Synthesis of 1,2-diamino-1,2-dideoxy-myo-inositol-derived ligands for the investigation of metal complex reactivity

Article abstract of DOI:10.1021/jo049521l

A method for the synthesis of chiral 1,2-diamino-1,2-dideoxy-myo-inositol- based bis-pyridyl ligands 3a and 3b from the corresponding myo-inositol precursor is described. These highly functionalized inosamine-bis-pyridyl ligands are expected to provide a useful platform for exploring the relationship between chiral ligand structure and enantioselective olefin oxidation catalyzed by their metal complexes.

Full text of DOI:10.1021/jo049521l

Syn th esis of 1,2-Dia m in o-1,2-d id eoxy-m yo-
in ositol-Der ived Liga n d s for th e
In vestiga tion of Meta l Com p lex Rea ctivity
The synthesis of 3a and 3b began with 3,4,5,6-tetra-
O-benzyl-myo-inositol 4 (Scheme 1). This precursor is
8
readily available in racemic form, or either enantiomer
9
may be prepared selectively from the appropriate enan-
tiomer of xylose, both of which are commercially avail-
able. Furthermore, since differentially protected ana-
logues of 4 have been prepared enantioselectively,
Viatcheslav N. Azev and Marc d’Alarcao*
1
0-13
Department of Chemistry, Tufts University,
6
2 Talbot Avenue, Medford, Massachusetts 02155
this method should allow the preparation of a variety of
O-substituted analogues of 3.
marc.dalarcao@tufts.edu
Received March 23, 2004
Conversion of diol 4 to diazide 5 followed the method
of Guedat et al. Dimesylation of 4 followed by nucleo-
philic substitutions with sodium azide afforded diazide
8
5
7
in 54% yield. In our hands, the hydrogenolysis of 5 to
was rather inconsistent, presumably due to poisoning
Abstr a ct: A method for the synthesis of chiral 1,2-diamino-
,2-dideoxy-myo-inositol-based bis-pyridyl ligands 3a and 3b
1
4
of the catalyst by the product. The crude diamine
prepared in this way could be purified via its bis-
trifluoroacetamide 10. However, a better method was to
1
from the corresponding myo-inositol precursor is described.
These highly functionalized inosamine-bis-pyridyl ligands
are expected to provide a useful platform for exploring the
relationship between chiral ligand structure and enantiose-
lective olefin oxidation catalyzed by their metal complexes.
circumvent the problem by addition of Boc
hydrogenolysis mixture15 of 5 and Pd/CaCO
THF (1:5), thereby affording Boc-protected diamine 6 in
2% yield. Removal of the Boc groups (HCl, MeOH/H O)
2
O to the
3
in EtOH/
7
2
produced diamine 7 (99% yield). Acid-catalyzed imine
formation from 7 and 2-pyridine carboxaldehyde, followed
Metal-catalyzed asymmetric epoxidation of olefins
remains a challenge for synthetic chemists. Despite im-
pressive advances, methods for the highly enantioselec-
tive catalytic epoxidation of terminal, electron-deficient,
or cis-olefins have not reached the same standards of
efficiency, practicality, and predictability as for other
classes of olefins. One limitation is the ready availability
of a sufficient variety of chiral ligands to enable a broad
structure-activity survey to identify so-called privileged
by reduction with BH ‚THF, and then acid hydrolysis
3
produced ligand 3a in 94% yield. Compound 3a was
converted to its ditosylate salt 11 for further character-
ization.
Unfortunately, we were unable to effectively dimethy-
late 3a to produce 3b despite a number of attempts,
including formylation/reduction and direct methylation,
either directly or with preliminary deprotonation of the
amine nitrogens. Accordingly, we elected to install the
methyl groups prior to the pyridyl component. Thus,
diamine 7 was diformylated by treatment with trifluo-
roethyl formate (93% yield). This method was superior
to formylation by heating in neat ethyl formate (75%
yield) or with formic acetic anhydride, which gave a
mixture of formylation and acetylation. Diamide 8 was
1
structures. The ligands derived from trans-cyclohexan-
1
,2-diamine, most notably salen ligand 1 and bis-pyridyl
ligand 2 (R,R-mcp), have proven especially useful in
2
producing effective asymmetric catalysts, particularly as
the Mn complexes.3
-5
Substituents on the cyclohexane
ring of cyclohexan-1,2-diamine-derived ligands can sig-
6
,7
nificantly affect the efficacy of the catalysts. To enable
a comprehensive study of the effect of ring substitution,
there is a need for synthetic methods to a variety of such
substituted ligands. In this Note, we report the synthesis
of myo-inositol-derived ligands 3a and 3b. The 1,2-
diamino-1,2-dideoxy-myo-inositol scaffold is well suited
to ligand development because (1) synthetic methods
exist for selective modification of several of the hydroxyl
groups, (2) unlike cyclohexan-1,2-diamine, the compound
is chiral even with the cis disposition of the amino groups,
and (3) differentially protected variants are available in
either antipode via efficient enatioselective syntheses.
reduced with BH
bis(methylamino)cyclohexane 9 in 92% yield.
3
‚THF affording, after acid hydrolysis,
(
3) J acobsen, E. N.; Zhang, W.; Muci, A. R.; Ecker, J . R.; Deng, L.
J . Am. Chem. Soc. 1991, 113, 7063-7064.
4) Murphy, A.; Dubois, G.; Stack, T. D. P. J . Am. Chem. Soc. 2003,
125, 5250-5251.
5) Schoumacker, S.; Hamelin, O.; Pecaut, J .; Fontecave, M. Inorg.
Chem. 2003, 42, 8110-8116.
6) Fiammengo, R.; Bruinink, C. M.; Crego-Calama, M.; Reinhoudt,
D. N. J . Org. Chem. 2002, 67, 8552-8557.
7) Paul, B. J .; Willis, J .; Martinot, T. A.; Ghiviriga, I.; Abboud, K.
A.; Hudlicky, T. J . Am. Chem. Soc. 2002, 124, 10416-10426.
8) Guedat, P.; Spiess, B.; Schlewer, G. Tetrahedron Lett. 1994, 35,
375-7378.
9) Kornienko, A.; d’Alarcao, M. Tetrahedron: Asymmetry 1999, 10,
27-829.
10) Kornienko, A.; Turner, D. I.; J aworek, C. H.; d’Alarcao, M.
Tetrahedron: Asymmetry 1998, 9, 2783-2786.
11) Sato, K.; Bokura, M.; Taniguchi, M. Bull. Chem. Soc. J pn. 1994,
7, 1633-1640.
12) Gou, D. M.; Liu, Y. C.; Chen, C. S. Carbohydr. Res. 1992, 234,
1-64.
13) Watanabe, Y.; Ogasawara, T.; Shiotani, N.; Ozaki, S. Tetrahe-
dron Lett. 1987, 28, 2607-2610.
14) Fristad, W. E.; Brandvold, T. A.; Peterson, J . R.; Thompson, S.
(
(
(
(
(
7
8
(
(
(
6
(
5
(
(
R. J . Org. Chem. 1985, 50, 3647-3649.
(15) Reddy, P. G.; Pratap, T. V.; Kumar, G. D. K.; Mohanty, S. K.;
Baskaran, S. Eur. J . Org. Chem. 2002, 3740-3743.
(
(
1) Yoon, T. P.; J acobsen, E. N. Science 2003, 299, 1691-1693.
2) Bennani, Y. L.; Hanessian, S. Chem. Rev. 1997, 97, 3161-3195.
1
0.1021/jo049521l CCC: $27.50 © 2004 American Chemical Society
Published on Web 06/12/2004
J . Org. Chem. 2004, 69, 4839-4842
4839

SCHEME 1
Attachment of the 2-methylpyridyl moiety to the ni-
trogens of 9 proved to be difficult. Acylation of 9 with
tert-butyl dicarbonate (111 mg, 510 µmol) and Pd/CaCO
3
(65 mg,
3
0.5 µmol) were added, and the reaction mixture was hydroge-
nated at 10-13 psig for 17 h. Completion of the reaction was
confirmed by HPLC (see General Methods in Supporting Infor-
mation); when the reaction was complete, the chromatogram
showed a single peak at 6.95 min. (Starting material 5 has a
retention time of 7.3 min.) The reaction mixture was diluted with
toluene (40 mL), filtered through Celite, and evaporated. The
residue was purified by flash chromatography (silica gel, 1:6 v/v
picolinyl chloride produced the corresponding diamide
1
(
the H NMR spectrum was very complex, presumably
due to slowly interconcerting rotamers), but we were not
able to find conditions for clean reduction of the diamide.
The problem was ultimately solved, albeit in the modest
yield of 39%, by direct alkylation of 9 with 2-chloro-
methylpyridine, thus providing the desired ligand 3b.
With chiral complexes 3a and 3b in hand, we are now
engaged in evaluating the catalytic activity of the corre-
sponding metal ion complexes in olefin epoxidation. These
data will be reported elsewhere.
EtOAc/hexane) to give 54 mg (72%) of white solid: R
f
) 0.29
(
1:5 v/v EtOAc/hexane); 1H NMR (CDCl
3
) δ 1.45 (s, 18 H,
3 3
O-C(CH ) ), 3.53 (ψt, J ) 7.9 Hz, 1H, H-6), 3.59-3.75 (m, 3H,
H-3, H-4, H-5), 3.90 (ψtd, J ) 9.2, 3.3 Hz, 1H, H-1), 4.43 (dψt,
J ) 9.1, 3.7 Hz, 1H, H-2), 4.51 (d, J ) 11.1 Hz, 1H, PhCH O),
2
4.61 (d, J ) 11.1 Hz, 1H, PhCH
(
2
2
O), 4.66-4.84 (m, 7H, PhCH O
6H) + 2-NH (1H)), 5.31 (br, 1H, 1-NH), 7.2-7.35 (m, 20H,
1 13
2 3
P h CH O); { H} C NMR (CDCl ) δ 138.72, 138.69, 138.1, 128.8,
1
8
Exp er im en ta l Section
28.75, 128.4, 128.3, 128.24, 128.21, 128.12, 128.1, 128.0, 82.0,
0.6, 80.2, 79.8, 79.4, 75.4, 75.35, 74.8, 72.5, 52.0, 49.5; LRMS
3
,4,5,6-Tetr a -O-ben zyl-1,2-dia zido-1,2-dideoxy-myo-in osi-
+
8
m/z 761.5 (M + Na ), calcd for C44
H
54
N
2
O
8
738.91. Anal. Calcd
tol (5). A solution of 4 (6.4 g, 11.9 mmol) in 50 mL of pyridine
was cooled to 0 °C with stirring. Methylsulfonyl chloride (2.85
mL, 35.5 mmol) was added, and the reaction mixture was
allowed to warm to 20 °C and stirred at this temperature for 20
h. The reaction mixture was then diluted with 200 mL of ethyl
acetate and poured into ice-water (250 mL). The organic layer
was washed with water (2 × 20 mL) and brine (2 × 25 mL) and
dried over sodium sulfate. The solvent was evaporated, and the
residue was coevaporated with 50 mL of heptane and then with
for C44
.35; N, 3.73.
3,4,5,6-Tet r a -O-ben zyl-1,2-d i-(N-t r iflu or oa cet yla m in o)-
54 2 8
H N O : C, 71.52; H, 7.37; N, 3.79. Found: C, 71.46; H,
7
1,2-d id eoxy-m yo-in ositol (10). A mixture of diazide 5 (660 mg,
1.12 mmol) and Lindlar catalyst (593 mg, 0.28 mmol) in 30 mL
of THF and 6 mL of ethanol was hydrogenated at 10-13 psi for
7.5 h. Completion of the reaction was confirmed by HPLC (see
General Methods in Supporting Information); when the reaction
was complete, the chromatogram showed a single peak (2.5 min).
The reaction mixture was diluted with toluene (70 mL), filtered
through Celite, and evaporated to give 650 mg of dark brown
oil. A similar experiment with 451 mg (0.763 mmol) of diazide
5 using 30 mol % Lindar catalyst gave 417 mg of light brown
product in 3 h. The combined material (1.067 g) was dissolved
5
0 mL of toluene. Toluene (5 mL) was added, and then heptane
was slowly added dropwise until no more precipitate formed.
The precipitate was collected by filtration (7.3 g) and placed in
a flask to which sodium azide (5.45 g, 83.8 mmol) was added
followed by DMF (80 mL) via syringe. The reaction mixture was
stirred and heated for 12 h at 110 °C behind a blast shield. The
reaction mixture was cooled to 20 °C, and the DMF was removed
by coevaporation with toluene; 50 mL of ethyl acetate were
added, and the organic phase was separated and washed with
2 2
in CH Cl and chilled to -10 °C under Ar. Diisopropylethylamine
(1.4 mL, 12 mmol) was added via syringe, followed by slow
addition of trifluoroacetic anhydride (0.85 mL, 9.85 mmol, 3
equiv). The reaction mixture was allowed to warm to 23 °C,
stirred for 12 h, and then chilled to 2 °C. Excess trifluoroacetic
anhydride was quenched with cold (2 °C) sodium bicarbonate
solution; the organic phase was washed with water (2 × 2 mL)
water (2 × 20 mL) and brine (2 × 20 mL), dried with Na
and carefully evaporated. Flash chromatography (silica gel, 1:9
v/v EtOAc/hexane) gave 3.78 g of pure 5 (54% for two steps); R
2 4
SO ,
f
1
)
0.48 (silica gel, 1:5 v/v EtOAc/hexane). H NMR (CDCl
IR (CH
Cl) are identical to those reported previously.8
,4,5,6-Tetr a-O-ben zyl-1,2-di-(N-t-bu toxycar bon ylam in o)-
,2-d id eoxy-m yo-in ositol (6). Diazide 5 (60 mg, 102 µmol) was
dissolved in a mixture of THF (1.5 mL) and EtOH (0.3 mL). Di-
3
) and
3
and brine (2 × 2 mL), dried with Na
2 4
SO , and evaporated. Flash
3
chromatography (silica gel, 1:7 to 1:5 v/v EtOAc/hexane) gave
830 mg of pure 10 (58% for two steps): R ) 0.17 (silica gel, 1:6
) δ 3.81-3.89 (m, 3H), 4.15
1
f
1
v/v EtOAc/hexane); H NMR (CDCl
3
4
840 J . Org. Chem., Vol. 69, No. 14, 2004

(
(
dd, J ) 4.2, 2.3 Hz, 1H), 4.22 (d, J ) 11.1, 1H, PhCH
d, J ) 11.4 Hz, 1H, PhCH O), 4.44 (d, J ) 11.4 Hz, 1H,
O), 4.48 (d, J ) 11.8, 1H, PhCH O), 4.54-4.68 (m, 4H),
.71-4.81 (m, 2H), 6.64 (br d, J ) 8.0, 1H, NH), 7.07-7.17 (m,
H, P h CH O), 7.22-7.36 (m, 20.8H, P h CH O (16H) + CHCl ),
.85 (br d, J ) 10.2, 1H, NH); { H} C NMR (CDCl ) δ 158.0,
2
O), 4.37
and the solid was washed with toluene (6 × 0.5 mL). The
combined filtrate was washed with 5% aqueous NaHCO
(3 ×
0.5 mL) at 0 °C and brine (2 × 0.5 mL) and dried (Na SO ). The
2
3
PhCH
2
2
2
4
4
4
7
1
1
1
7
solvent was evaporated, and the residue was coevaporated with
toluene (5 mL). A reflux condenser was attached, and the system
was evacuated and flushed with Ar (five times). Dry THF (0.5
mL) was introduced, and the reaction mixture was chilled to 2
°C. Borane-THF complex (320 µL of a 1 M solution in THF,
0.32 mmol) was added dropwise via a syringe, with stirring. The
reaction mixture was allowed to warm to 23 °C. Completion of
the reaction was confirmed by HPLC (see General Methods in
Supporting Information); when the reaction was complete, the
solution showed one peak (3.6 min). The reaction was carefully
quenched with 6 M HCl (0.2 mL) at 2 °C. The reaction mixture
was allowed to reach 23 °C, gently warmed at reflux for 1 h,
and then allowed to cool to 23 °C. The solvent was evaporated,
and the residue was dissolved in a mixture of 1 M NaOH (4 mL)
and toluene (3 mL); the aqueous layer was extracted with
toluene (3 × 0.5 mL), and the combined organic layers were
washed with water (3 × 0.5 mL) and brine (2 × 1 mL). The
2
2
3
1
13
3
57.5, 157.1, 157.0, 156.6, 156.5, 156.0, 137.2, 136.7, 136.2, 128.8,
28.6, 128.59, 128.56, 128.5, 128.3, 128.1, 127.95, 127.9, 121.4,
21.2, 117.6 117.4, 113.8, 113.6, 109.9, 109.8, 75.1, 74.2, 73.0,
2.8, 72.7, 72.4, 72.3, 48.8, 45.0; 19F NMR (CDCl
) δ -76.43,
3
-
76.47, -76.71, -76.74. Anal. Calcd for C38
H, 4.97; N, 3.83. Found: C, 62.33; H, 4.83; N, 3.73.
,4,5,6-Tetr a-O-ben zyl-1,2-diam in o-1,2-dideoxy-myo-in os-
36 6 2 6
H F N O : C, 62.46;
3
itol (7). Meth od A. Aqueous lithium hydroxide (2.2 mL of 1 M
solution in water, 2.2 mmol) was added to a solution of diamide
1
0 (159 mg, 0.218 mmol) in 2.2 mL of methanol at 23 °C. The
reaction mixture was heated at 45 °C for 24 h. Completion of
the reaction was confirmed by HPLC (see General Methods in
Supporting Information); when completed, the chromatogram
showed a single peak (2.5 min). (Compound 10 has a retention
time of 6.17 min.) Volatile materials were evaporated, and a
mixture of toluene (3 mL) and water (3 mL) at 2 °C was added.
The organic layer was separated, washed with water (2 × 1 mL)
organic phase was dried over Na
21.5 mg (94%) of a yellow oil, which slowly solidified: H NMR
(CDCl
2 4
SO and evaporated to give
1
3
) δ 2.62 (dd, J ) 10.1, 3.0 Hz, 1H, H-1), 2,67 (ψt, J ) 6
and brine (2 × 1 mL), dried with Na
2
SO
4
, and evaporated to
Hz, 1H, NH), 2.75 (ψt, J ) 7.3 Hz, 1H, NH), 3.38 (ψt, J ) 2.9
give 116 mg (99%) of pure 7.
Hz, 1H, H-2), 3.45 (dd, J ) 9.7, 2.7 Hz, 1H, H-3), 3.59 (ψt, J )
9
(
1
CH
PhCH
PhCH
(
.2 Hz, 1H, H-5), 3.65 (dd, J ) 14.2, 4.9 Hz, 1H, CH
2
Py), 3.75
Py), 3.98 (ψt, J ) 9.7 Hz,
H, H-6), 4.1 (dd, J ) 14.6, 6.8 Hz, 1H, CH Py), 4.27 (m, 1H,
Py), 4.32 (ψt, J ) 9.5 Hz, 1H, H-4), 4.62-4.76 (m, 3H,
Meth od B. Dicarbamate 6 (278 mg, 377 µmol) was suspended
dd, J ) 14.2, 8.8 Hz, 1H, CH
2
in methanol (12 mL). Aqueous HCl (0.25 mL of 6 M solution,
1
5
HPLC (see General Methods in Supporting Information); when
the reaction was complete, the chromatogram showed a single
peak (2.5 min). Volatile materials were evaporated, and toluene
.5 mmol) was added and the reaction mixture was heated at
5 °C for 13 h. Completion of the reaction was confirmed by
2
2
2
O), 4.83 (d, J ) 10.7 Hz, 2H, PhCH
O), 7.05-7.15 (m, 2H, PyH-5), 7.16-7.4 (m, 31H, P h CH
+ PyH-3 (2H)), 7.56 (ψt, J ) 7.7 Hz, 1H,
PyH-4), 7.57 (ψt, J ) 7.7 Hz, 1H, PyH-4), 8.47 (dq, J ) 4.9, 0.9
2
O), 4.9-5.2 (m, 3H,
2
2
20H) + CH Cl
3
(5 mL) was added to the residue. NaOH (2 mL of 1 M solution,
1
13
Hz, 1H, PyH-6), 8.51 (dq, J ) 4.8, 0.8 Hz, 1H, PyH-6); { H} C
NMR (CDCl ) δ 161.3, 159.8, 149.3, 139.12, 139.09, 138.9, 138.7,
36.5, 136.3, 128.63, 128.6, 128.5, 128.4, 128.3, 127.9, 127.8,
2
mmol) was added to the reaction mixture dropwise with
chilling (ice bath). If precipitation of the diamine occured,
methanol was added to the organic layer until the precipitate
dissolved. The organic extract was washed with 1 M aqueous
NaOH (2 × 2 mL), water (3 × 2 mL), and brine (1 × 2 mL) and
3
1
1
7
27.7, 122.75, 122.16, 122.06, 121.8, 86.0, 84.1, 82.4, 81.1, 76.0,
5.81, 75.75, 73.2, 60.74, 55.3, 53.7, 52.9; LRMS m/z 721.3 (M
+
+
1
+ H ) and 743.3 (M + Na ), calcd for C46H N O 720.4.
evaporated to give 203 mg (99%) of pure 7: H NMR (CDCl
3
) δ
48
4
4
2
3
1
.67 (dd, J ) 1.3, 5.2 Hz, 1H, H-1), 3.49 (m, 3H, H-2, H-3, H-5),
.77 (ψt, J ) 5.1 Hz, 1H, H-6), 3.74 (m, 1H, H-4), 4.64 (d, J )
1.2 Hz, 1H, PhCH O), 4.67 (s, 2H, PhCH O), 4.82 (d, J ) 10.6
O), 4.84 (d, J ) 11.0 Hz, 1H, PhCH O), 4.92 (d,
J ) 11.1 Hz, 1H, PhCH O), 4.95 (d, J ) 10.9 Hz, 1H, PhCH O),
.99 (d, J ) 10.8 Hz, 1H, PhCH O), 7.2-7.4 (m, 24.1H, P h CH
); { H} C NMR (CDCl ) δ 139.1, 139.05, 138.9,
3,4,5,6-Tetr a -O-ben zyl-1,2-d i-(N-p yr id in -2-yl-m eth yla m i-
n o)-1,2-d id eoxy-m yo-in ositol Ditosyla te (11). Ditosylate 11
was prepared by mixing equivalent amounts of acetonitrile
solutions of 3a and p-toluenesulfonic acid, filtering the resulted
solution through a 0.47 µ filter, and evaporating the filtrate until
the final volume reached approximately 0.5 mL. The solution
was kept at -20 °C for about 3 days and then filtered at 4 °C.
2
2
Hz, 1H, PhCH
2
2
2
2
4
2
2
O
1
13
(20H) + CHCl
3
3
1
1
1
5
38.6, 128.8, 128.75, 128.6, 128.58, 128.2, 128.0, 128.95, 128.90,
28.75, 128.65, 85.4, 82.12, 82.07, 82.0, 76.05, 75.94, 75.77, 72.5,
The resulting solid was recrystallized from acetonitrile: H NMR
-
(d
4
-MeOH) 2.32 (s, 6H, CH
3
C
6
H
4
SO
3
), 3.56 (dd, J ) 8.9, 3.8
+
+
1.5, 53.7; LRMS m/e 539.5 (M + H ) and 561.4 (M + Na ), calcd
Hz, 1H, H-1), 3.78 (ψt, J ) 7.5 Hz, 1H, 5-H), 3.90-3.98 (m,
2H, H-2, H-3), 4.12 (dd, J ) 8.9, 7.7 Hz, 1H, H-6), 4.16 (ψt, J )
for C34
38 2 4
H N O
538.7.
For analytical purposes, the di-p-toluenesulfonate salt of 7
was prepared by reaction of p-toluenesulfonic acid (2 equiv) with
7
7.5 Hz, 1H, H-4), 4.42 (d, J ) 17 Hz, 1H, CH
15.6 Hz, 1H, CH Py), 4.54 (d, J ) 15.5 Hz, 1H, CH
4.95 (m, 18.4H, CH
(5.4H), 7.14 (d, J ) 7.9, 4H, CH
20H, P h CH O), 7.14 (m, 4H, CH
2
Py), 4.46 (d, J )
2
2
Py), 4.67-
+
in CH
3
OH for 2 days, collection of the resulting crystals, and
2
Py (1H), PhCH
2
O (8H), NH
2
(4H), ROH
), 7.17-7.39 (m,
-
3 6 4 3
C H SO ), 7.42-7.49 (m, 2H,
1
-
3 6 4 3
C H SO
recrystallization from methanol: H NMR (d
4
-MeOH + d
), 3.90-3.95 (m, 2H), 4.02-
.09 (m, 2H), 4.11 (ψt, J ) 4.7 Hz, 1H, H-6), 4.17 (ψt, J ) 3.0
Hz, 1H, H-2), 4.55-4.73 (m, 8H, PhCH O), 7.2-7.4 (m, 24H,
(4H)), 7.68-7.75 (m, 4H,
-MeOH + d -MeCN) 143.4,
3
-
-
MeCN) δ 2.37 (s, 6H, CH
3
C
6
H
4
SO
3
2
4
PyH -3 (1H), PyH -5 (1H)), 7.62-7.68 (m, 4H), 7.73-7.83 (m,
2H, PyH-3′ (1H), PyH-5′ (1H)), 7.94 (dt, J ) 7.8, 1.7 Hz, 1H,
PyH-4), 8.31 (dt, J ) 7.9, 1.5 Hz, 1H, PyH-4′), 8.40 (dt, J ) 7.8,
2
-
3
P h CH
CH
1
1
7
2
O (20H) + CH
3
C
6
H
4
SO
-
1
13
13
1
C
6
H
4
SO
3
); { H} C NMR (d
4
3
1.7 Hz, 1H, PyH-6), 8.72 (m, 1H, PyH-6′); C{ H) 156.3, 153.1,
148.5, 145.7, 144.1, 143.4, 142.0, 141.0, 139.8, 139.5, 139.5, 139.2,
130.1, 129.8, 129.6, 129.55, 129.5, 129.3, 129.0, 128.9, 127.1,
126.7, 126.4, 125.6, 124.8, 81.1, 80.0 (br), 77.4, 76.2, 76.0, 75.4,
3
42.0, 138.9, 138.6, 138.4, 137.7, 130.1, 130.0, 129.9, 129.8, 129.7,
29.65, 129.60, 129.5, 129.48, 129.2, 129.16, 129.10, 127.0, 76.9,
5.8, 74.9, 74.5, 74.2, 74.1, 51.3, 48.5 (hidden by CHD
2
OD,
: C,
extracted from HMQC), 21.4. Anal. Calcd for C48
6
H
54
N
2
O
10
S
2
74.5, 60.1, 55.6, 51.6, 49.5 (hidden by CHD
HMQC), 21.3. Anal. Calcd for C48
N, 5.26. Found: C, 67.52; H, 6.14; N, 5.30.
2
OD, extracted from
H N O S : C, 67.65; H, 6.06;
54 2 10 2
5.28; H, 6.16; N, 3.17. Found: C, 64.88; H, 6.08; N, 3.19.
3
,4,5,6-Tetr a -O-ben zyl-1,2-d i-(N-p yr id in -2-yl-m eth yla m i-
n o)-1,2-Did eoxy-m yo-in ositol (3a ). Crushed activated 4 Å
molecular sieves (58 mg) and 0.6 mg (3.2 µmol, 0.1 equiv) of
p-toluenesulfonic acid were added to a solution of diamine 7 (17
mg, 32 µmol) in 0.5 mL of toluene in a 10 mL flask fitted with
a reflux condenser. The system was evacuated and flushed with
Ar (five times). Pyridine-2-carbaldehyde (305 µL of 0.22 mM
solution in toluene, 2.1 equiv) was introduced via syringe, and
the reaction was heated at 80-85 °C for 5 h and then allowed
to cool to 23 °C. The reaction mixture was filtered through Celite,
3,4,5,6-T e t r a -O -b e n zy l-1,2-d i-(N -fo r m y la m in o )-1,2-
d id eoxy-m yo-in ositol (8). Trifluoroethyl formate (0.5 mL) was
slowly added to diamine 7 with stirring, and the solution was
stirred for 16 h. Completion of the reaction was confirmed by
HPLC (see General Methods in Supporting Information); when
the reaction was complete, the chromatogram showed complete
replacement of starting material (2.5 min) with product (2.95
min). Volatile materials were evaporated, and the residue was
purified by preparative TLC (silica gel, 20:10:1 v/v EtOAc/
J . Org. Chem, Vol. 69, No. 14, 2004 4841

hexane/EtOH) to give 38 mg (93%) of a white solid. R
(
f
) 0.41
20:10:1 v/v EtOAc/hexane/EtOH). The H NMR spectra were
complex at 294 K, but coalesced above 390 K (DMSO-d ), as
expected for a diamide with restricted rotation: H NMR
diisopropylethylamine (53 µL, 247 µmol), anhydrous DMF (1
mL), and 80 µL of 0.68 M THF solution (494 µmol, 2 equiv) of
2-chloromethylpyridine (prepared by neutralization of the com-
1
6
1
2 3
mercially available hydrochloride with K CO ) were heated at
(
(
4
(
d
4
-MeOH, 294 K) δ 3.51-3.7 (m, 2H), 3.7-3.84 (m, 2H), 4.07
m, 0.1H), 4.18-4.3 (m, 0.9H), 4.5 (d, J ) 11 Hz, 1H, PhCH O),
.6-4.98 (m, 14.8H, PhCH O (7H) + Ins-H + CD OH), 7.2-7.4
m, 20H, P h CH O), 7.9 (s, 0.1H, N-CHO), 8.05-8.15 (m, 0.9
H, N-CHO), 8.16 (s, 0.1H, N-CHO), 8.3 (s, 0.9H, N-CHO);
80 °C for 4 days under Ar. The mixture was cooled to 23 °C; an
additional 40 µL of the 2-chloromethylpyridine solution was
added, and heating was continued for another 3 days. The
progress of the reaction was monitored by HPLC (see General
Methods in Supporting Information). After 7 days, the only major
peak in the chromatogram is the product (4.69 min). The reac-
tion mixture was evaporated to dryness, and the residue
was dissolved in 2 mL of toluene and 5 mL of water. The or-
ganic layer was washed with 1 M NaOH (6 × 1 mL), water
(6 × 1 mL), and brine (2 × 1 mL) and evaporated. The residue
was purified by preparative TLC (basic grade 1 alumina oxide,
2
2
3
2
1
13
{
1
1
8
4
H} C NMR (d -MeOH) 167.7, 165.2, 165.0, 164.0, 140.23,
40.15, 139.9, 139.6, 129.6, 129.5, 129.43, 129.41, 129.3, 129.2,
29.1, 129.0, 128.9, 128.83, 128.77, 128.75, 128.71, 84.9, 84.8,
2.4, 81.0, 79.9, 76.9, 76.6, 76.2, 73.3, 73.2, 55.3, 50.2, 47.9;
+
+
LRMS m/z 595.5 (M + H ) and 617.5 (M + Na ), calcd for
594.3. Anal. Calcd for C36 : C, 72.71; H, 6.44;
N, 4.71. Found: C, 73.05; H, 6.61; N, 4.72.
,4,5,6-T e t r a -O -b e n zy l-1,2-d i-(N -m e t h y la m in o )-1,2-
C
36
H
38
N
2
O
6
38 2 6
H N O
50:200:3 v/v EtOAc/CH
oil (∼90% pure by NMR, 39%), R
CH Cl /EtOH). The product was further purified by semi-
2
Cl
2
/EtOH) to give 8 mg of pale yellow
3
f
) 0.53 (50:200:3 v/v EtOAc/
d id eoxy-m yo-in ositol (9). Dry THF (0.5 mL) was added to 22
mg (37 µmol) of diamide 8, and the mixture was chilled to 2 °C.
Borane-THF complex (300 µL of a 1 M solution in THF, 0.3
mmol) was added dropwise via a syringe with stirring. The
reaction mixture was allowed to warm to 23 °C, gently warmed
at reflux for 1.5 h, and allowed to cool to 23 °C. The reaction
was carefully quenched with 6 M HCl (0.2 mL) at 2 °C. The
reaction mixture was allowed to warm to 23 °C and then warmed
at reflux for 1 h. After the mixture cooled back to 23 °C, the
volatile materials were evaporated. The residue was dissolved
in a mixture of 1 M NaOH (3 mL) and toluene (1.5 mL); the
aqueous layer was extracted with toluene (3 × 0.5 mL), and the
combined organic extracts were washed with water (3 × 0.5 mL)
and brine (2 × 1 mL). The organic phase was dried over
2
2
preparative HPLC (see General Methods in Supporting Infor-
mation for solvent gradient) on a C18 column (1.5 cm × 25 cm)
-
1
1
with UV detection (217 nm) eluting at 8 mL min
:
H NMR
(CDCl
3
) δ 2.55 (s, 3H, N-CH
3
), 2.55 (s, 3H, N-CH
3
), 2.95 (dd,
J ) 4.9, 10.3 Hz, 1H, H-1), 3.59 (ψt, J ) 4.3 Hz, 1H, H-2), 3.64
(ψt, J ) 8.9 Hz, 1H, H-5), 3.74 (dd, J ) 5.1, 8.3 Hz, 1H, H-3),
4.09-4.37 (m, 6H, H-4, H-6, NCH
Hz, 1H, PhCH O), 4.72-4.86 (m, 4H, PhCH
2H, PhCH O), 5.04 (d, J ) 11.0 Hz, 1H, PhCH
(m, 2H, Py-H), 7.21-7.37 (m, 26.8H, P h CH O (20H) + CHCl
7.38-7.53 (m, 4H, Py-H), 8.45-8.52 (m, 2H, Py-H); { H} C
NMR (CDCl ) δ 161.7, 161, 149, 139.1, 138.8, 138.79, 138.5,
2
Py (4H)), 4.68 (d, J ) 11.5
O), 4.88-4.93 (m,
O), 7.04-7.12
),
2
2
2
2
2
3
13
1
3
136.4, 128.6, 128.5, 128.5, 128.1, 128.0, 127.94, 127.8, 127.7,
127.6, 127.5, 123.0, 122.6, 121.8, 121.7, 86.9, 83.8, 82.8, 79.4,
75.9, 75.3, 73.8, 73.4, 65.9, 65.3, 64.9, 62.9, 41.8, 40.5; LRMS
Na
slowly crystallizes: H NMR (CDCl
.39 (dd, J ) 10.1, 3.24 Hz, 1H, H-1), δ 2.62 (s, 3H, NCH
ψt, J ) 3.1 Hz, 1H, H-2), 3.45 (dd, J ) 9.7, 3.0 Hz, 1H, H-3),
2 4
SO and evaporated to give 19.3 mg (92%) of clear oil, which
1
3
) δ 2.31 (s, 3H, NCH
3
), δ
+
+
2
(
3
4
4
4
3
), 3.38
m/z 749.6 (M + H ) and 771.7 (M + Na ); HRMS (ESI TOF)
+
53 4 4
m/z 749.4057 (M + H ), calcd for C48H N O 749.4067; error
.57 (ψt, J ) 9.1 Hz, 1H, H-5), 3.74 (ψt, J ) 9.7 Hz, 1H, H-6),
(ppm) 1.3.
.15 (ψt, J ) 9.4 Hz, 1H, H-6), 4.55 (d, J ) 11.1, 1H, PhCH
.68 (d, J ) 11.5, 1H, PhCH O), 4.74-4.85 (m, 3H, PhCH
.9-5.2 (m, 3H, PhCH O), 7.2-7.4 (m, 20H, P h CH
2
O),
2
2
O),
O); { H} C
Ack n ow led gm en t. We are grateful to Prof. Elena
Rybak-Akimova for insightful comments and sugges-
tions and to Tufts University for financial support.
1
13
2
2
NMR (CDCl
1
8
m/z 566.4 (M + H ), calcd for C36
36 42 2 4
C H N O
N, 4.96.
,4,5,6-Tetr a -O-ben zyl-1,2-d i-[N-p yr id in e-2-yl-m eth yl-N-
m eth yla m in o]-1,2-d id eoxy-m yo-in ositol (3b). Diamine 9 (14
mg, 24.7 µmol), finely powdered K CO (34 mg, 247 µmol),
3
) δ 139.2, 139.1, 138.9, 138.7, 128.7, 128.53, 128.51,
28.3, 128.2, 128.0, 127.74, 127.68, 127.62, 127.55, 85.8, 84.3,
2.5, 81.0, 76.1, 75.7, 75.5, 72.6, 62.3, 56.0, 38.4, 34.3. LRMS
+
42 2 4
H N O 566.3. Anal. Calcd for
Su p p or tin g In for m a tion Ava ila ble: General experimen-
tal methods and NMR spectra for all numbered compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
: C, 76.29; H, 7.47; N, 4.94. Found: C, 76.17; H, 7.58;
3
2
3
J O049521L
4
842 J . Org. Chem., Vol. 69, No. 14, 2004