An atom-economic and selective ruthenium-catalyzed redox isomerization of propargylic alcohols. An efficient strategy for the synthesis of leukotrienes

Article abstract of DOI:10.1021/ja804105m

Catalytic ruthenium complexes in conjunction with an indium cocatalyst and Broensted acid isomerize primary and secondary propargylic alcohols in good yields to provide trans enals and enones exclusively. Readily available indenylbis(triphenylphosphine)ruthenium chloride, in the presence of indium triflate and camphorsulfonic acid, gives the best turnover numbers and reactivity with the broadest range of substrates. Deuterium labeling experiments suggest that the process occurs through propargylic hydride migration followed by protic cleavage of the resultant vinylruthenium intermediate. Application of this method to the synthesis of leukotriene B₄ demonstrates its utility and extraordinary selectivity.

Full text of DOI:10.1021/ja804105m

Published on Web 08/15/2008
An Atom-Economic and Selective Ruthenium-Catalyzed
Redox Isomerization of Propargylic Alcohols. An Efficient
Strategy for the Synthesis of Leukotrienes
Barry M. Trost* and Robert C. Livingston
Department of Chemistry, Stanford UniVersity, Stanford, California 94305-5080
Received April 1, 2008; E-mail: bmtrost@stanford.edu
Abstract: Catalytic ruthenium complexes in conjunction with an indium cocatalyst and Bro¨nsted acid
isomerize primary and secondary propargylic alcohols in good yields to provide trans enals and enones
exclusively. Readily available indenylbis(triphenylphosphine)ruthenium chloride, in the presence of indium
triflate and camphorsulfonic acid, gives the best turnover numbers and reactivity with the broadest range
of substrates. Deuterium labeling experiments suggest that the process occurs through propargylic hydride
migration followed by protic cleavage of the resultant vinylruthenium intermediate. Application of this method
to the synthesis of leukotriene B4 demonstrates its utility and extraordinary selectivity.
Introduction
nonactivated secondary propargylic alcohols to mixtures of R,ꢀ-
and ꢀ,γ-unsaturated ketones.4 A recently reported kinetic
The preparation of R,ꢀ-unsaturated aldehydes and ketones
from propargylic alcohols has proven an important transforma-
tion, owing to the ease of preparation of the starting materials
and the broad utility of the products in organic synthesis.
Normally this process is carried out by sequential reduction to
the allylic alcohol followed by oxidation to the carbonyl
compound, which is rather inefficient, considering that stoichio-
metric or even excess reductant and oxidant must be applied
simply to effect reorganization of the internal oxidation pattern.
Selectivity issues may introduce further inefficiencies. For the
reduction step these include chemoselectivity in the presence
of other unsaturation, overreduction, and control of olefin
geometry. Oxidation is complicated by other alcohol functional-
ity, which generally requires protection, further compromising
the conciseness and atom economy of the synthesis. Aldol
condensation followed by dehydration provides an alternative
protocol, although self-condensation, oligomerization of the
product, and control of olefin geometry can be problematic.
Furthermore, the often harsh conditions render it of little
practical importance in the preparation of unsaturated aldehydes.
Phosphorus ylides likewise raise issues of atom economy and
control of olefin geometry, as well as further olefination of the
targeted unsaturated aldehyde.
resolution of secondary propargylic alcohols via rhodium-
catalyzed redox isomerization represents an important new
extension of this approach but proceeds poorly with primary
propargyl alcohols and alkyl-substituted secondary propargyl
alcohols.5 Prior to our efforts,6 only one catalyst system had
proven capable of isomerizing primary propargylic alcohols to
R,ꢀ-unsaturated aldehydes in reasonable yields, although it
required 10-20 mol % catalyst for 30-48 h at 110 °C and
broad substrate compatibility was not demonstrated.7 Our work
particularly focused on generation of R,ꢀ-unsaturated aldehydes
which are real tests of the utility of the method because of their
sensitivity, the failure of other catalysts for such substrates, their
importance as synthetic intermediates, and the cumbersomeness
of alternative modes of synthesis. This new method enhances
the “alkyne strategy” for the synthesis of complex natural
(1) Swaminathan, S.; Narayanan, K. V. Chem. ReV. 1971, 71, 429. For
recent metal-catalyzed versions see: Bustelo, E.; Dixneuf, P. H. AdV.
Synth. Catal. 2007, 349, 933. Cadierno, V.; Garcia-Garrido, S. E.;
Gimeno, J. AdV. Synth. Catal. 2006, 348, 101. Lopez, S. S.; Engel,
D. A.; Dudley, G. B. Synlett 2007, 949.
(2) For recent examples, see: Sonye, J. P.; Koide, K. J. Org. Chem. 2007,
72, 1846. Sonye, J. P.; Koide, K. J. Org. Chem. 2006, 71, 6254. Sonye,
J. P.; Koide, K. Org. Lett. 2006, 8, 199. Erenler, R.; Biellmann, J. F.
Tetrahedron Lett. 2005, 46, 5683. Bernotas, R. C. Synlett 2004, 2165.
Coelho, A.; Sotelo, E.; Ravin˜a, E. Tetrahedron 2003, 59, 2477.
Ishikawa, T.; Mizuta, T.; Hagiwara, K.; Aikawa, T.; Kudo, T.; Saito,
S. J. Org. Chem. 2003, 68, 3702.
Since a propargyl alcohol and the corresponding alkenyl
carbonyl partner are simply isomers, the ideal approach would
be to develop a catalyst to shuffle the hydrogens. An isomer-
ization of propargylic alcohols could avoid the above pitfalls
and offer significant advantages in economy and selectivity.
Despite the potential benefits, there have been surprisingly few
efforts to develop practical methods around this concept. The
classical Rupe and Meyer-Schuster rearrangements effect this
transformation, but with oxygen transposition.1 Of the examples
that proceed with retention of the oxygen connectivity, most
are highly activated substrates, which are known to rearrange
through base-2 or phosphine-promoted3 mechanisms. Transition
metal catalysts have proven effective for the isomerization of
(3) Lu, X.; Zhang, C.; Xu, Z. Acc. Chem. Res. 2001, 34, 535. Other
examples reported as metal-catalyzed are possibly phosphine me-
diated: Saiah, M. K. E.; Pellicciari, R. Tetrahedron Lett. 1995, 36,
4497.
(4) Guo, C.; Lu, X. J. Chem. Soc., Perkin Trans. 1 1993, 1921. Lu, X.;
Ji, J.; Guo, C.; Shen, W. J. Organomet. Chem. 1992, 428, 259. Lu,
X.; Ji, J.; Ma, D.; Shen, W. J. Org. Chem. 1991, 56, 5774. Ma, D.;
Lu, X. Tetrahedron Lett. 1989, 30, 2109.
(5) Tanaka, K.; Shoji, T.; Hirano, M. Eur. J. Org. Chem. 2007, 2687.
Tanaka, K.; Shoji, T. Org. Lett. 2005, 7, 3561.
(6) Trost, B. M.; Livingston, R. C. J. Am. Chem. Soc. 1995, 117, 9586.
(7) Ma, D.; Lu, X. J. Chem. Soc., Chem. Commun. 1989, 890.
9
11970 J. AM. CHEM. SOC. 2008, 130, 11970–11978
10.1021/ja804105m CCC: $40.75
2008 American Chemical Society

Ru-Catalyzed Redox Isomerization of Propargylic Alcohols
A R T I C L E S
Table 1. Redox Isomerization under Indium Trichloride
Cocatalysisa
Figure 1. Commercial catalysts for redox isomerization of propargylic
alcohols.
alcohol
R1
R2
time
yield (%)
3a
3b
3c
3d
3e
3f
3g
3h
3i
Ph(CH2)3
C6H11
H
H
H
H
H
H
H
75 min
90 min
90 min
90 min
90 min
90 min
90 min
24 h
88
90
80
86
87
83
67
86
83
products and is illustrated by a concise synthesis of the delicate
leukotrienes. A preliminary report of a portion of this work has
appeared.6
PhC(dO)(CH2)3
PhCH(OH)(CH2)6
PhCH(OAc)(CH2)3
CH3(CH2)3Ct C(CH2)6
(CH3)2CdCH
Results and Discussion
CH3(CH2)9
CH3(CH2)3
CH2CH2Ph
(CH2)8CHdCH2
Ruthenium complexes 1 and 2 (Figure 1) have proven
effective in the redox isomerization of allylic alcohols to
saturated aldehydes and ketones.8 Under these conditions, an
ammonium salt was used to promote loss of chloride and
generate the coordinatively unsaturated ruthenium species.
Unfortunately, while direct application of these conditions to
primary propargylic alcohols did promote sluggish isomerization
to the corresponding unsaturated aldehydes, the moderately high
temperatures and long reaction times resulted in extensive
decomposition of the sensitive products. The indenyl complex
2 gave improved rates relative to its cyclopentadienyl analogue,
presumably due to the opening of an additional coordination
site through valence tautomerization, although significant de-
composition was still observed.9
Running the reaction in an alcohol solvent, intended to protect
the sensitive aldehyde in situ as the acetal, gave primarily the
products of conjugate addition. Previous work in our group had
demonstrated the ability of indium(III) salts to promote additions
to carbonyl functionality relative to alkenes.10 Indeed, inclusion
of 40% indium trichloride in the catalyst system in refluxing
THF was found to give rapid conversion and satisfactory yields
of the sensitive products. The results summarized in Table 1
were obtained under these conditions. The ability to isolate
sensitive enals in high yields attests to the overall mildness of
the reaction conditions (3a-3g). The extraordinary chemose-
lectivity is illustrated by the compatibility of ketones (3c),
activated alcohols (3d), alkynes (3f), and alkenes (3g). Finally,
the isomerization of propargylic alcohols with extended con-
jugation provides an attractive synthesis of dienals (3g).
Mechanism. The stability of benzylic alcohols and isolated
alkenes to the reaction conditions suggested that intermolecular
hydrogen transfer, mediated through a ruthenium hydride
species, was not the mechanism of the reaction. This was further
probed through deuterium labeling experiments. Subjecting
labeled propargylic alcohol 5 to the standard reaction conditions
resulted in complete deuterium incorporation at the R carbon
as determined by proton NMR (hydride shift pathway, see
Scheme 1), in complete contrast to the isomerization of allyl
alcohols wherein the propargylic hydrogen is transferred
exclusively to the ꢀ carbon.
24 h
a Reactions were performed on 1 mmol scale at 0.25 M with 5%
catalyst 2 and 40% InCl3 in THF at reflux. For primary alcohols, 5%
NH4PF6 and 5% Et3NHPF6 were added. For secondary alcohols, 10%
Et3NHPF6 was added.
This result suggests a mechanism as depicted in Scheme 2,
wherein the product is formed by a net anti hydrometalation.
This proposal is consistent with the observation that the trans
products are obtained exclusively and is supported by the report
of an analogous aryl shift in the literature.11 The intramolecular
nature of the hydride migration was demonstrated by a crossover
experiment involving equimolar quantities of propargylic alcohol
3a and bisdeuterated substrate 5 to give 6 and no appearance
of label in enal 4a. Addition of deuterium oxide to the reaction
mixture resulted in roughly 50% deuterium incorporation at the
ꢀ carbon as detemined by proton NMR. This suggests liberation
of the catalyst by protonolysis of the vinylruthenium intermedi-
ate. Similar protic cleavages of vinylmetal species have been
invoked previously.12 In combination, these results suggest the
catalytic cycle shown in Scheme 2, which predicts both the
remarkable chemoselectivity of the reaction, and the stereospe-
cific formation of the trans product.
Not addressed by this proposal is the effect of the indium
cocatalyst, although formation of the active cationic ruthenium
species by scavenging chloride is one probable role. Two
possible modes for this activation can be envisaged: reversible
sequestration of chloride by formation of an ion pair with the
indiate complex (9) or an indium-bridged species (10) (Figure
2). The latter proposal has the additional advantage of relieving
the strain associated with complex 8b in the catalytic cycle
above.
Reaction Optimization. The above isomerization conditions,
while providing good yields under mild conditions, require
numerous reaction components and high loads of indium
trichloride. It was desirable to improve upon these results in
terms of both reaction simplicity and atom economy. The
proposed mechanism suggests that inclusion of a stronger proton
source could enhance the reaction rate by promoting the
cleavage of the vinylruthenium intermediate. Indeed, replacing
the weakly acidic ammonium hexafluorophosphate salts with
camphorsulfonic acid (CSA) allowed some reduction in the
(8) Trost, B. M.; Kulaweic, R. J. J. Am. Chem. Soc. 1993, 115, 2027.
Trost, B. M.; Kulaweic, R. J. Tetrahedron Lett. 1991, 32, 3039.
(9) Marder, T. B.; Roe, D. C.; Milstein, D. Organometallics 1988, 7, 1451.
Casey, C. P.; O’Connor, J. M. Organometallics 1985, 4, 384.
Bo¨nneman, H. Angew. Chem., Int. Ed. Engl. 1985, 24, 248. Borrini,
A.; Diversi, P.; Ingrosso, G.; Lucherini, A.; Serra, G. J. Mol. Catal.
1985, 30, 181. Rerek, M. E.; Basolo, F. J. Am. Chem. Soc. 1984, 106,
5908.
(11) Pilette, D.; Moreau, S.; Le Bozec, H.; Dixneuf, P. H.; Corrigan, J.;
Carty, A. J. J. Chem. Soc., Chem. Commun. 1994, 409.
(12) Kennedy-Smith, J. J.; Staben, S. T.; Toste, F. D. J. Am. Chem. Soc.
2004, 126, 4526. Drent, E.; Arnoldy, P.; Budzelaar, P. H. M. J.
Organomet. Chem. 1994, 475, 57. Drent, E.; Arnoldy, P.; Budzelaar,
P. H. M. J. Organomet. Chem. 1993, 455, 247. Komiya, S.; Ito, T.;
Cowie, M.; Yamamoto, A.; Ibers, J. J. Am. Chem. Soc. 1976, 98, 3874.
(10) Trost, B. M.; Sharma, S.; Schmidt, T. Tetrahedron Lett. 1993, 34,
7183. Trost, B. M.; Sharma, S.; Schmidt, T. J. Am. Chem. Soc. 1992,
114, 7903.
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A R T I C L E S
Trost and Livingston
Scheme 1. Deuterium Labeling Experiments
Scheme 2. Proposed Catalytic Cycle for Redox Isomerization
A wide variety of other catalysts and cocatalysts were
explored, and while none proved as practical as the above
conditions, several interesting observations were made. The
putative role of the indium cocatalyst, namely generation of the
active cationic ruthenium complex through chloride abstraction,
might be even better served by either silver or thallium, both
of which form insoluble chloride salts.14 Indeed, use of 1 equiv
of silver or thallium triflate relative to catalyst 2 resulted in
rapid isomerization at room temperature, although turnover
numbers were ultimately lower than those obtained with indium,
possibly due to poor stabilization of the active complex as the
concentration of alkyne decreases.
The cyclopentadienyl catalyst 1 had proven significantly less
active than the indenyl analogue 2 under indium trichloride
cocatalysis. While the new conditions actually widened the
discrepancy, the absolute level of activity for the cyclopenta-
dienyl catalyst nonetheless increased dramatically, making it
an acceptable alternative to the indenyl complex. For example,
5% of complex 1 in conjunction with 5% indium triflate and
20% CSA gave complete conversion of model compound 3a
after 4 h. By comparison, only 3% of the indenyl catalyst 2 in
conjunction with 3% indium triflate and 5% CSA gave complete
conversion in just 30 min. Both complexes are now com-
mercially available.
The modified cyclopentadienyl catalyst 11 (Figure 3) was
prepared for use in the constitutive condensation reaction of
terminal alkynes and allylic alcohols.15 Ultimately the catalyst
proved unsuitable for that purpose because of its propensity to
isomerize the allylic alcohol. For the isomerization of propar-
gylic alcohols, it proved to be roughly as active as the indenyl
catalyst, giving complete isomerization after 90 min under the
indium trichloride conditions. This higher reactivity as compared
to the unsubstituted cyclopentadienyl catalyst can be rationalized
by invoking more facile loss of phosphine and opening of an
additional coordination site induced by the bulky o-tolyl
substituent.
The methallyl catalyst 12 (Figure 3) was investigated with
the expectation that the elimination of the chloride and 1 equiv
of phosphine would result in an activated isomerization catalyst
that would exhibit reactivity on the order of the silver-
cocatalyzed system, that is, rapid conversion at room temper-
ature without the addition of a metal cocatalyst.16 However,
this hypothesis was not borne out experimentally. No reaction
was observed at room temperature, and conversion was low even
in THF at reflux. Addition of indium triflate dramatically
improved the situation with 60% conversion after 60 min at
reflux, but the reaction was still incomplete after 4 h. The activity
indium cocatalyst load without increasing the reaction time. For
simple substrates, inclusion of large quantities of CSA even
allowed complete conversion in the absence of indium salts,
although reaction times were longer and yields correspondingly
lower.
Another issue was the high concentration of chloride intro-
duced by the indium cocatalyst and the likely detrimental effect
in terms of available coordination sites on the ruthenium catalyst.
Indeed, indium triflate had proven superior to indium chloride
in the ruthenium-catalyzed addition of alkynes to vinyl ke-
tones.13 In the isomerization system, switching from indium
chloride to the triflate likewise resulted in more rapid reaction
and allowed drastic reduction of the cocatalyst load. In conjunc-
tion with camphorsulfonic acid, further rate improvements and
ultimately higher turnover numbers were observed. It was noted
that large indium-to-ruthenium ratios gave more rapid initial
reaction but ultimately lower turnover numbers. Use of sto-
ichiometric indium relative to ruthenium generally provided an
excellent balance between turnover number and reaction time
for primary alcohols. For secondary alcohols, the use of higher
indium-to-ruthenium ratios (10% In and 3% Ru) increased the
reaction rate roughly 10-fold. In contrast to our earlier observa-
tions in the indium trichloride system, a very small (<4% by
gas chromatography) migration of the terminal alkene was
observed when secondary alcohol 3i was isomerized under these
conditions. These modifications now constitute our standard
conditions.
Figure 2. Indium activation of cationic ruthenium species.
Figure 3. Other ruthenium complexes for redox isomerization.
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11972 J. AM. CHEM. SOC. VOL. 130, NO. 36, 2008

Ru-Catalyzed Redox Isomerization of Propargylic Alcohols
A R T I C L E S
Table 2. Isomerization under Indium Triflate Cocatalysis
a Reactions were performed on 1 mmol scale in THF at reflux. Yield refers to isolated yields. b The product in this case is 4-keto-n-decanal.
of indium on this catalyst suggests that sequestration of chloride
ion may not be the sole mechanism of its cocatalysis.
conversion to the dienal. Propargylic alcohol 3l reacted even
more sluggishly and suffered from even lower turnover numbers.
Increasing the concentration of substrate improved the turnover
numbers in this case and provided modest yields of the desired
ketone.
Additional Substrates. The new isomerization conditions
allowed expansion of the scope of this reaction to substrates
which had proven unreactive under the previously reported
protocol. In particular, the preparation of polyconjugated
carbonyl compounds from propargylic alcohols would dramati-
cally demonstrate the selectivity of the isomerization. The
indium trichloride conditions gave acceptable results for alcohol
3g, as mentioned previously. The indium triflate conditions gave
the desired dienal and dienone from alcohols 3j and 3k in good
yields (Table 2), although turnover numbers were lower than
those obtained with nonconjugated substrates, particularly for
the primary alcohol. This problem was alleviated by using
substoichiometric indium relative to ruthenium, which predict-
ably extended the reaction time but ultimately allowed good
Unsaturated aldehydes bearing 4-hydroxy substituents would
provide entry into several interesting natural product substruc-
tures.17 Unfortunately, attempts to access these compounds by
redox isomerization of monoprotected butynediols were unsuc-
cessful under the indium trichloride cocatalyzed conditions. Diol
3m gave only low yields of the expected ketoaldehyde, and
protection of the secondary hydroxyl as the acetate or PMB
ether resulted in unreactive substrates. Under the higher activity
of the indium triflate cocatalyst, diol 3m rapidly underwent dual
isomerization to the corresponding ketoaldehyde in 80% yield.
Protection of the secondary hydroxyl group as the PMB ether
dramatically curtailed the reactivity, but the desired aldehyde
could be isolated from 3n in an acceptable 62% yield. The
(13) Trost, B. M.; Portnoy, M.; Kurihara, H. J. Am. Chem. Soc. 1997, 119,
836. Trost, B. M.; Krause, L.; Portnoy, M. J. Am. Chem. Soc. 1997,
119, 11319.
(14) Evans, D. A.; Burgey, C. S.; Kozlowski, M. C.; Tregay, S. W. J. Am.
Chem. Soc. 1999, 121, 686.
(17) For some recent examples, see: Yadav, J. S.; Prathap, I.; Tadi, B. P.
Tetrahedron Lett. 2006, 47, 3773. Schneider, C.; Porter, N.; Brash,
A. R. Chem. Res. Toxicol. 2004, 17, 937. Sun, M.; Salomon, R. G.
J. Am. Chem. Soc. 2004, 126, 5699. Chakraborty, T. K.; Purkait, S.;
Das, S. Tetrahedron 2003, 59, 9127.
(15) Trost, B. M.; Vidal, B.; Thommen, M. Chem. Eur. J. 1999, 5, 1055.
(16) Lehmkuhl, H.; Mauermann, H.; Benn, R. Liebigs Ann. Chem. 1980,
754.
9
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A R T I C L E S
Trost and Livingston
Figure 4. Retrosynthesis of leukotriene B4.
corresponding acetate was essentially unreactive, while the tert-
butyldimethylsilyl (TBDMS) ether rapidly succumbed to
hydrolysis.
Scheme 3. Isomerization of 2,4-Diyn-1-ols
Hydrolysis of the protecting group under the acidic conditions
was an even greater issue for monoprotected 2-butyne-1,4-diols.
Fortunately, the tert-butyldiphenylsilyl (TBDPS) ether provided
adequate resistance, and the desired aldehyde could be isolated
from propargylic alcohol 3o in 62% yield. Lowering the
concentration of indium triflate helped to curtail the hydrolysis,
despite the somewhat longer reaction time.
rate of conversion was slow. The source of the slow isomer-
ization rate for conjugated diynes has not been fully elucidated,
and, as such, this class of substrate presents an opportunity for
further catalyst design and system optimization. Alternatively,
sequential reduction and oxidation under classical conditions
proceeded normally (Scheme 4). While this approach required
multiple steps and proceeded with low atom economy, it offered
higher throughput during the initial steps of the synthesis. The
monoprotected 2,4-hexadiyne-1,6-diol starting material could
be prepared by one of two methods. Copper-catalyzed coupling
of the TBDMS ether of 3-iodo-2-propyn-1-ol with propargyl
alcohol in pyrrolidine gave the desired monoprotected diynol
in 50% yield over two steps.19 However, due to thermochemical
safety concerns associated with this approach, an alternative
was sought for use on large scale. The commercially available
and easily prepared 2,4-hexadiyne-1,6-diol could be silylated
to give 62% yield of the monoprotected substrate, with bis-
silylated material comprising the balance.20 Regioselective
reduction of the unprotected propargylic moiety was achieved
using Red-Al in 88% yield. Oxidation of the resultant allylic
alcohol under Mofatt-Swern conditions gave the required
aldehyde 17 in 84% yield.21
The next challenge was introduction of the homopropargylic
alcohol moiety by addition of a propargyl metal equivalent to
aldehyde 17. Propargylic lithium and zinc species are known
to exist as equilibrating mixtures of propargyl and allenyl
species, and hence their addition to aldehydes typically yields
mixtures of allenyl and homopropargylic alcohols, the selectivity
being dependent on both the metal species and the steric
requirements of the substrate.22 Zweifel has shown that addition
of trialkylboranes to lithiated propargyl chloride generates
substituted allenylboranes (Scheme 5), which can subsequently
undergo addition to aldehydes with outstanding selectivity for
the homopropargylic alcohol, obtained after standard oxidative
workup.23 The required tripentylborane was readily prepared
from 1-pentene and borane dimethylsulfide complex. Treatment
Synthesis of Leukotriene B4. The arachidonic acid metabolite
leukotriene B4 has attracted significant interest due to its broad
biological activity, with its varied effects including the stimula-
tion of leukocyte formation, increased vascular permeability,
and smooth muscle contraction. Numerous total syntheses have
been reported since its structure was elucidated nearly two
decades ago.18 The challenging triene subunit, with its flanking
allylic alcohols, makes the molecule an attractive proving ground
for methodologies that facilitate the preparation of these
functionalities. Successful application of our ruthenium-
catalyzed redox isomerization of propargylic alcohols to this
target would demonstrate various aspects of its scope and testify
to the mildness and selectivity of the method. The retrosynthesis
outlined below capitalizes on the potential of generating both
trans alkenes of the triene unit via ruthenium-catalyzed redox
isomerization (Figure 4). In devising this synthetic approach, it
was established from the outset that the objective would be to
explore the chemoselectivity of the isomerization reaction, and
that efforts to address stereochemical issues would be put aside.
Isomerizations of model diynol 13 and monoprotected 2,4-
hexadiyne-1,6-diol 15 proceeded cleanly (Scheme 3), but the
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(22) Suzuki, M.; Morita, Y.; Noyori, R. J. Org. Chem. 1990, 55, 441.
9
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Ru-Catalyzed Redox Isomerization of Propargylic Alcohols
A R T I C L E S
a
Scheme 4. Synthesis of Leukotriene B4
a Reaction conditions: (a) NaH, TBDMSCl, 62%; (b) Red-Al, 88%; (c) (COCl)2, DMSO, Et3N, 84%; (d) borane 18, then NaOH, H2O2, 67%; (e) TBDPSCl,
imidazole, DMAP; (f) CSA, MeOH, 81% over two steps; (g) 2, In(OTf)3, CSA, 92%; (h) [(Ph3PCH2Br]Br, t-BuOK, 65%; (i) n-BuLi, OHC(CH2)3COOCH3,
27%, 67% brsm; (j) TBDPSCl, imidazole, DMAP; (k) H2, Lindlar, quinoline, 92%; (l) TBAF, 87%.
Scheme 5. Preparation of Allenylborane 18
aldehyde was by homologation to the alkyne and addition to
an appropriate glutaric moiety. The literature describes few
reliable methods for the conversion of enals, let alone dienals,
to the corresponding alkynes. Ultimately, acceptable results were
obtained by one-pot homologation to the vinyl bromide followed
by elimination to give the dienyne in 65% yield.24 This
marginally stable material contained roughly 15% of remaining
vinyl bromide and was taken to the subsequent addition
immediately following isolation. In what proved the most
problematic transformation of the synthesis, lithiation of the
dienyne and addition to methyl 5-oxopentanoate yielded only
27% of the eicosanoate backbone 22 (67% based on recovered
alkyne). Similar attempts described in the literature have also
been met with modest yields and significant recovery of starting
material.25 While no alternatives to the lithium acetylide were
explored, there is precedent to suggest that the use of the more
nucleophilic magnesium or cerium acetylides might give
superior results.26
Attempted semihydrogenation of the two alkyne moieties of
eicosanoate 22 under Lindlar conditions resulted in rapid
reduction of the propargylic alcohol to the desired cis allylic
alcohol. Reduction of the more sterically encumbered alkyne,
however, was competitive with over-reduction of the newly
formed triene unit. Protection of the hydroxyl group as the
TBDPS ether evened the steric accessibility and allowed the
double hydrogenation to proceed selectively in 92% yield.
Finally, global deprotection with tetrabutylammonium fluoride
gave the product in 87% yield.18 Although the product consisted
of four stereochemical isomers, the stereo centers were suf-
with lithiated propargyl chloride and addition of the resultant
allenylborane 18 to aldehyde 17 gave greater than 20:1
selectivity for homopropargylic alcohol over the allene by gas
chromatography. These regioisomers could be separated by silica
gel chromatography to give the key intermediate 19 in 67%
yield on multigram scale.
Protection of the secondary alcohol as the TBDPS ether and
selective removal of the TBDMS group with CSA in methanol
gave isomerization substrate 20 in 81% yield over two steps.
Redox isomerization using 5% of all components was complete
in 20 min and on large scale provided dienal 21 in 92% yield.
This result demonstrates the extraordinary selectivity of the
system, with isomerization proceeding cleanly in the presence
of the conjugated alkene, isolated alkyne, silyl protecting group,
and the sensitive dienal product. The high yield and rapid rate
of conversion contrast markedly with the results obtained
previously for the conjugated diynol, suggesting that the slow
kinetics and low turnover observed in that system are the
exception rather than the rule.
In light of our decision to set aside issues of stereochemical
control, the most direct route to the eicosanoate from the
(24) Matsumoto, M.; Kuroda, K. Tetrahedron Lett. 1980, 21, 4021.
(25) Morris, J.; Wishka, D. G. Tetrahedron Lett. 1986, 27, 803. Charoe-
nying, P.; Davies, D. H.; McKerrecher, D.; Taylor, R. J. K. Tetrahe-
dron Lett. 1996, 37, 1913.
(23) Zweifel, G.; Backlund, S. J.; Leung, T. J. Am. Chem. Soc. 1978, 100,
(26) Krasovskiy, A.; Kopp, F.; Knochel, P. Angew. Chem., Int. Ed. 2006,
45, 497.
5561.
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A R T I C L E S
Trost and Livingston
mmol) was introduced by syringe followed by THF (4 mL). The
red solution was stirred for several minutes at room temperature
and then gradually heated to gentle reflux. Thin-layer and gas
chromatography indicated that the reaction was complete within
75 min. The solvent was removed under reduced pressure, and the
residue was filtered through florisil with ether to remove the catalyst.
Removal of the solvent under reduced pressure and flash chroma-
tography on silica gel (10:1 hexanes:ethyl acetate) gave 153 mg of
clear oil (88% yield). All spectral data compared favorably to those
reported in the literature.29 IR (film): 3027, 2933, 2859, 2733, 1649,
1636, 1603, 1496, 1455, 1124, 784, 700. 1H NMR (300 MHz,
CDCl3): δ 9.51 (d, J ) 7.9 Hz, 1H), 7.33-7.14 (m, 5H), 6.85 (dt,
J ) 15.6, 6.7 Hz, 1H), 6.13 (dd, J ) 15.7, 7.9 Hz, 1H), 2.68 (t, J
) 7.6 Hz, 2H), 2.37 (q, J ) 6.7 Hz, 2H), 1.86 (quint, J ) 7.6 Hz,
2H).
Aldehyde 4a by Indium Triflate Cocatalyzed Isomeriza-
tion. 6-Phenyl-2-hexyn-1-ol (174 mg, 1.00 mmol), indenyl catalyst
2 (23.3 mg, 0.03 mmol), and camphorsulfonic acid (11.6 mg, 0.05
mmol) were combined in THF (5 mL), and the solution was stirred
under an inert atmosphere for several minutes. Indium triflate (16.9
mg, 0.03 mmol) was added, and the solution was brought to reflux
in a preheated oil bath. Thin-layer and gas chromatography indicated
that the reaction was complete within 30 min. The mixture was
diluted with ether and filtered through florisil to remove the catalyst.
Removal of the solvent under reduced pressure and flash chroma-
tography on silica gel (10:1 petroleum ether:ethyl acetate) gave 150
mg of clear oil (86% yield).
ficiently remote that spectroscopic characterization of the
material was not rendered unduly troublesome. Reverse-phase
HPLC showed the expected 1:1 mixture of diastereomers and
indicated greater than 94% chemical purity. Overall, the
synthesis proceeded in 12 steps from commercially available
2,4-hexadiyne-1,6-diol to give the target in 7% overall yield.
Conclusions
This new catalytic system currently constitutes the most
effective method to perform redox isomerization of both primary
and secondary propargyl alcohols with catalyst loadings as low
as 1%. Application of this method to the synthesis of sphingo-
fungins E and F27 and, more recently, to the enantioselective
synthesis of adociacetylene B28 further attests to the potential
scope of its synthetic utility. While some of the above systems
demonstrate the current limitations of the method with regard
to catalyst turnover, the extraordinary selectivity of the system
sets it apart from other methods of preparing enals and enones
from propargylic precursors. Particularly noteworthy is the
stability of alkenes, alkynes, aldehydes, ketones, and isolated
alcohols, all of which are, in principle, susceptible to redox side
reactions proceeding through ruthenium-catalyzed mechanisms.
Furthermore, the accelerating influence of electrophilic in-
dium(III) complexes on some ruthenium-catalyzed reactions,
first demonstrated in this system, has been proven operative in
a number of other applications.13 The recently reported rhodium-
catalyzed kinetic resolution of secondary propargylic alcohols
via redox isomerization, while apparently proceeding through
an allylmetal intermediate, represents an attractive potential
extension of this method.5 However, it should be noted that
this method isomerizes primary propargyl alcohols in poor
yields. Furthermore, the cost of ruthenium vs rhodium makes
catalysts based upon ruthenium more attractive. Finally, the
operative hydride shift mechanism, in addition to providing the
extraordinary chemoselectivity observed, suggests a number of
related reaction manifolds, several of which remain under active
investigation.
Ketone 4i by Indium Trichloride Cocatalyzed Isomeriza-
tion. 16-Heptadecen-5-yn-7-ol (250 mg, 1.00 mmol) was subjected
to the indium trichloride isomerization conditions described above,
except that 10 mol % triethylammonium hexafluorophosphate and
no ammonium hexafluorophosphate was used. After 24 h, standard
workup and purification of the product by flash chromatography
on silica gel (20:1 hexanes:ethyl acetate) gave 207 mg of clear oil
(83% yield). IR (film): 2928, 2855, 1698, 1676, 1631, 1465, 981,
1
909 cm-1. H NMR(300 MHz, CDCl3): δ 6.83 (dt, J ) 15.9, 6.9
Hz, 1H), 6.09 (dt, J ) 15.9,1.5 Hz, 1H), 5.86-5.77 (m, 1H),
5.03-4.90 (m, 2H), 2.52 (t, J ) 7.4 Hz, 2H), 2.22 (dq, J ) 7.1,
1.4 Hz, 2H), 2.03 (q, J ) 7.0 Hz, 2H), 1.62-1.29 (m, 16H), 0.92
(t, J ) 7.1 Hz, 3H). 13C NMR (75 MHz, CDCl3): δ 200.9, 147.2,
139.1, 130.3, 114.1, 40.0, 33.7, 32.1, 30.2, 29.32, 29.25 (2), 29.0,
28.8, 24.3, 22.2, 13.8. HRMS: calcd for C17H30O (M+), 250.2297;
found, 250.2292.
The mildness of this method is highlighted by its effectiveness
for the isomerization of enyne 20 to dienal 21. It also vividly
illustrates the effectiveness of the “alkyne strategy” for complex
molecule synthesis. The ease of access of eneyne 20 via a three-
component coupling provides most of the carbon skeleton of
the leukotrienes in simple fashion.
(E)-3-(1-Cyclohexenyl)-2-propenal (4j). 3-(1-Cyclohexenyl)-
2-propyn-1-ol (136 mg, 1.00 mmol), indenyl catalyst 2 (23.3 mg,
0.03 mmol), and camphorsulfonic acid (11.6 mg, 0.05 mmol) were
combined in THF (5 mL), and the solution was stirred under an
inert atmosphere for several minutes. Indium triflate (5.6 mg, 0.01
mmol) was added, and the solution was brought to reflux in a
preheated oil bath. After 2 h, the mixture was diluted with ether
and filtered through florisil to remove the catalyst. Removal of the
solvent under reduced pressure and flash chromatography on silica
gel (10:1 petroleum ether:ethyl acetate) gave 115 mg of clear oil
(85% yield). All spectral data compared favorably with those
reported in the literature.30 IR (film): 2934, 2862, 2824, 2727, 1679,
1624, 1603, 1129, 970 cm-1. 1H NMR (300 MHz, CDCl3): δ 9.52
(d, J ) 8.1 Hz, 1H), 7.06 (d, J ) 15.56 Hz, 1H), 6.28 (s, 1H), 6.05
(dd, J ) 15.6, 7.8 Hz, 1H), 2.24-2.15 (m, 4H), 1.74-1.58 (m,
4H). 13C NMR (75 MHz, CDCl3): δ 194.3, 156.2, 141.3, 135.8,
125.7, 26.7, 24.2, 21.9, 21.8.
Experimental Section
Representative Isomerization Procedures. Glassware was not
flame dried, but all solvents were freshly distilled under nitrogen
to ensure deoxygenation. The apparatus was flushed with nitrogen
or argon immediately following setup, and the reactions were
continued under an inert atmosphere. For particularly sensitive
systems, it was helpful to briefly sparge the solution with either
nitrogen or argon prior to heating. Reactions were typically sampled
by glass capillary under positive nitrogen pressure. Samples were
washed through a small plug of silica with ether and analyzed by
thin-layer or gas chromatography.
Aldehyde 4a by Indium Trichloride Cocatalyzed Isomeriza-
tion. Indium trichloride (88.5 mg, 0.40 mmol), indenyl catalyst 2
(28.8 mg, 0.05 mmol), triethylammonium hexafluorophosphate
(12.4 mg, 0.05 mmol), and ammonium hexafluorophosphate (8.3
mg, 0.05 mmol) were combined sequentially. The system was
purged with nitrogen, and 6-phenyl-2-hexyn-1-ol (174 mg, 1.00
(E)-1-(1-Cyclohexenyl)-1-nonen-3-one (4k). 1-(1-Cyclohex-
enyl)-1-nonyn-3-ol (220 mg, 1.00 mmol), indenyl catalyst 2 (23.3
mg, 0.03 mmol), and camphorsulfonic acid (11.6 mg, 0.05 mmol)
were combined in THF (5 mL), and the solution was stirred under
an inert atmosphere for several minutes. Indium triflate (16.9 mg,
(29) Takayama, H.; Koike, T.; Aimi, N.; Sakai, S. J. Org. Chem. 1992,
57, 2173.
(30) Zimmerman, B.; Lerche, H.; Severin, T. Chem. Ber. 1986, 119, 2848.
(27) Trost, B. M.; Lee, C. J. Am. Chem. Soc. 2001, 123, 12191.
(28) Trost, B. M.; Weiss, A. H. Org. Lett. 2006, 8, 4461.
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11976 J. AM. CHEM. SOC. VOL. 130, NO. 36, 2008

Ru-Catalyzed Redox Isomerization of Propargylic Alcohols
A R T I C L E S
0.03 mmol) was added, and the solution was brought to reflux in
a preheated oil bath. After 2 h, the mixture was diluted with ether
and filtered through florisil to remove the catalyst. Removal of the
solvent under reduced pressure and flash chromatography on silica
gel (20:1 petroleum ether:ethyl acetate) gave 163 mg of clear oil
(74% yield). The product appeared to decompose via electrocyclic
rearrangement upon standing at room temperature for several days.
IR (film): 2930, 2859, 1688, 1662, 1626, 1597, 1458, 1317, 1190,
1072, 974 cm-1. 1H NMR (300 MHz, CDCl3): δ 7.15 (d, J ) 15.9
Hz, 1H), 6.21 (s, 1H), 6.07 (d, J ) 16.1 Hz, 1H), 2.56 (t, J ) 7.7
Hz, 2H), 2.23-2.15 (m, 4H), 1.72-1.60 (m, 6H), 1.34-1.29 (m,
6H), 0.88 (t, J ) 6.6 Hz, 3H). 13C NMR (75 MHz, CDCl3): δ
201.4, 145.9, 139.7, 135.2, 123.2, 40.5, 31.6, 29.0, 26.6, 24.5, 24.1,
22.5, 22.0 (2), 14.0. HRMS: calcd for C15H24O (M+), 220.1827;
found, 220.1829.
mL) and oxidized by slow addition of 30% hydrogen peroxide (14.4
mL). Gas chromatography showed roughly 20:1 selectivity for the
desired isomer. The mixture was worked up with water (400 mL)
and ether (4 × 100 mL), and the combined extracts were dried
over magnesium sulfate. Removal of the solvent under reduced
pressure and flash chromatography on silica gel (10:1 petroleum
ether:ethyl acetate) gave 13.39 g of clear oil (67% yield). IR (film):
3416, 2957, 2931, 2859, 2218, 1636, 1255, 1085, 837, 779 cm-1
.
1H NMR (300 MHz, CDCl3): δ 6.16 (dd, J ) 15.9, 5.5 Hz, 1H),
5.80 (dd, J ) 15.9, 1.6 Hz, 1H), 4.43 (d, J ) 1.7 Hz, 2H), 4.27 (t,
J ) 5.4 Hz, 1H), 2.51-2.35 (m, 2H), 2.22 (br, 1H), 2.19-2.13
(m, 2H), 1.54-1.40 (m, 2H), 1.38-1.12 (m, 4H), 0.91 (s, 9H),
0.90 (t, J ) 6.7 Hz, 3H), 0.13 (s, 6H). 13C NMR (75 MHz, CDCl3):
δ 143.5, 110.3, 88.8, 83.9, 82.6, 74.8, 70.2, 52.1, 31.0, 28.6, 27.8,
25.8 (3), 22.2, 18.6, 18.3, 13.9, -5.2 (2). Anal. Calcd for
C20H34O2Si: C, 71.80; H, 10.24. Found: C, 71.68; H, 9.96.
(E)-6-(tert-Butyldimethylsilyl)oxy-2-hexen-4-yn-1-ol. To 6-(tert-
butyldimethylsilyl)oxy-2,4-hexadiyn-1-ol (16.43 g, 73.35 mmol) in
THF (150 mL) was added Red-Al (65% solution in toluene, 33.03
mL, 34.22 g, 110 mmol) at 0 °C. Reduction was complete after
stirring for 1 h at room temperature, and the reaction was quenched
at 0 °C with ethyl acetate (50 mL). The reaction was worked up
with 3 M sulfuric acid (300 mL) and ether (4 × 250 mL). The
combined extracts were washed with saturated aqueous sodium
bicarbonate (100 mL) and brine (100 mL) and dried over
magnesium sulfate. Removal of the solvent under reduced pressure
and flash chromatography on silica gel (5:1 petroleum ether:ethyl
acetate) gave 14.53 g of clear oil (88% yield). IR (film): 3360,
2956, 2930, 2858, 2218, 1635, 1472, 1363, 1256, 1086, 835, 779
cm-1. 1H NMR (300 MHz, CDCl3): δ 6.23 (dt, J ) 15.9, 5.1 Hz,
1H), 5.76 (dt, J ) 15.9, 1.6 Hz, 1H), 4.43 (d, J ) 1.7 Hz, 2H),
4.20 (br, 2H), 1.96 (br, 1H), 0.91 (s, 9H), 0.13 (s, 6H). 13C NMR
(75 MHz, CDCl3): δ 141.8, 109.9, 88.4, 82.7, 62.7, 52.1, 25.8 (3),
18.3, -5.2 (2). HRMS: calcd for C12H21O2Si (M+ - H), 225.1311;
found, 225.1308.
(E)-6-(tert-Butyldimethylsilyl)oxy-2-hexen-4-ynal (17). To ox-
alyl chloride (6.28 mL, 9.14 g, 72 mmol) in methylene chloride
(150 mL) at -78 °C was slowly added DMSO (6.39 mL, 7.03 g,
90 mmol). After stirring 10 min, a precooled solution of the above
alcohol (13.56 g, 60 mmol) in methylene chloride (50 mL) was
added via cannula. After 10 min, triethylamine (25.09 mL, 18.21
g, 180 mmol) was slowly added and stirring was continued at -78
°C for 30 min. After warming and stirring at room temperature for
30 min, the mixture was diluted with methylene chloride (200 mL)
and washed with 10% sodium bisulfate. After removal of the solvent
under reduced pressure, the residue was dissolved in ether (250
mL) and washed with saturated sodium bicarbonate (100 mL) and
water (2 × 100 mL). Drying over magnesium sulfate and removal
of the solvent under reduced pressure followed by filtration through
silica gel (10:1 petroleum ether:ethyl acetate) gave 11.31 g of clear
oil (84% yield). IR (film): 2956, 2930, 2858, 2729, 2213, 1689,
1606, 1256, 1089, 837, 779 cm-1. 1H NMR (300 MHz, CDCl3): δ
9.57 (d, J ) 7.6 Hz, 1H), 6.63 (dt, J ) 15.9, 1.8 Hz, 1H), 6.44 (dd,
J ) 15.9, 7.8 Hz, 1H), 4.53 (d, J ) 1.7 Hz, 2H), 0.92 (s, 9H), 0.14
(s, 6H). 13C NMR (75 MHz, CDCl3): δ 193.0, 139.6, 132.1, 103.2,
81.3, 52.2, 25.7 (3), 18.3, -5.2 (2). Anal. Calcd for C12H20O2Si:
C, 64.23; H, 8.99. Found: C, 64.06; H, 9.16.
(2E,4E)-6-(tert-Butyldiphenylsilyl)oxy-2,4-tetradecadien-
8-ynal (21). To (E)-6-(tert-butyldiphenylsilyl)oxy-4-tetradecene-
2,8-diyn-1-ol (916 mg, 2.00 mmol) in THF (10 mL) were added
indenyl catalyst 2 (77 mg, 0.10 mmol) and camphorsulfonic acid
(32 mg, 0.10 mg). The solution was sparged with argon for several
minutes, and indium triflate (56 mg, 0.10 mmol) was added. The
solution was brought to reflux in a preheated oil bath, and the
reaction was monitored by thin-layer chromatography. Isomerization
was complete within 20 min, at which point the solution was filtered
through florisil with ether to remove the catalyst. Removal of the
solvent under reduced pressure and flash chromatography on silica
gel (10:1 petroleum ether:ethyl acetate) gave 845 mg of clear oil
(92% yield). IR (film): 3072, 2958, 2932, 2859, 2732, 1688, 1646,
1428, 1106, 1009, 988, 741, 702 cm-1 1H NMR (300 MHz,
.
CDCl3): δ 9.53 (d, J ) 8.1 Hz, 1H), 7.73-7.60 (m, 4H), 7.46-7.32
(m, 6H), 7.06-6.98 (m, 1H), 6.36-6.32 (m, 2H), 6.03 (dd, J )
15.1, 8.1 Hz, 1H), 4.38 (dt, J ) 9.5, 4.8 Hz, 1H), 2.46-2.28 (m,
2H), 2.10-2.05 (m, 2H), 1.44-1.21 (m, 6H), 1.08 (s, 9H), 0.86 (t,
J ) 7.0 Hz, 2H). 13C NMR (75 MHz, CDCl3): δ 193.8, 151.6,
146.0, 135.8 (4), 133.5, 133.3, 131.7, 129.8 (2), 128.0, 127.6 (4),
83.1, 75.3, 72.1, 31.0, 28.5, 28.0, 26.9 (3), 22.2, 19.3, 18.6. HRMS:
calcd for C26H29O2Si (M+ - C4H9), 401.1937; found, 401.1939.
(6Z,8E,10E,14Z)-Methyl 5,12-Bis[(tert-butyldiphenylsilyl)-
oxy]-6,8,10,14-eicosatetraenoate. (8E,10E)-Methyl 5,12-bis[(tert-
butyldiphenylsilyl)oxy]-8,10-eicosadiene-6,14-diynoate (207 mg,
0.25 mmol) and Lindlar catalyst (50 mg) were suspended in ethyl
acetate (50 mL) containing quinoline (590 mL, 646 mg, 5.00 mmol).
The mixture was stirred under an atmosphere of hydrogen, and
reaction progress was carefully monitored by thin-layer chroma-
tography. The first semihydrogenation was complete within 1 h
(monohydrogenated Rf ) 0.34 in 20:1 petroleum ether:ethyl acetate),
but the second required 4 h to reach completion (dihydrogenated
Rf ) 0.39 in 20:1 petroleum ether:ethyl acetate). The mixture was
filtered through florisil with ethyl acetate to remove the catalyst,
and the solution was diluted with petroleum ether (50 mL). The
solution was washed with 1 M aqueous sulfuric acid (25 mL) and
saturated aqueous sodium bicarbonate (50 mL). The extracts were
dried over magnesium sulfate, and the solvent was removed under
reduced pressure. Flash chromatography on silica gel (20:1
petroleum ether:ethyl acetate) gave 191 mg of clear oil (92% yield).
All spectral data compared favorably with those reported in the
literature.18 IR (film): 3015, 2931, 2858, 1742, 1599, 1472, 1428,
1362, 1112, 1074, 998, 822, 740, 702 cm-1. 1H NMR (300 MHz,
CDCl3): δ 7.70-7.58 (m, 8H), 7.40-7.29 (m, 12H), 5.96-5.56
(m, 5H), 5.42-5.20 (m, 3H), 4.47 (br, 1H), 4.15 (br, 1H), 3.63
and 3.61 (s, 3H, diastereomers), 2.28-2.04 (m, 4H), 1.81-1.77
(m, 2H), 1.60-1.42 (m, 4H), 1.28-1.14 (m, 6H), 1.07 and 1.06
(s, 9H, diastereomers), 1.03 and 1.02 (s, 9H, diastereomers), 0.85
(t, J ) 6.1 Hz, 3H).
(E)-1-(tert-Butyldimethylsilyl)oxy-4-tetradecene-2,8-diyn-6-ol
(19). Tripentylborane was prepared by slow addition at 0 °C of
borane dimethyl sulfide complex (30 mL, 2 M in THF, 60.0 mmol)
to 1-pentene (19.73 mL, 12.63 g, 180 mmol) in THF (100 mL).
To propargyl chloride (4.34 mL, 4.47 g, 60 mmol) in ether (100
mL) at -90 °C was added n-butyllithium (37.5 mL, 1.6 M in
hexanes, 60 mmol). After stirring for 10 min, the mixture was
diluted with THF (150 mL), and the tripentylborane solution,
precooled to -78 °C, was transferred via cannula over 30 min.
After stirring for 30 min at -78 °C, a precooled solution of aldehyde
17 (11.31 g, 50.5 mmol) was transferred via cannula, and stirring
was continued 30 min. After warming to room temperature, the
mixture was treated with methanol (30 mL) and 3 N NaOH (21.6
Leukotriene B4. To the above eicosatetraenoate (135 mg, 0.16
mmol) in THF (1.6 mL) at 0 °C was added tetrabutylammonium
fluoride (0.60 mL, 1 M in THF, 1.6 mol). After stirring at room
temperature overnight, the mixture was poured into vigorously
9
J. AM. CHEM. SOC. VOL. 130, NO. 36, 2008 11977

A R T I C L E S
Trost and Livingston
stirred ether (10 mL) and pH 5 phosphate buffer (10 mL). The
aqueous layer was extracted with ether (3 × 10 mL), and the
combined extracts were dried over magnesium sulfate. Removal
of the solvent under reduced pressure and flash chromatography
on silica gel (20:1 to 10:1 ether:methanol) gave the product as 49
mg of clear oil (89% yield). Analysis by reverse-phase HPLC (300:
100:1 methanol:water:acetic acid) showed the expected 1:1 mixture
of diastereomers and greater than 94% purity. All spectral data
compared favorably with those reported in the literature.18 IR (film):
MHz, CDCl3): δ 178.2, 136.8, 134.1 (2), 133.5, 130.2 (2), 127.5,
124.1, 71.9, 67.6, 36.5, 35.4, 33.7, 31.5, 29.3, 27.5, 22.6, 20.6, 14.2.
Acknowledgment. We thank the National Science Foundation
and the National Institutes of Health (GM-13598) for their generous
support of our programs. Mass spectra were provided by the Mass
Spectrometry Regional Center of the University of California, San
Francisco, supported by the NIH Division of Research Resources.
Supporting Information Available: Experimental procedures,
characterization, and spectral data for all new intermediates and
products, including preparation of isomerization substrates. This
material is available free of charge via the Internet at http://
pubs.acs.org.
3382, 3013, 2959, 2928, 2858, 1716, 1457, 1243, 1038, 966 cm-1
.
1H NMR (500 MHz, CDCl3): δ 6.51 (t, J ) 13.0 Hz, 1H),
6.37-6.24 (m, 2H), 6.11 (t, J ) 11.2 Hz, 1H), 5.82 (dd, J ) 14.8,
6.0 Hz, 1H), 5.63-5.58 (m, 1H), 5.47-5.38 (m, 3H), 4.64 (br,
1H), 4.25 (br, 1H), 2.42-2.26 (m, 4H), 2.08-2.05 (m, 2H),
1.77-1.29 (m, 12H), 0.92 (t, J ) 6.8 Hz, 3H). 13C NMR (125
JA804105M
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11978 J. AM. CHEM. SOC. VOL. 130, NO. 36, 2008