Stereoselective Synthesis of Substituted Tetrahydropyrans and Isochromans by Cyclization of Phenylseleno Alcohols

Article abstract of DOI:10.1021/acs.joc.5b01199

A selenium-mediated strategy for the stereoselective synthesis of substituted tetrahydropyrans and isochromans has been developed starting from δ-phenylseleno ketones. After enantioselective reduction, the chiral nonracemic phenylseleno alcohols were oxidized to the corresponding selenones, which underwent an effcient 6-exo-tet ring-closure reaction.

Full text of DOI:10.1021/acs.joc.5b01199

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Stereoselective Synthesis of Substituted Tetrahydropyrans and Isochromans by
Cyclization of Phenylseleno Alcohols
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Andrea Temperini,*† Anna Barattucci, # Paola Maria Bonaccorsi,# Ornelio Rosati† and Lucio
Minuti‡
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†Dipartimento di Scienze Farmaceutiche, Università di Perugia, Via del Liceo 1, 06123 Perugia,
Italy
# Dipartimento di Scienze Chimiche, Università di Messina, Viale F. Stagno d’Alcontres 31, 98166
Messina, Italy
‡ Dipartimento di Chimica, Biologia e Biotecnologie, Università di Perugia, Via Elce di Sotto 8,
Perugia, Italy
andrea.temperini@unipg.it
SePh
O
O
OH
C-O bond
f ormation
C-O bond
f ormation
R
R
R
Tetrahydropyrans
R= Alky, Aryl or Heteroaryl
Isochromans
ABSTRACT: A seleniumꢀmediated strategy for the stereoselective synthesis of substituted
tetrahydropyrans and isochromans has been developed starting from δꢀphenylseleno ketones. After
enantioselective reduction, the chiral nonꢀracemic phenylseleno alcohols were oxidized to the
corresponding selenones which underwent an effcient 6ꢀexoꢀtet ringꢀclosure reaction.
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INTRODUCTION
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The tetrahydropyrans motif is one of the most common scaffolds found in natural products such
as antibiotics,1 marine toxins2 and pheromones.3 In spite of many strategies employed for the
synthesis of complex tetrahydropyrans4 (THPs), a few examples of 2ꢀsubstituted THPs synthesis
were accounted. Among these, CꢀO bond formation reactions are probably the most used
methodologies, such as alkene selenoꢀ and haloetherification,5 acid catalyzed cyclization of
vinylsilanes,6 goldꢀ or ytterbiumꢀhydroalkoxylation of alkenols7a and allenes,7b palladium catalyzed
allylic oxidation8 or oxidative cyclization of alkenols,9 water10a and goldꢀ or ironꢀcatalyzed10b,c
cyclization of monoallylic diols, goldꢀcatalyzed cyclic ether formation from diols,11 copperꢀ
catalyzed OꢀH insertion of ωꢀhydroxyꢀαꢀdiazoesters12 and cycloetherification via intramolecular
oxyꢀMichael addition.13 Other approaches have focused on the formation of CꢀC bond as the
reaction of cyclic oxonium ion with organometallic reagents,14 the boron trifluorideꢀcatalyzed
rearrangement of 2ꢀaryloxytetrahydropyrans,15 the CꢀH arylation/alkylation at α–position of
tetrahydropyran16a or dihydropyran16b and, finally, the rutheniumꢀcatalyzed ringꢀclosing
metathesis.17 Due to the limitation of the above mentioned synthetic methods, such as moderate
yields and low stereoselectivity, development of efficient and enantioselective methods for the
construction of 2ꢀsubstituted THPs still represents a challenge.
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Reports from our laboratory have demonstrated the utility of organochalcogen intermediates in
organic synthesis18 as well as their use in the synthesis of heterocycles.19 We recently described the
easy and stereoselective preparation of 2ꢀsubstituted tetrahydrofurans20 via intramolecular
displacement of phenylselenone group by hydroxy group.
Scheme 1. General Strategy for the Stereoselective Synthesis of 2-Substituted
Tetrahydropyrans
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O
O
Noyori
Negishi
Ar(Het)
SePh
Ar(Het)
SePh
or Stille
coupling
reduction
1
(R= OH)
3
(COCl)2
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2
(R= Cl)
O
PhSe
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O
OH
O
SN2
Oxidation
OH
Ar(Het)
SePh
Ar(Het)
4
5
Ar(Het)
Based on this process, we envisioned a strategy for the construction of chiral nonꢀracemic 2ꢀ
substituted THPs 5 (Scheme 1), starting from enantioenriched phenylseleno alcohols 4. The control
of the stereochemistry of the secondary alcohols 4, by using catalytic asymmetric transfer
hydrogenation (ATH) reaction21 of δꢀphenylseleno ketones 3, is the cornerstone of our strategy
because it allows the expedient generation of THPs 5 in both enantiomeric forms. To the best of our
knowledge, use of phenylseleno alcohol 4 as intermediate in the synthesis of 2ꢀsubstituted THPs has
not been previously investigated. Thus, in this study we report: i) investigation on the
stereoselective synthesis of substituted tetrahydropyrans, based on the enantioselective reduction of
δꢀphenylseleno ketones and oxidation/cyclization of the corresponding alcohols; ii) application of
this approach to the synthesis of variously substituted isochromans.
RESULTS AND DISCUSSION
Synthesis of 2-substituted THPs. The required δꢀphenylseleno ketones 3aꢀf (Table 1) have been
synthesized for the first time by new procedures. Treatment of 5ꢀ(phenylseleno)pentanoic acid 1
with oxalyl chloride afforded the acyl chloride 2 (Scheme 1), that was reacted with the appropriate
arylzinc reagent in the presence of Pd(0) catalyst22 (Negishi coupling). Ketones 3aꢀd were obtained
in 60ꢀ80% yields. The reaction of acyl chloride 2 with a suitable (hetero)aryl stannane23 (Stille
conditions) gave the ketone 3e in 65% yield (Scheme 1). Since ketone 3f was obtained in very low
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yield by the above described methodologies, it was prepared, in 69% yield, by reaction of methyl
4
5
6
ester of acid 1 with 2ꢀlithiothiazole.24 Chiral nonꢀracemic δꢀphenylseleno alcohols 4 were
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synthesized from ketones
3
employing the commercially available RuCl[(S,S)ꢀ
9
TsDPEN](mesitylene) as catalyst for the ATH process.21 We selected the Noyori ATH reaction
because of its efficiency and stability and low cost of the catalyst as well as for the simplicity of the
experiments.
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Table 1. Asymmetric Reduction of Ketones 3 into Alcohols 4
RuCl
(S,S)-TsDPEN
Ar(Het)
O
SePh
Ar(Het)
OH SePh
or CBS catalyst
3a f
4a f
-
-
alcohola
erc
entry
time
(h)
yield
(%)b
1
2.5
85
ꢀꢀꢀd
OH SePh
OH SePh
OH SePh
Br
4a
2
3
3
89e
82
ꢀꢀꢀd
MeO
NC
4b
3.5
89.5:10.5
4c
OH SePh
4
5
5
4
92f
92
91.4:8.6
97.2:2.8
CO2Et
4d
OH SePh
O
4e
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N
6
1.5
89
98.5:1.5
OH SePh
6
S
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9
4f
aConfiguration of the major enantiomers of compounds 4aꢀf was
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tentatively assumed according to the mechanism and their
c
rotation signs.21,22 bIsolated yield. Determined by chiral HPLC
analysis. dNot HPLC resolved, see Table 2. eRuCl[(R,R)ꢀ
TsDPEN](mesitylene) was employed. f(S) MeꢀCBS was used
The enantioenriched δꢀphenylseleno alcohols 4aꢀc, 4e and 4f were obtained in excellent yields
(Table 1) and in high enantiomeric ratio as shown by chiral HPLC analysis. However for
compounds 4a and 4b it was not possible to obtain a good enantiomeric separation with the
available chiral stationary phases. Thus, we decided to subject them, as enantioenriched mixtures, to
the final cyclization step and separate the corresponding enantioenriched mixtures of
tetrahydropyrans 5a and 5b (Table 2). Due to the instability of the ester group under the ATH
conditions, alcohol 4d was obtained by the enantioselective reduction of the corresponding ketone
with borane in the presence of (S)ꢀMeꢀCBSꢀoxazaborolidine catalyst25 (Table 1, entry 4). The
configuration of the major enantiomer of compounds 4aꢀf was tentatively assigned according to the
original mechanisms described by Noyori and Corey.21,25 Oxidation of δꢀphenylseleno alcohols 4a
in THF, with an excess of mꢀchloroperoxybenzoic acid (MCPBA) and dipotassium hydrogen
phosphate at rt, gave the phenylselenone intermediate, as deduced by thinꢀlayer chromatography
(TLC). Unfortunately, the selenone intermediate was unable to turn into the desired THP ring 5a
after addition of powdered potassium hydroxide. Compound 5a was isolated in 10% yield after 48h
from addition. No significant improvement of the yield was observed with solvent changes (CH2Cl2
or EtOAc). The use of magnesium monoperoxyphthalate as oxidant in methanol19a gave THP 5a in
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moderate yield (35%) alongside the olefine derived from the βꢀelimination of the selenoxide
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intermediate.
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Table 2. Oxidation/Cyclization of Alcohols 4aꢀf into Tetrahydropyrans 5aꢀf.
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1) m-CPBA, MeCN
K2HPO4, rt, 2h
Ar
Ar
OH SePh
4a f
2) KOH, rt
O
5a-f
-
entry
1
tetrahydropyran
time
(h)
yield
(%)a
erb
8
5
7
2
80
75
72
82
97.6:2.4
Br
O
5a
5b
5c
2
3
4
88.6:11.4
89.5:10.5
ꢀꢀꢀc
MeO
NC
O
O
O
EtO2C
5d
5
6
4
4
58
67
ꢀꢀꢀc
O
O
O
5e
5f
N
98.5:1.5
S
aIsolated yield. Determined by chiral HPLC analysis. Not
b
c
HPLC resolved
The yield of 5a increased up to 66% when we employed MCPBA in methanol. However, when the
oxidation/cyclization of 4a was performed in acetonitrile with an excess of MCPBA and
dipotassium hydrogen phosphate, the 2ꢀsubstituted THP 5a was obtained in excellent yield (80%,
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Table 2, entry 1) after addition of powdered potassium hydroxide, thus demonstrating that the
cyclization step is greatly favourited by polar aprotic solvent. Oxidation/cyclization of alcohols 4bꢀ
f was performed by using the same reaction conditions of 4a, leading to differently 2ꢀsubstituted
THPs 5bꢀf in good to excellent yields (Table 2, entries 2ꢀ6) and with good enantiomeric ratios. The
enantiomeric composition of THPs 5c and 5f reflected that of the corresponding selenoꢀalcohols 4c
and 4f, thus attesting that no racemization occurred in the oxidation/cyclization step. Although it
was not possible to establish the enantiomeric ratios of THPs 5d and 5e (Table 2), the composition
of the enantioenriched mixtures should be the same as that of the corresponding alcohols 4d and 4e,
also according to our previous observations.20 Results reported in Table 2 show that the presence of
different functional groups in the aryl moiety does not significantly affect the yields of oxidation
and cyclization steps. The high yields, simplicity and mildness of the experimental conditions of the
procedure, make our method a general and valuable synthetic process for obtaining chiral nonꢀ
racemic 2ꢀaryl and 2ꢀheteroaryl substituted THPs. Compounds 5b11 and 5e17 have been previously
synthesized by different strategies and they were obtained in comparable or lower yields as racemic
mixture. Interestingly, the presence of bromine substituent in compound 5a allows an easy
conversion into compound 6 (58% yield) by palladium(0) promoted vinylic substitution reaction,26
or biphenyl 7 (65% yield) by palladium(0) catalyzed crossꢀcoupling reaction27 (Scheme 2).
Scheme 2. THP 5a involved in Palladium(0) Catalyzed Coupling Reactions
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O
DMA, 80 °C, Pd(Ph3P)4
Br
O
ethyl acrylate, 36 h
DIPEA, 58% yield
5a
Pd(Ph3P)4
DME, 90 °C
NaHCO3
B(OH)2
3h, 65% yield
EtO
O
MeO
MeO
6
O
7
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Application to the Stereoselective Synthesis of 2- and 4-substituted Isochromans. We then
turned our attention to the stereoselective synthesis of various substituted isochromans, in order to
explore the potential of our approach in the construction of sixꢀmembered oxygenated heterocycles.
Substituted isochromans are present in drugs,28 natural products29 and cosmetics30 with a wide
range of activities such as analgesic, muscle relaxant, antidepressant, antihistaminic, anticoagulant
and antihypertensive (Figure 1). A number of methodologies have been reported for the synthesis of
isochromans, such as the oxaꢀPictetꢀSpengler cyclization,31 radical annulation,32 intramolecular OꢀH
insertion reaction of diazoesters,12 palladium catalyzed allylic oxidation,8 mercuryꢀactivated alkene
addition,33 cyclotrimerization34 and the CꢀH alkylation or arylation at 1–position of isochromans.35
Although these are all reliable methods, only a few enantioselective variants of the synthesis of 1ꢀ
or 4ꢀsubstituted isochromans have been described in literature to date.35d,36
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Figure 1. Selected biologically active isochromanes
SO2NH2
O
N
N
O
U-101387
D4 antagonist
GalaxolideR
O
OMe
MeHN
O
N
N
PNU-109291
5-HT1d agonist
We envisioned that the phenylselenone mediate ring closure reaction, proposed for the construction
of THPs, could be used for the building of the sixꢀmembered oxygenated heterocycle of
isochromans. Thus, the reaction sequence outlined in Scheme 3 started with the preparation of the
stillꢀunknown phenylseleno acid 9, by cleavage of isochromanꢀ1ꢀone 8 with sodium
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phenylselenolate. Compound 9 was reacted with oxalyl chloride to give the acyl chloride
intermediate which was coupled with the appropriate mixed magnesium cuprate reagent according
to our previous report20 to furnish the new ketones 10a and 10b in excellent yields (Scheme 3). We
also explored the direct palladium catalyzed coupling of acyl chloride of acid 9 with arylzinc
reagents, as for the synthesis of 3aꢀd, but the expected ketones were obtained in low yields.
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Scheme 3. Synthesis of 1-substituted Isochromans 12a and 12b
SePh
PhSeSePh, NaBH4
O
DMF, 110 °C, 6 h
83% yield
OH
9
8
O
O
SePh
1) (COCl)2, 0 °C, 14 h
THF, 0 °C, 6 h
O
.
2) THF, -40 °C, 5 h
R(2-Th)CuMgBr
BH3 Me2S
(S) Me-CBS
R
10a
9
: 86% from
10b: 83% from 9
SePh
1) m-CPBA, MeCN
OH
R
K2HPO4, rt, 2 h
O
2) KOH, rt, 16 h
R
11a:
11b:
90% (er= 77.4:22.6)
92% (er= 77.6:22.4)
12a: 67% (er not measured)
12b: 75% (er= 77.6:22.4)
a: R= TBDMSO-CH2(CH2)3CH2
b
: R= Et
The reduction of ketones 10a and 10b under Noyori conditions, as described for 3aꢀf, resulted in
significant lesser conversion and low level of stereoselectivity. Thus, the enantioenriched
phenylseleno alcohols 11a and 11b were obtained in excellent yields and good enantiomeric ratio
via the chiral oxazaborolidineꢀcatalyzed Corey procedure.25 The configuration of the major
enantiomer of compounds 11a and 11b was tentatively assigned according to the original
mechanisms described by Corey.25 The optically active 1ꢀsubstituted isochromans 12a and 12b
were finally obtained in good yields by our oxidation/cyclization procedure. Compound 12b has
been previously obtained by a different procedure in comparable yield as a racemic mixture.35a On
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the basis of HPLC analysis on chiral stationary phase, compound 12b showed the same
enantiomeric composition of its precursor 11b, thus supporting that no racemization occurred
during the cyclization process.20 Otherwise, for compound 12a was not possible to obtain a clear
separation of the two enantiomers by HPLC.
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We next explored the enantioselective synthesis of 4ꢀsubstituted isochromans 17a and 17b from
the corresponding phenylseleno alcohols 16a and 16b (Scheme 4). Ketoesters 13a and 13b were
converted, by a two steps procedure, into the intermediate αꢀphenylseleno ketones 14a and 14b
which were immediately reduced with borane in the presence of (S)ꢀMeꢀCBS oxazaborolidine to
give the unexpected diols 15a and 15b in 48% and 56% total yield respectively, in good
enantiomeric ratio (Scheme 4). It is known that ester group is stable under borane reduction
conditions37 but, in our case, the closerꢀinꢀspace hydroxy group, formed in the initial reductive step,
could affect the reactivity of the carbomethoxy group with borane, most probably through the
formation of a lactone intermediate. A high yielding three steps procedure led to the monoprotected
phenylseleno alcohols 16a and 16b.
Scheme 4. Synthesis of 4-substituted Isochromans 17a and 17b
O
O
1) (TMS)2NH
TMSI, -20 °C
hexane, 8 h
.
BH3 Me2S
SePh
(S) Me-CBS
O
2) PhSeCl
EE, -20 °C
THF, 0 °C, 6 h
R
R
CO2Me
14a,b
OMe
OH
13a,b
SePh
1)TBSCl, imd.
3) TBAF, THF
DMF, 0 °C, 16 h
OH
13a
R
2) PPTS, CH2Cl2
15a
: 48% from
; er= 82.4:17.6
15a
PMBTCA for
NaH, DMF, MeI
15b
;
15b: 56% from 13b; er= 87.9:12.1
for
OR1
OR1
O
SePh
1) m-CPBA, MeCN
K2HPO4, rt, 2 h
OH
R
R
2) KOH, rt, 20 h
16a: 77% from 15a
17a: 70% (er not measured)
17b
16b
15b
: 71% from
: 66% (er= 87.9:12.1)
a: R= H; R1= PMB
1
b
: R= Br; R = Me
PMBTCA= 4-Methoxybenzyl-2,2,2-trichloroacetimidate
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Oxidation of 16a and 16b with MCPBA occurred smoothly in MeCN at rt in the presence of
dipotassium hydrogen phosphate to give the corresponding phenylselenone intermediates, which
cyclized to the enantioenriched 4ꢀsubstituted isochromans 17a and 17b in 70% and 66% yields,
respectively, after the addition of potassium hydroxide. HPLC analysis of compound 17b revealed
the same enantiomeric composition of alcohol 16b, whereas isochroman 17a did not give
appreciable separation with the chiral stationary phases available.
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Application to the Synthesis of 1,1-disubstituted Isochromans. Our seleniumꢀbased
methodology was extended to the synthesis of 1,1ꢀdisubstituted isochromans. Compound 9 was
converted into the corresponding methyl ester and then treated with an excess of butylmagnesium
bromide to furnish the tertiary alcohol 18 (Scheme 5). The oxidation/cyclization of alcohol 18 gave
the 1,1ꢀdialkyl isochroman 19 in high yield. Moreover, the lithium phenylacetylide addition to
ketone 10b gave the racemic tertiary alcohol 20 in 63% yield. Oxidation of 20 and cyclization of the
phenylselenone intermediate gave the attractive 1ꢀalkylꢀ1ꢀalkynylꢀsubstituted isochroman 21 in
86% yield, showing clearly that tertiary benzylic and propargylic alcohols are not affected by the
reaction conditions employed for pyran ring closure.
Scheme 5. Preparation of 1,1ꢀdisubstituted Isochromans 19 and 21
1) m-CPBA, THF
SePh
OH
1) TMSCl, MeOH, rt, 24 h
K2HPO4, 2 h
9
O
2) n-BuMgCl, THF, -78 °C
4 h, 56% yield
2) KOH, 2 h
79% yield
nBu
nBu
nBu
nBu
18
19
SePh
1) m-CPBA, THF
n-BuLi, THF
-78 °C, 4 h, 63% yield
OH
K2HPO4, 2 h
O
Ph
10b
2) KOH, 3 h
86% yield
20
21
Ph
Ph
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CONCLUSIONS
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In conclusion, we have applied the seleniumꢀbased chemistry, via a new 6ꢀexoꢀtet ringꢀclosure
reaction, to the stereoselective synthesis of substituted THPs and isochromans. Our developed
methodology provides a mild, stereoselective and general approach to the preparation of 2ꢀ
substituted THPs and 1ꢀ or 4ꢀsubstituted isochromans, from phenylseleno alcohols, that favourably
compares with other previously reported methods. Within this work, a new synthetic strategy for
the preparation of δ−phenylseleno ketones was developed. Further application of this new 6ꢀexoꢀtet
ringꢀclosure reaction, directed to the synthesis of complex tetrahydropyrans as well as natural
products, are currently in progress.
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EXPERIMENTAL SECTION
General information. Proton nuclear magnetic resonance (1H NMR) spectra and (13C NMR)
spectra were recorded at 200 MHz and 50.3 MHz. Unless otherwise specified CDCl3 was used as
the solvent and chemical shifts (δ) are reported in parts per million (ppm). The proton signal of
residual, nonꢀdeuterated solvent (δ 7.27 for CHCl3) was used as an internal reference for 1H spectra.
1H NMR spectral data are tabulated in the order: multiplicity (s, singlet; d, doublet; t, triplet; q,
quartet; m, multiplet; and br, broadened), coupling constants, number of protons, assignment (where
possible). Coupling constant (J) quoted in Hertz (Hz) to the nearest 0.1 Hz. For 13C spectra,
chemical shifts are reported relative to the δ 77.00 resonance of CDCl3 and chemical shifts are
expressed in ppm. Infrared (IR) spectra were recorded on a Diffuse Reflectance sampling cell. Only
significant absorption maxima (νmax) are reported in wavenumbers (cmꢀ1). GCꢀMS analysis were
obtained with a gas chromatograph (HPꢀ5MS capillary column 29.0 m, ID 0.25, film 0.25 ꢀm)
equipped with a mass selective detector at an ionizing voltage of 70 eV; for the ions containing
selenium only the peaks arising from seleniumꢀ80 isotope are given. HPLC enantioseparation were
performed on HPLC system equipped with a UV/Vis detector with chiral columns and solvents
specified. Melting points were determined on a Kofler hotstage apparatus and are uncorrected.
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Optical rotations were measured in a 50 mm cell using the Dꢀline of sodium at the specified
temperature. [α]D values are given in 10ꢀ1 deg cm2 gꢀ1; concentrations (c) are quoted in g 100 mLꢀ1.
Combustion analyses were carried out on elemental analyzer. Reactions were monitored by thin
layer chromatography (TLC) carried out on aluminium foil sheets preꢀcoated with silica (Merck
silica gel 60 F254), which were visualized by the quenching of UV fluorescence (λmax254 nm) and/or
by staining with 0.5% w/v potassium permanganate aqueous solution followed by heating. Column
chromatography was performed using Kieselgel 60 (70ꢀ230 mesh) silica gel.
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All reaction of air and water sensitive organometallics were carried out in flameꢀdried glassware
under argon using standard techniques. The organozinc and Grignard reagents for the synthesis of
compounds 3a-d, 10b and 18 were purchased from Aldrich and used directly from the bottle. The
Grignard reagents for the preparation of ketone 10a were synthesized in large preparation by
standard method from commercially available 5ꢀbromoꢀ1ꢀpentanol38 and analyzed by the method of
Knochel39 prior to use. Freshly opened bottle of cuprous iodide was found to be satisfactory.
Commercial grade tetrahydrofuran, diethyl ether, dichloromethane, acetonitrile and methanol were
dried by using standard procedures. Unless indicated, all chemicals were used without further
purification. 3ꢀChloroperbenzoic acid ≤77% from Aldrich was employed.
The starting phenylseleno acid 1 and the corresponding acyl chloride 2 were prepared as
described in the literature.20 Compounds 840 and 13a41 have been previously described in the
literature.
General Procedure for the synthesis of ketones 3a-d. Acid 1 (3.00 mmol) was reacted with
oxalyl chloride (17.71 mmol) at room temperature for 14 h. The solution was evaporated under
reduced pressure. The residue was dissolved in dry dichloromethane (5 mL), the solvent was
removed and the acyl chloride 2 obtained was immediately taken in 30 mL of dry THF. The
reaction mixture was cooled at 0ꢀ5 °C, protected from atmosphere moisture and powdered
tetrakis(triphenylphosphine)palladium(0) (0.15 mmol), was added. Then a 0.5 M solution of
organozinc reagent (7.2 mL) was added slowly along the side of the reaction flask by using a
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syringe pump over 1.5 h with vigorous stirring. The dark solution was allowed to reach room
temperature gradually and then stirred at this temperature for 4 h. Saturated aqueous sodium
hydrogen carbonate solution (1.5 mL) was added and the slurry was filtered through a celite pad,
dried over sodium sulfate, filtrated and evaporated. The residue was purified by column
chromatography on silica using diethyl etherꢀhexane mixture as eluent afford ketone 3.
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1-(4-Bromophenyl)-5-(phenylselanyl)pentan-1-one (3a): Following the general procedure, 1
(0.77g, 3.00 mmol) was converted, with 4ꢀbromophenylzinc iodide, in dry THF to 3a (0.72 g, 61%
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yield); light yellow solid, mp 85ꢀ88 °C; H NMR (200 MHz, CDCl3) δ 7.81 (d, J = 8.6 Hz, 2H),
7.60 (d, J = 8.6 Hz, 2H), 7.54ꢀ7.44 (m, 2H), 7.35ꢀ7.15 (m, 3H), 3.08ꢀ2.82 (m, 4H), 1.98ꢀ1.70 (m,
4H); 13C NMR (50 MHz, CDCl3) δ 198.7, 135.6, 132.6 (2C), 131.9 (2C), 130.2, 129.5 (2C), 129.0
(2C), 128.1, 126.8, 37.8, 29.7, 27.5, 24.2; FTIR: 2942, 1733, 1682, 1478, 1072, 821, 732 cmꢀ1;
EIMS (70 eV) m/z: M+ 396 (12), 239 (82), 183 (100), 157 (39), 91 (10), 77 (15); Anal. Calcd. for
C17H17BrOSe: C, 51.54; H, 4.33. Found: C, 51.39; H, 4.57.
1-(4-Methoxyphenyl)-5-(phenylselanyl)pentan-1-one (3b). Following the general procedure, 1
(0.52 g, 2.00 mmol) was converted, with 4ꢀmethoxyphenylzinc iodide, in dry diethyl ether to 3b
1
(0.50 g, 72% yield): white solid, mp 87ꢀ89 °C; H NMR (200 MHz, CDCl3) δ 7.95 (d, J = 8.8 Hz,
2H), 7.56ꢀ7.48 (m, 2H), 7.32ꢀ7.23 (m, 3H), 6.96 (d, J = 8.8 Hz, 2H), 3.89 (s, 3H), 3.05ꢀ2.86 (m,
4H), 1.98ꢀ1.72 (m, 4H); 13C NMR (50 MHz, CDCl3) δ 198.5, 163.4, 132.5 (2C), 130.3 (2C), 129.9,
129.0, 128.4, 126.7 (2C), 113.7 (2C), 55.4, 37.5, 29.8, 27.5, 24.6; FTIR: 2937, 1676, 1599, 1255,
1169, 829, 733 cmꢀ1; EIMS (70 eV) m/z: M+ 348 (2), 191 (50), 135 (100), 92 (15), 77(29); Anal.
Calcd. for C18H20O2Se: C, 62.25; H, 5.80. Found: C, 62.03; H, 6.02.
4-[5-(Phenylselanyl)pentanoyl]benzonitrile (3c). Following the general procedure, 1 (1.03 g,
4.00 mmol) was converted, with 4ꢀcyanophenylzinc bromide, in dry diethyl ether to 3c (1.03 g,
1
73% yield): white solid, mp 80ꢀ82 °C; H NMR (200 MHz, CDCl3) δ 8.02 (d, J = 8.4 Hz, 2H), 7.78
(d, J = 8.4 Hz, 2H), 7.57ꢀ7.45 (m, 2H), 7.43ꢀ7.20 (m, 3H), 3.05ꢀ2.92 [t, partly overlapped t (J = 6.5
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Hz, 2H), t (J = 6.4 Hz, 2H)], 2.01ꢀ1.68 (m, 4H); C NMR (50 MHz, CDCl3) δ 198.3, 139.8, 132.6
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(2C), 132.5 (2C), 129.6, 129.0 (2C), 128.4 (2C), 126.8, 117.9, 116.3, 38.2, 29.6, 27.4, 23.9; FTIR:
3068, 2936, 2237, 1683, 1477, 1273, 834, 731 cmꢀ1; EIMS (70 eV) m/z: M+ 343 (9), 186 (68), 157
(15), 130 (100), 102 (42), 77(14); Anal. Calcd. for C18H17NOSe: C, 63.16; H, 5.01; N, 4.09. Found:
C, 62.97; H, 5.25; N, 4.23.
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Ethyl 3-[5-(phenylselanyl)pentanoyl]benzoate (3d). Following the general procedure, 1 (1.29 g,
5.00 mmol) was converted, with 3ꢀ(ethoxycarbonyl)phenylzinc iodide, in dry THF to 3d (1.07 g,
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55% yield): amorphous solid, mp 38ꢀ40 °C; H NMR (200 MHz, CDCl3) δ 8.58 (dd, J = 1.4, 1.7
Hz, 1H), 8.24 (dt, J = 1.4, 7.7 Hz, 1H), 8.03 (ddd, J = 1.4, 1.7, 7.8 Hz, 1H), 7.61ꢀ7.43 (m, 3H),
7.32ꢀ7.19 (m, 3H), 4.42 (q, J = 7.1 Hz, 2H), 3.02 (t, J = 6.8 Hz, 2H), 2.96 (t, J = 7.1 Hz, 2H), 1.99ꢀ
1.70 (m, 4H), 1.42 (t, J = 7.1 Hz, 3H) ; 13C NMR (50 MHz, CDCl3) δ 199.0, 165.8, 137.0, 133.7,
132.5 (2C), 132.0, 131.0, 130.2, 129.1 (2C), 129.0, 128.8, 126.7, 61.4, 38.0, 29.6, 27.5, 24.1, 14.3;
FTIR: 2934, 1721, 1690, 1205, 1023, 748 cmꢀ1; EIMS (70 eV) m/z: M+ 390 (6), 233 (83), 177 (100),
149 (30), 120 (15), 85 (26), 71 (31), 57 (52); Anal. Calcd. for C20H22O3Se: C, 61.70; H, 5.70.
Found: C, 61.47; H, 5.94.
Preparation of ketone 3e. Acyl chloride 2 (1.00 mmol) prepared as described above from 0.258
g of acid 1 and oxalyl chloride (0.5 mL, 5.90 mmol) was dissolved in dry THF (2 mL) at room
temperature. Tributyl(2ꢀfuryl)stannane (0.346 mL, 1.10 mmol) and powdered tetrakis
(triphenylphosphine)palladium(0) (0.02 g, 0.03 mmol), were then added and the reaction mixture
was stirred under argon atmosphere for 20 h.42 The orange solution was then concentrated and the
residue was subjected to purification by column chromatography on SiO2 (20% diethyl ether in
hexane) affording ketone 3e.
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1-(2-Furyl)-5-(phenylselanyl)pentan-1-one (3e): 0.20 g, 65% yield; light yellow oil; H NMR
(200 MHz, CDCl3) δ 7.58 (dd, J = 0.8, 1.8 Hz, 1H), 7.53ꢀ7.46 (m, 2H), 7.30ꢀ7.22 (m, 3H), 7.17 (dd,
J = 0.8, 3.6 Hz, 1H), 6.54 (dd, J = 1.8, 3.6 Hz, 1H), 2.95 (t, J = 7.1 Hz, 2H), 2.84 (t, J = 7.0 Hz,
2H), 1.95ꢀ1.70 (m, 4H); 13C NMR (50 MHz, CDCl3) δ 189.0, 152.6, 132.4 (2C), 130.2, 128.9 (3C),
126.6, 116.8, 112.1, 37.6, 29.6, 27.3 24.2; FTIR: 2930, 1676, 1568, 1468, 1022, 762, 736 cmꢀ1;
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EIMS (70 eV) m/z: M+ 308 (30), 157 (29), 151 (96), 123 (13), 95 (100), 77 (25); Anal. Calcd. for
C15H16O2Se: C, 58.64; H, 5.25. Found: C, 58.51; H, 5.47.
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Synthesis of ketone 3f. Dry methanol (1.0 mL) was added to a mixture of acid chloride 2 (1.36
mmol) in dry THF (10 mL) and triethyl amine (0.21 mL, 1.49 mmol) at 0 °C. The reaction mixture
was allowed to slowly warm to room temperature. After 3 h the reaction was quenched with 10 mL
of 2M hydrochloric acid and 50 mL of dichloromethane. The organic phase was separated and
washed with 10 mL of saturated aqueous sodium hydrogen carbonate solution. The organic layer
was dried over sodium sulfate, filtrated and evaporated to give the crude methyl ester derivative
which was dissolved in 3 mL of diethyl ether and then added dropwise at ꢀ78 °C to a solution of 2ꢀ
lithiothiazole (1.50 mmol) in diethyl ether (4.00 mL) prepared as described by Dondoni.24 After ten
minutes at ꢀ78 °C, the resulting mixture was allowed to warm to 25 °C (1 h) and quenched by
addition of 10 mL of saturated aqueous sodium bicarbonate solution. The mixture was extracted
with ethyl acetate (3 x 20 mL). The organic layer was dried over sodium sulfate, filtrated and
evaporated. The resulting oil was purified by chromatography on SiO2 (30% diethyl
ether/petroleum ether) to afford ketone 3f.
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5-(Phenylselanyl)-1-(1,3-thiazol-2-yl)pentan-1-one (3f): 0.72 g, 69% yield; colorless oil; H
NMR (200 MHz, CDCl3) δ 7.99 (d, J = 3.0 Hz, 1H), 7.67 (d, J = 3.0 Hz, 1H), 7.54ꢀ7.43 (m, 2H),
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7.35ꢀ7.18 (m, 3H), 3.18 (t, J = 6.8 Hz, 2H), 2.95 (t, J = 7.2 Hz, 2H), 2.01ꢀ1.70 (m, 4H); C NMR
(50 MHz, CDCl3) δ 193.5, 167.0, 144.6, 132.6 (2C), 130.2, 129.0 (2C), 126.7, 126.2, 37.8, 28.8,
27.3 24.0; FTIR: 2937, 1684, 1478, 1391, 734 cmꢀ1; EIMS (70 eV) m/z: M+ 325 (11), 168 (44), 157
(18), 140 (100), 128 (21), 112 (57), 86 (40), 77 (14); Anal. Calcd. for C14H15NOSSe: C, 51.85; H,
4.66; N, 4.32. Found: C, 51.63; H, 4.90; N, 4.11.
Typical Procedure for the Asymmetric Reduction of ketones 3a-c and 3e,f. Powdered
RuCl[(R,R)ꢀTsDPEN](mesitylene) (0.05 mmol) was added to a solution of ketone 3 (1.00 mmol) in
15 mL of degassed 2ꢀpropanol at 36 °C followed by 0.06 mmol of potassium hydroxide. The
resulting dark brown mixture is stirred vigorously at 36 °C. After the appropriate reaction time (see
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Table 1), the reaction mixture was quenched with 10 mL of saturated aqueous ammonium chloride
solution and then extracted with ethyl acetate (2 x 20 mL). The combined organic layers were
washed with saturated sodium bicarbonate solution, saturated NaCl solution, dried over sodium
sulfate, filtrated and evaporated. The residue was purified by chromatography on SiO2 using an
ethyl acetateꢀpetroleum ether mixture (2:8) as eluent.
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(1S)-1-(4-Bromophenyl)-5-(phenylselanyl)pentan-1-ol (4a). Following the general procedure
ketone 3a (0.97 g, 2.45 mmol) was reduced to 4a (0.83 g, 85% yield); amorphous solid, mp 35ꢀ37
°C; [α]D23 ꢀ9.08 (c 1.02, CHCl3); 1H NMR (200 MHz, CDCl3) δ 7.52ꢀ7.42 (m, 4H), 7.31ꢀ7.14 (m,
5H), 4.59 (dd, J = 5.7, 7.1 Hz, 1H), 2.89 (t, J = 7.2 Hz, 2H), 2.17 (br s, 1H), 1.89ꢀ1.28 (m, 6H); 13C
NMR (50 MHz, CDCl3) δ 143.6, 132.4 (2C), 131.4 (2C), 130.3, 128.9 (2C), 127.5 (2C), 126.6,
121.1, 73.6, 38.3, 29.9, 27.6, 25.7; FTIR: 3396, 2932, 1578, 1478, 1009, 826, 736 cmꢀ1; EIMS (70
eV) m/z: M+ 398 (75), 223 (49), 211 (51), 198 (24), 185 (71), 169 (47), 158 (76), 144 (41), 91 (38),
77 (100), 51 (26); Anal. Calcd. for C17H19BrOSe: C, 51.28; H, 4.81. Found: C, 51.01; H, 5.05.
(1R)-1-(4-Methoxyphenyl)-5-(phenylselanyl)pentan-1-ol (4b). Following the general procedure
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ketone 3b (0.35 g, 1.00 mmol) was reduced to 4b (0.31 g, 89% yield); colorless oil; [α]D +26.04
(c 1.64, CHCl3); 1H NMR (200 MHz, CDCl3) δ 7.52ꢀ7.40 (m, 2H), 7.31ꢀ7.13 (m, 5H), 6.88 (d, J =
8.7 Hz, 2H), 4.58 (t, J = 6.3 Hz, 1H), 3.80 (s, 3H), 2.89 (t, J = 7.2 Hz, 2H), 2.01 (br s, 1H), 1.88ꢀ
1.29 (m, 6H); 13C NMR (50 MHz, CDCl3) δ 158.9, 136.7, 132.3 (2C), 130.4, 128.9 (2C), 127.0
(2C), 126.6, 113.7 (2C), 73.9, 55.2, 38.2, 30.0, 27.6, 26.0; FTIR: 3420, 2934, 1612, 1513, 1247,
884, 734 cmꢀ1; EIMS (70 eV) m/z: [Mꢀ18]+ 332 (25), 207 (89), 159 (52), 147 (100), 121 (88), 91
(79), 78 (87); Anal. Calcd. for C18H22O2Se: C, 61.89; H, 6.35. Found: C, 61.70; H, 6.65.
4-[(1S)-1-Hydroxy-5-(phenylselanyl)pentyl]benzonitrile (4c). Following the general procedure
ketone 3c ( 0.78 g, 2.30 mmol) was reduced to 4c (0.64 g, 82% yield); colorless oil; [α]D20 ꢀ9.52 (c
1.49, CHCl3); 1H NMR (200 MHz, CDCl3) δ 7.62 (d, J = 8.2 Hz, 2H), 7.54ꢀ7.38 (m, 4H), 7.33ꢀ7.20
(m, 3H), 4.72 (t, J = 5.5 Hz, 1H), 2.90 (t, J = 7.2 Hz, 2H), 2.37 (br s, 1 H), 1.89ꢀ1.35 (m, 6H); 13C
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NMR (50 MHz, CDCl3) δ 150.1, 132.4 (2C), 132.2 (2C), 130.3, 129.0 (2C), 126.7, 126.5 (2C),
118.8, 111.0, 73.4, 38.5, 29.9, 27.5, 25.6; FTIR: 3423, 2934, 2228, 1608, 1478, 1073, 839, 739 cmꢀ
1; EIMS (70 eV) m/z: M+ 345 (54), 213 (18), 188 (33), 170 (36), 158 (100), 132 (33), 104 (51), 91
(33), 77(58); Anal. Calcd. for C18H19NOSe: C, 62.79; H, 5.56; N, 4.07. Found: C, 62.48; H, 5.90;
N, 3.88. HPLC analysis on Phenomenex® Lux Celluloseꢀ1 column (100 x 4.60 mm ID), nꢀ
hexane/2ꢀpropanol = 94:6, flow rate = 1.0 mL/min, 254 nm UV detector: tR (Rꢀenantiomer, minor)
= 13.2 min, tR (Sꢀenantiomer, major) = 15.8 min, er = 10.5:89.5.
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(1S)-1-(2-Furyl)-5-(phenylselanyl)pentan-1-ol (4e). Following the general procedure ketone 3e
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(0.57 g, 1.75 mmol) was reduced to 4e (0.53 g, 92% yield); light yellow oil; [α]D ꢀ5.07 (c 2.43,
CHCl3); 1H NMR (200 MHz, CDCl3) δ 7.57ꢀ7.42 (m, 2H), 7.38 (dd, J = 0.8, 1.8 Hz, 1H), 7.31ꢀ7.21
(m, 3H), 6.34 (dd, J = 1.8, 3.2 Hz, 1H), 6.22 (dd, J = 0.8, 3.2 Hz, 1H), 4.64 (t, J = 6.7 Hz, 1H), 2.91
(t, J = 7.1 Hz, 2H), 2.12 (br s, 1 H), 1.95ꢀ1.35 (m, 6H); 13C NMR (50 MHz, CDCl3) δ 156.5, 132.4
(2C), 130.3, 128.9 (2C), 125.6 (2C), 110.0, 105.8, 67.4, 34.8, 29.8, 27.5, 25.6; FTIR: 3365, 2933,
1578, 1478, 1007, 736 cmꢀ1; EIMS (70 eV) m/z: M+ 310 (68), 241 (17), 157 (59), 135 (40), 123
(52), 97 (100), 91 (36), 77 (46), 55 (20); Anal. Calcd. for C15H18O2Se: C, 58.25; H, 5.87. Found: C,
57.97; H, 6.11. HPLC analysis on Phenomenex® Lux Celluloseꢀ1 column (100 x 4.60 mm ID), nꢀ
hexane/2ꢀpropanol = 96:4, flow rate = 1.0 mL/min, 254 nm UV detector: tR (Rꢀenantiomer, minor)
= 10.5 min, tR (Sꢀenantiomer, major) = 11.4 min, er = 2.8:97.2.
(1S)-5-(phenylselanyl)-1-(1,3-thiazol-2-yl)pentan-1-ol (4f). Following the general procedure
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ketone 3f (0.30 g, 0.94 mmol) was reduced to 4f (0.27 g, 89% yield); yellow oil; [α]D ꢀ10.70 (c
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1.94, CHCl3); H NMR (200 MHz, CDCl3) δ 7.71 (d, J = 3.1 Hz, 1H), 7.54ꢀ7.42 (m, 2H), 7.32ꢀ7.20
(m, 4H), 4.99 (dd, J = 4.8, 7.4 Hz, 1H), 3.33 (br s, 1 H), 2.92 (t, J = 7.1 Hz, 2H), 2.10ꢀ1.50 (m,
6H); 13C NMR (50 MHz, CDCl3) δ 175.8, 141.9, 132.4 (2C), 130.3, 128.9 (2C), 126.6, 118.8, 71.3,
37.5, 29.8, 27.5 25.3; FTIR: 3230, 2935, 1578, 1477, 1072, 734 cmꢀ1; EIMS (70 eV) m/z: M+ 327
(14), 281 (10), 207 (36), 168 (42), 140 (100), 128 (51), 112 (75), 86 (92), 77 (30), 55 (26); Anal.
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Calcd. for C14H17NOSSe: C, 51.53; H, 5.25; N, 4.29;. Found: C, 51.20; H, 5.61; N, 4.02. HPLC
analysis on Phenomenex® Lux Celluloseꢀ1 column (100 x 4.60 mm ID), nꢀhexane/2ꢀpropanol =
96:4, flow rate = 1.0 mL/min, 254 nm UV detector: tR (Rꢀenantiomer, minor) = 15.7 min, tR (Sꢀ
enantiomer, major) = 18.9 min, er = 1.5:98.5
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Asymmetric reduction of ketone 3d. To a solution of (S)ꢀMeꢀCBS 1.0 M in toluene (0.33 mL,
0.33 mmol) in dry THF (20 mL) at 0 °C was added a 2.0 M boraneꢀdimethyl sulfide complex (0.82
ml, 1.64 mmol).25 A solution of ketone 3d (1.64 mmol) in dry THF (13 mL) was added slowly by
using a syringe pump over 2 h with vigorous stirring and the solution was allowed to warm to room
temperature. The mixture was stirred at room temperature until the ketone disappeared on TLC
monitoring (3 h). The mixture was quenched with methanol and saturated ammonium chloride
solution (5 mL). The mixture was extracted with ethyl acetate (3 x 20 mL). The combined extracts
were washed with brine (5 mL), dried (MgSO4), filtrated and concentrated in vacuo. The crude
product was purified on a silica gel column with a mixture of petroleum ether and ethyl acetate
80:20 as eluent to give the corresponding chiral secondary alcohol 4d.
Ethyl 3-[(1R)-1-hydroxy-5-(phenylselanyl)pentyl]benzoate (4d): 0.58 g, 90% yield; colorless oil;
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[α]D +10.37 (c 1.23, CHCl3); 1H NMR (200 MHz, CDCl3) δ 8.04ꢀ7.88 (m, 2H), 7.58ꢀ7.32 (m,
4H), 7.31ꢀ7.17 (m, 3H), 4.70 (dd, J = 5.5, 6.9 Hz, 1H), 4.37 (q, J = 7.1 Hz, 2H), 2.88 (t, J = 7.2 Hz,
2H), 2.30 (br s, 1 H), 1.84ꢀ1.32 [m, partly overlapped t (J = 7.1 Hz, 3H), m (6H)], 1.39; 13C NMR
(50 MHz, CDCl3) δ 166.6, 145.0, 132.4 (2C), 130.5, 130.3, 129.6, 128.9 (2C), 128.6, 128.4, 126.9,
126.6, 73.8, 61.0, 38.4, 29.9, 27.5, 25.8, 14.3; FTIR: 3504, 2933, 1718, 1478, 1283, 1192, 740 cmꢀ
1; EIMS (70 eV) m/z: [Mꢀ158]+ 234 (3), 192 (36), 179 (100), 151 (20), 105 (23), 79 (14); Anal.
Calcd. for C20H24O3Se: C, 61.38; H, 6.18. Found: C, 61.10; H, 6.47. HPLC analysis on
Phenomenex® Lux Celluloseꢀ1 column (100 x 4.60 mm ID), nꢀhexane/2ꢀpropanol = 95:5, flow rate
= 1.0 mL/min, 254 nm UV detector: tR (Sꢀenantiomer, minor) = 17.1 min, tR (Rꢀenantiomer, major)
= 21.6 min, er = 8.6:91.4.
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General Procedure for the Oxidation-Cyclization of Phenylseleno alcohols 3a-f. To a
solution of phenylseleno alcohol 4 (0.50 mmol) in acetonitrile (15 mL) at room temperature,
powdered potassium hydrogenphosphate (2.00 mmol) and m-CPBA (1.50 mmol) were added. The
reaction mixture was stirred until TLC analysis showed that the starting selenide was completely
converted into the corresponding selenone (2 h). Powdered potassium hydroxyde (3.75 mmol) was
then added at room temperature. The consumption of the selenone was monitored by TLC. After the
appropriate time reaction (see table 2), the mixture was then poured into water (20 mL) and
extracted with ethyl acetate (3 x 20 mL). The combined organic layers were washed with saturated
sodium carbonate solution, saturated NaCl solution, dried over sodium sulfate, filtrated and
evaporated. The reaction product was then purified by column chromatography on silica gel (diethyl
etherꢀ petroleum ether mixture) to afford the 2ꢀsubstituted THP 5.
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(2S)-2-(4-Bromophenyl)tetrahydro-2H-pyran (5a). Following the general procedure alcohol 4a
(0.20 g, 0.50 mmol) was converted to 5a (97 mg, 80% yield); light yellow oil; [α]D26 ꢀ33.90 (c 1.89,
CHCl3); 1H NMR (200 MHz, CDCl3) δ 7.46 (d, J = 8.5 Hz, 2H), 7.23 (d, J = 8.5 Hz, 2H), 4.30 (dd,
J = 1.8, 10.6 Hz, 1H), 4.21ꢀ4.08 (m, 1H), 3.70ꢀ3.52 (m, 1H), 2.02ꢀ1.43 (m, 6H); 13C NMR (50
MHz, CDCl3) δ 142.4, 131.3 (2C), 127.6 (2C), 121.0, 79.3, 69.0, 34.1, 25.8, 23.9; FTIR: 2936,
2847, 1489, 1089, 909, 817 cmꢀ1; EIMS (70 eV) m/z: M+ 240 (41), 185 (73), 161 (100), 156 (32),
105 (43), 77 (35), 55 (25); Anal. Calcd. for C11H13BrO: C, 54.79; H, 5.43. Found: C, 54.50; H, 5.77.
HPLC analysis on Phenomenex® Lux Celluloseꢀ2 column (250 x 4.60 mm ID), nꢀhexane/2ꢀ
propanol = 99.6:0.4, flow rate = 1.0 mL/min, 254 nm UV detector: tR (Rꢀenantiomer, minor) = 20.7
min, tR (Sꢀenantiomer, major) = 22.2 min, er = 2.4:97.6.
(2R)-2-(4-Methoxyphenyl)tetrahydro-2H-pyran (5b).43 Following the general procedure alcohol
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4b (0.31 g, 0.90 mmol) was converted to 5b (0.13 g, 75% yield); [α]D +33.51 (c 1.15, CHCl3);
HPLC analysis on Chiracel® ODꢀH column (250 x 4.60 mm ID), nꢀhexane/2ꢀpropanol = 98:2, flow
rate = 1.0 mL/min, 254 nm UV detector: tR (Rꢀenantiomer, major) = 8.1 min, tR (Sꢀenantiomer,
minor) = 15.6 min, er = 88.6:11.4.
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4-[(2S)-Tetrahydro-2H-pyran-2-yl]benzonitrile (5c). Following the general procedure alcohol 4c
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(0.28 g, 0.80 mmol) was converted to 5c (0.10 g, 67%); colorless oil; [α]D ꢀ51.47 (c 1.65,
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CHCl3); H NMR (200 MHz, CDCl3) δ 7.63 (d, J = 8.5 Hz, 2H), 7.47 (d, J = 8.5 Hz, 2H), 4.39 (dd,
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J = 2.3, 11.0 Hz, 1H), 4.22ꢀ4.10 (m, 1H), 3.70ꢀ3.53 (m, 1H), 2.10ꢀ1.31 (m, 6H); 13C NMR (50
MHz, CDCl3) δ 148.6, 132.0 (2C), 126.3 (2C), 118.9, 110.7, 78.9, 68.8, 34.0, 25.5, 23.7; FTIR:
2941, 2851, 2228, 1610, 1265, 1089, 827 cmꢀ1; EIMS (70 eV) m/z: M+ 187 (52), 158 (21), 130
(100), 116 (43), 102 (49), 84 (37), 55 (57); Anal. Calcd. for C12H13NO: C, 76.98; H, 7.00; N, 7.48.
Found: C, 76.66; H, 7.37; N, 7.20. HPLC analysis on Phenomenex® Lux Celluloseꢀ2 column (250 x
4.60 mm ID), nꢀhexane/2ꢀpropanol = 99:1, flow rate = 1.0 mL/min, 254 nm UV detector: tR (Sꢀ
enantiomer, major) = 16.3 min, tR (Rꢀenantiomer, minor) = 17.9 min, er = 89.5:10.5.
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Ethyl 3-[(2R)-tetrahydro-2H-pyran-2-yl]benzoate (5d). Following the general procedure alcohol
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4d (0.21 g, 0.54 mmol) was converted to 5d (0.10 g, 82% yield); colorless oil; [α]D +25.69 (c
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0.75, CHCl3); H NMR (200 MHz, CDCl3) δ 8.03 (t, J = 1.6 Hz, 1H), 7.95 (dt, J = 1.6, 7.7 Hz),
7.56 (dt, J = 1.6, 7.7 Hz), 7.41 (t, J = 7.7 Hz), 4.45ꢀ4.34 [m, partly overlapped q (J = 7.1 Hz, 2H), m
(1H)], 4.22ꢀ4.10 (m, 1H), 3.71ꢀ3.55 (m, 1H), 2.01ꢀ1.51 (m, 6H), 1.40 (t, J = 7.1 Hz, 3H); 13C NMR
(50 MHz, CDCl3) δ 165.6, 143.7, 130.4, 130.3, 128.4, 128.3, 126.9, 79.5, 68.9, 60.9, 34.0, 25.7,
23.9, 14.3; FTIR: 2937, 2845, 1718, 1280, 1085, 753 cmꢀ1; EIMS (70 eV) m/z: M+ 234 (37), 205
(33), 189 (47), 177 (37), 161 (100), 149 (51), 133 (66), 105 (59), 77 (30); Anal. Calcd. for
C14H18O3: C, 71.77; H, 7.74. Found: C, 71.50; H, 7.98.
(2S)-2-(2-Furyl)tetrahydro-2H-pyran (5e).17 Following the general procedure alcohol 4e (0.47 g,
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1.50 mmol) was converted to 5e (0.13 g, 58% yield): colorless oil; [α]D ꢀ2.42 (c 1.72, CHCl3);
FTIR: 2942, 2850, 1724, 1506, 1085, 902, 734 cmꢀ1; EIMS (70 eV) m/z: M+ 152 (57), 189 (47), 135
(24), 108 (15), 95 (100), 81 (24), 68 (17), 55 (20).
2-[(2S)-Tetrahydro-2H-pyran-2-yl]-1,3-thiazole (5f). Following the general procedure alcohol 4f
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(0.25 g, 0.77 mmol) was converted to 5f (85 mg, 67% yield); colorless oil; [α]D ꢀ39.66 (c 1.54,
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CHCl3); H NMR (200 MHz, CDCl3) δ 7.71 (d, J = 3.3 Hz, 1H), 7.27 (d, J = 3.3 Hz, 1H), 4.77ꢀ4.70
(m, 1H), 4.22ꢀ4.09 (m, 1H), 3.76ꢀ3.55 (m, 1H), 2.30ꢀ2.10 (m, 1H), 2.07ꢀ1.90 (m, 1H), 1.80ꢀ1.50
(m, 4H); 13C NMR (50 MHz, CDCl3) δ 172.7, 142.0, 118.5, 77.6, 68.8, 32.5, 25.5, 22.9; FTIR:
2940, 2850, 1506, 1090, 1048, 902, 725 cmꢀ1; EIMS (70 eV) m/z: M+ 169 (1), 141 (34), 112 (100),
86 (30), 58 (29); Anal. Calcd. for C8H11NOS: C, 56.77; H, 6.55; N, 8.28. Found: C, 56.49; H, 6.85;
N, 8.02. HPLC analysis on Phenomenex® Lux Celluloseꢀ1 column (100 x 4.60 mm ID), nꢀ
hexane/2ꢀpropanol = 98:2, flow rate = 1.0 mL/min, 254 nm UV detector: tR (Rꢀenantiomer, minor)
= 4.5 min, tR (Sꢀenantiomer, major) = 6.7 min, er = 1.5:98.5.
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Synthesis of compound 6. Powdered tetrakis(triphenylphosphine)palladium(0) (15 mg, 0.005
mmol), tetrabutylammonium chloride (7 mg, 0.025 mmol), compound 5a (0.06 g, 0.25 mmol), N,Nꢀ
diisopropylethylamine ( 0.09 mL, 0.50 mmol), and ethyl acrylate (0.06 mL, 0.50 mmol) were
dissolved in N,Nꢀdimethylacetamide (2 mL ), and the resulting mixture was heated to 80 °C for 36
h.44 The mixture was then cooled to rt, diluted with diethyl ether (30mL), washed with brine, dried
over sodium sulfate, filtrated and concentrated to afford the crude product, which was purified by
column chromatography on SiO2 (10% diethyl ether in hexane).
Ethyl (2E)-3-{4-[(2S)-tetrahydro-2H-pyran-2-yl]phenyl}acrylate (6): 38 mg, 58% yield: light
yellow oil; [α]
26 ꢀ60.32 (c 1.25, CHCl3); 1H NMR (200 MHz, CDCl3) δ 7.68 (d, J = 16.0 Hz, 1H),
D
7.50 (d, J = 8.3 Hz, 2H), 7.37 (d, J = 8.3 Hz, 2H), 6.42 (d, J = 16.0 Hz, 1H), 4.38ꢀ4.04 [m, partly
overlapped q (J = 7.1 Hz, 2H), m (1H), m (1H], 4.25, 3.69ꢀ3.54 (m, 1H), 2.00ꢀ1.49 (m, 6H), 1.34
(t, J = 7.1 Hz, 3H); 13C NMR (50 MHz, CDCl3) δ 167.0, 145.7, 144.3, 133.4, 128.0 (2C), 126.2
(2C), 117.8, 79.6, 68.9, 60.4, 33.9, 25.7, 23.9, 14.3; FTIR: 2937, 2842, 1714, 1636, 1169, 1041, 821
cmꢀ1; EIMS (70 eV) m/z: M+ 260 (53), 214 (51), 203 (40), 187 (100), 175 (57), 159 (51), 131 (67),
103 (47), 77 (24); Anal. Calcd. for C16H20O3: C, 73.82; H, 7.74. Found: C, 73.51; H, 7.99.
Synthesis of compound 7. A 25 mL roundꢀbottom flask was charged with compound 5a (0.12 g,
0.50 mmol), powdered tetrakis(triphenylphosphine)palladium(0) (17 mg, 0.015 mmol) and 4 mL of
dimetoxyethane. The red mixture was stirred for 15 min at room temperature under argon
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atmosphere, then 4ꢀmetoxyphenylboronic acid (91 mg, 0.60 mmol) and 1 mL of 2M sodium
bicarbonate solution were added.27 The mixture was stirred at 90 °C for 3 h and then allowed to
slowly warm to room temperature. The slurry was filtered through a celite pad, dried over sodium
sulfate, filtrated and evaporated. Purification of the crude product by chromatography on SiO2 (10%
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diethyl ether in hexane) afforded 89 mg of compound 7, 65% yield.
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(2S)-2-(4'-Methoxybiphenyl-4-yl)tetrahydro-2H-pyran (7): white solid, mp 100ꢀ102 °C; [α]D
ꢀ
34.86 (c 0.57, CHCl3); 1H NMR (200 MHz, CDCl3) δ 7.49ꢀ7.56 (m, 4H), 7.40 (d, J = 8.5 Hz, 2H),
6.98 (d, J = 8.8 Hz, 2H), 4.42ꢀ4.33 (m, 1H), 4.23ꢀ4.11 (m, 1H), 3.86 (s, 3H), 3.73ꢀ3.57 (m, 1H),
2.05ꢀ1.52 (m, 6H); 13C NMR (50 MHz, CDCl3) δ 159.0, 141.7, 139.7, 133.5, 128.0 (2C), 126.5
(2C), 126.2 (2C), 114.1(2C), 79.8, 69.0, 55.3, 33.9, 25.9, 24.0; FTIR: 2934, 2837, 1607, 1499,
1250, 1039, 821 cmꢀ1; EIMS (70 eV) m/z: M+ 268 (100), 211 (65), 197 (39), 184 (31), 152 (20),
141 (20), 115 (15), 55 (9); Anal. Calcd. for C18H20O2: C, 80.56; H, 7.51. Found: C, 80.31; H, 7.87.
Preparation of acid 9. Commercially available isochroman was oxidized to isochromanꢀ1ꢀone
with a mixture of potassium permanganate and copper sulfate pentahydrate as reported in the
literature.40 Isochromanꢀ1ꢀone (1.18 g, 8 mmol) was then cleaved with sodium phenyl selenolate in
dry dimethylformamide20 at reflux to give 1.75 g (83% yield) of acid 9.
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2-[2-(Phenylselanyl)ethyl]benzoic acid (9): light yellow solid,mp 100ꢀ102 °C; H NMR (200
MHz, CDCl3) δ 11.90 (br s, 1H), 8.10 (dd, J = 1.5, 7.8 Hz, 1H), 7.68ꢀ7.52 (m, 3H), 7.50ꢀ7.10 (m,
5H), 3.55ꢀ3.38 (m, 2H), 3.24ꢀ3.17 (m, 2H); 13C NMR (50 MHz, CDCl3) δ 172.9, 143.8, 133.2,
132.4 (2C), 131.9, 131.7, 130.2, 129.0 (2C), 127.8, 126.7 (2C), 35.7, 28.2; FTIR: 3001, 2812, 1699,
1273, 930, 706 cmꢀ1; EIMS (70 eV) m/z: M+ 308 (15), 157 (11), 149 (100), 135 (82), 103(33), 91
(25), 77 (39); Anal. Calcd. for C15H14O2Se: C, 59.02; H, 4.62. Found: C, 58.70; H, 4.97.
Synthesis of Ketones 10a and 10b. The ketones 10a and 10b were synthesized by acylation of
the appropriate mixed magnesium cuprate reagents obtained from 1ꢀbromoꢀ5ꢀtertꢀbutylꢀ
dimethylsilyloxypentane38 and ethylmagnesium bromide respectively, with the corresponding acyl
chloride of acid 9 as reported in the literature.20
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6-{[tert-Butyl(dimethyl)silyl]oxy}-1-{2-[2-(phenylselanyl)ethyl]phenyl}hexan-1-one (10a): 0.42
g, 86% yield; light yellow oil; 1H NMR (200 MHz, CDCl3) δ 7.66ꢀ7.15 (m, 9H), 3.63 (t, J = 6.2 Hz,
2H), 3.23ꢀ3.12 (m, 4H), 2.89 (t, J = 7.2 Hz, 2H), 1.80ꢀ1.22 (m, 6H), 0.90 (s, 9 H), 0.06 (s, 6 H); 13C
NMR (50 MHz, CDCl3) δ 204.5, 140.4, 138.2, 132.3 (2C), 131.5, 131.2, 130.4, 129.0 (2C), 128.5,
126.6, 126.4, 63.0, 41.7, 35.0, 32.7, 28.6, 26.0 (3C), 25.5, 24.1, 18.3, ꢀ5.3 (2C); FTIR: 2928, 1684,
1478, 1256, 1094, 835, 739 cmꢀ1; EIMS (70 eV) m/z: [Mꢀ57]+ 433 (63), 201 (25), 183 (31), 155
(19), 141 (53), 129 (24), 103 (22), 91 (28), 75 (100); Anal. Calcd. for C26H38O2SeSi: C, 63.78; H,
7.82. Found: C, 63.44; H, 8.09.
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1-{2-[2-(Phenylselanyl)ethyl]phenyl}propan-1-one (10b): 2.73 g, 83% yield; light yellow oil; 1H
NMR (200 MHz, CDCl3) δ 7.62 (dd, J = 1.5, 7.5 Hz, 1H), 7.55ꢀ7.48 (m, 2H), 7.45ꢀ7.21 (m, 6H),
3.40ꢀ3.05 (m, 4H), 2.90 (q, J = 7.3 Hz, 2H), 1.19 (t, J = 7.3 Hz, 3H); 13C NMR (50 MHz, CDCl3) δ
204.7, 140.3, 137.9, 132.1 (2C), 131.4, 131.1, 130.3 (2C), 128.9, 128.3, 126.5, 126.3, 34.9, 34.7,
28.5, 8.2; FTIR: 2936, 1648, 1478, 1216, 957, 735 cmꢀ1; EIMS (70 eV) m/z 318 (15), 161 (100),
157 (22), 143 (28), 128 (29), 103 (20), 91 (25), 77 (26); Anal. Calcd. for C17H18OSe: C, 64.35; H,
5.72. Found: C, 64.04; H, 6.07.
Asymmetric Reduction of Ketones 10a and 10b. The alcohols 11a and 11b were obtained by
asymmetric reduction of the corresponding ketones with (S)ꢀMeꢀCBS as reported above for ketone
4d.
(1R)-6-{[tert-Butyl(dimethyl)silyl]oxy}-1-{2-[2-(phenylselanyl)ethyl]phenyl}hexan-1-ol
(11a).
As reported above, ketone 10a (0.20 g, 0.50 mmol) was reduced to 11a (0.36 g, 90% yield);
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colorless oil: [α]D16 +10.1 (c 1.48, CHCl3); H NMR (200 MHz, CDCl3) δ 7.60ꢀ7.40 (m, 3H), 7.38ꢀ
7.06 (m, 6H), 4.79 (dd, J = 4.9, 7.7 Hz, 1H), 3.60 (t, J = 6.5 Hz, 2H), 3.19ꢀ2.95 (m, 4H), 1.90 (br s,
1H), 1.85ꢀ1.08 (m, 8H), 0.90 (s, 9H), 0.06 (s, 6H); 13C NMR (50 MHz, CDCl3) δ 142.6, 137.6,
133.0 (2C), 129.8, 129.5, 129.1 (2C), 127.5, 127.1, 127.0, 125.8, 70.1, 63.1, 38.7, 33.1, 32.7, 28.8,
26.0 (3C), 25.8 (2C), 18.3, ꢀ5.3 (2C); FTIR: 3335, 2929, 1578, 1472, 1255, 1098, 835, 774 cmꢀ1;
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EIMS (70 eV) m/z: [Mꢀ57]+ 435 (17), 207 (21), 185 (44), 157 (19), 143 (52), 129 (60), 117 (85),
105 (31), 91 (39), 75 (100); Anal. Calcd. for C26H40O2SeSi: C, 63.52; H, 8.20. Found: C, 63.15; H,
8.55; HPLC analysis on Phenomenex® Lux Amyloseꢀ2 column (250 x 4.60 mm ID), nꢀhexane/2ꢀ
propanol = 98:2, flow rate = 1.0 mL/min, 254 nm UV detector: tR (Rꢀenantiomer, major) = 12.4
min, tR (Sꢀenantiomer, minor) = 13.5 min, er = 77.4:22.6.
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(1R)-1-{2-[2-(Phenylselanyl)ethyl]phenyl}propan-1-ol (11b). As reported above, ketone 10b
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was reduced to alcohol 11b (0.90 g, 92% yield); light yellow oil: [α]D16 +6.00 (c 1.56, CHCl3); H
NMR (200 MHz, CDCl3) δ 7.61ꢀ7.42 (m, 3H), 7.37ꢀ7.11 (m, 6H), 4.72 (dd, J = 5.6, 7.4 Hz, 1H),
3.21ꢀ2.92 (m, 4H), 2.01 (br s, 1H), 1.88ꢀ1.57 (m, 2H), 0.92 (t, J = 7.3 Hz, 3H); 13C NMR (50 MHz,
CDCl3) δ 142.3, 137.8, 133.0, 129.4, 129.1 (3C), 127.3, 127.0, 126.9 (2C), 125.7, 71.4, 33.1, 31.4,
28.7, 10.5; FTIR: 3385, 2963, 1578, 1477, 1437, 972, 734 cmꢀ1; EIMS (70 eV) m/z 320 (26), 185
(12), 157 (13), 145 (79), 133 (100), 117 (38), 105 (98), 91 (64), 77 (41); Anal. Calcd. for
C17H20OSe: C, 63.95; H, 6.31. Found: C, 63.58; H, 6.59; HPLC analysis on Phenomenex® Lux
Celuloseꢀ2 column (250 x 4.60 mm ID), nꢀhexane/2ꢀpropanol = 98:2, flow rate = 1.0 mL/min, 254
nm UV detector: tR (Sꢀenantiomer, minor) = 13.9 min, tR (Rꢀenantiomer, major) = 16.1 min, er =
22.4:77.6.
General Procedure for the Oxidation-Cyclization of Phenylseleno alcohols 11a and 11b. To
a solution of the appropriate phenylseleno alcohol (1.00 mmol) in acetonitrile (15 mL) at room
temperature, powdered potassium hydrogenphosphate (4.00 mmol) and m-CPBA (3.00 mmol) were
added. The reaction mixture was stirred until TLC analysis showed that the starting selenide was
completely converted into the corresponding selenone (2.5 h). Powdered potassium hydroxyde
(7.50 mmol) was then added at room temperature. The consumption of the selenone was monitored
by TLC. After 16 h the mixture was poured into water (20 mL) and extracted with ethyl acetate (2 x
20 mL). The combined organic layers were washed with saturated sodium carbonate solution,
saturated NaCl solution, dried over sodium sulfate, filtrated and evaporated. The reaction product
was purified by column chromatography on SiO2 (4% diethyl ether in petroleum ether).
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(R)-tert-Butyl(5-(isochroman-1-yl)pentyloxy)dimethylsilane (12a). Following the general
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procedure, 11a (0.31 g, 0.63 mmol) was converted to 12a (0.14 g, 67% yield); colorless oil; [α]D
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+38.5 (c 1.14, CHCl3); H NMR (400 MHz, CDCl3) δ 7.24ꢀ7.04 (m, 4H), 4.77 (dd, J = 2.6, 8.0 Hz,
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1H), 4.16 (ddd, J = 3.7, 5.3, 11.2 Hz, 1H), 3.80 (ddd, J = 3.8, 9.6, 11.2 Hz, 1H), 3.64 (t, J = 6.5 Hz,
2H), 3.01 (ddd, J = 5.3, 9.6, 16.2 Hz, 1H), 2.72 (ddd, J = 3.7, 3.8, 16.2 Hz, 1H), 2.00ꢀ1.77 (m, 2H),
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1.64ꢀ1.25 (m, 6H), 0.92 (s, 9 H), 0.07 (s, 6 H); C NMR (100 MHz, CDCl3) δ 138.5, 133.9, 128.8,
126.1, 126.0, 124.7, 75.8, 63.2, 63.1, 36.0, 32.8, 29.2, 26.0 (3C), 25.9, 25.1, 18.4, ꢀ5.3 (2C); FTIR:
2933, 1471, 1254, 1104, 836, 742 cmꢀ1; EIMS (70 eV) m/z: [Mꢀ57]+ 277 (11), 185 (23), 143 (36),
133 (100), 129 (35), 117 (45), 105 (21), 75 (35); Anal. Calcd. for C20H34O2Si: C, 71.80; H, 10.24.
Found: C, 71.54; H, 10.59.
(1R)-1-Ethyl-isochroman (12b).35a Following the general procedure, 11b (0.29 g, 0.9 mmol) was
converted to 12b (0.11 g, 75% yield); colorless oil; [α]D23 +80.2 (c 1.50, CHCl3); HPLC analysis on
Phenomenex® Lux Celuloseꢀ2 column (250 x 4.60 mm ID), nꢀhexane/2ꢀpropanol = 98:2, flow rate
= 1.0 mL/min, 254 nm UV detector: tR (Rꢀenantiomer, major) = 4.6 min, tR (Sꢀenantiomer, minor)
= 5.4 min, er = 77.6:22.4.
Synthesis of ketoester 13b. Commercially available 5ꢀbromoꢀ2ꢀhydroxyꢀbenzaldehyde was
converted into the corresponding 2ꢀacetylꢀ5ꢀbromobenzaldehyde 22 by the method reported in the
literature.45
2-Acetyl-5-bromobenzaldehyde (22):45 1.52 g, 70% yield; light yellow solid, mp 73ꢀ75 °C (nꢀ
hexane); FTIR: 2893, 2748, 1765, 1676, 1192, 824, 710 cmꢀ1; Oxidation of 22 following the
literature procedure46 gave crude 2ꢀacetylꢀ5ꢀbromobenzoic acid which was immediately reacted
with methanol41 to give 13b.
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Methyl 2-acetyl-5-bromobenzoate (13b): 0.70 g, 68% yield; yellow oil; H NMR (200 MHz,
CDCl3) δ 7.97 (d, J = 2.0 Hz, 1H), 7.69 (dd, J = 2.0, 8.2 Hz, 1H), 7.32 (d, J = 8.2 Hz, 1H), 3.90 (s,
3H), 2.54 (s, 3 H); 13C NMR (50 MHz, CDCl3) δ 201.5, 166.2, 140.9, 134.9, 132.6, 130.8, 128.2,
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124.4, 52.8, 29.8; FTIR: 2952, 1732, 1705, 1262, 967, 830, 750 cmꢀ1; EIMS (70 eV) m/z 256 (5),
241 (100), 225 (31), 211 (16), 198 (11), 170 (13), 153 (13), 75 (21); Anal. Calcd. for C10H9BrO3: C,
46.72; H, 3.53. Found: C, 46.64; H, 3.58.
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Synthesis of diols 15a and 15b. A solution of methyl 2ꢀacetylbenzoate 13a (0.10 g, 0.60 mmol)
and hexamethyldisilazane (0.16 mL, 0.72 mmol) in hexane (8 mL) was cooled to ꢀ20 °C under
argon and trimethylsilyl iodide (0.10 ml, 0,60 mmol) was added.47 The mixture was stirred first at ꢀ
20 °C for 10 min then at 25 °C for 8 h. The slurry was filtered through a celite pad and the filtrate
was washed with 10 mL of cold saturated sodium hydrogen carbonate solution, dried over sodium
sulfate, filtrated and evaporated to give the crude trimethylsilylenol ether derivative which was
dissolved in 2 mL of dry diethyl ether at ꢀ20 °C. Phenylselenenyl chloride (0.13 g, 0.66 mmol)
dissolved in dry diethyl ether (2.0 mL) was added slowly and the reaction mixture was allowed to
slowly warm to room temperature. After 1 h the reaction was quenched with saturated aqueous
sodium hydrogen carbonate solution (10 mL) and then extracted with diethyl ether (2 x 10 mL). The
organic layer was dried over sodium sulfate, filtrated and evaporated. The residue was passed
through a short column of silica gel (20% diethyl ether in petroleum ether) to give the crude αꢀ
phenylselenoꢀketone intermediate 14a (0.18 g) of sufficient purity for use in subsequent
manipulation. The asymmetric reduction of crude 14a with an equimolecular amount of (S)ꢀMeꢀ
CBS in the presence of a twofold excess of borane dimethylsulfide complex8 gave 0.09 g of the diol
15a in 48% global yield from 13a.
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(1S)-1-[2-(Hydroxymethyl)phenyl]-2-(phenylselanyl)ethanol (15a): colorless oil; [α]D +8.9 (c
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1.68, CHCl3); H NMR (200 MHz, CDCl3) δ 7.63ꢀ7.15 (m, 9H), 5.02 (dd, J = 5.6, 8.4 Hz, 1H),
4.58 (s, 2H), 3.48ꢀ3.10 (m, 3H), 2.60 (brs, 1H);13C NMR (50 MHz, CDCl3) δ 140.6, 137.8, 133.1,
133.0, 129.8, 129.7, 129.2 (2C), 128.4, 128.1, 127.4, 126.5, 69.9, 63.2, 36.6; FTIR: 3325, 2974,
1578, 1340, 762 cmꢀ1; Anal. Calcd. for C15H16O2Se: C, 58.64; H, 5.25. Found: C, 58.29; H, 5.66;
HPLC analysis on Phenomenex® Lux Amyloseꢀ2 column (250 x 4.60 mm ID), nꢀhexane/2ꢀpropanol
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= 90:10, flow rate = 1.0 mL/min, 254 nm UV detector: tR (Rꢀenantiomer, minor) = 21.4 min, tR (Sꢀ
enantiomer, major) = 22.8 min, er = 17.6:82.4.
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(1S)-1-[4-Bromo-2-(hydroxymethyl)phenyl]-2-(phenylselanyl)ethanol (15b). Following the
above procedure, 13b (1.52 g, 6.00 mmol) was converted to 15b ( 1.30 g, 56% global yield from
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13b): light yellow oil; [α]D23 ꢀ10.70 (c 1.14, CHCl3); H NMR (200 MHz, CDCl3) δ 7.56ꢀ7.48 (m,
2H), 7.44ꢀ7.37 (m, 2H), 7.33ꢀ7.22 (m, 4H), 4.88 (dd, J = 4.4, 9.1 Hz, 1H), 4.48 (s, 2H), 3.20ꢀ2.90
[m, partly overlapped dd (J = 4.4, 12.8 Hz, 1H), dd (J = 9.1, 12.8 Hz, 1H), br s (2H)]; 13C NMR
(50 MHz, CDCl3) δ 139.8, 139.3, 133.3 (2C), 132.2, 131.3, 129.3 (2C), 128.7, 128.3, 127.6, 121.9,
69.3, 62.4, 36.6; FTIR: 3371, 2932, 1578, 1477, 1022, 828, 736 cmꢀ1; EIMS (70 eV) m/z: [Mꢀ18]+
368 (8), 170 (100), 169 (12), 118 (18), 90 (13), 77 (13); Anal. Calcd. for C15H15BrO2Se: C, 46.66;
H, 3.92. Found: C, 46.41; H, 4.22; HPLC analysis on Phenomenex® Lux Celluloseꢀ2 column (250 x
4.60 mm ID), nꢀhexane/2ꢀpropanol = 90:10, flow rate = 1.0 mL/min, 254 nm UV detector: tR (Sꢀ
enantiomer, major) = 12.8 min, tR (Rꢀenantiomer, minor) = 22.2 min, er = 87.9:12.1.
Preparation of alcohol 16a. tertꢀButyldiphenylsilyl chloride (0.40 mL. 1.57 mmol) was added
to a stirred solution of diol 15a (0.44 g, 1.43 mmol) and imidazole (0.12 g, 1.71 mmol) in dry
dimethylformamide (5.0 mL) at 0 °C under an Ar atmosphere. The mixture was stirred for 16 h and
then quenched with 10 mL of saturated aqueous ammonium chloride solution, extracted with
diethyl ether (2 x 30 mL) and the organic layer was dried over sodium sulfate. The solution was
filtrated, evaporated and the residue was dissolved in dichloromethane (5 mL) at room temperature.
To this solution 4ꢀmethoxybenzyl 2,2,2ꢀtrichloroacetimidate (0.65 g, 2.28 mmol) and pyridinium pꢀ
toluensulfonate polimer bound (50 mg) were added.48 After 24 h the mixture was filtrate through a
short celite pad and evaporated. The residue was dissolved in THF (15 mL) and TBAF (0.45 g, 1.43
mmol) was added. The reaction mixture was stirred for 6 h, poured into saturated aqueous sodium
hydrogen carbonate solution (20 mL) and extracted with ethyl acetate (3 x 20 mL). The organic
layer was dried over sodium sulfate, filtrated and evaporated. Pure 16a (0.48 g) was isolated after
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column chromatography on SiO2 (20% diethyl ether/petroleum ether) in a 77% global yield from
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{2-[(1S)-1-[(4-Methoxybenzyl)oxy]-2-(phenylselanyl)ethyl]phenyl}methanol (16a): light yellow
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oil; [α]D21 +29.4 (c 1.53, CHCl3); H NMR (200 MHz, CDCl3) δ 7.58ꢀ7.10 (m, 11H), 6.95ꢀ6.80 (m,
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2H), 4.89 (dd, J = 5.2, 8.5 Hz, 1H), 4.66ꢀ4.46 (AB system, 2H), 4.42 (d, J = 11.2 Hz, 1H), 4.25 (d, J
= 11.2 Hz, 1H), 3.80 (s, 3H), 3.40 (dd, J = 8.5, 12.4 Hz, 1H), 3.19 (dd, J = 5.2, 12.4 Hz, 1H), 2.39
(br s, 1H);13C NMR (50 MHz, CDCl3) δ 159.2, 139.3, 138.4, 132.8, 130.5, 129.9, 129.5, 129.4,
129.1, 129.0, 128.6, 128.4, 128.1, 127.6, 127.2, 126.9, 113.9, 113.8, 77.1, 70.5, 62.7, 55.3, 35.0;
FTIR: 3370, 3245, 1696, 1512, 1247, 837, 757 cmꢀ1; Anal. Calcd. for C23H24O3Se: C, 64.63; H,
5.66. Found: C, 64.29; H, 6.03.
Preparation of alcohol 16b. tertꢀButyldiphenylsilyl chloride (0.56 mL. 2.20 mmol) was added
to a stirred solution of diol 15b (0.77 g, 2.00 mmol) and imidazole (0.16 g, 2.40 mmol) in dry
dimethylformamide (6.0 mL) at 0 °C under an Ar atmosphere. The mixture was stirred for 16 h and
then quenched with 10 mL of saturated aqueous ammonium chloride solution, extracted with
diethyl ether (3 x 30 mL) and the organic layer was dried over sodium sulfate. The solution was
filtrated, evaporated and the residue was dissolved in dimethylformamide (20 mL) at 0 °C. To this
solution sodium hydride 60% dispersion in mineral oil (0.11 g, 2.8 mmol) was added. After 30
min, methyl iodide was added (0.16 mL, 2.60 mmol). The mixture was stirred for 8 h at rt and then
quenched with 10 mL of saturated aqueous ammonium chloride solution, extracted with ethyl ether
(3 x 30 mL) and the organic layer was dried over sodium sulfate. The solution was filtrated,
evaporated and the residue was dissolved in THF (30 mL) and TBAF (0.63 g, 2.00 mmol) was
added. The reaction mixture was stirred for 12 h, poured into saturated aqueous sodium hydrogen
carbonate solution (20 mL) and extracted with ethyl acetate (3 x 30 mL). The organic layer was
dried over sodium sulfate, filtrated and evaporated. Pure 16b (0.48 g) was isolated after column
chromatography on SiO2 (40% diethyl ether/petroleum ether) in a 71% global yield from 15b.
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{5-Bromo-2-[(1S)-1-methoxy-2-(phenylselanyl)ethyl]phenyl}methanol (16b): yellow oil; [α]D
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+14.95 (c 0.64, CHCl3); H NMR (200 MHz, CDCl3) δ 7.53ꢀ7.40 (m, 4H), 7.35ꢀ7.19 (m, 4H), 4.64
(dd, J = 5.6, 8.0 Hz, 1H), 4.58 (AB system, 2H), 3.31 (dd, J = 8.0, 12.5 Hz, 1H), 3.23 (s, 3H); 3.11
(dd, J = 5.6, 12.5 Hz, 1H), 2.40 (br s, 1H); 13C NMR (50 MHz, CDCl3) δ 140.5, 137.8, 133.0 (2C),
131.6, 131.2, 130.0, 129.1 (2C), 128.7, 127.6, 122.0, 79.4, 62.1, 57.0, 34.4; FTIR: 3381, 2931,
1578, 1477, 1091, 883, 739 cmꢀ1; EIMS (70 eV) m/z: 400 (15), 229 (91), 197 (100), 169 (36), 103
(18), 91 (22), 77 (15); Anal. Calcd. for C16H17BrO2Se: C, 48.02; H, 4.28. Found: C, 47,77; H, 4.59.
Oxidation-cyclization of alcohols 16a and 16b. To a solution of phenylseleno alcohol 16a
(0.43 g, 1.00 mmol) in acetonitrile (15 mL) at room temperature, powdered potassium
hydrogenphosphate (0.69 g, 4.00 mmol) and m-CPBA (0.52 g, 3.00 mmol) were added. The
reaction mixture was stirred until TLC analysis showed that the starting selenide was completely
converted into the corresponding selenone (2 h). Powdered potassium hydroxyde (0.42 g, 7.50
mmol) was then added at room temperature. The consumption of the selenone was monitored by
TLC. After 20 h the mixture was poured into water (20 mL) and extracted with ethyl acetate (2 x 20
mL). The combined organic layers were washed with saturated sodium carbonate solution, saturated
NaCl solution, dried over sodium sulfate, filtrated and evaporated. The reaction product was
purified by column chromatography on SiO2 (15% ethyl acetate in petroleum ether) to afford 17a.
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(4S)-4-(4-Methoxybenzyloxy)isochroman (17a): 0.19 g, 70% yield; white gum; [α]D +11.9 (c
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1.84, CHCl3); H NMR (200 MHz, CDCl3) δ 7.42ꢀ7.16 (m, 5H), 7.10ꢀ6.97 (m, 1H), 6.87 (d, J = 9.2
Hz, 2H), 4.86 (d, J = 15.0 Hz, 1H), 4.68 (d, J = 15.0 Hz, 1H), 4.63 (s, 2H), 4.45 (dd, J = 3.4, 3.6 Hz,
1H), 4.18 (dd, J = 3.6, 12.0 Hz, 1H), 3.90 (dd, J = 3.4, 12.0 Hz, 1H), 3.80 (s, 3H);13C NMR (50
MHz, CDCl3) δ 159.2, 135.3, 133.0, 130.4, 129.5 (2C), 129.2, 127.9, 126.7, 124.0, 113.8 (2C),
70.6, 70.3, 68.2, 67.8, 55.3, FTIR: 2840, 1730, 1513, 1247, 824, 749 cmꢀ1; EIMS (70 eV) m/z: 270
(5), 137 (29), 121 (100), 105 (19), 91 (21), 77 (21); Anal. Calcd. for C17H18O3: C, 75.53; H, 6.71.
Found: C, 75.20; H, 7.05.
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