Vinyl iodide fragment

One of the key steps during the first total synthesis of (-)-aspinolide B by A. de Meijere and co-workers was the NHK reaction to form the ten membered lactone ring. The precursor for this key macrocyclization step was prepared by forming an ester from a three-carbon monoprotected diol fragment and a seven-carbon vinyl iodide fragment. Deprotection of the primary alcohol and its subsequent oxidation afforded the desired vinyl iodide aldehyde precursor. Exposure of this precursor to 15 equivalents of CrCl2 doped with 0.5% of NiCb at high dilution in DMF afforded the desired diastereomer in a 1.5 1 ratio. 

The total synthesis of apoptolidin was accomplished in the laboratory of K.C. Nicolaou. The key C12-C28 vinyl iodide fragment was prepared using the Schwartz hydrozirconation of an internal alkyne followed by trapping of the alkenylzirconium intermediate with iodine (I2). The vinyl iodide was formed as a 6 1 mixture of regioisomers. Under the reaction conditions, the methyl orthoester was converted to the methyl glycoside moiety at C21, which was presumably facilitated by the complexation of Zr with the pyranoside oxygen atom. 

The C29-C34 fragment, trans vinyl iodide 159, is distinguished by two contiguous stereogenic centers, and it was surmised that both could be introduced in a single step through the application of Brown s effective asymmetric crotylboration methodology (see Scheme 48).79 Depro-... 

Z-vinyl iodide was obtained by hydroboration and protonolysis of an iodoalkyne. The two major fragments were coupled by a Suzuki reaction at Steps H-l and H-2 between a vinylborane and vinyl iodide to form the C(ll)-C(12) bond. The macrocyclization was done by an aldol addition reaction at Step H-4. The enolate of the C(2) acetate adds to the C(3) aldehyde, creating the C(2)-C(3) bond and also establishing the configuration at C(3). The final steps involve selective deprotonation and oxidation at C(5), deprotection at C(3) and C(7), and epoxidation. 

The coupled fragments were then converted to a vinyl iodide. The key steps were a Z-selective Lindlar reduction and iodinolysis of the vinyl silane, which was done using NIS in acetonitrile (sequence F-l to F-ll). 

The next reaction accomplishes coupling of the building blocks 9 and 10 Fragment 10 is prepared through iterative use of (R)-pina-nediol, the enantiomer of 2. by an addition-functionalization sequence similar to that already presented. The vinylic iodide is prepared with a hikai reaction (see Chapter 13). 

The retrosynthetic approach to welwitindolinone A isonitrile (6) used by the Wood group is shown in Scheme 33. After recognition of the possibility of deriving the vinyl isonitrile fragment from a ketone, the disconnection of 6 to 140 was proposed. A literature report of a samarium (II) iodide-mediated reductive coupling of acrylates with isocyanates to give amides, which could be expected to lead to a new spirooxindole synthesis, prompted the disconnection of 140 to 141. This compound was to be obtained from the readily available cyclohexadiene derivative 143, by way of bicyclic ketone 142. 

We selected the natural product thyrsiferol as an ideal target to test our ideas. Its total synthesis was envisioned to proceed as illustrated in the Scheme 28. The successful coupling between aldehyde 84 and vinyl iodide 82 via a Nozaki-Hiyama-Kishi (NHK) reaction [66] had been demonstrated previously [29]. We therefore sought to model our final steps after precedence presented by Forsyth for the union of these two fragments. The focus of our synthetic strategy centered around the stereoselective synthesis of the ABC framework (84) of thyrsiferol (1) as a scaffold to validate the scope of the Cp2TiCl reaction with epoxides toward the assembly of Q-C-glycosides and cyclic ethers. 

The Cl-Cl 9 fragment of (-)-mycalolide was assembled by J.S. Panek et al. via the NHK coupling between the C1-C6 vinyl iodide and C7-C19 aldehyde subunits. The desired allylic alcohol was obtained as a 1 1 mixture of stereoisomers and was oxidized to the corresponding ketone using Dess-Martin periodinane. The synthesis of the Cl-Cl 9 fragment was completed in three more steps. 

The coupling of two enantiomerically pure fragments to form an alkene of fixed geometry in the centre of ebelactone allows a convergent synthesis.50 One fragment, the vinyl iodide 285 is ultimately derived from a coupling between a chiral aldehyde and a chiral allyl boronate but more immediately by silyl-cupration of an alkyne 284 and iodination. 

The C16-C24 ketone fragment 11 was prepared from the homoallylic alcohol 2. After protection of 2 as a p-methoxybenzyl (PMB) ether [24], the oxidative cleavage led to an intermediate aldehyde which was converted to the cis vinyl iodide 9 by using the... 

Compound 34 was transformed to vinyl iodide 38, which corresponds to the C9-C14 fragment of discodermolide. After protection and reduction (Dibal-H), 34 was transformed to aldehyde 37 which was then converted to the (Z)-vinyl iodide 38 by using the iodoethylphosphonium (EtPPhal) [46]. The overall yield for the preparation for vinyl iodide 38 from 34 is 35% (Scheme 8). 

More recently an alternative synthesis has been proposed (91) in which the fragments C1-C5 and C6-C10 were joint together under Stille conditions (92). Starting from the suitably protected P-methyl-aspartic acid (1) its reduction to the aldehyde and conversion to the trans vinyl iodide followed by staimylation with hexamethyldistannane in the presence of freshly prepared Pd(PPh3)4 led to the trans vinylstannane 2 (Fig. 6). The commercially available (S)-phenyllactic acid (3) was converted to the Weinreb amide which was methylated at the secondary alcohol function and then converted to the propargylic ketone (4). Syn-stereoselective... 

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