Facile syntheses of valiolamine and its diastereomers from (-)-quinic acid.1 nucleophilic substitution reactions of 5-(hydroxymethyl)cyclohexane-1,2,3,4,5-pentol

Article abstract of DOI:10.1021/jo9607828

Valiolamine (1), 1-epi-valiolamine (2), 2-epi-valiolamine (3), (1R,2R)-valiolamine (4), and 2-amino regioisomer 17 have been prepared from (-)-quinic acid (6) in 14 (8.4% overall yield), 13 (9.0%), 15 (4.3%), 17 steps (2.5%), and 12 steps (13%), respectively. Charged nucleophilic ring-openings of cyclic sulfate (1R,2S,3S,4S,5S)-4,5-di-O-acetyl-3-O-benzyl-5-(benzyloxymethyl)-1,2-O,O- sulfonylcyclohexane-1,2,3,4,5-pentol (11) occurred regioselectively at C-2, whereas the corresponding ring-openings of its (1S,2R)-diastereomer 34 proceeded preponderantly at C-1. (1R,2S,3R,4S,5S)-2,4,5-Tri-O-acetyl-3-O-benzyl-5-((benzyloxy)methyl)-1-O- (trifluoromethanesulfonyl)cyclohexane-1,2,3,4,5-pentol (24) underwent novel internal displacement spontaneously to form (1S,2S,3R,4S,5S)-1,2,4-tri-O-acetyl-3-O-benzyl-5-((benzyloxy)methyl)cyclohexane- 1,2,3,4,5-pentol (25), whereas its 2-epimer was inert under the same conditions. Ruthenium-catalyzed dihydroxylation of alkene, (3R,4S,5S)-4,5-O-acetyl-3-O-benzyl-5-((benzyloxy)methyl)-1-cyclohexene-3,4,5- triol (31), gave the desired β-1,2-diol 32 in higher yield and stereoselectivity than the osmium tetraoxide protocol. The regioselectivity of charged nucleophilic ring-openings of cyclic sulfates 11, 34, and 38 is discussed.

Full text of DOI:10.1021/jo9607828

8468
J . Org. Chem. 1996, 61, 8468-8479
F a cile Syn th eses of Va liola m in e a n d Its Dia ster eom er s fr om
(-)-Qu in ic Acid .1 Nu cleop h ilic Su bstitu tion Rea ction s of
5-(Hyd r oxym eth yl)cycloh exa n e-1,2,3,4,5-p en tol
Tony K. M. Shing* and Leong H. Wan
Department of Chemistry, The Chinese University of Hong Kong, Shatin, Hong Kong
Received April 29, 1996X
Valiolamine (1), 1-epi-valiolamine (2), 2-epi-valiolamine (3), (1R,2R)-valiolamine (4), and 2-amino
regioisomer 17 have been prepared from (-)-quinic acid (6) in 14 (8.4% overall yield), 13 (9.0%), 15
(4.3%), 17 steps (2.5%), and 12 steps (13%), respectively. Charged nucleophilic ring-openings of
cyclic sulfate (1R,2S,3S,4S,5S)-4,5-di-O-acetyl-3-O-benzyl-5-(benzyloxymethyl)-1,2-O,O-sulfonyl-
cyclohexane-1,2,3,4,5-pentol (11) occurred regioselectively at C-2, whereas the corresponding ring-
openings of its (1S,2R)-diastereomer 34 proceeded preponderantly at C-1. (1R,2S,3R,4S,5S)-2,4,5-
Tri-O-acetyl-3-O-benzyl-5-((benzyloxy)methyl)-1-O-(trifluoromethanesulfonyl)cyclohexane-1,2,3,4,5-
pentol (24) underwent novel internal displacement spontaneously to form (1S,2S,3R,4S,5S)-1,2,4-
tri-O-acetyl-3-O-benzyl-5-((benzyloxy)methyl)cyclohexane-1,2,3,4,5-pentol (25), whereas its 2-epimer
was inert under the same conditions. Ruthenium-catalyzed dihydroxylation of alkene, (3R,4S,5S)-
4,5-O-acetyl-3-O-benzyl-5-((benzyloxy)methyl)-1-cyclohexene-3,4,5-triol (31), gave the desired â-1,2-
diol 32 in higher yield and stereoselectivity than the osmium tetraoxide protocol. The regioselectivity
of charged nucleophilic ring-openings of cyclic sulfates 11, 34, and 38 is discussed.
1. In tr od u ction
groscopicus subsp. limoneus IFO12703,8 which also pro-
duces antibiotic validamycin. Valiolamine has been
shown to be the most potent R-glucosidase inhibitor
among the pseudoaminosugars (carbaaminosugars)9 va-
lienamine, validamine,10 and hydroxyvalidamine ob-
tained from chemical or microbial degradation11 of val-
idamycin. The structure of valiolamine was deduced to
be (2S)-(1,2,4,5/3)-1-amino-5-C-(hydroxymethyl)-2,3,4,5-
cyclohexanetetrol (sugar numbering is adopted for all
synthetic compounds) on the basis of spectral studies, and
its absolute configuration was confirmed by a stereose-
lective transformation from valienamine or validamine.12
The N-[2-hydroxy-1-(hydroxymethyl)ethyl]valiolamine (5),
coded as AO-128, displayed higher activities than the
parent valiolamine and is undergoing clinical trials for
the treatment of diabetes.13 Figure 1 shows the struc-
tural resemblance between valiolamine and R-D-glucose
(sugar numbering is adopted for all synthetic intermedi-
ates and target molecules). Since valiolamine (1) is a
potent R-D-glucosidase inhibitor, (1R)-valiolamine (2) (1-
epi-valiolamine), which possesses a â-amino group, might
be a â-D-glucosidase inhibitor. Along this vein of reason-
ing, (2R)- and (1R,2R)-valiolamine, i.e., (3) (2-epi-vali-
olamine) and (4), may be an R-D-mannosidase or a â-D-
mannosidase inhibitor, respectively. Hence, syntheses
of these four carba-sugars are relevant with respect to
their potential use as antidiabetic or antiviral agents.
Three total syntheses of valiolamine (1) have been
reported with one starting from a Diels-Alder (furan-
There has been increasing interest in the chemistry
and biochemistry of glycosidase inhibitors2 because of
their potential use as chemotherapeutic agents, which
are being actively investigated.3 Glycosidases are en-
zymes for the cleavage of glycosidic bonds and are
responsible for glycoprotein processing on the surface of
the cell wall and for carbohydrate digestion in animals.
Inhibition of these enzymes has significant implications
for both antiviral and antidiabetic chemotherapy.4 Sev-
eral studies have confirmed the value of the inhibitors
of the processing enzyme glucosidase I in inhibiting the
human immunodeficiency virus (HIV) replicationsthe
etiologic agent for acquired immune deficiency syndrome
(AIDS) and AIDS-related complex.5 It has also been
demonstrated that inhibition of the glycoprotein process-
ing enzyme mannosidase I may provide leads for the
treatment of AIDS.6 In addition, these compounds may
have therapeutic application for the treatment of hyper-
glycemia and disorders related to these conditions such
as obesity and diabetes mellitus.7
In 1984, naturally occurring valiolamine (1) was iso-
lated from the fermentation broth of Streptomyces hy-
X Abstract published in Advance ACS Abstracts, November 1, 1996.
(1) (-)-quinic acid in organic synthesis. 7. Part 6: (a) Shing, T. K.
M.; Tai, V. W.-F. J . Org. Chem. 1995, 60, 5332. Part 5: (b) Tai, V.
W.-F.; Fung, P.-H.; Wong, Y.-S.; Shing, T. K. M. Tetrahedron: Asym-
metry 1994, 5, 1353.
(2) (a) Winchester, B; Fleet, G. W. J . Glycobiology 1992, 2, 199. (b)
Legler, G. Adv. Carbohydr. Chem. Biochem. 1990, 48, 319.
(3) (a) Fleet, G. W. J .; Fellows, L. E. In Natural Product Isolation;
Wagman, G. H., Cooper, R., Eds; Elsevier: Amsterdam, 1988; p 540.
(b) Humphries, M. J .; Matsumoto, K.; White, S. L.; Olden, K. Proc.
Natl. Acad. Sci. U.S.A. 1986, 83, 1752. (c) Elbein, A. Annu. Rev.
Biochem. 1987, 56, 497.
(8) Kameda, Y.; Asano, N.; Yoshikawa, M.; Takeuchi, M.; Yamagu-
chi, T.; Matsui, K.; Horii, S.; Fukase, H. J . Antibiot. 1984, 37, 1301.
(9) For a recent review on pseudosugars, see: (a) Suami, T.; Ogawa,
S. Adv. Carbohydr. Chem. Biochem. 1990, 48, 21. For general pseu-
dosugar synthesis, see: (b) Ogawa, S. J . Synth. Org. Chem. J pn. 1985,
43, 26. (c) Pingli, L.; Vandewalle, M. Synlett 1994, 228 and references
cited therein.
(10) Kameda, Y.; Horii, S. J . Chem. Soc., Chem. Commun. 1972,
746.
(11) Horii, S.; Iwasa, T.; Mizuta, E.; Kameda, Y. J . Antibiot. 1971,
24, 59.
(4) Fleet, G. W. J . Chem. Br. 1989, 25, 287.
(5) Fleet, G. W. J .; Karpas, A.; Dwek, R. A.; Fellows, L. E.; Tyms,
A. S.; Petursson, S.; Namgoong, S. K.; Ramsden, N. G.; Smith, P. W.;
Son, J . C.; Wilson, F.; Witty, D. R.; J acob, G. S.; Rademacher, T. W.
FEBS Lett. 1988, 237, 128 and references cited therein.
(6) Montefoiori, D. C.; Robinson, W. E.; Mitchell, W. M. Proc. Natl.
Acad. Sci. U.S.A. 1988, 85, 9248.
(7) (a) Truscheit, E.; Frommer, W.; J unge, B.; Mu¨ller, L.; Schmidt,
D. D.; Wingender, W. Angew. Chem., Int. Ed. Engl. 1992, 31, 288. (b)
Arends, J .; Willms, B. H. L. Horm. Metab. Res. 1986, 18, 761;
(12) Horii, S.; Fukase, H.; Kameda, Y. Carbohydr. Res. 1985, 140,
185.
(13) Horii, S.; Fukase, H.; Matsuo, T.; Kameda, Y.; Asano, N.;
Matsui, K. L. J . Med. Chem. 1986, 29, 1038.
S0022-3263(96)00782-7 CCC: $12.00 © 1996 American Chemical Society

Syntheses of Valiolamine and Its Diastereomers
J . Org. Chem., Vol. 61, No. 24, 1996 8469
F igu r e 2. Synthetic strategy.
Sch em e 1a
F igu r e 1. Structural relationship between sugars and hy-
droxylated cyclohexylamine inhibitors of glycosidases.
acrylic acid) cycloadduct,14 one from D-glucose via a
Ferrier rearrangement15 and the third one from 2,3,4,6-
tetra-O-benzyl-D-glucono-1,5-lactone employing an aldol
reaction as the key step.16 The last synthesis16 also
provided a fabrication of 1-epi-valiolamine (2). However,
the constructions of polyhydroxylated amines 3 and 4
have not been described. Our endeavors in pseudosugar
synthesis from (-)-quinic acid (6) have already furnished
2-((crotonyloxy)methyl)-(4R,5R,6R)-4,5,6-trihydroxycyclo-
hex-2-enone (COTC),17 pseudo-â-D-mannopyranose, pseudo-
â-D-fructopyranose,18 pseudo-R-D-glucopyranose, pseudo-
R-D-mannopyranose,19 cyclophellitol and its diastereo-
mers,20 peracetyl-validamine and -2-epi-validamine.1a In
continuation with our investigation into the preparation
of potential glycosidase inhibitors, we now report in detail
on the versatility of this approach in the facile syntheses21
of pseudoaminosaccharides 1, 2, 3, 4, and 17 and also on
a novel acetyl migration and internal displacement
reactions involving neighboring group participation.
Examination of the structures of the four target
molecules 1-4 shows that the stereogenic centers from
C-3 to C-5 of all the target molecules are the same.
Hence, the synthetic strategy was divided into two
parts: (i) to establish the chirality from C-3 to C-5 first
and then (ii) to establish the chirality of C-1 and C-2 as
well as the introduction of a nitrogen functionality with
the desired stereochemistry to C-1 (Figure 2).
a
Key: (a) five steps, (47%), see ref 20; (b) OsO4, H2O, Me3NO,
pyridine, ButOH, reflux, (75%); (c) Ac2O, DMAP, Et3N, reflux,
(90%); (d) TFA, H2O, CH2Cl2, (90%); (e) SOCl2, Et3N, CH2Cl2, 0
°C, then RuCl3‚H2O, NaIO4, CCl4, CH3CN, H2O, 0 °C (86%); (f)
LiN3, DMF, then 20% H2SO4, THF, (80%, 12:13 ) 1:10); (g) Ac2O,
DMAP, Et3N, CH2Cl2 (80% for 14; 86% for 15).
8 diastereoselectively as the sole product (Scheme 1).
Enhanced by the steric hindrance of the O-benzyl group
at the R-face of the alkene in 7, the osmium reagent was
more favored to add to the double bond from the less
hindered convex face (â-face) of the bicyclic skeleton. This
facial selectivity is predominately governed by the latter
factor as pointed out by one reviewer. The resultant
â-diol in compound 8 was then protected as the diacetate.
The tertiary hydroxy group in 8 was unreactive toward
acetic anhydride (3 equiv), triethylamine, or pyridine (5
equiv) and a catalytic amount of DMAP in methylene
chloride at room temperature or at reflux. Fortunately,
when a triethylamine (as solvent) solution of 8 was
heated under reflux with an excess of acetic anhydride
and 0.5 equiv of DMAP, the reaction was complete within
3 h and gave diacetate 9 as a colorless syrup.
The key intermediate 10 in the present synthetic
excursion was then obtained by hydrolytic removal of the
cyclohexylidene ketal in 9 with aqueous trifluoroacetic
acid in dichloromethane. The diol 10 was converted into
a relatively unstable cyclic sulfate 11 by the Sharpless
method.23 As in our previous synthesis of validamine,1a
azide anion was employed to introduce a nitrogen func-
2. Resu lts a n d Discu ssion
2.1. Syn th eses of 2-epi-Valiolam in e (3) an d 2-Am i-
n o Regioisom er 17. Our previous work has demon-
strated that (-)-quinic acid (6) could be easily trans-
formed into the alkene 7 in five steps with an overall
yield of 47%.20b cis-Dihydroxylation of the double bond
in 7 with a catalytic amount of osmium tetraoxide22 gave
(14) Ogawa, S.; Shibata, Y. Chem. Lett. 1985, 1581.
(15) Hayashido, M.; Sakairi, N.; Kuzuhara, H. J . Carbohydr. Chem.
1988, 7, 83.
(16) Fukase, H.; Horii, S. J . Org. Chem. 1992, 57, 3642 and 3651.
(17) (a) Shing, T. K. M.; Tang, Y. J . Chem. Soc., Chem. Commun.
1990, 312; (b) Tetrahedron 1990, 46, 6584.
(18) (a) Shing, T. K. M.; Tang, Y. J . Chem. Soc., Chem. Commun.
1990, 748; (b) Tetrahedron 1991, 47, 4571.
(19) (a) Shing, T. K. M.; Cui, Y.-X.; Tang, Y. J . Chem. Soc., Chem.
Commun. 1991, 756; (b) Tetrahedron 1992, 48, 2349.
(20) (a) Shing, T. K. M.; Tai, V. W.-F. J . Chem. Soc., Chem. Commun.
1993, 995; (b) J . Chem. Soc., Perkin Trans. 1 1994, 2017.
(21) Shing, T. K. M.; Wan, L. H. Angew. Chem., Int. Ed. Engl. 1995,
34, 1643.
(22) (a) Ray, R.; Matteson, D. S. Tetrahedron Lett. 1980, 21, 449.
(b) Review: Schroder, M. Chem. Rev. 1980, 80, 187.
(23) (a) Kim, B. M.; Sharpless, K. B. Tetrahedron Lett. 1989, 30,
655. (b) Gao, Y.; Sharpless, K. B. J . Am. Chem. Soc. 1988, 110, 7538.

8470 J . Org. Chem., Vol. 61, No. 24, 1996
Shing and Wan
Sch em e 2.a Syn th esis of 2-Am in o Regioisom er 17
Sch em e 3.a Syn th esis of 2-epi-Va liola m in e (3)
a
Key: (a) K2CO3, MeOH (100%); (b) Pd(OH)2, H2, EtOH (70%);
(c) Ac2O, pyridine, cat. DMAP (75%).
tionality to C-1. However, ring-opening reaction of the
cyclic sulfate 11 occurred regioselectively (vide infra) at
the undesired C-2 position, affording a mixture of azido
alcohols 12 and 13 with the latter regioisomer as the
preponderant product (12:13 ) 1:10).24 The regio- and
stereochemical assignments were based on 1H NMR
spectral analyses of their respective azido acetates 14 and
15. The H-2 in 14 resonated at δ 5.04 as a doublet of
doublets (J 2,3 ) 3.3, J 2,1 ) 7.2 Hz), indicating that the
C-2 acetyl group was at the axial position. The H-2 and
H-1 in 15 appeared at δ 3.58 and 4.86 as a triplet (J )
9.9 Hz) and a doublet of doublets of doublets (J 1,2 ) 9.9,
J 1,7eq ) 4.7, J 1,7ax ) 12.1 Hz), respectively, demonstrating
that both the C-2 azido and the C-1 acetyl groups were
at the equatorial positions. These assignments were
confirmed by spin-spin decoupling experiments, thus
providing evidence that the nucleophilic opening reac-
tions of the cyclic sulfate 11 were stereospecific and
proceeded with inversion of configuration, a corollary
consistent with our previous findings.1,20b
a
Key: (a) Tf2O (1 equiv), CH2Cl2, pyridine, 0 °C (93%); (b) Ac2O,
Et3N, CH2Cl2 (90%); (c) NaN3, benzo-15-crown-5, DMF (19 f 12,
60%; 20 f 14, 80%); (d) K2CO3, MeOH (72% from 14; 80% from
12); (e) H2, Pd(OH)2, EtOH (80%); (f) Ac2O, pyridine, cat. DMAP
(60%).
Sch em e 4.a Un exp ected In ter n a l Disp la cem en t of
Tr ifla te 24
Deacetylation of the diacetate 13 gave triol 16, which
was subjected to the removal of benzyl protecting groups
via hydrogenolysis and to hydrogenation of the azide
moiety to yield 2-amino regioisomer 17 (Scheme 2).
Compound 17 was thus prepared from quinic acid in 12
steps with an overall yield of 13% and was characterized
as its pentaacetate 18.
a
Key: (a) Bun4NOAc, THF then 20% H2SO4, THF (85%); (b)
Tf2O, CH2Cl2, pyridine, 0 °C (76%).
investigated initially and the configurations at C-1 and
C-2 of 11 had to be inverted. The aforedescribed chem-
istry of 11 predicted that the ring openings of the cyclic
sulfate moiety with nucleophiles would occur at C-2
preponderantly (vide supra). Tetrabutylammonium ac-
etate was used to invert the chirality at C-2, and the
reaction gave acetate 23 with excellent regioselectivity
in 85% yield (Scheme 4). The C-1 regiosiomer could not
be detected by TLC or NMR spectroscopy.
To introduce a nitrogen functionality to C-1 with
inversion of configuration via an SN2 displacement,
activation of the free alcohol at this site as a sulfonate
ester was investigated and the preparation of a triflate
ester was attempted first. Treatment of the alcohol 23
with triflic anhydride and pyridine in dichloromethane
led to an unexpected 1,2,4-triacetate 25, and none of the
desired product, triflate ester 24, was isolated. We
believed that the triflate 24 was formed initially and then
underwent a facile and efficient intramolecular substitu-
tion by the tertiary acetate at C-5 to give the C-1
â-acetate 25. Formation of the less nucleofugal mesylate
from the alcohol 23 was successful, and the desired
R-mesylate 26 was harvested without incident (Scheme
5). However, the subsequent intermolecular substitution
of 26 with tetrabutylammonium azide at 100 °C did not
afford any C-1 azide, and the only product isolated was
also 25, presumably derived from a similar internal
displacement.
Since the azido alcohol 12 was only obtained in poor
yield (ca. 5.5%) from the ring-opening of cyclic sulfate 11,
an alternate approach was investigated in order to afford
12 in good overall yield. Examination of the conforma-
tion of 10 shows that the OH-1 is at the equatorial
position while the other free alcohol is at the axial
position. Hence, selective esterification of the less hin-
dered OH-1 by 1 equiv of triflic anhydride in pyridine
gave the monotriflate 19 in 93% yield. When the triflate
19 was subjected to azide displacement in DMF, the azido
alcohol 12, obtained in fair yield (60%) (Scheme 3), was
identical in all respects to the minor product from the
azide opening of 11. If the monotriflate 19 was first
acetylated to 20 and then followed by azide attack, azido
acetate 14 was obtained and the yield of the substitution
reaction was improved from 60% to 80%. Deprotection
of the triacetate 14 with basic methanol provided triol
21, which was hydrogenolyzed to give 2-epi-valiolamine
(3) for the first time. Thus, the target molecule 3 was
synthesized form (-)-quinic acid (6) in 15 steps with an
overall yield of 4.3%. Acetylation of 3 furnished the
corresponding N,O-pentaacetate 22 for characterization.
2.2. Syn th esis of Va liola m in e (1). Un exp ected
In ter n a l Disp la cem en t. For the synthesis of valiola-
mine, the avenue involving the cyclic sulfate 11 was
Examination of the molecular models of sulfonate
esters 24 and 26 (OTf-1 or OMs-1 and OAc-2 trans-
disposed) shows that the tertiary acetate (OAc-5) is in
(24) For reviews on the chemistry of cyclic sulfates, see: (a) Lohray
B. B. Synthesis 1992, 1035. (b) Kolb, H. C.; Van Nieuwenhze, M. S.;
Sharpless, K. B. Chem. Rev. 1994, 94, 2483.

Syntheses of Valiolamine and Its Diastereomers
J . Org. Chem., Vol. 61, No. 24, 1996 8471
Sch em e 6.a Syn th esis of Va liola m in e (1)
F igu r e 3. Proposed pathway for the unexpected intramolecu-
lar displacement involving neighboring trans-disposed acetyl
group participation. The nucleophile in iv could also be water
during the workup. For clarity, the C-4 acetate in i or in ii is
not illustrated.
a
Key: (a) Tf2O, pyridine, CH2Cl2, 0 °C (90%); (b) Bun4NOAc,
THF (80%); (c) K2CO3, MeOH (91%); (d) H2, Pd(OH)2, EtOH (80%);
(e) Ac2O, pyridine, cat. DMAP (70%).
Sch em e 7.a Syn th esis of 1-epi-Va liola m in e (2)
Sch em e 5.a Un exp ected In ter n a l Disp la cem en t of
Mesyla te 25
a
Key: (a) MsCl, pyridine (80%); (b) Bun4NN3, DMF, 100 °C
(80%).
close proximity to the sulfonate leaving group and
intramolecular displacement should be facilitated. How-
ever, the dominance of the juxtaposed acetate (OAc-2)
over the tertiary acetate (OAc-5) in initiating the in-
tramolecular displacement is indicated by the fact that
the cyclic sufate 11 (with OAc-5 but no juxtaposed
acetate) did not yield an internal displacement product
when subjected to azide treatment (cf. 11 f 12 + 13).
Furthermore, the importance of the stereochemistry of
OAc-2 relative to the sulfonate-1 is demonstrated by the
fact that the 2-epimer of 24, i.e., the triflate acetate 20
(OTf-1 and OAc-2 cis-disposed), did not undergo the
internal substitution process. Only 24 and 26, both with
OAc-2 trans to the C-1 sulfonate, underwent intramo-
lecular inversion probably via neighboring group partici-
pation. In fact, the ionization of a mesylate assisted by
a neighboring trans-disposed acetate is not uncommon
in carbohydrate chemistry.25 The reaction pathway for
the internal displacement is proposed in Figure 3, and
the involvement of OAc-5 in the ionization of C-1 sul-
fonate to give vi directly is unlikely on the basis of the
aforedescribed findings.
The strategy for the construction of 1 was revised, and
the nitrogen functionality had to be introduced to C-1 in
10 first before inverting the C-2 configuration. Hence,
the diol 10 was transformed into the azido alcohol 12 as
described previously, and the stereogenic center at C-2
was inverted by trifluoromethanesulfonylation and sub-
sequent displacement with tetrabutylammonium acetate
to give azido triacetate 28 (Scheme 6). Deacetylation of
28 with basic methanol gave triol 29, which was hydro-
genolyzed to valiolamine (1) as a white amorphous solid.
Valiolamine (1) was thus synthesized from quinic acid
(6) in 14 steps with an overall yield of 8.4%. All the
a
Key: (a) 1,1′-(thiocarbonyl)diimidazole, toluene, reflux, then
P(OMe)3, reflux, (64% overall); (b) OsO4, H2O, pyridine, Me3NO,
ButOH, 10-2 M, reflux, 32 (20%), 31 (60%), 10 (10%); (c) OsO4,
H2O, pyridine, Me3NO, ButOH, 10-1 M, reflux, 33 (29%), 31 (46%),
10 (14%); (d) RuCl3‚H2O, NaIO4, CCl4, CH3CN, H2O, 0 °C (81%);
(e) SOCl2, Et3N, CH2Cl2, 0 °C, then RuCl3‚H2O, NaIO4, CCl4,
CH3CN, H2O, 0 °C (74%); (f) LiN3, DMF, then 20% H2SO4, THF
(50%) (g) K2CO3, MeOH (88%); (h) H2, Pd(OH)2/C, EtOH (85%);
(i) Ac2O, pyridine, cat. DMAP (80%).
physical data of 1 from this synthesis were in good
agreement with those reported by Kameda et al.11 ([R]22
D
+14.5 (lit.11 [R]20D +18.8)) except for the 1H NMR spectral
data; the NMR peaks overlapped heavily within the δ
3.4-3.9 region. Therefore, valiolamine (1) was deriva-
tized as its N,O,O,O,O-pentaacetate 30 whose physical
data (mp ) 137-138 °C and [R]20 -17.8 (lit.11 mp )
D
137-138 °C and [R]25 -14.8)) including the 1H NMR
D
spectral data were in good agreement with those re-
ported.11
2.3. Syn t h eses of 1-ep i-Va liola m in e (2) a n d
(1R,2R)-Va liola m in e (4). Un exp ected Acetyl Migr a -
tion . The aforedescribed diol 10 was converted into
alkene 31 uneventfully by the Corey-Winter reaction26
in 64% overall yield (Scheme 7). cis-Dihydroxylation of
a 10-2 M solution of the alkene 31 via osmium tetraoxide
catalysis27 resulted in 20% yield of the desired â-diol 32,
(26) Corey, E. J .; Winter, R. A. E. J . Am. Chem. Soc. 1963, 85, 2677.
(27) (a) Schroder, M. Chem. Rev. 1980, 80, 187. (b) Singh, H. S. In
Organic Syntheses by Oxidation with Metal Compounds; Mijs, W. J .,
de J onge, C. R. H. I., Eds.; Academic Press: New York, London, 1986;
p 633.
(25) For related internal displacement in sugars involving neigbor-
ing group participation, see: Goodman, L. Adv. Carbohydr. Chem.
1967, 22, 109.

8472 J . Org. Chem., Vol. 61, No. 24, 1996
Shing and Wan
F igu r e 5.
Sch em e 8. Attem p ted Hyd r oxya m in a tion
F igu r e 4. Proposed pathway for the unexpected acetyl
migration.
10% of R-diol 10, and 60% of the starting alkene 31. The
stereochemistry of the â-1,2-diol 32 was supported by the
1H NMR coupling constant data (J 1,2 ) 3.2, J 1,7eq ) 2.7,
J 1,7ax ) 2.8, J 2,3 ) 9.2 Hz). When the reaction was
repeated in a more concentrated solution (10-1 M), the
acetyl-migrated â-1,5-diol 33 (29% yield), R-diol 10 (14%
yield), and the starting alkene (46%) were obtained. The
acetyl-migration process is believed to be promoted by
pyridine and hence displayed a concentation effect.
Related acyl migrations have been observed in carbohy-
drates28 and inositols.29
catalyzed dihydroxylation was not acceptable from a
synthetic view point. A fruitless alternative had been
attempted to access 32 by Mitsunobu inversion34 of the
two hydroxy groups in 10 with trifluoroacetic acid in the
presence of sodium benzoate.35 Fortunately, the new
dihydroxylation protocol via ruthenium catalysis devel-
oped by us36 greatly improved the yield, the diastereo-
selectivity, the reaction time, and the workup procedure.
Thus, when the alkene 31 was treated with 0.1 equiv of
RuCl3‚H2O and 1.7 equiv of NaIO4 in CCl4-CH3CN-
water, the cis-dihydroxylation reaction was complete
within minutes at 0 °C. The yield of the desired â-diol
32 was improved from 20% to 81%, and no diastereomer,
acetyl-migrated product, or starting material was de-
tected. The diol 32 was then converted into 1,2-cyclic
sulfate 34 according to the Sharpless protocol23 (Scheme
7). The cyclic sulfate 34 was opened regioselectively by
lithium azide in DMF and was subsequently hydrolyzed
The mechansim for the acetyl-migration process is
proposed in Figure 4. This proposal is supported by the
fact that no corresponding migration was observed for
the R-diol 10 because the two hydroxy groups (OH-1,2)
are trans to the tertiary acetate (OAc-5). Since the
tertiary O-acetyl group is located at the axial position, it
tends to migrate to the relatively more stable secondary
axial hydroxy group and then to the most stable equato-
rial hydroxy group under equilibrating conditions.
The inertness of 31 may be due to its formation of the
very stable osmate ester with osmium tetraoxide. In fact,
formation of very stable osmate ester of some olefin with
osmium tetraoxide was reported and catalytic process is
not feasible in such situation.30,31 Addition of methane-
sulfonamide described by Sharpless31 could increase the
rate of hydrolysis of osmate ester but such reagent
showed no improvement to our system at 25 °C, at 60
°C, or at reflux. Besides, the diastereoselectivity of the
reaction was also poor. Attempts to use potassium
ferricyanide (K3Fe(CN)6)32 as an oxidant to replace tri-
methylamine N-oxide and to improve the stereoselectivity
gained no advantage. As an alternate approach, the
alkene 31 was subjected to the cis-hydroxyamination
procotol described by Sharpless,33 but the reaction was
not effective. The reaction was repeated under phase
transfer conditions,33 but only a trace amount of cis-
dihydroxylated products were obtained and no hydroxyam-
inated products were isolated (Scheme 8).
to give azide 35. The regio- and stereochemical assign-
1
ments were based on H NMR spectral analyses (J 1,2
)
9.6, J 1,7eq ) 4.4, J 1,7ax ) 12.3, J 2,3 ) 9.3 Hz). If the azide
anion had opened the ring at C-2, the dihedral angle
between H1 and H2 would be about 60° (Figure 5) and
the coupling constant between them would have been ca.
3-5 Hz.
Deacetylation of the azido acetate 35 with basic
methanol afforded azido triol 36. On the other hand, if
we started with the rearranged diol 33 (the unblocked
diol moiety in a 1,3-diaxial relationship) and followed the
presented reaction sequence (32 f 34 f 35 f 36), the
same product 36 would be obtained (Scheme 9). Hence,
the diol 33 was readily converted into 1,3-cyclic sulfate
38. Nucleophilic ring opening of the 1,3-cyclic sulfate 38
with azide ion gave azide 39 which on deacetylation
afforded the identical hydroxy azide 36.
Hydrogenolysis of the benzyl ethers and reduction of
the azide in 36, catalyzed by 10% Pd(OH)2 on charcoal,
proceeded smoothly to give the target molecule 1-epi-
valiolamine (2) in 85% yield (Scheme 7). Starting from
(-)-quinic acid, 13 steps were required to prepare 2 with
In order to synthesize 2, the (1S,2S)-diol 32 is the key
precursor from which cyclic sulfate 34 can be derived.
As discussed above, the yield of 32 from 31 via OsO4-
(28) Rowell, R. M. Carbohydr. Res. 1972, 23, 417.
(29) (a) Shvets, V. I. Russian Chem Rev. 1974, 43, 488. (b) Chung,
S.-K.; Chang, Y.-T.; Ryu, Y. Pure Appl. Chem. 1996, 68, 931.
(30) Akashi, K.; Palermo, R. E.; Sharpless, K. B. J . Org. Chem. 1978,
43, 2063.
(31) Sharpless, K. B.; Amberg, W.; Bennani, Y.; Crispino, G.;
Hartung, J .; J eong, K.; Kwong, H.-L.; Morikawa, K.; Wang, Z. M.; Xu,
D.; Zhang, X. L. J . Org. Chem. 1992, 57, 2768
(32) Kwong H.-L.; Sorato, C.; Ogino, Y.; Chen, H.; Sharpless, K. B.
Tetrahedron Lett. 1990, 31, 2999.
(33) (a) Sharpless, K. B.; Hori, T. J . Org. Chem. 1976, 41, 177. (b)
Herranz, E.; Sharpless, K. B. Ibid. 1978, 43, 2544.
(34) Mitsunobu, O. Synthesis 1981, 1.
(35) Varasi, M.; Walker, K. A. M.; Maddox, M. L. J . Org. Chem.
1987, 52, 4235.
(36) (a) Shing, T. K. M.; Tam, E. K. W.; Tai, V. W.-F.; Chung, I. H.
F.; J iang, Q. Chem. Eur. J . 1996, 2, 50. (b) Shing, T. K. M.; Tai, V.
W.-F.; Tam, E. K. W. Angew. Chem., Int. Ed. Engl. 1994, 33, 2312.

Syntheses of Valiolamine and Its Diastereomers
J . Org. Chem., Vol. 61, No. 24, 1996 8473
Sch em e 9a
F igu r e 6.
a
Key: (a) SOCl2, Et3N, CH2Cl2, 0 °C then RuCl3‚H2O, NaIO4,
CCl4, CH3CN, H2O, 0 °C (80%); (b) LiN3, DMF, then 20% H2SO4,
THF (80%); (c) K2CO3, MeOH (88%).
Sch em e 10.a Syn th esis of (1R,2R)-Va liola m in e (4)
F igu r e 7.
a
(a) Tf2O, pyridine, CH2Cl2 (78%); (b) Bun4NOAc, THF (95%);
(c) K2CO3, MeOH (80%); (d) H2, Pd(OH)2, EtOH (73%); (e) Ac2O,
pyridine, cat. DMAP (80%).
9.0% overall yield. 1-epi-Valiolamine (2) was acetylated
to the corresponding N,O,O,O,O-pentaacetate 37 for
characterization. The spectral data and physical con-
stants of our synthetic compound 2 are in close agree-
ment with those reported by Fukase ([R]20 -27.9 (lit.11
D
F igu r e 8.
[R]24 -23.2)).
D
Since (1R,2R)-valiolamine (4) is the 2-epimer of 2, 4
could readily be accessed by inverting the OH-2 in
compound 2. Thus, activation of the OH-2 in 35 with
trifluoromethanesulfonic anhydride afforded triflate 40,
which was subjected to nucleophilic substitution with
tetrabutylammonium acetate, leading to the protected
target molecule 41 (Scheme 10). Deacetylation of the
triacetate 41 gave triol 42 which was hydrogenolyzed to
furnish (1R,2R)-valiolamine (4) for the first time. The
overall yield of the target molecule 4 from (-)-quinic acid
is 2.5% in 17 steps. (1R,2R)-Valiolamine (4) was also
characterized as its N,O,O,O,O-pentaacetate 43.
For the ring opening of 34, nucleophilic attack at C-2
(path b) would induce dipoles that are aligned with two
existing dipoles at the vicinal carbon atoms (i.e., C-1 and
C-3), and the transition state energy is correspondingly
increased20b,38 (Figure 7). In addition, the 1,3-diaxial
interaction between the H-4 and the incoming nucleo-
phile also deters the process. However, if the nucleophilic
attack takes place at C-1, the induced dipole is only
aligned with one existing vicinal dipole and the 1,3-
diaxial interaction between OAc-5 and C-1 substitutent
is diminishing in the transition state, path a is therefore
preferred and only 35 was obtained.
2.4. Regioch em istr y of Nu cleop h ilic Atta ck of
Cyclic Su lfa tes 34, 11 a n d 38. Cyclic sulfates, from a
synthetic view point, are more or less the same as
epoxides. They can be opened by nucleophiles and give
vicinal alcohols after acid hydrolysis.24 If the epoxide or
the cyclic sulfate is located within a six-membered ring,
the regioselectivities of their ring openings are different.
For epoxides, nucleophilic attacks leading to diaxial
products are much more favored.37 For cyclic sulfates,
on the basis of our previous work summarized in Figure
6,1,20b there are two major factors that govern the regi-
oselectivity of charged nucleophilic openings, namely a
stereoelectronic factor37 (alignment of dipoles)38 and a
steric factor1a,20b (conformation of the substrate and the
size of the nucleophile).
For 11, the nucleophilic attack was also favored at C-1,
attributable to the stereoelectronic factor as described
above. However, due to the presence of the axial acetate
group at C-5, the 1,3-diaxial steric interaction is domi-
nant over the electronic effect and the attack at C-2 takes
precedence. The ring-opening reaction with lithium azide
furnished mainly 13 and only a small amount of 12
(Figure 8). Since steric interaction increases with the
size of nucleophile, the regioselectivity should increase
from using azide to using acetate as the nucleophile. This
has been shown to be the case and reaction of 11 with
tetrabutylammonium acetate gave the C-2 acetate 23 as
the sole product. The effect of the size of nucleophile on
regioselectivity is in accord with our previous findings.1a
For the 1,3-cyclic sulfate 38, both the electronic and
steric effects favored the nucleophilic attack at C-1, and
hence, C-1 azide 39 was produced as the sole product
(Figure 9).
(37) Deslongchamps, P. Stereoelectronic Effects in Organic Chem-
istry; Pergamon Press: Oxford, 1983.
(38) Buchanan, J . G. In MTP International Review of Science,
Organic Chemistry Series One; Aspinall, A. O., Ed.; University Park
Press: New York, 1973; Vol. 7, p 33.
Finally, it is noteworthy that all the nucleophilic ring
openings of cyclic sulfates studied in this and in our

8474 J . Org. Chem., Vol. 61, No. 24, 1996
Shing and Wan
(1H, t*, J ) 3.2 Hz), 2.06 (1H, dd, J ) 1.0, 3.5 Hz), 3.20-3.75
(6H, m) (*apparent splitting pattern); 13C NMR (D2O, dioxane
at 67.40 ppm) δ 34.96, 50.76, 66.58, 73.99 74.75, 75.12, 75.77;
MS m/z (CI) 194 (M+ + 1, 11.07). Anal. Calcd for C7H15O5N‚
0.45H2O: C, 41.77; H, 7.96; N, 6.95. Found: C, 41.73; H, 7.84;
N, 6.84.
(1S,2R,3R,4S,5S)-1-Am in o-5-(h yd r oxym eth yl)cycloh ex-
a n e-2,3,4,5-tetr ol (2-epi-Va liola m in e) (3). To a solution of
the dibenzyl ether 21 (32.8 mg, 0.082 mmol) in EtOH (5 mL)
was added 20% Pd(OH)2 on charcoal (30 mg), and H2 was
bubbled through the mixture under stirring until no UV active
species was shown by TLC. The solution was filtered through
a pad of Celite and the filtrate concentrated. Flash column
chromatography (CHCl3:MeOH:NH3(aq), 9:8:3) of the residue
followed by Amberlite CG-50 (NH4+) chromatography afforded
2-epi-valiolamine (3) as a white amorphous solid (13 mg,
80%): TLC Rf 0.14 (CHCl3:MeOH:NH3(aq), 9:8:3); [R]22D -11.1
(c ) 0.4, H2O); IR (neat) 3339 cm-1; 1H NMR (D2O) δ 1.78 (1H,
dd, J ) 4.8, 14.8 Hz), 2.02 (1H, dd, J ) 4.4, 14.8 Hz), 3.38
(1H, q*, J ) 4.5 Hz), 3.51 and 3.62 (2H, ABq, J ) 11.7 Hz),
3.75 (1H, d, J ) 8.0 Hz), 3.8-4.1 (2H, m) (*apparent splitting
pattern); 13C NMR (D2O, dioxane at 67.40 ppm) δ 31.05, 50.90,
66.22, 70.11, 71.42, 71.86, 76.22; MS m/z (CI) 194(M+ + 1, 100).
Anal. Calcd for C7H15O5N‚0.5H2O: C, 41.58; H, 7.98; N, 6.93.
Found: C, 41.53; H, 7.93; N, 6.75.
(1R,2R,3R,4S,5S)-1-Am in o-5-(h ydr oxym eth yl)cycloh ex-
a n e-2,3,4,5-tetr ol ((1R,2R)-Va liola m in e) (4). To a solution
of the dibenzyl ether 42 (31 mg, 0.078 mmol) in EtOH (5 mL)
was added 20% Pd(OH)2 on charcoal (100 mg), and H2 was
bubbled through the mixture under stirring until no UV-active
species was shown by TLC. The solution was filtered through
a pad of Celite and the filtrate concentrated. Flash column
chromatography (CHCl3:MeOH:NH3(aq), 9:8:3) of the residue
followed by Amberlite CG-50 (NH4+) chromatography fur-
nished (1R,2R)-valiolamine (4) (11 mg, 73%) as a white
F igu r e 9.
previous work1,20b are stereospecific and proceed with
inversion of configuration.
3. Exp er im en ta l Section
Melting points were determined with a Reichert apparatus
and are reported in °C (uncorrected). Optical rotations were
measured with an automatic digital polarimeter, operating at
589 nm. IR spectra were recorded on an FT-IR spectrometer
as thin films on NaCl disks. Unless stated to the contrary,
NMR spectra were measured in solutions of CDCl3 at 250 MHz
(1H) or at 62.9 MHz (13C). All chemical shifts were recorded
in ppm downfield from tetramethylsilane on the δ scale.
Spin-spin coupling constants (J ) were measured directly from
the spectra. Carbon and hydrogen elemental analyses were
carried out at either the Shanghai Institute of Organic
Chemistry, The Chinese Academy of Sciences, China, or the
MEDAC Ltd, Department of Chemistry, Brunel University,
Uxbridge, U.K. All reactions were monitored by analytical
TLC on aluminum precoated with silica gel 60F254 (E. Merck),
and compounds were visualized with a spray of either 5% w/v
dodecamolybdophosphoric acid in ethanol or 5% v/v concen-
trated sulfuric acid in ethanol and subsequent heating. All
columns were packed wet using E. Merck silica gel 60 (230-
400 mesh) as the stationary phase and eluted using flash39
chromatographic technique. Pyridine was distilled over barium
oxide and stored in the presence of potassium hydroxide
pellets. Absolute methanol was distilled over magnesium and
stored in the presence of 4 Å molecular sieves. THF was
distilled from sodium benzophenone ketyl under a nitrogen
atmosphere. CH2Cl2 was distilled over phosphorous pentoxide
and stored in the presence of 4 Å molecular sieves.
amorphous solid: TLC Rf 0.14 (CHCl3:MeOH:NH3(aq), 9:8:3);
1
[R]19 -13.7 (c ) 0.5, H2O); H NMR (D2O) δ 1.80-2.00 (2H,
D
m), 3.50-3.65 (1H, m), 3.50 and 3.60 (2H, ABq, J ) 11.3 Hz),
3.68 (1H, d, J ) 9.9 Hz), 3.78 (1H, dd, J ) 2.9, 9.9 Hz), 4.13
(1H, br s); 13C NMR (D2O, dioxane at 67.4 ppm) δ 31.63, 48.38,
66.40, 67.40*, 70.48, 71.62, 74.20 (*overlapped with dioxane);
MS m/z (CI) 194 (M+ + 1, 100). Anal. Calcd for C7H15O5N‚
0.8H2O: C, 40.50; H, 8.06; N, 6.75. Found: C, 40.79; H, 8.20;
N, 6.36.
(1S,2S,3R,4S,5S)-1-Am in o-5-(h yd r oxym eth yl)cycloh ex-
a n e-2,3,4,5-tetr ol (Va liola m in e) (1). To a solution of the
dibenzyl ether 29 (18 mg, 0.045 mmol) in EtOH (5 mL) was
added 20% Pd(OH)2 on charcoal (10 mg), and H2 was bubbled
through the mixture with stirring until no UV-active species
was shown by TLC. The solution was filtered through a pad
of Celite and the filtrate concentrated. Flash column chro-
matography (CHCl3:MeOH:NH3(aq), 9:8:3) of the residue gave
the crude product, which was further purified by Amberlite
CG-50 (NH4+) chromatography to yield valiolamine (1) (7 mg,
80%) as a white amorphous solid: TLC Rf 0.14 (CHCl3:MeOH:
NH3(aq), 9:8:3); [R]22 +15.4 (c ) 2.2, H2O) (lit.8 [R]20 +18.8
(1R,2R,3S,4S,5S)-3-O-Ben zyl-5-((b en zyloxy)m et h yl)-
1,2-O-cycloh exylid en ecycloh exa n e-1,2,3,4,5-p en tol (8). To
a solution of the alkene 720b (7.03 g, 16.7 mmol) in ButOH (70
mL) were added Me3NO (2.6 g, 23.3 mmol), pyridine (9 mL,
103.3 mmol), H2O (1.6 mL, 90 mmol), and OsO4 (2.5 wt%, 0.25
mL). The reaction mixture was refluxed for 12 h and then
cooled to rt, quenched with saturated Na2S2O3(aq) (20 mL),
and filtered through a short column of silica gel. The organic
phase was washed with brine (2 × 20 mL), dried (MgSO4),
filtered and the filtrate was concentrated. Flash column
chromatography (hexane:Et2O, 1:1) of the residue afforded the
diol 8 (5.7 g, 75%) as a white solid: mp 101-103 °C; TLC Rf
D
D
(c ) 1.0, H2O)); IR (neat) 3342 cm-1
;
1H NMR (D2O) δ 1.90
0.34 (hexane:Et2O, 1:2); [R]25 -27 (c ) 1.0, CHCl3); IR (neat)
(1H, dd, J ) 3.9, 15.9 Hz), 2.11 (1H, dd, J ) 2.4, 15.9 Hz),
3.4-3.9 (6H, m); 13C NMR (D2O, dioxane as the reference peak
at 67.8 ppm) δ 33.34, 51.57, 66.74, 72.42, 74.30, 74.93, 77.06
(lit.8 δ 35.0, 52.9, 68.2, 73.8, 76.3, 76.4, 78.7); MS m/z (CI) 194
(M+ + 1, 100).
D
3460 cm-1; 1H NMR δ 1.3-1.8 (11H, m), 2.02 (1H, dd, J ) 6.4,
14.4 Hz), 2.51 (1H, s), 2.75 (1H, s), 3.43 and 3.48 (2H, ABq, J
) 9.1 Hz), 3.80 (1H, dd, J ) 3.9, 9.5 Hz), 4.00 (1H, d, J ) 9.5
Hz), 4.25-4.45 (2H, m), 4.55 (2H, s), 4.70 and 4.80 (2H, ABq,
J ) 12.0 Hz), 7.2-7.5 (10H, m); MS m/z (EI) 538 (M+, 0.43),
241(M+ - 43, 84.7), 55 (100). Anal. Calcd for C27H34O6: C,
71.34; H, 7.54. Found: C, 71.33; H, 7.50.
(1R,2S,3R,4S,5S)-1-Am in o-5-(h yd r oxym eth yl)cycloh ex-
a n e-2,3,4,5-tetr ol (1-epi-Va liola m in e) (2). To a solution of
the dibenzyl ether 36 (29 mg, 0.073 mmol) in EtOH (7 mL)
was added 20% Pd(OH)2 on charcoal (30 mg), and H2 was
bubbled through the mixture with stirring until no UV-active
species was shown by TLC. The solution was filtered through
a pad of Celite and the filtrate concentrated. Flash column
chromatography (CHCl3:MeOH:NH3(aq), 10:7:3) of the residue
gave the crude product, which was further purified by Am-
berlite CG-50 (NH4+) to give 1-epi-valiolamine (2) as a white
amorphous solid (11 mg, 85%): TLC Rf 0.15 (CHCl3:MeOH:
NH3(aq), 10:7:3); [R]20D -27.9 (c ) 0.5, H2O) (lit.16 [R]24D -23.2
(1R,2S,3S,4S,5S)-4,5-Di-O-a cet yl-3-O-b en zyl-5-((b en -
zy lo x y )m e t h y l)-1,2-O -c y c lo h e x y lid e n e c y c lo h e x a n e -
1,2,3,4,5-p en tol (9). The diol 8 (2.9 g, 6.39 mmol) was
dissolved in Et3N (20 mL) and Ac2O (4.8 mL, 51.1 mmol). A
catalytic amount of DMAP was added to the solution at rt,
and the mixture was refluxed for 3 h. The cooled mixture was
quenched with saturated NH4Cl(aq) solution (20 mL), ex-
tracted with Et2O (2 × 40 mL), dried (MgSO4), and filtered,
and the filtrate was concentrated. Flash chromatography
(hexane:Et2O, 1:1) of the crude product provided the diacetate
9 (6.0 g, 90%) as a colorless syrup: TLC Rf 0.5 (hexane:Et2O,
(c ) 0.5, H2O)); IR (neat) 3351 cm-1
;
1H NMR (D2O) δ 1.65
1
(39) Still, W. C.; Kahn, M.; Mitra, A. J . Org. Chem. 1978, 43, 2923.
1:1); IR (neat) 1744 cm-1; H NMR δ 1.2-1.7 (11H, m), 1.88

Syntheses of Valiolamine and Its Diastereomers
J . Org. Chem., Vol. 61, No. 24, 1996 8475
(3H, s), 1.93 (3H, s), 2.72 (1H, dd, J ) 6.15, 14.6 Hz), 3.62 and
3.79 (2H, ABq, J ) 9.18 Hz), 3.90 (1H, dd, J ) 4.3, 10.0 Hz),
4.00-4.08 (1H, m), 4.29 (1H, m), 4.30 and 4.38 (2H, ABq, J )
12 Hz), 4.63 (2H, br s), 5.42 (1H, d, J ) 10.0 Hz), 7.18-7.31
(10H, m); MS m/z (EI) 538 (M+, 0.43), 91(C7H7, 100). Anal.
Calcd for C31H38O8: C, 69.13; H, 7.11. Found: C, 68.9; H, 7.29.
solution of the cyclic sulfate 11 (0.19 g, 0.37 mmol) in dry DMF
(20 mL) was added LiN340 (0.16 g, 2.42 mmol), and the solution
was stirred for 6 h at rt. The solvent was evaporated and the
residue was dissolved in THF (20 mL). Then 20% H2SO4(aq)
(2.5 mL) was added and the mixture was allowed to stir at rt.
After 1 h, saturated Na2CO3(aq) solution (20 mL) was added
and the aqueous phase was extracted with Et2O (2 × 10 mL).
The combined extracts were dried (MgSO4), filtered, and
concentrated. Flash chromatography of the residue (Et2O:
hexane, 1:1) furnished the 1-azide 12 (13 mg, 7.3%) and 2-azide
13 (0.13 g, 73%) as a colorless syrup: TLC Rf 0.53 (hexane:
Et2O, 1:2); [R]25D -62.6 (c ) 0.9, CHCl3); IR (neat) 3450, 2106,
(1R,2R,3R,4S,5S)-4,5-Di-O-a cet yl-3-O-b en zyl-5-((b en -
zyloxy)m eth yl)cycloh exa n e-1,2,3,4,5-p en tol (10). To a
solution of the ketal 9 (4.8 g, 8.92 mmol) in CH2Cl2 (20 mL)
were added TFA (0.5 mL) and H2O (1 mL). The mixture was
stirred vigorously at rt for 24 h. Then the reaction mixture
was quenched with saturated NaHCO3(aq) solution and the
aqueous layer was extracted with CH2Cl2 (2 × 20 mL). The
combined organic extracts were dried (MgSO4) and filtered.
Concentration of the filtrate followed by flash chromatography
(Et2O:hexane, 3:1) provided the diol 10 (3.5 g, 90%) as a white
amorphous solid: TLC Rf 0.19 (hexane:Et2O 1:3); [R]25D -13.5
1
1744 cm-1; H NMR δ 1.64 (1H, dd, J ) 11.7, 14.4 Hz), 1.79
(3H, s), 1.99 (3H, s), 2.29 (1H, br s), 2.88 (1H, dd, J ) 4.6, 14.0
Hz), 3.35 (1H, t*, J ) 9.6 Hz), 3.40-3.55 (1H, m), 3.57 and
3.85 (2H, ABq, J ) 9.0 Hz), 3.64 (1H, t*, J ) 9.7 Hz), 4.28 and
4.36 (2H, ABq, J ) 11.6 Hz), 4.58 and 4.75 (2H, ABq, J ) 10.9
Hz), 5.20 (1H, d, J ) 9.8 Hz), 7.1-7.34 (10H, m) (*apparent
splitting pattern); MS m/z (EI) 377(M+ - C7H6O, 1.22), 91
(100). Anal. Calcd for C25H29O7N3: C, 62.10; H, 6.05; N, 8.69.
Found: C, 61.93; H, 5.81; N, 8.46.
1
(c ) 0.4, CHCl3); IR (neat) 3425, 1740 cm-1; H NMR δ 1.93
(3H, s), 2.00-2.01 (1H, m,), 2.04 (3H, s), 2.62 (1H, br s), 2.74
(1H, dd, J ) 4.8, 13.8 Hz), 3.71 and 3.92 (2H, ABq, J ) 9.0
Hz), 3.73 (2H, dd, J ) 2.9, 10.0 Hz), 4.20 (1H, br s), 4.37 and
4.45 (2H, ABq, J ) 11.7 Hz), 4.60 and 4.66 (2H, ABq, J ) 12.1
Hz), 5.46 (1H, d, J ) 10.0 Hz), 7.20-7.40 (10H, m); MS m/z
(1S,2R,3R,4S,5S)-1-Azid o-2,4,5-t r ia cet yl-3-O-b en zyl-5-
((ben zyloxy)m eth yl)cycloh exa n e-2,3,4,5-tetr ol (14). (a )
F r om 20. To a solution of the triflate 20 (0.11 g, 0.17 mmol)
in dry DMF (5 mL) were added NaN3 (0.023 g, 0.34 mmol)
and benzo-15-crown-5 (0.1 g, 0.38 mmol). The mixture was
stirred overnight, and the solvent was then evaporated. The
residue was purified by flash chromatography (hexane:Et2O
2:1) to give the azido acetate 14 (0.07 g, 80%) as a colorless
(EI) 458 (M+, 0.08), 367 (M+ - C7H7, 0.18), 261 (M+ - C7H7
-
C7H6O, 73.4), 91 (100). Anal. Calcd for C25H30O8: C, 65.49;
H, 6.60. Found: C, 65.57; H, 6.84.
(1R,2S,3S,4S,5S)-4,5-Di-O-a cet yl-3-O-b en zyl-5-((b en -
zyloxy)m eth yl)-1,2-O,O-su lfon ylcycloh exan e-1,2,3,4,5-pen -
tol (11). A solution of the R-1,2-diol 10 (494 mg, 1.07 mmol)
and Et3N (0.47 mL, 4.31 mmol) in CH2Cl2 (20 mL) was cooled
to 0 °C. SOCl2 (0.28 mL, 3.77 mmol) was added with stirring
for 0.5 h. After a further 15 min at 0 °C, cold Et2O (10 mL)
and cold H2O (15 mL) were added. The aqueous phase was
extracted with Et2O (2 × 15 mL). The combined extracts were
dried (MgSO4) and filtered and the filtrate concentrated. The
residue was pumped under high vacuum for 1 h. The residue
was dissolved in CCl4-CH3CN (1:1) (20 mL) and the resulting
solution cooled to 0 °C. Then NaIO4 (0.92 g, 4.32 mmol), H2O
(10 mL), and a catalytic amount of RuCl3‚H2O was added. The
reaction mixture was stirred vigorously for 1 h at 0 °C, and
cold Et2O (5 mL) was added. The aqueous phase was extracted
by Et2O (2 × 15 mL), and the combined organic extracts were
washed with brine, dried (MgSO4), and filtered, and the filtrate
was concentrated. The crude product was purified by flash
chromatography (Et2O:hexane, 1:2) to give the cyclic sulfate
11 as a white amorphous solid (0.48 g, 86%): TLC Rf 0.48
syrup: TLC Rf 0.35 (hexane:Et2O, 3:2); [R]28 -5.0 (c ) 1.0,
D
CHCl3); IR (neat) 2108, 1744 cm-1
;
1H NMR δ 1.94 (3H, s),
1.96 (3H, s), 1.98 (3H, s), 2.15-2.50 (2H, m), 3.60-3.80 (1H,
m), 3.74 and 3.97 (2H, ABq, J ) 10.0 Hz), 3.88 (1H, dd, J )
3.4, 6.6 Hz), 4.32 and 4.45 (2H, ABq, J ) 11.9 Hz), 4.50 (2H,
s), 5.04 (1H, dd, J ) 3.3, 7.2 Hz), 5.61 (1H, d, J ) 6.6 Hz),
7.10-7.40 (10H, m); MS m/z (EI) 434 (M+ - C7H7, 0.4), 328
(M+ - C7H7 - C7H6O, 7.1). Anal. Calcd for C27H31O8N3: C,
61.71; H, 5.95. Found: C, 61.69; H, 6.09.
(b) F r om 12. To a solution of the azido alcohol 12 (0.1 g)
in dry CH2Cl2 (1 mL) were added excess Ac2O, Et3N, and a
catalytic amount of DMAP. The mixture was stirred for 1 h
at rt. The reaction mixture was quenched with H2O (1 mL),
washed with brine (2 × 10 mL), dried (MgSO4), and filtered,
and the filtrate was concentrated. Flash chromatography
purification of the crude product (hexane:Et2O, 1:1) afforded
the azido acetate 14 as a colorless syrup in 90% yield.
(1R,2S,3R,4S,5S)-2-Azid o-1,4,5-tr i-O-a cetyl-3-O-ben zyl-
5-((ben zyloxy)m eth yl)cycloh exa n e-1,3,4,5-tetr ol (15). To
a solution of the azido alcohol 13 (31 mg, 0.064 mmol) in dry
CH2Cl2 (5 mL) were added Ac2O (9.1 µL, 0.096 mmol), Et3N
(20.9 µL, 0.19 mmol), and a catalytic amount of DMAP. The
mixture was stirred for 1 h and then quenched with saturated
NH4Cl(aq) (1 mL), washed with brine (2 × 10 mL), dried
(MgSO4), and filtered and the filtrate concentrated. Flash
chromatography of the crude product (hexane:Et2O, 1:1) af-
forded the azido acetate 15 (29 mg, 86%) as a white amorphous
solid: TLC Rf 0.56 (Et2O:hexane 2:1); 1H NMR δ 1.75 (1H, dd,
J ) 12.3, 14.2 Hz), 1.89 (3H, s), 2.07 (3H, s), 2.10 (3H, s), 2.96
(1H, dd, J ) 4.8, 14.3 Hz), 3.58 (1H, t*, J ) 9.9 Hz), 3.59 and
3.98 (2H, ABq, J ) 8.9 Hz), 3.71 (1H, t*, J ) 9.8 Hz), 4.34 and
4.42 (2H, ABq, J ) 11.5 Hz), 4.63 and 4.84 (2H, ABq, J ) 11.0
Hz), 4.86 (1H, ddd, J ) 4.7, 9.9, 12.1 Hz), 5.30 (1H, d, J ) 9.7
Hz), 7.1-7.4 (10H, m) (*apparent splitting pattern).
(1R,2S,3R,4S,5S)-2-Azid o-3-O-b en zyl-5-((b en zyloxy)-
m eth yl)-cycloh exa n e-1,3,4,5-tetr ol (16). To a solution of
the diacetate 13 (0.47 g, 0.97 mmol) in MeOH (20 mL) was
added K2CO3 (0.1 g). The solution was stirred at rt for 1.5 h.
Then the solvent was evaporated, and H2O (20 mL) was added.
The aqueous phase was extracted with Et2O (2 × 20 mL), the
combined organic extracts were dried (MgSO4) and filtered,
and the filtrate was concentrated. The residue was purified
by flash chromatography (Et2O:hexane, 1:1) to afford the triol
16 (0.38 g, 100%) as a white solid: mp 100-101 °C; TLC Rf
1
(hexane:Et2O, 1:3); H NMR δ 1.95 (3H, s), 2.03 (3H, s), 2.39
(1H, dd, J ) 10.7, 14.7 Hz), 3.19 (1H, dd, J ) 6.5, 14.6 Hz),
3.64 and 3.90 (2H, ABq, J ) 9.2 Hz), 4.00 (1H, dd, J ) 3.8, 9.3
Hz), 4.37 and 4.47 (2H, ABq, J ) 12.1 Hz), 4.66 and 4.72 (2H,
ABq, J ) 12.1 Hz), 4.90 (1H, ddd, J ) 4.5, 6.5, 10.9 Hz), 5.20
(1H, t*, J ) 4.1 Hz), 5.52 (1H, d, J ) 9.4 Hz), 7.1-7.5 (10H,
m) (*apparent splitting pattern); MS m/z (EI) 429 (M+ - C7H7,
0.22), 323 (M+ - C7H7 - C7H6O, 1.79), 91 (100).
(1S,2R,3R,4S,5S)-1-Azid o-4,5-d i-O-a cetyl-3-O-ben zyl-5-
((ben zyloxy)m eth yl)cycloh exa n e-2,3,4,5-tetr ol (12). To a
solution of the hydroxy triflate 19 (185 mg, 0.031 mmol) in
dry DMF (8 mL) were added NaN3 (0.06 g, 0.92 mmol) and
benzo-15-crown-5 (0.27 g, 1.0 mmol). The mixture was stirred
overnight at rt and then diluted with CH2Cl2 (20 mL), washed
with brine (2 × 40 mL), dried (MgSO4), and filtered. Concen-
tration of the filtrate followed by flash chromatography (CHCl3:
MeOH:hexane, 3:5:65) afforded azido alcohol 12 (60%) as a
colorless syrup: TLC Rf 0.46 (hexane:Et2O, 1:2); [R]27 +9.9
D
1
(c ) 1.6, CHCl3); IR (neat) 3425, 2108, 1738.2 cm-1; H NMR
δ 2.00 (3H, s), 2.03 (3H, s), 2.37 (1H, br s), 2.39 (1H, br s),
2.57 (1H, br s), 3.6-3.7 (1H, m), 3.71 and 3.99 (2H, ABq, J )
9.8 Hz,), 3.8-3.9 (2H, m), 4.36 and 4.50 (2H, ABq, J ) 11.9
Hz), 4.58 and 4.69 (2H, ABq, J ) 11.5 Hz), 5.67(1H, d, J ) 6.7
Hz), 7.2-7.4 (10H, m); MS m/z (EI) 392 (M+ - C7H7, 3.36),
286 (M+ - C7H7 - C7H6O, 100), 376 (M+ - C7H7O, 4.02). Anal.
Calcd for C25H29O7N3: C, 62.10; H, 6.05; N, 8.69. Found: C,
62.14; H, 5.97; N, 8.59.
(1R,2S,3R,4S,5S)-2-Azid o-4,5-d i-O-a cetyl-3-O-ben zyl-5-
((ben yloxy)m eth yl)cycloh exa n e-1,3,4,5-tetr ol (13). To a
(40) Hofmann-Bang, N. Act. Chem. Scand. 1957, 11, 581.

8476 J . Org. Chem., Vol. 61, No. 24, 1996
Shing and Wan
0.28 (hexane:Et2O, 1:2); [R]25D -79.1 (c ) 0.9, CHCl3); IR (neat)
δ 1.95 (3H, s), 2.05 (3H, s), 2.17 (3H, s), 2.47 (1H, dd, J ) 12.6,
13.7 Hz), 2.96 (1H, ddd, J ) 0.59, 4.6, 13.8 Hz), 3.66 and 3.99
(2H, ABq, J ) 9.2 Hz), 3.78 (1H, dd, J ) 3.0, 10.1 Hz), 4.40
and 4.48 (2H, ABq, J ) 12.0 Hz), 4.43 and 4.71 (2H, ABq, J )
11.7 Hz), 4.94 (1H, ddd, J ) 3.1, 4.5, 12.6 Hz), 5.45 (1H, d, J
) 10.1 Hz), 5.85-5.92 (1H, m), 7.2-7.4 (10H, m).
1
3400, 2100 cm-1; H NMR δ 1.47 (1H, t*, J ) 12.3 Hz), 2.06
(1H, dd, J ) 4.8, 13.9 Hz), 2.50 (1H, br s), 2.81 (1H, br s), 2.89
(1H, br d, J ) 3.1 Hz), 3.25 (1H, t*, J ) 9.8 Hz), 3.42 (2H, s),
3.52 (1H, t*, J ) 9.4 Hz), 3.68 (1H, dd, J ) 2.6, 9.1 Hz), 3.65-
3.85 (1H, m), 4.51 (2H, s), 4.79 and 4.88 (2H, ABq, J ) 10.9
Hz), 7.2-7.5 (10H, m) (*apparent splitting pattern); MS m/z
(EI) 308.1 (M+ - C7H7, 1.03), 217.1 (M+ - 2C7H7, 0.14), 202
(M+- C7H7 - C7H6O, 0.44), 91 (100). Anal. Calcd for
C21H25O5N3: C, 63.15, H, 6.31, N, 10.52. Found: C, 63.3; H,
6.15; N, 10.43.
(1R,2S,3R,4S,5S)-2-Am in o-5-(h yd r oxym eth yl)cycloh ex-
a n e-1,3,4,5-tetr ol (17). To a solution of the azide 16 (538 mg,
0.135 mmol) in EtOH (15 mL) was added 20% Pd(OH)2 on
charcoal (0.4 g), and H2 was bubbled through the mixture with
stirring until no UV-active species was shown by TLC. The
solution was filtered through a pad of Celite and the filtrate
concentrated. Flash column chromatography (CHCl3:MeOH:
NH3(aq), 9:8:3) followed by purification with Amberlite CG-
50 (NH4+) gave the 2-amino-regioisomer 17 (18 mg, 70%) as a
white amorphous solid: TLC Rf 0.13 (CHCl3:MeOH:NH3(aq),
9:8:3); [R]21D -8.5 (c ) 0.6, H2O); IR (neat) 3333 cm-1; 1H NMR
(D2O) δ 1.60 (1H, t*, J ) 12.4, 13.0 Hz), 2.06 (1H, dd, J ) 4.6,
13.7 Hz), 2.89 (1H, J ) 10.4 Hz), 3.47 (1H, d, J ) 9.4 Hz),
3.47 and 3.56 (2H, ABq, J ) 11.5 Hz), 3.68 (1H, t*, J ) 9.9
Hz), 3.87 (1H, dt*, J ) 4.7, 0.7 Hz) (*apparent splitting
pattern); 13C NMR (D2O, dioxane at 67.39 ppm) δ 38.66, 60.19,
66.37, 66.70, 71.59, 74.14, 74.36; MS m/z (CI) 194 (M+ + 1,
100). Anal. Calcd for C7H17O6N‚0.2H2O: C, 42.72; H, 7.89;
N, 7.12. Found: C, 42.74; H, 7.92; N, 6.83.
(1S,2R,3R,4S,5S)-1-Azid o-3-O-b en zyl-5-((b en zyloxy)-
m eth yl)cycloh exa n e-2,3,4,5-tetr ol (21). (a ) F r om 14. To
solution of the azido acetate 14 (0.06 g, 0.11 mmol) in MeOH
(5 mL) was added K2CO3 (0.01 g). The solution was allowed
to stir at rt for 1.5 h. Then the solvent was evaporated, and
H2O (20 mL) was added. The aqueous phase was extracted
with Et2O (2 × 20 mL) and the combined organic phase was
dried (MgSO4) and filtered. Concentration of the filtrate
followed by flash chromatography (Et2O:hexane, 2:1) afforded
the triol 21 (33 mg, 72%) as a colorless syrup: TLC Rf 0.16
(hexane:Et2O, 1:1); [R]26 +29.1 (c ) 1.8, CHCl3); IR (neat)
D
3445, 2106 cm-1; H NMR δ 1.84 (1H, dd, J ) 6.5, 14.5 Hz),
1
2.03 (1H, dd, J ) 4.4, 14.5 Hz), 2.56 (1H, br d, J ) 3.7 Hz),
2.80 (1H, br s), 3.02 (1H, br s), 3.51 (2H, s), 3.71 (1H, dd, J )
6.2, 10.6 Hz), 3.83 (1H, dd, J ) 3.2, 7.0 Hz), 3.85-4.0 (2H, m),
4.48 and 4.55 (2H, ABq, J ) 12 Hz), 4.60 and 4.69 (2H, ABq,
J ) 11.5 Hz), 7.1-7.4 (10H, m); MS m/z (CI) 400 (M+ + 1,
1.91). Anal. Calcd for C21H25O5N3: C, 63.15; H, 6.31; N, 10.52.
Found: C, 63.37; H, 6.32; N, 10.45.
(b) F r om 12. To a solution of the azido alcohol 12 (21 mg,
0.043 mmol) in MeOH (5 mL) was added K2CO3 (5 mg). The
solution was allowed to stir at rt for 3 h. Then the solvent
was evaporated, and H2O (10 mL) was added. The aqueous
phase was extracted with Et2O (2 × 20 mL), and the combined
organic phase was dried (MgSO4), filtered, and concentrated
followed by flash chromatography (Et2O:hexane, 2:1) to afford
the triol 21 (15 mg, 80%) as a colorless syrup.
(1R ,2S ,3R ,4S ,5S )-2-Ace t a m id o-1,3,4-t r i-O-a ce t yl-5-
((a cetyloxy)m eth yl)-cycloh exa n e-1,3,4,5-tetr ol (18). To a
solution of the amino alcohol 17 (0.05 g) in pyridine (3 mL)
were added Ac2O (0.25 mL) and a catalytic amount of DMAP.
The reaction mixture was allowed to stir at rt overnight, and
the solvent was then removed under reduced pressure. The
crude product was purified by flash chromatography with 5%
MeOH in chloroform to afford N,O-pentaacetate 18 (78 mg,
75%) as a white solid: mp 200-201 °C; TLC Rf 0.27 (MeOH:
(1S,2R,3R,4S,5S)-1-N-Acet yl-2,3,4-t r i-O-a cet yl-5-((a c-
etyloxy)m eth yl)cycloh exa n e-2,3,4,5-tetr ol (22). To a solu-
tion of 3 (8 mg) in pyridine (2 mL) was added Ac2O (0.5 mL)
and a catalytic amount of DMAP. The reaction mixture was
stirred at rt overnight, and the solvent was removed under
reduced pressure. The residue was purified by flash chroma-
tography with 5% MeOH in chloroform to afford N,O-pentaac-
etate 22 (10 mg, 60%) as an amorphous solid: TLC Rf 0.29
CHCl3, 5:95); [R]27 -8.54 (c ) 0.8, CHCl3); IR (neat) 3400,
D
1747, 1666 cm-1
;
1H NMR δ 1.92 (3H, s), 2.03 (3H, s), 2.04
(MeOH:CHCl3, 5:95); [R]21 -18.1 (c ) 1.3, CHCl3); IR (neat)
(3H, s), 2.08 (3H, s), 2.10 (3H, s), 2.18 (1H, dd, J ) 4.8, 13.7
Hz), 3.36 (1H, br s), 3.86 and 4.03 (2H, ABq, J ) 11.4 Hz),
4.33 (1H, q*, J ) 10.2 Hz), 5.21 (1H, d, J ) 9.7 Hz), 5.30 (1H,
t*, J ) 9.9 Hz), 5.1-5.3 (1H, m), 6.13 (1H, br d, J ) 9.9 Hz,
D
3379, 1733, 1670 cm-1; 1H NMR (270 MHz) δ 1.97 (3H, s), 2.00
(3H, s), 2.09 (3H, s), 2.12 (3H, s), 2.13 (3H, s), 3.15 (1H, br s),
3.98 (2H, s), 4.1-4.2 (1H, m), 5.30 (1H, d, J ) 10.2 Hz), 5.37
(1H, t*, J ) 3.05 Hz), 5.42 (1H, dd, J ) 2.9, 10.2 Hz), 7.03
(1H, br d, J ) 7.8 Hz, NHAc) (*apparent splitting pattern);
MS m/z (CI) 404 (M+ + 1, 63.77).
NHAc) (*apparent splitting pattern); MS m/z (CI) 404 (M+
1, 70.75). Anal. Calcd for C17H25O10N: C, 50.62; H, 6.25; N,
3.47. Found: C, 50.24; H, 6.08; N, 3.35.
+
(1R,2S,3R,4S,5S)-4,5-Di-O-a cet yl-3-O-b en zyl-5-((b en -
zyloxy)m e t h yl)-1-O-(t r iflu or om e t h a n e su lfon yl)cyclo-
h exa n e-1,2,3,4,5-p en tol (19). To a solution of the 1,2-diol
10 (941 mg, 0.21 mmol) in dry CH2Cl2 (10 mL) at 0 °C were
added Tf2O (37 µL, 0.23 mmol) and pyridine (33 µL, 0.41
mmol). After 1 h, the mixture was quenched with H2O (1 mL),
washed with brine (2 × 10 mL), dried (MgSO4), and filtered
and the filtrate concentrated. Flash chromatography (hexane:
Et2O, 2:1) of the residue afforded the triflate 19 (115.5 mg,
93%) as white crystals: mp 100-101 °C; TLC Rf 0.33 (hexane:
(1R,2S,3R,4S,5S)-2,4,5-Tr i-O-a cetyl-3-O-ben zyl-5-((ben -
zyloxy)m eth yl)cycloh exa n e-1,2,3,4,5-p en tol (23). To a
solution of the cyclic sulfate 11 (53 mg, 0.01 mmol) in 5 mL
dry DMF (10 mL) was added Bun4NOAc (0.02 g, 0.05 mmol),
and the solution was stirred at rt for 6 h. The solvent was
evaporated, the residue was dissolved in THF (10 mL), and
10% H2SO4(aq) (5 mL) was added. The mixture was stirred
for 2 h, and then saturated Na2CO3(aq) (1 mL) solution was
added. The aqueous phase was extracted with Et2O (10 mL
× 2), the combined organic layer was dried (MgSO4) and
filtered, and the filtrate was concentrated. The crude product
was purified by flash chromatography (hexane:Et2O, 1:2) to
furnish the acetate 23 (43 mg, 85%) as a colorless syrup: TLC
Et2O, 3:2); [R]25 -19.1 (c ) 0.5, CHCl3); IR (neat) 3423, 1728
D
cm-1; H NMR δ 1.94 (3H, s), 2.07 (3H, s), 2.59 (1H, dd, J )
1
12.8, 13.4 Hz), 2.89 (1H, dd, J ) 4.4, 14.7 Hz), 3.66 and 3.97
(2H, ABq, J ) 9.1 Hz), 3.74 (1H, dd, J ) 2.7, 9.9 Hz), 4.37 and
4.46 (2H, ABq, J ) 11.7 Hz), 4.59 and 4.67 (2H, ABq, J ) 11.7
Hz), 24.89 (1H, ddd, J ) 2.8, 4.3, 12.4 Hz), 5.50 (1H, d, J )
9.9 Hz), 7.2-7.4 (10H, m).
Rf 0.24 (hexane:Et2O, 1:2); [R]21 -10.5 (c ) 0.4, CHCl3); IR
D
(neat) 3500 and 1745 cm-1; 1H NMR δ 1.73 (1H, dd, J ) 12.1,
14.5 Hz), 1.89 (3H, s), 2.02 (3H, s), 2.10 (3H, s), 2.99 (1H, dd,
J ) 4.8, 14.5 Hz), 3.67 and 3.95 (2H, ABq, J ) 9.0 Hz), 3.75
(1H, ddd, J ) 4.5, 9.4, 12.1 Hz), 3.85 (1H, t*, J ) 9.8 Hz), 4.37
and 4.44 (2H, ABq, J ) 11.5 Hz), 4.64 (2H, s), 4.96 (1H, t*, J
) 9.6 Hz), 5.29 (1H, d, J ) 10.0 Hz), 7.1-7.4 (10H, m)
(*apparent splitting pattern); MS m/z (EI) 409(M+ - C7H7),
303 (M+ - C7H7 - C7H6O, 100). Anal. Calcd for C27H32O9:
C, 64.79; H, 6.44. Found: C, 64.60; H, 6.47.
(1R,2S,3R,4S,5S)-2,4,5-Tr i-O-a cetyl-3-O-ben zyl-5-((ben -
zyloxy)m e t h yl)-1-O-(t r iflu or om e t h a n e su lfon yl)cyclo-
h exa n e-1,2,3,4,5-p en tol (20). To a solution of the alcohol 19
(116 mg, 0.20 mmol) in dry CH2Cl2 (8 mL) were added Ac2O
(92.8 mL, 0.98 mmol), pyridine (95.1 mL, 1.18 mmol), and a
catalytic amount of DMAP. The mixture was stirred for 0.5
h, quenched with H2O (1 mL), washed with brine (2 × 10 mL),
dried (MgSO4), and filtered, and the filtrate was concentrated.
Flash chromatography of the crude product (hexane:Et2O, 2:1)
afforded the triacetate 20 (0.11 g, 90%) as a colorless syrup:
TLC Rf 0.39 (hexane:Et2O, 1:1); IR (neat) 1754 cm-1; 1H NMR
(1S,2S,3R,4S,5S)-1,2,4-Tr i-O-a cetyl-3-O-ben zyl-5-((ben -
zyloxy)m eth yl)cycloh exan e-1,2,3,4,5-pen tol (25). (a) Fr om
26. To a solution of the mesylate 26 (26 mg) in DMF (2 mL)
was added an excess of Bun4NOAc. The solution was heated
to 100 °C for 1 d with stirring under N2. After cooling, the

Syntheses of Valiolamine and Its Diastereomers
J . Org. Chem., Vol. 61, No. 24, 1996 8477
solvent was removed under reduced pressure, and the crude
product was purified by flash chromatography (hexane:Et2O,
1:2) to afford 1,2,4-triacetate 25 (23 mg, 80%) as a colorless
added K2CO3 (58 mg). The solution was allowed to stir at rt
for 2 h, and the solvent was evaporated. The residue was
dissolved in Et2O (20 mL), washed with brine, dried (MgSO4),
and filtered and the filtrate concentrated. The residue was
purified by flash chromatography (hexane:Et2O, 1:1) to afford
the triol 29 (56 mg, 91%) as a colorless syrup: TLC Rf 0.17
syrup: TLC Rf 0.39 (hexane:Et2O, 1:2); [R]19 +20.0 (c ) 1.2,
D
CHCl3); IR (neat) 3450, 1744 cm-1; 1H NMR (250 MHz) δ 1.92
(3H, s), 1.96 (3H, s), 2.12 (3H, s), 3.25 and 3.32 (2H, ABq, J )
9.1 Hz), 4.15 (1H, t*, J ) 9.8 Hz), 4.42 and 4.48 (2H, ABq, J
) 11.6 Hz), 4.62 and 4.72 (2H, ABq, J ) 11.6 Hz), 4.96 (1H,
dd, J ) 3.4, 10.0 Hz), 5.18 (1H, d, J ) 9.6 Hz), 5.43 (1H, q*, J
) 3.4 Hz), 7.1-7.4 (10H, m) (*apparent splitting pattern); MS
m/z (EI) 393 (M+ - C7H7O), 303 (M+ - C7H7 - C7H6O).
(b) F r om 23. To a solution of the alcohol 23 (50 mg, 0.01
mmol) in dry CH2Cl2 (10 mL) at 0 °C were added Tf2O (3.8
mL, 0.024 mmol) and pyridine (3.4 µL, 0.042 mmol). The
mixture was warmed from 0 °C to rt in 3 h and then was
quenched with H2O (1 mL), washed with brine (2 × 10 mL),
dried (MgSO4), and filtered, and the filtrate concentrated.
Flash chromatography (hexane:Et2O, 1:2) of the crude residue
afforded the triacetate 25 (38 mg, 76%).
(hexane:Et2O, 1:1); [R]28 +12.7 (c ) 2.6, CHCl3); IR (neat)
D
3420, 2114 cm-1; H NMR δ 1.79 (1H, dd, J ) 3.8, 15.2 Hz),
1
1.94 (1H, dd, J ) 4.6, 15.2 Hz), 2.68 (1H, br d, J ) 5.8 Hz),
2.78 (1H, br s), 3.22 (1H, s), 3.25 and 3.44 (2H, ABq, J ) 9.2
Hz), 3.6-3.8 (3H, m), 3.90 (1H, q*, J ) 3.6 Hz), 4.45 (2H, s),
4.65 and 4.90 (2H, ABq, J ) 11.2 Hz), 7.1-7.4 (10H, m)
(*apparent splitting pattern); MS m/z (EI) 308 (M+ - C7H7,
1.38). Anal. Calcd for C21H25O5N3: C, 63.15; H, 6.31; N, 10.52.
Found: C, 62.90; H, 6.37; N, 10.26.
(1S,2S,3R,4S,5S)-1-N-Acet yl-2,3,4-t r i-O-a cet yl-5-((a c-
etyloxy)m eth yl)-cycloh exa n e-2,3,4,5-tetr ol (30). To a so-
lution of valiolamine (1) in pyridine (0.5 mL) were added Ac2O
(0.25 mL) and a catalytic amount of DMAP. The reaction
mixture was allowed to stir at rt overnight, and the solvent
was removed under reduced pressure. The crude product was
purified by flash chromatography with 5% MeOH in chloroform
to afford the pentaacetate 30 (29 mg, 70%) as a white solid:
mp 137-138 °C (lit.8 mp 137-138 °C); TLC Rf 0.26 (MeOH:
CHCl3, 5:95); [R]20 -17.8 (c ) 2.0, CHCl3) (lit.8 [R]25 -14.8
(1R,2R,3R,4S,5S)-2,4,5-Tr i-O-a cetyl-3-O-ben zyl-5-((ben -
zy lo x y )m e t h y l)-1-O -(m e t h a n e s u lfo n y l)c y c lo h e x a n e -
1,2,3,4,5-p en tol (26). To a solution of the alcohol 23 (33 mg,
0.066 mmol) in pyridine (1 mL) under N2 at 0 °C was added
MsCl (0.26 mmol). The reaction mixture was stirred for 10
min and quenched with H2O (10 mL). Then Et2O (10 mL) was
added, the mixture was washed with brine (2 × 10 mL), dried
(MgSO4), and filtered, and the filtrate was concentrated. Flash
chromatography (hexane:Et2O, 1:2) of the residue afforded the
mesylate 26 (31 mg, 80%) as a colorless syrup: TLC Rf 0.34
(hexane:Et2O, 1:2); [R]19D -4.35 (c ) 1.2, CHCl3); IR (neat) 1746
D
D
(c ) 1.0, CHCl3)); IR (neat) 3345, 1737, 1680 cm-1; 1H NMR δ
1.99 (6H, s), 2.02 (3H, s), 2.09 (3H, s), 2.10 (3H, s), 3.02 (1H,
s), 3.85 and 3.96 (2H, ABq, J ) 11.6 Hz), 4.7-4.8 (1H, m),
4.93 (1H, dd, J ) 4.4, 10.7 Hz), 5.08 (1H, d, J ) 9.8 Hz), 5.52
(1H, t*, J ) 10.3 Hz), 7.01 (1H, br d, J ) 8.7 Hz) (*apparent
splitting pattern); MS m/z (CI) 404 (M+ + 1, 9.98).
1
cm-1; H NMR δ 1.90 (3H, s), 2.00 (3H, s), 2.13 (3H, s), 2.97
(3H, s), 3.12 (1H, dd, J ) 5.0, 14.3 Hz), 3.61 and 3.98 (2H,
ABq, J ) 9.0 Hz), 3.89 (1H, t*, J ) 9.8 Hz), 4.37 and 4.44 (2H,
ABq, J ) 11.6 Hz), 4.62 (2H, s), 4.6-4.7 (1H, m), 5.23 (1H, t*,
J ) 9.7 Hz), 5.32 (1H, d, J ) 10.0 Hz), 7.1-7.4 (10H, m)
(*apparent splitting pattern); MS m/z (EI) 487 (M+ - C7H7,
0.16), 381 (M+ - C7H7 - C7H6O, 24.94).
(3R ,4S ,5S )-4,5-O-Ace t yl-3-O-b e n zyl-5-((b e n zyloxy)-
m eth yl)-1-cycloh exen e-3,4,5-tr iol (31). To a solution of the
diol 10 (0.4 g, 0.96 mmol) in toluene (50 mL) was added 1,1′-
(thiocarbonyl)diimidazole (0.19 g, 1.07 mmol). The reaction
mixture was heated to 90 °C for 1.5 h and then refluxed
overnight. Then saturated NH4Cl(aq) (50 mL) was added, and
the aqueous phase was extracted with Et2O (2 × 25 mL). The
combined extracts were washed with cold 0.1 N H2SO4(aq),
saturated KHCO3(aq), and brine, dried (MgSO4), and filtered.
Concentration of the filtrate followed by flash chromatography
(hexane:Et2O, 2:3) afforded the corresponding thiocarbonate
as a white solid (0.42 g, 87%), mp 68-70 °C. The thiocarbon-
ate was dissolved in P(OMe)3 (10 mL), and the solution was
refluxed for 24 h. Evaporation of the solvent under reduced
pressure followed by flash column chromatography (hexane:
Et2O, 2:1) furnished the alkene 31 (0.27 g, 74%) as a colorless
(1S,2R,3S,4S,5S)-1-Azid o-4,5-d i-O-a cetyl-3-O-ben zyl-5-
((ben zyloxy)m eth yl)-2-O-(tr iflu or om eth a n esu lfon yl)cy-
cloh exa n e-2,3,4,5-tetr ol (27). To a solution of the azido
alcohol 12 (105 mg, 0.22 mmol) in dry CH2Cl2 (10 mL) at 0 °C
were added Tf2O (0.18 mL, 1.08 mmol) and pyridine (0.18 mL,
2.17 mmol). The mixture was stirred for 10 min and quenched
with H2O (10 mL). Et2O (100 mL) was added, the organic
phase was washed with brine (2 × 10 mL), dried (MgSO4), and
filtered, and the filtrate was concentrated. Flash chromatog-
raphy of the crude (hexane:Et2O, 2:1) afforded the azido triflate
27 (0.12 g, 90%) as a colorless syrup: TLC Rf 0.40 (hexane:
syrup: TLC Rf 0.53 (hexane:Et2O, 1:1); [R]25 -50.6 (c ) 1.6,
D
Et2O, 3:2); [R]26 +11.0 (c ) 1.0, CHCl3); IR (neat) 2113, 1746
CHCl3); IR (neat) 3000-3200, 1746 cm-1; 1H NMR δ 1.93 (3H,
s), 1.94 (3H, s), 2.54 (1H, ddd, J ) 2.6, 4.4, 20.0 Hz), 2.82 (1H,
d, J ) 20.0 Hz), 3.81 and 3.94 (2H, ABq, J ) 9.6 Hz), 4.12-
4.20 (1H, m), 4.30 and 4.41 (2H, ABq, J ) 11.9 Hz), 4.57 (2H,
s), 5.56 (1H, d, J ) 6.1 Hz), 5.6-5.7 (2H, m), 7.1-7.30 (10H,
D
cm-1
;
1H δ 2.00 (3H, s), 2.03 (3H, s), 2.26 (1H, dd, J ) 8.5,
14.7 Hz), 2.59 (1H, dd, J ) 4.5, 14.2 Hz), 3.7-3.9 (1H, m), 3.82
and 4.00 (2H, ABq, J ) 10.3 Hz), 4.04 (1H, dd, J ) 3.3, 6.0
Hz), 4.33 and 4.51 (2H, ABq, J ) 12.0 Hz), 4.64 (2H, s), 4.82
(1H, dd, J ) 3.3, 8.1 Hz), 5.73 (1H, J ) 5.9 Hz), 7.1-7.5 (10H,
m).
m); MS m/z (EI) 333 (M+ - C7H7, 1.2), 227 (M+ - C7H7
-
C7H6O, 16.59), 242 (M+ - 2C7H7, 1.31), 91 (100). Anal. Calcd
for C25H28O6: C, 70.74; H, 6.65. Found: C, 70.98; H, 6.84.
(1S,2S,3R,4S,5S)-4,5-Di-O-a cet yl-3-O-b en zyl-5-((b en -
zyloxy)m eth yl)cycloh exa n e-1,2,3,4,5-p en tol (32). (a ) By
th e OsO4 Meth od . To a solution of the alkene 31 (0.23 g,
0.54 mmol), Me3NO (0.09 g, 0.76 mmol), pyridine (0.27 mL,
3.37 mmol), H2O (0.05 mL, 2.94 mmol) in ButOH (20 mL) was
added a catalytic amount of OsO4. The solution was refluxed
with stirring for 24 h under N2. After cooling, the reaction
mixture was quenched with saturated Na2S2O3(aq) solution
(20 mL) and was extracted with Et2O (2 × 20 mL). The organic
phase was filtered through a short column of silica gel and
the column eluted with Et2O (300 mL). Evaporation of solvent
followed by flash chromatography (hexane:Et2O, 1:3) afforded
the R-1,2-diol 10 (25 mg 10%), the starting material 31 (0.14
g, 60%), and the desired â-1,2-diol 32 (white solid, 50 mg,
(1S,2S,3R,4S,5S)-1-Azid o-2,4,5-tr i-O-a cetyl-3-O-ben zyl-
5-((ben zyloxy)m eth yl)cycloh exa n e-2,3,4,5-tetr ol (28). To
a solution of the azido triflate 27 (98 mg, 0.16 mmol) in dry
THF (20 mL) was added Bun4NOAc (0.14 g, 0.048 mmol), and
the solution was stirred for 1 h at rt. The solvent was removed
under reduced pressure and the residue purified by flash
chromatography (hexane:Et2O, 2:1) to afford the azido acetate
28 (67 mg, 80%) as a colorless syrup: TLC Rf 0.44 (hexane:
Et2O, 1:1); [R]25 -14.0 (c ) 1.5, CHCl3); IR (neat) 2102, 1743
D
cm-1; H NMR δ 1.91 (3H, s), 1.95 (1H, dd, J ) 3.7, 16.3 Hz),
1
2.04 (3H, s), 2.09 (3H, s), 3.04 (1H, dd, J ) 3.3, 15.9 Hz), 3.44
and 3.98 (2H, ABq, J ) 8.8 Hz), 4.13 (1H, t*, J ) 9.8 Hz),
4.1-4.2 (1H, m), 4.35 and 4.44 (2H, ABq, J ) 11.6 Hz), 4.66
and 4.73 (2H, ABq, J ) 11.7 Hz), 5.03 (1H, dd, J ) 4.1, 9.8
Hz), 5.29 (1H, d, J ) 9.7 Hz), 7.1-7.4 (10H, m) (*apparent
splitting pattern); MS m/z (EI) 328 (M+ - C7H7 - C7H6O,
43.49). Anal. Calcd for C27H31O8N3: C, 61.71; H, 5.95; N, 8.00.
Found: C, 61.61; H, 5.98; N, 7.92.
20%): mp 127-128 °C; TLC Rf 0.21 (hexane:Et2O, 1:2); [R]25
D
+21.9 (c ) 1.0, CHCl3); IR (neat) 3450, 1737 cm-1; 1H NMR δ
1.73 (1H, dd, J ) 2.8, 16 Hz), 1.96 (3H, s), 2.03 (3H, s), 2.54
(1H, br s), 2.75 (1H, br s), 3.13 (1H, dd, J ) 2.7, 16.0 Hz), 3.48
and 3.97 (2H, ABq, J ) 8.8 Hz), 3.62 (1H, dd, J ) 3.2, 9.2 Hz),
4.04 (1H, dd, J ) 9.2, 9.9 Hz), 4.1-4.2 (1H, m), 4.36 and 4.47
(1S,2S,3R,4S,5S)-1-Azid o-3-O-b en zyl-5-((b en zyloxy)-
m eth yl)cycloh exa n e-2,3,4,5-tetr ol (29). To a solution of the
azido acetate 28 (81 mg, 0.16 mmol) in MeOH (10 mL) was

8478 J . Org. Chem., Vol. 61, No. 24, 1996
Shing and Wan
(2H, ABq, J ) 11.7 Hz), 4.67 and 4.77 (2H, ABq, J ) 11.5 Hz),
5.27 (1H, d, J ) 9.9 Hz), 7.2-7.45 (10H, m); MS m/z (EI) 367
(M+ - C7H7, 18.36), 261 (M+ - C7H7 - C7H6O, 100). Anal.
Calcd for C25H30O8: C, 65.49; H, 6.60. Found: C, 65.03; H,
6.44.
(b) By th e Ru Cl3 Meth od . A solution of the alkene 31
(15 mg, 0.035 mmol) in (CCl4:CH3CN, 1:1) (5 mL) was cooled
to 0 °C. Then solution of NaIO4 (7.8 mg, 0.037 mmol) and a
catalytic amount of RuCl3‚H2O in H2O (5 mL) were added, and
the mixture was stirred vigorously for several min. Then
saturated Na2S2O3(aq) (2 mL) and Et2O (20 mL) were added.
The aqueous phase was extracted with Et2O (2 × 10 mL), the
combined organic extracts were washed with brine, dried
(MgSO4), filtered, and the filtrate was concentrated. Flash
chromatography (hexane:Et2O, 3:1) of the crude product af-
forded 32 (13 mg, 81%) as a white solid.
residue was dissolved in THF (20 mL), and 20% H2SO4(aq)
(2.5 mL) was added. The mixture was allowed to stir for 1 h
and then quenched with saturated Na2CO3(aq) solution (20
mL). The aqueous phase was extracted with Et2O (2 × 10 mL),
the combined extracts were dried (MgSO4) and filtered, and
the filtrate concentrated. The crude product was purified by
flash chromatography (hexane:Et2O, 1:1) to afford the hydroxy
azide 35 (0.03 g, 50%) as a colorless syrup: TLC Rf 0.37
(hexane:Et2O, 1:1); [R]27D -3.4 (c ) 0.9, CHCl3); IR (neat) 3470,
1
2105, 1739 cm-1; H NMR δ 1.62 (1H, dd, J ) 12.6, 14.7 Hz),
1.92 (3H, s), 2.12 (3H, s), 2.62 (1H, br d, J ) 2.4 Hz), 2.90 (1H,
dd, J ) 4.4, 14.6 Hz), 3.46 (1H, ddd, J ) 4.4, 9.6, 12.3 Hz),
3.59 (1H, dt*, J ) 2.4, 9.3 Hz), 3.62 and 3.94 (2H, ABq, J )
9.0 Hz), 3.73 (1H, dd, J ) 9.0, 9.8 Hz), 4.36 and 4.44 (1H, ABq,
J ) 11.6 Hz), 4.68 and 4.75 (1H, d, J ) 11.5 Hz), 5.21 (1H, d,
J ) 9.9 Hz), 7.1-7.4 (10H, m) (*apparent splitting pattern);
MS m/z (EI) 377 (M+ - C7H6O, 3.46), 286 (M+ - C7H7 - C7H6O,
1.76), 285 (M+ - C7H7 - C7H7O, 1.37), 91 (100). Anal. Calcd
for C25H29O7N3: C, 62.10; H, 6.05; N, 8.69. Found: C, 62.21;
H, 6.12; N, 8.33.
(1S,2S,3R,4S,5S)-2,4-Di-O-a cet yl-3-O-b en zyl-5-((b en -
zyloxy)m eth yl)cycloh exa n e-1,2,3,4,5-p en tol (33). To a
solution of the alkene 31 (0.26 g, 0.63 mmol), Me3NO (0.26 g,
2.33 mmol), pyridine (0.25 mL, 13.2 mmol), and H2O (56 µL,
3.15 mmol) in ButOH (3 mL) was added a catalytic amount of
OsO4. The solution was refluxed for 2 d under N2. After
cooling, the reaction mixture was quenched with saturated
aqueous Na2S2O3 solution (20 mL) and extracted with Et2O
(2 × 20 mL). The organic phase was filtered through a short
column of silica gel, and the column was eluted with Et2O (300
mL). The eluent was concentrated, and the residue was
purified by flash chromatography (hexane:Et2O, 1:3) to afford
the R-1,2-diol 10 (41 mg, 14%), the starting material 31 (0.12
g, 46%), and the acetyl-migrated â-1,5-diol 33 (85 mg, 29%)
as a white solid: mp 105-107 °C; TLC Rf 0.21 (hexane:Et2O,
(1R,2S,3R,4S,5S)-1-Azid o-3-O-b en zyl-5-((b en zyloxy)-
m eth yl)cycloh exa n e-2,3,4,5-tetr ol (36). (a ) F r om 35. To
a solution of the diacetate 35 (0.04 g, 0.083 mmol) in MeOH
(10 mL) was added K2CO3 (0.01 g). The solution was allowed
to stir at rt for 1.5 h. Then the solvent was evaporated, and
H2O (20 mL) was added. The aqueous phase was extracted
with Et2O (2 × 20 mL), and the combined organic phase was
dried (MgSO4) and filtered. Concentration of the filtrate
followed by flash chromatography (hexane:Et2O, 1:1) afforded
the triol 36 (0.029 g, 88%) as a colorless syrup: TLC Rf 0.3
(hexane:Et2O, 2:3); [R]23 -14.6 (c ) 1.0, CHCl3); IR (neat)
D
3450, 2103 cm-1; H NMR δ 1.41 (1H, t*, J ) 13.3 Hz), 2.03
1
1:2); [R]23 +21.5 (c ) 1.0, CHCl3); IR (neat) 3400, 1740 cm-1
;
D
1H NMR δ 1.79 (1H, dd, J ) 2.8, 15.2 Hz), 1.88 (3H, s), 2.06
(3H, s), 2.16 (1H, dd, J ) 3.4, 15.4 Hz), 3.27 and 3.35 (2H,
ABq, J ) 9.2 Hz), 3.53 (1H, s), 3.57 (1H, s), 4.18 (1H, t*, J )
10.0 Hz), 4.2-4.3 (1H, m), 4.42 and 4.48 (2H, ABq, J ) 11.4
Hz), 4.63 and 4.72 (2H, ABq, J ) 11.7 Hz), 4.89 (1H, dd, J )
3.1, 10.1 Hz), 5.15 (1H, d, J ) 9.8 Hz), 7.1-7.4 (10H, m)
(*apparent splitting pattern); MS m/z (EI) 367 (M+ - C7H7,
12.44), 276 (M+ - 2C7H7, 0.25), 261 (M+ - C7H7 - C7H6O,
59.12). Anal. Calcd for C25H30O8: C, 65.49; H, 6.60. Found:
C, 65.14; H, 6.4.
(1H, dd, J ) 4.5, 14 Hz), 2.68 (1H, br d, J ) 2.0 Hz), 2.83 (1H,
s), 2.88 (1H, d, J ) 3.08 Hz), 3.42 (3H, m), 3.54 (1H, t*, J )
8.9 Hz), 3.63 (1H, dd, J ) 2.8, 8.9 Hz), 3.74 (1H, ddd, J ) 4.7,
9.6, 12.4 Hz), 4.52 (2H, s), 4.84 (2H, ABq, J ) 11.5 Hz), 7.2-
7.5 (10H, m) (*apparent splitting pattern); MS m/z (CI) 400
(M+ + 1, 1.56). Anal. Calcd for C21H25O5N3: C, 63.15; H, 6.31;
N, 10.52. Found: C, 63.21; H, 6.46; N, 10.07.
(b) F r om 39. To a solution of the diacetate 39 (53 mg, 0.11
mmol) in MeOH (10 mL) was added K2CO3 (0.05 g), and the
resulting mixture was stirred at rt for 24 h. Then the solvent
was removed under reduced pressure, and Et2O (20 mL) was
added. The aqueous phase was extracted with Et2O (2 × 20
mL), the combined organic extracts were dried (MgSO4) and
filtered, and the filtrate was concentrated. The crude product
was purified by flash chromatography (hexane:Et2O, 1:1) to
afford 36 (0.04 g, 80%) as a colorless syrup.
(1S,2R,3S,4S,5S)-4,5-Di-O-a cet yl-3-O-b en zyl-5-((b en -
zyloxy)m eth yl)-1,2-O,O-su lfon ylcycloh exan e-1,2,3,4,5-pen -
tol (34). A solution of the â-1,2-diol 32 (0.08 g, 0.18 mmol)
and Et3N (76 µL, 0.69 mmol) in CH2Cl2 (15 mL) was cooled to
0 °C. Then SOCl2 (45 µL, 0.61 mmol) was added. The mixture
was allowed to stir for several min, and then cold Et2O (5 mL)
and cold water (15 mL) were added. The aqueous phase was
extracted with Et2O (2 × 10 mL), the combined extracts were
dried (MgSO4) and filtered, and the filtrate was concentrated.
The crude product was pumped under vacuum for 1 h. The
residue was dissolved in CCl4-CH3CN (1:1) (20 mL), and the
solution was cooled to 0 °C. Then NaIO4 (187 mg, 0.87 mmol),
H2O (10 mL), and a catalytic amount of RuCl3‚H2O were added
and the mixture stirred vigorously. After 1 h, Et2O (5 mL)
was added, and the aqueous phase was extracted by Et2O (2
× 10 mL). The combined organic extracts were washed with
brine, dried (MgSO4), and filtered. Concentration of the
filtrate followed by flash chromatography (hexane:Et2O, 2:1)
afforded the cyclic sulfate 34 (67 mg, 74%) as a white solid:
(1R,2S,3R,4S,5S)-1-N-Acet yl-2,3,4-t r i-O-a cet yl-5-((a c-
etyloxy)m eth yl)cycloh exa n e-2,3,4,5-tetr ol (37). To a solu-
tion of 2 (20 mg) in pyridine (2 mL) were added Ac2O (0.5 mL)
and a catalytic amount of DMAP. The reaction mixture was
allowed to stir at rt overnight, and the solvent was removed
under reduced pressure. The crude product was purified by
flash chromatography with 5% MeOH in chloroform to afford
N,O-pentaacetate 37 (33.4 mg, 80%) as a white solid: mp 231-
232 °C; TLC Rf 0.26 (MeOH:CHCl3, 5:95); [R]21 -14.2 (c )
D
1
2.3, CHCl3); IR (neat) 3386, 3274, 1731, 1660 cm-1; H NMR
(270 MHz) δ 1.58 (1H, t*, J ) 13.0 Hz), 1.91 (3H, s), 1.97 (3H,
s), 2.03 (3H, s), 2.05 (6H, s), 2.25 (1H, dd, J ) 4.6, 14.3 Hz),
3.65 (1H, br s), 3.79 and 4.01 (2H, ABq, J ) 11.1 Hz), 4.4-4.6
(1H, m), 4.93 (1H, t*, J ) 9.7 Hz), 5.05 (1H, d, J ) 10.0 Hz),
5.53 (1H, t*, J ) 10.0 Hz), 5.89 (1H, br s, NHAc) (*apparent
splitting pattern); MS m/z (CI) 404 (M+ + 1, 22.07). Anal.
Calcd for C17H25O10N: C, 50.62; H, 6.25; N, 3.47. Found: C,
50.35; H, 6.20; N, 3.34.
(1S,2R,3R,4S,5S)-2,4-Di-O-a cet yl-3-O-b en zyl-5-((b en -
zyloxy)m eth yl)-1,5-O,O-su lfon ylcycloh exan e-1,2,3,4,5-pen -
tol (38). A solution of the 1,3-diol 33 (85 mg, 0.17 mmol) and
Et3N (59 mg, 0.74 mmol) in CH2Cl2 (25 mL) was cooled to 0
°C. Then SOCl2 (0.03 g, 0.28 mmol) was added, and the
mixture was stirred for 15 min. Then cold Et2O (50 mL) and
cold water (25 mL) were added. The aqueous phase was
extracted with Et2O (100 mL), dried (MgSO4), and filtered, and
the filtrate concentrated. The crude product was pumped
under vacuum for 1 h. The residue was dissolved in CCl4-
mp 44-46 °C; TLC Rf 0.56 (hexane:Et2O, 1:3); [R]21 +42.2 (c
D
) 3.9, CHCl3); IR (neat) 1740 cm-1; H NMR δ 1.91 (3H, s),
1
2.07 (3H, s), 2.15 (1H, dd, J ) 3.8, 17.4 Hz), 3.43 and 4.05
(2H, ABq, J ) 8.7 Hz), 3.52 (1H, dd, J ) 1.7, 17.4 Hz), 4.33
and 4.47 (2H, ABq, J ) 11.8 Hz), 4.50 (1H, dd, J ) 7.8, 10.7
Hz), 4.64 and 4.84 (2H, ABq, J ) 11.5 Hz), 4.96 (1H, dd, J )
5.4, 7.9 Hz), 5.17-5.25 (1H, m), 5.25 (1H, d, J ) 10.6 Hz), 7.2-
7.4 (10H, m); MS m/z (EI) 413 (M+ - C7H7, 0.84), 323 (M+
-
C7H7 - C7H6O, 83.36). Anal. Calcd for C25H28O10S: C, 57.68,
H 5.42, S, 6.16. Found: C, 57.71; H, 5.46, S, 6.14.
(1R,2S,3R,4S,5S)-1-Azid o-4,5-d i-O-a cetyl-3-O-ben zyl-5-
(ben zyloxy)m eth yl)cycloh exa n e-2,3,4,5-tetr ol (35). To a
solution of the cyclic sulfate 34 (67 mg, 0.13 mmol) in dry DMF
(20 mL) was added LiN340 (33 mg, 0.52 mmol), and the solution
was stirred for 6 h at rt. The solvent was evaporated, the

Syntheses of Valiolamine and Its Diastereomers
J . Org. Chem., Vol. 61, No. 24, 1996 8479
CH3CN (1:1) (25 mL) and cooled to 0 °C. Then NaIO4 (0.12 g,
0.056 mmol), H2O (10 mL), and a catalytic amount of RuCl3‚H2O
were added, and the mixture was stirred vigorously. After 1
h, Et2O (50 mL) was added. The aqueous phase was extracted
with Et2O (100 mL), and the combined organic phase was
washed with brine, dried (MgSO4), and filtered. Concentration
of the filtrate followed by flash chromatography (hexane:Et2O,
1:1) afforded the cyclic sulfate 38 (77 mg, 80%) as a white
solid: mp 147-148 °C; TLC Rf 0.53 (hexane:Et2O, 1:2); IR
(1R,2R,3R,4S,5S)-1-Azid o-2,4,5-tr ia cetyl-3-O-ben zyl-5-
((ben zyloxy)m eth yl)cycloh exa n e-2,3,4,5-tetr ol (41). To a
solution of the triflate 40 (58 mg, 0.094 mmol) in dry THF (7
mL) was added Bun4NOAc (excess), and the solution was
stirred for 1 h at rt. The solvent was evaporated and the
residue was flash chromatographed (hexane:Et2O, 2:1) to give
the azido acetate 41 (47 mg, 95%) as a colorless syrup: TLC
Rf 0.40 (hexane:Et2O, 1:1); [R]29 -61.5 (c ) 0.7, CHCl3); IR
D
(neat) 2102, 1747 cm-1; H NMR δ 1.93 (3H, s), 2.05 (3H, s),
1
(neat) 1752 cm-1 1H NMR δ 1.94 (3H, s), 2.06 (3H, s), 2.15
;
2.18 (3H, s), 2.18 (1H, t*, J ) 12.3 Hz), 2.84 (1H, ddd, J ) 1.5,
4.3, 14.1 Hz), 3.44 (1H, ddd, J ) 2.8, 4.3, 13.0 Hz), 3.70 and
3.98 (2H, ABq, J ) 9.1 Hz), 3.73 (1H, dd, J ) 3.0, 10.2 Hz),
4.40 and 4.47 (2H, ABq, J ) 11.7 Hz), 4.42 and 4.71 (2H, ABq,
J ) 11.8 Hz), 5.40 (1H, d, J ) 10.2 Hz), 5.75 (1H, br), 7.33
(10H, m) (*apparent splitting pattern); MS m/z (EI) 328 (M+
(1H, d, J ) 16.5 Hz), 3.42 (1H, dd, J ) 4.8, 16.4 Hz), 3.50 (2H,
s), 4.25 (1H, t*, J ) 9.4 Hz), 4.43 and 4.53 (2H, ABq, J ) 11.6
Hz), 4.64 and 4.73 (2H, ABq, J ) 11.6 Hz), 4.96 (1H, dd, J )
2.1, 9.5 Hz), 5.11 (1H, m), 5.38 (1H, d, J ) 9.4 Hz), 7.1-7.5
(10H, m) (*apparent splitting pattern); MS m/z (EI) 429 (M+
- C7H7, 5.46), 323 (M+ - C7H7 - C7H6O, 39.08). Anal. Calcd
for C25H28O10S: C, 57.68; H, 5.42. Found: C, 57.36; H, 5.36.
(1R,2S,3R,4S,5S)-1-Azid o-2,4-d i-O-a cetyl-3-O-ben zyl-5-
((ben zyloxy)m eth yl)cycloh exa n e-2,3,4,5-tetr ol (39). To a
solution of the cyclic sulfate 38 (0.1 g, 0.21 mmol) in dry DMF
(10 mL) was added LiN340 (excess), and the solution was stirred
for 6 h. The solvent was evaporated, the residue was dissolved
in THF (10 mL), and 20% H2SO4(aq) (2 mL) was added. The
mixture was stirred for 1 h and then quenched with saturated
Na2CO3(aq) solution (10 mL). The aqueous phase was ex-
tracted with Et2O (2 × 20 mL), the combined phase was dried
(MgSO4) and filtered, and the filtrate was concentrated. Flash
chromatography of the crude product (Et2O:hexane, 3:1) af-
forded the azido alcohol 39 (82 mg, 80%) as a white solid: mp
- C7H7 - C7H6O, 25.16), 91 (100). Anal. Calcd for C27H31
-
O8N3: C, 61.71; H, 5.95; N, 8.00. Found: C, 61.88; H, 6.08;
N, 7.73.
(1R,2R,3R,4S,5S)-1-Azid o-3-O-b en zyl-5-((b en zyloxy)-
m eth yl)cycloh exa n e-2,3,4,5-tetr ol (42). To a solution of the
triacetate 41 (52 mg, 0.1 mmol) in MeOH (10 mL) was added
K2CO3 (0.05 g). The solution was allowed to stir at rt for 1.5
h, and the solvent was removed under reduced pressure. The
residue was dissolved in Et2O (20 mL), washed with brine,
dried (MgSO4), and filtered. Concentration of the filtrate
followed by flash chromatography (hexane:Et2O, 1:1) afforded
the triol 42 (32 mg, 73%) as a white solid: mp 100-102 °C;
TLC Rf 0.29 (hexane:Et2O, 1:1); [R]21 -47.9 (c ) 2.2, CHCl3);
D
1
IR (neat) 3492, 3415, 3344, 2104 cm-1; H NMR δ 1.88 (1H,
98-100 °C: TLC Rf (hexane:Et2O, 1:1); [R]21 +14.0 (c ) 0.4,
D
dd, J ) 4.4, 13.3 Hz), 2.07 (1H, t*, J ) 12.9 Hz), 2.48 (1H, br
s), 2.80 (1H, br s), 2.85 (1H, br d, J ) 2.5 Hz), 3.44 and 3.49
(2H, ABq, J ) 9.2 Hz), 3.49 (1H, dd, J ) 2.5, 10.6 Hz), 3.58
(1H, ddd, J ) 2.4, 4.4, 12.3 Hz), 3.93 (1H, dd, J ) 2.0, 9.2 Hz),
4.20 (1H, br s), 4.53 (2H, s), 4.63 and 4.69 (2H, ABq, J ) 11.7
Hz), 7.20-7.40 (10H, m) (*apparent splitting pattern); MS m/z
(CI) 400 (M+ + 1, 3.19). Anal. Calcd for C21H25O5N3: C, 63.15;
H, 6.31; N, 10.52. Found: C, 63.10; H, 6.36; N, 10.37.
CHCl3); IR (neat) 3408, 2101, 1740 cm-1; 1H NMR δ 1.51 (1H,
t*, J ) 12.8 Hz), 1.84 (3H, s), 2.01 (3H, s), 2.12 (1H, dd, J )
4.7, 14.0 Hz), 2.80 (1H, s), 3.27 and 3.39 (2H, ABq, J ) 9.1
Hz), 3.84 (1H, ddt*, J ) 4.7, 10.2, 12.4 Hz), 3.90 (1H, t*, J )
9.7 Hz), 4.44 (2H, s), 4.59 (2H, s), 5.05 (1H, t*, J ) 9.9 Hz,
H-2), 5.05 (1H, d, J ) 9.8 Hz), 7.1-7.4 (10H, m) (*apparent
splitting pattern); MS m/z (CI) 484 (M+ + 1, 16.0). Anal.
Calcd for C25H29O7N3: C, 62.10; H, 6.05; N, 8.69. Found: C,
61.99; H, 6.00; N, 8.41.
(1R,2R,3R,4S,5S)-1-N-Acet yl-2,3,4-t r i-O-a cet yl-5-((a c-
etyloxy)m eth yl)cycloh exa n e-2,3,4,5-tetr ol (43). To a solu-
tion of 4 (10 mg, 0.052 mmol) in pyridine (2 mL) were added
Ac2O (0.25 mL) and a catalytic amount of DMAP. The reaction
mixture was allowed to stir at rt overnight, and the solvent
was removed under reduced pressure. The crude product was
purified by flash chromatography with 5% MeOH in chloroform
to afford N,O-pentaacetate 43 (16.7 mg, 80%) as a white
(1R,2S,3S,4S,5S)-1-Azid o-4,5-d i-O-a cetyl-3-O-ben zyl-5-
((ben zyloxy)m eth yl)-2-O-(tr iflu or om eth a n esu lfon yl)cy-
cloh exa n e-2,3,4,5-tetr ol (40). To a solution of the alcohol
35 (57.8 mg, 0.12 mmol) in dry CH2Cl2 (10 mL) at 0 °C were
added Tf2O (0.2 mL, 1.22 mmol) and pyridine (0.2 mL, 2.44
mmol). The mixture was stirred for 1 h, quenched with H2O
(10 mL), washed with brine (2 × 10 mL), dried (MgSO4), and
filtered and the filtrate concentrated. Flash chromatography
of the crude residue (hexane:Et2O, 2:1) afforded the triflate
40 (58 mg, 78%) as a colorless syrup: TLC Rf 0.57 (hexane:
solid: mp 273-275 °C; TLC Rf 0.19 (MeOH:CHCl3, 5:95); [R]22
D
-15.6 (c ) 0.6, CHCl3); IR (neat) 3422, 1728, 1660 cm-1; H
1
NMR δ 1.96 (6H, s), 2.10 (6H, s), 2.28 (3H, s), 2.94 (1H, br s),
3.91 and 4.02 (2H, ABq, J ) 11.4 Hz), 4.6-4.7 (1H, m), 5.26
(1H, d, J ) 10.3 Hz), 5.34 (1H, dd, J ) 2.7, 10.4 Hz), 5.45-
5.55 (2H, m); MS m/z (CI) 404 (M+ + 1, 36.68).
Et2O, 1:1); [R]28 -20.0 (c ) 0.6, CHCl3); IR (neat) 2111, 1747
D
cm-1; 1H NMR δ 1.82 (3H, s), 1.82 (1H, t*, J ) 12.8 Hz), 2.15
(3H, s), 3.12 (1H, dd, J ) 4.9, 14.8 Hz), 3.61 and 3.95 (2H,
ABq, J ) 9.0 Hz), 3.67 (1H, ddd, J ) 4.8, 10.1, 12.8 Hz), 3.95
(1H, t*, J ) 9.8 Hz), 4.35 and 4.43 (2H, ABq, J ) 11.5 Hz),
4.59 and 4.84 (2H, ABq, J ) 10.8 Hz), 4.66 (1H, t*, J ) 9.8
Hz), 5.28 (1H, d, J ) 10.0 Hz), 7.25-7.40 (10H, m) (*apparent
splitting pattern).
Ack n ow led gm en t. This research was supported by
the RGC Earmarked Grant (Ref. No. CUHK69/92E)
J O9607828