A practical and enantiospecific conversion of d-galactose to a substituted α,β-unsaturated δ-lactone synthon

Article abstract of DOI:10.1016/j.tetlet.2007.10.141

A multi-gram synthesis of a substituted α,β-unsaturated δ-lactone synthon, 1, was developed from commercially available d-galactose. The use of a Horner-Wadsworth-Emmons reaction was able to furnish, with Z selectivity, the enone ester that spontaneously

Full text of DOI:10.1016/j.tetlet.2007.10.141

Available online at www.sciencedirect.com
Tetrahedron Letters 48 (2007) 9116–9119
A practical and enantiospecific conversion of D-galactose to
a substituted a,b-unsaturated d-lactone synthon
Benjamin E. Stephens and Fei Liu*
Department of Chemistry and Biomolecular Sciences, Macquarie University, Sydney, NSW 2109, Australia
Received 13 September 2007; revised 18 October 2007; accepted 25 October 2007
Available online 30 October 2007
Abstract—A multi-gram synthesis of a substituted a,b-unsaturated d-lactone synthon, 1, was developed from commercially available
D-galactose. The use of a Horner–Wadsworth–Emmons reaction was able to furnish, with Z selectivity, the enone ester that spon-
taneously lactonised to provide enantiomerically pure 1.
ꢀ 2007 Elsevier Ltd. All rights reserved.
Substituted a,b-unsaturated d-lactone skeletons are
common in bioactive natural products such as (+)-
asperlin,1 the styryllactones2 and the bisnorditerpene
dilactone3 family of natural products (Fig. 1). Enantio-
merically pure and substituted a,b-unsaturated d-lac-
tones, such as I and II, are also used frequently as
chiral synthons in carbohydrate or natural product syn-
thesis, typically as Michael acceptors4 or dipolarophiles
in cycloaddition reactions.5 While the preparative con-
version of commercially available D-glucose to the pro-
tected a,b-unsaturated d-lactone synthons such as 2 is
relatively efficient6 a comparably practical method for
accessing 1 from D-galactose remains absent.
Currently only one synthesis of 1 has been reported
(Scheme 1).7 This sequence requires the conversion of
D-galactose to a nitro sugar (4) as the key intermediate
for the subsequent isomerisation and denitration steps.
Other approaches to the analogues of 1, using different
protecting schemes on 4,6-diol, include dehydration of
hydroperoxide carbohydrates,8 stereoselective transfor-
mation of sugar-derived vinyl oxiranes9 and cyclisation
O
OH
OH
HO
HO
O
OMe
1) HCl, MeOH;
2) NaIO4;
OH
CHO CHO
OH
-galactose
90% over 2 steps
3
D
O
O
OMe
OH
HO
R
R
CH3NO2, NaOMe/MeOH
34%
O
O
O
O
Ph
ZnCl2
90%
H
O
O
5
5
HO
4
4
R2
R2
O
O
R
II
NO2
4
S
R1
R1
I
O
OMe
OH
O
OMe
OMe
O
HO
O
Ac2O, NaOAc/AcOH
S
O
O
Δ
O
O
Ph
O
Ph
O
O
NO2
NO2
5
6
50%
O
OH
H
O
O
OMe
O
O
O
O
O
O
O
basic Al2O3, toluene
O
H
Δ
O
Ph
O
O
Ph
HO
(+)-howiinol
AcO
(+)-asperlin
O
O
N
51%
7
NO2
O
O
O
8
podolactone C
O
O
O
Figure 1. Examples of bioactive natural products containing substi-
tuted a,b-unsaturated d-lactones.
O
O
Ph
Ph
O
1
NO2
9
*
Corresponding author. Tel.: +61 2 9850 8312; fax: +61 2 9850
8313; e-mail: fliu@alchemist.chem.mq.edu.au
Scheme 1.
0040-4039/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.10.141

B. E. Stephens, F. Liu / Tetrahedron Letters 48 (2007) 9116–9119
9117
of dihydroxylated vinyl furans.10 These syntheses, typi-
cally six to ten steps from commercially available build-
ing blocks with overall yields under 10%, are less
suitable to the preparative needs of chiral synthons.
Herein is reported a multi-gram conversion of D-galact-
ose to the D-threo-a,b-unsaturated d-lactone 1 in three
steps with one column chromatography at the end and
an overall yield of 22%.
of dibenzylated byproducts.15 However, the unreacted
D-galactose and the dibenzylated products could be
readily removed during work-up and recycled.17
Threose 11 was found to exist as a complex mixture of
the monomeric form 11a and oligomeric form 11b, as
1
the H NMR spectrum of crude 11 showed only weak
resonances attributable to the aldehyde form 11a. This
observation is consistent with that made for the eryth-
roses derived from D-glucose.18,19 Nevertheless, these
compounds react as aldehydes and had previously been
subjected to both the Wittig11–16,20,21 and E-selective
Horner–Wadsworth–Emmons (HWE)19 reactions. The
Z-selective HWE reaction was developed here, on the
basis of Ando’s work,22 to convert 11 to two olefinic
O
O
O
O
O
O
Ph
O
Ph
O
2
1
1
species, in an E:Z ratio of 19:81 by H NMR. Interest-
This sequence (Scheme 2) initiates with the diastereo-
selective benzylidene protection of the 4,6-diols of D-
galactose. Although a total of four diastereomers could
potentially form due to the benzylidene group and the
anomeric centre, only two were produced as an anomer-
ic mixture (10) of 6:1 (a:b) ratio with the benzylidene
carbon in the S configuration. All the common proce-
dures for this reaction involve mechanically stirring or
shaking a mixture of D-galactose, benzaldehyde and
ZnCl2 for approximately 24 h.11–16 While 4,6-O-benzyl-
idene-D-galactopyranose, 10, could be isolated by an
aqueous work-up followed by lypophilisation, repeated
cycles of solvent extraction and recrystallisations,11–15
Rochlin’s protocol,16 in which the aqueous solution of
10 after work-up could be directly subjected, without
further purification, to NaIO4 oxidation, was adopted
to provide a comparable, 38% yield of 2,4-O-benzyl-
idene-D-threose 11 over two steps from D-galactose.
This procedure could be performed on scales of up to
30 kg without reduction in efficiency.16 Although the
oxidation of 10 generally proceeds in nearly quantitative
yields at a pH above 7.0–7.5,11,13 the conversion of D-
galactose to 10 is the yield-limiting step due to incom-
plete reaction of D-galactose16 as well as the formation
ingly, the olefinic species with the Z geometry did not
contain an ethyl group, as would be expected from the
enone ester 13. Rather, this Z-olefin appeared to be
the cyclised lactone 1 resulting from spontaneous cycli-
sation of 13. After purification of the reaction mixture
by column chromatography, only lactone 1 could be iso-
lated, along with the E isomer 12 obtained as a stable
crystalline solid.23 The structure of 1 was ascertained
by the comparison of the NMR and specific optical
rotation data with those previously reported.7 Overall,
enantiomerically pure 1 was obtained in gram quantities
in two to three days requiring one column chromatogra-
phy at the end for purification.
This tandem olefination–lactonisation approach, while
new for the synthesis of 1 from D-galactose, has been
reported in the synthesis of 16 from D-glucose.6 The use
of a Wittig reaction is typical in the preparation of 15,
the lactonisation precursor of 16 (Scheme 3). The E/Z
selectivity is not controlled rigorously, and the E-isomer
for cyclisation can be converted to the Z-isomer in mod-
erate yields. The intramolecular lactonisation reaction is
performed at elevated temperatures using the Z-enone
ester precursor in its purified form. However, the Z-
selective HWE reaction has not been used in preparing
O
OH
OH
O
OH
OH
O
S
1) benzaldehyde, ZnCl2;
HO
HO
a) From
O
D-galactose
2) NaIO4, NaOH/H2O
38% over two steps
O
Ph
OEt
OH
O
OH
OH
O
OH
-galactose
1) oxidative cleavage
2) HWE reaction
O
O
10
D
Ph
O
O
OH
Ph
O
P
H
13
OH
O
10
O
OH
PhO
PhO
O
O
OEt
O
+
H
O
NaI, DBU
THF, -78 ˚C to 0 ˚C
68%
O
Ph
O
Ph
O
Ph
O
HO
11b
n
1
H
11a
OH
spontaneous
b) From
O
D
-glucose6
OH
O
CO2Et
cyclisation of
the -isomer
O
+
H
1) oxidative cleavage
O
OH
Z
Ph
O
2)
E
-selective
Ph
O
Ph
O
CO2Et
OH
OEt
O
Wittig reaction
12
13
O
OH
Ph
3)
E
to Z isomerization
O
OH
14
15
OH
O
O
O
H
O
+
145 ˚C
Δ
Ph
O
O
Ph
O
CO2Et
Ph
O
O
12
1
58%
O
10%
16
Scheme 2.
Scheme 3.

9118
B. E. Stephens, F. Liu / Tetrahedron Letters 48 (2007) 9116–9119
6. Friedrich, K.; Fraser-Reid, B. J. Carbohydr. Chem. 1994,
13, 631–640.
7. Baer, H. H.; Rank, W. Can. J. Chem. 1969, 47, 2811–2818.
8. Mieczkowski, J.; Jurczak, J.; Chmielewski, M.; Zamojski,
A. Carbohydr. Res. 1977, 56, 180–182.
9. Harris, J. M.; O’Doherty, G. A. Tetrahedron Lett. 1999,
41, 183–187.
10. (a) Domon, D.; Fujiwara, K.; Murai, A.; Kawai, H.;
Suzuki, T. Tetrahedron Lett. 2005, 46, 8285–8288; (b)
Bussolo, V. D.; Caselli, M. A.; Pineschi, M.; Crotti, P.
Org. Lett. 2002, 4, 3695–3698.
either 13 or 15 prior to this report. The use of DBU,
which is necessary in the HWE reaction to generate
the phosphonate ylid in situ, also provided an ancillary
advantage of promoting the lactonisation step that
would otherwise require much higher temperatures to
proceed as reported in the synthesis of 16 using the Wit-
tig reaction. A conformational analysis was performed
on the enone ester precursors 13 and 15.26 These two
esters exhibited comparable distances (difference within
˚
1 A) between the nucleophilic oxygen centre and the
11. Dulcos, R. I. Chem. Phys. Lipids 2001, 111, 111–138.
electrophilic carbonyl carbon, without the indication
of any conformation bias that would significantly
enhance the lactonisation in either case. This supports
indirectly the likely kinetic advantage of lactonisation
in the presence of an amidine base.
´
12. Figueroa-Perez, S.; Schmidt, R. R. Carbohydr. Res. 2000,
328, 95–102.
13. Zimmermann, P.; Schmidt, R. R. Liebigs Ann. Chem.
1988, 663–667.
14. Kiso, M.; Nakamura, A.; Nakamura, J.; Tomita, Y.;
Hasegawa, A. J. Carbohydr. Chem. 1986, 5, 335–340.
15. Gros, E. G.; Deulofeu, V. J. Org. Chem. 1964, 29, 3647–
3654.
In summary, a three-step, enantiospecific conversion of
D-galactose on a preparative scale to a chiral synthon
1 is described for the first time. The enantio-purity of
the final product was secured by a spontaneous intramo-
lecular lactonisation of a Z-enone ester formed after a
Horner–Wadsworth–Emmons reaction.
16. Rochlin, E. U. S. Patent 6,469,148, 2000; Chem. Abstr.
2000, 133, 335434.
17. 2,4-O-benzylidene-D-threose (11). Based on the procedure
of Rochlin.16 A mixture of ZnCl2 (3.2 g, 23 mmol) and
redistilled benzaldehyde (9.3 mL, 92 mmol) was mechan-
ically stirred for 30 min under a gentle stream of dry
nitrogen. To the resulting off-white slurry were added
anhydrous D-galactose (4.0 g, 22 mmol) and more redis-
tilled benzaldehyde (8.1 mL, 77 mmol), and this mixture
was vigorously stirred for a further 24 h. Unreacted D-
galactose was removed by filtration and the residue
washed with redistilled benzaldehyde (3 mL). The com-
bined filtrate and washings were diluted with diethyl ether
(8 mL) and petroleum ether (11 mL), then extracted with
ice-cold water (20 mL then 3 · 10 mL). A solution of
K2CO3 (5.1 g, 37 mmol) in water (6.8 mL) was used to
adjust the pH of the combined aqueous extracts to 9–10,
and the thick white precipitate (ZnCO3) was filtered off
and washed thoroughly with water (80 mL). After washing
the filtrate with CHCl3 (10 mL) and petroleum ether
(10 mL), the resulting solution of crude 10 (Rf = 0.32, 25%
ethanol in toluene) was buffered with K2HPO4Æ3H2O
(1.5 g, 6.5 mmol) and KH2PO4 (610 mg, 3.5 mmol) and
vigorously stirred during the portionwise addition of
NaIO4 (5.3 g in 500 mg portions over 3 h, 25 mmol). The
pH was kept in the range 7.0–7.5 by the addition of
aqueous KOH (20%) and the formation of 11 was
monitored by TLC (Rf = 0.64, 25% ethanol in toluene).
Once complete, the reaction mixture was lyophilised. The
orange residue was suspended in dry THF and filtered.
After thoroughly washing the residue with dry THF, the
combined extracts were dried over MgSO4, filtered and
evaporated at reduced pressure (8 Torr, 35 ꢁC) to afford
crude 11 (2.36 g, 8.4 mmol, 38%) as a yellow foam: 1H
NMR (400 MHz, CDCl3) d 10.0 (s, 0.05H), 9.67 (s, 1H),
9.26 (s, 0.2H), 7.60–7.30 (m, 60H). The remainder of the
spectrum was extremely complex with, for instance, at
least six broad singlets in the benzylic region (d 5.7–5.5).
18. Rhee, J. U.; Bliss, B. A.; RajanBabu, T. V. J. Am. Chem.
Soc. 2003, 125, 1492–1493.
Acknowledgement
This work is supported by an Australian Research
Council Discovery Grant to F.L. (ARC-DP0665068).
References and notes
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4, 595–624; A recent example: (b) Park, H. S.; Yodo, N.;
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171–177.
4. Recent examples: (a) Krishna, P. R.; Reddy, P. S.;
Narsingam, M.; Sateesh, B.; Sastry, G. N. Synlett 2006,
4, 595–599; (b) Zhao, G.-L.; Liao, W.-W.; Cordova, A.
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M.; Urbanczyk-Lipkowska, Z.; Chmielewski, M. Tetra-
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19. Fengler-Veith, M.; Schwardt, O.; Kautz, U.; Kra¨mer, B.;
Ja¨ger, V. Org. Synth. 2002, 78, 123–128.
20. Kiso, M.; Nakamura, A.; Tomita, Y.; Hasegawa, A.
Carbohydr. Res. 1986, 158, 101–111.
21. Schmidt, R. R.; Zimmermann, P. Tetrahedron Lett. 1986,
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J = 6.0 Hz, 2.2 Hz, 1H, CHCH@CH), 4.26 (m, 1H,
OCH2CH), 4.22 (dd, J = 13 Hz, 2.0 Hz, 1H, OCH2CH);
13C NMR (101 MHz, CDCl3) d 163.0, 139.2, 136.5, 129.2,
127.9, 125.9, 124.9, 100.7, 70.2, 68.5, 65.7; MS (EI, m/z):
231 (M+ꢀ1), 105 (C6H5C(O)+, base).
23. (2S,4aR,8aR)-2-phenyl-4,4a-dihydropyrano[3,2-d][1,3]di-
oxin-6(8aH)-one (1). Based on the procedure of Ando
et al.22d To a chilled (ice-bath) solution of ethyl diphenyl-
phosphonoacetate22c,24 (2.5 g, 7.7 mmol) in dry THF
(70 mL) under argon were added sodium iodide (2.2 g,
14.8 mmol) and DBU (1.2 mL, 8.1 mmol). The mixture
was stirred for 15 min, then cooled to ꢀ78 ꢁC. A solution
of crude 11 (1.7 g) in dry THF (20 mL) was subsequently
added and stirring continued for 2.5 h, after which time
the reaction mixture was transferred to an ice bath and
stirred for a further 1.5 h. The reaction mixture was
quenched with saturated NH4Cl (50 mL) and diluted with
ethyl acetate (150 mL). The aqueous layer was extracted
with ethyl acetate (3 · 100 mL) and the combined organic
phases were washed with water (25 mL), saturated aque-
ous NaHCO3 (50 mL) and brine (50 mL) then dried over
MgSO4. After filtration and evaporation of the solvent at
reduced pressure (8 Torr, 35 ꢁC), the resulting yellow
residue was purified by dry column vacuum chromatog-
raphy25 (0–80% ethyl acetate in hexane) to obtain 1
(1.05 g, 4.5 mmol, 58%) as colourless needles: mp 152–
(E)-Ethyl 3-((2S,4R,5R)-5-hydroxy-2-phenyl-1,3-dioxan-4-
yl)acrylate (12). Obtained as colourless needles (211 mg,
24
0.76 mmol, 10%): mp 101–103 ꢁC; ½aꢁD ꢀ36.2 (c 0.66,
CHCl3); 1H NMR (400 MHz, CDCl3) d 7.55–7.48 (m, 2H,
Ar), 7.42–7.35 (m, 3H, Ar), 6.95 (dd, J = 16 Hz, 3.8 Hz,
1H, CH@CHC(O)), 6.18 (dd, J = 16 Hz, 1.9 Hz, 1H,
CH@CHC(O)), 5.63 (s, 1H, CHPh), 4.62 (m, 1H,
CHCH@CH), 4.23 (dd, J = 12 Hz, 1.8 Hz, 1H,
CHOCH2), 4.19 (q, J = 7.1 Hz, 2H, OCH2CH3), 4.09
(dd, J = 12 Hz, 1.3 Hz, 1H, CHOCH2), 3.66 (m, 1H,
CH(OH)), 2.81 (br s, 1H, OH), 1.27 (t, J = 7.1 Hz, 3H,
OCH2CH3); 13C NMR (101 MHz, CDCl3) d 165.9, 143.1,
137.3, 129.1, 128.2, 125.9, 122.7, 101.1, 78.4, 72.2, 65.3,
60.4, 14.1; MS (EI, m/z): 277 (M+ꢀ1), 107 (C6H5CHOH+,
base).
24. Olpp, T.; Bruckner, R. Synthesis 2004, 2135–2152.
¨
25. Pedersen, D. S.; Rosenbohm, C. Synthesis 2001, 2431–
2434.
23
154 ꢁC (lit.7 mp 156–157 ꢁC); ½aꢁD ꢀ252 (c 1.1, CHCl3)
26. Mohamadi, F.; Richard, N. G. J.; Guida, W. C.; Liskamp,
R.; Lipton, M.; Caufield, C.; Chang, G.; Hendrickson, T.;
Still, W. C. J. Comput. Chem. 1990, 11, 440–467. Monte
Carlo conformational searches, using MM3* force field in
1000 steps as implemented in Macromodel, were
performed.
(lit.7 [a]D ꢀ256 (c 1.1, CHCl3)); 1H NMR (400 MHz,
CDCl3) d 7.51–7.47 (m, 2H, Ar), 7.39–7.35 (m, 3H, Ar),
6.93 (dd, J = 9.7 Hz, 6.0 Hz, 1H, CH@CHC(O)), 6.29 (d,
J = 9.7 Hz, 1H, CH@CHC(O)), 5.62 (s, 1H, CHPh), 4.55
(dd, J = 13 Hz, 1.3 Hz, 1H, OCH2CH), 4.50 (dd,