Butane 2,3-bisacetal protection of vicinal diequatorial diols

Full text of DOI:10.1021/jo960170n

J . Org. Chem. 1996, 61, 3897-3899
3897
and the bisethylene glycol acetal cis-1,6-dimethyl-2,5,7,-
10-tetraoxabicyclo[4.4.0]decane8 have been known for
some time. Protection of diethyl tartrate diol with
monoacetal 3,3-dimethoxybutan-2-one has recently been
reported.9 TMB reagent was prepared by refluxing a
methanol solution of trimethyl orthoformate and 2,3-
butanedione with a few drops of sulfuric acid followed
by purification of the crude product using distillation. The
experimental advantages of purification by distillation
and the ability to employ an inexpensive starting mate-
rial became apparent during the preparation of TMB in
50-60% yield on hundred-gram scale.
Selective protection of the C-3,4 vicinal diequatorial
hydroxyls of methyl quinate as butane 2,3-bisacetals
utilized reaction conditions similar to those employed for
CDA protection. A methanolic solution of quinate ester
was refluxed with TMB in the presence of trimethyl
orthoformate and catalytic (()-10-camphorsulfonic acid
for 12-18 h. The desired BBA-protected methyl quinate
was obtained in excellent yield. Fifty grams of quinic
acid were then routinely converted into the crystalline
BBA-protected methyl quinate as a one-pot procedure in
over 80% yield (Table 1, entry 1). The BBA protecting
group is compatible with a wide variety of reagents and
can be deprotected with aqueous trifluoroacetic acid in
methylene chloride.4
The scope of BBA protection has been extended beyond
quinic acid (Table 1). Reaction of myo-inositol with 2
equiv of TMB used the conditions previously described
for methyl quinate protection. A pure, crystalline product
precipitated out of the solution. This material displayed
a simple NMR spectrum which could only be attributed
to the highly symmetrical diprotected meso compound
(Table 1, entry 2). The yield of meso-diBBA inositol
derivative improved with longer reaction times. At
relatively short reaction times, low yields of meso-diBBA
product were obtained along with a complex mixture of
other components. The inositol protection pattern ob-
served for BBA has previously been obtained during
reaction of inositol with 1,3-dichloro-1,1,3,3-tetraiso-
propyldisiloxane (TIPSCl).10 While this silyl protecting
group has found some applications in inositol chemistry,
the cost of TIPSCl limits its use. BBA provides the same
protection pattern in higher yield and at a much lower
cost.
Reaction of TMB with carbohydrates provided an
additional test of the scope of BBA protection. In general,
BBA protection was observed to display selectivities
similar to those previously observed for CDA and Dispoke
protection.3 TMB reaction with methyl R-D-glucopyra-
noside gave an inseparable, equimolar mixture of 2,3- and
3,4-regioisomers (Table 1, entry 3). BBA protection of
methyl R-D-galactopyranoside gave the desired product
along with a small amount of its anomer (Table 1, entry
4). For the methyl pyranosides of D-mannose (Table 1,
entry 5), D-lyxose (Table 1, entry 6), L-rhamnose (Table
1, entry 7), and 2-deoxy-D-glucose (Table 1, entry 8) TMB
proved to be consistently selective for vicinal diequatorial
diol protection.
Bu ta n e 2,3-Bisa ceta l P r otection of Vicin a l
Diequ a tor ia l Diols
J ean-Luc Montchamp, Feng Tian, Matthew E. Hart, and
J . W. Frost*
Department of Chemistry, Michigan State University,
East Lansing, Michigan 48824-1322
Received J anuary 29, 1996
Selective hydroxyl group protection in polyhydroxy
molecules continues to be a challenge in synthetic
chemistry.1 For example, methods for selective protec-
tion of vicinal diequatorial diols are rare. Ley and co-
workers have introduced two very useful protecting
groups which exploit multiple anomeric effects to ac-
complish this task. Diol reaction with 3,3′,4,4′-tetra-
hydro-6,6′-spirobi-2H-pyran (bis-DHP) to give a dispiro-
acetal (Dispoke)2 and diol reaction with 1,1,2,2-tetra-
methoxycyclohexane (TMC) affording a cyclohexane 1,2-
diacetal (CDA)3 have been successfully applied to a
variety of carbohydrates and polyhydroxylated molecules.
However, bis-DHP is of limited utility for large-scale work
due to the synthetic steps required for its preparation.2b
TMC is readily prepared from cyclohexane-1,2-dione,
although this starting material is relatively expensive.
An additional practical difficulty is the need for chro-
matographic purification of both bis-DHP and TMC.2b,3
In response to the requirements imposed by large-scale
synthetic manipulations, reaction of vicinal diequatorial
diols with 2,2,3,3-tetramethoxybutane (TMB) to afford
butane 2,3-bisacetal (BBA) protection has been examined.
As part of efforts directed toward the synthesis of
3-dehydroquinate (DHQ) synthase inhibitors,4 the C-3,4
diequatorial hydroxyls of quinic acid needed to be selec-
tively protected. Previous protection of these hydroxyl
groups had been achieved in two ways. Knowles and co-
workers protected the C-3,4 diequatorial diol unit in 20%
yield by direct reaction of methyl quinate with benzyl
chloromethyl ether (BOMCl).5 Formation of multiple
products resulted in low yields and required a tedious
purification to obtain the desired product. Another
approach by Tisne`s and co-workers utilized O-stannylene
derivatives as part of a protection-deprotection sequence
also involving the axial C-5 hydroxyl group.6 Neither of
these strategies nor the aforementioned Dispoke or CDA
protecting groups seemed amenable to our need for gram-
scale quantities of final products and the multistep
syntheses required to synthesize these DHQ synthase
inhibitors. It occurred to us that TMB would be an
inexpensive alternative to TMC while retaining the
desired vicinal diequatorial diol protection selectivity.
TMB has apparently not been reported in the litera-
ture, although the monoacetal 3,3-dimethoxybutan-2-one7
(1) (a) Ziegler, T. Angew. Chem., Int. Ed. Engl. 1994, 33, 2272. (b)
Greene, T. W.; Wuts, P. G. M. Protective Groups in Organic Chemistry,
2nd ed.; Wiley: New York, 1991.
(2) (a) Ley, S. V.; Woods, M.; Zanotti-Gerosa, A. Synthesis 1992, 52.
(b) Ley, S. V.; Leslie, R.; Tiffin, P. D.; Woods, M. Tetrahedron Lett.
1992, 33, 4767. (c) Ley, S. V.; Boons, G.-J .; Leslie, R.; Woods, M.;
Hollinshead, D. M. Synthesis 1993, 689.
Overall, the BBA protecting group appears to be a
practical alternative to CDA or Dispoke for selective
(3) Ley, S. V.; Priepke, H. W. M.; Warriner, S. L. Angew. Chem.,
Int. Ed. Engl. 1994, 33, 2290.
(4) Tian, F.; Montchamp, J .-L.; Frost, J . W. Unpublished results.
(5) Bender, S. L.; Widlanski, T.; Knowles, J . R. Biochemistry 1989,
28, 7560.
(6) Chahoua, L.; Baltas, M.; Gorrichon, L.; Tisne`s, P.; Zedde, C. J .
Org. Chem. 1992, 57, 5798.
(8) Fuchs, B.; Goldberg, I.; Shmueli, U. J . Chem. Soc., Perkin Trans.
2 1972, 357.
(9) Berens, U.; Leckel, D.; Oepen, S. C. J . Org. Chem. 1995, 60, 8204.
(10) Watanabe, Y.; Mitani, M.; Morita, T.; Ozaki, S. J . Chem. Soc.,
Chem. Commun. 1989, 482.
(7) Braude, E. A.; Timmons, C. J . J . Chem. Soc. 1953, 3131.
S0022-3263(96)00170-3 CCC: $12.00 © 1996 American Chemical Society

3898 J . Org. Chem., Vol. 61, No. 11, 1996
Ta ble 1. Bu ta n e 2,3-Bisa ceta l P r otection of Ca r bocycles a n d Ca r boh yd r a tes
Notes
protection of vicinal diequatorial diols. BBA-protected
compounds appear to usually be crystalline materials. A
useful advantage over other protecting groups is the
simple NMR spectrum of the BBA group. Unlike the
cyclohexyl resonances that characterize CDA or Dispoke,
BBA displays only singlets which are very diagnostic and
minimize overlap with other resonances. The rigidity
resulting from the formation of the 2,3-dimethoxy-2,3-
dimethyl-1,4-dioxane moiety also provides an element for
conformational control that can be exploited in subse-
quent reactions.4 Finally, the inexpensive, large-scale
preparation of TMB and the reagent’s convenient puri-
fication by distillation makes BBA protection a particu-
larly appealing option for large-scale synthetic manipu-
lations.
Exp er im en ta l Section
Gen er a l Ch em istr y. See ref 11 for general experimental
information. Melting points were uncorrected and were deter-
mined using a Mel-Temp II melting point apparatus. For NMR
1
spectra in pyridine-d5, the H NMR spectrum was referenced to
internal TMS (δ ) 0.00 ppm), and the 13C NMR spectrum was
(11) Montchamp, J .-L.; Frost, J . W. J . Org. Chem. 1994, 59, 7596.

Notes
J . Org. Chem., Vol. 61, No. 11, 1996 3899
1
referenced to pyridine-d5 with the center of the middle triplet
at δ ) 135.5 ppm.
Glu cose p r otection (en tr y 3): H NMR (CDCl3) δ 4.80 (d,
J ) 4 Hz, 1 H), 4.74 (d, J ) 4 Hz, 1 H), 3.60-4.00 (m, 12 H),
3.43 (s, 3 H), 3.41 (s, 3 H), 3.30 (s, 3 H), 3.29 (s, 3 H), 3.26 (s, 6
H), 3.06 (br, 4 H), 1.34 (s, 3 H), 1.33 (s, 3 H), 1.31 (s, 3 H), 1.29
(s, 3 H); 13C NMR (CDCl3) δ 99.6, 99.4 (2), 99.3, 99.2, 97.8, 71.7,
69.8, 69.6, 69.5, 69.2, 68.0, 67.4, 65.6, 61.4, 60.7, 55.0, 54.8, 47.8,
47.7 (2), 47.6, 17.5 (2), 17.4 (2); HRMS (FAB) calcd for C13H24O8
2,2,3,3-Tetr a m eth oxybu ta n e. 2,3-Butanedione (68.0 mL,
0.775 mol), trimethyl orthoformate (200 mL, 1.83 mol), and
MeOH (100 mL) were treated with sulfuric acid (7 drops). The
resulting solution was refluxed 20 h under Ar, during which time
the solution turned dark brown. Powdered NaHCO3 (2.2 g) was
added to the cool reaction mixture. Concentration under reduced
pressure afforded an orange liquid which was diluted with ether
and washed with saturated aqueous NaHCO3 (2×). A clear
yellow liquid was obtained after concentration. Although this
material is impure, it can be used directly for the protection
reaction. This material was however routinely distilled to afford
a colorless liquid (73 g, 53%): bp 32-33 °C (0.8 mmHg); bp 172-
(M
-
H+) 307.1393, found 307.1401. Anal. Calcd for
C
13H24O8‚1/2H2O: C, 49.20; H, 7.94. Found: C, 49.29; H, 7.82.
Ga la ctose p r otection (en tr y 4): Mp 88-91 °C; 1H NMR
(CDCl3) δ 4.84 (d, J ) 2 Hz, 1 H), 4.20 (dd, J ) 10, 3 Hz, 1 H),
4.05-4.10 (m, 1 H), 3.80-4.00 (m, 5 H), 3.43 (s, 3 H), 3.26 (s, 3
H), 3.25 (s, 3 H), 2.77 (br, 2 H), 1.34 (s, 3 H), 1.31 (s, 3 H); 13C
NMR (CDCl3) δ 100.1, 98.3 (2), 70.1, 69.0, 66.1, 65.0, 62.6, 55.1,
47.9 (2), 17.7, 17.6; HRMS (FAB) calcd for C13H24O8 (M - H+)
1
174 °C (760 mmHg); H NMR (CDCl3) δ 3.31 (s, 12 H), 1.32 (s,
6 H); 13C NMR (CDCl3) δ 103.0, 49.3, 19.0. Anal. Calcd for
C8H18O4: C, 53.91; H, 10.18. Found: C, 54.01; H, 10.08.
Qu in ic Acid P r otection (En tr y 1). A suspension of quinic
acid (47.5 g, 0.247 mol) and Dowex 50 H+ (10 g) in MeOH (350
mL) was refluxed under Ar for 15 h. Heating was stopped, and
the mixture was filtered to remove the acid catalyst which can
be reused directly in subsequent runs. The filter was washed
with MeOH (2 × 25 mL). To the combined filtrates were added
trimethyl orthoformate (125 mL, 1.14 mol), 2,2,3,3-tetrameth-
oxybutane (44.8 g, 0.251 mol), and (()-10-camphorsulfonic acid
(2.22 g, 0.010 mol). The resulting solution was refluxed under
Ar for 22 h. The resulting dark brown solution was treated with
powdered NaHCO3 (8.9 g). Concentration afforded an orange
suspension which was partitioned between EtOAc and saturated
aqueous NaHCO3. The aqueous layer was reextracted once with
EtOAc and the combined organic layers were dried over MgSO4.
Filtration through silica and concentration afforded an orange
oil which started to crystallize. Addition of EtOAc/hexane (1:5,
v/v) caused complete crystallization into a single block. Recrys-
tallization (EtOAc and hexane) afforded a white solid (63.9 g,
81%). The brown mother liquor was purified by flash chroma-
tography (EtOAc) to afford an additional amount of product (4.9
g, 6%) as a white foamy solid: mp (crystals) 139.8-140.2 °C;
1H NMR (CDCl3) δ 4.31 (ddd, J ) 12, 10, 5 Hz, 1 H), 4.19 (ddd,
J ) 3, 3, 3 Hz, 1 H), 3.79 (s, 3 H), 3.60 (dd, 10, 3 Hz, 1 H), 3.26
(2 s, 2 × 3 H), 2.19 (ddd, J ) 15, 3, 3 Hz, 1 H), 2.10 (ddd, J ) 12,
5, 3 Hz, 1 H), 2.03 (dd, J ) 15, 3 Hz, 1 H), 1.92 (dd, J ) 12, 12
Hz, 1 H), 1.34 (s, 3 H), 1.30 (s, 3 H); 13C NMR (CDCl3) δ 174.1,
100.2, 99.6, 75.7, 72.6, 69.0, 62.3, 52.8, 47.8, 38.5, 37.3, 17.7,
17.5. Anal. Calcd for C14H24O8: C, 52.49; H, 7.55. Found: C,
52.56; H, 7.52.
.
307.1393, found 307.1380. Anal. Calcd for C13H24O8 1/2H2O: C,
49.20; H, 7.94. Found: C, 49.37; H, 7.98. Spectral data for the
â-anomer: 1H NMR (CDCl3) δ 4.42 (d, J ) 8 Hz, 1 H), 3.80-
4.05 (m, 6 H), 3.74 (dd, J ) 10, 3 Hz, 1 H), 3.55 (s, 3 H), 3.28 (s,
3 H), 3.27 (s, 3 H), 2.73, (br, 2 H), 1.33 (s, 3 H), 1.32 (s, 3 H); 13
C
NMR (CDCl3) δ 101.9, 100.1, 99.7, 74.9, 70.2, 68.0, 66.8, 62.1,
56.7, 48.0, 47.9, 17.6, 17.5.
Ma n n ose p r otection (en tr y 5): 1H NMR (CDCl3) δ 4.75 (s,
1 H), 4.11 (dd, J ) 10, 10 Hz, 1 H), 4.00 (dd, J ) 10, 3 Hz, 1 H),
3.93 (s, 1 H), 3.70-3.85 (m, 3 H), 3.37 (s, 3 H), 3.28 (s, 3 H),
3.26 (s, 3 H), 3.07 (s, 1 H), 2.49 (br, 1 H), 1.32 (s, 3 H), 1.29 (s,
3 H); 13C NMR (CDCl3) δ 101.0, 100.2, 99.7, 70.5, 69.5, 68.0,
62.7, 61.1, 54.8, 48.0, 47.8, 17.7, 17.6; HRMS (FAB) calcd for
C13H24O8 (M - H+) 307.1393, found 307.1404. Anal. Calcd for
C13H24O8: C, 50.64; H, 7.85. Found: C, 50.41; H, 7.90.
Lyxose p r otection (en tr y 6): mp 63-64 °C; 1H NMR
(CDCl3) δ 4.68 (s, 1 H), 4.05-4.25 (m, 1 H), 3.90-3.95 (m, 2 H),
3.55-3.70 (m, 2 H), 3.37 (s, 3 H), 3.27 (s, 3 H), 3.26 (s, 3 H),
2.82 (br, 1 H), 1.33 (s, 3 H), 1.28 (s, 3 H); 13C NMR (CDCl3) δ
101.1, 100.4, 99.6, 69.5, 68.6, 62.7, 60.4, 54.8, 47.9, 47.8, 17.6
(2); HRMS (FAB) calcd for C12H22O7 (M - H+) 277.1287, found
277.1296. Anal. Calcd for C12H22O7: C, 51.79; H, 7.97.
Found: C, 51.50; H, 7.84.
Rh a m n ose p r otection (en tr y 7): mp 144-147 °C; 1H NMR
(CDCl3) δ 4.67 (s, 1 H), 3.90-4.00 (m, 2 H), 3.65-3.85 (m, 2 H),
3.36 (s, 3 H), 3.27 (s, 3 H), 3.24 (s, 3 H), 2.53 (br, 1 H), 1.32 (s,
3 H), 1.29 (s, 3 H), 1.28 (d, J ) 6 Hz, 3 H); 13C NMR (CDCl3) δ
100.8, 100.1, 99.7, 69.7, 68.3, 68.2, 66.3, 54.6, 48.0, 47.6, 17.7,
17.6, 16.5; HRMS (FAB) calcd for C13H24O7 (M - H+) 291.1444,
found 291.1435. Anal. Calcd for C13H24O7: C, 53.41; H, 8.27.
Found: C, 53.33; H, 8.25.
2-Deoxy glu cose p r otection (en tr y 8): 1H NMR (CDCl3) δ
4.84 (d, J ) 3 Hz, 1 H), 4.12 (ddd, J ) 13, 10, 5 Hz, 1 H), 3.70-
3.85 (m, 3 H), 3.62 (dd, J ) 10, 10 Hz, 1 H), 3.32 (s, 3 H), 3.28
(s, 3 H), 3.27 (s, 3 H), 2.37 (br, 1 H), 1.99 (dd, J ) 13, 5 Hz, 1 H),
1.77 (ddd, J ) 13, 13, 3 Hz, 1 H), 1.29 (s, 6 H); 13C NMR (CDCl3)
δ 99.6, 99.5, 98.6, 69.9, 68.2, 64.6, 61.1, 53.4, 47.8, 47.6, 34.4,
17.6, 17.5. Anal. Calcd for C13H24O7: C, 53.41; H, 8.27.
Found: C, 53.23; H, 8.22.
In ositol P r otection (En tr y 2). A suspension of myo-inositol
(0.591 g, 3.28 mmol) in methanol (10 mL), 2,2,3,3-tetramethox-
ybutane (1.19 g, 6.66 mmol), and trimethyl orthoformate (2.9
mL, 26.50 mmol) was treated with CSA (0.042 g, 0.18 mmol).
The resulting mixture was refluxed under Ar. A white precipi-
tate appeared slowly over time. After 135 h at reflux, heating
was stopped and the cool reaction mixture was filtered. The
precipitate was washed with EtOAc/hexane (1:1, v/v). Drying
under vacuum afforded the diprotected product (1.05 g, 79%) as
1
a white solid: mp > 330 °C; H NMR (C5D5N) δ 4.80 (dd, J )
10, 9 Hz, 2, H), 4.71 (t, J ) 2 Hz, 1 H), 4.28 (t, J ) 9 Hz, 1 H),
4.16 (dd, J ) 10, 2 Hz, 2 H), 3.34 (s, 6 H), 3.24 (s, 6 H), 1.45 (s,
6 H), 1.44 (s, 6 H); 13C NMR (C5D5N) δ 100.1, 99.5, 71.0, 70.9,
70.0, 69.5, 47.7, 47.6, 18.1, 18.0; HRMS (FAB) calcd for C18H32O10
Ack n ow led gm en t. Research was supported by a
grant from the National Institutes of Health. Mass
spectral data were obtained at the Michigan State
University Mass Spectrometry Facility which is sup-
ported, in part, by a grant (DRR-00480) from the
Biotechnology Research Technology Program, National
Center for Research Resources, National Institutes of
Health. The NMR data were obtained on instrumenta-
tion that was purchased in part with funds from NIH
(1-S10-RR04750) and NSF (CHE-88-00770 and
92-13241).
(M
-
H+) 407.1917, found 407.1912. Anal. Calcd for
C
18H32O10: C, 52.93; H, 7.90. Found: C, 52.98; H, 7.90.
Gen er a l P r oced u r e for BBA P r otection . A suspension of
diol (2-5 mmol, 1 equiv) in a solution of 2,2,3,3-tetrameth-
oxybutane (1-1.2 equiv), trimethyl orthoformate (4 equiv) in
methanol (2-5 mL/mmol of diol) was treated with camphorsul-
fonic acid (0.05 equiv). The mixture was refluxed under Ar for
12-18 h. The cool reaction mixture was then treated with
powdered NaHCO3 (ca. 0.5 g) and concentrated under reduced
pressure. Purification by flash chromatography or radial chro-
matography (eluent EtOAc and hexane) provided the protected
carbohydrates.
J O960170N