A selective resin for trans-diequatorial-1,2-diols

Article abstract of DOI:10.1016/j.tetlet.2009.01.157

A selective resin for linking trans-diequatorial-1,2-diols to solid support is described. This linking was carried out under mild and aprotic conditions involving the use of trimethylsilyl methyl ether in the presence of trimethylsilyl trifluoromethanesul

Full text of DOI:10.1016/j.tetlet.2009.01.157

Tetrahedron Letters 50 (2009) 1795–1798
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A selective resin for trans-diequatorial-1,2-diols
*
Emilio Lence, Luis Castedo, Concepción González-Bello
Laboratorio de Química Orgánica (CSIC) y Departamento de Química Orgánica, Facultad de Química, Universidad de Santiago de Compostela, Avenida de las Ciencias s/n,
15782 Santiago de Compostela, Spain
a r t i c l e i n f o
a b s t r a c t
Article history:
A selective resin for linking trans-diequatorial-1,2-diols to solid support is described. This linking was
carried out under mild and aprotic conditions involving the use of trimethylsilyl methyl ether in the pres-
ence of trimethylsilyl trifluoromethanesulfonate. Cleavage from the resin was also carried out under mild
conditions by treatment with dichloromethane/trifluoroacetic acid/water (21:20:1). The usefulness of the
described cyclohexane-1,2-diketone resin 7 in quinic acid chemistry was also studied.
Ó 2009 Elsevier Ltd. All rights reserved.
Received 7 January 2009
Accepted 28 January 2009
Available online 6 February 2009
Carbohydrates are cheap and widely used starting materials for
the synthesis of very complex molecules. The use of these materi-
als in synthetic chemistry usually requires the selective protection
of their hydroxyl groups, for which a wide range of protecting
groups have been developed. Several protecting groups have been
developed for the selective protection of cis-1,2-diols, with acetals
probably being the most widely used. On the contrary, only until a
few years ago, the selective protection of cyclic trans-1,2-diols
could only be achieved using disiloxanyl protecting groups, which
are often incompatible with conventional transformations in car-
bohydrate chemistry. The solution was finally provided by Ley’s
group with the development of 1,2-diacetals.1
The use of 1,2-diacetals, which were initially developed as se-
lective protecting groups for trans-diequatorial-1,2-diols, has been
extended more recently to include other synthetic areas as a con-
sequence of the excellent diastereoselectivity control.2 This is the
case of important hydroxylated chiral templates containing trans-
1,2-diols, such as quinic and shikimic acids, and excellent building
blocks, such as glycerate, glycolate, and tartrate diacetal deriva-
tives. The protection of these diols as diacetals leads to a strong
conformational rigidity that induces excellent diastereoselectivity
control. Their integrity as protecting groups as well as the chemical
properties derived from its conformational rigidity makes diacetals
an extremely useful functional group. These important synthetic
properties have successfully been exploited in the total synthesis
of natural products, such as antascomicin B, (+)-aspicilin, herbaru-
min II, altenuene.2
synthetic precursors, cyclohexane-1,2-dione (3a) and 2,3-butane-
dione (3b), in combination with methanol.5
The advantages of solid phase chemistry are well known.6 Since
the pioneering work of Merrifield in 1963,7 solid phase chemistry
has become an important tool for synthetic chemists. In this meth-
odology, the selection of the solid support and the linker are two
important factors that determine the type of reactions that can
be employed. In this context, the integrity of 1,2-diacetals and
the wide ranges of reactions that can be performed with them
make them excellent candidates as solid phase linkers.
As part of our ongoing research into the synthesis of structurally
diverse polyhydroxylated cyclohexane derivatives,8 we investi-
gated the synthesis of a solid support for the selective linkage of
cyclic trans-diequatorial-1,2-diols. We synthesized 1,1,2,2-tetra-
methoxycyclohexane resins 5 and 6, and cyclohexane-1,2-dione
resin 7, and explored their usefulness in the chemistry of quinic
acid,9 an optically active precursor for the synthesis of cyclohex-
ane-substituted derivatives (Fig. 1).
The strategy for synthesizing resin 5 involved the initial prepa-
ration of hydroxyacetal 12 from commercially available cyclohex-
3-enylmethanol (8) as it is outlined in Scheme 2.
OMe
2 3
−
OH
OH
O
R
O
R
1
4
OMe
Typical 1,2-diacetals are 1,1,2,2-tetramethoxycyclohexane (2a,
TMC)3 and 2,2,3,3-tetramethoxybutane (2b, TMB),4 which provide
cyclohexane-1,2-diacetals 4a (CDA) and butane-2,3-diacetals 4b
(BDA), respectively, in good to excellent yields (Scheme 1). TMC
(2a) and TMB (2b) are frequently replaced by their corresponding
MeO
MeO
MeO
MeO
R
R
R
R
O
O
a R = -(CH2)4-
b
R = Me
2
3
* Corresponding author. Tel.: +34 981 563100; fax: +34 981 595012.
E-mail address: concepcion.gonzalez.bello@usc.es (C. González-Bello).
Scheme 1. Protection of trans-diequatorial-1,2-diols as cyclohexane- and butane-
1,2-diacetals.
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.01.157

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E. Lence et al. / Tetrahedron Letters 50 (2009) 1795–1798
ence of a benzyl ether bond, we replaced this benzyl ether with a
carbon–carbon bond. For this purpose, we carried out the synthesis
of resins 6 and 7 (Scheme 3).
MeO
MeO
MeO
MeO
O
O
X
7
The strategy for the synthesis of resin 6 involved the linkage of
the tetramethoxyacetal moiety by a nucleophilic substitution reac-
tion between lithium polystyrene resin and iodide 15, which was
synthesized from 12. Hydroxyacetal 12 was converted to 15 in a
five-step reaction sequence. First, oxidation of primary alcohol 12
was followed by the Horner–Emmons reaction with triethyl phos-
phonoacetate, and hydrogenolysis gave saturated ester 13 in good
yield. Hydride reduction of ester 13 followed by treatment of the
corresponding alcohol 14 with iodine and triphenylphosphine gave
the desired iodide 15 in 66% yield (two steps).
5 X = O
6 X = CH2
Figure 1. Functionalized polystyrene resins for the selective linkage of trans-1,2-
diols.
HO
OR
b
OBn
99%
HO
The next step involved linking of the tetramethoxyacetal moi-
ety to the solid support. This was achieved by nucleophilic substi-
tution of 15 by lithium polystyrene, which was obtained by
halogen–metal exchange between bromopolystyrene and nBuLi.11
Resin 6 was converted into the cyclohexane-1,2-diketone resin 7
by acid removal of the tetramethoxyacetal group. Gel phase FTIR
spectroscopy of 7 confirmed the efficiency of the reaction, and re-
vealed a strong band centered at 1720 cmꢀ1, corresponding to the
1,2-diketone group.
Attempts to link cyclohexane-1,2-diol (17) to resin 6 using
either MeOH/H+ or TMSOMe/TMSOTf conditions resulted in only
low yields of the corresponding 1,2-diacetal. However, the reac-
tion of resin 7 with TMSOMe in the presence of TMSOTf afforded
the corresponding cyclohexane-1,2-diacetal 18 in good yield
(Scheme 4).12
8
9
R = H
10
c, 96%
a, 99%
R = Bn
d, 67%
MeO
f
MeO
MeO
MeO
11 R = Bn
12
OR
5
40%
e, 99%
R = H
Scheme 2. Reagents and conditions: (a) (1) NaH, THF, 0 °C; (2) BnBr, TBAI (cat). (b)
OsO4 (cat), NMO, tBuOH–THF–H2O, rt; (c) (1) DMSO, TFAA, DCM, ꢀ78 °C; (2) Et3N,
ꢀ78 °C; (d) (MeO)3CH, MeOH, CSA (cat),
D; (e) Pd/C (10%), MeOH, 80 psi; (f) (1)
NaH, THF, 0 °C; (2) benzylbromide polystyrene, rt.
Linking of 12 to a solid support by treatment of Merrifield resin
with the sodium alkoxide of alcohol 12 gave the ether resin 5. Evi-
dence for the formation of 5 was obtained by examining its gel
phase 13C NMR spectrum. Distinctive signals for the tetrame-
thoxyacetal group were observed at 49.9 and 49.0 ppm (methoxy
groups) and at 102.0 ppm (quaternary centers). Linking of cyclo-
hexane-1,2-diol under standard conditions (i.e., heating of ether
resin 5 in DMF/MeOH solution under reflux in the presence of a
catalytic amount of sulfuric or camphorsulfonic acid) resulted in
cleavage of the tetramethoxy moiety from the resin. Milder reac-
tion conditions were also investigated, using trimethylsilyl methyl
ether (TMSOMe) in the presence of trimethylsilyl trifluorometh-
anesulfonate (TMSOTf). This method, which we had previously
developed,10 has been found to be a good alternative to the con-
ventional protic method, providing high yields of the correspond-
ing 1,2-diacetals even without reactive 1,2-diketones. However,
cleavage of the linker 12 from the resin also occurred. Based on
the assumption that the acid lability of resin 5 was due to the pres-
MeO
OH
OH
O
a, 7
3
99%
O
17
16
MeO
Scheme 4. Reagents and conditions: (a) TMSOMe, TMSOTf, 0 °C to rt.
EtO2C
EtO2C
OH
OH
EtO2C
EtO2C
O
O
7
a,
99%
18
5
19
RO2C
RO2C
OH
OH
O
1
HO
HO
7
a,
O
+
OH
OH
O
21a R = Me
20a
R = Me
i
O
i
21b
R = Pr
20b
R = Pr
MeO
R
O
a, 95%
b, 92%
MeO
MeO
HO
12
O
22
MeO
NHBu
NHBu
13
R = CO2Et
O
O
c, 72%
d, 92%
OG
OH
O
O
a, 7
99%
14 R = CH2OH
15 R = CH2I
1
5
RO
RO
OH
OG
X
15
f,
g
23a R = Bn; G = H
24a
R = Bn
6
7
23b
R = G = TMS
MeO
24b R = H
89%
99%
X = Br
X = Li
e
3
=
Scheme 3. Reagents and conditions: (a) (1) NMO, TPAP, DCM; (2) NaH,
(EtO)2POCH2CO2Et, THF; (b) H2, Pd(OH)2/C (cat), EtOAc; (c) Dibal-H, THF, 0 °C; (d)
MeO
I2, PPh3, Im, 0 °C to rt; (e) nBuLi, PhH,
D; (f) TMEDA, THF, rt; (g) DCM/TFA/H2O
(21:20:1), rt.
Scheme 5. Reagents and conditions: (a) TMSOMe, TMSOTf, 0 °C to rt.

E. Lence et al. / Tetrahedron Letters 50 (2009) 1795–1798
1797
chemistry of the addition reaction was confirmed by NOE experi-
ments. Irradiation of the methylene group in to the amide
CONHBu
O
O
a
a
99%
RO
24b
nitrogen led to a 1.1% enhancement of H-20 of the alkene.
In summary, the cyclohexane-1,2-diketone resin 7 can be used
for the selective and efficient linking of trans-1,2-diols, such as
cyclohexane-1,2-diol, tartrate or quinic acid derivatives, to a solid
support. However, use of the corresponding tetramethoxydiacetal
resin 6 is not efficient. In addition, replacement of the benzyl ether
bond in resin 5 proved to be a good strategy for avoiding cleavage of
the linker from the solid support. The linking of trans-1,2-diols to
the cyclohexane-1,2-diketone resin 7 was carried out using mild
and aprotic conditions involving the use of trimethylsilyl methyl
ether and trimethylsilyl trifluoromethanesulfonate. The usefulness
of cyclohexane-1,2-diketone resin 7 in solid phase organic synthe-
sis of quinic acid derivatives, an attractive optically active precur-
sors for the synthesis of a wide range of compounds, was
demonstrated through the synthesis of derivatives 28 and 29,
whose cleavage from resin was carried out under mild conditions
by treatment with DCM/TFA/H2O (21:20:1). To our knowledge, this
is the first example of a resin for linking trans-diequatorial-1,2-diols
to solid support.
O
25
d, 99%
CONHBu
b, 99%
BuHNOC
O
O
O
BnO
Allyl OH
c, 60%
OBn
26
EtO2C
c, 22%
O
27
BuHNOC
OH
O
4
HN
OH
OH
28
H
1´
EtO2C
1.1%
0.6%
OH
OH
29
Acknowledgments
Scheme 6. Reagents and conditions: (a) (COCl)2, DMSO, DCM, ꢀ78 °C then Et3N; (b)
NaH, (EtO)2OPCH2CO2Et, THF, DCM, 0 °C; (c) DCM/TFA/H2O (21:20:1), rt; (d)
AllylMgBr, THF, ꢀ78 °C.
This work was supported by Ministerio de Educación y Cultura
(SAF2007-63533) and the Xunta de Galicia (under projects
PGIDT07-PXIB209080PR and GRC2006/132).
The linkage of other trans-1,2-diols including tartrate and quinic
acid derivatives was investigated. Diethyl tartrate (18) was success-
fully linked to resin, affording the 1,2-diacetal 19 in good yield
(Scheme 5).13 However, attempts to link (ꢀ)-quinic acid methyl
ester (20a) gave only low yields of the desired 1,2-diacetal 21a.
Gel phase FTIR showed a strong band typical of lactones at
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2009.01.157.
1794 cmꢀ1
, together with the expected band centered at
1730 cmꢀ1 corresponding to the methyl ester. We reasoned that
the former IR band should correspond to the cis-2,3-linked product
22. The low loading obtained might be a consequence of the rapid
lactonization of 20a, prior to reaction with the solid support. The
long reaction times usually required for solid phase reactions, as
in this case, could favor this side reaction. Therefore, the use of a
quinic acid derivative in which lactonization is less favored should
provide better yields of the desired trans-junction. Indeed, replace-
ment of the methyl ester in 20a by an isopropyl ester 20b resulted
in an increased loading. It is worth highlighting that the low solubil-
ity of polyhydroxylated compounds of this type in the reaction
solvent (dichloromethane) limits the loading success. However, this
problem can be overcome by using more soluble quinic acid deriv-
atives, such as the benzyl amide 23a or the TMS protected amide
23b. Indeed, treatment of 7 with an excess of 23a, TMSOMe, and
TMSOTf gave the corresponding 1,2-diacetal 24a in excellent
yield.14
References and notes
1. Ley, S. V.; Baeschlin, D. K.; Dixon, D. J.; Foster, A. C.; Ince, S. J.; Priepke, H. W. M.;
Reynolds, D. J. Chem. Rev. 2001, 101, 53–80.
2. (a) Lence, E.; Castedo, L.; González-Bello, C. Chem. Soc. Rev. 2008, 37, 1689–
1708; (b) Ley, S. V.; Polara, A. J. Org. Chem. 2007, 72, 5943–5959.
3. Ley, S. V.; Priepke, H. W. M.; Warriner, S. L. Angew. Chem., Int. Ed. Engl. 1994, 33,
2290–2292.
4. Montchamp, J.-L.; Tian, F.; Hart, M. E.; Frost, J. W. J. Org. Chem. 1996, 61, 3897–
3899.
5. (a) Douglas, N. L.; Ley, S. V.; Osborn, H. M. I.; Owen, D. R.; Priepke, H. W. M.;
Warriner, S. L. Synlett 1996, 793–794; (b) Hense, A.; Ley, S. V.; Osborn, H. M. I.;
Owen, D. R.; Poisson, J.-F.; Warriner, S. L.; Wesson, K. E. J. Chem. Soc., Perkin
Trans. 1 1997, 2023–2031.
6. Dorner, B.; Blondelle, S. E.; Pinilla, C.; Appel, J.; Dooley, C. T.; Eicher, J.; Ostresh,
J. M.; Pérez-Paya, E.; Houghten, R. A. In Combinatorial Libraries Synthesis,
Screening and Application Potential; Cortese, R., Ed.; Walter de Gruyter: New
York, 1996; pp 1–25.
7. Merrifield, R. B. J. Am. Chem. Soc. 1963, 85, 2149–2154.
8. For some examples see: (a) González, C.; Carballido, M.; Castedo, L. J. Org. Chem.
2003, 68, 2248–2255; (b) Carballido, M.; Castedo, L.; González-Bello, C. Eur. J.
Org. Chem. 2004, 3663–3668; (c) Prazeres, V. F. V.; Castedo, L.; González-Bello,
C. Eur. J. Org. Chem. 2008, 3991–4003; (d) González-Bello, C.; Castedo, L.;
Cañada, F. J. Eur. J. Org. Chem. 2006, 1002–1011.
9. Barco, A.; Benetti, S.; De Risi, C.; Marchetti, P.; Pollini, G. P.; Zanirato, V.
Tetrahedron: Asymmetry 1997, 8, 3515–3545.
10. Lence, E.; Castedo, L.; González, C. Tetrahedron Lett. 2002, 43, 7917–7918.
11. Gel phase 13C NMR spectrum of resin 6 showed distinctive signals at 49.7 and
49.0 ppm (OMe), and at 102.0 ppm (quaternary).
The usefulness of resin 7 in solid phase organic synthesis of qui-
nic acid derivatives was investigated, as shown for the conjugated
ester 28 and the allyl derivative 29 (Scheme 6). Firstly, Swern oxi-
dation of the secondary alcohol resin 24a afforded ketone 25 in
good yield.15 Treatment of ketone 25 with triethylphosphonoace-
tate and sodium hydride produced the conjugated a,b-unsaturated
12. The extent of the reaction was monitored by gel phase FTIR spectroscopy,
following the disappearance of the band at 1720 cmꢀ1 corresponding to the
1,2-diketone group of resin 7.
ester resin 26, resulting from a b-elimination and a Horner–Em-
mons reaction. Cleavage of resin 27 under mild conditions by treat-
ment with DCM/TFA/H2O (21:20:1) at room temperature afforded
the unsaturated derivative 28.16 The Z/E stereochemistry of the
unsaturated ester was studied by NOE experiments. Irradiation of
H-4 led to a 0.6% enhancement of H-10.
Ketone resin 25 underwent efficient nucleophilic addition of al-
lyl magnesium bromide, giving the allyl derivative resin 27.17
Cleavage of resin 27 afforded the allyl derivative 28.18 The stereo-
13. The gel phase FTIR spectrum of 19 showed
1741 cmꢀ1 and its gel phase 13C NMR data have
170.2 ppm corresponding to its ester groups.
a
strong band centered at
,
a
distinctive signal at
14. The gel phase 13C NMR spectrum of 24a has distinctive signals at 98.6
(quaternary), 46.7 (OMe), and 13.6 (Me) ppm, and its gel phase FTIR spectrum
has a strong band centered at 1673 cmꢀ1 corresponding to the amide group.
15. The complete oxidation of the secondary hydroxyl group was confirmed in the
gel phase FTIR spectra of 25, which showed strong bands centered at
1724 cmꢀ1
.

1798
E. Lence et al. / Tetrahedron Letters 50 (2009) 1795–1798
16. Compound 28: 1H NMR (500 MHz, CDCl3) d: 7.93 (d, J = 2.4 Hz, 1H), 6.24 (s, 1H),
6.17 (t, J = 5.2 Hz, 1H, NH), 4.20 (dq, J = 7.2 and 2.3 Hz, 2H), 4.17 (m, 1H), 3.76
(m, 1H), 3.32 (dq, J = 7.2 and 2.1 Hz, 2H), 3.03 (dd, J = 18.0 and 5.5 Hz, 1H), 2.41
(ddd, J = 18.0, 9.2, and 2.0 Hz, 1H), 1.53 (q, J = 7.4 Hz, 2H), 1.36 (h, J = 7.4 Hz,
2H), 1.30 (t, J = 7.1 Hz, 3H) and 0.93 (t, J = 7.3 Hz, 3H) ppm. 13C NMR (63 MHz,
CDCl3) d: 167.4 (C), 166.5 (C), 150.5 (C), 138.0 (C), 124.6 (CH), 116.5 (CH), 73.9
(CH), 71.1 (CH), 60.4 (CH2), 39.7 (CH2), 31.5 (CH2), 29.7 (CH2), 20.1 (CH2), 14.2
(CH3) and 13.7 (CH3) ppm. MS (CI) m/z (%) 298 (MH+). HRMS calcd for
C15H24NO5 (MH+): 298.1654; found, 298.1650.
18. Compound 29: 1H NMR (500 MHz, CDCl3) d: 7.38 (m, 3H), 7.28 (m, 2H), 6.36
(t, J = 5.2 Hz, 1H), 5.80 (m, 1H), 5.12 (m, 2H), 4.59 (d, J = 11.0 Hz, 1H), 4.35 (d,
J = 11.0 Hz, 1H), 3.86 (m, 1H), 3.76 (s, 1H), 3.34ꢀ3.19 (m, 3H), 2.60 (br s, 1H),
2.48 (dt, J = 15.0 and 3.5 Hz, 1H), 2.41 (dd, J = 14.0 and 7.0 Hz, 1H), 2.34 (br s,
1H), 2.26 (dd, J = 14.0 and 8.0 Hz, 1H), 2.17 (dd, J = 15.0 and 12.0 Hz, 1H),
2.01 (dd, J = 15.5 and 3.0 Hz, 1H), 1.92 (d, J = 15.5 Hz, 1H), 1.45 (m, 2H), 1.29
(m, 2H) and 0.89 (t, J = 7.4 Hz, 3H) ppm. 13C NMR (63 MHz, CDCl3) d: 171.5
(C), 136.1 (C), 132.8 (CH), 129.0 (2 ꢁ CH), 128.6 (CH), 127.6 (2 ꢁ CH), 119.2
(CH2), 83.2 (C), 78.3 (CH), 74.8 (C), 68.8 (CH), 67.2 (CH2), 42.9 (CH2), 42.0
(CH2), 39.2 (CH2), 33.3 (CH2), 31.6 (CH2), 20.0 (CH2) and 13.7 (CH3) ppm. MS
(CI) m/z (%) 378 (MH+). HRMS calcd for C21H32NO5 (MH+): 378.2280; found,
378.2274.
17. A distinctive signal of the allyl group at 119.1 ppm in the gel phase 13C NMR
spectrum of 27 and the strong band centered at 3520 cmꢀ1 in its gel FTIR
spectrum confirmed the addition reaction.