Dirhodium catalyzed intramolecular enantioselective C-H insertion reaction of N-cumyl-N-(2-p-anisylethyl)diazoacetamide: Synthesis of (-)-Rolipram

Article abstract of DOI:10.1016/j.tetasy.2005.03.023

Cumyl(2,2-dimethyl-benzyl) was used as an N-protecting group for intramolecular C-H insertion reaction of α-diazoacetamide. Excellent chemoselectivity (>98:2) in C-H insertion over the aromatic addition of N-cumyl-N-(2-p-anisylethyl)diazoacetamide was obtained with Rh ₂[(4S)-MEOX)]₄ catalyst in moderate enantioselectivity (53% ee). The reaction was successfully applied in the synthesis of (-)-Rolipram in 15% total yield.

Full text of DOI:10.1016/j.tetasy.2005.03.023

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 16 (2005) 1693–1698
Dirhodium catalyzed intramolecular enantioselective C–H
insertion reaction of N-cumyl-N-(2-p-anisylethyl)diazoacetamide:
synthesis of (ꢀ)-Rolipram
Wei-Jun Liu, Zhen-Liang Chen, Zhi-Yong Chen and Wen-Hao Hu*
Key Laboratory of Asymmetric Synthesis and Chirotechnology of Sichuan Province and Union Laboratory of Asymmetric
Synthesis, Chengdu Institute of Organic Chemistry, Chinese Academy of Sciences, Chengdu 610041, China and Graduate School
of Chinese Academy of Sciences, Beijing, China
Received 8 February 2005; accepted 22 March 2005
Abstract—Cumyl(2,2-dimethyl-benzyl) was used as an N-protecting group for intramolecular C–H insertion reaction of
a-diazoacetamide. Excellent chemoselectivity (>98:2) in C–H insertion over the aromatic addition of N-cumyl-N-(2-p-anisylethyl)-
diazoacetamide was obtained with Rh2[(4S)-MEOX)]4 catalyst in moderate enantioselectivity (53% ee). The reaction was successfully
applied in the synthesis of (ꢀ)-Rolipram in 15% total yield.
ꢀ 2005 Elsevier Ltd. All rights reserved.
1. Introduction
the five-membered c-lactam product. Herein, we report
the application of this method for the preparation of
(ꢀ)-Rolipram 1 (Scheme 1).
The intramolecular enantioselective C–H insertion reac-
tion of a-diazo carbonyl compounds catalyzed by chiral
dirhodium(II) complexes is well recognized for the
construction of both stereogenic carbocyclic and hetero-
cyclic compounds in an efficient fashion.1 For example,
isodeoxypodophyllotoxin and enterolactone were
synthesized according to this method.2 Apart from
enantioselectivity, regioselectivity has remained a major
challenge in the construction of heterocycles. In the case
of N-protected diazoacetamide, the reaction of diazo
carbon to the N-protecting group usually occurs and
makes the regioselectivity issue more complicated. It is
well documented that the regioselectivity depends highly
on the substituents of the diazo carbon as well as the
N-protecting group on the amide moiety.3 Many N-pro-
tecting groups, such as t-butyl, phenyl, 4-nitrophenyl,
4-methoxyphenyl, benzhydryl, bis(trimethylsilylmethyl),
etc.,3b,c,4 have been used with varying degrees of success.
We have previously reported that cumyl (2,2-dimethyl-
benzyl) is a good N-protecting group for intramolecular
C–H insertion of a-diazoacetamide to give the c-lactam
in high regioselectivity.5 In addition, it was found that
the cumyl protecting group can be easily removed from
OMe
O
OMe
O
N2
O
N
O
N
H
Ph
(R)-(-)-Rolipram
1
2
Scheme 1.
In the family of functionalized c-lactam, Rolipram, ( )-
4-(3-cyclopentyloxyl-4-methoxylphenyl)-2-pyrrolidinone,
has been shown to be a potent and selective inhibitor of
phosphodiesterase type IV (PDE IV).6 As a consequence
Rolipram, which was initially developed as an
anti-depressant by Schering AG, has great potential as
an anti-inflammatory.7 Although both enantiomers are
active, the (R)-isomer has recently proven to be the most
active one. Due to the importance of (R)-Rolipram,
several stereoselective syntheses have already been
reported.8 For example, Hashimoto et al. reported a
high enantioselective and regioselective synthesis of
(R)-Rolipram from intramolecular C–H insertion of
diazoacetoacetamide with an electron withdrawing func-
*
Corresponding author. Tel.: +86 028 85256870; fax: +86 028
85229250; e-mail: huwh@cioc.ac.cn
8i
tional groupattached to the diazo carbon. However,
0957-4166/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2005.03.023

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W.-J. Liu et al. / Tetrahedron: Asymmetry 16 (2005) 1693–1698
Table 1. Regioselection in intramolecular C–H insertion reaction of
diazoacetamides 3a–c catalyzed by 1 mol % Rh2(cap)4
the diazo compound is less reactive towards dirhodium
catalysts due to the attachment of the electron with-
drawing group. An additional step was implemented
to remove the group. The high activity of N-cumyl-a-
diazoacetamide encouraged us to investigate its applica-
tion in synthesis of (R)-(ꢀ)-Rolipram 1.
Compound
R
Yield (%) of 4a
Yield (%) of 5a
3a
3b
3c
Cumyl
t-Butyl
Benzyl
73
71
40
10
11
Trace
a Isolated yield after column chromatography.
2. Results and discussion
2.1. Intramolecular C–H insertion reaction of N-2-p-
anisylethyl diazoacetamide
O
CF3COOH
4a
MeO
95%
NH
p-Anisylethyl diazoacetamides 3 were used as model
substrates while searching for conditions with the best
regio- and enantioselectivity of the C–H insertion reac-
tion. We began by looking at the reaction of N-cumyl-
N-(2-p-anisylethyl)-diazoacetamide 3awith1 mol %cata-
lyst Rh2(cap)4 [dirhodium(II) tetra(caprolactamate)] in
refluxing dichloromethane. C–H insertion product c-lac-
tam 4a was obtained in 73% yield. A major side reaction
was the aromatic cycloaddition, although no b-lactam
or side product from the attacking N-cumyl groupwas
found (Scheme 2, Table 1). Deprotection of c-lactam
4a was easily achieved with CF3COOH to give c-lactam
7 in 95% yield (Scheme 3). In contrast, a similar selectiv-
ity was obtained with N-tert-butyl diazoacetamide 3b.
The result is in agreement with that reported by Padwa
et al. earlier with 3b.9 The disadvantage of using 3b is the
difficulty in removing the tert-butyl protecting group
while maintaining the lactam ring. When benzyl was
used as the N-protecting group, the yield of c-lactam
7
Scheme 3.
4c decreased to 40%. Attack of the benzyl groupoc-
curred to give a side product 6c in 27% yield. This is
in contrast with the result from 4a, no such side reaction
occurred on the cumyl phenyl group. It is likely that the
conformation of the carbenoid intermediate from 4a
favors the one that the cumyl groupis placed away from
the carbenoid carbon due to steric reasons (Scheme 4).
O
Ph
OMe
H
O
N
H
N
(cap)4Rh2
Ph
(cap)4Rh2
OMe
Scheme 4.
R
N2
N
Rh2(Cap)4
MeO
A series of representative chiral dirhodium catalysts
such as those shown in Figure 1 were examined for
asymmetric C–H insertion, with the results shown in
Table 2. We can see that rhodium(II) carboxylates gave
poor chemoselectivity and low enantioselectivity.
Improved chemoselectivity was observed with the
Rh2[(5S)-MEPY]4 catalyst. When Rh2[(4S)-MEOX]4
was employed, excellent chemoselectivity (4a:5a > 98:2)
was obtained with moderate enantioselectivity (47% ee
of 4a). The absolute configuration of the insertion prod-
uct from the Rh2[(4S)-MEOX]4 catalyst was established
O
3
O
O
R
N
MeO
MeO
MeO
+
N
R
4
6
5
R
N
N
+
MeO
O
O
as S by comparison of the specific rotation of 7 with the
6c
25
D
literature {½aŠ ¼ þ20:7 (c 0.95, MeOH) [(R)-4-phenyl-
25
2-pyrrolidinone, ½aŠ ¼ ꢀ37:8 (c 0.95, MeOH)]}.10
Scheme 2.
D
O
O
H
N
O
S
O
C12H25
Z
N
R
COOMe
H
O
O
N
O
O
H
O
Rh
Rh
Rh Rh
Rh
Rh
8: R=tBu
9: R=CH2Ph Rh2[(S)-NTPA]4
Rh2[(S)-NTTL]4
10: Rh2[(S)-DOSP]4
11: Z=C, Rh2[(4S)-MEPY]4
12: Z=O, Rh2[(4S)-MEOX]4
Figure 1. Chiral catalysts used for diazo decomposition of 2a.

W.-J. Liu et al. / Tetrahedron: Asymmetry 16 (2005) 1693–1698
1695
Table 2. Product distribution from catalytic diazo decomposition of diazoacetamide 3a in refluxing CH2Cl2
Entry
Catalyst
4a:5aa
Yield (%) of 4ab
Ee (%) of 4ac
Configuration
1
2
3
4
5
Rh2[(S)-DOSP]4
Rh2[(S)-NTTL]4
Rh2[(S)-NTPA]4
Rh2[(5S)-MEPY]4
Rh2[(4S-MEOX]4
47:53
58:42
53:47
87:13
>98:2
36
25
36
53
72
3
2
R
R
R
S
13
18
47
S
a Determined by 1H NMR of crude reaction mixture.
b Isolated yield after column chromatography.
c Determined by HPLC using a chiral OD column.
Table 3. Intramolecular C–H insertion of diazoacetamide 3a catalyzed
by Rh2[(4S)-MEOX]4
CHO
CHO
OMe
O
(a)
(b)
Entry
Solvent
Temp
(ꢁC)
Yield (%)
of 4aa
Ee (%)
of 4ab
OH
O
OMe
14
OMe
OMe
1
2
3
4
5
6
7
8
CH2Cl2
CH2Cl2
CH2Cl2
(CH2Cl)2
Toluene
THF
Reflux
20
72
76
69
74
71
69
73
70
47
52
52
37
47
41
46
54
15
13
0
20
OMe
(d)
(c)
20
40
N
H
O
Ph
Et2O
Dioxane
Reflux
40
16
OMe
Ph
N
a Isolated yield after column chromatography.
b Determined by HPLC using a chiral OD column.
N2
O
O
O
(e)
N
O
Ph
MeO
We have previously reported that the solvent has a pro-
found effect on the enantioselectivity for C–H insertion
of N-(benzyloxyethyl)-N-(tert-butyl)-diazoacetamide.11
Several solvents were examined with varying reaction
temperatures (Table 3). However, both solvent and tem-
perature have limited effect on the yield and enantio-
selectivity in this particular case. The results are listed
in Table 3. The best ee was 54% in dioxane. In the mean-
time, the catalyst efficiency was examined by decreasing
the catalyst loading. With the catalyst Rh2[(4S)-
MEOX]4 loading of 0.1 mol %, 68% isolated yield and
44% ee was obtained.
17
46 %ee
2
OMe
O
(f)
O
N
H
1
Scheme 5. Reagents and conditions: (a) K2CO3, DMF, cyclopentyl
bromide, 91%; (b) Ph3PCH2OMeCl, LDA, ꢀ78 ꢁC, 96%; (c) CHCl3,
HCl (12 M), cumylamine, CH3OH, NaBH4, 58%; (d) diketene, THF,
p-ABSA, DBU, THF, LiOH, H2O, 72%; (e) Rh2(4R-MEOX)4,
CH2Cl2, 64%; (f) CF3COOH 65%.
2.2. Synthesis of (ꢀ)-Rolipram
With the conditions in hand, the present method was
applied to the synthesis of (R)-Rolipram (Scheme 5).
To this end, carbene precursor 2 was prepared from
the commercially available isovanillin 13 as shown in
Scheme 5. O-Alkylation of 13 with cyclopentyl bromide
in DMF gave 14 in 91% yield. Wittig reaction of 14 with
reagent Ph3PCH2OMeCl in the present of LDA
provided a mixture of enol methyl ether 15 in 96% yield.
Hydrolysis of 15 with HCl (12 M) in CHCl3 and fol-
lowed by reductive amination with cumylamine afforded
16 in 58% yield. Diazoacetamide 2 was formed in 72%
yield through diketene condensation/diazo transfer/
acetyl cleavage. Cyclization of 2 in CH2Cl2 with 1 mol %
of Rh2[(4R)-MEOX]4 proceeded smoothly to afford
the desired c-lactam 17 in 64% yield and 46% ee. Re-
3. Conclusion
In summary, excellent chemoselectivity and moderate
enantioselectivity were achieved from intramolecular
C–H insertion of N-cumyl-N-p-anisylethyl diazoacet-
amide. This efficient method has been successfully
applied to the synthesis of (R)-(ꢀ)-Rolipram.
4. Experimental
4.1. General
Melting points were determined on a digital melting
point apparatus and were uncorrected. NMR spectra
were recorded on a Brucker-300 MHz spectrometer.
HRMS spectra were recorded on TOF EI. Dichloro-
methane, 1,2-dichloroethane and toluene were distilled
over calcium hydride. Solvents THF, Et2O, and dioxane
were distilled over sodium.
moval of the cumyl groupfrom 17 furnished the desired
(R)-(ꢀ)-Rolipram 1in 65% yield, mp129–132 ꢁC, ½aŠ
25
D
¼
25
ꢀ17:8 (c 0.6, MeOH) {lit., mp131–133 ꢁC, ½aŠ ¼ ꢀ31:0
D
(c 0.5, MeOH)}. Upon two recrystallizations from
CH2Cl2–n-hexane, the ee value was increased to 88%.12

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W.-J. Liu et al. / Tetrahedron: Asymmetry 16 (2005) 1693–1698
4.2. General procedure for the rhodium(II) catalyzed C–H
insertion of 3a and 3c
51.6, 49.4, 44.2, 32.9; HRMS(EI) calcd for C18H19NO2
(M)+: 281.1416. Found: 281.1423.
Procedure A: To a solution of the catalyst (1 mol %) in
the indicated solvent (10 mL) at reflux was added dia-
zoacetamide in the same solvent (6 mL) via a syringe
pump over 1 h. After addition of the diazoacetamide
was complete, the reaction solution was stirred for an
additional 15 min. The solvent was removed under
reduced pressure. Products were purified through sil-
ica-gel column chromatography.
4.3. Synthesis of 4-p-anisyl-pyrolidin-2-one 7
The c-lactam 4a (120 mg, 0.4 mmol) was added to
CF3COOH (2 mL) at room temperature and stirred
for 5 h before the solvent was removed under reduced
pressure. Silica-gel column chromatography yielded 7
25
D
(73 mg, 95.3%). White solid; mp125–128 ꢁC; ½aŠ
¼
1
þ20:7 (c 0.95, MeOH); H NMR (300 MHz, CDCl3):
d 7.17 (d, J = 8.7 Hz, 2H), 6.87 (d, J = 8.7 Hz, 2H),
6.48 (br s, 1H), 3.81–3.62 (m, 5H), 3.37 (dd, J = 9.1,
7.2 Hz, 1H), 2.71 (dd, J = 17.0, 8.8 Hz, 1H), 2.46 (dd,
J = 17.0, 8.9 Hz, 1H); 13C NMR (75 MHz, CDCl3): d
178.0, 158.8, 134.2, 127.9, 114.4, 55.5, 49.9, 39.8, 38.2;
HRMS(EI) calcd for C11H13NO2 (M)+: 191.0946.
Found: 191.0952.
Procedure B: To a solution of catalyst (1 mol %) in the
indicated solvent (10 mL) at room temperature was
added the diazoacetamide in the same solvent (6 mL)
in one portion. After the reaction was complete, the sol-
vent was removed under reduced pressure and products
purified through silica-gel column chromatography.
4.2.1. 4-p-Anisyl-1-cumylpyrrolidin-2-one 4a. (Proce-
dure B, 73%); colorless oil; 1H NMR (300 MHz,
CDCl3): d 7.28–7.14 (m, 5H), 7.06 (d, J = 6.7 Hz, 2H),
6.78 (d, J=6.7 Hz, 2H), 3.70 (s, 3H), 3.63 (dd, J = 9.3,
7.7 Hz 1H), 3.40–3.34 (m, 1H), 3.26 (dd, J = 9.3,
7.6 Hz, 1H), 2.67 (dd, J = 16.5, 8.5 Hz, 1H), 2.48 (dd,
J = 16.5, 9.1 Hz, 1H), 1.88 (s, 3H), 1.67 (s, 3H); 13C
NMR (75 MHz, CDCl3): d 174.1, 158.6, 146.6, 134.2,
128.4, 127.8, 126.7, 125.0, 114.2, 59.1, 55.3, 54.2, 40.6,
36.7, 28.0, 27.9; HRMS(EI) calcd for C20H23NO2
(M)+: 309.1729. Found: 309.1725.
4.4. Synthesis of (R)-(ꢀ)-Rolipram
4.4.1. 3-Cyclopentyloxyl-4-methoxylbenzaldehyde 14.
See Ref. 8g.
4.4.2. N-[2-(3-Cyclopentyloxyl-4-methoxylphenyl)-ethyl]-
N-cumylamide 16. To a solution of Ph3PCH2OMeCl
in THF (40 mL) at ꢀ78 ꢁC was added LDA (10 mL,
1.5 M in THF). The reaction mixture was slowly
warmed upto room temperature. After 0.5 h, the deep
brown reaction mixture was cooled to ꢀ78 ꢁC again.
A solution of aldehyde 14 (2.20 g, 10 mmol) in THF
(10 mL) was added slowly then warmed upto room tem-
perature and stirred overnight, after which water
(70 mL) was added. The mixture was then extracted
with EtOAc (3 · 50 mL). The combined organic layers
were washed with brine and dried over MgSO4.
Removal of the solvent under reduced pressure and
silica-gel column chromatograph (PE/EA = 40:1) gave
a mixture enol 15 (2.40 g, 96%). (E)-1-Methyoxyl-2-
(3-cyclopentyloxyl-4-methoxylphenyl)-ethylene 15a: 1H
NMR (300 MHz, CDCl3): d 6.93 (d, J = 12.9 Hz, 1H),
6.82–6.78 (m, 3H), 5.79–5.75 (d, J = 12.9 Hz, 1H)
4.82–4.80 (m, 1H), 3.83 (s, 3H), 3.68 (s, 3H), 1.93–1.82
(m, 8H). (Z)-1-Methyoxyl-2-(3-cyclopentyloxyl-4-meth-
4.2.2. 3-Cumyl-9-methoxy-3-azabicyclo[5.4.0]undeca-
6,8,10-trien-2-one 5a. (Procedure B, 9.5%); colorless
1
oil; H NMR (300 MHz, CDCl3): d 7.34–7.18 (m, 5H),
6.04 (d, J = 10.0 Hz, 1H), 5.92 (d, J = 6.5 Hz, 1H),
5.74 (d, J = 6.5 Hz, 1H), 5.62 (dd, J = 10.0, 5.6 Hz,
1H), 3.66 (s, 3H), 3.44–3.41 (m, 2H), 2.77 (d,
J = 5.6 Hz, 1H), 2.56–2.52 (m, 2H), 1.81 (s, 3H), 1.77
(s, 3H); 13C NMR (75 MHz, CDCl3): d 170.9, 159.6,
148.2, 128.6, 128.5, 126.4, 124.7, 124.6, 122.9, 118.4,
103.6, 63.1, 55.0, 48.0, 45.8, 32.2, 28.5, 28.4; HRMS(EI)
calcd for C20H23NO2 (M)+: 309.1729. Found: 309.1725.
4.2.3. 4-p-Anisyl-1-benzylpyrrolidin-2-one 4c. (Proce-
dure A, 39.8%); colorless oil; 1H NMR (300 MHz,
CDCl3): d 7.33–7.25 (m, 5H), 7.07 (d, J = 6.7 Hz, 2H),
6.28 (d, J = 6.7 Hz, 2H), 4.50 (dd, J = 3.4, 3.4 Hz, 2H),
3.76 (s, 3H), 3.62–3.49 (m, 2H), 3.22 (dd, J = 9.2,
6.9 Hz, 1H), 2.58 (dd, J = 17.9, 8.5 Hz, 1H), 2.13 (dd,
J = 17.9, 9.3 Hz, 1H); 13C NMR (75 MHz, CDCl3): d
173.9, 158.6, 136.4, 134.3, 128.8, 128.3, 127.8, 127.7,
114.2, 55.3, 54.0, 46.6, 39.1, 36.5; HRMS(EI) calcd for
C18H19NO2 (M)+: 281.1416. Found: 281.1407.
1
oxylphenyl)-ethylene 15b: H NMR (300 MHz, CDCl3):
d 7.36–7.32 (m, 3H), 6.08–6.05 (d, J = 7.0 Hz, 1H), 5.18–
5.16 (d, J = 7.0 Hz, 1H), 4.82–4.80 (m, 1H), 3.84 (s, 3H),
3.77 (s, 3H), 1.61–1.59 (m, 8H).
Compound 15 (2.40 g) was dissolved in CHCl3 (20 mL)
and then concentrated hydrochloride acid (20 mL)
added. After stirring at room temperature for 1 h, water
(40 mL) was added. The mixture was extracted with
CH2Cl2 (2 · 40 mL). The combined organic layers were
washed with saturated NaHCO3, then brine, and dried
over MgSO4. Removal of the solvent under reduced
pressure afforded a yellow oil that was used directly in
next step. To the resulting yellow oil, cumylamide
(1.76 g, 13 mmol), and MeOH (30 mL) were added
and the resulting solution stirred for 30 min. After the
solution was cooled to 0 ꢁC, NaBH4 (0.76 g, 20 mmol)
was added in several portions over 1 h. The reaction
was warmed to ambient temperature and stirred over-
4.2.4. 3-(2-p-Anisylethyl)-3-azabicyclo[5.3.0]deca-5,7,9-
trien-2-one 6c. (Procedure A, 27.1%); yellow solid;
1
mp130–132 ꢁ C; H NMR (300 MHz, CDCl3): d 7.20
(d, J = 8.6 Hz, 2H), 6.83 (d, J = 8.6 Hz, 2H), 6.48–6.46
(m, 2H), 6.19–6.09 (m, 2H), 5.22 (dd, J = 9.5, 3.8 Hz,
1H), 4.08 (br s, 2H), 3.80 (s, 3H), 3.61 (t, J = 7.2 Hz,
2H), 3.04 (br s, 1H), 2.84 (t, J = 7.2 Hz, 2H); 13C
NMR (75 MHz, CDCl3): d 174.1, 158.4, 130.6, 130.4,
129.9, 129.7, 129.4, 126.9, 120.7, 119.4, 114.1, 55.3,

W.-J. Liu et al. / Tetrahedron: Asymmetry 16 (2005) 1693–1698
1697
night. After careful quenching with saturated NH4Cl
solution, the mixture was concentrated in vacuum. The
residue was dissolved in H2O (60 mL), and the solution
was extracted with EtOAc (3 · 50 mL). The combined
organic layers were washed with brine and dried over
MgSO4. The solvent was removed under reduced pres-
sure and silica-gel column chromatograph (CHCl3/
CH3OH = 3:1) purification yielded amide 16 as colorless
oil (3.42 g, 58% yield). 1H NMR (300 MHz, CDCl3)
7.28–7.18 (m, 5H), 6.80–6.65 (m, 3H), 4.71 (m, 1H),
3.83 (s, 3H), 2.66 (t, J = 6.1 Hz, 2H), 2.57 (t,
J = 6.1 Hz, 2H), 1.91–1.58 (m, 9H), 1.42 (s, 6H); 13C
NMR (75 MHz, CDCl3): d 148.6, 142.9, 147.7, 132.7,
128.2, 126.2, 125.7, 120.8, 115.8, 112.2, 80.4, 56.3,
55.8, 44.4, 36.4, 32.9, 29.6, 24.2; HRMS(EI) calcd for
C23H31NO2 (M)+: 353.2355. Found: 353.2348.
HRMS(EI) calcd for C25H31NO3 (M)+: 393.2304.
Found: 393.2300.
4.4.5. (R)-(ꢀ)-Rolipram 1. To pyrrolidinone 17 (35 mg,
0.09 mmol) was added CF3COOH (2 mL) at room tem-
perature and the resulting solution was stirred for 5 h.
Saturated NaHCO3 (20 mL) was added thereafter. The
solution was extracted with EtOAc (3 · 15 mL). The
combined organic layer was washed with brine and
dried over MgSO4. Removal of the solvent under re-
duced pressure and silica-gel column chromatograph
(CHCl3/CH3OH = 25:1) purification yielded (R)-(ꢀ)-
Rolipram 1 (16 mg, 65%) as white solid, mp129–
25
132 ꢁC; ½aŠ ¼ ꢀ17:8 (c 0.6, MeOH); 1H NMR
D
(300 MHz, CDCl3): d 6.84–6.76 (m, 3H), 6.60 (br s,
1H), 4.77 (m, 1H), 3.83 (s, 3H), 3.78–3.57 (m, 2H),
3.38 (dd, J = 9.0, 7.5 Hz, 1H), 2.71 (dd, J = 16.9,
8.8 Hz, 1H), 2.47 (dd, J = 16.9, 8.9 Hz, 1H), 1.92–1.59
(m, 8H); 13C NMR (75 MHz, CDCl3): d 177.9, 149.4,
148.1, 134.7, 119.0, 114.0, 112.4, 80.8, 56.3, 49.9, 40.2,
38.3, 33.0, 24.2; HRMS(ESI) calcd for C16H21NO3
(M+H)+: 276.1594. Found: 276.1599.
4.4.3. N-Cumyl-N-[2-(3-cyclopentyloxyl-4-methoxylphen-
yl)-ethyl]-diazoacetamide 2. To amide 16 (0.389 g,
1.1 mmol) in THF (20 mL) was added diketene
(0.26 mL, 0.278 g, 3.3 mmol) at room temperature and
the resulting solution stirred overnight. Solvent was
removed under reduced pressure and silica-gel column
chromatograph (PE/EA = 5:1) purification yielded a
yellow oil (0.416 g). The resulting yellow oil was
added to THF (20 mL) followed by 4-acetamidobenzene
sulfonylazide (0.291 g, 1.2 mmol) and 1,8-diazabicy-
clo[5,4,0]undec-7-ene (0.18 mL, 1.2 mmol), and the
resulting solution stirred at rt for 12 h. Aqueous lithium
hydroxide (0.185 g, 4.4 mmol) in water (10 mL) was
added to this mixture, and the resulting orange-brown
mixture stirred vigorously for 5 h. The reaction mixture
was diluted with ethyl acetate (60 mL) and the organic
layer washed with water (2 · 30 mL) and dried over
MgSO4. The solvent was removed under reduced pres-
sure to yield a red-brown oil. Silica-gel column chroma-
tography (PE/EA = 7:1) purification yielded a yellow oil
Acknowledgements
We acknowledge the financial support from the Chinese
Academy of Sciences and the National Science Founda-
tion of China (Grant No. 20202011).
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2 (0.334 g, 72.0% overall yield from the amine 16). H
NMR (300 MHz, CDCl3): d 7.38–7.24 (m, 5H), 6.84–
6.75 (m, 3H), 4.78 (m, 1H), 4.54 (s, 1H), 3.83 (s, 3H),
3.71 (t, J = 8.2 Hz, 2H), 2.95 (t, J = 8.2 Hz, 2H), 1.96–
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2
(137 mg,
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25
D
½aŠ ¼ ꢀ8:7 (c 1.08, MeOH); 1H NMR (300 MHz,
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80.7, 59.2, 56.3, 54.3, 40.7, 37.0, 33.0, 28.1, 28.0, 24.1;

1698
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