Highly regio-and stereoselective one-pot synthesis of carbohydrate-based butyrolactones

Article abstract of DOI:10.1021/ol102723c

The use of manganese(III) acetate allows the direct synthesis of diverse arrays of [4.3.0] bicyclic carbohydrate-based γ-lactone building blocks from glycals. A mechanism to explain the high regio-and stereoselectivity is proposed. The new reaction has th

Full text of DOI:10.1021/ol102723c

ORGANIC
LETTERS
2011
Vol. 13, No. 4
576–579
Highly Regio- and Stereoselective
One-Pot Synthesis of Carbohydrate-
Based Butyrolactones
Syed Khalid Yousuf, Debaraj Mukherjee,* Mallikharjunrao L, and Subhash C. Taneja
Natural Product Chemistry Division, Indian Institute of Integrative Medicine (CSIR),
Canal Road, Jammu, India 180001
dmukherjee@iiim.ac.in
Received November 10, 2010
ABSTRACT
The use of manganese(III) acetate allows the direct synthesis of diverse arrays of [4.3.0] bicyclic carbohydrate-based γ-lactone building blocks
from glycals. A mechanism to explain the high regio- and stereoselectivity is proposed. The new reaction has the potential to generate libraries for
biological screening.
Carbohydrate-fused γ-butyrolactone scaffolds consti-
tute integral components of a plethora of natural products
with promising bioological activities like antimicrobial,1
cytotoxic,2 fungicidal,3 selective insecticidal,4 and enzyme
inhibitory5 (due to in vivo ring-opening by biological nu-
cleophiles). Moreover, linking the reactive heterocycles to
carbohydrates improves their bioavailability.6 In synthetic
carbohydrate chemistry, the 1,2-lactone ring can be conceived
as a simultaneous protecting group for anomeric and C-2
positions, offering the products which can act as precursors
for the synthesis of glycosides, nucleosides, and complex
natural products. Thus, under a research program directed
toward the synthesis of natural product inspired new chemical
entities for biological screening, we became interested in the
synthesis of carbohydrate fused γ-butyrolactones.
A few approaches that are available for the construction
of this kind of fused motifs include intramolecular trans-
esterification of sugar-based esters with vicinal alcohol
obtained in multiple steps,7a-c multicomponent Poparov re-
action,8 NIS-mediated ring-opening of 1,2-cyclopropionated
(1) Husain, A.; Hasan, S. M.; Lal, S.; Alam, M. M. Indian J. Pharm.
Sci. 2006, 68, 536–538.
(2) (a) Oh, S.; Jeong, I. H.; Shin, W. S.; Wang, Q.; Lee, S. Bioorg.
Med. Chem. Lett. 2006, 16, 1656–1659. (b) El-Subbagh, H. I.; Abu-Zaid,
S. M.; Mahran, M. A.; Badria, F. A.; Al-Oabaid, A. M. J. Med. Chem.
2000, 43, 2915–2921.
(3) Rauter, A. P.; Ferreira, M. J.; Font, J.; Virgili, A.; Figueredo, M.;
Figueredo, J. A.; Ismael, M. I.; Canda, T. L. J. Carbohydr. Chem. 1995,
14, 929–948.
(4) Justino, J.; Rauter, A. P.; Canda, T.; Wilkins, R.; Mathews, E.
Pest. Manag. Sci. 2005, 61, 985–990.
(5) Recent review: Konaklieva, M. I.; Plotkin, B. J. Mini-Rev. Med.
(7) (a) Xavier, N. M.; Rauter, A. P. Org. Lett. 2007, 9, 3339–3341.
(b) Patil, N. T.; Tilekar, J. N.; Dhavale, D. D. J. Org. Chem. 2001, 66,
1065–1074. (c) Alker, D.; Jones, N.; Taylor, G. M.; Wood, W. W.
Tetrahedron lett. 1991, 32, 1667–1670.
Chem. 2005, 5, 73–95.
(6) Yin, J.; Linker, T. Chem.;Eur. J. 2009, 15, 49–52.
(8) Jimenez, O.; Rosa, G. D. L; Lavilla, R. Angew. Chem., Int. Ed.
2005, 44, 6521–6525.
r
10.1021/ol102723c
Published on Web 01/18/2011
2011 American Chemical Society

sugar derivatives,9 TiCl4-mediated ring-opening and alco-
hol trapping,10 condensation of Meldrum’s acid with pro-
tected sugar lactol derivatives,11 deglycosidation, ozonolysis
of orthogonally protected 1-pentenyl sugar derivatives,12
and radical cyclization of unsaturated carbohydrate de-
rived acetals.13 Recently, Linker and co-workers6 reported
the multistep synthesis of carbohydrate 1,2-lactones from
glycals. Thus, there are quitea few methodsinthe literature
for the synthesis of sugar-based lactones, but no general-
ized single-step method is available for such privileged
systems.
Contemporary organic synthesis demands the develop-
ment of simple methods for the rapid construction of
complex and biologically relevant compounds. With our
recent success in the development of new synthetic strate-
gies for the generation of new chemical entities from the
carbohydrate chiral pool,14 we envisaged to develop one-
pot regio- and stereoselective generalized synthetic routes
to fused lactone congeners at different positions of carbo-
hydrate templates. For the method to be of wide applic-
ability, certain criteria required to be fulfilled; e.g., the
regio- and stereoselectivity of these reactions must be
predictable.
The addition of Ac2O and use of elevated temperatures
(60-100 °C) ensured the formation of the product 2a,
albeit with moderate (∼35%) yields. In order to find a
suitable temperature and additive(s) for a typical radical
initiation, further optimization studies were then carried
out. As single-electron-transfer processes are generally
favored by ultrasound,17 irradiation of the reaction mix-
ture with high intensity ultrasound was resorted to, which
facilitated better conversion of the glycals into butyrolac-
tone. Addition of KOAc as a radical initiator or stabilizer
led to a marginal increase in yield. However, use of both
Ac2O and KOAc under sonication proved more effective,
allowing the reaction to be completed in ∼6 h with an
increase in yield (78%) and complete consumption of the
glycal (Scheme 1).
Scheme 1. Prior Art for the Synthesis of a Butyrolactone at the
1,2-Position of a Sugar
Radical reactions constitute a path breaking area in
organic synthesis.15 In comparison to traditional methods
for radical generation suchas TBTH/AIBN, etc., the use of
transition-metal salts and their oxides ensures remarkable
regioselectivity and efficiency even with polyfunctional
15
organic compounds. Among metal oxidants, Mn(OAc)3
has emerged as a versatile single-electron-transfer reagent
during the last two decades. However, in carbohydrate
chemistry its role is limited only to a single report of
malonate addition to glycals for the synthesis of 2-C
glycosides.16 The importance and requirements of the
natural product based scaffolds of defined regio-/stereo-
chemistry prompted us to probe the manganese(III) ace-
tate mediated reaction outcomes.
The absence of signals for olefinic protons and occur-
rence of extra signals for the -CH2 group at δ 2.54, 2.40 (in
1H NMR), and 40.6 ppm in 13C NMR confirmed the
formation of the 1,2-lactone. Regioselectivity of the reac-
tion was determined by spectroscopic analysis.18
Comparison of the rotation value of theproductwiththe
one reported in the literature6 established that the reaction
had proceeded with almost complete stereoselectivity.
Synthesis of the same derivative 2a previously needed four
linear steps and was achieved in <20% overall yield
(Scheme 1). Moreover, the route taken by Linker et al.6
is not applicable to compounds with ester protecting
groups, as the reaction sequence involves base mediated
hydrolysis of methyl esters.
Thus, initially 3,4,6-tri-O-benzyl-D-glucal (1a) was
reacted with AcOH, which served both as a solvent
and the source of carboxymethyl radical, in the presence
of Mn(OAc)3 2H2O (20 mol %). However, no reaction
3
occurred at room temperature, and the starting glycal
was fully recovered after workup (Supporting Informa-
tion, entry 1).
(9) Haveli, S. D.; Sridhar, P. R.; Suguna, P.; Chandrasekaran, S. Org.
Lett. 2007, 9, 1331–1334.
This encouraging observation led us to probe the gen-
erality and scope of this reaction for the construction of
diverse libraries of lactone fused sugar derivatives. Thus,
using optimized reaction conditions, a panel of 1,2-glycals
(gluco, galacto) were subjected to Mn(OAc)3-mediated
radical lactonization to yield the corresponding butyrolac-
tones in moderate to good yields (Table 1). Protecting
(10) Yu, M.; Pagenkopf, B. L. Tetrahedron. 2003, 59, 2765–2771.
(11) Popsavin, V.; Benedekovic, G.; Sreco, B.; Popsavin, M.;
Francuz, J.; Kojic, V.; Bogdanovic, G. Org. Lett. 2007, 9, 4235–4238.
(12) Veitch, G. E.; Beckmann, E.; Burke, B. J.; Boyer, A.; Maslen,
S. L.; Ley, S. V. Angew. Chem., Int. Ed. 2007, 46, 7629.
(13) Chapleur, Y.; Moufid, N. J. Chem. Soc., Chem. Commun. 1989,
39–40.
(14) (a) Mukherjee, D.; Shah, B. A.; Gupta, P.; Taneja, S. C. J. Org.
Chem. 2007, 72, 8965–8968. (b) Mukherjee, D.; Yousuf, S. K.; Taneja,
S. C. Org. Lett. 2008, 10, 4831–4834. (c) Thota, N.; Mukherjee, D.;
Reddy, M. V.; Yousuf, S. K.; Koul, S.; Taneja, S. C. Org. Biomol. Chem.
2009, 7, 1280–1283. (d) Yousuf, S. K.; Mukherjee, D.; Taneja, S. C.
J. Org. Chem. 2010, 75, 3097–3100.
(17) Luche, J. L.; Einhorn, C.; Einhorn, J.; Sinisterra-Gago, J. V.
Tetrahedron lett. 1993, 49, 10705–10714.
(18) Correlations between C-3 (δ 58.3)/H-7 (δ 2.67), H-3 (δ 4.18)/C-7
(δ 29.0), C-1 (δ 97.7)/H-7 (δ 2.67), and H-1 (δ 5.69)/C-7(δ 29.0) are in full
agreement with the proposed structure. No correlation was observed
between H-4 (δ 5.19) and the methylene carbon of lactone moiety, which
ruled out the other regioisomer.
(15) Snider, B. B. Chem. Rev. 1996, 96, 339–363.
(16) Linker, T.; Hartmann, K.; Sommermann, T.; Scheutzow, D.;
Ruckdeschel, E. Angew. Chem., Int. Ed. 1996, 35, 1730–1732.
Org. Lett., Vol. 13, No. 4, 2011
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Table 1. Mn(OAc)3-Mediated Synthesis of Sugar Lactones from
1,2-Glycals
Table 2. Mn(OAc)3-Mediated Synthesis of Sugar Lactones from
2,3-Glycals
a Reaction conditions: In all cases, the product was obtained by using
(a) Ac2O (17 mL), AcOH (3 mL), KOAc (15 mmol) or (b) Mn(OAc)3.
2H2O (3.7 mmol) and substrate (1.8 mmol).
linkages like ester (entries 1a, 1b, and 1c), ether (entry 1d),
or silyl ether (entry 1e) were well tolerated.
a Reaction conditions: In all cases, the product was obtained by using
(a) Ac2O (17 mL), AcOH (3 mL), KOAc (15 mmol) or (c) Mn(OAc)3
2H2O (3.7 mmol), and substrate (1.8 mmol).
In an effort to further increase the scope of the
reagent system, we next considered utilization of other
unsaturated sugar derivatives in order to mimic some
natural product skeleta. Gratifyingly, the reaction of
the azide 4,6-di-O-acetyl-2,3-dideoxy-D-erythro-hex-2-
enopyranoside under the optimized reaction conditions
afforded 4a in high yield (scheme 2). It is noteworthy
that the known synthesis of this type of 2,3-lactone
3
involved a multistep reaction sequence with poor over-
all yield.10
In order to determine the stereo- and regioselectivity of
lactone formation, spectroscopic analyses were performed.
The assigned regiochemistry became obvious from the
HMBC spectrum.18 The newly generated ring juncture
stereochemistry, which is expected to be cis, could be either
R-R or β-β in the bicyclic [4.3.0] butyrolactone system. In
the MM2 energy-minimized structure of R-R isomer 4a, the
Scheme 2. Reaction of Azide 4,6-Di-O-acetyl-2,3-dideoxy-D-
erythro-hex-2-enopyranoside
ꢀ
˚
distance between H-1 and H-3 is calculated as ∼3 A, signify-
ing that their signals should show correlation in the NOESY
spectrum. This correlation indeed was clearly observed.19
(19) Correlations of H-1β/H-2, H-1β/H-3 in the NOESY experi-
ments of 4a reveal that H-1, H-2, and H-3 are cofacial, which confirms
the R-R ring juncture stereochemistry of bicyclic lactone.
578
Org. Lett., Vol. 13, No. 4, 2011

The alternative cis structure (β-β) having H-1 and H-3
be conformationally flexible, and their conformational
preference is sensitive to hydroxyl protection. In the case
of 1,2-glycals, the ratio of normal half chair 4H5 (A) and
ꢀ
˚
distance of ∼4 A in the energy-minimized structure is not
expected to show a NOESY relationship between the two
signals. Therefore, the formation of the (β-β) structure
could be ruled out.
5
conformationally inverted isomer H4 (B) (Figure 1) can
affect the stereoselectivity of lactonization. It is well re-
cognized that the electron-withdrawing substituents at C-6
including benzyl favors the 5H4 (B) conformation and the
best stereoselectivity comes from the glycals existing pre-
ferably in conformation.20 The two faces of the conformer
(B) are well differentiated, the upper (β) face being hin-
dered by two pseudoaxial substituents, while the bottom
(R) face is shielded by only one axial C(4)-OR group. The
latter is therefore the favored face for the free radical
attack. It explains the R-selectivity of lactonistaion of
1,2-glycals.
We subsequently studied a series of 2,3-glycals having
different anomeric protections to synthesize the correspond-
ing lactones. In all cases, moderate to good yields were
observed (Table 2) without the formation of byproducts.
Understandably, all these reactions proceeded via a
radical reaction mechanism with the formation of a C-C
bond, followed by a lactonization step. The regioselectivity
is determined at the level of formation of the C-C bond.
Possibly, the key interactions are between the SOMO of
the electron-deficient acetoxy radical and the HOMO of
the glucal double bond, which determines the site of initial
attack of the acetoxy radical.
Similarly, 2,3-glycals also exist in two different confor-
5
mations, HO and OH5.21 Small anomeric substituents
generally favor the OH5 conformation. Assignment of
conformation was accomplished by NMR spectroscopy
of compound 3c where 3J3,4 = 2.3 Hz is indicative of the
OH5 conformation.21 In this situation, the upper face is
hindered by ring oxygen, driving the reaction to exclusive
R-R lactone formation.22
In summary, a regio- and stereoselective one-pot synthe-
sis of carbohydrate based butyrolactones has been accom-
plished. The method is applicable in the construction of
natural product based libraries for biological screening. A
plausible mechanism has also been given to explain the
high regio- and stereoselectivity of the SET reaction.
Acknowledgment. We are thankful to Dr. R. A.
Vishwakarma, Director, IIIM Jammu, for encouragement
and support and Mrs. Basant Purnima for 2D NMR
spectroscopy. S.K.Y. acknowledges DST (GAP-1145),
New Delhi, for the fellowship.
Figure 1. Conformational preference for (a) 1,2-glucal and
(b) 2,3-glucal.
Supporting Information Available. Experimental pro-
cedures; spectral and analytical data for all the com-
pounds. This material is available free of charge via the
Internet at http://pubs.acs.org
The high stereoselectivities of the lactonization may be
rationalized by considering the ground-state conforma-
tional distribution of glycals. The glycals are known to
(22) The attack of the carboxy methylene radical bonded to the
manganese, which may also coordinate with R-disposed anomeric
substitutents, could be an alternative explanation for the exclusive R
C-C bond formation leading to R-R lactonization as suggested by one
of the reviewers.
(20) Thiem, J.; Ossowski, P. J. Carbohydr. Chem. 1984, 3, 287–313.
(21) Franz, A. H.; Wei, Y.; Samoshin, V. V.; Gross, P. H. J. Org.
Chem. 2002, 67, 7662–7669.
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