3: 271.1312; found:
271.1310. Compound 14: [a]D25 –5.0 (c = 0.4, CHCl3). 1H
NMR (400 MHz, CDCl3): d = 7.31–7.46 (m, 5 H), 6.87 (ddd,
J = 2.5, 5.9, 9.6 Hz, 1 H), 6.04 (dd, J = 2.5, 9.6 Hz, 1 H), 5.24
(d, J = 8.6 Hz, 1 H), 4.42 (ddd, J = 2.5, 4.2, 11.7 Hz, 1 H),
3.82 (dd, J = 2.0, 8.6 Hz, 1 H), 2.63–2.75 (m, 1 H), 2.20–2.30
(m, 1 H), 1.59 (s, 3 H), 1.55 (s, 3 H). 13C NMR (100 MHz):
d = 163.6, 144.8, 137.1, 128.8, 128.6, 126.8, 121.2, 110.0,
83.9, 77.5, 73.5, 27.3, 26.7, 26.6. HRMS: m/z [M + Na] calcd
for C16H18O4: 297.1105; found: 297.1103.
O
O
Ph
ii) Grubbs' I catalyst (10 mol%)
CH2Cl2, r.t., 5 h, 90%
Ph
O
12
O
15
O
PCC (3 equiv)
pyridine (3 equiv)
44% yield
(72% based on
recovered starting material)
O
O
CH2Cl2, reflux, 8 h
Ph
O
14
Scheme 4
(7) All new compounds exhibited satisfactory spectral data.
Compound 8: [a]D25 –44.0 (c = 1, CHCl3). 1H NMR (300
MHz, CDCl3): d = 7.25–7.48 (m, 5 H), 5.12 (d, J = 8.4 Hz, 1
H), 4.11 (d, J = 8.4 Hz, 1 H), 4.04 (dd, J = 0.9, 8.4 Hz, 1 H),
3.74 (s, 3 H), 3.25 (dd, J = 1.8, 9.0 Hz, 1 H, OH,
Synlett 2007, No. 7, 1112–1114 © Thieme Stuttgart · New York

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