Regio- and stereoselective synthesis of aminoinositols and 1,2-diaminoinositols from conduritol B epoxide

Article abstract of DOI:10.1021/jo050521a

A systematic approach to the regio- and stereoselective synthesis of aminoinositols and 1,2-diaminoinositols arising from tetra-O-benzylconduritol B epoxide (9) and its aziridine analogue 22, respectively, is described. In all cases, the synthetic methodologies rely on the regio- and stereocontrolled azidolysis of the starting precursors to give the corresponding trans regioadducts. Subsequent functional group manipulation under strict configurational control affords the isomeric cis adducts. Chemoselective functionalization of the diamine moiety in 1,2-diaminoinositol derivatives can be achieved by the proper design of the reaction sequence and choice of reagents. The described protocols allow efficient access to each of the eight possible configurations of the 1,2-diamino and 1,2-amino alcohol moieties from chemical modifications of the epoxide moiety on the common precursor 9.

Full text of DOI:10.1021/jo050521a

Regio- and Stereoselective Synthesis of Aminoinositols and
1,2-Diaminoinositols from Conduritol B Epoxide
Pedro Serrano,†,‡ Amadeu Llebaria,‡ and Antonio Delgado*,†,‡
Unidad de Quı´mica Farmace´utica (Unidad Asociada al CSIC), Facultad de Farmacia, Universidad de
Barcelona, Avda. Juan XXIII, s/n, 08028 Barcelona, Spain, and Research Unit on Bioactive Molecules
(RUBAM), Departament de Quı´mica Orga`nica Biolo`gica, Institut d’Investigacions Quı´miques i
Ambientals de Barcelona (IIQAB-C.S.I.C), Jordi Girona 18-26, 08034 Barcelona, Spain
adelgado@cid.csic.es
Received March 15, 2005
A systematic approach to the regio- and stereoselective synthesis of aminoinositols and 1,2-
diaminoinositols arising from tetra-O-benzylconduritol B epoxide (9) and its aziridine analogue
22, respectively, is described. In all cases, the synthetic methodologies rely on the regio- and
stereocontrolled azidolysis of the starting precursors to give the corresponding trans regioadducts.
Subsequent functional group manipulation under strict configurational control affords the isomeric
cis adducts. Chemoselective functionalization of the diamine moiety in 1,2-diaminoinositol
derivatives can be achieved by the proper design of the reaction sequence and choice of reagents.
The described protocols allow efficient access to each of the eight possible configurations of the
1,2-diamino and 1,2-amino alcohol moieties from chemical modifications of the epoxide moiety on
the common precursor 9.
Aminoinositols constitute a wide group of natural
products with interesting biological properties. In par-
ticular, the aminocyclitol family of antibiotics1 has stimu-
lated the development of synthetic methodologies in the
search for analogues with an enhanced pharmacological
profile,2 as well as studies on the chemistry of the amino
sugar moiety3-5 and their use as synthetic intermediates
in natural products chemistry.6 In addition, aminocyclitol
analogues have also gained relevance as glycomimetics,7
as enzyme inhibitors with multiple biomedical applica-
tions,8 and also as pharmacological tools for the study of
(2) For examples of synthesis of cyclitol derivatives, see: (a) Gravier-
Pelletier, C.; Maton, W.; Dintinger, T.; Tellier, C.; Le Merrer, Y.
Tetrahedron 2003, 59, 8705-8720. (b) Miyabe, H.; Nishiki, A.; Naito,
T. Chem. Pharm. Bull. 2003, 51, 100-103. (c) Gomez, A. M.; Moreno,
E.; Valverde, S.; Lopez, J. C. Tetrahedron Lett. 2002, 43, 7863-7866.
(d) Marco-Contelles, J.; Rodriguez-Fernandez, M. C. R. Acad. Sci. Ser.
II C 2001, 4, 443-452. (e) Sellier, O.; Van de Weghe, P.; Le Nouen,
D.; Strehler, C.; Eustache, J. Tetrahedron Lett. 1999, 40, 853-856.
(3) Eguchi, T.; Sasaki, S.; Huang, Z.; Kakinuma, K. J. Org. Chem.
2002, 67, 3979-3984.
† Universidad de Barcelona.
‡ Institut d’Investigacions Qu´ımiques i Ambientals de Barcelona.
(1) Ogawa, S. In Carbohydrates in Drug Design; Witczak, Z.,
Nieforth, K., Eds.; Dekker: New York, 1997; pp 433-469.
(4) Agnelli, T.; Sucheck, S. J.; Marby, K. A.; Rabuka, D.; Yao, S. L.;
Sears, P. S.; Liang, F. S.; Wong, C. H. Angew. Chem., Int. Ed. 2004,
43, 1562-1566.
10.1021/jo050521a CCC: $30.25 © 2005 American Chemical Society
Published on Web 09/07/2005
J. Org. Chem. 2005, 70, 7829-7840
7829

Serrano et al.
SCHEME 1. Amino- and 1,2-Diaminoinositols Synthesized in This Work
the inositol phosphate cycle and related processes.9 On
the other side, albeit not so deeply explored, the 1,2-
diaminoinositol framework has also been incorporated
into new salen asymmetric catalysts10,11 and also into new
water-soluble antitumor platinum complexes12,13 and
other chelating agents.14 Moreover, amides derived from
the simple trans-1,2-cyclohexanediamine have been de-
scribed as “universal” gelling agents.15 However, there
are few general chemo- and stereoselective synthetic
protocols leading to N,N′-1,2-diaminoinositols, and most
of the described procedures afford identically trans-N,N′-
disubstituted compounds.16 Examples of cis derivatives
are scarce and the synthetic protocols described so far
also lead to identically bis-functionalized N,N′-diamino
adducts.17,18
In the context of our current research on the synthesis
and enzyme inhibitory studies of inositol derivatives,19
we were interested in the development of a versatile
synthetic approach for the chemo-, regio-, and stereose-
lective synthesis of N-octanoyl derivatives of amino- and
1,2-diaminoinositols, as pharmacological tools for our
current biochemical studies. Synthesis of the target
inositol derivatives has been devised from chemical
(5) Verhelst, S. H. L.; Wennekes, T.; van der Marel, G. A.; Over-
kleeft, H. S.; van Boeckel, C. A. A.; van Boom, J. H. Tetrahedron 2004,
60, 2813-2822.
(6) (a) Schilling, S.; Rinner, U.; Chan, C.; Ghiviriga, I.; Hudlicky,
T. Can. J. Chem. 2001, 79, 1659-1667. (b) Frontier, A. J.; Raghavan,
S.; Danishefsky, S. J. J. Am. Chem. Soc. 2000, 122, 6151-6159. (c)
Suzuki, T.; Tanaka, S.; Yamada, I.; Koashi, Y.; Yamada, K.; Chida, N.
Org. Lett. 2000, 2, 1137-1140.
(7) Carbohydrate Mimics, Concepts and Methods; Chapleur, Y., Ed.;
Wiley-VCH: Weinheim, 1998.
(8) For recent examples of inositol derivatives as enzyme inhibitors
see: (a) Bashir-Uddin Surfraz, M.; Miller, D. J.; Gani, D.; Allemann,
R. K. Tetrahedron Lett. 2003, 44, 7677-7679. (b) Mills, S. J.; Potter,
B. V. L. Bioorg. Med. Chem. 2003, 11, 4245-4253. (c) Mills, S. J.;
Backers, K.; Erneux, C.; Potter, B. Org. Biomol. Chem. 2003, 1, 3546-
3556. (d) Chang, Y.; Choi, G.; Bae, Y.; Burdett, M.; Moon, H.; Lee, J.;
Gray, N.; Schultz, P.; Meijer, L.; Chung, S.; Choi, K.; Suh, P.; Ryu, S.
ChemBioChem 2002, 3, 897-901. (e) Ahn, Y.; Chung, S. Bull. Korean
Chem. Soc. 2002, 23, 515-517.
(15) Menger, F. M. Proc. Natl. Acad. Sci. U.S.A. 2002, 99, 4818-
4822.
(16) For trans-1,2-diaminocyclitols from N-tosyl or N-acyl aziridines
see: (a) Reference 7. (b) Paul, B. J.; Martinot, T. A.; Willis, J.; Hudlicky,
T. Synthesis-Stuttgart 2001, 952-956. (c) Paulsen, H.; Mielke, B.
Liebigs Ann. Chem. 1990, 169-180. (d) Kresze, G.; Melzer, H. Liebigs
Ann. Chem. 1981, 1874-1879. From reaction of a trans-1,2-dimesylate
with sodium azide, see: (e) De Almeida, M. V.; Figueiredo, R. M.; Dos
Santos, H. F.; Da Silva, A. D.; De Almeida, W. B. Tetrahedron Lett.
2001, 42, 2767-2769. For general synthesis of trans-1,2-diaminocy-
clohexane derivatives from N-substituted aziridinecyclohexane deriva-
tives, see: (f) Watson, I. D.; Yudin, A. K. J. Org. Chem. 2003, 68, 5160-
5167. (g) Kolb, H. C.; Finn, M. G.; Sharpless, K. B. Angew Chem., Int.
Ed. 2001, 40, 2004-2021. (h) Karpf, M.; Trussardi, R. J. Org. Chem.
2001, 66, 2044-2051. (i) Mitchell, J. M.; Finney, N. S. Tetrahedron
Lett. 2000, 41, 8431-8434.
(9) (a) Clarke, J. H. Curr. Biol. 2003, 13, R815-817. (b) Brunn, G.;
Fauq, A. H.; Chow, S.; Kozikowski, A. P.; Gallegos, A.; Powis, G. Cancer
Chemother. Pharmacol. 1994, 35, 71-79 (c) Panayotou, G.; Waterfield,
M. D.; Clarke, J. H. Trends Cell Biol. 1992, 2, 358-360. (d) Powis, G.;
Aksoy, I. A.; Melder, D. C.; Aksoy, S.; Eichinger, H.; Fauq, A. H.;
Kozikowski, A. P. Cancer Chemother. Pharmacol. 1991, 29, 95-104.
(10) Paul, B. J.; Willis, J.; Martinot, T. A.; Ghiviriga, I.; Abboud, K.
A.; Hudlicky, T. J. Am. Chem. Soc. 2002, 124, 10416-10426.
(11) Azev, V. N.; D’Alarcao, M. J. Org. Chem. 2004, 69, 4839-4842.
(12) Suami, T.; Shiio, T.; Kazuo, O.; Kunisuke, I. (Ajinomoto Co.
Inc.). Japanese Patent Application JP 86-161529, 1988.
(13) Suami, T.; Takeshi, S. (Ajinomoto Co. Inc.). Japanese Patent
Application JP85-127551, 1986.
(17) Kresze, G.; Weisz, M.; Dittel, W. Liebigs Ann. Chem. 1984, 203-
212.
(18) Guedat, P.; Spiess, B.; Schlewer, G. Tetrahedron Lett. 1994, 35,
7375-7378.
(14) Ouadi, A.; Loussouarn, A.; Morandeau, L.; Remaud, P.; Faivre-
Chauvet, A.; Webb, J.; Gestin, J.-F. Eur. J. Med. Chem. 2004, 39, 467-
472.
(19) Egido-Gaba´s, M.; Serrano, P.; Casas, J.; Llebaria, A.; Delgado,
A. Org. Biomol. Chem. 2005, 3, 1195-1201.
7830 J. Org. Chem., Vol. 70, No. 20, 2005

Synthesis of Aminoinositols and 1,2-Diaminoinositols
SCHEME 2a
a Reagents and conditions: (a) NaN3, CH3CN, 2 N LiClO4 (91%); (b) LiAlH4, THF (92-99%) from 10a, 10b, and 11; (c) NaN3, 1.2 N
NH4Cl (MeOH/H2O) (89%); (d) NaH, BnCl, THF (95%).
TABLE 1. NMR Data of Azido Amines 23, 24, 28, and 30
relative
stereochemistry
entry
compound
R1 (a/e)a
R2 (a/e)a
CH-N3
CH-NH2
J H1-H2
C-N3 (calcd)b
C-NH2 (calcd)b
1
2
3
4
23
24
28
30
N3 (a)
NH2 (a)
N3 (e)
trans
trans
cis
4.21
3.26
4.07
3.38
3.41
2.68
2.61
4.21
3.9
10.2
3.0
63.1 (63.2)
67.0 (69.6)
63.5 (66.9)
68.8 (65.9)
50.9 (49.0)
53.9 (55.3)
52.5 (52.8)
63.2 (51.5)
NH2 (e)
NH2 (e)
N3 (e)
N3 (a)
NH2 (a)
cis
3.0
a (a/e) denotes the axial or equatorial disposition of the R group. b Calculated from ref 39.
manipulation of a suitably protected conduritol B epoxide
(9) (Scheme 1).20
these systems,23 azidolysis of 9 in the presence of 2 N
LiClO4 led to the C1 trans adduct 10a through a putative
“all-axial” conformation (Scheme 2).24 Further azide
reduction afforded aminoinositol 12, a representative of
the 1-amino-1-deoxy-scyllo-inositol series. Stereochemical
assignment in this series was unambiguously confirmed
by the simplification of the NMR pattern of fully ben-
zylated azide 10b, due to the inherent symmetry of the
resulting derivative.
Conversely, azidolysis under acidic “nonchelating”
conditions (MeOH/1.2 N NH4Cl (4:1), 80 °C) afforded the
regioisomeric C2 trans adduct 11 as precursor of the
1-amino-1-deoxy-chiro-inositol 13. The assigned stereo-
chemistry was inferred from the downfield chemical shift
for the C(H)N3 proton (around 4.05-4.10 ppm), as
observed in related amino azide 23 (see Table 1).25 This
reaction outcome is consistent with the expected epoxide
opening under the above conditions.26
The stereoselective opening of epoxycyclohexane de-
rivatives with nucleophiles to give the corresponding
trans adducts has been extensively reported in the
literature.21 However, examples on cyclitol epoxides are
less abundant and, in general, the regioselectivity of the
process is determined by conformational grounds that can
be modulated by proper choice of reaction conditions.
Closely related to our previous work22 on the role of
chelating Lewis acids on the regioselective opening of
(20) For the sake of simplicity, the synthetic methodology described
in this work has been carried out from the easily available racemic
tetra-O-benzylconduritol B epoxide 9, obtained from (()-conduritol B
by epoxidation (MCPBA, MeOH) followed by benzylation (BnBr, NaH,
DMF). For the synthesis of enantiopure 9, see ref 22. For general
syntheses of enantiopure conduritol B epoxide derivatives from the
chiral pool, see: (a) Falshaw, A.; Hart, J. B.; Tyler, P. C. Carbohydr.
Res. 2000, 329, 301-308. (b) Takahashi, H.; Iimori, T.; Ikegami, S.
Tetrahedron Lett. 1998, 39, 6939-6942. (c) Watanabe, Y.; Mitani, M.;
Ozaki, S. Chem. Lett. 1987, 123-126. Enantiopure conduritol B from
deracemization of conduritol B tetracarbonate: Trost, B. M.; Patterson,
D. E.; Hembre, E. J. Chem. Eur. J. 2001, 7, 3768-3775.
(21) (a) Bartok, M.; Lang, K. L. In Small Ring Heterocycles; Hassner,
A., Ed.; Wiley: New York, 1985. (b) Eliel, E. L.; Allinger, N. L.; Angyal,
S. J.; Morrison, G. A. Topics in Stereochemistry; Interscience: New
York, 1965; p 102. (c) Rickborn, B.; Murphy, D. K. J. Org. Chem. 1969,
34, 3209.
Installation of the cis stereochemistry leading to
amino-deoxy-myo-inositol derivatives (Scheme 1) was
(23) For the use of chelation-controlled aminolysis and azidolysis
of 1,2-epoxycyclohexanes bearing remote polar groups, see Calvani,
F.; Crotti, P.; Gardelli, C.; Pineschi, M. Tetrahedron 1994, 50, 12999-
13022 and references therein.
(24) A theoretical study of this reaction has been carried out.
Serrano, P.; Llebaria, A.; Vazquez, J.; de Pablo, J.; Anglada, J. M.;
Delgado, A. Chem. Eur. J. 2005, 11, 4465-4472.
(22) Serrano, P.; Llebaria, A.; Delgado, A. J. Org. Chem. 2002, 67,
7165-7167.
J. Org. Chem, Vol. 70, No. 20, 2005 7831

Serrano et al.
SCHEME 3a
a Reagents and conditions: (a) MsCl, Et3N, THF (88-92%); (b) DMF, 140 °C, sealed tube (82%); (c) LiAlH4, THF (87%).
attempted by stereochemical inversion of mesylate 14
arising from azido alcohol 10a. Thus, we were pleased
to observe that treatment of mesylate 14 in DMF in a
sealed tube at 140 °C for prolonged reaction times cleanly
afforded cis-azido alcohol 16 with exquisite stereocontrol
(Scheme 3).27 Again, the stereochemical assigment was
carried out by NMR, in particular the chemical shifts and
coupling constants of the vicinal C(H)N3 and C(H)OH
protons. Thus, C(H)N3 shows one large (J ) 10 Hz) and
one small J value (J′ ) 2.5 Hz) in agreement with its
axial disposition. On the other side, C(H)OH appears as
an apparent triplet of small coupling constants (J ) J′
) 2.5 Hz). The stereochemical outcome of this transfor-
mation can be rationalized by assuming a SN2 mesylate
displacement by DMF with formation of an intermediate
imidate ester salt, leading ultimately to azido alcohol
16.28,29 This transformation seems strongly dependent on
the configuration of the starting azido alcohol, since
regioisomeric trans-azido mesylate 15 was recovered
unaltered under otherwise identical reaction conditions
(Scheme 3).30 If we assume that conformational equilib-
rium is frozen in 14 and 15 by the “all-equatorial”
disposition of the OBn groups, azido mesylate 15 could
be expected to react faster than 14 due to the axial
disposition of the mesyloxy group.31 However, the ob-
served results are in agreement with the operation of
singular stereoelectronic effects, as described in related
systems.32 Finally, reduction of the azide group in 16
afforded 1-amino-1-deoxy-myo-inositol derivative 17.
Synthesis of regioisomeric 2-amino-2-deoxy-myo-inosi-
tol was next attempted from N-Boc amino alcohol mes-
ylate 19 (Scheme 4), configurationally equivalent to the
above azido mesylate 15. This alternative approach relied
on the configurational inversion of the carbon atom
bearing the mesyloxy group through a stereospecific in
situ intramolecular oxazolidinone formation, as described
(29) It is worth mentioning that this transformation is independent
of the water content, since identical results have been obtained by using
DMF systems containing variable amounts of water. For a similar
transformation, in a DMF-H2O system, see: Angyal, S. J.; Odier, L.
Carbohydr. Res. 1980, 80, 203-206.
(25) In all cases, the major conformation is assumed to be that
imposed by the “all-equatorial” disposition of the OBn groups.
(26) For epoxide opening under nonchelating conditions, see, inter
alia: (a) Uzan, R.; Letellier, P.; Ralainairina, R.; Beaupe`re, D. Synthesis
1994, 925-930. (b) Nakata, M.; Chong, C.; Niwata, Y.; Toshima, K.;
Tatsuta, K. J. Antibiot. 1993, 46, 1919-1922. (c) Letellier, P.; Ral-
lainirina, R.; Uzan, R.; Beaupe`re, D. Tetrahedron Lett. 1994, 35, 4555-
4558. (d) Ogawa, S.; Chida, N.; Suami, T. J. Org. Chem. 1983, 48,
1203-1207.
(30) Mesylate 15 also failed to react with other nucleophiles, such
as sodium azide, potassium phthalimide (see text), or benzoic acid/
CsF, whereas the corresponding triflate A gave the anti elimination
adduct B.
(27) Formation of minor amounts of azido alcohol 16 had already
been observed in reaction of mesylate 14 with other nucleophiles in
DMF (unpublished results from our group).
(28) Imidate esters salts have been proposed as reaction intermedi-
ates for the conversion of alcohols into formate esters. See, for
example: (a) Barluenga, J.; Campos, P. J.; Gonza´lez-Nu´n˜ez, E.;
Asensio, G. Synthesis 1985, 426-428. (b) Riley, A. M.; Jenkins, D. J.;
Potter, B. V. L. Carbohydr. Res. 1998, 314, 277-281. Although we have
never observed the corresponding formate ester, its formation and in
situ hydrolysis along the reaction course cannot be ruled out.
(31) Eliel, E.; Ro, R. S. J. Am. Chem. Soc. 1957, 79, 5995-6000.
(32) For related examples of the effect of stereoelectronic effects on
the reactivity of inositol derivatives, see: (a) Guidot, J. P.; Legall, T.
J. Org. Chem. 1993, 58, 5271-5273. (b) Shing, T. K.; Wan, L. H. J.
Org. Chem. 1996, 61, 8468-8479.
7832 J. Org. Chem., Vol. 70, No. 20, 2005

Synthesis of Aminoinositols and 1,2-Diaminoinositols
SCHEME 4a
a Reagents and conditions: (a) (Boc)2O, acetone (78%); (b) MsCl, Et3N, THF (84%); (c) DMF, 120 °C, 16 h; (d) 1 N NaOH-MeOH, 80
°C, 24 h (65%).
SCHEME 5a
a Reagents and conditions: (a) LiAlH4, THF, 0 °C (90%); (b) NaN3 (20 equiv); NH4Cl (1 equiv), MeOH:H2O (9:1), 80 °C (82%).
for related vicinal N-Boc amino alcohol mesylates.33 Thus,
aminoinositol 13 was converted into N-Boc aminocyclitol
mesylate 19, which, under thermal conditions (DMF, 120
°C) followed by in situ hydrolysis, afforded the required
2-amino-2-deoxy-myo-inositol derivative 21, presumably
through a putative oxazolidinone 20 intermediate, as
shown in Scheme 4. Stereochemical assignment of amino
alcohol 21 was corroborated from comparison with re-
gioisomeric amino alcohol 17, in particular the C(H)NH2
proton chemical shifts. Thus, while this proton is ob-
served at 2.64 ppm in 17, it is found around 1.0 ppm
downfield shifted in 21, in agreement with its expected
equatorial disposition.25
Diamino derivatives of the chiro and scyllo series,
showing a trans relationship between both nitrogen
atoms, have been obtained from the hitherto unprec-
edented aziridine 22 (Scheme 5). This was obtained, in
turn, by reduction of azido mesylates 14 or 15, followed
by in situ intramolecular displacement of the transient
amino mesylates. Opening of aziridine 22 with sodium
azide under acid catalysis afforded a 1:1 mixture of azido
amines 23 (chiro) and 24 (scyllo),34 which could be easily
separated by flash chromatography.
Regioselective synthesis of 1,2-diamino-1,2-dideoxy-
myo-inositol derivatives, showing a cis relationship be-
tween both nitrogen atoms, was first envisaged from
azido mesylate 14. Thus, nucleophilic displacement of the
mesyloxy group in 14 with potassium phthalimide (DMF,
140 °C, 48 h) afforded adduct 29 with complete configu-
rational inversion (Scheme 6).35 Hydrazinolysis of 29
afforded cis azido amine 30, a key synthetic precursor of
the 1,2-diamino-myo-inositol series. Access to the regio-
isomeric cis azido amine 28 was first attempted following
a similar procedure from mesylate 15. However, treat-
ment of 15 with excess (3 equiv/mol) potassium phthal-
imide led to the recovery of the starting material, even
(34) For a similar process, see: Rohloff, J. C.; Kent, K. M.; Postich,
M. J.; Becker, M. W.; Chapman, H. H.; Kelly, D. E.; Lew, W.; Louie,
M. S.; McGee, L. R.; Prisbe, E. J.; Schultze, L. M.; Yu, R. H.; Zhang, L.
J. J. Org. Chem. 1998, 63, 4545-4550.
(35) The reactivity of mesylate 14 with nonanionic nitrogen nucleo-
philes was somewhat sluggish. Thus, no reaction was observed with
butylamine or diethylamine under forcing conditions (10 equiv, DMF,
90 °C, 48 h, sealed tube). On the contrary, reaction of 14 with sodium
azide (DMF, 100 °C) afforded the expected cis-diazide, whose spectro-
scopic data matched those described in the literature (ref 18).
(33) Benedetti, F.; Norbedo, S. Tetrahedron Lett. 2000, 41, 10071-
10074.
J. Org. Chem, Vol. 70, No. 20, 2005 7833

Serrano et al.
SCHEME 6a
a Reagents and conditions: (a) potassium phthalimide, DMF, 140 °C, 72 h (56%); (b) N2H4, THF, 80 °C, (79%); (c) (Boc)2O, acetone, rt
(78%); (d) MsCl, DCM, TEA, rt (84%); (e) NaN3, DMF, 120 °C (75%) from 26; (f) HCl:AcOEt (1:20), rt (95%).
under forcing conditions (DMF, 140 °C, 72 h).30 This
result is illustrative of the dramatic influence of stereo-
electronic effects in the reactivity of inositol derivatives.
On the other hand, attempts to exploit the reactivity of
29 by reducing the azide group to the corresponding
amine were unsuccessful under a variety of conditions
(catalytic hydrogenation, Zn/NH4Cl or NaBH4).
As an alternative approach, we turned our attention
to trans amino alcohol 12, whose transformation into cis
azido amine 28 is outlined in Scheme 6. Protection of the
amino group, to give carbamate 25, followed by hydroxyl
group activation to mesylate 26, followed by azide
displacement36,37 and N-Boc removal, afforded the desired
amino azide intermediate 28.
Stereochemical assignments on the diamino-inositol
series were also carried out by NMR methods by com-
parison of C(1)H and C(2)H chemical shifts and coupling
constants of azido amines 23, 24, 28, and 30 (see Table
1).38 The observed results are in agreement with a major
or exclusive conformation with an “all-equatorial” dispo-
sition of the OBn groups. It is worth mentioning the
strong deshielding effect (between 0.8 and 1.5 ppm)
observed for CH-N3 and CH-NH2 equatorial protons
compared with their axial counterparts. Moreover, a large
H1-H2 coupling constant (around 10.2 Hz) is also ob-
served for 24, in agreement with the trans-diaxial
disposition for these protons. Concerning 13CNMR data,
an excellent fit between observed and calculated chemical
shifts for C-N3 and C-NH2 carbon atoms was found. The
only exception was observed in compound cis-30 (entry
4), where C-NH2 carbon atom was deshielded by around
12 ppm with respect to the expected value.
With protected aminoinositols 12, 13, 17, 21 and
1-amino-2-azidoinositols 23, 24, 28, and 30 in hand,
synthesis of our target inositols was next envisaged. Acyl
aminoinositols required acylation of the amino group and
final OBn deprotection. However, while acylation with
n-octanoyl chloride was straightforward, deprotection
was rather cumbersome and required a thorough exami-
nation. Initial experiments were carried out on amide 31
under standard hydrogenolysis conditions in the presence
of Pd(OH)2 or Pd-C as catalysts in MeOH as solvent. In
both cases, the reaction progress was very slow and
required several days for completion.40 Catalytic transfer
hydrogenation with formic acid as hydrogen source41 in
a mixture of t-BuOH/THF (1:1) at 40°C was also consid-
ered. Although amide 31 could be deprotected in good
yield under these conditions after 72 h, the reaction was
too sluggish for practical purposes. Gratifyingly, benzyl
removal could be efficiently achieved with BCl3 in CH2-
Cl2 at -78°C. Under these conditions, fully deprotected
1-(N-octanoylamino)-scyllo-inositol hydrochloride 1 was
obtained in excellent yield after a simple workup. The
above sequence of N-acylation and deprotection was used
for the remaining aminoinositol members 2-4, as shown
in Scheme 7.
Diaminoinositol derivatives were similarly obtained
from 1-amino-2-azidoinositols 23, 24, 28, and 30 (Scheme
8). It is worth mentioning the efficient, chemoselective
reduction of the azide group in tetra-O-benzyl N-acyl
derivatives 35, 37, 39, and 41 by catalytic hydrogenation
under mild conditions. In this case, the above-mentioned
poisonous effect of polybenzylated aminoinositols toward
benzyl ether hydrogenolysis40 was crucial for the success
of this transformation.42
In summary, the herein described methodology repre-
sents a versatile approach to the regio-, and stereoselec-
tive synthesis of N-acyl derivatives of amino- and 1,2-
(36) The relative configuration present in mesylates 14 and 26, in
which the mesyloxy group shows a trans relationship with respect to
both of the substituents on the adjacent carbon atoms, seems to be
the only one operative for intermolecular substitution with anionic
nitrogen nucleophiles. Compare, for example, the reactivity of the above
mesylates with that of diastereomeric mesylate 15 (see text) or triflate
A, as indicated in ref 30.
(37) For a similar sequence leading to differently functionalized
N,N′-cis-1,2-diaminocyclohexane derivatives, see: Govindaraju, T.;
Gonnade, R. G.; Bhadbhade, M. M.; Kumar, V. A.; Ganesh, K. N. Org.
Lett. 2003, 5, 3013-3016.
(38) Bidimensional nOe experiments from azido N-octanoyl deriva-
tive 35 were also in agreement with the stereochemical assignment
for precursor azido amine 23 (see Supporting Information).
(39) Pretsch, E.; Clerc, T.; Seibl, J.; Simon, W. Tablas para la
determinacio´n estructural por me´todos espectrosco´picos; Springer-
Verlag Ibe´rica: Barcelona, 1998.
(40) Polybenzylated aminocyclitols have been reported to be poison-
ous for the Pd/C catalysed hydrogenolysis of benzyl ethers (Surfraz,
M. B. U.; Akhtar, M.; Allemann, R. K. Tetrahedron Lett. 2004, 45,
1223-1226).
(41) Elamin, B.; Anantharamaiah, G. M.; Royer, G. P.; Means, G.
E. J. Org. Chem. 1979, 44, 3442-3444.
7834 J. Org. Chem., Vol. 70, No. 20, 2005

Synthesis of Aminoinositols and 1,2-Diaminoinositols
SCHEME 7a
a Reagents and conditions: (a) C7H15COCl, CH2Cl2, Et3N (78-90%); (b) 1 M in heptane BCl3, CH2Cl2 (65-83%).
SCHEME 8a
a Reagents and conditions: (a) C7H15COCl, CH2Cl2, Et3N (79-87%); (b) H2, Pd/C, THF, rt; (c) 1 M in heptane BCl3, CH2Cl2 (70-76%).
diaminoinositols derived from conduritol B epoxide as a
common precursor. Described protocols allow the “on
demand” access to each of the configurations of the
diamino and amino alcohol moieties present in these
systems. Interestingly, 2-azido-1-aminoinositols 23, 24,
28, and 30 are suitable synthetic intermediates for the
chemoselective functionalization of each of the nitrogen
atoms. These findings open new opportunities for the
synthesis of inositol analogues and the study of their
biological profiles.
Experimental Section
For General Methods, see the Supporting Information.
(1RS,2RS,3SR,4RS,5RS,6SR)-2-Azido-3,4,5,6-tetrakis-
benzyloxycyclohexanol (10a). A solution of the starting
epoxide 9 (500 mg, 0.96 mmol) in CH3CN (17 mL) was added
J. Org. Chem, Vol. 70, No. 20, 2005 7835

Serrano et al.
dropwise under argon over LiClO4 (160 mg, 1.50 mmol) at room
temperature. A solution of 624 mg (9.6 mmol) of NaN3 in CH3-
CN (4 mL) was added next and the reaction mixture was
stirred at 80 °C under argon. After 18 h, the reaction mixture
was cooled to room temperature, quenched with H2O (10 mL),
extracted with CH2Cl2 (3 × 20 mL), and dried over anhydrous
Na2SO4. Filtration and evaporation afforded crude azido
alcohol, which was purified by filtration through a plug of silica
and elution with hexanes/EtOAc (1:1) to afford 492 mg (0.87
mmol, 91%) of 10a. IR (film): 3331, 3057, 2107, 1489, 1457,
1359, 13C NMR (75 MHz): 66.4, 72.6, 75.7, 75.9, 75.8, 76.0,
81.1, 82.4, 82.6, 83.4, 127.6-128.5, 137.5-138.1; 1H NMR (300
MHz): 3.40-3.44 (m, 4H), 3.50-3.69 (m, 2H), 4.75-4.96 (m,
8H), 7.26-7.35 (m, 20H). Anal. Calcd for C34H35N3O5: C, 72.19;
H, 6.24; N, 7.43 Found: C, 72.23; H, 6.22; N, 7.39.
mL), and dried to afford the crude amino alcohol, which was
purified by flash chromatography using a mixture of hexane:
EtOAc/TEA (2:1/2% vol).
(1RS,2RS,3SR,4RS,5RS,6SR)-2-Amino-3,4,5,6-tetrakis-
benzyloxycyclohexanol (12a) (99%). IR (film): 3331, 3062,
3031, 2907, 1580, 1496, 1456, 1406. 13C NMR (75 MHz): 56.8,
74.5, 75.5-76.5 (4×), 81.0, 81.5, 82.5, 83.2, 127.6-128.5, 138.3.
1H NMR (300 MHz): 2.97 (t, J ) 9.9 Hz, 1H), 3.35 (m, 2H),
3.62 (m, 3H), 4.68-5.01 (m, 10H), 7.24-7.40 (m, 20H). Anal.
Calcd for C34H37NO5: C, 75.67; H, 6.91; N, 2.60. Found: C,
75.73; H, 7.12; N, 2.58.
(1RS,2SR,3RS,4SR,5SR,6RS)-2,3,4,5,6-pentakisbenzyl-
oxycyclohexylamine (12b) (99%). IR (film): 3331, 3062,
3031, 2907, 1580, 1496, 1456, 1406. 13C NMR (75 MHz): 56.8,
74.5, 75.5-76.5 (4×), 81.0, 81.5, 82.5, 83.2, 127.6-128.5,
138.3.1H NMR (300 MHz): 2.94 (t, J ) 9.9 Hz, 1H), 3.35 (t, J
) 9.0 Hz, 2H), 3.60-3.70 (m, 3H), 4.68-5.01(m, 10H), 7.24-
7.34 (m, 25H). Anal. Calcd for C41H43NO5: C, 78.19; H, 6.88;
N, 2.22. Found: C, 78.24; H, 6.76; N, 2.21.
(1RS,2RS,3SR,4SR,5RS,6SR)-1-azido-2,3,4,5,6-penta-
kisbenzyloxycyclohexane (10b). A solution of alcohol 10a
(1.4 g, 3.0 mmol) in anhydrous THF (20 mL) was added
dropwise over an ice-cooled suspension of sodium hydride (60%
dispersion in mineral oil, 270 mg, 11.25 mmol), previously
washed with hexane (3 × 10 mL) in tetrahydrofuran (25 mL)
under an atmosphere of argon. Stirring was continued until
complete gas evolution, and benzyl chloride (0.45 mL, 3.79
mmol) was added next. The reaction mixture was stirred at
room temperature for 24 h, quenched with water (10 mL), and
extracted with diethyl ether (3 × 25 mL). The combined
organic layers were washed with brine (20 mL), dried, and
concentrated. The resulting oil was purified by flash chroma-
tography using a mixture of hexane/ethyl acetate (4:1) as
eluent to afford azide 10b (95%); oil; IR (film): 3031, 2909,
(1RS,2RS,3RS,4SR,5SR,6RS)-2-Amino-3,4,5,6-tetrakis-
benzyloxycyclohexanol (13) (92%). IR (film): 3300, 3222,
3029, 2936, 1488, 1466, 1412. 13C NMR (125 MHz): 42.5, 61.8,
72.2, 75.5, 76.1, 76.2, 80.7, 83.3, 84.3, 85.3, 127.9-128.8, 138.5,
1
138.6, 138.9. H NMR (500 MHz): 2.52 (t, 10.0 Hz, 1H), 2.66
(m, 1H), 2.76 (m, 1H), 3.41 (t, J ) 9.0 Hz, 1H), 3.47 (t, J ) 9.9
Hz, 1H), 3.49 (t, J ) 9.0 Hz, 1H), 3.58 (t, J ) 9.5 Hz, 1H),
3.3.64 (t, J ) 9.0 Hz, 1H), 4.70-5.02 (m, 8H), 7.24-7.34 (m,
20H); Anal. Calcd for C34H37NO5: C, 75.67; H, 6.91; N, 2.60.
Found: C, 75.72; H, 6.79; N, 2.63.
(1RS,2SR,3RS,4SR,5SR,6RS)-2-Amino-3,4,5,6-tetrakis-
benzyloxycyclohexanol (17) (87%). IR (film): 3329, 3031,
2987, 1502, 1446, 1421. 13C NMR (125 MHz): 52.1, 68.9, 72.1,
75.0, 75.2, 75.3, 80.7, 81.3, 81.4, 84.0, 127.6-128.8, 138.3-
139.0. 1H NMR (500 MHz): 2.64 (dd, J ) 2.5, 10 Hz, 1H), 3.49
(m, 2H), 3.63 (t, J ) 9.5 Hz, 1H), 3.96 (t, J ) 10 Hz, 1H), 4.11-
4.18 (broad, 1H), 4.60-5.03 (m, 8H), 7.24-7.34 (m, 20H). Anal.
Calcd for C34H37NO5: C, 75.67; H, 6.91; N, 2.60. Found: C,
75.46; H, 6.81; N, 2.55.
Synthesis of Azido Mesylates 14 and 15. A solution of
the starting azido alcohol 10a or 11 (277 mg, 0.49 mmol) and
TEA (0.5 mL) in THF (20 mL) was treated with MsCl (58 mg,
0.51 mmol). The reaction mixture was stirred at room tem-
perature for 20 h, diluted with H2O (10 mL), extracted with
Et2O (4 × 15 mL), and dried over anhydrous Na2SO4. Filtration
and evaporation afforded crude azido mesylates which were
purified by filtration through a plug of silica and elution with
hexanes/EtOAc (2:1).
1
2107, 1496, 1454, 1359; H NMR (300 MHz): 3.34-3.38 (2H,
m, 2 × CH), 3.46-3.58 (4 H, m, 4 × CH), 4.84-4.90 (10H, m,
5 × OCH2Ph), 7.2-7.4 (25H, m, Ar). 13C NMR (75 MHz): 53.2,
66.9, 73.5 (2×), 75.9 (2×), 82.4, 83.1 (4×), 127.7-128.4, 137.7,
138.1. Anal. Calcd for C41H41N3O5: C, 75.09; H, 6.30; N, 6.41.
Found: C, 75.18; H, 6.27; N, 6.56.
(1RS,2RS,3RS,4SR,5SR,6RS)-2-Azido-3,4,5,6-tetrakis-
benzyloxycyclohexanol (11). A solution of the starting
epoxide 9 (260 mg, 0.5 mmol) in a 4:1 mixture of MeOH/
aqueous 1.2 N NH4Cl (10 mL) was treated with NaN3 (325
mg, 5 mmol). The reaction mixture was stirred at 80 °C for 20
h, cooled to room temperature, diluted with H2O (10 mL),
extracted with Et2O (4 × 15 mL), and dried over anhydrous.
Na2SO4. Filtration and evaporation afforded crude azido
alcohol, which was purified by filtration through a plug of silica
and elution with hexanes/EtOAc (1:1) to afford 475 mg (0.84
mmol, 89%) of 11; IR (film): 3342, 3090, 3036, 2980, 2106,
1497, 1369. 13C NMR (125 MHz): 61.2, 68.7, 73.6, 73.7, 76.1,
76.2, 79.7 (2×, 79.8, 81.6, 127.8-128.8, 137.2-138.0. 1H NMR
(500 MHz): 3.70 (dd, J ) 4.0, 8.0 Hz, 1H, H6), 3.78 (t, J ) 9.0
Hz, 1H, H4), 3.87 (t, J ) 9.5 Hz, 1H, H5), 3.97 (t, J ) 3.5 Hz,
1H, H1), 4.05-4.10 (m, 2H, H2, H3), 4.65 (d, J ) 11 Hz, 1H),
4.74-4.92 (m, 9H), 7.22-7.39 (m, 20H). Anal. Calcd for
C34H35N3O5: C, 72.19; H, 6.24; N, 7.43. Found: C, 72.09; H,
6.30; N, 7.48.
(1′RS,2′SR,3′SR,4′RS,5′SR,6′RS)-(2-Azido-3,4,5,6-tetra-
kisbenzyloxy)cyclohexyl methanesulfonate ester (14)
(289 mg, 0.45 mmol, 92%). IR (film): 3029, 2919, 2870, 2109,
1496, 1454, 1363. 13C NMR (75 MHz): 39.3, 64.6, 75.9, 76.0,
76.1, 76.2, 80.2, 80.7, 80.8, 82.1, 82.9, 127.7-128.7, 137.2-
137.9. 1H NMR (300 MHz): 3.05 (s, 3H), 3.50 (t, J ) 9 Hz,
1H), 3.58-3.70 (m, 4H), 4.48 (t, J ) 9 Hz, 1H), 4.80-5.00 (m,
8H), 7.23-7.35 (m, 20H). Anal. Calcd for C35H37N3O7S: C,
65.30; H, 5.79; N, 6.53. Found: C, 65.58; H, 5.68; N, 6.70.
(1′RS,2′SR,3′RS,4′SR,5′RS,6′SR)-(2-Azido-3,4,5,6-tetra-
kisbenzyloxy)cyclohexyl methanesulfonate ester (15)
(277 mg, 0.43 mmol, 88%). IR (film): 3031, 2920, 2870, 2109,
1469, 1454, 1354. 13C NMR (75 MHz): 38.68, 60.0, 73.8, 73.9,
75.9, 76.1, 76.7, 77.1, 79.2, 80.8, 81.4, 127.7-128.7, 137.2-
General Method for Azide Reduction: Synthesis of
Amino Alcohols 12a, 12b, 13, and 17. A solution of the
corresponding azido alcohol (0.4 mmol) in THF (2.5 mL) was
added to a suspension of LiAlH4 (19 mg, 0.5 mmol) in THF
(2.5 mL) at 0 °C. The reaction mixture was stirred for 2 h and
EtOAc (2 mL) was added at 0 °C. The resulting suspension
was diluted with H2O (10 mL), extracted with Et2O (4 × 10
1
138.4. H NMR (500 MHz): 2.95 (s, 3H), 3.74 (t, J ) 10 Hz,
1H), 3.80 (dd, J ) 3.0,10.0 Hz, 1H), 3.88 (t, J ) 9.0 Hz, 1H),
4.02 (dd, J ) 3.0,9.5 Hz, 1H), 4.10 (t, J ) 4.0 Hz), 4.71-5.02
(m, 9H), 7.23-7.35 (m, 20H). Anal. Calcd for C35H37N3O7S: C,
65.30; H, 5.79; N, 6.53. Found: C, 65.21; H, 5.59; N, 6.73.
(1RS,2SR,3RS,4SR,5SR,6RS)-2-Azido-3,4,5,6-tetrakis-
benzyloxycyclohexanol (16). A solution of 14 (100 mg, 0.15
mmol) in DMF (4 mL) was stirred at 140 °C in a sealed tube
for 96 h. After the solvent was removed under reduced
pressure, the resulting crude was taken up in Et2O (5 mL),
washed with H2O (3 × 2 mL), treated with brine, and dried
(42) This unexpected chemoselectivity can be used for the selective
functionalization of the amino group. The reductive amination of 36
with n-octanal to afford amino amide 43 (see below) is illustrative.
7836 J. Org. Chem., Vol. 70, No. 20, 2005

Synthesis of Aminoinositols and 1,2-Diaminoinositols
over anhydrous Na2SO4. Evaporation under reduced pressure
afforded a crude, which was purified by flash chromatography
on hexanes/EtOAc (1:1) to give 16 (76 mg, 82%); IR (film):
3298, 3050, 3036, 2970, 2105, 1489, 1369. 13C NMR (125 Hz):
63.6, 69.2, 73.3, 76.1, 76.2, 76.3, 80.2, 80.5, 81.5, 84.2, 127.9-
was added to a suspension of LiAlH4 (30 mg, 0.79 mmol) in
THF (3 mL) at 0 °C. The reaction mixture was stirred for 2 h
and EtOAc (2 mL) was added at 0 °C. The suspension was
diluted with water (10 mL), extracted with Et2O (4 × 10 mL),
and dried over anhydrous Na2SO4. Filtration and evaporation
afforded crude aziridine, which was chromatographed on silica
gel using a mixture of hexane/EtOAc (2:1) in the presence of
TEA (3%) to afford 229 mg (0.41 mmol, 90%) of 22. IR (film):
3292, 3062, 3031, 2920, 1858, 1488, 1454, 1365; 13C NMR (75
MHz): 34.2, 72.7 (broad), 72.8, 75.2, 75.7, 79.5, 79.7, 81.2, 84.2
(broad), 127.3-128.3, 138.0-138.9. 1H NMR (300 MHz): 2.36
(m, 1H), 2.51 (bb, 1H), 3.44 (dd, J ) 7.8,10.2 Hz, 1H), 3.65 (t,
J ) 9.3 Hz, 1H), 3.83-3.90 (m, 2H), 4.65-4.95 (m, 8H), 7.24-
7.34 (m, 20H). ESP(+): (M + H) 522.4. Anal. Calcd for C34H35-
NO4: C, 78.28; H, 6.76; N, 2.69;. Found: C, 78.45; H, 6.97; N,
2.81.
Synthesis of 2-Azido-1-amino Cyclitols 23 and 24 by
Ring Opening of Aziridine 22. A solution of the starting
aziridine 22 (250 mg, 0.48 mmol) and NH4Cl (0.48 mmol) in a
4:1 mixture of MeOH/H2O (10 mL) was treated with NaN3 (650
mg, 10 mmol). The reaction mixture was stirred at 80 °C until
the starting material could not be detected by TLC, cooled to
room temperature, diluted with H2O (10 mL), extracted with
Et2O (4 × 15 mL), and dried over anhydrous Na2SO4. Filtration
and evaporation afforded a 1:1 mixture of azidoaminocyclitols
23 and 24, which were isolated by flash chromatography on
elution with hexanes/EtOAc (2:1) in the presence of TEA (2%).
(1RS,2RS,3RS,4SR,5SR,6RS)-2-Azido-3,4,5,6-tetrakis-
benzyloxycyclohexylamine (23) (112 mg, 0.20 mmol, 42%).
IR (film): 3043, 3039, 3045, 3032, 2922, 2876, 2103, 1476,
1359. 13C NMR (75 MHz): 50.9, 63.1, 72.9, 73.5, 75.7, 75.8,
79.3, 79.4, 81.1 (broad), 81.9 (broad), 127.5-128.4, 138.1-
138.8; 1H NMR (300 MHz): 3.41 (t, J ) 3.9 Hz, 1H, H1), 3.72
(dd, J ) 3.9, 9.0 Hz, 1H), 3.79 (t, J ) 3.9 Hz, 1H), 3.84-3.89
(m, 2H), 4.21 (dd, J ) 3.3, 9 Hz, 1H, H2), 4.60-5.00 (m, 8H),
7.23-7.34 (m, 20H). HRMS: calcd for C34H36N4O4 (M + H+),
565.2737; found, 565.2759.
(1RS,2RS,3SR,4RS,5RS,6SR)-2-Azido-3,4,5,6-tetrakis-
benzyloxycyclohexylamine (24) (109 mg, 0.19 mmol, 40%).
IR (film): 3081, 3035, 2939, 2910, 2106, 1496, 1457. 13C NMR
(75 MHz): 53.9, 67.0, 75.8, 75.9, 77.0, 77.2, 82.5, 83.1, 83.9
(2×, 127.6-128.6, 137.5-138.2. 1H NMR (500 MHz): 2.68 (t,
J ) 9.9 Hz, 1H, H1), 3.26 (t, J ) 10.2 Hz, 1H, H2), 3.33 (t, J
) 9, 3 Hz, 1H), 3.50 (t, J ) 9.9 Hz, 1H), 3.56-3.67 (m, 2H),
4.68-5.05 (m, 8H), 7.29-7.38 (m, 20H). HRMS: calcd for
C34H36N4O4 (M + H+), 565.2737; found, 565.2748.
1
128.9, 137.7-138.6. H NMR (500 MHz): 3.36 (dd, J ) 2.5,
10.0 Hz, 1H, H2), 3.48 (dd, J ) 3.0, 10.5 Hz, H6), 3.55 (t, J )
9.5 Hz, 1H, H4), 3.97 (t, J ) 9.5 Hz, 1H, H5), 4.03 (t, J ) 10.0
Hz, 1H, H3), 4.17 (t, J ) 2.5 Hz, 1H, H1), 4.70-4.97 (m, 10H),
7.24-7.36 (m, 20H). Anal. Calcd for C34H35N3O5: C, 72.19; H,
6.24; N, 7.43. Found: C, 71.98; H, 6.14; N, 7.51.
(1RS,2RS,3SR,4SR,5RS,6RS)-N-(2,3,4,5-Tetrakisbenzyl-
oxy-6-hydroxycyclohexyl) Carbamic Acid tert-Butyl Es-
ter (18). A solution of 13 (97 mg, 0.18 mmol) in acetone (4
mL) was treated with (Boc)2O (42 mg, 0.24 mmol). The reaction
mixture was stirred at room temperature overnight. Evapora-
tion afforded crude 18, which was purified flash chromatog-
raphy on hexanes/EtOAc (5:1) to afford 89 mg (0.14 mmol,
78%) of carbamate 18. IR (film): 3342, 3063, 3030, 2976, 2901,
1687, 1534, 1497, 1453, 1365. 13C NMR (125 MHz): 28.2, 50.5
(broad), 60.3, 72.1, 72.6, 75.6, 77.2 (2×, 72.3, 79.8, 80.6, 81.4,
1
127.8-128.8, 138.1-138.9, 156.3. H NMR (500 MHz): 1.49
(s, 9H), 2.59 (bb, 1H), 3.62 (t, J ) 9.0 Hz, 1H), 3.74 (dd, J )
3.0, 9.0 Hz, 1H), 3.91 (t, J ) 9.5 Hz, 1H), 4.14 (dd, J ) 4.5, 9.9
Hz, 1H), 4.29 (m, 1H), 4.53 (m, 1H), 4.60-4.98 (m, 8H), 7.24-
7.38 (m, 20H). ESP(+): (M + Na) 662.3. Anal. Calcd for C39H45-
NO7: C, 73.22; H, 7.09; N, 2.19. Found: C, 73.43; H, 7.21; N,
2.24.
(1′RS,2′SR,3′RS,4′SR,5′RS,6′SR)-(2,3,4,5-Tetrakisbenzyl-
oxy-6-tert-butoxycarbonylamino)cyclohexyl Methane-
sulfonate Ester (19). A solution of the starting carbamate
18 (96 mg, 0.15 mmol) and TEA (0.1 mL) in CH2Cl2 (5 mL)
was treated with MsCl (22 mg, 0.19 mmol). The reaction
mixture was stirred at room temperature for 18 h, diluted with
H2O (5 mL), extracted with Et2O (4 × 10 mL), and dried over
anhydrous Na2SO4. Filtration and evaporation afforded crude
19, which was purified by filtration through a plug of silica
and elution with hexanes/EtOAc (9:1) to give 90 mg (0.12
mmol, 84%) of 19. IR (film): 3068, 2982, 2932, 1809, 1757,
1477, 1458, 1395. 13C NMR (125 MHz): 28.3, 38.9, 72.5, 73.1
(broad), 75.7 (broad), 75.8 (broad), 76.5, 76.8, 80.2, 127.9-
1
128.8, 138.1-138.9, 156.4. H NMR (500 MHz): 1.49 (s, 9H),
3.01 (s, 3H), 3.65 (t, J ) 9.5 Hz, 1H), 3.85 (m, 2H), 4.05 (m,
1H), 4.22 (broad, 1H), 4.70-5.00 (m, 9H), 5.78 (bb, 1H), 7.24-
7.38 (m, 20H). ESP(+): (M + Na) 740.3. Anal. Calcd for C40H47-
NO9S: C, 66.93; H, 6.60; N, 1.95. Found: C, 66.51; H, 6.49;
N, 1.89.
(1′RS,2′SR,3′RS,4′RS,5′SR,6′RS)-N-(2,3,4,5-Tetrakisben-
zyloxy-6-hydroxycyclohexyl) carbamic Acid tert-Butyl
Ester (25). A solution of 12a (97 mg, 0.18 mmol) in acetone
(4 mL) was treated with (Boc)2O (42 mg, 0.24 mmol). The
reaction mixture was stirred at room temperature overnight.
Evaporation afforded crude 25 which was purified by silica
flash chromatography on hexanes/EtOAc (5:1) to afford 89 mg
(0.14 mmol, 78%) of carbamate 25. IR (film): 3342, 3063, 3030,
2976, 2901, 1687, 1534, 1497, 1453, 1365. 13C NMR (125
MHz): 28.6, 56.8, 73.4, 75.8, 76.0, 76.1, 79.2, 80.4, 82.8 84.1,
(1RS,2SR,3SR,4RS,5RS,6SR)-2-Amino-3,4,5,6-tetrakis-
benzyloxycyclohexanol (21). A solution of carbamate 19 (50
mg, 0.096 mmol) in anhydrous DMF (2 mL) was heated at 120
°C. After the solution was stirred for 16 h, the solvent was
removed under reduced pressure and the resulting crude was
taken up in Et2O (10 mL), washed with H2O (2 × 5 mL),
treated with brine, and dried over anhydrous Na2SO4. The
resulting residue was treated with 1 N methanolic NaOH at
80 °C for 24 h. Then, methanol was removed under reduced
pressure and the resulting residue was extracted with Et2O
(3 × 5 mL). The combined organic phases were washed with
H2O, treated with brine, dried over anhydrous Na2SO4, and
the solvent was removed under reduced pressure. Crude amino
alcohol was purified by flash chromatography using a mixture
of hexane:EtOAc/Et3N (2:1/2% vol) to furnish 21 (34 mg, 0.063
mmol, 65%). IR (film): 3311, 3087, 3059, 3029, 2946, 1574,
1499, 1439. 13C NMR (125 MHz): 51.3, 71.9, 72.7, 75.7, 75.8,
76.1, 81.0, 81.4, 82.0, 84.1, 127.8-128.9, 138.5-139.0. 1H NMR
(500 MHz): 3.50-3.56 (m, 3H), 3.69 (t, J ) 3.5 Hz, 1H), 4.05
(t, J ) 9.5 Hz, 1H), 4.17 (t, J ) 9.5 Hz), 4.72-5.04 (m, 8H),
7.24-7.38 (m, 20H). Anal. Calcd for C34H37NO5: C, 75.67; H,
6.91; N, 2.60. Found: C, 75.92; H, 7.02; N, 2.54.
1
84.3, 127.8-128.8, 138.2-138.8, 157.0. H NMR (500 MHz):
1.48 (s, 9H), 3.18 (bs, 1H), 3.42-3.68 (m, 5H), 4.53 (d, J ) 7
Hz, 1H), 4.70 (d, J ) 11 Hz, 1H), 4.87-4.94 (m, 9H), 7.24-
7.40 (m, 20H). HRMS: calcd for C39H45NO7 (M + Na),
662.3094; found, 662.3117
(1′RS,2′RS,3′SR,4′RS,5′SR,6′SR)-(2,3,4,5-Tetrakisbenzyl-
oxy-6-tert-butoxycarbonylamino)cyclohexyl Methane-
sulfonic Ester (26). A solution of the starting carbamate 25
(96 mg, 0.15 mmol) and TEA (0.1 mL) in CH2Cl2 (5 mL) was
treated with MsCl (22 mg, 0.19 mmol). The reaction mixture
was stirred at room temperature for 18 h, diluted with H2O
(5 mL), extracted with Et2O (4 × 10 mL), and dried over
anhydrous Na2SO4. Filtration and evaporation afforded crude
26, which was purified by filtration through a plug of silica
and elution with hexanes/EtOAc (9:1) to give 90 mg (0.12
mmol, 84%) of 26. IR (film): 3068, 2974, 2862, 2105, 1698,
(1RS,2SR,3RS,4RS,5SR,6SR)-2,3,4,5-Tetrakisbenzyloxy-
7-azabicyclo[4.1.0]heptane (22). A solution of the starting
azido mesylates 14 or 15 (315 mg, 0.49 mmol) in THF (3 mL)
J. Org. Chem, Vol. 70, No. 20, 2005 7837

Serrano et al.
1463. 13C NMR (125 MHz): 28.6, 39.1, 54.7, 75.7, 75.9, 76.1,
3.58 (t, J ) 9.5 Hz, 1H), 4.01 (t, J ) 9.0 Hz, 1H), 4.07 (t, J )
10 Hz, 1H), 4.21 (t, J ) 2.5 Hz, 1H, H1), 4.70-4.80 (m, 2H),
4.88-5.00 (m, 6H), 7.24-7.40 (m, 20H). HRMS: calcd for
C34H36N4O4 (M + H+), 565.2737; found, 565.2744.
General Method for Reduction of the Azide Group. To
a solution of the corresponding azido amide (0.03 mmol) in
THF was added 8 mg of Degussa E196R/W Pd-C catalyst.
The reaction mixture was stirred at room temperature under
H2 (3 atm) until the presence of the azido group could not be
detected by IR analysis. The solutions were filtered through
Celite, and the catalyst was washed with MeOH (2 × 2 mL).
Evaporation afforded pure amino amides.
76.3, 79.2, 80.3, 80.9, 81.3, 82.6, 83.8, 127.9-128.7, 137.9-
1
138.4, 155.8. H NMR (500 MHz): 1.48 (s, 9H), 2.87 (s, 3H),
3.50-3.70 (m, 4H), 3.78 (q, J ) 9 Hz, 1H), 4.58 (m, 1H), 4.70-
4.98 (m, 10 H), 7.22-7.38 (m, 20 H). HRMS: calcd for C40H47-
NO9S (M + Na), 740.2870; found, 740.2847.
(1′RS,2′SR,3′SR,4′RS,5′RS,6′SR)-N-(2-Azido-3,4,5,6-tet-
rakisbenzyloxycyclohexyl)carbamic Acid tert-Butyl Es-
ter (27). A solution of 26 (108 mg, 0.15 mmol) in DMF (2 mL)
was treated with NaN3 (49 mg, 0.75 mmol) and the reaction
mixture was stirred at 120 °C. After 16 h, the reaction was
cooled to room temperature, diluted with H2O (10 mL),
extracted with Et2O (4 × 15 mL), and dried over anhydrous
Na2SO4. Filtration and evaporation afforded crude azido
carbamate 27, which was purified by filtration through a plug
of silica and elution with hexanes/EtOAc (1:1) to afford 75 mg
(0.11 mmol, 75%) of 27. IR (film): 3340, 3031, 2912, 2101,
1684, 1526, 1357. 13C NMR (125 MHz): 28.6, 51.6, 62.7, 73.4,
75.6, 76.1, 76.3, 79.2, 80.2, 81.1, 81.7, 84.3, 127.8-128.7,
137.7-138.6. 1H NMR (300 MHz): 1.43 (s, 9H), 3.51 (m, 2H),
3.70 (m, 2H), 3.89 (t, J ) 9.5 Hz, 1H), 4, 18 (m, 1H), 4.60-
4.98 (m, 8H), 7.24-7.38 (m, 20 H). HRMS: Calcd for C39H44N4O6
(M + Na), 687.3159; found, 687.3178.
(1RS,2SR,3SR,4RS,5RS,6SR)-(2-Azido-3,4,5,6-tetrakis-
benzyloxy)cyclohexylamine (28). Compound 27 (66.5 mg,
0.10 mmol) was solved in 2 mL of a 20:1 mixture of EtOAc:
aqueous 1 N HCl. The reaction mixture was stirred at room
temperature until the starting material could not be detected.
A solution of aqueous 1 N NaOH (5 mL) was then added, and
the reaction mixture was extracted with Et2O (4 × 15 mL)
and dried over anhydrous Na2SO4. Filtration and evaporation
afforded a residue, which was purified by filtration through a
plug of silica and elution on hexanes/EtOAc (2:1) in the
presence of TEA (2%) to afford 54 mg (0.095 mmol, 95%) of
azido amine 28. IR (film): 3377, 3063, 3030, 2914, 2101, 1697,
1585, 1496, 1454. 13C NMR (125 MHz): 52.5, 63.5, 73.4, 76.0,
76.13, 76.3, 81.6, 82.3, 82.7, 84.7, 127.9-128.88, 137.8-138.7;
1H NMR (300 MHz): 2.61 (dd, J ) 3, 9.5 Hz, 1H, H1), 3.42 (t,
J ) 9.5 Hz, 1H), 3.48 (t, J ) 9.5 Hz, 1H), 3.66 (dd, J ) 3, 9.5
Hz, 1H), 3.98 (t, J ) 9.5 Hz, 1H), 4.07 (t, J ) 3 Hz, 1H, H2),
4.65-5.00 (m, 8H), 7.24-7.38 (m, 20 H). HRMS: calcd for
C34H36N4O4 (M + H+), 565.2737; found, 565.2751.
(1′RS,2′RS,3′RS,4′SR,5′SR,6′RS)-N-(2-Amino-3,4,5,6-tet-
rakisbenzyloxy cyclohexyl)octanamide (36) (18 mg, 0.027
mmol, 82%). IR (film): 3291, 3029, 2925, 2853, 1638, 1557.
13C NMR (125 MHz): 14.3, 22.8, 26.2, 29.3, 29.5, 31.9, 37.5,
49.6, 50.9, 72.3, 72.4 (2×), 72.5, 75.4, 75.7, 79.7 (2×), 127.9-
1
128.7, 138.0-138.9, 174.4. H NMR (500 MHz): 0.89 (t, J )
6.9 Hz, 3H), 1.20-1.40 (m, 8H), 1.59 (m, 2H), 2.1 (t, J ) 7.5
Hz, 2H), 3.60 (t, J ) 8.5 Hz, 1H), 3.7 (dd, J ) 4.0, 8.5 Hz, 1H),
3.83 (t, J ) 4 Hz, 1H), 4.00 (t, J ) 8.0 Hz, 1H), 4.25 (dd, J )
4.0, 8.5 Hz, 1H), 4.34 (dd, J ) 5.0, 10 Hz), 4.55-4.66 (m, 5H),
4.77-4.86 (m, 4H), 5.61 (d, J ) 5.0 Hz, 1H), 7.24-7.40 (m, 20
H). HRMS: calcd for C42H52N2O5 (M + H+), 665.3876; found,
665.3895.
(1′RS,2′RS,3′SR,4′RS,5′RS,6′SR)-N-(2-Amino-3,4,5,6-tet-
rakisbenzyloxy-cyclohexyl)octanamide (38) (17 mg, 0.026
mmol, 87%). IR (film): 3301, 3054, 3037, 2955, 2849, 1678,
1499. 13C NMR (125 MHz): 14.3, 22.8, 26.2, 29.3, 29.5, 31.9,
37.5, 49.6, 50.9, 72.4, 72.5, 75.2, 75.6, 75.7, 77.2, 79.7, 127.9-
1
128.7, 138.0-138.9, 174.4. H NMR (500 MHz): 0.89 (t, J )
6.9 Hz, 3H), 1.20-1.40 (m, 8H), 1.59 (m, 2H), 2.10 (t, J ) 7.5
Hz, 2H), 3.60 (t, J ) 8.5 Hz, 1H), 3.70 (dd, J ) 4.0, 8.5 Hz,
1H), 3.83 (t, J ) 4 Hz, 1H), 4.00 (t, J ) 8.0 Hz, 1H), 4.25 (dd,
J ) 4.0, 8.5 Hz, 1H), 4.34 (dd, J ) 5.0, 10 Hz) 4.55-4.66 (m,
5H), 4.77-4.86 (m, 4H), 5.61 (d, J ) 5.0 Hz, 1H), 7.24-7.40
(m, 20H). HRMS: calcd for C42H52N2O5 (M + H+), 665.3876;
found, 665.3891.
(1′RS,2′SR,3′SR,4′RS,5′RS,6′SR)-N-(2-Amino-3,4,5,6-tet-
rakisbenzyloxy-cyclohexyl)octanamide (40) (16 mg, 0.025
mmol, 87%). IR (film): 3301, 3033, 2956, 2925, 2847, 1657,
1540, 1469. 1453. 13C NMR (125 MHz): 14.2, 22.8, 25.9, 29.2,
29.5-29.9 (rotamers), 31.9, 37.0, 49.4, 52.3, 72.6, 74.7, 75.8,
78.1, 81.0, 84.1, 127.8-129.0, 138.2-138.8, 173.5. 1H NMR
(500 MHz): 0.89 (t, J ) 6.9 Hz, 3H), 1.22-1.40 (m, 10H), 1.95
(m, 2H), 3.61 (m, 2H), 3.71 (t, J ) 1.5 Hz, 1H), 3.82-3.90 (m,
2H), 3.94 (t, J ) 9, 0 Hz, 1H), 4.62 (s, 2H), 4.81-4.88 (m, 6H),
5.49 (d, J ) 6.5 Hz, 1H), 7.24-7.40 (m, 20H). RMS. calcd for
C42H52N2O5 (M + H+), 665.3876; found: 665.3861.
(1′RS,2′SR,3′RS,4′SR,5′SR,6′RS)-N-(2-Amino-3,4,5,6-tet-
rakisbenzyloxy-cyclohexyl)octanamide (42) (17 mg, 0.026
mmol, 87%). IR (film): 3291, 3030, 2940, 2851, 1666, 1537.
13C NMR (125 MHz): 14.0, 22.5, 25.7, 29.3-29.5 (rotamers),
31.7, 32.2, 36.8, 63.1, 72.7, 74.5, 74.7, 78.2, 80.0, 127.7-128.3,
137.6-138.4, 173.0. 1H NMR (500 MHz): 0.89 (t, J ) 6.9 Hz,
3H), 1.25-1.45 (m, 8H), 1.59 (bs), 1.98 (m, 2H), 2.58 (t, J )
3.9 Hz, 1H), 2.83 (m, 1H), 3.36 (t, J ) 3.0 Hz, 1H), 3.28-3.77
(m, 5H), 4.58-4.98 (m, 8H), 6.40 (d, J ) 5.5 Hz, 1H), 7.24-
7.40 (m, 20H); RMS. calcd for C42H52N2O5 (M + H+), 665.3876;
found, 665.3888.
(1′RS,2′SR,3′RS,4′SR,5′SR,6′RS)-2-(2-Azido-3,4,5,6-tet-
rakisbenzyloxycyclohexyl)isoindole-1,3-dione (29). A so-
lution of azido mesylate 14 (244 mg, 0.38 mmol) in DMF (10
mL) was treated with potassium phthalimide (203 mg, 1.1
mmol). The reaction mixture was stirred at 140 °C for 72 h,
diluted with H2O (10 mL), extracted with Et2O (4 × 15 mL),
and dried over anhydrous Na2SO4. Filtration and evaporation
afforded a residue, which was purified by flash chromatogra-
phy on hexanes/EtOAc (9:1) to give 147 mg (0.21 mmol, 56%)
of 29. IR (film): 3063, 2925, 2858, 2107, 1715, 1495, 1459,
1370; 13C NMR (125 MHz): 48.5, 62.3, 73.3, 75.9, 76.0, 76.1,
78.5, 82.7, 83.3, 84.7, 123.9, 127.6-128.6, 134.6, 137.4, 138.1,
1
139.0, 169.4. H NMR (500 MHz): 3.63 (t, J ) 9.5 Hz, 1H),
3.82-3.86 (m, 2H), 4.48-4.57 (m, 3H), 4.67 (d, J ) 10.8 Hz,
1H), 4.80-5.02 (m, 6H), 5.25 (t, J ) 11.5 Hz, 1H), 7.24-7.40
(m, 20H), 7.78 (dd, J ) 3.5, J ) 6.0 Hz, 2H), 7.92 (dd, J ) 3.5,
J ) 6.0 Hz, 2H). HRMS: calcd for C42H38N4O6 (M + H+);
695.2791; found, 695.2768.
General Method for the Synthesis of N-octanoyl Ben-
zylaminoinositols (31-35, 37, 39, 41). A solution of the
corresponding aminocyclitol (0.1 mmol) and TEA (0.1 mL) in
CH2Cl2 (2 mL) was treated with octanoyl chloride (0.12 mmol).
The reaction mixture was stirred at room temperature until
the staring material could not be detected. Dilution with H2O
(5 mL), extraction with CH2Cl2, drying over anhydrous Na2-
SO4, and evaporation afforded a crude, which was purified by
flash chromatography on elution with hexanes/EtOAc (10:1 to
4:1).
(1RS,2SR,3RS,4SR,5SR,6RS)-(2-Azido-3,4,5,6-tetrakis-
benzyloxy)cyclohexylamine (30). A solution of 29 (69.5 mg,
0.1 mmol) in THF (4 mL) was treated with 2 mL of hydrazine
(1 N solution in THF). The reaction mixture was stirred at 80
°C until the starting material could not be detected. Evapora-
tion afforded crude 30, which was purified by flash chroma-
tography on elution with hexanes/EtOAc (2:1) in the presence
of TEA (2%) to give 44.8 mg (0.079 mmol, 79%) of 30. IR
(film): 3053, 2919, 2861, 2099, 1454, 1364. 13C NMR (125
MHz): 63.2, 68.8, 73.2, 76.1, 76.2, 76.3, 80.1, 80.5, 81.5, 84.2,
127.9-128.9, 137.9, 138.1, 138.9. 1H NMR (500 MHz): 3.38
(dd, J ) 3.0, 10 Hz, 1H, H2), 3.50 (dd, J ) 3.0, 10 Hz, 1H),
(1′RS,2′SR,3′RS,4′RS,5′SR,6′RS)-N-(2,3,4,5,6-Pentakis-
benzyloxycyclohexyl)octanamide (31) (65 mg, 86%). IR
7838 J. Org. Chem., Vol. 70, No. 20, 2005

Synthesis of Aminoinositols and 1,2-Diaminoinositols
(film): 3269, 3089, 3065, 3030, 2925, 2854, 1644, 1565, 1497,
1454. 13C NMR (75 MHz): 14.1, 22.7, 25.6, 29.3, 29.7, 31.9,
37.1, 53.8 (broad), 55.5, 74.9, 75.7, 75.8, 78.9, 82.7, 84.9, 127.6-
mmol, 89%). IR (film): 3282, 3064, 30 20, 2953, 2924, 2854,
210 3, 1646, 1546, 1453, 1357; 13C NMR (125 MHz): 14.3, 22.8,
22.9, 25.8, 29.2-29.5 (rotamers), 31.9, 36.9, 50.4, 61.6, 73.3,
75.1, 76.2, 76.3, 78.1, 80.9, 81.6, 84.3, 127.9-129.0 0, 137.7-
1
128.3, 138.4, 173.5; H NMR (300 MHz): 0.89 (t, J ) 6.7 Hz,
1
3H). 1.20-1.42 (m, 8H), 1.52 (m, 2H), 1.98 (t, J ) 7.5 Hz, 2H),
3.60-3.67 (m, 4H), 3.88 (m, 2H), 4.65-4.98 (m, 10H), 5. 43 (d,
J ) 5.4 Hz, 1H), 7.24-7.34 (m, 25H). Anal. Calcd for C49H57-
NO6: C, 77.85; H, 7.60; N, 1.85. Found: C, 78.23; H, 7.45; N,
1.91.
138.6, 173.6. H NMR (500 MHz): 0.89 (t, J ) 6.9 Hz, 3H),
1.22-1.40 (m, 10H), 1.95 (m, 2H), 3.55-3.62 (m, 2H), 3.73 (dd,
J ) 3.5, 9.5 Hz, 1H), 3.90-3.97 (m, 2H), 4.28 (t, J ) 3.5 Hz,
1H), 4.60-4.98 (m, 8H), 5.22 (d, J ) 7.5 Hz, 1H), 7.24-7.40
(m, 20H); HRMS: calcd for C42H50N4O5 (M + H+): 691.3781;
found, 691.3784.
(1′RS,2′RS,3′SR,4′SR,5′RS,6′RS)-N-(2,3,4,5-Tetrakisben-
zyloxy-6-hydroxycyclohexyl)octanamide (32) (57 mg, 86%).
IR (film): 3309, 3080, 3059, 2931, 1667, 1464. 13C NMR (125
MHz): 14.3, 22.8, 25.9, 29.2, 29.5, 31.9, 37.5, 50.0, 67.5, 72.4,
72.9, 75.7, 75.9, 79.6 (2×), 80.5, 81.4, 127.9-128.5, 137.9-
(1′RS,2′SR,3′RS,4′SR,5′SR,6′RS)-N-(2-Azido-3,4,5,6-tet-
rakisbenzyloxycyclohexyl)octanamide (41). (59 mg, 0.086
mmol, 86%). IR (film): 3068, 2974, 2862, 2105, 1698, 1463.
13C NMR (125 MHz): 14.0, 22.7, 24.8, 25.9, 29.0, 29.2, 31.7,
47.2, 62.4, 72.0, 76.2 (2×), 76.3, 78.2, 80.8, 81.4, 83.4, 127.9-
1
139.7, 174.6. H NMR (500 MHz): 0.90 (t, J ) 6.5 Hz, 3H),
1
1.20-1.38 (m, 8H), 1.61 (m, 2H), 2.17 (t, J ) 8.0 Hz, 1H), 2.65
(bb, 1H), 3.62 (t, J ) 8.5 Hz, 1H), 3.65 (d, J ) 8.5 Hz, 1H),
3.91 (t, J ) 9.0 Hz, 1H), 4.15 (dd, J ) 4.0, 9.0 Hz, 1H), 4.52
(m, 1H), 4.60-4.90 (m, 8H), 5.90 (d, J ) 4.0 Hz, 1H), 7.28-
7.34 (m, 20H). Anal. Calcd for C42H51NO6: C, 75.76; H, 7.72;
N, 2.10. Found: C, 76.29; H, 7.81; N, 2.14.
128.6, 137.5-138.2 (4×), 174.1; H NMR (300 MHz): 0.89 (t,
J ) 6.8 Hz, 3H), 1.20-1.40 (m, 8H), 1.60-1.68 (m, 3H), 2.15
(m, 2H), 2.18 (t, J ) 7.5 Hz, 1H), 3.55-3.65 (m, 5H), 4.52 (d,
J ) 7.5 Hz, 1H), 4.72-4.95 (m, 7H), 5.0 5(m, 1H), 5.41 (d, J )
9.0 Hz), 7.24-7.40 (m, 20H). HRMS: calcd for C42H50N4O5 (M
+ H+), 691.3781; found, 691.3794.
(1′RS,2′SR,3′RS,4′RS,5′SR,6′SR)-N-(2,3,4,5-Tetrakisben-
zyloxy-6-hydroxycyclohexyl)octanamide (33) (52 mg, 78%).
IR (film): 3309, 3080, 3059, 2931, 1667, 1464. 13C NMR (125
MHz): 14.3, 22.9, 25.9, 29.3, 29.5, 31.9, 37.1, 51.2, 69.2, 73.2,
75.4, 76.2, 79.1, 80.6, 81.5, 84.4, 127.9-128.9, 137.9-138.8,
N-(1′RS,2′RS,3′SR,4′SR,5′RS,6′RS)-(2,3,4,5-tetrakisben-
zyloxy-6-octylaminocyclohexyl)octanamide (43). To a
solution of 36 (33 mg, 0.05 mmol) in MeOH (2 mL) were added
AcOH (0.05 mmol) and NaBH3CN (4,5 mg, 0.07 mmol). After
10 min, octanaldehyde (7.7 mg, 0.06 mmol) was added and the
reaction mixture was stirred at room temperature. After 16
h, the solvent was evaporated and the residue diluted with
H2O (5 mL), extracted with Et2O (3 × 5 mL), and dried over
anhydrous Na2SO4. Filtration and evaporation afforded crude
amide 43, which was purified by filtration through a plug of
silica and elution with hexane/EtOAc (10:1) to give 27 mg
(0.036 mmol, 72%) of 43. IR: 3067, 3022, 2956, 2920, 1679,
1547, 1495. 1H NMR (500 MHz): 0.89 (m, 6H), 1.23-1.35
(broad, 22 H), 1.55-1.62 (m, 2H), 2.19 (t, J ) 6.5 Hz, 2H),
2.35 (t, J ) 6.5 Hz, 1H), 2.59 (m, 1H), 2.66 (m, 1H), 3.49 (t, J
) 3.0 Hz, 1H), 3.57 (t, J ) 9.0 Hz, 1H), 3.69 (dd, J ) 4.0 Hz,
9.5 Hz, 1H), 3.92 (t, J ) 9.0 Hz, 1H), 4.24 (dd, J ) 5.0, 9.5 Hz,
1H), 4.54 (m, 1H), 4.57-4.64 (m, 4H), 4.80-4.94 (m, 4H), 5.59
(d, J ) 6.0 Hz, 1H), 7.24-7.39 (m, 20H). HRMS: calcd for
C50H68N2O5 (M + H+), 777.5206; found: 777.5190.
General Method for the O-Debenzylation: Synthesis
of N-Octanoylaminoinositols (1-8). A solution of the
corresponding amide (0.05 mmol) in CH2Cl2 (1 mL) at -78 °C
was treated with 1 M BCl3 in heptane (2 equiv per OBn group).
The reaction mixture was allowed to warm to room temper-
ature and stirred for an additional 16 h. The mixture was then
cooled to -78 °C and quenched with methanol (0.5 mL).
Solvents were then removed under reduced pressure and
EtOAc (2 mL) was added next to the oily residue. After
sonication in an ultrasonic bath for 1 min, the suspended solid
was collected by filtration. Following this protocol, inositols
5-8 were obtained as the corresponding hydrochloride salts.
1
173.3. H NMR (500 MHz): 0.89 (t, J ) 7.5 Hz, 3H), 1.20-
1.38 (m, 8H), 1.56 (m, 2H), 2.05 (t, J ) 8.5 Hz, 1H), 3.57 (dd,
J ) 3.0, 9.6 Hz, 1H), 3.61 (t, J ) 9.0 Hz, 1H), 3.77 (t, J ) 10.5
Hz, 1H), 3.89 (t, J ) 9.0 Hz), 4.08 (m, 1H), 4.13 (t, J ) 3.0
Hz), 4.65-4.98 (m, 8H), 5.64 (d, J ) 9.0 Hz), 7.28-7.34 (m,
20H). Anal. Calcd for C42H51NO6: C, 75.76; H, 7.72; N, 2.10.
Found: C, 76.16; H, 7.83; N, 2.01.
(1′RS,2′RS,3′SR,4′SR,5′RS,6′SR)-N-(2,3,4,5-Tetrakisben-
zyloxy-6-hydroxycyclohexyl)octanamide (34) (60 mg, 90%).
IR (film): 3321, 3069, 3030, 2982, 2935, 1678, 1556, 1424.
1401. 13C NMR (125 MHz): 14.3, 22.8, 26.0, 29.3, 29.4, 31.9,
37.9, 51.7, 72.3, 72.5, 75.1, 75.5, 75.6, 77.6, 80.9, 81.3, 81.7,
1
127.8-128.8, 137.4-138.8, 176.3. H NMR (500 MHz): 0.89
(t, J ) 6.9 Hz, 3H), 1.20-1.38 (m, 8H), 1.65 (m, 2H), 2.28 (t,
J ) 7.0 Hz, 2H), 3.56 (t, J ) 8.0 Hz, 1H), 3.66 (t, J ) 8.0 Hz,
1H), 3.72 (m, 2H), 3.78 (dd, J ) 4.0, 8.5 Hz, 1H), 4.57 (m, 1H),
4.59 (m, 2H), 4.78-4.98 (m, 6H), 5.64 (d, J ) 9.0 Hz), 5.90 (d,
J ) 5.0 Hz, 1H), 7.28-7.34 (m, 20H). Anal. Calcd for C42H51-
NO6: C, 75.76; H, 7.72; N, 2.10. Found: C, 75.99; H, 7.59; N,
1.99.
(1′RS,2′RS,3′RS,4′SR,5′SR,6′RS)-N-(2-Azido-3,4,5,6-tet-
rakisbenzyloxycyclohexyl)octanamide (35) (60 mg, 0.087
mmol, 87%). IR (film):3327, 3035, 2933, 2913, 2860, 2106, 1736,
1707, 1653, 1536, 1454; 13C NMR (75 MHz): 14.0, 22.6, 25.7,
29.0, 29.2, 31.7, 35.2, 49.3, 58.5, 72.3, 72.8, 75.8, 76.0, 78.9,
80.6, 81.6, 127.7-128.5, 137.3-138.4, 174.4; 1H NMR (300
MHz): 0.89 (t, J ) 6.9 Hz, 3H), 1.22-1.40 (m, 8H), 1.61 (m,
2H), 2.15 (m, 2H), 3.54 (t, J ) 9.9 Hz, 1H), 3.75 (dd, J ) 3.9,
9.3 Hz, 1H), 3.87-3.97 (m, 2H), 4.26 (dd, J ) 1.5, 2.4 Hz),
4.58-4.98 (m, 9H), 5.55 (d, J ) 4.2 Hz, 1H), 7.24-7.40 (m,
20H). HRMS: calcd for C42H50N4O5 (M + H+), 691.3781; found,
691.3804.
(1′RS,2′RS,3′SR,4′RS,5′RS,6′SR)-N-(2-Azido-3,4,5,6-tet-
rakisbenzyloxy-cyclohexyl)octanamide (37). (54 mg, 0.079
mmol, 79%). IR (film): 3056, 3028, 2929, 2862, 2107, 1713,
1694, 1459, 1362. 13C NMR (125 MHz): 14.3, 22.8, 25.8, 29.3,
29.5, 31.9, 37.3, 44.7, 54.8, 64.0, 75.4, 76.0, 76.1, 79.1, 82.4,
83.4, 84.0, 128.0-128.7, 137.9-138.4, 174.0. 1H NMR (500
MHz): 0.89 (t, J ) 7.0 Hz, 3H), 1.22-1.32 (m, 10H), 2.09 (m,
2H), 3.41 (m, 2H), 3.55 (t, J ) 9.5 Hz, 1H), 3.62 (t, J ) 9.5 Hz,
1H), 3.85 (t, J ) 10.0 Hz, 1H), 4.62 (d, J ) 11 Hz, 1H), 4.86-
4.98 (m, 9H), 5.40 (d, J ) 8.0 Hz, 1H), 7.24-7.40 (m, 20H).
HRMS: calcd for C42H50N4O5 (M + H+): 691.3781; found;
691.3796.
(1′rs,2′RS,3′SR,4′sr,5′RS,6′SR)-N-(2,3,4,5,6-Pentahydroxy-
cyclohexyl)octanamide (1) (12.0 mg, 76%). 1H NMR (500
MHz, MeOD): 0.91 (t, J ) 7.0 Hz, 3H), 1.22-1.40 (m, 8H),
1.61 (m, 2H), 2.26 (t, J ) 8 Hz, 2H), 3.25 (m, 4H), 3.59 (t, J )
8.5 Hz, 1H), 3.68 (dd, J ) 4.5, 5.5 Hz, 1H). HRMS. calcd for
C14H27NO6 (M + H+), 306.1917; found, 306.1939.
(1′RS,2′SR,3′SR,4′SR,5′RS,6′SR)-N-(2,3,4,5,6-Pentahy-
droxycyclohexyl)octanamide (2) (11.5 mg, 75%). 1H NMR
(500 MHz, MeOD): 0.91 (t, J ) 7.0 Hz, 3H), 1.22-1.40 (m,
8H), 1.60 (m, 2H), 2.27 (t, J ) 8 Hz, 2H), 3.55 (m, 2H), 3.63 (t,
J ) 9.0 Hz, 1H), 3.94 (m, 2H), 4.31 (m, 1H). HRMS calcd for
C14H27NO6 (M + H+), 306.1917; found, 306.1951.
(1′RS,2′RS,3′SR,4′RS,5′RS,6′RS)-N-(2,3,4,5,6-Pentahy-
1
droxycyclohexyl)octanamide (3) (9.8 mg, 65%). H NMR
(500 MHz, MeOD): 0.91 (t, J ) 7.0 Hz, 3H), 1.22-1.40 (m,
8H), 1.65 (m, 2H), 2.27 (t, J ) 7.5 Hz, 2H), 3.23 (t, J ) 9.5 Hz,
1H), 3.42 (dd, J ) 3.0, 9.0 Hz, 1H), 3.60 (m, 2H), 3.76 (dd, J )
2.0, 9.0 Hz, 1H), 3.90 (m, 1H). HRMS calcd for C14H27NO6 (M
+ H+), 306.1917; found, 306.1932.
(1′RS,2′SR,3′SR,4′RS,5′RS,6′SR)-N-(2-Azido-3,4,5,6-tet-
rakis-benzyloxy-cyclohexyl)octanamide (39). (61 mg, 0.089
J. Org. Chem, Vol. 70, No. 20, 2005 7839

Serrano et al.
(1′rs,2′RS,3′SR,4′rs,5′RS,6′SR)-N-(2,3,4,5,6-Pentahydroxy-
cyclohexyl)octanamide (4) (12.7 mg, 83%). 1H NMR (500
MHz, MeOD): 0.91 (t, J ) 6.5 Hz, 3H), 1.22-1.40 (m, 8H),
1.62 (m, 2H), 2.32 (t, 7.5 Hz, 2H), 3.18 (t, J ) 9.0 Hz, 1H, H4),
3.47 (t, J ) 10 Hz, 2H, H3-H3′), 3.55 (dd, J ) 4.5, 10 Hz, 2H,
H2-H2′), 4.53 (t, J ) 4.5 Hz, 1H, H1). HRMS. calcd for C14H27-
NO6 (M + H+): 306.1917; found, 306.1931.
HRMS: calcd for C14H28N2O5 (M + H+, 305.2076; found,
305.2082.
(1′RS,2′SR,3′RS,4′SR,5′SR,6′RS)-N-(2-Amino-3,4,5,6-tet-
rahydroxycyclohexyl)octanamide (8) (HCl salt, 12.5 mg,
1
73%). H NMR (500 MHz, MeOD-D2O): 0.91 (t, 3H), 1.26-
1.32 (m, 8H), 1.71 (m, 2H), 1.91 (m, 2H), 3.32-3.36 (m, 4H),
3.63-3.66 (m, 2H), 7.91 (m, 1H), 8.21 (m, 1H). HRMS: calcd
for C14H28N2O5 (M + H+), 305.2076; found, 305.2085.
(1′RS,2′RS,3′RS,4′SR,5′SR,6′RS)-N-(2-Amino-3,4,5,6-tet-
rahydroxycyclohexyl)octanamide (5) (HCl salt, 12.9 mg,
1
76%). H NMR (500 MHz, MeOD-D2O): 0.92 (t, 3H), 1.33-
Acknowledgment. Financial support from Minis-
terio de Ciencia y Tecnolog´ıa (Spain), Project BQU2002-
03737, and DURSI (Generalitat de Catalunya), Projects
2001SGR00085 and 2001SGR00342, is acknowledged.
P.S. thanks Ministerio de Educacio´n y Cultura (Spain)
for a predoctoral fellowship. The authors also thank
Mrs. Meritxell Egido for experimental contributions.
1.36 (m, 8H), 1.65 (m, 2H), 2.32-2.35 (m, 2H), 3.58-3.71 (m,
2H), 3.88-4.01 (m, 3H), 4.59 (m, 1H). HRMS. Calcd for
C14H28N2O5 (M + H+), 305.2076; found, 305.2079.
(1′RS,2′RS,3′SR,4′RS,5′RS,6′SR)-N-(2-amino-3,4,5,6-tet-
rahydroxycyclohexyl)octanamide (6) (HCl salt, 12.2 mg,
1
72%). H NMR (500 MHz, MeOD-D2O): 0.93 (t, 3H), 1.25-
1.41 (m, 8H), 1.75 (m, 2H), 2.21 (m, 2H), 3.30-3.85 (m, 6H).
HRMS: calcd for C14H28N2O5 (M + H+), 305.2076; found,
305.2081.
Supporting Information Available: NMR spectra for all
the compounds described in this work. This material is
available free of charge via the Internet at http://pubs.acs.org.
(1′RS,2′SR,3′SR,4′RS,5′RS,6′SR)-N-(2-Amino-3,4,5,6-tet-
rahydroxycyclohexyl)octanamide (7) (HCl salt, 11.9 mg,
1
70%). H NMR (500 MHz, MeOD-D2O): 0.94 (t, 3H), 1.28-
1.39 (m, 8H), 1.70 (m, 2H), 2.36 (m, 2H), 3.40-3.90 (m, 6H).
JO050521A
7840 J. Org. Chem., Vol. 70, No. 20, 2005