Substituent effects in tandem ring-closing metathesis reactions of dienynes

Article abstract of DOI:10.1002/ejoc.200500645

Several dienynes bearing different substituents have been synthesized and subjected to a ring-closing metathesis (RCM) reaction using ruthenium carbene complexes. Dienynes containing a pre-existing ring and a quaternary center attached to the alkyne give

Full text of DOI:10.1002/ejoc.200500645

FULL PAPER
DOI: 10.1002/ejoc.200500645
Substituent Effects in Tandem Ring-Closing Metathesis Reactions of Dienynes
François-Didier Boyer[a] and Issam Hanna*[b]
Keywords: Cyclization / Enynes / Isomerization / Metathesis / Substituent effects
Several dienynes bearing different substituents have been
synthesized and subjected to ring-closing metathesis
(RCM) reaction using ruthenium carbene complexes. Dien-
ynes containing a pre-existing ring and a quaternary center
attached to the alkyne give the expected tandem metathesis
products in high yields. For these substrates, a high selectiv-
as the major product. In the absence of favorable factors, es-
pecially when the starting substrates contain hindered al-
kenes, a long tether chain and/or an ester group on the al-
kyne part, the tandem process is slowed down or completely
impeded. In these cases, dienynes behave like simple enynes
and afford initial metathesis products whose further reactions
a
ity for different ring sizes was achieved by modifying the re- give dimeric compounds.
activity of one alkene. In one case, an unusual non-meta-
thetic activity of the second-generation Grubbs catalyst was
observed and the cycloisomerization product was obtained
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2006)
Introduction
The tandem ring-closing metathesis (RCM) reaction[1] of
dienynes, first described by Grubbs and co-workers,[2a,2b]
has proved to be a powerful tool for the construction of
polycyclic ring systems from acyclic starting materials. The
triple bond positioned between the two olefins in substrates
such as 1 acts as an olefin metathesis relay.[2c,2d] When
treated with an RCM catalyst such as 2[3] or 3,[4] dienyne 1
undergoes an initial RCM enyne metathesis reaction[5] fol-
lowed by a second ring-closing α,ω-diene metathesis reac-
tion to produce fused bicyclic [m.n.0] systems. Depending
on the length of the alkene chains, these bicyclic systems
may contain five-, six-, seven-, and eight-membered
rings.[6,7] In these highly efficient tandem processes, two
rings are formed in a single step generally in high yields.
Multiple pathways and products are possible for these
metatheses: the starting substrate can cyclize with either
left-to-right or right-to-left endedness to give isomeric
dienes 4 (via A) or 5 (via B; Figure 1). Therefore, site-selec-
tive initiation seems necessary for selectivity. This can be
achieved by modifying the reactivity of the alkene moiety
by changing steric and/or stereoelectronic factors. In gene-
ral, the initial alkylidenation occurs at the more kinetically
reactive alkene, which is usually the unhindered terminal
monosubstituted double bond.
Figure 1. Two possible reaction pathways of dienyne metathesis.
In a previous report, we described the application of this
technique for the preparation of polyoxygenated fused bicy-
clic systems containing medium-sized rings from carbo-
hydrates.[8] As an extension of this work, we recently de-
scribed a concise formal synthesis[9] of guanacastepene A,
an antibacterial diterpenoid natural product with a novel
carbon skeleton.[10,11] Our approach was based on the si-
multaneous construction of the seven- and six-membered
rings through a tandem RCM reaction i.e., 6 Ǟ 7
(Scheme 1). Among the issues that had to be addressed to
achieve the synthesis of guanacastepene A was the elabora-
tion of the tricyclic core with the quaternary carbon center
at C8 (guanacastepene numbering) bearing conveniently
[a] Unité de Phytopharmacie et Médiateurs Chimiques, INRA,
78026 Versailles, France
[b] Laboratoire de Synthèse Organique associé au CNRS, Ecole
Polytechnique,
91128 Palaiseau, France
E-mail: hanna@poly.polytechnique.fr
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positioned oxygen functionalities. To this end, various dien- the triethylsilyloxy group has been replaced by a methyl
ynes 6a–g (R = CO2Me, H, Me, TMS; RЈ = OTES, H, Me) group (entry 5), undergoes a tandem RCM to provide triene
were prepared and submitted to the RCM reactions. This 7e in good yield. The reaction of dienyne 6f, which contains
paper describes our observations on the influence of sub- a tertiary propargylic center, needed a longer time to reach
strate substitution, in particular the ester group and the completion and gave 7f in 78% yield (entry 6).
quaternary propargylic center, on the tandem cyclization.
Table 1. Tandem RCM of dienynes 6a–6f.[a]
Scheme 1.
Results and Discussion
The reactivity of dienyne 6a[12] in the presence of cata-
lysts 2 and 3 was first examined. In all attempts, catalyst 2
was found to be ineffective and the starting dienyne was
recovered unchanged. Treating 6a with 10 mol-% of the sec-
ond-generation Grubbs catalyst 3 in CH2Cl2 at reflux led
3 in CH2Cl2.
to the disappearance of the starting material and the forma-
[a] Reactions carried out in the presence of (4–9)×10–2 m catalyst
Unexpectedly, under similar reaction conditions (10 mol-
% catalyst 3, CH2Cl2 at reflux for 12 h) dienyne 6g, which
lacks the ester group, furnished a mixture of products. The
main fraction, isolated by chromatography on silica gel, was
found to be a mixture of the metathesis product 7g and the
cycloisomerization product 8 (1:2 ratio) in 45% combined
yield. Besides 7g and 8, a minor product 9 was isolated
(11%) along with unchanged starting material (Table 2).
When the Hoveyda–Grubbs catalyst 10[16] (10 mol-%)
tion of an intractable mixture of products. However, when
this reaction was carried out at room temperature, the de-
sired product 7a was produced in 40–60% yield. The insta-
bility of this product[13] led us to investigate whether this
factor was responsible for this modest yield. After consider-
able experimentation, we found that by simply stirring the
solution of 6a and catalyst 3 (7.5 mol-%) in CH2Cl2 at room
temperature under a stream of nitrogen overnight, such that
the solvent slowly evaporated, the reaction was completed
and tricyclic triene 7a was obtained in 78–81% yield. As was used, further cycloisomerization occurred and a mix-
can be seen from the results compiled in Table 1, the inter- ture of 7g and 8 was isolated in a 1:4 ratio. This result sug-
posing alkyne tolerates methyl substitution (entry 2). In gests that the alkyne is more reactive toward the ruthe-
contrast, the hindered trimethylsilyl substituent directly at- nium–carbene complex than the terminal alkene for dienyne
tached to the alkyne impedes the diene-initiated RCM (en- 6g. Therefore, initial coordination preferentially occurs at
try 3). In this case the starting dienyne 6c remained un- the alkyne to give the metallacyclopentene D (path b) rather
changed.[14] Recourse to higher temperature (reflux in than at the double bond to give metallacyclobutane com-
CH2Cl2 or benzene), more catalyst, and longer reaction plex C (path a; Figure 2).[17]
times resulted in partial conversion of the starting dienyne
Although a variety of ruthenium compounds are known
and formation of inseparable mixture. The ester-substituted to catalyze the cycloisomerization of enynes,[17a] to the best
dienyne 6d requires more forcing conditions but succeeds in of our knowledge such a behavior has never been seen in
delivering the tricyclic product 7d in excellent reproducible the RCM reactions before. In order to confirm the structure
yield (entry 4). In this case, the tandem process must pass of 8, dienyne 6g was submitted to Alder ene reaction condi-
through a quite unstable enoic carbene complex, which un- tions. When 6g was treated with bis(triphenylphosphane)-
dergoes diene metathesis to produce 7d.[15] In contrast to palladium acetate [(PPh3)2Pd(OAc)2] (11)[18] in toluene at
7a,b, triene 7d is sufficiently stable to be isolated by room temperature overnight, compound 8 was isolated as
chromatography on silica gel. Similarly, triene 6e, in which the sole rearranged product as a mixture of diastereoiso-
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Substituent Effects in Tandem Ring-Closing Metathesis Reactions of Dienynes
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Table 2. RCM and cycloisomerization of dienyne 6g.
113.5 ppm, two CH at δ = 126.2 and 132.0 ppm, and three
quaternary carbons at δ = 146.8, 149.2, and 161.8 ppm.
Although the reason for this striking difference between
the reactivity of 6g and 6a is still unclear, the easy cycliza-
tion of dienyne 6a may be the result of a Thorpe–Ingold
effect of the triethylsilyloxy group. Presumably, replacing
OTES by methyl gives rise to an unfavorable conformation
that inhibits the reaction of the ruthenium–carbene com-
plex with the terminal double bond. More intriguing is the
heightened tendency for the tandem metathesis process
shown by dienyne 6e in comparison to its terminal alkyne
counterpart 6g, although it is known that in some cases
coordination of the evolving Ru–carbene to the ester group
may slow-down or completely impede the cyclization.[19]
This unexpected result prompted us to study the influ-
ence of the substrate substitution on the metathetic reactiv-
ity of dienynes in more detail. To probe the effects of the
pre-existing cyclopentene ring and the ester group, acyclic
dienynes 12a and 12b were prepared and subjected to the
metathesis conditions (Table 3). The synthesis of these com-
pounds was achieved starting from known nitrile 13.[20] Set-
ting up the quaternary center was accomplished by alky-
lation of 13 with 6-bromo-1-hexene in the presence of lith-
ium hexamethyldisilazide at room temperature. The re-
sulting nitrile 14 was reduced to aldehyde 15, which was
subjected to the action of dimethyl 1-diazo-2-oxopropyl-
phosphonate (the Ohira reagent)[21] in the presence of
K2CO3 in MeOH to give the acetylenic derivative 12a. Con-
version of 12a into 12b was effected in the usual way
(Scheme 2).
[a] Reactions in refluxing CH2Cl2 (10–2 m) for 12 h. [b] Determined
1
by H NMR spectroscopy. [c] Reaction in toluene at room temp.
mers along with the recovered starting dienyne (entry 3).
The spectroscopic data of this product are identical to those
When a dichloromethane solution of dienyne 12b and
obtained under metathesis conditions. Structure 8 was as- 5% of 3 was heated at reflux temperature for 3 h, the me-
1
signed on the basis of IR, MS, H and 13C NMR spectro- tathesis product 16b was isolated in 76% yield. Under the
scopic analysis. In particular, the mass spectrum established same conditions, dienyne 12a, which lacks the ester group,
that 6g and 8 are isomeric compounds (m/z = 312), the IR furnished a mixture of the expected bicyclic diene 16a and
spectrum shows the disappearance of the CH alkyne ab- the 12-membered ring dimeric product 17 (1:2 ratio) in 90%
sorption, and the 13C NMR spectrum exhibits eight signals combined yield.[22] The structure of 17 was assigned on the
1
of sp2 carbons: three CH2 at δ = 104.6, 112.3, and basis of its spectroscopic data. In particular, the H NMR
Figure 2. Metathesis and cycloisomerization pathways of dienyne 6g.
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Table 3. RCM and cycloisomerization of dienynes 12a and 12b.
usual behavior of 6g toward the metathesis catalysts could
be due to the pre-existing cyclopentene ring. As for 6g,
when dienyne 12a was treated with palladium-based cata-
lyst 11, only compound 18 was obtained. On the other
hand, treatment of 12a with a catalytic amount of PtCl2 in
toluene at 60 °C furnished 19 in good yield (entry 6).[23]
These results are in agreement with the well known behav-
ior of 1,6-dienynes: the coordination of palladium or plati-
num catalysts occurs at the alkyne part, leading to cyclo-
[24]
isomerization products.
To assess the effect of the quaternary center linked to the
alkyne, various acyclic dienynes were prepared (Schemes 3
and 4) and subjected to metathesis conditions. The results
shown in Table 4 are instructive in different ways. When
dienyne 35, which bears two monosubstituted alkene moie-
ties, was treated with the first-generation Grubbs catalyst 2
(entry 1), two bicyclic compounds 40 and 41 were isolated
in equal amounts. The 1:1 product ratio arises from the
unselective initial acyclic metathesis. Under the same condi-
tions, its counterpart 24 led only to the initial enyne RCM
product 42, which can be transformed into 40 by treatment
with catalyst 3 at reflux temperature. Treatment of 24 with
catalyst 3 in refluxing CH2Cl2 for 4 h gave the biyclic com-
pound 40 (59%). The ester-substituted dienyne 25 did not
afford any bicyclic compound, and the product of the initial
enyne metathesis 43 was isolated in 28% yield along with
the completely unexpected product 44 (entry 6). This struc-
ture, which was assigned after careful analysis of spectro-
scopic data, is the result of the Diels–Alder dimerization
reaction of 43. The high tendency of dienyne 25 to dimerize
[a] Reactions in refluxing CH2Cl2 for 3 h. [b] In toluene at 60 °C.
spectrum does not show any signals for terminal double after the initial enyne RCM may be explained by a possible
bonds and the 13C NMR spectrum contains resonances for coordination of the Ru–carbene to the ester, which com-
six secondary sp2 carbons. The ratio of 16a to 17 was re- pletely impedes the second cyclization.[19] Comparison of
versed when the reaction was carried out under more dilute these results with those of Table 1 (entries 4 and 5) under-
conditions (entry 3). At 10–3 m concentration, only the tan- lines the favorable effect of both the pre-existing cyclopen-
dem metathesis product 16a was obtained in 86% yield. In tene ring and the quaternary centers on the cyclization.
contrast to dienyne 6g, no cycloisomerization product such
as 18 was isolated.
Whereas dienyne 36, which possesses symmetrically teth-
ered alkenes, undergoes the tandem process with catalyst 3
This result confirms the favorable effect of the ester easily and selectively to furnish the [5.4.0]bicyclic derivative
group on the tandem process. It also suggests that the un- 45 in quantitative yield, its ester-substituted counterpart 38
Scheme 2.
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Substituent Effects in Tandem Ring-Closing Metathesis Reactions of Dienynes
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Scheme 3.
Scheme 4.
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Table 4. Tandem RCM of acyclic dienynes.[a]
[a] Reactions carried out at (1–4)×10–2 m in CH2Cl2.
failed to give any tandem cyclization product. However, in 51% yield (entry 12). Its mass, 1H, and 13C NMR spectra
when treated with catalyst 3 in refluxing CH2Cl2, 38 led to a are in agreement with the macrocyclic structure 47. In this
mixture of the expected bicyclic diene 46 in low yield (34%; case, the initial enyne RCM is followed by dimerization and
entry 10).
the resulting α,ω-diene undergoes cyclization to give 47.
The RCM reaction of dienynes possessing longer alkene The same product was obtained with a higher yield when
chains was next attempted. Treatment of 37 with catalyst 3 the reaction was carried out in more dilute solution. As for
in refluxing CH2Cl2 led to a mixture of products from 20, the ester-substituted dienyne 39 affords only the product
which one major compound was isolated as a white solid of the initial enyne metathesis 48 in 71% yield. This result
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Substituent Effects in Tandem Ring-Closing Metathesis Reactions of Dienynes
FULL PAPER
H), 0.65 (q, J = 7.9 Hz, 6/2 H), 0.55 (q, J = 7.9 Hz, 6/2 H) ppm.
13C NMR: δ = 150.5 (C), 139.5 (C), 130.6 (CH), 128.84 (CH),
128.75 (CH), 127.9 (CH), 127.4 (CH), 123.7 (CH), 75.7 (C), 58.0
(CH), 51.8 (C), 38.76 (CH2), 38.67 (CH2), 37.5 (CH2), 36.0 (CH2),
34.3 (CH2), 29.5 (CH), 25.7 (CH3), 23.12 (CH3), 23.04 (CH3+CH2),
22.7 (CH3), 22.5 (CH3), 7.4 (CH3), 6.9 (CH3+CH2), 6.4 (CH2) ppm.
is in agreement with the much higher cyclization rate of the
seven-membered ring over that of the eight-membered ring.
The lack of conformational constraints in these substrates
does not facilitate the assembly of the cyclooctyl moiety.[25]
IR (CCl ): ν = 3025, 2955, 2874, 2829, 1618, 1457, 1081 cm–1.
˜
4
Conclusions
HRMS (EI): m/z calcd. for C24H40OSi 372.28485; found 372.28511.
Tricyclic Compound 7b: Prepared from dienyne 6b (39 mg,
0.088 mmol) by the same procedure as for 7a (24 mg, 70%). Color-
less oil, two isomers (1:1). H NMR: δ = 6.08 (s, 0.5 H), 6.04 (s, 0.
5 H), 5.66 (br. s, 0.5 H), 5.58 (br. s, 0.5 H)), 5.52 (br. s, 0.5 H), 5.46
(br. s, 0.5 H), 2.52–2.25 (m, 3 H), 2.10–1.52 (m, 9 H), 1.89 (s, 3 H),
1.04–0.86 (2 s + 2 t + 4 d, 18 H), 0.61 (q, J = 7.5 Hz, 3 H), 0.51
(q, J = 7.7 Hz, 3 H) ppm. 13C NMR: δ = 150.7 (C), 141.8 (C),
132.4 (C), 127.9 (CH), 127.6 (CH), 126.1 (CH), 119.8 (CH), 77.2
(C), 57.1 (CH), 52.1 (C), 39.2 (CH2), 38.2 (CH2), 37.7 (CH2), 36.3
(CH2), 35.9 (CH2), 33.2 (CH2), 29.7 (CH), 29.6 (CH), 23.5 (CH2),
The examples presented here show the effect of substrate
substitution and tether length on the RCM reaction of dien-
ynes. The tandem-RCM of dienynes having quaternary cen-
ters attached to the alkyne and a pre-existing cycle proceeds
smoothly to afford tricyclic compounds in high yields. For
these substrates, a high selectivity for ring sizes has been
achieved by modifying the reactivity of one alkene with ste-
ric factors. However, in one case (dienyne 6g) an unprece-
dented non-metathetic activity of second-generation cata-
1
lysts 3 and 10 was observed. In this case, the cycloisomer- 23.2 (CH3), 23.0 (CH3), 22.8 (CH3), 21.0 (CH3), 7.4 (CH3), 7.3
(CH3), 6.8 (CH2), 6.2 (CH2) ppm. HRMS (EI): m/z calcd. for
C25H42OSi 386.30050; found 386.30005.
ization product was obtained as the major product. In the
absence of favorable factors, especially when the starting
substrates contain hindered alkenes, a long tether chain,
and/or ester group on the alkyne part, the tandem process
was slowed down or completely impeded. In these cases, the
dienynes behave like simple enynes to afford initial metathe-
sis products; further reactions would proceed to give di-
meric compounds, the cross-metathesis, or the intermo-
lecular Diels–Alder products.
Typical Procedure for the Metathesis Reaction of 6d–6g. Synthesis
of Tricyclic Compound 7d: Catalyst 3 (18 mg, 10 mol-%) was added
to a degassed solution of dienyne 6d (105 mg, 0.216 mmol) in dry
dichloromethane (3 mL) under nitrogen. The mixture was heated
at reflux for 4 h. The solvent was removed and the residue was
purified by flash chromatography (ethyl acetate/petroleum ether,
2.5:97.5) to give 7d (86 mg, 93%) as a colorless oil. Two isomers
(55:45). 1H NMR: δ = 6.74 (t, J = 3.9 Hz, 0.55 H), 6.57 (br. s, 0.55
H), 6.51 (br. s, 0.45 H), 6.25 (s, 0.45 H), 5.57 (br. s, 0.55 H), 5.44
(br. s, 0.45 H), 3.75 (s, 1.65 H), 3.73 (s, 1.35 H), 2.51–2.30 (m, 3
H), 2.21–2.11 (m, 2 H), 2.05–1.50 (m, 7 H), 1.04–0.84 (1 s + 2 t +
3 d, 18 H), 0.58 (q, J = 7.7 Hz, 6/2 H), 0.52 (q, J = 7.7 Hz, 6/2 H)
ppm. 13C NMR: δ = 168.1 (C), 168.0 (C), 150.0 (C), 149.6 (C),
138.6 (CH), 137.4 (br. C), 135.5 (C), 131.9 (C), 128.9 (CH), 124.1
(CH), 75.8 (C), 58.0 (CH), 56.5 (CH), 55.3 (C), 52.0 (C), 51.6
(CH3), 38.2 (CH2), 37.5 (CH2), 37.1 (CH2), 36.4 (CH2), 35.9 (CH2),
32.7 (CH2), 32.6 (CH2), 29.7 (CH), 29.4 (CH), 24.2 (CH2), 23.2
(CH2), 23.0 (CH3), 22.9 (CH3), 21.1 (CH3), 7.3 (CH3), 7.2 (CH3),
Experimental Section
General: Infrared spectra were recorded with neat substances or
1
solutions in CCl4. H and 13C NMR spectra were recorded with a
300 or 400 MHz instrument as solutions in CDCl3, using residual
protic solvent CHCl3 (δH = 7.27 ppm) or CDCl3 (δC = 77.0 ppm) as
internal reference. Mass spectra were obtained either by electronic
impact (EI) or chemical ionization with ammonia (CI, NH3). All
reactions were monitored by TLC carried out on 0.2-mm alumi-
num silica gel (60 F254) pre-coated plates using UV light and 5%
ethanolic phosphomolybdic acid and heat as developing agent.
Flash chromatography was performed on 40–63-µm (400–
230 mesh) silica gel 60 with ethyl acetate (EtOAc)/petroleum ether
(PE; boiling range 40–60 °C) or cyclohexane as eluents. Commer-
cially available reagents and solvents were purified and dried where
necessary by usual methods. THF, benzene, and Et2O were purified
by distillation under nitrogen from sodium/benzophenone. CH2Cl2,
HMPA, and MeOH were dried by distillation from calcium hydride
under argon.
6.7 (CH ), 6.2 (CH ) ppm. IR (CCl ): ν = 2954, 2874, 1720, 1456,
˜
2
2
4
1254, 1077 cm–1. HRMS (EI): m/z calcd. for C26H42O3Si
430.29033; found 430.29011.
Tricyclic Triene 7e: Yield: 514 mg (82%). Colorless oil, two isomers.
1H NMR: δ = 6.53 (br. s, 0.5 H), 6.25 (br. s, 0.5 H), 6.20 (br. s, 1
H), 5.55 (br. s, 0.5 H), 5.46 (br. s, 0.5 H), 3.76 (s, 1.5 H), 3.74 (s,
1.5 H), 2.45–2.15 (m, 3 H), 2.10–1.55 (m, 6 H), 1.50–1.10 (m, 3 H),
1.04–0.84 (2 s + 2 d, 12 H) ppm. 13C NMR (key signals): δ = 169.1
(C), 150.9 (C), 137.8 (C), 135.6 (CH), 135.4 (CH), 133.3 (C), 132.0
(br), 129.6 (CH), 129.4 (CH), 124.5 (CH), 124.4 (CH), 59.0 (CH),
51.6 (CH ) ppm. IR (CCl ): ν = 1722, 1618 cm–1. CI MS (NH ):
˜
3
4
3
General Procedure for the Metathesis Reaction of Dienynes 6a and
6b. Synthesis of Tricyclic Triene 7a: Catalyst 3 (11 mg, 7.5 mol-%)
m/z = 315 [M+ + 1], 332 [M+ + 18]. HRMS (EI): m/z calcd. for
C21H30O2, 314.22458; found 314.22302.
was added to
a degassed solution of dienyne 6a (75 mg,
0.175 mmol) in dry dichloromethane (2 mL). The mixture was then
stirred at room temperature overnight under a stream of nitrogen
such that the solvent slowly evaporated. The resulting residue was
purified by rapid chromatography on Florisil (eluting with pure
petroleum ether) to give compound 7a as a 1:1 mixture of two
Tricyclic Triene 7f: Yield: 18 mg (78%) Colorless oil. Two isomers.
1H NMR: δ = 6.49 (t, J = 4.5 Hz, 0.5 H), 6.43 (br. s, 0.5 H), 6.38
(t, J = 4.5 Hz, 0.5 H), 6.33 (br. s, 1 H), 5.57 (br. s, 0.5 H), 5.51 (br.
s, 0.5 H), 3.78 (s, 1.5 H), 3.76 (s, 1.5 H), 2.45–2.15 (m, 4 H), 2.10–
1.10 (m, 6 H), 1.50–2.10 (m, 3 H), 1.00–0.90 (2 s + 2 d, 12 H) ppm.
13C NMR (key signals): δ = 170.0 (C), 169.0 (C), 151.6 (C), 150.3
1
isomers (53 mg, 81%). Colorless oil. H NMR: δ = 5.98 (dd, J =
9.6, 2.4 Hz, 1 H), 5.89 (d, J = 5.8 Hz, 1 H), 5.80–5.65 (m, 1 H), (C), 136.3 (C), 136.0 (CH), 135.0 (C), 134.6 (C), 133.3 (C), 134.5
5.56 (br. s, 0.5 H), 5.49 (br. s, 0.5 H), 2.45–2.32 (m, 2 H), 2.10–1.90
(m, 3 H), 1.82–1.58 (m, 7 H), 1.73 (s, 3 H), 1.60 (s, 3 H), 1.03 (d,
J = 5.6 Hz, 3/2 H), 1.01 (s, 3/2 H), 0.99–0.87 (1 s + 2 t + 3 d, 15
(CH), 133.3 (C), 131.2 (CH), 129.7 (CH), 128.6 (C), 128.0 (C),
125.0 (CH), 124.7 (CH), 58.9 (CH), 58.3 (CH), 52.5 (C), 51.9
(CH3), 51.8 (CH3), 49.7 (C), 42.8 (CH), 41.6 (CH), 41.1 (CH2),
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40.2 (CH2), 36.4 (CH2), 35.9 (CH2), 32.8 (CH2), 32.1 (CH2), 31.1
(2CH2), 36.5 (C), 33.5 (CH2), 28.9 (CH2) 25.7 (CH3), 24.3 (CH2),
(CH2), 30.2 (CH2), 29.6 (CH), 29.5 (CH), 26.3 (CH2), 25.8 (CH2), 24.0 (CH ), 23.6 (CH ), 17.7 (CH ) ppm. IR (CCl ): ν = 3078,
˜
3
2
3
4
23.5 (CH3), 23.2 (CH3), 23.11 (CH3), 23.08 (CH3), 22.8 (CH3), 18.7
2232, 1641 cm–1. HRMS (EI): m/z calcd. for C15H25N 219.19870;
(CH ) ppm. IR (CCl ): ν = 1722, 1615 cm–1. CI MS (NH ): m/z =
found 219.19917.
˜
3
4
3
301 [M+ + 1], 196.
Aldehyde 15: A solution of DIBAL-H 1.0 m in hexane (2.4 mL) was
added dropwise to a solution of nitrile 14 (257 mg, 1.17 mmol) in
dry Et2O (3 mL) cooled to –70 °C and stirred under nitrogen. After
being stirred at this temperature for 30 min, EtOAc was added and
the mixture was slowly warmed up to room temp. A solution of
potassium sodium tartrate (Rochelle salt) was added and the mix-
ture was stirred for 30 min until the layers appeared clear. The
phases were separated and the aqueous layer was extracted three
times with Et2O. The combined organic phases were washed with
brine, dried with MgSO4, and concentrated to give crude 15. Flash
chromatography on silica gel (1.25% EtOAc in PE) gave 216 mg of
Metathesis of 6g: Treatment of 6g (12 mg, 0.038 mmol) with cata-
lyst 3 (10 mol-%) in refluxing CH2Cl2 for 12 h afforded 5 mg of an
inseparable mixture of 7g, 8 and 1 mg of 9 in 58% combined yield.
1
Tricyclic Triene 7g: Colorless oil. Two isomers. H NMR: δ = 5.97
(d, J = 10 Hz, 1 H), 5.87 (d, J = 6.8 Hz, 1 H), 5.75–5.70 (m, 1 H),
5.50 (br. s, 0.5 H)), 5.47 (br. s, 0.5 H), 2.45–2.15 (m, 3 H), 2.10–
1.55 (m, 6 H), 1.50–2.10 (m, 3 H), 1.08–0.91 (2 s + 2 d, 12 H) ppm.
CI MS (NH3): m/z = 257 [M+ + 1], 294 [M+ + 18].
Alder Ene Product 8: Colorless oil. Major isomer. 1H NMR (key
signals): δ = 6.21–6.12 (m, 1 H), 5.75 (br. s, 1 H), 5.42 (br. d, J =
18 Hz, 1 H), 5.02 (br. d, J = 11 Hz, 1 H), 4.86–4.95 (m, 4 H), 3.20–
3.17 (m, 1 H), 2.40–2.25 (m, 2 H), 2.10–1.10 (m, 10 H), 1.63 (s, 3
H), 1.90–1.63 (m, 12 H) ppm. 13C NMR (key signals): δ = 161.8
(C), 149.2 (C), 146.8 (C), 132.0 (CH), 126.3 (CH), 113.5 (CH2),
1
15 (89%) as a colorless liquid. Rf = 0.30 (pentane). H NMR: δ =
9.46 (s, 1 H), 5.83–5.75 (m, 1 H), 5.10 (t, J = 5.2 Hz, 1 H), 5.03
(dd, J = 12.6, 1.2 Hz, 1 H), 4.98 (d, J = 7.8 Hz, 1 H), 2.08 (q, J =
7.9 Hz, 2 H), 2.00–1.82 (m, 2 H), 1.71 (s, 3 H), 1.62 (s, 3 H), 1.60–
1.40 (m, 6 H), 1.16–1.08 (m, 2 H), 1.07 (s, 3 H) ppm. 13C NMR: δ
= 206.6 (C), 138.7 (CH), 132.2 (C), 123.9 (CH), 114.6 (CH2), 49.1
(C), 35.7 (CH2), 35.3 (CH2), 33.6 (CH2), 29.5 (CH2), 25.7 (CH3),
112.4 (CH2), 104.6 (CH2) ppm. CI MS (NH3): m/z = 313 [M+
+
1], 330 [M+ + 18]. HRMS (EI): m/z calcd. for C23H36 312.28170;
found 312.28308.
25.4 (CH ), 22.8 (CH ), 18.1 (CH ), 17.7 (CH ) ppm. IR (CCl ): ν
˜
2
2
3
3
4
= 1724, 1641 cm–1. HRMS (EI): m/z calcd. for C15H26O 222.19837;
1
Compound 9: Colorless oil, two isomers. H NMR: δ = 6.15–6.05
found 222.19943.
(m, 1 H), 6.02 (d, J = 16 Hz, 1 H), 5.73 (br. s, 1 H), 5.50 (d, J =
16 Hz, 1 H), 5.37 (d, J = 17 Hz, 1 H), 5.15–5.04 (m, 1 H), 4.97 (d,
J = 10 Hz, 1 H), 4.89 (s, 1 H), 4.88 (s, 1 H), 2.35–2.29 (m, 1 H),
2.10–1.90 (m, 1 H), 1.83 (s, 3 H), 1.67 (s, 3 H), 1.57 (s, 3 H), 1.90–
1.00 (m, 10 H), 0.98 (s, 3 H), 0.96 (s+d, 6 H), 0.89 (d, J = 6.4 Hz,
3 H) ppm. 13C NMR: δ = 149.2 (C), 142.41 (C), 142.38 (C), 139.80
Dienyne 12a: K2CO3 (640 mg, 4.62 mmol) was added to a solution
of aldehyde 15 (423 mg, 1.90 mmol) and dimethyl 1-diazo-2-oxo-
propylphosphonate[21] (760 mg, 2.71 mmol) in anhydrous MeOH
(34 mL) and stirring was continued under argon for 3 h. The reac-
tion mixture was diluted with Et2O (20 mL), washed with an aque-
(CH), 139.74 (CH), 132.0 (CH), 130.9 (C), 129.8 (CH), 129.7 (CH), ous solution of NaHCO3 (10%) and brine, and dried (MgSO4).
126.25 (CH), 126.23 (CH), 125.2 (2CH), 114.05 (CH2), 114.02 Evaporation of the solvents followed by flash chromatography on
(CH2), 113.5 (CH2), 50.7 (CH), 50.04 (C), 49.95 (C), 41.6 (CH2),
silica gel (pentane) gave 340 mg of 1-alkyne 12a (1.55 mmol, 83%)
1
41.1 (CH2), 38.8 (C), 38.7 (C), 36.2 (CH2), 36.0 (CH2), 35.12 (CH2), as a colorless liquid. Rf = 0.90 (pentane). H NMR: δ = 5.88–5.75
35.08 (CH2), 32.23 (CH2), 32.21 (CH2), 29.3 (CH), 25.6 (CH3), 23.3 (m, 1 H), 5.14–5.09 (m, 1 H), 5.05–4.93 (m, 2 H), 2.35–2.29 (m, 1
(CH3), 23.0 (CH2), 22.98 (CH2), 22.9 (CH3), 22.74 (CH3), 22.70 H), 2.12–2.05 (m, 5 H), 1.69 (s, 3 H), 1.63 (s, 3 H), 1.50–1.17 (m,
(CH3), 22.59 (CH3), 22.51 (CH3), 20.88 (CH3), 20.84 (CH3), 18.7 8 H), 1.18 (s, 3 H) ppm. 13C NMR: δ = 138.6 (CH), 131.4 (C),
(CH3), 17.6 (CH3) ppm. CI MS (NH3): m/z = 355 [M+ + 1], 372
[M+ + 18]. HRMS (EI): m/z calcd. for C26H42 354.32865; found
354.32764.
124.3 (CH), 114.5 (CH2), 90.6 (C), 68.9 (CH), 41.4 (CH2), 40.9
(CH2), 34.7 (C), 34.1 (CH2), 26.3 (2 CH2), 25.6 (CH2), 24.0 (CH3),
23.5 (CH ), 17.5 (CH ) ppm. IR (neat): ν = 3309, 1641 cm–1. CI
˜
3
3
MS (NH3): m/z = 219 [M+ + 1], 236 [M+ + 18]. HRMS (EI): m/z
Cycloisomerization of 6g. Alder Ene product 8: [Pd(OAc)2(PPh3)2]
(2 mg) was added to a degassed solution of 6g (8 mg, 0.02 mmol)
in dry toluene (0.2 mL) under nitrogen. The mixture was stirred at
room temp. for 24 h, then the solvent was evaporated under vac-
uum. Purification by flash chromatography (PE) afforded 2 mg of
8 (25%) followed by 2 mg of 6g (25%).
calcd. for C16H26 218.20345; found 218.20459.
Dienyne 12b: butyllithium (0.8 mmol, 0.32 mL, 2.5 m in hexane)
was added to a cold solution (–78 °C) of 1-alkyne 12a (109 mg,
0.5 mmol) in THF (2 mL) under nitrogen. The resulting mixture
was stirred for 1.25 h, freshly distilled ClCO2Me (0.8 mmol, 70 µL)
was added, and the reaction mixture warmed to 20 °C. The mixture
was then diluted with Et2O (15 mL) and washed with water
(10 mL). The aqueous phase was extracted with Et2O (2×10 mL)
and the combined organic layers washed with brine and dried with
MgSO4. The residue was purified by flash chromatography on silica
gel (2% EtOAc in PE) to give 132 mg (95%) of 12b as a colorless
Synthesis of Compounds 12
Nitrile 14: A solution of LiHMDS (8 mL, 1.0 m in THF) was added
dropwise, at room temp., to a solution of 13 (548 mg, 4 mmol) and
6-bromo-1-hexene (1.30 g, 8 mmol) in dry THF (7 mL). After being
stirred at this temperature for 1 h (TLC showed disappearance of
the starting material), the mixture was cooled to 0 °C and quenched
with water. The two phases were separated and the aqueous phase
was extracted with three 20-mL portions of Et2O. The combined
organic phases were washed with brine, dried with MgSO4, and
concentrated. The crude product was purified by flash chromatog-
raphy on silica gel (2.5% EtOAc in PE) to give 688 mg of 14 (78%)
as a colorless oil. Rf = 0.60 (2.5% EtOAc in PE). 1H NMR: δ =
5.90–5.70 (m, 1 H), 5.08 (t, J = 7.2 Hz, 1 H), 5.00 (d, J = 17.6 Hz,
1 H), 4.96 (d, J = 10 Hz, 1 H), 2.10–2.00 (m, 4 H), 1.68 (s, 3 H),
1.62 (s, 3 H), 1.52–1.35 (m, 8 H), 1.30 (s, 3 H) ppm. 13C NMR: δ
= 138.4 (CH), 132.7 (C), 124.5 (C), 122.7 (CH), 114.8 (CH2), 39.3
1
liquid. Rf = 0.20 (EtOAc/cyclohexane, 2:98). H NMR: δ = 5.85–
5.72 (m, 1 H), 5.09 (br. t, J = 6.0, 1 H), 5.03–4.93 (m, 2 H), 3.74
(s, 3 H), 2.15–2.00 (m, 4 H), 1.67 (s, 3 H), 1.61 (s, 3 H), 1.60–1.30
(m, 8 H), 1.21 (s, 3 H) ppm. 13C NMR: δ = 154.3 (C), 138.3 (CH),
131.9 (C), 123.7 (CH), 114.7 (CH2), 95.1 (C), 73.9 (C), 52.3 (CH3),
40.7 (CH2), 40.1 (CH2), 35.0 (C), 33.9 (CH2), 25.5 (CH2), 25.4 (2
CH ), 23.9 (CH ), 23.4 (CH ), 17.5 (CH ) ppm. IR (neat): ν =
˜
2
3
3
3
1714, 1641 cm–1. CI MS (NH3): m/z = 277 [M+ + 1], 294 [M+ + 18].
HRMS (EI): m/z calcd. for C18H28O2 276.20893; found 276.20950.
Bicyclic Diene 16a: The Grubbs catalyst 3 (5 mg, 5 mol-%) was
added to a degassed solution of dienyne 12a (22 mg, 0.1 mmol) in
478
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© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2006, 471–482

Substituent Effects in Tandem Ring-Closing Metathesis Reactions of Dienynes
FULL PAPER
dry CH2Cl2 (50 mL, 2×10–3 m) under nitrogen. The mixture was
heated at reflux for 3 h then cooled to room temp. The solvent was
removed and the residue submitted to flash chromatography on
silica gel (PE) to give the bicyclic compound 16a (14 mg, 86%) as
24.3 (CH2), 20.0 (CH3) ppm. CI MS (NH3): m/z = 219 [M+ + 1].
HRMS (EI): m/z calcd. for C16H26 218.20345; found 218.20355.
Synthesis of Compounds 24, 25, and 35–39
Alcohol 21: Prepared from tetrahydro-2H-pyran-2-ol[26] by Wittig
reaction with the ylide of isopropyltriphenylphosphonium iodide,
oxidation, and addition of homoallylmagnesium bromide to the
corresponding aldehyde.[27] Colorless liquid. Rf = 0.20 (EtOAc/cy-
1
a colorless oil. H NMR: δ = 5.94 (dd, J = 9.6, 2.4 Hz, 1 H), 5.61
(br. t, J = 7.6 Hz, 1 H), 5.54 (t, J = 6.4 Hz, 1 H), 2.40–2.10 (m, 3
H), 2.10–2.00 (m, 1 H), 1.90–1.10 (m, 11 H), 1.02 (s, 3 H) ppm.
13C NMR: δ = 144.6 (C), 132.2 (CH), 129.2 (CH), 124.9 (CH), 42.0
(CH2), 38.8 (CH2), 37.7 (C), 28.3 (CH2), 27.5 (CH2), 25.2 (CH2),
22.5 (CH2), 21.2 (CH3) ppm. CI MS (NH3): m/z = 163 [M+ + 1],
180 [M+ + 18]. HRMS (EI): m/z calcd. for C12H18 162.14085; found
162.14067.
1
clohexane, 1:4). H NMR: δ = 5.90–5.78 (m, 1 H), 5.13–5.08 (m, 1
H), 5.04 (qd, J = 17.2, 2.0 Hz, 1 H), 4.96 (br. d, J = 10.1 Hz, 1 H),
3.65–3.58 (br. s, 1 H), 2.25–2.08 (m, 2 H), 2.03–1.98 (m, 2 H), 1.68
(d, J = 1.0 Hz, 3 H), 1.59 (s, 3 H), 1.54–1.35 (m, 6 H) ppm. 13C
NMR: δ = 138.6 (CH), 131.0 (C), 124.4 (CH), 114.6 (CH2), 71.4
(CH), 37.0 (CH2), 36.4 (CH2), 30.0 (CH2), 27.9 (CH2), 25.8 (CH2),
25.6 (CH3), 17.6 (CH3) ppm. HRMS (EI): m/z calcd. for C12H22O
182.16707; found 182.16632.
Dimeric Compound 17: This compound was formed when 16a was
submitted to the metathesis reaction at a concentration higher than
1
2.5×10–3 m. Colorless oil. H NMR: δ = 5.92 (d, J = 12 Hz, 1 H),
5.91 (d, J = 12 Hz, 1 H), 5.85–5.78 (m, 1 H), 5.65–5.58 (m, 1 H),
5.61–5.59 (br. s, 1 H), 5.53 (t, J = 3 Hz, 1 H), 2.40–2.10 (m, 8 H),
2.10–1.78 (m, 6 H), 1.75–1.45 (m, 5 H), 1.35–1.25 (m, 5 H), 1.12
(s, 3 H), 1.09 (s, 3 H) ppm. 13C NMR: δ = 148.0 (C), 147.2 (C),
129.8 (CH), 129.1 (CH), 128.7 (CH), 126.82 (CH), 126.79 (CH),
126.0 (CH), 48.8 (C), 48.7 (C), 41.0 (CH2), 39.6 (CH2), 39.0 (CH2),
38.7 (CH2), 33.3 (CH2), 32.2 (CH2), 30.0 (CH2), 29.7 (CH2), 29.6
(CH2), 29.5 (CH2), 27.6 (CH3), 26.7 (CH3), 23.4 (CH2), 23.0 (CH2)
ppm. CI MS (NH3): m/z = 325 [M+ + 1]. HRMS (EI): m/z calcd.
for C24H36 324.28170; found 324.28195.
Nitrile 22: Tosyl chloride (1.97 g, 10.27 mmol) and 4-DMAP
(20 mg, 0.16 mmol) were added to a solution of alcohol 21 (1.7 g,
9.33 mmol) in pyridine (9.5 mL) under argon at –10 °C. The reac-
tion mixture was kept overnight at 6 °C under argon, then diluted
with Et2O (50 mL) and poured into a mixture of water and ice
(100 mL). The aqueous phase was extracted with Et2O (3×100 mL)
and the combined organic layers washed with 10% HCl, saturated
aqueous sodium hydrogen carbonate (10 mL) and brine (100 mL),
dried (MgSO4), and concentrated under reduced pressure. The
crude product was purified by chromatography (EtOAc/cyclohex-
ane, 10:90) to give 2.5 g (7.44 mmol, 79%) of the tosylate as a col-
orless oil. NaCN (420 mg, 8.34 mmol) was added to a solution of
the tosylate (2.5 g, 7.44 mmol) in dry HMPA (8.5 mL) under argon.
The reaction mixture was stirred for 18 h at room temperature, di-
luted with Et2O (100 mL) and washed with H2O (3×50 mL) and
brine (50 mL), dried (MgSO4), and concentrated under reduced
pressure. The crude product was purified by chromatography on
silica gel (EtOAc/cyclohexane, 10:90) to give 1.20 g (6.28 mmol,
67% 2 steps) of 22 as a colorless liquid. Rf = 0.80 (EtOAc/cyclohex-
Bicyclic Diene 16b: Prepared from dienyne 12b (70 mg, 0.11 mmol)
1
by the same procedure as for 12a (42 mg, 76%). Colorless oil. H
NMR: δ = 6.22 (br. s, 1 H), 5.90 (t, J = 6.4 Hz, 1 H), 3.74 (s, 3 H),
2.15–2.20 (m, 4 H), 1.90–1.10 (m, 8 H), 1.04 (s, 3 H) ppm. 13C
NMR: δ = 170.3, (C), 139.8 (C), 135.0 (C), 131.6 (CH), 129.8 (CH),
51.8 (CH3), 40.1 (CH2), 38.1 (CH2), 37.9 (C), 27.1 (CH2), 26.4
(CH ), 24.1 (CH ), 22.6(CH ), 21.3 (CH ) ppm. IR (CCl ): ν =
˜
2
2
2
3
4
1723 cm–1. CI MS (NH3): m/z = 221 [M+ + 1], 238 [M+ + 18].
HRMS (EI): m/z calcd. for C14H20O2 220.14633; found 220.14630.
1
ane, 5:95). H NMR: δ = 5.83–5.70 (m, 1 H), 5.12–5.02 (m, 3 H),
Alder Ene Product 18: [Pd(OAc)2(PPh3)2] (2 mg) was added to a
degassed solution of dienyne 12a (9 mg, 0.04 mmol) in dry toluene
(0.2 mL) under nitrogen. The mixture was stirred at room temp.
for 24 h, then the solvent was evaporated under vacuum. Purifica-
tion by flash chromatography (PE) afforded 3 mg of 18 (33%) fol-
lowed by 2 mg of 12a (22%).
2.60–2.55 (m, 1 H), 2.15–2.12 (m, 2 H), 2.08–1.95 (m, 2 H), 1.80–
1.25 (m, 6 H), 1.63 (s, 3 H), 1.60 (s, 3 H) ppm. 13C NMR: δ =
136.4 (CH), 132.3 (C), 123.5 (CH), 122.0 (C), 116.1 (CH2), 31.7
(CH2), 31.4 (CH2), 31.1 (CH2), 30.8 (CH), 27.3 (CH2), 27.2 (CH2),
25.6 (CH ), 17.6 (CH ) ppm. IR (neat): ν = 2236, 1641 cm–1.
˜
3
3
HRMS (EI): m/z calcd. for C13H21N 191.16740; found 191.16626.
1
18: Colorless oil. H NMR: δ = 5.90–5.65 (m, 1 H), 5.00 (d, J =
Aldehyde 23: Prepared from nitrile 22 by the same procedure as for
15 (1.70 g, 88%). Colorless liquid. Rf = 0.85 (EtOAc/cyclohexane,
1:9). 1H NMR: δ = 9.58 (d, J = 3 Hz, 1 H), 5.83–5.70 (m, 1 H),
5.10–4.97 (m, 3 H), 2.35–2.22 (m, 1 H), 2.10–1.96 (m, 4 H), 1.80–
1.30 (m, 6 H), 1.68 (s, 3 H), 1.59 (s, 3 H) ppm. 13C NMR: δ =
205.0 (C), 137.7 (CH), 131.9 (C), 123.9 (CH), 115.3 (CH2), 51.1
(CH), 31.1 (CH2), 28.4 (CH2), 28.0 (CH2), 27.9 (CH2), 27.1 (CH2),
17 Hz, 1 H), 4.94 (d, J = 9.6 Hz, 1 H), 4.90–4.70 (m, 4 H), 3.25–
3.10 (m, 1 H), 2.10–1.95 (m, 2 H), 1.80–1.65 (m, 2 H), 1.63 (s, 3
H), 1.60–1.20 (m, 8 H), 1.01 (s, 3 H) ppm. 13C NMR: δ = 146.8
(C), 139.2(C), 118.0 (CH), 114.2 (CH2), 112.4 (CH2), 104.4 (CH2),
54.4 (CH), 45.4 (C), 41.8 (CH2), 37.4 (CH2), 33.8 (CH2), 29.8
(CH2), 28.4 (CH2), 27.5(CH3), 24.3 (CH2), 18.1 (CH3) ppm. IR
(CCl ): ν = 3074, 1642 cm–1. CI MS (NH ): m/z = 219 [M+ + 1].
˜
4
3
25.6 (CH ), 17.6 (CH ) ppm. IR (neat): ν = 1724, 1641 cm–1.
˜
3
3
HRMS (EI): m/z calcd. for C16H26 218.20345; found 218.20306.
HRMS (EI): m/z calcd. for C13H22O 194.16707; found 194.16779.
Compound 19: PtCl2 (2 mg) was added to a degassed solution of
dienyne 12a (9 mg, 0.04 mmol) in dry toluene (0.3 mL) under nitro-
gen. The mixture was warmed to 60 °C for 2.5 h, then cooled to
room temp. and the solvent evaporated under vacuum. Purification
by flash chromatography (PE) afforded 8 mg of 19 (88%) as a col-
Alkyne 24: Prepared from 23 by the same procedure as for 12a
(610 mg, 58%) as a colorless liquid. Rf = 0.50 (pentane). 1H NMR:
δ = 5.88–5.75 (m, 1 H), 5.13–4.96 (m, 3 H), 2.45–2.18 (m, 3 H),
2.05 (s, 1 H), 2.02–1.98 (m, 1 H), 1.69 (s, 3 H), 1.61 (s, 3 H), 1.60–
1.30 (m, 6 H) ppm. 13C NMR: δ = 138.2 (CH), 131.4 (C), 124.4
(CH), 114.8 (CH2), 87.6 (C), 69.3 (CH), 34.5 (CH2), 34.1 (CH2),
31.4 (CH2), 30.9 (CH), 27.8 (CH2), 27.4 (CH2), 25.6 (CH3), 17.6
1
orless oil. H NMR: δ = 5.90–5.70 (m, 1 H), 5.49 (s, 1 H), 5.44 (s,
1 H), 5.00 (d, J = 17 Hz, 1 H), 4.93 (d, J = 11 Hz, 1 H), 2.40–2.25
(m, 2 H), 2.15–1.95 (q, J = 8 Hz, 1 H), 1.82 (s, 3 H), 1.79 (s, 3 H),
1.60–1.50 (m, 1 H), 1.20–1.12 (m, 7 H), 1.10–1.05 (m, 1 H), 1.00
(s, 3 H) ppm. 13C NMR: δ = 147.4 (C), 139.3 (CH), 136.2 (C),
125.8 (CH), 118.9 (CH), 114.1 (CH2), 49.8 (C), 39.9 (CH2), 36.0
(CH ) ppm. IR (neat): ν = 3308, 1641 cm–1. HRMS (EI): m/z calcd.
˜
3
for C14H22 190.17215; found 190.17131.
Ester 25: Prepared from 24 by the same procedure as for 12b
(CH2), 33.8 (CH2), 30.4 (CH2), 29.8 (CH2), 26.9 (CH3), 26.1 (CH3), (183 mg, 73%). Colorless oil. Rf = 0.50 (EtOAc/cyclohexane,
Eur. J. Org. Chem. 2006, 471–482
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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479

F.-D. Boyer, I. Hanna
FULL PAPER
2.5:97.5). 1H NMR: δ = 5.88–5.75 (m, 1 H), 5.08 (dt, J = 6.0,
1.2 Hz, 1 H), 5.03 (dd, J = 17.2, 1.5 Hz, 1 H), 4.97 (dd, J = 10.2,
1 H), 3.74 (s, 3 H), 2.48 (quint., J = 6.3 Hz, 1 H), 2.31–2.07 (m, 2
Aldehyde 32: Prepared from nitrile 29 by the same procedure as for
15 (1.84 g, 86%). Colorless liquid. Rf = 0.51 (EtOAc/cyclohexane,
5:95). H NMR: δ = 9.58 (d, J = 3 Hz, 1 H), 5.83–5.70 (m, 2 H),
1
H), 2.02–1.94 (m, 2 H), 1.68 (s, 3 H), 1.62–1.37 (m, 6 H), 1.58 (s, 5.00 (qd, J = 17.1, 1.5 Hz, 2 H), 4.99–4.94 (m, 2 H), 2.33–2.24 (m,
3 H) ppm. 13C NMR: δ = 154.1 (C), 137.4 (CH), 131.7 (C), 124.0 1 H), 2.09–2.02 (m, 4 H), 1.81–1.33 (m, 6 H) ppm. 13C NMR: δ =
(CH), 115.2 (CH2), 92.3 (C), 74.1 (C), 52.3 (CH3), 33.5 (CH2), 33.2 204.8 (C), 138.1 (CH), 137.6 (CH), 115.3 (CH2), 114.9 (CH2), 51.0
(CH2), 31.2 (CH2), 31.0 (CH), 27.6 (CH2), 27.3 (CH2), 25.5 (CH3), (CH), 33.6 (CH2), 31.1 (CH2), 28.1 (CH2), 27.9 (CH2), 26.1 (CH2)
17.5 (CH ) ppm. IR (neat): ν = 1714, 1641 cm–1. HRMS (EI): m/z
ppm. IR (neat): ν = 1724, 1641 cm–1.
˜
˜
3
calcd. for C16H24O2 248.17763; found 248.17830.
Aldehyde 33: Prepared from 30 by the same procedure as for 15
(710 mg, 91%). Colorless liquid. Rf = 0.50 (EtOAc/cyclohexane,
5:95). H NMR: δ = 9.55 (d, J = 3 Hz, 1 H), 5.83–5.70 (m, 2 H),
Alcohol 27: A solution of 1-bromo-5-pentene (9.4 g, 63 mmol) in
THF (45 mL) was added to magnesium turnings (1.53 g, 63 mmol)
in THF (5 mL). To initiate the reaction four drops of neat 1-bromo-
5-pentene were added to the mixture and the remainder of the 1-
bromo-5-pentene solution was then added dropwise over 15 min at
a rate sufficient to maintain reflux without heating. The resulting
solution was stirred under reflux for 60 min, cooled to room temp.,
and ethyl formate (2.02 g, 27.26 mmol) was added dropwise at this
temperature. The reaction mixture was stirred under reflux for 1 h,
cooled to 0 °C, quenched with sat. aq. NH4Cl and the mixture
stirred for 20 min. The aqueous phase was extracted with Et2O
(2×50 mL) and the combined organic layers washed with aqueous
saturated sodium hydrogen carbonate solution and brine, dried
(MgSO4), filtered, and evaporated under reduced pressure. The
crude product was purified by chromatography on silica gel
(EtOAc/cyclohexane, 15:85) to give 4.63 g (87%) of 27 as a color-
less liquid. Rf = 0.40 (EtOAc/cyclohexane, 15:85). 1H NMR: δ =
5.87–5.73 (m, 2 H), 5.00 (qd, J = 17.1, 1.5 Hz, 2 H), 4.97–4.92 (m,
2 H), 3.62–3.58 (br. s, 1 H), 2.09–2.03 (m, 4 H), 1.57–1.38 (m, 8 H)
ppm. 13C NMR: δ = 138.6 (2 CH), 114.5 (2 CH), 71.6 (CH), 36.8
(2 CH2), 33.7 (2 CH2), 24.8 (2 CH2) ppm.
1
5.00 (qd, J = 17.1, 1.5 Hz, 2 H), 4.97–4.93 (m, 2 H), 2.30–2.20 (m,
1 H), 2.08–2.01 (m, 4 H), 1.70–1.26 (m, 8 H) ppm. 13C NMR: δ =
205.1 (C), 138.1 (2 CH), 114.8 (2 CH2), 51.6 (CH), 33.6 (2 CH2),
28.1 (2 CH ), 26.2 (2 CH ) ppm. IR (neat): ν = 1724, 1641 cm–1.
˜
2
2
Aldehyde 34: Prepared from 31 by the same procedure as for 15
(1.89 g, 85%). Colorless liquid. Rf = 0.50 (EtOAc/cyclohexane,
1
5:95). H NMR: δ = 9.56 (d, J = 3 Hz, 1 H), 5.85–5.71 (m, 2 H),
5.00 (qd, J = 17.1, 1.5 Hz, 2 H), 4.97–4.91 (m, 2 H), 2.27–2.17 (m,
1 H), 2.06–2.00 (q, J = 6.6 Hz, 4 H), 1.68–1.56 (m, 2 H), 1.48–1.23
(m, 10 H) ppm. 13C NMR: δ = 205.3 (C), 138.6 (2 CH), 114.5 (2
CH2), 51.8 (CH), 33.4 (2 CH2), 28.9 (2 CH2), 28.7 (2 CH2), 26.5
(CH ) ppm. IR (neat): ν = 1724, 1641 cm–1. HRMS (EI): m/z calcd.
˜
2
for C14H24O 208.18272; found 208.18226.
Alkyne 35: Prepared from 32 by the same procedure as for 12a
1
(300 mg, 61%). Colorless liquid. Rf = 0.60 (pentane). H NMR: δ
= 5.88–5.75 (m, 2 H), 5.05 (qd, J = 17.1, 1.8 Hz, 1 H), 5.02 (qd, J
= 17.1, 1.8 Hz, 1 H), 5.00–4.94 (m, 2 H), 2.41–2.04 (m, 5 H), 2.07
(d, J = 2.4 Hz, 1 H), 1.68–1.43 (m, 6 H) ppm. 13C NMR: δ = 138.6
(CH), 138.1 (CH), 114.8 (CH2), 114.5 (CH2), 87.5 (C), 69.4 (CH),
34.3 (CH2), 34.2 (CH2), 33.5 (CH2), 31.4 (CH2), 30.9 (CH), 26.5
Alcohol 28: Prepared from 1-bromo-6-hexene and ethyl formate by
the same procedure as for 27 (4.68 g, 93%). Colorless liquid. Rf =
(CH ) ppm. IR (neat): ν = 3309, 1641 cm–1.
˜
2
1
0.10 (EtOAc/cyclohexane, 1:9). H NMR: δ = 5.88–5.74 (m, 2 H),
Alkyne 36: Prepared from 33 by the same procedure as for 12a
5.00 (qd, J = 17.1, 1.5 Hz, 2 H), 4.94 (qd, J = 12.3, 1.2 Hz, 2 H),
3.62–3.56 (br. s, 1 H), 2.10–2.03 (m, 4 H), 1.50–1.29 (m, 12 H)
ppm. 13C NMR: δ = 138.9 (2 CH), 114.3 (2 CH), 71.8 (CH), 37.3
(2 CH2), 33.7 (2 CH2), 28.9 (2 CH2), 25.1 (2 CH2) ppm. IR (neat):
1
(359 mg, 78%). Colorless liquid. Rf = 0.60 (pentane). H NMR: δ
= 5.88–5.75 (m, 2 H), 5.02 (qd, J = 17.1, 1.8 Hz, 2 H), 5.00–4.93
(m, 2 H), 2.39–2.30 (m, 1 H), 2.11–2.04 (m, 4 H), 2.05 (d, J =
2.1 Hz, 1 H), 1.68–1.41 (m, 8 H) ppm. 13C NMR: δ = 138.7 (2
CH), 114.5 (2 CH2), 87.8 (C), 69.2 (CH), 34.4 (2 CH2), 33.5 (2
ν = 3355, 1641 cm–1.
˜
Nitrile 29: Prepared from 26[28] by the same procedure as for 22
(2.10 g, 51%). Colorless liquid. Rf = 0.60 (EtOAc/cyclohexane, 1:9).
1H NMR: δ = 5.90–5.72 (m, 2 H), 5.12–4.97 (m, 4 H), 2.63–2.56
(m, 1 H), 2.37–2.05 (m, 4 H), 1.80–1.43 (m, 6 H) ppm. 13C NMR:
δ = 137.6 (CH), 136.4 (CH), 121.9 (C), 116.2 (CH2), 115.2 (CH2),
33.0 (CH2), 31.4 (CH2), 31.3 (CH2), 31.1 (CH2), 30.7 (CH), 26.2
CH ), 31.3 (CH), 26.5 (2 CH ) ppm. IR (neat): ν = 3307,
˜
2
2
1641 cm–1. HRMS (EI): m/z calcd. for C13H20 176.15650; found
176.15713.
Alkyne 37: Prepared from 34 by the same procedure as for 12a
1
(864 mg, 58%). Colorless liquid. Rf = 0.60 (pentane). H NMR: δ
= 5.89–5.76 (m, 2 H), 5.02 (qd, J = 17.1, 1.8 Hz, 2 H), 4.94 (dtd,
J = 10.2, 1.8, 1.2 Hz, 2 H), 2.35–2.29 (m, 1 H), 2.11–2.04 (m, 5 H),
1.57–1.33 (m, 12 H) ppm. 13C NMR: δ = 138.9 (2 CH), 114.3 (2
CH2), 88.0 (C), 69.1 (CH), 34.8 (2 CH2), 33.7 (2 CH2), 31.5 (CH),
(CH ) ppm. IR (neat): ν = 2237, 1641 cm–1.
˜
2
Nitrile 30: Prepared from 27 by the same procedure as for 22
(1.19 g, 61%). Colorless liquid. Rf = 0.40 (EtOAc/cyclohexane,
5:95). 1H NMR: δ = 5.83–5.70 (m, 2 H), 5.02 (qd, J = 17.1, 1.5 Hz,
2 H), 4.99–4.94 (m, 2 H), 2.58–2.43 (m, 1 H), 2.11–2.07 (m, 4 H),
1.63–1.50 (m, 8 H) ppm. 13C NMR: δ = 137.8 (2 CH), 122.2 (C),
115.4 (2 CH2), 33.2 (2 CH2), 31.7 (2 CH2), 31.6 (CH), 26.4 (2 CH2)
28.8 (2 CH ), 26.7 (2 CH ) ppm. IR (neat): ν = 3309, 1641 cm–1.
˜
2
2
HRMS (EI): m/z calcd. for C15H24 204.18780; found 204.18870.
Ester 38: Prepared from 36 by the same procedure as for 12b
(178 mg, 76%). Colorless oil. Rf = 0.54 (EtOAc/cyclohexane, 5:95).
1H NMR: δ = 5.85–5.71 (m, 2 H), 5.00 (qd, J = 17.4, 1.5 Hz, 2 H),
5.00 (qd, J = 10.2, 1.0 Hz, 2 H), 3.75 (s, 3 H), 2.51–2.43 (m, 1 H),
2.09–2.03 (m, 4 H), 1.64–1.41 (m, 8 H) ppm. 13C NMR: δ = 154.2
(C), 138.2 (2 CH), 114.8 (2 CH2), 92.5 (C), 74.1 (C), 52.3 (CH3),
33.5 (2 CH2), 33.4 (2 CH2), 31.5 (CH), 26.4 (2 CH2) ppm. IR
ppm. IR (neat): ν = 2237, 1641 cm–1.
˜
Nitrile 31: Prepared from 28 by the same procedure as for 22
(2.80 g, 63%). Colorless liquid. Rf = 0.40 (EtOAc/cyclohexane,
5:95). 1H NMR: δ = 5.85–5.72 (m, 2 H), 5.00 (qd, J = 17.1, 1.5 Hz,
2 H), 4.94 (qd, J = 12.3, 1.2 Hz, 2 H), 2.53–2.46 (br. s, 1 H), 2.10–
2.03 (m, 4 H), 1.62–1.40 (m, 12 H) ppm. 13C NMR: δ = 138.2 (2
(neat): ν = 1713, 1641 cm–1.
˜
CH), 122.1 (C), 114.7 (2 CH), 33.3 (2 CH2), 32.1 (2 CH2), 31.6 Ester 39: Prepared from 37 by the same procedure as for 12b
(CH), 28.3 (2 CH ), 26.5 (2 CH ) ppm. IR (neat): ν = 2237,
(320 mg, 83%). Colorless oil. Rf = 0.21 (EtOAc/cyclohexane, 1:99).
1H NMR: δ = 5.86–5.73 (m, 2 H), 5.03–4.91 (m, 4 H), 3.75 (s, 3
H), 2.51–2.42 (m, 1 H), 2.09–2.02 (m, 4 H), 1.51–1.36 (m, 12 H)
˜
2
2
1641 cm–1. HRMS (EI): m/z calcd. for C14H23N, 205.18305; found
205.18302.
480
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© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2006, 471–482

Substituent Effects in Tandem Ring-Closing Metathesis Reactions of Dienynes
FULL PAPER
ppm. 13C NMR: δ = 154.2 (C), 138.6 (2 CH), 114.4 (2 CH2), 92.8 25.6 (2 CH ), 23.6 (CH ), 17.7 (2 CH ) ppm. IR (neat): ν = 1732,
˜
3
2
3
(C), 73.9 (C), 52.4 (CH3), 33.9 (2 CH2), 33.5 (2 CH2), 31.7 (CH),
28.6 (2 CH2), 26.7 (2 CH2) ppm. HRMS (EI): m/z calcd. for
C17H26O2 262.19328; found 262.19552.
1714, 1648 cm–1. CI MS (NH3): m/z = 497 [M+ + 1], 514 [M+ + 18].
HRMS (EI): m/z calcd. for C32H48O4 496.35526; found 496.35359.
Bicyclic Compound 45: Prepared by the metathesis reaction of 36.
Yield: 26 mg (100%). Colorless liquid. Rf = 0.72 (pentane). 1H
NMR: δ = 5.96 (d, J = 12.0 Hz, 1 H), 5.62 (s, 1 H), 5.55 (dt, J =
12.0, 5.7 Hz, 1 H), 2.41–2.31 (m, 2 H), 2.10–2.08 (m, 3 H), 1.83–
1.25 (m, 8 H) ppm. 13C NMR: δ = 140.5 (C), 133.8 (CH), 128.5
(CH), 128.3 (CH), 37.6 (CH), 34.5 (CH2), 30.8 (CH2), 28.3 (CH2),
Typical Procedure for the Metathesis Reaction of Dienynes 24, 35,
38, and 39
Bicyclic Compound 40: Catalyst 3 (62 mg, 7.5 mol-%) was added to
a degassed solution of trienyne 24 (200 mg, 1.05 mmol) in dry
CH2Cl2 (11.3 mL) under argon. The mixture was heated at reflux
for 4 h. The solvent was removed and the residue was purified by
flash chromatography on Florisil (pentane) to give 40 (84 mg, 59%)
27.5 (CH ), 26.1 (CH ), 20.3 (CH ) ppm. IR (neat): ν = 3011, 2919,
˜
2
2
2
1450 cm–1.
Bicyclic Compound 46: Prepared from 38. Yield: 53 mg (34%). Col-
orless oil. Rf = 0.35 (EtOAc/cyclohexane, 5:95). 1H NMR: δ = 6.79
(t, J = 6.3 Hz, 1 H), 5.74 (t, J = 3.9 Hz, 1 H), 3.71 (s, 3 H), 2.40–
2.05 (m, 5 H), 1.80–1.45 (m, 8 H) ppm. 13C NMR: δ = 169.0 (C),
140.2 (CH), 137.3 (C), 134.8 (C), 129.1 (CH), 51.7 (CH3), 36.6
(CH), 35.8 (CH2), 29.7 (CH2), 28.8 (CH2), 25.6 (CH2), 24.9 (CH2),
1
as a colorless liquid. Rf = 0.74 (pentane). H NMR: δ = 6.22 (d, J
= 12.0 Hz, 1 H), 5.66–5.56 (m, 2 H), 2.65–2.60 (m, 1 H), 2.47–1.19
(m, 10 H) ppm. 13C NMR: δ = 146.8 (C), 130.9 (CH), 129.7 (CH),
125.9 (CH), 48.6 (CH), 34.7 (CH2), 33.6 (CH2), 31.3 (CH2), 31.0
(CH ), 27.4 (CH ) ppm. IR (neat): ν = 2922, 1455 cm–1. HRMS
˜
2
2
(EI): m/z calcd. for C10H14 134.10955; found 134.10983.
17.7 (CH ) ppm. IR (neat): ν = 2928, 1715, 1652 cm–1.
˜
2
Metathesis of 35. Formation of Bicyclic Compounds 40 and 41:
Using the same procedure as for 40 with catalyst 2, 35 afforded an
inseparable mixture of 40 and 41 (1:1; 118 mg, 95%). Colorless li-
Metathesis Reaction of Dienyne 37. Formation of Dimeric Com-
pound 47: Grubbs’ second-generation catalyst 3 (30 mg, 0.03 mmol,
10 mol-%) was added to a degassed solution of trienyne 37 (60 mg,
0.30 mmol) in dry CH2Cl2 (32 mL) under argon and the mixture
was heated at reflux for 3 h. The solvent was removed and the
residue was purified by flash chromatography on silica gel (pen-
tane) to give 27 mg of 47 (0.076 mmol, 51% from 37) as an insepa-
rable mixture (1:1) of two diastereomers (white solid). M.p. 122–
125 °C (recryst. from Et2O). Rf = 0.65 (pentane). 1H NMR: δ =
5.99 (d, J = 15.6 Hz, 1 H), 5.98 (d, J = 15.3 Hz, 1 H), 5.79 (dd, J
= 8.0, 6.0 Hz, 1 H), 5.75 (dd, J = 8.0, 5.2 Hz, 1 H), 5.60–5.56 (m,
2 H), 2.78–2.73 (m, 1 H), 2.67–2.65 (m, 1 H), 2.30–2.02 (m, 8 H),
1.83–1.70 (m, 8 H), 1.60–1.20 (m, 16 H) ppm. 13C NMR: δ = 145.7
(C), 145.6 (C), 136.0 (CH), 135.8 (CH), 130.0 (CH), 129.4 (CH),
126.7 (2 CH2), 38.8 (CH), 37.8 (CH), 33.1 (CH2), 32.77 (CH2),
32.71 (CH2), 32.54 (CH2), 32.41 (CH2), 32.30 (CH2), 29.8 (CH2),
29.7 (CH2), 28.2 (2 CH2), 28.1 (CH2), 27.8 (CH2), 27.7 (CH2), 27.6
1
quid. Rf = 0.74 (pentane). H NMR: δ = 6.02 (d, J = 9.6 Hz, 1 H),
5.71–5.62 (m, 1 H), 5.50–5.44 (br. s, 1 H), 2.47–1.16 (m, 11 H)
ppm. 13C NMR: δ = 137.6 (C), 129.5 (CH), 127.2 (CH), 123.5
(CH), 35.7 (CH), 30.7 (CH2), 30.5 (CH2), 30.2 (CH2), 26.0 (CH2),
22.6 (CH2) ppm.
Diene 42: Prepared from 24 and catalyst 2 by the same procedure
as for 40. Yield: 168 mg (84%). Colorless liquid. Rf = 0.72 (pen-
1
tane). H NMR: δ = 6.46 (dd, J = 17.7, 10.8 Hz, 1 H), 5.70 (s, 1
H), 5.17–5.03 (m, 3 H), 2.83 (t, J = 7.5 Hz, 1 H), 2.48–2.25 (m, 2
H), 2.10–1.98 (m, 3 H), 1.77–1.70 (m, 1 H), 1.71 (s, 3 H) 1.63 (s, 3
H), 1.47–1.20 (m, 4 H) ppm. 13C NMR: δ = 146.6 (C), 132.9 (CH),
131.1 (C), 130.4 (CH), 124.9 (C), 113.3 (CH2), 43.3 (CH), 32.8
(CH2), 31.0 (CH2), 29.8 (CH2), 28.2 (CH2), 27.8 (CH2), 25.6 (CH3),
17.6 (CH ) ppm. IR (neat): ν = 1636 cm–1.
˜
3
(CH ), 26.5 (CH ), 26.4 (CH ) ppm. IR (neat): ν = 3022, 2921,
˜
2
2
2
Ester 43: Prepared from 25 by the same procedure as for 40. Yield:
55 mg (73%). Colorless oil. Rf = 0.30 (EtOAc/cyclohexane, 1:99).
1H NMR: δ = 6.11–6.09 (br. s, 1 H), 6.02 (s, 1 H), 5.56 (s, 1 H),
5.12–5.07 (m, 1 H), 3.78 (s, 3 H), 2.91–2.87 (m, 1 H), 2.51–2.30 (m,
2 H), 2.10–1.90 (m, 2 H), 1.69–1.12 (m, 6 H), 1.68 (d, J = 0.9 Hz,
3 H) 1.59 (s, 3 H) ppm. 13C NMR: δ = 167.6 (C), 142.6 (C), 136.8
(C), 131.6 (CH), 131.3 (C), 124.7 (CH2), 123.0 (CH2), 51.7 (CH3),
45.2 (CH), 32.7 (CH2), 31.7 (CH2), 29.3 (CH2), 28.1 (CH2), 27.8
1640 cm–1. EI MS: m/z 352 (10) [M+], 67 (100). HRMS (EI): m/z
calcd. for C26H40 352.31300; found 352.31243.
Ester 48: Prepared from 39. Yield: 70 mg (71%). Colorless oil. Rf
= 0.22 (EtOAc/cyclohexane, 2:98). 1H NMR: δ = 5.90 (d, J =
1.8 Hz, 1 H), 5.83–5.73 (m, 2 H), 5.49 (d, J = 1.8 Hz, 1 H), 5.01–
4.90 (m, 2 H), 3.76 (s, 3 H), 2.35–2.24 (m, 1 H), 2.21–2.16 (m, 2
H), 2.06–2.00 (m, 2 H), 1.72–1.65 (m, 4 H), 1.51–1.12 (m, 8 H)
ppm. 13C NMR: δ = 168.1 (C), 146.1 (C), 139.1 (C), 131.1 (CH),
123.1 (CH2), 114.2 (CH2), 51.8 (CH3), 41.6 (CH), 33.7 (CH2), 30.3
(CH2), 29.5 (CH2), 29.1 (CH2), 28.0 (CH2), 27.33 (CH2), 27.30
(CH ), 25.6 (CH ), 17.6 (CH ) ppm. IR (neat): ν = 1723, 1640 cm–1.
˜
2
3
3
HRMS (EI): m/z calcd. for C16H24O2 248.17763; found 248.17757.
(CH ), 26.0 (CH ) ppm. IR (neat): ν = 1723, 1640 cm–1.
Metathesis Reaction of Dienyne 25. Formation of Diels–Alder Com-
pound 44: Grubbs’ first-generation catalyst 2 (25 mg, 0.03 mmol,
10 mol-%) was added to a degassed solution of trienyne 25 (75 mg,
0.3 mmol) in dry CH2Cl2 (7.8 mL) under argon and the mixture
was heated at reflux for 3 h. The solvent was then removed and the
residue was purified by flash chromatography on silica gel (EtOAc/
cyclohexane, 1:99 to 2:98) to give 21 mg of ester 43 (0.08 mmol,
28%) and 20 mg of 44 (0.04 mmol, 27%) as colorless oils. Rf = 0.25
(EtOAc/cyclohexane, 1:99). 1H NMR: δ = 5.48–5.45 (br. s, 1 H),
5.12 (t, J = 7.2 Hz, 1 H), 5.09 (t, J = 7.2 Hz, 1 H), 3.72 (s, 3 H),
3.69 (s, 3 H), 3.35–3.22 (br. s, 1 H), 2.91 (t, J = 9 Hz, 1 H), 2.62–
2.50 (br. s, 1 H), 2.34–2.12 (m, 5 H), 2.03–1.00 (m, 19 H), 1.69 (s,
6 H) 1.60 (s, 6 H) ppm. 13C NMR: δ = 176.2 (C), 167.7 (C), 161.9
(C), 143.0 (C), 131.3 (C), 131.2 (C), 127.5 (CH), 124.9 (CH), 124.7
(CH), 120.1 (C), 51.6 (CH3), 51.0 (CH3), 49.4 (C), 47.9 (CH), 47.3
(CH), 41.9 (CH), 36.2 (CH2), 33.5 (CH2), 30.5 (CH2), 30.3 (CH2),
29.0 (CH2), 28.3 (CH2), 28.2 (2 CH2), 27.8 (CH2), 25.7 (2 CH2),
˜
2
2
[1] For recent reviews concerning ring-closing metathesis reac-
tions, see: a) D. Astruc, New J. Chem. 2005, 29, 42–56; b) R. H.
Grubbs, Tetrahedron 2004, 60, 7117–7140; c) Handbook of Me-
tathesis (Ed.: R. H. Grubbs), Wiley-VCH: Weinheim, 2003, vol.
2; d) T. M. Trnka, R. H. Grubbs, Acc. Chem. Res. 2001, 34,
18–29; e) A. Fürstner, Angew. Chem. Int. Ed. 2000, 39, 3012–
3043. For a review on metathesis reactions in total syntheses
see: K. C. Nicolaou, P. G. Bulger, D. Sarlah, Angew. Chem. Int.
Ed. 2005, 44, 4490–4527.
[2] a) W. J. Zuercher, M. Scholl, R. H. Grubbs, J. Org. Chem. 1998,
63, 4291–4298; b) S.-H. Kim, W. J. Zuercher, N. B. Bowden,
R. H. Grubbs, J. Org. Chem. 1996, 61, 1073–1081; c) T. R.
Hoye, C. S. Jeffrey, M. A. Tennakoon, J. Wang, H. Zhao, J.
Am. Chem. Soc. 2004, 126, 10210–10211; d) For a recent review
on relay RCM see: D. J. Wallace, Angew. Chem. Int. Ed. 2005,
44, 1912–1915.
Eur. J. Org. Chem. 2006, 471–482
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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481

F.-D. Boyer, I. Hanna
FULL PAPER
[3]
[4]
[5]
[15] To the best of our knowledge, only one example of the RCM
reaction involving enoic carbene complexes has hitherto been
reported. See ref.[1a]. For cross-metathesis reactions involving
such complexes, see: a) T.-L. Choi, C. W. Lee, A. K. Grubbs,
R. H. Chatterjee, J. Am. Chem. Soc. 2001, 123, 10417–10418;
b) C. W. Lee, T.-L. Choi, R. H. Grubbs, J. Am. Chem. Soc.
2002, 124, 3224–3225.
P. Schwab, M. B. France, J. W. Ziller, R. H. Grubbs, Angew.
Chem. Int. Ed. Engl. 1995, 34, 2039–2041.
M. Scholl, S. Ding, C. W. G. Lee, R. H. Grubbs, Org. Lett.
1999, 1, 953–956.
For recent reviews on enyne metathesis, see: a) M. Mori, Hand-
book of Metathesis (Ed.: R. H. Grubbs), Wiley-VCH,
Weinheim, 2003; vol. 2, pp. 176–204; b) C. S. Poulsen, R.
Madsen, Synthesis 2003, 1–18; c) S. T. Diver, A. J. Giessert,
Chem. Rev. 2004, 104; 1317–1382. For a recent article on the
selectivity of RCM enyne metathesis see: E. C. Hansen, D. Lee,
J. Am. Chem. Soc. 2004, 126, 15074–15080.
For recent examples of the synthesis of carbobicyclic systems
by metathesis of dienynes, see: a) E. M. Codesido, L. Castedo,
J. R. Granja, Org. Lett. 2001, 3, 1483–1486; b) R. Garcia-Fand-
ino, E. M. Codesido, E. Sobarzo-Sanchez, L. Castedo, J. R.
Granja, Org. Lett. 2004, 6, 193–196.
For recent examples of the synthesis of heterobicyclic systems
by metathesis of dienynes, see: a) T.-L. Choi, R. Grubbs, Chem.
Commun. 2001, 2648–2649; b) J. Huang, H. Xiong, R. P.
Hsung, C. Rameshkumar, J. A. Mulder, T. P. Grebe, Org. Lett.
2002, 4, 2417–2420; c) K. Shimizu, M. Takimoto, M. Mori,
Org. Lett. 2003, 5, 2323–2326; d) C.-J. Wu, R. J. Madhushaw,
R.-S. Liu, J. Org. Chem. 2003, 68, 7889–7892; e) T. Honda, H.
Namiki, K. Kaneda, H. Mizutani, Org. Lett. 2004, 6, 87–89; f)
H. Fukumoto, T. Esumi, J. Ishihara, S. Hatakeyama, Tetrahe-
dron Lett. 2003, 44, 8047–8049; g) K. P. Kaliappan, R. S. Nan-
durdikar, Chem. Commun. 2004, 2506–2507.
[16] S. B. Garber, J. S. Kingsbury, B. L. Gray, A. H. Hoveyda, J.
Am. Chem. Soc. 2000, 122, 8168–8179.
[17] For a review of non-metathetic ruthenium-catalyzed C–C bond
formation, see: a) B. M. Trost, F. D. Toste, A. B. Pinkerton,
Chem. Rev. 2001, 101, 2067–2096; b) For a review of the behav-
ior of enynes in the presence of transition metals, see: C. Aub-
ert, O. Buisine, M. Malacria, Chem. Rev. 2002, 102, 813–834;
c) For an example of cycloisomerization of enynes promoted
by Grubbs’ carbene complex 3 in the presence of ethylene, see:
M. Mori, N. Saito, D. Tanaka, M. Takimoto, Y. Sato, J. Am.
Chem. Soc. 2003, 125, 5606–5607; d) For a review highlighting
the subject see: B. Schmidt, Angew. Chem. Int. Ed. 2003, 42,
4996–4999.
[18] For palladium-catalyzed cyclization of enynes see: B. M. Trost,
G. J. Tanoury, M. Lautens, C. Chan, D. T. MacPherson, J. Am.
Chem. Soc. 1994, 116, 4255–4267.
[19] For an example of chelation of a Ru–carbene to an ester group
see: A. Fürstner, K. Langemann, J. Am. Chem. Soc. 1997, 119,
9130–9136.
[20] Nitrile 13 was prepared starting from the commercially avail-
able 6-methyl-5-hepten-2-one by one-carbon homologation di-
rectly by treatment with tosylmethyl isocyanide (TosMIC) ac-
cording to van Leusen’s procedure, or in three steps via the
corresponding tosylate.
[21] S. Ohira, Synth. Commun. 1989, 19, 561–564. For a review see;
F. Eymery, B. Iorga, P. Savignac, Synthesis 2000, 185–213.
[22] For a related formation of dimeric compounds in metathesis
reactions of enynes see: a) M. Mori, T. Kitamura, N. Sakakib-
ara, Y. Sato, Org. Lett. 2000, 2, 543–545; b) M. Mori, Y. Ku-
suba, T. Kitamura, Y. Sato, Org. Lett. 2002, 4, 3855–3858; c)
T. Kitamura, Y. Kuzuba, Y. Sato, H. Wakamatsu, R. Fujita,
M. Mori, Tetrahedron 2004, 60, 7375–7389.
[23] For recent examples of cyclization of enynes catalyzed by PtCl2
see: a) B. M. Trost, G. A. Doherty, J. Am. Chem. Soc. 2000,
122, 3801–3810; b) E. Mainetti, V. Mouriès, L. Fensterbank,
M. Malacria, J. Marco-Contelles, Angew. Chem. Int. Ed. 2002,
41, 2132–2135; c) Y. Harrak, C. Blaszykowski, M. Bernard, K.
Cariou, E. Mainetti, V. Mouriès, A.-L. Dhimane, L. Fenster-
bank, M. Malacria, J. Am. Chem. Soc. 2004, 126, 8656–8657
and references cited therein.
[6]
[7]
[8]
F.-D. Boyer, I. Hanna, L. Ricard, Org. Lett. 2001, 3, 3095–
3098.
[9] a) F.-D. Boyer, I. Hanna, L. Ricard, Org. Lett. 2004, 6, 1817–
1820; b) F.-D. Boyer, I. Hanna, Tetrahedron Lett. 2002, 43,
7469–7472.
[10] Total and formal syntheses: a) D. S. Tan, G. B. Dudley, S. J.
Danishefsky, Angew. Chem. Int. Ed. 2002, 41, 2185–2188; b) S.
Lin, G. B. Dudley, D. S. Tan, S. J. Danishefsky, Angew. Chem.
Int. Ed. 2002, 41, 2188–2191; c) B. Shi, N. A. Hawryluk, B. B.
Snider, J. Org. Chem. 2003, 68, 1030–1042.
[11] For recent synthetic studies related to guanacastepene see inter
alia: a) P. Magnus, C. Ollivier, Tetrahedron Lett. 2002, 43,
9605–9609; b) W. D. Shipe, E. J. Sorensen, Org. Lett. 2002, 4,
2063–2366; c) T. M. Nguyen, R. J. Seifert, D. R. Mowrey, D.
Lee, Org. Lett. 2002, 4, 3959–3962; d) A. Nakazaki, U.
Sharma, M. A. Tius, Org. Lett. 2002, 4, 3363–3366; e) G.
Mehta, J. D. Umarye, K. Srinivas, Tetrahedron Lett. 2003, 44,
4233–4237; f) X. Du, H. V. Chu, O. Kwon, Tetrahedron Lett.
2004, 45, 8843–8846; g) K. M. Brummond, D. Gao, Org. Lett.
2003, 5, 3491–3494; h) C. C. Hughes, J. J. Kennedy-Smith, D. [24] No cyclopropanation product was observed under these condi-
Trauner, Org. Lett. 2003, 5, 4113–4115; i) A. Srikrishna, D. H.
Dethe, Org. Lett. 2004, 6, 165–168; j) P. Chiu, S. Li, Org. Lett.
2004, 6, 613–616.
tions. For cyclopropanation of dienynes with Grubbs’ ruthe-
nium carbenes see: a) B. P. Peppers, S. T. Diver, J. Am. Chem.
Soc. 2004, 126, 9524–9525; b) with PtCl2, see ref.[22c]
.
[12] Dienynes 6a–g were prepared as described in ref.[9] and sub-
jected to RCM as a mixture of two diastereoisomers.
[13] Trienes 7a and 7b were isolated by rapid chromatography on
Florisil using light petroleum ether as eluent. Chromatography
on silica gel led to a partial or total decomposition of these
products.
[25] For a recent review of the role of ring strain on the ring-closure
molecules see: C. Galli, L. Mandolini, Eur. J. Org. Chem. 2000,
3117–3125.
[26] G. F. Woods, Org. Synth. Coll. Vol. 3, 470–471.
[27] C. M. Hudson, M. R. Marzabadi, K. D. Moeller, D. G. New,
J. Am. Chem. Soc. 1991, 113, 7372–7385.
[14] The observation that the TMS group effectively shuts down
olefin–acetylene metathesis was previously reported by Grubbs
et al. with a similar dienyne.[1b] For the effect of a TMS group
on RCM of enynes see: T. Kitamura, Y. Sato, M. Mori, Adv.
Synth. Catal. 2002, 344, 678–693.
[28] Prepared from 5-hexen-1-ol by oxidation (PCC, CH2Cl2) and
addition of homoallylmagnesium bromide to the correspond-
ing aldehyde.
Received: August 25, 2005
Published Online: November 17, 2005
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