Stereoselective synthesis of allyl-C-mannosyl compounds: Use of a temporary silicon connection in intramolecular allylation strategies with allylsilanes

Ster eoselective Syn th esis of Allyl-C-m a n n osyl Com p ou n d s: Use of

a Tem p or a r y Silicon Con n ection in In tr a m olecu la r Allyla tion

Str a tegies w ith Allylsila n es

J ulien Beignet, J ames Tiernan, Chang H. Woo, Benson M. Kariuki, and Liam R. Cox*

School of Chemistry, The University of Birmingham, Edgbaston, Birmingham B15 2TT, U.K.

l.r.cox@bham.ac.uk

Received J une 4, 2004

Methyl mannoside 16 containing an allyldimethylsilyl ether at C(2) was synthesized in nine steps

from ^D-mannose. Reaction with TMSOTf in MeCN at room-temperature effected C-glycosylation

to provide the R-allyl-C-mannosyl product 18 with excellent stereoselectivity. Crossover experiments

over a range of reaction concentrations proved that reaction was proceeding via an intermolecular

pathway rather than the hoped-for intramolecular delivery route. The exceptionally high stereo-

selectivity of this allylation in the presence of an acid-scavenger, 2,6-DTBMP, can be attributed to

the allylsilyl ether 16 behaving as the allylating agent. Geometrical constraints in the seven-

membered ring transition state account for the lack of intramolecular allyl transfer. Attaching a

modified allylsilane 29a -c to C(2)OH of methyl mannoside 15 improved matters. Reaction of the

tethered mannosides 27a -c with TMSOTf in the presence of 2,6-DTBMP in MeCN at rt provided

a range of products, which depended on the size of the alkyl substituents at the silyl ether tether.

Diene products were the major compounds irrespective of the size of the alkyl substituents at the

silyl ether tether. Their formation can be understood by intramolecular allylation of the allylsilane

on to the activated anomeric center, followed by collapse of the intermediate carbocation by

preferential attack of an external nucleophile at the silyl ether tether, rather than at the allylic

silicon center. A cascade of further reactions rationalizes the formation of the 2-dienyl-substituted

tetrahydrofuran 30 and dienes 39 and 40. The desired â-allyl-C-mannosyl products 42 and 43 were

obtained, albeit in low yield, when bulky ethyl and isopropyl groups were employed at the silyl

ether tether. Stereospecific oxidative cleavage of the silyl tether in 42 and 43 provided the

corresponding stereodefined diols 44 and 45, respectively. Attempts to improve the yield and

diastereoselectivity of the desired â-allyl-C-mannosyls by moving to a sulfoxide mannosyl donor,

which could be activated at low temperature, proved unsuccessful.

In tr od u ction

chemistry programs as hydrolytically stable mimics of

O-glycosides.⁶

C-Glycosyl compounds are an important class of car-

bohydrate analogue.¹They occur in a number of impor-

tant families of natural products,²and have also proved

to be invaluable intermediates in more general natural

product synthesis.³Since it has been demonstrated that

C-glycosyl compounds can adopt similar conformations

to their corresponding O-glycosides,^4,5these compounds

have also found application in biological and medicinal

Allyl-C-glycosyl compounds (Figure 1) have proved to

be particularly important in synthesis owing to the

versatility of the terminal olefin functionality which can

be employed in a range of further transformations.⁷

A variety of methods has been developed for selectively

preparing allyl-C-glycosyl compounds. Of the two possible

(3) Avermectins: Wincott, F. E.; Danishefsky, S. J .; Schulte, G.

Tetrahedron Lett. 1987, 28, 4951-4954. Okadaic acid: Ichikawa, Y.;

Isobe, M.; Goto, T. Tetrahedron 1987, 43, 4749-4758. Halichondrin

B: Horita, K.; Sakurai, Y.; Nagasawa, M.; Hachiya, S.; Yonemitsu, O.

Synlett 1994, 43-45. Brevetoxin B: Nicolaou, K. C.; Duggan, M. E.;

Hwang, C.-K.; Somers, P. K. J . Chem. Soc., Chem. Commun. 1985,

1359-1362. Palytoxin: Fujioka, H.; Christ, W. J .; Cha, J . K.; Leder,

J .; Kishi, Y.; Uemura, D.; Hirata, Y. J . Am. Chem. Soc. 1982, 104,

7367-7369. Altohyrtin C: Evans, D. A.; Trotter, B. W.; Coˆte´, B.;

Coleman, P. J .; Dias, L. C.; Tyler, A. N. Angew. Chem., Int. Ed. Engl.

1997, 36, 2744-2747.

(4) For papers that demonstrate that C-glycosyls adopt similar

conformations to O-glycosides, see, for example: (a) Wu, T.-C.;

Goekjian, P. G.; Kishi, Y. J . Org. Chem. 1987, 52, 4819-4823. (b) Kishi,

Y. Pure. Appl. Chem. 1993, 65, 771-778. (c) Martin, O. R.; Lai, W. J .

Org. Chem. 1993, 58, 176-185. (d) Duda, C. A.; Stevens, E. S. J . Am.

Chem. Soc. 1993, 115, 8487-8488. (e) Ferritto, R.; Vogel, P. Tetrahe-

dron: Asymmetry 1994, 5, 2077-2092.

* Corresponding Author. Fax: +44 (0)121 414 4403. Tel: +44 (0)-

121 414 3524.

(1) For reviews on C-glycosyl compounds, see: (a) Du, Y.; Linhardt,

R. J .; Vlahov, I. R. Tetrahedron 1998, 54, 9913-9959. (b) Postema, M.

H. D. Tetrahedron 1992, 48, 8545-8599. (c) J aramillo, C.; Knapp, S.

Synthesis 1994, 1-20. (d) Togo, H.; He, W.; Waki, Y.; Yokoyama, M.

Synlett 1998, 700-717. (e) Beau, J .-M.; Gallagher, T. Top. Curr. Chem.

1997, 187, 1-54.

(2) For some examples of naturally occurring C-glycosyls, see the

following. Aquamycin: Sezaki, M.; Kondo, S.; Maeda, K.; Umezawa,

H.; Ohno, M. Tetrahedron 1970, 26, 5171-5190. Rubiflavin: Nadig,

H.; Se´quin, U. Helv. Chim. Acta 1987, 70, 1217-1228. Papulacandin:

Traxler, P.; Tosch, W.; Zak, O. J . Antibiot. 1987, 40, 1146-1164.

Vineomycin B2: Imamura, N.; Kakinuma, K.; Ikekawa, N.; Tanaka,

H.; Omura, S. J . Antibiot. 1981, 34, 1517-1518. Gilvocarcins: Taka-

hashi, K.; Yoshida, M.; Tomita, F.; Shirahata, K. J . Antibiot. 1981,

34, 271-275.

Published on Web 08/17/2004

J . Org. Chem. 2004, 69, 6341-6356

6341

Beignet et al.

SCHEME 1. Syn th esis of r- a n d

â-Allyl-C-m a n n osyls^a

F IGURE 1. Allyl-C-glycosyl compounds find widespread use

in synthesis.

diastereoisomers, 1 and 2, the stereoselective synthesis

of R-allyl-C-glycopyranosyl compounds 1 has proved to

be the most straightforward.^8-10This diastereoisomer is

most frequently prepared by reacting a nucleophilic

allylmetal with a glycosyl donor.⁸For example, Hosomi

and Sakurai demonstrated some time ago that allylsi-

lanes were particularly good allylating agents for this

process.^8aReaction with a range of methyl glycosides,

under Lewis acid activation, provided the corresponding

R-allyl-C-glycosyl compounds in excellent yield and ste-

reoselectivity. For example, methyl 2,3,4,6-tetra-O-ben-

zyl-R-^D-mannopyranoside 3 reacted with allyltrimethyl-

a

Reagents and conditions: (a) allyltrimethylsilane, TMSOTf (20

mol %), MeCN, rt, 25 h, 87%; (b) (allyl)MgBr, Et₂O, -78 °C; (c)

Et₃SiH, BF₃‚OEt₂, MeCN, 0 °C to rt, 67% (two steps).

silane, in the presence of TMSOTf, to provide exclusively,

the corresponding R-allyl-C-mannosyl product 4 in 87%

yield (Scheme 1). The corresponding glucosyl analogue

was prepared in a similar yield and 91:9 R/â diastereo-

selectivity.^8aThis intermolecular Lewis acid-mediated

allylation of methyl mannopyranosides currently provides

one of the best and most widely used routes to R-allyl-

C-mannosyls.

(5) For papers that demonstrate how C-glycosyls adopt different

conformations to O-glycosides, see, for example: (a) O’Leary, D. J .;

Kishi, Y. Tetrahedron Lett. 1994, 35, 5591-5594. (b) Espinosa, J .-F.;

Can˜ada, F. J .; Asensio, J . L.; Mart´ın-Pastor, M.; Dietrich, H.; Mart´ın-

Lomas, M.; Schmidt, R. R.; J ime´nez-Barbero, J . J . Am. Chem. Soc.

1996, 118, 10862-10871. (c) Espinosa, J .-F.; Bruix, M.; J arreton, O.;

Skrydstrup, T.; Beau, J . M.; J ime´nez-Barbero, J . Chem. Eur. J . 1999,

5, 442-448.

(6) (a) Nagy, J . O.; Wang, P.; Gilbert, J . H.; Schaefer, M. E.; Hill, T.

G.; Callstrom, M. R.; Bednarski, M. D. J . Med. Chem. 1992, 35, 4501-

4502. (b) Ko, K.-S.; Kruse, J .; Pohl, N. L. Org. Lett. 2003, 5, 1781-

1783. (c) Compain, P.; Martin, O. R. Bioorg. Med. Chem. 2001, 9, 3077-

3092. (d) Tsuruta, O.; Yuasa, H.; Kurono, S.; Hashimoto, H. Bioorg.

Med. Chem. Lett. 1999, 9, 807-810.

(7) Oxidative cleavage. Ozonolysis: (a) Shao, H.; Wang, Z.; Lacroix,

E.; Wu, S.-H.; J ennings, H. J .; Zou, W. J . Am. Chem. Soc. 2002, 124,

2130-2131. (b) Cabaret, D.; Wakselman, M. Carbohydr. Res. 1989,

189, 341-348. (c) Cupps, T. L.; Wise, D. S.; Townsend, L. B. J . Org.

Chem. 1982, 47, 5115-5120. Dihydroxylation/periodate cleavage: (d)

Tronchet, J . M. J .; Zse´ly, M.; Geoffroy, M. Carbohydr. Res. 1995, 275,

245-258. (e) Arimoto, H.; Asano, S.; Uemura, D. Tetrahedron Lett.

1997, 38, 7761-7762. Dihydroxylation: (f) Gurjar, M. K.; Mainkar,

A. S.; Syamala, M. Tetrahedron: Asymmetry 1993, 4, 2343-2346.

Epoxidation and iodoetherification: (g) Chiappe, C.; Crotti, P.; Men-

ichetti, E.; Pineschi, M. Tetrahedron: Asymmetry 1998, 9, 4079-4088.

Hydroxymercuration: (h) Lay, L.; Nicotra, F.; Pangrazio, C.; Panza,

L.; Russo, G. J . Chem. Soc., Perkin Trans. 1 1994, 333-338. Hydro-

boration: (l) Palomo, C.; Oiarbide, M.; Landa, A.; Gonza´lez-Rego, M.

C.; Garc´ıa, J . M.; Gonza´lez, A.; Odriozola, J . M.; Mart´ın-Pastor, M.;

Linden, A. J . Am. Chem. Soc. 2002, 124, 8637-8643. Hydrogenation:

(m) Ponte´n, F.; Magnusson, G. J . Org. Chem. 1997, 62, 7972-7977.

Olefin as a radical acceptor: (n) Qian, X.; Metallo, S. J .; Choi, I. S.;

Wu, H.; Liang, M. N.; Whitesides, G. M. Anal. Chem. 2002, 74, 1805-

1810. Wacker oxidation: (o) Nakamura, H.; Fujimaki, K.; Murai, A.

Tetrahedron Lett. 1996, 37, 3153-3156. Ring-closing metathesis: (p)

Fan, G.-T.; Hus, T.-S.; Lin, C.-C.; Lin, C.-C. Tetrahedron Lett. 2000,

41, 6593-6597. Cross-metathesis: (q) Blackwell, H. E.; O’Leary, D.

J .; Chatterjee, A. K.; Washenfelder, R. A.; Bussmann, D. A.; Grubbs,

R. H. J . Am. Chem. Soc. 2000, 122, 58-71. Olefin isomerization: (r)

Wong, C.-H.; Moris-Varas, F.; Hung, S.-C.; Marron, T. G.; Lin, C.-C.;

Gong, K. W.; Weitz-Schmidt, G. J . Am. Chem. Soc. 1997, 119, 8152-

8158. [3 + 2] Cycloadditions: (s) Westermann, B.; Walter, A.; Flo¨rke,

U.; Altenbach, H.-J . Org. Lett. 2001, 3, 1375-1378.

The stereoselective synthesis of â-allyl-C-glycosyl com-

pounds 2 has proved to be much more challenging.^11-14

The most commonly employed route to this diastereo-

isomer was developed by Kishi¹¹and exploits the pref-

erential addition of nucleophiles to the R-face of activated

glycopyranosides. In a two-step process, addition of an

allylmetal into a glyconolactone, provides a tertiary lactol

product. Subsequent Lewis acid-mediated reduction with

Et₃SiH generates the desired allyl-C-glycosyl, usually

with the â-diastereoisomer predominating (Scheme 1).

Another approach to this diastereoisomer involves react-

ing an allylmetal with a glycal epoxide.¹²However, only

by careful choice of allylating agent and/or activating

Lewis acid is the â-allyl-C-glycosyl prepared selectively.¹²

Unfortunately, the presence of an axially oriented

alcohol substituent at C(2) in mannopyranosides renders

the synthesis of â-allyl-C-mannosyls particularly difficult.

For example, application of Kishi’s methodology to the

perbenzylated mannonolactone 5 provided a 1:1 mixture

of the two diastereoisomeric products (Scheme 1). Kishi

proposed that a build-up of unfavorable steric interac-

tions in the transition state (T.S.) leading to the 1,2-syn

stereoisomer, i.e., the â-product, accounted for the poor

stereoselectivity of this reaction. In the corresponding

glucose system, where this type of steric interaction is

absent, the â-allyl-C-glucosyl product could be isolated

in excellent stereoselectivity (â/R, >10:1).¹¹

The formation of â-O-mannosides has, until recently,

also been one of the most difficult glycosidic bonds to

prepare stereoselectively, and a number of approaches

have been developed for addressing this specific prob-

(8) (a) Hosomi, A.; Sakata, Y.; Sakurai, H. Carbohydr. Res. 1987,

171, 223-232. (b) Nicolaou, K. C.; Dolle, R. E.; Chucholowski, A.;

Randall, J . L. J . Chem. Soc., Chem. Commun. 1984, 1153-1154. (c)

Kozikowski, A. P.; Sorgi, K. L.; Wang, B. C.; Xu, Z.-B. Tetrahedron

Lett. 1983, 24, 1563-1566. (d) Giannis, A.; Sandhoff, K. Tetrahedron

Lett. 1985, 26, 1479-1482. (e) Bennek, J . A.; Gray, G. R. J . Org. Chem.

1987, 52, 892-897.

(9) Toshima, K.; Miyamoto, N.; Matsuo, G.; Nakata, M.; Matsumura,

S. Chem. Commun. 1996, 1379-1380.

(10) (a) Keck, G. E.; Enholm, E. J .; Kachensky, D. F. Tetrahedron

Lett. 1984, 25, 1867-1870. (b) Ponte´n, F.; Magnusson, G. J . Org. Chem.

1996, 61, 7463-7466. (c) Sire, B.; Seguin, S.; Zard, S. Z.; Angew. Chem.,

Int. Ed. 1998, 37, 2864-2866.

(11) Lewis, M. D.; Cha, J . K.; Kishi, Y. J . Am. Chem. Soc. 1982,

104, 4976-4978.

(12) (a) Evans, D. A.; Trotter, B. W.; Coˆte´, B. Tetrahedron Lett. 1998,

39, 1709-1712. (b) Leeuwenburgh, M. A.; Kulker, C.; Overkleeft, H.

S.; van der Marel, G. A.; van Boom, J . H. Synlett 1999, 1945-1947.

(c) Best, W. M.; Ferro, V.; Harle, J .; Stick, R. V.; Tilbrook, D. M. G.

Aust. J . Chem. 1997, 50, 463-472.

(13) Praly, J .-P.; Chen, G.-R.; Gola, J .; Hetzer, G. Eur. J . Org. Chem.

2000, 2831-2838.

(14) Shulman, M. L.; Shiyan, S. D.; Khorlin, A. Y. Carbohydr. Res.

1974, 33, 229-235.

6342 J . Org. Chem., Vol. 69, No. 19, 2004

Stereoselective Synthesis of Allyl-C-mannosyl Compounds

SCHEME 2. J u d iciou s Ch oice of Allyla tin g Agen t

Lea d s to Im p r oved â-Selectivity

F IGURE 2. Use of an intramolecular delivery strategy to

synthesize â-allyl-C-mannosyls.

lem.¹⁵One of the most interesting and creative utilizes

the intramolecular aglycon delivery strategy,¹⁶first

introduced by Stork¹⁷and Hindsgaul.¹⁸Both groups

exploited the axial alcohol at C(2) to temporarily attach

the acceptor to a suitable glycosyl donor.¹⁹Activation of

the donor then resulted in intramolecular transfer of the

acceptor to the anomeric center to provide the corre-

sponding â-O-mannoside with essentially complete ste-

reocontrol.

Similar tethering strategies have also been used to

control the stereoselectivity of a variety of C-glycosylation

reactions, most of which have involved the generation of

a radical at the anomeric center, which has then been

trapped by a tethered acceptor.²⁰We are interested in

investigating the possibility of using a similar strategy

to prepare â-allyl-C-mannosyls by delivering an allyl

nucleophile that has been tethered to the alcohol at C(2)

through a silyl ether linkage (Figure 2). This would

provide an alternative strategy to the most commonly

employed approach to this class of compound, developed

by Kishi, which in the case of mannose derivatives is

frequently poorly stereoselective (although see Scheme

5).

C(2)OH in a range of methyl furanosides to tether and

subsequently deliver silyl nucleophiles to the activated

anomeric center.^21aIn a single example, methyl xylofura-

noside 6 was treated with SnCl₄in the presence of

allyldimethylsilyl chloride. The two allyl-C-furanosyl

products 7 and 8 were obtained in good yield with the

â-diastereoisomer predominating (Scheme 2).

Martin postulated that in situ formation of the 2-O-

allyldimethylsilyl derivative from 6, followed by SnCl₄-

mediated activation of the anomeric center, led to in-

tramolecular delivery of the allyl group to the anomeric

center. Molecular models suggested that in this case,

reaction through a seven-membered cyclic T.S. would

preferentially provide the observed 1,2-trans product, as

opposed to the 1,2-cis product that is normally obtained

using this type of delivery strategy.²¹This is a conse-

quence of a better alignment of the C-Si bond with the

reacting π-system affording improved stabilization of any

build-up of positive charge in the T.S. The only evidence

to suggest that the reaction was intramolecular came

from a comparison of the diastereoselectivity of the

reaction when allyltrimethylsilane was employed as the

allylating agent. In this case, a 1:1 mixture of R- and

â-allyl-C-furanosyls 7 and 8 was obtained (Scheme 2).

A number of related studies have shown that the C(2)-

OH of a saccharide can be used to deliver a nucleophile

to an activated glycosyl donor, usually to provide a 1,2-

syn-C-glycosyl product.²¹The most significant of these

for our purposes comes from Martin et al. who used the

(15) Pozsgay V. In Carbohydrates in Chemistry and Biology, Part

1: Chemistry of Saccharides; Ernst, B., Hart, G. W., Sinay¨, P., Eds.;

Wiley-VCH: Weinheim, 2000; Vol. 1, Chapter 13, pp 319-343.

(16) For a review on intramolecular aglycon delivery, see: Fair-

banks, A. J . Synlett 2003, 1945-1958 and references therein.

(17) (a) Stork, G.; Kim, G. J . Am. Chem. Soc. 1992, 114, 1087-1088.

(b) Stork, G.; La Clair, J . J . J . Am. Chem. Soc. 1996, 118, 247-248.

(18) (a) Barresi, F.; Hindsgaul, O. J . Am. Chem. Soc. 1991, 113,

9376-9377. (b) Barresi, F.; Hindsgaul, O. Synlett, 1992, 759-761. (c)

Barresi, F.; Hindsgaul, O. Can. J . Chem. 1994, 72, 1447-1465.

(19) For general reviews on the use of the temporary connection in

synthesis, see: (a) Cox, L. R.; Ley, S. V. In Templated Organic

Synthesis; Diederich, F., Stang, P. J ., Eds.; Wiley-VCH: Weinheim,

2000; Chapter 10, pp 275-375. (b) Bols, M.; Skrydstrup, T. Chem. Rev.

1995, 95, 1253-1277. (c) Fensterbank, L.; Malacria, M.; Sieburth, S.

M. Synthesis 1997, 813-854. (d) Gauthier, D. R., J r.; Zandi, K. S.; Shea,

K. J . Tetrahedron 1998, 54, 2289-2238.

(20) (a) Stork, G.; Suh, H. S.; Kim, G. J . Am. Chem. Soc. 1991, 113,

7054-7056. (b) Myers, A. G.; Gin, D. Y.; Widdowson, K. L. J . Am.

Chem. Soc. 1991, 113, 9661-9663. (c) Xin, Y. C.; Mallet, J .-M.; Sinay¨,

P. J . Chem. Soc., Chem. Commun. 1993, 864-865. (d) Vauzeilles, B.;

Cravo, D.; Mallet, J .-M.; Sinay¨, P. Synlett 1993, 522-524. (e) Che´nede´,

A.; Perrin, E.; Reka¨ı, E. D.; Sinay¨, P. Synlett 1994, 420-422. (f)

Skrydstrup, T.; Maze´as, D.; Elmouchir, M.; Doisneau, G.; Riche, C.;

Chiaroni, A.; Beau, J .-M. Chem. Eur. J . 1997, 3, 1342-1356. (g) Shuto,

S.; Terauchi, M.; Yahiro, Y.; Abe, H.; Ichikawa, S.; Matsuda, A.

Tetrahedron Lett. 2000, 41, 4151-4155.

Resu lts a n d Discu ssion

To ensure that allylation proceeded by the desired

intramolecular pathway, Martin et al. had to rely on in

situ tethering of the allylsilane being faster than any

competing intermolecular allylation process (Scheme 2).

Since the axial orientation of C(2) in mannose renders

derivatization of this alcohol relatively difficult, we took

the precautionary measure of separating these two

processes, choosing to form the silyl ether connection in

a first step and examine the C-glycosylation in a second.

Methyl mannoside 16 was therefore our first target; its

preparation is outlined in Scheme 3.

Synthesis began with peracetylation of commercially

available ^D-mannose, using the conditions reported by

Kartha and Field,²²to provide the corresponding pen-

taacetate 9 in quantitative yield and as a 3:1 mixture of

R/â anomers. These were used without purification in the

next step; thus exposure of 9 to HBr in acetic acid

provided the corresponding anomeric bromide 10, in

which anchimeric assistance of the acetate at C(2)

(21) (a) Martin, O. R.; Rao, S. P.; Kurz, K. G.; El-Shenawy, H. A. J .

Am. Chem. Soc. 1988, 110, 8698-8700. (b) Bu¨rli, R.; Vasella, A. Helv.

Chim. Acta 1996, 79, 1159-1168. (c) Leeuwenburgh, M. A.; Timmers,

C. M.; van der Marel, G. A.; van Boom, J . H.; Mallet, J .-M.; Sinay¨, P.

G. Tetrahedron Lett. 1997, 38, 6251-6254. (d) Rainier, J . D.; Cox, J .

M. Org. Lett. 2000, 2, 2707-2709. (e) Rousseau, C.; Martin, O. R.; Org.

Lett. 2003, 5, 3763-3766.

(22) Kartha, K. P. R.; Field, R. A. Tetrahedron 1997, 53, 11753-

11766.

J . Org. Chem, Vol. 69, No. 19, 2004 6343

Beignet et al.

SCHEME 3. P r ep a r a tion of Allyla tion P r ecu r sor 16 fr om D-Ma n n ose^a

a

Reagents and conditions: (a) Ac₂O, I₂, 0 °C to rt, 1 h; (b) HBr in AcOH (30%), AcOH, 0 °C to rt, 12 h; (c) 2,6-lutidine, MeOH-CHCl₃

(1:1), rt, 24 h, 63% (three steps); (d) K₂CO₃, MeOH, rt, 2 h; (e) NaH, BnBr, DMF, 0 °C to rt, 24 h, 90% (two steps); (f) TMSOTf, 4 Å MS,

CH₂Cl₂, 0 °C, 1 h, quant; (g) K₂CO₃, MeOH, rt, 1 h, quant; (h) allyldimethylsilyl chloride, imidazole, DMF, rt, 24 h, 80%.

SCHEME 4. P r ep a r a tion of r-Allyl-C-m a n n osyl 18^a

ensured the obtention of exclusively the R-stereoisomer.²³

Examining our target 16, we next needed to differentiate

the alcohol at C(2) from those at C(3), C(4), and C(6). This

was readily achieved by temporarily protecting C(2) as

an ortho ester. Thus, stirring a solution of bromide 10

and 2,6-lutidine in chloroform/methanol (1:1) provided

the desired ortho ester 11 in good yield.^24,25It was

a

Reagents and conditions: (a) allyltrimethylsilane, TMSOTf,

convenient to purify at this stage and recrystallization

MeCN, rt, 2.5 h; (b) TBAF, THF, rt, 20 h, 91% (two steps).

from ether-methanol provided ortho ester 11 (93:7, exo/

endo) in 63% yield over the three steps from ^D-mannose.

Crystals of exo-11 suitable for analysis by X-ray diffrac-

anomeric center to hopefully provide a â-allyl-C-mannosyl

product.

tion were grown from ether-methanol and confirmed the

To measure the stereoselectivity of the allylation

relative stereochemistry of the major diastereoisomer (see

reaction, we required a sample of the two diastereoiso-

the Supporting Information). With the alcohol at C(2)

meric allyl-C-mannosyl products that could be produced

successfully protected as a base-stable ortho ester, re-

from the reaction. These were prepared using modifica-

moval of the remaining acetate protecting groups at C(3),

tions of approaches already reported in the literature.

C(4), and C(6) with K₂CO₃in MeOH provided the

Synthesis of R-allyl-C-mannosyl 18 was achieved using

corresponding triol 12. This was directly benzylated

under standard conditions to provide tribenzyl ether 13

in excellent yield (90%) over the two steps. Once again,

large-scale purification was readily achieved by recrys-

tallization from EtOAc-hexane (see the Supporting

Information for a crystal structure of exo-13). TMSOTf-

mediated opening of the ortho ester in 13 provided the

desired methyl mannoside 14.²⁶Subsequent deacetyla-

tion unmasked the alcohol at C(2) in readiness for

attaching the allylsilane nucleophile. Silyl ether 16 was

prepared by treating alcohol 15 with commercially avail-

able allyldimethylsilyl chloride in the presence of imida-

zole in DMF. The reaction was slow (24 h), as we had

expected, although did furnish the desired product 16 in

good yield (80%), providing moisture was rigorously

excluded from the reaction.²⁷With our target in hand,

we were now ready to investigate the possibility of

intramolecularly transferring the allyl group to the

the methodology developed by Hosomi and Sakurai.^8a

Reaction of methyl 3,4,6-tri-O-benzyl-2-O-tert-butyldi-

methylsilyl-R-^D-mannopyranoside 17 (readily prepared

from alcohol 15) with allyltrimethylsilane, in the presence

of TMSOTf, provided the desired alcohol R-diastereo-

isomer 18 in good yield (R/â, 13:1) after TBAF deprotec-

tion of the crude silyl ether products and purification by

flash column chromatography (Scheme 4).

Since this route provided only small quantities of the

â-allyl-C-mannosyl compound 24, we used a modified

version of Kishi’s methodology¹¹to access larger quanti-

ties of this diastereoisomer (Scheme 5).

Ortho ester 13 has proved to be a versatile intermedi-

ate. For the present purposes, ring-opening in neat AcOH

provided two products, 19 (mixture of anomers) and 20,

in quantitative yield.^28,29In the next step, we needed to

oxidize lactol 19 to the corresponding lactone 21. Since

separating 19 and 20 by column chromatography proved

difficult, we envisaged this might be unnecessary if we

were to use tetra-n-propylammonium perruthenate

(TPAP)³⁰as the oxidant in the next step. This Ru(VII)-

based oxidant is particularly useful for lactol oxidation

and thus would provide the lactone 21 directly from lactol

(23) Horton, D.; Turner, W. N. J . Org. Chem. 1965, 30, 3387-3394.

(24) Mazurek, M.; Perlin, A. S. Can. J . Chem. 1965, 43, 1918-1923.

(25) Ortho ester 11 can also be prepared in good yield by treating

bromide 10 with N,N-dimethylformamide dimethyl acetal and tet-

rabutylammonium bromide in CH₂Cl₂: Banoub, J .; Boullanger, P.;

Potier, M.; Descotes, G. Tetrahedron Lett. 1986, 27, 4145-4148.

(26) Ogawa, T.; Beppu, K.; Nakabayashi, S. Carbohydr. Res. 1981,

93, C6-C9.

(27) In situ conversion of the silyl chloride into the corresponding

triflate, by treatment with AgOTf, provided a much more effective

silylating agent and afforded the desired silyl ether 16 in 79% yield

after only 3 h: (a) Denmark, S. E.; Griedel, B. D.; Coe, D. M.; Schnute,

M. E. J . Am. Chem. Soc. 1994, 116, 7026-7043. (b) Nagashima, H.;

Terasaki, H.; Saito, Y.; J inno, K.; Itoh, K. J . Org. Chem. 1995, 60,

4966-4967.

(28) Paulsen, H.; Reck, F.; Brokhausen, I. Carbohydr. Res. 1992,

236, 39-71.

(29) The use of TFA (10% in H₂O) in MeCN, as an alternative

approach, provided a similar ratio of products in equally good yield:

Franzyk, H.; Meldal, M.; Paulsen, H.; Bock, K. J . Chem. Soc., Perkin

Trans. 1 1995, 2883-2898.

(30) Ley, S. V.; Norman, J .; Griffith, W. P.; Marsden, S. P. Synthesis

1994, 639-666.

6344 J . Org. Chem., Vol. 69, No. 19, 2004

Stereoselective Synthesis of Allyl-C-mannosyl Compounds

SCHEME 5. P r ep a r a tion of â-Allyl-C-m a n n osyl 24^a

TABLE 1. Rela tive Ra tios of P r od u cts fr om th e

Rea ction of 16 w ith TMSOTf w ith a n d w ith ou t Acid

Sca ven ger s

additive^a

ratio^b18/24/15

no additive

2,6-lutidine

2,6-DTBMP

40:1:17

180:1:20

320:1:10

a

b

2 equiv. Ratio calculated by HPLC.

acetate at C(2) (dr > 20:1) compared with a benzyl ether

at the same site (dr 1:1) (Scheme 1). Presumably in our

case, interception of the oxocarbenium cation by the

neighboring acetate provides an acetoxonium-like inter-

mediate that more effectively blocks the â-face from

hydride attack. In the final step, deacetylation under

Zemplen conditions provided alcohol 24 in good yield.³³

The R- and â-allyl-C-mannosyls 18 and 24 exhibited

quite different ¹H NMR spectra and were also readily

separated by analytical HPLC; thus, we were now in a

position to investigate the allylation reaction of 16. The

reaction of acyclic acetals with allylsilanes and allylstan-

nanes under Lewis acid activation is frequently carried

out in CH₂Cl₂.³⁴Martin also employed CH₂Cl₂in his

allylation of methyl furanoside 6 (Scheme 2).^21aIn our

case, however, treating methyl mannoside 16 with a

range of Lewis acids (BF₃‚OEt₂, SnCl₄, TMSOTf) in CH₂-

Cl₂at either -78 °C or rt only resulted in cleavage of

the silyl ether and recovery of the alcohol 15. Activation

of the methyl glycoside was clearly slow relative to the

rate of cleavage of the dimethylsilyl ether tether. We were

not particularly surprised by this observation since

Hosomi and Sakurai reported similar results in their

intermolecular allylation study,^8aand just like this group,

we obtained more success employing the much more polar

solvent, MeCN (MeNO₂was also suitable but provided

lower yields of the desired allylation product). However,

even with MeCN as solvent, the only Lewis acid that

proved successful in effecting allylation with methyl

mannoside 16 was TMSOTf; SnCl₄and BF₃‚OEt₂both

cleaved the silyl ether tether preferentially resulting in

the recovery of alcohol 15 and the isolation of no allyla-

tion product. In contrast, reaction of methyl mannoside

16 with TMSOTf in MeCN at room temperature led to

rapid consumption of starting material (in 1-2 h). Two

major products were isolated and identified as the

R-allylation product 18, along with the silyl ether hy-

drolysis product 15. Only trace quantities of the â-allyl-

C-mannosyl product 24 were identified (Table 1). Car-

rying out the reaction at lower temperatures led to a

greatly reduced rate of activation of the anomeric center

and cleavage of the silyl ether occurred preferentially.

Although this reaction could potentially proceed with sub-

a

Reagents and conditions: (a) 95% AcOH in H₂O, rt, 20 min,

quant OR 10% CF₃CO₂H in H₂O, MeCN, 0 °C, 30 min, quant; (b)

19 and 20, TPAP (5 mol %), NMO, MeCN, 4 Å MS, rt, 10 min,

90%; (c) (allyl)MgBr, THF, -78 °C, 1.5 h, 70%; (d) Et₃SiH,

TMSOTf, MeCN, rt, 5 min, 47%; (e) NaOMe, MeOH, rt, 12 h, 85%.

19. However, we were also aware of a report that

suggested that the acetate at C(1) in the undesired

compound 20 would migrate on to C(2) in the presence

of amines to provide lactol 19 in situ.^31aSince TPAP is

employed in sub-stoichiometric quantities, along with a

co-oxidant, N-methylmorpholine N-oxide,^31bwe postu-

lated that we could use the amine byproduct from such

an oxidation constructively, to mediate an acetate migra-

tion from C(1) to C(2) in 20. In this way, providing

oxidation of the secondary alcohol in 20 was slow, relative

to the rate of acetate migration, then it would be possible

for both acetates 19 and 20 to converge on the desired

lactone product. This indeed proved to be the case and

we were delighted to observe that TPAP oxidation of the

mixture of alcohols 19 and 20 proceeded rapidly to afford

a single lactone product 21 in excellent yield. The

appearance of C(2)H in 21 as a doublet with a small (2.9

Hz) equatorial-axial ³J coupling to C(3)H confirmed that

no epimerization of the R-stereogenic center had occurred

during the oxidation.

The reaction between allylmagnesium bromide and

lactone 21 required some optimization³²in order to obtain

the desired tertiary lactol product 22 in good yield. We

found that reaction of 21 with 1.2 equiv of (allyl)MgBr

at -78 °C in THF led to the desired tertiary lactol product

22 in 70% yield (Scheme 5).¹¹Treatment of lactol 22 with

Et₃SiH in the presence of TMSOTf or BF₃‚OEt₂effected

ionic reduction to provide the desired â-allyl-C-mannosyl

product 23 in 47% yield after careful purification by

column chromatography.³²Once again, we observed some

differences to the original Kishi work.¹¹The reaction

exhibited much higher levels of stereoselectivity with an

(33) Removing the acetate protecting group at C(2) in â-allyl-C-

mannosyl 23 proved to be much slower than the same reaction

involving methyl mannoside 14 (e.g., the use of K₂CO₃in MeOH proved

ineffective). Presumably the equatorially oriented allyl group at C(1)

in 23 leads to a build-up of steric compression in the tetrahedral

intermediate in the hydrolysis process which serves to reduce the rate

of reaction.

(34) (a) Tsunoda, T.; Suzuki, M.; Noyori. R. Tetrahedron Lett. 1980,

21, 71-74. (b) Noyori, R.; Murata, S.; Suzuki, M. Tetrahedron 1981,

37, 3899-3910.

(31) (a) Wood, H. B., J r.; Fletcher, H. G., J r. J . Am. Chem. Soc. 1956,

78, 2849-2851 and references therein. (b) We acknowledge the

probability that the amine oxide is also mediating acetate migration:

stirring a solution of 19 and 20 in MeCN in the presence of NMO and

activated 4 Å molecular sieves for 1 h at rt did increase the amount of

acetate 19 in the reaction mixture.

(32) See the Supporting Information for more details.

J . Org. Chem, Vol. 69, No. 19, 2004 6345

Beignet et al.

SCHEME 6. Cr oss-Over Exp er im en t Con fir m ed

Th a t Rea ction Wa s P r oceed in g th r ou gh a n

In ter m olecu la r P a th w a y^a

the approximately 1:1 ratio of products suggested that

the allylating agent did not discriminate between the two

glycosyl donors, which was suggestive that reaction was

exclusively an intermolecular process. To further prove

this, we carried out the same crossover experiment at

different reaction concentrations; an increase in the

amount of 18 with dilution, and concomitant reduction

in the amount of crossover product 26 would suggest that

allylation might also be proceeding through an intramo-

lecular pathway to provide the same product. However,

when we carried out the reaction at 0.125 and 0.05 M

(at lower reaction concentrations, allylation was sluggish

and we only observed slow hydrolysis of the silyl ether),

we observed no significant change in the ratio of the two

allylation products. This suggested that, at least in this

concentration range, our attempted strategy to intra-

molecularly deliver an allyl nucleophile to the anomeric

position of mannose had proved unsuccessful.

Precedent that our proposed intramolecular delivery

strategy might have worked comes from the study by

Martin and co-workers who reacted methyl furanoside

6, possessing a free alcohol at C(2), with allyldimethyl-

silyl chloride in the presence of the Lewis acid SnCl₄

(Scheme 2).^21aWhile Martin did not conclusively prove

that the allylation was proceeding via an intramolecular

pathway, the improved stereoselectivity of the reaction

compared with a known intermolecular process, was

highly suggestive that the reaction was proceeding either

by intramolecular delivery of an allyl nucleophile teth-

ered at C(2)OH to the anomeric position or at least by a

different mechanism to the ‘standard’ intermolecular

pathway. Intrigued by the differences in reaction path-

way between our work and that from Martin and co-

workers, we performed a number of control reactions in

the hope that these might shed some light on our system.

Since Martin had not conclusively demonstrated that

a silane was the active allylating agent, we considered

other sources of a nucleophilic allylmetal. We postulated

that the SnCl₄Lewis acid might first react with allyldim-

ethylsilyl chloride, in analogy to the reaction with allyl-

tributylstannane,³⁷to provide the corresponding allyl-

trichlorostannane. This would be expected to react much

more readily with the Lewis basic alcohol at C(2), than

the silyl chloride, to provide a tethered allylstannane

ready for delivery on activation of the anomeric center

(Scheme 7). Alternatively, the Lewis acidity of this

species might also be capable of activating the anomeric

center itself and delivering the nucleophile through a

push-pull type of mechanism (Scheme 7).³⁸Allyltrichlo-

rostannane was prepared by treating allyltributylstan-

nane with SnCl₄at -78 °C in CH₂Cl₂.³⁹Unfortunately,

addition of the alcohol 15 at -78 °C led to no change in

the reaction mixture, nor did adding more SnCl₄and

warming to rt overnight; in all cases, the starting

material was recovered intact.

a

Reagents and conditions: (a) TMSOTf, MeCN, rt.

stoichiometric quantities of Lewis acid, this proved not

to be the case in our system, and the use of 20 mol %

TMSOTf just led to incomplete reaction.

Thus, to our dismay, the R-allyl-C-mannosyl product

18 proved to be the major compound using our tethered

allylsilane approach! Earlier studies had revealed that

our silyl ether temporary connection was acid-labile. We

considered that adventitious water in the reaction might

be generating triflic acid that would rapidly cleave the

tether,³⁵generating an allylating agent that could then

react intermolecularly. Carrying out the reaction in the

presence of an acid scavenger led to significant improve-

ments. Using 2,6-lutidine as the base, appreciably re-

duced the amount of alcohol 15, and the R-allylation

product 18 was now the major compound isolated (Table

1). The reaction was also significantly slower (reaction

required stirring overnight). The situation was further

improved when the even more sterically hindered base

2,6-di-tert-butyl-4-methylpyridine (2,6-DTBMP) was em-

ployed (Table 1).

We initially considered that reaction of 16, containing

our tethered allylsilane nucleophile, was indeed proceed-

ing through an intramolecular pathway, but that the ring

size of the T.S., and relatively long bonds to Si, favored

delivery of the nucleophile to the R-face, in analogy with

Martin’s results (Scheme 2). To verify whether this was

the case, we carried out a series of crossover experiments.

Methyl mannopyranoside 25, readily obtained by methy-

lation of alcohol 15 (NaH, MeI, DMF), was considered a

suitable substrate for these studies. Since silyl ethers and

alkyl ethers have similar activating effects on the reac-

tivity of glycosyl donors,³⁶both methyl glycosides would

be expected to have similar rates of activation in the

presence of TMSOTf. This would diminish the likelihood

of differential activation of the two donors biasing the

results. Reaction of 0.5 equiv of the two methyl glycosides

16 and 25 with 1 equiv of TMSOTf in the presence of

2,6-DTBMP in MeCN at room-temperature provided a

1.2:1.0 mixture of the two possible R-allyl-C-mannosyl

products 18 and 26 (the corresponding â-diastereoisomers

were again identified in trace amounts) (Scheme 6). A

similar result was also obtained in the absence of the acid

scavenger, the only difference being an increase in the

rate of reaction.

The isolation of the crossover product 26 therefore

provided conclusive evidence that allylation was proceed-

ing through an intermolecular pathway. Furthermore,

(37) (a) Naruta, Y.; Nishigaichi, Y.; Maruyama, K. Tetrahedron

1989, 45, 1067-1078. (b) Denmark, S. E.; Wilson, T.; Willson, T. M.

J . Am. Chem. Soc. 1988, 110, 984-986. (c) Keck, G. E.; Andrus, M. B.;

Castellino, S. J . Am. Chem. Soc. 1989, 111, 8136-8141.

(38) Pratt, M. R.; Leigh, C. D.; Bertozzi, C. R. Org. Lett. 2003, 5,

3185-3188.

(35) Davis, A. P.; J aspars, M. J . Chem. Soc., Chem. Commun. 1990,

1176-1178.

(36) Green, L. G.; Ley S. V. In Carbohydrates in Chemistry and

Biology, Part 1: Chemistry of Saccharides; Ernst, B., Hart, G. W., Sinay¨,

P., Eds.; Wiley-VCH: Weinheim, 2000; Vol. 1, Chapter 17, pp 427-

448.

(39) (a) Keck, G. E.; Abott, D. E.; Boden, E. P.; Enholm, E. J .

Tetrahedron Lett. 1984, 25, 3927-3930. (b) McNeill, A. H.; Thomas,

E. J . Tetrahedron Lett. 1990, 31, 6239-6242. (c) Hallett, D. J .; Thomas,

E. J . Synlett 1994, 87-88.

6346 J . Org. Chem., Vol. 69, No. 19, 2004

Stereoselective Synthesis of Allyl-C-mannosyl Compounds

SCHEME 7. P ossibility th a t Allyltr ich lor osta n n a n e

Wa s Actin g a s th e Allyla tin g Agen t Wa s

Discou n ted

of allylsilane 16, we therefore assume that the confor-

mational constraints imposed on the oxocarbenium cation

in the pyranose ring may be such as to render an

intramolecular delivery pathway, in which the developing

charge on the allylsilane can be stabilized by the C-Si

bond, conformationally unviable, the net result being that

intermolecular allylation pathways are followed instead

(Scheme 8). With these considerations in mind, we

envisaged that relocating the silyl ether temporary

connection to the γ-position of the allylsilane would

significantly improve matters. Tethering such a nucleo-

phile to C(2)OH of a methyl mannoside would afford silyl

ether 27 (Scheme 8). In this modified system, intramo-

lecular allylation would now proceed through a five-

membered T.S., rather than the seven-membered T.S.

that would be required using tethered allylsilane 16.

Furthermore, since the allylsilane in 27 would now be

exo to the cyclic T.S., rather than endo, as in 16, we would

hopefully encounter no problems with the allylic C_R-Si

bond adopting an orientation capable of stabilizing

developing positive charge in the T.S. Since reaction

through a five-membered T.S. should also be kinetically

more favorable and would also much more closely re-

semble the T.S.s found in other examples of intramo-

lecular aglycon delivery that have successfully delivered

a 1,2-syn product,^17,18,41-45we were more confident of

achieving our goal of generating a â-allyl-C-mannosyl.

This second-generation system possesses a range of other

attractive features. Owing to the silyl ether tether

remaining intact post allylation, two new stereogenic

centers would now be formed in the allylation product

28; thus, reaction of our second-generation allylsilane 27

would also benefit from increased levels of stereochemical

transcription.⁴⁶Bicycle 28 is also synthetically much

more versatile than the simple allyl-C-mannosyl products

(e.g., 18 and 24) that would be obtained using our first

generation system, 16.

In light of the significant reduction in the rate of

allylation when acid scavengers are used, we propose that

TfOH is responsible for activating the mannosyl donor

and for cleaving the silyl ether in the absence of base. In

the presence of a base, we propose that “TMS⁺” (from

TMSOTf) activates the anomeric site, albeit less ef-

fectively than H⁺(from TfOH), hence the reduced rate

in these cases; however, we also believe that TMSOTf

does not cleave the silyl ether tether to any appreciable

extent (allylsilanes are known to be much more unstable

to Brønsted acids than they are to Lewis acids). The

question then arises as to the identity of the active

nucleophile in these reactions. It is noteworthy that the

R/â stereoselectivity in the products from the reaction

between TBDMS-protected methyl mannoside 17 and

allyltrimethylsilane under TMSOTf activation was 13:1

as determined HPLC, while that from the reaction

involving allylsilyl ether 16 under TMSOTf activation in

the presence of base was >100:1 (as determined by

HPLC). We tentatively propose that in the presence of a

bulky base, the active nucleophile is the allylsilyl ether

itself. The improved R-stereoselectivity compared with

the intermolecular reaction involving allyltrimethylsilane

can be accounted for by the greatly increased steric bulk

of the ligands on the silicon (even though they are rather

remote from the reacting center in the T.S.). In the

presence of just TMSOTf there is more than one allyl

nucleophile operating, namely the allylsilyl ether 16, and

some silyl ether cleavage product (e.g., allyldimethylsilyl

triflate or allyldimethylmethoxysilane), which would

account for the decreased R/â stereoselectivity in this

case.

An allylsilane 29, suitable for tethering to the C(2)OH

in a methyl mannoside, was readily prepared using a

modified procedure developed by Tamao and Ito (Scheme

9).⁴⁷Although aminosilanes are not commonly used in

synthesis,^48-53they are attractive reagents for forming

silyl ethers. Since the only byproduct from the reaction

is a volatile secondary amine (Et₂NH in our case),

silylation of alcohols can be achieved without having to

include acid scavengers, which facilitates workup. The

(41) (a) Ito, Y.; Ogawa, T. Angew. Chem., Int. Ed. Engl. 1994, 33,

1765-1767. (b) Dan, A.; Ito, Y.; Ogawa, T. J . Org. Chem. 1995, 60,

4680-4681. (c) Dan, A.; Ito, Y.; Ogawa, T. Tetrahedron Lett. 1995, 36,

7487-7490. (d) Ito, Y.; Ogawa, T. J . Am. Chem. Soc. 1997, 119, 5562-

5566. (e) Dan, A.; Lergenmu¨ller, M.; Amano, M.; Nakahara, Y.; Ogawa,

T.; Ito, Y. Chem. Eur. J . 1998, 4, 2182-2190.

(42) (a) Krog-J ensen, C.; Oscarson, S.; J . Org. Chem. 1996, 61,

4512-4513. (b) Krog-J ensen, C.; Oscarson, S. J . Org. Chem. 1998, 63,

1780-1784.

(43) Packard, G. K.; Rychnovsky, S. D. Org. Lett. 2001, 3, 3393-

Allylsilanes are only more nucleophilic than simple

olefins because the presence of the C-Si bond can

stabilize the accumulation of positive charge on the

â-carbon (â-effect),⁴⁰thereby lowering the energy of

activation. If the C-Si bond cannot adopt a suitable

orientation to allow this charge stabilization, then the

reaction may be energetically unfavorable. In the case

3396.

(44) (a) Ennis, S. C.; Fairbanks, A. J .; Tennant-Eyles, R. J .; Yeates,

H. S. Synlett 1999, 1378-1390. (b) Seward, C. M. P.; Cumpstey, I.;

Aloui, M.; Ennis, S. C.; Redgrave, A. J .; Fairbanks, A. J . Chem.

Commun. 2000, 1409-1410.

(45) (a) Bols, M. J . Chem. Soc., Chem. Commun. 1992, 913-914.

(b) Bols, M. Acta Chem. Scand. 1993, 47, 829-834. (c) Bols, M. Acta

Chem. Scand. 1996, 50, 931-937.

(46) Smith, A. B., III; Empfield, J . R. Chem. Pharm. Bull. 1999, 47,

1671-1678.

(40) Lambert, J . B.; Zhao, Y.; Emblidge, R. W.; Salvador, L. A.; Liu,

X.; So, J .-H.; Chelius, E. Acc. Chem. Res. 1999, 32, 183-190 and

references therein.

(47) A detailed discussion of the synthesis of these allylsilanes will

be reported elsewhere. Tamao, K.; Nakajo, E.; Ito, Y. Tetrahedron 1988,

44, 3997-4007.

J . Org. Chem, Vol. 69, No. 19, 2004 6347

Beignet et al.

SCHEME 8. Reloca tin g th e Silyl Eth er Teth er to th e γ-P osition of th e Allylsila n e Sh ou ld F a vor

In tr a m olecu la r Allyla tion a n d P r ovid e a Syn th etica lly Mor e Ver sa tile P r od u ct

SCHEME 9. Use of γ-(Am in o)silyl-Su bstitu ted

Allylsila n es 29 in Teth er F or m a tion

SCHEME 10. Rea ction of Allylsila n e 27a P r ovid ed

a Tetr a h yd r ofu r a n P r od u ct

our first-generation allylsilane 16 (Table 1), treatment

of methyl mannoside 27a with TMSOTf in the presence

of 2,6-DTBMP in MeCN at rt for 8 h, provided what

appeared to be a single major product by TLC. Analysis

of the crude reaction mixture by NMR, however, sug-

gested the presence of two similar compounds, both

containing a terminal (E)-1,3-diene; there was no evi-

dence for our desired allylation compounds 28. Purifica-

tion of the reaction mixture by silica gel flash column

chromatography allowed the isolation of the two diene

compounds in modest yield (38%) owing to their apparent

instability on silica gel, and extensive NMR experiments

confirmed the structure of these products as the ring-

contracted tetrahydrofuran 30 (∼2:1 mixture of stereo-

isomers).

reaction between aminosilane 29a and alcohol 15 was

relatively slow (as had been expected). However, with no

strong exotherm, silyl ether formation was readily

achieved by simply mixing equimolar quantities of the

two reagents, in the absence of solvent, and with slight

warming to 40 °C to aid mixing of the two reactants. The

reaction was conveniently monitored visually (as well as

by TLC). At the beginning of the reaction, and without

vigorous stirring, two phases were clearly evident in the

reaction vessel (the aminosilane 29a is much less dense

than the alcohol 15). When the reaction had reached

completion, the mixture was a single phase containing

the product and residual diethylamine, which was readily

removed under reduced pressure. At the outset, we were

uncertain of the stability of the silyl ether linkage in 27a .

Fortunately, these concerns proved unfounded; the prod-

uct was air- and moisture-stable and could be purified

by silica gel column chromatography without having to

take any special precautions.

In our first approach, we had shown that the simple

allylsilane contained within mannoside 16 (Scheme 6)

reacted through an intermolecular pathway. We expected

the analogous intermolecular reaction involving our

second-generation allylsilane 27a as the reacting species

to be severely disfavored owing to the presence of a

massive substituent (a protected monosaccharide) at the

reacting γ-position of the allylsilane. Indeed, we were

unable to find any evidence of possible crossover products

when 27a was treated to our standard activation condi-

tions in the presence of methyl mannoside 25 containing

a methyl ether at C(2) (Scheme 11). While the ring-

contracted product could also be produced from an initial

intermolecular reaction (see below), the fact that man-

noside 25 was recovered intact, was highly suggestive

that intermolecular pathways were not operating. To

verify this further, an attempted intermolecular reaction

between γ-(isopropyloxy)dimethylsilyl-substituted allyl-

silane 31 (prepared from the reaction between 29a and

2-propanol)⁴⁷and mannoside 25, failed to provide any

products even after 2 days at rt, and both starting

materials were recovered intact (Scheme 11).

With our second-generation allylsilane 27a in hand,

we were now ready to investigate its application in

C-glycosylation (Scheme 10). Using the conditions that

had proved most efficient in effecting C-glycosylation with

(48) TMS protection: (a) Ruehlmann, K. Synthesis 1971, 236-253.

(b) Yankee, E. W.; Bundy, G. L. J . Am. Chem. Soc. 1972, 94, 3651-

3652. (c) Kerwin, S. M.; Paul, A. G.; Heathcock, C. H. J . Org. Chem.

1987, 52, 1686-1695. (d) Rychnovsky, S. D.; Griesgraber, G. J . Org.

Chem. 1992, 57, 1559-1563. (e) Tanabe, Y.; Murakami, M.; Kitaichi,

K.; Yoshida, Y. Tetrahedron Lett. 1994, 35, 8409-8412.

(49) TES protection: Holton, R. A.; Zhang, Z.; Clarke, P. A.;

Nadizadeh, H.; Procter, D. J . Tetrahedron Lett. 1998, 39, 2883-2886.

(50) TBDMS protection: see ref 48c.

(51) TIPS protection: Firouzabadi, H.; Iranpoor, N.; Naser, S.;

Hamid, R. Phosphorus, Sulfur Silicon Relat. Elem. 2000, 166, 71-82.

(52) PhMe₂Si protection: Liepin’sh, E. E.; Birgele, I. S.; Zelchan,

G. I.; Urtane, I. P.; Lukevits, E. J . Gen. Chem. USSR (Engl. Transl.)

1980, 50, 2212-2216.

(53) (Allyl)Me₂Si protection: Reetz, M. T.; J ung, A.; Bolm, C.

Tetrahedron 1988, 44, 3889-3898.

6348 J . Org. Chem., Vol. 69, No. 19, 2004

Stereoselective Synthesis of Allyl-C-mannosyl Compounds

â-hydroxy aldehydes 37.⁶¹In this system, we also found

that diene products were obtained exclusively with a

dimethylsilyl ether-tethered allylsilane. However, we

were able to efficiently suppress the formation of diene

products by increasing the steric bulk of the ligands about

the silyl ether linker; thus exchanging the methyl sub-

stituents for ethyl groups led to the formation of the

desired oxasilacycle products 36 in good to excellent yield

(Scheme 14).⁶¹

SCHEME 11. In ter m olecu la r Allyla tion P a th w a ys

Ar e Not Im p or ta n t w ith Allylsila n e 27a

Allylsilane 29b containing a (diethylamino)diethylsilyl

substituent in the γ position was readily prepared from

Et₂SiCl₂.⁴⁷Tethering to the C(2)OH in methyl mannoside

15, however, now proved to be unacceptably slow. We

found that this step could be improved significantly by

first converting the aminosilane 29b into the correspond-

ing chlorosilane 38b by treatment with freshly distilled

acetyl chloride.⁶²Without isolation, addition of mannoside

15 provided the desired silyl ether 27b in greatly

improved yield and reduced reaction time (Scheme 15).

Treatment of allylsilane 27b under our now-standard

activation conditions, provided a range of compounds

which were analyzed and separated by reversed-phase

HPLC (Scheme 16). Once more, diene compounds ac-

counted for the majority of the mass balance. The ring-

contracted tetrahydrofuran product 30 (isolated as a

similar ratio of diastereoisomers as was obtained from

the reaction with methyl mannoside 27a ) was again

identified, although this time in roughly equal propor-

tions with the silyl acetal 39. Although we initially

supposed that diene 39 might be a precursor to tetrahy-

drofuran 30, exposure of purified diene 39 to the glyco-

sylation reaction conditions for 24 h led to complete

recovery of the starting material. Presumably, the bulkier

ethyl groups at the silyl ether tether reduce the propen-

sity for the dienylic alcohol 34 (Scheme 12) to undergo

Lewis acid-mediated ionization (leading to formation of

the ring-contraction product), allowing this intermediate

to proceed along alternative pathways. In this case,

intramolecular nucleophilic displacement of the X group

in 34 by an alcohol nucleophile at C(5) would account

for the formation of silyl acetal 39.

We propose that the rather unusual tetrahydrofuran

product 30 is formed according to the mechanism out-

lined in Scheme 12.

Activation of the anomeric center in 27a provides an

oxocarbenium cation that is trapped by the tethered

allylsilane as desired. The carbocationic intermediate 32

can benefit from stabilization through the well-known

â-effect from both silicon substituents;⁵⁴it can therefore

collapse by external nucleophilic attack at either silicon

center. To provide the diene product 30 we propose that

an external nucleophile preferentially attacks the silyl

ether silicon which is more Lewis acidic than the trim-

ethylsilyl silicon owing to it being constrained into a five-

membered ring,^55,56and tethered to an oxygen substitu-

ent.⁵⁷Under the Lewis acidic reaction conditions, this

allylsilane product 33 reacts further. Lewis acid activa-

tion of the pyranose oxygen in 33 effects a vinylogous

silicon-mediated olefination⁵⁸providing the ring-opened

product 34 containing a (E)-1,3-diene. Such olefination

processes are known to be effected by Lewis acids, and

are also invariably (E)-selective.⁵⁸The stereoselectivity

of the reaction can be rationalized by assuming a reactive

conformation of the intermediate allylsilane in which A^1,3

-

interactions are minimized by the allylic hydrogen eclips-

ing the olefin (Scheme 13).⁵⁹

Under the Lewis acidic reaction conditions, the dienylic

alcohol in 34 (C(2) sugar numbering) then ionizes to

provide a pentadienyl cation 35 that is rapidly trapped

by the TMS ether at C(5) (sugar numbering) to provide

the tetrahydrofuran 30 as a mixture of stereoisomers

(Scheme 12). The lack of stereoselectvity in this final ring-

closure step suggests an S_N1 process is operating, rather

than the alternative S_N2 pathway, which would have

been expected to provide a single tetrahydrofuran prod-

uct.

More significantly in this reaction, we were delighted

to identify the desired intramolecular allylation products

42b and 43b, in approximately equal amounts. Thus, in

analogy to our reaction with aldehyde substrates (Scheme

14), moving to the bulkier diethylsilyl ether tether had

once again helped to redirect the course of the reaction

along our desired pathway, although admittedly far less

efficiently in this case, as diene compounds remained the

major products from the reaction. In contrast to the six-

membered ring products 36 derived from aldehyde 37

(Scheme 14), which were stable to purification by silica

gel column chromatography, the five-membered oxasila-

While carrying out this study, we were also investigat-

ing the reaction of our allylsilane tethered to a range of

(54) Fleming, I.; Langley, J . A. J . Chem. Soc., Perkin Trans. 1 1981,

1421-1423.

(55) Leighton and others have recently demonstrated the importance

of ring strain in controlling the Lewis acidity of allylsilanes: (a)

Kinnaird, J . W. A.; Ng, P. Y.; Kubota, K.; Wang, X.; Leighton, J . L. J .

Am. Chem. Soc. 2002, 124, 7920-7921. (b) Berger, R.; Rabbat, P. M.

A.; Leighton, J . L. J . Am. Chem. Soc. 2003, 125, 9596-9597. (c) Kubota,

K.; Leighton, J . L. Angew. Chem. Int. Ed. 2003, 42, 946-948. (d)

Robertson, J .; Hall, M. J .; Green, S. P. Org. Biomol. Chem, 2003, 1,

3635-3638. (e) Kira, M.; Sato, K.; Sakurai, H. J . Am. Chem. Soc. 1988,

110, 4599-4602.

(60) An anti E′ elimination is shown in Scheme 13; a syn E′

elimination would provide the same product stereoselectivity; similarly

the stereochemistry of the olefin in the intermediate allylsilane would

also not affect the (E)-selectivity; indeed if anything the (Z)-stereoiso-

mer might be even more stereoselective. E′ eliminations are not

stereospecific processes: Matassa, V. G.; J enkins, P. R.; Ku¨min, A.;

Damm, L.; Schreiber, J .; Felix, D.; Zass, E.; Eschenmoser, A. Isr. J .

Chem. 1989, 29, 321-343. See also: Fleming, I.; Morgan, I. T.; Sarkar,

A. K. J . Chem. Soc., Perkin Trans. 1 1998, 2749-2763.

(56) Silacyclobutane systems are similarly more Lewis acidic: Mat-

sumoto, K.; Oshima, K.; Utimoto, K. J . Org. Chem. 1994, 59, 7152-

7155.

(57) We presume that the inductive effect of the electronegative

oxygen substituent overrides any pπ-dπ back-bonding effects, which

would temper the Lewis acidity of the silicon center.

(58) (a) Stragies, R.; Blechert, S. Tetrahedron 1999, 55, 8179-8188.

(b) Bradley, G. W.; Thomas, E. J . Synlett 1997, 629-631. (c) Angoh,

A. G.; Clive, D. L. J . J . Chem. Soc., Chem. Commun. 1984, 534-536.

(59) Hoffmann, R. W. Chem. Rev. 1989, 89, 1841-1860.

(61) Beignet, J .; Cox, L. R. Org. Lett. 2003, 5, 4231-4234.

(62) Zechel, D. L.; Foucher, D. A.; Pudelski, J . K.; Yap, G. P. A.;

Rheingold, A. L.; Manners, I. J . Chem. Soc., Dalton Trans. 1995, 1893-

1899.

J . Org. Chem, Vol. 69, No. 19, 2004 6349

Beignet et al.

SCHEME 12. P r op osed Mech a n ism for th e F or m a tion of Dien e 30

SCHEME 13. Rea ctive Con for m a tion Lea d in g

assumption that this oxidation proceeds with retention

of configuration (Scheme 16).^64,65

Selectively to (E)-Dien e P r od u cts⁶⁰

Although moving to a diethylsilyl ether tether had

gratifyingly provided the allylation products 42b and

43b, dienes were still the major products. Furthermore,

owing to the increased reaction time required to consume

the starting material, Lewis acid-mediated cleavage of

the silyl ether became a competing reaction for the first

time, as evidenced by the isolation of TMS ether 41. Since

bulkier ligands at the silyl ether would hopefully sup-

press this undesirable pathway, we prepared methyl

mannoside 27c containing our allylsilane tethered at C(2)

through a diisopropylsilyl ether tether (Scheme 15).

C-Glycosylation of 27c under our standard conditions

once more provided a range of compounds but unfortu-

nately failed to improve significantly the amount of

â-allyl-C-mannosyl products that were isolated. However,

in line with our predictions, and despite a further

SCHEME 14. Dieth ylsilyl Eth er Teth er Su p p r esses

Dien e F or m a tion

i

increase in reaction time, using larger Pr ligands on the

silyl ether tether did efficiently suppress the Lewis acid-

mediated cleavage of the silyl ether, and TMS ether 41

was now isolated in only trace quantities. A diene

compound, this time acyclic 40, was the major product.

Presumably, moving from ethyl to isopropyl ligands at

the silyl ether slows the rate of the later steps in the

cascade process required to provide tetrahydrofuran 30

such that once again these intermediates are intercepted

and taken along alternative pathways.⁶⁶

Despite the low chemical yields of allyl-C-mannosyl

product, the stereoselectivity at C(1) demonstrated that

our strategy had successfully provided only â-C-manno-

syls. The low diastereoselectivity at the adjacent second

stereogenic center, however, implies that there is very

little difference in energy between the two transition

states in which the allylsilane adopts an exo or endo

orientation (Figure 3).

In an effort to increase the amount of â-allyl-C-

mannosyl products, we chose to replace the methyl

mannoside with a more reactive donor. Since glycosyl

sulfoxides have been used successfully in other examples

of intramolecular aglycon delivery,^17,43we elected to

investigate this type of reactive donor, hoping that

activation at lower temperature might not only allow the

SCHEME 15. In Situ F or m a tion of Silyl Ch lor id e

38 Allow ed a Mor e Efficien t Teth er in g to

Ma n n osid e 15^a

a

Reagents and conditions: (a) AcCl, CH₂Cl₂, rt, 8 h (R ) Et),

24 h (R ) ⁱPr), then (b) 15, imidazole, DMAP, rt, 24 h (R ) Et), 48

h (R ) Pr), 27b 80%, 27c 72%.

i

cycles 42b and 43b both proved to be rather labile, and

on standing gave what were presumed to be ring-opened

hydrolysis products (silanols, siloxanes, etc.). The pres-

ence of the vinyl substituent on the concave face in 43b

rendered this stereoisomer particularly susceptible to

ring-opening, presumably being driven by a greater

release in steric compression. The structures of 42b and

43b were fully elucidated by extensive 2D-NMR experi-

ments, and NOESY experiments allowed the assignment

of relative stereochemistry. Oxidative cleavage of the

silicon tether in 42b and 43b⁶³proceeded uneventfully

to provide allylic alcohols 44 and 45, respectively. The

structures were assigned based on the well-precedented

(63) Murakami, M.; Suginome, M.; Fujimoto, K.; Nakamura, H.;

Andersson, P. G.; Ito, Y. J . Am. Chem. Soc. 1993, 115, 6487-6498.

(64) Tamao, K.; Kakui, T.; Akita, M.; Iwahara, T.; Kanatani, R.;

Yoshida, J .; Kumada, M. Tetrahedron 1983, 39, 983-990.

(65) For a detailed review on this reaction: Fleming, I. Chemtracts:

Org. Chem. 1996, 9, 1-64.

(66) This type of diene (40) may actually be an intermediate in the

formation of tetrahydrofuran 30 when a dimethylsilyl ether tether is

employed.

6350 J . Org. Chem., Vol. 69, No. 19, 2004

Stereoselective Synthesis of Allyl-C-mannosyl Compounds

SCHEME 16. Usin g a Silyl Eth er Teth er w ith Bu lk ier Liga n d s P r ovid ed th e Desir ed â-Allyl-C-m a n n osyl

P r od u cts w h ich Un d er w en t Oxid a tive Teth er Clea va ge to Gen er a te th e Desir ed Diols

low temperature. Unfortunately, however, this change

in reaction conditions failed to improve the yield of the

desired â-allyl-C-mannosyl products, which were still

isolated in low yield. Direct oxidation of the crude

reaction mixture provided diols 44 and 45 in low yield

(<20% over the two steps). Thus, the change in donor

group and C-glycosylation conditions had failed to provide

preparatively useful yields of the â-allyl-C-mannosyls.

F IGURE 3. There is relatively little discrimination between

endo and exo T.S.’s.

It is constructive to compare the intramolecular ally-

lation of aldehyde 37 (Scheme 14) with the same reaction

SCHEME 17. P r ep a r a tion of Su lfoxid e Don or 47^a

involving the mannoside donors described in this paper.

In the former case, we were able to suppress diene

products and readily isolate the oxasilacyclic six-mem-

bered ring products 36 simply by moving from a dimeth-

yl- to a bulkier diethylsilyl ether tether. Although making

the same change in the sugar system gratifyingly allowed

a

Reagents and conditions: (a) PhSH, HgBr₂, MeCN, 4 and 5 Å

the isolation of two â-allyl-C-mannosyl products, dienes

MS, rt, 24 h; then NaOMe, MeOH, rt, 6 h, 71%; (b) 38c, 46,

were still the major products. Moving to an even larger

imidazole, DMAP, CH₂Cl₂, rt, 36 h, 76%; (c) m-CPBA, CH₂Cl₂, -78

diisopropylsilyl ether tether failed to significantly im-

°C, 88%.

prove matters, as did changing from a methyl mannoside

donor to a more reactive sulfoxide. We believe that this

difference in reactivity between the two systems is

yields but potentially also increase the diastereoselec-

isolation of the desired allylation products in increased

primarily a consequence of the reduced size of the cyclic

T.S. In the mannoside system, the result of reducing the

cyclic T.S. by one atom is to provide a more strained

cationic intermediate product. This serves to greatly

increase the Lewis acidity of the silyl ether such that

tivity of the reaction. The required mannosyl sulfoxide

47 (obtained as one diastereoisomer) containing our

allylsilane tethered through a diisopropylsilyl ether

tether was prepared uneventfully as outlined in Scheme

17. Of only note was the chemoselective oxidation of the

sulfide in the presence of the allylsilane.⁶⁷Activation of

sulfoxide 47 using standard conditions (Tf₂O, 2,6-DT-

BMP)⁶⁷led to rapid consumption of starting material at

(67) Kahne, D.; Walker, S.; Cheng, Y.;. van Engen, D. J . Am. Chem.

Soc. 1989, 111, 6881-6882.

J . Org. Chem, Vol. 69, No. 19, 2004 6351

Beignet et al.

organic extracts were washed with brine (3 mL) and then dried

(MgSO₄). Concentration under reduced pressure followed by

purification by flash column chromatography (10% EtOAc in

hexane) afforded silyl ether 16 as a pale yellow oil (94 mg,

exchanging the ligands from methyl to larger substitu-

ents now fails to suppress, to any appreciable extent,

reaction pathways that result from collapse of the car-

bocation by preferential attack on the silyl ether tether.

The pioneering work of Stork has demonstrated that

using a temporary silicon connection in an intramolecular

aglycon delivery strategy can provide an excellent route

into 1,2-syn-O-glycosides, including such difficult glyco-

sidic linkages as â-mannosides.¹⁷Although this strategy

has been successfully extended to radical chemistry,²⁰its

application to the intramolecular delivery of C-nucleo-

philes has received far less attention,¹⁹and currently

remains a more challenging problem, at least in the case

of C-mannosyl synthesis. An efficient solution to the

synthesis of â-allyl-C-mannosyls through intramolecular

aglycon delivery therefore remains elusive. The work

described in this paper has highlighted potential prob-

lems, identified some solutions, and perhaps hints that

a successful application of this methodology to â-allyl-

C-mannosyl synthesis may well remain elusive. Our

findings, however, should prove valuable for future work

in this area and do suggest alternative directions. We

have demonstrated that simply tethering an allylsilane

to the C(2)OH position of a mannosyl is not sufficient to

ensure an intramolecular C-mannosylation; the location

of the silyl connection in the tethered nucleophile is

crucial. Indeed, our first generation system resulted in

products derived exclusively from intermolecular allyla-

tion pathways. While our second-generation system

solved this problem and ensured intramolecular allyl

transfer, the presence of the silyl connection led to a

range of diene products resulting from preferential col-

lapse of the silyl tether. Thus, the tether, while ensuring

nucleophile delivery to the â-face, at the same time has

become the source of our chemoselectivity problems.

Since changing from a methyl mannoside (27) to a

sulfoxide donor (47) failed to improve the yield of â-allyl-

C-mannosyl products, even with a diisopropylsilyl ether

connection, we suggest that investigating other mannosyl

donors will not be productive and instead, propose that

changing the C-nucleophile will be a more profitable way

forward.⁶⁸We have recently had great success in cyclizing

propargylsilanes tethered to â-hydroxy aldehydes.⁶⁹The

silyl tether in these systems seems far less prone to

cleavage, most likely owing to its relative inability to

stabilize â-positive charge as efficiently as the propargylic

silicon. Future work will therefore be directed to using

this type of nucleophile in intramolecular aglycon deliv-

ery.

80%): [R]²⁵+0.025 (c 0.4, CHCl₃); R_f) 0.25 (10% Et₂O in

D

hexane); ν_max(film)/cm^-12953s, 2909s, 1630w; δ_H(500 MHz)

0.11 (s, 3H, SiCH₃), 0.13 (s, 3H, SiCH₃), 1.63 (br d, J 7.4, 2H,

SiCH₂CHdCH₂), 3.37 (s, 3H, OCH₃), 3.73-3.78 (stack, 3H,

5-H, 2 × 6-H), 3.80 (dd, J 9.2, 2.8, 1H, 3-H), 3.89 (apparent t,

J 9.0, 1H, 4-H), 4.07 (apparent t, J 2.5, 1H, 2-H), 4.52 (A of

AB, J 11.0, 1H, 4-COCH_AH_BPh), 4.56 (A of AB, J 12.5, 1H,

6-COCH_CH_DPh), 4.63 (d, J 2.0, 1H, 1-H), 4.67 (A of AB, J 11.0,

1H, 3-COCH_EH_FPh), 4.68 (B of AB, J 12.5, 1H, 6-COCH_CH_D-

Ph), 4.72 (B of AB, J 11.0, 1H, 3-COCH_EH_FPh), 4.83-4.89

(stack, 3H, 4-COCH_AH_BPh, SiCH₂CHdCH₂), 5.77-5.86 (m,

1H, SiCH₂CHdCH₂), 7.16-7.19 (m, 2H, PhH), 7.23-7.28

(stack, 13H, PhH); δ_C(125 MHz) -1.8 (CH₃, 1 × SiCH₃), -1.7

(CH₃, 1 × SiCH₃), 25.1 (CH₂, CH₂CHdCH₂), 54.7 (CH₃, OCH₃),

69.4 (CH₂, 6-C), 70.1 (CH, 2-C), 72.1 (CH, 5-C), 72.7 (CH₂,

3-COCH₂Ph), 73.2 (CH₂, 6-COCH₂Ph), 74.7 (CH, 4-C), 74.8

(CH₂, 4-COCH₂Ph), 80.1 (CH, 3-C), 101.6 (CH, 1-C), 113.5

(CH₂, SiCH₂CHdCH₂), [127.36 (CH, Ph), 127.44 (CH, Ph),

127.5 (CH, Ph), 127.6 (CH, Ph), 127.7 (CH, Ph), 127.9 (CH,

Ph), 128.2 (CH, Ph) some overlap], 134.3 (CH, CH₂CHdCH₂),

[138.5 (quat C, ipso Ph), 138.6 (quat C, ipso Ph) some overlap];

m/z (TOF MS ES+) 585.3 [(M + Na)⁺, 100]; HRMS calcd for

C

₃₃H₄₂O₆SiNa [M + Na]⁺585.2648, found 585.2654; HPLC t_R

) 3.4 min.

1-(3′,4′,6′-Tr i-O-b en zyl-R-^D-m a n n op yr a n osyl)p r op -2-

en e (18). Meth od A (fr om Silyl Eth er 17). TMSOTf (22 µL,

0.12 mmol) was added dropwise over 1 min to a stirred solution

of silyl ether 17 (72 mg, 0.12 mmol) and allyltrimethylsilane

(47 µL, 0.36 mmol) in MeCN (0.6 mL). The reaction mixture

was stirred for 2.5 h at rt, diluted with EtOAc (2 mL), and

poured into NaHCO₃solution (3 mL). The layers were sepa-

rated, and the aqueous phase was extracted with EtOAc (3 ×

2 mL). The combined organic extracts were washed with brine

(3 mL), dried (MgSO₄), and concentrated under reduced

pressure to provide a yellow oil. The residue was diluted with

THF (1 mL), and TBAF (180 µL, 1 M solution in THF, 5% H₂O)

was added dropwise at rt. The solution was stirred for 20 h,

poured into H₂O (2 mL), and extracted with EtOAc (3 × 3 mL).

The combined organic extracts were washed with brine (2 mL),

dried (MgSO₄), and concentrated under reduced pressure. The

residue was purified by flash column chromatography (10%

EtOAc in hexane) to afford alcohol 18 as a colorless oil (52

mg, 91%): [R]²¹+24.1 (c 1.0, CHCl₃); R_f) 0.30 (25% EtOAc

D

in hexane); ν_max(film)/cm^-13441w, 1639w, 1585w, 1088vs; δ_H-

(400 MHz) 2.27-2.43 (m, 2H, CH₂CHdCH₂), 2.45 (d, J 4.6,

1H, OH), 3.65-3.83 (stack, 5H, 3′-H, 4′-H, 5′-H, 2 × 6′-H),

3.83-3.85 (m, 1H, 2′-H), 3.92-3.99 (m, 1H, 1′-H), 4.53 (A of

AB, J 12.2, 1H, OCH_AH_BPh), 4.55 (A of AB, J 11.2, 1H,

OCH_CH_DPh), 4.59 (B of AB, J 12.2, 1H, OCH_AH_BPh), 4.60 (A

of AB, J 11.5, 1H, OCH_EH_FPh), 4.65 (B of AB, J 11.5, 1H,

OCH_EH_FPh), 4.75 (B of AB, J 11.2, 1H, OCH_CH_DPh), 5.03-

5.10 (stack, 2H, CH₂CHdCH₂), 5.75-5.87 (m, 1H, CH₂-

CH)CH₂), 7.21-7.24 (m, 2H, PhH), 7.27-7.34 (stack, 13H,

PhH); δ_C(100 MHz) 34.2 (CH₂, CH₂CHdCH₂), 68.3 (CH, 2′-

C), 69.0 (CH₂, 6′-C), 72.1 (CH₂, CH₂Ph), 72.9 (CH), 73.4 (CH₂,

CH₂Ph), 74.1 (CH), 74.2 (CH₂, CH₂Ph), 74.8 (CH, 1′-C), 79.0

(CH, 5′-C), 117.3 (CH₂, CH₂CHdCH₂), [127.5 (CH, Ph), 127.8

(CH, Ph), 128.0 (CH, Ph), 128.1 (CH, Ph), 128.3 (CH, Ph), 128.4

(CH, Ph), 128.6 (CH, Ph) some overlap], 134.1 (CH, CH₂-

CHdCH₂), 137.2 (quat C, ipso Ph), 138.1 (quat C, ipso Ph),

138.3 (quat C, ipso Ph); m/z (TOF MS ES+) 497.1 ([M + Na]⁺,

100); HPLC t_R) 8.9 min. Anal. Calcd for C₃₀H₃₄O₅: C, 75.92;

H, 7.22. Found: C, 75.86; H, 7.31.

Exp er im en ta l Section

Meth yl 2-O-Allyl(d im eth yl)sila n yl-3,4,6-tr i-O-ben zyl-R-

D-m a n n op yr a n osid e (16). Allyldimethylchlorosilane (37 µL,

0.25 mmol) was added to a solution of alcohol 15 (100 mg, 0.21

mmol) and imidazole (29 mg, 0.42 mmol) in DMF (0.5 mL) and

the mixture stirred for 24 h at rt. The reaction mixture was

then diluted with Et₂O (2 mL) and quenched with NaHCO₃

solution (2 mL). The layers were separated, and the aqueous

phase was extracted with Et₂O (2 × 2 mL). The combined

Meth od B (fr om Silyl Eth er 16). TMSOTf (32 µL, 0.18

mmol) was added dropwise over 1 min to a stirred solution of

allylsilyl ether 16 (100 mg, 0.18 mmol) and 2,6-DTBMP (45

mg, 0.22 mmol) in MeCN (0.4 mL). The reaction mixture was

stirred for 14 h, diluted with EtOAc (10 mL), and poured into

(68) Martin has recently shown that arylsilanes tethered through

C(2)OH of 4-pentenyl glucopyranosides can be successfully delivered

intramolecularly to provide exclusively the 1,2-cis-R-aryl-C-glucosyls:

see ref 21e.

(69) Cox, L. R.; Beignet, J .; Ramalho, R. P. S. Unpublished results.

6352 J . Org. Chem., Vol. 69, No. 19, 2004

Stereoselective Synthesis of Allyl-C-mannosyl Compounds

NaHCO₃solution (10 mL). The layers were separated, and the

aqueous phase was extracted with EtOAc (3 × 10 mL). The

combined organic extracts were washed with HCl (1 M, 10

mL), water (10 mL), and brine (10 mL) and then dried

(MgSO₄). Concentration under reduced pressure provided a

yellow oil which was purified by flash column chromatography

(10% EtOAc in hexane) to afford alcohol 18 as a colorless oil

(78 mg, 92%) that was identical in all respects to the material

produced from silyl ether 17.

(quat C, 1′-C), 121.6 (CH₂, CH₂CH)CH₂), [127.6 (CH, Ph),

127.70 (CH, Ph), 127.72 (CH, Ph), 127.9 (CH, Ph), 128.2 (CH,

Ph), 128.30 (CH, Ph), 128.34 (CH, Ph) some overlap], 131.2

(CH, CH₂CHdCH₂), 138.0 (quat C, ipso Ph), 138.5 (2 × quat

C, 2 × ipso Ph), 170.3 (quat C, OC(O)CH₃); m/z (TOF MS ES+)

555.2 ([M + Na]⁺, 100); HRMS calcd for C₃₂H₃₆O₇Na [M + Na]⁺

555.2359, found 555.2358. Anal. Calcd for C₃₂H₃₆O₇: C, 72.16;

H, 6.81. Found: C, 72.05; H, 6.99.

1-(2′-O-Acetyl-3′,4′,6′-tr i-O-ben zyl-â-^D-m an n opyr an osyl)-

p r op -2-en e (23). TMSOTf (92 µL, 0.51 mmol) was added

dropwise over 1 min to a stirred solution of lactol 22 (230 mg,

0.44 mmol) and Et₃SiH (101 µL, 0.64 mmol) in MeCN (4.4 mL)

at rt. After 5 min, the reaction mixture was quenched with

aqueous NaHCO₃solution (2 mL) and extracted with EtOAc

(3 × 3 mL). The combined organic layers were washed with

water (3 mL) and brine (3 mL) and dried (Na₂SO₄). Removal

of the volatiles and purification of the residue by flash column

chromatography (10% EtOAc in hexane) afforded acetate 23

2-O-Acet yl-3,4,6-t r i-O-b en zyl-^D-m a n n on o-1,5-la ct on e

(21). A mixture of acetates 19 and 20 (500 mg, 1.0 mmol) and

NMO (175 mg, 1.5 mmol) was dissolved in MeCN (2.0 mL)

containing activated powdered 4 Å molecular sieves (500 mg).

TPAP (17.5 mg, 0.05 mmol) was then added and the mixture

stirred at rt. After 5 min, TLC indicated consumption of both

starting materials and the formation of one new compound.

The solvent was removed under reduced pressure, and the

black residue was filtered through a large pad of silica gel,

washing with EtOAc (150 mL) to give a pale yellow solid which

was submitted to purification by flash column chromatography

(20% EtOAc in hexane) to afford lactone 21 as a white powder

as a colorless oil (107 mg, 47%): [R]²⁴+0.32 (c 2.3, CHCl₃);

D

R_f) 0.21 (10% EtOAc in hexane); ν_max(film)/cm^-12925s, 1740s,

1642w, 1605w, 1586w; δ_H(500 MHz) 2.18 (s, 3H, OC(O)CH₃),

2.21-2.29 (m, 1H, CH_aH_bCHdCH₂), 2.40-2.48 (m, 1H, CH_aH_b-

CHdCH₂), 3.44-3.53 (stack, 2H, 1′-H, 5′-H), 3.65 (dd, J 9.4,

3.8, 1H, 3′-H), 3.69-3.80 (stack, 3H, 4′-H, 2 × 6′-H), 4.49 (A

of AB, J 11.3, 1H, 3′-COCH_AH_BPh), 4.51 (A of AB, J 10.7, 1H,

4′-COCH_CH_DPh), 4.58 (A of AB, J 12.4, 1H, 6′-COCH_EH_FPh),

4.67 (B of AB, J 12.4, 1H, 6′-COCH_EH_FPh), 4.78 (B of AB, J

11.3, 1H, 3′-COCH_AH_BPh), 4.87 (B of AB, J 10.7, 1H, 4′-

COCH_CH_DPh), 5.08-5.13 (stack, 2H, CH₂CHdCH₂), 5.50 (d,

J 3.8, 1H, 2′-H), 5.77-5.87 (m, 1H, CH₂CH)CH₂), 7.13-7.20

(m, 2H, PhH), 7.22-7.40 (stack, 13H, PhH); δ_C(125 MHz) 21.0

(CH₃, OC(O)CH₃), 35.6 (CH₂, CH₂CHdCH₂), 68.4 (CH, 2′-C),

69.4 (CH₂, 6′-C), 71.6 (CH₂, 3′-COCH₂Ph), 73.5 (CH₂, 6′-COCH₂-

Ph), 74.6 (CH, 4′-C), 75.2 (CH₂, 4′-COCH₂Ph), 76.8 (CH, 1′-C),

79.5 (CH, 5′-C), 82.0 (CH, 3′-C), 117.9 (CH₂, CH₂CHdCH₂),

[127.56 (CH, Ph), 127.65 (CH, Ph), 127.7 (CH, Ph), 127.88 (CH,

Ph), 127.94 (CH, Ph), 128.2 (CH, Ph), 128.3 (CH, Ph), 128.4

(CH, Ph) some overlap], 133.6 (CH, CH₂CHdCH₂), 137.9 (quat

C, 3′-COCH₂ipso Ph), 138.35 (quat C, 4′-COCH₂ipso Ph),

138.38 (quat C, 6′-COCH₂ipso Ph), 170.7 (quat C, OC(O)CH₃);

m/z (TOF MS ES+) 539.3 ([M + Na]⁺, 100). See the Supporting

Information for more details on this reaction and for charac-

terization of byproducts.

(441 mg, 90%): [R]²⁴+0.23 (c 2.3, CHCl₃); R_f) 0.42 (30%

D

EtOAc in hexane); ν_max(Nujol)/cm^-12925s, 2854s, 1780s, 1750s,

1496w; δ_H(500 MHz) 2.22 (s, 3H, OC(O)CH₃), 3.64-3.69

(stack, 2H, 2 × 6-H), 3.89 (dd, J 6.9, 1.4, 1H, 4-H), 4.05 (dd, J

2.9, 1.4, 1H, 3-H), 4.31 (A of AB, J 11.4, 1H, 4-COCH_AH_BPh),

4.38-4.41 (stack including [4.40 (B of AB, J 11.4, 1H, 4-CO-

CH_AH_BPh)], 2H, 4-COCH_AH_BPh, 5-H), 4.51 (A of AB, J 11.9,

1H, 6-COCH_CH_DPh), 4.55 (B of AB, J 11.9, 1H, 6-COCH_CH_D-

Ph), 4.59 (A of AB, J 12.6, 1H, 3-COCH_EH_FPh), 4.69 (B of AB,

J 12.6, 1H, 3-COCH_EH_FPh), 5.62 (d, J 2.9, 1H, 2-H), 7.13-

7.19 (m, 2H, PhH), 7.28-7.36 (stack, 13H, PhH); δ_C(125 MHz)

20.7 (CH₃, OC(O)CH₃), 68.8 (CH₂, 6-C), 69.7 (CH, 2-C), 71.9

(CH₂, 4-COCH₂Ph), 72.6 (CH₂, 3-COCH₂Ph), 73.5 (CH₂,

6-COCH₂Ph), 75.1 (CH, 4-C), 76.0 (CH, 3-C), 79.0 (CH, 5-C),

[127.8 (CH, Ph), 128.0 (CH, Ph), 128.1 (CH, Ph), 128.3 (CH,

Ph), 128.4 (CH, Ph), 128.5 (CH, Ph), 128.6 (CH, Ph) some

overlap], 136.7 (quat C, ipso Ph), 137.2 (quat C, ipso Ph), 137.6

(quat C, ipso Ph), 166.4 (quat C, 1-C), 169.6 (quat C, OC(O)-

CH₃); m/z (TOF MS ES+) 529.2 ([M + K]⁺, 23), 513.2 (100, [M

+ Na]⁺). Anal. Calcd C₂₉H₃₀O₇: C, 71.00; H, 6.16. Found: C,

70.94; H, 6.20.

1-(2′-O-Acetyl-3′,4′,6′-tr i-O-ben zyl-1′-h yd r oxy-R-^D-m a n -

n op yr a n osyl)p r op -2-en e (22). A solution of (allyl)MgBr (0.60

mL, 0.47 mmol, 0.78 M in Et₂O) was added dropwise over 1 h

to a stirred solution of lactone 21 (192 mg, 0.39 mmol) in THF

(4.0 mL) at -78 °C. The mixture was stirred for a further 30

min at -78 °C, quenched with aqueous NH₄Cl solution (15

mL), and allowed to warm to rt. The resulting mixture was

extracted with EtOAc (3 × 10 mL), and the combined extracts

were washed with water (15 mL), brine (15 mL), dried (Na₂-

SO₄), and concentrated under reduced pressure to leave a

yellow syrup, which was purified by flash column chromatog-

raphy (20% EtOAc in hexane) to give lactol 22 as a colorless

1-(3′,4′,6′-Tr i-O-b en zyl-â-^D-m a n n op yr a n osyl)p r op -2-

en e (24). MeONa (7 mg, 0.12 mmol) was added to a solution

of acetate 23 (50 mg, 0.10 mmol) in MeOH (1 mL) at rt. The

reaction mixture was stirred overnight and then neutralized

with Amberlite IR-120(plus) (prewashed with MeOH). The

solution was filtered, washing with CH₂Cl₂(10 mL), washed

with water (3 mL) and brine (3 mL), dried (Na₂SO₄), and

concentrated under reduced pressure. The residue was purified

by flash column chromatography (20% EtOAc in hexane) to

give alcohol 24 as a colorless oil (41 mg, 85%): [R]²⁴-8.0 (c

D

1.0, CHCl₃); R_f) 0.26 (20% EtOAc in hexane); ν_max(film)/cm^-1

3456br, 2923s, 2868s, 1642w; δ_H(400 MHz) 2.36 (s, 1H, OH),

2.39-2.50 (m, 1H, CH_aH_bCHdCH₂), 2.51-2.60 (m, 1H, CH_aH_b-

CHdCH₂), 3.35 (apparent t, J 7.5, 1H, 1′-H), 3.41 (ddd, J 9.8,

4.9, 2.2, 1H, 5′-H), 3.58 (dd, J 9.8, 3.4, 1H, 3′-H), 3.67 (dd, J

11.3, 4.9, 1H, 1 × 6′-H), 3.74 (dd, J 11.3, 2.2, 1H, 1 × 6′-H),

3.76 (apparent t (br), J 9.8, 1H, 4′-H), 3.94 (d, J 3.4, 1H, 2′-

H), 4.52 (A of AB, J 10.9, 1H, OCH_AH_BPh), 4.56 (A of AB, J

12.3, 1H, OCH_CH_DPh), 4.61 (B of AB, J 12.3, 1H, CH_CH_DPh),

4.66 (A of AB, J 11.4, 1H, OCH_EH_FPh), 4.74 (B of AB, J 11.4,

1H, OCH_EH_FPh), 4.85 (B of AB, J 10.9, 1H, OCH_AH_BPh), 5.08

(dd, J 10.1, 1.0, 1H, CH₂CHdCH_cisH), 5.16 (dd, J 17.3, 2.1,

1H, CH₂CHdCHH_trans), 5.85 (ddt, J 17.3, 10.1, 7.7, 1H,

CH₂CH)CH₂), 7.11-7.19 (m, 2H, PhH), 7.21-7.41 (stack, 13H,

PhH); δ_C(100 MHz) 35.3 (CH₂, CH₂CHdCH₂), 67.5 (CH, 2′-

C), 69.3 (CH₂, 6′-C), 71.6 (CH₂, OCH₂Ph), 73.5 (CH₂, OCH₂-

Ph), 74.7 (CH, 4′-C), 75.2 (CH₂, OCH₂Ph), 77.6 (CH, 1′-C), 79.3

(CH, 5′-C), 83.5 (CH, 3′-C), 117.5 (CH₂, CH₂CH)CH₂), [127.5

(CH, Ph), 127.7 (CH, Ph), 127.86 (CH, Ph), 127.88 (CH, Ph),

oil (146 mg, 70%): [R]²⁵+0.34 (c 1.4, CHCl₃); R_f) 0.46 (30%

D

EtOAc in hexane); ν_max(film)/cm^-13414br, 1747s, 1642w,

1606w, 1586w; δ_H(500 MHz) 2.15 (s, 3H, OC(O)CH₃), 2.27 (dd,

J 16.3, 10.2, 1H, CH_aH_bCHdCH₂), 2.58 (dd, J 16.3, 10.2, 1H,

CH_aH_bCHdCH₂), 2.71 (s, 1H, OH), 3.68-3.76 (stack including

[3.70 (dd, J 11.2, 3.5, 1H, 1 × 6′-H), 3.74 (apparent t, J 9.6,

1H, 4′-H)], 3H, 2 × 6′-H, 4′-H), 3.97 (ddd, J 9.6, 5.6, 3.5, 1H,

5′-H), 4.10 (dd, J 9.6, 3.4, 1H, 3′-H), 4.49 (2 × A of AB, J 11.0,

2H, OCH_AH_BPh, OCH_CH_DPh), 4.54 (A of AB, J 12.5, 1H,

OCH_EH_FPh), 4.64 (B of AB, J 12.5, 1H, OCH_EH_FPh), 4.72 (B

of AB, J 11.0, 1H, OCH_AH_BPh), 4.85 (B of AB, J 11.0, 1H,

OCH_CH_DPh), 5.19 (br d, J 17.4, 1H, CH₂CHdCH_transH), 5.28

(br d, J 10.6, 1H, CH₂CHdCHH_cis), 5.41 (d, J 3.4, 1H, 2′-H),

5.81-5.91 (m, 1H, CH₂CHdCH₂), 7.14-7.19 (m, 2H, PhH),

7.22-7.39 (stack, 13H, PhH); δ_C(125 MHz) 21.1 (CH₃, OC-

(O)CH₃), 42.4 (CH₂, CH₂CHdCH₂), 69.4 (CH₂, 6′-C), 70.3 (CH,

2′-C), 71.7 (CH₂, OCH₂Ph), 72.4 (CH, 5′-C), 73.4 (CH₂, OCH₂-

Ph), 74.3 (CH, 4′-C), 75.0 (CH₂, OCH₂Ph), 78.9 (CH, 3′-C), 96.6

J . Org. Chem, Vol. 69, No. 19, 2004 6353

Beignet et al.

127.9 (CH, Ph), 128.0 (CH, Ph), 128.32 (CH, Ph), 128.34 (CH,

Ph), 128.5 (CH, Ph) some overlap], 134.4 (CH, CH₂CHdCH₂),

137.8 (quat C, ipso Ph), 138.2 (quat C, ipso Ph), 138.3 (quat

C, ipso Ph); m/z (TOF MS ES+) 497.4 ([M + Na]⁺, 100); HRMS

calcd for C₃₀H₃₄O₅Na [M + Na]⁺497.2304, found 497.2312;

HPLC t_R) 5.9 min. Anal. Calcd for C₃₀H₃₄O₅: C, 75.92; H,

7.22. Found: C, 75.99; H, 7.02.

Cr oss-Over Exp er im en t: Rea ction of Meth yl Ma n n o-

sid es 25 a n d 16 w ith TMSOTf. TMSOTf (36 µL, 0.20 mmol)

was added to a solution of methyl mannoside 25 (50 mg, 0.10

mmol), methyl mannoside 16 (56 mg, 0.10 mmol), and 2,6-

DTBMP (45 mg, 0.22 mmol) in MeCN (0.8 mL) at rt. The

reaction mixture was stirred for 14 h, diluted with EtOAc (3

mL), and poured into NaHCO₃solution (2 mL). The layers

were separated, and the aqueous phase was extracted with

EtOAc (3 × 3 mL). The combined organic extracts were washed

with HCl (1 M, 3 mL), water (3 mL), and brine (3 mL) and

then dried (MgSO₄). Concentration under reduced pressure

provided a yellow oil which was analyzed by mass spectrom-

etry and HPLC.

into NaHCO₃solution (2 mL). The layers were separated, and

the aqueous phase was extracted with CH₂Cl₂(2 × 3 mL). The

combined organic extracts were washed with brine (2 mL),

dried (MgSO₄), filtered, and concentrated under reduced

pressure to provide diene 30 as a yellow oil (152 mg, quantita-

tive yield, remaining mass accounting for 2,6-DTBMP and

silicon residues). The crude products from two reactions (2 ×

100 mg of allylsilane 27a ) were combined and purified by flash

column chromatography (5% EtOAc in hexane) to afford diene

30 as a colorless oil (56 mg, 38%, inseparable mixture of

anomers (2.2:1): HPLC t_R) 54.87 min; R_f) 0.25 (5% EtOAc

in hexane); ν_max(film)/cm^-13087m, 3063m, 3030m, 2864s,

1605m; δ_H(500 MHz) 3.49-3.62 (stack including [3.52 (d, J

4.5, 2H, 2 × H-1′_major)], 4H, 2 × 1′-H_major, 2 × 1′-H_minor), 3.83

(d, J 3.5, 1H, 4-H_minor), 3.87-3.92 (stack including [3.89 (app

t, J 4.5, 1H, 4-H_major)], 2H, 4-H_major, 3-H_minor), 4.01-4.07 (stack

including [4.04 (app t, J 3.8, 1H, 3-H_major)], 2H, 3-H_major

,

2-H_minor), 4.16 (app q, J 4.5, 1H, 2-H_major), 4.37-4.54 (stack,

14H, 3 × CH₂Ph_major, 5-H_major, 3 × CH₂Ph_minor, 5-H_minor), 5.07

(d, J 9.3, 2H, 4′′_cis-H_major, 4′′_cis-H_minor), 5.17 (d, J 16.5, 2H, 4′′_trans

-

(1′E)-Meth yl 3,4,6-Tr i-O-ben zyl-2-O-[d ieth yl(3′-tr im e-

t h ylsila n yl)p r op -1′-en yl]sila n yl-R-^D-m a n n op yr a n osid e

(27b). AcCl (130 µL, 1.83 mmol) was added dropwise to a

solution of aminosilane 29b (352 mg, 1.83 mmol) in CH₂Cl₂

(1.8 mL) at 0 °C, and the reaction was stirred for 8 h at rt.

This solution was transferred via cannula to a mixture of

alcohol 15 (850 mg, 1.83 mmol), imidazole (245 mg, 3.66 mmol),

and DMAP (11 mg, 0.09 mmol), and the resulting suspension

was stirred for 1 d at rt. The reaction mixture was then poured

over NaHCO₃solution (2 mL). The layers were separated, and

the aqueous phase was extracted with CH₂Cl₂(2 × 3 mL). The

combined organic extracts were washed with brine (2 mL),

dried (MgSO₄), filtered, and concentrated under reduced

pressure to leave a yellow residue which was purified by flash

column chromatography (6% EtOAc in hexane) to afford silyl

ether 27b as a colorless oil (971 mg, 80%): [R]²²_D+38.4 (c 2.0,

CHCl₃); R_f) 0.28 (6% EtOAc in hexane); ν_max(film)/cm^-1

2953s, 2910s, 1601s; δ_H(300 MHz) -0.03 (s, 9H, Si(CH₃)₃),

0.55-0.71 (stack, 4H, OSi(CH₂CH₃)₂), 0.80-1.00 (stack includ-

ing [0.94 (t, J 7.9, 3H, 1 × OSi(CH₂CH₃)₂)], 6H, OSi(CH₂CH₃)₂),

1.55-1.67 (m, 2H, CHdCHCH₂), 3.33 (s, 3H, OCH₃), 3.68-

3.80 (stack including [3.77 (dd, J 9.1, 2.5, 1H, 3-H)], 4H, 3-H,

5-H, 2 × 6-H), 3.91 (app t, J 9.1, 1H, 4-H), 4.10 (app t, J 2.5,

1H, 2-H), 4.49 (A of AB, J 10.7, 1H, OCH_AH_BPh), 4.55 (A of

AB, J 12.5, 1H, OCH_CH_DPh), 4.58-4.68 (stack, 3H, OCH₂Ph,

1-H), 4.70 (B of AB, J 12.5, 1H, OCH_CH_DPh), 4.83 (B of AB, J

10.7, 1H, OCH_AH_BPh), 5.37 (d, J 18.5, 1H, CHdCHCH₂), 6.18

(dt, J 18.5, 8.2, 1H, CHdCHCH₂), 7.11-7.39 (stack, 15H,

PhH); δ_C(75 MHz) -2.0 (CH₃, Si(CH₃)₃), 5.64 (CH₂, 1 ×

OSi(CH₂CH₃)₂), 5.67 (CH₂, 1 × OSi(CH₂CH₃)₂), 6.74 (CH₃, 1

× OSi(CH₂CH₃)₂), 6.78 (CH₃, 1 × OSi(CH₂CH₃)₂), 28.7 (CH₂,

CHdCHCH₂), 54.6 (CH₃, OCH₃), 69.3 (CH), 69.4 (CH₂), 71.9

(CH₂), 72.0 (CH), 73.1 (CH₂), 74.6 (CH), 74.8 (CH₂), 80.2 (CH),

101.6 (CH, 1-C), 122.9 (CH, dCH), [127.4 (CH, Ph), 127.5 (CH,

Ph), 127.9 (CH, Ph), 128.10 (CH, Ph), 128.14 (CH, Ph), 128.17

(CH, Ph) some overlap], 138.5 (quat C, ipsoPh), 138.6 (quat

C, ipsoPh), 138.7 (quat C, ipsoPh), 147.4 (CH, )CH); m/z (TOF

ES+) 685.4 [(M + Na)⁺, 100]. Anal. Calcd for C₃₈H₅₄O₆Si₂: C,

68.84; H, 8.21. Found: C, 68.80; H, 8.31.

H

_major, 4′′_trans-H_minor), 5.72 (dd, J 14.4, 7.3, 1H, 1′′-H_major), 5.84

(dd, J 14.6, 7.9, 1H, 1′′-H_minor), 6.18-6.37 (stack, 4H, 2′′-H_major

,

3′′-H_major, 2′′-H_minor, 3′′-H_minor), 7.18-7.29 (stack, 30H, PhH);

δ_C(125 MHz) 70.3 (CH₂, 1′-C_major), 70.5 (CH₂, 1′-C_minor), 71.6

(CH₂, OCH₂Ph_minor), 71.8 (CH₂, OCH₂Ph_minor), 71.9 (CH₂, OCH₂-

Ph_major), 72.1 (CH₂, OCH₂Ph_major), 73.3 (CH₂, OCH₂Ph_minor), 73.4

(CH₂, OCH₂Ph_major), 81.3 (CH, 2-C_major), 81.9 (CH, 5-C_minor), 82.3

(CH, 2-C_minor), 82.8 (CH, 5-C_major), 84.4 (CH, 3-C_minor), 84.5 (CH,

4-C_minor), 84.9 (CH, 3-C_major), 88.3 (CH, 4-C_major), 118.0 (CH₂,

4′′-C_minor), 118.1 (CH₂, 4′′-C_major), [127.4 (CH, Ph), 127.6 (CH,

Ph), 127.7 (CH, Ph), 128.3 (CH, Ph), 128.4 (CH, Ph) some

overlap], 128.7 (CH, 1′′-C_minor), 131.7 (CH, 1′′-C_major), 133.1 (CH,

dCH_major), 134.6 (CH, dCH_minor), 136.2 (CH, dCH_major), 136.4

(CH, dCH_minor), 137.77 (quat C, ipsoPh), 137.82 (quat C,

ipsoPh), 137.88 (quat C, ipsoPh), 137.93 (quat C, ipsoPh), 138.2

(quat C, ipsoPh), 138.3 (quat C, ipsoPh); m/z (TOF ES+) 479.3

(100, [M + Na]⁺); HRMS calcd for C₃₀H₃₂O₄Na [M + Na]⁺

479.2198, found 479.2209.

Allyla t ion of Ma n n osid e 27b : P r ep a r a t ion of 30, 39,

42b, 43b, a n d 41. TMSOTf (89 µL, 0.49 mmol) was added

dropwise to a solution of allylsilane 27b (325 mg, 0.49 mmol)

and TTBP (146 mg, 0.59 mmol) in MeCN (4.9 mL) at rt. The

reaction mixture was stirred for 12 h, diluted with EtOAc (5

mL), and poured into NaHCO₃solution (5 mL). The layers

were separated, and the aqueous phase was extracted with

EtOAc (3 × 5 mL). The combined organic extracts were washed

with brine (5 mL), dried (MgSO₄), filtered, and concentrated

under reduced pressure to provide a yellow oil which was

analyzed by preparative HPLC to afford a 4.8:1.3:1.0:1.6:3.4

ratio of 30/41/43b/42b/39.

(1R,3R,4R,5S,6S,9S)-4,5-Dib en zyloxy-3-b en zyloxym e-

t h yl-8,8-d ie t h yl-2,7-d ioxa -8-sila -9-vin ylb icyclo[4.3.0]-

n on a n e (43b):

(1′′E,2R,3R,4R,5R)-3,4-Diben zyloxy-2-ben zyloxym eth yl-

5-bu ta-1′′,3′′-dien yltetr ah ydr ofu r an an d (1′′E,2R,3R,4R,5S)-

3,4-Diben zyloxy-2-ben zyloxym eth yl-5-bu ta-1′′,3′′-dien yltet-

r ah ydr ofu r an (30) (Major Ster eoisom er Not Deter m in ed).

HPLC t_R) 59.60 min; R_f) 0.24 (6% EtOAc in hexane); ν_max

(film)/cm^-13064m, 3031m, 1628w; δ_H(C₆D₆, 500 MHz) 0.58-

0.74 (m, 2H, 1 × OSi(CH₂CH₃)₂), 0.88-1.11 (stack, 8H, 1 ×

OSi(CH₂CH₃)₂, OSi(CH₂CH₃)₂)), 2.00 (dd, J 9.7, 3.3, 1H, 9-H),

3.35 (d (+ unresolved fine coupling), J 9.6, 1H, 3-H), 3.45-

3.51 (stack including [3.48 (dd, J 9.6, 2.6, 1H, 5-H), 2H, 5-H,

1-H), 3.69-3.74 (stack, 2H, 2 × 1′-H), 3.82 (d, J 2.6, 1H, 6-H),

4.10 (app t, J 9.6, 1H, 4-H), 4.35-4.42 (m, 2H, C(1′)OCH₂Ph),

4.52 (A of AB, J 12.1, 1H, C(5)OCH_AH_BPh), 4.58-4.62 (m, 2H,

C(4)OCH₂Ph), 4.69 (B of AB, J 12.1, 1H, C(5)OCH_AH_BPh),

4.97-5.08 (m, 2H, 2 × 2′′-H), 6.38 (dt, J 17.3, 9.7, 1H, 1′′-H),

7.03-7.45 (stack, 15H, PhH); δ_C(C₆D₆, 125 MHz) [5.9, 6.1, 6.9,

7.0 (CH₂and CH₃, OSi(CH₂CH₃))], 38.4 (CH, 9-C), 70.0 (CH₂,

TMSOTf (29 µL, 0.16 mmol) was added dropwise to a solution

of allylsilane 27a (100 mg, 0.16 mmol) and 2,6-DTBMP (39

mg, 0.19 mmol) in MeCN (1.6 mL) at rt. The reaction mixture

was stirred for 8 h, diluted with CH₂Cl₂(3 mL), and poured

6354 J . Org. Chem., Vol. 69, No. 19, 2004

Stereoselective Synthesis of Allyl-C-mannosyl Compounds

1′-C), 70.8 (CH₂, C(5)OCH₂Ph), 73.4 (CH₂, C(1′)OCH₂Ph), 74.7

(CH, 4-C), 75.2 (CH₂, C(4)OCH₂Ph), 76.9 (CH, 6-C), 79.2 (CH,

3-C), 80.5 (CH, 1-C), 83.0 (CH, 5-C), 112.8 (CH₂, 2′′-C), [126.5

(CH, Ph), 126.8 (CH, Ph), 127.0 (CH, Ph), 127.5 (CH, Ph), 127.8

(CH, Ph), 128.0 (CH, Ph), 128.2 (CH, Ph), 128.5 (CH, Ph), 128.6

(CH, Ph), 129.1 (CH, Ph) some overlap], 135.8 (CH, 1′′-C),

[139.5 (quat C, ipsoPh), 139.8 (quat C, ipsoPh) some overlap];

Ph), 128.3 (CH, Ph) some overlap], 131.5 (CH, dCH), 133.7

(CH, 1′′-C), 136.6 (CH, dCH), 138.1 (quat C, ipsoPh), 138.5

(quat C, ipsoPh), 138.6 (quat C, ipsoPh); m/z (TOF ES+) 581.2

(100, [M + Na]⁺); HRMS calcd for C₃₄H₄₂NaO₅Si [M + Na]⁺

581.2699, found 581.2708.

Allyla tion of Ma n n osid e 27c: P r ep a r a tion of 42c, 43c,

41, and 40. TMSOTf (83 µL, 0.46 mmol) was added dropwise

to a solution of allylsilane 27c (315 mg, 0.46 mmol) and 2,6-

DTBMP (112 mg, 0.55 mmol) in MeCN (4.6 mL) at rt. The

reaction mixture was stirred for 18 h, diluted with EtOAc (5

mL), and poured into NaHCO₃solution (5 mL). The layers

were separated, and the aqueous phase was extracted with

EtOAc (3 × 5 mL). The combined organic extracts were washed

with brine (5 mL), dried (MgSO₄), filtered, and concentrated

under reduced pressure to provide a yellow oil which was

analyzed by preparative HPLC (t ) 0 f t ) 45 min, 0 f 100%

MeCN in H₂O) to afford a 1.0:7.2:5.2:7.6 ratio of 41/42c

(inseparable from two other compounds; data not provided)/

43c/40.

m/z (TOF ES+) 581.3 [(M + Na)⁺, 100]; HRMS calcd for C₃₄H₄₂

-

NaO₅Si [M + Na]⁺581.2699, found 581.2712.

(1R ,3R ,4R ,5S ,6S ,9R )-4,5-Dib e n zyloxy-3-b e n zyloxy-

m e t h y l-8,8-d i e t h y l-2,7-d i o x a -8-s i la -9-v i n y lb i c y c lo -

[4.3.0]n on a n e (42b):

HPLC t_R) 60.40 min; R_f) 0.26 (6% EtOAc in hexane); ν_max

(film)/cm^-13031w, 2874s, 1629w; δ_H(500 MHz) 0.80-1.04

(stack, 10H, Si(CH₂CH₃)₂), 2.25 (d, J 9.7, 1H, 9-H), 3.41 (dd, J

9.2, 5.3, 1H, 3-H), 3.57-3.61 (m containing d, ²J 10.5, 1H, 1′_A-

H), 3.62 (dd, J 9.2, 2.6, 1H, 5-H), 3.67-3.72 (m containing d,

²J 10.5, 1H, 1′_B-H), 3.76-3.82 (stack including [3.79 (app t, J

9.2, 1H, 4-H)], 2H, 1-H, 4-H), 4.21 (d, J 2.6, 1H, 6-H), 4.50-

4.58 (stack including [4.52 (A of AB, J 10.5, 1H, C(4)OCH_AH_B-

Ph)], 3H, C(4)OCH_AH_BPh, C(1′)OCH₂Ph), 4.75 (A of AB, J 12.4,

1H, C(5)OCH_CH_DPh), 4.80 (B of AB, J 12.4, 1H, C(5)OCH_CH_D-

Ph), 4.85 (d, J 17.0, 1H, 2′′_trans-H), 4.88 (d, J 9.7, 1H, 2′′_cis-H),

4.92 (B of AB, J 10.5, 1H, C(4)OCH_AH_BPh), 5.66 (dt, J 17.0,

9.7, 1H, 1′′-H), 7.08-7.40 (stack, 15H, PhH); δ_C(125 MHz) 4.6

(CH₂, 1 × OSi(CH₂CH₃)₂), 6.4 (1 × CH₂, 1 × CH₃, 1 × OSi(CH₂-

CH₃)₂, 1 × OSi(CH₂CH₃)₂), 6.8 (CH₃, 1 × OSi(CH₂CH₃)₂), 37.4

(CH, 9-C), 69.7 (CH₂, 1′-C), 71.5 (CH₂, C(5)OCH₂Ph), 73.2 (CH₂,

C(1′)OCH₂Ph), 74.4 (CH, 4-C), 75.3 (CH₂, C(4)OCH₂Ph), 75.4

(CH, 6-C), 78.5 (CH, 3-C), 81.3 (CH, 1-C), 81.9 (CH, 5-C), 112.4

(CH₂, 2′′-C), [127.4 (CH, Ph), 127.5 (CH, Ph), 127.6 (CH, Ph),

127.7 (CH, Ph), 127.8 (CH, Ph), 128.0 (CH, Ph), 128.25 (CH,

Ph), 128.34 (CH, Ph) some overlap], 135.0 (CH, 1′′-C), 138.4

(quat C, 2 × ipsoPh), 138.5 (quat C, ipsoPh); m/z (TOF ES+)

581.2 [(M + Na)⁺, 100]; HRMS calcd for C₃₄H₄₂NaO₅Si [M +

Na]⁺581.2699, found 581.2689.

(1R,3R,4R,5S,6S,9S)-4,5-Dib en zyloxy-3-b en zyloxym e-

th yl-8,8-d iisop r op yl-2,7-d ioxa -8-sila -9-vin ylbicyclo[4.3.0]-

n on a n e (43c):HPLC t_R64.59 min; R_f) 0.22 (3% EtOAc in

hexane); ν_max(film)/cm^-13064w, 3031w, 2941s, 2865s, 1629w;

δ_H(500 MHz) 1.02-1.10 (stack, 14H, OSi(CH(CH₃)₂)₂), 2.24

(dd, J 10.2, 3.5, 1H, 9-H), 3.37-4.43 (m, 1H, 3-H), 3.59 (dd, J

2

9.4, 2.8, 1H, 5-H), 3.61-3.66 (m containing d, J 9.9, 1H, 1′_A-

H), 3.71-3.76 (m containing d, ²J 9.9, 1H, 1′_B-H), 3.78 (d, J

3.5, 1H, 1-H), 3.84 (app t, J 9.4, 1H, 4-H), 3.91 (d, J 2.8, 1H,

6-H), 4.50-4.56 (m, 2H, C(1′)OCH₂Ph), 4.58 (A of AB, J 10.8,

1H, C(4)OCH_AH_BPh), 4.74-4.78 (br s, 2H, C(5)OCH₂Ph), 4.89

(d, J 10.2, 1H, 2′′_cis-H), 4.94 (B of AB, J 10.8, 1H, C(4)OCH_AH_B-

Ph), 4.98 (d, J 17.4, 1H, 2′′_trans-H), 6.16 (dt, J 17.4, 10.2, 1H,

1′′-H), 7.12-7.42 (stack, 15H, PhH); δ_C(125 MHz) 12.9 (CH, 1

× OSi(CH(CH₃)₂)₂), 13.3 (CH, 1 × OSi(CH(CH₃)₂)₂), [17.46,

17.53, 17.9 (CH₃, OSi(CH(CH₃)₂)₂)], 36.5 (CH, 9-C), 69.8 (CH₂,

2-C), 71.5 (CH₂, C(5)OCH₂Ph), 73.2 (CH₂, C(1′)OCH₂Ph), 74.7

(CH, 4-C), 75.3 (CH₂, C(4)OCH₂Ph), 77.3 (CH, 6-C), 78.7 (CH,

3-C), 79.9 (CH, 1-C), 82.1 (CH, 5-C), 112.9 (CH₂, 2′′-C), 127.4

(CH, Ph), 127.5 (CH, Ph), 127.61 (CH, Ph), 127.64 (CH, Ph),

127.8 (CH, Ph), 128.0 (CH, Ph), 128.1 (CH, Ph), 128.2 (CH,

Ph), 128.3 (CH, Ph), 135.6 (CH, 1′′-C), [138.56 (quat C, ipsoPh),

138.60 (quat C, ipsoPh) some overlap]; m/z (TOF ES+) 609.4

[(M + Na)⁺, 100]; HRMS calcd for C₃₆H₄₆NaO₅Si [M + Na]⁺

609.3012, found 609.3013.

5,6-Diben zyloxy-4-ben zyloxym eth yl-7-bu ta-1′′,3′′-dien yl-

2,2-d ieth yl-1,3,2-d ioxa silep a n e (39):

(3E ,5R ,6S ,7S ,8R )-6,7,9-Tr ib e n zyloxy-5-d iisop r op yl-

(m et h oxy)sila n yloxy-8-t r im et h ylsila n yloxyn on a -1,3-d i-

en e (40):

HPLC t_R) 62.63 min; R_f) 0.30 (6% EtOAc in hexane); ν_max

(film)/cm^-13088w, 3064m, 3031m, 2958s, 2877s, 1605m; δ_H

(400 MHz) 0.67 (q, J 8.1, 2H, 1 × Si(CH₂CH₃)₂), 0.68 (q, J 8.1,

2H, 1 × Si(CH₂CH₃)₂), 0.99 (t, J 8.1, 3H, 1 × Si(CH₂CH₃)₂),

1.01 (t, J 8.1, 3H, 1 × Si(CH₂CH₃)₂), 3.37 (app t, J 8.5, 1H,

6-H), 3.64 (app t, J 8.5, 1H, 5-H), 3.70-3.75 (m containing d,

²J 10.0, 1H, 1′_A-H), 3.76-3.81 (m containing d, ²J 10.0, 1H,

1′_B-H), 4.07 (ddd, J 8.5, 4.8, 2.4, 1H, 4-H), 4.47 (dd, J 8.5, 5.8,

1H, 7-H), 4.57 (A of AB, J 10.4, 1H, OCH_AH_BPh), 4.59 (A of

AB, J 11.7, 1H, OCH_CH_DPh), 4.62 (B of AB, J 11.7, 1H,

OCH_CH_DPh), 4.66 (A of AB, J 10.4, 1H, OCH_EH_FPh), 4.68 (B

of AB, J 10.4, 1H, OCH_AH_BPh), 4.80 (B of AB, J 10.4, 1H,

OCH_EH_FPh), 5.07-5.12 (m, 1H, 4′′_cis-H), 5.17-5.27 (m, 1H,

4′′_trans-H), 5.88-5.99 (m, 1H, 1′′-H), 6.30-6.44 (stack, 2H, 2′′-

H, 3′′-H), 7.16-7.36 (stack, 15H, PhH); δ_C(100 MHz) 3.93

(CH₂, Si(CH₂CH₃)₂), 6.36 (CH₃, 1 × Si(CH₂CH₃)₂), 6.43 (CH₃,

1 × Si(CH₂CH₃)₂), 71.9 (CH₂, 1′-C), 72.5 (CH, 7-C, 4-C), 73.4

(CH₂, OCH₂Ph), 75.0 (CH₂, OCH₂Ph), 75.1 (CH₂, OCH₂Ph),

83.0 (CH, 5-C), 87.1 (CH, 6-C), 117.1 (CH₂, 4′′-C), [127.3 (CH,

Ph), 127.5 (CH, Ph), 127.6 (CH, Ph), 128.0 (CH, Ph), 128.2 (CH,

HPLC t_R) 79.36 min; R_f) 0.33 (3% EtOAc in hexane); ν_max

(film)/cm^-13032w, 2946s, 2867s, 1604, 1095s; δ_H(300 MHz)

-0.09 (s, 9H, Si(CH₃)₃), 1.00-1.05 (br s, 14H, Si(CH(CH₃)₂)₂),

3.49 (s, 3H, OCH₃), 3.57 (dd, J 10.0, 6.2, 1H), 3.65 (app t, J

5.3, 1H), 3.71 (dd, J 10.1, 3.5, 1H), 3.79 (dd, J 5.9, 3.6, 1H),

4.05 (dd, J 8.0, 5.8, 1H), 4.49 (br s, 2H, OCH₂Ph), 4.53 (dd, J

7.8, 3.5, 1H), 4.64 (A of AB, J 10.8, 1H, OCH_AH_BPh), 4.68 (br

s, 2H, OCH₂Ph), 4.81 (B of AB, J 10.8, 1H, OCH_AH_BPh), 5.09

(d, J 9.9, 1H, 1_cis-H), 5.18 (d, J 16.6, 1H, 1_trans-H), 5.96 (dd, J

14.8, 7.8, 1H, 4-H), 6.21-6.43 (stack, 2H, 2-H, 3-H), 7.12-

7.46 (stack, 15H, PhH); δ_C(75 MHz) -0.6 (CH₃, Si(CH₃)₃),

12.28 (CH, 1 × Si(CH(CH₃)₂)), 12.35 (CH, 1 × Si(CH(CH₃)₂)),

J . Org. Chem, Vol. 69, No. 19, 2004 6355

Beignet et al.

17.4 (CH₃, 1 × Si(CH(CH₃)₂)), 17.52 (CH₃, 1 × Si(CH(CH₃)₂)),

17.54 (CH₃, 1 × Si(CH(CH₃)₂)), 17.6 (CH₃, 1 × Si(CH(CH₃)₂)),

51.2 (CH₃, OCH₃), 71.9 (CH₂), 72.7 (CH), 73.3 (CH₂), 74.6 (CH),

74.9 (CH₂), 75.0 (CH₂), 82.0 (CH), 84.0 (CH), 117.5 (CH₂, 1-C),

[127.27, 127.30, 127.4, 127.7, 127.9, 128.0, 128.12, 128.13,

128.3 (CH, Ph, dCH) some overlap], 133.1 (CH, dCH), 136.5

(CH, dCH), 138.4 (quat C, ipsoPh), 139.13 (quat C, ipsoPh),

139.16 (quat C, ipsoPh); m/z (TOF ES+) 713.5 [(M + Na)⁺,

100]; HRMS calcd for C₄₀H₅₈NaO₆Si₂[M + Na]⁺713.3670,

found 713.3665.

DTBMP (164 mg, 0.80 mmol) in CH₂Cl₂(4 mL) at -78 °C. The

reaction mixture was stirred for 10 min, and then NaHCO₃

solution (4 mL) was added dropwise at this temperature. The

slurry was allowed to warm to rt, and the layers were then

separated. The aqueous phase was extracted with CH₂Cl₂(3

× 4 mL), and the combined organic extracts were washed with

brine (4 mL), dried (MgSO₄), filtered, and concentrated under

reduced pressure to provide a yellow oil which was subjected

to oxidation (method A): H₂O₂(453 mg, 8.00 mmol, 60% in

H₂O), KHCO₃(200 mg, 2.00 mmol), and TBAF (2.00 mL, 2.00

mmol, 1 M solution in THF) were added to a solution of the

crude products in MeOH/THF (1:1) (4 mL). The resulting

mixture was stirred at rt for 3 d. The mixture was then poured

into Na₂S₂O₃solution (4 mL) and stirred for 30 min. The

solution was extracted with EtOAc (4 × 4 mL), and the

combined organic extracts were washed with brine (4 mL),

dried (MgSO₄), filtered, and concentrated under reduced

pressure. The residue was purified by flash column chroma-

tography (50% EtOAC in hexane) to afford diol 44 as a colorless

oil (19 mg, 10%).

(1R)-1-(3′,4′,6′-Tr i-O-ben zyl-â-^D-m a n n op yr a n osyl)p r op -

2-en -1-ol (45). H₂O₂(16 mg, 0.28 mmol, 60% in H₂O), KHCO₃

(7 mg, 70 µmol), and TBAF (70 µL, 70 µmol, 1 M solution in

THF) were added to a solution of silyl ether 43b (8 mg, 14

µmol) in MeOH/THF (1:1) (0.3 mL). The resulting mixture was

stirred at rt for 2 d. The mixture was then poured into Na₂S₂O₃

solution (1 mL) and stirred for 30 min. The solution was

extracted with EtOAc (4 × 1 mL), and the combined organic

extracts were washed with brine (1 mL), dried (MgSO₄),

filtered, and concentrated under reduced pressure. The residue

was purified by flash column chromatography (60% EtOAc in

hexane) to afford diol 45 as a colorless oil, which provided a

white amorphous solid upon storage at 4 °C (5 mg, 71%): R_f

) 0.25 (60% EtOAc in hexane); ν_max(film)/cm^-13435br s,

1646w; δ_H(500 MHz) 3.15 (d, J 7.0, 1H, 1′-H), 3.42 (ddd, J

9.5, 4.2, 2.5, 1H, 5′-H), 3.57 (dd, J 9.5, 3.1, 1H, 3′-H), 3.68-

3.78 (stack, 2H, 2 × 6′-H), 3.83 (app t, J 9.5, 1H, 4′-H), 4.04

(d, J 3.1, 1H, 2′-H), 4.48 (app t, J 7.0, 1H, 1-H), 4.53 (A of AB,

J 12.2, 1H, OCH_AH_BPh), 4.54 (A of AB, J 10.8, 1H, OCH_CH_D-

Ph), 4.61 (B of AB, J 12.2, 1H, OCH_AH_BPh), 4.66 (A of AB, J

11.5, 1H, OCH_EH_FPh), 4.71 (B of AB, J 11.5, 1H, OCH_EH_F-

Ph), 4.84 (B of AB, J 10.8, 1H, OCH_CH_DPh), 5.27 (d, J 10.5,

1H, 3_cis-H), 5.48 (d, J 17.2, 1H, 3_trans-H), 5.86 (ddd, J 17.2, 10.5,

7.0, 1H, 2-H), 7.17-7.20 (stack, 2H, PhH), 7.24-7.36 (stack,

13H, PhH); δ_C(125 MHz) 66.7 (CH, 2′-C), 69.1 (CH₂, 6′-C),

71.8 (CH₂, OCH₂Ph), 72.3 (CH, 1-C), 73.4 (CH₂, OCH₂Ph), 74.5

(CH, 4′-C), 75.2 (CH₂, OCH₂Ph), 79.2 (CH, 5′-C), 80.8 (CH, 1′-

C), 83.2 (CH, 3′-C), 118.2 (CH₂, 3-C), [127.6 (CH, Ph), 127.75

(CH, Ph), 127.85 (CH, Ph), 127.98 (CH, Ph), 128.02 (CH, Ph),

128.4 (CH, Ph), 128.6 (CH, Ph) some overlap], 135.4 (CH, 2-C),

137.7 (quat C, ipsoPh), 138.2 (quat C, 2 × ipsoPh); m/z (TOF

ES+) 513.2 [(M + Na)⁺, 100]; HRMS calcd for C₃₀H₃₄NaO₆[M

+ Na]⁺513.2253, found 513.2252.

(1S)-1-(3′,4′,6′-Tr i-O-ben zyl-â-D-m a n n op yr a n osyl)p r op -

2-en -1-ol (44). Meth od A. H₂O₂(26 mg, 0.46 mmol, 60% in

H₂O), KHCO₃(11 mg, 0.11 mmol), and TBAF (110 µL, 1 M

solution in THF) were added to a solution of silyl ether 42b

(13 mg, 23 µmol) in MeOH/THF (1:1) (0.3 mL), and the

resulting mixture was stirred at rt for 2 d. The mixture was

then poured into Na₂S₂O₃solution (2 mL) and stirred for 30

min. The solution was extracted with EtOAc (4 × 2 mL), and

the combined organic extracts were washed with brine (1 mL),

dried (MgSO₄), filtered, and concentrated under reduced

pressure. The residue was purified by flash column chroma-

tography (50% EtOAc in hexane) to afford diol 44 as a colorless

oil which solidified as an amorphous white solid upon storage

at 4 °C (8 mg, 69%): [R]²¹-12.7 (c 1.8, CHCl₃); R_f) 0.25

D

(50% EtOAc in hexane); ν_max(film)/cm^-13462br s, 1645w; δ_H

(400 MHz) 2.50-2.75 (br s, 2H, 2 × OH), 3.22 (d, J 5.8, 1H,

1′-H), 3.44 (ddd, J 9.6, 4.9, 2.0, 1H, 5′-H), 3.56 (dd, J 9.6, 3.0,

1H, 3′-H), 3.67-3.73 (m containing d, ²J 10.9, 1H, 6′_A-H), 3.73-

3.78 (m containing d, ²J 10.9, 1H, 6′_B-H), 3.83 (app t, J 9.6,

1H, 4′-H), 4.32 (d, J 3.0, 1H, 2′-H), 4.49-4.53 (stack including

[4.52 (A of AB, J 10.8, 1H, OCH_AH_BPh)], 2H, OCH_AH_BPh, 1-H),

4.55 (A of AB, J 12.2, 1H, OCH_CH_DPh), 4.61 (B of AB, J 12.2,

1H, OCH_CH_DPh), 4.65 (A of AB, J 11.5, 1H, OCH_EH_FPh), 4.76

(B of AB, J 11.5, 1H, OCH_EH_FPh), 4.86 (B of AB, J 10.8, 1H,

OCH_AH_BPh), 5.25 (dt, J 10.6, 1.4, 1H, 3_cis-H), 5.44 (dt, J 17.3,

1.4, 1H, 3_trans-H), 5.99 (ddd, J 17.3, 10.6, 5.2, 1H, 2-H), 7.12-

7.38 (stack, 15H, PhH); δ_C(100 MHz) 66.3 (CH, 2′-C), 69.3

(CH₂, 6′-C), 71.5 (CH₂, CH₂Ph), 72.2 (CH, 1-C), 73.4 (CH₂, CH₂-

Ph), 74.5 (CH, 4′-C), 75.2 (CH₂, CH₂Ph), 79.2 (CH, 1′-C), 79.5

(CH, 5′-C), 83.0 (CH, 3′-C), 116.1 (CH₂, 3-C), [127.7 (CH, Ph),

127.8 (CH, Ph), 127.9 (CH, Ph), 128.0 (CH, Ph), 128.3 (CH,

Ph), 128.5 (CH, Ph) some overlap], 137.3 (CH, 2-C), 137.8 (quat

C, ipsoPh), 138.2 (quat C, ipsoPh), 138.3 (quat C, ipsoPh); m/z

(TOF ES+) 513.2 [(M + Na)⁺, 100]; HRMS calcd for C₃₀H₃₄

-

NaO₆[M + Na]⁺513.2253, found 513.2259.

Meth od B. TMSOTf (58 µL, 0.32 mmol) was added dropwise

to a solution of allylsilane 27c (220 mg, 0.32 mmol) and 2,6-

DTBMP (79 mg, 0.38 mmol) in MeCN (3.2 mL) at rt. The

reaction mixture was stirred for 18 h, diluted with EtOAc (3

mL), and poured into NaHCO₃solution (3 mL). The layers

were separated, and the aqueous phase was extracted with

EtOAc (3 × 3 mL). The combined organic extracts were washed

with brine (3 mL), dried (MgSO₄), filtered, and concentrated

under reduced pressure to provide a yellow oil which was

subjected to oxidation (method A): H₂O₂(363 mg, 6.40 mmol,

60% in H₂O), KHCO₃(160 mg, 1.60 mmol), and TBAF (1.60

mL, 1 M solution in THF) were added to a solution of the crude

products in MeOH/THF (1:1) (3.2 mL), and the resulting

mixture was stirred at rt for 2 d. The mixture was then poured

into Na₂S₂O₃solution (2 mL) and stirred for 30 min. The

solution was extracted with EtOAc (4 × 3 mL) and the

combined organic extracts were washed with brine (3 mL),

dried (MgSO₄), filtered, and concentrated under reduced

pressure. The residue was purified by flash column chroma-

tography (50% EtOAc in hexane) to afford diol 44 as a colorless

oil (13 mg, 8% over two steps).

Ack n ow led gm en t. We thank the Engineering and

Physical Sciences Research Council (Grant No. GR/

N32556) for a studentship (to J .B.) and Pfizer for an

unrestricted award (to L.R.C.).

Su p p or tin g In for m a tion Ava ila ble: General experimen-

tal details, experimental procedures and full characterization

data for intermediates 9-15, 17, 19, 20, 25-27a ,c, 41, 46,

47, and 50-53, crossover experiment between 25 and 27a ,

preparation of (allyl)MgBr and titration details, and ¹H and

¹³C NMR data for all compounds. This material is available

free of charge via the Internet at http://pubs.acs.org.

Meth od C. Tf₂O (78 µL, 0.48 mmol) was added dropwise to

a solution of allylsilane 47 (318 mg, 0.40 mmol) and 2,6-

J O049061W

6356 J . Org. Chem., Vol. 69, No. 19, 2004

Article Doi

Stereoselective synthesis of allyl-C-mannosyl compounds: Use of a temporary silicon connection in intramolecular allylation strategies with allylsilanes

DOI: 10.1021/jo049061w

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Article abstract of DOI:10.1021/jo049061w

Full text of DOI:10.1021/jo049061w

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