The synthesis of an exhaustively stereodiversified library of cis-1,5 enediols by silyl-tethered ring-closing metathesis.

Article abstract of DOI:10.1021/ol0159569

[reaction: see text] This report describes the parallel synthesis of all 16 stereoisomers of the cis-1,5 enediol module 1. Compounds 1 derive from 2 by silicon-tethered ring-closing metathesis. Such libraries of stereodiversified ligands provide a unique

Full text of DOI:10.1021/ol0159569

ORGANIC
LETTERS
2001
Vol. 3, No. 14
2157-2159
The Synthesis of an Exhaustively
Stereodiversified Library of cis-1,5
Enediols by Silyl-Tethered Ring-Closing
Metathesis
Bryce A. Harrison and Gregory L. Verdine*
Department of Chemistry and Chemical Biology, HarVard UniVersity,
Cambridge, Massachusetts 02138
Verdine@chemistry.harVard.edu
Received April 6, 2001
ABSTRACT
This report describes the parallel synthesis of all 16 stereoisomers of the cis-1,5 enediol module 1. Compounds 1 derive from 2 by silicon-
tethered ring-closing metathesis. Such libraries of stereodiversified ligands provide a unique approach to ligand discovery that employs
exhaustive searching of conformational space.
Diversity-oriented synthesis aims to create arrays of low-
molecular-weight organic compounds having different mo-
lecular shapes, usually with the goal of discovering novel
bioactive substances.1 With few exceptions, these syntheses
have achieved diversity in shape through variation of
molecular constitution.2 A complementary approach is to vary
the stereochemistry of compounds having the same constitu-
tion.3 Whereas the former approach probes functional group
space by varying moieties presented from a common
scaffold, the latter explores conformational space through
geometric variation of the ligand scaffold. Stereochemistry
can profoundly affect the strength and specificity of recep-
tor-ligand interactions and may also influence pharmaco-
logic properties such as biodistribution, metabolism, and
toxicity.4,5
The synthesis of exhaustively stereodiversified libraries
presents a challenge in that it requires the implementation
of reactions that are highly stereoselective, together with
reactions that are highly tolerant of stereochemical context.
Indeed, few examples of exhaustively stereodiversified ligand
libraries have been reported, the first being the synthesis of
all 32 stereoisomers of a polyketide having 5 stereogenic
centers.6 We recently reported the synthesis of all 16
stereoisomers of the cis-1,4-enediol 5 (Figure 1).5 These
compounds are of interest because the dense packing of sp3
(1) Schreiber, S. L. Science 2000, 287, 1964-1969. Mayer, T. U.;
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1999, 1003-1014. Feng, Y.; Pattarawarapan, M.; Wang, Z.; Burgess, K.
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Jonczyk, A.; Kessler, H. J. Am. Chem. Soc. 1997, 119, 1328-1335.
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10.1021/ol0159569 CCC: $20.00 © 2001 American Chemical Society
Published on Web 06/14/2001

Scheme 1. Retrosynthetic Analysis of 1
protecting group was exchanged for an Fmoc group to give
(S,R)-3 and (S,S)-3. The procedure was repeated with the
Boc-D-Leu-OMe to give (R,S)-3 and (R,R)-3.
Figure 1.
stereocenters flanking the cis olefin results in strong torsional
constraints; the interactions of these ligands with receptors
are thus governed by acyclic stereocontrol. Moreover, the
molecules possess functionally differentiated termini that
allow for further elaboration into libraries having both
stereochemical and constitutional diversification. The syn-
thesis of stereoisomers 5 employed a convergent, stereocon-
trolled approach based on chiral auxiliary-directed aldol
reactions and silyl-tethered ring-closing metathesis (RCM).7
Exhaustive searching of stereochemical space might be
an especially apt strategy for the discovery of ligands that
bind peptide receptors. Whereas compounds 5 possess one
fewer atom in the main chain than a corresponding tripeptide,
the main chain of system 1 is isoatomic with a tripeptide
(Figure 1). Although both 1 and 5 are conformationally
constrained, 1 has greater flexibility owing to the presence
of an unsubstituted allylic position. This increased flexibility
may raise the entropic cost of binding a receptor; however,
it may also allow 1 to access biologically active conforma-
tions not available to 5. Moreover, the hydroxyl groups of 1
are chemically differentiated (allylic/homoallylic), unlike
those of 5 (allylic/allylic), thus raising the prospect for
selective hydroxyl-directed derivatization of the compounds
1. Herein we report the stereocontrolled, spacially separated
synthesis of all 16 stereoisomers of 1.
Scheme 2a
a Key: (a) DIBAL-H, toluene, -78 °C; (b) (+)-Ipc2B-allyl, Et2O,
60% 2 steps; (c) (-)-Ipc2B-allyl, Et2O, 61% 2 steps; (d) i. TFA,
CH2Cl2, ii. Fmoc-NHS, K2CO3, dioxane, H2O, 70%.
The four stereoisomers of 4 were synthesized according
to a published procedure.5 (R,S)- and (S,R)-4 were derived
from a chiral auxiliary-directed Evans aldol reaction,9 and
(R,R)- and (S,S)-4 were synthesized by a chiral auxiliary-
directed Masamune aldol reaction.10
In preparation for RCM, each stereoisomer of 4 was
covalently tethered to each stereoisomer of 3 through a
dimethylsilyl linker to generate the 16 stereoisomers of 2
(Scheme 3). Compounds 4 were monosilylated with 20 molar
equiv of Cl2SiMe2; the excess silane was removed in vacuo,
and then 1.2 molar equiv of 3 was added. The yield of the
Retrosynthetically, 1 derives through RCM from 2, which
is assembled by silyl-tethering of monomers 3 and 4 (Scheme
1). The four stereoisomers of 3 were prepared through Brown
allylation chemistry, utilizing a chiral allylborane to achieve
reagent-controlled stereoselective allylation (Scheme 2).8
Thus, Boc-L-Leu-OMe was reduced to aldehyde (S)-6 using
DIBAL-H and then allylated with (+)-Ipc2B-allyl to generate
(S,S)-7 (92:8 ratio of diastereomers) or with (-)-Ipc2B-allyl
to generate (S,R)-7 (93:7 ratio of diastereomers). The Boc
(7) Evans, P. A.; Murthy, V. S. J. Org. Chem. 1998, 63, 6768-6769.
Hoye, T. R.; Promo, M. A. Tetrahedron Lett. 1999, 40, 1429-1432.
(8) Jadhav, P. K.; Bhat, K. S.; Perumal, P. T.; Brown, H. C. J. Org.
Chem. 1986, 51, 432-439. Brown, H. C.; Bhat, K. S.; Randad, R. S. J.
Org. Chem. 1989, 54, 1570-1576.
(9) Evans, D. A.; Gage, J. R.; Leighton, J. L. J. Am. Chem. Soc. 1992,
114, 9434-9453.
(10) Abiko, A.; Liu, J.-F.; Masamune, S. J. Am. Chem. Soc. 1997, 119,
2586-2587.
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Org. Lett., Vol. 3, No. 14, 2001

toluene at 95 °C for 1 h gave excellent yields (78-94%,
Table 1) of the stereoisomeric cyclization products 8.
Scheme 3a
Table 1. Stereochemical Dependence of RCM of 2 To Form
8a
confign (N‚C) yield (%) catalyst (mol %) ring substitution
RRSR
RRSS
RSRR
RSRS
RRRS
RRRR
RSSS
RSSR
85
94
86
84
89
86
88
78
5
5
5
cis
cis
cis
cis
trans
trans
trans
trans
5
10
10
10
10
a Reactions were carried out under argon in toluene at 95 °C for 1 h.
a Key: (a) 4, Me2SiCl2, pyridine, then 3, pyridine, 55%; (b)
Cl2(PCy3)(IMes)RudCHPh, toluene, 95 °C, 89%; (c) HF/pyridine,
THF, 0 °C, 87%.
Although RCM to generate the products 8 having the ring
substituents oriented cis required less catalyst than that for
trans-substituted 8 (5% compared to 10%), the isolated yields
of the products were comparable. In all cases, elevated
reaction temperatures and the highly active second-generation
ruthenium catalyst were necessary to achieve these uniform
results. For example, (R,S,R,S)-2 and (R,R,R,S)-2 underwent
RCM at 95 °C in 84% and 89% yields, respectively, as
compared with 79% and 67% at 70 °C. On the other hand,
treatment of Boc-protected versions of (R,S,R,S)-2 and
(R,R,R,S)-2 with 75 mol % of Cl2(PCy3)2RudCHPh at 40
°C in CH2Cl2/THF for 42 h gave only 64% of (R,S,R,S)-8
and no observable (R,R,R,S)-8.
To complete the synthesis, the 16 stereoisomers of 8 were
deprotected with HF/pyridine in THF to give the 16
stereoisomers of 1 in 51-91% yield. Over the three steps
shown in Scheme 3, the yields for the products ranged from
18 to 78%. In yet to be published work, the entire panel of
stereoisomers has been found to undergo efficient incorpora-
tion into chimeric peptides, which are suitable for use in
biologic screening (B.A.H. and G.L.V, unpublished results).
silyl-tethered product was markedly dependent upon the
stereochemistry of 4, with (R,R)- and (S,S)-4 providing 69-
100% yield of the tethered product, vs 34-64% yield using
(R,S)- and (S,R)-4.
The RCM of 2 to form 8 involves the formation of an
eight-membered ring. The RCM of medium-sized rings
typically requires a certain amount of preorganization into a
quasicyclic structure.11 Consequently, we were concerned that
stereodiversity in RCM substrates 2 might give rise to
variability in cyclization, due to effects on the degree of
preorganization. Indeed, in the only other published RCM
of an eight-membered silyl-tethered heterocycle,12 the reac-
tion was found to be highly diastereoselective when per-
formed with the prototypical Grubbs metathesis catalyst13
Cl2(PCy3)2RudCHPh; however, this diastereoselectivity
could be overcome by using the more active catalyst Cl2-
(PCy3)(DHIMes)RudCHPh.14 In a similar manner, the RCM
of 2 with 5-10 mol % of Cl2(PCy3)(IMes)RudCHPh15 in
Acknowledgment. B.A.H. was supported by a fellowship
from NSF. This work was supported by gifts from Hoffmann-
La Roche and Enanta Pharmaceuticals. We are grateful to
Tiffany Gierasch and Milan Chytil for valuable discussions
and to Tiffany Gierasch for the preparation of monomers 4.
(11) Maier, M. E. Angew. Chem., Int. Ed. 2000, 39, 2073-2077.
(12) Boiteau, J.-G.; Van de Weghe, P.; Eustache, J. Tetrahedron Lett.
2001, 42, 239-242.
(13) Schwab, P.; France, M. B.; Ziller, J. W.; Grubbs, R. H. Angew.
Chem., Int. Ed. Engl. 1995, 34, 2039-2041. Schwab, P.; Grubbs, R. H.;
Ziller, J. W. J. Am. Chem. Soc. 1996, 118, 100-110.
(14) Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett. 1999, 1,
953-956. Sanford, M. S.; Ulman, M.; Grubbs, R. H. J. Am. Chem. Soc.
2001, 123, 749-750.
(15) Huang, J.; Stevens, E. D.; Nolan, S. P.; Petersen, J. L. J. Am. Chem.
Soc. 1999, 121, 2674-2678. Fu¨rstner, A.; Thiel, O.; Ackerman, L.; Schanz,
H.-J.; Nolan, S. P. J. Org. Chem. 2000, 65, 2204-2207. Weskamp, T.;
Kohl, F. J.; Hieringer, W.; Gleich, D.; Herrmann, W. A. Angew. Chem.,
Int. Ed. 1999. Scholl, M.; Trnka, T. M.; Morgan, J. P.; Grubbs, R. H.
Tetrahedron Lett. 1999, 40, 2247-2250.
Supporting Information Available: Experimental details
and characterization data regarding the preparation of all
synthetic intermediates and products. This material is avail-
able free of charge via the Internet at http://pubs.acs.org.
OL0159569
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