Stereoselective synthesis of eight-membered cyclic ethers by tandem Nicholas reaction/ring-closing metathesis: A short synthesis of (+)-cis-lauthisan

Article abstract of DOI:10.1021/ol052932j

Cis-2,8-disubstituted oxocanes and the parent unsaturated precursors were prepared from the corresponding Co₂(CO)₆-cycloalkynic ethers. Key steps in such synthesis were the ether linkage formation by intermolecular Nicholas reaction, RCM of the suitable acyclic dienyl ether and montmorillonite K-10 induced isomerization of the complexed cycloalkyne. A short synthesis of (+)-cis-lauthisan taking advantage of the developed methodology is described.

Full text of DOI:10.1021/ol052932j

ORGANIC
LETTERS
2006
Vol. 8, No. 5
871-873
Stereoselective Synthesis of
Eight-Membered Cyclic Ethers by
Tandem Nicholas Reaction/Ring-Closing
Metathesis: A Short Synthesis of
(+)-cis-Lauthisan
Nuria Ortega,† Toma´s Mart´ın,‡ and V´ıctor S. Mart´ın*,†
Instituto UniVersitario de Bioorga´nica “Antonio Gonza´lez”, UniVersidad de La
Laguna, Astrof´ısico Francisco Sa´nchez 2, 38206 La Laguna, Tenerife,
Canary Islands, Spain, and Instituto de Productos Naturales y Agrobiolog´ıa,
Consejo Superior de InVestigaciones Cient´ıficas, Astrof´ısico Francisco Sa´nchez 3,
38206 La Laguna, Tenerife, Canary Islands, Spain
Vmartin@ull.es
Received December 2, 2005
ABSTRACT
Cis-2,8-disubstituted oxocanes and the parent unsaturated precursors were prepared from the corresponding Co2(CO)6
−cycloalkynic ethers.
Key steps in such synthesis were the ether linkage formation by intermolecular Nicholas reaction, RCM of the suitable acyclic dienyl ether and
montmorillonite K-10 induced isomerization of the complexed cycloalkyne. A short synthesis of (+)-cis-lauthisan taking advantage of the
developed methodology is described.
Polyfunctionalized medium sized cyclic ethers are the
structural milestone of a wide range of biologically active
Scheme 1. Major Approaches Used in the Synthesis of
natural products, including ladder marine toxins, lauroxanes,
antibiotic, etc.1 Based on the construction of the ring two
major strategies to access such oxacycles have been devel-
oped: via a final C-O formation using a nucleophilic oxygen
or, alternatively, by C-C formation over a preconstructed
linear ether (Scheme 1).2
Polyfunctionalized Cyclic Ethers
Within the last approach, the combination of the synthesis
of the suitable unsaturated branched ether and RCM provided
† Universidad de La Laguna.
‡ Consejo Superior de Investigaciones Cient´ıficas.
(1) (a) Yasumoto, T.; Murata, M. Chem. ReV. 1993, 93, 1897-1909.
(b) Faulkner, D. J. Nat. Prod. Rep. 2002, 19, 1-48 and preceding issues.
(2) Alvarez, E.; Candenas, M. L.; Pe´rez, R.; Ravelo, J. L.; Mart´ın, J. D.
Chem. ReV. 1995, 95, 1953-1980. (b) Mori, Y. Chem. Eur. J. 1997, 3,
849-852. (c) Hoberg, L. O. Tetrahedron 1998, 54, 12631-12670. (d)
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a powerful methodology to the synthesis of isolated and fused
medium sized cyclic ethers.3,4 Two critical issues in such
strategy are the stereoselective access to the ether linkage
between two stereogenic secondary carbons and the unfavor-
able entropy factors of eight-membered rings.4
10.1021/ol052932j CCC: $33.50
© 2006 American Chemical Society
Published on Web 02/02/2006

In this paper, we report on a new approach to the
stereocontrolled synthesis of 2,8-dialkyl oxocanes 1 through
the parent 5,8-dihydro-2H-oxocine 2, taking advantage of
the chemical and structural properties induced by the
formation of Co2(CO)6 complexes in propargylic systems
(Scheme 2).5 We envisioned the synthesis of these hetero-
methodology based on the trapping of propargylic cations
using alcohols as nucleophiles.7 Initial work using (S)-non-
1-en-3-ol10 (7, R2 ) C6H13-n) (Scheme 3)11 as the incoming
Scheme 3. Preparation of (S)-Non-1-en-3-ol from
(2S,3S)-2,3-Epoxy-1-nonanol
Scheme 2. Retrosynthetic Analysis for the Stereoselective
Synthesis of 2,8-Dialkyl Oxocanes
alcohol over the cobalt complex of racemic oct-7-en-4-yn-
3-ol12 was fruitless yielding a complex mixture, presumably
by internal participation of the double bond of the enyne
substrate. Trying to overcome this difficulty, we turned our
attention on the cobalt complex of commercially available
racemic 1-pentyn-3-ol (6, R1 ) C2H5) relying the allylation
process for a latter step in the synthesis. However, when
applying the reported conditions7 yield and conversion to
the desired linear ether 5 were again scarce. Trying to
improve the conditions, we thoroughly examined many
experimental variables such as temperature, rate and order
of addition of reagents, amount of Lewis acid and concentra-
tion. As a result of this study, we found that the best
conditions needed relative high concentration (0.2 M), 2
equiv of Lewis acid and slow addition of the secondary
alcohol (Scheme 4).12 Although at this point of the synthesis
cycles through the Co2(CO)6-cycloalkynic ether 3 that could
be synthesized from the unsaturated alkyne-cobalt 4 by
means of a RCM.6 This precursor could be unveiled upon
allylation of alkyne 5. Finally, this propargylic ether, having
two stereogenic centers close to the oxygen, was disas-
sembled to the complexed propargylic alcohols 6 and the
secondary allylic alcohol 7 through an intermolecular
Nicholas reaction.7 The power of the developed methodology
is exemplified in the synthesis of (+)-cis-lauthisan (1, R1 )
C2H5, R2 ) C6H13-n).8,9
The synthesis of the cobalt-complexed ether 4 (R1 ) C2H5,
R2 ) C6H13-n) was initiated applying our previously reported
Scheme 4. Direct Preparation of Linear Ethers Having the
(3) For representative examples, see: (a) Hirama, M. Oishi, T.; Uehara,
H.; Inoue, M.; Maruyama, M.; Oguri, H.; Satake, M. Science 2001, 294,
1904-1907. (b) Crimmins, M. T.; She, J. J. Am. Chem. Soc. 2004, 126,
12790-12791. (c) Clark, J. S.; Kimber, M. C.; Robertson, J.; McErlean,
C. S. P.; Wilson, C. Angew. Chem., Int. Ed. 2005, 44, 6157-6162.
(4) (a) Crimmins, M. T.; Choy, A. L. J. Am. Chem. Soc. 1999, 121,
5653-5660. (b) Rhee, H. J.; Beom, H. Y.; Kim, H.-D. Tetrahedron Lett.
2004, 45, 8019-8022. (c) Denmark, S. E.; Yang S.-M. J. Am. Chem. Soc.
2004, 126, 12432-12440.
Linkage between Two Stereogenic Secondary Carbons
(5) For the synthesis of cyclic ethers by intramolecular Nicholas reactions,
see: (a) Mukai, C.; Yamaguchi, S.; Sugimoto, Y.; Miyakoshi, N.;
Kasamatsu, E.; Hanaoka, M J. Org. Chem. 2000, 65, 6761-6765 and
references therein. (b) Kira, K.; Tanda, H.; Hamajima, A.; Baba, T.; Takai,
S.; Isobe, M. Tetrahedron 2002, 58, 6485-6492 and references therein.
(c) Betancort, J. M.; Mart´ın, T.; Palazo´n, J. M.; Mart´ın, V. S. J. Org. Chem.
2003, 68, 3216-3224.
(6) (a) Green, J. R. Synlett 2001, 353-356. (b) Young, D. G. J.; Burlison,
J. A.; Peters, U. J. Org. Chem. 2003, 68, 3494-3497. (c) Yang, Z.-Q.;
Geng, X.; Solit, D.; Pratilas, C. A.; Rosen, N.; Danishefsky, S. J. J. Am.
Chem. Soc. 2004, 126, 7881-7889.
it was very difficult to ensure the stereoselection of the newly
created stereocenter in compound 5, more elaborated frag-
ments in the synthesis (vide infra) showed us a ratio of
approximately 1:1.7 of both diastereoisomers in favor of the
undesired stereoisomer.
With the ether 5 in hand, the preparation of the necessary
diene for the RCM step requires only a simple alkylation.
To this end, copper-catalyzed homologation of 5 with allyl
bromide provided the dienyl derivative 8 in excellent yield.
To overcome the unfavorable entropic and enthalpic factors
involved in the formation of the eight membered ring (the
final ring has an endocyclic triple bond) we decided to take
advantage of the bending in the acetylenic system when
(7) D´ıaz, D. D.; Mart´ın, V. S. Tetrahedron Lett. 2000, 41, 9993-9996.
(8) (a) Blunt, J. W.; Lake, R. J.; Munro, M. H. G.; Yorke, S. C. Aust. J.
Chem. 1981, 34, 2393-2400. (b) Fukazawa, A. Masamune, T. Tetrahedron
Lett. 1981, 22, 4081-4084.
(9) For a previously reported synthesis of lauthisan, see: (a) Reference
4b. (b) Carling, R. W.; Holmes, A. B. J. Chem. Soc., Chem. Commun. 1986,
565-567. (c) Kotsuki, H.; Ushio, Y.; Kadota, I.; Ochi, M. J. Org. Chem.
1989, 54, 5153-5161. Tsushima, K.; Murai, A. Chem. Lett. 1990, 761-
764. (d) Nicolaou, K. C.; McGarry, D. G.; Somers, P. K.; Kim, B. H.;
Ogilvie, W. W.; Yiannikouros, G.; Prasad, C. V. C.; Veale, C. A.; Hark,
R. R. J. Am. Chem. Soc. 1990, 112, 6263-6276. (e) Paquette, L. A.;
Sweeney, T. J. J. Org. Chem. 1990, 55, 1703-1704. (f) Udding, J. U.;
Giesselink, J. P. M.; Hiemstra, H.; Speckamp, W. N. J. Org. Chem. 1994,
59, 6671-6682. (g) Kim, H.; Ziani-Cherif, C.; Oh, J.; Cha, J. K. J. Org.
Chem. 1995, 60, 792-793. (h) Suh, Y.-G.; Koo, B.-A.; Kim, E.-N.; Choi,
N.-S. Tetrahedron Lett. 1995, 36, 2089-2092. (i) Coster, M. J.; De Voss,
J. J. Org. Lett. 2002, 4, 3047-3050. (j) Carren˜o, M. C.; Des Mazery, R.;
Urbano, A.; Colobert, F.; Solladie, G. Org. Lett. 2005, 7, 2039-2042.
(10) Mart´ın, V. S.; Woodard, S. S.; Katsuki, T.; Yamada, Y.; Ikeda, M.;
Sharpless, K. B. J. Am. Chem. Soc. 1981, 103, 6237-6240.
(11) Yadav, J. S.; Shekharam, T.; Gadgil, V. R. J. Chem. Soc., Chem.
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(12) See the Supporting Information for experimental details.
872
Org. Lett., Vol. 8, No. 5, 2006

forming the cobalt complex.6,13 In addition, the cobalt
complex should avoid the undesirable participation of the
triple bond in the metathesis process.14 Thus, when 8 was
submitted to Co2(CO)8 the cobalt complex 4 was obtained
in quantitative yield (Scheme 5). Any attempt to perform
proved to be highly efficient to perform the desired conver-
sion.17 The original mixture evolved quantitatively to a nice
cis/trans ratio of 17:1 (Scheme 6).
Scheme 6. Isomerization of 2,8-Dialkyl
Co2(CO)6-Cycloalkynic Ethers by Montmorillonite K-10
Scheme 5. Preparation of Co2(CO)6-Cycloalkynic Ethers by
RCM
The last steps required to complete the synthesis of the
target lauthisan were the cleavage of the cobalt complex and
reduction to the final oxacycle (Scheme 7). The reductive
Scheme 7. Reductive Cleavage of Co2(CO)6-Cycloalkynic
Ethers and Hydrogenation
cyclization using first-generation Grubbs’ catalyst led to
poor conversion and yields of cyclic ethers (ca. 18%).
Satisfactorily, when second-generation Grubbs’ catalyst
was used under diluted conditions (0.001 M) an 83% yield
of 3 was obtained.15 Interestingly, at this point of the
synthesis both diastereoisomers were separated very easily
by silica gel column chromatography. NOE studies of both
isomers permitted the assignment of the relative stereochem-
istry.
decomplexation reported by Isobe et al. produced very
efficiently the cyclodiene 2 (R1 ) C2H5, R2 ) C6H13-n),
although as a inseparable mixture of stereoisomers in the
newly created double bond.18 However, the hydrogenation
under standard conditions of 2 provided cleanly (+)-cis-
lauthisan 1, [R]25 ) +4.1 (c 0.9, CHCl3).9j
D
In summary, we have described a new and efficient ap-
proach to the stereocontrolled synthesis of saturated eight
membered 2,8-dialkyl cyclic ethers. Our methodology in-
volved a new way to prepare linear ethers having two secon-
dary carbons next to the oxygen. In addition to the ring form-
ation using RCM, a key step is also a new isomerization of
Co2(CO)6-cycloalkyne ether complexes catalyzed by mont-
morillonite K-10. All these procedures were exemplified in
the synthesis of (+)-cis-lauthisan.
As aforementioned, separation of both diastereoisomers
was very simple at this step. However, considering that the
major isomer isolated was trans-3, we pondered the pos-
sibility of performing an isomerization to the cis-isomer
considering that such stereoisomers are usually thermody-
namically more stable.7b Disappointingly, treatment of cis/
trans mixture of 3 under various acidic conditions (including
BF3‚OEt2, CF3COOH, and TsOH) produced either decom-
position or complete recovery of the starting mixture.16
Fortunately, our recently reported conditions relative to the
use of montmorillonite K-10 as acid in the Nicholas reaction
Acknowledgment. This research was supported by the
Ministerio de Ciencia y Tecnolog´ıa (PPQ2002-04361-C04-
02) and the Canary Islands Government.
(13) (a) Melikyan, G. G.; Bright, S.; Monroe, T.; Hardcastle, K. I.;
Ciurash, J. Angew. Chem., Int. Ed. 1998, 37, 163-164. (b) Young, D. G.
J.; Burlison, J. A.; Peters, U. J. Org. Chem. 2003, 68, 3494-3497.
(14) Diver, S. T.; Giessert, A. J. Chem. ReV. 2004, 104, 1317-1382.
(15) (a) Chatterjee, A. K.; Grubbs, R. H. Org. Lett. 1999, 1, 1751-
1753. (b) Trnka, T. M.; Grubbs, R. H. Acc. Chem. Res. 2001, 34, 18-29.
(16) For acid-induced isomerization in fused medium-sized Co2(CO)6-
cycloalkyne ethers, see: (a) Liu, T.-Z.; Li, J.-M.; Isobe, M. Tetrahedron
2000, 56, 10209-10219. (b) Reference 5c.
Supporting Information Available: Experimental de-
1
tails, spectroscopic characterization, and H NMR and 13C
NMR spectra for all new compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
OL052932J
(17) Criso´stomo, F. R. P.; Carrillo, R.; Mart´ın, T.; Mart´ın, V. S.
Tetrahedron Lett. 2005, 46, 2829-2832.
(18) (a) Hosokawa, S.; Isobe, M. Tetrahedron Lett. 1998, 39, 2609-
2612. (b) Shibuya, S.; Isobe, M. Tetrahedron 1998, 54, 6677-6698.
Org. Lett., Vol. 8, No. 5, 2006
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