Dihydroxylation of 4-substituted 1,2-dioxines: A concise route to branched erythro sugars

Article abstract of DOI:10.1021/jo900669u

(Chemical Equation Presented) The synthesis of 2-C-branched erythritol derivatives, including the plant sugar (±)-2-C-methylerythritol 2, was achieved through a dihydroxylation/reduction sequence on a series of 4-substituted 1,2-dioxines 3. The asymmetric dihydroxylation of 1,2-dioxines was examined, providing access to optically enriched dihydroxy 1,2-dioxanes 4. The synthesized 1,2-dioxanes were converted to other erythro sugar analogues and tetrahydrofurans through controlled cleavage of the endoperoxide linkage.

Full text of DOI:10.1021/jo900669u

Dihydroxylation of 4-Substituted 1,2-Dioxines: A
Concise Route to Branched Erythro Sugars
Tony V. Robinson,† Daniel Sejer Pedersen,†,§
Dennis K. Taylor,*,† and Edward R. T. Tiekink‡
FIGURE 1. Apiose 1 and 2-C-methylerythritol (ME) 2.
Department of Chemistry, The UniVersity of Adelaide,
South Australia 5005, Australia, and Department of
Chemistry, UniVersity of Texas at San Antonio, One UTSA
Circle, San Antonio, Texas 78249-0698
is the branched plant sugar 2-C-methylerythritol (ME, 2), which
has been implicated in the biosynthesis of isoprenoids via the
mevalonate independent methylerythritol phosphate (MEP)
pathway.5
Free ME has also been isolated from many plants, such as
ConVolVulus glomeratus.6 In addition, an important study by
Claeys et al. found significant quantities of methylerythritol and
its diastereomer methylthreitol in the atmosphere above the
Amazonian rainforest.7 It has been postulated that the tetrols
are formed from photooxidation of isoprene (emitted from the
forest) and are now considered significant secondary organic
aerosols worldwide.8
dennis.taylor@adelaide.edu.au
ReceiVed March 30, 2009
The recent discoveries of the role ME plays in nature has
provoked the development of several synthetic routes to both
racemic and enantiopure 2-C-methylerythritol, as well as various
phosphate derivatives.9 Given that animals lack the MEP
pathway, it seems an obvious target for the development of
herbicides and antibacterial agents.10 To this end efforts toward
the synthesis of other ME analogues have begun with the recent
reporting of trifluoromethyl11 and amino analogues.12 However,
to the best of our knowledge no general route to 2-C-branched
erythritol derivatives has been reported, which is vital for
providing access to a diverse range of compounds necessary
for further biochemical studies and biological testing.
It was proposed that a general and concise synthesis of 2-C-
branched erythritol derivatives, including ME, could be ac-
The synthesis of 2-C-branched erythritol derivatives, includ-
ing the plant sugar (()-2-C-methylerythritol 2, was achieved
through a dihydroxylation/reduction sequence on a series of
4-substituted 1,2-dioxines 3. The asymmetric dihydroxylation
of 1,2-dioxines was examined, providing access to optically
enriched dihydroxy 1,2-dioxanes 4. The synthesized 1,2-
dioxanes were converted to other erythro sugar analogues
and tetrahydrofurans through controlled cleavage of the
endoperoxide linkage.
M. Carbohydr. Res. 2005, 340, 455. (d) Hotchkiss, D. J.; Soengas, R.; Booth,
K. V.; Weymouth-Wilson, A. C.; Eastwick-Field, V.; Fleet, G. W. J. Tetrahedron
Lett. 2007, 48, 517. (e) Booth, K. V.; da Cruz, F. P.; Hotchkiss, D. J.; Jenkinson,
S. F.; Jones, N. A.; Weymouth-Wilson, A. C.; Clarkson, R.; Heinz, T.; Fleet,
G. W. J. Tetrahedron: Asymmetry 2008, 19, 2417.
(5) (a) Qureshi, N.; Porter, J. W. In Biosynthesis of Isoprenoid Compounds;
Porter, J. W., Spurgeon, S. L., Eds.; Wiley: New York, 1981; Vol. 1, pp 47-
94. (b) Bach, T. J. Lipids 1995, 30, 191. (c) Duvold, T.; Bravo, J.; Pale-
Grosdemange, C.; Rohmer, M. Tetrahedron Lett. 1997, 38, 4769. (d) Charon,
L.; Hoeffler, J.; Pale-Grosdemange, C.; Lois, L.; Campos, N.; Boronat, A.;
Rohmer, M. Biochem. J. 2000, 346, 737. (e) Hoeffler, J.; Grosdemange-Billiard,
C.; Rohmer, M. Tetrahedron Lett. 2000, 41, 4885.
(6) Anthonsen, T.; Hagen, S.; Kazi, M. A.; Shah, S. W.; Tagar, S. Acta Chem.
Scand. 1976, B30, 91.
(7) Claeys, M.; Graham, B.; Vas, G.; Wang, W.; Vermeylen, R.; Pashynska,
V.; Cafmeyer, J.; Guyon, P.; Andreae, M. O.; Artaxo, P.; Maenhaut, W. Science
2004, 303, 1173.
(8) (a) Kourtchev, I.; Ruuskanen, T.; Gelencser, A.; Maenhaut, W.; Claeys,
M. Atmos. Chem. Phys. 2005, 5, 2761. (b) Edney, E. O.; Kleindienst, T. E.;
Jaoui, M.; Levandowski, M.; Offenberg, J. H.; Wang, W.; Claeys, M. Atmos.
EnViron. 2005, 39, 5281. (c) Xia, X.; Hopke, P. K. EnViron. Sci. Technol. 2006,
40, 6934.
(9) (a) Anthonsen, T.; Hagen, S.; Sallam, M. A. E. Phytochemistry 1980,
19, 2375. (b) Fontana, A.; Messina, R.; Spinella, A.; Cimino, G. Tetrahedron
Lett. 2000, 41, 7559. (c) Giner, J.; Ferris, W. V. Org. Lett. 2002, 4, 1225. (d)
Koppisch, A. T.; Poulter, C. D. J. Org. Chem. 2002, 67, 5416. (e) Giner, J.;
Ferris, W. V.; Mullins, J. J. J. Org. Chem. 2002, 67, 4856. (f) Urbansky, M.;
Davis, C. E.; Surjan, J. D.; Coates, R. M. Org. Lett. 2004, 6, 135.
(10) (a) Rohmer, M. Prog. Drug Res. 1998, 50, 135. (b) Testa, C. A.; Brown,
M. J. Curr. Pharm. Biotechnol. 2003, 4, 248. (c) Rohdich, F.; Bacher, A.;
Eisenreich, W. Bioorg. Chem. 2004, 32, 292.
Branched-chain sugars represent a rare class of naturally
occurring carbohydrates found in plants and antibiotics.1 The
first and probably best-known example is apiose 1 (Figure 1),
which was initially isolated from parsley2 and is found in many
plants as a structural component of glycosides, such as apiin.3
Subsequently, numerous other examples of branched carbohy-
drates have been isolated from natural sources, and many non-
natural compounds have been synthesized.4 Of recent interest
† The University of Adelaide.
‡ The University of Texas at San Antonio.
§ Present address: University of Copenhagen, Faculty of Pharmaceutical
Sciences, Department of Medicinal Chemistry, Universitetsparken 2, 2100
Copenhagen, Denmark.
(1) (a) Williams, N. R.; Wander, J. D. In The Carbohydrates, Chemistry
and Biochemistry, 2nd ed.; Pigman, W., Horton, D., Eds.; Academic Press: New
York, 1980; pp 761-798. (b) Yoshimura, J. AdV. Carbohydr. Chem. Biochem.
1984, 42, 69.
(2) Hudson, C. S. AdVan. Carbohydr. Chem. 1949, 4, 57.
(3) (a) Watson, R. A.; Orenstein, N. S. AdV. Carbohydr. Chem. Biochem.
1975, 31, 135. (b) Beck, E.; Hopf, H. In Methods in Plant Biochemistry; Dey,
P. M., Harborne, J. B., Eds.; Academic Press: London, 1990; Vol. 2, pp 235-
289.
(4) (a) Ferrier, R. J. Carbohydrate Chemistry: Monosaccharides, Disaccha-
rides and Specific Oligosaccharides; The Royal Society of Chemistry: Cambridge,
1968-2001; Vols. 1-32. (b) Hricoviniova, Z.; Hricovini, M.; Petrus, L.
J. Carbohydr. Chem. 2000, 19, 827. (c) Hricoviniova, Z.; Lamba, D.; Hricovini,
(11) Wang, H.; Zhao, X.; Li, Y.; Lu, L. J. Org. Chem. 2006, 71, 3278.
(12) Lagisetti, C.; Urbansky, M.; Coates, R. M. J. Org. Chem. 2007, 72,
9886.
10.1021/jo900669u CCC: $40.75  2009 American Chemical Society
Published on Web 05/29/2009
J. Org. Chem. 2009, 74, 5093–5096 5093

SCHEME 1
SCHEME 2
TABLE 1. Asymmetric Dihydroxylation of 4-Substituted
1,2-Dioxines 3
entrya
R
ligand
product (yield)
ee
1
2
3
4
5
6
7
8
Ph
Ph
Ph
Ph
c-C6H11
c-C6H11
c-C6H11
1-Ad
(DHQD)2PHALb
(DHQD)2PHAL
(DHQD)2PHALc
(DHQ)2PHAL
(DHQD)2PHAL
(DHQD)2AQN
(DHQD)2PYR
(DHQD)2PHAL
(DHQD)2PHAL
(DHQD)2PHAL
(DHQD)2PHAL
4a (33)
4a (70)
4a (40)
4a (68)
4b (90)
4b (99)
4b (75)
4c (91)
4d (63)
4e (65)
4f (83)
87
93
89
85
85
70
89
80
10
40
93
1,2-dioxine caused by the presence of K2CO3.17 This was
somewhat surprising as trisubstituted olefins are considered
“standard” substrates in the Sharpless asymmetric dihydroxy-
lation and usually go to completion in under 24 h at 0 °C.16
To suppress decomposition, we decided to increase the reaction
rate by employing a “super” AD-mix (entry 2).18 As anticipated
the use of a super AD-mix consisting of 2 mol % K2OsO4 and 5
mol % phthalazine (PHAL) ligand gave a significant increase in
reaction rate and hence an increased yield as well as a slight
increase in ee, thus becoming the preferred conditions for the
asymmetric dihydroxylation of 4-substituted 1,2-dioxines. The use
of other readily available quinidine-based ligands produced slight
variations in yield and ee (entries 6 and 7).
9
10
11
Me
Bn
n-C6H13
a Reactions were typically performed using 0.3 mmol of olefin in H2O
(1.5 mL) and t-BuOH (1.5 mL), with K2CO3 (0.9 mmol), K3Fe(CN)6
(0.9 mmol), MeSO2NH2 (0.3 mmol), K2OsO4 (2 mol %), and chiral
ligand (5 mol %) at 25 °C unless otherwise stated. b Only 1 mol %
ligand and 0.4 mol
%
K2OsO4 ·2H2O were used. c Reaction was
perfomed at 0 °C until complete by TLC.
The remainder of the 1,2-dioxines were dihydroxylated using
the optimized super AD-mix conditions (entries 5, 8-11). While
the ee was high for bulky substituents (compounds 4a,b,c), there
was poor selectivity with methyl-substituted 1,2-dioxine 4d. This
was disappointing but not unexpected. Sharpless has previously
reported that for high asymmetric induction in cyclic trisubsti-
tuted olefins, the substituent must be bulky, with best results
for aryl substituents.16
The enantioselectivities were determined by derivatization of
the diols as their mono-TMS ethers, followed by 1H NMR chiral
shift experiments using the distinct TMS group as a reference
point, which is a method favored by Warren and co-workers.19
(see Supporting Information for conditions and characterization
data).
While the preliminary results presented above are promising,
some clear limitations for the asymmetric dihydroxylation of
4-substituted 1,2-dioxines are evident. The enantioselectivity of
the less bulky substituents (compounds 4d,e) was poor; therefore
other ligands may need to be explored to accommodate a broader
substitution pattern. Unfortunately 1,2-dioxines are inherently
base-sensitive, which results in decomposition using the Sharp-
less AD conditions. Ideally, asymmetric dihydroxylation of 1,2-
dioxines would be carried out under neutral or mildly acidic
conditions; however, no adequate methodology encompassing
these factors currently exists.
complished by application of the photooxidation, dihydroxyla-
tion, and reduction strategy, previously reported by us, to 1,3-
butadienes.13 The Sharpless asymmetric dihydroxylation has
previously been utilized for the de novo synthesis of carbohy-
drates.14 Application of this reaction to achiral 1,2-dioxines
should also provide access to optically enriched erythritols.
Moreover, cleavage of the endoperoxide bond can be controlled
under suitable conditions, which should provide access to other
branched erythro sugars from the common dihydroxy 1,2-
dioxane 4 starting material.
We now wish to report the first examples of the asymmetric
dihydroxylation of 1,2-dioxines and the conversion of the
dihydroxy 1,2-dioxanes to various branched erythro sugars and
tetrahydrofurans, including the plant sugar (()-2-C-methyl-
erythritol 2.
A series of known 4-substituted 1,2-dioxines 3 were conve-
niently prepared by photo-oxidation of the requisite 1,3-
butadienes. The racemic dihydroxylation of these endoperoxides
was then performed using the modified Upjohn conditions
described by Sharpless15 and previously reported by us13 (see
Supporting Information for yields). Logically we then examined
the asymmetric dihydroxylation of 1,2-dioxines, which has not
previously been reported (Scheme 1).
Phenyl-substituted 1,2-dioxine 3a was chosen as the model
substrate. We began with the conditions reported by Sharpless16
(Table 1, entry 1). Although high asymmetric induction was
achieved, the reaction was sluggish and the yield was low (33%),
mainly due to competing base-catalyzed decomposition of the
With the dihydroxy 1,2-dioxanes in hand, we next examined
reduction of the peroxide linkage to furnish the desired 2-C-
branched erythritol derivatives, Scheme 2.
For convenience the racemic diols were used. Hydrogenation
over palladium on carbon returned high yields of all of the
tetraols, which were readily purified by chromatography and/
or recrystallization from ethyl acetate. Tetraol 2 was spectro-
scopically consistent with data previously reported for the plant
sugar 2-C-methyl-D-erythritol.20
(13) Robinson, T. V.; Taylor, D. K.; Tiekink, E. R. T. J. Org. Chem. 2006,
71, 7236.
(14) (a) Henderson, I.; Sharpless, K. B.; Wong, C. H. J. Am. Chem. Soc.
1994, 116, 558. (b) Harris, J. M.; Keranen, M. D.; O’Doherty, G. A. J. Org.
Chem. 1999, 64, 2982. (c) Ahmed, M. M.; Berry, B. P.; Hunter, D. J.; Tomcik,
D. J.; O’Doherty, G. A. Org. Lett. 2005, 7, 745. (d) Ahmed, M. M.; O’Doherty,
G. A. J. Org. Chem. 2005, 70, 10576.
(15) Dupau, P.; Epple, R.; Thomas, A. A.; Fokin, V. V.; Sharpless, K. B.
AdV. Synth. Catal. 2002, 344, 421.
(16) Kolb, H. C.; VanNieuwenhze, M. S.; Sharpless, K. B. Chem. ReV. 1994,
94, 2483.
(17) Kornblum, N.; DeLaMare, H. E. J. Am. Chem. Soc. 1951, 73, 880.
(18) (a) Bennani, Y. L.; Sharpless, K. B. Tetrahedron Lett. 1993, 34, 2079.
(b) Hermitage, S. A.; Murphy, A.; Nielsen, P.; Roberts, S. M. Tetrahedron 1998,
54, 13185.
(19) Nelson, A.; Warren, S. J. Chem. Soc., Perkin Trans. 1 1997, 17, 2645.
5094 J. Org. Chem. Vol. 74, No. 14, 2009

SCHEME 3
SCHEME 4
TABLE 2. Ring Opening of Dihydroxy 1,2-Dioxanes 4 with
Co(SALEN)2
entry
R
products
yielda
6:7b
1
2
3
4
5
6
Ph
6a, 7a
6b, 7b
6c, 7c
6d, 7d
6e, 7e
6f, 7f
92
91
98
87
89
87
59:41
52:48
49:51
60:40
59:41
55:45
c-C6H11
1-Ad
Me
Bn
n-C6H13
a Refers to the combined isolated yield of both regio-isomers. b Ratio
was determined by isolated mass after chromatography.
Thus starting from isoprene, the synthesis of (()-2-C-
methylerythritol was accomplished in three steps using a photo-
oxidation/dihydroxylation/reduction sequence, with an overall
yield of 25%.
The reactions of endoperoxides with transition metals such
as Co(II) have been well documented.21 Thus when the racemic
dihydroxy 1,2-dioxanes 4 were treated with a catalytic quantity
of Co(SALEN)2 the 2- and 3-branched erythroses 6 and 7,
respectively, were obtained via a one-electron reduction process,
Scheme 3.
The regioisomers were readily separable by chromatography
and completely stable at room temperature, providing a high
combined yield for each example, Table 2. All compounds were
found to exist solely in the cyclic hemiacetal form(s) both when
neat and in solution, indicated by the absence of a carbonyl
group in both the IR and NMR spectra, respectively.
It was recently reported that the reaction of monocyclic 1,2-
dioxines and epoxy 1,2-dioxanes with triphenylphosphine may
yield tetrahydrofurans.22 Application of this methodology to the
dihydroxy 1,2-dioxanes 4 would provide direct access to novel
3,4-dihydroxy THFs 10, Scheme 4.
However, when subjected to the necessary conditions, only
the ring-opened products 6 and 7 were observed. We have
previously noted that dihydroxy 1,2-dioxanes tend to be
thermally unstable;13 however, elevated temperature is required
for oxygen extrusion to be favored. We also previously observed
that acetal protection of the diol unit dramatically increases the
stability of the 1,2-dioxanes. Therefore, after preparation of the
acetonide-protected 1,2-dioxanes 8 the reaction was repeated,
this time returning the desired THFs 9 in excellent yields.
Hydrolysis of the acetonide unit was accomplished with acidic
Dowex resin, furnishing the novel 3,4-dihydroxy THFs 10 in
high yield. Both the protected and dihydroxy THFs 9 and 10
all gave spectral data consistent with their molecular structures.
The extrusion of oxygen was confirmed by mass spectrometry
and elemental analysis. In addition, the structures of 9a and
10a were unambiguously confirmed by X-ray analysis.
In summary, we have presented the first examples of the
asymmetric dihydroxylation of 1,2-dioxines providing access
to optically enriched dihydroxy 1,2-dioxanes. By chemoselective
transformation of these central building blocks a general route
to branched erythritol, erythrose, and tetrahydrofuran core
structures was established. The efficiency of this methodology
was highlighted by the three-step synthesis of (()-2-C-meth-
ylerythritol.
Experimental Section
General Procedure for the Racemic Dihydroxylation of
4-Substituted 1,2-Dioxines 3 To Give Dihydroxy 1,2-Dioxanes
4. To a stirred solution of 1,2-dioxine (1 mmol) in t-BuOH or
CH3CN (5 mL) and water (5 mL) were added K2OsO4 (0.5 mol
%) and citric acid (2 mmol), followed by NMO (1.1 mmol), and
the bright yellow/green mixture stirred rapidly until complete by
TLC. Completion of the reaction was usually accompanied by a
characteristic fading of the yellow/green color. The reaction was
extracted with CH2Cl2 or ethyl acetate (4 × 50 mL), dried (Na2SO4),
and concentrated in vacuo, and the crude material purified by flash
chromatography to furnish the pure dihydroxy 1,2-dioxanes.
(()-(4S,5R)-4-Methyl-1,2-dioxane-4,5-diol (4d). Colorless oil
(569 mg, 85%); Rf 0.33 (7:3 ethyl acetate/hexane). IR (neat): 3418,
1
1429, 1374, 1242, 1161, 1014, 972 cm-1. H NMR (300 MHz,
CDCl3 + 2 drops d6-DMSO): δ 1.31 (s, 3H), 2.51 (br s, 2H), 3.63
(dd, J ) 4.5, 8.1 Hz, 1H), 4.07-4.09 (m, 2H), 4.12 (dd, J ) 8.1,
12.3 Hz, 1H), 4.24 (dd, J ) 4.5, 12.3 Hz, 1H). 13C NMR (75 MHz,
CDCl3 + 2 drops d6-DMSO): δ 21.3, 67.8, 69.2, 73.7, 79.2. MS
m/z (EI): 135 (M+ + H, 5), 117 (16), 91 (14), 74 (82), 61 (17), 43
(100). HRMS calcd for (M+ + Na) C5H10O4Na: 157.0477. Found:
157.0471.
General Method for the Reduction of Dihydroxy 1,2-Dioxanes
4 To Furnish Erythritols 2 and 5. To a stirred solution of 1,2-
dioxane 4 (1 mmol) in methanol (5 mL) was added 10% w/w of
5% palladium on carbon, and the mixture was stirred overnight
under an atmosphere of hydrogen. The suspension was then filtered
through a small pad of kenite washing with methanol, and the
solvent was removed in vacuo to give the crude polyol, which was
purified by flash chromatography or recrystallized from ethyl
acetate.
(20) Kis, K.; Wungsintaweekul, J.; Eisenreich, W.; Zenk, M. H.; Bacher, A.
J. Org. Chem. 2000, 65, 587.
(()-2-C-Methylerythritol (2).20 Colorless oil (120 mg, 73%);
Rf 0.23 (1:4 MeOH/CH2Cl2). 1H NMR (300 MHz, D2O): δ 1.11 (s,
3H), 3.46 (d, J ) 11.7 Hz, 1H), 3.57 (dd, J ) 8.4, 11.1 Hz, 1H),
3.57 (d, J ) 11.7 Hz, 1H), 3.65 (dd, J ) 2.1, 8.4 Hz, 1H), 3.82
(21) (a) Avery, T. D.; Jenkins, N. F.; Kimber, M. C.; Lupton, D. W.; Taylor,
D. K. Chem. Commun. 2002, 28. (b) Greatrex, B. W.; Jenkins, N. F.; Taylor,
D. K.; Tiekink, E. R. T. J. Org. Chem. 2003, 68, 5205. (c) Greatrex, B. W.;
Taylor, D. K. J. Org. Chem. 2005, 70, 470.
(22) Greatrex, B. W.; Taylor, D. K. J. Org. Chem. 2004, 69, 2577.
J. Org. Chem. Vol. 74, No. 14, 2009 5095

(dd, J ) 2.1, 11.1 Hz, 1H). 13C NMR (75 MHz, D2O): δ 21.0,
64.6, 68.9, 76.8, 77.6.
removed in vacuo, and the residue was purified by flash
chromatography.
(()-(3aS,6aR)-2,2,3a-Trimethyltetrahydrofuro-[3,4-
d][1,3]dioxole (9d). Volatile colorless oil (231 mg, 86%); Rf 0.36
(3:37 ether/CH2Cl2); IR (neat) 1456, 1378, 1261, 1206, 1142, 1101,
General Procedure for Ring Opening Dihydroxy 1,2-Dioxanes
4 with Co(SALEN)2 To Furnish Erythroses 6 and 7. To a stirred
solution of N,N′-bis(salicylidene)ethylene diaminocobalt(II) (0.025
mmol) in THF (5 mL) at ambient temperature was added 1,2-
dioxane (1 mmol), and the reaction left to stir until complete by
TLC (∼16 h). All volatiles were then removed in vacuo, and the
product purified by flash chromatography.
1
1067, 1023 cm-1. H NMR (300 MHz, CDCl3): δ 1.41 (s, 3H),
1.49 (s, 6H), 3.29 (d, J ) 9.9 Hz, 1H), 3.57 (dd, J ) 3.3, 10.8 Hz,
1H), 3.96 (d, J ) 9.9 Hz, 1H), 4.03 (d, J ) 10.8 Hz, 1H), 4.37 (d,
J ) 3.3 Hz, 1H). 13C NMR (75 MHz, CDCl3): δ 22.5, 27.2, 27.4,
74.0, 79.1, 86.6, 89.1, 112.1. MS m/z (EI): 158 (M+, 1), 143 (100),
115 (10), 97 (13), 83 (37), 55 (66), 43 (57). HRMS calcd for (M+
+ Na) C8H14O3Na: 181.0841. Found: 181.0838.
(()-2-C-Methyl-erythrofuranose (6d).23 Major anomer: color-
less oil (78 mg, 52%, 87% total); Rf 0.43 (1:4 MeOH/CH2Cl2). 1H
NMR (600 MHz, D2O): δ 1.34 (s, 3H), 3.73 (dd, J ) 6.0, 8.4 Hz,
1H), 4.22 (dd, J ) 6.0, 7.2 Hz, 1H), 4.26 (dd, J ) 7.2, 8.4 Hz,
1H), 5.16 (s, 1H). 13C NMR (150 MHz, D2O): δ 20.7, 72.6, 76.4,
80.7, 105.1. Minor anomer: 1H NMR (600 MHz, D2O): δ 1.33 (s,
3H), 3.93 (dd, J ) 4.2, 9.6 Hz, 1H), 4.03 (dd, J ) 4.2, 6.0 Hz,
1H), 4.16 (dd, J ) 6.0, 9.6 Hz, 1H), 5.04 (s, 1H). 13C NMR (150
MHz, D2O): δ 24.0, 74.0, 76.7, 78.6, 102.9.
General Procedure for the Hydrolysis of Acetonides 9 To
Give Diols 10. To a solution of acetonide-protected THF 9 (1 mmol)
dissolved in MeOH (10 mL) was added activated 50W Dowex X8
resin (1 g), and the mixture was stirred at 70 °C until complete by
TLC (ca. 2-5 days). The reaction was allowed to cool and then
filtered to remove the Dowex. The methanol was removed under
reduced pressure, and the residue was purified by flash chroma-
tography to give the pure diols.
(()-(3S,4R)-3-Methyltetrahydrofuran-3,4-diol (10d). Colorless
oil (113 mg, 82%); Rf 0.34 (ethyl acetate); IR (neat) 3400, 1462,
1379, 1103, 1042, 908 cm-1. 1H NMR (300 MHz, CDCl3): δ 1.36
(s, 3H), 2.75 (br s, 1H), 2.86 (br s, 1H), 3.63 (d, J ) 9.3 Hz, 1H),
3.73 (dd, J ) 4.5, 9.9 Hz, 1H), 3.77 (d, J ) 9.3 Hz, 1H), 3.91 (dd,
J ) 4.5, 5.7 Hz, 1H), 4.05 (dd, J ) 5.7, 9.9 Hz, 1H). 13C NMR (75
MHz, CDCl3): δ 23.1, 73.7, 76.3, 76.7, 77.2. MS m/z (EI): 118
(M+, 2), 75 (100), 58 (40), 55 (23), 45 (18). HRMS calcd for (M+
+ Na) C5H10O3Na: 141.0528. Found: 141.0528.
General Procedure for Acetonide Protection of Dihydroxy
1,2-Dioxanes. To a stirred solution of 1,2-dioxane 4 (1 mmol) in
dry CH2Cl2 (5 mL) was added 2,2-dimethoxypropane (3 mmol)
followed by p-toluenesulfonic acid (10 mol %), and the solution
was stirred under nitrogen until complete by TLC (∼1 h). The
reaction was diluted with CH2Cl2 (20 mL), washed with saturated
NaHCO3 (20 mL), and dried (Na2SO4), and the solvent removed
in vacuo. The residue was then purified by flash chromatography.
(()-(3aS,7aR)-2,2,3a-Trimethyltetrahydro-[1,3]dioxolo[4,5-
d][1,2]dioxine (8d). Volatile colorless oil (967 mg, 81%); Rf 0.27
(CH2Cl2); IR (neat) 1460, 1370, 1247, 1215, 1121, 1019 cm-1. 1H
NMR (300 MHz, CDCl3): δ 1.41 (s, 3H), 1.44 (s, 3H), 1.54 (s,
3H), 3.77 (ddd, J ) 0.9, 2.4, 12.6 Hz, 1H), 3.84 (br s, 1H), 4.31
(dd, J ) 0.9, 12.6 Hz, 1H), 4.40 (ddd, J ) 1.5, 2.4, 14.0 Hz, 1H),
4.50 (dd, J ) 1.8, 14.0 Hz, 1H). 13C NMR (75 MHz, CDCl3): δ
22.1, 27.1, 28.7, 71.3, 74.0, 75.7, 78.4, 109.1. MS m/z (EI): 174
(M+, 4), 227 (100), 209 (9), 167 (15), 149 (18), 83 (24). HRMS
calcd for (M+ + Na) C8H14O4Na: 197.0790. Found: 197.0785.
General Procedure for the Reaction of Triphenylphosphine
with 1,2-Dioxanes 8 To Furnish Tetrahydrofurans 9. To a solution
of 1,2-dioxane (1 mmol) dissolved in anhydrous CHCl3 (5 mL)
was added triphenylphosphine (1.5 mmol), and the reaction was
stirred under an atmosphere of N2. The reaction mixture was then
heated at reflux until complete by TLC (ca. 16 h). The solvent was
Acknowledgment. We would like to thank the Australian
Research Council for funding. T.V.R. would like to thank the
Australian Government for support in the form of a scholarship.
D.S.P. would like to thank Carlsbergfondet, Direktør Ib Hen-
riksens Fond, Brødrene Hartmanns Fond, and Torben & Alice
Frimodts Fond for funding.
Supporting Information Available: Experimental proce-
1
dures, full characterization, H and 13C NMR spectra for all
compounds, and crystallographic data and CIF files for 9a and
10a. This material is available free of charge via the Internet at
http://pubs.acs.org.
(23) Zhao, S.; Petrus, L.; Serianni, A. S. Org. Lett. 2001, 3, 3819.
JO900669U
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