A simple three-step method for preparing homochiral 5-trityloxymethyl-2-oxazolidinones from optically active 3-hydroxy-γ-butyrolactones

Article abstract of DOI:10.1016/S0957-4166(00)00438-9

A simple high-yield three-step route to O-tritylated optically active 5-hydroxymethyl oxazolidinones from optically active 3-hydroxy-γ-butyrolactones is described. The key intermediate is the 4-O-trityl ether of homochiral 3,4-dihydroxybutyramide, which is obtained in quantitative yield from 3-hydroxy-γ-butyrolactone by treatment with ammonia. It is readily transformed to the oxazolidinone by Hoffmann rearrangement in a two-phase system. The carbonyl group in the oxazolidinone is derived from C-1 of the amide, and a separate carbonylation reaction is not required. Oxazolidinones are key compounds in drug synthesis especially in the areas of antibacterials and behavior disorder therapy.

Full text of DOI:10.1016/S0957-4166(00)00438-9

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 11 (2000) 4429–4432
A simple three-step method for preparing homochiral
5-trityloxymethyl-2-oxazolidinones from optically active
3-hydroxy-g-butyrolactones
Guijun Wang and Rawle I. Hollingsworth*
Department of Chemistry, Michigan State University, East Lansing, MI 48824, USA
Received 23 June 2000; revised 5 October 2000; accepted 9 October 2000
Abstract
A simple high-yield three-step route to O-tritylated optically active 5-hydroxymethyl oxazolidinones
from optically active 3-hydroxy-g-butyrolactones is described. The key intermediate is the 4-O-trityl ether
of homochiral 3,4-dihydroxybutyramide, which is obtained in quantitative yield from 3-hydroxy-g-butyro-
lactone by treatment with ammonia. It is readily transformed to the oxazolidinone by Hoffmann
rearrangement in a two-phase system. The carbonyl group in the oxazolidinone is derived from C-1 of the
amide, and a separate carbonylation reaction is not required. Oxazolidinones are key compounds in drug
synthesis especially in the areas of antibacterials and behavior disorder therapy. © 2000 Elsevier Science
Ltd. All rights reserved.
Oxazolidinones have emerged as a very important class of compounds in drug development
especially in the areas of antimicrobials1–7 and behavioral disorders.8,9 They are thought to
function by the inhibition of protein synthesis and are especially active against some of the most
resistant human pathogens including vancomycin-resistant enterococci, methicillin-resistant
Staphylococcus aureus, cephalosporin-resistant Streptococcus pneumoniae and several organisms
that display penicillin resistance. Of the clinically important oxazolidinones, the one that has
perhaps the most prominence is Linezolid.3–7,10–13 This compound 1 was recently approved for
the treatment of infections from antibiotic-resistant bacterial strains especially those that are
resistant to vancomycin.
* Corresponding author. E-mail: rih@argus.cem.msu.edu
0957-4166/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(00)00438-9

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G. Wang, R. I. Hollingsworth / Tetrahedron: Asymmetry 11 (2000) 4429–4432
Homochiral oxazolidinones can, of course, be obtained by carbonylation of vicinal amino
alcohols obtained from the reduction of amino acids with reagents such as phosgene, ethyl
chloroformate and carbonyl imidazole. More recently,14 an interesting carbonylation reaction
involving palladium mediated carbonylation of amino alcohols was described. Oxazolidinones
derived from amino acids are, however, limited in structure not just with respect to the position
of the side chain (which must be adjacent to the ring nitrogen), but also by the type of side
chain.
A common strategy for synthesizing optically active oxazolidinones is to incorporate the
three-carbon core from an optically active glycidol or equivalent. This was, in fact, the strategy
used in the synthesis of Linezolid.15 In this case the source was glycidyl butyrate and the
synthesis involved the alkylation of this substrate with N-lithioarylcarbamates. The synthesis
required several steps for forming the oxazolidinone ring. Optically active 3,4-dihydroxy-
butanoic acids and their g-lactones are important sources of chirality. They can be obtained
from carbohydrates such as starch, lactose, maltodextrins, cellulose and arabinose by oxidative
degradation.16,17 In previous studies,18 we explored the synthesis of amino propane diols by
Hoffman degradation of the isopropylidene acetals of optically active 3,4-dihydroxybutyric acid
amide. This reaction proceeded smoothly to yield the desired product. Because an isocyanate
that is hydrolyzed with water is an intermediate species in the Hoffman rearrangement, in
principle a vicinal hydroxyl group can act as a nucleophile resulting in cyclization to form an
oxazolidinone system. In this case, a separate carbonylation reaction using phosgene, ethyl
chloroformate or some similar reagent would be avoided. This is illustrated for the 4-trityl ether
of (S)-3,4-dihydroxybutyric acid amide in Scheme 1. Similar trapping of an intermediate
isocyanate in related reactions involving migration to electron-deficient nitrogen centers have
been observed before.19–21
Scheme 1.
This process involves essentially only two steps. The first is the preparation of the trityl ether
from the dihydroxybutyric acid amide 2.22 The amide is obtained in quantitative yield by
treating the 3-hydroxy-g-butyrolactone with aqueous ammonia at room temperature.18 The
second step is the rearrangement of the trityl ether under conditions where the intermediate
isocyanate is protected from water allowing the neighboring hydroxyl group to participate.
Hoffman rearrangement using a two-phase solvent system, in this case tetrahydrofuran/water,23
gave the protected hydroxymethyl oxazolidinone 4 directly in >90% isolated yield and in >99%

G. Wang, R. I. Hollingsworth / Tetrahedron: Asymmetry 11 (2000) 4429–4432
4431
enantiomeric excess.24 This represents a tremendous economy in the synthesis of an important,
homochiral protected 5-(hydroxymethyl)-2-oxazolidinone in essentially four steps from starch,
maltose, lactose or similar 4-linked carbohydrate source. The trityl group can be selectively
removed allowing the hydroxymethyl function to be transformed into a wide variety of
substituents. The ring nitrogen can certainly be alkylated and should also be a good candidate
for arylation. The N-arylation of related functional groups such as lactams25,26 and acyclic
amides26 is well known. The more recent iteration of this variant of the Buchwald method is
applicable even to electron-rich aromatic compounds and to carbamates and sulfonamides. The
applicability to carbamates is of special relevance to the N-arylation of oxazolidinones. The
potential functionalizability of these compounds should allow ready access to a large spectrum
of possible drug candidates.
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22. (S)-3,4-Dihydroxybutyramide (11.9 g, 0.10 mol) was dissolved in 50 ml of tetrahydrofuran and 50 ml
of dimethylformamide and 10 ml of pyridine followed by 30.6 g (0.11 mol) of trityl chloride were added to the
flask. A drying tube filled with calcium chloride was used to exclude moisture. The reaction mixture was stirred at
room temperature for 36 hours. After this period of time, it was filtered to remove the solid. The liquid
was concentrated under reduced pressure to remove most of the solvent. The solution was poured into ice
water, stirred for half an hour and the water layer was removed from the trityl protected amide. The product
which was obtained as a viscous liquid was dried under vacuum. The excess trityl chloride was washed away

4432
G. Wang, R. I. Hollingsworth / Tetrahedron: Asymmetry 11 (2000) 4429–4432
by trituration with hexane. The yield was 33.0 g (91%). Physical data: mp 59.0–60.0°C. (from solvent
1
dichloromethane:hexane:acetone=6:3:0.5) [h]2D5= −53.5 (c=0.5, methanol). H NMR (300 MHz, CDCl3) ppm,
7.50–7.20 (m, 15 H), 6.17 (s, 1H), 5.62 (s, 1H), 4.19 (m, 1H), 3.17 (d, 2H, J=5.7 Hz), 2.41 (m, 2H). 13C NMR
(75 MHz, CDCl3) ppm, 174.8, 143.5, 128.3, 127.5, 126.7, 86.3, 67.4, 39.2 (one carbonyl carbon was not
observable). FTIR cm−1 3345, 1667, 1600, 1490, 1448, 1218, 1074, 763, 703.
23. Preparation of the (S)-5-trityloxymethyl-2-oxazolidinone 4: The (S)-4-trityloxy-3-hydroxybutyramide 3 (3.61g,
0.01 mol) was dissolved in 30 ml THF. 13% Sodium hypochlorite solution (15 ml) was added to the solution and
the mixture was stirred vigorously and then 1.6 g of sodium hydroxide dissolved in 10 ml of water was added.
The reaction was stirred at 55–60°C for 8 hours after which time the rearrangement was completed as indicated
1
by TLC and H NMR spectroscopy. The THF layer was separated from the water layer. The water layer was
extracted three times with THF. The combined organic layer was concentrated to remove solvent. The residue
was taken up in dichloromethane and the solution dried over sodium sulfate. It was concentrated to remove
solvent again and oxazolidinone was obtained as a white crystalline product (3.4 g, yield 95%). This crude
product normally did not need further purification. Mp (solvent: chloroform:hexane:acetone=6:3:1), 206.0–
207°C. [h]2D5=+35.5 (c=1.0, methanol). 1H NMR (300 MHz, CDCl3) ppm, 7.50–7.20 (m, 15 H), 5.88 (s, 1H), 4.75
(m, 1H), 3.61 (m, 1H), 3.45 (m, 1H), 3.40 (dd, 1H, J=10.2, 4.5 Hz), 3.23 (dd, 1H, J=10.2, 4.5 Hz). 13C NMR
(75 MHz, CDCl3) ppm, 159.8, 143.4, 128.6, 127.9, 127.2, 86.8, 75.4, 64.2, 42.6. IR cm−1 3272, 1753, 1489, 1448,
1085, 748.5, 705.5. MS (electron impact) m/z 105, 165, 183, 243, 258, 259, 282, 359. HRMS: MH+ C23H22NO3,
360.1590, theoretical molecular mass 360.1600.
24. The enantiomeric excess of the product was >99.9% e.e. based on GC analysis of (S)-(−)-a-methoxy-a-(tri-
fluoromethyl)phenylacetic acid (Mosher’s acid) derivatives.
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