Total synthesis of (-)-minquartynoic acid: An anti-cancer, anti-HIV natural product

Article abstract of DOI:10.1021/ol026145n

(Matrix presented) The tetraacetylenic compound, (S)-minquartynoic acid (1), is synthesized in seven linear steps and 17% overall yield from commercially available azelaic acid monomethyl ester. The key step is a one-pot three-component Cadiot - Chodkiewicz reaction to construct the tetrayne unit without using either a diyne or a triyne intermediate.

Full text of DOI:10.1021/ol026145n

ORGANIC
LETTERS
2
002
Vol. 4, No. 15
517-2519
Total Synthesis of (−)-Minquartynoic
Acid: An Anti-Cancer, Anti-HIV Natural
Product
2
Benjamin W. Gung* and Hamilton Dickson
Department of Chemistry and Biochemistry, Miami UniVersity, Oxford, Ohio 45056
gungbw@muohio.edu
Received May 7, 2002
ABSTRACT
The tetraacetylenic compound, (S)-minquartynoic acid (1), is synthesized in seven linear steps and 17% overall yield from commercially available
azelaic acid monomethyl ester. The key step is a one-pot three-component Cadiot−Chodkiewicz reaction to construct the tetrayne unit without
using either a diyne or a triyne intermediate.
Minquartynoic acid (1) was initially isolated from the stem
bark of Minquartia guianensis, which was one of the most
potent traditional anthelmintics used by the Quijos Quichua
Independent isolation and anti-HIV activity of 1 were also
reported by two other groups. A strong cytotoxicity of 1
3
,4
against the P-388 (leukemia) cell line with an ED50 of 0.18
1
1
people of Ecuador’s Amazonian lowlands. More recently,
µg/mL was reported. Compound 3 exhibited the most potent
along with two additional polyacetylenic natural products
activity among the three polyacetylenes against the KB,
(2 and 3, Figure 1), minquartynoic acid was also isolated
LNCaP (prostate cancer), and SW626 (ovarian cancer) cell
lines.
2
The structure of 1 was determined by a variety of
spectroscopic methods and was found to contain the unusual
2
four conjugated triple bonds. The configuration of the chiral
center was determined using Mosher’s ester method.2
,5
Recently, many other polyacetylenic compounds with bio-
6
logical activities have been reported. Their unusual property
combined with their unusual structure has sparked wide-
spread interest in the synthesis of polyacetylenes, both
7-11
12-14
natural
and unnatural products.
Recently, we reported
(
1) Marles, R. J.; Farnsworth, N. R.; Neill, D. A. J. Nat. Prod. 1989,
2, 261.
2) Ito, A.; Cui, B. L.; Chavez, D.; Chai, H. B.; Shin, Y. G.; Kawanishi,
Figure 1. Cytotoxic polyacetylenes from O. amentacea: (S)-
minquartynoic acid 1, 18-hydroxyminquartynoic acid 2, and (E)-
5
(
15,16-dihydrominquartynoic acid 3.
K.; Kardono, L. B. S.; Riswan, S.; Farnsworth, N. R.; Cordell, G. A.;
Pezzuto, J. M.; Kinghorn, A. D. J. Nat. Prod. 2001, 64, 246.
(
3) Fort, D. M.; King, S. R.; Carlson, T. J.; Nelson, S. T. Biochem. Syst.
Ecol. 2000, 28, 489.
4) Rashid, M. A.; Gustafson, K. R.; Cardellina, J. H.; Boyd, M. R. Nat.
Prod. Lett. 2001, 15, 21.
from a chloroform extract of the twigs of Ochanostachys
amentacea from southeast Asia. In recent in vitro tests, 1
showed broad cytotoxicity against 10 different tumor cell
lines.2
(
2
(
(
5) Dale, J. A.; Mosher, H. S. J. Am. Chem. Soc. 1973, 95, 512.
6) Faulkner, D. J. Nat. Prod. Rep. 2001, 18, 1.
(7) Lu, W.; Zheng, G. R.; Cai, J. C. Tetrahedron 1999, 55, 4649.
1
0.1021/ol026145n CCC: $22.00 © 2002 American Chemical Society
Published on Web 06/22/2002

a synthesis of (+)- and (-)-adociacetylene using a two-
The preparation of bromoalkyne 12 (Scheme 2) was
problematic using the same protocol for the preparation of
4. The precusor to 12 was obtained uneventfully by the
following sequence of reactions. Selective reduction of the
carboxylic acid function in 8 was conveniently accomplished
15,16
directional Negishi coupling approach.
To our knowledge,
no tetrayne-containing natural products have been synthe-
sized. The instability of the intermediates involved in these
syntheses presents a considerable challenge. Here we report
a short synthesis of (-)-minquartynoic acid using a triply
convergent approach.
by using 1 equiv of BH ‚THF complex in anhydrous THF
3
2
2
at 0 °C. Aldehyde 10 was prepared in quantitative yield
with PCC in the oxidation of the resulting primary alcohol.23
Dibromoolefin 11 was obtained uneventfully using a com-
The general strategy for our synthesis of (S)-minquartynoic
acid is depicted in Scheme 1. The tetrayne unit might be
2
0
3 4
bination of Ph P and CBr . However, no desired product
was isolated during the attempt to prepare bromoalkyne 12
by the elimination of one molar HBr from 11 under various
conditions.
Scheme 1
2
1
Complications from the enolization of ester 11 were
considered to be the cause of these unsuccessful trials. To
remove the acidity of the R-protons, we decided to protect
the carboxylic acid function as an ortho ester (Scheme 3).24
Scheme 3
constructed by the Cadiot-Chodkiewicz reaction through a
combination of bromoalkynes 4 and 6 and butadiyne 5.
Aldehyde 13 was obtained from azelaic acid monomethyl
ester (8) in two steps by protecting the carboxylic acid
function as an ortho ester and reducing the ester function
with DIBAL-H. However, after various reported procedures
for introducing the dibromoolefin unit from an aldehyde were
1
7,18
The bromoalkyne 4 should be available from (S)-methyl
lactate 7. Butadiyne 5 is known and can be prepared in one
1
7
step from commercially available 1,4-dichlorobutyne.
2
0,25-27
Bromoalkyne 6 should be obtained from commercially
available azelaic acid monomethyl ester 8.
attempted,
the desired dibromoolefin 14 could be
obtained only in poor yield by following Weinreb’s proce-
26
Dibromoolefin 9 was prepared from lactate 7 following a
dure. Significantly, the ortho ester is unstable toward silica
gel chromatography. We therefore turned our attention to
an alternate two-step procedure (Scheme 4).
19
literature procedure with (1) protection of the -OH group,
(
2) reduction of the ester function to an aldehyde group, and
20
(3) formation of the dibromoolefin. Significant loss of the
(
(
8) Zheng, G. R.; Lu, W.; Cai, J. C. J. Nat. Prod. 1999, 62, 626.
9) Garcia, J.; Lopez, M.; Romeu, J. Tetrahedron: Asymmetry 1999, 10,
TBS protecting group (Scheme 2) was observed when the
literature procedure was followed. This procedure was
modified by using more hexanes to partition the product in
the workup process to avoid the protecting group loss.
Elimination of one molar HBr from 9 was achieved with
NaHMDS to give bromoalkyne 4 in high yield.21
2
635.
(11) Morishita, K.; Kamezawa, M.; Ohtani, T.; Tachibana, H.; Kawase,
M.; Kishimoto, M.; Naoshima, Y. J. Chem. Soc., Perkin Trans. 1 1999,
513.
(12) Gao, K.; Goroff, N. S. J. Am. Chem. Soc. 2000, 122, 9320.
13) Heuft, M. A.; Collins, S. K.; Yap, G. P. A.; Fallis, A. G. Org. Lett.
(
2
001, 3, 2883.
14) Haley, M. M.; Bell, M. L.; Brand, S. C.; Kimball, D. B.; Pak, J. J.;
Wan, W. B. Tetrahedron Lett. 1997, 38, 7483.
15) Gung, B. W.; Dickson, H.; Shockley, S. Tetrahedron Lett. 2001,
2, 4761.
(
Scheme 2
(
4
(
(
16) Negishi, E.; Kotora, M.; Xu, C. D. J. Org. Chem. 1997, 62, 8957.
17) Brandsma, L. PreparatiVe Acetylenic Chemistry, 2nd ed.; Elsevier:
New York, 1988.
18) Siemsen, P.; Livingston, R. C.; Diederich, F. Angew. Chem., Int.
Ed. 2000, 39, 2633.
(
(
(
(
(
19) Marshall, J. A.; Xie, S. J. Org. Chem. 1995, 60, 7230.
20) Corey, E. J.; Fuchs, P. L. Tetrahedron Lett. 1972, 3769.
21) Grandjean, D.; Pale, P.; Chuche, J. Tetrahedron Lett. 1994, 35, 3529.
22) Yoon, N. M.; Pak, C. S.; Brown Herbert, C.; Krishnamurthy, S.;
Stocky, T. P. J. Org. Chem. 1973, 38, 2786.
(23) Corey, E. J.; Suggs, J. W. Tetrahedron Lett. 1975, 2647.
(24) Corey, E. J.; Raju, N. Tetrahedron Lett. 1983, 24, 5571.
(25) Wagner, A.; Heitz, M. P.; Mioskowski, C. J. Chem. Soc., Chem.
Commun. 1989, 1619.
(
(
26) McIntosh, M. C.; Weinreb, S. M. J. Org. Chem. 1993, 58, 4823.
27) Maercker, A. Org. React. 1965, 14, 270.
2518
Org. Lett., Vol. 4, No. 15, 2002

Scheme 4
Scheme 5
Aldehyde 10 was treated with the Ohira-Bestmann
28,29
reagent 15 to yield alkyne 16 in nearly quantitative yield.
The conversion of alkyne 16 to the bromoalkyne 12 was
also achieved in excellent yield using AgNO and NBS in
acetone. Since the Cadiot-Chodkiewicz reaction proceeds
3
30
17
best with polar substrates, methyl ester 12 was hydrolyzed
that of the terminal triynes isolated in the initial two-
component couplings. All three tetraynes (17-19) were
purified by column chromatography and were stable during
to its corresponding carboxylic acid (6) using LiOH in a
31
2
mixture of THF and H O.
With bromoalkynes 4 and 6 in hand, the stage was now
set for coupling via the Cadiot-Chodkiewicz reaction.
Coupling of either 4 and 5 or 5 and 6 produced the
corresponding triyne, which decomposed several hours after
isolation to a charcoal-like material. This led us to conclude
that a stepwise coupling strategy would not be viable.
A one-pot three-component coupling strategy was em-
ployed, in which 1 equiv of each of the reactants (4-6) was
loaded into the flask along with other reagents. A typical
literature procedure for the coupling reaction is usually
conducted at room temperature.17 However, CuCl caused
butadiyne 5 to immediately decompose at room temperature.
We modified the general procedure by first charging the flask
with all reactants and then adding CuCl to the mixture at
1
13
H and C NMR measurements. The TBS protecting group
31
of 19 was removed using HF‚Pyr complex in 72% yield
to give a product identical to the reported 1 in all spectro-
2
scopic determinations.
In summary, a highly efficient synthesis of (S)-minquar-
tynoic acid has been completed in seven linear steps and
1
7% overall yield from commercially available azelaic acid
monomethyl ester. This synthesis is amenable to the prepara-
tion of two other constituents (2 and 3) isolated from the
cytotoxic extract of O. amentacea. The total synthesis of 2
and 3 will be reported in due course.
Acknowledgment. This research is supported in part by
a grant from the National Institutes of Health (GM60263).
Acknowledgment is also made to the Donors of The
Petroleum Research Fund (PRF#36841-AC4) administered
by the American Chemical Society.
0
°C (Scheme 5). We were pleased to isolate three tetra-
acetylenic products (17-19) in a combined yield of 59%,
0% of which was the desired cross-coupling product 19.
The stability of these internal tetraynes is much greater than
3
Supporting Information Available: Experimental pro-
cedures and characterization of compounds 1 and 4-19. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(
28) Ohira, S. Synth. Commun. 1989, 19, 561.
(29) Mueller, S.; Liepold, B.; Roth, G. J.; Bestmann, H. J. Synlett 1996,
5
21.
30) Hofmeister, H.; Annen, K.; Laurent, H.; Wiechert, R. Angew. Chem.,
Int. Ed. Engl. 1984, 23, 727.
31) Nicolaou, K. C.; Webber, S. E. Synthesis 1986, 453.
(
(
OL026145N
Org. Lett., Vol. 4, No. 15, 2002
2519