Key words maresins - asymmetric synthesis - trienes - Swern oxidation
Resolvins and protectins, metabolized from polyunsaturated fatty acids, are specialized pro-resolving mediators (SPMs).[1 ] SPMs have been reported to actively promote the resolution of inflammation. In 2014, Serhan isolated maresin 2 from human macrophages as a metabolite derived from docosahexaenoic acid (Figure [1 ]).[2 ] This compound shows a strong antiinflammatory effect at 1 ng per mouse in a mouse peritonitis model.[2 ] Maresin 2n-3 DPA , possessing a single bond at the C4–C5 position of maresin 2, also shows an antiinflammatory effect.[3 ] Several SPMs are undergoing initial clinical trials, and maresin 1 has recently been reported to possess wound-healing activity.[4 ] Consequently, maresin 2 and maresin 2n-3 DPA are also of interest as candidates for drug-discovery research. However, maresins are available only in minute amounts from natural sources. In addition, commercially available maresin 2 is expensive, making it difficult to obtain sufficient amounts. The groups of Spur and Hansen have reported syntheses of these compounds through the chiral-pool method with 2-deoxy-d -ribose as a starting material.[5 ] However, drug-discovery research requires a flexible synthetic method that can efficiently supply the desired chiral centers. We have previously synthesized various lipid mediators by constructing chiral centers by asymmetric reactions.[6 ] Here, we report stereoselective syntheses of maresin 2 and maresin 2n-3 DPA by using asymmetric reactions.
Figure 1 Structures of maresins
Scheme [1 ] outlines our retrosynthetic analysis of maresin 2 (2 ). We planned to construct the triene of 2 by connecting two components, the terminal alkyne 4 and the iodoalkene 5 , by a Sonogashira coupling reaction, followed by acetylene reduction.[6 ] The internal cis -olefin 4 would be obtained from γ-butyrolactone by a Wittig reaction. The vicinal diol at C13–C14 would be constructed stereoselectively by a Sharpless asymmetric epoxidation, followed by an epoxide ring opening of the β,γ-epoxy aldehyde.
Scheme 1 Retrosynthetic analysis of maresin 2 (2 )
The first step in our synthesis of maresin 2 (2 ) involved the preparation of enyne 4 (Scheme [2 ]). Phosphonium salt 9 was synthesized from but-3-yn-1-ol (8 ) by a previously reported procedure.[7 ] The ring-opening reaction of γ-butyrolactone (10 ) with Et3 N/MeOH generated the corresponding alcohol, which was then oxidized with sulfur trioxide/pyridine (SO3 ·py) to yield aldehyde 11 . Wittig reaction of 11 with phosphonium salt 9 in the presence of NaHMDS afforded the terminal alkyne 4
[8 ] in 64% yield over the three steps.
Scheme 2 Synthesis of terminal alkyne 4
Next, the iodoolefin 5 was prepared via the epoxy alcohol 19 . Propane-1,3-diol (12 ) was converted into the silyl ether 13 by a reported procedure (Scheme [3 ]).[9 ] Oxidation of 13 by SO3 ·py was followed by the addition of alkyne 14
[10 ] to the resulting aldehyde to give alcohol rac -15 in 65% yield. Oxidation of rac -15 followed by asymmetric transfer hydrogenation[11 ] produced the optically active alcohol (S )-15 in 69% yield with 98% ee, as determined by 1 H NMR analysis of its α-methoxy-α-(trifluoromethyl)phenylacetic (MTPA) ester derivative. Treatment of (S )-15 with Red-Al not only reduced the triple bond, but also promoted deprotection of the TBDPS group. As a result, the resulting primary hydroxy group was protected once again with TBDPSCl to give allylic alcohol 17
[8 ] in 51% yield. This was then converted into the epoxy alcohol 18 by a Sharpless asymmetric epoxidation[6c ]
[12 ] in 75% yield with >99% ee, as determined by 1 H NMR analysis of the MTPA ester derivative. In this reaction, the enantiomeric purity was improved by kinetic resolution of 17 (98% ee). Protection of epoxy alcohol 18 followed by deprotection using DDQ afforded alcohol 19 in 58% yield.
Scheme 3 Synthesis of epoxy alcohol 19
Enal 20 ,[8 ] containing a vicinal diol, was prepared in 69% yield by oxidation of epoxy alcohol 19 followed by cleavage of the epoxide ring (Scheme [4 ]). Protection of 20 with TBSOTf in the presence of 2,6-lutidine gave the disilyl ether 21 in 83% yield; this was subsequently converted into enyne 22 (76% yield) by treatment with TMSCHN2 and LDA.[13 ] The (E )-stereoselectivity of the olefin in 22 was >99%, as determined by 1 H NMR spectroscopy. Hydrozirconation of 22 with Cp2 Zr(H)Cl, generated in situ from Cp2 ZrCl2 and DIBAL,[14 ] followed by iodination of the resulting vinylzirconium species with I2 produced vinyl iodide 23 .[8 ] The TBS and TBDPS groups in 23 were then replaced by TES groups in a two-step reaction to produce 24 . Swern oxidation[15 ] of 24 occurred regioselectively at the terminal carbon to afford an aldehyde that, upon Wittig reaction with phosphonium salt 7
[5a ] followed by desilylation, afforded iodoolefin 5
[8 ] in 59% yield over three steps.
Scheme 4 Synthesis of iodoolefin 5
In the last stage, the synthesis of maresin 2 (2 ) was completed, as shown in Scheme [5 ]. Polyene 25 was synthesized in 61% yield by Sonogashira coupling of the alkyne 4 and iodoolefin 5 .[6 ] Finally, reduction of 25 by Zn(Cu/Ag),[6b ]
[c ]
,
[16 ] followed by hydrolysis with aqueous LiOH afforded maresin 2 (2 ) in 63% yield.[17 ] The spectral data (NMR and UV) of 2 were in good agreement with those reported previously.[5b ]
Scheme 5 Synthesis of maresin 2 (2 )
Next, maresin 2n-3 DPA (3 ) was synthesized according to the method shown in Scheme [6 ]. Alkyne 28 was obtained by Sonogashira coupling of iodoolefin 5 with alkyne 27 , prepared from oct-7-yn-1-ol (26 ) in three steps. Maresin 2n-3 DPA (3 ) was then synthesized in a two-step reaction by using the same method as used for 2 . The spectral data (NMR and UV) and [α]
d
of 3 were consistent with those reported previously.[5a ]
Scheme 6 Synthesis of maresin 2n-3 DPA (3 )
In conclusion, we have accomplished asymmetric syntheses of maresin 2 (2 ) and maresin 2n-3 DPA (3 ). Alkyne 4 was synthesized from γ-butyrolactone (10 ) and phosphonium salt 7 in three steps. Meanwhile, vicinal diol 20 was constructed by a Sharpless asymmetric epoxidation and a Swern oxidation. Diol 20 was then converted into iodoolefin 5 by a multistep reaction. Finally, reaction of 4 with 5 gave maresin 2 (2 ) in 22 steps from propane-1,3-diol (12 ) with a total yield of 0.79%. We also synthesized 3 by using the same approach as that described for 2 in 22 steps from 12 , with a total yield of 0.58%. The spectral data for 2 and 3 were consistent with those previously reported.[5 ]
