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Total Synthesis of (−)-Minquartynoic
Vol. 4, No. 15
Acid: An Anti-Cancer, Anti-HIV Natural
2517-2519
Benjamin W. Gung* and Hamilton Dickson
Department of Chemistry and Biochemistry, Miami UniVersity, Oxford, Ohio 45056 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
Independent isolation and anti-HIV activity of 1 were also
bark of Minquartia guianensis, which was one of the most reported by two other groups.3,4 A strong cytotoxicity of 1
potent traditional anthelmintics used by the Quijos Quichua against the P-388 (leukemia) cell line with an ED50 of 0.18 people of Ecuador’s Amazonian lowlands.1 More recently, µg/mL was reported.1 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) celllines.2 The structure of 1 was determined by a variety of
spectroscopic methods and was found to contain the unusualfour conjugated triple bonds.2 The configuration of the chiralcenter was determined using Mosher’s ester method.2,5Recently, many other polyacetylenic compounds with bio-logical activities have been reported.6 Their unusual propertycombined with their unusual structure has sparked wide-spread interest in the synthesis of polyacetylenes, bothnatural7-11 and unnatural products.12-14 Recently, we reported (1) Marles, R. J.; Farnsworth, N. R.; Neill, D. A. J. Nat. Prod. 1989,
Figure 1. Cytotoxic polyacetylenes from O. amentacea: (S)-
minquartynoic acid 1, 18-hydroxyminquartynoic acid 2, and (E)-
(2) Ito, A.; Cui, B. L.; Chavez, D.; Chai, H. B.; Shin, Y. G.; Kawanishi, 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.
from a chloroform extract of the twigs of Ochanostachys (4) Rashid, M. A.; Gustafson, K. R.; Cardellina, J. H.; Boyd, M. R. Nat. amentacea from southeast Asia.2 In recent in vitro tests, 1
Prod. Lett. 2001, 15, 21.
(5) Dale, J. A.; Mosher, H. S. J. Am. Chem. Soc. 1973, 95, 512.
showed broad cytotoxicity against 10 different tumor cell (6) Faulkner, D. J. Nat. Prod. Rep. 2001, 18, 1.
(7) Lu, W.; Zheng, G. R.; Cai, J. C. Tetrahedron 1999, 55, 4649.
Published on Web 06/22/2002
a synthesis of (+)- and (-)-adociacetylene using a two- The preparation of bromoalkyne 12 (Scheme 2) was
directional Negishi coupling approach.15,16 To our knowledge, problematic using the same protocol for the preparation of no tetrayne-containing natural products have been synthe- 4. The precusor to 12 was obtained uneventfully by the
sized. The instability of the intermediates involved in these following sequence of reactions. Selective reduction of the syntheses presents a considerable challenge. Here we report carboxylic acid function in 8 was conveniently accomplished
a short synthesis of (-)-minquartynoic acid using a triply at 0 °C.22 Aldehyde 10 was prepared in quantitative yield
The general strategy for our synthesis of (S)-minquartynoic with PCC in the oxidation of the resulting primary alcohol.23 acid is depicted in Scheme 1. The tetrayne unit might be Dibromoolefin 11 was obtained uneventfully using a com-
bination of Ph3P and CBr4.20 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.21
Complications from the enolization of ester 11 were
considered to be the cause of these unsuccessful trials. Toremove the acidity of the R-protons, we decided to protectthe carboxylic acid function as an ortho ester (Scheme 3).24 constructed by the Cadiot-Chodkiewicz reaction through a Aldehyde 13 was obtained from azelaic acid monomethyl
combination of bromoalkynes 4 and 6 and butadiyne 5.17,18
ester (8) in two steps by protecting the carboxylic acid
The bromoalkyne 4 should be available from (S)-methyl
function as an ortho ester and reducing the ester function lactate 7. Butadiyne 5 is known and can be prepared in one
with DIBAL-H. However, after various reported procedures step from commercially available 1,4-dichlorobutyne.17 for introducing the dibromoolefin unit from an aldehyde were Bromoalkyne 6 should be obtained from commercially
attempted,20,25-27 the desired dibromoolefin 14 could be
available azelaic acid monomethyl ester 8.
obtained only in poor yield by following Weinreb’s proce- Dibromoolefin 9 was prepared from lactate 7 following a
dure.26 Significantly, the ortho ester is unstable toward silica literature procedure19 with (1) protection of the -OH group, gel chromatography. We therefore turned our attention to (2) reduction of the ester function to an aldehyde group, and an alternate two-step procedure (Scheme 4).
(3) formation of the dibromoolefin.20 Significant loss of theTBS protecting group (Scheme 2) was observed when 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,
literature procedure was followed. This procedure was modified by using more hexanes to partition the product in (10) Sharma, A.; Chattopadhyay, S. Tetrahedron: Asymmetry 1998, 9,
the workup process to avoid the protecting group loss.
(11) Morishita, K.; Kamezawa, M.; Ohtani, T.; Tachibana, H.; Kawase, Elimination of one molar HBr from 9 was achieved with
M.; Kishimoto, M.; Naoshima, Y. J. Chem. Soc., Perkin Trans. 1 1999,
NaHMDS to give bromoalkyne 4 in high yield.21
(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.
2001, 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,
(16) Negishi, E.; Kotora, M.; Xu, C. D. J. Org. Chem. 1997, 62, 8957.
(17) Brandsma, L. PreparatiVe Acetylenic Chemistry, 2nd ed.; Elsevier:
(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.
Org. Lett., Vol. 4, No. 15, 2002
Aldehyde 10 was treated with the Ohira-Bestmann
reagent 15 to yield alkyne 16 in nearly quantitative yield.28,29
The conversion of alkyne 16 to the bromoalkyne 12 was
also achieved in excellent yield using AgNO3 and NBS in
acetone.30 Since the Cadiot-Chodkiewicz reaction proceeds
best with polar substrates,17 methyl ester 12 was hydrolyzed
that of the terminal triynes isolated in the initial two- to its corresponding carboxylic acid (6) using LiOH in a
component couplings. All three tetraynes (17-19) were
purified by column chromatography and were stable during With bromoalkynes 4 and 6 in hand, the stage was now
1H and 13C NMR measurements. The TBS protecting group set for coupling via the Cadiot-Chodkiewicz reaction.
of 19 was removed using HF‚Pyr31 complex in 72% yield
Coupling of either 4 and 5 or 5 and 6 produced the
to give a product identical to the reported 1 in all spectro-
corresponding triyne, which decomposed several hours after isolation to a charcoal-like material. This led us to conclude In summary, a highly efficient synthesis of (S)-minquar- that a stepwise coupling strategy would not be viable.
tynoic acid has been completed in seven linear steps and A one-pot three-component coupling strategy was em- 17% overall yield from commercially available azelaic acid ployed, in which 1 equiv of each of the reactants (4-6) was
monomethyl ester. This synthesis is amenable to the prepara- loaded into the flask along with other reagents. A typical tion of two other constituents (2 and 3) isolated from the
literature procedure for the coupling reaction is usually cytotoxic extract of O. amentacea. The total synthesis of 2
conducted at room temperature.17 However, CuCl caused and 3 will be reported in due course.
butadiyne 5 to immediately decompose at room temperature.
We modified the general procedure by first charging the flask
Acknowledgment. This research is supported in part by
with all reactants and then adding CuCl to the mixture at a grant from the National Institutes of Health (GM60263).
0 °C (Scheme 5). We were pleased to isolate three tetra- Acknowledgment is also made to the Donors of The acetylenic products (17-19) in a combined yield of 59%,
Petroleum Research Fund (PRF#36841-AC4) administered 30% of which was the desired cross-coupling product 19.
The stability of these internal tetraynes is much greater than Supporting Information Available: Experimental pro-
(28) Ohira, S. Synth. Commun. 1989, 19, 561.
cedures and characterization of compounds 1 and 4-19. This
(29) Mueller, S.; Liepold, B.; Roth, G. J.; Bestmann, H. J. Synlett 1996,
material is available free of charge via the Internet at (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.
Org. Lett., Vol. 4, No. 15, 2002

Source: http://chemistry.muohio.edu/gung/pdfs/Minquart.pdf