Asymmetric dihydroxylation of vinyl sulfones: Routes to enantioenriched α-hydroxyaldehydes and the enantioselective syntheses of furan-2(5H)-ones

Article abstract of DOI:10.1016/j.tet.2003.08.003

The asymmetric dihydroxylation of α,β-unsaturated sulfones under Sharpless conditions affords enantioenriched α-hydroxyaldehydes in a complex mixture of dimeric species. These mixtures undergo olefination generating the corresponding α,β-unsaturated esters or furan-2(5H)-ones with high levels of enantiomeric excess. The application of this method for the rapid stereoselective synthesis of the furanone natural products; quercus lactone and maritolide, are described.

Full text of DOI:10.1016/j.tet.2003.08.003

Tetrahedron 59 (2003) 7973–7981
Asymmetric dihydroxylation of vinyl sulfones: routes
to enantioenriched a-hydroxyaldehydes and the
enantioselective syntheses of furan-2(5H)-ones
*
Paul Evans and Melanie Leffray
´
Department of Chemistry, University of Liverpool, Liverpool L69 7ZD, UK
Received 27 June 2003; revised 15 July 2003; accepted 7 August 2003
Abstract—The asymmetric dihydroxylation of a,b-unsaturated sulfones under Sharpless conditions affords enantioenriched a-hydroxy-
aldehydes in a complex mixture of dimeric species. These mixtures undergo olefination generating the corresponding a,b-unsaturated esters
or furan-2(5H)-ones with high levels of enantiomeric excess. The application of this method for the rapid stereoselective synthesis of the
furanone natural products; quercus lactone and maritolide, are described.
q 2003 Elsevier Ltd. All rights reserved.
1. Introduction
reagent and substrate control. More recently it has been
reported that a,b-unsaturated nitriles9a and phosphonates9
undergo racemic dihydroxylation. Affording, in these
instances, the corresponding base labile cyanohydr0ins
Asymmetric dihydroxylation, pioneered by Sharpless has
emerged as a most reliable method for the generation of
asymmetry from a prochiral alkene.1 This remarkable
reaction proceeds efficiently with both electron rich and
electron poor alkenes.1,2 Somewhat surprisingly this asym-
metric transformation has never been reported using readily
available a,b-unsaturated (vinyl) sulfones 1 as substrates
(see Fig. 1, where X¼SO2R0).3 We envisaged that this
reaction would provide an efficient route towards a one-step
procedure for the preparation of synthetically useful
optically enriched a-hydroxyl carbonyl molecules, of the
type 3,4 via the 1,2-elimination of the intermediate
a-hydroxyl sulfone 2.5
and phosphates
respectively).
2
(where X¼CN and PO(OR )2,
In relation to the proposed sulfonyl sequence, examples
demonstrate that in situ generated a-alkoxy sulfones
undergo a facile, spontaneous 1,2-elimination reaction,
affording the corresponding aldehyde, or ketone and
sulfinate anion. The most frequently used exemplification
of this type of transformation is the oxidation-elimination of
sulfonyl carbanions.10 An additional series of examples,
indicate that a,b-epoxy sulfones undergo ring opening in
the b-position by a suitable nucleophilic species (e.g. Br2,
etc.), and that the resultant oxide eliminates the sulfonyl
moeity thereby generating an aldehyde.11 This method has
subsequently been employed in an iterative sense for the
synthesis of poly-trans-fused tetrahydropyrans.12 Addition-
ally, it is widely reported that the products of Pummerer
rearrangements collapse 0in a similar manner following their
basic hydrolysis (X¼SR ).13
Similar examples employing different vinyl substituents
have been reported previously, in both racemic and
asymmetric senses. The dihydroxylation and subsequent
rearrangement of vinyl chlorides, bromides (where X¼Cl,
Br)6 and enol ethers (where X¼OR0),7,8 generating non-
enolisable a-hydroxyaldehydes 3a and ketones have all
been performed in an asymmetric manner under both
Figure 1. Asymmetric hydroxylation—1,2-hydroxyl elimination. Where X¼Cl, Br, OR0, SR0, SO2R0, NO2, CN, PO(OR0)2, etc.; R0¼alkyl, aryl, etc.
Keywords: asymmetric dihydroxylation; vinyl sulfones; prochiral alkene; a-hydroxyaldehydes.
*
Corresponding author. Tel.: þ44-7950283902; fax: þ44-151-794-2304; e-mail: pjevans@liv.ac.uk
0040–4020/$ - see front matter q 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2003.08.003

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P. Evans, M. Leffray / Tetrahedron 59 (2003) 7973–7981
2. Results and discussion
ments obtained for both products compare favourably with
the literature value measured for (R)-8 {[a]2D3¼220.2
(c¼1.0, CHCl3), 93% e.e}.15 More significantly analytical
HPLC of (R)- and (S)-8, using a Whelk stationary phase,
indicated that the enantiomeric excesses of (S)-8 and (R)-8,
following either reaction, were both approximately 90% e.e.
Due to slight peak overlap the calculation of more accurate
enantiomeric excess values was not possible.
At the outset a potential problem with the proposed
sequence was that the enantioenriched a-hydroxyaldehyde
3a may undergo enolisation into the corresponding ketone
3b with the concomitant erosion of optical activity (Fig. 1).
For this reason unprotected hydroxyl species such as 3a
have traditionally found limited use in organic synthesis.4
Nevertheless, in order to investigate the proposed reaction
sequence b-substituted phenyl vinyl sulfone 5 was syn-
thesised following a ruthenium catalysed cross metathesis
reaction. Thus, under conditions described,14 octene 4 and
phenyl vinyl sulfone were heated in the presence of 5 mol%
of the imidazoyl catalyst 6 affording the corresponding
trans-vinyl sulfone 5 in excellent yield. Treatment of
sulfone 5 with either AD mix-a, or AD mix-b, under
standard conditions, resulted in consumption of the starting
material and observation of a slower moving ‘streaking’
spot on thin layer chromatography. The identity of these
We were interested to apply this novel method to the
synthesis of optically active 5-alkyl substituted furan-
2(5H)-ones (g-butenolides) using the cis-selective Still–
Gennari modified Horner–Wadsworth–Emmons reac-
tion.16–18 The furan-2(5H)-one sub-structure appears in a
very large number of natural products; including those from
diverse species such as marine animals and plants.18
Furthermore, many such compounds possess interesting
biological activities, indeed in the case of the acetogenin
family19 it has been shown that the furan-2(5H)-one
functional group is responsible for their potent cytotoxity.
1
compounds appeared, by H NMR spectroscopy, to be a
complex mixture containing the a-hydroxyaldehyde (S/R)-7
and unidentified materials, likely to include the correspond-
ing homo-dimer (see Scheme 2). Rather than attempting to
purify these materials by flash column chromatography, it
was found that direct conversion into the corresponding
a,b-unsaturated ester using a Horner–Wadsworth–
Emmons (H–W–E) protocol gave improved yields of
characterisable materials (Scheme 1). Thus, AD mix-a
ultimately afforded ester (S)-8 in 52% yield for the 2 steps,
whereas AD mix-b gave enantiomeric (R)-8 in 49% yield
(Scheme 1).15 Concerns regarding the stereochemical
integrity of the a-hydroxyl group during these operations
proved to be unfounded and the optical rotation measure-
Thus, treatment of the crude (S)-7 under modified Still–
Genari conditions20 afforded a mixture of the ester (S)-8 and
the furan-2(5H)-one (S)-9 in approximately a 40:60 ratio
(1H NMR spectroscopy), evidently resulting from only a
moderately cis selective H–W–E reaction. Separation by
flash column chromatography gave the lactone (S)-9 in 26%
yield and the ester (S)-8 in 19% yield. Similarly, the
enantiomeric series was accessed using AD mix-b in
comparable yield (Scheme 1). The optical rotation measure-
ments were approximately equal and opposite and analytical
chiral HPLC using a Whelk column indicated enantiomeric
excesses of 88 and 95% for (S)- and (R)-9, respectively.
t
Scheme 1. (i) Phenyl vinyl sulfone, 6 (5 mol%), DCM (1.0 mol dm23), 408C, 15 h, 90%; (ii) AD-mix-a, MeSO2NH2, BuOH–H2O (1:1), 258C, 24 h;
(iii) (EtO)2POCH2CO2Me, NaH, THF, 208C, 12 h, 52% (yield from 5); (iv) (F3CCH2O)2POCH2CO2Me, NaH, THF, 2788C to 208C, 5 h, 26% (yield from 5);
t
(v) AD-mix-b, MeSO2NH2, BuOH–H2O (1:1), 258C, 24 h; (vi) (EtO)2POCH2CO2Me, NaH, THF, 208C, 12 h, 49% (yield from 5); (vii) (F3CCH2O)2-
POCH2Me, NaH, THF, 2788C to 208C, 12 h, 23% (yield from 5).

P. Evans, M. Leffray / Tetrahedron 59 (2003) 7973–7981
7975
Attempts to further optimise this two-step process were not
successful and it appears that the mass balance for this
reaction exists as polar unidentified materials. Additionally,
it seems possible that some of the intermediate aldehyde is
lost in the aqueous phase as the corresponding hydrate 16
(see Scheme 2).
The overall stereochemical outcome for these reactions,
based on the literature precedent for enantioenriched
(R)-8,15 is consistent with the Sharpless mnemonic1 in
which the phenyl sulfonyl moiety represents the largest group
(see Fig. 2).
Figure 2. Sharpless model for asymmetric dihydroxylation—AD mix-b
[L¼(DHQD)2PHAL]; AD mix-a [L¼(DHQ)2PHAL].
Based on the excellent enantioselectivity observed it
appears that the equilibrium between the a-hydroxyaldehyde
3a and the a-hydroxyketone 3b, via enol 15 (Scheme 2), and
the resultant erosion of enantiopurity, is not significant in
this case.4d A possible explanation for this is that in organic
solvents the reactive monomeric aldehyde 3a dimerises
forming the corresponding bis-hemiacetals 10 and 11, as a
complex mixture of diastereoisomers.13,21 Mass spec-
troscopy (ES) demonstrates the existence of this type of
dimeric compound where R¼nHex. Consequently it seems
plausible that these species serve to effectively ‘protect’ the
potentially labile asymmetric centre and that subsequent
reaction of 10, 11 or 3a under Horner–Wadsworth–
Emmons conditions generates the corresponding enantioen-
riched a,b-unsaturated esters. Similarly, in aqueous con-
ditions it has been shown that a-hydroxyaldehydes undergo
significant hydration (3a!16)4d again protecting the
asymmetric carbon from epimerisation.
called variously quercus (isolated from a species of white
oak), whisky and cognac lactone depending on its origin,22
was performed. Vinyl sulfone 17 was prepared following
cross metathesis as described above. On treatment, initially
with AD-mix-b, then with the bis-trifluoroethanol derived
phosphonate anion, 17 was converted into the correspond-
ing furan-2(5H)-one 20 {[a]2D0¼2103.0 (c¼1.05, CHCl3)}
and the ester 19 {[a]2D0¼221.0 (c¼1.0, CHCl3)} in 34 and
19% isolated yields, respectively.23 Stereoselective con-
jugate addition using Me2CuLi afforded the lactone 21,
whose data was entirely consistent with that previously
reported (Fig. 3).22,23 This sequence again providing
corroboration for the predictive approach of the putative
OsO4-L complex presented in Figure 2.
In a similar manner a short synthesis of both enantiomers of
maritolide 26 was approached. This relatively simple
5-alkyl furan-2(5H)-one was isolated in 1998 from the
shrub diospyros maritima a member of the ebony family
(ebenaceae) in Taiwan.24 Historically the stems of this
shrub have been used to treat rheumatic diseases in this
region. Maritolide 26 has not previously been prepared
synthetically and the absolute stereochemistry of the single
asymmetric carbon is not known.
Attempts to unambiguously characterise the crude reaction
mixture, following treatment of the vinyl sulfone 5 with AD
mix-b (where R¼nHex), by PDC oxidation afforded a
mixture of compounds from which only the unusual acetal
13 was isolated, as a single undetermined diastereoisomer in
12% yield. Notably throughout this study none of the
products resulting from the H–W–E reaction of the
a-hydroxyketone 3b, the ketone itself, or its dimer 14,
were detected.
Initially dec-9-en-1-ol 22 was oxidised using PDC to the
carboxylic acid 23, which was then esterified, under
standard Fischer type conditions, affording the ethyl ester
24 in 64% yield for the 2 steps. At this stage both the cross
metathesis catalytic loading and the catalyst itself were
In order to further exemplify and explore this process as a
rapid method for the construction of enantioenriched furan-
2(5H)-ones a short synthesis of the natural product 21,
Scheme 2.

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P. Evans, M. Leffray / Tetrahedron 59 (2003) 7973–7981
Figure 3. Synthesis of quercus lactone 21. (i) Phenyl vinyl sulfone, 6 (5 mol%), DCM, 408C, 12 h, 86%; (ii) AD-mix-b, tBuOH–H2O (1:1), 158C, 24 h; (iii)
(F3CH2CO)2POCH2CO2Me, NaH, THF, 2788C to rt, 24 h, 34% (yield from 17); (iv) Me2CuLi, Et2O, 2788C to 2208C, 1 h, 67%.
investigated in an attempt to prepare sulfone 25 in the most
efficient sequence. It was found that use of the biscyclo-
hexylphosphine Grubbs’ catalyst gave only the dimer
resulting from cross metathesis of 24 and recovered phenyl
vinyl sulfone.14 Use of 1 mol% of 6 afforded the vinyl
sulfone 25 in 44% yield, however, the remaining phenyl
vinyl sulfone proved difficult to separate. The corresponding
process using 5 mol% of 6 gave 25 in 89% yield following
essentially a complete cross metathesis reaction (Fig. 4).
from the literature value {[a]2D4¼23.4 (c¼0.2, CHCl3)},24
consequently we speculate that 26 underwent racemisation
during the isolation process, or is formed biosynthetically
without stereocontrol. Chiral HPLC data obtained for both
(R)-26 and (S)-26 indicate enantiomeric excesses of
approximately 96 and 95%, respectively (Chiralpak AD).
Similarly, as expected chiral HPLC analysis of (R)- and
(S)-27 indicated approximately identical enantiomeric ratios
to their furan-2(5H)-one counterparts (Whelk).
Treatment of 25 with either AD mix-a, or b gave the
intermediate aldehydes that were directly converted into the
corresponding (R)- and (S)-furanones 26 in 28 and 22%
yields, respectively. The corresponding (R)- and (S)-4-
hydroxyl esters 27 were also obtained following these
reactions in 13% yield in both instances. The spectroscopic
data obtained for 26 was entirely consistent with that
reported.24 However, the roughly equal and opposite optical
rotation values obtained for (R)- and (S)-26 differed greatly
3. Conclusion
To summarise, we have developed a novel method for
the synthesis of enantioenriched furan-2(5H)-ones and
4-hydroxyl a,b-unsaturated esters from the corre-
sponding vinyl sulfones. The main advantages of the
sequence described stem from the rapid access of func-
tionalised products in high enantiomeric purity and in a
Figure 4. Synthesis of (R)-maritolide and (S)-maritolide 26. (i) PDC, DMF, rt, 69%; (ii) cat. H2SO4, EtOH, 808C, 93%; (iii) phenyl vinyl sulfone, 6 (5 mol%),
DCM, 408C, 89%; (iv) (a) AD mix-b, tBuOH–H2O (1:1), 108C; (b) (F3CH2CO)2POCH2CO2Me, NaH, THF, 2788C to rt, 28% (from 25); (v) (a) AD mix-a,
tBuOH–H2O (1:1), 108C; (b) (F3CH2CO)2POCH2Me, NaH, THF, 2788C to rt, 22% (from 25).

P. Evans, M. Leffray / Tetrahedron 59 (2003) 7973–7981
7977
Scheme 3. (i) (a) AD-mix-a, MeSO2NH2, tBuOH–H2O (1:1), 208C, 24 h; (b) (EtO)2POCH2CO2Me, NaH, THF, 258C, 4 h, 20% (yield from 28); (ii) (a) AD-
mix-b, MeSO2NH2, tBuOH–H2O (1:1), 208C, 24 h; (b) (EtO)2POCH2CO2Me, NaH, THF, 258C, 12 h, 26% (yield from 28).
stereochemically predictable manner from readily available
vinyl sulfone starting materials. Preliminary results indicate
that this process may be more general than described in this
paper, for example, a,b-unsaturated nitro compound 2825
gave (S)- and (R)-8 under identical conditions to those
described (Scheme 3). Interestingly, the same overall
stereoselectivity was observed for the nitro variant as the
sulfonyl version, i.e. AD mix-a gave (S)-8, whereas AD
mix-b gave (R)-8 in approximately 90% e.e. for both cases.
However, the chemical yields observed were considerably
worse than those for the corresponding vinyl sulfone 5,
partly due to the competing hydrolysis/retro nitro-aldol
reaction of 28 under the asymmetric dihydroxylation
reaction conditions.
(356 mg, 0.42 mmol, 5 mol%) in DCM (10 cm3) was heated
to reflux for 12 h. Silica (ca. 5 g) was added and the solvent
was removed under reduced pressure. Purification by flash
column chromatography (Hex–EtOAc; 4:1) gave the vinyl
sulfone 5 (1.89 g, 90%) as a pale yellow oil. Rf¼0.3 (Hex–
EtOAc; 4:1); nmax (neat/cm21) 3035, 2927, 2856, 1624,
1446, 1305, 1147; m/z (CI) 270 (MNHþ4 , 100%); found
270.15350,
C14H20O2S·NH4
requires
270.15280
(þ2.9 ppm); dH (400 MHz, CDCl3) 0.89 (3H, t, J¼7.0 Hz,
CH3), 1.23–1.37 (6H, m, CH2), 1.48 (2H, pent, J¼7.0 Hz,
CH2), 2.23 (2H, dq, J¼7.0 Hz, CH2), 6.31 (1H, dt, J¼1.5,
15.0 Hz, CH), 7.00 (1H, dt, J¼7.0, 15.0 Hz, CH), 7.54 (2H,
t, J¼7.0 Hz, ArH), 7.62 (1H, t, J¼7.0 Hz, ArH), 7.89 (2H, d,
J¼7.0 Hz, ArH); dC (100 MHz, CDCl3) 13.9, 22.4, 27.5,
28.7, 31.4, 31.5, 127.5, 129.2, 130.4, 133.1, 140.9, 147.3.
Future work will focus both on improving the yields and to
further explore the substrate scope and limitations of the
1,2-elimination process described. Initial results indicate
that the asymmetric a-hydroxyl substituent is responsible
for the poor geometrical stereoselectivity of the Still–
Gennari olefination; under identical conditions to those
described aliphatic straight chain aldehydes gave the
expected, reported stereoselectivities (E/Z, 15:85) for this
H–W–E reagent.16,20
4.1.2. trans-4R-Hydroxydec-2-enoic acid methyl ester 8.
A solution of the vinyl sulfone (485 mg, 1.92 mmol,
t
1 equiv.) in BuOH (8 cm3) and H2O (8 cm3) was treated
with MeSO2NH2 (229 mg, 2.41 mmol, 1.25 equiv.) and AD
mix-b (7.7 g) for 24 h. DCM (25 cm3) and H2O (25 cm3)
were added and the mixture was partitioned for 0.5 h. The
resultant aqueous layer was further extracted with DCM
(4£25 cm3) and the combined organic extracts were dried
over MgSO4. Filtration followed by solvent evaporation
under reduced pressure afforded the crude aldehyde. Under
N2, at room temperature a solution of methyl diethylpho-
sphonoacetate (445 mg, 2.12 mmol, 1.1 equiv.) in dry THF
(20 cm3) was treated with 60% (w/w) NaH in mineral oil
(77 mg, 1.93 mmol, 1 equiv.) for 0.5 h. The crude aldehyde
in THF (5 cm3) was added and the reaction was stirred for
15 h. Et2O (25 cm3) and H2O (25 cm3) were added and the
resultant aqueous layer was further extracted with Et2O
(3£25 cm3). The combined extracts were dried over MgSO4
before filtration and solvent removal and purification by
flash column chromatography (Hex–EtOAc; 4:1) gave (R)-
8 (188 mg, 49%) as a clear liquid. Rf¼0.2 (Hex–EtOAc;
4:1); [a]2D0¼222.4 (c¼1.03, CHCl3) {lit. [a]2D3¼220.2
(c¼1.0, CHCl3), 93% e.e.};15 nmax (neat/cm21) 3432, 2930,
2857, 1726, 1659, 1435, 1277, 1169; m/z (CI) 218 (MNHþ4 ,
100%), 201 (MHþ, 50%); found 201.14956, C11H21O3·H
requires 201.14906 (þ2.8 ppm); dH (400 MHz, CDCl3) 0.89
(3H, t, J¼7.0 Hz, CH3), 1.22–1.46 (8H, m, CH2), 1.54–
1.63 (2H, m, CH2), 2.02 (1H, s(br), OH), 3.74 (3H, s, CH3),
4.25–4.33 (1H, m(br), CH), 6.02 (1H, dd, J¼1.5, 15.5 Hz,
CH), 6.94 (1H, dd, J¼5.0, 15.5 Hz, CH); dC (100 MHz,
CDCl3) 14.0, 22.5, 25.1, 29.1, 31.7, 36.7, 51.5, 71.1, 119.7,
150.6, 167.0. HPLC analysis (Whelk), Hex–EtOH; 95:5
(0.5 cm3/min): (S)-8 tr¼10.0 min, (R)-8 tr¼10.5 min; 90%
e.e.
4. Experimental
4.1. General
Starting materials were purchased from commercial sources
and were used without further purification. Anhydrous THF
was distilled under nitrogen from the sodium-benzophenone
ketyl radical, DCM was distilled from CaH2. 1H NMR
(400 MHz) and 13C NMR (100 MHz) spectra were recorded
using a Bruker AMX400 spectrometer. Infrared spec-
troscopy was performed on a Perkin–Elmer Paragon 1000
FTIR spectrometer. Optical rotation measurements were
recorded using a Optical Activity, Polaar 2001 polarimeter
at 589 nm and are quoted in units of 1021 deg cm2 g21
.
Flash column chromatography, under moderate pressure
˚
was performed using silica gel—ICN 32-63, 60 A. Analyti-
cal HPLC measurements were performed on a Gilson
analytical HPLC machine using either a (R,R)-Whelk
column (Merck), or a Chiralpak AD column (Daicel)
under conditions described in Section 4.
4.1.1. [(trans-Oct-1-ene)-1-sulfonyl]benzene 5.26 Under
N2, a solution of 1-octene (2.0 cm3, 12.7 mmol, 1.5 equiv.),
phenyl vinyl sulfone (1.41 g, 8.38 mmol, 1 equiv.) and 6

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P. Evans, M. Leffray / Tetrahedron 59 (2003) 7973–7981
4.1.3. trans-4S-Hydroxydec-2-enoic acid methyl ester 8.
In an identical procedure to that described above, treatment
of 5 (695 mg, 2.76 mmol) with AD mix-a followed by
methyl diethylphosphonoacetate afforded the enantiomeric
ester (S)-8 (285 mg, 52%) as a clear liquid. [a]2D0¼þ22.0
(c¼1.00, CHCl3). HPLC analysis (Whelk), Hex–EtOH;
95:5 (0.5 cm3/min): (S)-8 tr¼10.0 min, (R)-8 tr¼10.5 min;
90% e.e.
MgSO4, filtered and the solvent removed under reduced
pressure. The resultant mixture was re-dissolved in DCM
3
˚
(30 cm ) and 4 A molecular sieves (2.0 g) were added. The
mixture was stirred for 0.25 h before PDC (5.90 g,
15.68 mmol, 2.0 equiv.) was added. Stirring was continued
for 2 h before silica (ca. 10 g) was added and the solvent
removed in vacuo. The crude mixture was purified by flash
column chromatography (Hex–EtOAc; 9:1) affording the
acetal 13 (130 mg, 12%) as a colourless oil. Rf¼0.2 (Hex–
EtOAc; 9:1); nmax (neat/cm21) 2957, 2929, 2859, 1807,
1737, 1467, 1379, 1309, 1199; m/z (ESþ) 339 (MNaþþ
MeOH, 100%), 307 (MNaþ, 10%); found 339.2133,
C17H32O5·Na requires 339.2147 (24.3 ppm); found
307.1870, C16H28O4·Na requires 307.1885 (25.0 ppm); dH
(400 MHz, CDCl3); 0.86–0.92 (6H, m, CH3), 1.26–1.38
(12H, m, CH2), 1.43–1.53 (2H, m, CH2), 1.58–1.66 (2H, m,
CH2), 1.72–1.82 (1H, m, CH2), 1.88–1.99 (1H, m, CH2),
2.60 (2H, t, J¼7.5 Hz, CH2), 4.32 (1H, ddd, J¼1.0, 4.25,
7.5 Hz, CH), 5.48 (1H, d, J¼1.0 Hz, CH); dC (100 MHz,
CDCl3) 13.95, 14.0, 22.4, 22.5, 22.6, 24.8, 28.65, 28.7, 30.9,
31.45, 31.5, 36.6, 74.3, 99.6, 171.7, 201.7.
4.1.4. 5R-Hexyl-2(5H)-furanone 9.27 At room temperature
a solution of 5 (655 mg, 2.60 mmol, 1 equiv.) and
t
MeSO2NH2 (309 mg, 3.25 mmol, 1.25 equiv.) in BuOH
(11 cm3) and H2O (11 cm3) was treated with AD mix-b
(10.4 g) for 24 h. DCM (25 cm3) and H2O (25 cm3) were
added and the mixture was partitioned for 0.5 h. The
resultant aqueous layer was further extracted with DCM
(4£25 cm3) and the combined organic extracts were dried
over MgSO4. Filtration followed by solvent evaporation
under reduced pressure afforded the crude aldehyde. Under
N2, a solution of bis(2,2,2-trifluoroethyl) (methoxycarbo-
nylmethyl)phosphonate (951 mg, 2.99 mmol, 1.15 equiv.)
in THF (20 cm3) was treated with 60% (w/w) NaH in
mineral oil (111 mg, 2.78 mmol, 1.08 equiv.) at room
temperature. After 0.5 h the solution was cooled to 2788C
and the crude aldehyde in THF (5 cm3) was added. The
reaction was warmed to room temperature over 15 h. Et2O
(25 cm3) and H2O (25 cm3) were added and the resultant
aqueous layer was further extracted with Et2O (3£25 cm3).
The combined extracts were dried over MgSO4 before
filtration and solvent removal gave a mixture of 8 and 9.
Purification by flash column chromatography (DCM–Hex;
1:1) afforded the furan-2(5H)-one 9 (101 mg, 23%) as a
clear liquid, further elution (EtOAc) gave the ester 8 (97 mg,
19%) whose data was identical to that reported above.
Rf¼0.15 (DCM–Hex; 1:1); [a]2D0¼284.1 (c¼1.01, CHCl3);
nmax (neat/cm21) 3057, 2930, 2859, 1752, 1601, 1467,
1266, 1165; m/z (CI) 186 (MNHþ4 , 100%), 169 (MHþ,
25%); found 169.12290, C10H16O2·H requires 169.12286
(þ0.3 ppm); dH (400 MHz, CDCl3) 0.88 (3H, t, J¼7.0 Hz,
CH3), 1.25–1.36 (6H, m, CH2), 1.38–1.48 (2H, m, CH2),
1.60–1.79 (2H, m, CH2), 5.01–5.13 (1H, m, CH), 6.09 (1H,
dd, J¼1.75, 6.0 Hz, CH), 7.44 (1H, dd, J¼1.5, 6.0 Hz, CH);
dC (100 MHz, CDCl3) 13.9, 22.4, 24.9, 28.9, 31.5, 33.2,
83.4, 121.5, 156.2, 173.0. HPLC analysis (Whelk), Hex–
EtOH; 95:5 (0.5 cm3/min): (S)-9 tr¼16.7 min, (R)-9
tr¼17.7 min; 95% e.e.
4.1.7. [(trans-Hex-1-ene)-1-sulfonyl]benzene 17.28 A solu-
tion of hexene (1.7 cm3, 13.70 mmol, 1.5 equiv.) and phenyl
vinyl sulfone (1.53 g, 9.10 mmol, 1 equiv.) in DCM (9 cm3)
was treated with 6 (386 mg, 0.46 mmol, 5 mol%). The
mixture was heated to reflux under nitrogen for 15 h.
Addition of silica (ca. 5 g) and solvent removal under
reduced pressure and purification by flash column chroma-
tography (Hex–EtOAc; 5:1) gave 17 (1.78 g, 87%) as a
yellow liquid. Rf¼0.25 (Hex–EtOAc; 5:1); m/z (CI) 242
(MNHþ4 , 100%), 225 (MHþ, 5%); found 242.12171,
C12H16O2S·NH4 requires 242.12148 (þ1.0 ppm); dH
(400 MHz, CDCl3) 0.89 (3H, t, J¼7.5 Hz, CH3), 1.32 (2H,
sex, J¼7.5 Hz, CH2), 1.45 (2H, pent, J¼7.5 Hz, CH2), 2.33
(2H, dq, J¼1.5, 7.5 Hz, CH2), 6.32 (1H, dt, J¼1.5, 15.0 Hz,
CH), 6.98 (1H, dt, J¼7.5, 15.0 Hz, CH), 7.53 (2H, t,
J¼7.5 Hz, ArH), 7.60 (1H, t, J¼7.5 Hz, ArH), 7.87 (2H, d,
J¼7.5 Hz, ArH); dC (100 MHz, CDCl3) 13.6, 22.2, 29.6,
31.1, 127.5, 129.2, 130.4, 133.1, 140.8, 147.2.
4.1.8. 5R-Butyl-2(5H)-furanone 20.22,23 At 148C a solution
of vinyl sulfone 17 (893 mg, 3.99 mmol, 1 equiv.) and
t
MeSO2NH2 (474 mg, 4.98 mmol, 1.25 equiv.) in BuOH
(20 cm3) and H2O (20 cm3) was treated with AD mix-b
(16.0 g). Stirring was continued for 24 h before DCM
(50 cm3) and H2O (50 cm3) were added. The mixture was
vigorously partitioned for 0.5 h and the aqueous layer was
further extracted with DCM (5£50 cm3). The combined
organic extracts were dried over MgSO4. Filtration and
solvent removal in vacuo gave the crude aldehyde 18. Under
N2, at room temperature, a solution of bis(2,2,2-trifluoro-
ethyl) (methoxycarbonylmethyl)phosphonate in THF
(20 cm3) was treated with 60% w/w NaH in mineral oil
(175 mg, 4.38 mmol, 1.1 equiv.). Stirring was continued for
0.25 h before the reaction was cooled to 2788C. A solution
of the crude aldehyde 18 in THF (5 cm3) was added and the
mixture was stirred and warmed to room temperature over
15 h. Et2O (25 cm3) and H2O (25 cm3) were added and the
resultant aqueous layer was further extracted with Et2O
(3£25 cm3). The combined extracts were dried over MgSO4
before filtration, solvent removal and purification by flash
column chromatography (DCM–Hex; 3:1) gave 20
4.1.5. 5S-Hexyl-2(5H)-furanone 9.27 As described above,
treatment of 5 (672 mg, 2.67 mmol) with AD-mix-a
afforded the enantiomeric materials (S)-9 (116 mg, 26%)
and (S)-8 (99 mg, 19%) following purification by flash
column chromatography; [a]2D0¼þ81.0 (c¼1.00, CHCl3).
HPLC analysis (Whelk), Hex–EtOH; 95:5 (0.5 cm3/min):
(S)-9 tr¼16.7 min, (R)-9 tr¼17.7 min; 88% e.e.
4.1.6. 2-Heptanoyl-5-hexyl-1,3-dioxolan-4-one 13. At
room temperature a solution of 5 (1.99 g, 7.90 mmol,
1 equiv.) and MeSO2NH2 (0.94 g, 9.88 mmol, 1.25 equiv.)
in tBuOH (30 cm3) and H2O (30 cm3) was treated with AD
mix-b (20.0 g) and vigorously stirred for a period of 2 days.
DCM (75 cm3) and H2O (75 cm3) were added and the
resultant aqueous phase was further extracted with DCM
(4£50 cm3). The combined organic extracts were dried over

P. Evans, M. Leffray / Tetrahedron 59 (2003) 7973–7981
7979
(190 mg, 34%) as a clear liquid. Rf¼0.25 (DCM–Hex; 3:1);
[a]D20¼2103.0 (c¼1.05, CHCl3) {lit. [a]2D0¼299.0
(c¼1.38, CHCl3), 98% e.e.};23 m/z (CI) 158 (MNH4þ,
100%), 141 (MHþ, 40%); found 141.09155, C8H12O2·H
requires 141.09155 (0.00 ppm); dH (400 MHz, CDCl3) 0.89
(3H, t, J¼7.0 Hz, CH3), 1.28–1.49 (4H, m, CH2), 1.60–
1.79 (2H, m, CH2), 4.96–5.04 (1H, m, CH), 6.07 (1H, dd,
J¼1.5, 5.5 Hz, CH), 7.44 (1H, dd, J¼1.0, 5.5 Hz, CH); dC
(100 MHz, CDCl3) 13.7, 22.3, 26.9, 32.8, 83.3, 121.4,
156.3, 173.0.
dH (400 MHz, CDCl3) 1.30–1.44 (8H, m, CH2), 1.61–1.69
(2H, m, CH2), 2.02–2.08 (2H, m, CH2), 2.36 (2H, t,
J¼7.5 Hz, CH2), 4.92–5.03 (2H, m, CH2), 5.76–5.87 (1H,
m, CH), 11.15 (1H, s(br), OH); dC (100 MHz, CDCl3) 24.7,
28.8, 28.9, 29.0, 29.05, 33.7, 33.9, 114.2, 139.1, 179.4.
4.1.12. Ethyl 9-decenoate 24. A solution of the acid 23
(3.02 g, 17.74 mmol, 1 equiv.) in EtOH (45 cm3) was
treated with concentrated sulphuric acid H2SO4 (ca.
0.5 cm3). The mixture was heated to reflux for 22 h. Ether
(80 cm3) and a saturated aqueous solution of NaHCO3
(80 cm3) were added. The resultant aqueous layer was
extracted with ether (2£80 cm3). The combined organic
extracts were washed with water (100 cm3) and dried over
MgSO4. Filtration followed by solvent evaporation under
reduced pressure afforded the crude ester. Purification by
flash column chromatography (Hex–EtOAc; 19:1) gave the
ester 24 (3.26 g, 93%) as a yellow oil. Rf¼0.3 (Hex–EtOAc;
19:1); nmax (neat/cm21) 3076, 2978, 2928, 2855, 1738,
1641; m/z (CI) 216 (MNHþ4 , 10%), 199 (MHþ, 100%),
found 199.17025, C12H22O2·H requires 199.16980
(þ2.5 ppm); dH (400 MHz, CDCl3) 1.26 (3H, t, J¼7.0 Hz,
CH3), 1.29–1.36 (6H, m(br), CH2), 1.34–1.43 (2H, m(br),
CH2), 1.58–1.67 (2H, m, CH2), 2.01–2.08 (2H, m, CH2),
2.29 (2H, t, J¼7.5 Hz, CH2), 4.13 (2H, q, J¼7.0 Hz, CH2),
4.92–5.03 (2H, m, CH2), 5.76–5.86 (1H, m, CH); dC
(100 MHz, CDCl3) 13.9, 24.6, 28.5, 28.6, 28.8, 33.5, 34.1,
60.0, 114.4, 139.5, 174.4; found C, 72.89; H, 11.47%,
C12H22O2 requires C, 72.68; H, 11.18%.
4.1.9. trans-4R-Hydroxyoct-2-enoic acid methyl ester 19.
Further elution (EtOAc) gave the ester 19, which was re-
purified by flash column chromatography (Hex–EtOAc;
3:1) and isolated (131 mg, 19%) as a clear liquid. Rf¼0.2
(Hex–EtOAc; 3:1); [a]D20¼221.0 (c¼1.00, CHCl3) {lit.
[a]2D0¼218.3 (c¼1.05, CHCl3), 73% e.e.};15 m/z (CI) 190
(MNHþ4 , 100%), 173 (MHþ, 50%), 141 (M2OCHþ3 , 55%);
found 173.11715, C9H16O3·H requires 173.11777
(23.8 ppm); dH (400 MHz, CDCl3) 0.91 (3H, t, J¼7.0 Hz,
CH3), 1.28–1.45 (4H, m, CH2), 1.53–1.62 (2H, m, CH2),
2.16 (1H, s(br), OH), 3.72 (3H, s, CH3), 4.27–4.53 (1H, m,
CH), 6.03 (1H, d, J¼15.5 Hz, CH), 6.95 (1H, dd, J¼5.0,
15.5 Hz, CH); dC (100 MHz, CDCl3) 13.8, 22.5, 27.3, 36.3,
51.5, 71.0, 119.6, 150.3, 167.0.
4.1.10. 5R-Butyl-4S-methyl-dihydrofuran-2-one (quer-
cus lactone) 21.22 Under N2, a slurry of CuI (223 mg,
1.17 mmol, 1.6 equiv.) in Et2O (10 cm3) was treated with
1.6 M MeLi in hexanes (1.55 cm3, 2.48 mmol, 3.3 equiv.)
at 2788C. Stirring was continued for 1 h, during which
period the temperature rose to 08C. The solution of
Me2CuLi was re-cooled to 2788C and 20 (105 mg,
0.75 mmol, 1 equiv.) in Et2O (2 cm3) was added. Stirring
was continued for 1 h at 2788C to 2208C. Saturated
NH4Cl (25 cm3) was added and the mixture was extracted
with Et2O (3£25 cm3). The combined organic extracts
were dried over MgSO4. Filtration, solvent removal in
vacuo and purification by flash column chromatography
(Hex–EtOAc; 3:1) gave the lactone 21 (78 mg, 67%) as a
pale yellow oil. Rf¼0.3 (Hex–EtOAc; 3:1); [a]2D0¼þ77.4
(c¼0.93, MeOH) {lit. [a]2D1¼þ79.9 (c¼1.01, MeOH)};22c
m/z (CI) 174 (MNHþ4 , 100%), 157 (MHþ, 70%); found
157.12322, C9H16O2·H requires 157.12286 (þ2.4 ppm);
dH (400 MHz, CDCl3) 0.92 (3H, t, J¼7.0 Hz, CH3), 1.14
(3H, d, J¼6.5 Hz, CH3), 1.28–1.43 (2H, m, CH2), 1.43–
1.72 (4H, m, CH2), 2.14–2.25 (2H, m, CH2,CH), 2.61–
2.71 (1H, m, CH2), 4.01 (1H, ddd, apparent dt, J¼4.0,
7.75 Hz, CH); dC (100 MHz, CDCl3) 13.7, 17.4, 22.4,
27.7, 33.6, 35.9, 37.0, 87.3, 176.4.
4.1.13. (trans)-10-Benzenesulfonyl-dec-9-enoic acid ethyl
ester 25. Under N2, a solution of ester 24 (2.17 g,
10.93 mmol, 1 equiv.), phenyl vinyl sulfone (1.84 g,
10.93 mmol, 1 equiv.) and
6
(0.464 g, 0.55 mmol,
5 mol%) in CH2Cl2 (22 cm3) was heated to reflux for
18 h. Silica (ca. 5 g) was added and the solvent was removed
under reduced pressure. Purification by flash column
chromatography (Hex–EtOAc; 3:1) gave the product 25
(3.30 g, 89%) as a viscous yellow oil. Rf¼0.2 (Hex–EtOAc;
3:1); nmax (neat/cm21) 3058, 2980, 2931, 2856, 1732, 1625,
1319, 1147; m/z (CI) 357 (MNHþ4 , 35%), 339 (MHþ, 85%),
found 339.16236, C18H26O4S·H requires 339.16299
(22.0 ppm); dH (400 MHz, CDCl3) 1.25 (3H, t, J¼7.0 Hz,
CH3), 1.26–1.33 (8H, m, CH2), 1.41–1.50 (2H, m, CH2),
1.56–1.64 (2H, m, CH2), 2.19–2.30 (2H, m, CH2), 4.12
(2H, q, J¼7.0 Hz, CH2), 6.31 (1H, dt, J¼1.5, 15.0 Hz, CH),
6.98 (1H, dt, J¼6.75, 15.0 Hz, CH), 7.50–7.63 (3H, m,
ArH), 7.86–7.90 (2H, m, ArH); dC (100 MHz, CDCl3) 14.2,
24.8, 27.5, 28.8, 28.9, 28.95, 31.4, 34.3, 60.2, 127.6, 129.2,
130.5, 133.2, 140.9, 147.1, 173.7; found C, 63.71; H, 7.77%,
C18H26O4S requires C, 63.88; H, 7.74%.
4.1.11. 9-Decenoic acid 23.29 At room temperature, a
solution of 9-decen-1-ol 22 (4.57 cm3, 25.6 mmol, 1 equiv.)
and PDC (38.52 g, 102.4 mmol, 4 equiv.) in DMF (75 cm3)
was stirred for 10 h. Water (500 cm3) and ether (150 cm3)
were added. The resultant aqueous layer was extracted with
ether (2£150 cm3). The combined organic extracts were
dried over MgSO4. Filtration followed by solvent evapor-
ation under reduced pressure afforded the crude acid.
Purification by flash column chromatography (Hex–EtOAc;
5:1) gave the acid 23 (3.02 g, 69%) as a yellow oil. Rf¼0.15
(Hex–EtOAc; 3:1); m/z (CI) 188 (MNHþ4 , 100%), found
188.16519, C10H18O2·NH4 requires 188.16505 (þ0.8 ppm);
4.1.14. 8-(5R-Oxo-2,5-dihydrofuran-2-yl)octanoic acid
ethyl ester (maritolide) 26.24 At room temperature, a
solution of 25 (850 mg, 2.51 mmol, 1 equiv.) and MeSO2-
t
NH2 (299 mg, 3.14 mmol, 1.25 equiv.) in BuOH (11 cm3)
and H2O (11 cm3) was treated with AD mix-b (10 g) for
66 h. DCM (40 cm3) and water (40 cm3) were added and the
mixture was partitioned for 0.5 h. The resultant aqueous
layer was further extracted with DCM (4£25 cm3) and the
combined organic extracts were dried over MgSO4.
Filtration followed by solvent evaporation under reduced
pressure afforded the crude aldehyde. Under N2, a solution

7980
P. Evans, M. Leffray / Tetrahedron 59 (2003) 7973–7981
of bis(2,2,2-trifluoroethyl) (methoxycarbonylmethyl)phos-
phonate (0.61 cm3, 2.89 mmol, 1.15 equiv.) in THF
(20 cm3) was treated with 60% w/w NaH in mineral oil
(109 mg, 2.73 mmol, 1.08 equiv.) at room temperature.
After 0.5 h, the solution was cooled to 2788C and the crude
aldehydeinTHF(5 cm3)wasadded.Thereactionwasallowed
to warm to room temperature over 18 h, whereupon, Et2O
(25 cm3) and H2O (25 cm3) were added and the resultant
aqueous layer was further extracted with Et2O (3£25 cm3).
The combined extracts were dried over MgSO4 before
filtration and solvent removal gave a mixture of 26 and 27.
Initial purification by flash column chromatography (DCM–
EtOAc; 15:1) allowed the separation of 26 [Rf¼0.45 (DCM–
EtOAc; 15:1)] and 27 [Rf¼0.15 (DCM–EtOAc; 15:1)].
Further, purification by flash column chromatography
(Hex–EtOAc; 3:1) afforded the lactone 26 (178 mg, 28%)
as a pale yellow oil (amorphous solid at 258C). Rf¼0.10
(Hex–EtOAc; 3:1); [a]2D5¼258.6 (c¼0.99, CHCl3); nmax
(neat/cm21) 3087, 2933, 2858, 1732, 1601; m/z (CI) 255
(MHþ, 100%), found 255.15981, C14H22O4·H requires
255.15964 (þ0.7 ppm); dH (400 MHz, CDCl3) 1.24 (3H, t,
J¼7.0 Hz, CH3), 1.28–1.37 (6H, m, CH2), 1.39–1.47 (2H, m,
CH2), 1.58–1.80 (4H, m, CH2), 2.28 (2H, t, J¼7.5 Hz, CH2),
4.12 (2H, q, J¼7.0 Hz, CH2), 5.00–5.05 (1H, m, CH), 6.10
(1H, dd, J¼2.0, 5.75 Hz, CH), 7.46 (1H, dd, J¼1.5, 5.75 Hz,
CH);dC (100 MHz, CDCl3) 14.3, 24.85, 24.9, 28.9, 29.0, 29.1,
33.2, 34.3, 60.2, 83.3, 121.6, 156.1, 173.8. HPLC analysis
(Chiralpak AD), Hex–EtOH; 90:10 (1.0 cm3/min): (R)-26
tr¼15.1 min, (S)-26 tr¼19.4 min; 96% e.e.
Acknowledgements
Charterhouse Therapeutics, Oxford are gratefully acknowl-
edged for the provision of a lectureship (P. E). M. L
participated in the project whilst on placement from the
´
Ecole Nationale Superieure de Chemie de Mulhouse
(ENSCMu). Professor Stan Roberts, University of Liver-
pool is thanked for helpful advice and discussions. Mr
Roger Howard and Dr Peter McCormack, University of
Liverpool, are thanked for assistance with HPLC
measurements.
References
1. Kolb, H. C.; VanNiewenhze, M. S.; Sharpless, K. B. Chem.
Rev. 1994, 94, 2483.
2. For one of many examples of dihydroxylation with an a,b-
unsaturated carbonyl compounds see: Wang, Z.-M.; Kolb,
H. C.; Sharpless, K. B. J. Org. Chem. 1994, 59, 5104.
3. (a) Simpkins, N. S. Sulphones in Organic Chemistry;
Pergamon: Oxford, 1993. (b) Simpkins, N. S. Tetrahedron
1990, 46, 6951. (c) Fuchs, P. L.; Braish, T. F. Chem. Rev.
1986, 86, 903.
4. For representative synthetic applications of a-hydroxy alde-
hydes see: (a) Kobori, Y.; Myles, D. C.; Whitesides, G. M.
J. Org. Chem. 1992, 57, 5899. (b) Petasis, N.; Zavialov, I. A.
J. Am. Chem. Soc. 1998, 120, 11798. (c) Ko, K.-Y.; Frazee,
W. J.; Eliel, E. L. Tetrahedron 1984, 40, 1333. (d) Humphrey,
A. J.; Turner, N. J.; McCague, R.; Taylor, S. J. C. J. Chem.
Soc., Chem. Commun. 1995, 2475, and references therein.
5. To the best of our knowledge this type of transformation has
been reported previously on two occasions in the diastreo-
selective dihydroxylation of trisubstituted vinyl sulfones: (a)
Fiegelson, G. B. Tetrahedron Lett. 1998, 39, 3387. (b)
4.1.15. (trans)-4R-Hydroxy-dodec-2-enedioic acid 12-
ethyl ester 1-methyl ester 27. Similarly, re-purification
by flash column chromatography (Hex–EtOAc; 2:1)
afforded the alcohol 27 (91 mg, 13%) as a colourless oil.
Rf¼0.2 (Hex–EtOAc; 2:1); [a]2D5¼216.8 (c¼1.01, CHCl3);
nmax (neat/cm21) 3450, 2933, 2856, 1728, 1659; m/z (CI)
287 (MHþ, 100%), found 287.18630, C15H26O5·H requires
287.18585 (þ1.6 ppm); dH (400 MHz, CDCl3) 1.25 (3H, t,
J¼7.0 Hz, CH3), 1.29–1.70 (12H, m, CH2), 2.28 (2H, t,
J¼7.5 Hz, CH3), 3.75 (3H, s, CH3), 4.13 (2H, q, J¼7.0 Hz,
CH2), 4.26–4.35 (1H, s(br), CH), 6.04 (1H, dd, J¼1.5,
15.75 Hz, CH), 6.95 (1H, dd, J¼5.0, 15.75 Hz, CH); dC
(100 MHz, CDCl3) 14.3, 24.9, 25.1, 29.0, 29.05, 29.2, 34.3,
36.7, 51.6, 60.2, 71.1, 119.8, 150.3, 166.1, 173.8. HPLC
analysis (Whelk), Hex–EtOH; 95:5 (1.0 cm3/min): (S)-27
tr¼20.8 min, (R)-27 tr¼22.3 min; 97% e.e.
¨ ¨
Lofstrom, C. M. G.; Ericsson, A. M.; Bourrinet, L.; Juntunen,
¨
S. K.; Backvall, J.-E. J. Org. Chem. 1995, 60, 3586.
6. (a) Marquis, C.; Picasso, S.; Vogel, P. Synthesis 1999, 1441.
(b) Schaller, C.; Vogel, P. Helv. Chim. Acta 2000, 83, 193. (c)
Trost, B. M.; Pinkerton, A. B. J. Am. Chem. Soc. 2002, 124,
7376.
7. (a) Mizutani, T.; Honzawa, S.; Tosaki, S.; Shibasaki, M.
Angew. Chem., Int. Ed. Engl. 2002, 41, 4680. (b) Dyong, I.;
Meyer, W.; Thiem, J. Liebigs Ann. 1986, 613.
8. Hashiyama, T.; Morikawa, K.; Sharpless, K. B. J. Org. Chem.
1992, 57, 5067.
4.1.16. 8-(5S-Oxo-2,5-dihydrofuran-2-yl)octanoic acid
ethyl ester (maritolide) 26.24 Following the procedure
described above, 25 (850 mg, 2.51 mmol) was treated with
AD mix-a then the phosphonate affording (S)-26 (143 mg,
22%) as a colourless oil. Data as described for (R)-26;
[a]2D5¼þ63.4 (c¼1.02, CHCl3). HPLC analysis (Chiralpak
AD), Hex–EtOH; 90:10 (1.0 cm3/min): (R)-26 tr¼15.1 min,
(S)-26 tr¼19.4 min; 95% e.e.
9. (a) Dupau, P.; Epple, R.; Thomas, A. A.; Fokin, V. V.;
Sharpless, K. B. Adv. Synth. Catal. 2002, 421. (b) Thomas,
A. A.; Sharpless, K. B. J. Org. Chem. 1999, 64, 8379.
10. (a) For a general review see: Chemla, F. J. Chem. Soc., Perkin
Trans. 1 2002, 275 and references therein. (b) Hwu, J. R.
J. Org. Chem. 1983, 48, 4432. (c) Little, R. D.; Myong, S. O.
Tetrahedron Lett. 1980, 21, 3339. (d) for examples of this
method in target synthesis see: Caldwell, J. J.; Craig, D.; East,
S. P. Synlett 2001, 1602. (e) Paquette, L. A.; Barriault, L.;
Pissarnitski, D.; Johnson, J. N. J. Am. Chem. Soc. 2000, 122,
619.
4.1.17. (trans)-4S-Hydroxy-dodec-2-enedioic acid 12-
ethyl ester 1-methyl ester 27. As above, the corresponding
alcohol (S)-27 (97 mg, 13%) was also isolated as a
colourless oil. Data as described for (R)-27; [a]2D5¼þ16.7
(c¼0.96, CHCl3). HPLC analysis (Whelk), Hex–EtOH;
11. Ashwell, M.; Clegg, W.; Jackson, R. F. W. J. Chem. Soc.,
Perkin Trans. 1 1991, 897.
95:5
tr¼22.3 min; 93% e.e.
(1.0 cm3/min):
(S)-27
tr¼20.8 min,
(R)-27
12. Mori, Y.; Yaegashi, K.; Furukawa, H. J. Am. Chem. Soc. 1996,
118, 8158.

P. Evans, M. Leffray / Tetrahedron 59 (2003) 7973–7981
7981
13. Craig, D.; Daniels, K.; MacKenzie, A. R. Tetrahedron 1993,
49, 11263.
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Tetrahedron: Asymmetry 1993, 4, 1397.
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CHCl3), 98% e.e} see: Tsuboi, S.; Sakamoto, J.; Yamashita,
H.; Sakai, T.; Utaka, M. J. Org. Chem. 1998, 63, 1102.
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18. (a) Carter, N. B.; Nadany, A. E.; Sweeney, J. B. J. Chem. Soc.,
Perkin Trans. 1 2002, 2324. (b) Nagao, Y.; Bai, W.-M.;
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references therein.
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2160.
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