Ruthenium-catalyzed enyne cycloisomerizations. Effect of allylic silyl ether on regioselectivity

Article abstract of DOI:10.1021/ja046824o

The ruthenium-catalyzed cycloisomerization of 1,6- and 1,7-enynes substituted in the terminal allylic position with a tert-butyldimethylsilyl ether group emerges as an effective reaction to form unprecedented five- or six-membered rings possessing a geome

Full text of DOI:10.1021/ja046824o

Published on Web 11/09/2004
Ruthenium-Catalyzed Enyne Cycloisomerizations. Effect of
Allylic Silyl Ether on Regioselectivity
Barry M. Trost,* Jean-Philippe Surivet, and F. Dean Toste
Contribution from the Department of Chemistry, Stanford UniVersity,
Stanford, California 94305-5080
Received May 28, 2004; E-mail: bmtrost@stanford.edu
Abstract: The ruthenium-catalyzed cycloisomerization of 1,6- and 1,7-enynes substituted in the terminal
allylic position with a tert-butyldimethylsilyl ether group emerges as an effective reaction to form
unprecedented five- or six-membered rings possessing a geometrically defined enol silane. Straightforward
synthetic access to a variety of achiral 1,6- and 1,7-enynes, as well as chiral ones, is presented. Ruthenium
catalysts effect efficiently such single-step cycloisomerization at room temperature in acetone under neutral
conditions. The cycloisomerization functions with (E) or (Z) 1,2-disubstituted alkenes. Parameters influencing
the enol silane geometry are discussed. The level of selectivity depends on the alkyne substitution, the
geometry of the double bond, and the nature of the catalyst. Furthermore, examples of stereoinduction are
shown and lead to highly substituted carbo- and heterocycles with excellent diastereocontrol.
a cyclobutene that undergoes a conrotatory cycloreversion;7 and
(4) a metal alkylidene.8
Introduction
The development of novel and effective cyclization methods
constitutes a continuing challenge as five- and six-membered
cycles are essential structural units widely found in biologically
active molecules serving as pharmaceuticals or agrochemicals.1
Besides the transition-metal-catalyzed ring-closing metathesis,2
complementary intramolecular carbon-carbon bond-forming
processes have recently emerged, offering new possibilities for
the design and synthesis of cyclic templates. Among others, a
number of cycloisomerizations of enynes have evolved, leading
to a myriad of transition metal catalysts.3 One of the main
features of this reaction stems from the direct transformation
of a linear precursor to a cyclic product without additional
reactants and typically producing few byproducts. As such, the
cycloisomerization process appears ideal in terms of synthetic
efficiency and atom economy.4 The nature of the catalyst
determines the mechanistic pathway followed during the course
of the process. Four mechanisms can be identified: (1) initial
hydrometalation of the alkyne, followed by carbometalation of
the olefin;5 (2) initial formation of a metallacyclopentene,
followed by â-hydrogen elimination;6 (3) formation of a
metallacyclopentene, followed by reductive elimination to form
During the past years, efforts in these laboratories have been
focused on the discovery and development of new catalytic
systems for the intermolecular coupling of alkenes and alkynes.9
Through these studies we have shown that the alkene-alkyne
coupling was greatly improved with the use of the cationic
catalyst CpRu(CH3CN)3+PF6- (1)10 (or Cp*Ru(CH3CN)3+PF6
,
-
2), compared with the earlier complex 3, which functioned only
with monosubstituted alkenes.11 The enhanced reactivity ob-
served for complex 1 renders effective the intramolecular
reaction between the alkene and alkyne partners (henceforth
(6) For Pd, see: Trost, B. M.; Tanoury, G. J.; Lautens, M.; Chan, C.;
MacPherson, D. T. J. Am. Chem. Soc. 1994, 116, 4255-4267 and references
therein. For Ni-Cr, see: Trost, B. M.; Tour, J. M. J. Am. Chem. Soc.
1987, 109, 5268-5270. For Ni, see: Radetich, B.; Rajan Babu, T. V. J.
Am. Chem. Soc. 1998, 120, 8007-8008. For Co, see: Kraft, M. E.; Wilson,
A. M.; Dasse, O. A.; Bonaga, L.V. R.; Cheung, Y. Y.; Fu, Z.; Shao, B.;
Scott, J. L. Tetrahedron Lett. 1998, 38, 5911-5914. For Ti, see: Sturla,
S. J.; Kablaoui, N. M.; Buchwald, S. L. J. Am. Chem. Soc. 1999, 121,
1976-1977. For Rh, see: Cao, P.; Wang, B.; Zhang, X. J. Am. Chem.
Soc. 2000, 122, 6490-6491. For Ir, see: Chatani, N.; Inoue, H.; Morimoro,
T.; Muto, T.; Murai, S. J. Org. Chem. 2001, 66, 4433-4436. See also:
Trost, B. M.; Hashmi, A. S. K. Angew. Chem., Int. Ed. Engl. 1993, 32,
1085-1087. Chatani, N.; Kataoka, K.; Murai, S.; Furukawa, N.; Seki, Y.
J. Am. Chem. Soc. 1998, 120, 9104-9105.
(7) For Pd, see: Trost, B. M.; Trost, M. K. J. Am. Chem. Soc. 1991, 113,
1850-1852. For Pt, see: Chatani, N.; Furukawa, N.; Sakurai, H.; Murai,
S. Organometallics 1996, 15, 901-903. Fu¨rstner, A.; Steltzer, F.; Szillat,
H. J. Am. Chem. Soc. 2001, 123, 11863. Mainetti, E.; Mouries, V.;
Fensterbank, L.; M.; Marco-Contelles, J. Angew. Chem., Int. Ed. 2002, 41,
2132. For Ru, see: Chatani, N.; Morimoro, T.; Muto, T.; Murai, S. J. Am.
Chem. Soc. 1994, 116, 6049-6050.
(1) Weintraub, P. M.; Sabol, J. S.; Kane, J. M.; Borcherding, D. R. Tetrahedron
2003, 59, 2953-2989.
(2) (a) Grubbs, R. H.; Chang, S. Tetrahedron 1998, 54, 4413-4450. (b) Alkene
Metathesis in Organic Synthesis; Furstner, A., Ed; Springer: New York,
1998.
(3) For reviews, see: Trost, B. M.; Krische, M. J. Synlett 1998, 1-16. Aubert,
C.; Buisine, O.; Malacria, M. Chem. ReV. 2002, 102, 813-834. For
mechanistic overview, see: Lloyd-Jones, G. C. Org. Biomol. Chem. 2003,
1, 215-236. For asymmetric cycloisomerizations, see: Fairlamb, I. J. S
Angew. Chem., Int. Ed. 2004, 43, 1048-1052.
(4) Trost, B. M. Science 1991, 254, 1471-1477. Trost, B. M. Angew. Chem.
1995, 34, 259-281.
(5) For Pd, see ref 15. For Ru, see: Mori, M.; Kozawa, Y.; Nishida, M.;
Kanamura, M.; Onozuka, K.; Takimoto, M. Org. Lett. 2000, 2, 3245-
3247. Le Paih, J.; Rodriguez, D.; Derien, S. D.; Dixneuf, P. H. Synlett
2000, 95-97.
9
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J. AM. CHEM. SOC. 2004, 126, 15592-15602
10.1021/ja046824o CCC: $27.50 © 2004 American Chemical Society

Ruthenium-Catalyzed Enyne Cycloisomerizations
A R T I C L E S
called cycloisomerization of 1,6- and 1,7-enynes) to form
respectively five- and six-membered rings, through the inter-
mediacy of a ruthenacyclopentene.12 However, in the intriguing
case of a 1,6-enynoate, the introduction of a quaternary center
at the propargylic position completely changes the nature of
the reaction and its mechanism. A seven-membered ring forms
under equally mild conditions through a C-H insertion,
generating a π-allylruthenium intermediate.13
Subjection of propargyl and homopropargyl tosylamine 7a18
and 7b19 to similar reaction conditions afforded the correspond-
ing 1,6- and 1,7-enynes 8a and 8b in high yield (eq 3).
Following this initial work, we considered the effect of
heteroatom substituents, notably oxygen and nitrogen, at the
allylic position to form enol and enamide derivatives in
intermolecular reactions.14 While the simple allyl system worked
very well, extrapolating to more substituted allyl systems has
proved difficult to date. As a result, we initiated studies
involving an intramolecular process, namely one wherein the
alkyne and the allyl silyl ether are tethered through various
linkers. Such studies are important to provide a straightforward
access to highly substituted carbo- and heterocycles and to
extend further the scope of the ruthenium-catalyzed cyclo-
isomerization of enynes.
The formation of the cyclic template is accompanied with
the concomitant formation of an enol silane. Because the
geometry of the latter is crucial in influencing the stereochemical
outcome of potential subsequent events, the gain of a geo-
metrically defined enol silane remains of considerable impor-
tance. It is worth noting that the proposed ruthenium-catalyzed
process allows only the formation of the 1,4-diene, whereas the
related palladium-catalyzed cycloisomerization may produce
both 1,3- and 1,4-dienes (eq 1).15
The resulting products could be further derivatized. After
deprotonation of the acetylide, the anion was trapped with
methyl chloroformate (Cl-CO2Me) or chlorotrimethylsilane
(TMS-Cl) to give respectively enynoates 9a, 9b or TMS-alkyne
10.20
The corresponding cis isomers were generated using a
Mitsunobu-type reaction21 to preserve the integrity of the alkene
moiety. After monosilylation of cis-but-2-ene-1,4-diol,22 the
resulting alcohol 11 reacted with tosylamines 7a or 7b under
typical Mitsunobu conditions (DIAD, PPh3) to yield (Z)-olefins
12a and 12b in 74% and 49% yield.23 Alkyne 12a was
subsequently transformed to its corresponding enynoate 13 using
the aforementioned protocol (eq 4).
We then envisioned the preparation of enantiomerically pure
enynes starting from (S)-ethyl lactate 14. The chiral starting
material was transformed to the corresponding R,â-unsaturated
ester 15 using previously described procedures.24 The protective
group (TBDMS) was removed under acidic conditions (aqueous
trifluoroacetic acid),25 and the alcohol 16 was subsequently
reacted in a Mitsunobu-type reaction (DIAD, PPh3) using either
tosylamine 7a or 7b to give the R-isomers 17a and 17b26 in
respectively 74% and 49% yield. Subjection of the resulting
substances to an excess of DIBAL-H reduces the ester moiety
Preparation of Substrates
Different strategies were employed for the synthesis of enynes
and enynoates featuring the required terminal allylic alcohol
protected as a tert-butyldimethylsilyl ether. Palladium-catalyzed
allylic alkylation16 offers a rapid access to such entities. Thus,
the carbonate 417 was reacted with propargyl malonate 5 in the
presence of 2.5 mol % of (η3-C3H5PdCl)2, 20 mol % of
triphenylphosphine, and 2 equiv of cesium carbonate, to generate
the enyne 6 in 61% isolated yield (eq 2).
(15) Trost, B. M.; Romero, D. J.; Rise, F. J. Am. Chem. Soc. 1994, 116, 4268-
4278 and references therein.
(16) Consiglio, G.; Waymouth, R. M. Chem. ReV. 1989, 89, 257-276.
(17) Grzywacz, P.; Marczak, S.; Wicha, J. J. Org. Chem. 1997, 62, 529-5298.
(18) Masquelin, T.; Obrecht, D. Synthesis 1995, 276-284.
(19) Henry, J. R.; Marcin, L. R.; McIntosh, M. C.; Scola, P. M.; Harris, G. D.;
Weinreb, S. M. Tetrahedron Lett. 1989, 30, 5709-5712.
(20) The E-stereochemistry was confirmed with the J ) 15 Hz for the alkene
protons.
(8) For Ru, see: Mori, M.; Sakakibara, N.; Kinoshita, A. J. Org. Chem. 1998,
63, 6082-6083.
(9) Trost, B. M.; Toste, F. D. Tetrahedron Lett. 1999, 40, 7739-7743. For a
review, see: Trost, B. M.; Toste, F. D.; Pinkerton, A. B. Chem. ReV. 2001,
101, 2067-2096.
(21) Mitsunobu, O. Synthesis 1981, 1-28. Hughes, D. L. Org. Prep. Proced.
Int. 1996, 28, 127-164.
(22) Hull, M. H.; Knight, D. W. J. Chem. Soc., Perkin Trans. 1 1997, 857-
864.
(23) The Z-stereochemistry was confirmed with the J ) 11 Hz for the alkene
protons and by direct comparison with the NMR data recorded for the
corresponding E-isomers.
(10) For the preparation of catalyst 1, see: Trost, B. M.; Older, C. M.
Organometallics 2002, 21, 2544-2546. Catalyst 1 is available from Strem
Chemicals.
(11) (a) Trost, B. M.; Indolese, A. F.; Muller, T. J. J.; Martinez, J. J. Am. Chem.
Soc. 1995, 117, 615-623. (b) Trost, B. M.; Muller, T. J. J.; Martinez, J. J.
Am. Chem. Soc. 1995, 117, 1888-1889.
(12) Trost, B. M.; Toste, F. D. J. Am. Chem. Soc. 1999, 121, 9728-9729.
(13) Trost, B. M.; Toste, F. D. J. Am. Chem. Soc. 2000, 122, 714-715. Trost,
B.M.; Toste, F. D. J. Am. Chem. Soc. 2002, 124, 5025-5036.
(14) Trost, B. M.; Surivet, J.-P.; Toste, F. D. J. Am. Chem. Soc. 2001, 123,
2897-2898. For the related formation of enamides, see: Trost, B. M.;
Surivet, J.-P. Angew. Chem., Int. Ed. 2001, 40, 1468-1471.
(24) Brandange, S.; Lindqvist, B. Acta Chem. Scand. 1985, B39, 589592. Mulzer,
J.; Funk, G. Synthesis 1995, 101-112.
(25) For details on protective group manipulations, see: ProtectiVe Groups in
Organic Synthesis, 3rd ed.; Greene, T. W., Wuts, P. G., Eds.; Wiley: New
York, 1999.
(26) We assumed that the inversion of configuration normally proceeded without
loss of the chiral information.
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A R T I C L E S
Trost et al.
cleanly. The formed alcohols 18a and 18b were transformed
to the enynes 19a and 19b in an acceptable overall yield
(eq 5).
yield enynes 30a,b. Alkynoate 31 was also synthesized using
the standard carboxymethylation protocol (eq 8).
Cycloisomerization
Our first attempt concerned the cycloisomerization of 1,6-
enyne 6. Reaction conditions that were successfully developed
for the intermolecular version of this reaction, i.e., 10 mol %
of catalyst 1 in acetone, but lowering the substrate concentration
to 0.1 M, were used. After 20 min, the starting material was
entirely consumed, and simple chromatography afforded the
cyclic compound 32 in 93% yield as a 13:1 E:Z mixture of
isomers. NMR analysis of the crude mixture revealed that 1,4-
diene 32 was the only product formed. Indeed, no traces of 1,3-
diene nor degradation products could be observed, demonstrating
the mildness and the selectivity of the process. The E-geometry
of the major silyl enol ether was characterized by J ) 12 Hz
for the vinyl hydrogens (compared to J ) 6 Hz for the
Z-geometry) (eq 9).31 When a lower catalyst loading (5 mol %
of 1) was used, an incomplete conversion was observed after
the same reaction time (20 min). Allowing the reaction to
proceed for a longer time did not improve this result.
Enyne substrate 23 could also be obtained from the more
elaborated R,â-unsaturated ester 20.27 The protecting group
(TBDMS) was replaced by a tetrahydropyranyl ether (THP) in
two steps, and the ester moiety was further reduced using
DIBAL-H to provide the allylic alcohol 21. The latter was
reacted with TBDMS-Cl in the presence of triethylamine, and
the chemoselective removal of the THP group (MgBr2 in ether)28
furnished the secondary alcohol 22. A Mitsunobu-type reaction
with tosylamine 7a gave enyne 27 in an expected low 16% yield
(due to the competing â-elimination of the intermediate phos-
phonium salt) (eq 6).
Using these conditions (10 mol % of catalyst in acetone
[0.1 M]) as standard, linear precursors 8a, 9a, and 10 were
cleanly converted to the five-membered-ring derivatives 33, 34,
and 35 in good to excellent yields (eq 10, Table 1).
1,6-Enynes containing an oxygen atom in the linker were
obtained using well-established chemistry. Mono-propargylation
of cis-but-2-ene-1,4-diol gave allylic alcohol 24,29 which was
subsequently protected as the silyl ether 25. The terminal alkyne
was then transformed to the corresponding methoxycarbonyl
derivative 26 in standard fashion (eq 7).
Table 1. Cycloisomerization to Pyrrolidine
A gem-dialkyl-substituted substrate was constructed, starting
by converting the ester 27 to the corresponding R,â-unsaturated
esters 28a,b in four steps.30 The allylic silyl ethers 29a,b were
then obtained as already described (reduction and silylation).
Finally, TMS-alkynes were treated with K2CO3 in methanol to
substrate
R
catalyst
yield
E:Za
8a
8a
9a
9a
10
H
H
1
2
1
2
1
33, 89%
33, 95%
34, 77%
34, 95%
35, 97%
>32:1
12.5:1
2.4:1
1:5
CO2Me
CO2Me
TMS
(27) Trost, B. M.; Metz, P.; Hane, J. T. Tetrahedron Lett. 1986, 27, 5691-
5694.
32:1
(28) Kim, S.; Park, J. H. Tetrahedron Lett. 1987, 28, 439-442.
(29) Marco-Contelles, J. Synth. Commun. 1997, 27, 3163-3170.
(30) After alkylation of ester 27 with the corresponding iodide, esters moitey
were transformed in two steps (reduction to the alcohol and then Moffat-
Swern oxidation) to the aldehydes, which were subjected to an excess of
carbomethoxytriphenylphosphorane to yield respectively 28a or 28b. See
Supporting Information section for more details.
1
a Measured by H NMR.
Substrates 8a and 10 afforded respectively the desired
N-tosylpyrrolidines 33 and 35 with an excellent E:Z selectivity
using the catalyst 1 (Cp ligand). On the other hand, compound
34 was obtained in a modest 2.4:1 ratio starting from enynoate
(31) These observations are consistent with the coupling constants we observed
in the case of the intermolecular study; see ref 14.
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Ruthenium-Catalyzed Enyne Cycloisomerizations
A R T I C L E S
9a. The same experiments were carried out with catalyst 2 (Cp*
ligand). Unexpectedly, the use of the latter catalyst gave rise to
significantly different results. The E:Z ratio for product 33
decreased somewhat, while an inversion of geometrical selectiv-
ity occurred in the case of 34, wherein the Z-isomer predomi-
nated (Z:E 5:1).
min. The corresponding five-membered-ring products 33 and
34 formed in respectively 96% and 63% yield (eq 14).33 Even
though enynes 8a and 12a gave rise to 33 in a similar selectivity,
we noted that, in the case of the cyclic product 34, the E:Z
ratio jumped to 25:1 when Z-enyne 13 was used as a pre-
cursor.
Cyclization of 8b and 9b explores the effect of ring size as
summarized in eq 11 and Table 2. The linear starting materials
Table 2. Cycloisomerization to Piperidine
Similarly, Z-enyne 8b, when reacted in the presence of a
catalytic amount of complex 1, is transformed cleanly to the
N-tosylpiperidine 36 with an improved 9:1 selectivity in favor
of the E-enol silane (eq 15). The yield was slightly decreased
in the latter case due to a lower conversion.
substrate
R
catalyst
yield
E:Za
8b
8b
9b
9b
H
H
1
2
1
2
36, 99%
36, -c
37, 94%
37, 80%
4:1
1:1
3:1b
1:5
CO2Me
CO2Me
a Measured by 1H NMR. b As a mixture with respect to the R,â-
unsaturated ester that was obtained. c Low conversion.
were smoothly reacted at ambient temperature with the complex
1 as a catalyst to afford N-tosylpiperidine 36 and 37 in
respectively 99% and 94% yield. In stark contrast with the
selective formation of 33, 1H NMR showed a modest 4:1
selectivity in favor of the E-enol silane 36, and the cyclic product
37 was recovered as a mixture of isomers. In the latter case,
NMR data suggest that both the R,â-unsaturated ester and enol
silane moieties were formed as geometrical mixtures (see Table
2). The estimated ratios were confirmed after hydrolysis of the
silyl enol ethers in aqueous acid conditions (eqs 12 and 13). In
the case of 36, the hydrolysis led only to aldehyde 38, which
was reduced to the alcohol 39 (eq 12).32 Performing the same
Other substrates characterized by a cis double bond also
reacted cleanly to produce the corresponding cyclic products.
Thus, enyne 25 and alkynoate 26 gave rise to the substituted
tetrahydrofurans 41 and 42 respectively in good yield and
excellent selectivity (eq 16).
Using the more sterically congested 1,6-enyne 30a, the
cycloisomerization took place accordingly to yield the substi-
tuted cyclopentane 43 in 93% yield as a single E-isomer (eq
17). Unexpectedly, the corresponding 1,7-enyne 30b failed to
sequence with the cyclic compound 37 resulted in the formation
of the alcohol 40 in a 3.3:1 ratio of isomers with respect to the
R,â-unsaturated ester double bond (eq 13).
react under the same conditions, returning only the unchanged
starting material. Raising the temperature to 60 °C did not lead
to any reaction. Switching the solvent to DMF, still at 60 °C,
gave rise to a mixture of compounds containing only a trace
amount of a cyclic aldehyde, resulting from the hydrolysis of
the enol silane.
Placing a carbomethoxy substituent on the alkyne terminus
of 30a, as in 31, gave a mixture of products. An aqueous acidic
treatment of the latter greatly simplified the mixture to deliver,
after reduction of the resulting aldehyde with NaBH4, the alcohol
44 in 81% yield for the three steps (eq 18).
In contrast to the above results, using catalyst 2 to perform
the cycloisomerization of the 1,7-enyne 8b and enynoate 9b
provided a low conversion of derivative 36 in a poor yield and
with no selectivity (1:1 ratio). On the other hand, precursor 9b
participated in the reaction to give the cyclic product 37 in a
satisfying 80% yield. As observed in the case of the five-
membered ring 9a, the enol silane was formed mainly as the
Z-isomer (5:1 ratio).
To study the influence of the alkene geometry of the substrate,
Z-enynes 12a and 13 were submitted to our standard conditions
using 10 mol % of 1 in acetone at room temperature for 20
(32) The aldehyde was further reduced to the alcohol to ensure the standard
characterizations.
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A R T I C L E S
Trost et al.
at 6.26 and 6.17 ppm exhibiting a J ) 11.9 Hz), accounting for
a 2.2:1 induction. Increasing the steric demands of the catalyts
as in complex 2, the product 50 was obtained in 74% yield,34
almost as a single diastereomer. The minor isomer was detected
only as a trace. The assignment of the trans relationship between
the two groups was tentatively based on the observed coupling
constant for the major diastereomer, J2,3 ) 8.5 Hz. Further
support comes from the chemical shift differences for the
hydrogens of the terminal methylene group. Previous work
established that the trans isomer had a smaller difference
compared to the cis isomer.38 The observation that the major
isomer exhibited a ∆δ of 0.07, whereas the minor had a ∆δ of
0.14 ppm, is in good accord with the above assignment.
The effect of placing a substituent on the terminal alkyne
was examined in the cycloisomerization of the alkynoate 51
(eq 22). Stereoinduction due to the methyl group was very high
(>30:1) in both cases. Interestingly, the nature of the catalyst
directly influenced the stereochemistry of the enol silane. Indeed,
the enol silyl ether double bond processed mainly the E
geometry as in 52 when complex 1 was used, but predominantly
the Z geometry with complex 2.
Figure 1. Relative stereochemistry as determined by NOE experiments.
The effect of reversing the polarity of the alkynoate as in
ester 45, readily obtained by a Mitsunobu process,34 was
examined (eq 19). The cycloisomerization was performed under
our standard conditions (10 mol % 1 in acetone). Remarkably,
the desired cyclic product 46 could be obtained in 55% yield
(82% based on recovered starting material) as a single E-isomer.
Thus, the effect of a highly activated terminal acetylenic
hydrogen did not inhibit the reaction. This reaction serves as a
convenient entry into R-methylene-δ-butyrolactones, important
structural units of many bioactive natural products35 such as
anthecotuloide.36
Diastereoselective Cycloisomerization
The diastereoselectivity of the cycloisomerization was also
studied by employing substrates possessing stereogenic centers.
To examine this point as well as to compare the selectivity
between the Pd- and Ru-catalyzed cycloisomerizations, we
initially employed enyne 47, the substrate for our synthesis of
sterepolide (eq 20), which produced the conjugated diene 48
The cycloisomerization of the 1,7-enyne 19b under our
standard conditions gave rise to the expected N-tosylpiperidine
54 in 96% yield as a mixture of two isomeric enol silanes (E:Z
3.9:1) (eq 23). The 1,2 stereoinduction also turned out to be
very high, only one diastereomer in each case being observed.
regioselectively with Pd catalysis.37 In contrast, the Ru-catalyzed
reaction affords the enol silane 49 in 72% yield as a single
diastereomer (eq 20). The ability to form an enol silane in the
presence of a free hydroxyl group was already demonstrated in
the related intermolecular process. The cis relationship was
ascertained by NOE experiments as illustrated in Figure 1.
The cycloisomerization of the enyne 19a was carried out in
our standard conditions, using both complexes 1 and 2 (eq 21).
Using complex 1 as a catalyst gave rise to the trisubstituted
N-tosylpyrrolidine 50 in 94% yield.
The impact of additional stereogenic centers was also
examined. Treatment of the alkyne 23 under our standard
conditions resulted in the consumption of the starting material
within 5 min. Upon an acid treatment of the crude mixture, the
aldehyde 55 was isolated in 65% yield after purification. For
further characterization, the latter was reduced to the alcohol
56. The selectivity with respect to the newly formed stereogenic
1
center is excellent (only one isomer could be observed by H
(34) The purity of 45 is crucial for the success of the isomerization, since we
have noticed that contaminants (presumably hydrazine derivatives due to
the Mitsunobu reaction) poisoned the catalyst.
(35) For reviews, see: Hoffmann, H. M. R.; Rabe, J. Angew. Chem., Int. Ed.
Engl. 1985, 24, 94-110.
The enol silane moiety was formed as a unique E-isomer,
(36) van Klink, J.; Becker, H.; Andersson, S.; Boland, W. Org. Biomol. Chem.
2003, 1, 1503-1508.
but two diastereomers were observed by 1H NMR (two doublets
(37) Trost, B. M.; Chung, J. Y. L. J. Am. Chem. Soc. 1985, 107, 4586-4588.
(38) Cancho, Y.; Martin, J. M.; Martinez, M.; Llebaria, A.; Moreto, J. M.;
Delgado, A. Tetrahedron 1998, 54, 1221-1232.
(33) The lower chemical yield is explained by a lower conversion.
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Ruthenium-Catalyzed Enyne Cycloisomerizations
A R T I C L E S
intermediate ruthenacyclopentene 61 places the silyl ether group
in a favorable pseudoequatorial position. On the other hand,
starting from Z-enyne 13, the same group orients in a pseudo-
axial position in intermediate 62. The following â-hydrogen
elimination involves abstraction of that diastereotopic hydrogen
(Ha or Hb) in a best position for overlap of the breaking C-H
and C-Ru bond to form the new double bond.
The data suggest that conformer 61b (leading to the E-enol
silane) is slightly preferred over 61a (E:Z ratio 2.4:1), whereas
the differences are much larger in the case of 62b vs 62a. A
possible explanation is illustrated in Figure 3, where a strong
steric interaction between the silyl ether group and the pyrro-
lidine ring appears clearly in conformer 62a compared to
conformer 61a.
Figure 2. Assignment of the relative stereochemistry of substituted
piperidine 56.
NMR) (eq 24). The trans relationship was established by NOE
experiments (Figure 2).
Furthermore, increasing the size of the Cp group on the
ruthenium to Cp* shifts the selectivity in favor of the Z-isomer
(see Figure 4). The steric repulsion between the silyl ether group
and the ruthenium ligand disfavors Hb abstraction and favors
adoption of an orientation where Ha is proximal to the metal,
leading in this case to the opposite olefin geometry. The same
trend was observed to a somewhat smaller extent in the
transformation of enynoate 9b to the six-membered-ring deriva-
tive 37.
Interestingly, the cycloisomerations of 1,6-enyne 8a and 1,7-
enyne 8b using catalyst 1 returned contrasting results. The five-
membered-ring 33 is obtained in an excellent E:Z >32:1
selectivity; meanwhile, the corresponding six-membered-ring
36 is recovered in a modest E:Z 4:1. Furthermore, increasing
the size of the Cp fragment to Cp* results in a further loss of
selectivity (E:Z 1:1 for 36); meanwhile, using the 1,7-Z-enyne
8b significantly improves the selectivity (E:Z 9:1). As we
suggested in the case of the 1,6-enynoates (Figures 3 and 4),
this difference of selectivity between the 1,6-enynes and the
1,7-enynes is likely due to minute changes in the balance of
steric interactions between the Ru ligand and the silyl ether
group.
Discussion
Studies on the ruthenium-catalyzed enyne cycloisomerization
have demonstrated that the operative mechanism is directly
dictated by the nature of the substrate. The 1,6- and 1,7-enynes
normally react with ruthenium complexes to form a ruthena-
cyclopentene that evolves to form the corresponding five- or
six-membered ring. On the other hand, a 1,6-enynoate containing
a quaternary center next to the propargylic center gave rise to
a seven-membered ring, presumably via a π-allyl ruthenium
arising from a C-H insertion.13 In our present study, substrate
similarities suggest that the ruthenacyclopentene pathway should
dominate. Thus, complexation of coordinatively unsaturated
cyclopentadienylruthenium(2+) (57) to the enyne generates
complex 58. Tautomerization of the enyne provides the ruthe-
nium(4+) metallacycle 59, the product of an internal redox
process. A â-hydrogen elimination of Ha forms the vinylruthe-
nium(4+) hydride 60, which subsequently undergoes a reductive
elimination to regenerate the ruthenium(2+) catalyst and
provides the 1,4-diene product (Scheme 1).
Scheme 1 . Proposed Mechanism for the Ruthenium-Catalyzed
Cycloisomerization of Enynes
A putative rationale for the diastereoselectivity we observed
in the case of the formation of derivative 50 derives also from
the intermediacy of a ruthenacyclopentene. The isomerization
of 1,6-enyne 19a produced pyrrolidine 50 as a 2.2:1 mixture of
cis/trans isomers when complex 1 was used, while use of
complex 2 enabled the formation of the unique trans isomer.
Two diastereomeric ruthenacycles are accessible as depicted in
Figure 5.
In intermediate 63a, methyl group adopts an equatorial
orientation, whereas the same group occupies an axial one in
conformer 63b. However, the slight preference observed for
conformer 63a is greatly improved by switching the ligand on
the ruthenium to Cp*. Enhancement of the steric interaction
between the Cp fragment and the pseudoaxial methyl group in
63b by switching to Cp* favors conformer 64, which leads to
the trans isomer (Figure 5).
The presence of an electron-withdrawing group on the alkyne
also has a dramatic impact on these basic models, as shown for
the cycloisomerization of 1,6-enynoate 51. The nature of the
ligand no longer has an effect on the selectivity observed at the
level of the pyrrolidine ring, but guides the geometry of the
enol silane as we observed in the case of unbranched enynes.
Previous work with Pd catalysis suggested that the presence
of an allylic oxygen substituent impacted the regioselectivity
To a large extent, the ruthenacycle mechanism accounts for
the selectivity we have observed for the formation of the enol
silane during the ruthenium-catalyzed cycloisomerization. In the
case of enynoates 9a and 13, double-bond geometry isomers, a
10-fold increase of selectivity was observed for the formation
of the major enol silane 34 (from 2.4 to 25:1 going from the E-
to the Z-isomer). Starting from enyne 9a (E-isomer), the
9
J. AM. CHEM. SOC. VOL. 126, NO. 47, 2004 15597

A R T I C L E S
Trost et al.
Figure 3. Comparison of Cp-ruthenium(4+) metallacycle intermediate conformers.
Figure 4. Comparison of Cp- and Cp*-ruthenium(4+) metallacycle intermediate conformers.
Scheme 2. Transformations of the Cycloisomerization Products
Figure 5. Comparison of intermediate conformers leading to 59.
of the C-H abstraction observed in the cycloisomerization of
1,6- and 1,7-enynes to favor formation of the 1,3- rather than
1,4-dienes.36,39 The current results indicate that the Ru-catalyzed
process complements that of Pd and provides access to the
synthetically very useful enol silyl ethers. As carbonyl sur-
rogates, they can be easily hydrolyzed to unmask aldehydes. In
addition to those examples wherein the further transformations
were employed to facilitate characterization of the products (eq
12, 13, 18, and 24), hydrolysis followed by reduction of the
enol silyl ethers 52, 53, and 54 (eq 25 and 26) provided single
alcohols 65 and 66sa fact that confirms the presence of mixtures
derives from double bond rather than ring geometry. Scheme 2
illustrates a range of structural entities now readily available
via this cycloisomerization process.
The observation that prolonged reaction times in the sodium
borohydride reduction led to the bicyclic product 68 suggested
that the basic medium might be responsible for the conjugate
addition of the free alcohol. Support for this contention arises
from the smooth cyclizations to the [6.5]- and [5.5]bicycles 70
and 71 (eq 27 and 28).
9
15598 J. AM. CHEM. SOC. VOL. 126, NO. 47, 2004

Ruthenium-Catalyzed Enyne Cycloisomerizations
A R T I C L E S
Table 3.
Table 4.
substrates (mg, mmol)
catalysts (mg, mmol)
products (mg, mmol)
substrates (mg, mmol)
catalysts (mg, mmol)
products (mg, mmol)
8a; 118, 0.3
8a; 118, 0.3
9a; 135, 0.3
9a; 135, 0.3
10; 93; 0.2
1; 13, 0.03
2; 14, 0.03
1; 13, 0.03
2; 14, 0.03
1; 9, 0.02
33; 105, 0.266
33; 115, 0.292
34; 105, 0.232
34; 128, 0.283
35; 91, 0.195
8b, 96, 0.235
9b; 54, 0.116
9b; 136, 0.3
1; 10, 0.0235
2; 5, 0.0115
1; 14, 0.03
36; 95, 0.233
37; 0.051, 0.109
37; 120a
a Contaminated with starting material (∼20%).
C20H31NO3SSi: C, 61.03; H, 7.94; N, 3.55; S, 8.14. Found: C, 61.20;
H, 7.97; N, 3.52; S, 8.12.
Particularly intriguing is the ability in some cases to control
the geometry of the resultant enol silyl ether. Since the geometry
of the enol silyl ether can have subsequent consequences, such
as transforming into alkene geometry after subsequent cross-
coupling or into diastereomers after aldol additions or cyclo-
additions, this approach to enol silyl ethers has special merit.
The ability to tune the geometry by modifying the steric
demands of the catalyst is particularly noteworthy for the Ru
catalyst. The diastereoselectivity of the reaction, which is
exceptional, also derives from the steric demands of the catalyst
and the ability to tune it. Thus, this reaction represents an
attractive strategy for the diastereoselective formation of carbo-
and heterocycles from available acyclic precursors.
N-(4-Methylbenzenesulfonyl)-3-[(E) and (Z)-2-(tert-butyldimeth-
ylsilyloxy)vinyl]-4-methoxycarbonylmethylenepyrrolidine (34) was
isolated by flash chromatography, eluting with 2:1 petroleum ether-
diethyl ether, as a nonseparable 2.5:1 mixture of diastereomers as a
colorless oil. IR (film): 2953, 1716, 1662, 1351, 1164 cm-1. 1H NMR
(500 MHz, CDCl3): major diastereomer, δ 7.74 (d, J ) 8.3 Hz, 2H),
7.34 (d, J ) 8.3 Hz, 2H), 6.35 (d, J ) 11.7 Hz, 1H), 5.67 (m, 1H),
4.61 (dd, J ) 9.2, 11.7 Hz, 1H), 4.54 (dd, J ) 2.5, 18.3 Hz, 1H), 4.01
(dt, J ) 2.5, 18.3 Hz, 1H), 3.71-3.69 (m, 1H), 3.70 (s overlapped,
3H), 3.32 (br q, Japp ) 8 Hz, 1H), 2.59 (dd, J ) 9.2, 10.3 Hz, 1H),
2.45 (s, 3H), 0.92 (s, 9H), 0.15 (s, 6H); minor diastereomer, δ 7.74 (d,
J ) 8.3 Hz, 2H), 7.34 (d, J ) 8.3 Hz, 2H), 6.39 (d, J ) 5.8 Hz, 1H),
5,67 (m, 1H), 4.61 (dd, J ) 5.8, 8.5 Hz, 1H), 4.54 (dd, J ) 2.5, 18.3
Hz, 1H), 4.01 (dt, J ) 2.5, 18.3 Hz, 1H), 3.94 (app q, J ) 8.5 Hz,
1H), 3.73 (dd, J ) 8.3, 9.0 Hz, 1H), 3.69 (s, 3H), 2.63 (dd, J ) 9.5,
Experimental Section
10.2 Hz, 1H), 2.44 (s, 3H), 0.89 (s, 9H), 0.14 (s, 3H), 0.13 (s, 3H). 13
C
1,1-Bis(methoxycarbonyl)-3-[(E)-2-(tert-butyldimethylsilyloxy)-
vinyl]-4-methylenecyclopentane (32). To an argon-flushed test tube
containing Cp(CH3CN)3PF6 (1) (0.021 g, 0.05 mmol) was added via a
syringe a solution of enyne 6 (0.177 g, 0.5 mmol) in acetone (5 mL).
The reaction was then stirred at room temperature during 20 min. After
concentration in vacuo, the residue was directly chromatographed over
silica gel, eluting with 6:1 petroleum ether-diethyl ether, to afford 32
(0.165 g, 0.466 mmol) as a nonseparable 13:1 mixture of diastereomers
NMR (125 MHz, CDCl3): major diastereomer, δ 166.2, 161.7, 144.8,
143.8, 132.0, 129.7 (2), 127.2 (2), 113.7, 106.7, 52.8, 52.4, 51.4, 44.2,
25.3 (3), 21.5, 18.3, -5.2, -5.3; minor diastereomer, δ 166.1, 161.7,
143.7, 142.6, 132.2, 129.7 (2), 127.2 (2), 112.7, 105.4, 52.4, 52.0, 51.3,
40.1, 25.3 (3), 21.5, 18.3, -5.4. Anal. Calcd for C22H33NO5SSi (mixture
of diastereomers): C, 58.50; H, 7.36; N, 3.10; S, 7.09. Found: C, 58.60;
H, 7.41; N, 3.13; S, 6.89.
N-(4-Methylbenzenesulfonyl)-3-[(E)-2-(tert-butyldimethylsilyl-
oxy)vinyl]-4-(trimethylsilylmethylene)pyrrolidine (35) was isolated
by flash chromatography, eluting with 4:1 petroleum ether-ether, as a
32:1 mixture of diastereomers as a white solid. Mp: 83-84 °C. IR
1
as a colorless oil. IR (film): 2955, 1737, 1661, 1259, 1167 cm-1. H
NMR (500 MHz, CDCl3): δ 6.32 (d, J ) 5.8 Hz, 0.07H), 6.28 (d, J )
12 Hz, 0.93H), 4.95 (d, J ) 2.2 Hz, 0.93H), 4.90 (m, 0.07H), 4.84 (d,
J ) 2.2 Hz, 1H), 4.81 (dd, J ) 9.2, 12 Hz, 0.93H), 4.37 (dd, J ) 5.8,
8.7 Hz, 0.07H), 3.75 (s, 3H), 3.73 (s, 3H), 3.14 (m, 0.07H), 3.08 (d, J
) 17.1 Hz, 0.93H), 3.04 (m, 1H), 2.98 (dd, J ) 2.4, 17.1 Hz, 1H),
2.58 (dd, J ) 7.6, 12.8 Hz, 0.07H), 2.52 (dd, J ) 7.6, 13.0 Hz, 0.93H),
1.92 (dd, J ) 11.4, 12.9 Hz, 1H), 0.93 (s, 9H), 0.15 (s, 6H). 13C NMR
(125 MHz, CDCl3): major diastereomer, δ 172.3, 172.0, 151.5, 142.0,
112.1, 107.6, 58.2, 52.8, 52.7, 42.3, 41.5, 40.0, 25.8 (3), 18.3, -5,2,
-5.3. Anal. Calcd for C18H30O5Si: C, 60.98; H, 8.52. Found: C, 61.02;
H, 8.48.
(film): 2955, 1661, 1635, 1351, 1164 cm-1 1H NMR (500 MHz,
.
CDCl3): δ 7.70 (d, J ) 8.3 Hz, 2H), 7.34 (d, J ) 8.3 Hz, 2H), 6.25 (d,
J ) 12 Hz, 1H), 5.35 (d, J ) 2.4 Hz, 1H), 4.58 (dd, J ) 9.5, 12 Hz,
1H), 4.04 (dd, J ) 2.4, 14.0 Hz, 1H), 3.62 (m, 2H), 3.10 (dd, J ) 8.6,
9.5 Hz, 1H), 2.59 (t, J ) 9.5 Hz, 1H), 2.44 (s, 3H), 0.91 (s, 9H), 0.13
(s, 6H), 0.03 (s, 9H). 13C NMR (75 MHz, CDCl3): δ 155.3, 143.8,
143.6, 132.5, 129.6 (2), 127.7 (2), 121.6, 108.8, 53.2, 51.3, 45.1, 25.6
(3), 21.5, 18.3, -0.7 (3), -5.3 (2). Anal. Calcd for C23H39NO3SSi2: C,
59.30; H, 8.44; N, 3.00; S, 6.88. Found: C, 59.20; H, 8.224; N, 2.94;
S, 6.48.
Procedure for the Conversion of Alkynes 8b and 9b. To an argon-
flushed test tube containing the catalyst (see Table 4) was added via a
syringe a solution of substrate (see Table 4) in acetone (0.1 M). The
reaction was then stirred at room temperature for 20 min. After
concentration in vacuo, the residue was directly chromatographed over
silica gel (see below for eluting system) to afford the corresponding
product (see Table 4; see below for physical properties).
Procedure for the Conversion of Alkynes 8a, 9a, and 10. To an
argon-flushed test tube containing the Ru(I) catalyst (see Table 3) was
added via a syringe a solution of enyne (see Table 3) in acetone (0.1
M, 2 or 3 mL). The reaction was then stirred at room temperature for
20 min. After concentration in vacuo, the residue was directly
chromatographed over silica gel.
N-(4-Methylbenzenesulfonyl)-3-[(E)-2-(tert-butyldimethylsilyl-
oxy)vinyl]-4-methylenepyrrolidine (33) was isolated by flash chro-
matography, eluting with 2:1 petroleum ether-diethyl ether, as a >32:1
mixture of diastereomers as a colorless solid. Mp: 84-86 °C. IR
(neat): 2929, 1661, 1348, 1162 cm-1. 1H NMR (500 MHz, CDCl3): δ
7.72 (d, J ) 8.3 Hz, 2H), 7.34 (d, J ) 8.3 Hz, 2H), 6.30 (d, J ) 11.9
Hz, 1H), 4.94 (s, 1H), 4.88 (s, 1H), 4.64 (dd, J ) 9.3, 9.5 Hz, 1H),
4.05 (br d, J ) 14.1 Hz, 1H), 3.65 (m, 2H), 3.14 (m, 1H), 2.67 (t, J )
9.8 Hz, 1H), 2.45 (s, 3H), 0.91 (s, 9H), 0.14 (s, 6H). 13C NMR (125
MHz, CDCl3): δ 147.8, 143.6, 143.5, 132.6, 129.6 (2), 127.7 (2), 108.2,
107.7, 54.0, 51.7, 42.4, 25.5 (3), 21.5, 18.2, -5.3 (2). Anal. Calcd for
N-(4-Methylbenzenesulfonyl)-3-[(E)-2-(tert-butyldimethylsilyl-
oxy)vinyl]-4-methylenepiperidine (36) was isolated by flash chroma-
tography, eluting with 4:1 petroleum ether-diethyl ether, as a non-
separable 4:1 mixture of diastereomers as a colorless oil. IR (neat):
1
2955, 2930, 1662, 1162 cm-1. H NMR (500 MHz, CDCl3): major
diastereomer, δ 7.63 (d, J ) 8.3 Hz, 2H), 7.32 (d, J ) 8.3 Hz, 2H),
6.36 (d, J ) 11.9 Hz, 1H), 4.89 (dd, J ) 9.2, 11.9 Hz, 1H), 4.74 (s,
2H), 3.60 (m, 1H), 3.53 (ddd, J ) 1.7, 4.9, 11.2 Hz, 1H), 2.88 (m,
1H), 2.46 (m, 1H), 2.43 (s, 3H), 2.41-2.34 (m, 2H), 2.25 (t, J ) 10.8
Hz, 1H), 0.93 (s, 9H), 0.16 (s, 6H); minor diastereomer, δ 7.63 (d, J
) 8.3 Hz, 2H), 7.32 (d, J ) 8.3 Hz, 2H), 6.31 (d, J ) 5.8 Hz, 1H),
4.74 (s, 1H), 4.70 (s, 1H), 4.45 (dd, J ) 5.9, 9.1 Hz, 1H), 3.43 (m,
(39) In a recent report, monopropargyl ethers of 2-butene-1,4-diol have been
reported to cycloisomerize to the 1,4-dienes with Pd catalysis, see:
Kressierer, C. J.; Mu¨ller, T. J. J. Tetrahedron Lett. 2004, 45, 2155-2158.
9
J. AM. CHEM. SOC. VOL. 126, NO. 47, 2004 15599

A R T I C L E S
Table 5.
Trost et al.
Table 6.
substrates (mg, mmol)
alcohols (mg, mmol)
substrates (mg, mmol)
products (mg, mmol)
36; 155, 0.380
37; 101, 0.216
39; 94, 0.319
40; 55, 0.155
25; 72, 0.3
26; 90, 0.3
41; 58, 0.241
42; 75, 0.251
2H), 2.68 (td, J ) 3.6, 10.5 Hz, 1H), others signals are overlapped
with those from E-isomers. 13C NMR (125 MHz, CDCl3): major
diastereomer, δ 146.7, 143.4, 142.8, 133.1, 129.5 (2), 127.5 (2), 109.6,
108.6, 52.7, 47.4, 40.9, 33.6, 25.6 (3), 21.4, 18.2, -5.2, -5.3 (1); minor
diastereomer, δ 145.6, 143.2, 140.4, 133.1, 1129.5 (2), 127.5 (2), 108.8,
107.2, 51.9, 47.4, 37.3, 33.3, 25.5 (3), 18.1, -5.3, -5.4. Anal. Calcd
for C21H33NO3SSi (mixture of diastereomers): C, 61.87; H, 8.15; N,
3.43; S, 7.86. Found: C, 62.03; H, 8.16; N, 3.43; S, 7.69.
(ddd, J ) 4.5, 4., 13.6 Hz, 1H), 2.10 (s, 1H), 1.91 (tq, J ) 6.1, 7.6 Hz,
1H), 1.75 (tq, J ) 7.0, 13.6 Hz, 1H). 13C NMR (125 MHz, CDCl3): δ
145.9, 143.4, 133.0, 129.5 (2), 127.4 (2), 109.7, 60.2, 51.6, 47.7, 38.9,
32.8, 31.8, 21.3. Anal. Calcd for C15H21NO3S: C, 60.99; H, 7.16; N,
4.74; S, 10.85. Found: C, 61.17; H, 7.32; N, 4.71; S, 10.66.
N-(4-Methylbenzenesulfonyl)-3-(2-hydroxyethyl)-4-methoxycar-
bonylmethylenepiperidine (40) was recovered as an oil. IR (neat):
3534, 2951, 1715, 1652, 1597, 1163 cm-1 1H NMR (500 MHz,
.
N-(4-Methylbenzenesulfonyl)-3-[(E) and (Z)-2-(tert-butyldimeth-
ylsilyloxy)vinyl]-4-methoxycarbonylmethylenepiperidine (37) was
isolated as a colorless oil by flash chromatography, eluting with 4:1
petroleum ether-diethyl ether. IR (neat): 2953, 1716, 1655, 1353, 1253,
1165 cm-1. First diastereomers1H NMR (500 MHz, CDCl3): δ 7.64
(d, J ) 8.3 Hz, 2H), 7.32 (d, J ) 8.3 Hz, 2H), 6.35 (d, J ) 5.6 Hz,
1H), 5.74 (s, 1H), 4.48 (t, J ) 5.8, 8.5 Hz, 1H), 3.77 (br s, 1H), 3.65
(s, 3H), 3.58 (m, 1H), 3.42 (m, 1H), 3.32 (m, 1H), 2.91 (m, 1H), 2.79
(m, 1H), 2.71 (m, 1H), 2.44 (s, 3H), 0.91 (s, 9H), 0.16 (s, 3H), 0.11 (s,
3H). 13C NMR (125 MHz, CDCl3): δ 167.0, 158.1, 141.4, 133.1, 129.4
(2), 127.7 (2), 114.3, 105.8, 78.6, 51.7, 51.0, 46.8, 39.3, 27.3, 25.6,
25.5 (3), 18.1, -5.1 (2). Second diastereomers1H NMR (500 MHz,
CDCl3): δ 7.64 (d, J ) 8.3 Hz, 2H), 7.32 (d, J ) 8.3 Hz, 2H), 6.36 (d,
J ) 11.9 Hz, 1H), 5.71 (s, 1H), 4.86 (dd, J ) 9.3, 12.0 Hz, 1H), 3.64
(s, 3H), 3.63 (m, 1H), 3.55 (m, 1H), 2.98 (td, J ) 4.9, 9.1 Hz, 1H),
2.58 (m, 2H), 2.39 (dd, J ) 3.4, 11.5 Hz, 1H), 2.25 (dd, J ) 2.9, 11.5
Hz, 1H), 2.43 (s, 3H), 0.93 (s, 9H), 0.16 (s, 6H). 13C NMR (125 MHz,
CDCl3): δ 166.7, 158.8, 143.8, 143.1, 132.7, 129.6 (2), 127.5 (2), 114.9,
109.7, 52.4, 51.0, 47.3, 42.7, 34.8, 27.7, 25.5 (3), 21.4, 18.2, -5.4 (2).
Third diastereomers1H NMR (500 MHz, CDCl3): δ 7.64 (d, J ) 8.3
Hz, 2H), 7.32 (d, J ) 8.3 Hz, 2H), 6.60 (d, J ) 12.0 Hz, 1H), 5.55 (s,
1H), 5.32 (dd, J ) 8.1, 12.0 Hz, 1H), 4.61 (d, J ) 8.1 Hz, 1H), 3.93
(m, 1H), 3.65 (s, 3H), 3.55 (m, 1H), 3.32 (m, 1H), 2.86 (m, 1H), 2.81
(m, H), 2.43 (s, 3H), 2.09 (br d, J ) 14 Hz, 1H), 0.90 (s, 9H), 0.15 (s,
3H), 0.12 (s, 3H). 13C NMR (125 MHz, CDCl3): δ 166.1, 158.7, 143.6,
143.5, 132.7, 129.6 (2), 127.5 (2), 114.3, 107.1, 51.4, 51.0, 46.6, 32.3,
27.2, 25.6 (3), 21.4, 18.3, -5.2 (2). Anal. Calcd for C23H35NO5-
SSi: C, 59.32; H, 7.57; N, 3.00; S, 6.88. Found: C, 59.09; H, 7.65; N,
3.12; S, 6.96.
Experimental Procedure for Preparation of Alcohols 39 and 40.
To a solution of silyl enol ether (see Table 5) in CH2Cl2 (5 mL) were
added water (0.1 mL) and trifluoroacetic acid (2 mL). The solution
was stirred at room temperature for 15 min, and the volatiles were
removed in vacuo. The residue was chromatographed, eluting with 3:1
diethyl ether-petroleum ether, to afford respectively the corresponding
aldehyde (62 mg, 0.176 mmol, or 107 mg, 0.366 mmol). Each aldehyde
was taken up in MeOH (5 mL) and treated with sodium borohydride
(0.05 g, 1.35 mmol). The reaction was stirred at room temperature until
completion (between 15 and 20 min). Water (5 mL) was added, and
the volatiles were removed under reduced pressure. The residue was
partitioned between water (5 mL) and CH2Cl2 (10 mL). The aqueous
phase was extracted with CH2Cl2 (3 × 10 mL). The combined organic
layers were dried over MgSO4. After concentration in vacuo, the residue
was chromatographed, eluting with diethyl ether, to afford alcohol 39
or 40 (see Table 5).
CDCl3): δ 7.61 (d, J ) 8.1 Hz, 2H), 7.31 (d, J ) 8.1 Hz, 2H), 5.71 (s,
1H), 3.73 (dd, J ) 5.9, 10.9 Hz, 1H), 3.64 (s, 3H), 3.65-3.59 (m,
2H), 3.50 (dd, J ) 3.7, 11.5 Hz, 1H), 2.69 (m partially overlapped,
1H), 2.59 (m, 1H), 2.51 (dd, J ) 3.4, 11.0 Hz, 1H), 2.41 (s, 3H), 2.03
(br s, 1H), 1.90 (q, J ) 6.6 Hz, 2H). 13C NMR (125 MHz, CDCl3): δ
166.4, 158.3, 143.6, 132.7, 129.6, 127.4, 115.4, 59.7, 50.09, 50.06,
47.0, 40.8, 33.2, 25.8, 21.4. Anal. Calcd for C9H13NO4: C, 57.77; H,
6.56; N, 3.96. Found: C, 57.65; H, 6.37; N, 3.81.
[5-(4-Methylbenzenesulfonyl)hexahydrofuro[3,2-c]pyridin-7a-yl]-
acetic Acid Methyl Ester (70). To a solution of alcohol 40 (0.055 g,
0.155 mmol) in MeOH (3 mL) was added potassium carbonate (0.022
g, 0.155 mmol). The reaction mixture was stirred at room temperature
for 3 h. The volatiles were removed under reduced pressure, and the
residue was partitioned between 1 N NaHSO4 (3 mL) and CH2Cl2 (4
× 5 mL). The combined organic layers were dried over MgSO4. After
concentration in vacuo, the residue was purified by chromatography,
eluting with 1:4 petroleum ether-diethyl ether, to afford 70 (0.051 g,
0.144 mmol) as a colorless oil. IR (neat): 2952, 1734, 1598, 1338,
1167 cm-1. 1H NMR (500 MHz, CDCl3): δ 7.64 (d, J ) 8.0 Hz, 2H),
7.34 (d, J ) 8.0 Hz, 2H), 3.87 (m, 2H), 3.68 (s, 3H), 3.30 (dd, J )
6.6, 11.9 Hz, 1H), 3.20 (td, J ) 5.7, 11.9 Hz, 1H), 2.81 (ddd, J ) 3.9,
9.7, 13.4 Hz, 1H), 2.55 (dd, J ) 8.3, 11.9 Hz, 1H), 2.45 (s, 3H), 2.48-
2.44 (m, 2H), 2.38 (m, 1H), 2.18 (m, 1H), 2.06 (ddd, J ) 3.9, 5.1,
14.4 Hz, 1H), 2.00 (ddd, J ) 4.6, 10.0, 14.4 Hz, 1H), 1.78 (m, 1H).
13C NMR (125 MHz, CDCl3): δ 170.4, 143.5, 133.1, 129.7 (2), 127.5
(2), 79.2, 64.9, 51.7, 46.3, 42.4 (2), 40.5, 31.5, 28.4, 21.5. Anal. Calcd
for C17H23NO5S: C, 57.77; H, 6.56; N, 3.96. Found: C, 57.61; H, 6.72;
N, 3.91.
Procedure for the Conversion of Alkynes 25 and 26. To an argon-
flushed test tube containing 1 (13 mg, 0.03 mmol) was added via a
syringe a solution of substrate (see Table 6) in acetone (3 mL). The
reaction was then stirred at room temperature for 20 min. After
concentration in vacuo, the residue was directly purified (see below
for conditions) to afford the corresponding product (see Table 6).
2-[(E)-2-(tert-Butyldimethylsilyloxy)vinyl]-3-methylenetetrahy-
drofuran (41) was isolated by flash chromatography, eluting with 19:1
petroleum ether-ether, as a 19:1 mixture of diastereomers as a colorless
1
oil. IR (neat): 2930, 1661, 1167 cm-1. H NMR (500 MHz, CDCl3):
major diastereomer, δ 6.32 (d, J ) 11.9 Hz, 1H), 4.95 (app q, J ) 2.5
Hz, 1H), 4.90 (app q, J ) 2.5 Hz, 1H), 4.78 (dd, J ) 9.2, 11.9 Hz,
1H), 4.43 (br d, J ) 13.4 Hz, 1H), 4.27 (dq, J ) 2.2, 13.4 Hz, 1H),
4.04 (app t, J ) 8.3 Hz, 1H), 3.15 (br q, J ) 8.3 Hz, 1H), 0.92 (s, 9H),
0.15 (s, 6H). 13C NMR (125 MHz, CDCl3): δ 151.8, 142.8, 109.0,
104.6, 74.1, 71.3, 43.5, 25.6 (3), 18.3, -5.2 (2). Anal. Calcd for
C13H24O2Si: C, 64.94; H, 10.06. Found: C, 65.14; H, 10.17.
N-(4-Methylbenzenesulfonyl)-3-(2-hydroxyethyl)-4-methylenepi-
peridine (39) was recovered as an oil. IR (neat): 3351, 3070, 2943,
2-[(E)-2-(tert-Butyldimethylsilyloxy)vinyl]-3-ethoxycarbonylmeth-
ylenetetrahydrofuran (42) was isolated as a colorless oil by flash
chromatography, eluting with 9:1 petroleum ether-ether. IR (neat):
1
1651, 1597 cm-1. H NMR (500 MHz, CDCl3): δ 7.61 (d, J ) 8.3
1
Hz, 2H), 7.31 (d, J ) 8.3 Hz, 2H), 4.73 (s, 2H), 3.71 (td, J ) 6.1, 10.7
Hz, 1H), 3.65 (td, J ) 6.6, 10.7 Hz, 1H), 3.34 (td, J ) 5.4, 11.0 Hz,
1H), 3.15 (dd, J ) 4.4, 11.2 Hz, 1H), 2.84 (dd, J ) 3.9, 11.2 Hz, 1H),
2.71 (td, J ) 3.9, 10.1 Hz, 1H), 2.54-2.42 (m, 2H), 2.41 (s, 3H), 2.20
2954, 1716, 1663, 1350, 1168 cm-1. H NMR (500 MHz, CDCl3): δ
6.38 (d, J ) 11.9 Hz, 1H), 5.74 (app q, J ) 2.4 Hz, 1H), 4.93 (dd, J
) 2.4, 17.5 Hz, 1H), 4.76 (dd, J ) 9.2, 11.9 Hz, 1H), 4.66 (td, J )
2.4, 17.5 Hz, 1H), 4.09 (t, J ) 7.8 Hz, 1H), 3.72 (s, 3H), 3.37 (dd, J
9
15600 J. AM. CHEM. SOC. VOL. 126, NO. 47, 2004

Ruthenium-Catalyzed Enyne Cycloisomerizations
A R T I C L E S
) 8.5, 10.1 Hz, 1H), 3.30 (m, 1H), 0.94 (s, 9H), 0.17 (s, 6H). 13C
NMR (125 MHz, CDCl3): δ 166.68, 166.65, 144.1, 111.5, 107.0, 72.6,
72.0, 51.2, 45.2, 25.5 (3), 18.2, -5.23, -5.25. Anal. Calcd for C21H33-
NO3SSi: C, 60.36; H, 8.78. Found: C, 60.18; H, 8.60.
Table 7.
substrate (mg, mmol)
catalysts (mg, mmol)
products (mg, mmol)
19a, 81, 0.2
19a; 81, 0.2
1; 9, 0.02
2; 9, 0.02
50; 76, 0.186
50; 61, 0.149
1-[(E)-2-(tert-Butyldimethylsilyloxy)vinyl]-5,5-dimethyl-2-meth-
ylenecyclopentane (43) was obtained from alkyne 30a (0.08 g, 0.3
mmol) and catalyst 1 (0.013 g, 0.03 mmol) in acetone (3 mL) and was
isolated as a colorless oil by flash chromatography, eluting with 19:1
Table 8.
catalyst (mg, mmol)
substrate 51 (mg, mmol)
product (mg, mmol)
petroleum ether-diethyl ether. IR (neat): 2955, 1657, 1256, 1164 cm-1
.
1; 8, 0.0184
2; 9, 0.02
81, 0.2
85, 0.2
52 48, 0.103
53 81, 0.174
1H NMR (500 MHz, CDCl3): δ 6.21 (d, J ) 11.9 Hz, 1H), 4.88 (s,
1H), 4.81 (s, 1H), 4.78 (dd partially overlapped, J ) 10.5, 11.9 Hz,
1H), 2.39 (m, 3H), 1.62-1.44 (m, 2H), 0.99 (s, 3H), 0.96 (s, 9H), 0.72
(s, 3H), 0.18 (s, 3H). 13C NMR (125 MHz, CDCl3): δ 156.0, 142.3,
109.8, 106.3, 54.9, 41.8, 39.3, 29.3, 27.3, 25.7 (3), 21.3, 18.4, -5.1,
-5.2. Anal. Calcd for C16H30OSi: C, 72.11; H, 11.34. Found: C, 72.09;
H, 11.13.
CDCl3): δ 5.80 (ttd, J ) 1.4, 5.6, 11.2 Hz, 1H), 5.60 (ttd, J ) 1.4, 6.8,
11.2 Hz), 4.80 (d, J ) 6.8 Hz, 2H), 4.30 (d, J ) 5.6 Hz, 2H), 2.91 (s,
1H), 0.91 (s, 9H), 0.09 (s, 6H). 13C NMR (125 MHz, CDCl3): δ 152.44,
135.0, 122.7, 74.8, 74.4, 62.0, 59.5, 25.8 (3), 18.2, -5.3 (2). HRMS:
calcd for C13H22O3Si, [M+], 254.1195; found, 254.1211.
1-[2-Hydroxyethyl]-5,5-dimethyl-2-methoxycarbonylmeth-
ylenecyclopentane (44). To an argon-flushed test tube containing 1
(0.013 g, 0.03 mmol) was added via a syringe a solution of alkynoate
31 (0.097 g, 0.3 mmol) in acetone (3 mL). The reaction was then stirred
at room temperature for 20 min. After concentration in vacuo, the
residue was filtered over silica gel, eluting with 1:1 petroleum ether-
diethyl ether. After evaporation to dryness, the crude material was
diluted with CH2Cl2 (5 mL). Trifluoroacetic acid (5 mL) and water (1
mL) were added, and the reaction was stirred for 15 min. After
concentration in vacuo, the residue was chromatographed, eluting with
4:1 petroleum ether-diethyl ether, to afford the intermediate aldehyde.
The latter substance was dissolved in MeOH (5 mL), and sodium
borohydride (0.02 g, 0.5 mmol) was added. The reaction was stirred
for 5 min. Water (5 mL) was added, and the volatiles were removed
under reduced pressure. The residue was partitioned between water (5
mL) and Et2O (10 mL). The aqueous layer was extracted with Et2O (4
× 10 mL). The combined ethereal extracts were dried over MgSO4
and concentrated in vacuo. The residue was purified by chromatography,
eluting with 1:1 petroleum ether-diethyl ether, to afford alcohol 44
(0.052 g, 0.245 mmol) as an oil. IR (neat): 3426, 2953, 1715, 1651,
1198 cm-1. 1H NMR (300 MHz, CDCl3): δ 5.73 (q, J ) 2.4 Hz, 1H),
3.78 (ddd, J ) 6.0, 8.4, 10.9 Hz, 1H), 3.68 (s, 3H), 2.81 (m, 2H), 2.16
(m, 2H), 1.80-1.48 (m, 5H), 1.02 (s, 3H). 13C NMR (75 MHz,
CDCl3): δ 172.3, 167.2, 111.5, 61.7, 53.1, 50.8, 40.9, 38.4, 30.9, 29.9,
27.5, 21.4. Anal. Calcd for C12H20O3: C, 67.89; H, 9.49. Found: C,
68.05; H, 9.60.
4-[(E)-2-(tert-Butyldimethylsilyloxy)vinyl]-3-methylenedihydro-
furan-2-one (46). The typical procedure was carried out with alkyne
45 (76 mg, 0.3 mmol). After chromatography, eluting with 20:1
petroleum ether-diethyl ether, remaining 45 (25 mg, 0.0983 mmol)
and then lactone 46 (0.042 g, 0.165 mmol) were recovered as colorless
1
oils. IR (neat): 2930, 1769, 1662, 1254, 1172, 838 cm-1. H NMR
(500 MHz, CDCl3): δ 6.44 (d, J ) 12.0 Hz, 1H), 6.30 (d, J ) 3.0 Hz,
1H), 5.62 (d, J ) 3.0 Hz, 1H), 4.86 (dd, J ) 12.0, 9.3 Hz, 1H), 4.50
(t, J ) 9.0 Hz, 1H), 3.90 (t, J ) 8.7 Hz, 1H), 3.58 (ddt, J ) 3.0, 8.7,
9.0 Hz, 1H), 0.95 (s, 9H), 0.19 (s, 3H), 0.18 (s, 3H). 13C NMR (125
MHz, CDCl3): δ 170.3, 144.4, 138.4, 122.8, 107.8, 71.0, 39.2, 25.5
(3), 18.3, -5.3, -5.32. HRMS: calcd for C9H13O3Si, [M+ - C4H9],
197.0637; measd, 197.0633.
cis-1-Hydroxy-2-[(E)-2-(tert-butyldimethylsilyloxy)vinyl]-3-meth-
ylene-5,5-dimethylcyclopentane (49) was isolated as an oil. IR
(neat): 3483, 3072, 2957, 2931, 2859, 1655, 1471, 1256, 1169, 1073
1
cm-1. H NMR (500 MHz, C6D6): δ 6.35 (dd, J ) 12.1, 0.5 Hz, 1H),
5.23 (dd, J ) 12.1, 9.4 Hz, 1H), 5.09 (s, 1H), 5.06 (s, 1H), 3.35 (t, J
) 4.5 Hz, 1H), 3.18 (m, 1H), 2.43 (dd, J ) 16.2, 6.5 Hz, 1H), 2.03
(dd, J ) 16.2, 0.7 Hz, 1H), 1.16 (d, J ) 4.5 Hz, 1H), 1.01 (s, 3H),
0.93 (s, 9H), 0.83 (s, 3H), 0.08 (s, 6H). 13C NMR (125 MHz, C6D6):
δ 154.4, 143.9, 110.2, 109.0, 83.5, 48.5, 44.9, 27.3, 26.2, 23.1, 18.8,
-4.7, -4.8. HRMS: calcd for C16H30O2Si, [M+], 282.2015; found,
282.2013.
(2S,3R)-N-(4-Methylbenzenesulfonyl)-2-methyl-3-[(E)-2-(tert-
butyldimethylsilyloxy)vinyl]-4-methylenepyrrolidine (50). To an
argon-flushed test tube containing the catalyst (see Table 7) was added
via a syringe a solution of substrate (see Table 7) in acetone (2 mL).
The reaction was then stirred at room temperature for 20 min. After
concentration in vacuo, the residue was directly chromatographed over
silica gel, eluting with 9:1 petroleum ether-diethyl ether, to afford 50
(see Table 7) as a colorless oil. [R]D ) -28.7 (c 2.48, CHCl3). IR
(neat): 2930, 1661, 1463, 1349 cm-1. 1H NMR (500 MHz, CDCl3): δ
7.70 (d, J ) 8.3 Hz, 2H), 7.33 (d, J ) 8.3 Hz, 2H), 6.26 (d, J ) 111.9
Hz, 1H), 4.88 (q, J ) 2.2 Hz, 1H), 4.82 (q, J ) 2.2 Hz, 1H), 4.46 (dd,
J ) 9.5, 11.9 Hz, 1H), 4.17 (d, J ) 14.4 Hz, 1H), 3.80 (qd, J ) 2,
14.4 Hz, 1H), 2.90 (qd, J ) 6.3, 8.5 Hz, 1H), 2.70 (br t, J ) 9.5 Hz,
1H), 2.45 (s, 3H), 1.43 (d, J ) 6.3 Hz, 3H), 0.92 (s, 9H), 0.14 (s, 6H).
13C NMR (125 MHz, CDCl3): δ 146.2, 143.7, 143.4, 133.4, 129.6 (2),
127.7 (2), 108.6, 107.2, 61.9, 53.1, 51.4, 25.6 (3), 21.5, 19.8, 18.3,
-5.3 (2). Anal. Calcd for C21H33NO3SSi: C, 61.87; H, 8.15; S, 7.86;
N, 3.43. Found: C, 61.67; H, 7.94; S, 7.41; N, 3.38.
(4,4-Dimethylhexahydrocyclopenta[b]furan-6a-yl)acetic Acid Meth-
yl Ester (71). To a solution of alcohol 44 (0.05 g, 0.234 mmol) in
MeOH (2 mL) was added potassium carbonate (0.05 g, 0.36 mmol).
The reaction mixture was heated at 40 °C for 2 h. After concentration
in vacuo, the residue was chromatographed, eluting with 1:1 petroleum
ether-diethyl ether, to afford first bicycle 71 (0.037 g, 0.174 mmol)
as an oil and then remaining alcohol 44 (0.011 g, 0.051 mmol). IR
1
(neat): 2953, 1738, 1436 cm-1. H NMR (500 MHz, CDCl3): δ 3.84
(ddd, J ) 5.4, 7.1, 8.6 Hz, 1H), 3.73 (ddd, J ) 7.1, 8.5, 14.1 Hz, 1H),
3.70 (s, 3H), 2.68 (d, J ) 13.9 Hz, 1H), 2.58 (d, J ) 13.9 Hz, 1H),
2.11 (dd, J ) 5.9, 8.6 Hz, 1H), 2.0-1.90 (m, 3H), 1.80 (ddd, J ) 5.8,
7.0, 12.9 Hz, 1H), 1.61 (ddd, J ) 8.3, 11.2, 12.2 Hz, 1H), 1.38 (m,
1H), 1.00 (s, 3H), 0.99 (s, 3H). 13C NMR (125 MHz, CDCl3): δ 171.5,
92.7, 68.5, 58.1, 51.5, 44.6, 40.6, 38.7, 36.5, 29.6, 29.3, 24.7. HRMS:
calcd for C12H20O3, [M+], 212.1412; found, 212.1400.
[(Z)-4-(tert-Butyldimethylsilyloxy)but-2-enyl] Propynoate (45). To
an ice-cooled solution of alcohol 11 (1.0 g, 4.94 mmol) in THF (25
mL) were added triphenylphosphine (2.6 g, 9.91 mmol), propiolic acid
(0.608 mL, 9.88 mmol), and diisopropyl azodicarboxylate (1.94 mL,
9.85 mmol). The reaction mixture was stirred at room temperature for
2 h. The volatiles were removed under vacuum. The residue was directly
purified by chromatography, eluting with 15:1 petroleum ether-diethyl
ether, to yield alkyne 45 (0.480 g, 1.88 mmol) as a colorless oil. IR
(neat): 3265, 2956, 2122, 11719, 1362, 1220 cm-1. 1H NMR (500 MHz,
(2S,3R)-N-(4-Methylbenzenesulfonyl)-2-methyl-3-[(E)-2-(tert-
butyldimethylsilyloxy)vinyl]-4-methoxycarbonylmethylenepyrro-
lidine (52). The typical procedure, described previously, was employed
using the amounts listed in Table 8. 52 and 53 were isolated as a
colorless oil by flash chromatography, eluting with 9:1 petroleum
ether-ether.
Data for 52. IR (neat): 2930, 1715, 1654, 1358, 1166 cm-1. 1H NMR
(500 MHz, CDCl3) ((E)-enol silane): δ 7.73 (d, J ) 8.3 Hz, 2H), 7.34
9
J. AM. CHEM. SOC. VOL. 126, NO. 47, 2004 15601

A R T I C L E S
Trost et al.
(d, J ) 8.3 Hz, 2H), 6.31 (d, J ) 11.8 Hz, 1H), 5.65 (app q, J ) 2.5
Hz, 1H), 4.61 (dd, J ) 2.5, 18.5 Hz, 1H), 4.46 (dd, J ) 9.2, 11.8 Hz,
1H), 4.18 (br d, J ) 18.5 Hz, 1H), 3.71 (s, 3H), 2.86 (tt, J ) 2.2, 9.2
Hz, 1H), 2.78 (qd, J ) 5.8, 9.2 Hz, 1H), 2.45 (9s, 3H), 1.48 (d, J )
5.8 Hz, 3H), 0.93 (s, 9H), 0.16 (s, 6H). 13C NMR (125 MHz, CDCl3)
((E)-enol silane): δ 166.2, 159.8, 145.1, 143.7, 132.4, 129.7 (2), 127.9
(2), 113.2, 107.0, 60.4, 53.6, 52.9, 51.3, 25.5 (3), 21.5, 19.0, 18.2,
-5.29, -5.33.
raphy, eluting with 1:9 petroleum ether-diethyl ether, to give the
1
intermediate aldehyde. IR (neat): 2924, 1722, 1450, 1162 cm-1. H
NMR (300 MHz, CDCl3): δ 9.68 (s, 1H), 7.62 (d, J ) 8.3 Hz, 2H),
7.26 (d, J ) 8.3 Hz, 2H), 4.87 (s, 1H), 4.83 (s, 1H), 4.06 (dq, J ) 6.6,
17.3 Hz, 1H), 3.77 (ddd, J ) 5.8, 12.2, 22.2 Hz, 1H), 2.94 (dd, J )
7.5, 17.3 Hz, 1H), 2.84 (td, J ) 3.4, 12.4 Hz, 1H), 2.66 (m, 1H), 2.56
(ddd, J ) 1, 5.5, 22.2 Hz, 1H), 2.39 (s, 3H), 2.39 (m overlapped, 1H),
2.12 (br d, J ) 13.9 Hz, 1H), 0.84 (d, J ) 6.9 Hz, 3H). 13C NMR (75
MHz, CDCl3): δ 201.8, 143.3, 141.2, 137.3, 129.7 (2), 126.7 (2), 113.8,
52.7, 445.6, 42.7, 40.2, 30.4, 21.4, 14.7.
Data for 53. IR (neat): 2930, 1715, 1654, 1358, 1166 cm-1. 1H NMR
(500 MHz, CDCl3): δ 7.73 (d, J ) 8.3 Hz, 2H), 7.33 (d, J ) 8.3 Hz,
2H), 6.40 (d, J ) 5.6 Hz, 1H), 5.63 (q, J ) 2.5 Hz, 1H), 4.62 (dd, J
) 1.9, 18.5 Hz, 1H), 4.19 (dt, J ) 2.5, 18.5 Hz, 1H), 4.03 (dd, J )
5.6, 8.7 Hz, 1H), 3.69 (s, 3H), 3.67 (br t partially overlapped, J ) 8.7
Hz, 1H), 2.86 (qd, J ) 6.1, 9.0 Hz, 1H), 2.43 (s, 3H), 1.46 (d, J ) 6.1
Hz, 3H), 0.90 (s, 3H), 0.13 (s, 6H). 13C NMR (125 MHz, CDCl3): δ
166.3, 159.9, 143.5, 142.8, 132.8, 129.6 (2), 127.8 (2), 112.3, 105.4,
60.7, 53.6, 51.2, 48.5, 25.4 (3), 21.5, 19.5, 18.0, -5.43, -5.48. Anal.
Calcd (as mixture) for C23H35NO5SSi: C, 59.32; H, 7.57; N, 3.00; S,
6.88. Found: C, 59.23; H, 7.47; N, 3.03; S, 6.71.
(2S,3R)-N-(4-Methylbenzenesulfonyl)-2-methyl-3-[2-hydroxyethyl]-
4-methoxycarbonylmethylenepyrrolidine (65) was obtained using the
procedure described for the obtention of derivative 40. Alcohol 65 was
then recovered in 74% yield as a colorless oil. [R]D ) +67.0 (c 2.75,
CHCl3). IR (neat): 3534, 2951, 1715, 1667, 1162 cm-1. 1H NMR (500
MHz, CDCl3): δ 7.76 (d, J ) 8.3 Hz, 2H), 7.32 (d, J ) 8.3 Hz, 2H),
5.82 (td, J ) 1.4, 2.7 Hz, 1H), 4.51 (dd, J ) 2.2, 18.3 Hz, 1H), 4.33
(ddd, J ) 2.0, 2.9, 18.3 Hz, 1H), 3.86 (dq, J ) 1.7, 6.5 Hz, 1H), 3.71
(s, 3H), 3.57 (m, 2H), 2.63 (tq, J ) 1.3, 7.3 Hz, 1H), 2.42 (s, 3H),
1.71 (br s, 1H), 1.45 (ddt, J ) 5.6, 7.0, 12.7 Hz, 1H), 1.32 (m, 1H),
1.19 (d, J ) 6.3 Hz, 3H).13C NMR (125 MHz, CDCl3): δ 166.0, 161.2,
143.4, 135.9, 129.6 (2), 127.1 (2), 1114.3, 59.7, 59.4, 51.4, 499.9, 49.4,
35.9, 21.4, 20.9. Anal. Calcd for C17H23NO5S: C, 57.77; H, 6.56; N,
3.96; S, 9.07. Found: C, 57.88; H, 6.58; N, 3.91; S, 9.27.
The latter substance was then taken up in ether (3 mL), and lithium
aluminum hydride (0.025 g, 0.66 mmol) was added. The reaction was
stirred at room temperature for 5 min. Technical Et2O (3 mL) and a
saturated solution of Na2SO4 (0.1 mL) were added. After 10 min, the
heterogeneous mixture was filtered through a pad of silica (Et2O) to
afford pure 66 (0.060 g, 0.194 mmol) as a colorless oil. [R]D ) -44.0
1
(c 2.02, CHCl3). IR (neat): 3521, 2942, 1651, 1336, 1160 cm-1. H
NMR (500 MHz, CDCl3): δ 7.68 (d, J ) 8.3 Hz, 2H), 7.29 (d, J ) 8.3
Hz, 2H), 4.89 (t, J ) 2 Hz, 1H), 4.81 (t, J ) 1.7 Hz, 1H), 4.14 (q, J
) 6.8 Hz, 1H), 3.79 (dd, J ) 6.1, 12.2 Hz, 1H), 3.68 (td, J ) 5.6, 11.0
Hz, 1H), 3.60 (td, J ) 6.6, 11.0 Hz, 1H), 2.87 (td, J ) 3.1, 12.4 Hz,
1H), 2.42 (s, 3H), 2.42 (m overlapped, 1H), 2.25 (t, J ) 7.5 Hz, 1H),
2.09 (d, J ) 13.4 Hz, 1H), 1.86 (d, J ) 6.3 Hz, 1H), 1.83 (d, J ) 6.3
Hz, 1H), 1.63 (br s, 1H), 0.87 (d, J ) 6.8 Hz, 3H). 13C NMR (125
MHz, CDCl3): δ 143.3, 142.9, 137.8, 129.6 (2), 126.8 (2), 113.0, 60.7,
53.3, 46.3, 40.5, 34.2, 30.2, 21.4, 15.0. Anal. Calcd for C16H23NO3S:
C, 62.10; H, 7.49; N, 4.52; S, 10.36. Found: C, 61.97; H, 7.26; N,
4.39; S, 10.19.
(2S,3R,4R)-N-(4-Methylbenzenesulfonyl)-2,3-dimethyl-4-(2-hy-
droxyethyl)-5-methylenepiperidine (56) was obtained starting from
alkyne 23 (75 mg, 0.2 mmol) and using procedures reported before.
56 (0.031 g, 0.096 mmol) was recovered as a colorless oil. [R]D
)
11.2 (c 1.62, CHCl3). IR (neat): 3510, 2935, 1338, 1154 cm-1. 1H NMR
(500 MHz, CDCl3): δ 7.69 (d, J ) 8.3 Hz, 2H), 7.29 (d, J ) 8.3 Hz,
2H), 5.04 (s, 1H), 4.82 (s, 1H), 3.92 (d, J ) 13.4 Hz, 1H), 3.92 (m
overlapped, 1H), 3.75 (d, J ) 13.4 Hz, 1H), 3.66 (ddd, J ) 4.8, 7.5,
10.5 Hz, 1H), 3.59 (dt, J ) 7.3, 10.5 Hz, 1H), 2.43 (s, 3H), 2.11 (br t,
J ) 9.3 Hz, 1H), 1.75 (tdd, J ) 2.9, 7.8, 13.9 Hz, 1H), 1.53 (m, 1H),
1.42 (m, 1H), 1.61 (br s, 1H), 1.12 (d, 7.1 Hz, 3H), 0.89 (d, J ) 6.8
Hz, 3H). 13C NMR (125 MHz, CDCl3): δ 143.3, 143.0, 137.0, 129.5
(2) 127.0 (2), 111.8, 60.0, 54.0, 47.3, 38.8, 38.4, 32.3, 32.3, 21.4, 16.8,
13.1. Anal. Calcd for C17H25NO3S: C, 63.12; H, 7.79; N, 4.33; S, 9.91.
Found: C, 63.53; H, 7.39; N, 3.96; S, 9.56. HRMS: calcd for C17H25-
NO3S, [M+], 323.1555; found, 323.1551.
(2S,3R)-N-(4-Methylbenzenesulfonyl)-2-methyl-3-[(E)-2-(tert-
butyldimethylsilyloxy)vinyl]-4-methylenepiperidine (54) was ob-
tained by carrying out the typical procedure from alkyne 19b (0.085
g, 0.2 mmol). The crude product was directly chromatographed over
silica gel, eluting with 9:1 petroleum ether-ether, to afford 54 (0.082
g, 0.194 mmol) as a colorless oil. IR (neat): 2930, 1654, 1340, 1163
1
cm-1. H NMR (500 MHz, CDCl3): δ 7.66 (d, J ) 8.3 Hz, 2H), 7.24
(d, J ) 8.3 Hz, 2H), 6.29 (d, J ) 11.9 Hz, 0.8H), 6.12 (d, J ) 5.8 Hz,
0.2H), 5.14 (dd, J ) 7.6, 11.9 Hz, 0.8H), 4.76 (br s, 1H), 4.74 (m
overlapped, 0.2H), 4.71 (br s, 1H), 4.08 (q, J ) 6.6 Hz, 0.8H), 4.05 (q,
J ) 7.0 Hz, 0.2H), 3.74 (dd, J ) 5,8, 12.2 Hz, 0.2H), 3.70 (dd, J )
5.8, 12.2 Hz, 0.8H), 3.18 (br d, J ) 8.8 Hz, 0.2H), 2.86 (td, J ) 3.4,
12.4 Hz, 1H), 2.57 (d, J ) 7.5 Hz, 0.8H), 2.41 (m overlapped, 1H),
2.38 (s, 3H), 2.01 (br d, J ) 13.4 Hz, 1H), 0.89 (s, 9H), 0.11 (s, 3H),
0.10 (s, 3H). 13C NMR (125 MHz, CDCl3): δ 144.2, 143.5, 142.88,
142.82, 141.7, 138.79, 137.9, 129.5, 129.4, 127.05, 127.02, 111.82,
111.7, 109.8, 54.6, 54.2, 48.0, 44.5, 40.71, 40.68, 30.89, 30.4, 25.65,
25.55, 21.4, 18.2, 18.1, 15.33, 15.0, -5.22, -5.4. Anal. Calcd for
C22H35NO3SSi: C, 62.66; H, 8.36; N, 3.32; S, 7.60. Found: C, 62.49;
H, 8.31; N, 3.34; S, 7.44.
Acknowledgment. We thank the National Science Foundation
and National Institutes of Health, General Medical Sciences
(Grant 13598), for their generous support of our programs. Mass
spectra were provided by the mass Spectrometry Facility,
University of San Francisco, supported by the NIH Division of
Research Resources. Dr Pierre L. Fraisse is warmly thanked
for the generous gift of catalyst 2.
(2S,3R)-N-(4-Methylbenzenesulfonyl)-2-methyl-3-(2-hydroxyethyl)-
4-methylenepiperidine (66). To a solution of silyl enol ether 54
(prepared from 0.127 g, 0.3 mmol of alkyne 19b) in CH2Cl2 (5 mL)
were added water (0.2 mL) and trifluoroacetic acid (2 mL). The reaction
was stirred at room temperature for 15 min. The volatiles were removed
under reduced pressure, and the residue was purified by chromatog-
Supporting Information Available: Experimental procedure
for compounds 6, 8a, 8b, 9a, 9b, 10, 12a, 12b, 13, 16, 19a,
19b, 21, 22, 23, 25, 26, 30a, 30b, 31, 38, 39, 40. This material
is available free of charge via the Internet at http://pubs.acs.org.
JA046824O
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15602 J. AM. CHEM. SOC. VOL. 126, NO. 47, 2004