Enhanced trans diastereoselection in the allylation of cyclic chiral N-acyliminium ions. Synthesis of hydroxylated indolizidines

Article abstract of DOI:10.1016/S0040-4039(01)01084-X

A short synthesis of hydroxylated indolizidines is reported. The key steps were the allylation of chiral cyclic N-acyliminium ions derived from malic and tartaric acids, followed by ring-closing metathesis.

Full text of DOI:10.1016/S0040-4039(01)01084-X

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 5605–5608
Enhanced trans diastereoselection in the allylation of cyclic
chiral N-acyliminium ions. Synthesis of hydroxylated
indolizidines
Cle´cio Fernando Klitzke and Ronaldo Aloise Pilli*
Instituto de Qu´ımica, UNICAMP, PO Box 6154, Campinas, SP 13083-970, Brazil
Received 11 February 2001; revised 15 June 2001; accepted 19 June 2001
Abstract—A short synthesis of hydroxylated indolizidines is reported. The key steps were the allylation of chiral cyclic
N-acyliminium ions derived from malic and tartaric acids, followed by ring-closing metathesis. © 2001 Elsevier Science Ltd. All
rights reserved.
Polyhydroxylated indolizidine alkaloids are sugar mim-
ics which inhibit glycosidases with promising potential
as drugs against viruses, cancers and diabetes.1 A large
number of representative structures were isolated from
natural sources and the synthesis of the corresponding
stereoisomers and analogues is actively pursued particu-
larly for structure–activity studies.1,2 A variety of meth-
ods have been reported for the synthesis of indolizidine
alkaloids and lentiginosine, swainsonine, and cas-
tanospermine (Fig. 1) rank among the more popular
synthetic targets.
acyliminium ion derived from malic acid and reversal of
the sense of diastereoselection (up to 4:1 cis:trans ratio)
was observed when O-TBS and O-benzyl derivatives
were employed.3b,c
In the course of an investigation aimed to prepare
C-1/C8a trans-configured hydroxylated indolizidines,
we evaluated the influence of the Lewis acid on the
addition of allyltrimethylsilane and allyltributyltin to
N-acyliminium ions4 derived from malic and tartaric
acids.
An useful synthetic approach to the structural motif
found in this family of alkaloids is the allylation of the
N-acyliminium ion derived from malic or tartaric acids.
In fact, the stereochemical outcome of the addition of
allyltrimethylsilane to N-acyliminium ions derived from
To this purpose, N-allyl imide 2 was prepared from
inexpensive
L-malic acid in 92% yield, according to
literature procedure (Scheme 1).3a In order to investi-
gate the effect of the nature of the O-protective group
in the allylation reaction, imide 2 was converted to 3 by
treatment with acetyl chloride in ethanol, followed by
TBS protection. Regioselective reduction of 2 and 3,
and acetylation provided intermediates 4 and 5 in good
yield.
imides
2 and 3 has being examined previously.
Speckamp3a and Scolastico3b reported on the moderate
trans preference (up to 3:1 ratio) in the addition of
allyltrimethylsilane
to
the
O-acetyl
N-benzyl
Figure 1.
Keywords: hydroxylated indolizidines; allylation; N-acyliminium ions; olefin metathesis.
* Corresponding author. Fax: 55 19 37883023; e-mail: pilli@iqm.unicamp.br
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)01084-X

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C. F. Klitzke, R. A. Pilli / Tetrahedron Letters 42 (2001) 5605–5608
Scheme 1. Reagents and conditions: (a) (i) AcCl, reflux; (ii) allylamine, CH2Cl2, rt; (iii) AcCl, reflux (2, 92%); (b) (i) AcCl, EtOH;
(ii) TBSCl, imidazole, DMF (3, 80%); (c) (i) NaBH4, EtOH, −23°C; (ii) Ac2O, Et3N, DMAP, CH2Cl2 (4, 73%; 5, 65%); (d) see
Table 1; (e) 4 mol% Grubbs’ catalyst, CH2Cl2 (8, 82%; 95% d.e.); (f) (i) H2, Pd/C, AcOEt; (ii) LiAlH4, THF, reflux (9, 78%).
Table 1. Effect of Lewis acid and nucleophile in the allyl-
ation of chiral cyclic N-acyliminiumions derived from
malic and tartaric acids (See Scheme 1)a
N-allyl lactams 4 and 5 were treated with Lewis acids
(4.0 equiv.) to ensure in situ formation of the corre-
sponding N-acyliminium ion, followed by the addition
of the allyltrimethylsilane or tri-n-butylallyltin (Table
1). With most of the Lewis acid investigated, the addi-
tion to 4 proceeded in good yield but with trans prefer-
ence within the same range as observed earlier for the
N-benzyl analogue,3a,b including the use of 1.0 equiv. of
TiCl4.5 However, with 4.0 equiv. of TiCl4 preparatively
useful 7:1 trans:cis ratio (83% yield) was observed
(entry 6). Coordination of the oxophilic Lewis acid at
the neighboring OAc group enforced by the excess of
TiCl4 may be the reason for the enhancement of trans
selectivity.
Entry
Substrate
Nucleophile
Lewis acid cis:trans ratiob
1
2
3
4
5
6
7
8
4
4
4
4
4
4
4
4
4
4
4
4
5
5
5
5
Allylsilane
Allylsilane
Allylsilane
Allylsilane
Allylsilane
Allylsilane
Allylsilane
Allylstannane BF3·OEt2
Allylstannane SnCl4
Allylstannane InCl3
Allylstannane TiF4c
Allylstannane TiCl4
Allylsilane
Allylsilane
Allylstannane BF3·OEt2
Allylstannane MgBr2
Allylstannane TiCl4
TMSOTf
BF3·OEt2
SnCl4
1:3.5
1:2.5
1:3.2
1:4
1:2
1:7
InCl3
c
TiF4
TiCl4
K-10d
1:2.5
1:1.8
e
9
–
–
e
10
11
12
13
14
15
16
17
18
19
20
21
1:1
2:1
The addition of allyltributyltin afforded low trans selec-
tivity possibly as a result of its superior nucleophilicity.6
Surprisingly, allyltribuyltin did not react when SnCl4 or
BF3·OEt2
TiCl4
1.8:1
2.2:1
2.2:1
2.2:1
1.8:1
1:1
1:1
2.5:1
4:1
7
f
InCl3 were used as Lewis acid (entry 9 and 10) and the
use of TiCl4 led to reversal of selectivity (entry 12). At
this point, transmetalation to an allyltitanium species
able to coordinate to the O-acetyl group cannot be
ruled out to explain the cis preference observed in this
case.8
5
13
13
14
14
Allylsilane
Allylsilane
Allylsilane
BF3·OEt2
TiCl4
BF3·OEt2
Allylstannane BF3·OEt2
a Unless otherwise stated, all reactions were performed in dry CH2Cl2
at 0°C, adding 4 equiv. of Lewis acid to a solution of the substrate
and 3 equiv. of the nucleophile.
In analogy with previous results,3c low cis preference
(1.8–2.2:1 ratio) was observed for 3-O-TBS N-allyl
lactam 5 (entries 13–17), a result which may be ratio-
nalized through the stabilization of the emerging s*
orbital by interaction with the adjacent and antiperipl-
anar sCH bond.9
b Determined by 1H NMR and/or GC analysis.
c Reaction peformed in CH3CN/CH2Cl2.
d 80 mg Montmorillonite K-10 per mmol of substrate, rt.
e 5-Hydroxy lactam recovered.
f Reaction performed in toluene, rt.
The addition of allyltrimethylsilane to N-allyl lactam 13
derived from (2R,3R)-tartaric acid (Scheme 2) either in
the presence of 4.0 equiv. of TiCl4 or BF3·OEt2
occurred without stereochemical preference (entries 18
and 19). In order to enforce cis addition to N-allyl
3-O-TBS lactam 14, the use of BF3·OEt2 and
allytributyltin was necessary (entry 21).10

C. F. Klitzke, R. A. Pilli / Tetrahedron Letters 42 (2001) 5605–5608
5607
Scheme 2. Reagents and conditions: (a) (i) AcCl, reflux; (ii) allylamine, CH2Cl2, rt; (iii) AcCl, reflux (11, 99%); (b) (i) AcCl, EtOH;
(ii) TBSCl, imidazole, DMF (12, 83%); (c) (i) NaBH4, EtOH, −23°C; (ii) Ac2O, Et3N, DMAP, CH2Cl2 (13, 76%; 14, 69%); (d)
see Table 1 (15, 89%; cis:trans 1:1; 16, 95%; cis:trans 2.5:1); (e) 4 mol% Grubbs’ catalyst, CH2Cl2 (17, 44%; 18, 44%); (f) (i) H2,
PtO2, AcOEt; (ii) LiAlH4, THF, reflux (19, 82%; 20, 60%).
Acknowledgements
The results discussed above paved the way to convert 6
to bicyclic lactam 8 (82% yield) through ring-closing
metathesis11 which also provided a convenient way to
separate the minor epimer formed by column chro-
matography (Scheme 1). Finally, hydrogenation and
The authors thank FINEP for financial support and
CNPq for fellowships.
reduction of
8
afforded (1S,8aR) 1-hydroxyin-
dolizidine(9), the enantiomer of the biosynthetic precur-
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accordance with the proposed structures. Compound 8:
[h]2D6 +14.3 (c 2.37, CHCl3); IR (neat) 3037, 2929, 2848,
1
1737, 1699, 1656, 1440, 1375, 1236, 1055; H NMR (300
MHz, CDCl3): l 1.95–2.09 (m, 1H), 2.05 (s, 3H), 2.37–
2.47 (m, 2H), 2.77 (dd, J 8.1 and 18.4 Hz, 1H), 3.50–3.57
(m, 2H), 4.32 (dd, J 2.7 and 18.4 Hz, 1H), 4.94 (dt, J 2.5
and 7.7 Hz, 1H), 5.64–5.68 (m, 1H), 5.73–5.78 (m, 1H);
13C NMR (75 MHz, CDCl3): l 20.72, 28.62, 36.30, 39.85,
59.28, 71.67, 123.77, 123.81, 170.63, 170.66; HRMS (EI)
calcd for C10H13NO3 (M+.) 195.0895, found 195.0895.
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3016, 2936, 2852, 1749, 1725, 1653, 1432, 1371, 1239,
1
1058; H NMR (300 MHz, CDCl3): l 2.13 (s, 3H), 2.16
(s, 3H), 2.19–2.26 (m, 1H), 2.57 (dl, J 16.8 Hz, 1H), 3.51
(dt, J 4.6 and 10.5 Hz, 1H), 3.64 (d, J 18.8 Hz, 1H), 4.33
(dd, J 2.9 and 18.8 Hz, 1H), 5.08 (dd, J 5.1 and 5.3 Hz,
1H), 5.46 (dd, J 1.4 and 5.3 Hz, 1H), 5.72–5.75 (m, 1H),
5.82–5.85 (m, 1H); 13C NMR (75 MHz, CDCl3): l 20.67,
20.75, 30.02, 40.16, 55.22, 74.39, 77.69, 122.29, 123.53,
166.44, 170.00, 170.36; HRMS (EI) calcd for C12H15NO5
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+167.1 (c 1.12, CHCl3); IR (neat) 3040, 2935, 2858, 1744,
1
1715, 1595, 1433, 1375, 1256, 1069; H NMR (300 MHz,
CDCl3): l 2.01–2.19 (m, 2H), 2.14 (s, 3H), 2.17 (s, 3H),
3.61 (d, J 18.3 Hz, 1H), 4.02 (ddd, J 4.4, 6.9 and 11.2 Hz,
1H), 4.38 (dd, J 2.9 and 18.3 Hz, 1H), 5.43–5.50 (m, 2H),
5.70–5.74 (m, 1H), 5.80–5.87 (m, 1H); 13C NMR (75
MHz, CDCl3): l 20.37, 20.51, 24.95, 40.46, 52.35, 72.71,
73.71, 123.59, 123.84, 165.98, 170.09, 170.44; HRMS (EI)
calcd for C12H15NO5 (M+.) 253.0950, found 253.0956.
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