Catalytic enantioselective synthesis of the phosphodiesterase type IV inhibitor (R)-(-)-rolipram via intramolecular C-H insertion process

Article abstract of DOI:10.1055/s-1999-2958

A new route to the phosphodiesterase type IV inhibitor (R)-(-)-rolipram (1) has been developed, wherein the key step relies on enantioselective intramolecular C-H insertion of N-alkyl-N-4-nitrophenyl-α-methoxycarbonyl- α-diazoacetamide 7 catalyzed by chir

Full text of DOI:10.1055/s-1999-2958

LETTER
1775
Catalytic Enantioselective Synthesis of the Phosphodiesterase Type IV
Inhibitor (R)-(-)-Rolipram via Intramolecular C-H Insertion Process
Masahiro Anada, Orie Mita, Hiroko Watanabe, Shinji Kitagaki, Shunichi Hashimoto*
Graduate School of Pharmaceutical Sciences, Hokkaido University, Sapporo 060-0812, Japan
Fax +81 (11) 706 4981; E-mail: hsmt@pharm.hokudai.ac.jp
Received 24 August 1999
or a modified pyroglutamate,12 conjugate addition of cya-
nide to the chiral a,b-unsaturated oxazoline,13 palladium-
catalyzed, diastereoselective substitution of allylic car-
bonate by dimethyl malonate,14 a Claisen rearrangement
Abstract: A new route to the phosphodiesterase type IV inhibitor
(R)-(-)-rolipram (1) has been developed, wherein the key step relies
on enantioselective intramolecular C-H insertion of N-alkyl-N-4-ni-
trophenyl-a-methoxycarbonyl-a-diazoacetamide 7 catalyzed by
chiral dirhodium(II) complex. The dirhodium(II) carboxylate, process with the transfer of chirality,9 enantioselective
Rh2(S-BPTTL)4, incorporating N-benzene-fused-phthaloyl-(S)-
tert-leucinate as a bridging ligand has proven to be the catalyst of
deprotonation of 3-substituted cyclobutanone using chiral
lithium amide.15 However, a catalytic enantioselective
choice for this process, providing the desired 2-pyrrolidinone 8 in
synthesis of 1 has not yet been addressed. In this respect,
88% ee.
we have recently given a protocol for enantioselective
Key words: (R)-(-)-rolipram, phosphodiesterase inhibitor, enanti-
oselective synthesis, chiral dirhodium(II) catalyst, C-H insertion
construction of 4-substituted 2-pyrrolidinones (up to 82%
ee) via a site-selective C-H insertion catalyzed by dirhod-
ium(II) tetrakis[N-phthaloyl-(S)-tert-leucinate], Rh2(S-
PTTL)4.16 In order to demonstrate a synthetic potential of
this catalytic methodology, we have now explored a new
route to 1.
Rolipram, (±)-4-(3-cyclopentyloxy-4-methoxyphenyl)-2-
pyrrolidinone, originally developed as an antidepressant
by Schering AG has been shown to be a potent and selec-
tive inhibitor of phosphodiesterase type IV (PDE IV),1
one of the cyclic adenosine 3',5'-monophosphate (cAMP)-
specific phosphodiesterases.2 Inhibition of PDE IV is rap-
idly becoming recognized as a promising therapeutic tar-
get for the treatment of a number of disorders such as
asthma,3 atopy,4 and multiple sclerosis.5 While the thera-
peutic use of rolipram is hampered by nausea and emetic
side effects,6 rolipram has been not only used as a research
tool in determining PDE IV isozymes in disease state and
second messenger pathways but also chosen as a starting
point for subsequent structural modification.7 It has re-
cently been disclosed that the (R)-(-)-enantiomer (1) of ro-
lipram is primarily responsible for the pharmacological
effects.8 It is therefore not surprising that (R)-(-)-rolipram
(1) as the prototypical agent has elicited considerable at-
tention from synthetic chemists.9
O
N
O
N
R
R
H
O
H
O
O
O
O
O
Rh
Rh
Rh
Rh
R = Bn: Rh2(S-PTPA)4
R = Me: Rh2(S-PTA)4
R = i-Pr: Rh2(S-PTV)4
R = t-Bu: Rh2(S-PTTL)4
Rh2(S-BPTPA)4
Rh2(S-BPTA)4
Rh2(S-BPTV)4
Rh2(S-BPTTL)4
Toward this end, we selected N-2-(3-cyclopentyloxy-4-
methoxyphenyl)ethyl-N-4-nitrophenyl-a-methoxycarbo-
nyl-a-diazoacetamide 7 as a carbene precursor on the ba-
sis of our recent finding that the N-4-nitrophenyl
substituent plays a dual role as a nitrogen protecting group
as well as a site-control element.16 The synthesis of 7 was
implemented as shown in Scheme 1. O-Alkylation of
commercially available isovanillin (2) with cyclopentyl
bromide and K2CO3 in DMF followed by a Knoevenagel
condensation of 313 with nitromethane in the presence of
ammonium acetate17 provided trans-b-nitrostyrene 418 in
72% yield. Reduction of 4 with LiAlH4 followed by con-
densation with the 4-fluoronitrobenzene19 afforded 4-ni-
troaniline 5 in 60% yield. N-Acylation of 5 with methyl 3-
chloro-3-oxopropionate in the presence of N,N-dimethyl-
aniline and subsequent diazo transfer using 4-acetamido-
benzenesulfonyl azide20 and DBU21 furnished a-diazoace-
tamide 7 in 88% yield.
OMe
O
O
N
H
(R)-(-)-rolipram (1)
Numerous strategies have been developed to achieve
asymmetric syntheses of 1, including conjugate addition
of the chiral enolate of Evans' N-acetyloxazolidinones to
b-nitrostyrene,10 conjugate addition of an arylcopper re-
agent to Meyers' chiral a,b-unsaturated bicyclic lactam11
Synlett 1999, No. 11, 1775–1777 ISSN 0936-5214 © Thieme Stuttgart · New York

1776
M. Anada et al.
LETTER
OMe
O
OMe
OMe
(c), (d)
O
OMe
OMe
OR
(b)
O
O
HN
5
OHC
(a)
chiral Rh(II) complex
(2 mol %)
O2N
N2
4
MeO2C
MeO2C
2: R = H
N
N
O2N
3: R = cyclopentyl
OMe
CH2Cl2, 23 °C
O
O
OMe
O
O
NO2
NO2
7
8
N2
(f)
(e)
MeO2C
MeO2C
N
N
O
O
7
6
NO2
NO2
Reagents and conditions: (a) cyclopentyl bromide, K2CO3, DMF, 60
°C, 12 h, 91%; (b) MeNO2, NH4OAc, reflux, 3 h, 79%; (c) LiAlH4,
THF, reflux, 1.5 h; (d) 4-fluoronitrobenzene, Na2CO3, EtOH, sealed
tube, 150 °C, 12 h, 60% (2 steps); (e) MeO2CCH2COCl, Me2NC6H5,
CH2Cl2, 0 °C, 2 h, 97%; (f) 4-acetamidobenzenesulfonyl azide, DBU,
MeCN, 0 °C, 3 h, 91%.
Scheme 1
With the effectiveness of Rh2(S-PTTL)4 as a catalyst pre-
viously identified through a closely related C-H inser-
tion,16 we first examined cyclization of 7 with the aid of 2
mol % of Rh2(S-PTTL)4 (Table 1, entry 1). The reaction
in CH2Cl2 proceeded smoothly to give the 2-pyrrolidinone
derivative 8, [a]D25 +5.72 (c 1.06, CHCl3), in 75% yield,
with no trace of the 2-azetidinone derivative. The enanti-
oselectivity in this reaction was determined to be 78% ee
by 1H NMR spectroscopy using Eu(hfc)3 as a chiral shift
reagent. As might be expected from the precedent, the
preferred absolute configuration at the insertion site was
established as R by transformation of 8 into 1 (vide infra).
In a comparative experiment with 7, we then reexamined
the other chiral dirhodium(II) carboxylates previously
screened, Rh2(S-PTPA)4, Rh2(S-PTA)4, and Rh2(S-PTV)4,
derived from N-phthaloyl-(S)-phenylalanine, alanine, and
valine, respectively (entries 2-4). While a consistent sense
of enantioselection was observed in all cases, poor enan-
tioselectivities observed with them simply provided con-
firmation that Rh2(S-PTTL)4 characterized by a bulky
tert-butyl group proved to be by far the best choice. At this
point, we were intrigued by the feasibility of enhancement
of the enantioselectivity by means of the recently devel-
oped catalysts,22 Rh2(S-BPTTL)4, Rh2(S-BPTPA)4,
Rh2(S-BPTA)4, and Rh2(S-BPTV)4, derived from N-ben-
zene-fused-phthaloyl-(S)-tert-leucine, phenylalanine, ala-
nine, and valine, respectively (entries 5-8).23 Indeed, we
found that this class of catalysts characterized by an ex-
tension of the phthalimido wall with one more benzene
ring improved the enantioselectivities while the same
sense of enantioselection as above was observed in every
case. In particular, 88% ee with Rh2(S-BPTTL)4 was the
highest achievement (entry 5).
With highly optically active 2-pyrrolidinone 8 secured,
we then proceeded to the elaboration of the target mole-
cule, which also determined the preferred absolute config-
uration at the insertion site (Scheme 2).
Demethoxycarbonylation of 8 of 88% ee, [a]D24 +9.75 (c
1.47, CHCl3), under Krapcho conditions24 furnished 4-
substituted 2-pyrrolidinone 9, mp 98-99 °C, [a]D26 +29.1
(c 1.10, CHCl3), as pale yellow plates in 97% yield. Upon
one recrystallization from CH2Cl2-hexane, there was pro-
25
duced an optically pure sample, mp 99-102 °C, [a]D
+34.0 (c 1.00, CHCl3) in 71% yield, the homochirality of
which was confirmed by HPLC on Daicel Chiralpak
AD.25 One-pot conversion of the nitro group into the ace-
tamido group was effected under the influence of iron
powder in boiling acetic acid26 to give acetanilide 10, mp
120-121 °C, [a]D25 +28.4 (c 1.30, CHCl3) as colorless nee-
dles in 86% yield. Prior to an oxidative removal of the 4-
acetamidophenyl group with ceric (IV) ammonium nitrate
(CAN),27 concern arose over the compatibility of 3-cyclo-
pentyloxy-4-methoxyphenyl group in 10 with the reaction
conditions, since CAN was reported to oxidize 1,2-
dimethoxybenzene to give a complex mixture of prod-
ucts.28 Thus, we were gratified to find that treatment of 10
with CAN in aqueous MeCN at 0 °C uneventfully afford-
25
ed 1, mp 130-133 °C, [a]D -31.1 (c 1.08, MeOH) [lit.8
24
mp 131-133 °C, [a]D -31.0 (c 0.5, MeOH)], in 71%
yield.
Synlett 1999, No. 11, 1775–1777 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Catalytic Enantioselective Synthesis of the Phosphodiesterase Type IV Inhibitor
1777
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OMe
O
OMe
O
(d)
(a), (b)
8
O
(9) For a review on asymmetric synthesis of (R)-(-)-rolipram, see;
Mulzer, J. J. Prakt. Chem. 1994, 336, 287.
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N
R
N
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1
9: R = NO2
(c)
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Reagents and conditions: (a) NaCl, aq. DMSO, 160 °C, 2 h, 97%; (b)
recrystallization 71%; (c) Fe, AcOH, reflux, 2 h, 86%; (d)
Ce(NH4)2(NO2)6 (2.5 eq), aq. MeCN, 0 °C, 1 h, 71%.
(16) Anada, M.; Hashimoto, S. Tetrahedron Lett. 1998, 39, 79.
(17) Butterick, J. R.; Unrau, A. H. J. Chem. Soc., Chem. Commun.
1974, 307.
Scheme 2
(18) All new compounds exhibited satisfactory spectral (IR, 400
MHz 1H NMR and 100 MHz 13C NMR), analytical, and/or
high-resolution mass spectral characteristics.
(19) Lantz, R.; Obellianne, P. Bull. Soc. Chim. Fr. 1956, 311.
(20) Davies, H. M. L.; Cantrell, W. R., Jr.; Romines, K. R.; Baum,
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5678.
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In summary, we have achieved the first catalytic enanti-
oselective synthesis of (R)-(-)-rolipram from isovanillin
with an overall yield of 12% for the ten-step sequence,
wherein the effectiveness of the catalytic methodology
has been increased with the advent of Rh2(S-BPTTL)4.
The present protocol does not require sophisticated condi-
tions such as exclusion of moisture and oxygen as well as
low reaction temperatures, thus providing great potential
for a facile access to its novel analogues for biological and
pharmacological investigations.
(23) Typical procedure for enantioselective intramolecular C-H
insertion reaction (Table 1, entry 5): Bis(tetrahydrofuran)
adduct of Rh2(S-BPTTL)4 (6.4 mg, 0.004 mmol) was added in
one portion to a stirred solution of 7 (100 mg, 0.21 mmol) in
CH2Cl2 (2 mL) at 23 °C. The mixture was stirred at this
temperature for 8 h and the solvent was removed in vacuo. The
greenish residue was purified by column chromatography
(silica gel 10 g, 3:1Æ2:1 hexane/EtOAc) to provide 8 (70 mg,
74%) as yellow amorphous; [a]D24 +9.75 (c 1.47, CHCl3); IR
(film) n 1738, 1715, 1595 cm-1; 1H NMR (400 MHz, CDCl3)
d 1.55-1.63 (m, 2H), 1.79-1.93 (m, 6H), 3.80 (s, 3H), 3.82 (s,
3H), 3.84 (d, J = 10.0 Hz, 1H), 3.91 (t, J = 9.0 Hz, 1H), 4.02
(ddd, J = 8.1, 9.0, 10.0 Hz, 1H), 4.26 (dd, J = 8.1, 9.0 Hz, 1H),
4.76 (tt, J = 3.2, 5.8 Hz, 1H), 6.80-6.87 (m, 3H), 7.82 (d, J =
9.3 Hz, 2H), 8.21 (d, J = 9.3 Hz, 2H); 13C NMR (100 MHz,
CDCl3) d 24.0 (CH2), 32.7 (CH2), 40.7 (CH), 53.0 (CH3), 53.4
(CH2), 56.0 (CH3), 57.2 (CH), 80.5 (CH), 112.3 (CH), 113.7
(CH), 118.7 (CH), 119.0 (CH), 124.6 (CH), 130.4 (C), 143.7
(C), 143.9 (C), 147.9 (C), 149.7 (C), 168.6 (C), 168.7 (C); MS
(EI) m/z (rel. int. %) 454 (M+, 18), 386 (30), 328(100); HRMS
m/z 454.1737 [M+, calcd for C24H26N2O7 454.1740]. The
enantiomeric excess was determined to be 88% on the basis of
1H NMR spectrum (CDCl3) taken with 100 mol % of Eu(hfc)3
which exhibited the methoxy signals of the 3S,4R and 3R,4S
enantiomers at d 4.01 and 3.92, respectively.
Acknowledgement
This research was supported in part by a Grant-in-Aid for Scientific
Research on Priority Areas from the Ministry of Education, Sci-
ence, Sports and Culture, Japan. The authors thank the Japan Socie-
ty for the Promotion of Science for Research Fellowships for Young
Scientists (to M. A.).
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Article Identifier:
1437-2096,E;1999,0,11,1775,1777,ftx,en;Y17699ST.pdf
Synlett 1999, No. 11, 1775–1777 ISSN 0936-5214 © Thieme Stuttgart · New York