Diversity-oriented synthesis of functionalized polyheterocycles from Garner aldehyde

Article abstract of DOI:10.1055/s-0030-1260069

We report a diversity-oriented synthesis of diverse drug-like polyheterocycles from Garner aldehyde derived 1-hydroxy-1,3-dihydroisobenzofuran 20 as a key intermediate. The oxonium-mediated nucleophilic addition of 20 in the presence of boron tri-fluoride-diethyl ether complex provided enantiopure 1,3-disubstituted 1,3-dihydroisobenzofurans through 1,3-asymmetric induction. Further diversification of 20 allowed the diastereoselective syntheses of drug-like polyheterocycles including the 3-substituted isobenzofuran-1(3H)-one, 2,3-dihydro-1H-isoindol-1-one, and 3,4-disubstituted dihydroisoquinolinone ring systems. Georg Thieme Verlag Stuttgart ? New York.

Full text of DOI:10.1055/s-0030-1260069

SPECIAL TOPIC
2215
Diversity-Oriented Synthesis of Functionalized Polyheterocycles from Garner
Aldehyde
D
OS of Polyhetero
j
cycles
a
from
G
arne
y
r
Aldehyde Kumar Srivastava,a Heebum Song,a Seung Bum Park*a,b
a
Department of Chemistry, Seoul National University, Seoul 151-747, Korea
Department of Biophysics and Chemical Biology, Seoul National University, Seoul 151-747, Korea
Fax +82(2)8844025; E-mail: sbpark@snu.ac.kr
b
Received 9 April 2011
frameworks can be important for drug discovery and
chemical genomic research.6
Abstract: We report a diversity-oriented synthesis of diverse drug-
like polyheterocycles from Garner aldehyde derived 1-hydroxy-
1,3-dihydroisobenzofuran 20 as a key intermediate. The oxonium-
mediated nucleophilic addition of 20 in the presence of boron tri-
fluoride–diethyl ether complex provided enantiopure 1,3-disubsti-
In our laboratory, we have focused on the development of
new diversity-oriented synthesis strategies for the system-
atic construction of rigid polyheterocyclic skeletons em-
bedded with privileged substructures such as
benzopyrans,7a pyrroles,7b carbohybrids,7c and acetal-
fused pyranopyrones,7d in addition to diazabicycles,7e tet-
rahydro-b-carbolines,7f oxopiperazines,7g and benzodi-
azepines,7h all from a cyclic iminium intermediate. As
shown in our previous reports, we have developed new
methodologies through the incorporation of simple and
robust synthetic transformations to provide maximum
molecular diversity with minimal numbers of linear syn-
thetic steps.7 Our collection of drug-like polyheterocycles
has been subjected to various cell-based biological evalu-
ations and yielded novel small-molecule modulators for
the treatment of various diseases including type II diabe-
tes, osteoporosis, prostate cancers, etc.8
tuted
1,3-dihydroisobenzofurans
through
1,3-asymmetric
induction. Further diversification of 20 allowed the diastereoselec-
tive syntheses of drug-like polyheterocycles including the 3-substi-
tuted isobenzofuran-1(3H)-one, 2,3-dihydro-1H-isoindol-1-one,
and 3,4-disubstituted dihydroisoquinolinone ring systems.
Key words: diversity-oriented synthesis, Garner aldehyde, isoben-
zofuran, isoindole, isoquinoline
In the aftermath of the completion of the human genome
project,1 biomedical research communities have been fo-
cusing on the control of gene products with small-mole-
cule modulators. On the basis of genomic information, the
estimated number of potential drug targets has increased
up to 3,000–5,000 from 500 conventional enzyme targets.
Therefore, there is great demand for the construction of
drug-like compounds that cover a wide range of molecular
diversity for the identification of specific small-molecule
modulators. To fulfill this huge demand for drug-like
small molecules, synthetic organic chemists introduced
combinatorial techniques in the 1990s. However, the en-
hanced efficiency in the synthesis of a large number of
small molecules using conventional combinatorial chem-
istry did not significantly improve molecular diversity,
which is essential for the identification of new small-mol-
ecule modulators toward a variety of biological targets.2,3
To address this challenge, diversity-oriented synthesis
(DOS) was developed for efficiently populating chemical
space with diverse small molecules.4 Diversity-oriented
synthesis strategy aims to identify new chemical space
and access skeletally and stereochemically diverse molec-
ular frameworks with various appendices using complex-
ity-generating reactions.5 Among these diversity
elements, skeletal diversity can significantly contribute
towards maximizing molecular diversity with high rele-
vance to biological space. Therefore, the development of
new synthetic pathways to access novel polyheterocyclic
As a continuation of our efforts on the construction of
novel molecular frameworks, we reported a robust and ef-
ficient synthetic route to highly functionalized enan-
tiopure 1,2,3,4-tetrahydroisoquinolines 3, a privileged
structural motif that is frequently found in bioactive natu-
ral products and therapeutic agents.9 As shown in
Scheme 1 (Path A), a series of enantiopure bridged oxazo-
lidine intermediates 2 were synthesized from Garner alde-
hyde 1 and its inherent chirality was utilized via 1,2- and
1,3-/1,4-asymmetric inductions iteratively to obtain
1,2,3,4-tetrasubstituted 1,2,3,4-tetrahydroisoquinolines 3
through ytterbium(III) triflate catalyzed diastereoselec-
tive nucleophilic additions. We also accomplished the
first enantioselective total synthesis of 2-azapodophyllo-
toxin (4) with an overall yield of 35% (8 steps) from D-
Garner aldehyde 1 for the validation of this synthetic
methodology.
In this paper, we report the identification of new enan-
tiopure intermediate 6 from Garner aldehyde 1 and subse-
quent skeletal diversification into various biologically
important polyheterocycles such as 1,3-disubstituted 1,3-
dihydroisobenzofurans 8 and 9, 3-substituted isobenzofu-
ran-1(3H)-one 10, 2,3-dihydro-1H-isoindol-1-one 11, and
3,4-dihydroisoquinolinone 12. In fact, the resulting core
skeletons by this diversity-oriented synthesis pathway
(Scheme 1, Path B) share the key structural motifs in var-
ious bioactive small molecules. For example, unnatural
SYNTHESIS 2011, No. 14, pp 2215–2222
x
x.
x
x
.
2
0
1
1
Advanced online publication: 15.06.2011
DOI: 10.1055/s-0030-1260069; Art ID: C01411SS
© Georg Thieme Verlag Stuttgart · New York

2216
A. K. Srivastava et al.
SPECIAL TOPIC
HO2C
OBn
HO
O
*
NH
Boc
*
*
OH
*
R1
O
N
*
X = CH2, O, S, N
R
R2
N
Boc
*
7
X
R3
8
4 possible
diastereomers
3
HOH2C
*
OH
NH
O
O
*
*
*
O
*
O
*
*
Boc
O
N
BnO
O
N
N
path B
path A
ref. 9
Boc
O
*
*
N
*
R1
CHO
*
9
R
N
N
O
R2
Boc
N
O
MeO
OMe
1
*
2
OH
HOH2C
*
OMe
H
6
*
N
4
Boc
O
OBn
10
OH OH
H
HOH2C
*
*
N
*
OH
O
R1
*
Boc
*
*
N
N
R
NH
5
O
O
12
11
OMe
H
N
Me
O
O
O
HOO2C
HO2C
*
O
O
*
NH2
N
*
NH2
H
NO2
O
N
O
O
O
O
*
N
HO
*
Cl
N
O
Cl
N
OH
13 furanomycin
14
15
16
IC50 = 0.17 μM
17 plicamine
Scheme 1 A schematic representation of diversity-oriented synthesis of drug-like polyheterocycles from Garner aldehyde
amino acids containing 3-substituted 1,3-dihydroisoben- bridged oxazolidine 7 and the corresponding 3,4-dihy-
zofuran 8 are the benzo-fused analogues of non-proteo- droisoquinoline 21 through sequential deprotection of 20
genic amino acid furanomycin (13).10 1-Triazol-1-yl-1,3- using different hydrochloric acid concentrations such as 3
dihydroisobenzofuran 9 is an aza-oxidized version of a M and 6 M hydrochloric acid in tetrahydrofuran, respec-
1,3-dihydroisobenzofuran and 3-substituted isobenzofu- tively.9
ran-1(3H)-one 10 shares the structural motif of isobenzo-
furan-1(3H)-one-based unnatural amino acid 15, a folded
Due to the existing synthetic utility and biological impor-
tance of chiral 1,3-dihydroisobenzofurans, several asym-
baclofen analogue, which has been studied for its antago-
metric synthetic routes have been reported: alkylation of
nistic activity against GABA receptor.11 2,3-Dihydro-1H-
arenechromium tricarbonyl,14 benzylic deprotonative
isoindol-1-ones 11 and 3,4-dihydroisoquinolinones 12
also contain the identical core skeletons observed in re-
cently reported compound 16, as a potent inhibitor of mu-
rine double minute 2 (MDM2)-p53 protein-protein
interaction,12 and natural product plicamine (17),13 re-
spectively.
lithiation followed by alkylation,15 tandem addition/
cyclization of organozinc reagents to alk-2-ynyl alde-
hydes,16 and cyclization of ortho-lithiated chiral arylox-
iranes.17 Functionalized 1,3-dihydroisobenzofurans serve
as important intermediates for the generation of important
natural products and natural-product-like molecules.18
The key enantiopure intermediate was prepared as follows Therefore, we envisioned the transformation of intermedi-
(Scheme 2): Addition of freshly prepared Grignard re- ate 20 into 1,3-disubstituted 1,3-dihydroisobenzofurans
agent 18 to D-Garner aldehyde 1 at –78 °C produced the by following two synthetic methods:
corresponding alcohol anti-19 as the major product which
was further transformed to 1-hydroxy-1,3-dihydroisoben-
zofuran 20 via selective acetal deprotection, followed by
intramolecular hemiacetal formation under acidic condi-
tions, i.e. 2 M aqueous hydrochloric acid in tetrahydrofu-
ran (1:3). We also observed the formation of enantiopure
nucleophiles at –78 °C and observed the clean formation
1. Boron trifluoride–diethyl ether complex catalyzed dia-
stereoselective nucleophilic addition: To perform the
oxonium-mediated nucleophilic addition, we treated in-
termediate 20 with stoichiometric amount of boron tri-
fluoride–diethyl ether in presence of silane-based carbon
Synthesis 2011, No. 14, 2215–2222 © Thieme Stuttgart · New York

SPECIAL TOPIC
DOS of Polyheterocycles from Garner Aldehyde
2217
O
MgBr
O
OH
N
Boc
O
N
H
O
O
18
O
OH
N
b
CHO
O
a
Boc
Boc
1
O
20
anti-19
c
OH
OH OH
HO
O
OH
Boc
d
e
Boc
N
N
N
OH2
7
21
Scheme 2 Diastereoselective synthesis of a key intermediate, 1-hydroxy-1,3-dihydroisobenzofuran 20. Reagents and conditions: (a) THF,
–78 °C, anti-19 (67%), syn-19 (7%); (b) 2 M aq HCl–THF (1:3), 5 h, 74%; (c) 3 M aq HCl–THF (1:3), 4 h, 61%; (d) 6 M aq HCl–THF (1:3),
4 h, 59%; (e) (Boc)2O, THF, 91%.
Boc
of addition products 22a–e with excellent diastereoselec-
Boc
OH
OH
H
HN
HN
tivity via 1,3-asymmetric induction (Table 1, entries 1–3).
We also demonstrate the broad scope of this transforma-
tion by using nitrogen- and sulfur-based nucleophiles (en-
tries 4 and 5). The subsequent oxazolidine ring-opening
was achieved simply by warming the reaction mixture up
to room temperature. A clear crosstalk between a benzylic
proton at the C3 and C2¢ positions observed by 1D-NOE-
SY NMR experiments revealed the anti-stereochemistry
of new chiral center at C3 of the 1,3-dihydroisobenzo-
furans (Figure 1). The further transformation of 22a by
Jones’ oxidation yields 8a, which is a benzo-fused ana-
logue of non-proteogenic amino acid furanomycin (13).
2'
1'
H
H
H
1
H
H
O
O 2
H
3
H
CO2Et
oxy-Michael product 24
oxonium-mediated
alkylation product 22a
Figure 1 1D-NOESY correlations
23. The resulting trans-olefin 23 was treated with sodium
hydride at –78 °C to facilitate the intramolecular oxy-
Michael addition in a diastereoselective fashion. The reac-
tion mixture was warmed up to room temperature and fil-
tered through celite, followed by the oxazolidine
deprotection by pyridinium 4-toluenesulfonate in metha-
nol to provide 1,3-disubstituted 1,3-dihydroisobenzofuran
24 in quantitative yield (Scheme 3). The relative stereo-
2. Intramolecular diastereoselective oxy-Michael addi-
tion: Asymmetric synthesis of 1,3-disubstituted 1,3-dihy-
droisobenzofurans was also pursued via intramolecular
oxy-Michael cyclization. This synthetic route was initiat-
ed by Wittig reaction of 20 with ethyl (triphenylphospho-
ranylidene)acetate to provide (E)-a,b–unsaturated ester
Table 1 Synthesis of Benzofuranomycin Analogues
O
O
OH
H
H
HO
N
Boc
N
Boc
NH
H
H
Boc
O
Jones' oxidn
BF3⋅OEt2, CH2Cl2
O
O
Nu (R-TMS)
–78 °C to r.t.
R
H
8a
H
OH
20
22a–e
(synthesized from 22a)
Entry
Nucleophile
allylTMS
Product
22a
R
Yield (%) step 1
d.r.
1
2
3
4
5
CH2CH=CH2
CH2C(O)Ph
H
71
67
91
73
76
>99:1
>99:1
–
HC=C(OTMS)Ph
TMSH
22b
22c
PhSH
22d
SPh
>99:1
>99:1
morpholino-TMS
22ea
morpholino
a Oxazolidine ring intact. The oxazolidine ring-opened product was unstable, hence the reaction was quenched at –20 °C to avoid side reactions.
Synthesis 2011, No. 14, 2215–2222 © Thieme Stuttgart · New York

2218
A. K. Srivastava et al.
SPECIAL TOPIC
chemistry of the protons at C2¢ and C3 positions of 1,3-di- the presence of N-methylmorpholine N-oxide in good
hydroisobenzofuran 24 have an anti relationship which yield. Treatment of 27 with primary amines at 60 °C pro-
was confirmed by 1D-NOESY NMR experiments vided amide 28 through lactone opening. The resulting
(Figure 1).
chiral amido alcohol 28 was activated by treatment with
mesyl chloride and the subsequent substitution of amide
nitrogen at the benzylic position leading to the formation
of 2,3-dihydro-1H-isoindol-1-one 29 with a diastereomer-
ic ratio of 5.6:1. Isobenzofuran-1(3H)-one 27 was trans-
formed into seven-membered dihydrobenzoxepinone 30
upon the treatment with 5 M aqueous hydrochloric acid in
tetrahydrofuran, which leads to oxazolidine ring-opening
without Boc deprotection and spontaneous intramolecular
translactonization of the isobenzofuran-1(3H)-one moiety
with the C2¢ free alcohol in moderate yield. This unique
seven-membered lactone 30 containing a chiral amino al-
cohol moiety can be further converted into 3,4-dihy-
droisoquinolinone 31 by refluxing in 6 M aqueous
hydrochloric acid in tetrahydrofuran. This transformation
can be potentially utilized for the synthesis of natural
product plicamine (17).13
O
O
OH
O
N
H
N
Boc
b
N
Boc
a
Boc
H
OH
O
OH
CO2Et
H
20
23
24
CO2Et
Scheme 3 Diastereoselective synthesis of 1,3-disubstituted 1,3-di-
hydroisobenzofuran 24. Reagents and conditions: (a) Ph3PCHCO2Et,
CH2Cl2, 82%; (b) 1. NaH, THF, –78 °C to r.t.; 2. PPTS, MeOH, 50
°C, 3 h, 68% (2 steps).
After successful asymmetric synthesis of 1,3-disubstitut-
ed 1,3-dihydroisobenzofurans, we further applied this
methodology to the synthesis of 1-azido-1,3-dihy-
droisobenzofuran which can be readily transformed to 1-
triazol-1-yl-1,3-dihydroisobenzofurans by copper-cata-
lyzed 1,3-dipolar Huisgen cycloaddition with terminal
alkynes.19 For the diastereoselective synthesis of 1-tria-
zol-1-yl-1,3-dihydroisobenzofuran 25, our key intermedi-
ate 20 was treated with trimethylsilyl azide in the presence
of a catalytic amount of boron trifluoride–diethyl ether
complex at –78 °C. To avoid oxazolidine ring opening by
boron trifluoride–diethyl ether at room temperature, the
reaction was quenched by the addition of triethylamine at
–20 °C, which yielded 25 with a diastereomeric ratio of
12:1. The further treatment of 25 with terminal acetylenes
in the presence of Cu(PPh3)3Br produced 1-triazol-1-yl-
1,3-dihydroisobenzofurans 26a,b (Scheme 4).
O
O
O
N
Boc
Bn
N
N
Boc
b
H
Boc
H
OH
a
O
O
H
N
OH
O
20
28
27
O
c
d
O
HO
OH OH
NHBoc
H
N
e
Boc
N
Bn
NH
O
O
O
O
31
30
29
O
O
Scheme 5 Synthesis of 3-substituted 2,3-dihydro-1H-indol-1-one
29 and 3,4-dihydroisoqinolinone 31. Reagents and conditions: (a)
TPAP (5 mol%), NMO, CH2Cl2, 2 h, 81%; (b) BnNH2, CH2Cl2, 60
°C, 71%; (c) MsCl, CH2Cl2, 0 °C to r.t, 40%, d.r. 5.6:1; (d) 5 M aq
HCl–THF (1:3), 4 h, 53%; (e) 6 M aq HCl–THF (1:3), 60 °C, 58%.
O
N
N
N
H
Boc
a
H
H
Boc
b
Boc
O
O
O
R
N
OH
N3
25-major
As a continuation of our exploration in divergent diversi-
ty-oriented synthesis strategies, we have developed a con-
cise and efficient diversity-oriented synthesis pathway for
the diastereoselective synthesis of drug-like polyhetero-
cycles including functionalized 1,3-dihydroisobenzofu-
ran, isobenzofuran-1(3H)-one, 2,3-dihydro-1H-isoindol-
1-one, and dihydroisoquinolinone derivatives from
Garner aldehyde derived 1-hydroxy-1,3-dihydroisoben-
zofuran 20. The chirality of Garner aldehyde was system-
atically transferred to diverse polyheterocycles through
1,3-asymmetric induction. This synthetic methodology is
versatile and sufficiently flexible for application in high-
throughput synthesis of drug-like polyheterocycle librar-
ies, which is currently underway and will be reported in
due course along with their biological evaluations.
N
20
R
26a R = Ph
N
26b R = TMS
Scheme 4 Diastereoselective synthesis of 1-triazole-1,3-dihydro-
isobenzofurans. Reagents and conditions: (a) TMSN3, BF3·OEt2 (20
mol%), CH2Cl2, –78 °C, d.r. 12:1, 25-major (81%), 25-minor (6.4%);
(b) H–≡–R, Cu(PPh3)3Br (5 mol%), toluene, 60 °C, 26a (83%), 26b
(72%).
Next we turned our attention to the synthesis of isobenzo-
furan-1(3H)-one 27 via Ley oxidation of 20 and its subse-
quent transformation to 3-substituted 2,3-dihydro-1H-
isoindol-1-one 11 and 3,4-dihydroisoquinolinone 12
(Scheme 5). The hemiacetal intermediate 20 was oxidized
to isobenzofuran-1(3H)-one derivative 27 by treatment
with tetrapropylammonium perruthenate (TPAP, cat.) in
Synthesis 2011, No. 14, 2215–2222 © Thieme Stuttgart · New York

SPECIAL TOPIC
DOS of Polyheterocycles from Garner Aldehyde
2219
Some starting materials were synthesized from commercially avail-
with CH2Cl2 (3 ×). The combined organic extracts were washed
with brine and dried (Na2SO4). The filtrate was condensed under re-
duced pressure and purified by flash column chromatography (silica
gel) to provide desired hemiacetal 20; yield: 248.2 mg (74%);
Rf = 0.35 (30% EtOAc–hexanes).
1H NMR (500 MHz, CDCl3): d (mixture of rotamers and
diastereomers) = 7.44–7.31 (m, 6 H, ArH), 7.27–7.21 (m, 1 H,
ArH), 6.56 (t, J = 7.5 Hz, 1 H), 6.43 (m, 1 H), 5.80–5.59 (br m, 1
H), 5.49–5.36 (br m, 1 H), 4.42 (d, J = 8.0 Hz, 1 H), 4.26 (s, 1 H),
4.12–4.07 (m, 2 H), 3.93–3.65 (m, 4 H), 1.72 (3 H), 1.67 (s, 3 H),
1.54 (s, 3 H), 1.50 (s, 9 H), 1.45 (s, 9 H), 1.35 (s, 3 H).
1
able reagents. H and 13C NMR spectra were obtained on Varian
Inova-500 (Varian Assoc., Palo Alto, USA). Routine mass analyses
were performed on LC/MS system equipped with a reverse-phase
column (XDB C18, 5 mm, 4.6 × 50 mm) and photodiode array de-
tector using electron spray ionization (ESI). Conversions of starting
materials were monitored by TLC using silica gel plates (silica gel
60 F254 0.25 mm) and components were visualized by observation
under UV light (254 and 365 nm) or by treating TLC plates with
anisaldehyde, KMnO4, and ninhydrin followed by heating. All reac-
tions were conducted in oven-dried glassware or a 20-mL vial with
cap. The reaction mixture was purified by flash column chromatog-
raphy on silica gel (230–400 mesh) using eluent mixtures of EtOAc,
hexanes, and MeOH (1% Et3N).
13C NMR (125 MHz, CDCl3): d = 152.9, 152.1, 140.3, 140.0, 139.5,
129.6, 129.5, 129.3, 128.7, 128.6, 123.4, 123.3, 122.1, 122.0, 101.6,
101.4, 101.2, 94.5, 83.3, 82.7, 82.4, 81.6, 80.9, 80.2, 64.6, 64.4,
61.9, 61.4, 60.6, 28.6, 28.5, 26.9, 26.5, 25.1, 24.8, 23.5.
tert-Butyl (R)-4-{(S)-[2-(1,3-Dioxan-2-yl)phenyl](hydro-
xy)methyl}-2,2-dimethyloxazolidine-3-carboxylate (anti-19)
and tert-Butyl (R)-4-{(R)-[2-(1,3-dioxan-2-yl)phenyl](hydro-
xy)methyl}-2,2-dimethyloxazolidine-3-carboxylate (syn-19)
To a cooled (–78 °C) soln of freshly prepared Garner aldehyde 1 (1
equiv) in anhyd THF, Grignard reagent 18 (1.4 equiv) was added in
dropwise and the mixture was stirred for 2 h at the same tempera-
ture. After completion of reaction (TLC monitoring), the reaction
was quenched by the addition of sat. NH4Cl soln, followed by ex-
traction with EtOAc (3 ×). The combined organic extracts were
washed with brine and dried (Na2SO4). The filtrate was condensed
under reduced pressure and purified by flash column chromatogra-
phy (silica gel) to provide desired diastereomers anti-19 (67%) and
syn-19 (7%).
LRMS (ESI): m/z [M] calcd: 335; found: 318 [M – OH]+.
(1S,4S,5R)-8-(tert-Butyloxycarbonyl)-4-(hydroxy)-2,3-benzo-6-
oxa-8-azabicyclo[3.2.1]octane (7)
Prepared using the typical procedure for 20 with 3 M aq HCl for 4
h; yield: 125.2 mg (61%); Rf = 0.37 (30% EtOAc–hexanes).
1H NMR (500 MHz, CDCl3): d = 7.50 (d, J = 7.0 Hz, 1 H, ArH),
7.37 (t, J = 7.5 Hz, 1 H, ArH), 7.32 (t, J = 7.0 Hz, 1 H, ArH), 7.23
(d, J = 7.0 Hz, 1 H, ArH), 6.27 (s, 1 H), 4.92 (s, 1 H), 4.52 (d, J = 8.5
Hz, 1 H), 3.93 (t, J = 6.5 Hz, 1 H), 3.41 (d, J = 8.5 Hz, 1 H), 2.51
(br s, 1 H, OH), 1.49 (s, 9 H).
13C NMR (125 MHz, CDCl3): d = 155.2, 135.4, 134.1, 130.8, 129.6,
128.9, 125.6, 102.3, 82.0, 71.1, 63.9, 59.3, 28.3.
anti-19
LRMS (ESI): m/z [M] calcd: 277; found: 278 [M + H]+.
Yield: 2.36 g (67%); Rf = 0.39 (30% EtOAc–hexanes).
[a]D28 –12.7 (c 2.57, CHCl3).
(3R,4S)-3-(Hydroxymethyl)-3,4-dihydroisoquinolin-4-ol (21)
Prepared using the typical procedure for 20 with 6 M aq HCl for 4
h; yield: 77.4 mg (59%); Rf = 0.28 (10% MeOH–hexanes).
[a]D28 +31.4 (c 0.83, CHCl3).
1H NMR (500 MHz, CDCl3–CD3OD): d = 8.31 (s, 1 H), 7.64 (d,
J = 7.5 Hz, 1 H, ArH), 7.53 (t, J = 7.5 Hz, 1 H, ArH), 7.38 (t, J = 7.5
Hz, 1 H, ArH), 7.34 (d, J = 7.0 Hz, 1 H, ArH), 4.89 (d, J = 11.5 Hz,
1 H), 3.98 (ddd, J = 4.5, 11.5, 40.0 Hz, 2 H), 3.57 (d, J = 7.5 Hz, 1
H),
1H NMR (500 MHz, CDCl3): d = 7.66 (d, J = 7.0 Hz, 1 H, ArH),
7.59 (s, 1 H, ArH), 7.32 (d, J = 7.0 Hz, 1 H, ArH), 7.29–7.24 (m, 1
H, ArH), 6.12 (s, 1 H), 5.52 (s, 1 H), 4.23–4.09 (m, 6 H), 3.67 (s, 1
H), 2.97 (s, 1 H), 2.26–2.19 (m, 1 H), 1.58 (s, 3 H), 1.52 (s, 9 H),
1.46 (s, 3 H), 1.40–1.34 (m, 1 H).
13C NMR (125 MHz, CDCl3): d = 152.9, 138.5, 136.0, 129.1, 128.5,
127.8, 126.4, 125.8, 99.9, 98.0, 94.4, 80.5, 69.0, 67.7, 67.5, 67.3,
62.3, 28.6, 27.3, 26.1, 24.5.
13C NMR (125 MHz, CDCl3): d = 161.4, 139.2, 132.7, 128.2, 127.5,
125.1, 65.8, 64.6, 63.4.
LRMS (ESI): m/z [M] calcd: 393; found: 394 [M + H]+.
syn-19
LRMS (ESI): m/z [M] calcd: 177; found: 178 [M + H]+.
Yield: 247 mg (7%); Rf = 0.36 (30% EtOAc–hexanes).
[a]D28 –7.89 (c 4.01, CHCl3).
Diastereoselective Nucleophilic Addition To Give 22a–e; Gener-
al Procedure
1H NMR (500 MHz, CDCl3): d = 7.62 (d, J = 7.5 Hz, 1 H, ArH),
7.50 (d, J = 7.0 Hz, 1 H, ArH), 7.35 (t, J = 6.5 Hz, 1 H, ArH), 7.30
(t, J = 7.5 Hz, 1 H, ArH), 5.82 (s, 1 H), 5.49 (s, 1 H), 5.18 (dd,
J = 3.0, 9.0 Hz, 1 H), 4.32 (pseudo t, J = 4.5 Hz, 1 H), 4.27–4.22 (m,
2 H), 4.01–3.94 (m, 2 H), 3.65–3.60 (m, 2 H), 2.26–2.18 (m, 1 H),
1.65 (s, 3 H), 1.54 (s, 9 H), 1.51 (s, 3 H), 1.43 (d, J = 11.5 Hz, 1 H).
13C NMR (125 MHz, CDCl3): d = 156.2, 139.7, 136.6, 129.4, 128.1,
127.9, 126.6, 99.8, 94.6, 81.9, 74.4, 67.8, 67.7, 65.1, 64.2, 28.6,
27.6, 25.9, 24.6.
To a cooled soln of 20 (1 equiv) and nucleophile (1.5 equiv) in
CH2Cl2 at –78 °C, BF3·OEt2 (2.0 equiv) was added and the mixture
was warmed up to r.t.. After completion of the reaction (TLC mon-
itoring), it was quenched by the addition of Et3N (2 equiv) and ex-
tracted with EtOAc (3 ×). The combined organic extracts were
washed with brine and dried (Na2SO4). The filtrate was condensed
under reduced pressure and purified by flash column chromatogra-
phy (silica gel) to provide the desired products.
LRMS (ESI): m/z [M] calcd: 393; found: 394 [M + H]+.
tert-Butyl (R)-1-[(1S,3R)-3-Allyl-1,3-dihydroisobenzofuran-1-
yl]-2-hydroxyethylcarbamate (22a)
Yield: 167.8 mg (71%); Rf = 0.27 (30% EtOAc–hexanes).
[a]D28 +17.5 (c 1.42, CHCl3).
1H NMR (500 MHz, CDCl3): d = 7.32–7.25 (m, 3 H, ArH), 7.20–
7.17 (m, 1 H, ArH), 5.58–5.74 (m, 1 H), 5.50 (s, 2 H), 5.36–5.32 (m,
1 H), 5.12–5.06 (m, 2 H), 3.98–3.96 (m, 1 H), 3.65–3.62 (m, 1 H),
3.52 (d, J = 8.0 Hz, 1 H), 2.74 (s, 1 H), 2.59–2.47 (m, 2 H), 1.47 (s,
9 H).
tert-Butyl (4R)-4-[(1S)-3-hydroxy-1,3-dihydroisobenzofuran-1-
yl]-2,2-dimethyloxazolidine-3-carboxylate (20); Typical Proce-
dure
To a soln of anti-19 (1 mmol) in THF (3 mL), 2 M aq HCl (1 mL)
was added and the mixture was stirred for 5 h at r.t. After complete
consumption of the starting material (TLC monitoring), the reaction
was quenched by the addition of sat. NaHCO3 soln and extracted
Synthesis 2011, No. 14, 2215–2222 © Thieme Stuttgart · New York

2220
A. K. Srivastava et al.
SPECIAL TOPIC
13C NMR (125 MHz, CDCl3): d = 156.3, 141.8, 138.7, 133.7, 133.6,
128.4, 128.2, 122.0, 121.8, 118.3, 118.2, 85.6, 83.4, 80.0, 62.3,
55.9, 41.3, 41.1, 28.6, 28.3.
(S)-2-[(1S,3S)-3-Allyl-1,3-dihydroisobenzofuran-1-yl]-2-(tert-
butoxycarbonylamino)acetic Acid (8a)
To a soln of 22a (1 equiv) in acetone, Jones’ reagent (2.5 equiv) was
added at 0 °C and the mixture was stirred for 2 h. After completion
of the reaction (TLC monitoring), it was quenched with i-PrOH and
extracted with EtOAc. The combined organic extracts were washed
by brine and dried (Na2SO4). The filtrate was condensed under re-
duced pressure to obtain 8a as a sticky solid; yield: 103.3 mg (59%);
Rf = 0.16 (20% MeOH–CH2Cl2).
1H NMR (500 MHz, MeOD): d = 7.97–7.83 (m, 1 H, ArH), 7.76–
7.75 (m, 1 H, ArH), 7.72–7.67 (m, 2 H, ArH), 5.79–5.71 (m, 1 H),
5.10–5.07 (m, 3 H), 4.51 (s, 1 H), 4.16 (s, 1 H), 2.61–2.45 (m, 2 H),
1.48 (s, 9 H).
LRMS (ESI): m/z [M] calcd: 319; found: 320 [M + H]+.
tert-Butyl (R)-2-Hydroxy-1-[(1S,3R)-3-(2-oxo-2-phenylethyl)-
1,3-dihydroisobenzofuran-1-yl]ethylcarbamate (22b)
Yield: 197.1 mg (67%); Rf = 0.36 (30% EtOAc–hexanes).
[a]D28 –4.1 (c 1.33, CHCl3).
1H NMR (500 MHz, CDCl3): d = 7.96 (d, J = 8.0 Hz, 2 H, ArH),
7.59 (t, J = 7.5Hz, 1 H, ArH), 7.47 (t, J = 13.0 Hz, 2 H, ArH), 7.34–
7.27 (m, 4 H, ArH), 5.99–5.96 (m, 1 H), 5.51 (s, 1 H), 5.47 (d,
J = 8.0 Hz, 1 H), 4.01–3.99 (m, 1 H), 3.67 (dd, J = 4.0, 11.0 Hz, 1
H), 3.53 (dd, J = 7.0, 18.5 Hz, 2 H), 3.29 (dd, J = 5.0, 17.0 Hz, 1 H),
2.62 (s, 1 H), 1.47 (s, 9 H).
13C NMR (125 MHz, CDCl3): d = 197.5, 156.3, 141.9, 138.6, 137.0,
133.6, 128.9, 128.7, 128.5, 128.4, 122.1, 121.9, 85.6, 80.1, 62.1,
55.8, 45.8, 28.6.
LRMS (ESI): m/z [M] calcd: 333; found: 334 [M + H]+.
tert-Butyl (R)-4-[(S)-{2-[(E)-3-Ethoxy-3-oxoprop-1-enyl]phe-
nyl}(hydroxy)methyl]-2,2-dimethyloxazolidine-3-carboxylate
(23)
To a soln of 20 (1 equiv) in CH2Cl2, Ph3PCHCO2Et (1.5 equiv) was
added in dropwise and the mixture was stirred at r.t. for 3 h. After
completion of the reaction (TLC monitoring), the mixture was con-
densed under reduced pressure and purified by flash column chro-
matography (silica gel) to provide 23 as a colorless oil; yield: 246.1
mg (82%); Rf = 0.40 (30% EtOAc–hexanes).
LRMS (ESI): m/z [M] calcd: 397; found: 420 [M + Na]+.
tert-Butyl (R)-1-[(S)-1,3-Dihydroisobenzofuran-1-yl]-2-hydro-
xyethylcarbamate (22c)
Yield: 200.2 mg (91%); Rf = 0.21 (30% EtOAc–hexanes).
[a]D28 –7.17 (c 1.86, CHCl3).
[a]D28 +3.64 (c 0.64, CHCl3).
1H NMR (500 MHz, CDCl3): d = 8.19 (d, J = 15.5 Hz, 1 H), 7.64 (d,
J = 7.5 Hz, 1 H, ArH), 7.55 (d, J = 7.5 Hz, 1 H, ArH), 7.40 (t,
J = 7.5 Hz, 1 H, ArH), 7.29 (t, J = 7.5 Hz, 1 H, ArH), 6.37 (d,
J = 15.5 Hz, 1 H), 5.49 (s, 1 H), 4.25 (q, J = 6.5 Hz, 2 H), 4.02 (dd,
J = 5.0, 7.5 Hz, 1 H), 3.88 (br s, 1 H), 3.78 (s, 1 H), 3.77 (br s, 1 H,
OH), 1.49 (s, 12 H), 1.42 (s, 3 H), 1.35 (t, J = 6.5 Hz, 3 H).
13C NMR (125 MHz, CDCl3): d = 166.8, 154.3, 141.5, 140.4, 132.7,
129.9, 127.8, 127.3, 126.6, 120.7, 94.6, 80.9, 70.3, 63.4, 61.3, 28.4,
26.4, 24.2, 14.4.
1H NMR (500 MHz, CDCl3): d = 7.33–7.24 (m, 4 H, ArH), 5.45 (s,
1 H), 5.43 (s, 1 H), 5.13 (dd, J = 2.0, 10.0 Hz, 2 H), 4.03 (s, 1 H),
3.68 (d, J = 11.0 Hz, 1 H), 3.55 (s, 1 H), 2.57 (s, 1 H), 1.47 (s, 9 H).
13C NMR (125 MHz, CDCl3): d = 156.3, 139.4, 138.4, 128.9, 127.9,
121.9, 121.3, 86.4, 73.5, 62.3, 60.7, 55.4, 28.6.
LRMS (ESI): m/z [M] calcd: 279; found: 280 [M + H]+.
tert-Butyl (R)-2-Hydroxy-1-[(1S,3R)-3-(phenylthio)-1,3-dihy-
droisobenzofuran-1-yl]ethylcarbamate (22d)
Yield: 209.3 mg (73%); Rf = 0.24 (30% EtOAc–hexanes).
LRMS (ESI): m/z [M] calcd: 405; found: 406 [M + H]+.
[a]D28 –2.16 (c 1.32, CHCl3).
Ethyl 2-{(1R,3S)-3-[(R)-1-(tert-Butoxycarbonylamino)-2-hy-
droxyethyl]-1,3-dihydroisobenzofuran-1-yl}acetate (24)
To a soln of 23 (1 equiv) in THF, NaH (1.7 equiv) was added at –78
°C and mixture was warmed up to r.t. After completion of the reac-
tion (TLC monitoring), the mixture was filtered through celite and
filtrate was washed by brine. The organic layer was dried (Na2SO4)
and concentrated under reduced pressure to yield crude cyclized
product; Rf = 0.31 (20% EtOAc–hexanes).
1H NMR (500 MHz, CDCl3): d = 7.28–7.23 (m, 3 H, ArH), 7.17–
7.14 (m, 1 H, ArH), 4.72–4.59 (m, 1 H), 4.36 (s, 1 H), 4.20–4.15 (m,
2 H), 4.07–4.04 (m, 1 H), 3.88–3.73 (m, 1 H), 3.67–3.61 (m, 1 H),
2.80–2.72 (m, 2 H), 1.59 (s, 6 H), 1.54 (s, 9 H), 1.26 (m, 3 H).
1H NMR (500 MHz, CDCl3): d (mixture of rotamers) = 7.59 (d,
J = 7.5 Hz, 1 H, ArH), 7.47–7.44 (m, 1 H, ArH), 7.40–7.34 (m, 2 H,
ArH), 7.32–7.27 (m, 2 H, ArH), 7.26–7.19 (m, 2 H, ArH), 6.78–6.74
(m, 1 H, ArH), 5.64–5.38 (m, 2 H), 4.03 (t, J = 4.0 Hz, 1 H), 3.79
(d, J = 11.5 Hz, 1 H), 3.69–3.49 (m, 1 H), 2.94 (br s, 1 H), 2.46 (br
s, 1 H), 1.47 (s, 9 H).
13C NMR (125 MHz, CDCl3): d = 156.1, 138.8, 138.0, 133.8, 132.6,
131.7, 129.6, 129.4, 129.3, 129.0, 128.9, 128.8, 128.7, 127.9, 127.7,
123.3, 123.1, 122.1, 121.7, 92.8, 85.2, 80.2, 62.1, 55.4, 28.6.
LRMS (ESI): m/z [M] calcd: 387; found: 388 [M + H]+.
13C NMR (125 MHz, CDCl3): d = 170.9, 152.8, 141.8, 128.3, 128.1,
122.5, 121.5, 98.0, 94.7, 80.4, 65.3, 64.1, 61.6, 60.8, 42.3, 28.6,
26.8, 25.2, 23.6, 14.4.
tert-Butyl (R)-2,2-Dimethyl-4-[(1S,3R)-3-morpholino-1,3-dihy-
droisobenzofuran-1-yl]oxazolidine-3-carboxylate (22e)
Following the general procedure using BF3·OEt2 (1.0 equiv) was
used and reaction was quenched by Et3N at –20 °C; yield: 205.0 mg
(76%); Rf = 0.36 (30% EtOAc–hexanes).
LRMS (ESI): m/z [M] calcd: 405; found: 406 [M + H]+.
The resulting crude product was redissolved in MeOH and PPTS
was added. The mixture was stirred at 50 °C for 3 h. After comple-
tion of the reaction (TLC monitoring), sat. NaHCO3 soln was added
followed by the evaporation of MeOH and the crude mixture was
extracted with EtOAc. The combined organic extracts were washed
with brine and dried (Na2SO4). The filtrate was condensed in vacuo
and purified by flash column chromatography (silica gel) to furnish
24 as a colorless oil; yield: 150.8 mg (68%, 2 steps); Rf = 0.27 (30%
EtOAc–hexanes).
[a]D28 +28.3 (c 1.49, CHCl3).
1H NMR (500 MHz, CDCl3): d (mixture of rotamers) = 7.33–7.27
(m, 6 H, ArH), 7.21–7.15 (m, 2 H, ArH), 5.99 (s, 1 H), 5.89 (s, 1 H),
5.53 (s, 1 H), 5.34 (s, 1 H), 4.22–4.01 (m, 2 H), 3.91–3.65 (m, 9 H),
2.81–2.64 (m, 8 H), 1.64 (s, 6 H), 1.55 (s, 9 H), 1.54 (s, 9 H),1.32
(s, 6 H).
13C NMR (125 MHz, CDCl3): d = 156.1, 141.3, 138.3, 129.0, 128.9,
123.6, 122.8, 122.0, 99.7, 94.8, 82.7, 67.4, 65.1, 64.0, 61.9, 53.6,
47.5, 28.6, 26.4.
1H NMR (500 MHz, CDCl3): d = 7.33–7.31 (m, 2 H, ArH), 7.28–
7.27 (m, 1 H, ArH), 7.21 (d, J = 4.0 Hz, 1 H, ArH), 5.71 (s, 1 H),
LRMS (ESI): m/z [M] calcd: 404; found: 405 [M + H]+.
Synthesis 2011, No. 14, 2215–2222 © Thieme Stuttgart · New York

SPECIAL TOPIC
DOS of Polyheterocycles from Garner Aldehyde
2221
5.55–5.42 (m, 2 H), 4.21–4.17 (m, 2 H), 3.99 (t, J = 4.0 Hz, 1 H),
3.65 (d, J = 11.5 Hz, 1 H), 3.52 (d, J = 11.0 Hz, 1 H), 2.71–2.69 (m,
2 H), 1.48 (s, 9 H), 1.30–1.24 (m, 3 H).
(s, 1 H), 5.68 (s, 1 H), 4.30–4.37 (m, 1 H), 4.15 (br s, 1 H), 3.95–
3.92 (m, 1 H), 3.84–3.82 (m, 2 H), 3.65 (d, J = 8.0 Hz, 1 H), 1.53
(s, 9 H), 1.52 (s, 9 H), 1.30 (s, 6 H), 1.26 (s, 6 H), 0.29 (s, 18 H).
LRMS (ESI): m/z [M] calcd: 365; found: 366 [M + H]+.
LRMS (ESI): m/z [M] calcd: 458; found: 459 [M + H]+.
tert-Butyl (R)-4-[(1S,3S)-3-Azido-1,3-dihydroisobenzofuran-1-
yl]-2,2-dimethyloxazolidine-3-carboxylate (25-major) and tert-
Butyl (R)-4-[(1S,3R)-3-Azido-1,3-dihydroisobenzofuran-1-yl]-
2,2-dimethyloxazolidine-3-carboxylate (25-minor)
To a soln of 20 and TMSN3 in CH2Cl2, was added BF3·OEt2 (0.2
equiv) at –78 °C. After the completion of the reaction (TLC moni-
toring), Et3N was added at –20 °C and the mixture was warmed up
to r.t. The organic layer was washed with brine and condensed un-
der reduced pressure. The crude product was purified by flash col-
umn chromatography (silica gel); dr 25-major/25-minor 12:1.
tert-Butyl (R)-2,2-Dimethyl-4-[(S)-3-oxo-1,3-dihydroisobenzo-
furan-1-yl]oxazolidine-3-carboxylate (27)
To a soln of 20 (1 equiv) in CH2Cl2, NMO (1.2 equiv) was added
followed by TPAP (5 mol%) and the mixture was stirred at r.t. for
2 h. Progress of the reaction was monitored (TLC). After comple-
tion of the reaction, the mixture was filtered through celite and the
filtrate was concentrated under reduced pressure. The crude product
was purified by flash column chromatography (silica gel) to provide
27 as a sticky solid; yield: 199.8 mg (81%); Rf = 0.40 (30% EtOAc–
hexanes).
[a]D28 +73.4 (c 1.15, CHCl3).
1H NMR (500 MHz, CDCl3):
25-major
d (mixture of rotamers
Yield: 216.0 mg (81%); Rf = 0.56 (30% EtOAc–hexanes).
1.77:1.00) = 7.94–7.92 (m, 3 H, ArH), 7.68–7.63 (m, 3 H, ArH),
7.60–7.54 (m, 3 H, ArH), 7.50–7.46 (m, 3 H, ArH), 5.90 (d, J = 4.0
Hz, 1.77 H), 5.56 (d, J = 6.0 Hz, 1 H), 4.40 (t, J = 4.0 Hz, 1.96 H),
4.12 (t, J = 5.5 Hz, 1 H), 3.97 (m, 1.8 H), 3.89–3.87 (m, 1 H), 3.79
(dd, J = 6.5, 9.5 Hz, 1.78 H), 3.54 (dd, J = 1.5, 9.5 Hz, 1.80 H), 1.74
(s, 3 H), 1.69 (s, 6 H), 1.58 (s, 9 H), 1.52 (s, 27 H).
13C NMR (125 MHz, CDCl3): d = 171.2, 152.9, 147.6, 147.2, 134.3,
129.8, 126.7, 123.4, 122.7, 95.2, 94.8, 81.4, 80.8, 79.3, 65.1, 63.0,
60.5, 60.2, 58.5, 28.6, 27.0, 25.0, 23.3.
[a]D28 –54.4 (c 3.25, CHCl3).
1H NMR (500 MHz, CDCl3): d (mixture of rotamers) = 7.41–7.39
(m, 6 H, ArH), 7.28–7.23 (m, 2 H, ArH), 6.39 (s, 2 H), 5.85 (s, 1 H),
5.67 (s, 1 H), 4.29 (br s, 1 H), 4.10 (br s, 1 H), 3.82 (t, J = 8.5 Hz, 1
H), 3.77 (t, J = 7.0 Hz, 1 H), 3.67 (d, J = 9.0 Hz, 1 H), 3.56 (d,
J = 9.0 Hz, 1 H), 1.71 (s, 3 H), 1.66 (s, 3 H), 1.55 (s, 6 H), 1.52 (s,
18 H).
LRMS (ESI): m/z [M] calcd: 360; found: 361 [M + H]+.
LRMS (ESI): m/z [M] calcd: 333; found: 334 [M + H]+.
25-minor
Yield: 17.1 mg (6.4%); Rf = 0.53 (30% EtOAc–hexanes).
[a]D28 +73.0 (c 3.03, CHCl3).
tert-Butyl (R)-4-{(S)-[2-(Benzylcarbamoyl)phenyl](hy-
droxy)methyl}-2,2-dimethyloxazolidine-3-carboxylate (28)
To a soln of 27 in CH2Cl2, BnNH2 (3 equiv) was added and the mix-
ture was stirred at 60 °C for 3 h. The crude mixture was diluted with
CH2Cl2 and the organic layer was washed with 1 M HCl, followed
by water and brine. The organic layer was dried (Na2SO4) and the
filtrate was condensed under reduced pressure. Crude product was
purified by flash column chromatography (silica gel) to provide 28
as colorless oil; yield: 187.4 mg (71%); Rf = 0.33 (30% EtOAc–
hexanes).
1H NMR (500 MHz, CDCl3): d (mixture of rotamers) = 7.40–7.37
(m, 6 H, ArH), 7.28–7.23 (m, 2 H, ArH), 6.51 (s, 1 H), 6.40 (s, 1 H),
5.69 (d, J = 3.0 Hz, 1 H), 5.33 (d, J = 6.5 Hz, 1 H), 4.30 (br s, 1 H),
4.11 (t, J = 5.5 Hz, 1 H), 4.03 (d, J = 9.5 Hz, 1 H), 3.95–3.92 (m, 1
H), 3.85 (d, J = 8.5 Hz, 1 H), 3.81–3.78 (m, 1 H), 1.74 (s, 3 H), 1.69
(s, 3 H), 1.57 (s, 12 H), 1.52 (s, 12 H).
LRMS (ESI): m/z [M] calcd: 360; found: 361 [M + H]+.
1H NMR (500 MHz, CDCl3): d = 7.43–7.40 (m, 3 H, ArH), 7.35–
7.33 (m, 2 H, ArH), 7.30–7.29 (m, 2 H, ArH), 7.24 (m, 2 H, ArH),
6.95 (s, 1 H), 4.65 (br s, 2 H), 4.50 (d, J = 7.0 Hz, 1 H), 4.31 (d,
J = 8.0 Hz, 1 H), 4.19 (s, 1 H), 3.81 (br s, 1 H), 1.48 (s, 3 H), 1.40
(s, 3 H), 1.24 (s, 9 H).
tert-Butyl (R)-2,2-Dimethyl-4-[(1S,3S)-3-(4-phenyl-1H-1,2,3-
triazol-1-yl)-1,3-dihydroisobenzofuran-1-yl]oxazolidine-3-car-
boxylate (26a); Typical Procedure
To a soln of 25-major (1 equiv) and phenylacetylene (2 equiv) in
toluene, Cu(PPh3)3Br was added and the mixture was stirred at 60
°C. After completion of the reaction, solvent was evaporated and
the crude was purified by flash column chromatography (silica gel)
to provide a triazole product 26a as a sticky solid; yield: 230.1 mg
(83%); Rf = 0.33 (30% EtOAc–hexanes).
LRMS (ESI): m/z [M] calcd: 440; found: 441 [M + H]+.
tert-Butyl (S)-4-[(R)-2-Benzyl-3-oxo-2,3-dihydro-1H-isoindol-1-
yl]-2,2-dimethyloxazolidine-3-carboxylate (29)
To a soln of 28 in anhyd CH2Cl2, Et3N (3 equiv) was added and mix-
ture was cooled to 0 °C. MsCl (1.5 equiv) was added slowly to the
mixture at 0 °C and it was stirred for 10 min at this temperature.
Then, mixture was warmed up to r.t. and stirred for an additional 30
min. After completion of the reaction, the solvent was evaporated
and the crude was purified by flash column chromatography (silica
gel) to provide 29 as a colorless oil; yield: 71.9 mg (40%); Rf = 0.51
(33% EtOAc–hexanes).
[a]D28 +16.8 (c 0.82, CHCl3).
1H NMR (500 MHz, CDCl3):
1.82:1.00) = 7.77 (d, J = 7.0 Hz, 6 H, ArH), 7.64–762 (m, 2 H,
ArH), 7.51–7.28 (m, 20 H, ArH), 5.99 (s, 1.82 H), 5.71 (s, 1 H), 4.38
(t, J = 4.0 Hz, 2 H), 4.17 (t, J = 5.5 Hz, 1 H), 3.95–3.92 (m, 1 H),
3.85–3.82 (m, 3 H), 3.66–3.64 (m, 2 H), 1.65 (s, 6 H), 1.52 (s, 9 H),
1.51 (s, 16 H), 1.31 (s, 12 H).
d (mixture of rotamers
LRMS (ESI): m/z [M] calcd: 462; found: 463 [M + H]+.
[a]D28 +39.8 (c 0.85 CHCl3).
1H NMR (500 MHz, CDCl3): d (mixture of rotamers) = 7.92–7.88
(m, 2 H, ArH), 7.50–7.42 (m, 8 H, ArH), 7.37–7.31 (m, 6 H, ArH),
7.24–7.21 (m, 2 H, ArH), 5.99 (s, 1 H), 5.73 (d, J = 2.0 Hz, 1 H),
4.80–4.72 (m, 4 H), 4.40 (d, J = 6.0 Hz, 1 H), 4.17 (br s, 1 H), 3.81
(t, J = 9.0 Hz, 1 H), 3.73 (t, J = 9.0 Hz, 1 H), 3.63 (d, J = 9.0 Hz, 1
H), 3.46 (d, J = 9.5 Hz, 1 H), 1.74 (s, 3 H), 1.68 (s, 3 H), 1.54 (s, 9
H), 1.51 (s, 9 H), 1.40 (s, 6 H).
tert-Butyl (R)-2,2-Dimethyl-4-{(1S,3S)-3-[4-(trimethylsilyl)-1H-
1,2,3-triazol-1-yl]-1,3-dihydroisobenzofuran-1-yl}oxazolidine-
3-carboxylate (26b)
Following the typical procedure for 26a; yield: 197.9 mg (72%);
Rf = 0.38 (30% EtOAc–hexanes).
1H NMR (500 MHz, CDCl3): d (mixture of rotamers) = 7.67 (s, 1
H), 7.65 (s, 1 H), 7.48–7.36 (m, 6 H), 7.32–7.28 (m, 2 H, ArH), 5.95
Synthesis 2011, No. 14, 2215–2222 © Thieme Stuttgart · New York

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A. K. Srivastava et al.
SPECIAL TOPIC
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Shin, C. S.; Park, S. B. Med. Chem. Commun. 2011, 2, 76.
(b) Oh, S.; Nam, H. J.; Park, J.; Beak, S. H.; Park, B.
ChemMedChem 2010, 5, 529. (c) Oh, S.; Kim, S. J.; Hwang,
J. H.; Lee, H. Y.; Ryu, M. J.; Park, J.; Kim, S. J.; Jo, Y. S.;
Kim, Y. K.; Lee, C. H.; Kweon, K. R.; Shong, M.; Park, S.
B. J. Med. Chem. 2010, 53, 7405. (d) Zhu, M.; Kim, M. H.;
Lee, S.; Kim, S. H.; Park, S. B. J. Med. Chem. 2010, 53,
8760.
13C NMR (125 MHz, CDCl3): d = 152.8, 151.8, 143.8, 141.0, 131.6,
129.3, 128.5, 128.2, 126.6, 126.1, 123.9, 122.0, 121.9, 95.1, 94.5,
82.6, 81.7, 81.0, 80.6, 63.7, 62.3, 60.9, 51.5, 29.9, 28.6, 27.0, 26.5,
24.9.
LRMS (ESI): m/z [M] calcd: 422; found: 423 [M + H]+.
tert-Butyl (4R,5S)-5-Hydroxy-1-oxo-1,3,4,5-tetrahydroben-
zo[c]oxepin-4-ylcarbamate (30)
Compound 27 was dissolved in THF containing 5 M aq HCl (25%)
and mixture was stirred overnight at r.t. After complete consump-
tion of the starting material, sat. NaHCO3 soln was added, followed
by extraction with EtOAc. The combined organic layers were
washed with brine and dried (Na2SO4). The filtrate was condensed
under reduced pressure and purified by flash column chromatogra-
phy (silica gel) to provide 30; yield: 93.2 mg (53%) Rf = 0.26 (40%
EtOAc–hexanes).
[a]D28 +25.3 (c 1.14, CHCl3).
1H NMR (500 MHz, CDCl3): d = 7.92 (d, J = 5.5 Hz, 1 H, ArH),
7.68 (s, 1 H), 7.57–7.56 (m, 2 H), 5.64 (s, 1 H), 5.35 (s, 1 H), 4.08–
4.07 (m, 1 H), 3.78–3.74 (m, 1 H), 3.61–3.60 (m 1 H), 2.18 (s, 1 H),
1.46 (s, 9 H).
13C NMR (125 MHz, CDCl3): d = 170.3, 155.8, 147.3, 134.5, 129.8,
128.9, 126.2, 126.1, 123.0, 80.5, 79.8, 68.2, 61.4, 28.5.
LRMS (ESI): m/z [M] calcd: 293; found: 311 [M + OH]+.
(3R,4S)-4-Hydroxy-3-(hydroxymethyl)-3,4-dihydroisoquinolin-
1(2H)-one (31)
(9) Srivastava, A. K.; Koh, M.; Park, S. B. Chem. Eur. J. 2011,
17, 4905.
Compound 30 was dissolved in THF containing 6 M aq HCl (25%)
and the mixture was heated at 60 °C overnight. After complete con-
sumption of the starting material, sat. NaHCO3 soln was added, fol-
lowed by extraction with EtOAc. The combined organic layers were
washed by brine and dried (Na2SO4). The filtrate was condensed un-
der reduced pressure and purified by flash column chromatography
(silica gel) to provide 31; yield: 35.6 mg (58%); Rf = 0.23 (10%
MeOH–CH2Cl2).
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Haggerty, K.; Harrington, R. W.; Hutton, C.; Kemp, S.; Lu,
X.; McDonnell, J. M.; Newell, D. R.; Noble, M. E. M.;
Payne, S. L.; Revill, C. H.; Riedinger, C.; Xu, Q.; Lunec, J.
J. Med. Chem. 2011, 54, 1233.
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[a]D28 –19.7 (c 0.20, CHCl3).
1H NMR (500 MHz, CDCl3): d = 8.36 (s, 1 H), 7.64 (d, J = 7.0 Hz,
1 H, ArH), 7.55–7.54 (m, 1 H, ArH), 7.40–7.36 (m, 2 H, ArH), 4.95
(s, 1 H), 4.88 (s, 1 H), 4.09 (br s, 1 H), 3.77 (s, 1 H), 3.69–3.64 (m,
2 H).
LRMS (ESI): m/z [M] calcd: 193; found: 194 [M + H]+, 178 [M–
OH]+.
(16) Chai, Z.; Xie, Z.-F.; Liu, X.-Y.; Zhao, G.; Wang, J.-D.
J. Org. Chem. 2008, 73, 2947.
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Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.
J. Org. Chem. 2006, 71, 3984.
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Acknowledgment
This study was supported by the National Research Foundation of
Korea (NRF) and the WCU program of the NRF funded by the
Korean Ministry of Education, Science, and Technology (MEST).
A.K.S. and H.S are grateful for postdoctoral and predoctoral fel-
lowships, respectively, awarded by the BK21 Program.
References
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Synthesis 2011, No. 14, 2215–2222 © Thieme Stuttgart · New York