Ring-contraction vs ring-expansion reactions of spiro- cyclopropanecarboxylated sugars

Article abstract of DOI:10.1021/ol402021e

Electrophilic ring opening of spiro-cyclopropanecarboxylated sugars followed by reaction with DBU revealed interesting ring-contraction and ring-expansion reactions depending on the substrate and the kind of hydroxyl protective group present adjacent to the spiro center. A stereoselective method for accessing a new class of carbon chain extended keto-furanoses and C-glycosylated bicyclic compounds is reported.

Full text of DOI:10.1021/ol402021e

ORGANIC
LETTERS
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Vol. XX, No. XX
000–000
Ring-Contraction vs Ring-Expansion
Reactions of Spiro-
cyclopropanecarboxylated Sugars
Bandi Ramakrishna and Perali Ramu Sridhar*
School of Chemistry, University of Hyderabad, Hyderabad-500 046, India
p_ramu_sridhar@uohyd.ac.in
Received July 18, 2013
ABSTRACT
Electrophilic ring opening of spiro-cyclopropanecarboxylated sugars followed by reaction with DBU revealed interesting ring-contraction
and ring-expansion reactions depending on the substrate and the kind of hydroxyl protective group present adjacent to the spiro center.
A stereoselective method for accessing a new class of carbon chain extended keto-furanoses and C-glycosylated bicyclic compounds is reported.
Carbohydrates are ubiquitous chiral resources whose
chemistry has underpinned the discovery of many awe-
inspiring and fascinating new transformations inchemistry
and biology.1 Apart from designed methodologies, quite a
few surprising reactions/rearrangements have emerged in
“sugar chemistry”, and some are even unusual.2 In this
context, ring-contraction3 and ring-expansion4 reactions
involving carbohydrate derivatives are very significant.
Of several published protocols, the ring-contraction
of R-trifluoromethanesulfonylated aldonolactones5 and
Kirschning’s hypervalent iodine-mediated oxidative ring-
contraction of glycals6 to formyl glycosyl analogues are
noteworthy. Gin et al.7 cleverly implemented the IIII-mediated
ring-contraction of a glycal as a key step in the first total
synthesis of (þ)-pyrenolide D. However, the application of
such ring-contraction reactions, and the conversion of pyra-
noses to C-branched furanoses, in the stereoselective total
synthesis of complex natural products have been scarce.8
Likewise, there are very few reports of the conversion
of carbohydrates into the corresponding ring-expanded
versions. The classical Achmatowicz9 reaction involving
(1) (a) Boons, G.-J., Hale, K. J. Organic Synthesis with Carbohy-
drates; Sheffield Academic Press Ltd.: Sheffield, 2000; Part B, pp 175ꢀ333.
(b) Bols, M.Carbohydrate Building Blocks; John Wiley & Sons, Inc.:
New York, 1996.
(2) Redlich, H. Angew. Chem., Int. Ed. Engl. 1994, 33, 1345–1347.
(3) Ring contraction of cyclic ethers to carbocycles: (a) Verner, E. J.;
Cohen, T. J. Am. Chem. Soc. 1992, 114, 375–377. (b) Paquette, L. A.
J. Organomet. Chem. 2006, 691, 2083–2088. (c) Alonso, R. A.; Vite,
G. D.; McDevitt, R. E.; Fraser-Reid, B. J. Org. Chem. 1992, 57, 573–584.
(d) Ito, H.; Motoki, Y.; Taguchi, T.; Hanzawa, Y. J. Am. Chem. Soc.
1993, 115, 8835–8836. (e) Enholm, E. J.; Trivellas, A. J. Am. Chem. Soc.
ꢀ
1989, 111, 6463–6465. (f) Aurrecoechea, J. M.; Lopez, B. Tetrahedron
Lett. 1998, 39, 2857–2860. Ring contraction of pyranoses to furanoses:
(g) Bettelli, E.;D’Andrea, P.; Mascanzoni, S.; Passacantilli, P.; Piancatelli,
G. Carbohydr. Res. 1998, 306, 221–230. (h) Hanessian, S.; Tyler, P. C.;
Demailly, G.; Chapleur, Y. J. Am. Chem. Soc. 1981, 103, 6243–6246.
(5) (a) Estevez, J. C.; Saunders, J.; Besra, G. S.; Brennan, P. J.; Nash,
R. J.; Fleet, G. W. J. Tetrahedron: Asymmetry 1996, 7, 383–386. (b)
Bichard, C. J. F.; Brandstetter, T. W.; Estevez, J. C.; Fleet, G. W. J.;
Hughes, D. J.; Wheatley, J. R. J. Chem. Soc, Perkin Trans. 1 1996, 2151–
2156.
(6) (a) Kirschning, A. Eur. J. Org. Chem. 1998, 2267–2274. (b)
Kirschning, A. Liebigs Ann. Chem. 1995, 2053–2056.
(7) Engstrom, K. M.; Mendoza, M. R.; Navarro-Villalobos, M.; Gin,
D. Y. Angew. Chem., Int. Ed. Engl. 2001, 40, 1128–1130.
(8) Stoltz, B. M.; Wood, J. L. Tetrahedron Lett. 1996, 37, 3929–3930.
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(i) Kassou, M.; Castillon, S. J. Org. Chem. 1995, 60, 4353–4358. (j)
Hanessian, S.; Pernet, A. G. In Advances in Carbohydrate Chemistry and
Biochemistry; Academic Press: New York, 1976; Vol. 33, pp 111ꢀ188.
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2013, 69, 4302–4310. (c) Stoltz, B. M.; Wood, J. L. Tetrahedron Lett.
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r
10.1021/ol402021e
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the rearrangement of furfuryl alcohol derivatives to
dihydropyran systems has been used successfully in total
synthesis10 as well as in combinatorial chemistry.11 Ring-
expansion through the formation of a cyclopropane has
been effectively utilized to synthesize 7-membered oxygen
heterocycles, oxepines, as well as septanosides.12 1,2-
Cyclopropanated sugar derivatives have also been con-
verted to the corresponding ring-contracted counterparts.13
Very recently, spiroannulated donorꢀacceptor cyclopro-
pane derivatives were successfully converted to [n,5]-spir-
oketals (n = 5, 6) via ring enlargement of the cyclopropane
moiety.14 However, to the best of our knowledge, ring-
expansion of a furanose derivative to a C-glycosylated
pyranose has not been reported in the literature. In con-
tinuation of our investigations on the application of cyclo-
propanated sugar motifs,15 in the preparation of novel
chiral architectures, and in the total synthesis of natural
products, herein we disclose an interesting ring-contraction
reaction of spiro-cyclopropanecarboxylated sugar scaffolds
to give keto-furanose derivatives, as well as a ring-expansion
methodology for the diastereoselective synthesis of sugar-
fused bicyclic systems.
Cyclopropanation of exocyclic-glycal16 1 using methyl-
diazoacetate in CH2Cl2 under catalytic Rh2(OAc)4 condi-
tions provided the spiro-cyclopropane derivative 2 as
a mixture of diastereomers17 in 58% yield. Electrophilic
ring-opening of this donorꢀacceptor cyclopropane 2 with
N-iodosuccinimide (NIS) in dioxane:water (2:1) provided
the R,β-unsaturated ester 4 through the formation of
the iodo alcohol 3 followed by dehydrohalogenation, in
excellent yield. We assumed that compound 4, under
basic conditions, would undergo an intramolecular hetero
Michael addition (IHMA) reaction and provide the septa-
noside derivative 5.
Scheme 1. Ring Expansion vs Ring Contraction of a
Spiroannulated Sugar Derivative
Interestingly, treatment of compound 4 with DBU in
CH2Cl2 provided a single diastereomer. Detailed spectral
analysis revealed that the product was a keto-furanose
derivative 6 instead of a septanoside 5 (Scheme 1). The
structure of compound 6, and stereochemistry at the newly
formed quaternary center, were assigned by observing the
NOE between the pseudoequatorial hydrogen and the
methylene group adjacent to the carbonyl group.18
The generality of this serendipitous ring-contraction
reaction was investigated by applying it to a series of
spiro-cyclopropanecarboxylated sugar derivatives. Thus,
compound 7 was subjected to NIS mediated solvolytic
ring-opening to give R,β-unsaturated ester 8 which, upon
reaction with DBU in CH2Cl2, gave the furanoside 9 as a
1:1 mixture of diastereomers. Similarly, spiro-compounds
10, 13, 16, 19, and 22 upon NIS mediated ring-opening
provided the hemiketals 11, 14, 17, 20, and 23, respectively.
Reaction of these hemiketals with DBU resulted the for-
mation of C-glycosylated keto-furanose derivatives 12, 15,
18, 21, and 24 in good yield and stereoselectivity (Table 1,
entries 2ꢀ6).19 These compounds can serve as excellent
synthons for the preparation of bistetrahydrofuran deriv-
atives particularly present in annonaceous acetogenins20
by selective reduction of the ketone to the alcohol followed
by lactonization, as well as furan-annulated spirocyclic
natural products.21 Further, anomeric deoxygenation
could provide an access to the preparation of C-glycoside
derivatives.
(9) Achmatowicz, O.; Bukowski, P.; Szechner, B.; Zwierzchowska,
Z.; Zamojski, A. Tetrahedron 1971, 27, 1973–1996.
(10) (a) Yang, C.-F.; Xu, Y.-M.; Liao, L.-X.; Zhou, W.-S. Tetrahedron
Lett. 1998, 39, 9227–9228. (b) Kobayashi, Y.; Nakano, M.; Kumar, G. B.;
Kishihara, K. J. Org. Chem. 1998, 63, 7505–7515.
(11) Burke, M. D.; Berger, E. M.; Schreiber, S. L. J. Am. Chem. Soc.
2004, 126, 14095–14104.
(12) (a) Hoberg, J. O. J. Org. Chem. 1997, 62, 6615–6618. (b)
Ramana, C. V.; Murali, R.; Nagarajan, M. J. Org. Chem. 1997, 62,
7694–7703. (c) Batchelor, R.; Harvey, J. E.; Northcote, P. T.; Teesdale-
Spittle, P.; Hoberg, J. O. J. Org. Chem. 2009, 74, 7627–7632. (d) Hewitt,
R. J.; Harvey, J. E. J. Org. Chem. 2010, 75, 955–958. (e) Ganesh, N. V.;
Raghothama, S.; Sonti, R.; Jayaraman, N. J. Org. Chem. 2010, 75, 215–
218. (f) Sugita, Y.; Kimura, C.; Hosoya, H.; Yamadoi, S.; Yokoe, I.
Tetrahedron Lett. 2001, 42, 1095–1098.
Implementation of the electrophilic ring-opening reac-
tion on spiroannulated compounds 25 and 27, in which the
protecting group adjacent to the spiro center was a benzyl
group, provided the hemiketals 26 and 28, respectively,
(13) (a) Hewitt, R. J.; Harvey, J. E. Chem. Commun. 2011, 47, 421–
423. (b) Sridhar, P. R.; Seshadri, K.; Reddy, G. M. Chem. Commun.
2012, 48, 756–758.
(14) Brand, C.; Rauch, G.; Zanoni, M.; Dittrich, B.; Werz, D. B.
J. Org. Chem. 2009, 74, 8779–8786.
(15) (a) Sridhar, P. R.; Venukumar, P.; Seshadri, K.; Satyavathi, R.
Chem.;Eur. J. 2009, 15, 7526–7529. (b) Sridhar, P. R.; Venukumar, P.
Org. Lett. 2012, 14, 5558–5561.
(16) For reviews on cyclopropanated sugars, see: (a) Cousing, G. S.;
Hoberg, J. O. Chem. Soc. Rev. 2000, 29, 165–174. (b) Yu, M.; Pagenkopf,
B. L. Tetrahedron 2005, 61, 321–347. All of the exocyclic glycals were
synthesized by elimination of HI from the corresponding iodomethyl
pyranose/furanose or by methylenation of the corresponding protected
lactone with Petasis reagent.
(18) A 3D (energy minimized) structure of compound 6 is provided in
the Suporting Information.
(19) In all of the products, stereochemistry at the quaternary center
was assigned by NOE experiments. The reported diastereomeric ratio is
based on 1H NMR of the crude reaction mixture after workup.
(20) (a) Figadere, B. Acc. Chem. Res. 1995, 28, 359–365. (b) Zeng, L.;
Ye, Q.; Oberlies, N. H.; Shi, G.; Gu, Z.-M.; He, K.; McLaughlin, J. L.
Nat. Prod. Rep. 1996, 13, 275–306. (c) Kojima, N.; Maezaki, N.;
Tominaga, H.; Yanai, M.; Urabe, D.; Tanaka, T. Chem.;Eur. J.
2004, 10, 672–680.
(17) The two newly formed stereocenters will be destroyed in the
course of the reaction. Thus, no attempts were made to analyze the
diastereomeric ratio of this mixture.
(21) (a) Aho, J. E.; Pihko, P. M.; Rissa, T. K. Chem. Rev. 2005, 105,
4406–4440. (b) Perron, F.; Albizati, K. F. Chem. Rev. 1989, 89, 1617–
1661.
B
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ketone 29, under basic conditions, can undergo enolization
to form the corresponding enol 30. Baldwin et al.,22 re-
ported that enols of type 30 may form favorable allene
epoxides instead of cyclopropanone intermediate, which is
commonly observed in the classical Favorskii rearrange-
ment.23 Thus, we assumed that enol 30 could convert to the
allene epoxide 31 and this could eventually open to give the
planar dipole intermediate 32.24 Finally, an intramolecular
addition of O-nucleophile at the carbocation would provide
the ring-contracted furanose derivative6 (Scheme 2). Based
on this, we believe that the conversion of hemiketal 4 to
keto furanoside 6 depends on the formation of allene
epoxide 31. The driving force for the formation of inter-
mediate 31 may be a consequence of the steric hindrance in
intermediate enol 30. Thus, the presence of a bulky silyloxy
group on the enolic carbon might push the enol 30 to form
the allene epoxide 31. On the other hand, when the silyloxy
group was replaced with a benzyloxy group (Table 1,
entries 7 and 8), where as the steric hindrance would be
lower for an OBn compared to an OTBS, the reaction did
not proceed further to form the corresponding keto furano-
side derivative.
Table 1. Electrophilic Ring Opening Followed by Ring-
Contraction Reaction of Spiro-cyclopropanecarboxylated
Sugar Derivatives
Scheme 2. Proposed Mechanism for the Ring-Contraction
Reaction
a Yield refers pure and isolated products. b Major diastereomer is
represented. c Obtained in 30% ee (by HPLC). Stereochemistry at
anomeric center was not assigned. d No product was observed and the
starting material was recovered.
Keeping the above results in mind, we envisaged that
replacing the spiroannulated pyran with a furan moiety
might give the five membered hemiketal, upon NIS
mediated ring-opening, which could then undergo a ring-
expansion to a pyran derivative. Thus, compound 33 was
subjected to electrophilic ring-opening to give the furanosyl-
hemiketal 34 in 67% yield. However, compound 34 did
not provide the expected ring expansion product 35 in the
presence of DBU (Scheme 3).
The reason for the lack of reactivity of compound 34
is certainly due to its higher stability in the furanose
formcomparedtotheketo-pyranose35. Hence, decreasing
the flexibility of furanose-hemiketal might be expected
to giverise to the ring-expansion product. Therefore,
in good yield. However, treating these compounds with
DBU gave neither ring-contracted nor ring-expanded
product even after an extended period of time (∼3 days)
(Table 1, entries 7 and 8).
On the basis of the above observations, a plausible
mechanism is proposed for the formation of the ring-
contracted keto-furanoside 6 from the pyranosyl hemiketal
4. It is believed that cyclic hemiketal 4 exists in equilibrium
with hydroxy ketone 29 that likely can undergo intramolec-
ular hetero Michael addition to give ring-expanded septa-
nose 5. However, under the reaction conditions 5 can
undergo a reverse Michael addition reaction to give 29, to
set up an equilibrium between 5 and 29. On the other hand,
(23) Kende, A. S. Org. Reactions 1960, 11, 261.
(22) Baldwin, J. E.; Kruse, L. I. J. Chem. Soc. Chem. Commun. 1977,
233–235.
(24) Cookson, R. C.; Nye, M. J. J. Chem. Soc. 1965, 2009–2018.
Org. Lett., Vol. XX, No. XX, XXXX
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Table 2. Stereoselective synthesis of Fused Pyrano- or
Furo[3,2-b]pyrans from Spiro-cyclopropanecarboxylated
Sugar Derivatives
Scheme 3. Electrophilic Ring Opening of Spiro-cyclopropane-
Carboxylated Furanose Derivative
Scheme 4. Ring Expansion of Spiro-cyclopropanecarboxylated
Sugar Derivative
a Yield refers pure and isolated products. b Only a single diastereomer
was obtained.
ring systems are present in a number of bioactive natural
products.25 The present ring-expansion methodol-
ogy will provide a straightforward access to this kind of
bicyclic architecture from inexpensive sugar-based raw
materials.
In conclusion, an interesting ring contraction of spiro-
cyclopropanecarboxylated sugar derivatives to keto-
furanoses, involving NIS-mediated electrophilic ring-
opening followed by a DBU-mediated cyclization reaction,
has been discovered. The generality of this methodology
was investigated, and a plausible mechanism for the process
was proposed. Additionally, a ring-expansion protocol
for the diastereoselective synthesis of fused pyrano- or
furo[3,2-b]pyran frameworks has been developed. Further
investigations and applications of this methodology in the
synthesis of bioactive natural products are in progress.
spiro-cyclopropanecarboxylated fused bicycle 37 was
synthesized by cyclopropanation of the exocyclic vinyl
ether 36. Exposure of compound 37 to NIS resulted in
C-glycoside 38 which, upon reaction with DBU, provided
the expected ring-expanded bicyclic pyrano[3,2-b]pyran
derivative 39 as a single diastereomer. The stereochemistry
at the newly formed chiral center was assigned from the
NOE between the 1,3-diaxial hydrogen atoms present in
bicycle 39 (Scheme 4).
Similarly, the spiroannulated sugar derivative 40, upon
electrophilic ring opening, provided the C-glycoside 41,
which smoothly ring-expanded to the bicyclo-pyrano[3,2-b]-
pyran derivative 42 in excellent yield upon exposure to
DBU (Table 2, entry 1). On the other hand, reaction
of cyclopropanecarboxylated furo[3,2-b]furan derivatives
43 and 46 with NIS provided exclusively the bicyclic
hemiketals 44 and 47. However, in the presence of DBU,
the hemiketals 44 and 47 furnished the expected ring-
expansion products 45 and 48, respectively, in good yield.
These types of bicyclo-tetrahydrofuro- or pyrano[3,2-b]pyran
Acknowledgment. This work was supported by the
Council of Scientific and Industrial Research (CSIR),
New Delhi (Grant No. 01(2408)/10/EMR-II).
Supporting Information Available. Experimental pro-
cedures, full spectroscopic data, and 1H, 13C and DEPT
of all new compounds; COSY and NOESY of all final
products. This material is available free of charge via the
Internet at http://pubs.acs.org.
(25) (a) Nicolaou, K. C.; Hwang, C. K.; Duggan, M. E. J. Am. Chem.
Soc. 1989, 111, 6682–6690. (b) Evans, P. A.; Roseman, J. D.; Garber,
L. T. J. Org. Chem. 1996, 61, 4880–4881. (c) Saito, T.; Nakata, T. Org.
Lett. 2009, 11, 113–116.
The authors declare no competing financial interest.
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