Direct vinylogous aldol addition of γ-butyrolactones and γ- butyrolactams

Article abstract of DOI:10.1016/S0040-4039(00)00439-1

Deprotonation of N-benzyl-3-phenylselenylpyrrol-2(5H)-one 3 and furan- 2(5H)-one 4 and reaction with aldehydes affords regioselectively 5-(1'- hydroxy)-γ-butyrolactones and the aza-analogous butyrolactams with good diastereoisomeric excesses. The presence

Full text of DOI:10.1016/S0040-4039(00)00439-1

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 3669–3672
Direct vinylogous aldol addition of γ-butyrolactones and
γ-butyrolactams
Marco Bella,a,b,∗ Giovanni Piancatelli,a,∗ Antonella Squarcia a and Carla Trolli a
aDipartimento di Chimica, Piazzale Aldo Moro, 5, PO Box 34-Roma 62, 00185 Rome, Italy
bCentro CNR di Studio per la Chimica delle Sostanze Organiche Naturali, Piazzale Aldo Moro, 5, PO Box 34-Roma 62,
00185 Rome, Italy
Received 31 January 2000; accepted 13 March 2000
Abstract
Deprotonation of N-benzyl-3-phenylselenylpyrrol-2(5H)-one 3 and furan-2(5H)-one 4 and reaction with alde-
hydes affords regioselectively 5-(10-hydroxy)-γ-butyrolactones and the aza-analogous butyrolactams with good
diastereoisomeric excesses. The presence of Lewis acids enhances the diastereoisomeric ratios.
This methodology is an alternative to Lewis acid mediated silyloxydiene condensation. © 2000 Elsevier Science
Ltd. All rights reserved.
Keywords: regioselective aldol reaction; furanones; pyrrolidones.
The 5-(10-hydroxy)-γ-butyrolactone and γ-butyrolactam moieties are present in many naturally oc-
curring molecules of biological and pharmaceutical interest.1 Although oxygenated five-membered
compounds are more widespread in nature than the corresponding aza-analogues,2 the aza derivatives
of the butyrolactones can exhibit more interesting biological activity than the corresponding oxygenated
heterocycles.3 Furthermore, compounds such as 1 have been employed as useful intermediates in organic
synthesis as a growing literature witnesses (Fig. 1).4
Fig. 1.
Herein we describe a new and efficient protocol for the regio and diastereoselective functionalization
of the C5 position of suitable furan-2(5H)-ones and pyrrol-2(5H)-ones by direct vinylogous aldol
condensation with aldehydes. Usually, these reactions, carried out on simple model compounds, such
as butyrolactones and butyrolactams, give rise to the formation of mixtures of both regioisomeric
and diastereoisomeric products (C3 and C5 alkylation).5 Several methodologies have been introduced
to overcome the drawback of the limited selectivity of this reaction. Some procedures have utilized
∗
Corresponding authors. E-mail: piancatelli@axrma.uniroma1.it (G. Piancatelli)
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)00439-1
tetl 16719

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3- or 4-substituted heterocycles, such as methyl tetronate or methyl tetramate.6 A few years ago,
Ricci and co-workers described a multi-step sequence, which includes a base promoted enolization
of the starting butyro-lactones or -lactams, followed by silyl triflate trapping with formation of the
corresponding heterocyclic silyloxy diene, which can be functionalized only at the C5 position in the
reaction with electrophiles.7 In the last decade, Casiraghi’s group as well as other authors have exploited
this methodology to develop stereocontrolled syntheses of a large number of biologically interesting
molecules.8 In our method, we selected the phenylselenium moiety as a ‘protective group’ for the C3
position; particularly we utilized N-benzyl-3-phenylselenylpyrrol-2(5H)-one 3 and 3-phenylselenylfuran-
2(5H)-one 4. They can be easily prepared on large scale as single regioisomers starting from 2,5-
dimethoxy-3-phenylselenyl-(2,5H)-furan 2 (Scheme 1).9 It is noteworthy that the synthesis of similar
unsaturated heterocyclic systems is not as straightforward as the preparation of the analogous saturated
ones10 which are inexpensive and commercially available.
Scheme 1. Reagents and conditions. i, BnNH2, CH3COOH, 4 days, 60% acetone; ii, HCl (aq.), CH3CN, 85% or HCl (aq.), 65%
With the precursors in hand, the direct aldol condensation, conveniently performed by reaction of
the corresponding enolate of our synthons, generated in situ by the action of LHMDS in THF, with
model aldehydes, gave only the C5 functionalized products. The anti aldol products were predominantly
obtained in all reactions involving the N-benzyl-3-phenylselenylpyrrol-2(5H)-one 3 (Scheme 2); both
the yield (from 40% up to 80%) and the diastereoselectivity ratio (up to 50:1) were increased by using
11
stoichiometric amounts of Lewis acids (Table 1 entry 2–4 and 6–8). These results show clearly the
pivotal role played by a transition state in which a boron or a tin enolate is involved. It is known
that these enolates show lower interatomic distances with respect to lithium enolates,12 and that the
diastereoselectivity is increased because the transition state presents a more restricted geometry.
Scheme 2. Reagents and conditions. i, LHMDS, THF, 30 min, aldehyde (Table 1) then H2O
On the other hand, the aldol condensation of the analogous 3-phenylselenylfuran-2(5H)-one 4 with
benzaldehyde affords the corresponding alcohol as a 2:1 anti:syn mixture of diastereoisomers13 (Scheme
3 and Table 2 entry 1); this anti:syn ratio is increased up to 6:1 if Zn(OTf)2 is used as Lewis acid
and toluene as solvent. The reverse diastereoselectivity is observed in the presence of BF3·Et2O (1:6
anti:syn). When the addition reaction was performed with crotonaldehyde, only the formation of the
1,2-addition product was observed, with no detectable traces of the 1,4-adduct.
All the compounds described above were then treated under a deselenylation protocol based upon the
use of in situ generated nickel boride which resulted in simultaneous reduction of the olefinic double
bond (Scheme 4). We were usually able to obtain clean products in high yields without the need for
chromatographic purification; both the reductive deselenylation of alkyl or vinylic selenides and the
removal of the double bond in these heterocyclic systems have already been reported.14
In conclusion, our method allows the regioselective functionalization of N-benzyl-3-substituted-pyrrol-
2(5H)-ones and furan-2(5H)-ones at the C5 position in reactions with aldehydes, affording either 5-

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Table 1
Aldol reaction between 3 and various aldehydes
Scheme 3. Reagents and conditions. i, LHMDS, 30 min; aldehyde (Table 2) then H2O
Table 2
Aldol reaction between 4 and various aldehydes
Scheme 4. Reagents and conditions. i, NaBH4, NiCl2, THF/MeOH; X=O, yields from 40 to 60%; X=NBn yields from 90 to
95%
(10-hydroxy)-γ-butyrolactones or γ-butyrolactams with modest to excellent diasteroisomeric excesses,
in particular if tin or boron Lewis acids are employed. The reaction involves a ‘free’ carbanion that
is more nucleophilic than the heterocyclic silyloxy dienes activated with a Lewis acid and the overall
transformation is the first general example of synthesis of molecules such as 1 via the direct aldol
condensation.

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Further studies to apply this reactivity to electrophiles other than aldehydes as well as to the synthesis
of more complex molecules are in progress in our laboratory.
Acknowledgements
We wish to thank Murst Cofin 1998 for financial support.
References
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the C3 adduct (global yield 60%).
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with electrophiles, see for examples: (a) Honda, T.; Kondoh, H.; Okumaya, A.; Hayakawa, T.; Tsubuki, M.; Nagase, H.
Heterocycles 1992, 33, 67–72 and references cited therein. For the reaction of the aza-analogue, methyl tetramate, with
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11. Procedure for direct aldol reaction: To a cooled (−78°C) solution of 100 mg (0.305 mmol) of crystalline 3 in 2 ml of dry
THF, LHMDS, 0.32 ml (1 M solution in THF, 1.05 equiv.) was added dropwise. The reaction mixture was stirred at this
temperature for 30 min during which the colour of the solution changed from pale yellow to purple. A THF (1 ml) solution
of Lewis acid (0.305 mmol, 1.00 equiv., see Table 1) was then added followed by the addition of a THF (1 ml) solution of
aldehyde (0.457 mg, mmol 1.5 equiv., see Table 1). After 5 min NH4Cl (2 M solution, 5 ml) was added and the mixture
was diluted with ethyl acetate (10 ml) and diluted with brine. The organic layer was dried (Na2SO4) and evacuated in vacuo
to give an oil that was further purified by chromatographic column on silica gel (eluant hexane:ethyl acetate 3:1) to give a
mixture of compounds 5–8a–b.
12. Carey, F. A.; Sundberg, R. J. In Advanced Organic Chemistry, III edn.; Plenum Press: New York and London, 1992; Chapter
2, Part B.
13. The relative configuration of compounds 5–12 was assigned on the basis of the value of the coupling constant0between
the proton on C5 and C10 J5–1 ; a larger value of the constant and a lower chemical shift of the protons on C1 and C3
0
0
are generally associated with the anti diasteroisomers, while the syn diastereoisomers usually show a lower J5–1 value and
higher C10 and C3 proton chemical shift. See: Bigi, F.; Casnati, G.; Sartori, G.; Araldi, G. Gazz. Chim. Ital. 1989, 413.
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3815–3822. For the reduction of double bonds in butenolides, see: (b) Jefford, C. W.; Jaggi, D.; Boukouvalas, J. Tetrahedron
1987, 35, 4037–4040.