Stereoselective synthesis of substituted exo-glycals from 1-exo-methylene pyranoses

Article abstract of DOI:10.1016/S0040-4039(03)01455-2

Halo-exo-glycals of the gluco-, manno- and galacto- series, readily prepared by reaction of 1-exo-methylene pyranoses with iodonium dicollidinium triflate (IDCT), undergo Suzuki or B-alkyl Suzuki cross-coupling reactions with boronic acids or alkyl borane

Full text of DOI:10.1016/S0040-4039(03)01455-2

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 6111–6116
Stereoselective synthesis of substituted exo-glycals from
1-exo-methylene pyranoses
Ana M. Go´mez,* Ana Pedregosa, Seraf´ın Valverde and J. Cristo´bal Lo´pez*
Instituto de Qu´ımica Orga´nica General, CSIC, Juan de la Cierva 3, 28006 Madrid, Spain
Received 14 April 2003; revised 9 June 2003; accepted 9 June 2003
Abstract—Halo-exo-glycals of the gluco-, manno- and galacto- series, readily prepared by reaction of 1-exo-methylene pyranoses
with iodonium dicollidinium triflate (IDCT), undergo Suzuki or B-alkyl Suzuki cross-coupling reactions with boronic acids or
alkyl boranes to yield, in a stereoselective manner, functionalized exo-glycals.
© 2003 Elsevier Ltd. All rights reserved.
1-exo-Methylene pyranoses (2,6-anhydro-1-deoxyhept-
1-enitols), currently known as exo-glycals, 1,1–3 are
interesting compounds from a biological and from a
synthetic standpoint (Scheme 1). They have been used as
glycosidase inhibitors,4 and have proven to be valuable
synthetic intermediates owing to the versatility supplied
by the enol ether double bond for further elaboration.5–15
The first methods for the preparation of exo-glycals had
focused on the methylenation of the corresponding
lactones using the Tebbe, or Petasis, reagents.1,2,16 Very
recently, To´th and Somsa´k17 have described a novel
method for the preparation of 1. However, the prepara-
tion of substituted exo-glycals, 2, also of considerable
interest, has only been addressed recently. Contributions
in this area include: Wittig olefination of glycosyl
phosponium salts18 or sugar lactones,19 Keck reaction of
glycosyl dihalides,20 [2,3]-Wittig sigmatropic rearrange-
ment,21 nucleophilic addition to sugar lactones followed
by elimination22 and Ramberg–Ba¨cklund rearrangement
of S-glycosides.23,24 The latter approach, reported inde-
pendently by the groups of Taylor23 and Franck,24 is the
most general in terms of scope.23b
In this context, we have reported two methods for the
preparation of substituted furanosidic exo-glycals (2,5-
anhydro-1-deoxyhex-1-enitols),25,26 and in this Letter,
we report on the extension of one of these strategies26
for the stereoselective preparation of pyranosidic exo-
glycals.
The approach is based on the stereoselective iodination
of exo-glycals with IDCT (iodonium dicollidinium tri-
flate),27 followed by Suzuki,28 or B-alkyl Suzuki29 cross-
coupling reaction of the ensuing halo-glycals, 3, with
boronic acids or alkyl boranes, respectively (Scheme 2).
We illustrate the potential of the method with the
preparation of substituted exo-glycals derived from
gluco-, -manno- and -galactopyranose.
D-
D
D
Accordingly, methylenation of lactones 4–6,30 with the
Petasis reagent,31 generated exo-glycals, 7,2,32 8,16b 9,33
which upon treatment with IDCT27 yielded halo-exo-
glycals 10,6 11, and 12 (Scheme 3).
In order to evaluate the scope of the synthetic method
we chose diethyl borane, 13, and boronic acids 14–16
(Fig. 1) as coupling partners for the halo-exo-glycals
Scheme 1. exo-Glycal (1) and substituted exo-glycal (2).
Scheme 2. General strategy for the preparation of substituted
exo-glycals from 1-exo-methylene pyranoses.
* Corresponding author. Tel.: +34-91-5622900; fax: +34-91-5644853;
e-mail: anago@iqog.csic.es; clopez@iqog.csic.es
0040-4039/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)01455-2

6112
A. M. Go´mez et al. / Tetrahedron Letters 44 (2003) 6111–6116
terms of yields, and significant differences in reaction
times depending on the reaction conditions employed.
The use of KF as a base, as recommended by Fu and
co-workers,34 resulted in higher yields and reduced
reaction times (compare entries vii and viii; ix and x;
xii, xiii and xiv; xvii and xviii, Table 1).
The stereochemistry at the terminal position of the
exocyclic double bond was assigned as (Z-) for com-
pounds 17, 18, 19 and 21 on the basis of observed
NOEs between the vinylic protons (1-H) and the 3-H
protons and assumed, by analogy, to be the same for
the rest of the compounds. This assignment is in agree-
ment with mechanistic considerations on the preferred
formation of a (Z)-iodide isomer (Scheme 4), and with
the fact that Suzuki cross-coupling reactions take place
with retention of the configuration.28
Thus, formation of (Z)-halo-exo-glycals is considered
to proceed via an intermediary oxonium ion. Accord-
ingly, the in-situ released sym-collidine would abstract
a proton from a 1-iodomethyloxocarbenium ion to
generate the iodo-exo-glycal. The deprotonation would
take place from a preferred conformer (A, Scheme 4)
which has a CꢀH bond antiperiplanar to the p-orbitals
of the oxocarbenium and that would place the bulky
iodine atom away from the benzyl substituent at C-2.22c
Scheme 3. Synthesis of halo-exo-glycals, 10–12, from lac-
tones, 4–6, by methylenation and halogenation. Reagents and
conditions: (i) Cp2TiMe2 (Petasis reagent), toluene; (ii) IDCT,
CH2Cl2.
In summary, we have disclosed a novel synthetic route
that permits the transformation of, readily available,
1-exo-methylene pyranoses into substituted (Z)-exo-
glycals through a synthetic sequence, which involves:
stereoselective halogenation with IDCT, followed by
Suzuki, or B-alkyl Suzuki, cross coupling reaction.35–37
The use of KF in the Suzuki cross coupling reaction
results in reduced reaction times and good to excellent
yields. Further synthetic transformation of the substi-
tuted exo-glycals are under study and will be reported
in due course.
Figure 1.
(10–12) in the B-alkyl- and Suzuki cross-coupling reac-
tions, respectively. Our results are displayed in Table 1.
The B-alkyl Suzuki cross-coupling reaction of alkyl
borane 13, with halo-exo-glycals 10–12, was carried out
with Pd(PPh3)4 in the presence of NaOH, in THF/H2O
(9:1), and afforded good yields of coupled products
(17–19) in short reaction times (entries i–iii, Table 1).
For the Suzuki cross-coupling reactions we evaluated
three different sets of experimental conditions (B, C,
and D, Table 1). We have found slight differences in
Scheme 4. Preferred formation of a (Z)-halo isomer.

A. M. Go´mez et al. / Tetrahedron Letters 44 (2003) 6111–6116
6113
Table 1.

6114
A. M. Go´mez et al. / Tetrahedron Letters 44 (2003) 6111–6116
15. Gallos, J. K.; Sarli, V. C.; Koftis, T. V.; Coutouli-Argy-
Acknowledgements
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16. (a) Ali, M. H.; Collins, P. M.; Overend, W. G. Carbo-
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Tetrahedron 1991, 47, 1655; (c) Audrechy, A.; Sinay¨, P. J.
Org. Chem. 1992, 57, 4142; (d) Faivre-Buet, V.; Eynard,
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Generous financial support from Janssen-Cilag is grate-
fully acknowledged. This research was supported with
funds from the Direccio´n General de Ensen˜anza Supe-
rior (Grants: PB96-0822, PB97-1244, PPQ2000-1330,
and BQU2001-0582). A.P. thanks Janssen-Cilag for
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6115
35. General procedure for the B-alkyl Suzuki cross-coupling
reaction: To a solution of the halo-exo-glycal (100 mg,
0.15 mmol) in THF/H2O (9:1) were added 2 M NaOH
solution (2.3 equiv.) and alkyl borane 13 (1.3 equiv.).
Argon was then bubbled through the solution for 10 min
and Pd(PPh3)4 (10%, 0.015 equiv.) was next added. The
reaction mixture was heated at reflux, under an argon
atmosphere, for the time indicated in Table 1. The reac-
tion mixture was then allowed to cool and extracted with
EtOAc. The organic layer was dried (anhydrous MgSO4),
filtered and concentrated. Flash chromatography of the
residue (hexane:EtOAc) furnished the corresponding sub-
stituted glycal.
36. General procedure for the Suzuki cross-coupling reaction:
To a solution of the halo-exo-glycal (75 mg, 0.11 mmol)
in THF were added the corresponding boronic acid (1.3
equiv.) and KF (3.3 equiv.). Argon was then bubbled
through the solution for 10 min, after which time
Pd(PPh3)4 (10%, 0.015 equiv.) was added. The reaction
mixture was heated at reflux, under argon, for the time
indicated in Table 1. Work-up as above then furnished
the expected glycals.
127.0 (×2), 127.3, 127.4, 127.5, 130.1, 134.5, 136.9, 137.2,
146.2, 148.9, 151.8. API-ES positive: 614.1 [MH]+. Anal.
calcd for C40H39NO5: C, 78.28; H, 6.40. Found: C, 78.49;
H, 6.58.
(Z)-2,6-Anhydro-3,4,5,7-tetra -O-benzyl-1-deoxy-1-(3-
thiophenyl)-D-gluco-hept-1-enitol (20). 67 mg (72%):
hD=+11.0 (CHCl3, c 0.3); 1H NMR (300 MHz, CDCl3) l
(ppm): 3.55–3.90 (m, 8H), 4.03 (d, 1H, J=5.6 Hz), 4.07–
4.12 (m, 1H), 4.53–4.85 (m, 9H), 5.85 (s, 1H), 7.17–7.39
(m, 22H), 7.56 (d, 1H, J=2.9 Hz); 13C NMR (75 MHz,
CDCl3) l (ppm): 69.3, 71.8, 73.4, 73.6, 74.0, 76.8, 77.9,
78.9, 84.6, 104.3, 122.8, 124.4, 127.7 (×2), 127.8 (×2),
127.9 (×2), 128.3, 128.4, 128.5, 128.7, 135.6, 137.8, 138.0,
138.1, 147.9. API-ES positive: 636 [M+H2O]+.
(Z)-2,6-Anhydro-3,4,5,7-tetra-O-benzyl-1-deoxy-1 -(3-
thiophenyl)-D-manno-hept-1-enitol (21). 64 mg (69%):
hD=+15.6 (CHCl3, c 0.3); 1H NMR (300 MHz, CDCl3) l
(ppm): 3.64 (dd, 1H, J=3.2, and 8.9 Hz), 3.67–3.85 (m,
3H), 3.99 (d, 1H, J=3.2 Hz), 4.02–4.11 (m, 1H), 4.32–
4.58 (m, 6H), 4.68 (d, 1H, J=12.6 Hz), 4.90 (d, 1H,
J=10.9 Hz), 5.61 (s, 1H), 7.06 (dd, 1H, J=2.9 and 4.9
Hz), 7.11–7.35 (m, 21H), 7.55 (dd, 1H, J=0.7 and 2.7
Hz); 13C NMR (75 MHz, CDCl3) l (ppm): 68.1, 69.0,
70.4, 72.3, 73.4 (×2), 74.2, 78.6, 80.7, 108.7, 123.0, 123.8,
126.6 (×2), 126.7 (×2), 126.8 (×2), 126.9, 127.2, 127.4,
127.7, 134.2, 137.0, 137.2, 137.3, 146.1. API-ES positive:
641 [M+Na]+.
37. Data for selected compounds:
(Z)-2,6-Anhydro-3,4,5,7-tetra -O-benzyl-1-deoxy-1-(3-
pyridyl)-D-gluco-hept-1-enitol (17). 74 mg (89%): hD=
+53.4 (CHCl3, c 1.1); 1H NMR (300 MHz, CDCl3) l
(ppm): 3.64–3.81 (m, 4H), 3.94–3.96 (m, 1H), 4.04–4.10
(m, 1H), 4.42–4.71 (m, 8H), 5.55 (s, 1H), 7.03 (dd, 1H,
J=4.8 and 8.0 Hz), 7.07–7.30 (m, 20H), 8.07 (ddd, 1H,
J=1.6, 2.0 and 8.0 Hz), 8.27 (dd, 1H, J=1.6 and 4.8 Hz),
8.56 (d, 1H, J=2.0 Hz); 13C NMR (75 MHz, CDCl3) l
(ppm): 69.2, 72.0, 73.6, 73.7, 74.2, 77.0, 77.9, 79.0, 84.3,
106.0, 123.4, 127.9, 128.0, 128.1 (×2), 128.2, 128.6, 128.7,
129.0 (×2), 131.4, 135.5, 137.8, 138.2 (×2), 147.3, 150.0,
151.5. API-ES positive: 614.1 [MH]+. Anal. calcd for
C40H39NO5: C, 78.28; H, 6.40. Found: C, 78.53; H, 6.61.
(Z)-2,6-Anhydro-3,4,5,7-tetra-O-benzyl-1-deoxy-1-(3-
(Z)-2,6-Anhydro-3,4,5,7-tetra -O-benzyl-1-deoxy-1-(3-
thiophenyl)-D-galacto-hept-1-enitol (22). 73.5 mg (79%):
hD=+13.0 (CHCl3, c 1.0); 1H NMR (300 MHz, CDCl3) l
(ppm): 3.57 (dd, 1H, J=4.5 and 9.9 Hz), 3.64 (dd, 1H,
J=2.7 and 8.2 Hz), 3.75 (dd, 1H, J=7.1 and 9.9 Hz),
3.90–4.01 (m, 2H), 4.30–4.38 (m, 3H), 4.53 (d, 1H, J=
11.5 Hz), 4.60–4.74 (m, 4H), 4.83 (d, 1H, J=11.5 Hz),
5.95 (s, 1H), 7.03 (dd, 1H, J=2.9 and 4.8 Hz), 7.16–7.31
(m, 21H), 7.47 (dd, 1H, J=1.0 and 2.9 Hz); 13C NMR
(75 MHz, CDCl3) l (ppm): 70.0, 73.5, 73.7, 73.8, 74.4,
75.0, 77.0, 78.8, 82.0, 106.1, 123.5, 124.7, 127.9, 128.0,
128.1, 128.2, 128.3, 128.4, 128.7, 128.8, 129.3, 136.1,
138.4, 138.5, 138.7, 138.8, 149.4. API-ES positive: 636.1
[M+H2O]+.
pyridyl)-D-manno-hept-1-enitol (18). 75 mg (82%): hD=
+17.5 (CHCl3, c 1.6); 1H NMR (300 MHz, CDCl3) l
(ppm): 3.75 (dd, 1H, J=3.2, and 8.8 Hz), 3.84 (m, 3H),
4.14 (d, 1H, J=3.2 Hz), 4.21 (dd, 1H, J=8.8 and 9.0
Hz), 4.60 (m, 6H), 4.80 (d, 1H, J=12.4 Hz), 4.97 (d, 1H,
J=10.9 Hz), 5.56 (s, 1H), 7.08 (dd, 1H, J=4.8 and 8.0
Hz), 7.32 (m, 20H), 8.28 (ddd, 1H, J=1.7, 1.9, and 8.0
Hz), 8.40 (dd, 1H, J=1.7 and 4.8 Hz), 8.62 (d, 1H,
J=1.9 Hz); 13C NMR (75 MHz, CDCl3) l (ppm): 70.0,
70.2, 72.0, 73.8, 74.6, 75.3, 75.4, 80.2, 81.0, 111.0, 123.8,
127.6, 128.0, 128.1, 128.2, 128.5, 128.8 (×2), 129.5, 131.0,
136.0, 138.2, 138.4, 138.6 (×2), 148.2, 150.3, 151.3. API-
ES positive: 614.1 [MH]+. Anal. calcd for C40H39NO5: C,
78.28; H, 6.40. Found: C, 78.47; H, 6.69.
(Z)-2,6-Anhydro-3,4,5,7-tetra-O-benzyl-1-deoxy-1-(p-
methoxyphenyl)-D-gluco-hept-1-enitol (23). 68.3 mg
(88%): hD=+73.5 (CHCl3, c 0.4); 1H NMR (200 MHz,
CDCl3) l (ppm): 3.68 (s, 3H), 3.69–3.94 (m, 5H), 4.43–
4.75 (m, 9H), 5.61 (s, 1H), 6.68 (d, 2H, J=8.9 Hz),
7.07–7.29 (m, 20H), 7.53 (d, 2H, J=8.9 Hz); 13C NMR
(75 MHz, CDCl3) l (ppm): 55.6, 69.7, 72.2, 73.8, 74.0,
74.5 (×2), 78.3, 79.7, 85.2, 109.4, 114.0, 128.0, 128.1,
128.2, 128.3 (×3), 128.7 (×2), 128.8, 128.9, 130.3, 138.3,
138.5, 138.6, 147.7, 158.5. API-ES positive: 660.3 [M+
H2O]+.
(Z)-2,6-Anhydro-3,4,5,7-tetra-O-benzyl-1-deoxy-1-(3-
pyridyl)-D-galacto-hept-1-enitol (19). 75 mg (77%): hD=
(Z)-2,6-Anhydro-3,4,5,7-tetra -O-benzyl-1-deoxy-1-(p-
methoxyphenyl)-D-manno-hept-1-enitol (24). 56.6 mg
+44.5 (CHCl3, c 1.5); 1H NMR (300 MHz, CDCl3) l
(ppm): 3.67 (dd, 1H, J=2.6, and 8.2 Hz), 3.74 (dd, 1H,
J=6.9, and 9.9 Hz), 3.90–3.95 (m, 1H), 4.01 (m, 1H),
4.30–4.40 (m, 3H), 4.53 (d, 1H, J=11.5 Hz), 4.60–4.73
(m, 4H), 4.84 (d, 1H, J=11.5 Hz), 5.84 (s, 1H), 6.95 (dd,
1H, J=4.7 and 8.0 Hz), 7.10–7.30 (m, 20H), 8.10 (ddd,
1H, J=1.5, 1.6, and 8.0 Hz), 8.24 (dd, 1H, J=1.5 and 4.8
Hz), 8.51 (d, 1H, J=1.6 Hz); 13C NMR (50 MHz,
CDCl3) l (ppm): 68.2, 72.0, 72.5, 72.7, 73.1, 73.2, 76.1,
77.4, 80.6, 105.9, 122.2, 126.5, 126.7, 126.8 (×2), 126.9,
(73%): hD=+15.8 (CHCl3, c 0.9); 1H NMR (300 MHz,
CDCl3) l (ppm): 3.64–3.85 (m, 4H), 3.69 (s, 3H), 4.02 (d,
1H, J=3.2 Hz), 4.13 (t, 1H, J=9.1 Hz), 4.37–4.67 (m,
6H), 4.74 (d, 1H, J=12.6 Hz), 4.95 (d, 1H, J=10.9 Hz),
5.47 (s, 1H), 6.70 (d, 2H, J=8.9 Hz), 7.21–7.38 (m, 20H),
7.60 (d, 2H, J=8.9 Hz); 13C NMR (75 MHz, CDCl3) l
(ppm): 54.3, 68.0, 69.0, 70.4, 72.3, 73.5, 74.0, 74.2, 75.4,
81.0, 112.7 (×2), 113.9, 115.0, 126.2, 126.5, 126.7, 126.8
(×2), 126.9, 127.2, 127.4 (×2), 129.3, 137.2, 137.4, 145.6,
157.6.

6116
A. M. Go´mez et al. / Tetrahedron Letters 44 (2003) 6111–6116
(Z)-2,6-Anhydro-3,4,5,7-tetra -O-benzyl-1-deoxy-1-(p-
methoxyphenyl)- -galacto-hept-1-enitol (25). 75.6.3 mg
tolyl)-D-manno-hept-1-enitol (27). 57.0 mg (76%): hD=
+7.4 (CHCl3, c 1.2); 1H NMR (300 MHz, CDCl3) l
(ppm): 2.32 (s, 3H), 3.74 (dd, 1H, J=3.1 and 8.8 Hz),
3.77–3.91 (m, 3H), 4.11 (d, 1H, J=3.2 Hz), 4.22 (t, 1H,
J=9.2 Hz), 4.45–4.73 (m, 6H), 4.80 (d, 1H, J=12.6 Hz),
5.01 (d, 1H, J=10.9 Hz), 5.56 (s, 1H), 7.05 (d, 2H, J=8.3
Hz), 7.24–7.44 (m, 20H), 7.60 (d, 2H, J=8.3 Hz); 13C
NMR (75 MHz, CDCl3) l (ppm): 21.5, 69.3, 70.1, 71.6,
73.6, 74.6, 75.2, 75.4, 80.0, 82.2, 115.3, 127.7, 127.9 (×3),
128.0, 128.2, 128.4, 128.6 (×2), 129.1, 129.3, 131.8, 137.2,
138.4 (×2), 138.7, 147.9. API-ES positive: 649.2 [M+Na]+.
(Z)-2,6-Anhydro-3,4,5,7-tetra-O-benzyl-1-deoxy-1-(p-
D
(78%): hD=+13.4 (CHCl3, c 0.4); 1H NMR (200 MHz,
CDCl3) l (ppm): 3.58–3.81 (m, 3H), 3.66 (s, 3H), 3.92–
4.00 (m, 2H), 4.29–4.36 (m, 3H), 4.55 (d, 1H, J=11.5
Hz), 4.59–4.74 (m, 4H), 4.84 (d, 1H, J=11.5 Hz), 5.82 (s,
1H), 6.64 (d, 2H, J=8.9 Hz), 7.16–7.30 (m, 20H), 7.55 (d,
2H, J=8.9 Hz); 13C NMR (75 MHz, CDCl3) l (ppm):
54.3, 68.5, 72.2, 72.5, 73.0, 73.5, 75.7, 76.1, 76.5, 80.5,
109.8, 112.6, 126.6, 126.7, 126.8 (×2), 127.0 (×2), 127.4
(×2), 127.5 (×2), 129.2, 137.2, 137.5, 137.6, 147.1, 157.2.
API-ES positive: 665.2 [M+Na]+.
(Z)-2,6-Anhydro-3,4,5,7-tetra-O-benzyl-1-deoxy-1-(p-
tolyl)-D-gluco-hept-1-enitol (26). 64.5 mg (86%): hD=
tolyl)-D-galacto-hept-1-enitol (28). 78.9 mg (84%): hD=
+14.7 (CHCl3, c 1.8); 1H NMR (300 MHz, CDCl3) l
(ppm): 2.23 (s, 3H), 3.65 (dd, 1H, J=4.1 and 9.5 Hz),
3.70–3.81 (m, 2H), 3.92–4.06 (m, 2H), 4.32–4.78 (m, 8H),
4.85 (d, 1H, J=11.3 Hz), 5.87 (s, 1H), 6.96 (d, 2H, J=8.0
Hz), 7.16–7.30 (m, 20H), 7.50 (d, 2H, J=8.0 Hz); 13C
NMR (75 MHz, CDCl3) l (ppm): 21.6, 69.7, 73.5, 73.6,
73.8, 74.4, 74.8, 77.0, 78.6, 81.9, 111.3, 127.9, 128.0 (×2),
128.1, 128.2, 128.4 (×2), 128.7, 128.8 (×3), 129.2 (×2),
132.7, 136.5, 138.6, 149.7. API-ES positive: 644.2 [M+
H2O]+.
+11.2 (CHCl3, c 0.6); 1H NMR (200 MHz, CDCl3) l
(ppm): 2.32 (s, 3H), 3.77–3.90 (m, 4H), 4.03 (d, 1H,
J=5.0 Hz), 4.05–4.09 (m, 1H), 4.54–4.83 (m, 8H), 5.73 (s,
1H), 7.08 (d, 2H, J=8.0 Hz), 7.26–7.40 (m, 20H), 7.60 (d,
2H, J=8.0 Hz); 13C NMR (75 MHz, CDCl3) l (ppm):
21.6, 66.2, 69.6, 72.2, 73.8, 74.0, 74.4, 77.0, 79.7, 85.1,
109.8, 128.0, 128.1, 128.2 (×2), 128.3 (×2), 128.7, 128.8
(×2), 128.9, 129.0, 129.3, 130.6, 135.6, 135.7, 138.6, 148.7.
API-ES positive: 649.3 [M+Na]+.
(Z)-2,6-Anhydro-3,4,5,7-tetra-O-benzyl-1-deoxy-1-(p-