First example of carbohydrate-based Prins cyclization: a novel class of sugar-annulated tetrahydropyrans

Article abstract of DOI:10.1016/j.tetlet.2010.01.028

The secondary homoallylic alcohol derived from d-glucose undergoes smooth coupling with aldehydes in the presence of molecular iodine under mild reaction conditions to produce 7-iodofurano[3,2-b]pyrans in good yields. This method is highly stereoselective, affording cis-tetrahydropyrans exclusively.

Full text of DOI:10.1016/j.tetlet.2010.01.028

Tetrahedron Letters 51 (2010) 1475–1478
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Tetrahedron Letters
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First example of carbohydrate-based Prins cyclization: a novel class of
sugar-annulated tetrahydropyrans
a
a
a
b
J. S. Yadav a, , B. V. Subba Reddy , Ashutosh Pratap Singh , Dudhmal N. Chaya , Deepak Chatterjee ,
*
A. C. Kunwar b
a Division of Organic Chemistry, Indian Institute of Chemical Technology, Hyderabad 500 007, India
b Centre for Nuclear Magnetic Resonance, Indian Institute of Chemical Technology, Hyderabad 500 007, India
a r t i c l e i n f o
a b s t r a c t
Article history:
The secondary homoallylic alcohol derived from D-glucose undergoes smooth coupling with aldehydes in
Received 23 November 2009
Revised 23 December 2009
Accepted 9 January 2010
Available online 14 January 2010
the presence of molecular iodine under mild reaction conditions to produce 7-iodofurano[3,2-b]pyrans in
good yields. This method is highly stereoselective, affording cis-tetrahydropyrans exclusively.
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Prins cyclization
Molecular iodine
Oxabicycles
7-Iodofurano[3,2-b]pyrans
The Prins cyclization is very useful method for the synthesis of
six-membered tetrahydropyran derivatives.1 The tetrahydropyran
ring is frequently found in various natural products such as aver-
mectins, aplysiatoxins, oscillatoxins, latrunculins, talaromycins,
and acutiphycins.2 Tetrahydropyran derivatives are usually pre-
pared via Prins cyclization using acid catalysis.3 The Prins cycliza-
tion between homoallylic alcohols and aldehydes has been
reported using a variety of catalysts and nucleophiles to produce
a large number of tetrahydropyrans.4 Besides homoallylic alcohols,
homopropargylic alcohols are also known to undergo the Prins-
type cyclization to furnish dihydropyrans.5 In addition, silyl-mod-
ified Prins cyclization has also been reported to furnish tri-, tetra-,
and penta-substituted dihydropyrans.6 However, to the best of our
knowledge, there have been no reports on the Prins cyclization of
sugar-based homoallyl alcohols.
product 3a was obtained in 76% yield with all cis-selectivity
(Scheme 1).
The product 3a was characterized thoroughly with the help of
various NMR experiments including 2-D nuclear Overhauser effect
spectroscopy (NOESY, Fig. 1) and double quantum filter correlation
3
spectroscopy (DQFCOSY). The coupling constants: JH3–H4 = 1.7, 3J
3
3
3
3
0
H4–H5 = 3.4, JH5–H6 = 12.3, JH5–H6 = 4.5, JH6–H7 = 11.7, and JH6–
H7 = 1.7 Hz are consistent with 3C6 chair form of the six-membered
ring. Further, nOe cross peaks between H3/H5, H3/H7, and H5/H7
support their 1–3 axial disposition and are consistent with the
equatorial position of the iodo and phenyl moieties. NOe cross
peaks between CH3(pro-s) and H1 and H2 also support enveloped
conformation for the isopropylidene ring. Further support for the
assigned conformation comes from energy-minimized structure
(Fig. 2).
In continuation of our interest on the application of Prins cycli-
zation for new chemical entities,7 we herein report a simple and
metal catalyst-free Prins cyclization for the synthesis of highly
substituted tetrahydropyrans from sugar-based homoallylic
alcohols and aldehydes using molecular iodine under neutral con-
ditions. Initially, we have attempted the coupling of p-chlorobenz-
aldehyde (1) with chiral secondary homoallylic alcohol (2), derived
This result provided the incentive for further study of reactions
with other aldehydes. Interestingly, various aryl aldehydes such as
benzaldehyde, m-chlorobenzaldehyde, o-hydroxybenzaldehyde,
I
O
O
O
I2
CHO
O
from D-glucose in the presence of molecular iodine at room tem-
perature. The reaction was complete in 7 h and the corresponding
O
O
+
CH2Cl2, rt
O
HO
Cl
Cl
1
2
3a
* Corresponding author.
E-mail address: yadavpub@iict.res.in (J.S. Yadav).
Scheme 1. Prins cyclization of p-chlorobenzaldehyde with chiral homoallyl alcohol.
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.01.028

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J. S. Yadav et al. / Tetrahedron Letters 51 (2010) 1475–1478
Figure 1. Expansion of the NOESY spectrum showing the characteristic nOe correlations.
well with a wide range of aldehydes. In the absence of iodine,
H
I
the reaction failed to give the desired products even after long
reaction time (12 h) under reflux conditions. No reaction was
observed when metal salts such as LiI, NaI, and KI were used as
promoters. The reactions proceeded only with iodine at room tem-
perature with complete diastereocontrol, affording the cis-tetra-
hydropyrans exclusively. As a solvent, dichloromethane appeared
to give the best results. The reactions were clean and the products
were obtained in good yields and with high diastereoselectivity as
determined from the NMR spectrum of the crude product. Only a
single diastereoisomer was obtained from each reaction, the struc-
ture of which was confirmed by NMR studies. Mechanistically, the
reaction may proceed via an acetal formation by in situ generated
HI from iodine and alcohol as described in our earlier Letter.4b Thus
initially formed acetal may undergo dehydration to generate the
oxocarbenium ion. This highly reactive intermediate may undergo
Prins cyclization to give b-carbocation which may subsequently be
trapped by iodide ion to give the desired product (Scheme 2).
A rationale for the all cis-selectivity involves the formation of an
(E)-oxocarbenium ion via a chair-like transition state, which has
increased the stability relative to the open oxocarbenium ion due
to delocalization. The optimal geometry for this delocalization
places the hydrogen atom at C4 in a pseudo-axial position, which
O
H
O
H
O
CH3
H
H
O
CH3
Figure 2. Energy-minimized structure of 3a.
and p-methoxybenzaldehyde participated well in this reaction (Ta-
ble 1, entries b–e). Acid-sensitive hydrocinnamaldehyde is also
effective for the Prins cyclization (Table 1, entry f). 1,3,5-trioxane
also underwent smooth coupling with homoallyl alcohol to give
the corresponding product (Table 1, entry g). The Prins cyclization
also proceeded smoothly with aliphatic aldehydes such as propan-
aldehyde, isobutaraldehyde, and butaraldehyde (Table 1, entries
h–j). The scope and generality of this reaction are illustrated with
respect to various aldehydes, and the results are summarized in
Table 1.7 In all the cases, the desired six-membered tetrahydropy-
rans were exclusively formed in good yields. The reaction works
favors equatorial attack of the activated p
-bond nucleophiles.8
In summary, we have demonstrated an efficient approach for
the synthesis of sugar-based furano[3,2-b]pyrans under mild and
neutral conditions. The use of iodine makes this method simple,
convenient, and practical. This method provides an easy access
for a novel class of sugar-annulated pyrans in a single-step opera-
tion which may find application in drug discovery and also in nat-
ural products synthesis.

J. S. Yadav et al. / Tetrahedron Letters 51 (2010) 1475–1478
1477
Table 1
Synthesis of polyhydroxylated tetrahydropyrans from sugar-based homoallyl alcohol
Entry
Aldehyde
Alcohol
Producta
Reaction time (h)
7.0
Yieldb (%)
CHO
O
I
O
O
Cl
O
O
a
HO
76
O
O
Cl
CHO
O
I
O
O
O
b
c
O
O
8.0
6.0
7.0
74
72
76
HO
O
O
Cl
CHO
O
I
O
O
O
HO
Cl
O
O
OH
O
I
O
CHO
O
OH
O
d
O
HO
O
O
CHO
O
I
O
O
MeO
O
O
e
HO
8.0
74
O
O
MeO
CHO
O
I
O
O
f
6.0
8.0
8.0
7.0
6.0
76
68
72
75
76
O
HO
O
O
O
O
I
O
O
O
O
O
g
h
i
O
O
O
HO
O
O
CHO
CHO
O
I
O
O
O
O
HO
O
I
O
O
O
O
O
HO
O
O
O
I
CHO
O
O
j
O
O
HO
O
O
a
All products were characterized by 1H,13C NMR, IR, and mass spectroscopy.
Yield calculated after column chromatography.
b
Acknowledgments
O
O
I2
+
HI
+
O
O
HO
IO
A.P.S., D.N.C., and D.C. thank CSIR, New Delhi, for the award of
fellowships and also thank DST for the financial assistance under
the J. C. Bose fellowship scheme.
O
O
H
+
O
+
O
H+
O
H
R
O-H
O
+
O
R
H
HO
..
-H2O
References and notes
O
O
..
O
1. (a) Prins, H. J. Chem. Weekl. 1919, 16, 1072; (b) Adams, D. R.; Bhatnagar, S. P.
Synthesis 1977, 661; (c) Chandrasekhar, S.; Reddy, B. V. S. Synlett 1998, 851.
2. Nicolaou, K. C.; Sorensen, E. J. Classics in Total Synthesis; VCH: Weinheim, 1996.
3. (a) Wei, Z. Y.; Li, J. S.; Wang, D.; Chan, T. H. Tetrahedron Lett. 1987, 28, 3441; (b)
Perron, F.; Albizati, K. F. J. Org. Chem. 1987, 52, 4130; (c) Wei, Z. Y.; Wang, D.; Li, J.
S.; Chan, T. H. J. Org. Chem. 1989, 54, 5768; (d) Coppi, L.; Ricci, A.; Taddei, M. J.
Org. Chem. 1988, 53, 913.
4. (a) Olier, C.; Kaafarani, M.; Gastaldi, S.; Bertrand, M. P. Tetrahedron 2009, ASAP.;
(b) Yadav, J. S.; Reddy, B. V. S.; Narayana Kumar, G. G. K. S.; Swamy, T.
Tetrahedron Lett. 2007, 48, 2205–2208; (c) Yadav, J. S.; Reddy, B. V. S.; Narayana
I(-)
H
I
H
O
O
R
(+)
O
O
R
O
O
O
R
O
H
+
O
O
H
O
O
Scheme 2. A plausible reaction mechanism.

1478
J. S. Yadav et al. / Tetrahedron Letters 51 (2010) 1475–1478
Kumar, G. G. K. S.; Reddy, M. G. Tetrahedron Lett. 2007, 48, 4903–4906; (d) Yadav,
Ph), 6.08 (d, 1H, J = 3.7 Hz, C1H), 4.72 (d, 1H, J = 3.7 Hz, C2H), 4.56 (ddd, 1H,
J = 3.4, 4.5, 12.3, C5H), 4.38 (dd, 1H, J = 1.7, 11.7 Hz, C4H), 4.37 (dd, 1H, J = 1.7,
11.7 Hz, C7H), 4.19 (d, 1H, J = 1.7 Hz, C3H), 2.56 (q, 1H, J = 12.4 Hz, C6H), 2.29
(ddd, 1H, J = 1.7, 4.3, 12.2, C0 H), 1.54 (s, 3H, CH3), 1.33 (s, 3H, CH03). 13C NMR
(CDCl3, 150 MHz): d 19.1, 266.1, 26.6, 40.5, 79.3, 79.7, 84.8, 100.0, 104.7, 125.8,
128.4, 128.5, 128.5, 130.1, 133.7, 172.0. ESI-MS: m/z: 402 (M+H). (3c): White
J. S.; Kumar, N. N.; Reddy, M. S.; Prasad, A. R. Tetrahedron 2007, 63, 2689–2694;
(e) Yadav, J. S.; Reddy, B. V. S.; Maity, T.; Narayana Kumar, G. G. K. S. Tetrahedron
Lett. 2007, 48, 7155–7159; (f) Yadav, J. S.; Reddy, B. V. S.; Maity, T.; Narayana
Kumar, G. G. K. S. Tetrahedron Lett. 2007, 48, 8874–8877; (g) Yadav, J. S.; Reddy,
B. V. S.; Aravind, S.; Narayana Kumar, G. G. K. S.; Madhavi, C.; Kunwar, A. C.
Tetrahedron 2008, 64, 3025–3031; (h) Yadav, J. S.; Reddy, B. V. S.; Narayana
Kumar, G. G. K. S.; Aravind, S. Synthesis 2008, 48, 395–398.
solid, IR (neat):
m
3499, 2923, 2853, 1730, 1673, 1601, 1431, 1379, 1266, 1215,
1094, 1020, 966, 871, 791, 725 cmꢁ1
.
1H NMR (CDCl3, 500 MHz): d 7.32–7.24 (m,
5. (a) Miranda, P. O.; Diaz, D. D.; Padron, J. I.; Bermejo, J.; Martin, V. S. Org. Lett.
2003, 5, 1979–1982; (b) Miranda, P. O.; Diaz, D. D.; Padron, J. I.; Ramirez, M. A.;
Martin, V. S. J. Org. Chem. 2005, 70, 57–62.
4H Ph), 6.20 (d, 1H, J = 3.9 Hz), 4.77 (d, 1H, J = 2.9 Hz), 4.50 (ddd, 1H, J = 3.9, 7.8,
12.6 Hz), 4.30–4.38(q, 2H, J = 13.6, Hz), 4.11 (s, 1H), 2.41–2.48 (q, 1H,
J = 12.6 Hz), 2.29 (dd, 1H, J = 3.9, 8.7 Hz), 1.54 (s, 3H, CH3), 1.33 (s, 3H, CH3).
13C NMR (CDCl3, 75 MHz): d 18.3, 29.6, 40.1, 79.2, 78.7, 85.5, 105.0, 105.1, 114.2,
123.7, 124.4, 125.8, 126.3, 128.2, 129.7, 129.6. ESI-MS: m/z: 475 (M+K). (3d):
6. (a) Semeyn, C.; Blaauw, R. H.; Hiemstra, H.; Speckamp, W. N. J. Org. Chem. 1997,
62, 3426–3427; (b) Viswanathan, G. S.; Yang, J.; Li, C.-J. Org. Lett. 1999, 1, 993–
995; (c) Dobbs, A. P.; Martinovic, S. Tetrahedron Lett. 2002, 43, 7055–7057; (d)
Dobbs, A. P.; Guesne, S. J. J.; Martinovic, S.; Coles, S. J.; Hursthouse, M. B. J. Org.
Chem. 2003, 68, 7880–7883; (e) Meilert, K.; Brimble, M. A. Org. Lett. 2005, 7,
3497–3500; (f) Miranda, P. O.; Ramirez, M. A.; Martin, V. S.; Padron, J. I. Org. Lett.
2006, 8, 1633–1636; (g) Leon, L. G.; Miranda, P. O.; Martin, V. S.; Padron, J. I.;
Padron, J. M. Bioorg. Med. Chem. Lett. 2007, 17, 3087–3090.
7. Typical procedure: A mixture of homoallylic alcohol (0.312 g, 2 mmol), aldehyde
(0.2 g, 1.2 mmol), and iodine (0.127 g, 1 mmol) in dichloromethane (5 mL) was
stirred at 23 °C for the specified amount of time (Table 1). After completion of
the reaction as indicated by TLC, the reaction was quenched with water and
extracted with ether (2 ꢀ 10 mL). The combined organic layers were washed
with aq sodium thiosulfate and brine, and dried over anhyd Na2SO4. Removal of
the solvent followed by purification on silica gel (Merck, 100–200 mesh, ethyl
acetate–hexane, 0.5–9.5) gave the pure tetrahydropyran. The products thus
obtained were characterized by IR, NMR, and mass spectroscopy. (3b) IR (neat):
White solid, IR (neat):
m
3437, 2922, 2853, 1600, 1503, 1457, 1376, 1245, 1161,
1085, 1016, 859 cmꢁ1
.
1H NMR (CDCl3, 300 MHz): d 1.37 (s, 6H), 2.31 (ddd, 1H,
J = 5.0, 6.9, 2.2 Hz), 2.71 (q, 1H, J = 12.8 Hz), 4.16 (s, 1H), 4.32, (s, 1H), 4.44–4.57
(m, 2H), 4.67 (d, 1H, J = 3.5 Hz), 6.01 (d, 1H, J = 3.5 Hz), 6.58 (s, 1H, Ph), 6.80 (t,
1H, J = 5.6 Hz), 6.94 (d, 1H, J = 6.2 Hz), 7.11–7.17 (m, 1H), 9.80 (s, 1H, OH). 13C
NMR (CDCl3, 150 MHz): d 14.1, 17.3, 26.1, 26.5, 29.7, 38.4, 53.4, 79.5, 79.8, 84.6,
96.1, 104.5, 112.2, 117.0, 120.3, 126.7, 129.6. ESI-MS: m/z: 441 (M+ Na). (3i):
White solid, IR (neat):
m 2964, 2926, 1734, 1468, 1367, 1274, 1099, 1022, 870,
797, 682 cmꢁ1 1H NMR (CDCl3, 300 MHz): d 0.82–0.92 (m, 12H methyl), 2.02 (q,
.
1H, J = 4.9, 6.2 Hz), 2.16 (dd, 1H, J = 3.9,5.2 Hz), 2.96 (q, 1H, J = 4.9, 5.8 Hz), 3.38
(q, 1H, J = 4.9 Hz), 3.95 (d, 1H, J = 16.2 Hz), 4.28 (m, 1H), 4.42 (d, 1H, J = 3.7 Hz),
4.62 (d, 1H, J = 4.9 Hz), 5.85 (d, 1H, J = 3.9 Hz). 13C NMR (CDCl3, 75 MHz): d 18.0,
20.4, 22.6, 29.6, 31.8, 32.4, 35.6, 79.2, 79.4, 82.8, 85.3, 104.2, 108.7. ESI-MS: m/z:
407 (M+K).
8. (a) Alder, R. W.; Harvey, J. N.; Oakley, M. T. J. Am. Chem. Soc. 2002, 124, 4960–
4961; (b) Ramesh, J.; Rychnovsky, S. D. Org. Lett. 2006, 8, 2175–2178; (c)
Biermann, U.; Lutzen, A.; Metzger, J. O. Eur. J. Org. Chem. 2006, 2631–2637.
m
3449, 3033, 2959, 2925, 2855, 1732, 1603, 1495, 1455, 1377, 1262, 1216, 1142,
1090, 1019, 860, 798, 699 cmꢁ1 1H NMR (600 MHz, CDCl3): d 7.38–7.28 (m, 5H,
.