A Ru-catalyzed tandem alkyne-enone coupling/Michael addition: Synthesis of 4-methylene-2,6-cis-tetrahydropyrans

Article abstract of DOI:10.1021/ol0520065

(Chemical Equation Presented) A Ru-catalyzed tandem alkyne-enone coupling/Michael addition reaction is reported. It provides an efficient, atom-economic entry to 4-methylene-2,6-cis-tetrahydropyrans from simple, readily available homopropargylic alcohols

Full text of DOI:10.1021/ol0520065

ORGANIC
LETTERS
2005
Vol. 7, No. 21
4761-4764
A Ru-Catalyzed Tandem Alkyne−Enone
Coupling/Michael Addition: Synthesis of
4-Methylene-2,6-cis-tetrahydropyrans
Barry M. Trost,* Hanbiao Yang, and Georg Wuitschik
Department of Chemistry, Stanford UniVersity, Stanford, California 94305-5080
bmtrost@stanford.edu
Received August 18, 2005
ABSTRACT
A Ru-catalyzed tandem alkyne−enone coupling/Michael addition reaction is reported. It provides an efficient, atom-economic entry to 4-methylene-
2,6-cis-tetrahydropyrans from simple, readily available homopropargylic alcohols and
â,γ
-unsaturated enones in good yields. Further
functionalization of the resultant vinylsilane leads to the synthesis of either geometrically defined trisubstituted alkene exocyclic to the 2,6-
cis-dihydropyran.
Natural products provide constant challenges and inspiration
for synthetic chemists. The tetrahydropyran ring system is
present in a range of natural products as illustrated in the
case of the bryostatins, a family of marine natural products
isolated from the bryozoan invertebrates Bulgula neritina and
Amathia conVulata. They have attracted a great deal of
attention from the synthetic community owing to their diverse
biological activities and novel structural motif.1 While several
elegant total syntheses exist, the potential utility of this family
of compounds encourages the development of more concise
strategies.2-4 Among the challenges presented by the bryo-
statins, control of the alkene geometry exocyclic to the
tetrahydropyran rings (ring B and ring C) represents a
formidable task.3-6
Cycloaddition-type reactions enhance synthetic efficiency
by creating molecular complexity in a single event with a
high atom economy.7 As part of our ongoing effort to effect
a more efficient synthesis of bryostatin natural products, we
became intrigued by a proposal of forming 4-methylene-2,6-
cis-tetrahydropyrans in an annulation process as illustrated
in Scheme 1.8,9
(1) (a) Bryostatin 1 isolation and structure determination: Pettit, G. R.;
Herald, C. L.; Clardy, J.; Arnold E.; Doubek, D. L.; Herald, D. L. J. Am.
Chem. Soc. 1982, 104, 8648. (b) Mutter, R.; Wills, M. Bioorg. Med. Chem.
2000, 8, 1841. (c) Hale, K. J.; Hummersone, M. G.; Manaviazar, S.; Frigero,
M. Nat. Prod. Rep. 2002, 19, 413.
(2) (a) Masamune, S. Pure Appl. Chem. 1988, 60, 1587. (b) Kageyama,
M.; Tamaru, T.; Nantz, M. H.; Roberts, J. C.; Somfrai, P.; Whritenour, D.
C.; Masamune, S. J. Am. Chem. Soc. 1990, 112, 7407.
(3) (a) Evans, D. A.; Carter, P. H.; Carreira, E. M.; Prunet, J. A.; Charette,
A. B.; Lautens, M. Angew. Chem., Int. Ed. 1998, 37, 2354. (b) Evans, D.
A.; Carter, P. H.; Carreira, E. M.; Charette, A. B.; Prunet, J. A.; Lautens,
M. J. Am. Chem. Soc. 1999, 121, 7540.
(4) Ohmori, K.; Ogawa, Y.; Obitsu, T.; Ishikawa, Y.; Nishiyama, S.;
Yamamura, S. Angew. Chem., Int. Ed. 2000, 39, 2290.
Figure 1. Bryostatin 1.
10.1021/ol0520065 CCC: $30.25
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Table 1. Optimization of Alkyne-Enone Couplinga
connc cat. loading 2/1
Scheme 1. Proposed Tetrahydropyran Synthesis
yieldb
cis(trans)
entry
solvent
(M)
(mol %)
ratio
1
2
3
4
5
acetone
0.1
0.1
0.1
0.4
0.4
10
10
30
10
10
1
31%
acetone
acetone
acetone
acetone/H2O
(9/1)
1.8 43% (6%)
36%
1.2 41% (6%)
1
3
3
trace
6
acetone/DMF 0.4
(9/1)
10
mostly starting
material
7
8
2-butanone
acetone
0.4
0.4
10
10
3
3
63% (13%)
68% (15%)
a Reaction performed at room temperature with [CpRu(CH3CN)3]PF6 for
20 h. b Isolated yields of cis-isomer and trans-isomers (in parentheses) after
column chromatography.
To test the viability of the concept, 1-(4-methoxybenzyl-
oxy)-5-trimethylsilanylpent-4-ol 1a and 2,2-dimethylhex-5-
10
en-3-one 2a were treated with [CpRu(CH3CN)3]PF6 in
as the addition of water and DMF inhibited the reaction
(entries 5 and 6), while 2-butanone gave a slightly lower
yield (entry 7). Higher concentration led to better conversion
as expected from a typical bimolecular reaction (entry 4).
However, higher catalyst loading did not lead to a substan-
tially higher yield (entry 3). To achieve both reasonable
conversion and yield, excess enone was employed. The best
yield was achieved with acetone as solvent, 0.4 M concentra-
tion of alkyne, and 3 equiv of enone (entry 8).
acetone (Scheme 2). Gratifyingly, the reaction went smoothly
Scheme 2. A Model Study
To further probe the scope and limitations of this reaction,
a variety of propargylic alcohols and â,γ-unsaturated enones12
were prepared and subjected to the optimized conditions. The
results are summarized in Table 2. A variety of groups,
including TBDPS, benzyl, p-methoxybenzyl, acetyl, and the
hindered TBS, were tolerated. Since excess enone is neces-
sary to achieve good conversion and yield, the ability to
recover the unreacted enone after the reaction is desirable,
especially when it is precious. To our delight, enones with
tert-alkyl groups can be mostly recovered (entries 7, 8, and
10), which bodes well for the byrostatin synthesis. On the
other hand, when dec-1-en-4-one 2b was used, it was
recovered together with 15-20% of the isomerized R,â-
enone. The reaction tolerated branching at the propargylic
position, albeit with a slightly lower yield (entry 6). Interest-
ingly, complete chemoselectivity was observed for two
different types of alkenes (entry 10). No product derived from
the coupling of the alkene bearing an allylic oxygen with an
alkyne was detected. The cis/trans ratios ranged from 5/1 to
8/1.13
and provided the 2,6-cis-tetrahydropyran 311 and 4 as the
major product (Table 1, entry 1) without any detectable
amount of the hydroxyenone intermediate (Scheme 1).
Efforts to optimize the reaction are summarized in Table
1. It was found that the best solvent for the reaction is acetone
(5) A tandem palladium-catalyzed alkyne/alkynoate coupling has been
used to synthesize dihydropyrans with geometrically defined exocyclic alkyl
enoates, see: Trost, B. M.; Frontier, A. J. J. Am. Chem. Soc. 2000, 122,
11727.
(6) (a) Trost, B. M.; Machachek, M. Angew. Chem., Int. Ed. 2002, 41,
4693. (b) Hanson, E. C.; Lee, D. Tetrahedron Lett. 2004, 45, 7151.
(7) (a) Wender, P. A.; Miller, B. L. Organic Synthesis: Theory and
Application; Hudlicky, T., Ed.; JAI: Greenwich, 1993; Vol. 2, p 70. (b)
Bertz, S. H. New J. Chem. 2003, 27, 860.
Preliminary studies suggest the cis/trans-isomers are not
equilibrating under the reaction conditions.14 The preference
(8) (a) For an application of Ru-catalyzed alkyne/â,δ-unsaturated ester
coupling in synthesis, see: Trost, B. M.; Yang, H.; Probst, G. D. J. Am.
Chem. Soc. 2004, 126, 48. (b) For a pyran annulation reaction, see: Keck,
G. E.; Covel, J. A.; Schiff, T.; Yu, T. Org. Lett. 2002, 4, 1189.
(9) Michael addition has been used to assembly the B-ring of bryostatins,
see: (a) Ball, M.; Baron, A.; Bradshaw, B.; Omori, H.; MacCormick, S.;
Thomas, E. J. Tetrahedron Lett. 2004, 45, 8737. (b) O’Brien, M.; Taylor,
N. H.; Thomas, E. J. Tetrahedron Lett. 2002, 43, 5491. (c) Yadav, J. S.;
Bandyopadhyay, A.; Kunwar, A. C. Tetrahedron Lett. 2002, 43, 5491.
(10) (a) Gill, T. P.; Mann, K. R. Organometallics 1982, 1, 485. (b) Trost,
B. M.; Older, C. M. Organometallics 2002, 21, 2544. (c) Kundig, E. P.;
Monnier, F. R. AdV. Synth. Catal. 2004, 346, 901.
(12) Le Roux, C.; Dubac, J. Organometallics 1996, 15, 4646.
(13) The trans-isomers were not obtained pure after column chromatog-
raphy except entry 10. The ratios were determined by integrating two
different vinyl protons, which are usually separated by 0.03 PPM in the
5.20-5.30 region.
(14) Efforts trying to equilibrate the cis/trans-isomers under either basic
(NaOMe, LiOMe, Mg(OCH)2) or acidic (Amberlyst 15) conditions led to
decomposition. Resubjecting the trans-isomer of 5 to the reaction conditions
did not give any 5. However, similar diastereoselectivity was claimed to
be obtained under thermodynamically controlled conditions (ref 9b).
(11) The cis-configuration was established by NOE studies.
4762
Org. Lett., Vol. 7, No. 21, 2005

Table 2. Representative Examples of Tandem Alkyne-Enone Coupling/Michael Addition Reactiona
a Reactions performed at 0.5 M alkyne concentration with 3 equiv of enone and 10 mol % of [CpRu(CH3CN)3]PF6 in acetone at room temperature for
40 h. b Isolated yield of pure cis-isomer.
for formation of the cis product implicates a late transition
state for the cyclization wherein relative product stability
will play a more significant role. The variation in diaste-
reoselectivity for similar structures presumably arises as a
reflection of the relative importance of product stability in
the transition state of each cyclization. Attempts to establish
the thermodynamic ratio were thwarted by acid- and base-
catalyzed decomposition.14
The resultant geometrically defined exocyclic vinylsilane
provides a handle for further functionalization (Scheme 3).
Protodesilylation6a of 5 went smoothly to give 6 without
double bond migration. Vinyl iodide formation6a also pro-
ceeded efficiently and the product was subsequently carbo-
nylated15 to give methyl enoate 7. Furthermore, we were able
to invert the double bond geometry through an epoxidation,
bromohydrin formation, and siloxy elimination sequence16
to give the inverted bromide 8, which was also carbonylated17
with high efficiency. Thus, from one geometrically defined
vinylsilane either geometric isomer of the exocyclic enoate
is cleanly available.
In summary, a Ru-catalyzed tandem alkyne-enone cou-
pling/Michael addition reaction is reported. In no case has
the presumed enone intermediate been observed. Since
uncatalyzed additions of alcohols to enones are not antici-
(15) Beller, M.; Magnerlein, W.; Indolese, A. F.; Fischer, C. Synthesis
2001, 1098.
(16) Chou, S. S. P.; Kuo, H. L.; Wang, C. J.; Tsai, C. Y.; Sun, C. M. J.
Org. Chem. 1989, 54, 868.
(17) (a) Qing, F. L.; Yue, X. J. Tetrahedron Lett. 1997, 38, 8067. (b)
Cacchi, S.; Morea, E.; Ortar, G. Tetrahedron Lett. 1985, 26. 1109.
Org. Lett., Vol. 7, No. 21, 2005
4763

ated enones in good yield. The resultant vinylsilane provides
a handle for further fuctionalization, allowing protodesily-
lation and the synthesis of vinyl halides with either olefin
geometry. Subsequent metal-catalyzed cross-coupling reac-
tions lead to the synthesis of either geometrically defined
trisubstituted alkene exocyclic to the 2,6-cis-dihydropyran,
which are difficult to access through other synthetic means.
In addition, oxidative cleavage of the exocyclic double bonds
also provides access to 4-tetrahydropyranones and their
alcohol analogues.
Scheme 3. Transformations of the Vinylsilane
Acknowledgment. We thank the National Science Foun-
dation and National Institutes of Health, General Medical
Science (GM-13598), for their generous support. H.Y. was
partially supported by an Amgen Graduate Fellowship. G.W.
thanks Stidienstiftung des Deutschen Volkes and the Fritz-
ter-Meer-Stiftung for financial support. Mass spectra were
provided by the Mass Spectrometry Regional Center of the
UCSF Supported by the NIH Division of Research Re-
sources.
Supporting Information Available: Experimental pro-
cedures for the preparation of new compounds as well as
characterization data. This material is available free of charge
via the Internet at http://pubs.acs.org.
pated to be fast,9a it is likely that the Ru complex also
catalyzes this step. It provides an efficient, atom-economic
entry to 4-methylene-2,6-cis-tetrahydropyrans from simple,
readily available homopropargylic alcohols and â,γ-unsatur-
OL0520065
4764
Org. Lett., Vol. 7, No. 21, 2005