Stereoselective Total Synthesis of the Potent Anti-Asthmatic Compound CMI-977 (LDP-977)

Neste trabalho, uma síntese curta e eficiente para o CMI-977 (LDP-977), um potente agente antiasmático oralmente ativo, é descrita. As etapas chave envolveram uma ciclização oxidativa de Mukaiyama, fornecendo a unidade trans-THF (tetrahidrofurano) e uma reação de homologação de Seyferth-Gilbert para construção da tripla ligação da molécula alvo. A síntese do bloco de construção chiral chave foi realizada a partir do emprego da resolução cinética hidrolítica de Jacobsen.


Introduction
Asthma is a chronic inflammatory disease of the respiratory system that results in the reduction or even the obstruction of air flow into the lungs. 1 Over the last 40 years, there have been sharp increases in the global prevalence of asthma and the mortality due to this condition. In 2006, approximately 300 million people worldwide developed asthma, and there are approximately 180,000 deaths annually. 2 In Brazil, asthma is the third most common cause of hospitalization in the Brazilian Unified Health System (SUS). 3 The underdiagnosis and undertreatment of this disease have motivated the scientific community to search for new target-specific drugs to treat asthma and related respiratory diseases. 4 The compound CMI-977 (LDP-977) (1) was discovered by Cyto-Med Inc., USA, 5 and has been demonstrated to be a prominent candidate for the treatment of chronic asthma ( Figure 1). This compound inhibits the 5-lipoxygenase pathway, thus blocking the production of leukotrienes. 6 LDP-977 (1), containing a THF-2,5-trans-substituted ring with a (2S,5S) configuration, is orally active, and exhibits a good safety profile, a high degree of potency and excellent oral bioavailability relative to the three other stereoisomers. 5 Over the years, several synthetic routes have been proposed for the stereoselective synthesis of the THF moiety present in CMI-977 (1) (Scheme 1). 5,7,8 Intermediate 4 was prepared by Cyto-Med Inc., USA, using the first synthetic route developed, 5 which involved a chiral pool approach for the creation of the C9 stereogenic center (Scheme 1). A nucleophilic attack involving an oxonium electrophile intermediate, obtained from 3, produced C6, but a disappointing low degree of selectivity was observed. In a similar oxonium strategy, Ley and co-workers 7 employed an anomeric oxygen to promote the carbon rearrangement of an alkynyltributylstannane to access the THF unit, but their reaction also exhibited low selectivity (Scheme 1). Other similar strategies have led to similar results. 8 Gurjar et al. 9 reported a new stereoselective approach that installs the stereocenters at C6 and C9 in 6 using both Jacobsen hydrolytic kinetic resolution (HKR) and a Sharpless asymmetric epoxidation step (Scheme 1). The formation of a tandem propargyl alkoxide followed by  Ley and co-workers 10 also explored a similar tandem strategy providing the suitable intermediate 11, which in turn afforded the key fragment 7. These two new approaches were clearly superior for the construction of the 2,5-anti THF unit as higher levels of diastereoselectivity were achieved. However, numerous steps are involved in these synthetic routes.
In this paper, it is described our approach for the total synthesis of CMI-977 (LDP-977) (1). The biological importance of the target molecule and its structural features inspired us to devise a more concise and diastereoselective route to achieve the THF-2,5-trans ring of intermediate 7.

Results and Discussion
Retrosynthetic analysis of CMI-977 (LDP-977) (1) Our disconnection approach began with a long-established strategy for the insertion of the N-hydroxy urea moiety by alkylation involving acetylene 7 and epoxide 13, followed by a Mitsunobu-like reaction involving alcohol 4 and hydroxycarbamate 12 (Scheme 2). 9,10 The terminal acetylene 7 can be assembled via Seyferth-Gilbert homologation (using the Ohira-Bestmann protocol) 11 involving the aldehyde prepared from alcohol 14. It was intended to create the trans-THF configuration in our key fragment 14 using a Mukaiyama oxidative cyclization protocol with homoallylic alcohol 15. 12 The functional groups in fragment 15 could be installed starting from commercially available and inexpensive 4-fluorophenol 16, rac-epichlorohydrin 17 and allylbromomagnesium 18, in a strategy similar to that applied by Gurjar et al. 9 Preparation of the key fragment 14 Our approach to the total synthesis of CMI-977 (LDP-977) (1) began with the reaction of p-fluorophenol 16 with rac-epichlorohydrin 17 in the presence of KOH, providing rac-5 in 97% yield (Scheme 3). 13 The epoxide rac-5 was resolved by hydrolytic kinetic resolution under Jacobsen conditions, 14 using the catalyst (R,R)-(salen)Co III (OAc) (19, 0.5 mol%) and H 2 O (0.57 equiv) in tert-butyl methyl ether, providing (S)-5 in a 48% yield. 9 The next step involved the epoxide ring-opening of (S)-5 with allylmagnesium bromide (18) Ethylene oxide (13)

15 18
Cl O Mukaiyama protocol, 12 mediated by the Co(modp) 2 (20) (30 mol%) catalyst, 15 provided trans-THF 14 as the only observed diastereoisomer in an 84% yield. 8 This approach has proven to be a powerful strategy for accessing the 2,5-trans-THF unit in a highly diastereoselective fashion.

Preparation of the key fragment 4 and conclusion of the synthesis
The alcohol 14 was then oxidized to aldehyde 21 under Parikh-Doering conditions, followed by Seyferth-Gilbert homologation 16 using the Ohira-Bestmann reagent 22, 11 assembling the terminal acetylene 7 in a 75% yield over two steps (Scheme 5). The 1 H NMR and 13 C NMR spectra and the optical rotation of trans-THF 7 matched the reported values for this compound. 9 Next, the treatment of 7 with n-BuLi and ethylene oxide 13 led to alcohol 4 in a 70% yield. As shown in Scheme 5, the preparation of hydroxycarbamate 26 (53% yield), followed by its acetylation using acetyl chloride 27, provided 12 in a quantitative yield. A Mitsunobu-like reaction between alcohol 4 and N-hydroxycarbamate 12 provided 23 in a 93% yield. Finally, 23 was ammonolysed with NH 3 ·MeOH, yielding CMI-977 as a white solid in a 38% yield. The spectral and physical data of the synthetic sample were in complete agreement with those reported in the literature. 5

Conclusions
In conclusion, it was developed a novel total synthesis of CMI-977 (LDP-977) (1) involving 9 steps from fluorophenol 16. This route is more concise than the previous synthetic routes reported for CMI-977 (LDP-977) (1). Our synthetic strategy employed a high diastereoselective Mukaiyama oxidative cyclization provide the trans-THF ring, and this approach reduced the number of reaction steps necessary to achieve the acetylenic intermediate 4.
This intermediate was obtained in a highly stereoselective fashion using amenable and easily scalable reactions. Moreover, the key chiral epoxide was prepared by Jacobsen hydrolytic kinetic resolution, and the starting reagents are commercially and readily available.