Total syntheses of the highly potent anti-cancer polyacetylenes, (S)-18-hydroxyminquartynoic acid, (S)-minquartynoic acid and (E)-15,16-dihydrominquartynoic acid

Article abstract of DOI:10.1016/j.tetlet.2006.03.118

The total syntheses of three polyacetylenic natural products, (S)-18-hydroxyminquartynoic acid (1), (S)-minquartynoic acid (2) and (E)-15,16-dihydrominquartynoic acid (3), has been achieved. The Cadiot-Chodkiewicz cross-coupling reaction was used as the k

Full text of DOI:10.1016/j.tetlet.2006.03.118

Tetrahedron Letters 47 (2006) 4513–4516
Total syntheses of the highly potent anti-cancer polyacetylenes,
(S)-18-hydroxyminquartynoic acid, (S)-minquartynoic acid and
(E)-15,16-dihydrominquartynoic acid I
Gowravaram Sabitha,* Ch. Srinivas Reddy and J. S. Yadav
Organic Division I, Indian Institute of Chemical Technology, Hyderabad 500 007, India
Received 23 January 2006; revised 7 March 2006; accepted 17 March 2006
Abstract—The total syntheses of three polyacetylenic natural products, (S)-18-hydroxyminquartynoic acid (1), (S)-minquartynoic
acid (2) and (E)-15,16-dihydrominquartynoic acid (3), has been achieved. The Cadiot–Chodkiewicz cross-coupling reaction was
used as the key step for the construction of tetrayne and triyne units.
Ó 2006 Published by Elsevier Ltd.
Naturally occurring polyacetylenes are an intriguing
class of natural products.1 Many of them show remark-
able biological activities, such as antifungal, antimicro-
bial, cytotoxic, antiviral, antitumor, immuno-
suppressant and enzyme-inhibition.2 Recently, there
has been an increasing interest towards the synthetic
studies of natural acetylenic compounds.3 Three novel
polyacetylenic compounds (S)-18-hydroxyminquarty-
noic acid (1), (S)-(À)-minquartynoic acid (2) and (E)-
15,16-dihydrominquartynoic acid (3) were isolated from
a chloroform extract of the twigs of Ochanostachys
amentacea from south east Asia.4 (S)-(À)-Minquarty-
noic acid was previously isolated from the stem bark
of Minquartia guianensis,5 which was one of the most
potent traditional anthelmintics used by the Quijos
Quichua people of Ecuador’s Amazonian low lands.
All three compounds showed potent cytotoxicity against
ten different tumor cell lines,5 while compound 3 showed
the most potent activity among the three polyacetylenes
against the human hormone-dependent prostate and
ovarian cancer cell lines. Anti-HIV activity of 2 was also
reported by two other groups.6 The reported structure
of 2 was revised based on HMQC and HMBC experi-
ments, and the absolute stereochemistry was determined
by Mosher’s ester methodology.4,7 The structures of
compounds 1 and 3 were elucidated using 1D- and
2D-NMR spectroscopic methods. Compound 1 is
(S)-17,18-dihydroxy-9,11,13,15-octadecatetraynoic acid,
minquartynoic acid (2) is (S)-17-hydroxy-9,11,13,15-
octadecatetraynoic acid, and 3 is (S)-17-hydroxy-15E-
octadecen-9,11,13-triynoic acid. Reports by Gung
et al. have described8–10 the first total syntheses of these
polyacetylenes. The draw back of the reported proce-
dures is the isolation of a mixture of three possible
acetylenic products when a key step, one-pot, three-
component coupling strategy was employed, which
reduced the yield of the desired cross-coupling product.
Fascinated by the structures of these polyacetylenes,
together with their remarkable anti-cancer activities,
and as a part of our efforts towards the total synthesis
of polyacetylenic alcohols,11 we became interested in
the total synthesis of 1–3 using a Cadiot–Chodkiewicz
cross-coupling reaction12 as the key step.
Our retrosynthetic analysis for 1–3 is outlined in Scheme
1. We envisioned that both polyacetylenes 1 and 2 could
be constructed from the Cadiot–Chodkiewicz cross-cou-
pling reaction of polyacetylenic alcohol 4 and bro-
modiyne 6. Following a common strategy, 3 could be
conveniently synthesized by coupling hydroxy enyne 7
with the bromodiyne 6.
Keywords: Natural products; Polyacetylenes; Cadiot–Chodkiewicz
coupling; Anti-cancer activity; Anti-HIV activity.
q IICT Communication No.: 060109.
The syntheses of (S)-17-hydroxy-9,11,13,15-octadecate-
traynoic acid (1) and (S)-(À)-minquartynoic acid (2)
were started by preparing the chiral diacetylenic alcohol
*
Corresponding author. Tel./fax: +91 40 27160512; e-mail: sabitha@
iiictnet.org
0040-4039/$ - see front matter Ó 2006 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2006.03.118

4514
G. Sabitha et al. / Tetrahedron Letters 47 (2006) 4513–4516
HO
The right-hand fragment, bromodiyne 6, was prepared
as shown in Scheme 3. Accordingly, the cross-coupling
reaction of 9 with trans-1,2-dichloroethylene under
modified Sonogashira conditions14 proceeded to afford
10 in good yield, which was subsequently treated with
n-BuLi to produce terminal diyne 11. Oxidation under
Swern conditions, followed by treatment with NaClO2:
NaH2PO4 (1.5:0.2 equiv) in DMSO, furnished the corre-
sponding carboxylic acid 12. Esterification of 12 was
accomplished by treatment with CH2N2 to afford methyl
ester 13. Finally, bromination of diyne 13 to give bro-
modiyne 6 was achieved in two steps in excellent yield
by reaction with NBS and AgNO3 in acetone,15 followed
by hydrolysis with LiOH (Scheme 3).
R
1, R = OH, (S)-18-hydroxyminquartynoic acid
2, R = H, (S)-minquartynoic acid
COOH
R'O
+
Br
R
6
4, R = OBn, R' = H
5, R = H, R' = MOM
COOH
H
HO
H3C
H
3 (E)-15,16-dihydrominquartynoic acid
With bromodiyne 6 and alcohol 4 in hand, coupling via
the Cadiot–Chodkiewicz reaction12 produced the corre-
sponding tetrayne 14 in 72% yield. Removal of the benz-
yl group using TiCl4 at 0 °C to rt in DCM afforded the
target molecule, (S)-18-hydroxyminquartynoic acid (1)
in 70% yield (Scheme 4). The synthetic material 1 was
identical in all respects with the natural product.
COOH
H
MOMO
H3C
6
+
H
7
Scheme 1. Retrosynthetic analysis.
The synthesis of 2 also began with the known chiral
diacetylenic alcohol 4 by manipulating the following
reactions successfully (Scheme 5). The benzyl group in
4 was removed with TiCl4 in DCM, and the resulting
diol 15 was selectively tosylated by treatment with tosyl
chloride in pyridine at 0 °C to furnish the corresponding
tosylate 16 in 75% yield. After protecting the secondary
hydroxy group of compound 16 as its MOM ether, the
tosyl group of 17 was reduced to a methyl by treatment
with LAH in dry ether at room temperature to afford
compound 5. Adopting the same strategy as for the syn-
thesis of 1, the coupling of 5 with bromodiyne 6 under
Cadiot–Chodkiewicz conditions resulted in tetrayne 18
4 from L-(+)-tartatic acid 8 using the procedure devel-
oped by our group (Scheme 2).13
HO
HO
COOH
COOH
HO
ref 13
BnO
8
4
Scheme 2.
b
a
CH2OH
CH2OH
( )
( )
Cl
6
90%
6
80%
9
10
e
c, d
CH2OH
COOH
( )
( )
6
82%
6
85%
11
12
f, g
75%
COOH
COOMe
Br
( )
( )
6
6
6
13
Scheme 3. Reagents and conditions: (a) trans-1,2-dichloroethylene (1 equiv), Pd(PPh3)4, Et2NH (2 equiv), CuI (0.2 equiv), toluene, 30 min; (b) n-
BuLi/HMPA (1:1 equiv), À40 °C, 30 min; (c) (COCl)2, DMSO, TEA, À78 °C, 1 h; (d) NaClO2/NaH2PO4 (1.5:0.2 equiv), DMSO, 1 h; (e) CH2N2,
ether, 0 °C, 30 min; (f) NBS, AgNO3, acetone, 0 °C to rt, 20 min; (g) LiOH (1 equiv), THF/MeOH/H2O (3:1:1), 40 min.
HO
b
a
1
COOH
4 +
6
( )
70%
BnO
72%
6
14
Scheme 4. Reagents and conditions: (a) NH2OHÆHCl (1 equiv), EtNH2 (1 equiv), CuCl (0.2 equiv), MeOH (5 ml), H2O, 20 min; (b) TiCl4
(0.01 equiv), DCM, 0 °C to rt, 2 h.

G. Sabitha et al. / Tetrahedron Letters 47 (2006) 4513–4516
4515
Next, (E)-15,16-dihydrominquartynoic acid (3) was syn-
thesized using a different strategy starting from commer-
cially available propargyl alcohol, as illustrated in
Scheme 6. Protection of the hydroxyl group in 19 using
PMBBr and NaH in dry THF at 0 °C resulted in the cor-
responding PMB ether, which on reaction with the Grig-
nard reagent generated from EtBr and Mg, followed by
quenching with para-formaldehyde furnished the prop-
argyl alcohol derivative 20 in an overall yield of 80%.
Compound 20 was then converted into trans-allylic alco-
hol 21 in 79% yield by the reduction of the triple bond
using LAH in dry THF for 4 h. Alcohol 21 was then
converted to monoprotected enyne 7, as previously
reported.11
RO
HO
a
R'O
BnO
72%
15, R, R' = H
16, R = H, R' = Ts
17, R = MOM, R' = Ts,
4
b, 75%
c, 80%
MOMO
d
80%
6
+
5
e
MOMO
COOH
( )
6
70%
18
The coupling reaction of trans-enyne 7 with bromodiyne
6 under Cadiot–Chodkiewicz reaction conditions affor-
ded enetriyne 29, which on removal of the MOM group
provided the target molecule (E)-15,16-dihydrominqu-
artynoic acid (3) in 82% yield (Scheme 7). The data for
the synthetic material was identical to the natural prod-
uct in all respects.
f
2
78%
Scheme 5. Reagents and conditions: (a) TiCl4 (0.01 equiv), DCM, 0 °C
to rt, 2 h; (b) TsCl, pyridine, Et3N, 0 °C, 45 min; (c) MOMCl (5 equiv),
DIPEA (6 equiv), DCM, 0 °C to rt, 3 h; (d) LAH (1 equiv), ether, 0 °C
to rt, 45 min; (e) NH2OHÆHCl (1 equiv), EtNH2 (1 equiv), CuCl
(0.2 equiv), MeOH, H2O, 20 min; (f) 6 N HCl, 0 °C to rt, 2 h.
In summary, we have accomplished the total syntheses
of the highly potent anti-cancer agents, (S)-18-hydroxy-
minquartynoic acid, (S)-minquartynoic acid and
(E)-15,16-dihydrominquartynoic acid16 using the Cad-
iot–Chodkiewicz cross-coupling reaction as the key
step.
in 70% yield. Finally, removal of the MOM group pro-
vided the second target molecule, (S)-minquartynoic
acid (2) in 78% yield (Scheme 5). The spectral data of
2 was in accordance with the natural product.
a, b
c
OH
PMBO
HO
PMBO
OH
OH
79%
80%
21
19
20
O
f, g, h
O
e
d
PMBO
CO2Et
PMBO
78%
75%
80%
24
23
OR
OMOM
l
R'O
82%
25, R = H, R' = PMB
26, R = MOM, R' = PMB
27, R = MOM, R' = H
28, R = MOM, R' = Ts
7
i, 80%
j, 72%
k, 90%
Scheme 6. Reagents and conditions: (a) NaH (1 equiv), PMBBr (1 equiv), THF, 0 °C to rt, 6 h; (b) EtMgBr (1.5 equiv), HCHO (1 equiv) 0 °C to rt,
˚
4 h; (c) LAH (0.5 equiv), THF, 0 °C to rt, 4 h; (d) (+)-DIPT (0.3 equiv), Ti(OiPr)4 (0.3 equiv), 4 A MS, t-BuOOH (1.2 equiv), À25 °C, DCM, 4 h; (e)
1. (COCl)2, DMSO, TEA, DCM, 45 min; 2. Ph3P@CHCO2Et, benzene, 0 °C to rt, 4 h; (f) DIBAL-H (1 equiv), À10 °C to rt, 1 h; (g) TPP (1 equiv),
CCl4, reflux, 4 h; (h) LDA (3 equiv), HMPA:THF (1:5 equiv), À78 °C, 1 h; (i) MOMCl (5 equiv), DIPEA (6 equiv), DCM, 0 °C to rt, 4 h; (j) DDQ
(1.2 equiv), DCM/H2O (9:1), 30 min; (k) TsCl (1 equiv), Et3N, 0 °C, 1 h; (l) LAH (1 equiv), ether, 0 °C to rt, 30 min.
OMOM
b
82%
a
COOH
3
( )
6
7
+
6
78%
29
Scheme 7. Reagents and conditions: (a) NH2OHÆHCl (1 equiv), EtNH2 (1 equiv), CuCl (0.2 equiv), MeOH, H2O, 20 min; (b) 6 N HCl, 0 °C to rt, 2 h.

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G. Sabitha et al. / Tetrahedron Letters 47 (2006) 4513–4516
11. Sabitha, G.; Reddy, Ch. S.; Srihari, P.; Yadav, J. S.
Acknowledgement
Synthesis 2003, 2699.
12. Cadiot, P. C. R.; Chodkiewicz, W. In Chemistry of
Acetylenes; Viehe, H. G., Ed.; Marcel Dekker: New York,
1969; pp 597–647.
Ch.S.R. thanks UGC, New Delhi, for the award of
fellowship.
13. Yadav, J. S.; Maiti, A. Tetrahedron Lett. 2001, 42, 3909.
14. Sonogashira, K. Metal Catalyzed Cross Coupling Reac-
tions; Wiley-VCH: Weinheim, 1998.
References and notes
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16. Selected spectral data: (S)-18-Hydroxyminquartynoic acid
(1): solid, mp 96 °C (lit.4 mp 95 °C); [a]D À40.0 (c 0.50,
MeOH); lit.4 [a]D À38.4 (c 0.1, MeOH); 1H NMR
(300 MHz, CDCl3): d 1.30–1.60 (m, 10H), 2.26 (m, 4H)
3.56 (d, J = 6.7 Hz, 2H), 4.50 (t, J = 7.3 Hz, 1H); 13C
NMR (75 MHz, CDCl3): d 177.1, 81.8, 78.0, 70.1, 65.4,
64.3, 62.9, 62.5, 58.9, 33.7, 30.1, 29.6, 29.1, 28.9, 28.8, 28.6,
25.6, 19.1; IR (neat): 3415, 2932, 2485, 2280, 2215,
1616, 1512, 1104 cmÀ1; LCMS: m/z 323.12. (M = 323.1 =
M++23 i.e., Na).
(S)-(À)-Minquartynoic acid (2): solid, mp 132–135 °C (lit.4
mp 130–135 °C); [a]D À31.0 (c 0.50, MeOH); lit.4 [a]D
À29.4 (c 0.1, MeOH); 1H NMR (300 MHz, CDCl3): d
1.30–1.60 (m, 13H), 2.26 (m, 4H), 4.58 (q, J = 6.7 Hz, 1H);
13C NMR (50 MHz, CDCl3): d 179.0, 81.2, 80.8, 67.5,
65.0, 63.3, 62.7, 59.8, 57.3, 34.1, 29.1, 29.0, 28.8, 28.6, 28.0,
25.1, 23.7, 19.1; IR (neat): 3416, 2930, 1715, 1617, 1410,
1217, 1090 cmÀ1; LCMS: m/z 307.12 (M = 307.12 =
M++23 i.e., Na).
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3488.
(E)-15,16-dihydrominquartynoic acid (3): amorphous
solid, mp 50–52 °C (lit.10 mp 49–52 °C); [a]D À12.6 (c
0.50, MeOH); lit.4 [a]D À12.9 (c 0.1, MeOH); 1H NMR
(300 MHz, CDCl3): d 1.24–1.67 (m, 13H), 2.33 (m, 4H),
4.34 (m, 1H), 5.73 (d, J = 15.8 Hz, 1H), 6.37 (dd, J = 5.3,
15.8 Hz, 1H); 13C NMR (50 MHz, CDCl3): d 179.2, 151.4,
107.3, 82.7, 76.0, 74.4, 68.4, 67.5, 66.2, 59.8, 57.3, 34, 29.3,
29.6, 28.79, 24.5, 22.8, 19.7; IR (neat): 3416, 2930, 2395,
2260, 1617, 1560, 1143, 1030, 886 cmÀ1; LCMS: m/z 309.4
(M = 309.2 = M++23 i.e., Na).