Multi-gram-scale synthesis of a versatile syn-anti stereotriad by a short and cost-effective route

The polyketide family of natural products includes numerous biologically important molecules that exhibit a variety of complex structures. The biosynthesis of these diverse structures relies on the iterative assembly of individual segments controlled by the enzymes of the polyketide synthase (PKS) family. In the synthesis laboratory, access to stereospecifically-prepared ketide building blocks can be both challenging and cost-limiting. We report an efficient, multigram-scale synthesis of the syn-anti synthon (2 S ,3 R ,4 S )( E )-6-cyclohexyl-3- [(4-methoxybenzyl)oxy]-2,4-dimethylhex-5-en-1-ol from the commercially available cyclohexane-carboxaldehyde in excellent overall yield and purity.


Introduction
The polyketides are complex and diverse natural products. 1,2Many are in drug trials 1 and clinical use. 2 About 22% of prescription drugs that are derived from natural products contain polyketide units. 3The large number of asymmetric centers in most of these substances, often in contiguous runs, pose major obstacles to their synthetic construction.
5][6] An oftenused strategy in the laboratory synthesis of polyketides is the iterative coupling of small chiral building blocks. 6uch syntheses, which have largely focused on stereospecificity, can be costly on a large scale. 7,8For example, the practical total synthesis of discodermolide (Figure 1), a marine polyketide, remains a formidable challenge.We describe the multi-gram, catalytic, asymmetric preparation of stereotriad (1a) by a six-step route that offers convenience and promises further scalability.0][11] These synthons and their equivalents offer particularly attractive options for extending the polyketide chain in both directions.Of special note is the potential for ozonolysis as a method of liberating an aldehyde at one terminus.
To date, the syn-anti stereotriad unit (2) from Leighton, 12,13 (3) from Smith, 14,15 and the identical Novartis-Smith-Paterson [16][17][18][19][20] unit are the only examples of syn-anti building blocks that have been prepared on multi-gram scales.Each of these substances is easily modifiable at each terminus for ease of continued synthetic elaboration.
We report the large-scale synthesis of synthon 1a using Carreira's asymmetric addition reaction [21][22][23][24] as a key step in an expansion of our previous approach.This preparation is outlined in Scheme 1.

Results and Discussion
Our previously reported approach to stereotriad (1) was modified to improve the yield and ease of handling.
In the earlier work, [9][10][11] (-)-N-methylephedrine was used as a chiral auxiliary to direct a propenylation of cyclohexanecarboxyaldehyde (4) to produce the alcohol (6) in one step.These reaction conditions proved to be highly moisture sensitive, difficult to maintain in large batches, and challenging to reproduce.This step was replaced by a two-step procedure: Carreira propynylation and hydrogenation.The Carreira reaction [21][22][23][24] afforded the alcohol (5) in 97% yield with 95% ee.We note, however, that zinc triflate is an expensive source of zinc(II) ion.Thus, other zinc salts were considered to reduce the cost of this step while retaining yield and ee.These results (Table 1) highlight the clear advantage of zinc triflate over zinc bromide and zinc chloride.Despite the variation in overall yield depending on the zinc salt, the overall ee of the product remained unaffected.Although we were unable to find an acceptable alternative to zinc triflate, we were able to reduce the amount of salt to 10 mol % without sacrificing yield using extended reaction times.(-)-N-Methylephedrine can be recovered, quantitatively, from aqueous extraction. 25The subsequent reduction of alcohol ( 5) with Lindlar's catalyst provided the necessary (Z)-olefinic alcohol (6) in quantitative yield.Formation of ether (7) was performed under Finkelstein conditions. 26Our synthetic intermediate syn diad (8) was easily isolated after a [2,3]-Wittig rearrangement of 7. [27][28][29][30][31][32][33] Optimum conditions for this rearrangement required the use of excess t-BuLi (Table 2).This protocol afforded the rearranged 8 without side products. 33Unreacted starting material was easily recovered by chromatography.All reactions were performed with 100 mg of substrate (7) in THF under argon atmosphere for 4h.b.No byproduct was observed.c Yields reflect product isolated following chromatography.

Conclusions
In summary, we have successfully completed a multi-gram asymmetric synthesis of the syn-anti synthon (1a) in six steps in 54% overall yield with 95% ee.We envision this stereotriad to be a precursor to a variety of synthetically useful compounds that contain contiguous stereochemical centers.We believe that the cost effectiveness of this approach is advantageous for large-scale polyketide synthesis.

Experimental Section
General.Solvents were dried over calcium hydride.Thin-layer chromatography was performed on Agela plates, 0.25mm thickness, 60Å F254.Plates were stained with 15-20% phosphomolybdic acid (PMA) or visualized by UV (254 nm).Commercially-available reagents were purchased from Alfa Aesar.All NMR spectra were recorded on Bruker 500 MHz and 700 MHz spectrometers.NMR solvents were purchased from Cambridge Isotope Laboratories (Tewksbury, Massachusetts, USA).High-resolution mass spectra (HRMS) were acquired with electrospray ionization (positive mode) at the Stony Brook University Mass Spectrometry Lab on an Agilent LC-UV-TOF model G6224A oaTOF.IR spectra were collected on a Thermo Scientific Nicolet iS10 FTIR spectrophotometer.

Table 1 .
Summary of the optimization of Carreira's conditions a a All reactions were performed with toluene as the solvent.The ee, as determined by Mosher ester analysis, was unaffected by the Zn(II) source.