Synthesis of α,α′-disubstituted linear ethers by an intermolecular nicholas reaction - Application to the synthesis of (+)-cis/-trans-lauthisan and (+)-cis/(+)-trans-obtusan

Article abstract of DOI:10.1002/ejoc.200801063

A new and efficient methodology to prepare α,α'-disubstituted linear ethers through an intermolecular Nicholas reaction (interNR) is described. cis-2,8-Disubstituted oxocanes, cis-2,9-disubstituted oxonanes, their trans isomers, and their parent unsaturat

Full text of DOI:10.1002/ejoc.200801063

FULL PAPER
DOI: 10.1002/ejoc.200801063
Synthesis of α,αЈ-Disubstituted Linear Ethers by an Intermolecular Nicholas
Reaction – Application to the Synthesis of (+)-cis/(–)-trans-Lauthisan and
(+)-cis/(+)-trans-Obtusan
Nuria Ortega,[a] Tomás Martín,*[a,b] and Víctor S. Martín*[a]
Keywords: Cobalt / Natural products / Oxygen heterocycles / Total synthesis / Isomerization
A new and efficient methodology to prepare α,αЈ-disubsti-
tuted linear ethers through an intermolecular Nicholas reac-
tion (interNR) is described. cis-2,8-Disubstituted oxocanes,
cis-2,9-disubstituted oxonanes, their trans isomers, and their
parent unsaturated precursors were prepared from the corre-
sponding Co2(CO)6–cycloalkynic ethers. Key steps in such
syntheses were the ether linkage formation by interNR, RCM
of the suitable acyclic dienyl ether, and montmorillonite K-
10 induced isomerization of the complexed cycloalkyne. By
taking advantage of the developed methodology a short syn-
thesis of (+)-cis- and (–)-trans-lauthisan and (+)-cis- and (+)-
trans-obtusan are described.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2009)
Introduction
The structure of polyfunctionalized, medium-sized cyclic
ethers is widespread in marine natural products such as
brevetoxin A and B, yessotoxin, ciguatoxin, gambieric acid
A, the eunicellins, and maitotoxin. In addition, an impor-
tant 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 (acetogenins) that have been isolated from
red algae and species that feed on Laurencia. These com-
pounds display a wide range of biological activities, includ-
ing antitumor, antimicrobial, immunosuppressant, antifeed-
ant, pesticide activity, and so on.[1] The structural diversities
of these molecules are very wide, but all have in common
the presence of halogenated cyclic ethers with a defined
stereochemistry in the substituents and ring sizes ranging
from five to nine members. Such cyclic ethers are consid-
ered to be biogenetically derived from laurediols through
electrophilic cyclizations usually induced by a bromonium
ion.[1]
Figure 1. Representative C15 medium-sized ring ether marine
metabolites and their basic skeletons.
The fascinating structures and biological activities of
such naturally occurring medium-sized cyclic ethers have
stimulated the imagination of synthetic chemists, and a sig-
nificant level of effort has been focused on the development
of new methodologies for their synthesis. There are essen-
tially two strategies for the direct synthesis of medium-sized
cyclic ethers: through the formation of a C–O bond by
[a] Instituto Universitario de Bioorgánica “Antonio González”,
Universidad de La Laguna
Avenida Astrofísico Francisco Sánchez 2, 38206 La Laguna, using a nucleophilic oxygen reagent or by C–C bond forma-
tion by using a linear ether precursor (Scheme 1).[2] Within
Tenerife, Islas Canarias, Spain
Fax: +34-922318571
the last approach, the combination of the synthesis of the
suitably unsaturated branched ether and ring-closing me-
tathesis (RCM) provides a powerful method for the synthe-
sis of isolated and fused medium-sized cyclic ethers.[3] In
consequence, the preparation of the α,αЈ-disubstituted lin-
ear ether precursor has become a challenge for the synthesis
of oxacycles.
E-mail: vmartin@ull.es
[b] Instituto de Productos Naturales y Agrobiología, Consejo Su-
perior de Investigaciones Científicas,
Astrofísico Francisco Sánchez 3, 38206 La Laguna, Tenerife,
Islas Canarias, Spain
Fax: +34-922260135
E-mail: tmartin@ipna.csic.es
Supporting information for this article is available on the
WWW under http://www.eurjoc.org or from the author.
554
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2009, 554–563

Synthesis of (+)-cis/(–)-trans-Lauthisan and (+)-cis/(+)-trans-Obtusan
Scheme 2. Synthesis of cyclic ethers based on the intramolecular
Nicholas reaction (intraNR).
Scheme 1. Main strategies used in the synthesis of polyfunction-
alized cyclic ethers.
formation strategy). With this strategy, we can take advan-
tage of the bending in the acetylenic system when forming
the cobalt complex.[12,13] In addition, the cobalt complex
should avoid the undesirable participation of the triple
bond in the metathesis process.[14] Two alternative ap-
proaches can be planned for the synthesis of the oxacycles
with the use of these considerations (Scheme 3): (a) locating
the Co2(CO)6–alkyne complexed moiety exo to the cyclic
ether or (b) including such functionality in an endo posi-
tion. Considering that the presence of the Co2(CO)6–alkyne
complex in the chain possessing one of the terminal alkenes
could overcome the entropic disadvantages involved in the
cyclization step[15] and the increasing number of known
transformations of cyclic alkyne cobalt complexes, the last
route seemed more attractive.[16]
With the realization that the approach to the branched
ether linkage by a direct displacement strategy fails,[4] di-
verse alternatives have been used for the stereoselective syn-
thesis of these precursors. Accordingly, asymmetric
glycolate alkylations or aldolic additions were employed,
both following the Evans protocol, and in consequence with
the use of a chiral auxiliary.[5] Although the use of a chiral
auxiliary works well, it represents an increase in the total
number of synthetic steps. Recently, a stereoselective
glycolate alkylation was reported without the use of a chiral
auxiliary.[6] However, these reactions are not useful when
the ethers are sensitive to basic conditions, such as, for in-
stance, halogenated ethers, due to collateral elimination re-
actions. The development of methodologies oriented to-
ward the synthesis of ethers under neutral or acidic condi-
tions is highly desirable. For instance, a stereoselective syn-
thesis of α,αЈ-disubstituted linear ethers by intermolecular
allylation of an α-acetoxy ether with allyltributyltin and
boron trifluoride diethyl ether was reported.[7] Likewise, a
ring-opening reaction of a 1,3-dioxolanone with bis(tri-
methylsily)acetylene promoted by Lewis acid[4] and the use
of a -galactose derivative for the stereoselective introduc-
tion of allyl groups and further cleavage of the hexose ring
are additional examples of a such strategy.[8]
Scheme 3. Retrosynthetic analysis of cyclic ethers based on tandem
intermolecular Nicholas reaction (interNR) and RCM.
We developed a general procedure for the preparation of
cyclic ethers based on an intramolecular Nicholas reaction
(intraNR). A hydroxy group located in a suitable chain at-
tacks a carbocation generated by acid treatment of exo-
Co2(CO)6–propargylic alcohols to afford six-to-nine-mem-
bered cyclic ethers (C–O bond formation strategy) (R1 = R2
= R3 = H, Scheme 2).[9,10] Using this methodology, we can
In this paper we report on a simple method for the prep-
aration of α,αЈ-disubstituted linear ethers through an inter-
molecular Nicholas reaction (interNR) by treating second-
ary alcohols with secondary Co2(CO)6 complexed propar-
gylic alcohols under acidic conditions. In addition, we ac-
count full details of the total synthesis of (–)-trans- and (+)-
cis-lauthisan[17] and (+)-trans- and (+)-cis-obtusan from
these linear precursors by taking advantage of the chemical
and structural properties induced by the formation of
Co2(CO)6 complexes in propargylic systems.
also gain access to an oxane–oxepan system (R1–R2
=
CH2CH2CH2O, R3 = H or OBn, n = 2). However, this
methodology provided poor yields and conversions when
R1 ϶ H or R3 ϶ H to obtain isolated eight-membered cy-
clic ethers (n = 3).[11] Moreover, to obtain fused eight-mem-
bered cyclic ethers, such as an oxane–oxocane system (R1–
R2 = CH2CH2CH2O, R3 = OBn, n = 3), we need at least
two geometric control elements: a ring and a Z double bond
in the linear chain.[11]
Results and Discussion
To perform the synthesis of the necessary linear ether
precursors, we initially applied our previously reported
Taking into account this limitation, we considered the methodology based on the trapping of Co2(CO)6–propar-
possibility to develop a new strategy based on an intermo- gylic cations by using alcohols as nucleophiles.[18] Initial in-
lecular Nicholas reaction (interNR). Because RCM reac- vestigations began with the cobalt complex of commercially
tions have become the most powerful methodology to pro- available racemic 1-octyn-3-ol (1) and cyclohexanol as test
vide cyclic products, we envisioned formation of the cyclic substrates. However, these reported conditions worked well
ethers through a tandem interNR and RCM (C–C bond to obtain un- or monosubstituted linear ethers in the α or
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555

N. Ortega, T. Martín, V. S. Martín
FULL PAPER
αЈ position but failed to achieve the desired α,αЈ-disubsti- dered secondary alcohol (Table 2, Entry 8). Interestingly,
tuted linear ethers (Table 1, Entry 1). Considering that the when a tertiary alcohol such as tert-butyl alcohol is used as
C–O coupling reaction is intermolecular, it is reasonable to the incoming alcohol, the interNR takes place, although
expect that the yields could be improved by increasing the with poor yield (Table 2, Entry 11). Nevertheless, the reac-
concentration. A test regarding the concentration influence tion shows a poor level of stereoselectivity affording an
on autocoupling and/or elimination of complexed alkyne 1 anti/syn mixture of α,αЈ-disubstituted linear ethers.[20]
was performed. Satisfactorily, even at a concentration of
Table 2. Exploring the scope and limitations of the interNR.
0.5  over 2 h at 0 °C only trace amounts of the dimeric
species was detected. However, longer reaction times (ca.
24 h) provided substantial elimination of the propargylic
alcohol providing the corresponding Co2(CO)6 complex of
(E)-oct-3-en-1-yne (3) as the main isolated product.
Table 1. Optimization of the intermolecular Nicholas reaction.
Entry Cyclohexanol Conc. BF3·OEt2 T
t
Yield[a]
[%]
[equiv.]
[]
[equiv.]
[°C]
[h]
1
2
3
4
5
6
7
8
3
2
2
2
2
5
5
5
0.05
0.1
0.2
0.2
0.5
0.5
0.5
0.5
1
–20
0
0
0
0
0
0
25
3
2
2
2
2
1
1
1
trace
53
66
56
77
82
80
79
2.5
2.5
2.0
2.5
2.5
1.5
1.5
[a] Isolated yield after flash chromatography.
Once ensured that the conditions to avoid dimerization
and/or elimination of the starting Co2(CO)6–propargylic
alcohol were met, a variety of concentrations and relative
amounts of cyclohexanol and Lewis acid were screened
(Table 1). As a result of this study, we found that increasing
the amounts of the secondary alcohol and the Lewis acid
improved the yield and reduced the reaction time. We also
established that raising the temperature diminished the
yields (Table 1, Entry 8). Best conditions were achieved by
using a relatively high concentration (0.5 ), 5 equivalents
of cyclohexanol, and 2.5 equivalents of Lewis acid at 0 °C
(Table 1, Entry 6).
A variety of substrates possessing a secondary alcohol
were examined with the use of the optimized conditions
(Table 2). A wide substrate tolerance was observed. We
found the procedure to be highly general, affording the cor-
responding α,αЈ-disubstituted linear ethers in good yields.
[a] General reaction conditions: ROH (5 equiv.) and BF3·OEt2
(2.5 equiv.) in CH2Cl2 (0.5 ) at 0 °C. [b] The excess amount of
the nucleophilic alcohol can be easily recovered in the purification
process. [c] Yield given for isolated material after flash chromatog-
raphy. [d] Diastereoisomeric ratio of an indistinguishable mixture
of anti and syn isomers determined by 1H NMR spectroscopy.
[e] Numbers in parenthesis denote the yield when the reaction was
performed at a concentration of 0.2 .
Having developed a suitable protocol to achieve the syn-
Interestingly, the interNR can be achieved by using unsatu- thesis of the branched linear ethers, we decided to apply it
rated alcohols as nucleophiles, without the participation of to the synthesis of medium-sized cyclic ethers trough a tan-
the double and triple bonds in the reaction (Table 2, En- dem interNR and RCM. As targets, we chose the saturated
tries 1–3, 6, and 7). Dimeric ether 4 was obtained in excel- ethers lauthisan[21] and obtusan,[22] whose structures repre-
lent yield by using 1-octyn-3-ol as the incoming alcohol. In sent the basic skeletons present in a number of these natu-
addition, the ester and γ-lactone functions remain unaffec- rally occurring nonterpenoid eight- and nine-membered
ted under these conditions (Table 2, Entries 5 and 8). One ring ethers like (+)-laurencin, (+)-laurepinnacin, (+)-ob-
significant feature of our method is the compatibility with tusenyne, (–)-isolaurallene, and so on. (Figure 1). These
halogenated substrates (Table 2, Entries 9 and 10), provid- molecules have served several times as the testing ground
ing a very convenient method to obtain halo-substituted for the efficacy of oxocane and oxonane construction.[21,22]
ethers in good yields.[19] Noteworthy, the reaction takes
place, albeit with moderate yields, even with a sterically hin- Co2(CO)6–cycloalkynic ether 15, which could be synthe-
We envisioned the synthesis of these heterocycles through
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Synthesis of (+)-cis/(–)-trans-Lauthisan and (+)-cis/(+)-trans-Obtusan
sized from unsaturated alkyne–cobalt 16 by RCM. This
precursor is easily available from alkyne 17 (R3
=
CH2CH=CH2). Finally, this propargylic ether, having two
stereogenic centers close to the oxygen atom, was disas-
sembled to secondary allylic or homoallylic alcohol 18 and
complexed propargylic alcohol 19 through an interNR
(Scheme 4).
Scheme 5. Preparation of enantiomerically enriched alcohols 18a
(n = 0, R1 = n-C6H13) and 18b (n = 1, R1 = n-C5H11).
Scheme 4. Retrosynthetic analysis for the stereoselective synthesis
of cis-2,8-dialkyloxocanes and cis-2,9-dialkyloxonanes.
Our first aim, therefore, was the preparation of enantio-
merically enriched alcohols 18a (n = 0, R1 = n-C6H13) and
18b (n = 1, R1 = n-C5H11). The synthesis of 18a began with
commercially available heptaldehyde, which was subjected
to a two-carbon homologation by means of a Horner–Em-
mons reaction with the sodium salt of trimethyl phospho-
noacetate in benzene, affording the α,β-unsaturated ester
(E/Z Ͼ 20:1), which was reduced to allylic alcohol 20
(Scheme 5). With 20 in hand, we performed a Katsuki–
Sharpless asymmetric epoxidation using (+)-diethyl tartrate
as chiral auxiliary to afford 2,3-epoxy alcohol 21.[23] Epoxy
alcohol 21 was directly converted into vinyl carbinol 18a[24]
with an enantiomeric excess (ee) of 89%[25] by treatment
with bis(cyclopentadienyl)titanium(III) chloride.[26] In or-
der to obtain homoallylic alcohol 18b, the catalytic asym-
metric allylation protocol developed by Keck et al. was ap-
C6H13, R2 = C2H5, R3 = H) in good yield (Scheme 6). Al-
ternatively, the construction of ether 17b (n = 1, R1 = n-
C5H11, R2 = C2H5, R3 = H) was performed with the use of
18b as the nucleophilic alcohol and 19b as the cobalt com-
plex and by applying the optimized conditions for the in-
terNR described in Table 1 (Scheme 6).
plied.[27] Desired homoallylic alcohol 18b was formed in Scheme 6. Direct preparation of linear ethers having the linkage
between two stereogenic secondary carbon atoms.
good yield with 91%ee upon consecutive addition of hexa-
nal and allyltributylstannane to a solution of a catalyst
formed in situ from Ti(OiPr)4 and (R)-BINOL (1:2 ratio)
in the presence of 4 Å molecular sieves (MS).
Although at this point of the synthesis it was very diffi-
cult to ensure the stereoselection of the newly created ste-
Initial attempts to obtain 17 with the use of (S)-non-1- reocenter in compounds 17a and 17b, more elaborated frag-
en-3-ol (18a) as the incoming alcohol over the cobalt com- ments in the synthesis (vide infra) showed us a ratio of ap-
plex of racemic oct-7-en-4-yn-3-ol (19a, R2 = C2H5, R3 = proximately 1:1.7 for 17a and 1:1.1 for 17b of both dia-
CH2CH=CH2)[28] were fruitless yielding a complex mixture, stereoisomers in favor of the α,αЈ-anti-isomers. With ethers
presumably by internal participation of the double bond of 17a and 17b in hand, the preparation of the necessary
the enyne substrate. Trying to overcome this difficulty, we dienes for the RCM step required only a simple alkylation.
turned our attention to the cobalt complex of commercially To this end, copper-catalyzed homologation of 17a and 17b
available racemic 1-pentyn-3-ol (19b, R2 = C2H5, R3 = H), with allyl bromide provided dienyl derivatives 17c and 17d
relegating the allylation process to a later stage in the syn- in excellent yield. Because cyclization to form a medium-
thesis. In order to obtain the α,αЈ-disubstituted linear sized ring is impractical with a free alkyne as part of the
ethers, the optimized conditions for the interNR were ap- ring, the cobalt metallic core in 17c and 17d is crucial for
plied to cobalt complex 19b and allylic alcohol 18a, but a the ring closure. Thus, 17c and 17d were treated with
moderate yield was achieved. Fortunately, by decreasing the Co2(CO)8 to obtain cobalt complexes 16a (n = 0, R1 = n-
reaction concentration to 0.2  by using 2 equivalents of C6H13, R2 = C2H5, R3 = CH2CH=CH2) and 16b (n = 1,
Lewis acid and slow addition of the secondary alcohol we R1 = n-C5H11, R2 = C2H5, R3 = CH2CH=CH2) in quantita-
were able to obtain branched ether 17a (n = 0, R1 = n- tive yields (Scheme 7).
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N. Ortega, T. Martín, V. S. Martín
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As aforementioned, separation of both diastereoisomers
was very simple at this step. However, considering that the
major isomers isolated were trans-15a and trans-15b, we
pondered the possibility of performing an isomerization to
the cis isomer by considering that such stereoisomers are
usually thermodynamically more stable. Disappointingly,
treatment of a cis/trans mixture of 15a under various acidic
conditions (including BF3·OEt2, CF3COOH, and TsOH)
resulted in either decomposition or complete recovery of
the starting mixture.[30] Fortunately, 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 cation intermediate 25 (Scheme 8).[31] The
original mixture evolved quantitatively to a nice cis/trans
ratio of 17:1 for eight-membered ring 15a and a cis/trans
ratio of 21:1 for nine-membered ring 15b.
Scheme 7. Preparation of the Co2(CO)6 linear ethers for RCM.
Three 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;[14] second, the
bending[12,13] in the acetylenic system when forming the co-
balt complex could overcome the unfavorable entropic and
enthalpic factors involved in the formation of the eight- and
nine-membered rings[15] (the final ring has an endocyclic
triple bond); third, the Co2(CO)6–alkyne in the endo posi-
tion can be used as a stereochemical control agent for a
critical isomerization process in the final cyclic product.
Our first attempts to perform the cyclization reaction
with the use of first-generation Grubbs’ catalyst (22) led to
poor conversions and yields of the corresponding cyclic
ethers (Table 3, Entry 1). When the temperature was raised,
the yield was slightly improved (Table 3, Entry 2). Then, we
decided to explore the cyclization step using second-genera-
tion Grubbs’ catalyst (23), but unfortunately, at room tem-
perature starting material 16a was fully recover (Table 3,
Entry 3). Satisfactorily, when second-generation Grubbs’
catalyst (23) was used under reflux and diluted conditions
(0.001 ) in dichloromethane, an 83% yield of 15a was ob-
tained (Table 3, Entry 4). The use of Hoveyda’s catalyst (24)
was unfruitful, even after a long reaction time (Table 3, En-
try 5). The same conditions applied to obtain 15a were used
to obtain Co2(CO)6–cycloalkyne ether 15b in excellent yield
(Table 3, Entry 6).
Scheme 8. Isomerization of 2,8- and 2,9-dialkyl Co2(CO)6–cycloal-
kynic ethers promoted by montmorillonite K-10.
The last steps required to complete the synthesis of the
targets (+)-cis-lauthisan and (+)-cis-obtusan were the cleav-
age of the cobalt complex and reduction to the final oxa-
cycle (Scheme 9). The reductive decomplexation reported
by Isobe et al. produced cyclodienes 26 (n = 0, R1 = n-
C6H13) and 27 (n = 1, R1 = n-C5H11) very efficiently, al-
though as inseparable mixtures of stereoisomers in the
newly created double bond.[16a,16b] However, the hydrogena-
tion under standard conditions of 26 and 27 provided
cleanly (+)-cis-lauthisan [α]2D5 = +4.1 (c = 0.9, CHCl3)[21k]
and (+)-cis-obtusan [α]2D5 = +3.9 (c = 2.1, CHCl3), respec-
tively.
Table 3. RCM of Co2(CO)6 linear ethers 16a and 16b.
Entry
Sub-
Cata- Conc. T
t
Yield[a] cis/trans
strate
lyst
[mol-
%]
[m] [°C] [h]
[%]
1
2
3
4
5
6
16a
16a
16a
16a
16a
16b
22 (10)
22 (30)
23 (30)
23 (30)
24 (30)
23 (30)
5
1
1
1
1
1
25
35
25
35
35
35
5
2
48
2
24
2
18
1:1.7
1:1.7
–
1:1.7
–
45
[b]
–
83
[b]
–
93
1:1.1
Scheme 9. Reductive cleavage of Co2(CO)6–cycloalkynic ethers and
hydrogenation.
[a] Isolated yields after flash chromatography. [b] Starting material
was fully recovered.
Finally, in order to obtain the trans isomers of lauthisan
Interestingly, at this point of the synthesis both diastereo- and obtusan, we applied the same sequence of reactions
isomers of 15a and 15b were separated very easily by silica- shown above (Scheme 9) to trans-15a and trans-15b, pre-
gel column chromatography. NOE studies of both isomers viously available from the column chromatography purifica-
allowed the assignment of the relative stereochemistry.[29]
tion of the RCM reactions.[32] Accordingly, trans-(–)-lauthi-
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Synthesis of (+)-cis/(–)-trans-Lauthisan and (+)-cis/(+)-trans-Obtusan
san {[α]2D5 = –8.3 (c = 0.9, CHCl3)} and (+)-trans-obtusan
{[α]2D5 = +6.3 (c = 1.4, CHCl3)} were obtained in excellent
yields.
distilled H2O. The aqueous phase was extracted with Et2O (2ϫ).
The combined organic extracts were dried, filtered, concentrated,
and subjected to silica gel flash chromatography to yield 2 (171 mg,
1
82% yield) as an oil. H NMR (300 MHz, CDCl3): δ = 0.88 (m, 3
H), 1.22–1.35 (m, 8 H), 1.44 (m, 4 H), 1.67–1.73 (m, 4 H), 1.89 (m,
2 H), 2.35 (d, J = 2.1 Hz, 1 H), 3.55 (m, 1 H), 4.12 (ddd, J = 2.2,
6.6, 6.6 Hz, 1 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 13.7 (q),
22.3 (t), 23.8 (t), 23.9 (t), 24.8 (t), 25.6 (t), 31.0 (t), 31.2 (t), 33.1
(t), 35.9 (t), 65.9 (d), 72.1 (s), 75.3 (d), 84.1 (d) ppm. IR (film, NaCl
Conclusions
In summary, we described a new and efficient method to
prepare branched linear ethers having two secondary car-
bon atoms vicinal to the oxygen atom through an intermo-
lecular Nicholas reaction (interNR). The methodology is
practical, simple to use, and compatible with a wide range
of functional groups. A tandem interNR, RCM, and isom-
erization of Co2(CO)6–cycloalkyne ether complexes cata-
lyzed by montmorillonite K-10 are the basis for the
stereocontrolled synthesis of cis isomers of saturated and
unsaturated eight- and nine-membered 2,8-dialkyl and 2,9-
dialkyl cyclic ethers, respectively. All these procedures were
exemplified in the stereoselective synthesis of (+)-cis-lauthi-
san and (+)-cis-obtusan and also in the synthesis of their
trans isomers. Current efforts are focused on the expansion
of this strategy to the synthesis of natural products contain-
ing medium-ring ethers in their structures.
plates): ν = 3310, 2931, 2857, 1453, 1085 cm–1. C H O (208.3):
˜
14 24
calcd. C 80.71, H 11.61; found C 80.51, H 12.19.
3-(Oct-1-yn-3-yloxy)oct-1-yne (4): The general procedure for the
preparation of α,αЈ-disubstituted linear ethers described above was
applied to the cobalt complex of 1-octyn-3-ol (412 mg, 1 mmol)
and 1-octyn-3-ol (729 µL, 5 mmol), yielding a 1.5:1.0 mixture of
diastereoisomers 4 (241 mg, 97% yield) as an oil. 1H NMR
(300 MHz, CDCl3): δ = 0.89 (dd, J = 6.6, 6.6 Hz, 15 H), 1.31 (m,
20 H), 1.45 (m, 10 H), 1.63–1.82 (m, 10 H), 2.39 (d, J = 1.9 Hz, 3
H), 2.44 (d, J = 2.0 Hz, 2 H), 4.27 (ddd, J = 6.5, 6.5, 2.0 Hz, 2 H),
4.40 (ddd, J = 6.5, 6.5, 1.9 Hz, 3 H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 13.8 (q), 22.3 (t), 24.4 (t), 24.5 (t), 31.2 (t), 34.9 (t),
35.3 (t), 62.1 (s), 66.8 (t), 67.6 (t), 73.2 (s), 73.3 (s), 82.6 (s), 82.9
(s) ppm. IR (film, NaCl plates): ν = 3310, 2930, 2861, 1076 cm–1.
˜
C16H26O (234.4): calcd. C 81.99, H 11.18; found C 81.97, H 11.41.
3-(Hept-1-en-3-yloxy)oct-1-yne (5): The general procedure for the
preparation of α,αЈ-disubstituted linear ethers described above was
applied to the cobalt complex of 1-octyn-3-ol (412 mg, 1 mmol)
and hept-1-en-3-ol (679 µL, 5 mmol), yielding a 2.1:1.0 mixture of
diastereoisomers 5 (178 mg, 80% yield) as an oil. 1H NMR
(300 MHz, CDCl3): δ = 0.89 (s, 18.6 H), 1.10–1.73 (m, 43.4 H),
2.35 (d, J = 1.7 Hz, 2.1 H), 2.37 (d, J = 1.7 Hz, 1 H), 3.86–3.92
(m, 2 H), 3.97–4.11 (m, 4.2 H), 5.13–5.24 (m, 6.2 H), 5.54–5.66 (m,
2.1 H), 5.79–5.85 (m, 1 H) ppm. 13C NMR (75 MHz, CDCl3): δ =
13.7 (q), 13.8 (q), 22.0 (t), 22.4 (t), 27.3 (t), 29.4 (t), 31.0 (t), 31.7
(t), 34.9 (t), 68.7 (t), 70.4 (s), 80.2 (d), 116.1 (t), 116.2 (t), 126.3 (d),
Experimental Section
General: 1H NMR spectra were recorded at 500, 400, or 300 MHz,
and 13C NMR spectra were recorded at 75 or 100 MHz; chemical
shifts are reported relative to internal Me4Si. IR spectra were re-
corded as films on NaCl. Column chromatography was performed
on silica gel, 60 Å and 0.2–0.5 mm. Compounds were visualized by
use of UV light, 2.5% phosphomolybdic acid in ethanol, or vanillin
with acetic and sulfuric acid in ethanol with heating. All solvents
were purified by standard techniques. Reactions requiring anhy-
drous conditions were performed under an atmosphere of nitrogen.
Anhydrous magnesium sulfate was used for drying solutions.
134.1 (d), 139.2 (d), 139.6 (d) ppm. IR (film, NaCl plates): ν =
˜
3310, 2957, 2862, 1466, 1072, 926 cm–1. C15H26O (222.4): calcd. C
81.02, H 11.79; found C 81.06, H 11.57.
General Procedure for the Preparation of Cobalt-Complexed Propar-
gyl Alcohols: Solid Co2(CO)8 (376 mg, 1.1 mmol) was added to a
solution of the corresponding alkyne (1 mmol) in anhydrous
CH2Cl2 (5 mL) under a nitrogen atmosphere. The dark solution
was stirred at room temperature until TLC showed the formation
of the complex to be completed (ca. 2 h). The solvent of the re-
sulting reaction mixture was then removed under vacuum, and the
residue was used without further purification.
3-(Hepta-1,6-dien-4-yloxy)oct-1-yne (6): The general procedure for
the preparation of α,αЈ-disubstituted linear ethers described above
was applied to the cobalt complex of 1-octyn-3-ol (412 mg,
1 mmol) and hepta-1,6-dien-4-ol (649 µL, 5 mmol), yielding 6
(163 mg, 79% yield) as an oil. 1H NMR (300 MHz, CDCl3): δ =
0.87 (m, 3 H), 1.29 (dd, J = 3.5, 3.5 Hz, 4 H), 1.43 (m, 2 H), 1.66
(m, 2 H), 2.26–2.37 (m, 4 H), 2.37 (d, J = 0.5 Hz, 1 H), 3.71 (dd,
J = 5.8, 11.7 Hz, 1 H), 4.13 (ddd, J = 1.7, 6.5, 6.5 Hz, 1 H), 5.05
(m, 4 H), 5.82 (m, 2 H) ppm. 13C NMR (75 MHz, CDCl3): δ =
13.8 (q), 22.3 (t), 24.7 (t), 31.3 (t), 35.8 (t), 37.2 (t), 38.6 (t), 67.5
(d), 72.7 (d), 77.2 (d), 83.7 (s), 116.5 (t), 117.0 (t), 134.3 (d), 134.8
Preparation of (Oct-1-yn-3-yloxy)cyclohexane (2) as a Representa-
tive Example for the Preparation of α,αЈ-Disubstituted Linear
Ethers: To a cooled mixture of Co2(CO)6–1-octyn-3-ol (412 mg,
1 mmol) and cyclohexanol (533 µL, 5 mmol) in dry CH2Cl2 (2 mL,
0.5 ) was added BF3·OEt2 (317 µL, 2.5 mmol) under a nitrogen
atmosphere at 0 °C. After the addition, the reaction mixture was
stirred for 1 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 concen-
trated to yield the crude cobalt complex as an oil, which was used
without further purification. Such cobalt complex was dissolved in
reagent-grade acetone (10 mL) under a nitrogen atmosphere at
0 °C. Ceric ammonium nitrate (2.2 g, 4 mmol) was added in por-
tions with stirring until evolution of CO ceased and the CAN color
persisted (ca. 20 min). The solvent was removed under vacuum,
and the pink solid residue was then partitioned between Et2O and
(d) ppm. IR (film, NaCl plates): ν = 3309, 2928, 2859, 1083,
˜
913 cm–1LRMS (EI): m/z (%) = 219 (49) [M – H]+, 111 (7) [M –
C8H13]+, 57 (100). HRMS (EI): calcd. for C15H23O [M – H]+
219.1741; found 219.1749.
3-[(S)-Octan-2-yloxy]oct-1-yne (7): The general procedure for the
preparation of α,αЈ-disubstituted linear ethers above was applied
to the cobalt complex of 1-octyn-3-ol (412 mg, 1 mmol) and (S)-
octan-2-ol (792 µL, 5 mmol), yielding a 1.2:1.0 mixture of dia-
stereoisomers 7 (143 mg, 60% yield) as an oil. 1H NMR (400 MHz,
CDCl3): δ = 0.86–0.90 (m, 13.2 H), 1.09 (d, J = 6.0 Hz, 3 H), 1.20
(d, J = 6.1 Hz, 3.6 H), 1.27–1.46 (m, 30.8 H), 1.69 (m, 8.8 H), 2.33
(d, J = 2.1 Hz, 1 H), 2.36 (d, J = 2.0 Hz, 1.2 H), 3.66 (m, 2.2 H),
4.05 (m, 2.2 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 13.7 (q),
Eur. J. Org. Chem. 2009, 554–563
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
559

N. Ortega, T. Martín, V. S. Martín
FULL PAPER
13.8 (q), 18.8 (q), 20.6 (q), 22.3 (t), 24.7 (t), 24.9 (t), 25.3 (t), 29.1
= 3309, 2958, 2928, 2857, 1791, 1117 cm–1. LRMS (EI): m/z (%) =
(t), 29.2 (t), 31.3 (t), 31.6 (t), 35.7 (t), 35.8 (t), 35.9 (t), 37.1 (t), 66.3 223 (100) [M – CH3]+, 99 (54). HRMS (EI): calcd. for C14H22O3
(d), 67.4 (d), 72.2 (s), 72.9 (d), 74.5 (d), 84.3 (s) ppm. IR (film,
[M – CH3]+ 223.1334; found 223.1341.
NaCl plates): ν = 3311, 2928, 2858, 1118 cm–1. C H O (238.4):
˜
16 30
3-(1-Bromopropan-2-yloxy)oct-1-yne (12): The general procedure
for the preparation of α,αЈ-disubstituted linear ethers described
above was applied to Co2(CO)6–1-octyn-3-ol (412 mg, 1 mmol) and
1-bromo-2-propanol (454 µL, 5 mmol), yielding a 1.2:1.0 mixture
of diastereoisomers 12 (173 mg, 70% yield) as an oil. 1H NMR
(400 MHz, CDCl3): δ = 0.86 (m, 6.6 H), 1.24–1.44 (m, 15.4 H),
1.44–1.46 (m, 4.4 H), 1.65–1.74 (m, 4.4 H), 2.39 (dd, J = 2.5, 3 Hz,
2.2 H), 3.29–3.36 (m, 3.2 H), 3.48–3.51 (m, 1 H), 3.94 (m, 2.2 H),
calcd. C 80.61, H 12.68; found C 80.60, H 12.63.
(2R)-Ethyl 2-(Oct-1-yn-3-yloxy)propanoate (8): The general pro-
cedure for the preparation of α,αЈ-disubstituted linear ethers de-
scribed above was applied to the cobalt complex of 1-octyn-3-ol
(412 mg, 1 mmol) and (+)-(R)-ethyl lactate (568 µL, 5 mmol), yield-
ing a 1.9:1.0 mixture of diastereoisomers 8 (138 mg, 61% yield) as
an oil. 1H NMR (500 MHz, CDCl3): δ = 0.87 (m, 8.7 H), 1.26–
1.33 (m, 17.4 H), 1.40–1.51 (m, 11.6 H), 1.58 (m, 5.8 H), 1.75 (m, 4.12 (dd, J = 2.5, 18.5 Hz, 1 H), 4.16 (dd, J = 2.5, 8.5 Hz, 1.2 H)
5.8 H), 2.41 (d, J = 2.0 Hz, 2.9 H), 4.20 (m, 8.7 H), 4.37 (ddd, J =
ppm. 13C NMR (100 MHz, CDCl3): δ = 14.4 (q), 18.5 (q), 20.4 (q),
6.9, 13.8, 13.8 Hz, 2.9 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 22.9 (t), 25.2 (t), 25.3 (t), 31.8 (t), 31.8 (t), 36.8 (t), 36.8 (t), 37.2
13.8 (q), 14.0 (q), 18.7 (q), 22.3 (t), 24.5 (t), 31.2 (t), 35.5 (t), 60.5
(t), 68.5 (d), 71.8 (d), 73.6 (d), 82.4 (s), 173.0 (s) ppm. IR (film,
(t), 68.2 (d), 68.7 (d) 73.4 (d), 73.6 (d), 83.6 (s) ppm. IR (film, NaCl
plates): ν = 3308, 2932, 2861, 654 cm–1. LRMS (EI): m/z (%) = 167
˜
NaCl plates): ν = 3309, 3291, 3274, 2956, 2871, 1747, 1126 cm–1.
(1.2) [M – Br]+, 105 (100), 77 (42). HRMS (EI): calcd. for C11H19O
[M – Br]+ 167.1436; found 167.1431.
˜
C13H22O3 (226.3): calcd. C 68.99, H 9.80; found C 68.67, H 9.23.
3-(Oct-1-yn-3-yloxy)cyclohex-1-ene (9): The general procedure for
the preparation of α,αЈ-disubstituted linear ethers described above
was applied to the cobalt complex of 1-octyn-3-ol (412 mg,
1 mmol) and 2-cyclohexen-1-ol (491 µL, 5 mmol), yielding a 1.0:1.0
mixture of diastereoisomers 9 (190 mg, 92% yield) as an oil. 1H
NMR (400 MHz, CDCl3): δ = 0.89 (dd, J = 5.3, 6.5 Hz, 6 H), 1.2–
2.02 (m, 28 H), 2.38 (dd, J = 0.5, 1.3 Hz, 2 H), 4.16 (m, 4 H), 5.75
(m, 2 H), 5.87 (m, 2 H) ppm. 13C NMR (75 MHz, CDCl3): δ =
3-(1-Chloropropan-2-yloxy)oct-1-yne (13): The general procedure
for the preparation of α,αЈ-disubstituted linear ethers described
above was applied to Co2(CO)6–1-octyn-3-ol (412 mg, 1 mmol) and
1-chloro-2-propanol (425 µL, 5 mmol), yielding a 1.0:1.0 mixture
of diastereoisomers 13 (174 mg, 86% yield) as an oil. 1H NMR
(400 MHz, CDCl3): δ = 0.86 (m, 6 H), 1.21–1.43 (m, 14 H), 1.44–
1.49 (m, 4 H), 1.51–1.73 (m, 4 H), 2.40 (dd, J = 1, 2.5 Hz, 2 H),
3.41–3.48 (m, 3 H), 3.6 (m, 1 H), 3.95 (m, 2 H), 4.11 (m, 1 H), 4.17
13.8 (q), 18.8 (t), 19.0 (t), 22.3 (t), 24.7 (t), 24.8 (t), 24.9 (t), 25.0 (m, 1 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 14.4 (q), 117.7
(t), 27.4 (t), 29.4 (t), 31.2 (t), 35.9 (t), 36.0 (t), 66.5 (d), 66.9 (d), (q), 19.5 (q), 22.9 (t), 25.2 (t), 31.8 (t), 36.3 (t), 36.3 (t), 47.7 (t),
70.4 (d), 71.0 (d), 72.5 (s), 126.8 (d), 128.1 (d), 130.6 (d), 131.0 (d)
48.4 (t), 68.1 (d), 68.9 (d), 73.7 (d), 73.8 (d), 73.9 (d), 74.0 (d), 83.5
ppm. IR (film, NaCl plates): ν = 3308, 2933, 1716, 1075 cm–1.
(s), 83.8 (s) ppm. IR (film, NaCl plates): ν = 3303, 2957, 2932,
˜
˜
LRMS (EI): m/z (%) = 206 (0.84) [M]+, 98 (32), 81 (100). HRMS
667 cm–1. C11H19ClO (202.7): calcd. C 65.17, H 9.45; found C
65.21, H 9.33.
(EI): calcd. for C14H22O [M]+ 206.1671; found 206.1675.
4-(Oct-1-yn-3-yloxy)cyclohex-1-ene (10): The general procedure for
the preparation of α,αЈ-disubstituted linear ethers described above
3-tert-Butoxyoct-1-yne (14): The general procedure for the prepara-
tion of α,αЈ-disubstituted linear ethers described above was applied
was applied to Co2(CO)6–1-octyn-3-ol (412 mg, 1 mmol) and 3-cy- to Co2(CO)6–1-octyn-3-ol (412 mg, 1 mmol) and tert-butyl alcohol
clohexen-1-ol (491 µL, 5 mmol), yielding a 1.0:1.0 mixture of dia-
stereoisomers 10 (196 mg, 95% yield) as an oil. 1H NMR
(300 MHz, CDCl3): δ = 0.89 (dd, J = 6.6, 6.9 Hz, 6 H), 1.25–1.75
(m, 20 H), 2.12 (m, 8 H), 2.34 (dd, J = 2.0, 3.1 Hz, 1 H), 2.37 (dd,
J = 2.0, 3.1 Hz, 1 H), 3.70 (m, 1 H), 3.85 (m, 1 H) 4.05 (m, 1 H),
4.15 (ddd, J = 2.0, 6.7, 11.8 Hz, 1 H), 5.60 (m, 4 H) ppm. 13C
(478 µL, 5 mmol), yielding 14 (69 mg, 38% yield) as a oil. 1H NMR
(400 MHz, CDCl3): δ = 0.89 (m, 3 H), 1.25–1.44 (m, 15 H), 1.61–
1.67 (m, 2 H), 2.33 (s, 1 H), 4.08 (d, J = 13.3, 6.6 Hz, 1 H) ppm.
13C NMR (100 MHz, CDCl3): δ = 14.3 (q), 22.9 (t), 25.4 (t), 28.6
(d), 31.9 (t), 37.9 (t), 62.1 (d), 87.0 (s) ppm. IR (film, NaCl plates):
ν = 2956, 2928, 1596 cm–1. LRMS (EI): m/z (%) = 125 (1.6) [M –
˜
NMR (75 MHz, CDCl3): δ = 13.7 (q), 22.3 (t), 22.7 (t), 23.7 (t), tBu]+, 121 (32), 109 (4), 91 (40). HRMS (EI): calcd. for C12H23O
24.1 (t), 24.7 (t), 24.8 (t), 25.2 (t), 26.8 (t), 28.8 (t), 29.4 (t), 30.1 [M + H]+ 183.1749; found 183.1757.
(t), 30.7 (t), 31.2 (t), 32.3 (t), 32.5 (t), 35.9 (t), 66.4 (d), 72.0 (s),
(S)-3-[(R and S)-Pent-1-yn-3-yloxy]non-1-ene (17a): The general
72.3 (d), 72.3 (d), 72.4 (d), 72.5 (d), 123.7 (d), 124.4 (d), 126.3 (d),
procedure for the preparation of α,αЈ-disubstituted linear ethers de-
126.9 (d) ppm. IR (film, NaCl plates): ν = 3310, 2924, 2857, 1466,
˜
scribed above was applied to 1-pentyn-3-ol on (0.5 g, 5.9 mmol).
The reaction mixture was cooled to 0 °C and BF3·OEt2 was added
(1.5 mL, 11.9 mmol). Then, allylic alcohol 18a was dissolved in dry
CH2Cl2 (5 mL) and added to the reaction mixture with a syringe
pump (0.1 mLmin–1). 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 combined organic layer was dried (MgSO4), filtered, and
concentrated to yield the crude cobalt complex as an oil, which was
1088 cm–1. LRMS (EI): m/z (%) = 207 (1.5) [M + H]+, 111 (41),
98 (49), 67 (100). HRMS (EI): calcd. for C14H23O [M + H]+
207.1749; found 207.1750.
(3R)-4,4-Dimethyl-3-(oct-1-yn-3-yloxy)dihydrofuran-2(3H)-one (11):
The general procedure for the preparation of α,αЈ-disubstituted lin-
ear ethers described above was applied to Co2(CO)6–1-octyn-3-ol
(412 mg, 1 mmol) and (R)-(–)-pantolactone (651 mg, 5 mmol),
yielding a 1.4:1.0 mixture of diastereoisomers 11 (167 mg, 70%
yield) as an oil. 1H NMR (400 MHz, CDCl3): δ = 0.89 (dd, J = used without further purification. The cobalt complex previously
6.6, 6.6 Hz, 7.2 H), 1.07 (s, 7.2 H), 1.18 (s, 7.2 H), 1.29–1.33 (m, obtained was dissolved in reagent-grade acetone (30 mL) under a
9.6 H), 1.43 (m, 4.8 H), 1.65–1.98 (m, 4.8 H), 2.40 (d, J = 2.0 Hz,
1 H), 2.49 (d, J = 2.0 Hz, 1.4 H), 3.89 (m, 4.8 H), 4.07 (s, 1 H),
4.16 (s, 1.4 H), 4.33 (ddd, J = 2.0, 4.8, 4.8 Hz, 2.4 H) 4.67 (m, 2.4
H) ppm. 13C NMR (100 MHz, CDCl3): δ = 13.7 (q), 19.1 (q), 22.2
nitrogen atmosphere at 0 °C. Ceric ammonium nitrate (13.0 g,
23.8 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 parti-
(t), 22.6 (q), 24.3 (t), 31.2 (t), 35.1 (t), 39.9 (s), 68.9 (d), 73.9 (d), tioned between Et2O and distilled H2O. The aqueous phase was
76.2 (t), 78.6 (d), 82.2 (s), 175.3 (s) ppm. IR (film, NaCl plates): ν extracted with Et2O (2ϫ). The combined organic extracts were
˜
560
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Eur. J. Org. Chem. 2009, 554–563

Synthesis of (+)-cis/(–)-trans-Lauthisan and (+)-cis/(+)-trans-Obtusan
dried, filtered, concentrated, and subjected to silica-gel flash
chromatography, yielding a 1.7:1.0 mixture of diastereoisomers 17a
(780 mg, 63% yield) as an oil. 1H NMR (300 MHz, CDCl3): δ =
135.3 (d), 135.9 (d) ppm. IR (film, NaCl plates): ν = 2934, 2862,
˜
1604, 1126 cm–1. LRMS (EI): m/z (%) = 167 (9) [M – 2C3H5
H]+, 109 (3), 83 (30). HRMS (EI): calcd. for C11H19O [M –
+
0.87 (dd, J = 6.1, 6.8 Hz, 7.5 H), 0.99 (m, 7.5 H), 1.27–1.47 (m, 23 2C3H5+H]+ 167.1436; found 167.1437.
H), 1.58–1.75 (m, 7 H), 2.33 (d, J = 1.96 Hz, 1.5 H), 2.36 (d, J =
Preparation of Dicobalt Hexacarbonyl Complex of (S)-3-[(R and S)-
2.1 Hz, 1 H), 4.00 (m, 5 H), 5.18 (m, 5 H), 5.57 (ddd, J = 2.0, 8.1,
17.7 Hz, 1.5 H), 5.79 (m, 1 H) ppm. 13C NMR (75 MHz, CDCl3):
δ = 9.3 (q), 9.5 (q), 14.0 (q), 22.6 (t), 25.1 (t), 25.2 (t), 28.5 (t), 28.9
(t), 29.1 (t), 29.2 (t), 31.8 (t), 34.8 (t), 35.5 (t), 67.2 (d), 68.5 (d),
72.7 (d), 72.7 (d), 78.7 (d), 80.0 (d), 83.5 (s), 83.8 (s), 115.9 (t),
Oct-7-en-4-yn-3-yloxy]non-1-ene (16a): The general procedure for
the preparation of cobalt-complexed propargyl alcohols described
above was applied to 17c (700 mg, 2.8 mmol), yielding 16a (1.51 g,
quantitative) as a dark-red oil.
Preparation of Dicobalt Hexacarbonyl Complex of (S)-4-[(R and S)-
Oct-7-en-4-yn-3-yloxy]non-1-ene (16b): The general procedure for
the preparation of cobalt-complexed propargyl alcohols described
above was applied to 17d (600 mg, 2.4 mmol), yielding 16b (1.29 g,
quantitative) as a dark-red oil.
117.3 (t), 138.7 (d), 139.4 (d) ppm. IR (film, NaCl plates): ν = 3311,
˜
2930, 2858, 1458, 1102 cm–1. C14H24O (208.3): calcd. C 80.71, H
11.61; found C 80.92, H 11.75.
(S)-4-[(R and S)-Pent-1-yn-3-yloxy]non-1-ene (17b): The general
procedure for the preparation of α,αЈ-disubstituted linear ethers de-
scribed above was applied to Co2(CO)6–1-octyn-3-ol (0.5 g,
5.9 mmol) and (S)-non-1-en-4-ol (18b; 4.2 g, 29.5 mmol), yielding
a 1.1:1.0 mixture of diastereoisomers 17b (799 mg, 65% yield) as
Dicobalt Hexacarbonyl Complexes of (2R and 2S,8S)-2-Ethyl-8-
hexyl-3,4-didehydro-5,8-dihydro-2H-oxocine (cis-15a and trans-15a):
To a stirred solution of cobalt complexes 16a (250 mg, 0.47 mmol)
in dry CH2Cl2 (470 mL, 0.001 ) was added the 2nd generation
Grubbs catalyst (120 mg, 0.14 mmol, 30 mol-%). The reaction was
warmed at 35 °C and kept at such a temperature until TLC showed
complete conversion. Then, the solvent was evaporated, and the
residue was purified by column chromatography yielding cis-15a
(73 mg, 31% yield) and trans-15a (124 mg, 52% yield). Data for
cis-15a: 1H NMR (400 MHz, CDCl3): δ = 0.88 (d, J = 6.6 Hz, 3
H), 1.18 (dd, J = 7.3, 7.3 Hz, 3 H), 1.30–1.90 (m, 12 H), 3.45 (dd,
J = 7.9, 15.6 Hz, 1 H), 3.71 (m, 1 H), 4.11 (dd, J = 4.6, 8.3 Hz, 1
H), 4.53 (dd, J = 2.2, 9.7 Hz, 1 H), 5.55 (dd, J = 9.0, 10.0 Hz, 1
H), 6.08 (m, 1 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 11.3 (q),
13.8 (q), 22.3 (t), 25.0 (t), 29.0 (t), 30.6 (t), 31.5 (t), 31.9 (t), 36.2
(t), 75.4 (d), 83.8 (d), 99.5 (s), 101.4 (s), 131.6 (d), 136.3 (d) ppm.
Data for trans-15a: 1H NMR (400 MHz, CDCl3): δ = 0.85 (m, 6
H), 0.90–1.85 (m, 12 H), 3.50 (dd, J = 7.2, 17.4 Hz, 1 H), 3.80 (m,
1 H), 4.15 (m, 1 H), 4.45 (dd, J = 2.9, 9.0 Hz, 1 H), 5.55 (dd, J =
9.8, 9.8 Hz, 1 H), 6.18 (m, 1 H) ppm. 13C NMR (75 MHz, CDCl3):
δ = 11.3 (q), 13.8 (q), 22.3 (t), 25.0 (t), 29.0 (t), 30.6 (t), 31.5 (t),
31.9 (t), 36.2 (t), 75.4 (d), 83.8 (d), 101.4 (s), 131.5 (d), 136.3 (d)
ppm.
1
an oil. H NMR (400 MHz, CDCl3): δ = 0.86 (m, 6 H), 0.98 (ddd,
J = 2.4, 7.2, 7.2 Hz, 6 H), 1.24–1.73 (m, 20 H), 1.58 (s, 1 H), 2.22–
2.36 (m, 4 H), 3.57 (m, 2 H), 4.02 (m, 2 H), 5.04 (m, 4 H), 5.82
(m, 2 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 10.0 (q), 10.0
(q), 14.4 (q), 14.4 (q), 22.9 (t), 25.0 (t), 25.5 (t), 29.6 (t), 29.6 (t),
32.3 (t), 32.4 (t), 33.5 (t), 34.7 (t), 38.3 (t), 39.4 (t), 68.9 (d), 69.5
(d), 73.1 (d), 73.2 (d), 77.1 (d), 78.1 (d), 84.3 (s), 84.4 (s), 116.8 (t),
117.3 (t), 135.2 (d), 135.7 (d) ppm. IR (film, NaCl plates): ν = 3295,
˜
2927, 2854, 1158 cm–1.
Preparation of (S)-3-[(R and S)-Oct-7-en-4-yn-3-yloxy]non-1-ene
(17c) as a Representative Example for the Alkylation of Terminal
Alkynes with Allyl Bromide: To a stirred solution of terminal alkyne
17a (0.7 g, 3.4 mmol) in dry DMF (1.1 mL) was added K2CO3
(650 mg, 4.7 mmol) and copper(I) iodine (32 mg, 0.16 mmol) se-
quentially under an atmosphere of nitrogen at room temperature
After 10 min, allyl bromide (378 µL, 4.4 mmol) was added. The
reaction mixture was stirred for 40 h. Then, it was poured into H2O
and extracted with diethyl ether. The combined organic phase was
washed with brine, dried, and concentrated. The crude obtained
was purified by flash chromatography, yielding 17c (785 mg, 94%
yield) as an oil. 1H NMR (300 MHz, CDCl3): δ = 0.87 (dd, J =
6.0, 6.8 Hz, 10 H), 1.27 (m, 16 H), 1.64 (m, 5 H), 2.98 (ddd, J =
1.2, 3.2, 5.1 Hz, 3 H), 4.02 (m, 3 H), 5.11 (m, 6 H), 5.60 (m, 1 H),
5.80 (m, 2 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 9.5 (q), 9.7
(q), 14.0 (q), 22.6 (t), 22.6 (t), 23.0 (t), 25.1 (t), 25.3 (t), 28.8 (t),
29.1 (t), 29.2 (t), 31.8 (t), 34.8 (t), 35.5 (t), 62.3 (s), 67.7 (d), 69.0
(d), 78.4 (d), 79.5 (d), 81.5 (d), 81.6 (s), 82.2 (s), 82.5 (s), 115.6 (t),
115.8 (t), 115.8 (t), 116.9 (t), 132.5 (d), 132.6 (d), 139.0 (d), 139.7
Dicobalt Hexacarbonyl Complexes of (2R and 2S,9S)-2-Ethyl-9-pen-
tyl-3,4-didehydro-2,5,8,9-tetrahydrooxonine (cis-15b and trans-15b):
The same procedure used above to obtain compounds 15a was ap-
plied to 16a (250 mg, 0.47 mmol), yielding cis-15b (105 mg, 44%
yield) and trans-15b (116 mg, 49% yield). Data for cis-15b: 1H
NMR (400 MHz, CDCl3): δ = 0.94 (m, 3 H), 1.14 (dd, J = 7.6,
7.6 Hz, 3 H), 1.33–1.80 (m, 10 H), 1.93 (m, 1 H), 2.09 (m, 1 H),
2.73 (dd, J = 3.2, 11.2 Hz, 1 H), 3.41 (dd, J = 7.6, 14.8 Hz, 1 H),
3.78 (dd, J = 6.4, 15.2 Hz, 1 H), 3.91 (m, 1 H), 4.56 (dd, J = 3.4,
9.2 Hz, 1 H), 5.68 (m, 1 H), 5.94 (m, 1 H) ppm. 13C NMR
(75 MHz, CDCl3): δ = 11.2 (q), 14.4 (q), 22.9 (t), 26.5 (t), 31.7 (t),
32.3 (t), 32.3 (t), 32.7 (t), 35.1 (t), 80.1 (d), 82.6 (d), 99.6 (s), 102.1
(s), 129.7 (d), 130.2 (d) ppm. Data for trans-15b: 1H NMR
(400 MHz, CDCl3): δ = 0.94 (m, 3 H), 1.14 (m, 3 H), 1.37–1.78 (m,
10 H), 1.90 (m, 1 H), 2.07 (m, 1 H), 2.88 (m, 1 H), 3.50 (dd, J =
8, 15 Hz, 1 H), 3.74 (m, 2 H), 4.28 (dd, J = 2.8, 10.4 Hz, 1 H), 5.76
(m, 1 H), 5.94 (m, 1 H) ppm. 13C NMR (75 MHz, CDCl3): δ =
11.8 (q), 14.4 (q), 22.9 (t), 27.2 (t), 31.9 (t), 32.3 (t), 32.4 (t), 32.8
(t), 34.7 (t), 71.5 (d), 79.5 (d), 100.0 (s), 102.5 (s), 129.3 (d), 133.1
(d) ppm.
(d) ppm. IR (film, NaCl plates): ν = 2931, 2858, 1729, 1060 cm–1.
˜
LRMS (EI): m/z (%) = 163 (24) [M – C6H13]+, 125 (35), 107 (100).
HRMS (EI): calcd. for C16H25O [M – CH3]+ 233.1905; found
233.1907.
(S)-4-[(R and S)-Oct-7-en-4-yn-3-yloxy]non-1-ene (17d): The gene-
ral procedure for the alkylation of terminal alkynes with allyl bro-
mide described above was applied to 17b (0.7 g, 3.4 mmol), yielding
1
17d (667 mg, 79% yield) as an oil. H NMR (400 MHz, CDCl3): δ
= 0.81 (dd, J = 6.5, 9 Hz, 6 H), 0.92 (ddd, J = 3, 9, 9 Hz, 6 H),
1.18–2.18 (m, 20 H), 2.98 (dd, J = 2.5, 2.5 Hz, 4 H), 3.52 (m, 2 H),
3.99 (m, 2 H), 4.93–5.04 (m, 6 H), 5.24 (ddd, J = 1.5, 1.5, 21 Hz,
2 H), 5.73 (m, 4 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 10.1 Isomerization of 2,8-Dialkyl Co2(CO)6–Cycloalkynic Ethers by
(q), 10.2 (q), 14.3 (q), 14.4 (q), 22.9 (t), 23.0 (t), 23.4 (t), 23.4 (t),
Montmorillonite K-10: To a solution of Co2(CO)6 complexes cis-
25.1 (t), 25.6 (t), 29.9 (t), 29.9 (t), 32.3 (t), 32.4 (t), 33.6 (t), 34.8 15a and trans-15a (1:1.7, 197 mg, 0.39 mmol) in CH2Cl2 (4 mL)
(t), 38.4 (t), 39.6 (t), 69.4 (d), 69.9 (d), 76.8 (d), 77.8 (d), 81.8 (s),
81.9 (s), 82.9 (s), 82.9 (s), 116.2 (t), 116.5 (t), 117.1 (t), 132.9 (d),
was added Montmorillonite K-10 (591 mg), and the mixture was
stirred overnight at room temperature Then, the mixture was fil-
Eur. J. Org. Chem. 2009, 554–563
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N. Ortega, T. Martín, V. S. Martín
FULL PAPER
tered and concentrated, and the residue was purified by flash col-
umn chromatography, yielding cis-15a (186 mg) and trans-15a
(11 mg).
3.62 (m, 1 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 10.7 (q), 14.0
(q), 22.6 (t), 25.1 (t), 25.2 (t), 25.9 (t), 26.1 (t), 26.2 (t), 29.1 (t),
31.5 (t), 31.9 (t), 32.1 (t), 36.3 (t), 75.3 (d), 76.2 (d) ppm. IR (film,
NaCl plates): ν = 2956, 2926, 1462, 1087 cm–1. C H O (226.4):
˜
15 30
Isomerization of 2,9-Dialkyl Co2(CO)6–Cycloalkynic Ethers by
Montmorillonite K-10: The same procedure used above to the isom-
erization of 2,8-dialkyl Co2(CO)6–cycloalkynic ethers by Montmo-
rillonite K-10 was applied to Co2(CO)6 complexes cis-15b and
trans-15b (1:1.1, 47 mg, 0.09 mmol), yielding cis-15b (43 mg) and
trans-15b (2 mg).
calcd. C 79.58, H 13.36; found C 79.77, H 13.28.
Supporting Information (see footnote on the first page of this arti-
cle): Experimental details, spectroscopic characterization, and 1H
NMR and 13C NMR spectra for all new compounds.
(+)-cis-Lauthisan: To the solution of Co2(CO)6 complex cis-15a
(150 mg, 0.3 mmol) in benzene (30 mL) was added nBu3SnH
(0.97 mL, 3.6 mmol). After stirring for 2 h at 60 °C, the reaction
mixture was concentrated under reduced pressure. The remaining
residue was chromatographed on a silica-gel column to provide en-
docyclic diene 26 (62.6 mg, 94% yield) as an inseparable mixture
of trans and cis isomers in the newly created double bond. To a
stirred solution of 26 (50 mg, 0.22 mmol) in dry ethyl acetate
(2.3 mL) was added 10% Pd(C) (12 mg, 0.011 mmol) at room tem-
perature under an H2 atmosphere (1 atm). The reaction mixture
was stirred for 16 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 phase was
concentrated, and the crude obtained was purified by flash
chromatography to yield (+)-cis-lauthisan (43 mg, 87% yield).
[α]2D5 = +4.1 (c = 0.9, CHCl3). 1H NMR (300 MHz, CDCl3): δ =
0.90 (m, 6 H), 1.27–1.76 (m, 22 H), 3.33 (m, 1 H), 3.41 (m, 1 H)
ppm. 13C NMR (75 MHz, CDCl3): δ = 10.6 (q), 13.85 (q), 22.3 (t),
23.8 (t), 26.0 (t), 26.8 (t), 29.2 (t), 29.5 (t), 31.6 (t), 33.1 (t), 33.4
Acknowledgments
This research was supported by Ministerio de Educación y Ciencia
of Spain cofinanced by the European Regional Development Fund
(CTQ2005-09074-C02-01 and CTQ2005-09074-C02-02) and the
Canary Islands Government. N. O. thanks the Canary Islands
Government for a predoctoral fellowship.
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˜
2926, 2856, 1457, 1089 cm–1. C15H30O (226.4): calcd. C 79.58, H
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22.8 (t), 25.8 (t), 26.5 (t), 26.6 (t), 28.9 (t), 32.0 (t), 32.1 (t), 32.3
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(film, NaCl plates): ν = 2926, 2858, 1462, 1088 cm–1. C H O
˜
15 30
(226.4): calcd. C 79.58, H 13.36; found C 79.79, H 13.07.
(–)-trans-Lauthisan: The same procedure used above to obtain (+)-
cis-lauthisan was applied to trans-15a (80 mg, 0.16 mmol), yielding
in the first step endocyclic diene 28 (30 mg, 85% yield) as an in-
separable mixture of trans and cis isomers in the newly created
double bond, and in the second step (–)-trans-lauthisan (28 mg,
92% yield). [α]2D5 = –8.3 (c = 0.9, CHCl3). 1H NMR (300 MHz,
CDCl3): δ = 0.90 (m, 6 H), 1.13–1.64 (m, 22 H), 3.52 (m, 1 H),
3.60 (m, 1 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 10.4 (q), 13.9
(q), 22.4 (t), 25.6 (t), 25.8 (t), 25.9 (t), 26.4 (t), 29.3 (t), 29.3 (t),
31.6 (t), 31.9 (t), 32.3 (t), 36.5 (t), 74.1 (d), 75.1 (d) ppm. IR (film,
NaCl plates): ν = 2925, 2849, 1456, 1089 cm–1. C H O (226.4):
˜
15 30
calcd. C 79.58, H 13.36; found C 79.56, H 13.64.
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[25] The enantiomeric excess was determined by Mosher’s ester. See
the Supporting Information
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[32] The hydrogenation of the cis compounds was performed with
Pd(C) as catalyst. Although the use of Pd(C) for the trans iso-
mers produced decomposition of the starting material, the hy-
drogenation was successfully performed with the use of PtO2
as catalyst.
[20] Diastereoisomers anti and syn of the α,αЈ-disubstituted linear
ethers are defined as described in the figure below:
Received: October 29, 2008
Published Online: December 12, 2008
Eur. J. Org. Chem. 2009, 554–563
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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