Allyloxy and propargyloxy group migration: Role of remote group participation in the synthesis of 5-C-nucleosides and other sugar derivatives

Article abstract of DOI:10.1021/ol301851q

In 1-deoxy-xylofuranose derivatives possessing a good leaving group at 2-C, participation of allyloxy and propargyloxy substituents at 5-C results in loss of the 2-C substituent and attack of various nucleophiles at 5-C of the oxonium intermediate. Such p

Full text of DOI:10.1021/ol301851q

ORGANIC
LETTERS
2012
Vol. 14, No. 16
4186–4189
Allyloxy and Propargyloxy Group
Migration: Role of Remote Group
Participation in the Synthesis of
5‑C-Nucleosides and Other Sugar Derivatives
Subhrangshu Mukherjee, Prabhash N. Tripathi, and Sukhendu B. Mandal*
Chemistry Division, CSIR-Indian Institute of Chemical Biology,
4, Raja S. C. Mullick Road, Jadavpur, Kolkata 700 032, India
sbmandal@iicb.res.in
Received July 6, 2012
ABSTRACT
In 1-deoxy-xylofuranose derivatives possessing a good leaving group at 2-C, participation of allyloxy and propargyloxy substituents at 5-C results
in loss of the 2-C substituent and attack of various nucleophiles at 5-C of the oxonium intermediate. Such participation of a benzyloxy or crotyloxy
group leads to dioxabicyclo[2.2.1]heptane rings.
Protective groups play an important role in carbohy-
drate chemistry in controlling the regio- and stereoselectiv-
ities of target molecules. Various esters, commonly used as
protecting groups in carbohydrate synthesis, sometimes
undergo undesired migration and cleavage.1À5 Several
cases of 1,2-migration of, e.g., 2-oxoalkyl groups,6 thio-
or seleno-alkyl groups,7À15 N-sulfonamides,16À18 and tria-
zoline-derived aziridines19 in the stereoselective formation
of glycosides have been reported. The participation of an
(S)-(phenylthiomethyl)benzyl moiety at the 2-O or 6-O
positions has proven useful in the stereochemical synthesis
of R-glycosides.20 Long-range participation of an acyloxy
(1) Carbohydrates in Chemistry and Biology; Ernst, B., Hart, G. W.,
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(3) Oscarsson, S. Topics in Current Chemistry: Glycoscience;
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r
10.1021/ol301851q
Published on Web 08/08/2012
2012 American Chemical Society

substituent followed by acyl group migration and epimer-
ization is also common in sugar chemistry.21,22
Scheme 1. Participation of Benzyloxy Group to Form 2
Participation of 3-O-axial esters at the anomeric carbon
can lead to the stereoselective formation of β-glycosides
through cyclic dioxanyl cation intermediates, which
was convincingly proved by Crich et al.23 The presence
of 3-O-acetyl and 6-O-acetyl groups was found to direct
the formation of R-mannosides through their remote
participation at 1-C and subsequent nucleophilic attack
by the hydroxyl group of sugar acceptors.24 This participa-
tion was confirmed in one case by isolating a stable bicyclic
trichlorooxazine ring through trapping the anomeric ox-
ocarbenium ion with a 3-O-trichloroacetimidoyl group.
Interaction between a 4-O-axial acetyl group and the
C(2)-OTf of a methyl β-D-galactoside derivative, followed
by transfer of an Ac group to 2-C with inversion of
configuration, has been evidenced in the synthesis of a
methyl β-D-taloside derivative.22 Displacement of a C(2)-
OTf through the participation of a 3-O-Bn with formation
of a benzyloxiranium intermediate and subsequent migra-
tion of the OBn group to C(2), followed by an attack
of a nucleobase, to form the isonucleoside analogues,
has recently been reported by our laboratory.25 However,
participation of 5-O-benzyl, -allyl, -crotyl and -propargyl
groups in the displacement of leaving groups, as well as
their migration to different sites, is not known in the
literature. We now report such an unusual event in the
displacement of a C(2)-O-triflate. The concomitant 1,4-
migration of the allyloxy and propargyloxy groups allows
generation of C(5)-nucleosides and other novel sugar
derivatives using various nucleophiles.
Scheme 2. Participation of β-C(5)-Benzyloxy Group
was obtained. Thus, treatment of 5 (derived via crotylation
of 3-O-methyl-1,2-O-isopropylidene-R-D-xylofuranose27
with crotyl bromide/NaH) with allyltrimethylsilane in
the presence of a Lewis acid produced the allylated com-
pound 6 (Scheme 3). Attempted nucleosidation and phtha-
limideinsertion atC(2) of the triflateester of6 alsofailedto
occur. In each of these cases, the dioxabicycle derivative 7
was obtained instead. The same product was also obtained
from the ester by heating at reflux in DMF.
Scheme 3. Participation of Crotyloxy Group to Generate 7
As a part of a program on the synthesis of isonucleosides,
we planned the SN2 attack of a purine base nucleophile
on the O-triflate ester of a 1-deoxy-2-hydroxyfuranoside
derivative carrying a 4-CH2OBn group. Surprisingly, we
observed the formation of dioxabicyclo[2.2.1]heptane deri-
vatives through participation of the C(5)ÀOÀBn group
and loss of Bn. Thus the D-glucose-based tetrahydro-
furan derivative 1,26 after triflate formation, reacted with
6-chloropurine in DMF to afford the bicyclic compound 2
(Scheme 1). Indeed, the reaction carried out in DMF alone
at 110À120 °C, without the addition of 6-chloropurine,
furnished the same product in very good yield. However,
participation of the 3-O-Bn in the present case was not
observed.
An analogous result was obtained when the triflate deri-
vative of 326 was heated in DMF. This afforded (Scheme 2)
the dioxabicycloheptane derivative 4 through the participa-
tion of a β-benzyloxymethyl group at C(5) (anti-attack).
With a compound having a crotyloxy group at C(5) and
C-allyl functionality at the C(1) position, a similar result
The results shown in Schemes 1À3 revealed that parti-
cipation ofthe C(5)-benzyloxy and -crotyloxymoietieshad
occurred, leading to the formation of a dioxabicyclo-
[2.2.1]heptane ring in the cyclized products 2, 4, and 7.
However, the presence of an allyloxy substituent in the
same position of 9 produced a different outcome. Com-
pound 8, prepared via allylation of the corresponding
hydroxyl derivative,28 gave the C(1) allylated derivative 9
in excellent yield when treated with allyltrimethylsilane
€
(22) Dong, H.; Pei, Z.; Angelin, M.; Bystrom, S.; Ramstrom, O.
€
and BF3 OEt2 in CH2Cl2 for 3 h (Scheme 4). When the
hydroxy group of 9 was activated as a triflate, and the
J. Org. Chem. 2007, 72, 3694–3701.
3
(23) Crich, D.; Hu, T.; Cai, F. J. Org. Chem. 2008, 73, 8942–8953.
(24) Baek, J. Y.; Lee, B.-Y.; Jo, M. G.; Kim, K. S. J. Am. Chem. Soc.
2009, 131, 17705–17713.
ꢀ
ꢀ
(27) Boto, A.; Hernandez, D.; Hernandez, R.; Suarez, E. J. Org.
ꢀ
(25) Ghosh, R.; Maity, J. K.; Achari, B.; Mandal, S. B. J. Org. Chem.
2010, 75, 2419–2422.
Chem. 2006, 71, 1938–1948.
(26) Mukherjee, S.; Roy, B. G.; Das, S. N.; Mandal, S. B. Tetrahedron
Lett. 2012, 53, DOI: 10.1016/j.tetlet.2012.06.121.
(28) Srihari, P.; Kumaraswamy, B.; Bhunia, D. C.; Yadav, J. S.
Tetrahedron Lett. 2010, 51, 2903–2905.
Org. Lett., Vol. 14, No. 16, 2012
4187

Scheme 5. Synthesis of 5-C-Substituted Nucleoside and Other
Sugar Derivatives
Figure 1. Mechanism for migration of allyloxy group.
Scheme 4. Synthesis of 5-C Nucleoside via Participation and
Migration of Allyloxy Moiety
Scheme 6. Migration of Propargyloxy Group to 2-C
product was subjected to nucleosidation using 6-chloro-
purine and a crown-ether, in DMF at reflux, the C(5)-
nucleoside 10 was obtained. It is interesting to note that the
6-chloro group was replaced by a dimethylamino function-
ality during this transformation. This can be attributed to
the generation of dimethylamine from DMF under reflux
conditions, as previously observed by us.29 The formation
of 10 is due to formation of an allyloxonium ion inter-
mediate (Figure 1), generated through participation of the
allyloxy group during the displacement of the substituent
at C(2) of the sugar moiety; this then suffered subsequent
attack by the purine base at C(5), leading to migration of
the allyloxygroup tothe C(2) position. The structure of the
product 10 was conclusively proved by 2D NMR and mass
spectral analyses. The signals for the ipso protons for the
carbon carrying the heterocyclic ring were easily identified
through their characteristic HMBC correlations with 4-C
and 8-C atoms of the purine ring.
Similarly, use of various other nucleophiles such as
acetyloxy, formyloxy, fluoride, phthalimidyl, and tritylated
thymidinyl anions produced the corresponding C(5) sub-
stituted sugar derivatives. The 5-O-allyl sugar derivative
13, derived from 3-O-methyl-1,2-O-isopropylidene-R-D-
xylofuranose,27 via allylation of the hydroxyl group, was
C-allylated at C(1) using allyltrimethylsilane in the presence
of boron trifluoride etherate to produce 14 (Scheme 5).
When the intermediate triflate derivative 15 was treated
with sodium acetate in DMF at reflux, it furnished 16a.
In like fashion, treatment of 15 with sodium formate,
tetrabutylammonium fluoride, and potassiophthalimide
gave the corresponding coupling products 16bÀ16d. Most
interestingly, the thymidine base was successfully intro-
duced at C(5) of the sugar moiety using tritylated thymidine
in DMF in the presence of sodium hydride, affording 16e.
We next shifted our focus to the 5-O-propargyl sugar
18 to see whether this group could participate to pro-
duce the corresponding nucleoside with 6-chloropurine.
Ring-closing metathesis reaction of 10 using Grubbs
catalyst (2nd generation) afforded the desired cyclized
product 11, proving the migration of the allyloxy group
to C(2) of the furanoside. The olefin moiety could be
reduced by hydrogenation to provide the bicyclic nucleo-
side analogue 12 (Scheme 4).
(29) Roy, A.; Chakrabarty, K.; Dutta, P. K.; Bar, N. C.; Basu, N.;
Achari, B.; Mandal, S. B. J. Org. Chem. 1999, 64, 2304–2309.
4188
Org. Lett., Vol. 14, No. 16, 2012

with propargyl bromide (Scheme 6), was converted to
the C(1)-allyl sugar derivative 18. Treatment of 18 with
triflic anhydride/pyridine afforded the triflate intermedi-
ate, which subsequently furnished the nucleoside analogue
19following participation of the propargyloxymoiety, and
subsequent nucleophilic attack by the nucleobase. Repla-
cement of the chloro group by dimethylamine was again
observed in the product.
Table 1. Formation of Cyclized and Coupling Products
The yields of the cyclized and coupled products, under
different reaction conditions, have been summarized in
Table 1.
In conclusion, the work described herein documents an
unusual remote participation of 5-O-allyl and -propargyl
moieties during the displacement of a leaving group of
1-deoxy-xylofuranose sugar derivatives, followed by at-
tack of nucleophiles at C(5), and migration of the partici-
pating groups to C(2), to afford 5-C-nucleoside analogues
and other sugar derivatives. Similar participation and
migration could provide a method for the synthesis of
targeted sugar molecules. Use of 5-O-Bn or -O-crotyl
derivatives, however, ended with loss of the O-alkyl groups
from the oxonium ion intermediates, furnishing dioxabi-
cycloheptanederivatives. The allyl/propargyl groups differ
in their reactivity from benzyl/crotyl groups. We believe
that the greater stability of the carbocations derived from
the latter permits elimination of the corresponding alkyl
groups before attack by the nucleophile at 5-C.
cyclized coupling
product product
(yield %)a (yield %)a,b
entry substrate
conditions
1
1
6-chloropurine, NaH,
DMF, 110À120 °C, 12 h
DMF, 110À120 °C, 12 h
potassium phthalimide,
DMF, reflux, 12 h
2 (73)
À
2
3
3
6
4 (76)
7 (65)
À
À
4
9
6-chloropurine, K2CO3,
18-crown-6, DMF,
reflux, 14 h
À
10 (48)
5
6
14
14
NaOAc, DMF,
À
À
16a (51)
16b (62)
15-crown-5, reflux, 12 h
NaOCHO, DMF,
reflux, 10 h
7
8
14
14
TBAF, DMF, reflux, 16 h
potassium phthalimide,
DMF, reflux, 12 h
À
À
16c (50)
16d (60)
Acknowledgment. The authors thank CSIR, Govt. of
India for providing a Senior Research Fellowship (to
S.M.). We also thank B. Achari, ex-emeritus scientist of
the institute, for giving helpful suggestions.
9
14
18
tritylated thymidine,
NaH, DMF, reflux, 11 h
6-chloropurine, K2CO3,
18-crown-6, DMF,
reflux, 14 h
À
À
16e (48)
19 (51)
10
Supporting Information Available. Experimental pro-
C
cedures for compounds 2, 4À14, 16À19; their 1H and 13
a Product yields after purification. b Recovered starting material
NMR spectra including HSQC and HMBC spectra of 10
and 16d. This material is available free of charges via the
Internet at http://pubs.acs.org.
(8À10%) in each case.
To this end, the precursor 17, obtained from 3-O-benzyl-
1,2-O-isopropylidene-R-D-xylofuranose28 by treatment
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 16, 2012
4189