Direct Access to 2,3,4,6-Tetrasubstituted Tetrahydro-2H-pyrans via Tandem SN2′-Prins Cyclization

Article abstract of DOI:10.1021/acs.orglett.7b02270

A new, direct, and diastereoselective synthesis of activated 2,3,4,6-tetrasubstituted tetrahydro-2H-pyrans is described. In this reaction, iron(III) catalyzed an S_N2′-Prins cyclization tandem process leading to the creation of three new stereoc

Full text of DOI:10.1021/acs.orglett.7b02270

Letter
pubs.acs.org/OrgLett
Direct Access to 2,3,4,6-Tetrasubstituted Tetrahydro‑2H‑pyrans via
Tandem SN2′−Prins Cyclization
Jimena Scoccia,∥,⊥ Sixto J. Perez,‡ Victoria Sinka,† Daniel A. Cruz,‡ Juan M. Lopez-Soria,†
́
́
Israel Fernandez,§ Víctor S. Martín,‡ Pedro O. Miranda,*,† and Juan I. Padron*,‡,†
́
́
†Instituto de Productos Naturales y Agrobiología, CSIC, Francisco San
‡Instituto Universitario de Bio-Organ
ica “Antonio Gonzal
Departamento de Química Organica, Universidad de La Laguna, Francisco San
§Departamento de Química Organ
́
chez 3, 38206 La Laguna, Tenerife, Spain
́
́
ez” (CIBICAN), “Síntesis Organ
́
ica Sostenible, Unidad Asociada al CSIC”,
́
́
chez 2, 38206 La Laguna, Tenerife, Spain
́
́
ica I, Facultad de Ciencias Químicas, Centro de Innovacion en Química Avanzada
(ORFEO−CINQA), Universidad Complutense de Madrid, 28040 Madrid, Spain
∥Departamento de Química, Universidad Nacional del Sur, Av Alem 1253, 800 Bahía Blanca, Argentina
⊥INQUISUR, CONICET, Av Alem 1253, 800 Bahía Blanca, Argentina
S
* Supporting Information
ABSTRACT: A new, direct, and diastereoselective synthesis of
activated 2,3,4,6-tetrasubstituted tetrahydro-2H-pyrans is de-
scribed. In this reaction, iron(III) catalyzed an SN2′−Prins
cyclization tandem process leading to the creation of three new
stereocenters in one single step. These activated tetrahydro-2H-
pyran units are easily derivatizable through CuAAC conjugations
in order to generate multifunctionalized complex molecules.
DFT calculations support the in situ SN2′ reaction as a preliminary step in the Prins cyclization.
unctionalized tetrahydropyrans are structural motifs
instead of the expected seven-membered ring, the observed
Fubiquitous in a myriad of biologically active natural cyclic product turned out to be the six-membered oxacycle 4
products.1,2 Several approaches to the synthesis of such
(2,3,4,6-THP) adorned with four stereogenic centers, three of
them generated in one single step (Figure 1). The reaction
moieties have been developed throughout the years with
special emphasis on Prins cyclization recently.3−11Among the
plethora of substituted oxanes, 2,3,4,6-tetrasubstituted tetrahy-
dro-2H-pyrans (2,3,4,6-THPs) constitute attractive targets
since they are present in natural products,12,13 have great
potential as bioisosteres of amino acids,14 and are precursors of
vinylcyclopropanes15 and other species of high interest in
medicinal chemistry.16 Moreover, the introduction of four
different substituents in the tetrahydro pyran ring may indeed
affect its three-dimensional molecular structure and, therefore,
its biological activity.17,18 Also, it provides excellent oppor-
tunities toward the introduction of molecular complexity.
However, despite their attractiveness as synthetic targets, there
have been few reports on the synthesis of 2,3,4,6-THPs using
Prins cyclization conditions,19−22 most notably due to the
existence of competitive pathways that result in racemization
problems and/or mixtures of undesired products.8,23−26
Additionally, the creation of new stereogenic centers, controlled
by pre-existing stereochemical features, is often a challenge in
acyclic molecules since it is not always easy to reduce the
number of degrees of rotational freedom in a molecule.27 In the
present work, we report our findings on the stereocontrolled
one-pot synthesis of 2,3,4,6-THPs.
Figure 1. Initial approach for the synthesis of oxacycles.
proceeded with excellent stereocontrol and with all substituents
being in the equatorial position (see below, Figure 2). The
presence of a primary alkyl chloride at the 3-position is of
further interest since, by judicious choice of reaction conditions,
it can be converted into a wide variety of functional groups,
allowing us the preparation of more complicated derivatives.
First, we carefully explored the reaction conditions in order
to improve the reaction yield of the 2,3,4,6-THP 4a (Table 1).
Taking into account that in previous works DCM and TMSCl
have both proven to be suitable solvents and co-catalysts to
Initially, alcohol 1 was prepared in order to achieve the iron-
catalyzed synthesis of disubstituted seven-membered oxacycles
2 as precursors for Δ4-2,7-disubstituted oxepenes 3. However,
Received: July 24, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b02270
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Letter
a
Table 2. Scope of the Tandem SN2′−Prins Cyclization
b
entry
R1
R2
n-Bu
time (h)
0.5
yield 4 (%)
1
Et
Et
Et
Et
Et
Et
Et
Et
4b
4c
4d
4e
4f
89
99
72
61
77
69
88
93
60
63
56
71
62
2
Cy
1
6
3
3-butenyl
ethenyl
Ph
4
8
Figure 2. ORTEP plot and structure of triazole 7e.
5
18
20
20
20
18
20
19
20
20
6
p-OMe-Ph
p-NO2-Ph
p-F-Ph
i-Bu
4g
4h
4i
Table 1. Optimization of the Reaction Conditions for the
Tandem SN2′−Prins Cyclization of 1 with Isovaleraldehyde
7
a
8
9
7-octenyl
7-octenyl
n-decyl
4j
10
11
12
13
Ph
4k
4l
i-Bu
n-decyl
Ph
4m
4n
n-decyl
Cy
b
entry
cat. (equiv)
TMSCl (equiv)
time (h)
yield (%)
a
Reaction conditions: 1 (1.0 mmol), 5 (1.1 mmol), FeCl3 (20 mol %),
1
2
3
4
5
6
7
8
9
FeCl3 (1)
0.5
0.5
20
80
35
71
73
48
50
49
57
60
TMSCl (1.1 mmol) dry CH2Cl2 (0.1 M), rt. The stereochemistry of
b
InCl3 (1)
the THPs was assigned by GOESY experiments (see the SI). Yields
1
FeCl3 (0.1)
FeCl3 (0.2)
Fe(acac)3 (0.1)
Fe(acac)3 (0.2)
InCl3 (0.1)
1.1
1.1
1.1
1.1
1.1
1.1
1.1
of products determined by H NMR analysis with hexamethyldisilane
20
as the internal standard.
20
20
20
Our next goal was to increase the molecular complexity by
taking advantage of the presence of the primary alkyl chloride
in THPs of structure 4. In this sense, the copper(I)-catalyzed
alkyne azide cycloaddition (CuAAC) is a convenient, versatile,
and reliable two-step coupling procedure of two molecules that
allows the generation of complexity in a quick, simple, and
modular fashion.29−31 Moreover, the triazole moiety is a well-
known bioisoster of the peptidic bond which enhances its
biological interest.32 By way of a chemoselective SN2 displace-
ment of the primary chloride by azide ion in quantitative yield,
the subsequent CuAAC was achieved under microwave
conditions and with no need for azide purification.
The results gathered in Table 3 clearly highlight the utility of
these THP units as building blocks for the assembly of large
molecules by quickly “clicking” them with small building blocks
6. Thus, the use of homopropargylic alcohol (Table 3, entry a)
and phenylacetylene (Table 3, entry e) gave good yields as well
as the use of carbohydrate derivatives of glucosamine and
furanose (Table 3, entries b and c). On the contrary, the use of
glucal derivatives gave only moderate yields (Table 3, entry d).
The ability of carbohydrate moieties to form hydrogen bonds
and to provoke conformational changes in molecules makes
this combination very attractive from a pharmacological point
of view. Moreover, the relative configuration of the four
stereocenters in the final THP as well as its chairlike
conformation with the attached triazolyl moiety were confirmed
by X-ray diffraction analysis of 7e (Table 3, entry e) (Figure
2).33
InCl3 (0.2)
20
Fe(OTf)3 (0.1)
20
a
Reaction conditions: 1 (1.0 mmol), isovaleraldehyde (1.1 mmol),
[Fe], dry CH2Cl2 (0.1 M), rt, 0.5−20 h. The stereochemistry of the
THPs was assigned by GOESY experiments (see the Supporting
Information). Yields of products after purification by silica gel column
chromatography.
b
carry out Prins cyclizations, respectively,28 we focused on the
nature of the metal source. Although stoichiometric amounts of
FeCl3 were effective, the corresponding workup and
purification turned out to be inconvenient. Replacement of
the iron halide source with organoiron or indium catalysts did
not improve reaction yields. Thus, we settled on the use of 20
mol % of FeCl3 and 1.1 equiv of TMSCl as the best reaction
conditions (Table 1).
Next, we explored the scope of the reaction by using a variety
of aldehydes alongside alcohols bearing different substituents at
the R1 position (Table 2). The use of either alkyl and branched
aldehydes or unsaturated aldehydes gave excellent yields (Table
2, entries 1−4). Similarly, the use of aromatic aldehydes having
either electron-withdrawing or electron-donating groups gave
rise to the corresponding THP structures 4 in good yields
(Table 2, entries 5−8). On the other hand, long alkyl chain R1
substituents also led to THPs 4 with moderate to good yields
(Table 2, entries 9−13). The use of unsaturated aldehydes is
important from a synthetic point of view since the alkene
component allows the further functionalization of the molecule
in a straightforward manner. Thus, successful dehalogenation
with AIBN/(n-Bu)3SnH led to the corresponding 2,6-dialkyl-3-
methyl tetrahydro-2H-pyran (eq 1).
In order to gain more insight into the reaction mechanism
involved in the formation of THP 4a, alcohol 1a was treated
with substoichiometric amounts of FeCl3 (0.2 equiv, Scheme
1). This reaction leads to the chloro intermediate A, very likely
via an SN2′-type reaction. When this intermediate was reacted
with isovaleraldehyde under stoichiometric amounts of FeCl3,
THP 4a was obtained as the final product. Consequently, the
relative syn/anti stereochemistry at the chlorine atom in the
B
DOI: 10.1021/acs.orglett.7b02270
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transformed, in the presence of FeCl3, into INT1 in an
exothermic transformation; a strong interaction between the
chloride atom of 1 and the iron(III) center (the associated
computed Wiberg bond index for this Fe−Cl bond is 0.35)
evolves into INT2 in a slightly endothermic process (ΔER =
+1.9 kcal/mol) via transition state TS1 with an activation
barrier of +25.3 kcal/mol. This saddle point is associated with
the concomitant C3−Cl bond rupture/Cl−C1 bond formation
mediated by transition-metal fragment in an SN2′-type reaction.
INT2 is finally transformed into the observed intermediate A
via the release of FeCl3 which acts, therefore, as a catalyst for
the process. Alternatively, it can be suggested that INT1 can be
transformed into the allylic cation INT3 via a SN1 reaction.
However, the computed high endothermicity associated with
Table 3. CuAAC Reaction of Activated THPs
−
the FeCl4 release (ΔER = +27.9 kcal/mol) together with the
experimentally observed lack of formation of oxetane or
dihydropyran derivatives makes this alternative pathway highly
unlikely. The subsequent exothermic Prins cyclization from the
highly reactive intermediate A drives the complete trans-
formation forward and leads to the observed THP 4a.8
The transformation, therefore, involves a first step consisting
of an SN2′ reaction followed by a Prins cyclization in which no
competitive [3,3]-sigmatropic rearrangement is detected.
Hence, a stereoselective process should take place without
any further racemization. To check this hypothesis, an
enantioselective synthesis of conjugated THP 12 was carried
out (Scheme 2). Starting from the commercially available
a
Yield of isolated product.
Scheme 1. Mechanistic Experiments
Scheme 2. Synthesis of Enantioenriched Triazole 12
starting material is irrelevant for the outcome of the subsequent
Prins-cyclization reaction.
Density functional theory calculations at the dispersion-
corrected PCM(CH2Cl2)-B3LYP-D3/def2-SVP level support
the proposed SN2′ mechanism for the initial iron-mediated
transformation. As depicted in Figure 3, alcohol 1 is
racemic 1-epoxydodecane, a kinetic resolution was effected
using Jacobsen’s catalyst to obtain the epoxide 8.34,35 The
opening of this epoxide using the conditions described by
Miginiac and co-workers36 led us to enantioenriched alcohol 9,
with a completely defined stereocenter at the α-position of the
hydroxyl group. Since this stereocenter will be critical to the
successful generation of the three new stereocenters,
enantiomeric excess in the cyclization process was analyzed
using 4-oxobutyl benzoate as the aldehyde 10. As expected, the
overall outcome of the reaction was not affected by the possible
oxonium-Cope rearrangement, and consequently, no loss of the
stereochemical integrity was observed in the Prins cyclization
process leading to THP 11. CuAAC reaction was then fruitfully
performed with the α-glucal derivative 6d to afford the
enantiomerically pure triazole 12 with an overall yield of 54%.
In conclusion, we have developed a new method to obtain
2,3,4,6-tetrasubstituted tetrahydro-2H-pyrans with the creation
Figure 3. Computed reaction profile (PCM(CH2Cl2)-B3LYP-D3/
def2-SVP level) for the reaction between alcohol 1 and FeCl3. Relative
energies (ZPVE included) and bond distances are given in kcal/mol
and angstroms, respectively.
C
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stereoselective manner. These activated THPs are generated
through a tandem SN2′−Prins cyclization catalyzed by iron(III)
salts. DFT calculations support the in situ SN2′ reaction as a
preliminary step of the Prins cyclization. The chlorine unit is
easily derivatizable chemoselectively, via SN2 and click
chemistry, which generates multifunctionalized complex
molecules of interest from a biological point of view. We
expect this method will be useful to the synthetic community
and will change the approach to the synthesis of highly
functionalized 2,3,4,6-THPs.
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AUTHOR INFORMATION
Corresponding Authors
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*E-mail: jipadron@ipna.csic.es.
*E-mail: pmiranda@ipna.csic.es.
ORCID
Israel Fernandez: 0000-0002-0186-9774
́
Víctor S. Martín: 0000-0003-0300-9636
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Juan I. Padron: 0000-0002-0745-2259
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Notes
The authors declare no competing financial interest.
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Chemistry; Cengage Learning, Inc.: Belmont, CA, 2008
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This research was supported by the Spanish MINECO,
cofinanced by the European Regional Development Fund
(ERDF) (CTQ2014-56362-C2-1-P) and MINECO-FEDER
(CTQ2016-78205-P and CTQ2014-51912-REDC to I.F.).
D.A.C. thanks the Spanish MINECO for an F.P.I. fellowship.
J.M.L.-S. thanks the Canary Island Government (ACIISI) for a
predoctoral contract. P.O.M. was supported by a Marie Curie
IOF from the European Union’s Seventh Framework Program
FP7/2007-2013 under REA Grant Agreement No. 623155. We
thank technician Ms. J. Dudine for her experimental assistance.
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