Ring opening/fragmentation of dihydropyrones for the synthesis of homopropargyl alcohols

Article abstract of DOI:10.1021/ja801018r

Ring-opening/C-C bond cleavage reactions induced by nucleophilic addition of methyl Grignard to 5,6-dihydro-2-pyrone (DHP) triflates 1 furnish homopropargyl alcohols (1 → 2) stereospecifically with respect to the stereochemistry of 1. Carbonyl extrusion from DHP triflates provides a unified and operationally simple strategy for preparing chiral homopropargyl alcohols. Copyright

Full text of DOI:10.1021/ja801018r

Published on Web 03/22/2008
Ring Opening/Fragmentation of Dihydropyrones for the
Synthesis of Homopropargyl Alcohols
Jumreang Tummatorn†,‡ and Gregory B. Dudley*,†
Department of Chemistry and Biochemistry, Florida State UniVersity, Tallahassee, Florida
32306–4390, and Department of Chemistry, Faculty of Science, Chulalongkorn UniVersity,
Phyathai Road, Bangkok 10330, Thailand
Received February 9, 2008; E-mail: gdudley@chem.fsu.edu
Homopropargyl alcohols (HPAs) are fundamental building
blocks for the synthesis of complex polyketide and macrolide
structures. In principle, HPAs are available by means of nucleo-
philic propargyl addition to aldehydes or ketones (Figure 1), but
one can generally expect good stereo- and regioselectivity only in
pairings of aldehydes with allenylmetal reagents under carefully
prescribed conditions.1,2 In practice, HPAs 2 are often reached by
alternative methods, such as acetylide opening of epoxides or
alkynylation of ꢀ-hydroxy aldehydes.3
A new carbonyl extrusion strategy for preparing HPAs is
outlined herein: tandem ring-opening/carbon–carbon (C–C) bond
cleavage (1 f 2, Figure 1). Despite significant advances in acyclic
stereocontrol, synthetic chemists remain better equipped to ma-
nipulate rigid cyclic systems. Mechanisms for unraveling cyclic
systems in a controlled manner provide complex acyclic synthons
(e.g., HPAs 2) that otherwise may be difficult to prepare.
Figure 1. Strategies for the synthesis of homopropargyl alcohols (HPAs).
Scheme 1. Ring-Opening C–C Bond Cleavage (Fragmentation) of
Ene-Hydrazone Oxides (A) and Vinylogous Acyl Triflates (B)
A classic example of ring-opening C–C bond cleavage is the
Eschenmoser–Tanabe fragmentation of ene-hydrazone oxides (A,
Scheme 1).4 Alternative entry into this mechanistic pathway has
been demonstrated,5 most notably through the use of cyclic
vinylogous acyl triflates (B).6a This latter entry, a tandem nucleo-
philic addition/C–C bond cleavage reaction, provides efficient
access to carbon-tethered alkynyl ketones,6b amides, ꢀ-keto esters,6c
alcohols, and other functional groups.6d,e
Scheme 2. Postulated Reaction Pathway
This Communication describes the nucleophile-triggered de-
composition of 5,6-dihydro-2-pyrone (DHP) triflates for the
synthesis of homopropargyl alcohols (HPAs) (1 f 2, Figure 1).7
For the stereoselective synthesis of chiral HPAs, this carbonyl
extrusion strategy changes the nature of the challenge, from (a)
the difficult, specific task of controlling addition of propargyl nucleo-
philes to aldehydes and ketones1b to (b) the more general exercise
of preparing 4-oxygenated-5,6-dihydro-2-pyrones (i.e., 1).8–14
Table 1. Decomposition of DHP Triflate 1a under Various
Protocols18
DHP triflate 1a served as the prototype for testing the new bond
cleavage strategy. Table 1 shows the efficiency with which 1a
unravels under the action of 2.0 equiv of various carbanionic
nucleophiles.15 Toluene was a better solvent than THF (entries 2
and 3),6d and Grignard nucleophiles outperformed organolithiums
(entries 1 and 2; entries 6 and 7). Methylmagnesium bromide
(MeMgBr, entry 6) emerged as the optimal choice. DHP triflate
1a was prepared by triflation6,16 of 6-phenyl-2,4-oxanedione.17,18
The need for 2.0 equiv of nucleophile is informative with respect
to the reaction mechanism (Scheme 2). Nucleophilic addition to 1
provides a tetrahedral intermediate (I) that can either break down
along the conventional lines (path a) or undergo immediate
fragmentation (path b, not observed). The former path (path a)
gives rise to acyclic triflate II, which is then subject to addition/
entry
a
R-M
solvent
yield
b
THF
THF
48%
54%
84%
51%
70%
>95%
42%
15%
1
Ph-Li
c
2
3
4
5
6
7
8
Ph-MgBr
Ph-MgBr
c
toluene
toluene
toluene
toluene
toluene
toluene
d
p-MeO-C6H4-MgBr
e
n-Bu-MgCl
Me-MgBrc
f
Me-Li
g
i-Pr-Li
a -78 °C f 60 °C. b 2.0 M in butyl ether. c 3.0 M in ether. d 0.5 M
in THF. e 2.0 M in ether. f 1.6 M in ether. g 0.7 M in pentane.
C–C bond cleavage6 (II f III f 2).19 Ultimately, HPAs 2 arise
stereospecifically from cyclic dihydropyrones 1.20
Whereas propargyl addition to aldehydes (cf. Figure 1) is affected
by substituents on the carbonyl group, unraveling of DHP triflates
proceeds with high efficiency regardless of the substituent geminal
† Florida State University.
‡ Chulalongkorn University.
9
5050 J. AM. CHEM. SOC. 2008, 130, 5050–5051
10.1021/ja801018r CCC: $40.75
2008 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Decomposition of DHP Triflates with MeMgBr18
References
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entry
1
R3
2
yield
b
1
b
1a
1b
1c
1d
1e
1f
Ph
2a
2b
2c
2d
2e
2f
quant
99%
95%
92%
84%
quant
85%
91%
p-Br-C6H4
p-MeO-C6H4
3-furyl
cinnamyl
PhCH2CH2
cyclohexyl
t-butyl
2
b
3
c
4
b
5
6
7
8
1g
1h
2g
2h
c
a 3.0 M in ether. b -78 °C to rt, 1 h. c Overnight reaction (t ) 12 h).
Table 3. Decomposition of Substituted DHP Triflates18
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entry
1
R1
R2
R3
R4
2
yield
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R. A.; Reynolds, K. A.; Sherman, D. H. J. Am. Chem. Soc. 2003, 125,
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Shen, M. Tetrahedron Lett. 1997, 8, 3393. (b) Drochner, D.; Müller, M.
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1
2
1i
H
H
PhCH2CH2
Ph
Me
H
2i
82%
quant
92%
76%
78%
83%
1j
Me
Bn
H
H
2j
3
1k
1l
1m
1n
H
Ph
H
2k
2l
2m
2n
c
b
Me
Me
Bn
H
Cy
4
c
Cy
b
H
H
H
H
5
6
Ph
a 3.0 M in ether. b Cy ) cyclohexyl. c Overnight reaction (t ) 12 h).
to the oxygen atom (Table 2). Aryl substituents were well-tolerated
(entries 1–4), whether electron-rich (entries 3 and 4, 95 and 92%)
or electron-poor (entry 2, 99%). Fragmentation of cinnamyl-
substituted 1e furnished HPA 2e in 84% yield (entry 5). Alcohols
2f–h—formally the products of propargyl addition to linear,
branched, and tertiary aliphatic aldehydes—were produced in
excellent yields through this ring-opening/C–C bond cleavage
methodology (entries 6–8).
Table 3 presents experiments aimed at unraveling differentially
substituted DHP triflates 1. Geminal disubstitution was tolerated
in the synthesis of tertiary alcohol 2i (entry 1, 82%). Entries 2 and
3 illustrate the formation of internal alkynes (2j and 2k). The
nucleophile-promoted fragmentations yield 2 in a stereodefined
manner: 5,6-cis-DHP triflate 1l gives rise to syn-HPA 2l (entry 4,
76%), whereas trans-isomers 1m and 1n provide anti-HPAs 2m
and 2n (entries 5 and 6, 78 and 83%).
In conclusion, nucleophilic addition of methylmagnesium bro-
mide to 5,6-dihydro-2-pyrone (DHP) triflates induces a ring-
opening/fragmentation process to furnish homopropargyl alcohols.
The unified strategy of preparing and unraveling DHP triflates
provides chiral homopropargyl alcohols that may be difficult to
access by other means. The full scope and applications of this
process in chemical synthesis will be reported in due course.
Acknowledgment. This research is supported by a grant from
the James and Ester King Biomedical Research Program, Florida
Department of Health, the National Science Foundation (NSF-CHE
0749918), and an award from Research Corporation. J.T. is a Ph.D.
student of Prof. Dr. Sophon Roengsumran (Chulalongkorn Uni-
versity) and a recipient of the Royal Golden Jubilee Ph.D.
Fellowship (PHD/0239/2547) from the Thailand Research Fund
(14) For recent work and references on the asymmetric synthesis of isomeric
5,6-dihydro-4-pyrones using Danishefsky’s dienes, see: Yu, Z.; Liu, X.;
Dong, Z.; Xie, M.; Feng, X. Angew. Chem., Int. Ed. 2008, 47, 1308.
(15) Other nucleophiles and different stoichiometries were less effective.
(16) Cakir, S. P.; Mead, K. T. Tetrahedron Lett. 2006, 47, 2451.
(17) (a) Peterson, J. R.; Winter, T. J.; Miller, C. P. Synth. Commun. 1998, 18,
949. (b) de Souza, L. C.; dos Santos, A. F.; Goulart Sant, A. E.; de Oliveira
Imbroisi, D. Bioorg. Med. Chem. 2004, 12, 865. For the synthesis of
6-phenylpyran-2,4-dione in >99% ee, see: (c) Xu, C.; Yuan, C. Tetrahedron
2005, 61, 2169. For relevant discussions on the enantioselective synthesis
and diastereoselective hydrogenation of DHP acetates analogous to 1, see:
(d) Brandänge, S.; Färnbäck, M.; Leijonmarck, H.; Sundin, A. J. Am. Chem.
Soc. 2003, 125, 11942.
(18) See Supporting Information for details.
(19) As in previous reports,6 slow fragmentation of IV ensures consumption of
R–M (2 equiv) prior to formation of the ketone.
(20) A symmetrical ketone (i.e., acetone for R–M ) MeMgBr) is an expected
byproduct. Indeed, benzophenone (diphenyl ketone) was identified by NMR
spectroscopy following an experiment in which phenylmagnesium bromide
was employed as the nucleophile (Table 1, entry 3).
for study abroad. We are profoundly grateful for this support.
Supporting Information Available: Experimental procedures,
characterization data, and copies of NMR spectra. This material is
available free of charge via the Internet at http://pubs.acs.org.
JA801018R
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J. AM. CHEM. SOC. VOL. 130, NO. 15, 2008 5051