Iodine-induced cyclizations of N-alkoxyaminoalkenes. A stereocontrolled approach to trans-2,6-disubstituted piperidine alkaloids

Article abstract of DOI:10.3987/COM-04-S(P)26

Iodine-induced intramolecular cyclizations of γ-alkenyl-N-alkoxyamines preferentially produce 2,6-rans-disubstituted piperidines. Subsequent iodoetherifications of N-benzyloxypiperidines demonstrate the stereoselective transfer of oxygen to a proximate ca

Full text of DOI:10.3987/COM-04-S(P)26

HETEROCYCLES, Vol. 64, 2004
45
HETEROCYCLES, Vol. 64, 2004, pp. 45 - 50
Received, 23rd July, 2004, Accepted, 16th September, 2004, Published online, 17th September, 2004
IODINE-INDUCED CYCLIZATIONS OF N-ALKOXYAMINOALKENES.
A STEREOCONTROLLED APPROACH TO trans-2,6-DISUBSTITUTED
PIPERIDINE ALKALOIDS†
David R. Williams,* Martin H. Osterhout, and George S. Amato
Indiana University, Department of Chemistry, 800 East Kirkwood Avenue,
Bloomington, Indiana 47405-7102, U.S.A.
Abstract – Iodine-induced intramolecular cyclizations of γ-alkenyl-N-
alkoxyamines preferentially produce 2,6-trans-disubstituted piperidines.
Subsequent iodoetherifications of N-benzyloxypiperidines demonstrate the
stereoselective transfer of oxygen to a proximate carbon via formation of bicyclic
1,3-syn-isoxazolidines. The strategy facilitates preparation of nonracemic
piperidine diols from acyclic, optically active alcohols.
Piperidine alkaloids are among the most common heterocyclic natural products, and many studies have
examined the development of stereoselective pathways for the preparation of functionalized examples of
this family.1,2 In part, these efforts have significantly contributed toward the stereocontrolled formation of
amino alcohols as a central topic in medicinal chemistry.3 Thus, examples such as dihydroandrachcine
(1),4 sedinine (2),5 and clavepictine B (3)6 continue to be topics for chemical studies. Herein, we describe
the use of chiral, nonracemic N-alkoxyamines in iodine-induced cyclizations of acyclic alkenyl
derivatives for the stereocontrolled construction of hydroxylated trans-2,6-disubstituted piperidines.
H
H
H
OH
CH3
N
H
H
HO
H
OH
HH
N
OH
CH3
CH3
H3C
N
H
H
HO
CH3
CH3
CH3
3 (Clavepictine B)
1 (Dihydroandrachcine)
2 (Sedinine)
†Dedicated to Dr. Pierre Potier in celebration of his 70th birthday.

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HETEROCYCLES, Vol. 64, 2004
Intramolecular electrophilic cyclizations of olefinic precursors via amidomercuration or
amidohalogenation are well known.7 Amines are seldom used in this fashion owing to their increased
nucleophilicity which leads directly to oxidation.8 Previously, we have shown that N-alkoxyamines
provide for efficient ring closures in the five-exo mode affording pyrrolidines.9 As illustrated in Equation
1, high stereoselectivity may be achieved using Z-alkenes with a consideration for anti addition and
minimization of A(1,3)-strain.10
O
CH3
H
O
I2/CH3CN
O
O
H
I
H
CH3
H
(1)
0 °C/NaHCO3
30 mins
(83%)
N
CH3O
NH
CH3O
To advance this chemistry of the synthesis of piperidines alkaloids, we prepared a series of 1,3-syn- and
1,3-anti-N-benzyloxyamino alcohols (4) and (5) via the development of stereoselective reductions of E-
and Z-oximino ethers with the participation of a proximate hydroxyl group using tetramethylammonium
triacetoxyborohydride (TABH) as summarized below.11
R1
H
R1
H
R1
H
H
N
H
H
H
CH3CN-AcOH
TABH
CH3CN-AcOH
TABH
N
N
OBn
CH3
OBn
CH3
OBn
CH3
HO
HO
HO
–20 °C
[Z-oxime]
–20 °C
[E-oxime]
4
5
Table 1 summarizes the results of our iodine-induced cyclizations of γ-alkenylamines. General conditions
utilized the dropwise addition of a CH2Cl2 solution of iodine (3 equivs) into a solution of starting N-
alkoxyamine (CH2Cl2) containing a suspension of NaHCO3 (10 equivs) with stirring at 0 °C. The use of
solid NaHCO3 neutralized HI and served to stabilize acid-labile protecting groups. Upon completion,
reactions were quenched by the addition of saturated, aqueous NaHSO3 and diluted with Et2O leading to
the isolation of the desired piperidines in good yields. Crude reaction mixtures were usually cleaned up
by a rapid flash chromatography followed by NMR spectral assessment of diastereomeric mixtures of 2,6-
cis- and 2,6-trans-piperidines. Subsequently careful chromatography separated pure cis- and trans-
products for individual characterizations.
Cyclization of the amine of Entry 1, bearing a terminal alkene, was initially examined to evaluate the
inherent diastereofacial selectivity. trans-2,6-Disubstituted piperidine was identified as the major product
(approximately 2:1 trans/cis ratio). Owing to slow conformational isomerization and nitrogen inversion,
1H NMR spectra of pure trans-2,6-piperidines are characterized by broad, poorly-defined signals for C2
and C6 methine hydrogens, while cis-isomers reveal the expected patterns for 2,6-diequatorial
substitution. Eliel12 has shown that C2 and C6 carbon resonances of trans-2,6-disubstituted piperidines

HETEROCYCLES, Vol. 64, 2004
47
Table 1. Iodine Cyclizations of N-Alkoxyamines.
Starting
Amine
Major
Product
Isomer
Total
Yield
Entry
a
Ratio [trans/cis]
H
I
H
H
b
NH
O
1.
63 : 37
81%
N
O
OCH3
OCH3
H
I
H
H
NH
N
b
OBn
O
Bn
H
2.
80 : 20
65%
H
HO
HO
CH3
CH3
I
H
N
H
CH3
H
CH3
NH
O
H
b
Bn
H
3.
OBn
81 : 19
94%
HO
H
HO
CH3
CH3
I
H
N
H
CH3
H
CH3
NH
H
b
O
Bn
H
OBn
CH3
4.
76 : 24
33 : 67
82 : 18
86%
HO
H
HO
CH3
COOCH3
I
H
H
COOCH3
H
b,c
H
80%
5.
NH
O
N
O
H3C
H3C
OMe
H
OCH3
H
CH3
Bn
H
I
CH3
H
NH
N
b,c
OBn
6.
83%
O
H
H
HO
HO
CH3
CH3
CH3
I
H
N
H
CH3
H
H
H
H
NH
b,c
OBn
55 : 45
80 : 20
80 : 20
74%
7.
8.
9.
O Bn
H
H
H
H
HO
HO
HO
HO
CH3
CH3
H
I
H
N
CH3
H
CH3
NH
b,c
O Bn
H
OBn
86%
HO
CH3
CH3
I
H
N
H
CH3
H
CH3
NH
b,c
O Bn
H
OBn
CH3
87%
HO
CH3
a
Ratios were determined by integration of selected 1H NMR signals for product mixtures following silica gel flash
chromatography. Careful flash silica gel chromatography or preparative TLC led to pure individual diastereomers for
b
complete characterizations. Reactions were not optimized: Iodine (3.0 equivs), CH2Cl2, solid NaHCO3 (10 equivs), 0 °C. In
some cases, methylene chloride/ether (2:1 by volume) was used as solvent.
20 °C.
c
Reactions were initiated at 0 °C and warmed to

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HETEROCYCLES, Vol. 64, 2004
appear upfield (Δδ ≅ 6.6 ppm) compared to the corresponding signals of cis-isomers. Additionally, the
C4 carbon signal in trans compounds is also found upfield (Δδ ≅ 5.6 ppm) relative to the cis-isomer.
These trends proved to be diagonistic throughout our series of compounds. The infusion of pure cis-
product into reaction mixtures of Entry 1 failed to provide evidence for thermodynamic control. Thus,
trans:cis ratios reflect products of kinetic nonequilibrating reactions. Finally, our previous efforts9
leading to N-alkoxy-2,5-pyrrolidines included an X-Ray diffraction study which confirmed the anti-
periplanar addition of nitrogen and iodide. The results of Table 1 do not suggest evidence of a change in
mechanism. The incorporation of the β-hydroxyl substituent in Entry 2 coincides with enhanced
production of trans-piperidine, and this trend remains intact throughout the series of starting E-olefins
(Entries 3, 4, 8, 9). On the other hand, the interchange of O-methyl, O-benzyl and O-MOM protection in
the starting hydroxylamines had a negligible effect on the observed stereoselectivity for these reactions.
By comparison, the Z-alkene of Entry 5 led to a reversal of selectivity favoring the cis-isomer. In the case
of the syn-1,3-N-benzyloxyamino alcohol of Entry 6, this was not observed. Moreover, the anti-isomer
(Entry 7) underwent cyclization less efficiently producing nearly equal amounts of cis- and trans-
product.13 While our preliminary results have established a clear trend for cyclization to trans-2,6-
disubstituted piperidines, the latter examples require further studies and perhaps suggest effects due to
hydrogen bonding, which may lead to conformational preferences in the ring closure event.
Our N-alkoxypiperidines also allow an efficient, stereocontrolled transfer of oxygen along the carbon
skeleton. For example, protection (MOMCl, (i-C3H9)/NC2H5, DMAP, CH2Cl2, 94%) and SN2 elimination
(KOC(CH3)3, (C2H5)3N, DMF/THF (1:1 by volume) 65%) of the trans-product of Entry 4 gave the E-
alkene (6) (Scheme 1). Iodine-induced cyclization led to a five-endo ring closure with dealkylation of the
resulting oxonium species and formation of a single isoxazolidine (7) (65%).14 Reduction quantitatively
afforded the syn-1,3-disubstituted isoxazolidine (8) as confirmed by nOe studies.15 Acid hydrolysis and
Scheme 1.
H
N
X
H
N
H
N
CH3
CH3
H
H
OH
H
CH3
1) HCl/H2O
CH3OH (88%)
1) I2; THF
0.5 M KH2PO4 (65%)
H
H
H
O
O
H
H
HO
RO
RO
2) Zn/HOAc
C2H5OH/EDTA (93%)
2) (n-C4H9)3SnH
AIBN, PhH (99%)
Ph
CH3
CH3
CH3
9
7 (R = CH2OCH3; X = I)
8 (R = CH2OCH3; X = H)
6 (R = CH2OCH3)
1) I2; THF
H
H
H
N
0.5 M KH2PO4 (65%)
2) (n-C4H9)3SnH
AIBN, PhH (99%)
H
CH3
CH3
H
CH
3
H
N
H
H
OH
N
O
O
H
H
H
H
RO
RO
HO
3) HCl/H2O
Ph
CH3OH (79%)
4) Zn/HOAc
C2H5OH/EDTA (88%)
CH
3
CH3
10 (R = CH2OCH3)
CH3
11
12 (via 1,3-cycloaddition)

HETEROCYCLES, Vol. 64, 2004
49
N–O bond cleavage with zinc in acetic acid gave the piperidine diol (9). Similarly the isomeric E-alkene
(10) yielded the chiral, nonracemic amino diol (11). Interestingly, these observations are in contrast to
results obtained from dipolar cycloadditions of cyclic nitrones with terminal olefins, which exclusively
provide bicyclic anti-3,5-disubstituted isoxazolidines, as exemplified by 12.16
Overall, a synthesis strategy has been developed toward piperidine alkaloids, which utilizes nonracemic,
acyclic alcohols as starting precursors for the transmission of functionality and stereochemistry along the
carbon backbone. Our studies have described iodine-induced cyclizations of acyclic N-alkoxyamines
yielding trans-2,6-disubstituted piperidines as major products. Dehydrohalogenations permit sequential
iodine cyclizations in the five-endo mode to produce bicyclic syn-3,5-disubstituted isoxazolidines for
reduction to 1,3-syn-amino alcohols.
ACKNOWLEDGEMENTS
We gratefully acknowledge the National Institutes of Health (GM-41560) for generous support.
REFERENCES AND NOTES
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HETEROCYCLES, Vol. 64, 2004
10. For A(1,3) factors in THF formation: D. R. Williams, J. Grote, and Y. Harigaya, Tetrahedron Lett.,
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13. Less reactive alkenes failed to undergo cyclizations as shown by iodine oxidation of the example
below.
H
H
BnO
BnO
N
CH3
CH3
Ph
I2
H
NH
O
CH3CN
NaHCO3
[R = MOM]
O
H
H
RO
RO
Ph
CH3
CH3
14. For related five-exo cyclizations to isoxazolidines: F. Mancini, M. G. Piazza, and C. Trombini, J.
Org. Chem., 1991, 56, 4246.
15. The nOe study of isoxazolidine (11) confirmed the 1,3-syn stereoassignment via irradiation at HC
revealing a 3.3% nOe of HD and 1.3% of HF. Irradiation of HD gave 3.8% nOe of HC and 6.5% nOe
of HF. No nOe was observed for HC, HD or HF upon irradiation of HB.
HD
NMR signals for 11
HC
HE
CH3
HA 3.75 ppm
HB 3.28 ppm
HC 3.52 ppm
HD 2.29 ppm
HE 1.64 ppm
HF 3.91 ppm
HC
HD
N
HB
R1
N
O
HF
HE
HF
HA
HB
O
HO
CH3
CH3
16. Carruthers and coworkers prepared bicyclic 12 by 1,3-dipolar cycloaddition en route to alleged
andrachamine. However, their claim of a total synthesis was proven to be incorrect following our
studies which conclusively demonstrated the misassignment of the natural product. These efforts
demonstrated the conversion of 13 (from 8) to the diastereomeric alcohol (14), which was shown to
be identical to the product of N–O reduction from 12. See: (a) W. Carruthers, P. Coggins, and J. B.
Weston, J. Chem. Soc., Perkin Trans. I, 1990, 2323. (b) M. H. Osterhout, Ph.D. Thesis, Indiana
University, Department of Chemistry, Bloomington, U.S.A., 1991.
O
CH3
H
N
H
1) LiBH4
2) HCl
CH3OH/H2O
3) K2SO3
CH3
H
H
OH
N
CH3
H
H
H
HO
RO
O
CH3
CH3
13 (R = CH2OCH3)
14