Concise asymmetric syntheses of the (+)-2-C-methyltetritol isomers

Article abstract of DOI:10.1016/j.tetasy.2008.09.002

Two brief and facile syntheses of the title compounds have been developed using the diastereocontrolled addition of organometallics to a (R)-cyclohexylideneglyceraldehyde-derived ketone as the key steps. The addition of vinylmagnesium bromide to the ketone gave a 1:1 diastereomeric mixture of separable tertiary alcohols, which were converted to the target erythri- and threitols. On the other hand, the reaction of a dithianyl anion with the ketone gave only the single stereoisomer of a tertiary alcohol, which was converted to erythritol.

Full text of DOI:10.1016/j.tetasy.2008.09.002

Tetrahedron: Asymmetry 19 (2008) 2167–2170
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Tetrahedron: Asymmetry
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Concise asymmetric syntheses of the (+)-2-C-methyltetritol isomers
Anubha Sharma, Priyadip Das, Subrata Chattopadhyay *
Bio-Organic Division, Bhabha Atomic Research Centre, Mumbai 400 085, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Two brief and facile syntheses of the title compounds have been developed using the diastereocontrolled
addition of organometallics to a (R)-cyclohexylideneglyceraldehyde-derived ketone as the key steps. The
addition of vinylmagnesium bromide to the ketone gave a 1:1 diastereomeric mixture of separable ter-
tiary alcohols, which were converted to the target erythri- and threitols. On the other hand, the reaction
of a dithianyl anion with the ketone gave only the single stereoisomer of a tertiary alcohol, which was
converted to erythritol.
Received 24 July 2008
Accepted 2 September 2008
Available online 9 October 2008
Ó 2008 Elsevier Ltd. All rights reserved.
1
. Introduction
Isoprenoid compounds constitute one of the most chemically
Since the MEP pathway is absent in animal cells, new opportu-
nities have become available to develop herbicides and drugs
against pathogenic bacteria and the malaria parasite.6
a–e
MEP has
diverse families in nature, and are commonly biosynthesized via
the intermediacy of isopentenyl pyrophosphate (IPP) and dimeth-
ylallyl pyrophosphate (DMAPP) as key intermediates.1 Over the
last few years, independent studies have accumulated evidence
for the existence of a mevalonate-independent or methylerythritol
phosphate pathway (MIP/MEP) for the biosynthesis of terpenoids
also been identified as a critical metabolite in the development
of the parasite responsible for malaria, Plasmodium falciparum.7
Furthermore, the large amounts of 2-C-methyltetritols, present in
the air above the Amazonian rain forest, are claimed to be a conse-
8
quence of the photooxidation of isoprene.
Accordingly, it has become crucial to have a facile access to all
2
,3
9a–d
in gram-negative bacteria, algae, and plant chloroplasts.
new pathway involves the participation of branched isoprenoid
precursors, such as 2-C-methyl- -erythritol-4-phosphate 1a, de-
rived from the condensation of pyruvate and glyceraldehyde-3-
phosphate via 1-deoxy- -xylulose-5-phosphate. The MIP steps for
the biosynthesis of terpenoids that involve (+)-2-methylerythritol
b as a putative intermediate is of current interest. However, the
This
the stereomers of 1b. Most of the known syntheses of 1a
1b
and
1
0a–e
are based on asymmetric epoxidation/hydroxylation of
D
suitable substrates, or utilize carbohydrate precursors. More re-
1
0d
cently, a chemo-enzymatic synthesis
thesis using a chiral hydrazone auxiliary
all the stereomers of 1b. Herein, we report a new asymmetric syn-
as well as a chemical syn-
1
0e
D
has been reported for
4
1
1
1
thesis of 1b using the known glyceraldehyde derivative 2 as a
role of 1b, as well as the remaining steps of the MIP sequence, is
still to be fully clarified. Isotopic experiments have demonstrated
a very low incorporation of the tetrol 1b in the quinones of Esche-
richia coli, suggesting that other compounds may actually be in-
volved in the biosynthetic process. Tetrol (2S,3R)-1b was also
isolated from Convolvulus glomeratus,5a Liriodendron tulipifera,
chiral template.
2
. Results and discussion
Our recent strategy on the enantioselective synthesis of tertiary
5b
1
2a
12b
carbinols and its application
to the syntheses of (R)-mevalon-
5
d
and Ferula sinaica, while (2R,3R)-1b was found in Phlox sublata.
The chemical structures of 1a and 1b are shown in Figure 1.
olactone and (S)-oxybutynin led us to consider the route for the
synthesis of the stereomers of 1b. In those studies, we found that
OH
HO
OH
OH
OH
HO
OH
RO
HO
HO
HO
HO
OH
CH
OH
CH
OH
CH
OH
CH
OH
CH
3
HO
(2R,3R)-1b
3
HO
(2R,3S)-1b
3
HO
(2S,3S)-
1b
3
3
1
a R = PO 2-
(2S,3R)-1b
3
Figure 1.
*
Corresponding author.
E-mail address: schatt@barc.gov.in (S. Chattopadhyay).
0
957-4166/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2008.09.002

2
168
A. Sharma et al. / Tetrahedron: Asymmetry 19 (2008) 2167–2170
2
O
1
O
O
1. R MgX
R MgX
R2
O
R1
O
*
O
CHO
2. Oxidation
R1
O
HO
3
2
4
Scheme 1.
the addition of different Grignard reagents to ketones 3 derived
from 2 proceeds with excellent stereoselectivity (Scheme 1). Fur-
thermore, by altering the sequence of the addition of the required
Grignard reagents, we could synthesize the syn- as well as anti-iso-
mers of the tertiary carbinols 4.
mers for 1b. Herein, we report the efficacy of the method for the
synthesis of two of the stereomers of 1b. However, given that
(S)-2 is easily amenable from L-ascorbic acid, the other isomers
1
3
of 1b can also be synthesized following our route.
Having completed the above synthesis, we ventured toward a
better enantioselective route for 1b. The addition of alkyl or cyclo-
alkyl Grignard reagents to the glyceraldehyde-derived ketones had
For the synthesis (Scheme 2), aldehyde 2 was reacted with
MeMgI to give alcohol 5 as a diastereomeric mixture. Without sep-
arating the individual stereomers, carbinol 5 was oxidized with
buffered-pyridinium chlorochromate (PCC) to furnish the know-
1
2a
been previously found
to furnish enantiomerically pure tertiary
alcohols. As a result, we reacted ketone 6 with the 1,3-dithiane an-
1
2a
t
n
ketone 6. Upon reaction with vinylmagnesium bromide, this
ion, generated with BuOK in THF. According to our expectation,
gave the diastereomeric alcohols 7a and 7b in a 51:49 ratio. The re-
sult was consistent with our earlier observations, wherein the
reaction of ketone 6 with alkenylmagnesium bromides was found
to proceed with poor diastereoselectivity. After separation by col-
umn chromatography, alcohol 7a was subjected to reductive ozon-
this produced syn-10 as the sole product. Treatment of 10 with
MeI/CaCO in aqueous MeCN furnished aldehyde 8a, which was
3
conveniently converted to (2R,3R)-1b, as above.
olysis with O
3
3 2
/Ph P in CH Cl
2
to afford aldehyde 8a. Its reduction
3. Conclusion
with lithium aluminum hydride (LAH) furnished 9a, which after
acidic hydrolysis gave (2R,3R)-1b. Likewise, alcohol 7b was con-
verted to (2S,3R)-1b. Overall, we have developed a short synthesis
of the target compounds using inexpensive reagents, and opera-
tionally simple reaction conditions. Although the synthesis was
non-selective, the method is well suited for the designated target
compound, which is required in all possible isomers. Due to the
presence of two stereocenters, there are four possible stereoiso-
The development of simple and efficient strategies is a highly
desirable goal for organic synthesis. Despite impressive pro-
1
4a
gress,
asymmetric synthesis.
this remains a very dynamic and challenging area in
1
4b,c
The most practical methods are aimed
at producing target compounds via reliable routes, utilizing inex-
pensive and readily available materials. To this end, we have been
able to devise, by far the simplest strategy for the synthesis of the
O
O
O
O
iii
O
O
i
ii
O
+
O
Me
O
Me
OH
CH3
O
HO
7b
CH3
CHO
HO
O
5
6
2
7a
O
iv
v
O
vi
7
a
O
(2R,3R)-1b
(2S,3R)-1b
O
CHO
OH
CH3
HO
O
CH3
HO
9
a
8
a
iv
v
O
vi
7
b
O
O
CHO
CH3
OH
CH3
HO
viii
HO
9
b
8b
O
S
O
vii
O
8a
(2R,3R)-
1b
O
Me
S
CH3
HO
O
6
1
0
Scheme 2. Reagents and conditions: (i) MeMgI/Et
4% for 8b); (v) LAH/Et O (91% for 9a, 86% for 9b); (vi) aqueous TFA/CH
88%).
2
O (84%); (ii) PCC/NaOAc/CH
2
Cl
2
(86%); (iii) vinylmagnesium bromide/THF (88%); (iv) O
3
/CH
2
Cl
2
/ꢀ78 °C; Ph
3
P (81% for 8a,
O (4:1)
t
8
(
2
2
Cl (89% for 1a, 91% for 1b); (vii) 1,3-dithiane/ BuOK/THF (72%); (viii) MeI/CaCO
2
3
/MeCN–H
2

A. Sharma et al. / Tetrahedron: Asymmetry 19 (2008) 2167–2170
2169
target compounds under operationally simple conditions, using
inexpensive and readily available reagents/starting materials.
Interestingly, the poor diastereoselectivity of the first method
was responsible to furnish the erythritol and threitol stereomers
in appreciable quantities. On the other hand, the most notable fea-
tures of the second route was the complete stereocontrol in the
organometallic addition to the ketone, providing the required ter-
and 7b (combined yield: 1.72 g, 88%). Compound 7a: colorless
2
2
ꢀ1
1
oil; ½
NMR (CDCl
1.62 (m, 8H), 2.18 (s, 1H), 3.73–4.00 (m, 3H), 5.08–5.35 (m, 2H),
a
ꢂ
¼ þ11:3 (c 1.12, CHCl
3
); IR: 3475, 3087, 1643 cm
): d 1.23–1.38 (m containing a s at d 1.30, 5H), 1.42–
; H
D
3
1
3
5.72–5.86 (m, 1H); C NMR: d 23.6, 23.8, 25.0, 25.2, 34.6, 35.8,
64.6, 72.3, 80.6, 109.9, 114.2, 140.1. Anal. Calcd for C12 : C,
67.89; H, 9.50. Found: C, 68.03; H, 9.58. Compound 7b: colorless
20
H O
3
2
D
2
ꢀ1
1
tiary carbinol as
methylerythritol.
a
single diastereomer, and in turn, 2-C-
oil; ½
aꢂ
¼ þ20:6 (c 1.04, CHCl
3
); IR: 3452, 3086, 1640 cm
;
H
NMR: d 1.24 (s, 3H), 1.28–1.61 (m, 10H), 2.06 (s, 1H), 3.79–3.90
(
1
1
m, 1H), 3.95–4.16 (m, 2H), 5.11–5.36 (m, 2H), 5.87–6.00 (m,
1
3
H); C NMR: d 23.2, 23.6, 23.8, 25.0, 34.6, 35.8, 64.7, 72.5, 80.6,
09.9, 113.5, 142.0. Anal. Calcd for C12 : C, 67.89; H, 9.50.
4
4
. Experimental
20 3
H O
Found: C, 67.72; H, 9.65.
.1. General experimental details
4
8
.5. (2S,3R)-3,4-Cyclohexanedioxy-2-methyl-2-hydroxybutanal
a
All chemicals (Fluka and Lancanster) were used as received. The
other reagents were of AR grade. All anhydrous reactions were
carried out under an Ar atmosphere using freshly dried solvents.
Unless otherwise mentioned, the organic extracts were dried over
Ozone was bubbled through a cooled (ꢀ78 °C) solution of 7a
(
0.800 g, 3.77 mmol) in CH
2
Cl
2
(20 mL) until the solution turned
anhydrous Na
2 4
SO . The IR spectra as thin films were scanned with
1
blue. After 0.5 h, the excess O
3
was removed by purging with N
P (2.0 g, 7.55 mmol), and stirred
2
a Jasco model A-202 FT-IR spectrophotometer. The H NMR
200 MHz) and C NMR (50 MHz) spectra were recorded with a
1
3
(
gas), the mixture treated with Ph
3
(
for 16 h at room temperature. Most of the solvent was removed in
vacuo, and the residue was dissolved in hexane and chromato-
graphed (silica gel, 0–10% EtOAc/hexane) to furnish pure 8a. Yield:
Bruker AC-200 spectrometer. The optical rotations were recorded
with a Jasco DIP 360 digital polarimeter.
2
2
.2. (2S/R,3R)-3,4-Cyclohexanedioxybutan-2-ol 512a
0.654 g (81%); colorless oil; ½
a
ꢂ
D
¼ þ16:05 (c 1.52, CHCl
439, 2775, 1732 cm ; H NMR (CDCl ): d 1.26–1.40 (m contain-
ing a s at d 1.32, 5H), 1.56–1.63 (m, 8H), 2.19 (s, 1H), 3.90–4.08 (m,
3
); IR:
4
ꢀ1 1
3
3
To a well stirred suspension of MeMgI [prepared from Mg
1
3
3
H), 9.69 (s, 1H); C NMR: d 23.5, 23.8, 24.9, 33.8, 35.6, 64.1, 77.3,
8.3, 110.6, 203.5. Anal. Calcd for C11 : C, 61.66; H, 8.47.
(1.73 g, 0.072 mol) and MeI (8.52 g, 0.06 mol)] in diethyl ether
(80 mL) was added compound 2 (2.50 g, 0.015 mol) in diethyl ether
(25 mL), and the mixture was stirred until the completion of the
7
18 4
H O
Found: C, 61.48; H, 8.45.
reaction (cf. TLC, ꢁ4 h). The reaction mixture was quenched with
4
.6. (2R,3R)-3,4-Cyclohexanedioxy-2-methylbutane-1,2-diol 9a
aqueous 10% NH Cl. The mixture was filtered and concentrated
4
in vacuo. The residue was dissolved in diethyl ether. The organic
layer was washed with water, brine, and dried. Solvent removal
in vacuo and column chromatography of the residue afforded the
To a cooled (ꢀ5 °C) and stirred suspension of LAH (0.060 g,
.58 mmol) in diethyl ether (20 mL) was added 8a (0.650 g,
.04 mmol) in diethyl ether (10 mL). After stirring the mixture
1
3
22
alcohol 5. Yield: 2.30 (84%); colorless oil; ½
a
ꢂ
¼ þ2:4 (c 1.21,
D
ꢀ1
1
for 3 h at room temperature, the excess hydride was decomposed
with aqueous saturated Na SO , the ether layer was decanted,
CHCl
3
); IR: 3380, 1478 cm
;
3
H NMR (CDCl ): d 1.12 (d,
J = 6.6 Hz, 3H), 1.23–1.39 (m, 4H), 1.57–1.61 (m, 6H), 2.05 (br,
2
4
H), 3.62–3.68 (m, 1H), 3.84–4.03 (m, 3H); 13C NMR: d 18.4, 18.5,
3.5, 23.7, 24.9, 34.5, 34.6, 35.9, 36.1, 64.6, 65.4, 67.0, 68.6, 78.9,
9.8, 109.3, 109.8.
and the solid residue extracted with the same solvent. Concentra-
1
2
7
tion of the organic extract in vacuo afforded pure 9a. Yield: 0.597
2
D
2
(
3
91%); white solid; mp: 110 °C; ½
a
ꢂ
¼ þ11:6 (c 1.02, CHCl
3
); IR:
ꢀ1
1
402 cm ; H NMR (CDCl ): d 1.16 (s, 3H), 1.24–1.40 (m, 2H),
3
.3. (3R)-3,4-Cyclohexanedioxybutan-2-one 612a
1.56–1.65 (m, 8H), 2.18 (s, 1H), 3.45 (d, J = 11.4 Hz, 1H), 3.74 (d,
J = 11.4 Hz, 1H), 3.83–3.90 (m, 1H), 3.97–4.12 (m, 2H); 13C NMR:
d 19.7, 23.6, 23.9, 25.1, 34.2, 35.9, 64.6, 67.3, 72.6, 78.4, 109.6. Anal.
4
To a cooled (0 °C) and stirred suspension of PCC (3.48 g,
Calcd for C11
20 4
H O : C, 61.09; H, 9.32. Found: C, 61.24; H, 9.42.
1
2 2
6.13 mmol) and NaOAc (0.130 g, 1.61 mmol) in CH Cl (30 mL)
was added the alcohol 5 (2.0 g, 10.75 mmol) in one portion. After
stirring for 3 h, the reaction mixture was diluted with diethyl ether
4
.7. (2R,3R)-2-Methylbutane-1,2,3,4-tetrol 1b
(
(
30 mL) and the supernatant was passed through a pad of silica gel
2 ꢃ 1). Removal of solvent in vacuo followed by column chroma-
0
0
A mixture of 9a (0.216 g, 1.0 mmol) and 80% aqueous TFA
0.3 mL) in CH Cl (25 mL) was stirred at 0 °C until the completion
of the reaction (cf. 3.5 h). The reaction mixture was concentrated in
(
2
2
tography of the residue (silica gel, 0–10% EtOAc/hexane) furnished
2
D
2
pure 6. Yield: 1.70 g (86%); colorless oil; ½
a
ꢂ
¼ þ32:0 (c 1.62,
ꢀ1
1
vacuo, the residue taken in MeOH, and subjected to preparative
CHCl
3
); IR: 1730 cm
3
; H NMR (CDCl ): d 1.42–1.57 (m, 10H),
2
D
2
TLC to obtain pure 1b. Yield: 0.120 g (89%); ½
aꢂ
¼ þ11:19 (c
2
1
1
.25 (s, 3H), 3.93–4.00 (m, 1H), 4.13–4.21 (m, 1H), 4.32–4.42 (m,
1
0e
20
D
ꢀ1
1
3
1
.41, MeOH), [lit.
½
a
ꢂ
¼ þ13 (c = 0.5, MeOH)]; IR: 3427 cm
;
H); C NMR: d 23.5, 23.7, 24.8, 26.1, 34.3, 35.5, 65.8, 79.9,
1
4
H NMR (MeOH-d ): d 1.14 (s, 3H), 3.39–3.48 (m, 1H), 3.60–3.77
11.4, 208.4.
1
3
(
m, 4H); C NMR: d 19.4, 61.7, 66.8, 73.5, 74.5.
4
.4. (3R/S,4R)-4,5-Cyclohexanedioxy-3-methylpent-1-en-3-ol
7
a/7b
4.8. (2R,3R)-3,4-Cyclohexanedioxy-2-methyl-2-hydroxybutanal
8
b
To a cooled (0 °C) and stirred solution of 6 (1.70 g, 9.24 mmol)
in THF (mL) was injected vinylmagnesium bromide (13.86 mmol,
.0 M in THF). After stirring for 4 h at 0 °C, the reaction was worked
2
D
2
Colourless oil; ½
aꢂ
¼ þ18:1 (c 1.14, CHCl
3
); IR: 3455, 2780,
ꢀ
1
1
1
1733 cm ; H NMR (CDCl ): d 1.16–1.40 (m containing a s at d
3
up as above, and the crude product was subjected to column chro-
matography (silica gel, 0–10% EtOAc/hexane) to furnish pure 7a
1.27, 5H), 1.62–1.77 (m, 8H), 2.07 (s, 1H), 3.83–3.88 (m, 1H),
3.91–4.16 (m, 1H), 4.24–4.30 (m, 1H), 9.65 (s, 1H); 13C NMR: d

2
170
A. Sharma et al. / Tetrahedron: Asymmetry 19 (2008) 2167–2170
1
8.6, 23.3, 23.5, 24.7, 34.0, 35.2, 63.7, 76.4, 77.1, 110.3, 202.6. Anal.
References
18 4
Calcd for C11H O : C, 61.66; H, 8.47. Found: C, 61.51; H, 8.55.
1
2
.
.
Poulter, C. D.; Rilling, H. C.. In Biosynthesis of Isoprenoid Compounds; Porter, J.
W., Spurgeon, S. L., Eds.; Wiley: New York, 1981; Vol. 1, pp 162–209.
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H.; Bacher, A. Chem. Biol. 1998, 5, R221–R233; (b) Rohmer, M. Nat. Prod. Rep.
4
.9. (2S,3R)-3,4-Cyclohexanedioxy-2-methylbutane-1,2-diol 9b
2
D
2
); IR: 3433 cm ; 1
ꢀ1
1999, 16, 565–574.
Thick liquid; ½
NMR (CDCl ): d 1.04 (s, 3H), 1.32–1.44 (m, 2H), 1.47–1.65 (m,
H), 2.26 (s, 1H), 3.42 (d, J = 11.4 Hz, 1H), 3.72 (d, J = 11.4 Hz,
H), 3.91–4.11 (m, 3H); 13C NMR: d 19.7, 23.6, 23.8, 24.9, 34.6,
a
ꢂ
¼ þ12:8 (c 1.72, CHCl
3
H
3
.
(a) Arigoni, D.; Sagner, S.; Latzel, C.; Eisenreich, W.; Bacher, A.; Zenk, M. H. Proc.
Natl. Acad. Sci. U.S.A. 1997, 94, 10600–10605; (b) Duvold, T.; Bravo, J.-M.; Pale-
Grosdemange, C.; Rohmer, M. Tetrahedron Lett. 1997, 38, 4769–4772; (c)
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S.; Kuzuyama, T.; Watanabe, H.; Seto, H. Proc. Natl. Acad. Sci. U.S.A. 1998, 95,
3
8
1
3
6
5.5, 64.3, 68.3, 71.4, 79.4 109.8. Anal. Calcd for C11
1.09; H, 9.32. Found: C, 60.92; H, 9.38.
20 4
H O : C,
9879–9884.
4.
(a) Rohmer, M. A mevalonate-independent route to isopentenyl diphosphate.
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4
.10. (2S,3R)-2-Methylbutane-1,2,3,4-tetrol 1b
1
999; Vol. 2, pp 45–67; (b) Dewick, P. M. Nat. Prod. Rep. 2002, 19, 181–222.
2
D
2
¼ þ15:0 (c 1.44, MeOH), [lit.10e
20
D
½
aꢂ
½
a
ꢂ
¼ þ16:5 (c 0.5,
5. (a) Anthonsen, T.; Hagen, S.; Kazi, M. A.; Shah, S. W.; Tagar, S. Acta Chem. Scand.
1976, B30, 91–93; (b) Dittrich, P.; Angyal, S. J. Phytochemistry 1988, 27, 935–
MeOH)]; IR: 3443 cm ; 1H NMR (MeOH-d
ꢀ1
4
): d 1.21 (s, 3H),
9
36; (c) Ahmed, A. A.; Abd El-Razek, M. H.; Abu Mostafa, E. A.; Williams, H. J.;
13
3
1
4
.48–3.60 (m, 2H), 3.65–3.78 (m, 3H); C NMR (MeOH-d ): d
9.5, 61.8, 66.4, 73.5, 75.2.
Scott, A. I.; Reibenspies, J. H.; Mabry, T. J. J. Nat. Prod. 1996, 59, 1171–1173; (d)
Shakamoto, I.; Ichimura, K.; Ohrui, H. Biosci. Biotechnol. Biochem. 2000, 64,
1
915–1922.
6.
(a) Rohmer, M. Prog. Drug. Res. 1998, 50, 135–154; (b) Jomar, H.; Wisner, J.;
Sanderbrand, S.; Altineicek, B.; Weidemeyer, C.; Hintz, M.; Turbachova, I.; Eberl,
M.; Zeidler, J.; Lichtenthaler, H. K.; Soldati, D.; Beck, E. Science 1999, 285, 1573–
0
0
4
.11. (2S,3R)-3,4-Cyclohexanedioxy-2-methyl-2-(1 ,3 -
propanediyldithio)butan-2-ol 10
1576; (c) Zeidler, J.; Schwender, J.; Mueller, C.; Lichtenthaler, H. K. Biochem. Soc.
t
Trans. 2000, 28, 796–798; (d) Lichtenthaler, H. K.; Zeidler, J.; Schwender, J.;
Muller, C. Z. Naturforsch., C: Biosci. 2000, 55, 305–313; (e) Dubey, V. S. Curr. Sci.
2002, 83, 685–688.
To a cooled (0 °C) and stirred suspension of BuOK (0.370 g,
3
.3 mmol) in anhydrous THF (10 mL) was injected 1,3-dithiane
(
0
0.396 g, 3.3 mmol) in anhydrous THF (5 mL). After stirring for
.5 h, compound 6 (0.552 g, 3.0 mmol) in anhydrous THF (5 mL)
was injected into the reaction mixture. After stirring for 3 h at
°C, the mixture was poured in ice-cold H O, and extracted with
diethyl ether. The ether layer was washed with H O and brine,
7. Jomaa, H.; Wiesner, J.; Sanderbrand, S.; Altincicek, B.; Weidemeyer, C.; Hintz,
M.; Turbachova, I.; Eberl, M.; Zeidler, J.; Lichtenthaler, H. K.; Soldati, D.; Beck, E.
Science 1999, 285, 1573–1576.
8.
(a) Andrae, M. O.; Crutzen, P. J. Science 1997, 276, 1052–1058; (b) Claeys, M.;
Graham, B.; Vas, G.; Wang, W.; Vermeylen, R.; Pashynska, V.; Cafmeyer, J.;
Guyon, P.; Andrae, M. O.; Artaxo, P.; Maenhaut, W. Science 2004, 303, 1173–
0
2
2
1176.
and dried. Removal of the solvent was followed by column chro-
matography (silica gel, 0–10% EtOAc/hexane) to give pure 10.
9.
(a) Kis, K.; Wungsintaweekul, J.; Eisenreich, W.; Zenk, M. H.; Bacher, A. J. Org.
Chem. 2000, 65, 587–592; (b) Koppisch, A. T.; Blagg, B. S. J.; Dale Poulter, C. Org.
Lett. 2000, 2, 215–217; (c) Fontana, A. J. Org. Chem. 2001, 66, 2506–2508; (d)
Hoeffler, J.-F.; Pale-Grosdemange, C.; Rohmer, M. Tetrahedron 2000, 56, 1485–
2
D
2
Yield: 0.657 (72%); pale yellow oil; ½
a
ꢂ
¼ þ12:45 (c 2.86, CHCl
3
);
): d 1.21–1.40 (m containing
a s at d 1.24, 5H), 1.49 (s, 1H), 1.62–1.77 (m, 8H), 2.04–2.11 (m,
H), 2.83–2.92 (m, 4H), 3.89–4.08 (m, 2H), 4.18 (s, 1H), 4.24–4.30
ꢀ
1 1
IR: 3472, 1280 cm
; H NMR (CDCl
3
1489; (e) Urbansky, M.; Davis, C. E.; Surjan, J. D.; Coates, R. M. Org. Lett. 2004, 6,
135–138.
10. (a) Fontana, A.; Messina, R.; Spinella, A.; Cimino, G. Tetrahedron Lett. 2000, 41,
7559–7562; (b) Sakamoto, I.; Ichimura, K.; Ohrui, H. Biosci. Biotechnol. Biochem.
2
1
3
(
m, 1H); C NMR: d 19.3, 23.7, 25.1, 25.8, 30.6, 34.6, 35.8, 50.2,
6.6, 64.4, 74.3, 78.6, 109.8. Anal. Calcd for C14 : C, 55.23;
H, 7.95; S, 21.06. Found: C, 55.42; H, 7.81; S, 21.24.
2
000, 64, 1915–1922; (c) Giner, J.-L.; Ferris, W. V.; Mullins, J. J. J. Org. Chem.
2002, 67, 4856–4859; (d) Enders, D.; Peiffer, E.; Raabe, G. Synthesis 2007, 1021;
e) Moen, A. R.; Ruud, K.; Anthonsen, T. Eur. J. Org. Chem. 2007, 1262–1266.
1. (a) Sharma, A.; Chattopadhyay, S. Tetrahedron: Asymmetry 1999, 10, 883–890;
b) Sharma, A.; Chattopadhyay, S. Enantiomer 2000, 5, 175–179; (c) Salaskar, A.;
5
24 3 2
H O S
(
1
(
4
.12. (2S,3R)-3,4-Cyclohexanedioxy-2-methyl-2-
Mayekar, N. V.; Sharma, A.; Nayak, S. K.; Chattopadhyay, A.; Chattopadhyay, S.
Synthesis 2005, 2777–2781; (d) Salaskar, A.; Sharma, A.; Chattopadhyay, S.
Tetrahedron: Asymmetry 2006, 17, 325–329; (e) Mula, S.; Chattopadhyay, S. Lett.
Org. Chem. 2006, 3, 54–55; (f) Sharma, A.; Roy, S.; Goswami, D.; Chattopadhyay,
A.; Chattopadhyay, S. Lett. Org. Chem. 2006, 3, 741–743.
hydroxybutanal 8a
To a stirred solution of 10 (0.650 g, 2.14 mmol) in 4:1 MeCN–
O (25 mL) were added MeI (3.04 g, 21.4 mol) and CaCO
1.07 g, 10.7 mol). The reaction mixture was stirred for 24 h at
room temperature, treated with H O (30 mL) and diethyl ether
60 mL), and further stirred for 1 h. The organic layer was sepa-
rated, and the aqueous portion was extracted with diethyl ether.
The combined organic extracts were washed with H O and brine,
and dried. Removal of solvent followed by column chromatography
silica gel, 0–10% EtOAc/hexane) of the residue furnished pure 8a.
Yield: 0.402 g (88%).
H
(
2
3
12. (a) Roy, S.; Sharma, A.; Dhotare, B. B.; Vichare, P.; Chattopadhyay, A.;
Chattopadhyay, S. Synthesis 2007, 1082–1090; (b) Roy, S.; Sharma, A.;
Chattopadhyay, N.; Chattopadhyay, S. Tetrahedron Lett. 2006, 46, 7067–7069.
2
13. Benagila, M.; Caporale, M.; Puglisi, A. Enantiomer 2002, 7, 383–385.
(
14. (a) Nicolaou, K. C.; Vourloumis, D.; Winssinger, N.; Baran, P. S. Angew. Chem.,
Int. Ed. 2000, 39, 44–122; (b) Corey, E. J.; Guzman-Perez, A. Angew. Chem., Int.
Ed. 1998, 37, 388–401; (c) Noyori, R. Asymmetric Catalysis in Organic Synthesis;
Wiley: New York, 1994.
2
(