A conceptually new approach to the asymmetric synthesis of 3-aryl and alkyl poly-substituted isoindolinones

Article abstract of DOI:10.1016/j.tetasy.2008.11.021

A conceptually new and efficient asymmetric synthesis of C-3 arylated or alkylated poly-substituted isoindolinones is reported. The key step is the diastereoselective reduction of an N-acylhydrazonium species derived from the previously assembled corresponding hydroxyl derivative bearing the (S)-2-methoxymethylpyrrolidine (SMP) auxiliary.

Full text of DOI:10.1016/j.tetasy.2008.11.021

Tetrahedron: Asymmetry 19 (2008) 2735–2740
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
A conceptually new approach to the asymmetric synthesis of 3-aryl
and alkyl poly-substituted isoindolinones
*
Eric Deniau , Axel Couture, Pierre Grandclaudon
Université des Sciences et Technologies de Lille 1, LCOP, Bâtiment C3(2), 59655 Villeneuve d’Ascq, France
CNRS, UMR 8009 ‘Chimie Organique et Macromoléculaire’, 59655 Villeneuve d’Ascq, France
a r t i c l e i n f o
a b s t r a c t
Article history:
A conceptually new and efficient asymmetric synthesis of C-3 arylated or alkylated poly-substituted iso-
indolinones is reported. The key step is the diastereoselective reduction of an N-acylhydrazonium species
derived from the previously assembled corresponding hydroxyl derivative bearing the (S)-2-methoxym-
ethylpyrrolidine (SMP) auxiliary.
Received 18 November 2008
Accepted 25 November 2008
Available online 12 January 2009
Ó 2008 Elsevier Ltd. All rights reserved.
O
1. Introduction
O
N
N
S
N
N
Cl
Chiral non-racemic three-substituted isoindolinones have re-
cently attracted much attention from the scientific community since
they constitute the main core of an increasing number of biologically
active substances. Typical examples are the synthetic products
thiazoloisoindolone 11 (non-nucleosidic HIV-reverse transcriptase
inhibitor), pazinaclone 22 (anxiolytic drug candidate), PD 172938
33 (dopamine D4 receptor antagonist) as well as pyrroloisoindoli-
none 44 (Cyclin Dependent Kinase 1,2,4,6 inhibitor) (Fig. 1).
Paradoxically, despite the great progress made in the area of
asymmetric synthesis over the last decade, only a few flexible
and general methods are available for the synthesis of highly enan-
tioenriched chiral poly-substituted isoindolinones alkylated or ary-
lated at C-3 even though it has been well established that the
absolute configuration of this stereogenic center plays a crucial
role for the biological activity.3 Among these methods, the most
straightforward ones are those where the alkyl or aryl groups at
the C-3 position are introduced directly onto a pre-constructed
model equipped with a chiral auxiliary (Scheme 1). This has been
achieved via a diastereoselective nucleophilic addition5 (path a)
or hydride reduction6 (path b) of an N-acyliminium species. These
O
N
Me
O
O
Me
2
1
(R)-pazinaclone
O
O
N
NH
Me
Me
H
N
NH
N
N
O
N
3
(S)-PD172938
4
Figure 1.
been assembled by Heck11 or radical induced cyclization12 and
an elegant method based upon an anionic cyclization and re-aro-
matization of
a-aminocarbanionic species derived from N-ben-
chiral bicyclic lactams can also be accessed via an
a-amino alkyl-
zylbenzamide derivatives and
a chiral base has been also
ation reaction involving a three-metallated isoindolinone and var-
ious electrophiles7 (path c). An alternative synthetic approach
depicted on Scheme 1 is based upon the lactam ring construction
with concomitant creation of the stereogenic center at the C-3 po-
sition. This has been achieved by a two component reaction involv-
ing an ortho-lithiated dialkylbenzamide with chiral hydrazones8
(path d) or by a diastereoselective imine addition–cyclization se-
quence9,10 (path e, f). Enantioenriched isoindolinones have also
described.13
However, these elegant and complementary synthetic ap-
proaches suffer from several drawbacks, mainly from the restric-
tion in the choice of substituents at some specific sites on the
basic benzene nucleus and from difficulties associated with the
connection of aromatic and aliphatic groups, as well at the benzylic
position of the lactam ring, in a stereospecific manner. Accordingly,
the development of new efficient methods for the asymmetric syn-
thesis of these as diversely substituted isoindolinones still consti-
tutes an area of interest and alternative methods are currently
the object of synthetic endeavor.
* Corresponding author. Tel.: +33 (0)3 20 33 71 48; fax: +33 (0)3 20 33 63 09.
E-mail address: Eric.Deniau@univ-lille1.fr (E. Deniau).
0957-4166/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2008.11.021

2736
E. Deniau et al. / Tetrahedron: Asymmetry 19 (2008) 2735–2740
O
SMP-NH2
CH2Cl2, Et3N
O
I
O
R1
R2
COCl
I
*
R1
R2
SMP
A
N
H
*
N
A
N
88-94%
(d)
(a)
R3
17-19
R3
Ar
R, Ar
20-22
O
O
O
1) NaH, THF, r.t.
(e)
(b)
O
2) R4COCl 23a-c
THF, Δ
SMP
n-BuLi
THF, -78 °C
*
*
R1
R2
N
A
N A
N
N
*
A
*
O
R, Ar
R, Ar
78-91%
R4
H
I
(f)
R, Ar
(c)
R3
14a,b, 15a, 16b
O
O
*
O
N
A
SMP
O
O
N
R1
R2
R1
R2
H3O+
*
N
A
N
SMP
R
R, Ar
Li R4
77-85%
R4
R3
R3
OH
Scheme 1.
24
11a,b, 12a, 13b
Scheme 3.
2. Results and discussion
Herein, we report on an alternative and conceptually new syn-
thetic route that offers easy access to an array of optically active
three-substituted isoindolinones 5–7 of high enantiopurity. This
new procedure, which is depicted in the retrosynthetic Scheme 2,
relies upon the construction of the isoindolinone ring system via
a Parham type anionic cyclization14 reaction involving imides
14–16. The diastereoselective reduction of hemiaminals 11–13
equipped with a (S)-2-methoxymethylpyrrolidine (SMP)15 chiral
auxiliary would give access to the adducts 8–10. Finally, removal
of the SMP group from these adducts would deliver the targeted
enantioenriched poly-substituted isoindolinones 5–7.
11–13 was investigated and is shown in Scheme 4. This alternative
pathway is based upon the capture of a bis-metallated species 25,
easily obtained from the chiral hydrazides 20–22, with an array of
aliphatic or aromatic carboxylic acid esters 26a–d (Table 2). Inter-
Table 1
Compounds 11–16 prepared
R1
R2
R3
R4
14–16
Yielda (%)
11–13
Yielda (%)
H
H
OMe
H
H
OMe
H
H
OMe
H
Ph
14a
14b
15a
16b
85
91
78
87
11a
11b
12a
13b
77
85
79
84
4-MeOC6H4
Ph
4-MeOC6H4
O
O
OCH2O
R1
R2
R1
R2
a
NH
R4
N SMP
After purification.
R4
R3
5-7
R3
8-10
1) NaH, THF, r.t.
2) n-BuLi, THF
THF, 15 min
O
O
SMP
O
SMPH2
O
R1
R2
SMP
O
R1
R2
R1
R2
R1
R2
N
N
N
H
Na
N
SMP
I
R4
Li
I
R3
R3
R3
OH
R4
R3
20-22
25
14-16
11-13
4
O
26a-d
R CO2Me
THF, r.t.
SMP
Scheme 2.
O
R1
R2
R1
R2
H3O+
N
Na
N
SMP
The first facet of the synthesis was preliminary elaboration of the
chiralhydrazides 14–16, whichwere easilypreparedby couplingthe
ortho-halogenobenzoyl chlorides 17–19 with (S)-1-amino-2-meth-
oxymethylpyrrolidine (SAMP)16 (Scheme 3). Hydrazides 20–22
werethensmoothlydeprotonatedandallowedtoreactwithan array
of acyl chlorides 23a–c (Table 1) to give the imides 14–16 candidates
for the planned anionic cyclization process. Exposure of imides 14–
16 to n-BuLi at ꢀ78 °C ensured the mandatory halogen/lithium
interconversion giving rise to the aryllithiated species 24, led to
complete consumption of the starting material, and to the isolation
of the targeted hemiaminals 11–13 in fairly good yields as a mixture
of diastereomers.
72-83%
R4
R4
R3
OH
R3
O
27
11a-d, 12a, 13b
Et Et
TFA, Et3SiH
CH2Cl2
Et
Si
TfO
N
R1
R2
R3
H
-78 ºC to rt
83-88%
O
N
R4
MeO
28
O
It is worth noting that this approach was confined to the assem-
bly of hemiaminals equipped with pendant aromatic units at the
benzylic position of the lactam nucleus (R4 = Ar). This could be se-
cured owing to the absence of deprotonation sites, for example,
R4 = alkyl that can compete unfavorably with the required halo-
gen–metal interconversion process. To alleviate this problem, an
alternative and complementary synthetic route to hemiaminals
O
R1
R2
R1
R2
MMPP, MeOH, rt
77-91%
NH
R4
N
SMP
R4
8a-d, 9a, 10b
R3
R3
5a-d, 6a, 7b
Scheme 4.

E. Deniau et al. / Tetrahedron: Asymmetry 19 (2008) 2735–2740
2737
Table 2
Compounds 11–13 prepared
pling constants (J) are given in Hertz and rounded to the nearest
0.1 Hz. Elemental analyses were determined by the CNRS micro-
analysis center. TLC was performed with plates coated with Kies-
R1
R2
R3
R4
11–13
Yielda (%)
selgel
G (Merck). The silica gel used for flash column
H
H
H
H
H
H
H
H
H
H
H
H
OMe
H
Ph
11a
11b
11c
11d
12a
13b
81
78
76
80
83
72
chromatography was Merck Kieselgel of 0.040–0.063 mm particle
size. Dry glassware was obtained by oven-drying and assembly
under argon. Argon was used as the inert atmosphere and was
passed through a drying tube to remove moisture. The glassware
was equipped with rubber septa and reagent transfer was per-
formed by syringe techniques. Tetrahydrofuran (THF) was dis-
tilled from sodium benzophenone ketyl immediately before
use. Methanol was distilled from magnesium turning. 2-Iodoben-
zoyl chlorides 17, 18, 19 were prepared following a literature
method.20
4-MeOC6H4
3,4,5-MeOC6H2
Me
OMe
OMe
Ph
OCH2O
4-MeOC6H4
a
After purification.
estingly, these techniques give rise to poly and unsymmetrically
substituted models and offered, at least, complementary and at
best, significant advantages over classical methodology.6c
With the alkylated and arylated hemiaminals in hand, the
formation of the targeted virtually enantiopure C-3-substituted
isoindolinones was investigated. For this purpose, the resulting
3-hydroxy isoindolinone derivatives 11–13 were subsequently
treated with trifluoroacetic acid and triethylsilane17 in sequence;
this operation triggered the formation of the 3-alkyl and 3-aryl
isoindolinones 8–10 released from the hydroxy appendage
(Scheme 4) with a high level of diastereoselection.6c,18 Removal
of the chiral auxiliary without racemization was readily
achieved by oxidative cleavage of the nitrogen–nitrogen bond
promoted by magnesium mono-peroxyphthalate hexahydrate
(MMPP).19 This deamination method afforded the targeted enan-
tioenriched poly-substituted 3-alkyl and 3-aryl isoindolinones 5–
7 released from the stereocontrolling agent with satisfactory
yields (Table 3).
4.2. Typical procedure for the preparation of the hydrazides 20–
22
A solution of 2-iodoaroyl chloride 17–19 (20 mmol) in dry
CH2Cl2 (10 mL) was added dropwise under argon to a cooled
(0 °C) solution of (S)-aminomethylprolinol (SAMP) (2.9 g,
22 mmol) and Et3N (4.0 g, 40 mmol) in CH2Cl2 (100 ml). Stirring
was maintained for 3 h at room temperature. The reaction mixture
was then washed with water (20 mL) and dried over MgSO4. The
solvent was removed under vacuum and the residue was purified
by recrystallization from hexane–toluene to afford the hydrazides
20–22.
4.2.1. 2-Iodo-N-((S)-2-(2-methoxymethylpyrrolidin-1-yl)benzamide
20
Yield: 79%; mp 124–125 °C; ½a D21
ꢁ
¼ ꢀ39:1 (c 0.79, CHCl3); 1H
3. Conclusion
NMR (CDCl3): 1.56–1.72 (m, 1H), 1.76–1.91 (m, 2H), 1.93–2.08
(m, 1H), 2.95 (q, J = 8.5, 1H), 3.12–3.24 (m, 1H), 3.32 (s, 3H,
OMe), 3.34–3.48 (m, 2H), 3.58 (dd, J = 5.1, 9.5, 1H), 7.00 (br s, 1H,
NH), 7.02–7.09 (m, 1H, Harom), 7.29–7.34 (m, 2H, Harom), 7.80 (d,
J = 7.9, 1H, Harom); 13C NMR (CDCl3): C 168.0 (CO), 141.1, 92.8, CH
139.6, 131.1, 128.3, 128.0, 64.1, CH2 75.1, 55.0, 26.5, 21.3, CH3
59.2. Anal. Calcd for C13H17IN2O2: C, 43.35; H, 4.76; N, 7.78. Found:
C, 43.52; H, 4.49; N, 7.61.
In conclusion, we have completed a conceptually new approach
to the asymmetric synthesis of poly-substituted isoindolinones that
are both alkylated and arylated. This new route hinges upon the ini-
tial construction of the isoindolinone ring system equipped with an
hemiaminal moiety and subsequent diastereoselective reduction of
chiral iminium salts bearing the (S)-2-methoxymethylpyrrolidine
(SMP) auxiliary. We also believe that this work demonstrates a gen-
eral methodology widely adaptable for the preparation of natural
and/or biologically active compounds.
4.2.2. 2-Iodo-3,4,5-trimethoxy-N-((S)-2-(2-methoxymethylpyrroli-
din-1-yl)benzamide 21
Yield: 82%; mp 145–146 °C; ½a D21
ꢁ
¼ ꢀ44:3 (c 0.95, CHCl3); 1H
NMR (CDCl3): 1.61–1.77 (m, 1H), 1.82–1.96 (m, 2H), 1.97–2.06
(m, 1H), 2.98 (q, J = 8.5, 1H), 3.14–3.26 (m, 1H), 3.36 (s, 3H,
OMe), 3.39–3.52 (m, 2H), 3.64 (dd, J = 5.1, 9.5, 1H), 3.86 (s, 9H,
3 ꢂ OMe), 6.80 (br s, 2H, NH+Harom); 13C NMR (CDCl3): C 167.7
(CO), 154.0, 153.4, 143.3, 136.7, 81.4, CH 108.4, 64.3, CH2 75.3,
55.2, 26.6, 21.4, CH3 61.1, 60.9, 59.3, 56.3. Anal. Calcd for
C16H23IN2O5: C, 42.68; H, 5.15; N, 6.22. Found: C, 42.53; H,
5.12; N, 6.11.
4. Experimental
4.1. General
Melting points were determined on a Reichert-Thermopan
apparatus and are uncorrected. 1H (300 MHz) and 13C NMR
(75 MHz) spectra were recorded on a Bruker AM 300 spectrom-
eter and were referenced against internal tetramethylsilane. Cou-
Table 3
Isoindolinones 5–13 prepared
R1
R2
R3
R4
8–10
Yielda (%)
deb (%)
5–7
Yielda (%)
eed (%)
H
H
H
H
H
H
H
H
H
H
H
H
OMe
H
Ph
8a
8b
8c
8d
9a
91
88
83
85
86
81
>96
>96
>96
5a
5b
5c
5d
6a
7b
85
91
88
77
86
84
>96
>96
>96
>96
>96
>96
4-MeOC6H4
3,4,5-MeOC6H2
Me
84 (>96)c
>96
OMe
OMe
Ph
OCH2O
4-MeOC6H4
10b
>96
a
After purification.
b
c
Determined by 1H NMR spectroscopy.
After recrystallization from pentane.
d
In correlation to the value of the corresponding hydrazide 8–10 assuming that the deprotection step takes place without detectable racemization.6c,8

2738
E. Deniau et al. / Tetrahedron: Asymmetry 19 (2008) 2735–2740
4.2.3. 6-Iodo-1,3-benzodioxole-5-carboxylic acid ((S)-2-meth-
2H), 3.09 (s, 3H, OMe), 3.31–3.48 (m, 1H), 3.50–3.71 (m, 1H),
3.81 (s, 3H, OMe), 3.86–4.01 (m, 1H), 5.92 (s, 2H, OCH2O), 6.83–
6.94 (m, 3H, Harom), 7.02–7.21 (m, 1H, Harom), 7.76 (d, J = 8.6, 1H,
Harom); 13C NMR (CDCl3): C 172.9 (CO), 171.0 (CO), 162.5, 149.2,
148.0, 135.9, 126.5, 80.8, CH 131.7 (2 ꢂ CH), 118.8, 113.0
(2 ꢂ CH), 108.7, 61.9, CH2 102.1, 76.2, 51.6, 27.7, 23.4, CH3 58.5,
55.4. Anal. Calcd for C22H23IN2O6: C, 49.08; H, 4.31; N, 5.20. Found:
C, 49.12; H, 4.28; N, 5.17.
oxymethylpyrrolidin-1-yl)amide 22
Yield: 78%; mp 176–177 °C; ½a D21
ꢁ
¼ ꢀ35:8 (c 1.47, CHCl3); 1H
NMR (CDCl3): 1.41–1.62 (m, 1H), 1.72–2.33 (m, 3H), 2.97 (q,
J = 8.7, 1H), 3.10–3.22 (m, 1H), 3.36 (s, 3H, OMe), 3.32–3.48 (m,
2H), 3.61 (dd, J = 5.3, 9.5, 1H), 6.00 (s, 2H), 6.87 (s, 2H, NH+Harom),
7.20 (s, 1H, Harom); 13C NMR (CDCl3): C 167.6 (CO), 149.5, 148.2,
134.5, 81.7, CH 119.1, 108.9, 64.2, CH2 102.1, 75.2, 55.1, 26.5,
21.4, CH3 59.3. Anal. Calcd for C14H17IN2O4: C, 41.60; H, 4.24; N,
6.93. Found: C, 41.43; H, 4.31; N, 6.98.
4.4. Typical procedure for the preparation of the hemiaminals
11, 12, 13
4.3. Typical procedure for the preparation of hydrazimides 14–
16
Method A: A solution of imide 14–16 (5 mmol) in dry THF
(100 mL) was cooled to ꢀ78 °C under Ar, and n-BuLi (3.5 mL,
1.6 M in hexanes, 5.6 mmol) was added by syringe. The mixture
was then progressively warmed to ꢀ30 °C, quenched with a satu-
rated aqueous solution of NH4Cl (10 mL), and the aqueous layer
was extracted with Et2O (3 ꢂ 50 mL). The combined organic layers
were washed with brine (20 mL), dried over Na2SO4, and concen-
trated under vacuum to furnish the crude hemiaminals 11–13
which were purified by flash chromatography using CH2Cl2–
Et2O–hexane (5:3:2) as eluent.
Method B: A suspension of hydrazide 20–22 (10 mmol) and NaH
60% (460 mg, 12 mmol) in THF (25 mL) was stirred at room tem-
perature for 3 h and then cooled to ꢀ78 °C. Next, n-BuLi (7.5 mL,
1.6 M in hexanes, 12 mmol) was added by syringe and the mixture
was then progressively warmed to ꢀ30 °C and allowed to react
with a solution of carboxylic acid esters 26a–d (12 mmol) in THF
(5 mL). A saturated aqueous solution of NH4Cl (10 mL) was added
and the aqueous layer was extracted with Et2O (3 ꢂ 50 mL). The
combined organic layers were washed with brine (20 mL), dried
over Na2SO4, and concentrated under vacuum to furnish the crude
hemiaminals 11–13, which were purified by flash chromatography
using CH2Cl2–Et2O–hexane (5:3:2) as eluent.
A suspension of hydrazide 20–22 (10 mmol) and NaH 60%
(460 mg, 12 mmol) in THF (25 mL) was stirred at room tempera-
ture for 3 h and then allowed to react with a solution of acyl chlo-
ride 23a–d (12 mmol) in THF (5 mL). The mixture was refluxed for
6 h and then warmed to room temperature. Water (10 mL) was
added and the organic layer was separated. The aqueous solution
was extracted with CH2Cl2 (2 ꢂ 50 mL) and the combined organic
layers dried over MgSO4. Evaporation of the solvent furnished the
crude imides 14–16, which were purified by flash column chroma-
tography using CH2Cl2–Et2O–hexane (2:1:1) as an eluent.
4.3.1. N-(2-Iodobenzoyl)-N-((S)-2-methoxymethyl-pyrrolidin-
1-yl)benzamide 14a
Oil; ½a 2D1
ꢁ
¼ ꢀ88:2 (c 0.74, CHCl3); 1H NMR (CDCl3): 1.28–1.49
(m, 1H), 1.60–1.78 (m, 1H), 1.90–2.22 (m, 2H), 2.80–3.00 (m, 1H),
3.09 (s, 3H, OMe), 3.15–3.48 (m, 2H), 3.51–3.72 (m, 1H), 3.80–
4.08 (m, 1H), 6.97–7.12 (m, 1H, Harom), 7.25–7.47 (m, 5H, Harom),
7.61–7.83 (m, 3H, Harom); 13C NMR (CDCl3): C 173.7 (CO), 171.2
(CO), 142.6, 134.9, 91.5, CH 139.3, 131.5, 130.6, 129.0 (2 ꢂ CH),
127.9, 128.7, 127.6 (2 ꢂ CH), 61.7, CH2 76.3, 51.8, 27.8, 23.6, CH3
58.5. Anal. Calcd for C20H21IN2O3: C, 51.74; H, 4.56; N, 6.03. Found:
C, 51.80; H, 4.44; N, 6.21.
4.4.1. 3-Hydroxy-2-((S)-2-methoxymethylpyrrolidin-1-yl)-3-
phenyl-2,3-dihydro-1H-isoindol-1-one 11a
4.3.2. N-(2-Iodobenzoyl)-4-methoxy-N-((S)-2-methoxymethyl-
Oil; 1H NMR (CDCl3): 1.25–1.39 (m, 1H), 1.40–1.53 (m, 1H),
1.71–1.88 (m, 1H), 2.05–2.19 (m, 1H), 2.48 (dt, J = 3.1, 7.9, 1H),
3.26–3.37 (m, 3H), 3.30 (s, 3H, OMe), 3.93–4.16 (m, 1H), 6.59 (s,
1H, OH), 7.16 (dd, J = 1.0, 6.6, 1H, Harom), 7.18–7.27 (m, 3H, Harom),
7.32–7.44 (m, 4H, Harom), 7.72 (dd, J = 1.3, 6.6, 1H, Harom); 13C NMR
(CDCl3): C 165.8 (CO), 147.9, 140.4, 129.9, 90.1, CH 132.8, 128.1
(2 ꢂ CH), 128.0, 126.7 (2 ꢂ CH), 122.9, 122.8, 61.3, CH2 76.8, 53.5,
27.0, 23.6, CH3 58.6. Anal. Calcd for C20H22N2O3: C, 70.99; H,
6.55; N, 8.28. Found: C, 71.12; H, 6.41; N, 8.12.
pyrrolidin-1-yl)benzamide 14b
Oil; ½a 2D1
ꢁ
¼ ꢀ72:3 (c 1.77, CHCl3); 1H NMR (CDCl3): 1.35–1.48
(m, 1H), 1.64–1.85 (m, 1H), 1.96–2.26 (m, 2H), 2.89–3.10 (m,
2H), 3.12 (s, 3H, OMe), 3.33–3.48 (m, 1H), 3.52–3.72 (m, 1H),
3.80 (s, 3H, OMe), 3.89–4.04 (m, 1H), 6.87 (d, J = 11.0, 1H, Harom),
6.96–7.04 (m, 1H, Harom), 7.23–7.38 (m, 2H, Harom), 7.68–7.83 (m,
3H, Harom); 13C NMR (CDCl3): C 172.9 (CO), 171.4 (CO), 162.5,
142.6, 126.5, 91.4, CH 139.4, 131.7 (2 ꢂ CH), 130.6, 128.0, 113.0
(2 ꢂ CH), 61.9, CH2 76.1, 51.7, 27.8, 23.5, CH3 58.6, 55.4. Anal. Calcd
for C21H23IN2O4: C, 51.02; H, 4.69; N, 5.67. Found: C, 51.23; H, 4.72;
N, 5.60.
4.4.2. 3-Hydroxy-2-((S)-2-methoxymethylpyrrolidin-1-yl)-3-(4-
methoxyphenyl)-2,3-dihydro-1H-isoindol-1-one 11b
Oil; 1H NMR (CDCl3): 1.29–1.42 (m, 1H), 1.44–1.63 (m, 1H),
1.77–1.91 (m, 1H), 2.06–2.22 (m, 1H), 2.54 (dt, J = 3.1, 7.9, 1H),
3.27–3.40 (m, 3H), 3.31 (s, 3H, OMe), 3.73 (s, 3H, OMe), 3.97–
4.10 (m, 1H), 6.55 (s, 1H, OH), 6.80 (d, J = 8.8, 1H, Harom), 7.20 (d,
J = 7.2, 1H, Harom), 7.30 (d, J = 8.8, 1H, Harom), 7.33–7.50 (m, 2H, Har-
om), 7.73 (d, J = 7.2, 2H, Harom); 13C NMR (CDCl3): C 165.6 (CO),
159.3, 147.9, 132.3, 129.9, 90.0, CH 132.8, 128.9, 127.9 (2 ꢂ CH),
122.8, 122.7, 113.3 (2 ꢂ CH), 61.0, CH2 76.8, 53.4, 26.9, 23.5, CH3
58.5, 55.1.
4.3.3. N-(2-Iodo-3,4,5-trimethoxybenzoyl)-N-((S)-2-methoxym-
ethylpyrrolidin-1-yl)benzamide 15a
Oil; ½a 2D1
ꢁ
¼ ꢀ81:1 (c 1.58, CHCl3); 1H NMR (CDCl3): 1.31–1.52
(m, 1H), 1.63–1.76 (m, 1H), 1.97–2.15 (m, 2H), 2.81–3.28 (m,
2H), 3.13 (s, 3H, OMe), 3.32–3.51 (m, 1H), 3.56–4.12 (m, 2H),
3.79 (s, 3H, OMe), 3.83 (s, 6H, 2 ꢂ OMe), 6.77 (s, 1H, Harom),
7.22–7.43 (m, 5H, Harom); 13C NMR (CDCl3): C 173.7 (CO), 171.0
(CO), 153.9, 153.0, 142.9, 132.2, 130.1, 81.5, CH 131.4, 130.1
(2 ꢂ CH), 128.5 (2 ꢂ CH), 108.2, 61.8, CH2 76.5, 51.8, 27.7, 23.5,
CH3 61.0, 60.8, 58.6, 56.2. Anal. Calcd for C23H27IN2O6: C, 49.83;
H, 4.91; N, 5.05. Found: C, 50.03; H, 5.12; N, 4.88.
4.4.3. 3-Hydroxy-2-((S)-2-methoxymethylpyrrolidin-1-yl)-3-
(3,4,5-trimethoxyphenyl)-2,3-dihydro-1H-isoindol-1-one 11c
Oil; 1H NMR (CDCl3): 1.38–1.51 (m, 1H), 1.54–1.72 (m, 1H),
1.92–2.07 (m, 1H), 2.16–2.33 (m, 1H), 2.88 (dt, J = 3.1, 7.9, 1H),
3.38 (s, 3H, OMe), 3.36–3.43 (m, 2H), 3.51 (q, J = 8.5, 1H), 3.80 (s,
6H, 2 ꢂ OMe), 3.83 (s, 3H, OMe), 4.01–4.14 (m, 1H), 6.69 (s, 1H,
OH), 6.71 (s, 2H, Harom), 7.27 (d, J = 7.3, 1H, Harom), 7.41–7.55 (m,
4.3.4. N-(6-Iodo-1,3-benzodioxole-5-carbonyl)-4-methoxy-N-
((S)-2-methoxymethylpyrrolidin-1-yl)benzamide 16b
Oil; ½a 2D1
ꢁ
¼ ꢀ64:7 (c 1.98, CHCl3); 1H NMR (CDCl3): 1.33–1.52
(m, 1H), 1.63–1.84 (m, 1H), 1.92–2.17 (m, 2H), 2.91–3.11 (m,

E. Deniau et al. / Tetrahedron: Asymmetry 19 (2008) 2735–2740
2739
2H, Harom), 7.78 (d, J = 7.3, 1H, Harom); 13C NMR (CDCl3): C 166.0
(CO), 152.9, 147.7, 136.0, 129.4, 90.2, CH 132.8, 129.0, 123.0,
122.6, 103.8, 61.6, CH2 76.6, 53.8, 27.0, 23.7, CH3 60.7, 58.6, 56.0
(2 ꢂ CH3).
58.7, 55.3. Anal. Calcd for C21H24N2O3: C, 71.57; H, 6.86; N, 7.95.
Found: C, 71.40; H, 6.92; N, 7.74.
4.5.2. (R)-2-((S)-2-Methoxymethylpyrrolidin-1-yl)-3-(3,4,5-
trimethoxyphenyl)-2,3-dihydro-1H-isoindol-1-one 8c
4.4.4. 3-Hydroxy-2-((S)-2-methoxymethylpyrrolidin-1-yl)-3-
methyl-2,3-dihydro-1H-isoindol-1-one 11d
Mp 154–155 °C;
½
a 2D1
ꢁ
¼ ꢀ104:3 (c 0.83, CHCl3); 1H NMR
(CDCl3): 1.52–1.80 (m, 3H), 2.01–2.17 (m, 1H), 2.54 (dd, J = 3.8,
9.1, 1H), 2.66 (t, J = 8.3, 1H), 2.91 (s, 3H, OMe), 3.10 (dt, J = 2.3,
7.3, 1H), 3.22 (q, J = 8.3, 1H), 3.62–3.88 (m, 1H), 3.70 (s, 6H,
2 ꢂ OMe), 3.74 (s, 3H, OMe), 5.32 (s, 1H), 6.30 (s, 2H, Harom), 7.07
(d, J = 7.0, 1H, Harom), 7.31–7.48 (m, 2H, Harom), 7.77 (d, J = 7.5,
1H, Harom); 13C NMR (CDCl3): C 167.6 (CO), 153.4, 144.6, 138.1,
133.8, 131.2, CH 132.1, 128.4, 123.3, 123.2, 105.4 (2 ꢂ CH), 65.6,
61.9, CH2 75.3, 51.9, 27.7, 23.1, CH3 60.9, 58.8, 56.2 (2 ꢂ CH3). Anal.
Calcd for C23H28N2O5: C, 66.97; H, 6.84; N, 6.79. Found: C, 66.84; H,
6.93; N, 6.71.
Oil; 1H NMR (CDCl3): 1.41–1.58 (m, 1H), 1.70 (s, 3H, Me), 1.62–
1.84 (m, 1H), 2.00–2.24 (m, 2H), 3.25 (s, 3H, OMe), 3.20–3.29 (m,
1H), 3.37 (dd, J = 3.6, 9.9, 1H), 3.46 (dd, J = 8.5, 9.9, 1H), 3.59 (q,
J = 8.2, 1H), 3.98–4.11 (m, 1H), 5.81 (br s, 1H, OH), 7.37–7.45 (m,
1H, Harom), 7.46–7.58 (m, 2H, Harom), 7.69 (d, J = 7.4, 1H, Harom);
13C NMR (CDCl3):
C 164.5 (CO), 147.1, 129.2, 87.7, CH
132.4, 128.9, 122.9, 121.6, 60.6, CH2 76.6, 54.0, 27.0, 23.4, CH3
58.5, 24.2.
4.4.5. 3-Hydroxy-4,5,6-trimethoxy-2-((S)-2-methoxy-methyl-
pyrrolidin-1-yl)-3-phenyl-2,3-dihydro-1H-isoindol-1-one 12a
4.5.3. (R)-4,5,6-Trimethoxy-2-((S)-2-methoxymethyl-pyrroli-
din-1-yl)-3-phenyl-2,3-dihydro-1H-isoindol-1-one 9a
Mp 177–178 °C; ½a D21
ꢁ
¼ þ66:5 (c 1.39, CHCl3); 1H NMR (CDCl3):
1.33–1.47 (m, 1H), 1.50–1.59 (m, 1H), 1.80–1.97 (m, 1H), 2.13–2.26
(m, 1H), 2.50 (dt, J = 2.8, 8.0, 1H), 3.25–3.48 (m, 3H), 3.33 (s, 3H,
OMe), 3.41 (s, 3H, OMe), 3.86 (s, 3H, OMe), 3.93 (s, 3H, OMe),
6.66 (s, 1H, Harom), 7.14 (s, 1H, Harom), 7.23–7.38 (m, 3H, Harom),
7.47 (d, J = 6.6, 1H, Harom); 13C NMR (CDCl3): C 165.3 (CO), 155.4,
148.5, 146.4, 140.7, 133.1, 125.5, 89.2, CH 127.8, 127.7 (2 ꢂ CH),
126.7 (2 ꢂ CH), 101.4, 61.4, CH2 76.6, 53.5, 26.9, 23.6, CH3 60.9,
60.2, 58.8, 56.4.
Mp 71–72 °C; ½a 2D1
ꢁ
¼ ꢀ28:1 (c 1.21, CHCl3); 1H NMR (CDCl3):
1.53–1.90 (m, 3H), 2.02–2.18 (m, 1H), 2.37–2.66 (m, 2H), 2.57 (s,
3H, OMe), 3.11–3.35 (m, 2H), 3.28 (s, 3H, OMe), 3.62–3.80 (m,
1H), 3.86 (s, 3H, OMe), 3.94 (s, 3H, OMe), 5.43 (s, 1H), 7.18 (s,
1H, Harom), 7.16–7.24 (m, 2H, Harom), 7.27–7.42 (m, 3H, Harom);
13C NMR (CDCl3): C 167.1 (CO), 155.0, 148.3, 145.7, 138.6, 130.4,
126.9, CH 128.5 (2 ꢂ CH), 128.4 (2 ꢂ CH), 128.3, 101.4, 63.3, 61.5,
CH2 74.8, 52.0, 27.5, 23.1, CH3 60.9, 59.9, 58.6, 56.4. Anal. Calcd
for C23H28N2O5: C, 66.97; H, 6.84; N, 6.79. Found: C, 66.92; H,
7.01; N, 6.69.
4.4.6. 7-Hydroxy-6-((S)-2-methoxymethylpyrrolidin-1-yl)-7-(4-
methoxyphenyl)-6,7-dihydro-1,3-dioxolo-[4,5-f]-5H-isoindol-5-
one 13b
4.5.4. (R)-6-((S)-2-Methoxymethylpyrrolidin-1-yl)-7-(4-methoxy-
phenyl)-6,7-dihydro-1,3-dioxolo[4,5-f]-5H-isoindol-5-one 10b
Oil; 1H NMR (CDCl3): 1.32–1.43 (m, 1H), 1.47–1.62 (m, 1H),
1.82–1.95 (m, 1H), 2.10–2.24 (m, 1H), 2.57 (dt, J = 3.2, 7.9, 1H),
3.28–3.42 (m, 3H), 3.38 (s, 3H, OMe), 3.80 (s, 3H, OMe), 4.00–
4.11 (m, 1H), 6.00 (s, 2H), 6.52 (s, 1H, Harom), 6.65 (s, 1H, OH),
6.84 (d, J = 8.9, 2H, Harom), 7.16 (s, 1H, Harom), 7.34 (d, J = 8.9, 2H,
Harom); 13C NMR (CDCl3): C 165.4 (CO), 159.3, 151.9, 148.6, 143.8,
132.4, 123.7, 89.5,61.0, CH 127.9 (2 ꢂ CH), 113.3 (2 ꢂ CH), 103.5,
102.8, 61.0, CH2 76.8, 53.5, 26.9, 23.5, CH3 58.6, 55.2.
Mp 107–108 °C; ½a D21
ꢁ
¼ ꢀ1:6 (c 1.44, CHCl3); 1H NMR (CDCl3):
1.53–1.66 (m, 1H), 1.68–1.92 (m, 2H), 2.04–2.17 (m, 1H), 2.43–
2.54 (m, 1H), 2.61 (t, J = 7.6, 1H), 2.97 (s, 3H, OMe), 3.15 (dt,
J = 3.1, 7.5, 1H), 3.28 (q, J = 7.2, 1H), 3.68–3.81 (m, 1H), 3.80 (s,
3H, OMe), 5.30 (s, 1H), 6.01 (d, J = 1.2, 1H), 6.03 (d, J = 1.2, 1H),
6.51 (s, 1H, Harom), 6.87 (d, J = 8.8, 2H, Harom), 7.09 (d, J = 8.8, 2H,
Harom), 7.20 (s, 1H, Harom); 13C NMR (CDCl3): C 167.2 (CO), 159.9,
151.6, 148.2, 140.6, 130.1, 125.4, CH 130.0 (2 ꢂ CH), 114.1
(2 ꢂ CH), 103.7, 102.8, 64.3, 61.4, CH2 101.8, 74.9, 51.8, 27.5,
23.0, CH3 58.7, 55.3. Anal. Calcd for C22H24N2O5: C, 66.65; H,
6.10; N, 7.07. Found: C, 66.80; H, 6.02; N, 7.22.
4.5. Typical procedure for the preparation of three-substituted
isoindolinones 8–10
A solution of hemiaminals 11–13 (5.9 mmol) in a mixture of tri-
fluoroacetic acid (5 mL) and CH2Cl2 (25 mL) was cooled to ꢀ78 °C
and stirred under argon. The solution was then treated with trieth-
ylsilane (1.9 mL, 11.8 mmol), progressively warmed to room tem-
perature, and stirred until no starting material could be detected
(TLC control). The mixture was then poured into ice-water, made
alkaline by the addition of solid K2CO3, and extracted with Et2O
(3 ꢂ 50 mL). The extracts were combined, dried over MgSO4, con-
centrated under vacuum, and the residue purified by flash chroma-
tography on silica gel using diethyl ether–hexane (60:40) as eluent
to afford isoindolinones 8a,d,6c 8b,c, 9a, 10b.
4.6. Typical procedure for the preparation of isoindolinones 5–
7
At first, MMPP (1.9 g, 3.75 mmol) was added to a solution of
hydrazide 8, 9, 10 (1.5 mmol) in methanol (50 mL). Stirring at room
temperature was continued until no starting material remained
(TLC monitoring). The reaction mixture was then diluted with
CH2Cl2 (100 mL) and treated with a saturated aqueous NaHCO3
solution (20 mL). After phase separation, the aqueous layer was ex-
tracted with CH2Cl2 (2 ꢂ 50 mL). The combined organic extracts
were dried over Na2SO4 and the solvents removed under vacuum
to furnish the crude isoindolinones 5a,d,6c 5b,c, 6a, and 7b which
were finally recrystallized from EtOH.
4.5.1. (R)-2-((S)-2-Methoxymethylpyrrolidin-1-yl)-
(3-(4-methoxyphenyl)-2,3-dihydro-1H-isoindol-1-one 8b
Mp 115–116 °C; ½a D21
ꢁ
¼ 37:1 (c 0.94, CHCl3); 1H NMR (CDCl3):
1.57–1.70 (m, 1H), 1.71–1.96 (m, 2H), 2.07–2.22 (m, 1H), 2.46
(dd, J = 3.3, 7.8, 1H), 2.61 (t, J = 8.3, 1H), 2.97 (s, 3H, OMe), 3.19
(dt, J = 2.9, 8.0, 1H), 3.31 (q, J = 7.9, 1H), 3.72–3.83 (m, 1H), 3.81
(s, 3H, OMe), 5.43 (s, 1H), 6.87 (d, J = 8.6, 2H, Harom), 7.09 (d, J =
8.6, 2H, Harom), 7.13 (d, J = 7.0, 1H, Harom), 7.42–7.53 (m, 2H, Harom),
7.86 (dd, J = 1.5, 7.3, 1H, Harom); 13C NMR (CDCl3): C 167.3 (CO),
159.9, 145.0, 131.7, 130.1, CH 132.0, 130.1 (2 ꢂ CH), 128.2, 123.4,
123.1, 114.0 (2 ꢂ CH), 64.8, 61.4, CH2 75.0, 51.9, 27.6, 23.1, CH3
4.6.1. (R)-3-(4-Methoxyphenyl)-2,3-dihydro-1H-isoindol-1-one
5b
Mp 190–191 °C;
½
a 2D1
ꢁ
¼ ꢀ115:1 (c 0.95, CHCl3); 1H NMR
(CDCl3): 3.79 (s, 3H, OMe), 5.61 (s, 1H), 6.87 (d, J = 8.6, 2H, Harom),
7.19 (d, J = 8.6, 2H, Harom), 7.23 (d, J = 7.6, 1H, Harom), 7.41–7.53 (m,
2H, Harom), 7.77 (s, 1H, NH), 7.87 (d, J = 6.7, 1H, Harom); 13C NMR
(CDCl3): C 171.4 (CO), 159.6, 148.3, 131.0, 130.3, CH 132.2, 132.1,
128.2, 128.1, 123.6, 123.3, 114.3, 60.4, CH3 55.3. Anal. Calcd for

2740
E. Deniau et al. / Tetrahedron: Asymmetry 19 (2008) 2735–2740
Esnouf, R. M.; Hopkins, A. L.; Stuart, D. I.; Stammers, D. K. J. Med. Chem. 1999,
42, 3845–3851.
2. (a) Hussein, Z.; Mulford, D. J.; Bopp, B. A.; Granneman, G. R. Br. J. Clin. Pharmacol.
1993, 36, 357–361; . Chem. Abstr. 1994, 120, 23014; (b) Kondo, T.; Yoshida, K.;
Yamamoto, M.; Tanayama, S. Arzneim. Forsch. 1996, 46, 11–14; Chem. Abstr.
1995, 124, 306386.
3. Belliotti, T. R.; Brink, W. A.; Kesten, S. R.; Rubin, J. R.; Wustrow, D. J.; Zoski, K. T.;
Whetzel, S. Z.; Corbin, A. E.; Pugsley, T. A.; Heffner, T. G.; Wise, L. D. Bioorg. Med.
Chem. Lett. 1998, 8, 1499–1502.
4. Kawanishi, N.; Sugimoto, T.; Shibata, J.; Nakamura, K.; Masutani, K.; Ikuta, M.;
Hirai, H. Bioorg. Chem. Lett. 2006, 16, 5122–5126.
5. (a) Allin, S. M.; Northfield, C. J.; Page, M. I.; Slawin, A. M. Z. Tetrahedron Lett.
1997, 38, 3627–3630; (b) Allin, S. M.; Northfield, C. J.; Page, M. I.; Slawin, A. M.
Z. Tetrahedron Lett. 1998, 39, 4905–4908; (c) Allin, S. M.; Northfield, C. J.; Page,
M. I.; Slawin, A. M. Z. Tetrahedron Lett. 1999, 40, 141–142; (d) Deniau, E.;
Enders, D.; Couture, A.; Grandclaudon, P. Tetrahedron: Asymmetry 2005, 16,
875–881.
C15H13NO2: C, 75.30; H, 5.48; N, 5.85. Found: C, 75.20; H, 5.29; N,
5.62.
4.6.2. (R)-3-(3,4,5-Trimethoxyphenyl)-2,3-dihydro-1H-isoindol-
1-one 5c
Mp 179–180 °C;
½
a 2D1
ꢁ
¼ ꢀ139:9 (c 0.99, CHCl3); 1H NMR
(CDCl3): 3.81 (s, 6H, 2 ꢂ OMe), 3.82 (s, 3H, OMe), 5.58 (s, 1H),
6.49 (s, 2H, Harom), 7.30 (d, J = 7.0, 1H, Harom), 7.41–7.58 (m, 2H,
Harom), 7.80 (br s, 1H, NH), 7.87 (d, J = 7.2, 1H, Harom); 13C NMR
(CDCl3): C 171.5 (CO), 153.7 (2 ꢂ C), 147.8, 137.8, 133.9, 130.8,
CH 132.3, 128.4, 123.7, 123.2, 103.5, 61.1, CH3 60.8, 56.2
(2 ꢂ CH3). Anal. Calcd for C17H17NO4: C, 68.21; H, 5.72; N, 4.68.
Found: C, 68.33; H, 5.54; N, 4.77.
6. (a) Allin, S. M.; Northfield, C. J.; Page, M. I.; Slawin, A. M. Z. Tetrahedron Lett.
1999, 40, 143–146; (b) Allin, S. M.; Northfield, C. J.; Page, M. I.; Slawin, A. M. Z. J.
Chem. Soc., Perkin Trans. 1 2000, 1715–1721; (c) Deniau, E.; Enders, D.; Couture,
A.; Grandclaudon, P. Tetrahedron: Asymmetry 2003, 14, 2253–2258; (d) Chen,
M.-D.; Zhou, X.; He, M.-Z.; Ruan, Y.-P.; Huang, P.-Q. Tetrahedron 2004, 60, 1651–
1657; (e) Chen, M.-D.; He, M.-Z.; Zhou, X.; Huang, L.-Q.; Ruan, Y.-P.; Huang,
P.-Q. Tetrahedron 2005, 61, 1335–1344.
7. (a) Perard-Viret, J.; Prangé, T.; Tomas, A.; Royer, J. Tetrahedron 2002, 58, 5103–
5108; (b) Comins, D. L.; Schilling, S.; Zhang, Y. Org. Lett. 2005, 7, 95–98.
8. Enders, D.; Braig, V.; Raabe, G. Can. J. Chem. 2001, 79, 1528–1535.
9. (a) Clayden, J.; Turnbull, R.; Pinto, I. Tetrahedron: Asymmetry 2005, 16, 2235–
2242; (b) Sun, X.-W.; Liu, M.; Xu, M.-H.; Lin, G.-Q. Org. Lett. 2008, 10, 1259–1262.
10. Lamblin, M.; Couture, A.; Deniau, E.; Grandclaudon, P. Tetrahedron: Asymmetry
2008, 19, 111–123.
4.6.3. (R)-4,5,6-Trimethoxy-3-phenyl-2,3-dihydro-1H-isoindol-
1-one 6a
Mp 139–140 °C; ½a D21
ꢁ
¼ ꢀ70:5 (c 0.92, CHCl3); 1H NMR (CHCl3):
3.30 (s, 3H, OMe), 3.85 (s, 3H, OMe), 3.91 (s, 3H, OMe), 5.57 (s, 1H),
7.17 (s, 1H, Harom), 7.24–7.31 (m, 5H, Harom), 7.74 (br s, 1H, NH); 13
C
NMR (CHCl3): C 171.2 (CO), 155.1, 148.5, 145.8, 138.3, 133.8, 126.5,
CH 128.6 (2 ꢂ CH), 128.2, 127.4 (2 ꢂ CH), 101.6, 59.0, CH3 60.9,
60.1, 56.3. Anal. Calcd for C17H17NO4: C, 68.21; H, 5.72; N, 4.68.
Found: C, 68.29; H, 5.89; N, 4.89.
11. Grigg, R.; Dorrity, M. J. R.; Malone, J. F.; Mongkolauss-savaratana, T.; Norbert,
W. D. J. A.; Sridharan, V. Tetrahedron Lett. 1990, 31, 3075–3076.
12. Shen, L.; Hsung, R. P. Org. Lett. 2005, 7, 775–778.
13. Clayden, J.; Menet, C. J. Tetrahedron Lett. 2003, 44, 3059–3062.
14. (a) Parham, W. E.; Bradsher, C. K. Acc. Chem. Res. 1982, 15, 300–305; (b)
Moreau, A.; Couture, A.; Deniau, E.; Grandclaudon, P. Eur. J. Org. Chem. 2005,
3437–3442.
15. Enders, D.; Klatt, M. Synthesis 1996, 1403–1418.
16. Job, A.;Janeck, C. F.;Bettray, W.; Peters, R.; Enders, D. Tetrahedron 2002, 58, 2253–
2329.
4.6.4. (R)-7-(4-Methoxyphenyl)-6,7-dihydro-1,3-dioxolo[4,5-f]-
5H-isoindol-5-one 7b
Mp 208–209 °C; ½a D21
ꢁ
¼ ꢀ34:1 (c 1.20, CHCl3); 1H NMR (CDCl3):
3.77 (s, 3H, OMe), 5.44 (s, 1H), 5.98 (s, 1H), 6.02 (s, 1H), 6.57 (s, 1H,
Harom), 6.85 (d, J = 8.8, 2H, Harom), 7.14 (d, J = 8.8, 2H, Harom), 7.19
(s, 1H, Harom), 7.34 (br s, 1H, NH); 13C NMR (CDCl3): C 171.2 (CO),
160.0, 152.1, 148.7, 144.5, 130.6, 125.1, CH 128.3 (2 ꢂ CH), 114.7
(2 ꢂ CH), 103.7, 103.4, 60.4, CH2 102.3, CH3 55.6. Anal. Calcd for
C16H13NO4: C, 67.84; H, 4.63; N, 4.94. Found: C, 67.48; H, 4.48; N,
4.89.
17. Lebrun, S.; Couture, A.; Deniau, E.; Grandclaudon, P. Tetrahedron: Asymmetry
2003, 14, 2625–2632.
18. (a) Suzuki, H.; Aoyagi, S.; Kibayashi, C. Tetrahedron Lett. 1994, 35, 6119–6122;
(b) Suzuki, H.; Aoyagi, S.; Kibayashi, C. J. Org. Chem. 1995, 60, 6114–6122.
19. (a) Fernandez, R.; Ferrete, A.; Lassaletta, J. M.; Llera, J. M.; Monge, A. Angew.
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