Chiral hypervalent iodine-catalyzed enantioselective oxidative Kita spirolactonization of 1-naphthol derivatives and one-pot diastereo-selective oxidation to epoxyspirolactones

Article abstract of DOI:10.1016/j.tet.2010.04.060

We demonstrate here the rational design of a conformationally flexible C₂-symmetric iodosylarene 8g based on secondary n-σ or hydrogen-bonding interactions as a chiral catalyst for the enantioselective Kita oxidative spirolactonization of 1-nap

Full text of DOI:10.1016/j.tet.2010.04.060

Tetrahedron 66 (2010) 5841e5851
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Chiral hypervalent iodine-catalyzed enantioselective oxidative Kita
spirolactonization of 1-naphthol derivatives and one-pot diastereo-selective
oxidation to epoxyspirolactones
,b,
Muhammet Uyanik a, Takeshi Yasui a, Kazuaki Ishihara a
*
a Graduate School of Engineering, Nagoya University, Furo-cho, Chikusa-ku, Nagoya 464-8603, Japan
b Japan Science and Technology Agency (JST), CREST, Nagoya University, Furo-cho, Chikusa-ku, Nagoya, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
We demonstrate here the rational design of a conformationally flexible C2-symmetric iodosylarene 8g
Received 15 March 2010
Received in revised form 13 April 2010
Accepted 13 April 2010
based on secondary ne
s or hydrogen-bonding interactions as a chiral catalyst for the enantioselective
*
Kita oxidative spirolactonization of 1-naphthol derivatives 5. Iodosylarenes 8 were generated in situ from
iodoarenes 7 and mCPBA as a co-oxidant. Furthermore, epoxyspirolactone 15 was obtained by the one-
pot oxidation of 5 with mCBPA in the presence of 7g. Thus, the enantioselective oxidation of 5 to 6 and
the successive enantio- and diastereo-selective oxidation of 5 to 15 proceeded in good yields when we
controlled the amount of mCPBA.
Available online 18 April 2010
Keywords:
Hypervalent iodine
Asymmetric oxidation
Dearomatization
Spirolactone
Ó 2010 Elsevier Ltd. All rights reserved.
1. Introduction
Over the past two decades, hypervalent iodine compounds have
been the focus of great attention due to their mild and chemo-
selective oxidizing properties and the fact that they are environ-
mentally benign compared to toxic metal reagents.1 However, the
stoichiometric use of hypervalent iodine compounds has been
limited because of their potentially shock-sensitive explosiveness
and/or poor solubility in common organic solvents.1 Thus, the de-
velopment of hypervalent iodine-catalyzed oxidation reactions
with co-oxidants is needed.1,2 In particular, the development of
chiral hypervalent iodine-catalyzed enantioselective oxidative
coupling reactions is one of the most challenging areas in asym-
metric organocatalysis.3,4 There are some examples of in situ-
generated chiral iodosylarene(I(III)) or iodylarene(I(V)) catalysis
with meta-chloroperbenzoic acid (mCPBA)5 as a co-oxidant (Fig.1).4
Figure 1. Chiral iodoarene precatalysts 1e3 and iodosylarene 4.
1-naphthol derivatives 5 to spirolactones 6 with high enantiose-
lectivities (up to 86% ee) using stoichiometric chiral iodine(III) re-
agent 4, which has a conformationally rigid 1,1-spiroindanone
backbone (Scheme 1).6 They also succeeded in the catalytic use of 4
(30 mol % based on iodine) that was generated in situ from 3 and
mCPBA in the presence of acetic acid, although the enantiose-
lectivity was reduced to 69% ee (Scheme 1).6
Wirth and co-workers reported the enantioselective
a-oxy-
sulfonylation of ketones with 1 as a precatalyst.4a Quideau and co-
workers reported the enantioselective hydroxylative dearomati-
zation of 2-methyl-1-naphthol with 2 as a precatalyst.4b However,
the enantioselectivity has been modest. Recently, Kita and co-
workers reported the enantioselective oxidative dearomatization of
Scheme 1. Enantioselective oxidative spirolactonization of 1-naphthols (5) reported
* Corresponding author. Tel.: þ81 52 7893331; fax: þ81 52 7893222; e-mail
by Kita and co-workers.6
address: ishihara@cc.nagoya-u.ac.jp (K. Ishihara).
0040-4020/$ e see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.04.060

5842
M. Uyanik et al. / Tetrahedron 66 (2010) 5841e5851
Very recently, we reported conformationally flexible C2-sym-
metric chiral iodoarenes 7g as a highly effective precatalyst for
the enantioselective Kita oxidative spirolactonization (Scheme
2).7 In this report, we described a detailed investigation of
enantioselective oxidative spirolactonization. A broad range of
substrates and higher enantioselectivities of up to 92% ee were
achieved using iodosylarene 8g generated in situ from 7g and
mCPBA. To the best of our knowledge, the present catalysis
provides the highest asymmetric induction among previous
chiral hypervalent iodine-catalyzed enantioselective oxidative
reactions.3,4,6 Furthermore, we briefly highlight here the syn-
thetic utility of the present oxidation. The selective oxidation of 5
to spirolactones 6 and the successive oxidation of 5 to epox-
yspirolactones 15 proceeded in good yields when we controlled
the amount of mCPBA.
Scheme 4. Synthesis of chiral iodoarenes 7 and 11.
The starting materials 5 used in this study were prepared in good
yields in three steps from readily available 1-napthols 12 (Scheme 5).6b
Treatment of 12 with triethyl orthoacrylate in the presence of pivalic
acid afforded diethoxychromane 13.10 Acid hydrolysis of 13 furnished
dihydrocoumarin, which was transformed to 5 by hydrolysis.
Scheme 2. In situ-generated 8g-catalyzed enantioselective oxidative spirolactoniza-
tion of 5 with mCPBA.7
2. Results and discussion
C2-Symmetric chiral iodoarenes 7 consist of three units, in-
cluding an iodoaryl moiety (A), chiral linkers (B), and subfunc-
tional groups (C) (Scheme 3). These units can be easily combined
to give a wide variety of chiral iodoarenes 7. The iodosylarenes 8
generated in situ from iodoarenes 7 were expected to exhibit
Scheme 5. Synthesis of 1-naphthol derivatives 5.
intramolecular ne
s
*
interactions between the electron-deficient
orbital) of A and the Lewis-basic group
The chiral iodoarenes 7 were examined for use as pre-
catalysts for the enantioselective oxidative spirolactonization of
5a to spirolactone 6a in the presence of mCPBA as a co-oxidant
under Kita’s conditions (Table 1).6 The use of diester 7a and
iodine(III) center (CeI
s
*
of C (lone pair n), such as carbonyl groups (8-I).1,8 Alternatively,
intramolecular hydrogen-bonding interactions between the
acidic hydrogen of C (COYeH) and the ligand (L, such as an
acetoxy group) of iodine(III) might also be generated (8-II). We
envisioned that a suitable chiral environment might be con-
Table 1
Precatalyst screening for the oxidative spirolactonization of 5aa
structed around the iodine(III) center of
molecular interactions.
8 via such intra-
Entry
Precat. 7 or 11
Yieldb (%)
eec (%)
1
2
3
4
5
6
7
8
7a
7b
7c
7d
7e
7f
7g
7h
7i
7j
7k
7l
11a
11b
27
26
40
25
53
36
64
37
39
37
47
70
24
42
23
43
70
77
75
84
82
51
52
50
80
83
13
32
Scheme 3. Design of conformationally flexible iodoarenes 7 (precatalyst) and iodo-
sylarenes 8 (catalyst).
9
Chiral iodoarenes 7 were easily prepared in two or three steps
from 2-iodoresorcinol (Scheme 4). The Mitsunobu reaction of 2-
iodoresorcinol (9, R1¼H)9 with (ꢀ)-ethyl lactate (10, R2¼Me) gave
C2-symmetric chiral iodoarene 7a in 90% yield. Hydrolysis of 7a
gave 7b quantitatively without epimerization. Treatment of 7b with
thionyl chloride followed by several amines gave the corresponding
amides 7cei in good yields. 7jel, 11a,3g and 11b were also prepared
in a similar manner.
10
11
12
13
14
a
The reactions were performed with 0.05 mmol of 5a and 1.3 equiv of mCPBA in
the presence of 7 or 11 (15 mol %).
b
Isolated yield of 6a by column chromatography is shown.
The ee values of 6a were determined by chiral stationary phase HPLC.
c

M. Uyanik et al. / Tetrahedron 66 (2010) 5841e5851
5843
Table 3
dicarboxylic acid 7b gave (þ)-6a with 23% ee and 43% ee, re-
Scope and limitations of the spirolactonization reactiona
spectively (entries 1 and 2). In contrast, the use of bis(primary
amide) 7c gave (þ)-6a with 70% ee (entry 3), and the use of bis
(N-aryl amide)s 7deg further increased the enantioselectivity
(entries 4e7). Bis(N-mesityl amide) 7g was the best precatalyst
with respect to activity and enantioselectivity (entry 7, 64%
yield, 82% ee). The use of tertiary amides, such as 7h and 7i
gave moderate enantioselectivities (entries 8 and 9). Bis(N-
mesityl amide) 7j bearing a methyl group at the para-position
of the iodoaryl moiety (A) gave modest enantioselectivity (en-
try 10). In contrast, the use of F-substituted 7k gave (þ)-6a with
Entry
6
Conditions
CHCl3eCH3NO2,d 17 h
CHCl3, 30 h
Yieldb (%)
eec (%)
1
2
3
4
5
6
7
8
9
10
(þ)-6b
(þ)-6c
(þ)-6d
(þ)-6e
(R)-(ꢀ)-6f
(ꢀ)-6g
(ꢃ)-6h
(þ)-6i
59
72
67
62
94
88
28
40
3
84
90
85 (98)
87 (98)
83 (>99)
91
0
87
88
91
CHCl3, 16 h
i
80% ee (entry 11). Bis(N-mesityl amide) 7l bearing an Pr group
CHCl3, 27 h
CHCl3eCH3NO2,d 16 h
CHCl3, 30 h
on the chiral linker (B) also gave high enantioselectivity and
high catalytic activity as well as 5g (entry 12). Meanwhile, C2-
unsymmetrical iodoarenes, such as monoester 11a3g and mono
(N-mesityl amide) 11b gave low enantioselectivities (entries
13 and 14). Thus, the C2-symmetric chirality in 8 was essential
for the present enantioselective oxidative spirolactonization.
Next, we optimized the reaction conditions with 7g (Table 2).
Enantioselectivity was enhanced at lower temperatures and un-
der diluted conditions (entries 2 and 3). The highest enantiose-
lectivity (92% ee) was observed in chloroform (entries 5 and 6).
Notably, high or good enantioselectivities were observed re-
gardless of the polarity of the solvent (entries 5e12). In partic-
ular, (þ)-6a was obtained in 82% yield with 85% ee in
nitromethane (entry 9). In contrast, almost no reaction occurred
when the reaction was performed in tetrahydrofuran or diethyl
ether (entries 13 and 14).
CHCl3eCH3NO2,d 7 h
CHCl3eCH3NO2,d 18 h
CHCl3eCH3NO2,d 24 h
CHCl3, 18 h
(þ)-6j
(þ)-6k
53
a
The reactions were performed with 0.05 mmol of 5 and 1.2e1.5 equiv of mCPBA
in the presence of 7g (10 mol %).
b
Isolated yield of 6 by column chromatography is shown.
The ee values of 6 were determined by chiral stationary phase HPLC. Ee value in
c
parentheses is that obtained after single recrystallization.
d
Reaction was performed in CHCl3eCH3NO2 (2/1, v/v) mixed solvents.
recrystallization (ꢁ98% ee, entries 3e5).11 The absolute stereo-
chemistry of (ꢀ)-6f was determined to be (R) based on the
X-ray crystal analysis (>99% ee, entry 5, Fig. 2). Notably, the
oxidation of 4-benzoylnaphthol derivative 5f gave 6f in 94%
yield with 83% ee (entry 5). In sharp contrast, according to
Kita’s report, 4 gave racemic 6f.6b Although the oxidation of 4-
methoxynaphthol derivative 5h gave racemic 6h (entry 8), as
did Kita’s reagent 4,6 7g gave (þ)-6i with 87% ee, for the oxi-
dation of 6-methoxynaphthol derivative 5i (entry 8). Un-
fortunately, 3-methoxynaphthol derivative 5j gave (þ)-6j in
very low yield (entry 9). Notably, the oxidation of 3-benzyloxy-
methyl-substituted 5k gave (þ)-6k in good yield with 91%
ee (entry 10). Analogs of 6k may become new chiral in-
termediate candidates in enantioselective total syntheses of
Lactonamycin.12
Table 2
Optimization of the reaction conditionsa
Entry
Solvent
Conditions
Yieldb (%)
eec (%)
d
1
2
3
CH2Cl2
0 ꢂC, 3 h
64
56
75
70
60
55
46
23
82
14
66
63
<5
<5
65
82
88
90
83
92
92
77
83
85
81
70
41
n.d.
n.d.
90
CH2Cl2
CH2Cl2
CH2Cl2
0 ꢂC, 5 h
ꢀ20 ꢂC, 48 h
25 ꢂC, 5 h
0 ꢂC, 18 h
ꢀ20 ꢂC, 48 h
4
5e
6
CHCl3
CHCl3
7
8
9
10
11
12
13
14
15
Toluene
CH3CN
CH3NO2
EtOAc
CF3CH2OH
(CF3)2CHOH
THF
0
ꢂC, 5 h
0 ꢂC, 5 h
0 ꢂC, 5 h
0
ꢂC, 5 h
0 ꢂC, 5 h
0 ꢂC, 5 h
0
ꢂC, 5 h
Et2O
0 ꢂC, 5 h
0 ꢂC, 5 h
f
CHCl3eCH3NO2
a
Unless otherwise noted, the reactions were performed with 0.05 mmol of 5a
and 1.3 equiv of mCPBA in the presence of 7g (15 mol %).
b
Isolated yield of 6a by column chromatography is shown.
The ee values of 6a were determined by chiral stationary phase HPLC.
Reaction was performed in CH2Cl2 (0.5 mL, 0.2 M).
The reaction was performed with 1.0 mmol of 5a and 1.2 equiv of mCPBA.
c
d
e
f
Reaction was performed in CHCl3eCH3NO2 (2/1, v/v, 0.02 M) mixed solvents.
Figure 2. ORTEP drawing of (R)-(ꢀ)-6f (>99% ee).
To explore the generality and substrate scope of the present
spirolactonization, several 1-naphthol derivatives 5 were ex-
amined as substrates under optimized conditions using 7g
(10 mol %) and mCPBA (1.2e1.5 equiv) (Table 3). The oxidation
of 4-substituted naphthol derivatives 5beg gave the corre-
sponding spirolactones 6beg in good to high yields with high
enantioselectivities (entries 1e6). Fortunately, nearly enantio-
Iodosylarene diacetate 14, which was analogous to 8g, was
isolated through the oxidation of 7g with Selectfluor.6 Treatment of
5a with 1 equiv of 14 in dichloromethane at 0 ꢂC gave (þ)-6a with
85% ee (Scheme 6 and entry 1 in Table 2). Thus, iodine(III) generated
in situ from 7 should be the actual oxidant species for the present
catalytic oxidation.
merically pure 6def were obtained after
a
single

5844
M. Uyanik et al. / Tetrahedron 66 (2010) 5841e5851
Scheme 6. Preparation of iodosylarene 14 from 7g and the oxidation of 5a with 14.
Next, stoichiometric oxidations of 5 with 1 equiv of 14 were
investigated under optimal conditions (Table 4). The oxidation of
5a, 5b, 5i, and 5k gave corresponding spirolactone (þ)-6 in high
yields and with high enantioselectivities (entries 1e3 and 5). Fur-
thermore, (þ)-6j was obtained in 87% yield with 95% ee for the
stoichiometric oxidation of 5j (entry 4).
Scheme 8. Epoxidation of (þ)-6a to epoxyspirolactone (ꢀ)-15.
Bromohydrin spirolactone (þ)-17 was obtained in high yield and
high diastereoselectivity by treatment of (þ)-6a with NBS in
aqueous THF (Scheme 9).16 Treatment of (þ)-17 with K2CO3 gave
epoxyspirolactone (þ)-16, which was a diastereomer of (ꢀ)-15
(Scheme 9). Thus, both of the enantioenriched epoxyspirolactones
(ꢀ)-15 and (þ)-16 could be obtained selectively from 6a in good
yields (Schemes 8 and 9).
Table 4
Stoichiometric oxidation of 5 with iodosylarene 14a
Entry
6
Yieldb (%)
eec (%)
1
2
3
4
5
(þ)-6a
(þ)-6b
(þ)-6i
(þ)-6j
(þ)-6k
70
85
89
87
75
90
89
90
95
94
a
The reactions were performed with 0.05 mmol of 5 and 0.05 mmol of 14.
Isolated yield of 6 by column chromatography is shown.
The ee values of 6 were determined by chiral stationary phase HPLC.
b
c
Oxidation of 5a with 5 equiv of mCPBA in the presence of
10 mol % of 7g gave epoxyspirolactone (ꢀ)-15 in good yield.
(Scheme 7). Enantiomerically pure (ꢀ)-15 was obtained after
Scheme 9. Conversion of (þ)-6a to bromohydrin spirolactone (þ)-17, and conversion
of (þ)-17 to epoxyspirolactone (þ)-16.
3. Conclusion
In summary, we have demonstrated the rational design of
a conformationally flexible iodosylarene 8g as a chiral catalyst
Scheme 7. One-pot oxidation of 5a to epoxyspirolactone (ꢀ)-15.
based on secondary ne
s or hydrogen-bonding interactions for the
*
a single recrystallization. Thus, the selective oxidation of 5 to
spirolactone 6 and the successive enantio- and diastereo-selective
oxidation of 5 to epoxyspirolactone 15 proceeded in good yields
when we controlled the amount of mCPBA.13 The relative ste-
reochemistry of 15 was determined by the X-ray crystal analysis
of (ꢃ)-15 (Fig. 3).
enantioselective Kita oxidative spirolactonization. In a similar way,
it is likely that several precatalysts for other enantioselective oxi-
dative transformations will be found in the library of 7. Further-
more, we have briefly highlighted the synthetic utility of the
present oxidation. Epoxyspirolactone 15 was obtained by the one-
pot oxidation of 5a with mCPBA in the presence of 7g. Thus, the
enantioselective oxidation of 5 to 6 and the successive enantio- and
diastereo-selective oxidation of 5 to 15 proceeded in good yields
when we controlled the amount of mCPBA. Additionally, un-
saturated spirolactones 6 could be easily transformed to epoxy-
spirolactones 15 and bromohydrin spirolactones 17 in good yields
and with high diastereoselectivities. Basic treatment of 17 gave
epoxyspirolactone 16, which is diastereomer of 15. Thus, both of the
enantioenriched epoxyspirolactones 15 and 16 could be obtained
selectively from unsaturated spirolactone 6 in good yields. Studies
to elucidate the detailed mechanism of oxidative spirolactonization
are currently underway.
4. Experimental section
4.1. General methods
Figure 3. ORTEP drawing of (ꢃ)-15.
Epoxyspirolactone (ꢀ)-15 could also be obtained by the epoxi-
dation of unsaturated spirolactone (þ)-6a with in situ-generated
1H NMR spectra were measured on a Varian Gemini-2000
(300 MHz), Varian INOVA-500 (500 MHz) or a JEOL ECS-400
(400 MHz) spectrometer at ambient temperature. Data were
recorded as follows: chemical shift in parts per million from
15
peracetic acid14 or MeReO3eH2O2 in good yield and with higher
diastereoselectivity (Scheme 8).

M. Uyanik et al. / Tetrahedron 66 (2010) 5841e5851
5845
internal tetramethylsilane on the
d
scale, multiplicity (s¼singlet;
in vacuo. The residue was purified by flash column chromatography
on silica gel (eluent: hexaneeEtOAc¼1:2) to give 7c (0.15 g,
0.4 mmol) in 79% yield. White solid; TLC, Rf¼0.13
(hexaneeEtOAceCHCl3¼1:2:1); IR (KBr) 3455, 3398, 3217, 1709,
d¼doublet; t¼triplet; q¼quartet; m¼multiplet), coupling constant
(Hz), integration, and assignment. 13C NMR spectra were measured
on a Varian Gemini-2000 (75 MHz), Varian INOVA-500 (125 MHz)
or JEOL ECS-400 (100 MHz) spectrometers. Chemical shifts were
recorded in parts per million from the solvent resonance employed
as the internal standard (deuterochloroform at 77.00 ppm). High-
performance liquid chromatography (HPLC) analysis was con-
ducted using Shimadzu LC-10 AD coupled diode array-detector
SPD-MA-10A-VP and chiral column of Daicel CHIRALCEL OD-H
(4.6 mmꢄ25 cm) AD-3 (4.6 mmꢄ25 cm). For thin-layer chroma-
tography (TLC) analysis throughout this work, Merck precoated TLC
plates (silica gel 60 GF254 0.25 mm) were used. The products were
purified by column chromatography on silica gel (E. Merck Art.
9385). In experiments that required dry solvents, tetrahydrofuran
(THF), dichloromethane, and toluene were purchased from Wako as
the ‘anhydrous’ and stored over 4A molecular sieves. Other solvents
were purchased from Aldrich or Wako and used without further
purification. Other simple chemicals were analytical-grade and
obtained commercially and used without further purification.
1460, 1251, 1111 cmꢀ1
; d 1.47
1H NMR (DMSO-d6, 400 MHz)
(d, J¼6.8 Hz, 6H), 4.68 (q, J¼6.8 Hz, 2H), 6.51 (d, J¼8.0 Hz, 2H), 7.24
(t, J¼8.0 Hz, 1H), 7.30 (s, 2H), 7.42 (s, 2H); 13C NMR (DMSO-d6,
100 MHz)
d 18.6 (2C), 74.8 (2C), 80.6, 106.7 (2C), 129.9, 157.5 (2C),
172.9 (2C); HRMS (FABþ) m/z calcd for C12H16IN2O4 (MþH)
26
379.0155, found 379.0152; [
a
]
ꢀ120.9 (c 1.0, CHCl3).
D
4.2.4. (2R,20R)-2,20-(2-Iodo-1,3-phenylene)bis(oxy)bis(N-phenyl-
propanamide) (7d). This compound was prepared as 7c from 7b
with aniline in 69% yield. White solid; TLC, Rf¼0.37
(hexaneeEtOAc¼1:1); IR (KBr) 3402, 1685, 1600, 1529, 1439, 1242,
1104 cmꢀ1; 1H NMR (CDCl3, 400 MHz)
d
1.75 (d, J¼6.4 Hz, 6H), 4.96
(q, J¼6.4 Hz, 2H), 6.60 (d, J¼8.4 Hz, 2H), 7.16 (t, J¼8.0 Hz, 2H), 7.33
(t, J¼8.4 Hz, 1H), 7.37 (t, J¼8.0 Hz, 4H), 7.66 (d, J¼8.0 Hz, 4H), 8.79
(br s, 2H); 13C NMR (CDCl3, 100 MHz)
d 18.3 (2C), 76.1 (2C), 80.7,
107.2 (2C), 119.8 (4C), 124.7 (2C), 129.1 (4C), 130.8, 137.2 (2C), 156.7
(2C), 168.9 (2C); HRMS (FABþ) m/z calcd for C24H24IN2O4 (MþH)
25
4.2. Synthesis of chiral iodoarenes 7ael (Scheme 4)
531.0781, found 531.0794; [
a]
ꢀ229.4 (c 1.0, CHCl3).
D
4.2.1. (2R,20R)-Diethyl 2,20-(2-iodo-1,3-phenylene)bis(oxy)dipropa-
noate (7a). To a solution of 2-iodoresorcinol9 (9, 2.36 g,10.0 mmol),
PPh3 (6.56 g, 25.0 mmol) and (ꢀ)-lactic acid ethylester (10, 2.80 mL,
25.0 mmol) in THF (50 mL) was added slowly diisopropyl azodi-
carboxylate (DIAD, 1.9 M in toluene, 25.0 mmol, 13.2 mL) at 0 ꢂC.
The reaction mixture was allowed to warm to room temperature.
After stirring for 6 h, the resulting mixture was concentrated in
vacuo. The residue was purified by flash column chromatography
on silica gel (eluent: hexaneeEtOAc¼15:1) to give 7a (3.93 g,
9.0 mmol) in 90% yield. Colorless oil; TLC, Rf¼0.33
(hexaneeEtOAc¼4:1); IR (neat) 2985, 1753, 1587, 1461, 1252,
4.2.5. (2R,20R)-2,20-(2-Iodo-1,3-phenylene)bis(oxy)bis(N-(3,5-bis(tri-
fluoromethyl)phenyl)propanamide) (7e). This compound was pre-
pared as 7c from 7b with 3,5-di-trifluoromethylaniline in 80% yield.
White solid; TLC, Rf¼0.57 (hexaneeEtOAc¼1:1); IR (KBr) 3367,1701,
1543, 1460, 1383, 1279, 1132 cmꢀ1; 1H NMR (CDCl3, 400 MHz)
d 1.77
(d, J¼6.8 Hz, 6H), 5.00 (q, J¼6.8 Hz, 2H), 6.64 (d, J¼8.4 Hz, 2H), 7.38
(t, J¼8.4 Hz, 2H), 7.67 (s, 2H), 8.17 (s, 4H), 9.03 (br s, 2H); 13C NMR
(CDCl3, 100 MHz)
d 18.1 (2C), 76.1 (2C), 80.9, 107.6 (2C), 118.1 (2C),
119.5 (4C), 123.0 (d, JCeF¼271 Hz, 4C), 131.1, 132.3 (q, JCeF¼33 Hz,
4C), 138.6 (2C), 156.5 (2C), 169.5 (2C); 19F NMR (CDCl3, 376 MHz)
d
ꢀ62.8; HRMS (FABþ) m/z calcd for C28H20F12IN2O4 (MþH)
1135 cmꢀ1
;
1H NMR (CDCl3, 400 MHz)
d
1.24 (t, J¼7.2 Hz, 6H), 1.70
803.0276, found 803.0272; [
a
]
26 ꢀ147.3 (c 1.0, CHCl3).
D
(d, J¼6.8 Hz, 6H), 4.18e4.24 (m, 4 h), 4.75 (q, J¼6.8 Hz, 2H), 6.37 (d,
J¼8.4 Hz, 2H), 7.13 (t, J¼8.4 Hz, 1H); 13C NMR (CDCl3, 100 MHz)
4.2.6. (2R,20R)-2,20-(2-Iodo-1,3-phenylene)bis(oxy)bis(N-(3,5-di-
tertbutylphenyl)propanamide) (7f). This compound was prepared
as 7c from 7b with 3,5-di-tert-butylaniline in 62% yield. White
solid; TLC, Rf¼0.64 (hexaneeEtOAc¼1:1); IR (KBr) 3382, 3290,
d
14.0 (2C), 18.5 (2C), 61.2 (2C), 74.2 (2C), 80.6, 106.9 (2C), 129.4,
158.2 (2C), 171.6 (2C); HRMS (FABþ) m/z calcd for C16H22IO6 (MþH)
437.0461, found 437.0462; [
a]
26 ꢀ21.6 (c 1.0, CHCl3).
D
2962, 1690, 1669, 1457, 1248, 1113 cmꢀ1
;
1H NMR (CDCl3,
4.2.2. (2R,20R)-2,20-(2-Iodo-1,3-phenylene)bis(oxy)dipropanoic acid
(7b). To a solution of 7a (3.93 g, 9.0 mmol) in THF (25.0 mL) and
MeOH (25.0 mL) was added 2 M NaOH (25 mL) and stirred over-
night at room temperature. The reaction mixture was cooled to
0 ꢂC, quenched with 1 M HCl and extracted with EtOAc. The organic
layers were dried over anhydrous MgSO4 and the solvents were
removed in vacuo to give analytically pure 7b (3.42 g, 9.0 mmol) in
>99% yield. White solid; TLC, Rf¼0.15 (hexaneeEtOAceCHCl3¼
1:2:1 with a few drops of AcOH); IR (KBr) 3600e2700, 2525, 1715,
400 MHz)
2H), 6.62 (d, J¼8.4 Hz, 2H), 7.19 (s, 2H), 7.33 (t, J¼8.4 Hz, 2H), 7.51
(s, 4H), 8.72 (s, 2H); 13C NMR (CDCl3, 100 MHz)
18.3 (2C), 31.3
d
1.34 (s, 36H), 1.75 (d, J¼6.8 Hz, 6H), 4.93 (q, J¼6.8 Hz,
d
(12C), 34.9 (4C), 76.4 (2C), 80.7, 107.2 (2C), 114.4 (4C), 118.9 (2C),
130.8, 136.6 (2C), 151.8 (4C), 156.9 (2C), 168.8 (2C); HRMS (FABþ)
26
m/z calcd for C40H56IN2O4 (MþH) 755.3285, found 755.3277; [
a]
D
ꢀ180.9 (c 1.0, CHCl3).
4.2.7. (2R,20R)-2,20-(2-Iodo-1,3-phenylene)bis(oxy)bis(N-mesitylpro-
panamide) (7g). This compound was prepared as 7c from 7b with
mesitylaniline in 78% yield. White solid; TLC, Rf¼0.42
(hexaneeEtOAc¼1:1); IR (KBr) 3255, 1673, 1528, 1463, 1256,
1581, 1458, 1252 cmꢀ1 1H NMR (DMSO-d6, 400 MHz)
; d 1.54 (d,
J¼6.8 Hz, 6H), 4.84 (q, J¼6.8 Hz, 2H), 6.42 (d, J¼8.0 Hz, 2H), 7.21 (t,
J¼8.0 Hz, 1H); 13C NMR (DMSO-d6, 100 MHz)
d 18.4 (2C), 72.8 (2C),
79.6, 105.9 (2C),129.7, 157.8 (2C),172.7 (2C); HRMS (FABþ) m/z calcd
1138 cmꢀ1; 1H NMR (CDCl3, 400 MHz)
d
1.77 (d, J¼6.8 Hz, 6H), 2.15
for C12H13IO6 (M) 379.9757, found 329.9755; [
a
]
D
26 ꢀ6.4 (c 1.0, THF).
(s, 12H), 2.26 (s, 6H), 5.00 (q, J¼6.8 Hz, 2H), 6.64 (d, J¼8.4 Hz, 2H),
6.86 (s, 4H), 7.34 (t, J¼8.4 Hz, 1H), 8.02 (s, 2H); 13C NMR (CDCl3,
4.2.3. (2R,20R)-2,20-(2-Iodo-1,3-phenylene)bis(oxy)dipropan amide
(7c). A solution of 7b (190 mg, 0.50 mmol) in SOCl2 (4.0 mL) was
refluxed for 1 h. To the resulting mixture was added benzene
(2ꢄ2 mL), and excess reagents were removed in vacuo. The residue
was dissolved in CH2Cl2 (5 mL), and to the resulting mixture was
added excess NH3 gas with cooling (ꢀ78 ꢂC). The resulting mixture
was stirred at ꢀ78 ꢂC for 2 h, and gradually warmed to room
temperature. After stirring for overnight, the reaction mixture was
poured into 1 M HCl and extracted with CHCl3. The organic layers
were dried over anhydrous MgSO4 and the solvents were removed
100 MHz) d 18.2 (4C), 18.7 (2C), 20.8 (2C), 76.0 (2C), 80.4, 107.0 (2C),
128.9 (4C), 130.0 (2C), 130.6, 135.0 (4C), 137.1 (2C), 156.9 (2C), 169.6
(2C); HRMS (FABþ) m/z calcd for C30H36IN2O4 (MþH) 615.1720,
26
found 615.1717; [
a
]
ꢀ116.1 (c 1.0, CHCl3).
D
4.2.8. (2R,20R)-2,20-(2-Iodo-1,3-phenylene)bis(oxy)bis(1-(pyrrolidin-
1-yl)propan-1-one) (7h). This compound was prepared as 7c from
7b with pyrrolidine in >99% yield. White solid; TLC, Rf¼0.19
(hexaneeEtOAceCHCl3¼1:2:1); IR (KBr) 2980, 2875, 1650, 1461,
1428, 1255, 1103 cmꢀ1 1H NMR (CDCl3, 400 MHz)
; d 1.55e1.92 (m,

5846
M. Uyanik et al. / Tetrahedron 66 (2010) 5841e5851
8H), 1.68 (d, J¼6.8 Hz, 6H), 3.31 (dt, J¼6.8, 11.2 Hz, 2H), 3.42e3.53
(m, 4H), 3.72 (dt, J¼6.8, 11.2 Hz, 2H), 4.83 (q, J¼6.8 Hz, 2H), 6.46 (d,
J¼8.0 Hz, 2H), 7.16 (t, J¼8.0 Hz, 2H); 13C NMR (CDCl3, 100 MHz)
400 MHz)
172.0.
d 18.6, 52.3, 74.1, 87.2, 113.3, 123.5, 129.3, 139.7, 156.5,
d
17.4 (2C), 23.2 (2C), 26.5 (2C), 46.3 (2C), 46.8 (2C), 76.5 (2C), 78.5,
4.2.14. (R)-2-(2-Iodophenoxy)-N-mesitylpropanamide (11b). Com-
pound 11b was prepared as 7g from in 88% yield. Yellow solid;
TLC, Rf¼0.55 (hexaneeEtOAc¼1:1); IR (KBr) 3277, 1658, 1521, 1473,
106.0 (2C), 130.3, 157.6 (2C), 169.3; HRMS (FABþ) m/z calcd for
25
C20H28IN2O4 (MþH) 487.1094, found 487.1092; [
a]
ꢀ161.0 (c 1.0,
D
CHCl3).
1224, 1100 cmꢀ1
;
1H NMR (CDCl3, 400 MHz)
d
1.77 (d, J¼6.8 Hz,
3H), 2.14 (s, 6H), 2.27 (s, 3H), 4.96 (q, J¼6.8 Hz, 1H), 6.80 (t,
4.2.9. (2R,20R)-2,20-(2-Iodo-1,3-phenylene)bis(oxy)bis(N,N-diphenyl-
propanamide) (7i). This compound was prepared as 7c from 7b
with diphenylamine in 72% yield. White solid; TLC, Rf¼0.37
(hexaneeEtOAc¼1:1); IR (KBr) 3600e3200, 3448, 1686, 1491, 1458,
J¼7.6 Hz, 1H), 6.90e6.96 (m, 3H), 7.34 (t, J¼7.6 Hz, 1H), 7.82 (dd,
J¼1.6, 7.6 Hz, 1H), 8.00 (br s, 1H); 13C NMR (CDCl3, 100 MHz)
d 18.3
(2C), 18.7, 20.9, 75.8, 87.2, 113.1, 123.8, 129.0 (2C), 129.8, 130.0,
135.1 (2C), 137.2, 139.7, 155.1, 169.8; HRMS (FABþ) m/z calcd for
25
1247,1092 cmꢀ1; 1H NMR (CDCl3, 400 MHz)
d
1.62 (d, J¼6.4 Hz, 6H),
C18H21INO2 (MþH) 410.0617, found 410.0609; [
a
]
þ52.1 (c 1.0,
D
4.88 (q, J¼6.4 Hz, 2H), 6.40 (d, J¼8.4 Hz, 2H), 7.11 (t, J¼8.4 Hz, 2H),
CHCl3).
7.20e7.32 (m, 20H); 13C NMR (CDCl3, 75 MHz)
d
18.1 (2C), 73.6 (2C),
83.0, 108.8 (2C), 126.1 (m, 8C), 130.0 (m, 13C), 141.0 (m, 2C), 142.0
4.3. Synthesis of 1-napthol derivatives 5 (Scheme 5)
(m, 2C), 158.0 (2C), 170.5 (2C); HRMS (FABþ) m/z calcd for
26
C36H32IN2O4 (MþH) 683.1407, found 683.1407; [
a]
ꢀ30.8 (c 1.0,
4.3.1. 3-(1-Hydroxynaphthalen-2-yl)propanoic acid (5a)6,10. To
a stirred solution of 1-naphtol (12a, 4.33 g, 30 mmol) and triethyl
orthoacrylate (6.0 ml, 48 mmol) in toluene (100 ml) was added
pivalic acid (1.53 g, 15 mmol) and the resulting mixture was
refluxed for 1 day. The resulting mixture was poured into 1 M NaOH
(30 mL), extracted with Et2O (twice) and washed with brine. The
combined organic layers were dried over anhydrous Na2SO4 and
solvents were removed in vacuo. The residue was purified by flash
D
CHCl3).
4.2.10. (2R,20R)-2,20-(2-Iodo-5-methyl-1,3-phenylene)bis(oxy)bis(N-
mesitylpropanamide) (7j). This compound was prepared as 7g
from 2-iodo-5-methylresorcinol. White solid; TLC, Rf¼0.56
(hexaneeEtOAceCHCl3¼1:2:1); IR (KBr) 3234, 2918, 1668, 1578,
1508, 1440, 1239, 1108 cmꢀ1 1H NMR (CDCl3, 400 MHz)
; d 1.77
(d, J¼6.8 Hz, 6H), 2.14 (s, 12H), 2.26 (s, 6H), 2.35 (s, 3H), 4.98
column
chromatography
on
silica
gel
(eluent:
(q, J¼6.8 Hz, 2H), 6.48 (s, 2H), 6.90 (s, 4H), 7.97 (s, 2H); 13C NMR
hexaneeEtOAc¼15:1) to give 13a (8.17 g, 30 mmol, >99% yield) as
colorless oil. To a solution of 13a (8.17 g, 30 mmol) in Et2O (80 ml)
was added 2 M HCl (40 ml) and the resulting mixture was stirred
for overnight at room temperature. The resulting mixture was
extracted with EtOAc (twice) and washed with brine. The combined
organic layers were dried over anhydrous Na2SO4 and solvents
were removed in vacuo. To a solution of the crude product in THF
(30 mL) and MeOH (30 ml) was added 2 N NaOH (40 mL) and the
resulting mixture was stirred overnight at room temperature. The
resulting mixture was poured into 1 N HCl (100 mL), extracted with
EtOAc (twice) and washed with brine. The combined organic layers
were dried over anhydrous MgSO4 and solvents were removed in
vacuo. The residue was purified by flash column chromatography
on silica gel (eluent: hexaneeEtOAc¼4:1 to 1:2) to give 5a (4.05 g,
18.7 mmol) in 62% yield (2 steps). White solid; TLC, Rf¼0.27
(hexaneeEtOAceCHCl3¼1:2:1 with a few drops of AcOH); 1H NMR
(CDCl3, 100 MHz)
d 18.2 (4C), 18.8 (2C), 20.9 (2C), 21.8, 76.0 (2C),
76.2, 108.1 (2C), 129.0 (4C), 130.0 (2C), 135.0 (4C), 137.2 (2C),
141.4, 156.6 (2C), 169.7 (2C); HRMS (FABþ) m/z calcd for
23
C31H38IN2O4 (MþH) 629.1876, found 629.1870; [
a
]
ꢀ94.9 (c 1.0,
D
CHCl3).
4.2.11. (2R,20R)-2,20-(5-Fluoro-2-iodo-1,3-phenylene)bis(oxy)bis(N-
mesitylpropanamide) (7k). This compound was prepared as 7g
from 5-fluoro-2-iodoresorcinol. Pale purple solid; TLC, Rf¼0.60
(hexaneeEtOAceCHCl3¼1:2:1); IR (KBr) 3246, 2920, 1668, 1609,
1508, 1431, 1211, 1105 cmꢀ1 1H NMR (CDCl3, 400 MHz)
; d 1.78
(d, J¼6.8 Hz, 6H), 2.16 (s, 12H), 2.27 (s, 6H), 4.94 (q, J¼6.8 Hz, 2H),
6.46 (d, J¼10.1 Hz, 2H), 6.91 (s, 4H), 7.94 (s, 2H); 13C NMR (CDCl3,
100 MHz)
d 18.3 (4C), 18.6 (2C), 20.9 (2C), 73.5, 76.4 (2C), 95.4 (d,
JCeF¼27 Hz, 2C), 129.0 (4C), 129.9 (2C), 135.0 (4C), 137.4 (2C), 157.2
(d, JCeF¼13 Hz, 2C), 165.0 (d, JCeF¼247 Hz), 169.0 (2C); 19F NMR
(CDCl3, 400 MHz)
d 2.86e2.89 (m, 2H), 3.02e3.06 (m, 2H), 7.17 (d,
(CDCl3, 376 MHz)
d
ꢀ107.8; HRMS (FABþ) m/z calcd for
J¼8.4 Hz, 1H), 7.39 (d, J¼8.4 Hz, 1H), 7.40e7.47 (m, 2H), 7.65 (br s,
C30H35FIN2O4 (MþH) 633.1626, found 633.1612; [
a]
22 ꢀ122.2 (c 0.6,
1H), 7.73e7.76 (m, 1H), 8.24e8.27 (m, 1H); 13C NMR (CDCl3,
D
CHCl3).
100 MHz) d 24.1, 34.7, 120.0, 120.7, 122.1, 125.3, 125.7, 125.9, 127.3,
128.1, 133.7, 149.2, 180.5.
4.2.12. (2R,20R)-2,20-(2-Iodo-1,3-phenylene)bis(oxy)bis(N-mesityl-3-
methylbutanamide) (7l). Compound 7l was prepared as 7g in 30%
yield (three steps). Yellow solid; TLC, Rf¼0.48 (hexaneeEtOAc¼
4.3.2. 3-(1-Hydroxy-4-methylnaphthalen-2-yl)propanoic acid (5b).
This compound was prepared as 5a from 4-methylnaphthalen-1-
ol (12b) in 62% yield (three steps). White solid; TLC, Rf¼0.50
(hexaneeEtOAceCHCl3¼1:2:1 with a few drops of AcOH); IR
1:1); IR (KBr) 3376, 3246, 2967, 2921, 1665, 1459, 1246, 1079 cmꢀ1
;
1H NMR (CDCl3, 400 MHz)
d
1.19 (d, J¼7.2 Hz, 6H), 1.31 (d, J¼7.2 Hz,
6H), 2.05 (s, 12H), 2.24 (s, 6H), 2.45e2.52 (m, 2H), 4.73 (q, J¼6.8 Hz,
(film) 3500e3200, 3010, 1765, 1703, 1387, 1147 cmꢀ1 1H NMR
;
2H), 6.62 (d, J¼8.4 Hz, 2H), 6.86 (s, 4H), 7.28 (t, J¼8.4 Hz,1H), 7.60 (s,
(CDCl3, 400 MHz)
J¼6.9 Hz, 2H), 6.99 (s, 1H), 7.44e7.49 (m, 2H), 7.84e7.88 (m, 1H),
8.24e8.28 (m, 1H); 13C NMR (CDCl3, 100 MHz)
18.7, 24.0, 34.7,
d
2.57 (s, 3H), 2.85 (t, J¼6.9 Hz, 2H), 2.99 (t,
2H); 13C NMR (CDCl3, 100 MHz)
d 17.6 (2C), 18.5 (4C), 19.1 (2C), 20.8
(2C), 31.7 (2C), 79.3, 84.4 (2C), 106.5 (2C), 129.0 (4C), 130.0 (2C),
d
130.6, 134.8 (4C),137.1 (2C),157.6 (2C),168.4 (2C); HRMS (FABþ) m/z
119.5, 122.7, 123.8, 125.0, 125.7, 126.0, 126.6, 128.4, 132.5, 147.7,
180.3; HRMS (FABþ) m/z calcd for C14H15O3 (MþH) 231.1021,
found 231.1025.
26
calcd for C34H44IN2O4 (MþH) 671.2346, found 671.2342; [
a]
D
ꢀ63.7 (c 1.0, CHCl3).
4.2.13. (R)-Methyl 2-(2-iodophenoxy)propanoate (11a)3g. Com-
pound 11a was prepared as 7a from 2-iodophenol with (ꢀ)-lactic
acid methylester in 80% yield. Pale yellow oil; TLC, Rf¼0.40
4.3.3. 3-(4-Chloro-1-hydroxynaphthalen-2-yl)propanoic acid (5c).
This compound was prepared as 5a from 4-chloronaphthalen-1-ol
(12c) in 40% yield (three steps). White solid; TLC, Rf¼0.50
(hexaneeEtOAceCHCl3¼1:2:1 with a few drops of AcOH); IR (KBr)
3500e3200, 1691, 1595, 1449, 1381, 1259 cmꢀ1; 1H NMR (DMSO-d6,
(hexaneeEtOAc¼4:1); 1H NMR (CDCl3, 400 MHz)
d 1.69 (d,
J¼6.9 Hz, 3H), 3.75 (s, 3H), 4.88 (q, J¼6.9 Hz,1H), 6.64e6.77 (m, 2H),
7.24 (t, J¼7.8 Hz, 1H), 7.77 (dd, J¼1.8, 7.8 Hz, 1H); 13C NMR (CDCl3,
400 MHz)
d
2.57 (t, J¼7.8 Hz, 2H), 2.98 (t, J¼7.8 Hz, 2H), 7.48 (s, 1H),

M. Uyanik et al. / Tetrahedron 66 (2010) 5841e5851
5847
7.54e7.63 (m, 2H), 8.03 (d, J¼7.3 Hz, 1H), 8.27 (d, J¼7.3 Hz, 1H), 9.48
(br s, 1H), 12.18 (br s, 1H); 13C NMR (DMSO-d6, 100 MHz)
25.0,
34.0,120.5,122.5, 122.7,123.5,125.8, 126.5,126.8,128.5, 129.4,149.1,
174.1; HRMS (FABþ) m/z calcd for C13H12ClO3 (MþH) 251.0475,
found 251.0479.
(d, J¼8.4 Hz, 1H); 13C NMR (CDCl3, 100 MHz)
d
24.5, 34.7, 55.7,
d
105.5, 119.6, 121.6, 122.0, 125.3, 125.4, 126.0, 126.7, 142.7, 149.7,
180.3.
4.3.9. 3-(1-Hydroxy-6-methoxynaphthalen-2-yl)propanoic
acid
(5i). This compound was prepared as 5a from 6-methoxynaph-
thalen-1-ol (12i) in 60% yield (three steps). Yellow solid; TLC,
Rf¼0.50 (hexaneeEtOAceCHCl3¼1:2:1 with a few drops of AcOH);
4.3.4. 3-(4-Bromo-1-hydroxynaphthalen-2-yl)propanoic acid (5d)6.
This compound was prepared as 5a from 4-bromonaphthalen-1-ol
(12d) in 71% yield (3 steps). Yellow solid; TLC, Rf¼0.50
(hexaneeEtOAceCHCl3¼1:2:1 with a few drops of AcOH); IR (KBr)
IR (KBr) 3542, 3484, 1686, 1418, 1360, 1229, 1163 cmꢀ1 1H NMR
;
(DMSO-d6, 400 MHz)
d
2.50e2.53 (m, 2H), 2.91 (t, J¼7.3 Hz, 2H),
3500e3200, 1692, 1595, 1449, 1378, 1241 cmꢀ1
;
1H NMR (CDCl3,
3.84 (s, 3H), 7.07 (dd, J¼2.8, 9.2 Hz, 1H) 7.17e7.26 (m, 3H), 8.08 (d,
400 MHz) d 2.87e2.90 (m, 2H), 3.00e3.03 (m, 2H), 7.48 (s, 1H), 7.51
J¼9.0 Hz, 1H), 9.07 (br s, 1H), 12.10 (br s, 1H); 13C NMR (DMSO-d6,
(dt, J¼1.2, 7.2 Hz, 1H), 7.56 (dt, J¼1.2, 7.2 Hz, 1H), 7.50e7.70 (br s,
100 MHz) d 25.2, 34.4, 55.1, 105.7, 117.0, 118.2, 119.5, 120.6, 123.6,
1H), 8.08 (d, J¼7.2 Hz, 1H), 8.25 (d, J¼7.2 Hz, 1H); 13C NMR (CDCl3,
129.1, 134.6, 149.7, 156.8, 174.4; HRMS (FABþ) m/z calcd for C14H15O4
(MþH) 247.0970, found 247.0965.
100 MHz)
d 23.8, 34.6, 113.4, 121.0, 122.8, 126.1, 126.7, 127.1, 127.3,
131.4, 131.7, 149.4, 180.3; HRMS (FABþ) m/z calcd for C13H11BrO3 (M)
293.9892, found 293.9896.
4.3.10. 3-(1-Hydroxy-3-methoxynaphthalen-2-yl)propanoic
acid
(5j). This compound was prepared as 5a from 3-methoxynaph-
thalen-1-ol (12j) in 40% yield (three steps). Pale brown solid; TLC,
Rf¼0.46 (hexaneeEtOAceCHCl3¼1:2:1 with a few drops of AcOH);
4.3.5. 3-(1-Hydroxy-4-phenylnaphthalen-2-yl)propanoic acid (5e).
This compound was prepared as 5a from 4-phenylnaphthalen-1-
ol (12e) in 73% yield (three steps). Pale yellow solid; TLC, Rf¼0.50
(hexaneeEtOAceCHCl3¼1:2:1 with a few drops of AcOH); IR
IR (KBr) 3394, 3406, 2943, 1697, 1446, 1406, 1268, 1116 cmꢀ1 1H
;
NMR (DMSO-d6, 400 MHz)
d
2.42 (t, J¼8.0 Hz, 2H), 2.98 (t, J¼8.0 Hz,
(KBr) 3500e3200, 1699, 1578, 1391, 1304, 1220 cmꢀ1
;
1H NMR
2H), 3.87 (s, 3H), 6.87 (s, 1H), 7.27 (t, J¼7.3 Hz, 1H), 7.37 (t, J¼7.3 Hz,
(DMSO-d6, 500 MHz)
d
2.59 (t, J¼7.5 Hz, 2H), 3.03 (t, J¼7.5 Hz,
1H), 7.69 (d, J¼7.8 Hz, 1H), 8.08 (d, J¼8.2 Hz, 1H), 9.20 (br s, 1H),
2H), 7.23 (s, 1H), 7.39e7.51 (m, 7H), 7.73 (d, J¼7.5 Hz, 2H), 8.28 (d,
12.19 (br s, 1H); 13C NMR (DMSO-d6, 100 MHz)
d 19.1, 33.5, 55.5,
J¼7.5 Hz, 1H), 9.25 (br s, 1H), 12.05 (br s, 1H); 13C NMR (DMSO-d6,
97.8, 113.9, 121.2, 121.9, 122.4, 125.9, 126.4, 133.2, 150.4, 156.5, 174.8;
HRMS (FABþ) m/z calcd for C14H15O4 (MþH) 247.0970, found
247.0971.
100 MHz)
d 25.3, 34.3, 121.3, 122.4, 124.8, 125.0, 125.5, 125.6,
126.9, 128.4 (2C), 129.6, 129.9 (2C), 130.6, 131.0, 140.4, 149.2,
174.4; HRMS (FABþ) m/z calcd for C19H17O3 (MþH) 293.1178,
found 293.1174.
4.3.11. 3-(3-(Benzyloxymethyl)-1-hydroxynaphthalen-2-yl)prop-
anoic acid (5k). This compound was prepared as 5a from 3-
benzyloxymethylnaphthalen-1-ol (12k) in 53% yield (three
steps). Pale yellow solid; TLC, Rf¼0.38 (hexaneeEtOAce
CHCl3¼1:2:1 with a few drops of AcOH); IR (KBr) 3233, 2874,
4.3.6. 3-(4-Benzoyl-1-hydroxynaphthalen-2-yl)propanoic acid (5f)6.
This compound was prepared as 5a from (4-hydroxynaphthalen-
1-yl)(phenyl)methanone (12f) in 77% yield (three steps). White
solid; TLC, Rf¼0.50 (hexaneeEtOAceCHCl3¼1:2:1 with a few
drops of AcOH); IR (KBr) 3500e3200, 1685, 1562, 1503, 1269,
1696, 1362, 1250, 1033 cmꢀ1 1H NMR (CDCl3, 400 MHz)
; d 2.84 (t,
J¼5.0 Hz, 1H), 3.11 (t, J¼5.0 Hz, 1H), 4.56 (s, 2H), 4.65 (s, 2H),
1242 cmꢀ1
;
1H NMR (DMSO-d6, 400 MHz)
d
2.55 (t, J¼7.3 Hz, 2H),
7.24e7.46 (m, 8H), 7.71e7.73 (m, 1H), 8.22e8.23 (m, 1H); 13C
2.99 (t, J¼7.3 Hz, 2H), 7.40e7.57 (m, 5H), 7.67 (t, J¼7.3 Hz, 1H),
7.74 (d, J¼8.3 Hz, 2H), 8.21 (d, J¼8.3 Hz, 1H), 8.34 (d, J¼7.8 Hz,
1H), 10.10 (br s, 1H), 12.10 (br s, 1H); 13C NMR (DMSO-d6,
NMR (CDCl3, 100 MHz) d 20.0, 34.2, 71.5, 72.0, 119.9, 122.0, 122.4,
125.5, 125.7, 126.2, 127.3, 127.8, 128.1 (2C), 128.5 (2C), 132.9,
134.2, 137.7, 150.4, 180.8; HRMS (FABþ) m/z calcd for C21H21O4
(MþH) 337.1440, found 337.1434.
100 MHz)
d 25.2, 33.9, 119.8, 122.4, 125.2, 125.3, 125.5, 126.1,
127.0, 128.6 (2C), 129.9 (2C), 131.2, 132.7, 133.8, 138.9, 153.4, 174.0,
196.2; HRMS (FABþ) m/z calcd for C20H17O4 (MþH) 321.1127,
found 321.1133.
4.4. Preparation of iodosylarene 14 (Scheme 6)6
A
solution of 7g (61.5 mg, 0.1 mmol) and SelectfluorÒ
4.3.7. 3-(4-(4-Bromobenzoyl)-1-hydroxynaphthalen-2-yl)propanoic
acid (5g). This compound was prepared as 5a from (4-bromo-
phenyl)(4-hydroxynaphthalen-1-yl)methanone (12g) in 70% yield
(177 mg, 0.5 mmol) in AcOH (1 mL) and CH3CN (3.2 mL) was
stirred for 5 h at room temperature. After CH3CN was evapo-
rated in vacuo, water was added to the residue and the
resulting solution was extracted with CH2Cl2 (twice), and
washed with water. The combined organic layers were dried
over anhydrous Na2SO4. The solvents were removed in vacuo to
give 14 (66 mg, 0.09 mmol, contained ca. 10% of 7g) in 90%
yield. White powder; IR (film) 3317, 3008, 1677, 1517, 1464,
1252, 1094 cmꢀ1; The 1H and 13C NMR spectra of 14 were
assigned by using a combination of 2D NMR experiments,
which included HMQC and HMBC studies: 1H NMR (CDCl3,
(three
(hexaneeEtOAceCHCl3¼1:2:1 with a few drops of AcOH); IR (KBr)
3500e3200, 1716, 1699, 1628, 1570, 1509, 1260 cmꢀ1 1H NMR
(DMSO-d6, 400 MHz)
steps).
Pale
yellow
solid;
TLC,
Rf¼0.50
;
d
2.55 (t, J¼7.3 Hz, 2H), 2.99 (t, J¼7.3 Hz, 2H),
7.52 (s, 1H), 7.52e7.57 (m, 2H), 7.66 (d, J¼8.2 Hz, 2H), 7.74 (d,
J¼8.7 Hz, 2H), 8.23e8.27 (m,1H), 8.33e8.36 (m,1H),10.18 (br s,1H),
12.16 (br s, 1H); 13C NMR (DMSO-d6, 125 MHz)
d 25.1, 33.9, 119.8,
122.4, 125.2, 125.3 (2C), 125.5, 126.7, 127.2, 131.2, 131.6 (2C), 131.9
(2C), 134.3, 137.9, 153.7, 174.0, 196.1; HRMS (FABþ) m/z calcd for
C20H15BrO4 (M) 398.0154, found 398.0155.
400 MHz, Ar1¼Iodoarene, Ar2¼Mesitylene)
d 1.50 (s, 6H,
IOCOCH3), 1.80e1.90 (br s, 12H, 2-CH3eAr2), 1.88 (d, J¼6.5 Hz,
6H, eOCH(CH3)COe), 2.21 (s, 6H, 4-CH3eAr2), 5.15 (q, J¼6.5 Hz,
2H, eOCH(CH3)COe), 6.79 (s, 4H, 3HeAr2), 6.94 (d, J¼8.5 Hz, 2H,
3HeAr1), 7.57 (t, J¼8.5 Hz, 1H, 4HeAr1), 8.34 (s, 2H, NH); 13C
4.3.8. 3-(1-Hydroxy-4-methoxynaphthalen-2-yl)propanoic
acid
(5h)6. This compound was prepared as 5a from 4-methoxy-
naphthalen-1-ol (12h) in 54% yield (three steps). White solid;
TLC, Rf¼0.50 (hexaneeEtOAceCHCl3¼1:2:1 with a few drops of
NMR (CDCl3, 100 MHz)
d 17.6 (4C), 19.4 (2C), 19.5 (2C), 20.9 (4C),
76.2 (2C), 103.5, 106.3 (2C), 129.0 (4C), 129.6 (4C), 134.9 (2C),
136.5, 137.4 (2C), 156.0 (2C), 169.6 (2C), 176.7 (2C); HRMS
(FABþ) m/z calcd for C32H38IN2O6 (MeOAc) 673.1775, found
673.1779.
AcOH); 1H NMR (CDCl3, 400 MHz)
d
2.89 (t, J¼6.4 Hz, 2H), 3.04 (t,
J¼6.4 Hz, 2H), 3.95 (s, 3H), 6.49 (s, 1H) 7.18e7.28 (br s, 1H), 7.45
(t, J¼8.4 Hz, 1H), 7.50 (t, J¼8.4 Hz, 1H), 8.14 (d, J¼8.4 Hz, 1H), 8.21

5848
M. Uyanik et al. / Tetrahedron 66 (2010) 5841e5851
4.5. Representative procedure for 8g-catalyzed
enantioselective oxidative dearomatization of 5 with mCPBA
(Tables 1e3)
give colorless crystal (low ee). The enantioselectivities of the
mother liquid was 98% ee. White solid; TLC, Rf¼0.43
(hexaneeEtOAc¼1:1); IR (film) 3029, 1791, 1699, 1592, 1453,
1187 cmꢀ1
;
1H NMR (CDCl3, 400 MHz)
d
2.24 (ddd, J¼9.6, 11.0,
4.5.1. (þ)-10H,3H-Spiro[furan-2,20-naphthalene]-10,5(4H)-dione (6a,
Table 2, entry 3)6. A solution of 5a (216 mg, 1.0 mmol), 7g (92.2 mg,
0.15 mmol, 15 mol %), and mCPBA (269 mg, 1.2 mmol, 1.2 equiv) in
CHCl3 (50 mL) was stirred at 0 ꢂC. After 18 h, the resulting mixture
poured into aqueous Na2S2O3 (20 mL) and aqueous NaHCO3, and
extracted with CHCl3 (two times). The organic layers were dried
over anhydrous MgSO4 and solvents were removed in vacuo. The
residue was purified by flash column chromatography on silica gel
(eluent: hexaneeEtOAc¼10:1 to 4:1) to give 6a (129 mg, 0.6 mmol)
13.5 Hz, 1H), 2.46 (ddd, J¼2.3, 9.6, 13.5 Hz, 1H), 2.62 (ddd, J¼2.3,
9.6, 17.9 Hz, 1H), 2.90 (ddd, J¼9.6, 11.0, 17.9 Hz, 1H), 6.67 (s, 1H),
7.49e7.53 (m, 1H), 7.73e7.78 (m, 2H), 8.05 (d, J¼7.2 Hz, 1H); 13C
NMR (CDCl3, 100 MHz)
d 26.5, 31.2, 84.2, 122.5, 127.0, 128.0,
128.8, 130.1, 133.4, 135.1, 135.9, 175.7, 194.7; HRMS (FABþ) m/z
calcd for C13H10BrO3 (MþH) 292.9813, found 292.9814; HPLC
(OD-H column), hexaneeiPrOH¼85:15 as eluent, 1.0 mL/min,
26
tR¼18.8 min (major), 22.3 min (minor); [
a
]
þ91.8 (c 1.6, CHCl3)
D
for 98% ee.
in
60%
yield.
White
solid;
TLC,
Rf¼0.46
2.18
(hexaneeEtOAceCHCl3¼1:2:1); 1H NMR (CDCl3, 400 MHz)
d
4.6.4. (þ)-40-Phenyl-10H,3H-spiro[furan-2,20-naphthalene]-10,5 (4H)-
dione (6e; Table 3, entry 4). Recrystallization of 6e (87% ee) was
(ddd, J¼9.6,11.0,13.5 Hz,1H), 2.49 (ddd, J¼1.8, 9.6,13.5 Hz,1H), 2.60
(ddd, J¼1.8, 9.6, 17.6 Hz, 1H), 2.92 (ddd, J¼9.6, 11.0, 17.6 Hz, 1H), 6.21
(d, J¼10.4 Hz, 1H), 6.66 (d, J¼10.4 Hz, 1H), 7.26 (d, J¼8.0 Hz, 1H),
7.41 (t, J¼8.0 Hz, 1H), 7.62 (t, J¼8.0 Hz, 1H), 8.02 (d, J¼8.0 Hz, 1H);
i
carried out in the solution of PrOH at room temperature to give
colorless crystal (98% ee). TLC, Rf¼0.47 (hexaneeEtOAc¼1:1); IR
(film) 3027, 1783, 1687, 1593, 1280, 1176 cmꢀ1 1H NMR (CDCl3,
;
13C NMR (CDCl3, 100 MHz)
d
26.5, 31.2, 83.4, 127.3, 127.8, 127.9,
400 MHz)
d
2.27 (ddd, J¼9.6, 11.0, 13.3 Hz, 1H), 2.54 (ddd, J¼2.3, 9.6,
127.9, 129.0, 132.3, 135.7, 136.8, 176.5, 196.5; HPLC (OD-H column),
13.3 Hz, 1H), 2.63 (ddd, J¼2.3, 9.6, 17.6 Hz, 1H), 2.93 (ddd, J¼9.6,
11.0, 17.6 Hz, 1H), 6.12 (s, 1H), 7.15 (d, J¼7.3 Hz, 1H), 7.34e7.50 (m,
6H), 7.56 (dt, J¼1.4, 7.3 Hz, 1H), 8.10 (dd, J¼1.4, 7.3 Hz, 1H); 13C NMR
hexaneeiPrOH¼85:15 as eluent, 1.0 mL/min, tR¼19.4 min (major),
25.1 min (minor); [
a]
26 þ181.7 (c 1.2, CHCl3) for 92% ee.
D
(CDCl3, 100 MHz)
d 26.7, 31.5, 83.7, 127.4, 127.6, 128.2, 128.4, 128.6
4.6. Representative procedure for the stoichiometric
oxidation of 5 with 14 (Scheme 6 and Table 4)
(2C), 128.7 (2C), 128.9, 130.6, 135.3, 137.4, 137.6, 139.8, 176.3, 196.4;
HRMS (FABþ) m/z calcd for C19H15O3 (MþH) 291.1021, found
291.1021; HPLC (OD-H column), hexaneeiPrOH¼85:15 as eluent,
A
solution of 5a (10.8 mg, 0.05 mmol) and 14 (36.6 mg,
1.0 mL/min, tR¼20.0 min (minor), 31.2 min (major); [
a
]
26 þ115.9 (c
D
0.05 mmol) in CHCl3 (2.5 mL) was stirred at ꢀ20 ꢂC. After 19 h, the
resulting mixture poured into aqueous Na2S2O3 (5 mL) and aqueous
NaHCO3, and extracted with CHCl3 (two times). The organic layers
were dried over anhydrous MgSO4 and solvents were removed in
vacuo. The residue was purified by flash column chromatography
on silica gel (eluent: hexaneeEtOAc¼10:1 to 4:1) to give 6a (7.5 mg,
0.035 mmol) in 70% yield and 90% ee.
0.19, CHCl3) for 98% ee.
4.6.5. (ꢀ)-(R)-40-Benzoyl-10H,3H-spiro[furan-2,20-naphthalene]-10,5
(4H)-dione (6f; Table 3, entry 5)6. Colorless crystal; TLC, Rf¼0.40
(hexaneeEtOAc¼1:1); IR (KBr) 3069, 2944, 1783, 1692, 1591, 1455,
1190 cmꢀ1
;
1H NMR (CDCl3, 400 MHz)
d
2.27 (ddd, J¼9.6, 11.0,
13.3 Hz, 1H), 2.52 (ddd, J¼1.8, 9.6, 13.3 Hz, 1H), 2.63 (ddd, J¼1.8, 9.6,
17.6 Hz, 1H), 2.92 (ddd, J¼9.6, 11.0, 17.6 Hz, 1H), 6.39 (s, 1H), 7.41 (d,
J¼7.8 Hz, 1H), 7.46e7.52 (m, 3H), 7.60e7.67 (m, 2H), 7.96 (d,
J¼7.3 Hz, 2H), 8.12 (dd, J¼1.4, 7.8 Hz, 1H); 13C NMR (CDCl3,
4.6.1. (þ)-40-Methyl-10H,3H-spiro[furan-2,20-naphthalene]-10,5(4H)-
dione (6b; Table 3, entry 1 and Table 4, entry 2). Colorless amor-
phous; TLC, Rf¼0.40 (hexaneeEtOAc¼1:1); IR (film) 3027, 1783,
100 MHz)
d 26.3, 31.2, 82.7, 126.9, 127.4, 128.5, 128.9 (2C), 129.8,
1696, 1599, 1453, 1175 cmꢀ1; 1H NMR (CDCl3, 400 MHz)
d
2.12e2.24
130.1 (2C), 134.0, 134.2, 134.3, 135.8, 136.0, 1375, 175.8, 194.5, 195.2;
HRMS (FABþ) m/z calcd for C20H15O4 (MþH) 319.0970, found
319.0971; HPLC (OD-H column), hexaneeiPrOH¼85:15 as eluent,
(m, 1H), 2.21 (s, 3H), 2.41 (ddd, J¼1.8, 9.6, 13.3 Hz, 1H), 2.59 (ddd,
J¼1.8, 9.6, 17.6 Hz, 1H), 2.91 (ddd, J¼9.6, 11.4, 17.6 Hz, 1H), 6.03 (s,
1H), 7.40e7.46 (m, 2H), 7.69 (dt, J¼1.4, 7.8 Hz, 1H), 8.05 (dd, J¼1.4,
1.0 mL/min, tR¼32.4 min (major, R), 40.2 min (minor, S); [
(c 0.41, CHCl3) for >99% ee.
a
]
26 ꢀ35.2
D
7.8 Hz, 1H); 13C NMR (CDCl3, 125 MHz)
d 19.3, 26.8, 31.5, 83.5, 124.8,
127.3, 127.9, 128.7, 129.0, 133.1, 135.6, 137.9, 176.5, 196.8; HRMS
(FABþ) m/z calcd for C14H13O3 (MþH) 229.0865, found 229.0862;
HPLC (AD-3 column), hexaneeiPrOH¼85:15 as eluent, 0.7 mL/min,
4.6.6. X-ray crystallographic analysis of (ꢀ)-6f (Fig. 2). Re-
crystallization of (ꢀ)-6f (83% ee) was carried out in the solution
26 þ102.4 (c 0.61, CHCl3)
of PrOH at room temperature to give colorless crystal (>99% ee).
i
tR¼20.8 min (minor), 25.3 min (major); [
a
]
D
for 84% ee.
Mp: 153e155 ꢂC. Crystal data: formula C20H14O4, M¼318.31, col-
orless, crystal dimensions 0.50ꢄ0.40ꢄ0.20 mm3, orthorhombic,
4.6.2. (þ)-40-Chlorospiro[tetrahydrofuran-2,20-(10H-naphthaline)]-
10,5-dione (6c; Table 3, entry 2). White solid; TLC, Rf¼0.43
(hexaneeEtOAc¼1:1); IR (film) 3018, 1788, 1700, 1595, 1454,
space group P212121, a¼5.4071(16) A, b¼10.164(3) A, c¼28.448
ꢀ
ꢀ
(8) A, V¼1563.4(8) A , Z¼4, Dcalcd¼1.352 g/cm3, F(000)¼664,
m
3
ꢀ
ꢀ
(Mo K
a
)¼0.094 mmꢀ1, T¼173(2) K. X-ray crystallographic analy-
1293 cmꢀ1
;
1H NMR (CDCl3, 400 MHz)
d
2.23 (ddd, J¼9.6, 11.0,
sis was performed with a Bruker SMART APEX diffractometer
ꢀ
13.4 Hz, 1H), 2.45 (ddd, J¼2.3, 9.6, 13.4 Hz, 1H), 2.62 (ddd, J¼2.3, 9.6,
17.9 Hz, 1H), 2.91 (ddd, J¼9.6, 11.0, 17.9 Hz, 1H), 6.40 (s, 1H), 7.52 (dt,
J¼1.8, 7.4 Hz,1H), 7.70e7.79 (m, 2H), 8.06 (d, J¼7.4 Hz,1H); 13C NMR
(graphite monochromator, Mo K
a
radiation,
l
¼0.71073 A) and
the structure was solved by direct methods and expanded using
Fourier techniques (Sir97 and SHELXL17). 11,371 reflections col-
(CDCl3, 100 MHz)
d
26.5, 31.5, 83.4, 126.1, 127.3, 128.1, 129.1, 130.1,
lected,
3876
independent
reflections
with
I>2s(I)
131.8, 134.5, 135.8, 175.7, 194.7; HRMS (FABþ) m/z calcd for
C13H10ClO3 (MþH) 249.0318, found 249.0316; HPLC (OD-H col-
umn), hexaneeiPrOH¼85:15 as eluent, 1.0 mL/min, tR¼18.4 min
(2qmax¼28.33ꢂ), and 265 parameters were used for the solution
of the structure. The non-hydrogen atoms were refined aniso-
tropically. R1¼0.0411 and wR2¼0.0848, GOF¼1.017. Crystallo-
graphic data (excluding structure factors) for the structure
reported in this paper have been deposited with the Cambridge
Crystallographic Data Center as supplementary publication no.
CCDC-758468 for (ꢀ)-6f. Copies of the data can be obtained free
of charge on application to CCDC, 12 Union Road, Cambridge CB2
(major), 22.2 min (minor); [
a
]
24 þ99.0 (c 0.89, CHCl3) for 90% ee.
D
4.6.3. (þ)-40-Bromospiro[tetrahydrofuran-2,20-(10H-naphthaline)]-
10,5-dione (6d; Table 3, entry 3)6. Recrystallization of 6d (85% ee)
was carried out in the solution of CH3CN at room temperature to

M. Uyanik et al. / Tetrahedron 66 (2010) 5841e5851
5849
1EZ, UK [fax: int. code þ44 1223 336 033; e-mail: deposit@ccdc.
HPLC (OD-H column), hexaneeiPrOH¼85:15 as eluent, 1.0 mL/min,
23
cam.ac.uk].
tR¼27.4 min (minor), 69.0 min (major); [
a]
þ156.2 (c 0.5, CHCl3)
D
for 94% ee.
4.6.7. (ꢀ)-40-(4-Bromobenzoyl)-10H,3H-spiro[furan-2,20-naphtha-
lene]-10,5(4H)-dione (6g; Table 3, entry 6). White solid; TLC, Rf¼0.43
(hexaneeEtOAc¼1:1); IR (film) 3027, 1793, 1698, 1669, 1585, 1278,
4.7. One-pot oxidation of 5a to epoxyspirolactone (L)-15
(Scheme 7)
1172 cmꢀ1
;
1H NMR (CDCl3, 400 MHz)
d
2.27 (ddd, J¼9.6, 11.0,
13.3 Hz, 1H), 2.52 (ddd, J¼1.8, 9.6, 13.3 Hz, 1H), 2.63 (ddd, J¼1.8, 9.6,
17.6 Hz, 1H), 2.92 (ddd, J¼9.6, 11.0, 17.6 Hz, 1H), 6.38 (s, 1H), 7.37
(d, J¼7.8 Hz, 1H), 7.50 (dt, J¼0.9, 7.8 Hz, 1H), 7.60e7.66 (m, 3H), 7.83
(d, J¼8.7 Hz, 2H), 8.12 (dd, J¼1.4, 7.8 Hz, 1H); 13C NMR (CDCl3,
4.7.1. (ꢀ)-(1a0R,2R,7b0R)-1a0H,3H-Spiro[furan-2,20-naphtho[1,2-b]
oxirene]-30,5(4H,7b0H)-dione (15). A solution of 5a (10.8 mg,
0.05 mmol), 7g (4.6 mg, 0.0075 mmol, 10 mol %), and mCPBA
(43.1 mg, 0.25 mmol, 1.3 equiv) in CHCl3 (1.7 mL) and CH3NO2
(1.7 mL) mixed solvents was stirred at 0 ꢂC for 24 h and at room
temperature for 72 h. The solvents were removed in vacuo. The
conversion of 5a to epoxyspirolactones 15 and 16 (84% conv.) and
the diastereomeric ratio (15e16¼64:36) were determined by 1H
NMR analysis of the crude mixture. The residue was purified by
flash column chromatography on silica gel (eluent:
hexaneeEtOAc¼10:1 to 2:1) to give (ꢀ)-15 (6.0 mg, 0.026 mmol) as
a single compound in 52% yield. Recrystallization of (ꢀ)-15 (88% ee)
was carried out in the solution of EtOH at room temperature to give
colorless thin needles (>99% ee). TLC, Rf¼0.13 (hexanee
EtOAc¼1:1); IR (film) 1793, 1706, 1210, 1181 cmꢀ1; 1H NMR (CDCl3,
100 MHz)
d 26.2, 31.2, 82.5, 126.8, 127.3, 128.6, 129.8, 129.9, 131.4
(2C), 132.3 (2C), 133.7, 134.2, 134.7, 135.8, 137.2, 175.7, 193.5, 195.0;
HRMS (FABþ) m/z calcd for C20H14BrO4 (MþH) 397.0075, found
397.0079; HPLC (OD-H column), hexaneeiPrOH¼85:15 as eluent,
24
1.0 mL/min, tR¼44.3 min (major), 49.7 min (minor); [
(c 1.83, CHCl3) for 84% ee.
a
]
ꢀ44.0
D
4.6.8. 40-Methoxyspiro[tetrahydrofuran-2,20-(10H-naphthaline)]-10,5-
dione (6h; Table 3, entry 7)6. White solid; TLC, Rf¼0.33
(hexaneeEtOAc¼1:1); 1H NMR (CDCl3, 400 MHz)
2.17 (ddd, J¼9.6,
d
11.0, 13.6 Hz, 1H), 2.49 (ddd, J¼2.3, 9.6, 13.6 Hz, 1H), 2.61 (ddd,
J¼2.3, 9.6, 17.6 Hz, 1H), 2.95 (ddd, J¼9.6, 11.0, 17.6 Hz, 1H), 3.84 (s,
3H), 5.17 (s, 1H), 7.46 (t, J¼7.6 Hz, 1H), 7.67 (t, J¼7.6 Hz, 1H), 7.74 (d,
J¼7.6 Hz, 1H), 8.00 (d, J¼7.6 Hz, 1H); 13C NMR (CDCl3, 100 MHz)
400 MHz)
d 2.04e2.11 (m, 1H), 2.27e2.36 (m, 1H), 2.57e2.73 (m,
2H), 3.92 (d, J¼4.2 Hz, 1H), 4.18 (d, J¼4.2 Hz, 1H), 7.53e7.57 (m, 1H),
7.64e7.69 (m, 2H), 8.00 (d, J¼7.8 Hz,1H); 13C NMR (CDCl3,100 MHz)
d
27.6, 33.0, 55.1, 83.8, 99.9, 123.1, 127.2, 127.5, 129.4, 134.6, 135.3,
d 26.5, 28.7, 52.4, 55.9, 85.2, 129.0, 129.7, 130.0 (2C), 134.5, 137.8,
152.0, 176.6, 195.7.
175.7, 191.6; HRMS (FABþ) m/z calcd for C13H11O4 (MþH) 231.0657,
found 231.0657; HPLC (OD-H column), hexaneeEtOH¼4:1 as elu-
4.6.9. (þ)-60-Methoxy-10H,3H-spiro[furan-2,20-naphthalene]-10,5
(4H)-dione (6i; Table 3, entry 8 and Table 4, entry 3). White solid;
TLC, Rf¼0.27 (hexaneeEtOAc¼1:1); IR (KBr) 3027, 1787, 1683, 1597,
ent, 1.0 mL/min, tR¼19.8 min (major), 26.2 min (minor); [
(c 1.6, CHCl3) for 92% ee.
a]
24 ꢀ73.8
D
1273, 1176 cmꢀ1; 1H NMR (CDCl3, 400 MHz)
d
2.17 (ddd, J¼9.6, 11.0,
4.7.2. X-ray crystallographic analysis of (ꢃ)-15 (Fig. 3). Re-
crystallization of (ꢃ)-15 was carried out in the solution of EtOH at
room temperature to give colorless crystal. Mp: 199e201 ꢂC. Crystal
data: formula C13H10O4, M¼230.21, colorless, crystal dimensions
0.20ꢄ0.10ꢄ0.10 mm3, orthorhombic, space group Pbca, a¼8.8107
13.3 Hz, 1H), 2.40 (ddd, J¼2.2, 9.6, 13.3 Hz, 1H), 2.61 (ddd, J¼2.2, 9.6,
17.6 Hz, 1H), 2.95 (ddd, J¼9.6, 11.0, 17.6 Hz, 1H), 3.94 (s, 3H), 6.21 (d,
J¼9.6 Hz, 1H), 6.60 (d, J¼9.6 Hz, 1H), 6.72 (d, J¼2.8 Hz, 1H), 6.91 (dd,
J¼2.8, 8.7 Hz, 1H), 8.01 (d, J¼8.7 Hz, 1H); 13C NMR (CDCl3, 100 MHz)
3
ꢀ
ꢀ
ꢀ
ꢀ
d
26.8, 31.6, 55.7, 82.8, 112.9, 114.2, 120.6, 127.9, 130.5, 133.3, 139.1,
(19) A, b¼11.238(2) A, c¼21.064(4) A, V¼2085.6(8) A , Z¼8,
165.6, 176.3, 194.8; HRMS (FABþ) m/z calcd for C14H13O4 (MþH)
Dcalcd¼1.466 g/cm3, F(000)¼960,
m
(Mo K
a
)¼0.110 mmꢀ1, T¼143(2)
245.0814,
found
245.0810;
HPLC
(AD-3
column),
K. X-ray crystallographic analysis was performed with a Bruker
hexaneeiPrOH¼85:15 as eluent, 0.7 mL/min, tR¼33.8 min (minor),
SMART APEX diffractometer (graphite monochromator, Mo Ka ra-
25 þ146.8 (c 0.06, CHCl3) for 87% ee.
diation,
l
¼0.71073 A) and the structure was solved by direct
ꢀ
39.6 min (major); [
a]
D
methods and expanded using Fourier techniques (Sir97 and
4.6.10. (þ)-30-Methoxy-10H,3H-spiro[furan-2,20-naphthalene]-10,5
(4H)-dione (6j; Table 3, entry 9 and Table 4, entry 4). Pale yellow
solid; TLC, Rf¼0.50 (hexaneeEtOAc¼1:1); IR (KBr) 3027, 1792, 1691,
SHELXL17). 15,230 reflections collected, 2807 independent re-
flections with I>2
s
(I) (2qmax¼29.18ꢂ), and 162 parameters were
used for the solution of the structure. The non-hydrogen atoms
were refined anisotropically. R1¼0.0446 and wR2¼0.1271,
GOF¼1.061. Crystallographic data (excluding structure factors) for
the structure reported in this paper have been deposited with the
Cambridge Crystallographic Data Center as supplementary publi-
cation no. CCDC-769543 for (ꢃ)-15. Copies of the data can be
obtained free of charge on application to CCDC, 12 Union Road,
Cambridge CB2 1EZ, UK [fax: int. code þ44 1223 336 033; e-mail:
deposit@ccdc.cam.ac.uk].
1650, 1191, 1168 cmꢀ1 1H NMR (CDCl3, 400 MHz)
; d 2.34e2.48 (m,
2H), 2.70 (ddd, J¼5.0, 9.6, 17.6 Hz, 1H), 2.87 (ddd, J¼8.2, 10.6,
17.6 Hz, 1H), 3.82 (s, 3H), 5.73 (s, 1H), 7.15 (d, J¼7.3 Hz, 1H), 7.23 (dt,
J¼0.9, 7.3 Hz, 1H), 7.54 (dt, J¼1.4, 7.3 Hz, 1H), 7.95 (d, J¼7.3 Hz, 1H);
13C NMR (CDCl3, 100 MHz)
d 27.4, 30.5, 55.8, 82.8, 98.3, 124.7, 126.4,
126.8, 128.1, 136.0, 138.2, 157.6, 176.6, 195.2; HRMS (FABþ) m/z calcd
for C14H13O4 (MþH) 245.0814, found 245.0814; HPLC (AD-3 col-
umn), hexaneeiPrOH¼85:15 as eluent, 0.7 mL/min, tR¼28.2 min
(minor), 29.9 min (major); [
a
]
26 þ98.2 (c 0.53, CHCl3) for 95% ee.
D
4.8. Epoxidation of (D)-6a to (L)-15 with in situ-generated
4.6.11. (þ)-30-(Benzyloxymethyl)-10H,3H-spiro[furan-2,20-naphtha-
lene]-10,5(4H)-dione (6k; Table 3, entry 10 and Table 4, entry 5).
Colorless amorphous; TLC, Rf¼0.43 (hexaneeEtOAc¼1:1); IR (film)
peracid from UHP and Ac2O (Scheme 8)14
To
a stirred mixture of urea hydrogen peroxide (47 mg,
1784, 1697, 1600, 1455, 1290, 1180, 1097 cmꢀ1
;
1H NMR (CDCl3,
0.5 mmol), sodium hydrogen phosphate (62.5 mg, 0.44 mmol) and
400 MHz)
d
2.30e2.37 (m, 1H), 2.43e2.55 (m, 2H), 2.69e2.79 (m,
(þ)-6a (92% ee; 10.8 mg, 0.05 mmol) in CH2Cl2 (0.5 mL) was
1H), 4.25 (d, J¼12.8 Hz, 1H), 4.36 (d, J¼12.8 Hz, 1H), 4.60 (s, 2H),
6.70 (s, 1H), 7.25 (d, J¼7.8 Hz, 1H) 7.30e7.40 (m, 6H), 7.62 (t,
J¼7.8 Hz, 1H), 7.98 (d, J¼7.8 Hz, 1H); 13C NMR (CDCl3, 100 MHz)
added acetic anhydride (24 m
L, 0.25 mmol) dropwise at 0 ꢂC. The
resulting mixture was allowed to warm to room temperature and
stirred for additional 3 days. The resulting mixture was diluted
with CHCl3 and washed with brine. The aqueous layer was
extracted with CHCl3, and the combined organic layers were
dried over anhydrous Na2SO4 and solvents were removed in
d
26.1, 30.4, 68.9, 73.3, 85.8, 124.6, 126.7, 127.7, 127.8 (2C), 128.0 (2C),
128.5 (2C), 128.6 135.6, 136.8, 137.5, 140.0, 176.6, 196.9; HRMS
(FABþ) m/z calcd for C21H19O4 (MþH) 335.1283, found 335.1292;

5850
M. Uyanik et al. / Tetrahedron 66 (2010) 5841e5851
vacuo. The conversion (52%) of 6a to epoxyspirolactones and the
diastereomeric ratio (92:8) were determined by 1H NMR analysis
of the crude mixture. The residue was purified by flash column
chromatography on silica gel (eluent: hexaneeEtOAc¼5:1) to
give (ꢀ)-15 (92% ee; 5.4 mg, 0.024 mmol) as a single compound in
47% yield.
m/z calcd for C13H11O4 (MþH) 231.0657, found 231.0659; HPLC (OD-
H
column), hexaneeiPrOH¼85:15 as eluent, 1.0 mL/min,
24
tR¼24.9 min (major), 28.1 min (minor); [
a
]
þ197.7 (c 0.8, CHCl3)
D
for 92% ee.
Acknowledgements
4.9. Re-catalyzed epoxidation of (D)-6a to (L)-15 with H2O2
Financial support for this project was provided by JSPS.KAKENHI
(20245022), NEDO, the Shionogi Award in Synthetic Organic
Chemistry, Japan, the Nitto Foundation, and the Global COE Pro-
gram of MEXT.
(Scheme 8)15
To a solution of (þ)-6a (92% ee; 21.4 mg, 0.1 mmol), MeReO3 (5
m
g, 2 mmol) and 3-cyanopyridine (4.2 mg, 0.04 mmol) in CH2Cl2
(0.25 mL) was added slowly 30 wt % H2O2 (41.2 mL, 0.4 mmol) at
Supplementary data
room temperature. After stirring for 48 h at ambient temperature,
the resulting mixture was diluted with CHCl3 and washed with
brine. The aqueous layer was extracted with EtOAc, and the com-
bined organic layers were dried over anhydrous Na2SO4 and sol-
vents were removed in vacuo. The conversion (88%) of 6a to
epoxyspirolactones and the diastereomeric ratio (92:8) were de-
termined by 1H NMR analysis of the crude mixture. The residue was
purified by flash column chromatography on silica gel (eluent:
hexaneeEtOAc¼5:1) to give (ꢀ)-15 (92% ee; 16.0 mg, 0.07 mmol) in
70% yield.
Supplementary data associated with this article can be found in
online version at doi:10.1016/j.tet.2010.04.060. These data include
MOL files and InChIKeys of the most important compounds
described in this article.
References and notes
1. For recent reviews focused on hypervalent iodine chemistry, see: (a) Hyper-
valent Iodine Chemistry; Wirth, T., Ed.Top. Curr. Chem.; Springer: Berlin, 2003;
Vol. 224; (b) Wirth, T. Organic Synthesis Highlights V; Wiley-VCH: Weinheim,
2003; p 144; (c) Ciufolini, M. A.; Braun, N. A.; Canesi, S.; Ousmer, M.; Chang, J.;
Chai, D. Synthesis 2007, 3759e3772; (d) Quideau, S.; Pouysegu, L.; Deffieux, D.
Synlett 2008, 467e495; (e) Zhdankin, V. V.; Stang, P. J. Chem. Rev. 2008, 108,
5299e5358; (f) Pouységu, L.; Deffieux, D.; Quideau, S. Tetrahedron 2010, 66,
2235e2261.
2. For reviews focused on hypervalent iodine-catalyzed oxidation reactions, see:
(a) Richardson, R. D.; Wirth, T. Angew. Chem., Int. Ed. 2006, 45, 4402e4404; (b)
Ochiai, M.; Miyamoto, K. Eur. J. Org. Chem. 2008, 4229e4239; (c) Dohi, T.; Kita,
Y. Chem. Commun. 2009, 2073e2085; (d) Uyanik, M.; Ishihara, K. Chem. Com-
mun. 2009, 2086e2099; For our recent contributions, see: (e) Uyanik, M.; Yasui,
T.; Ishihara, K. Bioorg. Med. Chem. Lett. 2009, 48, 3848e3851; (f) Uyanik, M.;
Akakura, M.; Ishihara, K. J. Am. Chem. Soc. 2009, 131, 251e262; (g) Uyanik, M.;
Fukatsu, R.; Ishihara, K. Org. Lett. 2009, 11, 3470e3473.
3. For the stoichiometric use of the chiral hypervalent iodines, see: (a) Up to 53%
ee: Imamoto, T.; Koto, H. Chem. Lett. 1986, 15, 967e968; (b) Up to 56% ee: Ray,
D. G., III; Koser, G. F. J. Am. Chem. Soc. 1990, 112, 5672e5673; (c) Up to 53% ee:
Ochiai, M.; Takaoka, Y.; Masaki, Y. J. Am. Chem. Soc. 1999, 121, 9233e9234; (d)
Up to 72% ee: Tohma, H.; Takizawa, S.; Watanabe, H.; Fukuoka, Y.; Maegawa, T.;
Kita, Y. J. Org. Chem. 1999, 64, 3519e3523; (e) Up to 65% ee: Hirt, U. H.; Schuster,
M. F. H.; French, A. N.; Wiest, O. G.; Wirth, T. Eur. J. Org. Chem. 2001, 1569e1579;
(f) Up to 41% ee: Ladziata, U.; Carlson, J.; Zhdankin, V. V. Tetrahedron Lett. 2006,
47, 6301e6304; (g) Up to 64% ee: Fujita, M.; Okuno, S.; Lee, H. J.; Sugimura, T.;
Okuyama, T. Tetrahedron Lett. 2007, 48, 8691e8694; (h) Up to 77% ee: Boppi-
setti, J. K.; Birman, V. B. Org. Lett. 2009, 11, 1221e1223; (i) Up to 50% ee: Qui-
deau, S.; Lyvinec, G.; Marguerit, M.; Bathany, K.; Ozanne-Beaudenon, A.;
Buffeteau, T.; Cavagnat, D.; Chenede, A. Angew. Chem., Int. Ed. 2009, 48,
4605e4609.
4.10. Oxidation of (D)-6a with NBS to bromohydrin
16
spirolactone (D)-17
To a solution of (þ)-6a (92% ee; 10.7 mg, 0.05 mmol) in THF
(0.25 mL) was added water (0.25 mL) at 0 ꢂC until the solution
became cloudy. NBS (recrystallized, 17.8 g, 0.10 mmol) was then
added and the reaction was allowed to stir for 28 h at 0 ꢂC. The
resulting mixture was diluted with EtOAc and washed with brine.
The aqueous layer was extracted with EtOAc, and the combined
organic layers were dried over anhydrous Na2SO4 and solvents
were removed in vacuo. The residue was purified by flash column
chromatography on silica gel (eluent: hexaneeEtOAc¼10:1 to 4:1)
to give (þ)-16 (92% ee; 10.9 mg, 0.035 mmol) in 70% yield. White
amorphous; TLC, Rf¼0.20 (hexaneeEtOAc¼1:1); IR (film) 1793,
1699, 1602, 1456, 1210, 1175 cmꢀ1 1H NMR (CDCl3, 400 MHz)
;
d
2.39e2.47 (m, 1H), 2.81e2.86 (m, 2H), 3.01 (d, J¼4.1 Hz, 1H),
3.09e3.17 (m, 1H), 4.47 (d, J¼9.2 Hz,1H), 5.33 (dd, J¼4.1, 9.2 Hz,1H),
7.51 (t, J¼7.8 Hz, 1H), 7.73 (t, J¼7.8 Hz, 1H), 7.81 (d, J¼7.8 Hz, 1H),
8.07 (d, J¼7.8 Hz, 1H); 13C NMR (CDCl3, 100 MHz)
d 27.5, 28.5, 63.3,
70.1, 86.1, 127.4, 128.2, 128.4, 129.0, 135.7, 142.1, 175.5 188.5; HRMS
(FABþ) m/z calcd for C13H12BrO4 (MþH) 310.9919, found 310.9926;
HPLC (OD-H column), hexaneeEtOH¼4:1 as eluent, 1.0 mL/min,
4. For the catalytic use of the chiral hypervalent iodines generated in situ, see: (a)
Up to 44% ee: Altermann, S. M.; Richardson, R. D.; Page, T. K.; Schmidt, R. K.;
Holland, E.; Mohammed, U.; Paradine, S. M.; French, A. N.; Richter, C.; Bahar, A.
M.; Witulski, B.; Wirth, T. Eur. J. Org. Chem. 2008, 5315e5328; (b) Up to 29% ee:
Ref. 3i.
tR¼8.6 min (major), 9.7 min (minor); [
a]
22 þ137.8 (c 0.6, CHCl3) for
D
92% ee.
5. For the first use of mCPBA as co-oxidant for the in situ generation of hyper-
valent iodine compounds, see: (a) Tohma, H.; Maruyama, A.; Maeda, A.; Mae-
gawa, T.; Dohi, T.; Shiro, M.; Morita, T.; Kita, Y. Angew. Chem., Int. Ed. 2004, 43,
3595e3598; (b) Ochiai, M.; Takeuchi, Y.; Katayama, T.; Sueda, T.; Miyamoto, K. J.
Am. Chem. Soc. 2005, 127, 12244e12245; (c) Dohi, T.; Maruyama, A.; Yoshimura,
M.; Morimoto, K.; Tohma, H.; Kita, Y. Angew. Chem., Int. Ed. 2005, 44,
6193e6196.
6. (a) Dohi, T.; Maruyama, A.; Takenaga, N.; Senami, K.; Minamitsuji, Y.; Fujioka,
H.; Caemmerer, S. B.; Kita, Y. Angew. Chem., Int. Ed. 2008, 47, 3787e3790; (b)
Dohi, T.; Kita, Y.; Maruyama, A. Jpn. Kokai Tokkyo Koho 2009149564-A.
7. Uyanik, M.; Yasui, T.; Ishihara, K. Angew. Chem., Int. Ed. 2010, 49, 2175e2177.
8. We do not yet have any experimental proof of the non-bonding interactions
between the iodine(III)-center and functional groups in 8. However, there are
many reports on the intra- or intermolecular secondary interactions of iodine
(III and V). For selected examples, see: (a) Zhdankin, V. V.; Koposov, A. E.;
Smart, J. T. J. Am. Chem. Soc. 2001, 123, 4095e4096; (b) Ochiai, M. Coord. Chem.
Rev. 2006, 250, 2771e2781 and references therein.
4.11. Conversion of bromohydrin (D)-17 to epoxyspirolactone
(D)-16 (Scheme 9)
To a solution of (þ)-17 (92% ee; 12.4 mg, 0.04 mmol) in acetone
(0.8 mL) was added K2CO3 (13.8 mg, 0.1 mmol) at room tempera-
ture, and the resulting mixture was stirred for 21 h at ambient
temperature. The resulting mixture was filtered through Celite, and
the solvents were removed in vacuo. The residue was purified by
flash column chromatography on silica gel (eluent:
hexaneeEtOAc¼10:1 to 4:1) to give (þ)-16 (92% ee; 9.1 mg,
0.04 mmol) in >99% yield. White solid; TLC, Rf¼0.34
(hexaneeEtOAc¼1:1); IR (film) 3028, 1795, 1698, 1605, 1303,
; d 2.43e2.49 (m, 1H),
1185 cmꢀ1 1H NMR (CDCl3, 400 MHz)
9. Compound 9 was easily prepared from resorcinol, see: Tsujiyama, S.; Suzuki, K.;
Guthrie, D. B.; Gibney, H. M.; Curran, D. P. Org. Synth. 2007, 84, 272e284.
10. Kitani, Y.; Morita, A.; Kumamoto, T.; Ishikawa, T. Helv. Chim. Acta 2002, 85,
1186e1195.
11. Kita and co-workers also reported that enantiomerically pure 6d was obtained
after a single recrystallization, see: Ref. 6b.
2.71e2.80 (m,1H), 2.95e3.06 (m, 2H), 3.93 (d, J¼3.7 Hz,1H), 4.17 (d,
J¼3.7 Hz, 1H), 7.54 (t, J¼7.8 Hz, 1H), 7.62e7.70 (m, 2H), 7.99 (d,
J¼7.8 Hz, 1H); 13C NMR (CDCl3, 100 MHz)
d 27.7, 28.4, 52.7, 57.8,
80.7, 129.0, 129.6, 130.0 (2C), 134.4, 137.7, 175.6, 190.6; HRMS (FABþ)

M. Uyanik et al. / Tetrahedron 66 (2010) 5841e5851
5851
12. (a) Cox, C.; Danishefsky, S. J. Org. Lett. 2001, 3, 2899e2902; (b) Siu, T.; Cox, C. D.;
Danishefsky, S. J. Angew. Chem., Int. Ed. 2003, 42, 5629e5634.
13. For similar one-pot oxidation using mCPBA, see: (a) Ref. 3i; For epoxidation of
14. Cooper, M. S.; Heaney, H.; Newbold, A. J.; Sanderson, W. R. Synlett 1990, 533e535.
15. Copéret, C.; Adolfsson, H.; Sharpless, K. B. Chem. Commun. 1997, 1565e1566.
16. (a) McManus, H. A.; Fleming, M. J.; Lautens, M. Angew. Chem., Int. Ed. 2007, 46,
433e436; (b) Zoller, U.; Chen, F.-P. J. Org. Chem. 2000, 65, 8083e8085.
a
-tetralone-derived alkene with mCPBA, see: (b) Coogan, M. P.; Haigh, R.; Hall,
A.; Harris, L. D.; Hibbs, D. E.; Jenkins, R. L.; Jones, C. L.; Tomkinson, N. C. O.
Tetrahedron 2003, 59, 7389e7395.
17. Sheldrick, G. M. SHELXL-97, Program for Crystal Structure Refinement; University
€ €
of Gottingen: Gottingen, Germany, 1997.