Synthesis of enantiomerically pure 2,3,4,6-tetrasubstituted tetrahydropyrans by Prins-type cyclization of methyl ricinoleate and aldehydes

Article abstract of DOI:10.1002/ejoc.200500701

The AlCl₃-catalyzed Prins-type cyclization of methyl ricinoleate (1), an enantiomerically pure renewable compound, with aldehydes such as heptanal (2a), isobutyraldehyde (2b), pivaldehyde (2c) and benzaldehyde (2d) is a simple reaction for the diastereoselective synthesis of enantiomerically pure 2,3,6-trialkyl-substituted 4-chlorotetrahydropyrans. The respective 4-hydroxytetrahydropyrans are obtained e.g. with aldehydes 2a and 2d using montmorillonite KSF/O as the catalyst. Wiley-VCH Verlag GmbH & Co. KGaA, 2006.

Full text of DOI:10.1002/ejoc.200500701

FULL PAPER
DOI: 10.1002/ejoc.200500701
Synthesis of Enantiomerically Pure 2,3,4,6-Tetrasubstituted Tetrahydropyrans
by Prins-Type Cyclization of Methyl Ricinoleate and Aldehydes
Ursula Biermann,[a] Arne Lützen,[a] and Jürgen O. Metzger*[a]
Dedicated to Professor Marcel S. F. Lie Ken Jie on the occasion of his 65th birthday
Keywords: Aldehydes / Chiral pool / Cyclization / Diastereoselectivity / Renewable feedstocks / Tetrahydropyrans
The AlCl3-catalyzed Prins-type cyclization of methyl ricinole-
ate (1), an enantiomerically pure renewable compound, with
aldehydes such as heptanal (2a), isobutyraldehyde (2b), piv-
aldehyde (2c) and benzaldehyde (2d) is a simple reaction for
the diastereoselective synthesis of enantiomerically pure
2,3,6-trialkyl-substituted 4-chlorotetrahydropyrans. The re-
spective 4-hydroxytetrahydropyrans are obtained e.g. with
aldehydes 2a and 2d using montmorillonite KSF/O as the cat-
alyst.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2006)
co-workers found that the intermediates of the Prins cycli-
zation pathway could be trapped with carbon based nucleo-
philes such as allylTMS, TMSCN and AlMe3.[11]
Introduction
Tetrahydropyrans are important compounds that occur
as building blocks in many biologically active natural prod-
ucts.[1] Thus, considerable efforts have been made to develop
reliable synthetic procedures to establish these heterocycles.
One of them, the reaction of homoallylic alcohols and alde-
hydes under strongly acidic conditions, was found 50 years
ago and is known as the Prins cyclization giving rise to
alkyl-substituted tetrahydropyran derivatives.[2] Since then
a number of modifications were published that either varied
the substrates or made use of a broad spectrum of Brønsted
acids and Lewis acids as promoters.[3]
However nowadays, the issue of stereoselective synthesis
of highly functionalized tetrahydropyrans is becoming more
and more important. The reaction of homoallylic alcohols
containing an ω-double bond with aldehydes[3k,3l,4,5] as well
as the reaction of suitable derivatives of homoallylic
alcohols such as enol ethers[6] and α-acetoxy ethers,[7–9]
gives – with high diastereoselectivity – all-cis-2,6-dialkylsub-
stituted tetrahydropyrans carrying heteroatom substituents
at C-4 such as halide or acetate depending on the acid used.
In these cases all three substituents can be found in equato-
rial positions. This formation of 2,4,6-trisubstituted tetra-
hydropyrans can be rationalized by assuming a chair-like
transition state to give the all-cis-configured products.[8]
The formation of the cyclization products via delocalized
cationic intermediates is discussed by Alder.[10] Barry and
Reacting homoallylic alcohols containing an internal
double bond with formaldehyde gave 2,4,5-trisubstituted
tetrahydropyrans with the creation of two new stereocenters
with excellent stereocontrol.[12] The respective products
were obtained reacting homoallylic acetals of formaldehyde
under acidic conditions.[13] Reaction of higher aldehydes
with homoallylic alcohols with an internal double bond
gave 2,3,4,6-tetrasubstituted tetrahydropyrans with remark-
able diastereoselectivity forming three new stereocentres,
e.g. the reaction of such a homoallylic alcohol with alde-
hydes in the presence of TFA affords 2,3,6-trialkyl-4-hy-
droxyterahydropyrans.[14] Interestingly, when using (Z)-
homoallylic alcohols as substrates the all-cis-substituted
tetrahydropyran with the substituent at C-3 in axial posi-
tion was obtained. In contrast, the (E)-isomer stereoselec-
tively yielded the product with all four substituents in the
equatorial position. The respective stereochemical outcome
was reported for the acid catalyzed cyclization of homoal-
lylic α-acetoxy ethers.[15] Enantiomerically pure homoallyic
alcohols can give enantiomerically pure tetrahydropyrans
with the retention of the stereogenic center.[14,16] This po-
tential was used recently by Barry et al. for the stereoselec-
tive synthesis of the tetrahydropyran core of polycaverno-
side A, a naturally occurring toxin bearing its substituents
in equatorial positions at C-2, C-4 and C-6 and in the axial
position at C-3.[17] Epimerization via the oxonia-Cope re-
arrangement was also reported.[8,10] Quite recently Jasti et
al. discussed in detail when retention and epimerization of
the stereochemistry of the homoallylic alcohol will be ob-
[a] Institute of Pure and Applied Chemistry, University of
Oldenburg,
Carl von Ossietzky Strasse 9–11, 26111 Oldenburg, Germany
E-mail: juergen.metzger@uni-oldenburg.de
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U. Biermann, A. Lützen, J. O. Metzger
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served.[18] The oxonia-Cope rearrangement was shown to Table 1. AlCl3-catalyzed Prins-type cyclizations of methyl ricinole-
ate (1) with heptanal (2a), isobutyraldehyde (2b), pivaldehyde (2c)
and benzaldehyde (2d).
occur rapidly under typical Prins cyclization conditions
when the oxocarbenium ion resulting from the rearrange-
ment is similar to or lower in energy than the starting oxo-
carbenium ion. Oxonia-Cope rearrangements can be disfa-
vored by destabilizing the resultant oxocarbenium ion or by
stabilizing an intermediate tetrahydropyranyl cation.
Methyl ricinoleate [methyl (9Z,12R)-12-hydroxy-9-octa-
decenoate] is an enantiomerically pure homoallylic alcohol
from the chiral pool. It is commercially available and can
easily be obtained in high purity by transesterification from
castor oil which is a renewable raw material. It is of increas-
ing importance as an enantiomerically pure building block
in organic synthesis.[19]
We previously reported the aluminium chloride induced
addition of formaldehyde to alkenes via homoallylic
alcohols as a simple route to alkyl-substituted tetra-
hydropyrans.[12] The respective reaction of methyl ricinole-
ate (1) gave the corresponding 2,5-dialkyl-4-chlorotetra-
hydropyran as a mixture of two diastereomers (ratio: 3.8:1)
in 61% yield. In this paper, we report the diastereoselective
Prins-type cyclizations of 1 with higher aldehydes, such as
heptanal and benzaldehyde in the presence of AlCl3 or
montmorillonite KSF/O, yielding enantiomerically pure
2,3,4,6-tetrasubstituted tetrahydropyrans.
Results
We studied the AlCl3-induced reaction of methyl ricin-
oleate (1), a homoallylic alcohol with a cis-configured
double bond, with various aldehydes such as heptanal (2a),
isobutyraldehyde (2b), pivaldehyde (2c) and benzaldehyde
(2d) yielding the respective 2,3,6-trialkyl-substituted 4-chlo-
rotetrahydroyrans 3a–d (Table 1). The stereochemistry of [a] Isolated yields were obtained by column chromatography (see
Exp. Sect.). [b] Inversion of the absolute configuration at C2 in
the major products, which were obtained with high dia-
comparison to 3a, b because of priority rules.
stereoselectivity, was assigned by analysis of 1H NMR
coupling constants and by NOE measurements.
The reaction of the homoallylic alcohol 1 and aldehyde
2a gave the 4-chlorotetrahydropyran derivative 3a, after a tiomerically pure all-cis-(2R,3R,4S,6R)-3d as the main
reaction time of 3 h at room temperature, as a mixture of product together with small amounts of a minor dia-
three diastereomers (ratio: 86:9:5) with an isolated yield of stereomer (Table 1, entry 4).
76% (Table 1, entry 1). The main diastereomer was sepa-
In each of the described reactions (Table 1, entries 1, 2
rated by column chromatography and identified as the all- and 4), besides the main diastereomer which was separated
cis compound (2S,3R,4S,6R)-3a. The compound was op- by column chromatography, a second diastereomer could
tically active and showed a specific rotation of [α]2D0 = –22.5 be identified by its H and 13C NMR spectroscopic data.
1
(c = 3.1, CHCl3).
However, the assignments were made from spectra obtained
The reaction protocol was expected to be a simple from mixtures with the respective major products of 3a, 3b
method for the synthesis of a great variety of highly func- and 3d. In all cases the side products had all four substitu-
tionalized 4-chloro-tetrahydropyrans by variation of the al- ents in equatorial positions.
dehyde 2. Isobutyraldehyde (2b) was treated with methyl ri-
The reaction of 1 and pivaldehyde (2c) with AlCl3 pro-
cinoleate (1) giving product 3b as a mixture of dia- ceeded with the formation of tetrahydropyran 3c (Table 1,
stereomers in a ratio of 96:2:2. (Table 1, entry 2) The stereo- entry 3). The product was isolated in 77% yield as a mixture
chemistry of the main diastereomer, obtained by column of four diastereomers in a ratio of 60:27:9:4. The dia-
chromatography, was clearly identified as (2S,3R,4S,6R)-3b stereomers were distinguishable by GC-MS and two of
by NMR spectroscopy.
them were obtained by column chromatography with 91%
The AlCl3-induced cyclization of 1 and benzaldehyde and 55% enrichment (GC), respectively. The main com-
(2d) proceeded highly diastereoselectively yielding the enan- pound was the all-equatorial product (2R,3S,4S,6R)-3c.
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Enantiomerically Pure 2,3,4,6-Tetrasubstituted Tetrahydropyrans
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The all-cis compound (2R,3R,4S,6R)-3c was obtained as a
side product in 27% yield.
It has to be pointed out that the synthesis of the racemic
trialkyl-substituted 4-chlorotetrahydropyran 3a was pos-
sible with methyl 10-undecenoate (4) as the starting mate-
rial. Reaction of 4 with two equivalents of heptanal (2a)
catalyzed by AlCl3 after a reaction time of 3 h gave product
3a in 62% yield (Figure 1). The product was formed by re-
gioselective cyclization as a racemic mixture of two dia-
stereomers (ratio: 2.6:1) with the all-equatorial substituted
compound rel-(2S,3S,4S,6R)-3a as the main product.
Figure 2. Prins-type cyclization of methyl ricinoleate (1) with hep-
tanal (2a) and benzaldehyde (2d) to give diastereomeric mixtures
of 2,3,6-trialkyl-substituted 4-hydroxytetrahydropyrans 5a and 5d,
respectively, in the presence of montmorillonite clay KSF/O. Ratio
of diastereomers: (2S,3S,4S,6R)-5a: (2S,3R,4S,6R)-5a = 73:27;
(2R,3S,4S,6R)-5d: (2R,3R,4S,6R)-5d = 85:10. Inversion of the ab-
solute configuration at C3 in comparison to 3a,d because of pri-
ority rules.
chloride. HPLC analysis of both products showed one sin-
gle peak giving additional evidence that the tetrahydropy-
ranols were enantiomerically pure compounds.
Figure 1. AlCl3-induced Prins-type cyclization of methyl 10-unde-
cenoate (4) with heptanal (2a) to give a diastereomeric mixture of
rel-(2S,3S,4S,6R)-3a and rel-(2S,3R,4S,6R)-3a in a ratio of 2.6:1.
In contrast to the reaction of methyl ricinoleate (1) with 2a a race-
mic mixture of each diastereomer was obtained which is indicated
by the used nomenclature of relative stereochemistry.
Discussion
The AlCl3-induced reaction of methyl ricinoleate (1) and
aldehydes 2a, 2b and 2d yielded the respective 2,3,4,6-tet-
raalkyl-substituted tetrahydropyran derivatives 3a, 3b and
2,3,6-Trialkyl-4-hydroxytetrahydropyran 5a was obtained 3d as mixtures of diastereomers. A high diastereoselectivity
on reaction of methyl ricinoleate (1) and heptanal (2a) pro- was observed (Table 1, entries 1, 2 and 4). Comparable to
moted by montmorillonite KSF/O (Figure 2). The cycliza- numerous examples in the literature[4,5] the major products
tion was performed by heating the reaction mixture for 24 h of all three reactions show the substituents at C-2, C-4 and
in refluxing dichloromethane to give product 5a in 61% C-6 in equatorial positions. The axial orientation for the
1
yield as a mixture of two diastereomers in a ratio of 73:27. substituent at C-3 was clearly shown by the respective H
The all-cis diastereomer (2S,3S,4S,6R)-5a was the main and NMR spectroscopic data and by NOE studies.
(2S,3R,4S,6R)-5a the minor product. Under the same reac-
The stereochemical outcome of the AlCl3-induced Prins-
tion conditions, in the presence of montmorillonite clay type cyclization can be rationalized through a chairlike
KSF/O, 1 was treated with benzaldehyde (2d) affording transition state to give predominantly the all-cis products.
product 5d, however, only in 45% yield. The mixture of In the first step of the reaction the aldehyde-AlCl3 complex
three diastereomers in a ratio of 85:10:5 contained the en- 7 is formed and is trapped by the nucleophilic attack of the
antiomerically pure all-cis diastereomer as the main com- oxygen of the alcohol function giving, via the adduct 8,
pound. The stereochemistry of (2R,3S,4S,6R)-5d was as- oxocarbenium ion 8a as the intermediate (Scheme 1). The
1
signed by analysis of the H NMR coupling constants and alkyl group R3 of the aldehyde 2 demands the less hindered
by comparison of the 1H NMR spectroscopic data with position, in the preferred chairlike conformation of the re-
those of compound (2S,3S,4S,6R)-5a. The minor dia- gioselective electrophilic six-ring closure to position C-9 of
stereomer was (2S,3R,4S,6R)-5d.
ricinoleate 1, giving the cyclic carbenium ion 9. This is fol-
All tetrahydropyrans 3 and 5 derived from methyl lowed by the subsequent transfer of a chloride ion to posi-
ricinoleate 1 were optically active. To prove the enantio- tion C-10. The major product is obtained as the all-cis com-
meric purity we studied the 1H NMR spectra of tetra- pound, as shown in Scheme 1, with equatorial C-2, C-4 and
hydropyranols (2S,3S,4S,6R)-5a and (2R,3S,4S,6R)-5d by C-6 and axial C-3 positions. The stereochemistry of the
addition of tris[3-(trifluoromethyl-hydroxymethylene)-- main products obtained from reactions of the (Z)-homoal-
camphorato]europium() as a chiral shift reagent. For ex- lylic alcohol 1 and aldehydes 2a, 2b, and 2d, respectively, is
ample, the signal of H-4 was shifted downfield by 4 ppm, in agreement with those of Barry et al.[14] who obtained the
however, no splitting was observed. In addition, we esteri- respective tetrasubstituted tetrahydropyrans with the C-3-
fied both tetrahydropyranols with (1S)-(–)-camphanoyl substituent in axial position from Lewis acid mediated cy-
Eur. J. Org. Chem. 2006, 2631–2637
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U. Biermann, A. Lützen, J. O. Metzger
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Scheme 1. Mechanism of the AlCl3-catalyzed Prins-type cyclization of methyl ricinoleate (1) and heptanal (2a), isobutyraldehyde (2b)
and benzaldehyde (2d).
clizations of (Z)-homoallylic alcohols with aldehydes, while
using (E)-homoallylic alcohols as starting materials gave the
respective equatorial orientation.
We also performed the synthesis of 2,3,4,6-tetrasubsti-
tuted tetrahydropyrans in the presence of AlCl3 using sim-
ple alkenes such as methyl 10-undecenoate (4) as substrates.
However, in this case two equivalents of the aldehyde are
necessary to perform the cyclization reaction. The respec-
tive reaction of 4 and heptanal (2a) proceeds in two steps
(Figure 3). Induced by AlCl3 one equivalent of 2a reacts
with the C,C double bond of 4 in an ene reaction to give
the respective homoallylic alcohol 10. The ene adduct is
formed as a mixture of the (E)- and (Z)-isomers, with the
(E)-isomer as the major compound.[20,21] Addition of a sec-
ond equivalent of 2a to the ene adduct 10 gives the racemic
mixtures of the diastereomeric tetrahydropyrans 3a with rel-
(2S,3S,4S,6R)-3a as main product. In agreement with the
literature[8,15] it can be assumed that the formation of the
main diastereomer, with the equatorial substituent in 3-po-
sition, results from the reaction of the (E)-isomer of the
Figure 3. AlCl3-catalyzed cyclization of methyl 10-undecenoate (4)
and heptanal (2a).
ene adduct-intermediate, while the minor diastereomer rel- of 1 with 2a, 2b and 2d (Table 1, entries 1, 2 and 4), how-
(2S,3R,4S,6R)-3a with the axial substituent in 3-position is ever, in the case of tetrahydropyran 3b the respective dia-
formed by the reaction of the (Z)-isomer with 2a. The out- stereomer was observed only in traces of 2% (GC). The
come of this reaction supports the results of the AlCl3-in- formation of the all-equatorial compounds in cyclization re-
duced cyclizations of methyl ricinoleate (1) and aldehydes actions with (Z)-alkenes as starting materials is assumed by
2a, 2b and 2d to give the main diastereomers with the axial Rychnovsky and co-workers[15] to arise from small amounts
position at C-3.
of the respective (E)-alkene which can be already present as
While cyclizations of 1 with aldehydes 2a and 2d showed an impurity, formed by isomerization of the (Z)-alkene or
comparable results concerning the ratios of diastereomers by assuming a competing boat-like transition state in the
(Table 1, entries 1 and 4) the reaction of 1 with isobutyral- cyclization.
dehyde 2b showed a remarkably higher diastereoselectivity
Rychnovsky and co-workers concluded that the C-2-sus-
with a ratio of diastereomers of 96:2:2.The predominant tituent with the equatorial orientation in the incipient tetra-
formation of (2S,3R,4S,6R)-3b is probably due to steric ef- hydropyran ring influences the stereochemical outcome of
fects of the bulky isopropyl group.
the newly generated stereogenic centres.[8] This is in agree-
The minor diastereomers containing all substituents in ment with our results. AlCl3-induced cyclizations of 1 with
equatorial orientation were obtained by all three reactions higher aldehydes such as 2a, 2b and 2d proceed by creation
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Enantiomerically Pure 2,3,4,6-Tetrasubstituted Tetrahydropyrans
FULL PAPER
of three new stereogenic centres at C-2, C-3, and C-4 to 5d as the main compounds. It has been shown that these
give the respective 2,3,6-trialkyl-substituted 4-chlorotetra- compounds are enantiomerically pure. Thus, an oxonia-
hydropyrans, mainly with the axial position of the substitu- Cope rearrangement was not observed and is not expected
ent at C-3 (Table 1, entries 1, 2 and 4). However, the corre- in the systems studied.[15] The tetrahydropyranyl cation 9
sponding reaction of 1 with formaldehyde, which gives two (Scheme 2) will not be able to open to form the rearranged
new asymmetric centers at C-4 and C-5 (these positions cation 11 because 11 is higher in energy than 9 and much
correspond to positions C-4 and C-3 in compounds 2a–2d), higher in energy than cation 8.
takes place by formation of the respective 2,5-dialkyl-sub-
stituted 4-chlorotetrahydropyran with the substituent at C-
5 located in an equatorial orientation in the major prod-
Conclusion
uct.[12]
AlCl3-catalyzed Prins-type cyclizations of methyl ricin-
oleate and aldehydes give 2,3,6-trialkyl-substituted 4-chlo-
rotetrahydropyrans in good yields. The reactions with hep-
tanal, isobutyraldehyde and benzaldehyde proceed with
high diastereoselectivity without epimerization and yield
the enantiomerically pure all-cis products as the main com-
pounds. An exception is pivaldehyde giving the all-equato-
rial diastereomer as main product. 2,3,6-Trialkylsubstituted
With a ratio of diastereomers of 60:27:9:4 of product 3c
the reaction of 1 and pivaldehyde (2c) (Table 1, entry 3)
showed considerably less diastereoselectivity compared to
the corresponding cyclizations with aldehydes 2a, 2b and
2d. It is remarkable that the reaction of (Z)-homoallylic
alcohol 1 and 2c yielded the all-equatorial diastereomer as
the major product. This result shows that the stereochemis-
try of substituted cyclic products obtained by Prins cycliza-
4-hydroxytetrahydropyrans can be synthesized using the en-
tion reactions is not only influenced by the stereochemistry
vironmentally benign catalyst montmorillonite KSF/O to
give diastereoselectively and the enantiomerically pure all-
cis products.
of the homoallylic alcohol used as starting material, but
also by the structure of the reacting aldehyde. Possibly, in
this case the cyclization does not occur through a chair-like
transition intermediate as a consequence of steric factors
caused by the tert-butyl group. Maybe the boat-like transi-
tion state is preferred to give the all-equatorial diastereomer
as the major product.
Experimental Section
General: Methyl ricinoleate (93% purity) was obtained from Co-
gnis, Düsseldorf or by transesterification with methanol from cas-
tor oil. The amount of the starting olefin used in the reactions
was calculated based on 100% purity. Methyl 10-undecenoate was
obtained from Atochem and (1S)-(–)-camphanoyl chloride, tris[3-
(trifluoromethylhydroxymethylene)--camphorato]europium-
() and AlCl3 were obtained from Fluka and KSF/O from Süd-
Chemie, München, Germany. Heptanal, isobutyraldehyde and piv-
aldehyde (Aldrich) were used without further purification. Benzal-
dehyde was freshly distilled. For column chromatography Merck
60 silica gel, 70–230 mesh, was used.
The synthesis of highly functionalized tetrahydropyrans
in the presence of heterogeneous catalysts is of interest.
These compounds show considerable advantages compared
to homogeneous catalysts especially because of their envi-
ronmental compatibility, their reusability, low cost and sim-
ple removal from the reaction mixture by filtration or cen-
trifugation. It is known that in the presence of montmoril-
lonite clay KSF[4] or Amberlyst-15[5] homoallylic alcohols
with a terminal C=C bond give, on reaction with aldehydes,
the respective 2,6-dialkyl-substituted 4-hydroxytetra-
hydropyrans. Mediated by montmorillonite KSF/O methyl
ricinoleate (1), a homoallylic alcohol with an internal
double bond, reacts with one equivalent of aldehydes 2a
and 2d to give the 2,3,6-trialkyl-substituted 4-hydroxytetra-
hydropyrans 5a and 5d, respectively (Figure 2). However,
the clay promoted cyclizations showed a considerably lower
diastereoselectivity compared to the corresponding AlCl3-
catalyzed reactions. As expected, the clay catalyzed cycliza-
tions of (Z)-homoallylic alcohol (1) yielded, in analogy to
the AlCl3-induced reactions (Table 1, entries 1 and 4), the
all-cis diastereomers (2S,3S,4S,6R)-5a and (2R,3S,4S,6R)-
Analytical Equipment: Analytical GC was performed using a
Carlo–Erba GC series 4160 with an FID detector and fused silica
capillary column DB1, 29 m. Analytical HPLC was performed
using a Hitachi L-6250 (Merck) using a silica gel column (Si 60,
5 µm, LiChro 250–4, Merck) and detector RI-71 (Merck). 1H
NMR and 13C NMR spectra were recorded in CDCl3 using a
Bruker DRX 500 spectrometer at 300 K using residual non-deuter-
ated solvent (1H NMR) or CDCl3 (δ = 77.0 ppm, 13C NMR) as
internal standards. Assignment of the signals was carried out on
the basis of 1H, 13C, H,H-COSY, HMQC, HMBC and sel-1D-
NOESY spectra. Mass spectra were recorded using a Finnigan
MAT 95. All products were unambiguously identified by 1H NMR
and 13C NMR and by MS (EI) or GC/MS (EI). Specific rotations
[α]2D0 were recorded using a Perkin–Elmer polarimeter 343. Elemen-
tal analyses were performed by Mikroanalytisches Labor Beller,
37004 Göttingen, Germany.
Procedure 1: General Procedure for the Synthesis of 2,3,6-Trialkyl-
Substituted 4-Chlorotetrahydropyrans 3 with Methyl Ricinoleate (1):
A mixture of methyl ricinoleate (1) (5 mmol, 1.56 g) and the respec-
tive aldehyde 2a–d (5 mmol) in CH2Cl2 (10 mL) was stirred mag-
netically for 15 min at –15 °C. After addition of AlCl3 (2.5 mmol,
0.33 g) the sample was stirred for an additional 10 min at –15 °C,
then warmed up and stirred for an additional 3 h at room tempera-
Scheme 2. Oxonia-Cope rearrangement of oxocarbeniumion 8a
was not observed and is not expected because cation 11 is higher
in energy than cations 9 and 8a.[15]
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U. Biermann, A. Lützen, J. O. Metzger
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ture. The reaction was quenched by addition of petroleum ether
(%) = 403 (100)/405 (32) [MH+], 367 (2) [MH+ – HCl]. C23H43ClO3
60/80 (80 mL) and H2O (40 mL). 10% HCl was added until the (403.05): calcd. C 68.54, H 10.75; found C 68.60, H 10.70.
precipitated aluminium salts had dissolved. The organic layer was
2-tert-Butyl-4-chloro-6-hexyl-3-(7-methoxycarbonylheptyl)tetra-
separated, washed with H2O (4 × 30 mL) and dried with Na2SO4.
hydropyran (3c): Mixture of diastereomers (ratio: 60:27:9:4, GC),
After filtration the solvent was removed in vacuo. Purification was
yield: 1.6 g (77 %). The main diasteromers (2R,3S,4S,6R)-(–)-3c
and (2R,3R,4S,6R)-(–)-3c were obtained by column chromatog-
achieved by kugelrohr distillation or column chromatography [sil-
ica gel using petroleum ether/diethyl ether (8:2) as eluent]. Frac-
raphy with 91% and 55% enrichment (GC), respectively.
tions containing the tetrahydropyrans were collected, the solvent
1
(2R,3S,4S,6R)-(–)-3c: H NMR (500.1 MHz): δ = 3.92–3.80 (m, 2
was removed in vacuo and the residue was dried at 20 °C/
0.01 mbar.
H), 3.65 (s, 3 H), 3.54 (d, J = 3.8 Hz, 1 H), 2.40 (m, 1 H), 2.29 (t,
J = 6.4 Hz, 2 H), 1.95 (m, 1 H), 1.80 (m, 1 H), 1.67–1.55 (m, 5 H),
1.50 (m, 1 H), 1.45–1.23 (m, 16 H), 0.87 (s, 9 H), 0.86 (t, J = 6.6 Hz,
Procedure 2: General Procedure for the Synthesis of 2,3,6-Trialkyl-
3 H) ppm. 13C NMR (125.8 MHz): δ = 174.2, 89.2, 79.3, 67.0, 51.4,
47.8, 35.9, 35.9, 34.8, 34.5, 34.0, 31.8, 29.5, 29.1, 29.0, 28.9, 26.8,
26.3, 25.9, 24.9, 22.6, 14.0 ppm. MS/CI (isobutane): m/z (%): 417
(100)/419 (33) [MH+], 381 (1) [MH+ – HCl]. C24H45ClO3 (417.07):
calcd. C 69.12, H 10.88; found C 68.99, H 10.87.
(2R,3R,4S,6R)-(–)-3c: 1H NMR (500.1 MHz): δ = 4.11 (ddd, J =
12.1, 4.4, 4.1 Hz, 1 H), 3.64 (m, 1 H), 3.64 (s, 3 H), 2.28 (t, J =
7.4 Hz, 2 H), 2.00 (m, 1 H), 1.85 (m, 1 H), 1.77 (m, 1 H), 1.67–
1.55 (m, 5 H), 1.50–1.20 (m, 16 H), 0.93 (s, 9 H), 0.86 (t, J = 7.4 Hz,
3 H) ppm. 13C NMR (125.8 MHz): δ = 174.2, 88.1, 77.9, 64.4, 51.4,
43.0, 38.1, 35.8, 35.2, 34.0, 31.8, 31.3, 29.1, 29.1, 29.0, 27.3, 25.5,
24.9, 23.5, 22.6, 14.0 ppm. MS/CI (isobutene): m/z (%): 417 (100)/
419 (32) [MH+], 381 (4) [MH+ – HCl].
Substituted 4-Hydroxytetrahydropyrans 5: A mixture of methyl ri-
cinoleate (1) (5 mmol, 1.56 g), heptanal (2a, 5 mmol, 0.57 g) or
benzaldehyde (2d, 8 mmol, 0.84 g) and KSF/O (2 g) in CH2Cl2
(10 mL) was refluxed for 24 h. The catalyst was removed by fil-
tration and washed with CH2Cl2 (4 × 10 mL). The solvent from
the combined organic layers was evaporated in vacuo. Purification
of the products was achieved by column chromatography as de-
scribed in procedure 1.
4-Chloro-2,6-dihexyl-5-(7-methoxycarbonylheptyl)tetrahydropyran
(3a): Mixture of diastereomers (ratio: 86:9:5), yield: 1.7 g (76%).
(2S,3R,4S,6R)-(–)-3a was obtained by column chromatography
(GC), [α]2D0 = –22.5 (c = 3.1, CHCl3). H NMR (500.1 MHz): δ =
1
4.14 (ddd, J = 12.6, 4.4, 4.4 Hz, 1 H), 3.62 (s, 3 H), 3.21 (m, 2 H),
2.26 (t, J = 7.4 Hz, 2 H), 1.77 (m, 1 H), 1.65–1.50 (m, 3 H), 1.44–
1.20 (m, 31 H), 0.84 (2 t, J = 6.6, 6.8 Hz, 6 H) ppm. 13C NMR
(125.8 MHz): δ = 174.3, 80.7, 77.5, 62.8, 51.4, 45.3, 38.0, 35.8, 34.1,
33.3, 31.8, 31.8, 31.5, 29.7, 29.2, 29.2, 29.1, 29.0, 26.3, 25.5, 24.9,
23.2, 22.6, 14.0 ppm. GC/MS (EI): m/z (%) = 408 (1), 359 (40)/361
(13), 323 (100), 294 (24), 291 (23), 263 (25). C26H49ClO3 (445.13):
calcd. C 70.16, H 11.10; found C 70.20, H 10.94.
4-Chloro-6-hexyl-3-(7-methoxycarbonylheptyl)-2-phenyltetrahydro-
pyran (3d): Mixture of diastereomers (ratio: 95:5), yield: 1.6 g
(73%). (2R,3R,4S,6R)-(+)-3d was obtained by column chromatog-
raphy with 90% enrichment (GC). 1H NMR (300.1 MHz): δ = 7.34
(m, 4 H), 7.26 (m, 1 H), 4.55 (m, 1 H), 4.44 (ddd, J = 12.4, 4.5,
4.1 Hz, 1 H), 3.68 (s, 3 H), 3.48 (m, 1 H), 2.25 (t, J = 7.5 Hz, 2 H),
2.06 (m, 1 H), 1.93 (m, 1 H), 1.71 (m, 2 H), 1.60–1.46 (m, 5 H),
1.40–1.27 (m, 10 H), 1.15–0.97 (m, 5 H), 0.91 (m, 4 H) ppm. 13C
NMR (75.5 MHz): δ = 174.2, 140.7, 128.3, 127.9, 127.4, 126.8,
125.3, 80.4, 77.4, 62.4, 51.3, 47.2, 37.4, 35.7, 34.0, 31.7, 30.1, 29.3,
29.1, 28.9, 28.8, 28.5, 25.3, 24.8, 22.6, 22.5, 14.0 ppm. MS (EI):
m/z (%) = 436 (10)/438 (3) [M+], 400 (39), 351 (20)/353 (6), 295
(100), 263 (58). C26H41ClO3 (437.06): calcd. C 71.45, H 9.46; found
C 71.52, H 9.37.
A mixture of racemic rel-(2S,3S,4S,6R)-3a and racemic rel-
(2S,3R,4S,6R)-3a (ratio: 2.6:1, GC) was obtained on reaction of
methyl 10-undecenoate (4) with heptanal (2a): yield: 1.4 g (62%).
A mixture of heptanal (2a) (10 mmol, 1.14 g) and AlCl3 (7.5 mmol,
1.0 g) in CH2Cl2 (10 mL) was stirred magnetically for 15 min at
–15 °C. After the dropwise addition (over 1 h) of methyl 10-unde-
cenoate (4) (5 mmol, 1 g) the sample was stirred for an additional
10 min at –15 °C, then warmed up and stirred for an additional 3 h
at room temperature. The work-up of the sample and the isolation
of the product by column chromatography were performed as de-
scribed in the general procedure 1. The diasteromeric mixture of
racemic 3a was separated by HPLC with hexane/acetic acetate
2,6-Dihexyl-4-hydroxy-3-(7-methoxycarbonylheptyl)tetrahydropyran
(5a): Mixture of diastereomers (ratio: 2.7: 1, 13C NMR), yield: 1.3 g
(61%). (2S,3S,4S,6R)-(–)-5a was obtained with 90% enrichment
(GC) by column chromatography: 1H NMR (500.1 MHz): δ = 3.80
(ddd, J = 11.7, 4.5, 4.4 Hz, 1 H), 3.63 (s, 3 H), 3.15 (m, 2 H), 2.26
(t, J = 7.6 Hz, 2 H), 1.61–1.45 (m, 5 H), 1.44–1.20 (m, 31 H), 0.84
(m, 6 H) ppm. 13C NMR (125.8 MHz): δ = 79.5, 76.2, 72.2, 51.4,
44.7, 36.3, 36.0, 34.0, 33.0, 31.8, 31.4, 29.3, 29.2, 29.1, 29.1, 26.4,
25.6, 24.9, 22.6, 21.9, 14.0 ppm. MS/CI (isobutene): m/z (%): 409
(5) [MH+ – HCl]. C26H50O4 (426.68): calcd. C 73.19, H 11.81;
found C 73.20, H 11.75.
1
(95:5) as eluent. rel-(2S,3S,4S,6R)-3a: HNMR (CDCl3): δ = 3.88
(ddd, J = 11.4, 11.2, 4.4 Hz, 1 H), 3.64 (s, 3 H), 3.19 (m, 1 H), 3.06
(ddd, J = 9.3, 9.3, 1.6 Hz, 1 H), 2.28 (t, J = 7.5 Hz, 2 H), 2.13
(ddd, J = 11.4, 9.4, 4.4 Hz, 1 H), 1.60 (m, 5 H), 1.49 (m, 2 H), 1.39
(m, 6 H), 1.27 (m, 21 H), 0.86 (m, 6 H) ppm. 13 C NMR
(125.8 MHz): δ = 174.2, 79.6, 76.4, 62.1, 51.4, 49.2, 43.5, 35.8, 34.1,
33.1, 31.9, 31.6, 30.0, 29.5, 29.4, 29.2, 29.1, 29.0, 28.0, 25.5, 25.3,
25.0, 22.6, 22.5, 14.1, 14.0 ppm.
(2S,3S,4S,6R)-5a was treated with the shift reagent tris[3-(trifluoro-
methylhydroxymethylene)--camphorato]europium() as de-
scribed in ref.[22] The 1H NMR (500.1 MHz) spectra showed signifi-
cant shifts of the relevant hydrogen atoms but without any splitting
of the signals.
4-Chloro-6-hexyl-2-isopropyl-3-(7-methoxycarbonylheptyl)tetra-
hydropyran (3b): Mixture of diastereomers (ratio: 96:2:2), yield:
1.5 g (70 %). (2S,3R,4S,6R)-(–)-3b was obtained by column
chromatography (GC). [α]2D1 = –30.7 (c = 3.2, CHCl3). 1H NMR
(500.1 MHz): δ = 4.12 (ddd, J = 12.4, 4.4, 4.4 Hz, 1 H), 3.63 (s, 3
H), 3.17 (m, 1 H), 2.69 (d, 9.9 Hz, 1 H), 2.26 (t, J = 7.4 Hz, 2 H),
1.91 (m, 1 H), 1.79–1.73 (m, 2 H), 1.60–1.55 (m, 3 H), 1.53–1.23
(m, 20 H), 0.95 (d, J = 6.6 Hz, 3 H), 0.84 (d, J = 6.6 Hz, 3 H), 0.82
(t, J = 6.6 Hz, 3 H) ppm. 13C NMR (125.8 MHz): δ = 174.2, 87.0,
77.6, 63.1, 51.3, 42.6, 38.0, 35.8, 34.0, 31.8, 31.1, 29.9, 29.8, 29.1,
29.0, 25.5, 24.9, 22.6, 20.1, 19.0, 14.0 ppm. MS/CI (isobutane): m/z
(2S,3S,4S,6R)-5a was treated with (1S)-(–)-camphanyl chloride as
described in the literature.[23] The camphanoyl derivative was ana-
lyzed by HPLC using hexane/ethyl acetate (8.5:1.5) as the eluent.
The chromatogram showed one single peak confirming the enan-
tiomerical purity of the compound.
6-Hexyl-4-hydroxy-3-(7-methoxycarbonylheptyl)-2-phenyltetra-
hydropyran (5d): Mixture of diastereomers (ratio: 85:10:5), yield:
2636
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© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2006, 2631–2637

Enantiomerically Pure 2,3,4,6-Tetrasubstituted Tetrahydropyrans
FULL PAPER
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richment (GC) by column chromatography: 1H NMR
(300.1 MHz): δ = 7.23 (m, 4 H), 7.13 (m, 1 H), 4.39 (d, J = 1.9 Hz,
1 H), 4.01 (ddd, J = 12.1, 4.9, 4.5 Hz, 1 H), 3.58 (s, 3 H), 3.37 (m
1 H), 2.25 (m, 1 H), 2.15 (t, J = 7.5 Hz, 2 H), 1.88 (m, 1 H), 1.60
(m, 2 H), 1.42 (m, 5 H), 1.30–1.12 (m, 11 H), 1.04–0.88 (m, 5 H),
0.81 (m, 4 H) ppm. 13C NMR (75.5 MHz): δ = 174.3, 141.4, 128.3,
127.9, 127.6, 126.5, 125.4, 79.5, 76.1, 72.2, 51.4, 46.7, 36.0, 35.8,
34.0, 31.8, 30.2, 29.4, 29.4, 29.1, 28.6, 25.4, 24.8, 22.6, 21.3, 14.1
ppm. MS (EI): m/z (%) = 418 (2) [M+], 400 (26), 243 (18), 198 (26),
166 (20), 107 (100). C26H42O4 (418.62): calcd. C 74.60, H 10.11;
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Received: September 15, 2005
Published Online: March 22, 2006
Eur. J. Org. Chem. 2006, 2631–2637
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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