Organocatalytic asymmetric synthesis of versatile γ-lactams

Article abstract of DOI:10.1002/anie.200800329

A goodstarting point: Optically pure glactams have been prepared by organocatalytic enantioselective vinylic substitution. The parent lactam structure allows logical and systematic introduction of functionality around the periphery to access new derivativ

Full text of DOI:10.1002/anie.200800329

Angewandte
Chemie
DOI: 10.1002/anie.200800329
Asymmetric Synthesis
Organocatalytic Asymmetric Synthesis of Versatile g-Lactams**
Thomas B. Poulsen, Gustav Dickmeiss, Jacob Overgaard, and Karl Anker Jørgensen*
Molecules of natural origin containing a functionalized g-
lactam (pyrrolidin-2-one) ring system with a quaternary
stereocenter[1] at C5 hold a prominent position in chemistry
and biology. Important examples of these g-lactams include
the proteasome inhibitors lactacystin and salinosporamide A,
dysibetaine, and several examples from the oxazolomycin
family of antibiotics (Scheme 1).
The biological profiles of these molecules, combined with
the synthetic challenge of constructing the elaborate hetero-
cyclic core, have resulted in a number of inspiring enantio-
selective chemical syntheses.[2] Furthermore, recognizing the
potential for discovery of novel bioactive small molecules
based upon the g-lactam core structure, several research
groups have recently presented interesting multicomponent
or cascade approaches towards functionalized g-lactams.[3]
Unfortunately these methods do not offer stereochemical
control in an absolute sense. Consequently, we propose that a
catalytic enantioselective reaction which may pro-
vide access to both enantiomers of a simple
structure containing the g-lactam ring, a C5 qua-
ternary stereocenter, and functionalities to allow
the introduction of additional molecular complex-
ity would be an important development. Such a
structure could be the starting point, not only for
total synthesis, but also for more systematic
approaches to the diversification of the g-lactam
core. Application of robust and well-tested meth-
odologies to elaboration of the core structure may
eventually result in the discovery of new bioactive
compounds.
Scheme 1. g-Lactam-containing natural products.
Recently, organocatalysis has been the subject
of intensive development, with a special focus on
methodology.[4] An important step in making
organocatalysis a more mature field of research is
to demonstrate its potential usefulness for the
synthesis of important target structures.[5]
Scheme 2. Target structure and mechanistic hypothesis. PG=protecting group.
Herein, we demonstrate a novel use of the
organocatalytic enantioselective vinylic substitu-
tion reaction[6] for the single-step construction of C5 quater-
nary 3-halo-3-pyrrolin-2-ones 4 (Scheme 2). As will be
demonstrated, these structures are predisposed for function-
alization and may be regarded as common precursors for a
range of more complex structures built around the g-lactam
core.
[*] Dr. T. B. Poulsen, G. Dickmeiss, Dr. J. Overgaard,
Prof. Dr. K. A. Jørgensen
A key to the reaction is the use of the stereochemically
well-defined a,b-dihalogenated acrylate ester 3 as the electro-
phile in the substitution process.[7] Under the control of a
The Danish National Research Foundation:
Center for Catalysis, Department of Chemistry
Aarhus University, 8000 Aarhus C (Denmark)
Fax: (+45)8919-6199
ꢀ
chiral phase-transfer catalyst, enantioselective C C bond
formation by the stereospecific substitution of the chlorine
atom, with retention of configuration, by a 1,2-dinucleophile
such as 2 followed by immediate ring closure results in the
selective formation of 4 (Scheme 2).[8] The success of this
transformation pays tribute to the stereospecificity[6,9] of the
vinylic substitution reaction, as only the products that have
E-mail: kaj@chem.au.dk
[**] This work was funded bya grant from The Danish National Research
Foundation and the OChemSchool.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
Angew. Chem. Int. Ed. 2008, 47, 4687 –4690
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
4687

Communications
retained their configuration will undergo the desired cycliza-
tion.
From initial screening experiments (see the Supporting
Information) we identified the dihydrocinchonine-derived
phase-transfer catalyst HCn-1 (Scheme 3) as very active; it
delivered, for example, 4a in about 80% ee when the reaction
because of the poor performance of the true quasi-enantio-
meric catalyst.[10] The chloro-substituted product 4e (Table 1,
entry 7) was unfortunately not crystalline, but was isolated in
90% yield and with 85% ee after column chromatography. X-
ray crystallographic analysis of 4a and 4b allowed the
determination of the absolute stereochemistry.[11]
The optically active g-lactams 4 were easily modified
(Scheme 4). It was possible to introduce different substituents
at C3 by standard palladium-catalyzed cross-coupling meth-
Scheme 3. Structures of the catalysts.
was performed in toluene at ꢀ308C. Although improvements
were possible by performing the reaction at lower temper-
atures, we found that these conditions resulted in a good
compromise between reactivity and selectivity as the products
were easily recrystallized in enantiopure form and were
obtained in high yields (Table 1).
These considerations led to the reaction conditions shown
in Equation (1). The iodo-substituted products 4a–d (Table 1,
entries 1, 3, 5, and 6) were obtained as single enantiomers in
63–73% yield by recrystallization of the crude reaction
mixture.
Scheme 4. Different cross-coupling reactions with ent-4b. Reagents
and conditions: a) 10% [Pd(PPh3)4], PMP-B(OH)2, toluene, 2m aq
Na2CO3, 608C, 75 min, 71%; b) 10% [PdCl2(PPh3)2], 15% CuI, 1-
octyne, DIPEA, CH2Cl2, RT, 40 min, 83%; c) 5% [PdCl2(PPh3)2], ZnMe2,
DMF/THF (1:1), RT, 105 min, 86%. DMF=N,N-dimethylformamide,
PMP=para-methoxyphenyl, DIPEA=N,N-diisopropylethylamine.
For synthesis of the enantiomeric products, for example,
ent-4a and ent-4b (Table 1, entries 2 and 4), we employed the
isocinchonidine-derived phase-transfer catalyst isoCd-1
odologies. Suzuki coupling was used to introduce an aryl
group (!5, 73%), Sonogashira coupling allowed alkynyl
substitution (!6, 83%), and an alkyl substituent was
introduced through Negishi coupling (!7, 86%). Notably,
many g-lactam-containing natural products have a C3 methyl
group.
Table 1: The synthetic scope for the preparation of 3-halo-3-pyrrolin-2-
ones 4.[a]
The iodine atom of 4 can also be readily removed, as
demonstrated for ent-4a (Scheme 5). The resulting unsubsti-
tuted 3-pyrrolin-2-one 8 may be involved in 1,3-dipolar
cycloaddition reactions to introduce syn-related substituents
at the 3- and 4-positions of the g-lactam. Towards this end, 8
was treated with N-benzylnitrone under thermal conditions
and cycloadduct 9 (d.r. 4:1) was obtained as the major isomer.
As determined by X-ray analysis of the derivative 10,[11] the
ethyl ester group is syn to the isoxazolidine ring. For steric
reasons the observed selectivity is surprising, but it may be
attributed to an unfavorable dipolar interaction between the
nitrile group and the nitrone, which thus favors attack at the
opposite face of the molecule. Accordingly, this effect is
attenuated when the reaction is performed in polar media; in
acetonitrile the observed diastereoselectivity is 1:1. Cyclo-
adduct 9 may be a viable precursor to lactacystin or closely
related analogues.[12]
Entry Catalyst Acrylate Product ee [%][b] Yield [%][c] ee [%][b]
ester
(crude)
(config.)
1
HCn-1
3a
4a
ent-4a
4b
ent-4b
4c
4d
79
78
89
73[f]
91
80
85
73
68
71
62
63
64
90[g]
>99 (R)[d]
>99 (S)
>99 (R)[d]
>99 (S)
>99 (R)
>99 (R)
85 (R)
2[e]
3
isoCd-1 3a
HCn-1 3a
isoCd-1 3a
HCn-1
HCn-1
HCn-1
4[e]
5
6
3a
3a
3c
7
4e
[a] Reactions were performed with 1 mmol of 2. [b] Determined byHPLC
on a chiral stationaryphase using a Chiralpak AD column. [c] Yield of
isolated product after crystallization. [d] Configuration was determined
byX-rayanalysis. [e] Toluene/CHCl 3 (4:1) as the solvent. [f] See Ref. [10].
[g] Yield of isolated product after chromatography. Boc=tert-butoxycar-
bonyl, Cbz=benzyloxycarbonyl, Troc=2,2,2-trichloroethoxycarbonyl.
Selective hydrogenation from the a face of 7 (Scheme 6)
is an efficient method for the introduction of an additional
stereogenic center on the g-lactam ring. In fact, it was possible
to carry out this transformation with concomitant hydro-
genation of the nitrile and in situ Boc protection. Filtration of
4688 www.angewandte.org
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2008, 47, 4687 –4690

Angewandte
Chemie
Experimental Section
A precooled (ꢀ308C) solution of 50% aq K2CO3 (3.3 mL) was added
to a cooled (ꢀ308C) mixture of 2 (1 mmol), 1 (3 mol%, 0.03 mmol),
solvent (6.7 mL), and 3 (1.1 mmol). The reaction was vigorously
stirred until judged to be complete (as evident by TLC; Et2O/CH2Cl2
3:97) then allowed to warm to room temperature. The mixture was
diluted with H2O (10 mL) and Et2O (15 mL), and the phases were
separated. The aqueous phase was extracted with Et2O (2 ” 10 mL),
and the combined organic extracts were washed successively with
H2O (10 mL) and brine (10 mL). After drying with Na2SO4 the
mixture was concentrated and the resulting residue was rapidly
filtered through a short pad of SiO2 (3 ” 2 cm) with Et2O/CH2Cl2
(5:95; 100 mL), which upon concentration afforded the crude product
as a viscous yellow oil. Evaporation with pentane gave a solid
material which was recrystallized from EtOAc/n-hexane to afford the
enantiopure lactam 4.
Scheme 5. Iodine atom removal and nitrone 1,3-dipolar cycloaddition.
Reagents and conditions: a) Pd/C, quinoline, H2 (1 bar), NaOAc,
MeOH, RT, 2 h, 77–84%; b) BnN(O)CH2, toluene/c-hexane (1:1),
RT!408C, 40 h, 53%; c) 20% Mg(ClO4)2, CH2Cl2, 358C, 75 min,
100%. Bn=benzyl.
Representative example: (R)-1-tert-Butyl 2-ethyl 2-cyano-4-iodo-
5-oxo-1H-pyrrole-1,2(2H,5H)-dicarboxylate (4a) was isolated in
73% yield (> 99% ee) to give colorless crystals after recrystallization
(m.p. 126–1288C). 1H NMR (CDCl3): d = 7.40 (s, 1H), 4.36 (m, 2H),
1.56 (s, 9H), 1.36 ppm (t, J = 7.1 Hz, 3H). 13C NMR (CDCl3): d =
162.5, 160.9, 146.3, 143.5, 111.4, 99.1, 86.7, 66.2, 65.2, 27.8 (3C),
13.9 ppm. HRMS: m/z calcd for C13H15IN2NaO5 428.9923; found:
428.9922. The ee value was determined by HPLC on a chiral
stationary phase using a Chiralpak AD column; eluent: n-hexane/
iPrOH (98:2); flow rate: 1.0 mLminꢀ1; tmajor = 26.3 min, tminor
28.3 min. [a]RDT = ꢀ79.48 (c = 0.56 gcmꢀ3, CH2Cl2, > 99% ee).
=
Received: January 22, 2008
Published online: May 14, 2008
Keywords: asymmetric catalysis · cinchona alkaloids ·
.
natural products · phase-transfer catalysis · vinylic substitution
Scheme 6. Diastereoselective hydrogenation and amino acid synthesis.
Reagents and conditions: a) 1. H2 (10 bar), Pd/C, Boc2O, NEt3, EtOH/
THF (5:3), RT, 16 h; 2. 20% Mg(ClO4)2, CH2Cl2, reflux, 22 h, 82% (over
2 steps); b) TFA/CH2Cl2 (1:1), 3.5 h, RT, 86%. TFA=trifluoroacetic
acid.
[1] For reviews on the formation of quaternary stereocenters, see:
a) B. M. Trost, C. Jiang, Synthesis 2006, 369; b) J. Christoffers, A.
Baro, Angew. Chem. 2003, 115, 1726; Angew. Chem. Int. Ed.
2003, 42, 1688; c) E. J. Corey, A. Guzman-Perez, Angew. Chem.
1998, 110, 402; Angew. Chem. Int. Ed. 1998, 37, 388.
[2] First enantioselective synthesis of lactacystin, see: a) E. J. Corey,
G. A. Reichard, J. Am. Chem. Soc. 1992, 114, 10677; for synthesis
of salinosporamide A, see: b) L. R. Reddy, P. Saravanen, E. J.
Corey, J. Am. Chem. Soc. 2004, 126, 6230; c) A. Endo, S. J.
Danishefsky, J. Am. Chem. Soc. 2005, 127, 8298; for synthesis of
neooxazolomycin, see: d) A. S. Kende, K. Kawamura, R. J.
De Vita, J. Am. Chem. Soc. 1990, 112, 4070; e) E. O. Onyango, J.
Tsurumoto, N. Imai, K. Takahashi, J. Ishihara, S. Hatakeyama,
Angew. Chem. 2007, 119, 6823; Angew. Chem. Int. Ed. 2007, 46,
6703; for synthesis of dysibetaine, see: f) B. B. Snider, Y. Gu,
Org. Lett. 2001, 3, 1761; reviews: g) M. Shibasaki, M. Kanai, N.
Fukuda, Chem. Asian J. 2007, 2, 20; h) M. G. Moloney, P. C.
Trippier, M. Yaqoob, A. Wang, Curr. Drug DiscoveryTechnol.
2004, 1, 181.
[3] a) G. Ma, H. Nguyen, D. Romo, Org. Lett. 2007, 9, 2153; b) M.
Scansetti, X. Hu, B. P. McDermott, H. W. Lam, Org. Lett. 2007,
9, 2159; c) J. Wei, J. T. Shaw, Org. Lett. 2007, 9, 4077; d) J.
Isaacson, C. B. Gilley, Y. Kobayashi, J. Org. Chem. 2007, 72,
3913.
[4] Reviews on organocatalysis: a) P. I. Dalko, L. Moisan, Angew.
Chem. 2001, 113, 3840; Angew. Chem. Int. Ed. 2001, 40, 3726;
b) P. I. Dalko, L. Moisan, Angew. Chem. 2004, 116, 5248; Angew.
Chem. Int. Ed. 2004, 43, 5138; c) Chem. Rev. 2007, 107(12), issue
on organocatalysis; d) A. Berkessel, H. Gröger, Asymmetric
Organocatalysis, Wiley-VCH, Weinheim, 2004; e) Enantioselec-
the crude mixture through silica gel and selective removal of
the amide Boc group with catalytic Mg(ClO4)2 afforded 11 as
a single stereoisomer in 82% yield. The relative stereochem-
istry was established by X-ray analysis.[11] Standard depro-
tection under acidic conditions afforded (R)-pyroglutamic
acid derivative 12—a structure also related to the natural
product dysibetaine.[13]
In conclusion, we have developed a new organocatalytic
vinylic substitution reaction to prepare optically pure halo-
substituted pyrrolin-2-ones—compounds that are a flexible
starting point for the preparation of structurally diverse
optically active g-lactams. The overall process is very
practical, scalable, and chromatography-free. Through a
number of transformations we have demonstrated how the
products may be modified to yield derivatives of potential
biological relevance. Albeit still in its early stage of develop-
ment, the enantioselective vinylic substitution reaction is
emerging as a powerful tool for the expeditious assembly of
complex molecules, and the continued advancement and
application of this reaction is a prime focus of our current
research.
Angew. Chem. Int. Ed. 2008, 47, 4687 –4690
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org 4689

Communications
tive Organocatalysis (Ed.: P. I. Dalko), Wiley-VCH, Weinheim,
2007.
[9] a) G. Modena, Acc. Chem. Res. 1971, 4, 73; b) S. I. Miller,
Tetrahedron 1977, 33, 1211; c) Y. Apeloig, Z. Rappoport, J. Am.
Chem. Soc. 1979, 101, 5095.
[5] a) X. Linghu, J. J. Kennedy-Smith, F. D. Toste, Angew. Chem.
2007, 119, 7815; Angew. Chem. Int. Ed. 2007, 46, 7671; b) R. M.
de Figueiredo, R. Fröhlich, M. Christmann, Angew. Chem. 2008,
120, 1472; Angew. Chem. Int. Ed. 2008, 47, 1450; c) N. Satoh, T.
Akiba, S. Yokoshima, T. Fukuyama, Angew. Chem. 2007, 119,
5836; Angew. Chem. Int. Ed. 2007, 46, 5734; d) Y. Wang, X. Liu,
L. Deng, J. Am. Chem. Soc. 2006, 128, 3928; e) J. F. Austin, S.-G.
Kim, C. J. Sinz, W.-J. Xiao, D. W. C. MacMillan, Proc. Natl.
Acad. Sci. USA 2004, 101, 5482.
[6] a) T. B. Poulsen, L. Bernardi, M. Bell, K. A. Jørgensen, Angew.
Chem. 2006, 118, 6701; Angew. Chem. Int. Ed. 2006, 45, 6551; for
recent reviews of asymmetric phase-transfer catalysis, see:
b) M. J. OꢀDonnell in Catalytic Asymmetric Synthesis, 2nd ed.
(Ed.: I. Ojima), Wiley-VCH, Weinheim, 2000, pp. 727 – 755; c) T.
Ooi, K. Maruoka, Angew. Chem. 2007, 119, 4300; Angew. Chem.
Int. Ed. 2007, 46, 4222.
[7] a) T. Schlama, K. Gabriel, V. Gouverneur, C. Mioskowski,
Angew. Chem. 1997, 109, 2440; Angew. Chem. Int. Ed. Engl.
1997, 36, 2342; b) A. B. Lemay, K. S. Vulic, W. W. Ogilvie, J. Org.
Chem. 2006, 71, 3615.
[8] For previous examples of 1,2-dinucleophiles used to construct
pyrrolidin-2-ones with Michael reactions, see: a) L. Marzorati,
M. C. de Mattos, B. Wladislaw, C. de Vita, Synth. Commun.
2002, 32, 1427; b) E. P. Balskus, E. N. Jacobsen, J. Am. Chem.
Soc. 2006, 128, 6810.
[10] This strategy has been employed previously to reduce the
enantioselectivity differences between quasi-enantiomeric cin-
chona alkaloid catalysts involved in Pt–cinchona catalyzed
enantioselective hydrogenation, see: H.-U. Blaser, S. Burkhardt,
H. J. Kirner, T. Mössner, M. Studer, Synthesis 2003, 1679. We
have found that if isoCd-1 is pretreated with MeOH and silica
gel (see the Supporting Information), the enantioselectivity of
crude ent-4b can be increased to 94% ee. At present we do not
know the reason for this effect and have therefore decided not to
report this ee value in Table 1. However, this method was used to
prepare ent-4b on a gram scale. The reaction was performed
using 1.5 mol% catalyst: ent-4b: 94% ee (crude), 78% yield,
> 99% ee.
[11] CCDC 675042 (4a), 675043 (4b), 675044 (10), and 675045 (11),
contain the supplementary crystallographic data for this paper.
These data can be obtained free of charge from The Cambridge
Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_
request/cif.
[12] a) V. Caubert, N. Langlois, Tetrahedron Lett. 2006, 47, 4473; b) V.
Caubert, J. Massꢁ, P. Retailleau, N. Langlois, Tetrahedron Lett.
2007, 48, 381.
[13] R. Sakai, C. Oiwa, K. Takaishi, H. Kamiya, M. Tagawa,
Tetrahedron Lett. 1999, 40, 6941.
4690 www.angewandte.org
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2008, 47, 4687 –4690