Stereoselective synthesis of trisubstituted (E,E)-1,3-dienes by the site-selective reductive cross-coupling of internal alkynes with terminal alkynes: A fragment coupling reaction for natural product synthesis

Article abstract of DOI:10.1021/jo901451c

(Chemical Equation Presented) A highly selective convergent coupling reaction is described between alkynes for the synthesis of stereodefined trisubstituted (E,E)-1,3-dienes-structural motifs commonly found embedded in the skeletons of bioactive polyketid

Full text of DOI:10.1021/jo901451c

pubs.acs.org/joc
Stereoselective Synthesis of Trisubstituted (E,E)-1,3-Dienes by the Site-
Selective Reductive Cross-Coupling of Internal Alkynes with Terminal
Alkynes: A Fragment Coupling Reaction for Natural Product Synthesis
Lark J. Perez, Heidi L. Shimp, and Glenn C. Micalizio*,†
Department of Chemistry, Yale University, New Haven, Connecticut 06520. †Current address: Department
of Chemistry, The Scripps Research Institute, Scripps Florida, Jupiter, FL 33458.
micalizio@scripps.edu
Received July 9, 2009
A highly selective convergent coupling reaction is described between alkynes for the synthesis of
stereodefined trisubstituted (E,E)-1,3-dienes-structural motifs commonly found embedded in the skele-
tons of bioactive polyketide-derived natural products. While numerous multistep processes for the synthesis
of this stereodefined functional group exist, the current method represents a significant advance as it does
not require stereodefined olefinic coupling partners (vinyl halide or vinyl organometallic); it proceeds by a
single convergent C-C bond-forming event (avoiding multistep methods based on carbonyl olefination)
and is tolerant of a diverse array of functional groups including free hydroxyls. Through a systematic study
of titanium-mediated reductive cross-coupling reactions of internal alkynes with terminal alkynes, a
fragment coupling reaction of great utility in natural product synthesis has emerged. Here, use of a
proximal hydroxy group to control regioselection in the functionalization of a preformed titanacyclopro-
pene has led to the establishment of a highly selective bimolecular coupling process, where C-C bond
formation occurs in concert with the establishment of two stereodefined alkenes. Compared to the body of
literature known for related metal-mediated coupling reactions, the current work defines a powerful
advance, achieving site-selective bimolecular C-C bond formation without the need for using TMS-
alkynes or conjugated alkynes. Overall, complex 1,3-dienes relevant for the synthesis of polyketide-derived
natural products of varying stereochemistry were prepared with typically g20:1 selectivity, defining the
important role of an alkoxide directing group located δ to preformed titanacyclopropenes.
Introduction
of these methods in natural product synthesis. Nevertheless,
challenges remain in the area of organic chemistry focused
on their synthesis, as commonly encountered subsets of 1,3-
dienes often dictate the use of numerous chemical transfor-
mations to establish their stereodefined architectures.
Since the discovery of the Diels-Alder reaction, substi-
tuted 1,3-dienes have played an important role in organic
chemistry.1 In addition to their utility in cycloaddition
processes, substituted and stereodefined 1,3-dienes are a
structural motif found in a variety of complex bioactive
natural products (Figure 1).2 Not surprisingly, many syn-
thetic methods have appeared that provide access to this
structural motif, and countless examples highlight the utility
(2) For piericidin C7, see: (a) Hayakawa, Y.; Shirasaki, S.; Shiba, S.;
Kawasaki, T.; Matsuo, Y.; Adachi, K.; Shizuri, Y. J. Antibiot. 2007, 60, 196–
200. (b) Hayakawa, Y.; Shirasaki, S.; Kawasaki, T.; Matsuo, Y.; Adachi, K.;
Shizuri, Y. J. Antibiot. 2007, 60, 201–203. For a review of the leptomycins
(including callystatin), see: (c) Kalesse, M.; Christmann, M. Synthesis 2002,
981–1003. For the isolation and structure elucidation of arenicolide C, see:
(d) Williams, P. G.; Miller, E. D.; Asolkar, R. N.; Jensen, P. R.; Fenical, W.
J. Org. Chem. 2007, 72, 5025–5034. For the isolation and structure elucida-
tion of lycogalinoside A, see: (e) Rezanka, T.; Dvorakova, R. Phytochem
2003, 63, 945–952. For the isolation and structure elucidation of pectenotox-
in II, see: (f) Yasumoto, T.; Murata, M.; Oshima, Y.; Sano, M.; Matumoto,
G. K.; Clardy, J. Tetrahedron 1985, 41, 1019–1025.
(1) (a) Diels, O.; Alder, K. Liebigs Ann. Chem. 1928, 460, 98–122. For
recent reviews, see: (b) Fringuelli, F.; Taticchi, A., The Diels-Alder Reaction:
Selected Practical Methods. 2002, West Sussex, England: John Wiley & Sons.
340. (c) Reymond, S.; Cossy, J. Chem. Rev. 2008, 108, 5359–5406. (d) Sauer, J.;
Sustmann, R. Angew. Chem., Int. Ed. Engl. 1980, 19, 779–807.
DOI: 10.1021/jo901451c
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FIGURE 1. Stereodefined E,E-trisubstituted alkenes are structural motifs found embedded in the carbon skeleton of a variety of
architecturally complex natural products.
For example, the stereodefined (E,E)-trisubstituted 1,3-diene
substructure found in many complex natural products
(Figure 1) poses an underappreciated problem in stereo-
selective synthesis. Sequential carbonyl olefination reactions
have been established to provide a means of accessing such
architecture, yet they typically require several functional group
manipulations and redox processes that are not associated with
C-C bond formation.3 Alternatively, while modern palladium-
FIGURE 2. Reductive cross-coupling as a potential strategy for the
synthesis of stereodefined E,E-trisubstituted alkenes.
catalyzed coupling reactions define unique convergent processes
for the synthesis of 1,3-dienes,4 these catalytic reactions typically
require the use of two stereodefined coupling partners (the
vinylhalide and vinylorganometallic reagents), the syntheses of
which require the use of numerous stoichiometric transforma-
tions prior to the catalytic C-C bond-forming event.
An alternative to these established methods, for the
stereoselective synthesis of a subset of geometrically defined
trisubstituted 1,3-dienes, could derive from the reductive
cross-coupling of an appropriately functionalized internal
alkyne 1 with a terminal alkyne 2 (Figure 2). Such a process
would represent a potentially powerful fragment coupling
reaction for natural product synthesis (i.e., Figure 1). Here,
nonstereogenic functional groups (alkynes) define the sites of
reactivity for each coupling partner, and during the course of the
C-C bond-forming process, two stereodefined alkenes are
established, one of which is trisubstituted (3, Figure 2). To
further enhance the merit of such a bond construction, alkynes
possess orthogonal reactivity to a large array of functional
groups and can be installed by a variety of well-established
methods. Despite the significant potential of this class of
coupling reactions, barriers related to the control of reactivity
and selectivity have stood in the way of advancing useful
methods for broad application in natural product synthesis.
Background Associated with Regioselectivity in the Reduc-
tive Cross-Coupling of Alkynes. Over the last five decades,
(3) For a review of carbonyl olefination methods, see: (a) Takeda, T., ed.
Modern Carbonyl Olefination: Methods and Applications. 2004, Wiley-VCH.
365. (b) Maryanoff, B. E.; Reitz, A. B. Chem. Rev. 1989, 89, 863–927. For
selected examples of carbonyl olefination for the stereoselective generation of 1,3-
dienes in the context of natural product total synthesis, see: (c) Bonazzi, S.;
G€uttinger, S.; Zemp, I.; Kutay, U.; Gademann, K. Angew. Chem., Int. Ed. 2007,
46, 8707–8710. (d) Arai, N.; Chikaraishi, N.; Omura, S.; Kuwajima, I. Org. Lett.
2004, 6, 2845–2848. (e) Marshall, J. A.; Bourbeau, M. P. J. Org. Chem. 2002, 67,
2751–2754. (f) Lautens, M.; Stammers, T. A. Synthesis 2002, 1993–2012. (g)
Smith, A. B.; Brandt, B. M. Org. Lett. 2001, 3, 1685–1688. (h) Kobayashi, M.;
Wang, W.; Tsutsui, Y.; Sugimoto, M.; Murakami, N. Tetrahedron Lett. 1998, 39,
8291–8294. (i) Schnermann, M. J.; Romero, F. A.; Hwang, I.; Nakamaru-Ogiso,
E.; Yagi, T.; Boger, D. L. J. Am. Chem. Soc. 2006, 128, 11799–11807. (j) Evans,
D. A.; Rajapakse, H. A.; Chiu, A.; Stenkamp, D. Angew. Chem., Int. Ed. 2002,
41, 4573–4576.
(4) For reviews of palladium-catalyzed cross-coupling, see: (a) Miyaura,
N.; Suzuki, A. Chem. Rev. 1995, 95, 2457–2483. (b) de Souza, M. V. N. Curr.
Org. Synth. 2006, 3, 313–326. (c) Negishi, E.-I.; Huang, Z.; Wang, G.;
Mohan, S.; Wang, C.; Hattori, H. Acc. Chem. Res. 2008, 41, 1474–1485.
For selected examples of metal-mediated cross-coupling for the assembly of
dienes in the context of natural product synthesis, see: (d) Langille,
N. F.; Panek, J. S. Org. Lett. 2004, 6, 3203–3206. (e) Marshall, J. A.;
Bourbeau, M. P. Org. Lett. 2002, 4, 3931–3934. (f) Tortosa, M.; Yakelis,
N. A.; Roush, W. R. J. Am. Chem. Soc. 2008, 130, 2722–2723. (g) Nicolaou,
K. C.; Chakraborty, T. K.; Piscopio, A. D.; Minowa, N.; Bertinato, P. J. Am.
Chem. Soc. 1993, 115, 4419–4420.
FIGURE 3. Development of alkyne-alkyne reductive coupling
chemistry.
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FIGURE 4. Challenges with selective reductive cross-coupling of disubstituted alkynes and terminal alkynes, along with the methods known
for control.
FIGURE 5. Reductive cross-coupling methods known are not suitable for the bond construction of interest.
significant progress has been made in the reductive coupling
chemistry of alkynes. As illustrated in Figure 3, early observa-
tions of the dimerization of diphenylacetylene (4 f 5)5 have
been followed by diyne cyclization (7 f 8 f 9)6 and, most
recently, cross-coupling (10 f 11 f 12).7 Here, selective
“crossed” reductive coupling was made possible by the pre-
formation of complex 11 followed by exposure to 3-hexyne. A
notable feature of this reaction was the high regioselectivity
with which the terminal alkyne was functionalized: C-C bond
formation was observed at the terminal position of the alkyne.
Following these ground-breaking accomplishments, more
advanced cross-coupling reactions between alkynes began to
appear. Specifically, convergent assembly of trisubstituted
dienes was achieved through the regioselective coupling of
unsymmetrical internal alkynes with terminal alkynes
(Figure 4).8 In Zr-mediated processes, coupling produces a
mixture of isomeric metallacyclopentadienes (14 and 15), the
equilibration and subsequent protonation of which provide
asymmetrically substituted dienes (16) with very high levels
of selectivity (rs g98:2). Distinct from previously described
reductive cross-coupling processes between alkynes, in this
convergent coupling regiochemical control was achieved in
the functionalization of both alkynes.8,9 In related Ti-mediated
processes, TMS alkynes and conjugated internal alkynes re-
present the most general substrate classes known to react in
a regioselective fashion with terminal alkynes and provide
a means of accessing dienes of general structures 18 and 20.10
While reductive coupling of alkynes has been known for
nearly 50 years, the use of this mode of reactivity for the cross-
coupling of unsymmetrically substituted alkynes remains
significantly limited. As summarized in Figure 5, high levels
of regioselection can be obtained with only a small subset of
internal alkynes (21). The requirement of silyl substitution or
the use of a polarized conjugated alkyne restricts this bimo-
lecular bond construction to the synthesis of stereodefined
dienes of the substitution depicted in 23 and 24. In desiring a
reductive cross-coupling process to provide access to the
branched (E,E)-trisubstituted 1,3-diene substructure shared
by a variety of complex natural products, we set out to design
a means by which to control regioselection in alkyne-alkyne
reductive cross-coupling that would be amenable to the
selectiveformationof dienes 3 from alkynes 1 and2 (Figure5).
Results and Discussion
(5) Vol’pin, M. E.; Dubovitskii, V. A.; Nogina, O. V.; Kursanov, D. N.
Dokl. Akad. Nauk SSSR 1963, 151, 1100–1103.
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A common strategy for the design of regio- and stereo-
selective bond forming reactions in organic chemistry targets
(9) For an example of regioselective reductive cross-coupling between a
1-methylthioalkyne and a symmetrical internal alkyne, see: Van Wagenen, B.
C.; Livinghouse, T. Tetrahedron Lett. 1989, 30, 3495–3498.
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FIGURE 6. Design of a directed alkyne-alkyne reductive cross-coupling.
preassociation of a reagent with a substrate as a means to
render a reaction intramolecular.11 Reactions that proceed by
such preorganization often provide products with exquisite
levels of regio- and stereoselection as a function of the highly
ordered transition state geometries through which they pro-
ceed. As such, we aimed to develop a directed version of a
reductive cross-coupling reaction between alkynes.12
While a number of metals are known to participate in metalla-
cycle-mediated C-C bond formation, our selection of a reac-
tion system suitable for the synthetic problem at hand was
based on (1) the ability of metal alkoxides to undergo rapid and
reversible ligand exchange16 and (2) the previously demon-
strated reactivity of titanium alkoxide reagents in metallacycle-
mediated C-C bond forming reactions.17
Due to the density of heteroatom functionality typically
present in stereochemically complex natural products that
possess the trisubstituted 1,3-diene substructure of interest
(Figure 1),13 we sought a reductive coupling process capable
of being directed by neighboring hydroxy substituents.14,15
Our initial reaction design is outlined in Figure 6. We
speculated that an alkoxide proximal to the preformed tita-
nium-alkyne complex of an internal alkyne may associate
with the neighboring metal center in the transition state for
C-C bond formation.18 If so, we would anticipate that the
(11) For recent reviews of directed reactions, see: (a) Hoveyda, A. H.;
Evans, D. A.; Fu, G. C. Chem. Rev. 1993, 93, 1307–1370. (b) Catellani, M.;
Chiusoli, G. P.; Costa, M. J. Organomet. Chem. 1995, 500, 69–80. (c) Breit, B.
Chem.;Eur. J. 2000, 6, 1519–1524.
(12) For an olefin-directed Ni-mediated regioselective reductive coupling
of alkynes with aldehydes, see: (a) Mahandru, G. M.; Liu, G.; Montgomery,
J. J. Am. Chem. Soc. 2004, 126, 3698–3699. (b) Miller, K. M.; Luanphai-
sarnnont, T.; Molinaro, C.; Jamison, T. F. J. Am. Chem. Soc. 2004, 126,
4130–4131. (c) Miller, K. M.; Jamison, T. F. J. Am. Chem. Soc. 2004, 126,
15342–15343.
(13) For recent reviews of the isolation and synthesis of natural products
from polyketide biosynthetic origin, see: (a) Blunt, J. W.; Copp, B. R.; Hu,
W.-P.; Nunro, M. H. G.; Northcote, P. T.; Prinsep, M. R. Nat. Prod. Rep.
2008, 25, 35–94. (b) Morris, J. C.; Phillips, A. J. Nat. Prod. Rep. 2008, 25, 95–
117. (c) Davies-Coleman, M. T.; Garson, M. J. Nat. Prod. Rep. 1998, 15, 477–
493. (d) Polyketides: Biosynthesis, Biological Activity, and Genetic Engineer-
ing. Baerson, S. R., Ed. 2006, American Chemical Society. 296.
(14) For examples of hydroxyl-directed carbometalation reactions based
on titanium, see: (a) Coleman, R. A.; O’Doherty, C. M.; Tweedy, H. E.;
Harris, T. V.; Thompson, D. W. J. Organomet. Chem. 1976, 107, C15–C17.
(b) Brown, D. C.; Nichols, S. A.; Gilpin, A. B.; Thompson, D. W. J. Org.
Chem. 1979, 44, 3457–3461. (c) Ewing, J. C.; Ferguson, G. S.; Moore, D. W.;
Schultz, F. W.; Thompson, D. W. J. Org. Chem. 1985, 50, 2124–2128. For
hydroxyl-directed carbometalation based on magnesium, see: (d) Eisch, J. J.;
Merkley, J. H. J. Organomet. Chem. 1969, 20, P27–P31. (e) Eisch, J. J.
J. Organomet. Chem. 1980, 200, 101–117. (f) Richey, H. G.; Von Rein, F. W.
J. Organomet. Chem. 1969, 20, P32–P35. (g) Hoveyda, A. H.; Xu, Z. J. Am.
Chem. Soc. 1991, 113, 5079–5080. (h) Hoveyda, A. H.; Xu, Z.; Morken, J. P.;
Houri, A. F. J. Am. Chem. Soc. 1991, 113, 8950–8952. (i) Itami, K.; Mitsudo,
K.; Yoshida, J. Angew. Chem., Int. Ed. 2001, 40, 2337–2339. (j) Itami, K.;
Kamei, T.; Yoshida, J. J. Am. Chem. Soc. 2003, 125, 14670–14671. For
directed carbometalation based on tantalum, see: (k) Takai, K.; Yamada,
M.; Odaka, H.; Utimoto, K. J. Org. Chem. 1994, 59, 5852–5853. For directed
carbometalation based on aluminum/zirconium, see: (l) Ma, S.; Negishi,
E.-I. J. Org. Chem. 1997, 62, 784–785.
(15) For examples of alkoxide-directed reductive cross-coupling that does
not rely on preformation of a presumed fused bicyclic metallacyclopropene,
see: (a) Ryan, J.; Micalizio, G. C. J. Am. Chem. Soc. 2006, 128, 2764–2765.
(b) Reichard, H. A.; Micalizio, G. C. Angew. Chem., Int. Ed. 2007, 46, 1440–
1443. (c) McLaughlin, M.; Takahashi, M.; Micalizio, G. C. Angew. Chem.,
Int. Ed. 2007, 46, 3912–3914. (d) Shimp, H. L.; Micalizio, G. C. Chem.
Commun. 2007, 4531–4533. (e) Takahashi, M.; Micalizio, G. C. J. Am. Chem.
Soc. 2007, 129, 7514–7516. (f) McLaughlin, M.; Shimp, H. L.; Navarro, R.;
Micalizio, G. C. Synlett 2008, 735–738. These reports describe reactions
whereby selectivity arises from treatment of a preformed Ti-alkyne complex
with an unsaturated alkoxide. A sequence of ligand exchange and intramo-
lecular carbometalation are associated with the high levels of selectivity
observed in these processes. The reaction described in this manuscript derives
selectivity from a distinct process, whereby preformation of a Ti-alkyne
complex on the π-component containing the tethered alkoxide is followed by
intermolecular carbometalation with a terminal alkyne.
(16) (a) Sharpless, K. B.; Michaelson, R. C. J. Am. Chem. Soc. 1973, 95,
6136–6137. (b) Katsuki, T.; Sharpless, K. B. J. Am. Chem. Soc. 1980, 102,
5974–5976. (c) Katsuki, T.; Martin, V. S. Org. React. 1996, 48, 1–299.
(d) Sharpless, K. B.; Woodard, S. S.; Finn, M. G. Pure Appl. Chem. 1983,
55, 1823–1836. (e) Woodard, S. S.; Finn, M. G.; Sharpless, K. B. J. Am.
Chem. Soc. 1991, 113, 106–113.
(17) For reviews of titanium alkoxide-mediated C-C bond formation,
see: (a) Kulinkovich, O. G.; de Meijere, A. Chem. Rev. 2000, 100, 2789–2834.
(b) Sato, F.; Urabe, H.; Okamoto, S. Chem. Rev. 2000, 100, 2835–2886.
(18) This design was constrained by the requirement of pregenerating a
Ti-alkyne complex of the internal alkyne (rather than the terminal alkyne).
Attempted reductive coupling of terminal alkynes with aldehydes has been
reported to be unsuccessful: (a) Harada, K.; Urabe, H.; Sato, F. Tetrahedron
Lett. 1995, 36, 3203–3206. Surprisingly, some examples have reported that
related coupling reactions with terminal alkynes, that likely proceed by
formation of a titanium-alkyne complex are successful: (b) Yamaguchi,
S.; Jin, R.-Z.; Tamao, K.; Sato, F. J. Org. Chem. 1998, 63, 10060–10062. For
the generation of metallated titanacyclopropenes from terminal alkynes, see:
(c) Averbuj, C.; Kaftanov, J.; Marek, I. Synlett 1999, 1939–1941.
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TABLE 1. Initial Study of Alkoxide-Directed Reductive Cross-Cou-
pling of Internal Alkynes with Terminal Alkynes22
FIGURE 7. Generation of stereodefined coupling partners.
two metal-carbon bonds (a and b) of the asymmetrically
substituted metallacyclopropene 30 would differ in their levels
of reactivity in bimolecular carbometalation. Of the products
that would be reasonably expected from such a process
(26-29), we anticipated that isomers 27 and 29 were unlikely,
as others have demonstrated that functionalization of the
terminal alkyne component generally occurs at the terminal
carbon of the alkyne.10 Of the remaining isomeric products
(26 and 28), we expected that the transition state leading to the
metallacyclic precursor of 28 (B or C) would be destabilized
due to the significant strain associated with the formation of a
bridgehead alkene (via a carbometalation process that en-
gaged bond “a” of 30; see B) or require interruption of the
tethering interaction (σTi-O; en route to C).
Based on this design, and the desire to define a syntheti-
cally straightforward coupling process, it was essential that
the coupling partners be readily available, without the
requirement of numerous orthogonal functionalization
reactions to C-C bond formation. A variety of methods
are available for the synthesis of substituted alkynes, and
most of these install the alkyne through a process that
occurs with simultaneous chain extension (C-C bond
formation).19 Among the known methods, Marshall’s pro-
pargylation chemistry was particularly attractive, as C-C
bond formation occurs in concert with the establishment of
two stereogenic centers.20 Additionally, Marshall’s thor-
ough study of this process has led to stereodivergent
methods that allow for the synthesis of all possible stereo-
isomers of simple homopropargylic alcohols. As illustrated
in Figure 7, pentynylation of readily available chiral alde-
hydes provides direct and stereoselective access to all
diastereomers of a model substrate suitable for interroga-
tion of the proposed alkoxide-directed reductive cross-
coupling reaction.21
aYield based on terminal alkyne. bRegioisomeric ratio determined by
1H NMR of the product mixture after flash column chromatography
(see the Supporting Information for details). cCompound 39 is not the
major isomer from this coupling reaction. dClTi(Oi-Pr)3, c-C5H9MgCl,
-78 to -30 °C, then -78 °C and addition of terminal alkyne.
deliver complex products of potential utility in natural
product synthesis (Table 1).22 The coupling reactions were
conducted by initial deprotonation of the homopropargylic
alcohol, followed by exposure to the combination of ClTi-
(O-i-Pr)3 and cyclopentylmagnesium chloride (to form a
presumed intermediate metallacyclopropene), addition of
the terminal alkyne, and aqueous workup. As illustrated in
entries 1-4, the factors that contribute to selectivity in this
reductive cross-coupling process appeared more complex
than initially expected. In most cases, high to moderate
levels of regioselection were observed for the production of
the desired isomer (entries 1-3). Surprisingly, coupling of
Consistent with our goal of defining a general method
that was useful for the synthesis of a range of stereochemi-
cally complex targets, we began investigating the coupling
reaction of each stereodefined homopropargylic alcohol
(31-34) with a second chiral coupling partner (35) to
(19) For general reviews of acetylene chemistry, see: (a) Stang, P. J.;
Diederich, F., eds. Modern Acetylene Chemistry. 1995, Wiley-VCH. 527.
(b) Diederich, F.; Stang, P. J.; Tykwinski, R. R., eds. Acetylene Chemistry:
Chemistry, Biology, and Material Science. 2005, Wiley-VCH. 2005.
(20) For recent reviews, see: (a) Marshall, J. A. J. Org. Chem. 2007, 72,
8153–8166. (b) Marshall, J. A. Chem. Rev. 2000, 100, 3163–3185.
(21) Bahadoor, A. B.; Flyer, A.; Micalizio, G. C. J. Am. Chem. Soc. 2005,
127, 3694–3695.
(22) Shimp, H. L.; Micalizio, G. C. Org. Lett. 2005, 7, 5111–5114.
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FIGURE 8. Demonstration in the context of natural product synthesis.
the anti-syn isomer 34 was unselective, providing a nearly
equal distribution of isomers A-C.
studies proved to be of utility in complex molecule synthesis.
For example, initial studies toward a convergent total synth-
esis of callystatin explored the reductive cross-coupling of
the homopropargylic alcohol 46 with terminal alkyne 48
(Figure 8).23 While the desired product 49 was produced in
moderate yield and selectivity, we found in subsequent
studies that both yield and selectivity were increased in the
coupling reaction of the TMS-protected substrate 47 (75%,
rr = 5:1). In a related campaign in total synthesis targeting
dictyostatin, reductive cross-coupling between 51 and 52
provided the stereodefined tetraene 53 in 78% yield (rr =
7:1).24 In each case, the application of the alkyne-alkyne
reductive cross-coupling reaction proved quite useful, defin-
ing a highly convergent method for the assembly of natural
products of polyketide biosynthetic origin, while demon-
strating an impressive functional group compatibility profile
and substantial chemoselectivity.
These initial results demonstrated that relative stereo-
chemistry of the internal alkyne component plays a sig-
nificant role in site-selectivity for the reductive coupling
reaction. Interestingly, this stereochemical dependence on
regiochemistry applies not only to the functionalization of
the internal alkyne, but also to the terminal alkyne cou-
pling partner 35 (as demonstrated by the varying levels of
isomer C observed in entries 1-4 as a function of the
stereochemistry of the internal alkyne).22 While highlight-
ing a unique interplay between stereochemical pairing and
site-selective C-C bond formation, the observation of
isomer C in all of these reactions was surprising, as
previous studies of reductive cross-coupling reactions of
simple TMS-alkynes and polarized alkynes with terminal
alkynes did not lead to the formation of noticeable quan-
tities of this isomer.10
Observing a glimpse of the potential power of this cross-
coupling reaction in natural product synthesis, we aimed to
achieve higher levels of control in this fragment coupling
process. In considering the complexity associated with the
trends in regioselectivity illustrated in Table 1, the uncer-
tainty regarding the nature of the transition state for these
processes guided our next series of experiments. The initial
design for the alkoxide-directed reductive cross-coupling
was based on the proposition that a bicyclic metallacyclo-
propene plays a role in the transition state for C-C bond
formation. With this mechanistic picture in mind, the
homopropargylic alcohol substrates explored may not
represent ideal substrates to probe the merit of the design.
As depicted in Figure 9, we anticipated that the proposed
intermediate bicyclic metallacyclopropene 54 would be
destabilized by ring strain. As such, we recognized that
monocyclic (55) or oligomeric (56) species may play
a significant role in these cross-coupling reactions. To
further complicate understanding the trends in selectivity
observed, we expected that partitioning between 54, 55, and
To explore the impact of the tethered hydroxy substituent
on regioselection, several experiments were conducted with the
corresponding PMB ethers. While coordination of the ethereal
oxygen of the PMB ether might still be expected to play a role
in the transition state for reductive cross-coupling, we observed
a significant change in selectivity for these reactions. As
illustrated in entry 5, use of the PMB-protected anti-syn isomer
40 results in an enhancement of regioselection, providing
the desired trisubstituted 1,3-diene 41 in 82% yield (rr 3:1).
Unfortunately, this enhancement of regioselection with the
use of the fully protected internal alkyne is not uniform
throughout the stereoisomeric series. Coupling of the PMB-
protected syn-anti isomer 42 leads to a slight decrease in
regioselection compared to the homopropargylic alcohol
(entry 6 vs entry 2), while coupling of the PMB-protected
anti-anti isomer 44 leads to a modest increase in regioselection
(entry 7 vs entry 3).
Overall, these preliminary results suggested that the
factors that govern site-selectivity in this reductive cross-
coupling reaction are complex, affected by both the stereo-
chemistry of the internal alkyne component and the nature of
the substituents present on the tether (PMB vs alkoxide).
Nevertheless, the bond construction defined by these initial
(23) Reichard, H. A.; Rieger, J. C.; Micalizio, G. C. Angew. Chem., Int.
Ed. 2008, 47, 7837–7840.
(24) Shimp, H. L.; Micalizio, G. C. Tetrahedron 2009, 65, 5908–5915.
7216 J. Org. Chem. Vol. 74, No. 19, 2009

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TABLE 2. Highly Regioselective Alkoxide-Directed Reductive Cross-
Coupling Reactions of Internal Alkynes with Terminal Alkynes
FIGURE 9. Uncertainty regarding the nature of the titanium-alkyne
complex in the transition state for carbometalation and proposed
perturbation.
56 may also contribute to the complex structure-selectivity
relationships observed in these reductive cross-coupling
reactions.
While the precise nature of the reactive metallacycle in
the transition state for C-C bond formation is unknown,
we speculated that relocating the “directing” functional
group to a position further removed from the alkyne (as
in 57) may alleviate some of the anticipated ring strain
in the formation of a proposed bicyclic metallacyclopro-
pene (i.e 58 vs 54). If such a structural modification led
to the preferential participation of a structure like 58 in
the transition state for coupling, we would anticipate
selective carbometalation with a terminal alkyne to
deliver metallacyclopentadienes of general structure 59.
As before, this expectation is in accord with a transition-
state geometry that leads to the formation of a fused
bicyclic metallacyclopentadiene (via cleavage of bond
“b”) in preference to a bridged bicyclic isomer (via cleavage
of bond “a”).
To our delight, we found that stereodefined internal
alkynes of general structure 57 were superb substrates for
reductive cross-coupling with terminal alkyne 35 (Table 2).
In most cases, regioselection was g20:1 in favor of the
desired (E,E)-trisubstituted 1,3-diene product (entries
1-4). Furthermore, we observed that double-asymmetric
relationships do little to affect the regioselection of this cross-
coupling process. As illustrated in entries 5-8, coupling with
ent-35 is similarly effective with all stereoisomers of the
internal alkyne (rs g20:1 in all cases).
While each stereoisomer 60-63 demonstrated high levels
of regioselection in reductive cross-coupling reactions with
alkynes 35 and ent-35, the origins of regioselection remain a
complex function of alkyne structure. As demonstrated in
entry 9, replacing the PMB ether of 61 with a methyl ether
results in a modest decrease in regioselection in reductive
cross-coupling of alkyne 72 with 35, yet still delivers the
stereodefined (E,E)-trisubstituted 1,3-diene 73 in 78% as a
10:1 mixture of regioisomers.25
aYield based on terminal alkyne. bRegioisomeric ratio with respect to
functionalization of the internal alkyne (A/B) determined by 1H NMR
of the product mixture after a simple filtration column (see the Support-
ing Information for details). In a few cases, observable quantities of the
minor regioisomer “C” (as defined in Table 1) were observed (entry 4 =
12:1, entry 6 = 14:1, entry 7 = 17:1).
With a highly selective reductive cross-coupling reac-
tion in hand for the synthesis of stereochemically complex
1,3-dienes, we began to explore the basic functional group
compatibility and selectivity of the process (Figure 10).
In the cross-coupling of an array of differentially functiona-
lized terminal alkynes with a propionate-inspired internal
alkyne, uniformly high levels of regioselection were observed
(74-81). Among the observations made, terminal alkynes
(25) Perez, L. J.; Micalizio, G. C. Synthesis 2008, 627–648. Similarly,
removal of branching between the tethered alkoxide and the internal alkyne
also leads to significant decreases in regioselection. The quantitative effect of
each branched substituent on regioselection has not been determined.
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FIGURE 10. Structurally diverse terminal alkynes are compatible with the alkoxide-directed cross-coupling.
that lack R-branching are suitable substrates, the coupling is
compatible with fluorous technology (74),26 and a diverse
array of saturated and aromatic heterocycles are compatible
with this metal-mediated C-C bond-forming process
(76-81). In all cases, the diene products were produced with
very high levels of regioselection and as single stereoisomers.
cross-coupling reaction that provides an exceptionally di-
rect, stereo- and regioselective route to substituted 1,3-dienes
that are found embedded in the skeletons of many biologi-
cally active polyketide-derived natural products. Central to
this success, we have elucidated a means for the control of
regioselection based on the proximity of a tethered alkoxide
to the internal alkyne-containing coupling partner. While the
precise mechanistic implications of our observations remain
unclear, highest selectivities were observed with substrates
bearing an alkoxide γ to the internal alkyne. Due to the low
cost of the metal-containing reagents, ready availability of
the coupling partners, benign nature of the byproducts (TiO2
and Mg(II) salts), and substrate-controlled selectivity, the
current fragment coupling process is anticipated to be of
great utility in chemical synthesis.
Conclusion
Branched (E,E)-trisubstituted 1,3-dienes are structural mo-
tifs found in a range of complex bioactive natural products.
While stereoselective methods exist for their preparation,
these methods typically require numerous sequential transfor-
mations to (1) enable stepwise carbonyl olefination or (2)
prepare the stereodefined coupling partners required for cat-
alytic cross-coupling methodology (vinyl halides and vinyl
organometallic reagents). With a goal of defining chemical
methods to increase the efficiency with which complex natural
products can be prepared, we were guided by the substitution
pattern of a collection of polyunsaturated natural products
(Figure 1). We targeted the development of a reductive cross-
coupling reaction between suitably substituted alkynes to
define a process that forges a C-C bond in concert with
establishing the stereochemistry of two substituted alkenes.
Overall, attempting to define a convergent coupling reac-
tion that would avoid the multiple functional group manipula-
tions required in other common pathways to stereodefined
1,3-dienes.
Experimental Section
Representative Example of the Alkoxide-Directed Reductive
Cross-Coupling: (2S,3S,4R)-(5E,7E)-3-(4-Methoxybenzyloxy)-
2,4,6-trimethyl-8-((20R,40S,50R)-50-methyl-20-phenyl-10,30-dioxan-
40-yl)octa-5,7-dien-1-ol (64). To a solution of the internal alkyne
60 (20 mg, 0.072 mmol) in Et2O (725 μL, 0.1 M) at ambient
temperature was added n-BuLi (30 μL, 0.072 mmol, 2.5 M in
hexanes), followed by Ti(Oi-Pr)4 (32 μL, 0.109 mmol). The
resultant pale yellow solution was cooled to -78 °C and treated
with c-C5H9MgCl (110 μL, 0.217 mmol, 2.0 M in Et2O). The
mixture was allowed towarmto -30 °C over 1.5 h and was stirred
at -30 °C for 30 min. The resulting dark brown solution was
cooled to -78 °C and was treated with a solution of terminal
alkyne 35 (102 μL, 0.051 mmol, 0.5 M in Et2O). The mixture was
allowed to warm to 0 °C over 2 h, diluted with Et2O (2 mL), and
quenched by the addition of 1 N HCl (1 mL). After being stirred
at ambient temperature for 45 min, the biphasic mixture was
transferred to a separatory funnel, extracted with Et2O (3 ꢀ
10 mL), dried over MgSO4, filtered, and concentrated in vacuo.
Flash column chromatography on 10 mL of SiO2 eluting with
10% EtOAc/hexanes to 50% EtOAc/hexanes provided the
coupled product as a 17:1 mixture of regioisomers (15.8 mg,
64%). Isolation of the major regioisomer was achieved by
While the basic reactivity required for this bond construc-
tion, the reductive dimerization of alkynes, was discovered
nearly 50 years ago, lack of a suitable means to control
selectivity in these processes has greatly limited the impact
of this reductive cross-coupling in natural product syn-
thesis. Here, we define a titanium-mediated reductive
(26) For recent examples, see: (a) Curran, D. P. Science 2008, 321, 1645–
1646. (b) Chu, Q.; Henry, C.; Curran, D. P. Org. Lett. 2008, 10, 2453–2456.
(c) Jung, W.-H.; Guyenne, S.; Riesco-Fagundo, C.; Mancuso, J.; Nakamura,
S.; Curran, D. P. Angew. Chem., Int. Ed. 2008, 47, 1130–1133.
7218 J. Org. Chem. Vol. 74, No. 19, 2009

Perez et al.
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normal-phase HPLC using a gradient from 20% EtOAc/hexanes
LRMS (EI) calcd for C30H40O5Na 503.3 m/z (M þ Na), obsed
503.5 m/z (M þ Na)þ; HRMS (FT-ICR) calcd for C30H40O5Na
503.2768 m/z (M þ Na), obsd 503.2778 m/z (M þ Na)þ.
to 50% EtOAc/hexanes over 25 min: [R]20
þ32.4 (c 0.7,
589
1
CHCl3); H NMR (500 MHz, CDCl3) δ 7.51 (d, J = 6.9 Hz,
2H), 7.38-7.28 (m, 5H), 6.88 (d, J = 8.2 Hz, 2H), 6.31 (d, J =
15.8 Hz, 1H), 5.61 (dd, J = 15.8, 7.3 Hz, 1H), 5.55(s, 1H), 5.31 (d,
J = 9.8 Hz, 1H), 4.58 (A of AB, J = 10.7 Hz, 1H), 4.53 (B of AB,
J = 10.7 Hz, 1H), 4.18 (dd, J = 11.4, 4.7 Hz, 1H), 3.93 (dd, J =
9.8, 8.2 Hz, 1H), 3.80 (s, 3H), 3.59-3.52 (m, 3H), 3.41 (dd, J =
8.8, 2.2 Hz, 1H), 2.85-2.77 (m, 1H), 1.99-1.90 (m, 1H),
1.90-1.82 (m, 1H), 1.77 (m, 3H), 1.08 (d, J = 6.6 Hz, 3H),
0.86 (d, J = 6.9 Hz, 3H), 0.79 (d, J = 6.6 Hz, 3H); 13C NMR
(126 MHz, CDCl3) δ 159.2, 138.6, 138.5, 136.7, 132.1, 130.9,
129.4, 128.8, 128.3, 126.3, 124.8, 113.8, 101.4, 84.9, 83.8, 74.7, 73.1,
66.2, 55.3, 38.6, 36.5, 34.5, 31.6, 22.6, 17.9, 14.1, 12.7, 12.6, 10.7; IR
(thin film, NaCl) 3481, 2961, 2932, 2872, 2836, 1612, 1514, 1457,
1387, 1364, 1302, 1248, 1174, 1070, 1032, 967, 822, 752, 698;
Acknowledgment. We gratefully acknowledge financial
support of this work by the American Cancer Society
(RSG-06-117-01), the Arnold and Mabel Beckman Founda-
tion, Boehringer Ingelheim, Eli Lilly & Co., Bristol-Myers
Squibb (for a graduate fellowship to H.L.S.) and Novartis
(for a graduate fellowship to L.J.P.).
Supporting Information Available: Experimental proce-
dures, compound characterization, and copies of spectral data.
This material is available free of charge via the Internet at http://
pubs.acs.org.
J. Org. Chem. Vol. 74, No. 19, 2009 7219