Synthesis of (3S)-(tert-butyldimethylsilyloxy)methylcyclopentan-1-one as a key intermediate of sphingosine 1-phosphate-1 receptor agonists

Article abstract of DOI:10.1016/j.tetasy.2013.02.015

Herein we report the asymmetric synthesis of (3S)-(tert- butyldimethylsilyloxy)methylcyclopentan-1-one (S)-3 as a practical chiral synthon for a wide range of pharmaceutical and/or natural products, using Lipshutz's asymmetric copper-catalyzed conjugate reduction. This method makes it feasible to prepare a conformationally constrained cyclopentane analogue 12, which is one of the key intermediates for the synthesis of novel sphingosine 1-phosphate-1 receptor agonists.

Full text of DOI:10.1016/j.tetasy.2013.02.015

Tetrahedron: Asymmetry 24 (2013) 449–456
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Synthesis of (3S)-(tert-butyldimethylsilyloxy)methylcyclopentan-1-one
as a key intermediate of sphingosine 1-phosphate-1 receptor agonists
Masayoshi Asano, Tsuyoshi Nakamura, Yukiko Sekiguchi, Yumiko Mizuno, Takahiro Yamaguchi,
⇑
Takeshi Kuroda, Kazuhiko Tamaki, Takahide Nishi
Lead Discovery & Optimization Research Laboratories I, Daiichi-Sankyo Co., Ltd, 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 20 January 2013
Accepted 25 February 2013
Herein we report the asymmetric synthesis of (3S)-(tert-butyldimethylsilyloxy)methylcyclopentan-1-one
(S)-3 as a practical chiral synthon for a wide range of pharmaceutical and/or natural products, using
Lipshutz’s asymmetric copper-catalyzed conjugate reduction. This method makes it feasible to prepare
a conformationally constrained cyclopentane analogue 12, which is one of the key intermediates for
the synthesis of novel sphingosine 1-phosphate-1 receptor agonists.
Ó 2013 Elsevier Ltd. All rights reserved.
1. Introduction
with its biological activity, and that the (R)-configuration was
essential for S1P1 agonistic activity. In fact, the geometric optimi-
Enantiomeric 3-hydroxymethylcyclopentan-1-one
1
and its
zations of the scaffolds 9 and 11 were carried out using the semi-
empirical molecular orbital method PM3 from the program
SPARTAN. It was found that both compounds have very similar
conformations, as shown in Figure 3. Therefore, we focused our
attention on the asymmetric synthesis of cyclopentane analogues
such as 11. For the synthesis of highly enantiomerically pure ana-
logues, compounds 12 and (S)-3 are key intermediates (Fig. 2).
protected derivatives 2 and 3 are versatile synthetic precursors
due to the ubiquitous existence of a cyclopentane skeleton in the
structures of pharmaceuticals and biologically active natural
products (Fig. 1). For example, (R)-1 is known as a practical inter-
mediate for the synthesis of carbocyclic nucleosides such as carbo-
cyclic-ddA 41 and carbovir 52 which have been reported to show
high activity against HIV and hepatitis B virus, respectively.3 In
the total synthesis of Shahamin K 6 achieved by Lebsack et al.,4
(S)-2 was converted into cyclopentenone 7, which played an
important role in constructing the complicated C8–C14
r-bond.
O
N
NH2
In addition, both (R)-1 and (S)-1 are expected to be alternative chi-
ral intermediates for already-established racemic synthetic routes
such as the synthesis of ( )-methyl epijasmonate 8.5
N
N
N
N
NH
N
O
RO
∗
NH2
N
HO
During our recent research into therapeutics for autoimmunity,
we have focused on a series of sphingosine 1-phosphate (S1P)
receptor-1 (S1P1) agonists. S1P mediates wide-ranging physiologi-
cal processes such as cell differentiation, morphogenesis, angio-
genesis, and motility, among other, through its interaction with
the five-membered S1P receptors (S1P1–S1P5).6 S1P1 agonists7
have attracted attention as immunosuppressants induced by a un-
ique mechanism of lymphocyte trafficking.8 Encouraged by our
success in identifying several S1P1 agonists, including CS-0777
9,9 a promising clinical candidate, we continued to investigate
new S1P1 agonists based on the structure of the Abbott compound
(1R,3S)-107c (Fig. 2). Preliminary studies indicated that the stereo-
chemistry of the quaternary carbon center was closely associated
HO
1; R = H
2; R = Ac
3;
R = TBS
5
4
OAc
O
O
14
O
H
AcO
H
8
OAc
O
MeO2C
SO2Ph
H
8
7
6
Figure 1. Structures of 3-hydroxymethylcyclopentan-1-one 1, its protected deriv-
atives 2 and 3, carbocyclic-ddA 4, carbovir 5, Shahamin K 6 and its intermediate 7,
and methyl epijasmonate 8.
⇑
Corresponding author. Tel.: +81 3 3492 3131; fax: +81 3 5436 8563.
E-mail address: nishi.takahide.xw@daiichisankyo.co.jp (T. Nishi).
0957-4166/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetasy.2013.02.015

450
M. Asano et al. / Tetrahedron: Asymmetry 24 (2013) 449–456
Me
H2N
HO
N
(R)
HO
(R) ( )
S
NH2
O
Me
Me
Me
10
9
(CS-0777)
NBoc
O
H2N
TBSO
O
HO
(R) (S)
N
N
Me
O
Me
12
(S)-3
11
Figure 2. Structures of CS-0777 9, Abbott compound 10 and retrosynthesis of cyclopentane analogue 11.
Me
PhO2S
PhO2S
EtO2C
a
b, c
HO
HO
N
(R)
PhO2S
CO2Et
NH2
Me
TBSO
16
17
15
H2N
(R) (S)
PhO2S
N
f
d, e
O
O
TBSO
Me
TBSO
Figure 3. A stereoview of the superimposition of stable conformations of the
scaffold of (2R)-9 (gray) and (1R,3S)-11 (green).
19
18
Scheme 2. Reagents and conditions: (a) cis-1,4-Dichloro-2-butene, LiH, DMF; (b)
LiAlH4, THF; (c) TBSCl, imidazole, DMF, 87% over 3 steps; (d) BH3ꢀTHF, aq NaOH, aq
H2O2; (e) TEMPO, KBr, satd NaHCO3, aq NaOCl; (f) Et3N, THF, 77% over 3 steps.
Through an investigation of already published synthetic meth-
ods for the derivatives of 1, we found that only a couple of syn-
thetic efforts have been reported so far on its stereoselective
synthesis such as the diastereomeric separation method2a and an
asymmetric intramolecular hydroacylation protocol.1 Considering
the usefulness as a chiral synthon of 1 as well as the necessity
originating out of our exploration research on S1P1 agonists, we
implemented research on the practical synthesis of a tert-butyldi-
methylsilyl (TBS)-protected derivative 3.2,10 Herein we report a
new synthetic method for chiral compound 3 along with the syn-
thesis of the key intermediate 12 and our novel S1P1 agonist 11.11
commercially available methyl phenylsulfonylacetate 15,
cyclopentene 16 was synthesized by the reaction with cis-1,4-di-
chloro-2-butene.13 Subsequent reduction of the ethyl ester and
TBS-protection of the resultant primary alcohol provided interme-
diate 17 in good yield (87% yield over 3 steps). Next, compound 17
was subjected to hydroboration and catalytic TEMPO-oxidation to
afford cyclopentenone 18. The b-elimination of the phenylsulfonyl
group in 18 proceeded smoothly by heating with triethylamine in
THF to provide enone 19 in good yield (77%, over 3 steps from 17).
Next, we focused on identifying and establishing conditions for
the asymmetric copper-catalyzed conjugate reduction using 19.
The results are summarized in Table 1. First, we tested the typical
conditions described by Buchwald et al.,14 using (S)-p-tol-BINAP as
a chiral ligand and polymethylhydrosiloxane (PMHS) as a stoichi-
ometric reductant. The reaction proceeded sluggishly at room tem-
perature (30 h), resulting in the production of the (S)-enriched
product (85% ee) along with an unsatisfactory chemical yield
(38%) (run 1). In order to improve the yield and selectivity, the sec-
ond trial was carried out by choosing a lower temperature (0 °C)
and a longer reaction time (67 h at 0 °C and 24 h at room temper-
ature). As expected, a higher yield (73%) was obtained, however the
results were disappointing since the enantioselectivity decreased
(run 2). We then tested the condition described by Lipshutz
et al., in which (S)-DTBM-SEGPHOS was used as the chiral ligand.15
Using this method, both good yield (96%) and high enantiomeric
excess (95% ee) were finally attained (run 3). The degree of asym-
2. Results and discussion
Since resolution is one of the easiest techniques to simulta-
neously prepare both enantiomers of a racemate, we evaluated
the resolution of racemic rac-3. As shown in Scheme 1, racemic
3-tert-butyldimethylsilyloxymethylcyclopentan-1-one rac-3 was
prepared easily by successive subjection of the commercially avail-
able cyclopentene 13 to LAH-reduction, TBS-protection, hydrobo-
ration, and TEMPO-oxidation in good yield (85% over 4 steps).
Although rac-3 could be separated on a small scale by chiral HPLC
analysis, the difference in retention times was not enough to pre-
pare both pure enantiomers despite attempts to optimize the sep-
aration conditions (data not shown).
Next we turned our attention to an asymmetric synthetic
approach. In order to obtain both enantiomers efficiently, an
asymmetric conjugate reduction of enone 1912 was utilized. The
synthetic route to enone 19 is shown in Scheme 2. Starting from
c, d
a, b
MeO2C
TBSO
O
TBSO
14
13
-3
rac
inseparable by preparative
chiral column chromatography
Scheme 1. Reagents and conditions: (a) LiAlH4, THF; (b) TBSCl, imidazole, DMF; (c) BH3–THF, aq NaOH, aq H2O2; (d) TEMPO, KBr, satd NaHCO3, aq NaOCl, 85% over 4 steps.

M. Asano et al. / Tetrahedron: Asymmetry 24 (2013) 449–456
451
Table 1
O
O
see below
O
TBSO
TBSO
TBSO
or
3
(R)-
19
3
(S)-
Run
Ligands
Other conditions
Temp, Time
rt (30 h)
0 °C (67 h), rt (24 h)
rt (3 h)
Yield (%)
ee (%) (config)a
1
2
3
4
(S)-tol-BINAP (5 mol %)
(S)-tol-BINAP (5 mol %)
(S)-DTBM-SEGPHOS (1 mol %)
PMHS, CuCI, t-BuONa
PMHS, CuCI, t-BuONa
PMHS, Cu(OAc)2-H2O
PMHS, Cu(OAc)2-H2O
38
73
96
92
85 (S)
70 (S)
95 (S)
95 (R)
(R)-DTBM-SEGPHOS (1 mol %)
rt (3 h)
a
The enantiopurity was determined by HPLC analysis after conversion into its benzoyl ester, (see Section 4).
metric induction was assessed upon the conversion of 3 into the
benzoyl ester and analysis with a Chiralcel OJ HPLC column
hydrolysis under basic conditions by using aqueous K2CO3 in
MeOH to afford 23, quantitatively. The subsequent rhodium-cata-
lyzed C–H bond amination developed by Du Bois16 via a rho-
(4.6
u
ꢁ 150 mm) (eluent, 80:20 n-hexane–ethanol mixture; flow
rate, 1.5 mL/min; tR of (S)-isomer, 8.1 min; tR of (R)-isomer,
7.2 min). This synthetic method also led to the preparation of
(R)-3 with the opposite configuration by using (R)-DTBM-SEGPHOS
instead of (S)-DTBM-SEGPHOS as the chiral ligand for the copper-
catalyzed conjugate reduction (run 4).
dium-mediated
nitrene
mechanism
with
retained
stereochemistry provided oxazolidinone 24 (72%). The ratio of 24
to its minor diastereomer, which was derived from the hydrogena-
tion reaction, was confirmed to be 15:1 by 1H NMR. Oxazolidinone
24 was treated with Boc2O under basic conditions to provide 25 in
71% yield. Subsequent hydrolysis of oxazolidinone 25 gave the Boc-
protected aminoalcohol 26, which was treated with 2,2-dime-
thoxypropane in the presence of BF3ꢀEt2O to afford acetonide 27
in good yield (94% and 90%, respectively). During the purification
of 27 by silica gel column chromatography, the aforementioned
minor diastereomer was completely removed. Deprotection of
the tosyl group of 27 proceeded under basic conditions to afford
the pyrrole in 98% yield, which was methylated by treatment with
KHMDS and MeI to provide the key intermediate 12 (98%).
On the other hand, the 15:1 mixture of 24 and its diastereomer
was recrystallized from ethanol to afford a single crystal of 24 with
a moderate recovery rate (ca. 60%). The structure and absolute con-
figuration of 24 was confirmed by single crystal X-ray analysis as
shown in Figure 4.
With the chiral synthon (S)-3 in hand, we turned our attention
to a conformationally constrained key intermediate (1R,3S)-12 for
purposes of synthesizing novel pyrrole-based S1P1 agonists
(Scheme 3). As mentioned in the introduction, Abbott and Virginia
University synthesized a series of conformationally constrained
S1P1 agonists by using Iridium catalyzed diastereoselective hydro-
genation and Du Bois amination as the key steps.7c We used their
synthetic route for our derivatization with a slight modification.
Triflation of (S)-3 proceeded smoothly by successive treatment
with NaHMDS and N,N-bis(trifluoromethylsulfonyl)aniline in THF
to afford the mixture of regioisomers of enol triflate 20 in good
yield (91%). A Suzuki coupling reaction of triflate 20 with commer-
cially available boron ester 30 upon treatment with K2CO3 and a
catalytic amount of Pd(PPh)4 in 1,4-dioxane gave the coupling
product, quantitatively. Subsequent deprotection of the TBS group
was performed by treatment with TBAF in THF to afford alcohol 21
in good yield (98%). Crabtree’s catalyst efficiently hydrogenated the
olefin from the same face as the hydroxymethyl group to afford
cyclopentane 22 with (S) stereochemistry at the pyrrole ring in
95% yield.7c The primary hydroxyl group of 22 was carbamoylated
by treatment with trichloroacetyl isocyanate in CH2Cl2 followed by
The following synthetic route to a representative pyrrole-based
S1P1 agonist 11 is shown in Scheme 4. Acylation of 12 with
5-(p-tolyl)pentanoyl chloride at the 5-position of the pyrrole ring
was carried out in the presence of 1-Me-imidazole in toluene
and acetonitrile at 80 °C to afford the enol ester 28. The enol ester
moiety was cleaved by saponification with aqueous NaOH in
THF–MeOH to afford 29 in good yield (88% over 2 steps). After
a
b, c
d
O
OTf
TBSO
HO
h
TBSO
HO
N
Ts
3
20
21
(S)-
O
NH2
e
f
NR
N
O
O
N
O
N
Ts
Ts
Ts
22
23
24
; R = H
g
25; R = Boc
BocHN
HO
NBoc
i
N
O
N
R
Ts
26
27; R = Ts
12; R = Me
j, k
Scheme 3. Reagents and conditions: (a) NaHMDS, PhNTf2, THF, 91%; (b) 1-(p-toluenesulfonyl)pyrrole-2-boronic acid pinacol ester 30, Pd(PPh3)4, aq K2CO3, 1,4-dioxane,
quant.; (c) TBAF, THF, 98%; (d) H2, Crabtree’s catalyst, CH2Cl2, 95%.; (e) Cl3CC(O)NCO, CH2Cl2 then K2CO3, MeOH–H2O, quant.; (f) PhI(OAc)2, MgO, Rh2(esp)2, benzene, 72%; (g)
Boc2O, Et3N, DMAP, CH2Cl2, 71%; (h) K2CO3, MeOH–H2O, 94%; (i) 2,2-dimethoxypropane, BF3-Et2O, CH2Cl2, 90%; (j) aq NaOH, EtOH–dioxane, 98%; (k) MeI, KHMDS, THF, 98%.

452
M. Asano et al. / Tetrahedron: Asymmetry 24 (2013) 449–456
spectrophotometer, and the peaks were recorded in cmꢂ1. The
mass spectra were recorded on a JEOL JMS-AX505H. Optical rota-
tions were measured on an Autopol V Plus (Rudolph Research Ana-
lytical, Hackettstown, NJ). TLC analysis was performed on 60F254
plates. Column chromatography was performed on Silica gel 60
(Merck, 230–400) or Silica gel 60 N (Kanto Chemical, spherical,
neutral, 40–50 lm).
4.2. ( )-3-(tert-Butyldimethylsilyloxy)methylcyclopentan-1-one
rac-3
To a suspension of LiAlH4 (15.0 g, 396 mmol) in THF (300 mL)
was slowly added a solution of methyl cyclopent-3-ene-1-carbox-
ylate 13 (50.0 g, 396 mmol) in THF (200 mL) at 0 °C. After stirring
for 30 min at 0 °C, the reaction mixture was quenched by the addi-
tion of water (15 mL), aqueous 15% NaOH solution (15 mL), and
water (40 mL). To this was added Et2O (100 mL) and the suspen-
sion was stirred for 1 h. Then, the resulting solid was filtered and
the filtrate was concentrated in vacuo.
To a mixture of residue and imidazole (40.4 g, 594 mmol) in
DMF (300 mL) was added TBSCl (65.7 g, 436 mmol) at room tem-
perature. After completion of the reaction by adding further TBSCl
(13.2 g, 88 mmol) in two portions within 1 h, the mixture was
poured into water (300 mL) and extracted with n-hexane. The
combined organic layers were washed with brine, dried over
MgSO4, filtered and concentrated in vacuo. The residue was puri-
fied by flash column chromatography (silica gel, n-hexane/EtOAc
1:0 to 95:5) to afford 79.4 g of the colorless oil product 14.
To a solution of 14 in THF (300 mL) was added BH3ꢀTHF (205 ml,
1.09 M in THF, 224 mmol) at 0 °C over 15 min and the mixture was
stirred for 1 h at 0 °C. To the resulting mixture was slowly added
aqueous NaOH (2.0 M, 112 mL, 224 mmol) over 30 min and succes-
sively added aqueous 30% H2O2 (34 mL, 300 mmol) over 20 min.
After evaporating to 2/3 volume, the mixture was poured into
water (300 mL) and extracted with Et2O. The combined organic
layers were washed with brine, dried over MgSO4, filtered and con-
centrated in vacuo.
The residue was dissolved in CH2Cl2 (300 mL) and to this was
added satd NaHCO3 (100 mL), TEMPO (1.2 g, 7.5 mmol), and KBr
(4.4 g, 37 mmol). To the mixture was added aqueous NaOCl
(460 mL, >5.0% as available chlorine) at 0 °C. After stirring at 0 °C
for 1 h, the mixture was poured into water and extracted with
Et2O. The combined organic layers were washed with brine, dried
over MgSO4, filtered and concentrated in vacuo. The residue was
purified by flash column chromatography (silica gel, n-hexane/
EtOAc 97:3 to 92:8) to afford the title compound rac-3 (77.0 g,
337 mmol, 85% from 13) as a yellow oil. 1H NMR (400 MHz, CDCl3)
Figure 4. X-ray ORTEP of compound 24 hydrogen (white), carbon (black), oxygen
(red), nitrogen (blue), and sulfur (yellow).
simultaneous removal of both the Boc and acetonide groups with
TFA followed by salification with fumaric acid, target product 11
was obtained as a hemifumarate in 58% yield.
3. Conclusion
In conclusion, we have established an alternative and practical
synthetic method for (S)-3 using an asymmetric copper-catalyzed
conjugate reduction protocol. We have also demonstrated another
application of (S)-3 in preparing optically active cyclopentane
derivative 12, which is a key intermediate for the conformationally
constrained novel sphingosine 1-phosphate-1 receptor agonist 11.
These synthetic procedures allow for broad structural variation
and provide essential tools for evaluating the structure–activity
relationships of compound 11.
4. Experimental
4.1. General
1H NMR and 13C NMR spectra were recorded on a Varian Mer-
cury 400 or 500 spectrometer with tetramethylsilane as an internal
reference. The infrared spectra were recorded on a Jasco FT/IR-830
Me
NBoc
NBoc
a
b
O
N
O
N
O
O
Me
Me
Me
12
28
Me
Me
H2N
NBoc
c
HO
O
N
N
O
O
Me
Me
0.5 fumaric acid
11
29
Scheme 4. Reagents and conditions: (a) 5-(p-Tolyl)pentanoyl chloride, 1-Me-imidazole, toluene–CH3CN, 80 °C; (b) aq NaOH, THF–MeOH, 50 °C, 88% over 2 steps.; (c) TFA,
CH2Cl2 then fumaric acid (0.5 equiv), 58%.

M. Asano et al. / Tetrahedron: Asymmetry 24 (2013) 449–456
453
d 3.65–3.61 (m, 2H), 2.46–2.25 (m, 3H), 2.22–2.00 (m, 3H),
1.82–1.70 (m, 1H), 0.89 (s, 9H), 0.05 (s, 6H); 13C NMR (500 MHz,
CDCl3) d 219.6, 65.8, 41.5, 38.9, 38.0, 25.8, 18.2, ꢂ5.5; IR (ATR):
2953, 2929, 2856, 1742, 1254, 1097, 833, 774 cmꢂ1; MS (CI+)
m/z: 229 (M+H)+; HRMS (CI+): m/z calcd for C12H25O2Si, 229.1624
[M+H]+; found 229.1621.
washed with water and brine, dried over MgSO4, filtered and con-
centrated in vacuo. The residue was recrystallized from cold hex-
ane to give the title compound 19 (40.7 g, 180 mmol, 62%) as a
white solid. The filtrate was evaporated and purified by flash col-
umn chromatography (silica gel, n-hexane/EtOAc 20:1 to 2:1) to af-
ford the title compound 19 (10.0 g, 44 mmol, 15%). Total 50.7 g,
77% yield. Mp 68.7–69.0 °C; 1H NMR (400 MHz, CDCl3)
d
4.3. tert-Butyl(dimethyl){[1-(phenylsulfonyl)cyclopent-3-en-1-
yl]methoxy}silane 17
6.19–6.15 (m, 1H), 4.47 (s, 2H), 2.59–2.53 (m, 2H), 2.47–2.42 (m,
2H), 0.93 (s, 9H), 0.10 (s, 6H); 13C NMR (500 MHz, CDCl3) d 209.2,
181.4, 128.3, 63.2, 35.0, 27.8, 25.7, 18.2, ꢂ5.5; IR (KBr): 2957,
To a solution of methyl phenylsulfonylacetate 15 (76.0 g,
333 mmol) in DMF (400 mL) was added LiH (6.6 g, 833 mmol) at
0 °C, and warmed to room temperature. After stirring for 0.5 h,
the reaction mixture was cooled to 0 °C again and cis-1,4-di-
chloro-2-butene (42 mL, 400 mmol) was added. Next, the reaction
mixture was warmed to room temperature. After stirring for 4 h,
the reaction was quenched with satd NH4Cl (50 mL). The resulting
mixture was poured into water (300 mL) and extracted with Et2O.
The combined organic layers were washed with water, brine, dried
over MgSO4, filtered and concentrated in vacuo.
To a suspension of LiAlH4 (13.0 g, 333 mmol) in THF (300 mL) at
0 °C was slowly added a solution of the crude product in THF
(200 mL) dropwise over 0.5 h. After stirring for 1 h at 0 °C, the reac-
tion was quenched with water (13 mL), aqueous NaOH (5.0 M,
13 mL, 63 mmol), and water (38 mL). To the resulting mixture
was added Et2O (200 mL) and the mixture was stirred for several
hours. The resulting mixture was filtered through Celite and the fil-
trate was evaporated in vacuo. The residue was diluted with tolu-
ene (100 mL) and azeotropically evaporated in vacuo.
To a solution of the obtained crude product and imidazole
(34.0 g, 500 mmol) in DMF (300 mL) was added TBSCl (50.0 g,
333 mmol) at room temperature. After stirring for 15 h, the reac-
tion was quenched with water (30 mL). The reaction mixture was
poured into water (300 mL) and extracted with Et2O. The extract
was washed with water and brine, dried over MgSO4, filtered and
concentrated in vacuo. The residue was purified by flash column
chromatography (silica gel, n-hexane/EtOAc 19:1 to 17:3) to afford
the title compound 17 (102.0 g, 289 mmol, 87%) as a colorless oil.
1H NMR (500 MHz, CDCl3) d 7.94–7.89 (m, 2H), 7.61 (t, 2H,
J = 7.7 Hz), 7.50 (t, 1H, J = 7.7 Hz), 5.57 (s, 2H), 3.84 (s, 2H), 3.13
(d, 2H, J = 15.1 Hz), 2.46 (d, 2H, J = 15.1 Hz), 0.76 (s, 9H), ꢂ0.08
(s, 6H). MS (EI+) m/z: 285 (M+).
2929, 1699, 1626, 1432, 1265, 1142, 1077, 852, 843, 777 cmꢂ1
;
MS (CI+) m/z: 227 (M+H)+; HRMS (CI+): (m/z) calcd for C12H23O2Si,
227.1467 [M+H]+; found 227.1470.
4.5. (3S)-3-(tert-Butyldimethylsilyloxy)methylcyclopentan-1-
one (S)-3
A mixture of Cu(OAc)2–H2O (8.8 mg, 0.044 mmol, Kanto Chem-
ical) and (S)-DTBM-SEGPHOS (52.1 mg, 0.044 mmol, STREM
CHEMICALS) in degassed toluene (5.0 mL) was purged with Ar
thoroughly, and stirred at room temperature for 2 h under an Ar
atomosphere. To this was added PMHS (0.53 mL, 8.8 mmol, Alfa
Aesar) and the resulting mixture was stirred at room temperature
for 1 h. Separately, a solution of 19 (1.0 g, 4.4 mmol) in degassed
toluene (6.0 mL) was purged with Ar thoroughly and this substrate
solution was added to the above solution of reagents by a cannula.
The resulting mixture was stirred at room temperature for 3 h. The
reaction was diluted with THF (5.0 mL) and quenched by adding
aqueous NaOH solution (3.0 M, 5.0 mL). After stirring at room tem-
perature for 2 h, the reaction mixture was poured into water
(5.0 mL) and extracted with Et2O. The combined organic layers
were washed with brine, dried over Na2SO4, filtered and concen-
trated in vacuo. The residue was purified by flash column chroma-
tography (silica gel, n-hexane/EtOAc 1:0 to 4:1) to afford the title
compound (S)-3 (0.97 g, 4.2 mmol, 96% yield, 95.2% ee) as a color-
less oil. ½a 2D5
ꢃ
¼ ꢂ37:3 (c 1.06, CHCl3); 1H NMR, 13C NMR and IR are
same as ( )-3. MS (ESI) m/z: 229 (M+H)+; HRMS (ESI): m/z calcd for
C
12H25O2Si, 229.1624 [M+H]+; found 229.1621.
The enantiopurity was determined after conversion of the ob-
tained 3 into its benzoyl ester as follows.
To a solution of 3 (300 mg, 1.31 mmol) in THF (4.0 mL) was
added TBAF (1.0 M in THF, 1.57 mL, 1.57 mmol) and the mixture
was stirred at room temperature for 1 h. To the resulting mixture
were successively added DMAP (19.3 mg, 0.16 mmol), Et3N
(0.95 mL, 6.8 mmol), and BzCl (0.46 mL, 3.94 mmol) and the mix-
ture was stirred at room temperature overnight. The reaction mix-
ture was poured into water and extracted with Et2O. The combined
organic layers were washed with brine, dried over Na2SO4, filtered
and concentrated in vacuo. The residue was purified by flash col-
umn chromatography (silica gel, n-hexane/CH2Cl2 1:1 to 0:1 to
CH2Cl2/EtOAc = 95:5) to afford the benzoyl ester (273.9 mg,
1.25 mmol, 96%) as a colorless oil. 1H NMR (400 MHz, CDCl3) d
8.03 (d, 2H, J = 6.6 Hz), 7.62–7.54 (m, 1H), 7.51–7.41 (m, 2H),
4.48–4.22 (m, 2H), 2.82–2.65 (m, 1H), 2.55–2.18 (m, 4H), 2.12
(dd, 1H, J = 17.8, 10.0 Hz), 1.89–1.75 (m, 1H). The enantiopurity
4.4. 3-(tert-Butyldimethylsilyloxy)methylcyclopent-2-en-1-one
19
To a solution of 17 (103.0 g, 292 mmol) in THF (300 mL) was
added BH3ꢀTHF (160 mL, 1.0 M in THF, 160 mmol) at 0 °C over
25 min and the mixture was stirred for 1 h at 0 °C. To the resulting
mixture was slowly added aqueous NaOH (2.0 M, 85 mL,
170 mmol) and successively added aqueous 35% H2O2 (29 mL,
300 mmol). After stirring for 1 h, the mixture was poured into
water (300 mL) and extracted with Et2O. The combined organic
layers were washed with brine, dried over MgSO4, filtered and con-
centrated in vacuo.
The residue was diluted with CH2Cl2 (300 mL) and to this was
added satd NaHCO3 (100 mL), KBr (3.5 g, 29 mmol), and TEMPO
(0.9 g, 5.8 mmol). To the mixture was added aqueous NaOCl
(350 mL, >5.0% as available chlorine) at 0 °C. After stirring at 0 °C
for 1 h, the mixture was poured into water (100 mL) and extracted
with Et2O. The combined organic layers were washed with brine,
dried over MgSO4, filtered and concentrated in vacuo.
was determined by HPLC with
(4.6
rate, 1.5 mL/min; tR of (S)-isomer, 8.1 min; tR of (R)-isomer,
a
Chiralcel OJ column
u
ꢁ 150 mm); eluent, 80:20 n-hexane–ethanol mixture; flow
7.2 min), 25 °C, UV 210 nm.
4.6. (3R)-3-(tert-Butyldimethylsilyloxy)methylcyclopentan-1-
one (R)-3
A mixture of residue and Et3N (81 mL, 585 mmol) in THF
(300 mL) was heated at 50 °C for 2 h. After cooling to room temper-
ature, the mixture was poured into water (300 mL). The mixture
was extracted with Et2O and the combined organic layers were
The title compound (R)-3 (0.93 g, 4.1 mmol, 92% yield, 95.3% ee)
as a colorless oil was synthesized by conducting a reaction similar
to the one mentioned in Section 4.5 using Cu(OAc)2–H2O (8.8 mg,

454
M. Asano et al. / Tetrahedron: Asymmetry 24 (2013) 449–456
0.044 mmol), (R)-DTBM-SEGPHOS (52.1 mg, 0.044 mmol) and
PMHS (0.53 mL, 8.8 mmol) in toluene (5 mL), and 17 (1.0 g,
(m, 0.3H), 3.69–3.50 (m, 2H), 3.06–2.96 (m, 0.7H), 2.70–2.40
(m, 2.6H), 2.39 (s, 3H), 2.33–2.22 (m, 0.3H), 2.12–2.00 (m, 0.7H),
1.80–1.69 (m, 0.7H), 1.51 (br s, 1H); MS (FAB+) m/z: 318 ((M+H)+).
4.42 mmol) in toluene (6 mL). ½a D25
ꢃ
¼ þ36:8 (c 1.07, CHCl3); 1H
NMR, 13C NMR and IR are the same as ( )-3. MS (CI+) m/z: 229
(M+H)+; HRMS (CI+): m/z calcd for C12H25O2Si, 229.1624 [M+H]+;
found 229.1617.
4.9. [(1S,3S)-3-{1-[(4-Methylphenyl)sulfonyl]-1H-pyrrol-2-
yl}cyclopentyl]methanol 22
4.7. A mixture of (3S)-3-[(tert-butyldimethylsilyloxy)
methyl]cyclopent-1-en-1-yl trifluoromethanesulfonate and
(4S)-4-[(tert-butyldimethylsilyloxy)methyl]cyclopent-1-en-1-yl
trifluoromethanesulfonate 20
A solution of 21 (16.3 g, 51.4 mmol) and Crabtree’s catalyst
(1.3 g, 1.5 mmol) in CH2Cl2 (1000 mL) was degassed and saturated
with hydrogen gas, and the mixture was stirred at room tempera-
ture for 7.5 h. The solvent was removed in vacuo and the residue
was purified by flash column chromatography (neutralized silica
gel, n-hexane/EtOAc 2:1 to 1:1) to afford the title compound 22
(15.6 g, 48.8 mmol, 95%) as an orange oil in a diastereomeric ratio
of 15 to 1. 1H NMR (400 MHz, CDCl3) d 7.60 (dd, 2H, J = 8.6, 2.0 Hz),
7.28 (dd, 2H, J = 8.6, 2.2 Hz), 7.28–7.25 (m, 1H), 6.21 (t, 1H,
J = 3.3 Hz), 6.09–6.03 (m, 1H), 3.57–3.46 (m, 2H), 3.38 (quint, 1H,
J = 8.2 Hz), 2.41 (s, 3H), 2.33–2.05 (m, 1H), 1.98–1.85 (m, 2H),
1.75–1.46 (m, 4H), 1.37–1.27 (m, 1H); MS (FAB+) m/z: 320
((M+H)+).
To a solution of NaHMDS (1.0 M in THF, 122 mL, 122 mmol) in
THF (60 mL) was added dropwise a solution of (S)-3 (23.1 g,
101 mmol, >95% ee) in THF (40 mL) at ꢂ78 °C. After stirring for
30 min at ꢂ78 °C, PhNTf2 (37.5 g, 105 mmol) was added. The
resulting mixture was warmed to 0 °C and stirred for 1 h. The reac-
tion was quenched by the addition of satd NH4Cl (20 mL) at 0 °C.
The mixture was poured into water (200 mL) and extracted with
n-hexane. The combined organic layers were washed with brine,
dried over MgSO4, filtered and concentrated in vacuo. The residue
was purified by flash column chromatography (neutralized silica
gel, n-hexane/EtOAc 50:1 to 20:1) to afford the title compound
20 (32.7 g, 91 mmol, 91%) 1H NMR (400 MHz, CDCl3) d: 5.65–5.59
(m, 0.7H), 5.59–5.53 (m, 0.3H), 3.68–3.39 (m, 2H), 2.98–2.86 (m,
0.7H), 2.70–2.35 (m, 2.6H), 2.22–2.04 (m, 1H), 1.78–1.66 (m,
0.7H), 0.89 (s, 9H), 0.05 (s, 6H).
4.10. [(1S,3S)-3-{1-[(4-Methylphenyl)sulfonyl]-1H-pyrrol-2-
yl}cyclopentyl]methyl carbamate 23
To a solution of 22 (15.6 g, 48.8 mmol) in CH2Cl2 (200 mL) was
added trichloroacetylisocyanate (7.0 mL, 58.5 mmol) at 0 °C. After
stirring for 30 min at 0 °C, the mixture was concentrated in vacuo.
The residue was diluted with MeOH (300 mL) and THF (100 mL). To
this were added water (50 mL) and K2CO3 (33.7 g, 244 mmol) at
0 °C and the mixture was warmed to room temperature. After stir-
ring for 2 h, the mixture was filtered with a Celite pad and the fil-
trate was concentrated in vacuo. The residue was poured into
water (100 mL) and the mixture was extracted with EtOAc. The
combined organic layers were washed with water and brine, dried
over Na2SO4, filtered and concentrated in vacuo. The residue was
purified by flash column chromatography (neutralized silica gel,
n-hexane/EtOAc 2:1 to 1:1) to afford the title compound 23 quan-
titatively as a light yellow oil in a diastereomeric ratio of 15 to 1. 1H
NMR (400 MHz, CDCl3) d:7.61 (d, 2H, J = 8.6 Hz), 7.32–7.23 (m, 3H),
6.20 (t, 1H, J = 3.3 Hz), 6.08–6.02 (m, 1H), 4.59 (br s, 2H), 3.96–3.92
(m, 2H), 3.45 (quint, 1H, J = 8.2 Hz), 2.42–2.15 (m, 1H), 2.41 (s, 3H),
1.98–1.86 (m, 2H), 1.73–1.45 (m, 3H), 1.37–1.25 (m, 1H); MS
(FAB+) m/z: 363 ((M+H)+).
4.8. A mixture of [(1S)-3-{1-[(4-methylphenyl)sulfonyl]-1H-
pyrrol-2-yl}cyclopent-2-en-1-yl]methanol and [(1S)-3-{1-[(4-
methylphenyl)sulfonyl]-1H-pyrrol-2-yl}cyclopent-3-en-1-
yl]methanol 21
A mixture of 20 (18.9 g, 52.4 mmol), 1-(p-toluenesulfonyl)pyr-
role-2-boronic acid pinacol ester (20.0 g, 57.7 mmol), Pd(PPh3)4
(1.8 g, 1.6 mmol) and K2CO3 (14.5 g, 105 mmol) in water (50 mL),
and 1,4-dioxane (100 mL) was heated at 50 °C for 1 h. After cooling
to room temperature, the reaction mixture was poured into water
and extracted with Et2O. The combined organic layers were
washed with brine, dried over Na2SO4, filtered with a Celite pad
and concentrated in vacuo. The residue was purified by flash col-
umn chromatography (neutralized silica gel, n-hexane–EtOAc
50:1 to 10:1) and concentrated in vacuo to afford the TBS-pro-
tected precursor of 21 quantitatively as a light yellow oil. 1H
NMR (400 MHz, CDCl3) d: 7.55 (d, 2H, J = 8.2 Hz), 7.37–7.33 (m,
1H), 7.22 (dd, 2H, J = 8.2, 2.5 Hz), 6.22 (t, 1H, J = 3.3 Hz),
6.11–6.05 (m, 1H), 5.84–5.80 (m, 0.7 H), 5.80–5.77 (m, 0.3H),
3.57–3.45 (m, 2H), 2.98–2.88 (m, 0.7H), 2.60–2.40 (m, 2.3H), 2.38
(s, 3H), 2.28–2.17 (m, 0.6H), 2.04–1.94 (m, 0.7H), 1.65–1.55 (m,
0.7H), 0.91 (s, 6.3H), 0.89 (s, 2.7H), 0.07 (s, 2.1H), 0.06 (s, 2.1H),
0.05 (s, 0.9H), 0.04 (s, 0.9H); MS (FAB+) m/z: 432 ((M+H)+).
Deprotection of the TBS group into 21 was conducted as
follows:
To a solution of the obtained product in THF (200 mL) was
added tetrabutylammonium fluoride (1.0 M in THF, 100 mL,
100 mmol), and the resulting mixture was stirred at room temper-
ature for 1 h. The reaction mixture was poured into water (100 mL)
and extracted with EtOAc. The combined organic layers were
washed with water and brine, dried over Na2SO4, filtered and con-
centrated in vacuo. The residue was purified by flash column chro-
matography (neutralized silica gel, n-hexane/EtOAc 4:1 to 1:1) to
afford the title compound 21 (16.3 g, 51.4 mmol, 98%) as a light
yellow oil. 1H NMR (400 MHz, CDCl3) d: 7.54 (d, 2H, J = 8.2 Hz),
7.40–7.35 (m, 0.7H), 7.35–7.30 (m, 0.3H), 7.24 (d, 2H, J = 8.2 Hz),
6.25 (t, 0.7H, J = 3.3 Hz), 6.23 (t, 0.3H, J = 3.3 Hz), 6.15–6.11
(m, 0.7H), 6.09–6.05 (m, 0.3H), 5.82–5.78 (m, 0.7H), 5.76–5.72
4.11. (5R,7S)-7-{1-[(4-Methylphenyl)sulfonyl]-1H-pyrrol-2-yl}-
3-oxa-1-azaspiro[4.4]nonan-2-one 24
A
mixture of 23 (17.7 g, 48.8 mmol), PhI(OAc)2 (20.4 g,
63.4 mmol), MgO (4.5 g, 112 mmol), and Rh2(esp)2 (1.9 g,
2.4 mmol) in anhydrous benzene (500 mL) was heated at 60 °C
for 1 h. After cooling to room temperature, the reaction mixture
was filtered with a Celite pad. The filtrate was poured into water
(100 mL) and extracted with AcOEt. The organic layer was washed
with brine, dried over Na2SO4, filtered and concentrated in vacuo.
The residue was suspended in EtOH–n-hexane = 1:1 (100 mL) and
the resulting brown solid was filtered off to afford the crude prod-
uct of the title compound 24 (9.7 g). The filtrate was concentrated
in vacuo and purified by flash column chromatography (neutral-
ized silica gel, CH2Cl2–EtOAc 5:1 to 3:1) to afford the title com-
pound 24 (3.0 g) as a white solid. Total 12.7 g, 72% yield in a
diastereomeric ratio of 15 to 1. Recrystallization of the obtained
product (500 mg) from ethanol (22 mL) provided a single crystal
of 24 (310 mg, 62% recovery rate). Mp 203.3–203.8 °C;
½
a 2D5
ꢃ
¼ ꢂ3:9 (c 1.00, DMSO); 1H NMR (400 MHz, DMSO-d6) d:
7.89 (br s, 1H), 7.73 (ddd, 2H, J = 8.6, 2.0, 2.0 Hz), 7.44 (ddd, 2H,
J = 8.6, 2.7, 2.0 Hz), 7.32 (dd, 1H, J = 3.4, 1.8 Hz), 6.28 (t, 1H,

M. Asano et al. / Tetrahedron: Asymmetry 24 (2013) 449–456
455
J = 3.4 Hz), 6.25–6.23 (m, 1H), 4.15 (s, 2H), 3.39–3.30 (m, 1H), 2.38
(s, 3H), 2.07 (dd, 1H, J = 13.1, 7.6 Hz), 1.87–1.72 (m, 3H), 1.66–1.51
(m, 2H); 13C NMR (500 MHz, DMSO-d6) d 157.7, 145.2, 138.4, 135.6,
130.3, 126.4, 122.5, 111.8, 110.8, 75.8, 63.6, 45.7, 37.0, 34.4, 31.5,
21.0; IR (KBr): 3239, 3148, 2952, 1755, 1716, 1398, 1369, 1175,
1150, 1034, 944, 821, 670, 593, 538 cmꢂ1; MS (ESI) m/z: 361
((M+H)+); HRMS (ESI): (m/z) calcd for C18H21N2O4S, 361.1222
[M+H]+; found 361.1211. Crystal data: C18H20N2O4S, monoclinic,
space group P21, a = 9.2722(3) Å, b = 7.6497(2) Å, c = 12.4878(4) Å,
poured into water (50 mL) and extracted with CH2Cl2. The com-
bined organic layers were washed with brine, dried over Na2SO4,
filtered and concentrated in vacuo. The residue was purified by
flash column chromatography (neutralized silica gel, n-hexane/
EtOAc 10:1 to 5:1). The diastereomerically impure part was
purified by additional column chromatography, repeatedly (total
of three times). These fractions were combined to afford the title
compound 27 (10.1 g, 21.2 mmol, 90%) as a white solid. 1H NMR
(400 MHz, CDCl3) d: 7.60–7.54 (m, 2H), 7.31–7.24 (m, 3H), 6.27–
6.07 (m, 2H), 3.76–3.71 (m, 1H), 3.67–3.63 (m, 1H), 3.18–3.07
(m, 1H), 2.48–2.30 (m, 1H), 2.40 (s, 3H), 2.12–1.66 (m, 4H), 1.53–
1.41 (m, 16H). MS (FAB+) m/z: 474 (M+).
b = 106.365(2)°, V = 849.86(4) Å3, Z = 2, Dc = 1.408 g/cm3,
) = 19.219 cmꢂ1. The number of reflections collected at 93 K
was 9155, of which 3025 were independent and used for structure
refinement with R1 = 0.0339, wR2 = 0.0864, and Flack
parameter = ꢂ0.015(15).
l(Cu-
Ka
4.15. tert-Butyl (5R,7S)-2,2-dimethyl-7-(1-methyl-1H-pyrrol-2-
yl)-3-oxa-1-azaspiro[4.4]nonane-1- carboxylate 12
4.12. tert-Butyl (5R,7S)-7-{1-[(4-methylphenyl)sulfonyl]-1H-
pyrrol-2-yl}-2-oxo-3-oxa-1-azaspiro[4.4] nonane-1-carboxylate
25
To a solution of 27 (10.1 g, 21.2 mmol) in EtOH (250 mL) and 1,4-
dioxane (150 mL) was added an aqueous NaOH solution (5.0 M,
169 mL, 845 mmol). The mixture was heated at reflux and stirred
for 48 h. After cooling to room temperature, the organic solvent
was removed in vacuo and the mixture was extracted with Et2O.
The combined organic layers were washed with water and brine,
dried over Na2SO4, filtered and concentrated in vacuo. The residue
was purified by flash column chromatography (neutralized silica
gel, n-hexane/EtOAc 8:1 to 4:1) to afford the detosylated precursor
(6.6 g, 20.7 mmol, 98%) as a white solid. 1H NMR (400 MHz, CDCl3)
d: 9.37 (br s, 1H), 6.70 (br s, 1H), 6.17–6.06 (m, 1H), 5.97–5.87 (m,
1H), 3.87–3.69 (m, 2H), 3.22–2.77 (m, 1H), 2.61–2.31 (m, 2H),
2.21–1.82 (m, 3H), 1.67–1.44 (m, 16H). MS (FAB+) m/z: 320 (M+).
To a solution of KHMDS (0.5 M in toluene, 45.6 mL, 22.8 mmol)
in THF (70 mL) was added dropwise a solution of the obtained pre-
cursor (6.6 g, 20.7 mmol) in THF (30 mL) at ꢂ78 °C. After stirring
for 25 min at ꢂ78 °C, MeI (2.2 mL, 35.2 mmol) was added and the
mixture was stirred for 25 min. The resulting mixture was warmed
to room temperature and stirred for 1 h. After cooling to 0 °C, the
reaction was quenched with satd NH4Cl (30 mL). The resulting
mixture was poured into water (70 mL) and extracted with EtOAc.
The combined organic layers were washed with brine, dried over
Na2SO4, filtered and concentrated in vacuo. The residue was puri-
fied by flash column chromatography (neutralized silica gel, n-hex-
ane/EtOAc 10:1 to 5:1) to afford the title compound 12 (6.8 g,
To a solution of 24 (12.7 g, 35.2 mmol) in CH2Cl2 (350 ml) were
added Et3N (12.3 mL, 87.9 mmol), Boc2O (13.8 g, 63.3 mmol), and
DMAP (429 mg, 3.5 mmol). The mixture was stirred at room tem-
perature for 1 h and the reaction was quenched by the addition
of water (10 mL). The resulting mixture was poured into water
(100 mL) and extracted with CH2Cl2. The combined organic layers
were washed with brine, dried over Na2SO4, filtered and concen-
trated in vacuo. The residue was purified by flash column chroma-
tography (neutralized silica gel, n-hexane/EtOAc 5:1 to 2:1) to
afford the title compound 25 (11.6 g, 25.2 mmol, 71%) as a white
solid in a diastereomeric ratio of 15 to 1. 1H NMR (400 MHz, CDCl3)
d: 7.55 (d, 2H, J = 8.5 Hz), 7.33–7.24 (m, 3H), 6.27–6.23 (m, 1H),
6.22–6.16 (m, 1H), 4.09 (d, 1H, J = 8.3 Hz), 3.99 (d, 1H, J = 8.3 Hz),
3.32–3.21 (m, 1H), 2.60–2.52 (m, 1H), 2.42 (s, 3H), 2.18 (t, 1H,
J = 12.5), 2.00–1.88 (m, 3H), 1.70–1.60 (m, 1H), 1.55 (s, 9H).
4.13. tert-Butyl [(1R,3S)-1-(hydroxymethyl)-3-{1-[(4-methyl-
phenyl)sulfonyl]-1H-pyrrol-2-yl}cyclopentyl] carbamate 26
To a solution of 25 (11.6 g, 25.2 mmol) in MeOH (150 mL), THF
(50 mL), and water (25 mL) was added K2CO3 (17.4 g, 126 mmol)
and the mixture was stirred at room temperature for 2 h 15 min.
The reaction mixture was filtered through a Celite pad. The filtrate
was concentrated in vacuo and the residue was diluted with Et2O.
The mixture was poured into water (100 mL) and extracted with
Et2O. The combined organic layers were washed with water and
brine, dried over Na2SO4, filtered and concentrated in vacuo. The
residue was purified by flash column chromatography (silica gel,
n-hexane/EtOAc 10:0 to 1:1) to afford the title compound 26
(10.3 g, 23.6 mmol, 94%) as a white solid in a diastereomeric ratio
of 15 to 1. 1H NMR (400 MHz, CDCl3) d: 7.59 (d, 2H, J = 8.2 Hz),
7.30–7.27 (m, 3H), 6.22 (t, 1H, J = 3.3 Hz), 6.13–6.10 (m, 1H),
4.84–4.74 (br s, 1H), 3.75–3.56 (m, 3H), 3.43–3.35 (m, 1H), 2.41
(s, 3H), 2.24 (dd, 1H, J = 13.3, 7.8 Hz), 2.02–1.92 (m, 1H),
1.92–1.81 (m, 2H), 1.80–1.72 (m, 1H), 1.60–1.55 (m, 1H), 1.43 (s,
9H); MS (FAB+) m/z: 435 ((M+H)+).
20.2 mmol, 98%) as a white solid. Mp 97.3–98.9 °C; ½a D25
¼ ꢂ52:2
ꢃ
(c 1.05, CHCl3); 1H NMR (500 MHz, CDCl3) d: 6.54 (br s, 1H),
6.10–5.93 (m, 2H), 3.88–3.70 (m, 2H), 3.56 (m, 3H), 2.83–2.73
(m, 1H), 2.61–1.90 (m, 5H), 1.69–1.43 (m, 16H); IR (KBr): 2969,
2869, 1681, 1387, 1091, 1063, 853, 727 cmꢂ1; MS (ESI) m/z: 335
(M+H)+; HRMS (ESI): (m/z) calcd for C19H31N2O3, 335.2335
[M+H]+; found 335.2328.
4.16. tert-Butyl (5R,7S)-2,2-dimethyl-7-{1-methyl-5-[5-(4-meth-
ylphenyl)pentanoyl]-1H-pyrrol-2-yl}-3- oxa-1-azaspiro[4.4]
nonane-1-carboxylate 29
4.16.1. Preparation of 5-(p-tolyl)pentanoyl chloride
To a mixture of p-tolualdehyde (4.0 g, 33.3 mmol) and (3-carb-
oxypropyl)triphenylphosphonium bromide (17.2 g, 40.0 mmol) in
CH2Cl2 (41 mL) was added dropwise a solution of t-BuOK (9.3 g,
83.2 mmol) in THF (83 mL) at 0 °C. The resulting mixture was
warmed to room temperature and stirred for 20 h. After cooling
to 0 °C, the reaction was quenched with water (300 mL) and
washed with CH2Cl2. The aqueous phase was acidified with conc.
HCl and extracted with Et2O. The combined organic layers were
washed with water and brine, dried over MgSO4, filtered and con-
centrated in vacuo to afford 5-(p-tolyl)pent-4-enoic acid (5.8 g,
30.5 mmol, 92%) as a light yellow solid, which was used for the
next step without further purification.
4.14. tert-Butyl(5R,7S)-2,2-dimethyl-7-{1-[(4-methylphenyl)
sulfonyl]-1H-pyrrol-2-yl}-3-oxa-1-azaspiro [4.4]nonane-1-
carboxylate 27
To a solution of 26 (10.3 g, 23.6 mmol) in CH2Cl2 (240 mL) were
successively added 2,2-dimethoxypropane (29.1 mL, 240 mmol)
and BF3ꢀEt2O (0.30 mL, 2.4 mmol) at 0 °C. The resulting mixture
was warmed to room temperature and stirred at room tempera-
ture for 45 min. After cooling to 0 °C again, the reaction was
quenched with satd NaHCO3 (50 mL). The resulting mixture was

456
M. Asano et al. / Tetrahedron: Asymmetry 24 (2013) 449–456
A solution of the 5-(p-tolyl)pent-4-enoic acid (5.8 g, 30.5 mmol)
was stirred for 30 min. The precipitated powder was filtered off
and 10% Pd–C (0.58 g, 50% wet) in EtOH (120 mL) was degassed
and saturated with hydrogen gas and the mixture was stirred at
50 °C for 6 h. The reaction mixture was filtered through a Celite
pad and concentrated in vacuo to afford 5-(p-tolyl)pentanoic acid
(5.6 g, 29.2 mmol, 96%).
To a mixture of 5-(p-tolyl)pentanoic acid (1.7 g, 9.0 mmol) in
toluene (18 mL) were successively added SOCl2 (1.3 mL, 17.9 mmol)
and DMF (0.09 mL). After stirring at 80 °C for 2 h, the reaction
mixture was azeotropically evaporated in vacuo with toluene twice
to afford the crude product of 5-(p-tolyl)pentanoyl chloride, which
was used for the next step without further purification.
to give 11 (646 mg, 1.51 mmol, 95%). Mp (dec.) 190.7 °C;
½
a 2D5
ꢃ
¼ ꢂ36:1 (c 1.07, AcOH); 1H NMR (500 MHz, CD3CO2D) d:
7.07 (d, 1H, J = 4.3 Hz), 7.04 (s, 4H), 6.89 (s, 1H), 6.13 (d, 1H,
J = 4.3 Hz), 3.87 (s, 3H), 3.84 (br s, 2H), 3.22 (m, 1H), 2.79 (t, 2H,
J = 7.4 Hz), 2.58 (t, 2H, J = 7.4 Hz), 2.50 (dd, 1H, J = 13.6, 7.1 Hz),
2.26 (s, 3H), 2.22–2.12 (m, 2H), 2.02–1.90 (m, 3H), 1.74–1.61 (m,
4H); 13C NMR (500 MHz, CD3CO2D) d 193.7, 169.9, 146.5, 140.2,
136.0, 135.4, 131.7, 129.9, 129.2, 121.9, 106.7, 66.0, 65.6, 40.1,
39.8, 36.8, 36.0, 33.8, 33.6, 32.2, 31.6, 26.9, 21.1; IR (KBr): 3370,
3271, 2957, 2937, 2872, 1643, 1563, 1548, 1485, 1451, 1373,
1070, 1053, 814, 757, 666 cmꢂ1; MS (ESI) m/z: 369 (M+H)+; HRMS
(ESI): (m/z) calcd for
C
23H33N2O2, 369.2542 [M+H]+; found
4.16.2. Preparation of 29
369.2536.
To a solution of 12 (1.00 g, 2.99 mmol) in toluene (6 mL) and
CH3CN (6 mL) was added 1-Me-imidazole (0.73 mL, 9.27 mmol).
The mixture was stirred and warmed to 80 °C. To this was added
dropwise a solution of the crude 5-(p-tolyl)pentanoyl chloride
(9.00 mmol) in CH3CN (3.0 mL) and toluene (3.0 mL) at 80 °C. The
resulting mixture was stirred at 80 °C for 17 h. After cooling to
room temperature, the reaction mixture was poured into water
and extracted with Et2O. The combined organic layers were
washed with satd NaHCO3 and brine, dried over Na2SO4, filtered
and concentrated in vacuo. The residue was purified by flash col-
umn chromatography (silica gel, n-hexane/EtOAc 100:0 to 60:40)
to afford 2.37 g of the enol ester 28 as a brown oil.
To a solution of the obtained 28 in THF (18 mL) and MeOH
(18 mL) was added 5.0 M NaOH (6.0 mL, 29.9 mmol). The mixture
was stirred at 60 °C for 2 h. The organic solvent was removed in
vacuo and the resulting mixture was extracted with Et2O. The com-
bined organic layers were washed with aqueous 1 M NaOH, water
and brine, dried over MgSO4, filtered and concentrated in vacuo.
The residue was purified by flash column chromatography (silica
gel, n-hexane/EtOAc 100:0 to 65:35) to afford the title compound
29 (1.34 g, 0.26 mmol, 88% over 2 steps) as a colorless oil. 1H
NMR (500 MHz, CDCl3) d: 7.23 (s, 2H), 7.09–7.05 (m, 1H), 7.07 (s,
2H), 6.93–6.90 (m, 1H), 6.11 (br s, 0.5H), 5.99 (br s, 0.5H), 3.88
(s, 3H), 3.84 (m, 1H), 3.75 (m, 1H), 2.81 (m, 1H), 2.74 (t, 2H,
J = 7.3 Hz), 2.60 (t, 2H, J = 7.6 Hz), 2.77–2.27 (m, 2H), 2.30 (s, 3H),
2.20–1.94 (m, 4H), 1.78–1.47 (m, 18H).
Acknowledgements
We would like to thank Mrs. Tomoko Yoneyama for the single
crystal X-ray analysis and also thank Dr. Satoshi Shibuya for geom-
etry optimization in the program SPARTAN.
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4.17. 1-{5-[(1S,3R)-3-Amino-3-(hydroxymethyl)cyclopentyl]-1-
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hemifumarate 11
To a solution of 29 (1.34 g, 2.63 mmol) in CH2Cl2 (26 mL) was
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