A Highly Convergent and Biomimetic Total Synthesis of Portentol

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A Highly Convergent and Biomimetic Total Synthesis of Portentol Bichu Cheng, and Dirk Trauner J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.5b10009 • Publication Date (Web): 16 Oct 2015 Downloaded from http://pubs.acs.org on October 16, 2015

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Journal of the American Chemical Society

Biosynthetic Speculations 266x530mm (300 x 300 DPI)

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A Highly Convergent and Biomimetic Total Synthesis of Portentol Bichu Cheng, Dirk Trauner* Department of Chemistry and Center for Integrated Protein Science, Ludwig-Maximilians-Universität München, Butenandtstrasse 5-13, 81377 München Germany Supporting Information Placeholder ABSTRACT: An efficient total synthesis of the unu-

sual polyketide portentol is reported. Three boron aldol reactions were used to assemble the linear carbon chain of the natural product, which contains two challenging anti, anti-stereotriads. A biomimetic double cyclization cascade, triggered by an oxidation, then afforded portentol and its known dehydration product, anhydroportentol. The biosynthesis of portentol and the biosynthetic relevance of our key step are discussed.

which have enabled a short, highly convergent, and stereoselective total synthesis of portentol. Scheme 1. Biosynthetic Speculations (a) The structure of portentol and Overton's biosynthetic analysis: O Me

Me

O Me HO Me

O Me O Me

OH

OH

Me

O OH

Me Me Me O

2

portentol (1) O

Portentol (1) is a complex polyketide that is unusual in several respects. It was first isolated in 1967 from the lichen Roccella portentosa and subsequently found in a variety of other lichens and in extracts from the Brazilian nut tree Gustavia hexapetala.1 Biological testing showed moderate growth inhibition activity against several cancer cell lines.1j The molecule has a unique and complex structure, which after detailed NMR investigations and degradation studies was ultimately secured by single crystal X-ray analysis. Its densely functionalized spiro tricyclic core features nine consecutive stereocenters, including two adjacent tetrasubstituted ones, which renders portentol a challenging target for total synthesis. To the best of our knowledge, however, the synthesis of portentol or a comparable polyketide has not been reported to date.2 Biosynthetically, it has been proposed that portentol is formed from linear polyketide 3 via cyclohexadienone intermediate 2 (Scheme 1a).1g Isotopelabeling studies showed that acetate and malonate were incorporated into the carbon chain of portentol. While the terminal secondary methyl group originates from the C2 of acetate, the remaining five methyl groups are shown to come from methionine.3 Here, we report our own biosynthetic speculations and synthetic efforts toward this natural product,

O

O

11

O

O

O

7

1

OH

3 (b) Our biosynthetic analysis: Me Me

O Me O

Me OH

11 7

Me

OH

O Me O

Me Me O

1

O

Me OH

O Me 4

portentol (1)

Me O

OH

OH

O

Me Me

Me

O H Me Me

Me

O

5 OH Me

OH

O

OH

O

O 1

7

11

Me

Me

Me

Me 6

SR

Me

(c) Our previous work on the shimalactones: H

Me O

O O Me 7


H+

Me

steps

OH

Me Me

Me

O

O

O Me Me O 8

O Me Me O shimalactone A (9)


1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

We propose that portentol is formed via a cationic cyclization cascade (Scheme 1b). The last bond formation would involve the intramolecular nucleophilic addition of an enolized β-keto-δ-lactone moiety onto a cyclic oxocarbenium ion in intermediate 4.4 This intermediate, in turn, would stem from precursor 5 via nucleophilic attack of the hydroxy group at C11 onto the C7 carbonyl, followed by protonation and loss of water. Precursor lactone 5 would be assembled by a type II polyketide synthetase (PKS) via the fully linear enzyme-bound thioester 6. It is conceivable that the thioesterase domain of the PKS not only catalyzes the β-keto-δ-lactone formation but also the subsequent cationic cyclization to yield portentol. Analogous chemistry was used in our biomimetic synthesis of shimalactone A (Scheme 1c). It involved the cyclization of β-keto-δ-lactone 7, triggered by a protonation of its diene moiety, to yield oxabicyclo[2.2.1]heptane 8. 5 Our synthetic strategy towards portentol aimed to mimic our proposed biosynthesis (Scheme 2). We envisioned that the spirocyclic core of the natural product could be formed by an intramolecular double cyclization cascade starting from β-keto-δlactone 10. This compound is a masked form of intermediate 5 in our proposed biosynthesis and contains two anti-anti stereotriads.6 Triads of this type are a challenge, even after decades of progress in acyclic stereoselection.6 We envisioned that 10 could be synthesized by an anti aldol reaction of “left hand” ketone 11 and “right hand” aldehyde 12, two fragments of similar size and complexity. These compounds, in turn, would be assembled using two aldol reactions that would involve known ketones and aldehydes. Scheme 2. Retrosynthesis of Portentol. Me

O OH oxocarbenium/ Me β-keto lactone OR OR' O O O cyclization Me Me Me O Me O O Me Me Me Me O 10 aldol Me PMB TES TMS portentol (1) O O O O O O O

Me

Me

+ Me

H

N

Me

Me

11

12

aldol TES

O

Me

H Me

aldol TES

O

O

13

O O

H 14

Me

O

O

OBz

+

O

Me Bn

Me 15

N

+ Bn

16

O

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Accordingly, our synthesis of ketone 11 started from aldehyde 13 7 and ketone 14 8. Both were made in two steps using slightly modified literature procedures (supporting information). Paterson aldol reaction of aldehyde 13 and ketone 14 then afforded the corresponding aldol adducts with a 4:1 dr favoring the desired anti diastereomer 17.9 It could be isolated by flash column chromatography in 65% yield. Single crystal X-ray analysis of a derivative confirmed the assigned configuration (supporting information). Scheme 3. Synthesis of Ketone Fragment 11. TES

O

O

Me

H Me

13

+

a. Cy2BCl, Et3N

TES

dr ~ 4:1 (65%)

Me

O OBz

O

OH

O OBz

Me

b. TMSCl, TMS2NH, pyridine (99%)

Me 17

Me 14 TES TMS O O

TES TMS O O

O OBz

Me Me

Me 18

Me

c. SmI2 (97%)

O

Me Me

Me 11

Reagents and conditions: (a) Cy2BCl, Et3N, Et2O, −78 °C to 0 °C, then 13, −78 °C to −20 °C, 65% (4:1 dr); (b) TMSCl, TMS2NH, pyridine, rt, 99%; (c) SmI2, THF/MeOH, 0 °C, 97%. Next, we protected the secondary alcohol of 17. Reaction of 17 with tert-butyldimethylsilyl trifluoromethanesulfonate (TBSOTf) and triethylsilyl trifluoromethanesulfonate (TESOTf) afforded the corresponding silyl ethers cleanly, but it was later ascertained that these groups were difficult to remove at the final stage of the synthesis. We then decided to protect the alcohol as the trimethylsilyl (TMS) ether. After screening several conditions, TMS ether 18 was prepared in quantitative yield using hexamethyldisilazane (TMS2NH) and TMSCl in pyridine.10 Reductive removal of the α-benzoate with SmI2 then afforded the “left hand” ketone 11 in good yield (Scheme 3).11 The synthesis of “right-hand”-aldehyde 12 began with an Evans syn aldol reaction12 of known aldehyde 15, derived from the (R)-Roche ester, with oxazolidinone 16.13 The resulting aldol product 19 was protected as p-methoxybenzyl (PMB) ether 20,14 and the protected primary alcohol was desilylated and oxidized under Swern condition to give aldehyde 12 (Scheme 4).15


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Scheme 4. Synthesis of Aldehyde Fragment 12. TES O O

TES TMS O O

H Me 15 + O O N Bn

O

Scheme 5. Fragment Coupling.

a. Bu2BOTf, Et3N

TES O OH

O N

Me 19

O

O

Me Bn

b. PMB-OC(NH)CCl3, Sc(OTf)3

O

(52%, 2 steps)

16

TES PMB O O

O N

Me 20

Me Bn

O

c. DMSO, (COCl)2; Et3N (94%)

O

O

PMB O

H

O N

Me

Me Bn 12

O

Reagents and conditions: (a) Bu2BOTf, Et3N, DCM, 0 °C, then 15, −78 °C to 0 °C; (b) PMB-OC(NH)CCl3, Sc(OTf)3 (1 mol%), toluene, rt, 52% (2 steps, unoptimised); (c) DMSO, (COCl)2, DCM, −78 °C to −25 °C; Et3N, 94%. With both fragments 11 and 12 in hand, we started to investigate the key coupling reaction. The union of the two fragments followed a procedure reported by Evans with slight modification.16 Stirring ketone 11 with Cy2BCl and Et3N in diethyl ether for 1 hour at 0 °C and 2 hours at room temperature gave a boron enolate, which was added to a suspension of aldehyde 12 in diethyl ether at −78 °C. The reaction mixture was then stirred at −40 °C for 1−2 days until no aldehyde 12 remained, as determined by thin layer chromatography (TLC) analysis. Although the aldol product could be isolated, it was found that the desired lactonization occurred spontaneously if THF was added as a cosolvent during the workup. Separation by flash column chromatography gave analytically pure lactone 21 and recovered starting material 11. A 1H NMR study of the H-H coupling constant (3JH-H) on the lactone ring suggested that the desired stereochemistry was obtained at C5. Next, the PMB group was oxidatively cleaved with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) in dichloromethane (DCM) to generate alcohol 22. Adding water or pH 7 phosphate buffer to the reaction lead to byproduct formation, presumably due to the loss of silyl groups under these conditions (Scheme 5).

O

Me

O TES TMS Cy2BCl, Et3N, Et2O, Me 11 O O O O 0 °C to rt; then 12, −78 °C to −40 °C; + 5 Me OR then pH 7 buffer, PMB Me Me Me Me THF, H2O2. O O O O dr ~ 4:1, (71%) 21 R = PMB DDQ, DCM, rt H N O 22 R = H (84%) Me Me Bn 12 Me

Me

With the full carbon chain successfully assembled, we began to investigate the double cyclization cascade to complete the synthesis of portentol. After extensive screening, oxidation of the β-hydroxy lactone could be achieved under Swern condition with trifluoroacetic anhydride (TFAA) as the activator.17 Once the oxidation was complete, methanol was added to quench the reaction. To our delight, TLC and 1H NMR analysis of the crude reaction mixture showed that both portentol (1) and the known derivative anhydroportentol (23)1g were formed cleanly in a 0.7:1 ratio. These two compounds were readily separated by flash column chromatography (silica gel). Portentol was thus isolated in 35% yield, and anhydroportentol was isolated in 55% yield. Their spectroscopic data were in accord with literature values,1g, 1j and single crystal X-ray structures of both compounds confirmed our assignment (Scheme 6). Scheme 6. Total Synthesis of Portentol and Anhydroportentol. Me Me

O TES TMS O O O

Me

O

Me

OH Me

Me

Me 22

DMSO, TFAA, DCM; Et3N, −78 °C; MeOH, rt

Me

OH O

Me O

Me Me O

O Me 1 (35%) + Me Me O Me O

Me Me O

O 1

23

Me 23 (55%)

The proposed mechanism of this cascade is shown in Scheme 7. Oxidation of alcohol 22 presumably gave the corresponding β-keto lactone 10 in equilibrium with its enol form. The acid generated in situ during the workup removed the silyl protecting groups and induced the formation of oxocarbenium



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4, which is shown here as a mixture of two conformers. One of them, 4a, undergoes C2-C7 cyclization to yield portentol (1). Rotation along the C6-C7 bond yields 4b, which cannot undergo cyclization fast enough due to a steric clash of the C8 methyl group and C9 hydroxy group with the C2 methyl group, which is apparent in molecular models. Due to steric hindrance, the formation of the C2-C7 bond is presumably a relatively slow process. Therefore, proton transfer in 4, followed by elimination of water can compete in the cascade, which yields the unsaturated oxocarbenium ion 24, again as a mixture of rotamers. Among these, 24a undergoes cyclization to afford anhydroportentol (23). Its rotamer 24b suffers from a steric clash between the C2 and C8 methyl groups and an unfavorable A1,3-strain between the C6 and C8 methyl groups, which prevents rapid cyclization. Therefore, stereoisomers of portentol (1) and anhydroportentol (23) with respect to C7 are not observed. Given the high yield and ease of this cyclization process, we believe that a similar transformation occurs in Nature (as we proposed in Scheme 1b). Whether this happens spontaneously or requires enzymatic catalysis remains to be determined. The fact that anhydroportentol is easily formed but has not yet been isolated as a natural product points to the latter. Scheme 7. Proposed Mechanism of the Double Cyclization Cascade. Me OH Me 22

11

oxidation

HO

desilylation

Me

OH

1

O

Me HO

2

Me 10

O

– H 2O Me

Me 7

Me 6

2

O

Me

H+ Me

Me O 7 O

O 4a O Me

Me

O

8

Me

9

HO Me HO

O 4b O Me

– H 2O Me

Me

23

Me HO

O

Me

Me

8

O

O O Me

24a

Me 6

HO 2

O O Me

24b

In conclusion, we have achieved a total synthesis of portentol that owes its brevity and efficiency to a biomimetic key step and the convergent nature of our synthetic plan. Three diastereoselective boron

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aldol reactions, including one syn aldol reaction and two anti aldol reactions, were used to assemble the linear carbon chain. A double cyclization cascade formed the spirocyclic core and afforded portentol. Thus, this unusual and attractive natural product has finally yielded to total synthesis. ASSOCIATED CONTENT Supporting Information. Experimental procedures and compound characterization data, 1H, 13C NMR spectra of new synthetic compounds and cif files for X-ray structures. This material is available free of charge via the Internet at http://pubs.acs.org.

AUTHOR INFORMATION Corresponding Author

[email protected] Notes The authors declare no competing financial interest.

ACKNOWLEDGMENT We thank SFB 749 (Dynamics and Intermediates of Molecular Transformations) for financial support, and Dr. Peter Mayer (LMU Munich) for X-ray structure determination. We also thank Mr. James Frank and Mr. Benjamin Williams for helpful discussions during the preparation of this manuscript.

REFERENCES (1) (a) Huneck, S.; Trotet, G. Z. Naturforsch., B: Chem. Sci. 1967, 22b, 363. (b) Huneck, S.; Follmann, G.; Weber, W. A.; Trotet, G. Z. Naturforsch., B: Chem. Sci. 1967, 22b, 671–673. (c) Huneck, S.; Follmann, G. Z. Naturforsch., B: Chem. Sci. 1967, 22b, 1185–1188. (d) Huneck, S.; Mathey, A.; Trotet, G. Z. Naturforsch., B: Chem. Sci. 1967, 22b, 1367–1368. (e) Aberhart, D. J.; Overton, K. H. J. Chem. Soc., Chem. Commun. 1969, 162–163. (f) Ferguson, G.; Mackay, I. R. J. Chem. Soc., Chem. Commun. 1970, 665–666. (g) Aberhart, D. J.; Overton, K. H.; Huneck, S. J. Chem. Soc. (C) 1970, 1612–1623. (h) Huneck, S.; Roenneberg, H.; Liaaen-Jensen, S. Pharmazie 1982, 37, 866. (i) Quilhot, W.; Garbarino, J. A.; Gambaro, V. J. Nat. Prod. 1983, 46, 594–595. (j) Pettit, G. R.; Zhang, Q. W.; Pinilla, W.; Herald, D. L.; Doubek, D. L.; Duke, J. A. J. Nat. Prod. 2004, 67, 983–985. (2) Only one synthetic study on portenol has been reported by Jacolot, M.; Jean, M.; Levoin, N.; van de Weghe, P. Org. Lett. 2012, 14, 58–61. (3) Aberhart, D. J.; Corbella, A.; Overton, K. H. J. Chem. Soc. Chem. Comm. 1970, 664–665. (4) Schröckeneder, A. PhD thesis, University of Munich, 2012. (5) Sofiyev, V.; Navarro, N.; Trauner, D. Org. Lett. 2008, 10, 149–152. (6) Chen, M.; William R. Roush, W. R. J. Am. Chem. Soc. 2012, 134, 3925–3931, and references therein. We tried several other ways to make similar compounds with anti-anti stereotriads, but all failed. See ref. 4.


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(7) Scheidt, K. A.; Bannister, T. D.; Tasaka, A.; Wendt, M. D.; Savall, B. M.; Fegley, G. J.; Roush, W. R. J. Am. Chem. Soc. 2002, 124, 6981–6990. (8) Paterson, I.; Wallace, D. J.; Cowden, C. Synthesis 1998, 639–652. (9) Paterson, I.; Wallace, D. J.; Velázquez, S. M. Tetrahedron Lett. 1994, 35, 9083–9086. (10) Sweeley, C. C.; Bentley, R.; Makita, M.; Wells, W. W. J. Am. Chem. Soc. 1963, 85, 2497–2507. (11) Molander, G.; Hahn, G.; J. Org. Chem. 1986, 51, 1135– 1138. (12) Evans, D. A.; Bartroli, J.; Shih, T. L. J. Am. Chem. Soc. 1981, 103, 2127–2129. (13) Smith, A. B. III; Brandt, B. M. Org. Lett. 2001, 3, 1685– 1688. (14) Rai, A.; Basu, A. Tetrahedron Lett. 2003, 44, 2267–2269.

(15) Rodríguez, A.; Nomen, M.; Spur, B.; Godfroid, J. Tetrahedron Lett. 1999, 40, 5161–5164. (16) Evans, D. A.; Dart, M. J.; Duffy, J. L.; Rieger, D. L. J. Am. Chem. Soc. 1995, 117, 9073–9074. (17) Sakai, N.; Ohfune, Y. J. Am. Chem. Soc. 1992, 114, 998–1010.

Insert Table of Contents artwork here Me TMS TES O O

Me

O O

Me

O

Me

OH Me

Me

Me

Me

one-pot

OH O

Me O

Me Me O

O Me portentol


≡

A Highly Convergent and Biomimetic Total Synthesis of Portentol

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