Diastereoselective iodoamidation of 3-acetyloxybut-1-enylamines: Simple synthesis of a precursor of aza sugars involving a pyrrolidine ring

Article abstract of DOI:10.1039/a809083a

3-Acetyloxybut-1-enylamines 3-9 were easily transformed using iodine to pyrrolidine derivatives 3a-9a, precursors for aza sugars, via a diastereoselective iodoamidation.

Full text of DOI:10.1039/a809083a

Diastereoselective iodoamidation of 3-acetyloxybut-1-enylamines: simple
synthesis of a precursor of aza sugars involving a pyrrolidine ring
Woo Song Lee, Ki Chang Jang, Jin Hyo Kim and Ki Hun Park*
Department of Agricultural Chemistry, Gyeongsang National University, Chinju 660-701, Korea.
E-mail: khpark@gshp.gsnu.ac.kr
Received (in Cambridge, UK) 20th November 1998, Accepted 23rd December 1998
3-Acetyloxybut-1-enylamines 3–9 were easily transformed
using iodine to pyrrolidine derivatives 3a–9a, precursors for
aza sugars, via a diastereoselective iodoamidation.
compounds 8 and 9 were treated with I2 in THF to give the
corresponding trans-8a and cis-9a in 92% (based on 65%
conversion) and 88% (based on 80% conversion) yields,
respectively (Table 2). The structures of all pyrrolidines 3a–9a
were confirmed by their characteristic spectroscopic data.§
The relative stereochemistries of the products 3a and 4a were
Since the discovery that polyhydroxylated pyrrolidines are
potent glycosidase inhibitors with potential therapeutic utility in
the treatment of various diseases such as diabetes,1 cancer2 and
viral infections,3 much attention has been concentrated on the
development of convenient and efficient routes to these
compounds. In general, synthetic routes to aza sugars require
azide displacement/reduction and intramolecular N-alkylative
cyclisation with protecting group manipulation,4 starting from
carbohydrates or non-carbohydrates. Here we report the highly
diastereoselective iodoamidation of 3-acetlyoxybut-1-enyl-
amines 1 for the preparation of pyrrolidine derivatives 2 (e.g.
anisomycine,5 3,4-dihydroxyprolinol,6 swainsonine7 and lenti-
ginosine8) (Scheme 1).
The requisite substrates 3–9 were prepared easily by the usual
method from commercially available l-tyrosin, l-phenyl-
alanine and l-serine.9† Fortunately, each diastereomeric allylic
alcohol given by the Grignard reaction could be isolated in pure
form by column chromatography. We chose the 9-phenyl-
fluoren-9-yl (Pf) group for protection of the amine since this
protecting group has been shown to inhibit deprotonation at the
a-position of a-amino aldehydes.10 a-Amino aldehydes having
the Pf group are very stable to Grignard reaction conditions.11
Compound 3 was treated with I2 under biphasic conditions
(aq. NaHCO3–THF–Et2O = 2: 1: 1) at room temperature for
3 h to give the all trans pyrrolidine 3a (vide infra) as the sole
product in high yield via a diastereoselective iodoamidation.
Although THF, MeOH, CH2Cl2 and MeCN have been found to
be acceptable solvents for iodoamidation, these solvents
required much longer reaction times and resuted in 35–50%
recovery of the starting material. As shown in Table 1, the
optimum reaction conditions involved biphasic conditions to
improve reactivity and affording pyrrolidine 3a.
1
determined from their H NMR spectra based on the coupling
constant values and 2D NOE experiments. For trans-3a, proton
H3 (t like, J2,3, J3,4 = 5.1 Hz) adjacent to the acetyloxy group
gave weak correlation with protons (H2 and H4) adjacent to the
p-tolylmethyl and iodine groups, but strong NOE cross peaks
were observed between H2–H4 and H2–H5b, thereby allowing
one to assign its relative stereochemistry. In pyrrolidine cis-4a,
proton H3 (t like, J2,3, J3,4 = 6.9 Hz) adjacent to the acetyloxy
group displayed strong mutual correlation with the protons (H2
and H4) adjacent to the p-tolylmethyl and iodine groups, thereby
verifying the structure of cis-4a as shown in Fig. 1.
1
Based on the coupling constant values in the high-field H
NMR spectra of trans-3a and cis-4a, the stereochemistries of
trans-5a (H3, t like, J2,3, J3,4 = 5.1 Hz) and cis 6a (H3, t like,
J2,3, J3,4 = 6.9 Hz) could be determined from each coupling
constant value. The stereochemistries of trans-8a (H3, dd, J2,3
= 4.8, J3,4 = 3.4 Hz) and cis 9a (H3, dd, J2,3 = 2.4, J3,4 = 4.2
Hz) were also confirmed using coupling constant values.
Although numerous construction methods for the electro-
philic cyclisation have been developed,12 the closest literature
precedent to this haloamidation has been independently studied
by the groups of Takahata13 and Yoshida.14 Takahata has shown
that iodine-induced lactamization of g,d-unsaturated thioimi-
dates proceeds regioselectively to provide g-lactams. Yoshida
has reported that N-(p-tolylsulfonyl)pent-4-enylamines were
subjected to stereoselective haloamidation to afford mainly cis
substituted pyrrolidines. Although these methodologies have
been proven to be useful protocols, they are of limited use for
the direct synthesis of polyhydroxylated aza sugars because
these reactions proceed via 5-exo-trig cyclisation. Thus, we are
the first to observe chiral induction on the pyrrolidine ring
through an diastereoselective iodoamidation and to succeed in
Treatment of 4 under the same conditions afforded a 25 : 1
ratio of the cis and trans isomers of pyrrolidine 4a. Compounds
5 and 6 were cyclized according to these standard conditions to
give the expected the corresponding pyrrolidines trans-5a and
cis-6a in high yield, respectively. Compound 7 was also
exposed to the same reaction conditions to give cis-7a in a ratio
of 20: 1 in 66% yield. In the case of starting materials trans-8
and cis-9,‡ this solvent mixture was not suitable. Thus,
Table 1 Solvent effects in stereoselective iodoamidationa
OAc
AcO
I
MeO
I2
solvent
NH
Pf
3
N
MeO
Solvent
Pf
3a
AcO
I
OAc
I2/equiv.
t/h
Yield (%)b
I2
R
R
THF
3.0
3.0
3.0
3.0
3.0
15
18
6
6
3
48c
45d
50e
60f
92
N
Pf
NH
Pf
MeOH
CH2Cl2
MeCN
Biphaseg
a
1
2
Pf =
b
All reactions were carried out under room temperature. Isolated yield.
c 48% Recovery of starting material. d 40% Recovery of starting material.
e
f
50% Recovery of starting material. 35% Recovery of starting material.
g NaHCO3–THF–Et2O = 2:1:1.
Scheme 1
Chem. Commun., 1999, 251–252
251

Table 2 Diastereoselective iodoamidation of 3-acetoxybut-1-enylamines
with iodine
This work was supported by a grant from the High-
technology Development Project for Agriculture, Forestry and
Fisheries. We thank the Korea Science and Engineering
Foundation for a fellowship supporting the Postdoctoral
research of Dr Woo Song Lee.
Substratesa
Conditions
Productsb
Yieldc
AcO
I
OAc
92%
(sole)
I2,biphase,d
room temp. 3 h
R
R
N
Pf
NHPf
3 R = p-tolyl
3a
Notes and references
AcO
I
OAc
† Starting materials 3–9 were prepared by a sequential reaction, namely,
free animo acids were treated with TMSCl in MeOH to give methyl esters,
the amino groups of which were protected with PfBr in CH2Cl2. The methyl
esters were then subjected to reduction and Swern oxidation to afford
aldehydes, which were reacted with vinylmagnesium bromide to give
separable allylic alcohols.
‡ The relative stereochemistries of the corresponding acetonides trans-8 (J
= 8.1 Hz for the proton on oxygen) and cis-9 (J = 1.0 Hz for the a proton
on oxygen) were confirmed by coupling constant analysis.
90%
(25 : 1)
I2,biphase,
R
R
room temp. 3.5 h
N
NHPf
Pf
4 R = p-tolyl
4a
AcO
I
I
OAc
OAc
90%
(62 : 1)
I2,biphase,
room temp. 3 h
N
NHPf
Pf
5
6
5a
AcO
§ Selected data for 3a: colorless prisms, mp 67–68 °C; [a]2D2 +33.0 (c 1.3,
CHCl3); dH (500 MHz, CDCl3) 1.61 (3H,s), 2.37 (1H, dd, J 4.0, 13.6), 2.44
(1H, dd, J 6.7, 10.1), 2.67 (1H, dd, J 9.7, 13.6), 2.73 (1H, m), 3.00 (1H, dd,
J 2.7, 10.2), 3.28 (1H, dt, J 4.3, 5.1), 3.71 (3H, s), 4.56 (1H, t-like, J2,3, J3,4
5.1), 6.72 (2H, d, J 8.7), 6.89 (2H, d, J 8.7), 7.23–7.34 (13H, m). For 4a:
colorless prisms, mp 70–71 °C; [a]2D0 222.9 (c 1.2, CHCl3); dH (500 MHz,
CDCl3): 2.08 (3H, s), 2.19 (1H, dd, J 3.4, 14.1), 2.65 (1H, dd, J 3.7, 9.2),
2.86 (1H, dd, J 10.9, 14.1), 3.17 (1H, dd, J 9.2, 11.2), 3.43 (1H, ddd, J 3.5,
7.2, 10.8), 3.55 (1H, ddd, J 3.7, 7.2, 8.1), 5.17 (1H, t like, J2,3, J3,4 6.9), 6.65
(2H, d, J 8.7), 6.87 (2H, d, J 8.7), 7.24–7.75 (13H, m).
90%
(5 : 1)
I2,biphase,
room temp. 3 h
N
Pf
NHPf
OAc
6a
AcO
I
66%
(21 : 1)
I2,biphase,
room temp. 10 h
MOMO
MOMO
N
Pf
NHPf
7
7a
Me
O
Me
HO
I
O
92%e
(20 : 1)
I2,THF,
room temp. 10 h
HO
1 S. Horri, H. Fukase, T. Matsuo, Y. Kameda, N. Asano and K. Matsui,
J. Med. Chem., 1986, 29, 1038.
2 M. A. Spearman, J. C. Jamieson and J. A. Wright, Exp. Cell Res., 1987,
168, 116; K. Tsukamoto, A. Uno, S. Shimada and G. Imokaw, Clin.
Res., 1989, 37A, 722.
N
Pf
NHPf
8
Me
8a
Me
O
HO
I
O
88%f
(sole)
I2,THF,
room temp. 10 h
3 A. Karpas, G. W. J. Fleet, R. A. Dwek, S. Petursson, S. K. Mamgoong,
N. G. Ramsden, G. S. Jacob and T. W. Rademacher, Proc. Natl. Acad.
Sci. U.S.A., 1988, 85, 9229; G. W. J. Fleet, FEBS Lett., 1988, 237,
128.
4 G. Kinast and M. Schedel, Angew. Chem. Int. Ed. Engl., 1981, 20, 805;
A. Vasella and R. Voeffray, Helv. Chim. Acta, 1982, 65, 1134; H. Iida,
N. Yamazaki and C. Kibayashi, J. Org. Chem., 1987, 52, 3337; D.
Beaupere, B. Stasik, R. Uzan and G. Demailly, Carbohydr. Res., 1989,
191, 163; C. H. von der Osten, A. J. Sinskey, C. F. Barbas, R. L.
Pederson, Y.-F. Wang and C.-H. Wong, J. Am. Chem. Soc., 1989, 111,
3924; G. W. J. Fleet, N. M. Carpenter, S. Petursson and N. J. Ramsden,
Tetrahedron Lett., 1990, 31, 409; A. Straub, F. Effenberger and P.
Fischer, J. Org. Chem., 1990, 55, 3926.
5 D. P. Schumacher and S. S. Hall, J. Am. Chem. Soc., 1982, 104, 6076;
H. H. Baer and M. Zamkanei, J. Org. Chem., 1988, 53, 4786; R. Ballini,
E. Marcantoni and M. Petrini, J. Org. Chem., 1992, 57, 1316.
6 G. W. J. Fleet, S. J. Nicolas, P. W. Smith, S. V. Evans, L. E. Fellows and
R. J. Nash, Tetrahedron Lett., 1985, 26, 3127; N. Asano, K. Oseki and
K. Matsui, J. Med. Chem., 1994, 37, 3710.
7 H. Setoi, H. Takeno and M. Hashimoto, J. Org. Chem., 1985, 50, 3948;
R. B. B. III, J.-R. Choi, W. D. Montgomery and J. K. Cha, J. Am. Chem.
Soc., 1989, 111, 2580.
HO
N
Pf
NHPf
9
9a
a
b
All allylic alcohols are enantiomeric pure. The stereochemistry was
signed by 1H NMR and 2D NOE experiments. c Isolated yields. d 3 equiv.
e
of I2, aq. NaHCO3–THF–Et2O = 2:1:1. Based on 65% conversion of
starting material and 35% cleavage of the isopropylidene group of 8. f Based
on 80% conversion of starting material and 20% cleavage of the
isopropylidene group of 9.
Pf
Pf
I
I
H3 H5a
OAc
N
N
H4
H4
H5b
OAc
H2
H2
MeO
MeO
H3
NOE
NOE
NOE
3a
4a
Fig. 1 NOE interactions derived from NOESY experiments.
8 S. Nukui, M. Sodeoka, H. Sasaki and Shibasaki, J. Org. Chem., 1995,
60, 398.
using a strong electron-donating group, 9-phenylfluoren-9-yl
(Pf), on an amine moiety.
9 F. J. Sardina and H. Rapoport, Chem. Rev., 1996, 96, 1825.
10 W. D. Lubell and H. Rapoport, J. Am. Chem. Soc., 1987, 109, 236.
11 M. Gerspacher and H. Rapoport, J. Org. Chem., 1991. 56, 3700.
12 S. Robin and G. Rousseau, Tetrahedron, 1998, 54, 13681.
13 H. Takahata, T. Tamotsu and Y. Takao, J. Org. Chem., 1989, 54, 4812;
H. Takahata, K. Yamazaki, T. Takamatsu, T. Yamazaki and T. Momose,
J. Org. Chem., 1990, 55, 3947.
14 Y. Tamaru, S. Kawamura, K. Tanaka and Z. Yoshida, Tetrahedron Lett.,
1984, 25, 1063; Y. Tamaru, S.-i. Kawamura, T. Bando, K. Tanaka, M.
Hojo and Z.-i. Yoshida, J. Org. Chem., 1988, 53, 5491.
In conclusion, we found that optically active starting
materials 1 as chiral building blocks are converted easily to
pyrrolidine derivatives 2 via a diastereoselective iodoamidation.
These species should be valuable for the total synthesis of
polyhydroxylated aza sugars having a pyrrolidine ring and may
be suitable for substitution with various nucleophiles (NaN3,
amines, alcohols, thiols and Grignard compounds), giving novel
aza sugar derivatives. Thus, we are currently investigating the
preparation of all six diasteromers of anisomycin and other
3,4-dihydroxyprolinols.
Communication 8/09083A
252
Chem. Commun., 1999, 251–252