Unified approach to the asymmetric synthesis of higher homologues of (3-quinolyl)-alanine

Article abstract of DOI:10.1080/00397911.2014.882002

A new protocol based on a palladium-catalyzed Heck reaction of an amino acid-derived vinyl unit with 3-bromoquinoline has been developed to access the title compounds in good yield and optical purity. Copyright

Full text of DOI:10.1080/00397911.2014.882002

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Unified Approach to the Asymmetric
Synthesis of Higher Homologues of (3-
Quinolyl)-alanine
Shital K. Chattopadhyay a & Indranil Kundu a
a Department of Chemistry , University of Kalyani , Kalyani , West
Bengal , India
Accepted author version posted online: 16 Apr 2014.Published
online: 09 Jun 2014.
To cite this article: Shital K. Chattopadhyay & Indranil Kundu (2014) Unified Approach to the
Asymmetric Synthesis of Higher Homologues of (3-Quinolyl)-alanine, Synthetic Communications: An
International Journal for Rapid Communication of Synthetic Organic Chemistry, 44:14, 2112-2120,
DOI: 10.1080/00397911.2014.882002
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Synthetic Communications1, 44: 2112–2120, 2014
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2014.882002
UNIFIED APPROACH TO THE ASYMMETRIC
SYNTHESIS OF HIGHER HOMOLOGUES OF
(3-QUINOLYL)-ALANINE
Shital K. Chattopadhyay and Indranil Kundu
Department of Chemistry, University of Kalyani, Kalyani,
West Bengal, India
GRAPHICAL ABSTRACT
Abstract A new protocol based on a palladium-catalyzed Heck reaction of an amino acid–
derived vinyl unit with 3-bromoquinoline has been developed to access the title compounds in
good yield and optical purity.
Keywords a-Amino acids; Heck reaction; quinoline
INTRODUCTION
Synthesis of noncoded amino acids has remained an important activity over the
decades because of amino acids’ known importance in chemistry and biology.[1]
A
class of such nonproteinogenic amino acids are the heterocycle appended a-amino
acids, which are important because of their wide range of chemical and biological
applications as components of natural products and peptide nucleic acids, building
blocks in therapeutic lead generation, and conformational control elements in
the design and synthesis of modified peptides.[2] Thus, synthesis of a-amino acids
accommodating a side-chain heterocyclic units such as pyrrole,[3] furan,[4] pyridine,[5]
pyrimidine,[6] purine,[7] pyrrazole,[8] thiophene,[9] indole,[10] quinolone,[11] and
quinoxaline[12] have been described. Although superb catalytic methods are being
continuously developed,[13] conversion of simple coded amino acids into desired
targets have remained important. Thus, several amino-acid-based building blocks
have emerged.[14] One such type of building block is the a, b-, or c-vinylic oxazolidines
Received September 4, 2013.
Address correspondence to Shital K. Chattopadhyay, Department of Chemistry, University of
Kalyani, Kalyani 741235, West Bengal, India. E-mail: skchatto@yahoo.com
2112

HIGHER HOMOLOGUES OF (3-QUINOLYL)-ALANINE
2113
Figure 1. Background of the work.
of the general structure 1 (Fig. 1). Heck-type arylation of 1 and derivatives thereof
continue to be useful in the synthesis of aryl amino acids.[15] However, its utility
for the preparation of heteroaromatic amino acids has remained comparatively less
explored.
(3-Quinolyl)-alanine (2) has been extensively utilized as a replacement of histi-
dine residue in important peptides for the preparation of somatostatin analogs,[16]
gonadotropin-releasing-hormone-receptor antagonists,[17] and gramicidin channel
receptor agonists.[18] However, higher homologues of (3-quinolyl)-alanine are less
known. Herein, we report synthesis of three homologues of 2 having variation in
the chain length (n ¼ 2–4), involving Heck-type arylation of 3-bromoquinoline with
the olefins 1 as the key step.
RESULTS AND DISCUSSION
Our synthesis started with the preparation of the olefins 1a–c (Scheme 1).
Wittig-type methylenation of Garner’s aldehyde 3[19] has been found to be problem-
atic and prone to racemization as well as poor yielding when KH or n-BuLi was used
as base.[20] However, use of potassium hexamethyldisilazide (KHMDS) as base
circumvented both the problems.[21] Other conditions such as use of Me3Al=Zn=
CH2I2 combination for racemization-free olefination of 1a are also known.[20a,21]
However, we have found that a good yield conversion of 3 to 1a could simply be
achieved if the reaction is carried out at 0 ꢀC instead of ꢁ78 ꢀC in the presence of
Scheme 1. Preparation of starting materials.

2114
S. K. CHATTOPADHYAY AND I. KUNDU
n-BuLi as base. Moreover, the optical purity of the product also proved to be unaf-
fected because the product 1a displayed a specific rotation value, [a]D þ 17.2 (c 1.20,
CHCl3), in close agreement to those reported [[a]D þ 15.6 (c 2.0, CHCl3)]; [[a]D þ 15 (c
2.5, CHCl3)] for optically pure compound.[19,20] The aspartic-acid-derived aldehyde
4
[22,4e] and the glutamic acid-derived aldehyde 5 [23] were similarly methylenated under
the developed conditions to yield the corresponding olefins 1b and 1c respectively, in
good yields.
Having access to the required olefins 1a–c, we then focused on their projected
Heck-type coupling with 3-bromoquinoline. Palladium-catalyzed Mizoroki–Heck ole-
fination[24] is usually more regio- and stereoselective with electron-deficient olefins and
often been found to be problematic with nonactivated olefins, with poor regioselectiv-
ity and stereoselectivity being major concerns. After some experimentation, we have
found that olefination of 3-bromoquinoline (6) with olefin 1a proceeds better under
Jeffery’s two-phase protocol[25] involving use of n-Bu4NþBrꢁ as an additive, and the
coupled product 7 (Scheme 2) is obtained as the only isolable product in good yield.
The E-geometry of the newly formed double bond was easily secured from its
1H NMR spectrum, a 16-Hz coupling between the olefinic protons being diagnostic.
Moreover, characteristic rotamerism[26] of the oxazolidine moiety was reflected in
doubling of some signals in its 13C NMR spectrum. Rerecording the 13C NMR spec-
trum at higher temperature removed this commonly observed complexity and a single
set of signals was observed. We also observed signal broadening in the 1H NMR spec-
trum recorded in CDCl3. A better resolution of the peaks was observed when the
spectrum was recorded in DMSO-d6[see Supporting Information]. Catalytic hydro-
genation of the compound 7 led to the corresponding saturated compound 8 and a
one-pot deprotection of the oxazolidine unit in the latter followed by in situ oxidation
of the resulting primary alcohol using Jones’s oxidation reaction proceeded smoothly
to provide the a-amino acid derivative 9 in an overall yield of 66% over three steps.
Compound 9 was then subjected to peptide bond formation with L-Phe-OMe.HCl
Scheme 2. Preparation of (3-quinolyl)-homoalanine.

HIGHER HOMOLOGUES OF (3-QUINOLYL)-ALANINE
2115
Scheme 3. Synthesis of higher homologues of (3-quinolyl)-alanine.
and the resulting dipeptide 10 was analyzed by NMR and high-performance liquid
chromatography (HPLC) for its stereochemical purity. Pleasingly, compound 10
was found to be homogeneous, thereby indicating little racemization during the
sequence of reactions depicted in Scheme 2.
We then focused on the projected arylation of the olefins 1b and 1c. Separate
treatment of each of these olefins with 3-bromoquinoline under the developed con-
ditions furnished the corresponding coupled products 11 and 12 (Scheme 3) in good
yields in a regio- and stereoselective manner. Saturation of the olefinic unit in each of
these compounds proceeded uneventfully to provide the compounds 13 and 14
respectively. Repetition of the one-pot deprotection–oxidation sequence on these
compounds as detailed for the conversion 8 ! 9 then led to the desired a-amino acid
derivatives 15 and 16 in good overall yields of 53–55% over three steps. Each of these
a-amino acids were then converted to the corresponding dipeptides 17 and 18 under
conventional conditions. The latter were also found to be optically homogeneous.
In short, we have developed a three-step synthetic protocol for the access of
three homologues of the important a-amino acid (3-quinolyl)-alanine (viz. com-
pounds 9, 15, and 16) in good overall yields and optical purity. Easy access to the
starting olefins 1a–c has also been developed. The synthetic protocols may allow
access to related compounds of interest and hence may find application.
EXPERIMENTAL
Melting points were recorded in open capillaries and are uncorrected. Infrared
(IR) spectra were recorded on a Perkin-Elmer Spectrum-1 spectrophotometer. Proton
and carbon NMR spectra were recorded on a Bruker Avance-400 spectrometer

2116
S. K. CHATTOPADHYAY AND I. KUNDU
(purchased through DST-FIST Grant). Chemical shifts are recorded relative to
residual solvent peak. Data for rotamers are given within parentheses. Mass spectra
were recorded on a Jeol-JMS 600 instrument from I.I.C.B., Kolkata or IACS,
Kolkata. Petroleum ether refers to the fraction boiling in the range 60–80 ꢀC. Silica
gel (60–120, 200–230 mesh) for column chromatography was purchased from
Spectrochem, India.
General Procedure for the Synthesis of the Olefins 1a–c
(R)-tert-Butyl 2,2-dimethyl-4-vinyl-oxazolidine-3-carboxylate (1a). n-BuLi
(2 M in hexane, 1.7 mL, 3.45 mmol, 1.5 eqv.) was added to a stirred suspension of
methyltriphenylphosphonium bromide (1.23 g, 3.45 mmol, 1.5 eqv.) in dry THF
(10 mL) under argon at 0 ꢀC dropwise over 5 min, and the resulting solution was
allowed to stir for 20 min at 0 ꢀC. A solution of the aldehyde 3 (528 mg, 2.30 mmol)
in THF (5 mL) was then added dropwise over 5 min with stirring at the same
temperature. After 20 min, the solution was allowed to come to room temperature
and was stirred for another 4 h. The reaction mixture was quenched by addition
of aqueous NH4Cl solution (3 mL) and then extracted with ethyl acetate (2 ꢂ 50 mL).
The combined organic extract was washed successively with H2O (40 mL) and brine
solution (40 mL) and then dried over MgSO4. It was then filtered, and the filtrate was
concentrated under reduced pressure to leave the crude product, which was purified
by column chromatography over silica gel (EtOAc–PE, 1:19) to give the olefin 1a as
a colorless liquid; yield: 366 mg (70%); [a]D þ 17.2 (c 1.20, CHCl3); Lit.[21a] [[a]D þ
15.6 (c 2.0, CHCl3)]; lit.[20a] [[a]D þ 15 (c 2.5, CHCl3)].
IR (CHCl3): 2981, 1699, 1479, 1456, 1385, 1366, 1254 cmꢁ1.1H NMR (CDCl3,
400 MHz): d 5.76 (s, 1H), 5.20–5.09 (m, 2H), 4.35–4.22 (br m, 1H), 3.99 (td, J ¼ 6.4,
2.8 Hz, 1H), 3.70 (dd, J ¼ 9.2, 2.4 Hz, 1H), 1.56 (s, 3H), 1.46–1.38 (m, 12H). 1H NMR
(DMSO-d6, 400 MHz): d 5.78 (ddd, J ¼ 6.8, 10.0, 16.8 Hz, 1H), 5.20–5.09 (m, 2H),
4.35–4.22 (br m, 1H), 4.00 (dd, J ¼ 6.4, 8.8 Hz, 1H), 3.70 (dd, J ¼ 9.2, 2.0 Hz, 1H),
1.56 (s, 3H), 1.46–1.38 (two singlets, 12H). 13C NMR (CDCl3, 100 MHz): d 151.9,
137.3, 115.7, 93.9, 79.5, 68.1, 59.6, 28.3, 26.5, 23.6. MS (TOF, ESþ): m=z (%) ¼ 250
(100) [M þNa].
General Procedure for Heck-Type Olefination with 1a–c: (R,E)-tert-
Butyl 2,2-Dimethyl-4-(2-(quinolin-3-yl)vinyl)oxazolidine-3-
carboxylate (7)
A solution of the olefin 1a (170 mg, 0.75 mmol), 3-bromoquinoline (171 mg,
0.82 mmol, 1.1 eqv.), palladium acetate (8 mg, 0.04 mmol, 5 mol %), NaHCO3
(94 mg, 1.12 mmol, 1.5 eqv.), and n-Bu4NþBr-(723 mg, 2.24 mmol, 3 eqv.) in DMF
(5 mL) was taken in a sealed tube and stirred at 90 ꢀC for 18 h. The reaction mixture
was allowed to come to rt and then diluted with H2O (60 mL). It was then extracted
with EtOAc (2 ꢂ 50 mL). The combined organic extract was washed successively with
H2O (2 ꢂ 50 mL) and brine (50 mL), and then dried (MgSO4). It was filtered and
then concentrated in vacuo to leave a residue, which was purified over silica gel
(EtOAc–PE, 3:7) to provide the coupled product 7 as a colorless solid (238 mg,
90%). Mp 120–121 ꢀC. [a]D ꢁ 98.7 (c 0.42, CHCl3). IR (CHCl3): 2991, 2869, 1680,

HIGHER HOMOLOGUES OF (3-QUINOLYL)-ALANINE
2117
1494, 1390, 1361, 1255 cmꢁ1.1H NMR (400 MHz, CDCl3): d 8.98 (s, 1H), 8.08–8.05
(m, 2H), 7.78 (s, 1H), 7.66 (s, 1H), 7.52 (s, 1H), 6.75–6.61 (br m, 1H), 6.41 (s, 1H),
4.64–4.92 (br m, 1H), 4.16 (dd, J ¼ 8.8, 6.4 Hz, 1H), 3.89 (dd, J ¼ 8.8, 1.2 Hz, 1H),
1.71 (s, 3H), 1.57 (1.49) (s, 3H), 1.42 (s, 9H).1H NMR (400 MHz, DMSO-d6): d
9.06 (s, 1H), 8.38 (s, 1H), 8.00–7.95 (m, 2H), 7.72 (t, J ¼ 7.6 Hz, 1H), 7.60 (dd,
J ¼ 8.4, 6.8 Hz, 1H), 6.66 (d, J ¼ 16 Hz, 1H), 6.55 (dd, J ¼ 7.2, 15.6 Hz, 1H),
4.56–4.48 (br m, 1H), 4.13 (dd, J ¼ 8.8, 6.4 Hz, 1H), 3.84 (dd, J ¼ 8.8, 1.2 Hz, 1H),
1.48–1.35 (overlapping singlets, 15H).13C NMR (100 MHz, CDCl3): d 151.9, 149.2,
147.5, 132.7, 132.4, 131.2, 129.5, 129.2, 128.3, 128.0, 127.8, 127.0, 94.3 (93.8), 80.5
(79.9), 68.2, 59.5, 28.5, 27.6 (26.7), 24.7 (23.7). 13C NMR (100 MHz, DMSO-d6,
70 ꢀC): d 152.0, 149.8, 147.6, 132.7, 132.5, 130.2, 129.8, 129.3, 128.7, 128.3, 128.1,
127.5, 94.0, 79.7, 68.3, 59.6, 28.7, 26.4, 23.2. Anal. Calcd. for C21H26N2O3: C,
71.16; H, 7.39; N, 7.90; found: C, 71.31, H, 7.46; N, 7.85. MS (TOF, ESþ): m=z
(%) ¼ 355 (100) [M þH].
General Procedure for Hydrogenation of the Coupled Olefins: (R)-
tert-Butyl 2,2-Dimethyl-4-(2-(quinolin-3-yl)ethyl)oxazolidine-3-
carboxylate (8)
Pd–C (10 mol%; 14 mg) was added to a solution of the coupled product 7
(200 mg, 0.56 mmol) in MeOH (6 mL) at rt and the heterogeneous mixture was vigor-
ously stirred under hydrogen atmosphere for 2 h. It was then filtered through celite,
and the filter cake was thoroughly washed with MeOH (10 mL). The combined filtrate
was concentrated in vacuo to leave a crude mass, which was purified by chromato-
graphy over silica gel (EtOAc–PE, 3:7) to furnish the product 8 as a colorless solid
(189 mg, 95%). Mp 80–81 ꢀC. [a]D ꢁ 41.8 (c 0.61, CHCl3). IR (CHCl3): 2979, 2870,
1676, 1496, 1392, 1251 cmꢁ1.1H NMR (400 MHz, CDCl3): d 8.78 (s, 1H), 8.08
(d, J ¼ 8.4 Hz, 1H), 7.98–7.92 (br m, 1H), 7.77 (d, J ¼ 8.0 Hz, 1H), 7.66 (s, 1H), 7.53
(s, 1H), 4.06–3.86 (m, 3H), 2.90–2.70 (m, 2H), 2.30–1.97 (m, 2H), 1.66 (1.63) (s, 3H),
1.50 (s, 9H), 1.41 (s, 3H).13C NMR (100 MHz, CDCl3): d 151.9, 151.7, 146.9, 134.1,
129.2, 128.6, 128.1, 127.3, 126.6, 93.4, 80.2 (79.7), 66.8, 57.4 (56.8), 35.1 (34.4), 29.9,
28.5, 27.6 (26.8), 24.5 (23.2). Anal. calcd. for C21H28N2O3: C, 70.76; H, 7.92; N,
7.86. Found: C, 70.91, H, 7.84; N, 7.95. MS (TOF, ESþ): m=z (%) ¼ 357(100) [M þH].
General Procedure for Jones’s Oxidation: (R)-2-(tert-
Butoxycarbonylamino)-4-(quinolin-3-yl)butanoic Acid (9)
Jones’s reagent (2.67 M, 366 mL, 0.66 mmol) was added to a solution of the
appropriate oxazolidine derivative 8 (90 mg, 0.25 mmol) in acetone (3 mL) at 0 ꢀC.
The reaction mixture was stirred for 5 h and then quenched by addition of 2-propanol
(2.5 mL). The resulting reaction mixture was stirred for 10 min and then neutralized
with saturated aqueous NaHCO3 solution (pH ¼ 4–5). It was then extracted with ethyl
acetate (2 ꢂ 25 mL), and the combined organic extract was washed successively with
H2O (20 mL) and brine solution (15 mL) and then dried over MgSO4. It was then fil-
tered, and the filtrate was concentrated under reduced pressure to leave the crude pro-
duct, which was purified by column chromatography over silica gel (EtOAc–PE, 7:3)
to obtain compound 9 as a colorless solid (64 mg, 78%); Mp 176–178 ꢀC; [a]D– 51.5

2118
S. K. CHATTOPADHYAY AND I. KUNDU
(c 0.13, CHCl3). IR (CHCl3): 3402, 2976, 2479, 1716, 1584, 1521, 1364, 1282 cmꢁ1. 1H
NMR (400 MHz, CDCl3): d 13.28 (s, 1H), 8.84 (s, 1H), 8.14 (s, 1H), 8.01 (d,
J ¼ 8.0 Hz, 1H), 7.76 (d, J ¼ 8.0 Hz, 1H), 7.59 (t, J ¼ 6.8 Hz, 1H), 7.50 (t, J ¼ 7.6 Hz,
1H), 5.67 (d, J ¼ 7.2 Hz, 1H), 4.48 (d, J ¼ 5.2 Hz, 1H), 2.98 (d, J ¼ 6.8 Hz, 2H), 2.43
(d, J ¼ 6.4 Hz, 1H), 2.24 (d, J ¼ 6.4 Hz, 1H), 1.47 (s, 9H).13C NMR (100 MHz,
CDCl3): d 175.3, 155.6, 149.8, 143.8, 137.2, 134.6, 129.8, 128.2, 127.5, 127.4, 126.2,
79.7, 53.3, 33.9, 28.7, 28.4. HRMS (TOF, ESþ): m=z [Mþ þH] calcd. for C18H23N2
O4: 331.1658; found: 331.1651.
General Procedure for Peptide Coupling: (S)-Methyl 2-((R)-2-(tert-
Butoxycarbonylamino)-4-(quinolin-3-yl)butanamido)-3-
phenylpropanoate (10)
N-Methylmorpholine (75 mL, 0.75mmol) was added dropwise to a stirred suspen-
sion of L-Phe-OMe.HCl (50mg, 0.3 mmol, 1 eqv.) in dry CH2Cl2 (4 mL) at 0 ꢀC under
argon. After 10min, a solution of the carboxylic acid 9 (100 mg, 0.3 mmol, 1 eqv) in dry
CH2Cl2 (4 mL) was added dropwise and stirred for 10min. Then N-(3-dimethylamino-
propyl)-N0-ethylcarbodiimide hydrochloride (EDCꢃ HCl) (64 mg, 0.34mmol, 1.1 eqv.)
and 1-hydroxybenzotriazole (HOBT) (46 mg, 0.34mmol, 1.1 eqv.) were added succes-
sively in 10-min intervals at the same temperature. The reaction mixture was allowed
to come to room temperature and stirred for 18h. It was then diluted with water
(25 mL) and extracted with EtOAc (2ꢂ 25mL). The combined organic layer was
washed successively with H2O (2 ꢂ 20mL) and brine (15 mL). It was then dried over
Na2SO4 and filtered, and the filtrate was concentrated in vacuo to leave a pale yellow
liquid, which was purified by chromatography over silica gel (EtOAc–PE, 1:1) as eluent
to give the product 10 as a colorless solid (104mg, 70%). Mp 124–126 ꢀC. [a]D þ 36.7 (c
0.12, CHCl3). IR (CHCl3): 3337, 2991, 2858, 1736, 1681, 1661, 1537, 1522, 1435,
1281cmꢁ1.1H NMR (400 MHz, CDCl3): d 8.71 (s, 1H), 8.08 (d, J ¼ 8.4 Hz, 1H), 7.87
(s, 1H), 7.75 (d, J ¼ 8.0 Hz, 1H), 7.67 (dt, J ¼ 7.2, 1.2 Hz, 1H), 7.53 (t, J ¼ 7.6 Hz,
1H), 7.23 (d, J ¼ 7.6 Hz, 2H), 7.19 (d, J ¼ 6.8 Hz, 1H), 7.11 (d, J ¼ 7.6 Hz, 2H), 6.67
(d, J ¼ 7.2 Hz, 1H), 5.13 (d, J ¼ 7.6 Hz, 1H), 4.89 (dd, J ¼ 13.2, 6.8 Hz, 1H), 4.20 (d,
J ¼ 4.4 Hz, 1H), 3.73 (s, 3H), 3.18 (dd, J ¼ 14.0, 5.6 Hz, 1H), 3.05 (dd, J ¼ 14.0,
6.8 Hz, 1H), 2.74 (t, J ¼ 7.6 Hz, 1H), 2.20–2.15 (m, 1H), 1.94–1.87 (m, 2H), 1.43 (s,
9H).13C NMR (100MHz, CDCl3): d 171.9, 171.5, 155.7, 151.6, 146.7, 135.8, 134.5,
133.7, 129.2, 129.0, 128.9, 128.6, 128.0, 127.4, 127.2, 126.7, 80.2, 53.8, 53.1, 52.4,
37.8, 33.8, 28.9, 28.3. Anal. calcd for C28H33N3O5: C, 68.41; H, 6.77; N, 8.55. Found:
C, 68.64, H, 6.67; N, 8.61.MS (TOF, ESþ): m=z (%) ¼ 492 (100) [M þH].
ACKNOWLEDGMENT
This article is respectfully dedicated to the late Professor Alexander McKillop
in admiration of his immense contribution to organic chemistry.
FUNDING
Financial assistance from the Department of Science and Technology (DST),
New Delhi (Grant No. SR=S1=OC-92=2012) is gratefully acknowledged. One of

HIGHER HOMOLOGUES OF (3-QUINOLYL)-ALANINE
2119
the authors (I. K.) is also thankful to the University Grants Commission, New Delhi,
for a fellowship. Financial assistance from DST–PURSE and the University of
Kalyani is also thankfully acknowledged.
SUPPLEMENTARY CONTENT
1
Full experimental detail and H and 13C NMR spectra are included in the
Supplementary Content. This material can be can be accessed on the publisher’s
website.
REFERENCES
1. (a) Williams, R. M. In Synthesis of Optically Active a-Amino Acids; J. E. Baldwin, P. D.
Magnus (Eds.); Organic Chemistry Series; Pergamon Press: Oxford, 1989; Vol. 7;
(b) Barret, G. C. In Amino Acids, Peptides, and Proteins; Chemical Society: London,
2001; Vol. 32.
2. Matthews, J. L. Synthesis of peptides and peptidomimetics. In Houben-Weyl Methods in
Organic Chemistry; M. Goodman, A. Felix, L. Moroder, and C. Toniolo (Eds.); Thieme:
Stuttgart, 2001; Vol. E22C, p. 552.
3. (a) Do¨rr, A. A.; Lubell, W. D. Tetrahedron Lett. 2011, 52, 2159; (b) Sarkar, K.; Singha,
S. K.; Chattopadhyay, S. K. Tetrahedron: Asymmetry 2009, 20, 1719; (c) Adamczyk, M.;
Johnson, D. D.; Reddy, R. E. Tetrahedron: Asymmetry 2000, 11, 3063.
4. (a) Molina, L.; Moreno-Vargas, A. J.; Carmona, A. T.; Robina, I. Synlett 2006, 1327;
´
(b) Saaby, S.; Bayon, P.; Aburel, P. S.; Jørgensen, K. A. J. Org. Chem. 2002, 67, 4352;
(c) Reingruber, R.; Baumann, T.; Dahmen, S.; Brase, S. Adv. Synth. Catal. 2009, 351,
¨
1019; (d) Sakai, N.; Asano, J.; Shimano, Y.; Konakahara, T. Synlett 2007, 2675;
(e) Chattopadhyay, S. K.; Sarkar, K.; Karmakar, S. Synlett 2005, 2083.
5. (a) Dondoni, A.; Massi, A.; Minghini, E.; Sabbatini, S.; Bertolasi, V. J. Org. Chem. 2003,
68, 6172; (b) Adamczyk, M.; Akireddy, S. R.; Reddy, R. E. Org. Lett. 2001, 3, 3157;
(c) Walker, M. A.; Kaplita, K. P.; Chen, T.; Dalton King, H. Synlett 1997, 169; (d) Ye,
B.; Burke, Jr., T. R. J. Org. Chem. 1995, 60, 2640.
6. (a) Elmarrouni, A.; Guell, M.; Collell, C.; Heras, M. Tetrahedron 2010, 66, 612; (b) Font,
¨
D.; Heras, M.; Villalgordo, J. M. Tetrahedron 2008, 64, 5226; (c) Jones, R. C. F.;
Berthelot, D. J. C.; Iley, J. N. Chem. Commun. 2000, 2131.
ˇ
7. Capek, P.; Pohl, R.; Hocek, M. J. Org. Chem. 2005, 70, 8001.
8. De Luca, L.; Giacomelli, G.; Porcheddu, A.; Spanedda, A. M.; Falorni, M. Synthesis
2000, 1295.
9. Podea, P. V.; Tosa, M. I.; Paizs, C.; Irimie, F. Tetrahedron: Asymmetry 2008, 19, 500.
10. Sakai, N.; Asano, J.; Shimano, Y.; Konakahara, T. Synlett 2007, 17, 2675.
11. (a) Jones, S. W.; Palmer, C. F.; Paul, J. M.; Tiffin, P. D. Tetrahedron Lett. 1999, 40, 1211;
(b) Cabarrocas, G.; Rafel, S.; Ventura, M.; Villalgordo, J. M. Synlett 2000, 595;
´
(c) Cabarrocas, G.; Ventura, M.; Maestro, M.; Mahıa, J.; Villalgordo, J. M. Tetrahedron:
Asymmetry 2001, 12, 1851.
12. Staszewska, A.; Stefanowicz, P.; Szewczuk, Z. Tetrahedron Lett. 2005, 46, 5525.
´
13. For a recent review, see Najera, C.; Sansano, J. M. Chem. Rev. 2007, 107, 4584.
14. (a) Arnold, L. D.; May, R. G.; Vederas, J. C. J. Am. Chem. Soc. 1988, 110, 2237;
(b) Sasaki, N. A.; Hashimoto, C.; Potier, P. Tetrahedron Lett. 1987, 28, 6069; (c) Evans,
D. A.; Bach, T. Angew Chem. Int. Ed. 1993, 33, 1326; (d) Jackson, R. F. W.; Wishart, N.;
Wood, A.; James, K.; Wythes, M. J. J. Org. Chem. 1992, 57, 3397; (e) Harwood, L. M.;
Manage, A. C.; Robin, S.; Hopes, S. F. G.; Watkin, D. J.; Williams, C. E. Synlett 1993,

2120
S. K. CHATTOPADHYAY AND I. KUNDU
777; (f) Dondoni, A.; Marra, A.; Massi, A. J. Org. Chem. 1999, 64, 933; (g) Collier, P. N.;
Campbell, A. D.; Patel, I.; Raynham, T. M.; Taylor, R. J. K. J. Org. Chem. 2002, 67, 1802.
ˇ
15. (a) Liang, H.; Zhou, Y.; Ciufolini, M. A. Synthesis 2010, 2515; (b) Capek, P., Pohl, R.,
Hocek, M. J. Org. Chem. 2005, 70, 8001; (c) Della Sala, G.; Izzo, I.; Spinella, A. Synlett
2006, 1319; (d) Collier, P. N.; Patel, I.; Taylor, R. J. K. Tetrahedron Lett. 2002, 43, 3401;
(e) Gibson, S. E.; Jones, J. O.; Kalindjian, S. B.; Knight, J. D.; Mainolfi, N.; Rudd, M.;
Steed, J. W.; Tozer, M. J.; Wright, P. T. Tetrahedron 2004, 60, 6945; (f) Gurjar, M. K.;
Talukdar, A. Synthesis 2002, 315; (g) Huck, J.; Receveur, J.-M.; Roumestant, M.;
Martinez, J. Synlett 2001, 1467; (h) Møller, B.; Undheim, K. Tetrahedron 1998, 54,
5789; (i) Crisp, G. T.; Glink, P. T. Tetrahedron 1992, 48, 3541.
´
´
16. Ramon, R.; Martın-Gago, P.; Verdaguer, X.; Macias, M. J.; Martin-Malpartida, P.;
Fernandez-Carneado, J.; Gomez-Caminals, M.; Ponsati, B.; Lopez-Ruiz, P.; Cortes, M.
´
´
´
´
A.; Colas, B.; Riera, A. ChemBioChem. 2011, 12, 625.
17. (a) Huirne, J. A. F.; Lambalk, C. B. Lancet 2001, 358, 1793; (b) Yahalom, D.;
Rahimipour, S.; Koch, Y.; Nurit Ben-Aroya, N.; Fridkin, M. J. Med. Chem. 2000, 43,
2831.
18. Daumas, P.; Benamar, D.; Heitz, F.; Ranjalahy-Rasoloarijao, L.; Mouden, R.; Lazaro, R.;
Pullman, A. Int. J. Pep. Prot. Res. 1991, 38, 218.
19. Garner, P.; Park, J. M. J. Org. Chem. 1987, 52, 2361; Org. Synth. 1991, 70, 18.
20. (a) Moriwake, T.; Hamano, S.-i.; Saito, S.; Torii, S. Chem. Lett. 1987, 2085; (b) Beaulieu,
P. L.; Duceppe, J. S.; Johnson, C. J. Org. Chem. 1991, 56, 4196.
21. (a) McKillop, A.; Taylor, R. J. K.; Watson, R. J.; Lewis, N. Synthesis 1994, 31;
(b) Campbell, A. D.; Raynham, T. M.; Taylor, R. J. K. Synthesis 1998, 1707.
22. Shimamoto, K.; Ishida, M.; Shinozaki, H.; Ohfune, Y. J. Org. Chem. 1991, 56, 4167.
23. Truchot, C.; Wang, Q.; Sasaki, N. A. Eur. J. Org. Chem. 2005, 1765.
24. (a) Beletskaya, I.; Cheprakov, A. V. Chem. Rev. 2000, 100, 3009; (b) Brase, S.; de Meijere,
¨
A. In Metal-Catalyzed Cross-Coupling Reactions; F. Diederich and P. J. Stang (Eds.);
Wiley-VCH: Weinheim, 2004; (c) Heck, R. F. Org. React. 1982, 27, 345.
25. Jeffery, T. Tetrahedron Lett. 1985, 26, 2667.
´
26. Avenoza, A.; Busto, J. H.; Corzana, F.; Jimenez-Oses, G.; Peregrina, J. M. Tetrahedron
´
2003, 59, 5713.