Atom economical syntheses of oxygen heterocycles via tandem palladium-catalyzed reactions [2]

Full text of DOI:10.1021/ja0022268

J. Am. Chem. Soc. 2000, 122, 11727-11728
11727
Table 1. Effect of Reaction Conditions on Addition of Alkyne 7
Atom Economical Syntheses of Oxygen Heterocycles
via Tandem Palladium-Catalyzed Reactions
and Alkynoate 8aa
mol %
mol %
temp
°C
time/ % isolated ratio
entry Pd(Oac)2 TDMPP
days
yield
10:11
Barry M. Trost* and Alison J. Frontier
1
2
3
4
5
6
5
5
5
5
5
2
2
2
2
2
4
rt
5.5
61
61
57
30
23
61
>20:1
5.5:1
5.5:1
1.8:1
1.6:1
>20:1
rt to 50°b 2.5
Department of Chemistry, Stanford UniVersity
Stanford, CA 94305-5080
50°
2.25
rt to 80°b 1.5
ReceiVed June 22, 2000
80°
rt
1.0
2.5
10
The control of alkene geometry exocyclic to a ring represents
a formidable task. Recent work directed toward the synthesis of
bryostatins and other natural products because of their promising
antitumor activity demonstrates the problem of synthesizing a
tetrahydropyran exemplified by 1.1 Accessing such compounds
via the dihydropyran 2 suggested the prospect of a simple atom
economic strategy based upon the 6-endo-dig2 cyclization of 3
which could derive from the palladium-catalyzed addition of
terminal alkynes onto ynoates 4.3,4 Two potential competing
a All reactions performed in benzene at a concentration of 0.7 M in
substrates 7 and 8a. b Reaction run at rt for the first 24 h followed by
heating to the stated temperature.
yield of dihydropyran 10a was isolated as the only product. Using
these conditions, a variety of hydroxyalkynoates in the reaction
with 1-heptyne were examined as summarized in Table 2.7
Converting the primary alcohol into a secondary (entries 2-5)
and even tertiary (entry 6) one led to successful reaction albeit
with some yield loss in the last case. Remarkably, the reaction
tolerated a vicinal chlorohydrin (entry 5) with only a modest loss
in yield. On the other hand, the trans-hydroxyalkynoate 12 gave
the expected adduct 13 within 2 days (eq 2, 50% isolated yield).
Use of more forcing conditions gave no dihydropyran but only
lactone 14, which was isolated in 58% overall yield from 12.
processes to the 6-endo-dig cyclization are immediately apparents
a 5-exo-dig cyclization to diene 5 or a simple lactonization to
δ-pentanolactone 6. While such competing processes appear
Table 3 and eq 3 summarize the effects of varying the terminal
alkyne partner in the reactions with homopropargylic alcohol 8b.
While increasing the steric hindrance of R to cyclopentyl had no
discernible effect (entry 1), switching to tert-butyl dramatically
slowed the cyclization rate (entries 2 and 3). Envisioning that
highly probable, the prospect of a one-step simple synthesis of
dihydropyrans 2 led us to examine the feasibility of this strategy.5
To test the concept, the reaction of 1-heptyne (7) and methyl
5-hydroxy-2-pentynoate (8) (see eq 1) catalyzed by palladium
acetate with tris-(2,6-dimethoxyphenyl)phosphine6 as ligand was
examined as summarized in Table 1. Following the reaction by
thin-layer chromatography revealed that formation of the simple
adduct 9 occurred completely within 24 h; but cyclization
proceeded very slowly (entry 1). Allowing the reaction to proceed
for a prolonged period of time gave the dihydropyran 10a in
satisfactory yield as the only detectable product. Increasing the
the cyclization was also a palladium acetate-catalyzed reaction,
its rate should depend on the electrophilicity of the palladium(+2)
species wherein increasing electrophilicity should increase the
cyclization. We have previously noted the dramatic enhancement
of rate in formation of π-allylpalladium complexes from less
nucleophilic alkenes upon using palladium trifluoroacetate.8 In
the initial experiment, the trifluoroacetate salt was generated in
situ by simply adding trifluoroacetic acid to palladium acetate.
Indeed, the cyclization rate increased dramatically (complete
cyclization in 1 day), but a 1:1 mixture of the exocyclic alkene
reaction temperature after adduct 9 formed to 50 °C (entry 2) or
simply running the reaction at 50° (entry 3) led to a significant
reduction in reaction time with about the same yield but gave
rise to competitive formation of lactone 11. Repeating these
protocols but using 80 °C (entries 4 and 5) led to reduction in
time for consumption of starting materials but significant losses
in yield and selectivity. A workable solution was found by
increasing the catalyst loading (entry 6) whereby a 61% isolated
(2) (a) Baldwin, J. E. J. Chem. Soc., Chem. Commun. 1976, 734. (b)
Baldwin, J. E.; Cutting, J.; Dupont, W.; Kruse, L.; Silberman, L.; Thomas, R.
C. J. Chem. Soc., Chem. Commun. 1976, 736.
(3) Trost, B. M.; Sorum, M. T.; Chan, C.; Harms, A. E.; Ruhter, G. J. Am.
Chem. Soc. 1997, 119, 698.
(1) (a) Evans, D. A.; Carter, P. H.; Carriera, E. M.; Charette, A. B.; Prunet,
J. A.; Lautens, M. J. Am. Chem. Soc. 1999, 121, 7540. (b) Baxter, J.; Mata,
E. G.; Thomas, E. J. Tetrahedron 1998, 54, 14359. (c) Obitsu, T.; Ohmori,
K.; Ogawa, Y.; Hosomi, H.; Obha, S.; Nishiyama, S.; Yamamura, S.
Tetrahedron Lett. 1998, 39, 7349. For a review of earlier synthetic approaches
to the bryostatins, see: Norcross, R. D.; Paterson, I. Chem. ReV. 1995, 95,
2041.
(4) Trost, B. M.; McIntosh, M. C.; J. Am. Chem. Soc. 1995, 117, 7255.
(5) For recent examples of dihydropyran synthesis, see: (a) Evans, D. A.;
Johnson, J. S.; Olhava, E. J. J. Am. Chem. Soc. 2000, 122, 1635. (b) Cacchi,
S.; Fabrizi, G.; Larock, R. C.; pace, P.; Reddy, V. Synlett 1998, 888.
(6) Wada, M.; Higashizaki, S. J. Chem. Soc., Chem Commun. 1984, 482.
(7) All new compounds gave satisfactory spectral and physical data.
(8) Trost, B. M.; Metzner, P. J. J. Am. Chem. Soc. 1980, 102, 3572.
10.1021/ja0022268 CCC: $19.00 © 2000 American Chemical Society
Published on Web 11/08/2000

11728 J. Am. Chem. Soc., Vol. 122, No. 47, 2000
Table 2. Variation of Hydroxyalkynoatea
Communications to the Editor
6), but this fell off dramatically as it was moved farther away
from the triple bond (entries 7 and 8). A reasonable explanation
of this substitutent effect on regioselectivity derives from the
negative inductive effect of the electronegative hydroxyl group
which disfavors generation of positive charge at the proximal
alkyne carbon necessary for cyclization to dihydropyran. On the
other hand, the combination of the inductive effect and the steric
effect in entry 9 reverses the regioselectivity such that the 5-exo
dig product now dominates. The inductive effect also accounts
for the small deterioration of the regioselectivity in entry 10. The
two-stage one-pot catalytic system employing the combination
of palladium acetate and palladium trifluoroacetate allowed the
extension to the formation of seven-membered rings (eq 5), a
cyclization that completely fails in the absence of the palladium
trifluoroacetate.
a All reactions performed using 10% mol Pd(OAc)2 and 4% mol
TDMPP and a 1:1 ratio homopropargylic alcohol/alkyne at a concentra-
tion of 0.7 M in benzene at rt (Procedure A).
Table 3. Variation of Terminal Alkynea
It is possible to achieve selective oxidation of the enol ether
olefin of the dihydropyrans produced by this method (eq 6).
Treatment of dihydropyran 10a with m-CPBA in CH2Cl2/MeOH12
gave a 2.5:1 mixture of isomers at the anomeric center. Treatment
of this mixture with triethylsilane and boron trifluoride diethyl
etherate at low temperature effected reduction of the anomeric
center to give a single product assigned as E-22 based upon
coupling constants.
a All reactions performed using 10 mol % Pd(OAc)2 and 4 mol %
TDMPP in benzene at rt using 1:1 ratio of substrates at 0.7 M
(Procedure A) unless stated otherwise. b Determined by 1H NMR
spectroscopy. c N.A. ) not applicable. d Reaction performed in two
stages: stage 1 using 4 mol % Pd(OAc)2 and 4 mol % TDMPP and
stage 2 using 6 mol % Pd(OCOCF3)2 (Procedure B).
isomers of 16 (R ) t-C4H9) was isolated in 59% yield.9 When
ancillary experiments revealed that isomerization of double bond
geometry was catalyzed by Bronsted acids, the protocol was
changed to utilize a 1:1 mixture of palladium acetate and TDMPP
for the initial addition (stage one) followed by addition of
palladium trifluoroacetate for the cyclization (stage two).10 In this
way, a rapid conversion of the two alkyne starting materials
directly to the dihydropyran occurred in a one-pot reaction. The
effectiveness of this protocol is highlighted by the success of the
example of eq 4 wherein the dihydropyrans 18 are isolated in
good yieldssa type of substitution that bodes well for the more
complicated substrates needed for natural products syntheses.
This one-pot alkyne/alkynoate coupling provides complex
dihydropyrans in moderate to good yields and in a highly atom
economical fashion. The reaction utilizes simple starting materials
that, by themselves, are easily accessed taking advantage of alkyne
chemistry. For example, the homopropargylic alcohols needed
for the synthesis of dihydropyrans easily derive from the epoxide
ring opening with the acetylide derived from ethyl propiolate.
The reaction is also highly chemoselective tolerating esters, free
alcohols, silyl ethers, PMB ethers, nitriles, and alkyl chlorides.
The exocyclic double geometry is created with high control that
is mechanism-based. Indeed, both steps are palladium(+2)
catalyzed events. The dihydropyrans are promising intermediates
for complex pyrans that are difficult to access by other synthetic
means.
Acknowledgment. We thank the National Science Foundation and
the General Medical Science Institute of the National Institutes of Health
for their generous support of our programs. Mass spectra were provided
by the Mass Spectrometry facility at the University of California, San
Francisco, supported by the NIH Division of Research Resources.
Placing a conjugating substitutent like phenyl on the terminal
alkyne (entry 5) makes the 5-exo dig cyclization to 17c (R )
Ph) now compete with the 6-endo dig product (16c, R ) Ph)
although the latter was strongly preferred.11 A propargylic alcohol
substituent had a much stronger effect on this competition (entry
Supporting Information Available: Experimental details (PDF). This
material is available free of charge via the Internet at http://pubs.acs.org.
JA0022268
(11) Structure assignment was based on the observation of J-coupling
between a vinyl proton and the protons adjacent to a hydroxyl group, consistent
with the structure of the product of 5-exo dig cyclization rather than 6-endo
dig cyclization.
(12) Wender, P. A.; De Brabander, J.; Harran, P. G.; Jimenez, J.-M.;
Koehler, M. F. T.; Lippa, B.; Park, C.-M.; Shiozaki, M. J. Am. Chem. Soc.
1998, 120, 4534.
(9) The structure of the isomerized exocyclic enoate (E geometry) was
1
assigned on the basis of H NMR datasthe chemical shift of the vinyl ring
proton was shifted downfield relative to the Z-enoate, while the ring protons
allylic to the exocyclic enoate were shifted upfield relative to the Z-enoate.
(10) When palladium trifluoroacetate was used alone, cross-coupling of
the alkyne and the ynoate was unsuccessful.