A de novo synthesis of 2,6-dideoxy-C-aryl glycosides based on ring closing metathesis and diastereoselective epoxide cleavage/anomerization reactions.

Article abstract of DOI:10.1021/ol005522y

[formula: see text] This paper describes a synthesis of enantiomerically pure 2,6-dideoxy-C-aryl glycosides, starting from non-carbohydrate precursors. The synthesis starts from homoallylic alcohols (obtained in enantiomerically pure form by enzymatic resolution), which are elaborated to dihydropyrans using ring closing metathesis as the key step. Epoxidation and epoxide cleavage complete the synthesis. The stereochemical outcome of the sequence depends on the conditions of the epoxide cleavage reaction.

Full text of DOI:10.1021/ol005522y

ORGANIC
LETTERS
2000
Vol. 2, No. 6
791-794
A de Novo Synthesis of
2,6-Dideoxy-C-aryl Glycosides Based on
Ring Closing Metathesis and
Diastereoselective Epoxide Cleavage/
Anomerization Reactions
Bernd Schmidt
UniVersita¨t Dortmund, Fachbereich Chemie, Organische Chemie I,
Otto-Hahn-Strasse 6, D-44227 Dortmund, Germany
bschmidt@citrin.chemie.uni-dortmund.de
Received January 7, 2000
ABSTRACT
This paper describes a synthesis of enantiomerically pure 2,6-dideoxy-C-aryl glycosides, starting from non-carbohydrate precursors. The
synthesis starts from homoallylic alcohols (obtained in enantiomerically pure form by enzymatic resolution), which are elaborated to dihydropyrans
using ring closing metathesis as the key step. Epoxidation and epoxide cleavage complete the synthesis. The stereochemical outcome of the
sequence depends on the conditions of the epoxide cleavage reaction.
Tetracyclins, anthracyclins, and angucyclins are classes of
important antibiotics, which are biosynthetically formed via
a polyketide pathway.1-3 Several antibiotics of these classes
have a C-glycoside substructure with a partially deoxygen-
ated carbohydrate directly linked to the aromatic system.
Therefore, these compounds are often referred to as C-aryl
glycosides,4 although this is not a homogeneous group of
natural products if the biosynthesis is taken into account.
Examples are the gilvocarcins,5-7 ravidomycin,8,9 the chry-
somycins,10 the vineomycins,11 aquayamycin,12 medermy-
cin,13 and the pluramycins.14,15 In the case of the pluramycins
NMR spectroscopic evidence for the participation of the
C-glycosidic moiety in binding to specific DNA sequences
was presented.16 Quite recently the mechanism of the
C-glycosyl transfer was investigated for an angucycline-type
antibiotic.17
Several synthetic studies toward C-aryl glycosides have
been conducted, and there are excellent reviews available
on the synthesis of these compounds18 and on the synthesis
(9) Findlay, J. A.; Liu, J.-S.; Radics, L. Can. J. Chem. 1983, 61, 323-
327.
(10) Weiss, U.; Yoshihira, K.; Highet, R. J.; White, R. J.; Wei, T. T. J.
Antibiot. 1982, 35, 1194-1201.
(1) Gra¨fe, U. Biochemie der Antibiotika; Spektrum: Heidelberg, 1992.
(2) Rohr, J.; Thiericke, R. Nat. Prod. Rep. 1992, 103-137.
(3) Krohn, K.; Rohr, J. Top. Curr. Chem. 1997, 188, 127-195.
(4) Hacksell, U.; Daves, G. D. Prog. Med. Chem. 1985, 22, 1-65.
(5) Takahashi, K.; Yoshida, M.; Tomita, F.; Shirahata, K. J. Antibiot.
1981, 34, 271-275.
(11) Imamura, N.; Kakinuma, K.; Ikekawa, N.; Tanaka, H.; Omura, S.
J. Antibiot. 1981, 34, 1517-1518.
(12) Sezaki, M.; Kondo, S.; Maeda, K.; Umezawa, H.; Ohno, M.
Tetrahedron 1970, 26, 5171-5190.
(13) Okabe, T.; Nomoto, K.; Funabashi, H.; Okuda, S.; Suzuki, H.;
Tanaka, N. J. Antibiot. 1985, 38, 1333-1336.
(6) Hirayama, N.; Takahashi, K.; Shirahata, K.; Ohashi, Y.; Sasada, Y.
Bull. Chem. Soc. Jpn. 1981, 54, 1338-1342.
(14) Nadig, H.; Se´quin, U. HelV. Chim. Acta 1987, 70, 1217-1228.
(15) Se´quin, U. Fortschr. Chem. Org. Naturst. 1986, 50, 58-122.
(16) Hansen, M. R.; Hurley, L. H. Acc. Chem. Res. 1996, 29, 249-258.
(17) Ku¨nzel, E.; Faust, B.; Oelkers, C.; Weissbach, U.; Bearden, D. W.;
Weitnauer, G.; Westrich, L.; Bechthold, A.; Rohr, J. J. Am. Chem. Soc.
1999, 121, 11058-11062.
(7) Horii, S.; Fukase, H.; Mizuta, E.; Hatano, K.; Mizuno, K. Chem.
Pharm. Bull. 1980, 28, 3601-3611.
(8) Findlay, J. A.; Liu, J.-S.; Radics, L.; Rakhit, S. Can. J. Chem. 1981,
59, 3018-3020.
10.1021/ol005522y CCC: $19.00 © 2000 American Chemical Society
Published on Web 03/01/2000

of C-glycosides in general.19,20 Formation of the C-glycosidic
bond by glycosylation of aromatic systems is the most
common route to C-aryl glycosides. Recent examples for this
strategy have been published by the groups of Schmidt,21
Suzuki,22 Satoh,23 and Toshima.24 Examples for de novo
syntheses are the selenium-mediated cyclization of alkenols25
and the [4 + 2] cycloaddition of aromatic aldehydes and
dienes.26
Enzymatic resolution of racemic homoallylic alcohol 1 is
a convenient method to obtain both enantiomers.31 Best
results were obtained with an immobilized Lipase PS
(Amano, from Pseudomonas cepacia). Assignment of ab-
solute configuration was achieved by comparing the optical
rotation with the literature value.32 Determination of ee was
achieved by NMR shift measurements (500 MHz, C6D6)
using the Eu(hfc)3 reagent (Scheme 2).
The 2,6-dideoxy substitution pattern is very common for
C-aryl glycosides. If synthesis is accomplished by formation
of the C-glycosidic C-C bond, either one is limited to the
absolute and relative configurations and deoxygenation
patterns available from naturally occurring carbohydrates
such as olivose or laborious manipulations are necessary to
synthesize non-natural analogues from naturally occurring
carbohydrates.
Scheme 2. Enzymatic Resolution of Homoallylic Alcohol 1
In this communication we present a flexible de novo
approach to C-aryl glycosides with a 2,6-deoxygenation
pattern based on ring closing olefin metathesis27,28 as the
C-C bond forming key step (Scheme 1).29,30 Homoallylic
With both enantiomers in hand, the diastereomeric dihy-
dropyrans cis- and trans-5 were synthesized in enantiomeri-
cally pure form as described in Scheme 3 (synthesis shown
starting from (-)-(S)-1). Alkylation of (-)-1 with dl-ethyl-
2-bromopropionate yields an easily separable mixture of
diastereomeric esters (-)-2a and (-)-2b. NMR shift mea-
surements (500 MHz, C6D6, Eu(hfc)3) indicate that no
racemization occurs during this reaction, as the ee observed
for (-)-2a,b is identical with the one observed for the starting
material (-)-1.
Scheme 1. Retrosynthetic Approach to the 2,6-Dideoxy-C-aryl
Glycosides
Reduction of diastereomeric esters 2a,b to the aldehydes
3a,b and subsequent Wittig olefination to the metathesis
precursors 4a,b work without isomerization, as from both
reactions diastereomerically pure compounds were obtained.
Finally, ring closing metathesis33 of the allylic-homoallylic
ethers 4a and 4b yields dihydropyrans 5a and 5b, respec-
tively.34 Elucidation of relative configuration was achieved
by NOESY experiments.
The final steps in the synthesis of a C-aryl glycoside
involve epoxidation and epoxide cleavage. For conforma-
tionally rigid epoxides regioselectivity of nucleophilic attack
is ruled by the preferred formation of the trans-diaxial
cleavage products (“Fu¨rst-Plattner rule”).35 We have recently
studied the regio- and stereochemical outcome of dihydro-
alcohols are used as a starting material, because these are
accessible in enantiomerically pure form via several different
methods.
(18) Jaramillo, C.; Knapp, S. Synthesis 1994, 1-20.
(19) (a) Postema, M. H. D. Tetrahedron 1992, 48, 8545-8599 (b) Du,
Y.; Linhardt, R. J.; Vlahov, I. R. Tetrahedron 1998, 54, 9913-9959.
(20) (a) Postema, M. H. D. C-Glycoside Synthesis, 1st ed.; CRC Press:
Boca Raton, 1995. (b) Levy, D. E.; Tang, C. The Chemistry of C-Glycosides,
1st ed.; Elsevier Science: Oxford, 1995; Vol. 13.
(21) El Telbani, E.; El Desoky, S.; Hammad, M. A.; Abdel Rahman, A.
R. H.; Schmidt, R. R. Eur. J. Org. Chem. 1998, 2317-2322.
(22) Matsumoto, T.; Yamaguchi, H.; Suzuki, K. Tetrahedron 1997, 53,
16533-16544.
(31) Master, H. E.; Newadkar, R. V.; Rane, R. A.; Kumar, A. Tetrahedron
Lett. 1996, 37, 9253-9254.
(32) Yamada, K.; Tozawa, T.; Nishida, M.; Mukaiyama, T. Bull. Chem.
Soc. Jpn. 1997, 70, 2301-2308.
(23) Kuribayashi, T.; Gohya, S.; Mizuno, Y.; Shimojima, M.; Ito, K.;
Satoh, S. Synlett 1999, 737-740.
(33) Grubbs' catalyst was used: Schwab, P.; Grubbs, R. H.; Ziller, J.
W. J. Am. Chem. Soc. 1996, 118, 100-110.
(24) Toshima, K.; Matsuao, G.; Ishizuka, T.; Ushiki, Y.; Nakata, M.;
Matsumura, S. J. Org. Chem. 1998, 63, 2307-2313.
(34) For the use of 2-bromoacids in the synthesis of oxacycles, see: (a)
Schmidt, B.; Sattelkau, T. Tetrahedron 1997, 53, 12991-13000. (b) Clark,
J. S.; Kettle, J. G. Tetrahedron Lett. 1997, 38, 127-130. (c) Edwards, S.
D.; Lewis, T.; Taylor, R. J. K. Tetrahedron Lett. 1999, 40, 4267-4270.
For the use of Claisen rearrangement/RCM strategies, see: (d) Burke, S.
D.; Ng, R. A.; Morrison, J. A.; Alberti, M. J. J. Org. Chem. 1998, 63,
3160-3161. (e) Miller, J. F.; Termin, A.; Koch, K.; Piscopio, A. D. J.
Org. Chem. 1998, 63, 3158-3159. For the use of asymmetric aldol addition/
RCM strategies, see: (f) Crimmins, M. T.; Choy, A. L. J. Org. Chem. 1997,
62, 7548-7549. (g) Crimmins, M. T.; Choy, A. L. J. Am. Chem. Soc. 1999,
121, 5653-5660.
(25) Hart, D. J.; Merriman, G. H.; Young, D. G. J. Tetrahedron 1996,
52, 14437-14458.
(26) Danishefsky, S. J.; Uang, B. J.; Quallich, G. J. Am. Chem. Soc.
1984, 106, 2453-2455.
(27) Armstrong, S. K. J. Chem. Soc., Perkin Trans. 1 1998, 371-388.
(28) Grubbs, R. H.; Chang, S. Tetrahedron 1998, 54, 4413-4450.
(29) For an approach based on chromium carbene bennzannulation,
see: Pulley, S. R.; Carey, J. P. J. Org. Chem. 1998, 63, 5275-5279.
(30) For an approach based on enol ether metathesis, see: Calimente,
D.; Postema, M. H. D. J. Org. Chem. 1999, 64, 1770-1771.
(35) Parker, R. E.; Isaacs, N. S. Chem. ReV. 1959, 59, 737-799.
792
Org. Lett., Vol. 2, No. 6, 2000

Scheme 3. Synthesis of Dihydropyrans cis-5a and trans-5a
((-)-Enantiomer Shown)
Scheme 4. Synthesis of a Non-Natural C-Aryl Glycoside
((-)-Enantiomer Shown)
Scheme 5. Synthesis of a C-Aryl Glycoside with Natural
Absolute and Relative Configuration ((+)-Enantiomer Shown)
pyran oxide cleavage reactions36 and found that an aromatic
substituent will provide sufficient rigidity to ensure clean
trans-diaxial cleavage, regardless of the relative configuration
of the starting dihydropyran oxide. Thus, if the dihydropyran
oxide is cleaved with an O-nucleophile, there is no need to
control the diastereoselectivity of the epoxidation step. Upon
treatment of 5a with MCPBA a 1:1 mixture of dihydropyran
oxides trans- and cis-6a results, which are easily separated
by chromatography. Treatment of both diastereomers of 6a
(separately or as a mixture) with water in the presence of
sulfuric acid or CAN gives one single diastereomer of 7, a
C-aryl glycoside with the non-natural trans-diaxial arrange-
ment of the hydroxy groups (Scheme 4).
C-Aryl glycosides with equatorially configured substituents
become accessible via this synthesis by combination of a
Lewis acid mediated epoxide opening reaction with a Lewis
acid mediated anomerization (Scheme 5). Epoxidation of 5b
leads to a separable mixture of diastereomers of dihydropyran
(36) Schmidt, B. J. Chem. Soc., Perkin Trans. 1 1999, 2627-2637.
Org. Lett., Vol. 2, No. 6, 2000
793

oxides trans-6b and cis-6b. Attack of acetic acid in the
presence of BF3OEt2 leads, in the first instance, to regio-
isomeric C-glycosides 8 and 8′, which may well exist as an
equilibrium of conformers, with the aryl substituent in either
the equatorial or the axial position. Unfavorable 1,3-diaxial
interactions provide a strong driving force for an anomer-
ization to the thermodynamic products. This anomerization
proceeds via a mechanism first discussed by Suzuki et al. in
the course of their studies toward hafnium-mediated C-
glycosylation.37 The Lewis acid weakens the C1-O bond
by attack at the tetrahydropyran oxygen, leading to an open-
chain intermediate, which may undergo isomerization and
recyclization to the all-equatorial regioisomers 9 and 9′
(Scheme 6).
findings it cannot be judged if such an effect contributes to
the driving force for the rearrangement or if this rearrange-
ment is solely caused by steric effects (i.e., minimization of
unfavorable 1,3-trans-diaxial interactions).38 Deprotection of
9 and 9′ (separately or as a mixture of regioisomers) gives
the same C-aryl glycoside 10 with the all-equatorial arrange-
ment of substituents. Thus, from (S)-(-)-1 (1R,3R,4S,5R)-
(+)-1039 results, which has the absolute configuration of the
naturally occurring C-aryl glycosides, such as the vineomy-
cins or aquayamcycin.
In summary, this contribution presents a de novo approach
to C-aryl glycosides, exemplified for the 2,6-dideoxy sub-
stitution pattern. Naturally occurring as well as non-natural
configurations become accessible via the same methodology
from starting materials that are conveniently prepared in
enantiomerically pure form. Further synthetic studies toward
the synthesis of other C-aryl glycosides using this method
are currently underway.
Scheme 6. Mechanism of the Anomerization Step
Acknowledgment. I thank the Fonds der Chemischen
Industrie, the Deutsche Forschungsgemeinschaft, and Prof.
Dr. P. Eilbracht for generous support.
OL005522Y
(37) (a) Hosoya, T.; Takashiro, E.; Matsumoto, T.; Suzuki, K. J. Am.
Chem. Soc. 1994, 116, 1004-1015. (b) Hosoya, T.; Ohashi, Y.; Matsumoto,
T.; Suzuki, K. Tetrahedron Lett. 1996, 37, 663-666.
(38) (a) Kirby, A. J. The Anomeric Effect and Related Stereoelectronic
Effects at Oxygen; Springer: New York, 1983. (b) Perrin, C. L.; Armstrong,
K. B. J. Am. Chem. Soc. 1993, 115, 6825-6834. I thank one of the reviewers
for this interesting suggestion.
(39) Selected physical data for (-)-7: [R]D ) -11 (c 1.40, CHCl3); 1H
NMR (400 MHz, CDCl3) δ 7.26 (d, J ) 8.8 Hz, 2H), 6.84 (d, J ) 8.8 Hz,
2H), 4.71 (dd, J ) 12.0, 1.8 Hz, 1H), 4.12 (q, J ) 6.5 Hz, 1H), 4.03 (m,
1H), 3.75 (s, 3H), 3.28 (m, 1H), 2.01 (ddd, J ) 14.3, 12.0, 2.0 Hz, 1H),
1.71 (dm, J ) 14.3 Hz, 1H), 1.24 (d, J ) 6.5 Hz); 13C NMR (100 MHz,
CDCl3) δ 159.0, 134.1, 127.3, 113.7, 73.9, 70.9, 70.4, 68.0, 55.2, 34.8,
1
17.0. Selected physical data for (+)-10: [R]D ) +13 (c 1.40, CHCl3); H
NMR (400 MHz, CD3OD) δ 7.31 (d, J ) 8.8 Hz, 2H), 6.91 (d, J ) 8.8 Hz,
2H), 4.46 (dd, J ) 11.8, 2.0 Hz, 1H), 3.80 (s, 3H), 3.69 (ddd, J ) 11.3,
9.0, 5.0 Hz, 1H), 3.43 (dq, J ) 9.0, 6.3 Hz, 1H), 3.05 (dd, J ) 9.0, 9.0 Hz,
1H), 2.16 (ddd, J ) 12.8, 5.0, 2.0 Hz, 1H), 1.69 (ddd, J ) 12.8, 11.8, 11.3
Hz, 1H), 1.35 (d, J ) 6.3 Hz); 13C NMR (100 MHz, CD3OD) δ 160.6,
135.1, 128.4, 114.6, 78.8, 78.4, 77.5, 73.8, 55.7, 42.7, 18.5.
The fact that a positively charged aromatic substituent is
involved in the rearrangement may suggest that in addition
to the steric interactions mentioned above a reverse anomeric
effect is working here. However, from our experimental
794
Org. Lett., Vol. 2, No. 6, 2000