Regioselective dihydropyran formation from 4-iodo-2,6-disubstituted tetrahydropyran derivatives using In(OAc)3/LiI system as the promoter

Article abstract of DOI:10.1016/j.tet.2015.11.046

The rapid and regioselective synthesis of a series of 2,6-disubstituted dihydropyranic building-blocks bearing an oxygenated side chain is described. The corresponding 4-iodo tetrahydropyran precursors, easily prepared by Prins cyclization, underwent regi

Full text of DOI:10.1016/j.tet.2015.11.046

Tetrahedron 72 (2016) 318e327
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Regioselective dihydropyran formation from 4-iodo-2,
6-disubstituted tetrahydropyran derivatives using In(OAc)3/LiI
system as the promoter
,
c
b
a
Thibaut Chalopin a, Khaoula Jebali a , Catherine Gaulon-Nourry , Fabrice Denes ,
ꢀ ꢁ
a
a,
*
ꢀ
Jacques Lebreton , Monique Mathe-Allainmat
a
ꢀ
ꢀ
ꢁ
Universite de Nantes, CNRS, Laboratoire CEISAMeUMR 6230, Faculte des Sciences et des Techniques, 2 rue de la Houssiniere, BP 92208, 44322 Nantes
Cedex 3, France
b
ꢀ
Universite du Maine, IMMM UMR CNRS 6283, Avenue O. Messiaen, 72085 Le Mans, France
c University of Tunis El Manar, Faculty of Science, Campus, 2092, Laboratory of Selective Organic Synthesis and Biological Activity, Tunis, Tunisia
a r t i c l e i n f o
a b s t r a c t
Article history:
The rapid and regioselective synthesis of a series of 2,6-disubstituted dihydropyranic building-blocks
bearing an oxygenated side chain is described. The corresponding 4-iodo tetrahydropyran precursors,
easily prepared by Prins cyclization, underwent regioselective elimination in the presence of an In(OAc)3/
LiI system to provide the title compounds. The one-pot Prins cyclization-elimination process was also
studied and could be achieved with the TMSBr/LiI/In(OAc)3 system.
Received 29 September 2015
Received in revised form 18 November 2015
Accepted 19 November 2015
Available online 23 November 2015
Ó 2015 Elsevier Ltd. All rights reserved.
Keywords:
Oxygen heterocycles
Prins cyclization
Lewis acid
Elimination
Regioselectivity
1. Introduction
has been observed.8 From cyclic carbocation 2, nucleophile trap-
ping affords the 2,4,6-trisubstituted pyran 3 (Scheme 1). The
Polysubstituted dihydropyran (DHP) heterocycles are present in
a number of natural products of biological or therapeutic interest1
(Fig. 1) but these units are also important precursors of the
synthesis of more complex tetrahydropyran (THP) compounds es-
pecially by further functionalization of the olefin function.2 Some
synthetic approaches have been proposed in the literature for the
synthesis of a substituted dihydro-2H-pyran system by CeO bond
formation in metal-mediated3 or by Lewis-acid4 cyclization re-
actions. Carbon-carbon bond formation has also been reported
under various conditions. These include the ring closing metathesis
reaction,5 free radical conditions6 or a Prins-type cyclization
reaction with homoallylic alcohols bearing a TMS group at the
terminal carbon of the double bond.7 The commonly accepted Prins
cyclization mechanism depicted in Scheme 1 suggests the forma-
tion of oxocarbenium ion intermediate 1, which may undergo 6-
endo cyclization to give tetrahydropyranyl carbocation 2. In some
cases, an oxonia-Cope rearrangement leading to oxocarbenium 10
substituents at C2 and C6 of pyrans 3 formed under Prins cycliza-
tion conditions are preferentially cis,9 and the stereoselectivity of
nucleophile capture at C4 depends on both the reaction conditions
and the stability of the carbocationic intermediate.10 On the other
hand,
b
-silyl carbocation 2 (Scheme 1, R3¼TMS) can undergo
desilylation to give 2,6-cis dihydropyran 4.
Unlike the Prins cyclization reaction involving a homoallylic
alcohol bearing a vinylsilane moiety, which leads to dihydropyrans
in a highly regioselective manner,11 only a few examples of dihy-
dropyran formation have been reported starting from non-silylated
homoallylic alcohols, and these include substrates allowing for the
additional stabilization of the carbocation intermediate with, for
example, an alkyl substituent.12 However, the formation of the
carbon-carbon double bond is barely selective, giving both
regioisomers 4-Me and 40-Me (Scheme 1, R3¼H and R4¼Me). When
the Lewis acid anion is not nucleophilic enough (e.g., a triflate an-
ion), elimination might also occur during Prins cyclization
involving primary as well as secondary homoallylic alcohols as
substrates, also leading to
a
mixture of both expected
dihydropyrans.11c,13
* Corresponding author. Fax: þ33(0)2 51 12 57 12; e-mail address: monique.
ꢀ
mathe@univ-nantes.fr (M. Mathe-Allainmat).
http://dx.doi.org/10.1016/j.tet.2015.11.046
0040-4020/Ó 2015 Elsevier Ltd. All rights reserved.

T. Chalopin et al. / Tetrahedron 72 (2016) 318e327
319
Fig. 1. Natural products containing DHPs.
Scheme 1. Accepted Prins cyclization mechanism leading to THP or DHP formation.
2. Results and discussion
ozone gave the expected aldehyde 6g in 46% yield over the two
steps (see Supplementary data).19 The Prins cyclization was
investigated in known conditions with LiI and CeCl3 as the Lewis
acid. These conditions led to the expected 4-iodo tetrahydropyrans
( )-7aei and ( )-8aei in moderate yields (43%e76%) and a lack of
diastereoselectivity starting from O-benzylated aldehydes (Table 1,
entries 1e3 and 5e7) or not (Table 1, entries 8 and 9). In addition,
no cyclization occurred with the cyclopropylcarboxaldehyde com-
pound 6d (Table 1, entry 4). A significant quantity of alcohol 9 was
sometimes isolated starting with these specific aldehydes, pointing
towards an oxonia-Cope rearrangement and the relative stability of
the corresponding oxocarbenium. Similar results were obtained
with CeCl3$7H2O15 (data not shown). Because In(III) Lewis acid is
often used in Prins cyclization reactions, we also tested the cheap
and air-stable In(OAc)3 in the same conditions. Unfortunately, with
the bulky aldehyde 6a, the starting materials were recovered and
no cyclization occurred (Table 1, entry 10).
During the course of our work14a on the synthesis of analogues
of the natural pyranic macrocycle Peloruside A (Fig. 2), we have
focused our interest on simple access to specific tetrahydropyrans 3
or dihydropyrans 4 bearing a bulky
a-gem-disubstituted side chain
with terminal alcohol function (Scheme 1, e.g.,
a
R2¼C(Me)2CH2OPG). We thought that the targeted 4-halogeno
tetrahydropyrans 3 could be obtained in known Prins cyclization
conditions15 starting from commercial homoallylic alcohols such as
5 and bulky benzyloxyaldehydes 6aef (Table 1). Interestingly, few
examples of Prins cyclization starting from bulky aldehydes16 or
bulky secondary homoallylic alcohols17 are described in the
literature.
We first prepared a selection of the O-protected hydroxy alde-
hydes 6aef in two steps, starting with classic O-monobenzylation
of the corresponding diol18 (44%e94% yields) followed by Swern
oxidation (72%e97% yields, see Supplementary data). From 3-
buten-1-ol, O-benzylation followed by oxidative cleavage with
We then turned our attention to a possible double bond for-
mation from 2,4-cis-4-iodo-THP ( )-7a or 2,4-trans-4-iodo-THP
Fig. 2. Pelorusides and analogues.14b

320
T. Chalopin et al. / Tetrahedron 72 (2016) 318e327
Table 1
Synthesis of 4-iodo-2,6-disubstituted tetrahydropyrans 7:8
Entry
Aldehyde
R1
R2
R3
L. A.
7:8 [ratio]a
Yield (%)b
1
2
3
4
5
6
7
8
9
6a
6b
6c
6d
6e
6f
6g
6h
6i
CH2OBn
CH2OBn
CH2OBn
CH2OBn
CH2OBn
CH2OBn
CH2OBn
CH2Ph
Me
Pr
Me
Cyclopropyl
Cyclopentyl
Cyclohexyl
H
H
Me
Pr
CH2OBn
CeCl3
CeCl3
CeCl3
CeCl3
CeCl3
CeCl3
CeCl3
CeCl3
CeCl3
In(OAc)3
7a:8a [1.2:1]
7b:8b [1.2:1]
7c:8c [1:1.6]
7d:8d
7e:8e [1:1]
7f:8f [1:1]
7g:8g [1.2:1]
7h:8h [1:1]
7i:8i [1:1]
7a:8a
62
48
53
NRc
43
65
43
76
50
NRc
H
H
Me
Me
H
Me
Me
10
6a
CH2OBn
a
1H NMR determination of 7:8 ratio.
b
Global yield of both isomers 7:8 purified by column chromatography on silica gel. Only compounds ( )-7a, ( )-8a, ( )-7b, ( )-8b, ( )-7c, ( )-8c, ( )-7g and ( )-8g, could be
obtained pure and characterized.
c
NR¼no reaction.
( )-8a. We thought that the corresponding dihydropyran derivative
could easily be arranged to a dihydroxylated tetrahydropyran
fragment as found in the pyranic part of Peloruside A (Fig. 2). In the
literature, non-regioselective elimination has been observed during
the Prins cyclization reaction, with a sub-stoichiometric amount of
Lewis acid such as InCl312a or In(OTf)3.13 Selecting two potent In(III)
Lewis acids, such as indium triflate and iodide, we proposed to test
them in a potential elimination step and starting from preformed 4-
iodo THPs 7a:8a. The starting material was consumed at moderate
temperature, and 1H NMR spectrum analysis of the crude middle
revealed a complex mixture with traces of compound ( )-10a
(Table 2, entries 1e2). In fact with 1 equiv of InI3 as the Lewis acid,
and the addition of a mineral base such as K2CO3 in order to
neutralize residual acidity, dihydropyran ( )-10a could be obtained
in 48% yield (Table 2, entry 3). We pursued our investigations with
the easy to handle In(OAc)3 Lewis acid and performed the elimi-
nation step in the absence (Table 2, entry 4) or presence (Table 2,
entries 5 and 6) of an excess of LiI. Gratifyingly, with the iodide salt,
the dihydropyran derivative ( )-10a was obtained in a pure
regioisomeric form with a 70% or 75% yield from pure di-
astereoisomers ( )-7a or ( )-8a, respectively. The double bond lo-
cation was unambiguously confirmed from crystallographic data of
a silylated analogue (see Supplementary data). The effect of solvent
or additives on DHP ( )-10a formation was then examined. No
Table 2
Study of elimination conditions, starting from pure or an equimolar mixture of ( )-7a and ( )-8a
Entry
THP
Solvent
T (ꢀC)
In(III)a/Additiveb
(ꢁ)-10a Yield (%)c
1
2
3
4
5
6
7
8
7a:8a
7a:8a
7a:8a
7a:8a
7a
(ClCH2)2
(ClCH2)2
(ClCH2)2
(ClCH2)2
(ClCH2)2
(ClCH2)2
dioxane
MeCN
50
40
83
83
83
83
101
82
110
83
83
In(OTf)3
InI3
InI3/K2CO3
dd
dd
48
e
In(OAc)3
NRf
70
In(OAc)3/LiI
In(OAc)3/LiI
In(OAc)3/LiI
In(OAc)3/LiI
In(OAc)3/LiI
In(OAc)3/KI
In(OAc)3/DBU
8a
75
7a:8a
7a:8a
7a:8a
7a:8a
7a:8a
NRf
NRf
34
9
10
11
toluene
(ClCH2)2
(ClCH2)2
NRf
NRf
a
Reaction was performed either with 1 equiv of InI3 and In(OTf)3 or with 2 equiv of In(OAc)3.
Reaction was performed with 2 equiv of LiI or KI and with 3 equiv of K2CO3 or 1 equiv of DBU.
Yield refers to pure product isolated after column chromatography purification.
b
c
d
e
f
Degradation occurred at 40 ꢀC and higher temperature but some amount of compound ( )-10a was observed on 1H NMR spectrum.
No elimination occurred with K2CO3 alone in boiling solvent during 5 h.
NR¼no reaction and recovery of starting material.

T. Chalopin et al. / Tetrahedron 72 (2016) 318e327
321
elimination occurred at elevated temperature in dioxane20 or ace-
tonitrile21 while the expected DHP ( )-10a was obtained in mod-
erate yield in refluxing toluene (Table 2, entries 7e9). These results
could highlight that O- or N- donor solvents are able to block the
elimination mechanism probably by adduct formation with the
In(III) Lewis acid.22 This could prevent from complexation of the
Lewis acid with THPs’ benzyl ether and iodide substituents,
certainly involved in this regioselective elimination process to give
DHP ( )-10a. Moreover no elimination occurred when LiI was
replaced by the poorly soluble KI (Table 2, entry 10) or when
a base23 such as DBU was used to promote elimination (Table 2,
entry 11). Both results let us to suspect the formation of iodide
indium species from the In(OAc)3/LiI system, during the reaction.
Indeed InI3 was identified as an effective promoter to access to the
targeted DHP ( )-10a from THPs 7a:8a (Table 2, entry 3), but not
In(OAc)3 alone (Table 2, entry 4).
Therefore, In(OAc)3/LiI in refluxing 1,2-dichloroethane appeared
to be the best combination for regioselective elimination and these
conditions were applied to the set of iodo-THPs 7bei:8bei
previously prepared. Regioselective elimination was systematically
observed from a mixture of 4-iodo THPs 7:8 bearing gem-dialkyl or
cycloalkyl substituents at the benzyl ether side chain (Table 3,
entries 1e5). The best result was obtained with two benzyl ether
groups on the side chain (Table 3, entry 3). Next, reaction with the
2,4-trans 4-iodo stereoisomer ( )-8g with a non-substituted side
chain was investigated and also gave the expected DHP ( )-10g in
good yield (Table 3, entry 6). Complementary experiments carried
out with THPs bearing a phenethyl side chain 7h:8h or an isopropyl
side chain 7i:8i, emphasized the striking role of the terminal ether
function, because there was no elimination and degradation slowly
occurred after five hours in boiling solvent (Table 3, entries 9 and
10). It is also notable that no elimination occurred starting from the
4-chloro analogue of 7a.24
Under our optimized reaction conditions, In(OAc)3/LiI-mediated
elimination of 4-iodo THPs was highly selective and resulted in the
exclusive formation of a single regioisomer from precursors with
a benzyl ether group located on the alkyl side chain. The results of
this preliminary study clearly demonstrate the leading roles of the
protected alcohol function and 4-iodo substituent on THPs. Both
functions might be involved in the formation of an adduct with
indium species, to generate the regioselective elimination and DHP
formation. However it still needs further studies to propose an
exact mechanism and these are underway.
An extension of this reaction was also proved starting from C6-
allyl or C6-phenyl 4-iodo tetrahydropyrans. The 4-iodo THPs 13:14
and 15:16 were prepared by performing the reaction with CeCl3/LiI
or TMSBr/LiI25,26 systems, respectively (Scheme 2). As mentioned
earlier, cyclization of benzylic alcohol 12 and aldehyde 6a didn’t
work in standard conditions with CeCl3/LiI, however we observed
that the addition of one equivalent of a Brønsted acid27 such as
acetic acid in dichloroethane, for 12 h at room temperature,
afforded the single diastereoisomer ( )-16 in poor yield (10%) with
the recovery of the starting material. The elimination step worked
cleanly and gave the dihydropyrans ( )-17 and ( )-18 in around
45% yield, starting from
diastereoisomers.
a
mixture of cis- and trans-
Table 3
In(OAc)3/LiI-mediated regioselective elimination of 4-iodo-2,6-disubstituted tetrahydropyrans ( )-7 or ( )-8
Entry
THP
R1
R2
R3
DHP
Yield (%)
1
2
3
4
5
6
7
8
8a
CH2OBn
CH2OBn
CH2OBn
CH2OBn
CH2OBn
CH2OBn
CH2Ph
H
Me
Pr
Me
cyclopentyl
cyclohexyl
H
H
Me
Me
Pr
CH2OBn
10a
10b
10c
10e
10f
10g
10h
10i
75
56
80
67
75
68
da
da
7b:8b
7c:8c
7e:8e
7f:8f
8g
H
H
Me
7h:8h
7i:8i
a
No elimination but slow degradation.
Scheme 2. Reagents and conditions: a) for 13:14; CeCl3 (1 equiv), LiI (1.1 equiv), ClCH2CH2Cl, 3 h, reflux, global yield 42% (ratio 1.2:1); b) for 15:16; TMSBr (1 equiv), LiI (2 equiv),
ClCH2CH2Cl, room temperature, 1 h, global yield 70% (ratio 1:1.2); c) In(OAc)3 (2 equiv), LiI (2 equiv), ClCH2CH2Cl, reflux, 44% yield for ( )-17, 40% yield for ( )-18.

322
T. Chalopin et al. / Tetrahedron 72 (2016) 318e327
Scheme 3. Reagents and conditions: a) TMSBr (1 equiv), LiI (2 equiv), ClCH2CH2Cl, 0 ꢀC for 40 min, then In(OAc)3 (2 equiv), reflux, 45% yield for ( )-10a, 40% yield for ( )-10c and 41%
yield for ( )-10g.
Finally, because the Prins cyclization did not run with the
In(OAc)3/LiI system as the promoter (Table 1, entry 10), one
equivalent of TMSBr with LiI (2 equiv) was introduced prior to the
addition of In(OAc)3. In these conditions in refluxing solvent,
dihydropyrans ( )-10a, ( )-10c and ( )-10g11c were obtained in
a one-pot two-steps fashion in around 40% yield (Scheme 3).
Supplementary data as well as the NMR spectra of all the THP and
DHP compounds.
4.2. General procedure A for Prins cyclization, mediated by
CeCl3
To a solution of aldehyde 6 (5.20 mmol, 1 equiv), in di-
chloroethane (41 mL) was added alcohol 5 (1.1 equiv), cerium
chloride (1 equiv), and lithium iodide (2 equiv). The mixture was
refluxed for 3 h. It was cooled to room temperature, filtered on
Celite, and rinsed with dichloromethane. The organic layers were
washed with a saturated aqueous solution of Na2S2O3, a saturated
aqueous solution of NaHCO3, and brine then dried over anhydrous
MgSO4. They were filtered, and concentrated under reduced pres-
sure. Expected THP derivatives ( )-7 and ( )-8 were purified by
flash chromatography on silica gel. In some cases a small amount of
alcohol 9 resulting from oxonia Cope rearrangement could also be
isolated and characterized.
3. Conclusion
In conclusion, we have uncovered an original and unexpected
regioselective elimination reaction of specific 2,6-disubstituted 4-
iodo-tetrahydropyrans, bearing a benzyl ether function at C2. This
reaction occurred in apolar solvents in the presence of In(III) Lewis
acid. Air-stable and inexpensive In(OAc)3 with LiI reagent were
preferred and also proved to be more efficient than indium triflate
or iodide. Moreover, the regioselective one-pot access to the ex-
pected dihydropyran, from the corresponding aldehydes and the
non-silylated homoallylic alcohol precursors, was achieved by the
simple addition of trimethylsilyl bromide to the In(OAc)3/LiI sys-
4.2.1. (2S,4R,6S)-2-(1-(Benzyloxy)-2-methylpropan-2-yl)-4-iodo-6-
methyltetrahydro-2H-pyran [(ꢁ)-7a] and (2S,4S,6S)-2-(1-(benzy-
loxy)-2-methylpropan-2-yl)-4-iodo-6-methyltetrahydro-2H-pyran
[(ꢁ)-8a]. Following procedure A and starting from 6a (2.03 mmol,
1 equiv), purification by column chromatography on silica gel
(petroleum ether/toluene; 70:30) afforded the first di-
astereoisomer 2,4-cis ( )-7a (145 mg), the second diastereoisomer
2,4-trans ( )-8a (141 mg), and a 50/50 mixture of both compounds
(208 mg), in 62% global yield, as colourless oils. Some alcohol 9a
could also be isolated for identification. 2,4-cis diastereoisomer
[( )-7a]: FTIR (ATR) cmꢂ1: 3028, 2966, 2931, 2851, 1452, 1361,
1294, 1180, 1152, 1089, 1065, 1027, 734, 696, 519, 480. 1H NMR
tem. These conditions could induce Prins cyclization preceeding b-
elimination. These DHPs bearing a protected alcohol function at C2
and an alkyl/aryl moiety at C6 represent valuable building blocks
for the development of simple11c or more complex natural com-
pounds displaying a functionalized pyran ring.
4. Experimental section
4.1. General informations
All solvents used were reagent grade and In(OAc)3 reagent was
purchased from SigmaeAldrich. TLC was performed on silica-
covered aluminium sheets (Kieselgel 60F254, MERCK). Eluted TLC
(300 MHz, CDCl3):
d
¼7.36e7.22 (m, 5H, Har), 4.49 and 4.43 (d, A
and B part of AB system, JAB¼12.5 Hz, 2H, CH2Ph), 4.26 (tt, J¼4.3
and 12.3 Hz, 1H, CHI), 3.32e3.41 (m, 1H, CHMe), 3.33 and 3.10 (d, A
and B part of AB system, JAB¼8.6 Hz, 2H, CH2OBn), 3.24 (dd, J¼1.4
and 10.8 Hz, 1H, CHC(Me)2), 2.24 (m, 2H, 2ꢃ CHH0CHI), 1.85 (m, 2H,
2ꢃ CHH0CHI), 1.08 (d, J¼6.2 Hz, 3H, CH3), 0.88 (s, 3H, CH3), 0.87 (s,
was revealed using UV radiation (
l
¼254 nm), or molybdate solu-
tion. IR spectra were recorded on a Bruker Tensor spectrophotom-
eter using the Specac Quest ATR system and are reported in
wavenumbers (cmꢂ1). Flash column chromatography was per-
formed on silica gel 60 ACC 40e63
m
m (SDS-CarloErba). NMR
3H, CH3) ppm. 13C NMR (75 MHz, CDCl3):
d
¼138.92 (CIVar), 128.24
spectra were recorded on a BRUKER AC300 (300 MHz for 1H) or on
a BRUKER 400 (400 MHz for 1H) at room temperature, on samples
dissolved in an appropriate deuterated solvent. References of tet-
ramethylsilane (TMS) for 1H and deuterated solvent signal for 13C
(CHar), 127.30 (CHar), 81.92 (CHC(Me)2), 76.6 (CH2OBn), 74.80
(CHMe), 73.11 (CH2Ph), 47.14 (CH2CHMe), 39.26 (CH2CHI), 38.39
(CIV), 24.89 (CHI), 21.36 (2ꢃ CH3), 20.30 (CH3) ppm. HRMS (ESIþ):
calcd for C17H25O2NaI [MþNa]þ 411.0791; found 411.0789. 2,4-
trans diastereoisomer [( )-8a]: 1H NMR (300 MHz, CDCl3):
were used. Chemical displacement values (d) are expressed in parts
per million (ppm), and coupling constants (J) in Hertz (Hz). Low-
resolution mass spectra (MS) were recorded in the CEISAM labo-
ratory on a Thermo-Finnigan DSQII quadripolar at 70 eV (CI with
NH3 gas). High-Resolution Mass Spectrometry (HRMS in Da unit)
analyses were recorded on an LC-Q-TOF (Synapt-G2 HDMS, Waters)
in the IRS-UN center (Mass Spectrometry platform, Nantes) or on
a MALDI-TOF-TOF apparatus (Autoflex III from Bruker) in the INRA
center (BIBS platform, Nantes). The general procedure for diol
monobenzylation and aldehyde 6 preparation are detailed in the
d
¼7.36e7.22 (m, 5H, Har), 4.9 (m, 1H, CHI), 4.54 and 4.48 (d, A and
B part of AB system, JAB¼12.4 Hz, 2H, CH2Ph), 3.88 (ddq, J¼1.8 and
6.4 and 12.4 Hz, 1H, CHMe), 3.74 (dd, J¼1.8 and 10.2 Hz, 1H,
CHC(Me)2), 3.32 and 3.21 (d, A and B part of AB system, JAB¼8.8 Hz,
2H, CH2OBn), 1.94 (m, 2H, 2ꢃ CHH0), 1.52 (ddd, J¼3.6 and 10.7 and
14.5 Hz, 1H, CHH0CHI), 1.4 (ddd, J¼3.7 and 10.4 and 14.3 Hz, 1H,
CHH0CH(Me)), 1.15 (d, J¼6.1 Hz, 3H, CH3), 0.92 (s, 3H, CH3), 0.89 (s,
3H, CH3). 13C NMR (75 MHz, CDCl3):
d
¼139.1 (CIVar), 128.2 (CHar),
127.33 and 127.23 (CHar), 77.3 (CHC(Me)2), 76.6 (CH2OBn), 73.2

T. Chalopin et al. / Tetrahedron 72 (2016) 318e327
323
(CH2Ph), 69.7 (CHMe), 42.4 (CH2CH(Me)), 38.1 (CIV), 34.5 (CH2CHI),
32.7 (CHI), 21.5 (CH3), 21.2 (CH3), 20.7 (CH3) ppm. MS (CIþ): m/
z¼411.21 [MþNH4]þ; 389.07 [MþH]þ.
C(HH0)CHI), 1.88 (m, 2H, 2ꢃ C(HH0)CHI), 1.09 (d, J¼6.1 Hz, 3H,
CHCH3), 0.93 (s, 3H, CH3) ppm. 13C NMR (100 MHz, CDCl3):
d
¼139.4
(CIVar), 139.1 (CIVar), 128.63 (CHar), 128.58 (CHar), 127.6 (CHar), 80.4
(CHeO), 75.3 (CH(Me)), 73.6 (2ꢃ CH2Ph), 72.9 (CH2OBn), 72.6
(CH2OBn), 47.6 (CH2CHI), 43.3 (CIV), 39.7 (CH2CHI), 24.8 (CHI), 21.7
(CH3CH), 16.0 (CH3) ppm. 2,4-trans diastereoisomer [( )-8c]: 1H
Alcohol [9a]: 1H NMR (400 MHz, CDCl3):
d
¼7.39e7.24 (m, 5H,
Har), 5.93 (m, 1H, CHCH2), 5.15e5.65 (m, 2H, CHCH2), 4.51 (s, 2H,
CH2Ph), 3.54 (ddd, J¼2.6; 3.9 and 10.4 Hz, 1H, CHOH), 3.40 and 3.31
(d, A and B part of AB system, JAB¼8.9 Hz, 2H, CH2OBn), 3.03 (dd,
J¼3.9 and 0.7 Hz, 1H, OH), 2.29 (m, 1H, CHH0CH(OH)), 2.08 (m, 1H,
CHH0CH(OH)), 0.94 (s, 3H, CH3), 0.93 (s, 3H, CH3) ppm. 13C NMR
NMR (400 MHz, CDCl3):
d
¼7.23e7.35 (m, 10H, Har), 4.87 (m, 1H,
CHI), 4.53 and 4.49 (d, A and B part of AB system, JAB¼12.3 Hz, 2H,
CH2Ph), 4.48 (s, 2H, CH2Ph), 4.48 and 3.52 (d, A and B part of AB
system, J¼8.9 Hz, 2H), 3.88 (m, 2H, 2ꢃ CHeO), 3.41 and 3.33 (d, A
and B part of AB system, JAB¼9.1 Hz, 2H, CH2OBn), 1.93 (m, 2H, 2ꢃ
C(HH0)CHI), 1.60 (ddd, J¼3.6 and 10.7 and 14.6 Hz, 1H, C(HH0)CHI),
1.39 (ddd, J¼3.7 and 10.4 and 14.5 Hz, 1H, C(HH0)CHMe), 1.13 (d,
J¼6.1 Hz, 3H, CH3CH), 0.96 (s, 3H, CH3) ppm. 13C NMR (100 MHz,
(100 MHz, CDCl3):
d
¼138.0 (CIVar), 136.8 (CH2CH), 128.4 (CHar),
127.7 (CHar), 127.5 (CHar), 116.8 (CH2CH), 79.7 (CH2OBn), 77.4
(CHOH), 73.9 (CH2Ph), 38.6 (CIV), 36.7 (CH2), 22.8 (CH3), 19.8 (CH3)
ppm. MS (CIþ): m/z¼252.13 [MþNH4]þ; 235.10 [MþH]þ.
4.2.2. (2S,4R,6S)-2-(4-((Benzyloxy)methyl)heptan-4-yl)-4-iodo-6-
methyltetrahydro-2H-pyran [(ꢁ)-7b] and (2S,4S,6S)-2-(4-((benzy-
loxy)methyl)heptan-4-yl)-4-iodo-6-methyltetrahydro-2H-pyran
[(ꢁ)-8b]. Following procedure A and starting from 6b (2 mmol,
1 equiv), purification by column chromatography on silica gel (pe-
troleum ether/toluene; 90:10) afforded the first diastereoisomer
2,4-cis ( )-7b (54 mg), the second diastereoisomer 2,4-trans ( )-8b
(50 mg), and a 50/50 mixture of both compounds (328 mg), in 48%
global yield, as colourless oils. 2,4-cis diastereoisomer [( )-7b]: 1H
CDCl3):
d
¼139.15 (CIVar), 138.93 (CIVar), 128.20 (CHar), 127.37 (CHar),
127.28 (CHar), 127.25 (CHar), 127.20 (CHar), 75.49 (CHeO), 73.22 (2ꢃ
CH2Ph), 72.76 (CH2OBn), 72.54 (CH2OBn), 66.77 (CH(Me)), 42.62
(CIV), 42.51 (CH2CH(Me)), 34.69 (CH2CHI), 32.52 (CHI), 21.15
(CH3CH), 15.97 (CH3) ppm. MS (CIþ): m/z¼512.23 [MþNH4]þ;
495.20 [MþH]þ. HRMS (ESIþ) of 7c:8c mixture: calcd for C24H32O3I
[MþH]þ 495.1390, found 495.1388.
4.2.4. (2S,4R,6S)-2-(1-((Benzyloxy)methyl)cyclopentyl)-4-iodo-6-
methyltetrahydro-2H-pyran [(ꢁ)-7e] and (2S,4S,6S)-2-(1-((benzy-
loxy)methyl)cyclopentyl)-4-iodo-6-methyltetrahydro-2H-pyran
[(ꢁ)-8e]. Following procedure A and starting from 6e (2.29 mmol,
1 equiv), purification by column chromatography on silica gel
(petroleum ether/CH2Cl2/toluene, 80:10:10) afforded the two di-
astereoisomers ( )-7e and ( )-8e (417 mg) as a colourless oil in 43%
NMR (300 MHz, CDCl3):
d
¼7.32e7.24 (m, 5H, Har), 4.46 and 4.43 (d,
A and B part of AB system, JAB¼12.3 Hz, 2H), 4.25 (tt, J¼4.2 and
12.2 Hz, 1H), 3.32 (m, 1H), 3.32 and 3.26 (d, A and B part of AB
system, JAB¼9.2 Hz, 2H, CH2Ph), 3.24 (dd, J¼1.6 and 11.1 Hz, 1H,
CHeO), 2.27 (m, 2H, 2ꢃ C(HH0)CHI), 2.05 (m, 1H, C(HH0)CHI), 1.83
(m, 1H, (C(HH0)CH(Me)), 1.44e1.12 (m, 8H, 4ꢃ CH2),1.10 (d, J¼6.2 Hz,
3H, CH3), 0.864 (t, J¼7 Hz, 3H, CH3), 0.859 (t, J¼7 Hz, 3H, CH3) ppm.
global yield. 1H NMR (400 MHz, CDCl3):
d¼7.37e7.26 (m, 5H, Har),
13C NMR (100 MHz, CDCl3):
d¼139.0 (CIVar), 128.24 (CHar), 127.37
4.90 (m, 0.4H, CHI, trans-isomer), 4.49 and 4.46 (A and B part of AB
system, JAB¼12.4 Hz, 2H, CH2OBn), 4.27 (tt, J¼12.3 and 4.3 Hz, 0.6H,
CHI cis-isomer), 3.90 (ddq, J¼12.5; 6.4 and 1.8 Hz, 0.4H, trans-iso-
mer), 3.83 (dd, J¼10.8 and 1.5 Hz, 0.4H), 3.38 (m, 1.2H), 3.29 and
3.26 (A and B part of AB system, JAB¼9.0 Hz, 2H, trans-isomer), 2.27
(m, 2H), 1.96 (m, 2H), 1.89 (m, 1.2H, cis-isomer), 1.83 (m, 2H, cis-
isomer), 1.23e1.68 (m, 6H), 1.15 (d, J¼6.2 Hz, 1.23H, CH3 trans-iso-
mer), 1.10 (d, J¼6.2 Hz, 1.78H, CH3 cis-isomer) ppm. 13C NMR
(CHar),127.31 (CHar), 82.43 (CHeO), 75.16 (CH(Me)), 73.25 (CH2OBn),
73.14 (CH2Ph), 47.42 (CH2CH(Me)), 43.19 (CIV), 38.84 (CH2CHI), 35.12
(CH2), 34.74 (CH2), 25.37 (CHI), 21.44 (CH3), 16.94 (CH2), 16.77 (CH2),
15.23 (CH3), 15.15 (CH3) ppm. MS (CIþ): m/z¼445.21 [MþH]þ. 2,4-
trans diastereoisomer [( )-8b]: 1H NMR (300 MHz, CDCl3):
d¼7.35e7.23 (m, 5H, Har), 4.91 (m,1H, CHI), 4.47 and 4.43 (d, A and B
part of AB system, JAB¼12.2 Hz, 2H, CH2Ph), 3.85 (ddq, J¼1.7 and 6.2
and 12.2 Hz, 1H, (CH(Me)), 3.75 (dd, J¼1.4 and 10.7 Hz, 1H, CHeO),
3.42 and 3.25 (d, A and B part of AB system, JAB¼9.3 Hz, 2H, CH2OBn),
1.95 (m, 2H, 2ꢃ C(HH0)CHI), 1.67 (ddd, J¼3.5 and 10.7 and 14.6 Hz,
1H, C(HH0)CHI), 1.45e1.17 (m, 9H, C(HH0)CH(Me) and 2ꢃ CH2), 1.15
(d, J¼6.1 Hz, 3H, CH3), 0.87 (t, J¼7 Hz, 6H, 2ꢃ CH3) ppm. 13C NMR
(100 MHz, CDCl3):
d
¼139.0, 138.8, 128.30, 128.23, 127.44, 127.42,
81.91 (cis-isomer), 77.20 (trans-isomer), 74.87 (cis-isomer), 74.47,
74.43, 73.18, 69.72 (trans-isomer), 50.0 (cis-isomer), 49.76 (trans-
isomer), 47.3 (cis-isomer), 42.55 (trans-isomer), 40.31 (cis-isomer),
36.65 (trans-isomer), 32.95 (trans-isomer), 32.0, 31.87, 31.78, 31.27,
26.08, 26.049, 26.0, 24.89 (cis-isomer), 21.38 (cis-isomer), 21.21
(trans-isomer) ppm. MS (CIþ) of the 7e:8e mixture: m/z¼432.2
[MþNH4]þ; 415.2 [MþH]þ. HRMS (ESIþ) of the 7e:8e mixture: calcd
for C19H28O2I [MþH]þ 415.1128; found 415.1125.
(100 MHz, CDCl3):
d
¼139.2 (CIVar), 128.2 (CHar), 127.24 and 127.18
(CHar), 77.32 (CHeO), 73.52 (CH2OBn), 73.09 (CH2Ph), 69.99
(CH(Me)), 42.86 (CIV), 42.64 (CH2CH(Me)), 35.24 (CH2), 35.05
(CH2CHI), 34.6 (CH2), 33.84 (CHI), 21.24 (CH3), 16.74 (CH2), 16.69
(CH2), 15.23 (CH3), 15.17 (CH3) ppm. HRMS (ESIþ) of the 7b:8b
mixture: calcd for C21H33O2NaI [MþNa]þ 497.1417; found 467.1415.
4.2.5. (2S,4R,6S)-2-(1-((Benzyloxy)methyl)cyclohexyl)-4-iodo-6-
methyltetrahydro-2H-pyran [(ꢁ)-7f] and (2S,4S,6S)-2-(1-((benzy-
loxy)methyl)cyclohexyl)-4-iodo-6-methyltetrahydro-2H-pyran
[(ꢁ)-8f]. Following procedure A and starting from 6f (2.46 mmol,
1 equiv), purification by column chromatography on silica gel
(petroleum ether/CH2Cl2/toluene, 80:10:10) afforded the first di-
astereoisomer 2,4-cis ( )-7f (13 mg), the second diastereoisomer
2,4-trans ( )-8f (36 mg), and a 50/50 mixture of both compounds
( )-7f and ( )-8f (635 mg), in 65% global yield, as colourless oils.
2,4-cis diastereoisomer [( )-7f]: 1H NMR (300 MHz, CDCl3):
4.2.3. (2S,4R,6S)-2-(1,3-Bis(benzyloxy)-2-methylpropan-2-yl)-4-
iodo-6-methyltetrahydro-2H-pyran [(ꢁ)-7c] and (2S,4S,6S)-2-(1,3-
bis(benzyloxy)-2-methylpropan-2-yl)-4-iodo-6-methyltetrahydro-
2H-pyran [(ꢁ)-8c]. Following procedure A and starting from 6c
(4 mmol, 1 equiv), purification by column chromatography on silica
gel (petroleum ether/CH2Cl2/toluene; 80:10:10 to 60:30:10) affor-
ded the second diastereoisomer 2,4-trans 8c (441 mg), and a 42/57
mixture of 7c:8c (606 mg), in 53% global yield, as colourless oils.
2,4-cis diastereoisomer [( )-7c]: FTIR (ATR) cmꢂ1: 3028, 2968,
2929, 2855, 1452, 1365, 1297, 1176, 1088, 1062, 1026, 732, 695, 484,
d
¼7.38e7.26 (m, 5H, Har), 4.50 and 4.46 (d, A and B part of AB
system, JAB¼12.4 Hz, 2H, CH2Ph), 4.27 (tt, J¼4.4 and 12.3 Hz, 1H,
CHI), 3.46 and 3.40 (d, A and B part of AB system, JAB¼9.3 Hz, 2H,
CH2OBn), 3.36 (ddq, J¼2.0 and 6.1 and 12.4 Hz, 1H, CH(Me)), 3.25
(dd, J¼1.7 and 11.3 Hz, 1H, CHeO), 2.27 (m, 2H, 2ꢃ C(HH0)CHI), 2.02
(m, 1H, C(HH0)CHI), 1.81 (m, 1H, C(HH0)CHI), 1.61e1.14 (m, 10H, 5ꢃ
CH2), 1.11 (d, J¼6.2 Hz, 3H, CH3) ppm. 13C NMR (100 MHz, CDCl3):
451.1H NMR (400 MHz, CDCl3):
d
¼7.23e7.35 (m, 10H, Har), 4.51 and
4.46 (d, A and B part of AB system, JAB¼12.2 Hz, 2H, CH2Ph), 4.47 (s,
2H, CH2Ph), 4.24 (tt, J¼4.4 and 12.2 Hz, 1H, CHI), 3.38 (m, 1H,
CHeO), 3.48 and 3.44 (d, A and B part of AB system, JAB¼8.7 Hz, 2H,
CH2OBn), 3.41 and 3.31 (d, AB part of AB system, JAB¼8.9 Hz, 2H,
CH2OBn), 3.37 (dt, J¼5.0 and 3.2 Hz, 1H, CH(Me)), 2.24 (m, 2H, 2ꢃ
d¼138.96 (CIVar), 128.27 (CHar), 127.43 (CHar), 127.38 (CHar), 82.43

324
T. Chalopin et al. / Tetrahedron 72 (2016) 318e327
(CHeO), 75.04 (CH(Me)), 73.20 (CH2Ph), 70.64 (CH2OBn), 47.39
(CH2CH(Me)), 40.65 (CIV), 39.13 (CH2CHI), 28.52 (CH2), 28.45 (CH2),
26.12 (CH2), 25.46 (CHI), 21.65 (CH2), 21.62 (CH2), 21.37 (CH3) ppm.
HRMS (MALDI-DHB-PEG400): calcd for C20H29O2NaI [MþNaþ]
451.1104, found 451.1024. 2,4-trans diastereoisomer [( )-8f]: 1H
(2.2 mmol, 1 equiv), purification by column chromatography on
silica gel (petroleum ether/CH2Cl2, 95:5 to 80:20) afforded the first
diastereoisomer 2,4-cis ( )-7h (240 mg), the second di-
astereoisomer 2,4-trans ( )-8h (140 mg), and a 50/50 mixture of
both compounds ( )-7g and ( )-8g (120 mg), in a 76% global yield,
as colourless oils. 2,4-cis diastereoisomer [( )-7h]: 1H NMR
NMR (400 MHz, CDCl3):
d
¼7.36e7.24 (m, 5H, Har), 4.91 (m, 1H, CHI),
4.48 (s, 2H, CH2Ph), 3.88 (ddq, J¼1.6 and 6.3 and 12.4 Hz,1H, CHMe),
3.78 (dd, J¼1.4 and 10.7 Hz, 1H, CHeO), 3.46 and 3.36 (d, A and B
part of AB system, JAB¼9.3 Hz, 2H, CH2OBn), 1.95 (m, 2H, 2ꢃ C(HH0)
CHI), 1.65 (ddd, J¼3.5; 10.7 and 14.7 Hz, 1H, C(HH0)CHI), 1.57e1.27
(m, 11H, C(HH0)CHMe and 5ꢃ CH2), 1.15 (d, J¼6.1 Hz, 3H, CH3) ppm.
(300 MHz, CDCl3):
d
¼7.32e7.25 (m, 2H, Har), 7.20e7.16 (m, 3H, Har),
4.24 (tt, J¼4.3 and 12.36 Hz, 1H, CHI), 3.42 (m, 2H, CHeO), 3.25 (m,
2H, CHeO), 2.7 (m, 2H, CH2Ph), 2.3 (m, 2H, 2ꢃ CHH0), 1.89 (m, 3H,
CH2 and CHH0), 1.7 (m, 1H, CHH0), 1.20 (d, J¼6.2 Hz, 3H, CH3) ppm.
13C NMR (100 MHz, CDCl3):
d
¼141.81 (CIVar), 128.47 and 128.38
13C NMR (100 MHz, CDCl3):
d¼139.14 (CIVar), 128.20 (CHar), 127.31
(CHar), 125.82 (CHar), 77.58 (CHeO), 74.78 (CHMe), 47.0 (CH2), 45.0
(CH2), 37.16 (CH2), 31.49 (CH2), 22.72(CHI), 21.39 (CH3) ppm. HRMS
(ESIþ): calcd for C14H20OI [MþH]þ 331.0553; found 331.0555. 2,4-
trans diastereoisomer [( )-8h]: 1H NMR (400 MHz, CDCl3):
(CHar), 127.21 (CHar), 77.20 (CHeO), 73.16 (CH2Ph), 71.74 (CH2OBn),
70.00 (CHMe), 42.62 (CH2CH(Me)), 40.16 (CIV), 34.54 (CH2CHI),
33.82 (CHI), 29.36 (CH2), 29.06 (CH2), 26.2 (CH2), 21.74 (CH2), 21.52
(CH2), 21.21 (CH3) ppm. MS (CIþ): m/z¼429.20 [MþH]þ. HRMS
(MALDI-DHB-PEG400): calcd for C20H29O2NaI [MþNaþ] 451.1104;
found 451.1187.
d¼7.30e7.26 (m, 2H; Har), 7.21e7.16 (m, 3H; Har), 4.84 (q, J¼3.2 Hz,
1H, CHI), 3.95 (m, 1H, CHeO), 3.83 (m, 1H, MeCHeO), 2.81 (ddd, A
part of ABX2 system, J¼5.7,10.2 and 13.9 Hz,1H, CHH0Ph), 2.68 (ddd,
B part of ABX2 system, J¼6.35, 9.9 and 13.9 Hz,1H, CHH0Ph),1.99 (m,
2H, 2ꢃ C(HH0)CHI), 1.91e1.68 (m, X part of ABX system, 2H, CH2),
1.89 (m, 1H, CHH0CH2Ph), 1.73 (m, 1H, CHH0CH2Ph), 1.49 (m, 2H, 2ꢃ
C(HH0)CHI), 1.25 (d, J¼6.2 Hz, 3H, CH3) ppm. 13C NMR (100 MHz,
4 . 2 . 6 . ( 2 R , 4 R , 6 S ) - 2 - ( 2 - ( B e n z y l o x y ) e t h yl ) - 4 - i o d o - 6 -
methyltetrahydro-2H-pyran [(ꢁ)-7g] and (2R,4S,6S)-2-(2-(benzy-
l o x y ) e t h y l ) - 4 - i o d o - 6 - m e t h y l t e t r a h y d r o - 2 H - p y r a n
[(ꢁ)-8g]. Following procedure A and starting from 6g (3.88 mmol,
1 equiv), purification by column chromatography on silica gel
(petroleum ether/CH2Cl2/toluene, 40:40:20) afforded the first di-
astereoisomer 2,4-cis ( )-7g (299 mg), the second diastereoisomer
2,4-trans ( )-8g (135 mg), and a 50/50 mixture of both compounds
( )-7g and ( )-8g (164 mg), in a 43% global yield, as colourless oils.
Some alcohol 9g could also be isolated for characterization. 2,4-cis
CDCl3):
d
¼142.5 (CIVar), 128.8 and 128.7 (CHar), 126.1 (CHar), 73.2
(MeCHeO), 70.2 (CHeO), 42.7 (CH2CHMe), 40.8 (CH2CHI), 37.6
(CH2CH2), 32.0 (CH2Ph), 31.3 (CHI), 21.5 (CH3) ppm. HRMS (ESIþ):
calcd for C14H20OI [MþH]þ 331.0553; found 331.0550.
4.2.8. (2S,4R,6S)-4-Iodo-2-isopropyl-6-methyltetrahydro-2H-pyran
[(ꢁ)-7i] and (2S,4S,6S)-4-iodo-2-isopropyl-6-methyltetrahydro-2H-
diastereoisomer [( )-7g]: 1H NMR (300 MHz, CDCl3):
d
¼7.38e7.25
pyran [(ꢁ)-8i]. Following procedure
A and starting from 6i
(m, 5H, Har), 4.51 and 4.46 (d, A and B part of AB system,
JAB¼12.1 Hz, 2H, CH2Ph), 4.26 (tt, J¼4.3 and 12.3 Hz, 1H, CHI),
3.35e3.64 (m, 4H, CH2O and 2ꢃ CHeO), 2.29 (m, 2H, CH2CHI), 1.86
(m, 2H, CH2CHMe), 1.74 (m, 2H, CH2CH2O), 1.14 (d, J¼6.2 Hz, 3H,
(2.0 mmol, 1 equiv), purification by column chromatography on
silica gel (petroleum ether/CH2Cl2, 90:10 to 80:20) afforded the first
diastereoisomer 2,4-cis ( )-7h (100 mg), the second di-
astereoisomer 2,4-trans ( )-8h (70 mg), in a 33% global yield, as
colourless oils. 2,4-cis diastereoisomer [( )-7i]: 1H NMR (400 MHz,
CH3) ppm. 13C NMR (75 MHz, CDCl3):
d
¼138.5 (CIVar), 128.385
(CHar), 127.64 (CHar), 75.6 (CHeO), 74.7 (CHMe), 73.0 (CH2Ph), 66.2
(CH2OBn), 46.9 (CH2), 45.0 (CH2), 36.0 (CH2CH2), 22.8 (CHI), 21.3
(CH3) ppm. MS (CIþ): m/z¼378.15 [MþNH4]þ; 361.15 [MþH]þ. 2,4-
trans diastereoisomer [( )-8g]: 1H NMR (300 MHz, CDCl3):
CDCl3):
d
¼4.27 (tt, J¼4.3 and 12.3 Hz, 1H, CHI), 3.4 (m, 1H,
MeCHeO), 2.98 (ddd, J¼1.7 and 6.3 Hz, 1H, CHeO), 2.30 (m, 2H, 2ꢃ
CHH0CHI), 1.85 (m, 2H, 2ꢃ CHH0CHI), 1.67 (sex, J¼6.74 Hz, 1H,
CH(Me)2), 1.16 (d, J¼6.2 Hz, 3H, CH3CHeO), 0.92 (d, J¼6.76 Hz, 3H,
CH3), 0.88 (d, J¼6.8 Hz, 3H, CH3) ppm. 13C NMR (100 MHz, CDCl3):
d
¼7.40e7.24 (m, 5H; Har), 4.83 (tt, J¼3.3 and 2.9 Hz, 1H, CHI); 4.54
and 4.49 (d, A and B part of AB system, JAB¼11.65 Hz, 2H, CH2Ph),
3.96 (m, 2H, 2ꢃ CHeO), 3.62 and 3.56 (dt, A and B part of ABX2
system, JAB¼5.9 Hz, JAX¼9.4 Hz, JBX¼9.2 Hz, 2H, CH2OBn), 1.98 (m,
2H, 2ꢃ C(HH0)CHI), 1.91e1.68 (m, X part of ABX system, 2H, CH2),
1.47 (m, 2H, 2ꢃ C(HH0)CHI), 1.19 (d, J¼5.9 Hz, 3H, CH3) ppm. 13C
d
¼83.6 (CHeO), 74.8 (CHMe), 47.2 (CH2), 41.9 (CH2), 32.85
(CH(Me)2), 24.03 (CHI), 21.35 (CH3CHeO), 18.61 (CH3), 18.18 (CH3)
ppm. HRMS (ESIþ): calcd for C9H18OI [MþH]þ 269.0397; found
269.0396. 2,4-trans diastereoisomer [( )-8i]: 1H NMR (400 MHz,
CDCl3):
d
¼4.89 (q, 1H, CHI), 3.92 (m, 1H, MeCHeO), 3.49 (dd, J¼1.4
NMR (75 MHz, CDCl3):
d¼138.6 (CIVar), 128.4 (CHar), 127.6 and 127.5
and 6.6 Hz, 1H, CHeO), 1.99 (m, 2H, 2ꢃ CHH0CHI), 1.71 (sex,
J¼6.77 Hz, 1H, CH(Me)2), 1.43 (ddd, J¼3.6 and 10.4 Hz, 2H, 2ꢃ
CHH0CHI), 1.21 (d, J¼6.2 Hz, 3H, CH3CHeO), 0.96 (d, J¼6.74 Hz, 3H,
CH3), 0.88 (d, J¼6.8 Hz, 3H, CH3) ppm. 13C NMR (100 MHz, CDCl3):
(CHar), 72.9 (CH2Ph), 70.8 (CHeO), 69.6 (CHMe), 66.6 (CH2OBn),
42.2 (CH2CHMe), 40.5 (CH2CHI), 35.7 (CH2CH2), 30.9 (CHI), 21.1
(CH3) ppm. MS (CIþ): m/z¼378.13 [MþNH4]þ; 361.10 [MþH]þ.
HRMS (ESIþ): calcd for C15H21O2NaI [MþNa]þ 383.0478; found
383.0475.
d
¼78.39 (CHeO), 69.6 (CHMe), 42.41 (CH2), 37.21 (CH2), 32.5
(CH(Me)2), 31.98 (CHI), 21.17 (CH3CHeO), 18.72 (CH3), 18.32 (CH3)
ppm. HRMS (ESIþ): calcd for C9H18OI [MþH]þ 269.0397; found
269.0396.
Alcohol [9g]: 1H NMR (300 MHz, CDCl3):
d¼7.41e7.22 (m, 5H,
Har), 5.84 (ddt, J¼7.3 and 8.9 and 14.2 Hz, 1H, CH2CH), 5.12 (m, 1H,
J¼1.2 Hz, CH2CH), 5.08 (m,1H, J¼1.2 Hz, CH2CH), 4.52 (s, 2H, CH2Ph),
3.87 (tt, J¼5.9 and 5.9 Hz, 1H, CH(OH)), 3.72 and 3.64 (dt, A and B
part of ABX2 system, JAB¼9.4 Hz, JAX¼5.3 Hz, JBX¼6.5 Hz, 2H,
CH2OBn), 2.92 (br s,1H, OH), 2.25 (ddd, J¼1.2 and 6.2 and 7.2 Hz, 2H,
CH2CHCH2), 1.78 (m, X part of ABX2 system, 2H, CH2). 13C NMR
4.2.9. (2S,4R,6S)-2-Allyl-6-(1-(benzyloxy)-2-methylpropan-2-yl)-4-
iodotetrahydro-2H-pyran [(ꢁ)-13] and (2S,4S,6S)-2-allyl-6-(1-(ben-
zyloxy)-2-methylpropan-2-yl)-4-iodotetrahydro-2H-pyran
[(ꢁ)-14]. Following procedure A and starting from 11 (1.6 mmol,
1 equiv) and 6a (1 equiv), purification by column chromatography
on silica gel (petroleum ether/CH2Cl2, 80:20) afforded the first di-
astereoisomer 2,4-cis ( )-13 (80 mg), and a mixture of both com-
pounds ( )-13 and ( )-14 (200 mg), in 42% global yield, as
(75 MHz, CDCl3):
d
¼138.1 (CIV), 134.8 (CH2CH), 128.5 (CHar), 127.7
(CHar), 117.7 (CHar), 73.3 (CH2Ph), 70.3 (CHOH), 68.9 (CH2OBn), 41.9
(CH2CHCH2), 35.9 (CH2). MS (CIþ): m/z¼224.18 [MþNH4]þ; 207.08
[MþH]þ.
colourless oils. 2,4-cis diastereoisomer [( )-13]: FTIR (ATR) cmꢂ1
3028, 2963, 2933, 2848, 1641, 1452, 1362, 1075, 1027, 995, 912, 733,
699, 528, 465. 1H NMR (300 MHz, CDCl3):
¼7.38e7.28 (m, 5H, Har),
5.78 (m, 1H, CH]CH2), 5.04 (m, 2H, CH]CH2), 4.50 (s, 2H, CH2Ph),
:
4.2.7. (2S,4R,6R)-4-Iodo-2-methyl-6-phenethyltetrahydro-2H-pyran
[(ꢁ)-7h] and (2S,4S,6R)-4-iodo-2-methyl-6-phenethyltetrahydro-
2H-pyran [(ꢁ)-8h].28 Following procedure A and starting from 6h
d

T. Chalopin et al. / Tetrahedron 72 (2016) 318e327
325
4.47 (tt, J¼5.13 and 12.3 Hz, 1H, CHI), 3.33 (d, A part of AB system,
JAB¼8.69 Hz, CHH0OBn), 3.27 (m, 2H, 2ꢃ CHeO), 3.13 (d, B part of AB
system, JAB¼8.69 Hz, CHH0OBn), 2.31e2.07 (m, 4H, 2ꢃ CHH0CHI and
CH2CH]CH2), 1.91 (sept, J¼12.2 Hz, 2H, 2ꢃ CHH0CHI), 0.90 (s, 3H,
DHB-PEG400): calcd for C22H27IO2Na [MþNa]þ 473.0948; found
473.0956.
4.3. General procedure B for In(OAc)3/LiI-mediated
elimination
CH3), 0.89 (s, 3H, CH3) ppm. 13C NMR (75 MHz, CDCl3):
d¼138.90
(CIVar), 134.46 (CH]CH2),128.27 (CHar), 128.23 (CHar),127.37 (CHar),
116.82 (CH]CH2), 81.94 (CHeO), 78.11 (CHeO), 77.20 (CH2OBn),
73.18 (CH2Ph), 44.96 (CH2CHCH2), 42.6 (CH2CHI), 39.43 (CH2CHI),
38.53 (CIV), 24.71 (CHI), 21.33 (CH3), 20.31 (CH3) ppm. MS (CIþ): m/
z¼437.1 [MþNa]þ. HRMS (MALDI-DHB-PEG400): calcd for
To a solution of 4-iodo-tetrahydropyran ( )-7 or/and ( )-8
(0.38 mmol, 1 equiv), in dichloroethane (5 mL) was added indium
acetate (2 equiv), and lithium iodide (2 equiv) under argon. The
mixture was refluxed and, after total conversion of the starting
material, it was cooled to room temperature, filtered on Celite and
rinsed with dichloromethane. The organic layer was washed with
a saturated aqueous solution of Na2S2O3, a saturated aqueous so-
lution of NaHCO3 and brine. It was dried over anhydrous MgSO4,
filtered, and concentrated in vacuo. The dihydropyran ( )-10 was
purified by flash chromatography on silica gel.
C
19H27IO2Na [MþNaþ] 437.0948; found 437.0955. 2,4-trans di-
astereoisomer [( )-14]: 1H NMR (300 MHz, CDCl3):
d¼7.37e7.28
(m, 5H, Har), 5.83 (m, 1H, CH]CH2), 5.04 (m, 2H, CH2]CH), 4.91 (q,
J¼3 Hz, 1H, CHI), 4.50 (s, 2H, CH2Ph), 3.83 (m, 1H, CHeO), 3.74 (dd,
J¼10.57 and 1.5 Hz, 1H, CHeO), 3.32 (d, A part of AB system,
JAB¼8.76 Hz, CHH0OBn), 3.22 (d, B part of AB system, JAB¼8.76 Hz,
CHH0OBn), 2.12 (m, 2H CH2CH2]CH2), 1.94 (m, 2H, 2ꢃ CHH0CHI),
1.54 (m, 1H, CHH0CHI), 1.43 (m, 1H, CHH0CHI), 0.93 (s, 3H, CH3), 0.90
4.3.1. (2S,6S)-6-(1-(Benzyloxy)-2-methylpropan-2-yl)-2-methyl-3,6-
dihydro-2H-pyran [(ꢁ)-10a]. Following procedure B and starting
from ( )-7a or ( )-8a (0.18 mmol, 1 equiv), purification by column
chromatography on silica gel (petroleum ether/CH2Cl2, 80:20)
afforded dihydropyran ( )-10a (32 mg, 70%) as a colourless oil. FTIR
(ATR) cmꢂ1: 3036, 2930, 2890, 2849, 1651, 1453, 1361, 1086, 1028,
(s, 3H, CH3) ppm. 13C NMR (75 MHz, CDCl3):
d¼139.02 (CIVar),134.86
(CH]CH2), 128.25 (CHar), 127.35 (CHar), 127.24 (CHar), 116.53 (CH]
CH2), 77.23 (CHeO), 76.65 (CH2OBn), 73.12 (CH2Ph), 72.92 (CHeO),
40.30 (CH2CHI), 39.84 (CH2CHCH2), 38.21 (CIV), 34.62 (CH2CHI),
32.44 (CHI), 21.47 (CH3), 20.73 (CH3) ppm. MS (CIþ): m/z¼437.2
[MþNa]þ.
733, 693. 1H NMR (400 MHz, CDCl3):
d
¼7.36e7.22 (m, 5H, Har), 5.83
(m,1H, CH]CH), 5.72 (m,1H, CH]CH), 4.52 (s, 2H, CH2Ph), 4.06 (m,
1H, CHeO), 3.63 (ddq, J¼6.1 and 6.2 and 6.3 Hz,1H, CHMe), 3.45 and
3.22 (d, A and B part of AB system, JAB¼8.8 Hz, 2H, CH2OBn),1.88 (m,
2H, CH2), 1.16 (d, J¼6.2 Hz, 3H, CH3), 0.94 (s, 3H, CH3), 0.88 (s, 3H,
4.2.10. (2S,4R,6R)-2-(1-(Benzyloxy)-2-methylpropan-2-yl)-4-iodo-6-
phenyltetrahydro-2H-pyran [(ꢁ)-15] and (2S,4S,6R)-2-(1-(benzy-
loxy)-2-methylpropan-2-yl)-4-iodo-6-phenyltetrahydro-2H-pyran
[(ꢁ)-16]. To a solution of aldehyde 6a (1.3 mmol, 1.3 equiv) and
alcohol 12 (1 mmol, 1 equiv) in dichloroethane (6 mL) at 0 ꢀC, was
added lithium iodide (2 equiv) and TMSBr (1 equiv) under argon.
The solution was stirred for 1.5 h, filtered on Celite and rinsed with
dichloromethane. The organic layers were washed with a saturated
aqueous solution of Na2S2O3, then a saturated aqueous solution of
NaHCO3 and brine and finally dried over anhydrous MgSO4. They
were filtered, and concentrated under reduced pressure. Purifica-
tion by column chromatography on silica gel (petroleum ether/
Et2O, 98:2) afforded the first diastereoisomer 2,4-trans ( )-16
(100 mg), and a mixture of both compounds ( )-15 and ( )-16
(220 mg), in a 69% global yield, as colourless oils. 2,4-cis di-
astereoisomer [( )-15]: FTIR (ATR) cmꢂ1: 3028, 2963, 2933, 2849,
1604, 1495, 1451, 1362, 1298, 1209, 1182, 1088, 1059, 1028, 734, 695,
CH3) ppm. 13C NMR (100 MHz, CDCl3):
d¼139.41 (CIVar), 128.33
(CHar), 127.35 (CHar and CH]CH), 126.14 (CH]CH), 78.64 (CHeO),
75.7 (CH2O), 73.34 (CH2Ph), 69.75 (CHMe), 38.91 (CIV), 33.13 (CH2),
21.89 (CH3), 21.61 (CH3), 20.25 (CH3) ppm. MS (CIþ): m/z¼261.15
[MþH]þ. HRMS (MALDI-DHB-PEG400): calcd for C17H24O2Na
[MþNa]þ 283.1668; found 283.1660.
4.3.2. (2S,6S)-6-(4-((Benzyloxy)methyl)heptan-4-yl)-2-methyl-3,6-
dihydro-2H-pyran [(ꢁ)-10b]. Following procedure B and starting
from a mixture of 7b:8b (0.92 mmol, 1 equiv), purification by col-
umn chromatography on silica gel (petroleum ether/CH2Cl2, 90:10)
afforded dihydropyran ( )-10b (76 mg, 26%) as a colourless oil. FTIR
(ATR) cmꢂ1: 3034, 2957, 2929, 2869, 1650, 1453, 1376, 1190, 1071,
1028, 732, 696. 1H NMR (400 MHz, CDCl3):
d
¼7.34e7.23 (m, 5H,
548, 526, 462. 1H NMR (300 MHz, CDCl3):
d
¼7.34e7.23 (m, 10H,
Har), 5.83e5.73 (m, 2H, CH]CH), 4.46 and 4.45 (d, A and B part of
AB system, JAB¼12.4 Hz, 2H, CH2Ph), 4.13 (m, 1H, CHeO), 3.59 (m,
1H, CHMe), 3.41 and 3.34 (d, A and B part of AB system, JAB¼9.2 Hz,
2H, CH2OBn), 1.90 (m, 2H, CH2), 1.44e1.22 (m, 8H, 4ꢃ CH2), 1.16 (d,
J¼6.2 Hz, 3H, CH3), 0.85 (m, 6H, 2ꢃ CH3) ppm. 13C NMR (100 MHz,
Har), 4.47 (d, J¼3.78 Hz, 2H, CH2Ph), 4.42 (m, 1H, CHI), 4.30 (dd,
J¼11.1 and 2 Hz, 1H, CHeO), 3.48 (dd, J¼11.3 and 1.7 Hz, 1H, CHeO),
3.39 (d, A part of AB system, JAB¼8.72 Hz, CHH0OBn), 3.17 (d, B part
of AB system, JAB¼8.72 Hz, CHH0OBn), 2.56 (m, 1H, CHH0CHI), 2.34
(m, 1H, CHH0CHI), 2.07 (m, 2H, 2ꢃ CHH0CHI), 0.99 (s, 3H, CH3), 0.96
CDCl3):
d
¼139.52 (CIVar), 128.31 (CHar), 127.36 (CHar), 127.28 (CH]
(s, 3H, CH3) ppm. 13C NMR (75 MHz, CDCl3):
d
¼141.92 (CIVar), 138.8
CH), 125.13 (CH]CH), 78.20 (CHeO), 73.93 (CH2OBn), 73.34
(CH2Ph), 70.13 (CHMe), 43.68 (CIV), 35.35 (CH2), 33.23(CH2CH), 22.0
(CH3), 17.25 (CH2), 17.0 (CH2), 15.48 (CH3), 15.39 (CH3) ppm. MS
(CIþ): m/z¼317.3 [MþH]þ. HRMS (ESIþ): calcd for C21H32O2Na
[MþNa]þ 339.2294; found 339.2297.
(CIVar), 128.24 (CHar), 128.16 (CHar), 127.34 (CHar), 127.29 (CHar),
125.38 (CHar), 82.19 (CHeO), 80.19 (CHeO), 76.58 (CH2OBn), 73.15
(CH2Ph), 47.64 (CH2CHI), 39.23 (CH2CHI), 38.75 (CIV), 23.97 (CHI),
21.46 (CH3), 20.52 (CH3) ppm. MS (CIþ): m/z¼451.3 [MþH]þ. HRMS
(MALDI-DHB-PEG400): calcd for C22H27IO2Na [MþNaþ] 473.0948;
found 473.0963. 2,4-trans diastereoisomer [( )-16]: 1H NMR
4.3.3. (2S,6S)-6-(1,3-Bis(benzyloxy)-2-methylpropan-2-yl)-2-
methyl-3,6-dihydro-2H-pyran [(ꢁ)-10c]. Following procedure B and
starting from a mixture of 7c:8c (0.607 mmol, 1 equiv), purification
by column chromatography on silica gel (petroleum ether/Et2O,
99:1) afforded dihydropyran ( )-10c (176 mg, 80%) as a colourless
oil. FTIR (ATR) cmꢂ1: 3032, 2972, 2931, 2874, 1602, 1452, 1270,1070,
(300 MHz, CDCl3):
d
¼7.35e7.22 (m, 10H, Har), 4.99 (q, J¼2.9 Hz, 1H,
CHI), 4.87 (dd, J¼10.66 and 1.8 Hz, 1H, CHeO), 4.50 (s, 2H, CH2Ph),
3.95 (dd, J¼10.8 and 1.6 Hz, 1H, CHeO), 3.37 (d, A part of AB system,
JAB¼8.8 Hz, CHH0OBn), 3.27 (d, B part of AB system, JAB¼8.8 Hz,
CHH0OBn), 2.23 (m, 1H, CHH0CHI), 2.02 (m, 1H, CHH0CHI), 1.67 (m,
2H, 2ꢃ CHH0CHI), 0.96 (s, 3H, CH3), 0.91 (s, 3H, CH3) ppm. 13C NMR
1026, 737, 697. 1H NMR (400 MHz, CDCl3):
d
¼7.35e7.22 (m, 10H,
(75 MHz, CDCl3):
d
¼142.68 (CIVar), 138.93 (CIVar), 128.24 (CHar),
Har), 5.82 (m,1H, CH]CH), 5.74 (m,1H, CH]CH), 4.52 and 4.48 (d, A
and B part of AB system, JAB¼12.2 Hz, 4H, CH2Ph), 4.25 (m, 1H,
CHeO), 3.62 (m, 1H, CHMe), 3.59 and 3.50 (d, A and B part of AB
system, JAB¼9.1 Hz, 2H, CH2OBn), 3.56 and 3.42 (d, A and B part of
AB system, JAB¼9.1 Hz, 2H, CH2OBn), 1.88 (m, 2H, CH2), 1.16 (d, 3H,
128.16 (CHar), 127.32 (CHar), 127.23 (CHar), 125.56 (CHar), 77.64
(CHeO), 77.20 (CH2OBn), 75.14 (CHeO), 73.18 (CH2Ph), 43.03
(CH2CHI), 38.40 (CIV), 34.44 (CH2CHI), 31.97 (CHI), 21.62 (CH3),
20.93 (CH3) ppm. MS (CIþ): m/z¼451.3 [MþH]þ. HRMS (MALDI-

326
T. Chalopin et al. / Tetrahedron 72 (2016) 318e327
CH3), 0.96 (s, 3H, CH3) ppm. 13C NMR (100 MHz, CDCl3):
d
¼139.44
5.05 (m, 2H, CH]CH2), 4.51 (s, 2H, CH2Ph), 4.05 (m,1H, CHeO), 3.55
(m, 1H, CHeO), 3.44 (d, A part of AB system, JAB¼8.79 Hz, 1H,
CH2OBn), 3.22 (d, B part of AB system, JAB¼8.79 Hz, 1H, CH2OBn),
2.25 (m, 2H, CH2CHCH2), 1.89 (m, 2H, CH2CHI), 0.95 (s, 3H, CH3),
(CIVar), 139.27(CIVar), 128.35 (CHar), 128.32 (CHar), 127.54 (CHar and
CH]CH), 127.42 (CHar), 126.2 (CH]CH), 76.56 (CHeO), 73.44 and
73.11 (CH2Ph), 73.16 (CH2O), 72.84 (CH2O), 69.9 (CHMe), 43.41 (CIV),
33.14 (CH2), 21.86 (CH2), 15.87 (CH3) ppm. MS (CIþ): m/z¼384.24
[MþNH4]þ; 367.19 [MþH]þ. HRMS (ESIþ): calcd for C24H31O3
[MþH]þ 367.2267, found 367.2272.
0.87 (s, 3H, CH3) ppm. 13C NMR (75 MHz, CDCl3):
d¼139.23 (CIVar),
135.22 (CHCH2), 128.20, 127.32 (CHar), 127.27(CHar), 127.20 (CHar),
125.95 (CH]CH), 116.27 (CH2CH), 78.41 (CHeO), 76.87 (CH2OBn),
73.27 (CH2Ph), 72.99 (CHeO), 40.45 (CH2CHCH2), 38.87 (CIV), 30.78
(CH2), 21.41 (CH3), 20.08 (CH3) ppm. HRMS (ESIþ): calcd for
4.3.4. (2S,6S)-6-(1-((Benzyloxy)methyl)cyclopentyl)-2-methyl-3,6-
dihydro-2H-pyran [(ꢁ)-10e]. Following procedure B and starting
from a mixture of 7e:8e (1.01 mmol, 1 equiv), purification by col-
umn chromatography on silica gel (petroleum ether/CH2Cl2, 90:10
to 80:20) afforded dihydropyran ( )-10e (192 mg, 67%) as a col-
ourless oil. FTIR (ATR) cmꢂ1: 3033, 2949, 2863, 1651, 1453, 1361,
C
19H26O2Na [MþNa]þ 309.1831, found 308.1843.
4.3.8. (2R,6S)-6-(1-(Benzyloxy)-2-methylpropan-2-yl)-2-phenyl-3,6-
dihydro-2H-pyran [(ꢁ)18]. Following procedure B and starting
from 4-iodo derivatives 15:16 (0.2 mmol), purification by column
chromatography on silica gel (petroleum ether/Et2O, 98:2) afforded
dihydropyran ( )-18 (25 mg, 40%) as a colourless oil. FTIR (ATR)
cmꢂ1: 3032, 2963, 2894, 2846, 1651, 1603, 1452, 1362, 1087, 1061,
1082, 1028, 790, 732, 695. 1H NMR (400 MHz, CDCl3):
d
¼7.37e7.22
(m, 5H, Har), 5.83 (m, 1H, CH]CH), 5.74 (m, 1H, CH]CH), 4.51 (s,
2H, CH2Ph), 4.18 (m, 1H, CHeO), 3.63 (m, 1H, CHMe), 3.63 and 3.29
(d, A and B part of AB system, JAB¼8.8 Hz, 2H, CH2OBn), 1.90 (m, 2H,
1027, 745, 733, 695. 1H NMR (300 MHz, CDCl3):
d
¼7.22e7.18 (m,
CH2), 1.66e1.37 (m, 8H, 4ꢃ CH2), 1.17 (d, J¼6.2 Hz, 3H, CH3) ppm. 13
C
10H, Har), 5.88 (m, 1H, CH]CH), 5.76 (m, 1H, CH]CH), 4.53 (dd, J¼9
and 3 Hz, 1H, CHeO), 4.44 (s, 2H, CH2Ph), 4.20 (m, 1H, CHeO), 3.45
(d, A part of AB system, JAB¼9 Hz, 1H, CH2OBn), 3.23 (d, B part of AB
system, JAB¼8.79 Hz, 1H, CH2OBn), 2.14 (m, 2H, CH2CHI), 0.95 (s, 3H,
NMR (100 MHz, CDCl3):
d
¼139.46 (CIVar), 128.34 (CHar), 128.21
(CH]CH), 127.6 (CHar), 127.4 and 127.32 (CHar), 126.14 (CH]CH),
78.23 (CHeO), 75.3 (CH2OBn), 73.36 (CH2Ph), 69.9 (CHMe), 50.27
(CIV), 33.24 (CH2), 31.93 (CH2), 31.7 (CH2), 26.73 (CH2), 26.56 (CH2),
21.9 (CH3) ppm. MS (CIþ): m/z¼287.16 [MþH]þ.
CH3), 0.91 (s, 3H, CH3) ppm. 13C NMR (75 MHz, CDCl3):
d
¼143.65
(CIVar), 139.07 (CIVar), 128.17 (CHar), 128.14 (CHar), 127.40 (CH]CH),
127.23 (CHar), 127.18 (CHar), 126.94 (CHar), 125.97 (CH]CH), 125.43
(CHar), 79.05 (CHeO), 76.87 (CH2OBn), 74.92 (CHeO), 73.32
(CH2Ph), 39.19 (CIV), 33.52 (CH2), 21.52 (CH3), 20.31 (CH3) ppm. MS
(CIþ): m/z¼345.2 [MþNa]þ. HRMS (ESIþ): calcd for C22H27O2
[MþH]þ 323.2011, found 323.2025.
4.3.5. (2S,6S)-6-(1-((Benzyloxy)methyl)cyclohexyl)-2-methyl-3,6-
dihydro-2H-pyran [(ꢁ)-10f]. Following procedure B and starting
from a mixture of 7f:8f (0.635 mmol, 1 equiv), purification by col-
umn chromatography on silica gel (petroleum ether/CH2Cl2, 80:20)
afforded dihydropyran ( )-10f (143 mg, 75%) as a colourless oil.
FTIR (ATR) cmꢂ1: 3031, 2929, 2856, 1597, 1584, 1451, 12,696, 1070,
4.4. General procedure C for the one-pot synthesis of
dihydropyrans
1026, 712, 697. 1H NMR (400 MHz, CDCl3):
d¼7.34e7.23 (m, 5H,
Har), 5.80 (m, 2H, CH]CH), 4.49 (s, 2H, CH2Ph), 4.15 (m, 1H, CHeO),
3.63 (ddq, J¼6.2; 8.2 and 11.5 Hz,1H, CHMe), 3.54 and 3.44 (d, A and
B part of AB system, JAB¼9.4 Hz, 2H, CH2OBn), 1.89 (m, 2H, CH2),
1.64e1.21 (m, 10H, 5ꢃ CH2), 1.16 (d, J¼6.2 Hz, 3H, CH3) ppm. 13C
To a solution of aldehyde 6 (1 mmol, 1 equiv) in dichloroethane
(10 mL) was added but-4-en-2-ol 5 (1.6 equiv), and lithium iodide
(2 equiv) under argon. TMSBr (1 equiv) was added at 0 ꢀC followed
40 min later by addition of the Lewis acid In(OAc)3 (2 equiv). The
mixture was refluxed for 3 h. It was cooled to room temperature,
filtered on Celite and rinsed with dichloromethane. The organic
layers were washed with a saturated aqueous solution of Na2S2O3,
then a saturated aqueous solution of NaHCO3 and brine and finally
dried over anhydrous MgSO4. They were filtered, and concentrated
under reduced pressure to give a crude complex mixture. The ex-
pected DHP ( )-10 was purified by column chromatography on
silica gel.
NMR (100 MHz, CDCl3):
d
¼139.54 (CIVar), 128.32 (CHar), 127.76
(CH]CH), 127.39 (CHar), 127.3 (CHar), 125.58 (CH]CH), 77.94
(CHeO), 73.4 (CH2Ph), 71.35 (CH2OBn), 70.03 (CHMe), 41.30 (CIV),
33.3 (CH2), 28.44 (CH2), 28.35 (CH2), 26.38 (CH2), 21.94 (CH3), 21.89
(CH2), 21.85 (CH2) ppm. MS (CIþ): m/z¼301.2 [MþH]þ. HRMS (ESIþ):
calcd for C20H28O2Na [MþNa]þ 323.1981, found 323.1981.
4.3.6. (2S,6R)-6-(2-(Benzyloxy)ethyl)-2-methyl-3,6-dihydro-2H-py-
ran [(ꢁ)-10g]11c. Following procedure B and starting from ( )-8g
(0.375 mmol, 1 equiv), purification by column chromatography on
silica gel (petroleum ether/CH2Cl2, 80:20) afforded dihydropyran
( )-10g (55 mg, 68%) as a colourless oil. FTIR (ATR) cmꢂ1: 2970, 2930,
2872, 1601, 1452, 1368, 1274, 1069, 10,268, 738, 713, 698. 1H NMR
Acknowledgements
The authors thank A. Planchat (CEISAM laboratory) for X-ray
diffraction analysis. This work was also supported by financial
(400 MHz, CDCl3):
d
¼7.36e7.24 (m, 5H, Har), 5.78 (m, 1H, CH]CH),
5.63 (dq, J¼10.18 and 1.9 Hz, 1H, CH]CH), 4.51 (s, 2H, CH2Ph), 4.19
(m, 1H, CHeO), 3.58e3.71 (m, 3H, CH2O and CHMe), 1.94 (m, 2H,
CH2), 1.84 (m, 2H, CH2), 1.21 (d, J¼6.2 Hz, 3H, CH3) ppm. 13C NMR
ꢀ
^
contributions from the ‘Canceropole Grand-Ouest’ and the ‘Ligue
Contre le Cancer’.
(100 MHz, CDCl3):
d¼138.86 (CIVar), 130.33 (CH]CH), 128.48 (CHar),
Supplementary data
127.75 (CHar), 127.6 (CHar), 124.95 (CH]CH), 73.12 (CH2Ph), 72.35
(CHeO), 70.15 (CHMe), 67.01 (OCH2CH2), 35.93 (CH2), 33.05 (CH2),
21.80 (CH3) ppm. MS (CIþ): m/z¼249.94 [MþNH4]þ; 233.06 [MþH]þ.
Supplementary data related to this article can be found in the
online version, at http://dx.doi.org/10.1016/j.tet.2015.11.046.
4.3.7. (2S,6S)-2-Allyl-6-(1-(benzyloxy)-2-methylpropan-2-yl)-3,6-
dihydro-2H-pyran [(ꢁ)-17]. Following procedure B and starting
from a mixture of 4-iodo derivatives 13:14 (0.2 mmol), purification
by column chromatography on silica gel (petroleum ether/Et2O,
98:2) afforded dihydropyran ( )-17 (25 mg, 44%) as a colourless oil.
FTIR (ATR) cmꢂ1: 3037, 2963, 2900, 2849, 1642, 1453, 1363, 1186,
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327
€
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