Asymmetric synthesis of (S,S)- and (R,R)-2-methylthreitol

Article abstract of DOI:10.1055/s-2007-965967

The asymmetric synthesis of (S,S)- and (R,R)-2-methylthreitol was carried out, starting from the SAMP or RAMP hydrazone of 2,2-dimethyl-1,3-dioxan-5-one. The protocol involves an enantioselective α-alkylation as a key step. The second stereogenic center was installed by either nucleophilic 1,2-addition or diastereoselective epoxidation with bis(acetylacetonato)oxovanadium(IV) [VO(acac)₂] as catalyst. The title compounds were obtained in excellent diastereo- and enantiomeric excesses (≥98% de, 98% ee) and in good overall yields (40-61%). Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2007-965967

PAPER
1021
Asymmetric Synthesis of (S,S)- and (R,R)-2-Methylthreitol
A
symmetric Synth
i
esis of
e
(
S
,
S
)- and
t
R
,
R
)
-2-
e
M
ethylthre
r
itol Enders,* Evelyn Peiffer, Gerhard Raabe
Institut für Organische Chemie, RWTH Aachen, Landoltweg 1, 52074 Aachen, Germany
Fax +49(241)8092127; E-mail: enders@rwth-aachen.de
Received 24 January 2007
SAMP-derived hydrazone (S)-2, easily obtained in multi-
gram quantities by condensation of the chiral auxiliary
SAMP and the corresponding dioxanone,8,9 was metalated
with tert-butyllithium, and the azaenolate was trapped
Abstract: The asymmetric synthesis of (S,S)- and (R,R)-2-meth-
ylthreitol was carried out, starting from the SAMP or RAMP hydra-
zone of 2,2-dimethyl-1,3-dioxan-5-one. The protocol involves an
enantioselective a-alkylation as a key step. The second stereogenic
center was installed by either nucleophilic 1,2-addition or diastereo- with (benzyloxy)methyl chloride (BOMCl) (Scheme 2).
Acidic hydrazone cleavage10 gave the a-[(benzyloxy)meth-
selective epoxidation with bis(acetylacetonato)oxovanadium(IV)
[VO(acac)2] as catalyst. The title compounds were obtained in ex-
yl]-substituted dioxanone (S)-3, obtained in 48% yield
cellent diastereo- and enantiomeric excesses (≥98% de, 98% ee)
over two steps. Dioxanone (S)-3 was obtained in 98% ee
and in good overall yields (40–61%).
(determined by CSP-GC analysis), indicating that the hy-
Key words: asymmetric synthesis, epoxidation, tetrols, a-alkyla-
tion, SAMP/RAMP hydrazones, 1,2-addition
drazone alkylation occurred with virtually complete
asymmetric induction and that the auxiliary was removed
without any racemization. Next, ketone (S)-3 was reacted
with methyllithium to afford the tertiary alcohol (S,S)-4
(+)-2-Methylerythritol plays an important role in the me-
(Scheme 2), thus introducing the second and contiguous
valonate-free, methylerythritol phosphate (MEP) pathway
quaternary stereocenter. The nucleophilic 1,2-addition
for the biosynthesis of terpenoids in algae, plant chloro-
proceeded in good diastereoselectivity (84% de) and un-
plasts, and Gram-negative bacteria.1 This could be a start-
der optimized reaction conditions in 87% yield. The major
diastereomer (S,S)-4 could be efficiently separated (in
≥98% de) from its diastereomeric impurity by preparative
HPLC. Finally, two deprotection steps were performed to
obtain (S,S)-2-methylthreitol [(S,S)-1] (Scheme 2). The
acetonide function was hydrolyzed under acidic condi-
ing point for the development of new microbe-inhibiting
drugs.2,3 Up to now the effect of the other stereoisomers
on the MEP pathway are unknown. In addition, the tetrols
occur in the atmosphere, mainly above the rainforest,
where they act as condensation nuclei and scatter sun-
light.4 They arise by photooxidation of isoprene, leading
tions and the benzyloxy group was removed by hydro-
to a mixture of all four stereoisomers. Up to now only (+)-
genolysis, to afford the title compound almost
2-methylerythritol3,5 and (+)-2-methylthreitol3 have been
quantitatively over these two steps.
synthesized by asymmetric synthesis with moderate enan-
tiomeric excess. Very recently, a chemo-enzymatic syn-
H3CO
thesis of all four isomers was published.6
N
O
N
We envisaged a new diastereo- and enantioselective route
to both enantiomers of the title 2-methylthreitol (1) based
on a-hydroxymethylation of the SAMP- or RAMP-de-
rived hydrazone of 2,2-dimethyl-1,3-dioxan-5-one [(S)-
or (R)-2]7 and a nucleophilic 1,2-addition to generate the
quaternary stereocenter as key steps (Scheme 1).
a,b
O
48%
(2 steps)
O
O
O
O
H3C CH3
(S)-3 (ee ≥ 98%)
H3C CH3
(S)-2
H3CO
c
87%
O
41%
H3C
5 steps
N
N
H3C
O
OH
H3C
OH
OH
d,e
OH
O
O
OH
O
99%
α-hydroxymethylation,
nucleophilic 1,2-addition
OH OH
(2 steps)
OH OH
(S,S)-1 (de, ee ≥ 98%)
H3C CH3
H3C CH3
(S,S)-4
(S,S)-1
(S)-2
[(R,R)-1]
[(R)-2]
Scheme
2
Asymmetric synthesis of (S,S)-2-methylthreitol.
Reagents and conditions: (a) 1. t-BuLi, THF, –78 °C, 2. BOMCl,
–100 °C to r.t.; (b) sat. aq oxalic acid, Et2O, r.t.; (c) 1. MeLi, THF,
–90 °C, 2. epimer separation (HPLC); (d) H+, MeOH, r.t.; (e) Pd/C,
H2, MeOH, r.t.
Scheme 1 Retrosynthetic analysis for 2-methylthreitol
SYNTHESIS 2007, No. 7, pp 1021–1026
x
x
.
x
x
.2
0
0
7
Advanced online publication: 28.02.2007
DOI: 10.1055/s-2007-965967; Art ID: Z02307SS
© Georg Thieme Verlag Stuttgart · New York

1022
D. Enders et al.
PAPER
The absolute configuration was confirmed by an X-ray ed the alkene (S)-6 in 83% yield over two steps. Selective
crystal structure analysis of the alcohol (R,R)-4,11 which protection of the primary alcohol as a silyl ether produced
showed a trans orientation of the methyl and (benzyl- the allylic alcohol (S)-7. Screening of a series of epoxida-
oxy)methyl groups (Figure 1). The trans orientation was tion conditions showed allylic alcohol (S)-8 to react effi-
additionally confirmed by NOE measurements carried out ciently in the presence of a catalytic amount of
for alcohol (S,S)-4.
bis(acetylacetonato)oxovanadium(IV) and the terminal
oxidant tert-butyl hydroperoxide. The epoxide product
(S,S)-8 was obtained in high yield (89%) and as a single
diastereomer (≥98% de) (Scheme 3). Finally, the epoxide
(S,S)-8 could be ring-opened regio- and stereoselectively
by reaction with Super-Hydride™, to install the tertiary al-
cohol group and quaternary stereocenter of alcohol (S,S)-
9. The alcohol groups were deprotected by desilylation
with tetrabutylammonium fluoride to give triol (S,S)-10,
which was debenzylated with hydrogen and palladium on
carbon to afford (S,S)-2-methylthreitol [(S,S)-1] in 61%
overall yield (98% ee, ≥98% de) starting from ketone (S)-
3.
Figure 1 Crystal structure of alcohol (R,R)-4
In summary, we have developed two different routes for
the efficient enantio- and diastereoselective syntheses of
the tetrol (S,S)-2-methylthreitol and its enantiomer (R,R)-
2-methylthreitol.
The enantiomeric (R,R)-2-methylthreitol [(R,R)-1] was
synthesized by the same procedure, from RAMP hydra-
zone (R)-2 as starting material. Tetrol (R,R)-1 was ob-
tained in an overall yield of 40% as a single stereoisomer
(98% de and ee), as determined by CSP-GC, HPLC, and
NMR spectroscopy.
All reagents were of commercial quality and were used from freshly
opened containers. Solvents were dried and purified by convention-
al methods prior to use. THF was freshly distilled under argon from
Na/Pb alloy, CH2Cl2 was freshly distilled under argon from CaH2,
and 15% t-BuLi in n-pentane was purchased from Merck (Darm-
stadt). Standard Schlenk techniques were used for conducting the
reactions under argon. Preparative flash chromatography was car-
ried out on Merck silica gel 60 (particle size 0.040–0.063 mm; 230–
240 mesh). Analytical TLC analyses were performed on silica gel
60 F254 plates from Merck (Darmstadt). Visualization of the devel-
oped chromatograms was performed by UV irradiation (254 nm) or
staining with acidic (NH4)2MoO4 and KMnO4. Optical rotation val-
ues were measured on a Perkin-Elmer P241 polarimeter; solvents
used were of Merck UVASOL quality. Microanalyses were ob-
tained with an Elementar Vario EL instrument. Mass spectra were
acquired on Varian MAT 212 (EI, 70 eV, 1 mA) and on Finnigan
MAT SSQ 7000 (CI, 100 eV) spectrometers. HRMS data were ob-
tained on a Finnigan MAT, MAT 95 instrument. IR spectra were
In addition, we have developed an alternative route to
(S,S)-2-methylthreitol that preserves the ketone (S)-3 as a
key intermediate and involves a reductive epoxide ring-
opening reaction (Scheme 3). Thus, Wittig olefination of
ketone (S)-3 to (S)-5 followed by acetal hydrolysis afford-
O
CH2
O
a
O
83%
O
O
O
O
H3C CH3
H3C CH3
(S)-5
(S)-3
CH2
CH2
b
c
measured on a Perkin-Elmer FT/IR 1760 spectrometer. 1H and 13
C
O
O
O
95%
quant.
NMR spectra were recorded on Varian Gemini 300, Varian Inova
400, or Varian Unity 500 spectrometers, and all measurements were
performed with TMS as internal standard. Analytical HPLC was
performed on a Hewlett-Packard 1100 Series instrument. Melting
points were determined on a Tottoli melting point apparatus and are
uncorrected. The chiral auxiliaries SAMP and RAMP and the cor-
responding dioxanone hydrazones (S)- and (R)-2 were prepared
from (S)- and (R)-proline according to literature procedures.12
OH OH
TBSO
H3C
OH
(S)-6
(S)-7
O
OH
d
e
90%
O
89%
TBSO
OH
(S,S)-8
TBSO
OH
(S,S)-9
H3C
OH
H3C
OH
(4S)-4-[(Benzyloxy)methyl]-2,2-dimethyl-1,3-dioxan-5-one [(S)-
3]
f
g
O
OH
quant.
97%
OH OH
(S,S)-10
To a soln of (S)-2 (1.21 g, 5 mmol) in THF (20 mL) at –78 °C was
added 1.5 M t-BuLi in pentane (3.7 mL, 5.5 mmol). After stirring
for 2 h, the mixture was cooled to –100 °C and BOMCl (0.86 g,
5.5 mmol) diluted with THF (1 mL) was added dropwise. The mix-
ture was stirred at the same temperature for 2 h and then allowed to
slowly warm to r.t. overnight. The mixture was quenched by the ad-
dition of pH 7 buffer, diluted, and extracted with Et2O (4 × 10 mL).
The organic phase was washed with brine (5 mL), dried (MgSO4),
and concentrated in vacuo. Purification by flash chromatography
(silica gel, pentane–Et2O, 2:1) gave the alkylated hydrazone as a
OH OH
(S,S)-1
Scheme 3 Asymmetric synthesis of (S,S)-2-methylthreitol by ep-
oxidation. Reagents and conditions: (a) 1. [Ph3PMe]+Br–, t-BuOK,
THF, 0 °C, 2 h; 2. (S)-3, 3 h; (b) ion-exchange resin, MeOH, r.t.; (c)
1. imidazole, THF, 0 °C, 15 min; 2. TBSCl, 1 h, 0 °C, then r.t., over-
night; (d) 1. VO(acac)2, 4-Å MS, CH2Cl2, 0 °C, 10 min; 2. t-BuOOH,
0 °C, 1 h, then r.t., 20 h; (e) Super-Hydride™, THF, 0 °C, 3 h; (f)
TBAF, THF, r.t., 1 h; (g) Pd/C, H2, MeOH, r.t., 2 h.
Synthesis 2007, No. 7, 1021–1026 © Thieme Stuttgart · New York

PAPER
Asymmetric Synthesis of (S,S)- and (R,R)-2-Methylthreitol
1023
pure yellow oil. The purified hydrazone was dissolved in Et2O
(50 mL), sat. aq oxalic acid (20 mL) was added, and the mixture
was vigorously stirred. After 2 h, the mixture was extracted with
Et2O (10 mL) and the organic phase was washed with pH 7 buffer
(2 × 10 mL) and brine (5 mL), dried (MgSO4), and concentrated in
vacuo to give pure (S)-3 as a clear, colorless liquid in 98% ee.
11.8 Hz, 1 H, CHHCOH), 3.68 (dd, J = 3.5, 10.6 Hz, 1 H, CHCHH),
3.85 (dd, J = 3.5, 6.4 Hz, 1 H, OCH), 4.47 (s, 2 H, CH2C6H5), 7.28–
7.38 (m, 5 H, C6H5).
13C NMR (75 MHz, DMSO): d = 19.56 [C(CH3)2], 21.53
(COHCH3), 29.23 [C(CH3)2], 66.11 (COH), 69.74 (CHCH2), 69.93
(CH2COH), 72.62 (CH2C6H5), 75.35 (OCH), 98.48 [C(CH3)2],
127.87 (pCHPh), 128.07 (oCHPh), 128.71 (mCHPh), 138.98 (CPh).
Yield: 0.64 g (48%, over 2 steps); [a]D31 –150.1 (c 1.1, CHCl3).
IR (film): 3063 (w), 3031 (w), 2990 (s), 2936 (m), 2871 (s), 1799
(s), 1747 (vs), 1600 (w), 1497 (w), 1454 (m), 1379 (s), 1322 (w),
1224 (vs), 1160 (m), 1101 (vs), 989 (m), 913 (m), 848 (m), 744 (s),
700 (s), 608 (m), 535 (w), 465 (w) cm–1.
MS (EI, 70 eV): m/z (%) = 266 (1) [M]+, 190 (14), 147 (11), 115
(17), 107 (10), 91 (100), 72 (13), 59 (35), 58 (25).
Anal. Calcd for C15H22O4: C, 67.64; H, 8.33. Found: C, 68.08; H,
8.62.
1H NMR (300 MHz, CDCl3): d = 1.48 (s, 3 H, CH3), 1.49 (s, 3 H,
CH3), 3.74 (dd, J = 6, 11 Hz, 1 H, CHCHH), 3.88 (dd, J = 3, 11 Hz,
1 H, CHCHH), 3.96 [d, J = 16.8 Hz, 1 H, CHHC(O)], 4.29 [dd, J =
1.6, 16.9 Hz, 1 H, CHHC(O)], 4.46 (dd, J = 1.5, 3.0 Hz, 1 H, OCH),
4.58 (s, 1 H, CHHC6H5), 4.59 (s, 1 H, CHHC6H5), 7.25–7.35 (m, 5
H, C6H5).
13C NMR (75 MHz, CDCl3): d = 23.55 (CH3), 24.12 (CH3), 66.74
[CH2C(O)], 67.90 (CHCH2), 73.62 (CH2C6H5), 75.27 (OCH),
100.93 [C(CH3)2], 127.69 (pCHPh), 128.36 (oCHPh), 128.43 (mCHPh),
137.89 (CPh), 207.44 (CO).
(4R,5R)-4-[(Benzyloxy)methyl]-2,2,5-trimethyl-1,3-dioxan-5-ol
[(R,R)-4]
By the procedure described for its S-enantiomer, ketone (R)-3
(2.86 g, 11.4 mmol) was treated with 1.6 M MeLi in Et2O (22.0 mL,
34.2 mmol); after purification the corresponding alcohol (R,R)-4
was obtained as a colorless solid in 98% ee and 84% de.
The diastereomers could be separated by preparative HPLC (Li-
Chrosorb Si60, 7 mm, 250 mm × 25 mm; n-pentane–Et2O, 1:1; flow
rate: 25 mL/min; tR = 12.8 min and 18.9 min); this gave the major
diastereomer in ≥98% de.
MS (EI, 70 eV): m/z (%) = 250 (1) [M]+, 162 (10), 149 (12), 129
(10), 107 (18), 92 (10), 91 (100), 72 (23), 59 (11).
Yield: 2.13 g (70%); mp 40 °C; [a]D27 –9.0 (c 1.1, CHCl3)
MS (CI, 100 eV, methane): m/z (%) = 251 (7) [M+ + 1], 249 (10),
207 (25), 161 (16), 147 (12), 143 (24), 123 (10), 117 (44), 107 (60),
105 (40), 91 (100).
All spectroscopic data were consistent with those of the S-enan-
tiomer.
(4S)-4-[(Benzyloxy)methyl]-2,2-dimethyl-5-methylene-1,3-di-
oxane [(S)-5]
Anal. Calcd for C14H18O4: C, 67.18; H, 7.25. Found: C, 66.89; H,
7.24.
A 1 M soln of t-BuOK in THF (50 mL, 50 mmol) was added slowly
to a cooled (0 °C) soln of [Ph3PMe]+Br– (17.9 g, 50 mmol) in THF
(180 mL). The yellow reaction mixture was stirred at the same tem-
perature for 2 h, and then a soln of (S)-3 (2.50 g, 10 mmol) in THF
(17 mL) was added dropwise. After 3 h, the mixture was quenched
by the addition of H2O (30 mL), warmed to r.t., and extracted with
Et2O (3 × 50 mL). The organic phase was washed with brine (30
mL), dried (MgSO4), and concentrated in vacuo. Purification by
flash chromatography (silica gel, pentane–Et2O, 6:1) gave (S)-5 as
a colorless liquid in 98% ee.
(4R)-4-[(Benzyloxy)methyl]-2,2-dimethyl-1,3-dioxan-5-one
[(R)-3]
By the procedure described for its S-enantiomer, hydrazone (R)-4
(4.85 g, 20 mmol) was alkylated with BOMCl (3.45 g, 22 mmol).
After hydrolytic removal of the auxiliary, ketone (R)-3 was ob-
tained as a clear, colorless liquid in 98% ee.
Yield: 2.86 g (57%, over 2 steps); [a]D31 +146.3 (c 1.3, CHCl3).
All spectroscopic data were consistent with those of the S-enan-
Yield: 2.06 g (83%); [a]D25 –51.0 (c 1.0, CHCl3).
tiomer.
IR (film): 3065 (w), 3030 (m), 2989 (s), 2936 (s), 2903 (s), 2860 (s),
1657 (w), 1496 (m), 1454 (s), 1416 (w), 1375 (s), 1258 (m), 1222
(vs), 1162 (s), 1097 (vs), 1047 (m), 1028 (m), 905 (s), 860 (m), 833
(m), 740 (s), 699 (s), 611 (w), 517 (w), 459 (w) cm–1.
1H NMR (300 MHz, CDCl3): d = 1.41 (s, 3 H, CH3), 1.48 (s, 3 H,
CH3), 3.65 (dd, J = 6, 10.4 Hz, 1 H, CHCHH), 3.73 (dd, J = 4.7,
10.2, 1 H, CHCHH), 4.25 [m, 2 H, CH2C(CH2)], 4.57–4.65 (m, 3 H,
CH2C6H5, OCH), 4.89 (m, 2 H, CCH2), 7.25–7.35 (m, 5 H, C6H5).
13C NMR (75 MHz, CDCl3): d = 21.99 (CH3), 27.26 (CH3), 64.09
[CH2C(CH2)], 70.14 (OCH), 71.22 (CHCH2), 73.34 (CH2C6H5),
99.45 (C(CH3)2), 107.40 [C(CH2)], 127.46 (pCHPh), 127.58
(oCHPh), 128.17 (mCHPh), 137.88 (CPh), 143.05 (C(CH2)].
(4S,5S)-4-[(Benzyloxy)methyl]-2,2,5-trimethyl-1,3-dioxan-5-ol
[(S,S)-4]
To a soln of (S)-3 (1.73 g, 6.9 mmol) in THF (70 mL) at –90 °C was
slowly added 1.6 M MeLi in Et2O (17.4 mL, 13.8 mmol). After stir-
ring at the same temperature for 3 h, the mixture was quenched by
the addition of sat. aq NH4Cl (70 mL), warmed to r.t., and extracted
with Et2O (3 × 48 mL). The organic phase was washed with brine
(20 mL), dried (MgSO4), and concentrated in vacuo. Purification by
flash chromatography (silica gel, pentane–Et2O, 1:1) gave (S,S)-4 as
a colorless solid in 84% de.
The diastereomers could be separated by preparative HPLC (Li-
Chrosorb Si60, 7 mm, 250 mm × 25 mm; n-pentane–Et2O, 1:1; flow
rate: 25 mL/min; tR = 12.8 min and 18.9 min); this gave the major
diastereomer in ≥98% de.
MS (EI, 70 eV): m/z (%) = 190 (11), 160 (12), 127 (92), 92 (10), 91
(100), 85 (12), 69 (34), 59 (21).
MS (CI, 100 eV, methane): m/z (%) = 249 (7) [M+ + 1], 191 (10),
Yield: 1.37 g (75%); mp 40 °C; [a]D25 +8.9 (c 1.0, CHCl3).
IR (CHCl3): 3953 (w), 3571 (s), 3493 (s), 3241 (w), 3062 (m), 3030
(m), 2990 (vs), 2937 (vs), 2873 (vs), 2718 (w), 1722 (m), 1604 (w),
1497 (w), 1454 (s), 1379 (vs), 1292 (s), 1261 (s), 1201 (vs), 1159
(s), 1111 (vs), 1073 (vs), 994 (m), 974 (w), 938 (m), 899 (w), 847
(s), 745 (vs), 699 (s), 602 (m), 526 (m), 471 (w) cm–1.
1H NMR (300 MHz, DMSO): d = 0.96 (s, 3 H, COHCH3), 1.31 [s,
3 H, C(CH3)2], 1.36 [s, 3 H, C(CH3)2], 3.30 (d, J = 11.6 Hz, 1 H,
CHHCOH), 3.37 (dd, J = 6.4, 10.9 Hz, 1 H, CHCHH), 3.67 (d, J =
131 (13), 129 (17), 127 (56), 91 (100), 83 (23).
Anal. Calcd for C15H20O3: C, 72.55; H, 8.12. Found: C, 72.58; H,
8.10.
(4R)-4-[(Benzyloxy)methyl]-2,2-dimethyl-5-methylene-1,3-di-
oxane [(R)-5]
By the procedure described for its S-enantiomer, ketone (R)-3
(0.98 g, 3.9 mmol) underwent a Wittig reaction with [Ph3PMe]+Br–
Synthesis 2007, No. 7, 1021–1026 © Thieme Stuttgart · New York

1024
D. Enders et al.
PAPER
(6.96 g, 19.5 mmol) and 1 M t-BuOK in THF (19.5 mL,
19.5 mmol); after purification, the corresponding alkene (R)-5 was
obtained as a colorless liquid in 98% ee.
Yield: 0.80 g (83%); [a]D26 +58.3 (c 1.2, CHCl3).
13C NMR (75 MHz, CDCl3): d = –5.45 [Si(CH3)2], 18.26
[SiC(CH3)3], 25.87 [SiC(CH3)3], 64.33 (SiOCH2), 71.97 [CH(OH)],
73.35 (CH2C6H5), 73.73 (CHCH2), 111.95 [C(CH2)], 127.80 (pCHPh),
127.90 (oCHPh), 128.45 (mCHPh), 137.87 (CPh), 146.89 [C(CH2)].
MS (EI, 70 eV): m/z (%) = 201 (10), 157 (14), 91 (100), 75 (12), 73
(11).
MS (CI, 100 eV, methane): m/z (%) = 323 (57) [M+ + 1], 305 (30),
289 (12), 287 (12), 247 (10), 215 (20), 213 (10), 173 (39), 157 (19),
145 (17), 143 (11), 131 (20), 129 (48), 119 (12), 91 (100), 83 (12).
All spectroscopic data were consistent with those of the S-enan-
tiomer.
(3S)-4-(Benzyloxy)-2-methylenebutane-1,3-diol [(S)-6]
Ion-exchange resin (DOWEX™ 50X2-200, 2.0 g) was added to a
soln of (S)-5 (1.21 g, 4.9 mmol) in MeOH (24 mL) at r.t. After 3 h
the resin was removed by filtration and washed with MeOH, and the
filtrate was concentrated in vacuo. Purification by flash chromatog-
raphy (silica gel, pentane–Et2O, 1:2) gave pure (S)-6 as a colorless
liquid.
Anal. Calcd for C18H30O3Si: C, 67.03; H, 9.38. Found: C, 66.76; H,
9.40.
(3R)-4-(Benzyloxy)-1-[(tert-butyldimethylsilyl)oxy]-2-methyl-
enebutan-3-ol [(R)-7]
By the procedure described for its S-enantiomer, diol (R)-6 (1.14 g,
1.3 mmol) was mono-TBS-protected to give the corresponding allyl
alcohol (R)-7 as a colorless liquid after purification.
Yield: 1.0 g (100%); [a]D24 –18.5 (c 1.1, CHCl3).
IR (film): 3409 (vs), 3087 (w), 3064 (w), 3030 (m), 2866 (s), 1654
(m), 1496 (m), 1454 (s), 1363 (m), 1319 (w), 1207 (m), 1076 (vs),
1028 (vs), 913 (s), 816 (w), 740 (vs), 700 (s), 646 (w), 609 (w) cm–1.
Yield: 1.68 g (90%); [a]D25 +8.1 (c 1.1, CHCl3).
1H NMR (300 MHz, CDCl3): d = 3.54 (dd, J = 9.6, 21.8 Hz, 1 H,
CHCHH), 3.56 (dd, J = 9.6, 18.6 Hz, 1 H, CHCHH), 4.10 (d, J = 19
Hz, 1 H, CHHOH), 4.14 (d, J = 19 Hz, 1 H, CHHOH), 4.44 (dd,
J = 4, 7.4 Hz, 1 H, CHOH), 4.55 (s, 2 H, CH2C6H5), 5.16 [m, 2 H,
C(CH2)], 7.27–7.35 (m, 5 H, C6H5).
All spectroscopic data were consistent with those of the S-enan-
tiomer.
(1S)-2-(Benzyloxy)-1-[(2S)-2-{[(tert-butyldimethylsilyl)oxy]-
methyl}oxiran-2-yl]ethanol [(S,S)-8]
A soln of (S)-7 (0.59 g, 1.8 mmol) in CH2Cl2 (9.5 mL) was added to
a cooled (0 °C) soln of VO(acac)2 (29 mg, 6 mol%) and 4-Å MS
(180 mg) in CH2Cl2 (11.5 mL). After the mixture had stirred at the
same temperature for 10 min, t-BuOOH (0.54 mL, 2.8 mmol) was
added dropwise. The mixture was stirred at 0 °C for 1 h, allowed to
warm to r.t., and stirred for 20 h; it was then quenched by the addi-
tion of sat. aq NH4Cl (5.5 mL) and extracted with CH2Cl2 (3 × 7
mL). The organic phase was washed with brine (4 mL), dried
(MgSO4), and concentrated in vacuo. Purification by flash chroma-
tography (silica gel, pentane–Et2O, 3:1) gave pure (S,S)-8 as a col-
orless liquid in 98% ee.
13C NMR (75 MHz, CDCl3): d = 63.80 (CH2OH), 72.16 (CHOH),
73.45 (CH2C6H5), 73.73 (CHCH2), 113.39 [C(CH2)], 127.88 (pCHPh),
127.93 (oCHPh), 128.52 (mCHPh), 137.61 (CPh), 147.24 [C(CH2)].
MS (EI, 70 eV): m/z (%) = 99 (11), 92 (35), 91 (100), 87 (25), 69
(18), 65 (14).
MS (CI, 100 eV, methane): m/z (%) = 209 (9) [M+ + 1], 145 (13),
143 (11), 131 (17), 129 (16), 92 (11), 91 (100), 83 (12).
HRMS (EI): m/z calcd for C11H11O [M+ – CH5O2]: 159.08099;
found: 159.08092.
Yield: 0.55 g (89%); [a]D25 –2.2 (c 1.1, CHCl3).
(3R)-4-(Benzyloxy)-2-methylenebutane-1,3-diol [(R)-6]
By the procedure described for its S-enantiomer, the acetal of the
alkene (R)-5 (0.99 g, 4.0 mmol) was cleaved to give the correspond-
ing diol (R)-6 as a colorless liquid in 98% ee after purification.
IR (CHCl3): 3458 (s), 3063 (m), 3031 (m), 2930 (vs), 2858 (vs),
1723 (m), 1498 (w), 1465 (s), 1390 (m), 1362 (m), 1255 (vs), 1211
(m), 1102 (vs), 1029 (w), 1006 (w), 938 (m), 911 (m), 841 (vs), 779
(s), 741 (s), 699 (s), 670 (m), 615 (w) cm–1.
Yield: 0.82 g (100%); [a]D24 +18.0 (c 1.0, CHCl3).
1H NMR (400 MHz, CDCl3): d = 0.02 [s, 3 H, Si(CH3)2], 0.04 [s, 3
H, Si(CH3)2], 0.87 [s, 9 H, SiC(CH3)3], 2.66 (br s, 1 H, OH), 2.72 [d,
J = 5 Hz, 1 H, C(CHHO)], 2.89 [d, J = 5 Hz, 1 H, C(CHHO)], 3.60
(dd, J = 6.1, 10.2 Hz, 1 H, CHCHH), 3.67 (dd, J = 3.9, 10.2 Hz, 1
H, CHCHH), 3.69 (d, J = 11.8 Hz, 1 H, SiOCHH), 3.88 (d, J = 11.6
Hz, 1 H, SiOCHH), 4.05 [m, CH(OH)], 4.56 (s, 2 H, CH2C6H5),
7.25–7.34 (m, 5 H, C6H5).
13C NMR (100 MHz, CDCl3): d = –5.58 [Si(CH3)2], 18.19
[SiC(CH3)3], 25.76 [SiC(CH3)3], 48.00 [C(CH2O)], 59.68
[C(CH2O)], 63.93 (SiOCH2), 68.99 [CH(OH)], 70.88 (CH2C6H5),
73.33 (CHCH2), 127.54 (pCHPh), 127.68 (oCHPh), 128.21 (mCHPh),
137.69 (CPh).
All spectroscopic data were consistent with those of the S-enan-
tiomer.
(3S)-4-(Benzyloxy)-1-[(tert-butyldimethylsilyl)oxy]-2-methyl-
enebutan-3-ol [(S)-7]
A soln of (S)-6 (0.27 g, 1.3 mmol) in THF (4 mL) was added to a
cooled (0 °C) soln of imidazole (0.20 g, 3.1 mmol) in THF (4 mL).
After the mixture had stirred at the same temperature for 15 min,
TBSCl (0.23 g, 1.5 mmol) dissolved in THF (3 mL) was added
slowly. The mixture was stirred at the same temperature for 1 h, and
then allowed to warm to r.t. overnight. It was then filtered over
Celite, washed with Et2O, and concentrated in vacuo. Purification
by flash chromatography (silica gel, pentane–Et2O, 5:1) gave (S)-7
as a pure, colorless oil.
MS (EI, 70 eV): m/z (%) = 143 (12), 105 (10), 91 (100), 75 (12).
MS (CI, 100 eV, methane): m/z (%) = 339 (3) [M+ + 1], 215 (14),
213 (24), 207 (12), 171 (37), 159 (11), 143 (12), 91 (100).
Yield: 0.42 g (95%); [a]D25 –8.2 (c 1.0, CHCl3).
IR (film): 3436 (s), 3065 (w), 3031 (w), 2932 (vs), 2858 (vs), 1655
(w), 1465 (s), 1389 (m), 1362 (m), 1316 (w), 1255 (s), 1211 (m),
1080 (vs), 910 (m), 842 (vs), 778 (s), 740 (m), 698 (m), 672 (m),
615 (w), 465 (w) cm–1.
1H NMR (300 MHz, CDCl3): d = 0.06 [s, 6 H, Si(CH3)2], 0.90 [s, 9
H, SiC(CH3)3], 3.52 (d, J = 7.9 Hz, 1 H, CHCHH), 3.62 (dd, J = 4,
9.6 Hz, 1 H, CHCHH), 4.20 (m, 2 H, SiOCH2), 4.41 [m, 1 H,
CH(OH)], 4.57 (s, 2 H, CH2C6H5), 5.18 [m, 2 H, C(CH2)], 7.25–
7.35 (m, 5 H, C6H5).
Anal. Calcd for C18H30O4Si: C, 63.87; H, 8.93. Found: C, 63.68; H,
9.02.
(1R)-2-(Benzyloxy)-1-[(2R)-2-{[(tert-butyldimethylsilyl)oxy]-
methyl}oxiran-2-yl]ethanol [(R,R)-8]
By the procedure described for its S-enantiomer, allyl alcohol (R)-7
(0.97 g, 3.0 mmol) was epoxidized in the presence of cat.
VO(acac)2 (47 mg, 6 mol%) and t-BuOOH (0.90 mL, 4.7 mmol);
Synthesis 2007, No. 7, 1021–1026 © Thieme Stuttgart · New York

PAPER
Asymmetric Synthesis of (S,S)- and (R,R)-2-Methylthreitol
1025
this gave epoxide (R,R)-8 as a colorless liquid in 98% ee after puri-
fication.
CH), 3.68 (dd, J = 2.8, 9.7 Hz, 1 H, CHCHH), 4.48 (s, 2 H,
CH2C6H5), 7.27–7.35 (m, 5 H, C6H5).
Yield: 0.88 g (87%); [a]D25 +2.4 (c 1.1, CHCl3).
13C NMR (75 MHz, DMSO): d = 22.13 (COHCH3), 66.78
(CH2OH), 72.16 (CHCH2), 72.67 (CH2C6H5), 73.66 (COH), 74.28
(CH), 127.75 (pCHPh), 127.92 (oCHPh), 128.65 (mCHPh), 139.22
(CPh).
All spectroscopic data were consistent with those of the (S,S)-8
enantiomer.
(2S,3S)-4-(Benzyloxy)-1-[(tert-butyldimethylsilyl)oxy]-2-meth-
ylbutane-2,3-diol [(S,S)-9]
MS (EI, 70 eV): m/z (%) = 226 (1) [M]+, 107 (13), 92 (13), 91 (100),
75 (14).
To a cooled (0 °C) soln of epoxide (S,S)-8 (0.40 g, 1.1 mmol) in
THF (12.9 mL), a 1.0 M soln of Super-Hydride™ in THF (3.2 mL,
3.3 mmol) was slowly added. The mixture was stirred at the same
temperature for 3 h and then quenched by the addition of H2O
(6.5 mL) and extracted with Et2O (3 × 13 mL). The organic phase
was washed with brine (6 mL), dried (MgSO4), and concentrated in
vacuo; this gave crude (S,S)-9 as a colorless liquid. Further purifi-
cation by flash chromatography was not possible.
Anal. Calcd for C12H18O4: C, 63.70; H, 8.02. Found: C, 63.36; H,
8.31.
(2R,3R)-4-(Benzyloxy)-2-methylbutane-1,2,3-triol [(R,R)-10]
(a) From (R,R)-4: By the procedure described for its S,S-enan-
tiomer, the acetal of the alcohol (R,R)-4 (1.4 g, 5.3 mmol) was
cleaved with ion-exchange resin (DOWEX™ 50X2-200) to give the
corresponding triol (R,R)-10 as a colorless liquid in 98% ee after pu-
rification.
Yield: 0.34 g (90%).
1H NMR (300 MHz, CDCl3): d = 0.04 [s, 3 H, Si(CH3)2], 0.05 [s, 3
H, Si(CH3)2], 0.88 [s, 9 H, SiC(CH3)3], 1.22 (s, 3 H, COHCH3), 3.44
(d, J = 10.1 Hz, 1 H, SiOCHH), 3.52 (d, J = 10.0 Hz, 1 H, SiOCHH),
3.54 (d, J = 5.4 Hz, 1 H, CHCH2), 4.39 [m, CH(OH)], 4.55 (s, 1 H,
CHHC6H5), 4.58 (s, 1 H, CHHC6H5), 7.29–7.34 (m, 5 H, C6H5).
13C NMR (75 MHz, CDCl3): d = –5.54 [Si(CH3)2], 18.18
[SiC(CH3)3], 18.46 (COHCH3), 25.78 [SiC(CH3)3], 69.82
(SiOCH2), 70.23 (CH2C6H5), 73.44 (CHCH2), 78.97 [CH(OH)],
82.64 (COHCH3), 127.62 (pCHPh), 128.32 (oCHPh), 128.36 (mCHPh),
137.04 (CPh).
Yield: 1.19 g (100%).
(b) From (R,R)-9: By the procedure described for the S,S-enan-
tiomer, a 1 M soln of TBAF in THF (5.1 mL, 5.1 mmol) was used
to cleave (R,R)-9 (0.6 g, 1.7 mmol) to give the corresponding triol
(R,R)-10 as a colorless liquid after purification.
Yield: 0.37 g (97%); [a]D33 +8.6 (c 1.0, CHCl3).
All spectroscopic data were consistent with those of the S,S-enan-
tiomer.
(2S,3S)-2-Methylbutane-1,2,3,4-tetrol [(S,S)-1]
Pd/C (0.20 g) was added to a soln of (S,S)-10 (0.84 g, 3.5 mmol) in
MeOH (35 mL). The mixture was stirred under H2 for 2 h, and then
filtered over Celite, which was washed with MeOH; the filtrate was
then concentrated in vacuo. Purification by flash chromatography
(silica gel, MeOH–EtOAc, 1:5) gave pure (S,S)-1 as a colorless oil
in 98% de and ee.
(2R,3R)-4-(Benzyloxy)-1-[(tert-butyldimethylsilyl)oxy]-2-meth-
ylbutane-2,3-diol [(R,R)-9]
By the procedure described for its (S,S)-enantiomer, epoxide (R,R)-
8 (0.65 g, 1.7 mmol) was ring-opened with 1.0 M Super-Hydride™
in THF (5.2 mL, 5.2 mmol) to give the corresponding diol (R,R)-9
as a colorless liquid. Further purification by flash chromatography
was not possible.
Yield: 0.47 g (100%); [a]D24 –10.8 (c 0.7, MeOH).
Yield: 0.52 g (89%).
IR (CHCl3): 3747 (w), 3408 (s), 2943 (m), 2889 (m), 2510 (vs),
1699 (w), 1652 (w), 1460 (m), 1385 (m), 1215 (w), 1096 (m), 1042
(s), 791 (w), 670 (w) cm–1.
All spectroscopic data were consistent with those of the (S,S)-enan-
tiomer.
1H NMR (300 MHz, D2O): d = 0.99 (s, 3 H, CH3), 3.39 (d, J =
3.2 Hz, 2 H, CH2OH), 3.43 (dd, J = 11.5, 8.5 Hz, 1 H, CHCHH),
3.53 (dd, J = 8.2, 2.7 Hz, 1 H, CH), 3.64 (dd, J = 11.4, 2.7 Hz, 1 H,
CHCHH).
13C NMR (75 MHz, D2O): d = 19.05 (CH3), 61.79 (CHCH2), 66.06
(CH2OH), 74.01 (COH), 75.01 (CH).
(2S,3S)-4-(Benzyloxy)-2-methylbutane-1,2,3-triol [(S,S)-10]
(a) From (S,S)-4: Ion-exchange resin (DOWEX™ 50X2-200, 2.0 g)
was added to a soln of alcohol (S,S)-4 (1.16 g, 4.4 mmol) in MeOH
(9 mL) at r.t. After 1 h, the resin was removed by filtration and
washed with MeOH, and the filtrate was concentrated in vacuo. Pu-
rification by flash chromatography (silica gel, pentane–EtOAc, 1:5)
gave pure (S,S)-10 as a colorless liquid in 98% ee.
MS (EI, 70 eV): m/z (%) = 105 (36), 87 (15), 75 (100), 61 (18), 59
(12), 58 (14), 57 (44).
MS (CI, 100 eV, methane): m/z (%) = 137 (5) [M+ + 1], 119 (13),
115 (10), 101 (100), 83 (25), 79 (50), 75 (16), 71 (52), 61 (22).
HRMS (EI): m/z calcd for C4H9O3 [M+ – CH3O]: 105.05517; found:
105.05516.
Yield: 0.98 g (100%).
(b) From (S,S)-9: A 1 M soln of TBAF in THF (1.8 mL, 1.8 mmol)
was added dropwise to a soln of (S,S)-9 (0.20 g, 0.6 mmol) in THF
(3.0 mL) at r.t. After 4 h, the mixture was quenched by the addition
of pH 7 buffer (6.0 mL) and extracted with EtOAc (3 × 35 mL). The
organic phase was washed with brine (18 mL), dried (MgSO4), and
concentrated in vacuo. Purification by flash chromatography (silica
gel, pentane–EtOAc, 1:5) gave pure (S,S)-10 as a colorless liquid in
98% ee.
Anal. Calcd for C5H12O4+2H2O: C, 34.88; H, 9.37. Found: C, 34.71;
H, 9.71.
(2R,3R)-2-Methylbutane-1,2,3,4-tetrol [(R,R)-1]
Yield: 0.13 g (97%); [a]D32 –8.3 (c 1.2, CHCl3).
By the procedure described for its S,S-enantiomer, (R,R)-10 (0.37 g,
1.6 mmol) was debenzylated to give the corresponding tetrol (R,R)-
1 after purification as a colorless oil in 98% de and ee.
Yield: 0.22 g (100%); [a]D24 +11.7 (c 1.0, MeOH) {Lit.3 [a]D22 +7.3
(c 0.8, MeOH)}.
IR (film): 3409 (vs), 3064 (m), 3032 (m), 2976 (s), 2933 (s), 2875
(s), 1720 (s), 1497 (w), 1455 (m), 1374 (m), 1322 (w), 1274 (m),
1205 (w), 1051 (s), 918 (m), 801 (w), 743 (s), 701 (s), 614 (w), 465
(w) cm–1.
1H NMR (300 MHz, DMSO): d = 1.03 (s, 3 H, COHCH3), 3.23 (d,
J = 10.6 Hz, 1 H, CHHOH), 3.37 (d, J = 10.4 Hz, 1 H, CHHOH),
3.40 (d, J = 9.6 Hz, 1 H, CHCHH), 3.59 (dd, J = 2.7, 7.2 Hz, 1 H,
All spectroscopic data were consistent with those of the S,S-enan-
tiomer.
Synthesis 2007, No. 7, 1021–1026 © Thieme Stuttgart · New York

1026
D. Enders et al.
PAPER
(8) For organocatalytic applications of dioxanone, see:
Acknowledgment
(a) Enders, D.; Grondal, C. Angew. Chem. Int. Ed. 2005, 44,
1210; Angew. Chem. 2005, 117, 1235. (b) Enders, D.;
Grondal, C.; Vrettou, M.; Raabe, G. Angew. Chem. Int. Ed.
2005, 44, 4079; Angew. Chem. 2005, 117, 4147. (c)Enders,
D.; Grondal, C. Tetrahedron 2006, 62, 329. (d) Enders, D.;
Palecek, J.; Grondal, C. Chem. Commun. 2006, 655.
(e) Enders, D.; Vrettou, M. Synthesis 2006, 2155.
This work was supported by the Deutsche Forschungsgemeinschaft
(Graduiertenkolleg 440). We thank Bayer AG, BASF AG, Wacker
Chemie, and Degussa AG for the donation of chemicals.
References
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(9) For recent applications of the dioxanone method, see:
(a) Enders, D.; Breuer, I.; Raabe, G. Synthesis 2005, 3517.
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Road, Cambridge CB2 1EZ, UK [fax: +44(1223)336033,
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Synthesis 2007, No. 7, 1021–1026 © Thieme Stuttgart · New York