On the choice of Lewis acids for the Prins reaction; two total syntheses of (±)-Civet

Article abstract of DOI:10.1016/j.tet.2011.05.019

While developing new variations of the Prins cyclisation reaction, the effect of the choice of Lewis acid on the outcome of the reaction and the product(s) has been investigated, yielding hitherto unseen dihydropyran products in the Prins cyclisation reac

Full text of DOI:10.1016/j.tet.2011.05.019

Tetrahedron 67 (2011) 5107e5124
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
On the choice of Lewis acids for the Prins reaction; two total syntheses
of (ꢀ)-Civet
a
a
a
a
b
ꢀ
ꢀ
Freda K. Chio , Julie Warne , Damien Gough , Mark Penny , Sasa Green (nee Martinovic) ,
Simon J. Coles c, Mike B. Hursthouse c, Peter Jones d, Lorraine Hassall e, Thomas M. McGuire e,
Adrian P. Dobbs a
,
*
a School of Biological and Chemical Sciences, Queen Mary University of London, Mile End Road, London E1 4NS, UK
b Department of Chemistry, University of Exeter, Stocker Road, Exeter EX4 4QD, UK
c National Crystallography Service, School of Chemistry, University of Southampton, Southampton SO17 1BJ, UK
d Discovery Chemistry, Pfizer Global R&D, Sandwich, Kent CT13 9NJ, UK
e AstraZeneca, Alderley Park, Cheshire SK10 4TG, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
While developing new variations of the Prins cyclisation reaction, the effect of the choice of Lewis acid on
the outcome of the reaction and the product(s) has been investigated, yielding hitherto unseen dihy-
dropyran products in the Prins cyclisation reaction of homoallylic alcohols, and two new modifications of
the reaction: the triflate-trapped Prins adduct and the MukaiyamaeAldolesilyl-Prins reaction. Two of
these methods are employed in two complementary total syntheses of the important perfumery com-
pound, (ꢀ)-Civet.
Received 18 March 2011
Received in revised form 4 May 2011
Accepted 6 May 2011
Available online 13 May 2011
Keywords:
Ó 2011 Elsevier Ltd. All rights reserved.
Prins reaction
Silyl-Prins reaction
MukaiyamaeAldolesilyl-Prins reaction
Pyran
Dihydropyran
Fluorinated pyran
Lewis acid
Civet
1. Introduction
variants of the Prins reaction for a number of years, and yet still
have no definitive answer to why certain Lewis acids are better than
The classical Prins cyclisation reaction, where a homoallylic al-
cohol reacts with a carbonyl component under Bronsted or Lewis
acid-promoted conditions, has become one of the major methods for
di- and tetrahydropyran synthesis of the 21st century and there are
several excellent reviews on this process.1 More recently, the Prins
reaction has also been adapted for the preparation of nitrogen con-
taining heterocycles, the appropriately named aza-Prins reaction.2e9
However, with many variations and modifications of the Prins
reaction now appearing in the literature, what makes a particular
Lewis acid a good choice for a reaction? And are there still any
surprises to be uncovered in the influence of a Lewis acid on the
outcome of the Prins cyclisation? We have been developing
others at promoting different versions of these reactions. Herein we
report on the effects of Lewis acids on the outcomes of three new
incarnations of the Prins reaction, to give unexpected pyran-
containing products.
2. Results and discussion
2.1. Lewis acids in the Prins reaction
The generally accepted mechanism for the Prins reaction is illus-
trated in Scheme 1. After acid-promoted activation of the aldehyde,
there is oxocarbenium ion formation followed by 6-endo cyclisation
to a secondary tetrahydropyranyl carbocation, which may then be
trapped by a nucleophile, most commonly from the original acid.
Many Lewis acids have been used in the Prins reaction, most
commonly giving a halogen at the 4-position of the tetrahydropyran:
* Corresponding author. Tel.: þ44 0207 882 5251; fax: þ44 0207 882 7427;
e-mail address: A.Dobbs@qmul.ac.uk (A.P. Dobbs).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.05.019

5108
F.K. Chio et al. / Tetrahedron 67 (2011) 5107e5124
Bronsted acid
MXn-1
or
MXn-1
R1
O
O
Lewis Acid (MXn)
O
R1
H
R1
H
R
OH
R
O
H
X
X
R1
R
O
R1
R
O
R1
R
O
R
O
R1
R
O
R1
Scheme 1. Generalised Prins cyclisation.
in our own work and from others Cl from InCl3 or Br from InBr3;10,11
We commenced our studies by examining the Prins reaction of
but-3-en-1-ol with phenylacetaldehyde and TMSOTf. At room or
higher temperatures, and irrespective of the molar equivalents of
reagents used, nothing was recovered from the reaction and de-
composition occurred. At low temperature, however, the reaction
appeared to yield a single product in modest yield by TLC. This
proved to be two inseparable isomeric dihydropyrans in combined
32% yield (Scheme 4); this could be formed either by elimination
directly from the intermediate carbocation or from elimination
from the triflate product. The two dihydropyrans were completely
inseparable either by TLC and other forms of chromatographydGC
and HPLCdand signals were overlapping in the 1H NMR spectrum,
so it has been impossible to determine accurately the relative
abundance of each isomer, although crudely it looked to be ap-
proximately equal (Fig. 1).
other examples (but not a complete listing) include fluorine from
15
BF3$OEt2,12e14 HBF4 or Et4NF/5HF;16 Cl from FeCl3,2,17,18 TiCl4,
10,22
AlCl3,19 BiCl3, NbCl5,20 or SnCl4; bromine from TiBr4,21 InBr3
or
SnBr4;23,24 iodine from CeCl3$7H2O/LiI,25 TMSCl/NaI,26 TiI4/I27 or I2.27
More interestingly, there are a few examples of oxygenated nucleo-
philes incorporated, including OAc from BF3$OEt2/AcOH/TMSOAc;28
OH indirectly from TFA.29 External nucleophiles have also been in-
corporated intotetrahydropyransbyaddingadditives tothereaction,
such as sulfur-centred nucleophiles introducing thioaryl groups;30
nitrogen-centred
nucleophiles,
including
acetonitrile
in
PrinseRitter31e34 sequences and azides;35 carbon nucleophiles such
as tandem PrinseFriedeleCrafts reactions.36e38
When scandium triflate has been employed as the Lewis acid,
a mixture of two products was obtained: the 4-hydroxytetrahy-
dropyran and the corresponding ether (Scheme 2).39,40
TMS Tf
O
O
H
O
Ph
Ph
Ph
H
OH
O
O
O
O
O
D
M
C
O
-78oC
Sc(OTf)3 (5 mol%)
OH
H
DCM
reflux
Scheme 4.
R
66-86%
R
R
9-20%
49-73%
Scheme 2. Scandium triflate catalysed Prins reaction.
Intrigued by this result, we pondered why triflate, from the
parent Lewis acid, had not been trapped during the Prins reaction.
Indeed, to our knowledge, there are no reported examples of triflate
being trapped by Prins tetrahydropyranyl carbocations,15 although
there is an example of it adding to a vinyl carbocation in an alkynyl
Prins reaction.41 Therefore we decided to investigate further the
use of triflate-containing Lewis acids in the simple Prins cyclisation.
There are comparatively few examples of sulfonyl-ester contain-
ing Lewis acids being employed in the Prins reaction. Both TMSOTf42
and TESOTf43,44 have been utilised in cyclisation reactions where an
external nucleophile (to the Lewis acid), such as acetate (from
TMSOAc) or acetonitrile has trapped the carbocation, or the cyclisa-
tion has been intramolecular and an internal nucleophile has trapped
the carbocation, normally forming a second ring. In(OTf)3 has been
used with NH4SCN to trap eSCN at the 4-position45 and also with
benzaldehyde or anisole in an ionic liquid in a Prins-FriedeleCrafts
reaction46 and also bismuth triflate catalysed PrinseRitter
reactions.47,34 Both MsOH and TsOH sulfonic acids have been used in
the reaction between 2-(arylmethylene)cyclopropylcarbinols and
aldehydes to give 3-methylene-5-mesyl(tosyl)-tetrahydropyrans
(Scheme 3).48 Therefore any successful triflate trapping would be
novel and have wide potential for further reaction.
Fig. 1. 1H NMR spectrum of mixture of dihydropyrans obtained from reaction of
3-buten-1-ol and phenylacetaldehyde in the presence of 1 equiv TMSOTf.
From this intriguing result, other triflate-containing Lewis acids
were tested in the same reaction (Table 1). The majority was prac-
tically quite messy reactions, with many minor byproducts being
formed. Nevertheless, the mixture of dihydropyrans was observed
in most cases. Indium triflate was the outstanding candidate, giving
the same mixture of dihydropyrans as above but in 68% yield, and in
H
O
M
O
s
R
H
O
C
O
Ph
Ms
H
R
O
Ph
D
C
M, r.t.
Scheme 3. Trapping with OMs in the Prins reaction.

F.K. Chio et al. / Tetrahedron 67 (2011) 5107e5124
5109
Table 1
or 1.5 equiv of the Lewis acid made very little difference (65% and
68%, respectively), while the yields then dropped dramatically as the
equivalents dropped, with 0.5 equivgiving 38% product and 0.1 equiv
giving 8%, the remainder being starting materials in each case.
Finally, it should be noted that while indium triflate gave the
greatest yields of the dihydropyran mixture, from a practical aspect,
the lower yielding TMSOTf promoted reaction was often cleaner and
easier to purify. The use of a p-anisaldehyde based TLC dip was found
to bemosteffectiveinvisualisingthe products inall these reactions.49
With indium triflate generally giving the best yields, the gener-
ality of the reaction was tested using this particular Lewis acid and
a variety of aldehydes, and other carbonyl compounds (Table 2). It
was soon observed that although using 1 equiv of indium triflate
gave the greatest yield in the reaction with phenylacetaldehyde,
with all other carbonyl components tested, it was found that a slight
excess of indium triflate (1.5 equiv) was actually advantageous and
gave the greatest yield. Examples of the reaction with other alde-
hydes are presented in Table 2.
Each reaction in Table 2 gave a mixture of two isomeric dihy-
dropyran products, although the number of byproducts in each case
was variable, and this often caused difficulty during purification of
the products. As mentioned earlier (Scheme 2), it has been pre-
viously reported that when using scandium triflate to promote the
Prins reaction, it was possible to obtain both 4-hydroxytetrahy-
dropyrans (minor product) and the correspondingethers (where the
homoallylic alcohol has added to the tetrahydropyranyl cation) as
the major product. The same compounds were observed here, albeit
in small amounts, as the two main reaction byproducts; indeed,
analysis of the 1H NMR spectra obtained of the crude product mix-
tures would suggest that all three compound types were present in
all the reactions, but the minor products could not be separated and
isolated in every case. However, unlike the literature scandium tri-
flate examples (where no mention was made of any dihydropyran
being formed), the mixture of dihydropyrans was the major reaction
product in each case. It has beenimpossible to deriveany rationale as
to which of the alcohol or ether would be the side product in each
case, although a general observation was that the alcohol tended to
be formed in greater quantities with newer bottles of indium triflate
(possibly with greater water content) compared with older bottles,
which had been re-purified or lengthily stored under vacuum (and
which in turn gave more of the ether rather than the alcohol).
Table 3 presents the results obtained when using ketones or
epoxides (as masked carbonyl compounds). A similar mixture of
products was obtained.
Realising that the mixture of inseparable dihydropyrans was of little
use synthetically, the mixture of benzylpyrans was taken and subjected
to hydrogenation, simply using 10 mol % Pd/C and atmospheric pres-
sure of hydrogen (Scheme 5). This yielded a single tetrahydropyran 1 in
66% yield. When repeated using the methyl-substituted mixture of
dihydropyrans, again only a single diastereomeric product 2 was
obtained, in 45% yield. This was adjudged to be the cis isomer across the
oxygen, as indicated by NOE measurements.
While this methodology may not entirely lend itself to the prep-
aration of multi-substituted tetrahydropyrans, this has the potential
to bean excellent method forthe synthesisof2-substituted or2,6-cis-
disubstituted tetrahydropyrans. One such important, yet simple ex-
ample, is (þ)-(S,S)-(cis-6-methyltetrahydropyran-2-yl)acetic acid or
‘civet’, first isolated in 1979 by Maurer from the glandular secretions
of the Civet cat and one of the few important animal-derived addi-
tives for the perfumery industry. A number of differing approaches to
cis-6-methyltetrahydropyran-2-yl acetic acid, both in its racemic and
enantiomerically pure forms have been published. It occurred to us
that given the 2,6-cis-relationship of the two substituents across the
oxygen in the heterocycle, it made the Civet cat constituent an ex-
cellent initial target to showcase this new modification of the Prins
reaction in total synthesis and hence reduce the number of steps in
Triflate Lewis acid screening for the Prins reaction
Lewis acid
Conditions
% Yielda
1
2
3
4
5
6
7
Scandium triflate
Tin triflate
Zinc triflate
Yttrium triflate
TMSOTf
Indium triflate
Indium triflate
1.5 equiv, DCM, rt
1.5 equiv, DCM, rt
1.5 equiv, DCM, rt
1.5 equiv, DCM, rt
1.5 equiv, DCM, ꢁ78 ꢂC
1 equiv, DCM, rt
32
66
Starting materials
Starting materials
48
86
1.5 equiv, DCM, rt
68%þ17% recovered
aldehyde
8
9
Indium triflate
Indium triflate
1.5 equiv, DCM, ꢁ78 ꢂC,
quenched at ꢁ78 ꢂC
1.5 equiv, DCM, ꢁ78 ꢂC,
warmed to and quenched
at 22 ꢂC
1.5 equiv, DCM, 22 ꢂC
1.5 equiv, DCM, reflux
0.1 equiv, DCM, rt
Product traces
68
10
11
12
Indium triflate
Indium triflate
Indium triflate
69
68
8%þ57% recovered
phenylacetaldehyde
38%þ6% recovered
phenylacetaldehyde
24
13
Indium triflate
Indium triflate
0.5 equiv, DCM, rt
14
1 equiv, K2CO3, DCM, 22 ꢂ
C
a
All compounds purified by chromatography and gave satisfactory spectroscopic
and analytical data. Where product is indicated, this was always obtained as
a mixture of two inseparable dihydropyrans, and the combined yield is given.
61% yield when starting from 4-penten-2-ol. Both tin(II) triflate and
scandium(III) triflate (Table 1 entries 1 and 2) also gave some
dihydropyran, albeit in much lower yields, and in the case of scan-
dium with the 4-butenoxy ether also being formed, as reported
earlier. It is curious that the mixture of dihydropyrans has not been
observed in previous reported examples. Zinc and yttrium triflates
(entries 3 and 4) failed to promote any reaction and starting mate-
rials were fully recovered. Taking the best Lewis acid, indium triflate,
we went on to try and optimise the reaction. First, a slight excess
(1.5 equiv) of the Lewis acid was employed (entry 7) and although
this showed a decrease in the yield of the reaction (68%), this
appeared to be an anomaly, with the slight excess of indium triflate
proving to be the highest yielding equivalent with all other alde-
hydes. Varying these quantities with other Lewis acids, such as
scandium triflate, had no effect on the yield. Therefore the optimi-
sation studies were performed with 1.5 equiv of indium triflate.
Next, the effect of temperature on the reaction was examined. The
Prins cyclisation was performed with indium triflate at ꢁ78 ꢂC and
quenched at the same temperature (entry 8; 0% and starting ma-
terials recovered); the addition at ꢁ78 ꢂC and then warmed to room
temperature (22 ꢂC) before quenching (entry 9, 68%); with the ad-
dition performed at room temperature and the reaction quenched at
room temperature (69%) and finally heating the reaction under
reflux (entry 11, 68%). The low temperature reaction gave no product
and only recovered starting materials, with poor solubility of the
Lewis acid in dichloromethane at this temperature undoubtedly
playing an important role in this failure. The yields obtained in the
other two reactions were identical, suggesting that the temperature
of the addition does not matter, the reaction only occurs at around
22 ꢂC. Heating the reaction at reflux temperature gave no im-
provement in yield. Finally, it was suspected that triflic acid may be
being produced during the elimination, and that this may play a role
in further promoting an E1 type elimination reaction to form the
dihydropyrans. So the reaction was repeated in the presence of base
(potassium carbonate); this resulted in a considerable drop in re-
action yield of the dihydropyran mixture, suggesting that the
presence of acid may be crucial to product formation.
We were also curious to find out if the reaction to give the dihy-
dropyrans was catalytic or stoichiometric in the Lewis acid. Using 1

5110
F.K. Chio et al. / Tetrahedron 67 (2011) 5107e5124
Table 2
Reactions of homoallylic alcohols with aldehydes in the presence of indium triflate
Carbonyl Componenta
Phenylacetaldehyde
R2
H
Productsb
% Yield
68
Other product(s)
% Yield
17
1
2
Octanal
H
50
25
24
3
Cyclohexanecarboxyaldehyde
H
Traces
69
4
Benzaldehyde
H
9
Traces
5
6
4-Nitrobenzaldehyde
Phenylacetaldehyde
H
41
51
Me
Traces
7
Octanal
Me
18
75
8
9
Cyclohexanecarboxyaldehyde
Benzyl 3-oxopropanoate
Me
Me
21
13
1
Traces
a
All reactions performed at room temperature for 10.5 h in the ratio alcohol:carbonyl compound: Lewis acid 1:1.5:1.5.
All compounds purified by chromatography and gave satisfactory spectroscopic and analytical data. The product was always obtained as a mixture of two inseparable
b
dihydropyrans, and the combined yield is given.

F.K. Chio et al. / Tetrahedron 67 (2011) 5107e5124
5111
Table 3
Reactions of homoallylic alcohols with ketones or masked carbonyl compounds in the presence of indium triflate
Carbonyl Componenta
Cyclohexanone
R2
H
Productsb
% Yield
79
Other product(s)
% Yield
1
2
20
Cyclopentanone
H
41
Traces
3
4
Benzophenone
Styrene Oxide
H
H
Traces
18
75
Traces
5
6
Cyclohexanone
Cyclopentanone
Me
Me
51
13
Traces
7
Benzophenone
Me
Traces
a
All reactions performed at room temperature for 10.5 h in the ratio alcohol:carbonyl compound: Lewis acid 1:1.5:1.5.
All compounds purified by chromatography and gave satisfactory spectroscopic and analytical data. The product was always obtained as a mixture of two inseparable
b
dihydropyrans, and the combined yield is given.
H2
Ph
R = H or Me
Ph
Ph
%
Pd/C (10 mol%)
MeOH
R
R
R
O
O
O
=
1
R
H 66
=
2
R
Me 45
%
Scheme 5.
the overall synthesis of this economically important target. Starting
from 1,6-hex-3-enedioic acid 3, double esterification with benzyl
bromide gave the bis-benzyl ester 4 in 48% yield. Ozonolysis gave the
corresponding 1,3-ester aldehyde 5 (which was unstable to isolation
and chromatography), the precursor for the Prins reaction. Prins re-
action of this aldehyde with pent-4-en-2-ol 6 utilising indium triflate
gave the expected mixture of two dihydropyrans 7 in a disappointing
13% yield, although this is believed to be due to the volatility and
instability of the aldehyde rather than a failure of the Prins reaction.
Finally, catalytic hydrogen simultaneously removed the olefin moiety
and cleaved the benzyl ester to give a single compound, the racemic
Civet natural product 8, in 87% yield and overall 2.2% yield for the four
steps. Both Pd(OH)2 and Pd/C could be used in the hydrogenation,
althoughitwasnecessary towash thePd/Cwith 10%NaHCO3 solution

5112
F.K. Chio et al. / Tetrahedron 67 (2011) 5107e5124
prior to use, to prevent the formation of the methyl ester of Civet
duringthehydrogenationreaction. Althoughnot the highestyielding,
we believe that these four steps constitute the shortest synthesis of
racemic Civet to date (Scheme 6).
starting materials. Indeed, efforts to eliminate the triflate group
from these compounds using base was in fact difficult and low
yielding. The reason for obtaining the triflate-intercepted product
in this particular case is not known, although it may be that the
Benzyl
chloroformate
NEt3, DMAP
DCM
O
O
1. O3, solvent
2. Me2S
O
O
OH
OBn
HO
BnO
BnO
H
48%
O
O
3
4
5
used immediately
without purification
In(OTf)3
DCM
-78 oC to r.t.
13%
Me
OH
6
H2
O
O
O
Pd/C (5%)
O
OH
O
OBn
O
OBn
or Pd(OH)2 (5%)
MeOH
8
7
87%
Scheme 6. Total synthesis of (ꢀ)-Civet.
Concomitant with these studies, we have also been in-
vestigating the synthesis of fluorinated di- and tetrahydropyrans
using the Prins methodology and starting from 2-fluorobut-3-en-
1-ol 9.10 When employing indium trichloride and tribromide as
the Lewis acid, the expected 2-substituted 4-chloro (bromo)-5-
fluorotetrahydropyran 10 was obtained in good yield and as
a single, all-cis diastereomer.10 Attempts to eliminate the chlorine
to form a dihyropyran were unsuccessful.10 Given our results
above, it was quite expected that when using the identical con-
ditions employing In(OTf)3, we would obtain a mixture of fluori-
nated dihydropyrans. Intriguingly, however, these reactions were
practically much cleaner than the ones above and only a single
tetrahydropyran product was obtained directly, with the triflate
anion trapping in the 4-position 11. This is, we believe, the first
example of triflate being trapped in the Prins reaction. Also in
contrast to the previous observations, TMSOTf was now by far the
highest yielding Lewis acid (Scheme 7 and Table 4), with In(OTf)3
or any other Lewis triflate-containing Lewis acid (scandium or tin)
only giving traces of product, with unreacted starting materials
recovered irrespective of temperature (and some decomposition
at reflux). Perhaps even more surprising was that the product, as
with the chloride-trapped products, was obtained as a single, all-
cis diastereoisomer. There was no evidence of the mixture of
dihydropyrans, previously observed so abundantly, being formed
and the remaining mass balance was attributable to unreacted
Table 4
TMSOTf promoted Prins reaction of fluorinated substrates
Entry
Aldehydea
Productb
% Yield
42
1
Phenylacetaldehyde
2
3
4
Hexanal
38
58
52
Cyclohexanecarboxaldehyde
2-Ethylbutyraldehyde
X
In l D M
C 3/ C
O
F
H
O
5
Diphenylacetaldehyde
34
22
or
H
H
R
R
,
InBr3 DBM
F
9
R
O
10
X = l or Br
C
Tf
O
TM Tf
SO
O
F
6
Benzaldehyde
H
O
D M
C
F
R
O
11
o
-7
8 C
a
All reactions were performed in DCM at ꢁ78 ꢂC and with the reagents in the
TM Tf: 42 R = Bn)
SO
% (
In( Tf) 11
Bn)
ratio alcohol:aldehyde:Lewis acid 1:1.5:2 equiv.
O
:
% (R =
3
b
All compounds purified by chromatography and gave satisfactory spectroscopic
Scheme 7.
and analytical data.

F.K. Chio et al. / Tetrahedron 67 (2011) 5107e5124
5113
fluorine destabilises the carbocation to such an extent that it has
no option but to be trapped by the triflate counterion, which you
be expected to be held in close proximity owing to the solvent
being dichloromethane.
It is difficult to provide a satisfactory explanation for these dif-
fering observations in the use of triflate Lewis acids in the Prins
reaction. However, we would encourage anyone interested in de-
veloping the Prins reaction to attempt these Lewis acids under
a variety of conditions, and to expect the unexpected products.
1,3-benzyl ester-aldehyde 5. Monobenzyl protection and Swern
oxidation gave the aldehyde precursor 13 in 52% over the two steps.
The synthesis of the vinylsilane-homoallylic alcohol 14 was ach-
ieved from 4-pentyn-2-ol by deprotonation/silylation followed by
DiBAL-H reduction (52%). The crucial silyl-Prins reaction proceeded
over 16 h using InCl3 to give the dihydropyran 15 in excellent 95%
yield as a single diastereomer. The relative stereochemistry across
the oxygen atom was established by NOE studies, with a 9% en-
hancement observed between C(2)H and C(6)H. Catalytic hydro-
genation simultaneously deprotected the benzyl ether and
removed the olefin moiety and this alcohol was oxidised without
purification to the natural product 8 in 54% for the two steps (al-
though quantitative by TLC, this yield was low as separation from
the chromium residues was problematic) (Scheme 9).
Unlike the sample of Civet obtained earlier, which remained as
an oil, the sample of Civet prepared via the silyl-Prins reaction
rapidly crystallised and the X-ray structure obtained (Fig. 2).
Thus an extensive Lewis acid screening programme for the silyl-
Prins reaction has revealed that different Lewis acids will favour
this particular process.
2.2. Lewis acids in the silyl-Prins reaction
We have also worked extensively on the silyl-Prins reaction.50,51
By the introduction of a silicon moiety to the olefin component in
the Prins reaction, extra stabilisation is supplied to the tetrahy-
dropyranyl carbocationdformed during the cyclisation stepdvia
the b-effect from silicon. Rather than trapping of this carbocation
with an anion, elimination of the silyl moiety is a far more facile and
favourable process to generate with complete regioselectivity,
a dihydropyran (Scheme 8).
Bronsted acid
R
or
TMS
O
Lewis Acid (MXn)
OH
R1
H
R
O
R1
R
O
R1
TMS
Scheme 8. The silyl-Prins reaction.
A random screening approach revealed that many Lewis acids are
capable of promoting the silyl-Prins reaction (Table 5), with
threedBF3$OEt2 (Table 5 entry 1), TMSOTf (Table 5 entry 3) and InCl3
(Table 5 entry 6)dproving to be the most successful, and in fact, the
majority of our work has focussed on the use of InCl3, since it is far
easier to handle, is moisture tolerant and the reaction proceeds at
room temperature cf. the alternative high yielding Lewis acids. Fur-
ther, in these cases, the use of triflate-containing Lewis acids was poor
yielding at best, with starting materials being recovered in each case.
We decided to repeat the synthesis of Civet but using the silyl-
Prins methodology. On this occasion, we started from propan-1,3-
diol 12, to avoid the difficulties encountered previously with the
2.3. Lewis acids and development of the Mukaiyamae
Aldolesilyl-Prins reaction
Finally, following on from the work of Rychnovsky21,52,53 on the
MukaiyamaeAldolePrins reaction, we decided to investigate the
possibility of developing our own silyl-Prins reaction into a one pot
cascadeMukaiyamaeAldolesilyl-Prins(MAsP)reaction(Scheme10).
The vinyl ethers 16 and 17 were prepared from the corre-
sponding homoallylic alcohol by transetherification employing
ethyl vinyl ether and mercury(II) acetate, over 4e6 days. Since
indium trichloride is known both to promote the Mukaiyama-
eAldol reaction and the silyl-Prins reaction independently, it was
anticipated that it would similarly promote the domino reaction.
However, it failed to give any product, with only starting materials
recovered. Screening many other Lewis acids (Table 6), which
have been successful earlier herein (Table 6 entries 1 and 2) and in
the work of others, most either gave recovered starting materials,
or surprisingly in some cases, the product of the silyl-Prins re-
action, where the vinyl moiety had been clearly lost at some stage
during the reaction, and a normal silyl-Prins reaction taken place
(entries 3e5). In fact, of the many Lewis acids screened, it was
only titanium tetrachloride (entry 6) that successfully promoted
the MAsP to give 18, and this was in excellent yield. Adding the
base 2,6-di-tert-butylpyridine (entry 7) to prevent proton transfer
during the reaction (and widely employed by Rychnovsky) failed
to give any improvement in yield or selectivity, and so was
omitted from subsequent reactions. A range of aldehydes were
then employed in the reaction, together with vinyl ethers also
containing methyl and phenyl substituents (Table 7 entries 1e13).
All combinations gave similar yields, and always with a prefer-
ence for one (undetermined) diastereomer over the other, gen-
erally in ratios of up to ca. 3:1. Furthermore, it is not clear why
certain aldehydesdsuch as p-nitrobenzaldehyde (Table 7 entry
13) should give such a great preference for one diastereomer
compared with other aldehyde (Table 7).
Table 5
Lewis acid screening for the silyl-Prins reaction
Entry Lewis acida
Temperature/ꢂC Time/h % Yieldb
1
2
BF3$OEt2
BF3$OEt2
ꢁ78
5
5
90
Trace
0
(decomposition)
3
4
TMSOTf
TMSOTf
ꢁ78
5
5
86
Trace
0
(decomposition)
5
6
7
8
9
TiCl4
InCl3
InCl3 (0.5 equiv)
InCl3 (0.1 equiv)
AlCl3
ꢁ78
rt
rt
rt
rt
5
5
5
5
68
88
58
63
16
Trace
(decomposition)
71
5 or 24 77
5 or 24 45
5 or 24 33
10
11
12
13
14
15
16
18
19
20
FeCl3
rt
rt
rt
rt
5
Yb(OTf)3
Sn(OTf)2
In(OTf)3
Sc(OTf)3
PPTS
rt
5 or 24 32
0, rt or reflux
0, rt or reflux
5 or 24 SM
5 or 24 SM
5 or 24 SM and acetal
5 or 24 SM
5 or 24 SM
TFA
InCl3 in EtOH:H2O (9:1) 0, rt or reflux
InCl3 in THF:H2O (5:1)
InCl3 in H2O
0, rt or reflux
0, rt or reflux
It was unclear at this stage if the diastereomeric ratios in the
dihydropyrans were coming from cis and trans arrangements of the
substituents across the oxygen atom in the ring, or from the alcohol
a
All reactions were performed with alcohol:aldehyde:Lewis acid 1:1:1 on 2 mmol
scale.
b
Isolated and purified yields.

5114
F.K. Chio et al. / Tetrahedron 67 (2011) 5107e5124
O
Me
InCl3, DCM
TMS
BnO
H
Me
O
15
OBn
16 h, r.t.
95%
OH
13
14
1. H2, Pd/C (10%), EtOH
2. CrO3/H2SO4/H2O
54% over 2 steps
1. BnBr, KOH
DMSO-THF (1:9), r.t.
67%
2. DMSO, (COCl)2, NEt3
-78oC, DCM
77%
O
Me
O
8
OH
HO
OH
12
Scheme 9. Total synthesis of Civet using the silyl-Prins reaction.
oxygen being present, suggesting that the dr originated at the al-
cohol centre and was not a consequence of obtaining cis and trans
isomers across the oxygen. The reason why there should be some
selectivity in the formation of the alcohol, and for which isomer, is
currently under investigation and will be reported in due course
(Scheme 11).
3. Conclusions
So is there any way to predict the optimum Lewis acid for the
Prins reaction? Sadly no. Through extensive Lewis acid screening,
we have been able to report the development of new avenues of
exploration for the Prins reaction, including obtaining hitherto
unseen dihydropyran products and the inclusion of the silyl-
Prins reaction in a domino process. Finally, two of the methods
Fig. 2. X-ray crystal structure of (ꢀ)-Civet.
R
OH
TMS
O
Hg(OAc)2
r.t.
3-6 days
MXn-1
R
O
Lewis Acid
(MXn)
R
O
O
OH
R1
R1
H
O
R1
R
O
TMS
16
TMS
18
R = H 90%
17 R = Me 86%
Scheme 10. The MukaiyamaeAldolesilyl-Prins reaction.
centre. Thus in order to determine that the diastereomeric ratios
being obtained were solely from the alcoholic centre, two com-
pounds, 19 and 20 were subjected to Jones oxidation to convert the
alcohol to the corresponding ketone. These were both effectively
quantitative, and the product in each case was obtained as a single
diastereomer. In particular, when employing the 2,6-disubstituted
dihydropyran, oxidation yielded a single diastereisomer, which,
after NOE analysis, was found to have the two groups cis across the
oxygen atom. There was no evidence for any trans isomer across
developed have successfully been applied in natural product
total synthesis.
4. Experimental
4.1. General
Petroleum ether or petrol refers to the fraction boiling between
40 ꢂC and 60 ꢂC. Dichloromethane was distilled over calcium

F.K. Chio et al. / Tetrahedron 67 (2011) 5107e5124
5115
Table 6
Lewis acid screening for the MukaiyamaeAldolesilyl-Prins reaction
Entry
R
R1
Lewis acid
Conditions
Product
% Yielda
1
2
H
PhCH2
In(OTf)3
TMSOTf
rt (24 h)reflux (24 h)
ꢁ78 ꢂC (10 min)
SM recoveredSM recovered
Decomposition
3
InCl3
0 (10 min)rt (24 h)reflux (24 h)
SM recovered and dihydropyran
4
5
BF3$OEt2
SnCl4
ꢁ78 ꢂC (10 min)
ꢁ78 ꢂCrt
SM recovered and dihydropyran
SM recovered and dihydropyran
ꢁ78 ꢂC (5 min)
ꢁ40 ꢂC (5 min)
53 (3.2:1)
52 (3.2:1)
6
TiCl4
ꢁ78 ꢂC (5 min)
ꢁ40 ꢂC (5 min)
50 (3.2:1)
51 (3.2:1)
7
TiCl4þ2,6-di-tert-butylpyridine
a
Isolated and purified yields. Ratios obtained via a combination of GC and 1H NMR integrations.
Table 7
Results for the TiCl4-promoted MukaiyamaeAldolesilyl-Prins reaction
Entry
1
R
R1
Product
% Yielda
H
PhCH2
53 (3.2:1)
2
3
H
H
n-C5H11
48 (1.7:1)
47 (2.9:1)
c-C6H11
4
5
H
H
t-Bu
46 (1:23)
42 (3.7:1)
Ph2CH
6
7
H
4-NO2ePh
53 (1.3:1)
Me
Ph2CH
51 (3.2:1)
(continued on next page)
(continued on next page)

5116
F.K. Chio et al. / Tetrahedron 67 (2011) 5107e5124
Table 7 (continued )
Entry
R
R1
Product
% Yielda
8
Me
c-C6H11
42 (3.7.1)
9
Me
Me
Ph
4-NO2ePh
t-Bu
53 (1:3.1)
48 (2.9:1)
52 (1.8:1)
10
11
c-C6H11
12
Ph
Ph
t-Bu
47 (2.9:1)
13
4-NO2ePh
22 (15.7:1)
a
Isolated and purified yields. Ratios obtained via a combination of GC and 1H NMR integrations.
OH
O
O
O
O
19
NO2
NO2
CrO3, H2SO4, H2O
Acetone
quantitative
OH
O
O
20
Scheme 11.
hydride. Diethyl ether, THF and toluene were distilled over sodium
and benzophenone, which was used as an indicator. All other sol-
vents were obtained anhydrous and used directly in the reaction
vessel. All reactions were carried out under an atmosphere of ni-
trogen unless otherwise stated using vacuum/nitrogen manifold.
All glassware, syringes and needles were pre-dried in an oven
(120e140 ꢂC) and cooled in a nitrogen atmosphere prior to use.
Stirring was by internal magnetic follower. All chemicals were
purified by distillation or recrystallisation where appropriate.
Commercially available compounds were generally used without
further purification. All reactions were followed by TLC. Plates were
visualized under UV light (at 254 nm) or by staining with acidic
potassium permanganate followed by heating. Purification was by
flash chromatography or fluorous solid phase separation. Infrared
(IR) spectra were recorded in the range 4000-600 cmꢁ1; spectra
were recorded either directly from solids or from liquids dissolved
in CHCl3 (using CHCl3 as a blank). Proton (1H) NMR spectra were
recorded at 270 or 400 MHz and carbon (13C) NMR spectra at 75 or
100 MHz, respectively, in deuterated solvents. Fluorine (19F) NMR
ppm (parts per million) relative to an internal standard (CDCl3).
Coupling constants, J, are quoted as experimentally observed.
4.2. General Lewis acid screening procedure for Table 1
3-Buten-1-ol (1 equiv) and phenylacetaldehyde (1.5 equiv) were
added to dry DCM (0.42 mmol in 4 ml) under N2. This mixture was
stirred for 5 min before the addition of the Lewis acid (1.5 equiv) in
one portion. The reaction was allowed to stir at room temperature
for 10.5 h before quenching with water. The aqueous layer was
separated from the organic layer, extracted twice with DCM and
washed with brine. The combined organic phases were dried over
MgSO4 and concentrated in vacuo to yield a crude oil, which was
purified by flash chromatography.
4.3. General procedure for the preparation of dihydropyran
mixtures using indium triflate (Table 2)
The homoallylic alcohol (1 equiv) and carbonyl component
(1.5 equiv) were added to dry DCM (0.42 mmol in 4 ml) under N2.
were recorded at 282 MHz. NMR chemical shifts (d) are quoted in

F.K. Chio et al. / Tetrahedron 67 (2011) 5107e5124
5117
This mixture was stirred for 5 min before the addition of In(OTf)3
(1.5 equiv) in one portion. The reaction was allowed to stir at room
temperature for 10.5 h before quenching with water. The aqueous
layer was separated from the organic layer, extracted twice with
DCM and washed with brine. The combined organic phases were
dried over MgSO4 and concentrated in vacuo to yield a crude oil (in
the case of 4-nitrobenzaldehyde, a crude solid), which was purified
by flash chromatography.
In the case of using a ketone as the carbonyl component, the
reaction was allowed to stir at room temperature for 14.5 h before
quenching by the addition of water.
Data is only presented for the dihyropyran products. Full char-
acterisation data for the minor ether and alcoholic byproducts is
presented in the Supporting Information.
purification by flash chromatography (dichloromethane/n-hexane
3:1). Rf 0.63 (5% EtOAc in hexane); nmax/cmꢁ1 (CHCl3) 2924, 2854,
1464, 1358, 1113, 1086; 1H NMR (400 MHz, CDCl3) dH¼5.90e5.80
(1H, ddt, J¼13.4, 10.2, 6.8 Hz, CH]CH2), 5.14e5.05 (2H, m, over-
lapping CH2trans and CH2cis), 4.54e3.66 (2H, m, C(pyran)H2O),
3.57e3.52 (2H, m, C(pyran)HOCH2), 3.48e3.25 (2H, m, overlapping
C(pyran)HO and CH(ether)), 2.38e2.33 (2H, m, CH2CH]CH2),
2.02e1.43 (4H, overlapping CH2CH2CHOCH2CH(ether)), 1.66e1.16
(16H, m, C8H16CH3), 0.92e0.88 (3H, m, C8H16CH3); 13C NMR
(100 MHz, CDCl3) dC¼135.3 (CH), 116.3 (CH2), 76.7 (C(pyran)HO),
75.4 (CH(ether)), 67.0 (CH(ether)CH2), 66.0 (CH2OC(pyran)), 38.5
(CH2), 36.3 (CH2), 34.5 (CH2), 32.8 (CH2), 31.8 (CH2), 29.7 (CH2), 29.7
(CH2), 29.3 (CH2), 25.5 (CH2), 22.7 (CH2), 14.1 (CH3); m/z (EIþ) 183
(50% [C11H19O2]), 55 (100% [C4H7]). LRMS (NSI) found (Mþ) 254,
C16H30O2 requires 254.2246. HRMS could not be obtained.
4.3.1. Table 2 entry 1: (ꢀ)-2-benzyl-3,6-dihydro-2H-pyran and 2-
benzyl-3,6-dihydro-6H-pyran. The product mixture was obtained as
a clear oil (68%) after purification by flash chromatography
(dichloromethane/n-hexane 3:1). Data presented are for the major
isomer from the inseparable mixture. Rf 0.79 (20% EtOAc in hex-
ane); nmax/cmꢁ1 (CHCl3) 2924, 2853, 1722, 1029, 756; 1H NMR
(400 MHz, CDCl3) dH¼7.35e7.12 (5H, m, Ph), 5.80e5.55 (2H, m,
overlapping CH]CH), 4.24e3.89 (2H, m, CH2OCH]CH), 3.71e3.55
(1H, m, C(pyran)HO), 2.90e2.63 (2H, m, overlapping CH2Ph),
2.25e1.83 (2H, m, overlapping CH]CHCH2); 13C NMR (100 MHz,
CDCl3) dC¼138.6 (CH), 138.3 (CH), 138.0 (C), 129.5 (C(Ar)H), 129.3
(C(Ar)H), 128.3 (C(Ar)H), 128.2 (C(Ar)H), 127.1 (C(Ar)H), 74.9 (CH2),
74.5 (CH2), 66.1 (CH), 42.5 (CH), 41.87 (CH); m/z (EIþ) 55 (80%
[C4H7þ]), 83 (100% [C6H10þ]). HRMS (NSI) found (Mþ) 174.1042,
C12H14O requires 174.1045.
4.3.5. Table
2
entry
3:
(ꢀ)-4-(but-3-en-1-yloxy)-2-cyclo-
hexyltetrahydro-2H-pyran. The product was obtained as a clear oil
(24%) after purification by flash chromatography (dichloro-
methane/n-hexane 3:1). Rf 0.44 (10% EtOAc in hexane); nmax/cmꢁ1
(CHCl3) 2927, 2852, 2007, 1732, 1078, 612; 1H NMR (400 MHz,
CDCl3) dH¼5.91e5.80 (1H, ddt, J¼13.9, 10, 7.1 Hz, CH]CH2),
5.19e5.05 (2H, m, overlapping CH2trans and CH2cis), 4.06e3.33 (5H,
m overlapping C(pyran)H2OCH and CH2(ether)), 3.04e2.99 (1H, m,
CHOCH2), 2.36e2.35 (2H, m, CH2C]), 2.03e1.62 (4H, m, CH2),
1.50e0.98 (11H, m, C6H11); 13C NMR (100 MHz, CDCl3) dC¼135.3 (C),
116.4 (CH), 80.8 (CH2), 75.8 (CH2), 67.0 (CH), 66.1 (CH), 43.0 (CH2),
35.3 (CH), 34.5 (CH), 32.9 (CH),29.0 (CH), 28.6 (CH), 26.6 (CH), 26.2
(CH),25.4 (CH); m/z (EIþ) 167 (33% [C10H15O2]), 55 (67% [C4H7]), 83
(100% [C5H8O]). HRMS could not be obtained.
4.3.2. Table 2 entry 1: (ꢀ)-2-benzyl-4-(but-3-en-1-yloxy)tetrahydro-
2H-pyran. The product was obtained as a clear oil (17%) after
purification by flash chromatography (dichloromethane/n-hexane
3:1). Rf 0.54 (20% EtOAc in hexane); nmax/cmꢁ1 (CHCl3) 2923, 2851,
1495, 1454, 1084, 699; 1H NMR (400 MHz, CDCl3) dH¼7.26e7.10
(5H, m, Ph), 5.78e5.68 (1H, ddt, J¼14, 10.3, 6.7 Hz, CH]CH2),
5.03e4.94 (2H, m, overlapping CH2trans and CH2cis), 3.98e3.94 (1H,
dd, J¼11.7, 5.5 Hz, OCHCH2Ph), 3.67e3.26 (5H, m, overlapping CHO
and CH2O (of ether) and CH2O (ring)), 2.95e2.48 (2H, m, over-
lapping CH2Ph), 2.26e2.21 (2H, m, overlapping CH2CH2CH(ether)),
1.94e1.83 (2H, m, overlapping CHCH2CH(ether)), 1.57e1.49 (2H, m,
CH2); 13C NMR (100 MHz, CDCl3) dC¼129.4 (C(Ar)H), 128.3 (C(Ar)
H), 126.3 (C), 77.2 (CH), 76.5 (CH), 75.3 (CH), 67.1 (CH2), 66.1 (CH2),
42.9 (CH2), 38.2 (CH2), 34.5 (CH2), 32.6 (CH2); m/z (EIþ) 167 (33%
[C10H15O2]), 55 (67% [C4H7]), 83 (100% [C5H8O]). HRMS could not
be obtained.
4.3.6. Table
2
entry 3: (ꢀ)-2-cyclohexyltetrahydro-2H-pyran-4-
ol. The product was obtained as a clear oil (69%) after purification
by flash chromatography (dichloromethane/n-hexane 3:1). Rf 0.62
(10% EtOAc in hexane); nmax/cmꢁ1 (CHCl3) 2922, 2850, 1730,
1449, 1356, 1083, 1168; 1H NMR (400 MHz, CDCl3) dH¼3.97e3.93
(1H, m, 1H of CH2O), 3.55e3.47 (1H, m, C(pyran)CHO), 3.30e3.24
(1H, m, 1H of CH2O), 2.96e2.92 (1H, m, CHOC6H11), 1.88e1.77 (3H,
m, overlapping CH2O and CH2CHOH), 1.68e1.57 (5H, m, alkyl CH2s),
1.88e1.28 (16H, m); 13C NMR (100 MHz, CDCl3) dC¼80.8
(CHOC6H11), 77.2 (CHC6H11), 72.5 (CHOC(pyran)), 66.1 (CH2), 43.0
(CH), 36.0 (CH2O), 33.8 (CH2), 26.6 (CH2), 26.3 (CH2), 26.2 (CH2); m/z
(EIþ) 167 (33% [C10H15O2]), 55 (67% [C4H7]), 83 (100% [C5H8O]).
HRMS could not be obtained.
4.3.7. Table
2
entry 4: (ꢀ)-2-phenyl-3,6-dihydro-6H-pyran. The
product mixture was obtained as a clear oil (9%) after purification
by flash chromatography (dichloromethane/n-hexane 3:1). Data
presented are for the isolated major isomer (only traces of the other
isomer seen). Rf 0.58 (5% EtOAc in hexane); nmax/cmꢁ1 (CHCl3) 2924,
1722, 1028, 699; 1H NMR (400 MHz, CDCl3) dH¼7.33e7.21 (5H, m,
Ph), 5.89e5.73 (2H, m, CH]CH), 4.51e4.47 (1H, dd, J¼10.0, 3.8 Hz,
CHOPh), 4.32e4.29 (2H, m, CH2O), 2.36e2.15 (2H, CHOPhCH2CH);
13C NMR (100 MHz, CDCl3) dC¼128.4 (C(Ar)H ꢃ2), 126.1 (C(Ar)H
ꢃ2), 125.9 (CH), 124.5 (CH), 77.0 (CH), 76.5 (C), 66.6 (CH2), 32.9
(CH2). HRMS (EI) found (Mꢁ) 159.0802, C11H11O requires 159.0804.
4.3.3. Table 2 entry 2: (ꢀ)-2-heptyl-3,6-dihydro-2H-pyran and 2-
heptyl-3,6-dihydro-6H-pyran. The product mixture was obtained as
a clear oil (50%) after purification by flash chromatography
(dichloromethane/n-hexane 3:1). Data presented are for the in-
separable mixture of geometric isomers. Rf 0.75 (5% EtOAc in hex-
ane); nmax/cmꢁ1 (CHCl3) 2925, 2855, 1731, 1465, 1090, 754; 1H NMR
(400 MHz, CDCl3) dH¼5.77e5.55 (4H, m, (CH]CH) ꢃ2), 4.12e3.88
(2H, m, CH2O), 3.62e3.15 (1H, m, CHOC8H16CH3 from major iso-
mer), 2.32e1.82 (2H, m, CH2CH]CHCH2O from major isomer),
1.54e1.21 (16H, m, C6H12CH3), 0.82e0.79 (3H, m, C8H16CH3); 13C
NMR (100 MHz, CDCl3) dC¼126.4 (CH), 124.5 (CH3), 66.0 (CH2O),
36.1 (CHOCH2C7H14CH3), 35.5 (CH2), 31.9 (CH2), 31.1 (CH2), 29.7
(CH2), 29.4 (CH2), 29.3 (CH2), 25.5 (CH2), 25.4 (CH2), 22.7 (CH2),
14.13 (CH3); m/z (EIþ) 83 (50% [C5H7O]), 127 (50% [C9H19]). HRMS
(EI) found (Mþ) 182, C12H22O requires 182.1671.
4.3.8. Table 2 entry 5: (ꢀ)-2-(4-nitrophenyl)-3,6-dihydro-2H-pyr-
an. The product was obtained as a clear oil (41%) after purification
by flash chromatography (dichloromethane/n-hexane 3:1). Rf 0.30
(5% EtOAc in hexane); nmax/cmꢁ1 (CHCl3) 3037, 2844, 1605, 1513,
1342, 1085, 848, 748, 695; 1H NMR (400 MHz, CDCl3) dH¼8.15e8.13
(2H, d, J¼8.7 Hz, 2ꢃ CHNO2), 7.49e7.47 (2H, d, J¼8.4 Hz, 2ꢃ
CHCHNO2), 5.88e5.75 (2H, m, overlapping CH]CH), 4.61e4.58 (dd,
J¼9.6, 4.0 Hz, C(pyran)HO), 4.33e4.31 (2H, m, CH2O), 2.30e2.14
(2H, m, CHCH2CHPh); 13C NMR (100 MHz, CDCl3) dC¼150.0 (C),
4.3.4. Table 2 entry 2: (ꢀ)-4-(but-3-en-1-yloxy)-2-heptyltetrahydro-
2H-pyran. The product was obtained as a clear oil (25%) after

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F.K. Chio et al. / Tetrahedron 67 (2011) 5107e5124
147.2 (C), 126.5 (CH), 126.4 (CH), 123.8 (CH), 123.7 (CH), 74.5 (CH),
66.5 (CH2), 32.9 (CH2). HRMS (ASAP) found (Mþ) 206.0809,
C11H12NO3 requires 206.0812.
in hexane); nmax/cmꢁ1 (CHCl3) 2990, 2253, 1410, 1375, 1039; 1H
NMR (400 MHz, CDCl3) dH¼5.76e5.58 (2H, m, (CH]CH) ꢃ2),
3.75e3.71 (2H, m, overlapping of C(pyran)HOC6H12 of the minor
isomer with CHMe of the major isomer), 3.13e3.08 (2H, m, over-
lapping of C(pyran)HOC6H12 of the major isomer with CHMe of the
minor isomer), 1.96e1.86 (3H, m, overlapping CH2CH]CH with
C(pyran)HOC6H12 ꢃ2), 1.67e1.58 (11H, m, C6H12 ꢃ2), 1.38e1.30 (6H,
m, C(alkyl)H3 ꢃ2); 13C NMR (100 MHz, CDCl3) dC¼129.1 (CH), 125.3
(CH), 79.2 (CH), 76.7 (CH), 43.0 (CH), 29.3 (CH2), 28.8 (CH2), 28.7
(CH2), 28.5 (CH2), 26.7 (CH2), 26.3 (CH2), 26.1 (CH3); m/z (EIþ) 83
4.3.9. Table 2 entry 6: (ꢀ)-2-benzyl-6-methyl-3,6-dihydro-2H-pyran
and 2-benzyl-6-methyl-3,6-dihydro-6H-pyran. The product mixture
was obtained as a clear oil (61%) after purification by flash chro-
matography (diethyl ether/petroleum ether 1:5). Data presented
are for the inseparable mixture of stereoisomers. Rf 0.97 (10% EtOAc
in hexane); nmax/cmꢁ1 (CHCl3) 2924, 1724, 1602, 1454, 1216, 1028,
750, 700, 667; 1H NMR (400 MHz, CDCl3) dH¼7.22e7.10 (10Hma-
jor þ10Hminor, m, 2ꢃ Ph), 5.71e5.49 (2Hmajorþ2Hminor, m, over-
lapping 2ꢃ (CH]CH)), 4.30e4.12 (1Hmajor overlapping 1Hminor, m,
OCHMe), 3.73e3.57 (1Hmajor overlapping 1Hminor, m, OCHCH2Ph),
2.95e2.57 (2Hmajor overlapping 2Hminor, m, overlapping CH2Ph),
2.01e1.73 (2Hmajor overlapping 2Hminor, m, overlapping CH]
CHCH2), 1.25e1.14 (3Hmajor overlapping 3Hminor, m, overlapping
CHMe); 13C NMR (100 MHz, CDCl3) dC¼131.5 (CH), 129.9 (CH), 129.7
(C(Ar)H), 128.4 (C(Ar)H), 128.2 (C(Ar)H), 128.2 (C(Ar)H), 128 (C(Ar)
H), 127.9 (C(Ar)H), 126.2 (C(Ar)H), 126.1 (C(Ar)H), 126.1 (C(Ar)H),
125 (C(Ar)H),124.9 (CH),124 (CH), 76.7 (CHOCH2Ph), 75.9 (CHOMe),
71.2 (CHOCH2Ph), 70.1 (CHOMe), 42.6 (CH2), 42.5 (CH2), 31.6 (CH2),
30.7 (CH2), 21.7 (CH3), 21.4 (CH3); m/z (EIþ) 173 (80% [C12H13O]), 91
(100% [C7H7]). LRMS (GC-CI) found (M) 188, C13H16O requires
188.1201. HRMS could not be obtained.
(85% [C6H11þ]). HRMS could not be obtained.
4.3.13. Table 2 entry 8: (ꢀ)-4-(but-3-en-1-yloxy)-2-cyclohexyl-6-
methyltetrahydro-2H-pyran. The product was obtained as a clear oil
(1%) after purification by flash chromatography (dichloromethane/
n-hexane 3:1). Rf 0.72 (5% EtOAcin hexane); nmax/cmꢁ1 (CHCl3) 2921,
2853,1969, 638, 628, 604; 1H NMR (400 MHz, CDCl3) dH¼5.80e5.69
(1H, ddt, J¼14.3, 10.1, 7.4 Hz, CH]CH2), 5.03e5.00 (2H, m, over-
lapping CH2trans and CH2cis), 3.58e3.50 (1H, m, CHMe), 3.42e3.34
(1H, m, C(pyran)HOC6H11), 2.86e2.80 (2H,
m CH2CH]CH2),
2.25e1.83 (3H, m, overlapping C(pyran)HOC(ether) with CH2CH]
CH), 1.92e1.83 (4H, m, overlapping CHMeCH2CHOCH2), 1.66e1.59
(1H, m, CHC6H5), 1.25e0.99 (11H, m, C6H11), 0.95e0.82 (3H, m,
C(alkyl)CH3); 13C NMR (100 MHz, CDCl3) dC¼135.3 (CH),116.7 (CH2),
80.0 (CH), 76.7 (CH2), 76.5 (CH2), 74.3 (CH), 72.0 (CH), 43.0 (CH), 41.7
(CH2), 36.3 (CH2), 35.9 (CH2), 29.3 (CH2), 29.0 (CH2), 26.7 (CH2), 26.3
(CH2), 26.1 (CH2), 20.7 (CH3). HRMS could not be obtained.
4.3.10. Table 2 entry 7: (ꢀ)-2-heptyl-6-methyl-3,6-dihydro-2H-py-
ran and 2-heptyl-6-methyl-3,6-dihydro-6H-pyran. The product
mixture was obtained as a clear oil (81%) after purification by flash
chromatography (dichloromethane/n-hexane 3:1). Data presented
are for the inseparable mixture of isomers. Rf 0.67 (5% EtOAc in
hexane); nmax/cmꢁ1 (CHCl3) 2922, 2851, 1449, 1357, 1089, 914, 651;
1H NMR (400 MHz, CDCl3) dH¼5.81e4.95 (2H, m, (CH]CH) ꢃ2),
4.16e4.03 (2H, m, overlapping CHMe of major isomer with C(alkyl)
HO of minor isomer), 3.97e3.11 (6H, m, overlapping CHMe of minor
isomer with C(alkyl)HO of major isomer and with CH2CH]CH ꢃ2),
2.95e1.34 (16H, m, C8H16CH3 ꢃ2), 1.18e1.01 (6H, m, C(pyran)H3
ꢃ2), 0.95e0.83 (6H, m, C(alkyl)H3 ꢃ2); 13C NMR (100 MHz,
CDCl3) dC¼135.5 (CH), 129.0 (CH), 125.1 (CH), 124.6 (CH), 116.3 (CH),
116.2 (CH), 80.8 (CH), 42.9 (CH), 35.3 (CH2), 34.6 (CH2), 34.6 (CH2),
32.9 (CH2), 30.5 (CH2), 29.2 (CH2), 29.0 (CH2), 28.9 (CH2), 28.7 (CH2),
28.7 (CH2), 28.7 (CH2), 28.4 (CH2), 28.3 (CH2), 28.2 (CH2), 26.6 (CH3),
26.4 (CH3), 26.3 (CH3), 26.2 (CH3); m/z (EIþ) 111 (40% [C7H11]), 83
(100% [C5H7O]). HRMS could not be obtained.
4.3.14. Table 2 entry 9: (ꢀ)-benzyl 2-(6-methyl-3,6-dihydro-2H-py-
ran-2-yl)acetate and benzyl 2-(6-methyl-3,6-dihydro-6H-pyran-2-yl)
acetate. The product mixture was obtained as a clear oil (13%) after
purification by flash chromatography (diethyl ether/petroleum
ether 1:2). Data presented are for the inseparable mixture of ste-
reoisomers. Rf 0.82 (10% EtOAc in hexane); nmax/cmꢁ1 (CHCl3) 3019,
2928, 2856, 1732, 1215, 750, 697, 668; 1H NMR (400 MHz, CDCl3)
dH¼7.29e7.18 (10H, m, 2ꢃ Ph), 5.74e5.55 (4H, m, overlapping 2ꢃ
(CH]CH)), 5.10e5.05 (5H, m, 2ꢃ CH2Ph), 4.52e4.18 (2H, m, over-
lapping CH]CHCHO of one isomer and CH]CHCHMe of another
isomer), 3.97e3.95 (1H, m, CHOCH2), 3.64e3.40 (1H, m, CH2CHMe),
2.62e2.41 (4H, m, overlapping 2ꢃ CH2C]O), 1.93e1.88 (4H, m, 2ꢃ
CH2CH]CH), 1.15e1.12 (6H, m, 2ꢃ CH3); 13C NMR (100 MHz, CDCl3)
dC¼171.0 (C]O),131.5 (CH), 128.6 (CH), 128.5 (CH), 128.3 (CH), 128.1
(CH), 128.0 (CH), 125.8 (CH), 123.5 (CH), 71.6 (CH), 71.3 (CH), 70.6
(CH), 70.2 (CH), 66.2 (CH2), 41.2 (CH2), 40.8 (CH2), 32.6 (CH2), 30.5
(CH2), 21.6 (CH3). HRMS (NSI) found (Mþ) 247.1332, C12H19O3 re-
quires 247.1329.
4.3.11. Table 2 entry 7: (ꢀ)-4-(but-3-en-1-yloxy)-2-heptyl-6-meth-
yltetrahydro-2H-pyran. The product was obtained as a clearoil (75%)
after purification by flash chromatography (dichloromethane/n-
hexane 3:1). Rf 0.54 (5% EtOAc in hexane); nmax/cmꢁ1 (CHCl3) 2924,
2853, 1450, 1358, 1091; 1H NMR (400 MHz, CDCl3) dH¼5.91e5.81
(1H, ddt, J¼14.3, 10.9, 6.8 Hz, CH]CH2), 5.15e5.05 (2H, m, over-
lapping CH2trans and CH2cis), 4.07e4.02 (1H, m, CHMe), 3.60e3.34
(4H, m, overlapping C(pyran)HO and C(pyran)OCH2CH2CH]CH2),
3.05e3.00 (1H, m, CHCO(ether)), 2.38e2.33 (2H, m, CH2CH]CH2),
2.03e1.20 (16H, m, C8H16), 1.06e0.91 (3H, m, C(alkyl)CH3); 13C NMR
(100 MHz, CDCl3) dC¼135.3 (CH), 116.3 (CH2), 80.8 (CH), 76.7 (CH2),
75.9 (CH), 67.0 (CH2), 66.1 (CH2), 43.0 (CH), 35.3 (CH2), 34.6
(CH2), 32.9 (CH2), 29.0 (CH2), 28.7 (CH2), 26.6 (CH2), 26.3 (CH2), 26.2
(CH2), 22.7 (CH3), 14.1 (CH3); m/z (EIþ) 85 (55% [C5H8Oþ]), 167 (60%
[C10H15O2]), 55 (100% [C4H7]). HRMS could not be obtained.
4.3.15. Table 3 entry 1: 1-oxaspiro[5.5]undec-4-ene. The product
was obtained as a clear oil (79%) after purification by flash chro-
matography (dichloromethane/n-hexane 3:1). Rf 0.41 (5% EtOAc in
hexane); nmax/cmꢁ1 (CHCl3) 2995, 1710, 1362, 1216, 748, 667; 1H
NMR (400 MHz, CDCl3) dH¼5.70e5.66 (1H, dt, J¼10.9, 4.2 Hz, CH]
CHCH2O), 5.60e5.56 (1H, dt, J¼10.1, 2.5 Hz, CH]CHCH2O),
3.72e3.69 (2H, t, J¼5.4 Hz, CH2O), 2.01e1.97 (2H, m, CH]CHCH2C),
1.64e1.16 (10H, m, C5H10); 13C NMR (100 MHz, CDCl3) dC¼134.9
(CH), 123.2 (CH), 72.2 (C), 58.7 (CH2), 35.5 (CH2), 25.6 (CH2), 25.5
(CH2), 21.6 (CH2); m/z (EIþ) 109 (100% [C7H9O]). HRMS found (M)
152.1198, C10H16O requires 152.1196.
4.3.16. Table 3 entry 1: 1-oxaspiro[5.5]undec-3-ene. The product
was obtained as a clear oil (20%) after purification by flash chroma-
tography (dichloromethane/n-hexane 3:1). Rf 0.45 (5% EtOAc in hex-
ane); nmax/cmꢁ1 (CHCl3) 2923, 2853, 1462, 760, 620; 1H NMR
(400 MHz, CDCl3) dH¼5.70e5.56 (2H, m, CH]CHCH2O), 4.05e4.02
(2H, m, CH2O),1.91e1.88 (2H, m, CH]CHCH2CH2O),1.70e1.19(10H, m,
C5H10); 13C NMR (100 MHz, CDCl3) dC¼125.3 (CH),123.2 (CH), 70.6 (C),
4.3.12. Table 2 entry 8: (ꢀ)-2-cyclohexyl-6-methyl-3,6-dihydro-2H-
pyran and 2-cyclohexyl-6-methyl-3,6-dihydro-6H-pyran. The prod-
uct mixture was obtained as a clear oil (21%) after purification by
flash chromatography (dichloromethane/n-hexane 3:1). Data pre-
sented are for the inseparable mixture of isomers. Rf 0.92 (5% EtOAc

F.K. Chio et al. / Tetrahedron 67 (2011) 5107e5124
5119
60.3 (CH2), 35.4 (CH2), 34.9 (CH2), 25.6 (CH2), 21.6 (CH2); m/z (EIþ) 109
(100% [C7H9O]). HRMS found (M) 152.1197, C10H16O requires 152.1196.
1.40e1.02 (8H, m, overlapping C5H8), 1.17e1.16 (3H, d, J¼6.7 Hz,
CH3); 13C NMR (100 MHz, CDCl3) dC¼77.2 (C), 71.5 (CH), 66.1 (CH),
42.7 (CH2), 33.6 (CH2), 31.6 (CH2), 24.6 (CH2), 23.0 (CH2), 21.8 (CH2);
m/z (EIþ) 115 (60% [C6H11O2]). HRMS could not be obtained.
4.3.17. Table 3 entry 2: (ꢀ)-6-oxaspiro[4.5]decan-9-ol. The product
was obtained as a clear oil (41%) after purification by flash chro-
matography (dichloromethane/n-hexane 3:1). Rf 0.24 (10% EtOAc
in hexane); nmax/cmꢁ1 (CHCl3) 2923, 1780, 1072, 619; 1H NMR
(400 MHz, CDCl3) dH¼3.80e3.72 (2H, m, CH2O), 3.50e3.42 (1H, m,
C(pyran)CHOH), 1.83e1.30 (12H, m, overlapping CH2CHCH2 and
C5H8); 13C NMR (100 MHz, CDCl3) dC¼84.1 (C), 66.4 (CH), 60.4 (CH2),
44.7 (CH2), 41.0 (CH2), 35.7 (CH2), 33.5 (CH2), 24.4 (CH2), 23.2 (CH2);
m/z (EIþ) 139 (10% [C9H15O]). HRMS could not be obtained.
4.4. General procedure for the hydrogenation of
dihydropyrans
The dihydropyran mixture (0.04 g) was dissolved in dry meth-
anol (1.5 ml), followed by the addition of Pd/C catalyst (10 mol %,
0.004 g) under nitrogen. This stirring mixture was then fitted with
a 3-way tap connected to a H2 balloon. After evacuating the
remaining N2 and flushing the reaction mixture with hydrogen
three times, the mixture was left to stir with hydrogen blowing
under the surface at room temperature overnight. The next day the
crude mixture was filtered through a cake of Celite and the filtered
solution was concentrated in vacuo to yield the product pyran as
a clear oil.
4.3.18. Table 3 entry 4: (ꢀ)-2-benzyl-3,6-dihydro-2H-pyran and 2-
benzyl-3,6-dihydro-6H-pyran. The product mixture was obtained as
a clear oil (37%) after purification by flash chromatography
(dichloromethane/n-hexane 3:1). Data presented are for the major
isomer from the inseparable mixture. Rf 0.28 (5% EtOAc in hexane);
nmax/cmꢁ1 (CHCl3) 3085, 2923, 1495, 1246, 1085, 741, 698, 654; 1H
NMR (400 MHz, CDCl3) dH¼7.35e7.12 (5H, m, Ph), 5.80e5.55 (2H,
m, overlapping CH]CH), 4.24e3.89 (2H, m, CH2OCH]CH),
3.71e3.55 (1H, m, C(pyran)HO), 2.90e2.63 (2H, m, overlapping
CH2Ph), 2.25e1.83 (2H, m, overlapping CH]CHCH2); 13C NMR
(100 MHz, CDCl3) dC¼138.6 (CH), 138.3 (CH), 138.0 (C), 129.5 (C(Ar)
H), 129.3 (C(Ar)H), 128.3 (C(Ar)H), 128.2 (C(Ar)H), 127.1 (C(Ar)H),
74.9 (CH2), 74.5 (CH2), 66.1 (CH), 42.5 (CH), 41.87 (CH); m/z (EIþ) 55
(80% [C4H7þ]), 83 (100% [C6H10þ]). HRMS (CI) found (Mþ) 174.1042,
C12H14O requires 174.1039.
4.4.1. (ꢀ)-2-Benzylpyran 1. The product was obtained as a clear oil
(66%) after purification by flash chromatography (diethyl ether/
petroleum ether 1:5). Rf 0.80 (10% EtOAc in hexane); nmax/cmꢁ1
(CHCl3) 2935, 2848, 1496, 1454, 1087, 749, 670; 1H NMR (400 MHz,
CDCl3) dH¼7.23e7.11 (5H, m, Ph), 3.93e3.88 (1H, m, CH), 3.44e3.30
(2H, m, CH2O), 2.83e2.54 (2H, m, CH2Ph), 1.77e1.31 (6H, m,
CHOCH2CH2CH2); 13C NMR (100 MHz, CDCl3) dC¼129.4 (C(Ar)H),
128.2 (C(Ar)H), 126.1 (C(Ar)H), 78.8 (CH), 68.7 (CH2Ph), 43.2 (CH2),
31.5 (CH2), 26.1 (CH2), 23.5 (CH2); LRMS (GC-CI) found (Mþ) 177.1.
All other data are agreement with literature.54
4.3.19. Table 3 entry 4: 2-(but-3-en-1-yloxy)-1-phenylethanol. The
product was obtained as a clear oil (100%) after purification by flash
chromatography (dichloromethane/n-hexane 3:1). Rf 0.21 (5%
EtOAc in hexane); nmax/cmꢁ1 (CHCl3) 3437, 2866, 1641, 1453,
1348, 1102, 1043, 913, 756, 700, 637; 1H NMR (400 MHz, CDCl3)
dH¼7.41e7.29 (5H, m, Ph), 5.90e5.79 (1H, ddt, J¼13.6, 10.8, 6.8 Hz,
CH]CH2), 5.16e5.07 (2H, m, overlapping CH2trans and CH2cis),
4.47e4.43 (1H, dd, J¼8.4, 4.8 Hz, HCeOH), 3.72e3.40 (4H, m,
overlapping CH2OCH2), 2.42e2.36 (3H, m, overlapping COH and
CH2]CHCH2); 13C NMR (100 MHz, CDCl3) dC¼138.7 (C), 135.3
(CH), 128.5 (C(Ar)H), 128.1 (C(Ar)H), 126.8 (C(Ar)H), 116.7 (CH2),
83.0 (CH), 68.3 (CH2), 67.5 (CH2), 34.3 (CH2); m/z (EIþ) 167 (33%
[C10H15O2]), 55 (67% [C4H7]), 83 (100% [C5H7O]). LRMS (NSI)
found (M) 192, C12H16O2 requires 192.1150. HRMS could not be
obtained.
4.4.2. (ꢀ)-2-Benzyl-6-methylpyran 2. The product was obtained as
a clear oil (45%) and no further purification was carried out. Rf 0.78
(10% EtOAc in hexane); nmax (cmꢁ1) 2935, 2848, 1496, 1454, 1087,
749, 670; 1H NMR (400 MHz, CDCl3) dH¼7.21e7.09 (5H, m, Ph),
3.46e3.32 (2H, m, CH2O), 2.94e2.51 (2H, m, CH2Ph), 1.74e1.05 (9H,
m, CH3CHOCH2CH2CH2); 13C NMR (100 MHz, CDCl3) dC¼129.5
(C(Ar)H), 128.1 (C(Ar)H), 125.9 (C(Ar)H), 78.9 (CH), 74.0 (CH), 43.0
(CH2Ph), 31.1 (CH2), 30.6 (CH2), 23.6 (CH2), 23.6 (CH3). HRMS were
not obtained. All other data are in agreement with literature
values.54
4.5. General procedure for the formation of 5-fluoro-4-
trifluoromethanesulfonyl tetrahydropyrans
A solution of the aldehyde (1.5 equiv) in dry CH2Cl2 was cooled
to ꢁ78 ꢂC, treated with trimethylsilyl trifluoromethanesulfonate
(2.0 equiv) and stirred for 30 min at ꢁ78 ꢂC. The reaction mixture
was then treated with 2-fluorobut-3-en-1-ol10 (1.0 equiv) and
stirred for 3e4 h at ꢁ78 ꢂC. The reaction mixture was then warmed
to room temperature over 16 h before being quenched with water
(30 ml). The aqueous phase was separated from the organic phase,
extracted with CH2Cl2 (3ꢃ30 ml), the organic fractions combined,
dried over MgSO4, filtered and concentrated in vacuo. The residue
was purified by flash column chromatography.
4.3.20. Table 3 entry 5: 2-methyl-1-oxaspiro[5.5]undecan-4-ol. The
product mixture was obtained as a clear oil (51%) after purification
by flash chromatography (ethyl acetate/n-hexane 1:19). Rf 0.92 (10%
EtOAc in hexane); nmax/cmꢁ1 (CHCl3) 3350, 2931, 2857, 1449, 1379,
1145, 1030, 999, 753, 665; 1H NMR (400 MHz, CDCl3) dH¼3.98e3.90
(1H, m, C(pyran)CHOH), 3.68e3.60 (1H, m, MeCHO), 1.94e1.64 (4H,
m, overlapping CH2CHOHCH2), 1.58e1.17 (13H, m, overlapping C5H8
with CH3), 1.10e1.01 (1H, m, C(pyran)CHOH); 13C NMR (100 MHz,
CDCl3) dC¼77.2 (C), 65.3 (CH), 64.2 (CH), 43.6 (CH2), 40.3 (CH2), 31.3
(CH2), 26.2 (CH2), 22.6 (CH2), 22.2 (CH3), 21.9 (CH2), 21.6 (CH2); m/z
(EIþ) 167 (1% [C11H19O]), 184 (20% [C11H20O2]), 128 (96% [C7H12O2]).
LRMS (GC-EIP) found (M) 184.1, C11H20O2 requires 184.1463. HRMS
could not be obtained.
4.5.1. (ꢀ)-Trifluoromethanesulfonic acid 5-benzyl-2-fluorotetrahy-
dropyran-4-yl ester. Prepared according to general procedure using
phenylacetaldhyde (292.7
ml, 2.5 mmol), trimethylsilyl tri-
fluoromethanesulfonate (603.8 mg, 3.3 mmol), 2-fluorobut-3-en-
1-ol (150 mg, 1.7 mmol) and dry CH2Cl2 (15 ml) to afford the title
compound as a pale yellow oil (182.3 mg, 0.5 mmol, 32%); Rf 0.27 (5%
EtOAc in petrol); found [M]þ 342.0553; C13H14F4O4S requires
342.0549; nmax/cmꢁ1 (thin film) 3058 (m, aryl CeH), 2983-2846 (m,
CeH), 1602, 1493 (w, aryl CeH), 1419 (s, eSO2eOe), 1266 (s, CeF),
1218,1144 (s, eSO2eOe); dH (400 MHz, CDCl3) 7.34 (2H, m, aryl CH),
7.26 (3H, m, aryl CH), 4.96 (1H, m, CHOTf), 4.81 (1H, d, J¼49.8 Hz,
4.3.21. Table 3 entry 6: 7-methyl-6-oxaspiro[4.5]decan-9-ol. The
product was obtained as a clear oil (13%) after purification by flash
chromatography (dichloromethane/n-hexane 3:1). Rf 0.72 (10%
EtOAc in hexane); nmax/cmꢁ1 (CHCl3) 3387, 2949, 2868, 1702, 1452,
1375, 968, 755; 1H NMR (400 MHz, CDCl3) dH¼3.87e3.69 (1H, m,
MeCHO), 3.43e3.35 (1H, m, C(pyran)CHOH), 1.88e1.84 (1H, m,
C(pyran)CHOH), 1.80e1.40 (4H, m, overlapping CH2CHOHCH2),

5120
F.K. Chio et al. / Tetrahedron 67 (2011) 5107e5124
CHF), 4.26 (1H, ddd, J¼14, 9.4, 2.5 Hz, CH2CHF), 3.63 (1H, m,
CHCH2Ph), 3.51 (1H, dd, J¼36, 13.9 Hz, CH2CHF), 3.03 (1H, dd, J¼7.1
and 13.9 Hz, CH2Ph), 2.81 (1H, dd, J¼13.9, 5.7 Hz, CH2Ph), 2.16 (1H,
dd, J¼19.1, 11.5 Hz, CH2CHOTf), 2.06 (1H, m, CH2CHOTf); dC
(100 MHz, CDCl3) 137.3 (Cipso), 129.8, 129.7, 129.0, 128.9, 127.3(5ꢃ
aryl C), 85.5 (d, J¼185 Hz, C2), 84.2 (C3), 84.0 (C5), 68.4 (C1), 42.3
(C6), 33.0 (C4); dF (282.4 MHz, CDCl3) ꢁ75.7 (3F, s, CF3) and ꢁ202.4
(1F, m, CHF); m/z (EI) 343 [(MH)þ, 15%], 252 [(MH)þ, eCH2Ph, 35%],
193 [(MH)þ, eOTf, 26%].
CF3), ꢁ202.4 (1F, m, CHF); m/z (CI) 340.2 [(MþNH4)þ, 37%], 173.2
[(MþNH4)þ, eOTf, 94%].
4.5.5. (ꢀ)-Trifluoromethanesulfonic acid 5-benzhydryl-2-fluorote-
trahydropyran-4-yl ester. Prepared according the general procedure
using diphenylacetaldehyde (598
ml, 3.33 mmol), trimethylsilyl tri-
fluoromethanesulfonate (801 l, 4.44 mmol), 2-fluorobut-3-en-1-ol
m
(200 mg, 2.22 mmol) and dry CH2Cl2 (3 ml) to afford title compound
as a white powder (208 mg, 0.498 mmol, 22.4%); Rf 0.39 (10% EtOAc
in cylcohexane); found (MþNH4)þ 436.2067 C19H18F4O4S requires
418.4052; nmax/cmꢁ1 (KBr disc) 3053 (aryl C), 2991, 2947 (CH), 1463
(m, eSO2eOe), 1252 (s, CF), 1217 (s, CF), 1172 (m, eSO2eOe); dH
(400 MHz, CDCl3) 7.35 (4H, m, aryl CH), 7.24 (6H, m, aryl CH), 5.02
(1H, m, CHOTf), 4.80 (1H, d, J¼50.0 Hz, CHF), 4.26 (1H, ddd, J¼13.9,
9.6, 2.4 Hz, CH2CHF), 4.14 (1H, m, CHCH(Ph)2), 4.05 (1H, d, J¼3.2 Hz,
CHCH(Ph)2), 3.54 (1H, dd, J¼36, 13.6 Hz, CH2CHF), 2.15 (1H, q,
J¼12.0 Hz, CH2CHOTf), 1.91 (1H, dd, J¼12.4, 5.2 Hz, CH2CHOTf); dC
(100 MHz, CDCl3) 142.1 (Cipso)129.6,129.1,128.6,128.4,127.9 (5ꢃ aryl
C), 86.2 (C3), 84.3 (C2), 78.3 (C5), 68.2 (C1), 57.3 (C6), 31.9 (C4); dF
(376 MHz, CDCl3) ꢁ74.9 (3F, s, CF3), ꢁ202.2 (1F, m, CHF); m/z (CI)
436.2 [(MþNH4)þ, 41%], 269.4 [(M)þ, eOTf, 84%].
4.5.2. (ꢀ)-Trifluoromethanesulfonic acid 2-fluoro-5-pentyltetrahy-
dropyran-4-yl ester. Prepared according to the general procedure
using hexanal (300.4
ml, 2.5 mmol), trimethylsilyl tri-
fluoromethanesulfonate (603.8
ml, 3.3 mmol), 2-fluorobut-3-en-1-
ol (150 mg,1.7 mmol) and dry CH2Cl2 (15 ml) to afford title compound
as a pale yellow oil (150.6 mg, 0.5 mmol, 28%); Rf 0.68 (5% EtOAc in
petrol); found (MþNH4)þ340.1200 C11H18F4O4S requires 322.0862;
nmax/cmꢁ1 (thin film) 3058 (s, aryl CeH), 2983e2935 (s, CeH), 1419
(s, eSO2eOe), 1266 (s, CeF), 1215 (s, CeF), 1144 (m, eSO2eOe); dH
(400 MHz, CDCl3), 4.97 (1H, m, CHOTf), 4.80 (1H, d, J¼49.9 Hz, CHF),
4.25 (1H, ddd, J¼13.9, 9.4, 2.5 Hz, CH2CHF), 3.53 (1H, dd, J¼35.9,
13.9 Hz, CH2CHF), 3.39 (1H, m, CH(CH2)4CH3), 2.11 (1H, d, J¼21.2,
12.0 Hz, CH2CHOTf), 2.03 (1H, m, CH2CHOTf), 1.68 (1H, m,
CH(CH2)4CH3), 1.50 (2H, m, CH(CH2)4CH3), 1.31 (5H, m,
CH(CH2)4CH3), 0.89 (3H, t, J¼7.0 Hz, CH3); dC (100 MHz, CDCl3) 85.3
(C2), 84.1 (C3), 83.9 (C5), 68.0 (C1), 35.4(C6), 33.0 (C4), 31.6 (C7), 24.9
(C8), 22.5 (C9), 13.9 (C10); dF (282 MHz, CDCl3) ꢁ75.8 (3F, s, CF3),
ꢁ202.7 (1F, m, CHF); m/z (EI) 340.1 [(MþNH4)þ 100%], 322 [(Mþ),
12%], 173 [(MþH)þ, eOTf, 57%].
4.5.6. (ꢀ)-Trifluoromethanesulfonic acid 2-fluoro-5-phenyltetrah-
ydropyran-4-yl ester. Prepared according to the general procedure
using benzaldehyde (337
ml, 3.33 mmol), trimethylsilyl tri-
fluoromethanesulfonate (801
ml, 4.44 mmol), 2-fluorobut-3-en-1-ol
(200 mg, 2.22 mmol) and dry CH2Cl2 (3 ml) to afford title compound
as a pale yellow oil (157 mg, 0.479 mmol, 22%); Rf 0.42 (10% EtOAc in
cyclohexane); found (MþNH4)þ 346.0126 C12H12F4O4S requires
328.2808; nmax/cmꢁ1 (thin film) 3043 (aryl C), 2989 (CH), 1457 (m,
eSO2eOe), 1249 (s, CF), 1215 (s, CF), 1162 (m, eSO2eOe); dH
(400 MHz, CDCl3) 7.37 (5H, m, aryl CH), 5.15 (1H, m, CHOTf), 4.89 (1H,
d, J¼51.0 Hz, CHF), 4.46 (1H, m, CHPh), 4.39 (1H, m, CH2CHF), 3.73
(1H, dd, J¼36.2,14.0 Hz, CH2CHF), 2.47 (1H, q, J¼12.6 Hz, CH2CHOTf),
2.24 (1H, dd, J¼12.6, 5.1 Hz, CH2CHOTf); dC (100 MHz, CDCl3) 142.2
(Cipso)129.9,129.2,128.3,128.5,127.4 (5ꢃ aryl C), 86.2 (C3), 84.3 (C2),
78.3 (C5), 68.2 (C1), 31.9 (C4); dF (376 MHz, CDCl3) ꢁ75.2 (3F, s, CF3),
ꢁ202.9 (1F, m, CHF); m/z (CI) 346 [(MþNH4)þ, 71%], 329 [(MþH)þ,
19%], 179 [(M)þ, eOTf, 78%].
4.5.3. (ꢀ)-Trifluoromethanesulfonic acid 5-cyclohexyl-2-fluorote-
trahydropyran-4-yl ester. Prepared according to the general pro-
cedure using cyclohexanecarboxaldehyde (604.8
ml, 5.0 mmol),
trimethylsilyl trifluoromethanesulfonate (1.2 ml, 6.7 mmol), 2-
fluorobut-3-en-1-ol (300 mg, 3.3 mmol) and dry CH2Cl2 (30 ml)
to afford title compound as a pale yellow oil (578 mg, 1.7 mmol,
52%); Rf 0.35 (5% EtOAc in petrol); found [MþH, eOTf]þ 185.1337;
C12H18F4O4S requires 334.3254; nmax/cmꢁ1 (thin film) 3058, 2931,
2855 (m, CeH), 1415 (m, eSO2eOe), 1266 (s, CF), 1218 (br m, CF),
1142 (m, eSO2eOe); dH (400 MHz, CDCl3) 4.99 (1H, m, CHOTf),
4.86 (1H, d, J¼63.7 Hz, CHF), 4.24 (1H, ddd, J¼14.1, 9.5, 2.5 Hz,
CH2CHF), 3.50 (1H, dd, J¼36.1, 14.0 Hz, CH2CHF), 3.14 (1H, m,
CHCH(CH2)5), 2.09 (1H, m, CH2CHOTf), 1.88 (1H, d, J¼21 Hz,
CH2CHOTf), 1.70 (5H, m, (CH2)5), 1.44 (1H, m, CHCH(CH2)5), 1.19
(3H, m, (CH2)5), 1.04 (2H, m, (CH2)5); dC (100 MHz, CDCl3) 120.0
(C12), 86.3 (C2), 84.6 (C3), 80.2 (C5), 68.0 (C1), 42.3 (C6), 30.1
(C4), 28.6, 28.5, 26.3, 26.1, 25.9 (C7-11); dF (282.4 MHz, CDCl3)
ꢁ75.9 (3F, s, CF3) and ꢁ202.1 (1F, m, CHF); m/z (EI) 335 [(MH)þ,
62%], 251 [(MH)þ, eC6H12, 21%], 185 [(MH)þ, eOTf, 56%].
4.6. General procedure for the silyl-Prins reaction
Indium trichloride (1 equiv) was added to a 50 ml round bottom
flask containing a carbonyl compound (1 equiv) dissolved in dry
DCM (20 ml) under an atmosphere of nitrogen and the resulting
solution was stirred for 1 h. After this time the vinylsilyl alcohol
(1 equiv) was added and the reaction mixture stirred at room
temperature for a further 2e16 h (as indicated by TLC). The reaction
mixture was then quenched with distilled water (10 ml) and
the water layer was extracted with dichloromethane (40 ml). The
combined organic extracts were dried over magnesium sulfate. The
solvent was removed in vacuo and the reaction mixture purified by
flash column chromatography (normally hexane/diethyl ether
10:1) to give the desired product, usually as an oil.
4.5.4. (ꢀ)-Trifluoromethanesulfonic acid 5-(10-ethylpropyl)-2-fluo-
rotetrahydropyran-4-yl ester. Prepared according to the general
procedure using 2-ethylbutyraldehyde (406
ml, 3.33 mmol), trime-
thylsilyl trifluoromethanesulfonate (801 l, 4.44 mmol), 2-fluo-
m
robut-3-en-1-ol (200 mg, 2.22 mmol) and dry CH2Cl2 (3 ml) to afford
title compound as a pale yellowoil (297 mg, 0.922 mmol, 42%); Rf 0.48
(10% EtOAc in cyclohexane); found (MþNH4)þ 340.1201 C11H18F4O4S
requires 322.3172; nmax/cmꢁ1 (thin film) 2949, 2871 (m, CeH), 1417
(m, eSO2eOe), 1256 (s, CF), 1215 (br m, CF), 1142 (m, eSO2eOe); dH
(400 MHz, CDCl3) 4.97 (1H, m, CHOTf), 4.79 (1H, d, J¼50.0 Hz, CHF),
4.24 (1H, ddd, J¼14.0, 9.5, 2.4 Hz, CH2CHF), 3.50 (1H, dd, J¼36.2,
14.0 Hz, CH2CHF), 3.36 (1H, dd, J¼11.4, 4.8 Hz, CHCH(CH2CH3)2), 2.17
(1H, q, J¼12.4 Hz, CH2CHOTf), 1.95 (1H, ddd, J¼11.6, 4.0, 1.2 Hz,
CH2CHOTf), 1.41 (5H, m, CH(CH2CH3)2), 0.89 (6H, m, (CH2CH3)2); dC
(100 MHz, CDCl3) 87.7 (C2), 84.9 (C3), 78.1 (C5), 68.2 (C1), 45.7 (C6),
30.3 (C4), 22.0 (C7þ8),11.9(C9þ10); dF (376 MHz, CDCl3) ꢁ75.2 (3F, s,
4.6.1. 3-Benzyloxypropan-1-ol. Finely powdered potassium hy-
droxide (1.84 g, 33 mmol) was added to a solution of propane-1,3-
diol (350, 4.8 ml, 66 mmol) in THF/DMSO (9:1, 120 ml) and after
5 min benzyl bromide (3.9 ml, 33 mmol) was added while the re-
action mixturewas kept at 0 ꢂC (ice-bath). The mixturewas stirredat
room temperature for 24 h. After this time water/diethyl ether (1:1,
250 ml) was added to the reaction mixture and the layers separated.
The water layer was extracted with diethyl ether (2ꢃ200 ml) and
ethyl acetate (2ꢃ200 ml), the organic layers were combined, dried
(MgSO4) and concentrated in vacuo. The residue was purified by
column chromatography (petrol/diethyl ether¼1:1) to afford the

F.K. Chio et al. / Tetrahedron 67 (2011) 5107e5124
5121
title compound as a colourless oil (5.72 g, 44%); Rf 0.18 (petrol/diethyl
ether 1:1); nmax/cmꢁ1 (neat) 3385 (OH), 2939 [Ar(CeH)], 1659 (C]
C), 1485, 1460, 1367, 1198, 1081, 917, 748, 702; dH (300 MHz, CDCl3)
7.13e7.25 (5H, m, AreH), 4.39 (2H, s, PhCH2O), 3.62 (2H, m,
OCH2CH2CH2OH), 3.52 (2H, t, J¼5.9 Hz, CH2OCH2Ph), 2.67 (1H, br s,
OH), 1.73 (2H, m, OCH2CH2CH2OH); dC (75 MHz, CDCl3) 137.8 (Cipso),
128.0 [2ꢃ C(Ar)], 127.5 [2ꢃ C(Ar)], 127.4 (C(Ar)), 72.9, 68.8, 61.1 and
32.1 (4ꢃ CH2); m/z (CI) 167 [(MH)þ, 95%], 107 [(MH)þꢁC3H8O, 100].
43 ꢂC (lit.55 40 ꢂC). Rf 0.88 (10% EtOAc in hexane); nmax/cmꢁ1 (CHCl3)
2923, 1735, 1456, 1264, 1151, 970, 753, 698; 1H NMR (400 MHz;
CDCl3) dH¼7.42e7.33 (10H, m, 2ꢃ Ph), 5.77e5.75 (2H, m, CH]CH),
5.16 (4H, s, 2ꢃ CH2Ph), 3.18e3.17 (4H, m, CH2CH]CHCH2); 13C NMR
(100 MHz; CDCl3) dC¼171.3 (C]O), 135.8 (C), 128.6 (CH), 128.3 (CH),
128.2 (CH), 126.0 (CH), 66.5 (CH2), 37.8 (CH2); m/z LCMS [MHþ]
325.5. All other data are agreement with literature values.
4.7.3. Benzyl 3-oxopropanoate. A stirred solution of (E)-dibenzyl-
hex-3-enedioate (2.70 g, 8.33 mmol) in CH2Cl2 (150 ml, 18 ml/
mmol) was cooled to ꢁ78 ꢂC using an acetone/cardice bath. O3
(flow rate 70, voltage 200V) was bubbled through the solution for
half an hour, after which the solution turned blue. The bubbling of
ozone was carried on for another 20 min. Excess Me2S (3.06 ml,
41.65 mmol) was added to the mixture and the blue colour dis-
appeared immediately after three drops of the reagent was added.
The solution was concentrated in vacuo to yield a crude yellow oil.
The literature reports that the compound is unstable to any form of
purification, and this was found to be the case, even when using
a simple quick plug of silica rather than flash chromatography.
Therefore the product was used immediately in the next step
without further purification, in line with other reported applica-
tions of the compound. However, the impure IR and 1H NMR data is
presented. nmax/cmꢁ1 (CHCl3) 3452, 3065, 2955, 1734, 1171, 992,
739, 697; 1H NMR (400 MHz, CDCl3) dH¼9.76e9.75 (1H, t, J¼2.4 Hz,
CHO), 7.32e7.25 (5H, m, Ph), 5.15 (2H, s, CH2Ph), 3.37 (2H, d,
J¼2.5 Hz, COCH2CO); 13C NMR (100 MHz, CDCl3) dC¼128.7 (CH),
128.6 (CH), 128.5 (CH), 126.3 (CH), 67.0 (CH2), 48.5 (CH2); m/z LCMS
[Mþ] 179.3. HRMS were not obtained.
4.6.2. 3-Benzyloxy-1-propionaldehyde. Dimethyl
sufoxide
(1.1 ml, 16 mmol) was added to a solution of oxalyl chloride (0.7 ml,
8 mmol) in DCM (100 ml) at ꢁ78 ꢂC. The reaction mixture was
stirred for 10 min after which time 3-benzyloxypropan-1-ol (370,
1.20 g, 1 equiv) in DCM (5 ml) was added dropwise. After 15 min,
triethylamine (5.1 ml, 36 mmol) was added, the solution stirred for
5 min, and then the reaction mixture warmed to room temperature.
After stirring for 30 min the reaction was quenched with saturated
ammonium chloride solution (15 ml), and the aqueous phase was
washed with DCM (2ꢃ40 ml). The combined organic phase was
washed with saturated NaHCO3 (2ꢃ20 ml), brine (20 ml), dried
(MgSO4) and concentrated. Purification by flash chromatography
(petrol/diethyl ether¼2:1) gave the title compound as a clear oil
(0.91 g, 77%); Rf 0.35 (petrol/diethyl ether 2:1); nmax/cmꢁ1 (neat)
3032 [Ar(CeH)], 1726 (C]O), 1495, 1444, 1362, 1209, 1101, 906, 737,
691; dH (300 MHz, CDCl3) 9.82 (1H, s, CHO), 7.28e7.41 (5H, m,
AreH), 4.55 (2H, s, PhCH2O), 3.84 (2H, t, J¼6.1 Hz, CH2OCH2Ph), 2.72
(2H, t, J¼6.1 Hz, OCH2CH2CHO); dC (75 MHz, CDCl3) 200.9 (CHO),
137.6 (Cipso), 128.2 [2ꢃ C(Ar)], 127.5 [2ꢃ C(Ar)], 127.4 (C(Ar)), 72.9,
63.5 and 43.6 (3ꢃ CH2); m/z (CI) 165 [(MH)þ, 100%], 147
[(MH)þꢁH2O, 40], 107 [(MH)þꢁC3H8O, 95].
4.7.4. (ꢀ)-cis-6-(Methyltetrahydropyran-2-yl)acetic acid (Civet).
4.7.4.1. Method 1: hydrogenation of benzyl 2-(6-methyl-3,6-dihydro-
2H-pyran-2-yl)acetate and benzyl 2-(6-methyl-3,6-dihydro-6H-py-
ran-2-yl)acetate. The benzyl 2-(6-methyl-3,6-dihydropyran-2-yl)
acetate mixture (0.03 g) was dissolved in dry methanol (1 ml), fol-
lowed by the addition of Pd(OH)2 catalyst (10 mol %, 0.003 g) under
nitrogen. This stirring mixture was then fitted with a 3-way tap
connected to a H2 balloon. After evacuating the remaining N2 and
flushing the reaction mixture with hydrogen for 3 times, the mixture
was left to stir with hydrogen blowing under the surface at room
temperature overnight. The next day the crude mixture was filtered
through a cake of Celite and the filtered solutionwas concentrated in
vacuo to yield the product (ꢀ)-Civet as a clear oil (25 mg, 87%).
4.7. Total syntheses of ( )-Civet
4.7.1. (ꢀ)-cis-2-(2-Benzyloxyethyl)-6-methyl-5,6-dihydro-2H-pyr-
an. The title compound was prepared according to the general
procedure for the silyl-Prins cyclisation, using 3-benzyloxy-1-pro-
pionaldehyde (371, 0.40 g, 2.4 mmol), indium trichloride (0.54 g,
2.4 mmol) and (ꢀ)-Z-5-trimethylsilylpent-4-en-2-ol (239, 0.39 g,
2.4 mmol), and isolated by flash chromatography (petrol/diethyl
ether 5:1) as a colourless oil (0.54 g, 95%); Rf 0.25 (petrol/diethyl
ether 5:1); found [MþH]þ 233.1536; C15H21O2þH requires
233.1541; nmax/cmꢁ1 (neat) 2852 (OCH), 1700 (C]C), 1449, 1357,
1209, 1178, 1157, 1086 (CeO), 896, 732, 691; dH (400 MHz, CDCl3)
7.26e7.55 (5H, m, C(Ar)eH), 5.79 (1H, m, C(4)H), 5.64 (1H, dt,
J¼10.2, 1.9 Hz, C(3)H), 4.53 (2H, s, PhCH2OCH2), 4.31 (1H, m, C(2)H),
3.66 (3H, m, C(6)H, PhCH2OCH2), 1.95 (2H, m, C(5)H2), 1.85 (2H, m,
PhCH2OCH2CH2), 1.22 (3H, d, J¼6.2 Hz, C(6)CH3); dC (100 MHz,
CDCl3) 138.7 (Cipso), 130.2 (C(3)H), 128.3 [2ꢃ C(Ar)], 127.6 [2ꢃ
C(Ar)],127.4 (C(Ar)),124.8 (C(4)H), 72.9 (PhCH2O), 72.1 (C(2)H), 69.9
(C(6)H), 66.8 (CH2CH2OCH2Ph), 35.7 (CH2CH2OCH2Ph), 32.9 (C(5)
H2), 21.7 (C(6)CH3); m/z (CI) 233 [(MH)þ, 100%],189 [(MH)þꢁC2H4O,
40], 171 [(MH)þꢁC2H6O2, 55], 141 [(MH)þꢁC7H8, 60].
4.7.4.2. Method 2: hydrogenation and subsequent oxidation of 2-
(2-Benzyloxyethyl)-6-methyl-5,6-dihydro-2H-pyran. 2-(2-Benzylox-
yethyl)-6-methyl-5,6-dihydro-2H-pyran (372, 0.40 g, 1.7 mmol)
was dissolved in dry EtOH (4 ml) and Pd/C (0.04 g, 10 mol %) was
added under a nitrogen atmosphere. The solution was then sub-
jected to a hydrogen atmosphere by first flushing with hydrogen
and then slowly blowing hydrogen under the surface while the
solution was vigorously stirred at room temperature. After being
stirred under the atmosphere of hydrogen overnight (19 h), the
reaction mixture was filtered over Celite and the solvent was re-
moved in vacuo to afford 6-(methyltetrahydropyran-2-yl)ethanol
(0.24 g, 99%) which was used in the next step without further pu-
rification. dH (300 MHz, CDCl3) 3.81 (2H, m, CH2OH), 3.57 (1H, m,
C(2 or 6)H), 3.46 (1H, m, C(2 or 6)H), 3.10 (1H, br s, OH), 1.25e2.02
(8H, m, C(3,4,5 and 7)H2), 1.14 (3H, d, J¼6.2 Hz, C(6)CH3). 6-
(Methyltetrahydropyran-2-yl)ethanol (0.24 g, 1.7 mmol) was dis-
solved in acetone (20 ml) at 0 ꢂC and Jones reagent (12 ml) was
added dropwise while the reaction mixture was vigorously stirred.
[Preparation of the Jones reagent: concentrated sulfuric acid
(1.5 ml, 27 mmol) was added dropwise with swirling to a solution
of chromium trioxide (1.69 g, 17 mmol) in distilled water (24 ml) at
4.7.2. (E)-Dibenzylhex-3-enedioate. To a stirred solution of (E)-3-
hexenedioic acid (0.90 g, 6.24 mmol) in dry CH2Cl2 (50 ml, 8 ml/
mmol) was added dry triethylamine (1.91 ml, 13 mmol). This so-
lution was cooled to 0 ꢂC using an ice bath. Benzyl chloroformate
(1.76 ml, 12.48 mmol) was then added dropwise to this cooled
solution, followed by 4-(dimethylamino)pyridine (0.08 g,
0.62 mmol) in one portion. After warming the mixture to room
temperature, it was stirred for 12 h, then washed with 5% NaHCO3
solution (2ꢃ50 ml), 5% citric acid solution (2ꢃ50 ml) and brine
(2ꢃ50 ml). The organic extract was then dried (MgSO4), and con-
centrated in vacuo.
The product was obtained as white crystals (48%) after purifi-
cation by flash chromatography (ethyl acetate/n-hexane 1:3). Mp
0
ꢂC]. The reaction was warmed to room temperature and stirred

5122
F.K. Chio et al. / Tetrahedron 67 (2011) 5107e5124
for 3 h and followed by TLC. The mixture was poured into saturated
brine (20 ml) and extracted with chloroform (5ꢃ20 ml). The
combined organic phases were dried (MgSO4), filtered and the
solvent was removed in vacuo to give the crude oil, which was
purified by flash chromatography (DCM/diethyl ether¼3:1) to give
the title compound in the form of colourless crystals (0.15 g, 54%).
(1.01 g, 96%); Rf¼0.25 (petroleum ether (bp 40e60 ꢂC)); dH (270 MHz,
CDCl3) 6.30(1H, dd, J¼14.3 and6.8, OCH]CH2), 6.27 (1H, ddd, J¼14.3,
7.3 and 7.3, SiCH]CH), 5.61 (1H, d, J¼14.1, SiCH]CH), 4.27 (1H, dd,
J¼14.1 and 1.5, OCH]CHtrans), 3.99 (1H, dd, J¼6.7 and 1.5, OCH]
CHcis), 3.93 (1H, ddq, all J¼6.2, OCH(CH3)), 2.46 (1H, roofing AB dddd,
J¼14.3, 7.3, 6.2 and 1.2, CHaHb), 2.31 (1H, roofing AB dddd, J¼14.3, 7.3,
6.2 and 1.2, CHaHb), 1.21 (3H, d, J¼6.2, CH3), 0.11 (9H, s, SiMe3); dC
(68 MHz, CDCl3) 150.8 (OCH]CH2), 143.6 (SiCH]CH), 132.0 (SiCH]
CH), 88.4 (CH]CH2), 75.5 (CH(CH3)O), 39.9 (CH]CHCH2),19.6 (CH3),
0.2 (SiMe3); m/z (EI) 184 (Mþ, 4%),125 (12),101 (21), 73 (100), 59 (71),
45 (39). HRMS could not be obtained.
4.7.5. (ꢀ)-Civet. Identical spectral data were obtained from both
methods. However, the product from method 1 was a sticky oil
(trying to solidify) whereas the product from method 2 was col-
ourless crystals.
All data for Civet (from either method) are in the agreement with
previously published literature values.56,57 Mp 62e64 ꢂC (from
DCM/diethyl ether); Rf 0.33 (DCM/diethyl ether 3:1); found C 60.81,
H 8.90, C8H14O3 requires C 60.71, H 8.92; found [MþH]þ 159.1021;
C8H14O3þH requires 159.1021; nmax/cmꢁ1 (KBr) 3411 (COOH), 3098,
2934, 2868 (OCH),1716 (C]O),1434,1367,1301,1203,1060,1029; dH
(400 MHz, CDCl3) 10.29 (1H, br s, COOH), 3.76 (1H, m, C(2)H), 3.50
(1H, m, C(6)H), 2.56 (1H, dd, J¼15.6, 7.6 Hz, C(7)H2), 2.46 (1H, dd,
J¼15.6, 5.2 Hz, C(7)H2),1.18e1.84 (6H, m, C(3, 4 and 5)H2),1.16 (3H, t,
J¼6.2 Hz, C(6)CH3); dC (100 MHz, CDCl3) 175.8 [Cquat(COOH)], 74.4
(C(6)H), 73.9 (C(2)H), 41.3 (C(7)H2), 32.8, 30.8 and 23.2 (C(3-5)H2),
21.9 (C(6)CH3); m/z (CI) 159 [(MH)þ, 100%], 141 [(MH)þꢁH2O, 60],
100 [(MH)þꢁC3H7O, 5]. Crystal data for Civet at 120(2) K with MoKa
4.11. General procedure for the MukaiyamaeAldol silyl-Prins
reaction with aldehydes
To a ꢁ78 ꢂC solution of the silylated homoallylic vinyl ether
(1.0 equiv) and the aldehyde (1.0 equiv) in anhydrous dichloro-
methane (5 ml/mmol) was added titanium tetrachloride (1 M in
dichloromethane, 1.0 equiv). The reaction mixture was maintained
at this temperature for a period of 5 min after which time the quench
was affected with the addition of saturated NaHCO3 solution. The
biphasicmixturewasallowed towarmtoroomtemperature, andthe
layers were separated. The aqueous portion was extracted with
dichloromethane and the combined organic fractions were washed
with water, dried (MgSO4), filtered and concentrated in vacuo.
ꢁ
(¼ 0.71073A). M ¼ 158.19, Triclinic, P-1, a ¼ 6.8220(2), b ¼ 8.2332(2),
ꢁ
c ¼ 8.7991(3) A,
a
3
¼ 64.2870(10),
b
¼ 75.3220(10),
g
¼ 77.259(2)ꢂ,
ꢁ
V ¼ 427.27(2) A , Z ¼ 2, 9009 measured reflections, 1944 unique
reflections (Rint ¼ 0.0423), R ¼ 0.0376, wR ¼ 0.1047. Full crystallo-
graphic details have been deposited with the Cambridge Crystallo-
graphic Data Centre with reference number CCDC765666.
4.11.1. Table 7 entry 1 1-(5,6-dihydro-2H-pyran-2-yl)-3-phenyl-
propan-2-ol. Vinyl ether (0.17 g, 1.00 mmol, 1.0 equiv), phenyl-
acetaldehyde (0.12 ml, 1.00 mmol, 1.0 equiv), titanium tetrachloride
(1 M in dichloromethane, 1.0 ml, 1.00 mmol, 1.0 equiv) and anhy-
drous dichloromethane (5 ml) were mixed according to the general
procedure. Purification via preparative layer chromatography (pe-
troleum ether (bp 40e60 ꢂC)/diethyl ether, 4:1 v/v) gave the title
compound as a mixture of two diastereomers, as a colourless oil
(dr¼3.2:1,111 mg, 51%). nmax (cmꢁ1)2927, 2854,1701,1465,1102. Less
polar isomer: Rf¼0.61 (petroleum ether (bp 40e60 ꢂC)/dichloro-
methane, 1:2 v/v); (found [MꢁH2O]þ 200.1198, C14H18O requires
200.1196; found [MþNH4]þ 236.1644, C14H22O2N requires
236.1645); nmax(film)/cm-1 3421.5 (OeH), 1649.0 and 1494.7 (C]C),
1082 (CeO); dH (270 MHz, CDCl3) 7.31e7.19 (5H, m, 5ꢃ PheH),
5.90e5.84 (1H, m, C]CH), 5.51 (1H, d,J¼10.2, C]CH), 4.42 (1H, br s,
CHCH2CHOH), 4.15e4.08 (1H, m, CHOH), 3.99 (1H, dd, J¼11.2 and 5.8,
4.8. General procedure for the transetherification
of homoallylic alcohols
To a solution of the alcohol (1.0 equiv) in ethyl vinyl ether (3 ml/
mmol) was added mercury acetate (0.1 equiv). The solution was
stirred at room temperature for 2 days. The reaction mixture was
washed with saturated aqueous sodium hydrogencarbonate solu-
tion (3 ml/mmol), and the aqueous phase was extracted with ether
(3ꢃ5 ml/mmol). The combined organic phases were dried (MgSO4)
and the volatile liquids were removed in vacuo.
4.9. Z-Trimethylsilyl-4-vinyloxybut-1-ene
CHeqHaxOCH), 3.63 (1H, ddd appearing as td, J¼10.9 and 3.7, CHeq
-
HaxOCH), 3.02 (1H, s, OH), 2.81 (1H, dd, J¼13.6 and 7.4, PheCHaHb),
Z-4-Trimethylsilyl-3-buten-1-ol (0.49 g, 3.40 mmol, 1.0 equiv),
mercury acetate (0.11 g, 0.34 mmol, 0.1 equiv) and ethyl vinyl ether
(10 ml) were mixed according to the general procedure. Column
chromatography (petroleum ether (bp 40e60 ꢂC)) gave the title
compound as a colourless oil (0.56 g, 96%). Rf¼0.26 (petroleum ether
(bp 40e60 ꢂC)); dH (270 MHz, CDCl3) 6.47 (1H, dd, J¼14.3 and 6.9,
OCH]CH2), 6.30 (1H, dt, J¼14.1 and 7.2, SiCH]CH), 5.65 (1H, dt,
J¼14.1 and 1.2, SiCH]CH), 4.19 (1H, dd, J¼14.3 and 2.0, OCH]
CHtrans), 4.00 (1H, dd, J¼6.7 and 2.0, OCH]CHcis), 3.71 (2H, t, J¼6.9,
CH2O), 2.50 (2H, dtd, J¼7.2, 6.9 and 1.2, CH]CHCH2), 0.13 (9H, s,
SiMe3); dC (68 MHz, CDCl3) 151.8 (OCH]CH2), 143.7 (SiCH]CH),
132.1 (SiCH]CH), 86.5 (CH]CH2), 67.4 (CH2O), 33.1 (CH]CHCH2),
0.1 (SiMe3); m/z (EI) 170 (Mþ, 4%), 75 (38), 73 (100), 59 (67). HRMS
could not be obtained.
2.71 (1H, dd, J¼13.6 and 5.9, PheCHaHb), 2.37e2.25(1H, m, CHax
-
HeqC]C), 1.90 (1H, brd, J¼17.6, CHaxHeqC]C), 1.73e1.58 (2H, m,
OCH2CHOH); dC (68 MHz, CDCl3) 138.7 (Phipso), 129.8 (C]C), 129.4
(Phortho), 128.4 (Phmeta), 126.2 (Phpara), 125.5 (C]C), 72.5
(CHCH2CHOH), 69.6 (CHOH), 64.0 (CH2OCH), 44.0 (PhCH2), 40.5
(OCH2CHOH), 25.2 (CH2C]C); m/z (EI) 236.1 ([MþNH4]þ, 100%),
219.1 (Mþ, 90), 201.0 ([MꢁH2O]þ, 31), 83.0 (THP, 19).
4.11.2. Table
7 entry 2 1-(5,6-dihydro-2H-pyran-2-yl)heptan-2-
ol. Vinyl ether (0.24 g, 1.66 mmol, 1.0 equiv), hexanal (0.20 ml,
1.66 mmol, 1.0 equiv), titanium tetrachloride (1 M in dichloro-
methane, 1.7 ml, 1.66 mmol, 1.0 equiv) and anhydrous dichloro-
methane (7 ml) were mixed according to the general procedure.
Preparative layer chromatography (petroleum ether (bp 40e60 ꢂC)/
diethyl ether, 4:1 v/v) afforded the title compound as mixture of two
diastereoisomers as a colourless oil (95 mg, 48%). It was possible to
isolate a pure sample of the more polar isomer by preparative layer
chromatography. More polar isomer: Rf¼0.19 (petroleum ether (bp
40e60 ꢂC)/diethyl ether, 4:1 v/v); nmax (cmꢁ1) 2923, 2853, 1500,
1040; dH (270 MHz, CDCl3) 5.93e5.84 (1H, m, CH]C), 5.57 (1H, d,
J¼8.9, CH]CH), 4.45e4.38 (1H, br s, OCHCH]CH), 4.00 (1H, dd,
J¼11.0 and 5.7, CHaxHeqOCH), 3.89e3.79 (1H, m, CHOH), 3.62 (1H,
4.10. Z-Trimethylsilyl-4-vinyloxypent-1-ene
Following the general procedure for the transetherification of
alcohols, Z-5-trimethylsilyl-4-penten-2-ol XX (0.90 g, 5.69 mmol,
1.0 equiv), mercury acetate (0.18 g, 0.57 mmol, 0.1 equiv), and ethyl
vinyl ether (17 ml) were mixed. Column chromatography (petroleum
ether (bp 40e60 ꢂC)) gave the title compound as a colourless oil.

F.K. Chio et al. / Tetrahedron 67 (2011) 5107e5124
5123
td, J¼10.9 and 3.7, CHaxHeqOCH), 2.98 (1H, d, J¼3.2, OH), 2.41e2.24
(1H, m, CHaxHeqC]C), 1.95e1.83 (1H, m, CHaxHeqC]C), 1.70e1.63
(2H, m, CH2CHOH),1.50e1.22 (8H, m, (CH2)4), 0.87 (3H, t, J¼6.7, CH3);
dC (68 MHz, CDCl3) 129.9 (C]C), 125.6 (C]C), 72.7 (CHCH2CHOH),
68.7 (CHOH), 64.1 (CH2OCH), 41.1 (OCH2CHOH), 37.5 (CH(OH)CH2),
32.0 (CH2), 25.4 (CH2), 25.2 (CH2), 22.7 (CH2),14.1 (CH3); m/z (EI) 197
(Mþ,1%),137 (19),109(35), 83(100), 55(54). Less polarisomer(spectra
presented): Rf¼0.23 (petroleum ether (bp 40e60 ꢂC)/diethyl ether,
4:1 v/v); dH (270 MHz, CDCl3) 5.83e5.78 (1H, m, CH]C), 5.57 (1H, d,
J¼8.9, CH]CH), 4.30e4.24 (1H, br s, OCHCH]CH), 4.00 (1H, dd,
J¼11.0 and 5.7, CHaxHeqOCH), 3.89e3.79 (1H, m, CHOH), 3.64 (1H, td,
J¼10.9 and 3.7, CHaxHeqOCH), 3.20e2.87 (1H, br s, OH), 2.41e2.24
(1H, m, CHaxHeqC]C), 1.95e1.83 (1H, m, CHaxHeqC]C), 1.70e1.63
(2H, m, CH2CHOH),1.50e1.22 (8H, m, (CH2)4), 0.87 (3H, t, J¼6.7, CH3);
dC (68 MHz, CDCl3) 129.9 (C]C), 124.7 (C]C), 75.2 (CHCH2CHOH),
72.0 (CHOH), 63.3 (CH2OCH), 41.6 (OCH2CHOH), 37.6 (CH(OH)CH2),
32.0 (CH2), 25.4 (CH2), 25.2 (CH2), 22.7 (CH2),14.1 (CH3); m/z (EI) 197
(Mþ, 1%), 137 (19), 109 (35), 83 (100), 55 (54).
dichloromethane (5 ml) were mixed according to the general pro-
cedure. Purification via preparative layer chromatography (petro-
leum ether (bp 40e60 ꢂC)/diethyl ether, 4:1 v/v) yielded the title
compound as a mixture of two inseparable diastereoisomers as
a colourless oil (dr¼3.7:1, 124 mg, 42%). nmax (cmꢁ1) 2924, 2854,
1700, 1465, 1100. Less polar isomer: Rf¼0.20 (petroleum ether (bp
40e60 ꢂC)/diethyl ether, 4:1 v/v); dH (270 MHz, CDCl3) 7.44e7.16
(10H, m, AreH), 5.82e5.77(1H, m, CH]C), 5.52 (1H, dd, J¼10.5 and
1.9, C]CH), 4.73e4.63 (1H, m, CHCH2CHOH), 4.33 (1H, br s, CHOH),
3.99e3.84 (2H overlapping; [3.90, 1H, d, J¼8.8, Ph2CH] and [1H, m,
CHeqHaxOCH]), 3.65 (1H, ddd appearing as td, J¼10.9 and 3.7, CHeq
-
HaxOCH), 3.06e2.95 (1H, br s, OH), 2.42e2.21 (1H, m, CHaxHeqC]C),
1.91e1.86 (1H, m, CHaxHeqC]C), 1.63 (2H, dd appearing as t, J¼5.8,
CH2CHOH); dC (68 MHz, CDCl3) 142.7 (Aripso),129.9 (C]C),128.7 (Ar),
128.4 (Ar), 126.6 (Arpara), 125.6 (C]C), 72.3 (OCHCH2CHOH), 70.6
(CHOH), 63.7 (CH2OCH), 58.9 (Ph2CH), 39.5 (OCH2CHOH), 25.2
(CH2C]C); m/z (EI) 296 (Mþ,1%),167 (100),127 (29), 83 (82), 55 (26).
More polar isomer: Rf¼0.24 (petroleum ether (bp 40e60 ꢂC)/diethyl
ether, 4:1 v/v); dH (270 MHz, CDCl3) 7.44e7.16 (10H, m, AreH),
5.91e5.85(1H, m, CH]C), 5.52 (1H, dd, J¼10.5 and 1.9, C]CH),
4.73e4.63 (1H, m, CHCH2CHOH), 4.44 (1H, br s, CHOH), 3.99e3.84
4.11.3. Table 7 entry 3 1-cyclohexyl-2-(5,6-dihydro-2H-pyran-2-yl)
ethanol. Vinyl ether (0.17 g, 1.00 mmol, 1.0 equiv), cyclo-
hexanecarboxaldehyde (0.12 ml, 1.00 mmol, 1.0 equiv), titanium
tetrachloride (1 M in dichloromethane, 1.0 ml, 1.66 mmol, 1.0 equiv)
and anhydrous dichloromethane (5 ml) were mixed according to
the general procedure. Preparative layer chromatography (petro-
leum ether (bp 40e60 ꢂC)/diethyl ether, 4:1 v/v) afforded the title
compound as a mixture of two diastereomers (dr¼2.9:1, 99 mg,
47%). The more polar isomer was separated as a single diastereomer
using preparative layer chromatography. More polar isomer:
Rf¼0.20 (petroleum ether (bp 40e60 ꢂC)/diethyl ether, 4:1 v/v);nmax
(cmꢁ1) 3424, 2928, 2854, 1709, 1450, 1173, 1132, 754; dH (400 MHz,
CDCl3) 5.93e5.87 (1H, m, C(3)eH), 5.57 (1H, ddt, J¼10.3, 2.8 and 1.6,
C(4)eH), 4.46e4.40 (1H, m, C(5)eH), 4.01 (1H, dd, J¼11.2 and 5.8,
C(1)eHeq), 3.68 (2H overlapping, m, C(1)eHax and C(7)eH), 2.91
(1H, br s, OH), 2.40e2.29 (1H, m, C(2)eHax),1.95e1.60 (7H, m, C(2)e
Heq, C(6)eH, C (8)eH, cyclohex), 1.37e0.94 (7H,m, cyclohex); dC
(101 MHz, CDCl3) 129.9 (C(4)), 125.5 (C(3)), 72.8 (C(5)), 72.6 (C(7)),
64.1 (C(1)), 43.7, 38.1, 29.0, 28.3, 26.6, 26.3, 26.2, 25.1; m/z (EI) 209
(Mþ, 1%), 192 (21), 127 (9), 109 (31), 83 (100), 55 (48).
(2H overlapping; [3.90, 1H, d, J¼8.8, Ph2CH] and [1H, m, CHeqHax
-
OCH]), 3.64 (1H, ddd appearing as td, J¼10.9 and 3.7, CHeqHaxOCH),
3.06e2.95 (1H, br s, OH), 2.42e2.21 (1H, m, CHaxHeqC]C),1.99e1.92
(1H, m, CHaxHeqC]C),1.67 (2H, dd appearing as t, J¼5.7, CH2CHOH);
dC (68 MHz, CDCl3) 142.2 (Aripso), 129.8 (C]C), 128.8 (Ar),128.6 (Ar),
126.6 (Arpara), 124.9 (C]C), 74.9 (OCHCH2CHOH), 72.9 (CHOH), 63.3
(CH2OCH), 58.9 (Ph2CH), 40.1 (OCH2CHOH), 25.2 (CH2C]C); m/z (EI)
296 (Mþ, 1%), 167 (100), 127 (33), 83 (78), 55 (30).
4.11.6. Table 7 entry 6 2-(5,6-dihydro-2H-pyran-2-yl)-1-(4-nitro-
phenyl)ethanol. Vinyl ether (0.17 g, 1.00 mmol, 1.0 equiv), p-nitro-
benzaldehyde (0.15 g, 1.00 mmol, 1.0 equiv), titanium tetrachloride
(1 M in dichloromethane,1.0 ml,1.00 mmol,1.0 equiv) and anhydrous
dichloromethane (5 ml) were mixed according to the general pro-
cedure. Purification via preparative layer chromatography (petro-
leum ether (bp 40e60 ꢂC)/diethyl ether, 4:1 v/v) gave the title
compound as mixture of two diasteroisomers as a pale orange oil
(127 mg, 51%). More polar isomer: Rf¼0.23 (petroleum ether (bp
40e60 ꢂC)/diethyl ether, 4:1 v/v); dH (270 MHz, CDCl3) 8.13 (2H, d,
J¼8.7, AreH), 7.50 (2H, d,J¼8.6, AreH), 5.97e5.90 (1H, m, CH]C),
5.67 (1H, dd, J¼11.8 and 1.3, C]CH), 5.09e4.99 (1H, m, CHOH),
4.41e4.30 (1H, m, OCHCH]CH), 4.39 (1H, s, OH), 4.02 (1H, dd, J¼11.2
and 5.8, CHaxHeqOCH), 3.62 (1H, ddd appearing as td, J¼11.1 and 3.7,
CHaxHeqOCH), 2.43e2.21 (1H, m, CHeqHaxC]C), 2.00e1.74 (3H, m,
CH2CHOH and CHeqHaxC]C); dC (68 MHz, CDCl3) 152.3 (AreNO2),
147.1 (Aripso), 129.0 (C]C), 126.5 (Ar), 126.4 (C]C), 123.6 (Ar), 72.5
(OCHCH2CHOH), 70.6 (CHOH), 64.1 (CH2OCH), 43.1 (OCH2CHOH),
25.1 (CH2C]C); m/z (EI) 231 (34%), 152 (28), 106 (41), 83 (100), 55
(57). Less polar isomer: Rf¼0.26 (petroleum ether (bp 40e60 ꢂC)/
diethyl ether, 4:1 v/v); dH (270 MHz, CDCl3) 8.13 (2H, d, J¼8.7, AreH),
7.50 (2H, d,J¼8.6, AreH), 5.85e5.79 (1H, m, CH]C), 5.52 (1H, dd,
J¼11.8 and 1.3, C]CH) 5.09e4.99 (1H, m, CHOH), 4.41e4.30 (1H, m,
OCHCH]CH), 4.11 (1H, s, OH), 4.02 (1H, dd, J¼11.2 and 5.8, CHaxHe-
qOCH), 3.68 (1H, ddd appearing as td, J¼10.5 and 3.8, CHaxHeqOCH),
2.43e2.21 (1H, m, CHeqHaxOCH), 2.00e1.74 (3H, m, CH2CHOH and
CHeqHaxOCH); dC (68 MHz, CDCl3) 151.9 (AreNO2),147.2 (Aripso),129.1
(C]C), 126.6 (Ar), 125.4 (C]C), 123.6 (Ar), 74.8 (OCHCH2CHOH), 73.5
(CHOH), 63.5 (CH2OCH), 44.3 (OCH2CHOH), 25.0 (CH2C]C); m/z (EI)
231 (34%), 152 (28), 106 (41), 83 (100), 55 (57).
4.11.4. Table
7 entry 4 1-(5,6-dihydro-2H-pyran-2-yl)-3,3-dime-
thylbutan-2-ol. Vinyl ether (0.17 g, 1.00 mmol, 1.0 equiv), piv-
aldehyde (0.12 ml, 1.00 mmol, 1.0 equiv), titanium tetrachloride
(1 M in dichloromethane, 1.0 ml, 1.00 mmol, 1.0 equiv) and anhy-
drous dichloromethane (5 ml) were mixed according to the general
procedure. Preparative layer chromatography (petroleum ether (bp
40e60 ꢂC)/diethyl ether, 4:1 v/v) gave the title compound as
a mixture of two diastereoisomers (dr¼15.7:1, 40 mg, 22%). nmax
(cmꢁ1) 3415, 2957, 2870, 1731, 1364, 1058, 752, 666; Less polar
isomer: Rf¼0.26 (petroleum ether (bp 40e60 ꢂC)/diethyl ether, 4:1
v/v); dH (400 MHz, CDCl3) 5.93e5.87 (1H, m, C(3)eH), 5.58 (1H, ddt,
J¼10.3, 2.8 and 1.6, C(4)eH), 4.46e4.40 (1H, m, C(5)eH), 4.00 (1H,
dd, J¼11.2 and 5.8, C(1)eHeq), 3.74 (1H, td, J¼10.8 and 3.7, C(1)e
Hax), 3.52 (1H, dd appearing as t, J¼6.4 and 5.8, C(7)eH), 2.91 (1H,
br s, OH), 2.40e2.39 (1H, m, C(2)eHax), 1.90 (1H, br d, J¼17.43, 5.18,
3.34 and 1.63, C(2)eHeq), 1.66e1.62 (2H, m, C(6)eH), 0.88 (9H, s,
(C(9)eH3) ꢃ3); dC (101 MHz, CDCl3) 130.0 (C(4)), 125.6 (C(3)), 75.6
(C(7)), 72.9 (C(5)), 64.0 (C(1)), 35.7 (C(6)), 34.4 (C(8)), 25.6 (C(9)
ꢃ3), 25.1 (C(2)); m/z (EI) 184 (Mþ, 1%), 127 (13), 109 (33), 83 (100),
55 (36). More polar isomer: not visible by TLC, 1H NMR or 13C NMR;
m/z (EI) 184 (Mþ, 1%), 127 (15), 109 (37), 83 (100), 55 (34).
4.11.7. Table 7 entry 7 2,6-cis-3-(6-methyl-5,6-dihydro-2H-pyran-2-
yl)-1,1-diphenylpropan-2-ol. According to the general procedure, Z-
trimethylsilyl-4-vinyloxypent-1-ene (0.18 g, 1.00 mmol, 1.0 equiv),
diphenylacetaldehyde (0.18 ml, 1.00 mmol, 1.0 equiv), titanium tet-
rachloride (1 M in dichloromethane,1.0 ml,1.00 mmol,1.0 equiv) and
4.11.5. Table 7 entry 5 3-(5,6-dihydro-2H-pyran-2-yl)-1,1-diphenyl-
propan-2-ol. Vinyl ether (0.17 g, 1.00 mmol, 1.0 equiv), diphenyla-
cetaldehyde (0.18 ml, 1.00 mmol, 1.0 equiv), titanium tetrachloride
(1 M in dichloromethane, 1.0 ml, 1.00 mmol) and anhydrous

5124
F.K. Chio et al. / Tetrahedron 67 (2011) 5107e5124
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Simpson, T. J.; Smith, R. W.; Willis, C. L. Chem. Commun. 2001, 835e836.
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This paper does include one example of a tertiary carbcation, formed from
a Nicholas-Prins cyclisationd, being trapped by the triflate anion, although all the
examples cited currently involve secondary carbocations.
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dichloromethane (5 ml) were mixed. The title compound was isolated
as an inseparable mixture of diastereomers (51%, 3.2:1). nmax (cmꢁ1
)
3425, 3028, 2928, 1720, 1599, 1078, 750, 702. More polar isomer:
Rf¼0.25 (petroleum ether (bp 40e60 ꢂC)/diethyl ether, 4:1 v/v); dH
(270 MHz, CDCl3) 7.43e7.13 (10H, m, AreH), 5.91e5.85 (1H, m, CH]
C), 5.50 (1H, d, J¼10.3, C]CH), 4.69 (1H, t, J¼9.1, CHOH), 4.52e4.45
(1H, br s, OCHCH2CHOH), 3.90 (1H, d, J¼8.9, Ph2CH), 3.75e3.63 (1H,
m, CHCH3), 3.66 (1H, s, OH), 2.07e1.90 (2H, m, CH2C]C), 1.83e1.76
(1H, m, CHaHbCHOH), 1.63e1.53 (1H, m, CHaHbCHOH), 1.20 (3H, d,
J¼6.2, CH3); dC (101 MHz, CDCl3) 142.8e124.7 (Ar, C]C, C]C), 74.0
(OCHCH2CHOH), 74.0 (CHOH), 70.6 (CHCH3), 58.6 (Ph2CH), 39.4
(OCHCH2CHOH), 32.6 (CH2C]C), 21.7 (CH3); m/z (EI) 309 (Mþ, 1%),
167 (100), 97 (100). Less polar isomer: Rf¼0.27 (petroleum ether (bp
40e60 ꢂC)/diethyl ether, 4:1 v/v); dH (270 MHz, CDCl3) 7.43e7.13 (8H,
m, AreH), 5.76e5.70 (1H, m, CH]C), 5.46 (1H, d, J¼10.3, C]CH), 4.69
(1H, t, J¼9.1, CHOH), 4.43e4.36 (1H, br s, OCHCH2CHOH), 4.22 (1H, s,
OH), 3.90 (1H, d, J¼8.9, Ph2CH), 3.75e3.63 (1H, m, CHCH3), 2.07e1.90
(2H, m, CH2C]C),1.68e1.63 (1 H, m, CHaHbCHOH),1.60e1.52 (1H, m,
CHaHbCHOH), 1.21 (3H, d, J¼6.2, CH3); dC (101 MHz, CDCl3)
142.8e124.7 (Ar, C]C, C]C), 76.0 (OCHCH2CHOH), 70.7 (CHOH),
70.3(CHCH3), 58.8 (Ph2CH), 40.7 (OCHCH2CHOH), 32.5 (CH2C]C),
21.6 (CH3); m/z (EI) 309 (Mþ, 1%), 167 (100), 97 (100).
28. Rychnovsky, S. D.; Yang, G.; Hu, Y. Q.; Khire, U. R. J. Org. Chem. 1997, 62,
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We wish to thank the following: EPSRC (DTA studentships to F.C.
and M.P.); Pfizer (CASE award to M.P.); AstraZeneca (CASE award to
F.C.); Queen Mary University of London (studentships to D.G. and
J.W.); the University of Exeter (studentship to S.G.); Mr. Greg
Coumbarides for fluorine NMR spectra and other NMR experi-
ments. The EPSRC National Mass Spectrometry Service (Swansea,
UK) is gratefully acknowledged for running all high resolution mass
spectra. The EPSRC National Crystallography Service (University of
Southampton, UK) is gratefully acknowledged for running and
solving the crystal structure of Civet.
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Supplementary data
Copies of 1H and 13C NMR spectra of all new compounds and
additional experimental details may be found. Supplementary data
associated with this article can be found in the online version at
doi:10.1016/j.tet.2011.05.019.
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