Sequential alkoxy radical fragmentation-intermolecular allylation in carbohydrate systems

Article abstract of DOI:10.1016/S0040-4039(02)00911-5

The C-radical originated by β-fragmentation of carbohydrate anomeric alkoxy radicals, generated under reductive conditions by treatment of N-phthalimido glycosides with allyltri-n-butyltin/AIBN, may subsequently undergo an intermolecular allylation to giv

Full text of DOI:10.1016/S0040-4039(02)00911-5

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 4781–4784
Sequential alkoxy radical fragmentation–intermolecular allylation
in carbohydrate systems
Angeles Mart´ın, Ine´s Pe´rez-Mart´ın and Ernesto Sua´rez*
Instituto de Productos Naturales y Agrobiolog´ıa del CSIC, Carretera de La Esperanza 3, 38206 La Laguna, Tenerife, Spain
Received 25 March 2002; revised 3 May 2002; accepted 13 May 2002
Abstract—The C-radical originated by b-fragmentation of carbohydrate anomeric alkoxy radicals, generated under reductive
conditions by treatment of N-phthalimido glycosides with allyltri-n-butyltin/AIBN, may subsequently undergo an intermolecular
allylation to give hept-1-enitol derivatives. These compounds can be useful chiral synthons for the synthesis of polyhydroxylated
compounds. © 2002 Elsevier Science Ltd. All rights reserved.
In previous papers from this laboratory we have
described the oxidative b-fragmentation of glycopyran-
1-O-yl and glycofuran-1-O-yl radicals to give C2 radi-
cals. Weak electron-withdrawing groups (e.g. ethers)
bonded to C2 favour the oxidation of the C-radical (I)
to an oxycarbenium ion, and the final products are
derived by nucleophilic attack onto this ion.1 On the
other hand, stronger EWG (e.g. esters) inhibit the
oxidation step and a-iodoalkyl esters (II) were obtained
by radical addition to iodine atoms present in the
reaction medium (Scheme 1, path [a]).2 Radical inter-
molecular allylation of these compounds following the
Keck and Yates procedure gave 1,2,3-trideoxy-hept-1-
enitols (III).3
in a single step (Scheme 1, path [b]). Furthermore, the
alkoxy radical fragmentation (ARF) reaction should
give access to nucleophilic or electrophilic C-radicals at
will only by changing the protective group at C2.
Serial radical reactions where the C-radical formed
initially by an intramolecular cyclisation, subsequently
undergo intermolecular radical additions to allyltri-n-
butyltin have been described previously.4 The use of
C-radicals originated by ARF reaction in intramolecu-
lar addition to olefins has also been reported.5
We have used the initial fragmentation of a N-hydroxy-
phthalimide derivative to generate the alkoxy radical
and allyltri-n-butyltin as radical trap in the conditions
summarised in Table 1.6 N-Phthalimido glycosides were
prepared by reaction of the hemiacetal alcohol with
N-hydroxyphthalimide under Mitsunobu conditions.7
With these results in mind, we reasoned that generating
the alkoxy radicals under reductive conditions both
reactions, fragmentation and allylation, can be realised
Scheme 1. Reagents: (a) PhI(OAc)2, I2; (b) allyltri-n-butyltin, AIBN. NPht-=N-phthalimido group.
* Corresponding author. Fax: 34-922-260135; e-mail: esuarez@ipna.csic.es
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)00911-5

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A. Mart´ın et al. / Tetrahedron Letters 43 (2002) 4781–4784
Table 1. Sequential alkoxy radical fragmentation–intermolecular allylation reactiona
The phthalimide derivative of 2,3-O-isopropylidene-
ribofuranose 16 gave 1,2,3-trideoxy-4,5-O-isopropyli-
dene-
-arabino-hept-1-enitol 38 in moderate yield but
D
-
cally less stable cis-isomer was obtained (dr approxi-
mately 9:1).
D
with total diastereoselectivity (vide infra); only the trans
substituted dioxolane ring could be detected in the
reaction mixture (entry 1).
The C4 stereochemistry in compounds 3, 4 and 6 was
determined with the aid of NOESY spectra. The strong
NOE correlation between H-C4 and H-C5 in 6-cis
suggested a cis relative relationship of these g-lactone
ring protons. Moreover, no NOE interactions were
observed between these two protons in compounds 3, 4
and 6-trans where they are in a trans relationship.
The carbonate 26 was prepared in order to study the
effect of a stronger electron-withdrawing group at C2
that should decrease the electron density at this posi-
tion (entry 2). This should increase the electrophilic
character of the C2-radical and a faster reaction with
an electron-rich alkene such as allyltri-n-butyltin is
expected. A significantly better yield of the addition
product 48 is obtained as compared to the fragmenta-
tion of the 2,3-O-isopropylidene 1 (entry 1). The reac-
tion also occurs with total trans diastereoselectivity.
This methodology was also extended to the fragmenta-
tion of a carbohydrate of the pentose series in pyranose
form. The N-phthalimide glycoside of the D-arabinopy-
ranose derivative 7 gave the 1,2,3-trideoxyhept-1-enitol
88 as an almost equimolecular diastereoisomeric mix-
ture (dr 55:45). It was found that the isomers could be
more readily chromatographically separated after
hydrolysis of the formate group and hence both pri-
mary alcohols 11 and 128 were independently character-
ised (Scheme 2). The stereochemistry at C4 was
The ARF reaction of g-lactone 59 exhibited a similar
behaviour as the carbonate 2, although, apart from the
expected trans-isomer 6,8 a small amount of the steri-

A. Mart´ın et al. / Tetrahedron Letters 43 (2002) 4781–4784
4783
Acknowledgements
This work was supported by the Investigation Pro-
grammes No. BQU2000-0650 and BQU2001-1665 of
the Direccio´n General de Investigacio´n Cient´ıfica y
Te´cnica, Spain. I.P.-M. thanks the I3P-CSIC Pro-
gramme for a fellowship.
References
1. (a) Francisco, C. G.; Freire, R.; Gonza´lez, C.; Leo´n, E.
I.; Riesco-Fagundo, C.; Sua´rez, E. J. Org. Chem. 2001,
66, 1861–1866; (b) Francisco, C. G.; Gonza´lez, C.;
Sua´rez, E. J. Org. Chem. 1998, 63, 2099–2109; (c) Armas,
P.; Francisco, C. G.; Sua´rez, E. J. Am. Chem. Soc. 1993,
115, 8865–8866.
2. (a) Francisco, C. G.; Gonza´lez, C.; Sua´rez, E. J. Org.
Chem. 1998, 63, 8092–8093; (b) Gonza´lez, C. C.;
Kennedy, A. R.; Leo´n, E. I.; Riesco-Fagundo, C.; Sua´rez,
E. Angew. Chem., Int. Ed. 2001, 40, 2326–2328.
3. (a) Keck, G. E.; Yates, J. B. J. Am. Chem. Soc. 1982, 104,
5829–5831; (b) Keck, G. E.; Enholm, E. J.; Wiley, M. R.;
Yates, J. B. Tetrahedron 1985, 41, 4079–4094.
4. (a) Rosenstein, I. J. In Radicals in Organic Synthesis;
Renaud, P.; Sibi, M. P., Eds. Radical fragmentation
reactions. Wiley-VCH: Weinheim, 2001; Vol. 1, pp. 50–
71; (b) Pearce, A. J.; Mallet, J.-M.; Sinay¨, P. In Radicals
in Organic Synthesis; Renaud, P.; Sibi, M. P., Eds. Radi-
cals in carbohydrate chemistry. Wiley-VCH: Weinheim,
2001; Vol. 2, pp. 538–577; (c) Ferrier, R. J.; Petersen, P.
M.; Taylor, M. A. J. Chem. Soc., Chem. Commun. 1989,
1247–1248; (d) Lo´pez, J. C.; Go´mez, A. M.; Fraser-Reid,
B. J. Org. Chem. 1995, 60, 3871–3878.
5. (a) Mowbray, C. E.; Pattenden, G. Tetrahedron Lett.
1993, 34, 127–130; (b) Batsanov, A. S.; Begley, M. J.;
Fletcher, R. J.; Murphy, J. A.; Sherburn, M. S. J. Chem.
Soc., Perkin Trans. 1 1995, 1281–1294; (c) Herna´ndez, R.;
Marrero, J. J.; Sua´rez, E. Tetrahedron Lett. 1989, 30,
5501–5504.
Scheme 2. Reagents and conditions: (a) MeOH, reflux, 24 h;
(b) Ac2O, Py, rt, 18 h then n-Bu4NF, THF, rt, 18 h; (c)
(S)-MPA acid, DCC, DMAP, CH2Cl2, rt, 26 h; (d) (R)-
MPA acid, DCC, DMAP, CH2Cl2, rt, 16 h.
determined by conversion of the major isomer 11 into
the secondary alcohol 13 and then by treatment with
both (S)-(−)- and (R)-(+)-a-methoxyphenylacetic acid
(MPA) under standard esterification conditions to the
Mosher esters 14 and 15, respectively.10
The reaction of the phthalimido derivative of the a-D-
xylo-pentodialdo 96 gave a volatile alcohol which was
treated in situ with imidazole and tert-butyldimethylsil-
yl chloride to give 3-O-[tert-butyl(dimethyl)silyl]-5,6,7-
trideoxy-1,2-O-isopropylidene-b-L-arabino-hept-6-enofu-
ranose8 (10) in order not to lose material during the
work-up and purification steps. The coupling constant
J
3,4=0 Hz and the NOE interaction between H-C3
and H-C5 are consistent with the assigned (4S)-stereo-
chemistry for the major isomer. On the other hand, a
J3,4=2.5 Hz and a NOE interaction of H-C1 with
both protons at C-5 suggest a (4R)-stereochemistry for
the minor diastereoisomer.
6. Francisco, C. G.; Leo´n, E. I.; Martin, A.; Moreno, P.;
Rodr´ıguez, M. S.; Sua´rez, E. J. Org. Chem. 2001, 66,
6967–6976.
7. (a) Mitsunobu, O. Synthesis 1981, 1–28; (b) Grochowski,
E.; Jurczak, J. Synthesis 1976, 682–684.
No evidence of side-products derived from the O- and
C2-radical intermediates were observed in reactions
described in entries 1–4. Notwithstanding a small
amount (7%) of 3-O-(tert-butyldimethylsilyl)-1,2-O-
8. All new compounds gave correct elemental analysis.
1
Compound 3: oil; [h]D +12.0 (CHCl3, c=0.31); H NMR
isopropylidene-b-L
-threofuranose,6 probably arising
(CDCl3, 500 MHz) 0.04 (6H, s), 0.86 (9H, s), 1.36 (3H, s),
1.38 (3H, s), 2.30 (1H, ddd, J=14.6, 7.2, 7.2 Hz), 2.44
(1H, m), 3.74 (1H, dd, J=11.3, 5.9 Hz), 3.86 (1H, dd,
J=7.1, 6.6 Hz), 3.88 (1H, dd, J=11.3, 3.9 Hz), 4.05 (1H,
ddd, J=7.4, 7.4, 4.1 Hz), 5.03 (1H, ddd, J=5.9, 5.9, 4.0
Hz), 5.06–5.13 (2H, m), 5.83 (1H, dddd, J=17.2, 10.2,
7.0, 7.0 Hz), 8.10 (1H, s); 13C NMR (CDCl3, 50.3 MHz)
−5.5 (2×), 18.1, 25.7 (3×), 26.8, 27.2, 37.6, 61.7, 74.4,
76.9, 77.9, 109.2, 117.7, 133.5, 160.2. Compound 6-cis:
from intermolecular hydrogen abstraction of the C4-
radical intermediate, was obtained in the reaction of
N-phthalimido derivative 9 (Entry 5).
This methodology may be useful for the synthesis of
chiral synthons. For example, as can be observed from
Table 1 (entries 1, 2 and 4, 5) a number of 1,2,3-
trideoxyhept-1-enitol derivatives possessing different
patterns of protection and stereochemistries have been
synthesised from readily accessible carbohydrates.
Using the rich sugar chemistry available, the carbohy-
drate skeleton can also be conveniently modified to
afford the required synthetic intermediate (e.g. entry
3).
1
oil; [h]D −31.7 (CHCl3, c=0.40); H NMR (CDCl3, 500
MHz) 1.06 (9H, s), 2.19–2.30 (2H, m), 2.29 (1H, dd,
J=17.5, 12.0 Hz), 2.46 (1H, dd, J=17.6, 8.8 Hz), 3.26
(1H, m), 3.67 (1H, dd, J=11.5, 3.7 Hz), 3.84 (1H, dd,
J=12.0, 3.2 Hz), 4.65 (1H, ddd, J=8.3, 8.3, 3.7 Hz), 5.07
(1H, ddd, J=10.6, 3.2, 3.2 Hz), 5.14 (1H, d, J=9.2 Hz),

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A. Mart´ın et al. / Tetrahedron Letters 43 (2002) 4781–4784
5.15 (1H, dd, J=17.6, 0.9 Hz), 5.79 (1H, dddd, J=17.1,
(2H, m), 2.96 (1H, dd, J=7.0, 7.0 Hz, OH), 3.56 (1H,
ddd, J=11.7, 6.5, 6.4 Hz), 3.71 (1H, ddd, J=11.7, 6.6,
6.6 Hz), 4.05 (1H, dd, J=5.4, 4.7 Hz), 4.14 (1H, ddd,
J=6.2, 6.0, 4.6 Hz), 4.17 (1H, ddd, J=6.2, 6.2, 5.7 Hz),
5.08–5.14 (2H, m), 5.81 (1H, dddd, J=17.3, 10.2, 7.2,
7.2 Hz); 13C NMR (CDCl3, 50.3 MHz) −4.6, −4.5, 18.0,
25.6, 25.7 (3×), 28.0, 39.3, 61.6, 70.4, 77.0, 78.1, 107.5,
118.0, 133.5. Compound 12: oil; [h]D −28.6 (CHCl3,
10.2, 6.5, 6.5 Hz), 7.38–7.47 (6H, m), 7.60–7.63 (4H, m),
7.90 (1H, s); 13C NMR (CDCl3, 125.7 MHz) 19.1, 26.7
(3×), 30.3, 34.5, 38.9, 63.8, 72.6, 80.2, 119.1, 127.8 (2×),
127.9 (2×), 130.0 (2×), 132.1, 132.4, 132.5, 135.4 (2×),
135.5 (2×), 159.8, 174.8. Compound 6-trans: oil; [h]D
−9.9 (CHCl3, c=0.60); 1H NMR (CDCl3, 500 MHz)
1.06 (9H, s), 2.29 (1H, dd, J=17.8, 7.2 Hz), 2.36 (1H,
ddd, J=13.8, 6.4, 6.4 Hz), 2.54 (1H, m), 2.63 (1H, dd,
J=18.0, 9.7 Hz), 2.80 (1H, m), 3.72 (1H, dd, J=11.5,
4.6 Hz), 3.75 (1H, dd, J=11.6, 4.7 Hz), 4.48 (1H, ddd,
J=6.0, 6.0, 6.0 Hz), 5.04 (1H, ddd, J=6.9, 4.6, 4.6 Hz),
5.16 (1H, dd, J=8.7, 1.3 Hz), 5.17 (1H, dd, J=17.1, 1.3
Hz), 5.78 (1H, dddd, J=17.1, 10.6, 6.9, 6.9 Hz), 7.39–
7.46 (6H, m), 7.61–7.64 (4H, m), 8.00 (1H, s); 13C NMR
(CDCl3, 125.7 MHz) 19.1, 26.7 (3×), 31.4, 38.9, 39.3,
63.0, 74.7, 80.9, 119.5, 127.9 (4×), 130.1 (2×), 131.7,
132.4 (2×), 135.4 (2×), 135.5 (2×), 160.0, 175.0. Com-
1
c=0.71); H NMR (CDCl3, 500 MHz) 0.07 (3H, s), 0.08
(3H, s), 0.89 (9H, s), 1.35 (3H, s), 1.47 (3H, s), 2.18 (1H,
ddd, J=14.6, 7.4, 7.4 Hz), 2.30–2.38 (2H, m), 3.64 (2H,
dd, J=6.2, 5.5 Hz), 3.84 (1H, ddd, J=7.7, 7.7, 3.6 Hz),
4.07 (1H, dd, J=7.9, 5.9 Hz), 4.15 (1H, ddd, J=6.5,
5.8, 5.8 Hz), 5.07 (1H, br d, J=10.3 Hz), 5.08 (1H, br
d, J=16.8 Hz), 5.84 (1H, dddd, J=17.1, 10.3, 7.2, 7.2
Hz); 13C NMR (CDCl3, 125.7 MHz) −4.7, −4.3, 18.2,
25.3, 25.8 (3×), 27.9, 38.8, 61.5, 70.7, 77.1, 79.6, 108.2,
117.3, 134.6.
1
9. Glucose was converted into 5-O-(tert-butyldimethylsil-
yl)-3-deoxy-3-[(ethoxycarbonyl)methylene]-1,2- O-iso-
pound 10-a: oil; [h]D −26.0 (CHCl3, c=1.23); H NMR
(CDCl3, 500 MHz) 1.08 (9H, s), 1.26 (3H, s), 1.45 (3H,
s), 1.98 (1H, ddd, J=14.2, 7.0, 7.0 Hz), 2.25 (1H, ddd,
J=14.3, 8.0, 6.3 Hz), 3.96 (1H, dd, J=7.8, 7.0 Hz), 4.15
(1H, s), 4.52 (1H, d, J=3.8 Hz), 4.83–4.87 (2H, m), 5.42
(1H, dddd, J=17.1, 10.4, 7.1, 7.1 Hz), 5.95 (1H, d,
J=3.8 Hz), 7.37–7.45 (6H, m), 7.62–7.66 (4H, m); 13C
NMR (CDCl3, 125.7 MHz) 19.1, 26.0, 26.7, 26.9 (3×),
38.0, 78.9, 87.0, 88.3, 105.9, 112.1, 117.1, 127.7 (2×),
127.8 (2×), 129.9 (2×), 133.0, 133.1, 134.2, 137.8 (4×).
Compound 10-b: oil; [h]D −11 (CHCl3, c=0.38); 1H
NMR (CDCl3, 500 MHz) 1.09 (9H, s), 1.12 (3H, s), 1.39
(3H, s), 2.33 (1H, ddd, J=14.6, 6.2, 6.2 Hz), 2.54 (1H,
ddd, J=14.7, 7.4, 7.4 Hz), 4.10 (1H, ddd, J=8.0, 5.7,
2.5 Hz), 4.21 (1H, d, J=2.5 Hz), 4.26 (1H, d, J=3.8
Hz), 5.04 (1H, dd, J=10.2, 0.8 Hz), 5.09 (1H, dd, J=
17.2, 1.5 Hz), 5.80 (1H, dddd, J=17.0, 10.2, 6.7, 6.7
Hz), 5.83 (1H, d, J=3.9 Hz), 7.39–7.46 (6H, m), 7.63–
7.69 (4H, m); 13C NMR (CDCl3, 125.7 MHz) 19.5, 26.0,
26.6, 26.9 (3×), 32.8, 77.2, 80.7, 84.7, 104.4, 111.1, 116.8,
127.8 (4×), 129.9, 130.0, 132.7, 133.8, 134.8, 135.7 (2×),
135.8 (2×). Compound 11: oil; [h]D −46.2 (CHCl3, c=
0.76); 1H NMR (CDCl3, 500 MHz) 0.12 (3H, s), 0.14
(3H, s), 0.90 (9H, s), 1.32 (3H, s), 1.44 (3H, s), 2.39–2.43
propylidene-a-D-erythro-pentofuranose ((a) Xie, M.;
Berges, D. A.; Robins, M. J. J. Org. Chem. 1996, 61,
5178–5179; (b) Robins, M. J.; Doboszewski, B.; Timo-
shchuk, V. A.; Peterson, M. A. J. Org. Chem. 2000, 65,
2939–2945; (c) Lourens, G. J.; Koekemoer, J. M. Tetra-
hedron Lett. 1975, 16, 3719–3722), which was subse-
quently hydrogenated (Pd/C, EtOH, rt, 4 h), hydrolysed
(TFA/H2O, 3:7, rt, 72 h), silylated (TBDPSCl, imida-
zole, DMF, 0°C, 30 min, 40% three steps), and treated
with N-hydroxyphthalimide under Mitsunobu conditions
(89%) to give compound 5.
10. The S configuration at C-4 was assigned on the basis of
Dl=(lR−lS)×103 calculated by the 1H NMR and
COSY spectra of 14 and 15 [Dl >0 for protons C1
through C3 (+364 to +120) and Dl <0 for protons C-5
to C-7 (−72 to −421)]. See: (a) Latypov, Sh. K.; Seco, J.
M.; Quin˜oa´, E.; Riguera, R. J. Org. Chem. 1996, 61,
8569–8577. For the determination of the absolute
configuration of a related homoallylic alcohol, see: (b)
Mohapatra, D. K.; Datta, A. J. Org. Chem. 1998, 63,
642–646; (c) Ling, R.; Yoshida, M.; Mariano, P. S. J.
Org. Chem. 1996, 61, 4439–4449.