A combined, 6-exo-dig radical cyclization-palladium catalyzed allylic amination, approach to aminocarbasugar analogs: Synthesis of novel N-substituted aminocyclitols from D-mannose

Article abstract of DOI:10.1016/S0040-4039(02)01919-6

A novel approach, which features a stereoselective 6-exo-dig radical cyclization and a palladium-catalyzed allylic amination, permits a six steps synthesis of aminocyclitol analogs from D-mannose.

Full text of DOI:10.1016/S0040-4039(02)01919-6

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 7863–7866
A combined, 6-exo-dig radical cyclization-palladium catalyzed
allylic amination, approach to aminocarbasugar analogs:
synthesis of novel N-substituted aminocyclitols from
D-mannose
Ana M. Go´mez,* Eduardo Moreno, Seraf´ın Valverde and J. Cristo´bal Lo´pez*
Instituto de Qu´ımica Orga´nica General, C.S.I.C., Juan de la Cierva3, 28006 Madrid, Spain
Received 23 July 2002; revised 5 September 2002; accepted 6 September 2002
Abstract—A novel approach, which features a stereoselective 6-exo-dig radical cyclization and a palladium-catalyzed allylic
amination, permits a six steps synthesis of aminocyclitol analogs from
reserved.
D-mannose. © 2002 Elsevier Science Ltd. All rights
Carbocyclic polyols are important constituents of many
biologically active molecules. They display a variety of
biological effects, which range from cellular regulation
to the selective inhibition of enzymes, which play key
roles in living organisms.1 Accordingly, structures
which incorporate the cyclohexitol (polyhydroxylated
cyclohexanoids) or the aminocyclohexitol core have
raised widespread synthetic interest.2 In this context,
carbasugars,3 e.g. 1,4,5 and aminocarbasugars, e.g. 2, 3,
4, have proved to be potent glycomimics (Scheme 1).6
Validamine 2, valienamine 3 and valiolamine 4, were
first isolated by the chemical or microbial degradation
of validamycins,7 and some of their derivatives have
found commercial use. Although in aminocarbasugars
2–4, the amino group is located at C-1, many new types
of aminocarbasugars or aminocyclitols have been syn-
thesized in recent years and subjected to biological
evaluation.8
Accordingly, our synthetic route starts with the prepa-
ration of 11, in four steps from -mannose (Scheme
3).9b Mannose-diacetonide, 8 (Scheme 2), prepared in
D
one single step from
D-mannose by kinetic acetona-
tion,12 was treated with lithium trimethylsilylacetylide
to yield after work-up, alkyne 9 as a 2:1 epimeric
mixture at C-1 in 68% isolated yield. Chemoselective
Our group has recently been interested in the synthesis
of carbasugars from monosaccharides,9,10 and in this
context we disclose herein a synthetic approach to the
preparation of a novel class of homologated N-substi-
tuted aminocarbasugar analogs 14. Our approach
(Scheme 2), which is not only confined to carbohydrate
derivatives, correlates retrosynthetically the amino-
methyl group in 5, with an allylic carbonate in a
methylenecyclohexane (e.g. 6). The latter could thus be
obtained by 6-exo-dig radical cyclization11 of a propar-
gylic carbonate (e.g. 7).
Scheme 1. Carbasugars and aminocarbasugars.
Scheme 2. Synthesis of aminomethyl cyclohexanes from
* Corresponding author. Tel.: +34 91 5622900; fax: +34 91 5644853;
e-mail: anago@iqog.csic.es; clopez@iqog.csic.es
acyclic precursors.
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)01919-6

7864
A. M. Go´mez et al. / Tetrahedron Letters 43 (2002) 7863–7866
protection of the propargylic hydroxyl group was
accomplished by use of ethyl chloroformate (55%).13
The hydroxyl group at C-5 in 10 was next treated with
phenylchlorothionoformate14 to furnish cyclization pre-
cursor 11 (76%).
access to the 1,5-diol moiety in one step. The latter (e.g.
9) is chemoselectively protected at the prop-2-ynilic
hydroxy group (1-OH) as a carbonate, which plays a
dual role in our strategy: As a protecting group (for
1-OH), and as an activator of the double bond in the
forthcoming allylic amination. We have illustrated the
synthetic potential of this approach with the prepara-
Radical cyclization of 1115 takes place with excellent
stereoselectivity to afford carbonate 1216 (Scheme 4),
which upon treatment with palladium acetate and
triphenylphospine in acetonitrile, in the presence of a
primary or a secondary amine 13a–h, yields aminocycli-
tol analogs 14a–h17,18 (Table 1).
tion of compounds 14a–h from
D-mannose. Neverthe-
less, the use of different monosaccharide diacetonides,19
as well as the use of nucleophiles other than amines in
the Pd-catalyzed reaction20–22 could give rise to a large
variety of cyclitol analogs. Furthermore, the double
bond is susceptible to chemical modifications. Use of
the above strategy for the preparation of highly func-
tionalized cyclitols and derivatives thereof is underway
in our laboratory and will be described in due course.
The results in Table 1 show the scope of the Pd-cata-
lyzed reaction. Pyrrolidine (Table 1, entry iv), pipe-
ridine (entry v), piperazines (entries vi and vii), and
morpholine (entry viii), as well as acyclic primary
amines (entries i, ii, iii) were used as nucleophiles. The
Pd-catalyzed amination, except in the case of (R)-(+)-a-
methylbenzylamine (13c, Table 1 entry iii), took place
in a few hours, giving moderate to good yields of allylic
amines 14.
Table 1. Preparation of N-substituted analogs of amino-
cyclitols 14, by palladium-catalyzed allylic amination of
allylic carbonate 12 with amines 13
In summary, we have reported an efficient strategy for
the synthesis of a novel class of N-substituted aminocy-
clitol analogs, 14, from
D-mannose. The approach per-
mits the above-mentioned transformation to be carried
out in six steps, and benefits from a series of chemose-
lective transformations.
D
-Mannose diacetonide, 8,
leaves only the hemiacetal function exposed to reaction
and, upon reaction with the alkynyl nucleophile, grants
Scheme 3. Synthesis of alkynyl carbonates 11 from
D-man-
nose.
Scheme 4. Synthesis of aminocyclitol analogs, 14, from
D-
mannose.

A. M. Go´mez et al. / Tetrahedron Letters 43 (2002) 7863–7866
7865
Acknowledgements
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This research was supported with funds from the Direc-
cio´n General de Ensen˜anza Superior (Grants PB97-
1244, PPQ2000-1330, and BQU2001-0582). E.M.
thanks Janssen-Cilag S.A. and C.S.I.C. for a fellowship.
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15. Procedure for radical cyclization. A thoroughly degassed
(argon) solution of thiocarbonate 11 in toluene (0.02 M)
was heated to 85°C under argon. A solution of Bu3SnH
(1.6 equiv.) and AIBN (0.1 equiv.) in toluene (5 mL/
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Tetrahedron Lett. 2002, 44, 5559. The corresponding C-5-
6-epi derivative (as an epimeric mixture at C-1) was also
detected, albeit in low yield (<5%).
17. General procedure for palladium-catalyzed allylic amina-
tion. To a solution of compound 12 (100 mg, 0.29 mmol)
in acetonitrile (10 mL) under argon, Pd(OAc)2 (13 mg,
0.058 mmol), PPh3 (76 mg, 0.29 mmol), and the corre-
sponding amine 13 (0.38 mmol) were added. The reaction
was then heated to 85°C for the time indicated in Table
1. After cooling, the organic solvent was evaporated and
the residue dissolved in ethyl acetate and washed with
water. The organic layer was then dried (sodium sulfate)
and evaporated to furnish a residue, which was purified
by flash chromatography using hexane:ethyl acetate mix-
tures as eluent.
18. Data for selected compounds: Allylic amine 14b. (ethyl
acetate): [h]D21 +52.3 (c 0.51, CHCl3), 1H NMR (300
MHz, CDCl3) l (ppm): 5.77 (s, 1H), 4.61 (s, 1H), 4.49 (t,
J=3.0 Hz, 1H), 4.19 (m, 2H), 4.02 (dd, J=2.6, 11.8 Hz,
1H), 3.60–3.53 (m, 2H), 3.30–3.23 (m, 2H), 2.79 (m, 1H),
2.25 (s, 2H), 2.15 (s, 2H), 1.47 (s, 3H), 1.36 (s, 6H), 1.30
(s, 3H), 1.06 (d, J=6.1 Hz, 3H). 13C NMR (75 MHz,
CDCl3) l (ppm): 134.7, 125.0, 108.6, 98.6, 74.0, 71.8,
68.4, 65.8, 60.4, 53.4, 49.9, 31.7, 29.2, 27.8, 26.3, 19.0,
16.5. 14d. (hexane:ethyl acetate; 6:4): [h]D21 +36.1 (c 0.64,
CHCl3), 1H NMR (300 MHz, CDCl3) l (ppm): 5.67 (s,
1H), 4.57 (m, 1H), 4.49 (t, J=3.3 Hz, 1H), 4.27 (dd,
J=1.8, 12.4 Hz, 1H), 4.16 (t, J=4 Hz), 3.98 (dd, J=3.3,
12.4 Hz, 1H), 3.63 (d, J=13 Hz, 1H), 2.68 (d, J=13 Hz,
1H), 1.44 (s, 4H), 2.23 (m, 1H), 1.73 (s, 4H), 1.45 (s, 3H),
1.36 (s, 6H), 1.28 (s, 3H). 13C NMR (50 MHz, CDCl3) l
(ppm): 134.8, 124.5, 108.4, 98.2, 74.0, 73.0, 68.1, 60.6,
60.4, 53.8 (×2), 31.6, 29.0, 27.7, 26.3, 23.5 (×2), 19.0.
M/e=323.2 (M+), 308.2 (M+−15), 265.2. Anal. calcd for
C18H29NO4: C, 66.84; H, 9.04, N, 4.33. Found: C, 67.12;
H, 8.91, N, 4.19. 14g. (hexane:ethyl acetate; 9:1): [h]D21
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7866
A. M. Go´mez et al. / Tetrahedron Letters 43 (2002) 7863–7866
+27.4 (c 1.2, CHCl3), 1H NMR (300 MHz, CDCl3) l
J=4.5 Hz, 1H), 3.98 (dd, J=3.4, 12.3 Hz, 1H), 3.64 (m,
4H), 3.37 (d, J=13 Hz, 1H), 2.70 (d, J=13 Hz, 1H), 2.35
(m, 3H), 2.10 (s, 1H), 1.46 (s, 3H), 1.36 (s, 3H), 1.34 (s,
3H), 1.29 (s, 3H). 13C NMR (50 MHz, CDCl3) l (ppm):
133.3, 126.0, 108.4, 98.3, 74.0, 71.9, 68.1, 67.3 (×2), 63.1,
60.5, 53.5 (×2), 31.7, 29.1, 27.8, 26.3, 19.0. Anal. calcd for
C18H29NO5: C, 63.69; H, 8.61; N, 4.13. Found: C, 63.82;
H, 8.52; N, 3.97.
(ppm): 7.02–6.82 (m, 5H), 5.73 (s, 1H), 4.60 (m, 1H), 4.51
(t, J=3.3 Hz, 1H), 4.31 (dd, J=1.6, 12.3 Hz, 1H), 4.19 (t,
J=4.4 Hz, 1H), 4.01 (dd, J=3.3, 12.3 Hz, 1H), 3.86 (s,
3H, OMe), 3.44 (d, J=13.2 Hz, 1H), 3.03 (m, 4H), 2.78
(d, J=13.2 Hz, 1H), 2.62–2.55 (m, 4H), 2.20 (s, 1H), 1.49
(s, 3H), 1.39 (s, 6H), 1.31 (s, 3H). 13C NMR (50 MHz,
CDCl3) l (ppm): 152.4, 141.6, 134.1, 125.6, 122.7, 121.0,
148.2, 111.5, 108.5, 98.4, 74.2, 72.1, 68.3, 62.9, 60.8, 56.4,
53.4, 50.7, 31.9, 29.2, 27.9, 26.4, 19.2. M/e=444.4 (M+),
429.35 (M+−15), 386.3, 371.3, 357.3, 308.3. Anal. calcd
for C25H36N2O5: C, 67.54; H, 8.16; N, 6.30. Found: C,
67.82; H, 7.91; N, 6.16. 14h. (hexane:ethyl acetate; 8:2):
[h]D21 +28.1 (c 0.39, CHCl3), 1H NMR (300 MHz,
CDCl3) l (ppm): 5.69 (s, 1H), 4.57 (m, 1H), 4.49 (t,
J=3.4 Hz, 1H), 4.25 (dd, J=1.6, 12.3 Hz, 1H), 4.17 (t,
19. Go´mez, A. M.; Danelo´n, G. O.; Valverde, S.; Lo´pez, J.
C. Carbohydr. Res. 1999, 320, 138.
20. Malonates: Trost, B. M.; Van Vranken, D. L.; Bingel, C.
J. Am. Chem. Soc. 1992, 114, 9327.
21. Sulfinates: Trost, B. M.; Organ, M. G.; O’Doherty, G. A.
J. Am. Chem. Soc. 1995, 117, 9662.
22. Azide: Trost, B. M.; Stenkamp, D.; Pulley, S. R. Chem.
Eur. J. 1995, 1, 168.