Concise, scalable and enantioselective total synthesis of prostaglandins

Prostaglandins are among the most important natural isolates owing to their broad range of bioactivities and unique structures. However, current methods for the synthesis of prostaglandins suffer from low yields and lengthy steps. Here, we report a practicability-oriented synthetic strategy for the enantioselective and divergent synthesis of prostaglandins. In this approach, the multiply substituted five-membered rings in prostaglandins were constructed via the key enyne cycloisomerization with excellent selectivity (>20:1 d.r., 98% e.e.). The crucial chiral centre on the scaffold of the prostaglandins was installed using the asymmetric hydrogenation method (up to 98% yield and 98% e.e.). From our versatile common intermediates, a series of prostaglandins and related drugs could be produced in two steps, and fluprostenol could be prepared on a 20-gram scale. Current methods for the synthesis of prostaglandins suffer from low yields and lengthy steps. Now, a strategy for their enantioselective synthesis has been developed with rhodium-catalysed enyne cycloisomerization as the key step. This concise route was scaled up, enabling the preparation of fluprostenol on a 20-gram scale.


Abstract
Prostaglandins are among the most signi cant natural isolates owing to their broad range of bioactivities and unique structures.However, the current synthesis of prostaglandins still suffers from low yields and lengthy steps.Here, We reported a practicability-oriented synthetic strategy for the enantioselective and divergent synthesis of PGs.In this approach, the multiply substituted ve-membered rings in prostaglandins were constructed via the key Zhang enyne cycloisomerization with excellent selectivity (> 20:1 dr, 98% ee).The crucial chiral center on the scaffold of prostaglandins was installed using the asymmetric hydrogenation method (up to 98% yield and 98% ee).From our versatile common intermediates, a series of PGs and related drugs could be produced in two steps, and uprostenol could be prepared on a 20-gram scale.

Main Text
Prostaglandins (PGs) are widely regarded as among the most signi cant natural isolates ever discovered owing to their broad range of bioactivities 1,2,3,4 and unique structures.To date, more than 20 prostaglandin analogues have been marketed worldwide 5 .The development of e cient methods to synthesize PGs has been a goal of synthetic chemists for almost 50 years 5,6 .However, the current synthesis of PGs still suffers from low yields and lengthy steps, and a concise and scalable synthetic route for a more e cient and green production of PGs and related drugs is still highly desirable.Herein, we report a practicability-oriented synthetic strategy for the enantioselective and divergent synthesis of PGs.In this work, multiply substituted ve-membered rings in PGs were constructed e ciently via the key Zhang enyne cycloisomerization 7 with excellent selectivity (> 20:1 dr, 98% ee).In addition, the crucial chiral center on the scaffold of PGs was e ciently installed using the asymmetric hydrogenation method developed in our group (up to 98% yield and 98% ee) 8 .From our newly-proposed common intermediate, a series of PGs and related drugs could be produced in only two steps.Additionally, uprostenol could be prepared on a 20-gram scale from readily available starting materials.Our new strategy for the synthesis of PGs will not only promote rapid access to the entire family of PGs but also serve as a versatile platform for synthesizing molecules containing highly functionalized ve-membered rings.
Prostaglandins (PGs) were rst discovered in the 1930s by von Euler 9 , and their structures were identi ed in the 1960s by Bergström et al. 10,11,12 .PGs are a family of hormones that play a signi cant role in a wide range of essentially biological processes and pathogeneses 1,2,3,4,13 .The most complex prostaglandin, PGF 2α (Fig. 1; 1), features a core cyclopentane bearing four contiguous stereocentres and two aliphatic side chains (Fig. 1a).Owing to their unique structures and broad spectra of biological activities, PGs have drawn extensive interest in basic research and have become popular targets for organic chemists since the 1970s 5,6 .Following with Corey's pioneering synthesis of PGF 2α 14 , Woodward 15 , Stork 16 , Noyori 17 , Danishefsky 18 , Aggarwal 19 , Baran 20 , Grubbs 21 , Chen 22 , and many other groups 22,23,24,25 also made important contributions to the development of new synthetic strategies for PGs 5,6,27 .From the perspective of applied science, PGs have displayed their importance and value in pharmaceutical chemistry.At present, there are more than 20 drugs that are derived from PGs 5 , including the billion-dollar drug bimatoprost (4) (Fig. 1a).The synthesis of some PGs and related drugs 28 mainly relies on the Corey 14 lactone (10), which was prepared from cyclopentadiene (9) in nine steps (Fig. 1b).However, additional multi-transformations were needed to access PGs from Corey lactone (10), with some even requiring more than ten steps 28 .In 2012, Aggarwal et al. described a novel short synthesis of PGF 2α via cascade aldol condensation, which could furnish the cyclopentane framework with two adjacent chiral centres in one step; however, low yields remain a great concern 19 .Although remarkable progress has been made in the total synthesis of PGs, the reported syntheses still suffer from low e ciency, lengthy sequences.Usually, these reported methods are also di cult to be scaled up.In particular, a readily approachable and transformable common intermediate is highly needed for achieving a divergent and exible synthesis of the whole family of PGs.Herein, we report a concise and scalable total synthesis of PGF 2α in only 6 steps from readily available starting materials (Fig. 1c) as well as the synthesis of several PGs related drugs.
The major challenge in the asymmetric synthesis of PGs is to accurately control the stereochemistry of the four contiguous chiral centers on the core cyclopentane ring and arrange the appropriate functionalities for the installation of the two side chains.Some powerful ring formation reactions, such as Pauson-Khand reaction and Nazarov reaction 7 , have been devised for furnishing ve-membered rings.
Enyne cycloisomerization can promptly increase the molecule complexity and establish stereocentres in a more predictable way, therefore, it represents another e cient and step-economical technique for the construction of ve-membered rings 29 .Notably, the rst rhodium-catalyzed cycloisomerization of 1,6enyne was reported by our group in 2000 30 and was named as Zhang enyne cycloisomerization in 2014 (Fig. 2a) 7 .There are many advantages to this rhodium-catalyzed reaction.On one hand, excellent enantioselectivities could be achieved during the formation of various hetero or carbocyclic vemembered rings under mild conditions with inexpensive BINAP as the ligand.On the other hand, the regiochemistry and geometry of exocyclic ole ns could be speci cally controlled, allowing further manipulations easier.
As aforementioned, we believe that Zhang enyne cycloisomerization could serve as a suitable tool for building the core cyclopentane ring of PGs in a more e cient manner than that of previous synthetic techniques.Herein, we proposed an ideal standard intermediate 12 (Fig. 2b), primed with proper functionalities for connection of the two side chains.From this intermediate and with different α and ω chains, PGF 2α series compounds can be rapidly obtained through Grubbs cross-metathesis and Wittig ole nation 14 .Then, intermediate 12 could be traced back to 16 through successive reductions and deprotections.It was obvious that compound 16 was a typical product of Zhang enyne cycloisomerization originating from 17.By nucleophilic addition, compound 17 could be converted to Weinreb amide 18.The enantioenriched compound 18 was readily accessible through asymmetric hydrogenation, which is in our eld of expertise.Furthermore, after conformational analysis, we conclude that the rst stereogenic centre was able to induce the three other stereocentres in PGs.
As depicted in Fig. 3, we initiated our synthesis of PGs with the asymmetric hydrogenation of the easily available Weinreb amide 11.Nevertheless, potential obstacles went beyond our anticipation due to the low reactivity of compound 11 and the instability of the reduced product under certain basic conditions.
One apparent side reaction was the retro aldol-type reaction, which released crotonaldehyde.After an extensive screening of the reaction conditions (see supplementary table S1 for details), Ir(I)/f-amphox was found to be the best catalyst, and compound 11 can be hydrogenated and protected by TBS in one pot to produce compound 18 in 70% yield and 94% ee (S/C = 1000).In the next step, the nucleophilic addition of lithiated 19 to Weinreb amide 18 provided 1,6-enyne 17 in 96% yield.Other four 1,6-enyne substrates bearing different alkyne moieties (e.g., diethylacetal propiolaldehyde, triethylsilyl propargyl alcohol, trimethylsilylacetylene, and free acetylene) were obtained as well (see supplementary Figure S3 for details).Under the standard protocol, only the cycloisomerization of substrate 17 proceeded smoothly and afforded the desired product in high yield.(S)-BINAP matched better with the enyne substrate by delivering 16 in 85% yield and 98% ee.In contrast, (R)-BINAP could only give 16 with < 10% yield and 40% ee.Key intermediates 12 and 20 could be obtained from 16 in one pot by a sequential reduction in the presence of Ph 2 SiH 2 and LiBEt 3 H, followed by full or partial deprotection.This one-pot reaction could also proceed following a stepwise manner (see supplementary information for details).In the conjugate 1,4-reduction, Ph 2 SiH 2 and Sn( n Bu) 3 H both have similar performance in gaining excellent diastereoselectivity (dr > 20:1).In the later stereo-controlled 1,2-reduction, inexpensive super hydride was found to be the best reductant upon screening.Finally, the TBS and the acetal groups could be removed simultaneously with aqueous HCl solution to afford 12, or TBS was selectively detached in the presence of TBAF to give 20.The relative con guration of these two key intermediates was further determined by X-ray crystallographic analysis.The single crystal of compound (±)-21 derived from racemic 20 showed that all stereocentres exactly matched those of PGF 2α (Fig. 3, for details see the supplementary information).
We customized different synthetic methods for various ω side chains (Fig. 4).Compounds 22 and 23 could be hydrogenated enantioselectively on the gram scale with the protocol developed by our group 8 with excellent yields and enantioselectivity.Resulting diols 24 and 25 were transformed into corresponding epoxides 26 and 27 through mono-tosylation and intramolecular nucleophilic substitution.
Treatment of deprotonated trimethyl sulfonium iodide with epoxides led to allylic alcohols 28 and 29 (Fig. 4a).The chiral tertiary allylic alcohol 32 was conveniently obtained from 30 via Sharpless epoxidation and subsequent reductive ring-opening reaction (Fig. 4b).Another synthetic route for the ω side chains bearing different aromatic rings was also devised.Substituted phenols 33 and 34 were subjected to epichlorohydrin, affording epoxides 35 and 36 in high yields.Afterwards, following the same operations as employed for 26 and 27, epoxides 35 and 36 were converted to the relevant allylic alcohols 37 and 38 in 90% and 91% yield, respectively (Fig. 4c).
With the enantioenriched key intermediates 12 and 28, the cross-metathesis reaction was tested with the assistance of the Hoveyda-Grubbs 2nd generation catalyst (Fig. 5a) 22 .The desired product 15 was furnished in 66% yield.Finally, hemiacetal 15 underwent a Wittig reaction with phosphonium salt 39 to afford PGF 2α in 55% yield.Starting from readily available material 11, the total synthesis of PGF 2α was thus accomplished in 6 steps from 11 with 15% overall yield.From versatile building block 12, the synthesis of latanoprost (3), carboprost (5), and cloprostenol (40) were also achieved (Fig. 5b).
Latanoprost (3) was synthesized in 5.7% overall yield after 8 steps from 11 (additional hydrogenation and esteri cation steps were needed for Latanoprost).Carboprost (5), and cloprostenol (40) were synthesized in 23% and 19% overall yield, respectively, in 6 steps from 11.According to our investigation, intermediate 20 was more stable under cross metathesis conditions and usually resulted in higher yields than 12.A one-more-step longer yet more scalable route was thus invented based on intermediate 20.
Taking cross metatheses of 20 and 38 as a representative, 26 g of acetal 41 could be obtained in 81% yield (93% brsm.) from 23 g of intermediate 20.Hydrolysis of the acetal 41 in aqueous HCl followed by Wittig ole nation gave 23.1 g of uprostenol (42) in 81% yield.Travoprost ( 6) was then gathered in 74% yield after a simple esteri cation.
In addition, the formal synthesis of PGE 2 (2) from 16 was also established (Fig. 5d).Another useful intermediate (43) possessing a carbonyl group was obtained by conjugated 1,4-reduction and simultaneous deprotection in one pot.Following cross-metathesis of 43 and allylic alcohol 28, compound 44 was produced in 67% yield.This precursor would render PGs containing carbonyl groups, such as PGA, PGB and PGE 6 , easy to access.In an effort to obtain PGE 2 directly, 44 was subjected to phosphonium salt 39, adhering to many classic Wittig ole nation protocols.However, all attempts failed and only resulted in the decomposition of 44.Fortunately, the aldehyde could be converted to terminal alkene (45) with a moderate yield.PGE 2 (2) could be obtained after one-step cis-cross metathesis of 45 according to the reported procedure 25 .

Conclusion >
In conclusion, we have successfully achieved the short, highly enantioselective, and scalable syntheses of PGs with Zhang enyne cycloisomerization as the key step from readily available starting materials.In this synthesis, the asymmetric hydrogenation protocol developed in our group played a critical role in introducing key stereogenic centers.All reactions could be carried out on a multi-gram scale and most on a decagram scale.Additionally, our common intermediates in this work, alongside various α and ω side chains, facilitated the divergent synthesis of PGs.These versatile common precursors would help to expand the existing chemical space of PGs and provide access to more promising therapeutic analogues.
We have also presented that the key Zhang enyne cycloisomerization could offer a novel strategic insight into designing new synthetic routes towards multi-functionalized ve-membered rings.In particular, this work has a high possibility to be developed into industrial production.Therefore, a new renaissance of new medicinal chemistry programs on PGs is foreseeable.

Declarations Figures
PGs and their synthetic methods.a, Representative examples of PGs and related drugs, the sales data were obtained from IMS database.b, Corey's synthesis of PGF2α via Corey lactone.c, Our concise synthesis of PGF2α via our proposed key intermediate.API, active pharmaceutical ingredient.

Figure 2 Our
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Figure 2 Our
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Figure 3 E
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Figure 3 E
Figure 3