reduction of the thus obtained indanone proceeded only with
poor enantioselectivity and therefore prevented a truly
asymmetric approach to this set of natural products.
The transition metal catalyzed [2 + 2 + 2] alkyne
cycloaddition is a powerful reaction for the construction of
highly substituted benzenes.8 However, despite its versatility
and its atom- and step-economic features, applications of this
capable catalytic method in natural product synthesis still
remain rare.9 One drawback of this methodology seems to
be the often cumbersome synthesis of the functionalized
triyne serving as the cyclotrimerization precursor. However,
we have previously described the asymmetric synthesis of
alcyopterosin E (2) that gains its advantage from the
assembly of the triyne through a simple esterification.9k
We disclose here a synthetic strategy that is based on a
modular approach to gain access to a set of alcyopterosins
having either a tricyclic or a bicyclic core, and either one or
two independent asymmetric centers. We envisaged that the
alcyopterosin skeleton could be assembled through an ABC-
ring formation approach based on transition metal catalyzed
[2 + 2 + 2] cycloaddition reactions with suitable function-
alized triynes 8 (Scheme 1). Depending on the tether lengths
in 8, this strategy should provide access to the angular fused
[5-6-6]-, as well as the [5-6-5]-ring system of the
targeted alcyopterosins. In turn the cyclotrimerization precur-
sors, the triynes 8, will be obtained via operational simple
esterifications or ether formations. Furthermore, the overall
synthetic strategy will take advantage of the use of chiral
building blocks such as the diyne (S)-9, that should be
received through an enantioselective reduction of the readily
available ynone 10.
Scheme 1. Retrosynthetic Analysis
Scheme 2. Preparation of the Key Building Block (S)-9
(5) Tanaka, R.; Nakano, Y.; Suzuki, D.; Urabe, H.; Sato, F. J. Am. Chem.
Soc. 2002, 124, 9682.
(6) Nakao, Y.; Hirata, Y.; Ishihara, S.; Oda, S.; Yukawa, T.; Shirakawa,
E.; Hiyama, T. J. Am. Chem. Soc. 2004, 126, 15650.
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(8) (a) Shibata, T.; Tsuchikama, K. Org. Biomol. Chem. 2008, 6, 1317.
(b) Tanaka, K. Synlett 2007, 1977. (c) Galan, B. R.; Rovis, T. Angew. Chem.,
Int. Ed. 2009, 48, 2830. (d) Agenet, N.; Buisine, O.; Slowinski, F.; Gandon,
V.; Aubert, C.; Malacria, M. Organic Reactions; Ranjan Babu, T. V., Ed.;
John Wiley & Sons: Hoboken, NJ, 2007; Vol. 68, pp 1-302. (e) Chopade,
P. R.; Louie, J. AdV. Synth. Catal. 2006, 348, 2307. (f) Saito, S.; Yamamoto,
Y. Chem. ReV. 2000, 100, 2901.
Scheme 2 summarizes the synthesis of the key building
block (S)-9. Propargylation10 of ethyl butyrate (11) with
propargyl bromide was followed by saponification and
conversion of the thus received carboxylic acid into the acid
chloride 12 with thionyl chloride. Treatment of 12 with bis-
trimethylsilyl acetylene in the presence of AlCl3 resulted in
a straightforward monoacylation of the bis-silylated acety-
lene11 to give the ynone 10 (94% yield). Enantioselective
transfer hydrogenation of 10 utilizing Noyori’s catalyst12
(1S,2S)-13 in 2-propanol afforded the corresponding chiral
alcohol with an excellent enantioselectivity (74% yield, 99%
ee).13 The thus obtained chiral propargylic alcohol was
thereafter MOM-protected to provide the desired key building
block (S)-9 in 86% yield. Other enantioselective ketone
reductions utilizing LiAlH4/Darvon alcohol (46% yield, 31%
ee),14 or BH3-SMe2 in the presence of Garcia’s (S)-
oxazoborolidine (72% yield, 88% ee),15 were less effective
with 10. These results confirm that Noyori’s catalyst has
(9) For the synthesis of natural products by transition metal mediated
[2 + 2 + 2] cycloadditions, see: (a) (() Cryptoacetalide: Zou, Y.; Deiters,
A. J. Org. Chem. 2010, 75, 5355. (b) Antiostatin A1: Alayrac, C.;
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B: Nicolaou, K. C.; Tang, Y.; Wang, J. Angew. Chem., Int. Ed. 2009, 48,
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(e) Illudinine: Teske, J. A.; Deiters, A. J. Org. Chem. 2008, 73, 342. (f)
(-)-Bruguierol A: Ramana, C. V.; Salian, S. R.; Gonnade, R. G. Eur. J.
Org. Chem. 2007, 5483. (g) (-)-8-O-Methyltetrangomycin: Kesenheimer,
C.; Groth, U. Org. Lett. 2006, 8, 2507. (h) (() Viridin: Anderson, E. A.;
Alexanian, E. J.; Sorensen, E. J. Angew. Chem., Int. Ed. 2004, 43, 1998.
(i) Taiwanin: Sato, Y.; Tamura, T.; Mori, M. Angew. Chem., Int. Ed. 2004,
43, 2436. (j) (+)-Rubiginone: Kalogerakis, A.; Groth, U. Synlett 2003, 1886.
(k) Alcyopterosin E: Witulski, B.; Zimmermann, A.; Gowans, N. D. Chem.
Commun. 2002, 2984. (l) Clausine C and hyellazole: Witulski, B.; Alayrac,
C. Angew. Chem., Int. Ed. 2002, 41, 3281. (m) (S)-3-n-Butylphthalide:
Witulski, B.; Zimmermann, A. Synlett 2002, 1855. (n) (()-Strychnine:
Eichberg, M. J.; Dorta, R. L.; Grotjahn, D. B.; Lamottke, K.; Schmidt, M.;
Vollhardt, K. P. C. J. Am. Chem. Soc. 2001, 123, 9324. (o) (()-Lysergene:
Saa, C.; Crotts, D. D.; Hsu, G.; Vollhardt, K. P. C. Synlett 1994, 487. (p)
(()-Stemodin: Germanas, J.; Aubert, C.; Vollhardt, K. P. C. J. Am. Chem.
Soc. 1991, 113, 4006. (q) Camptothecin: Earl, R. A.; Vollhardt, K. P. C.
J. Am. Chem. Soc. 1983, 105, 6991. (r) Pterosin Z and (()-calomelano-
lactone: Neeson, S. J.; Stevenson, P. J. Tetrahedron 1989, 45, 6239. (s)
(()-Estron: Funk, R. L.; Vollhardt, K. P. C. J. Am. Chem. Soc. 1980, 102,
5253.
(10) Magnus, P.; Slater, M. J.; Principe, L. M. J. Org. Chem. 1989, 54,
5148.
(11) Birkofer, L.; Ritter, A.; Uhlenbrauck, H. Chem. Ber. 1963, 96, 3280.
(12) Haack, K.-J.; Hashiguchi, S.; Fujii, A.; Ikariya, T.; Noyori, R.
Angew. Chem., Int. Ed. 1997, 36, 285.
(13) The ee value was determined by chiral GC (CP-Chirasil-Dex CB)
after its MOM-protection to give compound (S)-9.
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