Common-intermediate strategy for synthesis of conduritols and inositols via beta-hydroxy cyclohexenylsilanes.

Article abstract of DOI:10.1021/ol034349d

[reaction: see text] Syntheses of conduritols B-D and F and d-(+)-chiro- and neo-inositols from cyclohexenylsilane intermediates are described. The key cyclohexylsilane intermediates 5 and 14 were synthesized by stereoselective olefin dihydroxylation of t

Full text of DOI:10.1021/ol034349d

ORGANIC
LETTERS
2003
Vol. 5, No. 10
1697-1700
Common-Intermediate Strategy for
Synthesis of Conduritols and Inositols
via â-Hydroxy Cyclohexenylsilanes
Jung-Nyoung Heo, Edward B. Holson, and William R. Roush*
Department of Chemistry, UniVersity of Michigan, Ann Arbor, Michigan 48109
roush@umich.edu
Received February 27, 2003
ABSTRACT
Syntheses of conduritols B−D and F and D-(+)-chiro- and neo-inositols from cyclohexenylsilane intermediates are described. The key
cyclohexylsilane intermediates 5 and 14 were synthesized by stereoselective olefin dihydroxylation of the corresponding cyclohexenylsilanes.
Selective Peterson elimination reactions and Fleming−Tamao oxidations of 5 and 14 then delivered the targeted cyclitol derivatives.
The conduritols1 and the inositols2 belong to a large and
important family of natural products known as the cyclitols.
Conduritol A analogues act as insulin modulators,3 and
conduritol epoxides and aminoconduritols act as glycosidase
inhibitors;4 cyclophellitols are potent inhibitors of human
immunodeficiency virus (HIV) and glycosidases.5 A number
of conduritol derivatives also possess antifeedant, antibiotic,
antileukemic, and growth-regulating activity.1a The inositols
and their phosphate derivatives possess an interesting array
of biological activities.2b,6,7 In particular, D-myo-inositol-1,4,5-
trisphosphate [Ins(1,4,5)P3, (1)] is a second messenger in the
intracellular signal transduction pathway that regulates the
release of calcium ions in pancreatic acinar cells.8
Six stereoisomers are possible in the conduritol family.
Two members of this group are meso compounds (A and
D), while the remaining four are d,l-diastereomers (B, C, E,
and F) (Figure 1). Among these, conduritols A and F are
the only naturally occurring members. The inositols are
1,2,3,4,5,6-cyclohexanehexols and can exist as nine stereo-
(1) (a) Balci, M. Pure Appl. Chem. 1997, 69, 97 and references therein.
(b) For a recent review on the synthesis of conduritols and inositols, see:
Hudlicky, T.; Entwistle, D. A.; Pitzer, K. K.; Thorpe, A. J. Chem. ReV.
1996, 96, 1195. (c) Balci, M.; Su¨tbeyaz, Y.; Sec¸en, H. Tetrahedron 1990,
46, 3715.
(2) (a) Odom, A. R.; Stahlberg, A.; Wente, S. R.; York, J. D. Science
2000, 287, 2026. (b) Potter, B. V. L.; Lampe, D. Angew. Chem., Int. Ed.
Engl. 1995, 34, 1933 and references cited therein. (c) Berridge, M. J. Nature
1993, 361, 315.
(3) Billington, D. C.; Perron-Sierra, F.; Beaubras, S.; Duhault, J.; Espinal,
J.; Challal, S. Bioorg. Med. Chem. Lett. 1994, 4, 2307.
(4) (a) Legler, G.; Herrchen, M. FEBS Lett. 1981, 135, 139. (b) Legler,
G.; Bause, E. Carbohydr. Res. 1973, 28, 45.
(5) (a) Atsumi, S.; Iinuma, H.; Nosaka, C.; Umezawa, K. J. Antibiot.
1990, 43, 1579. (b) Atsumi, S.; Umezawa, K.; Iinuma, H.; Naganawa, H.;
Nakamura, H.; Iitaka, Y.; Takeuchi, T. J. Antibiot. 1990, 43, 49.
(6) Streb, H.; Irvine, R. F.; Berridge, M. J.; Schulz, I. Nature 1983, 306,
67.
Figure 1. Conduritols A-F.
10.1021/ol034349d CCC: $25.00 © 2003 American Chemical Society
Published on Web 04/15/2003

isomers: myo, scyllo, cis, D-(+)-chiro, L-(-)chiro, epi, allo,
muco, and neo inositols (Figure 2). Among this group, the
myo (the most abundant), scyllo, cis, D-(+)-chiro, and L-
(-)-chiro-inositols are naturally occurring.
cyclitol derivatives via the desymmetrization of cyclohexa-
dienylsilanes.14b Continued exploration of the structure-
activity relationships of inositol phosphates and their bio-
macromolecule targets has fueled an ongoing interest in
the development of efficient syntheses of these com-
pounds.2b,15
In the preceding paper,16 we described a strategy for
synthesis of enantiomerically pure cyclohexenylsilanes via
a stereoselective aldehyde γ-silylallylboration followed by
a RCM reaction sequence. Here we report the application
of this procedure to the synthesis of highly functionalized
cyclohexenylsilanes that serve as intermediates in the
synthesis of several conduritols (B, C, E, and F) and inositols
(D-(+)-chiro and neo).
An important feature of our strategy was the recognition
that members of the conduritol or inositol family could be
synthesized from cyclohexenylsilane intermediates by simple
trifurcation of the synthetic sequence. As illustrated in Figure
3, conduritols F and B and D-(+)-chiro-inositol can be
accessed from â-hydroxy cyclohexylsilane 5. The two
stereochemically distinct â-hydroxy silane units in 5 are
substrates for regioselectively distinct Peterson elimination
reactions,17 while the silyl group can serve as a hydroxyl
surrogate via Fleming-Tamao oxidation.18 â-Hydroxy cy-
clohexylsilane 5 would derive from diene 6 via RCM
followed by a catalytic olefin dihydroxylation reaction. We
anticipated that diene 6, in turn, would be prepared by
stereoselective γ-allylboration of aldehyde 816 with chiral
γ-silylallylborane 7.19 In addition, we recognized that con-
duritols C and E and neo-inositol could be accessed by an
analogous sequence simply by employing the enantiomeric
silylallylborating reagent, ent-7, in the allylboration of 8.
Treatment of (E)-γ-silylallylborane 7 with aldehyde 816
gave hydroxysilane 6 in 83% yield with 9:1 diastereoselec-
tivity (Scheme 1). Subsequent RCM of 6 using Grubbs’
Figure 2. Inositols and Ins(1,4,5)P3.
Considerable effort has been devoted toward the synthesis
of all of the conduritol and inositol stereoisomers.1a,9
Recently, syntheses of optically pure conduritols have been
developed starting from sugars10 and tartrate derivatives,11
by sequences involving ring-closing metathesis (RCM)
reactions. The use of chemical12 or enzymatic13 resolution
of racemic conduritols or their precursors has also provided
access to enantiomerically pure cyclitol derivatives.
Various approaches for the synthesis of inositols and their
phosphate derivatives have been developed, including the
use of commercially available inositols14c-e,h,15 and sugars,10e,14a,
microbial oxidation of arenes,14f and hydrogenation of
tetrahydroxyquinone.14g Landais has synthesized several
Scheme 1
(7) (a) Hanck, T.; Stricker, R.; Krishna, U. M.; Falck, J. R.; Chang, Y.
T.; Chung S. K.; Reiser, G. Eur. J. Biochem. 1999, 261, 577. (b) Chung, S.
K.; Shin, B. G.; Chang, Y. T.; Suh, B. C.; Kim, K. T. Bioorg. Med. Chem.
Lett. 1998, 8, 659.
(8) For a review, see: Berridge, M. J.; Irvine, R. F. Nature 1989, 341,
197.
(9) For recent examples, see: (a) de Sousa, S. E.; O’Brien, P.; Pilgram,
C. D. Tetrahedron 2002, 58, 4643. (b) Kadota, K.; Takeuchi, M.; Taniguchi,
T.; Ogawawara, K. Org. Lett. 2001, 3, 1769. (c) Cere´, V.; Mantovani, G.;
Peri, F.; Pollicino, S.; Ricci, A. Tetrahedron 2000, 56, 1225. (d) Ley, S.
V.; Parra, M.; Redgrave, A. J.; Sternfeld, F. Tetrahedron 1990, 46, 4995.
(10) (a) Jorgensen, M.; Iversen, E. H.; Paulsen, A. L.; Madsen, R. J.
Org. Chem. 2001, 66, 4630. (b) Hyldtoft, L.; Madsen, R. J. Am. Chem.
Soc. 2000, 122, 8444. (c) Ackermann, L.; Tom, D. E.; Fu¨rstner, A.
Tetrahedron 2000, 56, 2195. (d) Gallos, J. K.; Koftis, T. V.; Sarli, V. C.;
Litinas, K. E. J. Chem. Soc., Perkin Trans. 1 1999, 3075. (e) Kornienko,
A.; d’Alarcao, M. Tetrahedron: Asymmetry 1999, 10, 827.
(11) (a) Conrad, R. M.; Grogan, M. J.; Bertozzi, C. R. Org. Lett. 2002,
4, 1359. (b) Lee, W.-W.; Chang, S. Tetrahedron: Asymmetry 1999, 10,
4473.
(12) (a) Trost, B. M.; Patterson, D. E.; Hembre, E. J. J. Am. Chem. Soc.
1999, 121, 10834. (b) Innes, J. E.; Edwards, P. J.; Ley, S. V. J. Chem.
Soc., Perkin Trans. 1 1997, 795.
(13) (a) Kwon, Y. U.; Chung, S. K. Org. Lett. 2001, 3, 3013. (b)
Sanfilippo, C.; Patti, A.; Nicolosi, G. Tetrahedron: Asymmetry 2000, 11,
1043. (c) Yoshizaki, H.; Ba¨ckvall, J. E. J. Org. Chem. 1998, 63, 9339.
catalyst 920 provided cyclohexenylsilane 10, which was
subjected to catalytic dihydroxylation conditions21 to provide
trihydroxysilane 5 as a single isomer in 94% yield. As
expected, the dihydroxylation reaction proceeded in an anti
manner to both the allylic dimethylphenylsilyl and benzyloxy
substituents.
The dimethylphenylsilyl unit in 5 possesses two â-
hydroxyls, one in a cis and the other in a trans relationship.
1698
Org. Lett., Vol. 5, No. 10, 2003

Figure 3. Retrosynthetic Analysis.
Treatment of 5 with KHMDS at -78 °C in the presence of
18-crown-6 provided the conduritol F derivative 222 via
Peterson elimination of the cis-hydroxysilane with high
selectivity (>20:1 dr) (Scheme 2). We had anticipated that
with excellent stereoselectivity. However, subjection of 5 to
a variety of basic reaction conditions afforded a mixture of
elimination products 2 and 3.24 The base-promoted Peterson
elimination of the trans-â-hydroxysilane unit in 5 (leading
to 3) must occur via a stepwise pathway.23
On the other hand, treatment of 5 with sulfuric acid
furnished conduritol B derivative 3 as the sole product via
Peterson elimination of the trans-hydroxysilane. Removal
of the benzyl ether protecting groups in 2 and 3 under
dissolving metal conditions25 provided conduritols F and B,
respectively.26 Hydroxysilane 5 was also converted to D-(+)-
chiro-inositol via Fleming-Tamao oxidation followed by
hydrogenolytic debenzylation of tetrol 4.
Scheme 2
To extend this strategy to the synthesis of conduritols C
and E and neo-inositol, we targeted the diastereomeric
â-hydroxy cyclohexylsilane 14 as a key intermediate. Silyl-
allylboration of aldehyde 8 with ent-7, prepared from (+)-
Ipc2BOMe, afforded the â-hydroxyallylsilane diastereomers
6 and 11 as a 1:1 mixture (Scheme 3).27 After separation of
the two products by column chromatography, RCM cycliza-
tion of 11 provided cyclohexene 12 in 87% yield. Treatment
the base-promoted Peterson elimination reaction would
proceed via a concerted reaction mechanism23 and that cyclic
â-hydroxy silanes such as 5 would undergo syn elimination
(22) Compound 2 constitutes a formal synthesis of D-myo-inositol-1,4,5-
triphosphate 1 (Figure 2) and was in agreement with reported spectral data;
see ref 9d.
(23) Staden, L. F.; Gravestock, D.; Ager, D. J. Chem. Soc. ReV. 2002,
31, 195 and references cited therein.
(24) (a) KH, THF, 0 °C, 8 h; 80% (2:3 ) 16:1). (b) KHMDS, THF,
-78 °C, 6 h; 50-88% (2:3 ) 6-20:1). (c) KOtBu, THF, 0 °C, 2 h; 33%
(2:3 ) 6:1). (d) KOtBu, 18-C-6, THF, 0 °C, 1 h; 58% (2:3 ) 16:1).
(25) Sulikowski, M. M.; Ellis Davies, G. E. R.; Smith, A. B., III. J.
Chem. Soc., Perkin Trans. 1 1992, 979.
(14) For recent examples, see: (a) Takahashi, H.; Kittaka, H.; Ikegami,
S. J. Org. Chem. 2001, 66, 2705. (b) Angleaud, R.; Babot, O.; Charvat, T.;
Landais, Y. J. Org. Chem. 1999, 64, 9613. (c) Riley, A. M.; Jenkins, D. J.;
Potter, B. V. L. Carbohydr. Res. 1998, 314, 277. (d) Husson, C.; Odier, L.;
Votte´ro, P. J. A. Carbohydr. Res. 1998, 307, 163. (e) Gigg, J.; Gigg, R.
Carbohydr. Res. 1997, 299, 77. (f) Desjardins, M.; Brammer, L. E., Jr.;
Hudlicky, T. Carbohydr. Res. 1997, 304, 39. (g) Angyal, S. J.; Odier, L.;
Tate, M. E. Carbohydr. Res. 1995, 266, 143. (h) Bruzik, K. S.; Tsai, M.-D.
J. Am. Chem. Soc. 1992, 114, 6361.
(15) Liu, C.; Riley, A. M.; Yang, X.; Shears, S. B.; Potter, B. V. L. J.
Med. Chem. 2001, 44, 2984.
(16) Heo, J.-N.; Micalizio, G. C.; Roush, W. R. Org. Lett. 2003, 5,
1693.
(26) All known compounds exhibited acceptable 1H NMR, 13C NMR,
optical rotation, and HRMS compared to literature values.
(27) Diastereoselectivity of silylallylboration en route to the stereotetrad
in 11 has been improved by using the acetonide-protected aldehyde 21 (cf.
8), which gave â-hydroxyallylsilane 22 with >15:1 dr. Compound 22 readily
underwent RCM to provide cyclohexene 23 in good yield. Further
elaboration of 23 to cyclitol derivatives will be reported in our subsequent
papers in this series.
(17) Hudrlik, P. F.; Peterson, D. J. Am. Chem. Soc. 1975, 97, 1464.
(18) For a review, see: Jones, G. R.; Landais, Y. Tetrahedron 1996, 52,
7599.
(19) Roush, W. R.; Pinchuk, A. N.; Micalizio, G. C. Tetrahedron Lett.
2000, 41, 9413.
(20) Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett. 1999, 1,
953.
(21) VanRheenen, V.; Kelly, R. C.; Cha, D. Y. Tetrahedron Lett. 1976,
23, 1973.
Org. Lett., Vol. 5, No. 10, 2003
1699

Peterson elimination of 14 under the basic conditions
developed previously (KHMDS, 18-C-6, THF, -78 °C) for
the conversion of 5 to 2 provided a 4:1 mixture of 18 and
19. Purification of 18 using HPLC followed by removal of
the benzyl protecting groups under dissolving metal condi-
tions provided conduritol C.26
Scheme 3
The surprising formation of 19 from 14 under basic
conditions again strongly implicates a stepwise mechanism
for the base-promoted Peterson elimination reaction.23 How-
ever, at present, the factors that influence the partition
between the base-promoted syn and anti elimination path-
ways are uncertain. Studies probing the unexpected lack of
stereoselectivity in these elimination reactions are in progress
and will be reported separately.
For the synthesis of conduritol E, concomitant removal
of the TBS protecting group and acidic Peterson elimination
occurred when 16 was treated with TsOH/CH3CN. This
provided 19 as a single isomer in 95% yield. Subsequent
removal of the benzyl protecting groups afforded conduritol
E. Finally, subjection of 14 to Fleming-Tamao oxidation
and hydrogenolysis of 20 provided neo-inositol in good
overall yield.
of 12 under a variety of dihydroxylation conditions28 failed
to provide 14 with acceptable levels of diastereoselectivity.
Consequently, we protected the free hydroxyl group of 12
as the tert-butyldimethylsilyl ether to block the â-face. Silyl
ether 13 was then subjected to catalytic olefin dihydroxyl-
ation conditions29 to provide hydroxysilanes 16 and 17 with
good selectivity (6.6:1 dr).
In summary, we have synthesized a variety of cyclitol
derivatives in a highly divergent manner utilizing cyclo-
hexenylsilanes as common intermediates. The unique reac-
tivity of the silane moiety permitted trifurcation of the
synthetic sequence such that the three cyclitols were accessed
from a single cyclohexenylsilane intermediate. Further ap-
plications of cyclohexenylsilanes in organic synthesis will
be reported in due course.
Treatment of 16 with HF-pyridine gave the corresponding
alcohol 14 in 70% yield along with small amounts of the
elimination product 19 (<10%) (Scheme 4). Subsequent
Scheme 4
Acknowledgment. We thank the National Institutes of
Health (GM 38907) for financial support.
Supporting Information Available: Experimental pro-
cedures and spectral data for compounds 2-6 and 10-20.
This material is available free of charge via the Internet at
http://pubs.acs.org.
OL034349D
(28) Kolb, H. C.; VanNieuwenhze, M. S.; Sharpless, K. B. Chem. ReV.
1994, 94, 2483.
(29) Andersson, P. G.; Sharpless, K. B. J. Am. Chem. Soc. 1993, 115,
7047.
1700
Org. Lett., Vol. 5, No. 10, 2003