5-Exocyclic products, 2,3,5-trisubstituted tetrahydrofurans via Prins-type cyclization

Article abstract of DOI:10.1021/ol061528x

5-Exocyclic products, 2,3,5-trisubstituted tetrahydrofurans, were synthesized from homopropargylic alcohols with terminally substituted alkynes and various aldehydes via Prins-type cyclization. It is of interest that the exocyclic vinyl cation generated a

Full text of DOI:10.1021/ol061528x

ORGANIC
LETTERS
2006
Vol. 8, No. 16
3617-3619
5-Exocyclic Products,
2,3,5-Trisubstituted Tetrahydrofurans via
Prins-Type Cyclization†
Satish N. Chavre, Hyunah Choo, Joo Hwan Cha, Ae Nim Pae, Kyung Il Choi, and
Yong Seo Cho*
Biochemicals Research Center, Korea Institute of Science and Technology, P.O. Box
131, Cheongryang, Seoul 130-650, Korea
ys4049@kist.re.kr
Received June 22, 2006
ABSTRACT
5-Exocyclic products, 2,3,5-trisubstituted tetrahydrofurans, were synthesized from homopropargylic alcohols with terminally substituted alkynes
and various aldehydes via Prins-type cyclization. It is of interest that the exocyclic vinyl cation generated as a result of Prins-type cyclization
could be trapped as a vinyl triflate when CH2Cl2 was used as a solvent, whereas in ethereal solution the vinyl cation underwent hydrolysis to
give the corresponding ketone product.
Prins-type cyclization from homoallylic alcohols and alde-
hydes is a powerful method of preparing cis-2,6-disubstituted
tetrahydropyrans,1 which has been applied to the syntheses
of many natural products.2 Prins-type cyclization of homoal-
lylic alcohols prefers 6-endocyclic products (tetrahydropy-
rans) to 5-exocyclic products (tetrahydrofurans).3 Tetrahy-
drofurans are also ubiquitous in nature, occurring in a wide
range of biologically active substances. Therefore, there has
been much interest in the development of methods for the
stereoselective synthesis of these subunits.4,5 Rarely has pure
Prins-type cyclization been used for the synthesis of tet-
rahydrofurans, though Prins-type cylcization followed by
pinacol rearrangement gives tetrahydrofurans.6
There are two examples of synthesizing substituted tet-
rahydrofurans via Prins-type cyclization from a homoallylic
or homopropargylic alcohol and aldehydes which utilize a
functional group such as a trimethylsilyl group to stabilize
the generated carbocation, resulting in driving 5-exo cy-
clization to tetrahydrofurans instead of 6-endo cyclization
to tetrahydropyrans.7 Previous investigations in our laboratory
have shown that Lewis acid catalyzed Prins-type cyclization
† This paper is dedicated to Dr. Moon Ho Chang (KIST) on the occasion
of his 61st birthday.
(1) (a) Hanschke, E. Chem Ber. 1955, 88, 1053. (b) Stapp, P. R. J. Org.
Chem. 1969, 34, 479.
(4) (a) Heitzman, C. L.; Lambert, W. T.; Mertz, E.; Shotwell, J. B.;
Tinsley, J. M.; Va, P.; Roush, W. R. Org. Lett. 2005, 7, 2405. (b) Yadav,
V. K.; Balamurugan, R. Org. Lett. 2003, 5, 4281. (c) Cassidy, J. H.;
Marsden, S. P.; Stemp, G. Synlett 1997, 1411. (d) Taber, D. F.; Song, Y.
J. Org. Chem. 1996, 61, 6706.
(5) For brief review, see: (a) Overman L. E. Acc. Chem. Res. 1992, 25,
352. (b) Overman L. E. Aldrichim. Acta 1995, 28, 107. (c) Boivin, T. L. B.
Tetrahedron 1987, 43, 3309.
(6) (a) Cohen, F.; MacMillan, D. W. C.; Overman, L. E.; Romero, A.
Org. Lett. 2001, 3, 1225. (b) Hopkins, M. H.; Overman, L. E.; Rishton, G.
M. J. Am. Chem. Soc. 1991, 113, 5354. (c) Hopkins, M. H.; Overman, L.
E. J. Am. Chem. Soc. 1987, 109, 4748.
(7) (a) Shin, C.; Chavre, S. N.; Pae, A. N.; Cha, J. H.; Koh, H. Y.; Chang,
M. H.; Choi, J. H.; Cho, Y. S. Org. Lett. 2005, 7, 3283. (b) Mohr, P.
Tetrahedron Lett. 1993, 34, 6251.
(2) (a) Gremyachinskiy, D. E.; Samoshin, V. V.; Gross, P. H. Tetrahedron
Lett. 2003, 44, 6587. (a) Muramoto, S.; Jaber, J. J.; Vitale, J. P.; Rychnovsky,
S. D. Org. Lett. 2002, 4, 3919. (b) Welch, S. C.; Chou, C.; Grubber, J. M.;
Assercq, J. M. J. Org. Chem. 1985, 50, 2668.
(3) (a) Lee, C.-H. A.; Loh, T.-P. Tetrahedron Lett. 2006, 47, 1641. (b)
Chan, K.-P.; Loh, T.-P. Org. Lett. 2005, 7, 4491. (c) Miranda, L. S. M.;
Vasconcellos, M. L. A. A. Synthesis 2004, 1767. (d) Miranda, L. S. M.;
Marinho, B. G.; Leitao, S. G.; Matheus, M. E.; Fernandes, P. D.;
Vasconcellos, M. L. A. A. Bioorg. Med. Chem. Lett. 2004, 14, 1573. (e)
Cho, Y. S.; Kim, H. Y.; Cha, J. H.; Pae, A. N.; Koh, H. Y.; Choi, J. H.;
Chang, M. H. Org. Lett. 2002, 4, 2025. (f) Jaber, J. J.; Mitsui, K.;
Rychnovsky, S. D. J. Org. Chem. 2001, 66, 4679.
10.1021/ol061528x CCC: $33.50
© 2006 American Chemical Society
Published on Web 07/04/2006

of a homopropargylic alcohol with a trimethylsilylmethyl
group and aldehydes induces 5-exo cyclization to give cis-
2,5-disubstituted 3-allenyltetrahydrofurans.7a To expand the
scope of this useful Prins-type cyclization, we set out to
devise a novel cyclization substrate which can introduce a
substitutent at the 3-position. In this paper, we report Prins-
type cyclization and the stereochemistry of homopropargylic
alcohols with terminally substituted alkynes.
Prins-type cyclization of a homopropargylic alcohol 1a
with 4-nitrobenzaldehyde 2a (1.0 equiv, -78 °C, Et2O) in
the presence of TMSOTf (3.0 equiv) for 8 h gave all cis-
configured product 3a in 35% yield (Scheme 1). In general,
Table 1. Synthesis of 3-Furanylidene Derivatives
entry
R1
R2
no.
yielda (%)
1
2
3
4
5
6
7
8
9
methyl
methyl
methyl
methyl
methyl
methyl
methyl
methyl
methyl
methyl
phenyl
4-nitrophenyl
phenyl
2-naphthyl
4-chlorophenyl
2-nitrophenyl
methyl
ethyl
isopropyl
n-pentyl
2-phenylethyl
4-nitrophenyl
4a
4b
4c
4d
4e
4f
4g
4h
4i
77
68
68
76b
35
68
69c
60
65
61c
64
Scheme 1. Synthesis of 2,3,5-Trisubstituted Tetrahydrofurans
10
11
4j
4k
a Isolated yields. Two stereoisomers (cis/trans) were obtained in ratios
of 8:1b and 5:1,c respectively, which were determined by 1H NMR
spectroscopy.
a homoallylic alcohol with an alkyl substituent at the terminal
carbon of the alkene undergoes the reaction in a 6-endocyclic
manner to give a tetrahydropyran.3f However, this Prins-type
cyclization provided 5-exocyclic products. The reaction was
highly stereoselective to give a single stereoisomer of which
relative stereochemistry was confirmed to be all-cis by
single-crystal X-ray crystallography.8 As with other Prins-
type cyclization,2,3 the complete cis stereoselectivity between
the C2 and C5 positions must be the result of a cyclic
transition state, and the stereochemistry at the C3 center
results from the protonation from the R-face during the
hydrolysis. Thus, a series of aliphatic or aromatic aldehydes
2a-d with a methyl-substituted homopropargylic alcohol 1b
were tested under the Prins-type cyclization conditions to
give the corresponding tetrahydrofuran analogues 3b-e
(Scheme 1).
is obvious that the propargylic alcohols 1 and an aldehyde
make an adduct, an oxocarbenium ion A to avoid steric
hindrance between the phenyl group of 1 and R group of
the aldehyde, resulting in the preferred cis-configuration of
the two groups (Figure 1). After Prins-type cyclization, the
To optimize the reaction conditions, the solvent was
changed from Et2O to CH2Cl2 resulting in significant
improvement in yield up to 77% (Table 1). However, to our
surprise, the obtained tetrahydrofuran analogues were proven
to have an exocyclic vinyl triflate moiety instead of the
desired 3-acetyl moiety by single-crystal X-ray crystal-
lography.8 A series of aromatic and aliphatic aldehydes were
employed in this cyclization to give the corresponding
exocyclic vinyl triflate analogues (4a-k). Aromatic alde-
hydes gave the cyclization products in higher yields than
aliphatic aldehydes except o-nitrobenzenaldehyde (entry 5).
Electron-withdrawing substituents in the aromatic alde-
hydes also gave higher yields (entry 1 and 4). Two
diastereomers (cis/trans) were obtained in a ratio of 8:1 (entry
4) to 5:1 (entries 7 and 10).
Figure 1. Proposed mechanism for the two different solvent
systems.
exocyclic vinyl cation B would be transiently formed. It is
plausible that the production of exocyclic vinyl triflates 4a-k
was the result of trapping the exocyclic vinyl cation B by
the triflate anion, which attacks the vinyl cation B from the
front rather than from the back because of steric hindrance
It is of interest that the same conditions except for the
solvent (Et2O or CH2Cl2) afforded two different products. It
(8) See the ORTEP drawings in the Supporting Information.
3618
Org. Lett., Vol. 8, No. 16, 2006

with R group of the aldehyde. On the other hand, tetrahy-
drofuran products (3a-e) in Et2O suggest that the exocyclic
vinyl cation B would be stabilized by ether solvent itself
(refer C) and hydrolyzed by H2O to give the enol D which
is tautormerized to the corresponding tetrahydrofurans (3a-
e). During the tautomerization, the proton could attack the
enol from the less hindered side, that is, R-face to give all-
cis trisubstituted tetrahydrofurans (3a-e).
Scheme 3. Application to Chiral Synthesis
Additionally, the exocyclic vinyl triflates 4a-c could be
readily converted to the 3-acetyltetrahydrofurans (3b, 3c, and
5), respectively, by treatment with aqueous NaOH in a 2:1
mixture of 1,4-dioxane and methanol at room temperature
with 97-98% yields (Scheme 2).
Scheme 2. Hydrolysis of 3-Furanylidene Derivatives
In summary, the key features of this new tetrahydrofuran
synthesis are that all cis-configured 2,3,5-trisubstituted
tetrahydrofurans were synthesized via Prins-type cyclization
and that the exocyclic vinyl triflates were obtained, which
can be applied for the preparation of various synthetically
useful intermediates as a new scaffold. It is also of great
interest to note that the exocyclic vinyl cation generated as
a result of Prins-type cyclization could be trapped as a vinyl
triflate when CH2Cl2 was used as a solvent, whereas in
ethereal solution the same intermediate underwent hydrolysis
to give the corresponding ketone product. Further manipula-
tion of the vinyl triflates such as Suzuki cross-coupling would
give more various trisubstituted tetrahydrofurans, which
could be good intermediates to synthesize natural products.
To expand our synthetic method, the Prins-type cyclization
was applied to a chiral nonracemic starting material, (S)-
glycidol 6 (Scheme 3). (S)-Glycidol 6 was treated with
benzoyl chloride and 4-DMAP in CH2Cl2 to give benzoylated
glycidol 7 in 50% yield, which was converted under the
known conditions to compound 8.9 Compound 8 underwent
Prins cyclization to give a furanylidene derivative 9 in 84%
yield with a [R]D value of +72.84. The diasteromeric ratio
of compound 9 was over 99:1, which was detected by
HPLC.10
Acknowledgment. This work was supported by the Korea
Institute of Science and Technology (2E18800, 2E18970).
Supporting Information Available: Experimental pro-
cedures and spectral data of all new compounds including
ORTEP drawings of compounds 3a and 4a. This material is
available free of charge via the Internet at http://pubs.acs.org.
(9) Yamaguchi, M.; Hirao, I, Tetrahedron lett. 1983, 24, 391.
(10) Retention time: 3.63 min, HPLC conditions: column type. CHIRAL-
PAK AD (Daicel Chemical Industries, LTD, Japan); column size, 4.6 mm
i.d. × 250 mm; column temperature, rt; flow rate 1.0 mL min-1; detection,
256 nm; eluent, 5% 2-propanol in hexane.
OL061528X
Org. Lett., Vol. 8, No. 16, 2006
3619