Application of the Cosford cross-coupling protocol for the stereoselective synthesis of (R)-(+)-goniothalamin, (R)-(+)-kavain and (S)-(+)-7,8-dihydrokavain

Article abstract of DOI:10.1016/j.tetlet.2006.09.122

An efficient and versatile synthetic method has been developed and utilized for the stereoselective synthesis of (R)-(+)-goniothalamin 1, (R)-(+)-kavain 2 and (S)-(+)-7,8-dihydrokavain 3. Application of the Cosford protocol and direct conversion of aldehydes to β-keto-esters are the key steps in our approach.

Full text of DOI:10.1016/j.tetlet.2006.09.122

Tetrahedron Letters 47 (2006) 8599–8602
Application of the Cosford cross-coupling protocol for
the stereoselective synthesis of (R)-(+)-goniothalamin,
(R)-(+)-kavain and (S)-(+)-7,8-dihydrokavainI
Gowravaram Sabitha,* K. Sudhakar and J. S. Yadav
Organic Division I, Indian Institute of Chemical Technology, Hyderabad 500 007, India
Received 18 July 2006; revised 12 September 2006; accepted 21 September 2006
Available online 16 October 2006
Abstract—An efficient and versatile synthetic method has been developed and utilized for the stereoselective synthesis of (R)-(+)-
goniothalamin 1, (R)-(+)-kavain 2 and (S)-(+)-7,8-dihydrokavain 3. Application of the Cosford protocol and direct conversion
of aldehydes to b-keto-esters are the key steps in our approach.
Ó 2006 Elsevier Ltd. All rights reserved.
Carbon–carbon bond forming reactions represent
important processes in organic synthesis. When per-
formed intermolecularly, they are used to couple small
fragments to make larger units. Among the numerous
methods for carbon–carbon bond formation, palla-
dium-catalyzed transformations have come to play a
leading role,1 and one of the most widely applicable
reactions of this type is the arylation of alkynes.
larvicide and also shows a weak antibacterial and signif-
icant antifungal activity against a wide range of gram-
positive and gram-negative bacteria and fungi.9 It is
one of a new class of compounds with potential anti-
cancer properties, displaying cytotoxic, and antitumor
properties.10 (R)-Goniothalamin has shown in vitro
cytotoxic effects, especially through inducing apoptosis
on different cancer cell lines such as cervical carcinoma,
gastric carcinoma, breast carcinoma, leukemia, and
ovarian carcinoma. In vivo studies have shown that
(R)-goniothalamin displays tumoricidal and tumori-
static effects on Prague-Dawley rats with 7,12-dimethyl-
benzanthracene (DMBA)-induced mammary tumors.11
Among the many approaches to goniothalamin,12 sev-
eral utilize the Wittig reaction for construction of the
styryl double bond. Kavain and dihydrokavain are lac-
tones isolated from the Kava plant (Piper methysticum).
The kava lactones are believed to be responsible for the
biological activity, which include local anaesthetic prop-
erties, sedative, analgesic, anticonvulsive, antispas-
modic, antimycotic, antifungal, antithrombotic,13 and
central muscular relaxing properties. This has led to its
popular use in Europe and North America for the treat-
ment of anxiety disorders. Kava root, commonly avail-
able in dietary supplements labeled ‘Kava Kava’, is
also noted for its anxiolytic and soporific qualities.
Kavain and dihydrokavain noncompetitively inhibit
the specific binding of [3H]-b-trachotoxinin-A 20-a-
benzoate to receptor site 2 of voltage-gated Na+ chan-
nels.14 Racemic syntheses of the kava lactones are
numerous,15 but there are fewer enantioselective
Lactone rings constitute structural features of a broad
range of natural products2 that display important bio-
logical activities such as anti-HIV, antifungal, antibacte-
rial, pheromonal, and antitumor properties.3 a-Pyrones
have been utilized as intermediates for synthetic trans-
formations,4 and much attention has been paid to their
synthesis. To the best of our knowledge, this is the first
report of the preparation of 6-substituted lactones using
arylation of acetylenes.
Goniothalamin, a naturally occurring styryl lactone was
isolated in 1967 from the dried bark of Cryptocarya
caloneura.5 Later it was isolated from Cryptocarya mos-
chata,6 Bryonopsis laciniosa7 and various species of
Goniothalamus.8 Goniothalamin is a potent mosquito
Keywords: 6-Substituted lactones; Cosford protocol; Natural products;
Acetylenic alcohol.
q IICT Communication No: 060619.
*
Corresponding author. Tel./fax: +91 40 27160512; e-mail:
sabitha@iictnet.org
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.09.122

8600
G. Sabitha et al. / Tetrahedron Letters 47 (2006) 8599–8602
syntheses of (+)-kavain16 and (+)-dihydrokavain.17
These two kava lactones differ only in the presence or
absence of a double bond linking the two rings.
ter 11 in an 80% yield. The TBDMS group was removed
using TBAF in THF to afford the hydroxy ester, which
on refluxing in benzene in the presence of a catalytic
amount of PTSA afforded the target molecule, gonio-
thalamin 124 in a 75% yield (Scheme 3).
Delighted by a recent report18 on a practical and effi-
cient process for the preparation of tazarotene based
on a Cosford protocol,19 and as a part of our program
on the synthesis of naturally occurring bio-active lac-
tones,20 herein, we report the development of a versatile
method which involves the Cosford cross-coupling pro-
tocol, starting from iodobenzene and an acetylenic alco-
hol. This novel method utilizes heterogeneous palladium
on carbon (Pd/C) as an alternative to the standard
homogeneous catalysts for carbon–carbon bond forma-
tion. The resulting key intermediate 4 was used for the
stereoselective synthesis of goniothalamin, kavain, and
7,8-dihydrokavain21 (Scheme 1).
The synthesis of (+)-kavain 2 started from aldehyde 10,
which was converted into b-keto ester 13 by reaction
with ethyl diazoacetate in the presence of a catalytic
amount of tin(II) chloride.25 The TBDMS group was re-
moved using TBAF to afford d-hydroxy-b-ketoester 14
in an 85% yield. Lactonization of 14 was smoothly
accomplished to furnish the target molecule 226 follow-
ing a reported procedure (Scheme 4).15a
The synthesis of 7,8-dihydrokavain 3 started from the
key intermediate 4. The triple bond of compound 4
was reduced using Pd/C in EtOAc to afford fully satu-
rated alcohol 15 in a 90% yield. The secondary hydroxy
group was protected and the THP group was cleaved
using PPTS in MeOH (Scheme 5). The primary alcohol
was oxidized to the corresponding aldehyde 18 in a
90% yield which was then converted into the target
molecule 327 in analogous three steps as shown in
Scheme 4.
Coupling of iodobenzene 5 and alkyne 622 was achieved
by heating in DME/water solution in the presence of
K2CO3 as base and Pd/C (cat.), CuI (cat.) and PPh3
(0.1 equiv) to afford the propargylic alcohol 423 in a
90% yield (Scheme 2).
The key intermediate 4 was utilized for the synthesis of
1, 2, and 3 as shown in Schemes 3–5. The triple bond in
compound 4 was partially reduced using LAH in THF
to afford compound 7 in a 90% yield. The secondary hy-
droxyl group was silylated with TBDMSCl to provide 8
and subsequently the primary THP group was cleaved
using PPTS in MeOH to afford compound 9. The alco-
hol was subjected to oxidation in the presence of IBX in
DCM to furnish the corresponding aldehyde in a good
yield, which was subjected to Still’s modified Horner–
Wadsworth–Emmons reaction to yield the Z-olefinic es-
In summary, we have applied a Cosford cross-coupling
protocol for the reaction of iodobenzene with an
acetylenic alcohol and utilized the intermediate for the
synthesis of goniothalamin, kavain, and 7,8-dihy-
drokavain. This method could readily be extended to a
diverse range of coupling partners and, as such, should
allow for the rapid generation of novel compound
libraries for biological evaluation. This strategy
should provide rapid access to the entire family of
O
O
OMe
O
O
OH
(R)-(+)-kavain 2
OTHP
O
O
4
(R)-(+)-goniothalamin 1
OMe
OH
I
(S)-(+)-dihydrokavain 3
+
OTHP
6
5
Scheme 1. Retrosynthesis of goniothalamin, kavain, and dihydrokavain.
OH
OH
I
a
OTHP
+
OTHP
6
4
5
Scheme 2. Reagents and conditions: (a) 10% Pd/C (cat.), CuI (4 cat.), Ph3P (0.1 equiv), K2CO3, H2O/DME, 80 °C, 2 h, 90%.

G. Sabitha et al. / Tetrahedron Letters 47 (2006) 8599–8602
8601
OTBDMS
OH
d
a
b
OR
OTHP
4
7
8, R = THP
9, R = H
c
O
OTBDMS
CHO
OR
O
g
e
CO2Me
10
11, R = TBDMS
12, R = H
f
(R)-(+)-goniothalamin 1
Scheme 3. Reagents and conditions: (a) LiAlH4, THF, 0 °C to rt, 2 h, 90%; (b) TBDMSCl, imidazole, DCM, DMAP, 2 h, 95%; (c) PPTS, MeOH,
12 h, 90 %; (d) IBX, DMSO, DCM, 0 °C to rt, 2 h, 75%; (e) i. NaH/THF, ꢀ78 °C, 30 min; ii. (CF3CH2O)2P(O)CH2COOCH3, THF, ꢀ70 °C, 30 min,
80%; (f) TBAF, THF, 2 h, 80%; (g) benzene, reflux, PTSA, 1 h, 75%.
O
OR
O
O
CO2Et
a
c
10
OMe
13, R = TBDMS
14, R = H
b
(R
)-(+)-kavain 2
Scheme 4. Reagents and conditions: (a) anhyd SnCl2 (cat.), N2CHCOOEt, DCM, 0 °C to rt, 40 min, 80%; (b) TBAF, THF, 2 h, 85%; (c) i. K2CO3,
MeOH, 2 h, ii. (CH3)2SO4, acetone, 12 h, 75%.
OTBDMS
OH
b
d
a
OR
OTHP
4
15
16, R = THP
17, R = H
c
O
OTBDMS
CHO
OR
O
CO2Et
O
g
e
OMe
18
19, R = TBDMS
20, R = H
f
(S)-(+)-7,8-dihydrokavain 3
Scheme 5. Reagents and conditions: (a) Pd/C, EtOAc, 90%; (b) TBDMSCl, imidazole, DCM, DMAP, 2 h, 95%; (c) PPTS, MeOH, 12 h, 90%; (d)
IBX, DMSO, DCM, 2 h, 90%; (e) anhyd SnCl2, N2CHCOOEt, DCM, 0 °C to rt, 40 min, 80%; (f) TBAF, THF, 2 h, 85%; (g) i. K2CO3, MeOH, 2 h,
ii. (CH3)2SO4, acetone, 12 h, 75%.
Soc., Perkin Trans. 1 1999, 1377–1395; (d) Caster, N. B.;
Nadany, A. E.; Sweeney, J. B. J. Chem. Soc., Perkin
Trans. 1 2002, 2324–2342.
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progress and the results will be published in due
course.
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Acknowledgment
K.S. thanks UGC, New Delhi, for the award of a
fellowship.
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(m, 2H), 2.85 (br s, 1H), 3.42–4.24 (m, 4H), 4.59–4.82 (m,
1H), 4.79 (dd, J = 4.6, 7.0 Hz, 1H) 7.23–7.31 (m, 3H)
7.35–7.43 (m, 2H); 13C NMR (100 MHz, CDCl3): d 131.5,
128.1, 122.5, 98.8, 89.4, 84.7, 64.6, 62.1, 61.4, 36.8, 30.3,
25.1, 19.2; IR (neat): 2943, 1618, 1490, 1353, 1200, 1073,
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24. R-(+)-Goniothalamin 1: white crystalline solid, mp 80–
25
25
82 °C, lit.12c 85 °C; ½aꢁD +160 (c 1.7, CHCl3), lit.12c ½aꢁD
+164 (c 1.7, CHCl3); 1H NMR (200 MHz, CDCl3): d 2.55
(m, 2H), 5.10 (m, 1H), 6.09 (dt, J = 9.8, 1.5 Hz, 1H), 6.25
(dd, J = 16.0, 6.2 Hz, 1H), 6.74 (d, J = 15.9 Hz, 1H), 6.90
(dt, J = 9.6, 4.3 Hz, 1H), 7.28 (m, 5H); 13C NMR
(75 MHz, CDCl3): d 30.0, 77.8, 121.0, 124.9, 126.6,
128.4, 133.2, 134.9, 144.9, 164.1; IR (KBr): 3054, 3026,
2925, 1724, 1242, 814, 691 cmꢀ1; LCMS: 223 (M+Na).
25. Holmquist, C. R.; Roskamp, E. J. J. Org. Chem. 1989, 54,
3258–3260.
26. R-(+)-Kavain 2: white crystalline solid, mp 112–114 °C,
25
20
lit.15b 105–106 °C; ½aꢁD +121.4 (c 1, EtOH), lit.15a ½aꢁD
1
+124.3 (c 1, EtOH); H NMR (300 MHz, CDCl3): d 2.54
(dd, J = 17.1, 4.5 Hz, 1H), 2.67 (dd, J= 17.1, 10.5 Hz,
1H), 3.78 (s, 3H), 5.02–5.10 (m, 1H), 5.20 (s, 1H), 6.25 (dd,
J = 15.8, 6.0 Hz, 1H), 6.75 (d, J = 15.1 Hz, 1H), 7.25–7.45
(m, 5H, ArH); 13C NMR (75 MHz, CDCl3): d 33.6, 56.5,
76.2, 91.1, 125.8, 127.2, 128.4, 129.3, 133.8, 136.4, 167.4,
172.4.; IR (KBr): 1703, 1624, 1391, 1250, 1233, 1062, 1024,
973, 742, 690; LCMS: 253 (M+Na).
27. S-(+)-7,8-Dihydrokavian 3: white crystalline solid, mp 56–
25
25
58 °C, lit.16 56–58 °C; ½aꢁD +33.4 (c 1, MeOH), lit.15a ½aꢁD
+31.1 (c 1, MeOH); 1H NMR (300 MHz, CDCl3): d 1.85–
2.00 (m, 1H), 2.05–2.20 (m, 1H), 2.30 (dd, J = 17.0,
3.9 Hz, 1H), 2.50 (dd, J = 17.0, 11.9 Hz, 1H), 2.72–2.95
(m, 2H), 3.72 (s, 3H), 4.30–4.42 (m, 1H), 5.15 (s, 1H),
7.15–7.32 (m, 5H, Ar–H); 13C NMR (75 MHz, CDCl3): d
30.8, 33.0, 36.1, 56.1, 74.4, 90.2, 126.1, 128.5, 128.4, 140.8,
167.2, 172.6; IR (KBr): 3026, 2940, 2852, 1706, 1623, 1494,
1454, 1441, 1394, 1372, 1290, 1222, 1094, 1038, 997, 869,
822, 771, 752, 701 cmꢀ1; LCMS: 255 (M+Na).
20. Tarchonanthuslactone: (a) Sabitha, G.; Sudhakar, K.;
Reddy, N. M.; Rajkumar, M.; Yadav, J. S. Tetrahedron