Synthesis of cis and trans 2,4,6-tetrahydropyranols via prins-type cyclization and Mitsunob inversion

Article abstract of DOI:10.14233/ajchem.2017.20882

Prins cyclization of substituted homoallylic alcohol with aryl/aliphatic aldehyde in the presence of a boron trifluoride etherate and trifluoro acetic acid followed by hydrolysis of the resulting trifluoroacetate give substituted cis 2,4,6- tetrahydropyranol products 1-5(c), then Mitsunobu inversion subsequent methanolysis furnished trans 2,4,6-tetrahydropyranol products 1-5(d) stereoselectively in good yield. Our present work reports the synthesis and characterization of these 1-5(c,d) products.

Full text of DOI:10.14233/ajchem.2017.20882

Asian Journal of Chemistry; Vol. 29, No. 12 (2017), 2771-2775
ASIAN JOURNAL OF CHEMISTRY
https://doi.org/10.14233/ajchem.2017.20882
Synthesis of cis and trans 2,4,6-Tetrahydropyranols via Prins-Type Cyclization and Mitsunob Inversion
1
2
N. MARUTHI RAJU1,2,*, J. MOSES BABU and B. VENKATESWARA RAO
1Custom Pharmaceutical Services, Dr. Reddy’s Laboratories Limited, Bollaram Road, Miyapur, Hyderabad-500 049, India
2Department of Organic Chemistry, Foods, Drugs and Water andhra University, Visakhapatnam-530 003, India
*Corresponding author: E-mail: raju1001@gmail.com
Received: 22 June 2017;
Accepted: 17 August 2017;
Published online: 30 October 2017;
AJC-18631
Prins cyclization of substituted homoallylic alcohol with aryl/aliphatic aldehyde in the presence of a boron trifluoride etherate and
trifluoro acetic acid followed by hydrolysis of the resulting trifluoroacetate give substituted cis 2,4,6- tetrahydropyranol products 1-5(c),
then Mitsunobu inversion subsequent methanolysis furnished trans 2,4,6-tetrahydropyranol products 1-5(d) stereoselectively in good
yield. Our present work reports the synthesis and characterization of these 1-5(c,d) products.
Keywords: Prins cyclization, Mitsunobu reaction, Tetrahydropyranols, Lewis acid, Homoallylic alcohols.
receptors a (ERa) and b (ERb) are ligand-inducible trans-
cription factors that are involved in regulating cell growth,
propagation and separation in various normal and cancerous
tissues [11].
INTRODUCTION
Saturated oxygen heterocyclic six membered rings are
an integral part of so many biologically active products [1].
The Prins cyclization of the substituted homoallylic alcohols
and aryl/aliphatic aldehydes are generally promoted by strong
Brønsted or Lewis or protic acidic conditions is an old reaction
[2,3] that is now emerging as an efficient method for the substi-
tuted tetrahydropyrans synthesis [4,5]. Oxygen hetero atoms
can be captured at the 4-position of the tetrahydropyranols
ring, although most acids lead to esters that must be hydrolyzed
to form 4-hydroxy tetrahydropyranols products [6,7]. The
majority Prins cyclizations use super stoichiometric acid to
promote the reaction due to the acid counterion is trapped in
the product, thus consuming the acid [3]. In general, 2,4,6-cis
tetrahydropyranols all equatorial substituted are obtained in
high diastereoselectivity [5]. Rychnovsky et al. [8] developed
the first axial-selective Prins cyclization method to the hetero
atom at the 4-position, escalating the synthetic scope of this
reaction. In fact, selective methodology for the axial/equatorial
4-position synthesis substituent via Prins cyclization are depen-
dent on the reactants, experimental conditions and Lewis acids
[2].
Vasconcellos et al. [12,13] reported the biological activities
compounds via Prins cyclization reaction synthesis. Herein,
the diastereoselective syntheses of tetrahydropyran derivatives
compounds 1-5(c,d) (Table-1) and their configurational determi-
nations by NMR spectroscopy.
One surprising aspect of the boron trifluoride etherate and
trifluoro acetic acids reaction is the isolation equatorial of tetra-
hydropyranols product (1c) as a significant component. Prins
reactions generally give predominantly equatorial 4-hetero-
atom products and all previously reported 4-oxygen tetrahydro-
pyranols showed high equatorial selectivity [6,7]. Rychnovsky
et al. [14] mentioned that the axial selectivity was a function
of lifetime and reactivity of the ion pair, with reactive nucleophiles,
such as bromide anion, leading to high axial selectivity. Typical
oxygen nucleophiles, such as CF3CO2– orAcO·BF3–, have low
nucleophilicity and lead to about 20:1 selectivity for the equa-
torial product [15]. The boron trifluoride etherate and trifluoro
acetic acids reaction, still favouring the equatorial product shows
a much lower level of selectivity.
Tetrahydropyran analogues of the alcohol 3,6-dimethyl-
2-phenyltetrahydro-2H-pyran-4-ol (1c, Table-1) are part of a
products isolated series from Plectranthus sylvestris (labiatae)
extracts which present potent antioxidant and anti-infla-
mmatory properties [9]. In addition, protein database (PDB)
[10] revealed that the compound 1c presents 100 % of structural
similarity with a drug crystallized in estrogen receptor. Estrogen
EXPERIMENTAL
All dry reactions were performed under a positive pressure
of nitrogen in an oven-dried glassware. Dichloromethane was
degassed and dried by filtration through alumina. Ethyl acetate,
toluene and hexanes were distilled over CaH2 under nitrogen

2772 Raju et al.
Asian J. Chem.
TABLE-1
BF3·OEt2/TFA MEDIATED PRINS CYCLIZATION OF ALDEHYDES WITH HOMOALLYLIC ALCOHOLS AND MITSUNOBU REACTION
Productsa
Time
Yield
Entry
Alcohol (a)
Aldehyde (b)
(c/d)(h) (c/d)(%)b
cis-2,4,6-Tetrahydropyranol (c) trans-2,4,6- Tetrahydropyranol (d)
OH
OH
O
1
0.5/10
54/48
Ph
H
O
OH
1a
O
1c
Ph
O
Ph
1b
1d
OH
OH
2
3
4
0.3/12
0.6/10
0.4/14
62/45
58/46
47/53
H
H
Ph
OH
1a
O
Ph
O
Ph
2b
2d
2c
OH
OH
O
Ph
OH
Ph
Ph
Ph
O
Ph
Ph
O
Ph
2b
3a
3c
3d
OH
OH
OHC
OH
Ph
O
Ph
O
3b
3a
4c
4d
OH
OH
O
O
5
0.5/10
58/51
H
OH
O
O
O
O
4b
1a
5c
5d
aAll products were characterized by 1H & 13C NMR and EIMS; bProducts yields are after isolation by column chromatography.
at atmospheric pressure prior to use.All available commercially
reagents were used as received, unless otherwise stated. Thin
layer chromatography was performed on Whatman K6F (250
µm) silica gel plates and visualized using p-anisaldehyde stain.
1H NMR and 13C NMR spectra were recorded at room temperature
at 500 and 125 MHz, respectively. 1H NMR reported spectra are
in ppm on δ scale and referenced with internal tetramethylsilane.
13C NMR spectra are reported in ppm relative to CDCl3.
General procedure for the cis-2,4,6-tetrahydropyranols
derivative (1c): To a solution of 4-hexen-2-ol (1.0 g, 10 mmol)
in 10 mL of dichloromethane, benzaldehyde (1.38 g, 13 mmol)
was added. The reaction mixture was cooled to 0-5 °C and
slow addition of trifluoro acetic acid (3.42 g, 30 mmol) at the
same temperature. Then boron trifluoride etherate (2.83 g, 20
mmol) was added drop-wise at 0-5 °C. Reaction mixture was
stirred for 3 h at 0-5 °C. After completion of reaction 5 %
sodium bicarbonate solution (10 mL) was added, followed by
extraction with dichloromethane (3 × 10 mL). The combined
organic layer dried over sodium sulfate and solvent evaporated
under reducing pressure. The crude was dissolved in methanol
(10 mL) and added potassium carbonate (1.38 g, 10 mmol).
Reaction mixture was stirred for 1 h at room temperature. Then
methanol was removed under reduced pressure and water
(10 mL) was added. The reaction mixture was extracted with
dichloromethane (2 × 10 mL) and combined organic layer
was dried over sodium sulfate. Solvent was removed under
reduced pressure. The crude was purified by column chroma-
tography on silica gel (30-60 % ethyl acetate/hexanes) to get
cis-2,4,6 tetrahydropyranol derivative (1c).
General procedure for trans-2,4,6-tetrahydropyranols
derivative (1d): To a solution of (2S,4R,6S)-3,6-dimethyl-2-
phenyltetrahydro-2H-pyran-4-ol (1c) (0.75 g, 3.63 mmol) in
7.5 mL of toluene, 4-nitrobenzoic acid (0.66 g, 4.0 mmol)
and triphenylphosphine (1.43 g, 5.45 mmol) were added under
dry nitrogen. The reaction mixture was cooled to 0-5 ºC and
slow addition of diethylazodicarboxylate (0.82 g, 4.72 mmol)
at the same temperature. Then reaction mixture was heated to
80-90 ºC. Reaction mixture was stirred for 10 h at the same
temperature. Solvents distilled under reduced pressure. 5 %
sodium bicarbonate solution (10 mL) was added, followed by
extraction with dichloromethane (3 × 10 mL). The combined
organic layer dried over sodium sulfate and solvent evaporated
under reduced pressure. The crude was dissolved in methanol
(10 mL) and added potassium carbonate (1 g, 7.27 mmol).
Reaction mixture was stirred for 1 h at room temperature. Fil-
tered the solids and then methanol was removed under reduced
pressure and water (10 mL) was added. The reaction mixture
was extracted with dichloromethane (2 × 10 mL) and combined

Vol. 29, No. 12 (2017)
Synthesis of cis and trans 2,4,6-Tetrahydropyranols via Prins-Type Cyclization and Mitsunob Inversion 2773
organic layer was dried over sodium sulfate. Solvent was
removed under reduced pressure. The crude was purified by
column chromatography on silica gel (30-60 % ethyl acetate/
hexanes) to get trans-2,4,6 tetrahydropyranol derivative (1d).
(2S,4R,6S)-3,6-dimethyl-2-phenyltetrahydro-2H-
pyran-4-ol (1c): Rf = 0.35 (1:4 ethyl acetate-hexanes); IR (KBr)
3464, 2971, 1643, 1136; 1H NMR (500 MHz, CDCl3) δ 0.68
(d, J = 7.0 Hz, 3H), 1.33 (d, J = 6.4 Hz, 3H), 1.50 (m, 2H),
1.76 (m, 1H), 2.11-2.19 (m, 1H), 3.64 (qdd, J = 16.3, 12.2,
2.5, 1H), 4.14 (ddd, J = 10.1, 7.2, 4.3 Hz, 1H), 4.52 (d, J = 2.5
Hz, 1H), 7.21-7.33 (m, 5H); 13C NMR (125 MHz, CDCl3) δ
5.0, 21.6, 36.7, 40.2, 71.3, 72.3, 79.8, 125.5, 126.6, 127.9,
141.0; Mass: (m/z) 206.28 found 207 (M+1).
J = 13.5, 10.3, 7.0, 3.5 Hz, 2H), 1.86 (dtd, J = 14.4, 9.5, 5.4
Hz, 2H), 2.72 (ddd, J = 13.5, 9.1, 7.4 Hz, 2H), 2.89 (ddd, J =
14.2, 9.1, 5.4 Hz, 2H), 4.25 (q, J = 2.5 Hz, 1H), 3.76–3.71 (m,
2H), 7.30–7.17 (m, 10H); 13C NMR (125 MHz, CDCl3) δ
142.4, 128.60, 128.4, 125.8, 70.7, 65.0, 39.0, 38.1, 32.0; Mass:
(m/z) 324.4 found 325 (M+1).
(2S,4R,6S)-2-isopropyl-3-methyl-6-phenethyltetrahydro-
2H-pyran-4-ol (4c): Rf = 0.5 (1:4 ethyl acetate-hexanes); Colour-
less oil; IR (KBr) 3367, 3028, 2951, 2871, 1050, 700 cm–1; 1H
NMR (500 MHz, CDCl3) δ 0.90 (d, J = 6.5 Hz, 3H), 1.0 (d,
J = 6.8 Hz, 3H), 1.2–1.12 (m, 2H), 1.75–1.65 (m, 2H), 1.93–
1.85 (m, 2H), 2.00–1.97 (m, 1H), 2.75 (m, 1H), 2.82 (m, 1H),
2.90 (ddd, J = 11.5, 7.3, 1.7 Hz, 1H), 3.22–3.17 (m, 1H), 3.74
(tt, J = 10.5, 4.4 Hz, 1H), 7.19–7.16 (m, 3H), 7.29–7.25 (m,
2H); 13C NMR (125 MHz, CDCl3) δ 142.3, 128.6, 128.4, 125.8,
80.7, 74.0, 68.8, 41.5, 38.4, 37.8, 33.2, 31.8, 19.0, 18.8; Mass:
(m/z) 262.39 found 263 (M+1).
(2S,4S,6S)-3,6-dimethyl-2-phenyltetrahydro-2H-
pyran-4-ol (1d): Rf = 0.40 (1:4 ethyl acetate-hexanes); white
solid; m.p.: 110-115 °C; IR (KBr) 3464, 2971, 1643, 1136;
1H NMR (500 MHz, CDCl3) δ 0.70 (d, J = 6.8 Hz, 3H), 1.28
(d, J = 6.2 Hz, 3H), 1.57-1.62 (m, 1H), 1.75 (m, 3.0 Hz, 1H),
1.84-1.94 (m, 1H), 4.06 (dd, J = 4.1, 2.4 Hz, 1H), 4.08 (qdd,
J = 15.3, 14.2, 2.5 Hz, 1H), 5.07 (dd, J = 2.8 Hz, 1H), 7.19
(m, 1H), 7.28-7.35 (m, 4H); 13C NMR (125 MHz, CDCl3) δ
11.1, 21.9, 35.7, 40.6, 68.7, 70.8, 75.2, 125.5, 126.4, 127.9,
141.8; Mass: (m/z) 206.28 found 207 (M+1).
(2S,4S,6S)-2-isopropyl-3-methyl-6-phenethyltetrahydro-
2H-pyran-4-ol (4d): Rf = 0.4 (1:4 ethyl acetate-hexanes);
Colourless oil; IR (KBr) 3390, 3028, 2947, 1057, 737, 700;
1H NMR (500 MHz, CDCl3) δ 0.92 (d, J = 6.5 Hz, 3H), 1.12
(d, J = 6.9 Hz, 3H), 1.33 (s, 1H), 1.51–1.43 (m, 2H), 1.60–
1.55 (m, 2H), 1.67–1.63 (m, 2H), 1.80 (m, 1H), 2.73–2.65
(m, 1H), 2.83 (m, 1H), 3.36 (ddd, J = 11.5, 7.2, 1.9 Hz, 1H),
3.70–3.65 (m, 1H), 4.26 (q, J = 2.5 Hz, 1H), 7.22–7.15 (m,
3H), 7.29–7.25 (m, 2H); 13C NMR (125 MHz, CDCl3) δ 142.5,
128.6, 128.3, 125.7, 76.7, 70.5, 65.2, 39.1, 38.1, 36.0, 33.4,
31.9, 19.0, 18.7; Mass: (m/z) 262.39 found 263 (M+1).
(2S,4R,6S)-2-(furan-2-yl)-3,6-dimethyltetrahydro-2H-
pyran-4-ol (5c): Rf = 0.35 (1:4 ethyl acetate-hexanes); IR
(KBr) 3412, 2916, 1454, 1102; 1H NMR (500 MHz, CDCl3) δ
0.83 (d, J = 6.4 Hz, 3H), 1.32 (d, J = 6.8 Hz, 3H), 1.44 (m,
1H), 1.70-1.76 (m, 1H), 2.26-2.29 (m, 1H), 3.64 (m, 1H), 4.0
(ddd, J = 10.2, 7.0, 4.5 Hz, 1H), 4.52 (d, J = 2.6 Hz, 1H), 6.24
(2R,4R,6S)-3,6-dimethyl-2-phenethyltetrahydro-2H-
pyran-4-ol (2c): Rf = 0.3 (1:4 ethyl acetate-hexanes); IR (KBr)
3410, 2973, 1451, 1102; 1H NMR (500 MHz, CDCl3) δ 0.91
(d, J = 6.5 Hz, 3H), 1.27 (d, J = 7.1 Hz, 3H), 1.36 (m, 1H),
1.6-1.71 (m, 3H), 1.80-1.85 (m, 1H), 1.94 (m, 1H), 2.63 (m,
1H), 2.8 (m, 1H), 3.29 (ddd, J = 8.6, 4.5, 2.2 Hz, 1H), 3.46
(dqd, J = 11.2, 6.5, 2.1 Hz, 1H), 3.82 (m, 1H), 7.19-7.34 (m,
5H); 13C NMR (125 MHz, CDCl3) δ 4.9, 21.6, 32.2, 34.3, 37.1,
37.9, 71.1, 72.1, 125.7, 128.3, 128.4, 142.1; Mass: (m/z) 234.33
found 235 (M+1).
(2R,4S,6S)-3,6-dimethyl-2-phenethyltetrahydro-2H-
pyran-4-ol (2d): Rf = 0.35 (1:4 ethyl acetate-hexanes); IR
1
(KBr) 3452, 3090, 3024, 2970, 2924, 1540, 1480; H NMR
13
(m, 1H), 6.34 (m, 1H), 7.36 (d, J = 1.9 Hz, 1H); C NMR
(125 MHz CDCl3) δ 5.7, 21.6, 36.8, 38.1, 70.6, 72.8, 75.7,
106.1, 110.1, 141.3, 153.6; Mass: (m/z) 196.24 found 197 (M+1).
(2S,4S,6S)-2-(furan-2-yl)-3,6-dimethyltetrahydro-2H-
pyran-4-ol (5d): Rf = 0.40 (1:4 ethyl acetate-hexanes); IR
(KBr) 3435, 2973, 1724, 1147; 1H NMR (500 MHz, CDCl3) δ
0.88 (d, J = 7.0 Hz, 3H), 1.24 (d, J = 6.2 Hz, 3H), 1.50-1.56
(m, 1H), 1.70 (m, 1H), 1.94-2.0 (m, 2H), 3.98 (m, 1H), 4.06
(qdd, J = 15.2, 14.8, 2.2 Hz, 1H), 5.06 (d, J =2.6 Hz, 1H),
6.24 (m, 1H), 6.34 (m, 1H), 7.37 (m,1H); 13C NMR (125 MHz,
CDCl3) δ 11.8, 21.8, 35.5, 38.7, 69.1, 70.2, 71.3, 106.0, 109.9,
141.2, 153.4; Mass: (m/z) 196.24 found 197 (M+1).
(500 MHz, CDCl3) δ 0.92 (d, J = 7.2 Hz, 3H), 1.23 (d, J = 7.8
Hz, 3H), 1.46-1.64 (m, 5H), 1.89 (m, 1H), 2.62 (m, 1H), 2.80
(m, 1H), 3.85 (qdd, J = 16.2, 15.2, 2.8 Hz, 1H), 3.87 (dd, J =
5.2, 2.4 Hz, 1H), 4.52 (d, J = 9.4 Hz, 1H), 7.13- 7.31 (m, 5H);
13C NMR (125 MHz, CDCl3) δ 11.0, 21.8, 32.3, 34.5, 36.0,
38.3, 68.4, 70.9, 73.3, 125.6, 128.3, 128.4, 142.3; Mass: (m/z)
234.33 found 235 (M+1).
(2R,4R,6S)-3-methyl-2,6-diphenethyltetrahydro-2H-
pyran-4-ol (3c): Rf = 0.6 (1:4 ethyl acetate-hexanes); m.p.:
94–96 °C; IR (KBr) 3392, 3026, 2941, 2920, 1059, 700; White
1
solid; H NMR (500 MHz, CDCl3) δ 1.20 (q, J = 11.6 Hz,
RESULTS AND DISCUSSION
2H), 1.41 (s, 1H), 1.75 (dddd, J = 13.4, 9.8, 7.0, 4.5 Hz, 2H),
1.98–1.91 (m, 4H), 2.73 (ddd, J = 13.5, 8.6, 7.5 Hz, 2H), 2.87
(ddd, J = 14.2, 9.2, 5.4 Hz, 2H), 3.27–3.23 (m, 2H), 3.75 (tt, J
= 10.5, 4.4 Hz, 1H), 7.30–7.19 (m, 10H); 13C NMR (125 MHz,
CDCl3) δ 142.2, 128.6, 128.4, 125.8, 74.4, 68.3, 41.5, 37.8,
32.0; Mass: (m/z) 324.4 found 325 (M+1).
The synthetic route for the diastereoselective preparation
of 1-5(c) compounds is shown in Scheme-I. Initially, 4-hexen-
2-ol (1a) and 1-phenylhept-5-en-3-ol (3a) were prepared in
high yields in an aqueous medium from the Barbier reaction
between acetaldehyde and 1-bromobut-2-ene and 3-phenyl-
propanal and 1-bromobut-2-ene, respectively promoted by tin(II)
chloride. Compounds 1c, 2c and 5c were prepared on total
2,4,6-equatorial diastereoselectivity from Prins cyclization
reaction between 4-hexen-2-ol (1a) and benzaldehyde (1b),
3-phenylpropanal (2b) and furnaldehyde (4b), respectively.
(2R,4S,6S)-3-methyl-2,6-diphenethyltetrahydro-2H-
pyran-4-ol (3d): Rf = 0.5 (1:4 ethyl acetate-hexanes); White
solid: m.p.: 69-72 °C; IR (KBr) 3392, 3026, 2918, 1093, 750,
700; 1H NMR (500 MHz, CDCl3) δ 1.30 (d, J = 2.8 Hz, 1H),
1.54–1.49 (m, 2H), 1.64 (dd, J = 14.5, 2.6 Hz, 2H), 1.70 (dddd,

2774 Raju et al.
Asian J. Chem.
OH
OH
R2
i. 4-nitrobenzoic acid, DEAD,
PPh3, toluene, 80-90 °C, 10 h
i. BF3.OEt2, CF3COOH,
DCM, 0-5 °C
R2
R2
R3
O
ii. K2CO3, MeOH,
rt, 1 h
R3
H
ii. K2CO3, MeOH,
rt, 1 h
R1
OH
(a)
R1
O
R1
O
R3
(c)
(b)
(d)
Scheme-I: Prins cyclization with BF3.OEt2, TFA and Mitsunobu inversion
Compounds 3c and 4c were prepared between 1-phenylhept-
5-en-3-ol (3a) and 3-phenylpropanal (2b), 3-methylbutanal
(3b) respectively, only by BF3·OEt2 (Lewis acid) and trifluoro
acetic acid (TFA), in moderate to good yields and on mild
conditions. Then compounds 1-5(c) undergo Mitsunobu inversion
and subsequent methanolysis efficiently furnished the trans-
2,4,6 tetrahydropyranols 1-5(d) [16].
H
H
Ph
O
H3C
HO
CH3
Hc
Ha
H
Hb
(
J
= 10.1, 7.2, 4.3 Hz)
(
J
= 16.3, 12.2, 2.5 Hz)
Some general mechanistic proposals have been described
to explain the high selectivity of 2,4,6-cis in the Prins reaction.
Based on some most accepted reaction mechanisms explaining
the 2,4,6-cis preferential geometry for this cyclization, proposed
by Farrugia [17], we proposed a general mechanism Scheme-
II. The mechanism starts with the nucleophilic attack of alcohol
‘A’ on the complexed aldehyde-Lewis acid (stage-i) leading
to intermediate ‘B’ formation. Stage-ii is a proton exchange
followed by elimination (stage-iii) with intermediate ‘D’formation.
The stage-iv subsequently occurs by synchronously nucleo-
philic attack through the transition state ‘E’, which produce
‘F’. It should be noted that the nucleophilic attack on step ‘E’
occurs preferentially on equatorial position which is a more
stable transition state and axial position which is a lower stable
transition state. Another proposal explaining the equatorial
stereoselectivity on C4 of tetrahydropyran derivatives was
based on the theoretical studies by Farrugia et al. [18].
The 2,4,6-cis geometry determination in the compounds
1-5(c) were made based on the NMR spectroscopy. In these
cis-2,4,6-tetrahydropyranols compounds spectra there is a
strong spatial coupling between the hydrogens Ha, Hb and Hc
in 1c. Such coupling would not be observed in the trans-2,4,6-
tetrahydropyranols (1d) (Fig. 1).
H
H
Ph
O
H3C
Hb
CH3
Hc
Ha
= 15.3, 14.2, 2.5 Hz)
H
HO
(J
(J = 4.1, 2.4 Hz)
Fig. 1. Coupling constants of the products 1c and 1d
Conclusion
In this work, the Lewis acids such as BF3.OEt2 and trifluoro
acetic acid (TFA) are proved to be a useful and novel reaction
catalytic system for Prins-cyclization, avoiding the expensive
catalysts. The substrates shows significant increasing in reactivity,
reducing the reaction time and improving the yields. Finally,
we are able to prepare in good yields cis-2,4,6-tetrahydropyranols
and trans-2,4,6- tetrahydropyranols derivatives 1-5(c-d) in the
presence of BF3.OEt2 andTFA followed by Mitsunobu inversion.
We determinate its cis/trans configurations by spectroscopy
studies.
R2
R2
R2
LA
H
O
LA
LA
O
Nu
HO
O
R1
OH
R3
stage-i
stage-ii
R1
O
H
B
R3
R1
R3
A
C
LA
HO
stage-iii
R2
Nu
R2
Nu
R2
Nu
R2
R3
R1
R1
stage-v
O
stage-iv
O
R3
R3
R1
O
F
R1
O
R3
E
D
Scheme-II: General mechanisms to obtained the 1-5(c,d) cis/trans compounds from the Prins cyclization reactions

Vol. 29, No. 12 (2017)
Synthesis of cis and trans 2,4,6-Tetrahydropyranols via Prins-Type Cyclization and Mitsunob Inversion 2775
7. (a) I.T. Kay and E.G. Williams, Tetrahedron Lett., 24, 5915 (1983);
ACKNOWLEDGEMENTS
https://doi.org/10.1016/S0040-4039(00)94237-0.
(b) I.T. Kay and D. Bartholomew, Tetrahedron Lett., 25, 2035 (1984);
https://doi.org/10.1016/S0040-4039(01)90106-6.
(c) J.J. Jaber, K. Mitsui and S.D. Rychnovsky, J. Org. Chem., 66, 4679
(2001);
The author thanks Dr. Reddy’s Laboratories, Hyderabad,
India for permitting this research work.
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