Diastereoselection of the addition of silyloxyfurans to five-, six- and seven-membered N-acyliminium ions

Article abstract of DOI:10.1016/S0040-4039(01)01388-0

The addition of silyloxyfuran 1a to five-, six- and seven-membered N-acyliminium ions 2 afforded threo-3 as the major isomers (the structures of 3a, 3g and 3m were determined by X-ray analysis). The diastereoisomeric ratio increased with bulkier carbamate

Full text of DOI:10.1016/S0040-4039(01)01388-0

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 6995–6997
Diastereoselection of the addition of silyloxyfurans to five-, six-
and seven-membered N-acyliminium ions
Maria da Conceic¸a˜o F. de Oliveira, Leonardo Silva Santos and Ronaldo Aloise Pilli*
Instituto de Qu´ımica, UNICAMP, PO Box 6154, 13083-970 Campinas, SP, Brazil
Received 20 February 2001; revised 17 April 2001; accepted 27 July 2001
Abstract—The addition of silyloxyfuran 1a to five-, six- and seven-membered N-acyliminium ions 2 afforded threo-3 as the major
isomers (the structures of 3a, 3g and 3m were determined by X-ray analysis). The diastereoisomeric ratio increased with bulkier
carbamate groups (Boc>Cbz>CO2Me) with the five- and seven-membered N-acyliminium ions more selective than the six-mem-
bered ones. However, erythro-4 isomers predominated when 5-methylsilyloxyfuran 1b was employed (the structures were
determined by NOE studies on the corresponding bicyclic lactams 6a,b and 7a,b) and the formation of regioisomer 5 was observed
for N-acyliminium ions with Boc (seven-membered series) and Cbz (six- and seven-membered series) groups. © 2001 Elsevier
Science Ltd. All rights reserved.
Over the last few years 2-trialkylsilyloxyfurans1 have
been used as versatile reagents for the preparation of
enantiomerically pure compounds of biological interest,
among which homopumiliotoxins and Stemona alka-
loids have attracted our interest.2 We have investigated
the nucleophilic addition of carbon nucleophiles to
cyclic N-acyliminium ions and found the relevant role
played by the N-acyliminium ring size in the stereo-
chemical outcome of the reaction.3 As studies involving
the intermolecular nucleophilic addition of 2-trialkylsil-
yloxyfurans to cyclic N-acyliminium ions are so far
restricted to five-membered N-acyliminium ion rings
and mainly to N-carbobenzyloxy derivatives,4 we
decided to extend these studies to six- and seven-
membered rings containing Boc and CO2Me groups as
well.
H
n
H
n
H
2
n
TMSOTf
n
2
1«
N
R1
+
+
1«
N
R1
OR4
+
N
R1
5
OR2
R3 O
R3
O
R3 O
O
O
N
O
CH2Cl2
-78oC
R1
1a - R3=H, R4=TBS
1b - R3 =Me, R4=TIPS
O
4
3
n=3 3a/4a/5a - R1=Boc, R3=H
n=3 - 2a - R1=Boc, R2=Et
2b- R1=CBz, R2=Et
3b/4b/5b - R1=CBz, R3=H
3c/4c/5c - R1=CO2Me, R3=H
3d/4d/5d - R1=Boc, R3=Me
3e/4e/5e - R1=CBz, R3=Me
2c - R1=CO2Me, R2=Et
n=2 - 2d - R1=Boc, R2=Et
2e - R1=CBz, R2=Me
3f/ 4f/5f - R1=CO2Me, R3=Me
2f - R1=CO2Me, R2=Me
n=2 3g/4g/5g - R1=Boc, R3=H
3h/4h/5h - R1=CBz, R3=H
n=1 - 2g - R1=Boc, R2=Et
2h - R1=CBz, R2=Me
3i/ 4i /5i - R1=CO2Me, R3=H
3j/ 4j/ 5j - R1=Boc, R3=Me
3k/4k/5k - R1=CBz, R3=Me
3l/ 4l/ 5l - R1=CO2Me, R3=Me
2i - R1=CO2Me, R2=Me
n=1 3m/4m/5m - R1=Boc, R3=H
3n/4n/5n
- R1=CBz, R3=H
3o/4o /5o - R1=CO2Me, R3=H
Figure 1. Addition of 1a,b to 2a–i catalyzed by TMSOTf.
* Corresponding author. E-mail: pilli@iqm.unicamp.br
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)01388-0

6996
M. C. F. de Oli6eira et al. / Tetrahedron Letters 42 (2001) 6995–6997
ment was observed when the same experiment was
carried out with 6a and 6b. The relative stereochemistry
of the major isomers 4d,f and 4j,l8 was determined to be
the same as that for 4e and 4k after chemical correla-
tion as described above for 3b,c and 3h,i. The olefinic
hydrogens in the butenolide ring proved to be diagnos-
tic of the relative configuration of the adducts, as
previously mentioned by Martin4a for the H-2 signal: in
the erythro series the olefinic hydrogens are deshielded
as compared to the same ones in the minor threo
isomers. Additionally, the hitherto not observed
regioisomers 5d, 5e and 5j (relative configuration not
determined) were formed due to increased steric hin-
drance at C-5 in silyloxyfuran 1b.
The reactions involving the addition of 2-trialkylsilyl-
oxyfurans 1a,b to cyclic N-acyliminium ions 2a–f were
carried out in CH2Cl2 at −78°C using a catalytic
amount (10 mol%) of TMSOTf under an inert atmos-
phere (Fig. 1).5 The results are summarized in Table 1.
The relative configurations of the major stereoisomers
3a and 3g, obtained from non-substituted 2-silyloxy-
furan 1a, were determined by X-ray diffraction
analysis6 and the 2R*,1%R* configuration agrees nicely
with the one determined previously for the addition to
five-membered N-acyliminium ions.4a,b Compounds
3b,c or 3h,i were assigned the same relative configura-
tion as 3a and 3g, respectively, after chemical correla-
tion: Boc deprotection of 3a and 3g followed by
reprotection with benzyl or methyl chloroformate
afforded 3b,c and 3h,i, respectively. Interestingly, N-
Boc derivatives always provided the best diastereoselec-
tivities despite the ring size of the N-acyliminium ion
involved.
H
OH
N
( )
n
Me
Motivated by the influence of the nature of the carba-
mate group in the stereochemical outcome of the reac-
tion, we decided to investigate the corresponding
addition of 1a to 2g–i. In fact, the highest diastereoiso-
meric ratio in this series was observed for Boc deriva-
tive 2g (3m:4m=19:1), which represents a significant
improvement over the results described by Figade`re
and co-workers under different experimental condi-
tions.4c The 2R*,1%R* relative configuration of 3m was
established by X-ray analysis.6 As expected, lower selec-
tivities were observed for the carbomethoxy and car-
bobenzyloxy derivatives 2h and 2i.
O
6a, n=1
6b, n=2
H
Me
N
( )
n
OH
O
7a, n=1
7b, n=2
In the series derived from 5-methyl-2-silyloxyfuran 1b,
the 2R*,1%S* relative stereochemistry of the major iso-
mer was established through NOE experiments on the
corresponding bicyclic lactams 7a,b and 6a,b derived
from 3e,k and 4e,k,7 respectively: irradiation of the
methyl group in 7a and 7b provided a 2.5 and 3.4%
increment in H-9a/H-10a, respectively, while no incre-
Although the observed diastereoselectivity in the addi-
tion of silyloxyfuran 1a to cyclic N-acyliminium ions is
consistent with it’s acid-catalyzed additions to cyclic
electrophiles, which give preferentially threo adducts,4
the formation of the major isomers 4d–f and 4j–l in the
reactions of 1b with 2a–f is rather unexpected.
Table 1. Addition of silyloxyfurans 1a,b to carbamates 2a–i
Entry
n
Reagent
R1
R3
Products
dr (3:4:5)a
Yield (%)b
1
2
3
4
5
6
3
3
3
3
3
3
2a
2b
2c
2a
2b
2c
Boc
CBz
CO2Me
Boc
CBz
H
H
H
Me
Me
Me
3a:4a
3b:4b
3c:4c
3d:4d:5d
3e:4e:5e
3f:4f
12.6:1:0
6:1:0
4:1:0
1:3.8:3.5
1:9.1:7.4
1:2.3:0
83
46
49
80
75
70
CO2Me
7
8
9
10
11
12
2
2
2
2
2
2
2d
2e
2f
2d
2e
2f
Boc
CBz
CO2Me
Boc
CBz
H
H
H
Me
Me
Me
3g:4g
3h:4h
3i:4i
3j:4j:5j
3k:4k
3l:4l
7.5:1:0
2:1:0
3:1:0
1:18.5:11
1:2:0
1:5.2:0
58
63
74
67
75
70
CO2Me
13
14
15
1
1
1
2g
2h
2i
Boc
CBz
CO2Me
H
H
H
3m:4m
3n:4n
3o:4o
19:1:0
4:1:0
5:1:0
82
76
70
a Diastereoselectivity determined by GC and confirmed by 1H NMR analysis.
b Yields determined after column chromatography on silica gel of the crude mixture.

M. C. F. de Oli6eira et al. / Tetrahedron Letters 42 (2001) 6995–6997
6997
In conclusion, the data described herein clearly show
the role of the ring size of the N-acyliminium ion
controlling the diastereoselection, particularly for N-
Boc derivatives, to afford threo adducts as the major
isomers from silyloxyfuran 1a. Additionally, the forma-
tion of threo isomer 3 was enhanced by more sterically
hindered carbamates (Boc>Cbz>CO2Me). For silyloxy-
furan 1b, the picture was not as clear due to the
competitive formation of regioisomers 5d,e and 5j, but
for both six- and seven-membered N-acyliminium ions
erythro isomer 4 predominated over threo-3.
G.; Pinna, L.; Mor, M.; Culeddu, N.; Casiraghi, G. J. Org.
Chem. 1998, 63, 1368; (f) Martin, S. F.; Barr, K. J.; Smith,
D. W.; Bur, S. K. J. Am. Chem. Soc. 1999, 121, 6990; (g)
Pilli, R. A.; D’Oca, M. G. M.; Vencato, I. Tetrahedron
Lett. 2000, 41, 9709.
5. Pilli, R. A.; Russowsky, D. J. Chem. Soc., Chem. Commun.
1987, 14, 1053.
6. We are indebted to Professor Ivo Vencato, Departamento
de Qu´ımica, UFSC, Brazil, for kindly carrying out the
X-ray analyses. Crystallographic data (excluding structure
factors) for the structures 3m, 3g and 3a in this paper have
been deposited with the Cambridge Crystallographic Data
Centre as supplementary publication numbers CCDC-
158008, -158009 and -158010, respectively. Copies of the
data can be obtained, free of charge, on application to
CCDC, 12 Union Road, Cambridge CB2 1EZ, UK [fax:
+44 (0) 1223-336033 or e-mail: deposit@ccdc.cam.ac.uk].
7. Compounds 3e and 4e were hydrogenated (H2, Pd–C,
ethyl acetate), followed by cyclization (MeONa, MeOH,
rt) to afford lactams 6b and 7b, respectively (92 and 76%
yield, respectively).
An application of the results above in the total synthe-
sis of ( )-homopumiliotoxin 223G is described in the
following communication.
Acknowledgements
We thank Fapesp and CNPq for financial support and
fellowships.
8. Analytical data. Compound 3g: IR (film): 3097, 2979,
1
1743, 1685, 1597, 1454 cm−1; H NMR (300 MHz, CDCl3,
293 K): l 1.41 (s, 9H), 1.64 (m, br, 2H), 1.82 (m, br, 4H),
2.83 (d, br, J=13.1 Hz, 1H), 4.00 (s, br, 1H), 4.41 (s, br,
1H), 5.19 (s, br, 1H), 6.07 (s, br, 1H), 7.54 (d, br, J=4.9
Hz, 1H); 13C NMR (75.54 MHz, CDCl3, 293 K): l 19.8,
24.5, 27.0 (br), 28.2, 41.2 (br), 51.1 (br), 80.0, 87.1 (br),
121.1 (br), 154.9 (br), 172.8; HRMS (EI, 40 eV):
211.08752; calcd for C10H13NO4 (M+−C4H8): 211.08446.
Compound 4j: IR (film): 3086, 2976, 2937, 2871, 1768,
References
1. For reviews on the use of silyloxyfurans, see: (a) Casiraghi,
G.; Rassu, G. Synthesis 1995, 607; (b) Rassu, G.; Zanardi,
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2. Pilli, R. A.; de Oliveira, M. C. F. Nat. Prod. Rep. 2000, 17,
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3187; (b) Pilli, R. A.; Alves, C. D.; Bo¨ckelmann, M. A.;
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Alves, C. F. J. Braz. Chem. Soc., in press.
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acyliminium ions, see inter alia: (a) Martin, S. F.; Corbett,
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1
1689, 1452 cm−1; H NMR (300 MHz, CDCl3, 293 K): l
1.41 (s, 3H), 1.46 and 1.42 (2×s, 9H), 1.54–1.70 (m, br,
4H), 1.98 (d, br, J=6.9 Hz, 1H), 3.12 (t, br, J=12.8, 1H),
{[3.82 (d, br, J=12.8 Hz), 4.0 (d, br, J=12.8 Hz), 4.05–
4.20 (m, br), 4.30 (m, br) and 4.50 (s, br)], 3H}, {[5.90 (s,
br) and 6.07 (d, J=5.5 Hz)], 1H}, {[7.39 (d, J=5.5 Hz)
and 7.55 (s, br)], 1H}; 13C NMR (75.4 MHz, CDCl3, 293
K): 18.9 (br) and 20.4; 21.4 and 22.0 (br), 23.4, 24.0, 24.8,
28.2 and 28.3, 39.5 (br) and 40.8, 52.7 and 54.0 (br), 79.9,
118.4 (br) and 120.9, 156.4 (br), 159.5 (br) and 160.4, 172.2
(br); HRMS (IE, 40 eV): 224.0924; calcd for C11H14NO4
(M+−C4H9): 224.0923.