An approach to lauroxanes by iterative use of Co2(CO) 6-acetylenic complexes. A formal synthesis of (+)-laurencin

Article abstract of DOI:10.1021/jo101566x

A new approach to lauroxanes by a powerful and highly convergent methodology based on iterative use of Co₂(CO)₆-acetylenic complexes is described. The strategy employs an intermolecular Nicholas reaction to form unsaturated branched linear ethers, a ring closing metathesis to obtain the cobalt complex cyclic ethers, and an isomerization promoted by montmorillonite K-10. A short synthesis of cyclic ethers of seven-, eight-, and nine-membered rings is described. Additionally, the methodology is exemplified by the formal synthesis of (+)-laurencin, a red algae metabolite.

Full text of DOI:10.1021/jo101566x

pubs.acs.org/joc
An Approach to Lauroxanes by Iterative Use of Co2(CO)6-Acetylenic
Complexes. A Formal Synthesis of (þ)-Laurencin†
,†
n,* and Tomas Martı
Nuria Ortega,† Victor S. Martı
´
´
n*,†,‡
ꢀ
†
´
ꢀ
ꢀ
ꢀ
Departamento de Quımica Organica, Instituto Universitario de Bioorganica “Antonio Gonzalez”,
´
Universidad de La Laguna, Astrofısico Francisco Sanchez 2, 38206 La Laguna, Tenerife, Islas Canarias,
ꢀ
‡
Spain, and Instituto de Productos Naturales y Agrobiologıa, Consejo Superior de Investigaciones
´
Cientıficas, Astrofısico Francisco Sanchez 3, 38206 La Laguna, Tenerife, Islas Canarias, Spain
´
´
ꢀ
vmartin@ull.es; tmartin@ipna.csic.es
Received August 9, 2010
A new approach to lauroxanes by a powerful and highly convergent methodology based on iterative
use of Co2(CO)6-acetylenic complexes is described. The strategy employs an intermolecular Nicholas
reaction to form unsaturated branched linear ethers, a ring closing metathesis to obtain the cobalt
complex cyclic ethers, and an isomerization promoted by montmorillonite K-10. A short synthesis of
cyclic ethers of seven-, eight-, and nine-membered rings is described. Additionally, the methodology
is exemplified by the formal synthesis of (þ)-laurencin, a red algae metabolite.
Introduction
the presence of halogenated cyclic ethers with a defined
stereochemistry in the substituents and ring size ranging
from five to nine members. Most have cis stereochemistry
at the positions adjacent (R,R0) to the oxygen atom of the
ether. Such cyclic ethers are considered to be biogenetically
originated from linear laurediols, which occur in nature as
various stereoisomers, through electrophilic cyclizations
usually induced by a bromonium ion.1e
The fascinating structures and biological activities of such
naturally occurring medium-ring oxacycles have stimulated the
imagination and have been a challenge for synthetic chemists,
and therefore a significant level of effort has been focused on the
development of new methodologies for their synthesis. In gen-
eral terms, the unfavorable entropy and enthalpy of activation
associated with the formation of medium sized cyclic ethers have
been a disadvantage for their synthesis. However, a plethora
of methods have been developed to construct these systems.2
Essentially, theycanbesummarizedmainlyontwomajorstrate-
gies: through the formation of a C-O bond, using a nucleophilic
Medium-ring oxacycles are important structural features
present and widespread in many marine natural products
such as brevetoxin A and B, yessotoxin, ciguatoxin, gambie-
ric acid A, the eunicellins, and maitotoxin, some of them
implicated in massive fish kills and ciguatera seafood poison-
ing.1 In addition, an important group of marine natural
products, called lauroxanes, contain medium-ring ethers
(Figure 1). Lauroxanes are a series of nonterpenoid C15-
metabolites derived from fatty acid metabolism (acetoge-
nins) that have been isolated from the Laurencia species of
red algae, and those marine organisms which feed on L. sp.
These compounds display a wide range of biological activity
including antitumor, antimicrobial, immunosuppressant,
antifeedant, pesticide activity, etc.1 The structural diversity
of this kind of molecules is very wide, but all have in common
†
ꢀ
Dedicated to Professor Jose Barluenga Mur on the occasion of his 70th
birthday.
(1) (a) Moore, R. E. In Marine Natural Products; Scheuer, P. J., Ed.;
Academic Press: New York, 1978; Vol. 1, pp 43-121. (b) Erickson, K. L. In
Marine Natural Products; Scheuer, P. J., Ed.; Academic Press: New York,
1983; Vol. V, pp 131-257. (c) Yasumoto, T.; Murata, M. Chem. Rev. 1993,
93, 1897–1909. (d) Faulkner, D. J. Nat. Prod. Rep. 2002, 19, 1–48. and
preceding issues. (e) Kurozawa, E.; Fukuzawa, A.; Irie, T. Tetrahedron Lett.
1972, 2121–2124.
ꢀ
(2) (a) Alvarez, E.; Candenas, M. L.; Perez, R.; Ravelo, J. L.; Martın,
´
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) Nicolaou,
K. C.; Vourloumis, D.; Winssinger, N.; Baran, P. S. Angew. Chem., Int. Ed.
€
2000, 39, 44–122. (e) Marmsater, F. P.; West, F. G. Chem.;Eur. J. 2002, 8,
4346–4353.
6660 J. Org. Chem. 2010, 75, 6660–6672
Published on Web 09/02/2010
DOI: 10.1021/jo101566x
r
2010 American Chemical Society

Ortega et al.
JOCArticle
SCHEME 2. Retrosynthetic Analysis of Cyclic Ethers Based on
Tandem Intermolecular Nicholas Reaction (interNR) and RCM
challenge for the synthesis of the oxacycles. Even more
interesting is to develop a tandem strategy that allows us to
perform the formation of linear ether precursor and con-
secutively a RCM. In this sense we focused our attention on
an intermolecular Nicholas reaction4 (interNR) to build up
the linear precursor.5 With the branched linear ethers in
hand, the next step would be the synthesis of the medium
sized cyclic ethers through a RCM.6 This tandem strategy
has two alternative approaches (Scheme 2): (a) locating the
alkyne Co2(CO)6-complexed moiety in an endo position with
respect to the cyclic ether or (b) where such functionality is
placed in an exo position.
FIGURE 1. Representative C15 medium sized cyclic ether marine
metabolites.
SCHEME 1. Main Strategies Used in the Synthesis of Poly-
functionalized Cyclic Ethers
Recently, using the endo strategy, path a in Scheme 2, we
were able to obtain the saturated ethers (þ)-cis- and (-)-
trans-lauthisan and (þ)-cis- and (þ)-trans-obtusan, whose
structures represent the basic skeletons present in a number of
these naturally occurring nonterpenoid eight- and nine-mem-
bered ring ethers.7,8 However, this approach has two important
drawbacks. First, we could not use an allyl group in position R3
of the Co2(CO)6-complexed propargylic alcohols, since the
double bond of the substrate competes with the incoming oxygen
by an intramolecular Nicholas reaction (intraNR). This compe-
tition forced us to introduce the allyl group after the linear ether
was formed, lengthening the synthesis in several steps. Second, as
suggested by our earlier exploratory investigations, with this
approach we could not obtain seven-membered oxacycles.
On the basis of the alternative exo approach, herein, we
report a powerful and highly convergent methodology that
oxygen, or by C-C bond formation using a linear ether
precursor (Scheme 1).2
Within the last approach, the combination of the synthesis
of the suitable unsaturated branched ether and ring-closing
metathesis (RCM) provided a powerful methodology to the
synthesis of isolated and fused medium sized cyclic ethers.3
In consequence, the preparation of the R,R0-disubstituted
linear ether precursor has become an intriguing synthetic
(3) For representative examples, see: (a) Nicolaou, K. C.; Postema,
M. H. D.; Claiborne, C. F. J. Am. Chem. Soc. 1996, 118, 1565–1566. (b)
Clark, J. S.; Kettle, J. G. Tetrahedron Lett. 1997, 38, 123–126. (c) Linderman,
R. J.; Siedlecki, J.; O’Neill, S. A.; Sun, H. J. Am. Chem. Soc. 1997, 119, 6919–
6920. (d) Crimmins, M. T.; Choy, A. L. J. Org. Chem. 1997, 62, 7548–7549.
(e) Hirama, M.; Oishi, T.; Uehara, H.; Inoue, M.; Maruyama, M.; Oguri, H.;
Satake, M. Science 2001, 294, 1904–1907. (f) Kadota, I.; Uyehara, H.;
Yamamoto, Y. Tetrahedron 2004, 60, 7361–7365. (g) Denmark, S. E.; Yang,
S.-M. J. Am. Chem. Soc. 2004, 126, 12432–12440. (h) Crimmins, M. T.; She,
J. J. Am. Chem. Soc. 2004, 126, 12790–12791. (i) Clark, J. S.; Kimber, M. C.;
Robertson, J.; McErlean, C. S. P.; Wilson, C. Angew. Chem., Int. Ed. 2005,
44, 6157–6162. (j) Fujiwara, K.; Yoshimoto, A.; Souma, S.-I.; Mishima, H.;
Murai, A.; Kawai, H.; Suzuki, T. Tetrahedron Lett. 2005, 46, 6819–6822. (k)
Sato, K.; Sasaki, M. Angew. Chem., Int. Ed. 2007, 46, 2518–2522. (l) Park, J.;
Kim, B.; Kim, H.; Kim, S.; Kim, D. Angew. Chem., Int. Ed. 2007, 46, 4726–
4728. (m) Sasaki, M.; Oyamada, K.; Takeda, K. J. Org. Chem. 2010, 75,
3941–3943.
(4) (a) Lockwood, R. F.; Nicholas, K. M. Tetrahedron Lett. 1977, 4163–
4167. (b) Nicholas, K. M. Acc. Chem. Res. 1987, 20, 207–214. (c) Schreiber,
S. L.; Sammakia, T.; Crowe, W. E. J. Am. Chem. Soc. 1996, 108, 3128–3130.
(d) Green, J. R. Curr. Org. Chem. 2001, 5, 809–826. (e) Teobald, B. J.
Tetrahedron 2002, 58, 4133–4170. (f) Diaz, D. D.; Betancort, J. M.; Martin,
V. S. Synlett 2007, 343–359. (g) Green, J. R. Eur. J. Org. Chem. 2008, 6053–
6062.
(5) For the synthesis of cyclic ethers by intramolecular Nicholas reac-
tions, see: (a) Mukai, C.; Yamaguchi, S.; Sugimoto, Y.; Miyakoshi, N.;
Kasamatsu, E.; Hanaoka, M. J. Org. Chem. 2000, 65, 6761–6765. and
ꢀ
references cited therein. (b) Crisostomo, F. R. P.; Martın, T.; Martın, V. S.
´ ´
Org. Lett. 2004, 66, 565–568 and references cited therein. (c) Hamajima, A.;
Isobe, M. Org. Lett. 2006, 8, 1205–1208. and references cited therein.
(d) Hamajima, A.; Isobe, M. Angew. Chem., Int. Ed. 2009, 48, 2941–2945.
and references cited therein.
(6) For a RCM with cobalt alkyne complex, see: (a) Green, J. R. Synlett
2001, 353–356. (b) Burlison, J. A.; Gray, J. M.; Young, D. G. J. Tetrahedron
Lett. 2001, 42, 5363–5365. (c) Young, D. G. J.; Burlison, J. A.; Peters, U. J.
Org. Chem. 2003, 68, 3494–3497. (d) Rosillo, M.; Casarrubios, L.; Dom-
ꢀ
ınguez, G.; Perez-Castells, J. Org. Biomol. Chem. 2003, 1, 1450–1451. (e)
´
Yang, Z.-Q.; Geng, X.; Solit, D.; Pratilas, C. A.; Rosen, N.; Danishefsky,
S. J. J. Am. Chem. Soc. 2004, 126, 7881–7889.
(7) Ortega, N.; Martı
563.
(8) Ortega, N.; Martı
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n, T.; Martı
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n, V. S. Eur. J. Org. Chem. 2009, 554–
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n, T.; Martı
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n, V. S. Org. Lett. 2006, 8, 871–873.
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SCHEME 3. Preparation of Co2(CO)6-Propargylic Alcohols
SCHEME 4. Evaluation of the Cobalt Complex in the exo
Bearing Remote Terminal Alkenea
Approacha
aReagents and conditions: (a) allylmagnesium bromide, Et2O, -78 °C,
94%; (b) Me3SiCtCH, n-BuLi, THF, -78 °C, 89%; (c) (i) (COCl)2,
DMSO, CH2Cl2, -78 °C, 1 h, then Et3N, -78 °C f rt, (ii) Me3SiCtCH,
n-BuLi, THF, -78 °C, 87% over two steps; (d) Co2(CO)8, CH2Cl2, rt,
quantitative.
allows us a very short synthesis of seven-, eight-, and nine-
membered cyclic ethers by a real tandem interNR and RCM.
When the target product has a cis stereochemical relation-
ship in the R,R0 position, a consecutive isomerization step can
be used. Additionally, using this strategy, we disclose a
formal synthesis of the enantiomer of the natural product
(þ)-laurencin.
aReagents and conditions: (a) BF3 OEt2, CH2Cl2 (0.5 M), 0 °C;
3
(b) BF3 OEt2, CH2Cl2 (0.5 M), -20 °C.
3
(Scheme 5). The preparation of the enantiomerically en-
riched alcohols 11 and 12 has been previously described,7
and the alcohol 13 was obtained, as a racemic mixture, by
addition of n-butyllithium to the commercially available
4-pentenal. The optimized conditions for the interNR7
afforded in very good yields the doubly branched ethers
14, 15, and 16, respectively. At this point of the synthesis, the
stereoselection of the newly created stereocenter in com-
Results and Discussion
Our study started with the exploration of the suitable
position of the double bond in R2 of the cobalt complex in
order to avoid undesirable intramolecular Nicholas or elim-
ination reactions. Thus, the synthesis of a series of substrates
was achieved, in which propargylic alcohol and a terminal
alkene were linked through an alkyl chain with a variable
length. To perform the synthesis of these compounds, we
used as starting materials the appropriate commercially
available aldehydes or alcohols (Scheme 3). In this way,
propargylic alcohols 1,9 2,6c and 3 could be obtained by a
simple addition of the suitable organometallic compound to
aldehydes, and subsequent complexation with Co2(CO)8
providing the corresponding alkyne complexes 4, 5, and 6.
The next step was to determine in which of these cobalt
complexes occurs the interNR. Thus, we selected the 1,6-
heptadien-4-ol as a common nucleophile to carry out this
reaction (Scheme 4). We found that the cobalt complex 5 was
the optimal, since we obtained the desired linear ether 9 with
very good yields. Alternatively, the complex 6 gave mixtures
including carbocycle 10 via an intramolecular carbon-cycli-
zation reaction instead of the desired interNR. The use of 4
provided mainly the fully conjugated compound 7, due to the
elimination of the propargyl alcohol. Interestingly, 4 gave
the desired interNR at lower temperatures (-20 °C), albeit
contaminated with some elimination product. Taking into
account these results we decided to use the cobalt complex 5
as a model for our exo approach to the synthesis of medium-
sized cyclic ethers.
1
pound 14 could be determined by its H NMR spectrum,
observing a ratio of approximately 1.0:1.1, as later con-
firmed, in favor of the R,R0-anti-isomer.12 Although it was
very difficult to ensure the stereoselection in compounds 15,
a more elaborated fragment in the synthesis (vide infra)
showed us a ratio of approximately 1.1:1.0, in favor of the
R,R0-syn-isomers.12 Unfortunately, we were unable to deter-
minate the stereoselection obtained from compound 16, even
using more advanced intermediates.
Having accomplished the important task of creating the
proper substituted linear ether, we could now embark on the
construction of cyclic ethers by the ring-closing metathesis
process. Two major advantages can be attained from the use
of the cobalt alkyne complex in the RCM process: first, the
cobalt complex should avoid the undesirable participation of
the triple bond in the metathesis process,13 and second, the
Co2(CO)6-alkyne in the exo position can be used as a
functional group for further transformations and also as a
stereochemical control agent for a critical isomerization
process in the final cyclic product. With the diene complex
14 in hand, closure of the oxepene with the second-genera-
tion Grubbs’ catalyst was performed. Thus, exposure of
diene cobalt complex 14 to 30 mol % of the catalyst in
dichloromethane (0.001 M) at reflux cleanly produced the
(12) Diastereoisomers anti and syn of the R,R0-disubstituted linear ethers
are defined as described below:
With the optimal cobalt complex 5 in hand, the following
step was to perform the interNR using the allylic 11, homo-
allylic 12,10 and bishomoallylic 1311 alcohols as nucleophiles
(9) The physical data are in agreement with the literature values:
Darvesh, S.; Grant, A. S.; MaGee, D. I.; Valenta, Z. Can. J. Chem. 1991,
69, 712–722.
(10) The physical data are in agreement with the literature values: Emde,
U.; Koert, U. Eur. J. Org. Chem. 2000, 1889–1904.
(11) The physical data are in agreement with the literature values: Janza,
B.; Studer, A. J. Org. Chem. 2005, 70, 6991–6994.
(13) For representative examples of enyne metathesis, see: Diver, S. T.;
Giessert, A. J. Chem. Rev. 2004, 104, 1317–1382.
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SCHEME 5. Tandem Process of interNR and RCM To Synthesize the Cobalt Complexes of Medium-Ring Oxacycles
SCHEME 6. Isomerization of 2,7-Disubstituted Oxepene 17
and 2,8-Disubstituted Oxocene 18 Co2(CO)6 Complexes Pro-
moted by Montmorillonite K-10
In an attempt to validate our methodology for the con-
struction of medium-sized cyclic ethers, we decided to carry
out the synthesis of the saturated systems. These molecules
have served several times as the testing ground for the
efficacy of medium-ring oxacycles construction. Therefore,
the last steps required to complete the synthesis of the basic
skeletons present in a number of these naturally occurring
nonterpenoids were decomplexation of the Co2(CO)6 com-
plexes cis-17 and cis-18, cleavage of the TMS by TBAF, and
further catalytic hydrogenation providing the saturated
oxacycles cis-22 and (þ)-cis-lauthisan (cis-23) (Scheme 7)
in excellent yields. It should be emphasized that, to the best of
our knowledge, it is the shortest synthesis of (þ)-cis-lauthi-
san, the fully saturated core of the natural derivative (þ)-
laurencin (Figure 1), and the one with highest overall yields
reported up to this date, 53% over six steps from the cobalt
complex 5 and the homoallylic alcohol 12.16
Once we had established a methodology that allowed us to
synthesize medium size cyclic ethers in a very efficient
manner, the next step was to address the synthesis of (þ)-
laurencin. This compound is one of the most representative
members from the group of lauroxanes and it was first
isolated from the extracts of the red algae Laurencia glandu-
lifera by Irie and Masamune and co-workers in 1965.17 Its
structure was determined by a combination of chemical
degradation, spectroscopic methods, and X-ray crystallo-
graphy, and the absolute configuration was assigned by the
desired cycle-complex 17 with excellent yields, as a mixture of
isomers (cis:trans = 1.0:1.1). Using the same experimental con-
ditions we carried out the cyclization of diene cobalt complexes
15 and 16, obtaining the oxocene 18, as a mixture of isomers
(cis:trans = 1.1:1.0), and the oxonene 19 in excellent yields
(Scheme 5). Interestingly, at this point of the synthesis both
diastereoisomers of 17 and 18 were very easily separated by
silica gel column chromatography. The stereochemistry of both
isomers was clearly determined by NOE studies.
As aforementioned, separation of both diastereoisomers was
very simple at this step. However, considering that both isomers
were isolated in nearly equimolecular amounts, we pondered the
possibility of performing an isomerization to the cis-isomer
considering that such stereoisomers are usually thermodynami-
cally more stable.14 The use of our recently reported conditions
relative to the use of montmorillonite K-10 as acid in the
Nicholas reaction proved to be highly efficient to perform the
desired conversion, presumably through a process involving a
cation intermediate (Scheme 6).15 The original mixture evolved
quantitatively to a cis/trans ratio of 3.0:1.0 for the seven-mem-
bered ring 17 and a cis/trans ratio of 5.7:1.0 for the eight-mem-
bered ring 18. Considering that in the oxocene 19 we were unable
to distinguish both isomers, cis and trans, by TLC chromatog-
(16) For previously reported syntheses of lauthisan, see: (a) Tripathi, D.;
Pandey, S. K.; Kumar, P. Tetrahedron 2009, 65, 2226–2231. (b) Reference 7.
(c) Miyakoshi, N.; Ohgaki, Y.; Masui, K.; Mukai, C. Heterocycles 2007, 74,
~
185–189. (d) Reference 8. (e) Carreno, M. C.; Des Mazery, R.; Urbano, A.;
Colobert, F.; Solladie, G. Org. Lett. 2005, 7, 2039–2042. (f) Rhee, H. J.;
Beom, H. Y.; Kim, H.-D. Tetrahedron Lett. 2004, 45, 8019–8022. (g) Coster,
M. J.; De Voss, J. J. Org. Lett. 2002, 4, 3047–3050. (h) Suh, Y.-G.; Koo,
B.-A.; Kim, E.-N.; Choi, N.-S. Tetrahedron Lett. 1995, 36, 2089–2092.
(i) Kim, H.; Ziani-Cherif, C.; Oh, J.; Cha, J. K. J. Org. Chem. 1995, 60, 792–
793. (j) Udding, J. H.; Giesselink, J. P. M.; Hiemstra, H.; Speckamp, W. N.
J. Org. Chem. 1994, 59, 6671–6682. (k) Carling, R. W.; Clark, J. S.; Holmes, A. B.
J. Chem. Soc., Perkin Trans. 1 1992, 83–94. (l) Paquette, L. A.; Sweeney, T. J.
J. Org. Chem. 1990, 55, 1703–1704. (m) 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. (n) Tsushima,
K.; Murai, A. Chem. Lett. 1990, 761–764. (o) Kotsuki, H.; Ushio, Y.; Kadota, I.;
Ochi, M. J. Org. Chem. 1989, 54, 5153–5161. (p) Carling, R. W.; Holmes, A. B.
J. Chem. Soc., Chem. Commun. 1986, 565–567.
1
raphy or by H NMR and 13C NMR, even at low or high
temperature, we did not perform the isomerization step.
(14) 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,
ꢀ
n, T.; Palazon, J. M.; Martı
56, 10209–10219. (b) Betancort, J. M.; Martı
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´
n,
V. S. J. Org. Chem. 2003, 68, 3216–3224.
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hedron Lett. 2005, 46, 2829–2832.
(15) Crisostomo, F. R. P.; Carrillo, R.; Martı
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(17) Irie, T.; Suzuki, M.; Masamune, T. Tetrahedron Lett. 1965, 6, 1091–
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SCHEME 7. Synthesis of the Saturated Oxacycles
SCHEME 8. Retrosynthetic Analysis for the Stereoselective
Synthesis of Overman’s Intermediate (24)
SCHEME 9. First Approach to the Synthesis of Alcohol 27a
aReagents and conditions: (a) AD-mix-β, CH3SO2NH2, tBuOH:H2O
(1:1), 0 °C; (b) TBSCl, imidazole, CH2Cl2, rt, 92% over two steps;
(c) TIPSOTf, 2,6-lutidine, CH2Cl2, rt, 76% over two steps; (d) (i) DIBAL-H
(1 equiv), Et2O, -78 °C, (ii) CH3PPh3þBr-, n-BuLi, THF, -78 to -20 °C,
overnight, 72% for 27 þ 270 (P = TBS) over two steps and 74% for27 þ 270
(P = TIPS) over two steps.
isomer (cis-25), RCM of the unsaturated branched ether
cobalt complex 26, and the interNR using the alcohol 27 and
the acetylenic cobalt complex 4. However, we were aware
that the cobalt complex 4 is not the ideal substrate for the
synthesis of cyclic ethers since, as mentioned above, the
interNR needs to be carried out at -20 °C to avoid the
formation of the elimination product 7.
Prelog atrolactic acid method on a side-chain degradation
product.17,18,19 Since its isolation as the first medium-ring
ether from an algae, (þ)-laurencin has been the subject of
significant synthetic efforts and has been prepared by several
different strategic approaches.20 Our route to oxocanes
seemed well suited to interface with a total synthesis of
(þ)-laurencin developed by Overman’s group.20k In this
synthesis the oxocene 24 is an advanced intermediate and
has been converted in eight steps into the enantiomerically
pure (þ)-laurencin (Scheme 8). Therefore, this molecular
block represents an interesting synthetic target inasmuch as
its synthesis achieved in some alternative manner represents
a new formal synthesis of the natural compound. As depicted
in the retrosynthesis in Scheme 8, we envisaged that oxocene
24 might be secured via a simple sequence of reactions from
the cobalt hexacarbonyl complex cis-25. Alkyne complex cis-
25 would be accessible by the three key steps used in our
methodology: isomerization of the mixture of diastereomers
25 mediated by montmorillonite K-10 to obtain only the cis
Our first aim, therefore, was the preparation of enantio-
merically enriched alcohol 27. As a first approach, we chose
as protecting group P the same that is present in the target
molecule 24, i.e. tert-butyldimethylsilyl (TBS). The synthesis
of 27 (P = TBS) began with the commercially available ethyl
trans-3-hexenoate, which was submitted to a Sharpless
asymmetric dihydroxylation reaction21 using AD-mix-β
yielding the β-hydroxy-γ-lactone 28 (Scheme 9).22 With this
step we simultaneously achieved two important goals: first,
we introduced the correct stereochemistry in the two stereo-
centers of the final molecule, and second, by spontaneous
regioselective lactonization we performed the chemical dif-
ferentiation between the two hydroxy groups. Protection of
the free secondary alcohol as a tert-butyldimethylsilyl (TBS)
ether afforded the γ-lactone 29. For the completion of the
synthesis, the γ-lactone 29 was reduced with 1 equiv of
DIBAL-H and the lactol submitted to Wittig olefination
with the ylide derived from commercially available methyl-
triphenylphosphonium bromide. Unsatisfactorily, instead of
the expected 27, a mixture of two alkenes resulting from
migration of the silyl group was obtained.23 In light of this
result, we use the triisopropylsilyl ether as the protective
(18) Irie, T.; Suzuki, M.; Masamune, T. Tetrahedron 1968, 24, 4193–4205.
(19) (a) Cameron, A. F.; Cheung, K. K.; Ferguson, G.; Robertson, J. M.
J. Chem. Soc., Chem. Commun. 1965, 638. (b) Cameron, A. F.; Cheung,
K. K.; Ferguson, G.; Robertson, J. M. J. Chem. Soc. B 1969, 559–564.
(20) For a racemic total synthesis of laurencin, see: (a) Murai, A.;
Murase, H.; Matsue, H.; Masamune, T. Tetrahedron Lett. 1977, 18, 2507–
2510. For asymmetric total syntheses of laurencin, see: (b) Adsool, V. A.;
Pansare, S. V. Org. Biomol. Chem. 2008, 6, 2011–2015. (c) Fujiwara, K.;
Yoshimoto, S.; Takizawa, A.; Souma, S.; Mishima, H.; Murai, A.; Kawai,
H.; Suzuki, T. Tetrahedron Lett. 2005, 46, 6819–6822. (d) Baek, S.; Jo, H.;
Kim, H.; Kim, H.; Kim, S.; Kim, D. Org. Lett. 2005, 7, 75–77. (e) Crimmins,
M. T.; Emmitee, K. A. Org. Lett. 1999, 1, 2029–2032. (f) Crimmins, M. T.;
(21) (a) Kolb, H. C.; VanNieuwenhze, M. S.; Sharpless, K. B. Chem. Rev.
ꢀ
1994, 94, 2483–2547. (b) Jacobsen, E. N.; Marko, I.; Mungall, W. S.;
Shroder, G.; Sharpless, K. B. J. Am. Chem. Soc. 1988, 110, 1968–1970.
€
ꢀ
Choy, A. L. J. Am. Chem. Soc. 1999, 121, 5653–5660. (g) Mujica, M. T.;
Afonso, M. M.; Galindo, A.; Palenzuela, J. A. J. Org. Chem. 1998, 63, 9728–
9729. (h) Burton, J. W.; Clark, J. S.; Derrer, S.; Stork, T. C.; Bendall, J. G.;
(22) For a previous synthesis of the β-hydroxy-γ-lactone 28, see: (a) Wang,
Z. M.; Zhang, X. L.; Sharpless, K. B.; Sinha, S. C.; Sinha-Bagchi, A.; Keinan, E.
Tetrahedron Lett. 1992, 33, 6407–6410. For synthesis of other β-hydroxy-
€
Holmes, A. B. J. Am. Chem. Soc. 1997, 119, 7483–7498. (i) Kruger, J.;
Hoffman, R. W. J. Am. Chem. Soc. 1997, 119, 7499–7504. (j) Mujica, M. T.;
Afonso, M. M.; Galindo, A.; Palenzuela, J. A. Synlett 1996, 983–984.
(k) Bratz, M.; Bullock, W. H.; Overman, L. E.; Takemoto, T. J. Am. Chem.
Soc. 1995, 117, 5958–5966. (l) Tsushima, K.; Murai, A. Tetrahedron Lett.
1992, 33, 4345–4348.
γ-lactones using Sharpless asymmetric dihydroxylation, see: (b) Garcıa, C.;
´
ꢀ
Martın, T.; Martın, V. S. J. Org. Chem. 2001, 66, 1420–1428. (c) Martın, T.;
´ ´ ´
´
Martın, V. S. Tetrahedron Lett. 2000, 41, 2503–2505. (d) Harcken, C.; Bruckner,
€
R. Angew. Chem., Int. Ed. Engl. 1997, 36, 2750–2752.
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(23) Mulzer, J.; Schollhorn, B. Angew. Chem., Int. Ed. Engl. 1990, 29,
431–432.
6664 J. Org. Chem. Vol. 75, No. 19, 2010

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JOCArticle
SCHEME 10. Synthesis of alcohols 27 (P = TIPS, Bn, PMB)
SCHEME 11. Synthesis of alcohols 27 (P = TBS, TBDPS)a
and the interNR with 4a
aReagents and conditions: (a) (i) DIBAL-H (1 equiv), Et2O, -78 °C,
(ii) Tebbe reagent, THF, 0 °C, 30% over two steps; (b) BF3 OEt2,
aReagents and conditions: (a) DHP, POCl3 (cat), CH2Cl2, rt, 92%;
(b) (i) DIBAL-H (1 equiv), Et2O, -78 °C, (ii) CH3PPh3þBr-, n-BuLi,
THF, -78 °to -20 °C, 3 h, 82% over two steps; (c) NaH, BnBr, TBAI
(cat), DMF, 0 °Cfrt, overnight, 95%; (d) TBSOTf, Me2S, CH2Cl2, -50
°C, 82%; (e) DDQ, Buffer pH 7, ClCH2CH2Cl, 40 °C, overnight, 91%
for 27 (P = TBS) and 89% for 27 (P = TBDPS); (f) (i) Dowex 50Wx8,
MeOH, rt, overnight, (ii) TBDPSCl, imidazole, CH2Cl2, rt, overnight,
98% over two steps.
3
CH2Cl2 (0.5 M), -20 °C; (c) (i) BnBr, Ag2O, TBAI (cat), DMF, rt, 3
days, 72%, (ii) DIBAL-H (1 equiv), Et2O, -78 °C, (iii) CH3PPh3þBr-,
n-BuLi, THF, -78 °Cfrt, overnight, 67% over two steps; (d) (i) p-
MeOC6H4CH2OC(dNH)CCl3, La(OTf)3 (cat), toluene, rt, 73%, (ii)
DIBAL-H (1 equiv), Et2O, -78 °C, (iii) CH3PPh3þBr-, n-BuLi, THF,
-78 °Cfrt, overnight, 75% over two steps.
group, which is well-known to have less propensity to
migrate.24 However, when we carried out the reduction to
the lactol of the γ-lactone 30 and tried a variety of conditions
in the Wittig homologation, we observed similar results to
those described above (Scheme 9). Therefore, we tested as an
alternative the methylenation using the Tebbe reagent25 in
the lactol obtained from the γ-lactone 30. In this way we
could obtain, as the only isomer without any migration, the
target alcohol 27 (P = TIPS), albeit with low yields (Scheme 10).
Unfortunately, this approach failed when we used the lactol
obtained from the γ-lactone 29. Despite the low yield, this
method provided us with enough alcohol 27 (P = TIPS) to
carry out the interNR with cobalt complex 4. Disappoint-
ingly, even performing the reaction at -20 °C we obtained
exclusively the elimination compound 7. In a similar manner
as described in Scheme 9, we also prepared alcohols 27 bear-
ing as protecting groups benzyl (P=Bn)26 and p-methoxy-
benzyl (P = PMB). In these cases, the interNR of these alco-
hols with the cobalt complex 4 also failed, affording mainly
the elimination product 7. Having been unable to construct
the desired linear ether we had to improve the synthesis of 27
and to look for a synthetic equivalent of 4.
A new approach was developed to avoid the migration of
the silyl-protecting group. In this sense, we used as starting
material the previously prepared β-hydroxy-γ-lactone 28,
which after protection of the free secondary alcohol as
tetrahydropyranyl ether 31 was converted to the protected
homoallylic alcohol 32 by two consecutive steps: reduction
with 1 equiv of DIBAL-H and one-carbon homologation by
the Wittig-olefination of the lactol obtained. Protection of
the free alcohol as benzyl ether gave the compound 33 in
excellent yields (Scheme 11). The tetrahydropyranyl ether in
33 was converted directly into a tert-butyldimethylsilyl ether,
affording 34.27 Finally, the cleavage of the benzyl group,
using DDQ in a buffer solution at pH 7, provided the desired
nucleophilic alcohol 27 (P = TBS) in good overall yield
without any migration of the silyl group.
With 27 (P = TBS) in hand, we turned our attention to the
design of a new cobalt complex as electrophile for the Nicholas
reaction. This cobalt complex should meet two key require-
ments: first, to have a lower tendency for elimination reactions,
and second, to have a suitable terminal functional group in
order to transform it into a double bond in later stages.
Considering the above requirements, we synthetized two alter-
native cobalt complexes 36 and 37 (Figure 2).
FIGURE 2. New synthetic equivalents of 4.
Analyzing the retrosynthetic plan described in Scheme 8 and
considering the structure of the target 24, we should avoid the
silyl-protection group in 36, considering as plausible the alter-
native use of benzyl as the protecting group (P = Bn). The syn-
thesis of the cobalt complex 36 (P = Bn) started with a selective
monobenzylation of commercially available butane-1,4-diol,
providing the alcohol 38, which was oxidized by a Swern reac-
tion,28 and the crude aldehyde treated with the lithium acetylide
of (trimethylsilyl)acetylene providing the propargylic alcohol
39. Further complexation of the acetylene moiety by direct reac-
tion with Co2(CO)8 in CH2Cl2 afforded the complexed alcohol
36 (P = Bn) (Scheme 12). Cobalt complex 37 was easily pre-
pared from commercially available ethyl 4-bromobutyrate,
which was reduced to the corresponding aldehyde and treated
with the lithium acetylide of (trimethylsilyl)acetylene providing
the propargylic alcohol 40. Complexation of 40 with Co2(CO)8
afforded the complexed alcohol 37 (X = Br) (Scheme 12).
Once we had successfully synthesized the cobalt complex 36
(P = Bn), we examined the interNR with the alcohol 27 (P=
TBS) at different temperatures. Unfortunately, when the reac-
tion was conducted at 0 °C, the unprotected diol 41 and the
elimination product 42 were obtained. Interestingly, when
the interNR was carried out at -20 °C, the reaction delivered
the desire branched ethers 43, as a mixture of protected and free
(24) Wuts, P. G. M.; Greene, T. W. Greene’s Protective Groups in Organic
Synthesis, 4th ed.; Wiley-VCH: New York, 2007.
(25) Tebbe, F. N.; Parshall, G. W.; Reddy, G. S. J. Am. Chem. Soc. 1978,
100, 3611–3613.
(26) Crimmins and co-workers synthesized the protected homoallylic
alcohol 27 (P = Bn) using asymmetric glycolate alkylation of an acyl
oxazolidinone, see ref 20e.
(28) Swern, D.; Mancuso, A. J.; Huang, S. J. Org. Chem. 1978, 43, 2480–
(27) Kim, S.; Kee, I. S. Tetrahedron Lett. 1990, 31, 2899–2900.
2482.
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Ortega et al.
SCHEME 14. Approach to the Synthesis of the Dienes 48
JOCArticle
SCHEME 12. Synthesis of the Cobalt Complex 36 (P = Bn)
and 37 (X = Br)a
aReagents and conditions: (a) NaH, BnBr, TBAI (cat), THF, 0 °C, 3 h,
85%; (b) (COCl)2, DMSO, CH2Cl2, -78 °C, 1 h, then Et3N, -78 °Cfrt;
(c) Me3SiCtCH, n-BuLi, THF, -78 °C, 75% over two steps for 39 and
51% over two steps for 40; (d) Co2(CO)8, CH2Cl2, rt, quantitative;
(e) DIBAL-H (1 equiv), Et2O, -78 °C.
solution at pH 7 to obtain the free alcohols 46, which were
submitted to the one-pot protocol described by Grieco et al.
in a fruitless manner (Scheme 14).29 Alternatively, the alco-
hols 46 were converted to the methanesulfonates 47, and
treated under standard elimination conditions. However,
these reactions also failed.
SCHEME 13. Synthesis of the Branched Ethers Using the
Alcohols 27 (P = TBS, TBDPS) and the Cobalt Complex 36a
In light of these results we focused our attention on the
cobalt complex 37 (X = Br) hoping that the elimination
reaction could be carried out on the brominated derivative. It
should be mentioned that based on our previous studies,
halogen atoms are compatible with the Nicholas conditions
providing a very convenient method to obtain halo-substi-
tuted ethers.7,30 Gratifyingly, when the interNR was applied
to 37 (X = Br) using as incoming alcohol 27 (P = TBDPS)
the corresponding ethers 49, after complex cleavage, were
obtained as a mixture of isomers, ca. 1.0:1.0 (Scheme 15).
Dienes 48 were readily elaborated from bromide derivatives
49 using a variant of the Grieco reaction.31 Before the
cyclization step by RCM, the complexation of the alkyne
group was carried out with Co2(CO)8, affording the cobalt
complexes 26 (P = TBDPS). This complexation generated a
series of advantages that were described above. With the key
linear precursors in hand, we proceeded to address the
construction of the oxocene core by using a RCM reaction.
Exposure of dienes 26 (P = TBDPS) to the RCM conditions
using the second-generation Grubbs’ catalyst gave the eight-
membered ring ethers in 99% yields. The oxocenes 25 (P=
TBDPS) were obtained as a mixture of cis and trans diaster-
eomers in the propargyl carbon (ca. 1.0:1.0). This mixture of
isomers cis and trans was transformed into the cis isomer
quantitatively by treatment with montmorillonite K-10 in
CH2Cl2 under reflux for 48 h.
The completion of the formal synthesis from alkyne-
cobalt complex cis-25 (P = TBDPS) dealt with the transfor-
mation of the terminal alkyne to an allylic alcohol. To
achieve this goal, an oxidative demetalation was performed
to obtain the alkyne 50. Selective removal of the trimethylsi-
lyl protecting group under basic conditions followed by
coupling of paraformaldehyde with the lithium salt of the
terminal alkyne furnished the propargylic alcohol 51 in
excellent yields (Scheme 15). Finally, the reduction of 51 to
the allylic alcohol 52, with LiAlH4, provided an analogue of
Overman’s intermediate. Although compound 52 has a
protective group of the same nature as Overman’s inter-
mediate, and therefore, it could be used to complete the
aReagents and conditions: (a) BF3 OEt2, CH2Cl2 (0.5 M), 0 °C; (b) BF3
3
3
OEt2, CH2Cl2 (0.5 M), -20 °C; (c) CAN, acetone, 0 °C, 81% for 45 over
two steps.
secondary alcohol 44, probably due to the Lewis acid presence.
It is noteworthy that the elimination product was not detected
(Scheme 13). Once we established that the cobalt complex 36
(P = Bn) worked properly, we pondered the use of alcohol 27
with a more robust silyl-protecting group stable to the Nicholas
reaction conditions. Therefore, we synthesized the alcohol 27
(P = TBDPS) in accordance with Scheme 11. In such a synthe-
sis we used compound 33, previously used for the synthesis of
the alcohol 27 (P = TBS). Removal of the tetrahydropyranyl
ether in 33, followed by protection of the free secondary alcohol
as a tert-butyldiphenylsilyl ether provided 35, which after
further cleavage of the benzyl ether delivered the alcohol 27
(P = TBDPS) in good overall yields. Gratifyingly it was found
that the interNR took place, with very good yields, when the
alcohol 27 (P = TBDPS) was used as nucleophile (Scheme 13).
With this satisfactory result in our hands the next step was
the elimination reaction to obtain the dienes 48 required for
the RCM. First we used DDQ in the presence of a buffer
(30) Dıaz, D. D.; Martın, V. S. Tetrahedron Lett. 2000, 41, 9993–9996.
´ ´
(31) (a) Sharpless, K. B.; Young, M. W. J. Org. Chem. 1974, 40, 947–949.
(b) Burke, S. D.; Voight, E. A. Org. Lett. 2001, 237–240.
(29) Grieco, P. A.; Gilman, S.; Nishizawa, M. J. Org. Chem. 1976, 41,
1485–1486.
6666 J. Org. Chem. Vol. 75, No. 19, 2010

Ortega et al.
JOCArticle
SCHEME 15. Synthesis of the Overman’s Intermediate (24)
synthesis of the natural product, in order to check the
structure of this compound and to achieve the formal synthe-
sis of (þ)-laurencin a change in the protecting group in the
secondary alcohol should be performed. Thus, cleavage of
the TBDPS group with TBAF at 40 °C provided the corre-
sponding diol, which was treated with TBSOTf to give the
diprotected compound. The last step was a selective depro-
tection of the primary silyl ether with trifluoroacetic acid to
give Overman’s intermediate (24) with excellent yields,
whose spectroscopic and physical data were in good agree-
ment with those reported from Overman and co-workers.20k
combined organic layers were dried (MgSO4), filtered, and
concentrated. The crude was purified by chromatographic
column to give 14 as a dark red oil with a 1.0:1.1 mixture of
1
isomers (488 mg, 82% yield): H NMR (500 MHz, CDCl3) δ
0.30 (s, 18H), 0.86 (m, 6H), 1.25-1.38 (m, 16H), 1.39-1.97 (m,
8H), 2.05-2.39 (m, 4H), 3.87 (m, 1H), 4.03 (dd, J = 6.7, 12.0 Hz,
1H), 4.55 (m, 2H), 5.12 (m, 8H), 5.62 (m, 2H), 5.70 (m, 2H); 13
C
NMR (125 MHz, CDCl3) δ 0.77 (q), 13.8 (q), 22.3 (t), 22.3 (t),
24.7 (t), 25.1 (t), 29.0 (t), 29.1 (t), 29.7 (t), 30.2 (t), 31.5 (t), 31.5
(t), 34.6 (t), 35.1 (t), 36.3 (t), 39.0 (t), 74.2 (d), 74.8 (d), 79.5 (d),
80.3 (d), 114.7 (t), 114.9 (t), 117.9 (t), 118.4 (t), 137.4 (d), 137.8
(d), 138.9 (d), 139.1 (d), 200.23 (s); IR (film, NaCl plates) 2930,
2087, 2048, 841, 520 cm-1
.
Dicobalt Hexacarbonyl Complex of (2S)- and (2R)-(((7S)-
Hexyl-2,3,6,7-tetrahidrooxepine-2-yl)etinyl)trimethylsilane (17).
To a stirred solution of cobalt complexes 14 (400 mg, 0.67 mmol)
in dry CH2Cl2 (670 mL, 0.001 M) was added 30 mol % of second
generation Grubbs catalyst (172 mg, 0.20 mmol). The reaction was
warmed at 40 °C and kept at that temperature until TLC showed
complete conversion. Then, the solvent was evaporated and the
residue was purified by column chromatography yielding 531 mg
of 17 as a mixture of cis/trans isomers (93% yield): 1H NMR (300
MHz, CDCl3) δ 0.30 (s, 18H), 0.87 (m, 6H), 1.26-1.42 (m, 16H),
1.51-1.80 (m, 6H), 2.15-2.55 (m, 6H), 4.20 (s, 1H), 4.57 (s, 1H),
4.70 (m, 1H), 5.04 (dd, J = 5.1, 11.2 Hz, 1H), 5.58 (d, J = 14.9 Hz,
2H), 5.80 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 0.5 (q), 0.6 (q),
13.8 (q), 22.4 (t), 24.7 (t), 24.7 (t), 25.1 (t), 27.1 (t), 29.2 (t), 29.3 (t),
31.5 (t), 31.6 (t), 35.2 (t), 35.8 (t), 36.4 (t), 37.3 (t), 71.2 (d), 78.1 (d),
79.1 (d), 80.3 (d), 129.7 (d), 130.1 (d), 132.6 (d), 134.40 (d); IR (film,
Conclusion
The iterative use of the Co2(CO)6 acetylenic complex provides
a powerful synthetic methodology to address the synthesis of
medium-sized cyclic ethers. The strategy is based on three key
steps: intermolecular Nicholas reaction, ring closing metathesis,
and isomerization. One of the main goals of this methodology
was the finding of the suitable position of the double bond in the
cobalt complex in order to avoid undesirable intramolecular
Nicholas or elimination reactions. In this manner a tandem
strategy could be applied to the synthesis of seven-, eight-, and
nine-membered cyclic ethers. We also validated our strategy by a
formal synthesis of (þ)-laurencin, one of the most representative
lauroxanes. Current efforts are focused on the expansion of this
strategy to the synthesis of other natural products containing
medium ring ethers in their structures.
NaCl plates) 2931, 2087, 2019, 841 cm-1
.
Dicobalt Hexacarbonyl Complex of (((2S,7S)-7-Hexyl-2,3,-
4,7-tetrahydrooxepin-2-yl)ethynyl)trimethylsilane (cis-17). To a
solution of the Co2(CO)6 complexes 17 (cis:trans, 1.0:1.1) (300
mg, 0.53 mmol) in CH2Cl2 (53 mL) was added montmorillonite
K-10 (900 mg) and the mixture was refluxed overnight. Then,
the mixture was filtered and concentrated and the residue was
purified by flash column chromatography, yielding cis-17 (214
Experimental Section
Dicobalt Hexacarbonyl Complex of Trimethyl (3-((S)-Non-1-
en-3-yloxy)hept-6-en-1-yn-1-yl)silane (14). Solid Co2(CO)8 (376
mg, 1.1 mmol) was added to a solution of 1-(trimethylsilyl)hept-
6-en-1-yn-3-ol (2) (188 mg, 1 mmol) in anhydrous CH2Cl2
(5 mL) under N2 atmosphere. The dark solution was stirred at
room temperature until TLC showed the formation of the
complex to be completed (ca. 2 h). The reaction mixture was
cooled to 0 °C, and the alcohol 11 was added (710 mg, 5 mmol),
1
mg) and trans-17 (71 mg) (95% yield): H NMR (500 MHz,
CDCl3) δ 0.29 (s, 9H), 0.87 (m, 3H), 1.26 (m, 6H), 1.42 (m, 2H),
1.59 (m, 2H), 1.75 (m, 1H), 2.17 (m, 2H), 2.52 (m, 1H), 4.22 (s,
1H), 4.73 (dd, J = 5.0, 11.0 Hz, 1H), 5.61 (d, J = 14.0 Hz, 1H),
5.83 (ddd, J = 5.0, 7.5, 12 Hz, 1H); 13C NMR (125 MHz,
CDCl3) δ 0.5 (q), 13.8 (q), 22.4 (t), 24.7 (t), 25.1 (t), 29.2 (t), 31.5
(t), 35.8 (t), 37.3 (t), 79.1 (d), 80.3 (d), 129.7 (d), 134.40 (d); IR
followed by the slow addition of BF3 OEt2 (317 μL, 2.5 mmol).
3
After the addition, the reaction mixture was stirred for an
additional 2 h. The mixture was poured into saturated aqueous
NaHCO3. The aqueous layer was extracted with CH2Cl2 and the
(film, NaCl plates) 2931, 2087, 2019, 841 cm-1
.
J. Org. Chem. Vol. 75, No. 19, 2010 6667

Ortega et al.
JOCArticle
(2S,7S)-2-Ethynyl-7-hexyl-2,3,4,7-tetrahydrooxepine (cis-20).
Co2(CO)6 complex cis-17 (180 mg, 0.32 mmol) was dissolved in
3.2 mL of reagent grade acetone at 0 °C. Ceric ammonium
nitrate (702 mg, 1.28 mmol) was added in small portions with
stirring until evolution of CO ceased and the CAN color
persisted (20 min). The solvent was removed under vacuum
and the pink solid residue was then partitioned between Et2O
and H2O. The aqueous phase was extracted additionally twice
with Et2O. The combined organic extracts were dried, filtered,
concentrated, and subjected to silica gel flash chromatography
additional 2 h. The mixture was poured into saturated aqueous
NaHCO3. The aqueous layer was extracted with CH2Cl2 and the
combined organic layers were dried (MgSO4), filtered, and
concentrated. The crude was purified by chromatographic
column to give 15 as a dark red oil with a mixture of isomers
1
(1.1:1.0) (509 mg, 84% yield): H NMR (400 MHz, CDCl3) δ
0.32 (s, 18H), 0.88 (m, 6H), 1.18-1.79 (m, 22H), 1.80-1.99 (m,
2H), 2.15-2.45 (m, 8H), 3.63 (m, 2H), 4.55 (dd, J = 7.8, 15.6 Hz,
2H), 5.15 (m, 8H), 5.78 (m, 4H); 13C NMR (100 MHz, CDCl3) δ
0.8 (q), 13.8 (q), 22.4 (t), 24.7(t), 24.8 (t), 25.4 (t), 28.9 (t), 29.3 (t),
29.3 (t), 29.8 (t), 29.9 (t), 31.5 (t), 31.6 (t), 33.1 (t), 35.8 (t),
36.8 (t), 37.2 (t), 37.8 (t), 37.8 (t), 75.1(d), 75.5 (d), 75.6 (d),
114.93 (t), 114.9 (t), 116.5 (t), 116.9 (t), 134.5 (d), 134.8 (d), 137.3
(d), 137.4 (d); IR (film, NaCl plates) 2931, 2859, 2087, 2020,
yielding the free alkyne (89 mg, quantitative) as an oil: [R]25
D
1
-21.8 (c 0.9, CHCl3); H NMR (400 MHz, CDCl3) δ 0.16 (s,
9H), 0.87 (m, 3H), 1.34 (m, 7H), 1.42-1.69 (m, 2H), 1.86 (m,
1H), 1.75 (m, 1H), 2.11 (m, 2H), 2.47 (m, 1H), 4.00 (s, 1H), 4.41
(dd, J = 5.8, 9.3 Hz, 1H), 5.52 (ddd, J = 2.0, 3.9, 14.7 Hz, 1H),
5.75 (m, 1H); 13C NMR (100 MHz, CDCl3) δ -0.3 (q), 13.9 (q),
22.4 (t), 24.9 (t), 25.3 (t), 28.9 (t), 31.6 (t), 34.9 (t), 35.9 (t), 70.9
(d), 77.7 (d), 105.6 (s), 130.8 (d), 134.2 (d); IR (film, NaCl plates)
2956, 2857, 1101, 1074, 845 cm-1; MS (EI) m/z (rel intensity) 278
(M)þ (2.4), 263 (M - CH3)þ (6.5), 219 (100), 193 (M - C6H13)þ
(32.7); HRMS (EI) calcd for C17H30OSi (M)þ 278.2066, found
278.2078.
841, 520 cm-1
.
Dicobalt Hexacarbonyl Complex of (2S,5Z)- and (2R,5Z)-
((8R-Hexyl-3,4,7,8-tetrahydro-2H-oxocin-2-yl)ethynyl)trimethyl-
silane (18). To a stirred solution of cobalt complexes 15 (450 mg,
0.74 mmol) in dry CH2Cl2 (740 mL, 0.001 M) was added 30 mol
% of second generation Grubbs catalyst (188 mg, 0.22 mmol).
The reaction was warmed at 40 °C and kept at that temperature
until TLC showed complete conversion. Then, the solvent was
evaporated and the residue was purified by column chromatog-
raphy yielding 389 mg of 18 as a mixture of cis:trans isomers
To a solution of free alkyne (62 mg, 0.22 mmol) in THF (2.2
mL, 0.1 M) at room temperature was added nBu4NF (440 μL of
a 1 M solution) dropwise. Then the reaction mixture was stirred
at room temperature until TLC showed complete conversion,
and then the mixture was poured into water and extracted with
Et2O. The combined organic extracts were dried, filtered, con-
centrated, and subjected to silica gel flash chromatography
yielding the terminal alkyne cis-20 (45 mg, quantitative) as an
oil: [R]25D -2.8 (c 0.8, CHCl3); 1H NMR (400 MHz, CDCl3) δ
0.87 (m, 3H), 1.54-1.72 (m, 8H), 1.93 (m, 1H), 2.17 (m, 2H),
2.48 (s, 2H), 2.53 (m, 2H), 4.06 (s, 1H), 4.46 (s, 1H), 5.55 (dd, J =
1.2, 11.0 Hz, 1H), 5.69 (m, 1H); 13C NMR (100 MHz, CDCl3) δ
14.0 (q), 22.6 (t), 25.0 (t), 25.5 (t), 29.2 (t), 26.7 (d), 30.3 (t), 34.9
(t), 36.3 (t), 70.4 (d), 77.9 (d), 84.1 (s), 130.9 (d), 134.3 (d); IR
(film, NaCl plates) 2954, 2876, 1677, 731 cm-1; MS (EI) m/z (rel
intensity) 205 (M - H)þ (14.8), 135 (M - C5H11)þ (10.1), 121 (M
- C6H13)þ (100); HRMS (EI) calcd for C14H22O (M)þ 206.1671,
found 206.1673.
(2R,7S)-2-Ethyl-7-hexyl-2,3,4,7-tetrahydrooxepine (cis-22).
To a stirred solution of cis-20 (30 mg, 0.14 mmol) in dry ethyl
acetate (1.4 mL, 0.1 M) was added 10% Pd(C) (8 mg, 0.011
mmol) at room temperature under H2 atmosphere (1 atm). The
reaction mixture was stirred for 12 h, after which time TLC
showed the end of the reaction. The solution was filtered
through a pad of Celite and the filter was washed with EtOAc.
The combined organic phases were concentrated, and the crude
obtained was purified by flash chromatography to yield cis-22
(26 mg, 87% yield): [R]25D þ0.4 (c 0.7, CHCl3); 1H NMR (400
MHz, CDCl3) δ 0.83-0.95 (m, 6H), 1.24-1.58 (m, 14H),
1.60-1.85 (m, 6H), 3.35 (m, 1H), 3.42 (m, 1H); 13C NMR
(100 MHz, CDCl3) δ 10.6 (q), 14.1 (q), 22.6 (t), 24.0 (t), 26.3
(t), 27.1 (t), 29.5 (t), 29.8 (t), 31.9 (t), 33.3 (t), 33.6 (t), 37.0 (t),
79.6 (d), 81.1 (d); IR (film, NaCl plates) 2926, 2857, 1459, 1090
cm-1; MS (EI) m/z (rel intensity) 197 (M - CH3)þ (21), 168 (M
- C3H8)þ (9), 97 (C6H9O)þ (68), 55 (100); HRMS (EI) calcd for
C12H23O (M - C2H5)þ 183.1749, found 183.1744.
1
(1.1:1.0) (91% yield): H NMR (400 MHz, CDCl3) δ 0.30 (s,
18H), 0.87 (m, 6H), 1.28 (m, 16H), 1.55-2.55 (m, 16H), 3.43 (m,
1H), 3.91 (m, 1H), 4.66 (dd, J = 9.5, 9.5 Hz, 1H), 4.84 (dd, J =
3.8, 13.8 Hz, 1H), 5.81 (m, 4H); 13C NMR (100 MHz, CDCl3) δ
0.6 (q), 0.7 (q), 13.8 (q), 22.3 (t), 23.7 (t), 24.5 (t), 25.5 (t), 26.4 (t),
29.1 (t), 29.2 (t), 31.0 (t), 31.4 (t), 31.5 (t), 32.6 (t), 32.7 (t), 35.9 (t),
39.1 (t), 41.1 (t), 71.9 (d), 78.8 (d), 80.9 (d), 127.6 (d), 128.4 (d),
130.9 (d), 131.7 (d), 200.3 (s); IR (film, NaCl plates) 2931, 2087,
2047, 841 cm-1
.
(((2S,8S,Z)-8-Hexyl-3,4,7,8-tetrahydro-2H-oxocin-2-yl)ethy-
nyl)trimethylsilane (cis-18). To a solution of the Co2(CO)6
complexes 18 (350 mg, 0.6 mmol) in CH2Cl2 (121 mL) was
added montmorillonite K-10 (1.05 g) and the mixture was
stirred at room temperature overnight. Then, the mixture was
filtered and concentrated and the residue was purified by flash
column chromatography, yielding 295 mg of the cis isomer 18
1
(85% yield): H NMR (400 MHz, CDCl3) δ 0.31 (s, 9H), 0.89
(m, 3H), 1.28 (m, 9H), 1.58 (m, 2H), 1.71 (m, 1H), 1.85 (m, 2H),
2.12 (m, 2H), 2.62 (m, 1H), 3.45 (m, 1H), 4.67 (dd, J = 8.8, 8.8
Hz, 1H), 5.83 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 0.8 (q),
14.0 (q), 22.6 (t), 23.9 (t), 25.6 (t), 29.4 (t), 31.8 (t), 32.8 (t), 36.1
(t), 39.3 (t), 79.1 (d), 81.1 (d), 128.6 (d), 131.2 (d); IR (film, NaCl
plates) 2931, 2087, 2047, 841 cm-1
.
(2S,8S,Z)-2-Ethynyl-8-hexyl-3,4,7,8-tetrahydro-2H-oxocine
(cis-21). Co2(CO)6 complex cis-18 (200 mg, 0.34 mmol) was
dissolved in 3.4 mL of reagent grade acetone at 0 °C. Ceric
ammonium nitrate (745 mg, 1.28 mmol) was added in portions
with stirring until evolution of CO ceased and the CAN color
persisted (20 min). The solvent was removed under vacuum
and the pink solid residue was then partitioned between Et2O
and distilled H2O. The aqueous phase was extracted addition-
ally twice with Et2O. The combined organic extracts were
dried, filtered, concentrated, and subjected to silica gel flash
chromatography yielding the free alkyne (97 mg, 98% yield) as
Dicobalt Hexacarbonyl Complex of (3-((S)-Dec-1-en-4-yloxy)-
hept-6-en-1-yn-1-yl)trimethylsilane (15). Solid Co2(CO)8 (376
mg, 1.1 mmol) was added to a solution of 1-(trimethylsilyl)hept-
6-en-1-yn-3-ol (2) (188 mg, 1 mmol) in anhydrous CH2Cl2
(5 mL) under N2 atmosphere. The dark solution was stirred at
room temperature until TLC showed the formation of the
complex to be completed (ca. 2 h). The reaction mixture was
cooled to 0 °C, and the alcohol 12 was added (781 mg, 5 mmol),
an oil: [R]25 -38.9 (c 0.3, CHCl3); 1H NMR (400 MHz,
D
CDCl3) δ 0.15 (s, 9H), 0.87 (m, 3H), 1.34 (m, 8H), 1.54 (m,
2H), 1.64 (m, 1H), 1.97 (m, 3H), 2.27 (m, 1H), 2.48 (m, 1H),
3.31 (dd, J = 11.0, 11.0 Hz, 1H), 4.18 (m, 1H), 5.63 (ddd, J =
9.6, 12.4, 14.0 Hz, 1H), 5.78 (ddd, J = 10.8, 10.8, 12.8 Hz, 1H);
13C NMR (100 MHz, CDCl3) δ -0.3 (q), 13.9 (q), 22.4 (t), 22.7
(t), 26.0 (t), 28.9 (t), 31.8 (t), 34.5 (t), 35.8 (t), 36.4 (t), 69.1 (d),
82.12 (d), 106.0 (s), 128.7 (d), 130.0 (d); IR (film, NaCl plates)
2956, 2930, 2174, 1086, 844 cm-1; MS (EI) m/z (rel intensity)
292 (M)þ (0.2), 277 (M - CH3)þ (1.0), 109 (C7H9O)þ (51.8),
followed by the slow addition of BF3 OEt2 (317 μL, 2.5 mmol).
3
After the addition, the reaction mixture was stirred for an
6668 J. Org. Chem. Vol. 75, No. 19, 2010

Ortega et al.
JOCArticle
73.0 (C3H9Si)þ (100); HRMS (EI) calcd for C18H32OSi (M)þ
292.2222, found 292.2216.
(m, 3H), 1.23-1.68 (m, 8H), 1.87 (m, 4H), 2.73 (m, 2H), 3.75
(dd, J = 4.4, 8.8 Hz, 1H), 4.78 (dd, J = 5.2, 5.2 Hz, 1H), 5.56
(dd, J = 5.6, 9.2 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 0.82
(q), 0.86 (q), 13.9 (s), 19.9 (t), 20.7 (t), 23.0 (t), 28.1 (t), 29.5 (t),
29.7 (t), 34.1 (t), 34.9 (t), 72.6 (d), 73.7 (d), 129.9 (d), 130.3 (d); IR
To a solution of the free alkyne (90 mg, 0.31 mmol) in THF
(3.1 mL, 0.1 M) at room temperature was added TBAF (620 μL
of a 1 M solution) dropwise. The reaction mixture was stirred at
room temperature until TLC showed complete conversion, and
then was poured into water and extracted with Et2O. The
combined organic extracts were dried, filtered, concentrated,
and subjected to silica gel flash chromatography yielding cis-21
(film, NaCl plates) 2932, 2087, 2047, 839 cm-1
.
(4R,5R)-5-Ethyl-4-((tetrahydro-2H-pyran-2-yl)oxy)dihydro-
furan-2(3H)-one (31). The γ-lactone 28 was dissolved in CH2Cl2
(47 mL, 0.3 M) in a flask under nitrogen, and then DHP (2.5 mL,
28 mmol) and a catalytic amount of POCl3 were added. After 1 h
the TLC showed that the reaction finished, then it was quenched
with Et3N and concentrated under vacuum. The resulting residue
was purified by column chromatography yielding 31 (2.7 g, 92%
yield): 1H NMR (400 MHz, CDCl3) δ 0.99 (m, 6H), 1.51 (m, 8H),
1.77 (m, 8H), 2.45-2.67 (m, 2H), 2.68 (d, J = 3.6 Hz, 2H), 3.43
(dd, J = 5.1, 5.6 Hz, 2H), 3.72 (m, 2H), 4.28 (m, 3H), 4.43 (dd, J =
4.4, 4.8 Hz, 1H), 4.56 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 9.8
(q), 10.1 (q), 19.1 (t), 19.1 (t), 21.8 (t), 25.1 (t), 25.1 (t), 30.4 (t), 35.8
(t), 37.7 (t), 62.4 (t), 62.5 (t), 70.8 (t), 74.9 (t), 85.5 (t), 85.7 (t), 95.5
(t), 100.4 (t), 175.3 (s), 175.6 (s); IR (film, NaCl plates) 3536, 2943,
1777 cm-1; MS (EI) m/z (rel intensity) 215 (M þ H)þ (2), 113
(C6H9O2)þ (48), 85 (C5H9O)þ (100); HRMS (ESI) calcd for
C11H18O4Na (M þ Na)þ 237.1103, found 237.1108.
as a colorless oil (68 mg, quantitative): [R]25 -19.6 (c 0.2,
D
CHCl3); 1H NMR (400 MHz, CDCl3) δ 0.87 (m, 3H), 1.37 (m,
8H), 1.53 (m, 2H), 1.69 (m, 1H), 2.05 (m, 3H), 2.29 (m, 1H), 2.45
(s, 1H), 2.55 (m, 1H), 3.33 (m, 1H), 4.21 (d, J = 14.5 Hz 1H),
5.65 (ddd, J = 9.2, 12.8, 13.6 Hz, 1H), 5.80 (ddd, J = 10.4, 10.8,
13.2 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 13.9 (q), 22.4 (t),
22.7 (t), 25.9 (t), 28.9 (t), 31.6 (d), 34.3 (t), 35.9 (t), 36.4 (t), 68.4
(d), 72.4 (s), 82.41 (d), 84.1 (s), 128.7 (d), 130.0 (d); IR (film,
NaCl plates) 2920, 1737, 733, 485 cm-1; MS (EI) m/z (rel
intensity) 220 (M)þ (1.3), 106 (C8H10)þ (100), 91 (C7H7)þ
(85.9); HRMS (EI) calcd for C15H24O (M)þ 220.1827 found,
220.1834.
(þ)-cis-Lauthisan (cis-23). To a stirred solution of cis-21 (55
mg, 0.25 mmol) in dry ethyl acetate (2.5 mL, 0.1 M) was added
10% Pd(C) (13.6 mg, 0.019 mmol) at room temperature under
H2 atmosphere (1 atm). The reaction mixture was stirred for
15 h, after which time TLC showed the end of the reaction. The
solution was filtered through a pad of Celite and the filter
washed with EtOAc. The combined organic phases were con-
centrated, and the crude obtained was purified by flash chro-
matography to yield (þ)-cis-Lauthisan (cis-23) (56.6 mg, 83%
yield), whose spectroscopic and physical data were in good agree-
ment with those reported previously:16e [R]25D þ6.0 (c 0.2, CHCl3)
[lit. [R]25D þ4.0 (c 0.15, CHCl3)]; 1H NMR (400 MHz, CDCl3) δ
(3R,4R)-4-((Tetrahydro-2H-pyran-2-yl)oxy)hept-6-en-3-ol (32).
The γ-lactone 31 (2.6 g, 12.13 mmol) was disolved in Et2O (121
mL, 0.1 M) at -78 °C under nitrogen, and DIBAL-H (12.1 mL of a
1 M solution) was added dropwise. After 30 min the TLC showed
that the reaction was complete, and the reaction mixture was
quenched with water. Then the reaction was warmed at room
temperature, and a white precipitate was observed. The reaction
mixture was dried with MgSO4 and filtrated through a pad of
Celite, then the aldehyde obtained was used in the next step without
further purification. Ph3PCH3Br (13 g, 36.4 mmol) was placed in a
dry flask at -20 °C under nitrogen with THF (60 mL) and nBuLi
(13.8 mL of a solution 2.2 M in hexano) was added dropwise. The
reaction mixture was stirred at this temperature for 30 min, and
then the stirring was stopped to let the salts precipitate. In another
flask the aldehyde obtained previously was dissolved in dry THF
(60 mL) and was cooled at -20 °C. Then the orange solution of the
ylide was added dropwise, and the reaction mixture was stirred for
3 h. The reaction was quenched with H2O (100 mL) and the
aqueous phase was extracted with Et2O. The combined organic
layers where dried with MgSO4, filtered, and concentrated. The
crude was purified by chromatographic column to give 32 (2.1 g,
82% yield): 1H NMR (400 MHz, CDCl3) δ 0.92 (m, 6H),
1.28-2.65 (m, 22H), 3.45 (m, 6H), 3.88 (m, 2H), 4.42 (d, J = 3.6
Hz, 1H), 4.63 (d, J = 2.8 Hz, 1H), 4.98 (m, 4H), 5.77 (m, 2H); 13C
NMR (100 MHz, CDCl3) δ 10.1 (q), 19.6 (t), 20.9 (t), 21.0 (t), 25.0
(t), 25.3 (t), 25.3 (t), 25.3 (t), 25.4 (t), 25.6 (t), 26.2 (t), 30.6 (t), 30.9
(t), 31.0 (t), 31.1 (t), 32.1 (t), 33.4 (t), 35.7 (t), 36.3 (t), 62.3 (t), 64.7
(t), 73.4 (d), 73.9 (d), 80.8 (d), 82.8 (d), 100.1 (d), 100.5 (d), 116.9
(t), 117.3 (t), 134.4 (d), 134.8 (t); IR (film, NaCl plates) 3441, 2941,
1641, 1028 cm-1; MS (EI) m/z (rel intensity) 199 (M - CH3)þ (2),
185 (M - C2H5)þ (3), 85 (C5H9O)þ (100); HRMS (EI) calcd for
C11H19O3 (M - CH3)þ 199.1334, found 199.1335.
0.91 (m, 6H), 1.15-1.72 (m, 22H), 3.53 (m, 1H), 3.60 (m, 1H); 13
C
NMR (100 MHz, CDCl3) δ 10.6 (q), 13.9 (q), 22.4 (t), 23.8 (t), 26.1
(t), 26.8 (t), 29.2 (t), 29.5 (t), 31.7 (t), 33.1 (t), 33.3 (t), 36.8 (t), 79.4
(d), 81.8 (d).
Dicobalt Hexacarbonyl Complex of Trimethyl(3-(non-1-en-5-
yloxy)hept-6-en-1-yn-1-yl)silane (16). Solid Co2(CO)8 (376 mg,
1.1 mmol) was added to a solution of 1-(trimethylsilyl)hept-6-
en-1-yn-3-ol (2) (188 mg, 1 mmol) in anhydrous CH2Cl2 (5 mL)
under N2 atmosphere. The dark solution was stirred at room
temperature until TLC showed the formation of the complex to
be completed (ca. 2 h). The reaction mixture was cooled to 0 °C,
and the alcohol 13 was added (711 mg, 5 mmol), followed by the
slow addition of BF3 OEt2 (317 μL, 2.5 mmol). After the
3
addition, the reaction mixture was stirred for an additional
2 h. The mixture was poured into saturated aqueous NaHCO3.
The aqueous layer was extracted with CH2Cl2 and the combined
organic layers were dried (MgSO4), filtered, and concentrated.
The crude was purified by chromatographic column to give 16 as
a dark red oil (450 mg, 76% yield): 1H NMR (300 MHz, CDCl3)
δ 0.32 (s, 9H), 0.89 (dd, J = 6.3, 6.3 Hz, 3H), 1.31 (m, 4H),
1.50-1.67 (m, 6H), 1.93 (m, 2H), 2.21 (m, 2H), 3.58 (m, 1H),
4.52 (dd, J = 5.1, 5.7 Hz, 1H), 5.00 (m, 4H), 5.80 (m, 2H); 13
C
NMR (75 MHz, CDCl3) δ 0.86 (q), 13.7 (s), 22.7 (t), 27.0 (t), 27.2
(t), 29.2 (t), 29.9 (t), 32.1 (t), 32.7 (t), 32.9 (t), 36.8 (t), 75.1 (d),
75.7 (d), 114.2 (t), 114.3 (t), 115.0 (t), 137.3 d), 138.2 (d), 138.7
2-(((4R,5R)-5-(Benzyloxy)hept-1-en-4-yl)oxy)tetrahydro-2H-
pyran (33). NaH (409 mg, 10.2 mmol) was placed in a dry flask at
0 °C under nitrogen with DMF (47 mL, 0.2 M). Then the alcohol
32 (2 g, 9.33 mmol) was added slowly and after 5 min benzyl
bromide (1.3 mL, 11.1 mmol) and a catalytic amount of TBAI
were added. After 12 h the TLC showed that the reaction was
complete, then the reaction was quenched with 50 mL of water
and extracted with ether (3 ꢀ 30 mL). The combined organic
layers were dried with MgSO4, filtered, and concentrated. The
crude was purified by chromatographic column to give 33 (2.7 g,
95% yield): 1H NMR (400 MHz, CDCl3) δ 1.04 (m, 6H),
1.45-1.92 (m, 16H), 2.21 (m, 2H), 2.52 (m, 2H), 3.52 (m, 4H),
3.93 (m, 4H), 4.66 (m, 6H), 5.14 (m, 4H), 5.95 (m, 2H), 7.37 (m,
(d); IR (film, NaCl plates) 2936, 2088, 2048, 841 cm-1
.
Dicobalt Hexacarbonyl Complex of (Z)-((9-Butyl-2,3,4,7,8,9-
hexahydrooxonin-2-yl)ethynyl)trimethylsilane (19). To a stirred
solution of cobalt complexes 16 (400 mg, 0.67 mmol) in dry
CH2Cl2 (670 mL, 0.001 M) was added 30 mol % of second
generation Grubbs catalyst (172 mg, 0.20 mmol). The reaction
was refluxed until TLC showed complete conversion (1 h).
Then, the solvent was evaporated and the residue was purified
by column chromatography yielding 305 mg of the complex 19
1
(80% yield): H NMR (400 MHz, CDCl3) δ 0.45 (s, 9H), 0.92
J. Org. Chem. Vol. 75, No. 19, 2010 6669

Ortega et al.
JOCArticle
10H); 13C NMR (100 MHz, CDCl3) δ 10.2 (q), 10.8 (q), 19.7 (t),
19.8 (t), 22.4 (t), 22.8 (t), 25.5 (t), 25.6 (t), 30.8 (t), 31.1 (t), 34.0
(t), 35.8 (t), 62.5 (t), 62.6 (t), 72.5 (t), 72.7 (t), 98.9 (d), 99.1 (d),
116.4 (t), 116.7 (t), 127.4 (d), 127.4 (d), 127.5 (d), 127.6 (d), 127.7
(d), 127.7 (d), 127.8 (d), 127.9 (d), 127.9 (d), 128.0 (d), 128.1 (d),
128.2 (d), 128.2 (d), 128.3 (d), 128.4 (d), 128.6 (d), 135.7 (d),
135.8 (d), 138.9 (s), 139.1 (s); IR (film, NaCl plates) 2929, 1720,
1026, 484 cm-1; MS (EI) m/z (rel intensity) 219 (M - C5H9O)þþ
(100 MHz, CDCl3) δ 10.3 (q), 19.5 (s), 26.8 (t), 27.1 (q), 38.1 (t),
73.9 (d), 75.6 (d), 117.5 (t), 127.6 (d), 127.8 (d), 129.8 (d),
129.9 (d), 133.4 (s), 134.0 (d), 134.1 (d), 135.9 (d), 136.0 (d); IR
(film, NaCl plates) 3466, 2934, 1428, 1110, 703 cm-1; MS (EI) m/z
t
(rel intensity) 311 (M - Bu)þ (12.7), 199 (C12H11OSi)þ (100);
t
HRMS (EI) calcd for C19H23O2Si (M - Bu)þ 311.1467, found
311.1471.
6-Bromo-1-(trimethylsilyl)hex-1-yn-3-ol (40). To a solution of
ethyl 4-bromobutyrate (1 g, 5.12 mmol) in dry Et2O (51 mL, 0.1
M) at -78 °C under nitrogen was added DIBAL-H (5.1 mL of a
1 M solution) dropwise. After 30 min the TLC showed that the
reaction was complete, and the reaction mixture was quenched
with water. Then the reaction mixture was warmed at room
temperature, and a white precipitate was observed. The reaction
mixture was dried with MgSO4 and filtrated with Celite, then the
aldehyde obtained was used in the next step without further
purification. On the other hand, ethynyltrimethylsilane (739 μL,
5.27 mmol) was dissolved in dry THF (26 mL, 0.1 M) at 0 °C
under nitrogen. Afterward, nBuLi was added (3.3 mL of a
solution 2.1 M in hexane) and the reaction mixture was stirred
for 15 min. Then, the mixture was cooled at -78 °C and the
crude aldehyde was added dissolved in dry THF (5 mL). The
reaction was kept at that temperature until TLC showed com-
plete conversion, and then was poured into saturated NH4Cl
and extracted with ethyl ether (2 ꢀ 25 mL). The combined
organic extracts were dried, filtered, concentrated, and sub-
jected to silica gel flash chromatography yielding 40 (650 mg,
51% overall yield): 1H NMR (CDCl3) δ 0.22 (s, 9H), 1.81 (br s,
1H), 1.88 (m, 2H), 2.08 (m, 2H), 3.50 (m, 2H), 4.44 (dd, J = 5.2,
5.2 Hz, 1H); 13C NMR (CDCl3) δ -0.17 (q), 28.4 (t), 33.3 (t),
36.0 (t), 62.0 (d), 90.1 (s), 106.0 (s); HRMS (ESI) calcd for
C9H1779BrOSiNa (M þ Na)þ 271.0130, found 271.0129.
Preparation of (7R,8R)-8-Allyl-5-(3-bromopropyl)-7-ethyl-
2,2,11,11-tetramethyl-10,10-diphenyl-6,9-dioxa-2,10-disiladodec-
3-yne (49). The general procedure for the preparation of cobalt-
complexed propargyl alcohols described above was applied to 40
(336 mg, 1.35 mmol). The dark solution was stirred at room
temperature until TLC showed the formation of the complex to
be completed (ca. 1 h), yielding the complex 37 (X = Br). The
reaction mixture was cooled to 0 °C, and the alcohol 27 (P=
TBDPS) (2.5 g, 6.75 mmol) was added followed by the slow
þ
(3), 197 (M - C7H7O)þ (4), 91 (C7H7) (77), 85 (C5H9O)
(100); HRMS (EI) calcd for C19H28O3 (M)þ 304.2038, found
304.2031.
(((4R,5R)-5-(Benzyloxy)hept-1-en-4-yl)oxy)(tert-butyl)diphe-
nylsilane (35, P = TBDPS). To a solution of 33 (2.6 g, 8.54
mmol) in MeOH (43 mL, 0.2 M) was added Dowex 50Wx8 and
the reaction mixture was stirred at room temperature until the
TLC showed that the reaction was completed. The mixture was
filtrated through a pad of Celite and concentrated under
vacuum. The resulting oil was purified by chromatographic
column to give the secondary alcohol (1.88 g, quantitative):
[R]25D - 3.9 (c 2.6, CHCl3); 1H NMR (400 MHz, CDCl3) δ 0.99
(dd, J = 7.2, 7.6 Hz, 3H), 1.64 (ddd, J = 7.0, 7.0, 13.0 Hz, 1H),
1.76 (ddd, J = 7.0, 7.0, 14.0 Hz, 1H), 2.28 (m, 1H), 2.36 (m, 1H),
3.31 (dd, J = 5.0, 10.0 Hz, 1H), 3.69 (m, 1H), 4.53 (d, J = 11.6
Hz, 1H), 4.68 (d, J = 11.6 Hz, 1H), 5.11 (s, 1H), 5.14 (d, J =
10.4 Hz, 1H), 5.89 (m, 1H), 7.35 (m, 5H); 13C NMR (400 MHz,
CDCl3) δ 9.4 (q), 22.7 (t), 38.1 (t), 71.5 (d), 72.3 (t), 82.4 (d),
117.2 (t), 127.7 (d), 127.8 (d), 127.9 (d), 128.4 (d), 128.5 (d),
135.0 (d), 138.4 (s); IR (film, NaCl plates) 3417, 2932, 2857,
1112, 703 cm-1
.
The secondary alcohol obtained above (1.8 g, 8.17 mmol) was
dissolved in CH2Cl2 (27 mL, 0.3 M) under nitrogen at room
temperature, and then TBDPSCl (3.2 mL, 12.3 mmol) and
imidazole (1.7 g, 24.5 mmol) were added. The reaction mixture
was stirred until TLC showed that the reaction was finished (ca.
12 h) then it was quenched with 20 mL of water and extracted
with CH2Cl2 (3 ꢀ 20 mL). The combined organic layers where
dried with MgSO4, filtrated, and concentrated. The crude was
purified by chromatographic column to give 35 (P = TBDPS)
1
(3.7 g, 98% yield): [R]25 þ3.9 (c 0.8, CHCl3); H NMR (400
D
MHz, CDCl3) δ 0.86 (dd, J = 7.2, 7.6 Hz, 3H), 1.06 (s, 9H), 1.44
(m, 1H), 1.77 (m, 1H), 2.18 (m, 1H), 2.37 (m, 1H), 3.11 (m, 1H),
3.93 (dd, J = 4.4, 8.0 Hz, 1H), 5.71 (d, J = 10.0 Hz, 1H), 5.75 (d,
J = 10.0 Hz, 1H), 4.91 (m, 2H), 5.73 (m, 1H), 7.13-7.45 (m,
10H), 7.68 (m, 5H); 13C NMR (100 MHz, CDCl3) δ 10.8 (q),
19.4 (t), 21.8 (t), 26.8 (q), 27.1 (q), 36.3 (t), 71.9 (t), 72.9 (d), 83.4
(d), 116.4 (t), 127.3 (d), 127.4 (d), 127.5 (d), 127.6 (d), 127.7 (d),
128.1 (d), 128.1 (d), 134.1 (s), 135.5 (d), 136.0 (d), 136.1 (d), 136.2
(d), 138.9 (s); IR (film, NaCl plates) 3070, 2933, 2858, 1109, 702
cm-1; MS (EI) m/z (rel intensity) 401 (M - tBu)þ (4.1), 233 (M -
C13H17OSi)þ (66.6), 105 (C6H5Si) (100); HRMS (EI) calcd for
C26H29O2Si (M - tBu)þ 401.1937, found 401.1925.
addition of BF3 OEt2 (257 μL, 2 mmol). After the addition, the
3
reaction mixture was stirred for an additional 6 h. The mixture
was poured into saturated aqueous NaHCO3. The aqueous layer
was extracted with CH2Cl2 and the combined organic layers were
dried (MgSO4), filtered, and concentrated. The cobalt complex
was then dissolved (14 mL, 0.1 M) in reagent grade acetone at
0 °C. Ceric ammonium nitrate (2.9 g, 5.4 mmol) was added in
portions with stirring until evolution of CO ceased and the CAN
color persisted (20 min). The solvent was removed under vacuum
and the pink solid residue was then partitioned between Et2O
and distilled H2O. The aqueous phase was extracted additionally
twice with Et2O. The combined organic extracts were dried,
filtered, concentrated, and subjected to silica gel flash chroma-
tography yielding 49 as a mixture 1.0:1.0 of isomers (672 mg,
83% yield): 1H NMR (400 MHz, CDCl3) δ 0.14 (s, 9H), 0.18 (s,
9H), 0.82 (dd, J = 7.2, 7.6 Hz, 3H), 1.00 (dd, J = 7.2, 7.2 Hz,
3H), 1.12 (s, 18H), 1.30-2.41 (m, 18H), 2.51 (m, 1H), 3.15 (dd,
J = 4.0, 4.0 Hz, 2H), 3.30-3.51 (m, 5H), 3.65 (dd, J = 5.6, 6.0
Hz, 2H), 4.28 (m, 1H), 4.99 (m, 4H), 5.78 (m, 2H), 7.44 (m, 12H),
7.75 (m, 8H); 13C NMR (100 MHz, CDCl3) δ -0.1 (q), -0.1 (q),
10.7 (q), 10.8 (q), 19.4 (t), 19.5 (t), 21.1 (t), 21.5 (t), 27.0 (q), 27.1
(q), 28.6 (t), 33.2 (t), 33.5 (t), 34.2 (t), 34.7 (t), 36.2 (t), 67.5 (d),
68.2 (d), 72.7 (d), 72.9 (d), 81.3 (d), 82.8 (d), 89.8 (s), 89.9 (s),
105.3 (s), 105.5 (s), 116.3 (t), 116.5 (t), 127.5 (d), 127.5 (d), 127.5
(d), 127.6 (d), 127.6 (d), 127.6 (d), 127.7 (d), 129.6 (d), 129.7 (d),
129.7 (d), 129.8 (d), 133.8 (s), 133.9 (s), 134.2 (s), 134.4 (s), 135.9
(d), 136.0 (d), 136.0 (d), 136.0 (d), 136.1 (d), 136.1 (d), 136.2 (d),
(3R,4R)-4-((tert-Butyldiphenylsilyl)oxy)hept-6-en-3-ol (27, P=
TBDPS). 35 (P=TBDPS) (3.6 g, 7.85 mmol) was dissolved in
1,2-dichloroethane (157 mL, 0.05 M) and then a buffer solution at
pH 7 (66.7 mL, 8.5 mL ꢀ mmol of starting material) and DDQ
(7.13 g, 31.4 mmol) were added. The reaction mixture was stirred
at 40 °C until TLC showed complete conversion of the starting
material (ca. 12 h). Then it was cooled at room temperature,
poured into a saturated aqueous NaHCO3 (200 mL), and stirred
vigorously for 12 h to give a dark red solution. The layers where
separated, and the aqueous layer was extracted with CH2Cl2. The
combined organic layers where dried with MgSO4, filtrated, and
concentrated. The crude was purified by chromatographic column
to give 27 (P = TBDPS) (2.6 g, 89% yield): [R]25 -9.7 (c 1.4,
D
CHCl3); 1H NMR (400 MHz, CDCl3) δ 0.88 (dd, J = 7.2, 7.2 Hz,
3H), 1.10 (s, 9H), 1.48 (m, 2H), 1.59 (s, 1H), 2.14 (m, 1H), 2.40 (m,
1H), 3.41 (dd, J = 2.4, 2.4 Hz, 1H), 3.64 (dd, J = 4.0, 8.0 Hz, 1H),
4.91 (m, 2H), 5.58 (m, 1H), 7.45 (m, 6H), 7.70 (m, 4H); 13C NMR
6670 J. Org. Chem. Vol. 75, No. 19, 2010

Ortega et al.
JOCArticle
136.3 (d), 136.4 (d); IR (film, NaCl plates) 2961, 1251, 1108, 844,
703 cm-1; MS (EI) m/z (rel intensity) 541 (M - tBu)þ (1.1), 311
(61.2), 135 (C9H11O)þ (100), 73 (C3H9Si)þ (45.2); HRMS (EI)
0.86 mmol) was dissolved in reagent grade acetone (8.6 mL, 0.1
M) at 0 °C. Ceric ammonium nitrate (1.9 g, 3.44 mmol) was
added in portions with stirring until evolution of CO ceased
and the CAN color persisted (20 min). The solvent was
removed under vacuum and the pink solid residue was then
partitioned between Et2O and distilled H2O. The aqueous
phase was extracted additionally twice with Et2O. The com-
bined organic layers were dried, filtered, concentrated, and
subjected to silica gel flash chromatography yielding the alkyne
50 (317 mg, 75% yield) as an oil: [R]25D -12.5 (c 0.5, CHCl3); 1H
NMR (400 MHz, CDCl3) δ 0.19 (s, 9H), 0.94 (dd, J = 7.2, 7.2
Hz, 3H), 1.04 (s, 9H), 1.39 (m, 1H), 1.91 (m, 2H), 2.26 (m, 1H),
2.75 (m, 2H), 3.23 (m, 1H), 3.71 (m, 1H), 3.94 (dd, J = 1.2, 10.4
Hz, 1H), 5.39 (m, 1H), 5.68 (m, 1H), 7.40 (m, 6H), 7.75 (m, 4H);
13C NMR (100 MHz, CDCl3) δ 0.0 (q), 10.8 (q), 19.5 (s), 25.9
(t), 27.1 (q), 33.4 (t), 36.4 (t), 73.4 (d), 85.6 (d), 88.1 (s), 105.8 (s),
127.6 (d), 127.6 (d), 128.4 (d), 129.4 (d), 129.6 (d), 130.2 (d),
134.8 (s), 135.9 (d), 136.2 (d); IR (film, NaCl plates) 2961, 2858,
1074, 848, 705 cm-1; MS (EI) m/z (rel intensity) 433 (M - tBu)þ
(36.6), 199 (C12H11OSi)þ (79.8), 135 (C9H11O)þ (100), 73
(C3H9Si)þ (78.5); HRMS (EI) calcd for C30H42O2Si2 (M)þ
490.2723, found 490.2726.
Preparation of 3-((2R,7R,8R,Z)-7-((tert-Butyldiphenylsilyl)-
oxy)-8-ethyl-3,6,7,8-tetrahydro-2H-oxocin-2-yl)prop-2-yn-1-ol
(51). To a solution of the alkyne 50 (300 mg, 0.61 mmol) in
methanol (6.1 mL, 0.1 M) at room temperature was added
K2CO3 (42 mg, 0.31 mmol). After TLC showed complete con-
version, the reaction mixture was filtrated through a Celite pad
and concentrated, yielding the terminal alkyne (quantitative).
Then, the terminal alkyne was dissolved in dry THF (6.1 mL, 0.1
M) and cooled at -40 °C. Then n-BuLi (419 μL of a 1.6 M
solution) was added and 15 min later paraformaldehyde (37 mg,
1.22 mmol). The reaction mixture was warmed at room tem-
perature and after 2 h the TLC showed complete conversion.
The reaction mixture was poured into saturated aqueous NH4Cl
and extracted with ether. The combined organic layers were
dried with MgSO4, filtrated, concentrated, and subjected to
silica gel flash chromatography yielding 51 as a colorless oil
(260 mg, 95% yield): [R]25D -17.8 (c 2.4, CHCl3); 1H NMR (400
MHz, CDCl3) δ 0.93 (dd, J = 7.2, 7.2 Hz, 3H), 1.04 (s, 9H), 1.26
(s, 1H), 1.35 (m, 1H), 1.94 (m, 2H), 2.25 (m, 1H), 2.74 (m, 2H),
3.28 (d, J = 8.8 Hz, 1H), 3.68 (m, 1H), 3.99 (d, J = 10.4 Hz, 1H),
4.35 (s, 2H), 5.40 (m, 1H), 5.64 (m, 1H), 7.38 (m, 6H), 7.74 (m,
4H); 13C NMR (100 MHz, CDCl3) δ 10.8 (q), 19.5 (s), 25.9 (t),
27.1 (q), 33.4 (t), 36.3 (t), 51.3 (t), 72.7 (d), 76.8 (d), 82.5 (s), 85.3
(d), 85.8 (s), 127.3 (d), 127.6 (d), 128.2 (d), 129.4 (d), 129.7 (d),
130.4 (d), 133.6 (s), 134.7 (s), 136.0 (d), 136.1 (d); IR (film, NaCl
plates) 3045, 2932, 2859, 1072, 704 cm-1; HRMS (EI) calcd for
C24H27O3Si (M - tBu)þ 391.1729, found 391.1723.
t
calcd for C28H3979BrO2Si2 (M þ H - Bu)þ 542.1672, found
542.1671.
Preparation of (7R,8R)-5,8-Diallyl-7-ethyl-2,2,11,11-tetrame-
thyl-10,10-diphenyl-6,9-dioxa-2,10-disiladodec-3-yne (48). To a
solution of o-NO2PhSeCN (257 mg, 1.13 mmol) in ethanol (10.3
mL, 0.1 M) at 0 °C was added slowly NaBH4 (46 mg, 1.24
mmol). After 15 min 49 (620 mg, 1.03 mmol) was added, and the
reaction mixture was stirred at room temperature for 12 h. After
this time, the TLC showed that the reaction was not complete,
and an additional 0.04 equiv of o-NO2PhSeCN and 0.1 equiv of
NaBH4 were added. After 5 h the reaction was complete, and the
reaction mixture was poured into water and extracted with
CH2Cl2 (3 ꢀ 15 mL). The combined organic extracts were dried,
filtered, concentrated, and subjected to silica gel flash chroma-
tography yielding 48 as a colorless oil (498 mg, 85% yield): 1H
NMR (400 MHz, CDCl3) δ 0.15 (s, 9H), 0.18 (s, 9H), 0.81 (dd,
J = 7.2, 7.6 Hz, 3H), 0.98 (dd, J = 7.2, 7.2 Hz, 3H), 1.10 (s,
18H), 1.39 (m, 3H), 1.82 (m, 2H), 2.27 (m, 6H), 2.51 (m, 1H),
3.14 (d, J = 4.4 Hz, 1H), 3.41 (dd, J = 6.4, 6.4 Hz, 2H), 3.62 (d,
J = 6.8 Hz, 1H), 3.68 (dd, J = 4.0, 4.0 Hz, 1H), 4.15 (dd, J =
3.2, 4.0 Hz, 1H), 5.03 (m, 8H), 5.77 (m, 4H), 7.43 (m, 12H), 7.74
(m, 8H); 13C NMR (100 MHz, CDCl3) δ -0.2 (q), -0.1 (q), 10.7
(q), 10.8 (q), 19.4 (t), 19.5 (t), 21.2 (t), 21.5 (t), 27.0 (q), 27.1 (q),
36.0 (t), 36.2 (t), 40.2 (t), 40.8 (t), 68.5 (d), 68.9 (d), 81.5 (d), 82.9
(d), 89.6 (s), 105.4 (s), 105.6 (s), 116.2 (t), 116.4 (t), 117.2 (t),
117.4 (t), 127.4 (d), 127.5 (d), 127.6 (d), 127.6 (d), 127.6 (d), 129.5
(d), 129.6 (d), 129.7 (d), 133.9 (d), 133.9 (d), 133.9 (d), 134.5 (s),
136.0 (d), 136.0 (d), 136.1 (d), 136.1 (d), 136.1 (d), 136.2 (d),
136.4 (d), 136.6 (d); IR (film, NaCl plates) 2961, 2859, 1251,
1108, 843, 703 cm-1; MS (EI) m/z (rel intensity) 477 (M -
C3H5)þ (1.7), 311 (C19H23O2Si)þ (68.8), 135 (C9H11O)þ (100),
73 (C3H9Si)þ (78.5); HRMS (EI) calcd for C29H41O2Si2 (M -
C3H5)þ 477.2645, found 477.2658.
Preparation of the Hexacarbonyl Dicobalt Complex of tert-
Butyl(((2R,3R,8R,Z)-2-ethyl-8-((trimethylsilyl)ethynyl)-3,4,7,
8-tetrahydro-2H-oxocin-3-yl)oxy)diphenylsilane (cis-25, P =
TBDPS). The general procedure for the preparation of cobalt-
complexed propargyl alcohols described above was applied to
48 (470 mg, 0.9 mmol), to yield a mixture of cobalt complexes
(729 mg, quantitative). To a stirred solution of cobalt complexes
(470 mg, 0.9 mmol) in dry CH2Cl2 (450 mL, 0.002 M) was added
30 mol % of second generation Grubbs catalyst (229 mg, 0.27
mmol). The reaction was warmed at 40 °C and kept at that
temperature until TLC showed complete conversion. Then, the
solvent was evaporated and the residue was purified by column
chromatography yielding 692 mg of 25 (P = TBDPS) as a
mixture of cis:trans isomers (1.0:1.0) (99% yield). To a solution
of the Co2(CO)6 complexes 25 (P = TBDPS) (1.0:1.0) (692 mg,
0.89 mmol) in CH2Cl2 (356 mL, 0.0025 M) was added mon-
tmorillonite K-10 (2.1 g) and the mixture was refluxed for 48 h.
Then, the mixture was filtered and concentrated and the residue
was purified by flash column chromatography, yielding 692 mg
Preparation of (E)-3-((2R,7R,8R,Z)-7-((tert-Butyldiphenyl-
silyl)oxy)-8-ethyl-3,6,7,8-tetrahydro-2H-oxocin-2-yl)prop-2-en-
1-ol (52). To a solution of 51 (240 mg, 0.53 mmol) in dry THF
(5.3 mL, 0.1 M) under nitrogen and at room temperature was
added LiALH4 (802 μL of a 1 M solution) dropwise. After 12 h
the TLC showed complete conversion and the reaction mixture
was quenched with water. The mixture was dried, filtered,
concentrated, and subjected to silica gel flash chromatography
to yield 203 mg of 52 (85% yield): [R]25D -37.6 (c 0.8, CHCl3);
1H NMR (400 MHz, CDCl3) δ 0.87 (dd, J = 7.2, 7.2 Hz, 3H),
1.04 (s, 9H), 1.33 (m, 1H), 1.79 (m, 1H), 1.91 (dd, J = 5.6, 6.0 Hz,
1H), 2.06 (m, 2H), 2.42 (m, 1H), 2.74 (ddd, J = 10.8, 10.8, 10.8
Hz, 1H), 3.39 (ddd, J = 3.2, 3.2, 6.4 Hz, 1H), 3.76 (m, 2H), 4.20
(d, J = 5.2 Hz, 2H), 5.40 (dd, J = 1.6, 6.8 Hz, 1H), 5.67 (m, 1H),
5.85 (m, 1H), 5.92 (m, 1H), 7.38 (m, 6H), 7.76 (m, 4H); 13C NMR
(100 MHz, CDCl3) δ 10.9 (q), 19.6 (s), 26.2 (t), 27.1 (q), 33.3 (t),
35.2 (t), 63.3 (t), 76.9 (d), 81.5 (d), 84.0 (d), 127.2 (d), 127.5 (d),
128.7 (d), 129.1 (d), 129.3 (d), 129.6 (d), 129.6 (d), 133.5 (d),
135.0 (s), 135.9 (d), 136.1 (d); IR (film, NaCl plates) 3381, 2932,
1
of cis-25 (P = TBDPS) (quantitative): H NMR (400 MHz,
CDCl3) δ 0.45 (s, 9H), 0.89 (m, 3H), 0.99 (s, 9H), 1.59 (m, 1H),
1.77 (m, 1H), 2.01 (m, 1H), 2.32 (m, 1H), 2.68 (m, 1H), 2.85 (m,
1H), 3.59 (dd, J = 6.0, 6.0 Hz, 1H), 3.72 (dd, J = 8.4, 13.2 Hz,
1H), 4.47 (d, J = 10.0 Hz, 1H), 5.54 (ddd, J = 7.6, 8.4, 9.2 Hz,
1H), 5.79 (ddd, J = 7.6, 8.3, 9.2 Hz, 1H), 7.42 (m, 6H), 7.75 (m,
4H); 13C NMR (100 MHz, CDCl3) δ 0.9 (q), 11.1 (q), 19.4 (s),
25.6 (t), 26.9 (q), 29.7 (t), 33.5 (t), 39.4 (t), 75.7 (d), 80.9 (d), 83.2
(d), 127.2 (d), 127.5 (d), 127.6 (d), 128.7 (d), 129.3 (d), 129.6 (d),
130.7 (d), 133.6 (s), 136.0 (d), 136.1 (d).
Preparation of tert-Butyl(((2R,3R,8R,Z)-2-ethyl-8-((trime-
thylsilyl)ethynyl)-3,4,7,8-tetrahydro-2H-oxocin-3-yl)oxy)diphe-
nylsilane (50). Co2(CO)6 complex cis-25 (P = TBDPS) (670 mg,
J. Org. Chem. Vol. 75, No. 19, 2010 6671

Ortega et al.
JOCArticle
2858, 1071, 704 cm-1; MS (EI) m/z (rel intensity) 307
(C19H19O2Si)þ (7.2), 199 (C12H11OSi)þ (100), 135 (C9H11O)þ
(48.7); HRMS (EI) calcd for C24H29O3Si (M - tBu)þ 393.1886,
found 393.1874.
graphy to yield 24 (70 mg, 98%), whose spectroscopic and physical
data were in good agreement with those reported for Overman and
co-workers:20k [R]25D -4.3 (c 0.26, CHCl3) [lit. [R]25D -6.3 (c 0.85,
CHCl3)]; 1H NMR (500 MHz, CDCl3) δ 0.08 (s, 3H), 0.09 (s, 3H),
0.90 (s, 9H), 1.30 (m, 3H), 1.59 (s, 1H), 1.65 (m, 2H), 2.11 (m, 2H),
2.55 (m, 1H), 2.76 (ddd, J= 11.0, 11.0, 11.0 Hz, 1H), 3.44 (ddd, J=
3.0, 3.0, 9.5 Hz, 1H), 3.75 (m, 2H), 4.18 (d, J = 4.5 Hz, 2H),
5.32-589 (m, 4H); 13C NMR (125 MHz, CDCl3) δ -4.7 (q), -4.2
(q), 10.9 (d), 18.3 (s), 26.0 (q), 33.6 (t), 35.1 (t), 63.3 (t), 76.1 (d), 81.8
(d), 84.1 (d), 128.9 (d), 129.4 (d), 129.5 (d), 133.5 (d).
Preparation of (E)-3-((2R,7R,8R,Z)-7-((tert-Butyldimethylsilyl)-
oxy)-8-ethyl-3,6,7,8-tetrahydro-2H-oxocin-2-yl)prop-2-en-1-ol (24).
To a solution of 52 (100 mg, 0.22 mmol) in dry THF (2.2 mL,
0.1 M) under nitrogen at room temperature was added TBAF (333
μL of a 1 M solution) dropwise. The reaction mixture was stirred at
40 °C for 12 h, when the TLC showed complete conversion. The
reaction was then quenched with water and extracted with ether.
The combined organic layers were dried with MgSO4, filtrated, and
concentrated. The crude was dissolved in dry DMF (2.2 mL, 0.1 M)
and imidazole (45 mg, 0.7 mmol) and TBSOTf (0.15 mL, 0.5 mmol)
were added. The reaction mixture was stirred for 12 h, and the TLC
showed complete protection of the secondary alcohol. The reaction
was quenched with an aqueous solution of HCl at 5%, and extracted
with ether. The combined organic layers were dried on MgSO4,
filtrated, and concentrated under vacuum. The crude was dissolved
in a mixture THF/H2O (1:1) (1.1 mL of THF and 1.1 mL of H2O) at
0 °C and CF3CO2H was added dropwise (8 μL, 0.11 mmol). After
5 min the TLC showed the complete cleavage of the primary alcohol,
and the reaction was quenched with saturated aqueous NaHCO3
and extracted with ether. The combined organic layers were dried,
filtered, concentrated, and subjected to silica gel flash chromato-
Acknowledgment. This research was supported by the
Spanish MICINN-FEDER (CTQ2008-06806-C02-01/BQU
and CTQ2008-03334/BQU), FICIC, MSC (RTICC RD06/
0020/1046), and the Canary Islands FUNCIS (PI 01/06). The
authors thank Dr. David Tejedor for helpful discussions. N.
O. thanks the Canary Islands Government for a predoctoral
fellowship.
Supporting Information Available: Experimental proce-
dures and spectroscopic data for compounds 1-3, 11-13, and
1
28, as well as copies of H and 13C NMR spectra for all new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
6672 J. Org. Chem. Vol. 75, No. 19, 2010