Chiral oxazolidinones as electrophiles: Intramolecular cyclization reactions with carbanions and preparation of functionalized lactams

Abstract

The intramolecular cyclizations of oxazolidinones with carbanions adjacent to sulfones, sulfoxides and phosphonates proceed in high yields to obtain functionalized γ and δ lactams. The chiral oxazolidinone precursors can be readily synthesized from commercial amino acids. The lactams from this study are useful synthetic intermediates, as demonstrated by the synthesis of a precursor for levetiracetam, an antiepileptic drug.

It is generally thought that carbamates are unreactive toward nucleophilic attack and it is this feature that has made them the protecting groups of choice for amines. Benzyloxycarbonyl and t-butoxycarbonyl derivatives of amines are extensively used in synthesis due to their stability when exposed to basic nucleophiles and ease of subsequent removal. In reality, carbamates can serve as electrophiles in certain situations and have more potential than appreciated in synthetic transformations.

The reactions of N-Boc amines with internal oxygen and nitrogen nucleophiles have been used extensively for the synthesis of heterocycles including oxazolidinones and imidazolidinones.¹ There have been some reports in the literature in which carbamates act as electrophiles upon treatment with carbanionic nucleophiles. For example, a general route to amides via treatment of carbamates of primary amines with highly basic Grignard reagents has recently been disclosed.² The reactions of carbamates with sulfonyl carbanions have been used to synthesize amidosulfones in good yields.³ Similar reactions of carbamates with α-phosphono carbanions have also been reported.⁴

In contrast, there are only a few examples of intramolecular reaction of carbamates with carbon nucleophiles. The formal synthesis of the indole alkaloid deplancheine utilizing the cyclization of a phosphonate with an internal trichloroethyl carbamate is one particularly relevant example.⁵ Previous research in our laboratory demonstrated that carbamate derivatives of aminosulfones undergo intramolecular cyclization upon treatment with strong base to give α-sulfonyl lactams.⁶

The last few decades have witnessed an explosion in the use of oxazolidinones, cyclic carbamates, as chiral auxiliaries.⁷ Oxazolidinones, like their acyclic carbamates, have not been exploited as potential electrophiles in carbon-carbon bond forming reactions. In an interesting example, N-arylsulfonyl derivatives of oxazolidinones were found to undergo ortho or benzylic metalation. Intramolecular cyclization of the metalated intermediates on the oxazolidinone carbonyl led to the formation of various sulfamyl containing heterocycles including saccharins.⁸ Intramolecular cyclization of an aryllithium on an oxazolidinone has been used to prepare isoindolinones.⁹ Also, the intramolecular rearrangement of oxazolidinones to succinamides in the presence of base has been reported.¹⁰

As discussed, so far there has been very little interest in exploiting the electrophilic chemistry of oxazolidinones for synthetic purposes. A broad variety of chiral oxazolidinones can be readily accessed from commercially available amino acid starting materials.¹¹ In this paper, we disclose the results of our study on the intramolecular cyclization reactions of chiral oxazolidinones with stabilized carbanions and their applications in the preparation of functionalized lactams.

We hypothesized that oxazolidinones such as those shown in Scheme 1 carrying sulfones, sulfoxides and phosphonates should undergo deprotonation with LHMDS and then cyclize to give a bridged intermediate. Since oxygen is generally a better leaving group than nitrogen, the intermediate would collapse to give the lactam product. There was some question as to whether steric constraints would allow formation of the bicyclic intermediate in the intramolecular cyclization. One would expect the size of the newly generated ring to be critical for the success of this reaction.

Scheme 1.

Proposed Cyclization Reaction of Oxazolidinones

The requisite sulfonyl, sulfinyl and phosphono oxazolidinones (n=1) for the cyclization studies were conveniently accessed from alcohol 1a which has been previously prepared from L-aspartic acid (Scheme 2).¹² The alcohol 1b (n=2) was prepared in a similar manner starting from L-glutamic acid. Selective N-benzylation of 1a–b was achieved upon treatment of the substrates with benzyl bromide and KF/Al₂O₃. Subsequent treatment of N-benzyl oxazolidinones 2a–b with methanesulfonyl chloride in the presence of triethylamine in DCM gave the corresponding mesylates 3a–b in good yields.

Scheme 2.

Synthesis of Mesylates 3a and 3b

The oxazolidinones 3a–b were easily converted to the corresponding sulfonyl, sulfinyl and phosphono derivatives (Scheme 3). Mesylates 3a–b reacted with thiophenol in the presence of DBU in benzene to give phenyl sulfides 4a–b. These were oxidized to give the sulfones 5a–b and sulfoxides 6a–b using mCPBA and NaIO₄, respectively. Reaction of the mesylates with the sodium salt of diethyl phosphite gave phosphonates 7a–b. N-allyl oxazolidinone 8b was prepared for this study from the N-benzyl oxazolidinone 5b, which was in hand. The oxazolidinone 5b was debenzylated by hydrogenolysis in the presence of PdCl₂ to give 8a, which was then treated with allyl bromide and KF/Al₂O₃ to give N-allyl oxazolidinone 8b.

Scheme 3.

Synthesis of Sulfone, Sulfoxide and Phosphono Oxazolidinones 5–8

With oxazolidinones 5–8 in hand, their intramolecular cyclization reactions were examined. In a representative example, the sulfone 5a was treated with LHMDS (2.1 eq) in THF at −78°C for five hours and then the reaction mixture warmed to 0°C for an additional hour. The reaction mixture was quenched with acetic acid and worked up using standard procedures. As predicted, the hydroxymethyl lactam 9a was obtained as the major product (~40%) along with surprisingly some of its O-trimethylsilyl derivative (presumably formed by the silylation of the alkoxide of 9a with hexamethyldisilazane under the reaction conditions). Subsequent reactions were worked up with 2N HCl in order to isolate only the desired product. With this change in work up, the yield of the cyclization improved dramatically to give 9a in a yield of 95% after chromatographic purification. Using the same reaction protocol, the intramolecular cyclizations of the other sulfonyl, sulfinyl and phosphono oxazolidinone derivatives 5–8 were found to proceed in excellent yields (Table 1).¹³

Table 1.

Results of the Cyclization Reactions of Oxazolidinones 5–8

Oxazolidinone	Conditions	Lactama	Yield (%)
5a	LHMDS (2.1 eq) THF, N2 −78°C, 5h; 0°C, 1h		95
5b	LHMDS (2.1 eq) THF, N2 −78°C, 2h; 0°C, 1h		81
6a	LHMDS (2.1 eq) THF, N2 −78°C, 5h; 0°C, 1h		90
6b	LHMDS (2.1 eq) THF, N2 −78°C, 5h; 0°C, 1h		94
7a	LHMDS (2.1 eq) THF, N2 −78°C, 2h; 0°C, 1h		96
7b	LHMDS (2.1 eq) THF, N2 −78°C, 4h; 0°C, 1h		98
8	LHMDS (2.1 eq) THF, N2 −78°C, 3.5h; 0°C, 1h		Quant.

^aisolated as mixtures of diastereomers

The intramolecular cyclization of oxazolidinones provided access to a variety of functionalized chiral lactams. The chemistry of the sulfoxide and phosphonate lactams was of particular interest as they have the potential to be valuable synthetic intermediates. When sulfoxide lactams 9c and 9d were heated at 100°C in the presence of PPh₃ on polystyrene, α,β-unsaturated lactams 10a and 10b were obtained in good yields after chromatography (Scheme 4). It is important to note that stereoselective 1,4-additions to α,β-unsaturated lactams have found much use in the synthesis of biologically active targets.^14,15 Indeed, the stereoselective 1,4-addition of an aryl cuprate to the O-silylated N-Boc analog of 10a has been used in the asymmetric synthesis of (R)-(−)-Rolipram, a potent inhibitor of cardiac cyclic AMP phosphodiesterase¹⁶, and (R)-Baclofen, a derivative of the inhibitory neurotransmitter GABA.¹⁷ It is our belief that the ready availability of 10a and 10b should allow preparation of some drugs of interest and their analogs.

Scheme 4.

Thermal Elimination of Sulfinyl Lactams 9c and 9d

It was also of interest to study the Horner-Wadsworth-Emmons (HWE) reactions of phosphonolactams 9e and 9f. Lactam 9e was treated with propionaldehyde in the presence of DBU and LiCl to give the α,β-unsaturated lactam which was subjected to Pd/C catalyzed hydrogenation giving 11a in 56% yield after column chromatography (Scheme 5). Phosphonolactam 9f was treated in a similar manner with propionaldehyde in the presence of DBU and LiCl. In this case, in an attempt to aid in product isolation, the crude HWE product was treated with TBDMSCl, TEA and DMAP to give the O-silylated product 11b, which was easily isolated in high purity after chromatographic purification. The O-silylated product was then hydrogenated and the silyl group was removed by treatment with TBAF to give 11c in good yield. In the case of both 11a and 11c, only one stereoisomer, presumed to be cis, was isolated after purification. Both ¹H and ¹³C NMR spectra clearly indicated that the hydrogenations proceed with high diastereoselectivity.¹⁸

Scheme 5.

HWE Reaction and Hydrogenation of Phosphono lactams 9e and 9f

The intramolecular cyclizations of oxazolidinones 5–8 proceeded to give functionalized lactams in excellent yields. Now it was of interest to see whether such cyclization reactions could be extended to oxazolidinones of the type I, in which the electron withdrawing moiety is attached to the nitrogen of the oxazolidinone ring system and not tethered to a carbon in the ring (Scheme 6). An important driving force for this study was a desire to apply our new methodology to the synthesis of a key lactam intermediate 12, which has found use in the synthesis of the anti-epileptic drug levetiracetam, which is marketed under the name of Keppra®.¹⁹ Although a number of other multi-step racemic and chiral syntheses have also been reported for levetiracetam²⁰, our method would be new and would provide a pathway to make analogs of the drug including the corresponding δ-lactam.

Scheme 6.

Retrosynthetic Analysis of Levetiracetam and Potential Analogs

The required starting material for this synthesis, (S)-4-ethyl-2-oxazolidinone, was readily prepared from (S)-2-amino-1-butanol.²¹ Treatment of the oxazolidinone with phenylsulfinylpropyl bromide and KF/Al₂O₃ gave the sulfide, which was oxidized with NaIO₄ to give cyclization substrate 13 in 73% yield (Scheme 7). The oxazolidinone 13 underwent cyclization upon treatment with LHMDS to give sulfinyl lactam 14 in 93% yield after chromatographic purification. Attempts to directly remove the sulfinyl group using Ni₂B led to the isolation of a mixture of products.²² Thus, desulfinylation of lactam 14 was achieved via thermal elimination of the sulfoxide by heating with PS-PPh₃ followed by hydrogenation to give the known intermediate 12²³, which has been converted to levetiracetam in two steps.

Scheme 7.

Synthesis of Levetiracetam Intermediate 12

In summary, the intramolecular cyclizations of oxazolidinones with carbanions of sulfones, sulfoxides and phosphonates are a useful and hitherto unexplored class of reactions. The results detailed in this paper clearly demonstrate that these cyclic carbamates are effective electrophiles and can serve as precursors to prepare functionalized chiral γ and δ lactams that can be further manipulated. The oxazolidinone cyclization chemistry was also used to access a key intermediate in the synthesis of an important medicinal compound, levetiracetam. Our studies stress the need for further investigation on the electrophilic chemistry of oxazolidinones. This includes extension of the intramolecular cyclizations to the corresponding six-membered 1,3-oxazinan-2-ones and applications to the synthesis of other biologically interesting azacyclic systems.