Diastereoselective synthesis of 1-(tetrahydrofuran-3-yl)-1,3- dihydroisobenzofuran derivatives via Prins bicyclization

Article abstract of DOI:10.1016/j.tetlet.2013.01.006

The homoallylic alcohol tethered with a benzylic hydroxyl group, that is, (E)-4-(2-(hydroxymethyl)phenyl)but-3-en-1-ol undergoes smooth Prins bicyclization with various aldehydes in the presence of 20 mol % Sc(OTf) ₃ and 4 ? MS at 80 °C to affo

Full text of DOI:10.1016/j.tetlet.2013.01.006

Tetrahedron Letters 54 (2013) 1519–1523
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Diastereoselective synthesis of 1-(tetrahydrofuran-3-yl)-1,3-
dihydroisobenzofuran derivatives via Prins bicyclization
B. V. Subba Reddy a, , Sayed Jalal a, Prashant Borkar a, J. S. Yadav a, P. Gurava Reddy b, A. V. S. Sarma b
⇑
a Natural Product Chemistry, CSIR-Indian Institute of Chemical Technology, Hyderabad 500 607, India
b Centre for Nuclear Magnetic Resonance, CSIR-Indian Institute of Chemical Technology, Hyderabad 500 607, India
a r t i c l e i n f o
a b s t r a c t
Article history:
The homoallylic alcohol tethered with a benzylic hydroxyl group, that is, (E)-4-(2-(hydroxymethyl)-
Received 17 October 2012
Revised 31 December 2012
Accepted 3 January 2013
Available online 10 January 2013
phenyl)but-3-en-1-ol undergoes smooth Prins bicyclization with various aldehydes in the presence of
20 mol % Sc(OTf)3 and 4 Å MS at 80 °C to afford
a novel series of 1-(tetrahydrofuran-3-yl)-1,3-
dihydroisobenzofuran derivatives in good yields with high diastereoselectivity.
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Lewis acid
4-(2-(Hydroxymethyl)phenyl)but-3-en-1-ol
Aldehydes
1-(Tetrahydrofuran-3-yl)-1,3-
dihydroisobenzofuran
Prins bicyclization
The five-membered oxygen containing heterocycles are often
present in many natural products such as lignans, polyether ino-
phores, and macrodiolides.1 These molecules are known to exhibit
various biological activities such as antitumor, antimalarial, and
antimicrobial behavior.2 In particular, 1,3-dihydroisobenzofuran
core is found in naturally occurring molecules such as flavimycins
A and B.3 The flavimycins A and B (Fig. 1) are novel dimeric 1,3-
dihydroisobenzofurans isolated, as inhibitors of peptide deformyl-
ase, from cultures of Aspergillus flavipes. These compounds are
found to inhibit the staphylococcus aureus peptide deformylase
CH3
R1
R2
O
HO
HO
Flavimycins A
R1 and R2 = H or OH, R3 = CH3
OH
R3
H
H
OH
OH
OH
Flavimycins B
R1 and R2 = H or OH, R3 = CH2OCH3
O
with IC50 values of 35.8 and 100.1 lM, respectively.
Figure 1. Naturally occuring flavimycins A and B.
Prins cyclization has emerged as a powerful strategy for the
synthesis of a wide range of substituted tetrahydropyran deriva-
tives and related compounds.4,5 In addition to this, bicyclic tetrahy-
dropyran derivatives are reported using Prins bicyclization
strategy.6 However, the formation of the tetrahydrofuran ring is
unusual under Prins cyclization.7 In a few cases, the tetrahydrofu-
ran ring is formed through the five-membered oxocarbenium ion
that can be trapped by a nucleophile.8 To the best of our knowl-
edge, there are no reports on the synthesis of tetrahydrofuranyl
substituted 1,3-dihydroisobenzofurans via Prins bicyclization.
Following our interest on Prins cyclization,9 we herein report a
novel strategy for the synthesis of 1-(tetrahydrofuran-3-yl)-1,3-
dihydroisobenzofuran derivatives by means of Prins bicyclization.
Accordingly, we first attempted the Prins cyclization of (E)-4-(2-
(hydroxymethyl)phenyl)but-3-en-1-ol (1) with 2,5-dimethoxy-
benzaldehyde (2a) using 20 mol % Sc(OTf)3 in the presence of 4 Å
MS in 1,2-dichloroethane. The reaction was found to be very slug-
gish at room temperature. But by increasing the temperature from
25 to 80 °C, the corresponding product, 1-(tetrahydrofuran-3-yl)-
1,3-dihydroisobenzofuran 3a was obtained in 78% yield as a major
diastereomer (Scheme 1, Table 1, entry a). The diastereomeric ratio
(95:5) was determined on the basis of 1H NMR spectrum of a crude
product. The two diastereomers could easily be separated by silica
gel column chromatography.
The stereochemistry of 3a was assigned by extensive NMR
experiments including 2-D nuclear overhauser effect spectroscopy
(NOESY) and double quantum filtered correlation spectroscopy
(DQFCOSY). The assignments were made with a help of DQFCOSY
⇑
Corresponding author. Tel.: +91 40 27193535; fax: +91 40 27160512.
E-mail address: basireddy@iict.res.in (B.V. Subba Reddy).
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.01.006

1520
B. V. Subba Reddy et al. / Tetrahedron Letters 54 (2013) 1519–1523
OMe
OMe
HO
O
OMe
O
CHO
20 mol% Sc(OTf)3
H
O
H
+
H
+
MeO
H
O
MeO
1,2-dichloroethane
4Å MS, 80 °C
OH
OMe
(major)
4a (minor)
3a
1
2a
Diastereomeric ratio = 95:5
Scheme 1. Reaction of 4-(2-(hydroxymethyl)phenyl) but-3-en-1-ol with 2,5-dimethoxybenzaldehyde.
Table 1
Sc(OTf)3-catalyzed preparation of 1-(tetrahydrofuran-3-yl)-1,3-dihydroisobenzofuransa
O
O
HO
R
R
20 mol% Sc(OTf)3
H
H
O
H
H
R-CHO
+
+
1,2-dichloroethane
4Å MS, 80 °C
OH
O
3
2
1
4
(major)
(minor)
Yieldc (%)
Entry
Aldehyde (2)
Product (3)b
Time (h)
Diastereomeric ratio
MeO
CHO
OMe
O
OMe
a
9
78
95:5
H
H
MeO
O2N
O
CHO
O
H
b
c
O2N
10
9
56
68
68
70:30
90:10
85:15
H
O
CHO
O
EtO
H
EtO
H
O
CHO
O
H
d
8
H
O
MeO
CHO
MeO
O
e
10
10
62
59
80:20
75:25
H
H
O
CHO
NO2
NO2
H
O
f
H
O
CHO
Br
Br
H
O
g
8
8
55
70
78:22
85:15
H
O
CHO
O
Cl
H
Cl
h
H
O

B. V. Subba Reddy et al. / Tetrahedron Letters 54 (2013) 1519–1523
1521
Table 1 (continued)
Entry
Aldehyde (2)
Product (3)b
Time (h)
Yieldc (%)
Diastereomeric ratio
CHO
O
i
7
72
90:10
H
H
O
CHO
CHO
O
74d
70d
75d
68:32
70:30
75:25
H
j
6
5
6
H
O
O
C3H7
H
k
H
O
CHO
O
C5H11
H
l
H
O
a
Reaction was performed with 0.5 mmol olefin, 0.55 mol % aldehyde and 20 mol% Sc(OTf)3.
All the products were characterized by 1H and 13C NMR, IR, and mass spectroscopy.
Yield refers to pure single diastereomers after column chromatography.
b
c
d
Combined yield of two diastereomers which were inseparable on column chromatography.
experiment in which doublet was assigned to H1 proton at d 5.36
with JH1–H2 = 6.2 Hz. The coupling constant JH2–H5 = 2.0 Hz corre-
sponds to dihedral angle H2–C2–C5–H5 ꢀ 58° (but in compound
3a it is found to be 49°) also indicating the cis orientation of H2
and H5 protons. The following nOe correlations H1/H5, H1/H40,
H2/H11, H30/H60, H5/H10, H6/H7, and H4/H11 support the pro-
posed structure. All the couplings and nOes are in good agreement
with the proposed structure as shown in Figure 2. The double-
edged arrows show characteristic nOe correlations of 3a.10
9
8
7
10
12
11
5
13
14
6
1
Likewise, the coupling of 4-nitrobenzaldehyde (2b) with a
homoallylic alcohol (1) under similar reaction conditions afforded
the diastereomeric products 3b (major, 56% yield) and 4b (minor,
24% yield) (Table 1, entry b). These diastereomers could easily be
separated by silica gel column chromatography. The stereochemis-
try of 3b and 4b was also characterized by extensive NMR experi-
ments like 3a. In the case of compound 3b, JH2–H5 = 2.5 Hz
corresponds to dihedral angle H2–C2–C5–H5 ꢀ 55° (but in com-
H
2
H'
3
H'
4
H'
H
H
Figure 3. Characteristic nOes and energy minimized structure of 3b.
H
H'
7
6
8
9
8
10
7
9
13
10
12
12
5
2
11
5
11
H
13
2
6
14
1
1
H'
H'
H'
3
3
H
4
H
4
H
H'
H'
Figure 2. Characteristic nOes and energy minimized structure of 3a.
H
Figure 4. Characteristic nOes and energy minimized structure of product 4b.

1522
B. V. Subba Reddy et al. / Tetrahedron Letters 54 (2013) 1519–1523
HO
O
CHO
O
O2N
O2N
MeO
20 mol% Sc(OTf)3
MeO
MeO
H
O
H
+
H
+
H
1,2-dichloroethane
4Å MS, 80 °C
OH
O
NO2
OMe
OMe
MeO
6b (minor)
(major)
6a
Diastereomeric ratio = 75:25
5
2a
Scheme 2. Reaction of (E)-4-(2-(hydroxymethyl)-4,5-dimethoxyphenyl)but-3-en-1-ol with 4-nitrobenzaldehyde.
yield) as depicted in Scheme 2. The diastereomers could easily be
separated by silica gel column chromatography.
δ
R
O
δ
O
Sc(OTf)3
_
All the products were characterized and confirmed by NMR, IR,
and mass spectrometry. The effect of various acid catalysts such as
TsOH, In(OTf)3, and Sc(OTf)3 was studied for this conversion.
Among them, Sc(OTf)3 was found to give the best results in terms
of yields. As solvent, 1,2-dichloroethane gave the best results.
The reaction was assumed to proceed via the formation of
oxocarbenium ion A generated from hemi-acetal which is in turn
formed by the reaction of homoallylic alcohol 1 with aldehyde 2
likely after activation through Sc(III). This is followed by the attack
of an internal olefin resulting in the formation of more stable ben-
zylic carbocation B which is simultaneously trapped by a tethered
hydroxyl group, leading to the formation of 1-(tetrahydrofuran-3-
yl)-1,3-dihydroisobenzofuran 3. The intermediate B has more flex-
ibility in terms of C–C bond rotation therefore which can result in
the formation of 3 and 4. In contrast, a thermodynamically more
stable diastereomer 3 can form predominantly (Scheme 3).
In summary, we have developed a novel strategy for the synthe-
sis of 1-(tetrahydrofuran-3-yl)-1,3-dihydroisobenzofuran deriva-
tives by means of Sc(OTf)3 catalyzed Prins bicyclization. The end
products are structural analogues of flavimycins A and B and hence
can be evaluated for biological activity.
OH
+
R
H
2
OH
OH
1
OH
A
O
O
R
H
O
R
O
H
R
H
H
H
O
+
_
H
OH
3
4
(major)
(minor)
B
Scheme 3. A plausible reaction pathway.
pound 3b it is found to be 44°) also indicating the cis orientation of
H2 and H5 protons. The following nOe correlations H1/H5, H1/H11,
H1/H40, H5/H11, H5/H10, H30/H60, H4/H14, and H6/H7 support the
proposed structure. All the couplings and nOes are perfectly
matching with the structure as shown in Figure 3.10
For compound 4b, the presence of a strong nOe correlation be-
tween H1/H60 and H30/H10 suggests that C2–C5 bond is con-
strained. The energy minimized structure shown in the Figure 4
is well supported by H5/H30, H5/H10, H1/H11, H1/H40, H4/H14,
and H2/H14 nOe correlations. The value of 30° for the dihedral an-
Acknowledgements
S.J. and P.B. thank CSIR, New Delhi for the award of fellowships.
Author is thankful to Mr. S. Jeelani Basha for constant help in NMR
analysis of the products.
3
gle H2–C2–C5–H5 corresponds to JH2–H5 = 5.2 Hz (using Karplus
relations), which is similar to the experimental value of 5.2 Hz.
Compound 4b differs from compound 3b by configuration change
at the C5 carbon. The double-edged arrows show characteristic
nOe correlations of 4b (Fig. 4).10
Supplementary data
The scope of the reaction is illustrated with other aromatic alde-
hydes and the results are summarized in Table 1.11 Interestingly,
several aromatic aldehydes such as 4-ethoxybenzaldehyde, benzal-
dehyde, 3-methoxybenzaldehyde, 2-nitrobenzaldehyde, 2-bromo-
benzaldehyde, and 4-chlorobenzaldehyde underwent a smooth
Prins bicyclization with a homoallylic alcohol (1) to furnish the
Supplementary data (compound characterization) associated
with this article can be found, in the online version, at http://
dx.doi.org/10.1016/j.tetlet.2013.01.006.
References and notes
respective
1-(tetrahydrofuran-3-yl)-1,3-dihydroisobenzofuran
1. (a) Saleem, M.; Kim, H. J.; Ali, M. S.; Lee, Y. S. Nat. Prod. Rep. 2005, 696; (b) Faul,
M. M.; Huff, B. E. Chem. Rev. 2000, 100, 2407; (c) Kang, E. J.; Lee, E. Chem. Rev.
2005, 105, 4348.
2. (a) Wolfe, J. P.; Hay, M. B. Tetrahedron 2007, 63, 261; (b) Clarke, P. A.; Santos, S.
Eur. J. Org. Chem. 2006, 2045.
derivatives (Table 1, entries c–i) in moderate to good yields. The
reaction was successful with both electron-deficient and elec-
tron-rich aromatic aldehydes. Interestingly, aliphatic aldehydes
such as cyclohexanecarboxaldehyde, n-butanal, and n-hexanal
gave the corresponding alkyl substituted 1-(tetrahydrofuran-3-
yl)-1,3-dihydroisobenzofuran derivatives in good yields (Table 1,
entries j–l). Therefore, the present method works not only with
aromatic aldehydes but also with aliphatic aldehydes. In all cases,
the product was formed as a mixture of two diastereomers. In the
case of aliphatic aldehydes, the diastereomers were inseparable by
silica gel column chromatography.
Next attempt was made to study the effect of substituent on the
aromatic ring of homoallylic diol. Thus treatment of (E)-4-(2-
(hydroxymethyl)-4,5-dimethoxyphenyl)but-3-en-1-ol (5) with 4-
nitrobenzaldehyde under similar reaction conditions gave the dia-
stereomeric products 6a (major, 45% yield) and 6b (minor, 15%
3. Kwon, Y.-J.; Sohn, M.-J.; Kim, C.-J.; Koshino, H.; Kim, W.-G. J. Nat. Prod. 2012, 75,
271.
4. For excellent recent reviews on Prins reactions see (a) Olier, C.; Kaafarani, M.;
Gastaldi, S. S.; Bertrand, M. P. Tetrahedron 2010, 66, 413. and references cited
therein; (b) Adams, D. R.; Bhatnagar, S. R. Synthesis 1977, 661; (c) Arundale, E.;
Mikeska, L. A. Chem. Rev. 1952, 51, 505; (d) Pastor, I. M.; Yus, M. Curr. Org. Chem.
2007, 11, 925; (e) Crane, E. A.; Scheidt, K. A. Angew. Chem., Int. Ed. 2010, 49,
8316; (f) Overman, L. E.; Pennington, L. D. J. Org. Chem. 2003, 68, 7143.
5. (a) Epstein, O. L.; Rovis, T. J. Am. Chem. Soc. 2006, 128, 16480; (b) Overman, L. E.;
Velthuisen, E. J. J. Org. Chem. 2006, 71, 1581; (c) Yadav, J. S.; Reddy, B. V. S.;
Maity, T.; Kumar, G. G. K. S. N. Tetrahedron Lett. 2007, 48, 7155; (d) Rychnovsky,
S. D.; Thomas, C. R. Org. Lett. 2000, 2, 1217; (e) Miranda, P. O.; Ramirez, M. A.;
Martin, V. S.; Padron, J. I. Org. Lett. 2006, 8, 1633; (f) Bolla, M. L.; Patterson, B.;
Rychnovsky, S. D. J. Am. Chem. Soc. 2005, 127, 16044; (g) Barry, C. S.; Bushby, N.;
Charmant, J. P. H.; Elsworth, J. D.; Harding, J. R.; Willis, C. L. Chem. Commun.
2005, 5097; (h) Borkar, P.; Weghe, P. V. D.; Reddy, B. V. S.; Yadav, J. S.; Gree, R.
Chem. Commun. 2012, 48, 9016.

B. V. Subba Reddy et al. / Tetrahedron Letters 54 (2013) 1519–1523
11. General experimental procedure: To
1523
6. (a) Elsworth, J. D.; Willis, C. L. Chem. Commun. 2008, 1587; (b) Bunt, A. J.; Bailey,
C. D.; Cons, B. D.; Edwards, S. J.; Elsworth, J. D.; Pheko, T.; Willis, C. L. Angew.
Chem., Int. Ed. 2012, 51, 1; (c) Yadav, J. S.; Chakravarthy, P. P.; Borkar, P.; Reddy,
B. V. S.; Sarma, A. V. S. Tetrahedron Lett. 2009, 50, 5998; (d) Yadav, J. S.; Borkar,
P.; Chakravarthy, P. P.; Reddy, B. V. S.; Sarma, A. V. S.; Sridhar, B.; Grée, R. J. Org.
Chem. 2010, 75, 2081; (e) Reddy, B. V. S.; Narasimhulu, G.; Reddy, Y. V.;
Chakravarthy, P. P.; Yadav, J. S.; Sridhar, B. Tetrahedron Lett. 2012, 53, 3100.
7. (a) Suzuki, Y.; Niwa, T.; Yasui, E.; Mizukami, M.; Miyashita, M.; Nagumo, S.
Tetrahedron Lett. 2012, 53, 1337; (b) Spivey, A. C.; Laraia, L.; Bayly, A. R.; Rzepa,
H. S.; White, A. J. P. Org. Lett. 2010, 12, 900; (c) Reddy, B. V. S.; Anjum, S. R.;
Reddy, G. M.; Rao, T. P. Synlett 2011, 20, 2951; (d) Chavre, S. N.; Choo, H.; Lee, J.
K.; Pae, A. N.; Kim, Y.; Cho, Y. S. J. Org. Chem. 2008, 73, 7467; (e) Chavre, S. N.;
Choo, H.; Cha, J. H.; Pae, A. N.; Choi, K. I.; Cho, Y. S. Org. Lett. 2006, 8, 3617.
8. (a) Unaldi, S.; Ozlugedik, M.; Frohlich, R.; Hoppe, D. Adv. Synth. Catal. 2005, 347,
1621; (b) Sarkar, T. K.; Haque, H. A.; Basak, A. Angew. Chem., Int. Ed. 2004, 43,
1417; (c) Lou, T. P.; Hu, Q.-Y.; Tan, K.-P.; Cheng, H.-S. Org. Lett. 2001, 3, 2669; (d)
Lou, T. P.; Hu, Q.-Y.; Tan, K.-P.; Ma, L.-T. J. Am. Chem. Soc. 2001, 123, 2450; (e)
Linderman, R. J.; Godfrey, A. J. Am. Chem. Soc. 1988, 110, 6249.
a
stirred solution of (E)-4-(2-
(hydroxymethyl)phenyl)but-3-en-1-ol (1) (89 mg, 0 0.5 mmol), 2,5-dimethoxy
benzaldehyde (2a) (91 mg, 0.55 mmol) and 4 ÅA MS in anhydrous 1,2-
dichloroethane (5 mL) was added Sc(OTf)3 (20 mol %) under nitrogen
atmosphere. The resulting mixture was stirred at 80 °C for 7 h. After
completion of the reaction as indicated by TLC, the mixture was quenched
with sat. aqueous NaHCO3 solution (2 mL) and then extracted with dichloro
methane (2x10 mL). The organic extracts were washed with brine (2 ꢁ 5 mL),
dried over anhydrous Na2SO4 and concentrated in vacuo. The resulting crude
product was purified by column chromatography (silica gel, 100–200 mesh)
using a gradient mixture of ethyl acetate/hexane to afford the pure product 3a
(126 mg, 78%). Spectral data for selected compounds.
(S⁄)-1-((2S⁄,3R⁄)-2-(2,5-Dimethoxyphenyl)tetrahydrofuran-3-yl)-1,3-dihydroiso-
benzofuran (3a;Table 1 entry a): Yield, 78%; Viscous liquid; 1H NMR (600 MHz,
CDCl3) d 7.28–7.21 (m, 3H), 7.13–7.10 (m, 1H), 7.07 (d, J = 3.2 Hz, 1H), 6.82 (d,
J = 8.9 Hz, 1H), 6.78 (dd, J = 8.9 and 3.2 Hz, 1H), 5.57–5.54 (m, 1H), 5.36 (d,
J = 6.2 Hz, 1H), 5.21–5.13 (m, 2H), 4.11–4.07 (m, 1H), 4.03–3.98 (m, 1H), 3.80
(s, 3H), 3.79 (s, 3H), 2.62–2.57 (m, 1H), 1.78–1.68 (m, 2H); 13C NMR (150 MHz,
CDCl3): d 153.8, 150.9, 141.2, 139.6, 132.9, 127.5, 127.3, 121.3, 121.0, 112.7,
112.5, 111.5, 83.6, 78.1, 73.4, 68.9, 55.9, 55.8, 52.8, 26.5; IR (neat): mmax 2926,
2858, 1497, 1271, 1049, 755 cmꢂ1; MS (ESI): m/z 349 (M+Na)+. HRMS (ESI)
calcd for C20H22O4Na: 349.1416 (M+H)+, found 349.1425.
9. (a) Yadav, J. S.; Thrimurtulu, N.; Gayathri, K. U.; Reddy, B. V. S.; Prasad, A. R.
Tetrahedron Lett. 2008, 49, 6617; (b) Yadav, J. S.; Lakshmi, K. L.; Reddy, N. M.;
Prasad, A. R.; Reddy, B. V. S. Tetrahedron 2010, 44, 334; (c) Yadav, J. S.;
Padmavani, B.; Reddy, B. V. S.; Venugopal, Ch.; Rao, A. B. Synlett 2007, 2045.
10. The energy-minimization of the structures was done with steepest descent
followed by conjugate gradient methods in Insight II/Discover program
employing an SGI workstation.