Iodine-mediated ring closing alkene iodoamination with N-debenzylation for the asymmetric synthesis of polyhydroxylated pyrrolidines

Article abstract of DOI:10.1055/s-2004-820031

An iodine-mediated ring closing alkene iodoamination with N-debenzylation protocol provides a direct route for the asymmetric synthesis of polyhydroxylated pyrrolidines from homochiral β-amino acid derivatives.

Full text of DOI:10.1055/s-2004-820031

LETTER
901
Iodine-mediated Ring Closing Alkene Iodoamination with N-Debenzylation
for the Asymmetric Synthesis of Polyhydroxylated Pyrrolidines
I
odine-mediat
t
ed Ring
e
Closing A
p
lkene Iodoam
h
ination
w
ith
e
N-Debenz
n
ylation G. Davies,* Rebecca L. Nicholson, Paul D. Price, Paul. M. Roberts, Andrew D. Smith
Department of Chemistry, Chemistry Research Laboratory, University of Oxford, Mansfield Road, Oxford, OX1 3TA, UK
E-mail: steve.davies@chemistry.oxford.ac.uk
Received 4 February 2004
racemisation of the N-a-methylbenzyl stereocentre had
Abstract: An iodine-mediated ring closing alkene iodoamination
occurred during the Ritter reaction. This N-deprotection
protocol shows remarkable chemoselectivity, with the
with N-debenzylation protocol provides a direct route for the asym-
metric synthesis of polyhydroxylated pyrrolidines from homochiral
selective removal of the N-a-methylbenzyl group in the
presence of the N-benzyl group being in direct contrast to
the previously reported chemoselective N-debenzylations
under oxidative10 or hydrogenative11 conditions that have
been developed upon similar systems from within this
laboratory. The isolation of racemic N-a-methylbenzyl-
acetamide (6) and pyrrolidines 4 and 5 from this reaction
manifold is consistent with the mechanism of this trans-
formation involving iodonium ion formation and intra-
molecular trapping by the tethered tertiary amine to give
quaternary ammonium species 3. Preferential SN1 loss of
the N-a-methylbenzyl protecting group from 3 accounts
for the remarkable chemoselectivity observed in this reac-
tion, with trapping of the resultant carbocation with
MeCN and subsequent hydrolysis giving (RS)-N-a-meth-
ylbenzylacetamide (6) (Scheme 1). This protocol of
cyclisation and N-debenzylation therefore offers a simple
direct stereoselective entry to polyhydroxylated pyrrol-
idines.12,13
b-amino acid derivatives.
Key words: conjugate addition, iodoamination, debenzylation,
cyclisation, pyrrolidine
The stereoselective syntheses of pyrrolidines and piper-
idines are of widespread academic and pharmaceutical in-
terest, both as natural product targets and for potential
applications in asymmetric synthesis. Within this expand-
ing field, the synthesis of polyhydroxylated derivatives of
these nitrogen heterocycles is of particular interest, as
these sugar mimics exhibit a diverse range of biological
activities, including potential as anti-HIV candidates1 and
as glycosidase inhibitors.2 As a result, a range of method-
ologies for their synthesis has been developed, including
manipulation of carbohydrates3 and the application of
asymmetric synthesis.4 Previous work from this laborato-
ry has shown that the conjugate addition of homochiral
lithium amides derived from a-methylbenzylamine to
a,b-unsaturated esters provides a general methodology for
the asymmetric synthesis of b-amino acids.5 As an exten-
sion of this versatile methodology we report herein a
stereoselective iodine-mediated ring closing alkene iodo-
amination with concomitant N-debenzylation for the
asymmetric synthesis of polyhydroxylated pyrrolidine b-
amino acid derivatives.6
With the pyrrolidine skeleton in hand from this novel
debenzylation protocol, functionalisation of the primary
iodide was investigated. Treatment of iodide 4 (>98% de)
with AgOAc in toluene gave the acetate 7 as a single dia-
stereoisomer in 79% yield after purification. However,
similar exposure of the diastereoisomeric iodide 5 to iden-
tical conditions gave an inseparable 45:55 mixture of the
pyrrolidine and piperidine acetates 9:10 in 82% overall
yield. The possible intermediacy of an aziridinium ion in
these transformations from participation of the adjacent
N-atom is well precedented,14 with mechanistic studies in-
dicating that the regioselectivity of aziridinium opening is
dependent upon the nature of the nucleophile15 and
solvent16 and both steric and electronic substituent ef-
fects.17 To probe the involvement of an aziridinium ion in
this protocol, treatment of iodide 4 with AgBF4 gave the
isolable aziridinium 8 in quantitative yield, which upon
treatment with NaOAc in toluene gave acetate 7 as a sin-
gle diastereoisomer in 70% yield. Treatment of the diaste-
reoisomeric iodide 5 with AgBF4 similarly gave a
quantitative yield of aziridinium 11, which upon treatment
with NaOAc in toluene gave a 45:55 mixture of the
pyrrolidine and piperidine acetates 9:10 in 62% isolated
yield, confirming the intermediacy of an aziridinium ion
in each AgOAc promoted displacement (Scheme 2).
Conjugate addition of homochiral lithium (R)-N-benzyl-
N-a-methylbenzylamide to the a,b-unsaturated acceptor
(4S,5R)-17 gave b-amino ester (3S,4S,5R)-2 in 88% de,
and after purification in 70% isolated yield with >98%
de.8 Treatment of b-amino ester (3S,4S,5R)-2 with iodine
in MeCN in the presence of NaHCO3 gave a chromato-
graphically separable 81:19 mixture of N-benzyl pyrrol-
idines 4:5 in 63% and 17% isolated yield respectively and
as single diastereoisomers in each case, in which ring clo-
sure to the pyrrolidine and chemoselective N-deprotection
had been effected in a single reaction step. Furthermore,
N-a-methylbenzylacetamide (6) was also isolated, whose
25
25
specific rotation {[a]D –3.8 (c 0.7, CHCl3); lit.,9 [a]D
+129.5 (c 1.0, CHCl3)} indicated that essentially complete
SYNLETT 2004, No. 5, pp 0901–0903
Advanced online publication: 04.03.2004
DOI: 10.1055/s-2004-820031; Art ID: D02304ST.pdf
© Georg Thieme Verlag Stuttgart · New York
0
2.
0
4.
2
0
0
4

902
S. G. Davies et al.
LETTER
Ph
In the major diastereoisomeric series, N-debenzylation of
7 followed by basic hydrolysis of the acetate gave the al-
cohol 12 in good yield and as a single diastereoisomer, the
absolute configurations within which were established
unambiguously by X-ray crystallographic analysis, rela-
tive to the known absolute configurations of the (3R,4S)-
stereocentres derived from D-ribose (Figure 1).18 Subse-
quent acidic hydrolysis and ion exchange gave the desired
b-amino acid 13 in 78% yield as a single diastereoisomer
(Scheme 3).
Ph
N
t
t
i
CO2 Bu
CO2 Bu
O
O
O
O
2, 70%, >98% d.e.
1
ii
Ph
Ph
O
Ph
I
Ph
I
t
t
CO2 Bu
CO2 Bu
Ph
N
N
t
t
OH
CO2 Bu
iii, iv
OAc
CO2 Bu
i, ii
61%
OH
CO2H
H
N
H
N
Ring
Closure
N
O
O
O
78%
O
O
O
O
OH
HO
3
13
7
12
Ph
O
Ph
N
t
t
I
CO2 Bu
I
CO2 Bu
Scheme 3 Reagents and conditions: (i) Pd(OH)2 on C, MeOH, H2
(1 atm); (ii) K2CO3, MeOH; (iii) TFA then H2O; (iv) Dowex 50W-X8.
O
N
+
Ph
N
+
H
O
O
O
6, 73%
4:5 81:19
4, Major
63%, >98% d.e.
5, Minor
17%, >98% d.e.
Scheme 1 Reagents and conditions: (i) Lithium (R)-N-benzyl-N-a-
methylbenzylamide, Et2O, –20 °C; (ii) I2, NaHCO3, MeCN.
(ii) quant
–
Ph
O
BF4
Ph
Ph
t
t
t
Figure 1 Chem 3D representation of the X-ray crystal structure of
(2R,3R,4S,5S)-12.
CO2 Bu
I
CO2 Bu
OAc
CO2 Bu
iii
N
N
N
i
70%
79%
In conclusion, the protocol described herein delineates a
rapid and efficient route for the asymmetric synthesis of
polyhydroxylated pyrrolidines. The generality of this
transformation and its application to natural product syn-
thesis is currently under investigation.
O
O
O
O
O
4
7
8
Ph
Ph
Ph
t
CO2 Bu
t
t
I
CO2 Bu
OAc
CO2 Bu
N
N
N
+
i
82%
Acknowledgement
AcO
O
O
O
O
O
O
The authors wish to thank New College, Oxford for a Junior Re-
search Fellowship (A. D. S).
5
9
10
62%
iii
References
–
Ph
BF4
t
CO2 Bu
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(ii) AgBF4, CH2Cl2, r.t.; (iii). NaOAc, toluene, r.t.
Synlett 2004, No. 5, 901–903 © Thieme Stuttgart · New York

LETTER
Iodine-mediated Ring Closing Alkene Iodoamination with N-Debenzylation
903
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Synlett 2004, No. 5, 901–903 © Thieme Stuttgart · New York