Total synthesis of quercitols: (+)- allo -, (-)- proto -, (+)- talo -, (-)- gala -, (+)- gala -, neo -, and (-)- epi -quercitol

Article abstract of DOI:10.1055/s-0034-1379603

The cyclohexenenones exo- and endo-2 were converted into the cyclohexenyl acetates exo- and endo-3 and exo- and endo-5 with a diastereoselectivity of >99:1 (2 steps). Ether cleavage with DDQ in CH₂Cl₂/H₂O (20:1) and in situ ketal hydrolysis afforded the cyclohexenones 6 and 7 in up to 83% and 87% yield, respectively. Compound 6 was converted into (+)-allo- and (-)-proto-quercitol with a diastereoselectivity of 100:0 (4 steps). Moreover, 6 was carried on to (-)-talo-quercitol whereas 7 furnished the four remaining title quercitols (3-5 steps) including both enantiomers of gala-quercitol.

Full text of DOI:10.1055/s-0034-1379603

SYNLETT
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
© Georg Thieme Verlag Stuttgart · New York
2015, 26, 250–258
letter
250
J. Aucktor, R. Brückner
Letter
Synlett
Total Synthesis of Quercitols: (+)-allo-, (–)-proto-, (+)-talo-,
(–)-gala-, (+)-gala-, neo-, and (–)-epi-Quercitol
Johannes Aucktor
BzO
O
PMP
R and S
O
OH
*
*
3 or 4 steps
Reinhard Brückner*
R
PMP
R
O
H
R
O
O
Institut für Organische Chemie, Albert-Ludwigs-Universität
Freiburg, Albertstr. 21, 79104 Freiburg, Germany
reinhard.brueckner@organik.chemie.uni-freiburg.de
OH
HO
HO
OH
AcO
R and S
OH
3–5 steps
3 steps
ds > 99:1
*
*
*
*
*
*
*
OH
O
OH
Received: 25.09.2014
Accepted after revision: 29.10.2014
Published online: 17.12.2014
exo- and endo-3 under Mitsunobu conditions (inversion of
configuration; this work, Scheme 1) and into the diastereo-
meric acetates exo- and endo-5 by standard esterification
(retention of configuration,1 Scheme 1). We then cleaved
their PMB ethers explicitly and the remaining ketal moi-
eties en passant (see details below). This delivered the ste-
reopure cyclohexenonediol monoacetates 6 and 7. We cre-
ated a glycol moiety from their C2=C3 bond and a hydroxy
group from their C1=O bond. The result was that the sp2
centers of monoacetates 6 and 7 had given way to 1,2,3-tri-
ol motifs. Ammonolyses in methanol liberated (+)-allo-
quercitol (8a),3 (–)-proto-quercitol (8b4),5 and (+)-talo-
quercitol (8c4)6 from follow-up products of the cyclohexen-
onediol monoacetate 6. Analogous ammonolyses released
(–)-gala-quercitol (8d),7 (+)-gala-quercitol (depicted in
Scheme 6),8 neo-quercitol (8e),9 and (–)-epi-quercitol (8f)10
from follow-up products of the diastereomeric cyclohexen-
onediol monoacetate 7.
In our route to quercitols 8 we abolished the tricyclic
cyclohexanetriol triacetates of our previous communica-
tion.1 Instead, we took to the cyclohexenonediol monoace-
tates 6 and 7 as precursors. This change was caused by the
following observations: Cleaving the benzylic C–O bond in
the 1,4-dioxane moiety of several of the mentioned tricyclic
cyclohexanetriol triacetates 41 with DDQ,11–13 and benzoy-
lation rendered ketone-substituted spiroketals 9 alright
(Scheme 2; for details, see footnote 14). However, they
marked dead-ends for our endeavor. This is because they
could not be hydrolyzed to the underlying cyclohexanones
11.15 Their resilience is plausibly due to the destabilization
of the carboxonium ion intermediate 10 – via which the hy-
drolysis of ketal 9 should proceed – by the acyloxy substitu-
ents highlighted in Scheme 2. Replacing one of them by an
OH group and the other by a C=C bond the structure of car-
boxonium ion 14 is derived. Since an OH group is less elec-
tron withdrawing than an acyloxy substituent and a C=C
bond other than an acyloxy substituent donates electron
density, the carboxonium ion 14 should be more stable
than 10. From this consideration we inferred that type-13
spiroketals might be amenable to hydrolyses.
DOI: 10.1055/s-0034-1379603; Art ID: st-2014-b0804-l
Abstract The cyclohexenenones exo- and endo-2 were converted into
the cyclohexenyl acetates exo- and endo-3 and exo- and endo-5 with a
diastereoselectivity of >99:1 (2 steps). Ether cleavage with DDQ in
CH2Cl2/H2O (20:1) and in situ ketal hydrolysis afforded the cyclohexen-
ones 6 and 7 in up to 83% and 87% yield, respectively. Compound 6 was
converted into (+)-allo- and (–)-proto-quercitol with a diastereoselectiv-
ity of 100:0 (4 steps). Moreover, 6 was carried on to (–)-talo-quercitol
whereas 7 furnished the four remaining title quercitols (3–5 steps) in-
cluding both enantiomers of gala-quercitol.
Key words cyclohexenones, diastereoselectivity, ether cleavage,
α-hydroxy ketone, oxidation, reduction
Recently, we described six- and five-step syntheses, re-
spectively, of the enantiomerically pure cyclohexenones
exo-2 and endo-2 (Scheme 1).1 Starting from hydroquinone
monobenzoate and trans-4-(4-methoxyphenyl)but-3-en-1-
ol, we prepared the enantiopure key intermediate diol 1 by
a Mitsunobu etherification and an asymmetric Sharpless
dihydroxylation. Elaborating the diol 1 into the cyclohexen-
ones 2 entailed an oxidative cyclization with PhI(O2CCF3)2
and an intramolecular oxa-Michael addition.
Upon treatment with LiAlH4 the cyclohexenones exo-
and endo-2 afforded the cyclohexenols exo- and endo-4
with perfect stereocontrol (Scheme 1).1 The scaffolds, of
which these substructures make part, allowed to dihydrox-
ylate their C=C bonds and reduce their C=O bonds stereose-
lectively. This provided tricyclic cyclohexanetriol triace-
tates1 41 (for their formulas, see Scheme 8, footnote 14).
They looked like precursors of cyclohexitols (= polyhydrox-
ycyclohexanes and -hexenes) in general and of quercitols
(= pentahydroxycyclohexanes) more specifically.2
However, proceeding from 2-based tricycles to querci-
tols required avoiding the tricyclic cyclohexanetriol triace-
tates mentioned above. Therefore, we reversed the original-
ly anticipated order of C=C bond functionalization and
protecting-group removal.1 Accordingly, we began by trans-
forming the cyclohexenols exo- and endo-4 into the acetates
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J. Aucktor, R. Brückner
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PMP
BzO
O
PMP
H
HO
HO
O
*
H
O
O
O
PMP = para-methoxyphenyl
4 steps
PMP
PMP
1
exo-2 (> 99% ee):
endo-2 (> 99% ee):
ref. 1
(> 99.9% ee;
from asymmetric
dihydroxylation)
3 steps
LiAlH4 (stereospecific)1
AcO
PMP HO
a)
PMP AcO
PMP
O
O
O
O
O
O
*
*
*
Ac2O
ds >
H
cat.
H
H
99:1
DMAP1
O
O
O
PMP
PMP
PMP
PMP
PMP
PMP
exo-5:
exo-3:
exo-4:
endo-4:
endo-5:
endo-3:
AcO
OH
O
AcO
OH
O
this study´s objectives
3
3
1
2
1
2
6
7
HO
HO
OH
OH
HO
HO
OH
OH
HO
HO
OH
OH
OH
OH
(–)-proto-quercitol (8b)4
OH
(+)-talo-quercitol (8c)4
(+)-allo-quercitol (8a)
HO
OH
HO
OH
HO
HO
OH
OH
HO
OH
HO
OH
OH
(–)-gala-quercitol (8d)
OH
(–)-epi-quercitol (8f)
OH
neo-quercitol (8e)
Scheme 1 Targeting quercitols 8 from the cyclohexenones exo- and endo-21 via the cyclohexenyl acetates exo- and endo-3 (new; → 8a–c) or exo- and
endo-5 (known;1 → 8d–f). Reagents and conditions: (a) For exo-3: AcOH (1.5 equiv), DIAD (1.3 equiv), Ph3P (1.3 equiv), THF, r.t., 30 min; 91%. For endo-3:
AcOH (1.5 equiv), DIAD (1.3 equiv), Ph3P (1.3 equiv), THF, 0 °C, 15 min; 93%. DIAD = diisopropyl azodicarboxylate.
DDQ11–13 in CH2Cl2/H2O (20:1) cleaved the benzylic C–O
bond in the respective 1,4-dioxane moiety of the tricyclic
cyclohexenyl acetates exo-3/endo-3 and exo-5/endo-5
(Scheme 3). To our surprise as much as delight these sub-
strates reacted beyond the type-13 spiroketal stage. The
only substrate, which rendered a spiroketal – besides nearly
70% overreaction – was exo-3; it gave 22% 17 after three
days. The major product or exclusive products were the cy-
clohexenonediol monoacetates 6 (starting from 3) and 7
(starting from 5). This implies that the spiroketals 17 and
18, which resulted along with one equivalent of the acidic16
hydroquinone 16 from the oxidation step, hydrolyzed in
situ in the water-containing reaction mixtures. Complete
hydrolyses took six days starting from exo-3 or endo-3 (→ 6)
and three days starting from exo-5 or endo-5 (→ 7). The fi-
nal products 6 and 7 were best obtained from endo-3 (83%
yield) and from exo-5 (87% yield), respectively. They served
as precursors of all quercitols obtained in the sequel. These
were, from 6: (+)-allo-quercitol (8a), (–)-proto-quercitol
(8b, both Scheme 4), and (+)-talo-quercitol (8c, Scheme 5);
from 7: (–)-gala-quercitol (8d) plus (+)-gala-quercitol (ent-
8d, both Scheme 6), neo-quercitol (8e), and (–)-epi-querci-
tol (8f, both Scheme 7).
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 250–258

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J. Aucktor, R. Brückner
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Scheme 2 Hydrolysis suppression vs. hydrolysis support by substituents with a –I vs. +M effect in the carboxonium ions 10 and 14, respectively. Car-
boxonium ions 10 and 14 are expected to form in the rate-determining step of the elusive hydrolyses of type-9 ketals (the preparation of which is
described in footnote 14) vs. the ready hydrolyses of type-13 ketals (the preparation of which became part of the present study).
OH
Cl
Cl
CN
CN
AcO
PMP
H
AcO
PMP
H
O
O
O
O
OH
16
(pKa = 5.14)16
O
O
a)
b)
exo-3
exo-5
AcO
OH
O
AcO
OH
O
O
O
PMP
PMP
O
O
17
18
(not observed)
a) a)
(contd)
b)
(contd)
b)
AcO
PMP
H
AcO
PMP
H
O
O
O
O
O
O
endo-3
endo-5
AcO
OH
AcO
OH
O
O
6
7
Scheme 3 Deprotection of cyclohexenyl acetates 3 and 5 through DDQ-induced tandem oxidations (→ spiroketals 17 and 18)/in situ hydrolyses (→
cyclohexenones 6 and 7). Reagents and conditions: (a) DDQ (1.2 equiv), CH2Cl2/H2O (20:1), r.t.; 27% 17, <70% 6 (impure) from exo-3 after 3 d; or no 17
and 81% 6 from exo-3 after 6 d, respectively; 83% 6 from endo-3 after 6 d. (b) DDQ (1.2 equiv), CH2Cl2/H2O (20:1), r.t., 3 d; 87% 7 (from exo-5); 82% 7
(from endo-5). DDQ = dichlorodicyanobenzoquinone.
Scheme 4 shows how we converted the cyclohexenone-
diol monoacetate 6 with perfect stereoselectivity into (–)-
proto-quercitol (8b) using either of two different pathways.
They converged after three steps at (–)-proto-quercitol pen-
taacetate (25), and the latter furnished (–)-proto-quercitol
(8b)5 quantitatively by ammonolysis in methanol.17–19 The
pentaacetate 25 was reached from 6 either in 87% overall
yield by the step order reduction (→ 19), acetylation (→
2020–22), and dihydroxylation–acetylation, or in 39% overall
yield by the step order acetylation (→ 21), dihydroxylation
(→ 23), and reduction–acetylation. The dihydroxylations
both of cyclohexene 20 and of cyclohexenone 21 were per-
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J. Aucktor, R. Brückner
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AcO
OH
OH
AcO
OAc
OAc
AcO
AcO
OH
a)
b)
ds = 100:0
O
19
20
6
c)
d) ds = 100:0
OAc
AcO
HO
OAc
O
OAc
21
OH
22
e) ds = 100:0
OAc
d) contd
AcO
AcO
OAc
AcO
HO
AcO
HO
OAc
OH
f)
f) contd
ds = 100:0
OAc
O
OAc
OH
OH
23
24
25
h)
g) ds = 100:0
OAc
HO
HO
OH
OH
HO
HO
OH
AcO
AcO
h)
OH
OH
OAc
OH
OAc
(+)-allo-quercitol (8a)
[α]D = +34.9
(−)-proto-quercitol (8b)4
[α]D = −27.1
26
(c 1.0, H2O)
(c 0.61, H2O)
Scheme 4 Preparation of (+)-allo-quercitol (8a) and (–)-proto-quercitol (8b). Reagents and conditions: (a) Me4N+ –BH(OAc)3 (2.0 equiv), AcOH (2.0
equiv), MeCN, 0 °C to r.t., 15 h; 91%. (b) Ac2O (4.0 equiv), DMAP (20 mol%), pyridine (5.0 equiv), CH2Cl2, r.t., 20 h; 96%. (c) AcCl (1.5 equiv), DMAP (15
mol%), pyridine (2.0 equiv), CH2Cl2, r.t., 2 h; 87%. (d) K2OsO2(OH)4 (5 mol%), citric acid (2.0 equiv), NMO (1.5 equiv), t-BuOH/H2O (1:1), r.t., 1 h; Ac2O
(4.0 equiv), DMAP (20 mol-%), pyridine (5.0 equiv.), CH2Cl2, r.t., 15 h; 99%. (e) K2OsO2(OH)4 (5 mol%), citric acid (2.0 equiv), NMO (1.5 equiv.), t-BuOH/H2O
(1:1), r.t., 2 h; 77%. (f) Me4N+ –BH(OAc)3 (2.0 equiv), AcOH (4.0 equiv), MeCN, 0 °C to r.t., 5 h; aqueous workup; Ac2O (28 equiv), DMAP (0.5 equiv),
pyridine (34 equiv), THF, reflux, 15 h; 58%. (g) LiBH(s-Bu)3 (4.0 equiv), THF, –78 °C to –10 °C, 5 h; Ac2O (27 equiv), DMAP (0.5 equiv), r.t., 15 h; 71%. (h)
NH3 (gas), MeOH, r.t., 3 h; 100% (for 8a and 8b, respectively). DMAP = 4-(dimethylamino)pyridine; NMO = N-methylmorpholine-N-oxide.
formed with Sharpless’ OsO4/NMO/citric acid protocol,23
even if 20 would have subsided also to other oxidants.24,25
Carbonyl reduction in either pathway to (–)-proto-quercitol
Scheme 5 starts with the closest we came to a stereo-
complementary reduction of the cyclohexenonediol mono-
acetate 6. With Me4N+ –BH(OAc)3,26 6 had given the cis-1,2-
diol 19 selectively (Scheme 4). Indeed, whatever the reduc-
pentaacetate (25) was effected using Me4N+ –BH(OAc)3 as
26
30
an ‘OH-directable’ reductant. The respective substrates,
namely the cyclohexenone 6 and the cyclohexanone 23,
rendered exclusively the desired trans-1,2-diol units in the
resulting cyclohexene 19 and cyclohexane 24. This could be
expected on grounds of literature precedence.26
tant was, 19 formed preferentially. At best NaBH4/CaCl2
delivered a 62:38 mixture of the unavoidable cis-1,2-diol 19
and the desired trans-1,2-diol 27. Separation by flash chro-
matography on silica gel31 furnished 30% of the latter. After
acetylation to the cyclohexene triacetate 30,32 dihydroxyl-
ation with OsO4/NMO/citric acid23 exhibited little stereo-
control. This was plausible since the allylic acetoxy groups
The cyclohexanone 23 was a precursor not only of syn-
thetic (–)-proto-quercitol (8b) but of synthetic (+)-allo-
quercitol (8a),3 too (Scheme 4). This is because LiBH(s-Bu)3
flank the C=C bond of substrate 30 from opposite sides.33
A
27
reduced the cyclohexanone 23 with perfect stereocomple-
mentarity relative to Me4N+ –BH(OAc)3.26 This reduction and
an ensuing acetylation afforded 71% of the (+)-allo-quercitol
pentaacetate 26.3 Ammonolysis28 led to (+)-allo-quercitol
(8a)3 in 100% yield.29
78:22 mixture of diastereomeric diols 29 and 28 resulted in
91% yield. Inseparable by flash chromatography,31 the major
diol 29 was obtained diastereomerically pure by crystalliza-
tion from Et2O in 67% yield. Its ammonolysis delivered
(+)-talo-quercitol (8c)6 in 98% yield.18,34
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J. Aucktor, R. Brückner
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AcO
OH
O
AcO
OH
OH
AcO
OH
OH
AcO
AcO
OAc
O
AcO
AcO
OH
O
a)
c)
a)
+
dr =
62:38
(diastereoisomers
separated
chromatographically)
7
31
b)
27
6
19
(separable by
chromatography)
b)
OR1
OR2
OAc
OAc
AcO
OAc
+
dr =
40:60
AcO
HO
OAc
OAc
AcO
HO
OAc
OAc
AcO
OAc
OAc
c)
+
OH
33a (R1 = Ac, R2 = H)
33b (R1 = H, R2 = Ac)
32
34
ds =
dr =
22:78
30
OH
28
OH
ds =
d)
(inseparable by
chromatography)
29
e)
100:0
100:0
(purified by
HO
HO
OH
OH
crystallization)
AcO
HO
OAc
HO
HO
OH
OH
HO
HO
OH
f)
d)
OAc
OH
OH
(+)-talo-quercitol (8c)4
[α]D = +55.8
OH
35
OH
OH
(–)-gala-quercitol
(8d)
(+)-gala-quercitol
(ent-8d)
(c 0.90, H2O)
[α]D = −50.0
[α]D = +50.8
(c 1.0, H2O)
(c 0.45, H2O)
Scheme 5 Preparation of (+)-talo-quercitol (8c). Reagents and condi-
tions: (a) NaBH4 (0.5-fold molar amount), CaCl2 (1.0 equiv), MeOH, –20 °C,
30 min; 50% 19 and 30% 27 after separation by flash chromatography.
(b) Ac2O (4 equiv), DMAP (15 mol%), pyridine (6 equiv), CH2Cl2, r.t., 3 h;
94%. (c) K2OsO2(OH)4 (5 mol%), citric acid (2.0 equiv), NMO (1.5 equiv),
t-BuOH/H2O (1:1), r.t., 2 h; 91% of a 22:78 mixture of 28 and 29; the
latter (67% yield) was obtained diastereomerically pure by crystalliza-
tion from Et2O, whereas 28 (86:14 dr, 23% yield) was isolated from the
mother liquors. (d) NH3 (gas), MeOH, r.t., 1 h; 98%.
Scheme 6 Preparation of both enantiomers of gala-quercitol (8d). Re-
agents and conditions: (a) AcCl (1.5 equiv), DMAP (15 mol%), pyridine
(2.0 equiv), CH2Cl2, r.t., 2 h; 82%. (b) NaBH4 (0.4-fold molar amount),
MeOH, –20 °C, 45 min; 38% of an inseparable 43:57 mixture of 33a and
33b chromatographically separated from 57% 34. (c) Ac2O (2.0 equiv),
DMAP (15 mol%), pyridine (3.0 equiv), CH2Cl2, r.t., 6 h; 98%. (d)
K2OsO2(OH)4 (5 mol%), citric acid (2.0 equiv), NMO (1.5 equiv), t-BuOH/
H2O (1:1), r.t., 1 h; 99%. e) H2O2 (30% aqueous solution, 3.8 equiv),
HCO2H, r.t., 2 d; NH3 (gas), MeOH, r.t., 3 h; 98%. (f) NH3 (gas), MeOH,
r.t., 2 h; 94%.
The cyclohexenonediol monoacetate 7 allowed us to
embark on the pair of quercitol syntheses shown in Scheme
6. They provide, as one desires, either (–)-gala-quercitol
(8d) or (+)-gala-quercitol (ent-8d) and are ‘enantiodiver-
gent’ therefore. The diacetate 31, prepared from monoace-
tate 7 in 82% yield, and NaBH4 reacted to give a mixture of
alcohols. It contained a major diastereomer 34, a minor dia-
stereomer 33a, and its ‘regioisomer’ 33b, which resulted
from 33a by an acyl shift. Flash chromatography on silica
gel31 rendered the diacetate 34 in 57% yield and a 43:57
mixture of the ‘regioisomeric’ diacetates 33a and 33b in
38% yield; acetylation allowed this mixture to converge as
triacetate 3235–37 (98% yield).
Finishing our synthetic quercitols 8d and ent-8d re-
quired dihydroxylating the C=C bond of triacetate 32 cis-se-
lectively and the C=C bond of diacetate 34 trans-selectively
(Scheme 6). The cis-dihydroxylation of triacetate 32 was ac-
complished by the OsO4/NMO/citric acid procedure of Sharp-
less et al.23. As a single product we obtained glycol 3538,39
(99% yield). Its ammonolysis furnished (–)-gala-quercitol
(8d6a–c,7) in 94% yield.40 The trans-dihydroxylation of diace-
tate 34 was realized with H2O2 (30%) in formic acid.41 This
mixture reacts by peracid formation, epoxidation, SN2 ring
opening by HCO2H, and subsequent (partial) formylation of
OH groups.42 The resulting mixture was ammonolyzed to
isolate (+)-gala-quercitol (ent-8d)8 as a single diastereoiso-
mer in 98% yield.43
The cyclohexenetriol diacetate 34 (preparation: Scheme
6) was coerced into giving two further quercitols. As de-
tailed in Scheme 7, this started with forming the corre-
sponding cyclohexenetriol triacetate 38. If a diastereoselec-
tive cis-dihydroxylation of its C=C bond had been possible,
we would have advanced readily to neo-quercitol (8e) or to
(–)-epi-quercitol (8f). Such diastereoselectivities remained
elusive, however. The present study rather underscores that
cis-vic-dihydroxylations of cyclohexenes, which contain
two allylic O–H or O–acyl substituents, are highly diastereo-
selective only if they are cis substituents, yet lack diastereo-
control otherwise. This is illustrated by the dihydroxyl-
ations of cyclohexenes 20 (Scheme 4) and 32 (Scheme 6) vs.
30 (Scheme 5) and 38 (Scheme 7): A dihydroxylation of the
cyclohexene 38 by the OsO4/NMO/citric acid protocol23 pro-
vided a 59:41 mixture (98% of the diastereomeric diols 39
and 40).44 This ratio did not change substantially when the
cyclohexene 38 was subjected to Sharpless’ asymmetric di-
hydroxylation conditions:45 In the presence of (DHQ)2PHAL
(ingredient of AD-mix a45a,b) and NaHCO3 a mixture of diols
39 and 40 resulted, which, after acetylation of the crude
product, gave a 42:58 mixture46) of pentaacetates 368b,9e
and 37.7f,47 Employing (DHQD)2PHAL (ingredient of AD-
mix β45a,b), a 52:48 mixture of the pentaacetates 36 and 37
was obtained.48
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J. Aucktor, R. Brückner
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AcO
OAc
AcO
AcO
OAc
OAc
AcO
AcO
OAc
OAc
+
OH
34
OAc
OAc
(inseparable by
chromatography)
(synthesis: Scheme 6)
36
37
(purified by
a)
crystallization,
see caption c)
b)
c) or
d) or
e)
AcO
OAc
OAc
AcO
OAc
AcO
OAc
OAc
+
dr39:40
HO
OAc
HO
c)
d)
e)
59:41
42:58
52:48
38
OH
OH
(inseparable by
chromatography)
39
40
(purified by
crystallization)
g)
f)
HO
OH
HO
HO
OH
OH
HO
OH
OH
OH
neo-quercitol (8e)
(−)-epi-quercitol (8f)
(dr = 98:2)
[α]D = −6.8
(meso)
(c 0.40, H2O)
Scheme 7 Preparation of neo-quercitol (8e) and (–)-epi-quercitol (8f). Reagents and conditions: (a) Ac2O (2.0 equiv), DMAP (15 mol%), pyridine (3.0
equiv), CH2Cl2, r.t., 6 h; 98%. (b) For a 59:41 mixture of 39 and 40: Ac2O (8 equiv), DMAP (15 mol%), pyridine (12 equiv), CH2Cl2, r.t., 15 h; 98% of a
59:41 mixture of 36 and 37, from which only 36 (54% yield) was obtained diastereomerically pure by crystallization from Et2O–pentane (1:2), whereas
37 (93:7 dr, 44% yield) was isolated from the mother liquors. (c) K2OsO2(OH)4 (5 mol%), citric acid (2.0 equiv), NMO (1.5 equiv), t-BuOH/H2O (1:1), r.t.,
1 h; 98% of a 59:41 mixture of 39 and 40, from which 39 was obtained diastereomerically pure by crystallization from Et2O. (d) K2OsO2(OH)4 (2 mol%),
(DHQ)2PHAL (4 mol%), PhSO2NH2 (1.0 equiv), K3Fe(CN)6 (3.0 equiv), K2CO3 (3.0 equiv), NaHCO3 (3.0 equiv), t-BuOH/H2O (1:1), 0 °C, 5 d; 16% of starting
material recovered by chromatography; acetylation of crude product: Ac2O, DMAP, pyridine, CH2Cl2, r.t., 15 h; 27% of a 42:58 mixture of 36 and 37.46
(e) Same as (d), but (DHQD)2PHAL (4 mol%) instead of (DHQ)2PHAL; 28% of a 52:48 mixture of 36 and 37, 10% of starting material recovered by chro-
matography. (f) NH3 (gas), MeOH, r.t., 1 h; 100%. (g) Starting from a 93:7 mixture of 37 and 36: NH3 (gas), MeOH, r.t., 1 h; crude product: 97% of a 93:7
mixture of 8f and 8e; after crystallization from MeOH: 73% of a 98:2 mixture of 8f and 8e.
The diols 39 and 40 were inseparable by flash chroma-
tography on silica gel;31 gratifyingly, the major diol 39 crys-
tallized from Et2O diastereomerically pure (Scheme 7). Its
ammonolysis provided neo-quercitol (8e)9 diastereomeri-
cally pure in quantitative yield.49,50 Acetylation of the 59:41
mixture of the diastereomeric diols 39 and 40 (obtained by
the OsO4/NMO/citric acid protocol) gave a 59:41 mixture of
the corresponding pentaacetates 36 and 37.47 Crystalliza-
tion from Et2O gave the pure major pentaacetate 36 in 54%
yield; the mother liquors rendered the minor pentaacetate
37 with 93:7 diasteromeric ratio in 44% yield. Ammonolysis
of this compound followed by crystallization from metha-
nol gave (–)-epi-quercitol (8f)10 with 98:2 diasteromeric ra-
tio in 73% yield.49,51
mations were often, but not always, highly stereoselective.
Stereocontrol might improve if the C=C bond functionaliza-
tions could be performed prior to cleaving the tricyclic scaf-
fold. With that goal in mind it might be worthwhile to in-
vestigate the reductive cleavage of the C–O bond of all tricy-
clic PMB ethers, at which we had not looked previously.1,15
Supporting Information
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0034-1379603.
S
u
p
p
o
nrtIo
g
f
rmoaitn
S
u
p
p
ortiInfogrmoaitn
References and Notes
We demonstrated that the tricyclic cyclohexenones exo-
2 and endo-2 are progenitors of the cyclohexenonediol
monoacetates 6 and 7. These, compounds in turn, served as
progenitors of three dextrorotatory quercitols (8a, 8c, ent-
8d), three levorotatory quercitols (8b, 8d, 8f), and one
meso-configured quercitol (8e).52 The underlying transfor-
(1) Aucktor, J.; Anselmi, C.; Brückner, R.; Keller, M. Synlett 2014, 25,
1312.
(2) (a) Reviews: Hudlicky, T.; Cebulak, M. Cyclitols and their Deriva-
tives: A Handbook of Physical, Spectral, and Synthetic Data;
Verlag Chemie: Weinheim, 1993. (b) Gueltekin, M. S.; Celik, M.;
Balci, M. Curr. Org. Chem. 2004, 8, 1159.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 250–258

256
J. Aucktor, R. Brückner
Letter
Synlett
(3) Synthesis of (+)-allo-quercitol (8a): Yadav, J. S.; Maiti, A.;
Sankar, A. R.; Kunwar, A. C. J. Org. Chem. 2001, 66, 8370.
(4) C-3 of this compound represents a chirotopic nonstereogenic
center. Because of the latter attribute it suffices to connect C-3
and 3-OH by an ‘ordinary bond’ rather than by a wedge or by
hatches.
(5) Syntheses of (–)-proto-quercitol (8b): (a) McCasland, G. E.;
Naumann, M. O.; Durham, L. J. J. Org. Chem. 1968, 33, 4220.
(b) Angyal, S. J.; Odier, L. Carbohydr. Res. 1982, 101, 209.
(c) Gültekin, M. S.; Çelik, M.; Turkut, E.; Tanyeli, C.; Balci, M. Tet-
rahedron: Asymmetry 2004, 15, 453; corrigendum: Tetrahedron:
Asymmetry 2004, 15, 1959.
(6) Syntheses of (+)-talo-quercitol (8c): (a) McCasland, G. E.;
Furuta, S.; Johnson, L. F.; Shoolery, J. N. J. Am. Chem. Soc. 1961,
83, 2335. (b) Angelaud, R.; Babot, O.; Charvat, T.; Landais, Y.
J. Org. Chem. 1999, 64, 9613. (c) Hydloft, L.; Madsen, R. J. Am.
Chem. Soc. 2000, 122, 8444. (d) Ref. 3.
(7) Syntheses of (–)-gala-quercitol (8d): (a) Ref. 6a. (b) Dubreuil, D.;
Cleophax, J.; Vieira de Almeida, M.; Verre-Sebrié, C.; Liaigre, J.;
Vass, G.; Gero, S. D. Tetrahedron 1997, 53, 16747. (c) Ref. 6b.
(d) Maezaki, N.; Nagahashi, N.; Yoshigami, R.; Iwata, C.; Tanaka,
T. Tetrahedron Lett. 1999, 40, 3781. (e) Ref. 6c. (f) Shih, T.-L.; Lin,
Y.-L. Synth. Commun. 2005, 35, 1809. (g) Murugan, A.; Yadav, A.
K.; Gurjar, M. K. Tetrahedron Lett. 2005, 46, 6235.
(8) Syntheses of (+)-gala-quercitol (ent-8d): (a) Ref. 5b. (b) Shih,
T.-L.; Lin, Y.-L.; Kuo, W.-S. Tetrahedron 2005, 61, 1919.
(9) Syntheses of neo-quercitol (8e): (a) Ref. 5b. (b) Kühlmeyer, R.;
Keller, R.; Schwesinger, R.; Netscher, T.; Fritz, H.; Prinzbach, H.
Chem. Ber. 1984, 117, 1765. (c) Ref. 8b. (d) Murali, C.; Gurale, B.
P.; Shashindhar, M. S. Eur. J. Org. Chem. 2010, 755. (e) Aydin, G.;
Savran, T.; Aktaş, F.; Baran, A.; Balci, M. Org. Biomol. Chem. 2013,
11, 1511.
(10) Syntheses of (–)-epi-quercitol (8f): (a) Ref. 7b. (b) Biamonte, M.
A.; Vasella, A. Helv. Chim. Acta 1998, 81, 688. (c) Horne, G.;
Potter, B. V. L. Chem. Eur. J. 2001, 7, 80. (d) Ref. 7f; therein 8f was
referred to as dextrorotatory. In accordance therewith, syn-
thetic ent-8f was referred to as levorotatory in ref. 8b. The two
findings disagree with our synthetic 8f being levorotatory
(Scheme 7).
1) DDQ
(1.2 equiv),
CH2Cl2/H2O
(20:1),
PMP
r.t., 1 d
AcO
AcO
AcO
AcO
OBz
O
O
O
O
9
8
*
*
PMP
7
H
*
2) PhCOCl
(1.5 equiv),
DMAP
(15 mol%),
pyridine,
r.t., 15 h
O
O
AcO
AcO
41a–e
9a–e
9
Configuration at
C-7 C-8 C-9
Yield
(2 steps)
a
b
c
d
e
(S) (S) (S)
(S) (S) (R)
(S) (R) (R)
(R) (R) (S)
(R) (R) (R)
96%
97%
87%
87%
87%
Scheme 8
(15) (a) In the tricyclic cyclohexanetriol triacetate 41b (which now
rendered the spiroketal 9b by oxidative cleavage as depicted in
Scheme 8) we had been able to cleave1 the benzylic C–O bond
by an ionic hydrogenolysis with Et3SiH/F3CCO2H.15b We then
effected a benzylic bromination, whereupon treatment with Zn
induced a reductive elimination; it ring-opened the spiroketal
moiety.1 The scope and limitations of that approach have not
yet been investigated. (b) Ma, Z.; Hu, H.; Xiong, W.; Zhai, H.
Tetrahedron 2007, 63, 7523.
(16) pKa1 of DDQ-H2 (16): Akutagawa, T.; Saito, G. Bull. Chem. Soc.
Jpn. 1995, 68, 1753.
(17) Ammonolysis of pentaacetate rac-25: see ref. 22c.
(18) In the present work we terminated the synthesis of each querci-
tol by an ammonolysis, the substrate of which was a pentaace-
tate (Scheme 4: 25 → 8g, 26 → 8a; Scheme 7: 37 → 8f), a triace-
tate (Scheme 5: 29 → 8c; Scheme 6: 35 → 8d; Scheme 7: 39 →
8e) or a mixed oligocarboxylate (Scheme 6; post-34 → ent-8d).
Each ammonolysis was executed under conditions described by
Balci et al.22c for two analogous ammonolyses.
(19) NMR Data of (–)-proto-Quercitol (8b, Figure 1)
1H NMR (500 MHz, D2O):  = 1.80 (ddd, Jgem = 14.0 Hz, J6-Hax,1
=
(11) DDQ oxidations of primary PMB ethers of primary or secondary
alcohols giving p-methoxybenzaldehyde plus these alcohols:
Oikawa, Y.; Yoshioka, T.; Yonemitsu, O. Tetrahedron Lett. 1982,
23, 885.
11.7 Hz, J6-Hax,5 = 3.1 Hz, 1 H, 6-Hax), 1.98 (dddd, Jgem = 14.0 Hz,
J6-Heq,1 = 4.8 Hz, J6-Heq,5 = 3.3 Hz, 4J6-Heq,4 = 1.2 Hz, 1 H, 6-Heq), 3.55
(dd, J2,3 = 9.7 Hz, J2,1 = 9.1 Hz, 1 H, 2-H), 3.70 (dd, J3,2 = 9.7 Hz,
J3,4 = 3.3 Hz, 1 H, 3-H), 3.74 (ddd, J1,6-Hax = 11.7 Hz, J1,2 = 9.1 Hz,
J1,6-Heq = 4.8 Hz, 1 H, 1-H), 3.92 (ddd, J4,5 = 3.6 Hz, J4,3 = 3.3 Hz,
4J4,6-Heq = 1.2 Hz, 1 H, 4-H), 4.01 (ddd, J5,4 = 3.6 Hz, J5,6-Heq = 3.3
Hz, J5,6-Hax = 3.1 Hz, 1 H, 5-H) ppm.
(12) DDQ oxidations of secondary PMB ethers (specifically: p-
methoxybenzhydryl ethers) of primary alcohols giving p-
methoxybenzophenone plus these alcohols: Sharma, G. V. M.;
Prasad, T. R.; Rakesh, S. B. Synth. Commun. 2004, 34, 941.
(13) DDQ oxidations of secondary PMB esters of carboxylic acids
giving p-methoxyacetophenone plus these carboxylic acids:
Yoo, S.-E.; Kim, H. R.; Yi, K. Y. Tetrahedron Lett. 1990, 31, 5913.
(14) The benzylic C–O bond in the 1,4-dioxane moieties of the tri-
cyclic cyclohexanetriol triacetates1 41 was cleaved with DDQ in
CH2Cl2/H2O (20:1), and the resulting alcohols were benzoylated.
This provided the nonhydrolyzable spiroketals 9a–e in overall
yields around 90% (Scheme 8).
6
HO
HO
OH
OH
5
OH
1
2
1
6
5
OH
OH
3
4
4
OH2
3
8b
OH
OH
Figure 1
(20) Preparation of cyclohexenetriol triacetate 20 from cyclohexa-
1,4-diene by an oxidation to endo-peroxide/hydroperoxide and
an enzymatic kinetic resolution: see ref. 5c.
(21) Preparation of cyclohexenetriol triacetate ent-20 from D-(–)-quinic
acid: Shih, T.-L.; Kuo, W.-S.; Lin, Y.-L. Tetrahedron Lett. 2004, 45,
5751.
(22) Syntheses of cyclohexenetriol triacetate rac-20 from cyclohexa-
1,4-diene: (a) Seçen, H.; Salamci, E.; Sütbeyaz, Y.; Balci, M.
Synlett 1993, 609. (b) Gültekin, M. S.; Salamci, E.; Balci, M. Car-
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257
J. Aucktor, R. Brückner
Letter
Synlett
6
bohydr. Res. 2003, 338, 1615. (c) Salamci, E.; Seçen, H.; Sütbeyaz,
Y.; Balci, M. J. Org. Chem. 1997, 62, 2453. (d) Salamci, E.; Seçen,
H.; Sütbeyaz, Y.; Balci, M. Synth. Commun. 1997, 27, 2223.
(23) Method: Dupau, P.; Epple, R.; Thomas, A. A.; Fokin, V. V.;
Sharpless, K. B. Adv. Synth. Catal. 2002, 344, 421.
OH
1
HO
HO
OH
OH
5
4
1
6
5
OH
4
HO
3
2
3
2
HO
OH
8c
OH
(24) Dihydroxylation of cyclohexenetriol triacetate 20 with OsO4/
N-methylmorpholine-N-oxide: see ref. 5c.
(25) Dihydroxylations of cyclohexenetriol triacetates ent-20 and rac-
20 with KMnO4: see ref. 21, 22a,c.
Figure 3
(35) For a different synthesis of cyclohexenetriol triacetate 32: see
ref. 32.
(36) Synthesis of cyclohexenetriol triacetate ent-32 from D-(–)-quinic
acid: see ref. 8b.
(37) Synthesis of cyclohexenetriol triacetate rac-32 from cyclohexa-
1,4-diene: see ref. 22c.
(38) Dihydroxylation of cyclohexenetriol triacetate rac-32 with
OsO4/NMO: see ref. 22c.
(26) OH-Directed triacetoxyborohydride reductions of β-hydroxyke-
tones were studied in depth by (a) Evans, D. A.; Chapman, K. T.
Tetrahedron Lett. 1986, 27, 5939. (b) Evans, D. A.; Chapman, K.
T.; Carreira, E. M. J. Am. Chem. Soc. 1988, 110, 3560. OH-Directed
diastereoselective triacetoxyborohydride reduction of an
α-hydroxycyclohexenone: (c) Bao, X.; Cao, Y.-X.; Chu, W.-D.;
Qu, H.; Du, J.-Y.; Zhao, X.-H.; Ma, X.-Y.; Wang, C.-T.; Fan, C.-A.
Angew. Chem. Int. Ed. 2013, 52, 14167. OH-Directed diastereose-
lective triacetoxyborohydride reduction of an α-hydroxybi-
cyclo[2.2.2]octanone: (d) Griffith, D. R.; Botta, L.; St Denis, T. G.;
Snyder, S. A. J. Org. Chem. 2014, 79, 88. OH-Directed diastereose-
lective triacetoxyborohydride reduction of a 4-hydroxydihydro-
2H-pyran-3(4H)-one: (e) Shangguan, N.; Kiren, S.; Williams, L. J.
Org. Lett. 2007, 9, 1093.
(39) Dihydroxylations of cyclohexenetriol triacetate ent-32 with
KMnO4 or RuO4: see ref. 8b.
(40) NMR Data of (–)-gala-Quercitol (8d, Figure 4)
1H NMR (500 MHz, D2O):  = 1.72 (ddd, Jgem = 12.3 Hz, J6-Hax,5
=
11.4 Hz, J6-Hax,1 = 10.6 Hz, 1 H, 6-Hax), 2.00 (dddd, Jgem = 12.3 Hz,
J6-Heq,1 = 4.6 Hz, J6-Heq,5 = 4.4 Hz, 4J6-Heq,4 = 1.3 Hz, 1 H, 6-Heq), 3.67
(dd, J2,1 = 9.1 Hz, J2,3 = 3.2 Hz, 1 H, 2-H), 3.79 (ddd, J1,6-Hax = 10.6
Hz, J1,2 = 9.1 Hz, J1,6-Heq = 4.6 Hz, 1 H, 1-H), 3.92 (ddd, J4,3 = 4.3 Hz,
J4,5 = 3.1 Hz, 4J4,6-Heq = 1.3 Hz, 1 H, 4-H), 4.00 (dd, J3,4 = 4.3 Hz, J3,2
= 3.2 Hz, 1 H, 3-H), 4.01 (ddd, J5,6-Hax = 11.4 Hz, J5,6-Heq = 4.4 Hz,
J5,4 = 3.1 Hz, 1 H, 5-H) ppm.
(27) Example for stereocomplementary diastereoselective α-hydroxy-
cyclohexanone reductions with LiBH(s-Bu)3 vs. triacyloxyboro-
hydride: Breit, B.; Bigot, A. Chem. Commun. 2008, 6498.
(28) The ammonolysis of the pentaacetate ent-26 was described in
ref. 8b.
6
1
HO
HO
5
4
OH
OH
6 OH
1
5
HO
HO
OH
(29) NMR Data of (+)-allo-Quercitol (8a, Figure 2)
3
4
3
1H NMR (500 MHz, D2O; 323 K): δ = 1.59 (ddd, Jgem = 14.1 Hz,
J6-Hax,5 = 9.4 Hz, J6-Hax,1 = 3.3 Hz, 1 H, 6-Hax), 2.12 (ddd, Jgem = 14.1
Hz, J6-Heq,1 = 6.1 Hz, J6-Heq,5 = 4.4 Hz, 1 H, 6-Heq), 3.56 (dd, J4,5 = 8.0
Hz, J4,3 = 3.1 Hz, 1 H, 4-H), 3.79 (dd, J2,3 = 3.1 Hz, J2,1 = 3.1 Hz, 1 H,
2-H), 4.01 (ddd, J3,2 = 3.1 Hz, J3,4 = 3.1 Hz, 4J3,1 = 1.3 Hz, 1 H, 3-H),
4.03 (ddd, J5,6-Hax = 9.4 Hz, J5,4 = 8.0 Hz, J5,6-Heq = 4.4 Hz, 1 H, 5-H),
4.05 (dddd, J1,6-Heq = 6.1 Hz, J1,6-Hax = 3.3 Hz, J1,2 = 3.1 Hz, 4J1,3 = 1.3
Hz, 1 H, 1-H) ppm.
2
2
8d
OH
OH
Figure 4
(41) Method: (a) Adkins, H.; Roebuck, A. K. J. Am. Chem. Soc. 1948, 70,
4041. (b) Ogawa, S.; Aoki, Y.; Takagaki, T. Carbohydr. Res. 1987,
164, 499. (c) Doddi, V. R.; Kumar, A.; Vankar, Y. D. Tetrahedron
2008, 54, 9117.
(42) In principle, the epoxidation of cyclohexenol 34 may lead to the
syn- and/or the anti-epoxide (Scheme 9). If the Fürst–Plattner
rule is respected, the ring opening of either epoxide should
deliver the respective ‘diaxially substituted dihydroxyformate’
initially, that is, compounds 43 and iso-43, respectively. In the
sequel, each of these dihydroxyformates would furnish (+)-
gala-quercitol (ent-8d).
6
HO
HO
5
OH
OH
1
2
6
2
1
OH
5
3
HO
3
4 O
H
4
HO
8a
OH
OH
Figure 2
(30) Method: Fujii, H.; Oshima, K.; Utimoto, K. Chem. Lett. 1991,
1847.
(31) Still, W. C.; Kahn, M.; Mitra, A. J. Org. Chem. 1978, 43, 2923.
(32) Synthesis of cyclohexenetriol triacetate 30 by an asymmetric
eliminative epoxide opening: de Sousa, S. E.; O’Brien, P.;
Pilgram, C. D. Tetrahedron 2002, 58, 4643.
(33) Dihydroxylations of cyclohexenetriol triacetate ent-30 with
KMnO4 or RuO4 gave an almost 1:1 ratio of the corresponding
glycols ent-28 and ent-29; after peracetylation, the combined
overall yield was 74%, see ref. 8b.
(34) NMR Data of (+)-talo-Quercitol (8c, Figure 3)
1H NMR (500 MHz, D2O, 313 K):  = 1.82–1.92 (m, 2 H, 6-H2),
3.71 (dd, J4,3 = 9.9 Hz, J4,5 = 3.1 Hz, 1 H, 4-H), 3.75 (dd, J3,4 = 9.9
pseudo-eq
OAc
pseudo-eq
OAc
AcO
OAc
OH
AcO
HCO3H
AcO
and/or
OH
OH
O
O
34
syn-42
HCO2H
eq / ax
anti-42
HCO2H
eq / ax
AcO
OAc
AcO
HO
OAc
HO
HO
OH
OH
and/or
HCO2
OH
OH
HCO2
OH
OH
Hz, J3,2 = 2.7 Hz, 1 H, 3-H), 3.99 (ddd, J1,6-Hax = 10.6 Hz, J1,6-Heq
=
(+)-gala-quercitol
(ent-8d)
5.9 Hz, J1,2 = 2.8 Hz, 1 H, 1-H), 4.03 (ddd, J2,1 = 2.8 Hz, J2,3 = 2.7 Hz,
4J2,6-Heq = 1.2 Hz, 1 H, 2-H), 4.07 (ddd, J5,6-Heq = 3.3 Hz, J5,6-Hax = 3.3
Hz, J5,4 = 3.3 Hz, 1 H, 5-H) ppm.
43
iso-43
Scheme 9
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 250–258

258
J. Aucktor, R. Brückner
Letter
Synlett
(43) NMR Data of (+)-gala-Quercitol (ent-8d, Figure 5)
1H NMR (500 MHz, CD3OD): δ = 1.77 (ddd, Jgem = 12.3 Hz, J6-Hax,1
= 10.4 Hz, J6-Hax,5 = 10.4 Hz, 1 H, 6-Hax), 1.90 (dddd, Jgem = 12.3
Hz, J6-Heq,1 = 4.4 Hz, J6-Heq,5 = 4.4 Hz, 4J6-Heq,2 = 1.2 Hz, 1 H, 6-Heq),
AcO
1
3
1
5
5
OAc
OAc
AcO
AcO
OAc
OAc
AcO
3
OAc
36
37
AcO
3.64 (dd, J4,5 = 8.5 Hz, J4,3 = 3.2 Hz, 1 H, 4-H), 3.73 (ddd, J5,6-Hax
=
Figure 6
10.0 Hz, J5,4 = 8.6 Hz, J5,6-Heq = 4.4 Hz, 1 H, 5-H), 3.81 (dd, J2,3 = 5.0
Hz, J2,1 = 2.9 Hz, 1 H, 2-H), 3.91 (dd, J3,2 = 5.0 Hz, J3,4 = 3.3 Hz, 1 H,
3-H), 3.95 (ddd, J1,6-Hax = 10.6 Hz, J1,6-Heq = 4.4 Hz, J1,2 = 2.9 Hz, 1
H, 1-H) ppm.
(47) The authors of ref. 8b peracetylated the mixture of glycols ent-
39 and ent-40 (mentioned in ref. 44) to obtain the pentaacetates
(meso)-36 and ent-37. They separated the latter compounds by
flash chromatography on silica gel, which we could not.
(48) Complementary diastereocontrol of cyclohexene dihydroxyl-
ations due to the presence of DHQ- vs. DHQD-substituted
ligands: (a) Chida, N.; Ohtsuka, M.; Nakazawa, K.; Ogawa, S. J.
Org. Chem. 1991, 56, 2976. (b) Mahapatra, T.; Nanda, S. Tetrahe-
dron: Asymmetry 2010, 21, 2199.
(49) According to ref. 8b, an ammonolysis of the pentaacetate
(meso)-36 (mentioned in ref. 47) rendered the quercitol 8e.
Likewise, an ammonolysis of the pentaacetate ent-37 (also
mentioned in ref. 47) gave the quercitol ent-8f. Both quercitols
were diastereomerically pure.
6
HO
HO
OH
OH
1
2
5
4
OH
5
3
1
6
OH
OH
HO
ent-8d
3
2
4
OH
OH
Figure 5
(44) Dihydroxylations of cyclohexenetriol triacetate ent-38 with
KMnO4 or RuO4 provided the glycols ent-39 and ent-40 with dr
= 58:42 in 65% and 77% combined yield, respectively; see ref. 8b.
(45) First descriptions of the AD-mix protocols: (a) Sharpless, K. B.;
Amberg, W.; Bennani, Y. L.; Crispino, G. A.; Hartung, J.; Jeong,
K.-S.; Kwong, H.-L.; Morikawa, K.; Wang, Z.-M.; Xu, D.; Zhang,
X.-L. J. Org. Chem. 1992, 57, 2768; (in the presence of
MeSO2NH2). (b) See footnote 6 in: Jeong, K.-S.; Sjö, P.; Sharpless,
K. B. Tetrahedron Lett. 1992, 33, 3833; (in the absence of
MeSO2NH2). Recent reviews: (c) Zaitsev, A. B.; Adolfsson, H. Syn-
thesis 2006, 1725. (d) Noe, M. C.; Letavic, M. A.; Snow, S. L.;
McCombie, S. Org. React. 2005, 66, 109. (e) Kolb, H. C.; Sharpless,
K. B. In Transition Metals for Organic Synthesis; Vol. 2; Beller, M.;
Bolm, C., Eds.; Wiley-VCH: Weinheim, 2004, 275–298.
(50) NMR Data of neo-Quercitol (8e, Figure 7)
1H NMR (500 MHz, D2O): δ = 1.32 (dt, Jgem = 12.3 Hz, J6-Hax,1
J6-Hax,5 = 11.8 Hz, 1 H, 6-Hax), 2.18 (dt, Jgem = 12.3 Hz, J6-Heq,1
=
=
J6-Heq,5 = 4.8 Hz, 1 H, 6-Heq), 3.44 (dd, J2,1 = 9.7 Hz, J2,3 = 3.0 Hz, 2
H, 2-H and 4-H), 3.79 (ddd, J1,6-Hax = 11.8 Hz, J1,2 = 9.7 Hz, J1,6-Heq
=
4.8 Hz, 2 H, 1-H and 5-H), 4.03 (t, J3,2 = J3,4 = 3.0 Hz, 1 H, 3-H)
ppm.
6
HO
HO
1
2
OH
OH
5
4
OH
5
1
6
HO
HO
OH
OH
3
3
2
(46) The relative amounts of the quercitol pentaacetates 36 and 37
were determined from the integrals over non-overlapping 1H
NMR signals (400 MHz, CDCl3) of this mixture. Their resonances
are printed in boldface in the following enumerations:
4
8e
OH
Figure 7
(51) NMR Data of (–)-epi-Quercitol (8f, Figure 8)
1H NMR (400 MHz, D2O): δ = 1.74 (mc, 1H, 6-Hax), 1.96 (mc, 1 H,
6-Heq), 3.67 - 3.54 (m, 3 H, 3-H, 4-H, 5-H), 3.77 (ddd, J1,6-Hax
NMR Data of Pentaacetate 36
1H NMR (400 MHz, CDCl3): δ = 1.53 (dt, Jgem = 12.5 Hz, J6-Hax,1
=
=
J6-Hax,5 = 11.7 Hz, 1 H, 6-Hax), 1.99 (s, 6 H, 2 × O2CCH3), 2.02 (s, 6
H, 2 × O2CCH3), 2.15 (s, 3 H, 3-O2CCH3), 2.52 (dt, Jgem = 12.5 Hz,
J6-Heq,1 = J6-Heq,5 = 5.1 Hz, 1 H, 6-Heq), 5.03 (dd, J2,1 = 10.2 Hz, J2,3 =
2.9 Hz, 2 H, 2-H and 4-H), 5.24 (ddd, J1,6-Hax = 11.7 Hz, J1,2 = 10.2
Hz, J1,6-Heq = 5.1 Hz, 2 H, 1-H and 5-H), 5.59 (t, J3,2 = J3,4 = 2.9 Hz,
1 H, 3-H) ppm.
12.3 Hz, J1,6-Heq = 4.5 Hz, J1,2 = 2.7 Hz, 1 H, 1-H), 3.98 (mc, 1 H, 2-
H) ppm.
6
HO
HO
5
4
OH
OH
1
2
1
5
6
OH
OH
HO
2
3
3
OH4
NMR Data of Pentaacetate 37 (Figure 6)
8f
1H NMR (400 MHz, CDCl3): δ = 1.99 (s, 3 H, O2CCH3), 2.00 (s, 3 H,
O2CCH3), 2.01 (s, 3 H, O2CCH3), 2.03 (s, 3 H, O2CCH3), 2.04 (ddd,
J6-Hax,1 = 12.5 Hz, Jgem = 12.1 Hz, J6-Hax,5 = 11.9 Hz, 1 H, 6-Hax), 2.17
OH
OH
Figure 8
(52) We reached five quercitols of the present study via a total of
four diastereoisomeric cyclohexenetriol triacetate precursors:
20 [Scheme 4; → (–)-proto-quercitol (8b)], 30 [Scheme 5; → (+)-
talo-quercitol (8c)], 32 [Scheme 6; → (–)-gala-quercitol (8d)],
and 38 [Scheme 7; → neo-quercitol (8e) and (–)-epi-quercitol
(8f)]. The value of the eight stereoisomeric cyclohexenetriol tri-
acetates as precursors of synthetic cyclohexitols was recognized
previously by Balci et al.22 and by: Kee, A.; O’Brien, P.; Pilgram,
C. D.; Watson, S. T. Chem. Commun. 2000, 1521.
(s, 3 H, O2CCH3), 2.22 (dddd, Jgem = 12.1 Hz, J6-Heq,5 = 5.2 Hz,
4
J6-Heq,1 = 4.7 Hz, J6-Heq,2 = 1.3 Hz, 1 H, 6-Hax), 4.95 (ddd, J5,6-Hax
11.9 Hz, J5,4 = 9.7 Hz, J5,6-Heq = 5.2 Hz, 1 H, 5-H), 4.97 (dd, J3,4
10.5 Hz, J3,2 = 2.8 Hz, 1 H, 3-H), 4.98 (ddd, J1,6-Hax = 12.5 Hz, J1,6-Heq
=
=
=
4.7 Hz, J1,2 = 2.6 Hz, 1 H, 1-H), 5.40 (dd, J4,3 = 10.5 Hz, J4,5 = 9.7
Hz, 1 H, 4-H), 5.55 (ddd, J2,3 = 2.8 Hz, J2,1 = 2.6 Hz, 4J2,6-Heq, = 1.3
Hz, 1 H, 2-H) ppm.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 250–258

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