Stereoselective synthesis of sugar fused β-disubstituted γ-butyro-lactones: C-spiro-glycosides from 1,2-cyclopropanecarboxylated sugars

Article abstract of DOI:10.1039/c1cc16417a

A stereoselective methodology was developed for the construction of C-spiro-glycosides in two steps involving bromonium ion activated solvolytic ring opening of sugar derived 1,2-cyclopropanecarboxylates followed by a one-pot dehydrohalogenation, intramolecular hetero-Michael addition (IHMA) and ester hydrolysis. The obtained spirocyclic lactols were further converted to enantiomerically pure spirolactones.

Full text of DOI:10.1039/c1cc16417a

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COMMUNICATION
Stereoselective synthesis of sugar fused b-disubstituted c-butyro-lactones:
C-spiro-glycosides from 1,2-cyclopropanecarboxylated sugarsw
Perali Ramu Sridhar,* Kalapati Seshadri and Gadi Madhusudhan Reddy
Received 15th October 2011, Accepted 16th November 2011
DOI: 10.1039/c1cc16417a
A stereoselective methodology was developed for the construction of
C-spiro-glycosides in two steps involving bromonium ion activated
solvolytic ring opening of sugar derived 1,2-cyclopropanecarboxy-
lates followed by a one-pot dehydrohalogenation, intramolecular
hetero-Michael addition (IHMA) and ester hydrolysis. The obtained
spirocyclic lactols were further converted to enantiomerically
pure spirolactones.
provide an access for further functional group interconversions
to increase the molecular complexity.15 To the best of our
knowledge, this is the first report on the development of a
general methodology for the stereoselective construction of
sugar fused b-disubstituted-g-butyro-lactones, which are a kind
of C-spiro-glycosides.
We envisaged that a more efficient approach for spirolactone 1
can be visualized by a stereoselective IHMA of a,b-unsaturated
ester 3a followed by a chemoselective reduction of the aldehyde
functionality. We reasoned that out of two possible Michael
addition pathways 5-exo-trig (path a) cyclization will be more
favourable leading to the formation of spirocyclic compound 1
than 6-endo-trig (path b) cyclization leading to the formation of
1,2-fused bicyclic lactone 2. Also we assumed that compound 3a
will exist in equilibrium with more stable cyclic hemi-acetal 3b
that resembling a 2-C-branched sugar derivative. Further
analysis suggested that IHMA substrate 3b would be readily
accessible by a dehydrohalogenation reaction of bromohydrin 4,
which could be prepared by an electrophilic ring opening of
1,2-cyclopropanecarboxylate 5 (Scheme 1).
Attaining complex molecular architectures from carbohydrate
building blocks with defined stereochemistry and structural
rigidity is an evergreen technology in chemical synthesis of
complex natural products.1 One of the interesting areas of
carbohydrate chemistry that has not been explored is the stereo-
selective formation of an oxa-quaternary carbon center at the
anomeric position in the form of a C-spiro-glycoside.2 In this
context, 1,7-dioxaspiro[4.4]nonane is one of the significant struc-
tural units present in a number of bio-active natural products.3
Some of these include syringolide 1 and 2,4 secosyrins 1 and 2,
syributins 1 and 2, prehispanolone,5 sphydrofuran,6 longianone7
biyouyanagin A8 and potential GABAA inhibitors etc.9
Based on this strategy, the initial starting material bromo-
hydrin 7 was synthesized by electrophilic ring opening of
1,5-anhydro-2-deoxy-2-C-(exo-carbomethoxymethylene)-3,4,6-tri-
O-benzyl-a-D-glucitol 6 with N-bromosuccinimide (NBS) in
dioxane : water (2 : 1). Treatment of 716 with a mild inorganic
base, K2CO3 in MeOH,17 gave a diastereomeric mixture in
92% yield. Detailed spectral analysis of this mixture revealed
that the product is an epimeric mixture of spirocyclic lactol 8
resulted by consecutive dehydrohalogenation, IHMA18 and
ester hydrolysis in one-pot. The structure of compound 8 was
further confirmed by reducing it with LiAlH4 to give the
Despite their wide occurrence, general methods for the stereo-
selective construction of these spirocyclic motifs are scarce.10
A
major challenge in the formation of these spirocycles is the
stereoselective formation of a quaternary carbon center. Among
the reported methods application of semipinacol rearrangement
reaction,11 intramolecular C–H insertion reaction12 and ring
closing metathesis13 is noteworthy. In our investigations towards
the synthesis and application of 2-C-branched carbohydrate
derivatives,14 we came across a sugar unit that can be utilized
for the construction of carbohydrate derived spirocyclic systems,
C-spiro-glycosides. In this communication, we report a novel ring-
contraction strategy involving a one-pot dehydrohalogenation,
stereoselective intramolecular hetero-Michael addition (IHMA)
and ester hydrolysis to produce a carbohydrate fused C-spiro-
cyclic-lactol framework starting from 1,2-cyclopropanecar-
boxylated sugar derivatives. The methodology was extended
to the synthesis of a number of sugar fused b-disubstituted
g-butyrolactones. Moreover, the present discovery will also
School of Chemistry, University of Hyderabad, Hyderabad, 500 046,
India. E-mail: prssc@uohyd.ernet.in; Fax: +91 4023012460;
Tel: +91 4066794823
w Electronic supplementary information (ESI) available. See DOI:
10.1039/c1cc16417a
Scheme 1 Retrosynthetic analysis of sugar fused b-disubstituted
g-butyro-lactones.
c
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Table 1 Solvolytic ring opening and K2CO3 mediated one-pot multistep
reaction: synthesis of C-spiro-glycosides
Scheme 2 Stereoselective synthesis of the sugar fused spirocyclic
lactol motif and its derivatives from 1,2-cyclopropanecarboxylated
carbohydrates.
C-glycoside derived di-ol 9. On the other hand, passing
diazomethane into a solution of 8 in ether produced carbonyl
ester 10. Fortunately, compound 8 can also serve as an important
precursor for the construction of a spirocyclic lactone skeleton.
Therefore, dehydroxylation of 8 using Et3SiH/CF3COOH
provided the expected spirocyclic lactone 11 in excellent yield
(90%) (Scheme 2). Interestingly, all the three derivatization
reactions provided only a single diastereomer that provides the
evidence for the highly stereoselective IHMA reaction. The
stereochemistry at the quaternary center was assigned based
on NOE experiments (please see the ESIw).
The aforementioned ring-opening and one-pot spirocyclization
reaction could also be extended to the other sugar derivatives.
Thus, 1,2-cyclopropanecarboxylated sugars 12, 16, 20 and 2419
upon ring opening with NBS/dioxane : water produced bromo-
hydrins 13, 17, 21 and 25. All the bromohydrins underwent a
smooth one-pot reaction to give rise to the spirocyclic lactols
14, 18, 22 and 26, respectively, in good yield with very high
diastereoselectivity at the newly formed quaternary carbon
center. The epimeric mixtures of all spirocyclic lactols were
further converted to the b-disubstituted g-butyrolactones 15,
19, 23 and 27 (Table 1, entries 1–4). The configuration at the
spirocenter was assigned by observing the NOE between 4-CH
and 6-CH2 hydrogens.
a
b
Yield refers to pure and isolated products. TBS was deprotected
c
under reaction conditions. The primary hydroxyl group in 29 was
d
protected with TBS. Epimeric mixture at the quaternary center and
e
the major product was represented. An inseparable mixture.
intermediate in the first total synthesis of (+)-secosyrins 1
and 2 and (+)-syributins 1 and 2.18b
Interestingly, NBS mediated ring opening of tricyclic donor–
acceptor cyclopropanecarboxylate 37 provided the a,b-unsaturated
bicyclic lactone 3820 as a single product in good yield (Table 1,
entry 7). Formation of 38 can be accounted by in situ oxidation
of bromohydrin to the lactone followed by dehydrohalogenation
under similar reaction conditions.21 On the other hand, bromo-
hydrin 40 derived from 1,2-cyclopropanecarboxylated pentose 39
upon exposing to K2CO3/MeOH produced the a,b-unsaturated
ester 41 in excellent yield (Table 1, entry 8). Formation of 41
could be explained through a Grob fragmentation22 of 40 followed
by deformylation in methanol under mild basic conditions.
The highly stereoselective formation of spirocyclic lactol can
be explained by two consecutive stereospecific reactions involved
in the reaction pathway. (1) Ring opening of 1,2-cyclopropane-
carboxylate by a stereospecific ‘‘edge attack’’ of bromine to give
a single stereocenter at a-position to the ester.
Treatment of compound 28 with NBS/dioxane : water furnished
bromohydrin 29 in which the TBS has been deprotected.
Protecting the free hydroxyl with TBS to give compound 30
followed by treatment with K2CO3/MeOH provided the expected
spirocyclic lactol 31 in excellent yield (92%) as an epimeric
mixture (Table 1, entry 5). Further dehydroxylation of this lactol
31 with Et3SiH/BF3ÁEt2O provided the C-spiro-glycoside 32 as
a 9 : 1 diastereomeric mixture at the newly formed quaternary
center.
However, the rhodium catalyzed cyclopropanation of 3,4-
di-O-benzyl-D-xylal provided an inseparable 4 : 1 (exo : endo)
diastereomeric mixture of cyclopropanecarboxylate 33.
Solvolytic ring opening of this mixture gave 34, then treating
with K2CO3/MeOH gave a diastereomeric mixture of spiro-
cyclic lactol 35 which upon dehydroxylation resulted again in
an inseparable 4 : 1 diastereomeric mixture 36 (Table 1, entry
6). It is worth mentioning that spirolactone 36 is an advanced
(2) Stereoselective dehydrohalogenation to provide an E-olefin
intermediate. As shown in Scheme 3, dehydrobromination of
bromohydrin 7 would give an E-olefinic cyclic lactonate 42a
intermediate which will be in equilibrium with the acyclic
c
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2 L. E. Paquette, M. J. Kinney and U. Dullweber, J. Org. Chem.,
1997, 62, 1713–1722.
3 For a review: H. N. C. Wong, Eur. J. Org. Chem., 1999,
1757–1765.
4 (a) M. J. Smith, E. P. Mazzola, J. J. Sims, S. L. Midland,
N. T. Keen, V. Burton and M. M. Stayton, Tetrahedron Lett.,
1993, 34, 223–226; (b) S. L. Midland, N. T. Keen, J. J. Sims,
M. M. Midland, M. M. Stayton, V. Burton, M. J. Smith,
E. P. Mazzola, K. J. Graham and J. Clardy, J. Org. Chem.,
1993, 58, 2940–2945.
5 P. M. Hon, C. M. Lee, H. S. Shang, Y. X. Cui, H. N. C. Wong and
H. M. Chang, Phytochemistry, 1991, 30, 354–356.
6 (a) S. Umezawa, T. Usui, H. Umezawa, T. Tsuchiya, T. Takeuchi
and M. Hamada, J. Antibiot., 1971, 24, 85–92; (b) S. Umezawa,
T. Tsuchiya, H. Naganawa, T. Takeuchi and H. Umezawa,
J. Antibiot., 1971, 24, 93–106.
7 R. L. Edwards, D. J. Maitland, C. L. Oliver, M. S. Pacey,
L. Shields and A. J. S. Whalley, J. Chem. Soc., Perkin Trans. 1,
1999, 715–719.
8 N. Tanaka, M. Okasaka, Y. Ishimaru, Y. Takaishi, M. Sato,
M. Okamoto, T. Oshikawa, S. U. Ahmed, L. M. Consentino and
K.-H. Lee, Org. Lett., 2005, 7, 2997–2999.
Scheme 3 Proposed mechanism for the diastereoselectivity of one-
pot reaction.
9 (a) A. C. Arau´ jo, A. P. Rauter, F. Nicotra, C. Airoldi, B. Costa
and L. Cipolla, J. Med. Chem., 2011, 54, 1266–1275;
(b) S. L. Midland, N. T. Keen and J. J. Sims, J. Org. Chem.,
1995, 60, 1118–1119.
10 (a) N. Noguchi and M. Nakada, Org. Lett., 2006, 8, 2039–2042;
(b) N. Haddad, I. Rukhman and Z. Abramovich, J. Org. Chem.,
1997, 62, 7629–7636.
11 (a) Q.-W. Zhang, C.-A. Fan, H.-J. Zhang, Y.-Q. Tu, Y.-M. Zhao,
P. Gu and Z.-M. Chen, Angew. Chem., Int. Ed., 2009, 48,
8572–8574; (b) L. A. Paquette, J. C. Lanter and J. N. Johnsto,
J. Org. Chem., 1997, 62, 1702–1712.
12 (a) M. P. Doyle and A. B. Dyatkin, J. Org. Chem., 1995, 60,
3035–3038; (b) M. N. Villalobos and J. L. Wood, Tetrahedron Lett.,
2009, 50, 6450–6453.
13 M. Lejkowski, P. Banerjee, J. Runsink and H.-J. Gais, Org. Lett.,
2008, 10, 2713–2716.
14 (a) P. R. Sridhar, K. C. Ashalu and S. Chandrasekaran, Org. Lett.,
2004, 6, 1777–1779; (b) P. R. Sridhar, P. V. Kumar, K. Seshadri
and R. Satyavati, Chem.–Eur. J., 2009, 15, 7526–7529.
15 L. Cipolla, E. Forni, J. Jimenez-Barbero and F. Nicotra,
´
Chem.–Eur. J., 2002, 8, 3976–3983.
Scheme 4 Stereoselective synthesis of a carbohydrate fused spirocyclic
1,8-dioxaspiro[5.4]decane system.
E-olefinic aldehyde 42b.23 IHMA reaction of intermediate 42b
via transition state 43 would give carbonyl ester 1024 which
upon hydrolysis will provide spirocyclic lactol 8.
16 The stereochemistry at C7 carbon was assigned based on our
previous experiments: ref. 14a and b.
Encouraged with the above results, we further planned
to extend the methodology towards the synthesis of the 1,8-
dioxaspiro[5.4]decane skeleton. Thus, cyclopropanation of
septanal 44 using Rh2(OAc)4/N2CHCOOMe in CH2Cl2 provided
an inseparable diastereomeric mixture of 1,2-cyclopropane-
carboxylate 45 in 59% yield.25 NBS mediated electrophilic
ring opening of 45 afforded a complex mixture in which TBS
was completely deprotected. Protection of free hydroxyl with
TBS provided compounds 46 and 4726 in a ratio of 3 : 7,
respectively, as an inseparable mixture in 82% yield. Subjecting
this mixture to K2CO3/MeOH, fortunately, provided the
expected diastereomeric mixture of spirocyclic lactol 4827 in
good yield (65%) (Scheme 4).
17 Several organic and inorganic bases were screened for this
reaction out of which K2CO3/MeOH was found to be more
suitable.
18 For
a few unsuccessful IHMA reactions for spirolactones:
(a) T. Honda, H. Mizutani and K. Kanai, J. Org. Chem., 1996,
61, 9374–9378; (b) C. Mukai, S. M. Moharram, S. Azukizawa and
M. Hanaoka, J. Org. Chem., 1997, 62, 8095–8103.
19 C. M. Timmers, M. A. Leeuwenburgh, J. C. Verheijen, G. A. van
der Marel and J. H. van Boom, Tetrahedron: Asymmetry, 1996, 7,
49–52.
20 The E-configuration was assigned based on the very high chemical
shift value for the olefinic proton.
21 E. J. Corey and M. Ishiguro, Tetrahedron Lett., 1979, 20,
2745–2748.
22 C. A. Grob, Angew. Chem., Int. Ed. Engl., 1969, 8, 535–546.
23 For the important role of double-bond geometry in IHMA reactions:
(a) Y. Guindon, F. Soucy, C. Yoakim, W. W. Ogilvie and
L. Plamondon, J. Org. Chem., 2001, 66, 8992–8996; (b) M. Labelle
and Y. Guindon, J. Am. Chem. Soc., 1989, 111, 2204–2210.
24 Using 1 equivalent of K2CO3 provided enantiomerically pure
carbonyl ester 10 with substantial amount of spirocyclic lactol 8.
25 No attempts were made to find the stereochemistry at newly
formed stereocenters.
In conclusion, an efficient methodology for the enantio-
selective synthesis of C-spiro-glycosides was developed. This
novel method may provide an easy access to spirocyclic
frameworks with defined stereochemistry.
We thank Department of Science and Technology (DST),
New Delhi, for a FAST track project grant.
26 Formation of 47 provides the evidence for the a,b-unsaturated
ester intermediate in the one-pot IHMA reaction.
27 The formation of a spirocyclic system was confirmed by observing
the a-methylene protons at d 2.65 and d 3.02 in 1H NMR and a
slight down field shift of lactol carbon in 13C NMR (please see the
ESIw spectra).
Notes and references
1 K. C. Nicolaou and H. J. Mitchell, Angew. Chem., Int. Ed., 2001,
40, 1576–1624.
c
758 Chem. Commun., 2012, 48, 756–758
This journal is The Royal Society of Chemistry 2012