Enantio- and diastereoselective synthesis of tetrahydrofurochromenes by sequential asymmetric homoaldol reaction and a Mukaiyama-type tetrahydrofuran cyclization

Article abstract of DOI:10.1055/s-2006-950194

Herein, we report on a flexible strategy for the stereoselective construction of highly substituted tetrahydrofurochromene derivatives by Mukaiyama-type cyclizations of enantioenriched enol carbamates with O-protected salicylaldehydes. The chromenes are g

Full text of DOI:10.1055/s-2006-950194

PAPER
3111
Enantio- and Diastereoselective Synthesis of Tetrahydrofurochromenes by
Sequential Asymmetric Homoaldol Reaction and a Mukaiyama-Type
Tetrahydrofuran Cyclization
Stereoselective
Sy
s
nthesis of
t
Substit
r
uted Tet
i
rahydro
d
furochromene
s
Brüns, Birgit Wibbeling,1 Roland Fröhlich,1 Dieter Hoppe*
Westfälische Wilhelms-Universität Münster, Organisch-Chemisches Institut, Corrensstraße 40, 48149 Münster, Germany
Fax +49(251)8336531; E-mail: dhoppe@uni-muenster.de
Received 10 April 2006; revised 6 June 2006
R3
M
Abstract: Herein, we report on a flexible strategy for the stereose-
lective construction of highly substituted tetrahydrofurochromene
derivatives by Mukaiyama-type cyclizations of enantioenriched
enol carbamates with O-protected salicylaldehydes. The chromenes
are generated as pure diastereomers and under complete chirality
transfer.
H3C
H
Cb = C(O)Ni-Pr2
R2
A
H
H3C
R1
O
OCb
H
OH
+
R2
R1
O
O
H
O
B
C
D
Key words: heterocycles, homoaldol reaction, lithiation, salicylal-
dehydes, stereoselective synthesis
Scheme 1 Retrosynthetic route for the construction of tetrahydrofu-
rochromenes.
sparteine-mediated, asymmetric homoaldol reaction
(Scheme 2).6,7 Enantioselective a-deprotonation of (E)-
but-2-enyl N,N-diisopropylcarbamate (3) gives (–)-
sparteine–lithium compound 4, which reacts with inver-
sion of configuration with titanium(IV) isopropoxide.8
The configurationally stable titanate 5 undergoes addition
to aldehydes in a highly stereoselective manner with com-
plete 1,3-transfer of chirality to form the (Z)-anti-4-hy-
droxyalk-1-enyl carbamates 6 with an enantiomeric ratio
of up to 97:3 (Table 1).
The development of synthetic methods for the construc-
tion of tetrahydrofuran and tetrahydropyran rings as well
as their polycyclic analogues has attracted considerable
attention in recent years.2 These structures are present in a
number of biologically active natural products and func-
tional molecules such as cordigol (1)3 or the pterocarpane
indigocarpan (2),4 which contain the tetrahydrofuro-
chromene structure and exhibit fungicidal or COX-inhib-
itory activity, respectively (Figure 1).
HO
(a)
H3C
H3C
Li . (–)-sparteine
OCb
H
O
OH
OCH3
OH
OCb
O
H3CO
OH
3
4
HO
H
O
O
H
OH
HO
(c)
(b)
H3C
Ti(Oi-Pr)3
R1
O
indigocarpan (2)
H
HO
OCb
CH3 OCb
HO
5
6
cordigol (1)
Scheme 2 (–)-Sparteine-mediated homoaldol reaction of allyl carb-
amate 3. Reagents and conditions: (a) n-BuLi, (–)-sparteine, n-pen-
tane–cyclohexane (7:1), –78 °C, 2 h; (b) Ti(Oi-Pr)4, –78 °C, 30 min;
(c) (i) R1CHO, –78 °C, 2 h, then –78 °C to r.t.; (ii) 2 M HCl.
Figure 1 Tetrahydrofurochromenes occurring in nature.
Herein, we report a method for the synthesis of substituted
tetrahydrofurochromenes of type D that has a wide degree
of versatility (Scheme 1). An enantioenriched a-metallo-
crotyl carbamate (building block A), an aldehyde B, and a
substituted salicylaldehyde C are sequentially attached to
form the stereochemically homogeneous framework of D.
As published in our initial report,5a enol carbamates of
type 6 condense with aldehydes or ketones under the in-
fluence of BF3·OEt2 in a Mukaiyama-type10 reaction to
form diastereomerically pure 2,3-cis-3,4-trans-4,5-trans-
tetrahydrofurans; during this reaction the chiral informa-
tion of 6 is completely retained.11
The key step of this reaction sequence is the boron tri-
fluoride mediated synthesis of tetrahydrofuran carbalde-
hydes,5 based on O-(4-hydroxyalk-1-enyl)-substituted
carbamates 6, which are readily accessible by the (–)-
By applying the above-described method for the conden-
sation of homoaldol adducts 6 with O-protected, substitut-
ed salicylaldehydes 7, we established a new entry to
tetrahydrofurochromenes (Scheme 3, Table 2). In the
presence of 1.1 equivalents of BF3·OEt2, O-TBDPS-pro-
tected salicylaldehyde 7a and some ring-substituted de-
SYNTHESIS 2006, No. 18, pp 3111–3121
x
x.
x
x
.
2
0
0
6
Advanced online publication: 15.08.2006
DOI: 10.1055/s-2006-950194; Art ID: T05806SS
© Georg Thieme Verlag Stuttgart · New York

3112
A. Brüns et al.
PAPER
Table 1 Synthesis of (Z)-anti-4-Hydroxyalk-1-enyl Carbamates 6a
chromenols 12 as mixtures of anomers in 73–99% yield
over two steps.12 Further diastereomers could not be de-
tected by 1H NMR. The high double diastereofacial selec-
tion can be explained by the (E)-oxonium ion intermediate
8 that adopts the depicted conformation, which avoids
1,3-allylic strain13 and is therefore highly favored over the
Z-isomer. Due to signal overlap of the anomers in chiral
HPLC analysis, the determination of the enantiomeric ra-
tios of chromenols 12 were carried out at the stage of the
oxidized products 13.
Entry
R1
Product Yieldb (%) Ratioc
erd
anti/syn
1
2
3
4
5
6
7
i-Pr
6ae
6b
6ce
6d
6ee
6f
91
67
78
78
76
45
69
95:5
95:5
95:5
95:5
95:5
94:6
95:5
97:3
93:7
96:4
95:5
95:5
75:25
94:6
t-Bu
Cy
Bn
Ph
Compounds 12 were purified by silica gel chromatogra-
phy and then oxidized to the corresponding chromenones
13. While pyridinium chlorochromate and pyridinium
dichromate oxidation of 12 under various conditions was
less efficient, the mild conditions of the Ley oxidation14
with tetra-n-propylammonium perruthenate (TPAP) and
N-methylmorpholine N-oxide furnished diastereomerical-
ly pure chromenones 13, as expected, with the enantio-
meric enrichment of the starting homoaldol adducts 6
(er 75:25 to 97:3, dr ≥93:7, 63–97% yield).
2-BrC6H4
2-naphthyl 6g
a For reaction conditions, see Scheme 2.
b Ratio Z/E ≥98:2; determined by GC.
c Determined by 1H NMR.
d Determined for the major diastereomer by chiral HPLC (column:
ChiraGrom 1, solvent: n-hexane–i-PrOH 50:1 to 200:1).
e Known compounds: 6a,6 6c,9 and 6e.6
The relative configuration of chromenol rac-12ea and
chromenone 13ba was elucidated by single-crystal X-ray
analysis (Figures 2 and 3).15 The absolute configuration is
concluded from starting material 6, since the methyl-bear-
ing C3 carbon atom does not change its configuration dur-
ing the reaction sequence.
rivatives 7b–h and carbamates 6 were converted into the
diastereomerically pure tetrahydrofurancarbaldehydes 10.
Subsequent desilylation at the aromatic hydroxy group us-
ing tetrabutylammonium fluoride led to spontaneous lac-
tolization of the intermediate aldehydes 11 to give the
Table 2 Synthesis of Tetrahydrofurochromenols 12 and Tetrahydrofurochromenones 13a
Entry
Substrate R1
(er)
Aldehyde R2
Chromenol Yield (%) Chrom-
Yield (%) drb of 13 erc of 13
of 13
of 12
enone
13aa
13ba
13ca
13da
13ea
13fa
13ga
13ab
13ac
13ad
13ae
13af
13ag
13ah
1
2
6a (97:3) i-Pr
6b (93:7) t-Bu
7a
7a
7a
7a
7a
7a
7a
7b
7c
7d
7e
7f
H
12aa
12ba
12ca
12da
12ea
12fa
12ga
12ab
12ac
12ad
95
93
95
92
92
96
75
76
86
92
84
96
97
65
63
95:5
95:5
95:5
95:5
95:5
95:5
95:5
95:5
95:5
95:5
93:7
95:5
95:5
95:5
97:3
93:7
96:4
95:5
94:6
75:25
94:6
97:3
97:3
97:3
>95:5
97:3
97:3
97:3
H
89
3
6c (96:4)
6d (95:5) Bn
6e (95:5) Ph
Cy
H
91
4
H
94
5
H
92d
91d
95
6
6f (75:25) 2-BrC6H4
6g (94:6) 2-naphthyl
6a (97:3) i-Pr
6a (97:3) i-Pr
6a (97:3) i-Pr
6a (97:3) i-Pr
6a (97:3) i-Pr
6a (97:3) i-Pr
6a (97:3) i-Pr
H
7
H
8
3-Me
5-Me
3-Ph
92
9
99
10
11
12
13
14
83
5-Br-3-OMe 12ae
74d
73d
98
4-OMe
5-Cl
12af
12ag
12ah
7g
7h
5-Br
94
a For reaction conditions, see Scheme 3.
b Ratio between major diastereomer and the sum of all minor diastereomers; determined by 1H NMR.
c Determined by chiral HPLC (column: ChiraGrom 2, solvent: n-hexane–i-PrOH, 100:1 to 400:1).
d For entries 5 and 6: 30 min reaction time; for entries 11 and 12: 90 min reaction time.
Synthesis 2006, No. 18, 3111–3121 © Thieme Stuttgart · New York

PAPER
Stereoselective Synthesis of Substituted Tetrahydrofurochromenes
3113
H
O
O
CbO
H
H
H3C
R1
H3C
R1
H3C
R1
+ H2O
OPG
(a)
OTBDPS
= Ar
+
6
R2
O
Ar
OCb
– HOCb
R2
Ar
O
O
7
8
9
10 PG = TBDPS
11 PG = H
(b)
HO
O
H
H
H3C
H3C
O
O
4
3a
(c)
5a
3
2
6
9b
R2
R2
7
R1
R1
O
H
H 9a
O
9
8
12
13
Scheme 3 Synthesis of tetrahydrofurochromenones 13 by Mukaiyama-type cyclizations of (Z)-anti-4-hydroxyalk-1-enyl carbamates 6 and
subsequent lactolization–oxidation. Reagents and conditions: (a) BF3·OEt2, CH2Cl2, 0 °C to r.t., 1 h; (b) TBAF, THF, r.t., 1 h; (c) TPAP, NMO,
activated MS 3Å, MeCN, r.t., 4 h.
R1
R1
CH3 H3C
H
H3C
R1
O
O
H
H
H
O
H
(a)
12
O
R2
+
O
H
O
O
14
R2
15
R2
Scheme 4 Reduction of chromenols 12 by ionic hydrogenation.
Reagents and conditions: (a) Et3SiH, BF3·OEt2, MeCN, 0 °C to r.t., 30
min.
Figure 2 Single-crystal X-ray analysis of chromenol rac-12ea.
the dimerization of the major enantiomers of the homo-
chiral ‘dimerization precursors’.
In conclusion, an elegant and powerful approach to com-
plex tetrahydrofurochromene derivatives, starting from
allyl carbamates and aldehydes, has been developed. A se-
quential asymmetric homoaldol reaction, followed by a
Mukaiyama-type tetrahydrofuran cyclization with O-pro-
tected salicylaldehydes, gave anomeric chromenols in
high yields and with high diastereoselectivities with com-
plete transfer of chirality. Subsequent oxidation or ionic
hydrogenation leads to tetrahydrofurochromenones or
-chromenes, respectively. An expansion of this protocol
for the synthesis of the aza-analogous heterocycles is cur-
rently under investigation and will be reported in due
course.
Figure 3 Single-crystal X-ray analysis of chromenone 13ba.
Reduction of the tetrahydrofurochromenols 12 by ionic
hydrogenation16 with triethylsilane/boron trifluoride–
diethyl ether complex proceeded smoothly to yield the
diastereomerically pure chromenes 14 (Scheme 4,
Table 3). Surprisingly, the enantiomeric ratios differed
from those of the starting homoaldol adducts 6; they were
slightly decreased. In addition, the optically active dimer-
ic acetals 15 were isolated as single diastereomers in 13–
31% yield.
All reactions were performed in flame-dried glassware under argon
atmosphere. Unless otherwise specified, materials were obtained
from commercial sources and used without purification. All sol-
vents were dried according to standard procedures and purified by
distillation prior to use. Flash column chromatography was per-
formed on Merck 60 silica gel, 40–63 mm, or on ICN Biomedicals
aluminum oxide B, activity 1, and monitored by TLC on Merck 60
Fortunately, suitable single-crystals for an X-ray analysis
were obtained from rac-15ea (Figure 4),15,17 which was
isolated as single side product in the reduction of rac-
14ea. It revealed that 15 consists of two homochiral parts,
being connected by an oxido bridge over both the exo fac-
es of the subunits. As expected, due to mutual kinetic re-
solution, the enantiomeric ratios of dimers 15 are higher
than those of the starting materials 12. Consequently, the
decreased enantiomeric ratios of products 14 are due to
F
254 silica gel. Chiral HPLC analyses were carried out with the col-
umns ChiraGrom 1 and ChiraGrom 2, 2 × 250 mm and 2 × 60 mm,
purchased from Grom Analytic and HPLC GmbH, with n-hexane–
i-PrOH solvent mixtures (50:1 to 400:1). Melting points were mea-
sured on a MFB 595 melting point apparatus from Gallenkamp,
UK, and are uncorrected. IR absorption spectra were recorded on a
Nicolet FT-IR 5DXC spectrophotometer. NMR spectra were re-
corded in CDCl3 on a Bruker ARX 300 or AMX 400 spectrometer
Synthesis 2006, No. 18, 3111–3121 © Thieme Stuttgart · New York

3114
A. Brüns et al.
PAPER
Table 3 Ionic Hydrogenation of Tetrahydrofurochromenols 12a
Entry
Substrate (er of 6) R1
Products
Yield (%)
erb
Yield (%)
erb
99:1
1
2
3
4
5
12aa (97:3)
12ba (93:7)
12ca (96:4)
12da (95:5)
12ea (95:5)
i-Pr
14aa
14ba
14ca
14da
14ea
73
81
78
63
65
96:4
92:8
94:6
92:8
92:8
15aa
15ba
15ca
15da
15ea
22
16
13
31
32
t-Bu
Cy
98:2
c
–
Bn
99:1
Ph
>97:3
a For reaction conditions, see Scheme 4.
b Determined by chiral HPLC [column: ChiraGrom 2, solvent: n-hexane–i-PrOH 100:1 (14), 100:1 to 200:1 (15)].
c Not determined.
and dried (MgSO4). The crude product was subjected to flash col-
umn chromatography (silica gel, Et2O–pentane mixtures) to yield
the pure homoaldol adduct 6.
(1Z,3S,4S)-4-Hydroxy-3,5,5-trimethylhex-1-enyl N,N-Diisopro-
pylcarbamate (6b)
White solid; yield: 0.95 g (67%); mp 62–63 °C; [a]D20 –12.4 (c 0.82,
CHCl3); er 93:7.
IR (KBr): 3509, 2976, 1684, 1446, 1295, 1065 cm–1.
1H NMR (300 MHz): d = 0.93 (s, 9 H), 1.12 (d, J = 7.0 Hz, 3 H),
1.26/1.27 (d, J = 6.5 Hz, 12 H), 1.58 (d, J = 5.0 Hz, 1 H), 3.02 (m,
1 H), 3.18 (br s, 1 H), 3.96 (br d, 2 H), 4.95 (dd, J = 10.0, 6.5 Hz, 1
H), 6.98 (d, J = 6.5 Hz, 1 H).
13C NMR (75 MHz): d = 20.5, 20.6, 21.3, 26.5, 31.6, 35.7, 45.9,
46.6, 83.0, 112.4, 134.2, 152.9.
Anal. Calcd for C16H31NO3 (285.42): C, 67.33; H, 10.95; N, 4.91.
Found: C, 67.33; H, 11.01; N, 4.82.
(1Z,3S,4R)-4-Cyclohexyl-4-hydroxy-3-methylbut-1-enyl N,N-
Diisopropylcarbamate (6c)9
Colorless oil; yield: 1.22 g (78%); [a]D +16.1 (c 0.95, CHCl3);
er 96:4.
20
IR (film): 3482, 2923, 1702, 1440, 1306, 1061 cm–1.
1H NMR (300 MHz): d = 1.04 (d, J = 6.9 Hz, 3 H), 1.07–2.00 (m,
23 H), 2.09 (m, 1 H), 3.14 (t, J = 5.8 Hz, 1 H), 3.95 (br d, 2 H), 4.72
(dd, J = 10.0, 6.5 Hz, 1 H), 7.08 (dd, J = 6.5, 0.7 Hz, 1 H).
Figure 4 Single-crystal X-ray analysis of ‘dimeric’ acetal rac-15ea.
13C NMR (75 MHz): d = 17.9, 20.5, 21.3, 26.1, 26.4, 26.5, 27.1,
with TMS as internal standard. Elemental analyses were performed
on an Elementar Analysensysteme Vario El III analyzer. Optical ro-
tations were measured using a Perkin-Elmer 341 polarimeter, exact
mass measurements were carried out on a Micromass Quattro LCZ.
30.0, 33.0, 40.6, 46.0, 46.6, 79.4, 112.5, 136.0, 152.8.
Anal. Calcd for C18H33NO3 (311.46): C, 69.41; H, 10.68; N, 4.50.
Found: C, 69.34; H, 10.79; N, 4.42.
(1Z,3S,4R)-4-Hydroxy-3-methyl-5-phenylpent-1-enyl N,N-Di-
Homoaldol Reaction of 3; General Procedure
isopropylcarbamate (6d)
Colorless oil; yield: 1.24 g (78%); [a]D +29.0 (c 1.25, CHCl3);
er 95:5.
In a 3-necked flask with cooled dropping funnel and mechanical
stirrer carbamate 36 (0.997 g, 5.0 mmol) and (–)-sparteine (1.23 g,
5.25 mmol) were dissolved in a mixture of n-pentane (7 mL) and cy-
clohexane (1 mL) and cooled to –78 °C; 1.6 M n-BuLi in n-hexane
(3.44 mL, 5.5 mmol) was added dropwise. The mixture was stirred
for 2 h and a soln of Ti(Oi-Pr)4 (4.26 g, 15.0 mmol) in n-pentane (15
mL), precooled to –78 °C, was added. After a transmetalation time
of 30 min, a soln of the aldehyde (10.0 mmol) in n-pentane (2 mL)
was added at –78 °C, and stirring was continued for an additional 2
h. The soln was warmed to r.t., t-BuOMe (10 mL) was added and
the mixture was poured into 2 M HCl (50 mL). The aqueous layer
was separated and extracted with t-BuOMe (3 × 50 mL). The com-
bined organic extracts were washed with sat. NaHCO3 soln (20 mL)
20
IR (film): 3455, 2971, 1715, 1301, 1066, 762 cm–1.
1H NMR (300 MHz): d = 1.12 (d, J = 7.0 Hz, 3 H), 1.21/1.23 (d,
J = 6.7 Hz, 12 H), 1.59 (br s, 1 H), 2.68 (dd, J = 13.8, 8.6 Hz, 1 H),
2.73–2.90 (m, 2 H), 3.73 (m, J = 8.6, 4.4 Hz, 1 H), 3.88 (br d, 2 H),
4.80 (dd, J = 9.9, 6.5 Hz, 1 H), 7.13 (d, J = 6.5 Hz, 1 H), 7.15–7.35
(m, 5 H).
13C NMR (75 MHz): d = 17.5, 20.5, 21.5, 35.6, 41.2, 45.9, 46.6,
75.8, 111.8, 126.3, 128.4, 129.5, 136.1, 138.7, 152.8.
Synthesis 2006, No. 18, 3111–3121 © Thieme Stuttgart · New York

PAPER
Stereoselective Synthesis of Substituted Tetrahydrofurochromenes
3115
Anal. Calcd for C19H29NO3 (319.44): C, 71.44; H, 9.15; N, 4.38.
Found: C, 71.81; H, 9.52; N, 4.54.
13C NMR (75 MHz): d = 19.6, 20.3, 26.5, 120.1, 126.3, 128.0,
128.1, 130.2, 131.9, 135.4, 136.2, 156.7, 190.1.
Anal. Calcd for C24H26O2Si (374.55): C, 76.96; H, 7.00. Found: C,
76.99; H, 7.01.
(1Z,3S,4S)-4-(2-Bromophenyl)-4-hydroxy-3-methylbut-1-enyl
N,N-Diisopropylcarbamate (6f)
Pale yellow solid; yield: 0.89 g (45%); mp 63–65 °C; [a]D20 –15.3
(c 0.17, CHCl3); er 75:25.
2-(tert-Butyldiphenylsilyloxy)-4-methoxybenzaldehyde (7f)
White solid; yield: 1.54 g (79%); mp 118 °C.
IR (KBr): 2943, 1681, 1594, 1260, 1102, 982, 826 cm–1.
1H NMR (300 MHz): d = 1.14 (s, 9 H), 3.33 (s, 3 H), 5.94 (d, J = 2.3
Hz, 1 H), 6.47 (ddd, J = 8.8, 2.3, 0.8 Hz, 1 H), 7.36–7.50 (m, 6 H),
7.74 (dd, 4 H), 7.78 (d, J = 8.8 Hz, 1 H), 10.61 (d, J = 0.8 Hz, 1 H).
13C NMR (100 MHz): d = 19.7, 26.4, 55.1, 104.5, 108.9, 120.6,
128.1, 129.8, 130.4, 131.8, 135.4, 160.7, 165.3, 188.4.
IR (film): 3447, 2966, 1682, 1323, 1059, 756 cm–1.
1H NMR (300 MHz): d = 1.11 (d, J = 6.9 Hz, 3 H), 1.19 (d, J = 6.8
Hz, 12 H), 2.22 (d, J = 3.0 Hz, 1 H), 3.10 (m, 1 H), 3.82 (br d, 2 H),
4.80 (dd, J = 10.1, 6.5 Hz, 1 H), 4.97 (dd, J = 5.3, 3.0 Hz, 1 H), 7.01
(dd, J = 6.5, 0.8 Hz, 1 H), 7.08 (m, 1 H), 7.30 (m, 1 H), 7.45–7.50
(m, 2 H).
13C NMR (75 MHz): d = 18.1, 20.3, 21.4, 37.2, 46.0, 46.6, 76.2,
111.0, 122.6, 127.4, 128.2, 128.6, 132.3, 136.4, 142.2, 152.5.
Anal. Calcd for C24H26O3Si (390.55): C, 73.81; H, 6.71. Found: C,
73.80; H, 6.76.
Anal. Calcd for C18H26BrNO3 (384.31): C, 56.26; H, 6.82; N, 3.64.
Found: C, 55.89; H, 6.56; N, 3.38.
2-(tert-Butyldiphenylsilyloxy)-5-chlorobenzaldehyde (7g)
White solid; yield: 1.51 g (77%); mp 111 °C.
IR (KBr): 2956, 1687, 1472, 1273, 1115, 873, 703 cm–1.
1H NMR (400 MHz): d = 1.12 (s, 9 H), 6.44 (d, J = 8.9 Hz, 1 H),
7.06 (dd, J = 8.9, 2.8 Hz, 1 H), 7.37–7.50 (m, 6 H), 7.70 (dd, 4 H),
7.77 (d, J = 2.8 Hz, 1 H), 10.68 (s, 1 H).
(1Z,3S,4S)-4-Hydroxy-3-methyl-4-(2-naphthyl)but-1-enyl N,N-
Diisopropylcarbamate (6g)
Colorless oil; yield: 1.22 g (69%); [a]D –46.8 (c 0.90, CHCl3);
er 94:6.
20
IR (film): 3442, 2979, 1682, 1308, 1057, 758 cm–1.
13C NMR (100 MHz): d = 19.6, 26.4, 121.3, 126.9, 127.5 127.8,
128.2, 130.5, 131.2, 135.0, 135.3, 157.1, 188.6.
1H NMR (400 MHz): d = 1.07 (d, J = 6.9 Hz, 3 H), 1.20 (br d, 12
H), 2.40 (br s, 1 H), 3.15 (m, 1 H), 3.87 (br d, 2 H), 4.64 (dd, J = 9.8,
6.5 Hz, 1 H), 4.73 (d, J = 6.0 Hz, 1 H), 6.91 (d, J = 6.5 Hz, 1 H),
7.36–7.51 (m, 3 H), 7.70–7.85 (m, 4 H).
Anal. Calcd for C23H23ClO2Si (394.97): C, 69.94; H, 5.87. Found:
C, 69.88; H, 5.84.
13C NMR (100 MHz): d = 16.0, 20.3, 21.4, 37.6, 45.8, 46.7, 77.7,
112.7, 124.6, 125.1, 125.6, 125.9, 127.5, 127.5, 127.9, 132.8, 133.0,
135.1, 140.4, 152.6.
5-Bromo-2-(tert-butyldiphenylsilyloxy)benzaldehyde (7h)
White solid; yield: 1.81 g (82%); mp 106 °C.
IR (KBr): 2959, 1683, 1470, 1267, 1118, 815, 701 cm–1.
1H NMR (400 MHz): d = 1.11 (s, 9 H), 6.39 (d, J = 8.9 Hz, 1 H),
7.20 (dd, J = 8.9, 2.7 Hz, 1 H), 7.37–7.50 (m, 6 H), 7.70 (dd, 4 H),
7.92 (d, J = 2.7 Hz, 1 H), 10.68 (s, 1 H).
13C NMR (100 MHz): d = 19.6, 26.4, 114.1, 122.2, 128.9, 128.2,
130.5, 130.9, 131.2, 135.3, 137.8, 157.6, 188.5.
Anal. Calcd for C22H29NO3 (355.47): C, 74.33; H, 8.22; N, 3.94.
Found: C, 74.32; H, 8.40; N, 3.78.
O-tert-Butyldiphenylsilyl Protection of Salicylaldehydes;
General Procedure, Method A
A stirred soln of the salicylaldehyde (5.0 mmol), DMAP (0.064 g,
0.5 mmol), and Et3N (1.1 mL, 7.5 mmol) in CH2Cl2 (10 mL) at 0 °C
was treated dropwise with TBDPSCl (1.38 mL, 5.25 mmol). The
mixture was stirred at r.t. for 12 h and then sat. NaHCO3 soln (10
mL) was added. The aqueous layer was extracted with t-BuOMe
(3 × 30 mL) and the combined organic extracts were dried
(Na2SO4). The crude product was purified by flash column chroma-
tography on aluminum oxide B (Et2O–pentane mixtures).
Anal. Calcd for C23H23BrO2Si (439.42): C, 62.87; H, 5.28. Found:
C, 62.71; H, 5.28.
O-tert-Butyldiphenylsilyl Protection of Salicylaldehydes;
General Procedure, Method B
To a stirred soln of salicylaldehyde (5.0 mmol), imidazole (0.375 g,
5.5 mmol), and Et3N (1.1 mL, 7.5 mmol) in DMF (10 mL) was add-
ed dropwise TBDPSCl (1.38 mL, 5.25 mmol). The mixture was
stirred at r.t. for 16–24 h until TLC analysis showed complete con-
version. Workup and purification was performed as described in
Method A.
2-(tert-Butyldiphenylsilyloxy)benzaldehyde (7a)
White solid; yield: 1.78 g (99%); mp 84 °C.
IR (KBr): 3048, 2930, 1688, 1247, 1106, 922, 703 cm–1.
1H NMR (300 MHz): d = 1.13 (s, 9 H), 6.52 (dd, J = 8.4, 0.9 Hz, 1
H), 6.92 (ddd, J = 7.8, 7.3, 0.8 Hz, 1 H), 7.11 (ddd, J = 8.4, 7.3, 1.9
Hz, 1 H), 7.33–7.49 (m, 6 H), 7.73 (dd, 4 H), 7.83 (dd, J = 7.8, 1.9
Hz, 1 H), 10.79 (d, J = 0.8 Hz, 1 H).
13C NMR (75 MHz): d = 16.6, 26.4, 120.3, 121.3, 126.7, 128.0,
128.3, 130.3, 131.7, 135.3, 135.3, 158.6, 189.8.
2-(tert-Butyldiphenylsilyloxy)-3-methylbenzaldehyde (7b)
Colorless oil; yield: 1.05 g (56%).
IR (film): 2959, 1678, 1470, 1222, 1115, 920, 704 cm–1.
1H NMR (400 MHz): d = 1.13 (s, 9 H), 2.10 (s, 3 H), 6.91 (dd,
J = 7.9, 7.4 Hz, 1 H), 7.28 (dd, J = 7.4, 1.9 Hz, 1 H), 7.32–7.46 (m,
6 H), 7.58 (dd, J = 7.9, 1.9 Hz, 1 H), 7.69 (dd, 4 H), 10.21 (d, 1 H).
13C NMR (100 MHz): d = 18.2, 20.4, 26.7, 121.7, 126.1, 127.1,
127.2, 127.9, 130.2, 132.0, 135.3, 137.4, 157.0, 189.5.
Anal. Calcd for C23H24O2Si (360.52): C, 76.62; H, 6.71. Found: C,
76.28; H, 6.67.
2-(tert-Butyldiphenylsilyloxy)-5-methylbenzaldehyde (7c)
Anal. Calcd for C24H26O2Si (374.55): C, 76.96; H, 7.00. Found: C,
76.93; H, 6.99.
White solid; yield: 1.55 g (83%); mp 56–57 °C.
IR (KBr): 3050, 2929, 1680, 1246, 1115, 903, 699 cm–1.
1H NMR (300 MHz): d = 1.11 (s, 9 H); 2.22 (s, 3 H), 6.41 (d, J = 8.5
Hz, 1 H), 6.94 (dd, J = 8.5, 2.3 Hz, 1 H), 7.33–7.49 (m, 6 H), 7.62
(d, J = 2.3 Hz, 1 H), 7.72 (dd, 4 H), 11.75 (s, 1 H).
2-(tert-Butyldiphenylsilyloxy)-3-phenylbenzaldehyde (7d)18
White solid; yield: 1.43 g (66%); mp 171–172 °C.
Synthesis 2006, No. 18, 3111–3121 © Thieme Stuttgart · New York

3116
A. Brüns et al.
PAPER
IR (KBr): 2950, 1681, 1401, 1246, 1114, 920, 699 cm–1.
3.95 (br s, 1 H), 4.78 (d, J = 5.9 Hz, 1 H), 5.03 (d, J = 7.9 Hz, 1 H),
6.80–7.50 (m, 4 H).
13C NMR (100 MHz): d = 20.5, 26.3, 33.5, 36.0, 51.9, 72.7, 94.2,
94.8, 116.9, 121.5, 121.7, 129.3, 130.4, 152.3.
1H NMR (400 MHz): d = 0.78 (s, 9 H), 7.07 (ddd, J = 7.7, 7.5, 0.8
Hz, 1 H), 7.23–7.54 (m, 15 H), 7.50 (dd, J = 7.5, 2.0 Hz, 1 H), 7.58
(dd, J = 7.7, 2.0 Hz, 1 H), 9.86 (d, J = 0.8 Hz, 1 H).
13C NMR (100 MHz): d = 19.1, 26.2, 122.1, 127.3, 127.5, 127.8,
128.2, 128.4, 130.0, 130.2, 131.2, 135.4, 135.6, 137.2, 138.3, 155.4,
188.0.
Anal. Calcd for C16H22O3 (262.34): C, 73.25; H, 8.45. Found: C,
73.21; H, 8.48.
(2R,3S,3aS,9bR)-2-Cyclohexyl-3-methyl-2,3,3a,9b-tetrahydro-
4H-furo[3,2-c]chromen-4-ol (12ca)
Anal. Calcd for C29H28O2Si (436.62): C, 79.77; H, 6.48. Found: C,
79.59; H, 6.52.
White solid; yield: 0.526 g (91%); mp 135 °C; [a]D20 +11.7 (c 0.98,
CHCl3).
5-Bromo-2-(tert-butyldiphenylsilyloxy)-3-methoxybenzalde-
hyde (7e)
IR (KBr): 3313, 2929, 1451, 1242, 1159, 1057, 755 cm–1.
Pale yellow solid; yield: 0.93 g (40%); mp 102 °C.
IR (KBr): 2956, 1692, 1485, 1263, 1117, 845, 699 cm–1.
1H NMR (400 MHz): d = 1.06 (s, 9 H), 2.90 (s, 3 H), 6.84 (d, J = 2.4
Hz, 1 H), 7.32–7.43 (m, 6 H), 7.54 (d, J = 2.4 Hz, 1 H), 7.66 (dd, 4
H), 10.68 (s, 1 H).
1H NMR (400 MHz): d = 0.90–2.05 (m, 12 H), 1.18 (d, J = 6.8 Hz,
3 H), 2.00 (m, J = 7.4, 6.1 Hz, 1 H), 3.31 (d, J = 7.0 Hz, 1 H), 3.33
(br s, 1 H), 4.82 (d, J = 6.1 Hz, 1 H), 5.07 (d, J = 7.4 Hz, 1 H), 6.83–
7.45 (m, 4 H).
13C NMR (100 MHz): d = 19.2, 26.0, 26.2, 26.5, 29.3, 29.4, 38.2,
42.2, 51.4, 72.7, 90.5, 94.9, 116.9, 121.6, 122.0, 129.4, 130.5,
152.0.
13C NMR (100 MHz): d = 20.3, 26.6, 54.3, 113.7, 119.9, 121.7,
127.5, 127.9, 129.6, 133.4, 134.3, 148.4, 150.9, 188.5.
Anal. Calcd for C18H24O3 (288.38): C, 74.97; H, 8.39. Found: C,
74.79; H, 8.56.
Anal. Calcd for C24H25BrO3Si (469.44): C, 61.40; H, 5.37. Found:
C, 61.01; H, 5.41.
(2R,3S,3aS,9bR)-2-Benzyl-3-methyl-2,3,3a,9b-tetrahydro-4H-
furo[3,2-c]chromen-4-ol (12da)
Mukaiyama-Type Cyclization of Homoaldol Adducts 6;
General Procedure
Colorless oil; yield: 0.556 g (94%); [a]D20 +35.3 (c 0.97, CHCl3).
A soln of homoaldol adduct 6 (2.0 mmol) and O-TBDPS-protected
salicylaldehyde 7 (2.2 mmol) in CH2Cl2 (3 mL) at 0 °C was treated
dropwise with BF3·OEt2 (0.28 mL, 2.2 mmol). The mixture was
then warmed to r.t. and stirred for 60 min. Sat. NaCl soln (20 mL)
was added and the aqueous layer was extracted with t-BuOMe
(3 × 40 mL) and the combined organic extracts were dried
(MgSO4). The solvents were evaporated in vacuo and the crude
product was dissolved in THF (10 mL). The soln was treated with 1
M TBAF in THF (4.0 mL, 4.0 mmol) at r.t. and stirred for 1 h. Then
H2O (10 mL) and t-BuOMe (10 mL) were added, the aqueous layer
was extracted with t-BuOMe (3 × 20 mL), the combined organic
phases were dried (MgSO4), and the solvent was removed under re-
duced pressure. The residue was purified by flash column chroma-
tography (silica gel, Et2O–pentane mixtures) to give chromenol
12.19
IR (film): 3339, 2961, 1460, 1235, 1136, 949, 754 cm–1.
1H NMR (400 MHz): d = 1.01 (d, J = 6.8 Hz, 3 H), 1.99 (m, 1 H),
2.10 (q, J = 6.8 Hz, 1 H), 2.75 (dd, J = 13.8, 5.4 Hz, 1 H), 2.85 (dd,
J = 13.8, 6.9 Hz, 1 H), 3.23 (d, J = 4.5 Hz, 1 H), 3.77 (m, 1 H), 4.90
(d, J = 6.9 Hz, 1 H), 5.06 (d, J = 5.8 Hz, 1 H), 6.83–7.47 (m, 9 H).
13C NMR (100 MHz): d = 17.2, 40.1, 41.0, 41.1, 50.8, 72.6, 86.6,
94.9, 117.1, 121.8, 122.6, 126.3, 128.2, 129.4, 129.3, 130.2, 138.3,
151.3.
Anal. Calcd for C19H20O3 (296.36): C, 77.00; H, 6.80. Found: C,
76.78; H, 7.81.
(2S,3S,3aS,9bR)-3-Methyl-2-phenyl-2,3,3a,9b-tetrahydro-4H-
furo[3,2-c]chromen-4-ol (12ea)
White solid; yield: 0.521 g (92%); mp 159–161 °C; [a]D20 –48.7 (c
0.98, CHCl3).
(2R,3S,3aS,9bR)-2-Isopropyl-3-methyl-2,3,3a,9b-tetrahydro-
4H-furo[3,2-c]chromen-4-ol (12aa)
IR (KBr): 3408, 2919, 1454, 1112, 1011, 871, 757 cm–1.
Colorless liquid; yield: 0.471 g (95%); [a]D20 +23.8 (c 1.04, CHCl3).
1H NMR (400 MHz): d = 1.20 (d, J = 6.7 Hz, 3 H), 2.13 (m, 1 H),
2.35 (dt, J = 7.5, 5.0 Hz, 1 H), 3.09 (d, J = 4.8 Hz, 1 H), 4.40 (d,
J = 9.0 Hz, 1 H), 5.15 (d, J = 7.5 Hz, 1 H), 5.30 (d, J = 5.0 Hz, 1 H),
6.88–7.53 (m, 9 H).
13C NMR (100 MHz): d = 15.8, 44.9, 50.6, 73.0, 88.4, 94.7, 117.2,
122.1, 122.7, 127.8, 126.4, 128.3, 129.4, 130.3, 140.6, 150.9.
IR (film): 3377, 2963, 1455, 1239, 1146, 1031, 759 cm–1.
1H NMR (400 MHz): d = 0.89/0.90 (d, J = 6.9 Hz, 6 H), 1.18 (d,
J = 6.6 Hz, 3 H), 1.65 (m, 1 H), 2.06 (m, 2 H), 3.32 (dd, J = 7.1, 6.4
Hz, 1 H), 3.64 (br d, 1 H), 4.86 (d, J = 5.9 Hz, 1 H), 5.10 (br d, 1 H),
6.83–7.45 (m, 4 H).
13C NMR (100 MHz): d = 18.8, 18.9, 18.9, 32.2, 38.3, 51.3, 72.6,
91.3, 94.7, 116.9, 121.6, 121.6, 129.3, 130.4, 151.7.
Anal. Calcd for C18H18O3 (282.33): C, 76.57; H, 6.43. Found: C,
76.28; H, 6.27.
Anal. Calcd for C15H20O3 (248.32): C, 72.55; H, 8.12. Found: C,
72.15; H, 8.20.
X-ray crystal structure analysis for rac-12ea: formula C18H18O3,
M = 282.32,
colorless
crystal
0.45 × 0.30 × 0.25
mm,
a = 10.474(1), b = 16.381(1), c = 9.189(1) Å, b = 113.82(1)°,
V = 1442.3(2) Å3, rcalc = 1.300 g cm–3, m = 0.705 mm–1, empirical
absorption correction (0.742 £ T £ 0.844), Z = 4, monoclinic, space
group P21/c (No. 14), l = 1.54178 Å, T = 223 K, w and j scans,
3678 reflections collected ( h, k, l), [(sinq)/l] = 0.58 Å–1, 2348
independent (Rint = 0.023) and 2020 observed reflections [I ≥ 2
s(I)], 193 refined parameters, R = 0.042, wR2 = 0.127, max. residu-
al electron density 0.19 (–0.20) e Å–3, hydrogen atoms calculated
and refined as riding atoms.
(2S,3S,3aS,9bR)-2-tert-Butyl-3-methyl-2,3,3a,9b-tetrahydro-
4H-furo[3,2-c]chromen-4-ol (12ba)
White solid; yield: 0.465 g (89%); mp 100 °C; [a]D20 +46.0 (c 1.07,
CHCl3).
IR (KBr): 3359, 2973, 1466, 1241, 1148, 999, 757 cm–1.
1H NMR (400 MHz): d = 0.88 (s, 9 H), 1.20 (d, J = 6.9 Hz, 3 H),
1.98 (m, 1 H), 2.18 (sext, J = 7.4 Hz, 1 H), 3.28 (d, J = 7.4 Hz, 1 H),
Synthesis 2006, No. 18, 3111–3121 © Thieme Stuttgart · New York

PAPER
Stereoselective Synthesis of Substituted Tetrahydrofurochromenes
3117
(2S,3S,3aS,9bR)-2-(2-Bromophenyl)-3-methyl-2,3,3a,9b-tetra-
hydro-4H-furo[3,2-c]chromen-4-ol (12fa)
White solid; yield: 0.659 g (91%); mp 118 °C; [a]D20 –24.7 (c 1.21,
CHCl3).
(2R,3S,3aS,9bR)-2-Isopropyl-3-methyl-6-phenyl-2,3,3a,9b-
tetrahydro-4H-furo[3,2-c]chromen-4-ol (12ad)
Colorless oil; yield: 0.268 g (83%) from 1.0 mmol of 6a; [a]D
+50.9 (c 0.47, CHCl3).
20
IR (KBr): 3437, 2927, 1456, 1195, 1107, 1013, 754 cm–1.
IR (film): 3357, 2958, 1459, 1228, 1079, 989, 758 cm–1.
1H NMR (400 MHz): d = 1.29 (d, J = 6.8 Hz, 3 H), 2.17 (m, 1 H),
2.32–2.39 (m, J = 7.5 Hz, 1 H), 3.61 (d, J = 4.9 Hz, 1 H), 5.10 (d,
J = 8.4 Hz, 1 H), 5.18 (d, J = 7.5 Hz, 1 H), 5.25 (d, J = 5.2 Hz, 1 H),
6.87–7.55 (m, 8 H).
1H NMR (400 MHz): d = 0.89/0.91 (d, J = 6.8 Hz, 6 H), 1.15 (d,
J = 6.7 Hz, 3 H), 1.66 (sext, J = 6.8 Hz, 1 H), 1.96–2.13 (m, 2 H),
3.29 (t, J = 6.8 Hz, 1 H), 3.58 (br s, 1 H), 4.86 (d, J = 6.1 Hz, 1 H),
4.95 (d, J = 6.9 Hz, 1 H), 6.99–7.60 (m, 8 H).
13C NMR (100 MHz): d = 16.3, 45.9, 50.6, 73.2, 85.8, 94.5, 117.3,
122.1, 122.5, 122.9, 128.6, 129.0, 129.5, 130.3, 132.5, 132.5, 140.1,
150.9.
13C NMR (100 MHz): d = 18.8, 19.0, 19.0, 32.2, 38.7, 51.2, 72.9,
91.2, 95.1, 121.4, 122.7, 126.9, 127.9, 129.5, 129.7, 130.5, 131.4,
138.1, 150.2.
Anal. Calcd for C18H17BrO3 (361.23): C, 59.85; H, 4.74. Found: C,
59.84; H, 4.72.
HRMS-ESI: m/z [M + Na]+ calcd for C21H24NaO3: 347.1623; found:
347.1618.
(2S,3S,3aS,9bR)-3-Methyl-2-(2-naphthyl)-2,3,3a,9b-tetrahy-
dro-4H-furo[3,2-c]chromen-4-ol (12ga)
(2R,3S,3aS,9bR)-8-Bromo-2-isopropyl-6-methoxy-3-methyl-
2,3,3a,9b-tetrahydro-4H-furo[3,2-c]chromen-4-ol (12ae)
White solid; yield: 0.198 g (74%) from 0.75 mmol of 6a; [a]D
–14.1 (c 0.56, CHCl3).
20
Colorless oil; yield: 0.629 g (95%); [a]D20 –20.8 (c 0.90, CHCl3).
IR (film): 3383, 3052, 1458, 1215, 1111, 990, 757 cm–1.
IR (KBr): 3480, 2957, 1487, 1228, 1154, 1024, 838 cm–1.
1H NMR (400 MHz): d = 1.18 (d, J = 6.7 Hz, 3 H), 2.18 (m, 1 H),
2.35 (dt, J = 6.4, 5.5 Hz, 1 H), 3.51 (d, J = 5.0 Hz, 1 H), 4.66 (d,
J = 8.9 Hz, 1 H), 5.18 (d, J = 7.4 Hz, 1 H), 5.28 (d, J = 5.5 Hz, 1 H),
6.87–7.84 (m, 11 H).
13C NMR (100 MHz): d = 15.8, 44.8, 50.6, 73.2, 88.5, 94.6, 117.2,
122.1, 122.7, 124.2, 125.5, 125.8, 126.0, 127.6, 127.8, 128.3, 129.5,
130.4, 133.1, 133.1, 138.0, 151.0.
1H NMR (400 MHz): d = 0.87/0.91 (d, J = 6.7 Hz, 6 H), 1.17 (d,
J = 6.7 Hz, 3 H), 1.60 (sext, J = 6.2 Hz, 1 H), 2.03 (m, 1 H), 2.13
(m, 1 H), 3.33 (dd, J = 7.8, 6.2 Hz, 1 H), 3.83 (s, 3 H), 4.48 (br s, 1
H), 4.85 (d, J = 6.7 Hz, 1 H), 5.24 (d, J = 5.9 Hz, 1 H), 6.89 (d,
J = 2.2 Hz, 1 H), 7.17 (d, J = 2.2 Hz, 1 H).
13C NMR (100 MHz): d = 18.4, 18.5, 19.1, 32.1, 38.2, 51.7, 56.1,
71.7, 91.4, 94.9, 113.2, 114.2, 122.8, 124.4, 139.9, 148.9.
Anal. Calcd for C22H20O3 (332.39): C, 79.50; H, 6.06. Found: C,
79.43; H, 6.07.
Anal. Calcd for C16H21BrO4 (357.27): C, 53.79; H, 5.93. Found: C,
53.89; H, 6.07.
(2R,3S,3aS,9bR)-2-Isopropyl-3,6-dimethyl-2,3,3a,9b-tetrahy-
dro-4H-furo[3,2-c]chromen-4-ol (12ab)
(2R,3S,3aS,9bR)-2-Isopropyl-7-methoxy-3-methyl-2,3,3a,9b-
tetrahydro-4H-furo[3,2-c]chromen-4-ol (12af)
White solid; yield: 0.203 g (73%) from 1.0 mmol of 6a; mp 89 °C;
[a]D20 +14.4 (c 0.96, CHCl3).
White solid; yield: 0.241 g (92%) from 1.0 mmol of 6a; mp 92–
93 °C; [a]D20 +25.9 (c 0.93, CHCl3).
IR (KBr): 3403, 2966, 1472, 1222, 1150, 977, 749 cm–1.
IR (KBr): 3384, 2963, 1625, 1508, 1441, 1282, 1143, 991, 829
cm–1.
1H NMR (400 MHz): d = 0.91/0.92 (d, J = 6.2 Hz, 6 H), 1.19 (d,
J = 6.9 Hz, 3 H), 1.67 (sext, J = 6.7 Hz, 1 H), 1.99 (m, 1 H), 2.09
(m, 1 H), 2.21 (s, 3 H), 3.30 (dd, J = 7.2, 6.7 Hz, 1 H), 3.49 (br s, 1
H), 4.82 (d, J = 6.2 Hz, 1 H), 5.07 (d, J = 7.4 Hz, 1 H), 6.87 (t,
J = 7.0 Hz, 1 H), 7.07 (d, 1 H), 7.25 (d, J = 7.8 Hz, 1 H).
13C NMR (100 MHz): d = 16.0, 18.9, 18.9, 19.2, 32.3, 38.4, 51.5,
73.0, 91.2, 95.0, 120.9, 121.4, 126.0, 127.9, 130.4, 150.2.
1H NMR (400 MHz): d = 0.89/0.90 (d, J = 6.7 Hz, 6 H), 1.17 (d,
J = 6.8 Hz, 3 H), 1.66 (sext, J = 6.7 Hz, 1 H), 1.98 (m, 1 H), 2.06
(m, 1 H), 3.29 (dd, J = 7.0, 6.7 Hz, 1 H), 3.74 (s, 3 H), 3.74 (br s, 1
H), 4.79 (d, J = 6.1 Hz, 1 H), 5.06 (d, J = 7.2 Hz, 1 H), 6.39 (d,
J = 2.5 Hz, 1 H), 6.54 (dd, J = 8.5, 2.5 Hz, 1 H), 7.29 (d, J = 8.5 Hz,
1 H).
Anal. Calcd for C16H22O3 (262.34): C, 73.25; H, 8.45. Found: C,
73.01; H, 8.46.
13C NMR (100 MHz): d = 18.8, 18.9, 19.1, 32.2, 38.3, 51.3, 55.2,
72.5, 91.2, 95.0, 101.5, 108.6, 114.4, 131.1, 153.0, 161.3.
(2R,3S,3aS,9bR)-2-Isopropyl-3,8-dimethyl-2,3,3a,9b-tetrahy-
dro-4H-furo[3,2-c]chromen-4-ol (12ac)
Anal. Calcd for C16H22O4 (278.34): C, 69.04; H, 7.97. Found: C,
68.69; H, 8.00.
Colorless oil; yield: 0.260 g (99%) from 1.0 mmol of 6a; [a]D20 –9.1
(c 0.99, CHCl3).
(2R,3S,3aS,9bR)-8-Chloro-2-isopropyl-3-methyl-2,3,3a,9b-
tetrahydro-4H-furo[3,2-c]chromen-4-ol (12ag)
Colorless oil; yield: 0.276 g (98%) from 1.0 mmol of 6a; [a]D
–13.4 (c 1.00, CHCl3).
IR (film): 3384, 2962, 1465, 1236, 1144, 1020, 817 cm–1.
20
1H NMR (400 MHz): d = 0.91 (t, J = 6.8 Hz, 6 H), 1.19 (d, J = 6.8
Hz, 3 H), 1.68 (m, J = 6.8, 6.4 Hz, 1 H), 2.01 (m, 1 H), 2.08 (m, 1
H), 2.27 (s, 3 H), 3.31 (dd, J = 7.4, 6.4 Hz, 1 H), 3.32 (br s, 1 H),
4.80 (d, J = 6.2 Hz, 1 H), 5.05 (d, J = 7.2 Hz, 1 H), 6.77 (d, J = 8.5
Hz, 1 H), 7.01 (dd, J = 8.5, 2.2 Hz, 1 H), 7.22 (d, J = 2.2 Hz, 1 H).
13C NMR (100 MHz): d = 18.8, 19.1, 19.1, 20.5, 32.1, 38.3, 51.6,
72.8, 91.3, 94.9, 116.7, 121.7, 130.1, 130.6, 131.2, 149.7.
IR (film): 3356, 2959, 1481, 1214, 1105, 1011, 825 cm–1.
1H NMR (400 MHz): d = 0.87/0.91 (d, J = 6.7 Hz, 6 H), 1.17 (d,
J = 6.5 Hz, 3 H), 1.64 (sext, J = 6.7 Hz, 1 H), 1.99–2.10 (m, 2 H),
3.33 (dd, J = 7.3, 6.3 Hz, 1 H), 3.64 (d, J = 4.7 Hz, 1 H), 4.82 (d,
J = 6.1 Hz, 1 H), 5.11 (d, J = 5.9 Hz, 1 H), 6.79 (d, J = 8.8 Hz, 1 H),
7.14 (dd, J = 8.8, 2.6 Hz, 1 H), 7.39 (d, J = 2.6 Hz, 1 H).
13C NMR (100 MHz): d = 18.6, 18.6, 19.0, 32.1, 38.2, 51.0, 72.0,
91.4, 94.8, 118.4, 124.0, 126.5, 129.4, 129.9, 150.1.
Anal. Calcd for C16H22O3 (262.34): C, 73.25; H, 8.45. Found: C,
73.13; H, 8.49.
Anal. Calcd for C15H19ClO3 (282.76): C, 63.71; H, 6.77. Found: C,
63.66; H, 6.81.
Synthesis 2006, No. 18, 3111–3121 © Thieme Stuttgart · New York

3118
A. Brüns et al.
PAPER
(2R,3S,3aS,9bR)-8-Bromo-2-isopropyl-3-methyl-2,3,3a,9b-
tetrahydro-4H-furo[3,2-c]chromen-4-ol (12ah)
Colorless oil; yield: 0.306 g (94%) from 1.0 mmol of 6a; [a]D
–20.2 (c 0.82, CHCl3).
wR2 = 0.094, Flack parameter 0.01(17), max. residual electron den-
sity 0.17 (–0.11) e Å–3, hydrogen atoms calculated and refined as
riding atoms.
20
(2R,3S,3aS,9bR)-2-Cyclohexyl-3-methyl-2,3,3a,9b-tetrahydro-
4H-furo[3,2-c]chromen-4-one (13ca)
IR (film): 3377, 2961, 1478, 1239, 1147, 1014, 818 cm–1.
1H NMR (400 MHz): d = 0.87/0.91 (d, J = 6.9 Hz, 6 H), 1.18 (d,
J = 6.6 Hz, 3 H), 1.64 (sext, J = 6.2 Hz, 1 H), 1.99–2.10 (m, 2 H),
3.32 (dd, J = 6.9, 6.2 Hz, 1 H), 3.40 (br s, 1 H), 4.82 (d, J = 6.0 Hz,
1 H), 5.11 (d, J = 6.1 Hz, 1 H), 6.74 (d, J = 8.7 Hz, 1 H), 7.23 (dd,
J = 8.7, 2.4 Hz, 1 H), 7.53 (d, J = 2.4 Hz, 1 H).
13C NMR (100 MHz): d = 18.6, 18.7, 19.0, 32.1, 38.2, 51.0, 72.0,
91.4, 94.8, 113.8, 118.9, 124.5, 132.3, 132.9, 150.7.
White solid; yield: 0.079 g (92%); mp 119 °C; [a]D20 –21.6 (c 0.64,
CHCl3); er 96:4.
IR (KBr): 2927, 1755, 1463, 1222, 1161, 1015, 769 cm–1.
1H NMR (400 MHz): d = 0.86–1.83 (m, 11 H), 1.26 (d, J = 6.9 Hz,
3 H), 2.69 (m, 1 H), 2.86 (dd, J = 6.2, 5.2 Hz, 1 H), 3.37 (t, J = 6.6
Hz, 1 H), 4.95 (d, J = 6.2 Hz, 1 H), 7.06 (dd, J = 8.1, 1.1 Hz, 1 H),
7.18 (dt, J = 7.5, 1.1 Hz, 1 H), 7.35 (m, 1 H), 7.46 (dd, J = 7.5, 1.7
Hz, 1 H).
13C NMR (100 MHz): d = 19.0, 25.9, 26.0, 26.4, 29.0, 29.1, 41.0,
41.9, 51.0, 73.4, 90.9, 116.8, 120.2, 124.6, 129.7, 130.3, 150.4,
168.5.
Anal. Calcd for C15H19BrO3 (327.21): C, 55.06; H, 5.85. Found: C,
55.24; H, 6.10.
Tetra-n-propylammonium Perruthenate/N-Methylmorpholine
N-Oxide Oxidation of Chromenols 12; General Procedure
The tetrahydrofurochromenol 12 (0.3 mmol), NMO (0.053 g, 0.45
mmol), and freshly activated, powdered MS 3Å were suspended in
MeCN and treated with TPAP (0.011 g, 0.03 mmol). The resulting
mixture was stirred at r.t. for 4 h and was then directly transferred
onto a silica gel column for purification by flash column chroma-
tography (Et2O–pentane mixtures).
Anal. Calcd for C18H22O3 (286.37): C, 75.50; H, 7.74. Found: C,
75.21; H, 7.77.
(2R,3S,3aS,9bR)-2-Benzyl-3-methyl-2,3,3a,9b-tetrahydro-4H-
furo[3,2-c]chromen-4-one (13da)
20
Colorless oil; yield: 0.081 g (92%); [a]D +6.2 (c 1.23, CHCl3),
er 95:5.
(2R,3S,3aS,9bR)-2-Isopropyl-3-methyl-2,3,3a,9b-tetrahydro-
4H-furo[3,2-c]chromen-4-one (13aa)
Colorless oil; yield: 0.069 g (93%); [a]D –34.3 (c 1.06, CHCl3);
er 97:3.
IR (film): 2927, 1764, 1456, 1368, 1226, 1192, 759 cm–1.
1H NMR (400 MHz): d = 1.12 (d, J = 6.8 Hz, 3 H), 2.48 (m, 1 H),
2.73 (dd, J = 13.8, 5.6 Hz, 1 H), 2.83 (dd, J = 13.8, 7.2 Hz, 1 H),
2.96 (t, J = 7.2 Hz, 1 H), 3.84 (m, 1 H), 5.09 (d, J = 7.0 Hz, 1 H),
7.02–7.55 (m, 9 H).
20
IR (film): 2962, 1766, 1461, 1368, 1227, 1154, 760 cm–1.
1H NMR (400 MHz): d = 0.87/0.90 (d, J = 6.7 Hz, 6 H), 1.27 (d,
J = 7.0 Hz, 3 H), 1.66 (sext, J = 6.7 Hz, 1 H), 2.63 (m, 1 H), 2.89
(dd, J = 6.4, 5.7 Hz, 1 H), 3.38 (d, J = 6.6 Hz, 1 H), 5.00 (d, J = 6.4
Hz, 1 H), 7.05 (dd, J = 8.2, 1.0 Hz, 1 H), 7.18 (dt, J = 7.6, 7.4 Hz, 1
H), 7.34 (dt, J = 8.2, 7.4, 1.6 Hz, 1 H), 7.46 (dd, J = 7.6, 1.6 Hz, 1
H).
13C NMR (75 MHz): d = 16.9, 41.1, 43.8, 50.6, 73.7, 86.9, 116.8,
120.9, 124.8, 126.5, 128.4, 129.2, 129.4, 130.2, 137.8, 149.7, 168.0.
Anal. Calcd for C19H18O3 (294.34): C, 77.53; H, 6.16. Found: C,
77.32; H, 6.24.
(2S,3S,3aS,9bR)-3-Methyl-2-phenyl-2,3,3a,9b-tetrahydro-4H-
furo[3,2-c]chromen-4-one (13ea)
13C NMR (100 MHz): d = 18.4, 18.7, 18.8, 32.0, 41.1, 51.1, 73.5,
91.6, 116.8, 120.4, 124.6, 129.6, 130.3, 150.2, 168.4.
20
Colorless oil; yield: 0.081 g (96%); [a]D –92.6 (c 0.68, CHCl3);
Anal. Calcd for C15H18O3 (246.30): C, 73.15; H, 7.37. Found: C,
73.21; H, 7.58.
er 94:6.
IR (film): 2967, 1769, 1457, 1348, 1192, 1021, 760 cm–1.
1H NMR (300 MHz): d = 1.26 (d, J = 6.7 Hz, 3 H), 2.51 (m, 1 H),
3.18 (dd, J = 8.7, 7.7 Hz, 1 H), 4.54 (d, J = 8.8 Hz, 1 H), 5.31 (d,
J = 7.7 Hz, 1 H), 7.04–7.63 (m, 9 H).
13C NMR (75 MHz): d = 15.3, 47.4, 50.7, 74.0, 88.5, 116.8, 120.8,
125.0, 128.2, 126.6, 128.5, 129.5, 130.4, 139.1, 149.3, 167.5.
(2S,3S,3aS,9bR)-2-tert-Butyl-3-methyl-2,3,3a,9b-tetrahydro-
4H-furo[3,2-c]chromen-4-one (13ba)
White solid; yield: 0.074 g (95%); mp 123 °C; [a]D20 +0.3 (c 1.07,
CHCl3); er 93:7.
IR (KBr): 2958, 1758, 1457, 1375, 1225, 1161, 764 cm–1.
1H NMR (300 MHz): d = 0.87 (s, 9 H), 1.29 (d, J = 6.9 Hz, 3 H),
2.79 (dd, J = 5.6, 3.0 Hz, 1 H), 2.87 (m, 1 H), 3.30 (d, J = 6.2 Hz, 1
H), 4.86 (d, J = 5.6 Hz, 1 H), 7.07 (dd, J = 8.1, 1.1 Hz, 1 H), 7.18
(dt, J = 7.5, 1.1 Hz, 1 H), 7.36 (m, J = 1.7 Hz, 1 H), 7.45 (dd,
J = 7.5, 1.7 Hz, 1 H).
13C NMR (75 MHz): d = 20.7, 25.9, 33.4, 39.2, 51.3, 73.4, 94.9,
116.9, 119.5, 124.5, 130.2, 130.6, 151.1, 168.6.
Anal. Calcd for C18H16O3 (280.32): C, 77.17; H, 5.75. Found: C,
76.74; H, 5.84.
(2S,3S,3aS,9bR)-2-(2-Bromophenyl)-3-methyl-2,3,3a,9b-tetra-
hydro-4H-furo[3,2-c]chromen-4-one (13fa)
Pale yellow solid; yield: 0.081 g (75%); mp 147 °C; [a]D20 –39.2 (c
1.12, CHCl3); er 75:25.
IR (KBr): 2888, 1767, 1458, 1371, 1228, 1160, 751 cm–1.
Anal. Calcd for C16H20O3 (260.33): C, 73.82; H, 7.74. Found: C,
73.85; H, 7.79.
1H NMR (400 MHz): d = 1.44 (d, J = 6.9 Hz, 3 H), 2.77 (m, 1 H),
3.13 (t, J = 7.1 Hz, 1 H), 5.14 (d, J = 7.0 Hz, 1 H), 5.32 (d, J = 7.1
Hz, 1 H), 7.05–7.59 (m, 8 H).
13C NMR (100 MHz): d = 16.9, 47.7, 50.3, 74.4, 85.9, 117.0, 119.9,
122.7, 125.0, 127.8, 128.0, 129.4, 129.9, 130.6, 132.7, 139.1, 150.0,
167.5.
X-ray crystal structure analysis: formula C16H20O3, M = 260.32,
colorless crystal 0.35 × 0.25 × 0.25 mm, a = 9.474(1), b = 6.560(1),
c = 11.925(3) Å, b = 105.27(1)°, V = 715.0(2) Å3, rcalc = 1.209 g
cm–3, m = 0.661 mm–1, empirical absorption correction (0.802 £ T £
0.852), Z = 2, monoclinic, space group P21 (No. 4), l = 1.54178 Å,
T = 223 K, w/2q scans, 3047 reflections collected ( h, k, +l),
[(sinq)/l] = 0.62 Å–1, 2909 independent (Rint = 0.026) and 2763 ob-
served reflections [I ≥ 2 s(I)], 177 refined parameters, R = 0.031,
Anal. Calcd for C18H15BrO3 (359.21): C, 60.18; H, 4.21. Found: C,
60.05; H, 4.23.
Synthesis 2006, No. 18, 3111–3121 © Thieme Stuttgart · New York

PAPER
Stereoselective Synthesis of Substituted Tetrahydrofurochromenes
IR (film): 2968, 1768, 1488, 1364, 1271, 1155, 856 cm–1.
3119
(2S,3S,3aS,9bR)-3-Methyl-2-(2-naphthyl)-2,3,3a,9b-tetra-
hydro-4H-furo[3,2-c]chromen-4-one (13ga)
Colorless oil; yield: 0.075 g (76%); [a]D –59.5 (c 1.10, CHCl3);
er 94:6.
1H NMR (300 MHz): d = 0.87/0.90 (d, J = 6.8 Hz, 6 H), 1.25 (d,
J = 6.8 Hz, 3 H), 1.64 (m, 1 H), 2.58 (sext, J = 6.9 Hz, 1 H), 2.89 (t,
J = 6.6 Hz, 1 H), 3.37 (dd, J = 6.9, 6.4 Hz, 1 H), 3.88 (s, 3 H), 4.95
(d, J = 6.6 Hz, 1 H), 7.03 (d, J = 2.2 Hz, 1 H), 7.19 (d, J = 2.2 Hz, 1
H).
13C NMR (75 MHz): d = 18.3, 18.4, 18.8, 31.9, 41.2, 50.8, 56.4,
73.2, 91.7, 113.4, 116.0, 122.0, 123.4, 138.7, 148.0, 167.0.
20
IR (film): 2960, 1755, 1464, 1217, 1160, 823, 763 cm–1.
1H NMR (400 MHz): d = 1.29 (d, J = 6.7 Hz, 3 H), 2.62 (m, 1 H),
3.23 (dd, J = 8.7, 7.6 Hz, 1 H), 4.71 (d, J = 8.8 Hz, 1 H), 5.37 (d,
J = 7.6 Hz, 1 H), 7.07–7.85 (m, 11 H).
13C NMR (100 MHz): d = 15.4, 47.3, 50.8, 74.2, 88.7, 116.9, 120.8,
124.0, 125.0, 126.0, 126.1, 126.2, 127.7, 127.9, 128.5, 129.6, 130.3,
133.1, 133.3, 136.5, 149.3, 167.6.
HRMS-ESI: m/z [M + MeOH + Na]+ calcd for C17H23BrNaO5:
409.0627; found: 409.0617.
(2R,3S,3aS,9bR)-2-Isopropyl-7-methoxy-3-methyl-2,3,3a,9b-
tetrahydro-4H-furo[3,2-c]chromen-4-one (13af)
White solid; yield: 0.080 g (97%); mp 69 °C; [a]D20 –26.6 (c 1.04,
CHCl3); er 97:3.
HRMS-ESI: m/z [M + MeOH + Na]+ calcd for C23H22NaO4:
385.1416; found: 385.1415.
(2R,3S,3aS,9bR)-2-Isopropyl-3,6-dimethyl-2,3,3a,9b-tetra-
hydro-4H-furo[3,2-c]chromen-4-one (13ab)
IR (KBr): 2964, 1756, 1661, 1513, 1440, 1157, 849 cm–1.
20
Colorless oil; yield: 0.067 g (86%); [a]D –9.9 (c 0.78, CHCl3);
1H NMR (400 MHz): d = 0.88 (t, J = 6.9 Hz, 6 H), 1.26 (d, J = 6.9
Hz, 3 H), 1.67 (m, 1 H), 2.65 (m, 1 H), 2.84 (m, J = 6.1 Hz, 1 H),
3.34 (dd, J = 6.7, 6.5 Hz, 1 H), 3.80 (s, 3 H), 4.93 (d, J = 6.1 Hz, 1
H), 6.58 (d, J = 2.5 Hz, 1 H), 6.73 (dd, J = 8.5, 2.5 Hz, 1 H), 7.35
(d, J = 8.5 Hz, 1 H).
13C NMR (100 MHz): d = 18.5, 18.6, 19.0, 32.0, 41.1, 51.1, 55.5,
73.3, 91.5, 101.9, 111.1, 112.4, 130.5, 151.4, 161.2, 168.6.
er 97:3.
IR (film): 2960, 1759, 1473, 1385, 1214, 1152, 779 cm–1.
1H NMR (300 MHz): d = 0.88/0.90 (d, J = 6.6 Hz, 6 H), 1.27 (d,
J = 6.9 Hz, 3 H), 1.67 (m, 1 H), 2.32 (s, 3 H), 2.67 (m, 1 H), 2.84
(dd, J = 6.2, 5.2 Hz, 1 H), 3.35 (t, J = 6.6 Hz, 1 H), 4.94 (d, J = 6.2
Hz, 1 H), 7.02–7.32 (m, 3 H).
13C NMR (75 MHz): d = 15.7, 18.6, 18.6, 19.0, 32.0, 41.1, 51.0,
73.8, 91.7, 119.9, 124.1, 126.0, 127.2, 131.8, 148.6, 168.5.
Anal. Calcd for C16H20O4 (276.33): C, 69.54; H, 7.30. Found: C,
69.47; H, 7.37.
Anal. Calcd for C16H20O3 (260.33): C, 73.82; H, 7.74. Found: C,
73.62; H, 7.78.
(2R,3S,3aS,9bR)-8-Chloro-2-isopropyl-3-methyl-2,3,3a,9b-
tetrahydro-4H-furo[3,2-c]chromen-4-one (13ag)
White solid; yield: 0.055 g (65%); mp 92 °C; [a]D20 –48.3 (c 0.30,
CHCl3); er 97:3.
(2R,3S,3aS,9bR)-2-Isopropyl-3,8-dimethyl-2,3,3a,9b-tetra-
hydro-4H-furo[3,2-c]chromen-4-one (13ac)
20
White solid; yield: 0.072 g (92%); [a]D –50.6 (c 0.90, CHCl3);
IR (KBr): 2968, 1764, 1474, 1226, 1190, 1154, 815 cm–1.
er 97:3.
1H NMR (400 MHz): d = 0.87/0.91 (d, J = 6.7 Hz, 6 H), 1.27 (d,
J = 6.8 Hz, 3 H), 1.65 (m, 1 H), 2.57 (m, 1 H), 2.91 (t, J = 6.3 Hz, 1
H), 3.39 (dd, J = 6.9, 6.3 Hz, 1 H), 4.97 (d, J = 6.5 Hz, 1 H), 7.00
(d, J = 8.7 Hz, 1 H), 7.30 (dd, J = 8.7, 2.6 Hz, 1 H), 7.45 (d, J = 2.6
Hz, 1 H).
13C NMR (100 MHz): d = 18.3, 18.4, 18.8, 31.9, 41.2, 50.8, 73.0,
91.7, 118.2, 122.2, 129.9, 129.4, 130.3, 148.6, 167.7.
IR (KBr): 2962, 1747, 1501, 1391, 1216, 1174, 826 cm–1.
1H NMR (300 MHz): d = 0.89 (t, J = 6.6, 6 H), 1.26 (d, J = 6.8 Hz,
3 H), 1.67 (sext, J = 6.6 Hz, 1 H), 2.33 (s, 3 H), 2.64 (m, 1 H), 2.85
(m, J = 5.3 Hz, 1 H), 3.36 (t, J = 6.6 Hz, 1 H), 4.93 (d, J = 6.2 Hz,
1 H), 6.88–7.31 (m, 3 H).
13C NMR (100 MHz): d = 18.6, 18.9, 18.4, 20.6, 31.9, 41.1, 51.1,
73.6, 91.6, 116.5, 119.8, 129.9, 130.9, 134.2, 148.3, 168.6.
Anal. Calcd for C15H17ClO3 (280.75): C, 64.17; H, 6.10. Found: C,
63.81; H, 6.17.
Anal. Calcd for C16H20O3 (260.33): C, 73.82; H, 7.74. Found: C,
73.83; H, 7.83.
(2R,3S,3aS,9bR)-8-Bromo-2-isopropyl-3-methyl-2,3,3a,9b-
tetrahydro-4H-furo[3,2-c]chromen-4-one (13ah)
White solid; yield: 0.061 g (63%); mp 102 °C; [a]D20 –91.3 (c 0.39,
CHCl3); er 97:3.
(2R,3S,3aS,9bR)-2-Isopropyl-3-methyl-6-phenyl-2,3,3a,9b-
tetrahydro-4H-furo[3,2-c]chromen-4-one (13ad)
20
Colorless oil; yield: 0.081 g (84%); [a]D +13.5 (c 0.26, CHCl3);
er 97:3.
IR (KBr): 2970, 1763, 1474, 1227, 1153, 928, 814 cm–1.
IR (film): 2965, 1768, 1462, 1385, 1155, 763, 699 cm–1.
1H NMR (400 MHz): d = 0.87/0.91 (d, J = 6.9 Hz, 6 H), 1.26 (d,
J = 6.8 Hz, 3 H), 1.65 (m, 1 H), 2.57 (m, 1 H), 2.90 (dd, J = 6.4, 6.1
Hz, 1 H), 3.38 (dd, J = 6.7, 6.5 Hz, 1 H), 4.96 (d, J = 6.5 Hz, 1 H),
6.94 (d, J = 8.7 Hz, 1 H), 7.45 (dd, J = 8.7, 2.4 Hz, 1 H), 7.60 (d,
J = 2.4 Hz, 1 H).
13C NMR (100 MHz): d = 18.3, 18.5, 18.8, 31.9, 41.2, 50.8, 73.0,
91.7, 117.1, 118.6, 122.6, 132.4, 133.2, 149.2, 167.6.
1H NMR (400 MHz): d = 0.90/0.91 (d, J = 6.7 Hz, 6 H), 1.27 (d,
J = 6.9 Hz, 3 H), 1.69 (m, 1 H), 2.69 (m, J = 6.6, 5.2 Hz, 1 H), 2.88
(dd, J = 6.0, 5.2 Hz, 1 H), 3.83 (t, J = 6.6 Hz, 1 H), 5.02 (d, J = 6.0
Hz, 1 H), 7.23–7.54 (m, 8 H).
13C NMR (100 MHz): d = 18.6, 18.7, 19.0, 32.0, 41.1, 50.9, 73.9,
91.8, 120.7, 129.4, 128.3, 129.5, 124.5, 127.2, 129.0, 132.0, 136.4,
147.2, 168.0.
Anal. Calcd for C15H17BrO3 (325.20): C, 55.40; H, 5.27. Found: C,
55.52; H, 5.39.
HRMS-ESI: m/z [M + MeOH + Na]+ calcd for C25H23NaO4:
377.1729; found: 377.1740.
Ionic Hydrogenation of Chromenols 12 with Boron Trifluo-
ride–Diethyl Ether/Triethylsilane; General Procedure
To a stirred soln of the tetrahydrofurochromenol 6 (0.3 mmol) and
Et3SiH (0.19 mL, 1.2 mmol) in MeCN (5 mL) at 0 °C was added
dropwise BF3·OEt2 (0.08 mL, 0.6 mmol). The mixture was warmed
to r.t. and stirred for 30 min, and then sat. NaHCO3 soln (5 mL) was
(2R,3S,3aS,9bR)-8-Bromo-2-isopropyl-6-methoxy-3-methyl-
2,3,3a,9b-tetrahydro-4H-furo[3,2-c]chromen-4-one (13ae)
Slightly yellow oil; yield: 0.102 g (96%); [a]D –41.9 (c 0.42,
CHCl3); er 95:5.
20
Synthesis 2006, No. 18, 3111–3121 © Thieme Stuttgart · New York

3120
A. Brüns et al.
PAPER
added. The aqueous layer was extracted with t-BuOMe (3 × 15
mL), the combined organic extracts were dried (MgSO4), and the
solvents were removed in vacuo. Flash column chromatography
(silica gel, Et2O–pentane mixtures) gave the purified chromenes 14
along with the dimeric products 15.
1H NMR (400 MHz): d = 0.90–1.90 (m, 12 H), 1.15 (d, J = 6.9 Hz,
3 H), 2.05 (m, 1 H), 3.28 (t, J = 6.8 Hz, 1 H), 3.67 (t, J = 10.8 Hz, 1
H), 4.09 (m, J = 10.8 Hz, 1 H), 4.66 (d, J = 5.4 Hz, 1 H), 6.85 (dd,
J = 8.3, 1.1 Hz, 1 H), 6.93 (dt, J = 7.5, 1.1 Hz, 1 H), 7.18 (m, 1 H),
7.39 (dd, J = 7.6, 1.7 Hz, 1 H).
13C NMR (100 MHz): d = 19.2, 26.0, 26.2, 26.5, 29.3, 29.6, 38.2,
42.4, 44.8, 65.5, 71.8, 90.3, 116.7, 120.9, 121.7, 129.2, 131.4,
155.0.
HRMS-ESI: m/z [M + MeOH + Na]+ calcd for C18H25O2: 273.1855;
found: 273.1853.
(2R,3S,3aR,9bR)-2-Isopropyl-3-methyl-2,3,3a,9b-tetrahydro-
4H-furo[3,2-c]chromene (14aa)
Colorless oil; yield: 0.051 g (73%); Rf = 0.67 (Et2O–pentane, 1:5);
[a]D20 –27.4 (c 0.95, CHCl3); er 96:4).
IR (film): 2960, 1488, 1456, 1224, 1094, 1011, 757 cm–1.
1H NMR (400 MHz): d = 0.91 (d, J = 6.8 Hz, 6 H), 1.17 (d, J = 6.8
Hz, 3 H), 1.54–1.77 (m, 2 H), 2.08 (m, 1 H), 3.29 (t, J = 6.8 Hz, 1
H), 3.71 (t, J = 10.7 Hz, 1 H), 4.11 (t, J = 10.7 Hz, 1 H), 4.71 (d,
J = 5.6 Hz, 1 H), 6.77–7.58 (m, 4 H).
4,4¢-Oxidobis[(2R,3S,3aS,4R,9bR)-2-cyclohexyl-3-methyl-
2,3,3a,9b-tetrahydro-4H-furo[3,2-c]chromene] (15ca)
Colorless liquid; yield: 0.011 g (13%); Rf = 0.66 (Et2O–pentane,
1:5).
13C NMR (100 MHz): d = 18.9, 19.0, 19.0, 32.4, 38.1, 45.0, 65.4,
1H NMR (300 MHz): d = 0.80–1.94 (m, 24 H), 1.04 (d, J = 6.7 Hz,
6 H), 2.12 (m, 2 H), 3.27 (dd, J = 7.5, 6.6 Hz, 2 H), 4.84 (d, J = 6.5
Hz, 2 H), 5.32 (d, J = 6.5 Hz, 2 H), 6.84 (d, J = 8.2 Hz, 2 H), 6.97
(t, 2 H), 7.20 (t, 2 H), 7.39 (d, J = 7.6 Hz, 2 H).
13C NMR (100 MHz): d = 18.3, 25.8, 26.0, 26.3, 28.9, 29.1, 37.6,
41.9, 49.6, 72.1, 90.3, 95.9, 116.7, 121.6, 122.8, 129.0, 130.1,
151.1.
71.9, 91.2, 116.7, 120.9, 121.9, 129.2, 131.3, 154.9.
Anal. Calcd for C15H20O2 (232.32): C, 77.55; H, 8.68. Found: C,
77.19; H, 8.76.
4,4¢-Oxidobis[(2R,3S,3aS,4R,9bR)-2-isopropyl-3-methyl-
2,3,3a,9b-tetrahydro-4H-furo[3,2-c]chromene] (15aa)
Colorless oil; yield: 0.016 g (22%); Rf = 0.57 (Et2O–pentane, 1:5).
(2R,3S,3aR,9bR)-2-Benzyl-3-methyl-2,3,3a,9b-tetrahydro-4H-
furo[3,2-c]chromene (14da)
1H NMR (300 MHz): d = 0.81/0.82 (d, J = 6.7 Hz, 12 H), 1.04 (d,
J = 6.7 Hz, 6 H), 1.53 (m, 2 H), 1.83 (m, 2 H), 2.14 (q, J = 6.5 Hz,
2 H), 3.27 (dd, J = 7.8, 6.3 Hz, 2 H), 4.87 (d, J = 6.8 Hz, 2 H), 5.34
(d, J = 6.2 Hz, 2 H), 6.85 (dd, J = 8.2, 1.1 Hz, 2 H), 6.98 (dt, J = 7.6,
1.1 Hz, 2 H), 7.19 (m, 2 H), 7.39 (dd, J = 7.6, 1.7 Hz, 2 H).
Colorless oil; yield: 0.044 g (63%) from 0.25 mmol of 12da; Rf =
0.56 (Et2O–pentane, 1:5); [a]D20 +12.1 (c 1.04, CHCl3); er 92:8.
IR (film): 3029, 2922, 1490, 1453, 1222, 1010, 758 cm–1.
13C NMR (100 MHz): d = 18.3, 18.6, 19.1, 32.2, 38.1, 49.9, 72.2,
1H NMR (400 MHz): d = 0.96 (d, J = 6.8 Hz, 3 H), 1.71 (m, 1 H),
2.11 (m, 1 H), 2.75 (dd, J = 13.8, 5.9 Hz, 1 H), 2.93 (dd, J = 13.8,
6.6 Hz, 1 H), 3.68 (dd, J = 11.1, 9.4 Hz, 1 H), 3.76 (m, 1 H), 4.10
(dd, J = 11.1, 4.6 Hz, 1 H), 4.75 (d, J = 6.1 Hz, 1 H), 6.85 (dd,
J = 8.2, 1.2 Hz, 1 H), 6.96 (dt, J = 7.6, 1.2 Hz, 1 H), 7.16–7.29 (m,
6 H), 7.41 (dd, J = 7.6, 1.7 Hz, 1 H).
91.3, 96.0, 116.9, 121.9, 123.2, 129.2, 130.3, 151.1.
(2S,3S,3aR,9bR)-2-tert-Butyl-3-methyl-2,3,3a,9b-tetrahydro-
4H-furo[3,2-c]chromen (14ba)
Colorless oil; yield: 0.060 g (81%); Rf = 0.76 (Et2O–pentane, 1:5);
[a]D20 –3.6 (c 0.77, CHCl3); er 92:8.
13C NMR (100 MHz): d = 17.3, 40.6, 41.2, 44.9, 65.6, 72.2, 86.6,
116.8, 121.1, 122.2, 126.3, 128.2, 129.2, 129.4, 131.1, 138.3, 154.9.
IR (film): 2957, 1491, 1467, 1223, 1096, 1009, 753 cm–1.
1H NMR (400 MHz): d = 0.89 (s, 9 H), 1.18 (d, J = 6.8 Hz, 3 H),
1.73 (m, 1 H), 2.05 (m, 1 H), 3.25 (d, J = 7.1 Hz, 1 H), 3.68 (t,
J = 11.0 Hz, 1 H), 4.08 (dd, J = 11.0, 5.0 Hz, 1 H), 4.65 (d, J = 5.2
Hz, 1 H), 6.86 (dd, J = 8.2, 1.2 Hz, 1 H), 6.94 (dt, J = 7.7, 1.2 Hz, 1
H), 7.19 (m, 1 H), 7.40 (dd, J = 7.7, 1.8 Hz, 1 H).
13C NMR (100 MHz): d = 20.3, 26.4, 33.4, 36.0, 45.2, 65.2, 71.6,
94.0, 116.6, 120.8, 122.8, 129.2, 131.6, 155.1.
Anal. Calcd for C19H20O2 (280.36): C, 81.40; H, 7.19. Found: C,
81.08; H, 7.24.
4,4¢-Oxidobis[(2R,3S,3aS,4R,9bR)-2-benzyl-3-methyl-
2,3,3a,9b-tetrahydro-4H-furo[3,2-c]chromene] (15da)
Colorless liquid; yield: 0.022 g (31%) from 0.25 mmol of 12da; Rf
= 0.34 (Et2O–pentane, 1:5).
1H NMR (300 MHz): d = 0.83 (d, J = 6.7 Hz, 6 H), 1.73 (q, J = 7.0
Hz, 2 H), 2.17 (m, 2 H), 2.60 (dd, J = 13.6, 5.1 Hz, 2 H), 2.76 (dd,
J = 13.6, 6.9 Hz, 2 H), 3.69 (m, 2 H), 4.90 (d, J = 7.2 Hz, 2 H), 5.39
(d, J = 5.5 Hz, 2 H), 6.83–7.50 (m, 18 H).
Anal. Calcd for C16H22O2 (246.34): C, 78.01; H, 9.00. Found: C,
77.96; H, 9.03.
4,4¢-Oxidobis[(2S,3S,3aS,4R,9bR)-2-tert-butyl-3-methyl-
2,3,3a,9b-tetrahydro-4H-furo[3,2-c]chromene] (15ba)
Colorless oil; yield: 0.012 g (16%); Rf = 0.79 (Et2O–pentane, 1:5).
13C NMR (100 MHz): d = 16.5, 41.0, 41.2, 49.5, 72.3, 86.7, 95.7,
117.1, 122.2, 123.6, 126.2, 128.2, 129.3, 129.3, 130.2, 138.4, 150.7.
1H NMR (300 MHz): d = 0.92 (s, 18 H), 1.27 (d, J = 6.7 Hz, 6 H),
2.14–2.27 (m, 4 H), 3.29 (d, J = 7.2 Hz, 2 H), 4.77 (d, J = 5.7 Hz, 2
H), 5.06 (d, J = 8.1 Hz, 2 H), 6.91 (dd, J = 8.3, 1.0 Hz, 2 H), 6.97
(dt, J = 7.6, 7.5 Hz, 2 H), 7.22 (m, J = 1.6 Hz, 2 H), 7.39 (dd,
J = 7.6, 1.6 Hz, 2 H).
13C NMR (100 MHz): d = 20.2, 26.4, 33.6, 35.9, 50.4, 72.6, 94.2,
97.2, 116.9, 121.6, 122.2, 129.3, 130.7, 152.0.
(2S,3S,3aR,9bR)-3-Methyl-2-phenyl-2,3,3a,9b-tetrahydro-4H-
furo[3,2-c]chromene (14ea)
Colorless oil; yield: 0.052 g (65%); Rf = 0.48 (Et2O–pentane, 1:5);
[a]D20 –105.9 (c 1.20, CHCl3); er 92:8.
IR (film): 2960, 1487, 1454, 1222, 1088, 1023, 759 cm–1.
1H NMR (400 MHz): d = 1.20 (d, J = 6.7 Hz, 3 H), 1.93 (m, 1 H),
2.31 (m, 1 H), 3.91 (dd, J = 11.1, 8.1 Hz, 1 H), 4.19 (dd, J = 11.1,
4.3 Hz, 1 H), 4.50 (d, J = 8.4 Hz, 1 H), 5.01 (d, J = 6.8 Hz, 1 H),
6.90 (dd, J = 8.3, 1.1 Hz, 1 H), 7.00 (dt, J = 7.6, 1.1 Hz, 1 H), 7.19–
7.30 (m, 6 H), 7.47 (dd, J = 7.6, 1.7 Hz, 1 H).
13C NMR (100 MHz): d = 16.1, 44.4, 45.3, 65.5, 73.0, 88.4, 116.9,
121.3, 122.8, 126.3, 127.7, 128.3, 129.2, 131.2, 141.0, 154.8.
(2R,3S,3aR,9bR)-2-Cyclohexyl-3-methyl-2,3,3a,9b-tetrahydro-
4H-furo[3,2-c]chromene (14ca)
Colorless liquid; yield: 0.064 g (78%); Rf = 0.75 (Et2O–pentane,
1:5); [a]D20 –4.6 (c 1.04, CHCl3); er 94:6.
IR (film): 2926, 2850, 1488, 1451, 1221, 1012, 754 cm–1.
Synthesis 2006, No. 18, 3111–3121 © Thieme Stuttgart · New York

PAPER
Stereoselective Synthesis of Substituted Tetrahydrofurochromenes
3121
Anal. Calcd for C18H18O2 (266.33): C, 81.17; H, 6.81. Found: C,
80.82; H, 7.09.
(7) For reviews, see: (a) Hoppe, D.; Hense, T. Angew. Chem.,
Int. Ed. Engl. 1997, 36, 2282. (b) Hoppe, D.; Marr, F.;
Brüggemann, M. Top. Organomet. Chem. 2003, 5, 61.
(c) Christoph, G.; Hoppe, D. In The Chemistry of
Organolithium Compounds; Rappoport, Z.; Marek, I., Eds.;
Wiley: Chichester, 2004, 1055.
4,4¢-Oxidobis[(2S,3S,3aS,4R,9bR)-3-methyl-2-phenyl-
2,3,3a,9b-tetrahydro-4H-furo[3,2-c]chromene] (15ea)
White solid; yield: 0.026 g (32%); Rf = 0.24 (Et2O–pentane, 1:5);
mp 176 °C.
1H NMR (400 MHz): d = 0.99 (d, J = 6.7 Hz, 6 H), 1.86 (m, 2 H),
2.34 (m, 2 H), 4.41 (d, J = 9.3 Hz, 2 H), 5.10 (d, J = 7.7 Hz, 2 H),
5.49 (d, J = 5.1 Hz, 2 H), 6.79 (dd, J = 8.2, 1.2 Hz, 2 H), 6.99 (dt,
J = 7.7, 1.2 Hz, 2 H), 7.08–7.28 (m, 12 H), 7.43 (dd, J = 7.7, 1.7 Hz,
2 H).
(8) Reviews: (a) Reetz, M. T. Organotitanium Reagents in
Organic Synthesis; Springer: Berlin, 1986. (b) Weidmann,
B.; Seebach, D. Angew. Chem., Int. Ed. Engl. 1983, 22, 32.
(c) Reetz, M. T. In Organometallics in Synthesis, 2nd ed.;
Schlosser, M., Ed.; Wiley: Chichester, 2002, 817.
(9) Risatti, C. A.; Taylor, R. E. Angew. Chem. Int. Ed. 2004, 43,
6671.
(10) (a) Mukaiyama, T.; Kobayashi, S. Org. React. 1994, 46, 1.
(b) Mukaiyama, T. Tetrahedron 1999, 55, 8609.
(c) Mukaiyama, T. Angew. Chem. Int. Ed. 2004, 43, 5590.
(11) For mechanistically related syntheses, see: (a) Hoffmann,
R. W.; Giesen, V.; Fuest, M. Liebigs Ann. Chem. 1993, 629.
(b) Hanaki, N.; Link, J. T.; McMillan, D. W. C.; Overman,
L. E.; Trankle, W. G.; Wurster, J. A. Org. Lett. 2000, 2, 223.
(12) The chromenols 12 were isolated as mixtures of anomers in
ratios between 61:29 and 91:9 (measured by 1H NMR in
CDCl3). The configuration at the anomeric carbon atom was
not determined.
13C NMR (100 MHz): d = 15.1, 44.5, 49.4, 72.8, 88.4, 95.7, 117.2,
122.3, 123.4, 126.6, 127.7, 128.3, 129.3, 130.2, 140.4, 150.3.
X-ray crystal structure analysis for rac-15ea: formula C36H34O5,
M = 546.63, colorless crystal 0.35 × 0.30 × 0.20 mm, a = 9.127(1),
b = 24.957(1), c = 12.965(1) Å, b = 101.75(1)°, V = 2891.3(4) Å3,
r
calc = 1.256 g cm–3, m = 0.661 mm–1, empirical absorption correc-
tion (0.802 £ T £ 0.879), Z = 4, monoclinic, space group P21/c (No.
14), l = 1.54178 Å, T = 223 K, w and j scans, 28341 reflections
collected ( h, k, l), [(sinq)/l] = 0.58 Å–1, 4632 independent
(Rint = 0.060) and 4186 observed reflections [I ≥ 2 s(I)], 372 refined
parameters, R = 0.046, wR2 = 0.121, max. residual electron density
0.20 (–0.21) e Å–3, hydrogen atoms calculated and refined as riding
atoms.
(13) Review: Hoffmann, R. W. Chem. Rev. 1989, 89, 1841.
(14) Review: Ley, S.; Norman, J.; Griffith, W. P.; Marsden, S. P.
Synthesis 1994, 639.
(15) Data sets were collected with Enraf Nonius CAD4 and
Nonius KappaCCD diffractometers, programs used:
(a) Data collection EXPRESS: Nonius B.V., 1994. (b) Data
collection COLLECT: Nonius B.V., 1998. (c) Data
reduction MolEN: Fair K., Enraf-Nonius B.V., 1990.
(d) Data reduction Denzo-SMN: Otwinowski, Z.; Minor, W.
Meth. Enzymol 1997, 276, 307. (e) Absorption correction
data for CCD data Denzo: Otwinowski, Z.; Borek, D.;
Majewski, W.; Minor, W. Acta Cryst., Sect. A 2003, 59,
228. (f) Structure solution SHELXS-97: Sheldrick, G. M.
Acta Cryst., Sect. A 1990, 46, 467. (g) Structure refinement
SHELXL-97: Sheldrick G. M., Universität Göttingen, 1997.
(h) Graphics SCHAKAL: Keller E., Universität Freiburg,
1997. CCDC 602901 – 602903 contain the supplementary
crystallographic data for this paper. These data can be
obtained free of charge at www.ccdc.cam.ac.uk/conts/
retrieving.htm [or from the Cambridge Crystallographic
Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax:
+44(1223)336033, E-mail: deposit@ccdc.cam.ac.uk].
(16) Review: Kursanov, D. N.; Parnes, Z. N.; Loim, N. M.
Synthesis 1974, 633.
Acknowledgment
This work was supported by the Deutsche Forschungsgemeinschaft
(SFB 424) and the Fonds der Chemischen Industrie. Astrid Brüns
would like to thank Dr. Matthias Kauch for numerous helpful dis-
cussions concerning the present work.
References
(1) Responsible for X-ray crystal structure data.
(2) Morimoto, Y.; Nishikawa, Y.; Tanaka, T. Angew. Chem. Int.
Ed. 2006, 45, 810.
(3) Marston, A.; Zagorski, M. G.; Horstettmann, K. Helv. Chim.
Acta 1988, 71, 1210.
(4) Selvam, C.; Jachak, S. M.; Gnana Oli, R.; Thilagavathi, R.;
Chakraborti, A. K.; Bhutani, K. K. Tetrahedron Lett. 2004,
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(5) (a) Hoppe, D.; Krämer, T.; Freire Erdbrügger, C.; Egert, E.
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Özlügedik, M.; Fröhlich, R.; Hoppe, D. Adv. Synth. Catal.
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(17) Racemic material of compounds 12–15 were obtained
starting with racemic homoaldol adducts 6 prepared by
analogous TMEDA mediated deprotonation–substitution.
(18) The starting 2-hydroxy-3-phenylbenzaldehyde was
synthesized by a new directed ortho-lithiation-formylation
protocol: (a) Kauch, M.; Hoppe, D. Synthesis 2006, 1575.
(b) Kauch, M.; Snieckus, V.; Hoppe, D. J. Org. Chem. 2005,
70, 7149.
(6) (a) Hoppe, D.; Zschage, O. Angew. Chem., Int. Ed. Engl.
1989, 28, 69. (b) Paulsen, H.; Graeve, C.; Hoppe, D.
Synthesis 1996, 141.
(19) NMR data are given for the major anomer of chromenol 12;
see ref. 12.
Synthesis 2006, No. 18, 3111–3121 © Thieme Stuttgart · New York