Handbook of Functionalized Organometallics Applications in S

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14 Polyfunctional Electrophilic Multihapto-Organometallics for Organic Synthesis
14.5.9
Design Efficiency in the Synthetic Applications of Multihapto-Complexes
Finally, turning to work in Norwich that aims to complete an enantiocontrolled
asymmetric synthesis of the alkaloid hippeastrine (110; Table 14.1: entry 31) provides
the chance to establish important points about access to enantiopure complexes,
and conceptual issues concerning the steps that introduce and remove the
metal in the synthetic applications of multihapto-complexes. We have long been
interested in replacing standard complexation and decomplexation steps by reactions
that form significant skeletal bonds in the same process [323]. Indeed, in the
case of complexation reactions, some nice examples are available from the work of
other groups [324±331]. Similarly, the internal nucleophile additions discussed in
Section 14.3.8, which can be followed by carbonylative cyclizations [67,205±208],
provide examples of carbon±carbon bond formation during decomplexation,
though as yet they lack generality of application [332]. Decomplexation of tricarbonyl[(1,2,3,4-g)-cyclobutadiene)iron(0)
can be combined with cycloaddition reactions
[333±336]. This also achieves useful bond formation. The method has been
used in the synthesis of cubane [337]. Our work towards hippeastrine starts with a
standard diastereoselective complexation reaction that gives access to 111 in enantiopure
form [338] but ends with a novel in situ trapping procedure that uses nitrosocycloaddition
to intercept the diene ligand during the decomplexation step
[339,340]. In this way, two key stereogenic (ªchiralº) centers in the C ring of the
target are made during the step that removes the metal. Prior to that stage, by an
iterative approach (g 5 ® g 4 ® g 5 ® g 4 ) the stereochemistry of the B/C ring junction
is established starting from 112 [76]. We also have methods [340] that use the
ipso-directing effect of a 1-ethoxy donor substituent to introduce the CH 2CH 2X
(X=OAc; in hippeastrine: X = NMe) side-chain to the C ring that will be needed to
access the key building block 113 (ultimately this will form the D ring by means
of a modified Mitsunobu ring closure with X = OH [341]). This allows the anticipated
synthesis to start with a microbial biodioxygenation of phenetol, followed by
diastereoselective introduction of the tricarbonyliron complex [340] to give access
to enantiomerically pure complexes that are equipped with several leaving groups
to allow a series of iterative nucleophile addition steps [starting from 111, the prospective
route is g 5 ® g 4 ® g 5 (113)® g 4 ® g 5 ® g 4 ]. This is on-going work, but
the series of successful model studies for key steps establish the principles of the
route [76,338], and the efficient utilization of the decomplexation step to make key
skeletal bonds [339,340], and the subsequent successful closure of the D ring
[341]. The absolute configuration of the key tricarbonyliron complex {(1S,6S)-(±)tricarbonyl[(1,2,3,4,5-g)-1-ethoxy-6-methoxycyclohexadienyl]ironhexafluorophosphate}
(111) has been established in this work [340].