Simple and versatile synthesis of branched polyols: (+)-2-C-methylerythritol and (+)-2-C-methylthreitol

Article abstract of DOI:10.1016/S0040-4039(00)01296-X

The paper reports a new approach for the enantioselective synthesis of 2-C-methyl tetrols. The procedure has been utilized for preparing methylthreitol and methylerythritol, a putative intermediate in the mevalonate-independent biosynthesis of terpenoids in bacteria, algae and higher plants. The methodology offers straightforward access to related compounds and isotopically labeled derivatives. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)01296-X

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 7559–7562
Simple and versatile synthesis of branched polyols:
(+)-2-C-methylerythritol and (+)-2-C-methylthreitol
Angelo Fontana,a,* Rossella Messina,a Aldo Spinellab and Guido Ciminoa
aIstituto per la Chimica di Molecole di Interesse Biologico (ICMIB), Consiglio Nazionale delle Ricerche (CNR),
Via Toiano 6, 80072 Arco Felice (Na), Italy
bDipartimento di Chimica, Facolta` di Scienze, Universita` degli Studi di Salerno, Baronissi (Sa), Italy
Received 31 May 2000; revised 17 July 2000; accepted 28 July 2000
Abstract
The paper reports a new approach for the enantioselective synthesis of 2-C-methyl tetrols. The
procedure has been utilized for preparing methylthreitol and methylerythritol, a putative intermediate in
the mevalonate-independent biosynthesis of terpenoids in bacteria, algae and higher plants. The method-
ology offers straightforward access to related compounds and isotopically labeled derivatives. © 2000
Elsevier Science Ltd. All rights reserved.
Keywords: terpenoids; biosynthesis; labeling; mevalonate independent route.
In the last few years, independent studies have accumulated evidence for the existence in
Gram-negative bacteria, algae and plant chloroplasts of a mevalonate-independent pathway
(MIP) for the biosynthesis of terpenoids.1–3 Besides the general interest in a new biosynthetic
route, the MIP steps are perfect targets for the development of new antimicrobial drugs.4,5 In the
MIP, the isoprene unit is derived from condensation of pyruvate and glyceraldehyde-3-phos-
phate via 1-deoxy- -xylulose-5-phosphate (DXP). Methylerythritol (1) that is formed by DXP-
D
reductoisomerase from DXP, has also been indicated as a putative intermediate for the
formation of isopentenyl phosphate (IP). The role of 1, as well as the remaining steps of the
MIP sequence, is still to be fully clarified. Isotopic experiments have, in fact, demonstrated that
the tetrol 1 is incorporated in the quinones of Escherichia coli with very low yield,6 thus
suggesting that other compounds (e.g. 2) can be actually involved in the biosynthetic process.6–8
Very recently, it has also been reported that a cytidylyltransferase that catalyzes the formation
of 4-(cytidine-5%-diphospho)-2-C-methylerythritol (3) from 2, may be involved in terpenoid
synthesis by MIP.9 It is, however, clear that more experiments with labeled compounds are
necessary. Accordingly, it has become crucial to have a facile access to these products. Recently,
* Corresponding author. Fax: +39 081 8041770; e-mail: afontana@icmib.na.cnr.it
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)01296-X

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three syntheses of 1 and its 4-phosphate derivative (2) have been independently reported.10–12 In
this paper we wish to describe a further approach for the enantioselective synthesis of
2-C-methyltetrols, such as 1 and 4, and, potentially, of other related molecules (e.g. 2).
(+)-2-C-Methyl- -erythritol (1) was obtained as reported in Scheme 1. The five-carbon
D
scaffold of 1 was achieved by one pot reaction starting from dimethylfumarate (5). In fact,
ozonolysis of 5 followed by Wittig reaction with the commercially available 6 gave the aldehyde
7.13 Direct reduction of this latter product prevented any loss of the volatile compound and
yielded, after chromatographic purification, the alcohol 8 in 86% overall yield. Under the
experimental conditions, addition of the triphenylphosphoranylidene 6 was highly specific and
the E isomer was obtained with 99% selectivity.14 Furthermore, this sequence of reactions
allowed the regiodifferentiation of the carbon atoms that correspond to C-1 and C-4 of
methylerythritol (1).† Benzylation of 8, followed by reduction of the ester 9 with DIBALH in dry
Scheme 1. i. O3, Ph3PꢀC(CH3)CHO (6); ii. NaBH4 (86% from 6); iii. BnBr, NaH, THF (56%); iv. DIBALH −78°C,
THF (87%); v. Ti(i-PrO)4, (+)-DET, t-BuOOH, −23°C in CH2Cl2 (93:7, 78%); vi. t-BuOH, 0.5 N NaOH, H2O, 75°C
(93%); vii. 10 Pd/C, H2 (100%)
† Preparation of 9. In a typical procedure, 11 g of dimethyl fumarate (73.6 mmol) in dry CH2Cl2 (600 mL) were
reacted with ozone at −78°C. When the starting material was totally consumed, 10 g (31.1 mmol of 2-triphenylphos-
phoranylidene)-3-propionaldehyde and 20 mL of Et3N were added slowly, and stirring was continued for 30 min. The
reaction mixture was left to warm up to room temperature and stirred for a further 4 h. The clear mixture was then
concentrated at reduced pressure. The slurry residue was dissolved in MeOH (400 mL) and an excess of NaBH4 was
added over a period of 30 min. The reaction was stirred at room temperature overnight. After evaporation of the
solvent and addition of 1N HCl, the mixture was extracted with Et2O three times. The organic layers were evaporated
and the colorless oil was fractionated on SiO2 column (petroleum ether/Et2O 80:20) to give 3.45 g (26.6 mmol) of 8,
that, after benzylation with benzylbromide and NaH, afforded 9 (48% from 6).

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THF led to the desired substrate (10) for the Sharpless epoxidation. A Payne rearrangement was
used to open the epoxide 11 with very high stereoselectivity and 93% yield.14 Hydrogenolysis of
the triol 12 yielded (+)-methylerythritol (1) in 84% enantiomeric excess and 31% overall yield
after 6 steps.‡
In a similar manner, the benzyl derivative 9 was converted to optically active threitol (4)
(Scheme 2). In this case, enantioselective dihydroxylation with AD-mix b was used to prepare
the diol 13 in 82% enantiomeric excess. Reduction of 13 with DIBALH led to the 1-benzyl
derivative of 2-C-methylthreitol (14) in almost quantitative yield. Deprotection of 14 afforded
(+)-4 in 78% enantiomeric excess and 38% overall yield.§
Scheme 2. i. AD-mix b, t-BuOH–H2O, −4°C (89%); ii. DIBALH −78°C, THF (91%); iii. 10% Pd/C, H2 (97%)
‡ Conversion of 9 to (+)-2-C-methylerythritol (1). In dry THF, the benzyl derivative 9 (358 mg, 1.63 mmol) was
reduced with 1M DIBALH in hexane (10.9 mL) at –78°C. The reaction was quenched by addition of MeOH/H2O 1:1.
The slurry suspension was diluted with Et2O and filtered through silica to give an oily residue from which 10 (270 mg,
1.42 mmol) was purified by SiO2 column (n-hexane/EtOAc 85:15). To a stirred solution of titanium(IV)isopropoxide
(284 mL, 0.9 mmol) and (+)-diethyl tartrate (61.8 mg, 1.18 mmol) in dry CH2Cl2 was added 10 (152 mg, 0.79 mmol)
at −23°C. The mixture was stirred at −23°C for 15 min and then TBHP in nonane (1.61 mmol) was added through
the septum. After 18 h at −23°C, the reaction was quenched with Na2SO4 and Et2O. The epoxide 11 (128 mg, 0.62
mmol) was obtained as colorless oil after extraction of the reaction mixture and purification on SiO2 column
(n-hexane/EtOAc 80:20). Compound 11 (120 mg, 0.58 mmol) was dissolved in 10 mL t-BuOH. To this solution were
added 5 mL 0.5M NaOH and 15 mL of distilled water. The clear mixture was stirred at 75°C for 8 h and then
extracted by EtOAc. The organic layer was evaporated at reduced pressure to give 122 mg (0.54 mmol) of 12. After
purification on silica gel, hydrogenation of 12 by 10% Pd/C gave quantitatively (+)-2-C-D-methylerythritol (1).
[h]D=+7.2 (c 0.4, MeOH) (lit. Ref. 6 and bibliography cited therein [h]D=+7.6 (c 1.6, MeOH), {[h]D=+14.6 (c 0.3,
1
H2O), ) (lit. Ref. 10 and bibliography cited therein [h]D=+9.0 (c 1.0, H2O)}; H NMR (400 MHz, D2O) l 1.03 (3H,
s, H3-5), 3.37 (1H, d, J=11.7 Hz, H-1a), 3.48 (1H, d, J=11.7 Hz, H-1b), 3.51 (1H, d, J=11.4 Hz, H-4a), 3.57 (1H,
bd, J=8.8 Hz, H-3), 3.73 (1H, d, J=11.4 Hz, H-4b); 13C NMR (100 MHz, D2O) l 20.4 (C-5), 63.2 (C-4), 63.9 (C-1),
73.2 (C-2), 76.9 (C-3). CIMS m/z 137 (35, M+H+), 119 (45), 101 (100). The enantiomeric excess (e.e.) was determined
by esterification with camphanic chloride of racemic and optically active 12. Integration of the signals at l 5.42 and
1
5.46 (dd, J=8.7 and 2.1 Hz, H-3) in the H NMR spectrum was used to calculate the reported e.e.
§ Conversion of 9 to (+)-2-C-methylthreitol (1). The alcohol 9 (367 mg, 1.66 mmol) was added at 0°C to 2.27 g
AD-mix b and 166 mg methanesulfonamide in 18 mL t-BuOH/H2O (1:1). The mixture was stirred at −4°C for 72 h.
The reaction was quenched by adding of Na2SO3 (2.47 g), and stirring was continued for 1 h at room temperature.
The yellow suspension was extracted with CH2Cl2 and the organic layer was washed with 2N NaOH and
concentrated. Column fractionation of the slurry gave 375 mg (1.47 mmol) of colorless oil 13. This latter compound
was reduced to 14 (305 mg, 1.34 mmol) with DIBALH under the experimental conditions described above. Final
removal of the benzyl group afforded (+)-2-C-methylthreitol (4) in almost quantitative yield (178 mg, 1.31 mmol).
Compound 4 was obtained as colorless oil, [h]D=+7.3 (c 0.8, MeOH); 1H NMR (400 MHz, D2O) l 1.11 (3H, s,
H3-5), 3.48 (1H, d, J=12.0 Hz, H-1a), 3.53 (1H, d, J=12.0 Hz, H-1b), 3.60 (1H, bd, J=11.5 Hz, H-4a), 3.68 (1H,
bm, H-3), 3.76 (1H, d, J=11.5 Hz, H-4b); 13C NMR (100 MHz, D2O) l 21.5 (C-5), 64.2 (C-4), 68.5 (C-1), 76.4 (C-2),
77.5 (C-3). CIMS m/z 137 (35, M+H+), 119 (75), 101 (100), 89 (20). HRCIMS (isobutane) m/z 137.1551 (required
137.1543 for C5H12O4+H+). The enantiomeric excess (e.e.) was determined by NMR analysis of the camphanyl
derivatives of racemic and optically active 13 and 14.

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One of the most interesting aspects of the methodology described here is its versatility. Simple
and quantitative reduction with LiAlD4 or similar reagents gives access easily to deuterium
containing products. Otherwise, the use of the commercially available [U-13C]-fumarate may
lead to [3,4-13C2]-2-C-methyl-
-erythritol in an easy and convenient manner. As demonstrated
D
by the short synthesis of (+)-4, the methodology has a very general application and can reliably
afford related products (e.g. 2). With respect to other syntheses, one of which leads to
enantiopure 2, the approach we have reported in this paper offers the possibility to introduce
labeling isotopes (2H or 13C) in every position of the erythritol molecule starting from
commercially available precursors. Syntheses of these compounds are now under way and they
will be the subject of a further communication.
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