First total synthesis of (-)-AL-2

Article abstract of DOI:10.1021/ol0300569

(Matrix presented) Treatment of the 3,4-dioxygenated-9-hydroxy-1-nonyn-5-one derivative, derived from diethyl L-tartrate, with a palladium catalyst in methanol under a CO atmosphere effected an intramolecular acetalization and a stereoselective constructi

Full text of DOI:10.1021/ol0300569

ORGANIC
LETTERS
2003
Vol. 5, No. 13
2335-2338
First Total Synthesis of (−)-AL-2
Naoki Miyakoshi and Chisato Mukai*
Faculty of Pharmaceutical Sciences, Kanazawa UniVersity,
Takara-machi, Kanazawa 920-0934, Japan
cmukai@kenroku.kanazawa-u.ac.jp
Received April 25, 2003
ABSTRACT
Treatment of the 3,4-dioxygenated-9-hydroxy-1-nonyn-5-one derivative, derived from diethyl L-tartrate, with a palladium catalyst in methanol
under a CO atmosphere effected an intramolecular acetalization and a stereoselective construction of the (E)-methoxycarbonylmethylidene
functionality resulting in formation of the core framework of the diacetylenic spiroacetal enol ether natural products. Chemical transformations
of the 1,6-dioxaspiro[4.5]decane derivative thus formed led to the first total synthesis of (−)-AL-2.
A wide range of biological and pharmacological activities
of the genus Artemisia have been reported with more than
10 diacetylenic spiroacetal enol ether derivatives being
isolated from this plant family.1 These diacetylenic spiro-
acetal enol ethers have a common structural feature, the (2E)-
(2,4-hexadiynylidene)-1,6-dioxaspiro[4.5]decane framework,1f,2
as exemplified by several related natural products 1-4
(Figure 1). The representative diacetylenic spiroacetal enol
ether epoxide, the so-called AL-1 (1), has been found to be
a specific inhibitor of the activation phase in H2O2 production
induced by TPA treatment.1f,3 Thus, it was discovered that
AL-1 (1) strongly inhibits 12-O-tetradecanoylphorbol-13-
acetate (TPA)-induced tumor promotion.1f,3 The 8-deiso-
valeryloxy congener, the so-called AL-2 (2),4 also showed
similar antitumor activities, although they were much weaker
than those of AL-1 (1).1f,3 Despite its unique structural
features and promising biological activity, no previous
reports5 have dealt with the total syntheses of AL-1 (1) and
AL-2 (2) or any of the other related diacetylenic spiroacetal
enol ether natural products except for the total synthesis of
(1) For examples, see: (a) Bohlmann, F.; Herbst, P.; Arndt, C.;
Scho¨nowsky, H.; Gleinig, H. Chem. Ber. 1961, 94, 3193. (b) Bohlmann,
F.; Arndt, C.; Bornowski, H.; Kleine, K.; Herbst, P. Chem. Ber. 1964, 97,
1179. (c) Bohlmann, F.; Burkhardt, T.; Zdero, C. In Naturally Occurring
Acetylenes; Academic Press: London, 1973. (d) Bohlmann, F.; Ates, N.;
Jakupovic, J.; King, R. M.; Robinson, H. Phytochemistry 1982, 21, 2691.
(e) Mart´ınez, V.; Barbera, O.; Sa´nchez-Parareda, J.; Marco, J. A. Phyto-
chemistry 1987, 26, 2619. (f) Marco, J. A.; Sanz, J. F.; Jakupovic, J.;
Huneck, S. Tetrahedron 1990, 46, 6931. (g) Nakamura, Y.; Ohto, Y.;
Murakami, A.; Jiwajinda, S.; Ohigashi, H. J. Agric. Food Chem. 1998, 46,
5031.
(2) For structure determination, see: (a) Wurz, G.; Hofer, O.; Sanz-
Cervera, J. F.; Marco, J. A. Ann. Chem. 1993, 99. (b) Birnecker, W.;
Wallno¨fer, B.; Hoffer, O.; Greger, H. Tetrahedron 1988, 44, 267.
(3) Nakamura, Y.; Kawamoto, N.; Ohto, Y.; Torikai, K.; Murakami, A.;
Ohigashi, H. Cancer Lett. 1999, 140, 37.
(4) According to the IUPAC nomenclature system, (-)-AL-2 (2) should
be described as (-)-(2E,3S,4R,5R)-3,4-epoxy-(2,4-hexadiynylidene)-1,6-
dioxaspiro[4.5]decane. This numbering system is used for the dioxaspiro
compounds in this manuscript.
Figure 1.
10.1021/ol0300569 CCC: $25.00 © 2003 American Chemical Society
Published on Web 05/30/2003

(()-4,6 the racemic 3,4-deoxygenated analogue of 2, which
did not control the stereochemistry of an enediyne moiety.
As part of our program7 to design a highly stereocontrolled
total synthesis of natural products from commercially avail-
able tartaric acid derivatives, we have focused considerable
attention on the total synthesis of a series of diacetylenic
spiroacetal enol ether natural products. A general retro-
synthetic analysis of not only AL-1 (1) and AL-2 (2) but
also of their related natural products is outlined in Scheme
1. We envisioned that the two chiral centers of L-tartrate
of Kato and Akita,8 which involve (i) palladium(II)-catalyzed
formation of the intermediate 8 and/or the hemiacetal species
8′,10 (ii) followed by intramolecular capture of the transient
oxonium ion species 8 by the terminal hydroxyl group, and/
or nucleophilic attack of the hemiacetal hydroxyl group on
the activated triple bond of 8′, and finally (iii) the palladium-
mediated carbon monoxide insertion reaction (conversion of
7 into 6) leading to the 1,6-dioxaspiro[4.5]decane skeleton
6 having an (E)-alkoxycarbonylmethylidene moiety. This 1,6-
dioxaspiro[4.5] compound 6 would be a useful intermediate
for further chemical elaboration resulting in the stereoselec-
tive synthesis of various diacetylenic spiroacetal enol ether
natural products 5. This Letter describes our preliminary
results regarding (i) the stereocontrolled construction of the
(2E)-methoxycarbonylmethylidene-3,4-dioxygenated-1,6-
dioxaspiro[4.5]decane framework and (ii) its application to
the first total synthesis of (-)-AL-2 (2).
Scheme 1
The required alkyne derivatives 14 possessing suitable
functionalities for the palladium-catalyzed ring closure
reaction was prepared by conventional means as depicted in
Scheme 2. The selective introduction of a pivaloyl group on
Scheme 2a
would be incorporated into the C-3 and C-4 positions of the
target natural products 5. Kato and Akita8 very recently
reported the palladium(II)-catalyzed formation of the 2-meth-
oxy-(5E)-methoxycarbonylmethylidenetetrahydrofuran frame-
work from the corresponding 1-yne-4-one and 2-yn-5-one
derivatives.9 Thus, the 3,4-dioxygenated-9-hydroxy-1-nonyn-
5-one species 9, prepared from diethyl L-tartrate, would be
expected to undergo a one-pot construction of the core
framework of the target natural products under the conditions
a Reaction conditions: (a) PivCl, Et3N, CH2Cl2, -78 °C; (b)
TBDPSCl, imidazole, DMF, 50 °C; (c) EtMgBr, Et2O rt, (76%);
(d) Dess-Martin oxidation, CH2Cl2, 0 °C to room temperature;
(e) CBr4, PPh3, CH2Cl2, 0 °C; (f) nBuLi, THF, -78 °C, (72%); (g)
PPTS, MeOH, rt, (75%); (h) TBDMSO(CH2)4MgI, CH2Cl2, -78
°C, (74%).
(5) For synthetic studies on total synthesis, see: (a) Toshima, H.;
Furumoto, Y.; Inamura, S.; Ichihara, A. Tetrahedron Lett. 1996, 37, 5707.
(b) Toshima, H.; Aramaki, H.; Furumoto, Y.; Inamura, S.; Ichihara, A.
Tetrahedron 1998, 54, 5531. (c) Toshima, H.; Aramaki, H.; Ichihara, A.
Tetrahedron Lett. 1999, 40, 3587.
the primary alcohol moiety of the known diol 10, derived
from diethyl L-tartrate according to Saito’s procedure,11 was
followed by treatment with tert-butyldiphenylsilyl (TBDPS)
chloride and then ethylmagnesium bromide to afford 11 in
76% yield. Dess-Martin oxidation of 11 gave the corre-
sponding aldehyde, which was subsequently exposed to
Corey’s conditions (dibromoolefination conditions with
carbon tetrabromide and triphenylphosphine and then n-
butyllithium treatment)12 to produce the alkyne derivative
(6) Bohlmann, F.; Florentz, G. Chem. Ber. 1966, 99, 990.
(7) (a) Mukai, C.; Moharram, S. M.; Kataoka, O.; Hanaoka, M. J. Chem.
Soc., Perkin Trans. 1 1995, 2849. (b) Mukai, C.; Moharram, S. M.; Hanaoka,
M. Tetrahedron Lett. 1997, 38, 2511. (c) Mukai, C.; Moharram, S. M.;
Azukizawa, S.; Hanaoka, M. J. Org. Chem. 1997, 62, 8095. (d) Mukai, C.;
Miyakoshi, N.; Hanaoka, M. J. Org. Chem. 2001, 66, 5875.
(8) (a) Kato, K.; Yamamoto, Y.; Akita, H. Tetrahedron Lett. 2002, 43,
4915. (b) Kato, K.; Yamamoto, Y.; Akita, H. Tetrahedron Lett. 2002, 43,
6587.
(9) For similar palladium(II)-catalyzed reactions, see: (a) Utimoto, K.
Pure Appl. Chem. 1983, 54, 1845. (b) Imi, K.; Imai, K.; Utimoto, K.
Tetrahedron Lett. 1987, 28, 3127. (c) Fukuda, Y.; Shiragami, H.; Utimoto,
K.; Nozaki, H. J. Org. Chem. 1991, 56, 5816. (d) Okumoto, H.; Nishihara,
S.; Nakagawa, H.; Suzuki, A. Synlett 2000, 217. (e) Asao, N.; Nogami, T.;
Takahashi, K.; Yamamoto, Y. J. Am. Chem. Soc. 2002, 124, 764 and
references therein.
(10) Yamamoto suggested the intermediacy of the hemiacetal species
for the palladium(II)-catalyzed formation of oxacycles from the carbon-
tethered acetylenic aldehydes on the basis of the 13C NMR experiments.
See ref 9e.
(11) Saito, S.; Kuroda, A.; Tanaka, K.; Kimura, R. Synlett 1996, 231.
2336
Org. Lett., Vol. 5, No. 13, 2003

12 in 72% yield. A selective desilylation of the primary silyl
ether of 12 was realized by treatment with pyridinium
p-toluenesulfonate (PPTS) in methanol to furnish 13 in 75%
yield. Transformation of 13 into the required alkyne 14 was
accomplished as follows. Oxidation of 13 with Dess-Martin
periodinane gave the aldehyde, which was reacted with the
functionalized C4-Grignard reagent. The resulting secondary
hydroxyl compound was oxidized by Dess-Martin periodi-
nane to provide 14 in 74% yield.
Scheme 4a
According to the retrosynthetic analysis described in
Scheme 1, the crucial transformation of 14 into the (2E)-2-
(methoxycarbonylmethylidene)-1,6-dioxaspiro[4.5]decane
framework was investigated. A selective desilylation of 14
was carried out by p-TsOH in THF at room temperature to
afford the corresponding primary hydroxyl compound, which
was then exposed to catalytic amounts of palladium(II)
catalysts in the presence of an oxidizing agent such as
benzoquinone under various conditions.13 However, the
isolable product from the reaction mixture was not the desired
15 but the tetrahydropyran derivative 16,14 although a trace
amount of 15 was sometimes detected. The structure of 16
was confirmed by conversion to 17 under conventional
conditions. The preferential formation of 16 over 15 was
tentatively rationalized in terms of the Lewis acidic property
of the palladium(II) catalyst,9e which might have catalyzed
intramolecular acetalization prior to activation of the triple
bond. After screening several conditions, we finally found
that by using a catalytic amount of palladium(0) catalyst and
excess amounts of oxidizing reagent, in which only a minimal
amount of the active palladium(II) catalyst would be present
in the reaction vessel, we were able to retard the formation
of the undesired acetal. Thus, the primary hydroxyl com-
pound, prepared from 14, was submitted to 5 mol %
Pd2(dba)3‚CHCl3 and 20 equiv of benzoquinone in methanol
under a carbon monoxide atmosphere at room temperature
to produce the desired 15 in 41% yield as the sole
product.15,16 We could now synthesize the (2E)-2-(methoxy-
a Reaction conditions: (a) DIBAL-H, CH2Cl2, -78 °C; (b)
LiDBB, THF, -78 °C, (19: 72%); (c) MnO2, CH2Cl2, rt; (d)
n
TMSCHN2, BuLi, THF, -78 °C, (22: 84%); (e) BzCl, pyridine,
rt; (f) TBAF, THF, rt, (23: 95%); (g) CH3CtC-I, CuI, pyrrolidine,
rt, (25: 60%); (h) MsCl, Et3N, CH2Cl2, 0 °C; (i) K2CO3, MeOH,
rt, (2: 79%).
compound 15 was reduced with diisobutylaluminum hydride
(DIBAL-H) to give 18, which was subsequently transformed
into 20 by the standard method.17 However, introduction of
the propyne moiety to the triple-bond terminus of 20 could
not be realized, even under various conditions, presumably
because of the bulkiness of the silyl protecting group on the
C3-hydroxyl moiety. Thus, the hydroxyl congener 21,
prepared from 20 by removal of the TBDPS group on the
C3-hydroxyl functionality, underwent a coupling reaction
with 1-propynyl iodide in the presence of copper(I) iodide18
to produce 24. It turned out that debenzylation of 24 under
various conditions led to the formation of an intractable
mixture, presumably due to the instability of the enediyne
moiety. Protection of the C3-hydroxyl group of 24 was also
found to be ineffective for the debenzylation reaction. On
the basis of these unsuccessful preliminary experiments, two
considerations became apparent. To complete the transfor-
Scheme 3
(12) Corey, E. J.; Fuchs, P. L. Tetrahedron Lett. 1972, 3769.
(13) Reaction was monitored under various conditions by changing the
kinds of palladium(II) catalysts and oxidizing reagents as well as the amounts
of catalysts and oxidizing reagents.
(14) Mixture of diastereoisomers was obtained.
(15) Structure of 15 was elucidated by spectral evidence. In particular,
NOE experiments revealed no enhancement between the vinylic proton and
H-3 or between H-4 and H-10. In the 3-related (4R,5S)-compounds, an
enhancement between H-4 and H-10 was observed in the NOE ex-
periments.1f,5c
(16) Exclusive formation of the (5R)-isomer might be tentatively
explained by assuming that the reaction proceeds via oxonium intermediate
8.8
carbonylmethylidene)-1,6-dioxaspiro[4.5]decane framework
with suitable oxygen functionalities, in which all of the
stereogenic centers of (-)-AL-2 (2) were constructed in a
stereocontrolled fashion. Therefore, our next efforts focused
on the first total synthesis of (-)-AL-2 (2). The oxaspiro
(17) Procedure similar to the conversion of 19 into 22 was employed.
(18) Alami, M.; Ferri. F. Tetrahedron Lett. 1996, 37, 2763.
Org. Lett., Vol. 5, No. 13, 2003
2337

mation of 15 into the target natural product, (-)-AL-2 (2),
removal of the bulky silyl protecting group on the C3-
hydroxyl moiety prior to the introduction of the terminal
propyne moiety was essential, and the benzyl group on the
C4-hydroxyl group had to be changed to a suitable protecting
group before constructing the enediyne moiety. With these
considerations in mind, the first total synthesis of (-)-AL-2
(2) was completed as follows. DIBAL-H reduction of 15
was followed by debenzylation with lithium di-tert-butyl-
biphenylide (LiDBB)19 in THF at -78 °C to furnish the diol
19 in 72% yield. Compound 19 was oxidized with MnO2 to
provide the corresponding aldehyde, which was subsequently
exposed to lithium trimethylsilyldiazomethylide20 to afford
22 in 84% yield. Conversion of 22 into 23 was realized by
consecutive introduction of a benzoyl group on a C4-hydroxyl
group and desilylation under conventional conditions to
afford 23 in 95% yield. Construction of the enediyne moiety
was achieved by exposure of 23 to 1-propynyl iodide in the
presence of copper(I) iodide and pyrrolidine18 at room
temperature to produce 25 in 60% yield. The final phase of
this synthesis was the formation of the epoxide. Compound
25 was treated with mesyl chloride and triethylamine to give
the C3-mesyloxy derivative, which was then exposed to
potassium carbonate in methanol to produce (-)-AL-2 (2)
in 79% yield. The synthetic (-)-AL-2 (2) was identical to
the natural compound on the basis of their spectral data.
Thus, we achieved the first total synthesis of (-)-AL-2
(2) highly stereoselectively from diethyl L-tartrate. (+)-AL-
2, ent-2, can also be prepared from commercially available
D-tartrate according to this newly developed synthetic
protocol. On the other hand, the 3,4-epoxy functionality of
2 was shown to be susceptible to nucleophilic ring-opening
reaction at the C3-position2b with inversion of stereochemistry.1g
In addition, epimerization of the C6-stereogenic center1g,2b
was also observed. On the basis of these facts, it can be
assumed that the chemical transformation of (-)-2 and/or
(+)-2 to other related natural products would be feasible.
Studies on the total synthesis of similarly related diacetylenic
spiroacetal enol ether natural products are now in progress.
Acknowledgment. This work was supported in part by
a Grant-In-Aid for Scientific Research from the Ministry of
Education, Culture, Sports, Science and Technology, Japan,
to which the authors thanks are due.
Supporting Information Available: Experimental pro-
cedures for conversion of 10 to (-)-2 and 1H and 13C NMR
spectra for 2, 11-15, 19, 22, 23, and 25. This material is
available free of charge via the Internet at http://pubs.acs.org.
(19) Freeman, P. K.; Hutchinson, L. L. J. Org. Chem. 1980, 45, 1924.
(20) Ohira, S.; Okai, K.; Moritani, T. J. Chem. Soc., Chem. Commun.
1992, 721.
(21) Aoyama, T.; Sonoda, N.; Yamauchi, M.; Toriyama, K.; Anzai, M.;
Ando, A.; Shioiri, T. Synlett. 1998, 35.
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