Asymmetric synthesis of conformationally constrained trans-2,3-piperidine- dicarboxylic acid derivatives

Article abstract of DOI:10.1055/s-2007-968029

An efficient asymmetric synthesis of conformationally constrained (2S,3S)-piperidinedicarboxylic acid derivatives starting from L-aspartic acid β-tert-butyl ester and 3-chloro-2-(chloromethyl)-1-propene is described. The key steps involve N-alkylation of

Full text of DOI:10.1055/s-2007-968029

460
LETTER
Asymmetric Synthesis of Conformationally Constrained trans-2,3-Piperidine-
dicarboxylic Acid Derivatives
S
ynthesis
i
of tran
n
-
2,3-Piperid
c
inedicarbox
o
ylic
A
cidD
e
n
rivatives g Zhuo,* David M. Burns, Colin Zhang, Meizhong Xu, Lingkai Weng, Ding-Quan Qian, Chunhong He,
Qiyan Lin, Yun-Long Li, Eric Shi, Costas Agrios, Brian Metcalf, Wenqing Yao*
Incyte Corporation, Medicinal Chemistry Division, Experimental Station, Wilmington, DE 19880, USA
Fax +1(302)4252704; E-mail: JZhuo@incyte.com; E-mail: WYao@incyte.com
Received 8 August 2006
Abstract: An efficient asymmetric synthesis of conformationally
OR3
O
constrained (2S,3S)-piperidinedicarboxylic acid derivatives starting
from L-aspartic acid b-tert-butyl ester and 3-chloro-2-(chlorometh-
yl)-1-propene is described. The key steps involve N-alkylation of
the aspartic acid ester followed by a stereoselective enolate intra-
molecular cyclization (>95:5 dr). Various synthetic strategies were
explored to achieve the cyclopropanation of the resulting olefin,
including the Simmons–Smith reaction and palladium-catalyzed
cyclopropanation.
O
OR2
O
OH
N
R1
N
H
O
O
1
2
Figure 1 Pipecolic acid derivatives
Key words: cyclopropanation, allylic amine, Simmons–Smith re-
agent, asymmetric synthesis, spiro piperidine
incorporated into a peptide and have proved to be a useful
tool in the field of peptidomimetics.10
We were interested in trans-2,3-piperidine-dicarboxylic
acid derivatives as templates for the inhibition of a pro-
tease that is implicated in the pathogenesis of various
cancers. We hypothesized that imparting additional con-
formational rigidity to the piperidine ring by incorporat-
ing a spiro cyclopropyl group at the C5-position, as
depicted in compound 2, could result in improved
pharmacokinetic and pharmacodynamic properties.
In response to the high attrition rate of drug candidates in
clinical trials due to poor pharmacokinetic properties,
there has been considerable interest in understanding the
molecular properties that govern the oral bioavailability
of drugs and drug candidates.1 Most notably, is Lipinski’s
‘rule of five’ which has been augmented by the recent fo-
cus on rotatable bonds and polar surface area.2,3 Good oral
bioavailability due to a decrease in rotatable bonds is be-
lieved to be one reason that cyclic molecules are ubiqui-
tous among priviliged structures and substructures in drug
discovery.4 The molecular rigidity that is attributed to
cyclic molecules may also aid in reducing entropic costs
that are associated with enzyme and receptor binding. In
addition, the defined spatial arrangement of cyclic struc-
tures may be valuable in ascertaining information about
the bioactive conformation, which can then be used to at-
tenuate the binding properties, i.e. potency and selectivity.
Agami et al. have reported an asymmetric synthesis of cis-
and trans-3-(methoxycarbonyl)-2-piperidine carboxylic
acids starting from (2S)-phenylglycinol and proceeding
through an aza-annulation process.11 In addition, Rapo-
port et al. reported two asymmetric synthetic routes to
obtain a-tert-butyl b-methyl (2S,3R)-3-ethylhexahydro-
quinolinate starting from L-aspartic acid.12 Xue et al. re-
cently reported a variation of one of Rapoport’s synthetic
routes for the synthesis of trans-2,3-piperidinedicarboxy-
lic acid derivatives 1.13 However, the key asymmetric
enolate addition proceeded with modest diastereoselectiv-
ity (6:1 dr). We hypothesized that the diastereoselectivity
could be improved upon by reversing the synthetic reac-
tion sequence, such that the aspartic acid amino N-atom is
alkylated and then intramolecular ring closure is achieved
at C-3.
Due to its cyclic nature, high degree of functionality, and
diverse range of biological activity, the pipecolic acid
scaffold is emerging as a novel privileged structure. In
particular, recent attention has been ascribed to the trans-
2,3-piperidine-dicarboxylic acid derivatives 1, which pos-
sess multiple therapeutic indications, especially in the
areas of TNF-a converting enzyme (TACE) inhibition,5
dopamine and serotonin transport inhibition,6 antitumor
properties,7 herpes simplex virus ribonucleotide reduc-
tase,8 and most notably N-methyl-D-aspartic acid
(NMDA) receptor agonist/antagonist (Figure 1).9 Further-
more, pipecolic acid derivatives induce a b-turn once
Our synthesis began with the protection of the a-carboxy-
lic acid and concomitant mono-N-benzylation of L-aspar-
tic acid b-tert-butyl ester 3 (Scheme 1). It was speculated
that the inexpensive benzyl protecting group should be
sufficient to suppress any undesired a-deprotonation that
may occur during the enolate formation. Subsequent N-
alkylation using 3-chloro-2-(chloromethyl)-1-propene in
the presence of sodium iodide afforded the key intermedi-
ate 5 for investigation of the intramolecular cyclization.
SYNLETT 2007, No. 3, pp 0460–0464
1
5.
0
2.
2
0
0
7
Advanced online publication: 07.02.2007
DOI: 10.1055/s-2007-968029; Art ID: S15806ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
Synthesis of trans-2,3-Piperidinedicarboxylic Acid Derivatives
461
O
Cl
O
O
CH2=C(CH2Cl)2,
K2CO3, NaI, MeCN
BnBr, DBU, PhMe
(46%)
O
O
O
(70%)
HN
Bn
CO2Bn
N
CO2Bn
H2N
CO2H
Bn
3
5
4
I
O
O
O
O
O
O
NaI, Me2CO
(96%)
LiHMDS, THF,
O
CbzCl
(93%)
–78 °C to –30 °C
(72%)
OBn
N
OBn
N
CO2Bn
N
Bn
Bn
O
Cbz
6
7
8
Scheme 1 Synthesis of piperidine ring 8
Treatement of ester 5 with sodium hexamethyldisilazide Once the C2 and C3 chiral centers were established, our
(NaHMDS) at –78 °C in THF followed by warming the attention was shifted to the cyclopropanation of the exo-
reaction mixture to –30 °C resulted in both poor yield and cyclic olefin. One of the most widely used methods to
diastereoselectivity. The poor reactivity was attributed to introduce a cyclopropane ring from an olefin is the Sim-
the chloride anion being a poor leaving group. Therefore, mons–Smith reaction.14,16 Under optimum Simmons–
the chlorine was exchanged for the more electrophilic io- Smith reaction conditions, a heteroatom directing group is
dine by treatment of 5 with NaI in acetone. Subsequent present to coordinate to the Zn reagent and direct the re-
enolate formation of 6 using either NaHMDS or KHMDS agent to the olefin, thus lowering entropic costs.15 Despite
under the reaction conditions described above resulted in the coordinative potential of a neighboring amino group,
the formation of a 1:1 mixture of the trans- and cis-dia- allylic amines or olefins containing an amino group with-
stereoisomers. Changing the base to LiHMDS provided out a chelating group have not been directly applied to the
the desired trans-2,3-piperidinedicarboxylate ester (7) Simmons–Smith reaction due to the propensity of these
with excellent diastereoselectivity (>95:5 dr), which was compounds to undergo N-ylide formation.19 It was, there-
confirmed by NMR analysis.
fore, not surprising that cyclopropanation of olefin 7 was
unsuccessful using both standard and Shi’s modified Sim-
mons–Smith conditions17 or using Denmark’s activated
IZnCH2Cl reagent.18
One explanation for the drastic improvement in the dia-
stereoselectivity observed with LiHMDS is that the Li cat-
ion could coordinate more tightly to the two carbonyl
oxygens to form a [6,7]-bicyclic transition state. If SN2 In an effort to alleviate the presumed formation of zinc-
displacement occurs from the pro-S face, of the enolate complexed ammonium ylides, the benzyl amino protect-
the electrophile is in a favorable pseudo-equatorial posi- ing group of 7 was converted into the non-nucleophilic
tion in the six-membered ring (Figure 2). Conversely, if benzyl carbamate group. This was achieved by simply
bond formation occurs from the pro-R face, the alkyl ha- heating 7 in the presence of CbzCl to afford 8, with no
lide would have to approach from the pseudo-axial posi- observed epimerization at the C2-position.
tion via a cis-[6,7]-bicyclic transition state in which the
methylene and OBn groups would have unfavorable steric
interactions.
Initial investigation of the cyclopropanation of the tert-
butyl ester 8 using Denmark’s activated IZnCH2Cl afford-
ed ca. 10% of the desired product (Table 1, entry 1).
Despite the poor yield the results were promising, con-
sidering that there was no product observed with the Bn
I
R2
R2
H
H
protecting group. Simply prolonging the reaction time did
not improve the yield (Table 1, entry 2). Heating the reac-
tion mixture to 50 °C in the absence or presence of DME
led to a slight improvement in yield, however, this was
mitigated by the formation of a complicated mixture of
by-products. Spectroscopic evidence (HPLC and LCMS)
suggested that these by-products could mostly be attribut-
ed to cleavage of the tert-butyl group. In addition to being
labile, the sterically bulky tert-butyl group may be inter-
O
O
H
I
H
Li
H
Li
O
BnO
BnO
O
N
N
O
O
R1
H
R1
H
pro-S face
pro-R face
Figure 2 Proposed [6,7]-bicyclic transition state
The excellent diastereoselectivity observed for this ap- fering with the cyclopropanation either directly through
proach supports our hypothesis, that preassembling the unfavorable steric interactions or indirectly by altering the
enolate and electrophile via N-alkylation can facilitate the conformation of the piperidine ring. Therefore, the tert-
formation of a tightly bound cyclic transition state result- butyl ester 8 was converted into the corresponding methyl
ester by treatment with HCl in methanol. It should be
ing in improved diastereoselectivity in comparison to an
intermolecular approach.
Synlett 2007, No. 3, 460–464 © Thieme Stuttgart · New York

462
J. Zhuo et al.
LETTER
noted that there was no observed epimerization at the C2- as previously described. It was found that the cyclopropa-
position.
nation of the resulting 3-methyl ester N-methylcarbamate
piperidine occurred in low yield (ca. 16%) by using eight
equivalents of CH2I2 alone (Table 1, entry 9). Using Shi’s
conditions, 4 equivalents of CH2I2 and TFA (Table 1, en-
try 10), the reaction produced about 60% cyclopropana-
tion derivative. The addition of three aliquots of CH2ICl
and Et2Zn as described above afforded 91% conversion
into the desired cyclopropane compound with an isolated
yield of 62–78% (Table 1, entry 10 in parenthesis). These
results are comparable to that observed for the analogous
benzyl carbamate and suggest that the alkyl group of
the carbamate does not play a critical role in the cyclopro-
panation.
Cyclopropanation of the methyl ester resulted in a five-
fold increase in yield compared to the corresponding tert-
butyl ester (Table 1, entry 5 vs. entry 2). Utilization of
Denmark’s activated IZnCH2Cl was also found to be
essential for the modest observed conversion to occur
(Table 1, entry 6). Interestingly, implementation of Shi’s
reaction conditions led to a reversal in the reactivity of
CH2ICl and CH2I2 (Table 1, entries 7 and 8). It was found
that Shi’s reaction conditions using four equivalents of
TFA, CH2I2, and Et2Zn at –10 °C followed by gradually
warming the reaction mixture to room temperature for 22
hours provided a modest yield of the desired product (50–
61%, Table 1, entry 8). Similar to the tert-butyl ester, sim- To the best of our knowledge, this is the first successful
ply prolonging the reaction time did not improve the yield. example of cyclopropanation of an allylic amine by mask-
Presumably, the lack of improvement is due to the decom- ing the amine as a carbamate without the presence of a
position of the active carbenoid species. It was found that chelating group (OH or OR) under Simmons–Smith con-
after approximately 18 hours, the addition of four equiva- ditions.19–22 It is also important to note that the absence of
lents of CH2ICl and two equivalents of Et2Zn was required a zinc chelating group was overcome by the application of
for the reaction to progress. After repeating this process at Shi’s modified Simmons–Smith conditions with good
time points of 24 hours and 40 hours, the olefin was effec- yields, albeit the addition of multiple aliquots of reagents
tively converted into the desired cyclopropane with an was required to successfully drive the reaction to comple-
isolated yield of 65–71% (Table 1, entry 8 in parenthesis). tion.
In a second approach to change the conformation of the Alternatively, the cyclopropanation reaction could be
piperidine ring to a more favorable one, the Cbz group achieved under Suda’s conditions using a catalytic
was exchanged for the methyl carbamate by treatment of amount of palladium acetate and diazomethane.23 Initial
benzyl piperidine 7 with methyl chloroformate followed attempts to introduce the spiro cyclopropane ring to the
by conversion of the tert-butyl ester into the methyl ester benzyl-protected piperidine 7 provided poor yields (ca.
Table 1 Cyclopropanation of 5-Methylenepiperidine-2,3-dicarboxylic Acid Ester
R2
R2
O
O
O
4 equiv Et2Zn, DCE
reagents, temp, time
O
O
O
O
N
R1
N
R1
Bn
Bn
O
Entry
R1
R2
Reagents (equiv)
CH2ICl (4)
Temp
r.t.
Time (h)
Conv. (%)a,b
1
2
Cbz
t-Bu
t-Bu
t-Bu
t-Bu
Me
Me
Me
Me
Me
Me
3
24
3
10
Cbz
CH2ICl (4)
r.t.
10
3
Cbz
CH2ICl (4)
50 °C
50 °C
r.t.
22
4
Cbz
CH2ICl (4), DME (4)
CH2ICl (8)
3
25
5
Cbz
23
18
22
22
18
18
50 (65)
25
6
Cbz
CH2I2 (8)
r.t.
7
Cbz
CH2ICl (4), TFA (4)
CH2I2 (4), TFA (4)
CH2I2 (8)
–10 °C to r.t.
20
8
Cbz
–10 °C to r.t.
50–61 (86)c
16 (71)
61 (91)d
9
CO2Me
CO2Me
r.t.
r.t.
10
CH2I2 (4), TFA (4)
a Conversion (%) was measured by HPLC and LCMS data.
b In parenthesis is the conversion (%) after 46 h with additional aliquots of 4 equiv of CH2ICl/additive and 2 equiv of Et2Zn being added to the
reaction mixture after ca. 18 h, 24 h, and 40 h.
c Isolated yield: 65–71%.
d Isolated yield: 62–78%.
Synlett 2007, No. 3, 460–464 © Thieme Stuttgart · New York

LETTER
Synthesis of trans-2,3-Piperidinedicarboxylic Acid Derivatives
463
IR (neat): 3065, 2977, 1729, 1454, 1367, 1256, 1150, 1001, 900,
740, 698 cm–1.
for the Cbz protecting group by using methods previously 1H NMR (400 MHz, CDCl3): d = 1.42 (s, 9 H), 2.44 (dd, J = 14.0,
10%). This could be due to the nucleophilicity of the ter-
tiary amine.19 Therefore, the benzyl group was exchanged
5.4 Hz, 1 H), 2.49 (dd, J = 14.0, 7.5 Hz, 1 H), 2.98 (d, J = 12.9 Hz,
1 H), 3.01 (ddd, J = 7.5, 6.6, 5.4 Hz, 1 H), 3.34 (d, J = 12.9 Hz, 1
H), 3.57 (d, J = 13.7 Hz, 1 H), 3.77 (d, J = 13.7 Hz, 1 H), 3.93 (d,
J = 6.6 Hz, 1 H), 4.71 (s, 1 H), 4.84 (s, 1 H), 5.16 (d, J = 12.1 Hz, 1
H), 5.22 (d, J = 12.1 Hz, 1 H), 7.21–7.26 (m, 5 H), 7.31–7.40 (m, 5
H).
13C NMR (400 MHz, CDCl3): d = 28.18, 33.28, 44.17, 54.78, 57.90,
64.72, 66.86, 81.17, 111.37, 127.28, 128.41, 128.61, 128.78,
128.81, 129.08, 135.88, 138.54, 140.40, 171.94, 172.00.
described above. Cyclopropanation of the olefin 8 was
accomplished by treatment with Pd(OAc)2 and diazo-
methane, generated in situ from Diazald and KOH
(Scheme 2). Deprotection of the CO2Bn and NCbz groups
was accomplished in the presence of the cyclopropane
ring by treatment of 9 with the mild reducing catalyst Pd/
BaSO4 to afford the designed polyfunctionalized chiral
building block 2.24
MS (ESI): m/z = 422.3 [M + H]+.
5,6-Dibenzyl 7-tert-Butyl (6S,7S)-5-Azaspiro[2.5]octane-5,6,7-
tricarboxylate (9)
O
O
O
O
Pd(OAc)2
CH2N2
H
2, Pd/BaSO4
O
O
A solution of Diazald (5.0 g, 23.3 mmol) in Et2O (50 mL) was added
dropwise to a mixture of KOH (2.65 g, 47.3 mmol) dissolved in
di(ethylene)ethyl ether (5 mL), H2O (4 mL) and Et2O (5 mL) at 60
°C. The diazomethylene formed was directly distilled into a reac-
tion flask that contained a mixture of 8 (4.0 g, 8.6 mmol) and palla-
dium(II) acetate (50 mg, 0.22 mmol) in Et2O (30 mL) at –20 °C. The
reaction mixture was allowed to warm to r.t. and stirred for 3 h. The
mixture was filtered and concentrated in vacuo. The residue was pu-
rified by Combiflash chromatography (hexane and EtOAc: gradient
0–10% during 12 min) to afford the desired product (4.03 g, 98%).
[a]D20 –10.74 (c 0.546 g/dL in MeOH).
2
(98%)
(98%)
OBn
OBn
N
N
Cbz
Cbz
8
9
Scheme 2 Cyclopronation and formation of (2S,3R)-piperidine
dicarboxylic acid derivative
In conclusion, an efficient asymmetric synthesis of
(2S,3S)-piperidinedicarboxylic acid derivative 2 starting
from L-aspartic acid b-tert-butyl ester 3 has been devel-
oped. The excellent diastereoselectivity observed by
preassembling the nucleophile and electrophile via N-
alkylation and intramolecular cyclization, may make this
approach a viable synthetic strategy for the asymmetric
synthesis of a variety of other piperidine derivatives. We
have demonstrated that the cyclopropanation of allylic
amines can be achieved by conversion of the amine into a
carbamate followed by utilization of either Shi’s modified
Simmons–Smith reaction or Suda’s Pd(OAc)2/CH2N2
conditions. These approaches may be broadly applied to
the cyclopropanation of unactivated allylic amine deriva-
tives where conventional methods have failed. The spiro
piperidine intermediate 2 should serve as a polyfunction-
alized chiral building block due to the high degree of
chiral functionality present and may prove to be a valu-
able pharmaceutical template due to the conformational
rigidity of the piperidine ring.
IR (neat): 3065, 2977, 2867, 1729, 1706, 1423, 1303, 1215, 1151,
988, 849, 754, 698 cm–1.
1H NMR (400 MHz, CDCl3): d = 0.25–0.41 (m, 3 H), 0.42–0.52 (m,
1 H), 1.33–1.46 (m, 1 H), 1.41 (s, 9 H), 1.85–1.98 (m, 1 H), 3.15–
3.42 (m, 3 H), 5.02–5.26 (m, 3 H), 5.53 (s, 0.5 H), 5.63 (s, 0.5 H),
7.27–7.38 (m, 10 H).
13C NMR (400 MHz, CDCl3): d = 9.22, 9.30, 13.16, 15.46, 15.63,
28.14, 31.62, 31.86, 42.52, 49.72, 50.01, 55.16, 55.31, 67.24, 67.47,
67.64, 81.62, 127.98, 128.13, 128.37, 128.45, 128.51, 128.64,
128.69, 128.76, 128.79, 128.89, 135.58, 135.68, 136.81, 137.03,
156.12, 156.29, 170.93, 171.02, 171.33, 171.38.
MS (ESI): m/z = 502.3 [M + Na]+, 380.3 [M + H – CO2(t-Bu)]+.
(6S,7S)-7-(tert-Butoxycarbonyl)-5-azaspiro[2.5]octane-6-car-
boxylic acid (2)
A mixture of 9 (2.0 g, 4.2 mmol) and 5% Pd–BaSO4 (750 mg) in
MeOH (100 mL) was placed under a hydrogen atmosphere (hydro-
gen balloon) and stirred at r.t. for 3 h. The catalyst was removed by
filtration and the filtrate was concentrated in vacuo to provide the
20
desired product (1.06 g, 98%). [a]D –13.2 (c 0.412 g/dL in
MeOH).
IR (neat): 3426, 2977, 2933, 1727, 1641, 1368, 1280, 1155, 1025,
846, 732 cm–1.
2-Benzyl 3-tert-Butyl (2S,3S)-1-Benzyl-5-methylenepiperidine-
2,3-dicarboxylate (7)
1H NMR (500 MHz, CDCl3): d = 0.33–0.37 (m, 1 H), 0.44–0.49 (m,
1 H), 0.56–0.61 (m, 1 H), 0.61–0.66 (m, 1 H), 1.26–1.30 (m, 1 H),
1.49 (s, 9 H), 2.29 (ddd, J = 1.5, 12.2, 13.2 Hz, 1 H), 2.61 (ddd,
J = 4.4, 11.2, 12.2 Hz, 1 H), 2.99 (dd, J = 1.5, 13.2 Hz, 1 H), 3.82
(dd, J = 2.2, 13.4 Hz, 1 H), 4.21 (d, J = 11.2 Hz, 1 H).
13C NMR (500 MHz, MeOD): d = 11.6, 12.3, 15.9, 28.7 (3 C), 36.0,
45.1, 52.0, 60.5, 83.0, 172.4, 174.3.
MS (ESI): m/z = 256.1 [M + H]+, 200.1 [M + H – t-Bu]+. HRMS
(ESI): m/z calcd for C13H21NO4: 256.15488 [M + H]+; found:
256.1553 [M + H]+.
LiHMDS (1.0 M in THF, 20.2 mL) was added dropwise over a pe-
riod of 30 min to a –78 °C solution of 1-benzyl 4-tert-butyl ester (6,
9.2 g, 16.8 mmol) in THF (50 mL) under N2. The resulting mixture
was stirred at –78 °C for 1 h and then was allowed to warm to
–30 °C over a 3 h period. The reaction mixture was quenched
with 10% citric acid (10 mL) and diluted with brine (100 mL).
The mixture was extracted with EtOAc (4 × 75 mL) and the
combined organic layers were dried over MgSO4 and concentrated
under reduced pressure. The residue was purified by Combi-
flash chromatography (hexane and EtOAc: gradient 0–5% during
20
12 min) to afford the desired trans-product (5.09 g, 72%). [a]D
–17.23 (c 1.178 g/dL in MeOH).
Synlett 2007, No. 3, 460–464 © Thieme Stuttgart · New York

464
J. Zhuo et al.
LETTER
General Procedure for the Simmons–Smith Cyclopropanation
Reaction: 6-Benzyl 5,7-Dimethyl (6S,7S)-5-Azaspiro[2.5]oc-
tane-5,6,7-tricarboxylate
Duan, J.; Decicco, C. P. Bioorg. Med. Chem. Lett. 2004, 14,
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To a –10 °C solution of 1,2-dichloroethane (1.00 mL) was added se-
quentially Et2Zn (1.00 M in 1,2-dichloroethane, 0.40 mL) and TFA
(0.5 M in 1,2-dichloroethane, 0.80 mL) slowly over ca. 10 min. Af-
ter the reaction mixture was stirred at –10 °C for 15 min, a solution
of CH2ICl (1.00 M in 1,2-dichloroethane, 0.40 mL) was added.
After 10 min, a solution of 2-benzyl 1,3-dimethyl 5-methylenepip-
eridine-1,2,3-tricarboxylate (34.7 mg, 0.000100 mol) in 1,2-dichlo-
roethane (1.0 mL) was added and the reaction mixture was allowed
to warm slowly to r.t. for 18 h. According to LCMS data the starting
material was converted into the desired product {ca. 61%; LCMS:
362.2 [M + H]+}. To drive the progression of the reaction, Et2Zn
(1.00 M in 1,2-dichloroethane, 0.40 mL) and CH2ICl (1.00 M in
1,2-dichloroethane, 0.80 mL) were added. After stirring the reaction
mixture at r.t. for an additional 18 h, 80% of the starting material
was converted into the desired product. This final step was repeated
twice more, at the time points of 24 h and 40 h. After the starting
material was almost consumed (by HPLC and LCMS), the mixture
was diluted with EtOAc (40 mL) and washed with sat. NH4Cl solu-
tion (15 mL) and brine (15 mL). The organic layer was dried over
Na2SO4, filtered, and concentrated under reduced pressure. The res-
idue was purified by Combiflash chromatography eluting with
EtOAc–hexane to afford the desired product (25 mg, 72%).
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Acknowledgment
The authors wish to thank Mei Li, Jin Liu, and Laurine Galya for va-
rious technical support.
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Synlett 2007, No. 3, 460–464 © Thieme Stuttgart · New York