Total synthesis of (R)-(+)-goniothalamin and (R)-(+)-goniothalamin oxide: first application of the sulfoxide-modified Julia olefination in total synthesis

Article abstract of DOI:10.1016/j.tetlet.2006.06.054

A short and efficient synthesis of (R)-(+)-goniothalamin 1 and (R)-(+)-goniothalamin oxide 2 is described. During this approach, the sulfoxide-modified Julia olefination was used as a key step to connect aldehyde 5 to sulfoxide 6. The desired styryl-containing adduct is obtained in good yield and with excellent E/Z selectivity.

Full text of DOI:10.1016/j.tetlet.2006.06.054

Tetrahedron Letters 47 (2006) 5933–5937
Total synthesis of (R)-(+)-goniothalamin and
(R)-(+)-goniothalamin oxide: first application of the
sulfoxide-modified Julia olefination in total synthesis
*
´
´ˇ
´
´
Jirˇı Pospısil and Istvan E. Marko
ˆ
Universite´ catholique de Louvain, De´partement de Chimie, Batiment Lavoisier, Place Louis Pasteur 1,
B-1348 Louvain-la-Neuve, Belgium
Received 5 May 2006; revised 26 May 2006; accepted 8 June 2006
Available online 30 June 2006
Abstract—A short and efficient synthesis of (R)-(+)-goniothalamin 1 and (R)-(+)-goniothalamin oxide 2 is described. During this
approach, the sulfoxide-modified Julia olefination was used as a key step to connect aldehyde 5 to sulfoxide 6. The desired styryl-
containing adduct is obtained in good yield and with excellent E/Z selectivity.
Ó 2006 Elsevier Ltd. All rights reserved.
Chiral lactones are commonly present in a number of
natural and synthetic products, including various phero-
mones and medicinal compounds. Interestingly, these
small exogenous molecules exert powerful effects on
the cell functions, making them useful tools for under-
standing life processes and for treating life-threatening
diseases.
O
O
O
O
O
(
R
)-(+)-goniothalamin 1
(R
)-(+)-goniothalamin oxide 2
O
O
Styryl lactones are a group of secondary metabolites
commonly isolated from the genus Goniothalamus.1
Recent studies have demonstrated that these compounds
display cytotoxic and antitumour properties. (R)-(+)-
Goniothalamin 1 is a typical representative of this class
of compounds (Fig. 1).
O
O
OH
O
OH
OH
(+)-4-dehydroxygoniotriol 3
Ph
(+)-9-deoxygoniopypyrone 4
(R)-(+)-Goniothalamin 1 was isolated in 1967 from the
dried bark of Cryptocarya caloneura2 and given the (S)-
configuration. A decade later, the configuration of the
stereocentre was revised and established as being (R).3
Later on, (R)-(+)-1 was isolated from Cryptocarya mos-
chata,4 Bryonopsis laciniosa5 and various other species of
Goniothalamus6 (115 species7 distributed throughout the
tropics and subtropics). Some of the isolated goniothal-
amin-based derivatives are shown in Figure 1.
Figure 1. Some of the isolated goniothalamin-based derivatives.
(R)-(+)-Goniothalamin 1 displays in vitro cytotoxic
effects on different cell lines, including MCF-7, T47D
and MDA-MB-231 (breast carcinoma), HeLa cells (hu-
man cervical carcinoma), gastric carcinoma (HGC-27),
leukemia carcinoma (HL-60) and ovarian carcinoma
(Caov-3).1a,8,9b This cytotoxic activity, which results
from the selective induction of apoptosis9 on the cancer
cell lines, was shown to be surprisingly low on nonmalig-
nant cells.
Keywords: Goniothalamin; Julia olefination; Sulfoxide; Goniothalamin
In vivo studies revealed that (R)-(+)-1 possessed tumouri-
cidal and tumouristatic properties on Sprague–Dawley
oxide; Metathesis.
*
Corresponding author. E-mail: marko@chim.ucl.ac.be
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.06.054

5934
J. Pospı´sˇil, I. E. Marko´ / Tetrahedron Letters 47 (2006) 5933–5937
rats with 7,12-dimethylbenzanthracene (DMBA)-in-
duced mammary tumours.10
O
O
sulfoxide-
modified Julia
olefination
1
2
3
O
S
O
2
3
O
7
+
Ph
Due to the interesting biological activity of (R)-1, sev-
eral successful approaches to this natural product have
been reported.11 Even though the most commonly used
antithetic approach to 1 is based on the C2–C3 and/or
C6–C7 double bond disconnections (Fig. 2), other meth-
ods, such as asymmetric hetero-Diels–Alder cycloaddi-
tions and intramolecular nucleophilic additions to
ketenes, have been employed.
O
Ph
5
Ph
4
6
6
6
5
(R)-(+)-goniothalamin 1
O
2
3
O
O
OPG
6
6
OPG
4
8
Our interest in the total synthesis of (R)-(+)-1 arose
from the observation that all previous syntheses, that
relied upon various olefination methods to establish
the C6–C7 double bond, provided the styryl lactone
either in poor yields and/or with mediocre selectiv-
ity.11a,1 It was surmised that our recently developed sulf-
oxide-modified Julia olefination might serve as an ideal
method to accomplish the desired olefination in high
yield and selectivity.12 The successful implementation
of this approach will also enable us to prepare rapidly
a varied library of goniothalamin 1 analogues from a
common precursor, aldehyde 5.
7
Scheme 1. Retrosynthesis of (R)-(+)-goniothalamin 1.
To test the generality of our approach, it was decided
to also evaluate the influence of four commonly used
protecting groups (Bn, PMB, TBS and TBDPS) on the
yields and selectivity of this sequence.
Our synthesis began with commercially available (R)-
glycidol 9, which was protected with PMB, TBS and
TBDPS-groups, yielding the corresponding epoxy ethers
8b–d (Scheme 2).13 Copper-catalyzed opening of epoxi-
des 8 with vinyl magnesium bromide furnished the opti-
cally enriched homoallylic alcohols 10a–d in excellent
yields and purities.
Our retrosynthesis of (R)-(+)-1 is presented in Scheme 1.
(R)-(+)-Goniothalamin 1 was disconnected at the C6–
C7 bond, leading to aldehyde 5 and sulfoxide 6. It was
envisioned that aldehyde 5 might be easily assembled
from the optically pure glycidol ether 8 via a ring open-
ing/acylation/metathesis sequence. The benzylic sulfox-
ide 6 would be readily prepared by oxidation of the
corresponding, commercially available, sulfide.
Acylation of alcohols 10a–d, using either acryloyl chlo-
ride or acrylic acid, afforded smoothly the metathesis
precursors 7a–d (Scheme 3).
Finally, the metathesis step was evaluated. It was ob-
served that the nature of the protecting group in sub-
strate 7 had a significant influence on the reaction rate
(Table 1). Indeed, when the benzyl protected ester 7a
was treated with the 1st generation Grubbs’ catalyst
(GC-1), only poor conversion of 7a into 11a was ob-
served (Table 1, entry 1). It was thought that the lone
pairs of the oxygen present in the benzyl ether function14
could compete with the olefins for the vacant coordina-
tion sites present in GC-1. Even though this process is
reversible, it decreases the reaction rate by sequestering
O
1
2
O
7
3
5
4
6
(R)-(+)-goniothalamin 1
Figure 2. Most common (R)-(+)-goniothalamin
1
retrosynthetic
disconnections.
MgBr
(1.5 eq)
OH
O
O
OPG
6
OH
OPG
6
6
CuCN (0.2 eq)
THF, -20 ˚C
4
4
4
9
8
10a, PG = Bn, 99%
Yielda
[%]
10b, PG = PMB, 99%
10c, PG = TBS, 99%
10d, PG = TBPDS, 99%
Entry
Product
PG
Conditions
-
b
1
2
8a
8b
Bn
-
NaH, PMBCl
TBAI, DMF
PMB
86
99
99
TBSCl, Im,
CH2Cl2
3
4
8c
8d
TBS
TBDPSCl, Im,
CH2Cl2
TBDPS
a Refers to pure isolated compounds
b Commercially available compound
Scheme 2. Synthesis of homoallylic alcohols 10.

J. Pospı´sˇil, I. E. Marko´ / Tetrahedron Letters 47 (2006) 5933–5937
5935
Table 2. Deprotection of alcohol 11
O
O
O
O
OH
O
X
OPG
X
OPG
6
4
6
4
O
O
OPG
OH
6
4
6
4
10
PG
Bn
7
Yielda
[%]
11
12
Product
Entry
Conditions
Entry
PG
Conditions
FeCl3, CH2Cl2, rt, 5 min
BCl3, CH2Cl2, ꢀ78 °C, 2 h
DDQ, CH2Cl2, rt, 2.5 h
TBAF, THF, 0 °C, 3 h
TBAF, DMF, 0 °C, 12 h
TBAF, DMF, 0 °C, 12 h
Yielda (%)
DCC, CH2Cl2, r.t.,12 h
DCC, CH2Cl2, r.t.,12 h
1
2
3
4
OH
OH
Cl
7a
7b
7c
7d
94
91
89
91
1
2
3
4
5
6
Bn
Bn
80
83
92
43
87
88
PMB
TBS
TEA, CH2Cl2, 0 ˚C, 30 min
TEA, CH2Cl2, 0 ˚C, 30 min
PMB
TBS
TBS
TBDPS
Cl
a Refers to pure isolated compounds
TBDPS
Scheme 3. Synthesis of metathesis precursors 7.
a Refers to pure, isolated compounds.
the catalyst, resulting in a competitive thermal decom-
position of the ruthenium species and therefore requir-
ing a higher catalyst loading.
of the benzyl group was efficiently accomplished, in the
presence of the activated olefins, by treatment of 11a
with FeCl3 (Table 2, entry 1).16 Unfortunately, this reac-
tion proved to be temperamental17 and an alternative
method, using BCl3, was employed (Table 2, entry 2).
To overcome this problem, and as originally proposed
by Furstner, Ti(OPri) was added as an additive15 with
¨
4
the aim of preferentially blocking the ether oxygen lone
pairs. In the event, treatment of substrate 7a with GC-1/
Ti(OPri)4 resulted in the smooth formation of the
desired lactone 11a in 92% yield (Table 1, entry 2).
Pleasingly, DDQ-mediated deprotection of the PMB
group proceeded smoothly, yielding alcohol 12 in 92%
yield (Table 2, entry 3).
The unravelling of both silicon-containing substrates
was achieved using TBAF. Interestingly, it was observed
that the polarity of the solvent strongly influenced the
product distribution (Table 2, entries 4–6). Indeed, when
THF was used as a solvent, a large amount of noniden-
tified side products were generated, accompanied by the
desired alcohol 12, which was isolated in only 43% yield
(Table 2, entry 5). On the other hand, if DMF was em-
ployed as the solvent,18 TBAF-mediated deprotection of
11c and d cleanly furnished alcohols 12 in 87% and 88%
yields, respectively.
A similar situation was encountered with the PMB-pro-
tected derivative 11b (Table 1, entries 3–5), though in
this case, even the use of GC-1/Ti(OPri)4 did not lead
to complete conversion of 7b to 11b. Therefore, the
more reactive 2nd generation Grubbs’ catalyst (GC-2)/
Ti(OPri)4 had to be employed (Table 1, entry 5).
As for the TBS and TBPDS-containing substrates 7c
and d, the addition of Ti(OPri)4 was unnecessary since
the steric bulk of these protecting groups effectively
inhibits any undesired interaction between the ether
and Grubbs’ catalyst (Table 1, entries 6 and 7).
Swern oxidation of alcohol 12 yielded the unstable alde-
hyde 5, which was immediately reacted with sulfoxide 6
under our standard sulfoxide-modified Julia olefination
sequence, producing (R)-(+)-goniothalamin 119 in 78%
yield (starting from alcohol 12) and with excellent
E/Z-selectivity (Scheme 4).
Having obtained lactones 11a–d, we next investigated
their selective deprotection (Table 2). Initially, removal
Table 1. Optimization of the metathesis reaction
It is important to note that our sulfoxide-modified Julia
olefination afforded the natural product (R)-(+)-1 with
both an excellent yield and nearly perfect control of
the C6–C7 double bond geometry. Such an observation
stands in sharp contrast to the results obtained using
alternative olefination methods, such as Wittig, classical
Julia and Kociensky–Julia protocols, which accom-
plished this transformation either in low yields and/or
modest selectivity (Table 3).
O
O
O
O
Δt
OPG
6
4
OPG
6
4
CH2Cl2, 15 h
7
11
Entry PG
Grubb’s cat. Additive Product Yielda (%)
(equiv)
1
2
3
4
5
6
7
Bn
Bn
PMB
PMB
PMB
TBS
GC-1 (0.1)
GC-1 (0.1)
GC-1 (0.1)
GC-1 (0.1)
—
11a
Ti(OPri)4 11a
11b
Ti(OPri)4 11b
45
92
<10
78
99
96
Since it is known that (R)-(+)-goniothalamin 1 is a pre-
cursor to other related natural products,20 its stereo-
selective conversion to (R)-(+)-goniothalamin oxide 2
was attempted. After brief optimization of the reaction
conditions, (R)-(+)-goniothalamin oxide 2 was isolated
in 98% yield in a satisfactory 19:1 diastereomeric ratio
(Table 4).
—
GC-2 (0.05) Ti(OPri)4 11b
GC-1 (0.1)
—
—
11c
11d
TBDPS GC-1 (0.1)
89
a Refers to pure, isolated compounds.

5936
J. Pospı´sˇil, I. E. Marko´ / Tetrahedron Letters 47 (2006) 5933–5937
O
O
O
1) LDA (1.1 eq), 6 (1.0 eq)
THF, -78 ˚C, 30 min
2) 5 (1.05 eq), -78 ˚C, 2 h
O
Swern ox.
O
O
O
OH
6
4
3) BzCl (1.5 eq), -78 ˚C to r.t.
4) Me2N(CH2)3NH2 (1.55 eq)
5) SmI2 (4.0 eq), HMPA (4.0 eq)
THF, -78 ˚C, 30 min
Ph
12
5
(R)-(+)-Goniothalamin 1
78% over two steps
E/Z = >98:1
Scheme 4. Sulfoxide-modified Julia olefination.
Table 3. Comparison of the various olefination methods in the context
of the synthesis of (R)-(+)-goniothalamin
properties of the phenyl group strongly influence the
biological activity of this family of natural products,
our approach enables the efficient assembly of a variety
of goniothalamin 1 analogues by uniting the common
intermediate 5 with a range of different sulfoxides 6.
O
O
O
O
O
Ph
Finally, (R)-(+)-goniothalamin oxide 2 has been ob-
tained in excellent yield by diastereoselective epoxida-
tion of (R)-(+)-1.
(R
)-Goniothalamin 1
5
Entry Olefination
Conditions
Yield E/Z
(%)
1a
2b
3a
4
Wittig
Wittig
BnPPh3þClꢀꢀ; n-BuLi 53
1:3
1:9
>98:1
n.d.
BnPPh3þBr ; n-BuLi 57
Acknowledgements
Kociensky–Julia PTSO2Bn, KHMDS
Julia
Sulfoxide–Julia
18
<5
78
BnSO2Ph
BnS(O)Ph
´
Financial support of this work by the Universite
5
>98:1
catholique de Louvain, Rhodia Ltd. (studentship to
J.P.) and SHIMADZU Benelux (financial support for
the acquisition of a FTIR-8400S spectrometer) is grate-
fully acknowledged.
a Ref. 11l.
b Ref. 11a.
Table 4. Total synthesis of (+)-goniothalamin oxide 2
Supplementary data
O
O
Supplementary data associated with this article can
be found, in the online version, at doi:10.1016/j.tetlet.
2006.06.054.
O
O
O
Ph
Ph
(R)-(+)-goniothalamin 1
(R)-(+)-goniothalamin oxide 2
Entry Conditions
Yield dr
(%)
References and notes
m-CPBAa (4.0 equiv), CH2Cl2, D, 4 h
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69
97
3:2
10:1
19:1
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J = 6.5 Hz, J = 1.2 Hz), 6.10 (dt, 1H, J = 9.7 Hz,
J = 1.7 Hz), 6.29 (dd, 1H, J = 16.1 Hz, J = 6.5 Hz), 6.74
(d, 1H, J = 15.8 Hz), 6.94 (dt, 1H, J = 9.7 Hz,
J = 4.4 Hz), 7.30–7.42 (m, 5H). 13C NMR (75 MHz,
CDCl3) d (ppm): 30.1, 78.1, 121.9, 125.8, 133.3, 144.8,
126.9–136.0 (arom. CH and Cq), 164.1. Mp = 82–83 °C;
lit.11l 81–82 °C. MS (APCI), m/z (%): 201.0 (39) [M++H],
20
10. Meenakshii, N.; Lee, A.; Azimahtol, H. L. P.; Hasidah, S.
Malays. Appl. Biol. 2000, 29, 121–126.
11. Selected examples: (a) O’Connor, B.; Just, G. Tetrahedron
Lett. 1986, 27, 5201–5202; (b) Bennet, F.; Knight, D. W.
Tetrahedron Lett. 1988, 29, 4625–4828; (c) Bennett, F.;
183.1 (100), 155.2 (66), 130.1 (41). ½aꢁD +169.8 (c 1.45,
25
CHCl3); lit.6c ½aꢁD +170.3 (c 1.38, CHCl3).
20. Lan, Y.-H.; Chang, F.-R.; Yu, J.-H.; Yang, Y.-L.; Chang,
Y.-L.; Lee, S.-J.; Wu, Y.-C. J. Nat. Prod. 2003, 66, 487–
490.