Synthetic studies towards (+)-Dihydroampullicin. Michael addition of N-Boc-2-(tert-butyldimethylsiloxy)-3-methyl-pyrrole to α-methylene lactones

Article abstract of DOI:10.1016/S0040-4039(00)01499-4

The Michael addition of N-(tert-butoxycarbonyl)-2-(tert-butyldimethylsiloxy)-3-methyl-pyrrole (4) to several α-methylene lactones catalyzed by fluoride ions yielded the corresponding homologated products (26-30) with good yields. Application of this react

Full text of DOI:10.1016/S0040-4039(00)01499-4

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 8451–8455
Synthetic studies towards (+)-Dihydroampullicin. Michael
addition of N-Boc-2-(tert-butyldimethylsiloxy)-
3-methyl-pyrrole to a-methylene lactones
Isabel Marcos, Elena Redero and Francisco Bermejo*
Departamento de Qu´ımica Orga´nica, Facultad de Qu´ımicas, Universidad de Salamanca,
Pza de la Merced s.n. 37008 Salamanca, Spain
Received 25 July 2000; accepted 6 September 2000
Abstract
The Michael addition of N-(tert-butoxycarbonyl)-2-(tert-butyldimethylsiloxy)-3-methyl-pyrrole (4) to
several a-methylene lactones catalyzed by fluoride ions yielded the corresponding homologated products
(26–30) with good yields. Application of this reaction to the sililoxy bicyclic lactone (5) allowed us to
isolate the tricyclic lactone (26), a highly valuable intermediate in our synthetic strategy leading to the
growth regulator (+)-Dihydroampullicin (1). © 2000 Elsevier Science Ltd. All rights reserved.
Keywords: lactones; lactams; Michael reactions; terpenes and terpenoids; pyrrolinones.
Among the fungal metabolites isolated from a culture filtrate of Ampulliferina-like fungus sp.
No. 27, (+)-Dihydroampullicin 1, Ampullicin 2 and Isoampullicin 3 (Fig. 1) were found to
exhibit remarkable root growth activity in lettuce seedlings.1 At a dose of 300 mg/L, (+)-Dihy-
droampullicin accelerated the root growth of lettuce seedlings by 160% as compared with
controls, but did not affect hypocotyl growth.2
Figure 1.
* Corresponding author. Fax: 34 923 294574; e-mail: fcobmjo@gugu.usal.es
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)01499-4

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As part of a program aimed at the synthesis of 1, 2 and 3, we envisaged the synthesis of 1 by
intramolecular alkylation of the tosylate 6 (Fig. 2) by generation of the lactone enolate under
basic conditions. We have successfully applied the same strategy to access the tricyclic lactone
when we synthesized 2 and 3.3–5
Figure 2.
Preparation of the tosylate 6 requires the development of a procedure mainly consisting of the
Michael addition of N-(tert-butoxycarbonyl)-2-(tert-butyldimethylsiloxy)-3-methyl-pyrrole (4)
to the a-methylene lactone 5. In this paper, we wish to describe the results obtained for this
particular transformation and assess the synthetic viability of the strategy envisaged. Some
examples in the literature illustrate the successful addition of 2-(trialkylsiloxy)furans to a,b-
unsaturated systems;6 however, to the best of our knowledge, there are none describing the
Michael addition of 2-(trialkylsiloxy)pyrroles to a-methylene lactones.7–12
The a-methylene lactones 5, 18 and 25 were successfully synthesized from the corresponding
bicyclic lactones3,5 following standard procedures.13,14
The bicyclic methylene lactone 18 was prepared from 2-methyl-2-cyclohexenone 8 by applica-
tion of a 10-step sequence, with 15% overall yield (Scheme 1).15,16
Scheme 1. Reagents: i: NaBH4, CH3OH, 0°C, 95%; ii: Ac2O, pyr, rt, 8 h; 95%; iii: (a) Pd(PPh3)4, PPh3, THF, reflux,
0.5 h; (b) NaCH(COOEt)2, THF, reflux, 15 h, 85%; iv: NaCl, H2O, DMSO, 160°C, 15 h, 70%; v: KOH, H2O, MeOH,
85%; vi: NBS, acetone, 0°C, 85%; vii: nBu3SnH, AIBN, THF, 55°C, 1 h, 75%; viii: LDA, THF, −78°C, (HCHO)x,
65%; ix: MsCl, CH2Cl2, pyr, DMAP, 85%; x: DBU, THF, rt, 1 h, 95%
The methylene lactones 5 and 25 were prepared from the bicyclic lactones 19 and 20, readily
available from R-(−)-carvone.5
Treatment of 19 and 20 with excess of tert-butoxybis (dimethylamino)methane (Bredereck’s
reagent) followed by dibah reduction of the resulting enamines afforded 5 and 25 with 60 and
65% yields, respectively (Scheme 2). However, addition of the Eschenmoser salt to the kinetic
enolates resulting from the LDA deprotonation of lactones 19 and 20, followed by quaterniza-
tion of the resulting amines and further elimination, afforded 5 and 25 in higher yields (72 and
78%, respectively).17,18

8453
t
Scheme 2. Reagents: i: (a) BuOCH2(NMe2)2, 90°C; (b) K2CO3, MeOH, reflux, 45 min.; ii: dibah (20 equiv.), −78°C,
3 h; iii: LDA, THF, −78°C, CH2ꢀN(Me)2 I−; iv: ICH3, CH3OH, KHCO3
The results obtained for the Michael addition of N-(tert-butoxycarbonyl)-2-(tert-
butyldimethylsiloxy)-3-methyl-pyrrole 4 to several a-methylene lactones are summarized in
Table 1.
Table 1
Michael addition of 4 to a-methylene lactones catalyzed by fluoride ionsa
a All reactions were run in THF by dropwise addition of the ethereal solution of 4 (1.2 equiv.) to the a-methylene
lactone (1 equiv.) at −78°C followed by addition of a THF solution of Bu4NFxH2O (1.3 equiv.). The reaction
mixture was stirred for 15 h at that temperature and quenched by addition of sat. NH4Cl aqueous solution.20 No
condensation product at the a position of the pyrrolinone moiety was found in any case.

8454
The addition of 4 to the commercially available a-methylene-g-butyrolactone 7 catalyzed by
fluoride ions (entry 1, Table 1) afforded a mixture of diastereomers 27:28 in a 1:1 ratio, with
moderate yields. The two diastereomers were successfully separated by flash chromatography.
1
The structural elucidation of both isomers was accomplished by a complete H and 13C NMR
analysis.19
However, the reaction of 4 with methylene lactones 5, 18 and 25 under identical conditions
took place stereoselectively from the exo face. Only one diastereomer was present in the reaction
mixture in all cases. We assume that the configuration at C-3 is that shown above by
comparison with the chemical shifts described for other derivatives obtained in previous
synthetic work.3–5 Indetermination of the configuration at C-9 in the pyrrolinone moiety does
not affect the homogeneity of the product since according to the complete spectroscopic analysis
all the isolated products, 26, 29 and 30, were chromatographically pure.
The reaction of 4 with the a-methylene lactone 5 yielded the lactone 26, whose trivial
transformation into the tosylate 6 opens access to the natural product 1 and demonstrates the
viability of our synthetic strategy leading to 1. The key cyclization step of our synthesis was
successfully achieved when we synthesized 2 and 3 to gain access to the tricyclic lactone core
present in this interesting series of sesquiterpenic amides.3–5
In conclusion, we have developed a homologation method of a-methylene lactones by Michael
addition with N-(tert-butoxycarbonyl)-2-(tert-butyldimethylsiloxy)-3-methyl-pyrrole 4 catalyzed
by fluoride ions. This reaction proved to be a clean transformation; it takes place under very soft
conditions and the yields are acceptable in all cases (65–78%).
Acknowledgements
We thank the ‘Direccio´n General de Investigacio´n Cient´ıfica y Te´cnica., Spain for financial
support (DGICYT, Grant PB 98-0251). We also gratefully acknowledge the help of Professor G.
Casiraghi (University of Parma, Italy), for providing us with reprints of his main contributions
to the topic.
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