Catalytic Dehydrative Lactonization of Allylic Alcohols

Article abstract of DOI:10.1021/acs.orglett.8b01063

A convenient strategy for the synthesis of phthalides and ?-butyrolactones is reported. The method utilizes readily prepared allylic alcohols in formal Au(I)- and Pd(II)-catalyzed S_N2′ reactions. Using these catalysts, exclusive formation of the desired five-membered lactones is observed, completely avoiding the competing direct lactonization pathway that forms the undesired seven-membered ring with protic acids and alternative metal salts. This mild and operationally simple method notably tolerates exomethylene groups and should find use in both phthalide and terpene syntheses.

Full text of DOI:10.1021/acs.orglett.8b01063

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Catalytic Dehydrative Lactonization of Allylic Alcohols
Ji Liu,‡ Romain J. Miotto,‡ Julien Segard, Ashley M. Erb, and Aaron Aponick*
Florida Center for Heterocyclic Compounds and Department of Chemistry, University of Florida, Gainesville, Florida 32611, United
States
S
* Supporting Information
ABSTRACT: A convenient strategy for the synthesis of phthalides
and γ-butyrolactones is reported. The method utilizes readily
prepared allylic alcohols in formal Au(I)- and Pd(II)-catalyzed SN2′
reactions. Using these catalysts, exclusive formation of the desired
five-membered lactones is observed, completely avoiding the
competing direct lactonization pathway that forms the undesired
seven-membered ring with protic acids and alternative metal salts.
This mild and operationally simple method notably tolerates exomethylene groups and should find use in both phthalide and
terpene syntheses.
hthalides are a prevalent class of natural products with a
myriad of biological activities1 that are important for lead
of a carboxylate onto a cis-allylic alcohol (path a, Scheme 1). This
seemed particularly attractive because the requisite substrate 8
P
compounds2 and even find clinical use (e.g., noscapine,3 4 Figure
1). The family comprises nearly 200 compounds isolated from
Scheme 1. Proposed Lactone Synthesis
should be preparable from inexpensive and readily available
benzoic acids 9 and propargylic starting materials, 10, by
Sonogashira coupling9 followed by partial reduction of the
ensuing alkyne.10 If successful, the strategy would be direct and
also introduce a vinyl group that could potentially enable further
transformations and provide facile access to this important
structural motif.
A survey of the literature revealed little with regard to similar
substrates, especially cis-olefins, which are readily prepared from
alkynes, but may suffer direct formation of the seven-membered
lactone and could pose a problem in the presence of Bronsted
acids or oxophilic Lewis acid catalysts (path b, Scheme 1).11
Kitamura reported an elegant Ru-catalyzed cyclization of a trans-
allylic alcohol to prepare a phthalide,12 and the majority of the
substrates described were aliphatic trans-allylic alcohols, which
worked best. Their reaction proceeds at 100 °C in DMA via a π-
allyl intermediate formed by the action of a sophisticated
bifunctional catalyst that features both soft Ru and hard Bronsted
acid sites. The authors point out that with more traditional π-
allylmetal systems the lactone likely reversibly opens, and this
may be why there are not more reports utilizing π-allyl chemistry
for phthalide synthesis.
Figure 1. Representative phthalide natural products (1−5) and γ-
butyrolactone terpene 6.
more than 100 plant sources.4 The highly diverse structures are
derived from the polyketide biosynthetic machinery and also may
fall the under alkaloid classification when basic nitrogen atoms
are present.5 Structurally, these compounds are characterized by
a benzo-fused γ-butyrolactone motif with substitution on the
arene, as well as at the γ-position of the lactone. The γ-
butyrolactone moiety is also found in a variety of terpene natural
products,6 as illustrated by parthenolide 6,7 and this widespread
distribution among different natural product classes makes it an
interesting target nucleus for developing new synthetic strategies.
Although many strategies have been reported,8 in their
comprehensive review,8a Mal and co-workers categorize
phthalide syntheses into nine distinct groups, the principal of
which is lactone formation, and the chemistries for this are quite
diverse. It occurred to us that a direct strategy for the
introduction of the lactone could be through an SN2′ reaction
Received: April 4, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b01063
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
As part of a program aimed at developing dehydrative
cyclization reactions, we have found that, while the possibility
for both Bronsted acidity and traditional Lewis acidity exists,
Au(I)-13 and Pd(II)-catalysts14 efficiently act as π-acids in our
systems to effect formal SN2′ reactions.15,16 As such, it seemed
possible that these complexes could efficiently moderate the
proposed transformation (path a, Scheme 1) and avoid the
aforementioned issue; however, this would present a suitable
stress-test for these catalyst systems as phthalide-forming
substrates, in particular, are likely prone to direct lactonization.
Herein, we report our studies in this area, which have resulted in
an efficient strategy for the formation of γ-butyrolactones from
benzoic acid derivatives and propargyl alcohols.
Table 2. Phthalide Substrate Scope
At the outset, benzoic acid 11a was prepared and subjected to
several sets of conditions to test the feasibility of this idea (Table
1). Initial attempts focused on employing simple metal salts that
Table 1. Catalyst Screening
entry
catalyst (mol %)
AuCl (10)
time (h)
yield (%)
12/13
1
2
3
4
5
6
7
8
9
10
20
20
20
1
<5
48
88
99
99
n.r.
75
56
94
94
n.d.
AuCl3 (10)
83:17
15:85
>99:1
>99:1
FeCl3·6H2O (10)
Ph3PAuCl/AgOTf (5)
PdCl2(CH3CN)2 (10)
AgOTf (10)
0.25
20
0.5
5
TfOH (10)
1:>99
1:>99
1:>99
1:>99
HCl in ether (10)
CSA (10)
5
TsOH·H2O (10)
5
had previously been reported in dehydrative cyclization reactions
of allylic alcohols to form ethers17 and nitrogen heterocycles.18
While using AuCl as a catalyst demonstrated a very low reactivity
19
(entry 1), the use of the more strongly electrophilic AuCl3
produced both the five- and seven-membered ring lactones 12a
and 13a in 48% yield with an 83:17 ratio, respectively (entry 2).
While these initial results demonstrated the viability of the idea, it
was clear that both the selectivity and yield would need to be
improved and other conditions were screened. Cossy’s Fe-
catalyzed conditions20 completely reversed the chemoselectivity,
favoring 13a (entry 3), but a ligated Au(I) catalyst gave the
desired γ-butyrolactone 12a in quantitative yield with near
perfect selectivity (entry 4). Use of PdCl2(CH3CN)2 also yielded
12a with similar results (entry 5), and both systems would be
explored further. Control experiments with AgOTf and TfOH
demonstrated that neither the silver salt nor the protic acid were
catalyzing the γ-butyrolactone-forming reaction (entries 6 and
7), and other common protic acids were also demonstrated to
form lactone 13a (entries 8−10). These results further
demonstrated that competitive formation of 13a with protic
acids and Lewis acidic metal-based catalysts could be problem-
atic.21
a
EtOAc was used as solvent. Under the standard conditions A and B,
no conversion and low conversion were observed, respectively, likely
The scope of the reaction was then examined under both Au-
and Pd-catalyzed conditions A and B, respectively (Table 2).
Electron donating and electron withdrawing groups on the
aromatic ring would be expected to impact the electronic
character of both the carboxyl group and the allylic alcohol
depending on the position. A variety of phthalides were produced
b
because 11f displays poor THF solubility. trans/cis = 3:1.
in good to excellent yields with minimal exception. Under Au-
catalysis, groups that donate to both the carboxylate and the
B
DOI: 10.1021/acs.orglett.8b01063
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
allylic alcohol functioned better in the reaction than those with
electron-withdrawing groups in these positions (cf. 11b vs 11c,
entries 3 and 5; and 11d vs 11e, entries 7 and 9). With Pd-
catalysis, these electronic effects were less pronounced. As seen
in Table 2, phthalide products with a variety of substituents were
formed in excellent yields, mostly >90%. Furthermore, with
Pd(II), substituents were tolerated at the allylic position (e.g.,
12i, formed in 91%). This difference may be due to the ability of
the Pd-catalyst to access alternative reaction pathways as
previously described and supported by computational stud-
ies.22,23 Both Au- and Pd-catalysts also functioned to form the six-
membered lactone 12j, suggesting that the strategy may be
utilized for targets other than phthalides.
Table 3. γ-Butyrolactone Substrate Scope
The substrates described thus far contain a cis-olefin due to
their convenient preparation from the propargylic intermediates
that result from the Sonogashira coupling strategy. While it has
been previously observed that, in related Au-catalyzed
dehydrative cyclizations of allylic diols,24 cis-allylic alcohols are
more reactive than the corresponding trans-substrates, the trans-
allylic alcohols still function quite well in those reactions. To test
the relative reactivity of the olefins, the trans-substrate 14 was
prepared and subjected to both sets of conditions (Scheme 2).
Much to our surprise, no reaction was observed under the Au-
catalysis conditions, and 12a was isolated in only 11% under the
Pd(II) conditions.
Scheme 2. Reactivity of trans-Olefin
a
b
No reaction was observed after 20 h. The major diastereomer
isolated (16c) was 3,5-trans, dr = 1.75:1.
To expand the scope of the reaction, we also sought to deploy
this strategy for the synthesis of aliphatic butenolides where it
might find use in terpene syntheses.25 As can be seen in Table 3,
the reaction also functions quite well for these simple
butenolides. The Pd(II) conditions were again more robust,
and extremely rapid in some cases (e.g., entries 2 and 4),
providing all the products in excellent yield. One of the most
noteworthy reactions is that of 15e to produce the highly
electrophilic exomethylene containing lactone 16e in 90% after a
30 min reaction time with the Pd-conditions. Interestingly, the
differential reactivity with the two catalyst systems is most
striking when the degree of substitution is reduced. Using the
catalyst generated in situ from Ph3PAuCl and AgOTf, the
reaction appeared to be sensitive to entropic effects, as observed
in entries 3, 5, and 7 where the yield drops from 95% for 16b to
no observable product for 16c/d. In these cases, it is also possible
that enolizable substrates are problematic; but regardless of the
source of the issue with Au-catalysis, the Pd(II)-conditions were
still quite efficient.
The reaction conditions described employ somewhat high
catalyst loadings, and it would be desirable to reduce this for
larger scale reactions. To study the feasibility of this, substrate
11a was treated under the Pd(II)-conditions and the loading
varied. As can be seen in Table 4, the reaction was nearly as rapid
and high yielding with a 5 mol % loading, but this dropped off
precipitously when 2 and 1 mol % PdCl2(CH3CN)2 were
employed (entries 2−4). It occurred to us that reduced catalyst
concentration might be responsible for this sluggish reactivity. As
can be seen in entry 5, when the concentration was increased, the
Table 4. Catalyst Loading Studies
entry
catalyst loading (mol %)
time (h)
yield (%)
1
2
3
4
10
5
0.25
0.33
12
99
97
2
22
1
12
trace
96
a
5
b
2
12
6
2
12
95
a
b
0.5 M in 11a 2 mmol scale.
product was again isolated in high yield. The reaction was also
scaled up to 2 mmol at 2 mol % loading (entry 6) with no loss in
yield.
The products of the transformation described here contain an
olefin that we initially hypothesized would be useful for further
functionalization. Although a myriad of transformations are
known for the conversion of alkenes into other synthetic handles,
considering the substitution patterns in this family of natural
products, it would be particularly important for phthalide
synthesis if oxygenation could be introduced at the terminal
position. To explore this, the simple natural products
isoochracinic acid and isoochracinol1a were targeted. To this
C
DOI: 10.1021/acs.orglett.8b01063
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(b) Xiong, M. J.; Li, Z. H. Curr. Org. Chem. 2007, 11, 833. (c) Xu, Z.; Hu,
end, after protection of the phenol 12b as its silyl ether, the olefin
was readily oxidized under Wacker conditions known to produce
the aldehyde instead of the more traditional methyl ketone
product.26 Further oxidation of 17 to the carboxylic acid or
reduction to the alcohol and deprotection produced the natural
products 18 and 19, respectively (Scheme 3).
G. Y.; Tan, G. S. Chin. J. Modern Med. 2004, 93. (d) Holler, U.; Gloer, J.
̈
B.; Wicklow, D. T. J. Nat. Prod. 2002, 65, 876. (e) Radcliff, F. J.; Fraser, J.
D.; Wilson, Z. E.; Heapy, A. M.; Robinson, J. E.; Bryant, C. J.; Flowers, C.
L.; Brimble, M. A. Bioorg. Med. Chem. 2008, 16, 6179. (f) Maneerat, W.;
Phakhodee, W.; Ritthiwigrom, T.; Cheenpracha, S.; Promgool, T.;
Yossathera, K.; Deachathai, S.; Laphookhieo, S. Fitoterapia 2012, 83,
1110.
Scheme 3. Conversion to Isoochracinic Acid and
Isoochracinol
(2) (a) Blasko, G.; Gula, D.; Shamma, M. J. Nat. Prod. 1982, 45, 105.
(b) Di Mola, A.; Palombi, L.; Massa, A. Curr. Org. Chem. 2012, 16, 2302.
(3) (a) Ye, K.; Ke, Y.; Keshava, N.; Shanks, J.; Kapp, J. A.; Tekmal, R.
R.; Petros, J.; Joshi, H. C. Proc. Natl. Acad. Sci. U. S. A. 1998, 95, 1601.
(b) Mahmoudian, M.; Mehrpour, M.; Benaissa, F.; Siadatpour, Z. Eur. J.
Clin. Pharmacol. 2003, 59, 579. (c) Mahmoudian, M.; Rahimi-
Moghaddam, P. Recent Pat. Anti-Cancer Drug Discovery 2009, 4, 92−97.
(4) (a) Lin, G.; Chan, S. S.-K.; Chung, H.-S.; Li, S.-L. Chemistry and
Biological Action of Natural Occurring Phthalides. In Studies in Natural
Products Chemistry; ur-Rahman, A., Ed.; Elsevier: Amsterdam, 2005; Vol.
32, pp 611−669. (b) Beck, J. J.; Chou, S. C. J. Nat. Prod. 2007, 70, 891.
(5) Hopwood, D. A. Chem. Rev. 1997, 97, 2465−2497.
(6) Seitz, M.; Reiser, O. Curr. Opin. Chem. Biol. 2005, 9, 285.
(7) (a) Hehner, S. P.; Hofmann, T. G.; Droge, W.; Schmitz, M. L. J.
̈
Immunol. 1999, 163, 5617. (b) Kwok, B. H. B.; Koh, B.; Ndubuisi, M. I.;
Elofsson, M.; Crews, C. M. Chem. Biol. 2001, 8, 759. (c) Zhang, S.; Ong,
C.-N.; Shen, H.-M. Cancer Lett. 2004, 208, 143.
In summary, we have described a direct route for the formation
of butenolides. The reaction proceeds from readily available
precursors and is enabled by Au(I) and Pd(II) catalysts that
catalyze the transformation without the direct lactone formation
observed with protic or oxophilic Lewis acids. It is also important
to note that, although Au-catalysis has made a tremendous
impact on the field, Pd(II)-based catalyst systems can function
equally well and, in this case, proved to be more general than the
Au(I)-catalysts employed. The method described is applicable to
both phthalide and aliphatic butenolide synthesis and is
predicted to find widespread use in synthetic schemes.
(8) For a review on phthalide synthesis, see: (a) Karmakar, R.; Pahari,
P.; Mal, D. Chem. Rev. 2014, 114, 6213. For select recent examples, see:
(b) Sueki, S.; Wang, Z.; Kuninobu, Y. Org. Lett. 2016, 18, 304.
(c) Mahendar, L.; Satyanarayana, G. J. Org. Chem. 2016, 81, 7685.
(d) Arcadi, A.; Fabrizi, G.; Goggiamani, A.; Marinelli, F. J. Org. Chem.
2015, 80, 6986. (e) Gandeepan, P.; Rajamalli, P.; Cheng, C.-H. Chem. -
Eur. J. 2015, 21, 9198. (f) Ma, J.; Yuan, Z.-Z.; Kong, X.-W.; Wang, H.; Li,
Y.-M.; Xiao, H.; Zhao, G. Org. Lett. 2016, 18, 1450. (g) Mao, W.; Zhu, C.
Org. Lett. 2015, 17, 5710. (h) Beneteau, R.; Despiau, C. F.; Rouaud, J.-
C.; Boussonniere, A.; Silvestre, V.; Lebreton, J.; Denes, F. Chem. - Eur. J.
2015, 21, 11378. For select examples using C−H functionalization, see:
(i) Shen, Z. M.; Dornan, P. K.; Khan, H. A.; Woo, T. K.; Dong, V. M. J.
Am. Chem. Soc. 2009, 131, 1077. (j) Lian, Y. J.; Bergman, R. G.; Ellman, J.
A. Chem. Sci. 2012, 3, 3088. (k) Yang, Y. X.; Zhou, B.; Li, Y. C. Adv.
Synth. Catal. 2012, 354, 2916. (l) Tan, P. W.; Juwaini, N. A. B.; Seayad, J.
Org. Lett. 2013, 15, 5166. (m) Yang, J. F.; Yoshikai, N. J. Am. Chem. Soc.
2014, 136, 16748.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.8b01063.
(9) Sonogashira, K.; Tohda, Y.; Hagihara, N. Tetrahedron Lett. 1975,
16, 4467.
(10) (a) Lindlar, H. Helv. Chim. Acta 1952, 35, 446. (b) Lindlar, H.;
Dubois, R. Org. Synth. 1966, 4689.
(11) For leading references on lactone formation from hydroxy acids,
see: (a) Maier, M. In Science of Synthesis; Carreira, E. M., Panek, J. S.,
Eds.; Thieme: Stuttgart, 2010; Vol. 20, pp 1421−1551. (b) Posner, G.
H.; Weitzberg, M.; Hamill, T. G.; Asirvatham, E.; Cun-heng, H.; Clardy,
J. Tetrahedron 1986, 42, 2919. (c) Janecki, T.; Blaszczyk, E. Tetrahedron
Lett. 2001, 42, 2919. (d) Ling, Q.; Huang, Y.; Zhou, Y.; Cai, Z.; Xiong,
B.; Zhang, Y.; Ma, L.; Wang, X.; Li, X.; Li, J.; Shen, J. Bioorg. Med. Chem.
2008, 16, 7399.
Experimental procedures and spectral data for all new
compounds (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: aponick@chem.ufl.edu.
ORCID
Aaron Aponick: 0000-0002-4576-638X
Author Contributions
‡These authors contributed equally.
Notes
(12) Suzuki, Y.; Seki, T.; Tanaka, S.; Kitamura, M. J. Am. Chem. Soc.
2015, 137, 9539.
(13) (a) Furstner, A. Chem. Soc. Rev. 2009, 38, 3208. (b) Pflasterer, D.;
Hashmi, A. S. K. Chem. Soc. Rev. 2016, 45, 1331.
̈
̈
The authors declare no competing financial interest.
(14) Cannon, J. S.; Overman, L. E. Acc. Chem. Res. 2016, 49, 2220.
(15) For gold-catalyzed reactions, see: (a) Aponick, A.; Li, C.-Y.;
Palmes, J. A. Org. Lett. 2009, 11, 121. (b) Aponick, A.; Li, C.-Y.; Malinge,
J.; Marques, E. F. Org. Lett. 2009, 11, 4624. (c) Paioti, P. H. S.; Ketcham,
J. M.; Aponick, A. Org. Lett. 2014, 16, 5320. (d) Paioti, P. H. S.; Aponick,
A. Top. Curr. Chem. 2014, 357, 63. (e) Mukherjee, P.; Widenhoefer, R.
A. Org. Lett. 2011, 13, 1334. (f) Bandini, M.; Bottoni, A.; Chiarucci, M.;
Cera, G.; Miscione, G. P. J. Am. Chem. Soc. 2012, 134, 20690.
(g) Chiarucci, M.; Locritani, M.; Cera, G.; Bandini, M. Beilstein J. Org.
Chem. 2011, 7, 1198.
ACKNOWLEDGMENTS
■
The authors thank the University of Florida, the Herman Frasch
Foundation (647-HF07), and the James and Esther King
Biomedical Research Program (09KN01) for their generous
support of their programs.
REFERENCES
■
(1) (a) Cui, L. Y.; Zhu, Y. C.; Gao, S.; Wang, J. M.; Peng, B.; Ni, J.;
Zhou, L. X.; He, J.; Ma, X. Q. Chin. Med. J. (Eng.) 2013, 126, 3405.
D
DOI: 10.1021/acs.orglett.8b01063
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
(16) For palladium-catalyzed reactions, see: (a) Borrero, N. V.;
Aponick, A. J. Org. Chem. 2012, 77, 8410. (b) Palmes, J. A.; Paioti, P. H.
S.; de Souza, L. P.; Aponick, A. Chem. - Eur. J. 2013, 19, 11613.
(c) Harrington, P. J.; Hegedus, L. S.; McDaniel, K. F. J. Am. Chem. Soc.
1987, 109, 4335. (d) Hande, S. M.; Kawai, N.; Uenishi, J. J. Org. Chem.
2009, 74, 244. (e) Makabe, H.; Kong, L. K.; Hirota, M. Org. Lett. 2003, 5,
27.
(17) Aponick, A.; Li, C.-Y.; Biannic, B. Org. Lett. 2008, 10, 669.
(18) Borrero, N. V.; DeRatt, L. G.; Abboud, K. A.; Aponick, A. Org.
Lett. 2015, 17, 1754.
(19) (a) Hashmi, A. S. K.; Frost, T. M.; Bats, J. M. J. Am. Chem. Soc.
2000, 122, 11553. (b) Hashmi, A. S. K. Angew. Chem., Int. Ed. 2000, 39,
2285. (c) Hashmi, A. S. K. Angew. Chem., Int. Ed. Engl. 1995, 34, 1581.
(20) (a) Anxionnat, B.; Guer
Tetrahedron Lett. 2009, 50, 3470. (b) Guer
Gnamm, C.; Bensoussan, C.; Reymond, S.; Cossy, J. Org. Lett. 2010, 12,
1808.
́
inot, A.; Reymond, S.; Cossy, J.
́
inot, A.; Serra-Muns, A.;
(21) For an early discussion of this, see: (a) Hashmi, A. S. K.; Schwarz,
L.; Rubenbauer, P.; Blanco, M. C. Adv. Synth. Catal. 2006, 348, 705.
(b) Hashmi, A. S. K. Catal. Today 2007, 122, 211.
(22) Ghebreghiorgis, T.; Biannic, B.; Kirk, B. H.; Ess, D. H.; Aponick,
A. J. Am. Chem. Soc. 2012, 134, 16307.
(23) Ghebreghiorgis, T.; Kirk, B. H.; Aponick, A.; Ess, D. H. J. Org.
Chem. 2013, 78, 7664.
(24) Biannic, B.; Ghebreghiorgis, T.; Aponick, A.; Beilstein. Beilstein J.
Org. Chem. 2011, 7, 802.
́
(25) (a) Mao, B.; Fananas-Mastral, M.; Feringa, B. Chem. Rev. 2017,
̃
117, 10502. (b) Welsch, M. E.; Snyder, S. A.; Stockwell, B. R. O. Curr.
Opin. Chem. Biol. 2010, 14, 347. (c) Zhang, Q.; Lu, Y.; Ding, Y.; Zhai, J.;
Ji, Q.; Ma, W.; Yang, M.; Fan, H.; Long, J.; Tong, Z.; Shi, Y.; Jia, Y.; Han,
B.; Zhang, W.; Qiu, C.; Ma, X.; Li, Q.; Shi, Q.; Zhang, H.; Li, D.; Zhang,
J.; Lin, J.; Li, L.-Y.; Gao, Y.; Chen, Y. J. Med. Chem. 2012, 55, 8757.
(d) Schall, A.; Reiser, O. Eur. J. Org. Chem. 2008, 2008, 2353.
(26) Choi, P. J.; Sperry, J.; Brimble, M. A. J. Org. Chem. 2010, 75, 7388.
E
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