TARGET-ORIENTED AND DIVERSITY-ORIENTED ORGANIC SYNTHESIS - Modern Tools for the Synthesis of Complex Bioactive Molecules - page 518

and ene-yne-yne RCM, leading to a collection of optically pure tetrahydropyridines
and dihydropyrroles (compounds 33 - 38 ). The tricyclic product 39 was obtained as a
racemic mixture and displayed an additional asymmetric center that resulted from a
serendipitous cascade, involving a 6 p -electrocyclization followed by a 1,5-hydrogen
shift. Subsequently, dienes

were reacted with 4-methyl-1,2,4-triazoline-3,5-
dione to afford five rigid polycyclic products (compounds

35 - 39

). In most cases,
excellent diastereofacial selectivities were imposed by the preexisting stereogenic
centers of the dienes. The diverse ring-closing metatheses could be compared to
folding processes, whereas the following Diels-Alder cycloadditions compared to a
posttranslational modification. It is noteworthy that the sequence of each oligomer
encoded for the chemical transformation that resulted in the structure of the final
product. The absolute stereochemistry of each compound originated from those of
the corresponding monomers

40 - 44

. Simple organic substrates were effectively
converted into complex and structurally diverse products in a few synthetic steps
using a single set of reagents including a Grubbs catalyst. The common reactivity
shared by the substrates is an interesting feature of this strategy as it offers the
opportunity of being exploitable in a split-pool protocol. This example emphasizes
the power of folding processes with regard to the generation of skeletal diversity and
their relevance to DOS.

24 - 25

15.4.4.2. Branching Pathway: Control by the Reagent In order to
implement molecular diversity, it is also possible to take advantage of the pluripotent
reactivity of a single substrate that will be converted into structurally distinct molecular
skeleton upon exposure to different reagents. In this case, the chemical transformation is
nolongercontrolledbythenatureof thesubstratebutentirelydictatedbythereagent, each
of them leading to a different transformation and a novel structure. Schreiber and
coworkers have introduced such transformations as “differentiating processes”
evocative of the differentiation of stem cells into more specialized tissues when
exposed to differentiating factors. Although particularly challenging, this strategy
offers the advantage of being applicable to a collection of structurally unrelated
compounds, provided the substrates share a common reactive element.
Kumagai et al. developed a remarkable pathway illustrating this concept,
essentially based on metal-catalyzed cyclizations (Scheme 15.6) [34]. ( S )-Lactol
45 , L-phenylalaninemethyl ester 46 , and ( E )-2-cyclopropylvinylboronic acid 47 were

first assembled into the amino alcohol via a diastereoselective three-component

Petasis/Mannich condensation [35,36], followed by propargylation of the resulting
secondary amine to produce

48

was obtained as a single anti -
diastereoisomer directed by the stereogenic center adjacent to the intermediate imine,
regardless of the absolute configuration of the amino ester. It is worth noting that

49 . Compound 48

49
containspolar nucleophilic (alcohol, amine) andelectrophilic (ester) functionalities, as
well as nonpolar ones (terminal alkyne, cyclopropane), all of which contribute to the
pluripotent reactivity of the substrate. Compound

was then subjected to a series of
differentiating processes. Hence, in the presence of Pd(PPh 3 ) 2 (OAc) 2 ,

49

49

underwent a

cycloisomerization to afford the triene 50 as a single isomer [37], whereas CpRu

(CH 3 CN) 3 PF 6 catalyzed a [5 2] cycloaddition [38,39] to afford the seven-membered

ring 51 as a single isomer. Compound 49 was also converted with an excellent

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