An asymmetric Maitland-Japp reaction: A highly enantioselective synthesis of tetrahydropyran-4-ones

Article abstract of DOI:10.1016/j.tet.2011.04.043

A highly enantioselective synthesis of functionalized tetrahydropyran-4- ones has been achieved by the development of a catalytic asymmetric Maitland-Japp reaction using Chan's diene as the nucleophile. This reaction has been used to synthesize the tetrah

Full text of DOI:10.1016/j.tet.2011.04.043

Tetrahedron 67 (2011) 4960e4966
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Tetrahedron
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An asymmetric MaitlandeJapp reaction: a highly enantioselective synthesis
of tetrahydropyran-4-ones
*
Mudassar Iqbal, Nimesh Mistry, Paul A. Clarke
Department of Chemistry, University of York, Heslington, York, North Yorkshire YO10 5DD, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
A highly enantioselective synthesis of functionalized tetrahydropyran-4-ones has been achieved by the
development of a catalytic asymmetric MaitlandeJapp reaction using Chan’s diene as the nucleophile.
This reaction has been used to synthesize the tetrahydropyran ring of (ꢀ)-centrolobine and the C9eC19
tetrahydropyran ring of (þ)-phorboxazole B.
Received 24 January 2011
Received in revised form 28 March 2011
Accepted 12 April 2011
Available online 20 April 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Tetrahydropyran-4-ones
Asymmetric
MaitlandeJapp reaction
Chan’s diene
1. Introduction
of methyl acetoacetate (Chan’s diene10 1), as the different reactivity
of the a- and g-positions of the diene would allow us to introduce
Natural products containing highly substituted tetrahydropyr-
ans continue to be targets of interest to synthetic organic chemists.1
This interest can be attributed to two main reasons: (i) the struc-
tures of these natural products present a number of non-trivial
synthetic challenges, which need to be overcome and, (ii) these
natural products have, more often than not, potent bioactivity in
a number of cell assays and may provide new treatments for
a number of different diseases. This interest has led to a number of
reactions being developed for the enantioselective synthesis of
substituted tetrahydropyrans. Such strategies include hetero-Diel-
seAlder cyclizations,2 Prins cyclizations,3 PetasiseFerrier rear-
rangements,4 intramolecular oxy-Michael reactions,5 cyclization
onto epoxides6 and the reduction of cyclic hemi-ketals,7 to name
a few. Our own group has a continuing interest in the synthesis of
tetrahydropyran containing natural products, and in 2005 we
reported an updated variation of the MaitlandeJapp reaction.8 The
original MaitlandeJapp reaction9 was the condensation of pentan-
3-one with benzaldehyde to give a symmetrical tetrahydropyran-4-
one in a low yield (Scheme 1). However, this reaction could never
be made into a general synthesis of tetrahydropyran-4-ones due to
the symmetrical nature of the products produced by the restriction
of using aromatic aldehydes and a symmetrical ketone. In our re-
port in 2005, we replaced pentan-3-one with the bis-silyl enolether
different aldehyde partners and thus expand the range of the
tetrahydropyran-4-ones formed (Scheme 1). The utility of this
procedure was demonstrated at the time by the shortest, highest
yielding synthesis of (ꢁ)-centrolobine.11 However, this synthesis
did highlight the need to develop an asymmetric version of the
reaction.
The Original Maitland-Japp Reaction
O
CHO
KOH, EtOH/H2O
O
O
Revised Chan's Diene Maitland-Japp Reaction
TiCl4, RCHO, CH2Cl2,
O
OH
-78 oC
OTMS
TMSO
MeO2C
R1
MeO2C
R1
MeO
then
1
O
2
R
O
3
R
TFA, R1CHO,
-65 oC to rt
Scheme 1. The original and revised MaitlandeJapp reactions.
In order to achieve this we turned our attention to the use of
diketene instead of Chan’s diene as a nucleophile. This enabled us
to develop an asymmetric MaitlandeJapp reaction12 (Scheme 2),
where enantioselective addition of diketene to the aldehyde gen-
erated enantioenriched
cyclized to the tetrahydropyran-4-one with no loss of enantiomeric
d-hydroxy-b-ketoesters, which could be
* Corresponding author. Tel.: þ44 1904 322614; fax: þ44 1904 322516; e-mail
address: paul.clarke@york.ac.uk (P.A. Clarke).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.04.043

M. Iqbal et al. / Tetrahedron 67 (2011) 4960e4966
4961
integrity. While this did allow us to complete an asymmetric syn-
thesis of the C1eC19 bis-pyran fragment of phorboxazole B,13 it
became clear that the long reaction times (>5 days) and the
moderate enantioselectivities (56e85%) did require further work. It
was for these reasons that we refocused our attentions back to the
use of Chan’s diene as a nucleophile, and in this paper we report the
successful development of a highly enantioselective MaitlandeJapp
synthesis of tetrahydropyran-4-ones.
addition of 2 equiv of LiCl resulted in reproducibly excellent yields
and enantioselectivities. Test reactions we carried out on both an
aromatic and aliphatic aldehyde indicated that this was indeed the
case, with the d-hydroxy-b-ketoesters products being formed in
good yields and excellent enantioselectivities (Table 1).
Table 1
Asymmetric addition of Chan’s diene to aldehydes
Ti(Oi-Pr)4/Binol (2 mol%),
LiCl (4 mol%), RCHO
OMe OTMS
O
O
OH
O
TMSO
MeO
R
MeO2C
R1
t-Bu
THF, rt, 12 h
1
5
Ti(Oi-Pr)4, 4, RCHO,
O
R
O
MeOH, CH2Cl2, -78 o
C
R
Catalyst
Yield (%)
% eea
Ph
2
t-Bu
O
OH
OH
a
b
Ph
Pr
(R)-Binol
(S)-Binol
89
83
97 (R)
i-Pr
N
then
99 (R)b
MeO2C
R1
TiCl4, R1CHO, -20 o
C
4
a
Determined by chiral shift 1H NMR with Eu(hfc)3.
(R)-Binol and (S)-Binol give products in the opposite enantiomeric series,
OH
O
R
b
3
however, the absolute configuration of 5a and 5b are both assigned as (R) due to the
priorities of the CIP rules.
Scheme 2. Asymmetric diketene MaitlandeJapp reaction.
We believe that the discrepancy between Soriente’s report14b,c
and those of later workers trying to repeat it arises from the
manner in which Chan’s diene was prepared. We prepared Chan’s
2. Results and discussion
There are a couple of reports in the literature of the asymmetric
addition of Chan’s diene to aldehydes to generate -hydroxy-
diene from methyl acetoacetate by first forming the
a-mono silyl
d
b-
enolether with Et3N and TMSCl, removing the precipitated am-
ketoesters.14 The most notable is the procedure of Evans, which
uses a Cu(S,S-pybox) complex.14a However, this reaction only gen-
erates high enantioselectivities when benzyloxy acetaldehyde is
the electrophile, thus limiting its usefulness. A procedure, which
offered to obviate this problem was reported by Soriente, who
demonstrated that the Keck reagent (Ti(Binol)2) could be used to
catalyze the asymmetric addition of Chan’s diene to a wider range
of aldehyde electrophiles14b,c (Scheme 3).
monium salts by filtration. The a-mono silyl enolether was then
treated with LDA at ꢀ78 ꢂC followed by TMSCl. After 1 h the sol-
vents were removed in vacuo and the salts removed by trituration
ꢂ
€
with hexane, followed by Kugelrohr distillation (0.1 Torr, <80 C) of
the crude Chan’s diene product to remove any unreacted starting
material. This procedure also effectively removes all of the LiCl
generated in the formation of the second silyl enolether. In their
original report Soriente makes no mention of the procedure used
for the synthesis of Chan’s diene and it is entirely possible that they
used the method in Chan’s original reports,10 which do not advo-
2
O
O
N
€
cate purification by Kugelrohr distillation. We therefore believe
N
N
OMe OTMS
Cu
O
O
OH
that in the work of Soriente, the Chan’s diene used was un-
knowingly contaminated with adventitious LiCl leading to the im-
pressive, yet irreproducible results reported.
With the problem of the asymmetric addition of Chan’s diene to
aldehydes solved, we next turned our attention to the inclusion of
this step in the asymmetric MaitlandeJapp reaction (Table 2). Chan’s
diene was added to a range of aldehydes using the Ti(Oi-Pr)4/Binol/
Ph
Ph
OBn
TMSO
MeO
O
99% e.e.
OBn
H
O
O
Ti
2
LiCl conditions discussed above, and the resulting d-hydroxy-b-
ketoesters were subjected to our established cyclization conditions
to generate tetrahydropyran-4-ones 2 and 3 in moderate to good
yields. As Ti(Oi-Pr)4/Binol complex does not catalyze the Knoeve-
nagel/Michael steps of the MaitlandeJapp reaction, TiCl4 is used
when an equivalent of the second aldehyde is added. The reaction
mixture is then slowly warmed tort, with pyranformation occurring
at temperatures above ꢀ65 ꢂC. Our earlier work had shown that the
OMe OTMS
O
O
OH
TMSO
MeO
R
RCHO
83-98% e.e.
7 examples
Scheme 3. Asymmetric addition of Chan’s diene to aldehydes.
In our hands application of the Soriente conditions led to dis-
appointing results as the -hydroxy- -ketoesters were formed in
d
b
cyclization of d-hydroxy-b-ketoesters to tetrahydropyran-4-ones 2
low yields (<20%) and low enantioselectivities (0e85% ee). Frus-
tratingly, on most occasions the results of repeated reactions were
irreproducible, suggesting that there was some variable we were
unaware of which was crucial to the reaction success, and that we
were failing to control. We noted that the presence or absence of
and 3 proceeded withouterosionof the enantiomeric integrityof the
tetrahydropyran-4-ones.8b,12 We even demonstrated that 2 and 3
could also be separated and re-equilibrated under the cyclization
reaction conditions without erosion in their enantiomeric ex-
cesses.13 As can be seen from Table 2 a range of aromatic, aliphatic
and heteroatom-containing aldehydes can be used either as the al-
dol acceptor or as the second aldehyde in the cyclization reaction.
The enantiomeric excess of the products are uniformly excellent. In
the cases of entries a and e the enantiomeric excess of the THP
product appears to have been enhanced in the cyclization reaction.
In actuality this is due to the fact that these THPs are solids and
preferential crystallization of the major enantiomer may have oc-
curred during purification to give products with an enhanced en-
antiomeric excess. In the case of entry d some erosion of the
ꢀ
4 A molecular sieves did have a dramatic influence on the outcome
of the reaction. In their absence, or if dried by exhaustive heating,
the product
d-hydroxy-b-ketoesters were racemic, however, when
they were dried by heating at 180 ꢂC for 12 h under a stream of
nitrogen, the d-hydroxy-b-ketoester product was formed in a vari-
able, but low, enantiomeric excess.15 We were therefore very in-
terested in a report, which appeared contemporaneously to our
own studies, which examined the effect of achiral additives on the
outcome of the Soriente reaction.16 This report indicated that the

4962
M. Iqbal et al. / Tetrahedron 67 (2011) 4960e4966
enantiomeric excess did occur. para-Anisaldehdye is problematic in
the MaitlandeJapp reaction11 as it tends to undergo Knoevenagel
condensation/cyclization slowly and in lower yields than the other
aldehydes investigated. We believe that this is due to it being less
electrophilic than the other aldehydes studied. This reduction in
reactivity led to a prolonged reaction time, which resulted in some
loss of the enantiomeric integrity of the product. The mechanism for
this erosion of enantiomeric integrity is probably the TiCl4 mediated
formation of a carbocation, which is stabilized by delocalization into
the phenyl ring. It is reassuring to note that this erosion is only seen
when extended cyclization times are required.
was synthesized via the diketene version of the MaitlandeJapp
reaction. The diketene MaitlandeJapp reaction generated the
C9eC19 THP 7 with an enantiomeric excess of only 73%, which
required the development of a resolving second MaitlandeJapp
reaction to install the second THP unit. This strategy did provide the
bis-pyran unit 8 enantiomerically pure, but in a reduced yield due
to loss of material in the form of an unwanted diastereomer formed
by the reaction of enantiomerically pure
d-hydroxy-b-ketoester
with the minor enantiomer of 7. The asymmetric Chan’s diene
MaitlandeJapp reaction which generated 2k in a higher 84% ee, will
obviate this loss of material, thus a more efficient second genera-
tion synthesis of the C1eC19 unit of phorboxazole B 8 can now be
realized (Scheme 5).
Table 2
Asymmetric MaitlandeJapp reactiona
O
1) Ti(Oi-Pr)4/(R)-Binol/LiCl, THF
1) Ti(OiPr)4, Binol, LiCl
O
O
OH
MeO2C
RCHO, THF, rt
O
OMe OTMS
MeO2C
R1
MeO2C
R1
OMe OTMS
H
C6
R
OBn
TMSO
2) TiCl4, R1CHO, CH2Cl2, rt
O
R
O
O
N
TMSO
2) TiCl4, TFA, CH2Cl2,
-78 oC - rt
2
3
CHO
N
O
BnO
2k
Entry
R
R1
Yield (%)
Ratio 2/3
%eeb
ac
bc
cc
dc
ec
fe
Ph
Ph
Ph
Ph
Ph
Pr
i-Pr
CH2OBn
cy-Hex
4-TBSO
Ph
i-Pr
86
69
36
40
70
77
90
30
70
55
1:2
10:1
1:10
1:3.8
1:2
1:1
1:2.8
0:1
99g
97h
97g
93i
OTIPS
2-furyl
4-MeOC6H4
4-NO2C6H4
4-MeOC6H4
Ph
4 steps; ref 13
ref 13
99h
99i
O
O
CHO
N
gd
hc
ic
99g
97i
C9
7
Ph
Ph
C19
1:1.5
2:1
99g
91g
jf
4-MeOC6H4
OTIPS
O
C6H4(CH2)2
BnO(CH2)2
kf
2-Me-oxazole
69
2:1
84g
a
Reaction scheme shows relative stereochemistry only.
Determined either by chiral shift 1H NMR with Eu(hfc)3 or chiral HPLC. See
b
O
O
8
Experimental section for details.
N
c
(R)-Binol used; absolute stereochemistry of C6 centre is (R).
(S)-Binol used; absolute stereochemistry of C6 centre is (S).
(S)-Binol used; absolute stereochemistry of C6 centre is (R).
(R)-Binol used; absolute stereochemistry of C6 centre is (S).
%ee of both 2 and 3 determined.
%ee of 2 determined.
%ee of 3 determined.
d
C19
Boc(Ph)NOC
Br
e
C1
Scheme 5. Formal synthesis of the C9eC19 unit of (þ)-phorboxazole B.
f
g
h
i
3. Conclusions
Entries j and k in Table 2 are particularly interesting as they are
key compounds on route to our syntheses of (ꢁ)-centrolobine 6 and
the C1eC19 bis-pyran unit 8 of (þ)-phorboxazole B, respectively.
Our earlier synthesis of centrolobine 6 was racemic, but did provide
the natural product in only four steps and in a 50% overall yield.11
With the development of an asymmetric MaitlandeJapp reaction
we now have a formal total synthesis of (ꢀ)-centrolobine 6
(Scheme 4).
We have developed a highly enantioselective MaitlandeJapp
reaction for the synthesis of functionalized tetrahydropyran-4-
ones. The reaction has a wide scope and can accommodate aryl,
alkyl, branched alkyl and heteroatom-containing aldehydes as ei-
ther the first or second aldehyde reaction partner. The yields of the
tetrahydropyran-4-ones are moderate to good and the enantio-
meric excesses are excellent, ranging between 91 and 99% for most
substrates investigated. The utility of this reaction has been dem-
onstrated by the asymmetric synthesis of tetrahydropyran units
present in the natural products (ꢀ)-centrolobine 6 and (þ)-phor-
boxazole B, and mark an improvement over the group’s previously
described routes.
1) Ti(Oi-Pr)4/(R)-Binol/LiCl, THF
O
O
H
MeO2C
OMe OTMS
OTBS
O
TMSO
2) Yb(OTf)3, anisaldehyde,
CH2Cl2, rt
4. Experimental section
4.1. General
MeO
2j
TBSO
3 steps; ref 11
All reactions were carried out under N2 unless otherwise speci-
fied. IR analyses were carried out onThermoNicolet Avatar 370 FT-IR
and ThermoNicolet IR100 spectrometer using NaCl plates or cae-
sium fluoride solution cell. Nuclear magnetic resonance spectra
were recorded on a Jeol ECX-400 MHz, a Jeol ECS-400 MHz and
Bruker AV-500 MHz spectrometer at ambient temperature; chem-
ical shifts are quoted in parts per million (ppm) and were referenced
as follows: chloroform-d, dH 7.26 ppm; chloroform-d, dC 77.0 ppm,
O
6
MeO
OH
Scheme 4. Formal synthesis of (ꢀ)-centrolobine.
Our first generation synthesis of the C1eC19 fragment of
phorboxazole B 8 was asymmetric.13 However, the C9eC19 THP 7

M. Iqbal et al. / Tetrahedron 67 (2011) 4960e4966
4963
benzene-d, dH 7.16 ppm; benzene-d, dC 128.02 ppm. Mass spec-
trometry was performed by the University of York mass spectrom-
etry service using ESI, EI or CI ionization techniques. Microanalysis
was performed by the microanalytical unit at The University of
Nottingham. Melting points were determined using a Stuart SMP3
apparatus and remain uncorrected. Optical rotations were recorded
at ambient temperature using a JASCO DIP-370 digital polarimeter.
Thin layer chromatography was performed on glass-backed plates
coated with Merck Silica gel 60 F254, and developed using ultraviolet
light, acidic aqueous ceric ammonium molybdate, basic aqueous
potassium permanganate or ethanolic anisaldehyde. Liquid chro-
matography was performed using forced flow (flash column) with
the solvent systems indicated. The stationary phase was silica gel 60
(220e240 mesh) supplied by Fluorochem or silica gel Merck TLC
grade 11695 supplied by SigmaeAldrich. Dichloromethane was
distilled from calcium hydride; THF and diethyl ether were distilled
from sodium/benzophenone ketyl; toluene was dried over sodium
wire prior to use. All other solvents and reagents were used as re-
ceived from commercial suppliers.
12 h. The solvent was removed in vacuo and the residue dissolved
in dry MeOH (10 ml), to which was added PPTS (255 mg, 1 mmol)
and the mixture was stirred at ꢀ12 ꢂC for 2 h. After this time the
volatiles were removed in vacuo and the residue was dissolved in
EtOAc and washed successively with aqueous solutions of saturated
NaHCO3 solution and brine. The organics were then dried with
MgSO4 and concentrated in vacuo to give a brownish oil.
Neat TiCl4 (60 mg, 0.32 mmol) was added to a stirred solution of
aldol product (0.3 mmol) and second aldehyde (0.32 mmol) in dry
CH2Cl2 (1.5 ml) and the reaction mixture was stirred for 1.5 h. After
this time, the reaction mixture was diluted with diethyl ether and
the organics washed successively with saturated aqueous sodium
bicarbonate solution, brine, dried with MgSO4 and concentrated in
vacuo. The residue was purified by flash column chromatography
(petroleum ether/EtOAc, 10:1 to 1:1) to yield both trans and cis
diastereomers.
4.3.1. (2S,3R,6R)-2,6-Diphenyl-4-oxo-tetrahydro-pyran-3-carboxylic
acid methyl ester (2a). White solid; mp: 133e135 ꢂC; [
a
]
D23
þ17.3 (c
0.4, CHCl3); nmax (film) 2953, 2921,1747,1717,1496,1455,1274,1067,
4.2. General procedure for the asymmetric addition of Chan’s
757, 699 cmꢀ1; 1H NMR (400 MHz; CDCl3)
d
7.50e7.30 (10H, m), 5.13
diene to aldehydes (5a and 5b)
(1H, d, J¼10.6 Hz), 4.95 (1H, dd, J¼11.3, 3.0 Hz), 3.77 (1H, dd, J¼10.6,
0.8 Hz), 3.70 (3H, s), 2.86 (1H, dd, J¼14.3, 3.0 Hz), 2.79 (1H, ddd,
Neat Ti(Oi-Pr)4 (28 mg, 0.1 mmol) was added to a solution of
Binol (29 mg, 0.1 mmol) in THF (10 ml) and stirred for 20 min at rt
undera N2 atmosphere. After this time dry LiCl (8 mg, 0.2 mmol) was
added and the reaction mixture was stirred for a further 30 min.
After this time a solution of aldehyde (5 mmol) in THF (3 ml) was
added and the reaction mixture was stirred at rt for 20 min. A so-
lution of Chan’s diene (2.6 g, 10 mmol) in THF (3 ml) was added
slowly via a syringe pump at a rate of 30 ml/h. When the addition
was complete the reaction mixture was stirred at rt for 12 h. The
solvent was removed in vacuo and the residue dissolved in dry
MeOH (10 ml), to which was added PPTS (255 mg, 1 mmol) and the
mixture was stirred at ꢀ12 ꢂC for 2 h. After this time the volatiles
were removed in vacuo and the residue was dissolved in EtOAc and
washed successively with aqueous solutions of saturated NaHCO3
solution and brine. The organics were then dried with MgSO4 and
concentrated in vacuo to give a brownish oil. The residue was pu-
rified by flash column chromatography (1:10/1:1 EtOAc/petro-
J¼14.3, 11.2, 0.8 Hz) ppm; 13C NMR (67.8 MHz; CDCl3)
d 201.1, 167.8,
139.9, 138.6, 128.8, 128.8, 128.6, 128.1, 126.8, 125.6, 81.0, 78.9, 64.6,
52.1, 48.9 ppm; m/z (CIþ) 310 (62%, Mþ), 293 (100%, MþꢀOH); HRMS:
found (Mþ) 310.1195. C19H18O4 requires (Mþ) 310.1205. Anal. Calcd
for C19H18O4: C, 73.53; H, 5.85. Found: C, 73.22; H, 5.95%; 99% ee as
determined by HPLC analysis: CHIRACEL OD-H, hexane/isopropanol
99:1, flow rate¼0.1 ml/min, T¼20 ꢂC, tR, (major)¼86.9 min.
4.3.2. (2S,6R)-2,6-Diphenyl-4-hydroxy-3,4-dihydro-2H-pyran-3-car-
boxylic acid methyl ester (3a). White solid; mp: 118e120 ꢂC; [
a]
D23
þ37.2 (c 1.1, CHCl3); nmax (film) 2955, 2918, 2849, 1745, 1662, 1443,
1269, 1219, 1063, 698 cmꢀ1; 1H NMR (400 MHz; CDCl3)
12.38 (1H,
d
s), 7.57e7.28 (10H, m), 5.80 (1H, d, J¼1.0 Hz), 4.59 (1H, dd, J¼10.8,
3.9 Hz), 3.67 (3H, s), 2.73 (1H, ddd, J¼18.1, 10.8, 1.0 Hz), 2.60 (1H, dd,
J¼18.1, 3.9 Hz) ppm; 13C NMR (67.8 MHz; CDCl3)
d 171.2, 165.8,
141.0, 140.8, 128.8, 128.4, 128.0, 127.9, 126.9, 126.0, 98.7, 73.7, 68.3,
52.2, 35.6 ppm; m/z (CIþ) 310 (50%, Mþ), 279 (10%, MþꢀOMe), 233
(77%, MþꢀPh); HRMS: found (Mþ) 310.1205. C19H18O4 requires
(Mþ) 310.1205. Anal. Calcd for C19H18O4: C, 73.53; H, 5.85. Found: C,
73.32; H, 5.75%; 99% ee as determined by HPLC analysis: CHIRACEL
OD-H, hexane/isopropanol 99:1, flow rate¼0.1 ml/min, T¼20 ꢂC, tR,
(major)¼70.4 min.
leum ether mixtures) to give the
d-hydroxy-b-ketoester 5a or 5b.
4.2.1. (R)-Methyl 5-hydroxy-3-oxo-5-phenylpentanoate (5a). Spe-
ctroscopic data identical to that reported in the literature.17,18
[a]
D23
27.3 (c 2.9, CHCl3), 97% ee, as determined by 1H NMR (400 MHz,
CDCl3) shift reagent experiments with tris[3-(heptafluorop-
ropylhydroxy-methylene)-
D
-camphorato]europium(III) (15 mol %).
4.3.3. (2R,3R,6R)-2-(2-Methyl-ethyl)-6-phenyl-4-oxo-tetrahydro-py-
ran-3-carboxylic acid methyl ester (2b). White solid; mp 99e101 ꢂC;
D25
4.2.2. (R)-Methyl 5-hydroxy-3-oxooctanoate (5b). Spectroscopic
[
a
]
þ64.9 (c 1.0, CHCl3); nmax (film) 2966, 2934, 1746, 1715, 1454,
data identical to that reported in the literature.17,18
[a
]
ꢀ16.5 (c
1361, 1132, 1073 cmꢀ1; 1H NMR (400 MHz; CDCl3)
d 7.43e7.32 (5H,
D23
2.38, CHCl3), 99% ee, as determined by 1H NMR (400 MHz, CDCl3)
m), 4.73 (1H, dd, J¼11.7, 2.5 Hz), 4.00 (1H, dd, J¼10.8, 2.9 Hz), 3.79
(3H, s), 3.53 (1H, dd, J¼10.8, 1.0 Hz), 2.75 (1H, dd, J¼14.2, 2.5 Hz),
2.52 (1H, ddd, J¼14.2, 11.7,1.0 Hz), 1.84 (1H, d septets, J¼6.8, 2.9 Hz),
1.10 (3H, d, J¼6.8 Hz), 1.05 (3H, d, J¼6.8 Hz) ppm; 13C NMR
shift reagent experiments with tris[3-(heptafluoropropylhydroxy-
methylene)-D-camphorato]europium(III) (17 mol %).
4.3. General procedure for the asymmetric MaitlandeJapp
reaction (2aei,k/3aei/k)
(67.8 MHz; CDCl3) d 202.4, 168.6, 140.8, 128.5, 127.9, 125.2, 82.3,
77.9, 60.5, 52.1, 48.8, 31.5, 19.7, 15.3 ppm; m/z (CIþ) 276 (5%, Mþ),
233 (100%, Mþꢀ(CH3)2CH); HRMS: found (Mþ) 276.1360. C16H20O4
requires (Mþ) 276.1362; 97% ee as determined by HPLC analysis:
CHIRACEL OD-H, hexane/isopropanol 99:1, flow rate¼0.1 ml/min,
T¼20 ꢂC, tR (minor)¼45.2 min, tR (major)¼49.4 min.
Neat Ti(Oi-Pr)4 (28 mg, 0.1 mmol) was added to a solution of
Binol (29 mg, 0.1 mmol) in THF (10 ml) and stirred for 20 min at rt
under a N2 atmosphere. After this time dry LiCl (8 mg, 0.2 mmol)
was added and the reaction mixture was stirred for a further
30 min. After this time a solution of aldehyde (5 mmol) in THF
(3 ml) was added and the reaction mixture was stirred at rt for
20 min. A solution of Chan’s diene (2.6 g, 10 mmol) in THF (3 ml)
was added slowly via a syringe pump at a rate of 30 ml/h. When the
addition was complete the reaction mixture was stirred at rt for
4.3.4. (2S,3R,6R)-2-Furyl-6-phenyl-4-oxo-tetrahydro-pyran-3-car-
boxylic acid methyl ester (2c). White solid; mp 88e90 ꢂC; [
þ20.2 (c 0.35, CHCl3); nmax (film) 2950, 2920, 2845, 1745, 1716, 1657,
1440, 1345, 1264, 1217 cmꢀ1; 1H NMR (400 MHz; CDCl3)
7.44 (1H,
dd, J¼1.8, 0.6 Hz), 7.43e7.30 (5H, m), 6.44 (1H, d, J¼3.2 Hz), 6.37 (1H,
a]
D23
d

4964
M. Iqbal et al. / Tetrahedron 67 (2011) 4960e4966
dd, J¼3.2,1.8 Hz), 5.20 (1H, d, J¼11.1 Hz), 4.89 (1H, dd, J¼10.8, 3.4 Hz),
4.03 (1H, dd, J¼11.1, 0.9 Hz), 3.73 (3H, s), 2.83 (1H, dd, J¼14.6, 3.4 Hz),
2.77 (1H, ddd, J¼14.6, 10.8, 0.9 Hz) ppm; 13C NMR (67.8 MHz; CDCl3)
ee as determined by HPLC analysis: CHIRACEL OD-H, hexane/iso-
propanol 99:1, flow rate¼0.1 ml/min, T¼20 ꢂC, tR, (major)¼
58.6 min.
d
200.7,183.2,150.7,143.3,128.7,128.6,126.1,125.9,110.4,109.1, 78.6,
73.8, 60.6, 52.4, 48.7 ppm; m/z (CIþ) 318 (62%, MþþNH4), 301 (22%,
MþþH), 283 (28%, MþꢀOH), 222 (58%), 205 (52%, MþþHꢀfurfural);
HRMS: found (MþþNH4) 318.1342. C17H16O5 requires (MþþNH4)
318.1341; 96% ee as determined by HPLC analysis: CHIRACEL OD-H,
hexane/isopropanol 99:1, flow rate¼0.1 ml/min, T¼20 ꢂC, tR
(minor)¼68.8 min, tR (major)¼79.0 min.
4.3.9. (2R,3S,6S)-2-Phenyl-6-(2-methyl-ethyl)-4-oxo-tetrahydro-py-
ran-3-carboxylic acid methyl ester (2g). White solid; mp 59e61 ꢂC;
D23
[a
]
þ7.8 (c 1.0, CHCl3); nmax (film) 3031, 2964, 1746, 1717,
1250 cmꢀ1 1H NMR (500 MHz; CDCl3)
; d 7.40e7.29 (5H, m), 4.90
(1H, d, J¼10.4 Hz), 3.62 (1H, ddd, J¼11.6, 6.7, 2.4 Hz), 3.61 (3H, s),
3.57 (1H, d, J¼10.4 Hz), 2.57 (1H, dd, J¼14.0, 11.6 Hz), 2.45 (1H, dd,
J¼14.0, 2.4 Hz), 1.91 (1H, octet, J¼6.7 Hz), 0.99 (3H, d, J¼6.7 Hz),
4.3.5. (2R,6R)-2-Furyl-4-hydroxy-6-phenyl-3,4-dihydro-2H-pyran-
3-carboxylic acid methyl ester (3c). White solid; mp 81e83 ꢂC;
0.97 (3H, d, J¼6.7 Hz) ppm; 13C NMR (100 MHz; CDCl3)
d 202.6,
168.1, 139.2, 128.6, 128.6, 126.7, 81.9, 80.6, 52.1, 43.9, 33.1, 18.8,
17.8 ppm; m/z (CIþ) 276 (72%, Mþ), 199 (100%, MþꢀPh), 167 (75%);
HRMS: found (Mþ) 276.1359, C16H20O4 requires (Mþ) 276.1362; 99%
ee as determined by HPLC analysis: CHIRACEL OD-H, hexane/iso-
propanol 99:1, flow rate¼0.1 ml/min, T¼20 ꢂC, tR (major)¼42.1 min.
D23
[
a]
þ35.9 (c 1.2, CHCl3); nmax (film) 2958, 2930, 1729, 1466, 1275,
1124, 1073 cmꢀ1 1H NMR (400 MHz; CDCl3)
; d 12.16 (1H, s), 7.42
(1H, dd, J¼1.8, 0.9 Hz), 7.37e7.28 (5H, m), 6.35 (1H, dd, J¼3.2,
1.8 Hz), 6.26 (1H, ddd, J¼3.2, 0.9, 0.6 Hz), 5.77 (1H, br s), 4.74 (1H,
dd, J¼10.8, 4.1 Hz), 3.71 (3H, s), 2.69 (1H, ddd, J¼18.1, 10.8, 0.9 Hz),
2.58 (1H, dd, J¼18.1, 4.1 Hz) ppm; 13C NMR (67.8 MHz; CDCl3)
4.3.10. (2R,6S)-2-Phenyl-6-(2-methyl-ethyl)-4-hydroxy-3,4-dihydro-
d
171.0, 170.7, 153.3, 142.8, 140.6, 128.5, 127.9, 125.9, 110.0, 109.8,
2H-pyran-3-carboxylic acid methyl ester (3g). White solid; mp:
97.1, 69.2, 67.0, 51.7, 35.5 ppm; m/z (EIþ) 300 (23%, Mþ), 268 (100%),
250 (43); HRMS: found (Mþ) 300.0994. C17H16O5 requires (Mþ)
300.0998; 98% ee as determined by HPLC analysis: CHIRACEL OD-H,
hexane/isopropanol 99:1, flow rate¼0.1 ml/min, T¼20 ꢂC, tR
(minor)¼66.7 min, tR (major)¼81.0 min.
57e58 ꢂC; [
a
]
D23
þ22.4 (c 1.66, CHCl3); nmax (film) 2957, 1661, 1624,
1442, 1269, 1223 cmꢀ1 1H NMR (400 MHz; CDCl3)
; d 12.32 (1H, s),
7.38e7.30 (5H, m), 5.65 (1H, s), 3.65 (3H, s), 3.14 (1H, ddd, J¼10.8,
6.8, 3.9 Hz), 2.38 (1H, dd, J¼18.1, 10.8 Hz), 2.25 (1H, dd, J¼18.1,
3.9 Hz), 1.63 (1H, oct, J¼6.8 Hz), 0.83 (3H, d, J¼6.8 Hz), 0.80 (3H, d,
J¼6.8 Hz) ppm; 13C NMR (100 MHz; CDCl3)
d 171.8, 171.0, 140.9,
4.3.6. (2S,6R)-2-(4-Methoxyphenyl)-4-hydroxy-6-phenyl-3,4-dihy-
dro-2H-pyran-3-carboxylic acid methyl ester (3d). White solid; mp
128.4, 127.9, 127.6, 98.5, 72.5, 71.4, 51.5, 32.6, 32.2, 18.3, 17.7 ppm;
m/z (CIþ) 276 (65%, Mþ), 199 (100%, MþꢀPh), 167 (82%); HRMS:
found (Mþ) 276.1360. C16H20O4 requires (Mþ) 276.1362; 99% ee as
determined by HPLC analysis: CHIRACEL OD-H, hexane/isopropanol
99:1, flow rate¼0.1 ml/min, T¼20 ꢂC, tR (major)¼43.7 min.
112e114 ꢂC; [
a
]
D23
þ38.9 (c 1.3, CHCl3); nmax (solution, CHCl3) 3012,
2931, 1660, 1624, 1510, 1444, 1271, 1250, 1221, 1174, 1062,
1032 cmꢀ1; 1H NMR (500 MHz, CDCl3): 12.32 (1H, s), 7.32e7.22 (7H,
m), 6.89e6.85 (2H, m), 5.73 (1H, s), 4.56 (1H, dd, J¼11.0, 4.0 Hz),
3.80 (3H, s), 3.64 (3H, s), 2.70 (1H, dd, J¼18.0, 11.0 Hz), 2.57 (1H, dd,
4.3.11. (2S,6R)-2-Phenyl-6-((benzyloxy)methyl)-4-hydroxy-3,4-dihy-
J¼18.0, 4.0 Hz) ppm; 13C NMR (100 MHz, CDCl3)
d
171.0, 170.9,
dro-2H-pyran-3-carboxylic acid methyl ester (3h). Oil; [
1.0, CHCl3); nmax (solution, CHCl3) 3016, 1718, 1496, 1446, 1439,
1348, 1282, 1217, 1106, 1056 cmꢀ1 1H NMR (400 MHz; CDCl3)
12.23 (1H, s), 7.39e7.21 (10H, m), 5.60 (1H, s), 4.44 (1H, d,
a
]
þ9.5 (c
D23
159.2, 140.9, 132.8, 129.7, 128.4, 127.8, 125.9, 113.5, 98.8, 72.7, 67.9,
55.2, 51.6, 35.4 ppm; m/z (ESIþ) 341 (MþþH), 363 (MþþNa); HRMS:
found (MþþNa) 363.1189. C20H20NaO5 requires (MþþNa) 363.1203;
93% ee as determined by HPLC analysis: CHIRACEL OD-H, hexane/
isopropanol 99:1, flow rate¼0.1 ml/min, T¼20 ꢂC, tR, (minor)¼68.9,
tR (major)¼90.7 min.
;
d
J¼12.0 Hz), 4.37 (1H, d, J¼12.0 Hz), 3.69e3.64 (1H, m), 3.55 (3H, s),
3.37 (2H, dd, J¼4.4, 2.1 Hz), 2.53 (1H, dd, J¼18.2, 1.0 Hz), 2.17 (1H,
dd, J¼18.2, 3.9 Hz) ppm; 13C NMR (100 MHz, CDCl3)
d 171.1, 171.0,
140.5, 137.9, 128.5, 128.3, 128.1, 127.9, 127.6, 98.5, 73.3, 72.8, 71.9,
65.9, 51.6, 30.9, 29.7 ppm; m/z (ESIþ) 355 (MþH)þ, 377 (MþNa)þ;
HRMS: found (MþNa)þ 377.1357. C21H22NaO5 requires (MþNa)þ
377.1359; 90% ee, as determined by 1H NMR (400 MHz, CDCl3) shift
reagent experiments with tris[3-(heptafluoropropylhydroxy-
4.3.7. (2R,3R,6R)-2-(4-Nitro-phenyl)-6-phenyl-4-oxo-tetrahydro-py-
D23
ran-3-carboxylic acid methyl ester (2e). Oil; [
þ1.1 (c 1.1, CHCl3); nmax (solution; CHCl3) 3019, 1746, 1720, 1526,
1438, 1350, 1213, 1129 cmꢀ1; 1H NMR (500 MHz; CDCl3)
8.24 (2H,
a
]
þ1.1 (c 1.11), [a]
D23
d
br d, J¼9.0 Hz), 7.68 (2H, br d, J¼9.0 Hz), 7.42e7.34 (5H, m), 5.25
(1H, d, J¼11.0 Hz), 4.97 (1H, dd, J¼11.5, 2.5 Hz), 3.68 (3H, s), 3.67
(1H, d, J¼11.0 Hz), 2.91 (1H, dd, J¼14.5, 2.5 Hz), 2.81 (1H, dd, J¼14.5,
methylene)-D-camphorato] europium(III) (17 mol %).
4.3.12. (2S,3R,6R)-2-Phenyl-6-cyclohexyl-4-oxo-tetrahydro-pyran-3-
carboxylic acid methyl ester (2i). Oil; [
þ11.3 (c 0.9, CHCl3); nmax
(film) 2927, 2854, 1748, 1716, 1453, 1338, 1136, 1066, 1030, 760,
699 cmꢀ1; 1H NMR (400 MHz; CDCl3)
7.40e7.30 (5H, m), 4.89 (1H,
11.5 Hz) ppm; 13C NMR (125 MHz, CDCl3)
d
199.8, 167.5, 148.1, 145.6,
a]
D23
139.4, 128.9, 128.6, 127.8, 125.6, 123.9, 79.8, 79.2, 64.2, 52.4,
48.8 ppm; m/z (ESIþ) 378 (100%, MþþNa); HRMS: found (MþþNa)
378.0948. C19H17NNaO6 requires (MþþNa) 378.0954; 99% ee as
determined by HPLC analysis: CHIRACEL OD-H, hexane/isopropanol
99:1, flow rate¼0.1 ml/min, T¼20 ꢂC, tR (major)¼22.6 min.
d
d, J¼10.5 Hz), 3.63 (1H, ddd, J¼11.4, 6.1, 2.6 Hz), 3.61 (3H, s), 3.57 (1H,
dd, J¼10.5, 0.6 Hz), 2.58 (1H, dd, J¼14.0, 2.6 Hz), 2.46 (1H, ddd,
J¼14.0, 11.4, 0.6 Hz), 1.91 (1H, m), 1.80e1.55 (5H, m), 1.27 (5H, m)
ppm; 13C NMR (67.8 MHz; CDCl3)
d 202.7, 168.1, 139.2, 128.7, 128.6,
4.3.8. (2R,6R)-2-(4-Methoxyphenyl)-6-propyl-4-hydroxy-3,4-dihy-
126.8, 81.5, 80.7, 64.9, 52.1, 44.4, 43.0, 28.6, 28.2, 26.4, 26.0 ppm; m/z
(ESþ) 380 (100%, MþþNaþCH3CN), 339 (77%, MþþNa), 211 (46%);
HRMS: found (MþþNaþCH3CN) 380.1866. C19H24O4 requires
(MþþNaþCH3CN) 380.1838. Anal. Calcd for C19H24O4: C, 72.13; H,
7.65. Found C, 72.12; H, 7.72%; 99% ee as determined by HPLC anal-
ysis: CHIRACEL OD-H, hexane/isopropanol 90:10, flow rate¼0.1 ml/
min, T¼20 ꢂC, tR (major)¼22.6 min.
D23
dro-2H-pyran-3-carboxylic acid methyl ester (3f). Oil; [
2.5, CHCl3); nmax (film) 3417, 2932, 1661, 1623, 1510, 1443, 1247,
1218, 823 cmꢀ1; 1H NMR (400 MHz; CDCl3)
12.28 (1H, s), 7.24 (2H,
a
]
þ9.8 (c
d
d, J¼8.8 Hz), 6.87 (2H, d, J¼8.8 Hz), 5.58 (1H, d, J¼1.0 Hz), 3.83 (3H,
s), 3.64 (3H, s), 3.48 (1H, m), 2.32 (1H, ddd, J¼18.1, 10.3, 1.0 Hz), 2.24
(1H, dd, J¼18.1, 4.4 Hz), 1.52e1.13 (4H, m), 0.76 (3H, t, J¼6.9 Hz)
ppm; 13C NMR (67.8 MHz; CDCl3)
d 171.4, 171.1, 159.0, 133.2, 129.5,
113.2, 98.8, 72.1, 65.8, 55.1, 51.5, 37.6, 34.7, 18.2, 13.7 ppm; m/z (CIþ)
306 (84%, Mþ), 275 (50%, MþꢀOMe), 247 (80%, MþꢀCO2Me);
HRMS: found (Mþ) 306.1454. C17H22O5 requires (Mþ) 306.1467; 99%
4.3.13. (2S,6R)-2-Phenyl-6-cyclohexyl-4-hydroxy-3,4-dihydro-2H-
D23
pyran-3-carboxylic acid methyl ester (3i). Oil; [
CHCl3); nmax (film) 2924, 2852, 1661, 1624, 1443, 1361, 1277, 1242,
a
]
þ31.2 (c 2.1,

M. Iqbal et al. / Tetrahedron 67 (2011) 4960e4966
4965
1218, 1051 cmꢀ1
;
1H NMR (400 MHz; CDCl3)
d
12.28 (1H, s),
Oil; [
a
]
þ6.6 (c 1.0, CHCl3); nmax (solution, CHCl3) 3051, 2901.
D25
7.35e7.28 (5H, m), 5.60 (1H, s), 3.63 (3H, s), 3.14 (1H, ddd, J¼10.8,
7.3, 3.9 Hz), 2.36 (1H, dd, J¼17.6, 10.8 Hz), 2.23 (1H, dd, J¼17.6,
3.9 Hz), 1.86 (1H, m), 1.70e1.47 (4H, m), 1.36e1.01 (4H, m), 0.85
(1H, ddd, J¼24.5, 12.7, 3.9 Hz), 0.66 (1H, ddd, J¼24.5, 12.7, 3.9 Hz)
2887, 1752, 1716 cmꢀ1 1H NMR (400 MHz, CDCl3)
; d 7.03 (2H, d,
J¼7.0 Hz, Ph), 6.75 (2H, d, J¼7.0 Hz), 4.07 (1H, m, H-5), 3.74 (3H, s,
H-14), 3.47 (2H, s, H-2), 2.80 (1H, br s, OeH), 2.76e2.57 (4H, m, H-
3þH-7), 1.84e1.75 (1H, m, H-6), 1.71e1.63 (1H, m, H-6), 0.97 (9H, s,
ppm; 13C NMR (67.8 MHz; CDCl3)
d
171.9, 140.9, 128.5, 127.9, 127.6,
H-13), 0.18 (6H, s, H-11) ppm; 13C NMR (100 MHz, CDCl3)
d 200.1,
98.5, 72.5, 70.6, 51.5, 42.3, 32.3, 28.6, 26.3, 25.9, 25.6 ppm; m/z
(CIþ) 334 (100%, MþþNH4), 317 (55%, MþþH); HRMS: found
(MþþNH4) 334.2013. C19H24O4 requires (MþþNH4) 334.2013.
Anal. Calcd for C19H24O4: C, 72.13; H, 7.65. Found C, 71.93; H, 7.72%;
99% ee as determined by HPLC analysis: CHIRACEL OD-H, hexane/
isopropanol 90:10, flow rate¼0.1 ml/min, T¼20 ꢂC, tR (major)¼
29.1 min.
167.7, 153.8, 129.6, 129.3, 120.0, 62.3, 52.5, 34.5, 31.3, 30.3, 25.8, 18.3,
ꢀ4.3 ppm; MS (ESI): m/z 381 (MþþH); HRMS: found 381.2091.
C20H33O5Si requires 381.2097; 91% ee as determined by 1H NMR
experiments with tris[3-(heptafluoropropylhydroxy-methylene)-
D-camphorato]europium(III) (CDCl3, 400 MHz, 25 mol %).
To a slurry of Yb(OTf)3 (162 mg, 0.262 mmol) in CH2Cl2 (0.5 ml)
stirring at ꢀ78 ꢂC under a N2 atmosphere was added a solution of
d-
hydroxy-
b
-ketoester
(from
above
procedure)
(100 mg,
4.3.14. (2S,3S,6R)-2-(2-Methyloxazol-4-yl)-6-(2-benzyloxyethyl)-4-
0.262 mmol) in CH2Cl2 (1.0 ml) followed by a solution of anisalde-
hyde (43 mg, 0.315 mmol) in CH2Cl2 (1 ml). After 5 min the mixture
was warmed to rt and stirred for 18 h. The mixture was then diluted
with Et2O (20 ml) and washed with a 5% aqueous solution of
NaHCO3 (2ꢃ20 ml), brine (20 ml), dried (MgSO4) and concentrated
to give a yellow oil. Purification by flash column chromatography
using a 10:1 petroleum ether/EtOAc gradient afforded the tetra-
hydropyrans 2j (53 mg, 41%) and 3j (18 mg, 14%) as colourless oils.
oxo-tetrahydro-pyran-3-carboxylic acid methyl ester (2k). Oil; mp
80e82 ꢂC; [
a
]
ꢀ0.5 (c 0.90, CHCl3); nmax (solution; CHCl3) 3018,
D25
2954, 2867, 1746, 1717, 1584, 1437, 1358, 1341, 1322, 1217, 1106,
755 cmꢀ1; 1H NMR (500 MHz; CDCl3)
d
7.50 (1H, s), 7.34e7.26 (5H,
m), 4.92 (1H, d, J¼10.5 Hz), 4.50 (1H, d, J¼12.0 Hz), 4.46 (1H, d,
J¼12.0 Hz), 4.04 (1H, dddd, J¼11.5, 9.5, 4.5, 2.5 Hz), 3.90 (1H, d,
J¼10.5 Hz), 3.69 (3H, s), 3.62 (1H, m), 3.55 (1H, m), 2.57 (1H, dd,
J¼14.5, 2.5 Hz), 2.46 (1H, dd, J¼14.5, 11.5 Hz), 2.44 (3H, s), 2.05 (1H,
m), 1.87 (1H, m) ppm; 13C NMR (125 MHz; CDCl3)
d
201.3, 167.9,
4.4.1. (2S,3R,6S)-2-(4-Methoxyphenyl)-6-(2-(4-tert-butylbimethylsi-
lanyloxy)-phenyl-ethane)-4-oxo-tetrahydro-pyran-3-carboxylic acid
162.2, 138.2, 138.0, 136.0, 128.4, 127.6, 127.6, 74.6, 73.0, 72.9, 65.8,
61.1, 52.2, 47.0, 36.2, 14.0 ppm; m/z (ESIþ) 374 (100%, MþþH);
HRMS: found (MþþH) 374.1598. C20H24NO6 requires (MþþH)
374.1604; 81% ee as determined by 1H NMR experiments with tris
[3-(heptafluoropropylhydroxy-methylene)-D-camphorato]euro-
pium(III) (C6D6, 400 MHz, 17 mol %).
D23
methyl ester (2j). Oil; [
a
;
]
ꢀ22.6 (c 0.25, CHCl3); nmax (film) 2955,
2930, 1744, 1715 cmꢀ1
1H NMR (400 MHz, CDCl3)
d
7.33 (2H, d,
J¼8.5 Hz), 7.00 (2H, d, J¼8.5 Hz), 6.89 (2H, d, J¼8.5 Hz), 6.74 (2H, d,
J¼8.5 Hz), 4.81 (1H, d, J¼10.5 Hz), 3.81 (3H, s), 3.78 (1H, m), 3.60
(3H, s), 3.59 (1H, d, J¼10.5 Hz), 2.68 (2H, m), 2.53 (1H, dd, J¼14.5,
2.5 Hz), 2.43 (1H, dd, J¼14.5, 11.5 Hz), 2.02 (1H, m), 1.83 (1H, m),
4.3.15. (2S,6R)-2-(2-Methyloxazol-4-yl)-6-(2-benzyloxyethyl)-4-hy-
0.97 (9H, s), 0.18 (6H, s) ppm; 13C NMR (100 MHz; CDCl3)
d 202.1,
droxy-3,4-dihydro-2H-pyran-3-carboxylic acid methyl ester (3k). Oil;
168.2, 159.9, 133.8, 131.2, 129.4 128.3, 120.1, 114.6, 80.5, 76.3, 64.7,
55.4, 52.3, 47.2, 37.9, 31.7, 30.5, 25.8, 18.3, ꢀ4.2 ppm; m/z (ESI) 499
(MþþH); HRMS: found (MþþH) 499.2505. C28H39O6Si requires
499.2516; 91% ee as determined by 1H NMR experiments with tris
[3-(heptafluoropropylhydroxy-methylene)-D-camphorato]euro-
pium(III) (CDCl3, 400 MHz, 15 mol %).
D25
[
a]
þ1.6 (c 1.31, CHCl3); nmax (solution; CHCl3) 3016, 1717,
1662 cmꢀ1; 1H NMR (400 MHz; CDCl3)
d 12.25 (1H, s), 7.34 (1H, s),
7.33e7.20 (4H, m), 7.18 (2H, br d, J¼7.5 Hz), 5.50 (1H, s), 4.39 (1H, d,
J¼12.0 Hz), 4.37 (1H, d, J¼12.0 Hz), 3.94 (1H, dddd, J¼11.0, 6.5, 4.0,
4.0 Hz), 3.67 (3H, s), 3.54 (2H, br t, J¼6.0 Hz), 2.37 (1H, dd, J¼18.0,
11.0 Hz), 2.34 (3H, s), 2.27 (1H, dd, J¼18.0, 4.0 Hz), 1.85e1.75 (2H,
m) ppm; 13C NMR (100 MHz, CDCl3)
d
171.5, 170.7, 161.8, 140.7,
4.4.2. (2S,6S)-2-(4-Methoxyphenyl)-6-(2-(4-tert-butylbimethylsila-
nyloxy)-phenyl-ethane)-4-hydroxy-3,4-dihydro-2H-pyran-3-carbox-
138.4, 136.8, 128.3, 127.5, 127.3, 97.8, 73.0, 66.3, 66.2, 64.3, 51.6, 35.3,
34.4, 13.9 ppm; MS (ESI): m/z 374 (MþþH); HRMS: found (MþþH)
374.1598. C20H24NO6 requires (MþþH) 374.160; 81% ee as de-
termined by 1H NMR experiments with tris[3-(hepta-
D23
;
ylic acid methyl ester (3j). Oil; [
a
]
ꢀ29.5 (c 0.30, CH2Cl2); nmax
(film) 3354, 2924, 2853, 1715 cmꢀ1
1H NMR (400 MHz, CDCl3)
d
12.25 (1H, s), 7.24 (2H, d, J¼7.0 Hz), 6.88 (2H, d, J¼7.0 Hz), 6.64 (2H,
fluoropropylhydroxy-methylene)-
D
-camphorato]europium(III)
d, J¼6.5 Hz), 6.57 (2H, d, J¼6.5 Hz), 5.59 (1H, s), 3.84 (3H, s), 3.62 (3H,
s), 3.45 (1H, m), 2.57 (1H, ddd, J¼13.5, 8.5, 5.0 Hz), 2.32 (2H, m), 2.18
(1H, dd, J¼18.0, 4.0 Hz),1.75 (1H, dddd, J¼17.0,14.0, 8.5, 5.0 Hz),1.59
(1H, m), 0.96 (9H, s), 0.15 (3H, s), 0.07 (3H, s) ppm; 13C NMR
(C6D6, 400 MHz, 25 mol %).
4.4. Procedure for the MaitlandeJapp cyclization to give the
(L)-centrolobine precursor (2j/3j)
(100 MHz; CDCl3) d 171.3,171.0,159.5,133.3,133.1,129.4,129.2,120.1,
114.6, 113.5, 99.1, 72.0, 64.7, 55.5, 52.3, 37.9, 34.8, 30.5, 25.7, 18.3,
ꢀ4.2 ppm; m/z (ESI) 499 (MþþH); HRMS: found (MþþH) 499.2521.
C28H39O6Si requires 499.2516; 91% ee as determined by 1H NMR
experiments with tris[3-(heptafluoropropylhydroxy-methylene)-D-
camphorato]europium(III) (CDCl3, 400 MHz, 20 mol %).
To a solution of Ti(Oi-Pr)4 (11.8 mg, 0.04 mmol) in THF (10 ml)
stirring at rt under a N2 atmosphere was added (R)-Binol (11.5 mg,
0.04 mmol). The solution was stirred for 20 min then treated with
dry LiCl (3.4 mg, 0.08 mmol) and stirred for a further 30 min. The
solution was treated with 3-(4-tertbutyldimethylsilyloxyphenyl)-
propanal (528 mg, 2.00 mmol) over a 10 min period followed by
Chan’s diene (1.04 g, 4.00 mmol) over a 10 min period. The reaction
mixture was stirred for 16 h then concentrated in vacuo to give an
orange oil. The crude material was taken up in MeOH (10 ml) and
charged with PPTS (50 mg, 0.20 mmol). The orange slurry was
stirred for 2 h then concentrated in vacuo to give an orange oil that
was dissolved in EtOAc (100 ml) and washed with a saturated
aqueous solution of NaHCO3, brine, dried (MgSO4) and concen-
trated in vacuo to give an orange oil. Purification by flash column
chromatography using a 9:1 to 8:2 petroleum ether/EtOAc gradient
afforded a yellow oil (624 mg, 82%).
Acknowledgements
We thank the Higher Education Commission of Pakistan and the
Wild Fund at the Department of Chemistry, University of York
(M.I.), and the Wellcome Trust VIP award (N.M.) for funding.
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