Bio-inspired synthesis of rare and unnatural carbohydrates and cyclitols through strain driven epimerization

Article abstract of DOI:10.1039/c4cc00868e

We report a bio-inspired, strain driven epimerization of trans-ketals to cis-ketals through an enolate intermediate. Swern oxidation of a hydroxyl group adjacent to a trans-ketal effects both oxidation and its epimerization to cis-ketal. This novel and general strategy allows inversion of up to three contiguous stereocenters and has been illustrated by the synthesis of several unnatural/rare isomers of carbohydrates/cyclitols from their naturally abundant isomers. This journal is the Partner Organisations 2014.

Full text of DOI:10.1039/c4cc00868e

Showcasing research from Prof. Kana M. Sureshan’s
Laboratory, Indian Institute of Science Education and Research,
Thiruvananthapuram (IISER-TVM), Kerala, India
As featured in:
Bio-inspired synthesis of rare and unnatural carbohydrates and
cyclitols through strain driven epimerization
Swern oxidation of a hydroxy group adjacent to a trans-ketal
effects both oxidation and its epimerization to cis-ketal. This
novel and general strategy allows inversion of up to three
contiguous stereocenters and has been illustrated by the
synthesis of several unnatural/rare isomers of carbohydrates/
cyclitols from their naturally abundant isomers.
See Kana M. Sureshan et al.,
Chem. Commun., 2014, 50, 6707.
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Bio-inspired synthesis of rare and unnatural
carbohydrates and cyclitols through strain
driven epimerization†‡
Cite this: Chem. Commun., 2014,
50, 6707
Received 2nd February 2014,
Accepted 11th March 2014
Raja Mohanrao, Aromal Asokan and Kana M. Sureshan*
DOI: 10.1039/c4cc00868e
www.rsc.org/chemcomm
We report a bio-inspired, strain driven epimerization of trans-ketals
to cis-ketals through an enolate intermediate. Swern oxidation of a
hydroxyl group adjacent to a trans-ketal effects both oxidation and
its epimerization to cis-ketal. This novel and general strategy allows
inversion of up to three contiguous stereocenters and has been
illustrated by the synthesis of several unnatural/rare isomers of
carbohydrates/cyclitols from their naturally abundant isomers.
Carbohydrates and cyclitols are two important classes of bio-
logically active polyols involved in many physiological pro-
cesses such as cellular signaling, structure, and storage, etc.1
However, only seven of the many possible pentoses and hexoses
and one (myo-inositol) of the nine possible inositols (major class
of cyclitols) are naturally abundant. Hence there has been a
tremendous interest in the synthesis of especially the unnatural
Fig. 1 (A) Mechanism of enzyme mediated epimerization of uloses, (B)
proposed strain driven epimerization of a trans-ketal to a cis-ketal.
or rare isomers of these polyols as tools for biological investiga- exploiting the stability difference for the stereochemical inver-
tions.2 Synthesis of rare/unnatural polyols from their cheaply sion, is appealing, creating such a stability difference is a
available isomers by inversion of one or more hydroxyl groups formidable challenge. Ketalization is one of the best methods
through oxidation–reduction,3 the Mitsunobu reaction4 or SN2 to protect vicinal diols of cyclitols and carbohydrates.7 It is known
substitution5 are the common methods. However, these methods that a simple trans-ketal, formed from anti-diols has a greater
are not suitable for efficient synthesis of isomers with more than steric strain than the cis-ketal, formed from syn-diols.8 We
one configurational difference with respect to the starting isomer. envisioned that this steric strain can be exploited for the
We herein report a novel and general strategy for inversion of up epimerization of a trans-ketal adjacent to a keto group to a
to three contiguous stereocenters.
cis-ketal through the enolate (Fig. 1B). Oxidation of a hydroxyl
Many isomerases, enzymes involved in the biosynthesis of group adjacent to a trans-ketal to ketone and its subsequent
unusual sugars from common sugars, use enolate chemistry for enolization using a base would result in the epimerization of a
the isomerization of a carbon center adjacent to a carbonyl group trans-ketal to a cis-ketal. Furthermore, the keto group can be
(Fig. 1A).6 In such cases, factors such as increased stability of the reduced selectively by using appropriate reducing agents, thus
product (at least in the enzyme environment) dictate the direction allowing stereochemical inversion of more than one center.
of the reaction. While synthetically mimicking such a strategy,
In order to test this hypothesis, ketone 2, prepared from the
D-xylose derivative 1 was treated with triethylamine. Gratifyingly,
the cis-ketal ketone 3 could be isolated in good yield, which could
be reduced to D-ribose derivative 4. Similarly, myo-inositol deri-
vative 5 upon oxidation gave ketone 7, which could be epimerized
to the symmetrical ketone 9 by treatment with triethylamine.
As anticipated, only the trans-ketal underwent epimerization.
Ketone 8 obtained from the cyclohexylidene derivative 6 also
underwent smooth epimerization to 10 under basic conditions.
School of Chemistry, Indian Institute of Science Education and Research,
Thiruvananthapuram, CET-Campus, Thiruvananthapuram-695016, India.
E-mail: kms@iisertvm.ac.in
† Dedicated to Prof. Horst Kunz.
‡ Electronic supplementary information (ESI) available: Quantum mechanical
calculations, experimental procedures, characterization data and crystallographic
data for 33A, 37, 38, 39, 38A, 49 & 50. CCDC 973079–973085. For ESI and crystallo-
graphic data in CIF or other electronic format see DOI: 10.1039/c4cc00868e
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Both the ketones 9 and 10 upon reduction gave the corre- the derivatives 24 and 27 of the very rare sugar, 6-deoxy-
sponding epi-inositol derivatives 11 and 12, respectively.
allopyranose,9 in good yields. Interestingly, a prolonged reac-
Having established the proof of concept, we, next, were tion of 25 gave ketone 28 with inverted stereochemistry at both
curious to know whether Swern oxidation would directly lead to C3 and C5, which could be reduced to get L-pneumose deriva-
the formation of the epimerized product (ketone with cis-ketal) as tive 29. This provides possible access to other rare and bio-
the triethylamine used in the Swern oxidation reaction can, logically important L-hexoses such as L-rhamnose (C4 epimer).
in principle, effect the epimerization of the trans-ketal to the
It is worthy of note that by using our method, we could syn-
cis-ketal in situ. To test this hypothesis, xylose derivative 1 was thesize expensive sugars such as allose and ribose in their ortho-
subjected to Swern oxidation. To our satisfaction, ketone 3 was gonally protected form from cheaply available sugars. Since all but
obtained in good yield. Ketone 3 on reduction gave the D-ribose one hydroxyl groups are protected, the corresponding epimeric
derivative 4 (98%) as expected (Table 1). To check the generality sugars can be accessed easily, in principle, via conventional
of this methodology, D-glucose derivative 13 was subjected to epimerization methods. For instance, allose derivatives 18 and
Swern oxidation. As anticipated, epimerised pyranosid-2-ulose 14 21, in principle, provide easy access to their epimeric hexoses
was formed in very good yield, which on reduction with sodium viz. D-gulose (C4 epimer) and D-altrose (C2 epimer), respectively.
borohydride gave D-allose derivative 15 as a single isomer in Also there is a possibility of stereoselective reduction of the keto
almost quantitative yield. Similarly, differently protected ketals 16 group using different reducing agents.
and 19 underwent a smooth oxidation–epimerization reaction
Having shown the utility of this methodology in carbo-
giving corresponding uloses 17 and 20, respectively, which could hydrates, we turned our attention to cyclitols. As quinic acid
be reduced to D-allopyranoside derivatives 18 and 21 in good is a chiral pool cyclitol for the synthesis of natural products,10
yields. D-Quinovose derived ketals 22 and 25 also gave epimerized application of isomerisation would be of tremendous interest
ketones 23 and 26, respectively, which on reduction gave synthetically. Thus, quinic acid derivative 30 was subjected to
Swern oxidation (Table 2). Ketone 31 and enone 34 were isolated
Table 1 Isomerization of sugars
as a mixture both with cis-isopropylidene groups. A prolonged
reaction leads to the formation of protocatechuic acid methyl
a orb
ƒƒ!
c
Substrate
Oxidised product
Reduced product
!
ester (Scheme S5, ESI‡), a natural product with antioxidant, anti-
inflammatory and anti-cancer activities, biosynthesized from
shikimic acid. While the reduction of enone 34 gave alcohol 35
irrespective of the reducing agent, ketone 31 gave exclusively
lactone 32 and alcohol 33 when reduced with NaBH4 and
NaBH(OAc)3, respectively.
Of all nine inositols, allo-, neo-, epi-, muco- and cis-inositols
are unnatural isomers. However, these unnatural inositols and
derivatives are essential for chemical biology exploration of
inositide signaling. This prompted us to investigate the possibi-
lity of adopting our methodology for the synthesis of unnatural
inositol derivatives from the cheaply available myo-inositol. Thus,
myo-inositol derivative 5, was subjected to Swern oxidation. As
anticipated, the symmetric ketone 9 was obtained in very good
yield, which on reduction gave epi-inositol derivative 11 as before
(Scheme 1). Similarly, the dicyclohexylidene derivative 6 also
underwent a smooth oxidation–epimerization sequence to
form the symmetrical ketone 10 under the Swern oxidation
conditions as expected.
Swern oxidation of myo-inositol derivative 36 gave inosose 37,
whose crystal structure (ESI‡) showed the presence of two cis-
isopropylidene groups. Reduction of 37 with sodium borohydride
gave a 1: 1 mixture of allo-inositol derivative 38, wherein two
contiguous centers are inverted, and neo-inositol derivative 39,
whose structures were confirmed by solving their X-ray crystal
structures (ESI‡). Interestingly, reduction of 37 with K-selectride
gave exclusively neo-inositol derivative 39 (93%). The best condi-
tion in favour of allo-inositol derivative 38 was the use of sodium
triacetoxyborohydride for reduction and the selectivity was 2 : 1
(Table S5, ESI‡). Thus by choosing appropriate conditions, the
required isomeric inositol derivative 38 or 39 could be obtained.
Similarly, Swern oxidation of myo-inositol derivative 40 gave the
a
b
(COCl)2, DMSO, Et3N, CH2Cl2, 0.5–1 h. (COCl)2, DMSO, Et3N,
c
CH2Cl2, 96 h. NaBH4, MeOH, 0 1C, 0.5 h.
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Table 2 Isomerization of cyclitolse
b=c=d
ƒƒƒ!
a
Substrate
Oxidised product
Reduced product
!
Scheme 1 Proof of concept: (a) Dess–Martin periodinane, CH2Cl2 (b) Et3N,
CH2Cl2, rt (c) NaBH4, MeOH, 0 1C, 0.5 h.
inosose 41, which on reduction with sodium borohydride gave
a mixture of allo-inositol derivative 42 and neo-inositol deriva-
tive 43. Swern oxidation of myo-inositol derivative 44 gave the
epimerized product 45. A prolonged reaction leads to the E1cB
elimination giving an a,b-unsaturated ketone (ESI‡). Reduction
of 45 with sodium borohydride yielded two differently protected
allo- and neo-inositol derivatives 46 and 47, respectively, in a
2 : 1 ratio (ESI‡).
One of the interesting unnatural isomers among the inositols is
cis-inositol, which forms complexes with metal cations.11 We were
curious to know whether we can make a cis-inositol derivative from
a myo-inositol derivative by epimerization of two trans-ketals,
simultaneously. Swern oxidation of 4812 gave the epimerized
ketone 49, whose crystal structure (ESI‡) showed the presence
of two cis-isopropylidene groups. As anticipated, sodium boro-
hydride reduction of 49 gave cis-inositol derivative 50 exclu-
sively. The structural identity of 50 could be proved by solving
its single crystal X-ray structure (ESI‡). As both the trans-ketals
could be isomerized to cis-ketals, it is possible to invert three
contiguous stereocenters by adopting our methodology. This
was exemplified by the Swern oxidation of neo-inositol deriva-
tive 51 which gave the ketone 49, which on reduction gave the
cis-inositol derivative 50, where in three contiguous stereo-
centers are inverted compared to starting alcohol 51. It is
worthy of note that stereochemical inversions of more than
one adjacent chiral center are difficult by existing methods due
to complications arising from neighbouring group participation,
other side reactions or steric crowding.13
In order to exploit the utility of this methodology in natural
product synthesis, we have synthesized the natural product,
Gabosine J from the known pentol 52.14 As Gabosine J can be
synthesized by oxidation of the allylic alcohol and inversion of
the homoallylic center in pentol 52, our strategy seems to be
ideal for its synthesis. Ketalization of 52 gave the known diketal
53 exclusively in very good yield, which on Swern oxidation gave
the epimerized enone 54. Acidic hydrolysis of enone 54 gave
Gabosine J in overall excellent yield (Scheme 2).
In summary, taking a cue from Nature, for the first time, we
reported a reliable strain driven epimerization of trans-ketals to
cis-ketals under Swern oxidation conditions. Judicious selec-
tion of reagents for the reduction of the resultant keto group
offers additional stereochemical control. While stereochemical
a
b
(COCl)2, DMSO, Et3N, CH2Cl2, 0.5–1 h. NaBH4, MeOH, 0 1C, 0.5 h.
c
d
e
NaBH(OAc)3, CH2Cl2, rt. K-selectride, THF, ꢀ78 1C. All the inositols
derivatives are either racemic or meso compounds.
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1 h, 90%; (b) (COCl)2, DMSO, Et3N, DCM, ꢀ78 1C, 5–6 h, 84%; (c) TFA
(10% in DCM), rt, 1 h, 92%.
inversions of more than one adjacent chiral center are difficult
by existing methods, our methodology allows inversion of up to
three contiguous chiral centers. The fact that the epimerization of
an alcoholic center can be done without removing the protecting
groups is beneficial in the context of multistep synthesis. The use
of our novel methodology has been illustrated by the expedient
syntheses of several expensive, rare and unnatural sugars and
cyclitols from cheaply available isomers. As Swern oxidation is
one of the common synthetic transformations, there is great
potential for the application of this methodology for oxidation-
cum-epimerization in natural product synthesis.
K.M.S. thanks the Department of Science and Technology
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