Carbon-branched carbohydrate chirons: synthesis of C-3 and C-4-branched sugar lactones derived from d-erythronolactone

Article abstract of DOI:10.1016/j.tetasy.2009.08.029

Two carbon chain extensions using a Wittig reaction on both a 1-deoxy ribulose derivative and a C-2-branched erythrose derivative are reported. Subsequent dihydroxylation resulted in the synthesis of C-3 and C-4 methyl-branched sugar lactones, the useful

Full text of DOI:10.1016/j.tetasy.2009.08.029

Tetrahedron: Asymmetry 20 (2009) 2357–2367
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Carbon-branched carbohydrate chirons: synthesis of C-3 and C-4-branched
sugar lactones derived from D-erythronolactone
a
b
a
b
Sarah F. Jenkinson a, , K. Victoria Booth , Amalia M. Estévez Reino , Graeme Horne , Ramón J. Estévez ,
*
George W. J. Fleet a
a Chemistry Research Laboratory, Department of Organic Chemistry, University of Oxford, Mansfield Road, Oxford OX1 3TA, UK
b Departamento de Química Orgánica, Universidade de Santiago, 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:
Two carbon chain extensions using a Wittig reaction on both a 1-deoxy ribulose derivative and a
C-2-branched erythrose derivative are reported. Subsequent dihydroxylation resulted in the synthesis
of C-3 and C-4 methyl-branched sugar lactones, the useful synthetic building blocks. Control of the
stereoselectivity of both the Wittig reaction and the dihydroxylation is investigated, and 3-C-methyl
Received 11 August 2009
Accepted 27 August 2009
Available online 28 September 2009
and 4-C-methyl
D
-altrono-1,4-lactones and
D-glucono-1,4-lactone and 4-C-hydroxymethyl-
D-altrono-
1,4-lactone were synthesised.
Ó 2009 Elsevier Ltd. All rights reserved.
1. Introduction
building blocks are easily accessible and therefore there are only a
small number of examples of their use in synthesis.7 Several meth-
ods for the synthesis of branched chain sugars, including addition
to a carbonyl functionality,8 crossed aldol and other condensation
reactions,9 the Petersen olefination,4 the Kiliani ascension of 2-C-
substituted carbohydrates10 and the Wittig reaction,2a,8c,11 have
been employed in the synthesis of C-3 and C-4-branched sugars.
Recent biological studies on branched mannose derivatives have
shown that this class of compounds could have potential therapeu-
tic utility.12
The discovery of many branched chain sugars in a variety of
antibiotics has prompted much research into their synthesis
and biological activity.1 For example, 3-C-methyl-
D-mannose 1
(Fig. 1) has been found to be one of the three sugars in the trisac-
charide-repeating unit from the outer membrane of Helicobacter
pylori. This bacterium is thought to be the major cause of chronic
gastritis, gastric and duodenal ulcers and has been linked to the
development of gastric cancer.2 A derivative of 3-C-methyl-
L-man-
nose is one of the sugars in the pentasaccharide hapten of Myco-
The Wittig reaction has been previously used to introduce
branch points into sugars by the addition of the phosphorous ylid
to a ketone functionality on the carbohydrate backbone.8c This pa-
per demonstrates that the Wittig-dihydroxylation reaction se-
quence can be applied to sugar lactols to simultaneously effect a
two carbon chain extension and introduce a branch point. This
could be carried out with 1-deoxy-sugars, sugars already contain-
ing a branching point or alternatively with straight chain sugars
and a substituted Wittig reagent. In this fashion, after dihydroxyla-
tion and subsequent ring closure, sugar lactones branched at the C-
2, C-3 and/or C-4 positions could be synthesised (Scheme 1).
The formation of both E- and Z-alkenes followed by the syn ste-
reospecific dihydroxylation would give rise to 4 possible esters
which on ring closure would allow access to four d-lactones
(Scheme 2). The formation of the E-alkene should lead to the gen-
eration of gluco and altro lactones whereas the Z-alkene should
give rise to the allo and manno lactones. Therefore, by stereo con-
trol of both the Wittig and the dihydroxylation reactions all four
products would be accessible in both series leading to four possible
C-3-branched lactones and four possible C-4-branched lactones.
Application of this methodology to the corresponding starting
bacterium avium serovar 19.3 Another 3-C-methyl-branched sugar,
L
-olivomycose 2, has been found to be present in the trisaccharide
unit of several antitumour antibiotics of the aureolic acid group.4
Additionally, moenuronic acid 3, a 4-C-methyl-branched sugar, is
found in moenomycin A, a trans-glycosylation inhibitor.5
Me
HO
OH
CO2H
CH3
O
HO
HO
H3C
HO
HO
HO
O
O
OH
CH3
HO
OH
OH
HO
1
2
3
Figure 1.
Carbohydrates are readily available and are an extensive family
of chirons for use in synthesis.6 In contrast, few C-branched sugar
* Corresponding author. Tel.: +44 01865 275655.
E-mail address: sarah.jenkinson@chem.ox.ac.uk (S.F. Jenkinson).
0957-4166/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2009.08.029

2358
S. F. Jenkinson et al. / Tetrahedron: Asymmetry 20 (2009) 2357–2367
CO2Me
OH
HO
R''
R'
OH
R''
HO
R'
CO2Me
R
O
O
HO
HO
CO2Me
HO
O
H+
OsO4
R
R
R'
Ph3P
R'
R
OH
R''
R''
O
O
O
O
O
O
HO
R - H or alkyl group
R', R'' - H, alkyl, aryl, or substituted alkyl
Scheme 1.
materials derived from threose would give access to the remaining
the fused ring compound 8 (Scheme 2). This could arise from an
four sugar lactones, that is, gulo, ido, galacto and talo.
intramolecular Michael reaction of the C-5 hydroxyl group with
the
a,b-unsaturated ester, followed by an intramolecular conden-
sation reaction of the neopentyl hydroxyl group with the ester
group to give the lactone. In order to prevent the latter of the
two intramolecular reactions from occurring two options were
investigated; either selectively protecting the neopentyl hydroxyl
group with tertbutyldiphenylsilyl chloride to give 9 (Scheme 3),
or alternatively reducing the side chain to a methyl group to give
13. The reduction of the side chain was achieved by bromine
oxidation of the lactol 4, this reaction proceeded smoothly to give
the lactone in 87% yield. This is in direct contrast to work by Peder-
sen et al. who report the difficulty in oxidising a 2-C-methyl-ery-
throse derivative in this fashion.14 The hydroxymethyl branch
was then either activated as the trifluoromethanesulfonate ester
and displaced with iodide or reacted directly with triphenylphos-
phine and iodine to give iodide 12, subsequent reduction with
hydrogen and palladium gave the 2-C-methyl-branched lactone
13. This was then reduced, with diisobutylaluminium hydride, to
give the desired lactol 14 in good yield.
2. Results and discussion
The two readily available D-erythrose derivatives 4 and 5 (Fig. 2)
are convenient starting materials to test the synthetic pathway.
Initially the Wittig reaction was carried out on 1-deoxy ribulose
5,13 obtained by the reaction of methyl magnesium bromide with
2,3-O-isopropylidene-D-erythronolactone, and the ylid and lactol
were heated at 40 °C for 48 h (Scheme 3). After this time a mixture
of E- and Z-alkenes 6 was formed in 94% yield, in a 6:1 E/Z ratio. If
the reaction mixture was allowed to remain at 40 °C then a second
product 7, arising from an intramolecular Michael addition reac-
tion, began to form. Interestingly the Michael addition product 7
was found to be unstable and on standing in CDCl3 the formation
of an additional product was observed. This was identified, by
NOE experiments, as the epimer at C-3 arising from a reverse Mi-
chael reaction in the slightly acidic conditions followed by closure
on the opposite face of the alkene.
Both the lactols 10 and 14 were subjected to the same condi-
tions for the Wittig reaction as described earlier to generate the
E-alkenes 10 and 15 in excellent yields (90% and 92%, respectively).
Again, as in the case of the 1-deoxy ribulose 5, the major product
was the E-alkene, and much greater selectivity was observed with
the aldose rather than the ketose system. No Michael reaction
product was seen in either case. Reaction with an alternative ylid
Ph3PCHCO2Me was seen to be slower and again only the E-alkene
was observed. Interestingly when the reaction was performed un-
der anhydrous conditions the major product formed was that aris-
ing from Michael addition.
Me
O
O
OH
OH
OH
O
O
O
O
5
4
Figure 2.
The 2-C-hydroxymethyl derivative 4 was synthesised from D-
erythronolactone via reduction to the lactol followed by a Ho Aldol
Dihydroxylation reactions proceed syn stereospecifically to gen-
erate cis-diols. Therefore it was expected that two products would
reaction.9c The subsequent Wittig reaction, however, yielded only
CO2Me
OH
R
R
O
HO
HO
Ylid
CO2Me
R
R
R
R
O
O
O
O
O
O
E
Z
i) OsO4
ii) H+
i) OsO4
ii) H+
HO
OH
HO
OH
HO
OH
HO
OH
O
O
O
O
OH
O
O
O
R
R
R
R
R
HO
R
HO
R
HO
R
HO
OH
OH
OH
OH
manno
gluco
altro
allo
R - H, alkyl, substituted alkyl
Scheme 2.

S. F. Jenkinson et al. / Tetrahedron: Asymmetry 20 (2009) 2357–2367
2359
CO2Me
CO2Me
Me
OH
OH
O
O
O
O
O
OH
OH
OH
OTBDPS
O
i)
iii), iv)
58%
v)
ii)
OTBDPS
OTBDPS
99%
90%
O
O
O
O
O
O
O
O
O
O
O
O
5
90%
10
0%
11
4
9
2,3-O-isopropylidene-
i)
D-erythronolactone
vi)
28%
99%
O
O
vii), viii)
or xi)
63-78%
ii)
O
O
O
O
O
8
CO2Me
O
CO2Me
CO2Me
OH
Me
O
O
O
O
O
OH
HO
Ylid
toluene, 40oC
x)
xi)
Me
I
Me
Me
Me
99%
74%
O
O
O
O
O
O
O
O
O
O
14
15
E:Z
6
7
12
13
Ylid
Yield
Yield E:Z
After 48h 94% 6:1
> 48h 45% E only
Bu3PCHCO2Me
Ph3PCHCO2Me
92% 20:1
79% 40:1
0%
15%
Scheme 3. Reagents and conditions: (i) MeMgBr, THF, ꢀ78 °C; (ii) Bu3PCHCO2Me, toluene, 40 °C; (iii) DIBALH, DCM, ꢀ78 °C; (iv) CH2O, K2CO3, MeOH, 70 °C; (v) TBDPSCl, TEA,
DMAP, DCM; (vi) NaOMe, MeOH; (vii) Br2, K2CO3, H2O, 0 °C; (viii) Tf2O, Pyr., DCM, ꢀ30 to ꢀ10 °C; then Bu4NI, THF; (ix) I2, PPh3, imidazole, toluene, 85 °C; (x) H2, Pd, TEA,
EtOH; (xi) DIBALH, DCM, ꢀ78 °C.
be formed from the E-alkenes 6 and 10. Standard Upjohn condi-
tions15 (potassium osmate and 4-methylmorpholine-N-oxide
(NMO)) were applied to the 1-deoxy ribulose system 6 and the
reaction was seen to proceed in a very poor yield giving only 16%
of a single product, later found to be 17. Modified Sharpless condi-
tions16 were next investigated and alkene 6 was reacted with
potassium osmate, NMO and (DHQ)2PHAL (Scheme 4). The yield
of the reaction was improved to a total of 46% and two products
were observed in a 1:3 ratio (16:17). It has been shown in the lit-
erature17 that dihydroxylations may show a pH dependency and
addition of certain acids can increase the rate of reactivity and alter
the selectivity of the reaction, therefore a number of acids were
reaction. Interestingly the selectivity of the reaction was reversed
with both of these reactions favouring the formation of triol 16 (Ta-
ble 1). As
the enantiomeric
maintain the high yields. This, however, was not seen to be the
case. The reaction with -tartaric acid was high yielding but again
L
-tartaric acid is chiral it was wondered whether use of
D
-tartaric acid would reverse the selectivity but
D
gave triol 16 as the major product, with the selectivity only slightly
decreasing from 6:1 to 4:1.
Separation of the two triols by column chromatography was dif-
ficult and therefore the mixture was treated with acidic resin to
deprotect the acetonide-protecting group and effect ring closure
to the lactone. The mixture of lactones was then reprotected with
anhydrous copper sulfate, acetone and catalytic sulfuric acid to
give both the altronolactone 18 and the gluconolactone 19
(Scheme 4) which could be cleanly isolated and the stereochemis-
try firmly determined. Subsequent deprotection using Dowex (H+)
investigated. In the case of
tion proceeded at a faster rate there was little change in both the
yields and selectivity. Addition of citric and -tartaric acid, how-
ever, greatly increased both the overall yield and the rate of the
L-malic acid (Table 1) although the reac-
L
CO2Me
CO2Me
CO2Me
OH
O
OH
Me
Me
Me
HO
K2OsO4, NMO
HO
HO
H
H
OH
OH
H2O, tBuOH
Ligand
O
O
O
O
O
6
16
17
i) Dowex, H2O
ii) CuSO4, H2SO4
acetone
HO
HO
O
O
O
O
O
O
O
O
O
O
HO
HO
O
Dowex, H2O
70oC, 56%
Dowex, H2O
88%
O
Me
HO
Me
HO
Me
HO
Me
HO
OH
OH
OH
OH
gluco
19
gluco
21
altro
20
altro
18
Scheme 4.

2360
S. F. Jenkinson et al. / Tetrahedron: Asymmetry 20 (2009) 2357–2367
Table 1
used to simultaneously deprotect and close the compounds to
Ratios determined by integration in 1H NMR
the desired C-3 and C-4-branched lactones. Recently, chemically
synthesised 2-C-methyl-pentoses and 2-C-methyl-hexoses have
been modified by the biotechnology of Izumoring18 to 4-C-
methyl-pentoses19 and 5-C-methyl-hexoses.20 A similar synergy
of chemistry and biotechnology may allow the hexoses reported
herein to be transformed into a wide range of 3-C- and 4-C-
methyl-carbohydrates.
Ligand
Yield of 16 (%)
Yield of 17 (%)
(DHQ)2PHAL (2 mol %), 72 h
14
9
32
28
15
21
10
13
14
L
-Malic acid (0.5 equiv), 18 h
Citric acid (0.5 equiv), 18 ha
42
63
61
56
55
Citric acid (0.75 equiv), 18 h
L
-Tartaric acid (0.5 equiv), 18 h
-Tartaric acid (0.75 equiv), 18 h
L
D-Tartaric acid (0.5 equiv), 18 h
3. Experimental
a
38% starting material was recovered from this reaction.
All commercial reagents were used as supplied. Tetrahydrofu-
ran and N,N-dimethylformamide were purchased dry from the Al-
drich chemical company in sure-seal bottles. Pyridine was
purchased dry from the Sigma–Aldrich chemical company in
sure-seal bottles. All other solvents were used as supplied (analyt-
ical or HPLC grade), without prior purification. The reactions were
performed under an atmosphere of nitrogen or argon, unless stated
otherwise. Thin layer chromatography (TLC) was performed on
aluminium sheets coated with 60 F254 silica. The sheets were visu-
alised using a spray of 0.2% w/v cerium(IV) sulfate and 5% ammo-
nium molybdate in 2 M sulfuric acid. Flash chromatography was
performed on Sorbsil C60 40/60 silica. Melting points were re-
corded on a Kofler hot block and are uncorrected. Optical rotations
were recorded on a Perkin–Elmer 241 polarimeter with a path
length of 1 dm. The concentrations are quoted in g 100 mLꢀ1. Ele-
mental analyses were performed by the microanalysis service of
the Inorganic Chemistry Laboratory, Oxford. Infrared spectra were
recorded on a Perkin–Elmer 1750 IR Fourier Transform spectropho-
tometer using thin films on NaCl or Ge plates (thin film). Only the
characteristic peaks are quoted. Low resolution mass spectra (m/z)
were recorded on VG MassLab 20–250, Micromass BIOQ-II, Micro-
mass Platform 1, Micromass TofSpec 2E, or Micromass Autospec
500 OAT spectrometers and high resolution mass spectra (HRMS
m/z) on a Micromass Autospec 500 OAT spectrometer. The tech-
niques used were electrospray (ESI), chemical ionisation (CI NH3),
or atmospheric pressure chemical ionisation (APCI). Nuclear mag-
netic resonance (NMR) spectra were recorded on Bruker AMX
500 (1H: 500 MHz and 13C: 125.7 MHz) and Bruker DPX 400 and
DQX 400 spectrometers (1H: 400 MHz and 13C: 100.6 MHz) in the
deuterated solvent stated. All chemical shifts (d) are quoted in
ppm and coupling constants (J) in hertz. Residual signals from
the solvents were used as an internal reference.
resin in water gave the fully deprotected altronolactone 20 and
gluconolactone 21.
The same reaction conditions were applied to the 2-C-hydroxy-
methyl-branched system 10 and the 2-C-methyl-branched system
15 (Scheme 5). In the case of 10 the acid which gave both the best
yield and the greatest stereoselectivity was found to be citric acid.
Additionally the triols were separable, giving the major product 22
in 79% yield and the minor product 23 in 9% yield. The stereochem-
istry of the major product 22 was at this point unknown, however,
deprotection and ring closure to the lactone in acidic conditions
gave both the fully and partially deprotected products 24 and 25
(Scheme 5), the stereochemistries of which were confirmed by
NOE experiments to again be altro. For the case of the 2-C-
methyl-branched system 15 less selectivity was shown with L-tar-
taric and citric acid giving a 5:3 or 5:4 ratio of products, respec-
tively. The altro 26 was found to again be the favoured product.
Interestingly, when using (DHQ)2PHAL as the ligand the selectivity
remained in favour of the altro product 26.
In summary, chain extension of branched sugar lactols by use of
the Wittig reaction and subsequent dihydroxylation has provided
access to C-3 and C-4-branched sugar lactones. The E-alkene was
selectively formed in high yield and the subsequent dihydroxyla-
tion reactions in the presence of citric or tartaric acid proceeded
in good yield. In both cases the predominant isomer was the altro
rather than the gluco isomer arising from the formation of the E-al-
kene in the Wittig reaction followed by dihydroxylation predomi-
nantly on the upper face of the a,b-unsaturated ester. For the C-2-
substituted systems, when the size of the C-2 substituent was re-
duced, from a silyl-protected hydroxymethyl group to a methyl
group, the selectivity of the dihydroxylation reaction decreased
allowing easier access to the gluco isomer. Acidic conditions were
CO2Me
CO2Me
CO2Me
CO2Me
i)
CO2Me
CO2Me
OH
O
OH
OH
O
OH
OH
OH
H
H
H
H
HO
HO
i)
HO
HO
H
H
H
H
OH
OH
OH
OH
OTBDPS
Me
OTBDPS
OTBDPS
Me
Me
O
O
O
O
O
O
O
O
O
O
23
22
10
15
26
27
Ligand - tartaric acid (0.75 eq.)
Ligand - citric acid (0.75 eq.)
Ligand - (DHQ)2PHAL (2 mol%)
Ligand - citric acid (0.75 eq.)
59%
53%
50%
36%
42%
15%
9%
79%
ii)
iii)
iii)
HO
HO
OH
O
HO
OH
HO
OH
HO
OH
O
O
O
O
O
O
O
TBDPSO
Me
HO
Me
HO
HO
OH
HO
OH
OH
OH
24
53%
28
25
15%
29
79%
75%
Scheme 5. Reagents and conditions: (i) K2OsO4, NMO, H2O, tBuOH, ligand; (ii) TFA, H2O, dioxane; (iii) Dowex (50W X8, H+), H2O.

S. F. Jenkinson et al. / Tetrahedron: Asymmetry 20 (2009) 2357–2367
2361
3.1. 1-Deoxy-3,4-O-isopropylidene-
D
-erythro-pentulofuranose 5
CH3C), 1.98 (3H, s, Me), 3.42–3.47 (1H, dd, H6, J 5.9, 11.7), 3.57–
3.61 (1H, dd, H60, J 3.7, 11.7), 3.69 (3H, s, OMe), 4.66–4.70 (1H,
ddd, H5, J 3.7, 5.8, 8.0), 5.67 (1H, d, H4, J 8.0), 5.84–5.85 (1H, a-
dd, H2, J 1.4, 2.9); dC (CDCl3, 100 MHz): 22.1, 22.2 (CH3C), 26.5
(Me), 51.3 (OMe), 61.5 (C6), 76.2 (C4), 78.7 (C5), 108.6 (CH3C),
117.0 (C2), 159.0 (C3), 166.4 (C@O); m/z (ESI+ve): 280
([M+MeOH+NH4]+, 100%).
2,3-O-Isopropylidene- -erythronolactone (16.72 g, 0.106 mol)
D
was dissolved in dry tetrahydrofuran (400 mL), the solution was
cooled to ꢀ78 °C and methyl magnesium bromide (3 M solution
in ether, 39 mL) was added dropwise. The reaction mixture was
stirred at ꢀ78 °C for 30 min after which time ammonium chloride
(satd aq, 30 mL) was added and the reaction mixture was allowed
to warm to room temperature. The mixture was partitioned be-
tween ethyl acetate (200 mL) and water (300 mL). The aqueous
layer was extracted with ethyl acetate (2 ꢁ 100 mL) and then the
combined organics were dried (magnesium sulfate) and concen-
trated under reduced pressure to give the ketose 5 as a (8:1) mix-
ture of anomers (18.2 g, 99%) which was used without further
purification. Mp: 82–85 °C [lit.21 87–89 °C]; mmax (thin film): 3423
(m, br, OH); NMR data for major anomer: dH (CDCl3, 400 MHz):
1.31 (3H, s, OCHCH3), 1.46 (3H, s, OCHCH3), 1.51 (3H, s, CH3),
3.89 (1H, d, H5, J 10.2), 3.97–4.00 (1H, dd, H50, J 3.8, 10.3), 4.38
(1H, d, H3, J 6.0), 4.82–4.85 (1H, m, H4); dC (CDCl3, 100 MHz):
22.3 (CH3), 25.0 (OCHCH3), 26.3 (OCHCH3), 70.9 (C5), 80.8 (C4),
85.0 (C3), 105.9 (C2), 112.3 (OCH(CH3)2); m/z (ESIꢀve): 173
([MꢀH]ꢀ, 100%).
3.2.3. Data for methyl 3,6-anhydro-2-deoxy-4,5-O-isopropyl-
idene-3-C-methyl-D-ribo-hexanoate 7
HRMS (ESI+ve) found: 253.1049 [M+Na]+; C11H18O5Na re-
quires: 253.1046; ½a D15
¼ ꢀ17:8 (c 1.13, CHCl3); mmax (thin film):
ꢂ
3454 (m, br, OH), 1740 (s, C@O); dH (CDCl3, 400 MHz): 1.33
(3H, s, C(CH3)2), 1.41 (3H, s, CH3), 1.52 (3H, s, CH3C), 2.42 (2H,
a-s, H2, H20), 3.68 (3H, s, OMe), 3.78–3.81 (1H, dd, H6, J 4.2,
11.0), 3.93 (1H, d, H60, J 10.9), 4.58 (1H, d, H4, J 6.2), 4.84–4.87
(1H, ddd, H5, J 0.7, 4.2, 6.0); dC (CDCl3, 100 MHz): 20.2 (CH3),
26.2, 26.8 (CH3C), 41.0 (C2), 51.8 (OMe), 71.0 (C6), 81.7 (C5),
83.5 (C3), 84.6 (C4), 112.5 (CH3C), 170.6 (C@O); m/z (ESI+ve):
253 ([M+Na]+,100%).
3.3. Methyl 4,5-O-isopropylidene-3-C-methyl-
and methyl 4,5-O-isopropylidene-3-C-methyl-
D
-altronoate 16
-gluconate, 17
D
3.2. (4S,5R,E)-Methyl 6-hydroxy-4,5-O-isopropylidene-3-
methyl-hex-2-enoate 6 and (4S,5R,Z)-methyl 6-hydroxy-4,5-O-
isopropylidene-3-methyl-hex-2-enoate and methyl 3,6-
anhydro-2-deoxy 4,5-O-isopropylidene-3-C-methyl-D-ribo-
hexanoate 7
Alkene 6 (59 mg, 0.26 mmol) was dissolved in tert-butyl alcohol
(0.95 mL) and water (0.95 mL), stirring under an atmosphere of ar-
gon. Citric acid (40 mg, 0.19 mmol) was added and allowed to dis-
solve before the addition of potassium osmate dihydrate (1 mg,
2.6 lmol) and 4-methylmorpholine N-oxide (33 mg, 0.28 mmol).
[Bu3PCH2CO2Me]+Brꢀ (2.40 g, 6.77 mmol) was dissolved in
dichloromethane (30 mL) and shaken with sodium hydroxide
(1 M aq, 30 mL) for 5 min. The organic layer was washed with brine
(2 ꢁ 20 mL), dried (magnesium sulfate) and the solvents were con-
The suspension was stirred at room temperature for 16 h. After this
time, TLC analysis (ethyl acetate) showed complete consumption
of the starting material (Rf 0.64) and the formation of two products
(Rf 0.43 and 0.34). The reaction mixture was concentrated in vacuo
and the residue was purified by flash column chromatography
(ethyl acetate) to afford methyl 4,5-O-isopropylidene-3-C-
methyl-D-gluconoate 17 (14 mg, 21%) and methyl 4,5-O-isopropyl-
idene-3-C-methyl-D-altronoate 16 (43 mg, 63%), both as colourless
oils.
centrated in vacuo. A solution of 1-deoxy-3,4-isopropylidine-D-er-
ythro-pentolofuranose 5 (471 mg, 2.71 mmol) in toluene (5.5 mL)
was added to the residue and the reaction mixture was stirred at
40 °C for 48 h. TLC analysis (ethyl acetate/cyclohexane 1:1) showed
the formation of two UV active products (Rf 0.42 and 0.38). Purifi-
cation by flash column chromatography (ethyl acetate/cyclohex-
ane 1:4?1:1) afforded (4S,5R,Z)-methyl 6-hydroxy-4,5-O-
isopropylidene-3-methyl hex-2-enoate (Rf 0.42, 89 mg, 14%) and
(4S,5R,E)-methyl 6-hydroxy-4,5-O-isopropylidene-3-methyl hex-
2-enoate 6 (Rf 0.38, 497 mg, 80%) as colourless oils. If the reaction
mixture was allowed to remain at 40 °C for greater than 48 h a
third product, a pale yellow oil, was obtained which was found
to be methyl 3,6-anhydro-2-deoxy-4,5-O-isopropylidene-3-C-
3.3.1. Data for methyl 4,5-O-isopropylidene-3-C-methyl-
D-altronoate 16 (major product, Rf 0.43)
C11H20O7 requires: C, 49.49; H, 7.63. Found: C, 49.00; H, 8.11;
HRMS (ESI+ve) found: 287.1111 [M+Na]+; C11H20O7Na requires:
287.1101; ½a 1D7
¼ þ17:8 (c 1.65, acetone); mmax (thin film): 3418
ꢂ
(s, br, OH), 1738 (s, C@O); dH (acetone-d6, 400 MHz): 1.31, 1.32
(2 ꢁ 3H, s, CH3C), 1.41 (3H, s, Me), 3.57–3.62 (1H, m, H6), 3.70
(3H, s, OMe), 3.90–4.00 (1H, m, H60), 4.15 (1H, d, H2, J 8.0), 4.24
(1H, s, 6-OH), 4.35 (1H, m, H4, H5) 4.41 (1H, d, 2-OH, J 8.2), 4.44
(1H, s, 3-OH); dC (acetone-d6, 100 MHz): 20.2 (Me), 27.2, 27.0
(CH3C), 51.5 (OMe), 61.1 (C6), 75.0 (C3), 76.2 (C5), 78.7 (C4), 79.0
(C2), 107.4 (CH3C), 172.7 (C@O); m/z (ESIꢀve): 263 ([MꢀH]ꢀ,
100%).
methyl-D-ribo-hexanoate 7.
3.2.1. Data for (4S,5R,E)-methyl 6-hydroxy-4,5-O-isopropyl-
idene-3-methyl-hex-2-enoate 6
HRMS (ESI+ve) found: 253.1046 [M+Na]+; C11H18O5Na requires:
253.1046; ½a 1D7
¼ þ41:7 (c 1.28, CHCl3); mmax (thin film): 3423 (s,
ꢂ
br, OH), 1719 (s, C@O); dH (CDCl3, 400 MHz): 1.31, 1.45 (2 ꢁ 3H,
s, CH3C), 2.05 (3H, a-d, Me, J 1.3), 2.52 (1H, br, s, OH), 3.29–3.33
(1H, dd, H6, J 4.8, 11.4), 3.33–3.38 (1H, dd, H60, J 7.7, 11.4), 3.62
(3H, s, OMe), 4.28–4.33 (1H, ddd, H5, J 4.9, 6.9, 7.5), 4.58–4.61
(1H, a-dd, H4, J 1.1, 6.7), 5.96–5.97 (1H, a-dd, H2, J 1.3, 2.7); dC
(CDCl3, 100 MHz): 21.0 (Me), 27.8, 25.9 (CH3C), 51.1 (OMe), 61.7
(C6), 78.2 (C5), 82.9 (C4), 109.3 (CH3C), 115.8 (C2), 157.7 (C3),
166.7 (C@O); m/z (ESIꢀve): 229 ([MꢀH]ꢀ, 70%).
3.3.2. Data for methyl 4,5-O-isopropylidene-3-C-methyl-
D-gluconate 17 (minor product Rf 0.34)
C11H20O7 requires: C, 49.49; H, 7.63. Found: C, 49.00; H, 8.11;
HRMS (ESI+ve) found: 287.1111 [M+Na]+; C11H20O7Na requires:
287.1101; ½a 1D8
¼ þ19:6 (c 0.55, acetone); mmax (thin film): 3418
ꢂ
(s, br, OH), 1738 (s, C@O); dH (acetone-d6, 400 MHz): 1.30, 1.41
(3H, s, CH3C), 1.33 (3H, s, Me), 2.82, 2.85 (2H, 2 ꢁ s, O-H), 3.57–
3.62 (1H, m, H6), 3.67–3.73 (1H, m, H60), 3.75 (3H, s, OMe), 4.12
(1H, m, H5), 4.26 (1H, dd, H4, J 1.2, 5.5), 4.48 (1H, a-d, H2, J 5.1),
4.43–4.51 (1H, m, OH); dC (acetone-d6, 100 MHz): 23.3 (Me),
27.7, 26.0 (CH3C), 52.4 (OMe), 62.6 (C6), 74.2 (C3), 76.23 (C5),
78.9 (C4), 79.0 (C2), 108.0 (CH3C), 166.7 (C@O); m/z (ESIꢀve):
263 ([MꢀH]ꢀ, 100%).
3.2.2. Data for (4S,5R, Z)-methyl 6-hydroxy-4,5-O-isopropyl-
idene-3-methyl-hex-2-enoate
HRMS (ESI+ve) found: 253.1046 [M+Na]+; C11H18O5Na requires:
253.1046; ½a 2D1
ꢂ
¼ þ45:7 (c 0.6, CHCl3);
mmax (thin film): 3444 (s, br,
OH), 1644 (s, C@O); dH (CDCl3, 400 MHz): 1.40, 1.54 (2 ꢁ 3H, s,

2362
S. F. Jenkinson et al. / Tetrahedron: Asymmetry 20 (2009) 2357–2367
3.4. 5,6-O-Isopropylidene-3-C-methyl-D-glucono-1,4-lactone 19
12.3), 3.90–3.93 (1H, ddd, H5, J 2.8, 5.6, 9.2), 4.25 (1H, d, H4, J
and 5,6-O-isopropylidene-3-C-methyl-
D
-altrono-1,4-lactone 18
9.1), 4.64 (1H, s, H2); dC (D2O, 125.7 MHz): 14.5 (CH3), 63.4 (C6),
69.7 (C5), 76.3 (C2), 78.7 (C3), 80.5 (C4), 176.5 (C@O); m/z
(ESIꢀve): 191 ([MꢀH]ꢀ, 100%).
A mixture of methyl 4,5-O-isopropylidene-3-C-methyl-altronate
16 and methyl 4,5-O-isopropylidene-3-C-methyl-gluconate 17, in a
4:3 ratio (135 mg, 0.51 mmol) was dissolved in water (4 mL) and
stirred with DowexÒ (50W X8, H+) resin (100 mg) for 48 h. After this
time, the resin was filtered away, and the solution was concentrated
in vacuo to give a colourless oil (98 mg, 100%). The crude mixture of
3.6. 3-C-Methyl-D-glucono-1,4-lactone 21
Protected gluconolactone 19 (16 mg, 0.07 mmol) was dissolved
in water (1 mL), and DowexÒ (50W X8, H+) was added. The reaction
mixture was stirred at room temperature for 48 h, after which time
TLC (ethyl acetate) showed the formation of one product (Rf 0.0) and
unreacted starting material (Rf 0.71). The reaction mixture was
heated to 70 °C and after a further 3 h the reaction mixture was fil-
tered and concentrated in vacuo and purified by column chromatog-
3-C-methyl-D-glucono/altrono-1,5-lactone and 3-C-methyl-D-gluc-
ono/altrono-1,4-lactone was used without further purification. This
crude was treated with acetone (2 mL), anhydrous copper sulfate
(163 mg, 1.02 mmol) and a catalytic quantity of concentrated sulfu-
ric acid. TLC analysis (ethyl acetate) after 48 h revealed complete
consumption of the starting material (Rf 0.0?0.15) and the presence
of two major products (Rf 0.71, 0.59). The reaction mixture was neu-
tralised with excess sodium carbonate and the salts were filtered
away through a pad of CeliteÒ. The filtratewas concentratedin vacuo
to leave an oily residue (124 mg). Purification by flash column chro-
matography (ethyl acetate/cyclohexane 2:1) afforded 5,6-O-isopro-
raphy (10% isopropanol in ethyl acetate) to give 3-C-methyl-D-
glucono-1,4-lactone 21 as a colourless oil (7 mg, 56%). HRMS
(ESI+ve) found: 215.0533 [M+Na]+; C7H12NaO6 requires: 215.0526;
½
a 2D0
ꢂ
¼ þ47:1 (c 0.48, H2O);
mmax (thin film): 3148 (s, br, OH), 1772
(s, C@O); dH (500 MHz, D2O): 1.35 (3H, s, CH3), 3.67 (1H, dd, H6, J
3.4, 12.1), 3.75 (1H, dd, H60, J 5.8, 12.1), 4.00 (1H, ddd, H5, J 3.4, 5.9,
6.9), 4.29 (1H, d, H4, J 7.1), 4.40 (1H, s, H2); dC (125 MHz, D2O):
19.8 (CH3), 62.6 (C6), 69.9 (C5), 74.7 (C2), 76.7 (C3), 84.5 (C4),
176.8 (C1); m/z (ESIꢀve): 191 ([MꢀH]ꢀ, 100%).
pylidene-3-C-methyl-D-glucono-1,4-lactone 19 (24 mg, 25%, Rf
0.71) and 5,6-O-isopropylidene-3-C-methyl-
18 (53 mg, 54%, Rf 0.59).
D-altrono-1,4-lactone
3.4.1. Data for 5,6-O-isopropylidene-3-C-methyl-D-glucono-1,4-
3.7. 2,3-O-Isopropylidene-
D-erythrofuranose
lactone 19 (minor product, Rf 0.71)
HRMS (ESIꢀve) found: 249.0970 [M+OH]ꢀ; C10H17O7 requires:
2,3-O-Isopropylidene- -erythronolactone (1.02 g, 6.46 mmol)
D
249.0969; ½a 2D1
ꢂ
¼ þ74:7 (c 0.25, acetone); mmax (thin film): 3452
was dissolved in dichloromethane (25 mL) and cooled to ꢀ78 °C.
Diisobutylaluminium hydride (1.7 M in toluene, 4.2 mL, 7.1 mmol)
was added dropwise and the reaction mixture was stirred at
ꢀ78 °C for 2 h after which time IR analysis still showed the presence
of a small carbonyl peak. Further, diisobutylaluminium hydride
(2 mL)wasadded dropwiseand thereactionmixturewasstirred fur-
ther for an hour. IR analysis showed the complete disappearance of
the carbonyl group. (TLC analysis (ethyl acetate/cyclohexane, 1:1)
showed that the product co-spotted with the starting material (Rf
0.43)). The reaction was quenched with methanol and the reaction
mixture was allowed to warm to room temperature. Ethyl acetate
(2 mL) was added followed by potassium dihydrogen orthophos-
phate (6.5 g) and sodium hydrogencarbonate (satd, aq, 10 mL). The
mixture was dried (magnesium sulfate), filtered through Celite and
concentrated under reduced pressure to give the crude lactol
(1.02 g, 99%), a colourless oil, as a 7:1 mixture of anomers, which
was used without further purification. HRMS (ESI+ve) found:
(s, br, OH), 1772 (s, C@O); dH (acetone-d6, 400 MHz): 1.32, 1.39
(2 ꢁ 3H, s, CH3C), 1.47 (3H, s, CH3), 3.88 (1H, d, H2, J 5.0), 3.92–
3.95 (1H, dd, H6, J 5.8, 8.6), 4.07–4.11 (1H, dd, H60, J 6.5, 8.6),
4.33 (1H, d, H4, J 6.3), 4.47 (1H, a-q, H5, J 6.2), 4.59 (1H, s, 3-OH),
5.62 (1H, d, 2-OH, J 5.1); dC (acetone-d6, 100 MHz): 23.3 (CH3C),
25.6 (CH3), 27.0 (C(CH3)2), 66.9 (C6), 73.6 (C5), 76.8 (C3), 77.1
(C2), 85.8 (C4), 109.6 (C(CH3)2), 175.4 (C@O); m/z (ESIꢀve): 463
([2MꢀH]ꢀ, 20%), 291 ([M+OCOCH3]ꢀ, 45%), 249 ([M+OH]ꢀ, 50%),
231 ([MꢀH]ꢀ, 73%), 203 (100%).
3.4.2. Data for 5,6-O-isopropylidene-3-C-methyl-D-altrono-1,4-
lactone 18 (major product, Rf 0.59)
HRMS (ESIꢀve) found: 231.0860 [MꢀH]ꢀ; C10H15O6 requires:
231.0863; ½a 1D9
¼ þ50:4 (c 0.46, acetone); mmax (thin film): 3420
ꢂ
(s, br, OH), 1788 (s, C@O); dH (acetone-d6, 400 MHz): 1.28 (3H, s,
CH3); 1.33 (3H, s, C(CH3)2), 1.42 (3H, s, C(CH3)2), 3.86–3.92 (1H,
dd, H6, J 5.2, 8.5), 4.10–4.14 (1H, dd, H60, J 6.2, 8.6), 4.19 (1H, d,
H4, J 7.4), 4.28–4.33 (1H, ddd, H5, J 5.3, 6.2, 7.3), 4.41 (1H, d, H2,
J 5.7), 4.44 (1H, s, 3-OH), 5.24 (1H, d, 2-OH, J 5.8); dC (acetone-d6,
100 MHz): 16.2 (CH3), 25.5, 27.0 (C(CH3)2), 67.1 (C6), 74.4 (C5),
76.7 (C2), 78.1 (C3), 83.6 (C4), 110.1 (C(CH3)2), 174.3 (C@O); m/z
(ESIꢀve): 231 ([MꢀH]ꢀ, 100%).
183.0628 [M+Na]+; C7H12NaO4 requires: 183.0628; ½a D20
¼ ꢀ70:8
ꢂ
(c 1.005, CHCl3); mmax (thin film): 3419 (s, br, OH); dH (CDCl3,
400 MHz) (data given for major anomer): 1.29 (3H, s, CH3C), 1.44
(3H, s, CH3C), 3.94 (1H, br, s, OH), 3.98 (1H, d, H4, J 10.4), 4.02–4.05
(1H, dd, H40, J 3.4, 10.4), 4.54 (1H, d, H2, J 5.8), 4.80–4.82 (1H, dd,
H3, J 3.4, 5.8), 5.36 (1H, s, H1); dC (CDCl3, 100 MHz): 24.7 (CH3C),
26.1 (CH3C), 71.8 (C4), 79.9 (C3), 85.1 (C2), 101.6 (C1), 112.3
(CH3C); m/z (ESI+ve): 183 ([M+Na]+, 100%).
3.5. 3-C-Methyl-D-altrono-1,4-lactone 20
Protected altronolactone 18 (28 mg, 0.12 mmol) was dissolved
in water (0.5 mL), and DowexÒ (50W X8, H+) was added. The reac-
tion mixture was stirred at room temperature for 16 h, after which
time TLC (ethyl acetate) showed the formation of one major prod-
uct (Rf 0.1) and a small amount of unreacted starting material (Rf
0.59). After 72 h the reaction mixture was filtered and concen-
trated in vacuo and purified by column chromatography (20%
3.8. 2-C-Hydroxymethyl-2,3-O-isopropylidene-
D-erythrofuranose 4
2,3-O-Isopropylidene-D-erythrofuranose (1.617 g, 10.1 mmol)
was dissolved in methanol (15 mL). Potassium carbonate (1.53 g,
11.1 mmol) and formaldehyde (37% aq, 8.3 mL) were added and
the reaction was refluxed for 6 h. After this time TLC (ethyl ace-
tate/cyclohexane, 1:1) showed the conversion of the starting mate-
rial (Rf 0.57) to one major product (Rf 0.18). The reaction mixture
was concentrated in vacuo and the residue was partitioned
between ethyl acetate (50 mL) and water (50 mL) and the aqueous
layer was further extracted with ethyl acetate (2 ꢁ 50 mL). The
combined organics were dried (magnesium sulfate) and concen-
methanol in ethyl acetate) to give 3-C-methyl-D-altrono-1,4-lac-
tone 23 as a colourless oil (21 mg, 88%). HRMS (ESI+ve) found:
215.0526 [M+Na]+; C7H12NaO6 requires: 215.0526; ½a D22
¼ þ63:3
ꢂ
(c 0.15, MeOH); mmax (thin film): 3385 (s, br, OH), 1782 (m,
C@O); dH (D2O, 500 MHz): dH (D2O, 500 MHz): 1.31 (3H, s, Me-4),
3.67–3.70 (1H, dd, H6, J 5.6, 12.2), 3.77–3.80 (1H, dd, H60, J 2.8,

S. F. Jenkinson et al. / Tetrahedron: Asymmetry 20 (2009) 2357–2367
2363
trated under reduced pressure to give the crude lactol which was
purified by column chromatography (ethyl acetate/cyclohexane,
1:1) to yield 2-C-hydroxymethyl-2,3-O-isopropylidene-D-erythrof-
uranose 4 (1.116 g, 58%), a colourless oil, as a 3:2 mixture of ano-
mers. C8H14O5 requires: C, 50.52, H, 7.42. Found: C, 50.00, H, 7.44;
CH3CN); mmax (thin film): 3442 (m, br, OH); dH (CD3CN, 400 MHz)
(1:1 mixture of anomers): 1.07 (9H, s, CH3CSi), 1.31 (3H, s, CH3C),
1.38 (3H, s, CH3C), 1.47 (3H, s, CH3C), 1.49 (3H, s, CH3C), 3.54–
3.57 (1H, dd, H4B, J 3.3, 11.0), 3.81 (2H, a-s, H20B, H200B), 3.83–
3.85 (1H, m, H40B), 3.84 (1H, d, H4A, J 10.5), 3.93 (1H, d, H20A, J
11.2), 3.87 (1H, d, H20A, J 11.2), 3.97–4.01 (1H, dd, H40A, J 3.9,
10.4), 4.01 (1H, d, OHB, J 11.7), 4.19 (1H, d, OHA, J 4.4), 4.65–4.66
(2H, m, H3A, H3B), 4.96 (1H, d, H1B, J 11.7), 5.25 (1H, d, H1A, J
4.3), 7.40–7.52 (12H, m, ArH), 7.69–7.78 (8H, m, ArH); dC (CD3CN,
100 MHz): 19.7 (2 ꢁ CH3CSi), 26.9 (CH3C), 27.2 (CH3CSi), 27.3
(CH3C), 28.1 (CH3C), 28.3 (CH3C), 64.6 (C20A), 65.1 (C20B), 68.2
(C4B), 72.6 (C4A), 83.1 (C3B), 83.3 (C3A), 89.5 (C2B), 95.6 (C2A),
99.1 (C1B), 103.5 (C1A), 113.9 (CH3C), 114.0 (CH3C), 128.7
(2 ꢁ ArCH), 128.8 (ArCH), 130.8 (2 ꢁ ArCH), 131.0 (ArCH), 133.6
(ArC), 133.7 (ArC), 134.0 (ArC), 134.2 (ArC), 136.4 (ArCH), 136.5
(ArCH); m/z (ESIꢀve): 427 ([MꢀH]ꢀ, 45%), 206 (100%).
½
a 2D0
ꢂ
¼ ꢀ51:3 (c 0.91, CHCl3); mmax (thin film): 3424 (s, br, OH); dH
(CD3CN, 400 MHz) (3:2 mixture of anomers, A—major anomer):
1.38 (3H, s, CH3CA), 1.42 (6H, s, CH3CA, CH3CB), 1.50 (3H, s, CH3CB),
3.46–3.51 (1H, dd, H4B, J 3.4, 11.0), 3.61–3.69 (2H, br, m, H20B),
3.71–3.78 (2H, br, m, H20A), 3.81 (1H, d, H40B, J 11.0), 3.85 (1H, d,
H4A, J 10.6), 3.97–4.00 (1H, dd, H40A, J 3.5, 10.5), 4.00 (1H, d,
OH1B, J 11.6), 4.45 (1H, br, s, OH1A), 4.59–4.61 (2H, m, H3A, H3B),
4.79 (1H, d, H1B, J 11.5), 5.21 (1H, s, H1A); dC (CD3CN, 100 MHz):
26.5 (CH3CB), 26.9 (CH3CB), 27.4 (2 ꢁ CH3CA), 62.3 (C20B), 62.5
(C20A), 67.6 (C4B), 72.2 (C4A), 82.4 (C3B), 83.1 (C3A), 89.4 (C2B),
94.3 (C2A), 98.5 (C1B), 103.5 (C1A), 113.1 (CH3CA), 113.4 (CH3CB);
m/z (ESIꢀve): 379 ([2MꢀH]ꢀ, 15%), 249 ([M+CH3CO2]ꢀ, 30%), 189
([MꢀH]ꢀ, 100%).
3.11. 2-C-Hydroxymethyl-2,3-O-isopropylidene-D-erythrono-
1,4-lactone
3.9. 3,6-Anhydro-2-deoxy-4-C-hydroxymethyl-4,5-O-
isopropylidene-
D
-ribo-hexono-1,40-lactone 8
2-C-Hydroxymethyl-2,3-O-isopropylidene-D-erythrofuranose 4
(953 mg, 5.0 mmol) was dissolved in water (7.5 mL) and cooled
to 0 °C and potassium carbonate (1.04 g, 7.5 mmol) was added.
Bromine (0.39 mL, 7.5 mmol) was added dropwise and the reaction
mixture was stirred at 0 °C for 2.5 h after which time TLC (ethyl
acetate/cyclohexane, 1:1) showed the complete conversion of the
starting material (Rf 0.17) to one major product (Rf 0.32). The reac-
tion was quenched with sodium thiosulfate (satd, aq) until the
reaction mixture became colourless. The mixture was extracted
with ethyl acetate (3 ꢁ 20 mL) and the combined organic layers
were washed with water (20 mL), dried (magnesium sulfate) and
concentrated in vacuo to give the pure lactone (823 mg, 87%) as
a white crystalline solid. C8H12O5 requires: C, 51.06, H, 6.43. Found:
C, 50.66, H, 6.53; HRMS (ESI+ve) found: 211.0585 [M+Na]+;
[Bu3PCH2CO2Me]+Brꢀ (1.06 g, 3 mmol) was dissolved in dichlo-
romethane (10 mL) and washed with sodium hydroxide (1 M aq,
10 mL) for 5 min. The organic layer was then washed with brine
(5 mL) and the brine was re-extracted with dichloromethane
(2 ꢁ 5 mL). The combined organics were dried (magnesium sul-
fate), filtered and concentrated in vacuo. The resulting ylid was
added to a solution of 2,3-O-isopropylidene-2-C-hydroxymethyl-
D
-erythrofuranose 4 (228 mg, 1.2 mmol) in toluene (2.5 mL) and
the reaction mixture was heated to 40 °C for 48 h. After this time
TLC (ethyl acetate/cyclohexane, 1:1) showed the formation of 2
major compounds (Rf 0.67 (UV active), Rf 0.33). The reaction mix-
ture was concentrated in vacuo and the residue was dissolved in
dichloromethane (10 mL) and washed with brine (5 mL). The or-
ganic layer was dried (magnesium sulfate), filtered and concen-
trated under reduced pressure and the residue was purified by
column chromatography (ethyl acetate/cyclohexane, 1:6) to give
the bicyclic Michael addition product 8 (Rf 0.33) as a colourless
oil (71 mg, 28%). HRMS (ESI+ve) found: 237.0734 [M+Na]+;
C8H12NaO5 requires: 211.0582; mp: 64–66 °C; ½a D22
¼ ꢀ103:4 (c
ꢂ
1.26, CHCl3); mmax (thin film): 3475 (m, br, OH), 1773 (s, C@O);
dH (CDCl3, 400 MHz): 1.40 (3H, s, CH3C), 1.46 (3H, s, CH3C), 2.90
(1H, br, s, OH), 3.85–3.89 (1H, dd, H20, J 1.9, 11.4), 3.99 (1H, d,
H200, J 11.4), 4.38–4.40 (2H, a-dd, H4, J 2.9, 10.7), 4.82–4.83 (1H,
a-dd, H3, J 1.0, 2.9); dC (CDCl3, 100 MHz): 26.2 (CH3C), 26.9
(CH3C), 61.6 (C20), 70.5 (C4), 78.5 (C3), 84.6 (C2), 113.6 (CH3C),
176.6 (C@O); m/z (ESI+ve): 211 ([M+Na]+, 100%).
C10H14NaO5 requires: 237.0733; ½a D20
¼ ꢀ78:3 (c 0.98, CH3CN);
ꢂ
mmax (thin film): 1763 (s, C@O); dH (CD3CN, 400 MHz): 1.39 (3H,
s, CH3C), 1.49 (3H, s, CH3C), 2.58–2.63 (1H, dd, H2, J 5.5, 15.8),
2.83–2.89 (1H, dd, H20, J 5.4, 15.8), 3.89–3.93 (1H, dd, H6, J 3.7,
11.1), 3.94–3.98 (1H, dd, H60, J 1.8, 11.1), 4.34 (1H, t, H3, J 5.4),
4.44 (2H, a-s, H40, H400), 4.72–4.73 (1H, dd, H5, J 1.8, 3.7); dC
(CD3CN, 100 MHz): 26.7 (CH3C), 27.7 (CH3C), 35.1 (C2), 70.5 (C40),
72.8 (C6), 82.1 (C3), 85.8 (C5), 89.2 (C4), 114.9 (CH3C), 171.4
(C@O); m/z (ESI+ve): 451 ([2M+Na]+, 100%).
3.12. (4R,5R,E)-Methyl 6-hydroxy-4-C-hydroxymethyl-4,5-O-
isopropylidene-40-O-tert-butyldiphenylsilyl-hex-2-enoate 10
[Bu3PCH2CO2Me]+Brꢀ (1.04 g, 2.9 mmol) was dissolved in
dichloromethane (20 mL) and shaken with sodium hydroxide
(1 M aq, 20 mL) for 5 min. The organic layer was then washed with
brine (10 mL) and the brine was re-extracted with dichlorometh-
ane (2 ꢁ 10 mL). The combined organics were dried (magnesium
sulfate), filtered and concentrated in vacuo. The resulting ylid
was added to a solution of silyl-protected lactol 9 (499 mg,
1.17 mmol) in toluene (10 mL) and the reaction mixture was
heated to 40 °C for 48 h. After this time TLC (ethyl acetate/cyclo-
hexane, 1:4) showed the complete conversion of the starting mate-
rial (Rf 0.42) to one major compound (Rf 0.32). The reaction
mixture was concentrated in vacuo and the residue was dissolved
in dichloromethane (20 mL) and washed with brine (10 mL). The
organic layer was dried (magnesium sulfate), filtered and concen-
trated under reduced pressure and the residue was purified by col-
umn chromatography (ethyl acetate/cyclohexane, 1:6) to give the
E-alkene 10 as a colourless oil (507 mg, 90%). HRMS (ESI+ve)
found: 507.2173 [M+Na]+; C27H36NaO6Si requires: 507.2173;
3.10. 2-C-hydroxymethyl-2,3-O-isopropylidene-20-O-tert-
butyldiphenylsilyl-
D-erythrofuranose 9
2-C-Hydroxymethyl-2,3-O-isopropylidene-
D-erythrofuranose 4
(703 mg, 3.7 mmol) was dissolved in dichloromethane (20 mL)
and cooled to 0 °C. Triethylamine (0.57 mL, 4.07 mmol), tert-butyl-
diphenylsilyl chloride (1.06 mL, 4.07 mmol) and dimethylamino-
pyridine (45 mg, 0.37 mmol) were added. The reaction mixture
was stirred at room temperature for 5 h after which time TLC
(ethyl acetate/cyclohexane, 1:1) showed the complete conversion
of the starting material (Rf 0.33) to one major product (Rf 0.90).
The reaction mixture was concentrated under reduced pressure
and the residue was purified by column chromatography (ethyl
acetate/cyclohexane, 1:6) to give the monosilylated compound 9
as a colourless oil (1.43 g, 90%). HRMS (ESI+ve) found: 451.1912
½
a 2D0
ꢂ
¼ þ1:9 (c 1.275, CH3CN); mmax (thin film): 3490 (m, br, OH),
[M+Na]+; C24H32NaO5Si requires: 451.1911; ½a 2D1
¼ ꢀ3:5 (c 0.82,
ꢂ
1726 (s, C@O); dH (CD3CN, 400 MHz): 1.06 (9H, s, CH3CSi), 1.39

2364
S. F. Jenkinson et al. / Tetrahedron: Asymmetry 20 (2009) 2357–2367
(3H, s, CH3C), 1.49 (3H, s, CH3C), 3.12 (1H, a-t, OH, J 5.4), 3.58–3.62
(1H, m, H6), 3.66–3.70 (1H, dd, H60, J 5.6, 11.2), 3.72 (3H, s, OMe),
3.75 (1H, d, H40, J 10.4), 3.80 (1H, d, H400, J 10.4), 4.30–4.33 (1H, dd,
H5, J 5.5, 6.5), 6.18 (1H, d, H3, J 15.5), 7.03 (1H, d, H2, J 15.5), 7.40–
7.50 (6H, m, ArH), 7.69–7.73 (4H, m, ArH); dC (CD3CN, 100 MHz):
19.8 (CH3CSi), 26.8 (CH3C), 27.1 (CH3CSi), 28.2 (CH3C), 52.1
(OMe), 62.1 (C6), 69.0 (C40), 81.6 (C5), 85.5 (C4), 110.0 (CH3C),
123.0 (C3), 128.7 (ArCH), 128.8 (ArCH), 130.9 (ArCH), 133.7 (ArC),
133.9 (ArC), 136.4 (ArCH), 136.5 (ArCH), 147.8 (C2), 167.1 (C@O);
m/z (ESI+ve): 543 ([M+MeCN+NH4]+, 100%).
3473 (s, br, OH), 1741 (s, C@O); dH (CD3CN, 400 MHz): 1.07 (9H,
s, CH3CSi), 1.43 (3H, s, CH3C), 1.46 (3H, s, CH3C), 3.32 (1H, dd,
OH6, J 5.8, 6.3), 3.51 (1H, d, OH2, J 7.2), 3.61 (3H, s, OMe), 3.78
(1H, d, OH3, J 7.7), 3.81–3.86 (1H, m, H6), 3.90–3.96 (1H, m, H60),
3.94 (1H, d, H40, J 11.5), 4.06–4.08 (1H, dd, H3, J 1.0, 7.7), 4.14
(1H, d, H400, J 11.5), 4.56–4.58 (1H, dd, H2, J 1.0, 7.2), 4.63–4.66
(1H, dd, H5, J 5.2, 6.4), 7.43–7.52 (6H, m, ArH), 7.72–7.78 (4H, m,
ArH); dC (CD3CN, 100 MHz): 19.5 (CH3CSi), 26.5 (CH3C), 26.9
(CH3CSi), 28.3 (CH3C), 52.6 (OMe), 60.7 (C6), 63.0 (C40), 70.3 (C2),
72.4 (C3), 79.0 (C5), 85.1 (C4), 108.5 (CH3C), 128.5 (ArCH), 128.6
(ArCH), 130.6 (ArCH), 130.7 (ArCH), 133.6 (ArC), 133.7 (ArC),
136.2 (ArCH), 136.3 (ArCH), 174.8 (C@O); m/z (ESIꢀve): 1035
([2MꢀH]ꢀ, 20%), 517 ([MꢀH]ꢀ, 100%).
3.13. Methyl 3,6-anhydro-2-deoxy-4-C-hydroxymethyl-4,5-O-
isopropylidene-40-O-tert-butyldiphenylsilyl-
D-gluconate 11
Alkene 10 (79 mg, 0.16 mmol) was dissolved in methanol
(1.5 mL), and sodium methoxide (10 mg, 0.18 mmol) was added.
The reaction mixture was stirred at room temperature for 1.5 h
after which time TLC (ethyl acetate/cyclohexane, 1:1) showed the
complete conversion of the starting material (Rf 0.82) to one prod-
uct (Rf 0.87). The reaction mixture was neutralised with DowexÒ
(50W X8, H+) resin, filtered and concentrated in vacuo to give the
Michael addition product 11 as a colourless oil (78 mg, 99%). HRMS
(ESI+ve) found: 485.2346 [M+H]+; C27H37O6Si requires: 485.2330;
3.14.2. Data for methyl 4-C-hydroxymethyl-4,5-O-isopropyl-
idene-40-O-tert-butyldiphenylsilyl-
product, Rf 0.33)
D-gluconate 23 (minor
HRMS (ESI+ve) found: 541.2227 [M+Na]+; C27H38NaO8Si re-
quires: 541.2228; ½a D20
¼ ꢀ15:5 (c 1.255, CH3CN); mmax (thin film):
ꢂ
3474 (s, br, OH), 1746 (s, C@O); dH (CD3CN, 400 MHz): 1.09 (9H, s,
CH3CSi), 1.30 (3H, s, CH3C), 1.47 (3H, s, CH3C), 3.41 (1H, t, OH6, J
5.5), 3.47 (1H, d, OH2, J 5.7), 3.60 (1H, d, OH3, J 7.6), 3.73 (3H, s,
OMe), 3.75 (1H, d, H40, J 10.7), 3.83 (1H, d, H400, J 10.5), 3.92–4.02
(2H, m, H6, H60), 4.21–4.24 (1H, dd, H3, J 1.0, 7.7), 4.27 (1H, a-t,
H5, J 4.9), 4.32 (1H, d, H2, J 5.7), 7.44–7.53 (6H, m, ArH), 7.69–
7.72 (4H, m, ArH); dC (CD3CN, 100 MHz): 19.5 (CH3CSi), 26.4
(CH3C), 27.0 (CH3C, CH3CSi), 52.4 (OMe), 61.0 (C6), 68.1 (C40),
70.7 (C3), 72.3 (C2), 83.5 (C5), 85.5 (C4), 109.5 (CH3C), 128.7
(ArCH), 130.9 (2 ꢁ ArCH), 133.2 (ArC), 133.4 (ArC), 136.3 (ArCH),
136.5 (ArCH), 173.7 (C@O); m/z (ESIꢀve): 1035 ([2MꢀH]ꢀ, 8%),
517 ([MꢀH]ꢀ, 100%).
½
a 2D0
ꢂ
¼ ꢀ9:8 (c 1.22, CHCl3); mmax (thin film): 1743 (s, C@O); dH
(CDCl3, 400 MHz): 1.09 (9H, s, CH3CSi), 1.28 (3H, s, CH3C), 1.49
(3H, s, CH3C), 2.61–2.66 (1H, dd, H10, J 4.0, 16.4), 2.67–2.73 (1H,
dd, H100, J 8.5, 16.4), 3.60–3.64 (1H, dd, H4, J 3.3, 10.7), 3.71 (3H,
s, OMe), 3.75 (1H, d, H20, J 10.6), 3.79 (1H, d, H200, J 10.6), 4.02
(1H, d, H40, J 10.7), 4.23–4.26 (1H, dd, H1, J 4.0, 8.5), 4.63 (1H, d,
H3, J 3.3), 7.39–7.49 (6H, m, ArH), 7.68–7.71 (4H, m, ArH); dC
(CDCl3, 100 MHz): 19.3 (CH3CSi), 26.9 (CH3C, CH3CSi), 27.2
(CH3C), 35.1 (C10), 51.9 (OMe), 65.4 (C20), 72.7 (C4), 79.1 (C1),
84.5 (C3), 91.7 (C2), 113.1 (CH3C), 127.9 (ArCH), 128.0 (ArCH),
130.1 (ArCH), 132.6 (ArC), 132.9 (ArC), 135.7 (ArCH), 135.9 (ArCH),
172.1 (C@O); m/z (ESI+ve): 991 ([2M+Na]+, 5%), 543
([M+MeCN+NH4]+, 100%), 507 ([M+Na]+, 15%).
3.15. 4-C-Hydroxymethyl-D-altrono-1,4-lactone 24 and 4-C-
hydroxymethyl-40-O-tert-butyldiphenylsilyl-
D-altrono-1,4-
lactone 25
The major diol product 22 (71 mg, 0.14 mmol) was dissolved in
water (1 mL) and dioxane (1.2 mL) and trifluoroacetic acid (0.5 mL)
was added. The reaction mixture was stirred at room temperature
for 18 h after which time TLC (ethyl acetate) showed the formation
of two products (Rf 0.44, 0.05). The reaction mixture was concen-
trated in vacuo and the residue was purified by column chroma-
tography to give the silylated minor product 25 (9 mg, 15%) and
the fully deprotected major product 24 (15 mg, 53%), both as col-
ourless oils. These were both found to be the altro furanose
products.
3.14. Methyl 4-C-hydroxymethyl-4,5-O-isopropylidene-
40-O-tert-butyldiphenylsilyl-
D
-altronate 22 and methyl
4-C-hydroxymethyl-4,5-O-isopropylidene-40-O-tert-
butyldiphenylsilyl- -gluconate 23
D
Alkene 10 (366 mg, 0.76 mmol) was dissolved in tert-butanol
(2.75 mL) and water (2.75 mL), and citric acid (119 mg, 0.57 mmol)
was added. Potassium osmate (3 mg, 7.6 lmol) and 4-methylmor-
pholine N-oxide (112 mg, 0.83 mmol) were added and the reaction
mixture was stirred at room temperature for 18 h. The reaction
mixture initially turned bright green which faded to almost colour-
less, overnight. After this time TLC (ethyl acetate/cyclohexane, 1:1)
showed the conversion of the starting material (Rf 0.82) to one ma-
jor (Rf 0.67) product and one minor (Rf 0.49) product. The reaction
mixture was concentrated in vacuo and partitioned between ethyl
acetate (20 mL) and water (10 mL), the aqueous layer was re-ex-
tracted with ethyl acetate (2 ꢁ 10 mL) and the combined organics
were dried (magnesium sulfate), filtered and concentrated in va-
cuo. The residue was purified by column chromatography (ethyl
acetate/cyclohexane, 1:6?1:4?1:2) to give the major diol 22
(275 mg, 70%) and the minor diol 23 (21 mg, 5%) as colourless oils
and a mixture of the two (50 mg, 13%, 2:1 mixture of major:minor
products) giving a total combined yield of 88%.
3.15.1. Data for 4-C-hydroxymethyl-40-O-tert-butyldiphenyl-
silyl-D-altrono-1,4-lactone 25 (minor product, Rf 0.44)
HRMS (ESI+ve) found: 469.1644 [M+Na]+; C23H30NaO7Si requires:
469.1653; ½a 2D0
ꢂ
¼ ꢀ9:8 (c 0.97, CH3CN);
mmax (thin film): 3406 (s, br,
OH), 1775 (s, C@O); dH (CD3CN, 400 MHz): 0.99 (9H, s, CH3CSi), 3.27
(1H, br, s, OH6), 3.37–3.41 (1H, m, H6), 3.54–3.58 (1H, m, H60), 3.63
(1H, d, H40, J 11.1), 3.75 (1H, a-s, br, H5), 4.09 (1H, d, H400, J 11.1),
4.13 (1H, d, br, OH2, J 4.8), 4.20 (1H, d, br, OH3, J 3.5), 4.52–4.55
(1H, dd, H3, J 2.2, 8.8), 4.73–4.76 (1H, dd, H2, J 3.3, 8.7), 7.37–7.53
(6H, m, ArH), 7.69–7.78 (4H, m, ArH); dC (CD3CN, 100 MHz): 19.6
(CH3CSi), 27.6 (CH3CSi), 62.8 (C6), 63.6 (C40), 72.4 (C5), 74.4 (C3),
74.5 (C2), 88.1 (C4), 128.6 (ArCH), 128.9 (ArCH), 130.4 (ArCH),
133.4 (ArC), 133.6 (ArC), 136.5 (ArCH), 137.1 (ArCH), 175.4 (C@O);
m/z (ESIꢀve): 505 ([M+CH3CO2]ꢀ, 47%), 445 ([MꢀH]ꢀ, 100%).
3.14.1. Data for methyl 4-C-hydroxymethyl-4,5-O-isopropyl-
idene-40-O-tert-butyldiphenylsilyl-
product, Rf 0.67)
D
-altronate 22 (major
3.15.2. Data for 4-C-hydroxymethyl-D-altrono-1,4-lactone 24
(major product, Rf 0.05)
HRMS (ESI+ve) found: 541.2218 [M+Na]+; C27H38NaO8Si re-
HRMS (ESI+ve) found: 231.0475 [M+Na]+; C7H12NaO7 requires:
quires: 541.2228; ½a D20
ꢂ
¼ þ4:8 (c 1.24, CH3CN); mmax (thin film):
231.0475; ½a 2D0
¼ ꢀ11:4 (c 1.13, MeOH); mmax (thin film): 3357 (s,
ꢂ

S. F. Jenkinson et al. / Tetrahedron: Asymmetry 20 (2009) 2357–2367
2365
br, OH), 1774 (s, C@O); dH (MeOD, 400 MHz): 3.54–3.58 (1H, dd,
H6, J 6.6, 11.8), 3.63 (1H, d, H40, J 12.4), 3.65–3.69 (1H, dd, H60, J
3.5, 11.8), 3.80–3.82 (1H, dd, H5, J 3.5, 6.6), 4.02 (1H, d, H400, J
12.3), 4.53 (1H, d, H3, J 8.8), 4.64 (1H, d, H2, J 8.8); dC (MeOD,
100 MHz): 61.8 (C40), 63.1 (C6), 73.5 (C5), 75.1 (C3), 75.2 (C2),
89.2 (C4), 177.0 (C@O); m/z (ESIꢀve): 207 ([MꢀH]ꢀ, 100%).
found: 297.9712 [M]Å; C8H11IO4 requires: 297.9702; ½a D22
ꢂ
¼ ꢀ72:1
(c 0.89, CHCl3); mmax (thin film): 1782 (s, C@O); dH (CDCl3,
400 MHz): 1.44 (3H, s, CH3C), 1.47 (3H, s, CH3C), 3.36 (1H, d, H20,
J 10.5), 3.51 (1H, d, H200, J 10.6), 4.39 (1H, d, H4, J 10.9), 4.46–
4.50 (1H, dd, H4’, J 4.0, 11.0), 4.72 (1H, d, H3, J 4.0); dC (CDCl3,
100 MHz): 1.2 (C20), 26.5 (CH3C), 27.0 (CH3C), 70.8 (C4), 80.5
(C3), 80.5 (C3), 83.4 (C2), 114.3 (CH3C), 173.4 (C@O); m/z (FI+ve):
298 ([M]Å, 100%).
3.16. 2-C-Hydroxymethyl-2,3-O-isopropylidene-20-O-
trifluoromethanesulfonyl-
D-erythrono-1,4-lactone
3.18. 2,3-O-Isopropylidene-2-C-methyl-D-erythrono-1,4-
2-C-Hydroxymethyl-2,3-O-isopropylidene-
D-erythrono-1,4-lac-
lactone 13
tone (823 mg, 4.3 mmol) was dissolved in dichloromethane
(5.5 mL) and pyridine (1.06 mL, 13.1 mmol) was added. The reac-
tion mixture was cooled to ꢀ30 °C and triflic anhydride (1.18 mL,
7.0 mmol) was added. The reaction mixture was stirred at ꢀ30 to
ꢀ10 °C for 3 h. After this time TLC (ethyl acetate/cyclohexane,
1:1) showed the complete consumption of the starting material
(Rf 0.26) and the formation of one major product (Rf 0.53). The
reaction mixture was diluted with dichloromethane (25 mL) and
washed with hydrochloric acid (1 M, aq, 15 mL), and the aqueous
layer was extracted with dichloromethane (3 ꢁ 10 mL). The com-
bined organic layers were washed with brine (20 mL), dried (mag-
nesium sulfate) and concentrated under reduced pressure to give
the crude triflate (1.31 g, 94%) as a crystalline solid which was used
without further purification. C9H11F3O7S requires: C, 33.75, H, 3.46.
Found: C, 33.92, H, 3.37; HRMS (ESI+ve) found: 343.0070 [M+Na]+;
2-C-Iodomethyl-2,3-O-isopropylidene-D-erythrono-1,4-lactone
12 (928 mg, 3.1 mmol) was dissolved in ethanol (30 mL), and tri-
ethylamine (1.3 mL, 9.3 mmol) and palladium black (93 mg) were
added. The reaction mixture was flushed with argon and hydrogen
and was stirred at rt for 18 h after which time TLC (ethyl acetate/
cyclohexane, 1:1) showed the complete conversion of the starting
material (Rf 0.74) to one major product (Rf 0.60). The reaction
mixture was flushed with argon, filtered through Celite and con-
centrated in vacuo. The residue was partitioned between dichloro-
methane (25 mL) and sodium thiosulfate (satd, aq, 15 mL). The
aqueous layer was re-extracted with dichloromethane (2 ꢁ 5 mL)
and the combined organic layers were washed with water
(10 mL), dried (magnesium sulfate) and concentrated under re-
duced pressure to give 2,3-O-isopropylidene-2-C-methyl-D-erythr-
C9H11F3NaO7S requires: 343.0075; mp: 106–108 °C; ½a D17
ꢂ
¼ ꢀ52:7
ono-1,4-lactone 13 (530 mg, 99%) as a light yellow oil. HRMS
(c 0.7, CHCl3); dH (CDCl3, 400 MHz): 1.45 (3H, s, CH3C), 1.52 (3H,
s, CH3C), 4.40–4.44 (1H, dd, H4, J 3.9, 11.2), 4.52 (1H, d, H40, J
11.2), 4.68 (1H, d, H20, J 11.0), 4.77 (1H, d, H200, J 11.0), 4.91 (1H,
d, H3, J 3.9); dC (CDCl3, 100 MHz): 25.9 (CH3C), 26.8 (CH3C), 70.0
(C4), 71.1 (C20), 77.3 (C3), 81.9 (C2), 115.0 (CH3C), 172.3 (C@O);
m/z (ESI+ve): 343 ([M+Na]+, 100%).
(CI+ve) found: 190.1076 [M+NH4]+; C8H16NO4 requires:
190.1079; ½a 2D0
¼ ꢀ95:5 (c, 0.69 in CHCl3); mp: 51–53 °C; mmax
ꢂ
(thin film): 1785 (s, C@O); dH (CDCl3, 400 MHz): 1.42 (3H, s,
CH3C), 1.47 (3H, s, CH3C), 1.55 (3H, s, Me), 4.30–4.34 (1H, dd, H4,
J 3.5, 11.1), 4.41 (1H, d, H40, J 11.0), 4.48 (1H, d, H3, J 3.4); dC (CDCl3,
100 MHz): 18.4 (Me), 26.5 (CH3C), 26.9 (CH3C), 68.9 (C4), 80.3 (C3),
81.4 (C2), 113.0 (CH3C), 176.7 (C@O); m/z (CI+ve): 190 ([M+NH4]+,
100%).
3.17. 2-C-Iodomethyl-2,3-O-isopropylidene-D-erythrono-1,4-
lactone 12
3.19. 2,3-O-Isopropylidene-2-C-methyl-
D-erythronofuranose 14
Method 1: Crude 2-C-hydroxymethyl-2,3-O-isopropylidene-20-
O-trifluoromethanesulfonyl- -erythrono-1,4-lactone (1.3 g, 4.06
D
2,3-O-Isopropylidene-2-C-methyl- -erythronolactone 13 (530
D
mmol) was dissolved in tetrahydrofuran (15 mL) and tetrabutyl-
ammonium iodide (3.0 g, 8.12 mmol) was added. The reaction
mixture was stirred at room temperature for 18 h in the dark
after which time TLC (ethyl acetate/cyclohexane, 1:1) showed
the conversion of the starting material (Rf 0.53) to one major
product (Rf 0.74). The reaction mixture was concentrated under
reduced pressure and the residue was taken up in ethyl acetate
(30 mL) and washed with water (15 mL) and sodium thiosulfate
(satd aq, 15 mL), dried (magnesium sulfate) and concentrated in
vacuo. The crude product was purified by column chromatogra-
phy (ethyl acetate/cyclohexane, 1:6?1:3?1:1) to give the pure
iodide 12 (928 mg, 77%) as a light yellow oil.
mg, 3.1 mmol) was dissolved in dichloromethane (15 mL) and
cooled to ꢀ78 °C. Diisobutylaluminium hydride (1 M in toluene,
3.2 mL) was added dropwise and the reaction mixture was
stirred at ꢀ78 °C for 3.5 h. After this time IR showed the presence
of a small amount of remaining starting material and therefore a
further portion of diisobutylaluminium hydride (0.6 mL) was
added. The reaction mixture was stirred for a further 1 h after
which time IR showed the complete disappearance of the carbonyl
peak and the formation of an OH signal. The reaction was
quenched with methanol and the reaction mixture was allowed
to warm to room temperature. Ethyl acetate (2 mL), potassium
dihydrogen orthophosphate (2 g) and sodium hydrogencarbonate
(satd aq, 2 mL) were added and the mixture was stirred for
10 min. The mixture was dried (magnesium sulfate), filtered
through Celite and concentrated in vacuo to give the crude lactol
which was purified by column chromatography (ethyl acetate/
Method 2: Imidazole (1.56 g, 22.9 mmol), triphenylphosphine
(3.62 g, 13.8 mmol) and iodine (3.5 g, 13.8 mmol) were added to
a stirred solution of 2-C-hydroxymethyl-2,3-O-isopropylidene-D-
erythrono-1,4-lactone (1.2 g, 6.3 mmol) in toluene (29 mL) and
stirred at 85 °C for 2 h. The reaction mixture was allowed to cool
to room temperature, concentrated in vacuo and then partitioned
between dichloromethane (50 mL) and saturated sodium hydrog-
encarbonate solution (50 mL). The resulting solution was extracted
with dichloromethane (3 ꢁ 50 mL) and the combined organic lay-
ers were washed with water (2 ꢁ 50 mL), dried (magnesium sul-
fate), filtered and concentrated in vacuo. The resulting residue
was purified by flash column chromatography (ethyl acetate/cyclo-
cyclohexane, 1:4) to give 2,3-O-isopropylidene-2-C-methyl-D-ery-
throfuranose 14 as a pale yellow oil (426 mg, 74%) as a 5:8 mixture
of anomers. HRMS (ESI+ve) found: 197.0784 [M+Na]+; C8H14NaO4
requires: 197.0790; ½a D21
¼ ꢀ56:8 (c 1.01, CHCl3); mmax (thin film):
ꢂ
3442 (s, OH); dH (CDCl3, 400 MHz) (5:8 mixture of anomers, A—ma-
jor anomer): 1.41 (3H, s, CH3CA), 1.45 (3H, s, MeB), 1.46 (6H, s,
CH3CA, CH3CB), 1.49 (3H, s, MeA), 1.53 (3H, s, CH3CB), 2.82–2.86
(1H, br, m, OHA), 3.55–3.59 (1H, dd, H4B, J 3.4, 11.1), 3.84 (1H, d,
OHB, J 11.5), 3.92 (1H, d, H4A, J 10.4), 3.96 (1H, d, H40B, J 11.1),
4.07–4.11 (1H, dd, H40A, J 3.5, 10.4), 4.39 (1H, d, H3B, J 3.4), 4.42
(1H, d, H3A, J 3.6), 4.64 (1H, d, H1B, J 11.4), 5.26 (1H, d, H1A, J
hexane 6:1) to afford the 2-C-iodomethyl-2,3-O-isopropylidene-D-
erythrono-1,4-lactone as a light yellow oil (1.776 g, 95%). C8H11IO4
requires: C, 32.24, H, 3.72. Found: C, 32.19, H, 3.75; HRMS (FI+ve)

2366
S. F. Jenkinson et al. / Tetrahedron: Asymmetry 20 (2009) 2357–2367
2.7); dC (CDCl3, 100 MHz): 19.7 (MeA), 21.5 (MeB), 26.7 (CH3CB),
27.0 (CH3CB), 27.5 (CH3CA), 27.7 (CH3CA), 67.2 (C4B), 71.8 (C4A),
85.1 (C3B), 86.1 (C2B), 86.2 (C3A), 91.5 (C2A), 101.5 (C1B), 103.4
(C1A), 112.5 (CH3CA), 113.1 (CH3CB); m/z (ESI+ve): 197 ([M+Na]+,
100%).
3.21.1. Data for methyl 4-C-methyl-4,5-O-isopropylidene-
D-
altronate 26 (major product, Rf 0.35)
HRMS (ESIꢀve) found: 263.11356 [MꢀH]+; C11H19O7 requires:
263.11363; ½a 2D5
ꢂ
¼ ꢀ4:5 (c, 0.605 in CHCl3), ½a D25
¼ ꢀ11:3 (c 0.15,
ꢂ
CHCl3); mmax (thin film): 3442 (s, br, OH), 1741 (s, C@O); dH (CHCl3,
400 MHz): 1.40 (3H, s, CH3C), 1.41 (3H, s, Me-4), 1.45 (3H, s, CH3C),
2.83–2.87 (1H, m, 6-OH), 3.26 (1H, d, 2-OH, J 4.4), 3.32 (1H, d, 3-
OH, J 9.1), 3.85 (3H, s, OMe), 3.90–3.96 (3H, m, H5, H6, H60),
4.05–4.07 (1H, dd, H3, J 0.8, 9.1), 4.66–4.68 (1H, dd, H2, J 0.8,
4.4); dC (CHCl3, 100.6 MHz): 19.4 (Me-4), 26.4 ((CH3)2C), 28.1
((CH3)2C), 53.2 (C6), 69.0 (C2), 70.9 (C3), 82.3 (C4), 83.8 (C5),
108.1 ((CH3)2C), 175.0 (C@O); m/z (ESIꢀve): 263 ([MꢀH]+, 100%),
527 ([2MꢀH]+, 15%).
3.20. (4S,5R,E)-Methyl 6-hydroxy-4,5-O-isopropylidene-4-C-
methyl-hex-2-enoate 15 and (4S,5R,Z)-methyl 6-hydroxy-4,5-O-
isopropylidene-4-C-methyl-hex-2-enoate
[Bu3PCH2CO2Me]+Brꢀ (418 mg, 1.18 mmol) was dissolved in
dichloromethane (20 mL) and shaken with sodium hydroxide
(1 M aq, 10 mL) for 5 min. The organic layer was then washed with
brine (10 mL) and the brine was re-extracted with dichlorometh-
ane (2 ꢁ 5 mL). The combined organics were dried (magnesium
sulfate), filtered and concentrated in vacuo. The resulting ylid
3.21.2. Data for methyl 4-C-methyl-4,5-O-isopropylidene-
D-
gluconate 27 (minor product, Rf 0.25)
was added to
a
solution of silyl-protected lactol (82 mg,
HRMS (ESIꢀve) found: 263.11353 [MꢀH]ꢀ; C11H19O7 requires:
0.47 mmol) in toluene (4 mL) and the reaction mixture was heated
to 40 °C for 96 h. After this time TLC (ethyl acetate/cyclohexane,
1:1) showed the complete conversion of the starting material (Rf
0.59) to one major compound (Rf 0.55). The reaction mixture was
concentrated in vacuo and the residue was dissolved in dichloro-
methane (20 mL) and washed with brine (10 mL). The organic layer
was dried (magnesium sulfate), filtered and concentrated under re-
duced pressure and the residue was purified by column chroma-
tography (ethyl acetate/cyclohexane, 1:6) to give an inseparable
mixture of E-alkene 15 and Z-alkene as a colourless oil (97 mg,
89%, E:Z, 20:1).
263.11363; ½a 2D5
¼ ꢀ16:3 (c 0.3, CHCl3); mmax (thin film): 3447 (s,
ꢂ
br, OH), 1759 (s, C@O); dH (CDCl3,400 MHz): 1.46 (3H, s, Me-4),
1.55 (3H, s, CH3C), 1.64 (3H, s, CH3C), 2.42 (1H, t, 6-OH, J 5.2),
3.23 (1H, d, 3-OH, J 8.1), 3.55 (1H, d, 2-OH, J 3.9), 3.83 (3H, s,
OMe), 3.87–3.90 (1H, dd, H3, J 1.0, 8.1), 3.97–4.07 (2H, m, H6,
H60), 4.06–4.10 (1H, m, H5), 4.49–4.51 (1H, dd, H2, J 1.1, 3.8); dC
(CDCl3, 100.6 MHz): 23.8 (Me-4), 26.1 ((CH3)2C), 27.1 ((CH3)2C),
52.8 (OMe), 60.2 (C6), 72.0 (C3), 72.1 (C2), 83.7 (C4), 85.0 (C5),
109.1 ((CH3)2C), 172.9 (C@O); m/z (ESIꢀve): 263 ([MꢀH]ꢀ, 87%),
527 ([2MꢀH]+, 15%).
3.22. 4-C-Methyl-D-altrono-1,4-lactone 28
3.20.1. Data for (4S,5R,E)-methyl 6-hydroxy-4,5-O-
isopropylidene-4-C-methyl-hex-2-enoate 15
Methyl 4-C-methyl-4,5-O-isopropylidene-D-altronate 26 (119 mg,
0.45 mmol) was dissolved in water (3.6 mL) and stirred with Dow-
exÒ (50W X8, H+) resin (90 mg) for 48 h. After this time, the reac-
tion mixture was filtered, and the solution was concentrated in
dH (CDCl3, 400 MHz): 1.40 (3H, s, CH3C), 1.41 (3H, s, CH3C), 1.47
(3H, s, Me), 2.66–2.68 (1H, t, OH, J 5.2), 3.59–3.68 (2H, m, H6, H60),
3.72 (3H, s, OMe), 4.03–4.06 (1H, dd, H5, J 5.2, 6.5), 6.06 (1H, d, H3,
J 15.5), 6.82 (1H, d, H2, J 15.5); dC (CDCl3, 100 MHz): 25.3 (CH3C),
26.5 (CH3C), 27.9 (Me), 51.7 (OMe), 61.4 (C6), 81.3 (C4), 84.5
(C5), 109.1 (CH3C), 120.6 (C3), 148.9 (C2), 166.9 (C@O).
vacuo to give 4-C-methyl-D-altrono-1,4-lactone 28 as a colourless
oil (86 mg, 75%). HRMS (ESI+ve) found: 215.0530 [M+Na]+;
C7H12NaO6 requires: 215.0526; ½a D25
¼ ꢀ2:8 (c 1.09, MeOH); mmax
ꢂ
(thin film): 3383 (s, br, OH), 1774 (s, C@O); dH (MeOD,
400 MHz): 2.39 (3H, s, Me), 4.67 (1H, dd, H6, J 2.1, 10.8), 4.72–
4.81 (2H, m, H5, H60), 4.97 (1H, d, H3, J 8.3), 5.62 (1H, d, H2, J
8.3); dC (MeOD, 100 MHz): 22.9 (Me), 63.6 (C6), 75.0 (C2), 78.1
(C5), 82.7 (C3), 86.7 (C4), 176.8 (C@O).
3.20.2. Data for (4S,5R,Z)-methyl 6-hydroxy-4,5-O-
isopropylidene-4-C-methyl-hex-2-enoate
dH (CDCl3, 400 MHz): 1.38 (6H, s, 2 ꢁ Me), 1.40 (3H, s, Me),
2.74–2.77 (1H, dd, OH, J 5.4, 7.0), 3.59–3.68 (2H, m, H6, H60),
3.70 (3H, s, OMe), 4.19–4.22 (1H, dd, H5, J 5.1, 7.4), 5.79 (1H,
d, H3, J 12.8), 6.13 (1H, d, H2, J 12.8); dC (CDCl3, 100 MHz):
25.5 (CH3C), 26.5 (CH3C), 28.7 (Me), 51.7 (OMe), 61.7 (C6),
83.2 (C4), 84.2 (C5), 108.8 (CH3C), 120.2 (C3), 146.3 (C2),
167.0 (C@O).
3.23. 4-C-Methyl-D-glucono-1,4-lactone 29
The gluconate product 27 (80 mg, 0.30 mmol) was dissolved in
water (2.4 mL) and stirred with DowexÒ (50W X8, H+) resin
(60 mg) for 48 h. After this time, the reaction mixture was filtered,
and the solution was concentrated in vacuo to give 4-C-methyl-D-
3.21. Methyl 4-C-methyl-4,5-O-isopropylidene-
D-altronate 26
glucono-1,4-lactone 29 as a white crystalline solid (60 mg, 79%)
HRMS (ESI+ve) found: 215.0527 [M+Na]+; C7H12NaO6 requires:
and methyl 4-C-methyl-4,5-O-isopropylidene- -gluconate 27
D
215.0526; mp: 121–124 °C; ½a D25
¼ þ22:2 (c 0.34, MeOH); mmax
ꢂ
Alkene 15 (40 mg, 0.18 mmol) was dissolved in tert-butanol
(0.65 mL) and water (0.65 mL), and -(+)-tartaric acid (20 mg,
0.14 mmol) was added. Potassium osmate (1 mg, mol) and 4-
(thin film): 3356 (s, br, OH), 1771 (s, C@O); dH (MeOD,
400 MHz): 2.39 (3H, s, Me), 4.58 (1H, dd, H6, J 7.1, 12.1), 4.68–
4.73 (2H, m, H5, H60), 5.39 (1H, d, H2, J 9.3), 5.43 (1H, d, H3, J
9.3); dC (MeOD, 100 MHz): 17.8 (Me), 63.2 (C6), 74.1 (C3), 74.3
(C2), 76.3 (C5), 87.1 (C4), 176.0 (C@O); m/z (ESIꢀve): 383
([2MꢀH]ꢀ, 100%), 191 ([MꢀH]ꢀ, 55%).
L
l
methylmorpholine N-oxide (23 mg, 0.20 mmol) were added and
the reaction mixture was stirred at room temperature for 24 h.
The reaction mixture initially turned bright green which faded to
almost colourless, overnight. After this time TLC (ethyl acetate)
showed the conversion of the starting material (Rf 0.62) to one ma-
jor (Rf 0.35) product and one minor (Rf 0.25) product. The reaction
mixture was concentrated in vacuo. The residue was purified by
column chromatography (ethyl acetate) to give the major diol 26
(20 mg, 44%) and the minor diol 27 (13 mg, 29%) as a colourless
oil and a mixture of the two (10 mg, 22%, 2:1) giving a total com-
bined yield of 95%.
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