Iron(III)-catalyzed prins cyclization towards the synthesis of trans-Fused bicyclic tetrahydropyrans

Article abstract of DOI:10.1055/s-0034-1380013

trans-Fused bicyclic tetrahydropyrans have been synthesized through an intramolecular Prins cyclization catalyzed by iron(III). The cyclization process is stereoselective, leading exclusively to an all-cis configuration in the newly generated ring. This u

Full text of DOI:10.1055/s-0034-1380013

SYNTHESIS
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
© Georg Thieme Verlag Stuttgart · New York
2015, 47, 1791–1798
paper
1791
S. J. Pérez et al.
Paper
Synthesis
Iron(III)-Catalyzed Prins Cyclization towards the Synthesis of
trans-Fused Bicyclic Tetrahydropyrans
Sixto J. Péreza
Pedro O. Mirandab
Daniel A. Cruza
Israel Fernándezc
Víctor S. Martín*a
Juan I. Padrón*a,b
O
*
O
O
O
*
*
*
*
X
X
+
X
R2
O
R2
H
*
O
R2
OH
*
Cl
H
H
H
O
OMe
OMe
O
OMe
RCHO
Fe(acac)3, TMSCl
a Instituto Universitario de Bio-Orgánica ‘Antonio González’ (CIBICAN),
Departamento de Química Orgánica, Universidad de La Laguna,
C/Astrofísico Francisco Sánchez 2, 38206 La Laguna, Tenerife, Spain
b Instituto de Productos Naturales y Agrobiología, CSIC, C/Astrofísico
Francisco Sánchez 3, 38206 La Laguna, Tenerife, Spain
jipadron@ipna.csic.es
HO
R
O
OMe
H
H
OMe
OMe
50–70%
c Departamento de Química Orgánica I, Facultad de Ciencias Químicas,
Universidad Complutense de Madrid, 28040 Madrid, Spain
Received: 10.12.2014
Accepted: 13.01.2015
The use of iron(III) salts as catalysts has permitted us to
develop new methodologies to access a wide variety of het-
erocycles of different sizes.3 The vast majority of our efforts
has been focused on the synthesis of cyclic ethers, mainly
featuring six-membered rings.4 On the other hand, poly-
functionalized cyclic ethers are the structural cores of a
wide range of biologically active natural products, including
polyether antibiotics,5 ladder marine toxins6 and laurox-
anes7 (Figure 1). The structures of these natural products
include a unique and characteristic trans-fused polycyclic
ether ring system containing six-, seven- and eight-mem-
bered cyclic ethers. These marine natural products have at-
tracted the attention of numerous synthetic organic chem-
ists, who have developed new and efficient methodologies
and strategies towards the construction of the ether ring
systems and their application to total synthesis.6,8
Published online: 18.02.2015
DOI: 10.1055/s-0034-1380013; Art ID: ss-2014-c0745-st
Abstract trans-Fused bicyclic tetrahydropyrans have been synthesized
through an intramolecular Prins cyclization catalyzed by iron(III). The
cyclization process is stereoselective, leading exclusively to an all-cis
configuration in the newly generated ring. This useful methodology al-
lows for easy access to a variety of bicyclic ethers present in a wide
range of bioactive natural products. Remarkably, the cyclization reac-
tion works well when more challenging aldehydes bearing a functional
group, such as a double bond or an acetate, are used. In addition, we
present a computational study which rationalizes the results and ex-
plains the complete cis stereoselectivity in the newly formed tetrahy-
dropyran ring.
Key words iron, cyclic ethers, sustainable metal catalysis, bicyclic tet-
rahydropyrans, Prins cyclization
Three major approaches to access such oxacycles have
been developed, namely (i) via a final C–O formation using a
nucleophilic oxygen, (ii) by C–C bond formation through a
preconstructed linear ether, or (iii) by the simultaneous C–
O and C–C bonding in a single step.9 This last approach is
based on a rapid and direct access to tetrahydropyran rings
through a Prins cyclization catalyzed by Lewis acids. In our
case, we have used iron(III) salts as catalysts in a sustain-
able metal catalysis context. This methodology therefore
combines the formation of a C–O bond and a C–C bond in
an oxacyclic ring in a single reaction step (Scheme 1).
During the last decades, many synthetic chemists have
finished their strategies and methodologies with a model
related to alcohol 1 (or activated cyclic ethers which could
be transformed into 1), which possesses the internal sec-
ondary homoallylic alcohol required for the Prins cycliza-
tion (Scheme 2).8g,10,11 We envisioned this model 1 as a sub-
strate in which an additional tetrahydropyran ring could be
constructed through an intramolecular Prins cyclization.12
The advent of the concept of sustainability has driven
new research areas of catalysis in organic chemistry.1 The
catalysis needs to be sustainable with respect to the sub-
strate-to-product conversion, solvent, energy source, and
the nature of the catalyst. One of these new areas of cataly-
sis is sustainable metal catalysis, based upon abundant, in-
expensive and biorelevant metals, such as iron.2
Iron occupies an important place amongst the biologi-
cally relevant metals and there is growing interest in the
use of its salts as sustainable catalysts for organic transfor-
mations. A good number of biological systems and func-
tions rely upon the chemistry of iron-containing enzymes.
Moreover, iron is one of most abundant and inexpensive
metals in the earth’s crust, and is an attractive metal for
man-made synthetic transformations as no severe toxicity
or side effects exist. Therefore, iron salts fulfill the criteria
of perfect sustainable catalysts.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 1791–1798

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S. J. Pérez et al.
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Synthesis
Me
H
brevetoxin B
HO
Me
O
H
H
Me
O
O
CHO
O
H
Me
O
O
H
H
H
O
O
O
H
O
H
H
O
HO
Me
H
Me
H
O
O
H
O
Me
H
H
H
OH
O
Me
Me
H
H
H
H
O
H
H
H
HO
O
H
H
( )3
O
H
O
O
Me
OH
H
H
H
O
Me
H
O
Me
gambierol
H
H
OH
O
O
H
O
Me
H
H
H
H
Me
Me
H
H
H
H
H
O
NaO3SO
O
O
Me
yessotoxin
Me
NaO3SO
O
O
H
H
H
Figure 1 Selected examples of natural products with cyclic ethers in their structures
sulting fused tetrahydropyran would thus be pre-fixed in
the starting material used as the template. The known un-
saturated alcohol 3 was obtained from the known alcohol 2
by a simple three-step sequence consisting of oxidation to
the corresponding aldehyde by the Parikh–Doering reac-
tion, Wittig methylenation (Ph3P=CH2) and protecting
group removal (Scheme 3).13
O
O
+
R1
O
R2
R1
O
R2
*
R1
OH
*
H
H
R2
*
O
*
O
O
*
*
*
*
X
X
+
X
R2
O
R2
*
O
R2
OH
*
Scheme 1 Strategy for the synthesis of cyclic ethers: concomitant C–O
and C–C bond formation through a Prins cyclization
O
O
O
ref. 13a
a–c
AcO
AcO
HO
HO
TBSO
H
H
H
H
H
H
2
OAc
3
O
O
OH
OPG
CO2R
tri-O-acetyl-D-glucal
Scheme 3 Synthesis of tetrahydropyran model 3. Reagents and condi-
tions: a) SO3·Py, DMSO, Et3N, CH2Cl2, 0 °C; b) Ph3P=CH2, THF, 54% over 2
steps; c) TBAF, THF, r.t., 99%.
O
O
OH
H
H
H
H
H
H
PG = protecting group
O
O
OH
In order to test our hypothesis, we submitted the ho-
moallylic alcohol 3 to the intramolecular Prins cyclization
using isovaleraldehyde and stoichiometric amounts of
iron(III) chloride in dichloromethane at room temperature.
Unfortunately, we only isolated 5% of the desired bicycle 4.
To our delight, under catalytic conditions and using 10
mol% of iron(III) acetylacetonate [Fe(acac)3] as iron source,
we improved the yield of trans-fused tetrahydropyran 4 up
to 65% (Scheme 4). Total control of the stereochemistry of
the two new centers generated during the Prins cyclization
was obtained. Noteworthy is the excellent stereoselectivity
observed where only the all-cis configuration in the new
ring was observed.
1
H
H
H
H
H
H
H
H
O
CHO
OH
O
O
O
OTBS
Scheme 2 Possible access routes to Prins cyclization precursor 1 in the
synthesis of trans-fused cyclic ethers
With this idea in mind, we first decided to synthesize a
simple model such as 3 to check the viability of the forma-
tion of trans-fused bicyclic tetrahydropyrans. This species
can be obtained from commercially available tri-O-acetyl-
D-glucal (Scheme 3). The final trans configuration of the re-
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 1791–1798

1793
S. J. Pérez et al.
Paper
Synthesis
Cl
Then, we moved to a more complex template to avoid
H
H
O
the main shortcomings of the above process, namely, the
volatility of 3 and limitations on the possibility to extend
the Prins cyclization in an iterative process. To this end,
methyl α-D-glucopyranoside, which possesses two reactive
positions to introduce a double bond (the hydroxymethyl
and the anomeric carbon as reactive centers), was chosen
as starting material (Scheme 5).
O
i-BuCHO
CH2Cl2, r.t.
trans
O
HO
H
3
4
cis
FeCl3 (1 equiv)
5%
Fe(acac)3, TMSCl 65%
The tetrahydropyran model 9 was obtained in good re-
action yield in five steps (Scheme 5). Thus, p-methoxyben-
zylidene formation from methyl α-D-glucopyranoside, fol-
lowed by methylation of the resulting 4,6-O-p-methoxy-
Scheme 4 Intramolecular Prins cyclization to generate the trans-fused
tetrahydropyran 4
benzylidene
5 and regioselective opening of the p-
reactive centers
methoxybenzylidene group in 6 with lithium aluminum
hydride, afforded the desired alcohol 7.14 The free 6-hy-
droxy group was submitted to a three-step sequence,
namely oxidation to the corresponding aldehyde, Wittig
methylenation and p-methoxybenzyl group removal, lead-
ing to the desired homoallylic alcohol 9.
Next, by applying the catalytic conditions that combine
Fe(acac)3 and trimethylsilyl chloride, we were able to ob-
tain several trans-fused bicyclic tetrahydropyrans in mod-
erate yields (Scheme 6). Thus, in one step, using the enan-
tiopure template 9, we have generated a new tetrahydropy-
ran ring, one carbon–carbon bond, one carbon–oxygen
bond and one carbon–chloro bond with absolute control of
the stereochemistry at the two new centers. The iron(III)-
catalyzed Prins cyclization performed really well even
though a highly oxygenated substrate such as the unsatu-
rated alcohol 9 was used, and the current iron catalytic sys-
tem efficiently promoted the Prins cyclization with differ-
ent types of aldehydes.
O
OMe
c
O
OMe
OH
O
OMe
OMe
O
a
HO
HO
HO
PMP
O
OR
PMBO
OR
OH
OMe
α-methyl-D-glucopyranoside
7
5 R = H
6 R = Me
b
O
OMe
OMe
O
OMe
f
d,e
PMBO
HO
OMe
OMe
OMe
9
8
Scheme 5 Synthesis of tetrahydropyran model 9. Reagents and condi-
tions: a) p-MeOC6H4CH(OMe)2, p-TsOH, DMF, 60 °C, 99%; b) MeI, NaOH,
DMSO, 99%; c) LiAlH4, AlCl3, CH2Cl2, Et2O, 99%; d) SO3·Py, Et3N, DMSO,
CH2Cl2, 0 °C; e) Ph3P=CH2, toluene, 73% over 2 steps; f) CAN, MeCN–
H2O (9:1), 0 °C, 99%.
Cl
H
O
OMe
OMe
Cl
H
O
H
H
Cl
O
O
OMe
OMe
H
OMe
O
OMe
OMe
10
O
Ph
H
H
i-BuCHO
OMe
70%
H
H
OMe
14
52%
60%
11
H
CyCHO
PhCH2CHO
O
OMe
HO
OMe
H
OMe
CHO
AcO(CH2)3CHO
57%
9
55%
Cl
Cl
O
H
H
O
OMe
O
OMe
OMe
AcO
O
OMe
H
H
H
H
OMe
OMe
12
13
Scheme 6 Synthesis of trans-fused bicyclic tetrahydropyrans. Reagents and conditions: Fe(acac)3, TMSCl, CH2Cl2, r.t.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 1791–1798

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S. J. Pérez et al.
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Synthesis
We first undertook the Prins cyclization of homoallylic
alcohol 9 with isovaleraldehyde, which afforded the trans-
fused bicyclic tetrahydropyran 10 in 70% yield when
Fe(acac)3 was employed; the use of iron(III) chloride led to a
poorer yield of 10.15 Again, the enantiopure template 9 con-
trols the stereochemistry of the process, which leads to an
all-cis configuration in the new oxacyclic ring. In this con-
text, the Prins cyclization worked well with either aliphatic
or aromatic-containing aldehydes (Scheme 6, trans-fused
products 11 and 14). Importantly, the iron catalyst also
proved efficient in the cyclization process of more challeng-
ing aldehydes bearing a functional group, such as an acetate
or a double bond (Scheme 6, formation of 12 and 13).
Furthermore, the chlorine atom can be easily removed,
yielding the desired fused bicycles. In the case of chloride
10, this dehalogenation step afforded the corresponding bi-
cyclic tetrahydropyran 15 in 95% yield (Scheme 7).
which leads exclusively to the cis-tetrahydropyrans. To this
end, we have explored the two possible ring closures from
the oxocarbenium ion intermediate INT1, initially formed
by reaction of alcohol 9 and isovaleraldehyde in the pres-
ence of iron(III).17 Figure 2 shows the computed reaction
profile [PCM(CH2Cl2)-B3LYP-D3/6-31G(d) level] which
gathers the relative free energies (ΔG298, at 298 K) in di-
chloromethane as solvent.
From the data in Figure 2, it is clear that the cyclization
reaction involving INT1 exclusively leads to the formation
of the cis-adduct INT2-cis through the transition state TS-
cis (ΔG≠ = 4.9 kcal/mol). Complete regioselectivity of the
process takes place under both kinetic and thermodynamic
control, in view of the significantly higher activation energy
(ΔG≠ = 8.1 kcal/mol) and endergonicity (ΔGR = 6.2 kcal/mol)
associated with the formation of the alternative trans-ad-
duct INT2-trans. This finding can be mainly ascribed to the
destabilizing pseudo-1,3-diaxial interaction between the
isobutyl group and the hydrogen atom of the initial tetrahy-
dropyran ring, which is present in TS-trans but not in its cis
counterpart TS-cis (see Figure 2).
Cl
H
Bu3SnH
AIBN
H
H
O
OMe
OMe
O
OMe
OMe
toluene
reflux
95%
As previously reported,17 once carbocation INT2-cis is
formed, it is transformed into compound 10 by the nucleo-
philic addition of Cl– (Scheme 8). This reaction is reported
to proceed along an equatorial trajectory due to the pseu-
doaxial geometry adopted by the hydrogen atom attached
to the carbocationic center.17 Moreover, our calculations in-
dicate that the equatorial product INT3-eq is also thermo-
dynamically favored over the corresponding axial isomer
O
O
H
H
H
OMe
OMe
15
10
Scheme 7 Synthesis of the bicyclic tetrahydropyran 15
Density functional theory (DFT) calculations16 were fi-
nally carried out to gain more insight into the complete ste-
reoselectivity of the above-described transformation,
Figure 2 Computed reaction profile for the cyclization reaction involving oxocarbenium ion INT1. Relative free energies (ΔG298, at 298 K) and bond
distances are given in kcal/mol and Å, respectively; all data have been computed at the PCM(CH2Cl2)-B3LYP-D3/6-31G(d) level.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 1791–1798

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S. J. Pérez et al.
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Synthesis
Scheme 8 Axial and equatorial reaction products formed upon addition of Cl– to carbocation INT2-cis. All data have been computed at the
PCM(CH2Cl2)-B3LYP-D3/6-31G(d) level.
INT3-ax (ΔG298 = 1.2 kcal/mol). This is again due to the pres-
ence of destabilizing 1,3-diaxial Cl–H interactions in the lat-
ter species which are absent in the former isomer (see
Scheme 8).
phy was performed using silica gel (0.015–0.04 mm) and n-hexane–
EtOAc solvent systems. All reagents were obtained from commercial
sources and used without further purification. Solvents were dried
and distilled before use.
In conclusion, we have synthesized several functional-
ized trans-fused bicyclic tetrahydropyrans through the
Prins cyclization, using iron(III) salts as sustainable metal
catalysts. This intramolecular Prins cyclization is controlled
and directed by the stereochemistry of the enantiopure ho-
moallylic alcohol template, leading to an all-cis stereoselec-
tive process. Our DFT study on the key cyclization reaction
suggests that the formation of the all-cis final bicycles is fa-
vored under both kinetic and thermodynamic control. This
method allows the direct synthesis of these tetrahydropy-
rans, along with the introduction of new modifications in
the side chain. The possible iteration approach through the
anomeric carbon and the in vitro antiproliferative activity
of the derivatives are being evaluated with promising re-
sults, which will be reported in due course.
(2S,3R,4S,5R,6R)-2,3,4-Trimethoxy-5-((4-methoxybenzyl)oxy)-6-
vinyltetrahydro-2H-pyran (8)
DMSO (18 mL, 252.7 mmol), Et3N (21 mL, 153.4 mmol) and SO3·Py
(10.5 g, 65.7 mmol) were added to a stirred solution of tetrahydropy-
ran 7 (7.5 g, 21.9 mmol) in anhydrous CH2Cl2 (220 mL) at 0 °C under
argon. The vigorously stirred mixture was maintained at 0 °C and the
reaction course was followed by TLC. Then, the mixture was diluted
with EtOAc (300 mL), and washed with 1 M HCl (100 mL), sat. aq
NaHCO3 (100 mL) and sat. aq NaCl (75 mL). The organic layer was
dried over MgSO4 and filtered, and the solvent was removed under re-
duced pressure. The corresponding aldehyde thus obtained was used
in the next reaction step without further purification.
The phosphonium ylide was prepared by the addition at 0 °C of
LiHMDS (19.7 mmol) to a solution of methyltriphenylphosphonium
bromide (7.8 g, 21.9 mmol) in anhydrous toluene (100 mL) at 0 °C un-
der argon, and the reaction mixture was stirred for 15 min. Then, the
mixture was cooled to –78 °C, and a solution of the above-prepared
aldehyde in toluene (20 mL) was added. The reaction mixture was al-
lowed to reach r.t., until analysis via TLC showed complete formation
of the final product. The reaction was quenched by adding sat. NH4Cl
solution (100 mL), and the mixture was diluted with Et2O (150 mL),
and washed with water (7 mL) and sat. aq NaCl (7 mL). The organic
layer was dried over MgSO4 and filtered, and the solvent was removed
under reduced pressure. This crude mixture was purified by silica gel
column chromatography (n-hexane–EtOAc, 90:10, v/v) to obtain 8;
yield: 5.41 g (73%).
NMR spectra were recorded on Bruker Avance instruments, at 300,
400 or 500 MHz for 1H NMR spectra, and at 75, 100 or 125 MHz for 13
C
NMR spectra (VTU: 298.0 K). Chemical shifts are reported in parts per
million, and the residual solvent peak was used as an internal refer-
ence (CDCl3: δH 7.26, δC 77.0). Optical rotations were measured on a
Perkin-Elmer 241 polarimeter by using a Na lamp. IR spectra were re-
corded on a Bruker IFS 55 spectrometer. HRMS (ESI) data were col-
lected on a Micromass Autospec spectrometer. For analytical TLC, sili-
ca gel ready-made foils were used, which were developed with UV
light (254 nm) and/or by spraying with a solution of vanillin in EtOH–
H2SO4–AcOH (15:1:1.3) and heating at 200 °C. Column chromatogra-
[α]D25 +99.3 (c 1.40, CHCl3).
IR (film): 2907, 2835, 1514, 1249, 1089 cm–1
.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 1791–1798

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S. J. Pérez et al.
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Synthesis
1H NMR (300 MHz, CDCl3): δ = 3.13 (t, J = 9.6 Hz, 1 H), 3.22 (dd, J = 3.6,
9.6 Hz, 1 H), 3.38 (s, 3 H), 3.58 (m, 7 H), 3.78 (s, 3 H), 4.00 (m, 1 H),
4.53 (d, J = 10.5 Hz, 1 H), 4.68 (d, J = 10.2 Hz, 1 H), 4.81 (d, J = 3.6 Hz, 1
H), 5.26 (d, J = 10.2 Hz, 1 H), 5.40 (d, J = 17.4 Hz, 1 H), 5.89 (m, 1 H),
6.86 (d, J = 8.4 Hz, 2 H), 7.26 (d, J = 8.7 Hz, 2 H).
13C NMR (100 MHz, CDCl3): δ = 22.3, 22.9, 24.5, 25.5, 29.5, 42.6, 44.4,
58.8, 68.2, 75.0, 76.9, 83.7.
Anal. Calcd for C12H21ClO2 (232.75): C, 61.92; H, 9.09. Found: C, 62.07;
H, 9.20.
13C NMR (75 MHz, CDCl3): δ = 54.8, 55.0, 58.8, 60.9, 71.0, 74.5, 81.6,
81.7, 83.1, 97.1, 113.5, 117.7, 129.5, 130.2, 135.0, 159.0.
(2S,3R,4S,4aS,6R,8S,8aS)-8-Chloro-6-isobutyl-2,3,4-trimethoxyoc-
tahydropyrano[3,2-b]pyran (10)
Anal. Calcd for C18H26O6 (338.40): C, 63.89; H, 7.74. Found: C, 63.95;
H, 7.75.
Following the general procedure described above, to a solution of
Fe(acac)3 (16.7 mg, 0.046 mmol) in anhydrous CH2Cl2 (4.6 mL) were
added TMSCl (0.06 mL, 0.458 mmol), the unsaturated alcohol 9 (100
mg, 0.458 mmol) and isovaleraldehyde (40.3 mg, 0.458 mmol). After
workup, the crude mixture was purified by silica gel column chroma-
tography (n-hexane–EtOAc, 80:20) to give 10 as a colorless oil; yield:
103.5 mg (70%).
(2R,3R,4S,5R,6S)-4,5,6-Trimethoxy-2-vinyltetrahydro-2H-pyran-3-
ol (9)
To a solution of p-methoxybenzyl ether 8 (1.50 g, 4.44 mmol) in
MeCN–H2O (9:1, 50 mL) at 0 °C was added, in several portions, CAN
(4.9 g, 8.86 mmol). The reaction mixture was stirred at this tempera-
ture and monitored by TLC until complete formation of the alcohol.
Then, the mixture was diluted with EtOAc (50 mL) and washed with
water (100 mL). The organic layer was dried over MgSO4 and filtered,
and the solvent was removed under reduced pressure. This crude
mixture was purified by silica gel column chromatography (n-hex-
ane–EtOAc, 60:40, v/v) to obtain 9; yield: 959 mg (99%).
[α]D25 +96.4 (c 1.5, CHCl3).
1H NMR (500 MHz, CDCl3): δ = 0.90 (d, J = 4.0 Hz, 3 H), 0.91 (d, J = 4.0
Hz, 3 H), 1.25 (m, 1 H), 1.54 (m, 1 H), 1.72 (m, 1 H), 1.79 (m, 1 H), 2.23
(m, 2 H), 3.05 (t, J = 9.4 Hz, 1 H), 3.22 (dd, J = 9.4, 3.7 Hz, 1 H), 3.45 (t,
J = 9.9 Hz, 1 H), 3.47 (s, 3 H), 3.52 (t, J = 9.1 Hz, 1 H), 3.53 (s, 3 H), 3.59
(s, 3 H), 3.92 (m, 1 H), 4.86 (d, J = 3.8 Hz, 1 H).
13C NMR (125 MHz, CDCl3): δ = 22.0, 23.2, 24.7, 42.3, 44.2, 55.1, 57.9,
59.4, 60.9, 72.1, 75.3, 80.7, 81.0, 81.3, 97.7.
[α]D25 +148.7 (c 1.50, CHCl3).
1H NMR (300 MHz, CDCl3): δ = 3.24 (m, 2 H), 3.44 (m, 7 H), 3.61 (s, 3
H), 3.95 (t, J = 7.2 Hz, 1 H), 4.83 (d, J = 3.6 Hz, 1 H), 5.28 (dd, J = 1.0,
10.4 Hz, 1 H), 5.40 (dd, J = 1.2, 17.2 Hz, 1 H), 5.87 (m, 1 H).
HRMS (ESI+): m/z [M + Na]+ calcd for C15H27ClO5: 345.1426; found:
345.1436.
13C NMR (75 MHz, CDCl3): δ = 55.0, 58.3, 62.1, 71.6, 73.3, 81.5, 82.3,
97.2, 118.4, 134.7.
(2S,3R,4S,4aS,6R,8S,8aS)-6-Benzyl-8-chloro-2,3,4-trimethoxyocta-
hydropyrano[3,2-b]pyran (11)
Anal. Calcd for C10H18O5 (218.25): C, 55.03; H, 8.31. Found: C, 55.13;
H, 8.50.
Following the general procedure described above, to a solution of
Fe(acac)3 (16.7 mg, 0.046 mmol) in anhydrous CH2Cl2 (4.6 mL) were
added TMSCl (0.06 mL, 0.458 mmol), the unsaturated alcohol 9 (100
mg, 0.458 mmol) and phenylacetaldehyde (55.0 mg, 0.458 mmol). Af-
ter workup, the crude mixture was purified by silica gel column chro-
matography (n-hexane–EtOAc, 80:20) to give 11 as a colorless oil;
yield: 85.0 mg (52%).
trans-Fused Bicyclic Tetrahydropyrans by the Iron(III) Salt/TMSCl
Catalyzed Intramolecular Prins Cyclization; General Procedure
To a solution of the iron salt [FeCl3 (1.0 equiv) or Fe(acac)3 (0.1 equiv)]
in anhydrous CH2Cl2 (0.1 M) was added TMSCl (1.0 equiv) and then
the unsaturated alcohol 3 or 9 (1.0 equiv) and the corresponding alde-
hyde (1.0 equiv) in this order. The reaction mixture was stirred at r.t.
for 24 h. The reaction was quenched by the addition of water with
stirring for 60 min, and the mixture was extracted with CH2Cl2. The
combined organic layers were dried over MgSO4 and filtered, and the
solvent was removed under reduced pressure. This crude mixture was
purified by silica gel column chromatography (n-hexane–EtOAc sol-
vent systems).
[α]D25 +55.0 (c 1.6, CHCl3).
1H NMR (400 MHz, CDCl3): δ = 1.78 (m, 1 H), 2.25 (m, 1 H), 2.76 (dd,
J = 14, 6.4 Hz, 1 H), 2.97 (dd, J = 14, 6.4 Hz, 1 H), 3.07 (t, J = 9.2 Hz, 1 H),
3.22 (dd, J = 9.2, 3.6 Hz, 1 H), 3.51 (m, 11 H), 3.67 (m, 1 H), 3.89 (m, 1
H), 4.87 (d, J = 3.2 Hz, 1 H), 7.25 (m, 5 H).
13C NMR (100 MHz, CDCl3): δ = 41.2, 41.6, 55.1, 57.8, 59.3, 61.0, 71.9,
77.8, 80.7, 81.1, 97.8, 126.6, 128.4, 129.4, 137.5.
HRMS (ESI+): m/z [M + Na]+ calcd for C18H25ClO5: 379.1288; found:
379.1279.
(2R,4S,4aS,8aS)-4-Chloro-2-isobutyloctahydropyrano[3,2-b]pyran
(4)
3-((2R,4S,4aS,6S,7R,8S,8aS)-4-Chloro-6,7,8-trimethoxyoctahydro-
pyrano[3,2-b]pyran-2-yl)propyl Acetate (12)
Following the general procedure described above, to a solution of
Fe(acac)3 (21 mg, 0.0582 mmol) in anhydrous CH2Cl2 (5 mL) were
added TMSCl (0.1 mL, 0.7 mmol), the unsaturated alcohol 3 (74.5 mg,
0.582 mmol) and isovaleraldehyde (61.6 mg, 0.70 mmol). After work-
up, the crude mixture was purified by silica gel column chromatogra-
phy (n-hexane–EtOAc, 80:20) to give 4 as a colorless oil; yield: 88 mg
(65%).
[α]D25 +12.5 (c 1.20, CHCl3).
IR (film): 2955, 2867, 1106, 772 cm–1
1H NMR (400 MHz, CDCl3): δ = 0.89 (dd, J = 2.2, 6.6 Hz, 6 H), 1.23 (m, 1
H), 1.50 (m, 3 H), 1.70 (m, 3 H), 2.04 (m, 1 H), 2.21 (dd, J = 3.3, 9.9 Hz,
1 H), 3.04 (m, 2 H), 3.42 (m, 2 H), 3.91 (m, 1 H), 4.02 (d, J = 9.5 Hz, 1 H).
Following the general procedure described above, to a solution of
Fe(acac)3 (16.7 mg, 0.046 mmol) in anhydrous CH2Cl2 (4.6 mL) were
added TMSCl (0.06 mL, 0.458 mmol), the unsaturated alcohol 9 (100
mg, 0.458 mmol) and 4-acetoxybutanal (59.6 mg, 0.458 mmol). After
workup, the crude mixture was purified by silica gel column chroma-
tography (n-hexane–EtOAc, 80:20) to give 12 as a colorless oil; yield:
95.8 mg (57%).
.
[α]D25 +103.0 (c 1.0, CHCl3).
1H NMR (400 MHz, CDCl3): δ = 1.69–1.78 (m, 4 H), 2.03 (s, 3 H), 2.30
(m, 2 H), 3.04 (t, J = 9.6 Hz, 1 H), 3.20 (m, 1 H), 3.41–3.46 (m, 6 H), 3.52
(s, 3 H), 3.58 (s, 3 H), 3.91 (m, 1 H), 4.06 (m, 2 H), 4.85 (d, J = 3.2 Hz, 1
H).
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Synthesis
13C NMR (100 MHz, CDCl3): δ = 20.9, 24.9, 31.6, 41.8, 55.1, 57.6, 59.3,
13C NMR (125 MHz, CDCl3): δ = 22.1, 23.3, 24.7, 29.1, 31.4, 44.8, 55.1,
61.0, 64.1, 71.9, 76.4, 80.6, 81.0, 81.1, 97.7, 171.1.
59.4, 60.8, 66.7, 75.8, 80.7, 81.3, 82.7, 98.1.
HRMS (ESI+): m/z [M + Na]+ calcd for C16H27ClO7: 389.1343; found:
HRMS (ESI+): m/z [M + Na]+ calcd for C15H28O5: 311.1834; found:
389.1341.
311.1843.
(2S,3R,4S,4aS,6R,8S,8aS)-6-(But-3-en-1-yl)-8-chloro-2,3,4-tri-
methoxyoctahydropyrano[3,2-b]pyran (13)
Acknowledgment
Following the general procedure described above, to a solution of
Fe(acac)3 (16.7 mg, 0.046 mmol) in anhydrous CH2Cl2 (4.6 mL) were
added TMSCl (0.06 mL, 0.458 mmol), the unsaturated alcohol 9 (100
mg, 0.458 mmol) and 4-pentenal (38.5 mg, 0.458 mmol). After work-
up, the crude mixture was purified by silica gel column chromatogra-
phy (n-hexane–EtOAc, 80:20) to give 13 as a colorless oil; yield: 80.8
mg (55%).
This research was supported by the Spanish MINECO, cofinanced by
the European Regional Development Fund (ERDF) and FEDER
(CTQ2011-28417-C02-01/BQU, CTQ2011-22653, CTQ2013-44303-P)
and IMBRAIN project (FP7-REGPOT-2012-CT2012-31637-IMBRAIN),
funded under the 7th Framework Programme (CAPACITIES). S.J.P.
thanks the Spanish MINECO for a FPU fellowship.
[α]D25 +110.0 (c 0.8, CHCl3).
1H NMR (400 MHz, CDCl3): δ = 1.54 (m, 1 H), 1.74 (m, 2 H), 2.15 (m, 3
H), 3.06 (t, J = 9.2 Hz, 1 H), 3.23 (m, 1 H), 3.44–3.51 (m, 9 H), 3.62 (s, 3
H), 3.92 (m, 1 H), 4.88 (s, 1 H), 5.01 (m, 2 H), 5.79 (m, 1 H).
Supporting Information
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0034-1380013.
S
u
p
p
ortiInfogrmoaitn
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u
p
p
o
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f
rmoaitn
13C NMR (100 MHz, CDCl3): δ = 29.7, 34.3, 41.8, 55.1, 57.8, 59.4, 61.0,
72.0, 76.1, 80.7, 81.0, 81.1, 97.7, 115.2, 137.7.
HRMS (ESI+): m/z [M + Na]+ calcd for C15H25ClO5: 343.1288; found:
343.1294.
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Following the general procedure described above, to a solution of
Fe(acac)3 (16.7 mg, 0.046 mmol) in anhydrous CH2Cl2 (4.6 mL) were
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(2S,3R,4S,4aR,6S,8aR)-6-Isobutyl-2,3,4-trimethoxyoctahydropyra-
no[3,2-b]pyran (15)
To a solution of the trans-fused bicyclic chloride 10 (90 mg, 0.28
mmol) in anhydrous toluene (0.1 M) under N2 atmosphere, n-Bu3SnH
(325 mg, 1.12 mmol) and AIBN (19 mg, 0.112 mmol) were added. The
mixture was heated under reflux for 2 h. Then, evaporation of the sol-
vent was followed by purification of the crude reaction mixture by
silica gel column chromatography (n-hexane–EtOAc, 70:30) to give 15
as a colorless oil; yield: 77.0 mg (95%).
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© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 1791–1798

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Synthesis
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(16) For computational details, see the Supporting Information.
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© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 1791–1798