Synthesis of optically active homotryptophan and its oxygen and sulfur analogues

Article abstract of DOI:10.1016/j.tet.2011.10.055

d-Homotryptophan and its sulfur analogue have been synthesized by Sonogashira coupling between 3-iodoheteroarenes and ethynyloxazolidine followed by reduction of triple bond and oxidation of alcohol to acid. l-Homotryptophan and its oxygen analogue have b

Full text of DOI:10.1016/j.tet.2011.10.055

Tetrahedron 68 (2012) 280e286
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Synthesis of optically active homotryptophan and its oxygen and sulfur analogues
,
,
Koushik Goswami a, Sibasish Paul a, Sandesh T. Bugde b y, Surajit Sinha a
*
a Department of Organic Chemistry, Indian Association for the Cultivation of Science, Jadavpur, Kolkata 700032, India
b Department of Chemistry, Goa University, Goa 403206, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 25 June 2011
Received in revised form 12 October 2011
Accepted 14 October 2011
Available online 29 October 2011
D
-Homotryptophan and its sulfur analogue have been synthesized by Sonogashira coupling between
3-iodoheteroarenes and ethynyloxazolidine followed by reduction of triple bond and oxidation of alcohol
to acid. -Homotryptophan and its oxygen analogue have been synthesized from silylated internal alkyne
using Larock’s heteroannulation as the key reaction. The alkynyloxazolidines were synthesized from
-serine and -glutamic acid, respectively.
L
L
L
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Unnatural amino acid
Homotryptophan
Alkynyloxazolidine
Sonogashira coupling
Larock’s heteroannulation
1. Introduction
substrate binding, the protein undergoes conformational changes
that allow Si site to accommodate a wide range of compounds of
different structures and these can act as either an effector or an in-
hibitor. Due to this allosteric effect the design of compounds tar-
geting the Si site may provide a handle to control the activity of
catalytic active site. Tryptophananaloguesconstitute oneclassofIDO
Indoleamine 2,3-dioxygenase (IDO) is a heme-containing gly-
coprotein that uses superoxide to cleave the indole 2,3-double
bond of L-tryptophan to kynurenine via the formation of N-for-
mylkynurenine. Further metabolism of kynurenine produced
anthranilic acid, quinolinic acid, and kynurenic acid and elevation
of their concentration are known to be responsible for many in-
flammatory and neurodegenerative diseases including cancers. So,
inhibitors of the IDO enzyme have important clinical implications
as potential therapeutic agents.1
The crystal structure of tryptophan bound TDO (tryptophan 2,3-
dioxygenase)2 shows that the N1 nitrogen of the indole ring is
hydrogen-bonded to the side chain of His55 (Fig. 1). Thus, N-
methyl-tryptophan becomes inactive against TDO probably be-
cause the methyl group sterically interacts with this residue. His55
in TDO is replaced by Ser167 in IDO, which has a smaller side chain
and creates a small pocket to accommodate the methyl group. This
may be why N-methyl-tryptophan is the most potent inhibitor of
IDO known till date.3 A larger substrate binding pocket also may
explain why IDO can accommodate many tryptophan analogues in
its active site.
Recent study4 shows that human IDO (hIDO) has two binding
sites, an active and an inhibitory substrate binding site (Si site). Upon
* Corresponding author. Tel.: þ91 33 2473 4971; fax: þ91 33 2473 2805; e-mail
address: ocss5@iacs.res.in (S. Sinha).
y
Determination of ee using HPLC.
Fig. 1. Tryptophan bound TDO.
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.10.055

K. Goswami et al. / Tetrahedron 68 (2012) 280e286
281
inhibitors.5 Hence, synthesis as well as testing3,6 of several trypto-
phan analogues have already been reported. Herein, we report the
synthesis of optically active homotryptophan and its O, S analogues.
According to their procedure, tosyl-protected-2-iodoaniline was
used as a starting material, which after Sonogashira coupling gave
indole as the major product as was expected from the literature.8
Interestingly, the unprotected 2-iodoaniline gave exclusively
Sonogashira coupled product 4a, which was then protected to ob-
tain 4a1. After iodocyclization and silyl-deprotection, protected 3-
iodoindole 2a was obtained in 41% overall yield. Similarly, com-
pound 2b9 was synthesized from 2-iodothioanisole according to
Larock’s methodology (Scheme 2).
Except L-homotryptophan, the ‘O’ and ‘S’ analogues have not
been reported so far. Cook and his group were the first to report the
enantioselective synthesis of homotryptophan using a two-carbon
homologation of an indole moiety to be followed by diaster-
6b,d
€
oselective alkylation of the Schollkopf chiral auxiliary.
In our
method, chiral center has been derived from naturally occurring
amino acids -serine and -glutamic acid, respectively.
L
L
To get efficient Sonogashira coupling10 between 3-iodoindole 2a
and ethynyloxazolidine 3,11 choice of base was very important. We
were pleased to find that the combination of diisopropylethylamine
(DIPEA) and Pd(OAc)2 gave 6a in 66% yield.
2. Results and discussion
Comparable yield was also obtained when PdCl2(PPh3)2 was
used as a catalyst. Using the same protocol, 6b was obtained in 73%
yield. The presence of trimethylsilyl group at C-2 position of 3-
iodoindole gave poor coupling yield (20%). Next step was the re-
duction of triple bond to single bond and it is worth to mention
here that 6b underwent smooth catalytic reduction12 whereas 6a
gave problem. Initial attempt to reduce the triple bond of pure 6a
catalytically (Pd/C) using either triehylsilane12 or hydrogen under
atmospheric pressure12 was not successful. Interestingly, the re-
covered starting material from the Pd/C reaction above smoothly
afforded the reduced product on subsequent repetition of the same
reaction. Following, it was revealed that prior treatment with ac-
tivated charcoal was necessary to carry out the catalytic reduction
of column purified 6a. After charcoal treatment, triethylsilane-
mediated reduction was completed within 15 min whereas atmo-
spheric hydrogen pressure took overnight stirring. After acetal
deprotection, oxidation followed by diazomethane treatment13
Retrosynthetic strategy
-homotryptophan and its ‘S’ analogue by way of intermediate 6
whereas that of B was used for -isomer and its ‘O’ analogue using
A was used for the synthesis of
D
L
Larock’s heteroannulation as the key reaction. The masked form of
alkynylated amino acids 3 and 10 has been used in order to avoid
the epimerization at the
a
-C6d as well as intramolecular nucleo-
philic (O or N) attack to the Pd(II)/alkyne complexes6c,e (Scheme 1).
BocHN
TBDMS
∗
CO2Me
Retrosynthesis B
I
X = N, O
+
X
NBoc
O
X
1a X = NH
1b X = O
1c X = S
10
tosyl-protected
obtained. Detosylation was carried out in the presence of Mg/
MeOH/NH4Cl14a to obtain
-homotryptophan derivative ( )-1a in
15.6% overall yield from 6a (Scheme 3). Detosylation of ( )-9 by
TBAF/THF14b or Cs2CO3 in THF/MeOH14c failed. In both cases, the
corresponding free acid was obtained. The 60% ee of ( )-1a was
D-homotryptophan and its thio-analogue were
X = N, S
L-Glutamic acid
D
D
O
I
BocN
D
NBoc
O
3
+
D
X
determined by HPLC using Chiralcel OD (250ꢀ4.6 mm) column.
2
X
6
L-Serine
O
O
Retrosynthesis A
BocN
BocN
Scheme 1. Retrosynthetic pathway.
I
The synthesis of 3-iodoindole 2a and 3-iodobenzothiophene 2b
has been described in Scheme 2. Protected 3-iodoindole 2a was
prepared from 2-iodoaniline according to Knight’s procedure7 with
a slight modification.
b
a
X
X
X
6a X = NTs, 66% (D)- 7a X = NTs, 84%
6b X = S, 73%
7b X = S, 80%
I
BocHN
c
CO2Me
d
2a = NTs, 84%
2b = S, 92%
X
NHBoc
CH2OH
e
TMS
c
I
I
X
X
a
(D)- 9 X = NTs, 51%
1c X = S, 48%
(D)- 8a X = NTs, 78%
8b X = S, 85%
TMS
X
X
X = SMe
X
e
4a X = NH2, 85%
4b X = SMe, 68%
5a X = NTs, 65%
5b X = S, 85%
(D)- 9
(D)-1a
70%
b
Scheme 3. Synthesis of D-homotryptophan derivative and its sulfur analogue. Reaction
conditions: (a) 3, Pd(OAc)2, PPh3, CuI, DIPEA, 65 ꢁC, 3.5e4 h; (b) 10% Pd/C, Et3SiH,
MeOH, 15 min, rt, for (D)-7a; 10% Pd/C, MeOH, H2 (atmospheric pressure), overnight, rt,
for 7b; (c) PTSA, MeOH, 2 h, rt; (d) (i) 1 M Jones reagent, acetone, 0 ꢁC, (ii) CH2N2,
ether; (e) Mg, MeOH, NH4Cl.
TMS
d
NHTs
4a1
Scheme 2. Preparation of 3-iodobenzofused heterocycles. Reaction conditions: (a)
TMS-acetylene, Pd(PPh3)2Cl2, CuI, Et3N; (b) TsCl, THF/pyridine mixture (8:2); (c) I2,
DCM; (d) I2, K2CO3, CH3CN; (e) TBAF, THF.
According to retrosynthetic route A, 3-iodobenzofuran was re-
quired for the synthesis of oxygen analogue 1b. To the best of our

282
K. Goswami et al. / Tetrahedron 68 (2012) 280e286
knowledge there is no suitable method for the synthesis of 3-
iodobenzofuran. Larock attempted15a to synthesize this com-
pound but landed with a complex mixture and Cacchi15b got aro-
matic electrophilic substituted product instead of iodocyclisation.
To overcome the problem associated with trimethylsilylacetylene,
we used triisopropylsilylacetylene and following Cacchi’s method
we obtained a complex mixture from where 11 was isolated in very
small amount (Scheme 4). Next, we prepared 3-bromobenzofuran
from benzofuran according to the literature procedure. Un-
fortunately, the coupling did not take place under standard Sono-
gashira conditions.
The internal alkyne 10 was in turn synthesized from L-glutamic
acid via the formation of aldehyde 19 (Scheme 6). The synthesis of
aldehyde 19 has been previously reported17 but the synthetic steps
were different. The aldehyde was subsequently converted to alkyne
using BestmanneOhira reagent18 and silylation was carried out
using a method reported for alkynylglycine derivatives.19
CO2Me
a
85%
L-Glutamic acid
NHBoc
MeO2C
16
61%
b
I
TIPS
I
CH2OH
CH2OH
TIPS
c
O
I2, NaHCO3,
CH3CN
NBoc
65%
O
BocHN
OH
I
11
CH2OH
18
17
Scheme 4. Attempted synthesis of 3-iodobenzofuran.
d
O
O
P
OMe
OMe
CHO
So, retrosynthetic strategy B was followed to prepare
L
-homo-
e.
tryptophan and its ‘O’-analogue using Larock’s heteroannulation16
N2
20
as the key step.
NBoc
75%
after 2 steps
)
NBoc
According to Larock’s protocol, 2-iodophenol was treated with
silylated internal alkyne 10 to provide 2,3-disubstituted benzofuran
12a, which after silyl-deprotection furnished 13. Without depro-
tection of oxazolidine ring when 13 was subjected for Jones oxi-
dation followed by diazomethane treatment, a complex mixture
was obtained from where the keto-amino acid 15 was isolated in
15% yield. Interestingly, after acetal deprotection, the aminoalcohol
14, under same oxidizing condition afforded the desired compound
O
O
(
21
19
f
73%
10
Scheme 6. Synthesis of silylated internal alkyne from L-glutamic acid. Reaction con-
ditions: (a) (i) SOCl2, MeOH, ꢂ5 ꢁC to rt; (ii) Boc2O, THF, Et3N, 0 ꢁC; (b) LiBH4, THF/
1b in 41% yield. Similarly L-homotryptophan derivative (L)-1a has
been synthesized in 94% ee from N-tosyl-2-iodoaniline following
the protocol as described for oxygen analogue (Scheme 5).
MeOH mixture,
0
ꢁC; (c) 2,2-dimethoxypropane, BF3$OEt2, acetone, rt, 2 h; (d)
DesseMartin periodinane, DCM, rt, 30 min (e) 20, K2CO3, MeOH, 0 ꢁ
C to rt, 4 h;
(f) n-BuLi, THF, ꢂ78 ꢁC, TBDMSCl, rt, 12 h.
3. Conclusion
Boc
N
In conclusion, the synthesis of optically active homotryptophan
and its ‘O’, ‘S’ analogues is described. Though the synthesis of
L-
O
I
homotryptophan was reported by Cook and his group with a high
overall yield (65%), but many functional groups may not survive
under their conditions as strong reagents like t-BuLi and n-BuLi
were used. Our synthetic route is mild and flexible and manipula-
tion of starting materials can give several other tryptophan
analogues.
a
+
10
TBDMS
X
X
12a
X = O, 66%
12b
X = NTs, 52%
BocHN
b
CH2OH
c
NBoc
4. Experimental section
4.1. General information
O
X
X
14
X = O, 85%
13 X = O, 80%
(L)- 7a X = NTs, 80%
(L)- 8a
X = NTs, 84%
All reagents were purchased from commercial sources and used
without further purification, unless otherwise stated. Petroleum
ether (PE) refers to the fraction of petroleum boiling between 60
and 80 ꢁC. THF is the abbreviation of tetrahydrofuran. All reactions
were carried out in oven-dried glassware under an argon atmo-
sphere using anhydrous solvents and standard syringe and septum
techniques unless otherwise indicated. Organic extracts were dried
over anhydrous Na2SO4 and then filtered prior to removal of all
volatiles under reduced pressure on rotary evaporation. Chro-
matographic purification of products was accomplished using col-
umn chromatography on silica gels (mesh 100e200). Thin-layer
chromatography (TLC) was carried out on aluminum sheets, Silica
Gel 60 F254 (Merck; layer thickness 0.25 mm). Visualization of the
developed chromatogram was performed by UV light and/or
phosphomolybdic acid stains. Optical rotations were measured at
d
X = O
d
O
NHBoc
CO2Me
CO2Me
NHBoc
X
OH
15%
1b X = O, 41%
(L)- 9 X = NTs, 46%
15,
e
(L)-1a
(L)- 9
74%
Scheme 5. Synthesis of L-homotryptophan derivative and its oxygen analogue.
Reaction conditions: (a) Pd(OAc)2, LiCl, Na2CO3, DMF, 80 ꢁC, 12e20 h; (b) TBAF, THF,
1.5 h, rt; (c) PTSA, MeOH, 2 h, rt; (d) (i) 1 M Jones reagent, acetone, 0 ꢁC, (ii) CH2N2,
ether; (e) Mg, MeOH, rt.

K. Goswami et al. / Tetrahedron 68 (2012) 280e286
283
stated temperature and solvent; Concentration was in gm/100 mL
when [
D was recorded. 1H and 13C NMR spectra were recorded at
300 or 500 MHz and 75 or 125 MHz, respectively, using CDCl3 as
solvent. Chemical shifts ( ) are given in parts per million relative to
the solvent residual peak or TMS as internal standard. The follow-
ing abbreviations are used for multiplicity of NMR signals:
s¼singlet, d¼doublet, t¼triplet, m¼multiplet, br¼broad.
131.0, 130.9, 129.9, 126.8, 124.8, 124.7, 123.1, 122.7, 122.6, 122.4,
119.4, 113.9, 93.9, 93.4 , 80.2, 79.6 , 66.9, 57.5, 57.0 , 32.9, 32.2
28.5, 27.7, 26.9 , 24.6, 23.3
(ESI) for
a
]
*
*
*
*
,
*
*
, 21.8, 21.6 (*asterisk denotes conformer
d
peaks);
HRMS
(MþNa)þ
calculated
C27H34N2O5SNaþ¼521.2086, found 521.2086.
4.2.4. (R)-tert-Butyl 4-(2-(benzo[b]thiophen-3-yl)ethyl)-2,2-
dimethyloxazolidine-3-carboxylate (7b). A solution of 6b (34 mg,
0.095 mmol) in methanol (1.5 mL) containing 10% Pd/C (5 mg) was
evacuated, before being exposed to hydrogen atmosphere and
stirred for overnight under atmospheric hydrogen pressure. The
suspension was filtered and the solvent was removed in vacuo. The
crude residue was purified by short silica gel column chromatog-
raphy, eluting with petroleum ether/AcOEt (95:5), to afford 7b as
4.2. Experimental procedure
4.2.1. (R)-tert-Butyl-2,2-dimethyl-4-(2-(1-tosyl-1H-indol-3-yl)ethy-
nyl)oxazolidine-3-carboxylate (6a). To a stirred degassed solution of
N-tosyl-3-iodoindole 2a (170 mg, 0.43 mmol) and
3 (114 mg,
0.51 mmol) in diisopropylethylamine (5 mL) under nitrogen were
added Pd(OAc)2 (9.6 mg, 0.043 mmol), PPh3 (45 mg, 0.17 mmol),
and copper iodide (8 mg, 0.043 mmol), respectively. The yellowish
solution was degassed again and heated at 65 ꢁC for 4 h. The re-
action mixture was diluted with ether and filtered through a Celite
pad. After solvent evaporation in vacuo residue was directly
charged in silica gel column, eluting with petroleum ether/AcOEt
(9:1), to give 6a, 158 mg (74%) as yellowish white foam.
a white solid (29 mg, 80%).
26
Rf (10% AcOEt/PE) 0.52; [
a
]
ꢂ27.4 (c 1.24, CHCl3); 1H NMR
D
(500 MHz, CDCl3)
d
7.85 (d, 1H, J¼7 Hz), 7.73 (d, 1H, J¼7 Hz),
7.34e7.39(m, 2H), 7.10 (s, 0.5H), 7.23(s, 0.4H), 3.79e4.10 (m, 3H), 2.86
(br s, 2H), 2.10e2.26 (two br s, 1H), 1.96e2.03 (m, 1H), 1.38e1.63 (m,
15H); 13C NMR (125 MHz, CDCl3)
d
152.4, 152.0
*
, 140.7, 139.1, 139.0
, 80.2,
, 25.4,24.7,
*
,
*
135.9, 124.4, 124.3 , 124.0, 123.1, 123.0 , 121.6, 121.4, 94.0, 93.4
*
*
Treatment of 6a (yellowish white foam) with activated charcoal
in methanol (5 mL) was performed and filtered through Celite.
After solvent removal, the material was passed through a short
79.8
*
, 67.0, 57.6, 57.2
*
, 33.1, 32.3
*
, 28.7, 28.6,28.4,27.8, 27.0
*
23.4
*
(*asterisk denotes conformer peaks); HRMS (ESI) (MþNa)þ
calculated for C20H27NO3SNaþ¼384.1609, found 384.1608.
silica gel column to get 6a, 140 mg (66.2%) as white foam.
26
Rf (20% AcOEt/PE) 0.70; [
CHCl3)
a]
ꢂ87.9 (c 1.07, CHCl3); IR: (neat/
4.2.5. tert-Butyl (R)-1-hydroxy-4-(1-tosyl-1H-indol-3-yl)butan-2-
ylcarbamate (D)-8a. To a solution of (D)-7a (350 mg, 0.7 mmol) in
D
n
2235, 1699 cmꢂ1; 1H NMR (500 MHz, CDCl3)
d
7.95 (d, 1H,
J¼8.5 Hz), 7.75 (d, 2H, J¼8.0 Hz),7.69 (s, 1H), 7.58 (d, 1H, J¼7.5 Hz),
7.33 (t, 1H, J¼7 Hz), 7.25 (m, 1H), 7.20 (d, 2H, J¼8.0 Hz), 4.78e4.89
(br m, 1H), 4.10e4.14 (m, 2H), 2.31 (s, 3H), 1.69 (s, 3H), 1.50e1.54 (m,
methanol (5 mL) was added p-toluensulfonic acid (PTSA) mono-
hydrate (66 mg, 0.350 mmol) and stirred at rt for 2 h. The solution
was then neutralized with saturated aqueous NaHCO3, diluted with
AcOEt (8 mL), and washed with brine (2ꢀ5 mL). The organic phase
was dried (Na2SO4) and concentrated. The residue was eluted from
12H); 13C NMR (125 MHz, CDCl3)
d
151.6, 145.4, 135.0, 134.3, 131.0,
130.1, 128.9, 127.0, 125.5, 123.8, 120.4, 113.7, 104.9, 94.6, 94.2 , 92.7,
, 24.5, 21.6 (*as-
*
80.8
*
, 80.4, 73.3, 69.1, 49.4, 28.6, 27.2
*
, 26.2, 25.4
*
a silica gel column with petroleum ether/AcOEt (7: 3) to give (
(250 mg, 78%) as white foam.
D
)-8a
terisk denotes conformer peaks); HRMS (ESI) (MþNa)þ calculated
for C27H30N2O5SNaþ¼517.1773, found 517.1771.
Rf (30% AcOEt/PE) 0.20; [
CHCl3)
a]
26ꢂ2.7 (c 1.22, CHCl3); IR: (neat/
D
n
3404, 1693 cmꢂ1; 1H NMR (500 MHz, CDCl3)
d 7.96 (d, 1H,
4.2.2. (R)-tert-Butyl 4-(2-(benzo[b]thiophen-3-yl)ethynyl)-2,2-
dimethyloxazolidine-3-carboxylate (6b). According to the pro-
cedure outlined for 6a, 3-iodobenzo[b]thiophene 2b (34 mg,
0.13 mmol) and 3 were heated for 3.5 h to yield the coupling
J¼8 Hz), 7.73 (d, 2H, J¼8 Hz), 7.45 (d, 1H, J¼7.5 Hz), 7.34 (s, 1H), 7.29
(t, 1H, J¼7.5 Hz), 7.20 (d, 1H, J¼8.0 Hz), 7.17 (d, 2H, J¼8.0 Hz), 4.89
(br s,1H), 4.10e4.12 (m, 2H), 3.59 (dd,1H, J¼5.2,10.5 Hz), 2.68e2.77
(m, 3H), 2.29 (s, 3H), 1.89e1.92 (m, 1H), 1.78e1.83 (m, 1H), 1.45 (s,
product 6b (34 mg, 73%) as white solid.
9H); 13C NMR (125 MHz, CDCl3)
d 156.5, 144.8, 135.4, 135.3, 130.9,
26
Rf (10% AcOEt/PE) 0.50; [
CHCl3)
a
]
D
ꢂ148.8 (c 0.30, CHCl3); IR: (neat/
129.9, 126.8, 124.8, 123.1, 122.9, 122.6, 119.5, 113.8, 79.8, 65.6, 52.6,
30.9, 28.5, 21.6, 21.5; HRMS (ESI) (MþNa)þ calculated for
C24H30N2O5SNaþ¼481.1773, found 481.1732.
n
2227,1699 cmꢂ1; 1H NMR (500 MHz, CDCl3)
d 7.92 (br s,1H),
7.84 (d, 1H, J¼7.5 Hz), 7.57 (s, 1H), 7.37e7.44 (m, 2H), 4.83e4.93 (br
m, 1H), 4.14e4.17 (m, 2H), 1.72 (s, 3H), 1.57 (s, 3H), 1.52 (s, 9H); 13C
NMR (75 MHz, CDCl3)
d
151.5, 139.2, 138.7, 129.8, 125.0, 124.6, 122.8,
4.2.6. tert-Butyl (R)-4-(benzo[b]thiophen-3-yl)-1-hydroxybutan-2-
122.5, 117.8, 94.4, 90.9, 80.3, 75.8, 68.9, 49.2, 28.4, 27.1
*
, 26.1, 25.3
*
,
ylcarbamate (8b). Starting oxazolidine 7b (29 mg, 0.08 mmol)
24.4 (*asterisk denotes conformer peaks); HRMS (ESI) (MþNa)þ
according to the procedure described for ( )-8a, gave the amino-
D
calculated for C20H23NO3SNaþ¼380.1296, found 380.1292.
alcohol 8b (22 mg, 85%) as white solid.
26
Rf (20% AcOEt/PE) 0.20; [
a
]
D
þ9.4 (c 2.41, CHCl3); IR: (neat/
4.2.3. (R)-tert-Butyl 2,2-dimethyl-4-(2-(1-tosyl-1H-indol-3-yl)ethyl)
CHCl3) n d 7.85 (d, 1H,
3352, 1685 cmꢂ1; 1H NMR (500 MHz, CDCl3)
oxazolidine-3-carboxylate (
D
)-7a. To the methanolic solution of
J¼7.5 Hz), 7.73 (d, 1H, J¼8.0 Hz), 7.32e7.38 (m, 2H), 7.14 (s, 1H), 4.74
(br s, 1H), 3.60e3.74 (m, 3H), 2.88e2.97 (m, 2H), 2.41(br s, 1H),
1.95e2.01 (m, 1H), 1.85e1.89 (m, 1H), 1.46 (s, 9H); 13C NMR
white foamy 6a (140 mg, 0.28 mmol) were added 10% Pd/C (20 mg)
followed by triethylsilane (0.44 mL, 2.8 mmol) dropwise under ar-
gon atmosphere. The reaction started with evolution of gas. After
completion of the reaction (TLC), the reaction mixture was filtered
through Celite, and the solvent was removed in vacuo. The crude
product was purified by short silica gel column chromatography,
eluting with petroleum ether/AcOEt (9:1), to obtain 117 mg (84%) of
(125 MHz, CDCl3)
d 156.3, 140.5, 138.7, 135.7, 124.2, 123.8, 122.9,
121.5, 121.4, 79.7, 65.7, 52.5, 31.0, 28.3, 25.0; HRMS (ESI) (MþNa)þ
calculated for C17H23NO3SNaþ¼344.1296, found 344.1298.
4.2.7. tert-Butyl (R)-1-(methoxycarbonyl)-3-(1-tosyl-1H-indol-3-yl)
(
D
)-7a, as white foam.
Rf (20% AcOEt/PE) 0.70; [
propylcarbamate (D)-9. To a solution of aminoalcohol (D)-8a
26
a
]
ꢂ24.2 (c 1.18, CHCl3); 1H NMR
(42 mg, 0.092 mmol) in acetone (1.5 mL) at 0 ꢁC was added freshly
prepared Jones reagent (1 M, 0.28 mL, 0.28 mmol) dropwise under
nitrogen. After completion of the reaction (TLC), it was quenched
with isopropyl alcohol (0.3 mL) and partitioned with AcOEt (20 mL)
and saturated NH4Cl (7 mL). After stirring the solution for 1 h, the
aqueous layer was separated and re-extracted with AcOEt (20 mL),
D
(500 MHz, CDCl3)
d
7.89 (d, 1H, J¼8.0 Hz), 7.66 (d, 2H, J¼8.0 Hz),
7.37 (d, 1H, J¼7.5 Hz), 7.32 (s, 0.5H), 7.20e7.23 (m, 1.5H), 7.14 (br s,
1H), 7.10 (d, 2H, J¼7.5 Hz), 3.66e3.93 (m, 3H), 2.56 (br s, 2H), 2.22 (s,
3H), 2.09 (br s, 0.5H), 1.95 (br s, 0.5H), 1.81e1.87 (m, 1H), 1.26e1.53
(m, 15H); 13C NMR (125 MHz, CDCl3)
d
152.4, 151.9 , 144.7, 135.5,
*

284
K. Goswami et al. / Tetrahedron 68 (2012) 280e286
and the combined organic layers were dried, filtered, and concen-
trated in vacuo to about 7 mL in volume. The solution of the crude
acid was cooled to 0 ꢁC. Excess ethereal diazomethane was added,
and the reaction mixture was stirred for 10 min. The diazomethane
was blown off with nitrogen, the organic layer was washed with
aqueous NaHCO3 (7 mL), saturated NH4Cl (7 mL), dried, filtered,
and concentrated in vacuo to give the crude product, which was
purified by silica gel column chromatography, eluting with DCM/
flushed with argon three times. Palladium acetate (12.7 mg, 0.057)
was added; the reaction mixture was again flushed with argon
and heated at 80 ꢁC for overnight. The reaction mixture was
cooled to rt and the solvent was removed. The crude residue was
subjected for column purification, eluting with petroleum ether/
AcOEt (96:4), to afford 12a as colorless oil (172 mg, 66%).
27
Rf (10% AcOEt/PE) 0.65; [
a
]
þ33.5 (c 1.16, CHCl3); 1H NMR
D
(500 MHz, CDCl3)
d
7.54e7.59 (m, 1H), 7.47 (d, 1H, J¼7.5 Hz),
AcOEt (95:5), to afford (
D
)-9 (23 mg, 51%) as white foam.
7.23e7.28 (m,1H), 7.22 (t,1H, J¼7.25 Hz), 3.88e4.06 (m, 3H), 2.79 (br
Comparable yield (48%) was obtained in two steps oxidation via
s, 2H), 2.01 (br s, 2H),1.45e1.66 (m,15H), 0.99 (s, 9H), 0.41 (s, 6H); 13C
the formation of aldehyde using DesseMartin periodinane.
NMR (125 MHz, CDCl3)
128.9,124.4,124.3 ,121.9,119.7,119.4
80.1, 79.7 , 67.2, 57.6, 57.4
26.6, 24.6, 23.3
d
158.0, 156.2, 152.4, 152.0
*
, 130.7, 130.4
*
,
,
26
Rf (5% AcOEt/CH2Cl2) 0.85; [
a
]
ꢂ17.8 (c 0.91, CHCl3); IR: (neat/
*
*
, 111.5, 111.4 ,110.5, 94.0, 93.5
*
*
D
CHCl3)
n
3394, 1743, 1712 cmꢂ1; 1H NMR (500 MHz, CDCl3)
d
7.96 (d,
*
*
, 34.9, 34.5 , 28.6, 28.4, 27.6, 26.9, 26.7,
*
1H, J¼8.5 Hz), 7.75 (d, 2H, J¼8.5 Hz), 7.44 (d,1H, J¼7.5 Hz), 7.34 (s,1H),
7.30 (t, 1H, J¼7.5 Hz), 7.20e7.24 (m, 3H,), 5.10 (br d,1H, J¼7.0 Hz), 4.38
(br d,1H, J¼5 Hz), 3.70 (s, 3H), 2.70e2.75 (m, 2H), 2.33 (s, 3H), 2.21 (br
s, 1H), 1.98e2.01(m, 1H), 1.46 (s, 9H); 13C NMR (125 MHz, CDCl3)
*
, 21.4, 18.1, 17.6, ꢂ5.2; HRMS (ESI) (MþNa)þ calcu-
lated for C26H41NO4SiNaþ¼482.2703, found 482.2704.
4.2.11. (S)-tert-Butyl 4-(2-(2-(tert-butyldimethylsilyl)-1-tosyl-1H-in-
d
173.0, 155.4, 144.8, 135.4, 130.8, 129.9, 126.9, 124.8, 123.13, 123.08,
dol-3-yl)ethyl)-2,2-dimethyloxazolidine-3-carboxylate
(12b). The
121.6, 119.4, 113.9, 80.2, 53.2, 52.4, 32.1, 28.4, 21.6, 21.0; HRMS (ESI)
heteroannulation for N-tosyl-2-iodoaniline was carried out on
0.134 mmol scale using 1.2 equiv of 10, as described for compound
12a. Yield: 52% (43 mg).
(MþNa)þ calculated for C25H30N2O6SNaþ¼509.1722, found 509.1722.
4.2.8. tert-Butyl (R)-1-(methoxycarbonyl)-3-(1H-indol-3-yl)propylc-
Rf (20% AcOEt/PE) 0.80; 1H NMR (500 MHz, CDCl3)
d 7.93 (br s,
arbamate (
from a mixture of activated Mg turnings (40 mg, 1.7 mmol) and dry
methanol (2.5 mL) was added a solution of compound ( )-9 (20 mg,
D
)-1a. After the commencement of H2 gas evolution
1H), 7.37e7.43 (m, 3H), 7.21 (br s,1H), 7.16 (t,1H, J¼7.25 Hz), 7.06 (d,
2H, J¼8.0 Hz), 3.80e4.14 (m, 3H), 2.87 (br m, 2H), 2.27 (s, 3H), 1.90
(br s, 2H), 1.48e1.62 (m, 15H), 1.07 (s, 9H), 0.49 (s, 6H); 13C NMR
D
0.04 mmol) in methanol (1 mL) followed by (16 mg, 0.3 mmol) of
ammonium chloride. The reaction mixture was stirred for 3 h at rt
and was quenched with saturated ammonium chloride solution
(2 mL). It was extracted with EtOAc (3ꢀ5 mL). The whole organic
layers were washed with brine, dried, filtered, and concentrated in
vacuo to give the crude product, which was purified by silica gel
(125 MHz, CDCl3)
136.0, 132.3, 129.3, 126.3, 125.3, 123.4, 119.4, 119.2
94.1, 93.7 , 80.2, 80.0 , 67.2, 67.0 , 57.5, 34.4, 28.6, 27.5, 26.8
23.4, 23.2
d
152.6, 152.1
*
, 143.9, 140.3, 139.2, 138.8
, 116.1, 116.0
, 24.5,
*
, 136.9,
*
*
,
*
*
*
*
*
, 21.5, 19.0, 0.81 (*asterisk denotes conformer peaks);
HRMS (ESI) (MþNa)þ calculated for C33H48N2O5SSiNaþ¼635.2951,
found 635.2952.
column chromatography to afford (
foam. Enantiomeric excess (60% ee) was determined by HPLC with
a Chiralcel OD (250ꢀ4.6 mm, particle size 10 m) column (iso-
propanol/hexane¼20:80, 1 mL/min), tR (major)¼11 min ( -isomer),
D
)-1a (9.2 mg, 70%) as white
4.2.12. (S)-tert-Butyl 4-(2-(benzofuran-3-yl)ethyl)-2,2-
dimethyloxazolidine-3-carboxylate (13). To a solution of 12a
(150 mg, 0.32 mmol) in THF (5 mL) was added tetrabutyl ammo-
nium fluoride (0.4 mL of 1.0 M in THF, 0.4 mmol) at 0 ꢁC and stirred
at rt for 1 h. After removal of solvent the crude residue was charged
directly into silica gel column, eluting with petroleum ether/AcOEt
m
D
tR (minor)¼17.76 min (
Rf (5% AcOEt/CH2Cl2) 0.60; [
CHCl3)
L-isomer).
a
]
D
26 ꢂ18.6 (c 0.22, CHCl3); IR: (neat/
n
3373, 3363, 1737, 1693 cmꢂ1
;
1H NMR (500 MHz, CDCl3)
d
7.96 (br s, 1H), 7.57 (d, 1H, J¼8.0), 7.34 (d, 1H, J¼8.0 Hz), 7.19 (t, 1H,
(94:6), to give 13 as a white solid (98 mg, 80%).
26
J¼7.5 Hz), 7.11 (t, 1H, J¼7.3 Hz), 7.02 (s, 1H), 5.09 (br d, 1H, J¼7.0 Hz),
4.41 (br d, 1H, J¼5 Hz), 3.67 (s, 3H), 2.83 (t, 2H, J¼7.75 Hz),
2.22e2.26 (m, 1H), 2.02e2.08 (m, 1H), 1.46 (s, 9H); 13C NMR
Rf (10% AcOEt/PE) 0.50; [
a
]
þ28.6 (c 1.00, CHCl3); 1H NMR
D
(500 MHz, CDCl3)
d 7.54 (br s, 1H), 7.43e7.46 (m, 2H), 7.23e7.28 (m,
2H), 3.81e4.07 (m, 3H), 2.69 (br s, 2H), 2.20 (br s, 0.5H), 2.06(br s, 0.5H),
(125 MHz, CDCl3)
d 173.5, 155.6, 136.5, 127.4, 122.2, 121.8, 119.5,
1.94e2.00 (m, 1H), 1.39e1.65 (m, 15H); 13C NMR (125 MHz, CDCl3)
118.9, 115.1, 111.3, 80.1, 53.4, 52.3, 33.1, 28.5, 21.1; HRMS (ESI)
d
155.6,152.5,152.0
*
,141.4,141.1
*
*
,128.2,124.4,124.3
*
,122.4,119.8,119.6,
(MþNa)þ calculated for C18H24N2O4Naþ¼355.1634, found 355.1635.
119.5,111.6, 94.0, 93.4
, 80.2, 79.7
*
,67.0, 57.6,57.2 , 33.1, 32.4
*
*
, 28.6, 27.8,
27.0
*
, 24.7, 23.4
, 20.5 (*asterisk denotes conformer peaks); HRMS (ESI)
*
4.2.9. tert-Butyl (R)-1-(methoxycarbonyl)-3-(benzo[b]thiophen-3-yl)
propylcarbamate (1c). The aminoalcohol 8b (20 mg, 0.064 mmol),
similarly converted to methylester 1c in 48% (10.8 mg) yield as
(MþNa)þ calculated for C20H27NO4Naþ¼368.1838, found 368.1838.
4.2.13. (S)-tert-Butyl
ethyl)oxazolidine-3-carboxylate (
was carried out as described above for compound 13 on
2,2-dimethyl-4-(2-(1-tosyl-1H-indol-3-yl)
white solid using the procedure described for (
D
)-9.
L
)-7a. The silyl deprotection of 12b
26
Rf (20% AcOEt/PE) 0.50; [
a]
D
ꢂ29.5 (c 0.34, CHCl3); IR: (neat/
CHCl3)
n
3367, 1761, 1681 cmꢂ1; 1H NMR (500 MHz, CDCl3)
d
7.85 (d,
0.062 mmol scale. After silica gel chromatography ( )-7a was ob-
L
1H, J¼7.5 Hz), 7.71 (d, 1H, J¼7.0 Hz), 7.32e7.39 (m, 2H), 7.14 (s, 1H),
5.14 (br d, 1H, J¼7.0 Hz), 4.45 (br d, 1H, J¼5 Hz), 3.71 (s, 3H),
2.88e2.93 (m, 2H), 2.28e2.30 (m,1H), 2.07e2.10 (m,1H),1.46 (s, 9H);
tained as white foam (25 mg, 80%).
þ34.0 (c 1.18, CHCl3); 1H NMR
26
Rf (20% AcOEt/PE) 0.70; [
a
]
D
(500 MHz, CDCl3)
d
7.97 (d, 1H, J¼8.5 Hz), 7.75 (d, 2H, J¼8.5 Hz), 7.46
13C NMR (75 MHz, CDCl3)
d
173.0, 155.4, 140.5, 138.7, 135.0, 124.3,
(d, 1H, J¼7.5 Hz), 7.39 (s, 0.5H), 7.31 (s, 1.5H), 7.16e7.24 (m, 3H),
3.74e3.93(m, 3H), 2.64(brs, 2H),2.33(s, 3H), 2.17(brs,0.5H), 2.02(br
s, 0.5H), 1.89e1.95 (m, 1H), 1.35e1.61 (m, 15H); 13C NMR (125 MHz,
123.9,122.9,121.8,121.5, 80.1, 53.2, 52.4, 32.2, 28.3, 24.3; HRMS (ESI)
(MþNa)þ calculated for C18H23NO4SNaþ¼372.1245, found 372.1241.
CDCl3)
d
152.4, 152.0
*
, 144.8, 135.6, 131.1, 129.9, 126.9, 126.4, 124.9,
, 80.3, 79.7
, 26.0, 24.6, 23.3 , 22.8, 21.9,
4.2.10. (S)-tert-Butyl 4-(2-(2-(tert-butyldimethylsilyl)benzofuran-3-
124.8, 123.2, 122.8, 122.7, 122.4, 119.5, 113.9, 94.0, 93.5
*
*
,
yl)ethyl)-2,2-dimethyloxazolidine-3-carboxylate (12a). To
a
solu-
67.0, 57.6, 57.1
*
, 33.0,32.3
*
, 28.6, 27.8, 27.0
*
*
tion of 2-iodophenol (151 mg, 0.68 mmol) and (S)-tert-butyl-4-
(4-(tert-butyldimethylsilyl)but-3-ynyl)-2,2-dimethyloxazolidine-
3-carboxylate 10 (210 mg, 0.57 mmol) in dry DMF (3 mL) were
added lithium chloride (24 mg, 0.57 mmol) and sodium carbonate
(181 mg, 1.7 mmol). The reaction vessel was evacuated and
21.7 (*asterisk denotes conformer peaks); HRMS (ESI) (MþNa)þ cal-
culated for C27H34N2O5SNaþ¼521.2086, found 521.2085.
4.2.14. tert-Butyl (S)-4-(benzofuran-3-yl)-1-hydroxybutan-2-
ylcarbamate (14). According to the procedure described for (D)-

K. Goswami et al. / Tetrahedron 68 (2012) 280e286
285
8a, oxazolidine 13 (93 mg, 0.26 mmol) gave the aminoalcohol 14
53.4, 52.3, 33.1, 28.5, 21.1; HRMS (ESI) (MþNa)þ calculated for
C18H24N2O4Naþ¼355.1634, found 355.1633.
(68 mg, 85%) as white solid.
26
Rf (20% AcOEt/PE) 0.20; [
CHCl3)
a]
ꢂ14.4 (c 1.31, CHCl3); IR: (neat/
D
n
3358, 1687 cmꢂ1; 1H NMR (500 MHz, CDCl3)
d
7.53 (d, 1H,
4.2.19. tert-Butyl (S)-1-(methoxycarbonyl)-4-oxopentylcarbamate
J¼7.5 Hz), 7.44e7.46 (m, 2H), 7.25e7.29 (m, 1H), 7.22 (t, 1H,
J¼7.5 Hz), 4.78 (br d, 1H, J¼7.5 Hz), 3.58e3.70 (m, 3H), 2.71e2.78
(m, 2H), 2.58 (br s, 1H), 1.91e1.97 (m, 1H), 1.80e1.86 (m, 1H), 1.45 (s,
(16). Freshly distilled thionyl chloride (0.60 mL, 8.16 mmol) was
added dropwisewith stirring to a cooled suspension of L-glutamic acid
(1.0 g, 6.8 mmol) in anhydrous methanol (7 mL). The reaction mixture
was stirred at rt for 2 h and was refluxed for 8 h. The solvent was re-
moved under reduced pressure and co-evaporated with methanol
(3ꢀ7 mL) to afford crude product as sticky liquid. To a solution of this
crude product in THF (20 mL) were added triethylamine (2.0 mL,
14.6 mmol) and a solution of di-tert-butyl dicarbonate (1.78 g,
8.16 mmol) in THF (10 mL) at 0 ꢁC. The reaction mixture was stirred at
rt for 8 h. After completion of the reaction, solvent was removed in
vacuo and the residue partitioned between AcOEt (20 mL) and water
(20 mL). The aqueous phase was extracted with AcOEt (2ꢀ15 mL) and
the combined organic layers were washed with 3% HCl (15 mL), sat-
urated NaHCO3 (15 mL), and brine (20 mL), dried (Na2SO4), and
evaporation of the solvent gave 16 (1.5 g, 85%) as a colorless liquid.
9H); 13C NMR (125 MHz, CDCl3)
d 156.6, 155.5, 141.4, 128.1, 124.3,
122.4, 119.7, 119.6, 111.6, 79.9, 65.7, 52.6, 31.1, 28.5, 20.3; HRMS (ESI)
(MþNa)þ calculated for C17H23NO4Naþ¼328.1525, found 328.1523.
4.2.15. tert-Butyl (S)-1-hydroxy-4-(1-tosyl-1H-indol-3-yl)butan-2-
ylcarbamate (
L
)-8a. According to the procedure described for (
D
)-
8a, oxazolidine (L)-7a (25 mg, 0.05 mmol) gave the aminoalcohol
( )-8a (19.3 mg, 84%) as white solid.
L
26
Rf (30% AcOEt/PE) 0.25; [
a]
þ2.92 (c 2.01, CHCl3); 1H NMR
D
(500 MHz, CDCl3)
d
7.96 (d,1H, J¼8.5 Hz), 7.74 (d, 2H, J¼8.5 Hz), 7.46
(d,1H, J¼8.0 Hz), 7.34 (s,1H), 7.23 (t,1H, J¼7.5 Hz), 7.19e7.23 (m, 3H),
3.59e3.70 (m, 3H), 2.71e2.77 (m, 2H), 2.32 (s, 3H),1.92e1.93 (m,1H),
1.79e1.82 (m, 1H), 1.46 (s, 9H); 13C NMR (125 MHz, CDCl3)
d
156.5,
[
a
]
26 þ13.7 (c 0.89, CHCl3), lit.20
[
a
]
25 þ12.5 (c 2, CHCl3); 1H NMR
D
D
144.8, 135.51, 135.49, 130.9, 129.9, 126.9, 124.8, 123.2, 123.0, 122.5,
119.5, 113.9, 79.9, 65.9, 52.6, 30.9, 28.5, 21.7, 21.6; HRMS (ESI)
(MþNa)þ calculated for C24H30N2O5SNaþ¼481.1773, found 481.1771.
(300 MHz, CDCl3)
d
5.16 (br d,1H, J¼6.4 Hz), 4.28 (br d,1H, J¼4.6 Hz),
3.69 (s, 3H), 3.63 (s, 3H), 2.33e2.42 (m, 2H), 2.10e2.16 (m, 1H),
1.86e2.00 (m, 1H), 1.38 (s, 9H); 13C NMR (75 MHz, CDCl3)
d
173.2,
172.7, 155.4, 80.0, 52.9, 52.4, 51.8, 30.1, 28.3, 27.7; HRMS (ESI)
4.2.16. tert-Butyl (S)-1-(methoxycarbonyl)-3-(benzofuran-3-yl)pro-
pylcarbamate (1b). According to the procedure outlined for ester
(MþNa)þ calculated for C12H21NO6Naþ¼298.1267, found 298.1266.
(
D
)-9, aminoalcohol 14 (18.3 mg, 0.06 mmol) afforded the methyl-
4.2.20. tert-Butyl (S)-1,5-dihydroxypentan-2-ylcarbamate (17). To
a solution of diester 16 (1.46 g, 5.33 mmol) in THF (20 mL) was
added LiBH4 portionwise at 0 ꢁC followed by MeOH (0.37 mL) in
THF (7 mL) dropwise and left for overnight stirring at rt. After
solvent removal, ethyl acetate (50 mL) and water (60 mL) were
added at 0 ꢁC. The organic layer was then washed with brine
(30 mL), dried (Na2SO4), concentrated under reduced pressure, and
chromatographed on silica gel (petroleum ether/AcOEt 1:1) to yield
17 (712 mg, 61%) as a sticky liquid.
ester 1b (8.2 mg, 41%) as white solid.
26
Rf (20% AcOEt/PE) 0.55; [
a
]
þ25.6 (c 0.53, CHCl3); IR: (neat/
1H NMR (500 MHz, CDCl3)
7.52
CHCl3)
n
3369, 1759, 1685 cmꢂ1D
;
d
(d, 1H, J¼7.5 Hz), 7.44e7.47 (m, 2H), 7.22e7.30 (m, 2H), 5.12 (br d,
1H, J¼7.0 Hz), 4.42 (br d, 1H, J¼4.5 Hz), 3.71 (s, 3H), 2.73e2.77 (m,
2H), 2.25e2.26 (m, 1H), 2.01e2.06 (m, 1H), 1.46 (s, 9H); 13C NMR
(125 MHz, CDCl3)
d 173.2, 155.6, 141.6, 128.0, 124.4, 122.5, 119.6,
119.1, 111.7, 80.2, 53.4, 52.5, 32.2, 28.5, 28.2, 19.7; HRMS (ESI)
(MþNa)þ calculated for C18H23NO5Naþ¼356.1474, found 356.1474.
IR: (neat/CHCl3)
5.11 (br s, 1H), 3.56e3.61 (m, 5H), 3.39e3.42 (br m, 2H), 1.41e1.61
n ,
3340, 1687 cmꢂ1 1H NMR (500 MHz, CDCl3)
d
4.2.17. tert-Butyl (S)-1-(methoxycarbonyl)-3-(1-tosyl-1H-indol-3-yl)
(m, 13H); 13C NMR (125 MHz, CDCl3)
d 156.7, 79.7, 65.0, 62.2, 52.4,
propylcarbamate (
aminoalcohol ( )-8a (19 mg, 0.041 mmol) afforded the ester (
46% yield (9.1 mg) as white foam.
L
)-9. Using the procedure outlined for ester (
D
)-9,
28.8, 28.5, 28.1; HRMS (ESI) (MþNa)þ calculated for
L
L)-9 in
C10H21NO4Naþ¼242.1368, found 242.1367.
Rf (5% AcOEt/CH2Cl2) 0.80; [
a
]
26 þ26.8 (c 1.03, CHCl3); IR: (neat/
4.2.21. (S)-tert-Butyl 4-(3-hydroxypropyl)-2,2-dimethyloxazolidine-
3-carboxylate (18). To a solution of diol 17 (1.1 g, 4.6 mmol) in
a mixture of acetone (15 mL) and 2,2-dimethoxypropane (5 mL) was
added BF3$OEt2 (0.03 mL) and the resulting solution was stirred for
2 h. After the consumption of starting material, solvent was removed
and the residual oil was taken up in dichloromethane (15 mL). The
resulting solution was washed with a mixture of saturated NaHCO3
and H2O (1:1, 10 mL), brine (10 mL), and dried over Na2SO4. After
filtration and solvent removal, the crude oil was purified by column
chromatography to give 18 (700 mg, 65%) as a colorless oil.
D
CHCl3)
n
3381, 1743, 1701 cmꢂ1; 1H NMR (500 MHz, CDCl3)
d
7.96 (d,
1H, J¼8.0 Hz), 7.75 (d, 2H, J¼8.0 Hz), 7.44 (d,1H, J¼7.5 Hz), 7.34 (s,1H),
7.30 (t, 1H, J¼8.0 Hz), 7.19e7.23 (m, 3H), 5.10 (br d,1H, J¼7.0 Hz), 4.37
(br s, 1H), 3.70 (s, 3H), 2.70e2.74 (m, 2H), 2.32 (s, 3H), 2.17e2.22 (m,
1H),1.98e2.02(m,1H),1.46 (s, 9H);13C NMR (125 MHz, CDCl3)
d 173.1,
155.5, 144.9, 135.5, 130.8, 130.0, 127.0, 124.9, 123.2, 123.1, 121.7, 119.4,
113.9, 80.2, 53.3, 52.3, 32.2, 28.5, 21.7, 21.0; HRMS (ESI) (MþNa)þ
calculated for C25H30N2O6SNaþ¼509.1722, found 509.1720.
26
25
4.2.18. tert-Butyl
pylcarbamate ( )-1a. The tosyl deprotection of (
as described above for compound ( )-1a on 0.022 mmol scale. After
silica gel chromatography ( )-1a was obtained as white foam
(5.4 mg, 74%). Enantiomeric excess (94% ee) was determined by
HPLC with a Chiralcel OD (250ꢀ4.6 mm, particle size 10 m) col-
umn (isopropanol/hexane¼20:80, 1 mL/min), tR (minor)¼11.3 min
(S)-1-(methoxycarbonyl)-3-(1H-indol-3-yl)pro-
[a
]
þ28.5 (c 0.89, CHCl3), lit.17
[a
]
þ31 (c 1.0, CHCl3); IR:
D
D
L
L)-9 was carried out
(neat/CHCl3) n ;
3444, 1697 cmꢂ1 1H NMR (500 MHz, CDCl3)
D
d
3.64e3.93 (m, 5H), 2.15 (br s, 2H), 1.49e1.61 (m, 18H); 13C NMR
(125 MHz, CDCl3) 152.4, 151.8 , 93.7, 93.2 , 80.2, 79.5 , 67.1, 62.4,
57.1, 30.0, 29.7 , 29.4, 28.9 , 28.4, 27.5, 26.7 , 24.5, 23.2
(*asterisk
L
d
*
*
*
*
*
*
*
m
denotes conformer peaks); HRMS (ESI) (MþNa)þ calculated for
C14H25NO4Naþ¼282.1681, found 282.1681.
(D
-isomer), tR (major)¼17.6 min (
L-isomer).
Rf (5% AcOEt/CH2Cl2) 0.60; [
CHCl3)
a
]
26 þ26.6 (c 0.50, CHCl3); IR: (neat/
4.2.22. (S)-tert-Butyl 4-(but-3-ynyl)-2,2-dimethyloxazolidine-3-
carboxylate (21). To a solution of aminoalcohol 18 (500 mg,
D
n
3371, 1735, 1697 cmꢂ1; 1H NMR (500 MHz, CDCl3)
d
7.97 (s,
1H), 7.56 (d, 1H, J¼7.5 Hz), 7.35 (d, 1H, J¼8.0 Hz), 7.19 (t, 1H,
J¼7.5 Hz), 7.11 (t, 1H, J¼7.5 Hz), 7.02 (s, 1H), 5.09 (d, 1H, J¼7.5 Hz),
4.41 (d, 1H, J¼5 Hz), 3.67 (s, 3H), 2.83 (t, 2H, J¼7.75 Hz), 2.20e2.27
(m, 1H), 2.01e2.08 (m, 1H), 1.46 (s, 9H); 13C NMR (125 MHz, CDCl3)
1.93 mmol) in dichloromethane (16 mL) was added solid period-
inane (982 mg, 2.3 mmol) portionwise and stirred for 0.5 h. After
consumption of starting material (TLC), it was diluted with ether
(40 mL) and the resulting suspension was added to 1.3 M NaOH
(16 mL). The reaction mixture was stirred for 15 min, ether layer
d
173.5, 155.6, 136.5, 127.4, 122.2, 121.8, 119.4, 118.9, 115.0, 111.3, 80.1,

286
K. Goswami et al. / Tetrahedron 68 (2012) 280e286
was washed with a mixture of 1.3 M NaOH (16 mL) and water
(24 mL). The organic layer was dried, filtered, concentrated in
vacuo, and used in the next step without further purification.
To a cooled (0 ꢁC) stirred solution of above crude aldehyde 19
and phosphonate 20 (555 mg, 2.89 mmol) in MeOH (11 mL) was
added K2CO3 (530 mg, 3.86 mmol) portionwise. The reaction mix-
ture was stirred at 0 ꢁC for 1 h, and then warmed to rt. Stirring was
continued until the reaction was completed (w5 h) as indicated by
TLC (9:1 petroleum ether/AcOEt). The mixture was then diluted
with saturated aqueous NH4Cl (15 mL) and extracted with diethyl
ether (3ꢀ15 mL). The combined organic layers were dried (Na2SO4)
and concentrated. The residue was eluted from a silica gel column
with petroleum ether/AcOEt (95:5) to give 21 (370 mg, 75%, after
Supplementary data
Spectroscopic data as well as copies of the spectra of all new
compounds are provided. Supplementary data associated with this
article can be found in online version, at doi:10.1016/
j.tet.2011.10.055.
References and notes
€
1. (a) Rohrig, U. F.; Awad, L.; Grosdidier, A.; Larrieu, P.; Stroobant, V.; Colau, D.;
Cerundolo, V.; Simpson, A. J. G.; Vogel, P.; Van den Eynde, B. J.; Zoete, V.; Michielin,
O. J. Med. Chem. 2010, 53, 1172; (b) Botting, N. P. Chem. Soc. Rev. 1995, 24, 401.
2. Forouhar, F.; Anderson, J. L. R.; Mowat, C. G.; Vorobiev, S. M.; Hussain, A.;
Abashidze, M.; Bruckmann, C.; Thackray, S. J.; Seetharaman, J.; Tucker, T.; Xiao,
R.; Ma, L. C.; Zhao, L.; Acton, T. B.; Montelione, G. T.; Chapman, S. K.; Tong, L.
Proc. Natl. Acad. Sci. U.S.A. 2007, 104, 473.
3. Cady, S. G.; Sono, M. Arch. Biochem. Biophys. 1991, 291, 326.
4. Lu, C.; Lin, Y.; Yeh, S. R. J. Am. Chem. Soc. 2009, 131, 12866.
5. (a) Peterson, A. C.; Migawa, M. T.; Martin, M. J.; Hamaker, L. K.; Czerwinski, K.
M.; Zhang, W.; Arend, R. A.; Fisette, P. L.; Ozaki, Y.; Will, J. A.; Brown, R. R.; Cook,
J. M. Med. Chem. Res. 1994, 3, 531; (b) Peterson, A. C.; Laloggia, A. J.; Hamaker, L.
K.; Arend, R. A.; Fisette, P. L.; Ozaki, Y.; Will, J. A.; Brown, R. R.; Cook, J. M. Med.
Chem. Res. 1993, 3, 473.
6. (a) Podea, P. V.; Tos¸ a, M. I.; Paizs, C.; Irimie, F. D. Tetrahedron: Asymmetry 2008,
19, 500; (b) Ma, C.; Yu, S.; He, X.; Liu, X.; Cook, J. M. Tetrahedron Lett. 2000, 41,
2781; (c) van Esseveldt, B. C. J.; van Delft, F. L.; Smits, J. M. M.; de Gelder, R.;
Schoemaker, H. E.; Rutjes, F. P. J. T. Adv. Synth. Catal. 2004, 346, 823; (d) Ma, C.;
Liu, X.; Li, X.; Flippen-Anderson, J.; Yu, S.; Cook, J. M. J. Org. Chem. 2001, 66,
4525; (e) van Esseveldt, B. C. J.; van Delft, F. L.; de Gelder, R.; Rutjes, F. P. J. T. Org.
Lett. 2003, 5, 1717.
two steps) as a crystalline solid.
26
Rf (10% AcOEt/PE) 0.60; [
CHCl3)
3.94e3.98 (m, 2H), 3.80e3.83 (m, 1H), 2.18e2.24 (m, 2H),
1.89e2.01 (m, 2H), 1.74e1.78 (m, 1H), 1.48e1.59 (m, 15H); 13C NMR
(125 MHz, CDCl3) 152.3, 151.8 , 93.8, 93.3 , 83.7, 83.4 , 80.2, 79.8
69.0, 66.8, 57.1, 56.6 , 32.1, 31.7 , 28.6, 27.7, 26.9 , 24.5, 23.3 , 15.6
a
]
þ1.41 (c 0.89, CHCl3); IR: (neat/
D
n
3308, 3263, 2117, 1697 cmꢂ1 1H NMR (500 MHz, CDCl3)
;
d
d
*
*
*
*
,
*
*
*
*
(*asterisk denotes conformer peaks); HRMS (ESI) (MþNa)þ calcu-
lated for C14H23NO3Naþ¼276.1576, found 276.1573.
4.2.23. (S)-tert-Butyl 4-(4-(tert-butyldimethylsilyl)but-3-ynyl)-2,2-
dimethyloxazolidine-3-carboxylate (10). To
a
solution of 21
(800 mg, 3.2 mmol) in anhydrous THF (10 mL) at ꢂ78 ꢁC was added
dropwise n-butyllithium (2.4 mL, 1.2 equiv, 1.6 M in hexane) fol-
lowed by a solution of tert-butyl dimethyl silylchloride (528 mg,
1.1 equiv) in THF (5 mL) under an argon atmosphere. The reaction
mixture was allowed to warm up to 25 ꢁC and stirred overnight.
Quenching was performed by the addition of cold water (15 mL).
The aqueous phase was extracted with ethyl acetate (3ꢀ7 mL). The
combined organic layers were dried, concentrated, and purified to
7. Amjad, M.; Knight, D. W. Tetrahedron Lett. 2004, 45, 539.
8. Suzuki, N.; Yasaki, S.; Yasuhara, A.; Sakamoto, T. Chem. Pharm. Bull. 2003, 51,
1170.
9. Yue, D.; Larock, R. C. J. Org. Chem. 2002, 67, 1905.
10. (a) Sonogashira, K.; Tohda, Y.; Hagihara, N. Tetrahedron Lett. 1975, 16, 4467; (b)
ꢀ
Chinchilla, R.; Najera, C. Chem. Rev. 2007, 107, 874.
11. (a) Garner, P.; Park, J. M. Org. Synth. 1991, 70, 18; (b) McKillop, A.; Taylor, R. J. K.;
Watson, R. J.; Lewis, N. Synthesis 1994, 31; (c) Dondoni, A.; Perrone, D. Synthesis
1997, 527; (d) Crisp, G. T.; Jiang, Y. L.; Pullman, P. J.; Savi, C. D. Tetrahedron 1997,
53, 17489.
12. (a) Mandal, P. K.; McMurray, J. S. J. Org. Chem. 2007, 72, 6599; (b) Sauvage, J. F.;
Baker, R. H.; Hussey, A. S. J. Am. Chem. Soc. 1960, 82, 6090; (c) Jourdant, A.;
Gonzalez-Zamora, E.; Zhu, J. J. Org. Chem. 2002, 67, 3163.
13. Dondoni, A.; Giovannini, P. P.; Massi, A. Org. Lett. 2004, 6, 2929.
14. (a) Inuki, S.; Oishi, S.; Fujii, N.; Ohno, H. Org. Lett. 2008, 10, 5239; (b) Nishikawa,
T.; Koide, Y.; Kanakubo, A.; Yoshimura, H.; Isobe, M. Org. Biomol. Chem. 2006, 4,
yield 10 (857 mg, 73%) as a colorless oil.
26
Rf (10% AcOEt/PE) 0.75; [
a]
þ3.04 (c 1.63, CHCl3); IR: (neat/
D
CHCl3) ; d 3.89e3.95
n
2173, 1701 cmꢂ1 1H NMR (500 MHz, CDCl3)
(m, 3H), 2.26e2.30 (m, 2H), 1.90e1.99 (m, 1H), 1.76 (m, 1H),
1.47e1.58 (m, 15H), 0.92 (s, 9H), 0.07 (s, 6H); 13C NMR (75 MHz,
CDCl3)
d
152.3, 151.8
*
,107.1,106.5
*
, 93.8, 93.3
*
, 83.5, 80.2, 79.7
*
, 67.0,
ꢁ
1268; (c) Bajwa, J. S.; Chen, G.-P.; Prasad, K.; Repic, O.; Blacklock, T. J. Tetrahe-
dron Lett. 2006, 47, 6425.
57.6, 56.9
*
, 32.2, 32.1
*
, 28.6, 27.6, 26.9
*
, 26.2, 24.6, 23.3
*
, 17.1, 16.6,
ꢂ4.4 (*asterisk denotes conformer peaks); HRMS (ESI) (MþNa)þ
15. (a) Yue, D.; Yao, T.; Larock, R. C. J. Org. Chem. 2005, 70, 10292; (b) Arcadi, A.;
Cacchi, S.; Fabrizi, G.; Marinelli, F.; Morob, L. Synlett 1999, 1432.
16. Larock, R. C.; Yum, E. K.; Refvik, M. D. J. Org. Chem. 1998, 63, 7652.
17. Truchot, C.; Wang, Q.; Sasaki, N. A. Eur. J. Org. Chem. 2005, 1765.
18. (a) Ohira, S.; Okai, K.; Moritani, T. J. Chem. Soc., Chem. Commun. 1992, 721;
calculated for C20H37NO3SiNaþ¼390.2440, found 390.2441.
Acknowledgements
€
(b) Roth, G. J.; Liepold, B.; Muller, S. G.; Bestmann, H. J. Synthesis 2004, 59.
19. Meffre, P.; Gauzy, L.; Branquet, E.; Durand, P.; Goffic, F. L. Tetrahedron 1996, 52,
S.S. thanks DST, India, for financial support by a grant [SR/S1/OC-
11215.
38/2007]. K.G. and S.P. are thankful to CSIR for their fellowship.
20. Varala, R.; Adapa, S. R. Org. Process Res. Dev. 2005, 9, 853.