The addition of 2-tert-butyldimethylsilyloxyfuran to cyclic N-acyliminium ions containing cyclohexyl-based chiral auxiliaries

Article abstract of DOI:10.1016/S0040-4039(00)01749-4

The vinylogous Mannich addition of silyloxyfuran 5 to chiral five- and six-membered N-acyliminium ions derived from 3/4a,b occurred exclusively through the addition to the N-acyliminium Si face to provide threo-6/7a,b as the major isomer (73-84% yield, 2:1-7:1 diastereoisomeric ratio) which were converted to the corresponding bicyclic lactams 10 and 11 with efficient recovery of the chiral auxiliary. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)01749-4

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 9709–9712
The addition of 2-tert-butyldimethylsilyloxyfuran to cyclic
N-acyliminium ions containing cyclohexyl-based chiral
auxiliaries
Marcelo G. M. D’Oca,a Ronaldo A. Pillia,* and Ivo Vencatob
aInstituto de Qu´ımica, Unicamp, Campinas SP 13083-970, Brazil
bDepartamento de Qu´ımica, UFSC, Floriano´polis SC 88040-900, Brazil
Received 18 August 2000; accepted 4 October 2000
Abstract
The vinylogous Mannich addition of silyloxyfuran 5 to chiral five- and six-membered N-acyliminium
ions derived from 3/4a,b occurred exclusively through the addition to the N-acyliminium Si face to
provide threo-6/7a,b as the major isomer (73–84% yield, 2:1–7:1 diastereoisomeric ratio) which were
converted to the corresponding bicyclic lactams 10 and 11 with efficient recovery of the chiral auxiliary.
© 2000 Elsevier Science Ltd. All rights reserved.
The development of synthetic methodologies for the preparation of optically active pyrro-
lidine and piperidine derivatives constitutes an area of living interest due to the presence of these
heterocycles in many biologically active natural compounds. Particularly, the addition of carbon
nucleophiles to N-acyliminium ions has been the key step in several approaches to
azaheterocycles.1
Comins and coworkers revealed that the addition of Grignard reagents2 and zinc enolates3 to
chiral N-acylpyridinium salts containing cyclohexyl-based chiral auxiliaries4 such as 8-phenyl-
menthyl and trans-2(a-cumyl)cyclohexyl afforded 2,3-dihydro-4-pyridones in good yield and
diastereoselectivity.
We were attracted by the possibility of using (1R,2S)-trans-phenylcyclohexyl and (1R,2S,5R)-
8-phenylmenthyl as chiral auxiliaries during the addition of carbon nucleophiles to the chiral
five- and six-membered N-acyliminium ions formed in situ from the corresponding 2-methoxy
pyrrolidines 3a,b and 2-methoxy piperidines 4a,b available through anodic oxidation5 of chiral
carbamates 1a,b and 2a,b, respectively (62–76% yield).
Our ongoing interest in the chemistry of the Stemona6 and pumiliotoxin7 alkaloids led us to
investigate the vinylogous Mannich addition of 2-tert-butyldimethylsilyloxyfuran (5)8 to chiral
* Corresponding author. E-mail: pilli@iqm.unicamp.br
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)01749-4

9710
N-acyliminium ions derived from 3a,b and 4a,b (Scheme 1). The reaction of 2-methoxy
carbamates 3a and 4a with silyloxyfuran 5 was initially carried out in CH2Cl2 at −78°C with
TiCl4 as the Lewis acid to afford in both cases only two out of four possible diastereoisomers
in 60 and 55% yield, respectively. Later, we found that catalytic amounts of trimethylsilyl
trifluoromethanesulfonate (TMSOTf)9 afforded improved yields of 6a/8a and 7a/9a (84 and
75%, respectively).
Scheme 1.
The diastereoisomeric ratio for butenolides 6a/8a and 7a/9a could not be unambiguously
established at this stage neither by GC–MS analyses (partial thermal epimerization) nor by
NMR spectroscopy (broad and multiple signals due to rotational isomers). However, the
diastereoisomeric ratios were determined to be 3:1 and 7:1 after hydrogenation of butenolides
6a/8a and 7a/9a, respectively, and GC–MS analyses of the corresponding g-butyrolactones. The
relative stereochemistry of the major diastereoisomer 7a which crystallized from ethyl acetate–
hexane (mp 130.1–130.3°C) was established as 2%R,5R after X-ray diffraction analysis (Fig. 1),
Figure 1. ORTEP drawing of 7a

9711
in accordance with the relative threo stereochemistry reported by Martin,10 Morimoto11 and
Figade`re12 in the addition of silyloxyfurans to cyclic five-membered N-acyliminium ions.
The 2%R,5R configuration of 6a, the major butenolide obtained from 3a, was assigned after
X-ray diffraction analysis of the corresponding g-butyrolactone obtained by catalytic hydro-
genation and purified by crystallization from ethyl acetate–hexane (mp 122.3–122.6°C, Fig. 2).
Catalytic hydrogenation of 6a/8a followed by methanolysis afforded hydroxy lactam 10 (70%
yield overall) readily separated from the minor isomer 12 by column chromatography on silica
gel, accompanied by efficient recovery of (1R,2S)-trans-phenylcyclohexanol (>88% yield). The
same experimental protocol afforded hydroxy lactam 11 in 68% yield from 7a/9a. As expected
from the 2%R,5R configuration of 7a, (5R,6R)-5-hydroxy-1-azabicyclo[4.4.0]decane-2-one (11)
displayed cis relationship between H-5 and H-6 as shown by NOE experiments: 1.1% increment
was observed for H-6 upon irradiation of H-5 while no such increment was observed for 13 thus
indicating a trans relationship between H-5 and H-6 in the later compound.
Figure 2. ORTEP drawing of g-butyrolactone derived from 6a
The absolute configuration of 13 was suggested to be 5S,6R after the conversion of both 11
and 13 to the corresponding Mosher esters which revealed H-6 shielded in the ester prepared
from 11 and (S)-MTPA when compared to the one obtained from (R)-MTPA (Dl=−0.15 ppm).
The opposite behavior was observed when the Mosher esters derived from 13 and (S)- and
(R)-MTPA (Dl=+0.15 ppm) were compared. The relative shielding observed for H-6 in the
(S)-MTPA derived from 11 translated into R configuration at C-6 when the Mosher model13 or
the Kakisawa model for cyclic secondary alcohols14 were applied, as expected from the known
5R,6R configuration of 11. Accordingly, the relative deshielding of H-6 in the (S)-MTPA ester
derived from 13 can only be accounted for once S configuration is assumed for C-6. Analogous
observations for the MTPA esters of (5R,6R)-5-hydroxy-1-azabicyclo[4.3.0]nonane-2-one (10),
prepared from the major isomer 6a and minor isomer 12 (from minor isomer 8a) led us to assign
the 5S,6R configuration to 12.
Finally, the diastereoisomeric ratio and the relative configuration of 6b/8b and 7b/9b
(obtained from 3b and 4b in 80 and 73% yield, respectively) were established after conversion
(H2, Pd–C; then MeONa/MeOH, 110°C) of 6b/8b to a 2:1 mixture of hydroxy lactams 10/12
(75% yield) and 7b/9b to a 2:1 mixture of 11/13 (70% yield) with recovery of (1R,2S,5R)-8-
phenylmenthol in >85% yield.

9712
Overall, these results reveal the exclusive addition of silyloxyfuran 5 to the Si face of the
N-acyliminium ions derived from 3a,b and 4a,b and disclose an attractive route to enantiomer-
ically pure pyrrolidine and piperidine derivatives, particularly bicyclic lactam 11 (45% overall
yield from readily prepared 4a) which is a potentially useful intermediate for the asymmetric
synthesis of quinolizidine alkaloids.
Acknowledgements
The authors would like to thank FAPESP, CNPq and FAEP/UNICAMP for financial
support.
References
1. (a) Koning, H.; Speckamp, W. N. In Stereoselective Synthesis (Houben-Weyl); Helmchen, G.; Hoffmann, R. W.;
Mulzer, J.; Schaumann, E.; Eds.; Georg Thieme Verlag: Stuttgard, 1996; E 21 Vol. 3, p. 1953. (b) Pilli, R. A.;
Russowsky, D. Trends Org. Chem. 1997, 6, 101. (c) Speckamp, W. N.; Moolenaar, M. J. Tetrahedron 2000, 56,
3817.
2. (a) Comins, D. L.; Goehring, R. R.; Joseph, S. P.; O’Connor, S. J. J. Org. Chem. 1990, 55, 2574; (b) Comins,
D. L.; Joseph, S. P.; Goehring, R. R. J. Am. Chem. Soc. 1994, 116, 4719; (c) Comins, D. L.; LaMunyon, D. H.;
Chen, X. J. Org. Chem. 1997, 62, 8182.
3. Comins, D. L.; Kuethe, J. T.; Hong, H.; Lakner, F. J.; Concolino, T. E.; Rheingold, A. L. J. Am. Chem. Soc.
1999, 121, 2651.
4. Whitesell, J. K. Chem. Rev. 1992, 92, 953.
5. Shono, T.; Matsumura, Y.; Tsubata, K. Org. Synth. 1985, 63, 206.
6. Pilli, R. A.; de Oliveira, M. C. F. Nat. Prod. Rep. 2000, 17, 117.
7. (a) Franklin, A. S.; Overman, L. E. Chem. Rev. 1996, 96, 505; (b) Garraffo, H. M.; Caceres, J.; Daly, J. W.;
Spande, T. F.; Andriamaharavo, N. R.; Andriantsiferana, M. J. Nat. Prod. 1993, 56, 1016.
8. Casiraghi, G.; Rassu, G. Synthesis 1995, 607.
9. Pilli, R. A.; Russowsky, D. J. Chem. Soc., Chem. Commun. 1987, 1053.
10. (a) Martin, S. F.; Corbett, J. W. Synthesis 1992, 55. (b) Martin, S. F.; Barr, K. J.; Smith, D. W.; Bur, S. K. J.
Am. Chem. Soc. 1999, 121, 6990. (c) Martin, S. F.; Bur, S. K. Tetrahedron 1999, 55, 8905.
11. Morimoto, Y.; Nishida, K.; Hayashi, Y.; Shirahama, H. Tetrahedron Lett. 1993, 34, 5773.
12. Pichon, M.; Figade`re, B.; Cave´, A. Tetrahedron Lett. 1996, 37, 7963.
13. (a) Dale, J. A.; Dull, D. L.; Mosher, H. S. J. Org. Chem. 1969, 34, 2543; (b) Dale, J. A.; Mosher, H. S. J. Am.
Chem. Soc. 1973, 95, 512; (c) Sullivan, G. R.; Dale, J. A.; Mosher, H. S. J. Org. Chem. 1973, 38, 2143.
14. Ohtani, I.; Kusumi, T.; Kashman, Y.; Kakisawa, H. J. Am. Chem. Soc. 1991, 113, 4092.
.