Unexpected One-Pot Epoxy Sulfone - Enaminone Transformation. Synthesis of 5a-Carba-β-mannopyranosylamine

Full text of DOI:10.1021/jo991468r

2580
J . Org. Chem. 2000, 65, 2580-2582
Sch em e 1
Un exp ected On e-P ot Ep oxy
Su lfon e-En a m in on e Tr a n sfor m a tion .
Syn th esis of
5a -Ca r ba -â-m a n n op yr a n osyla m in e
J ose´ Luis Acen˜a, Odo´n Arjona,* Rosa Man˜as, and
J oaqu´ın Plumet*
Sch em e 2
Departamento de Quı´mica Orga´nica I, Facultad de
Quı´mica, Universidad Complutense, 28040 Madrid, Spain
Received September 16, 1999
The nucleophilic ring opening of 1,2-epoxy sulfones is
a well-established protocol for the preparation of R-sub-
stituted ketones via nucleophilic addition with a con-
comitant desulfonation process (Scheme 1).1
In a previous paper concerning the total synthesis of
(()-validamine and its C1 and C2 stereoisomers2 we
speculated that the ring opening of both epoxy sulfones
A and B by an azide ion3 would give azido ketones C and
D, respectively, direct precursors of the target compounds
(Scheme 2).
In our hands the reaction of sulfones A and B (P )
Bn) with sodium azide (DMF, 100 °C) resulted in the
recovering of starting material. However, when sulfones
1a and 1b were treated under the same conditions, the
enaminone 2a was obtained in 95% and 85% isolated
yields, respectively, as the only product, as established
by its spectral properties, especially from the distinctive
IR and 13C NMR data (see experimental and complemen-
tary material) (Scheme 3). The exceptional ease with
which the persilyl epoxides 1 react with azide is possibly
due to anchimeric assistance4 provided by the silyl group
at C-3.
In addition to the well-known synthetic utility of the
enaminone moiety in the field of heterocyclic synthesis,5
we envisaged the possibility of using this unexpected
process for the synthesis of aminocarbasugars with well-
established stereochemistry.6 As an example, we have
developed a short synthesis of 5a-carba-â-mannopyrano-
sylamine, a C1 and C2 diastereomer of validamine7
(Scheme 4).
duction of 3 (NaBH4, 100%) gave rise to the protected
aminocarbasugar 4. Treatment of 4 with tetrabutylam-
monium fluoride yielded the N-acetyl-5a-carba-â-man-
nopyranosylamine, which was fully characterized as the
pentaacetate2 (70% two-step yield).
The transformation of the N-acetylenaminone 2b into
compound 3 with concomitant TBS group migration
should be produced through the related enolic form to
give the most stable stereoisomer with all substituents
in equatorial position8 (Scheme 5).
Regarding the reaction path for the one-pot transfor-
mation of the epoxy sulfones 1 into compound 2a , we
propose as a reasonable hypothesis the sequence indi-
cated in the Scheme 6. The attack of the nucleophilic
agent on the epoxy sulfones should occur in the normal
fashion to give the first intermediate 6, which would
undergo desulfonation affording 7. Evolution of nitrogen
in 7 should give nitrene 8, which, after a 1,2 hydrogen
shift,9 would afford intermediate 9. This intermediate
Thus, reaction of 2a with Ac2O/pyridine followed by
catalytic hydrogenation of the resulting N-acetylenami-
none 2b afforded amido ketone 3 (46% isolated yield,
together with 22% of recovered starting material). Re-
(6) For a general account on the chemistry and biological properties
of carbasugars, see the following. Ogawa, S. In Carbohydrate Mimics:
Concepts and Methods; Chapleur, Y., Ed.; Wiley-VCH: Weinheim,
1998. For some selected synthetic approach to aminocarbasugars, see
the following. (a) Paulsen, H.; Heiker, F. R. Angew. Chem., Int. Ed.
Engl. 1980, 19, 904-905. (b) Schmidt, R. R.; Ko¨hn, A. Angew. Chem.,
Int. Ed. Engl. 1987, 26, 482-483. (c) Knapp, S.; Naughton, A. B. J .;
Murali Dhar, T. G. Tetrahedron Lett. 1992, 33, 1025-1028. (d) Fukase,
H.; Horii, S. J . Org. Chem. 1992, 57, 3651-3658. (e) Park, T. K.;
Danishefsky, S. J . Tetrahedron Lett. 1994, 35, 2667-2670. (f) Shing,
T. K. M.; Wan, L. H. Angew. Chem., Int. Ed. Engl. 1995, 34, 1643-
1645.
(7) For the biological importance and previous synthesis of valid-
amine and some stereoisomers see the references quoted in refs 2, 5,
and the following. (a) Shing, T. K. M.; Tai, V. W.-F. J . Org. Chem.
1995, 60, 5332-5334. (b) Afarinkia, K.; Mahmood, F. Tetrahedron
1999, 55, 3129-3140.
(8) For some studies concerning the migration of silyl protecting
groups, see the following. (a) Ogilvie, K. K.; Beaucage, S. L.; Schifman,
A. L.; Theriault, N. Y.; Sadana, K. L. Can. J . Chem. 1978, 56, 2768-
2780. (b) J ones, S. S.; Reese, C. B. J . Chem. Soc., Perkin Trans. 1 1979,
2762-2764.
(9) For a discussion of the generation of nitrenes from azides and
1,2 hydrogen shifts in these systems, see the following. Moody, Ch. J .;
Whitham, G. H. In Reactive Intermediates; Oxford Science Publica-
tions: Oxford, U.K., 1995; Chapter 4, pp 52-53, 61-62.
(1) Simpkins, N. S. Sulfones in Organic Synthesis; Tetrahedron
Organic Chemistry Series 10; Pergamon Press: Oxford, U.K, 1993;
pp 56, 362. For other related references, see the following. (a) Durst,
T.; Tin, K. C.; de Reinach-Hirtzbach, F.; Decesare, J . M.; Ryan, M. D.
Can. J . Chem. 1979, 57, 258-266. (b) Taylor, E. C.; Maryanoff, C. A.;
Skotnicki, J . S. J . Org. Chem. 1980, 45, 2512-2515. (c) Adamczyk,
M.; Dolence, E. K.; Watt, D. S.; Christy, M. R.; Reibenspies, J . H.;
Anderson, O. P. J . Org. Chem. 1984, 49, 1378-1382.
(2) Acen˜a, J . L.; Arjona, O.; Ferna´ndez de la Pradilla, R.; Plumet,
J .; Viso, A. J . Org. Chem. 1994, 59, 6419-6424.
(3) For the ring opening of R,â-epoxy sulfones by azide ion, see the
following. (a) Barone, A. D.; Snitman, D. L.; Watt, D. S. J . Org. Chem.
1978, 43, 2066-2068. (b) Thang, T. T.; Laborde, M. A.; Olesker, A.;
Lukacs, G. J . Chem. Soc., Chem. Commun. 1988, 1581-1582.
(4) Papini, A.; Ricci, A.; Taddei, M.; Seconi, G.; Dembech, P. J . Chem.
Soc., Perkin Trans. 1 1984, 2261-2265. We thank one of the reviewers
for the comment given on the importance of silyl groups to facilitate
the epoxide opening.
(5) For selected reviews, see the following. (a) Dehaen, W.; Becher,
J . Acta Chem. Scand. 1993, 47, 244-254. (b) Lue, P.; Greenhill, J . V.
Adv. Heterocycl. Chem. 1997, 67, 207-343.
10.1021/jo991468r CCC: $19.00 © 2000 American Chemical Society
Published on Web 03/30/2000

Notes
J . Org. Chem., Vol. 65, No. 8, 2000 2581
Sch em e 3
Sch em e 4
Sch em e 5
Sch em e 6
sodium and benzophenone, 2,6-lutidine, and N,N-dimethylform-
would evolve to 10 via 1,2-silyl migration of its enolic
form. After the workup of the reaction crude, two
sequences of keto-enol and imine-enamine tautomerism
should give rise to the final observed product 2a . This
proposed mechanism is supported by the observation that
both stereoisomeric epoxides 1a and 1b were transformed
into 2a under the same reaction conditions and in almost
the same isolated yields.10
amide from CaH2. The remaining solvents and chemicals were
1
commercial and used as received. H NMR and 13C NMR were
recorded at 200 or 300 MHz. Chemical shifts (δ) are reported in
ppm from internal (CH3)4Si. Flash chromatography was per-
formed using 230-400 mesh silica gel. Analytical TLC was
carried out on silica gel plates. Melting points are uncorrected.
Elemental analyses were performed at the Universidad Com-
plutense de Madrid.
P r ep a r a tion of (1S*,2S*,3R*,4R*,6S*)-2,3-Bis((ter t-bu tyl-
d im et h ylsilyl)oxy)-4-(((ter t-b u t yld im et h ylsilyl)oxy)m e-
t h yl)-1-(p h en ylsu lfon yl)-7-oxa b icyclo[4.1.0]h ep t a n e (1b ).
To a solution of (1S*,2S*,3R*,4R*,6S*)-3-((tert-butyldimethyl-
silyl)oxy)-4-(((tert-butyldimethylsilyl)oxy)methyl)-1-(phenylsul-
fonyl)-7-oxabicyclo[4.1.0]heptan-2-ol2 (65 mg, 0.12 mmol) in
anhydrous CH2Cl2 (0.12 mL) were added dropwise dry 2,6-
lutidine (0.09 mL, 0.74 mmol) and tert-butyldimethylsilyl triflate
(0.11 mL, 0.49 mmol). After the solution was stirred for 3 days
at room temperature, the aqueous layer was separated and
extracted with CH2Cl2 and the combined organics were washed
with cold sodium bicarbonate and dried over Na2SO4. The solvent
was removed in vacuo, and the crude was purified by column
chromatography (silica gel, hexane/EtOAc 20:1) to afford 1b as
In summary a new transformation epoxy, sulfone-
enaminone, via treatment with NaN3 and restricted to
the use of silyl protecting groups has been described. This
transformation allowed us to develop a short synthesis
of 5a-carba-â-mannopyranosylamine.
Exp er im en ta l Section
Gen er a l. Reagents and solvents were handled by using
standard syringe techniques. Tetrahydrofuran was distilled from
(10) We thank one of the reviewers for suggesting the experiment
starting from 1b in order to clarify the proposed mechanism.

2582 J . Org. Chem., Vol. 65, No. 8, 2000
Notes
a yellow oil (79 mg, 100%). 1H NMR (CDCl3, 300 MHz): δ -0.10
(s, 3 H), -0.03 (s, 3 H), 0.04 (s, 3 H), 0.05 (s, 3 H), 0.16 (s, 3 H),
0.32 (s, 3 H), 0.67 (s, 9 H), 0.89 (s, 9 H), 0.96 (s, 9 H), 1.84-1.90
(m, 1 H), 2.01 (ddd, 1 H, J ) 14.7, 9.8, 1.5 Hz), 2.23 (ddd, 1 H,
J ) 14.7, 6.4, 2.9 Hz), 3.45-3.59 (m, 3 H), 3.77 (bs, 1 H), 4.25
(d, 1 H, J ) 2.0 Hz), 7.54 (t, 2 H, J ) 6.8 Hz), 7.65 (t, 1 H, J )
7.3 Hz), 7.92 (d, 2 H, J ) 7.3 Hz). 13C NMR (CDCl3, 50 MHz):
δ -5.4, -5.3, -5.1, -4.7, -4.6, -3.4, 17.6, 18.1, 18.4, 25.5, 26.0,
29.7, 41.4, 56.1, 65.6, 71.5, 72.1, 72.5, 128.8, 129.6, 133.9, 136.1.
IR (KBr): ν 2957, 2930, 1472, 1325, 1103, 1084 cm-1. Anal. Calcd
for C31H58O6SSi3: C, 57.94; H, 9.03. Found: C, 58.04; H, 9.13.
P r ep a r a tion of (5R*,6R*)-3-Am in o-2,6-bis((ter t-bu tyld i-
m eth ylsilyl)oxy)-5-(((ter t-bu tyld im eth ylsilyl)oxy)m eth yl)-
cycloh ex-2-en -1-on e (2a ). To a suspension of NaN3 (58 mg,
0.90 mmol) in DMF (0.9 mL) was slowly added a solution of 1a 2
(115 mg, 0.18 mmol) in DMF (0.9 mL). The mixture was stirred
at 100 °C for an hour and quenched with water. The whole was
extracted with Et2O/CH2Cl2 (7:3), the organic extracts were dried
(MgSO4), and the solvent was eliminated under reduced pres-
sure. The crude was purified by column chromatography on silica
gel using a 10:1 mixture of hexanes-EtOAc as eluant, yielding
88 mg (95%) of 2a as a white solid.
MeOH. This crude was purified by column chromatography
(silica gel, hexane/EtOAc 10:1) to afford 3 as a yellow oil (18
mg, 46%) together with 22% of the recovered starting material:
1H NMR (CDCl3, 300 MHz): δ -0.04 (s, 3 H), 0.03 (s, 6 H), 0.07
(s, 3 H), 0.09 (s, 3 H), 0.13 (s, 3 H), 0.87 (s, 9 H), 0.92 (s, 9 H),
0.97 (s, 9 H), 1.14 (c, 1 H, J ) 12.7 Hz), 1.94-1.99 (m, 1 H), 2.04
(s, 3 H), 2.49 (ddd, 1 H, J ) 10.3, 5.9, 3.4 Hz), 3.56 (t, 1 H, J )
8.8 Hz), 3.66 (dd, 1 H, J ) 9.8, 4.9 Hz), 3.73 (dd, 1 H, J ) 9.8,
3.4 Hz), 4.21 (d, 1 H, J ) 8.8 Hz), 4.57 (dt, 1 H, J ) 12.2, 5.9),
6.38 (d, 1 H, J ) 6.4). 13C NMR (CDCl3, 50 MHz): δ -5.5, -5.3,
-4.6, -4.5, -3.5, -2.5, 18.1, 18.3, 18.6, 23.3, 26.0, 26.2, 26.3,
29.7, 43.2, 55.4, 62.4, 76.2, 82.1, 169.7, 204.5. IR (KBr): ν 3416,
1711, 1670 cm-1. Anal. Calcd for C27H57NO5Si3: C, 57.96; H,
10.20; N, 2.50. Found: C, 58.16; H, 10.35; N, 2.60.
P r ep a r a tion of (1R*,2R*,3R*,4R*,6R*)-6-Aceta m id o-2,3-
b is((ter t-b u t yld im et h ylsilyl)oxy)-4-(((ter t-b u t yld im et h yl-
silyl)oxy)m eth yl)cycloh exa n ol (4). A stirred solution of 3 (20
mg, 0.04 mmol) in MeOH (0.4 mL) was cooled to 0 °C in an ice
bath. To the cooled mixture was added sodium borohydride (6
mg, 0.16 mmol). The mixture was stirred for 30 min at 0 °C
before water was added. The solvent was eliminated under
reduced pressure, yielding 20 mg (100%) of 4 as a yellow oil. 1H
NMR (CDCl3, 300 MHz): δ 0.03 (s, 3 H), 0.04 (s, 3 H), 0.12 (s, 3
H), 0.14 (s, 3 H), 0.16 (s, 3 H), 0.17 (s, 3 H), 0.89 (s, 9 H), 0.91
(s, 9 H), 0.95 (s, 9 H), 1.59-1.66 (m, 1 H), 1.93 (s, 3 H), 1.95-
1.98 (m, 1 H), 2.13-2.27 (m, 1 H), 3.55 (dd, 1 H, J ) 9.8, 5.9
Hz), 3.62-3.65 (m, 1 H), 3.92 (t, 2 H, J ) 9.8 Hz), 3.96-4.06 (m,
1 H), 4.08 (bs, 1 H), 4.11-4.18 (m, 1 H), 6.48 (d, 1 H, J ) 8.3).
13C NMR (CDCl3, 50 MHz): δ -5.4, -5.3, -5.0, -4.8, -4.7, 22.5,
22.7, 23.5, 25.7, 25.9, 25.9, 29.4, 31.9, 43.0, 49.2, 64.9, 71.1, 72.5,
From 1b, 2a was also obtained under the same reaction
conditions (78 mg, 85%): mp 134-135 °C. 1H NMR (CDCl3, 300
MHz): δ 0.06 (s, 6 H), 0.08 (s, 3 H), 0.19 (s, 3 H), 0.21 (s, 3 H),
0.23 (s, 3 H), 0.90 (s, 18 H), 0.96 (s, 9 H), 2.11-2.19 (m, 1 H),
2.45 (d, 2 H, J ) 7.3 Hz), 3.69 (dd, 1 H, J ) 9.8, 6.4 Hz), 3.78
(dd, 1 H, J ) 9.8, 3.9 Hz), 3.99 (d, 1 H, J ) 10.3 Hz), 4.33 (bs, 2
H). 13C NMR (CDCl3, 50 MHz): δ -5.6, -5.5, -5.4, -4.2, -3.8,
-3.6, 18.3, 18.6, 18.8, 25.9, 26.1, 26.3, 28.2, 43.8, 63.3, 73.8,
126.3, 146.0, 188.1. IR (KBr): ν 3500, 3390, 1660, 1610 cm-1
.
73.7, 169.1. IR (KBr): ν 3369, 1655 cm-1. Anal. Calcd for C27H59
-
Anal. Calcd for C25H53NO4Si3: C, 58.25; H, 10.29; N, 2.72.
Found: C, 58.14; H, 10.15; N, 2.52.
NO5Si3: C, 57.75; H, 10.52; N, 2.50. Found: C, 57.95; H, 10.68;
N, 2.41.
P r epar ation of (5R*,6R*)-3-Acetam ido-2,6-bis((ter t-bu tyl-
d im eth ylsilyl)oxy)-5-(((ter t-bu tyld im eth ylsilyl)oxy)m eth -
yl)cycloh ex-2-en -1-on e (2b). To a solution of 2a (102 mg, 0.20
mmol) in 0.2 mL of THF was added 0.43 mL of acetic anhydride
and 0.004 mL of pyridine. This mixture was heated slowly until
starting material dissolved, and then it was refluxed for 4 h.
The solvent was removed in vacuo, and the residue was purified
by column chromatography on silica gel using a 20:1 mixture of
hexanes-EtOAc as eluant to yield 2b (102 mg, 92%) as a yellow
oil. 1H NMR (CDCl3, 300 MHz): δ 0.06 (s, 3 H), 0.08 (s, 6 H),
0.20 (s, 3 H), 0.21 (s, 3 H), 0.24 (s, 3 H), 0.91 (s, 9 H), 0.92 (s, 9
H), 0.97 (s, 9 H), 2.05-2.19 (m, 1 H), 2.12 (s, 3 H), 2.95 (dd, 1 H,
J ) 19.3, 10.5 Hz), 3.38 (dd, 1 H, J ) 19.3, 5.1 Hz), 3.70 (dd, 1
H, J ) 10.0, 3.2 Hz), 3.82 (dd, 1 H, J ) 10.2, 5.1 Hz), 4.12 (d, 1
H, J ) 11.3), 7.71 (bs, 1 H). 13C NMR (CDCl3, 50 MHz): δ -5.5,
-5.5, -5.3, -4.1, -3.9, -3.9, 18.3, 18.6, 18.7, 25.0, 26.0, 26.1,
26.3, 29.7, 44.3, 62.6, 73.7, 130.9, 137.9, 168.1, 192.1. IR (KBr):
ν 3402, 1713, 1682, 1624 cm-1. Anal. Calcd for C27H55NO5Si3:
C, 58.14; H, 9.87; N, 2.51. Found: C, 58.57; H, 9.67; N, 2.31.
P r ep a r a tion of (2S*,3R*,4R*,6R*)-6-Aceta m id o-2,3-bis-
((ter t-bu tyld im eth ylsilyl)oxy)-4-(((ter t-bu tyld im eth ylsilyl)-
oxy)m eth yl)cycloh exa n on e (3). A solution of 2b (41 mg, 0.07
mmol) and 10% Pd/C (87 mg, 0.08 mmol) in MeOH (3.8 mL) was
hydrogenated (38-40 psi) for 4 h at room temperature. The
reaction mixture was filtered through a short path of SiO2 with
P r ep a r a tion of P en ta -N,O-a cetyl-5a -ca r ba -â-m a n n op y-
r a n osyla m in e (5). To a solution of 4 (50 mg, 0.09 mmol) in THF
(0.6 mL) was added tetrabutylammonium fluoride (0.54 mL, 0.54
mmol). The mixture was stirred for 1 h at room temperature.
After that time, the reaction mixture was quenched with distilled
water and concentrated under reduced pressure. The residue
was acetylated with acetic anhydride (0.4 mL), pyridine (0.4 mL),
and DMAP (ca. 2 mg) for 3 days. The solvent was removed in
vacuo, and the crude was purified by column chromatography
on silica gel using EtOAc as eluant to give 5 as a white solid (24
mg, 70% overall yield). Its spectral features were identical to
those reported in the literature.2
Ack n ow led gm en t. Financial support was obtained
from the Ministerio de Educacio´n y Cultura, Spain,
through Grant No. 96-0641. R.M. thanks Universidad
Complutense de Madrid and Ministerio de Educacio´n y
Cultura for a predoctoral fellowship.
Su p p or t in g In for m a t ion Ava ila b le: 1H NMR and 13C
NMR spectra for compounds 1b, 2a ,b, 3, and 4. This material
is available free of charge via the Internet at http://pubs.acs.org.
J O991468R