Once we achieved the total syntheses of (-)-depudecin and its stereoisomeric analogues, (+)-depudecin and the epimer at C10 position, as well as homodepudecin, we focused on the extension of the previous synthetic strategy, based on the olefin cross-metathesis reaction, for the generation of cyclopropyl depudecin analogues. The substitution of the oxirane rings by cyclopropyl rings could allow us to prove if the epoxides are essential upon the biological activity in an analogue that keeps the same spatial conformation that the natural product. In addition, we will be able to complete a structure-activity relationship (SAR) study in order to identify new leads based on depudecin.263 With this objective in mind, we envisioned the synthesis of the cyclopropyl depudecin analogues 507-509 as shown in Scheme 63, part A, via an olefin cross-metathesis reaction of precursors 473/510 and 474/511. The installation of the cyclopropyl rings was planned through a Charette enantioselective cyclopropanation264 mediated by the chiral dioxaborolane 512. Thus, we started with the preparation of the required cross-metathesis precursors. For the consecution of compound 511, allylic alcohol 513 was treated with Et2Zn, CH2I2 and borolane 512 (Charette’s reaction conditions) to obtain 514 in high yield (89%). Subsequent Parikh-Doering oxidation of the alcohol 514, followed by a Wittig reaction and TBS deprotection provided alkene 516 in moderate yields. Thus, alcohol 516 was transformed into the corresponding aldehyde, which was subjected to a subsequent Wittig reaction to yield ,-unsaturated aldehyde 517 in a disappointing 1% yield over two steps. This unforeseen difficulty found working
263 For a review about the benefits of the cyclopropyl moiety in preclinical/clinical drugs see: Talele, T. T. J. Med. Chem. 2016, 59, 8712–8756.
264 For a review of cyclopropanation strategies see: Ebner, C.; Carreira, E. M. Chem. Rev. 2017, 117, 11651–11679.
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with these substrates was probably due to their highly volatile character that could explain the low yield obtained in the synthetic sequence (Scheme 63, part B).
Scheme 63. Retrosynthetic Analysis of Cyclopropyl Depudecin Analogues (A) and Attempts towards the Synthesis of Precursor 511 (B)
With the aim to obtain the cross-metathesis precursor 511 in an efficient manner, we decided to avoid the preparation of the problematic aldehyde 517. With this purpose, we started the synthesis from the known -unsaturated alcohol 518,265 which was subjected to a Charette cyclopropanation to yield cyclopropyl derivative 519 in an excellent 98% yield. Then, a two-steps sequence, involving an oxidation and a Wittig reaction, provided 520, which was treated with TBAF to obtain allylic alcohol 521. To our delight, a final Sharpless asymmetric epoxidation of 521 provided metathesis precursor 511 in a 71% yield. In parallel to these synthetic works, we carried out the preparation of the required second metathesis precursor, compound 510, from allylic alcohol 522 via a Charette cyclopropanation under the same reactions conditions showed above, followed by the introduction of the alkene moiety through an oxidation/Wittig reaction sequence without difficulty (Scheme 64, part A). For the assembly of cyclopropyl olefin units 511 and 510, a cross-metathesis of alkenes under the influence of the HG-II (6) catalyst in refluxing dichloromethane was attempted. However, despite the use of the same reactions conditions employed in the synthesis of (-)-depudecin and related analogues showed above, in this case the reaction met with failure, without detection of the expected metathesis product 525, instead starting material together with degradation products were obtained. Additional attempts that included more forcing conditions (toluene, 100 ºC) and other catalysts (Grubbs 1st and 2nd generations, Hoveyda-Grubbs 1st generation) were thwarted, with similar results than before. These disappointing results pointed out that the cyclopropyl rings may play a key role in the
265 Dias, L. C.; de Luca, Jr. E. C. J. Org. Chem. 2017, 82, 3019–3045.
107 outcome of this reaction. In a last attempt, we carried out the cross-metathesis reaction of compounds 511 and 473 under the same reaction conditions for related cases.
Unfortunately, the result of this reaction was similar as the previous case, with no detection of the desired compound 524 (Scheme 64, part B).
Scheme 64. Towards the Synthesis of Cyclopropyl Depudecin Analogues via Cross-Metathesis Reaction:
Synthesis of Precursors 510 and 511 (A) and Attempts of the Cross-Metathesis Reaction (B)
Due to the failure of the cross-metathesis reaction, we decided to use a linear strategy in order to access these cyclopropyl analogues. This new synthetic plan was based on the retrosynthetic analysis depicted in Scheme 65, Part A. Thus, the key precursors 524-526 could be achieved via Sharpless asymmetric epoxidation (SAE) from the allylic alcohols 527-529. In turn, 527-529 could be obtained through a SAE or Charette cyclopropanation from -unsaturated alcohol 530 or 531 followed by a subsequent homologation reaction. With this synthetic plan in mind, we started with the synthesis of -unsaturated ester 533 from epoxy alcohol 473 through a two-steps sequence involving a Parikh-Doering oxidation followed by a Wittig reaction yielding 533 in 47% over two steps. The next seemingly simple reduction of this ester however proved more problematic than expected. For example, treatment of 533 with DIBAL-H provided a complex mixture of degradation products, with no detection of the expected alcohol 530. Others attempts of reduction, for example the use of 1.0 equiv of DIBAL-H to obtain the corresponding aldehyde 534 met in failure with similar results as the previous case. We surmised that the reason of the failure of this reduction was due to the
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epoxide opening as a side reaction.266 This hypothesis was confirmed when we carried out the reduction of the -unsaturated ester 535, under the same reaction conditions than for 533, yielding in this case the desired alcohol 531 in 77% yield. Unfortunately, on this occasion, the subsequent Sharpless asymmetric epoxidation (SAE) of 531 did not yield the expected epoxy alcohol 536, instead a complex mixture of degradation products were obtained. Several attempts of this reaction confirmed the difficulties of such SAE (Scheme 65, Part B).
Scheme 65. Towards the Synthesis of Cyclopropyl Depudecin Analogues via Linear Strategy:
Retrosynthetic Analysis (A) and Attemps of Synthesis of 530 and 531 (B)
266 For epoxide opening competing with ester reduction in a similar structural system see: Takamura, H.; Wada, H.; Lu, N.; Kadota, I. Org. Lett. 2011, 13, 3644–3647.
109 The failures of the cross-metathesis reaction in the convergent strategy as well as the reduction and SAE reactions in the linear strategy towards the cyclopropyl depudecin analogues forced us to abandon the preparation of these analogues in favour of truncated depudecin analogues. The design of these new analogues was based on structural modifications which would allow us to complete a preliminary structure-activity relationship (SAR) study for depudecin. With this aim, we decided to prepare truncated analogues which could retain or modify the hydroxyl groups, the oxirane rings and/or the olefins contained in the natural depudecin in order to test the effect of these functional groups upon the biological activity. Futhermore, the stereochemistry of the designed analogues could be modified or retained. The proposed truncated depudecin analogues 537-544 are shown in Figure 8.
Figure 8. Proposed Truncated Depudecin Analogues
With this purpose, for the synthesis of analogue 537 we started from ,-unsaturated ester 545 obtained from allylic alcohol 522 in two steps, which was transformed into -unsaturated alcohol 546 by use of DIBAL-H in a 90% yield.
However, the next Sharpless asymmetric epoxidation (SAE) of 546 did not provided the corresponding epoxy alcohol 547. The result of this SAE was similarly than for previously shown allylic alcohol 531, instead a complex mixture of degradation products were obtained. In order to avoid this problematic SAE, we decided to carry out the epoxidation reaction by use of m-CPBA, obtaining epoxy alcohol 548 in a 88% yield as a 1:1 inseparable mixture of diastereoisomers. Then, 548 was transformed into ,-unsaturated aldehyde 549 in a 63% yield over two steps and was followed by DIBAL-H reduction of 549 to provide allylic alcohol 550 in a 68% yield. In this case, the SAE provided diepoxy alcohol 551 (~72%, impurified with (+)-DET after column chromatography) which was undertaken under a similar three-steps sequence as in
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previous cases (tosyl protection/iodation/reductive elimination) to obtain allylic alcohol 554 in a 85% overall yield. To complete the synthesis, a final TBDPS deprotection step by treatment of 554 with TBAF afforded depudecin analogue 555 as a inseparable mixture of isomers (ratio 1:1). Despite this stereochemical outcome, this mixture of isomers could be of interest for the planned SAR study (Scheme 66).
Scheme 66. Towards the Synthesis of Truncated Depudecin Analogues: Synthesis of Analogue 555
The synthetic efforts towards analogue 539 started from epoxy alcohol 472 which was transformed into diepoxy alcohol 558 in four steps and good yields, as shown in steps a)-d) in Scheme 67. Then, diepoxy alcohol 558 was oxidized to the corresponding aldehyde and was followed by treatment with excess of Ph3P=CHCHO to afford the
-unsaturated aldehyde 559 in a modest 31% yield over two steps. Once again, as in the previous case for the reduction of -unsaturated ester 533, the next seemingly simple reduction of aldehyde 559 was found to be very problematic. Thus, a first attempt of reduction of 559 with DIBAL-H afforded a complex mixture of degradation products, with no detection of alcohol 560. We surmised that the reason of the failure of this reduction was due to the competition of the 1,2- and 1,4-hydride additions. Others attempts of reduction, for example the selective 1,2-reduction under Luche’s conditions267 or even the selective reduction by the action of 9-BBN268 met in failure with similar results as the previous case. Indeed, the same problem was found in the the preparation of depudecin analogue 543 during the reduction of the -unsaturated aldehyde 561
267 Luche, J. L. J. Am. Chem. Soc. 1978, 100, 2226-2227.
268 Krishnamurthy, S.; Brown, H. C. J. Org. Chem. 1977, 42,1197-1201.
111 in order to obtain alcohol 562 (Scheme 67). Similarly disappointing were the synthetic attempts towards analogues 538, 3-epi-538, 542, 544 and 3-epi-544, for which the last TBDPS deprotection step did not afford the expected products, instead a complex mixture of unidentified degradation products were obtained in all cases (Scheme 68).
Scheme 67. Towards the Synthesis of Truncated Depudecin Analogues: Attempts towards the Synthesis of Analogues 539 and 543
In light of these discouraging results, we focused our efforts in the synthesis of the last two remaining proposed truncated depudecin analogues, compounds 540 and 541 (Scheme 69). For this purpose, we decided to take advantage of the chemistry of sulfonium salts in order to avoid the problems that appeared in the reduction reactions of
-unsaturated esters or aldehydes as well as in the SAE of -unsaturated alcohols, that proved more problematic than expected. Thus, we started from epoxy amide 564269 which was subjected to a two-steps sequence, involving a Red-Al reduction followed by a Wittig-Martin reaction, to yield -unsaturated ester 570 in 28% yield over two steps. Subsequent reduction of 570 by treatment with DIBAL-H afforded allylic alcohol 571, albeit in a poor yield (22%). To complete the synthesis, TBDPS group in
269 Epoxy amide 564 was prepared in exactly the same manner as its enantiomer reported in reference 248.
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571 was removed by use of TBAF to obtain depudecin analogue 540 in a 40% yield (Scheme 69).
Scheme 68. Towards the Synthesis of Truncated Depudecin Analogues: Attempts towards the Synthesis of Analogues 538, 3-epi-538, 542, 544 and 3-epi-544
For the consecution of depudecin analogue 541, we started from allylic alcohol ent-522, which was subjected to a Swern oxidation to obtain the corresponding aldehyde.
The crude obtained aldehyde was then reacted with the sulfonium salt ent-457 to obtain epoxy amide 572 in 57% over two steps. Epoxy amide 572 was treated with Red-Al and the resulting epoxy aldehyde reacted with sulfonium salt ent-457 to obtain diepoxy amide 573 in a 38% over two steps. Then, treatment of diepoxy amide 573 with Red-Al followed by NaBH4 afforded the corresponding diepoxy alcohol which was then tosylated to obtain 574 in 27% over three steps from 573. Subsequent iodide displacement of the tosyl group in 574 was followed by a reductive epoxide opening process by the action of BuLi to provide 576 in 90% yield. Finally, a deprotection step of the TBDPS group in 576 afforded depudecin analogue 541 in 20% yield (Scheme 69).
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Scheme 69. Towards the Synthesis of Truncated Depudecin Analogues: Synthesis of Analogues 540 and 541