Regulation of cyclization for the stereoselective synthesis of substituted tetrahydrofurans and tetrahydrooxepines

Article abstract of DOI:10.1021/ol7026569

(Chemical Equation Presented) Dramatic solvent effect is observed during the cyclization of 1. Synthesis of 2 is achieved from the reaction of 1 with a hexamethylditin-catalyzed palladium complex followed by aldehydes in the presence of TMSOTf in THF, whereas 3 is formed in CH₂Cl₂. The method described herein is successful with various substrates 1 in good yields and high levels of diastereoselectivity.

Full text of DOI:10.1021/ol7026569

ORGANIC
LETTERS
2008
Vol. 10, No. 2
265-268
Regulation of Cyclization for the
Stereoselective Synthesis of Substituted
Tetrahydrofurans and
Tetrahydrooxepines
Sang-Hoon Kim, Seung-Ju Oh, Pil-Su Ho, Sin-Cheol Kang, Kyung-Jin O, and
Chan-Mo Yu*
BK-21 School of Chemical Materials Science and Department of Chemistry,
Sungkyunkwan UniVersity, Suwon 440-746, Korea
cmyu@chem.skku.ac.kr
Received November 1, 2007
ABSTRACT
Dramatic solvent effect is observed during the cyclization of 1. Synthesis of 2 is achieved from the reaction of 1 with a hexamethylditin-
catalyzed palladium complex followed by aldehydes in the presence of TMSOTf in THF, whereas 3 is formed in CH2Cl2. The method described
herein is successful with various substrates 1 in good yields and high levels of diastereoselectivity.
One of the recent goals of synthetic chemistry is the
development of new reactions that allow for the efficient
conversion of simple starting materials into complex products
via transition metal catalysis.1 In this regard, allene has been
proved to be a useful substrate for a variety of transition
metal catalytic reactions, particularly, for cyclizations in the
construction of carbo- and heterocycles.2 Recently, we have
developed several cyclization methods using allenes as
substrates or intermediates,3 as part of a sequential allylic
transfer strategy.4 The characteristic features of this approach,
in terms of the chemical efficiency of the stereoselective
three-component assembly and the structural features of the
products, have encouraged us to carry out further investiga-
tions to introduce other functionalities. As a consequence,
we became quite interested in designing an intramolecular
allylic transfer reaction from 1 to 2 with the generation of
three stereogenic centers as depicted in Scheme 1.
Scheme 1
(1) General discussions: (a) Zeni, G.; Larock, R. C. Chem. ReV. 2006,
106, 4644-4680. (b) Transition Metals for Organic Synthesis; Beller, M.,
Bolm, C., Eds.; Wiley-VCH: Weinheim, Germany, 2004. (c) Trost, B. M.;
Toste, A. B. Chem. ReV. 2001, 101, 2067-2096.
(2) (a) Ma, S. Chem. ReV. 2005, 105, 2829-2871. (b) Mandai, T. In
Modern Allene Chemistry; Krause, N., Hashmi, A. S. K., Eds.; Wiley-
VCH: Weinheim, Germany, 2004; Vol. 2, pp 925-972. (c) Ma, S. Eur. J.
Org. Chem. 2004, 1175-1183. (d) Trost, B. M. Acc. Chem. Res. 2002, 35,
695-705.
It was envisaged that the allylic transfer reaction starting
from 1 with an aldehyde (R2CHO) leading to the formation
(3) (a) Kim, S.-H.; Oh, S.-J.; Kim, Y.; Yu, C.-M. Chem. Commun. 2007,
5025-5027. (b) Yu, C.-M.; Youn, J.; Lee, M.-K. Org. Lett. 2005, 7, 3733-
3736. (c) Yu, C.-M.; Hong, Y.-T.; Lee, J. J. Org. Chem. 2004, 69, 8506-
8509. (d) Kang, S.; Hong, Y.-T.; Lee, J.-H.; Kim, W.-Y.; Lee, I.; Yu,
C.-M. Org. Lett. 2003, 5, 2813-2816.
10.1021/ol7026569 CCC: $40.75
© 2008 American Chemical Society
Published on Web 12/13/2007

of 2 could be realized by the two-step sequence as described
in Scheme 1. To provide direct access to the product 2, we
considered an oxonium A as a crucial intermediate. This
transformation involves the distannylation of an allene, the
formation of an oxonium species A with an aldehyde
mediated by a Lewis acid and subsequent intramolecular
allylic transfer reaction.
sponding 2 could not be satisfied with a variety of Lewis
acids including SnCl4, TiCl4, and EtAlCl2 under various
reaction conditions. We observed the formation of only a
trace of product except the decomposition of the intermediate.
We found that BF3‚OEt2 could be a promoter for this
purpose. Initial experiments on the distannylation of 1a
followed by intramolecular allylic transfer with aldehyde in
the presence of BF3‚OEt2 (1.5 equiv) at -78 °C in CH2Cl2
afforded two products. Although 2a was produced as a major
component along with unexpected 3a during the reaction,
moderate selectivity (2:3 ) 73:27) and low chemical yield
(13% combined) remained to be solved. We were surprised
to find that the destannylated tetrahydrooxepine 3a was
formed.
Substituted tetrahydrofurans are found in a wide range of
useful biologically active molecules.5 In general, these
molecules contain various substituents and stereogenic
centers around and adjacent to the tetrahydrofuran ring.
Notable methods for the synthesis of tetrahydrofuran units
have been developed in recent years to achieve stereoselec-
tivity,6 the useful strategy of which involves construction of
the oxacyclic ring by carbon-carbon bond formation from
an oxonium intermediate via electrophilic cyclization.7 The
realization of this method for the three-component assembly
to achieve multiple stereoselectivity, illustrated in Scheme
1, should be valuable because synthetic application can be
foreseen for the products. We report herein our discovery
of a general and useful method in the construction of trisub-
stituted tetrahydrofurans 2 and disubstituted tetrahydro-
oxepines 3 from 1 in a single operation. During the inves-
tigations, the dramatic solvent effects to regulate reaction
pathways for the formation of five- or seven-membered
oxacycles were observed.
Fortunately, we observed that the use of TMSOTf turned
out to be the most effective promoter for this transformation,
as can be seen in Table 1. After exploring numerous sets of
Table 1. Preliminary Investigations
With this issue in mind, our investigations began with 1a
(R1 ) PhCH2CH2) as a model substrate. Reaction of 1a (1
equiv) with hexamethylditin (1.2 equiv) in the presence of
(π-allyl)2Pd2Cl2 (0.5 mol %) at 0 °C in CH2Cl2 afforded a
distannylated product within 3 h. The stage was thus set for
the cyclization reaction with aldehydes mediated by a Lewis
acid based on the conditions mainly developed by Marko
and co-workers.8 Attempts of a cyclization reaction, without
separation of the distannylated intermediate, with hydrocin-
namaldehyde indicated that the conversion to the corre-
Lewis acid
(equiv)
yieldc
(%)
entry
solvent
2a:3ab
1
2
3
4
5
6
7
8
9
10
11
12
13
BF3‚OEt2 (1.5)
BF3‚OEt2 (1.5)
SnCl4 (1.5)
CH2Cl2
toluene
CH2Cl2
CH2Cl2
CH2Cl2
THF
THF
CH3CN
Et2O
73:27
-
-
-
-
2a only
2a only
2a only
2a only
9:91
8:92
3:97
2:98
13
trace
trace
trace
trace
67
83
23
32
73
TiCl4 (1.5)
EtAlCl2 (1.5)
TMSOTf (1.1)
TMSOTf (1.5)
TMSOTf (1.5)
TMSOTf (1.5)
TMSOTf (1.5)
TMSOTf (1.5)
TMSOTf (1.5)
TMSOTf (1.5)
CH2Cl2
CHCl3
CH2Cl2
CH2Cl2
(4) (a) Yu, C.-M.; Youn, J.; Jung, J. Angew. Chem., Int. Ed. 2006, 45,
1553-1556. (b) Yu, C.-M.; Youn, J.; Hong, Y.-T.; Yoon, S.-K. Org. Lett.
2005, 7, 4507-4510. (c) Yu, C.-M.; Kim, J.-M.; Shin, M.-S.; Yoon, M.-O.
Chem. Commun. 2003, 1744-1745. (d) Yu, C.-M.; Lee, J.-Y.; So, B.; Hong,
J. Angew. Chem., Int. Ed. 2002, 41, 161-163.
(5) (a) Faul, M. M.; Huff, B. E. Chem. ReV. 2000, 100, 2407-2474. (b)
Saleem, M.; Kim, H. J.; Ali, M. S.; Lee, Y. S. Nat. Prod. Rep. 2005, 22,
696-716.
(6) Reviews: (a) Wolfe, J. P. Eur. J. Org. Chem. 2007, 571-581. (b)
Kang, E. J.; Lee, E. Chem. ReV. 2005, 105, 4348-4378. (c) Boivin, T. L.
Tetrahedron 1987, 43, 3309-3362.
65
71
42
d
e
a Reaction conditions: (i) (Me3Sn)2 (1.2 equiv), (π-allyl)2Pd2Cl2 (0.5
mol %), 0 °C, 3 h; (ii) R2CHO (1.5 equiv), Lewis acid, -78 °C, 4 h, solvent.
b Determined by 1H NMR. c Refer to isolated product. d Performed at -40
°C. e Performed at -10 °C.
(7) Related to our studies: (a) Loh, T.-P.; Hu, Q.-Y.; Tan, K.-T.; Cheng,
H.-S. Org. Lett. 2001, 3, 2669-2672. (b) Loh, T.-P.; Hu, Q.-Y.; Ma, L.-T.
J. Am. Chem. Soc. 2001, 123, 2450-2451. (c) Mohr, P. Tetrahedron Lett.
1993, 34, 6251-6254.
conditions, we found that the choice of solvents led to the
formation of 2a or 3a selectively. Reaction produced only
2a in THF (entry 7), whereas 3a was formed in CH2Cl2 (entry
12). We also observed inverse temperature effects for the
formation of 3a, but yields were decreased by increasing
temperature (entries 12 and 13). We realized that the
synthesis of seven-membered oxacycles is also important
because the related structures are considerably distributed
in nature and play a variety of biological roles.9
(8) (a) Jaques, T.; Marko, I. E.; Prospisil, J. In Multicomponent Reactions;
Zhu, J., Bienayme, H., Eds.; Wiley-VCH: Weinheim, Germany, 2005; pp
398-452 and references cited therein. (b) Liu, F.; Loh, T.-P. Org. Lett.
2007, 9, 2063-2066. (c) Fearnley, S. P.; Lory, P. Org. Lett. 2007, 9, 3507-
3510. (d) Jasti, R.; Rychnovsky, S. D. Org. Lett. 2006, 8, 2175-2178. (e)
Pospisil, J.; Kumamoto, T.; Marko, I. Angew. Chem., Int. Ed. 2006, 45,
3357-3360. (f) Innis, L. v.; Plancher, M.; Marko, I. Org. Lett. 2006, 8,
6111-6114. (g) Overman, L. E.; Velthuisen, E. J. Org. Chem. 2006, 71,
1581-1587. (h) Bolla, M. L.; Patterson, B.; Rychnovsky, S. D. J. Am. Chem.
Soc. 2005, 127, 16044-16045. (i) Marko, I. E.; Dumeunier, R.; Leclercq,
C.; Leroy, B.; Plancher, J.-M.; Mekhalfia, A.; Bayston, D. J. Synthesis 2002,
958-972. (j) Roush, W. R.; Dilley, G. J. Synlett 2001, 955-959. (k) Huang,
H.; Panek, J. S. J. Am. Chem. Soc. 2000, 122, 9836-9837. (l) Semeyn, C.;
Blaauw, R. H.; Hiemstra, H.; Speckamp, W. N. J. Org. Chem. 1997, 62,
3426-3427. (m) Mohr, P. Tetrahedron Lett. 1995, 36, 2453-2456.
(9) For examples, see: (a) Blunt, J. W.; Copp, B. R.; Hu, W.-P.; Munro,
M. H. G.; Northcote, P. T.; Prinsep, M. R. Nat. Prod. Rep. 2007, 24, 31-
86. (b) Blunt, J. W.; Copp, B. R.; Munro, M. H. G.; Northcote, P. T.;
Prinsep, M. R. Nat. Prod. Rep. 2006, 23, 26-78.
266
Org. Lett., Vol. 10, No. 2, 2008

With the notion that this protocol might lead to a general
and efficient method for the synthesis of 2, we set out to
determine the scope of the reaction with various 1 (Table
example, compound 2a was converted to 4 by the Stille
coupling.10 Elimination of 6 with NaHMDS in DMF yielded
7. Carbonylation of 6 in the presence of Pd(0) under CO
pressure in MeOH gave 8 in good yield.11
In light of the above results for the synthesis of the
tetrahydrofuran 2, we next turned our attention to the
application of this approach to extend to the synthesis of
seven-membered oxacycles based on the preliminary inves-
tigations (Table 1, entry 12). Under similar conditions for
the synthesis of 2a, except the use of CH2Cl2 instead of THF
as a solvent, 3a was obtained as a single diastereomer in
71% yield. Indeed, the method is successful with various 1
and affords products of high purity as listed in Table 3. It is
Table 2. Cyclization of 1 to 2 in THF
yield
(%)
entry
product
R1
R2
1
2
3
4
5
6
7
8
9
2a
2b
2c
2d
2e
2f
2g
2h
2i
PhCH2CH2
PhCH2CH2
n-C5H11
n-C5H11
n-C5H11
Me
Me2CH
Ph
Ph
PhCH2CH2
Me
PhCH2CH2
Me
83
77
75
71
69
87
76
67
53
Table 3. Cyclization of 1 to 3 in CH2Cl2
CH2Cl
PhCH2CH2
PhCH2CH2
PhCH2CH2
Me2CH
yield
(%)
entry
product
R1
R2
3:2
1
2
3
4
5
6
7
8
9
3a
3b
3c
3d
3e
3f
3g
3h
3i
PhCH2CH2
PhCH2CH2
PhCH2CH2
n-C5H11
n-C5H11
PhCH2
Me
PhCH2CH2
Me
Ph
PhCH2CH2
Ph
PhCH2CH2
PhCH2
PhCH2
Me2CH
97:3
95:5
98:2
96:4
98:2
94:6
93:7
3 only
99:1
71
75
67
66
61
80
71
67
64
2). Upon optimal conditions, the reaction was conducted by
a dropwise addition of a mixture of 1a (1 equiv) and
Me3SnSnMe3 (1.2 equiv) in THF to a solution of (π-
allyl)2PdCl2 (0.5 mol %) at 0 °C in THF. After 3 h at 0 °C,
the reaction mixture was cooled to -78 °C, and then
aldehyde (1.5 equiv) and TMSOTf (1.5 equiv) were added.
Reaction was usually complete within 4 h. Workup and
chromatography on silica gel afforded 2a in 83% yield as a
diastereomerically pure form. Indeed, the method is suc-
cessful with a variety of compounds 1 and affords products
of high diastereomeric purity as it can be seen in Table 1. It
is noteworthy that other diastereomers were not detected by
analysis of 1H NMR. Stereochemical relationship was
unambiguously deduced by a series of NMR experiments
with 5 (see Supporting Information). Crucial evidence was
the NOE enhancements between H2-H3 and H2-H5.
Product 2 is readily amenable for further conversion to
synthetically useful compounds by functional group trans-
formations of vinylstannane as depicted in Scheme 2. For
Ph
Ph
noteworthy that reaction produced less than 7% of five-
membered oxacycles 2 according to the analysis of 1H NMR
spectra of crude products. Stereochemical relationship of 3a
was proved by comparison of NMR data with literature.12
In order to prove retention of stereochemistry during the
cyclizations, enantiomerically enriched (+)-1a was pre-
pared from the corresponding propargyl alcohol.13 As illu-
strated in Scheme 3, we demonstrated that the cyclizations
Scheme 3
Scheme 2
of (+)-1a, both for five- and seven-membered oxacycles,
proceeded with complete retention of stereochemistry as
determined by chiral HPLC analysis.
Org. Lett., Vol. 10, No. 2, 2008
267

Although the exact mechanistic aspects of this transforma-
tion have not been rigorously elucidated, the following
pathway is a probable stereochemical route on the basis of
product formations and our observations as illustrated in
Scheme 4. The exceptional stereoselectivity for tetrahydro-
However, the origin of the formation of seven-membered
oxacycles 3 depending on solvent is not clear at this moment.
There are two possibilities governing reaction pathways for
the second allylic transfer reaction. First, we speculated that
the formation of 3 could be explained by assuming that
reaction produced 17 from 2 by R-addition through the 1,3-
migration of allylic tin reagent followed by a destannylation
to 2 under the reaction conditions or during a workup process.
However, the experiments could not support this claim: a
vinylstannyl group was stable under the same reaction
conditions, and the addition of NBS before quenching the
reaction did not afford a vinylbromide compound. Another
possibility is a formation of 13 as a crucial intermediate.
Subsequent cyclization of 13 and an aldehyde in the presence
of TMSOTf could give rise to 3 as depicted in Scheme 4, a
similar pathway described by Overman.12a The formation of
13 was confirmed by a control experiment. During the
distannylation, we did not find any formation of 13. After
the introduction of TMSOTf, the formation of 13 was
observed at -40 °C in CH2Cl2 for 1 h in more than 75%
conversion as judged by NMR. However, we do not have
the answer at this time, if this reaction pathway is plausible,
why the route from 10 to 13 is faster than the route to 2
under the reaction conditions. We only know that the reaction
of 1 in CH2Cl2 produced 3 as a major component.
Scheme 4
In summary, this paper describes the synthesis of five-
and seven-membered oxacycles selectively by simply chang-
ing the solvent. We also demonstrated that the reaction
proceeded with a retention of stereochemistry. Studies are
in progress to extend this protocol to other heterocycles
containing nitrogen atoms.
furan 2 from 1 can be predicted by comparison of stereo-
chemical models 11 and 12. The major reaction pathway
could be dependent on the stability in the transition state
under a kinetic control such as orientations and steric factors
offered by existing substituents: geometrical preference of
12 for a minimum strain with existing components compared
to 11 owing to a severe steric repulsion.
Acknowledgment. Generous financial support from the
Korea Research Foundation (KRF-2006-312-C00234 and
KRF-2005-005-J11901) and Korea Science & Engineering
Foundation (CMDS and R01-2005-000-10381-0) is gratefully
acknowledged.
Supporting Information Available: General experimen-
(10) Nakao, Y.; Shirakawa, E.; Tsuchimoto, T.; Hiyama, T. J. Orgnomet.
Chem. 2004, 689, 3701-3721.
(11) Martin, L. D.; Stille, J. K. J. Org. Chem. 1982, 47, 3630-3633.
(12) (a) Castaneda, A.; Kusera, D, J.; Overman, L. E. J. Org. Chem.
1989, 54, 5695-5707. (b) Berger, D.; Overman, L. E. Synlett 1992, 811-
813.
tal procedure details and characterization data for all
1
products. H and 13C NMR for all products and 2-D NMR
spectra for 5. This material is available free of charge via
the Internet at http://pubs.acs.org.
(13) Yu, C.-M.; Yoon, S.-K.; Choi, H.-S.; Baek, K. Chem. Commun.
1997, 763-764.
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Org. Lett., Vol. 10, No. 2, 2008