The stereoselective syntheses of 1-aryl-1,6-dideoxyinositol derivatives

Article abstract of DOI:10.1016/j.tetlet.2011.07.066

This Letter describes the first report of a highly stereoselective synthesis of triethereal cyclohexanones via copper(I) mediated 1,4-addition of organometallic reagents to glucose-derived triethereal cyclohexenone. The cyclohexanones generated can be red

Full text of DOI:10.1016/j.tetlet.2011.07.066

Tetrahedron Letters 52 (2011) 5417–5420
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Tetrahedron Letters
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The stereoselective syntheses of 1-aryl-1,6-dideoxyinositol derivatives
⇑
Jianwei Bian, Steven R. Schneider, Robert J. Maguire
Worldwide Medicinal Chemistry, Pfizer Worldwide Research, Eastern Point Road, Groton, CT 06340, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
This Letter describes the first report of a highly stereoselective synthesis of triethereal cyclohexanones via
copper(I) mediated 1,4-addition of organometallic reagents to glucose-derived triethereal cyclohexe-
none. The cyclohexanones generated can be reduced with modest stereoselectivity to afford a variety
of substituted inositol derivatives as potential pyranose sugar mimetics. The protocol generated a range
of substituted cyclohexanones in good yield as single stereoisomers.
Received 6 June 2011
Revised 11 July 2011
Accepted 14 July 2011
Available online 30 July 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Inositols
Carbsugars
Stereoselective synthesis
Organocuprate addition
The stereoselective synthesis of C-glycosides has received in-
creased attention in recent years as interest has grown in the
development of selective inhibitors of glycoside transporter pro-
teins for clinical application.1 The inhibition of sodium dependent
glucose cotransporter-2 (SGLT-2), a transporter protein located in
the kidney responsible for the reabsorption of glucose in the kid-
ney, has received particular consideration as potential treatment
of type II diabetes mellitus and obesity. This interest has led to sev-
eral C-glycoside compounds, such as Dapagliflozin 1 and Canagli-
flozin 2, reaching advanced clinical trials to investigate this
mechanism (Fig. 1).2 During the investigation of the spirocyclic
SGLT-2 inhibitor 3, we became interested in the utility of inositol
carbocyclic mimics of the pyranose sugar core as SGLT-2
inhibitors.3
describing copper(I) mediated addition to this system.6 The
organocuprate addition to cyclic enones is an established approach
to substituted cyclohexanones, however, the introduction of a b-
oxygen function impacts the stability of the products due to elim-
ination to cyclohexenones under basic conditions or aromatization
to phenol 7.6b,7 The inclusion of an ether group adjacent to the ke-
tone, will further increase the acidity of the ketone
a-proton,
enhancing the system’s propensity to eliminate and aromatize to
a phenol (Scheme 2).6b There is no literature precedent for copper
mediated 1,4-additions to cyclohexenones with ethereal groups at
The proposed targets in this series were to be biaryl substituted
inositols such as 4 to emulate the activity of the pyranose system.
The ideal approach would be to introduce the aryl group at the ino-
sitol C-1 position at a late stage of the route, followed by manipu-
lation of the functionality at the inositol C-5 (Scheme 1). We
believed that we could achieve our synthetic goal by entering the
system via the known triethereal cyclohexenone 5 using 1,4-addi-
tion of organocuprate reagents.4,5
The ketone of cyclohexanone 6 would then offer ample scope to
vary the functionality of the inositol C-5 position. The initial targets
in this series would be the C-5 hydroxy compounds 4 that would
require a stereoselective reduction of ketone 6.
Currently, minimal literature precedent exists for the 1,4-addi-
tion to triethereal cyclohexenones, such as 5, and no reports exist
⇑
Corresponding author. Tel.: +1 860 441 3756; fax: +1 860 715 7569.
E-mail address: robert.j.maguire@pfizer.com (R.J. Maguire).
Figure 1. Recently published SGLT-2 inhibitor C-glycosides.
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.07.066

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J. Bian et al. / Tetrahedron Letters 52 (2011) 5417–5420
Scheme 3. Optimization of copper(I) mediated 1,4-addition.
Table 1
Scheme 1. Synthetic approach to aryl inositol targets.
Summary of copper(I) mediated addition optimization
Aryl
n-BuLi (equiv)
CuI (equiv)
T (°C)
Add (equiv)
Products
10a
10a
10a
3
3
3
3
3
1.5
À20
À20
À20
None
TMS–Cl (3)
BF3ÁEt2O (1)
7
5
7 (25%)
11a (25%)
11b (75%)
10b
5
2.5
À78
BF3ÁEt2O (2)
product 7 (Scheme 3, Table 1). It is well established that certain
additives alter the outcome of organocuprate reagents.8 When tri-
methylsilyl chloride was included in the reaction, we were encour-
aged to find that the reaction returned starting material 5 rather
than the phenol elimination product 7, suggesting that the condi-
tions could be effectively modulated to improve substrate stability
during the addition reaction. Indeed, it was found that the addition
of 1 equiv of boron(III) fluoride etherate complex to the mixture
and performing the addition at À20 °C afforded 25% conversion
to the desired cyclohexane 11a as a single stereoisomer and 25%
yield of phenol 7.8b,c Further optimization found that performing
the reaction at À78 °C with 2.5 equiv of aryl organocuprate in the
presence of 2 equiv of boron(III) fluoride etherate afforded cyclo-
hexane 11b in 75% yield as a single stereoisomer (Table 1). We
found that quenching the reaction by slow addition of 1 N HCl at
À78 °C was key to preventing epimerization of the inositol C-4
ethereal carbon.9
Scheme 2. Literature precedent for 1,4-addition approach. Reagents and condi-
tions: (a) Ref. 6b; dimethylmalonate, NaH or NaOEt, THF, rt, 45 min; (b) Ref. 6a;
TBSOC(OEt)@CH2, LiClO4, Et2O, rt, 48 h; (c) Ref. 6a; ethyl 1,3-dithiolane-2-carbox-
ylate, n-BuLi, THF, À78 to À20 °C, 3 h.
both alpha- and beta-positions relative to the ketone. The stereo-
chemical outcome of the addition was also unclear. Of the two
reports detailing 1,4-addition to triethereal cyclohexenones such
as 5, one describes the anti-addition product 9 that would be antic-
ipated from addition to c
-substituted enone,6a whereas the other
report describes a lithium perchlorate mediated syn-addition of
silyl enol ether to afford 8.6b
The stereochemistry of the addition products were confirmed
by NOE experiments and subsequently via the X-ray crystal struc-
ture of the 4-chlorophenyl adduct 12c (Fig. 2).
The prototype experiments to add aryl groups 10–5 via the gen-
eration of an organocuprate without additives at a range of tem-
peratures and stoichiometries afforded the phenol elimination
Figure 2. X-ray structure of 4-chlorophenyl adduct 12c.

J. Bian et al. / Tetrahedron Letters 52 (2011) 5417–5420
5419
Having established conditions in hand to generate cyclohexa-
nones such as 11 in good yield as single stereoisomers, we sought
to investigate the scope of the reaction as a general method for
generating triethereal substituted cyclohexanones via this novel
methodology.
We were gratified to find that the reaction did indeed translate
to a broader application and allowed a range of organocuprates to
be added to cyclohexenone 5 ((Scheme 4), Table 2). A range of aryl
rings, with a variety of steric and electronic characteristics could be
added in good yield and as single stereoisomers 12a–12l. Even the
challenging o-tolyl cuprate successfully afforded product 12h in
70% yield. Simple alkyl (methyl adduct 12i), cyclic alkyl (cyclobu-
tane adduct 12j), and t-butyl adduct 12k groups were added in
50–77% yield and as a single stereoisomer. The addition of furanyl
ester (12l) suggested the potential to incorporate heterocycles
using this methodology.
Scheme 5. Selective reduction of cyclohexanone adducts. Reagents and conditions:
(a) NaBH4, THF–MeOH, À10 °C; 13a:13b = 8:1; (b) DIBALH, THF–toluene, À78 °C;
13a:13b = 1:4 (1:12 recrystallized).
With a general method for the stereoselective generation of
cyclohexanones 12a–12l in hand, attention turned to the stereose-
lective reduction of the cyclohexanone and deprotection to com-
plete the synthesis of 1-substituted-1,6-dideoxyinositols
(Scheme 5). Our approach to exploring SAR required that we
needed access to both inositol C-5 stereoisomers. The initial condi-
tions attempted were the reduction of tolyl adduct 12d with so-
dium borohydride at 0 °C to afford an inseparable 5:1 mixture of
C-5 epimers (
ity of the reduction was improved to 8:1
a
:13a and b:13b) in 99% yield.11a The stereoselectiv-
:b ratio by cooling to
a
À10 °C. Testing a range of alternative reducing agents did not af-
ford highly stereoselective conditions, a finding consistent with
the results reported for related carbasugar systems.11
Figure 3. X-ray structure of 1-(3-methoxyphenyl)-1,6-dideoxyinositol 15.
The stereochemical outcome of the reduction could be inverted
by the addition of cerium(III) chloride heptahydrate which gener-
ated a 1:3
butylaluminium hydride at À78 °C and warming to 0 °C afforded a
1:4
:b C-5 epimer ratio in 99% yield.12 The ratio of diastereoiso-
mers could be enhanced to a 1:12 :b C-5 epimer mix by a single
a:b C-5 epimer ratio in 90% yield. The addition of di-iso-
a
a
recrystallization from heptanes. It has been reported by Gomez
that a hydroxyl group adjacent to the cyclohexanone carbonyl
greatly enhances the stereoselectivity in the reduction step by
affording anchimeric delivery of the borohydride reagent to the
carbonyl.11c However, in this system removal of the benzyl pro-
tecting groups from 12d resulted in epimerization of the hydroxyl
group adjacent to the ketone during the hydrogenation, and subse-
quent sodium borohydride reduction afforded a complex mixture.
The route to the 1-substituted-1,6-dideoxyinositol targets was
completed by hydrogenolysis of 13a to deprotect the hydroxyl
groups. Once the protecting groups had been removed, the diaste-
reomeric aryl inositol products could be separated either by chro-
matography or crystallization. The p-tolyl adduct 12d was
converted into p-tolyl dideoxyinositol 14 as a single isomer in
53% overall yield. This chemistry was applied to meta-methoxy ad-
duct 12f to afford crystalline product 15 that confirmed the inositol
C-5 stereochemical assignment by X-ray crystallography (Fig. 3).
In this Letter, we have demonstrated the stereoselective synthe-
sis of 1-aryl-1,6-dideoxyinositols via the first reported organocup-
rate addition of aryl groups to a triethereal cyclohexenone derived
from glucose. The highly substituted cyclohexanone provides a
useful synthon for further elaboration into carbasugar systems. In
this Letter, the novel cyclohexanone products were reduced with
modest stereoselectivity and deprotected to afford either inositol
C-5 hydroxyl stereoisomers.
Scheme 4. Scope of copper(I) mediated addition.
Table 2
Conditions and results of copper(I) mediated additions
Entry
R
R’
Condition
Yield (%)
12a
12b
12c
12d
12e
H
F
A
B
75
73
83
76
82
R'
Cl
Me
CO2Et
A
A
C
12f
12g
OMe
F
A
A
79
72
R'
Me
12h
12i
—
—
A
A
70
50
Me
12j
—
—
A
A
61
77
12k
t-Bu
Acknowledgments
O
12l
—
D
65
O
OMe
We thank B. Samas for X-ray crystallography determinations.
We also thank Dr. Jotham Coe and Dr. Stephen Wright for assisting
in the preparation of this manuscript. All are from Pfizer World-
wide Research, Groton, Connecticut, USA.
Conditions: A—commercial Grignard reagent; B—lithium/halogen exchange at
À78 °C for 1 h; C—magnesium/iodine exchange at À40 °C for 40 min (see Ref. 10);
D—magnesium/bromine exchange at À15 °C for 40 min.

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J. Bian et al. / Tetrahedron Letters 52 (2011) 5417–5420
Lipshutz, B. H.; Wood, M. R. J. Am. Chem. Soc. 1995, 117, 6126; (e) Yamamoto, Y.
References and notes
Angew. Chem., Int. Ed. Engl. 1986, 25, 947.
6. (a) Paulsen, H.; Von Deyn, W. Liebigs Ann. Chem. 1987, 133; (b) Lastdrager, B.;
Timmer, M. S. M.; van der Marel, G. A.; Overkleeft, H. S.; Overhand, M. J.
Carbohydr. Chem. 2007, 26, 41.
7. (a) Ohnemüller, U. K.; Nising, C. F.; Encinas, A.; Bräse, S. Synthesis 2007, 2175;
(b) Hareau-Vittini, G.; Hikichi, S.; Sato, F. Angew. Chem., Int. Ed. 1998, 37, 2099.
8. (a) Bergdahl, M.; Lindstedt, E.-L.; Nilsson, M.; Olsson, T. Tetrahedron 1988, 44,
2055; (b) Soll, R. M.; Humber, L. G.; Deininger, D.; Asselin, A. A.; Chau, T. T.;
Weichman, B. M. J. Med. Chem. 1986, 29, 1457; (c) Lipshutz, B. H.; Elsworth, E.
L.; Shiahaan, T. J. J. Am. Chem. Soc. 1989, 111, 1351.
9. It was observed that using 4-methoxybenzyl ether as the hydroxyl protecting
group on the cyclohexenone rather than a benzyl ether resulted in a mixture of
products rather than clean conversion.
10. Krasovskiy, A.; Knochel, P. Angew. Chem., Int. Ed. 2004, 43, 3333.
11. (a) Gómez, A. M.; Moreno, E.; Valverde, S.; López, J. C. Tetrahedron Lett. 2002, 43,
5559; (b) Pang, L.-J.; Wang, D.; Zhou, J.; Zhang, L.-H.; Ye, X. Org. Biomol. Chem.
2009, 7, 4252; (c) Gómez, A. M.; Moreno, E.; Valverde, S.; López, J. C. Eur. J. Org.
Chem. 2004, 1830.
1. (a) Oku, A.; Ueta, K.; Arakawa, K.; Ishihara, T.; Nawano, M.; Kuronuma, Y.;
Matsumoto, M.; Saito, A.; Tsujihara, K.; Anai, M.; Asano, T.; Kanai, Y.; Endou, H.
Diabetes 1999, 48, 1794; (b) Tsujihara, K.; Hongu, M.; Saito, K.; Kawanishi, H.;
Kuriyama, K.; Matsumoto, M.; Oku, A.; Ueta, K.; Tsuda, M.; Saito, A. J. Med.
Chem. 1999, 42, 5311.
2. (a) Meng, W.; Ellsworth, B. A.; Nirschl, A. A.; McCann, P. J.; Patel, M.; Girotra, R.
N.; Wu, G.; Sher, P. M.; Morrison, E. P.; Biller, S. A.; Zahler, R.; Deshpande, P. P.;
Pullockaran, A.; Hagan, D. L.; Morgan, N.; Taylor, J. R.; Obermeier, M. T.;
Humphreys, W. G.; Khanna, A.; Discenza, L.; Robertson, J. G.; Wang, A.; Han, S.;
Wetterau, J. R.; Janovitz, E. B.; Flint, O. P.; Whaley, J. M.; Washburn, W. N. J. Med.
Chem. 2008, 51, 1145; (b) Nomura, S.; Sakamaki, S.; Hongu, M.; Kawanishi, E.;
Koga, Y.; Sakamoto, T.; Yamamoto, Y.; Ueta, K.; Kimata, H.; Nakayama, K.;
Tsuda-Tsukimoto, M. J. Med. Chem. 2010, 53, 6355.
3. Mascitti, V.; Robinson, R. P.; Preville, C.; Thuma, B. A.; Carr, C. L.; Reese, M. R.;
Maguire, R. J.; Leininger, M. T.; Lowe, A.; Steppan, C. M. Tetrahedron Lett. 2010,
51, 1880.
4. (a) Semeria, D.; Philippe, M.; Delaumeny, J.-M.; Sepulchre, A.-M.; Gero, S. D.
Synthesis 1983, 710; (b) Takahashi, H.; Ikegami, S. Molecules 2005, 10, 901.
5. (a) Taylor, R. J. K. Synthesis 1985, 364; (b) Lipshutz, B. H.; Sengupta, S. Org. React.
2004, 135; (c) Breit, B.; Demel, P. Mod. Organocopper Chem. 2002, 188; (d)
12. Honzumi, M.; Taniguchi, T.; Ogasawara, K. Org. Lett. 2001, 3, 1355.