γ-Lactam synthesis via C-H insertion: Elaboration of N-benzyl protecting groups for high regioselectivity toward the total synthesis of rolipram

Article abstract of DOI:10.1021/ol0345834

(Matrix presented) By intramolecular C-H insertion of α-diazo-α -(phenylsulfonyl)acetamides, γ-lactams such as the antidepressant agent rolipram were efficiently synthesized in a highly regioselective manner. N-Benzyl moieties were elaborated as amide protecting groups to enhance regioselectivity in C-H activation as well as chemoselectivity over addition reactions.

Full text of DOI:10.1021/ol0345834

ORGANIC
LETTERS
2003
Vol. 5, No. 13
2259-2262
γ-Lactam Synthesis via C−H Insertion:
Elaboration of N-Benzyl Protecting
Groups for High Regioselectivity toward
the Total Synthesis of Rolipram
Cheol Hwan Yoon, Advait Nagle, Chiliu Chen, Drashti Gandhi, and
Kyung Woon Jung*
Department of Chemistry (SCA 400), UniVersity of South Florida,
4202 E. Fowler AVenue, Tampa, Florida 33620-5250
kjung@chuma.cas.usf.edu
Received April 3, 2003
ABSTRACT
By intramolecular C−H insertion of r-diazo-r-(phenylsulfonyl)acetamides, γ-lactams such as the antidepressant agent rolipram were efficiently
synthesized in a highly regioselective manner. N-Benzyl moieties were elaborated as amide protecting groups to enhance regioselectivity in
C−H activation as well as chemoselectivity over addition reactions.
Intramolecular C-H insertion is a practical method for the
formation of functionalized γ-lactams, which are versatile
intermediates for the synthesis of numerous natural products.1
Despite the extensive work on C-H insertion with diazo-
amides, this methodology has not been widely used for the
synthesis of γ-lactams due to the formation of regioisomers
such as â-lactams. The extent of side reactions was deter-
mined by three elements: amide conformational effects, ster-
eoelectronic effects, and substituent effects.1d,e,2,3 In particular,
R-substituents of diazoamides and N-protecting groups play
an important role in C-H insertion by alteration of electronic
character of the carbenoid center and amide conformation
during insertion, respectively.
(1) For the synthesis of γ-lactams by intramolecular C-H insertion
reactions, see: (a) Doyle, M. P.; McKervey, M. A.; Ye, T. In Modern
Catalytic Methods for Organic Synthesis with Diazo Compounds; Wiley-
Interscience: New York, 1998, and references therein. (b) Doyle, M. P.;
Taunton, J.; Pho, H. Q. Tetrahedron Lett. 1989, 30, 5397. (c) Doyle, M.
P.; Pieters, R. J.; Taunton, J.; Pho, H. Q. J. Org. Chem. 1991, 56, 820. (d)
Wee, A. G. H.; Liu, B.; Zhang, L. J. Org. Chem. 1992, 57, 4404. (e) Padwa,
A. P.; Austin, D. J.; Price, A. T.; Semones, M. A.; Doyle, M. P.;
Protopopova, M. N.; Winchester, W. R.; Tran, A. J. Am. Chem. Soc. 1993,
115, 8669. (f) Zaragoza, F.; Zahn, G. J. Prakt. Chem. 1995, 292. (g) Wee,
A. G. H.; Slobodian, J. J. Org. Chem. 1996, 61, 2897. (h) Doyle, M. P.;
Kalinin, A. V. Tetrahedron Lett. 1996, 37, 1371. (i) Hashimoto, S.-I.; Anada,
M. Tetrahedron Lett. 1998, 39, 79. (j) Wee, A. G. H.; Liu, B.; McLeod, D.
D. J. Org. Chem. 1998, 63, 4218. (k) Moody, C. J.; Miah, S.; Slawin, A.
M. Z.; Mansfield, D. J.; Richards, I. C. Tetrahedron 1998, 54, 9689. (l)
Wee, A. G. H.; Duncan, S. C. Tetrahedron Lett. 2002, 43, 6173.
Recently, we reported intramolecular C-H insertion of
R-diazo-R-(phenylsulfonyl)acetamides to afford γ-lactams
with high regio- and stereoselectivities, both attributed to
the presence of the phenylsulfonyl moiety.3 On the basis of
the success of this methodology, we decided to apply it to
the total synthesis of rolipram (Scheme 1).4,5 For this purpose,
we required the optimal protecting group, which could be
easily introduced, control the regioselectivity during the
(2) Padwa, A.; Austin, D. J. Angew. Chem., Int. Ed. Engl. 1994, 33,
1797.
(3) Yoon, C. H.; Zaworotko, M. J.; Moulton, B.; Jung, K. W. Org. Lett.
2001, 3, 3539.
10.1021/ol0345834 CCC: $25.00 © 2003 American Chemical Society
Published on Web 05/30/2003

However, R-diazo-R-(phenylsulfonyl)-acetamide 11 under-
went the C-H insertion to afford trans-γ-lactam 12 pre-
dominantly.7 The trans stereochemistry of γ-lactams 6, 9,
and 12 was determined by comparison of the coupling
constant of C3-C4 with the reported data of corresponding
analogues.8 This result suggested that the N-benzyl moiety
was a suitable protecting group for the regioselective C-H
insertion of R-diazo-R-(phenylsulfonyl)acetamides.
Scheme 1
To improve the regioselectivity, we introduced more
electron-withdrawing benzyl protecting groups, which would
reduce the electron density of the benzylic position, thereby
disfavoring insertion into this center. C-H insertion of the
diazo compound 14 possessing a 4-nitrobenzyl group sur-
prisingly afforded γ-lactam 15 and â-lactam 16 in a ratio of
7:1, which was lower than that produced by 11 possessing
a benzyl group (Table 1, entries 1 and 2). The cyclization
insertion, and be easily cleaved later in the synthesis. To
improve the regioselectivity, some protecting groups such
as p-methoxyphenyl,1d p-nitrophenyl,5c and BTMSM (bis-
(trimethylsilyl)methyl)1l have been developed. In the cases
of p-methoxyphenyl and BTMSM, however, the regioselec-
tivity was variable depending on the substrate, and harsh
reaction conditions were needed for the introduction and
deprotection of p-nitrophenyl group.
Table 1. Electronic Effect of Protecting Groups on C-H
Insertion
We began with benzyl moieties, which are well-known
protecting groups for amines.6 However, it was previously
reported that benzyl moieties were not effective protecting
groups for C-H insertion of diazoamides due to side reac-
tions, namely, â-lactam formation and aromatic cycloaddition.1f
First, we investigated the C-H insertion of various N-benzyl
diazo compounds with differing R-substituents (Scheme 2).
yield
(%)
â-lactam
entry
reactant (Ar)
11 (Ph)
14 (4-NO2Ph)
17 (2-NO2Ph)
20 (4-MeOPh)
23 (2-MeOPh)
26 (2,4-(MeO)2Ph)
γ-lactam
(ratioa)
1
2
3
4
5
6
83
92
61
85b
70b
91b
12
15
18
21
24
27
13 (12:1)
16 (7:1)
19 (7:1)
22 (14:1)
25 (12:1)
28 (22:1)
1
a Ratio was determined by H NMR. b Solvent: ClCH2CH2Cl.
Scheme 2
with more sterically hindered N-2-nitrobenzyl diazo com-
pound 17 also gave a 7:1 ratio of 18 and 19 in moderate
yield (entry 3). In the case of a 2- or 4-methoxy benzyl group,
however, there was no significant improvement in the
regioselectivity despite the electron-donating ability com-
pared to the parent benzyl group (entries 4 and 5). Only the
reaction with N-2,4-dimethoxybenzyl compound 26 showed
higher regioselectivity (entry 6). These unexpected results
were contrary to the general C-H insertion reaction ten-
dency, in which the electron-rich C-H bond is a more
favorable reaction site for insertion of an electronically
deficient metallocarbenoid.9
To confirm the reverse electronic selectivity for the for-
mation of â-lactam with R-diazo-R-(phenylsulfonyl)acet-
amides, we conducted the competition experiment using 29,
which has two electronically opposing benzyl moieties,
4-nitro and 4-methoxybenzyl groups (Scheme 3). The steric
effect between the carbenoid substituent and the phenyl group
was negligible since each aromatic substituent was located
at the same para position on the corresponding phenyl ring.
The cyclization of 29 afforded 30 and 31 in a ratio of 2:1,
thus confirming that the electron-deficient benzylic position
was a favorable reaction site for the formation of â-lactam.10
C-H insertion of the R-diazo-R-acetoacetamide 5 and
R-methoxycarbonyl-R-diazoacetamide 8 afforded the corre-
sponding â- and γ-lactams, respectively, with low selectivity.
(4) For the synthesis of (+)-rolipram, see: (a) Barluenga, J.; Ferna´ndez-
Rodr´ıguez, M. A.; Aguilar, E.; Ferna´ndez-Mar´ı, F.; Salinas, A.; Olano, B.
Chem. Eur. J. 2001, 7, 4323. (b) Demniz, J.; LaVecchia, L.; Bacher, E.;
Keller, T. H.; Schurch, F.; Weber, H. P.; Pombo-Villar, E. Molecules 1998,
3, 107. (c) Mulzer, J. J. Prakt. Chem. 1994, 336, 287 and references therein.
(5) For the synthesis of (-)-rolipram, see: (a) Itoh, K.; Kanemasa, S. J.
Am. Chem. Soc. 2002, 124, 13394. (b) Barnes, D. M.; Ji, J.; Fickes, M. G.;
Fitzgerald, M. A.; King, S. A.; Morton, H. E.; Plagge, F. A.; Preskill, M.;
Wagaw, S. H.; Wittenberger, S. J.; Zhang, J. J. Am. Chem. Soc. 2002, 124,
13097. (c) For the synthesis of (-)-rolipram via C-H insertion reaction,
see: Anada, M.; Mita, O.; Watanabe, H.; Kitagaki, S.; Hashimoto, S. Synlett
1999, 1775.
2260
Org. Lett., Vol. 5, No. 13, 2003

(entry 3). Using dichloroethane as the solvent, the starting
material was completely consumed and the selectivity
improved slightly (entry 4). Therefore, the regioselectivity
for C-H insertion of N-benzyl-protected R-diazo-R-(phen-
ylsulfonyl)acetamides was marginally influenced by rho-
dium ligands or solvents, and Rh2(OAc)4 in dichloroethane
was chosen as the optimal reaction conditions.
Scheme 3
In the previous report, the bulky tert-butyl protecting group
affected the conformational control during C-H insertion
of R-diazoamides and resulted in the exclusive formation of
γ-lactams.3 Considering these results, we introduced various
bulky benzyl protecting groups to the substrate (Scheme 4).
Likewise, reaction with R-diazo-R-acetoacetamide 32
afforded two â-lactams 33 and 34 along with heptatriene 35
via cycloaddition to the 4-methoxy phenyl group.11 Cycliza-
tion with R-methoxycarbonyl-R-diazoacetamide 36 gave
â-lactam 37 and heptatriene 38 without the â-lactam
compound from the insertion to 4-methoxy benzylic position.
There was no cycloaddition compound to the electron-poor
4-nitrophenyl group in all cases, implying that the aromatic
cycloaddition was affected by an electronic effect of aromatic
groups. The cycloaddition to the electron-rich 4-methoxy
phenyl group that was observed in the cases of 32 and 36
was due to the lower electron density of the corresponding
carbenoid centers than that of 29. Presumably, the phenyl-
sulfonyl group would stabilize the electrophilic carbenoid
center, causing the addition to the phenyl group to be less
favorable and the insertion reaction to proceed through a
relatively late transition state with a resulting increase in
regio- and chemoselectivity.12
Scheme 4
Diazo decomposition of diazoamides 39 and 41 afforded
γ-lactams 40 and 42, respectively, in moderate yield due to
the side reaction through the hydride abstraction of the
N-benzyl hydrogen.13 In the absence of N-benzyl hydrogen,
the cyclization of 43 gave γ-lactam 44 in a high yield.
Interestingly, in the absence of substitution at the benzylic
position, diazoamide 45 protected with the 2,4,6-trimethyl
Next, we studied the effects of the Rh ligands and solvent
on C-H insertion of 23 (Table 2). In the case of rhodium
(7) General Procedure for C-H Insertion Reactions. Rh2(OAc)4 (11
mg, 2.5 mol %) was added to a solution of an R-diazo-R-(phenylsulfonyl)-
acetamide (1 mmol) in dry CH2Cl2 (20 mL, C ) 0.05 M). The mixture
was refluxed for 12 h under N2, cooled to room temperature, and
concentrated. The residue was chromatographed to give γ- and â-lactams.
(8) For 6 analogues, see ref 1c,e: J3,4 (trans) ) 6.1-7.6 Hz; J3,4 (6) )
7.5 Hz. For 9 analogues, see ref 1d: J3,4 (trans) ) 7.8-9.0 Hz; J3,4 (9) )
8.9 Hz. For 12 analogues, see ref 3: J3,4 (trans) ) 1.0-3.0 Hz; J3,4 (12) )
3.5 Hz.
Table 2. Ligand and Solvent Effects on C-H Insertion
(9) (a) Taber, D. F.; Ruckle, R. E., Jr. J. Am. Chem. Soc. 1986, 108,
7686. (b) Doyle, M. P.; Westrum, L. J.; Wolthuis, W. N. E.; See, M. M.;
Boone, W. P.; Bagheri, V.; Pearson, M. M. J. Am. Chem. Soc. 1993, 115,
958.
entry
reaction conditionsa
yield (%)
ratiob (24:25)
(10) Structure of â-lactam 30 was determined by 1H NMR analysis after
the deprotection of the 4-methoxybenzyl group. See Supporting Information.
(11) For the aromatic cycloaddition of diazoamides, see: (a) Doyle, M.
P.; Shanklin, M. S.; Pho, H. Q. Tetrahedron Lett. 1988, 29, 2639. (b) Doyle,
M. P.; Shanklin, M. S.; Oon, S. M.; Pho, H. Q.; van der Heide, F. R.; Veal,
W. R. J. Org. Chem. 1988, 53, 3386. (c) Padwa, A.; Austin, D. J.;
Hornbuckle, S. F.; Semones, M. A.; Doyle, M. P.; Protopopova, M. N. J.
Am. Chem. Soc. 1992, 114, 1874. (d) Miah, S.; Slawin, A. M. Z.; Moody,
C. J.; Sheehan, S. M.; Marino, J. P., Jr.; Semones, M. A.; Padwa, A.
Tetrahedron 1996, 52, 2489. (e) Merlic, C. A.; Zechman, A. L.; Miller, M.
M. J. Am. Chem. Soc. 2001, 123, 11101.
1
2
3
4
Rh2(OAc)4, CH2Cl2
Rh2(pfb)4, CH2Cl2
85c
80c
81c
87
12:1
8:1
10:1
14:1
d
Rh2(CAP)4, C6H6
Rh2(OAc)4, ClCH2CH2Cl
a Reactions were run at reflux. b Ratio was determined by 1H NMR.
c Starting material remained. d Reaction did not occur when CH2Cl2 was
used as a solvent.
(12) Davies, H. M. L.; Panaro, S. A. Tetrahedron 2000, 56, 4871.
(13) (a) Doyle, M. P.; Dyatkin, A. B.; Autry, C. L. J. Chem. Soc., Perkin
Trans. 1 1995, 34, 78. (b) ref 1f.
catalyst with electron-withdrawing ligands, the selectivity
was reduced compared to Rh2(OAc)4 (entry 2). Use of
electron-donating ligands, which required higher tempera-
tures for the reaction to proceed, did not affect selectivity
(6) Greene, T. W.; Wuts, P. G. In ProtectiVe Groups in Organic
Synthesis; Wiley-Interscience: New York, 1999.
Org. Lett., Vol. 5, No. 13, 2003
2261

benzyl group also afforded γ-lactam 46 exclusively, albeit
in slightly lower yield. Practical and economic considerations
render the 2,4,6-trimethyl benzyl moiety the choice of
protecting group for the regioselective C-H insertion of
R-diazo-R-(phenylsulfonyl)acetamides.14
Finally, we applied this methodology to the synthesis of
rolipram, which has been known as a selective inhibitor of
phosphodiesterase (PDE) type IV, an antiinflammatory agent
and antidepressant (Scheme 5).15 Although a number of
enantioselective syntheses of (+)- and (-)-rolipram have
been reported, both enantiomers are known to be active.4,5
For the synthesis of rolipram, we envisioned 49 as the
insertion precursor, obtainable from previously reported
compound 47, which was derived from isovaniline.5c Reduc-
tive benzylation of 47 with 2,4,6-trimethylbenzaldehyde
afforded secondary amine 48. N-Acylation of 48 with
bromoacetyl bromide followed by the treatment with sodium
benzenesulfinate provided the R-phenylsulfonylacetamide.
Diazo transfer using p-ABSA and DBU yielded diazo
compound 49, which underwent insertion with Rh2(OAc)4
in dichloroethane to give γ-lactam 50 as a single isomer.
The phenylsulfonyl and N-benzyl groups of 50 were cleaved
simultaneously with Li/NH3 to afford rolipram (4) in high
yield.
Scheme 5 a
In conclusion, C-H insertion of N-benzylated R-diazo-
R-(phenylsulfonyl)acetamides afforded the γ-lactams with
high regioselectivity, which was utilized for the synthesis
of rolipram. High regioselectivity for γ-lactam formation is
attributed to the ability of the R-phenylsulfonyl group to alter
the electronic character of metallocarbenoid carbon during
C-H insertion.
Acknowledgment. We acknowledge the generous finan-
cial support from the National Institutes of Health (R01 GM
62767).
Supporting Information Available: Representative ex-
perimental procedures with spectral data. This material is
available free of charge via the Internet at http://pubs.acs.org.
OL0345834
(14) Diazocompound 43 was derived from cumylamine (2,2,-dimethyl-
benzylamine), which was very expensive ($91.15/5 mL, available from TCI).
Despite the higher yield of cyclization of 26, the 2,4-dimethoxy benzyl
protecting group was excluded due to the formation of â-lactam.
(15) (a) Seika, M. Drugs Future 1998, 23, 108. (b) Sommer, N.;
Loeschmann, P. A.; Northoff, G. H.; Weller, M.; Steinbrecher, A.; Steinbach,
J. P.; Richtenfiels, R.; Meyermann, R.; Reithmueller, A.; Fontana, A.;
Dichgans, J.; Martin, R. Nat. Med. 1995, 1, 244. (c) Baures, P. W.;
Egglestone, D. S.; Erhard, K. F.; Cieslinski, L. B.; Trophy, T. J.; Christensen,
S. B. J. Med. Chem. 1993, 36, 3274.
a Conditions: (a) ArCHO, ClCH2CH2Cl, MgSO4; (b) NaBH4,
MeOH (75% for two steps); (c) BrCH2COBr, TEA, CH2Cl2; (d)
PhSO2Na, DMF (70% for two steps); (e) p-ABSA, DBU, CH3CN
(70%); (f) cat. Rh2(OAc)4, DCE, reflux (75%); (g) Li, NH3, -78
°C (90%)
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Org. Lett., Vol. 5, No. 13, 2003