Diastereoselective construction of new 5a-substituted carbaallose by exo-β-selective conjugate addition to endo-exo cross-conjugated cyclohexadienone as key reaction

Article abstract of DOI:10.1055/s-0030-1258028

Practical synthesis of a new chiral endo-exo cross-conjugated cyclohexadienone was achieved, and its synthetic utility was illustrated by highly exo-β-selective conjugate addition with various nucleophiles. Further diastereoselective transformation of the adduct to an unprecedented 5a-substituted carbaallose is also described. Georg Thieme Verlag Stuttgart - New York.

Full text of DOI:10.1055/s-0030-1258028

LETTER
2279
Diastereoselective Construction of New 5a-Substituted Carbaallose by
exo-b-Selective Conjugate Addition to endo-exo Cross-Conjugated
Cyclohexadienone as Key Reaction
C
onstructionof
a
Ne
w
5a-Su
k
bstitute
d
Ca
a
r
baallose shi Fujishima, Fukashi Kitoh, Tomotsugu Yano, Ryo Irie*
Department of Chemistry, Graduate School of Science and Technology, Kumamoto University,
2-39-1 Kurokami, Kumamoto 860-8555, Japan
Fax +81(96)3423379; E-mail: irie@sci.kumamoto-u.ac.jp
Received 17 June 2010
stereoselective construction of 1 (R = Bz) and its transfor-
Abstract: Practical synthesis of a new chiral endo-exo cross-conju-
gated cyclohexadienone was achieved, and its synthetic utility was
illustrated by highly exo-b-selective conjugate addition with vari-
ous nucleophiles. Further diastereoselective transformation of the
adduct to an unprecedented 5a-substituted carbaallose is also de-
scribed.
mation into an unprecedented 5a-substituted carbaallose.6
O
O
exo-β
conjugate addition
to the exo-β site
Nu
∗
∗
∗
∗
∗
Key words: rearrangement of endoperoxide, cross-conjugated di-
enone, regioselective conjugate addition, stereoselective synthesis,
carbasugar
endo-β
OR OR
OR OR
1
OH
HO
There are a number of fascinating synthetic targets with a
six-membered carbocyclic skeleton with various func-
tional groups on the stereogenic ring-carbon atoms.1
Among them are 5a-carbapyranoses,2 which named after
their structural similarity to the parent monosaccharides:
the original pyranose ring-oxygen atom is replaced by car-
bon atom. So far, a large range of 5a-carbapyranoses,
which are typically 5a-methylene variants, have been ei-
ther isolated from natural sources or synthesized to unveil
their unique biological functions.2 It is interesting to note
that human cannot distinguish between a pyranose and its
5a-methylene analogue as exemplified by the fact that 5a-
carba-a-D-glucopyranose is felt sweet like a-D-glucopy-
ranose.3 These structural and biologic aspects have moti-
vated us for further modification of the carbapyranoses. In
particular, we envisioned that the carbasugars could enjoy
any extra property by the introduction of a substituent to
the 5a-carbon center, keeping the biological roles of their
parent saccharides intact. To the best of our knowledge,
however, such chiral carbapyranoses with an asymmetric
5a-carbon center have been scarcely scrutinized.4 Thus,
the development of a versatile stereoselective method for
the synthesis of 5a-substituted carbapyranoses should be
significant to accelerate the research on the functional
sugar mimics. We assigned the endo-exo cross-conjugat-
5a
∗
1) dihydroxylation
2) reduction
3) deprotection
∗
∗
Nu
∗
∗
∗
HO
OH OH
carbasugar derivatives
Scheme 1 Chiral endo-exo cross-conjugated cyclohexadienone 1 as
a useful synthetic building block for 5a-substituted carbapyranoses
(*: stereogenic center)
The requisite 1 was synthesized as shown in Scheme 2.
The photooxygenation of 27 in the presence of tetraphe-
nylporphyrin (TPP) as a sensitizer afforded endoperoxide
3 in 45% yield. The relative stereochemistry of 3 was un-
doubtedly determined by X-ray crystallographic analysis
(Figure 1).8 Upon treatment with an excess amount of tri-
ethylamine, the endoperoxide 3 underwent Kornblum–
DeLaMare rearrangement9 to the 4-hydroxycyclohex-2-
enone derivative 4, which was found to be susceptible to
a b-elimination of the benzoyl group under the applied ba-
sic conditions to give the endo-exo cross-conjugated cy-
clohexadienone 5 in excellent yield. The subsequent one-
pot treatment of 5 with benzoyl chloride, triethylamine,
and DMAP gave 1 in 94% yield for the three steps from 3.
We next examined the conjugate addition to 1. With a
ed cyclohexadienone5 1 to be a potential synthetic build- higher-order cuprate10 prepared from phenyllithium and
ing block, because the regioselective conjugate addition to cuprous cyanide, the conjugate addition proceeded in ex-
the exo-b carbon atom provides a cyclohex-2-enone cellent chemo- and regioselective manners to give the de-
framework for further stereoselective functionalizations sired exo-b adduct 6a as a single diastereomer in high
to access carbapyranoses with a variety of substituents at chemical yield (Table 1, entry 1). The relative configura-
5a-position (Scheme 1). In this paper, we disclose the dia- tion of 6a was determined to be 1R*,2S*,6S* by X-ray
crystallography of a derivative (vide infra, Figure 3). The
diastereoselectivity in the protonation to a dienolate inter-
mediate primarily generated upon the conjugate addition
could be explained by the transition-state model either A
SYNLETT 2010, No. 15, pp 2279–2282
Advanced online publication: 09.08.2010
DOI: 10.1055/s-0030-1258028; Art ID: U05610ST
© Georg Thieme Verlag Stuttgart · New York
x
x
.x
x
.2
0
1
0

2280
T. Fujishima et al.
LETTER
Table 1 exo-b-Selective Conjugate Addition to 1 with Higher-
or B depicted in Figure 2. In the model A, the dienolate lo-
cates the substituents on the two stereogenic ring-carbon
centers in an anti-periplanar conformation so that the pro-
tonation should occur at a quasi-equatorial site to avoid a
1,3-repulsive interaction with the benzoyl group. Alterna-
tively, the model B with a gauche conformation for the
two relevant substituents should account for the protona-
tion at a quasi-axial site from a stereoelectronic effect.11
The conformation of the dienolate is thermodynamically
more stable in A than in B, whereas the axial attack by a
proton source as in B is kinetically preferable to the equa-
torial attack as in A. Other higher-order cuprates were also
examined and those with aromatic ligands such as 2-meth-
oxyphenyl, 1-naphthyl, and 2-naphthyl exhibited similar-
ly excellent regio- and diastereoselectivities (entries 2–4).
Butyl group was also transferred to the exo-methylene in
good yield, though a very small amount of unidentified
byproduct12 accompanied in this case (entry 5). It should
be noted that the undesired endo-b adduct was not detect-
ed in each reaction. That would be partly because the on-
coming nucleophile feels higher steric hindrance at the
endo-b than at the exo-b site. Not only higher-order cu-
prates but also a stabilized carbanion derived from dime-
thyl malonate underwent highly regioselective Michael
addition at the exo-b position of 1 followed by the diaste-
reoselective protonation event to afford 7 (Scheme 3,
left). Corey–Chaykovsky cyclopropanation13 was also ef-
fected with an exo-b-selective manner to provide 8
(Scheme 3, right).
Order Cupratesa
O
O
H
1) R2CuCN⋅Li2
THF, –78 °C
R
2) aq NH4Cl
OBz OBz
OBz OBz
1
6a–e
Entry
Cuprate (R)
Ph
Time (min) Product
Yield (%)b
1
2
3
4
5
15
20
20
20
15
6ac
6bc
6cc
6dc
6ed
91
74
62
80
77
2-MeOC6H4
1-C10H7
2-C10H7
n-Bu
a Reaction was carried out with a 1:1 molar ratio of 1 and
R2CuCN·Li2.
b Isolated yield.
c Diastereomeric byproduct was not detected by 1H NMR analysis.
d Accompanied by a small amount (<5%) of unidentified byproduct
with a similar pattern of 1H NMR spectrum to that of 6e.
H+
MO
H+
MO
1,3-repulsive interaction
OBz
A
B
R
R
OBz
OBz
H+
axial attack
OBz
gauche repulsion
H+
O
Figure 2 Transition-state models A and B accounting for the obser-
ved diastereoselectivity in the protonation of a dienolate intermediate
generated upon the conjugate addition to 1.
OBz
OBz
OBz
OBz
OBz
OBz
i
O
O
ii
3
2
OH
MeO2C
4
O
O
O
O
CO2Me
i
ii
iii
1
OBz
OBz
OBz
OBz
OBz
OBz
OH
OBz
8
7
5
1
Scheme 3 Michael addition and Corey–Chaykovsky cyclopropana-
tion. Reagents and conditions: i) dimethyl malonate, NaH, THF,
–78 °C, 3 h, 67%; ii) trimethylsulfonium iodide, NaH, THF–DMSO,
r.t., 4.5 h, 48%.
Scheme 2 Synthesis of the endo-exo cross-conjugated cyclo-
hexadienone 1. Reagents and conditions: i) O2 (air), TPP, hn (110 V,
150 W, halogen lamp), CH2Cl2, r.t., 5.5 h; 45%, ii) Et3N, CH2Cl2, r.t.,
19 h; iii) BzCl, Et3N, DMAP, CH2Cl2, r.t., 1.5 h, 94% (2 steps).
Eventually, the synthesis of a new 5a-substituted carbaal-
lose was achieved from 6a (Scheme 4). Thus, osmium-
catalyzed dihydroxylation of 6a afforded a 3.5:1 diastere-
omeric mixture of 9a and 9b. After separation of these di-
astereomers by column chromatography on silica gel, the
major isomer 9a was subjected to the carbonyl reduction
with NaBH4 to give the triol 10 quantitatively as a sole di-
astereomer. A single crystal of 10 was subjected to X-ray
crystallography14 and its relative stereochemistry was un-
ambiguously determined to be 1R*,2R*,3S*,4S*,5S*,6S*
(Figure 3). This also established the stereochemical out-
Figure 1 An ORTEP diagram for the X-ray structure of 3. Hydro-
gen atoms are omitted for clarity.
Synlett 2010, No. 15, 2279–2282 © Thieme Stuttgart · New York

LETTER
Construction of New 5a-Substituted Carbaallose
2281
come in the conjugate addition–protonation sequence on
the cross-conjugated dienone 1 (Figure 2). Methanolysis
of the benzoyl groups of 10 with sodium methoxide in
methanol followed by neutralization with an acidic resin
afforded a 5a-carba-a-allopyranose 11 in quantitative
yield.
Acknowledgment
This work was supported by the Asahi Glass Foundation. We are
grateful to Professor Katsuhiko Tomooka of Kyushu University for
his helpful suggestions. We also thank Professor Fumito Tani, Ms.
Eri Okazaki, and Mr. Taisuke Matsumoto of Kyushu University for
high resolution mass spectrometry and X-ray crystallographic ana-
lysis.
O
O
HO
HO
HO
HO
References and Notes
Ph
Ph
i
6a
+
OBz
OBz
(1) Marco-Contelles, J.; Molina, M. T.; Anjum, S. Chem. Rev.
2004, 104, 2857.
(2) Arjona, O.; Gómez, A. M.; López, J. C.; Plumet, J. Chem.
OBz
OBz
9a
9b
Rev. 2007, 107, 1919.
(3) Suami, T.; Ogawa, S.; Toyokuni, T. Chem. Lett. 1983, 611.
(4) The relevant six-membered carbocyclic sugar alcohol is
known as chiro-inositol. For reviews, see: (a) Hudlicky, T.;
Entwistle, D. A.; Pitzer, K. K.; Thorpe, A. J. Chem. Rev.
1996, 96, 1195. (b) Singleton, J.; Hoberg, J. O. Mini-Rev.
Org. Chem. 2009, 6, 1.
OH
OH
HO
HO
iii, iv
ii
Ph
Ph
9a
OBz
OH
HO
HO
OBz
OH
(5) For the synthetic studies on the related endo-exo cross-
conjugated cyclohex-2-enones, see: (a) Sasson, I.; Labovitz,
J. J. Org. Chem. 1975, 40, 3670. (b) Hutchinson, J. H.;
Money, T. Tetrahedron Lett. 1985, 26, 1819.
10
11
Scheme 4 Synthesis of a 5a-carba-a-allopyranose 11 from 6a.
Reagents and conditions: i) K2OsO4·2H2O, NMO, DABCO, acetone–
H2O, r.t., 3 h, 96%, 9a/9b (3.5:1); ii) NaBH4, MeOH, –78 °C, 1 h,
81%; iii) NaOMe, MeOH, r.t., 2 h; iv) Dowex HCR W-2, 99% (2
steps).
(c) Katsumura, S.; Kimura, A.; Isoe, S. Tetrahedron 1989,
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Takeshita, H.; Suzuki, S.; Toyota, M.; Ihara, M. J. Chem.
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Figure 3 An ORTEP diagram for the X-ray structure of 10. Hydro-
gen atoms and solvate molecule are omitted for clarity.
In summary, we were able to construct a novel endo-exo
cross-conjugated cyclohexadienone 1, which was demon-
strated to undergo regioselective conjugate addition at the
exo-b position with various nucleophiles followed by
highly diastereoselective protonation of a dienolate inter-
mediate. Furthermore, one of the adducts, 6a, was suc-
cessfully converted to the unprecedented carbaallose
derivative 11 with a chiral 5a-carbon center, which will be
subjected to screenings for the assessment of its biological
activities. Asymmetric synthesis of the optically active
endo-exo cross-conjugated cyclohexadienones15 and their
further synthetic applications are also currently under way
in our laboratory.
(6) For the construction of a 5a-carba-a-D-allose, see: Gomez,
A. M.; Moreno, E.; Valverde, S.; Lopez, J. C. Synlett 2002,
891.
(7) Yano, T.; Fujishima, T.; Irie, R. Synthesis 2010, 818.
(8) We have deposited the crystallographic data for 3 with the
Cambridge Crystallographic Data Center as supplementary
publication number CCDC 779019.
(9) Kornblum, N.; DeRaMare, H. E. J. Am. Chem. Soc. 1951,
73, 880.
(10) Lipshutz, B. H.; Wilhelm, R. S.; Kozlowski, J. A.
Tetrahedron 1984, 40, 5005.
(11) Uriac, P.; Bonnic, J.; Huet, J. Tetrahedron 1985, 41, 5051.
(12) This byproduct could be the diastereomer of 6e. However,
no confirmation has been yet obtained as these two products
are not separated by TLC and their 1H NMR signals (600
MHz) are extensively overlapping.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
Synlett 2010, No. 15, 2279–2282 © Thieme Stuttgart · New York

2282
T. Fujishima et al.
LETTER
(13) Corey, E. J.; Chaykovsky, M. J. Am. Chem. Soc. 1962, 84,
3782.
(14) We have deposited the crystallographic data for 10 with the
Cambridge Crystallographic Data Center as supplementary
publication number CCDC 779020.
(15) In a preliminary experiment, the enantioenriched dienone 5
(90% ee) was obtained by asymmetric Kornblum DeLaMare
rearrangement of 3 under Toste’s conditions.16 For details,
see the Supporting Information.
(16) Staben, S. T.; Xin, L.; Toste, F. D. J. Am. Chem. Soc. 2006,
128, 12658.
Synlett 2010, No. 15, 2279–2282 © Thieme Stuttgart · New York

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