An asymmetric tandem conjugative addition-intramolecular cyclisation process to provide functionalised 3,6-dihydropyrans and 4,5- epoxytetrahydropyrans

Article abstract of DOI:10.1002/ejoc.200901145

The synthesis of 3,6-dihydropyrans and 4,5-epoxytetrahydropyrans starting from enantiomerically pure β-hydroxy aldehyde (prepared by an organocatalytic aldol reaction) is described. The key step is a tandem sequence, which consists of a base-promoted conjugative addition to a vinyl onium salt, followed by either an intramolecular Wittig process to provide 3,6-dihydropyran derivatives or an intramolecular cyclisation/epoxidation process to afford 4,5-epoxytetrahydropyran scaffolds. The products obtained by this method are common substructures in polyketide natural products.

Full text of DOI:10.1002/ejoc.200901145

FULL PAPER
DOI: 10.1002/ejoc.200901145
An Asymmetric Tandem Conjugative Addition-Intramolecular Cyclisation
Process to Provide Functionalised 3,6-Dihydropyrans and
4,5-Epoxytetrahydropyrans
Silvia Catalán-Muñoz,[a] Constanze A. Müller,[a] and Steven V. Ley*[a]
Keywords: Epoxidation / Organocatalysis / Aldol reactions / Wittig reactions
The synthesis of 3,6-dihydropyrans and 4,5-epoxytetra-
ium salt, followed by either an intramolecular Wittig process
hydropyrans starting from enantiomerically pure β-hydroxy to provide 3,6-dihydropyran derivatives or an intramolecular
aldehyde (prepared by an organocatalytic aldol reaction) is
described. The key step is a tandem sequence, which con-
sists of a base-promoted conjugative addition to a vinyl on-
cyclisation/epoxidation process to afford 4,5-epoxytetra-
hydropyran scaffolds. The products obtained by this method
are common substructures in polyketide natural products.
Introduction
Pyran derivatives are a common structural motif in nu-
merous polyketide natural products, some of which have
shown interesting biological activities. For example, the lau-
limalide family of macrolides contain the dihydropyran
framework as a characteristic element. Laulimalide (1) and
Fijianolide G (2) (Figure 1) were found to be a potent
microtubule-stabilising agents and thereby inhibit the pro-
liferation of several tumour cancer cell lines in a similar
manner to Paclitaxel.[1] Owing to the importance of the py-
ran framework several strategies towards its preparation
have been developed, including Prins cyclisations,[2] hetero
Diels–Alder reactions,[3] ring closing metathesis,[4] Ferrier-
type reactions,[5] and intramolecular nucleophilic reac-
tions.[6]
Thus far, only a few organocatalytic syntheses have been
described.[7] Asymmetric organocatalysis has emerged as a
powerful tool to synthesise optically pure substances in a
simple manner.[8] Among the enantioselective reactions pro-
moted by chiral amines, aldol reactions are of particular
value. The direct combination of two carbonyl substrates
leads to important building blocks and often proceeds with
excellent chemo- and stereoselectivity.[9]
We have recently used these methods for the preparation
of chiral 1,2-oxazines and pyridazines.[10] Starting from
achiral aldehydes and ketones, an α-oxyamination with ni-
trosobenzene in presence of pyrrolidinyl-tetrazole followed
by conjugative addition to a vinylphosphonium salt gener-
Figure 1. Pyran-containing polyketide natural products.
ates an ylide. This then cyclises to give the dihydro-1,2-ox-
azine in this one-pot process. Similarly, chiral pyridazines
were prepared by applying α-amination instead of oxyamin-
ation in the first part of the transformation. The products
of these reactions were obtained in good to excellent yield
with high enantioselectivity. Herein, we have designed a re-
lated route directed towards the synthesis of pyran deriva-
tives from aldol adducts 6 and various onium salts 7
(Scheme 1).
Reaction of a β-hydroxy aldehyde 6 with a vinylphospho-
nium salt 7a should lead to the formation of 3,6-dihydropy-
rans 8 whereas the corresponding and complimentary sul-
fur derivatives 7b were expected to afford access to 4,5-ep-
oxytetrahydropyrans 9.
[a] Department of Chemistry, University of Cambridge,
Lensfield Road, Cambridge, CB2 1EW, UK
Fax: +44-1223-336442
E-mail: svl1000@cam.ac.uk
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.200901145.
Eur. J. Org. Chem. 2010, 183–190
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
183

S. Catalán-Muñoz, C. A. Müller, S. V. Ley
FULL PAPER
Table 1. Base screening for the synthesis of 3,6-dihydropyran 8a
from β-hydroxy aldehyde 6a.[a]
Entry Base [equiv.]
Solvent [0.1 ]
Method[c] Yield 8a
[%]
1
2
3
4
5
6
7
8
KH [2.0]
KN(TMS)2 [2.5] DMSO
THF/DMSO[b]
A
A
B
A
B
A
A
A
17
30
11
40
12
43
0
K2CO3 [2.5]
K2CO3 [2.5]
Cs2CO3 [2.5]
Cs2CO3 [2.5]
Li2CO3 [2.5]
DBU [2.0]
DMF
DMF
DMF
DMF
DMSO
DMSO
38
[a] All reactions were performed with 1.5 equiv. of vinylphospho-
nium salt 7a at room temp. with reaction times of 1–4 h. [b] Mix-
ture of THF/DMSO [1:1], 0.05 . [c] Method A: base was added
to a stirred solution of 6a and 7a; Method B: deprotonation of 6a
first, followed by addition of 7a.
Scheme 1. Synthesis of pyran derivatives from β-hydroxy aldehydes
and vinyl ylides.
Because the results with K2CO3 and Cs2CO3 were prom-
ising an extensive solvent screening was undertaken. These
experiments showed that the reaction did not work well in
ethereal solvents such as dioxane, dimethoxethane or THF
(Table 2, Entry 1–3) and varying yields were obtained with
polar aprotic solvents (Table 2, Entry 4–7, and 10). DMSO
was eventually chosen to be the best solvent, yielding dihy-
dropyran 8a in 48% yield after 1 h at room temperature.
Similar results were obtained in 1,2-dichloroethane
(Table 2, Entry 9) and dichloromethane was less effective.
However, due to the toxicity of these halogenated solvents
no further investigation was carried out.
Results and Discussion
The initial β-hydroxy aldehydes 6 can be synthesised with
a well established asymmetric aldol reaction between an
α,α-dialkyl aldehyde 3 with an aromatic aldehyde 4. Al-
though this method could be applied to different α,α-dialkyl
aldehydes we have limited our study to the gem-dimethyl
group. This transformation was then followed by a base-
promoted nucleophilic attack of the resulting hydroxy
group to a vinylphosphonium salt[11] 7a to provide a tran-
sient ylide intermediate, which was cyclised through an in-
tramolecular Wittig reaction to furnish the 3,6-dihydropy-
ran product 8.
Table 2. Solvent screening.[a]
Entry
Solvent [0.1 ]
Yield 8a[c]
[%]
Using the same conditions that had been successfully ap-
plied to the preparation of chiral 1,2-oxazines (KH, THF/
DMSO, 1:1),[10c] the desired product 8a was only isolated
in an unacceptable 17% yield (Table 1, Entry 1). While an
improvement of the yield was observed using potassium bis-
(trimethylsilyl)amide, competing retro-aldol reaction was
found to significantly limit the outcome of the process
(Table 1, Entry 2). To circumvent this problem, milder bases
such as K2CO3 or Cs2CO3 were examined. In this study we
were able to determine that both the order of base addition,
as well as the counterion, were of utmost importance. Ini-
tial deprotonation of the hydroxy aldehyde 6a, followed by
subsequent reaction with the phosphonium salt 7a resulted
in low yields (Table 1, Entry 3 and 5). However, by direct
base addition to a reagent mixture the yield was increased
to 43% (Table 1, Entry 4 and 6). Comparable results were
1
2
3
4
5
6
7
8
dioxane
dimethoxyethane
THF/DMF
25
traces
traces
48
43
23
19
33
47
24
DMSO
DMSO[b]
DMPU
N-methyl-2-pyrrolidone (NMP)
CH2Cl2
1,2-dichloroethane
CH3CN
1-butyl-3-methylimidazolin tetrafluorobo-
rate
9
10
11
10
[a] All reactions were performed according to method A on sub-
strate 6a with 1.5 equiv. of 7a and 2.5 equiv. of Cs2CO3 at room
temp. with reaction times of 1–4 h. [b] K2CO3 was used as the base.
[c] Yield of isolated product based on β-hydroxy aldehyde 6a.
The influence of additives on the reaction was then inves-
obtained with 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) as tigated. Firstly it was found that addition of phase-transfer
a base (Table 1, Entry 8). Interestingly, with Li2CO3 the catalysts, such as tetrabutylammonium salts, crown ethers
retro-aldol reaction prevailed and no dihydropyran forma- or molecular sieves had no effect on the reaction profile.
tion occurred (Table 1, Entry 7).[12]
Interestingly, the process was completely inhibited when
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3,6-Dihydro- and 4,5-Epoxytetrahydropyrans
conducted in presence of lithium salts, again showing the dition–cyclisation process is sufficiently fast to maintain
significant influence of the counterion. Furthermore, the high enantiomeric excess in the product. Dihydropyran 8a
transformation was shown to be not markedly water-sensi- was isolated with er 96:4 starting from 97:3 enantiomer-
tive, because dihydropyran 8a was isolated in 48% yield by ically enriched β-hydroxy aldehyde 6a which was obtained
using either freshly dried or moist DMSO and Cs2CO3.
according to the previously reported procedure of Bar-
We also observed that the relative proportion of the rea- bas.[13a]
gents was crucial for achieving acceptable yields. When the
Encouraged by these results, we further explored the
reaction was performed in presence of 15 equiv. of 7a in scope of this reaction with a series of aromatic β-hydroxy
DMSO only 19% of the desired product 8a was obtained. aldehydes under the optimised conditions. A solution of the
Pleasingly however we were able to increase the yield to respective substrate 6[13] and vinylphosphonium salt 7a in
56% using stoichiometric amounts of phosphonium salt 7a DMSO was treated with Cs2CO3 at room temperature. The
(Table 3, Entry 1). The amount of Cs2CO3 used in the reac- results of these studies are depicted in Table 3.
tion was also varied although 2.5 equiv. were found to be
All reactions proceeded with moderate to good yields of
optimal with regard to temperature. At 0 °C the conjugate 34–56% with the p-nitro-substituted aldehyde 6a giving the
addition and Wittig reaction were slower and retro-aldol best. The competing retro-aldol reaction could not be fur-
process was found to dominate, whereas at temperatures ther suppressed and formation of 10 and 11 limited the
above room temperature decomposition of the starting ma- overall outcome of the process (Scheme 2).
terial was observed prior to any coupling reaction.
Table 3. Substrate scope for the synthesis of 3,6-dihydropyrans 8.
Scheme 2. Side reactions in the synthesis of 3,6-dihydropyrans.
The initial β-hydroxy aldehyde 6 can either react with
vinylphosphonium salt 7a, followed by an intermolecular
Wittig reaction with the aromatic aldehyde 4 to give 10 as
E/Z mixture, or the retro-aldol products 3 and 4 can be
transformed into aldehyde 11 in a similar manner. Never-
theless the yields of the cyclised product 8 were considered
acceptable given the structural features incorporated into
the product.
We have also shown that the synthesis of 3,6-dihydropy-
rans can be performed as a one-pot process (Scheme 3).
Starting from isobutyraldehyde (3) and p-nitrobenzaldehyde
(4a) the product was obtained in an isolated 33% yield and
excellent er.
Aggarwal and co-workers have recently demonstrated the
use of vinylsulfonium salts in stereocontrolled asymmetric
synthesis of epoxide- and aziridine-fused heterocycles.[14]
Starting from α,β- and γ-amino aldehydes and ketones five-,
six- and seven-membered epoxide-fused rings were obtained
in high yields. In addition, by using alanine-derived amido
[a] Yield of isolated product based on β-hydroxy aldehyde 6. [b]
Determined by HPLC analysis on a chiral phase (Chiralpak AS,
AD-H). [c] Incompletely separated enantiomeric mixture.
ketones a highly syn-diastereoselective epoxy annulation
We also tested the susceptibility of aldehyde 6a towards has been developed.[15]
racemisation in the presence of Cs2CO3. Although the sub-
We envisioned that 4,5-epoxy-tetrahydropyrans could be
strate racemises under these conditions the conjugate ad- prepared by a related process as shown in Scheme 4.
Eur. J. Org. Chem. 2010, 183–190
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185

S. Catalán-Muñoz, C. A. Müller, S. V. Ley
FULL PAPER
0 °C. The reaction was warmed to room temperature and
afforded the desired epoxide 9a in 45% (Table 4, Entry 1).
By contrast, the use of lower temperatures led to poor
yields (Table 4, Entry 2), as in the case of the dihydropyrans
8. The best result was observed at room temperature with
a yield of 56%. Increasing the amount of sulfonium salt
also lowered the yield (Table 4, Entry 4) and the use of sol-
vents other than dichloromethane did not lead to improve-
ment (Table 4, Entry 5 and 6). For comparison, the reaction
with Cs2CO3 as base afforded only 37% yield of the epoxy
product (Table 4, Entry 7).
The product was formed in a diastereomeric ratio (dr) of
10:1 with the anti-epoxide being the major isomer. In ad-
dition, we explored the scope of the reaction with a series
of aromatic β-hydroxy aldehydes under the optimised con-
ditions (Table 4, Entry 3).
Scheme 3. One pot process to synthesis 3,6-dihydropyran 8a.
9b–9f were also formed as a diastereomeric mixture
[10:1]; the major isomer was always the anti-epoxide easily
separable by flash column chromatography. The yields ob-
tained in these studies are slightly lower, but comparable
to those reported for the synthesis of dihydropyrans using
phosphonium salts (Table 3). p-Nitro substitution at the
Table 5. Substrate scope for the synthesis of 4,5-epoxy-tetra-
hydropyrans 9.
Scheme 4. An annulation reaction mediated by a vinylsulfonium
salt for the synthesis of 4,5-epoxy-tetrahydropyrans 9.
We began our studies towards the synthesis of 4,5-epoxy-
tetrahydropyrans 9 by applying conditions, which were de-
emed optimal in Aggarwal’s epoxy-annulation procedure.[14]
Initially, a solution of β-hydroxy aldehyde 6a and 1.2 equiv.
of sulfonium salt 7b were treated with 2.0 equiv. of DBU at
Table 4. Screening for the synthesis of 4,5-epoxy-tetrahydropyrans
9a from β-hydroxy aldehyde 6a.[a]
En- Base
try
Solvent
CH2Cl2
7b
T
Yield
9a
[equiv.] [°C]
[%]
1
DBU
1.2
0 Ǟ room
45
temp.
–10
room temp. 58
room temp. 47
room temp. 35
2
3
4
5
DBU
DBU
DBU
DBU
CH2Cl2
CH2Cl2
CH2Cl2
1,2-dichloroe-
thane
1.2
1.2
1.8
1.2
14
6
7
DBU
Cs2CO3 CH2Cl2
DMSO
1.2
1.2
room temp. 29
room temp. 37
[b]
[a] 2.0 equiv. of base was added to a stirred solution (0.1 ) of
hydroxy aldehyde 6a and vinylsulfonium salt 7b and the reaction
stirred for 1–3 h. [b] Reaction was carried out with 2.5 equiv. of
Cs2CO3.
[a] Yield of isolated anti-epoxide (major). [b] Determined by HPLC
analysis on a chiral phase (Chiralpak AS and Chiralcel OD, OD-
H).
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3,6-Dihydro- and 4,5-Epoxytetrahydropyrans
Advance DPX- 400 spectrometer. The resonance of CDCl3 (δC
=
aromatic ring of β-hydroxy aldehyde was found optimal and
the desired product 9a was isolated in 58% yield (Table 5,
Entry 1). Although this tandem transformation also suffers
from the reto-aldol reaction we did not notice any other
side products that could be readily characterised.
The structure and relative configuration of the major
product isomer 9a was also confirmed by single-crystal X-
ray diffraction analysis.
77.0 ppm, t) was used as an internal reference. 13C DEPT-135 and
two-dimensional (COSY and HMQC) NMR experiments were
used where appropriate, to support the assignment of signals in the
1H and 13C spectra. Mass spectra and accurate mass data were
obtained on an LCT Premier spectrometer by Waters using a
Micromass MS software at the Department of Chemistry, Univer-
sity of Cambridge. The enantiomeric ratios (er) were determined
by high-performance liquid chromatography (HPLC), performed
with Hewlett–Packard Agilent 1100 chromatographs, or by super-
critical fluid chromatography (SFC) with a Berger Minigram using
a Chiralpak AS (0.46ϫ25 cm), Chiralpak ADH (0.46ϫ25 cm),
Chiralcel OD (0.46ϫ25 cm) or Chiralcel OD-H (0.46ϫ25 cm) col-
umn as noted. The diastereomeric ratios (dr) were determined by
1H NMR spectroscopy of crude products. The racemic materials
were prepared using pyrrolidine as catalyst in the presence of acetic
acid according to literature.[16]
Conclusions
In this work, a new method for the preparation of pyran
derivatives 8 and 9 starting from aldol adducts 6 and onium
salts was developed, which consists of a tandem conjugate
addition–cyclisation process. Reaction of aromatic β-hy-
droxy aldehydes 6 and vinylphosphonium salts in presence
of Cs2CO3 affords 3,6-dihydropyrans in moderate to good
yields. Using optically pure aldol adducts 6 as starting ma-
terial a high enantiomeric excess in the product can be con-
served. This reaction was performed as one-pot process to
generate the β-hydroxy aldehyde in situ. However, reto-al-
dol reaction was found to be a significant side process lead-
ing to the formation of unwanted products. The method
was extended to the diastereoselective formation of 4,5-ep-
oxy-tetrahydropyrans. Conjugate addition of aldol adduct
6 to a vinylsulfonium salt, followed by a subsequent cycli-
sation process gave the epoxides in good yields and high
diastereoselectivity in presence of DBU as a base.
General Procedure for the Synthesis of 3,6-Dihydropyrans 8: Caes-
ium carbonate (179 mg, 0.55 mmol) was added to a stirred solution
of the appropriate aldol adduct 6a–f (0.22 mmol) and triphenylvi-
nylphosphonium bromide (81.2 mg, 0.22 mmol) in anhydrous
DMSO (2.2 mL). The resulting suspension was stirred vigorously
at room temperature under argon until TLC analysis indicated
complete conversion of the starting material 6a–f. The reaction
mixture was quenched with water (10 mL) and extracted with Et2O
(3ϫ10 mL). The combined organic layers were washed with brine
and dried with Mg2SO4. The solvent was evaporated to dryness
and the resultant residue was purified by column chromatography
on silica gel with PE/EtOAc (50:1) mixture to provide the dihy-
dropyrans 8.
(R)-3,6-Dihydro-3,3-dimethyl-2-(4-nitrophenyl)-2H-pyran
White solid; yield 56% (28.6 mg); m.p. 70–72 °C. Rf = 0.56 (PE 40–
60/EtOAc, 4:1). [α]2D5 = +143.1 (c = 1.0, CHCl ). IR (neat): ν
(8a):
=
max
˜
3
2843, 1605, 1512, 1465, 1344, 1150, 1092, 1030, 997, 861, 851, 796
Experimental Section
1
cm–1. H NMR (400 MHz, CDCl3, 25 °C): δ = 0.78 (s, 3 H, CH3),
General Information: All reactions were performed under argon un-
less otherwise stated. Solvents: tetrahydrofuran (THF) was distilled
from lithium aluminium hydride using triphenylmethane as indi-
cator; 1,2-dimethoxyethane (DME), acetonitrile and dichlorometh-
ane (CH2Cl2) from calcium hydride prior to use. Anhydrous di-
methyl sulfoxide (DMSO), dimethylformamide (DMF), dioxane,
N-methyl-2-pyrrolidone (NMP) and 1,2-dichloroethane were used
as supplied. “PE” refers to petroleum ether with a boiling range of
40–60 °C. Reagents: were used as supplied or purified using stan-
dard procedures as necessary. Chromatography: flash column
chromatography was carried out using silica gel 60 (0.040–
0.063 mm) 230–400 mesh under pressure unless otherwise indi-
cated. Analytical thin layer chromatography was performed using
pre-coated glass-backed plates (Merck Kieselgel 60 F254) and visu-
alised by ultraviolet radiation (254 nm), acidic ceric ammonium
molybdate, or basic potassium permanganate solutions as appro-
priate. Data collection: melting points were performed with a Re-
ichert hot-stage apparatus, and are uncorrected. Optical rotations
were measured with a Perkin–Elmer 343 digital polarimeter using
a sodium lamp (589 nm) as the light source, [α]D values are re-
ported in 10–1 degcm2 g–1. Infrared spectra were recorded as thin
films with a Perkin–Elmer Spectrum One FT-IR 1600 spectrometer
0.96 (s, 3 H, CH3), 4.30 (d, JH,H = 16.5 Hz, 1 H, CH2), 4.37 (d,
JH,H = 16.5 Hz, 1 H, CH2), 4.39 (s, 1 H, OCH), 5.65–5.72 (m, 2 H,
CH=CH), 7.50 (d, JH,H = 8.7 Hz, 2 H, Ar-CH), 8.19 (d, JH,H
=
8.7 Hz, 2 H, Ar-CH) ppm. 13C NMR (100 MHz, CDCl3, 25 °C):
δ = 22.0, 25.8, 35.8, 66.6, 83.7, 122.7, 123.4, 128.4, 136.2, 146.7,
147.3 ppm. HRMS (ESI): calcd. for C13H16NO3 [M + H]+
234.1124; found 234.1130. SFC (Chiralpak AS, 10% iPrOH in
CO2, 2 mLmin–1, 100 bar, 254 nm) tR(major) = 38.0 min, tR(minor)
= 48.0 min.
4-[(R)-3,6-Dihydro-3,3-dimethyl-2H-pyran-2-yl]benzonitrile
White solid; yield 48% (22.6 mg); m.p. 114–116 °C. Rf = 0.57 (PE
40–60/EtOAc, 3:1). [α]2D5 = +143.8 (c = 1.0, CHCl ). IR (neat): ν
(8b):
˜
3
max
= 2963 (m), 2818 (m), 1725 (w), 1361 (w), 1148 (m), 1086 (s), 1032
1
(m), 903 (m), 859 (s), 796 (m), 710 (s) cm–1. H NMR (400 MHz,
CDCl3, 25 °C): δ = 0.77 (s, 3 H, CH3), 0.93 (s, 3 H, CH3), 4.28 (d,
JH,H = 16.5 Hz, 1 H, CH2), 4.33 (s, 1 H, OCH), 4.36 (d, JH,H
16.5 Hz, 1 H, CH2), 5.64–5.70 (m, 2 H, CH=CH), 7.44 (d, JH,H
=
=
8.2 Hz, 2 H, Ar-CH), 7.62 (d, JH,H = 8.2 Hz, 2 H, Ar-CH) ppm.
13C NMR (100 MHz, CDCl3, 25 °C): δ = 22.0, 25.8, 35.8, 66.6,
83.9, 111.1, 118.9, 123.4, 128.3, 131.4, 136.2, 144.7 ppm. HRMS
(ESI): calcd. for C14H15NONa [M + Na]+ 236.1053; found
236.1046. HPLC (Chiralpak AS, 99:1 hexane/iPrOH, 1 mLmin–1,
230 nm) tR(major) = 8.6 min, tR(minor) = 14.2 min.
1
fitted with an ATR sampling accessory. H NMR spectra were re-
corded at 400 MHz with Bruker Advance DPX-400 spectrometer
with residual protic solvent CDCl3 as the internal reference (δH
=
(R)-3,6-Dihydro-2-(4-methoxyphenyl)-3,3-dimethyl-2H-pyran (8c):
White solid; yield 43% (20.7 mg); m.p. 54–56 °C. Rf = 0.63 (PE 40–
7.26 ppm) and are reported as follows: chemical shift δ/ppm
(number of protons, multiplicity, coupling constant J/Hz, assign-
ment). 13C NMR spectra were recorded at 100 MHz with Bruker
60/EtOAc, 3:1). [α]2D5 = +89.1 (c = 1.0, CHCl ). IR (neat): ν
=
˜
3
max
2954, 2928, 1725, 1610, 1513, 1467, 1439, 1300, 1247, 1175, 1117,
Eur. J. Org. Chem. 2010, 183–190
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S. Catalán-Muñoz, C. A. Müller, S. V. Ley
FULL PAPER
1085, 1037, 994, 899, 803, 694 cm–1. H NMR (400 MHz, CDCl3,
1
column chromatography on silica gel with PE/EtOAc (10:1) mix-
25 °C): δ = 0.83 (s, 3 H, CH3), 0.90 (s, 3 H, CH3), 3.81 (s, 3 H, ture to provide the epoxides 9.
OCH3), 4.25 (s, 1 H, OCH), 4.28 (d, JH,H = 16.6 Hz, 1 H, CH2),
(1S,3S,6R)-2,2-Dimethyl-3-(4-nitrophenyl)-4,7-dioxabicyclo[4.1.0]-
4.34 (d, JH,H = 16.6 Hz, 1 H, CH2), 5.66 (s, 2 H, CH=CH), 6.86
(d, JH,H = 8.6 Hz, 2 H, Ar-CH), 7.24 (d, JH,H = 8.7 Hz, 2 H, Ar-
CH) ppm. 13C NMR (100 MHz, CDCl3, 25 °C): δ = 22.2, 25.9,
35.8, 55.3, 66.8, 84.3, 113.0, 123.3, 128.7, 131.5, 136.8, 158.8 ppm.
HRMS (ESI): calcd. for C14H18O2Na [M + Na]+ 241.1208; found
241.1199. HPLC (Chiralcel OD-H, 99:1 hexane/iPrOH,
1 mLmin–1, 215 nm) tR(major) = 5.4 min, tR(minor) = 7.8 min.
heptane (9a): White solid; yield 58% (31.8 mg); m.p. 59–61 °C. Rf
= 0.65 (PE 40–60/EtOAc, 3:1). [α]2D5 = +33.1 (c = 1.0, CHCl3). IR
(neat): ν
= 2967, 2985, 16004, 1513, 1470, 1343, 1144, 1102,
˜
max
1000, 864, 849, 744, 674 cm–1. 1H NMR (400 MHz, CDCl3, 25 °C):
δ = 0.86 (s, 3 H, CH3), 1.03 (s, 3 H, CH3), 3.08 (d, JH,H = 4.2 Hz,
1 H, CHOCHCH2), 3.39 (d, JH,H = 4.1 Hz, 1 H, CHOCHCH2),
4.07 (d, JH,H = 13.5 Hz, 1 H, CH2), 4.31 (d, JH,H = 13.5 Hz, 1 H,
CH2), 4.37 (s, 1 H, CHOCH2), 7.39 (d, JH,H = 8.8 Hz, 2 H, Ar-
CH), 8.15 (d, JH,H = 8.8 Hz, 2 H, Ar-CH) ppm. 13C NMR
(100 MHz, CDCl3, 25 °C): δ = 17.9, 22.9, 35.3, 52.7, 60.9, 65.4,
78.4, 122.7, 128.4, 145.9, 147.3 ppm. HRMS (ESI): calcd. for
C13H16NO4 [M + H]+ 250.1085; found 250.1074. HPLC (Chiralpak
AS, 99:1 hexane/iPrOH, 1 mL min–1, 230 nm) tR(major) =
16.9 min, tR(minor) = 21.3 min.
(R)-3,6-Dihydro-3,3-dimethyl-2-[4-(trifluoromethyl)phenyl]-2H-pyr-
an (8d): Colourless oil; yield 34% (19.2 mg). Rf = 0.56 (PE 40–60/
EtOAc, 4:1). [α]2D5 = +43.0 (c = 0.7, CHCl ). IR (neat): νmax = 2966,
˜
3
1621, 1323, 1163, 1119, 1067, 1018, 849, 796, 707, 661 cm–1. 1H
NMR (400 MHz, CDCl3, 25 °C): δ = 0.80 (s, 3 H, CH3), 0.94 (s,
3 H, CH3), 4.29 (d, JH,H = 16.4 Hz, 1 H, CH2), 4.35 (s, 1 H, OCH),
4.35–4.39 (m, 1 H, CH2), 5.67 (d, JH,H = 11.2 Hz, 1 H, CH), 5.70
(d, JH,H = 11.2 Hz, 1 H, CH), 7.44 (d, JH,H = 8.1 Hz, 2 H, Ar-CH),
7.58 (d, JH,H = 8.2 Hz, 2 H, Ar-CH) ppm. 13C NMR (100 MHz,
CDCl3, 25 °C): δ = 22.0, 25.8, 35.7, 66.7, 84.1, 123.4, 124.3 (1JC,F
4-[(1S,3S,6R)-2,2-Dimethyl-4,7-dioxabicyclo[4.1.0]heptan-3-yl]ben-
zonitrile (9b): White solid; yield 46% (23.1 mg); m.p. 99–101 °C. Rf
= 0.53 (PE 40–60/EtOAc, 3:1). [α]2D5 = +61.0 (c = 1.0, CHCl3). IR
= 276.4 Hz), 124.5 (3JC,F = 3.8 Hz), 127.9, 136.5, 143.3 (5JC,F
=
(neat): νmax = 2971, 2874, 2229, 1708, 1610, 1470, 1365, 1148, 1018,
˜
1
849, 830, 772, 700 cm–1. H NMR (400 MHz, CDCl3, 25 °C): δ =
1.3 Hz) ppm. HRMS (ESI): calcd. for C14H15F3ONa [M +
Na]+ 279.0973; found 279.0981. Incompletely separated enantio-
meric mixture.
0.85 (s, 3 H, CH3), 1.01 (s, 3 H, CH3), 3.07 (d, JH,H = 4.3 Hz, 1 H,
CHOCHCH2), 3.38 (d, JH,H = 4.2 Hz, 1 H, CHOCHCH2), 4.06 (d,
JH,H = 13.6 Hz, 1 H, CH2), 4.30 (dd, JH,H = 13.9, 4.0 Hz, 1 H,
CH2), 4.31 (s, 1 H, CHOCH2), 7.34 (d, JH,H = 8.6 Hz, 2 H, Ar-
CH), 7.59 (d, JH,H = 8.6 Hz, 2 H, Ar-CH) ppm. 13C NMR
(100 MHz, CDCl3, 25 °C): δ = 18.0, 22.9, 35.3, 52.7, 61.0, 65.4,
78.6, 111.3, 118.8, 128.3, 131.3, 143.9 ppm. HRMS (ESI): calcd.
for C14H15NO2Na [M + Na]+ 252.0997; found 252.0995. HPLC
(Chiralcel OD-H, 99:1 hexane/iPrOH, 1 mL min–1, 215 nm)
tR(major) = 18.8 min, tR(minor) = 15.9 min.
(R)-2-(4-Bromophenyl)-3,6-dihydro-3,3-dimethyl-2H-pyran (8e):
White solid; yield 48% (28.2 mg); m.p. 58–60 °C. Rf = 0.63 (PE 40–
60/EtOAc, 3:1). [α]2D5 = +72.5 (c = 0.9, CHCl ). IR (neat): ν
=
˜
3
max
2957, 1725, 1487, 1467, 1402, 1360, 1238, 1165, 1088, 1009, 896,
837, 720 cm–1. 1H NMR (400 MHz, CDCl3, 25 °C): δ = 0.79 (s,
3 H, CH3), 0.91 (s, 3 H, CH3), 4.25 (s, 1 H, OCH), 4.28 (d, JH,H
=
16.8 Hz, 1 H, CH2), 4.35 (dd, JH,H = 16.7, 1.9 Hz, 1 H, CH2), 5.63–
5.69 (m, 2 H, CH=CH), 7.19 (d, JH,H = 8.6 Hz, 2 H, Ar-CH), 7.45
(d, JH,H = 8.6 Hz, 2 H, Ar-CH) ppm. 13C NMR (100 MHz, CDCl3,
25 °C): δ = 22.0, 25.8, 35.6, 66.7, 84.0, 121.2, 123.3, 129.3, 130.6,
136.5, 138.3 ppm. HRMS (ESI): calcd. for C13H15BrONa [M +
Na]+ 289.0196; found 289.0203. HPLC (Chiralpak AD-H, 0.2%
iPrOH in hexane, 0.2 mL min–1, 230 nm) tR(major) = 21.8 min,
tR(minor) = 23.2 min.
(1S,3S,6R)-3-(4-Methoxyphenyl)-2,2-dimethyl-4,7-dioxabicyclo-
[4.1.0]heptane (9c): White solid; yield 25% (12.9 mg); m.p. 70–
72 °C. Rf = 0.47 (PE 40–60/EtOAc, 3:1). [α]2D5 = +47.6 (c = 0.87,
CHCl ). IR (neat): νmax = 2971, 2859, 1684, 1609, 1513, 1442, 1300,
˜
3
1246, 1177, 1147, 1036, 1021, 996, 911, 845, 831, 774 cm–1. 1H
NMR (400 MHz, CDCl3, 25 °C): δ = 0.91 (s, 3 H, CH3), 0.97 (s,
3 H, CH3), 3.06 (d, JH,H = 4.3 Hz, 1 H, CHOCHCH2), 3.36 (d,
JH,H = 4.2 Hz, 1 H, CHOCHCH2), 3.79 (s, 3 H, OCH3), 4.07 (d,
JH,H = 13.7 Hz, 1 H, CH2), 4.22 (s, 1 H, CHOCH2), 4.28 (dd, JH,H
= 13.7, 4.1 Hz, 1 H, CH2), 6.83 (d, JH,H = 8.8 Hz, 2 H, Ar-CH),
7.14 (d, JH,H = 8.7 Hz, 2 H, Ar-CH) ppm. 13C NMR (100 MHz,
CDCl3, 25 °C): δ = 18.2, 23.0, 35.2, 52.9, 55.3, 61.3, 65.5, 78.8,
112.9, 128.7, 132.0, 158.9 ppm. HRMS (ESI): calcd. for
C14H18O3Na [M + Na]+ 257.1157; found 257.1148. HPLC (Chi-
ralcel OD-H, 99:1 hexane/iPrOH, 1 mLmin–1, 230 nm) tR(major)
= 8.7 min, tR(minor) = 11.9 min.
(R)-2-(4-Chlorophenyl)-3,6-dihydro-3,3-dimethyl-2H-pyran (8f):
White solid; yield 40% (19.5 mg); m.p. 85–87 °C. Rf = 0.63 (PE 40–
60/EtOAc, 3:1). [α]2D5 = +128.7 (c = 0.7, CHCl ). IR (neat): ν
=
˜
3
max
2957, 2839, 1727, 1490, 146 (m), 1407, 1360, 1239, 1166, 1090,
1
1026, 1011, 896, 839, 788, 720 cm–1. H NMR (400 MHz, CDCl3,
25 °C): δ = 0.80 (s, 3 H, CH3), 0.91 (s, 3 H, CH3), 4.27–4.37 (m, 3
H, OCH and CH2), 5.66 (s, 2 H, CH), 7.25 (d, JH,H = 8.6 Hz, 2 H,
Ar-CH), 7.31 (d, JH,H = 8.6 Hz, 2 H, Ar-CH) ppm. 13C NMR
(100 MHz, CDCl3, 25 °C): δ = 22.1, 25.9, 35.7, 66.7, 84.0, 123.3,
127.7, 129.0, 133.0, 136.6, 137.8 ppm. HRMS (ESI): calcd. for
C13H16ClO [M + H]+ 223.0882; found 223.0890. HPLC (Chiralpak
AD-H, 0.2% iPrOH in hexane, 0.2 mLmin–1, 230 nm) tR(major) =
21.5 min, tR(minor) = 20.6 min.
(1S,3S,6R)-2,2-Dimethyl-3-[4-(trifluoromethyl)phenyl]-4,7-dioxabi-
cyclo[4.1.0]heptane (9d): Colourless oil; yield 35% (20.9 mg). Rf =
0.55 (PE 40–60/EtOAc, 3:1). [α]2D5 = +19.8 (c = 0.8, CHCl3). IR
(neat): νmax = 2973, 1622, 1513, 1472, 1350, 1163, 1107, 1067, 999,
˜
1
General Procedure for the Synthesis of 4,5-Epoxytetrahydropyrans
9: DBU (67 µL, 0.44 mmol) was added to a stirred solution of the
appropriate aldol adduct 6a–f (0.22 mmol) and diphenylvinylsulfo-
nium trifluoromethanesulfonate (95.6 mg, 0.26 mmol) in anhydrous
CH2Cl2 (2.2 mL). The resulting solution was stirred at room tem-
perature under argon until the reaction was determined to be com-
plete by TLC. The reaction mixture was quenched with water
(10 mL) and extracted with CH2Cl2 (3ϫ10 mL). The combined or-
ganic phase was washed with brine, dried with Mg2SO4, filtered,
and concentrated in vacuo. The resulting residue was purified by
850, 830, 661 cm–1. H NMR (400 MHz, CDCl3, 25 °C): δ = 0.88
(s, 3 H, CH3), 1.02 (s, 3 H, CH3), 3.08 (d, JH,H = 4.1 Hz, 1 H,
CHOCHCH2), 3.39 (d, JH,H = 4.1 Hz, 1 H, CHOCHCH2), 4.08 (d,
JH,H = 13.6 Hz, 1 H, CH2), 4.30 (dd, JH,H = 13.6, 3.3 Hz, 1 H,
CH2), 4.33 (s, 1 H, CHOCH2), 7.35 (d, JH,H = 8.1 Hz, 2 H, Ar-
CH), 7.56 (d, JH,H = 8.1 Hz, 2 H, Ar-CH) ppm. 13C NMR
(100 MHz, CDCl3, 25 °C): δ = 18.0, 22.9, 35.1, 52.8, 61.0, 65.5,
78.7, 124.2 (1JC,F = 272 Hz), 124.4 (3JC,F = 4 Hz), 127.9, 129.6
(2JC,F = 32 Hz), 142.5 (5JC,F = 2 Hz) ppm. HRMS (ESI): calcd.
for C14H15F3O2Na [M + Na]+ 295.0913; found 295.0916. HPLC
188
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Eur. J. Org. Chem. 2010, 183–190

3,6-Dihydro- and 4,5-Epoxytetrahydropyrans
(Chiralcel OD-H, 0.1 % iPrOH in hexane, 1 mL min–1, 215 nm)
tR(major) = 12.2 min, tR(minor) = 10.3 min.
2005, 7, 4491–4494; e) Y. Lian, R. J. Hinkle, J. Org. Chem.
2006, 71, 7071–7074.
[3]
[4]
a) E. Wada, W. Pei, H. Yasuoka, U. Chin, S. Kanemasa, Tetra-
hedron 1996, 52, 1205–1220; b) J. Thorhauge, M. Johannsen,
K. A. Jørgensen, Angew. Chem. Int. Ed. 1998, 37, 2404–2406;
c) D. A. Evans, J. S. Johnson, E. J. Olhava, J. Am. Chem. Soc.
2000, 122, 1635–1649; d) V. Ya. Sosnovskikh, I. A. Khalym-
badzha, R. A. Irgashev, P. A. Slepukhin, Tetrahedron 2008, 64,
10172–10180.
a) F. P. J. T. Rutjes, T. M. Kooistra, H. Hiemstra, H. E. Schoe-
maker, Synlett 1998, 192–194; b) H. W. Lee, Ch.-S. Jeong, S. H.
Yoon, I.-Y. Ch. Lee, Bull. Korean Chem. Soc. 2001, 22, 791–
792; c) A. E. Sutton, B. A. Seigal, D. F. Finnegan, M. L. Snap-
per, J. Am. Chem. Soc. 2002, 124, 13390–13391; d) H.
Wildemann, P. Dünkelmann, M. Müller, B. Schmidt, J. Org.
Chem. 2003, 68, 799–804; e) S. H. Park, H. W. Lee, Bull. Korean
Chem. Soc. 2008, 29, 1661–1662.
a) I. Hanna, P. Wlodyka, J. Org. Chem. 1997, 62, 6985–6990;
b) A. K. Ghosh, P. Mathivanan, J. Cappiello, Tetrahedron Lett.
1997, 38, 2427–2430; c) T. Momose, M. Setoguchi, T. Fujita,
H. Tamura, N. Chida, Chem. Commun. 2000, 2237–2238; d)
J. S. Yadav, B. V. Subba Reddy, K. Premalatha, T. Swamy, Tet-
rahedron Lett. 2005, 46, 2687–2690; e) R. Kartika, J. D. Frein,
R. E. Taylor, J. Org. Chem. 2008, 73, 5592–5594.
For some examples in total syntheses, see: a) M. Christmann,
U. Bhatt, M. Quitschalle, E. Claus, M. Kalesse, Angew. Chem.
Int. Ed. 2000, 39, 4364–4366; b) D. R. Williams, D. C. Ihle,
S. V. Plummer, Org. Lett. 2001, 3, 1383–1386; c) S. Takahashi,
A. Kubota, T. Nakata, Tetrahedron 2003, 59, 1627–1638; d) F.
Hilli, J. M. White, M. A. Rizzacasa, Org. Lett. 2004, 6, 1289–
1292.
(1S,3S,6R)-3-(4-Bromophenyl)-2,2-dimethyl-4,7-dioxabicyclo[4.1.0]-
heptane (9e): White solid; yield 30% (18.6 mg); m.p. 81–84 °C. Rf
= 0.73 (PE 40–60/EtOAc, 5:1). [α]2D5 = +68.7 (c = 0.6, CHCl3). IR
(neat): ν
= 2970, 2869, 1490, 1470, 1147, 1109, 998, 837, 827,
˜
max
771, 668 cm–1. 1H NMR (400 MHz, CDCl3, 25 °C): δ = 0.87 (s,
3 H, CH3), 0.98 (s, 3 H, CH3), 3.06 (d, JH,H = 4.2 Hz, 1 H,
CHOCHCH2), 3.37 (d, JH,H = 4.2 Hz, 1 H, CHOCHCH2), 4.06 (d,
JH,H = 13.7 Hz, 1 H, CH2), 4.23 (s, 1 H, CHOCH2), 4.28 (dd, JH,H
= 13.7, 4.2 Hz, 1 H, CH2), 7.09 (d, JH,H = 8.4 Hz, 2 H, Ar-CH),
7.42 (d, JH,H = 8.4 Hz, 2 H, Ar-CH) ppm. 13C NMR (100 MHz,
CDCl3, 25 °C): δ = 18.0, 22.9, 35.1, 52.8, 61.1, 65.5, 78.6, 121.3,
129.3, 130.6, 137.4 ppm. HRMS (ESI): calcd. for C13H16BrO2 [M
+ H]+ 283.0326; found 283.0328. HPLC (Chiralcel OD-H, 0.1%
iPrOH in hexane, 1 mL min–1, 230 nm) tR(major) = 22.4 min,
tR(minor) = 19.9 min.
[5]
[6]
(1S,3S,6R)-3-(4-Chlorophenyl)-2,2-dimethyl-4,7-dioxabicyclo[4.1.0]-
heptane (9f): White solid; yield 24% (12.6 mg); m.p. 104–106 °C. Rf
= 0.49 (PE 40–60/EtOAc, 3:1). [α]2D5 = +61.4 (c = 1.0, CHCl3). IR
(neat): ν
= 2971, 2969 (w), 1594, 1489, 1469, 1365, 1146, 1113,
˜
max
1010, 997, 893, 830, 767 cm–1. 1H NMR (400 MHz, CDCl3, 25 °C):
δ = 0.88 (s, 3 H, CH3), 0.99 (s, 3 H, CH3), 3.06 (d, JH,H = 4.2 Hz,
1 H, CHOCHCH2), 3.37 (d, JH,H = 4.2 Hz, 1 H, CHOCHCH2),
4.07 (d, JH,H = 13.6 Hz, 1 H, CH2), 4.25 (s, 1 H, CHOCH2), 4.28
(dd, JH,H = 13.6, 4.0 Hz, 1 H, CH2), 7.16 (d, JH,H = 8.4 Hz, 2 H,
Ar-CH), 7.27 (d, JH,H = 8.4 Hz, 2 H, Ar-CH) ppm. 13C NMR
(100 MHz, CDCl3, 25 °C): δ = 18.0, 22.9, 35.1, 52.8, 61.1, 65.5,
78.6, 127.7, 128.9, 133.1, 136.9 ppm. HRMS (ESI): calcd. for
C13H16ClO2 [M + H]+ 239.0836; found 239.0833. HPLC (Chiralcel
OD, 0.1% iPrOH in hexane, 0.5 mLmin–1, 230 nm) tR(major) =
36.4 min, tR(minor) = 33.3 min.
[7]
[8]
a) T. Mukaiyama, T. Tozawa, H. Nagao, Y. Yamane, Chem.
Asian J. 2007, 2, 123–134; b) K. A. Jørgensen, P. T. Franke, B.
Richter, Chem. Eur. J. 2008, 14, 6317–6321; c) J.-T. Liu, Y.
Zhao, X.-J. Wang, Synlett 2008, 1017–1020.
For selected examples see: a) A. Berkessel, H. Gröger, Asym-
metric Organocatalysis, Wiley-VCH, Weinheim, Germany,
2005; b) G. Lelais, D. W. C. MacMillan, Aldrichimica Acta
2006, 39, 79–87; c) M. J. Gaunt, C. C. C. Johansson, A.
McNally, N. T. Vo, Drug Discovery Today 2007, 12, 8–27; d) G.
Gillena, D. J. Ramón, M. Yus, Tetrahedron: Asymmetry 2007,
18, 693–700; e) R. Marcia de Figueiredo, M. Christmann, Eur.
J. Org. Chem. 2007, 2575–2600; f) P. I. Dalko, Enantioselective
Organocatalysis, Wiley-VCH, Weinheim, Germany, 2007.
For recent reviews see: a) S. J. Miller, E. R. Jarvo, Tetrahedron
2002, 58, 2481–2495; b) B. List, S. Mukherjee, J. W. Yang, S.
Hoffmann, Chem. Rev. 2007, 107, 5471–5569; c) G. Guillena,
C. Nájera, D. J. Ramón, Tetrahedron: Asymmetry 2007, 18,
2249–2293; d) H. Pellisier, Tetrahedron Lett. 2007, 63, 9267–
9331; e) Y. Lu, L.-W. Xu, Org. Biomol. Chem. 2008, 6, 2047–
2053; f) H. Kotsuki, H. Ikishima, A. Okuyama, Heterocycles
2008, 75, 493–529, and references cited therein.
a) S. Kumarn, A. J. Oelke, D. M. Shaw, D. A. Longbottom,
S. V. Ley, Org. Biomol. Chem. 2007, 5, 2678–2689; b) A. J.
Oelke, S. Kumarn, D. A. Longbottom, S. V. Ley, Synlett 2006,
16, 2548–2552; c) S. Kumarn, D. M. Shaw, S. V. Ley, Chem.
Commun. 2006, 3211–3213; d) S. Kumarn, D. M. Shaw, D. A.
Longbottom, S. V. Ley, Org. Lett. 2005, 7, 4189–4191.
a) E. Schweizer, J. Am. Chem. Soc. 1964, 86, 2744–2744; b) E.
Schweizer, G. J. O’Neill, J. Org. Chem. 1965, 30, 2082–2083; c)
E. Schweizer, J. G. Liehr, J. Org. Chem. 1968, 33, 583–584; d)
F. R. Kinder Jr., M. A. Jarosinski, W. K. Anderson, J. Org.
Chem. 1991, 56, 6475–6477; e) P. Kumar, K. Saravanan, Tetra-
hedron 1998, 54, 2161–2168; f) A. Ramazani, A. R. Kazemiza-
deh, E. Ahmadi, N. Noshiranzadeh, A. Souldozi, Curr. Org.
Chem. 2008, 12, 59–82; g) H. Ishikawa, T. Suzuki, Y. Hayashi,
Angew. Chem. Int. Ed. 2009, 48, 1304–1307.
Supporting Information (see also the footnote on the first page of
1
this article): Copies of the H and 13C NMR spectra for 8a–f and
9a–f.
Acknowledgments
[9]
The authors thank Merck Research Laboratories for support
through the Academic Development Program (S. V. L.), the Span-
ish Ministerio de Educación y Ciencia (MEC) and Fundación Es-
pañola para la Ciencia y la Tecnológía (FECYT) for a postdoctoral
fellowship (to S. C. M.), the Swiss National Science Foundation for
a postdoctoral fellowship (to C. A. M.) and Alexander J. Oelke for
preliminary results in the area. We also thank Dr. John Davies at
the Cambridge University Chemistry Laboratory for X-ray crystal-
lography.
[10]
[11]
[1] a) A. Gollner, K.-H. Altmann, J. Gertsch, J. Mulzer, Chem.
Eur. J. 2009, 15, 5979–5997; b) E. Quinoa, Y. Kakou, P. Crews,
J. Org. Chem. 1988, 53, 3642–3644; c) D. G. Corley, R. Herb,
R. E. Moore, P. J. Scheuer, V. J. Paul, J. Org. Chem. 1988, 53,
3644–3646; d) T. Higa, J.-i. Tanaka, G. Bernardinelli, C. W.
Jefford, Chem. Lett. 1996, 255–256; e) T. Higa, J.-i. Tanaka, D.
Garcia Gravalos, WO 9710242, 1997; f) T. A. Johnson, K. Ten-
ney, R. H. Cichewicz, B. I. Morinaka, K. N. White, T. Ama-
gata, B. Subramanian, J. Media, S. L. Mooberry, F. A. Valeri-
ote, P. Crews, J. Med. Chem. 2007, 50, 3795–3803.
[2] a) G. S. Viswanathan, J. Yang, C.-J. Li, Org. Lett. 1999, 1, 993–
995; b) A. P. Dobbs, S. Martinovic´, Tetrahedron Lett. 2002, 43,
7055–7057; c) V. K. Yadav, N. V. Kumar, J. Am. Chem. Soc.
2004, 126, 8652–8653; d) K.-P. Chan, T.-P. Loh, Org. Lett.
[12]
a) L. D. Bergelson, M. M. Shemyakin, Angew. Chem. Int. Ed.
Engl. 1964, 3, 250–260; b) L. D. Bergelson, V. A. Vauer, L. I.
Varsukov, M. M. Shemyakin, Tetrahedron Lett. 1964, 5, 2669–
Eur. J. Org. Chem. 2010, 183–190
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
189

S. Catalán-Muñoz, C. A. Müller, S. V. Ley
FULL PAPER
2674; c) L. D. Bergelson, L. I. Barsukov, M. M. Shemyakin,
Tetrahedron 1967, 23, 2709; d) M. Schlosser, D. F. Christmann,
Justus Liebigs Ann. Chem. 1967, 708, 1–35; e) C. Sreekumar,
K. P. Darst, W. C. Still, J. Org. Chem. 1980, 45, 4260; f) E.
Vedejs, G. P. Meier, K. A. J. Snoble, J. Am. Chem. Soc. 1981,
103, 2823–2831; g) A. B. Reitz, S. O. Nortey, A. D. Jordan Jr.,
M. S. Mutter, B. E. Maryanof, J. Org. Chem. 1986, 51, 3302–
3308; h) V. K. Aggarwal, Chem. Commun. 2003, 2644–2651.
[13] a) N. Mase, F. Tanaka, C. F. Barbas III, Angew. Chem. Int. Ed.
2004, 43, 2420–2423; b) W. Wang, H. Li, J. Wang, Tetrahedron
Lett. 2005, 46, 5077–5079.
[14]
[15]
a) M. G. Unthank, N. Hussain, V. K. Aggarwal, Angew. Chem.
Int. Ed. 2006, 45, 7066–7069; b) V. K. Aggarwal, Chem. Com-
mun. 2003, 2644–2651.
M. G. Unthank, B. Tavassoli, V. K. Aggarwal, Org. Lett. 2008,
10, 1501–1504.
[16] C. F. Barbas III, N. Mase, F. Tanaka, Org. Lett. 2003, 5, 4369–
4372.
Received: October 9, 2009
Published Online: November 28, 2009
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Eur. J. Org. Chem. 2010, 183–190