Biosynthesis-inspired intramolecular oxa-conjugate cyclization of α,β-unsaturated thioesters: Stereoselective synthesis of 2,6-cis-substituted tetrahydropyrans

Article abstract of DOI:10.1021/ol200333p

Intramolecular oxa-conjugate cyclization of α,β-unsaturated thioesters under Bronsted acid catalysis, inspired by biosynthesis of polyketide natural products, provides a variety of 2,6-cis-substituted tetrahydropyran derivatives with excellent diastereose

Full text of DOI:10.1021/ol200333p

ORGANIC
LETTERS
2011
Vol. 13, No. 7
1820–1823
Biosynthesis-Inspired Intramolecular
Oxa-Conjugate Cyclization of r,β-
Unsaturated Thioesters: Stereoselective
Synthesis of 2,6-cis-Substituted
Tetrahydropyrans
Haruhiko Fuwa,* Kenkichi Noto, and Makoto Sasaki
Graduate School of Life Sciences, Tohoku University, 2-1-1 Katahira, Aoba-ku, Sendai 980-8577, Japan
hfuwa@bios.tohoku.ac.jp
Received February 3, 2011
ABSTRACT
Intramolecular oxa-conjugate cyclization of R,β-unsaturated thioesters under Brønsted acid catalysis, inspired by biosynthesis of polyketide natural
products, provides a variety of 2,6-cis-substituted tetrahydropyran derivatives with excellent diastereoselectivities. An added bonus of this methodology
is that the product tetrahydropyrans could be readily elaborated to various derivatives by exploiting the unique reactivity of the thioester group.
Tetrahydropyrans are an important structural motif that
can be widely found in a plethora of naturally occurring
substances and as such represent valuable scaffolds for the
design and synthesis of biologically active small molecules.1
Accordingly, numerous methodologies have been developed
for the synthesis of tetrahydropyran derivatives. Intramole-
cular oxa-conjugate cyclization (IOCC), often referred to as
oxa-Michael cyclization, of R,β-unsaturated esters stands as
one of the renowned methodologies for tetrahydropyran
synthesis, and the products of this reaction have served as
important intermediates in the total synthesis of complex
natural products.2,3 In general, the stereoselectivity of base-
catalyzed IOCC of R,β-unsaturated esters depends on the
reaction conditions.4,5 It is known that the reaction provides
2,6-trans-substituted tetrahydropyrans under kinetic control,
while 2,6-cis-substituted tetrahydropyrans are formed only
when 2,6-trans and 2,6-cis isomers are in thermodynamic
equilibrium.6 Unfortunately, despite the fact that the majority
of tetrahydropyran-containing natural products have 2,6-cis
stereochemistry, the reaction sometimes results in poor dia-
stereoselectivity under thermodynamic conditions.7 It has
(5) Schneider, C.; Schuffenhauer, A. Eur. J. Org. Chem. 2000, 73.
(6) In some special cases, the stereoselectivity would depend on the
local structure of substrates. For example, IOCC of R,β-unsaturated
esters having a pro-axial δ-substituent favors 2,6-cis-substituted tetra-
(1) For recent reviews on the synthesis of tetrahydropyrans, see: (a)
Larrosa, I.; Romea, P.; Urpı, F. Tetrahedron 2008, 64, 2683. (b) Clarke,
P. A.; Santos, S. Eur. J. Org. Chem. 2006, 2045.
(2) For a recent review on oxa-conjugate addition, see: Nising, C. F.;
ꢀ
hydropyrans under kinetic control; see: (a) Pattenden, G.; Gonzalez,
€
Brase, S. Chem. Soc. Rev. 2008, 37, 1218.
M. A.; Little, P. B.; Millan, D. S.; Plowright, A. T.; Tornos, J. A.; Ye, T.
Org. Biomol. Chem. 2003, 1, 4173. (b) Crimmins, M. T.; Siliphaivanh, P.
Org. Lett. 2003, 5, 4641. (c) Fuwa, H.; Kainuma, N.; Tachibana, K.;
Sasaki, M. J. Am. Chem. Soc. 2002, 124, 14983.
(3) Our group has reported the total synthesis of tetrahydropyran-
containing natural products relying on IOCC. See: (a) Fuwa, H.; Saito,
A.; Sasaki, M. Angew. Chem., Int. Ed. 2010, 49, 3041. (b) Fuwa, H.;
Yamaguchi, H.; Sasaki, M. Tetrahedron 2010, 66, 7492. (c) Fuwa, H.;
Yamaguchi, H.; Sasaki, M. Org. Lett. 2010, 12, 1848. (d) Fuwa, H.;
Sasaki, M. Org. Lett. 2010, 12, 584. (e) Fuwa, H.; Noto, K.; Sasaki, M.
Heterocycles 2010, 82, 641.
(4) (a) Betancort, J. M.; Martın, V. S.; Padron, J. M.; Palazon, J. M.;
Ramırez, M. A.; Soler, M. A. J. Org. Chem. 1997, 62, 4570. (b) Ramırez,
M. A.; Padron, J. M.; Palazon, J. M.; Martın, V. S. J. Org. Chem. 1997,
62, 4584.
(7) For recent examples, see: (a) Wang, B.; Hansen, T. M.; Wang, T.;
Wu, D.; Weyer, L.; Ying, L.; Engler, M. M.; Sanville, M.; Leitheiser, C.;
Christmann, M.; Lu, Y.; Chen, J.; Zunker, N.; Cink, R. D.; Ahmed, F.;
Lee, C.-S.; Forsyth, C. J. J. Am. Chem. Soc. 2011, 133, 1484. (b) Bates,
R. W.; Song, P. Synthesis 2010, 2935. (c) Uenishi, J.; Iwamoto, T.;
ꢀ
ꢀ
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Tanaka, J. Org. Lett. 2009, 11, 3262. (d) Ferrie, L.; Boulard, L.; Pradaux,
ꢀ
ꢀ
F.; BouzBouz, S.; Reymond, S.; Capdevielle, P.; Cossy, J. J. Org. Chem.
2008, 73, 1864.
r
10.1021/ol200333p
Published on Web 03/03/2011
2011 American Chemical Society

also been reported that strongly basic, harsh conditions
and/or prolonged reaction times are in some cases necessary
for the selective formation of 2,6-cis-substituted tetrahydr-
opyrans.3a-c,8 On the other hand, acid-catalyzed IOCC of
R,β-unsaturated esters normally does not take place presum-
ably because of the low nucleophilicity of alcohols and
the low reactivity of R,β-unsaturated esters as conjugate
acceptors.6b,9,10
Recent biosynthetic studies have postulated that the
tetrahydropyrans of several polyketide natural products
would be formed via IOCC catalyzed by pyran synthase
(PS).11 As illustrated in Scheme 1a, the reaction is thought to
Inspired by the biosynthetic origin of tetrahydropyrans,
we envisioned that IOCC of R,β-unsaturated thioesters
based on carbonyl activation under acid catalysis would
represent a biomimetic methodology for the synthesis of 2,6-
cis-substituted tetrahydropyran derivatives (Scheme 1b).
We thought that this reaction would favor the formation
of synthetically useful 2,6-cis-substituted tetrahydropyrans
because its diastereoselectivity would depend on a late
transition model (vide infra). In addition, we expected that
the products of this reaction could be readily transformed
into a series of derivatives by exploiting the unique reactivity
of thioesters.
To test the viability of our idea, we first prepared a
variety of R,β-unsaturated thioesters 2a-f by exploiting
the olefin cross-metathesis reaction13,14 (Table 1). Treatment
Scheme 1. (a) Postulated Biosynthesis of Tetrahydropyrans of
Polyketide Natural Products and (b) Biomimetic Methodology
for Synthesis of 2,6-cis-Substituted Tetrahydropyrans
Table 1. Preparation of R,β-Unsaturated Thioesters
entry
R
yield/%
1
2
3
4
5
6
Et
2a: 93
2b: 94
2c: 92
2d: 82
2e: 94
2f: 87
Ph
p-MeC6H4
p-MeOC6H4
p-NO2C6H4
1-naphthyl
of hydroxy olefin 1 with an appropriate thioacrylate in the
presence of the Hoveyda-Grubbs second-generation cat-
alyst (HG-II)15 in CH2Cl2 at 35 °C provided 2a-f in high
yields. A brief investigation on the cyclization promoter
indicated that Brønsted acids, such as CSA, p-TsOH•H2O,
TFA, and CH3SO3H, were able to catalyze the cyclization,
while Lewis acids (e.g., MgBr2•OEt2, InCl3, Zn(OTf)2,
Cu(OTf)2, Sc(OTf)3, Yb(OTf)3) were uniformly ineffective
(no reaction or decomposition of the material).16 To probe
the reactivity of thioesters, 2a-f were individually exposed
occur during their polyketide biosynthesis; an R,β-unsatu-
rated thioester bound to an acyl carrier protein (ACP)
would be activated by a PS probably through hydrogen
bonding(s) and serve as an acceptor for the proximal
hydroxy group. We thought that the feasibility of the
biosynthetic formation of tetrahydropyrans would partly
stem from the enhanced reactivity of R,β-unsaturated thioe-
sters when compared with the corresponding oxoesters.12
(8) Micalizio, G. C.; Pinchuk, A. N.; Roush, W. R. J. Org. Chem.
2000, 65, 8730.
(12) There are only limited reports that describe the use of R,β-
unsaturated thioesters as conjugate acceptors. See: (a) Rigby, C. L.;
Dixon, D. J. Chem. Commun. 2008, 3798. (b) Mazery, R. D.; Pullez, M.;
(9) In contrast, IOCC of R,β-unsaturated ketones proceeds under
acidic conditions due to their high reactivity. For examples, see: (a)
Reddy, C. R.; Rao, N. N. Tetrahedron Lett. 2010, 51, 5840. (b) Bates,
R. W.; Song, P. Tetrahedron 2007, 63, 4497. (c) Liu, J.; Yang, J. H.; Ko,
C.; Hsung, R. P. Tetrahedron Lett. 2006, 47, 6121. (d) Chandrasekhar,
S.; Prakash, S. J.; Shyamsunder, T. Tetrahedron Lett. 2005, 46, 6651. See
also ref 7b.
(10) A single example of acid-catalyzed IOCC of an R,β-unsaturated
ester, presumably promoted by the gem-dimethyl substitution effect, has
recently been reported. See: Hajare, A. K.; Ravikumar, V.; Khaleel, S.;
Bhuniya, D.; Reddy, D. S. J. Org. Chem. 2011, 76, 963.
(11) (a) Irschik, H.; Kopp, M.; Weissman, K. J.; Buntin, K.; Piel, J.;
ꢀ
Lopez, F.; Harutyunyan, S. R.; Minnaard, A. J.; Feringa, B. L. J. Am.
Chem. Soc. 2005, 127, 9966. (c) Bandini, M.; Melloni, A.; Tommasi, S.;
Umani-Ronchi, A. Helv. Chim. Acta 2003, 86, 3753. (d) Agapiou, K.;
Krische, M. J. Org. Lett. 2003, 5, 1737. (e) Keck, G. E.; Welch, D. S. Org.
Lett. 2002, 4, 3687. (f) Emori, E.; Arai, T.; Sasai, H.; Shibasaki, M. J.
Am. Chem. Soc. 1998, 120, 4043.
(13) For a review on the olefin cross-metathesis reaction, see: Con-
non, S. J.; Blechert, S. Angew. Chem., Int. Ed. 2003, 42, 1900.
(14) Van Zijl, A. W.; Minnaard, A. J.; Feringa, B. L. J. Org. Chem.
2008, 73, 5651.
(15) Garber, S. B.; Kingsbury, J. S.; Gray, B. L.; Hoveyda, A. H.
J. Am. Chem. Soc. 2000, 122, 8168.
(16) Spencer et al. have reported that hetero-Michael reactions are
actually catalyzed by protons. See: Wabnitz, T. C.; Yu, J,-Q.; Spencer,
J. B. Chem.;Eur. J. 2004, 10, 484.
€
Muller, R. ChemBioChem 2010, 11, 1840. (b) Sudek, S.; Lopanik, N. B.;
Waggoner, L. E.; Hildebrand, M.; Anderson, C.; Liu, H.; Patel, A.;
Sherman, D. H.; Haygood, M. G. J. Nat. Prod. 2007, 70, 67. (c) Julien,
B.; Tian, Z.-Q.; Reid, R.; Reeves, C. D. Chem. Biol. 2006, 13, 1277. (d)
Piel, J. Proc. Natl. Acad. Sci. U.S.A. 2002, 99, 14002.
Org. Lett., Vol. 13, No. 7, 2011
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Table 2. Brønsted Acid Catalyzed Cyclization of R,β-Unsatu-
Table 3. Application to Various Substrates (Tol = p-tolyl)a
rated Thioestersa
entry
2
R
time/h yield/% (rsm) cis/transb
1c
2
2a
2b
2c
Et
21
40
40
44
45
73
3a: 43 (26)
3b: 56 (41)
3c: 72 (12)
3d: 69 (16)
3e: 29 (65)
3f: 56 (35)
15:1
>20:1
>20:1
>20:1
>20:1
>20:1
Ph
3
p-MeC6H4
4
2d p-MeOC6H4
5
2e
2f
p-NO2C6H4
6
1-naphthyl
a All reactions were performed using 20 mol % of CSA in CH2Cl2 at
room temperature unless otherwise noted and quenched when cleavage
of the MPM group was observed by TLC analysis. b The ratio of 2,6-cis
and 2,6-trans isomers was estimated by 600 MHz 1H NMR analysis.
c The reaction was performed using 70 mol % of CSA.
to CSA in CH2Cl2 at room temperature to deliver the
2,6-cis-substituted tetrahydropyrans 3a-f, respectively, in
moderate to good yields (Table 2). Since 2c showed the
highest reactivity among others in these preliminary ex-
periments (entry 3), further investigations were carried out
using S-(p-tolyl) thioesters as the substrate.
To probe the scope of the reaction, we next examined a
series of R,β-unsaturated thioesters 4-10 (Table 3).
Although the cyclization of 4 only proceeded slowly at
room temperature, the reaction was complete in a reason-
able time simply by running the reaction in 1,2-dichlor-
oethane (DCE) at 70 °C, giving 11 in 88% yield as a single
stereoisomer. In a similar manner, thioesters 5-10 were
treated with 20 mol % of CSA (DCE, 70 °C) to afford the
2,6-cis-substituted tetrahydropyrans 12-17, respectively,
in excellent yields with high diastereoselectivity.17 Interest-
ingly, we found that δ-substituted R,β-unsaturated thioe-
sters (i.e., 5, 6, 7, 9, and 10) cyclized more rapidly than
unsubstituted ones (i.e., 4 and 8). For each product, the
2,6-cis stereochemistry was confirmed by NOE experiment-
(s) and/or 3JH,H values.18
The observed stereoselectivity of the Brønsted acid catalyzed
IOCC of R,β-unsaturated thioesters can be explained by
considering a late transition state model, wherein unfavorable
steric interactions between substituents are avoided as much as
possible (Scheme 2). The possibility that the preferential
formation of 2,6-cis isomers is due to thermodynamic equili-
bration was ruled out because isomerization of trans-14 to the
thermodynamically more stable cis-14 was not observed under
the cyclization conditions (CSA, DCE, 70 °C, 6 h).
a All reactions were performed using 20 mol % of CSA in DCE at
70 °C. b The ratio of 2,6-cis and 2,6-trans isomers was determined by
600 MHz 1H NMR analysis.
On the other hand, IOCC of 7 under basic conditions
(KOt-Bu, THF, -78 °C) gave the cyclization product as a
4:1 mixture of diastereomers favoring trans-14 (Scheme 2).
The diastereoselectivity of the cyclization was exactly the
same as that of the corresponding oxoester 18. The prefer-
ential formation of 2,6-trans isomers under these conditions
could be reasoned by the chelation-controlled model.4
Finally, we examined derivatization of the tetrahy
dropyran 11 as summarized in Scheme 3. Reduction
of 11 under the Fukuyama conditions (Et3SiH, 10%
Pd/C)19 gave aldehyde 20 in 86% yield. Amidation of 11
with piperidine in the presence of AgOCOCF320 proceeded
smoothly to provide amide 21 in 99% yield. Moreover,
(17) Here, we confirmed that treatment of the corresponding oxoe-
ster of 5 with CSA resulted only in decomposition of the material. This
clearly demonstrates that thioesters are more reactive toward the con-
jugate addition of oxygen nucleophiles than the corresponding
oxoesters.
(19) Fukuyama, T.; Lin, S. C.; Li, L. J. Am. Chem. Soc. 1990, 112,
(18) See the Supporting Information for details.
7050.
1822
Org. Lett., Vol. 13, No. 7, 2011

Scheme 2. Mechanistic Considerations
Scheme 3. One-Step Derivatization of Thioester 11
palladium-catalyzed reactions of thioesters enabled unsym-
metric ketone synthesis from 11.21 Coupling of 11 with tri(n-
butyl)vinylstannane under the Liebeskind conditions22 gave
enone 22 in 79% yield. Coupling of 11 with phenylboronic
acid23 afforded phenyl ketone 23 in 57% yield. A Sonogashira-
type reaction24 of 11 with phenylacetylene under our previo-
usly optimized conditions25 delivered ynone 24 in 76% yield.
In conclusion, we have shown that Brønsted acid cata-
lyzed IOCC of R,β-unsaturated thioesters represents a
biomimetic methodology for the stereoselective
synthesis of 2,6-cis-substituted tetrahydropyran de-
rivatives. The ready availability of R,β-unsaturated
thioesters via olefin cross-metathesis and the syn-
thetic versatility of the cyclization products due to
the unique reactivity of the thioester group are addi-
tional benefits of our methodology.
Acknowledgment. We thank Dr. Kenji Sugimoto
(University of Toyama) for his advice on the preparation
of S-ethyl thioacrylate. This work was supported in part by
a Grant-in-Aid for Scientific Research from the Ministry
of Education, Culture, Sports, Science and Technology,
Japan.
(20) Kurosu, M. Tetrahedron Lett. 2000, 41, 591.
ꢀ
(21) For reviews, see: (a) Prokopcova, H.; Cappe, C. O. Angew.
Chem., Int. Ed. 2009, 48, 2276. (b) Fukuyama, T.; Tokuyama, H.
Aldrichimica Acta 2004, 37, 87.
(22) (a) Wittenberg, R.; Srogl, J.; Egi, M.; Liebeskind, L. S. Org. Lett.
2003, 5, 3033. (b) Li, H.; Yang, H.; Liebeskind, L. S. Org. Lett. 2008, 10,
4375.
(23) Liebeskind, L. S.; Srogl, J. J. Am. Chem. Soc. 2000, 122, 11260.
(24) Tokuyama, H.; Miyazaki, T.; Yokoshima, S.; Fukuyama, T.
Synlett 2003, 1512.
Supporting Information Available. Experimental proce-
dures, spectroscopic data, stereochemical assignment of
1
the cyclization products, and copies of H and 13C NMR
spectra for all new compounds. This material is available free
of charge via the Internet at http://pubs.acs.org.
(25) Fuwa, H.; Matsukida, S.; Sasaki, M. Synlett 2010, 1239.
Org. Lett., Vol. 13, No. 7, 2011
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