Synthesis of the C18-C27 Fragment of Georatusin

Anti -configured 1,3-dimethyl deoxypropionate motifs are important sub-structures in natural products. We describe a bidirectional approach for the rapid construction of highly reduced polyketide fragments for the synthesis of georatusin employing our mono-Zweifel protocol.


Introduction
In the context of our program to establish synthetic access to various natural products [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16] we focused on those featuring the 1,3-(poly)deoxypropionate motif.A structurally challenging example is the polyketide-peptide hybrid georatusin (1) which was isolated from the soil fungus Geomyces auratus in 2018 by Bode and coworkers. 17Georatusin (1) features a highly reduced and methylated polyketide fragment (blue) fused to a Dtryptophan moiety (red) forming a 13-membered ring (Figure 1). 17This 13-membered ring contains nine of the overall eleven stereogenic centers.The Bode group was able to determine the absolute configuration of the tryptophan unit via comparison of the ECD spectra of L-and Dtryptophan whereas the other stereogenic centers were determined in a relative fashion using different NMR experiments but could not be set into relation with the D-tryptophan moiety. 17Due to its highly reduced carbon skeleton georatusin (1) is challenging to synthesize without several functional group interconversions using classic aldol chemistry.We planned to synthesize most of the carbon skeleton via lithiation-borylation chemistry using C2-symmetric 1,3-bis(boronic ester) 3 and its derived fragments 4 and 5 (Scheme 1).The strategic advantage of this strategy is the fact, compound 5 can be directly obtained through hydrogenation from 4 and the C2-symmetric compound 3 on the other hand allows rapid access to 4. Due to the C2-symmetry no side differentiation of 3 is required prior to the Zweifel olefination.Scheme 1.First generation retrosynthetic analysis of georatusin (1).
Based on deprotonation experiments of carbamate 9 we observed that the H-D exchange was only 35% using the standard lithiation conditions.The best result was obtained with a lithiation time of 16 h and slightly increased equivalents of (+)-sparteine and sBuLi (Table 1).The use of different bases did not lead to lithiation or in the case of iPrLi only to moderate yields.Therefore, we switched to the corresponding TIB ester 11 21,22 which could be completely lithiated under the standard conditions.With an effective lithiation strategy in hands, we again performed the fragment coupling and obtained the desired 1,4-bis(boronic ester) 10 in 41% yield.Since the desired product was hard to separate from the double homologation product, we started to optimize the borylation step (Table 2).The addition of additives like Et3N and PPh3 which should form an ate-complex with one of the boronic esters did not improve the yield.Short time for ate-complex formation (1 h) increases the mono:di ratio in a significant way but an even shorter atecomplex formation (< 1 h) resulted in a remarkable drop of the yield.Due to the low yields and the impractical separation of the desired product 10 from the double homologation product, we reconsidered our retrosynthetic approach.In our second generation retrosynthesis we shifted the bonds formed via lithiation-borylation chemistry by one carbon atom each, making middle fragment 13 and mono-Zweifel product 14 the new target molecules (Scheme 4).
With middle fragment 13 and our mono-Zweifel product 14 19 in hands, we investigated the new fragment coupling using lithiation-borylation chemistry.Secondary alcohol 20 was isolated in a good yield of 64% over two steps.The following hydrogenation with Wilkinson's catalyst proceeds smoothly to give us 21.Our first intention was a PMB protection of secondary alcohol 21 that could not be performed employing different conditions.So, a two-step sequence of TIPS-protection and selective TBS-deprotection led to primary alcohol 22 (Scheme 6).With alcohol 22 in hands, next in line was another TIB-esterification 22 but unfortunately the best result we could achieve was a yield of 31% (Table 3).Higher temperatures for the Mitsunobu reaction as well as usage of TIB chloride led to decomposition.a. sBuLi, (+)-sparteine, Et2O, −78 °C, 5 h, then

Conclusions
In conclusion, we have developed a rapid access to complex, highly reduced polyketide fragments using lithiation-borylation chemistry and our developed mono-Zweifel protocol. 19With our strategy we were able to synthesize the C18-C27 fragment of the polyketide-peptide hybrid georatusin (1) in 8% over twelve steps in the longest linear sequence.Completion of the synthesis will be reported in due course.

Experimental Section
General.Unless otherwise noted all reactions were carried out under an argon atmosphere using a Drierite TM gas-drying unit.The used glassware was flame dried under high vacuum.Air-and moisture-sensitive liquids and solutions were transferred via syringe flushed with argon prior to use.All reagents were purchased from commercial suppliers and used without further purification unless otherwise noted.Stated temperatures, except room temperature, refer to bath temperatures.Dry solvents: Dichloromethane and all amine bases were distilled under an inert atmosphere over calcium hydride.Tetrahydrofuran, diethyl ether, methanol and 1,2-dichloroethane were purchased from Acros Organics over molecular sieves and under inert atmosphere.Benzene was bought from Sigma Aldrich.
(+)-Sparteine was purchased from Chem-Impex and was distilled under high vacuum and stored under argon at −25 °C.
Flash column chromatography was performed using silica gel (0.04-0.063 mm, 240-400 mesh) obtained from MACHEREY-NAGEL.The applied petroleum ether fraction had a bp of 40-60 °C.The eluent is given in volume ratios (v/v).
High Resolution Mass Spectra (HRMS) were obtained either using a Q-Tof Premier (Waters), a LCT Premier (Waters) or a GC-system Agilent 6890 coupled with an Agilent 5973.Both the masses found and the masses calculated are given.
Chiral HPLC was performed on a Merck/Hitachi L-7150 system with a Merck/Hitachi L-7400 UV-detector using a Daicel Chiralcel® OD-H column (4.6 x 250 mm, 5 µm).Further information can be found in the individual procedure.The names of the compounds not shown were created using ChemDraw 19.1.

Table 2 .
Optimization of first generation fragment coupling