A new access to enantiopure syn- and anti-2-methyl-1,3-diol moieties from chiral nonracemic α-bromo α′-sulfinyl ketones promoted by samarium diiodide

Article abstract of DOI:10.1002/ejoc.200500782

syn- and anti-2-Methyl-1,3-diols have been prepared by a two-step sequence that involves a SmI₂-promoted stereoselective Reformatsky addition of chiral nonracemic α-bromo α′-sulfinyl ketones to various aldehydes followed by stereoselective redu

Full text of DOI:10.1002/ejoc.200500782

FULL PAPER
DOI: 10.1002/ejoc.200500782
A New Access to Enantiopure syn- and anti-2-Methyl-1,3-diol Moieties
from Chiral Nonracemic α-Bromo αЈ-Sulfinyl Ketones Promoted by
Samarium Diiodide
Françoise Colobert,*[a] Michel Obringer,[a] and Guy Solladié[a]
Keywords: Asymmetric synthesis / Reformatsky reaction / 2-Methyl-1,3-diol moiety / Sulfoxides / Samarium
syn- and anti-2-Methyl-1,3-diols have been prepared by a
two-step sequence that involves a SmI2-promoted stereose- a boat transition state. Functionalization of the aldehyde and
lective Reformatsky addition of chiral nonracemic α-bromo removal or transformation of the chiral sulfoxide will allow
αЈ-sulfinyl ketones to various aldehydes followed by stereo- this methodology to be applied to the total synthesis of biolo-
The observed stereoselectivities can be explained in terms of
selective reduction of the Reformatsky adduct. The absolute
configuration of the products was determined by comparison
with literature data and by 1H NMR NOESY experiments.
gically active molecules.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2006)
their lower yields and diastereoselectivities.[2] The attain-
ment of high stereoselectivity for this reaction is key to the
further extension of its applicability. To date a few examples
of highly diastereo- and enantioselective Reformatsky reac-
tions have been reported.[3]
Introduction
Reformatsky reactions have been recognized as one of
the most useful methods for the formation of carbon–car-
bon bonds. The scope of the Reformatsky reaction has pro-
gressed over the years and has been the subject of several
Samarium diiodide[4] has shown remarkable versatility in
reviews.[1] The reaction has a broad applicability and a great promoting numerous synthetic transformations with gen-
versatility in both inter- and intramolecular reactions in- erally high chemoselectivity and high levels of stereochemi-
volving a great variety of electrophiles. This reaction is also cal control. The samarium reagent has been used exten-
recognized as being a good alternative to base-induced al- sively and efficiently to promote intramolecular Reformat-
dol reactions, the advantage being that it proceeds under sky reactions to give medium- and large-sized carbo-
neutral conditions. In fact, no base or acid is required to cycles.[3g,5] Its use in intermolecular asymmetric reactions
generate the enolate or activate the electrophile, respectively. has already been reported. Fukuzawa et al.[3b] has described
However, in contrast to the aldol reaction, the most seri- the SmI2-mediated Reformatsky reaction of chiral 3-bro-
ous limitations attributed to Reformatsky reactions are moacetyl-2-oxazolidinones with various aldehydes.
Scheme 1.
Recently we reported on the intermolecular diastereo-
selective Reformatsky reaction of chiral α-bromo αЈ-sulfinyl
ketones and alkyl aldehydes in the presence of SmI2. Up
to 96% syn diastereomeric excess was obtained with linear
[a] Laboratoire de stéréochimie associé au CNRS, Université Louis
Pasteur (ECPM),
25 Rue Becquerel, 67087 Strasbourg, France
Fax: +33-3-90242742
E-mail: fcolober@chimie.u-strasbg.fr
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F. Colobert, M. Obringer, G. Solladié
FULL PAPER
aldehydes.[6] Further reduction of the Reformatsky adducts
furnished anti- and syn-2-methyl-1,3-diol moieties
(Scheme 1).
Results and Discussion
Search for the Optimum Experimental Conditions for the
Reformatsky Reaction between α-Bromo αЈ-Sulfinyl Ketones
and Benzaldehyde
Taking into account our interest in the total synthesis of
biologically active molecules, we report herein our results
as well as the application of this methodology to the Re-
formatsky reaction with various functionalized aldehydes
such as α,β-unsaturated aldehydes, protected α-hydroxy al-
Chiral α-bromo αЈ-sulfinyl ketones were prepared ac-
dehydes, and protected α-keto aldehydes. The absolute con- cording to the procedure of Bravo and Resnati[7]
figurations of the aldol adducts were confirmed by compar- (Scheme 2).
ing the physical data obtained in this work with those of
Treatment of the lithiated anion of (+)-(R)-methyl p-tolyl
1
synthetic intermediates reported in the literature and by H sulfoxide, (–)-(R)-methyl tert-butyl sulfoxide or (+)-(R)-
NMR NOESY experiments. We also propose transition- methyl o-(dimethylamino)phenyl sulfoxide with methyl 2-
state models to rationalize the observed stereochemical out- bromopropionate afforded the α-bromo αЈ-sulfinyl ketones
comes.
1–3 in 92, 95 and 98% yields, respectively.
Scheme 2. Synthesis of the α-bromo αЈ-sulfinyl ketones 1–3.
Scheme 3. Diastereoselective Reformatsky reaction between α-bromo αЈ-sulfinyl ketones 1–3 and aldehydes.
Table 1. Diastereoselective Reformatsky reaction of α-bromo αЈ-sulfinyl ketone 1 with benzaldehyde.[a]
Entry
Salt
T [°C]
syn/anti[b]
syn1/syn2[b]
Yield[c] [%]
1
2
3
4
5
6
7
GeI2/K
room temp.
0
room temp.
–78 Ǟ –10
–78 Ǟ –20
–78
65:35
60:40
40:60
45:55
70:30
70:30
70:30
45:55
55:45
40:60
70:30
45:55
85:15
80:20
15
57
60
55
45
47
47
ZnEt2/RhCl(PPh3)3
CrCl2/LiI
CrCl2
CrCl2/LiI
SmI2
SmI2
–100
[a] Reaction conditions: 1 (1 equiv.), PhCHO (1.1 equiv.), SmI2 (2 equiv.), THF, 30 min. [b] Determined by 1H NMR analysis of the
product. [c] Yield of the isolated mixture of diastereomers.
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Synthesis of Enantiopure syn- and anti-2-Methyl-1,3-diols
Table 2. Diastereoselective Reformatsky reaction of α-bromo αЈ-sulfinyl ketones 1–3 with SmI2 and benzaldehyde.[a]
FULL PAPER
Entry
RЈ
T [°C]
syn/anti[b]
syn1/syn2[b]
anti1/anti2[b]
Yield [%][c]
1
2
3
4
5
pTol
pTol
tBu
tBu
–78
–100
–78
–100
–100
70:30
70:30
75:25
75:25
75:25
85:15
80:20
90:10
96:4
50:50
60:40
70:30
70:30
70:30
47
47
45
51
60
o-Me2NC6H4
96:4
1
[a] Reaction conditions: 1–3 (1 equiv.), PhCHO (1.3 equiv.), SmI2 (2 equiv.), THF, 30 min. [b] Determined by H NMR analysis of the
product. [c] Yield of the isolated mixture of diastereomers.
These enantiomerically pure α-bromo αЈ-sulfinyl ketones 7). Use of activated germanium,[3a] diethylzinc with a rho-
1–3 should be good Reformatsky donors from the view- dium catalyst and chromium dichloride with or without
point of yield and stereoselectivity (Scheme 3).
lithium iodide did not improve the diastereoselectivity of
Initially we studied the reaction of α-bromo αЈ-p-tolylsul- the reaction (Table 1, entries 1–5).
finyl ketone 1 (RЈ = p-Tol) with benzaldehyde using dif-
We then used this activated samarium metal in the Re-
ferent Lewis acids [GeI2/K; ZnEt2/RhCl(PPh3)3; CrCl2/LiI; formatsky reaction between the α-bromo αЈ-sulfinyl ketones
CrCl2; SmI2] (Table 1).
2 and 3, which have a more hindered substituent on the
SmI2 in THF at low temperatures (–78 to –100 °C) was sulfur atom, and benzaldehyde. In fact we observed a higher
found to give the best syn selectivity (Table 1, entries 6 and diastereofacial selectivity with RЈ = tBu and o-Me2NC6H4;
Table 3. Diastereoselective Reformatsky reaction with various aromatic and aliphatic aldehydes.[a]
Entry
RЈ
R
syn/anti[b]
syn1(4a–h)/syn2[b]
Yield [%][c]
1
2
3
4
5
6
7
8
tBu
tBu
tBu
tBu
tBu
tBu
tBu
pTol
Ph
75:25
80:20
90:10
98:2
98:2
98:2
96 (4a):4
80 (4b):20
90 (4c):10
95 (4d):5
95 (4e):5
95 (4f):5
92 (4g):8
85 (4h):15
51 (61)[d]
86
p-O2NC6H4
(CH3)2CHCH2
C2H5
45 (55)[d]
79 (85)[d]
85 (85)[d]
67 (77)[d]
65 (75)[d]
65
n-C3H7
n-C7H15
n-C5H11
n-C5H11
98:2
85:15
1
[a] Reaction conditions: 1 or 2 (1 equiv.), RCHO (1.3 equiv.), SmI2 (2 equiv.), THF, 30 min. [b] Determined by H NMR analysis of the
product. [c] Yield of the isolated mixture of diastereomers. [d] Reaction conditions for yield in parentheses: 1 (2 equiv.), RCHO (1 equiv.),
SmI2 (2 equiv.), THF, 30 min.
Table 4. Correlation of configuration by reductive elimination of sulfoxide.
Entry
R
[α]eDxp.
[α]tDheor.
Configuration
yield [%]
1
2
C2H5
n-C5H11
+45 (c = 1.1, CHCl3)
+26.7 (c = 1.1, CHCl3)
+44 (c = 1.0–1.2, CHCl3)
+26.3 (c = 1.0–1.2, CHCl3)
(+)-(3R,4S)
(+)-(3R,4S)
80
90
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a syn ratio of 96:4 was obtained compared with 80:20 for model in which samarium is chelated to the oxygen of the
p-tolylsulfinyl derivatives at –100 °C (Table 2).
sulfoxide group, the oxygen of the enolate and the oxygen
of the aldehyde.
That is to say, the reduction of 2 with the samarium salt
occurs through coordination models 6 and 7 in which the
samarium interacts with the carbonyl oxygen, bromine and
sulfoxide oxygen atoms. Here, taking into account the non-
binding interaction between the methyl and sulfinyl groups,
7 should be highly preferred over 6 to preferentially give
the (Z)-enolate 8. In the addition to the (Z)-enolate, the
aldehyde approaches from the less hindered face (the sulfox-
ide’s tert-butyl group is at the back) to form a boat transi-
tion state 9 in which the R group of the aldehyde is in a
quasi-equatorial position.
Reformatsky-Type Reaction with Alkyl and Aryl Aldehydes
The addition of α-bromo αЈ-tert-butylsulfinyl ketone 2 to
various aromatic and aliphatic aldehydes was accomplished
under the optimized reaction conditions (Table 3).
Linear aliphatic aldehydes (Table 3, entries 4–7) afforded
Reformatsky adducts 4d–g in moderate-to-good yields with
diastereoselectivities as high as 95:5 for the syn product.
The yields were slightly improved when excess amounts of
α-bromo αЈ-tert-butylsulfinyl ketones 2 (2 equiv. instead of
1 equiv.) were employed. Isovaleraldehyde (Table 3, entry 3)
also served as a viable substrate although a diminished yield
was obtained. The stereoselectivity was lower with p-ni-
trobenzaldehyde than with benzaldehyde (Table 3, entries 1
and 2). In all cases the major diastereomers were easily
purified by chromatography.
Alternatively a coordinated chair structure 10, in agree-
ment with the observed stereoselectivity, would result in the
R group of the aldehyde in an axial position, resulting in
destabilized 1,3-diaxial interactions (Figure 2).
To confirm the strong effect of the tert-butyl group on
the sulfinyl moiety on the diastereofacial selectivity, we car-
ried out the condensation of α-halo αЈ-p-tolylsulfinyl ketone
1 with n-hexanal and found as expected a lower diastereose-
lectivity (syn/anti: 85:15; syn1/syn2: 85:15) (Table 3, en-
try 8).
The absolute stereochemistry of 4d (R = C2H5) and 4g
(R = n-C5H11) was determined after reductive cleavage of
the sulfoxide with aluminium amalgam giving the known
methyl ketones 5d[8] and 5g[8] (Table 4).
To rationalize the observed stereochemical outcomes, we
propose the transition-state models shown in Figure 1.
No attempt has been made to determine the geometry of
Figure 2. Chair transition state of 10.
Boat and twist-boat transition states have been calcu-
the enolate but on the basis of the absolute configuration lated[9] to lie within 1.5 kcal/mol of the more commonly
of the major products, the observed syn/anti selectivity of proposed chair transition states and recently, on the basis
the present Reformatsky reaction can be deduced from the of calculated transition-state energies, Evans et al.[10] have
formation of the (Z)-enolate and the diastereofacial selec- proposed that aldol reactions with thiazolidinethiones pro-
tivity can be explained on the basis of a transition-state ceed via a boat transition state.
Figure 1. Proposed transition-state models for the SmI2-mediated Reformatsky reaction of α-bromo αЈ-sulfinyl ketone 2 and aldehydes.
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Synthesis of Enantiopure syn- and anti-2-Methyl-1,3-diols
FULL PAPER
Reformatsky-Type Reaction with Functionalized Aldehydes
ium amalgam giving the known methyl ketone[11] 14b
(Scheme 4).
Taking into account our interest in total synthesis, we
wanted to extend the scope of the reaction to functionalized
aldehydes.
First, with α,β-unsaturated aldehydes such as acrolein
and trans-2-hexenal, the relative syn selectivity was slightly
lower (Table 5, entries 1 and 2). To improve the relative dia-
stereoselectivity, additives such as Lewis acids, tri-
phenylphosphane or TMEDA were used in the Reformat-
sky reaction with acrolein (Table 5, entries 3–6). Of these
the use of PPh3 slightly increased the relative diastereoselec-
tivity (up to 85:15) but without improving the diastereofa-
cial selectivity.
Scheme 4. Correlation of the configuration of 13b.
Next we turned our attention to the Reformatsky reac-
tion with α-keto aldehydes protected as dioxolane. These
We then studied the Reformatsky reaction with protected aldehydes were synthesized starting from dimethyl tartrate
α-hydroxylated aldehydes. Excellent diastereoselectivities using known methodologies.
were obtained with α-hydroxylated aldehydes protected
Protection of dimethyl tartrate as acetonide with dimeth-
with a tert-butyldimethylsilyl or benzyl group (Table 6, en- oxypropane in the presence of p-toluenesulfonic acid fol-
tries 1–4). However, low yields were obtained whatever the lowed by treatment with N-methylmethoxyhydroxylamine
reaction time (Table 6, entries 2 and 4). Protection with and an excess of AlMe3 afforded the bis-Weinreb amide[12]
MEM gave similar results (Table 6, entry 5).
16 in 72% overall yield. Amide 16 reacted with an excess
The absolute configuration of 13b (P = Bn) was deter- of phenylmagnesium bromide in THF to afford the 1,4-di-
mined after reductive cleavage of the sulfoxide with alumin- ketone 17a in 47% yield (unoptimized), whereas alkyl deriv-
Table 5. Diastereoselective Reformatsky reaction with α,β-insaturated aldehydes with or without additives.[a]
Entry
R
Additives (equiv.)
syn/anti[a]
syn1/syn2[b]
yield [%][c]
1
2
3
4
5
6
H
n-C3H7
H
H
H
H
–
–
70:30
45:55
76:24
60:40
85:15
67:33
84:16
80:20
85:15
60:40
80:20
82:18
59
77
68
59
56
27
BF3–Et2O (3)
Et2AlCl (3)
PPh3 (1)
TMEDA (1)
[a] Reaction conditions: 2 (1 equiv.), RCHO (3 equiv.), SmI2 (2 equiv.), THF, 30 min. [b] Determined by 1H NMR analysis of the product.
[c] Yield of the isolated mixture of diastereomers.
Table 6. Diastereoselective Reformatsky reaction with protected α-hydroxylated aldehydes.[a]
Entry
P
Time [min]
syn/anti[b]
syn1 (13a–c)/syn2[b]
Yield [%][c]
1
2
3
4
5
TBDMS
TBDMS
Bn
Bn
MEM
20
180
20
240
30
98:2
98:2
98:2
92 (13a):8
92 (13a):8
92 (13b):8
92 (13b):8
90 (13c):10[d]
40
37
30
50
50
98:2
90:10[d]
[a] Reaction conditions: 2 (1 equiv.), RCHO (3 equiv.), SmI2 (2 equiv.), THF. [b] Determined by 1H NMR analysis of the product. [c] Yield
1
of the isolated mixture of diastereomers. [d] Determined after irradiations by H NMR 400 MHz.
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F. Colobert, M. Obringer, G. Solladié
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ative 17b was obtained from 16 by treatment with n-heptyl- gave high diastereofacial selectivity but poor syn/anti selec-
magnesium bromide in THF in 78% yield. Derivatives tivity (Table 7, entry 1).
17a,b were submitted to acetal hydrolysis in the presence of
trifluoroacetic acid and water to give 18a,b in excellent
yields. An attempt to oxidatively cleave 18a with either
Synthesis of the syn- or anti-2-Methyl-1,3-diols
NaIO4 or Pb(OAc)4 did not succeed. We then protected the
In order to obtain the syn- or anti-2-methyl-1,3-diol moi-
carbonyl functions as dioxolane to afford 19a,b which were eties we performed the well-known diastereoselective re-
then oxidatively cleaved with Pb(OAc)4 in CH2Cl2 to give duction of the β-keto sulfoxides[14,15] obtained in the Re-
the desired protected α-keto aldehydes 20a,b in good formatsky reactions either with only DIBALH or with DI-
yields.[13] These aldehydes were directly used without fur- BALH in the presence of a Lewis acid.
ther purification in the Reformatsky-type reaction
(Scheme 5).
Starting from the adduct 4d (obtained by Reformatsky
condensation with propanal) the syn-2-methyl-1,3-diol 22
We applied our SmI2-promoted Reformatsky-type reac- was obtained in excellent yield and diastereoselectivity in
tion to the aldehydes 20a,b. Excellent diastereoselectivity the presence of DIBALH (Table 8, entry 1).
and a good yield were obtained with aldehyde 20b (Table 7,
In order to obtain the anti-2-methyl-1,3-diol 23 we
entry 2). Surprisingly, aldehyde 20a with a phenyl group studied the reduction of 4d in the presence of DIBALH
Scheme 5. Synthesis of the protected α-keto aldehydes.
Table 7. Diastereoselective Reformatsky reaction with protected α-keto aldehydes.[a]
Entry
R
syn/anti[a]
syn1/syn2[b]
anti1/anti2[b]
Yield [%][c]
1
2
C6H5
n-C7H15
63:37
92:8
21a Ͼ99:1
21b Ͼ99:1
Ͼ99:1
Ͼ99:1
67
73
[a] Reaction conditions: 2 (1 equiv.), RCHO (1.3 equiv.), SmI2 (2 equiv.), THF, 30 min. [b] Determined by 1H NMR analysis of the
product. [c] Yield of the isolated mixture of diastereomers.
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Synthesis of Enantiopure syn- and anti-2-Methyl-1,3-diols
Table 8. Reduction of β-keto sulfoxide 4d.
FULL PAPER
Entry
Reductant (equiv.)
Configuration
de [%][a]
Yield [%][b]
1
2
3
4
5
6
DIBALH (2.4)
S (diol syn)
R (diol anti)
R (diol anti)
R (diol anti)
R (diol anti)
R (diol anti)
Ͼ98
10
40
60
90
22 90
23 85
23 86
23 83
23 81
23 85
DIBALH (4)/ZnCl2 (2.4)
DIBALH (4)/ZnBr2 (2.4)
DIBALH (4)/ZnI2 (2.4)
DIBALH (4)/Yb(OTf)3 (2.4)
DIBALH (2.4)/Yb(OTf)3 (1.2)
90
1
[a] Determined by H NMR analysis of the product. [b] Yield of the isolated mixture of diastereomers.
and a Lewis acid. Use of 2.4 equivalents of zinc halide with
The (S) absolute configuration at the formed hydroxylic
4 equivalents of DIBALH afforded the anti-2-methyl-1,3- carbon of 22 as well as the (R) absolute configuration at C-
diol 23 in good yield but modest selectivity (60% de with 2 of 23 could be deduced not only from the mechanism
ZnI2) (Table 8, entries 2–4). The best results were obtained already published for the reduction of such β-keto sulfox-
1
in the presence of Yb(OTf)3 (1.2 equiv.) and DIBALH ides[15] but also from the H NMR spectra of the products.
(2.4 equiv.); a 95:5 mixture of the two possible dia- From numerous reported examples of the reduction of β-
stereomeric carbinols was obtained from which the major keto sulfoxides, a noticeable difference in the nonequiva-
compound bearing the (R) absolute configuration at the lence of the methylene hydrogen atoms α to the sulfoxide of
newly created stereogenic center could be isolated after the (S,RS) and (R,RS) epimers has been observed. For the
flash chromatography of the corresponding acetonide 24 (2S,3R,4S,RS)-22 configuration, the ∆υ value for these two
(Scheme 6).
hydrogen atoms is larger (∆υ = 79 Hz in 22) than that for
these hydrogen atoms in (2R,3R,4S,RS)-23 (∆υ = 50 Hz in
23).
The anti relative configuration of the diol in compound
24 was ascertained from the small nonequivalence of the
two methyl groups of the acetonide observed in the 13C
NMR spectrum: δ = 24.0 and 24.9 ppm.[16] Typical values
for the syn-diol acetonide methyl groups are δ = 20.0 and
30.2 ppm.[17] Furthermore the (2R,3R,4S,RS) relative con-
Scheme 6.
Scheme 7.
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F. Colobert, M. Obringer, G. Solladié
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1
2 equiv.) was added to a solution of diisopropylamine (5.25 mmol,
2.1 equiv.) in THF (5 mL) at –78 °C. After 1 h at –78 °C, a solution
of sulfoxide (5.00 mmol, 2 equiv.) in THF (5 mL) was added to the
lithium diisopropylamide at –78 °C. The mixture was stirred under
these conditions for 1 h. Then methyl 2-bromopropionate
(2.50 mmol, 1 equiv.) in THF (5 mL) was added at –78 °C to the
lithiated sulfoxide anion. The resulting solution was stirred at –
78 °C for 30 min. The solution was quenched with a saturated
NH4Cl solution (10 mL) and additional water. The reaction mix-
ture was extracted with CH2Cl2 (3×50 mL) and the combined or-
figuration of 24 was confirmed by H NMR NOESY ex-
periments.
The efficacy of this methodology was then checked with
the Reformatsky adduct 21b in which the carbonyl func-
tionality is protected as a dioxolane.
Treatment of 21b with DIBALH afforded the corre-
sponding syn-2-methyl-1,3-diol 25b in an excellent yield and
with a diastereoselectivity of up to 85%. The major dia-
stereomer, which has the (S) absolute configuration at the
newly created stereogenic center, was isolated after flash ganic extracts were dried with MgSO4, filtered and concentrated
under reduced pressure. The crude product was purified by flash
chromatography over silica gel.
chromatography of the corresponding acetonide 26b
(Scheme 7). The absolute configuration (2S,3R,4R,RS) of
the major compound 26b was confirmed by 1H NMR spec-
(RS)-3-Bromo-1-(p-totylsulfinyl)butan-2-one (1): A mixture of two
diastereomers. Yellow solid (92% yield); Rf = 0.3 and 0.4 (hexane/
1
tra and H NMR NOESY experiments.
EtOAc, 1:1). IR (neat): ν = 3044–2861, 1717, 1492, 1442, 1354,
˜
When DIBALH with Yb(OTf)3 was used to reduce the
adduct 21b compound (2R,3R,4R,RS)-27b was obtained as
the major diastereomer (de Ͼ 85%).
1
1260, 1081, 1045, 1023, 1014, 971, 795 cm–1. H NMR (300 MHz,
CDCl3): δ = 7.47 and 7.42 (A2B2, JAB = 8.1 Hz, ∆ν = 63.9 and
41.2 Hz, 4 H, HpTol), 4.42 and 4.43 (q, J = 6.7 Hz, 1 H, CHBr), 4.07
and 4.13 [AB, JAB = 13.8 and 13.4 Hz, ∆ν = 102.5 and 161.9 Hz, 2
H, CH2S(O)], 2.44 and 2.43 (s, 3 H, CH3,pTol), 1,70 and 1,63 (d, J
= 6.7 Hz, 3 H, CHBrCH3) ppm. 13C NMR (75 MHz, CDCl3): δ =
195.1 (C=O), 194.4 (C=O), 142.5 (CpTol), 142,4 (CpTol), 139,9
(CpTol), 138,8 (CpTol), 130,3 (CHpTol), 130,2 (CHpTol), 124,0
(CHpTol ×2), 65.9 [CH2S(O)], 63.5 [CH2S(O)], 48.5 (CHBr), 48.4
(CHBr), 21.5 (CH3,pTol ×2), 19.0 [CH(Br)CH3], 18.9 [CH(Br)
CH3] ppm.
Conclusions
This new methodology constitutes an efficient access to
enantiomerically pure syn- and anti-2-methyl-1,3-diols
using an asymmetric Reformatsky-type reaction followed
by diastereoselective reduction of the β-keto sulfoxide. Re-
formatsky adducts were obtained in good yields with both
high syn/anti and diastereofacial selectivities. A boat transi-
tion state has been proposed to explain the observed stereo-
selectivities. Extension of this study to α-functionalized al-
dehydes as well as to substrates with a sulfinyl group has
allowed the synthesis of important precursors for total syn-
thesis.
(RS)-3-Bromo-1-(tert-butylsulfinyl)butan-2-one (2): A mixture of
two diastereomers. Yellow solid (95% yield); Rf = 0.40 (EtOAc).
IR (neat): ν = 2991–2865, 1716, 1469, 1374, 1364, 1267, 1177, 1060,
˜
1
1030, 1020, 983 cm–1. H NMR (300 MHz, CDCl3): δ = 4.67 and
4.63 (q, J = 6.6 Hz, 1 H, CHBr), 3.85 and 3.77 [AB, JAB = 13.7
and 12.5 Hz, ∆ν = 71 and 81.5 Hz, 2 H, CH2S(O)], 1.81 and 1.77
[d, J = 6.6 Hz, 3 H, CH(Br)CH3], 1.30 (s, 9 H, tBu) ppm. 13C NMR
(75 MHz, CDCl3): δ = 196.8 (C=O), 196.4 (C=O), 55.1 [CH2S(O)],
55.0 [C(CH3)3], 54.9 [C(CH3)3], 54.3 [CH2S(O)], 48.9 (CHBr), 47.7
(CHBr), 22.8 [C(CH3)3], 22.6 [C(CH3)3], 19.5 [CH(Br)CH3], 19.0
[CH(Br)CH3] ppm.
Experimental Section
General Remarks: THF and diethyl ether were freshly distilled un-
der nitrogen from sodium benzophenone ketyl immediately before
use. All aldehydes were also freshly distilled according to the usual
protocol[18] and stored under nitrogen. Diisopropylamine was dis-
tilled from calcium hydride and stored over potassium hydroxide.
All other reagents and solvents were used as received from commer-
cial sources. Moisture-sensitive reactions were conducted in oven-
or flame-dried glassware under argon. Sulfoxides were prepared ac-
cording to literature procedures.[19] All reactions were magnetically
stirred and monitored by thin-layer chromatography using pre-
coated silica gel (60 F254) plates. Column chromatography was car-
ried out with the indicated solvents on silica gel 60 (40–63 µm,
Merck) or on unmetalled silica gel. NMR spectra were recorded at
room temperature using CDCl3 (δ = 7.26 ppm) as the reference
(Bruker AC-200, Bruker Avance 300 and Bruker Avance 400 spec-
trometers, 1H at 200, 300 and 400 MHz and 13C at 50, 75 and
100 MHz, respectively). All chemical shifts (δ) are quoted in parts
per million (ppm) and coupling constants (J) in Hertz. 13C chemi-
cal shifts are referenced to CDCl3 (δ = 77.0 ppm). Melting points
were obtained on a Büchi 535 apparatus. Optical rotations were
determined from a Perkin–Elmer 241 MC polarimeter operating at
the sodium D line at 20 °C. IR spectra were recorded using a Per-
(RS)-3-Bromo-1-[o-(dimethylamino)phenylsulfinyl]butan-2-one (3): A
mixture of two diastereomers. Yellow solid (98% yield); Rf = 0.32
and 0.45 (hexane/EtOAc, 1:1). IR (neat): ν = 2998–2796, 1720,
˜
1588, 1475, 1451, 1432, 1371, 1316, 1260, 1154, 1129, 1058, 1045,
1
1027, 979, 940, 875, 764, 724 cm–1. H NMR (200 MHz, CDCl3):
δ = 7.85 and 7.72 (dd, 1 H, J = 7.6 and 1.5 Hz, HAr), 7.48 (td, J =
7.6 and 1.5 Hz, 1 H, HAr), 7.32 and 7.30 (td, J = 7.6 and 1.2 Hz,
1 H, HAr), 7.18 and 7.20 (dd, J = 7.9 and 1.1 Hz, 1 H, HAr), 4.23
and 4.65 (q, J = 6.8 Hz, 1 H, CHBr), 4.24 and 4.32 (AB, JAB
=
13.2 and 13.0 Hz, ∆ν = 40.3 and 152.2 Hz, 2 H, CH2), 2.75 and
2.72 [s, 6 H, N(CH3)2], 1.69 and 1.56 (d, J = 6.6 Hz, 3 H, H3) ppm.
13C NMR (75 MHz, CDCl3): δ = 195.2 (C=O), 194.8 (C=O), 151.0
(CAr), 150.7 (CAr), 136.2 (CAr ×2), 132.3 (CHAr), 132.2 (CHAr),
124.9 (CHAr ×3), 124.8 (CHAr), 120.6 (CHAr), 120.1 (CHAr), 62.1
[CH2S(O)], 59.2 [CH2S(O)], 48.7 (CHBr), 48.5 (CHBr), 44.8
[N(CH3)2], 19.2 [CH(Br)CH3], 18.7 [CH(Br)CH3] ppm.
General Procedure for the Samarium(II) Iodide Mediated Reformat-
sky-Type Reaction: The following is a description of a typical ex-
perimental procedure for the Reformatsky-type reaction of a chiral
γ-bromo-β-keto sulfoxide with an aldehyde (only the major syn dia-
stereomer is described).
kin–Elmer Spectum One spectrometer; ν values are given in cm–1.
˜
A solution of SmI2, prepared by the addition of diiodomethane
(0.78 mmol, 2 equiv.) in THF (8 mL) to samarium powder
(0.86 mmol, 2.2 equiv.), was stirred at room temperature for 2 h.
General Procedure for the Preparation of α-Bromo αЈ-Sulfinyl
Ketones 1–3: A solution of nBuLi (1.6  in hexane) (5.00 mmol,
1462
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© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2006, 1455–1467

Synthesis of Enantiopure syn- and anti-2-Methyl-1,3-diols
FULL PAPER
The solution was cooled to –78 °C and a solution of γ-bromo-β-
keto sulfoxide (0.39 mmol, 1 equiv.) in THF (1.5 mL) was added
dropwise. The mixture was stirred under these conditions for
10 min. A solution of aldehyde (0.51 mmol, 1.3 equiv.) in THF
(1.5 mL) was then added at –78 °C. The resulting mixture was
stirred at –78 °C for 30 min. The solution was quenched with a
0.1  hydrochloric acid solution (30 mL) and brine (20 mL). The
reaction mixture was extracted with diethyl ether (3×40 mL). The
organic phase was washed with aqueous sodium thiosulfate
(50 mL) to remove liberated iodine and brine (2×50 mL) and then
dried with MgSO4, filtered and concentrated under reduced pres-
sure. The residue was purified by unmetalled silica gel chromatog-
raphy.
(+)-(3R,4S,RS)-1-(tert-Butylsulfinyl)-4-hydroxy-3-methylnonan-2-
one (4g): Yellow oil (75% yield); Rf = 0.2 (CH2Cl2/EtOAc, 7:3).
[α]2D0 = +145 (c = 1, CHCl ). IR (neat): ν = 3382, 2957–2861, 1713,
˜
3
1463, 1368, 1256, 1178, 1143, 1032, 935 cm–1. 1H NMR (200 MHz,
CDCl3): δ = 4.13–4.02 (m, 1 H, CHOH), 3.65 [AB, JAB = 12.6 Hz,
∆ν = 112.7 Hz, 2 H, CH2S(O)], 3.25 (d, J = 5.1 Hz, 1 H, OH), 2.86
(qd, J = 7.0, 3.0 Hz, 1 H, CHCH3), 1.55–1.35 [m, 8 H, (CH2)4CH3],
1.29 (s, 9 H, tBu), 1.11 (d, J = 6.7 Hz, 3 H, CHCH3), 0.88 (t, J =
6.5 Hz, 3 H, CH2CH3) ppm. 13C NMR (75 MHz, CDCl3): δ =
206.9 (C=O), 71.0 (CHOH), 56.2 [CH2S(O)], 54.3 [C(CH3)3], 53.7
(CHCH3), 33.4 (CH2CHOH), 31.7 (CH2), 25.9 (CH2), 22.7
[C(CH3)3], 22.6 (CH2), 14.0 (CHCH3), 8.9 [(CH2)4CH3] ppm.
C14H28O3S (276.44): C 60.83, H 10.21; found C 60.91, H 10.30.
(3R,4S,RS)-1-(tert-Butylsulfinyl)-4-hydroxy-3,6-dimethylheptan-2-
one (4c): Yellow oil (55% yield); Rf = 0.20 (CH2Cl2/EtOAc, 1:1).
1H NMR (400 MHz, CDCl3, major diastereomer): δ = 4.15 (d, J
= 9.2 Hz, 1 H, CHOH), 3.64 [AB, JAB = 12.8 Hz, ∆ν = 210.8 Hz,
2 H, CH2S(O)], 3.20 (br. s, 1 H, OH), 2.83 (qd, J = 7.0, 3.0 Hz, 1
H, CHCH3), 1.80–1.70 [m, 1 H, CH(CH3)2], 1.48–1.41 and 1.17–
1.11 [m, AB part of ABXM, 2 H, CH2CH(CH3)2], 1.27 (s, 9 H,
tBu), 1.09 (d, J = 6.8 Hz, 3 H, CHCH3), 0.91 and 0.89 [d, J =
6.6 Hz, 3 H, CH(CH3)2] ppm.
(3R,4S,RS)-4-Hydroxy-3-methyl-1-(p-tolylsulfinyl)nonan-2-one (4h):
White solid (65% yield); Rf = 0.33 (CH2Cl2/EtOAc, 7:3). IR (neat):
ν = 3371, 3010–2857, 1693, 1455, 1252, 1106, 1083, 1035, 1003,
˜
1
931, 803 cm–1. H NMR (300 MHz, CDCl3): δ = 7.45 (A2B2, JAB
= 8.1 Hz, ∆ν = 61.6 Hz, 4 H, CHpTol), 4.07–4.00 (m, 1 H, CHOH),
3.95 [AB, JAB = 13.7 Hz, ∆ν = 88.8 Hz, 2 H, CH2S(O)], 2.83 (d, J
= 4.7 Hz, 1 H, OH), 2.68 (qd, J = 7.0, 3.0 Hz, 1 H, CHCH3), 2.43
(s, 3 H, CH3,pTol), 1.53–1.20 [m, 8 H, (CH2)4CH3], 1.02 (d, J =
7.0 Hz, 3 H, CHCH3), 0.88 (t, J = 6.8 Hz, 3 H, CH2CH3) ppm. 13
C
NMR (75 MHz, CDCl3): δ = 205.5 (C=O), 142.3 (CpTol), 139.5
(CpTol), 130.2 (CHpTol), 124.0 (CHpTol), 71.0 (CHOH), 67.3
[CH2S(O)], 53.1 (CHCH3), 33.6 (CH2CHOH), 31.7 (CH2), 25.8
(CH2), 22.6 (CH2), 21.4 (CH3,pTol), 14.0 (CHCH3), 8.7 [(CH2)
4CH3] ppm. C17H26O3S (310.46): C 65.77, H 8.44; found C 66.17,
H 8.38.
(+)-(3R,4S,RS)-1-(tert-Butylsulfinyl)-4-hydroxy-3-methylhexan-2-
one (4d): Yellow oil (85% yield); Rf = 0.10 (CH2Cl2/EtOAc, 1:1).
[α]2D0 = +190 (c = 1, CHCl ). IR (neat): ν = 3405, 2980–2871, 1706,
˜
3
1462, 1364, 1357, 1140, 1077, 1038, 1028, 1007, 962, 935 cm–1. H
1
NMR (300 MHz, CDCl3): δ = 4.04–3.94 (m, 1 H, CHOH), 3.65
[AB, JAB = 12.8 Hz, ∆ν = 173.3 Hz, 2 H, CH2S(O)], 3.18 (d, J =
5.3 Hz, 1 H, OH), 2.89 (qd, J = 7.0, 3.0 Hz, 1 H, CHCH3), 1.60–
1.40 (m, 2 H, CH2CH3), 1.30 (s, 9 H, tBu), 1.12 (d, J = 7.0 Hz, 3
(+)-(3R,4R,RS)-5-(tert-Butyldimethylsilyloxy)-1-(tert-butylsulfinyl)-
4-hydroxy-3-methylpentan-2-one (13a): Pale yellow oil (40% yield);
H, CHCH3), 0.98 (t, J = 7.3 Hz, 3 H, CH2CH3) ppm. 13C NMR Rf = 0.25 (CH2Cl2/EtOAc, 7:3). [α]2D0 = +92.8 (c = 0.5, CHCl3). IR
(75 MHz, CDCl3): δ = 207.0 (C=O), 72.5 (CHOH), 56.2 (neat): ν = 3352, 2956–2858, 1713, 1472, 1463, 1365, 1255, 1122,
˜
1
[CH2S(O)], 54.4 [C(CH3)3], 53.5 (CHCH3), 26.4 (CH2CH3), 22.8 1040, 1008, 838, 778 cm–1. H NMR (300 MHz, CDCl3): δ = 4.17
[C(CH3)3], 10.7 (CHCH3), 8.9 (CH2CH3) ppm. C11H22O3S (td, J = 6.4, 4.0 Hz, 1 H, CHOH), 3.67 [AB, JAB = 13.0 Hz, ∆ν =
(234.36): C 56.38, H 9.46; found C 55.89, H 9.51.
86.3 Hz, 2 H, CH2S(O)], 3.61 (AB part of ABX, JAB = 10.2, JAX
= 6.4, JBX = 6.4 Hz, ∆ν = 16.1 Hz, 2 H, CH2CHOH), 3.00 (qd, J
= 7.0, 4.0 Hz, 1 H, CHCH3), 1.30 [s, 9 H, S(O)tBu], 1.11 (d, J =
7.0 Hz, 3 H, CHCH3), 0.90 (s, 9 H,SitBu), 0.08 [s, 6 H, Si(CH3)
2] ppm. 13C NMR (75 MHz, CDCl3): δ = 205.7 (C=O), 70.7
(CHOH), 63.8 (CH2CHOH), 56.6 [CH2S(O)], 54.3 [S(O)C(CH3)3],
50.3 (CHCH3), 25.9 [Si-C(CH3)3], 22.8 [S(O)C(CH3)3], 18.2 [Si-
C(CH3)3], 9.2 (CHCH3), –5.4 (Si-CH3), –5.5 (Si-CH3) ppm.
(+)-(3R,4S,RS)-1-(tert-Butylsulfinyl)-4-hydroxy-3-methylheptan-2-
one (4e): Yellow oil (85% yield); Rf = 0.2 (CH2Cl2/EtOAc, 1:1).
[α]2D0 = +175 (c = 1, CHCl ). IR (neat): ν = 3391, 2960–2873, 1713,
˜
3
1463, 1368, 1258, 1178, 1144, 1028, 968 cm–1. 1H NMR (300 MHz,
CDCl3): δ = 4.11–4.01 (m, 1 H, CHOH), 3.64 [AB, JAB = 12.8 Hz,
∆ν = 158.4 Hz, 2 H, CH2S(O)], 3.25 (d, J = 5.3 Hz, 1 H, OH), 2.84
(qd, J = 7.0, 3.0 Hz, 1 H, CHCH3 ), 1.56–1.30 (m, 4 H,
CH2CH2CH3), 1.27 (s, 9 H, tBu), 1.09 (d, J = 7.0 Hz, 3 H,
(+)-(3R,4R,RS)-5-Benzyloxy-1-(tert-butylsulfinyl)-4-hydroxy-3-meth-
CHCH3), 0.91 (t, J = 7.3 Hz, 3 H, CH2CH3) ppm. 13C NMR ylpentan-2-one (13b): White solid (50% yield); Rf = 0.20 (EtOAc);
(75 MHz, CDCl3): δ = 206.8 (C=O), 70.7 (CHOH), 56.2 m.p. 48 °C. [α]2D0 = +121 (c = 0.5, CHCl ). IR (neat): ν = 3351,
˜
3
[CH2S(O)], 54.3 [C(CH3)3], 53.7 (CHCH3), 35.6 (CH2CHOH), 22.7 3089–2869, 1711, 1455, 1367, 1256, 1177, 1102, 1029, 1012, 741,
[C(CH3)3], 19.4 (CH2CH3), 13.9 (CHCH3), 9.0 [(CH2)2CH3] ppm. 700 cm–1. 1H NMR (300 MHz, CDCl3): δ = 7.40–7.28 (m, 5 H,
C12H24O3S (248.39): C 58.03, H 9.74; found C 58.17, H 9.93.
C6H5), 4,54 (AB, JAB = 11.9 Hz, ∆ν = 12.9 Hz, 2 H, CH2Ar), 4.34
(td, J = 5.9, 4.1 Hz, 1 H, CHOH), 3.64 [AB, JAB = 13.0 Hz, ∆ν =
109.0 Hz, 2 H, CH2S(O)], 3.53 (AB part of ABX, JAB = 9.5, JAX
= 6.3, JBX = 5,8 Hz, ∆ν = 16.7 Hz, 2 H, CH2CHOH), 3.01 (qd, J
= 6.8, 4.1 Hz, 1 H, CHCH3), 2.87 (s, 1 H, OH), 1.28 (s, 9 H, tBu),
1.15 (d, J = 7.5 Hz, 3 H, CHCH3) ppm. 13C NMR (75 MHz,
CDCl3): δ = 202.7 (C=O), 137.8 (CIV-Ar), 128.4 (CIII-Ar), 127.9
(CIII-Ar), 127.8 (CIII-Ar), 73.5 (CH2-O), 71.1 (CH2-O), 69.6
(CHOH), 56.5 [CH2S(O)], 54.3 [C(CH3)3], 50.9 (CHCH3), 22.8
[C(CH3)3], 9.5 (CHCH3) ppm. C17H26O4S (326.46): C 62.55, H
8.03; found C 62.75, H 8.09.
(+)-(3R,4S,RS)-1-(tert-Butylsulfinyl)-4-hydroxy-3-methylundecan-2-
one (4f): Yellow oil (77% yield); Rf = 0.25 (CH2Cl2/EtOAc, 1:1).
[α]2D0 = +130 (c = 1, CHCl ). IR (neat): ν = 3370, 2956–2856, 1701,
˜
3
1465, 1366, 1248, 1232, 1178, 1144, 1113, 1016, 997, 958 cm–1. H
1
NMR (300 MHz, CDCl3): δ = 4.11–4.03 (m, 1 H, CHOH), 3.64
[AB, JAB = 12.6 Hz, ∆ν = 166.5 Hz, 2 H, CH2S(O)], 3.18 (d, J =
5.3 Hz, 1 H, OH), 2.86 (qd, J = 7.0, 3.0 Hz, 1 H, CHCH3), 1.56–
1.20 [m, 12 H, (CH2)6CH3], 1.29 (s, 9 H, tBu), 1.11 (d, J = 7.0 Hz,
3 H, CHCH3), 0.87 (t, J = 6.6 Hz, 3 H, CH2CH3) ppm. 13C NMR
(75 MHz, CDCl3): δ = 206.9 (C=O), 71.0 (CHOH), 56.2
[CH2S(O)], 54.4 [C(CH3)3], 53.7 (CHCH3), 33.5 (CH2), 31.8 (CH2), (3R,4R,RS)-1-(tert-Butylsulfinyl)-4-hydroxy-5-(methoxyethoxymeth-
29.5 (CH2), 29.2 (CH2), 26.3 (CH2), 22.8 [C(CH3)3], 22.6 (CH2), yl)-3-methylpentan-2-one (13c): Pale yellow oil (50% yield); Rf =
14.1 (CHCH3), 8.9 [(CH2)6CH3] ppm. C16H32O3S (304.49): C 0.13 (EtOAc/MeOH, 95:5). IR (neat): ν = 3351, 3089–2869, 1711,
˜
1
63.11, H 10.59; found C 63.25, H 10.71.
1455, 1367, 1256, 1177, 1102, 1029, 1012, 741, 700 cm–1. H NMR
Eur. J. Org. Chem. 2006, 1455–1467
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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1463

F. Colobert, M. Obringer, G. Solladié
FULL PAPER
(300 MHz, CDCl3): δ = 4,74 (s, 2 H, O-CH2-O), 4.26 (m, 1 H, (75 MHz, CDCl3): δ = 213.8 (C=O), 72.4 (CHOH), 50.4 (CHCH3),
CHOH), 3.75–3.54 (m, 6 H, O-CH2CH2-O and O-CH2CHOH), 29.1 (COCH3), 26.9 (CH2CH3), 10.4 (CH3), 9.5 (CH3) ppm.
3.68 [AB, JAB = 13.2 Hz, ∆ν = 88.8 Hz, 2 H, CH2S(O)], 3.39 (s, 3
(+)-[3R,4S]-4-Hydroxy-3-methylnonan-2-one (5g): Colorless liquid
H, OCH3), 3.00 (qd, J = 7.0, 4.1 Hz, 1 H, CHCH3), 1.30 (s, 9 H,
(90% yield); Rf = 0.20 (hexane/EtOAc, 8:2). [α]2D0 = +26.3 (c = 1.1,
tBu), 1.18 (d, J = 7.0 Hz, 3 H, CHCH3) ppm. 13C NMR (75 MHz,
CHCl3), {ref.[8] [α]2D0 = +26.7 (c = 1.0–1.2, CHCl3)}. 1H NMR
CDCl3): δ = 205.6 (C=O), 96.1 (O-CH2-O), 71.8 (CH2-O), 70.0
(200 MHz, CDCl3): δ = 3.98–3.90 (m, 1 H, CHOH), 2.56 (qd, J =
(CHOH), 69.9 (CH2-O), 67.3 (CH2-O), 59.0 (O-CH3), 56.9
7.3, 3.0 Hz, 1 H, CHCH3), 2.19 (s, 3 H, COCH3), 2.13–2.03 (m, 1
[CH2S(O)], 54.4 [C(CH3)3], 50.7 (CHCH3), 22.8 [C(CH3)3], 9.9
H, OH), 1.55–1.23 [m, 8 H, (CH2)4CH3], 1.14 (d, J = 7.3 Hz, 3
(CHCH3) ppm.
H, CHCH3), 0.88 (t, J = 6.6 Hz, 3 H, CH2CH3) ppm. 13C NMR
(100 MHz, CDCl3): δ = 213.1 (C=O), 71.0 (CHOH), 51.0
(CHCH3), 34.2 (CH2), 32.0 (CH2), 29.4 (COCH3), 25.9 (CH2), 22.6
(CH2), 14.3 (CHCH3), 10.0 [(CH2)4CH3] ppm.
1-(tert-Butylsulfinyl)-4-hydroxy-3-methyl-4-(2-phenyl-[1,3]dioxolan-
2-yl)butan-2-one (21a): A mixture of two diastereomers syn (A) and
anti (B)]. White solid (67% yield); Rf = 0.18 (AcOEt). 1H NMR
(300 MHz, CDCl3): δ = 7.50–7.33 (m, 5 H, CHAr A and B), 4.29
(d, J = 6.0 Hz, 1 H, CHOH A), 4.16–4.02 and 3.86–3.77 (m, 4 H,
OCH2CH2O A and B), 3.93 (d, J = 4.2 Hz, 1 H, CHOH B), 3.64
[AB, JAB = 18.6 Hz, ∆ν = 27.6 Hz, 2 H, CH2S(O) B], 3.55 [s, 2 H,
CH2S(O) A], 2.96 (qd, J = 7.2 and 4.2 Hz, 1 H, CHCH3 B), 2.85
(qt, J = 7.2 Hz, 1 H, CHCH3 A), 2.03 (s, 1 H, OH), 1.29 (s, 9 H,
tBu B), 1.26 (s, 9 H, tBu A), 1.22 (d, J = 7.2 Hz, 3 H, CHCH3 A),
1.21 (d, J = 7.2 Hz, 3 H, CHCH3 B) ppm. 13C NMR (75 MHz,
CDCl3): δ = 206.5 (C=O B), 204.1 (C=O A), 139.3 (CIV-Ar A), 139.0
(CIV-Ar B), 128.7 (CIII-Ar A), 128.6 (CIII-Ar B), 128.3 (CIII-Ar A),
128.2 (CIII-Ar B), 126.5 (CIII-Ar A), 126.4 (CIII-Ar B), 110.0
[C(OCH2-)2 A and B], 78.8 (CHOH B), 75.0 (CHOH A), 65.5 and
64.5 (O-CH2CH2-O A), 65.1 and 65.0 (O-CH2CH2-O B), 59.0
[CH2S(O) B], 57.3 [CH2S(O) A], 54.1 [C(CH3)3 A], 53.8 [C(CH3)3
B], 48.6 (CHCH3 A), 46.3 (CHCH3 B), 22.9 [C(CH3)3 B], 22.8
[C(CH3)3 A], 14.7 (CHCH3 B), 11.5 (CHCH3 A) ppm. C18H26O5S
(354.47): C 60.99, H 7.39; found C 60.67, H 7.25.
(+)-[3R,4R]-5-Benzyloxy-4-hydroxy-3-methylpentan-2-one (14b):
Colorless liquid (96% yield); Rf = 0.43 (CH2Cl2/Et2O, 7:3). [α]2D0
=
+4.6 (c = 1.0, CHCl3), {ref.[11] [α]2D0 = +4.7 (c = 0.99, CHCl3).} IR
(neat): ν = 3345, 3089–2966, 1705, 1455, 1360, 1094, 1028, 741,
˜
699 cm–1. 1H NMR (300 MHz, CDCl3): δ = 7.39–7.26 (m, 5 H,
HAr), 4.54 (s, 2 H, CH2C6H5), 4.12 (dt, J = 6.4, 5.0 Hz, 1 H,
CHOH), 3.47 (AB part of ABX, JAB = 9.4, JAX = 5.0, JBX
=
6.4 Hz, ∆ν = 15.3 Hz, 2 H, CH2CHOH), 2.76 (qd, J = 7.2, 5.0 Hz,
1 H, CHCH3), 2.70 (br. s, 1 H, OH), 2.19 (s, 3 H, COCH3), 1.16
(d, J = 7.3 Hz, 3 H, CHCH3) ppm. 13C NMR (75 MHz, CDCl3):
δ = 212.3 (C=O), 137.8 (CAr), 128.4 (CAr), 127.8 (CAr ×2), 73.4
(CH2-O), 71.6 (CH2-O), 70.3 (CHOH), 48.6 (CHCH3), 29.3
(COCH3), 11.1 (CHCH3) ppm.
General Procedure for the Diastereoselective Reduction of the Re-
formatsky-Type Reaction Adduct: The following is a description of
a typical experimental procedure for the diastereoselective re-
duction of the Reformatsky adduct with DIBALH.
(3R,4R,RS)-1-(tert-Butylsulfinyl)-5,5-ethylenedioxy-4-hydroxy-3-
methyldodecan-2-one (21b): Pale yellow oil (73% yield); Rf = 0.16
A solution of the β-keto sulfoxide (0.307 mmol, 1 equiv.) in THF
(6 mL) was cooled to –78 °C and a solution of DIBALH
(0.737 mmol, 2.4 equiv.) in hexane was added dropwise. The mix-
ture was stirred under these conditions for 30 min. The solvent was
removed in vacuo and the residue was dissolved in ethyl acetate
(10 mL) and a saturated disodium -tartrate solution (10 mL). The
mixture was stirred overnight and extracted with ethyl acetate
(3×10 mL). The organic phases were dried with magnesium sulfate,
filtered and concentrated under reduced pressure. The residue was
purified by unmetalled silica gel chromatography (EtOAc/MeOH,
98:2).
(CH Cl /AcOEt, 4:1). IR (neat): ν = 3391, 2931–2820, 1713, 1463,
˜
2
2
1368, 1251, 1176, 1117, 1040, 849 cm–1 1H NMR (300 MHz,
.
CDCl3): δ = 4.02–3.86 (m, 4 H, O-CH2-CH2-O), 3.93 (d, J =
10.4 Hz, 1 H, CHOH), 3.58 [AB, JAB = 21.4 Hz, ∆ν = 16.3 Hz, 2
H, CH2S(O)], 2.89 (qt, J = 10.4 Hz, 1 H, CHCH3), 2.24 (br. s, 1
H, OH) 1.87–1.54 [m, 2 H, CH2(CH2)5CH3], 1.43–1.13 [m, 10 H,
CH2(CH2)5CH3], 1.29 (s, 9 H, tBu), 1.27 (d, J = 10.4 Hz, 3 H,
CHCH3), 0.88 [t, J = 9.9 Hz, 3 H, CH2(CH2)5CH3] ppm. 13C NMR
(75 MHz, CDCl3): δ = 204.1 (C=O), 111.5 [C(OCH2)2], 74.4
(CHOH), 65.5 (O-CH2CH2-O), 65.3 (O-CH2CH2-O), 57.6
[CH2S(O)], 54.1 [C(CH3)3], 48.7 (CHCH3), 33.7 (CH2), 31.8 (CH2),
29.8 (CH2), 29.3 (CH2), 22.8 [C(CH3)3], 22.9 (CH2), 22.6 (CH2),
14.1 (CHCH3), 12.6 [(CH2)6CH3] ppm.
(+)-(2S,3R,4S,RS)-1-(tert-Butylsulfinyl)-3-methylhexane-2,4-diol
(22): Orange oil. (90% yield); Rf = 0.65 (EtOAc/MeOH, 90:10).
[α]2D0 = +35.5 (c = 1, CHCl ). IR (neat): ν = 3480, 2972–2879, 1463,
˜
3
1399, 1368, 1285, 1180, 1142, 1113, 1050, 1015, 970, 805 cm–1. H
1
General Procedure for the Reductive Elimination of the Reformatsky-
Type Reaction Product: The following is a description of a typical
experimental procedure for sulfoxide reductive cleavage.
NMR (300 MHz, CDCl3): δ = 4.69 (m, 1 H, OH), 4.39 (m, 1 H,
CHOH), 3.80 (m, 1 H, CHOH), 3.65 (m, 1 H, OH), 2.55 [AB part
of ABX, JAB = 12.4, JAX = 10.2, JBX = 2.3 Hz, ∆ν = 79.2 Hz, 2
H, CH2S(O)], 1.73–1.35 (m, 3 H, CHCH3 and CH2CH3), 1.42 (s,
9 H, tBu), 0.95 (d, J = 7.1 Hz, 3 H, CHCH3), 0.93 (t, J = 7.3 Hz,
3 H, CH2CH3) ppm. 13C NMR (75 MHz, CDCl3): δ = 76.6
(CHOH), 69.8 (CHOH), 59.7 [C(CH3)3], 50.4 [CH2S(O)], 41.2
(CHCH3), 27.8 (CH2CH3), 23.2 [C(CH3)3], 10.4 [CHCH3], 5.5
[CH2CH3] ppm.
Small fractions of aluminium amalgam made from aluminium foils
(35.00 mmol, 100 equiv.) were added to a solution of the Reformat-
sky-type reaction product (0.35 mmol, 1 equiv.) dissolved in THF
(27 mL) and water (3 mL), the temperature being maintained be-
tween 15 and 20 °C. The mixture was stirred under these conditions
for 1 h, filtered through Celite, washed with diethyl ether, dried
with Na2SO4 and concentrated under reduced pressure. The residue
was purified by unmetalled silica gel chromatography.
(+)-(2S,3R,4R,RS)-1-(tert-Butylsulfinyl)-5,5-ethylenedioxy-3-methyl-
(+)-(3R,4S)-4-Hydroxy-3-methylhexan-2-one (5d): Colorless liquid dodecane-2,4-diol (25b): Pale yellow oil (85 % yield); Rf = 0.20
(80% yield); Rf = 0.30 (hexane/EtOAc, 8:2). [α]2D0 = +45 (c = 1.1,
CHCl3) {ref.[8] [α]2D0 = +44 (c = 1.0–1.2, CHCl3)}. 1H NMR
(300 MHz, CDCl3): δ = 3.88–3.81 (m, 1 H, CHOH), 2.65 (br. s, 1
H, OH), 2.58 (qd, J = 7.2, 3.0 Hz, 1 H, CHCH3), 2.20 (s, 3 H,
COCH3), 1.59–1.31 (m, 2 H, CH2CH3), 1.13 (d, J = 7.2 Hz, 3 H,
(EtOAc/MeOH, 95:5). [α]2D0 = +79.4 (c = 1.0, CHCl ). IR (neat): ν
˜
3
= 3383, 2955–2854, 1463, 1377, 1177, 1034 cm–1 1H NMR
.
(300 MHz, CDCl3 ): δ = 4.42 (dt, J = 12.4, 2.1 Hz, 1 H,
CH2CHOH), 4.08–3.92 (m, 4 H, O-CH2CH2-O), 3.88 (d, J =
2.1 Hz, 1 H, CHOH), 3.64 (br. s, 1 H, OH), 2.62 (br. s, 1 H, OH),
CHCH3), 0.94 (t, J = 7.5 Hz, 3 H, CH2CH3) ppm. 13C NMR 2.59 (AB part of ABX, JAB = 12.4, JAX = 10.4, JBX = 2.1 Hz, ∆ν
1464
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© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2006, 1455–1467

Synthesis of Enantiopure syn- and anti-2-Methyl-1,3-diols
FULL PAPER
= 83.0 Hz, 2 H, CH2CHOH), 1.96–1.87 (m, 1 H, CHCH3), 1.77– (+)-(2R,3R,4S,RS)-1-(tert-Butylsulfinyl)-2,4-(isopropylidenedioxy)-
1.52 [m, 2 H, CH2(CH2)5CH3], 1.43–1.10 [m, 10 H, CH2(CH2)5- 3-methylhexane (24): Pale yellow oil (88% yield); Rf = 0.25 (pure
CH3], 1.27 (s, 9 H, tBu), 1.07 (d, J = 7.0 Hz, 3 H, CHCH3), 0.89 EtOAc). [α]2D0 = +109.0 (c = 1, CHCl ). IR (neat): ν = 2966–2877,
˜
3
[t, J = 7.0 Hz, 3 H, (CH2)6CH3] ppm. 13C NMR (75 MHz, CDCl3):
1462, 1380, 1226, 1177, 1151, 1041, 993 cm–1. 1H NMR (300 MHz,
δ = 112.1 [C(OCH2)2], 77.0 (CHOH), 69.9 (CH2CHOH), 66.2 (O- CDCl3): δ = 3.84–3.75 (m, 2 H, CHOH×2), 2.75 [AB part of ABX,
CH2CH2-O), 65.6 (O-CH2CH2-O), 52.7 [C(CH3)3], 50.6 [CH2S(O)],
JAB = 13.2, JAX = 6.6, JBX = 5.4 Hz, ∆ν = 45.2 Hz, 2 H, CH2S(O)],
38.6 (CHCH3), 34.7 (CH2), 32.8 (CH2), 29.9 (CH2), 29.2 (CH2), 2.05 (qtd, J = 6.6, 4.8 Hz, 1 H, CHCH3), 1.53–1.34 (m, 2 H,
23.0 (CH2), 22.9 [C(CH3)3], 22.6 (CH2), 14.1 (CHCH3), 7.2 CH2CH3), 1.39 [s, 3 H, C(CH3)2], 1.37 [s, 3 H, C(CH3)2], 1.28 (s, 9
[(CH2)6CH3] ppm.
H, tBu), 0.98 (d, J = 6.6 Hz, 3 H, CHCH3), 0.95 (t, J = 7.2 Hz, 3
H, CH2CH3) ppm. 13C NMR (75 MHz, CDCl3): δ = 101.1 [C-
(CH3)2], 71.2 (CHORЈ), 70.7 (CHORЈ), 53.3 [C(CH3)3], 52.2
[CH2S(O)], 38.9 (CHCH3), 24.9 [C(CH3)2], 24.0 [C(CH3)2], 23.4
(CH2CH3), 22.8 [C(CH3)3], 11.9 (CH3), 10.5 (CH3) ppm.
Typical Experimental Procedure for the Diastereoselective Reduction
of the Reformatsky Adduct with DIBALH in the Presence of
Yb(OTf)3: A solution of the β-keto sulfoxide (0.306 mmol, 1 equiv.)
in THF (4 mL) was added to a solution of Yb(OTf)3 (0.368 mmol,
1.2 equiv.) in THF (4 mL) at 0 °C. The mixture was stirred for
15 min at 0 °C and then cooled to –78 °C. A solution of DIBALH
(0.735 mmol, 2.4 equiv.) in hexane was then added dropwise. The
mixture was stirred at –78 °C for 30 min. The solvent was removed
in vacuo and the residue was dissolved in ethyl acetate (10 mL) and
a saturated disodium -tartrate solution (10 mL). The mixture was
stirred overnight and extracted with ethyl acetate (3×10 mL). The
organic phases were dried with magnesium sulfate, filtered and con-
centrated under reduced pressure. The residue was purified by un-
metalled silica gel chromatography (AcOEt/MeOH, 98:2).
(+)-(2S,3R,4R,RS)-1-(tert-Butylsulfinyl)-5,5-ethylenedioxy-2,4-(iso-
propylidenedioxy)-3-methyldodecane (26b): Obtained as the product
of the protection of the syn-1,3-diol 25b with an acetonide. White
solid (85% yield); Rf = 0.30 (pure EtOAc); m.p. 63–64 °C. [α]2D0
=
+95.2 (c = 1, CHCl ). IR (neat): ν = 2981–2853, 1465, 1389, 1379,
˜
3
1261, 1205, 1158, 1136, 1067, 1030, 1012, 957, 941, 905 cm–1. 1H
NMR (300 MHz, CDCl3): δ = 4.44 [dt, J = 10.4, 2.1 Hz, 1 H,
CHCH2S(O)], 4.09–3.84 (m, 4 H, O-CH2CH2-O), 3.99 (d, J =
2.1 Hz, 1 H, CHORЈ), 2.47 [AB part of ABX, JAB = 12.4, JAX
=
10.4, JBX = 2.1 Hz, ∆ν = 83.0 Hz, 2 H, CH2S(O)], 1.67–1.53 (m, 1
H, CHCH3), 1.48 [s, 3 H, C(CH3)2], 1.43 [s, 3 H, C(CH3)2], 1.45–
1.18 [m, 12 H, (CH2)6CH3], 1.26 (s, 9 H, tBu), 1.04 (d, J = 6.8 Hz,
3 H, CHCH3), 0.89 (t, J = 6.4 Hz, 3 H, CH2CH3) ppm. 13C NMR
(75 MHz, CDCl3): δ = 110.8 [C(OCH2)2], 99.6 [C(CH3)2], 77.5
(CHORЈ), 67.9 [CHCH2S(O)], 66.6 (O-CH2CH2-O), 65.8 (O-
CH2CH2-O), 52.6 [C(CH3)3], 49.7 [CH2S(O)], 35.1 (CH2), 33.6
(CHCH3), 31.8 (CH2), 29.9 (CH2), 29.8 [C(CH3)2], 29.3 (CH2), 22.8
[C(CH3)3], 22.7 (CH2), 22.6 (CH2), 19.4 [C(CH3)2], 14.1 (CHCH3),
6.6 (CH2CH3) ppm.
(+)-(2R,3R,4S,RS)-1-(tert-Butylsulfinyl)-3-methylhexane-2,4-diol
(23): Orange solid (85% yield); Rf = 0.40 (EtOAc/MeOH, 90:10).
[α]2D0 = +30.0 (c = 1, CHCl ). IR (neat): ν = 3434, 3256, 2977–2878,
˜
3
1462, 1366, 1253, 1176, 1130, 1053, 1038, 1022, 1003, 981, 964,
938 cm–1. 1H NMR (300 MHz, CDCl3): δ = 4.88 (m, 1 H, OH),
4.34 (m, 1 H, CHOH), 3.81 (m, 1 H, CHOH), 3.19 (m, 1 H, OH),
2.68 [AB part of ABX, JAB = 12.8, JAX = 9.1, JBX = 2.6 Hz, ∆ν =
49.8 Hz, 2 H, CH2S(O)], 1.77–1.33 (m, 3 H, CHCH3 and
CH2CH3), 1.26 (s, 9 H, tBu), 0.98 (d, J = 7.0 Hz, 3 H, CHCH3),
0.95 (t, J = 7.3 Hz, 3 H, CH2CH3) ppm. 13C NMR (75 MHz,
CDCl3): δ = 73.4 (CHOH), 73.1 (CHOH), 53.9 [C(CH3)3], 47.0
[CH2S(O)], 42.2 (CHCH3), 26.8 (CH2CH3), 22.5 [C(CH3)3], 10.8
(CH3), 10.7 (CH3) ppm. C11H24O3S (236.38): C 55.90, H 10.23;
found C 55.80, H 10.21.
Synthesis of Glyoxal-Derived Aldehydes: The following is a descrip-
tion of a typical experimental procedure for the synthesis of the
aldehydes 20a and 20b.
(+)-(9R,10R)-9,10-(Isopropylidenedioxy)octadecane-8,11-dione
(17b): A solution of heptyl bromide (4.43 mL, 28.20 mmol,
4.1 equiv.) in Et2O (25 mL) was slowly added to magnesium turn-
ings (669 mg, 27.51 mmol, 4.0 equiv.) recovered by Et2O (2 mL).
At the end of the addition, the mixture was refluxed for 30 min
and then allowed to cool to room temperature. The mixture was
added dropwise to a solution of the bis-Weinreb amide 16[20]
(1.90 g, 6.88 mmol, 1 equiv.) in THF (55 mL) cooled to –10 °C. Af-
ter 15 min at –10 °C, the reaction was quenched with saturated
NH4Cl and the mixture acidified with 10% HCl and extracted with
EtOAc (3×40 mL). The combined organic extracts were washed
with brine, dried with magnesium sulfate, filtered and concentrated
under reduced pressure. The residue was purified by silica gel
chromatography (hexane/EtOAc, 9:1, Rf = 0.45) to give pure 17b
in 78% yield (1.91 g, 5.38 mmol). Colorless liquid. [α]2D0 = +4.7 (c
(2R,3R,4R,RS)-1-(tert-Butylsulfinyl)-5,5-ethylenedioxy-3-methyldo-
decane-2,4-diol (27b): Pale yellow solid (80% yield); Rf = 0.12 (pure
1
EtOAc). H NMR (300 MHz, CDCl3): δ = 5.08 (br. s, 1 H, OH),
4.37–4.28 (m, 1 H, CH2CHOH), 4.10–3.92 (m, 4 H, O-CH2CH2-
O), 3.94–3.92 (m, 1 H, CHOH), 3.13 (br. s, 1 H, OH), 2.76 (AB
part of ABX, JAB = 13.0, JAX = 10.0, JBX = 1.9 Hz, ∆ν = 57.9 Hz,
2 H, CH2CHOH), 2.02–1.94 (m, 1 H, CHCH3), 1.77–1.50 [m, 2 H,
CH2(CH2)5CH3], 1.42–1.10 [m, 10 H, CH2(CH2)5CH3], 1.27 (s, 9
H, tBu), 1.10 (d, J = 7.2 Hz, 3 H, CHCH3), 0.87 [t, J = 6.6 Hz, 3
H, (CH2)6CH3] ppm. 13C NMR (75 MHz, CDCl3): δ = 112.3
[C(OCH2)2], 73.3 (CHOH), 73.0 (CHOH), 66.3 (O-CH2CH2-O),
65.5 (O-CH2CH2-O), 54.0 [C(CH3)3], 47.4 [CH2S(O)], 39.2
(CHCH3), 34.8 (CH2), 31.8 (CH2), 29.9 (CH2), 29.3 (CH2), 23.0
(CH2), 22.7 [C(CH3)3], 22.6 (CH2), 14.1 (CHCH3), 10.0 [(CH2)6-
CH3] ppm.
= 1, CHCl ). IR (neat): ν = 2990–2857, 1727, 1463, 1404, 1375,
˜
3
1260, 1211, 1153, 1081, 862 cm–1. H NMR (300 MHz, CDCl3): δ
1
= 4.55 (s, 2 H, CHORЈ), 2.73–2.56 [AB part of ABMN, 2nd order,
4 H, CH2(CH2)5CH3], 1.67–1.52 (m, 4 H, CH2), 1.43 [s, 6 H,
C(CH3)2], 1.34–1.24 [m, 16 H, (CH2)4CH3], 0.88 [t, J = 7.2 Hz, 6
H, (CH2)6CH3] ppm. 13C NMR (75 MHz, CDCl3): δ = 208.7
(C=O), 112.4 [C(CH3)2], 81.5 (CHORЈ), 39.1 (CH2), 31.6 (CH2),
29.1 (CH2), 29.0 (CH2), 26.2 [C(CH3)2], 23.1 (CH2), 22.6 (CH2),
14.0 (CH3) ppm. C21H38O4 (354.53): C 71.15, H 10.80; found C
71.15, H 10.62.
General Procedure for the Acetonide Protection of the 1,3-Diol: The
following is a description of a typical experimental procedure for
the acetonide protection of a syn- or anti-1,3-diol.
A catalytic quantity of pTsOH (0.09 mmol, 0.1 equiv.) was added
to a solution of the 1,3-diol (0.90 mmol, 1 equiv.) in 2,2-dimethoxy-
propane (2 mL). The mixture was stirred for 45 min at room tem-
perature, diluted with Et2O (4 mL) and washed with a saturated
solution of NaHCO3 (5 mL). The organic phase was dried with
magnesium sulfate, filtered and concentrated under reduced pres-
sure. The residue was purified by silica gel chromatography.
(–)-(2R,3R)-2,3-(Isopropylidenedioxy)-1,4-diphenylbutane-1,4-dione
(17a): Obtained by the addition of 4 equiv. of PhMgBr to the bis-
Eur. J. Org. Chem. 2006, 1455–1467
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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1465

F. Colobert, M. Obringer, G. Solladié
FULL PAPER
Weinreb amide 16. White solid (47% yield, unoptimized); Rf = 0.20
(CH2)5CH3], 1.48–1.20 [m, 20 H, (CH2)5CH3], 0.90 [t, J = 6.6 Hz,
6 H, (CH2)6CH3] ppm. 13C NMR (75 MHz, CDCl3): δ = 112.4
[C(OCH2)2], 71.0 (CHOH), 65.9 (O-CH2CH2-O), 65.7 (O-
CH2CH2-O), 34.4 (CH2), 31.8 (CH2), 29.8 (CH2), 29.3 (CH2), 23.0
(CH2), 22.6 (CH2), 14.1 (CH3) ppm.
(cyclohexane/CH2Cl2, 1:1); m.p. 51 °C. [α]2D0 = –78.7 (c = 1, CHCl3).
IR (neat): ν = 3058–2932, 1679, 1597, 1580, 1449, 1376, 1319, 1281,
˜
1242, 1206, 1143, 1091, 1003, 831, 773, 703, 685, 657 cm–1 1H
.
NMR (300 MHz, CDCl3): δ = 8.12 (d, J = 7.2 Hz, 4 H, CHAr),
7.61 (t, J = 7.2 Hz, 2 H, CHAr), 7.49 (t, J = 7.2 Hz, 4 H, CHAr),
4.85 (s, 2 H, CHORЈ), 1.44 [s, 6 H, C(CH3)2] ppm. 13C NMR
(75 MHz, CDCl3): δ = 196.3 (C=O), 134.8 (CAr), 133.8 (CHAr),
129.5 (CHAr), 128.6 (CHAr), 113.3 [C(CH3)2], 79.0 (CHORЈ), 26.7
[C(CH3)2] ppm.
(–)-(1R,2R)-1,2-Bis(2-phenyl-1,3-dioxolan-2-yl)ethane-1,2-diol
(19a): Obtained by ethylene ketal protection of the dione 18a.
White solid (58% yield, unoptimized); Rf = 0.13 (CH2Cl2/Et2O,
4:1); m.p. 196 °C. [α]2D0 = –18.1 (c = 1, CHCl ). IR (neat): ν = 3524,
˜
3
3062–2886, 1447, 1217, 1169, 1130, 1074, 1040, 1024, 997, 941, 877,
1
771, 701 cm–1. H NMR (200 MHz, CDCl3): δ = 7.41–7.27 (m, 10
(–)-(9R,10R)-9,10-Dihydroxyoctadecane-8,11-dione (18b): A mix-
ture of trifluoroacetic acid/water (9:1, v/v) (13 mL) was added to
17b (2.50 g, 7.06 mmol, 1 equiv.) cooled to 0 °C. After storage of
the mixture at this temperature for 2 h, the aqueous acid was re-
moved under reduced pressure and the residue was triturated with
Et2O (5 mL). The supernatant liquid was removed by means of a
Pasteur pipette. The remaining solid was washed with diethyl ether
(3×3 mL), leaving a crystalline solid, the major portion of the hy-
drolysis product 18b. The ethereal supernatant liquid and the wash-
ings were combined, concentrated under reduced pressure, and the
residue thus obtained triturated and washed with diethyl ether in
a similar manner to that used for the initial residue to afford a
second crystalline portion of the hydrolysis product 18b. The two
portions were combined to obtain pure 18b in 83% yield (1.84 g,
5.85 mmol). White solid; Rf = 0.30 (hexane/EtOAc, 8:2); m.p. 98–
H, CHAr), 4.18–3.72 (m, 8 H, O-CH2CH2-O), 4.04 (s, 2 H, CHOH),
3.30 (s, 2 H, CHOH) ppm. 13C NMR (75 MHz, CDCl3): δ = 139.1
(CAr), 128.6 (CHAr), 128.1 (CHAr), 126.3 (CHAr), 110.7 [C(OCH2)
2], 72.0 (CHOH), 65.5 (O-CH2CH2-O), 64.7 (O-CH2CH2-O) ppm.
C20H22O6 (358.39): C 67.03, H 6.19; found C 67.15, H 6.04.
[1] a) A. Fürstner, Synthesis 1989, 571–590; b) M. W. Rathke, P.
Weipert, in Comprehensive Organic Synthesis (Eds.: B. M.
Trost, I. Fleming), Pergamon Press, New York, 1991, vol. 2,
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9325–9374.
[2] J. P. Guette, in Organometaliques Fonct, Ambidents, Recl. Com-
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1980, pp. 123–129.
100 °C. [α]2D0 = –72 (c = 1, CHCl ). IR (neat): ν = 3434, 2953–2850,
˜
3
1717, 1690, 1469, 1399, 1376, 1276, 1158, 1124, 1103, 1082,
1
1049 cm–1. H NMR (300 MHz, CDCl3): δ = 4.56 (d, J = 6.5 Hz,
[3] a) H. Kagoshima, Y. Hashimoto, D. Oguro, K. Saigo, J. Org.
Chem. 1998, 63, 691–697; b) S.-I. Fukuzawa, H. Matsuzawa,
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K. Soai, A. Oshio, T. Saito, J. Chem. Soc., Chem. Commun.
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G. A. Molander, C. R. Harris, Chem. Rev. 1996, 96, 307–338;
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2 H, CHOH), 3.68 (d, J = 6.5 Hz, 2 H, CHOH), 2.73–2.51 [AB
part of ABMN, 2nd order, 4 H, CH2(CH2)5CH3], 1.75–1.64 (m, 4
H, CH2), 1.40–1.25 [m, 16 H, (CH2)4CH3], 0.88 [t, J = 6.9 Hz, 6
H, (CH2)6CH3] ppm. 13C NMR (75 MHz, CDCl3): δ = 207.8
(C=O), 77.0 (CHOH), 38.0 (CH2), 31.6 (CH2), 29.1 (CH2), 29.0
(CH2), 23.4 (CH2), 22.6 (CH2), 14.0 (CH3) ppm. C18H34O4
(314.47): C 68.75, H 10.90; found C 68.67, H 10.87.
(–)-(2R,3R)-2,3-Dihydroxy-1,4-diphenylbutane-1,4-dione (18a): Ob-
tained by the hydrolysis of the acetonide function of 17a. White
solid (88% yield); Rf = 0.40 (CH2Cl2/EtOAc, 9:1); m.p. 148–150 °C.
[α]2D0 = –191.5 (c = 1, CHCl ). IR (neat): ν = 3452, 1677, 1595,
˜
3
1452, 1397, 1310, 1244, 1115, 1080, 966, 793, 746, 692, 666 cm–1.
1H NMR (300 MHz, CDCl3): δ = 8.00 (br. d, J = 7.0 Hz, 4 H,
CHAr), 7.72 (t, J = 7.3 Hz, 2 H, CHAr), 7.49 (t, J = 7.2 Hz, 4 H,
CHAr), 5.39 (d, J = 7.5 Hz, 2 H, CHOH), 3.93 (d, J = 7.5 Hz, 2
H, CHOH) ppm. 13C NMR (75 MHz, CDCl3): δ = 197.6 (C=O),
134.2 (CHAr), 133.8 (CAr), 129.2 (CHAr), 128.3 (CHAr), 74.7
(CHOH) ppm. C16H14O4 (270.28): C 71.10, H 5.22; found C 70.82,
H 5.34.
(–)-(1R,2R)-1,2-Bis(2-heptyl-1,3-dioxolan-2-yl)ethane-1,2-diol (19b):
A solution of the diketone 18b (1.26 g, 4.02 mmol, 1 equiv.),
pTsOH (77 mg, 0.40 mmol, 0.1 equiv.) and ethylene glycol
(0.68 mL, 12.06 mmol, 3 equiv.) in benzene (40 mL) was refluxed
for 16 h in a Dean–Stark trap. Benzene was then removed by evapo-
ration and the crude product was diluted in AcOEt (40 mL),
washed with saturated NaHCO3 (20 mL) and water (20 mL), dried
with magnesium sulfate, filtered and concentrated under reduced
pressure. The residue was purified by silica gel chromatography (pe-
troleum ether/EtOAc, 1:1, Rf = 0.40) to obtain pure 19b in 74%
yield (1.20 g, 2.98 mmol). White solid; m.p. 47 °C. [α]2D0 = –3.8 (c =
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1, CHCl ). IR (neat): ν = 3436, 2956–2853, 1468, 1395, 1379, 1215,
˜
3
1161, 1105, 1031, 951, 891, 790, 726, 686 cm–1 1H NMR
.
(300 MHz, CDCl3): δ = 4.13–3.99 (m, 8 H, O-CH2CH2-O), 3.86 (s,
2 H, CHOH), 2.03 (s, 2 H, CHOH), 1.87–1.57 [m, 4 H, CH2
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Synthesis of Enantiopure syn- and anti-2-Methyl-1,3-diols
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Received: October 9, 2005
Published Online: December 30, 2005
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