Group 4 metals in polyketide synthesis: A convergent strategy for the synthesis of polypropionate-derived (E,E)-trisubstituted 1,3-dienes

Article abstract of DOI:10.1021/ol052241n

(Chemical Equation Presented) A convergent Group 4 metal-mediated coupling process is described for the synthesis of polypropionate-derived (E,E)-1,3-dienes. Both the stereochemistry of the internal alkyne and the presence/absence of a tethered alkoxide o

Full text of DOI:10.1021/ol052241n

ORGANIC
LETTERS
2005
Vol. 7, No. 22
5111-5114
Group 4 Metals in Polyketide Synthesis:
A Convergent Strategy for the Synthesis
of Polypropionate-derived
(E,E)-Trisubstituted 1,3-Dienes
Heidi L. Shimp and Glenn C. Micalizio*
Sterling Chemistry Laboratory, Department of Chemistry, Yale UniVersity,
New HaVen, Connecticut 06520-8107
glenn.micalizio@yale.edu
Received September 15, 2005
ABSTRACT
A convergent Group 4 metal-mediated coupling process is described for the synthesis of polypropionate-derived (E,E)-1,3-dienes. Both the
stereochemistry of the internal alkyne and the presence/absence of a tethered alkoxide on this
in dictating the regiochemical course of these reactions.
π-component were found to play critical roles
Natural products of polyketide biosynthetic origin represent
an important class of synthetic targets that display a range
of potent and diverse biological activities.1,2 These activities
range from antibacterial and antifungal to cytotoxic and
immunosuppressive. Members of this class have long served
to stimulate the development of reactions designed to access
their highly functionalized acyclic architectures. As such, a
variety of powerful carbon-carbon bond-forming reactions
have been developed that enable the synthesis of complex
polypropionate-derived targets.3-6 Trisubstituted 1,3-dienes
are commonly found embedded in polypropionate regions
of natural products (Figure 1).7-9 This stereodefined func-
tional group represents a challenge for streamlined synthesis
of such targets as current methods for 1,3-diene synthesis
often require either (1) multistep olefination-based pro-
cesses10 or (2) convergent cross-coupling strategies that
dictate the preparation of stereodefined olefinic partners prior
to coupling.11 Either approach requires deviation from
iterative aldol or allymetal-based bond construction-strate-
gies that are often employed for polyketide synthesis. To
(5) Denmark, S. E.; Almstead, N. G. Allylation of Carbonyls: Methodol-
ogy and Stereochemistry; In Modern Carbonyl Chemistry; Otera, J., Ed.;
Wiley-VCH: Weinheim, 2000; p 299.
(6) Chemler, S. R.; Roush, W. R. Recent Applications of the Allylation
Reaction to the Synthesis of Natural Products; In Modern Carbonyl
Chemistry; Otera, J., Ed.; Wiley-VCH: Weinheim, 2000; p 403.
(7) Kobayashi, M.; Higuchi, K.; Murakami, N.; Tajima, H.; Aoki, S.
Tetrahedron Lett. 1997, 38, 2859-2862.
(8) Dilip de Silva, E.; Williams, D. E.; Andersen, R. J.; Klix, H.; Holmes,
C. F. B.; Allen, T. M. Tetrahedron Lett. 1992, 33, 1561-1564.
(9) Hamill, R. L.; Haney, M. E. J.; Stamper, M.; Wiley: P. F. Antibiot.
Chemother. 1961, 11, 328-334.
(10) Modern Carbonyl Olefination: Methods and Applications; Takeda,
T., Ed.; Wiley-VCH: Weinheim, 2004.
(1) Macrolide Antibiotics. Chemistry, Biology, and Practice, 2nd ed.;
Omura, S., Ed.; Academic Press: New York, 2002.
(2) Davies-Coleman, M. T.; Garson, M. J. Nat. Prod. Rep. 1998, 15,
477-493.
(3) Paterson, I.; Cowden, C. J.; Wallace, D. J. Stereoselective Aldol
Reactions in the Synthesis of Polyketide Natural Products; In Modern
Carbonyl Chemistry; Otera, J., Ed.; Wiley-VCH: Weinheim, 2000; p 249.
(4) Carreira, E. M. Aldol Reaction: Methodology and Stereochemistry;
In Modern Carbonyl Chemistry; Otera, J., Ed.; Wiley-VCH: Weinheim,
2000; p 279.
10.1021/ol052241n CCC: $30.25
© 2005 American Chemical Society
Published on Web 10/04/2005

whereby the homopropargylic alcohol (6) could be func-
tionalized by a modified Group 4 metal-mediated coupling
process with a terminal alkyne (9).14 This reaction pathway
would provide a direct approach to the synthesis of highly
functionalized 1,3-dienes and, in combination with our earlier
report,12 greatly increase the generality of metallacycle-based
bond-construction processes for polyketide assembly (6 f
8 or 6 f 10). Herein, we describe a regio- and stereoselective
titanium-mediated coupling reaction of homopropargylic
alcohols (6) with terminal alkynes (9) that provides direct
access to functionalized 1,3-dienes (10) relevant to the
synthesis of complex polyunsaturated polypropionates.
Figure 1. Trisubstituted (E,E)-1,3-dienes: Common structural
motifs found in natural products of polyketide biosynthetic origin.
enable the efficient preparation of such complex polyketide-
derived targets, synthetic methods are needed that provide
access to this stereodefined structural motif, while remaining
tolerant of a wide variety of functional groups. Herein, we
report (1) a convergent approach to this synthetic problem
that greatly expedites the synthesis of such molecular
architecture and (2) an unprecedented interplay between
stereochemistry and the presence of tethered alkoxides in
the control of regioselection in Group 4 metal-mediated diyne
coupling reactions.
Previously, we reported a two-step method for the
convergent coupling of differentially functionalized alde-
hydes that enables the synthesis of ene-1,5-diols in a regio-
and stereoselective manner (4 f 6 f 8; Figure 2).12 In line
Figure 3. Concerning regioselection.
Although titanium alkoxide based coupling reactions of
differentially functionalized alkynes have been reported, high
regioselectivities for functionalization of the internal alkyne
component have been achieved only with TMS-substituted
alkynes and conjugated 2-alkynoates, requirements that
prevent the broad utility of these coupling processes for
polyketide assembly.14-17 Our previous report on Group 4
metal alkoxide-mediated coupling reactions for the synthesis
of ene-1,5-diols highlighted the effectiveness of highly
branched polyketide architecture in dictating the regiochemi-
cal course of reductive coupling reactions of internal alkynes
with branched aldehydes (Figure 3a).12 Concerning the utility
of Group 4 metal alkoxide-mediated coupling processes for
Figure 2. Group 4 metal alkoxide mediated reactions for the
synthesis of complex polyketides.
with our goal of developing a general strategy for the
efficient synthesis of architecturally complex and structurally
diverse polypropionates, we envisioned a divergent pathway13
(11) Huo, S.; Negishi, E. Palladium-Catalyzed Alkenyl-Aryl, Aryl-Alkenyl,
and Alkenyl-Alkenyl Coupling Reactions; John Wiley & Sons: New York,
2002; Vol. 1 of 2.
(12) Bahadoor, A. B.; Flyer, A.; Micalizio, G. C. J. Am. Chem. Soc.
2005, 127, 3694-3695.
(13) Schreiber, S. L. Science 2000, 287, 1964-1969.
(14) Hamada, T.; Suzuki, D.; Urabe, H.; Sato, F. J. Am. Chem. Soc.
1999, 121, 7342-7344.
(15) Tanaka, R.; Yuza, A.; Watai, T.; Suzuki, D.; Takayama, Y.; Sato,
F.; Urabe, H. J. Am. Chem. Soc. 2005, 127, 7774-7780.
5112
Org. Lett., Vol. 7, No. 22, 2005

the assembly of polyunsaturated polyketides, inspection of
the potential orientation of coupling partners 6 and 9 leads
to the identification of four distinct pathways that have the
potential to provide the regioisomeric dienes A-D (Figure
3b). At the outset, we anticipated that the branched polyketide
architecture present in 6 would serve to destabilize the tran-
sition states leading to the formation of dienes B and D,
hence providing a selective coupling procedure for the
formation of the (E,E)-trisubstituted 1,3-diene product A.
Additionally, because of the compatibility of this class of
coupling reactions with metal alkoxides,12,18-22 we anticipated
that carbon-carbon bond formation en route to stereodefined
dienes of general structure A would ensue without required
protection of the homopropargylic alcohol, a factor that
should lead to increased efficiency in polyketide synthesis.
coupling reactions of polyketide-derived internal alkynes with
aldehydes, the syn-anti and syn-syn stereoisomers (11 and
14) provided the highest levels of regioselection, while the
anti-syn stereoisomer (18) exhibited the lowest levels of
regioselection in this diyne-based coupling reaction. Interest-
ingly, the stereochemistry present on the internal alkyne
component was found to significantly influence the product
distribution, providing variable levels of regiosomer C.
The production of regioisomer C in these coupling
reactions is surprising, as this isomer is typically not observed
in Group 4 metal alkoxide-mediated diyne couplings.14-17
Interestingly, removing the tethered alkoxide in anti-syn
stereoisomer 18 led to a significant enhancement in regio-
selection favoring the production of regioisomer A, while
eliminating the production of a third regioisomer C (Table
1, entry 5; rr ) 3:1:0). These results suggest that the
combined effect of stereochemistry and the presence of a
tethered alkoxide plays a significant role in regioselection,
an influence that has not preViously been described in Group
4 metal-mediated C-C bond-forming processes.
Table 1. Construction of Complex Polyketides by
Regioselective Coupling Reactions of Branched
Homopropargylic Alcohols and Terminal Alkynes
Following up on this interesting result, use of protected
homopropargylic ethers 22 or 24, in coupling reactions with
terminal alkyne 12, provided the functionalized dienes 23
Table 2. Flexible Convergent Method for Assembly of
(E,E)-Trisubstituted 1,3-Dienes
a Yield based on terminal alkyne. b Regioisomeric ratio determined by
1H NMR of the product mixture after flash column chromatography (see
Supporting Information for details). c ClTi(Oi-Pr)3, c-C5H9MgCl, -78 to
-30 °C, then -78 °C and addition of terminal alkyne.
As anticipated, deprotonation of the syn-anti homopro-
pargylic alcohol 11, followed by exposure to the combination
of ClTi(Oi-Pr)3 and cyclopentylmagnesium chloride, and
addition of the terminal alkyne 12 provided, after aqueous
workup, the 1,3-diene 13 in 50% yield (regioisomeric ratio
(rr) ) 15:2:1). Similarly, coupling of the diastereomeric
homopropargylic alcohols 14, 16 and 18 with terminal alkyne
12 provided the 1,3-diene products 15, 17 and 19. Consistent
with our previous study of Group 4 metal-mediated reductive
a Regioisomeric ratio determined by 1H NMR of the product mixture
after flash column chromatography. b Regioisomeric ratio reported as A:B
(as depicted in Table 1). c Yield and regioisomeric ratio reported after
deprotection of the silyl ether (TBAF, THF).
and 25 in 70% and 87% yield (rr g 5:1). Consistent with
our earlier observation, the regioselection of each coupling
process was influenced by protection of the homopropargylic
Org. Lett., Vol. 7, No. 22, 2005
5113

alcohol; evidence for production of a third regioisomer (C)
was not observed in either of these cases.
to natural products of polyketide biosynthetic origin. Our
preliminary studies have defined (1) a new regioselective
carbon-carbon bond-forming process for the synthesis of
unsaturated polypropionates that greatly expands the role of
Group 4 metals in the synthesis of complex polyketides, (2)
the impact of stereochemistry and the homopropargylic
functional group on regioselection in these Group 4 metal-
mediated diyne coupling reactions, and (3) a coupling process
for the synthesis of 1,3-dienes that is tolerant of aromatic
halides and triflates. As such, this method is anticipated to
greatly facilitate the efficient synthesis of complex polyketide-
derived targets. Progress along these lines, as well as
exploration of the role of tethered alkoxides in Group 4
metal-mediated C-C bond-forming processes, will be re-
ported in due course.
Next, variation in the structure of the terminal alkyne was
explored. High levels of regioselection were seen in the
coupling reaction between a homopropargylic ether (26) and
a terminal alkyne lacking R-branching (27; entry 3); again,
only two regioisomers were observed (A and B). Coupling
of the aryl-substituted alkynes 29 and 31 with the homopro-
pargylic ether 26 were similarly effective, and provided
regioselective access to the dienes 30 and 32 (entries 4 and
5). Importantly, each of these products bears a functional
group that would complicate the use of modern cross-
coupling methods to install the central stereodefined diene.11
Overall, we have described a general metal-mediated
coupling reaction of homopropargylic alcohols and ethers
with terminal alkynes that provides highly functionalized
(E,E)-trisubstituted 1,3-dienes, a structural motif common
Acknowledgment. We gratefully acknowledge financial
support of this work by the Arnold and Mabel Beckman
Foundation, Boehringer Ingelheim, Eli Lilly & Co., and Yale
University.
(16) Kulinkovich, O. G.; Meijere, A. Chem. ReV. 2000, 100, 2789-2834.
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2886.
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Supporting Information Available: Experimental pro-
cedures and tabulated spectroscopic data for new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(20) Sung, M. J.; Pang, J.-H.; Park, S.-B.; Cha, J. K. Org. Lett. 2003, 5,
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