A short and general approach to the synthesis of styryllactones: (+)-Goniodiol, its acetates and β-trifluoromethyl derivative, (+)-7-epi-Goniodiol and (+)-9-deoxygoniopypyrone

Article abstract of DOI:10.1055/s-2002-32977

(+)-Goniodiol, its acetates and β-trifluoromethyl derivative, (+)-7-epi-Goniodiol and (+)-9-deoxygoniopypyrone, the representatives of styryllactones have been synthesized in a short and general way. The key steps involve the regioselective asymmetric dihydroxylation and the palladium-catalyzed cross-coupling of cyclic allylic carbonate with vinyltributylstannane.

Full text of DOI:10.1055/s-2002-32977

LETTER
1265
A Short and General Approach to the Synthesis of Styryllactones:
(+)-Goniodiol, its Acetates and -Trifluoromethyl Derivative, (+)-7-epi-
Goniodiol and (+)-9-Deoxygoniopypyrone
A
S
hort an
i
d Gen
a
ral
A
pproa
n
c
h
to the
S
ynthesis
C
of Styryllactone
h
s
en, Guo-Qiang Lin,* Zhi-Min Wang, Han-Quan Liu
Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 354 Fenglin Road, Shanghai, 200032, P. R. China
Fax +86(21)64166263; E-mail: lingq@pub.sioc.ac.cn
Received 26 May 2002
O
Abstract: (+)-Goniodiol, its acetates and -trifluoromethyl deriva-
OR1
O
tive, (+)-7-epi-Goniodiol and (+)-9-deoxygoniopypyrone, the rep-
resentatives of styryllactones have been synthesized in a short and
general way. The key steps involve the regioselective asymmetric
dihydroxylation and the palladium-catalyzed cross-coupling of cy-
clic allylic carbonate with vinyltributylstannane.
19, R1=Ac, R2=H;
24, R1=H, R2=Ac.
8, R1=R2=H;
25, R1=R2=Ac;
OR2
O
O
H
H
O
OH
O
OH
O
O
Key words: (+)-Goniodiol, styryllactones, synthesis, asymmetric
dihydroxylation, cross-coupling
O
CF3
HO
OH
29
H
OH
16
31
Figure
The Asian trees of the genus Goniothalamus have long
been recognized as a source of chemotherapeutic agents.
The extracts from leaves of Goniothalamus have tradi-
tionally been used for the treatment of edema and rheuma-
tism,1a as well as a pain killer and arbortifacient.1b,c Recent
publications by McLaughlin2 have disclosed the isolation
and characterization of a number of novel so-called styryl-
lactones from Goniothalamus giganteus, which were
found to be marginally to significantly cytotoxic against
various human tumors. Because of their unique structural
features and potent biological activities, much efforts
have been centered on the development of methodology
for the synthesis of these styryllactones.3 Most of the syn-
thetic strategies in the literatures are starting from chiral
materials, such as sugars, tartaric acid, mandelic acid and
2,3-O-isopropylidene-D-glyceraldehyde.4 Herein, we de-
scribe a short and general route to asymmetric synthesis of
the representatives of styryllactones, such as (+)-Goniodi-
ols (8, 19, 16, 24, 25), (+)-7-epi-goniodiol (29) and (+)-9-
deoxygoniopypy-rone (31) (Figure), where the key steps
involve the regioselective asymmetric dihydroxylation
and the palladium-catalyzed cross-coupling of cyclic al-
lylic carbonate with vinyltrimethylstananne.
the double bond distal to the aromatic ring (Scheme 1).
This preference for attacking the outer double bond is not
surprising given that oxidation occurred at the internal site
leading to greater disruption of conjugation. In contrast, in
the case of -naphthyl substituted diene 2a the internal
double bond is oxidized predominantly, implying that the
‘disruption of conjugation’ effect has somehow been
overcome. They attributed this preference for dihydroxyl-
ation of the internal double bond to favorable stacking in-
teractions between the naphthyl group and the binding
pocket of the phthalazine ligand.
OH
OH
AD
OH
OH
1c
1a
1b
:
Ratio
1
4 (92% ee)
OH
OH
AD
OH
OH
2b
2a
2c
Our synthesis began with the enantioselective dihydroxyl-
ation of (E)-1-phenyl-1, 3-butadiene 3a. Olefins with con-
jugated aromatic substituents are of particular interest as
substrates for the asymmetric dihydroxylation since the
products obtained are always encountered with high ees
together with unpredictable regioselectivities.5a–c Sharp-
less reported5a that regioselectivities of the asymmetric di-
hydroxylation of these conjugated aromatic dienes, such
as compound 1a, showed a slightly greater preference for
1
Ratio
4 (98% ee) :
Scheme 1 Asymmetric dihydroxylation of conjugated dienes using
(DHQD)2-PHAL as ligand at 0 °C.
We therefore were interested in exploration of the situa-
tion of asymmetric dihydroxylation taken place on the ter-
minal conjugated double bonds such as the substrate (E)-
1-phenyl-1, 3-butadiene 3a.6 The dihydroxylation oc-
curred smoothly which resulted in a slightly greater pref-
erence for the internal double bond with a ratio of 2.2 to 1
and an ee of 95% for the major product 3b, when phthal-
azine ligands were used (Scheme 2). We rationalized this
‘disruption of conjugation’ due to the preference of the
Synlett 2002, No. 8, Print: 30 07 2002.
Art Id.1437-2096,E;2002,0,08,1265,1268,ftx,en;U01202ST.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0936-5214

1266
J. Chen et al.
LETTER
phthalazine ligands for trans-disubstituted double bond
to terminal double bond. Moreover, when the general
phthalazine ligands were changed to the terminal double
bond preferred pyridine ligands5d without addition the
usual used additive of methyl sulfonyl amide, the asym-
metric dihydroxylation proceeded in the result of a mod-
erate preference for oxidation of the outer terminal double
bond with the ratio of 1:2.5 without remarkable decrease
in the ee for both compounds 3b and 3c (Table).7 In con-
clusion, these different results obtained could be tentative-
ly rationalized in term of the presence of the terminal
double bond of substrate 3a.
O
O
OH
Bu3Sn
CO2Me
5
a
b
O
OH
4
3b
OH
OH OH
OH
c
CO2Me
CO2Me
6
7
O
OH
O
d
(+)-Goniodiol
OH
8
Scheme 3 Reagents and conditions: a) triphosgene, Et3N, CH2Cl2,
0 °C, 2 h, 98%; b) PdCl2(CH3CN)2 (5 mol%), 1.2 equiv 5, DMF/H2O
(4:1), 0 °C, 1 h, 71%; c) AD-mix- , 83%; d) PTS, toluene, 80 °C,
84%.
Asymmetric dihydroxylation of (E)-1-phenyl-1, 3-butadi-
ene using the phthalazine and pyridine ligands (Scheme 2,
Table).
OH
OH
in two steps procedure.12 Then, 3-iodo-4,4,4-trifluo-2-(Z)-
butenoate 12 was prepared by reaction of 11 with sodium
iodide in a sealed tube below 70 °C with 75% isolated
yield according to literature.13 Finally, addition of 12 to
the solution of Bu3SnCl in DMAC in the presence of acti-
vated zinc dust afforded the building block 13
(Scheme 4).
OH
AD
OH
3c
3a
3b
(2R) for AD-mix-β
(2S) for AD-mix-α
(1R, 2R) for AD-mix-β
(1S, 2S) for AD-mix-α
Scheme 2
Table
Br-
Ph3P
O
CO2Et
CF3
+
F
F
F
O
Ph3P
a
b
Ligands
Yield
3b:3c (Ratio)
2.3:1
3b, 3c (ee, %)
95, 91
CO2Et
OEt
11
10
(DHQ)2-PHAL
(DHQD)2-PHAL
(DHQ)2-PYR
(DHQD)2-PYR
83%
84%
81%
81%
9
Bu3Sn
F3C
CO2Et
I
CO2Et
2.2:1
96, 91
d
c
F3C
1:2.5
92, 91
13
12
1:2.3
92, 90
Scheme 4 Reagents and conditions: a) Et3N, (CF3CO)2O, 0 °C, 2 h,
90%; b) , 150–220 °C, 88%; c) CH3CN, NaI, <70 °C, 6 h, 75%;
d) Bu3SnCl, Zn, DMAC, r.t., 2 h, 83%.
Protection of the diol 3b with triphosgene furnished in
nearly quantitative yield of 4. Then the allylic cyclic car-
bonate 4 was coupled with (Z)-vinyltributylstannane 58 in
the presence of PdCl2(CH3CN)2 (5 mol%) according to
the known protocol9 to afford the (E)-substituted-allylic
alcohol 6, where the chemo-selectivity of E to Z is
97.2:2.8.10 Dihydroxylation of 6 with Sharpless AD-mix-
furnished the triol 7 with high yield and high diastereo-
selectivity (de 96:4). Finally, acidic treatment the com-
pound 7 resulted in the lactone formation to provide the
natural product (+)-goniodiol 8 with an overall yield of
46% in 5 steps. To the best of our knowledge, this is prob-
ably the shortest asymmetric route to goniodiol 8
(Scheme 3).
Palladium-catalyzed cross-coupling of cyclic carbonate 4
with the trifluoromethylated building block 13 provided
the alcohol 14 with the yield of 51%. As the trifluorome-
thyl group possesses powerful electron-withdrawing abil-
ity, the coupling reaction was taken place under prolonged
reaction time and loaded amount of catalyst with lower
yield, compared to that of (Z)-vinyltributylstannane 5 as
substrate. Finally, dihydroxylation of compound 14 fol-
lowed by acid assisted lactonization afforded -trifluo-
romethylgoniodiol 1614 in the same manner as described
in the synthesis of (+)-goniodiol with the overall yield of
31% in three steps from compound 4 (Scheme 5).
(+)-Goniodiol-8-monoacetate, (+)-goniodiol-7-monoace-
tate and (+)-goniodioldiacetate were isolated from the
leaves of Goniothalamus amuyon in 1992,15 belonging to
acetate derivatives of (+)-goniodiol. Simple acetylation of
(+)-goniodiol with acetic anhydride always resulted in
formation of a mixture of them.16 We described herein an
efficient route to synthesize them independently
(Scheme 6).
Trifluoromethylated molecules often confer significant
changes in their chemical and physical properties.11 Upon
the completion of goniodiol 8, we plan to synthesize its -
trifluoromethyl derivatives by changing the vinyltributyl-
stananne 5 to (Z)- -trifluoromethyl -substituted vinyl-
tributylstananne 13 in the palladium catalyzed coupling of
cyclic allylic carbonate with vinyltributylstananne. The
synthesis of 13 was started from ethyl 4,4,4-trifluoro-2-
butynoate 11, which is easily prepared from compound 9
Synlett 2002, No. 8, 1265–1268 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
A Short and General Approach to the Synthesis of Styryllactones
1267
F3C
concerned on the asymmetric synthesis of 7-epi-Goniodi-
ol 29 and (+)-9-deoxygoniopypyrone 31.2b,17 The synthe-
sis started with compound 3c, the other product of
asymmetric dihydroxylation of (E)-1-phenyl-1, 3-butadi-
ene (Scheme 7).
O
OH
CF3
O
Bu3Sn
CO2Me
13
CO2Me
a
O
14
OH
4
O
OH OH CF3
O
b
OH
c
CF3
O
OH
15
CO2Me
OH
a
OH
16
3c
26
Scheme 5 Reagents and conditions: a) PdCl2(CH3CN)2 (10 mol%),
1.5 equiv 13, DMF/H2O, r.t., 12 h, 51%; b) AD-mix- , 81%; c) PTS,
toluene, 80 °C, 83%.
O
OH
OH
c
b
27
OAc
O
O
OH
a
b
O
OH
O
CO2Me 87%
CO2Me
CO2Me
91%
AD-mix-β
6
17
28
29
O
OH
Goniothalamin
7-epi-Goniodiol
OAc OH
OAc O
AD-mix-α
c
O
72%
OH
18
OH
19
Goniodiol-8-monoacetate
OTBS
H
H
O
OH
O
O
OH
O
d
b
OH
HO
H
90%
96%
CO2Me
O
(+)-9-Deoxygoniopypyrone
CO2Me
CO2Me
30
20
TBSO
6
31
OH
TBSO
O
Scheme 7 Reagents and conditions: a) (1) TsCl, Pyridine, –30 °C,
(2) K2CO3, MeOH, r.t., 40 min, 83% in two steps; b) propiolic acid,
LDA (2 equiv), –78 °C to r.t., 94%; c) (1), Lindlar reduction, (2), PTS,
toluene, 80 °C, 81% in two steps.
c
OH
81%
OH
21
22
O
O
O
OH
O
TBSO
The diol 3c was efficiently converted into the terminal
epoxide 26 in two steps by initial treatment with p-tolue-
nesulfonyl chloride followed by stirring with K2CO3 in
MeOH with the overall yield of 83%. The epoxide 26 was
added to a dianion generated from propiolic acid and LDA
to yield an acid 27 with the yield of 94%. Lindlar reduc-
tion of 27 was followed by lactonization to give gonio-
thalamin 28. To our delight, the substrate Goniothalamin
matches phthalazine ligands very well in both AD-mix-
reaction and AD-mix- reaction. Dihydroxylation of go-
niothalamin 28 with AD-mix- reaction ocurred smoothly
to give the natural product 7-epi-goniodiol 29 with the
yield of 87% and 96:4 de. In addition, Dihydroxylation of
goniothalamin 28 with the AD-mix- reaction directly
gave the natural product 9-deoxygoniopypyrone 31 with
the yield of 84% and 94:6 de, although compound 30 is an
isolable compound which maybe due to the in situ het-
eroatom-Michael addition followed by the asymmetric di-
hydroxylation reaction.
e
a
81% from 22
OAc
(+)-Goniodiol-
7-acetate
OAc
23
24
O
(+)-Goniodiol-
8-monoacetate
or
(+)-Goniodiol-
7-monoacetate
OAc O
OAc
a
94-96%
25 (+)-Goniodiol-diacetate
Scheme 6 Reagents and conditions: a) Ac2O, Et3N, cat. DMAP,
0 °C, 1 h; b) AD-mix- , 0 °C, 16 h; c) PTS, toluene, 80 °C; d) TBSCl,
Et3N, DMF, r.t., 6 h, 91%; e) TBAF, THF, r.t.
Protection the C7-OH of 6 with Ac and TBS, followed by
Sharpless AD-mix- dihydroxylation provided the com-
pound 18 and 21, respectively, with high diastereoselec-
tivity (de 95:5). (+)-Goniodiol-8-monoacetate 19 and
compound 22 were obtained via acid assisted lactoniza-
tion in the same manner as described in (+)-goniodiol.
Protection of the 7-OH of compound 22 with Ac followed
by deprotection the TBS protection group provided the
sole natural product (+)-goniodiol-7-monoacetate 24. Fi-
nally, treatment of either (+)-goniodiol-7-monoacetate or
(+)-goniodiol-8-monoacetate with access acetic anhy-
dride gave (+)-goniodioldiacetate 25 successfully.
In summary, we have shown herein a short and general
route to total synthesis of styryllactones: (+)-goniodiols,
7-epi-goniodiol and 9-deoxygoniopypyrone using the
asymmetric hydroxylation and the Pd(0)-catalyzed cross-
coupling of allylic carbonate with vinyltributylstannane
as the key steps.
After completion of (+)-goniodiol and its acetates and -
trifluoromethyl substituted derivatives, our interests were
Synlett 2002, No. 8, 1265–1268 ISSN 0936-5214 © Thieme Stuttgart · New York

1268
J. Chen et al.
LETTER
3b (1-Phenyl-but-3-ene-1,2-diol) for (1S, 2S): [ ]D20 –9.7
to 10.3 (c 0.7, CHCl3). (1R, 2R): [ ]D20 +10.6 to 11.1 (c 0.3,
CHCl3). IR (neat): 3390, 3087, 3032, 1645, 1604, 1495,
1454, 1198, 1126, 1054, 997, 928, 843, 763 cm–1. 1H NMR
(300 MHz, CDCl3): = 7.35 (s, 5 H), 5.7 (m, 1 H), 5.25 (dd,
J = 3.0 Hz, J = 15.8 Hz, 1 H), 5.15 (dd. J = 3 Hz, J = 10 Hz,
1 H), 4.5 (d, J = 7 Hz, 1 H), 4.2 (m, ???H), 3.0 (s, 1 H), 2.7
(s, 1 H). MS (EI): m/z = 164 (M, 7.88), 146 (M – 18, 1.50),
114 (71.83), 107(100), 79 (68.72). HRMS for C10H12O2:
164.0838. E. A for C10H12O2: C, 72.99%; H, 7.27%.
3c (4-Phenyl-but-3-ene-1,2-diol) for (2R): [ ]D24 –38.4 (c
1.8, CHCl3). (2S): [ ]D24 +36.4 (c 1.45, CHCl3). IR (neat):
3341, 3066, 3036, 1638, 1495, 1128, 1087, 942, 813, 751
cm–1. 1H NMR (300 MHz, CDCl3): = 7.37 (s, 5 H), 5,74 (d,
1 H, J = 12.6 Hz), 5.87 (dd, 1 H, J = 12.6 Hz, J = 7.4 Hz),
4.26 (m, 1 H), 3.75 (d, 2 H, J = 6.5 Hz), 3.1 (br, s, 1 H), 2.6
(br, s, 1 H). MS (EI) m/z = 164 (M, 7.88), 146 (M – 18, 1.50),
114 (71.83), 91(100), 79 (68.72). HRMS: Calcd for
C10H12O2: 164.0838. E. A. for C10H12O2: C, 72.92%; H,
7.18%.
Acknowledgement
We acknowledge the financial assistance by the NSFC. We also
thanked Dr. Xin-Sheng Lei and Dr. Hong-Feng Luo for H NMR
performances.
1
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Synlett 2002, No. 8, 1265–1268 ISSN 0936-5214 © Thieme Stuttgart · New York