Efficient desymmetrization of "pseudo"-C2-symmetric substrates: Illustration in the synthesis of a disubstituted butenolide from arabitol

Article abstract of DOI:10.1021/jo026696r

A short synthesis of the homochiral disubstituted butenolide 1 is described in four steps from arabitol. The key steps are the selective kinetic protection of arabitol and the cyclization of 11 to form the butenolide ring. This last transformation represents a rare example of a fully stereoselective cyclitive desymmetrization process of a "pseudo"-C₂-symmetric substrate.

Full text of DOI:10.1021/jo026696r

Efficien t Desym m etr iza tion of “P seu d o”-C2-Sym m etr ic Su bstr a tes:
Illu str a tion in th e Syn th esis of a Disu bstitu ted Bu ten olid e fr om
Ar a bitol
Bruno Linclau,* A. J ames Boydell, Philip J . Clarke, Richard Horan,# and Claire J acquet‡
Department of Chemistry, Southampton University, Highfield, Southampton SO17 1BJ , United Kingdom
bruno.linclau@soton.ac.uk
Received November 12, 2002
A short synthesis of the homochiral disubstituted butenolide 1 is described in four steps from
arabitol. The key steps are the selective kinetic protection of arabitol and the cyclization of 11 to
form the butenolide ring. This last transformation represents a rare example of a fully stereoselective
cyclitive desymmetrization process of a “pseudo”-C2-symmetric substrate.
Butenolides [2(5H)-furanones] are substructures found
in many natural products. The wide range of biological
activities displayed by these natural products include the
following: cytotoxic, antitumor, antimalarial, immuno-
suppressive, antiviral, antibacterial, and antifungal ac-
tivity.1,2 The important biological role of butenolides is
further underlined by the synthesis, including synthesis
on solid support, of unnatural butenolide-containing
products.3 Because of their intrinsic reactivity, buteno-
lides are versatile building blocks for the synthesis of a
wide variety of biologically active compounds,4 and they
are also used as advanced intermediates in the synthesis
of complex natural products.5 Consequently, the develop-
ment of methodologies to access butenolides has received
much attention and continues to be an active research
field.2-6
As part of a research program in developing efficient
desymmetrization methodologies, we became interested
in the synthesis of homochiral butenolides starting from
carbohydrates.7 The selected target 1 (Scheme 1) contains
chiral centers both in the ring and the â-substituent. Very
few butenolides with this substitution pattern have been
reported,7c but 1 is an interesting synthetic building block
with good opportunities for subsequent diastereoselective
#
Southampton University undergraduate project student.
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(b) Hegedus, L. S.; Geisler, L. J . Org. Chem. 2000, 65, 4200-4203. (c)
Tsuboi, S.; Sakamoto, J .-I.; Yamashita, H.; Sakai, T.; Utaka, M. J . Org.
Chem. 1998, 63, 1102-1108. (d) Feringa, B. L.; de Lange, B.; J ansen,
J . F. G. A.; de J ong, J . C.; Lubben, M.; Faber, W.; Schudde, E. P. Pure
Appl. Chem. 1992, 64, 1865-1871.
‡ ERASMUS exchange student, Universite´ Paul Sabatier, Depar-
tement de Chimie at Castres.
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2001, 64, 925-931. (c) Siddiqui, B. S.; Afsan, F.; Ghiasuddin; Faizi,
S.; Naqvi, S. N.-ul-H.; Tariq, R. M. J . Chem. Soc., Perkin Trans. 1 1999,
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1999, 40, 7513-7514. (e) Alali, F. Q.; Liu, X. X.; McLaughlin, J . L. J .
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10.1021/jo026696r CCC: $25.00 © 2003 American Chemical Society
Published on Web 02/01/2003
J . Org. Chem. 2003, 68, 1821-1826
1821

Linclau et al.
SCHEME 1. Retr osyn th etic An a lysis
disubstituted acetonide, which is more stable than a
terminal acetonide.11b,12
Although the desired bis-protected arabitol 6 is acces-
sible in four steps from mannose,13 it was decided to
investigate the direct protection of arabitol in more detail.
Since it is known that primary alcohols react faster in
an acetonide formation reaction,12a kinetic protection
protocols were investigated. We based our first experi-
ments on literature procedures for selective terminal
acetonide formation of substrates containing a terminal
triol moiety.14 Gratifyingly, it was found that reaction of
arabitol with acetone/2,2-dimethoxypropane and 50 mol
% of camphor sulfonic acid (CSA) at room temperature
led to the desired 1,2:4,5-di-O-isopropylidene product 6
in 58% yield, with 9% of the undesired regioisomer 5. The
reaction could easily be monitored by visual disappear-
ance of arabitol, which has a low solubility in the reaction
mixture. The NMR of the reaction mixture was remark-
ably clean, with 5 and 6 present as the two major
compounds and a small amount of mono-acetonide spe-
cies. The mixture of the 1,2:4,5-di-O-isopropylidene and
2,3:4,5-di-O-isopropylidene regioisomers could be sepa-
rated by careful column chromatography,15 with the
mono-acetonide derivatives being easily removed during
the same separation process.
transformations, and is a valuable precursor for the
synthesis of nucleoside and carbohydrate derivatives.
As can be seen from the retrosynthetic analysis (Scheme
1), the synthesis of 1 is designed to exploit the sym-
metrical nature of the starting material, arabitol 4, and
of the intermediate products. The first key step is the
regioselective protection of arabitol (4 f 3), which,
surprisingly, was not described at the outset of this work.
The second key step in the proposed synthesis is an
efficient desymmetrization of the ester 2 to form the
butenolide ring system.8 We have identified 2 as a novel
subclass (see below) of “pseudo”-C2-symmetric9 sub-
strates, and the described desymmetrization methodology
should be applicable to other systems as well and hence
be of general interest.10 Unlike most carbohydrate-based
starting materials, arabitol is commercially available in
both enantiomeric forms at similar cost.
In this paper, we disclose our results for the arabitol
protection and subsequent butenolide synthesis. Using
the butenolide synthesis as an example, we introduce a
novel subclass of “pseudo”-C2-symmetric substrates and
show that for this subclass, desymmetrization with
complete diastereoselectivity is possible.
Although useful quantities of 6 could be obtained by
using this procedure, the separation of 5 and 6 was time-
consuming and prohibited further up-scaling. In addition,
an improvement regarding yield was also desirable.
Further optimization has led us to use 3,3-dimethoxy-
pentane leading to the di-O-isopentylidene acetal 7 (Table
1) with refluxing tetrahydrofuran (THF) as solvent and
using very short reaction times. The formation of iso-
Resu lts a n d Discu ssion
As can be seen from the retrosynthetic analysis, the
first aim was the regioselective protection of arabitol as
the 1,2:4,5-bis-acetal product 5. Unfortunately, literature
reports revealed that the protection of arabitol as its bis-
acetonide under typical conditions results in the forma-
tion of the undesired 2,3:4,5-di-O-isopropylidene arabitol
5 (eq 1).11 The isomer 5 contains an internal trans-
(11) (a) Bukhari, M. A.; Foster, A. B.; Lehmann, J .; Webber, J . M.;
Westwood, J . H. J . Chem. Soc. 1963, 2291-2295. (b) Nakagawa, T.;
Tokuoka, H.; Shinoto, K.; Yoshimura, J .; Sato, T. Bull. Chem. Soc. J pn.
1967, 40, 2150-2154. (c) After our initial studies in the area, the
protection of arabitol in DMF as solvent (12 h, rt) was reported to yield
the 1,2:4,5-bis-acetonide, although no detailed experimental was given
(Terauchi, T.; Terauchi, T.; Sato, I.; Tsukada, T.; Kanoh, N.; Nakata,
M. Tetrahedron Lett. 2000, 41, 2649-2653.
(12) (a) Grindley, T. B.; Wickramage, C. Carbohydr. Res. 1987, 167,
105-121. (b) Clode, D. M. Chem. Rev. 1979, 79, 491-513.
(13) Francisco, C. G.; Leo´n, E. I.; Martin, A.; Moreno, P.; Rodriguez,
M. S.; Sua´rez, E. J . Org. Chem. 2001, 66, 6967-6976. D-Mannose is
reported to yield ent-6.
(7) Examples: (a) Chandrasekhar, M.; Chandra, K. L.; Singh, V.
K. Tetrahedron Lett. 2002, 43, 2773-2775. (b) de March, P.; Figueredo,
M.; Font, J .; Raya, J . Tetrahedron Lett. 1999, 40, 2205-2208. (c)
Mulzer, J .; Pietschmann, C.; Scho¨llhorn, B.; Buschmann, J .; Luger, P.
Liebigs Ann. 1995, 1433-1439. (d) Mann, J .; Partlett, N. K.; Thomas,
A. J . Chem. Res. (S) 1987, 369. (e) Vekemans, J . A. J . M.; Franken, G.
A. M.; Chittenden, G. J . F.; Godefroi, E. F. Tetrahedron Lett. 1987,
28, 2299-2300. (f) Chen, S.-Y.; J oullie´, M. M. J . Org. Chem. 1984, 49,
2168-2174. (g) Ireland, R. E.; Anderson, R. C.; Badoud, R.; Fitzsim-
mons, B. J .; McGarvey, G. J .; Thaisrivongs, S.; Wilcox, C. S. J . Am.
Chem. Soc. 1983, 105, 1988-2006. See also refs 2g,h and 3a.
(8) Butenolides have been synthesized from symmetric, achiral
ketones: Lattmann, E.; Hoffmann, H. M. R. Synthesis 1996, 155-163.
(9) The term “pseudo”-C2-symmetric refers to molecules that would
be C2-symmetric if they did not contain a central chirotopic, nonste-
reogenic carbon center ((a) Poss, C. S.; Schreiber, S. L. Acc. Chem. Res.
1994, 27, 9-17. (b) Schreiber, S. L. Chem. Scr. 1987, 27, 563-566).
See also further in the text and ref 22.
(14) Examples: (a) Kilonda, A.; Compernolle, F.; Peeters, K.; J oly,
G. J .; Toppet, S.; Hoornaert, G. J . Tetrahedron 2000, 56, 1005-1012.
(b) Ko¨lln, O.; Redlich, H. Synthesis 1996, 963-969. (c) Ko¨lln, O.;
Redlich, H. Synthesis 1996, 826-832.
(15) Identification of the isomers by 1H NMR was very straightfor-
ward: the secondary hydroxyl group of the desired isomer 5 appeared
as a doublet at 2.30 ppm, while the primary alcohol proton of the
thermodynamic isomer 6 appeared as a doublet of doublets at 2.34
ppm. In addition, the observed 13C NMR chemical shift values for the
isopropylidene acetal- and methyl carbons correlated well with the
general chemical shift regions reported for five-membered acetonides:
Buchanan, J . G.; Chaco´n-Fuertes, M. E.; Edgar, A. R.; Moorhouse, S.
J .; Rawson, D. I.; Wightman, R. H. Tetrahedron Lett. 1980, 21, 1793-
1796. Buchanan, J . G.; Edgar, A. R.; Rawson, D. I.; Shahidi, P.;
Wightman, R. H. Carbohydr. Res. 1982, 100, 75-86.
(10) During the course of this work, an example of a similar
symmetry-breaking tactic was published: Hale, K. J .; Hummersone,
M. G.; Bhatia, G. S. Org. Lett. 2000, 2, 2189-2192.
1822 J . Org. Chem., Vol. 68, No. 5, 2003

Desymmetrization of “Pseudo”-C2-Symmetric Substrates
TABLE 1. Op tim iza tion of th e Ar a bitol P r otection
Rea ction
Having achieved a practical large-scale synthesis of the
desired bis-protected arabitol 7, we proceeded with the
synthesis of the butenolide 1 (Scheme 3). Parikh-Doering
oxidation17 of 7 gave the C2-symmetrical ketone 10 in 99%
yield without any detectable trace of epimerization to the
meso-isomer (1H and 13C NMR). The increase in molec-
ular symmetry resulted in a significant simplification of
1
both the H and 13C NMR spectra, which confirmed that
both acetonide groups in the bis-protected arabitol were
situated at the terminal positions.
Reaction of 10 with (ethoxycarbonylmethylene)triphen-
ylphosphorane18 led to the desired unsaturated ester 11
in excellent yield without epimerization. Because the
double bond of 11 is nonstereogenic,19,20 the formation of
E/Z diastereoisomers is not possible. However, the double
bond does not coincide with a symmetry plane or inver-
sion axis, which leads us to assign the double bond as
being chirotopic.19,21 In addition, the central double bond
does not coincide with a C2-axis either, which allows us
to classify alkenes such as 11 into an interesting subclass
of “pseudo”-C2-symmetric compounds,22 which to the best
of our knowledge has not yet been identified as such. The
symmetry of 11 is comparable to that of arabitol, which
contains a nonstereogenic and chirotopic carbon center.9
The variation in having a “pseudo”-C2-symmetric center
or a “pseudo”-C2-symmetric double bond (axis)20 will
prove crucial for the efficiency of the following cyclization
step.
time
CSA
dimethoxypentane yield of yield of
entry (min) (mol %)
(equiv)
7 (%)a
8 (%)a
1
2
3
4
5
6
5
240
5
5
5
4b
4b
10
35
10
30
2.2
2.2
2.2
2.2
4.4
4.4
69
13
71
37
66
80
9
50
10
31
6
5
12
a
b
Isolated yields. p-Toluenesulfonic acid was used.
pentylidene acetals should increase selectivity for 1,3-
dioxolane over 1,3-dioxane isomers under the kinetic
conditions employed. The high temperature was found
necessary because of the low solubility of arabitol in the
reaction mixture, which resulted in long reaction times
and low yields. A summary of the optimization process
is listed in Table 1. A good yield and isomer ratio was
obtained after only 5 min. The use of long reaction times,
resulting in thermodynamic reaction conditions, yielded
8 as the major isomer (entry 2 vs 1). Increasing the
amount of acid catalyst to 35 mol % also promoted the
isomerization to 8 (entry 4 vs 3). However, when employ-
ing 4.4 equiv of 3,3-dimethoxypentane, we found that a
high catalyst loading was required for optimum results
(30 mol %, entry 6 vs 5). Under those conditions, an
isolated yield for 7 of 80% was obtained, with 12% of 8
isolated as well.
Having obtained an improved yield for the desired
“pseudo”-C2-symmetric bis-acetal 7, we next aimed to
improve the isolation procedure, although chromato-
graphic separation turned out to be somewhat easier for
7 and 8 than for the mixture of 5 and 6. Since the
undesired 8 contains a more reactive primary alcohol
group compared to the sterically hindered secondary
alcohol in 7, we decided to investigate a scavenger
approach. In the event, the crude reaction mixture
containing 7, 8, and monoprotected arabitol species was
reacted with succinic anhydride (Scheme 2). The unre-
acted product 7 was easily separated from the reaction
product 9 and similar products that were formed from
monoprotected arabitol species, by a basic aqueous
extraction, obviating the need for chromatographic sepa-
ration. The arabitol protection reaction was successfully
carried out on 10 g scale by using the anhydride scaveng-
ing workup.16 However, when working on large scale we
found that there were still trace amounts of impurities
present in the product that was isolated after the basic
extraction procedure. These impurities were very easily
removed by column chromatography. Nevertheless, the
whole process including the necessary chromatography
can be carried out in less than 1 day.
Treatment of 11 with CSA in methanol leads to diol
deprotection, followed by cyclization. The resulting buteno-
lide 1 was isolated in 95% yield. The observed multiplici-
1
ties of the alcohol protons in the H NMR spectrum, one
doublet and two triplets, suggested that the cyclization
proceeded as expected. In addition, a D2O-exchange
experiment clearly indicated the presence of two primary
alcohols, with both CH2 groups appearing as a set of
doublets of doublets, and one secondary alcohol (see
Supporting Information). The cyclization of 11 results in
a differentiation of the diastereotopic diol chains and in
the double bond becoming stereogenic, which formally
allows us to characterize the reaction as a desymmetri-
zation23 step. The desymmetrization reaction features
some interesting stereochemical aspects. Whereas ter-
minus differentiation through monocyclization of “pseudo”-
C2-symmetric compounds that possess a nonstereogenic,
chirotopic carbon atom typically led to a mixture of
diastereomers,9,24 there is the possibility that the corre-
sponding process for compounds that possess a nonste-
reogenic, chirotopic double bond yields a single diaste-
(17) Parikh, J . R.; Doering, W von E. J . Am. Chem. Soc. 1967, 89,
5505-5507.
(18) Vidyasagar Reddy, G.; Sreevani, V.; Iyengar, D. S. Tetrahedron
Lett. 2001, 42, 531-532.
(19) Permutation of two ligands of the double bond does not lead to
a stereoisomer. For a clear discussion about stereogenicity/chirotopicity,
see: (a) Eliel, E. L.; Wilen, S. H. Stereochemistry of Organic Com-
pounds; Wiley: New York, 1994; Chapters 3 and 5, pp 53 and 123. (b)
Helmchen, G. In Methods of Organic Chemistry (Houben-Weyl), 4th
ed.; Helmchen, G., Hoffmann, R. W., Mulzer, J ., Schaumann, E., Eds.;
Georg Thieme Verlag: Stuttgart, Germany, 1995: Vol. E21a, Chapter
1, pp 17-21.
(20) Both a single carbon and an olefinic double bond (axis) can be
stereogenic elements. See ref 19a, pp 52-53 and 1208, and ref 19b, pp
11-13.
(21) Mislow, K.; Siegel, J . J . Am. Chem. Soc. 1984, 106, 3319-3328.
(22) Following Schreiber’s description of “pseudo”-C2-symmetry (ref
9), 11 would be C2-symmetric if it did not contain a central chirotopic,
nonstereogenic double bond (axis).
(16) The protection of arabitol as its bis-pentylidene acetal has been
communicated very recently: Maleczka, R. E., J r.; Terrell, L. R.; Geng,
F.; Ward, J . S., III Org. Lett. 2002, 4, 2841-2844.
J . Org. Chem, Vol. 68, No. 5, 2003 1823

Linclau et al.
SCHEME 2. Sep a r a tion of th e Bis-a ceta l Regioisom er s 7 a n d 8, Usin g a Sca ven gin g Ap p r oa ch a
a
Conditions and reagents: (i) 3,3-dimethoxypentane, CSA, THF, reflux, 5 min; aq NaOH. (ii) succinic anhydride, Et3N, DCM; basic
aqueous extraction.
SCHEME 3. Syn th esis of th e Bu ten olid e
reoisomer only. As after desymmetrization the double
bond becomes stereogenic, there is the possible formation
of E/Z isomers. The diastereotopic group selection in the
terminus differentiation process is now determined by
the difference in product stability of the possible E/Z
isomers. For small ring sizes, the product with the
E-configuration is not formed, resulting in complete
selectivity. Hence, no tedious diastereomer separation is
required, which should make such cyclization processes
useful for general synthetic applications.10
Protection of the diol moiety of 1 was achieved by
subsequent acetonide formation. The presence of the
residual primary alcohol of 12 could be observed in the
1H NMR and the IR showed the characteristic absorption
(1744 cm-1) for a butenolide carbonyl group. The protec-
tion of the diol moiety effectively differentiates both
primary alcohol groups, adding to the synthetic utility
of the building block.
to the 1,2:4,5-bis-isopentylidene acetal is described. In
addition, we were able to identify a novel subclass of
“pseudo”-C2-symmetric substrates, based on a full ste-
reochemical description of 11 according to the chirotop-
icity/stereogenicity concept.
Exp er im en ta l Section
Arabitol was obtained from commercial sources, and used
without further purification. Reaction solvents were dried
immediately before use as follows: acetone was distilled from
ZnCl2, THF was distilled from Na/benzophenone, Et3N and
CH2Cl2 were distilled from CaH2, and toluene was distilled
from Na. DMSO was distilled from CaH2 and stored over
molecular sieves. Glassware was flame dried immediately prior
to use. All reactions were carried out under an atmosphere of
nitrogen. Solvents for chromatography were HPLC-grade.
Column chromatography was performed on 230-400 mesh
silica gel. Reactions were monitored by TLC (Merck) with
detection by UV-light or through alkaline KMnO4 oxidation.
1,2:4,5-Di-O-isop r op ylid en e-L-a r a bitol (6) a n d 2,3:4,5-
Di-O-isop r op ylid en e-L-a r a bitol (5). To a stirred suspension
of L-arabitol (1.0 g, 6.6 mmol) in acetone (48 mL) and
2,2-dimethoxypropane (12 mL, 0.1 mol) at room temperature
was added CSA (0.77 g, 3.3 mmol). The reaction was stopped
after 10 min by rapidly adding saturated aqueous NaHCO3
(50 mL). After the solution was stirred for 30 min, acetone
was removed in vacuo. The aqueous solution was extracted
with ethyl acetate (3 × 50 mL). The combined organic phases
were dried over anhydrous Na2SO4. After the solvent was
removed in vacuo, the crude product was purified by column
chromatography (hexane/ethyl acetate 7:3). The silica gel was
treated with eluent containing 0.1% Et3N before use. This
yielded a colorless oil (1.1 g, 66%) that was further purified
In conclusion, we have synthesized an enantiopure
disubstituted butenolide using an efficient desymmetri-
zation process of a “pseudo”-C2-symmetric substrate. A
practical kinetic protection protocol for arabitol leading
(23) Desymmetrization of a compound that contains a “pseudo”-C2-
symmetric center is characterized by terminus differentiation, and by
the transition of the nonstereogenic, chirotopic center to a stereogenic,
chirotopic center. However, the term “desymmetrization” could rightly
be questioned in this context. Desymmetrization formally indicates a
removal of
a symmetry element. Since a “pseudo”-C2-symmetric
molecule does not possess any symmetry elements, there can strictly
speaking be no desymmetrization process. Nevertheless, there is
common agreement in the synthetic organic community to use the term
“desymmetrization of “pseudo”-C2-symmetric compounds” (refs 9 and
24).
1824 J . Org. Chem., Vol. 68, No. 5, 2003

Desymmetrization of “Pseudo”-C2-Symmetric Substrates
by preparative HPLC (hexane/ethyl acetate 65:35). This
yielded 6 (889 mg, 58%) and 5 (131 mg, 9%) as colorless oils.
Data for 6: [R]D +3.9 (c 0.94, CHCl3, 27 °C), lit.13a [R]D -14.3
(c 0.21, CHCl3) (for ent-6); CIMS, m/z (%) 233 ((M + H)+, 40),
217 (40), 101 (100); HRMS (CI) calcd for C10H17O5 (M - CH3)+•
217.1076, found 217.1077. The IR and 1H and 13C NMR spectra
corresponded to the reported data.13a
Data for 5: [R]D +1.2 (c 1.21, CHCl3, 26 °C), lit.11a [R]D ca.
+1 (c 1.2, CHCl3); 1H NMR (400 MHz, CDCl3) δ 4.17 (1H, dd,
J ) 8.5, 6.0 Hz), 4.10-3.97 (3H, m), 3.85-3.73 (2H, m), 3.72
(1H, t, J ) 8.3 Hz), 2.34 (1H, dd, J ) 8.5, 4.3 Hz), 1.44 (3H, s),
1.41 (3H, s), 1.40 (3H, s), 1.36 (3H, s) ppm; CIMS, m/z (%) 233
((M + H)+, 42), 217 (36), 101 (100); HRMS (CI) calcd for
C11H21O5 (M + H)+ 233.1389, found 233.1387. The IR and 13C
NMR spectra corresponded to the reported data.5f,25
(2S,4S)-1,2:4,5-Di-O-(3,3-p en tylid en e)a r a bitol (7) a n d
(2S,3R,4S)-2,3:4,5-Di-O-(3,3-p en tylid en e)a r a bitol (8). To a
refluxing suspension of L-arabitol (0.51 g, 3.35 mmol) in 3,3-
dimethoxypentane (1.96 g, 14.8 mmol) and THF (5 mL) was
added CSA (0.23 g, 0.99 mmol) and the reaction was stirred
at reflux for 5 min. Triethylamine (1 mL) was added to the
refluxing reaction, and the mixture was concentrated in vacuo
and loaded directly onto a silica gel column (hexane/ethyl
acetate 8:2). This yielded a colorless oil that was further
purified by preparative HPLC (hexane/acetone 95:5) to give 7
(0.76 g, 80%) and 8 (0.155 g, 12%) as colorless oils.
was added. The reaction was stirred at reflux until the
presence of 2 was undetectable by TLC (approximately 1 h),
and then quenched with NaHCO3 (aq, 5%, 100 mL) at reflux
temperature. After cooling, the layers were separated and the
aqueous solution extracted with CH2Cl2 (2 × 100 mL). The
combined organic phases were dried over anhydrous Na2SO4,
filtered, and concentrated in vacuo. The resulting product was
finally purified by column chromatography (column diameter
8 cm, with 13 cm silica gel; eluted with hexane/ethyl acetate
85:15). After collection of a 900-mL prefraction 13 × 100 mL
fractions were collected and concentrated to yield pure 7 as a
pale yellow oil (14.09 g, 74%).
(2S ,4S )-1,2:4,5-B is (3,3-p e n t y lid e n e d io x y )-3-p e n t a -
n on e (10). A suspension of SO3‚pyridine (0.85 g, 5.4 mmol) in
CH2Cl2 (3.5 mL) was dissolved in DMSO (8.5 mL) and Et3N
(0.9 mL, 6.5 mmol). This solution was immediately added
dropwise to a stirred solution of 7 (0.5 g, 1.7 mmol) in CH2Cl2
(12 mL) and DMSO (25 mL) at -5 °C, and the reaction mixture
was stirred at 0 °C for 6 h. The reaction mixture was poured
into a solution of saturated aqueous NH4Cl:water:Et2O:pen-
tane (1:1:1:1, 100 mL), and the aqueous phase was extracted
with an Et2O:pentane mixture (1:1, 3 × 25 mL). The combined
organic phases were dried over anhydrous Na2SO4. After the
solvent was removed in vacuo the obtained pale yellow oil was
purified by column chromatography (hexane/ethyl acetate 9:1)
to yield a colorless oil (483 mg, 99%).
Data for 7: [R]D -5.8 (c 0.9, CHCl3, 20 °C); IR 3477 (m),
2973 (s), 2941 (s), 2883 (s), 1082 (s) cm-1; 1H NMR (400 MHz,
CDCl3) δ 4.20 (1H, m), 4.14 (1H, dd, J ) 7.8, 5.8 Hz), 4.08
(1H, dd, J ) 8.0, 6.5 Hz), 3.98 (1H, m), 3.93 (1H, app. t, J )
7.3 Hz), 3.86 (1H, app. t, J ) 8.0 Hz), 3.46 (1H, dt, J ) 7.5,
5.3 Hz), 2.39 (1H, d, J ) 5.5 Hz), 2.4-1.56 (8H, m), 0.94-0.86
(12H, m); 13C NMR (100 MHz, CDCl3) δ 113.30, 112.92, 76.82,
76.47, 72.99, 67.87, 66.55, 29.54, 29.52, 29.05, 28.96, 8.19, 8.17,
8.04 ppm; CIMS, m/z (%) 289 ((M + H)+, 38), 259 (25), 203
(100); HRMS (EI) calcd for C13H23O5 (M - CH2CH3)+ 259.1546,
found 259.15484. Anal. Calcd for C15H28O5: C, 62.47; H, 9.79.
Found: C, 62.36; H, 9.49.
Data for 8: [R]D -7.1 (c 0.9, CHCl3, 20 °C); IR 3493 (m),
2973 (s), 2941 (s), 2882 (s), 1085 (s) cm-1; 1H NMR (400 MHz,
CDCl3) δ 4.20 (1H, dd, J ) 8.3, 6.3 Hz), 4.05-3.99 (2H, m),
3.91 (1H, dd, J ) 8.3, 6.3 Hz), 3.85-3.74 (2H, m), 3.65 (1H, t,
J ) 8.4 Hz), 2.46 (1H, dd, J ) 8.5, 4.5 Hz), 1.70-1.59 (8H, m),
0.92-0.86 (12H, m); 13C NMR (100 MHz, CDCl3) δ 113.86,
113.10, 81.40, 79.75, 76.95, 68.74, 62.88, 30.39, 30.27, 29.50,
28.81, 8.15, 8.00, 7.91; CIMS, m/z (%) 289 ((M + H)+, 44), 259
(86), 203 (100); HRMS (EI) calcd for C13H23O5 (M - CH2CH3)+
259.1546, found 259.1541. Anal. Calcd for C15H28O5: C, 62.47;
H, 9.79. Found: C, 62.37; H, 9.76.
(2S,4S)-1,2:4,5-Di-O-(3,3-p en tylid en e)a r a bitol (7) (in -
clu d in g sca ven gin g w or k u p ). A refluxing suspension of
L-arabitol (10.0 g, 65.72 mmol) and 3,3-dimethoxypentane26
(38.25 g, 0.29 mol) in THF (100 mL) was stirred for 15 min.
CSA (4.58 g, 19.72 mmol) was added and the reaction was
stirred at reflux for 5 min. The reaction was quenched by
addition of NaOH (aq, 2 M, 20 mL) at reflux. Diethyl ether
(50 mL) and water (10 mL) were added and the layers
separated. The aqueous solution was extracted with diethyl
ether (3 × 50 mL). The combined organic layers were dried
over anhydrous Na2SO4, filtered, and concentrated in vacuo
to give a colorless oil. The crude product was dissolved in CH2-
Cl2 (200 mL) and Et3N (10 mL) was added. The mixture was
heated to reflux and succinic anhydride (1.71 g, 17.09 mmol)
[R]D -71.6 (c 0.42, CHCl3, 27 °C); IR 2969 (s), 2945 (s), 2884
(s), 1739 (s), 1469 (s), 1086 (s) cm-1; 1H NMR (400 MHz, CDCl3)
δ 4.79 (2H, t, J ) 7.3 Hz), 4.28 (2H, t, J ) 8.3 Hz), 3.94 (2H,
dd, J ) 8.3, 7.1 Hz), 1.72-1.62 (8H, m), 0.91 (12H, dd, J )
15.3, 7.5 Hz) ppm; 13C NMR (100 MHz, CDCl3) δ 205.2, 114.8,
78.7, 66.2, 29.1, 28.2, 8.1, 7.9 ppm; EIMS, m/z (%) 257 ((M -
CH2CH3)+, 4), 57 (100); HRMS (ES+) calcd for C15H26O5Na
(M + Na)+ 309.1674, found 309.1672.
Eth yl-3,3-bis[(4R)-2,2-d ieth yl-1,3-d ioxola n -4-yl] P r op e-
n oa te (11). (Ethoxycarbonylmethylene)triphenylphosphorane
(5.7 g, 16.2 mmol) was added to a solution of 10 (2.32 g, 8.1
mmol) in toluene (25 mL) and the resulting mixture was
stirred at reflux temperature for 1 h. The reaction mixture
was allowed to cool and the solvent was evaporated in vacuo.
The resulting mixture was purified by column chromatography
(hexane/ethyl acetate 85:15), which yielded 11 as a colorless
oil (2.83 g, 98%).
[R]D -116.7 (c 1.10, CHCl3, 28 °C); IR 2969 (s), 2941 (s),
2879 (s), 1715 (s), 1649 (s), 1465 (s), 1148 (s), 883 (w) cm-1; 1H
NMR (400 MHz, CDCl3) δ 6.26 (1H, t, J ) 1.7 Hz), 5.59 (1H,
td, J ) 7.5, 1.8 Hz), 5.00 (1H, ddd, J ) 8.0, 6.5, 1.5 Hz), 4.49
(1H, t, J ) 8.3 Hz), 4.34 (1H, dd, J ) 7.8, 6.8 Hz), 4.14 (2H,
m), 3.53 (1H, t, J ) 7.8 Hz), 3.37 (1H, t, J ) 8.0 Hz), 1.75-
1.61 (8H, m), 1.28 (3H, t, J ) 7.0 Hz), 0.97-0.85 (12H, m) ppm;
13C NMR (100 MHz, CDCl3) δ 166.0, 157.5, 114.9, 113.2, 112.9,
74.6, 74.3, 69.6, 69.1, 60.2, 29.5, 29.0, 28.9, 26.6, 14.2, 8.4, 8.3,
8.2, 8.1 ppm; CIMS, m/z (%) 357 ((M + H)+, 10), 327 (16), 271
(100); HRMS (ES+) calcd for C19H32O6Na (M + Na)+ 379.2092,
found 379.2091.
(5S)-4-[(1R)-1,2-(Dih yd r oxy)et h yl]-5-h yd r oxym et h yl-
fu r a n -2-(5H)-on e (1). To a solution of 11 (366 mg, 1.0 mmol)
in methanol (5 mL) and H2O (0.1 mL) was added CSA (37 mg,
0.16 mmol). The mixture was stirred at room temperature for
48 h. Solid NaHCO3 (40 mg) was added, and the reaction was
stirred for 15 min. The suspension was directly loaded onto a
silica gel column (CH2Cl2/methanol 95:5). Elution with a 8:2
mixture of the same solvent yielded 1 as a colorless oil (165
mg, 95%).
(24) Magnuson, S. R. Tetrahedron 1995, 51, 2167-2213.
(25) Kim, J . H.; Yang, M. S.; Lee, W. S.; Park, K. H J . Chem. Soc.,
Perkin Trans. 1 1998, 2877-2880.
[R]D +25.8 (c 0.88, CH3OH, 26 °C); IR 3363 (s, br), 2938 (m),
1
2883 (m), 1732 (m), 1640 (m), 1058 (m) cm-1; H NMR (400
(26) Napolitano, E.; Fiaschi, R.; Mastrorilli, E. Synthesis 1986, 122-
125. The preparation was slightly modified: CSA was used instead of
p-TsOH, and 5 equiv of methanol was used instead of 15 equiv. We
found that it was important to purify the 3,3-dimethoxypentane by
fractional distillation (bp 125 °C, atmospheric pressure) before use in
the protection reaction.
MHz, d6-acetone) δ 6.04 (1H, t, J ) 1.7 Hz), 5.16 (1H, td, J )
3.6, 1.8 Hz), 4.73 (1H, d, J ) 5.1 Hz), 4.70 (1H, ddd, J ) 10.5,
5.2, 1.6 Hz), 4.23 (1H, t, J ) 6.2 Hz), 4.21 (1H, t, J ) 6.0 Hz),
3.97 (1H, ddd, J ) 12.2, 6.5, 3.7 Hz), 3.90 (1H, ddd, J ) 12.2,
6.5, 3.7 Hz), 3.79 (1H, dt, J ) 11.1, 5.6 Hz), 3.74 (1H, ddd,
J . Org. Chem, Vol. 68, No. 5, 2003 1825

Linclau et al.
J ) 11.1, 6.1, 5.1 Hz) ppm; 13C NMR (100 MHz, d6-acetone) δ
173.1, 173.0, 117.7, 84.4, 70.6, 66.5, 62.3 ppm; ES, m/z (%)
371.1 (2M + Na)+, 197.1 (M + Na)+, 175.1 (M + H)+; HRMS
(CI) calcd for C7H11O5 (M + H)+ 175.0607, found 175.0608.
(5S)-4-[(1R)-1,2-(Isopr opyliden edioxy)eth yl]-5-h ydr oxy-
m eth yl-fu r a n -2-(5H)-on e (12). To a stirred solution of 1 (87
mg, 0.5 mmol) in acetone (5 mL) was added CSA (30 mg) and
the mixture was stirred for 48 h. A 5% solution of NaHCO3
(15 mL) was added followed by extraction with DCM (4 × 15
mL). The combined organic phases were dried over anhydrous
Na2SO4 and filtered and the solvent removed in vacuo. The
residue was purified by column chromatography (hexane/
acetone 6:4), which yielded 12 as a colorless oil (75 mg, 86%).
HRMS (CI) calcd for C10H15O5 (M + H)+ 215.0920, found
215.0919.
Ack n ow led gm en t. We thank the University of
Southampton, the EPSRC, and the Royal Society (re-
search grant ref 21440) for support of this work. C.J .
thanks ERASMUS for support. We are indebted to J oan
Street and Neil Wells for NMR support and Dr. J ohn
Langley and J ulie Herniman for MS support. We wish
to acknowledge the use of the EPSRC's Chemical
Database Service at Daresbury.27
Su p p or t in g In for m a t ion Ava ila b le: 1H NMR and 13C
NMR spectra of all compounds, including D2O-exchange
experiments for 1, 5, 6, 7, and 12. This material is available
free of charge via the Internet at http://pubs.acs.org.
[R]D -85.0 (c 0.81, CHCl3, 26 °C); IR 3437 (br m), 2988 (w),
2931 (w), 1744 (s), 1640 (w), 1370 (m), 1062 (s) cm-1; 1H NMR
(400 MHz, CDCl3) δ 6.10 (1H, m), 5.05 (1H, td, J ) 4.0, 1.8
Hz), 5.01 (1H, td, J ) 6.9, 1.2 Hz), 4.28 (1H, dd, J ) 8.3, 7.2
Hz), 4.04 (1H, ddd, J ) 12.3, 6.3, 4.0 Hz), 3.96-3.90 (2H, m),
2.18 (1H, t, J ) 6.8 Hz), 1.49 (3H, s), 1.43 (3H, s) ppm; 13C
NMR (100 MHz, d6-CDCl3) δ 171.8, 166.9, 118.0, 110.8, 83.0,
72.0, 67.8, 61.6, 26.2, 25.0 ppm; CIMS, m/z 214 (M+, 100);
J O026696R
(27) The United Kingdom Database Service. Fletcher, D. A.;
McMeeking, R. F.; Parkin, D. J . Chem. Inf. Comput. Sci. 1996, 36,
746.
1826 J . Org. Chem., Vol. 68, No. 5, 2003