Substitution and remote protecting group influence on the oxidation/addition of α-substituted 1,2-anhydroglycosides: A novel entry into C-Ketosides

Article abstract of DOI:10.1021/ol0501469

(Chemical Equation Presented) C-Ketosides are valuable intermediates in chemical synthesis and as glycoside mimics. This manuscript describes the efficient generation of these substrates from α-alkyl-substituted glycals and an oxidative, C-C bond-forming

Full text of DOI:10.1021/ol0501469

ORGANIC
LETTERS
2005
Vol. 7, No. 6
1141-1144
Substitution and Remote Protecting
Group Influence on the Oxidation/
Addition of
r-Substituted
1,2-Anhydroglycosides: A Novel Entry
into C-Ketosides
Scott W. Roberts and Jon D. Rainier*
Department of Chemistry, UniVersity of Utah, 315 S 1400 E,
Salt Lake City, Utah 84112
rainier@chem.utah.edu
Received January 21, 2005
ABSTRACT
C-Ketosides are valuable intermediates in chemical synthesis and as glycoside mimics. This manuscript describes the efficient generation of
these substrates from
was critical.
r-alkyl-substituted glycals and an oxidative, C
−C bond-forming sequence where the choice of C(3) protecting group
Carbon (C)-glycosides that contain two exocyclic C-C
bonds at C(1) (C-ketosides) and the analogous agents having
one exocyclic C-C bond (C-glycosides) have attracted the
interest of the synthetic community for a number of reasons.
For some, these agents have served as valuable precursors
to other targets.1 For a number of others, their intrinsic
stability and resulting utility as glycoside mimics has made
C-glycosides and C-ketosides attractive targets.2,3 Regardless
of the reasons for being interested in these compounds, to
the best of our knowledge, they can only be accessed through
chemical synthesis. Along these lines, while arrays of
synthetic methods are available for C-glycosides, the list of
procedures to generate the corresponding C-ketosides is much
shorter. To date, these have included the following: (1) the
coupling of carbon nucleophiles with pyranose hemiketals
in the presence of Lewis acids;4 (2) acid-catalyzed ring
expansion reactions of glycal-derived carbinols;5 (3) [1,2]-
Wittig rearrangements of anomeric ketals;6 (4) electrophilic
alkylations of exocyclic enol ethers;7 (5) free-radical coupling
reactions;8 (6) the generation of spiro-fused cyclopropyl
sugars from glycosidic carbenes;9 (7) [4 + 3] cycloadditions
(4) (a) Go´mez, A. M.; Uriel, C.; Jarosz, S.; Valverde, S.; Lo´pez, J. C.
Tetrahedron Lett. 2002, 43, 8935. (b) Go´mez, A. M.; Uriel, C.; Jarosz, S.;
Valverde, S.; Lo´pez, J. C. Eur. J. Org. Chem. 2003, 4830.
(5) Paquette, L. A.; Kinney, M. J.; Dullweber, U. J. Org. Chem. 1997,
62, 1713.
(6) Tommoka, K.; Yamamoto, H.; Nakai, T. J. Am. Chem. Soc. 1996,
118, 3317.
(7) (a) Wilcox, C. S.; Long, G. W.; Suh, H. Tetrahedron Lett. 1984, 25,
395. (b) Lay, L.; Nicotra, F.; Panza, L.; Russo, G.; Caneva, E. J. Org. Chem.
1992, 57, 1304.
(8) (a) Dupuis, J.; Giese, B.; Hartung, J.; Leising, M. J. Am. Chem. Soc.
1985, 107, 4332. (b) Lo´pez, J. C.; Go´mez, A. M.; Fraser-Reid, B. J. Org.
Chem. 1995, 60, 3871.
(1) (a) Lewis, M. D.; Cha, J. K.; Kishi, Y. J. Am. Chem. Soc. 1982, 104,
4976. (b) Allwein, S. P.; Cox, J. M.; Howard, B. E.; Johnson, H. W. B.;
Rainier, J. D. Tetrahedron 2002, 58, 1997. (c) Johnson, H. W. B.; Majumder,
U.; Rainier, J. D. J. Am. Chem. Soc. 2005, 127, 848.
(2) For reviews see: Postema, M. H. D. In Glycochemistry Principles,
Synthesis and Applications; Bertozzi, C., Wang, P. G., Eds.; Marcel
Dekker: New York, 2000; pp 77-131. (b) Du, Y.; Lindhart, R. J.; Vlahov,
I. R. Tetrahedron 1998, 54, 9913.
(3) (a) Kihlberg, J.; Elofsson, M. Curr. Med. Chem. 1997, 4, 85. (b)
Weatherman, R. V.; Kiessling, L. L. J. Org. Chem. 1996, 61, 534. (c)
Weatherman, R. V.; Mortell, K. H.; Chervenak, M.; Kiessling, L. L.; Toone,
E. J. Biochemistry 1996, 35, 3619.
(9) Praly, J.-P.; Kharraf, Z. E.; Descotes, G. Tetrahedron Lett. 1990,
31, 4441. (b) Waldraff, C.; Bernet, B.; Vasella, A. HelV. Chim. Acta 1997,
80, 1882.
10.1021/ol0501469 CCC: $30.25
© 2005 American Chemical Society
Published on Web 02/15/2005

and subsequent fragmentations;10 (8) samarium enolate-
aldehyde condensations;11 (9) electrophilic cyclizations of
hydroxy-alkenes;12 and (10) acid-catalyzed cyclizations of
styrenyl alcohols.13
As part of our program targeting the synthesis of the
polycyclic ether-containing natural products hemibrevetoxin
B,14 gambierol,15 and gambieric acid,16 C-ketosides emerged
as necessary targets. From the various possibilities, we opted
to pursue the same approach that had proven successful for
us in the generation of the corresponding C-glycosides,1,17,18
one involving a single flask enol ether oxidation/carbon-
carbon bond-forming sequence (Scheme 1).
transformations. Of interest to us was the influence of the
nucleophile and substitution about the anhydride on the
reaction. The results of these efforts are described here.
We initially studied the influence of C(3) silyl ether
substitution on the addition of C-nucleophiles to R-methyl
anhydrides. Surprisingly, the choice of silyl ether proved to
be critical; while C(3) TBDPS ether 5 gave 6 in 92% yield
with >95:5 diastereoselectivity when exposed to 2-methyl-
propenylmagnesium bromide (Table 1, entry 1), the use of
Table 1.
Scheme 1
Unfortunately, our early attempts to generate C-ketosides
from anhydrides were mostly unsuccessful. We were unable
to stereoselectively add any nucleophiles other than trimethyl
aluminum to R-substituted glycals.19 This changed for the
better during our gambierol work when we found that anhy-
dride 5 underwent a stereoselective coupling reaction with
2-methylpropenylmagnesium bromide, propenylmagnesium
chloride, and propargylmagnesium chloride to give â-C-keto-
sides 6, 7, and 8, respectively.20 Hopeful that 5 and related
substrates might enable us to finally solve the anhydride to
C-ketoside problem, we elected to examine the scope of these
the anhydride from the corresponding TBDMS ether 9 gave
C-ketoside 12 in 80% yield as a 2:1 mixture of isomers
(Table 2, entry 1). Similarly, the anhydride from 9 coupled
Table 2.
(10) (a) Turner, D.; Vogel, P. Synlett 1998, 31. (b) Carrel F.; Vogel, P.
Tetrahedron: Asymmetry 2000, 11, 4661.
(11) Wang, Q.; Wolff, M.; Polat, t.; Du, Y.; Linhardt, R. J. Bioorg. Med.
Chem. Lett. 2000, 10, 941.
(12) Notz, W.; Hartel, C.; Waldscheck, B.; Schmidt, R. R. J. Org. Chem.
2001, 66, 4250.
(13) Waldscheck, B.; Streiff, M.; Notz, W.; Kinzy, W.; Schmidt, R. R.
Angew. Chem., Int. Ed. 2001, 40, 4007.
(14) Prasad, A. V. K.; Shimizu, Y. J. Am. Chem. Soc. 1989, 111, 6476.
(15) (a) Satake, M.; Murata, M.; Yasumoto, T. J. Am. Chem. Soc. 1993,
115, 361. (b) Morohashi, A.; Satake, M.; Yasumoto, T. Tetrahedron Lett.
1998, 39, 97.
(16) (a) Nagai, H.; Murata, M.; Torigoe, K.; Satake, M.; Yasumoto, T.
J. Org. Chem. 1992, 57, 5448. (b) Morohashi, A.; Satake, M.; Nagai, H.;
Oshima, T.; Yasumoto, T. Tetrahedron 2000, 56, 8995.
(17) Rainier, J. D.; Allwein, S. P. J. Org. Chem. 1998, 63, 5310.
(18) (a) Bellosta, V.; Czernecki, S. J. Chem. Soc., Chem. Commun. 1989,
199. (b) Best, W. M.; Ferro, V.; Harle, J.; Stick, R. V.; Tilbrook, D. M. G.
Aust. J. Chem. 1997, 50, 463. (c) Evans, D. A.; Trotter, B. W.; Coleman,
P. J.; Coˆte´, B. Tetrahedron Lett. 1998, 39, 1709. (d) Evans, d. A.; Trotter,
B. W.; Coleman, P. J.; Coˆte´, B.; Dias, L. C.; Rajapakse, H. A.; Tyler, A.
N. Tetrahedron 1999, 55, 8671. (e) Timmmers, C. M.; Dekker, M.;
Buijsman, R. C.; van der Marel, G. A.; Ethell, B.; Anderson, G.; Burchell,
B.; Mulder, G. J.; Van Boom J. H. Bioorg. Med. Chem. Lett. 1997, 7, 1501.
(f) Guo, J. S.; Duffy, K. J.; Stevens, K. L.; Dalko, P. I.; Roth, R. M.;
Hayward, M. M.; Kishi, Y. Angew. Chem., Int. Ed. 1998, 37, 187.
(19) (a) Rainier, J. D.; Allwein, S. P.; Cox, J. M. J. Org. Chem. 2001,
66, 1380. (b) Rainier, J. D.; Allwein, S. P.; Cox, J. M. Org. Lett. 2000, 2, 231.
(20) Majumder, U. Cox, J. M.; Rainier, J. D. Org Lett. 2003, 5, 913.
with propenylmagnesium chloride to give 13 as a 4:1 mixture
of diastereomers in 56% yield (entry 2), while TBDPS ether
1142
Org. Lett., Vol. 7, No. 6, 2005

5 gave 7 in a 97% yield with >95:5 stereoselectivity (Table
1, entry 2). Substrates containing smaller silyl ethers (TES;
Table 2, entry 3) were even less successful, and substrates
containing silyl ethers of comparable size to TBDPS (TIPS;
Table 2, entry 4) gave the corresponding ketoside in high
yield and selectivity.
Table 4.
Having demonstrated that R-methylglycals having the
appropriate C(3) substituent can be used to stereoselectively
synthesize C-ketosides, we became interested in determining
whether glycals of higher synthetic utility might also undergo
these transformations and settled upon R-benzyloxyglycal
16. We were pleased to find that the anhydride 17 from the
oxidation of 16 with DMDO was efficiently converted into
â-C-ketosides 18 and 19 when subjected to propenyl and
propynylmagnesium chloride, respectively (Table 3). In
Table 3.
NMR coupling constants,23 the pyranyl ring in 24 exists in
a boat conformation.24 Presumably, this conformation mini-
mizes relatively severe gauche interactions between the C(2)
TBDMS and C(3) TBDPS ethers and, as outlined below,
may explain the stereochemical outcome of the subsequent
addition reaction.
contrast to related substrates, anhydride 17 was surprisingly
robust, as exemplified by its recovery following aqueous
workup and its stability to silica gel chromatography.21
The disparate stereochemical outcomes described above
can be rationalized (Figures 1-3). For propargyl and allyl
Next, we examined the efficiency with which nonallylic
and propargylic Grignard nucleophiles coupled with 5 (Table
4). Interestingly, ethenylmagnesium bromide and phenyl-
magnesium chloride both coupled with 5 to give the
R-anomers 20 and 21, respectively. As in the propenylmag-
nesium chloride additions, 4 and 11 gave identical results
(entries 2 and 3).
Figure 1.
Anhydride 5 was also employed in Mukaiyama-type
addition reactions with ketene acetal 23 (eq 1).22 The addition
of 23 to 5 in the presence of TBSOTf gave â-C-ketoside 24
in 77% yield as a single diastereomer. To the best of our
knowledge, the generation of 24 is novel in that it represents
the first example of the addition of any ketene acetal to a
nucleophiles, coordination of the Mg counterion to the axial
lone pair of the pyranyl oxygen and ligand transfer via six-
membered transition structure 25 would lead to the observed
â-addition products. The importance of C(3) substitution on
1
glycosyl anhydride. As evidenced by its C(3) and C(4) H
(23) J1,3 values for H(2),H(3) and H(3),H(4) were much smaller than
(21) Isolated 17 from silica gel chromatography was coupled with
propenylmagnesium chloride to give ketoside 18.
(22) For the addition of silyl ketene acetals to epoxides, see: Maslak,
V.; Matovic, R.; Saicic, R. N. Tetrahedron 2004, 60, 5987.
one would expect for equatorially substituted pyranosides (i.e., JH(2),H(3)
1.0 Hz, JH(3),H(4) ) 4.2 Hz).
)
(24) Calculated low-energy conformer of 24 is also a boat conformation.
See ref 26.
Org. Lett., Vol. 7, No. 6, 2005
1143

these reactions is presumably tied to the ability of the
substituent to sterically protect the epoxide and inhibit the
competitive formation of oxocarbenium ion intermediates.
Nucleophiles (phenyl, vinyl, and silyl ketene acetals)
incapable of forming a six-membered transition structure
presumably react through oxocarbenium ion intermediates.
Curiously, while ketene acetal 23 adds to the si-face of the
oxocarbenium ion intermediate, Grignard nucleophiles add
to the re-face. The Grignard additions can be rationalized
either by invoking the conformation having all groups
equatorial and a chair transition state as depicted in 26 or
through a directed addition and a boat conformer as il-
lustrated for 27.25
the adjacent pseudoaxial TBDMS ether would give the
observed product.
To conclude, we have investigated the role of C(1)
substitution, C(3) protecting group, and nucleophile on the
generation of C-ketosides from from R-substituted glycal
anhydrides. Successful coupling is highly dependent upon
the size of the C(3) silyl ether and the nucleophile used with
allyl, propargyl, and ketene acetal nucleophiles giving
â-substituted products and Grignards giving R-products. We
are continuing to explore these reactions, including their
application to total synthesis problems.
Acknowledgment. We are grateful to the National
Institutes of Health, General Medical Sciences (GM56677),
for support of this research. The authors would also like to
thank Dr. Charles Mayne and Dr. Anita Orendt for help with
NMR experiments and computations, respectively. An al-
location of computer time from the Center for High
Performance Computing at the University of Utah is grate-
fully acknowledged. The computational resources for this
project have been provided by the National Institutes of
Health (NCRR 1 S10 RR17214-01) on the Arches Meta-
cluster, administered by the University of Utah Center for
High Performance Computing.
Figure 2.
Supporting Information Available: Experimental pro-
cedures and spectroscopic data for all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
In an effort to explain si-face addition for 23, we calculated
the low-energy conformer for the oxocarbenium resulting
from the interaction of anhydride 5 with TBSOTf and found
it to exist in a boat conformation as depicted by 28.26
OL0501469
(25) For an excellent discussion of the influence of substituents on the
conformations of oxocarbenium ions, see: Ayala, L.; Lucero, C. G.; Romero,
J. A. C.; Tabacco, S. A.; Woerpel, K. A. J. Am. Chem. Soc. 2003, 125,
15521.
(26) Structure optimization was completed using Gaussian03 using the
B3LYP hybrid functional and the D95** basis set. See: (a) Frisch, M. J.;
Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb, M. A.; Cheeseman,
J. R.; Montgomery, J. A., Jr.; Vreven, T.; Kudin, K. N.; Burant, J. C.;
Millam, J. M.; Iyengar, S. S.; Tomasi, J.; Barone, V.; Mennucci, B.; Cossi,
M.; Scalmani, G.; Rega, N.; Petersson, G. A.; Nakatsuji, H.; Hada, M.;
Ehara, M.; Toyota, K.; Fukuda, R.; Hasegawa, J.; Ishida, M.; Nakajima,
T.; Honda, Y.; Kitao, O.; Nakai, H.; Klene, M.; Li, X.; Knox, J. E.;
Hratchian, H. P.; Cross, J. B.; Adamo, C.; Jaramillo, J.; Gomperts, R.;
Stratmann, R. E.; Yazyev, O.; Austin, A. J.; Cammi, R.; Pomelli, C.;
Ochterski, J. W.; Ayala, P. Y.; Morokuma, K.; Voth, G. A.; Salvador, P.;
Dannenberg, J. J.; Zakrzewski, V. G.; Dapprich, S.; Daniels, A. D.; Strain,
M. C.; Farkas, O.; Malick, D. K.; Rabuck, A. D.; Raghavachari, K.;
Foresman, J. B.; Ortiz, J. V.; Cui, Q.; Baboul, A. G.; Clifford, S.; Cioslowski,
J.; Stefanov, B. B.; Liu, G.; Liashenko, A.; Piskorz, P.; Komaromi, I.;
Martin, R. L.; Fox, D. J.; Keith, T.; Al-Laham, M. A.; Peng, C. Y.;
Nanayakkara, A.; Challacombe, M.; Gill, P. M. W.; Johnson, B.; Chen,
W.; Wong, M. W.; Gonzalez, C.; Pople, J. A. Gaussian 03, revision C.02;
Gaussian, Inc.: Pittsburgh, PA, 2003. (b) Lee, C.; Yang, W.; Parr, R. G.
Phys. ReV. B: Condes. Matter 1988, 37, 785. Becke, A. D. J. Phys. Chem.
1993, 98, 5648 (c) Dunning, T. H., Jr. J. Chem. Phys. 1989, 90, 1007.
Figure 3.
Assuming 28 to also be the reactive conformer, approach of
the nucleophile to the oxocarbenium from the face opposite
1144
Org. Lett., Vol. 7, No. 6, 2005