Stereospecific entry to [4.5]spiroketal glycosides using alkylidenecarbene C-H insertion.

Article abstract of DOI:10.1021/ol016975l

[reaction: see text] A novel method for the stereospecific preparation of [4.5]spiroketal glycosides utilizing the 1,5 C-H bond insertion of alkylidenecarbenes is described. Treatment of 2-oxopropyl beta-pyranosides A with lithium (trimethylsilyl)diazomet

Full text of DOI:10.1021/ol016975l

ORGANIC
LETTERS
2002
Vol. 4, No. 4
489-492
Stereospecific Entry to [4.5]Spiroketal
Glycosides Using Alkylidenecarbene
C−H Insertion
Duncan J. Wardrop,* Wenming Zhang, and Joseph Fritz
Department of Chemistry, UniVersity of Illinois at Chicago, 845 West Taylor Street,
Chicago, Illinois 60607-7061
wardropd@uic.edu
Received October 30, 2001
ABSTRACT
A novel method for the stereospecific preparation of [4.5]spiroketal glycosides utilizing the 1,5 C−H bond insertion of alkylidenecarbenes is
described. Treatment of 2-oxopropyl â-pyranosides A with lithium (trimethylsilyl)diazomethane in THF at −78 °C afforded 1,6-dioxaspiro[4,5]-
decenes B in good yield. Submission of the corresponding r-glycosides C to the same reagent gave the isomeric insertion products D in
moderate to high yield.
The intramolecular C-H bond insertion reaction of alkyli-
denecarbenes is a powerful method for the preparation of
five-membered carbocyclic1 and heterocyclic rings.2 Gilbert
and co-workers have demonstrated that the ease with which
this transformation occurs is dependent on, among other
things, the dissociation energy of the C-H bond undergoing
insertion.3 Accordingly, insertion into C-H bonds flanked
by one or more heteroatoms, such as those in acetals, is
favored since these bonds are significantly weakened by the
adjoining atoms.4 Bearing this effect in mind, we reasoned
that alkylidenecarbene 2, generated from 2-oxopropyl pyra-
noside 1, would readily undergo insertion at the adjoining
activated anomeric C-H bond and thereby provide a
convenient and stereospecific entry to [4.5]spiroketal gly-
cosides 3.5 The 1,6-dioxaspiro[4,5]decane ring system thus
formed constitutes the core structure of a wide range of
biologically active natural products6 including the phyllantho-
statins,7a breynins,7a and attenols7b in addition to the spiro-
phostins, a group of adenophostin A analogues recently
prepared by van Boom.7c Although the intramolecular
insertion of alkylidenecarbenes into acetal C-H bonds has
been reported by Wills8a and others,8b-e to the best of our
(1) For reviews covering the 1,5-C-H insertion of alkylidenecarbenes,
see: (a) Stang, P. J. Chem. ReV. 1978, 78, 383-405. (b) Stang, P. J. Angew.
Chem., Int. Ed. Engl. 1992, 31, 274-285. (c) Taber, D. F. In Methods of
Organic Chemistry, 4th ed.; Helmchen, G., Ed.; Georg Thieme Verlag:
Stuttgart, New York, 1995; Vol. E21, pp 1127-1148. (d) Kirmse, W.
Angew. Chem., Int. Ed. Engl. 1997, 36, 1164-1170.
(2) For selected examples of the formation of 2,5-dihydrofurans, see:
(a) Walsh, R. A.; Bottini, A. T. J. Org. Chem. 1970, 35, 1086-1092. (b)
Buxton, S. R.; Holm, K. H.; Skattebøl, L. Tetrahedron Lett. 1987, 27, 2167-
2168. (c) Baird, M. S.; Baxter, A. G. W.; Hoorfar, A.; Jefferies, I. J. Chem.
Soc., Perkin Trans. 1 1991, 2575-2581. (d) Taber, D. F.; Christos, T. E.
Tetrahedron Lett. 1997, 38, 4927-4930. (e) Ohira, S.; Kitamura, T.; Tsuda,
K.; Fujiwara, Y. Tetrahedron Lett. 1998, 39, 5375-5376. (f) Singh, G.;
Vankayalapati, H. Tetrahedron: Asymmetry 2000, 11, 125-138.
(3) Gilbert J. C.; Giamalva, D. H.; Weerasooriya, U. J. Org. Chem. 1983,
48, 5251-5256.
(4) Malatesta, V.; Ingold, K. U. J. Am. Chem. Soc. 1981, 103, 609-614
and references therein.
(5) Despite the presence of numerous oxygen-activated C-H bonds in
carbohydrates, reports of alkylidenecarbene insertion involving these
substrates have been limited: (a) Hauske, J. R.; Guadliana, M.; Desai, K.
J. Org. Chem. 1982, 47, 5019-5021. (b) Pe´rez-Pe´rez, M.-J.; Camarasa,
M.-J. Tetrahedron 1994, 50, 7269-7282. (c) Ohira, S.; Sawamoto, T.;
Yamoto, M. Tetrahedron Lett. 1995, 36, 1537-1538.
(6) Jacobs, M. F.; Kitching, W. Curr. Org. Chem. 1998, 2, 395-436.
(7) (a) Smith, A. B., III; Empfield, J. R. Chem. Pharm. Bull. 1999, 47,
1671-1678. (b) Takada, N.; Suenaga, K.; Yamada, K.; Zheng, S.-Z.; Chen,
H.-S.; Uemura, D. Chem. Lett. 1999, 1025-1026. (c) de Kort, M.;
Regenbogen, A. D.; Valentijn, A. R. P. M., Challis, R. A. J.; Iwata, Y.;
Miyamoto, S.; van der Marel, G. A.; van Boom, J. H. Chem. Eur J. 2000,
6, 2696-2704.
10.1021/ol016975l CCC: $22.00 © 2002 American Chemical Society
Published on Web 01/26/2002

knowledge there have been no reports of insertion into the
anomeric C-H bond of a carbohydrate.9 Herein we therefore
report the first examples of this transformation and demon-
strate its potential as a method for the preparation of [4.5]-
spiroketal glycosides.
Scheme 2. Preparation of 2-Oxopropyl Pyranosides 1a
Scheme 1. C-H Bond Insertion Strategy for the Preparation of
[4.5]Spiroketal Glycosides
An initial review of the literature revealed two practical
methods for accessing the 2-oxopropyl pyranosides 1 re-
quired for our study: (i) Wacker oxidation of allyl pyrano-
sides10 and (ii) oxymercuration of propargyl pyranosides, as
recently reported by Mereyala.11 Known â-glycosides 1a and
1b (Table 1) were therefore prepared from D-glucose
pentaacetate and D-galactose pentaacetate, respectively, fol-
lowing this later procedure. R-Mannopyranoside 1f (Scheme
2), while not reported by Mereyala, was also prepared using
this protocol. Thus, reaction of R-D-mannose pentaacetate
(7) with propargyl alcohol and BF3‚Et2O (1.5 equiv) in
refluxing CH2Cl2 furnished the corresponding propargyl
mannopyranoside as a single anomer in 77% yield. Zemple´n
de-O-acetylation, per-O-benzylation, and oxymercuration
then gave 1f in 76% yield. The stereochemistry at the
anomeric center was determined by a gated decoupled 13C
NMR experiment, which revealed a JC1H1 value of 175 Hz
consistent with the R-anomer.12
The corresponding â-mannoside 1c was prepared from
thioglycoside 413 using Crich’s method.14 Thus, activation
of 4 with 1-benzenesulfinyl-piperidine (BSP)/trifluoromethane-
sulfonic anhydride (Tf2O), in the presence of 2,4,6-tri-tert-
butylpyrimidine (TTBP) and addition of propargyl alcohol,
furnished the desired â-mannoside in high yield. Hydrolysis
of the 4,6-benzylidene acetal, di-O-benzylation, and oxymer-
curation now gave 1c. Glycosylation of 2,3,4,6-tetra-O-
benzyl R-D-glucopyranose (5) with methallyl alcohol using
a Reagents and conditions: (a) (i) BSP, TTBP, Tf2O, CH2Cl2, 3
Å ms, -60 °C, 5 min; (ii) HCtCCH2OH, -60 °C f rt, 30 min,
79%; (b) AcOH, H2O, 70 °C, 5 h, 70%; (c) NaH, BnBr, THF, 0
°C f rt, 8 h, 88%; (d) Hg(O2CCF3)2 (0.2 equiv), acetone, H2O, rt,
18 h, 77%; (e) TsCl, Bu3NEtBr, methallyl alcohol, CH2Cl2, NaOH,
H2O, rt, 34 h; (f) OsO4, NaIO4, py, THF, H2O, rt, 2 h, 64% from
5; (g) NaH, BnBr, Bu4NI, DMF, rt, 6 h, 92%; (h) (1) O2, PdCl2
(0.3 equiv), CuCl (3 equiv), DMF-H2O (6:1), 40 °C, 8 h, 94%,
(2) NaClO2, CH3CN, 2-methyl-2-butene, 60% from 6; (i)
HCtCCH2OH, BF3‚Et2O, CH2Cl2, reflux, 12 h, 77%; (j) (1)
MeONa (0.1 equiv), MeOH, rt, 1 h; (2) NaH, BnBr, Bu4NI, DMF,
rt, 15 h, 84%; (k) Hg(O2CCF3)2 (0.2 equiv), acetone, H2O, rt, 18
h, 92%.
Szeja’s method15 gave a 4:1 mixture of anomers, which
although spectroscopically distinguishable proved to be
inseparable by flash chromatography. This mixture was
therefore directly submitted to Lemieux-Johnson oxidation,
which when buffered with 1 equiv of pyridine gave methyl
ketones 1a and 1d. Separation of these components by flash
chromatography afforded 1d in 64% yield from 5. Substrate
1e was prepared from allyl R-D-galactopyranoside (6) via
per-O-benzylation and Wacker oxidation, which proceeded
to give a 3:1 mixture of 1e and the aldehyde (3-oxopropyl
glycoside) resulting from anti-Markovnikov hydration.16,17
As this aldehyde could not be separated from 1e chromato-
graphically, the mixture was directly submitted to NaClO2
oxidation and the resulting carboxylic acid was then removed
by flash chromatography to provide 1e in 60% yield from
6. The configuration of the anomeric stereocenters of 1d and
(8) (a) Walker, L. F.; Connolly, S.; Wills, M. Tetrahedron Lett. 1998,
39, 5273-5276. (b) Schildknegt, K.; Bohnstedt, A. C.; Feldman, K. S.;
Sambandam, A. J. Am. Chem. Soc. 1995, 117, 7544-7545. (c) Harada, T.;
Fujiwara, T.; Iwazaki, K.; Oku, A. Org. Lett. 2000, 2, 1855-1857. (d) Sakai,
A.; Aoyama, T.; Shioiri, T. Tetrahedron Lett. 2000, 41, 6859-6863. (e)
Taber, D. F.; Yu, H.; Incarvito, C. D.; Rheingold, A. L. J. Am. Chem. Soc.
1998, 120, 13285-13290.
(9) The intramolecular insertion of cyclopropylidenecarbenes into acetal
C-H bonds has been reported: (a) Slessor, K. N.; Oehlschlager, A. C.;
Johnston, B. D.; Pierce, H. D.; Grewal, S. K.; Wickremesinghe, L. K. G.
J. Org. Chem. 1980, 45, 2290-2297. (b) Brinker, U. H.; Haghani, A.;
Gomann, K. Angew. Chem., Int. Ed. Engl. 1985, 24, 230-231.
(10) Lu¨ning, J.; Mo¨ller, U.; Debski, N.; Welzel, P. Tetrahedron Lett.
1993, 34, 5871-5874.
(11) (a) Mereyala, H. B.; Gurrala, S. R. Chem. Lett. 1998, 863-864.
(b) Mereyala, H. B.; Gurrala, S. R. Carbohydr. Res. 1998, 307, 351-354.
(12) (a) Bock, K.; Pederson, C. J. Chem. Soc., Perkin Trans. 2 1974,
293-297. (b) Singh, G.; Vankayalapati, H. Tetrahedron: Asymmetry 2000,
11, 125-138.
(13) Crich, D.; Cai, W. J. Org. Chem. 1999, 64, 4926-4930.
(14) Crich, D.; Smith, M. J. Am. Chem. Soc. 2001, 123, 9015-9020.
(15) Szeja, W. Synthesis 1988, 223-224.
(16) For a discussion of the influence that heteroatoms have over the
regiochemistry of the Wacker oxidation, see: (a) Pellissier, H.; Michellys,
P.-Y.; Santelli, M. Tetrahedron Lett. 1994, 35, 6481-6484. (b) Lu¨ning, J.;
Mo¨ller, U.; Debski, N.; Welzel, P. Tetrahedron Lett. 1993, 34, 5871-5874.
(17) In contrast to our finding, the Wacker oxidation of this substrate
has previously been reported to lead to double bond isomerization and
formation of a η2-vinyl palladium complex of the resulting prop-1-enyl
glycoside: Mereyala, H. B.; Lingannagaru, S. R. Tetrahedron 1997, 53,
17501-17512.
(18) Ohira, S.; Okai, K.; Moritani, T. J. Chem. Soc., Chem. Commun.
1992, 721-722.
490
Org. Lett., Vol. 4, No. 4, 2002

Table 1. Alkylidenecarbene Insertion at the Anomeric C-H
Bond23
Figure 1. Selected NOESY correlations for [4.5]spiroketal pyra-
nosides 3a and 3d.
confirmed our expectation that the singlet carbene generated
under these conditions would undergo insertion with retention
of configuration.21 â-Galactopyranoside 1b and mannopy-
ranoside 1c (entries 2 and 3) also underwent insertion with
retention of configuration to provide 3b and 3c, respectively.
Having established the viability of insertion into axial
anomeric C-H bonds, we now examined the corresponding
R-pyranosides. Thus, treatment of 1d and 1e (entries 4 and
5) with LTDM, at -78 °C, for 1.5 h gave spiroketals 3d
and 3e in reasonable yield. The configuration of the acetal
stereocenters, as shown for 3d in Figure 1, was determined
by a NOESY experiment, which revealed a correlation
between H-4 and H-10. The formation of 3d and 3e was
also accompanied by small amounts of a polar product, as
indicated by thin-layer chromatography. These were isolated
and, to our surprise, found to be D-glucopyranose (10)22a
(14%) and D-galactopyranose 1122b (20%), respectively. One
possible rationale for the formation of these unexpected
byproducts is outlined in Scheme 3. Reaction of 8 with
lithium trimethylsilanoate, generated during the formation
of 8, and protonation of the resulting R-silanoxy vinyl anion
would provide 9.23 Hydrolysis of this enol ether would then
form the corresponding â-alkoxy aldehyde, which upon
elimination of methacrolein24 would lead to pyranoses 10
and 11.
Because, compared to equatorial anomeric C-H bonds,
axial C-H bonds have a decreased dissociation energy4 and
(19) Typical Procedure for the Preparation of [4.5]Spiroketal Gly-
cosides (3a). To a solution of (trimethylsilyl)diazomethane (118 µL, 2.0
M in hexanes, 236 µmol) in THF (3 mL), at -78 °C, was added
n-butyllithium (113 µL, 2.0 M in cyclohexane, 226 µmol). After 5 min of
stirring, a solution of 1a (70.7 mg, 119 µmol) in THF (1 mL) was added,
and the resulting mixture was stirred for 30 min before saturated aqueous
NaHCO3 (1 mL) was added to quench the reaction. After warming to room
temperature, this mixture was extracted with CH2Cl2 (3 × 4 mL), and the
combined organic extracts were dried (Na2SO4), filtered, and concentrated
under reduced pressure. The resulting residue was purified by flash
chromatography over silica gel (EtOAc/hexanes/Et3N, 38:212:1) to provide
3a (60.1 mg, 85% yield). The insertion reaction of the R-pyranosides 1d-f
was carried out as described above, but the reaction time was extended to
1.5 h. In the case of substrates 1d-f, shorter reaction times resulted in the
formation of complex mixtures of products and significantly lower yields
of 3d-f.
a Isolated yields after purification over Et3N-deactivated silica gel.
b 2,3,4,6-Tetra-O-benzyl D-glucopyranose (10) (14%) was also isolated.
c 2,3,4,6-Tetra-O-benzyl D-galactopyranose (11) (20%) was also isolated.
1e was confirmed as being R by measurement of the H1-
H2 (1d, JH1H2 ) 3.6 Hz; 1e, JH1H2 ) 3.7 Hz) and C1-H1
(1d, JC1H1 ) 169 Hz; 1e, JC1H1 ) 170 Hz) coupling
constants.14
With the requisite collection of 2-oxopropyl glycosides 1
assembled, we now proceeded with our investigation of the
insertion reaction. The results of this study are shown in
Table 1. Gratifyingly, reaction of 1a with lithium (trimeth-
ylsilyl)diazomethane (LTDM)18 for 30 min cleanly furnished
3a in 85% yield after purification by flash chromatography
(entry 1).19,20 As indicated in Figure 1, a NOESY experiment
revealed correlations between H-4, H-7, and H-9 while no
cross-peak was observed between H-4 and H-10. This
(20) In agreement with observations made by Skattebøl2b and Wills,8a
the 2-alkoxydihydrofuran moiety of 3 proved to be acid-sensitive. As a
result, the purification of all insertion products was carried out over Et3N-
deactivated silica gel. Further details of this reactivity will be reported
elsewhere.
(21) (a) Gilbert, J. C.; Giamalva, D. H.; Baze, M. E. J. Org. Chem. 1985,
50, 2557-2563. (b) Ohira, S.; Ishi, S.; Shinohara, K.; Nozaki, H.
Tetrahedron Lett. 1990, 31, 1039-1040.
(22) (a) Liaigre, J.; Dubreuil, D.; Prade`re; Bouhours, J.-H. Carbohydr.
Res. 2000, 325, 265-277. (b) Desai, T.; Gigg, J.; Gigg, R. Aust. J. Chem.
1996, 49, 305-309.
Org. Lett., Vol. 4, No. 4, 2002
491

contrast to R-mannoside 1c, which undergoes insertion less
efficiently than either 1a or 1b.26 Whether the reversal in
yields for the mannose series suggests a lack of correlation
between anomeric stereochemistry and insertion efficiency
or is a consequence of the axial C-2 benzyloxy substituent
present in substrates 1c and 1f remains to be established.
In summary, we report a new strategy for the preparation
of [4.5]spiroketal glycosides 3 involving the C-H insertion
of alkylidenecarbenes at the anomeric position of gluco-,
galacto-, and mannopyranosides. In contrast to existing
methods for the synthesis of spiroketals,27,28 the approach
reported here does not rely upon thermodynamic or kinetic
control to set the configuration of the acetal stereocenter but
rather capitalizes on the fact that alkylidenecarbene insertion
proceeds with retention of configuration. As a result, both
isomers of 3 are equally accessible by starting from the
appropriate anomer of 1. Work to extend this methodology
to other carbohydrate substrates and the preparation of
spiroketal natural products is underway; our progress will
be reported in due course.
Scheme 3. Rationale for the Formation of Pyranoses 10 and 11
display increased reactivity in a number of reactions,
including radical H-abstraction4 and insertion of ozone,25 it
is tempting in our case to correlate the proclivity of C-H
insertion with the configuration of the anomeric center.
Indeed, 1a and 1b did give significantly higher yields of
insertion than the corresponding R-anomers. However,
R-mannoside 1f (entry 6) underwent insertion to give 3f in
excellent yield with no mannopyranose byproduct being
observed. Furthermore, the increased yield in this case is in
Acknowledgment. We thank the University of Illinois
at Chicago and the National Institutes of Health (GM59157-
01) for financial support. W.Z. thanks the University of
Illinois for a University Graduate Fellowship. We also thank
Professor David Crich and Dr. Mark Smith for generously
providing quantities of thioglycoside 4 and acknowledge K.
Gao for a preliminary study.
(23) Generation of alkylidenecarbenes in the presence of alcohols and/
or alkoxides has been reported to produce enol ethers: (a) Newman, M.
S.; Okorodudu, A. O. M. J. Org. Chem. 1969, 34, 1220-1224. (b) Gilbert,
J. C.; Weerasooriya, U. J. Org. Chem. 1983, 48, 448-453. (c) Oku, A.;
Harada, T.; Hattori, K.; Nozuki, Y.; Yamaura, Y. J. Org. Chem. 1988, 53,
3089-3098.
(24) (a) Bayle, C.; Defaye, J.; Horton, D.; Lehmann, J. Carbohydr. Res.
1992, 232, 375-380. (b) Shipova, E. V.; Bovin, N. V. MendeleeV Commun.
2000, 2, 63-64. (c) Lu¨ning, J.; Mo¨ller, U.; Debski, N.; Welzel, P.
Tetrahedron Lett. 1993, 34, 5871-5874.
(25) Delongchamps, P.; Atlani, P.; Fre´hel, D.; Malaval, A.; Moreau, C.
Can. J. Chem. 1974, 52, 3651-3665.
(26) It is also of interest to note that the yield of insertion is lower for
those substrates in which the intermediate alkylidenecarbene and the C-2
benzyloxy substituent are syn to one another and can potentially undergo
reversible formation of a seven-membered ylide: (a) Sueda, T.; Nagaoka,
T.; Goto, S.; Ochiai, M. J. Am. Chem. Soc. 1996, 118, 10141-10149. (b)
Kim, S.; Cho, C. M. Tetrahedron Lett. 1995, 36, 4845-4848.
Supporting Information Available: Full experimental
procedures and spectral data for compounds 1a-f and 3a-f
and intermediates. This material is available free of charge
via the Internet at http://pubs.acs.org.
OL016975L
(27) Perron, F.; Albizati, K. F. Chem. ReV. 1989, 89, 1617-1673.
(28) For selected recent approaches to [n.5]spiroketal glycosides, see:
(a) Martin, A.; Salazar, J. A.; Sua´rez, E. J. Org. Chem. 1996, 61, 3999-
4006. (b) van Hooft, P. A. V.; Leeuwenburgh, M. A.; Overkleeft, H. S.;
van der Marel, G. A.; van Boeckel, C. A. A.; van Boom, J. H. Tetrahedron
Lett. 1998, 39, 6061-6064. (c) Alcaraz, M.-L.; Griffin, F. K.; Paterson, D.
E.; Taylor, R. J. K. Tetrahedron Lett. 1998, 39, 8183-8186.
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Org. Lett., Vol. 4, No. 4, 2002