A Single-Flask Synthesis of Morita-Baylis-Hillman Adducts from Ethoxyacetylene and Carbonyl Compounds: Synthesis of Subamolides D and e

Article abstract of DOI:10.1021/acs.orglett.6b01772

Sequential treatment of (ethoxyethynyl)lithium with aldehydes and/or ketones (2 and 4) and BF₃·OEt₂ gives rise to β-hydroxyenoates 5 in good to excellent overall yields. Similarly, the combination of 1 (M = Li) and dicarbonyl compounds 6 (X = O) or keto/aldehyde acetals (X = OMe) followed by the addition of a Lewis acid leads to five-, six-, and seven-membered hydroxycycloalkene carboxyates. The utility of this method is demonstrated in the synthesis of the α-alkylidene lactone natural products subamolide D and E.

Full text of DOI:10.1021/acs.orglett.6b01772

Letter
pubs.acs.org/OrgLett
A Single-Flask Synthesis of Morita−Baylis−Hillman Adducts from
Ethoxyacetylene and Carbonyl Compounds: Synthesis of
Subamolides D and E
Kevin Ng and Thomas G. Minehan*
Department of Chemistry and Biochemistry, California State University, Northridge 18111 Nordhoff Street, Northridge, California
91330-8262, United States
S
* Supporting Information
ABSTRACT: Sequential treatment of (ethoxyethynyl)lithium with aldehydes and/or ketones (2 and 4) and BF3·OEt2 gives rise
to β-hydroxyenoates 5 in good to excellent overall yields. Similarly, the combination of 1 (M = Li) and dicarbonyl compounds 6
(X = O) or keto/aldehyde acetals (X = OMe) followed by the addition of a Lewis acid leads to five-, six-, and seven-membered
hydroxycycloalkene carboxyates. The utility of this method is demonstrated in the synthesis of the α-alkylidene lactone natural
products subamolide D and E.
he Morita−Baylis−Hillman (MBH) reaction, which
Tinvolves the coupling of activated alkenes or alkynes
and electrophiles under Lewis base catalysis, is a versatile
reaction in organic synthesis for the formation of carbon−
carbon bonds.1 The intramolecular variant of this process, in
which the activated alkene and electrophile components are
present in the same molecule, allows the preparation of diverse
carbocyclic and heterocyclic systems.2 In addition to tertiary
amines and alkyl (aryl) phosphines, both Bronsted and Lewis
acids have been demonstrated to be efficient promoters for this
process, and asymmetric reactions employing chiral catalysts
allow the synthesis of optically active products.3 Since Morita−
Baylis−Hillman adducts are densely functionalized molecules,
they are highly useful as intermediates in the synthesis of
Figure 1. Previous (a) and current (b) single-flask transformations of
interesting natural and designed products of medicinal
metalated ynol ether 1.
import.4−7 In view of the importance of MBH adducts in
organic synthesis, the development of new methods for their
fashion. We wished to extend this process to the preparation of
MBH adducts by sequentially combining metalated exthox-
yacetylene and two carbonyl compounds in the presence of a
Lewis acid; however, a potential side reaction which could
complicate this process is the facile Meyer−Schuster rearrange-
ment of intermediate 3, which has been extensively utilized for
the synthesis of α,β-unsaturated esters of the type 7 from
metaled ynol ethers and aldehydes and ketones.10
We initiated our studies by combining (ethoxyethynyl)-
lithium (2.1 mmol) with benzaldehyde (1.4 mmol) at −78 °C
in THF (Scheme 1); after a brief warming to 0 °C (10 min),
complete consumption of benzaldehyde was observed by thin
efficient preparation is of great importance. In the present
Letter, we describe a useful condensation of ynol ethers and
carbonyl compounds in the presence of Lewis acids that affords
cyclic and acyclic Morita−Baylis−Hillman adducts in a one-pot
reaction.
Electron-rich alkynes, such as ynamines and ynol ethers, are
functional groups that possess significant potential in organic
chemistry for the formation of C−C bonds.8 We have
previously shown that five- and six-membered Z-α-alkylidene-
and Z-α-benzylidene lactones can be prepared efficiently in a
single flask from the reaction of metalated ethoxyacetylene,
epoxides or oxetanes, and aldehydes or ketones in the presence
of BF3OEt2 as a promoter (Figure 1).9 Three new carbon−
carbon bonds and a ring are created in the process, with a
significant increase in molecular complexity realized in a rapid
Received: June 28, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b01772
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Letter
Table 1 shows the extension of this method to the
preparation of Morita−Baylis−Hilman adducts from two
different carbonyl components.
Scheme 1. Reaction of Ynol Ethers 1 with Aldehydes in the
Presence of BF3·OEt2
Table 1. Scope of Reaction of 1 with Aldehydes and Ketones
layer chromatography. After recooling to −78 °C, the lithium
alkoxide intermediate was treated with BF3·OEt2 (2.1 mmol),
followed by addition of a second equivalent of benzaldehyde
(1.4 mmol). TLC showed no conversion of the initial aldehyde
adduct, and the mixture was allowed to warm to 0 °C and stir
for 30 min. An 81% yield of alcohol 3a was isolated after
column chromatrography; less than 10% of ethyl cinnamate 7a
was also produced. This result indicated that the lithium
alkoxide−BF3·OEt2 complex did not significantly undergo a
Meyer−Schuster reaction between −78 and 0 °C. The
experiment was then repeated, and the lithium alkoxide
intermediate was combined with BF3·OEt2 (2.1 mmol),
benzaldehyde (2.1 mmol), and an additional equivalent of
BF3·OEt2 (2.1 mmol) at −78 °C in THF. Upon warming to 0
°C, MBH adduct 5a was produced in 69% yield, along with
13% of 7a. It was found that the amount of cinnamate
produced could be decreased by lowering the amount of the
second addition of BF3·OEt2 to 20 mol % (0.42 mmol). In this
manner, a 73% isolated yield of 5a could be secured, with less
than 5% of 7a produced in the reaction mixture.
Applying this protocol to dihydrocinnamaldehyde, acrolein,
and isobutyaldehyde gave adducts 5b−5d in 54−82% isolated
yields, respectively. Although the second addition of a full
equivalent (2.1 mmol) of BF3·OEt2 was required for optimal
yields of products 5b and 5d, the corresponding Meyer−
Schuster products 7b and 7d were formed in only trace
quantitites (>5%), indicating that the acid-promoted rearrange-
ment process is less favored for alkoxide intermediates derived
from addition of (ethoxyethynyl)lithium to aliphatic aldehydes.
It is interesting to note that while 5a and 5c, both derived from
unsaturated aldehydes, are produced as the E-alkene stereo-
isomer predominantly (as verified by NOESY experiments, see
a
All reactions were carried out using ethoxyacetylene (2.1 mmol) in
THF (1 M), n-BuLi (2.1 mmol), 2 (1.4 mmol), BF3·OEt2 (2.1 mmol),
4 (2.1 mmol), and BF3·OEt2 (2.1 mmol). Isolated yields after column
chromatography. Isolated as a 5:1 E/Z mixture of alkene isomers.
b
c
A variety of hindered and unhindered aliphatic (entries 1−4),
aromatic (electron-deficient, sterically encombered, and elec-
tron-rich entries 3, 5, and 6), and α,β-unsaturated (entries 5
and 7) aldehydes and both cyclic and acyclic ketones (entries 4,
6, and 7) participate in this process as either the first (2) or
second (4) carbonyl component. The Z-alkene geometry
predominates in all cases except when both 2 and 4 are
unsaturated carbonyl compounds (entry 5). Intriguingly, the
sequential combination of (ethoxyethynyl) lithium, cyclo-
1
Supporting Information, and comparison of H NMR spectra
with literature data18), the predominant isomer of compounds
5b and 5d is of the Z configuration. Whereas the E isomer of 5a
and 5c may be favored by π−π type interactions, A-1,3 strain
present in the E isomers of 5d and 5d may favor acid-promoted
E-to-Z isomerization, as has been previously shown for both
cyclic and acyclic enoates.9
B
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pentanone (carbonyl component 1), and dihydro-cinnamalde-
hyde (carbonyl component 2, entry 4) according to the above-
described protocol gave the rearranged β-hydroxy enoate 5h
exclusively. Reversing the order of carbonyl addition also gave
5h, albeit in lower overall yield (35%), implying a Lewis acid
mediated equilibrium process favoring the formation of the
more stable tetrasubstituted enoate product (see below).
We were interested in preparing adducts of the type 5m
(Scheme 2) as advanced precursors for the synthesis of α-
Scheme 3. Synthesis of ( )-Subamolides E and D
Scheme 2. Formation of Product Mixtures with Acrolein and
Undecanal
be the shortest synthetic pathway to this class of natural
products.15
Next, we wished to explore the possibility of forming cyclic
MBH adducts through the use of dicarbonyl compounds as
reaction partners. Indeed, the combination of (ethoxyethynyl)-
lithium (1.5 equiv) with phthalic dicarboxyaldehyde (1.0 equiv)
in THF at −78 °C, followed by warming to 0 °C for 10 min,
recooling to −78 °C, and treatment with BF3·OEt2 (2.4 equiv),
gave rise to hydroxycyclopentene carboxylate 8a in 71%
isolated yield after warming to −20 °C for 15 min (Table 2,
entry 1). Employing acetonyl acetone (Table 2, entry 2) as the
dicarbonyl compound gave the desired tertiary alcohol 8b in
62% yield upon quenching the reaction mixture at −20 °C; if
the mixture was instead allowed to warm to room temperature,
cyclopentadiene 8b′ (see Supporting Information) was the
major product, likely arising from Lewis acid mediated
elimination of the tertiary alcohol. To circumvent the
elimination process at elevated temperatures, we investigated
the use of keto-acetal and aldehyde-acetal substrates instead of
dicarbonyl compounds, since we have previously shown that
intramolecular condensation of ynol-ether acetals takes place
rapidly at room temperature in the presence of Lewis acids to
form alkoxycycloakene carboxylates.16 Indeed, exposure of
(ethoxyethynyl)lithium to aldehyde-acetals (6c−6e, 6g, entries
3−5, 7) or keto acetal (6f, entry 6) in THF from −78 °C to rt,
followed by addition of BF3·OEt2 at −78 °C and warming to
room temperature, gave the corresponding five-, six-, and
seven-membered hydroxycycloalkene carboxylates 8c−8g in
good to excellent yields (Table 2) with no evidence of diene
formation.
alkylidene lactone natural products. However, exposure of
(ethoxyethynyl)lithium to acrolein, followed by successive
treatment with BF3·OEt2, undecanal, and BF3·OEt2, gave rise to
a 1:3 mixture of alcohol 5m and rearranged alcohol 5l in 75%
yield. Quenching the reaction at lower temperatures (−40 °C,
−10 °C) did not increase the proportion of 5m formed, and
lowering the amount of Lewis acid added in the second step
(50 mol %, 20 mol %) decreased the overall yields of adducts
obtained without significantly effecting the 5l:5m ratio. Again,
reversing the order of aldehyde addition led to the same ratio of
products 5l and 5m in 68% yield. It is likely that the
combination of ynol ether intermediate A with undecanal and
BF3·OEt2 gives rise to oxonium ion B, in equilibrium with
oxonium ion C, which produce 5m and 5l, respectively, upon
ring opening. The predominance of 5l may be due to the
greater stability of the conjugated diene unit relative to the
isolated diene of 5m.
It was nonetheless possible to transform the mixture of 5l
and 5m into 5m exclusively in high yield (85%) by a sequence
involving acylation (Ac2O, Pyr), allylic substitution with sodium
phenylselenide (NaSePh, THF, rt, 10 min),11 and oxidation
(H2O2, pyr, CH2Cl2, 0 °C, 20 min).12 This protocol
conveniently provides a separable 3:1 mixture of E and Z
enoates 5m (Scheme 3).
In summary we have developed an efficient and direct
method for the synthesis of cyclic and acyclic Morita−Baylis−
Hillman adducts from ethoxyacetylene and carbonyl com-
pounds. This one-pot process results in the formation of three
new carbon−carbon bonds, and the products are richly
functionalized to allow further bond formations via conjugate
addition or allylic substitution reactions.17 The utility of this
process has been demonstrated in the synthesis of subamolides
D and E. We are continuing to explore the applications of this
method in natural product synthesis.
Subamolides D and E are two naturally occurring α-
alkylidene lactones which have been shown to be DNA
damaging agents capable of inducing apoptosis in malignant
cells (Scheme 3).13 Hydrolysis of the ethyl ester of (E)-5m and
oxidative cyclization of the unsaturated acid with catalytic
quantities of Cl2Pd(PPh3)2 and Cu(OAc)2 under an atmos-
phere of oxygen14 directly afforded racemic subamolide E in
61% overall yield; an analogous treatment of (Z)-5m gave
( )-subamolide D in 53% overall yield. To date this appears to
C
DOI: 10.1021/acs.orglett.6b01772
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Letter
NMR spectra of new compounds in Tables 1 and 2 and
Schemes 1−3 (PDF)
Table 2. Scope of Reaction of 1 with Carbonyl Compounds
6
a
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: thomas.minehan@csun.edu.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This Letter is dedicated to Professor Peter B. Dervan on the
occasion of his 70th birthday. We acknowledge the National
Science Foundation (CHE-1508070), the National Institutes of
Health (SC3 GM 096899-01), and the donors of the American
Chemical Society Petroleum Research Fund (53693-URI) for
their generous support of this research.
REFERENCES
■
(1) For reviews, see: (a) Bhowmik, S.; Batra, S. Curr. Org. Chem.
2015, 18, 3078. (b) Wang, F.-J.; Wei, Y.; Shi, M. RSC Catal. Ser. 2011,
8, 485. (c) Zhao, M.-X.; Wei, Y.; Shi, M. RSC Catal. Ser. 2011, 8, 1.
(d) Guillena, G.; Ramon, D. J.; Yus, M. Catalysis 2012, 24, 223.
(e) Mansilla, J.; Saa, J. M. Molecules 2010, 15, 709. (f) Basavaiah, D.;
Reddy, B. S.; Badsara, S. S. Chem. Rev. 2010, 110, 5447.
(2) Bharadwaj, K. C. RSC Adv. 2015, 5, 75923.
(3) (a) Masson, G.; Housseman, C.; Zhu, J. Angew. Chem., Int. Ed.
2007, 46, 4614. (b) Mansilla, J.; Saa, J. M. Molecules 2010, 15, 709.
(4) Yamane, T.; Ogasawara, K. Synlett 1996, 1996, 925.
(5) Yamakoshi, H.; Shibuya, M.; Tomizawa, M.; Osada, Y.; Kanoh,
N.; Iwabuchi, Y. Org. Lett. 2010, 12, 980.
(6) Candish, L.; Lupton, D. W. Org. Lett. 2010, 12, 4836.
(7) Tan, Y. X.; Santhanakrishnan, S.; Yang, H. Y.; Chai, C. L. L.;
Tam, E. K. W. J. Org. Chem. 2014, 79, 8059.
(8) For recent reviews of the chemistry of ynol ethers, see: (a) 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. (b) Witulski, B.; Alayrac, C. Science of Synthesis 2005, 24, 933−956.
(9) Ng, K.; Tran, V.; Minehan, T. G. Tetrahedron Lett. 2016, 57, 415.
(10) (a) Engel, D. A.; Dudley, G. B. Org. Lett. 2006, 8, 4027. (b) Puri,
S.; Thirupathi, N.; Reddy, M. S. Org. Lett. 2014, 16, 5246.
(11) Sharpless, K. B.; Young, M. W. J. Org. Chem. 1975, 40, 947.
(12) Nishiyama, H.; Itagaki, K.; Sakuta, K.; Itoh, K. Tetrahedron Lett.
1981, 22, 5285.
(13) (a) Kuo, S.-Y.; Hsieh, T.-J.; Wang, Y.-D.; Lo, W.-L.; Hsui, Y.-R.;
Chen, C.-Y. Chem. Pharm. Bull. 2008, 56, 97. (b) Wang, H.-M.; Chiu,
C.-C.; Wu, P.-F.; Chen, C.-Y. J. Agric. Food Chem. 2011, 59, 8187.
(14) Rudler, H.; Harris, P.; Parlier, A.; Cantagrel, F.; Denise, B.;
Bellassoued, M.; Vaissermann, J. J. Organomet. Chem. 2001, 624, 186.
(15) For the synthesis of a similar natural product (peumusolide A)
and its analogs, see: (a) Tamura, S.; Tonokawa, M.; Murakami, N.
Tetrahedron Lett. 2010, 51, 3134. (b) Tamura, S.; Doke, S.; Murakami,
N. Tetrahedron 2010, 66, 8476.
a
All reactions were carried out using ethoxyacetylene (2.1 mmol) in
THF (1 M), n-BuLi (2.1 mmol), 6 (1.4 mmol), and BF3·OEt2 (3.4
mmol). Isolated yields after column chromatography. The reaction
mixture was quenched at −20 °C instead of rt.
(16) Tran, V.; Minehan, T. G. Org. Lett. 2012, 14, 6100.
(17) Dambrin, V.; Villieras, M.; Janvier, P.; Toupet, L.; Amri, H.;
Lebreton, J.; Villieras, J. Tetrahedron 2001, 57, 2155.
b
c
(18) Kim, S. J.; Lee, H. S.; Kim, J. M.; Kim, J. N. Bull. Korean Chem.
Soc. 2008, 29, 265.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.6b01772.
Experimental procedures, spectroscopic and analytical
data (PDF)
D
DOI: 10.1021/acs.orglett.6b01772
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