Lewis acid catalyzed intramolecular condensation of ynol ether-acetals. synthesis of alkoxycycloalkene carboxylates

Article abstract of DOI:10.1021/ol303026v

Treatment of ynol ether-tethered dialkyl acetals with catalytic quantities of scandium triflate in CH₃CN gives rise to five-, six-, and seven-membered alkoxycycloalkene carboxylates in good to excellent yields. Tri- and tetrasubstituted carbocyclic and heterocyclic alkenes may be formed by this method, and the products obtained may serve as useful intermediates for natural product synthesis.

Full text of DOI:10.1021/ol303026v

ORGANIC
LETTERS
2012
Vol. 14, No. 23
6100–6103
Lewis Acid Catalyzed Intramolecular
Condensation of Ynol Ether-Acetals.
Synthesis of Alkoxycycloalkene
Carboxylates
Vincent Tran and Thomas G. Minehan*
Department of Chemistry and Biochemistry, California State University,
Northridge 18111 Nordhoff Street, Northridge, California 91330, United States
thomas.minehan@csun.edu
Received November 3, 2012
ABSTRACT
Treatment of ynol ether-tethered dialkyl acetals with catalytic quantities of scandium triflate in CH3CN gives rise to five-, six-, and seven-membered
alkoxycycloalkene carboxylates in good to excellent yields. Tri- and tetrasubstituted carbocyclic and heterocyclic alkenes may be formed by this
method, and the products obtained may serve as useful intermediates for natural product synthesis.
Alkoxycycloalkene carboxylates are highly useful
starting materials for organic synthesis (Figure 1).
Stereoselective introduction of carbon substituents
β to the ester functional group may be accomplished
by allylic substitution or Michael addition reactions,
as shown by Villieras et al.1 Ogasawara has prepared
the nitraria alkaloids (þ)-nitramine, (þ)-isonitramine, and
(ꢀ)-sibirine from 2-carboethoxy-2-cyclohexen-1-ol.2 Simi-
larly, Iwabuchi’s recent synthesis of idesolide commences
from 2-carbomethoxy-2-cyclohexen-1-ol.3 Lupton has
also accomplished an elegant total synthesis of 7-deoxylo-
ganin from 2-carboethoxy-2-cyclopenten-1-ol.4 In all cases,
the hydroxycycloalkene carboxylate starting material is
prepared in moderate yields by the HornerꢀWadsworthꢀ
Emmons reaction of an appropriate dialdehyde with
trialkyl phosphonacetate.5 Since the efficiency of this proto-
col is often low, the development of an alternative method for
the preparation of cycloalkenol carboxylates of varying ring
sizes would clearly be of value for natural product synthesis.
Here we report our efforts toward the realization of this goal
and detail a novel Lewis acid catalyzed condensation of ynol
ether-acetals that yields alkoxycycloalkene carboxylates in
high yields.
Electron-rich alkynes, such as ynamines and ynol ethers,
are functional groups that possess significant potential in
organic chemistry for the formation of CꢀC bonds.6 Due to
their linear geometry, alkynyl ethers are relatively unhindered
(5) (a) Brady, W. T.; Giang, Y. F. J. Org. Chem. 1985, 50, 5177. (b)
Graff, M.; Al Dilaimi, A.; Seguineau, P.; Rambaud, M.; Villieras, J.
Tetrahedron Lett. 1986, 27, 1577.
(6) For reviews of the chemistry of ynol ethers and the methods for
the synthesis of ynol ethers, see: (a) Brandsma, L.; Bos, H. J.; Arens, J. F.
In The Chemistry of Acetylenes; Viehe, H. G., Ed.; Marcel Dekker: New
York, 1969, pp 751ꢀ860. (b) Stang, P. J.; Zhdankin, V. V. In The
Chemistry of Triple-Bonded Functional Groups; Patai, S., Ed.; John Wiley
& Sons: New York, 1994; Chapter 19. For a review of the chemistry of
ynamines and ynamides, see: (a) DeKorver, K. A.; Li, H.; Lohse, A. G.;
Hayashi, H.; Lu, Z.; Zhang, Y.; Hsung, R. P. Chem. Rev. 2010, 110, 5064–
5106. (b) Zificsak, C. A.; Mulder, J. A.; Hsung, R. P.; Rameshkumar, C.;
Wei, L. L. Tetrahedron 2001, 57, 7575–7606. (b) Mulder, J. A.; Kurtz,
K. C. M.; Hsung, R. P. Synlett 2003, 10, 1379–1390. (c) Al-Rashid, Z. F.;
Hsung, R. P. Org. Lett. 2008, 10, 661.
(1) (a) Dambrin, V.; Villieras, M.; Janvier, P.; Toupet, L.; Amri, H.;
Lebreton, J.; Villieras, J. Tetrahedron 2001, 57, 2155. (b) Amri, H.;
Villieras, J. Tetrahedron Lett. 1987, 28, 5521. (c) Amri, H.; Rambaud,
M.; Villieras, J. Tetrahedron 1990, 46, 3535. (d) Amri, H.; Rambaud, M.;
Villieras, J. J. Organomet. Chem. 1986, 308, C27. (e) Dambrin, V.;
Villieras, M.; Moreau, C.; Amri, H.; Toupet, L.; Villieras, J. Tetrahedron
Lett. 1996, 37, 6323.
(2) Yamane, T.; Ogasawara, K. Synlett 1996, 925.
(3) Yamakoshi, H.; Shibuya, M.; Tomizawa, M.; Osada, Y.; Kanoh,
N.; Iwabuchi, Y. Org. Lett. 2010, 12, 980.
(4) Candish, L.; Lupton, D. W. Org. Lett. 2010, 12, 4836.
r
10.1021/ol303026v
Published on Web 11/21/2012
2012 American Chemical Society

resulting propargylic alcohol) with 5 mol % I2 in acetone8
at rt for 5 min gave rise to silyloxycycloalkene carboxyate
3aa in 45% yield, as well as a 1:1 mixture of the more polar
methyl esters 3ab and 3ac in 40% yield. Interestingly,
treatment of ethyl alkynyl ether 2ab with Sc(OTf)3 in
CH3CN led to the formation of ethyl ester 3ad cleanly in
80% yield; however, addition of up to 15 mol % of catalyst
was necessary in order to achieve optimal conversion of
2ab to 3ad. On large scale (>500 mg), the increased
amounts of Lewis acid catalyst required led to side prod-
ucts arising from cleavage of the silyl ether protecting
group and lower (60ꢀ70%) yields of 3ad.
These initial results prompted us to evaluate the use of
other Lewis acids to catalyze the apparent cyclocondensa-
tion process (Table 1). Addition of Sc(OTf)3 (5 mol %) to
substrate 2aa in CH3CN gave a 78% yield of 3aa within
5 min at room temperature with only trace amounts of 3ab
Figure 1. Utility of alkoxycycloalkene carboxylates in natural
product synthesis.
9a
and 3ac formed. In(OTf)3 and Zn(OTf)2 also provided
3aa, although in significantly lower yields (50% and 25%,
respectively); moreover, complete consumption of 2a was
never achieved, even with the addition of excess catalyst
(up to 15 mol %) to the reaction mixture.
to approach by functional groups present in the same or
different molecules; furthermore, alkynyl ethers can pro-
spectively form up to three new bonds in a single reaction
(Figure 2).
Scheme 1. Attempted Deprotection of Dimethyl
Acetals 2aa, 2ab
Figure 2. Reactivity of 1-alkynyl ethers and their transformation
to cyclobutanones.
9b
Treatment of 2aa with the Lewis acids AgOTf or BiCl3
in CH3CN led to significant amounts of substrate decom-
position, with only minute quantities (<5%) of 3aa recov-
ered from the reaction mixtures. In contrast, no reac-
tion occurred when 2aa was stirred in the presence of
InCl3, even after 1 h. Finally, treatment of 2a with 5 mol %
TMSOTf in CH2Cl2 at ꢀ78 °C gave 3aa in 70% yield after
silica gel chromatography.
A possible mechanistic pathway for this process (Scheme 2)
might involve Lewis acid coordination of the acetal oxygen
atom, followed by ionization and [2 þ 2] cycloaddition.
Loss of isobutylene accompanied by ring opening would
then furnish either unsaturated methyl ester 3aa or ketene
A. A methanol trap of A would provide 3ac; Lewis acid
We have recently shown that tert-butyl ynol ethers
bearing tethered alkenes form substituted cyclobutanones
in high yields under mild thermal conditions.7a In attempt-
ing to extend this method to the preparation of β-lactones
and lactams through thermolysis of ketone and aldehyde-
tethered ynol ethers, we discovered that attempted depro-
tection of the acetal precursors led to the formation of
alkoxycycloalkene carboxylates rather than the desired
carbonyl-containing ynol ethers (Scheme 1). Thus, treat-
ment of acetal 2aa (prepared from aldehyde 1a by addition
of tert-butoxyethynyllithium7b and silyl protection of the
(8) Sun, J.; Dong, Y.; Cao, L.; Wang, X.; Wang, S.; Hu, Y. J. Org.
Chem. 2004, 69, 8932.
(9) (a) Gregg, B. T.; Golden, K. C.; Quinn, J. F. J. Org. Chem. 2007,
72, 5890. (b) Swamy, N. R.; Venkateswarlu, Y. Tetrahedron Lett. 2002,
43, 7549.
(7) (a) Tran, V.; Minehan, T. G. Org. Lett. 2011, 13, 6588. (b) tert-
Butoxyethynyllithium was prepared from 1,2-dichlorovinyl tert-butyl
ether by the protocol of Danheiser: Mak, X. Y.; Ciccolini, R. P.;
Robinson, J. M.; Tester, J. W.; Danheiser, R. L. J. Org. Chem. 2009, 74,
9381.
Org. Lett., Vol. 14, No. 23, 2012
6101

Table 1. Screen of Lewis Acid Catalysts for the Transformation
of 2aa to 3aaa
Scheme 3. Possible Mechanism for Formation of 3ad
time
% yield
3aab
entry
catalyst
I2
solvent
(min)
1
2
3
4
5
6
7
8
acetone
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH2Cl2
5
45
78
50
25
<5c
<5c
nr
Table 2. Scope of Lewis Acid Catalyzed Intramolecular
Cyclocondensation, 2f3a
Sc(OTf)3
In(OTf)3
Zn(OTf)2
AgOTf
5
10
10
10
10
60
10
BiCl3
InCl3
TMSOTfd
70
a All reactions were performed with 5 mol % catalyst in solvent
(0.15 M) at rt before quenching with saturated NaHCO3 solution.
b Isolated yield after silica gel chromatography. c Substrate decomposi-
tion occurred. d Reaction performed at ꢀ78 °C for 10 min.
mediated allylic substitution of 3aa with the liberated
methanol molecule could give rise to 3ab. Ester 3ac does
not convert into 3aa upon prolonged exposure to Lewis
acid; however, extended reaction times and/or the
addition of excess Lewis acid results in the conversion
of unsaturated ester 3aa into methyl ether 3ab. A simi-
lar pathway from 2ab to 3ad could proceed through
SN2-like cleavage of the oxonium methyl group, fol-
lowed by pericyclic ring opening of the oxetene inter-
mediate (Scheme 3).10
Scheme 2. Possible Mechanism for Formation of 3aaꢀ3ac
a R1 = tert-butyldiphenylsilyl; R2 = tert-butyldimethylsilyl. b Con-
ditions: (A) Sc(OTf)3 (5 mol %), CH3CN, rt, 10 min; (B) I2 (5 mol %),
acetone, rt, 5 min; (C) TMSOTf (5 mol %), CH2Cl2, ꢀ78 °C, 10 min.
c Isolated yield after column chromatography.
To explore the scope of this process, substrates 2bꢀ2g
(Table 2) were prepared in a similar fashion (see Support-
ing Information (SI))12 and treated with catalytic amounts
of a Lewis acid at rt or ꢀ78 °C. While scandium triflate
was an effective Lewis acid for ketone-derived acetals,
TMSOTf proved to be similarly efficient for aldehyde
derived acetals. Five- (entries 1ꢀ4) and six- (entries 5ꢀ7)
(11) For a recent review of the MeyerꢀSchuster rearrangement, see:
Engel, D. A.; Dudley, G. B. Org. Biomol. Chem. 2009, 7, 4149.
(12) Substrates 2aꢀ2g were obtained from the corresponding 1,4- or
1,5-oxocarboxylic acids in 40ꢀ61% overall yields. See SI.
(10) (a) Kurtz, K. C. M.; Hsung, R. P.; Zhang, Y. Org. Lett. 2006, 8,
231. (b) Shindo, M.; Mori, S. Synlett 2008, 2231. (c) Yoshikawa, T.;
Shindo, M. Org. Lett. 2009, 11, 5378.
6102
Org. Lett., Vol. 14, No. 23, 2012

Table 3. Preparation of Seven-Membered Cycloalkenesa
Scheme 4. Requirements for Seven-Membered Ring Formation
membered rings may be prepared in good to excellent
yields in this manner. Furthermore, both trisubstituted
(entries 3 and 7) and tetrasubstituted (entries 1, 2, and 4ꢀ6)
cycloalkenes are formed with similar efficiencies. Silyl
protecting groups employed in cyclization substrates
2 include TBS (entry 2) and TBDPS (tert-butyldiphenylsi-
lyl, entries 1 and 3ꢀ7) and are necessary to avoid the
facile MeyerꢀSchuster rearrangement11 that is observed
for the corresponding propargylic alcohols under Lewis
acidic reaction conditions. It was subsequently discovered
(Table 3, entry 2) that protection of tertiary propargylic
alcohols as their methyl ethers was also suitable for the
cyclocondensation process (vide infra).
a Reaction conditions: 0.33 M 2 in CH3CN, Sc(OTf)3 (10 mol %), rt,
10 min. b For preparation of 2iꢀ2m, see SI and refs 13ꢀ17. c Isolated
yield after column chromatography. d Compounds 2k, 2l, 3k, and 3l are
composed of a 2:1 mixture of diastereomers. See text and refs 15 and 16.
e Compounds 2m and 3m are composed of a 3:1 mixture of diastereo-
mers. See text and ref 17.
Extension of this chemistry to the synthesis of seven-
membered alkoxycycloalkene carboxylates was also pos-
sible. While substrate 2h disappointingly gave only a 5:1
mixture of acyclic ketoester 4 and unsaturated ester 5 upon
exposure to catalytic quantities of scandium triflate, under
the same conditionsdiethylacetal2i gavea 72% yield of the
expected ethyl ester 3i (Scheme 4). From these data it
appears that substrate preorganization to allow the proxi-
mity of the ynol ether and acetal termini is important for
successful application of this method to the synthesis of
medium-ring containing products. Table 3 shows several
additional examples of the preparation of trisubstituted
(entries 1ꢀ3, 5) and tetrasubstituted (entry 4) cycloalkenes
containing 5ꢀ7 and 6ꢀ7 ring systems utilizing this meth-
odology. Seven-membered cyclic ethers such as 3j may be
prepared containing a tertiary methyl ether (entry 2).
Moreover, fused 5ꢀ7 ring systems similar to that found
in guaiane-type sesquiterpene natural products (3m, entry 5)
could also be synthesized in moderate yields. Compounds
2kꢀ2m and 3kꢀ3m were obtained as a mixture of diaster-
eomers (2:1 for 2k, 2l, 3k, and 3l, and 3:1 for 2m and 3m)
resulting from the low stereoselectivity of the addition of
(ethoxyethynyl)lithium to the corresponding aldehyde
precursors.
In summary, we have shown that acetal-tethered alkynyl
ethers undergo facile intramolecular condensation reactions
under Lewis acid catalysis to form 5, 6, and 7-membered
alkoxycycloalkene carboxylates, compounds which are use-
ful intermediates for natural product synthesis. We are
currently exploring methods for the preparation of optically
enriched cycloalkene carboxylates from the asymmetric ad-
dition of alkynyl ether anions to aldehyde and ketones, and
the results of this study will be reported in due course.
Acknowledgment. We thank the National Institutes
of Health (SC3 GM096899-01) and the Henry Dreyfus
TeacherꢀScholar Award for their generous support of our
research program. We would also like to thank a reviewer
for providing the information in ref 10.
(13) Compound 2i was prepared in 41% overall yield from 2-bromo-
benzaldehyde diethylacetal. See SI and (a) Mukherjee, A.; Liu, R.-S.
Org. Lett. 2011, 13, 660. (b) Sajiki, H. Tetrahedron Lett. 1995, 36, 3465.
(14) Compound 2j was prepared in 53% overall yield from
salicylaldehyde. See SI and: Martinez-Peragon,A.;Millan,A.;Campana,
A. G.; Rodriguez-Marquez, I.; Resa, S.; Miguel, D.; Alvarez de Cienfuegos,
L.; Cuerva, J. M. Eur. J. Org. Chem. 2012, 8, 1499.
(15) Compound 2k was prepared in 35% overall yield from 2-allyl-
cyclohexanone. See SI and: Asao, N.; Lee, S.; Yamamoto, Y. Tetra-
hedron Lett. 2003, 44, 4265.
(16) Compound 2l was prepared in 22% overall yield from 2-allylcy-
clohexanone. See SI and: Smith, A. B.; Cho, Y. S.; Friestad, G. K
Tetrahedron Lett. 1998, 39, 8765.
Supporting Information Available. Experimental details,
characterization data, 1H, 13C spectra of all products. This
material is available free of charge via the Internet at http://
pubs.acs.org.
(17) Compound 2m was prepared in 29% overall yield from 2-allyl-
cyclopentanone. See SI.
The authors declare no competing financial interest
Org. Lett., Vol. 14, No. 23, 2012
6103