Studies on the generation of enolate anions from butane-2,3-diacetal protected glycolic acid derivatives and subsequent highly diastereoselective coupling reactions with aldehydes and acid chlorides

Article abstract of DOI:10.1039/b412790k

Highly diastereoselective coupling reactions of enolates derived from butane-2,3-diacetal protected glycolic acids 1 and 2 and their alkylated derivatives with aldehydes are reported together with their efficient acid-catalysed deprotection to yield enant

Full text of DOI:10.1039/b412790k

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A R T I C L E
Studies on the generation of enolate anions from butane-2,3-diacetal
protected glycolic acid derivatives and subsequent highly
diastereoselective coupling reactions with aldehydes and acid
chlorides
Steven V. Ley,* Darren J. Dixon, Richard T. Guy, Maria A. Palomero, Alessandra Polara, Fe´lix
Rodr´ıguez and Tom D. Sheppard
Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge, UK CB2
1EW. E-mail: svl1000@cam.ac.uk; Fax: +44 (0)1223 336442; Tel: +44 (0)1223 336398
Received 19th August 2004, Accepted 29th September 2004
First published as an Advance Article on the web 17th November 2004
Highly diastereoselective coupling reactions of enolates derived from butane-2,3-diacetal protected glycolic acids 1
and 2 and their alkylated derivatives with aldehydes are reported together with their efficient acid-catalysed
deprotection to yield enantiopure anti-2,3-dihydroxyesters. A procedure to provide the corresponding
syn-2,3-dihydroxyesters is also described in two cases, proceeding via an acylation–reduction sequence. An usual
double addition reaction of butane-2,3-diacetal protected glycolic acid to small aliphatic acid chlorides provides a
synthetically useful, densely-functionalised lactone after acidic deprotection.
Introduction
The importance of the aldol reaction in organic synthesis is
well recognised owing to the fact that up to two stereogenic
centres are created in a single carbon–carbon bond forming
event.1 For this reason, the reaction is commonly used in
Scheme 1 (a) LHMDS (1.05 eq), THF, −78 ◦C, then RCHO.
natural product synthesis programmes. Similarly, the a-hydroxy
acid motif occurs frequently in many biologically significant
molecules and correspondingly has engendered considerable
synthetic attention.2,3
We believe that the major diastereoisomeric product arises
through attack of the aldehyde to the re-face of the glycolate
enolate, avoiding the steric clash with the 1,3-related axial
methoxy group. Assuming chelation of the lithium cation of the
enolate to the aldehyde oxygen and a six-membered ring chair-
like transition state, placement of the R group of the aldehyde in
the equatorial position (away from the dioxane ring) rationalizes
the stereochemistry of the major product (Fig. 2).
In a preceding paper4 and in earlier communications5–7
we described the excellent levels of stereochemical control
resulting from reactions of the lithium enolate derived from the
desymmetrised butane-2,3-diacetal (BDA) of glycolic acid 1 or
its enantiomer 2 (Fig. 1).
Similar, highly stereoselective adducts were also obtained by
coupling of the enolates from BDA glycolate 2 with ketones.9
We then examined the addition of the lithium enolates of 1
and 2 to aldehydes bearing a stereogenic center at the a-position
to evaluate the “matched” and “mismatched” combinations of
the coupling partners (Scheme 2). Treatment of the enolate
from (S,S)-2 with the tert-butyldimethylsilyl-protected chiral
aldehyde 21 gave an inseparable mixture of the aldol products
22 and 23 in the ratio 48 : 52 and an excellent combined
yield of 82%.10 However, reaction of the enantiomeric (R,R)-1
derivative with 21 gave alcohol 24 as the major product, in 87%
yield and >95% de. Assuming Felkin–Nguyen control,11,12 these
selectivities are consistent with the model described above and
the coupling of the enolate of 1 with 21 represents the matched
combination.
The reaction of glycolates (S,S)-1 and (R,R)-2 with chiral
aldehyde 25 was investigated as a key step in the synthesis
of the C22-C28 fragment of the natural immunosuppressant
rapamycin.13,14 In this case, both (S,S)-1 and (R,R)-2 gave a
single diastereoisomer of the aldol product (Scheme 3). The
stereochemistry of compound 28 was inferred by comparison
of the spectroscopic data of the two hydrolysis derivatives (vide
infra). Aldehyde 25 exerts less influence on the stereochemical
outcome of the reaction than aldehyde 21 as it lacks an
electronegative atom at the chiral centre. As a consequence, the
directing influence of the aldehyde can be overridden using the
butanediacetal auxiliary.
Fig. 1 Structures of butane-2,3-diacetal of glycolic acid (1) and its
enantiomer (2).
These chiral building blocks are crystalline and readily
prepared on a multigram scale from (S)- or (R)-3-halopropane-
1,2-diols4,5 or from alternative sources of chirality such as
mannitol and ascorbic acid.8 In this work we describe in full
the deprotonation of these building blocks and their subsequent
highly diastereoselective reactions with aldehydes and acid
chlorides. We have published previously in detail on the related
reactions with ketones.9
Results and discussion
In the first series of experiments, compound 2 was readily
deprotonated with 1.05 eq of lithium bis(trimethylsilylamide)
(LHMDS) in THF at −78 ◦C. After 10 min an aldehyde was
added via syringe and, after stirring for a further 5 min, the
reaction was quenched by the addition of acetic acid to give the
corresponding aldol products 12–20 (Scheme 1) in very good
yields and with extremely high selectivity (Table 1).
3 6 1 8
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2 , 3 6 1 8 – 3 6 2 7
T h i s j o u r n a l i s
T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 4
©

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Table 1 Glycolate aldol reactions
Aldehyde
Yield/%
86
de/%
92
Product
3
12
4
5
86
89
>95
>95
13
14
6
7
92
90
95
15
16
Scheme 3 (a) LHMDS (1.1 eq), THF, −78 ◦C, then 25, 79% (26), 84%
(28); (b) p-NO2C6H4COCl, Et3N, DMAP, rt, 98%.
>95
8
9
96
70
>95
17
18
94
Scheme 4 (a) KHMDS (1.05 eq), THF, −78 ◦C, then RCHO.
Table 2 Aldol reactions of alkylated derivatives
Glycolate
Aldehyde
Product
Yield/%
79
10
11
86
60
>96
>95
19
20
29
3
32
33
34
29
30
4
3
53
73
Fig. 2 Proposed transition state model leading to major diastereomer.
30
31
9
3
35
36
67
24
mono-alkylated BDA glycolates were prepared as in a pre-
ceding paper.4 Unexpectedly, these alkylated derivatives failed
to react successfully under the standard aldol conditions de-
scribed above. However, when deprotonated with potassium
bis(trimethylsilylamide) (KHMDS) at −78 ◦C, a successful
reaction occurred to afford the coupled products 32–36 in a
stereoselective fashion (Table 2), as anticipated from earlier
results. Although an excellent yield of product 32 was obtained,
the more sterically crowded products 33–36 are only produced
in moderate yield, possibly due to the lower stability of the
potassium enolate.
Scheme 2 (a) LHMDS (1.05 eq), THF, −78 ◦C, then 21, 82% (22 and
23), 87% (24).
We have also compared the reactivity of a selected number
of mono-alkylated BDA-glycolates (29, 30 and 31, Scheme 4)
during subsequent deprotonation and aldol reaction. These
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2 , 3 6 1 8 – 3 6 2 7
3 6 1 9

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Since the stereochemical outcome of the aldol reactions with
the desymmetrized BDA glycolates was, in most cases, highly
stereoselective, we briefly examined a complimentary process to
afford the alternative C-3 hydroxylic stereogenic centre. This
was achieved in a two-step process: reaction of the enolate
with an acyl chloride gave an enolised b-keto product (37 or
38) (Scheme 5), which was subsequently reduced with tetra-N-
butylammonium borohydride in CH2Cl2 to the corresponding
hydroxyl derivatives 39 and 40 with high stereoselectivity
(Scheme 6). The stereochemistry obtained was shown to be
complimentary to the products obtained from direct aldol
reaction.
cation (Scheme 8 and Table 4). Accordingly, aldehyde adducts
12–19 were readily converted to the corresponding 2,3-dihydroxy
methyl esters 47–54. These reactions occur in good to excellent
yields, and in some cases the structures of the products were
assigned by comparison with literature data.
Scheme 8 (a) HCl, MeOH, rt; (b) CSA, MeOH, reflux; (c) TFA, H2O,
rt.
These results provide further evidence for the selectivity of the
coupling reactions and in addition show that no isomerisation
occurs on hydrolysis.
The contiguous triol feature embedded in the aldol products
22–24 could be of use in further synthesis programmes and,
upon acidic hydrolysis in methanol with camphor sulfonic acid,
the inseparable aldol products 22 and 23 were converted to
a separable mixture of lactones 55 and 56 in 45% and 34%
yields, respectively. These lactones were known from previous
studies and therefore, by careful spectroscopic comparison with
the literature, we confirmed the stereochemical outcome of
these aldol reactions.15–17 The product of the matched aldol
reaction 24 was deprotected to a known lactone 57 in 75% yield.
Similarly, the aldol products 28 and 29 were subjected to acetal
deprotection conditions to yield the methyl esters 58 and 59 with
concomitant removal of the primary acetate.
Scheme 5 (a) LHMDS (1.05 eq), THF, −78 ◦C, then RCOCl, 73% (37),
68% (38)
Alcohol 44 contains two diastereotopic butanediacetal pro-
tected lactones which can be successfully differentiated by acidic
methanolysis to give the lactone 60. This creates a chiral centre
at the tertiary alcohol, favouring the syn-diol lactone 60 in a 13
: 1 ratio. Acidic hydrolysis gave the corresponding acid 61 as a
more favourable 25 : 1 ratio of diastereoisomers. Spectroscopic
data was insufficient to determine the stereochemistry of these
products but conversion to the tosylate derivative 62 enabled the
absolute and relative stereochemistry to be determined by X-ray
diffraction techniques (Scheme 9).†
Scheme 6 (a) Bu4NBH4, CH2Cl2, 68% (39), 76% (40)
When the enolate of 1 or 2 was reacted with less hindered
acyl chlorides 41–43, dimeric adducts 44–46 were obtained
in moderate to excellent yield as white crystalline solids after
simple trituration of the crude reaction product (Scheme 7 and
Table 3). These unusual bis-BDA derivatives result from addition
of two equivalents of the glycolate enolate to the acid chloride,
suggesting that under the reaction conditions the intermediate
ketone is consumed faster than the acid chloride.
Scheme 7 (a) LHMDS (1.05 eq), THF, −78 ◦C, then RCOCl (41–43)
Scheme 9 (a) Me2NC(Cl) CHMe, CH2Cl2, then MeOH, 59%; (b)
=
TsCl, pyridine, rt, 33%
We investigated the removal of the BDA protecting group in
selected examples by acid mediated hydrolysis or transesterifi-
Conclusions
Table 3 Double addition to unhindered acid chlorides
In summary, the BDA-desymmetrised glycolates 1 and 2 have
been shown to undergo highly anti-selective lithium enolate
aldol reactions which provide anti-2,3-dihydroxyesters in good
yield upon deprotection. Potassium enolate aldol reactions
of substituted lactones provide protected 2,2-disubstituted-
2,3-dihydroxyacids with excellent selectivity. A complimentary
acylation–reduction sequence was developed to provide the
protected syn-2,3-dihydroxyesters. The discovery of a novel
double addition reaction of the lithium enolate of 1 with acid
chlorides provided highly crystalline bis-BDA compounds which
upon deprotection provide a usefully differentiated contigu-
ous secondary–tertiary–secondary triol unit. Further highly
diastereoselective reactions of 1 and 2 will be reported shortly.
Acid chloride
Product
Yield/%
88
41
44
42
43
45a
46
41a
10
a (S,S)-glycolate 2 was used.
† CCDC reference number 251197. See http://www.rsc.org/suppdata/
ob/b4/b412790k/ for crystallographic data in .cif format.
3 6 2 0
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2 , 3 6 1 8 – 3 6 2 7

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Table 4 Acidic deprotection of the BDA group
Experimental
All reactions were performed under an atmosphere of argon
and carried out using oven dried glassware, cooled under a
continuous stream of argon prior to use, unless otherwise
stated. Diethyl ether (Et2O) and tetrahydrofuran (THF) were
distilled from sodium benzophenone ketyl; dichloromethane
(CH2Cl2), acetonitrile (MeCN), toluene (PhMe) and benzene
(PhH) from calcium hydride; methanol (MeOH) from mag-
nesium methoxide and triethylamine (Et3N) from potassium
hydroxide. All other reagents and solvents were purified by
standard procedures or were used as supplied from commercial
sources as appropriate. Ozonolysis reactions were performed
using a Peak Scientific ozone generator. The BDA-glycolates 1
and 2 were recrystallised to >99% ee (as measured by chiral GC)
before use. Flash column chromatography was carried out using
Merck Kieselgel (230–400 mesh) or prepacked silica columns
(FLASH Biotage). Unless otherwise stated, all compounds
containing the butanediacetal protected lactone functionality
were purified on columns that had been packed with solvent
containing 1% triethylamine by volume; 1% triethylamine was
also added to the eluent. Melting points were performed on
a Reichert hot stage apparatus and are uncorrected. Boiling
points were measured during distillation. Optical rotations were
measured using a Perkin Elmer Model 343 polarimeter and [a]D25
values are given in 10−1 deg cm2 g−1, concentration (c) in g
per 100 ml. Infrared spectra were recorded on a Perkin Elmer
“Spectrum One” spectrometer equipped with an attenuated total
reflectance (ATR) sampling accessory. Spectra were recorded
on thin films deposited from chloroform, dichloromethane or
methanol solutions. Microanalyses were determined using a CE-
440 Elemental Analyser. Mass spectra were obtained on Kratos
Concept 1H, Micromass Q-TOF or Bruker BIOAPEX 4.7E T
FTICR spectrometers, using electron impact (EI) or electrospray
(ESI) techniques. NMR spectra were recorded on Bruker DRX-
600, DRX-500 or DPX-400 spectrometers, in CDCl3 at 300 K,
unless otherwise stated. Chemical shifts (d) in ppm are given
relative to Me4Si, coupling constants (J) in Hz.
Lactone
Conditions
Ba
Product
Yield/%
75
12
47
48
49
50
13
14
15
A
A
A
86
89
93
16
17
18
19
A
A
A
A
51
52
53
54
73
85
99
57
22 and 23
B
B
B
55
56
57
45
34
75
Representative procedure for lithium enolate aldol reaction: pre-
paration of (+)-(3R, 5S, 6S, 1ꢀR)-5,6-dimethoxy-5,6-dimethyl-
3-(1ꢀ-ol-1ꢀ-p-methoxyphenyl-1ꢀ-yl)-[1,4]-dioxan-2-one (17)
Lithium bis(trimethylsilylamide) (1.0 M in THF, 0.86 ml, 0.86
mmol) was added to a solution of lactone 1 (155 mg, 0.82
mmol) in THF (2.5 ml) at −78 ◦C. After stirring for 10 min,
p-anisaldehyde (0.1 ml, 0.90 mmol) was added in one portion
and the reaction mixture was stirred for a further 5 min before
quenching with acetic acid (0.1 ml, 1.6 mmol) and warming to rt.
Diethyl ether (2 ml) was added and the reaction mixture filtered
through a small plug of silica eluting with Et2O (15 ml). The
filtrate was concentrated under reduced pressure and purified by
column chromatography to give the aldol product 17 (250 mg,
96%) as a white crystalline solid; mp 67–69 ◦C (from Et2O); [a]3D1
+107.1 (c 1.37, CHCl3); mmax (film)/cm−1 3488, 1754, 1150; dH
(400 MHz, CDCl3) 1.39 (3H, s, CH3), 1.47 (3H, s, CH3), 3.28
(3H, s, OCH3), 3.32 (3H, s, OCH3), 3.74 (1H, d, J 2.0, OH),
3.80 (3H, s, ArOCH3), 4.31 (1H, d, J 4.0, COCH), 5.08 (1H,
dd, J 2 and 4, CHOH), 6.87 (2H, d, J 9.0, Ar), 7.32 (2H, d, J
9.0, Ar); dC (100 MHz, CDCl3) 16.8, 17.9, 49.3, 50.1, 55.2, 74.0,
75.4, 98.3, 105.0, 113.4, 128.1, 130.5, 159.3, 167.0; Found (ES):
[MNa]+, 349.1274. C16H22O7 requires MNa, 349.1258.
24
26
28
44
Ba
Ba
A
58
59
60
88
85
100
(+)-(3R, 5S, 6S, 1ꢀR)-5,6-Dimethoxy-5,6-dimethyl-
ent-44
C
61
99
3-(1ꢀ-ethanol-1ꢀ-yl)-[1,4]-dioxan-2-one (12)
[a]3D1 +165.5 (c 0.89, CHCl3); mmax (film)/cm−1 3514, 1749;
dH(400 MHz, CDCl3) 1.31 (3H, d, J 6.5, CH3COH), 1.41 (3H, s,
CH3), 1.49 (3H, s, CH3), 3.29 (1H, d, J 2.0, OH), 3.32 (3H, s,
OCH3), 3.42 (3H, s, OCH3), 4.06 (1H, d, J 3.7, COCH), 4.16–
4.14 (1H, m, CH3CHOH); dc (100 MHz, CDCl3) 16.8, 17.6, 17.8,
a Reaction carried out at rt.
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2 , 3 6 1 8 – 3 6 2 7
3 6 2 1

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49.2, 50.2, 68.7, 75.1, 98.1, 104.9, 167.4; Found (ES): [MNa]+,
257.1004. C10H18O6 requires MNa, 257.0995.
−78 ◦C and was allowed to warm to rt. Diethyl ether was added
(20 ml) and the heterogeneous mixture was filtered through
a short plug of silica eluting with Et2O (150 ml). The filtrate
was concentrated under reduced pressure. The reaction de was
found to be >95% by integration of the signals in the 600 MHz
proton NMR spectrum. Biotage flash chromatography eluting
with Et2O–petrol, 1 : 2 gave the desired isomer (1.66 g, 86%) as
a colourless oil. [a]3D1 −151.6 (c 1.24, CHCl3); (Found: C, 52.07;
H, 7.27. Calc. for C11H18O6: C, 53.65; H, 7.37); mmax(film)/cm−1
3487, 2951, 1741, 1032; dH 1.42 (3H, s, CH3), 1.49 (3H, s, CH3),
3.32 (3H, s, OCH3), 3.42 (3H, s, OCH3), 4.19 (1H, d, J 3.5,
COCH), 4.49 (1H, m, CHOH), 5.26 (1H, d, J 10.5, CHCHH),
5.37 (1H, d, J 17.2, CHCHH), 6.04–5.96 (1H, m, CHCH2); dc
16.8, 17.8, 49.3, 50.1, 73.7, 75.0, 98.2, 104.8, 117.3, 134.8, 166.7;
Found: [MNa]+, 269.1005, C11H18O6 requires MNa 269.1001.
(+)-(3R, 5S, 6S, 1ꢀR)-5,6-Dimethoxy-5,6-dimethyl-
3-(1ꢀ-propanol-1ꢀ-yl)-[1,4]-dioxan-2-one (13)
◦
mp 42–43 C (from Et2O); [a]3D1 +155.7 (c 1.27, CHCl3); mmax
(film)/cm−1 3502, 1751, 1150; dH (400 MHz, CDCl3) 1.03–0.99
(3H, t, J 7.4, CH2CH3), 1.41 (3H, s, CH3), 1.49 (3H, s, CH3),
1.72–1.66 (2H, m, CH2), 3.30 (1H, d, J 2.0, OH), 3.32 (3H, s,
OCH3), 3.43 (3H, s, OCH3), 3.89–3.86 (1H, m, CHOH), 4.12
(1H, d, J 3.6, COCH); dc (100 MHz, CDCl3) 10.1, 16.8, 17.8,
24.7, 49.2, 50.2, 74.05, 74.1, 98.1, 104.8, 167.4; Found (ES):
[MNa]+, 271.1162. C11H20O6 requires MNa, 271.1152
(+)-(3R, 5S, 6S, 1ꢀR)-5,6-Dimethoxy-5,6-dimethyl-3-(2ꢀ,2ꢀ-
dimethyl-1ꢀ1-propanol-1ꢀ-yl)-[1,4]-dioxan-2-one (14)
(3R,5S,6S)-3-((R)-1-Hydroxy-hexadecyl)-5,6-dimethoxy-5,6-
dimethyl-[1,4]dioxan-2-one (20)
[a]D31 +149.5 (c 1.78, CHCl3); mmax (film)/cm−1 3496, 1733, 1150;
dH (400 MHz, CDCl3) 1.02 (9H, s, C(CH3)3), 1.38 (1H, s, CH3),
1.49 (3H, s, CH3), 3.25 (1H, d, J 4.7, OH), 3.31 (3H, s, OCH3),
3.44 (3H, s, OCH3), 3.65 (1H, dd, J 5.0 and 4.7, CHCOH),
4.23 (1H, d, J 5.0, COCH); dc (100 MHz, CDCl3) 16.9, 17.9,
26.3, 35.0, 49.2, 50.2, 72.8, 79.4, 98.1, 105.1, 169.3; Found (ES):
[MNa]+, 299.1461. C13H24O6 requires MNa, 299.1465.
Lithium bis(trimethylsilyl)amide (1.0 M in THF, 0.60 ml, 0.60
mmol) was added dropwise to a stirred solution of (S,S)-2
(109 mg, 0.57 mmol) in THF (1.5 ml) at −78 ◦C. After stirring for
15 min, hexadecanal (151 mg, 0.63 mmol) was added dropwise
via canula as a solution in THF (2 ml). The reaction was stirred
for 2 h at −78 ◦C before quenching with acetic acid (68 ll, 1.2
mmol). The resulting gel was filtered through a short plug of
silica, washing with Et2O (20 ml) and then concentrated. The
residue was purified by column chromatography (Et2O–petrol,
1 : 4) to give the alcohol as a white powder (147 mg, 60%); mp
(+)-(3R, 5S, 6S, 1ꢀR)-5,6-Dimethoxy-5,6-dimethyl-3-(2ꢀbuten-
1ꢀ-ol-1ꢀ-yl)-[1,4]-dioxan-2-one (15)
◦
mp 93–95 C (from Et2O); [a]3D1 +128.9 (c 0.81, CHCl3); mmax
(film)/cm−1 3497, 1750; dH (400 MHz, CDCl3) 1.42 (3H, s, CH3),
1.48 (3H, s, CH3), 1.72 (3H, d, J 6.0, CHCHCH3), 3.19 (1H,
d, J 3.1, OH), 3.32 (3H, s, OCH3), 3.41 (3H, s, OCH3), 4.19
(1H, d, J 3.5, COCH), 4.45–4.41 (1H, m, CHOH), 5.69 (1H,
dd, J 15.5 and 7.5, CH3CHCH), 5.80 (1H, dq, J 15.5 and 6.5,
CH3CHCH); dc (100 MHz, CDCl3) 16.8, 17.8, 17.9, 49.3, 50.1,
73.9, 75.0, 98.2, 104.8, 127.8, 129.9, 166.8; Found (ES): [MNa]+,
283.1165. C12H20O6 requires MNa, 283.1152.
◦
50–51 C; [a]3D1 +104.0 (c 0.60, CHCl3); (Found: C, 66.54; H,
10.71. Calc. for C24H46O6: C, 66.94; H, 11.77); mmax (film)/cm−1
3506, 2919, 2850, 1754, 1464, 1378; dH (CDCl3) 0.88 (3H, t, 6.8,
MeCH2), 1.2–1.4 (26H, m, CH2), 1.38 (3H, s, Me), 1.50 (3H, s,
Me), 1.55–1.72 (2H, m, CH2CHOH), 3.26 (1H, br d, J 0.5, OH),
3.33 (3H, s, OMe), 3.43 (3H, s, OMe), 3.95 (1H, m, CHOH),
4.11 (1H, d, J 3.4, axial H); dC 14.5, 17.2, 18.3, 23.1, 26.2, 29.3,
29.56, 29.57, 29.60, 29.64, 29.65, 29.67, 29.68, 31.7, 31.9, 49.7,
50.6, 73.2, 75.0, 98.5, 105.2, 167.7; Found (ES): [MNa]+ 453.3195
C24H46O6 requires MNa, 453.3192.
(+)-(3R, 5S, 6S, 1ꢀR)-5,6-Dimethoxy-5,6-dimethyl-3-(1ꢀol-
3ꢀphenyl-2ꢀpropen-1ꢀ-yl)-[1,4]-dioxan-2-one (16)
◦
mp 94–95 C (from Et2O); [a]3D1 +95.4 (c 0.76, CHCl3); mmax
2-(tert-Butyl-dimethyl-silanyloxy)-propionaldehyde (21)
(film)/cm−1 3496, 1752, 1600; dH (400 MHz, CDCl3) 1.45 (3H, s,
CH3), 1.50 (3H, s, CH3), 3.33 (1H, br s, OH), 3.34 (3H, s, OCH3),
3.37 (3H, s, OCH3), 4.30 (1H, d, J 3.3, COCH), 4.68 (1H, m,
CHOH), 6.40 (1H, dd, J 16.0 and 7.0, ArCHCH), 6.69 (1H, d, J
16.0, ArCH), 7.43–7.21 (5H, m, Ar); dc (100 MHz, CDCl3) 16.8,
17.8, 49.3, 50.2, 73.7, 75.0, 98.3, 104.9, 126.1, 127.7, 127.8, 128.5,
132.7, 136.6, 166.8; Found (ES): [MNa]+, 345.1320. C17H22O6
requires MNa, 345.1308.
The aldehyde was prepared from (S)-ethyl lactate, according◦to
the published procedure, as a colourless oil (61%);10 bp 67–68 C
at 14 mm Hg; [a]3D1 −11.1 (c 2.7, CHCl3).
(3R,5S,6S)-3-[(1R,2S)-2-(tert-Butyl-dimethyl-silanyloxy)-1-
hydroxy-propyl]-5,6-dimethoxy-5,6-dimethyl-[1,4]dioxan-2-
one (23) and (3R,5S,6S)-3-[(1S,2S)-2-(tert-butyl-dimethyl-
silanyloxy)-1-hydroxy-propyl]-5,6-dimethoxy-5,6-dimethyl-
[1,4]dioxan-2-one (22)
(+)-(3R, 5S, 6S, 1ꢀR)-5,6-Dimethoxy-5,6-dimethyl-3-(1ꢀ-ol-1ꢀ-p-
nitrophenyl-1ꢀ-yl)-[1,4]-dioxan-2-one (18)
Lithium bis(trimethylsilyl)amide (1.0 M in THF, 0.86 ml, 0.86
mmol) was added dropwise to a stirred solution of (S,S)-1
(155 mg, 0.82 mmol) in THF (2.5 ml) at −78 ◦C. After stirring
for 15 min aldehyde 21 (171 mg, 0.96 mmol) was added and
the resulting solution stirred for 20 min at −78 ◦C. Acetic acid
(90 ll, 1.5 mmol) was added and the solution warmed to rt
and filtered through a short plug of silica gel eluting with ether
(50 ml). The filtrate was concentrated under reduced pressure
and then purified by column chromatography (Et2O–petrol, 1
: 9) to give the alcohols (246 mg, 0.65 mmol, 79%) as prisms;
[a]D31+115.5 (c 0.98, CHCl3); mmax (film)/cm−1 3491, 2955, 2932,
2857, 1749; major isomer 23: dH 0.07 (3H, s, SiMe), 0.10 (3H, s,
◦
mp 120–122 C (from Et2O); [a]3D1 +83.3 (c 0.73, CHCl3); mmax
(film)/cm−1 3486, 1755, 1524; dH (400 MHz, CDCl3) 1.41 (3H, s,
CH3), 1.50 (3H, s, CH3), 3.30 (3H, s, OCH3), 3.40 (3H, s, OCH3),
4.04 (1H, d, J 1.6, OH), 4.33 (1H, d, J 4.4, COCH), 5.21 (1H,
dd, J 4.4 and 1.6, CHOH), 7.58 (2H, d, J 8.7, Ar), 8.20 (2H,
d, J 8.7, Ar); dc (100 MHz, CDCl3) 16.8, 17.8, 49.5, 50.4, 73.6,
75.4, 98.4, 105.2, 123.2, 127.6, 145.6, 147.5, 166.3; Found (ES):
[MNa]+, 364.1000. C15H19NO8 requires MNa, 364.1003.
(3S,5R,6R)-3-((S)-1-Hydroxy-allyl)-5,6-dimethoxy-5,6-
dimethyl-[1,4]dioxan-2-one (19)
SiMe), 0.88 (9H, s, tBu), 1.24 (3H, d, J 5.9, MeCOSiMe2 BuH),
t
Lithium bis(trimethylsilyl)amide (1.0 M in THF, 8.3 ml, 8.3
mmol) was added to a stirred solution of the◦(R,R)-glycolate 1
(1.50 g, 7.89 mmol) in THF (40 ml) at −78 C. After 10 min,
freshly distilled acrolein◦(0.63 ml, 9.47 mmol) was added and the
solution stirred at −78 C for further 5 min. The reaction was
then quenched by addition of acetic acid (0.9 ml, 15.78 mmol) at
1.42 (3H, s, Me), 1.50 (3H, s, Me), 3.19 (1H, d, J 10.61, OH),
3.34 (3H, s, OMe), 3.43 (3H, s, OMe), 3.70 (1H, m CHOH),
3.82 (1H, dq, J 8.8, 6.0, CHOSiMe2 BuMe), 4.59 (1H, br s, axial
H); dC −4.8, −3.7, 16.8, 17.9, 18.0, 20.7, 25.8, 49.5,50.2, 68.0,
71.0, 76.1, 98.0, 104.4, 169.2; minor isomer 22: dH. 0.09 (3H, s,
SiMe), 0.10 (3H, s, SiMe), 0.90 (9H, s, tBu), 1.27 (3H, d, J 6.3,
t
3 6 2 2
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2 , 3 6 1 8 – 3 6 2 7

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t
MeCOSiMe2 BuH), 1.39 (3H, s, Me), 1.49 (3H, s, Me), 2.90 (1H,
dd, J 10.8, 7.0, CH2OAc), 3.94 (1H, dd, J 10.8, 5.2, CH2OAc),
4.05 (1H, d, J 6.3, axial H); dC(100 MHz, CDCl3) 14.4, 17.2,
18.1, 18.3, 21.3, 30.1, 31.1, 37.6, 49.6, 50.6, 69.4, 71.8, 74.8,
98.5, 105.4, 168.8, 171.6; Found: [MNa]+, 385.1838. C17H30O8
requires MNa 385.1838.
d, J 5.5, OH), 3.31 (3H, s, OMe), 3.42 (3H, s, OMe), 3.61 (1H,
m CHOH), 4.12 (1H, d, J 5.7 axial H), 4.19 (1H, dq, J 4.4,6.3
t
CHOSiMe2 BuMe); dC −4.7, −4.2, 16.8, 17.9, 17.9, 18.0, 20.4,
25.8, 49.5, 50.0, 67.3, 71.6, 78.0, 98.3, 104.4, 168.0; Found (ES):
[MNa]+ 401.19860 C17H34O7Si requires MNa, 401.1972.
(3R,5R,6R)-3-[(1S,2R,4S)-5-Acetyloxy-2,4-dimethyl-5-para-
nitrobenzoyloxypentanyl]-5,6-dimethoxy-5,6-dimethyl-
[1,4]dioxan-2-one (27)
(3S,5R,6R)-3-[(1R,2S)-2-(tert-Butyl-dimethyl-silanyloxy)-1-
hydroxy-propyl]-5,6-dimethoxy-5,6-dimethyl-[1,4]dioxan-2-
one (24)
Alcohol 26 (175 mg, 0.47 mmol) in dry CH2Cl2 (10 ml) was
successively treated with triethylamine (129 lL, 0.93 mmol), p-
nitrobenzoyl choride (172 mg, 0.93 mmol) and DMAP (6 mg,
0.05 mmol). After stirring for 45 min, the reaction mixture was
diluted with ether (50 ml) and washed twice with a saturated
ammonium chloride solution. The organic layer was dried
(Mg2SO4), concentrated under reduced pressure and purified
by column chromatography (Et2O–petrol, 1 : 1) to give the
ester 27 (242 mg, 0.46 mmol, 98%) as a colourless oil, that
was crystallised from hexane–ether; mp 114 ◦C (from Et2O–
hexane); [a]3D1 −53.4 (c 0.95, CHCl3); mmax (film)/cm−1 1733, 1266;
dH (400 MHz, CDCl3) 0.90 (3H, d, J 6.7, Me), 1.00–1.05 (1H, m,
CHMe), 1.02 (3H, d, J 6.8, Me), 1.33 (3H, s, Me), 1.35–1.39 (1H,
m, CHMe), 1.42 (3H, s, Me), 1.89 (3H, s, MeCO), 1.91–1.92 (1H,
m, CH2), 2.40 (1H, ddd, J 7.5, 6.8, 3.7, CH2), 3.24 (3H, s, OMe),
3.35 (3H, s, OMe), 3.82 (2H, d, J 6.1, CH2OAc), 4.25 (1H, d, J
6.1, axial H), 5.46 (1H, dd, J 7.8, 3.3, CHOPNP), 8.13 (2H, d,
J 8.8, CHCCO), 8.21 (2H, d, J 8.8, CHCNO2); dC(100 MHz,
CDCl3) 14.4, 16.8, 16.9, 17.8, 20.7, 29.7, 30.2, 37.3, 49.1, 50.1,
69.0, 69.5, 74.7, 98.5, 105.0, 123.4, 130.9, 135.5, 150.6, 164.1,
167.1, 171.0; Found: [MNa]+, 534.1938. C24H33NO11 requires
MNa 534.1951.
Lithium bis(trimethylsilyl)amide (1.0 M in THF, 0.86 ml, 0.86
mmol) was added dropwise to a stirred solution of (R,R)-1
(155 mg, 0.82 mmol) in THF (2.5 ml) at −78 ◦C. After stirring
for 15 min aldehyde 21 (171 mg, 0.96 mmol) was added and
the resulting solution stirred for 20 min at −78 ◦C. Acetic acid
(90 ll, 1.5 mmol) was added and the solution warmed to rt and
filtered through a short plug of silica gel eluting with ether (50
ml). The filtrate was concentrated under reduced pressure and
then purified by column chromatography (Et2O–petrol, 1 : 9) to
give the alcohol (260 mg, 0.69 mmol, 84%) as a colourless oil;
[a]3D1 −74.7 (c 0.45, CHCl3); (Found: C, 54.12; H, 9.03. Calc. for
C17H34O7Si: C, 53.94; H, 9.05); mmax (film)/cm−1 3493, 2955, 2931,
2857, 1755; dH 0.11 (3H, s, SiMe), 0.12 (3H, s, SiMe), 0.89 (9H, s,
t
tBu), 1.23 (3H, d, J 6.2, MeCOSiMe2 BuH), 1.41 (3H, s, Me),
1.49 (3H, s, Me), 3.17 (1H, d, J 2.2, OH), 3.32 (3H, s, OMe),
3.43 (3H, s, OMe), 3.67 (1H, br dt, J 8.4, 2.2, CHOH), 4.12
t
(1H, dq, J 8.4, 6.2, CHOSiMe2 BuMe), 4.51 (1H, d, J 2.2, axial
H); dC −5.0, −4.2, 16.8, 17.8, 17.9, 20.6, 25.8, 49.1, 50.2, 67.3,
72.5, 78.1, 98.0, 104.5, 166.6; Found (ES): [MNa]+ 401.19860
C17H34O7Si requires MNa, 401.1972.
(2R,4S)-5-Acetoxy-2,4-dimethylpentanal (25)
(3R,5S,6S)-3-[(1R,2R,4S)-5-Acetyloxy-5-hydroxy-2,4-
dimethylpentanyl]-5,6-dimethoxy-5,6-dimethyl-[1,4]dioxan-2-
one (28)
The
described
(2R,4S)-5-acetoxy-2,4-dimethylpentanol13
(190 mg, 1.1 mmol) in dry CH2Cl2 (15 ml) was successively
treated with Hunig’s base (0.76 ml, 4.4 mmol) and a solution
of sulfur trioxide–pyridine complex (520 mg, 3.3 mmol) in dry
Lithium bis(trimethylsilyl)amide (1.0 M in hexanes, 1.10 ml,
1.10 mmol) was added dropwise to a stirred solution of (S,S)-
2 (190 mg, 1.00 mmol) in dry THF (20 ml) at −78 ◦C. After
stirring for 15 min aldehyde 25 (172 mg, 1.00 mmol) was added
◦
DMSO (0.5 ml) at 0 C. The reaction was stirred at the same
temperature for 2 h and then quenched with pH 7 phosphate
buffer (15 ml). The crude was diluted with ether (50 ml)
and washed four times with a saturated ammonium chloride
solution. The organic layer was dried (Mg2SO4), concentrated
under reduced pressure and used directly in the next step; [a]D31
+3.6 (c 0.85, CHCl3), dH (400 MHz, CDCl3) 0.82 (3H, d, J
6.7, Me), 0.98 (3H, d, J 7.0, Me), 1.01–1.09 (1H, m, CH),
1.67–1.79 (2H, m, CH2), 1.92 (3H, s, MeCOO), 2.28–2.36 (1H,
m, CHCHO), 3.73–3.81 (2H, m, CH2OAc), 9.45 (1H, d, J 2.2,
CHO); dC(100 MHz, CDCl3) 14.5, 17.5, 21.2, 30.6, 34.8, 44.2,
69.1, 171.4, 204.8.
◦
and the resulting solution stirred for 30 min at −78 C. Acetic
acid (90 lL, 1.5 mmol) was added and the solution warmed to rt
and filtered through a short plug of silica gel eluting with ethyl
acetate (50 ml). The filtrate was concentrated under reduced
pressure and then purified by column chromatography (Et2O–
petrol, 1 : 1) to give the alcohol 28 (285 mg, 0.79 mmol, 79%)
as a colourless oil; [a]3D1 +109.6 (c 0.29, CHCl3); mmax (film)/cm−1
1734; dH (400 MHz, CDCl3) 0.92 (3H, d, J 6.7, Me), 0.97 (3H,
d, J 6.7, Me), 0.99–1.05 (1H, m, CHMe), 1.37 (3H, s, Me), 1.46
(3H, s, Me), 1.61–1.68 (1H, m, CHMe), 1.90–1.99 (2H, m, CH2),
2.01 (3H, s, MeCO), 3.29 (3H, s, OMe), 3.39 (3H, s, OMe), 3.57
(1H, dd, J 7.4, 4.4, CHOH), 3.73 (1H, dd, J 10.8, 7.4, CH2OAc),
3.99 (1H, dd, J 10.8, 5.1, CH2OAc), 4.18 (1H, d, J 4.4, axial H);
dC (100 MHz, CDCl3) 16.5, 16.8, 17.8, 18.7, 21.0, 30.0, 31.6,
36.7, 49.4, 50.3, 65.8, 69.3, 72.3, 77.1, 98.1, 104.8, 168.1, 171.3;
Found: [MNa]+, 385.1839. C17H30O8 requires MNa 385.1838.
(3R,5R,6R)-3-[(1S,2R,4S)-5-Acetyloxy-5-hydroxy-2,4-
dimethylpentanyl]-5,6-dimethoxy-5,6-dimethyl-[1,4]dioxan-2-
one (26)
Lithium bis(trimethylsilyl)amide (1.0 M in hexane, 1.10 ml, 1.10
mmol) was added dropwise to a stirred solution of (R,R)-1
(190 mg, 1.00 mmol) in dry THF (20 ml) at −78 ◦C. After
stirring for 15 min aldehyde 25 (172 mg, 1.00 mmol) was added
(3S,5R,6R)-3-((S)-1-Hydroxy-ethyl)-5,6-dimethoxy-3,5,6-
trimethyl-[1,4]dioxan-2-one (32)
◦
and the resulting solution stirred for 30 min at −78 C. Acetic
acid (90 lL, 1.5 mmol) was added and the solution warmed to rt
and filtered through a short plug of silica gel eluting with ethyl
acetate (50 ml). The filtrate was concentrated under reduced
pressure and then purified by column chromatography (Et2O–
petrol, 1 : 1) to give the alcohol 26 (305 mg, 0.84 mmol, 84%)
as a colourless oil; [a]3D1 −88.8 (c 0.10, CHCl3); mmax (film)/cm−1
1737; dH (400 MHz, CDCl3) 0.89 (3H, d, J 6.5, Me), 0.91 (3H,
d, J 6.5, Me), 0.94–1.07 (1H, m, CHMe), 1.33 (3H, s, Me), 1.43
(3H, s, Me), 1.46–1.53 (1H, m, CHMe), 1.85–1.90 (1H, m, CH2),
1.95–1.97 (1H, m, CH2), 1.98 (3H, s, MeCO), 3.27 (3H, s. OMe),
3.35 (3H, s. OMe), 3.62 (1H, dd, J 6.3, 5.3, CHOH), 3.78 (1H,
Potassium bis(trimethylsilyl)amide (0.5 M in toluene, 0.99 ml,
0.50 mmol) was added dropwise to a stirred solution of (R,R)-29
◦
(92 mg, 0.45 mmol) in THF (0.9 ml) at −78 C. After stirring
for 15 min, acetaldehyde (103 ll, 1.8 mmol) was added in one
portion. The solution was stirred for a further 60 min then acetic
acid (54 ll, 0.9 mmol) was added and the solution warmed to
rt. The reaction mixture was filtered through a small plug of
silica gel, eluting with ether (20 ml) and the filtrate concentrated
under reduced pressure. The residue was purified by column
chromatography (Et2O–petrol, 1 : 4 then 3 : 7) to give the alcohol
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2 , 3 6 1 8 – 3 6 2 7
3 6 2 3

View Article Online
◦
as white prisms (88 mg, 0.18 mmol, 79%); mp 50–51 C (from
1523, 1457, 1434, 1381, 1346; dH 1.51 (3H, s, Me), 1.56 (3H, s,
Et2O); [a]31 −134.8 (c 0.56, CHCl3); (Found: C, 53.53; H, 8.18.
Calc. for DC11H20O6: C, 53.21; H, 8.12); mmax (film)/cm−1 3504,
3000, 1750, 1454, 1377; dH 1.22 (3H, d, J 6.4, MeCHOH), 1.39
(6H, s, 2 × Me), 1.48 (3H, s, Me), 3.31 (3H, s, OMe), 3.39 (3H, s,
OMe), 3.81 (1H, q, J 6.4, CHOH), 3.85 (1H, br s, OH); dC 16.3,
17.4, 18.0, 22.7, 49.8, 50.0, 73.7, 80.7, 98.6, 105.5, 169.6; Found
(ES): [MNa]+ 271.1163 C11H20O6 requires MNa, 271.1158.
Me), 2.43 (1H, dd, J 16.5, 8.4, CHHCH CH2), 2.63 (1H, ddt,
J 16.5, 4.8, 2.2, CHHCH CH2), 3.33 (3H, s, OMe), 3.50 (3H, s,
=
=
OMe), 4.58 (1H, s, OH), 5.06 (1H, s, CHOH), 5.20 (1H, br d, J
=
=
17.6, CH CHH), 5.31 (1H, br d, J 10.2, CH CHH), 6.09 (1H,
dddd, J 17.2, 10.6, 8.4, 4.4), 7.57 (2H, br d, J 8.4, meta to NO2),
8.14 (2H, br d, J 9.1, ortho to NO2); dC 17.3, 18.2, 36.0, 50.3,
50.4, 76.2, 82.1, 99.4, 105.7, 119.7, 122.5, 129.3, 131.7, 145.0,
147.7, 167.9; Found (ES): [MNa]+ 404.1321 C18H23NO8 requires
MNa, 404.1321.
(3S,5R,6R)-3-((S)-1-Hydroxy-propyl)-5,6-dimethoxy-3,5,6-
trimethyl-[1,4]dioxan-2-one (33)
(3S,5R,6R)-3-Benzyl-3-((S)-1-hydroxy-ethyl)-5,6-dimethoxy-
Potassium bis(trimethylsilyl)amide (0.5 M in toluene, 0.7 ml,
0.35 mmol) was added dropwise to a stirred solution of (R,R)-
29 (68 mg, 0.33 mmol) in THF (0.7 ml) at −78 ◦C. After stirring
for 15 min, propionaldehyde (50 ll, 0.67 mmol) was added in
one portion. The solution was stirred for a further 60 min then
acetic acid (42 ll, 0.7 mmol) was added and the solution warmed
to rt. The reaction mixture was filtered through a small plug of
silica gel, eluting with ether (20 ml) and the filtrate concentrated
under reduced pressure. The residue was purified by column
chromatography (Et2O–petrol, 1 : 4) to give the alcohol as a
colourless oil (46 mg, 0.18 mmol, 53%); [a]3D1 −133 (c 0.30,
CHCl3); mmax (film)/cm−1 3491, 2955, 1750, 1455; dH 1.00 (3H, t,
J 7.3, MeCH2), 1.40 (3H, s, Me), 1.42 (3H, s, Me), 1.50 (3H, s,
Me), 1.50–1.65 (2H, m, CH2), 3.32 (3H, s, OMe), 3.41 (3H, s,
OMe), 3.51 (1H, br d, J 10.2, CH), 3.73 (1H, br s, OH); dC
11.2, 17.5, 18.1, 22.8, 23.6, 48.8, 50.0, 79.1, 80.5, 98.7, 105.5,
170.1; Found (ES): [MNa]+ 297.1320 C13H22O6 requires MNa,
297.1314.
5,6-dimethyl-[1,4]dioxan-2-one (36)
Potassium bis(trimethylsilyl)amide (0.5 M in toluene, 0.54 ml,
0.27 mmol) was added dropwise to a stirred solution of (R,R)-31
(49 mg, 0.26 mmol) in THF (1.0 ml) at −78 C. After stirring
◦
for 15 min, acetaldehyde (44 ll, 0.78 mmol) was added in one
portion. The solution was stirred for a further 150 min then
acetic acid (16 ll, 0.26 mmol) was added and the solution
warmed to rt. The reaction mixture was filtered through a small
plug of silica gel, eluting with ether (20 ml) and the filtrate
concentrated under reduced pressure. The residue was purified
by column chromatography (Et2O–petrol, 1 : 9 then 3 : 7) to give
the alcohol as white prisms (20 mg, 0.06 mmol, 24%); mp 158–
159 ◦C (from Et2O); [a]31 −36.5 (c 0.17, CHCl3); mmax (film)/cm−1
3490, 2950, 1749, 1497,D1455; dH 1.16 (3H, d, J 6.6, MeCHOH),
1.57 (3H, s, Me), 1.58 (3H, s, Me), 3.26 (1H, d, J 15.8, CHHPh),
3.31 (1H, d, J 16.1, CHHPh), 3.45 (3H, s, OMe), 3.46 (3H, s,
OMe), 3.79 (1H, q, J 6.6), 3.91 (1H, br s, OH), 7.26 (1H, br t, J
7.3, para-H), 7.30 (2H, br t, J 7.3, meta-H), 7.48 (2H, d, J 7.3,
ortho-H); dC 15.9, 17.6, 18.4, 40.6, 50.2, 50.8, 70.9, 84.4, 99.4,
105.5, 126.8, 128.4, 130.1, 136.0, 168.5; Found (ES): [MNa]+
347.1478 C17H24O6 requires MNa, 347.1471.
(3S,5R,6R)-3-Allyl-3-((S)-1-hydroxy-ethyl)-5,6-dimethoxy-5,6-
dimethyl-[1,4]dioxan-2-one (34)
Potassium bis(trimethylsilyl)amide (0.5 M in toluene, 1.02 ml,
0.51 mmol) was added dropwise to a stirred solution of (R,R)-30
(110 mg, 0.48 mmol) in THF (1.0 ml) at −78 ◦C. After stirring
for 15 min, acetaldehyde (82 ll, 1.43 mmol) was added in one
portion. The solution was stirred for a further 60 min then acetic
acid (61 ll, 1.02 mmol) was added and the solution warmed to
rt. The reaction mixture was filtered through a small plug of
silica gel, eluting with ether (20 ml) and the filtrate concentrated
under reduced pressure. The residue was purified by column
chromatography (Et2O–petrol, 1 : 9 then 1 : 4) to give the alcohol
(5S,6S)-3-[1-Hydroxy-2,2-dimethyl-prop-(E)-ylidene]-5,6-
dimethoxy-5,6-dimethyl-[1,4]dioxan-2-one (37)
Lithium bis(trimethylsilyl)amide (1.0 M in THF, 2.1 ml, 2.1
mmol) was added dropwise to a stirred so◦lution of (S,S)-2
(200 mg, 10.5 mmol) in THF (5 ml) at −78 C. After stirring
for 15 min, trimethylacetyl chloride (141 ll, 1.16 mmol) was
added in one portion. The solution was stirred for a further
15 min then acetic acid (121 ll, 2.1 mmol) was added and the
solution warmed to rt. The reaction mixture was filtered through
a small plug of silica gel, eluting with ether (50 ml) and the
filtrate concentrated under reduced pressure. The residue was
purified by column chromatography (Biotage, ether–petrol, 1 :
9) to give the enol as prisms (205 mg, 0.77 mmol, 73%); mp 68–
69 ◦C (from Et2O); [a]D31 +116.0 (c 2.0, CHCl3); (Found: C, 56.82;
H, 8.08. Calc. for C13H22O6: C, 56.82; H, 8.08); mmax (film)/cm−1
2961, 1654, 1599, 1456, 1401, 1386, 1275, 1195, 1148, 1112, 1076,
1037, 983, 864, 813; dH 1.24 (9H, s, tBu), 1.40 (3H, s, Me), 1.45
(3H, s, Me), 3.23 (3H, s, OMe), 3.35 (3H, s, OMe), 12.29 (1H, s,
OH); dC 16.7, 17.5, 27.5, 37.4, 49.2, 49.7, 97.8, 103.6, 117.8,
166.7, 171.8; Found (ES): [MNa]+ 297.1324 C13H22O6 requires
MNa, 297.1314.
◦
as white prisms (96 mg, 0.35 mmol, 73%); mp 57–58 C (from
Et2O); [a]3D1 −57.4 (c 0.91, CHCl3); (Found: C, 57.21; H, 8.01.
Calc. for C13H22O6: C, 56.92; H, 8.08); mmax (film)/cm−1 3494,
2953, 1749, 1640, 1456, 1381; dH 1.21 (3H, d, J 6.6, MeCHOH),
1.43 (3H, s, Me), 1.50 (3H, s, Me), 2.59 (1H, ddt, J 15.7, 5.1,
=
=
1.8, CHHCH CH2), 2.70 (1H, dd, J 15.7, 9.1, CHHCH CH2),
3.32 (3H, s, OMe), 3.41 (3H, s, OMe), 3.91 (1H, q,J 6.6, CHOH),
3.90 (1H, br s, OH), 5.13 (1H, br dd, J 1.8, 1.3), 5.15–5.18 (1H,
=
m), 5.85–5.96 (1H, m, CH CH2); dC 15.5, 17.4, 18.2, 39.6, 50.10,
50.13, 71.6, 82.8, 98.9, 105.2, 118.9, 131.4, 168.4; Found (ES):
[MNa]+ 297.1304 C13H22O6 requires MNa, 297.1314.
(3S,5R,6R)-3-Allyl-3-[(S)-hydroxy-(4-nitro-phenyl)-methyl]-5,6-
dimethoxy-5,6-dimethyl-[1,4]dioxan-2-one (35)
(5R,6R)-3-[1-Cyclohexyl-1-hydroxy-meth-(E)-ylidene]-5,6-
Potassium bis(trimethylsilyl)amide (0.5 M in toluene, 0.72 ml,
0.36 mmol) was added dropwise to a stirred solution of (R,R)-30
(79 mg, 0.34 mmol) in THF (0.72 ml) at −78 ◦C. After stirring
for 30 min, 4-nitrobenzaldehyde (58 lg, 0.38 mmol) was added
in one portion. The solution was stirred for a further 60 min
then acetic acid (43 ll, 0.72 mmol) was added and the solution
warmed to rt. The reaction mixture was filtered through a small
plug of silica gel, eluting with ether (20 ml) and the filtrate
concentrated under reduced pressure. The residue was purified
by column chromatography (Et2O–petrol, 1 : 4 then 1 : 1) to give
the alcohol as a yellow oil (87 mg, 0.23 mmol, 67%); [a]3D1 −37.7
(c 1.16, CHCl3); mmax (film)/cm−1 3459, 2953, 1749, 1639, 1606,
dimethoxy-5,6-dimethyl-[1,4]dioxan-2-one (38)
Lithium bis(trimethylsilyl)amide (1.0 M in THF, 1.1 ml, 1.1
mmol) was added dropwise to a stirred so◦lution of (S,S)-2
(200 mg, 10.5 mmol) in THF (5 ml) at −78 C. After stirring
for 15 min, cyclohexylcarbonyl chloride (159 ll, 1.16 mmol) was
added in one portion. The solution was stirred for a further
15 min then acetic acid (121 ll, 2.1 mmol) was added and the
solution warmed to rt. The reaction mixture was filtered through
a small plug of silica gel, eluting with ether (50 ml) and the
filtrate concentrated under reduced pressure. The solvent was
evaporated under reduced pressure and the residue was purified
3 6 2 4
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2 , 3 6 1 8 – 3 6 2 7

View Article Online
by column chromatography (Biotage Flash 12Mi, ether–petrol,
1 : 9) to give the enol as plates (201 mg, 0.71 mmol, 68%); mp 130–
131 ◦C (from Et2O); [a]D31 −100 (c 1.0, CHCl3); (Found: C, 60.12;
H, 7.94. Calc. for C15H24O6: C, 59.98; H, 8.05); mmax (film)/cm−1
2937, 2855, 1770, 1664, 1617, 1452, 1395, 1348, 1295, 1263, 1227,
1151, 1117, 1037, 984, 915, 866, 811, 743; dH 1.32–1.21 (4H, m,
cyclohexyl), 1.48 (s, Me), 1.52 (3H, s, Me), 1.54–1.82 (6H, m,
915, 865, 734; dH 1.38 (3H, s, Me), 1.43 (3H, s, Me), 1.49 (3H, s,
Me), 1.50 (3H, s, Me), 1.55 (3H, s, MeR2COH), 3.35 (3H, s,
OMe), 3.36 (3H, s, OMe), 3.42 (3H, s, OMe), 3.46 (3H, s, OMe),
3.94 (1H, s, OH), 4.55 (1H, s, CH), 4.63 (1H, s, CH); dC 17.2,
17.3, 18.2, 18.5, 19.2, 49.3, 49.5, 50.2, 50.6, 73.2, 74.5, 76.3, 98.5,
98.6, 105.0, 105.6, 166.6, 166.9; Found (ES): [MNa]+ 445.1699
C18H30O11 requires MNa, 445.1686.
=
cyclohexyl), 2.80 (1H, br tt, J 3.5, 11.6, CH(HO)C C), 3.23
(3H, s, OMe), 3.43 (3H, s, OMe), 11.56 (1H, s, OH); dC 16.8, 17.6,
25.7, 25.8, 26.0, 28.8, 29.2, 37.2, 48.8, 50.2, 98.1, 104.2, 117.1,
166.1, 169.6; Found (ES): [MNa]+ 323.1466 C15H24O6 requires
MNa, 323.1471.
1,1-Bis[(1R,5S,6S)-5,6-dimethoxy-5,6-dimethyl-[1,4]dioxan-2-
one]-propanol (45)
Lithium bis(trimethylsilyl)amide (1.0 M in THF, 1.65 ml, 1.65
mmol) was added dropwise to a stirred solution of (S,S)-2
(300 mg, 2.63 mmol) in THF (6 ml) at −78 ◦C. After stirring for
15 min, propionoyl chloride (71 ll, 0.79 mmol) was added at a
rate of 5 ll min−1 using a syringe pump. The solution was stirred
for a further 10 min then acetic acid (180 ll, 3 mmol) was added
and the solution warmed to rt. The gel was filtered through a
small plug of silica gel, eluting with ether (20 ml), CH2Cl2 (20 ml)
and ethyl acetate (20 ml). The filtrate was concentrated under
reduced pressure and the residue triturated with Et2O–petrol (3
: 7, 5 ml) to give the alcohol as prisms (140 mg, 41%); mp 137–
138 ◦C (from Et2O); [a]D31 +216 (c 1.0, CHCl3); (Found: C, 52.22;
H, 7.30. Calc. for C19H32O11: C, 52.29; H, 7.39); mmax (film)/cm−1
3475, 2951, 2840, 1748, 1458, 1379, 1328, 1261, 1219, 1146, 1106,
1033, 1007, 985, 972, 956, 912, 864, 828, 768, 730; dH 0.99 (3H,
t, J 7.5, MeCH2), 1.35 (3H, s, Me), 1.39 (3H, s, Me), 1.46 (6H, s,
2 × Me), 2.02 (1H, quintet, J 7.4, CHHMe), 2.06 (1H, quintet, J
7.4, CHHMe), 3.32 (3H, s, OMe), 3.34 (3H, s, OMe), 3.41 (3H, s,
OMe), 3.42 (3H, s, OMe), 4.01 (1H, br s, OH), 4.64 (1H, s, axial
H), 4.69 (1H, s, axial H); dC 8.4, 17.2, 17.3, 18.2, 18.5, 26.6, 49.4,
49.5, 50.4, 50.6, 72.4, 73.4, 78.2, 98.7, 98.8, 105.1, 105.8, 166.6,
169.3; Found (ES): [MNa]+ 459.1848 C19H32O11 requires MNa,
459.1842.
(3R,5S,6S)-3-((S)-1-Hydroxy-2,2-dimethyl-propyl)-5,6-
dimethoxy-5,6-dimethyl-[1,4]dioxan-2-one (39)
Enol 37 (50 mg, 0.18 mmol) was dissolved in CH2Cl2 (2 ml) and
cooled to 0 ◦C. Tetra-N-butylammonium borohydride (111 mg,
0.4 mmol) was added in one portion and the reaction stirred for
15 min at 0 ◦C. The solution was then allowed to warm to rt and
then stirred for a further 5 h before diluting with ether (5 ml). The
organic solution was washed with water (5 ml) and brine (5 ml),
dried (MgSO4) and concentrated under reduced pressure. The
residue was purified by column chromatography (ether–petrol,
1 : 9) to give the alcohol as needles (35 mg, 68%); mp 72–74 ◦C
(from Et2O); [a]3D1 +94.4 (c 0.54, CHCl3); (Found: C, 56.80; H,
8.68. Calc. for C13H24O6: C, 56.51; H, 8.75); mmax (film)/cm−1
3530, 2345, 1752, 1460, 1382, 1275, 1165, 1123, 1034, 964, 919,
863; dH 0.93 (9H, s, tBu), 1.34 (3H, s, Me), 1.42 (3H, s, Me), 3.08
(1H, d, J 10.1, OH), 3.26 (3H, s, OMe), 3.38 (3H, s, OMe), 3.63
(1H, dd, J 1.2, 10.1, CHOH), 4.34 (1H, d, J 1.2, axial H); dC 17.2,
18.1, 26.9, 35.9, 49.7, 50.5, 68.2, 80.0, 98.2, 104.7, 169.8; Found
(ES): [MNa]+ 299.1479 C13H24O6 requires MNa, 299.1471.
(3S,5R,6R)-3-((S)-Cyclohexyl-hydroxy-methyl)-5,6-dimethoxy-
5,6-dimethyl-[1,4]dioxan-2-one (40)
2-Chloro-1,1-bis[(1S,5R,6R)-5,6-dimethoxy-5,6-dimethyl-
[1,4]dioxan-2-one]-ethanol (46)
Enol 38 (50 mg, 0.16 mmol) was dissolved in CH2Cl2 (2 ml) and
cooled to 0 ◦C. Tetrabutylammonium borohydride (111 mg, 0.4
mmol) was added in one portion and the reaction stirred for
15 min at 0 ◦C. The solution was then allowed to warm to rt
and then stirred for a further 5 h before diluting with ether (5
ml). The organic solution was washed with water (5 ml) and
brine (5 ml), dried (MgSO4) and concentrated under reduced
pressure. The residue was purified by column chromatography
(ether–petrol, 1 : 9) to give the alcohol as needles (38 mg, 76%);
[a]3D1 −267.4 (c 0.1, CHCl3); mmax (film)/cm−1; dH 0.83–1.29 (4H,
m, cyclohexyl), 1.43 (3H, s, Me), 1.50 (3H, s, Me), 1.52–1.77
(6H, m, cyclohexyl), 2.09 (1H, br d, J 10.5, CHCHOH), 2.74
(1H, d, J 10.5, OH), 3.28 (3H, s, OMe), 3.43 (3H, s, OMe), 3.65
(1H, t, J 10.5, CHOH), 4.33 (1H, s, axial H); dC 16.8, 17.8, 25.8,
25.9, 26.2, 40.5, 49.3, 50.1, 67.9, 77.3, 98.0, 104.4, 169.3; Found
(ES): [MNa]+ NN C15H26O6 requires MNa, 302.1729.
Lithium bis(trimethylsilyl)amide (1.0 M in THF, 1.1 ml, 1.1
mmol) was added dropwise to a stirred solution of (S,S)-1
(200 mg, 1.05 mmol) in THF (2.5 ml) at −78 ◦C. After stirring for
15 min, chloroacetyl chloride (44 ll, 0.55 mmol) was added at a
rate of 5 ll min−1 using a syringe pump. The solution was stirred
for a further 10 min then acetic acid (132 ll, 2.2 mmol) was added
and the solution warmed to rt. The gel was filtered through a
small plug of silica gel, eluting with ether (20 ml), CH2Cl2 (20 ml)
and ethyl acetate (20 ml). The filtrate was concentrated under
reduced pressure and the residue triturated with Et2O–petrol (3
: 7, 5 ml)) to give the alcohol as prisms (94 mg, 40%); mp 124–
126 ◦C (from Et2O); [a]D25 −106 (c 1.0, CHCl3); mmax (film)/cm−1
3348, 1746; dH 1.33 (3H, s, Me), 1.35 (3H, s, Me), 1.42 (3H, s,
Me), 1.44 (3H, s, Me), 3.26 (3H, s, OMe), 3.29 (3H, s, OMe), 3.38
(3H, s, OMe), 3.40 (3H, s, OMe), 4.04 (1H, s, J 11.3, CHHCl),
4.23 (1H, s, J 11.3, CHHCl), 4.36 (1H, s, axial H), 4.39 (1H, s,
axial H), 4.79 (1H, s, OH); dC 16.8, 16.9, 17.8, 18.1, 44.8, 49.1,
49.2, 50.3, 50.6, 69.5, 71.6, 77.6, 98.4, 98.6, 105.0, 105.2, 166.2,
168.4; Found (ES): [MNa]+ 479.1320 C18H29ClO11 requires MNa,
479.1296.
1,1-Bis[(1S,5R,6R)-5,6-dimethoxy-5,6-dimethyl-[1,4]dioxan-2-
one]-ethanol (44)
Lithium bis(trimethylsilyl)amide (1.0 M in THF, 2.76 ml, 2.76
mmol) was added dropwise to a stirred solution of (R,R)-1
(500 mg, 2.63 mmol) in THF (10 ml) at −78 ◦C. After stirring
for 15 min, acetyl chloride (95 ll, 1.31 mmol) was added at a
rate of 5 ll min−1 using a syringe pump. The solution was stirred
for a further 30 min then acetic acid (420 ll, 7 mmol) was added
and the solution warmed to rt. The gel was filtered through a
small plug of silica gel, eluting with ether (30 ml), CH2Cl2 (40 ml)
and ethyl acetate (30 ml). The filtrate was concentrated under
reduced pressure and the residue triturated with Et2O–petrol (2
: 8, 10 ml) to give the alcohol as needles (488 mg, 88%); mp 199–
200 ◦C (from Et2O); [a]D31 −206 (c 1.0, CHCl3); (Found: C, 51.27;
H, 7.11. Calc. for C18H30O11: C, 51.18; H, 7.16); mmax (film)/cm−1
3486, 2952, 2839, 1753, 1463, 1381, 1264, 1148, 1130, 1035, 978,
Representative procedure for the ( )-CSA promoted
methanolysis of the aldol adducts–preparation of
(−)-(2R,3R)-methyl-2,3-dihydroxy-butanoate (47)
To a stirred solution of 12 (41 mg, 0.18 mmol) in dry methanol
(3 ml) at rt was added ( )-camphor sulfonic acid (44 mg, 1.1 eq).
After stirring at the same temperature for 12 h the solution was
evaporated in vacuo to leave a pale yellow oil. Purification by
flash chromatography, eluting with ether gave 47 (17 mg, 75%)
as a colourless oil; [a]3D1 −17.3 (c 0.585, CHCl3); mmax (film)/cm−1
3383, 1737; dH (400 MHz, CDCl3) 1.20 (3H, d, J 6.5, COHCH3),
2.23 (1H, d, J 7.0, OH), 2.99 (1H, d, J 5.3, OH), 3.80 (3H, s,
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2 , 3 6 1 8 – 3 6 2 7
3 6 2 5

View Article Online
CH3OCO), 4.08–4.04 (1H, m, CHOHCH3), 4.21 (1H, dd, J 5.3
and 4.0, COCHOH); dC (100 MHz, CDCl3) 17.4, 52.6, 69.1,
74.3, 173.1; Found: [MNa]+, 157.0477. C5H10O4 requires MNa
157.0471.
CH3OCO), 4.50 (1H, dd, J 5.5 and 4.5, CHOH), 5.12 (1H, dd, J
5.5 and 4.5, CHOH), 7.52 (2H, d, J 9.0, Ar), 8.20 (2H, d, J 9.0,
Ar); dC (100 MHz, CDCl3) 52.0, 74.0, 74.2, 123.4, 127.3, 145.9,
147.7, 171.9; Found: [MNa]+, 264.0479. C10H11O6 requires MNa
264.0479.
Representative procedure for the HCl promoted methanolysis of
the aldol adducts–preparation of (−)-(2R, 3R)-methyl-2,3-
dihydroxy-pentanoate (48)
(2S,3S)-2,3-Dihydroxy-pent-4-enoic acid methyl ester (54)
To a stirred solution of 13 (27.5 mg, 0.1 mmol) in methanol
(1 ml) at rt was added a solution of trimethylsilyl chloride in
methanol (0.3M, 2.5 ml). After stirring at the same temperature
for 10 min the solution was evaporated in vacuo to leave a pale
yellow oil. Purification by flash chromatography, eluting with
ether gave 48 (14 mg, 86%) as a white solid; mp 50–51 ◦C (from
Et2O); [a]31 −18.9 (c 0.65, CHCl3); mmax (KBr)/cm−1 3356, 1738,
1132; dH (D400 MHz, CDCl3) 1.00 (3H, t, J 7.5, CH2CH3), 1.61–
1.48 (2H, m, CH2CH3), 2.22 (1H, d, J 6.5, OH), 3.05 (1H, d, J
5.5, OH), 3.77 (1H, m, COHCH2), 3.81 (3H, s, CH3OCO), 4.23
(1H, m, COCHOH); dC (100 MHz, CDCl3) 10.2, 24.9, 52.6, 73.7,
74.7, 173.2; Found: [MNa]+, 171.0630. C6H12O4 requires MNa
171.0628.
Acetyl chloride (0.5 M in methanol, 1.48 ml) was added in
one portion to a stirred solution of 19 (1.67 g, 6.7 mmol) in
methanol (5 ml). The solution was stirred for 30 min and then
all volatiles were removed in vacuo. This process was repeated
then purification by Biotage flash chromatography eluting with
Et2O afforded the desired ester (560.4 mg, 57%) as colourless
oil; [a]3D1 +10.5 (c 1.1, CHCl3); mmax (film)/cm−1 3426, 1732; dH
3.03 (1H, br s, OH), 3.43 (1H, br s, OH), 3.71 (3H, s, OMe), 4.04
(1H, d, J 6.5, CHCO), 4.28 (1H, t, J 6.5, CHCHCH2), 5.17 (1H,
d, J 10.6, CHCHH), 5.24 (1H, d, J 17.3, CHCHH), 5.87–5.79
(1H, m, CHCH2); dC 52.9, 74.2, 74.4, 118.3, 135.1, 172.9; Found:
[MNa]+, 169.0473, C6H10O4Na requires, 169.0471.
(−)-(2R, 3R)-Methyl-2,3-dihydroxy-4,4-dimethyl-
(3R,4R,5S)-3,4-Dihydroxy-5-methyl-dihydro-furan-2-one (55)
and (3R,4S,5S)-3,4-dihydroxy-5-methyl-dihydro-furan-2-
one (56)
pentanoate (49)
[a]D31 −45.3 (c 0.84, CHCl3); mmax (film)/cm−1 3438 (OH), 1735
=
(C O); dH (400 MHz, CDCl3) 0.98 (9H, s, C(CH3)3), 2.30
The mixture of alcohols 22 and 23 (35 mg, 0.092 mmol) was
dissolved in methanol (2 ml) and camphor sulfonic acid (23 mg)
was added. The solution was stirred overnight at rt, toluene (2
ml) was added, and the methanol distilled out of the reaction
mixture. The remaining solvent was removed under vacuum and
the residue purified by column chromatography (EtOAc–petrol,
1 : 1 then 7 : 3) to give the lactones 55 (5.4 mg, 0.041 mmol, 45%)
and 56 (4.1 mg, 0.031 mmol, 34%); 55: [a]3D1 −29.4 (c 0.68, EtOH)
[lit. [a]3D1 −37.0 (c 1.1, EtOH)]15; dH (400 MHz, MeOD) 1.46 (3H,
d, J 6.3, Me), 3.81 (1H, t, J 8.4, CHCHCO2R), 4.19 (1H, qd J
6.3, 8.3, CHMe), 4.33 (1H, d, J 8.8, CHCO2R); dC (100 MHz,
MeOD) 18.2, 75.7, 78.7, 80.8, 176.5. 56: [a]3D1 −32.3 (c 0.34,
MeOH) [lit. [a]3D1 −34 (c 0.99, MeOH)]16; dH (400 MHz, MeOD)
1.41 (3H, d, J 6.5, Me), 4.25 (1H, dd, J 2.8, 4.7, CHCHCO2R),
4.55 (1H, d, J 4.8, CHCO2R), 4.57 (1H, qd, J 6.6, 2.6, CHMe).
dC (100 MHz, MeOD) 14.2, 72.3, 72.6, 78.5, 178.6.
(1H, d, J 8, OH), 2.89 (1H, d, J 8.0, OH), 3.48 (1H, m,
CHOHC(CH3)3), 3.79 (3H, s, CH3OCO), 4.27 (1H, dd, J 8.0
and 4.5, COCHOH); dC (100 MHz, CDCl3) 26.1, 34.8, 52.3,
72.1, 81.4; Found: [MNa]+, 199.0944. C8H16O4 requires MNa
199.0940.
(−)-(2R, 3R)-Methyl-2,3-dihydroxy-hex-4-enoate (50)
[a]3D1 −19.2 (c 0.77, CHCl3); mmax (film)/cm−1 3385, 1741; dH
(400 MHz, CDCl3) 1.71 (3H, d, J 6.5, CHCH3), 2.33 (1H, br s,
OH), 2.93 (1H, br s, OH), 3.80 (3H, s, CH3OCO), 4.29 (1H, d, J
3.5, CHOH), 4.34 (1H, d, J 7.0, CHOH), 5.50 (1H, dd, J 15 and
7.0, CHCHCH3), 5.79 (1H, dq, J 15.0 and 6.5, CHCHCH3);
dC (100 MHz, CDCl3) 17.8, 52.6, 73.9, 74.1, 127.5, 130.1, 172.6;
Found: [MNa]+, 183.0624. C7H12O4 requires MNa 183.0628.
(−)-(2R, 3R)-Methyl-2,3-dihydroxy-6-phenyl-pent-4-enoate (51)
◦
mp 153–154 C (from Et2O); [a]31 −27.6 (c 0.94, CHCl3); mmax
(KBr)/cm−1 3356, 1753, 1125; dHD(400 MHz, CDCl3) 2.52 (1H,
d, J 7.0, OH), 3.06 (1H, d, J 6.0, OH), 3.40 (1H, dd, J 6.0 and
4.0, CHOH), 3.81 (3H, s, CH3OCO), 4.59 (1H, m, CHOH), 6.20
(1H, dd, J 16.0 and 6.5, ArCHCH), 6.68 (1H, d, J 16.0, ArCH),
7.38–7.24 (5H, m, Ar); dC (100 MHz, CDCl3) 52.7, 73.9, 74.1,
125.7, 126.6, 128.1, 128.6, 133.1, 136.2, 172.1; Found: [MNa]+,
245.0789. C12H14O4 requires MNa 245.0784.
(3S,4R,5S)-3,4-Dihydroxy-5-methyl-dihydro-furan-2-one (57)
Alcohol 24 (40 mg, 0.105 mmol) was dissolved in methanol
(4 ml) and camphor sulfonic acid (5 mg) was added. The
solution was refluxed for 1 h and then toluene (4 ml) was added
and the methanol distilled out of the reaction mixture. The
remaining solvent was removed under vacuum and the residue
purified by column chromatography (EtOAc–petrol, 7 : 3 ) to
give the lactone 57 (10.6 mg, 0.079 mmol, 75%); [a]3D1 −19.6 (c
1.02,MeOH) [lit. enantiomer [a]3D1 +17.0 (c 1.0, MeOH)]17; dH
(400 MHz, D2O) 1.36 (3H, d, J 7.0, Me), 4.25 (1H, d, J 5.1,
CHCHCO2R), 4.64 (1H, q, J 7.0, CHMe), 4.76 (1H, d, J 5.1,
CHCO2R); dC (100 MHz, D2O) 17.4, 69.0, 72.8, 83.7, 178.7.
(−)-(2R, 3R)-Methyl-2,3-dihydroxy-3-p-methoxyphenyl-
propanoate (52)
◦
mp 120–121 C (from Et2O); [a]31 −41.8 (c 0.54, CHCl3); mmax
(KBr)/cm−1 3488, 1754, 1150; dHD(400 MHz, CDCl3) 2.77 (1H,
d, J 6.0, OH), 2.82 (1H, d, J 6.5, OH), 3.71 (3H, s, CH3OCO),
3.80 (3H, s, ArOCH3), 4.48 (1H, dd, J 6.5 and 4.5, CHOH), 4.95
(1H, dd, J 5.0 and 5.0, CHOH), 6.87 (2H, d, J 9.0, Ph), 7.24 (2H,
d, J 9.0, Ph); dC (100 MHz, CDCl3) 172.4, 159.5, 127.6, 113.7,
74.5, 65.8, 55.2, 52.3, 15.2; Found: [MNa]+, 249.0745. C11H14O5
requires MNa 249.0733.
(2R,3R,4R,6S)-Methyl-2,3,7-trihydroxy-4,6-
dimethylheptanoate (58)
[a]3D1 +7.0 (c 0.20, CHCl3); mmax (film)/cm−1 3381, 1732; dH
(400 MHz, CDCl3) 0.90 (3H, d, J 5.6, Me), 0.92 (3H, d, J 5.6,
Me), 1.63–1.70 (3H, m, CH2 and CHMe), 1.72–1.82 (1H, m,
CHMe), 2.95–2.99 (1H, m, CHOH), 3.38 (1H, dd, J 10.7, 4.5,
CH2OH), 3.51 (1H, dd, J 7.2, 4.5, CH2OH), 3.75 (3H, s, OMe),
4.23 (1H, d, J 4.7, CHOH); dC (100 MHz, CDCl3) 17.5, 19.1,
33.1, 33.4, 36.2, 52.9, 67.1, 72.9, 78.6, 174.1; Found: [MNa]+,
243.1209. C10H20O5 requires MNa 243.1208.
(−)-(2R, 3R)-Methyl-2,3-dihydroxy-3-p-nitrophenyl-
propanoate (53)
◦
mp 108–109 C (from Et2O); [a]31 −45 (c 0.66, CHCl3); mmax
(KBr)/cm−1 3404, 1736, 1518, 1D104; dH (400 MHz, CDCl3)
3.18 (1H, d, J 5.5, OH), 3.23 (1H, d, J 5.5, OH), 3.69 (3H, s,
3 6 2 6
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2 , 3 6 1 8 – 3 6 2 7

View Article Online
(2S,3S,4R,6S)-Methyl-2,3,7-trihydroxy-4,6-dimethylheptanoate
(59)
(c, 0.98, MeOH), (Found: C, 49.13; H, 4.60. Calc. for C14H16O8S:
C, 48.83; H, 4.68); mmax (film)/cm−1 3497, 2926, 1810, 1764. 1597;
dH (400 MHz, CDCl3) 1.70 (3H, s, Me), 2.46 (3 H, s, MeAr), 3.85
(3H, s, OMe), 4.73 (1 H, s, CH), 5.06 (1H, s, CH), 7.37 (2H, d, J
8.1, m-H), 7.88 (2H, d, J 8.4, o-H); dC (100 MHz, CDCl3)21.7,
21.9, 52.9, 76.0, 78.1, 80.5, 128.3, 130.0, 132.2, 146.1, 165.1,
167.2; Found (ES): [MNa]+ 367.0464 C14H16O8S requires MNa,
367.0464.
[a]3D1 +10.3 (c 0.38, CHCl3); mmax (film)/cm−1 3383, 1736;
dH(400 MHz, CDCl3) 0.85 (3H, d, J 6.7, Me), 0.86 (3H, d, J
6.7, Me), 1.49–1.55 (1H, m, CHMe), 1.62–1.67 (1H, m, CHMe),
1.79–1.86 (2H, m, CH2), 3.35 (1H, dd, J 10.6, 5.8, CH2OH), 3.41
(1H, dd, J 10.6, 5.4, CH2OH), 3.59 (1H, dd, J 6.3, 4.8, CHOH),
3.73 (3H, s, OMe), 4.17 (1H, d, J 6.3, CHOH); dC (100 MHz,
CDCl3) 17.5, 19.1, 33.1, 33.4, 36.2, 52.9, 67.1, 72.9, 78.6, 174.1;
m/z (+ESI) 385 (MNa+); Found: MNa+, 243.1213. C10H20O5Na
requires 243.1208.
References
1 C. H. Heathcock in Comprehensive Organic Synthesis, ed. B. M. Tro-
stand I. Fleming, Pergamon Press, Oxford, 1991, vol. 2, pp. 181–238.
2 A. I. Meyers, G. Knaus and P. M. Kendall, Tetrahedron Lett., 1974,
15, 3495; D. Seebach and R. Naef, Helv. Chim. Acta, 1981, 64,
2704; D. Seebach, in Modern Synthetic Methods, Springer, Berlin,
1986, pp. 125–257; J. D’Angelo, O. Pages, J. Maddaluno, F. Dumas
and G. Revial, Tetrahedron Lett., 1983, 24, 5869; G. Helmchen and
R. Wierzchowski, Angew. Chem., Int. Ed. Engl., 1984, 23, 60; M.
Enomoto, Y. Ito, T. Katsuki and M. Yamaguchi, Tetrahedron Lett.,
1985, 26, 1343; T. R. Kelly and A. Arvanitis, Tetrahedron Lett., 1984,
25, 39; J. W. Ludwig, M. Newcomb and D. E. Bergbreiter, Tetrahedron
Lett., 1986, 27, 2731; W. H. Pearson and M. C. Cheng, J. Org. Chem.,
1986, 51, 3746; P. Renaud and D. Seebach, Angew. Chem., Int. Ed.
Engl., 1986, 25, 843; S. G. Davies and M. Wills, J. Organomet. Chem.,
1987, 328, C29; G. Cardillo, M. Orena, M. Romero and S. Sandri,
Tetrahedron, 1989, 45, 1501; P. Renaud and S. Abazi, Helv. Chim.
Acta, 1996, 79, 1696; J. W. Chang, D. P. Jang, B. J. Uang, F. L. Liao
and S. L. Wang, Org. Lett., 1999, 1, 2061; J. E. Jung, H. Ho and
H. D. Kim, Tetrahedron Lett., 2000, 41, 1793; M. T. Crimmins, K. A.
Emmitte and J. D. Katz, Org. Lett., 2000, 2, 2165; M. B. Andrus,
B. Sekhar, E. L. Meredith and N. K. Dalley, Org. Lett., 2000, 2,
3035; M. B. Andrus, B. Sekhar, T. M. Turner and E. L. Meredith,
Tetrahedron Lett., 2001, 42, 7197; R. K. Boeckman, D. J. Boehmler
and R. A. Musselman, Org. Lett., 2001, 3, 3777; M. B. Andrus, K. G.
Mendenhall, E. L. Meredith and B. Sekhar, Tetrahedron Lett., 2002,
43, 1789; H. W. Yu, C. E. Ballard, P. D. Boyle and B. H. Wang,
Tetrahedron, 2002, 58, 7663.
3 F. A. Davis and B. C. Chen, Chem. Rev., 1992, 92, 919; T. Ooi, T.
Miura, K. Takaya, H. Ichikawa and K. Maruoka, Tetrahedron, 2001,
57, 867; W. Adam, M. Lazarus, C. R. Saha-Moller and P. Schreier,
Acc. Chem. Res., 1999, 32, 837; Z. Wang, B. La, J. M. Fortunak, X. J.
Meng and G. W. Kabalka, Tetrahedron Lett., 1998, 39, 5501; M. J.
Burk, C. S. Kalberg and A. Pizzano, J. Am. Chem. Soc., 1998, 120,
4345; I. S. Byun and Y. H. Kim, Synth. Commun., 1995, 25, 1963;
H. C. Brown, B. T. Cho and W. S. Park, J. Org. Chem., 1986, 51, 3396;
M. B. Andrus, E. J. Hicken and J. C. Stephens, Org. Lett., 2004, 6,
2289.
4 S. V. Ley, E. Diez, D. J. Dixon, R. T. Guy, P. Michel, G. L.
Natrass and T. D. Sheppard, Org. Biomol. Chem., 2004, 2,
DOI: 10.1039/b412788a.
5 E. Diez, D. J. Dixon and S. V. Ley, Angew. Chem. Int. Ed., 2001, 40,
2906.
Methyl (2S,3R,4S)-3,4-dihydroxy-3-methyl-5-oxo-tetrahydro-
furan-2-carboxylate (60)
Alcohol 44 (81 mg, 0.19 mmol) was dissolved in a solution
of acetyl chloride in methanol (0.5 M, 3 ml, 1.5 mmol) and
stirred for 10 min at rt. The solvent was removed under reduced
pressure and then the residue was redissolved in methanolic
HCl (3 ml) and stirred for a further 10 min. The solvent was
evaporated and the residue azeotroped with methanol (20 ml)
and the residue dried under high vacuum to give the mixture of
lactones as a white powder (36 mg, 100%); A pure sample of the
major lactone isomer was obtained by chromatography (EtOAc–
petrol, 7 : 3 ).‡ as white needles; mp 113–115 ◦C (from MeOH);
[a]3D1 +33.0 (c 1.25, MeOH); (Found: C, 44.46; H, 5.40. Calc. for
C7H10O6: C, 44.21; H, 5.30); mmax (film)/cm−1 3600–2900, 1738;
dH (400 MHz, MeOD) 1.53 (3H, s, Me), 3.79 (3H, s, OMe), 4.27
(1H, s, CHOH), 4,85 (1H, s, CHCO2Me); dC (100 MHz, MeOD)
22.0, 53.2, 75.4, 78.1, 83.0, 168.9, 176.8; Found (ES): [MNa]+
213.0376 C7H10O6 requires MNa, 213.0375.
(2R,3S,4R)-3,4-Dihydroxy-3-methyl-5-oxo-tetrahydro-furan-2-
carboxylate (61)
Alcohol 44 (436.0 mg, 1.03 mmol) was dissolved in a 2 : 1 mixture
of trifluoroacetic acid–water (3 ml) and left to stand for 10 min,
with occasional swirling. The solvents were removed in vacuo
to furnish a clear oil, which was four times redissolved in water
(3 ml), evaporated, and then dried on a lyopholiser overnight.
1
to give the acid as a white gum (199.1 mg, 99% yield by H
NMR using 1,2,3-trimethoxybenzene as an internal standard);
mp 129 ◦C; [a]3D1 −23.0 (c 1.59, acetone); mmax (film)/cm−1 3523,
3154 (br), 1794, 1743, 1725; dH (100 MHz, acetone) 1.64 (3H, s,
Me), 4.41 (1H, s, CHOH), 4.89 (1H, s, CHCO2H); dC (100 MHz,
acetone) 21.9, 74.7, 77.2, 81.2, 168.4, 174.6; Found (ES): [MNa]+
199.0219 C6H8O6 requires MNa, 199.02030.
Conversion into methyl ester ent-60
6 D. J. Dixon, S. V. Ley, A. Polara and T. Sheppard, Org. Lett., 2001, 3,
3749; S. V. Ley, D. K. Baeschlin, D. J. Dixon, A. C. Foster, S. J. Ince,
H. W. M. Priepke and D. J. Reynolds, Chem. Rev., 2001, 101, 53.
7 D. J. Dixon, S. V. Ley and F. Rodriguez, Org. Lett., 2001, 3, 3753;
D. J. Dixon, S. V. Ley and F. Rodriguez, Angew. Chem. Int. Ed., 2001,
40, 4763.
Acid 61 (41.5 mg, 0.236 mmol) was suspended in dichloro-
methane and 1-chloro-N,N-2-trimethylpropenylamine (0.13 ml,
0.943 mmol) was added. The mixture was stirred until all the
acid had dissolved (1 h) then dry methanol (1 ml) was added
dropwise and the solution stirred for 15 min. The solvents were
removed in vacuo to give the ester ent-60 (59% by 1H NMR using
1,2,3-trimethoxybenzene as an internal standard).
8 P. Michel and S. V. Ley, Synthesis, 2003, 1598.
9 D. J. Dixon, A. Guarna, S. V. Ley, A. Polara and F. Rodriguez,
Synthesis, 2002, (sp. iss.), 1973.
10 Y. Ito, Y. Kobayashi, T. Kawabata, M. Takase and S. Terashima,
Tetrahedron, 1989, 45, 5767.
11 The surname of the author “Nguyen Trong Anh” is actually Nguyen,
see D. A. Evans, E. Hu and J. S. Tedrow, Org. Lett., 2001, 3, 3133,
ref. 7.
Methyl (1S,2S,3S)-2-hydroxy-2-methyl-4-oxo-3-(toluene-4-
sulfonyloxy)-cyclopentanecarboxylate (62)
Lactone 44 (43 mg, 0.23 mmol) was dissolved in pyridine (0.2 ml)
and tosyl chloride (55 mg) was added in one portion. The
reaction was stirred overnight at rt before quenching with water
(2 ml). The aqueous solution was extracted with Et2O (2 × 5 ml).
The combined organic layers were washed with saturated copper
sulfate solution (2 × 5 ml), and brine (5 ml), dried (MgSO4),
and concentrated to give the tosylate as white prisms (26 mg,
12 M. Cherest, H. Felkin and N. Prudent, Tetrahedron Lett., 1968, 9,
2199; T. A. Nguyen and O. Eisenstein, Nouv. J. Chim., 1977, 1, 61;
T. A. Nguyen, Top. Curr. Chem., 1980, 88, 146.
13 S. V. Ley, J. C. Anderson and S. P. Marsden, Tetrahedron Lett., 1994,
35, 2087.
14 A. K. C. Ve´zina and S. N. Sehgal, J. Antibiot., 1975, 28, 721.
15 A. M. Fernandez and L. Duhamel, J. Org. Chem., 1996, 61, 8698.
16 H. Kaiser and W. Keller-Schierlein, Helv. Chim. Acta, 1981, 407.
17 C. Papageorgiou and C. Benezra, Tetrahedron Lett., 1984, 25, 6041.
◦
0.076 mmol, 33%); mp 154–155 C (from Et2O); [a]3D1 +115.5
‡ The lactone 60 appears to partially decompose on silica gel.
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2 , 3 6 1 8 – 3 6 2 7
3 6 2 7