A ring fragmentation approach to medium-sized cyclic 2-alkynones

Article abstract of DOI:10.1021/ol2030422

Bicyclic γ-silyloxy-β-hydroxy-α-diazoketones, in which the Cβ-Cγ bond is the ring fusion bond, productively fragment when treated with tin(IV) chloride to provide medium-sized cyclic 2-alkynones. This method provides good to excellent yields of 10-, 11-,

Full text of DOI:10.1021/ol2030422

ORGANIC
LETTERS
2012
Vol. 14, No. 1
264–267
A Ring Fragmentation Approach to
Medium-Sized Cyclic 2-Alkynones
Nikolay P. Tsvetkov, Ali Bayir, Samuel Schneider, and Matthias Brewer*
Department of Chemistry, The University of Vermont, 82 University Place, Burlington,
Vermont 05405, United States
Matthias.Brewer@uvm.edu
Received November 10, 2011
ABSTRACT
Bicyclic γ-silyloxy-β-hydroxy-R-diazoketones, in which the CβꢀCγ bond is the ring fusion bond, productively fragment when treated with tin(IV)
chloride to provide medium-sized cyclic 2-alkynones. This method provides good to excellent yields of 10-, 11-, and 12-membered alkynone products.
In view of the synthetic utility of ynones, and the fact
that medium-sized rings are an underexplored1 but
important2 structural motif in biologically active com-
pounds, medium-sized cyclic 2-alkynones should be decid-
edly useful synthetic intermediates. However, these
types of compounds have rarely been used in synthetic
sequences;3ꢀ7 a fact that can undoubtedly be attributed
to a lack of available methods to prepare this structural
motif. While functional group manipulations on medium-
sized cycloalkynes8ꢀ12 or medium sized cycloalkenes13
have on occasion been used to prepare cyclic 2-alkynones,
methods to directly prepare these compounds from pre-
cursors that do not contain a medium-sized ring are limited
to the aluminum trichloride promoted intramolecular
cyclization of silylalkynes and acid chlorides developed
by Utimoto and co-workers.14 Unfortunately, this strategy
suffers from the common limitation of macrocyclization
strategies, namely the requirement of high dilution condi-
tions. With this in mind, we became interested in determin-
ing whether the Lewis acid promoted fragmentation of
cyclic γ-silyloxy-β-hydroxy-R-diazocarbonyls (e.g., 1 to 2,
Figure 1) we recently discovered15,16 could be applied to
the direct formation of medium-sized cyclic 2-alkynones.
(1) Greve, B.; Imming, P.; Laufer, S. Angew. Chem., Int. Ed. Engl.
1996, 35, 1221.
(2) Yet, L. Chem. Rev. 2000, 100, 2963.
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M.; Lopez, M.; Ortiz, J. J. Org. Chem. 2004, 69, 5307.
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T.; Nozaki, H. Bull. Chem. Soc. Jpn. 1983, 56, 3088.
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4845.
Figure 1. Fragmentation of cyclic γ-silyloxy-β-hydroxy-R-dia-
zoesters yields aldehyde tethered ynoates.
In this letter we wish to report that bicyclic γ-silyloxy-β-
hydroxy-R-diazoketones, in which the CβꢀCγ bond is the
ring fusion bond, productively fragment to provide med-
ium-sized cyclic 2-alkynones in good to excellent yields.17
To test our hypothesis that bicyclic diazoketones could
be precursors to medium-sized cyclic 2-alkynones we
(7) Utimoto, K.; Kato, S.; Tanaka, M.; Hoshino, Y.; Fujikura, S.;
Nozaki, H. Heterocycles 1982, 18, 149.
(8) Netland, K. A.; Gundersen, L. L.; Rise, F. Synth. Commun. 2000,
30, 1767.
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(10) Gleiter, R.; Merger, M. Synthesis 1995, 969.
(11) Pfaltz, A.; Bulic, B.; Luecking, U. Synlett 2006, 1031.
(12) Bodenmann, B.; Keese, R. Tetrahedron Lett. 1993, 34, 1467.
(13) Eaton, P. E.; Stubbs, C. E. J. Am. Chem. Soc. 1967, 89, 5722.
(14) Utimoto, K.; Tanaka, M.; Kitai, M.; Nozaki, H. Tetrahedron
Lett. 1978, 19, 2301.
(15) Bayir, A.; Draghici, C.; Brewer, M. J. Org. Chem. 2010, 75, 296.
(16) Draghici, C.; Brewer, M. J. Am. Chem. Soc. 2008, 130, 3766.
r
10.1021/ol2030422
Published on Web 12/01/2011
2011 American Chemical Society

Table 1. Fragmentation of Fused Bicyclic Substrates
Scheme 1. Preparation of Bicyclic Fragmentation Substrates
prepared the diastereomeric bicyclo[4.4.0]decane diazo
compounds 7a and 8a by the route shown in Scheme 1.
d’Angelo-type18 conjugate addition provided ester 4a in
78% yield, and subsequent hydrogenolysis provided the
free acid 5a in 98% yield. The requisite diazo carbonyl 6a
was then formed in 63% yield over two steps from acid 5a
via the corresponding mixed anhydride. It was interesting
to note the facility by which the pendant diazo ketone (6a)
underwent intramolecular aldol-type addition to provide
bicycles 7a and 8a; this intramolecular reaction was
achieved with the mild base DBU over the course of 12 h.
Intermolecular aldol-type additions of diazo carbonyl
compounds to ketones require the generation of a lithiated
diazo species, which is most often formed by deprotona-
tion of the corresponding diazo carbonyl with either n-
butyl lithium or LDA.19,20 Due to their greater electro-
philicity, aldehydes do react with diazo carbonyl com-
pounds in the presence of DBU,21 and in our case the
proximity of the reacting partners likely makes the aldol-
type addition more favorable. Potassium hydroxide in
methanol induced the ring closure22 more efficiently and
provided bicycles 7a and 8a as a separable mixture of
diastereomersin60% and 30% yield respectivelyafteronly
15 min.23
(17) The EschenmoserꢀTanabe fragmentation has been used to
generate cyclic alkynes: Reese, C. B.; Sanders, H. P. Synthesis 1981,
276. Tanabe, M.; Crowe, D. F.; Dehn, R. L. Tetrahedron Lett. 1967,
3943. Tanabe, M.; Crowe, D. F.; Dehn, R. L.; Detre, G. Tetrahedron
Lett. 1967, 3739. Eschenmoser, A.; Felix, D.; Ohloff, G. Helv. Chim.
Acta 1967, 50, 708. Schreiber, J.; Felix, D.; Eschenmoser, A.; Winter, M.;
Gautschi, F.; Schulte-Elte, K. H.; Sundt, E.; Ohloff, G.; Kalovoda, J.;
Kaufmann, H.; Wieland, P.; Anner, G. Helv. Chim. Acta 1967, 50 (7),
2101. Lange, G. L.; Hall, T.-W. J. Org. Chem. 1974, 39, 3819. Gordon,
D. M.; Danishefsky, S. J.; Schulte, G. K. J. Org. Chem. 1992, 57 (26),
7052. Dudley and Tummatorn have recently extended the vinylogous
acyl triflate fragmentation strategy to the preparation of cycloalkynes:
With the requisite fragmentation precursors in hand, we
turned our attention to the fragmentation reaction. Treating
the cis-fused bicyclo[4.4.0]decane diazo 7a with 1 mol equiv
of SnCl4 at 0 °C resulted in observable gas evolution and
provided essentially pure cyclodec-5-yne-1,4-dione (9, Table 1)
in near-quantitative yield as determined by 1H and
(23) The relative stereochemistry of diastereomer 7a and 8a were
easily distinguishable by NMR. The conformational flexibility of cis-
fused bicyclic 7a led to broad signals in the 1H and 13C NMR spectra,
which sharpened upon warming. Trans-fused diastereomer 8a, on the
other hand, had sharp signals in the 1H and 13C NMR spectra at room
temperature. The structures of the other diastereomers were assigned by
analogy based on the following consistent observations: (a) the hydroxyl
proton appeared further downfield in each bicyclic structure assigned as
cis-fused, presumably due to intramolecular hydrogen bonding with the
adjacent silyl ether; (b) the methyl groups of the silyl ether showed a
greater difference in chemical shift for the bicycles assigned as trans-
fused compared to the cis-fused diastereomers.
Tummatorn, J.; Dudley, G. B. Org. Lett. 2011, 13 (6), 1572.
0
€
(18) d Angelo, J.; Desmaele, D.; Dumas, F.; Guingant, A. Tetrahe-
dron: Asymmetry 1992, 3 (4), 459.
€
(19) Schollkopf, U.; Frasnelli, H. Angew. Chem., Int. Ed. Engl. 1970,
9, 301.
(20) Pellicciari, R.; Natalini, B.; Sadeghpour, B. M.; Marinozzi, M.;
Snyder, J. P.; Williamson, B. L.; Kuethe, J. T.; Padwa, A. J. Am. Chem.
Soc. 1996, 118, 1.
(21) Jiang, N.; Wang, J. Tetrahedron Lett. 2002, 43, 1285.
(22) Burkoth, T. L. Tetrahedron Lett. 1969, 10, 5049.
Org. Lett., Vol. 14, No. 1, 2012
265

13C NMR analysis. Purification resulted in some compound
loss, and isolation by chromatography returned cyclic
ynone 9 in 80% yield. The trans-fused diastereomer 8a also
productively fragmented to give alkyne 9 in 71% yield.
Applying the same sequence of reactions shown in
Scheme 1 to the corresponding 2-silyloxycycloheptanone
(3b) and 2-silyloxycyclooctanone (3c) provided the diazo
bicyclo[5.4.0]undecane and bicyclo[6.4.0]dodecane systems
(7b, 8b and 7c, 8c; Table 1) respectively. While the intra-
molecular cyclization of diazo compound 6b occurred in
high yield (92%) to give the expected diastereomeric aldol-
products 7b and 8b, the cyclization of diazo compound 6c
did not go to completion. Under the reaction conditions
this latter system existed as an equilibrium mixture of the
starting material 6c and the two diastereomeric products
(7c and 8c) in a 4.6 to 1.2 to 1 ratio. Separating these
compounds was trivial, and the isolated bicyclic products
were stable once removed from the basic reaction condi-
tions. However, resubjecting bicycle 7c to the cyclization
reaction conditions provided the same equilibrium mixture
of starting material and diastereomeric products, which
highlights the reversibility of this aldol-type addition reac-
tion. Attempts to shift the equilibrium toward the ring
closed products by changing the solvent or base, or by
trapping the bicyclic products as the silyl protected tertiary
alcohols, failed. It seems likely that transannular interac-
tions in the bicyclo[6.4.0]dodecane system make the ring
closed form less favorable at equilibrium.
medium-sized rings to be formed from a common 5-
or 6-membered ring precursor. Our synthetic routes to
the bicyclo[4.3.0]nonane systems 15 and 16 and bicyclo-
[5.4.0]undecane systems 20a and 21a, in which the diazo
functional group resides on a 5- and 7-membered ring
respectively, are shown in Schemes 2 and 3. The known24
2-silyloxycyclohex-2-enone (12) was converted in two steps
to R-silyloxy ketone 13 by Grignard addition followed by
base catalyzed silyl migration.25 The olefin was oxidatively
cleaved to the carboxylic acid, which was subsequently
converted to diazo ketone 14 under standard conditions.
Diazo compound 14 smoothly cyclized to diastereomeric
bicycles 15 and 16 in 43 and 45% yield respectively. Frag-
mentation of 15 and 16 provided complex mixtures which
appeared to contain ynone 17 in up to 40% yield, but the
desired product was isolated in at most 3% yield. Ynone 17
proved to be unstable and upon standing decomposed to an
intractable mixture of products. It is not clear at this point if
the low yield obtained of ynone 17 is due to an unproductive
fragmentation or the inherent instability of 17.
Scheme 3. Preparation and Fragmentation of Bicyclo-
[5.4.0]undecane Ring System
Scheme 2. Preparation of Bicyclo[4.3.0]nonane Fragmentation
Precursor
Diazo compounds 20a and 21a were prepared from
ketone 13 by cross metathesis26,27 to incorporate the
requisite side chain functionality and subsequent simulta-
neous reduction of the alkene and hydrogenolysis of the
benzyl ester to provide acid18a. Incorporation ofthe diazo
functionality under standard conditions proceeded as ex-
pected to provide diazo ketone 19a. Subsequent intramo-
lecular aldol-type cyclization to form the 7-membered ring
failed in the presence of DBU and KOH in methanol, but
diazo compound 19a did provide the expected cis- and
trans-fused bicycles 20a and 21a in 44% and 14% yield
a Compound 17 appears to decompose during purification. Based on NMR
analysis of crude reaction mixture, the initial yield was estimated at 40%.
Both the cis (7b) and trans (8b) diastereomers of the
bicyclo[5.4.0]undecane system productively fragmented to
provide cycloundec-5-yne-1,4-dione (10) in 99% and 93%
yield respectively after purification. The larger bicyclo-
[6.4.0]dodecane systems (7c and 8c) were also competent
fragmentation substrates and provided cyclododec-5-yne-
1,4-dione (11) in 93% and 80% yield respectively after
purification.
(24) Kadow, J. F.; Saulnier, M. G.; Tun, M. M.; Langley, D. R.;
Vyas, D. M. Tetrahedron Lett. 1989, 30, 3499.
~
(25) Gulı
Org. Lett. 2003, 5, 1975.
(26) BouzBouz, S.; Simmons, R.; Cossy, J. Org. Lett. 2004, 6 (20),
3465.
´
as, M.; Rodrıguez, J. R.; Castedo, L.; Mascarenas, J. L.
´
In order to extend the utility of this transformation we
examined the possibility of varying the size of the diazo
containing ring, which would allow a variety of different
(27) Garber, S. B.; Kingsbury, J. S.; Gray, B. L.; Hoveyda, A. H.
J. Am. Chem. Soc. 2000, 122, 8168.
266
Org. Lett., Vol. 14, No. 1, 2012

respectively upon treatment with LDA. Fragmentation of
bicycle 20a with SnCl4 returned cycloundec-6-yne-1,5-
dione (22) in 67% yield. Ynone 22 differs from ynone 10
by the relative positions of the carbonyls. Attempts to
apply thissame sequencetothe preparation ofthe bicyclo-
[6.4.0]dodecane system (20b and 21b), in which the
diazo resides on an 8-member ring, were also made.
Although the linear diazo precursor 19b was formed with-
out incident, all attempts to induce cyclization failed to
yield any of the desired bicyclic products. We suspect that
in this case the unfavorable equilibrium noted above
for the closure of diazo compound 6c is compounded by
the fact that 8-member rings are inherently more difficult
to form,28 which prevents a productive cyclization from
occurring.
inherent limitation of this method to form 9-membered
ynones, or if this low yield is due to the instability of 17
under the reaction conditions. Further studies of this
medium-sized ring forming reaction and applications of
this method toward the synthesis of medium-ring contain-
ing natural products are underway and will be disclosed in
future publications.
Acknowledgment. We thank Dr. John Greaves
(University of California, Irvine), Dr. Jonathan Karty
(Indiana University), and Mr. Bruce O’Rourke (University of
Vermont) for obtaining mass spectral data and Dr. Bruce
Deker (University of Vermont) for assistance with NMR
characterization. This work was financially supported by the
NIH (National Institute of General Medical Sciences Award
Number R01GM092870). The National Science Founda-
tion supported this work through Instrumentation Grant
CHE-0821501.
The preliminary results presented here demonstrate that
bicyclic γ-silyloxy-β-hydroxy-R-diazoketones are compe-
tent fragmentation substrates that can provide access to
10-, 11-, and 12-membered cyclo 2-alkynone products in
good to excellent yields. It is not clear if the low yield
obtained for the 9-membered cyclo 2-alkynone (17) is an
Supporting Information Available. Experimental de-
tails and spectroscopic data for all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(28) Illuminati, G.; Mandolini, L. Acc. Chem. Res. 1981, 14, 95.
Org. Lett., Vol. 14, No. 1, 2012
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