Template-directed intramolecular C-glycosidation. Synthesis of the central tetrahydrofuran fragment of the elfamycin antibiotic aurodox

Article abstract of DOI:10.1055/s-1998-3144

A 14-step synthesis of the central tetrahydrofuran portion 4 of the elfamycin antibiotic aurodox is described, starting from the D-lyxose derivative 5. The key steps are template-directed intramolecular C-glycosidation by cation-mediated cyclisation of thioglycoside 6, and chelation-controlled addition of ethynylmagnesium bromide to aldehyde 8.

Full text of DOI:10.1055/s-1998-3144

1264
LETTERS
SYNLETT
Template-Directed Intramolecular C-Glycosidation. Synthesis of the Central
Tetrahydrofuran Fragment of the Elfamycin Antibiotic Aurodox
Donald Craiga*, Andrew H. Paynea and Peter Warnerb
aCentre for Chemical Synthesis, Department of Chemistry, Imperial College of Science, Technology and Medicine, London SW7 2AY, U.K.
bZENECA Pharmaceuticals, Mereside, Alderley Park, Macclesfield, Cheshire SK10 4TG, U.K.
fax: +44 171-594 5804; e-mail: dcraig@ic.ac.uk
Received 5 August 1998
Abstract: A 14-step synthesis of the central tetrahydrofuran portion 4
of the elfamycin antibiotic aurodox is described, starting from the D-
lyxose derivative 5. The key steps are template-directed intramolecular
C-glycosidation by cation-mediated cyclisation of thioglycoside 6, and
chelation-controlled addition of ethynylmagnesium bromide to
aldehyde 8.
seemed an ideal target molecule to exemplify our intramolecular
delivery-based approach.4 Secondly, it contains a fully oxygenated five-
membered sugar-derived template; we considered that the crowded
environment created by the all-β disposition of the oxygenated
substituents, and the potentially destabilising effect of these substituents
on the anomeric cationic intermediate would provide a stern test for our
strategy. Finally, unlike the major products 2 of the previous cyclisation
reactions on six-membered templates, compound 4 bears a syn
relationship between the ex-anomeric hydrogen atom and the
substituent on the vicinal exocyclic stereocentre. Inspection of our
pictorial model for the cyclisation process led us to believe that the anti-
selectivity observed previously would be reversed on account of the
crowded nature of the substrate β-face, favouring 7 over 9 (Scheme 3),
and we were keen to test this hypothesis. This Letter reports the results
of these investigations.
As part of our programme to develop template-directed cyclisation
reactions for C-glycoside synthesis,1 we recently described2 the silver(I)
triflate-mediated conversion of thioglycosidic silyl enol ethers 1 into
bicyclic C-glycosides 2 (Scheme 1). These transformations proceeded in
good yields and with good diastereoselectivities; further synthetic
elaboration gave the products (or their derivatives) of overall
intermolecular delivery of nucleophilic carbon functionality to the
anomeric centre, syn- with respect to the neighbouring hydroxyl group.
O
O
H
Ph
O
R
O
Ph
H
AgOTf
O
?
O
O
O
O
OSiR3
H
O
PyS
OTBDMS
O
O
H
H
H
R
H
1
2
OSiR3
O
H
major product
Scheme 1
syn-
anti-
H
H
O
O
We became interested in the application of this methodology to target-
oriented synthesis, and chose fragment 4 corresponding to the central
tetrahydrofuran portion of the elfamycin antibiotic aurodox 33 as an
appropriate candidate. The retrosynthetic analysis is shown in Scheme
2; our plan was to introduce the dienyl side-chain by chelation-
controlled addition of an appropriate organometallic nucleophile to the
aldehyde 8, which would be made from the product 7 of cyclisation of
substrate 6, in turn derived from D-lyxose derivative 5.
O
O
O
O
7
9
O
O
O
O
Ph
Ph
Scheme 3
Target substrate 6 (Scheme 2) was readily assembled from protected D-
lyxose 55 according to the route used in our methodological studies.6
Thus, thioglycosidation7 of 5 and desilylation gave thioglycosidic
alcohol 10, whose sodium salt was alkylated with tosylate 11.8 The
resulting ether was subjected to ozonolysis, followed by silyl enol
Compound 4 was a compelling goal for several reasons. Firstly, it
possesses a syn-relationship between the anomeric C–C bond and the
neighbouring oxygen atom on the five-membered ring, and as such
OH
syn-
O
O
O
OH
O
H
H
O
O
OH
OH
MeN
N
H
O
OMe
syn-
OMe
OSiEt3
OH
HO
OH
O
Ph
3: Aurodox
4
SPy
O
H
H
O
O
O
O
OH
OTBDMS
O
O
O
O
O
Ph
O
O
O
O
O
O
OSiEt3
OSiEt3
Ph
Ph
Ph
5
6
7
8
Scheme 2

November 1998
SYNLETT
1265
etherification to give the Z- enol ether 6 in good overall yield as a single
regioisomer. Addition of a solution of 6 to silver(I) triflate in CH2Cl2
resulted in clean formation of a single product, which was identified as 7
on the basis of n.O.e.s between H-1 and H-6 (11%), and H-5 and the
benzylidene ortho-proton (2%).9 Next, compound 7 was subjected to
regioselective Baeyer–Villiger reaction in the presence of buffered
peracetic acid containing TFA and MgSO4 as a drying agent; the
expected structure of the resulting crystalline lactone–acetal 12 was
confirmed by X-ray crystallography.10 Treatment of 12 with
HN(Me)OMe·HCl–Me3Al11 resulted in smooth ring-opening to give the
crystalline N-methoxyamide 13, which was silylated, and reduced using
LiAlH4–THF12 to give the aldehyde 8 (Scheme 4).
by flash column chromatography.16 Finally, coupling of 16 with E-3-
iodo-2-propen-1-ol17 mediated by copper(I) thiophene-2-carboxylate18
gave the target compound 4 in an unoptimised yield of 35%.19 The
completion of the synthesis of 4 is shown in Scheme 5.20
H
O
O
i
O
O
H
OH
85%
3:1 S-:R-
O
O
OSiEt3
OSiEt3
Ph
Ph
8
14: S-
15: R-
H
5
O
4'
SnBu3
2'
1'
3'
4
1
O
3
2
ii, iii
16
OMe
O
O
OH
SPy
O
OH
HO
5'
50%
i, ii
Ph
O
O
OTs
iv
35%
73%
O
O
OSiEt3
OH
11
H
O
H
Ph
Ph
5
10
O
SPy
H
O
Ph
O
O
O
7
OMe
OSiEt3
OH
OSiEt3
iii-v
vi
77%
Ph
O
O
OTBDMS
O
O
O
4
17
Ph
54%
O
O
O
O
Scheme 5: (i) HCCMgBr, THF, 0°C; (ii) NaH, MeI, DMF, 0°C→rt;
(iii) n-Bu3Sn(Bu)CuCNLi2 (4 equiv), MeI (20 equiv), THF–DMPU (10:1),
-78°C→rt; (iv) copper(I) thienyl-2-carboxylate, E-3-iodo-2-propen-1-ol,
N-methylpyrrolidone, rt.
Ph
6
H
H
O
O
N(Me)OMe
O
vii
viii
O
82%
O
O
O
O
74%
O
O
OH
O
Ph
Ph
In summary, we have demonstrated that template-directed
intramolecular C-glycosidation is an effective strategy for the assembly
of a stereochemically complex C-glycoside, with good to excellent
stereoselectivity. We are investigating also the application of this
approach to the synthesis of C-disaccharides, and the results of these
studies will be published in due course.
12
13
H
O
ix, x
O
OSiEt3
77%
O
Ph
8
Scheme 4: (i) PySSPy, n-Bu3P, CH2Cl2, 0°C; (ii) n-Bu4NF, CH2Cl2, 0°C;
(iii) 10 + 11 + n-Bu4NI in DMF added to NaH, 0°C; (iv) O3, CH2Cl2, -78°C,
then PPh3, -78°C→rt; (v) TBDMSOTf, Et3N, CH2Cl2, 0°C→rt; (vi) AgOTf
(2 equiv), 4Å mol sieves, CH2Cl2, -20°C, 5 h; (vii) CH3CO3H, NaOAc, TFA
(cat.), MgSO4, CH2Cl2; (viii) i-PrMgCl, MeONHMe·HCl, THF, -20°C;
(ix) Et3SiOTf, Py, CH2Cl2, 0°C; (x) LiAlH4, Et2O, 0°C.
Acknowledgements
We thank the EPSRC and ZENECA Pharmaceuticals21 (CASE
Studentship to A. H. P.) for financial support of this research, and
Professor James D. White (University of Oregon) for useful discussions
about the stannylcupration chemistry.
The final stages of our synthesis of 4 involved introduction of the E,E-
configured 1,3-diene-containing side-chain. Our plan was to effect syn-
carbometallation of an ethynyl group and then chain-extend this by
References and Notes
1.
(i) Craig, D.; Munasinghe, V. R. N. Tetrahedron Lett. 1992, 33,
663-666; (ii) Craig, D.; Pennington, M. W.; Warner, P.
Tetrahedron Lett. 1993, 34, 8539-8542; (iii) Craig, D.;
Pennington, M. W.; Warner, P. Tetrahedron Lett. 1995, 36, 5815-
5818.
coupling with
a suitable hydroxy-containing iodoalkene. It was
anticipated that the correct stereochemistry adjacent to the requisite
terminal alkyne would be secured by delivery of acetylide anion in a
chelation-controlled fashion to the re- face of the carbonyl function in
silyloxyaldehyde 8. In the event, addition of ethynylmagnesium
2.
3.
Craig, D.; Payne, A. H.; Warner, P., submitted.
bromide to
8 resulted in the high-yielding formation of two
Dolle, R. E.; Nicolaou, K. C. J. Am. Chem. Soc. 1985, 107, 1691-
1694; Dolle, R. E.; Nicolaou, K. C. J. Am. Chem. Soc. 1985, 107,
1695-1698.
diastereomeric secondary alcohols 14 and 15 in a ca. 3:1 ratio.
Assignment of S-configuration to the newly-formed stereocentre in the
major compound followed from the observation of its CF3 resonance
120 Hz upfield from that of the minor, R-isomer in the 19F nmr
spectrum (376.5 MHz) of the derived Mosher's esters.13 Also, the major
product 17 of addition of isopropenylmagnesium bromide to 8 was
shown by X-ray crystallographic analysis10 to have the S-configuration
at this centre. Separation of 14 and 15 could be achieved by reversed-
phase HPLC, but it was found to be more convenient to process these as
4.
Martin and co-workers have reported extensively on
intramolecular C-arylation of glycosides using cation-mediated
transformations. See: Martin, O. R.; Hendricks, C. A. V.;
Deshpande, P. P.; Cutler, A. B.; Kane, S. A.; Rao, S. P.
Carbohydr. Res. 1990, 196, 1-58 and references therein.
5.
6.
D-Lyxonolactone was protected as the benzylidene acetal,
triethylsilylated and reduced with DIBAL-H to give 5.
a mixture. Thus, methylation of 14/15 under standard conditions,
followed by stannylcupration14 using Bu3Sn(Bu)CuCNLi2
and
All yields cited herein are of isolated, purified materials which
gave satisfactory 1H, 13C nmr and IR spectra, and which showed
low-resolution MS and either elemental combustion analysis or
15
quenching with iodomethane gave 16 in 50% yield, together with ca.
20% of the minor diastereomer; the isomers were now readily separated

1266
7.
LETTERS
SYNLETT
high-resolution MS characteristics in accord with the assigned
structures.
H-1), 3.22 (3H, s, OCH3), 1.90-1.82 (1H, m, H-1’), 1.63 (3H, s, C-
3’ CH3), 1.50 (6H, m, 3 x Bu3Sn CH2), 1.30 (6H, m, 3 x Bu3Sn
CH2), 1.00-0.84 (27H, C-1’CH3 + SiEt3 CH3 + 3 x Bu3Sn CH2 +
Bu3Sn CH3), 0.59 (6H, q, J 8.0 Hz, SiEt3 CH2); δC (CDCl3, 75
MHz) 151.8, 138.5, 129.0, 128.6, 128.0, 126.5, 99.6, 91.7, 79.1,
76.6, 75.1, 70.8, 67.5, 56.1, 35.6, 29.4, 27.4, 17.7, 13.8, 11.5,
10.2, 6.8, 4.8.
Stewart, A. O.; Williams, R. M. J. Am. Chem. Soc. 1985, 107,
4289-4296. S-Glycosidation of 5 resulted in the formation of a ca.
7:2 β:α anomeric mixture, together with a small amount of the N-
glycoside.1(i) Separation of the isomers was carried out after
desilylation; only the β-anomer was taken through the rest of the
sequence.
17. E-3-Iodo-2-propen-1-ol was made by DIBAL-H reduction of
methyl E-3-iodo-2-propenoate, which was prepared according to a
literature procedure: Biougne, J.; Théron, F.; Normant, M. H.
Comptes Rendus Acad. Sci. C 1971, 272, 858-861.
8.
9.
The alcohol precursor of 11 was made by CuI-mediated addition
of ethylmagnesium bromide to propargyl alcohol: Duboudin, J.
G.; Jousseaume, B. J. Organometal. Chem. 1979, 168, 1-11.
We thank Mr Dick Sheppard and Mr Paul Hammerton of this
department for these determinations.
18. Allred, G. D.; Liebeskind, L. S. J. Am. Chem. Soc. 1996, 118,
2748-2749.
10. We thank Professor David J. Williams and Dr Andrew J. P. White
of this department for these determinations.
19. Yield based on recovered stannane (30% recovery).
25
20. Compound 4: [α]D -36.8 (c 0.75, CHCl3); δH (CDCl3, 400
11. Clardy, J.; Evans, D. A.; Jones, T. K.; Kaldor, S. W.; Stout, T. J. J.
Am. Chem. Soc. 1990, 112, 7001-7031.
MHz) 7.50-7.45 (2H, m, ortho-Ph), 7.35-7.29 (3H, m, meta- and
para-Ph), 6.52 (1H, dd, J 15.0, 10.5 Hz, H-5') 6.02 (1H, d, J 10.5
Hz, H-4'), 5.82 (1H, dt, J 15.0, 6.0 Hz, H-6'), 5.48 (1H, s, PhCH),
4.61 (1H, dd, J 9.0, 5.0 Hz, H-2), 4.55 (1H, dd, J 9.0, 1.0 Hz, H-1
or H-3), 4.41 (1H, d, J 13.0 Hz, H-5), 4.21 (2H, d, J 6.0 Hz, H-7'),
4.18-4.10 (2H, m, H-3 or H-1 + H-5), 3.57 (1H, br s, H-4), 3.47
(1H, d, J 10.5 Hz, H-2'), 3.18 (3H, s, OCH3), 1.98-1.89 (1H, m, H-
1'), 1.65 (3H, s, C-3' CH3), 1.00-0.81 (12H, m, C-1' CH3 + SiEt3
CH3), 0.57 (6H, q, J 8.0 Hz, SiEt3 CH2); δC (CDCl3, 100 MHz)
138.4, 137.2, 131.5, 128.7, 128.6, 128.0, 127.5, 127.2, 126.4,
99.5, 89.2, 78.9, 76.4, 75.0, 70.7, 67.4, 63.7, 56.1, 35.8, 11.5,
12. Nahm, S.; Weinreb, S. M. Tetrahedron Lett. 1981, 22, 3815-3818.
13. Sullivan, G. R.; Dale, J. A.; Mosher, H. S. J. Org. Chem. 1973, 38,
2143-2147.
14. White, J. D.; Holoboski, M. A.; Green, N. J. Tetrahedron Lett.
1997, 38, 7333-7336.
15. Lipshutz, B. H.; Ellsworth, E. L.; Dimock, S. H.; Reuter, D. C.
Tetrahedron Lett. 1989, 30, 2065-2068.
16. The yield of 16 cited is that obtained from the mixture of 14 and
15. Compound 16: [α]D25 -16.3 (c 0.55, CHCl3); δH (CDCl3, 300
MHz) 7.53-7.48 (2H, m, ortho-Ph), 7.37-7.28 (3H, m, meta- and
para-Ph), 5.75 (1H, s, H-4’), 5.51 (1H, s, PhCH), 4.62-4.51 (2H,
m, H-2 + H-1 or H-3), 4.40 (1H, d, J 13.0 Hz, H-5), 4.18-4.05 (2H,
m, H-5 + H-2’), 3.58 (1H, br s, H-4), 3.49 (1H, t, J 10.5 Hz, H-3 or
10.5, 6.7, 4.7; m/z (CI) 473 [M - OCH3]+, 455 [M - OCH3
H2O]+, 341, 323, 282, 250, 141, 132, 121 (Found: [M - OCH3]+,
473.2724; C28H44O6Si requires [M - OCH3]+, 473.2723).
-
21. ZENECA in the U.K. is part of ZENECA Limited.